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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PMID:  Int J Mol Sci. 2023 Jan 11 ;24(2). Epub 2023 Jan 11. PMID: 36674937 Abstract Title:  Polysaccharide Ameliorated Antibiotic-Associated Diarrhea in Mice via Regulating the Homeostasis of the Gut Microbiota and Intestinal Mucosal Barrier. Abstract:  polysaccharides (PCP) have been validated for several biological activities, including antitumor, anti-inflammatory, antioxidant, immunomodulatory, hepatoprotective and modulation on gut microbiota. In this research, we aim to demonstrate the potential prebiotic effects and the therapeutic efficacies of PCP in the treatment of antibiotic-associated diarrhea (AAD), and confirm the beneficial effects of PCP on gut dysbiosis. Antibiotic-associated diarrhea mice models were established by treating them with broad-spectrum antibiotics in drinking water for seven days. Mice in two groups treated with probiotics and polysaccharide were given Bifico capsules (4.2 g/kg/d) and PCP (250 mg/kg/d) for seven days using intragastric gavage, respectively. To observe the regulatory effects of PCP on gut microbiota and intestinal mucosal barrier, we conducted the following experiments: intestinal flora analysis (16S rDNA sequencing), histology (H&E staining) and tight junction proteins (immunofluorescence staining). The levels of mRNA expression of receptors associated with inflammation and gut metabolism were assessed by real-time reverse transcription-polymerase chain reaction (RT-PCR). The study revealed that PCP can comprehensively improve the clinical symptoms of AAD mice, including fecal traits, mental state, hair quality, etc., similar to the effect of probiotics. Based on histology observation, PCP significantly improved the substantial structure of the intestine of AAD mice by increasing the expression levels of colonic tight junction protein zonula-occludens 1 (ZO-1) and its mRNA. Moreover, PCP not only increased the abundance of gut microbiota, but also increased the diversity of gut microbiota in AAD mice, including alpha diversity and beta diversity. Further analysis found that PCP can modulate seven characteristic species of intestinal flora in AAD mice, including,,,,,andFinally, enrichment analysis predicted that PCP may affect intestinal mucosal barrier function, host immune response and metabolic function by regulating the microbiota. RT-PCR experiments showed that PCP can participate in immunomodulatory and modulation on metabolic by regulating the mRNA expression of forkhead-box protein 3 (FOXP3) and G protein-coupled receptor 41 (GPR41). These results indicated thatpolysaccharide may ameliorate antibiotic-associated diarrhea in mice by regulating the homeostasis of the gut microbiota and intestinal mucosal barrier. In addition, polysaccharide-derived changes in intestinal microbiota were involved in the immunomodulatory activities...

PMID:  Front Nutr. 2023 ;10:1119583. Epub 2023 Mar 27. PMID: 37051119 Abstract Title:  Characteristics and properties of a polysaccharide isolated fromas potential dietary supplement for IBS. Abstract:  INTRODUCTION: As low FODMAP (Fermentable oligosaccharides, disaccharides, monosaccharides and polyols) diet therapy is recommended for most of Irritable Bowel Syndrome (IBS) patients, the consequent insufficient of dietary fibers (DFs) intake exert an adverse impact on intestinal health. It is necessary to find suitable DFs for IBS patients.METHODS: This study extracted a water-insoluble polysaccharide from(WIP) by alkali-extraction and acid-precipitation method. Its molecular weight was detected by high performance gel permeation chromatography (HPGPC) analysis. The structure of WIP was analyzed by Fourier transform infrared (FT-IR) spectrum, Nuclear Magnetic Resonance (NMR) spectra and X-ray diffraction (XRD). The properties related to stability, digestion, viscosity, osmotic activity, adsorption and fermentation were investigated, aimed to explore the feasibility of WIP as a new DF supplement for patients with IBS. In addition, 16S rRNA sequencing analysis was conducted to explore its effects on IBS-related gut microbiota.RESULTS AND DISCUSSION: The results showed that WIP had a single homogeneous composition and the molecular weight was 8.110Da. WIP was indicated as a kind of pyranose form withanomeric configuration and the main chain of WIP was 1,3--glucan with amorphous structure. In addition to good thermal stability, WIP also has low bioavailability and can reach the colon mostly without being digested. Moreover, the low viscosity and osmotic activity, the high water- swelling and water/oil-holding capacity, fructose adsorption capacity and poor fermentation performance of WIP demonstrated that it is suitable for IBS patients. It is worth noting that WIP regulates IBS associated gut microbiota effectively, such as the abundance of Lachnospiraceae and Prevotella. These findings provide a theoretical basis for the development of WIP as a dietary supplement for IBS patients with low FODMAP diet therapy. GRAPHICAL ABSTRACT.

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PMID:  Life (Basel). 2023 Mar 27 ;13(4). Epub 2023 Mar 27. PMID: 37109422 Abstract Title:  Bioactive Compounds and Signaling Pathways ofin Suppressing Inflammatory Response by Network Pharmacology. Abstract:  (WE) is a medicinal mushroom and an excellent source of naturally occurring anti-inflammatory substances. However, the particular bioactive compound(s) and mechanism(s) of action against inflammation have yet to be determined. Here, we studied anti-inflammatory bioactive compounds and their molecular mechanisms through network pharmacology. Methanol (ME) extract of WE (MEWE) was used for GC-MS analysis to identify the bioactives, which were screened by following Lipinski's rules. Public databases were used to extract selected bioactives and inflammation-related targets, and Venn diagrams exposed the common targets. Then, STRING and Cytoscape tools were used to construct protein-protein (PPI) network and mushroom-bioactives-target (M-C-T) networks. Gene Ontology and KEGG pathway analysis were performed by accessing the DAVID database and molecular docking was conducted to validate the findings. The chemical reactivity of key compounds and standard drugs was explored by the computational quantum mechanical modelling method (DFT study). Results from GC-MS revealed 27 bioactives, and all obeyed Lipinski's rules. The public databases uncovered 284 compound-related targets and 7283 inflammation targets. A Venn diagram pointed to 42 common targets which were manifested in the PPI and M-C-T networks. KEGG analysis pointed to the HIF-1 signaling pathway and, hence, the suggested strategy for preventing the onset of inflammatory response was inhibition of downstream NFKB, MAPK, mTOR, and PI3K-Akt signaling cascades. Molecular docking revealed the strongest binding affinity for "N-(3-chlorophenyl) naphthyl carboxamide" on five target proteins associated with the HIF-1 signaling pathway. Compared to the standard drug utilized in the DFT (Density Functional Theory) analysis, the proposed bioactive showed a good electron donor component and a reduced chemical hardness energy. Our research pinpoints the therapeutic efficiency of MEWE and this work suggests a key bioactive compound and its action mechanism against inflammation.

