PMID:  Arch Pharm Res. 2023 Apr ;46(4):339-359. Epub 2023 Mar 13. PMID: 36913116 Abstract Title:  Apocynin abrogates methotrexate-induced nephrotoxicity: role of TLR4/NF-B-p65/p38-MAPK, IL-6/STAT-3, PPAR-, and SIRT1/FOXO3 signaling pathways. Abstract:  The present study was designed to evaluate the potential renoprotective impacts of apocynin (APC) against nephrotoxicity induced by methotrexate (MTX) administration. To fulfill this aim, rats were allocated into four groups: control; APC (100 mg/kg/day; orally); MTX (20 mg/kg; single intraperitoneal dose at the end of the 5th day of the experiment); and APC+MTX (APC was given orally for 5 days before and 5 days after induction of renal toxicity by MTX). On the 11th day, samples were collected to estimate kidney function biomarkers, oxidative stress, pro-inflammatory cytokines, and other molecular targets. Compared to the MTX control group, treatment with APC significantly decreased urea, creatinine, and KIM-1 levels and improved kidney histological alterations. Furthermore, APC restored oxidant/antioxidant balance, as evidenced by a remarkable alleviation of MDA, GSH, SOD, and MPO levels. Additionally, the iNOS, NO, p-NF-B-p65, Ace-NF-B-p65, TLR4, p-p38-MAPK, p-JAK1, and p-STAT-3 expressions were reduced, while the IB, PPAR-, SIRT1, and FOXO3 expressions were significantly increased. In NRK-52E cells, MTX-induced cytotoxicity was protected by APC in a concentration-dependent manner. In addition, increased expression of p-STAT-3 and p-JAK1/2 levels were reduced in MTX-treated NRK-52E cells by APC. The in vitro experiments revealed that APC-protected MTX-mediated renal tubular epithelial cells were damaged by inhibiting the JAK/STAT3 pathway. Besides, our in vivo and in vitro results were confirmed by predicting computational pharmacology results using molecular docking and network pharmacology analysis. In conclusion, our findings proved that APC could be a good candidate for MTX-induced renal damage due to its strong antioxidative and anti-inflammatory bioactivities.

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PMID:  Br J Pharmacol. 2023 Mar 12. Epub 2023 Mar 12. PMID: 36908040 Abstract Title:  Inhibition of oxidative stress by apocynin attenuated chronic obstructive pulmonary disease progression and vascular injury by cigarette smoke exposure. Abstract:  BACKGROUND AND PURPOSE: Cardiovascular disease affects up to half of the patients with chronic obstructive pulmonary disease (COPD), exerting deleterious impact on health outcomes and survivability. Vascular endothelial dysfunction marks the onset of cardiovascular disease. The present study examined the effect of a potent NADPH Oxidase (NOX) inhibitor and free-radical scavenger, apocynin, on COPD-related cardiovascular disease.EXPERIMENTAL APPROACH: Male BALB/c mice were exposed to either room air (Sham) or cigarette smoke (CS) generated from 9 cigarettesday, 5 days a week for up to 24weeks with or without apocynin treatment (5 mgkgday, intraperitoneal injection).KEY RESULTS: Eight-weeks of apocynin treatment reduced airway neutrophil infiltration (by 42%) and completely preserved endothelial function and endothelial nitric oxide synthase (eNOS) availability against the oxidative insults of cigarette smoke exposure. These preservative effects were maintained up until the 24-week time point. 24-week of apocynin treatment markedly reduced airway inflammation (reduced infiltration of macrophage, neutrophil and lymphocyte), lung function decline (hyperinflation) and prevented airway collagen deposition by cigarette smoke exposure.CONCLUSION AND IMPLICATIONS: Limiting NOX activity may slow COPD progression and lower cardiovascular disease risk, particularly when signs of oxidative stress become evident.

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PMID:  J Surg Res. 2023 May ;285:51-58. Epub 2023 Jan 12. PMID: 36640610 Abstract Title:  Combination Therapy of Niacin and Apocynin Attenuates Lung Injury During Sepsis in Rats. Abstract:  INTRODUCTION: Oxidative stress contributes to tissue injury through reactive oxygen species-dependent signaling pathways during sepsis. We studied therapeutic benefits of the combination therapy of niacin, which increased reduced glutathione levels, and apocynin, which suppressed reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (Nox) activity, in septic rats.MATERIALS AND METHODS: Polymicrobial sepsis was induced through cecal ligation and puncture (CLP) with antibiotics in male Sprague-Dawley rats (n = 189). The rats were randomly divided into sham, CLP, CLP + niacin, CLP + apocynin, and CLP + niacin + apocynin groups. Six hours after CLP, vehicle, niacin (360 mg/kg through the orogastric tube), and/or apocynin (20 mg/kg through intraperitoneal injection) were administered. The occurrence of mortality for 72 h after CLP was observed. Next, a separate set of animals was euthanized at 24 h post-CLP for lung tissue analyses.RESULTS: Combination therapy with niacin and apocynin significantly improved survival in rats with sepsis (75.0% versus 28.8%, P = 0.006) but monotherapy with niacin or apocynin did not. Monotherapy with niacin and apocynin appeared to increase NADPH levels and decrease Nox levels and activity, respectively, but failed to show statistical significances. However, combination therapy significantly decreased Nox levels and activity, increased NADPH and glutathione levels, decreased intranuclear nuclear factor-B (NF-B) p65 levels, reduced inflammatory cytokine expression and malondialdehyde levels, and attenuated histological lung injuries.CONCLUSIONS: Combination therapy with niacin and apocynin synergistically attenuated lung injuries and improved survival in rats with sepsis through niacin-induced glutathione redox cycle activation and apocynin-induced Nox suppression.

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PMID:  Int J Pharm. 2023 Jan 25 ;631:122536. Epub 2022 Dec 23. PMID: 36572262 Abstract Title:  Apocynin-loaded PLGA nanomedicine tailored with galactosylated chitosan intrigue asialoglycoprotein receptor in hepatic carcinoma: Prospective targeted therapy. Abstract:  Nature serves as a priceless source for phytomedicines to treat different types of cancer, including hepatocellular carcinoma (HCC). Apocynin (APO), an anti-cancer phytomedicine, is a particular nicotinamide adenine dinucleotide phosphate-oxidase (NADPH-oxidase) inhibitor, which has recently dawned for its multilateral pharmacological activities. As far as we are aware, no investigation has been carried out yet to develop a targeted-nanostructured delivery system of APO to HCC. Consequently, chitosan derivative with galactose groups namely; galactosylated chitosan (GC), particularly recognized by the asialoglycoprotein receptor (ASGR), was synthesized and its chemical structure was thoroughly characterized by substantial techniques. Afterwards, GC-coated nanoplatform for hepatocyte attachment "APO-loaded galactosylated chitosan-coated poly(d,l-lactide-co-glycolide) nanoparticles (APO-loaded GC-coated PLGA NPs)" was developed. The prosperous APO-loaded GC-coated PLGA NPs would be comprehensively appraised through extensive investigations. Their solid state characterization using Fourier transform-infrared spectroscopy, powder X-ray diffraction, and differential scanning calorimetry proved APO's encapsulation in the polymeric matrix. Transmission electron microscopy imaging of the investigated NPs highlighted their spherical architecture with a nanosized range and a characteristic halo-like appearance traceable to the GC coating of the NPs' surface. Saliently, the results of in vitro cytotoxicity screening revealed the spectacular anti-cancer efficacy of APO-loaded GC-coated PLGA NPs formula against the HepG2 cell line. Moreover, the fluorescence microscope disclosed the distinguished cellular uptake of such formula via ASGPR mediated endocytosis. Inclusively, a multifunctional nano-phytomedicine delivery system with a promising active hepatocyte-targeting, effective uptake into HepG2 cells, and sustained drug release pattern was successfully developed.

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PMID:  Life Sci. 2023 Feb 1 ;314:121313. Epub 2022 Dec 22. PMID: 36565813 Abstract Title:  Apocynin and its chitosan nanoparticles attenuated cisplatin-induced multiorgan failure: Synthesis, characterization, and biological evaluation. Abstract:  Cisplatin (CDDP) is an effective chemotherapeutic drug that has been used successfully in treating various tumors. Although its higher antineoplastic agent activity, CDDP exhibited severe side effects that limit its use. CDDP-induced toxicity is attributed to oxidative stress and inflammation. Apocynin (APO) is a bioactive phytochemical with potent antioxidant and anti-inflammatory properties. However, pharmaceutical experts face significant hurdles due to the limited bioavailability and quick elimination of APO. Therefore, we synthesized a chitosan (CTS)-based nano delivery system using the ionic gelation method to enhance APO bioactivity. CTS-APO-NPs were characterized using different physical and chemical approaches, including FTIR, XRD, TGA, Zeta-sizer, SEM, and TEM. In addition, the protective effect of CTS-APO-NPs against CDDP-induced nephrotoxicity, hepatotoxicity, and cardiotoxicity in rats was evaluated. CTS-APO-NPs restored serum biomarkers and antioxidants to their normal levels. Also, histopathological examination was used to assess the recovery of heart, kidney, and liver tissues. CTS-APO-NPs attenuated the oxidative stress mediated by Nrf2 activation while it dampened inflammation mediated by NF-B suppression. CTS-APO-NPs is a potentially attractive target for more therapeutic trials.

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PMID:  Biotech Histochem. 2023 Apr ;98(3):172-178. Epub 2022 Nov 28. PMID: 36440649 Abstract Title:  Effects of apocynin on sciatic nerve injury in rabbits. Abstract:  We investigated the effects of apocynin (APO) on experimental sciatic nerve compression injury in rabbits. We used 21 male rabbits divided randomly into three groups of seven. The control group was subjected to sciatic nerve compression with no further intervention. The APO treated group was subjected to compression injury and 20mg/kg APO was administered daily for 21days by intraperitoneal injection beginning the day after the injury. The sham group was treated with APO without injury. The control group exhibited shrinkage of axons, disruption of myelin sheaths and loss of nerve fibers. The damage for the control group was significantly greater than for the sham group. The severity of histopathology was decreased in the APO treated group compared to the control group, as was the oxidative stress index. Our findings suggest that APO treatment may contribute to healing of sciatic nerve damage.

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PMID:  Neuroscience. 2022 Oct 15 ;502:91-106. Epub 2022 Aug 4. PMID: 35934251 Abstract Title:  Oxidative Stress Inhibition Via Apocynin Prevents Medullary Respiratory Neurodegeneration and Respiratory Pattern Dysfunction in a 6-Hydroxydopamine Animal Model of Parkinson's Disease. Abstract:  Parkinson's Disease (PD) is a neurogenerative disorder characterized by the death of dopaminergic neurons in the Substantia Nigra pars compacta (SNpc), leading to motor, cognitive, learning, and respiratory dysfunctions. New evidence revealed that breathing impairment in PD mainly results from oxidative stress (OS) that initiates apoptotic signaling in respiratory neurons. Here, we investigated the role of OS inhibition using apocynin (non-specific NADPH oxidase inhibitor) in a 6-OHDA PD animal model in the neural control of breathing. The PD model was confirmed with a 70% reduction in TH-expressing neurons within the SNpc. After 20 and 40days of PD induction, no differences were observed in superoxide anion levels in any respiratory nuclei. At 30days after PD induction, 6-OHDA animals presented OS that was prevented in all respiratory nuclei by adding apocynin to the drinking water for 10days. Forty days after PD animal model induction, impaired motor and breathing function, reduced Phox2b and NK1 receptors-expressing neurons in the medullary respiratory areas; decreased latency to fall in the rotarod motor test; and attenuated respiratory frequency and minute ventilation parameters at rest and under hypercapnia conditions were observed. After 20days of apocynin treatment, neurodegeneration of respiratory nuclei and breathing dysfunction in 6-OHDA animals were prevented. Thus, OS contributes to respiratory neuron death, consequently leading to breathing dysfunction in the 6-OHDA PD animal model. Furthermore, these results present a new perspective for preventing the onset and progression of PD-related respiratory impairments.

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PMID:  Spectrochim Acta A Mol Biomol Spectrosc. 2022 Oct 15 ;279:121495. Epub 2022 Jun 9. PMID: 35700610 Abstract Title:  Apocynin reduces cytotoxic effects of monosodium glutamate in the brain: A spectroscopic, oxidative load, and machine learning study. Abstract:  Herein, we examined the modulatory effects ofApocynum (APO) on Monosodium Glutamate (MSG)-induced oxidative damage on the brain tissue of rats after long-term consumption of blood serum components by biochemical assays, Fourier transform infrared spectroscopy(FTIR), and machine learning methods. Sprague-Dawley male rats were randomly divided into the Control, Control + APO, MSG, and MSG + APO groups (n = 8 per group). All administrations were made by oral gavage saline, MSG, or APO and they were repeated for 28 days of the experiments. Brain tissue and blood serum samples were collected and analyzed for measurement levels ofmalondialdehyde (MDA),glutathione (GSH),myeloperoxidase (MPO), superoxide dismutase (SOD) activity, and Spectroscopic analysis. After 29 days, the results were evaluated using machine learning (ML). The levels of MDA and MPO showed changes in the MSG and MSG + APO groups, respectively. Changes in the proteins and lipids were observed in the FTIR spectra of the MSG groups. Additionally, APO in these animals improved the FTIR spectra to be similar to those in the Control group. The accuracy of the FTIR results calculated by ML was 100%. The findings of this study demonstrate that Apocynin treatment protectsagainst MSG-induced oxidative damage by inhibitingreactive oxygen speciesand upregulatingantioxidant capacity, indicating its potential in alleviatingthe toxic effects of MSG.

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PMID:  Life (Basel). 2022 May 1 ;12(5). Epub 2022 May 1. PMID: 35629342 Abstract Title:  Apocynin Attenuates Diabetes-Induced Skeletal Muscle Dysfunction by Mitigating ROS Generation and Boosting Antioxidant Defenses in Fast-Twitch and Slow-Twitch Muscles. Abstract:  In response to diabetes mellitus, skeletal muscle is negatively affected, as is evident by reduced contractile force production, increased muscle fatigability, and increased levels of oxidative stress biomarkers. Apocynin is a widely used NADPH oxidase inhibitor, with antioxidant and anti-inflammatory potential. It has been effective for amelioration of a variety of disorders, including diabetic complications. Therefore, the present study was conducted to evaluate the effects and action mechanisms of apocynin in slow- and fast-twitch diabetic rat muscles. Male Wistar rats were rendered diabetic by applying intraperitoneally a single dose of streptozotocin (45 mg/kg). Apocynin treatment (3 mg/kg/day) was administered over 8 weeks. Fasting blood glucose (FBG), insulin tolerance and body weight gain were measured. Both slow (soleus) and fast (extensor digitorum longus, EDL) skeletal muscles were used for muscle function evaluation, oxidative stress markers, and evaluating gene expression using qRT-PCR. Treatment with apocynin significantly reduced FBG levels and enhanced insulin tolerance. Apocynin also prevented muscle contractile dysfunction in EDL muscle but had no significant effect on this parameter in soleus muscles. However, in both types of muscles, apocynin mitigated the oxidative stress by decreasing ROS levels and increasing total glutathione levels and redox state. Concomitantly, apocynin also statistically enhanced Nrf-2 and GLU4 mRNA expression and downregulated NOX2, NOX4, and NF-B mRNA. Collectively, apocynin exhibits properties myoprotective in diabetic animals. These findings indicate that apocynin predominantly acts as an antioxidant in fast-twitch and slow-twitch muscles but has differential impact on contractile function.

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PMID:  Turk J Ophthalmol. 2021 Dec 28 ;51(6):344-350. PMID: 34963261 Abstract Title:  Effects ofL. Extract and Apocynin on Lens Oxidative Damage and Boron Levels in Rats with a High Fat-Diet. Abstract:  OBJECTIVES: Nutritional obesity causes oxidant damage in the body and cataract formation in the lenses by increasing the formation of free radicals. Myrtus communis leaf extracts (Myr) have antioxidant properties, and apocynin (Apo) is an effective NADPH-oxidase inhibitor. The data on tissue boron levels are quite lacking. The aim of this novel study was to investigate the effects of Myr and Apo treatment on boron levels and oxidative lens damage in rats fed a high-fat diet (HFD).MATERIALS AND METHODS: Wistar albino male rats were randomly divided into four groups: the control group, HFD group, HFD + Myr group, and HFD + Apo group. Body weight and blood lipids were determined before and after the experiment. After decapitating the rats, the lenses were removed and homogenized. Catalase (CAT) and superoxide dismutase (SOD) activities and boron, malondialdehyde (MDA), and reduced glutathione (GSH) levels in the lens homogenates were determined.RESULTS: The HFD increased serum triglyceride (p

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PMID:  J Glaucoma. 2023 Jun 1 ;32(6):443-450. Epub 2023 Mar 20. PMID: 36946914 Abstract Title:  Associations Between Niacin Intake and Glaucoma in the National Health and Nutrition Examination Survey. Abstract:  PRCIS: This study examined the association between dietary niacin intake and glaucoma in the 2005-2008 National Health and Nutrition Examination Survey (NHANES). Increased niacin intake was associated with lower odds of glaucoma overall and among women.PURPOSE: To examine the association between dietary niacin intake and glaucoma in the 2005-2008 NHANES.MATERIALS AND METHODS: This cross-sectional study included adult participants of the 2005-2008 NHANES. The exposure was dietary niacin intake, which was examined as a continuous and categorical variable. The outcome was glaucoma as defined by regraded disc images. Covariates included age, sex, race/ethnicity, education level, income, body mass index, smoking status, alcohol use, cardiovascular disease, diabetes mellitus, daily energy intake, vitamin B2 and B6 consumption, and macular degeneration. Adjusting for all covariates, logistic regression was performed to examine the association between niacin intake and glaucoma in the overall population and stratified by sex.RESULTS: The weighted population included 5371 individuals (109,734,124 weighted), of whom 55 (1.0%) had glaucoma. Each 1 mg increase in niacin intake was associated with a 6% decreased odds of glaucoma odds [adjusted odds ratio (aOR) = 0.94, 95% CI = 0.90, 0.98]. Among women, increased niacin intake was associated with decreased odds of glaucoma both with niacin as a continuous (aOR = 0.89, 95% CI = 0.80, 0.99 per 1 mg increase in niacin intake) and binary variable (aOR = 0.35, 95% CI = 0.14, 0.90 for higher vs lower niacin intake).CONCLUSIONS: In the 2005-2008 NHANES population, higher levels of niacin intake were associated with decreased odds of glaucoma overall and in women. Further studies are needed to examine the potential protective effects of niacin on glaucoma risk.

