PMID:  Antioxidants (Basel). 2023 Mar 3 ;12(3). Epub 2023 Mar 3. PMID: 36978874 Abstract Title:  Rosemary (L.) Glycolic Extract Protects Liver Mitochondria from Oxidative Damage and Prevents Acetaminophen-Induced Hepatotoxicity. Abstract:  L. (rosemary) is an aromatic culinary herb. Native to the Mediterranean region, it is currently cultivated worldwide. In addition to its use as a condiment in food preparation and in teas, rosemary has been widely employed in folk medicine and cosmetics. Several beneficial effects have been described for rosemary, including antimicrobial and antioxidant activities. Here, we investigated the mechanisms accounting for the antioxidant activity of the glycolic extract of() in isolated rat liver mitochondria (RLM) under oxidative stress conditions. We also investigated its protective effect against acetaminophen-induced hepatotoxicity in vivo. A crude extract was obtained by fractionated percolation, using propylene glycol as a solvent due to its polarity and cosmeceutical compatibility. The quantification of substances with recognized antioxidant action revealed the presence of phenols and flavonoids. Dereplication studies carried out through LC-MS/MS and GC-MS, supported by The Global Natural Product Social Molecular Networking (GNPS) platform, annotated several phenolic compounds, confirming the previous observation. In accordance,decreased the production of reactive oxygen species (ROS) elicited by Feor-BOOH and inhibited the lipid peroxidation of mitochondrial membranes in a concentration-dependent manner in RLM. Such an effect was also observed in liposomes as membrane models.also prevented the oxidation of mitochondrial protein thiol groups and reduced glutathione (GSH). In model systems,exhibited a potent scavenger activity toward 2,2'-diphenyl-1-picrylhydrazyl (DPPH) radicals and superoxide anions. It also demonstrated an Fechelating activity. Moreover,did not exhibit cytotoxicity or dissipate the mitochondrial membrane potential () in rat liver fibroblasts (BRL3A cells). To evaluate whether such antioxidant protective activity observed in vitro could also be achieved in vivo, a well-established model of hepatotoxicity induced by acute exposure to acetaminophen (AAP) was used. This model depletes GSH and promotes oxidative-stress-mediated tissue damage. The treatment of rats with 0.05%, administered intraperitoneally for four days, resulted in inhibition of AAP-induced lipid peroxidation of the liver and the prevention of hepatotoxicity, maintaining alanine and aspartate aminotransferase (ALT/AST) levels equal to those of the normal, non-treated rats. Together, these findings highlight the potent antioxidant activity of rosemary, which is able to protect mitochondria from oxidative damage in vitro, and effects such as the antioxidant and h...

PMID:  Food Funct. 2023 Apr 24 ;14(8):3849-3862. Epub 2023 Apr 24. PMID: 37013966 Abstract Title:  Carnosic acid protects against doxorubicin-induced cardiotoxicity through enhancing the Nrf2/HO-1 pathway. Abstract:  Doxorubicin (DOX) is used extensively in anticancer therapy, but its clinical application is limited due to its cardiotoxicity. Carnosic acid (CA) is a bioactive compound found in rosemary. It has been shown to reduce inflammation and reactive oxygen species. The purpose of this study was to investigate the potential cardioprotective effects of CA in response to DOX-induced cardiotoxicity. Here, C57BL/6 mice were administered an intraperitoneal injection of DOX (5 mg kg, ip) once a week for three consecutive weeks and treated with CA (40 mg kg, ig) for a three-week experimental period. Forstudy, neonatal rat ventricular cardiomyocytes were used to validate the protective effects of CA (20M) in response to DOX-induced cardiotoxicity. CA markedly suppressed oxidative stress, apoptosis, and pyroptosis responses in the mouse hearts, eventually improving cardiac function. CA showed its antioxidant effect by activating nuclear factor erythroid 2-related factor (Nrf2) and its downstream heme oxygenase-1 (HO-1); CA also reduced oxidative stress by lowering the MDA and lipid ROS levels and raising the SOD and GSH-px levels. Additionally, CA treatment significantly increased Bcl-2 and inhibited Bax and Caspase-3 cleavage in DOX-induced cardiotoxicity. Moreover, CA suppressed the NOD-like receptor protein 3 (NLRP3) pathway to mitigate pyroptosis, as evidenced by lowered caspase1, interleukin-18, and interleukin-1. Consistently, the transfection of Nrf2-siRNA eliminated the protective effects of CA on cardiomyocytes. Altogether, our findings demonstrated that CA inhibited NLRP3 inflammasomesactivating the Nrf2-related cytoprotective system and protected the heart from oxidative damage, apoptosis, and pyroptosis, implying that the use of CA could be a potential therapeutic strategy in the prevention of DOX-associated myocardiopathy.