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PMID:  Food Sci Nutr. 2023 May ;11(5):2356-2371. Epub 2023 Mar 9. PMID: 37181308 Abstract Title:  Effects ofextract and protein powder mixture on glucolipid metabolism and rhythm changes in obese mice. Abstract:  Herein, we explored the effects ofextract, protein powder mixture, and their combined intervention on weight loss in high-fat diet (HFD)-induced obese mice. Male C57BL/6J mice were selected and fed a HFD for 8weeks; obese mice that were successfully modeled were divided into modeling and five intervention groups, and given the corresponding treatment for 10weeks. Body weight, fat, and muscle tissue, blood glucose, lipids, inflammatory factors, and other glucose and lipid metabolism-related indicators were measured to evaluate the effect of. and protein powder intervention on weight loss in obese mice. The body weight of the intervention group was reduced compared with the HFD group. Fat content of mice in F3PM group decreased significantly ( 

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PMID:  AMB Express. 2023 Mar 10 ;13(1):29. Epub 2023 Mar 10. PMID: 36897423 Abstract Title:  A fabricated hydrogel of hyaluronic acid/curcumin shows super-activity to heal the bacterial infected wound. Abstract:  High risk of acute morbidities and even mortality from expanding the antibiotics resistant infectious wounds force indefinite efforts for development of high performance wound-healing materials. Herein, we design a procedure to fabricate a hyaluronic acid (HA)-based hydrogel to conjugate curcumin (Gel-H.P.Cur). The highlight of this work is to provide a favorite condition for capturing curcumin while protecting its structure and intensifying its activities because of the synchronization with HA. Accordingly, HA as a major component of dermis with a critical role in establishing skin health, could fortify the wound healing property as well as antibacterial activity of the hydrogel. Gel-H.P.Cur showed antibacterial properties against Pseudomonas aeruginosa (P. aeruginosa), which were examined by bactericidal efficiency, disk diffusion, anti-biofilm, and pyocyanin production assays. The effects of Gel-H.P.Cur on the inhibition of quorum sensing (QS) regulatory genes that contribute to expanding bacteria in the injured place was also significant. In addition, Gel-H.P.Cur showed high potential to heal the cutaneous wounds on the mouse excisional wound model with repairing histopathological damages rapidly and without scar. Taken together, the results strongly support Gel-H.P.Cur as a multipotent biomaterial for medical applications regarding the treatment of chronic, infected, and dehiscent wounds.

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PMID:  J Ginseng Res. 2023 Mar ;47(2):173-182. Epub 2022 Oct 6. PMID: 36926617 Abstract Title:  The ways for ginsenoside Rh2 to fight against cancer: the molecular evidencesand. Abstract:  Cancer is a global public health issue that becomes the second primary cause of death globally. Considering the side effects of radio- or chemo-therapy, natural phytochemicals are promising alternatives for therapeutic interventions to alleviate the side effects and complications. Ginsenoside Rh2 (GRh2) is the main phytochemical extracted from Panax ginseng C.A. Meyer with anticancer activity. GRh2 could induce apoptosis and autophagy of cancer cells and inhibit proliferation, metastasis, invasion, and angiogenesisand. In addition, GRh2 could be used as an adjuvant to chemotherapeutics to enhance the anticancer effect and reverse the adverse effects. Here we summarized the understanding of the molecular mechanisms underlying the anticancer effects of GRh2 and proposed future directions to promote the development and application of GRh2.

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PMID:  J Ginseng Res. 2023 Mar ;47(2):274-282. Epub 2022 Sep 3. PMID: 36926615 Abstract Title:  Ginsenoside compound K reduces ischemia/reperfusion-induced neuronal apoptosis by inhibiting PTP1B-mediated IRS1 tyrosine dephosphorylation. Abstract:  BACKGROUND: Ginsenoside compound K (CK) stimulated activation of the PI3K-Akt signaling is one of the major mechanisms in promoting cell survival after stroke. However, the underlying mediators remain poorly understood. This study aimed to explore the docking protein of ginsenoside CK mediating the neuroprotective effects.MATERIALS AND METHODS: Molecular docking, surface plasmon resonance, and cellular thermal shift assay were performed to explore ginsenoside CK interacting proteins. Neuroscreen-1 cells and middle cerebral artery occlusion (MCAO) model in rats were utilized asandmodels.RESULTS: Ginsenoside CK interacted with recombinant human PTP1B protein and impaired its tyrosine phosphatase activity. Pathway and process enrichment analysis confirmed the involvement of PTP1B and its interacting proteins in PI3K-Akt signaling pathway. PTP1B overexpression reduced the tyrosine phosphorylation of insulin receptor substrate 1 (IRS1) after oxygen-glucose deprivation/reoxygenation (OGD/R) in neuroscreen-1 cells. These regulations were confirmed in the ipsilateral ischemic hemisphere of the rat brains after MCAO/R. Ginsenoside CK treatment reversed these alterations and attenuated neuronal apoptosis.CONCLUSION: Ginsenoside CK binds to PTP1B with a high affinity and inhibits PTP1B-mediated IRS1 tyrosine dephosphorylation. This novel mechanism helps explain the role of ginsenoside CK in activating the neuronal protective PI3K-Akt signaling pathway after ischemia-reperfusion injury.

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PMID:  J Ginseng Res. 2023 Mar ;47(2):210-217. Epub 2021 Apr 22. PMID: 36926614 Abstract Title:  Longevity, tumor, and physical vitality in rats consuming ginsenoside Rg1. Abstract:  BACKGROUND: Effects of the major ginsenoside Rg1 on mammalian longevity and physical vitality are rarely reported.PURPOSE: To examine longevity, tumor, and spontaneous locomotor activity in rats consuming Rg1.METHODS: A total of 138 Wistar rats were randomized into 2 groups: control (N = 69) and Rg1 (N = 69). Rg1 (0.1 mg/kg per day) were orally supplemented from 6 months of age until natural death. Spontaneous mobility was measured by video-tracking together with body composition (dual energy x-ray absorptiometry) and inflammation markers at 5, 14, 21, and 28 months of age.RESULTS: No significant differences in longevity (control: 706 days; Rg1: 651 days, = 0.77) and tumor incidence (control: 19%; Rg1: 12%, = 0.24) were observed between the two groups. Movement distance in the control group declined significantly by60% at 21 months of age, together with decreased TNF-( = 0.01) and increased IL-10 ( = 0.02). However, the movement distance in the Rg1 group was maintained50% above the control groups ( = 0.01) at 21 months of age with greater magnitudes of TNF-decreases and IL-10 increases. Glucose, insulin, and body composition (bone, muscle and fat percentages) were similar for both groups during the entire observation period.CONCLUSION: The results of the study suggest a delay age-dependent decline in physical vitality during late life by lifelong Rg1 consumption. This improvement is associated with inflammatory modulation. Significant effects of Rg1 on longevity and tumorigenesis were not observed.