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PMID:  Exp Clin Endocrinol Diabetes. 2023 May 22. Epub 2023 May 22. PMID: 36805533 Abstract Title:  Association of Dietary Niacin Intake with Diabetes in Adults in the United States. Abstract:  OBJECTIVE: Previous studies have shown inconsistent associations between niacin supplementation and diabetes, and little is known about the relationship between dietary niacin intake and the risk of diabetes in the general population. Our study aimed to explore the association between dietary niacin intake and the risk of diabetes in the adult population in the United States.METHODS: Data from the 2005-2016 National Health and Nutrition Examination Surveys were analyzed. Diabetes was diagnosed according to the American Diabetes Association criteria. Multivariate logistic regression models were used to estimate the association between dietary niacin intake and diabetes. Covariates included age, sex, race, family income, educational level, drinking status, smoking status, marital status, and physical activity.RESULTS: This study included 24494 participants, of which 13.63% had diabetes. In the fully adjusted model, a high niacin intake was significantly associated with a reduced risk of diabetes in a dose-dependent manner. When extreme quintiles of niacin intake were compared, the multivariable-adjusted odds ratio was 0.66 (95% confidence interval: 0.49, 0.88) for diabetes, and per ten-unit increment in dietary niacin intake was associated with a 14% lower risk of diabetes. When niacin intake was less than 15.01mg/d, a ten-unit increment in niacin intake was associated with a 24% higher risk of diabetes. However, the effect was not statistically significant.CONCLUSIONS: Our results suggest that the consumption of adequate amounts of niacin can reduce the risk of diabetes. Furthermore, this protective effect disappeared when the niacin intake was insufficient (less than 15.01mg/d).

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PMID:  Molecules. 2023 Mar 2 ;28(5). Epub 2023 Mar 2. PMID: 36903551 Abstract Title:  Neuroprotective Effects of Carnosic Acid: Insight into Its Mechanisms of Action. Abstract:  Carnosic acid is a diterpenoid abundantly present in plants belonging to the genusandof the familyaccounting for their application in traditional medicine. The diverse biological properties of carnosic acid that include antioxidant, anti-inflammatory, and anticarcinogenic activities have instigated studies on its mechanistic role, providing further insights into its potential as a therapeutic agent. Accumulating evidence has established the relevance of carnosic acid as a neuroprotective agent exhibiting therapeutic efficacy in combatting neuronal-injury-induced disorders. The physiological importance of carnosic acid in the mitigation of neurodegenerative disorders is just beginning to be understood. This review summarizes the current data on the mode of action through which carnosic acid exerts its neuroprotective role that may serve to strategize novel therapeutic approaches for these debilitating neurodegenerative disorders.

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PMID:  Behav Brain Res. 2023 Feb 25 ;440:114257. Epub 2022 Dec 13. PMID: 36526017 Abstract Title:  Biochemical and behavioral effects of rosmarinic acid treatment in an animal model of Parkinson's disease induced by MPTP. Abstract:  Parkinson's disease (PD) is the second most common neurodegenerative disease worldwide. The main therapeutic approach available nowadays relieves motor symptoms but does not prevent or stop neurodegeneration. Rosmarinic acid (RA), an ester of caffeic and 3,4-dihydroxyphenylacetic acids, is obtained from numerous plant species such as Salvia officinalis L. (sage) and Rosmarinus officinalis (rosemary). This compound has a wide spectrum of biological activities, such as antioxidant and anti-inflammatory, and could be an additional therapy for neurodegenerative disorders. Here we evaluated the potential neuroprotective effects of RA treatment in a murine model of PD induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Mice were separated into four groups: CN, Control/saline; RA, Rosmarinic acid/vehicle; MPTP, MPTP/saline; MPTP+RA, MPTP/RA. RA (20 mg/kg, or vehicle) was administered orally by intra-gastric gavage for 14 days, one hour before MPTP or saline injection. MPTP groups received the drug (30 mg/kg, intraperitoneally) once a day for five days (fourth to the eighth day of the experiment). MPTP-treated animals displayed hyperlocomotion behavior, which was significantly prevented by RA treatment. In addition, RA treatment increased dopaminergic signaling in the parkinsonian mice and improved the monoaminergic system in healthy animals. Analysis of alterations in the striatal mRNA expression of dopaminergic system components showed that MAO-A expression was increased in the MPTP+AR group. Overall, this study brings new evidence of the potential neuroprotective properties of RA not only in preventing behavioral features observed in PD, but also by improving neurotransmission in the healthy brain.

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PMID:  Int Immunopharmacol. 2023 Apr ;117:110003. Epub 2023 Mar 15. PMID: 36931000 Abstract Title:  Rosmarinic acid ameliorates skin inflammation and pruritus in allergic contact dermatitis by inhibiting mast cell-mediated MRGPRX2/PLC1 signaling pathway. Abstract:  BACKGROUND: Allergic contact dermatitis (ACD) is one of the most common dermatoses, which has high disease burden and quality of life impairment. Anti-histamine is not effective in a part of the ACD patients. Thus, the discovery of novel antipruritic therapy is of highly demand.OBJECTIVE: In this study, we investigated the anti-pruritic effects of rosmarinic acid (RA) and explored the underlying mechanism.METHOD: SPF Balb/c mice were randomly divided into control group, ACD model group, RA group (1.0 mg/kg) and loratadine (LORA) group (1.5 mg/kg). Back epidermal thickness was recorded. H&E staining was used for pathological observation. Mast cell degranulation was assessed by toluidine blue staining. ELISA assay was employed to detect cytokines levels. Cortistatin-14 (CST-14) and Mas-related G protein-coupled receptor X2 (MRGPRX2) expression was detetcted by RT-PCR and western blot. Molecular docking assay was used to predict the affinity of RA and MRGPRX2. Surface plasmon resonance (SPR) assay was used to verify structure affinity of RA and MRGPRX2.RESULTS: RA treatment significantly decreased epidermal keratinization and inflammatory cell infiltration in ACD mouse model. Administration of RA significantly reduced secretion of histamine, IL-13, and mRNA expression of CST-14. Furthermore, RA treatment increased mRNA expression of MRGPRX2. In addition, Molecular docking results predict that RA has a good affinity with MRGPRX2. RA displayed a structure affinity (K = 8.89  10) with MRGPRX2 by SPR. RA inhibited CST-14 and Compound 48/80 (C48/80)-induced mast cell activation via MRGPRX2-PLC1-PKC-NF-B signaling pathway.CONCLUSION: RA exhibits anti-pruritic and anti-inflammatory effects in ACD mice by inhibiting MRGPRX2-PLC1-PKC-NF-B signaling pathway. RA might emerge as a potential drug for the treatment of pruritus and skin inflammation in the setting of ACD.

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PMID:  J Eur Acad Dermatol Venereol. 2023 Mar ;37 Suppl 2:12-19. PMID: 36729401 Abstract Title:  Myrtus communis and Celastrol enriched plant cell culture extracts control together the pivotal role of Cutibacterium acnes and inflammatory pathways in acne. Abstract:  INTRODUCTION: Acne is a multifactorial inflammatory disease of the pilosebaceous unit in which Cutibacterium acnes is one of the main triggers. A strong predominance of C. acnes phylotype IA1 is present in acne skin with higher biofilm organization and virulence, promoting local immuno-inflammation, especially the Th17 pathway.OBJECTIVES: We evaluated the single and combined pharmacological properties of the plant extracts, Myrtus communis (Myrtacine) and Celastrol enriched plant cell culture (CEE) extracts on the C. acnes/Th17 pathway.METHODS: The effect of Myrtacineon the virulence of C. acnes phylotype IA1 was quantified according to the expression of several related genes. The activity of Myrtacineand CEE on the inflammatory cascade was assessed using monocytes-derived dendritic cells (Mo-DC) stimulated with membranes or biofilms of the C. acnes phylotype IA1. Finally, the effect of CEE on the Th17 pathway was studied using C. acnes stimulated sebocyte 2D cultures and 3D skin tissue models containing preactivated Th17 cells.RESULTS: Myrtacinehad an anti-virulence effect, evident as a significant and strong inhibition of the expression of several virulence factor genes by 60%-95% compared to untreated controls. Myrtacineand CEE significantly inhibited proinflammatory cytokine (IL-6, IL-8, IL-12p40 and TNF-) production by Mo-DC in response to C. acnes phylotype IA1. Interestingly, these two ingredients resulted in synergistic inhibition of most cytokines when used in combination. Finally, we demonstrated an inhibitory effect of CEE, in solution or formulated at 0.3%, specifically on IL-17 release by Th17 lymphocytes in a C. acnes-stimulated sebocyte 2D cultures and by Th17-lymphocytes integrated in a 3D skin models.CONCLUSIONS: 2D and 3D models were developed to represent relevant and specific pathways involved in acne. Myrtacineand CEE were shown to alter one or more of these pathways, indicating their potential beneficial effects on this disease.

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PMID:  Nutrients. 2022 Nov 27 ;14(23). Epub 2022 Nov 27. PMID: 36501085 Abstract Title:  Antileukemic, Antioxidant, Anti-Inflammatory and Healing Activities Induced by a Polyphenol-Enriched Fraction Extracted from Leaves ofL. Abstract:  Natural products have offered a number of exciting approaches in cancer treatment over the years. In this study, we investigated the prophylactic and therapeutic effects of the polyphenol-enriched fraction extracted from(PEMC) on acute and chronic leukemia. According to the UHPLC-MS, the fraction is rich in flavonoids. Protective activity of the PEMC was assessed by evaluating the antioxidant, anti-inflammatory, wound healing, and hemolysis potential in a series of in vivo and in vitro assays, while the therapeutic approach consisted of the evaluation of cytotoxic activity of the PEMC against HL60 and K562 leukemia cell lines. Safety of the fraction was also evaluated on a non-cancerous Vero cell line and by an acute toxicity test performed in mice. The PEMC demonstrated a significant anti-inflammatory and healing potential. The activities found at the dose of 100 mg/kg were better than those observed using a reference drug. The PEMC demonstrated a significant antioxidant effect and a specific cytotoxicity towards HL60 (IC= 19.87M) and K562 (IC= 29.64M) cell lines being non-toxic to the Vero cell line. No hemolytic activity was observed in vitro and no toxicity effect was found in mice. Thus, the PEMC has a pharmacological potential as both preventive and therapeutic agent. However, further research is necessary to propose its mechanism of action.

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PMID:  J Cereb Blood Flow Metab. 2022 Aug ;42(8):1425-1436. Epub 2022 Feb 9. PMID: 35137612 Abstract Title:  Treatment with apocynin selectively restores hippocampal arteriole function and seizure-induced hyperemia in a model of preeclampsia. Abstract:  Preeclampsia (PE) is a hypertensive disorder of pregnancy associated with neurovascular dysfunction, cognitive impairment and increased seizure susceptibility. Here, we sought to determine if treatment of experimental PE (ePE) rats with apocynin could prevent hippocampal arteriolar (HA) dysfunction and impaired seizure-induced hyperemia within the hippocampus, a brain region central to cognition and seizure generation. Isolated and pressurized HAs from Sprague Dawley rats that were normal pregnant (Preg; n=8), ePE (n=8) or ePE treated with apocynin for 2weeks of gestation (ePE+apo; n=8) were compared. Hippocampal blood flow (n=6/group) was measured using hydrogen clearance before and during seizure. Aorta elastin was quantified using histochemistry. ePE was associated with HA dysfunction including reduced contraction to endothelin-1 and diminished dilation to the endothelium-dependent vasodilator NS309 that was prevented by apocynin. However, apocynin had no effect on ePE-induced impairment of dilation to the nitric oxide donor sodium nitroprusside, but increased myogenic tone and substantially increased HA distensibility. Seizure-induced hyperemia was impaired in ePE rats that was restored by apocynin. Aorta from ePE rats had reduced elastin content, suggesting large artery stiffness, that was unaffected by apocynin. Thus, while apocynin partially prevented HA dysfunction, its restoration of functional hyperemia may be protective of seizure-induced injury during eclampsia.

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PMID:  Brain Res Bull. 2022 May ;182:1-11. Epub 2022 Feb 7. PMID: 35143926 Abstract Title:  Post-treatment with apocynin at a lower dose regulates the UPR branch of eIF2and XBP-1 pathways after stroke. Abstract:  Stroke leads to disturbance in the physiology of the ER (Endoplasmic Reticulum) that triggers UPR (Unfolded Protein Response) pathways aimed to compensate neuronal cell damage. However, sustained UPR causes stressful conditions in the ER lumen forming abnormal protein aggregates. Stroke-induced oxidative stress also amalgamates with UPR to safeguard and ensure the proper functioning of brain cells. Thus we tested the effect of apocynin (a potent antioxidant) post-treatment in experimental stroke on the outcome of ER stress and UPR branch pathways. We administered a low dose of apocynin at 1 mg/kg (intraperitoneal) to adult Sprague-Dawley rats subjected to Middle Cerebral Artery Occlusion (MCAO) for two-time points. The first dose immediately after re-establishing the blood flow and another at 6 h of reperfusion. Apocynin post-treatment significantly reduced ROS (Reactive Oxygen Species) generation at an early reperfusion time point of 4 h. It preserved neuronal morphology, dendritic spine density, reduced protein aggregation, and brain damage after 24 h of reperfusion. Apocynin post-treatment regulates the two UPR branch pathways in our experimental paradigm. 1) Down-regulation of eIF2(Eukaryotic Initiation Factor 2) phosphorylation, and CHOP (C/EBP homologous protein) 2) by reducing the XBP-1 (X-Box binding Protein-1) mRNA splicing downstream to PERK (Protein Kinase RNA-Like ER Kinase) and IRE1(Inositol Requiring Enzyme 1alpha) UPR pathways, respectively. Bioinformatics prediction showed that apocynin has binding sites for PERK (Protein Kinase RNA-Like ER Kinase) and IRE1proteins. The amino acid residues interacting with apocynin were Cys891 and Gln889 (for PERK), and the amino acids Ser726, Arg722, and Ala719 (for IRE1) lying within their activation loop. Overall, these studies indicate that apocynin post-treatment might regulate ER stress/UPR pathways and minimize stroke brain damage, thus having implications for developing newer strategies for stroke treatment.

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PMID:  Behav Brain Res. 2022 Feb 15 ;419:113699. Epub 2021 Nov 29. PMID: 34856299 Abstract Title:  Neuroprotective role of apocynin against pentylenetetrazole kindling epilepsy and associated comorbidities in mice by suppression of ROS/RNS. Abstract:  Epilepsy is a neurological disease that transpires due to the unusual synchronized neuronal discharge within the central nervous system, which drives repetitious unprovoked seizures. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase is a complex enzyme accountable for reactive oxygen species (ROS) production, neurodegeneration, neurotoxicity, memory impairment, vitiates normal cellular processes, long term potentiation, and thus, implicated in the pathogenesis of epilepsy. Therefore, the present study was sketched to examine the neuroprotective effect of apocynin, NADPH oxidase inhibitor in pentylenetetrazole kindling epilepsy, and induced comorbidities in mice. Mice (either sex) were given pentylenetetrazole (35 mg/kg, i.p.) every other day up to 29 days, and a challenge test was executed on the 33day. Pretreatment with apocynin (25, 50, and 100 mg/kg, i.p.) was carried out from 1to 33day. Rotarod and open field test were performed on the 1, 10, 20, and 30days of the study. Animals were tutored on the morris water maze from 30to 33day, and the retention was registered on the 34day. Tail suspension test and elevated plus maze were sequentially performed on the 32and 33day of the study. On the 34day, animals were sacrificed, and their brains were isolated to conduct biochemical estimation. NADPH oxidase activation due to chronic pentylenetetrazole treatment resulted in generalized tonic-clonic seizures, enhanced oxidative stress, remodeled neurotransmitters' level, and resulted in comorbidities (anxiety, depression, and memory impairment). Pretreatment with apocynin significantly restricted the pentylenetetrazole induced seizure severity, ROS production, neurotransmitter alteration, and comorbid conditions by inhibiting the NADPH oxidase enzyme.

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PMID:  Eur J Pharmacol. 2021 Oct 15 ;909:174402. Epub 2021 Aug 1. PMID: 34348125 Abstract Title:  Apocynin attenuates diabetic cardiomyopathy by suppressing ASK1-p38/JNK signaling. Abstract:  Diabetic cardiomyopathy (DCM) significantly increased the morbidity of heart failure in diabetic patients. Long-time oxidative stress is an indisputable contributor for DCM development. Apocynin (APO) has been suggested to be a potential drug against oxidative stress. The study aims to find out the effects of APO on DCM and the related mechanisms. Mice were randomly divided into four groups: control (CON), APO, DCM and DCM + APO. Echocardiography analyses, histological analyses, Western blot and RT-PCR were used to explore the roles and mechanisms of APO in DCM. Isolated neonatal rat cardiomyocytes (NRCMs) and cardiac fibroblasts (CFs) were used for further confirming the APO treatment effects in vitro. Deteriorated cardiac function, enlarged cardiomyocytes, excess cardiac fibrosis and significant cardiac oxidative stress were observed in DCM group. However, APO treatment successfully improved cardiac function, decreased cardiac hypertrophy and fibrosis, and depressed oxidative stress. Mechanistically, APO treatment markedly suppressed apoptosis signal regulating kinase 1(ASK1)-p38/c-jun N-terminal kinase (JNK) signaling and reduced apoptosis. It also inhibited NRCM apoptosis and CF activation via depressing ASK1-p38/JNK signaling in vitro. Moreover, adenovirus-mediated ASK1 overexpression completely removed the protection of APO in vitro. In conclusion, APO treatment could effectively attenuate DCM-associated injuries in vivo and protect against high glucose-induced NRCM and CF injuries in vitro via suppressing ASK1-p38/JNK signaling. APO might be a potential ASK1 inhibitor for treating DCM.