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PMID:  Biomedicines. 2023 Mar 9 ;11(3). Epub 2023 Mar 9. PMID: 36979808 Abstract Title:  Carnosic Acid Ameliorates Indomethacin-Induced Gastric Ulceration in Rats by Alleviating Oxidative Stress and Inflammation. Abstract:  Nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin and indomethacin (IND) are the most commonly prescribed for inflammation or pain. However, widespread use causes several adverse effects, such as gastric ulcers, upper gastric system bleeding, and erosions. Carnosic acid (CA) is an important natural antioxidant found in rosemary (Rosmarinus essentials) and exhibits a protective effect by suppressing oxidative stress and inflammation. This study aimed to investigate the impact of CA on IND-induced gastric ulceration. Wistar male rats received CA (100 mg/kg) or esomeprazole (ESP) (20 mg/kg, standard drug) by oral gavage for 14 days, after that gastric ulceration was induced by oral administration of 100 mg/kg IND. CA pretreatment attenuated both gross morphological lesions and histopathological alterations. CA strongly reduced IND-induced oxidative stress, verified by a decrease in MDA (

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PMID:  Metabolites. 2023 Jan 16 ;13(1). Epub 2023 Jan 16. PMID: 36677061 Abstract Title:  Anti-and Anti-Inflammatory Potential ofMetabolites: In Vitro and In Silico Studies. Abstract:  Due to its rising antibiotic resistance and associated inflammations,poses a challenge in modern medicine., a member of the Lamiaceae family, is a promising medicinal herb. In this regard, a phytochemical screening followed by GC-MS and LC-MS was done to evaluate the chemical profile of the total ethanolic extract (TES) and the essential oil, respectively. The anti-and the anti-inflammatory activities were evaluated by a micro-well dilution technique and COX-2 inhibition assay. Potential anti-inhibitors were determined by an in silico study. The results revealed that the main metabolites were flavonoids, sterols, volatile oil, saponins, and carbohydrates. The LC-MS negative ionization mode demonstrated 12 compounds, while GC-MS showed 21 compounds. Carnosic acid (37.66%), epirosmanol (20.65%), carnosol1 (3.3%), and 12--methyl carnosol (6.15%) were predominated, while eucalyptol (50.04%) and camphor (17.75%) were dominant in LC-MS and GC-MS, respectively. TES exhibited the strongest anti-activity (3.9g/mL) asymptotic to clarithromycin (0.43g/mL), followed by the oil (15.63g/mL). Carnosic acid has the best-fitting energy to inhibit(-46.6769 Kcal/mol). TES showed the highest reduction in Cox-2 expression approaching celecoxib with IC= 1.70.27g/mL, followed by the oil with IC= 5.30.62g/mL. Our findings suggest thatmetabolites with anti-inflammatory capabilities could be useful inmanagement. Further in vivo studies are required to evaluate and assess its promising activity.

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PMID:  Life (Basel). 2022 Dec 29 ;13(1). Epub 2022 Dec 29. PMID: 36676050 Abstract Title:  ALS-L1023 fromAlleviates Liver Fibrosis in a Non-Alcoholic Fatty Liver Disease Model. Abstract:  ALS-L1023 is an ingredient extracted fromL. (Labiatae; lemon balm), which is known as a natural medicine that suppresses angiogenesis. Herein, we aimed to determine whether ALS-L1023 could alleviate liver fibrosis in the non-alcoholic fatty liver disease (NAFLD) model. C57BL/6 wild-type male mice (age, 6 weeks old) were fed a choline-deficient high-fat diet (CDHFD) for 10 weeks to induce NAFLD. For the next 10 weeks, two groups of mice received the test drug along with CDHFD. Two doses (a low dose, 800 mg/kg/day; and a high dose, 1200 mg/kg/day) of ALS-L1023 were selected and mixed with feed for administration. Obeticholic acid (OCA; 10 mg/kg/day) was used as the positive control. Biochemical analysis revealed that the ALS-L1023 low-dose group had significantly decreased alanine transaminase and aspartate transaminase. The area of fibrosis significantly decreased due to the administration of ALS-L1023, and the anti-fibrotic effect of ALS-L1023 was greater than that of OCA. RNA sequencing revealed that the responder group had lower expression of genes related to the hedgehog-signaling pathway than the non-responder group. ALS-L1023 may exert anti-fibrotic effects in the NAFLD model, suggesting that it may provide potential benefits for the treatment of liver fibrosis.