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PMID:  J Ginseng Res. 2023 Mar ;47(2):237-245. Epub 2022 Aug 6. PMID: 36926610 Abstract Title:  Protective effect and mechanism of ginsenoside Rg2 on atherosclerosis. Abstract:  BACKGROUND: Ginsenoside Rg2 (Rg2) has a variety of pharmacological activities and provides benefits during inflammation, cancer, and other diseases. However, there are no reports about the relationship between Rg2 and atherosclerosis.METHODS: We used 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) to detect the cell viability of Rg2 in vascular smooth muscle cells (VSMCs) and human umbilical vein endothelial cells (HUVECs). The expression of inflammatory factors in HUVECs and the expression of phenotypic transformation-related marker in VSMCs were detected at mRNA levels. Western blot method was used to detect the expression of inflammation pathways and the expression of phenotypic transformation at the protein levels. The rat carotid balloon injury model was performed to explore the effect of Rg2 on inflammation and phenotypic transformation.RESULTS: Rg2 decreased the expression of inflammatory factors induced by lipopolysaccharide in HUVECs-without affecting cell viability. These events depend on the blocking regulation of NF-B and p-ERK signaling pathway. In VSMCs, Rg2 can inhibit the proliferation, migration, and phenotypic transformation of VSMCs induced by platelet derived growth factor-BB (PDGF-BB)-which may contribute to its anti-atherosclerotic role. In rats with carotid balloon injury, Rg2 can reduce intimal proliferation after injury, regulate the inflammatory pathway to reduce inflammatory response, and also suppress the phenotypic transformation of VSMCs.CONCLUSION: These results suggest that Rg2 can exert its anti-atherosclerotic effect at the cellular level and animal level, which provides a more sufficient basis for ginseng as a functional dietary regulator.

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PMID:  J Ginseng Res. 2023 Mar ;47(2):319-328. Epub 2022 Oct 5. PMID: 36926609 Abstract Title:  Korean Red Ginseng and Rb1 facilitate remyelination after cuprizone diet-induced demyelination. Abstract:  BACKGROUND: Demyelination has been observed in neurological disorders, motivating researchers to search for components for enhancing remyelination. Previously we found that Rb1, a major ginsenoside in Korean Red Ginseng (KRG), enhances myelin formation. However, it has not been studied whether Rb1 or KRG function in remyelination after demyelination.METHODS: Mice were fed 0.2% cuprizone-containing chow for 5 weeks and returned to normal chow with daily oral injection of vehicle, KRG, or Rb1 for 3 weeks. Brain sections were stained with luxol fast blue (LFB) staining or immunohistochemistry. Primary oligodendrocyte or astrocyte cultures were subject to normal or stress condition with KRG or Rb1 treatment to measure gene expressions of myelin, endoplasmic reticulum (ER) stress, antioxidants and leukemia inhibitory factor (LIF).RESULTS: Compared to the vehicle, KRG or Rb1 increased myelin levels at week 6.5 but not 8, when measured by the LFBor GST-piarea within the corpus callosum. The levels of oligodendrocyte precursor cells, astrocytes, and microglia were high at week 5, and reduced afterwards but not changed by KRG or Rb1. In primary oligodendrocyte cultures, KRG or Rb1 increased expression of myelin genes, ER stress markers, and antioxidants. Interestingly, under cuprizone treatment, elevated ER stress markers were counteracted by KRG or Rb1. Under rotenone treatment, reduced myelin gene expressions were recovered by Rb1. In primary astrocyte cultures, KRG or Rb1 decreased LIF expression.CONCLUSION: KRG and Rb1 may improve myelin regeneration during the remyelination phase, potentially by directly promoting myelin gene expression.

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PMID:  J Ginseng Res. 2023 Mar ;47(2):337-346. Epub 2022 Nov 11. PMID: 36926607 Abstract Title:  Ginsenoside Rb2 suppresses cellular senescence of human dermal fibroblasts by inducing autophagy. Abstract:  BACKGROUND: Ginsenoside Rb2, a major active component of, has various physiological activities, including anticancer and anti-inflammatory effects. However, the mechanisms underlying the rejuvenation effect of Rb2 in human skin cells have not been elucidated.METHODS: We performed a senescence-associated-galactosidase staining assay to confirm cellular senescence in human dermal fibroblasts (HDFs). The regulatory effects of Rb2 on autophagy were evaluated by analyzing the expression of autophagy marker proteins, such as microtubule-associated protein 1A/1B-light chain (LC) 3 and p62, using immunoblotting. Autophagosome and autolysosome formation was monitored using transmission electron microscopy. Autophagic flux was analyzed using tandem-labeled GFP-RFP-LC3, and lysosomal function was assessed with Lysotracker. We performed RNA sequencing to identify potential target genes related to HDF rejuvenation mediated by Rb2. To verify the functions of the target genes, we silenced them using shRNAs.RESULTS: Rb2 decreased-galactosidase activity and altered the expression of cell cycle regulatory proteins in senescent HDFs. Rb2 markedly Moreover, Rb2 increased lysosomal function and red puncta in tandem-labeled GFP-RFP-LC3, which indicate that Rb2 promoted autophagic flux. RNA sequencing data showed that the expression of DNA damage-regulated autophagy modulator 2 (DRAM2) was induced by Rb2. In autophagy signaling, Rb2 activated the AMPK-ULK1 pathway and inactivated mTOR.knockdown inhibited autophagy and Rb2-restored cellular senescence.CONCLUSION: Rb2 reverses cellular senescence by activating autophagy via the AMPK-mTOR pathway and induction of DRAM2, suggesting that Rb2 might have potential value as an antiaging agent.

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PMID:  J Ginseng Res. 2023 Mar ;47(2):183-192. Epub 2022 Nov 17. PMID: 36926608 Abstract Title:  Antiviral Potential of the Genus: An updated review on their effects and underlying mechanism of action. Abstract:  Viral infections are known as one of the major factors causing death. Ginseng is a medicinal plant that demonstrated a wide range of antiviral potential, and saponins are the major bioactive ingredients in the genuswith vast therapeutic potential. Studies focusing on the antiviral activity of the genusplant-derived agents (extracts and saponins) and their mechanisms were identified and summarized, including contributions mainly from January 2016 until January 2022.,, andwere included in the review as valuable medicinal herbs against infections with 14 types of viruses. Reports from 9 extracts and 12 bioactive saponins were included, with 6 types of protopanaxadiol (PPD) ginsenosides and 6 types of protopanaxatriol (PPT) ginsenosides. The mechanisms mainly involved the inhibition of viral attachment and replication, the modulation of immune response by regulating signaling pathways, including the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway, cystathionine-lyase (CSE)/hydrogen sulfide (HS) pathway, phosphoinositide-dependent kinase-1 (PDK1)/ protein kinase B (Akt) signaling pathway, c-Jun N-terminal kinase (JNK)/activator protein-1 (AP-1) pathway, and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-B) pathway. This review includes detailed information about the mentioned antiviral effects of the genusextracts and saponinsand, and in human clinical trials, which provides a scientific basis for ginseng as an adjunctive therapeutic drug or nutraceutical.