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PMID:  Biomolecules. 2021 Jun 15 ;11(6). Epub 2021 Jun 15. PMID: 34203655 Abstract Title:  Apocynin Prevents Anxiety-Like Behavior and Histone Deacetylases Overexpression Induced by Sub-Chronic Stress in Mice. Abstract:  Anxiety disorders are common mental health diseases affecting up to 7% of people around the world. Stress is considered one of the major environmental risk factors to promote anxiety disorders through mechanisms involving epigenetic changes. Moreover, alteration in redox balance and increased reactive oxygen species (ROS) production have been detected in anxiety patients and in stressed-animal models of anxiety. Here we tested if the administration of apocynin, a natural origin antioxidant, may prevent the anxiety-like phenotype and reduction of histone acetylation induced by a subchronic forced swimming stress (FSS) paradigm. We found that apocynin prevented the enhanced latency time in the novelty-suppressed feeding test, and the production of malondialdehyde induced by FSS. Moreover, apocynin was able to block the upregulation of p47phox, a key subunit of the NADPH oxidase complex. Finally, apocynin prevented the rise of hippocampal,and, and the reduction of histone-3 acetylation levels promoted by FSS exposure. In conclusion, our results provide evidence that apocynin reduces the deleterious effect of stress and suggests that oxidative stress may regulate epigenetic mechanisms.

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PMID:  Biotech Histochem. 2022 Apr ;97(3):228-235. Epub 2021 Jun 14. PMID: 34120545 Abstract Title:  Protective effects of apocynin against ionizing radiation-induced hepatotoxicity in rats. Abstract:  Radiation hepatotoxicity is thought to be due to free oxygen radicals. We investigated the protective effects of apocynin (APO) against ionizing radiation induced oxidative stress in liver tissue following whole body ionizing radiation. We divided rats into four groups. The control group was injected intraperitoneally (i.p.) with saline for five consecutive days. A second group was injected i.p. with saline for 5 days and after 24 h, a single-dose of radiation (800 cGy) was administered to the whole abdomen. A third group was injected i.p. with 20 mg/kg APO for 5 days. A fourth group was injected i.p. with APO for 5 days and after 24 h, the rats were exposed to radiation. Ionizing radiation induced hepatotoxicity was demonstrated biochemically by significant changes in oxidative and antioxidant parameters. Our findings suggest that APO treatment may be protective against radiation induced hepatic injury by decreasing oxidative stress and increasing antioxidant activity.

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PMID:  Bratisl Lek Listy. 2021 ;122(1):78-84. PMID: 33393325 Abstract Title:  Apocynin ameliorates cognitive deficits in streptozotocin-induced diabetic rats. Abstract:  AIMS: The aim was to investigate the improvement properties of apocynin and its potential mechanism on diabetes-associated cognitive decline.METHODS: In this study, the model of diabetic rat was established by STZ (50 mg/kg) and treated with apocynin (16 mg/kg/d for 12 weeks). The cognitive ability was evaluated by Morris water maze test. The indicators of oxidative stress (SOD and MDA) were analyzed by spectrophotometer. The inflammatory cytokines were measured by real time-PCR and ELISA. The protein expressions of Nrf-2, HO-1, Bcl-2 and Bax were determined by Western blot.RESULTS: Treatment with apocynin ameliorated diabetes-related learning and memory injury, as represented by decreasing escape latency and enhancement of the number of times of crossing platform, in the Morris water maze test. In hippocampus, apocynin markedly augmented SOD activity and inhibited MDA level to alleviate oxidative stress. Moreover, apocynin obviously relieved inflammatory reaction by suppressing TNF-, IL-1and IL-6 concentrations. Concomitantly, apocynin also statistically enhanced Nrf-2 and HO-1 protein expression to improve DACD. Lastly, apocynin notably ameliorated Bax/Bcl-2 ratio by regulating Bax and Bcl-2 protein expression to mitigate apoptosis.CONCLUSION: Our results have shown that apocynin may be a valid therapeutic agent against DACD via modulation of antioxidant, anti-inflammatory, and anti-apoptosis (Tab. 1, Fig. 18, Ref. 35).

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PMID:  Pregnancy Hypertens. 2020 Oct ;22:210-215. Epub 2020 Oct 14. PMID: 33099123 Abstract Title:  Apocynin inhibits placental TLR4/NF-B signaling pathway and ameliorates preeclampsia-like symptoms in rats. Abstract:  OBJECTIVE: We aimed to investigate the potency of apocynin in ameliorating preeclampsia and explore the underlying mechanisms.METHODS: Preeclampsia model was constructed in rats by administering 200 mg/kg/day L-NAME. Apocynin was given orally in drinking water. Systolic blood pressure and proteinuria were monitored during treatment. Survival rate rate of the pups and placental weight were assessed. Serum sFlt-1, PIGF, IL-6 and placental TLR4 levels were measured using ELISA or qRT-PCR.RESULTS: Apocynin dose-dependently decreased systolic blood pressure and proteinuria during gestation. Survival rate of the pups and placental weight were improved by apocynin treatment. Apocynin ameliorated the imbalance of sFlt-1 and PIGF in serum and placenta of rats with preeclampsia. Apocynin attenuated serum inflammatory cytokine expression and placental inflammation most likely due to downregulation of the placental TLR4/NF-kB pathway in L-NAME treated rats.CONCLUSIONS: Apocynin potently ameliorates the L-NAME-induced preeclampsia, which is achieved by re-balancing the sFlt-1 and PIGF levels, attenuating inflammation, and inhibiting TLR4/NF-B p65 signaling.

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PMID:  Bone Joint Res. 2020 Jan ;9(1):23-28. Epub 2020 May 16. PMID: 32435452 Abstract Title:  Evaluation of apocynin in vitro on high glucose-induced oxidative stress on tenocytes. Abstract:  AIMS: The purpose of this study was to evaluate the in vitro effects of apocynin, an inhibitor of nicotinamide adenine dinucleotide phosphate oxidase (NOX) and a downregulator of intracellular reactive oxygen species (ROS), on high glucose-induced oxidative stress on tenocytes.METHODS: Tenocytes from normal Sprague-Dawley rats were cultured in both control and high-glucose conditions. Apocynin was added at cell seeding, dividing the tenocytes into four groups: the control group; regular glucose with apocynin (RG apo+); high glucose with apocynin (HG apo+); and high glucose without apocynin (HG apo-). Reactive oxygen species production, cell proliferation, apoptosis and messenger RNA (mRNA) expression of NOX1 and 4, and interleukin-6 (IL-6) were determined in vitro.RESULTS: Expression of NOX1, NOX4, and IL-6 mRNA in the HG groups was significantly higher compared with that in the RG groups, and NOX1, NOX4, and IL-6 mRNA expression in the HG apo+ group was significantly lower compared with that in the HG apo- group. Cell proliferation in the RG apo+ group was significantly higher than in the control group and was also significantly higher in the HG apo+ group than in the HG apo- group. Both the ROS accumulation and the amounts of apoptotic cells in the HG groups were greater than those in the RG groups and were significantly less in the HG apo+ group than in the HG apo- group.CONCLUSION: Apocynin reduced ROS production and cell death via NOX inhibition in high-glucose conditions. Apocynin is therefore a potential prodrug in the treatment of diabetic tendinopathy.2020;9(1):23-28.

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PMID:  Behav Brain Res. 2020 Jun 18 ;388:112643. Epub 2020 Apr 24. PMID: 32339552 Abstract Title:  Apocynin as an antidepressant agent: in vivo behavior and oxidative parameters modulation. Abstract:  Depression is one of the most common mood disorders, which affects one in six people at some point in life. However, the treatment of this disease is still a challenge. Chronic corticosterone administration (CCA) is a widely used animal model to study the mechanisms involved, as well as possible therapeutic strategies for the treatment of depression. Moreover, elevated oxidative stress has been observed in psychiatric disorders, including major depression and, in this context, antioxidant therapy may be a potential therapeutic alternative. In this study, we investigated the effect of seven days of treatment with apocynin, an antioxidant of natural origin, on depressive-like behavior and oxidative parameters in mice submitted to CCA. After 21 days of corticosterone administration (20 mg/Kg/day, subcutaneously, s.c.), we observed the development of depressive-like behavior with an increase in immobility time on tail suspension test and forced swimming test and reduction in total grooming time on splash test. Also, we found high superoxide dismutase activity and hydrogen peroxide levels whereas catalase activity was reduced in the prefrontal cortex, hippocampus and striatum. Seven days of treatment with apocynin (100 mg/Kg/day orally, p.o), performed immediately after corticosterone administration in the last week of protocol, was able to reverse the most of these changes, revealing its antidepressant-like effect. In conclusion, our results suggest apocynin as an antidepressant-like agent with a mechanism of action based on the attenuation of oxidative changes induced by CCA.

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PMID:  Turk J Med Sci. 2020 Aug 26 ;50(5):1409-1420. Epub 2020 Aug 26. PMID: 32394677 Abstract Title:  Protective effects of apocynin on damaged testes of rats exposed to methotrexate. Abstract:  BACKGROUND/AIM: Methotrexate (MTX), widely used as a drug in cancer, has many adverse effects on tissues. Apocynin (APO) is a NADPH oxidase inhibitor and is known with many antioxidant properties. In this study, we aimed to evaluate the adverse effects of MTX on testicular tissue and the protective effects of APO at two different doses (20 mg/kg and 50 mg/kg) on MTX-induced testicular damage.MATERIALS AND METHODS: Fifty adult male Wistar albino rats (8 weeks old and weighing 200250 g) were divided into five groups of 10 rats each: 1. saline control, 2. dimethyl sulfoxide (DMSO) control, 3. MTX, 4. APO-20 + MTX, and 5. APO-50 + MTX. All injections were performed intraperitoneally. At the end of day 28, all rats were sacrificed under anesthesia. The testes were evaluated histologically and the blood samples were analyzed biochemically.RESULTS: According to histological and biochemical analyses, there was no significant difference between the DMSO and control groups. In terms of the histological findings, MTX group was significantly the worst affected group compared to the others, and in this group, apoptotic cell number (P = 0.011) was significantly increased in comparison with the control group. Except MTX, there was no significant difference in apoptotic cell number of the other groups compared to the control group. In the MTX group, malondialdehyde (MDA, P = 0.017) and myeloperoxidase (MPO, P

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PMID:  Reprod Sci. 2020 Feb ;27(2):722-730. Epub 2020 Jan 1. PMID: 32046403 Abstract Title:  TLR4/NF-B Signaling Pathway Participates in the Protective Effects of Apocynin on Gestational Diabetes Mellitus Induced Placental Oxidative Stress and Inflammation. Abstract:  Gestational diabetes mellitus (GDM) is a temporary form of diabetes during pregnancy which influences the health of both mother and child. Both inflammation and oxidative stress have been implicated in the pathophysiology of GDM. Apocynin, acetophenone with anti-oxidative and anti-inflammation activities, has been shown to protect against insulin resistance. In the current study, the effects of apocynin on GDM symptoms, productive outcomes, oxidative stress, and inflammation were evaluated and the underlying mechanisms were explored. We administrated apocynin to GDM mice and monitored the GDM symptoms including body weight, serum levels of glucose, insulin, lipid profile, and the fetal outcomes in GDM mice. We also evaluated the effects of apocynin on placental oxidative stress, inflammation, and activation of TLR4/NF-B signaling pathway in GDM mice. Here, we reported that apocynin treatment significantly reduced serum levels of glucose, cholesterol, triglyceride, and low-density lipoprotein in GDM mice, while significantly increased serum level of insulin and high-density lipoprotein. Apocynin improved fetal outcomes in GDM mice. Apocynin ameliorated placental oxidative stress and inflammation and inhibited TLR4/NF-B signaling pathway activation in GDM mice. We concluded that apocynin suppressed oxidative stress and inflammation in GDM by inhibiting the TLR4/NF-B signaling pathway.

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PMID:  Phytomedicine. 2020 Feb ;67:153152. Epub 2019 Dec 19. PMID: 31887479 Abstract Title:  Targeting cellular microtubule by phytochemical apocynin exhibits autophagy-mediated apoptosis to inhibit lung carcinoma progression and tumorigenesis. Abstract:  BACKGROUND: Lung cancer is the leading cause of cancer-related deaths worldwide. Several targets have been identified for lung cancer therapy, amongst which 'Microtubule' and its dynamics are the most widely studied and used in therapy. Tubulin-microtubule polymer dynamics are highly sought after targets in the field of anti-cancer drug designing. Natural compounds are important sources for developing anticancer therapeutics owing to their efficacy and lower cytotoxicity. Evidence suggested that therapeutic targeting of microtubule by natural compounds is amongst the most widely used interventions in numerous cancer therapies including lung cancer.PURPOSE: To determine the efficacy of apocynin (a natural compound) in suppressing the progression of lung carcinoma both in vitro and in vivo, along with the identification of targets and the underlying mechanism for developing a novel therapeutic approach.METHODS: We have demonstrated themicrotubule depolymerizing role of apocynin by established protocols in cellular and cell-free system. The efficacy of apocynin to inhibit lung carcinoma progression was studied on A549 cells.The tumoricidal ability of apocynin was studied in BALB/c mice model as well.Mice were classified into 4 groups namely-group II mice as tumor control; group III-IV mice asalso tumor-induced but treated with differential apocynin doses whereas group I mice were kept as normal.RESULTS: Apocynin, showed selective cytotoxicity towards lung cancer cells rather than normal lung fibroblast cells. Apocynin inhibited oncogenic properties including growth, proliferation (p 

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PMID:  Andrologia. 2019 May ;51(4):e13227. Epub 2019 Jan 8. PMID: 30623469 Abstract Title:  Apocynin alleviates cisplatin-induced testicular cytotoxicity by regulating oxidative stress and apoptosis in rats. Abstract:  The aim of this study was to investigate possible protective effects of apocynin (APO), an NADPH oxidase (NOX2) inhibitor, on cisplatin (CIS)-induced testicular damage. Four groups of Sprague Dawley rats were used: control, APO, CIS and CIS+APO. Following a single intraperitoneal dose of CIS (7 mg/kg), either dimethyl sulfoxide or APO (25 mg/kg) was administered orally for 5 days. Testis samples were evaluated microscopically for general histopathology and ultrastructure, proliferating and apoptotic cells, and NOX2 localization. Sperm parameters were evaluated. Malondialdehyde (MDA) and glutathione (GSH) levels and superoxide dismutase (SOD), myeloperoxidase (MPO) and 8-hydroxy-2-deoxyguanosine (8-OHdG) activities were analysed biochemically. The CIS group had a greater number of abnormal spermatozoa, atrophic seminiferous tubules, apoptotic and NOX2-immunoreactive cells; numerous large vacuole formations in the cytoplasm of germinal epithelial cells; degenerated intercellular tight junctions; higher MDA, 8-OHdG and MPO levels; decreased numbers of spermatozoa; and lower proliferative index and GSH and SOD levels. All these histologic and biochemical results were better in the CIS+APO group. CIS causes testicular damage by decreasing spermatogenic cell lines and increasing NOX2 activity and apoptosis through oxidative stress. APO prevents testicular damage, possibly by its antioxidant effects.

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PMID:  Molecules. 2023 May 24 ;28(11). Epub 2023 May 24. PMID: 37298776 Abstract Title:  Evaluation of the Analgesic Effect of High-Cannabidiol-Content Cannabis Extracts in Different Pain Models by Using Polymeric Micelles as Vehicles. Abstract:  Currently, cannabis is considered an attractive option for the treatment of various diseases, including pain management. Thus, developing new analgesics is paramount for improving the health of people suffering from chronic pain. Safer natural derivatives such as cannabidiol (CBD) have shown excellent potential for the treatment of these diseases. This study aimed to evaluate the analgesic effect of a CBD-rich cannabis extract (CE) encapsulated in polymeric micelles (CBD/PMs) using different pain models. The PEG-PCL polymers were characterized by gel permeation chromatography andH-NMR spectroscopy. PMs were prepared by solvent evaporation and characterized by dynamic light scattering (DLS) and transmission electron microscopy. The analgesic activity of CBD/PMs and nonencapsulated CE rich in CBD (CE/CBD) was evaluated using mouse thermal, chemical, and mechanical pain models. The acute toxicity of the encapsulated CE was determined by oral administration in mice at a dose of 20 mg/kg for 14 days. The release of CBD from the nanoparticles was assessed in vitro using a dialysis experiment. CBD/PMs with an average hydrodynamic diameter of 63.8 nm obtained from a biocompatible polyethylene glycol-block-polycaprolactone copolymer were used as nanocarriers for the extract formulations with 9.2% CBD content, which corresponded with a high encapsulation efficiency of 99.9%. The results of the pharmacological assays indicated that orally administered CBD/PMs were safe and exerted a better analgesic effect than CE/CBD. The micelle formulation had a significant analgesic effect in a chemical pain model, reaching a percentage of analgesia of 42%. CE was successfully encapsulated in a nanocarrier, providing better stability. Moreover, it proved to be more efficient as a carrier for CBD release. The analgesic activity of CBD/PMs was higher than that of free CE, implying that encapsulation is an efficient strategy for improving stability and functionality. In conclusion, CBD/PMs could be promising therapeutics for pain management in the future.

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PMID:  Foods. 2022 Nov 28 ;11(23). Epub 2022 Nov 28. PMID: 36496645 Abstract Title:  Evaluation of Chemical Constituents of Litchi Pericarp Extracts and Its Antioxidant Activity in Mice. Abstract:  Litchi pericarp is the main byproduct of litchi processing and contains several polyphenols. However, the chemical constituents and the antioxidant effect in litchi pericarp extracts (LPE) have been rarely studied. The result of the quantitative analyses of the major monomers in LPE indicated that procyanidin A2, procyanidin B2, epicatechin, rutin, and catechin were the major polyphenol compounds of LPE. The LPE exhibited high radical scavenging activity, as indicated by the results of the 1,1-diphenyl-2-picrylhydrazyl (DPPH) and ascorbic acid, 2,2'-Azinobis-3-ethylbenzothiazoline-6-sulfonic acid (ABTS) tests. Moreover, administrating D-galactose in mice led to the reduced activity of antioxidant enzymes, aggravated lipid peroxidation, and induced protein oxidation. The results were improved in the aging mice after the LPE treatment was performed. The above results suggest that LPE has an excellent antioxidant effect. Accordingly, litchi pericarp can serve as a promising source of dietary antioxidants.