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PMID:  Nutr Metab Insights. 2023 ;16:11786388221146683. Epub 2023 Jan 12. PMID: 36655201 Abstract Title:  Antiviral Potential of Melissa officinalis L.: A Literature Review. Abstract:  The use of synthetic drugs has increased in recent years; however, herbal medicine is yet more trusted among a huge population worldwide; This could be due to minimal side effects, affordable prices, and traditional beliefs. Lemongrass () has been widely used for reducing stress and anxiety, increasing appetite and sleep, reducing pain, healing wounds, and treating poisonous insect bites and bee stings for a long time. Today, research has shown that this plant can also fight viruses including Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), Herpes Simplex Virus (HSV), and Human Immunodeficiency Virus (HIV) through various mechanisms such as inhibiting HSV-1 from binding to host cell, inhibiting HSV-1 replication during the post-adsorption or inhibiting main protease and spike protein of SARS-CoV-2, furthermore, be effective in treating related diseases. This Review investigated the antiviral properties ofand its effect on viral diseases. More in vitro and in vivo studies are needed to determineunderlying mechanism, and more randomized controlled trials should be done to identify its effect in humans. Also, due to the usefulness and lack of side effects, it can be used more as a complementary medicine.

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PMID:  Ann Nucl Med. 2023 Mar ;37(3):166-175. Epub 2022 Dec 5. PMID: 36469234 Abstract Title:  Melissa Officinalis L. aqueous extract pretreatment decreases methotrexate-induced hepatotoxicity at lower dose and increasesTc-phytate liver uptake, as a probe of liver toxicity assessment, in rats. Abstract:  OBJECTIVE: Hepatotoxicity remains amongst the restricting factors of Methotrexate (MTX)-associated cancer therapy, especially in high doses of chemo-drugs or prolonged treatment. Due to the known protective effects of Melissa officinalis (M. officinalis), the aqueous extract of this plant was evaluated to ameliorate MTX-associated hepatotoxicity in rats.METHODS: Adult female Wistar rats were received or not M. officinalis aqueous extract at doses of 100 mg/kg (for 14 and 24 consecutive days) and 2 g/kg (for 14 consecutive days) by gavage technique. MTX (20 mg/kg) was intraperitoneally injected on the 10th- and 20th-day post-M. officinalis treatment. 24 h after the last day of treatment,Tc-phytate was intravenously injected through the tail of rats. Animals were killed at 20 min after radiocolloid injection, and vital tissues including the liver and spleen were isolated, weighed, and their radioactivity was counted. As well,Tc-phytate scintigraphy and histopathology of the liver were performed for higher accuracy.RESULT: A significant increase in liver radioactivity was detected in M. officinalis+MTX receiving groups compared with the MTX rats which were more robust at a dose of 100 mg/kg for 14 days. Also, a significant reduction in liver radioactivity was evident with M. officinalis extract at a dose of 2 g/kg for 14 days in comparison with the control group, this reduction was not significant at the lower dose of 100 mg/kg. Gamma scintigraphy and histopathological examinations confirmed the hepatoprotective effect of M. officinalis vs MTX-induced liver injury in rats.CONCLUSION: In conclusion, we highlighted the liver uptake ofTc-phytate as a valuable method for assessment of liver toxicity and addressed that M. officinalis pretreatment (100 mg/kg for 14 days) ameliorates the MTX-associated hepatotoxicity in rats; however, M. officinalis itself induces liver toxicity at higher doses.