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n/a PMID:  J Ginseng Res. 2023 Mar ;47(2):255-264. Epub 2022 Aug 19. PMID: 36926604 Abstract Title:  Effect of fermented red ginseng on gut microbiota dysbiosis- or immobilization stress-induced anxiety, depression, and colitis in mice. Abstract:  BACKGROUND: Red ginseng (RG) alleviates psychiatric disorders. Fermented red ginseng (fRG) alleviates stress-induced gut inflammation. Gut dysbiosis causes psychiatric disorders with gut inflammation. To understand the gut microbiota-mediated action mechanism of RG and fRG against anxiety/depression (AD), we investigated the effects of RG, fRG, ginsenoside Rd, and 20(S)--D-glucopyranosyl protopanaxadiol (CK) on gut microbiota dysbiosis-induced AD and colitis in mice. METHODS: Mice with AD and colitis were prepared by exposing to immobilization stress (IS) or transplanting the feces of patients with ulcerative colitis and depression (UCDF). AD-like behaviors were measured in the elevated plus maze, light/dark transition, forced swimming, and tail suspension tests. RESULTS: Oral gavage of UCDF increased AD-like behaviors and induced neuroinflammation, gastrointestinal inflammation, and gut microbiota fluctuation in mice. Oral administration of fRG or RG treatment reduced UCDF-induced AD-like behaviors, hippocampal and hypothalamic IL-6 expression, and blood corticosterone level, whereas UCDF-suppressed hippocampal BDNFNeuNcell population and dopamine and hypothalamic serotonin levels increased. Furthermore, their treatments suppressed UCDF-induced colonic inflammation and partially restored UCDF-induced gut microbiota fluctuation. Oral administration of fRG, RG, Rd, or CK also decreased IS-induced AD-like behaviors, blood IL-6 and corticosterone and colonic IL-6 and TNF-levels, and gut dysbiosis, while IS-suppressed hypothalamic dopamine and serotonin levels increased. CONCLUSION: Oral gavage of UCDF caused AD, neuroinflammation, and gastrointestinal inflammation in mice. fRG mitigated AD and colitis in UCDF-exposed mice by the regulation of the microbiota-gut-brain axis and IS-exposed mice by the regulation of the hypothalamic-pituitary-adrenal axis.

PMID:  J Ginseng Res. 2023 Mar ;47(2):193-198. Epub 2022 Dec 5. PMID: 36926605 Abstract Title:  Protective effects of Korean Red Ginseng against toxicity of endocrine-disrupting chemicals. Abstract:  Several chemicals have been developed owing to the progression of industrialization, among which endocrine-disrupting chemicals (EDCs; essential for plastic production) are used as plasticizers and flame retardants. Plastics have become an essential element in modern life because they provide convenience, thus increasing EDCs exposure to humans. EDCs cause adverse effects such as deterioration of reproductive function, cancer, and neurological abnormalities by disrupting the endocrine system and hence are classified as "dangerous substances." Additionally, they are toxic to various organs but continue to be used. Therefore, it is necessary to review the contamination status of EDCs, select potentially hazardous substances for management, and monitor the safety standards. In addition, it is necessary to discover substances that can protect against EDC toxicity and conduct active research on the protective effects of these substances. According to recent research, Korean Red Ginseng (KRG) exhibits protective effects against several toxicities caused by EDCs to humans. In this review, the effects of EDCs on the human body and the role of KRG in protection against EDC toxicity are discussed.

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PMID:  J Ginseng Res. 2023 Mar ;47(2):218-227. Epub 2021 Dec 2. PMID: 36926602 Abstract Title:  Ginsenoside Re inhibits myocardial fibrosis by regulating miR-489/myd88/NF-B pathway. Abstract:  BACKGROUND: Myocardial fibrosis (MF) is an advanced pathological manifestation of many cardiovascular diseases, which can induce heart failure and malignant arrhythmias. However, the current treatment of MF lacks specific drugs. Ginsenoside Re has anti-MF effect in rat, but its mechanism is still not clear. Therefore, we investigated the anti-MF effect of ginsenoside Re by constructing mouse acute myocardial infarction (AMI) model and Anginduced cardiac fibroblasts (CFs) model.METHODS: The anti-MF effect of miR-489 was investigated by transfection of miR-489 mimic and inhibitor in CFs. Effect of ginsenoside Re on MF and its related mechanisms were investigated by ultrasonographic, ELISA, histopathologic staining, transwell test, immunofluorescence, Western blot and qPCR in the mouse model of AMI and the Ang-induced CFs model.RESULTS: MiR-489 decreased the expression of-SMA, collagen, collagenand myd88, and inhibited the phosphorylation of NF-B p65 in normal CFs and CFs treated with Ang. Ginsenoside Re could improve cardiac function, inhibit collagen deposition and CFs migration, promote the transcription of miR-489, and reduce the expression of myd88 and the phosphorylation of NF-B p65.CONCLUSION: MiR-489 can effectively inhibit the pathological process of MF, and the mechanism is at least partly related to the regulation of myd88/NF-B pathway. Ginsenoside Re can ameliorate AMI and Anginduced MF, and the mechanism is at least partially related to the regulation of miR-489/myd88/NF-B signaling pathway. Therefore, miR-489 may be a potential target of anti-MF and ginsenoside Re may be an effective drug for the treatment of MF.