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PMID:  Rinsho Ketsueki. 2022 ;63(11):1491-1496. PMID: 36476786 Abstract Title:  [Spontaneous remission of primary breast diffuse large B-cell lymphoma]. Abstract:  A 71-year-old woman became aware of a 25-mm mass in her right breast as identified by her previous doctor. Needle biopsy findings suggested malignant lymphoma, and she was referred to our hospital for further evaluation. She was diagnosed with diffuse large B-cell lymphoma (DLBCL) at our hospital. Positron emission tomography-computed tomography (PET-CT) revealed an elevated SUVmax (maximum standardized uptake value; 10.3), with the mass localized in the right breast, but magnetic resonance imaging findings revealed that the mass had shrunk to 10 mm. Needle biopsy was repeated in our hospital, and lymphoma cells were absent. Two months later, CT scan revealed complete disappearance of the mass, and, since then, the patient has been free of recurrence. Although there are reports of spontaneous remission of nonHodgkin's lymphoma, it is rare in the case of high-grade B-cell lymphoma. The mechanism of spontaneous remission is unclear; however, advancing age, localized stage, activated B-cell (ABC) or nongerminal center B-cell (GCB) type, and a history of infection are the associated factors. The findings from this case suggest that DLBCL can be cured without therapeutic intervention; however, careful followup may be needed.

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PMID:  Cureus. 2022 Oct ;14(10):e30783. Epub 2022 Oct 27. PMID: 36447731 Abstract Title:  Spontaneous Regression of the Pulmonary Metastases in Adenoid Cystic Carcinoma of the Parotid Gland: A Case Report. Abstract:  Adenoid cystic carcinoma (ACC) is a rare epithelial tumor of the salivary glands with an indolent course and usually bears a long-term survival rate even when metastasized. Spontaneous regression of such a resistant tumor is an even scarce event. We report a case of a patient with ACC of the parotid gland with pulmonary metastases, which spontaneously resolved following resection and post-surgical radiation of the primary tumor. Among the numerous theories proposed to explain such a phenomenon, immunogenic mechanisms and the abscopal effect are the most plausible explanations in this case.

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PMID:  J Cancer Res Ther. 2022 ;18(6):1817-1819. PMID: 36412453 Abstract Title:  Spontaneous regression in a primary adenocarcinoma of lung with epidermal growth factor receptor mutation. Abstract:  Spontaneous regression (SR) has been reported sporadically in few tumor types. Its occurrence in non-small-cell lung cancer is relatively rare, more so with adenocarcinoma histology. Various mechanisms of SR have been postulated in literature that may play a role in triggering immune response. However, the exact underlying mechanism has yet to be ascertained. We report a rare case of true SR in a primary adenocarcinoma of lung with tumor-infiltrating lymphocytes and epidermal growth factor receptor mutation.

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PMID:  Front Surg. 2022 ;9:972446. Epub 2022 Sep 12. PMID: 36338628 Abstract Title:  Occurrence-regression-recurrence of hepatocellular carcinoma without any intervention: A case report. Abstract:  BACKGROUND: Spontaneous regression of primary liver cancer is a rare event, and currently the exact pathogenesis of spontaneous tumor regression remains unclear.CASE DESCRIPTION: Clinical information was collected from a patient with spontaneous regression of liver cancer at our center. The patient was a 41-year-old male. He was admitted to the hospital on 3 May 2019, appetite, and abdominal distension. Laboratory examination results included hepatitis B surface antigen positivity, hepatitis B e antigen positivity, and hepatitis B core antibody positivity and tumor marker levels of alpha-fetoprotein 142,938.20g/L, abnormal prothrombin 4,599.91mAU/ml, and carbohydrate antigen 19-9 82.05U/ml. Upper abdominal enhanced computed tomography indicated right hepatocellular carcinoma with portal vein tumor thrombus formation. The patient declined any treatment. The tumor in the right lobe of the liver completely regressed after 1 year, and the patient is still undergoing follow-up.CONCLUSIONS: We encountered a hepatocellular carcinoma patient who underwent spontaneous regression, but the exact pathogenesis remains unknown. Understanding the pathogenesis of spontaneous regression of hepatocellular carcinoma has the potential to contribute to the development of an effective treatment for hepatocellular carcinoma.

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PMID:  Clin J Gastroenterol. 2023 Feb ;16(1):105-109. Epub 2022 Oct 10. PMID: 36214971 Abstract Title:  Spontaneous regression in solid pseudopapillary neoplasm of pancreas. Abstract:  A solid pseudopapillary neoplasm (SPN) of the pancreas is a rare neoplasm that mainly occurs in young women. We herein report the case of spontaneous regression in SPN of the pancreas. A 48-years-old female was found to have a mass in the head of the pancreas on examination for her back pain and referred to our hospital in 20XX. Laboratory data showed no abnormalities in serum levels of pancreatic enzymes and tumor markers. A contrast CT scan of upper abdomen showed a slightly enhanced lesion (2319 mm in diameter) without cystic component or fibrous capsule in the head of the pancreas. An MRI scan showed the mass as low-intensity in T1-WI and high-intensity in T2-WI. She admitted to our hospital for further examination of a pancreatic mass by EUS-FNA in 20XX+4. EUS showed a slightly hypoechoic mass (3019 mm in diameter) compared with the neighboring normal pancreas. Tumor margin was relatively clear and the internal echo image was homogenous. Histological findings revealed a solid and pseudopapillary proliferation of eosinophilic polygonal cells with oval nuclei. The tumor cells were positive for vimentin and CD10 in the cytoplasm and-catenin in the nuclei, which led to the diagnosis of SPN. We recommended this patient to undergo surgical resection, however, the patient chose follow-up examinations. Follow-up study after 1 year using MRI scan showed spontaneous regression, which was coincided with her menopause. These findings suggest that the natural regression of SPN may occur and female sex hormone changes may regulate the growth of SPN.

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PMID:  Rev Esp Patol. 2022 Sep ;55 Suppl 1:S69-S73. Epub 2019 Nov 6. PMID: 36075667 Abstract Title:  Complete spontaneous regression of a primary renal cell carcinoma. Report of a pathological proven case and review of the literature. Abstract:  Regression of primary renal cell carcinoma (RCC) is a rare phenomenon and for several reasons many of the reported cases have been questioned. We present a case that can be considered a true spontaneous and complete regression of a primary RCC. A 79-year-old female underwent nephrectomy because a renal tumor. At the time of surgery image studies showed a small para-aortic lymph node. The tumor measured 3cm and was analyzed completely. Histology showed a fibro-inflammatory lesion with necrosis, foamy macrophages and inflammatory cells. No neoplastic cells were observed and the lesion was interpreted as a localized type of xanthogranulomatous pyelonephritis. One year later a CT control scan, showed that the para-aortic lymph node had increased in size to 4cm. Fine needle aspiration revealed features of clear RCC. Metastatic dissemination was limited so surgical removal of the para-aortic lymph node was performed and the cytologic diagnosis confirmed.

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PMID:  Int J Hematol. 2023 Jan ;117(1):137-142. Epub 2022 Sep 6. PMID: 36066839 Abstract Title:  Spontaneous regression of dasatinib-related primary effusion lymphoma-like lymphoma. Abstract:  Primary effusion lymphoma-like lymphoma (PEL-LL) shows a unique clinical presentation, characterized by lymphomatous effusions in the body cavities. PEL-LL may be associated with hepatitis C virus infections and fluid overload states; and owing to its rarity, no standard therapies have been established. We report a case of a 55-year-old woman who developed PEL-LL during treatment with dasatinib, for chronic myeloid leukemia (CML). She presented to our hospital with dyspnea lasting for approximately a month and showed pericardial and bilateral pleural effusions. The pericardial effusion was exudative, and cytopathological and immunophenotypic examinations showed numerous CD 20-positive, large atypical lymphoid cells, which were also positive for the Epstein-Barr virus gene. No evidence of lymphadenopathy or bone marrow infiltration was found. We diagnosed PEL-LL, immediately discontinued dasatinib, and performed continuous drainage of the pericardial effusions. Complete response was achieved, and remission was maintained for 15 months. Two months after discontinuation of dasatinib, she was administered imatinib and a deep molecular response for the CML was maintained. PEL-LL occurring during dasatinib treatment is rare. We compared the results of previous reports with this case, and found that early diagnosis of PEL-LL, discontinuation of dasatinib, and sufficient drainage can improve the prognosis of PEL-LL.

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PMID:  Case Rep Oncol. 2022 ;15(2):630-635. Epub 2022 Jun 17. PMID: 35949899 Abstract Title:  Complete Spontaneous Regression of Squamous-Cell Lung Cancer: A Case Report. Abstract:  Spontaneous regression of cancer is an extremely rare phenomenon, and it has been described in only a few cases of pulmonary cancer. We report a case of complete spontaneous regression of squamous-cell lung cancer (SCLC) following a core needle biopsy in a 67-year-old female patient with two previous lung cancers and concomitant follicular lymphoma. The patient was diagnosed with SCLC after 4 core needle biopsies from a nodule in the left upper lobe and at the same time suspected of having follicular lymphoma. Treatment for the lung cancer was delayed by approximately 8 weeks because the diagnosis of lymphoma was both challenging and time-consuming. A computed tomography scan was performed in relation to the scheduled treatment for SCLC, showing that the pulmonary nodule had disappeared completely. Most other cases of spontaneous regression of lung cancer hint at the involvement of immunological factors, and this case possibly involves a combination of mechanical and local immunological factors. Genetic and immunological analysis of patients showing spontaneous regression of cancers could provide valuable information.

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PMID:  Drugs. 2023 Apr ;83(5):403-427. Epub 2023 Mar 21. PMID: 36941490 Abstract Title:  Overall and Sex-Specific Effect of Berberine for the Treatment of Dyslipidemia in Adults: A Systematic Review and Meta-Analysis of Randomized Placebo-Controlled Trials. Abstract:  BACKGROUND: Berberine is a nutraceutical that can improve lipid metabolism. Berberine may also affect sex hormones and exert sex-specific lipid-modifying effects, which have been overlooked. This study aimed to comprehensively review the efficacy and safety of berberine in adults for the treatment of dyslipidemia with consideration of potential sex disparity. Data Sources We searched Medline, Embase, Wanfang, CNKI, ClinicalTrials.gov, and the WHO International Clinical Trials Registry Platform from inception to 13 December 2022. No language restrictions were applied. This study was registered in PROSPERO (CRD42021293218) prior to completing the literature search. Study Selection Two blinded reviewers assessed studies for inclusion. Eligible studies were randomized controlled trials in adults that compared berberine versus placebo, and measured blood lipids or lipoproteins. Data Extraction and Synthesis Data extraction was performed by two blinded reviewers using a structured form in Covidence. Risk of bias was assessed using the Cochrane risk of bias tool for randomized trials. Mean differences (MD) were estimated using inverse variance weighting with random effects models for lipid outcomes using R. Adverse events (AEs) were described narratively. Main Outcomes Primary outcomes were low-density lipoprotein (LDL) cholesterol, total cholesterol, triglycerides, high-density lipoprotein (HDL) cholesterol, and apolipoprotein B. Secondary outcomes were gastrointestinal and muscle-related AEs.RESULTS: Eighteen studies (n = 1788 participants), conducted mainly in mainland China and Hong Kong (15 studies [83%]), were included with treatment durations ranging from 4 to 24 weeks. Berberine reduced LDL cholesterol (- 0.46 mmol/L, 95% CI - 0.62 to - 0.30, 14 studies, n = 1447), total cholesterol (- 0.48 mmol/L, 95% CI - 0.63 to - 0.33, 17 studies, n = 1637), triglycerides (- 0.34 mmol/L, 95% CI - 0.46 to - 0.23, 18 studies, n = 1661) and apolipoprotein B (- 0.25 g/L, 95% CI - 0.40 to - 0.11, 2 studies, n = 127). Berberine increased HDL cholesterol by 0.06 mmol/L (95% CI 0.00 to 0.11, 15 studies, n = 1471). Notably, the effect on HDL cholesterol was different in women (0.11 mmol/L, 95% CI 0.09 to 0.13) from that in men (- 0.07 mmol/L, 95% CI - 0.16 to 0.02). Among 16 studies that reported AEs, no serious AEs were reported for berberine. Gastrointestinal AEs were reported in 12 studies and tended to be more frequent in participants allocated to berberine versus placebo (2-23% vs 2-15%).CONCLUSIONS: Berberine produces small reductions i...

PMID:  Pulm Circ. 2023 Jan ;13(1):e12207. Epub 2023 Jan 1. PMID: 36937151 Abstract Title:  Beneficial effects of berberine against pulmonary complications of experimental pulmonary arterial hypertension in rats and some relevant mechanisms. Abstract:  Pulmonary arterial hypertension (PAH) is a severe disease that leads to pulmonary vascular remodeling characterized by a rise in pulmonary vascular resistance and pressure. We assessed the effects of an herbal compound, berberine (BB), and some related mechanisms on PAH in rats. Male Wistar rats were assigned to seven groups: control, monocrotaline (MCT), MCT+vehicle, and MCT+BB (with doses of 10, 20, 30, and 40mg/kg) groups. Three weeks after induction of PAH by MCT, treatment groups received daily intraperitoneal injections of vehicle or BB for 3 weeks. On Day 43, the right ventricular systolic pressure (RVSP, as an index of pulmonary arterial pressure) and the ratio of RV to LV+septum weight (as RV hypertrophy index, right ventricle hypertrophy [RHVI]) were measured. Inflammatory and oxidative stress indices and histopathology of the lungs were also assessed. RVSP (89.48.2 vs. 233.3), RVHI (0.630.08 vs. 0.260.04), and lung inflammatory cytokines TNF-(2.030.25 vs. 1.210.3) and IL-6 (8.80.59 vs. 6.30.95) significantly increased in the MCT group compared to the control group. MCT also raised the level of Malondialdehyde (0.110.01 vs. 0.090.01) and diminished total antioxidant capacity (6.50.51 vs. 8.30.62), the activity of superoxide dismutase (1.190.22 vs. 1.930.2), glutathione peroxidase (0.020.002 vs. 0.030.005), catalase (2.10.29 vs. 2.80.20) and Bax/Bcl-2 ratio (0.410.07 vs. 0.610.09) in the lungs. Treatment with BB significantly recovered all of these alterations. BB ameliorated pulmonary vascular remodeling by decreasing inflammation and fibrosis and increasing apoptosis and antioxidant/oxidant balance. Therefore, this herbal derivative may be considered a therapeutic goal against PAH.

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PMID:  Front Oncol. 2023 ;13:1098429. Epub 2023 Mar 3. PMID: 36937441 Abstract Title:  The inhibitory effect of 6-gingerol and cisplatin on ovarian cancer and antitumor activity:,, and. Abstract:  BACKGROUND: Epithelial ovarian cancer is very common in women and causes hundreds of deaths per year worldwide. Chemotherapy drugs including cisplatin have adverse effects on patients' health. Complementary treatments and the use of herbal medicines can help improve the performance of medicine. 6-Gingerol is the major pharmacologically active component of ginger. In this study, we compared the effects of 6-gingerol, cisplatin, and their combination in apoptotic and angiogenetic activities, in test tubes, and inassays against two ovarian cancer cell lines: OVCAR-3 and human umbilical vein endothelial cells (HUVECs).METHODS: The drug-treated cell lines were evaluated for their cytotoxicity, cell cycle, and apoptotic and angiogenetic gene expression changes.RESULTS: The proportion of apoptosis treated by 6-gingerol coupled with cisplatin was significantly high. In the evaluation of the cell cycle, the combination therapy also showed a significant promotion of a higher extent of the S sequence. The expression of p53 level, Caspase-8, Bax, and Apaf1 genes was amplified again with combination therapy. Conversely, in both cell lines, the cumulative drug concentrations reduced the expression of VEGF, FLT1, KDR, and Bcl-2 genes. Similarly, in the control group, combination treatment significantly decreased the expression of VEGF, FLT1, KDR, and Bcl-2 genes in comparison to cisplatin alone.CONCLUSIONS: The findings of the present study demonstrated that the cisplatin and 6-gingerol combination is more effective in inducing apoptosis and suppressing the angiogenesis of ovarian cancer cells than using each drug alone.

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PMID:  Biomed Pharmacother. 2022 Oct ;154:113643. Epub 2022 Sep 7. PMID: 36942597 Abstract Title:  Potential cardioprotective effects of Amentoflavone in doxorubicin-induced cardiotoxicity in mice. Abstract:  Doxorubicin (DOX) is an available chemotherapeutic drug for treating various tumors. However, its effectiveness is limited by cardiotoxicity. Amentoflavone (AMF), a natural biflavonoid separated from Cycas thouarsii ethyl acetate fraction, displays promising anticancer, anti-inflammatory, and antioxidant effects. Thus, our research aims to explore whether AMF could boost cardioprotective effects against DOX cardiotoxicity and reveal the potential underlying mechanisms of cardioprotection. Mice were classified into four groups; Normal control, Untreated DOX group, and DOX groups treated with AMF (40 and 80 mg/kg, respectively) intraperitoneal injection daily for four days before doxorubicin administration and for additional three days following DOX administration to assess cardiotoxicity. Echocardiography showed that AMF 80 treated group was protected from DOX cardiotoxicity. Additionally, it alleviated histopathological structural alterations and effectively restored heart weight and body weight ratio. These effects were confirmed biochemically by a substantially reduced serum creatine kinase-MB (CK-MB) and aspartate aminotransferase (AST) levels. AMF effectively restored nuclear respiratory factor-1(NRF-1), mitochondrial transcription factor A (TFAM), and normalized heat shock protein - 27(HSP-27) expression levels compared to the DOX group. Moreover, AMF mitigated oxidative stress conditions and significantly suppressed NADPH oxidase (NOX) expression levels. It also showed significant anti-inflammatory effects via suppressing interleukin-6 (IL-6) expression and decreasing nuclear factor Kabba B (NF-b) immune-staining. In addition, AMF markedly reduced FAS ligand (FASL) expression and p53 immune staining in cardiac tissue. This study is the first for the in vivo potential beneficial effects of AMF against acute DOX cardiotoxicity, possibly via exerting antioxidant, anti-inflammatory, and anti-apoptotic effects and restoring mitochondrial function.