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PMID:  Arch Razi Inst. 2022 Aug ;77(4):1389-1395. Epub 2022 Aug 31. PMID: 36883161 Abstract Title:  Cytotoxic Effect of the Crude Alcoholic Extract of the Fruits ofon Human Hepatocyte Carcinoma (Hep-G2). Abstract:  Theis a perennial herbaceous plant belonging to the family. Several pharmacological investigations have been performed based on the medicinal application of. The anticancer and antidiabetic activities of fruit and seed extracts ofhave been studied. Newly developed anticancer/antitumor medications appear to have been developed based on the extracted chemicals fromdue to the high contents of cucurbitacins. The present study aimed to identify the cytotoxic effect of the crude alcoholic extract of plants ofon the growth of human hepatocyte carcinoma (Hep-G2). The results of the chemical (preliminary) examination of the extract indicated that the fruits contain most of the secondary metabolites including Flavonoids, Tannins, Sapiens, Resins, Amino acids, Glycosides, Terpenes, Alkaloids, and Flavonoids. The toxicological effect of the crude extract was investigated by using six half dilutions concentrations of 20,10,5,2.5,1.25, and 0.625g/m at three exposure periods of 24,48, and 72 h using MTT testing. The toxicological effect of the extract appeared for all six concentrations in the Hep-G2 cell line. The highest concentration of 20g/ml had the highest percentage inhibition rate with a significant difference (0.01) and reached 93.361.61 after 72 h of exposure. While the lowest concentration of 0.625g/ml was recorded rate of inhibition of 23.362.34 after 24 h of exposure. The findings of the present study concluded that theis one of the most promising medicinal plants which effectively treats cancer through its inhibitory effect and fatal toxicity on cancer cells.

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PMID:  Molecules. 2023 Feb 19 ;28(4). Epub 2023 Feb 19. PMID: 36838963 Abstract Title:  A Natural Glucan from Black Bean Inhibits Cancer Cell Proliferation via PI3K-Akt and MAPK Pathway. Abstract:  A natural-1,6-glucan named BBWPW was identified from black beans. Cell viability assay showed that BBWPW inhibited the proliferation of different cancer cells, especially HeLa cells. Flow cytometry analysis indicated that BBWPW suppressed the HeLa cell cycle in the G2/M phase. Consistently, RT-PCR experiments displayed that BBWPW significantly impacts the expression of four marker genes related to the G2/M phase, including,,, and. To explore the molecular mechanism of BBWPW to induce cell cycle arrest, a transcriptome-based target inference approach was utilized to predict the potential upstream pathways of BBWPW and it was found that the PI3K-Akt and MAPK signal pathways had the potential to mediate the effects of BBWPW on the cell cycle. Further experimental tests confirmed that BBWPW increased the expression ofandand decreased the expression ofandThese results suggested that BBWPW could regulate the PI3K-Akt and MAPK pathways to induce cell cycle arrest and ultimately inhibit the proliferation of HeLa cells, providing the potential of the black bean glucan to be a natural anticancer drug.

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PMID:  Biol Pharm Bull. 2023 ;46(4):630-635. PMID: 37005308 Abstract Title:  Apigenin Alleviates Endoplasmic Reticulum Stress-Mediated Apoptosis in INS-1-Cells. Abstract:  The improvement of type 2 diabetes mellitus induced by naturally occurring polyphenols, known as flavonoids, has received considerable attention. However, there is a dearth of information regarding the effect of the trihydroxyflavone apigenin on pancreatic-cell function. In the present study, the anti-diabetic effect of apigenin on pancreatic-cell insulin secretion, apoptosis, and the mechanism underlying its anti-diabetic effects, were investigated in the INS-ID-cell line. The results showed that apigenin concentration-dependently facilitated 11.1-mM glucose-induced insulin secretion, which peaked at 30M. Apigenin also concentration-dependently inhibited the expression of endoplasmic reticulum (ER) stress signaling proteins, CCAAT/enhancer binding protein (C/EBP) homologous protein (CHOP) and cleaved caspase-3, which was elevated by thapsigargin in INS-1D cells, with peak suppression at 30M. This was strongly correlated with the results of flow cytometric analysis of annexin V/propidium iodide (PI) staining and DNA fragmentation analysis. Moreover, the increased expression of thioredoxin-interacting protein (TXNIP) induced by thapsigargin was remarkably reduced by apigenin in a concentration-dependent manner. These results suggest that apigenin is an attractive candidate with remarkable and potent anti-diabetic effects on-cells, which are mediated by facilitating glucose-stimulated insulin secretion and preventing ER stress-mediated-cell apoptosis, the latter of which may be possibly mediated by reduced expression of CHOP and TXNIP, thereby promoting-cell survival and function.