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PMID:  Acta Biochim Biophys Sin (Shanghai). 2023 Mar 14 ;55(4):633-648. PMID: 36916297 Abstract Title:  Ginsenoside Rh2 suppresses colon cancer growth by targeting the miR-150-3p/SRCIN1/Wnt axis. Abstract:  Ginsenoside Rh2, which is extracted from ginseng, exerts antitumor activity. Recent studies suggest that Rh2 may suppress the growth of colon cancer (CC). However, the underlying mechanism remains unclear. In this study, we identified the relative levels of miR-150-3p in CC tissues and cells by a comprehensive strategy of data mining, computational biology, and real-time reverse transcription PCR (qRT-PCR) experiments. The regulatory effects of miR-150-3p/SRCIN1 on the proliferative and invasive abilities of CC cells are evaluated by CCK-8, EdU, wound healing, and transwell assays. Cell cycle- and apoptosis-related protein levels are assessed by western blot analysis. Antumor formation assay was conducted to explore the effects of miR-150-3p on tumor growth. Furthermore, bioinformatics and dual luciferase reporter assays are applied to determine the functional binding of miRNA to mRNA of the target gene. Finally, the relationship between Rh2 and miR-150-3p was further verified in SW620 and HCT-116 cells. miR-150-3p is downregulated in CC tissues and cell lines. Functional assays indicate that the upregulation of miR-150-3p inhibits tumor growth bothand. In addition, SRCIN1 is upregulated in CC and predicts a poor prognosis, and it is the direct target for miR-150-3p. Moreover, the miR-150-3p mimic decreases Topflash/Fopflash-dependent luciferase activity, resulting in the inhibition of Wnt pathway activity. Rh2 can suppress the growth of CC by increasing miR-150-3p expression. Rh2 alleviates the accelerating effect on Wnt pathway activity, cell proliferation/migration, and colony formation caused by miR-150-3p inhibition. Rh2 inhibits the miR-150-3p/SRCIN1/Wnt axis to suppress colon cancer growth.

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PMID:  Exp Cell Res. 2023 May 1 ;426(1):113552. Epub 2023 Mar 11. PMID: 36914061 Abstract Title:  Ginsenoside Rg1 attenuates cerebral ischemia-reperfusion injury through inhibiting the inflammatory activation of microglia. Abstract:  It is recognized that the cerebral ischemia/reperfusion (I/R) injury triggers inflammatory activation of microglia and supports microglia-driven neuronal damage. Our previous studies have shown that ginsenoside Rg1 had a significant protective effect on focal cerebral I/R injury in middle cerebral artery occlusion (MCAO) rats. However, the mechanism still needs further clarification. Here, we firstly reported that ginsenoside Rg1 effectively suppressed the inflammatory activation of brain microglia cells under I/R conditions depending on the inhibition of Toll-likereceptor4 (TLR4) proteins. In vivo experiments showed that the ginsenoside Rg1 administration could significantly improve the cognitive function of MCAO rats, and in vitro experimental data showed that ginsenoside Rg1 significantly alleviated neuronal damage via inhibiting the inflammatory response in microglia cells co-cultured under oxygen and glucose deprivation/reoxygenation (OGD/R) condition in gradient dependent. The mechanism study showed that the effect of ginsenoside Rg1 depends on the suppression of TLR4/MyD88/NF-B and TLR4/TRIF/IRF-3 pathways in microglia cells. In a word, our research shows that ginsenoside Rg1 has great application potential in attenuating the cerebral I/R injury by targeting TLR4 protein in the microglia cells.

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PMID:  Front Pharmacol. 2023 ;14:1071516. Epub 2023 Feb 22. PMID: 36909162 Abstract Title:  (20R)-panaxadiol improves obesity by promoting white fat beigeing. Abstract:  Obesity is an important cause of a range of metabolic diseases. However, the complex mechanisms of obesity and its related diseases make some weight loss methods ineffective or have safety issues. Ginseng, a specialty of Jilin Province in China with both edible and medicinal value, contains mainly ginsenosides and other components. In order to study the anti-obesity effect of ginseng, network pharmacology was used to predict and screen the active ingredients, action targets and signaling pathways of ginseng. We found (20R)-panaxadiol (PD) is a more desirable active ingredient due to its high drug-like properties and high bioavailability. Moreover, it is closely related to cAMP pathway which is more important in metabolism regulation. The corresponding pharmacodynamic targets of PD include ADRB2 (the gene encoding the-adrenoceptor receptor). Our study aimed to investigate whether Panaxadiol can promote white adipocyte beigeing and increase thermogenesis through modulating the/cAMP pathway to exert anti-obesity effects., we established high-fat feeding obesity model, genotypically obese mice (ob/ob) model, and administered PD (10 mg/kg). PD treatment in ob/ob mice along withreceptor inhibitor ICI118551., differentiated mature 3T3-L1 cells were given palmitate (PA) to induce hypertrophy model along with PD (20 M).The results of this study demonstrated that PD significantly reduced body weight, improved glucose tolerance and lipid levels in high-fat-induced obese mice and ob/ob mice, and also reduced lipid droplet size in PA-treated hypertrophic adipocytes. Molecular biology assays confirmed that cAMP response element binding protein (CREB) phosphorylation was increased after PD administration, and the expression of thermogenesis-related proteins UCP1, PRDM16 and mitochondrial biosynthesis-related proteins PGC-1, TFAM and NRF1 were increased. Molecular docking results showed a low binding energy betweenreceptors and PD, indicating an affinity between thereceptor and PD. In addition, thereceptor inhibition, reversed the anti-obesity effect of PD on the body weight, lipid droplets, the expression of thermogenesis-related proteins and CREB phosphorylation in ob/ob mice.These results suggest that PD may promote the expression of thermogenic proteins through phosphorylation of CREB2 receptor activation, and thus exert anti-obesity effects.

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PMID:  Anticancer Drugs. 2023 Jul 1 ;34(6):705-714. Epub 2022 Nov 18. PMID: 36730497 Abstract Title:  Panaxadiol targeting IL2 inducible T cell kinase promotes T cell immunity in radiotherapy. Abstract:  Ginseng, as a traditional Chinese medicine, has a good protective effect against radiotherapy, but its mechanism in radiotherapy still needs to be further explored. The active ingredients of Ginseng were analyzed according to pharmacodynamics in the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) database, and the target genes of active ingredients were screened by UniProt, PubChem and Swiss target prediction database. The differentially expressed genes of GSE6871 and GSE20162 were analyzed from the GEO database. Further, cluster analysis and enrichment analysis were carried out through protein-protein interaction network to determine hub gene. Next, build the drug-disease target network, conduct molecular docking simulation, and determine the key ingredients and targets of Ginseng on radiotherapy. We screened 16 active ingredients of Ginseng and 747 target genes from the TCMSP database. Eighty-two common differentially expressed genes were obtained by the GEO database. After topological analysis, we finally determined CD28, FYN, IL2 inducible T cell kinase (ITK), MYC and CD247 as hub genes. After integrating the drug-disease target network and molecular docking, we found that Panaxadiol, as an active ingredient of Ginseng, can target ITK to participate in T cell signal receptor pathway and act on radiotherapy. Panaxadiol can act on the key target ITK of radiotherapy, participate in T cell signal receptor pathway, and then affect the proliferation, differentiation and immune response of radiotherapy T cells, so as to reduce the side effects of radiotherapy.