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PMID:  Microbiol Immunol. 2023 Jun ;67(6):281-292. Epub 2023 Apr 4. PMID: 36929353 Abstract Title:  Amentoflavone inhibits hepatitis B virus infection via the suppression of preS1 binding to host cells. Abstract:  Hepatitis B virus (HBV) is a leading cause of chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. Current therapeutic drugs for chronic HBV infection use IFN and nucleos(t)ide analogs; however, their efficacy is limited. Thus, there is an urgent need to develop new antivirals for HBV therapy. In this study, we identified a plant-derived polyphenolic bioflavonoid, amentoflavone, as a new anti-HBV compound. Amentoflavone treatment dose-dependently inhibited HBV infection in HBV-susceptible cells with HepG2-hNTCP-C4 and primary human hepatocyte PXB-cells. A mode-of-action study showed that amentoflavone inhibits the viral entry step, but not the viral internalization and early replication processes. Attachment of HBV particles as well as HBV preS1 peptide to HepG2-hNTCP-C4 cells was inhibited by amentoflavone. The transporter assay revealed that amentoflavone partly inhibits uptake of sodium taurocholate cotransporting polypeptide (NTCP)-mediated bile acid. Furthermore, effect of various amentoflavone analogs on HBs and HBe production from HBV-infected HepG2-hNTCP-C4 cells was examined. Robustaflavone exhibited comparable anti-HBV activity to that of amentoflavone and an amentoflavone-7,4', 4-trimethyl ether derivative (sciadopitysin) with moderate anti-HBV activity. Cupressuflavone or the monomeric flavonoid apigenin did not exhibit the antiviral activity. Amentoflavone and its structurally related biflavonoids may provide a potential drug scaffold in the design of a new anti-HBV drug inhibitor targeting NTCP.

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PMID:  Environ Toxicol. 2023 May ;38(5):1078-1089. Epub 2023 Feb 2. PMID: 36727907 Abstract Title:  Amentoflavone induces caspase-dependent/-independent apoptosis and dysregulates cyclin-dependent kinase-mediated cell cycle in colorectal cancer in vitro and in vivo. Abstract:  Colorectal cancer (CRC) is recognized as the third most common malignancy and the second most deadly in highly developed countries. Although the treatment of CRC has improved in the past decade, the mortality rate of CRC is still increasing. Amentoflavone, one of the flavonoids detected in medical plants, is reported to possess potential anticancer properties in various cancers. However, its role in CRC has not been studied. This study aimed to investigate the role and underlying mechanism of amentoflavone on CRC in vitro and in vivo. We identified the cytotoxicity, apoptosis effect, cell cycle alteration, DNA damage induction and tumor progression inhibition of amentoflavone in HT-29 model by using MTT assay, flow cytometry, immunofluorescence (IF) staining, Western blotting and animal experiments. Amentoflavone induced cytotoxicity is caused by triggering G1 arrest, DNA damage and apoptosis in HT-29 cells. The expression of cyclin D1, CDK4 and CDK6 was decreased by amentoflavone; in contrast, the phosphorylation of ATM and CHK2 and the expression of p21 and p27 were increased. The apoptosis induction of amentoflavone in CRC is not only caspase-dependent but also increases EndoG and AIF nuclear translocation in a caspase-independent manner. Importantly, the apoptosis induction of amentoflavone is not affected by the activity of p53 in CRC. Amentoflavone suppressed the progression of CRC by initiating G1 arrest and ATM/CHK2-mediated DNA damage-responsive, caspase-dependent/independent apoptotic effects. We uncovered a novel tumor-inhibitory role of amentoflavone in CRC that is not associated with p53 activity, which may serve as a potential treatment for CRC.

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PMID:  Mediators Inflamm. 2022 ;2022:5184721. Epub 2022 Dec 6. PMID: 36523959 Abstract Title:  Amentoflavone Exerts Anti-Neuroinflammatory Effects by Inhibiting TLR4/MyD88/NF-B and Activating Nrf2/HO-1 Pathway in Lipopolysaccharide-Induced BV2 Microglia. Abstract:  BACKGROUND: Amentoflavone, a natural biflavone, exerts anti-inflammation, antioxidation, and antiapoptosis effects on many diseases. However, the mechanism of amentoflavone on neuroinflammation-related diseases has not been comprehensively examined clearly.METHODS: BV2 microglial cells were treated with amentoflavone (10M), followed by lipopolysaccharide (LPS). Microglial activation and migration ability and the expression of proinflammatory cytokines and other signaling proteins were determined using immunohistochemistry, immunofluorescence, quantitative real-time polymerase chain reaction, Western blotting, enzyme-linked immunosorbent assay, and wound-healing assays.RESULTS: Amentoflavone restored LPS-induced microglia activation, migration, and inflammation response which depends on regulating toll-like receptor 4 (TLR4)/myeloid differentiation factor 88 (MyD88)/nuclear factor kappa B (NF-B) pathway. In addition, amentoflavone also enhanced nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) levels in LPS-treated BV2 microglial cells.CONCLUSIONS: Amentoflavone ameliorated LPS-induced neuroinflammatory response and oxidative stress in BV2 microglia. These data provide new insight into the mechanism of amentoflavone in the treatment of neuroinflammation-related diseases. Therefore, amentoflavone may be a potential therapeutic option for neurological disorders.

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PMID:  J Mol Model. 2022 Dec 16 ;29(1):9. Epub 2022 Dec 16. PMID: 36522514 Abstract Title:  Amentoflavone and methyl hesperidin, novel lead molecules targeting epitranscriptomic modulator in acute myeloid leukemia: in silico drug screening and molecular dynamics simulation approach. Abstract:  INTRODUCTION: MA modification in transcriptome is critical in regulating different cellular processes, including cancer. In human beings, METTL3 is the major mA writer that works in association with METTL14, an accessory protein. Extensive study revealed that cancer progression for acute myeloid leukemia, gastric cancer, colorectal cancer, hepatocellular carcinoma, and lung cancer is directly contributed by irregular expression of METTL3.OBJECTIVE: Targeting METTL3 has opened a new window in the development of novel inhibitors/drugs.METHODS: In this study, commercially available natural compounds were randomly screened to avoid the bias of screening small molecules on the basis of structural similarity. From 810 compounds that were screened, 80 commercially available compounds were showing better score when compared with the existing substrate/substrate-analogue and the inhibitor bound crystal structures in terms of docking score and binding energy calculation.RESULTS AND CONCLUSION: Among this pool of compounds, the best seven small molecules have been selected and further validated by different computational tools like binding energy calculation, molecular dynamics simulation, ADME analysis, and toxicity prediction. The novel hits found in this study can function as lead compounds which can be developed into inhibitors as well as drugs, specific against METTL3.

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PMID:  Inform Med Unlocked. 2023 ;38:101216. Epub 2023 Mar 11. PMID: 36935867 Abstract Title:  In-silico studies ofextracts as potential candidates against SARS-CoV-2 targeting human main protease enzyme (M). Abstract:  , a well-known plant called bitter melon, has been shown to have antibacterial, anti-diabetic, and antiviral properties against HIV infection. The goal of this work was to investigate the inhibitory effect of phytocompounds found inleaf extracts on SARS-CoV-2 3CL protease (also known as the Main protease, M) utilizing GC-MS analysis and molecular docking studies. The Crystal Structure of the SARS-CoV-2 3CL protease in complex with an inhibitor N3 was downloaded from RCSB using PDB ID 6LU7 with resolution: 2.16 . In the present study, in silico molecular docking analysis of phytoconstituents present inmethanolic leaf extract detected by GC-MS was studied against SARS-CoV-2 M. The results revealed 13 phytochemical constituents derived from the GC-MS analysis. Quercetin 3-galactopyranoside, Rutin, and Hyperin were ranked the highest with binding scores ranging from -8.9 kcal/mol to -8.5 kcal/mol compared with the standard, Nirmatrelvir, with a binding score of -7.7 kcal/mol. From the results obtained, it can be concluded that Quercetin 3-galactopyranoside, Rutin, and Hyperin act against Covid-19 by inhibiting the SARS-COV-2 Mand therefore can be further developed into potent drugs for Covid-19 treatment.

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PMID:  J Mol Model. 2022 Nov 29 ;28(12):404. Epub 2022 Nov 29. PMID: 36445575 Abstract Title:  In silico evaluation of flavonoids as potential inhibitors of SARS-CoV-2 main nonstructural proteins (Nsps)-amentoflavone as a multitarget candidate. Abstract:  Despite the development of vaccines against COVID-19 disease and the multiple efforts to find efficient drugs as treatment for this virus, there are too many social, political, economic, and health inconveniences to incorporate a fully accessible plan of prevention and therapy against SARS-CoV-2. In this sense, it is necessary to find nutraceutical/pharmaceutical drugs as possible COVID-19 preventives/treatments. Based on their beneficial effects, flavonoids are one of the most promising compounds. Therefore, using virtual screening, 478 flavonoids obtained from the KEGG database were evaluated against non-structural proteins Nsp1, Nsp3, Nsp5, Nsp12, and Nsp15, which are essential for the virus-host cell infection, searching for possible multitarget flavonoids. Amentoflavone, a biflavonoid found mainly in Ginkgo biloba, Lobelia chinensis, and Byrsonima intermedia, can interact and bind with the five proteins, suggesting its potential as a multitarget inhibitor. Molecular docking calculations and structural analysis (RMSD, number of H bonds, and clustering) performed from molecular dynamics simulations of the amentoflavone-protein complex support this potential. The results shown here are theoretical evidence of the probable multitarget inhibition of non-structural proteins of SARS-CoV-2 by amentoflavone, which has wide availability, low cost, no side effects, and long history of use. These results are solid evidence for future in vitro and in vivo experiments aiming to validate amentoflavone as an inhibitor of the Nsp1, 3, 5, 12, and 15 of SARS-CoV-2.

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PMID:  Int J Mol Sci. 2023 Feb 28 ;24(5). Epub 2023 Feb 28. PMID: 36902074 Abstract Title:  The Effects ofon Type 2 Diabetes Mellitus and Alzheimer's Disease. Abstract:  T2DM is a complex metabolic disorder characterized by hyperglycemia and glucose intolerance. It is recognized as one of the most common metabolic disorders and its prevalence continues to raise major concerns in healthcare globally. Alzheimer's disease (AD) is a gradual neurodegenerative brain disorder characterized by the chronic loss of cognitive and behavioral function. Recent research suggests a link between the two diseases. Considering the shared characteristics of both diseases, common therapeutic and preventive agents are effective. Certain bioactive compounds such as polyphenols, vitamins, and minerals found in vegetables and fruits can have antioxidant and anti-inflammatory effects that allow for preventative or potential treatment options for T2DM and AD. Recently, it has been estimated that up to one-third of patients with diabetes use some form of complementary and alternative medicine. Increasing evidence from cell or animal models suggests that bioactive compounds may have a direct effect on reducing hyperglycemia, amplifying insulin secretion, and blocking the formation of amyloid plaques. One plant that has received substantial recognition for its numerous bioactive properties is, otherwise known as bitter melon, bitter gourd, karela, and balsam pear.is utilized for its glucose-lowering effects and is often used as a treatment for diabetes and related metabolic conditions amongst the indigenous populations of Asia, South America, India, and East Africa. Several pre-clinical studies have documented the beneficial effects ofthrough various postulated mechanisms. Throughout this review, the underlying molecular mechanisms of the bioactive components ofwill be highlighted. More studies will be necessary to establish the clinical efficacy of the bioactive compounds withinto effectively determine its pertinence in the treatment of metabolic disorders and neurodegenerative diseases, such as T2DM and AD.

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PMID:  Int J Ophthalmol. 2023 ;16(3):342-347. Epub 2023 Mar 18. PMID: 36935798 Abstract Title:  Effect of epigallocatechin gallate in green tea on preventing lens opacity andB-crystallin aggregation in rat model of diabetes. Abstract:  AIM: To evaluate the effect of epigallocatechin gallate (EGCG) in preventing lens opacity and the aggregation of lensB-crystallin in model rats of diabetes mellitus (DM).METHODS: This experimental study included Wistar rats for DM asmodels and divided into 5 groups. The treatment groups were administered EGCG by orally for 20d and were then assessed for their degree of lens opacity with binocular microscope and lensB-crystallin expression from Western blot analyze.RESULTS: Pearson correlation test and regression analysis on EGCG exposure and final random blood sugar (RBS) obtained a significance level of

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PMID:  J Ethnopharmacol. 2023 Apr 24 ;306:116154. Epub 2023 Jan 10. PMID: 36634725 Abstract Title:  Effects of dietary wild bitter melon (Momordica charantia var. abbreviate Ser.) extract on glucose and lipid metabolism in HFD/STZ-induced type 2 diabetic rats. Abstract:  ETHNOPHARMACOLOGICAL RELEVANCE: Plant-based extracts to interfere with the onset of diabetes may be a promising approach towards type 2 diabetes mellitus (T2DM). Bitter gourd (Momordica charantia L.) is popularly consumed as an edible and medicinal resource with hypoglycemic effect in China. Wild bitter gourd (Momordica Charantia var. abbreviata Ser.) is a variant of bitter gourd, but there are relatively few studies on it.AIM OF THE STUDY: The purpose of the experiment is to first screen out the most effective extraction part of Momordica charantia L. and Momordica Charantia var. abbreviata Ser. through the hypoglycemic activity experiment in vitro, and by using a high-fat and high-sugar diet with STZ-induced diabetic rat model in vivo to explore the possible mechanism of action against diabetes.MATERIALS AND METHODS: This study first performed-glucosidase, PTP1B and lipase activities inhibition experiments on the alcohol and water extracts of Momordica charantia L. and Momordica Charantia var. abbreviata Ser. Sprague Dawley rats were either given normal feed or a high sugar and fat diet for four weeks, followed STZ (25 mg/kg, via i. p.) was given. Rats with fasting blood glucose11.1 mmol/l after one week were deemed to be diabetic, treatments were administered for four weeks, and then blood samples were used to evaluate hematological and biochemical indicators, and liver was removed for post-analysis. The expression levels of p-AMPK, AMPK, p-PI3K, PI3K, p-AKT, AKT, p-GSK3, GSK3, p-IRS-1, IRS-1, GLUT2 were determined by Western blot. At the same time, the chemical components was identified by liquid-mass spectrometry.RESULTS: Data showed that the ethanol extract of wild bitter gourd (WBGE) had the best ability to regulate glucose and lipid metabolism in vitro. Therefore, we further investigated the antidiabetic effects of oral consumption of WBGE on high-fat diet (HFD) and streptozotocin (STZ)-induced T2DM in SD rats. WBGE effectively reduced blood glucose and lipid levels, alleviated glucose intolerance and insulin resistant. Moreover, WBGE consumption could also inhibited oxidant responses and inflammatory damage. Mechanism studies have shown that WBGE may act by regulating AMPK/PI3K signaling pathway. On the other hand, the content of total phenol, total flavonoids, total saponins and total polysaccharide were measured by UV, 27 compounds were identified by LC-MS.CONCLUSIONS: These studies explored the role and mechanism of WBGE in regulating glucose and lipid metabolism, and may support the utilization and fur...

PMID:  Front Pharmacol. 2023 ;14:1042093. Epub 2023 Mar 3. PMID: 36937888 Abstract Title:  Emodin ameliorates renal injury and fibrosisregulating the miR-490-3p/HMGA2 axis. Abstract:  Renal fibrosis is a major pathological feature of chronic kidney disease (CKD). While emodin is reported to elicit anti-fibrotic effects on renal injury, little is known about its effects on microRNA (miRNA)-modulated mechanisms in renal fibrosis. In this study, we established a unilateral ureteral obstruction (UUO) model and a transforming growth factor (TGF)-1-induced normal rat renal tubular epithelial cell line (NRK-52E) model to investigate the protective effects of emodin on renal fibrosis and its miRNA/target gene mechanisms. Dual-luciferase assay was performed to confirm the direct binding of miRNA and target genes in HEK293 cells. Results showed that oral administration of emodin significantly ameliorated the loss of body weight and the increase in physicochemical parameters, including serum uric acid, creatinine, and urea nitrogen in UUO mice. Inflammatory cytokines, including tumor necrosis factor-, monocyte chemoattractant protein-1, and interleukin (IL)-1, but not IL-6, were down-regulated by emodin administration. Emodin decreased the expression levels of TGF-1 and fibrotic-related proteins, including alpha-smooth muscle actin, Collagen IV, and Fibronectin, and increased the expression of E-cadherin. Furthermore, miR-490-3p was decreased in UUO mice and negatively correlated with increased expression of high migration protein A2 (HMGA2). We further confirmed HMGA2 was the target of miR-490-3p. Transfection of miR-490-3p mimics decreased, while transfection of miR-490-3p inhibitors increased fibrotic-related proteins and HMGA2 expression levels in TGF-1-induced NRK-52E cells. Furthermore, transfection of miR-490-3p mimics enhanced the anti-fibrotic effects of emodin, while transfection of miR-490-3p inhibitors abolished the protective effects of emodin. Thus, as a novel target of emodin that prevents renal fibrosis in the HMGA2-dependent signaling pathway, miR-490-3p has potential implications in CKD pathology.

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PMID:  Biomed Pharmacother. 2022 Oct ;154:113667. Epub 2022 Sep 7. PMID: 36942603 Abstract Title:  Inhibition of oxidative stress, IL-13, and WNT/-catenin in ovalbumin-sensitized rats by a novel organogel of Punica granatum seed oil saponifiable fraction. Abstract:  Bronchial asthma is a chronic inflammatory disease marked by inflammation, oxidative stress, and structural remodeling. Here, we prepared two pomegranate fractions from the seed oil, saponifiable (Sap) and unsaponifiable (UnSap). Two organogels (Orgs) were also formulated with the Sap (Org1) or the UnSap (Org2) fraction and beeswax (BW). All preparations were evaluated in vitro for their antioxidant and anti-inflammatory impacts. The transdermal delivery of the most efficient one was evaluated against ovalbumin (OV)-induced bronchial asthma in rats compared to dexamethasone (DEX). The results showed that the prepared pomegranate fractions and BW had considerable amounts of phenolics (flavonoids and tannins) and triterpenoids. Org1 was shown to be the most effective antioxidant and anti-inflammatory fraction with synergistic activities (combination index, 1), as well as having protective and therapeutic influences on OV-sensitized rats. Org1 inhibited the multiple OV-induced signaling pathways, comprising ROS, WNT/-catenin, and AKT, with an efficiency superior to DEX. Subsequently, the pro-inflammatory (COX-2, NO, and IL-13), and pro-fibrotic (COL1A1) mediators, oxidative stress, and mucin secretion, were all down-regulated. These outcomes were verified by the histopathological results of lung tissue. Collectively, these outcomes suggest that the transdermal delivery of Org1 to OV-sensitized rats shows promise in the protection and treatment of the pathological hallmarks of asthma.