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PMID:  Acta Pharmacol Sin. 2023 Jun ;44(6):1217-1226. Epub 2023 Jan 17. PMID: 36650291 Abstract Title:  Ginseng-derived panaxadiol ameliorates STZ-induced type 1 diabetes through inhibiting ROR/IL-17A axis. Abstract:  Retinoic-acid-receptor-related orphan receptor(ROR) is a major transcription factor for proinflammatory IL-17A production. Here, we revealed that the RORdeficiency protects mice from STZ-induced Type 1 diabetes (T1D) through inhibiting IL-17A production, leading to improved pancreatic isletcell function, thereby uncovering a potential novel therapeutic target for treating T1D. We further identified a novel RORinverse agonist, ginseng-derived panaxadiol, which selectively inhibits RORtranscriptional activity with a distinct cofactor recruitment profile from known RORligands. Structural and functional studies of receptor-ligand interactions reveal the molecular basis for a unique binding mode for panaxadiol in the RORligand-binding pocket. Despite its inverse agonist activity, panaxadiol induced the C-terminal AF-2 helix of RORto adopt a canonical active conformation. Interestingly, panaxadiol ameliorates mice from STZ-induced T1D through inhibiting IL-17A production in a ROR-dependent manner. This study demonstrates a novel regulatory function of RORwith linkage of the IL-17A pathway in pancreaticcells, and provides a valuable molecule for further investigating RORfunctions in treating T1D.

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PMID:  J Agric Food Chem. 2022 Sep 21 ;70(37):11560-11571. Epub 2022 Sep 12. PMID: 36094400 Abstract Title:  In Vivo Metabolites of Panaxadiol Inhibit HepG-2 Cell Proliferation by Inducing G1 Arrest and ROS-Mediated Apoptosis. Abstract:  In this study, 10 metabolites were obtained by collecting and extracting fecal samples after oral administration of panaxadiol (PD). Of these 10 metabolites, M7 (3,21,22-hydroxy-24-norolean-12-ene), M8 (21,22-hydroxy-24-norolean-12-ene-3-one), M9 (3,30-hydroxy-24-norolean-22,30-epoxy-12-ene), and M10 (3,21-hydroxy-24-norolean-12-ene) were new compounds. MTT screening of the isolated compounds revealed that the inhibitions of cancer cells by M2, M4, M7, M8, and M10 were significantly stronger than that by the mother drug M0, with the activity of M2 being the most significant. Further, we investigated the anticancer mechanism of M2. The results showed that M2 significantly increased the level of ROS in cells; regulated the expressions of Bax, Bcl-2, and Cyt-C through the mitochondrial pathway; triggered the caspase cascade; and induced apoptosis. M2 could also induce G1 phase arrest and significantly regulate cell cycle-related proteins. In conclusion, the experimental results provide data for further study on the metabolic mechanism of PD in vivo and the potential of developing new anti-cancer drugs.

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PMID:  J Ginseng Res. 2023 Mar ;47(2):265-273. Epub 2022 Aug 31. PMID: 36926616 Abstract Title:  Korean Red Ginseng extract treatment prevents post-antibiotic dysbiosis-induced bone loss in mice. Abstract:  BACKGROUND: The intestinal microbiota is an important regulator of bone health. In previous studies we have shown that intestinal microbiota dysbiosis, induced by treatment with broad spectrum antibiotics (ABX) followed by natural repopulation, results in gut barrier dysfunction and bone loss. We have also shown that treatment with probiotics or a gut barrier enhancer can inhibit dysbiosis-induced bone loss. The overall goal of this project was to test the effect of Korean Red Ginseng (KRG) extract on bone and gut health using antibiotics (ABX) dysbiosis-induced bone loss model in mice.METHODS: Adult male mice (Balb/C, 12-week old) were administered broad spectrum antibiotics (ampicillin and neomycin) for 2 weeks followed by 4 weeks of natural repopulation. During this 4-week period, mice were treated with vehicle (water) or KRG extract. Other controls included mice that did not receive either antibiotics or KRG extract and mice that received only KRG extract. At the end of the experiments, we assessed various parameters to assess bone, microbiota andintestinal permeability.RESULTS: Consistent with our previous results, post-ABX- dysbiosis led to significant bone loss. Importantly, this was associated with a decrease in gut microbiota alpha diversity and an increase in intestinal permeability. All these effects including bone loss were prevented by KRG extract treatment. Furthermore, our studies identified multiple genera includingandas well asto be potentially linked to the effect of KRG extract on gut-bone axis.CONCLUSION: Together, our results demonstrate that KRG extract regulates the gut-bone axis and is effective at preventing dysbiosis-induced bone loss in mice.

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PMID:  J Ginseng Res. 2023 Mar ;47(2):199-209. Epub 2020 Dec 18. PMID: 36926612 Abstract Title:  Notoginseng leaf triterpenes ameliorates mitochondrial oxidative injury via the NAMPT-SIRT1/2/3 signaling pathways in cerebral ischemic model rats. Abstract:  Due to the interrupted blood supply in cerebral ischemic stroke (CIS), ischemic and hypoxia results in neuronal depolarization, insufficient NAD+, excessive levels of ROS, mitochondrial damages, and energy metabolism disorders, which triggers the ischemic cascades. Currently, improvement of mitochondrial functions and energy metabolism is as a vital therapeutic target and clinical strategy. Hence, it is greatly crucial to look for neuroprotective natural agents with mitochondria protection actions and explore the mediated targets for treating CIS. In the previous study, notoginseng leaf triterpenes (PNGL) fromstems and leaves was demonstrated to have neuroprotective effects against cerebral ischemia/reperfusion injury. However, the potential mechanisms have been not completely elaborate.: The model of middle cerebral artery occlusion and reperfusion (MCAO/R) was adopted to verify the neuroprotective effects and potential pharmacology mechanisms of PNGL. Antioxidant markers were evaluated by kit detection. Mitochondrial function was evaluated by ATP content measurement, ATPase, NAD and NADH kits. And the transmission electron microscopy (TEM) and pathological staining (H&E and Nissl) were used to detect cerebral morphological changes and mitochondrial structural damages. Western blotting, ELISA and immunofluorescence assay were utilized to explore the mitochondrial protection effects and its related mechanisms.:, treatment with PNGL markedly reduced excessive oxidative stress, inhibited mitochondrial injury, alleviated energy metabolism dysfunction, decreased neuronal loss and apoptosis, and thus notedly raised neuronal survival under ischemia and hypoxia. Meanwhile, PNGL significantly increased the expression of nicotinamide phosphoribosyltransferase (NAMPT) in the ischemic regions, and regulated its related downstream SIRT1/2/3-MnSOD/PGC-1pathways.: The study finds that the mitochondrial protective effects of PNGL are associated with the NAMPT-SIRT1/2/3-MnSOD/PGC-1signal pathways. PNGL, as a novel candidate drug, has great application prospects for preventing and treating ischemic stroke.