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PMID:  J Asthma Allergy. 2021 ;14:1511-1525. Epub 2021 Dec 15. PMID: 34938083 Abstract Title:  Embelin Alleviates Severe Airway Inflammation in OVA-LPS-Induced Rat Model of Allergic Asthma. Abstract:  BACKGROUND: Asthma is a chronic lung disease, which causes wheezing, tightness in the chest, shortness of breath and coughing. In the wake of coronavirus disease 2019 (COVID-19), which affect the lungs, asthma patients are at high risk. Embelin, a natural benzoquinone obtained mainly fromBurm, has excellent biological properties, including protection against acute asthma. However, since asthma is a chronic and multi-factorial inflammatory disease, asthma conferred by a single allergen in an animal may not be clinically significant. Therefore, the purpose of the current study was to evaluate the effectiveness of embelin against ovalbumin (OVA)-lipopolysaccharide (LPS)-induced severe airway inflammation in experimental animals and to investigate the plausible mechanism of action.METHODS: Rats (n=36) were divided into six groups. Group I served as a normal control. Groups II-VI were sensitised with severe allergens (OVA and LPS) on day 7, 14 and 21, followed by OVA and LPS challenge for 30 min three times/week for 3 weeks. Group II acted as an asthmatic disease control and received only vehicle. On the other hand, groups III-V received embelin (12.5, 25 and 50 mg/kg, P.O. respectively) while group VI received a standard dexamethasone (2.5 mg/kg, P.O.) for 15 days from day 27. Lung function parameters, including the respiratory rate, tidal volume and airflow rate were measured at the end of the experiment (day 42). The total and differential counts of leukocytes in the blood and bronchoalveolar fluid (BALF) were calculated. Th2-mediated serum pro-inflammatory cytokines such as interleukin (IL)-4, IL-5 and IL-13 levels were analyzed. At the end of the study protocol, the lung tissues were removed for a histopathology study. Additionally, a molecular docking simulation on embelin and standard dexamethasone was applied to support the in vivo findings.RESULTS: Significant inhibition of eosinophils, neutrophils, lymphocytes and monocytes in the blood and the BALF was seen in the groups, which received embelin (25 and 50 mg/kg) and dexamethasone (2.5 mg/kg). Moreover, the lung function parameters were normalised by embelin (25 and 50 mg/kg) treatment significantly. The lung histopathological changes confirmed the protective effect of embelin against severe airway inflammation. The docking findings indicated good binding efficacy of embelin to IL-13.CONCLUSION: Overall, our findings indicate that embelin can alleviate severe airway inflammation in OVA-LPS-induced model of allergic asthma occurring by suppression of Th2-mediated immune response. Due to its promising anti-asthmatic effect, it is recom...

PMID:  Oral Dis. 2023 Jan 27. Epub 2023 Jan 27. PMID: 36705399 Abstract Title:  Salvianolic acid B as a potent nano-agent for enhanced ALA-PDT of oral cancer and leukoplakia cells. Abstract:  BACKGROUND: Photodynamic therapy (PDT) relies on the light activation of a photosensitizers to generate reactive oxygen species such as singlet oxygen, but its effect on cancer therapy is limited dramatically by hypoxia in the tumor microenvironment.OBJECTIVES: To determine the potential of a nano-photosensitizer loaded salvianolic acid B (SalB) and 5-aminolevulinic acid (ALA) for enhancing the efficacy of PDT in oral squamous cell carcinoma Cal27 cells and leukoplakia Leuk1 cells.RESULTS: Singlet oxygen sensor green (SOSG) assay showed that nano-SalB-ALA generated higher levels of singlet oxygen, compared to nano-SalB and nano-ALA. Cellular uptake assay showed that nano-SalB-ALA effectively absorbed by Leuk1 cells. Importantly, cell counting kit-8 and flow cytometry revealed that PDT with nano-SalB-ALA effectively inhibited the viability and induced the apoptosis of Cal27 and Leuk1 cells, respectively. Moreover, the tumor xenograft study revealed that PDT with nano-SalB-ALA had a stronger inhibitory effect on tumor growth of nude mice, compared to control groups.CONCLUSIONS: The novel photosensitizer nano-SalB-ALA remarkably enhanced the efficacy of PDT by improving singlet oxygen production, inhibiting cell proliferation, promoting cell apoptosis, and suppressing tumor growth. These suggest PDT with nano-SalB-ALA could be a clinically significant and potent treatment for oral cancer and leukoplakia.

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PMID:  Antiviral Res. 2023 Apr ;212:105570. Epub 2023 Mar 1. PMID: 36863496 Abstract Title:  Pinostrobin from plants and propolis against human coronavirus HCoV-OC43 by modulating host AHR/CYP1A1 pathway and lipid metabolism. Abstract:  Coronaviruses, as enveloped positive-strand RNA viruses, manipulate host lipid compositions to enable robust viral replication. Temporal modulation of the host lipid metabolism is a potential novel strategy against coronaviruses. Here, the dihydroxyflavone pinostrobin (PSB) was identified through bioassay that inhibited the increment of human coronavirus OC43 (HCoV-OC43) in human ileocecal colorectal adenocarcinoma cells. Lipid metabolomic studies showed that PSB interfered with linoleic acid and arachidonic acid metabolism pathways. PSB significantly decreased the level of 12, 13- epoxyoctadecenoic (12, 13-EpOME) and increased the level of prostaglandin E2. Interestingly, exogenous supplement of 12, 13-EpOME in HCoV-OC43-infected cells significantly stimulated HCoV-OC43 virus replication. Transcriptomic analyses showed that PSB is a negative modulator of aryl hydrocarbon receptor (AHR)/cytochrome P450 (CYP) 1A1signaling pathway and its antiviral effects can be counteracted by supplement of FICZ, a well-known AHR agonist. Integrative analyses of metabolomic and transcriptomic indicated that PSB could affect linoleic acid and arachidonic acid metabolism axis through AHR/CYP1A1 pathway. These results highlight the importance of the AHR/CYP1A1 pathway and lipid metabolism in the anti-coronavirus activity of the bioflavonoid PSB.

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PMID:  Braz J Med Biol Res. 2023 ;56:e12578. Epub 2023 Feb 27. PMID: 36856256 Abstract Title:  Pinostrobin from Boesenbergia rotunda attenuates oxidative stress and promotes functional recovery in rat model of sciatic nerve crush injury. Abstract:  Oxidative stress plays a role in the delay of peripheral nerve regeneration after injury. The accumulation of free radicals results in nerve tissue damage and dorsal root ganglion (DRG) neuronal death. Pinostrobin (PB) is one of the bioflavonoids from Boesenbergia rotunda and has been reported to possess antioxidant capacity and numerous pharmacological activities. Therefore, this study aimed to investigate the effects of PB on peripheral nerve regeneration after injury. Male Wistar rats were randomly divided into 5 groups including control, sham, sciatic nerve crush injury (SNC), SNC + 20 mg/kg PB, and SNC + 40 mg/kg PB. Nerve functional recovery was observed every 7 days. At the end of the study, the sciatic nerve and the DRG were collected for histological and biochemical analyses. PB treatment at doses of 20 and 40 mg/kg reduced oxidative stress by up-regulating endogenous glutathione. The reduced oxidative stress in PB-treated rats resulted in increased axon diameters, greater number of DRG neurons, and p-ERK1/2 expression in addition to faster functional recovery within 4 weeks compared to untreated SNC rats. The results indicated that PB diminished the oxidative stress-induced nerve injury. These effects should be considered in the treatment of peripheral nerve injury.

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PMID:  Arch Pharm Res. 2018 Dec ;41(12):1199-1210. Epub 2017 Dec 14. PMID: 29243040 Abstract Title:  Protective effect of acacetin on sepsis-induced acute lung injury via its anti-inflammatory and antioxidative activity. Abstract:  Sepsis is a clinical syndrome with no effective protective or therapeutic treatments. Acacetin, a natural flavonoid compound, has anti-oxidative and anti-inflammatory effects which can potentially work to reduce sepsis. We investigated the potential protective effect of acacetin on sepsis-induced acute lung injury (ALI) ALI and dissect out the underlying mechanisms. Mice were divided into five groups: a sham group, a sepsis-induced ALI group, and three sepsis groups pre-treated with 20, 40, and 80 mg/kg body weight of acacetin. We found that acacetin significantly attenuated sepsis-induced ALI, in histological examinations and lung edema. Additionally, acacetin treatment decreased protein and inflammatory cytokine concentration and the number of infiltrated inflammatory cells in BALF compared with that in the non-treated sepsis mice. Pulmonary myeloperoxidase (MPO) activity was lower in the acacetin-pre-treated sepsis groups than in the sepsis group. The mechanism underlying the protective effect of acacetin on sepsis is related to the regulation of certain antioxidation genes, including inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), superoxide dismutases (SODs), and heme oxygenase 1 (HO-1).Taken together, our results indicate that acacetin pre-treatment inhibits sepsis-induced ALI through its anti-inflammatory and antioxidative activity, suggesting that acacetin may be a potential protective agent for sepsis-induced ALI.

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PMID:  Bioorg Med Chem Lett. 2017 Dec 1 ;27(23):5207-5212. Epub 2017 Oct 20. PMID: 29089232 Abstract Title:  Acacetin inhibits neuronal cell death induced by 6-hydroxydopamine in cellular Parkinson's disease model. Abstract:  Acacetin (5,7-dihydroxy-4'-methoxyflavone), a flavonoid compound isolated from Flos Chrysanthemi Indici, chrysanthemum, safflower, and Calamintha and Linaria species has been shown to have anti-cancer activity, indicating its potential clinical value in cancer treatment. In this study, we sought to study the potentials of acacetin in preventing human dopaminergic neuronal death via inhibition of 6-hydroxydopamine (6-OHDA)-induced neuronal cell death in the SH-SY5Y cells. Our results suggest that acacetin was effective in preventing 6-OHDA-induced neuronal cell death through regulation of mitochondrial-mediated cascade apoptotic cell death. Pretreatment with acacetin significantly inhibited neurotoxicity and neuronal cell death through reactive oxygen species (ROS) production and mitochondrial membrane potential (MMP) dysfunction. Acacetin also markedly acted on key molecules in apoptotic cell death pathways and reduced phosphorylation of c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinases (PI3K)/Akt, and glycogen synthase kinase-3beta (GSK-3). These results suggested that acacetin could inhibit 6-OHDA-induced neuronal cell death originating from ROS-mediated cascade apoptosis pathway. Thus, the results of our study suggest that acacetin is a potent therapeutic agent for PD progression.

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PMID:  Inflammopharmacology. 2018 Apr ;26(2):635-643. Epub 2017 Oct 7. PMID: 28988328 Abstract Title:  Acacetin attenuates mice endotoxin-induced acute lung injury via augmentation of heme oxygenase-1 activity. Abstract:  Acacetin, a natural product, has a wide spectrum of biological activities such as antioxidant properties. In the present study, we examined whether Acacetin has any beneficial role on lipopolysaccharide (LPS)-induced acute lung injury (ALI) and, if so, whether its effect is mediated via heme oxygenase-1 (HO-1), an antioxidant enzyme playing an important role in ALI. Male BALB/c mice were stimulated with LPS intratracheal instillation to induce ALI. Acacetin was administrated 2 h after LPS challenge. Samples were harvested 10 h after LPS administration. We demonstrated that LPS challenge significantly induced lung histological alterations such as inflammation and edema. Acacetin administration notably attenuated these changes and reduced tumor necrosis factor-and interleukin-1in lung tissues. The LPS-induced reactive oxygen species generation was markedly suppressed by Acacetin. Furthermore, Acacetin treatment significantly elevated pulmonary HO-1 and nuclear factor erythroid-2-related factor 2 (Nrf2) activities. However, the beneficial action of Acacetin was markedly abolished when pretreated with zinc protoporphyrin, an inhibitor of HO-1. In in vitro studies, Acacetin notably increased the HO-1 expression in pulmonary microvascular endothelial cells. During knockdown of Nrf2 by siRNA, the effect of Acacetin on HO-1 expression was significantly reversed. Acacetin attenuates LPS-induced ALI in mice. This protective effect of Acacetin may be mediated, in part, through an HO-1-dependent pathway.

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PMID:  PLoS One. 2017 ;12(8):e0182870. Epub 2017 Aug 31. PMID: 28859099 Abstract Title:  Acacetin enhances the therapeutic efficacy of doxorubicin in non-small-cell lung carcinoma cells. Abstract:  BACKGROUND: Anthracyclines are efficient and potent agents to treat broad range of cancers but cytotoxicity induced by them limits their use in therapeutics. Use of plant-derived agents help to prevent or delay the process of cancer progression and their combination increases the anti-cancer potential of mainstream compound. However, multidrug resistance is major cause of treatment failure in cancer patients.PURPOSE: In this study, combination treatments of fisetin or acacetin with doxorubicin were explored for their potential synergistic effect on non-small-cell lung carcinoma (NSCLC) cells.STUDY DESIGN: During this study, NSCLC model cell lines A549 and H1299 were used to determine the combinatorial effect of phytochemicals namly acacetin and fisetin with doxorubicin.METHODS: The effects of individual compounds and their combination on cell viability, clonogenic potential and cell cycle progression were studied. Efflux of doxorubicin was measured by spectrofluorophotometer, whereas accumulation inside the cells was analyzed by flow cytometry and confocal microscopy. Expression of MDR1 was checked by semi-quantitative PCR.RESULTS: The results showed that the cell viability of A549 and H1299 cells were significantly decreased in time- and dose-dependent manner, although A549 cells showed more sensitivity toward doxorubicin than H1299 cells. Mostly, combination of doxorubicin showed good synergy with acacetin in both the cell lines whereas, fisetin exerted synergistic effect only at 72 h of treatment in H1299 cells. Acacetin with doxorubicin caused G2/M arrest by downregulating CDK-cyclin complex in A549 cells. Acacetin-doxorubicin combination decreased the clonogenic potential of A549 and H1299 cells upto 82% and 59%, respectively, as compared to control. Acacetin also decreased efflux of doxorubicin by 59% after 30 mins of exposure to A549 cells and further increased accumulation of doxorubicin inside the cells upto 55% in 2 h. The modulatory effect of acacetin-doxorubicin combination on doxorubicin influx and efflux was mediated through downregulation of MDR1 treansporter in NSCLC cells.CONCLUSION: These findings suggested that acacetin augments the cytotoxicity of doxorubicin at lower concentrations in lung cancer cells. Their combination leads to more retention of doxorubicin in the cells by modulating drug trasporter and thus enhances its therapeutic potential.

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PMID:  Sci Rep. 2016 Nov 7 ;6:36435. Epub 2016 Nov 7. PMID: 27819271 Abstract Title:  Water-soluble acacetin prodrug confers significant cardioprotection against ischemia/reperfusion injury. Abstract:  The morbidity and mortality of patients with ischemic cardiomyopathy resulted from ischemia/reperfusion injury are very high. The present study investigates whether our previously synthesized water-soluble phosphate prodrug of acacetin was cardioprotective against ischemia/reperfusion injury in an in vivo rat model. We found that intravenous administration of acacetin prodrug (10mg/kg) decreased the ventricular arrhythmia score and duration, reduced ventricular fibrillation and infarct size, and improved the impaired heart function induced by myocardial ischemia/reperfusion injury in anesthetized rats. The cardioprotective effects were further confirmed with the parent compound acacetin in an ex vivo rat regional ischemia/reperfusion heart model. Molecular mechanism analysis revealed that acacetin prevented the ischemia/reperfusion-induced reduction of the anti-oxidative proteins SOD-2 and thioredoxin, suppressed the release of inflammation cytokines TLR4, IL-6 and TNF, and decreased myocyte apoptosis induced by ischemia/reperfusion. Our results demonstrate the novel evidence that acacetin prodrug confer significant in vivo cardioprotective effect against ischemia/reperfusion injury by preventing the reduction of endogenous anti-oxidants and the release of inflammatory cytokines, thereby inhibiting cardiomyocytes apoptosis, which suggests that the water-soluble acacetin prodrug is likely useful in the future as a new drug candidate for treating patients with acute coronary syndrome.

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PMID:  J Microbiol Biotechnol. 2017 Jan 28 ;27(1):197-205. PMID: 27817185 Abstract Title:  Pharmacologic Inhibition of Autophagy Sensitizes Human Acute Leukemia Jurkat T Cells to Acacetin-Induced Apoptosis. Abstract:  Exposure of Jurkat T cell clone (J/Neo cells) to acacetin (5,7-dihydroxy-4'-methoxyflavone), which is present in barnyard millet ((A. Braun)) grains, caused cytotoxicity, enhancement of apoptotic sub-Grate, Bak activation, loss of mitochondrial membrane potential (), activation of caspase-9 and caspase-3, degradation of poly(ADP-ribose) polymerase, and FITC-Annexin V-stainable phosphatidylserine exposure on the external surface of the cytoplasmic membrane without accompanying necrosis. These apoptotic responses were abrogated in Jurkat T cell clone (J/Bcl-xL) overexpressing Bcl-xL. Under the same conditions, cellular autophagic responses, including suppression of the Akt-mTOR pathway and p62/SQSTM1 down-regulation, were commonly detected in J/Neo and J/Bcl-xL cells; however, formation of acridine orange-stainable acidic vascular organelles, LC3-I/II conversion, and Beclin-1 phosphorylation (Ser-15) were detected only in J/Neo cells. Correspondingly, concomitant treatment with the autophagy inhibitor (3-methyladenine or LY294002) appeared to enhance acacetin-induced apoptotic responses, such as Bak activation,loss, activation of caspase-9 and caspase-3, and apoptotic sub-Gaccumulation. This indicated that acacetin could induce apoptosis and cytoprotective autophagy in Jurkat T cells simultaneously. Together, these results demonstrate that acacetin induces not only apoptotic cell death via activation of Bak, loss of, and activation of the mitochondrial caspase cascade, but also cytoprotective autophagy resulting from suppression of the Akt-mTOR pathway. Furthermore, pharmacologic inhibition of the autophagy pathway augments the activation of Bak and resultant mitochondrial damage-mediated apoptosis in Jurkat T cells.