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PMID:  Chem Biol Drug Des. 2023 Jun ;101(6):1416-1424. Epub 2023 Mar 17. PMID: 36866966 Abstract Title:  Panax notoginseng saponins promote hair follicle growth in mice via Wnt/-Catenin signaling pathway. Abstract:  Panax notoginseng saponins (PNS), the active ingredients of the traditional Chinese medicine Panax notoginseng, have strong neuroprotective and anti-platelet aggregation effects. To investigate whether PNS can promote hair follicle growth in C57BL/6J mice, the optimal concentration of PNS was initially determined, followed by clarification of the mechanism underlying their effects. Twenty-five male C57BL/6J mice had the hair on a 23 cmarea of the dorsal skin shaved and were equally divided into five groups: control group, 5% minoxidil (MXD) group, and three PNS treatment groups [2% (10 mg/kg), 4% (20mg/kg), and 8% (40mg/kg) PNS]. They were then intragastrically administered the corresponding drugs for 28days. The effects of PNS on C57BL/6J mice were analyzed by subjecting their dorsal depilated skin samples to different assessments, including hematoxylin and eosin staining, immunohistochemistry, immunofluorescence, quantitative real-time polymerase chain reaction (qRT-PCR), and Western blotting (WB). The group with 8% PNS exhibited the largest number of hair follicles from 14days onwards. Compared with the control group, the number of hair follicles increased significantly in the mice treated with 8% PNS and 5% MXD, which significantly increased in a PNS-dose-dependent manner. Immunohistochemistry and immunofluorescence results revealed that treatment with 8% PNS activated the metabolism of hair follicle cells, with them showing higher rates of proliferation and apoptosis than those in the normal group. In qRT-PCR and WB analysis, the expression of-catenin, Wnt10b, and LEF1 was upregulated in the PNS and MDX groups compared with that in the control group. Examination of the WB bands revealed that the greatest inhibitory effect of Wnt5a occurred in mice in the 8% PNS group. PNS may promote the growth of hair follicles in mice, with 8% PNS demonstrating the strongest effect. The mechanism behind this may be related to the Wnt/-catenin signaling pathway.

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PMID:  Acta Pharmacol Sin. 2023 Jan 31. Epub 2023 Jan 31. PMID: 36721009 Abstract Title:  Notoginsenoside R1 protects against myocardial ischemia/reperfusion injury in mice via suppressing TAK1-JNK/p38 signaling. Abstract:  Previous studies show that notoginsenoside R1 (NG-R1), a novel saponin isolated from Panax notoginseng, protects kidney, intestine, lung, brain and heart from ischemia-reperfusion injury. In this study we investigated the cardioprotective mechanisms of NG-R1 in myocardial ischemia/reperfusion (MI/R) injury in vivo and in vitro. MI/R injury was induced in mice by occluding the left anterior descending coronary artery for 30min followed by 4h reperfusion. The mice were treated with NG-R1 (25mg/kg, i.p.) every 2h for 3 times starting 30min prior to ischemic surgery. We showed that NG-R1 administration significantly decreased the myocardial infarction area, alleviated myocardial cell damage and improved cardiac function in MI/R mice. In murine neonatal cardiomyocytes (CMs) subjected to hypoxia/reoxygenation (H/R) in vitro, pretreatment with NG-R1 (25M) significantly inhibited apoptosis. We revealed that NG-R1 suppressed the phosphorylation of transforming growth factor-activated protein kinase 1 (TAK1), JNK and p38 in vivo and in vitro. Pretreatment with JNK agonist anisomycin or p38 agonist P79350 partially abolished the protective effects of NG-R1 in vivo and in vitro. Knockdown of TAK1 greatly ameliorated H/R-induced apoptosis of CMs, and NG-R1 pretreatment did not provide further protection in TAK1-silenced CMs under H/R injury. Overexpression of TAK1 abolished the anti-apoptotic effect of NG-R1 and diminished the inhibition of NG-R1 on JNK/p38 signaling in MI/R mice as well as in H/R-treated CMs. Collectively, NG-R1 alleviates MI/R injury by suppressing the activity of TAK1, subsequently inhibiting JNK/p38 signaling and attenuating cardiomyocyte apoptosis.

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PMID:  Phytomedicine. 2023 May ;113:154681. Epub 2023 Jan 30. PMID: 36893674 Abstract Title:  Ginsenoside Re attenuates myocardial ischemia/reperfusion induced ferroptosis via miR-144-3p/SLC7A11. Abstract:  BACKGROUND: Ginsenoside Re is an active component in ginseng that confers protection against myocardial ischemia/reperfusion (I/R) injury. Ferroptosis is a type of regulated cell death found in various diseases.PURPOSE: Our study aims to investigate the role of ferroptosis and the protective mechanism of Ginsenoside Re in myocardial ischemia/reperfusion.METHODS: In the present study, we treated rats for five days with Ginsenoside Re, then established the myocardial ischemia/reperfusion injury rat model to detect molecular implications in myocardial ischemia/reperfusion regulation and to determine the underlying mechanism.RESULTS: This study identifies the mechanism behind ginsenoside Re's effect on myocardial ischemia/reperfusion injury and its regulation of ferroptosis through miR-144-3p. Ginsenoside Re significantly reduced cardiac damage caused by ferroptosis during myocardial ischemia/reperfusion injury and glutathione decline. To determine how Ginsenoside Re regulated ferroptosis, we isolated exosomes from VEGFR2endothelial progenitor cells after ischemia/reperfusion injury and performed miRNA profiling to screen the miRNAs aberrantly expressed in the process of myocardial ischemia/reperfusion injury and ginsenoside Re treatment. We identified that miR-144-3p was upregulated in myocardial ischemia/reperfusion injury by luciferase report and qRT-PCR. We further confirmed that the solute carrier family 7 member 11 (SLC7A11) was the target gene of miR-144-3p by database analysis and western blot. In comparison with ferropstatin-1, a ferroptosis inhibitor, in vivo studies confirmed that ferropstatin-1 also diminished myocardial ischemia/reperfusion injury induced cardiac function damage.CONCLUSION: We demonstrated that ginsenoside Re attenuates myocardial ischemia/reperfusion induced ferroptosis via miR-144-3p/SLC7A11.

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PMID:  J Burn Care Res. 2023 Mar 11. Epub 2023 Mar 11. PMID: 36905210 Abstract Title:  Notoginsenoside R1 facilitates cell angiogenesis by inactivating the Notch signaling during wound healing. Abstract:  The development of chronic, non-healing wounds is a persistent medical problem that drives patient morbidity and increases healthcare costs. Angiogenesis is a critical accompanying activity in the proliferation stage during the wound healing process. Notoginsenoside R1 (NGR1) isolated from Radix notoginseng has been reported to alleviate diabetic ulcers by promoting angiogenesis and decreasing inflammatory responses and apoptosis. In the present study, we investigated the effect of NGR1 on angiogenesis and its therapeutic functions in cutaneous wound healing. For in vitro evaluation, cell counting kit-8 assays, migration assays, Matrigel-based angiogenic assays and western blotting were conducted. The experimental results showed that NGR1 (10-50M) had no cytotoxicity to human skin fibroblasts (HSFs) and human microvascular endothelial cells (HMEC), and NGR1 treatment facilitated the migration of HSFs and enhanced angiogenesis in HMECs. Mechanistically, NGR1 treatment inhibited the activation of Notch signaling in HMECs. For in vivo analysis, hematoxylin-eosin staining, immunostaining, and Masson's trichrome staining were performed, and we found that NGR1 treatment promoted angiogenesis, reduced wound widths, and facilitated wound healing. Furthermore, HMECs were treated with DAPT (a Notch inhibitor), and DAPT treatment was found to exert pro-angiogenic effects. Simultaneously, DAPT was administrated into experimental cutaneous wound healing model, and we found that DAPT administration prevented the development of cutaneous wounds. Collectively, NGR1 promotes angiogenesis and wound repair via activation of the Notch pathway and exhibits therapeutic effects on cutaneous wound healing.

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PMID:  Front Med (Lausanne). 2022 ;9:1055252. Epub 2023 Jan 6. PMID: 36714147 Abstract Title:  Notoginsenoside Fc ameliorates renal tubular injury and mitochondrial damage in acetaminophen-induced acute kidney injury partly by regulating SIRT3/SOD2 pathway. Abstract:  INTRODUCTION: Mitochondria dysfunction is one of the primary causes of tubular injury in acute kidney injury (AKI). Notoginsenoside Fc (Fc), a new saponin isolated from Panax notoginseng, exhibited numerous pharmacological actions. However, the beneficial effects of Fc on renal tubular impairment and mitochondrial dysfunction in AKI have not been fully studied.METHODS: In this study, we established acetaminophen (APAP)-induced AKI model in mice to examine the therapeutic impacts of Fc on AKI.RESULTS: Our results showed that Fc could decrease the levels of the serum creatinine (Scr), blood urea nitrogen (BUN) and Cystatin C in mice with AKI. Fc also ameliorated renal histopathology, renal tubular cells apoptosis and restored expression of apoptosis-related proteins such as Bax, Bcl-2 and caspase3 (C-caspase3). Additionally, Fc increased the protein expression of SIRT3 and SOD2 in kidneys from mice with AKI.studies further showed Fc reduced the apoptosis of HK-2 cells exposure to APAP, attenuated the loss of mitochondrial membrane potential and decreased the formation of mitochondrial superoxide. Fc also partly restored the protein expression of Bax, Bcl-2, C-Caspase3, SIRT3, and SOD2 in HK-2 cells exposure to APAP.CONCLUSION: In summary, Fc might reduce renal tubular injury and mitochondrial dysfunction in AKI partly through the regulation of SIRT3/SOD2 pathway.

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PMID:  Oxid Med Cell Longev. 2023 ;2023:9645789. Epub 2023 Jan 30. PMID: 36756298 Abstract Title:  RRP Regulates Autophagy through the AMPK Pathway to Alleviate the Effect of Cell Senescence on Atherosclerosis. Abstract:  Autophagy is closely associated with atherosclerosis and other cardiovascular diseases (CVD). Compound Danshen prescription is widely used as a clinical antiatherosclerotic drug. In our previous studies, we have shown that the combined active component, ginsenoside Rg1-notoginsenoside R1-protocatechualdehyde (RRP), can effectively alleviate endothelial dysfunction and reduce atherosclerotic plaques. However, the association between cellular senescence, caused by reduced autophagy, and atherosclerosis remains unclear. In this study, we investigated whether RRP can enhance autophagy and alleviate cell senescence through the AMPK pathway. Our results showed that RRP reduced the secretion of inflammatory factors in the serum of atherosclerotic mice, enhanced autophagy, and alleviated aortic aging in mice, thus reducing atherosclerotic plaques. In human aortic endothelial cells (HAECs), RRP effectively enhanced autophagy and inhibited senescence by activating the AMPK pathway. When AMPKwas silenced, the effect of RRP was inhibited, thus reversing its antiaging effect. Overall, our results show that RRP regulates autophagy through the AMPK pathway, thereby inhibiting cell senescence and alleviating the progression of atherosclerosis, suggesting that RRP may be a potential candidate drug for the treatment of atherosclerosis.

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PMID:  J Pers Med. 2022 Dec 27 ;13(1). Epub 2022 Dec 27. PMID: 36675720 Abstract Title:  Astragaloside IV Targets Macrophages to Alleviate Renal Ischemia-Reperfusion Injury via the Crosstalk between Hif-1and NF-B (p65)/Smad7 Pathways. Abstract:  (1) Background: Astragaloside IV (AS-IV) is derived from Astragalus membranous (AM), which is used to treat kidney disease. Macrophages significantly affect the whole process of renal ischemia-reperfusion (I/R). The regulation of macrophage polarization in kidneys by AS-IV was the focus. (2) Methods: Renal tubular injury and fibrosis in mice were detected by Hematoxylin and Eosin staining and Masson Trichrome Staining, separately. An ELISA and quantitative real-time polymerase chain reaction were used to explore the cytokine and mRNA expression. Western blot was used to determine protein expression and siRNA technology was used to reveal the crosstalk of signal pathways in RAW 264.7 under hypoxia. (3) Results: In the early stages of I/R injury, AS-IV reduced renal damage and macrophage infiltration. M1-associated markers were decreased, while M2 biomarkers were increased. The NF-B (p65)/Hif-1pathway was suppressed by AS-IV in M1. Moreover, p65 dominated the expression of Hif-1. In the late stages of I/R injury, renal fibrosis was alleviated, and M2 infiltration also decreased after AS-IV treatment. Hif-1expression was reduced by AS-IV, while Smad7 expression was enhanced. Hif-1interferes with the expression of Smad7 in M2. (4) Conclusions: AS-IV promoted the differentiation of M1 to M2, relieving the proinflammatory response to alleviate the kidney injury during the early stages. AS-IV attenuated M2 macrophage infiltration to prevent kidney fibrosis during the later stages.

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