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n/a PMID:  Complement Med Res. 2023 Mar 8. Epub 2023 Mar 8. PMID: 36889292 Abstract Title:  Reduction of viral load in patients with acute sore throats: Results from an observational clinical trial with Echinacea / Salvia lozenges. Abstract:  BACKGROUND: Acute tonsillopharyngitis or sore throat is an initial sign of viral respiratory tract infection (RTI) and an optimal indicator for early antiviral and anti-inflammatory intervention. Both of these actions have been attributed to Echinacea purpurea and Salvia officinalis. METHODS: 74 patients (age 13-69 years) with acute sore throat symptoms (<48 h) were treated with five Echinacea/Salvia lozenges per day (4'000 mg Echinacea purpurea extract [Echinaforce] and 1'893 mg Salvia officinalis extract [A. Vogel AG, Switzerland] daily) for 4 days. Symptom intensities were recorded in a diary and oropharyngeal swab samples collected for virus detection and quantification via RT-qPCR. RESULTS: The treatment was exceptionally well tolerated, no complicated RTI developed and no antibiotic treatment was required. A single lozenge reduced throat pain by 48% (p<0.001) and tonsillopharyngitis symptoms by 34% (p<0.001). Eighteen patients tested virus positive at inclusion. Viral loads in these patients was reduced by 62% (p<0.03) after intake of a single lozenge and by 96% (p<0.02) after 4-days of treatment compared to pre-treatment. CONCLUSIONS: Echinacea/Salvia lozenges represent a valuable and safe option for the early treatment of acute sore throats capable to alleviate symptoms and contribute to reducing viral loads in the throat.

PMID:  Innovation (Camb). 2023 Mar 13 ;4(2):100391. Epub 2023 Feb 9. PMID: 36873268 Abstract Title:  -derived homogeneous polysaccharide exerts anti-tumor efficacy via facilitating M1 macrophage polarization. Abstract:  modulates tumor progression, but the underlying mechanism is poorly defined. We isolated and purified a novel homogeneous polysaccharide from.(EPPA), which was shown to be an arabinogalactan with a mean molecular mass (Mr) of 3.8  10Da and with- (15) -L-Arabinan as the backbone and-L-Araf-(1,6)--D-Galp-(1, and4)--D-GalpA-(1as the side chains. Interestingly, oral administration of EPPA suppresses tumor progressionand shapes the immune cell profile (e.g., facilitating M1 macrophages) in tumor microenvironment by single-cell RNA sequencing (scRNA-seq) analysis. More importantly, EPPA activates the inflammasome through a phagocytosis-dependent mechanism and rewires transcriptomic and metabolic profile, thereby potentiating M1 macrophage polarization. Collectively, we propose that EPPA supplementation could function as an adjuvant therapeutic strategy for tumor suppression.

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PMID:  Antioxidants (Basel). 2023 Feb 9 ;12(2). Epub 2023 Feb 9. PMID: 36829986 Abstract Title:  Fractions Represent Promising Plant-Based Anti-Inflammatory Formulations. Abstract:  is traditionally used in the treatment of inflammatory diseases. Therefore, we investigated the anti-inflammatory capacity ofdichloromethanolic (DE) and ethanolic extracts obtained from flowers and roots (R). To identify the class of compounds responsible for the strongest bioactivity, the extracts were fractionated into phenol/carboxylic acid (F1) and alkylamide fraction (F2). The chemical fingerprint of bioactive compounds in the fractions was evaluated by LC-HRMS.extracts and fractions significantly reduced pro-inflammatory cytokines (interleukin 6 and/or tumor necrosis factor) and reactive oxygen and nitrogen species (ROS/RNS) production by lipopolysaccharide-stimulated primary human monocyte-derived macrophages. Dichloromethanolic extract obtained from roots (DE-R) demonstrated the strongest anti-inflammatory activity. Moreover, fractions exhibited greater anti-inflammatory activity than whole extract. Indeed, alkylamides must be the main compounds responsible for the anti-inflammatory activity of extracts; thus, the fractions presenting high content of these compounds presented greater bioactivity. It was demonstrated that alkylamides exert their anti-inflammatory activity through the downregulation of the phosphorylation of p38, ERK 1/2, STAT 3, and/or NF-B signaling pathways, and/or downregulation of cyclooxygenase 2 expression.extracts and fractions, mainly DE-R-F2, are promising and powerful plant-based anti-inflammatory formulations that can be further used as a basis for the treatment of inflammatory diseases.

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PMID:  Molecules. 2023 Jan 25 ;28(3). Epub 2023 Jan 25. PMID: 36770844 Abstract Title:  Extraction Optimization, Antioxidant, Cosmeceutical and Wound Healing Potential ofGlycerolic Extracts. Abstract:  is a plant with immunomodulating properties, often used in topical preparations for treatment of small superficial wounds. In the presented study, the best conditions for ultrasound-assisted extraction of caffeic acid derivatives (caftaric and cichoric acid) (TPA-opt extract), as well as the conditions best suited for preparation of the extract with high radical scavenging activity (RSA-opt extract), fromaerial parts were determined. A Box-Behnken design based on glycerol content (%,/), temperature (C), ultrasonication power (W) and time (min) as independent variables was performed. Antioxidant, antiaging and wound healing effects of the two prepared extracts were evaluated. The results demonstrate that glycerol extraction is a fast and efficient method for preparation of the extracts with excellent radical scavenging, Fechelating and antioxidant abilities. Furthermore, the extracts demonstrated notable collagenase, elastase and tyrosinase inhibitory activity, indicating their antiaging properties. Well-pronounced hyaluronidase-inhibitory activities, with ICvalues lower than 30L extract/mL, as well as the ability to promote scratch closure in HaCaT keratinocyte monolayers, even in concentrations as low as 2.5L extract/mL (for RSA-opt), demonstrate promising wound healing effects ofThe fact that the investigated extracts were prepared using glycerol, a non-toxic and environmentally friendly solvent, widely used in cosmetics, makes them suitable for direct use in specialized cosmeceutical formulations.

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PMID:  Molecules. 2023 Feb 1 ;28(3). Epub 2023 Feb 1. PMID: 36771045 Abstract Title:  Chemical Characterization and Antimicrobial Properties of the Hydroalcoholic Solution of(L.) Moench. and Propolis from Northern Italy. Abstract:  In this study, for the first time, the chemical composition of(L.) Moench. and propolis (EAP) hydroalcoholic solution from the Trentino Alto Adige region of northern Italy was investigated by using SPME-GC-MS to describe the volatile content and GC-MS after silylation to detect the non-volatile compounds in the extractable organic matter. The antimicrobial activity of EAP hydroalcoholic solution was evaluated by Minimum Inhibitory Concentration (MIC) determination on 13 type strains, food and clinical isolates. Time Kill Kinetics (TKK) assays and the determination on swimming and swarming motility for 48 h gave more details on the mode of action of EAP solution. The results highlighted the presence of some terpenes and a large number of compounds belonging to different chemical classes. Among these, sugars and organic acids excelled. The EAP hydroalcoholic solution exhibited a strong antimicrobial activity in terms of MIC, with a clear decrease in the cellular load after 48 h. However, the bacterial motility may not be affected by the EAP treatment, displaying a dynamic swarming and swimming motility capacity over time. Given the complexity of chemical profile and the strong antimicrobial effectiveness, the EAP hydroalcoholic solution can be considered a source of bioactive molecules, deserving further investigation for the versatility of application.

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PMID:  J Ethnopharmacol. 2023 May 10 ;307:116221. Epub 2023 Feb 6. PMID: 36754188 Abstract Title:  Echinacea purpurea (L.) Moench extract suppresses inflammation by inhibition of C3a/C3aR signaling pathway in TNBS-induced ulcerative colitis rats. Abstract:  ETHNOPHARMACOLOGICAL RELEVANCE: Echinacea purpurea (L.) Moench (EP) is a perennial herbaceous flowering plant, commonly known as purple conical flower. It was widely used to treat skin inflammation and gastrointestinal diseases.AIM OF STUDY: Ulcerative colitis (UC) is a chronic and nonspecific inflammatory disease. Recent evidence shows that immune disorders are involved in the pathogenesis of UC. To evaluate the protective effect of Echinacea purpurea (L.) Moench exact (EE) on UC and explore the role of complement system in the treatment of UC.MATERIALS AND METHODS: UC model was induced in rats by 2,4,6-trinitrobenzene sulfonic acid (TNBS), and then rats were administered with EE for 10 days. Collect colon tissues for analysis of relevant mechanisms.RESULTS: EE could reduce the weight loss and diarrhea of UC rats. In addition, EE could improve the integrity of intestinal epithelial barrier in UC rats. EE inhibited the level of proinflammatory cytokines and promoted the antioxidation. Furthermore, EE suppressed the expression of C3aR, CFB, CD55, TLR4 and NLRP3.CONCLUSION: These results indicate that EE may achieve therapeutic effect by inhibiting C3a/C3aR signal pathway, suggesting that EE may be used as a medicinal plant to alleviate UC.

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PMID:  J Chem Neuroanat. 2023 Mar ;128:102234. Epub 2023 Jan 11. PMID: 36640914 Abstract Title:  Evaluation of anti-Alzheimer activity of Echinacea purpurea extracts in aluminum chloride-induced neurotoxicity in rat model. Abstract:  Alzheimer's disease (AD) is one of the neurodegenerative illnesses that impair individual life&increase the demand for caregivers with no available curative medication right now. Therefore, there is a growing concern about employing herbal medicine to limit AD progression&improve patients' life quality, thus potentiating its add-on therapy. In addition, herbs are cost-effective&accessible with nearly no side effects. In the same vein, our study aimed to investigate the potency of Echinacea purpurea (EP) flower extracts to ameliorate the neurodegenerative effect of Aluminum chloride (AlCl3) in a rat model. Moreover, mechanistic studies, including impact on the cholinesterase activity, redox status, inflammatory mediators, behavior performance, glucose level&histopathology, were carried on. Our results showed that 250 mg/kg of Aqueous (AQ)&Alcoholic (AL) extracts of EP inhibited cholinesterase, restored oxidative balance, down-regulated IL-6&TNF-cytokines&improved behavior performance in vivo that was reflected in the brain picture by decreasing neuronal degeneration&amyloid plaques in cerebral cortex&hippocampus. The potency of both extracts was compared to reference drugs&AlCl3 positive control group. The AQ extract showed greater potency against COX-1, COX-2&-amylase in vitro, while the AL extract was more potent against cholinesterase in vitro, inflammatory cytokines, behavior&pathological improvement in vivo. Conclusively EP overcame AlCl3-induced neurobehavioral toxicity in the rat model via different pathways, which support its regular administration to postpone progressive neural damage in AD patients.

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PMID:  Int J Mol Sci. 2022 Dec 22 ;24(1). Epub 2022 Dec 22. PMID: 36613632 Abstract Title:  Ameliorative Effect of Ethanolicagainst Hyperthyroidism-Induced Oxidative Stress via AMRK and PPAR Signal Pathway Using Transcriptomics and Network Pharmacology Analysis. Abstract:  (L.) Moench (EP) is a well-known botanical supplement with antioxidant characteristics. However, the effects of EP on oxidative stress induced by hyperthyroidism have not yet been studied. This study was designed to evaluate the antioxidative effect of ethanolic(EEP) on hyperthyroidism-induced oxidative stress mice using an integrated strategy combining transcriptomics with network pharmacology analysis. Firstly, a hyperthyroidism mice model was induced via thyroxine (160 mg/kg) and EEP (1, 2, or 4 g/kg) once daily for 2 weeks. Body weight, thyroid-stimulating hormones, and oxidative stress markers were tested. Secondly, EEP regulating the potential genes at transcript level were analyzed. Thirdly, a network pharmacology based on the constituents of EEP identified using UPLC-Q-TOF-MS analysis was adopted. Finally, a joint analysis was performed to identify the key pathway. The results showed that EEP significantly changed the thyroid-stimulating hormones and oxidative stress markers. Meanwhile, RT-qPCR and Western Blotting demonstrated that the mechanism of the antioxidant effect of EEP reversed the mRNA expression of EHHADH, HMGCR and SLC27A2 and the protein expression of FABP and HMGCR in AMPK and PPAR signaling pathways. This study integrates transcriptomics with network pharmacology to reveal the mechanism of ameliorative effect of EEP on hyperthyroidism-induced oxidative stress.

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PMID:  Dent Res J (Isfahan). 2022 ;19:98. Epub 2022 Nov 17. PMID: 36605140 Abstract Title:  Evaluation of the efficacy ofon clinical indices of Erosive Oral Lichen Planus: A randomized double-blind clinical trial. Abstract:  BACKGROUND: Oral lichen planus (OLP) is a chronic immune-mediated mucocutaneous disorder, with an unknown etiology. Since, both pain and discomfort are observed in patients with the erosive type, many drugs have been studied to alleviate pain and clinical symptoms. The present study aimed to assess the effectiveness of systemicon clinical indices of OLP.MATERIALS AND METHODS: In this randomized, double-blind, placebo-controlled trial, 70 patients with erosive OLP were randomly divided into two groups, and each was treated withtablets or placebo, 3 times a day, for 35 days. In addition, betamethasone lotion (0.1%) or nystatin (100,000 units) mouthwash were used by patients. The pain severity (visual analog scale [VAS]), lesion size, and the number of lesions were assessed at baseline and on days 10, 25, and 35 after study initiation. Finally, the obtained data were analyzed by statistical software, and Mann-Whitney test, Wilcoxon test, KaplanMeier, Chi-squared, and paired-test.RESULTS: The VAS scores in thegroup were significantly reduced at each visit compared to the placebo group (

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PMID:  Phytother Res. 2023 May ;37(5):1911-1923. Epub 2022 Dec 28. PMID: 36578266 Abstract Title:  Echinacea purpurea against neuropathic pain: Alkamides versus polyphenols efficacy. Abstract:  Chemotherapy-induced neuropathy represents the main dose-limiting toxicity of several anticancer drugs, such as oxaliplatin, leading to chronic pain and an impairment of the quality of life. Echinacea purpurea n-hexane extract (EP-R; rich in alkamides) and butanolic extract (EP-R; rich in polyphenols) have been characterized and tested in an in vivo model of oxaliplatin-induced neuropathic pain, addressing the endocannabinoid system with alkamides and counteracting the redox imbalance with polyphenols. Thermal hypersensitivity was evaluated by the Cold Plate test. EP-Rshowed a dose-dependent anti-hyperalgesic profile. The extract was more effective than its main constituent, dodeca-2E,4E,8Z,10E/Z-tetraenoic acid isobutylamide (18mgkg, twofold to equimolar EP-R30mgkg), suggesting a synergy with other extract constituents. Administration of cannabinoid type 2 (CB2) receptor-selective antagonist completely blocked the anti-allodynic effect of EP-R, differently from the antagonism of CB1 receptors. EP-R(30mgkg) exhibited anti-neuropathic properties too. The effect was mainly exerted by chicoric acid, which administered alone (123gkg, equimolar to EP-R30mgkg) completely reverted oxaliplatin-induced allodynia. A synergy between different polyphenols in the extract had not been highlighted. Echinacea extracts have therapeutic potential in the treatment of neuropathic pain, through both alkamides CB2-selective activity and polyphenols protective properties.

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PMID:  Microorganisms. 2022 Oct 29 ;10(11). Epub 2022 Oct 29. PMID: 36363737 Abstract Title:  Broad Antiviral Effects ofagainst SARS-CoV-2 Variants of Concern and Potential Mechanism of Action. Abstract:  SARS-CoV-2 variants of concern (VOCs) represent an alarming threat as they show altered biological behavior and may escape vaccination effectiveness. Broad-spectrum antivirals could play an important role to control infections. The activity of(Echinaforceextract, EF) against (i) VOCs B1.1.7 (alpha), B.1.351.1 (beta), P.1 (gamma), B1.617.2 (delta), AV.1 (Scottish), B1.525 (eta), and B.1.1.529.BA1 (omicron); (ii) SARS-CoV-2 spike (S) protein-pseudotyped viral particles and reference strain OC43 as well as (iii) wild type SARS-CoV-2 (Hu-1) was analyzed. Molecular dynamics (MD) were applied to study the interaction ofphytochemical markers with known pharmacological viral and host cell targets. EF extract broadly inhibited the propagation of all investigated SARS-CoV-2 VOCs as well as the entry of SARS-CoV-2 pseudoparticles at ECs ranging from 3.62 to 12.03g/mL. The preventive addition of 25g/mL EF to epithelial cells significantly reduced sequential infection with SARS-CoV-2 (Hu-1) and OC43. MD analyses showed constant binding affinities to VOC-typical S protein variants for alkylamides, caftaric acid, and feruloyl-tartaric acid in EF extract and interactions with serine protease TMPRSS-2. EF extract demonstrated stable virucidal activity across seven tested VOCs, likely due to the constant affinity of the contained phytochemical substances to all spike variants. A possible interaction of EF with TMPRSS-2 partially would explain the cell protective benefits of the extract by the inhibition of membrane fusion and cell entry. EF may therefore offer a supportive addition to vaccination endeavors in the control of existing and future SARS-CoV-2 virus mutations.

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PMID:  Int J Mol Sci. 2022 Nov 6 ;23(21). Epub 2022 Nov 6. PMID: 36362404 Abstract Title:  On the Bioactivity ofExtracts to Modulate the Production of Inflammatory Mediators. Abstract:  Inflammatory diseases are the focus of several clinical studies, due to limitations and serious side effects of available therapies. Plant-based drugs (e.g., salicylic acid, morphine) have become landmarks in the pharmaceutical field. Therefore, we investigated the immunomodulatory effects of flowers, leaves, and roots from. Ethanolic (EE) and dichloromethanolic extracts (DE) were obtained using the Accelerated Solvent Extractor and aqueous extracts (AE) were prepared under stirring. Their chemical fingerprint was evaluated by liquid chromatography-high resolution mass spectrometry (LC-HRMS). The pro- and anti-inflammatory effects, as well as the reduction in intracellular reactive oxygen and nitrogen species (ROS/RNS), of the different extracts were evaluated using non-stimulated and lipopolysaccharide-stimulated macrophages. Interestingly, AE were able to stimulate macrophages to produce pro-inflammatory cytokines (tumor necrosis factor -TNF-, interleukin -IL-1, and IL-6), and to generate ROS/RNS. Conversely, under an inflammatory scenario, all extracts reduced the amount of pro-inflammatory mediators. DE, alkylamides-enriched extracts, showed the strongest anti-inflammatory activity. Moreover,extracts demonstrated generally a more robust anti-inflammatory activity than clinically used anti-inflammatory drugs (dexamethasone, diclofenac, salicylic acid, and celecoxib). Therefore,extracts may be used to develop new effective therapeutic formulations for disorders in which the immune system is either overactive or impaired.

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PMID:  Molecules. 2016 Sep 26 ;21(10). Epub 2016 Sep 26. PMID: 27681715 Abstract Title:  Acacetin Protects Mice from Staphylococcus aureus Bloodstream Infection by Inhibiting the Activity of Sortase A. Abstract:  () is a major cause of infection in hospitals and communities. Widespread dissemination of multi-drug resistantis a serious threat to the health of humans and animals. An anti-virulence strategy has been widely considered as an alternative therapeutic approach. Inhibitors of virulence factors are able to treatinfections without influencing the growth or viability of bacteria and rarely lead to bacterial resistance. Sortase A (SrtA) is a membrane-associated cysteine transpeptidase that catalyzes up to 25 surface proteins that covalently bind to cell wall peptidoglycans. In, most of these surface proteins have been identified as important virulence factors that are vital in bacterial pathogenesis. In the present study, we show that acacetin, a natural flavonoid compound, inhibits the activity of SrtA in(IC= 36.464.69g/mL, 128M) which affects the assembly of protein A (SpA) to cell walls and reduces the binding ofto fibrinogen (Fg). The mechanism of the interaction between acacetin and SrtA were preliminarily discussed using molecular dynamics simulations. The results suggested that acacetin adopted a compact conformation binding at the pocket of the SrtA via residues Arg-139 and Lys-140. By performing an animal infection model, we demonstrated that acacetin was able to protect mice from renal abscess formation induced byand significantly increased survival rates. Taken together, these findings suggest that acacetin may be a promising candidate for the development of anti-drugs.

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PMID:  Free Radic Res. 2016 Aug ;50(8):861-74. Epub 2016 Jun 2. PMID: 27150237 Abstract Title:  Acacetin promotes healthy aging by altering stress response in Caenorhabditis elegans. Abstract:  The progression in lifespan has been associated with elevated intracellular reactive oxygen species (ROS) and oxidative stress level which contributes to development of age related disorders. The discovery of lifespan modulating phytomolecules may promote development of natural therapies against age related afflictions. Acacetin (5,7-dihydroxy-4-methoxyflavone), is a naturally occurring flavonoid known to possess therapeutic properties. To this end, the present study evaluates effect of acacetin (AC) on lifespan, stress and neurotoxicity for the first time by using well-established free living, multicellular Caenorhabditis elegans model system. The 25M dose of AC significantly prolonged the mean lifespan of worms by 27.31% in comparison to untreated control and other tested doses of AC. Additionally, AC enhanced stress resistance against oxidative and thermal stress in worms. Furthermore, AC attenuated age related intracellular ROS level, aggregation of age pigment lipofuscin and increased the mean survival in stress hypersensitive mev-1 mutant by 40.5%. AC supplementation also reduced the alpha synuclein aggregation in transgenic worm model of Parkinson's disease. The enhanced stress resistance, lifespan and alleviation of age related pathology can be attributed to increment in stress modulatory enzymes like superoxide dismutase (SOD) and catalase (CAT) level. Altogether the results suggest AC exposure maintains stress level, health span and extends mean lifespan of C. elegans. The longevity promoting and neuromodulatory effects of AC are mediated by up regulation of the stress response genes sod-3 and gst-4. The present finding gives new insights of natural remedies and their future prospects in developing therapeutic interventions for managing age related diseases.

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PMID:  Arch Oral Biol. 2015 Sep ;60(9):1283-98. Epub 2015 Jun 8. PMID: 26099663 Abstract Title:  The mechanism of acacetin-induced apoptosis on oral squamous cell carcinoma. Abstract:  BACKGROUND: Acacetin (5,7-dihydroxy-40-methoxyflavone), present in safflower seeds, plants, flowers, Cirisium rhinoceros Nakai, has been reported to be able to exert anti-peroxidative, anti-inflammatory, anti-plasmodial, and anti-proliferative activities by inducing apoptosis and blocking the progression of cell cycles.OBJECTIVE AND DESIGN: The objective of this study is to investigate the mechanism of acacetin-induced apoptosis of oral squamous cell carcinoma cell line (HSC-3).RESULTS: Acacetin caused 50% growth inhibition (IC50) of HSC-3 cells at 25g/mL over 24h in the MTT assay. Apoptosis was characterized by DNA fragmentation and increase of sub-G1 cells and involved activation of caspase-3 and PARP (poly-ADP-ribose polymerase). Maximum caspase-3 activity was observed with 100g/mL of acacetin for 24h. Caspase-8 and -9 activation cascades mediated the activation of caspase-3. Acacetin caused reduction of Bcl-2 expression leading to an increase of the Bax:Bcl-2 ratio. It also caused a loss of mitochondrial membrane potential that induced release of cytochrome c into the cytoplasm. Pretreatment with casapse-3 (Z-DEVD-FMK), -8 (Z-IETD-FMK), and 9 inhibitor (z-LEHD-fmk) inhibited the acacetin-induced loss of mitochondrial membrane potential and release of cytochrome c. The mitogen-activated protein kinases (MAPKs) were activated by acacetin. Moreover, pretreating the cells with each of the caspase inhibitor or MAPKs specific inhibitors apparently inhibited acacetin-induced cytotoxicity of HSC-3 cells.CONCLUSION: In conclusion, acacetin induce the apoptosis of oral squamous cell carcinoma cell line, which is closely related to its ability to activate the MAPK-mediated signaling pathways with the subsequent induction of a mitochondria- and caspase-dependent mechanism. These results strongly suggest that acacetin might have cancer inhibition and therapeutic potential.

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PMID:  J Cell Mol Med. 2015 Aug ;19(8):1910-5. Epub 2015 Apr 9. PMID: 25856795 Abstract Title:  Acacetin inhibits expression of matrix metalloproteinases via a MAPK-dependent mechanism in fibroblast-like synoviocytes. Abstract:  It is well known that rheumatoid arthritis (RA) is an autoimmune joint disease in which fibroblast-like synoviocytes (FLSs) play a pivotal role. In this study, we investigated the anti-arthritic properties of acacetin in FLSs. The expression of matrix metalloproteinase (MMP)-1, MMP-3 and MMP-13 were investigated by quantitative RT-PCR and western blot at gene and protein levels. At the same time, the phosphorylation of mitogen-activated protein kinases (MAPK) was investigated. The DNA-binding activity of NF-B was investigated by electrophoretic mobility shift assay. We found that acacetin inhibits p38 and JNK phosphorylation and reduces MMP-1, MMP-3 and MMP-13 expression in interleukin-1-induced FLSs. Our results suggest that acacetin has antiarthritic effects in FLSs. Thus, acacetin should be further studied for the treatment of arthritis.

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PMID:  Biomed Pharmacother. 2023 May ;161:114534. Epub 2023 Mar 16. PMID: 36933376 Abstract Title:  Chrysin protects against cerebral ischemia-reperfusion injury in hippocampus via restraining oxidative stress and transition elements. Abstract:  Chrysin is a natural flavonoid compound that has antioxidant and neuroprotective effects. Cerebral ischemia reperfusion (CIR) is closely connected with increased oxidative stress in the hippocampal CA1 region and homeostasis disorder of transition elements such as iron (Fe), copper (Cu) and zinc (Zn). This exploration was conducted to elucidate the antioxidant and neuroprotective effects of chrysin based on transient middle cerebral artery occlusion (tMCAO) in rats. Experimentally, sham group, model group, chrysin (50.0 mg/kg) group, Ginaton (21.6 mg/kg) group, Dimethyloxallyl Glycine (DMOG, 20.0 mg/kg) + chrysin group and DMOG group were devised. The rats in each group were performed to behavioral evaluation, histological staining, biochemical kit detection, and molecular biological detection. The results indicated that chrysin restrained oxidative stress and the rise of transition element levels, and regulated transition element transporter levels in tMCAO rats. DMOG activated hypoxia-inducible factor-1 subunit alpha (HIF-1), reversed the antioxidant and neuroprotective effects of chrysin, and increased transition element levels. In a word, our findings emphasize that chrysin plays a critical role in protecting CIR injury via inhibiting HIF-1against enhancive oxidative stress and raised transition metal levels.

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PMID:  Genes Nutr. 2023 Mar 11 ;18(1):4. Epub 2023 Mar 11. PMID: 36906524 Abstract Title:  Impairment of electron transport chain and induction of apoptosis by chrysin nanoparticles targeting succinate-ubiquinone oxidoreductase in pancreatic and lung cancer cells. Abstract:  BACKGROUND: Flavonoids may help ameliorate the incidence of the major causes of tumor-related mortality, such as pancreatic ductal adenocarcinoma (PDAC) and lung cancer, which are predicted to steadily increase between 2020 to 2030. Here we compared the effect of chrysin and chrysin nanoparticles (CCNPs) with 5-fluorouracil (5-FLU) on the activity and expression of mitochondrial complex II (CII) to induce apoptosis in pancreatic (PANC-1) and lung (A549) cancer cells.METHODS: Chrysin nanoparticles (CCNPs) were synthesized and characterized, and the ICwas evaluated in normal, PANC-1, and A549 cell lines using the MTT assay. The effect of chrysin and CCNPs on Cactivity, superoxide dismutase activity, and mitochondria swelling were evaluated. Apoptosis was assessed using flow cytometry, and expression of the C and D subunits of SDH, sirtuin-3 (SIRT-3), and hypoxia-inducible factor (HIF-1) was evaluated using RT-qPCR.RESULTS: The ICof CII subunit C and D binding to chrysin was determined and used to evaluate the effectiveness of treatment on the activity of SDH with ubiquinone oxidoreductase. Enzyme activity was significantly decreased (chrysin

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PMID:  BMC Complement Med Ther. 2023 Jan 28 ;23(1):23. Epub 2023 Jan 28. PMID: 36709296 Abstract Title:  Total flavonoids of Chrysanthemum indicum L inhibit acute pancreatitis through suppressing apoptosis and inflammation. Abstract:  Acute pancreatitis (AP) is one of the most common acute abdomen. Inflammation and apoptosis are closely linked with AP development. Total flavonoids of Chrysanthemum indicum L (TFC) has been proved to inhibit inflammation and apoptosis. If TFC could suppress AP remains unclear. AP animal and cell models were established with Cerulein. The pancreatic tissue injury was measured with HE staining. Inflammatory factors were detected with ELISA method. The protein expression was evaluated with Western blotting. Inhibition of AP in vivo was achieved by TFC by inhibiting serum amylase, myeloperoxidase (MPO), and water content of pancreatic tissue. The increased inflammatory response and activation of NF-B signaling pathway in AP rats were inhibited after TFC treatment. The activation of NF-B signaling pathway, increase of cell apoptosis and inflammatory factors in AR42J cells were suppressed by TFC. We demonstrated that TFC could significantly inhibit AP through restraining serum amylase, MPO, water content of pancreatic tissue, inflammation levels, apoptosis, and NF-B signaling pathway activation. This study might clarify the potential inhibition mechanism of TFC in AP development.

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PMID:  Cancer Prev Res (Phila). 2013 Oct ;6(10):1128-39. Epub 2013 Aug 13. PMID: 23943785 Abstract Title:  Acacetin inhibits in vitro and in vivo angiogenesis and downregulates Stat signaling and VEGF expression. Abstract:  Angiogenesis is an effective target in cancer control. The antiangiogenic efficacy and associated mechanisms of acacetin, a plant flavone, are poorly known. In the present study, acacetin inhibited growth and survival (up to 92%; P

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PMID:  Immunopharmacol Immunotoxicol. 2013 Aug ;35(4):471-7. PMID: 23855486 Abstract Title:  Acacetin inhibits expression of E-selectin on endothelial cells through regulation of the MAP kinase signaling pathway and activation of NF-B. Abstract:  Since E-selectin-mediated adhesion of leukocytes or tumor cells to the vascular endothelium is a key early event in the initiation of inflammatory response and cancer metastasis, E-selectin inhibition is thought to be a good target for therapeutic intervention. Several flavones have been shown to have anti-inflammatory and anticancer properties. In the present study, we investigated the effects of plant flavones on expression of E-selectin in human umbilical vein endothelial cells. Among 11 flavones, acacetin strongly inhibited TNF--induced E-selectin expression in HUVECs. Acacetin suppressed the TNF--induced phosphorylation of p38 but did not inhibit TNF--induced phosphorylations of JNK and ERK. Acacetin also inhibited the activation of NF-B by stimulation with TNF-. Furthermore, adhesion of monocytes to TNF--treated endothelial cells was inhibited by cotreatment with acacetin. These results suggest that acacetin inhibits the expression of E-selectin by regulation of the p38 MAPK signaling pathway and activation of NF-B.

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PMID:  Evid Based Complement Alternat Med. 2012 ;2012:910520. Epub 2012 Sep 24. PMID: 23049614 Abstract Title:  Dietary acacetin reduces airway hyperresponsiveness and eosinophil infiltration by modulating eotaxin-1 and th2 cytokines in a mouse model of asthma. Abstract:  A previous study found that eosinophil infiltration and Th2 cell recruitment are important causes of chronic lung inflammation in asthma. The plant flavonoid acacetin is known to have an anti-inflammatory effect in vitro. This study aims to investigate the anti-inflammatory effect of orally administered acacetin in ovalbumin- (OVA-) sensitized asthmatic mice and its underlying molecular mechanism. BALB/c mice were sensitized by intraperitoneal OVA injection. OVA-sensitized mice were fed acacetin from days 21 to 27. Acacetin treatment attenuated airway hyperresponsiveness and reduced eosinophil infiltration and goblet cell hyperplasia in lung tissue. Additionally, eotaxin-1- and Th2-associated cytokines were inhibited in bronchoalveolar lavage fluid and suppressed the level of OVA-IgE in serum. Human bronchial epithelial (BEAS-2B) cells were used to examine the effect of acacetin on proinflammatory cytokines, chemokines, and cell adhesion molecule production in vitro. At the molecular level, acacetin significantly reduced IL-6, IL-8, intercellular adhesion molecule-1, and eotaxin-1 in activated BEAS-2B cells. Acacetin also significantly suppressed the ability of eosinophils to adhere to inflammatory BEAS-2B cells. These results suggest that dietary acacetin may improve asthma symptoms in OVA-sensitized mice.

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PMID:  Biol Pharm Bull. 2012 ;35(8):1287-94. PMID: 22863927 Abstract Title:  Acacetin protects dopaminergic cells against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neuroinflammation in vitro and in vivo. Abstract:  Acacetin (5,7-dihydroxy-4'-methoxyflavone), a constituent of flavone naturally present in plants, has anti-cancer and anti-inflammatory activities. Neuroinflammation is thought to be one of the major pathological mechanisms responsible for Parkinson's disease (PD), and has been a primary target in the development of treatment for PD. In the present study, we evaluated the neuroprotective effect of acacetin in PD induced by 1-methyl-4-phenylpyridine (MPP+)/or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and examined the related pathways in vitro and in vivo. In primary mesencephalic culture, acacetin protected dopaminergic (DA) cells and inhibited production of inflammatory factors such as nitric oxide, prostaglandin E2, and tumor necrosis factor-against MPP+-induced toxicity in a dose-dependent manner. Then, we confirmed the effect of acacetin (10mg/kg/d for 3d, per os (p.o.)) in a mouse model of PD induced by MPTP (30mg/kg/d for 5d, intraperitoneally (i.p.)). In the behavioral test (pole test), the acacetin-treated mice showed decreased time of turning and locomotor activity, which were longer in MPTP-only treated mice. In addition, the acacetin-treated group inhibited degeneration of DA neurons and depletion of dopamine level induced by MPTP toxicity in the substantia nigra and striatum of the brain. Moreover, the acacetin-treated group inhibited microglia activation, accompanied by production of inducible nitric oxide synthases and cyclooxygenase-2. These results suggest that acacetin can protect DA neurons against the neurotoxicity involved in PD via its anti-inflammatory action.

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PMID:  Neurochem Res. 2012 Jul ;37(7):1560-7. Epub 2012 Mar 24. PMID: 22447574 Abstract Title:  Acacetin attenuates neuroinflammation via regulation the response to LPS stimuli in vitro and in vivo. Abstract:  Under normal conditions in the brain, microglia play roles in homeostasis regulation and defense against injury. However, over-activated microglia secrete proinflammatory and cytotoxic factors that can induce progressive brain disorders, including Alzheimer's disease, Parkinson's disease and ischemia. Therefore, regulation of microglial activation contributes to the suppression of neuronal diseases via neuroinflammatory regulation. In this study, we investigated the effects of acacetin (5,7-dihydroxy-4'-methoxyflavone), which is derived from Robinia pseudoacacia, on neuroinflammation in lipopolysaccharide (LPS)-stimulated BV-2 cells and in animal models of neuroinflammation and ischemia. Acacetin significantly inhibited the release of nitric oxide (NO) and prostaglandin E(2) and the expression of inducible NO synthase and cyclooxygenase-2 in LPS-stimulated BV-2 cells. The compound also reduced proinflammatory cytokines, tumor necrosis factor-and interleukin-1, and inhibited the activation of nuclear factor-B and p38 mitogen-activated protein kinase. In an LPS-induced neuroinflammation mouse model, acacetin significantly suppressed microglial activation. Moreover, acacetin reduced neuronal cell death in an animal model of ischemia. These results suggest that acacetin may act as a potential therapeutic agent for brain diseases involving neuroinflammation.

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