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PMID:  Ann Agric Environ Med. 2023 Mar 31 ;30(1):61-64. Epub 2023 Feb 27. PMID: 36999857 Abstract Title:  Antimicrobial synergistic effects of apigenin, (-)-epigallocatechin-3-gallate, myricetin and luteolin in combination with some antibiotics. Abstract:  INTRODUCTION AND OBJECTIVE: Antimicrobial resistance, which is considered one of the most important problems of the 21 st century, brings many problems with it, such as increasing mortality rates and treatment costs. Difficulties in the treatment of infections caused by resistant microorganisms have led to the search and need for new antimicrobials or new molecules that interact synergistically with antimicrobials. The aim of this study is to investigate whether various flavonoids have synergistic effects with some antibiotics.MATERIAL AND METHODS: During this study, standard bacterial strainsATCC 25922,ATCC 700603,ATCC 9027,ATCC 29213 andATCC 43300 were used. Minimal inhibitory concentrations of all antibiotics and flavonoids were found by the broth microdilution method. Interactions between antibiotics and flavonoids were then determined by using the checkerboard method. Interactions between antibiotics and flavonoids were evaluated according to the FIC index (FIC) results.RESULTS: According to the results of the microdilution test, the bacterial strains used in this study (except for MRSA) were generally sensitive to antibiotics. Interaction study results showed promising results regarding the synergistic interactions of antibiotics with flavonoids. Epigallocatechin gallate and luteolin especially showed synergistic interaction with antibiotics in many microorganisms. It was found that myricetin showed synergistic interaction only with levofloxacin. Likewise, it was detected that apigenin had limited synergistic interaction with antibiotics.CONCLUSIONS: The obtained results highlight that flavonoids may be a useful tool in overcoming antibiotic resistance.

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PMID:  Toxicol Appl Pharmacol. 2023 May 1 ;466:116478. Epub 2023 Mar 20. PMID: 36940862 Abstract Title:  Kaempferol ameliorates pulmonary vascular remodeling in chronic hypoxia-induced pulmonary hypertension rats via regulating Akt-GSK3-cyclin axis. Abstract:  Excessive proliferation of pulmonary artery smooth muscle cells (PASMCs) is considered a major contributor to elevated pulmonary vascular resistance and a key mechanism of vascular remodeling in hypoxia-induced pulmonary hypertension (HPH). Kaempferol is a natural flavonoid compound and can be derived from numerous common medicinal herbs and vegetables, which exhibit antiproliferative and proapoptotic properties, however, the effects of kaempferol on vascular remodeling in HPH remain unexplored. In this study, SD rats were placed in a hypobaric hypoxia chamber for four weeks to establish a pulmonary hypertension model and given either kaempferol or sildenafil (an inhibitor of PDE-5) during days 1-28, after which the hemodynamic parameter and pulmonary vascular morphometry were assessed. Furthermore, primary rat PASMCs were exposed to hypoxic conditions to generate a cell proliferation model, then incubated with either kaempferol or LY294002 (an inhibitor of PI3K). Immunoblotting and real-time quantitative PCR assessed the protein and mRNA expression levels in HPH rat lungs and PASMCs. We found that kaempferol reduced pulmonary artery pressure and pulmonary vascular remodeling, and alleviated right ventricular hypertrophy in HPH rats. The mechanistic analysis demonstrated that kaempferol reduced the protein levels of phosphorylation of Akt and GSK3, leading to decreased expression of pro-proliferation (CDK2, CDK4, Cyclin D1, and PCNA) and anti-apoptotic related proteins (Bcl-2) and increased expression of pro-apoptosis proteins (Bax and cleaved caspase 3). These results collectively demonstrate that kaempferol ameliorates HPH in rats by inhibiting PASMC proliferation and pro-apoptosis via modulation of the Akt/GSK3/CyclinD axis.

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PMID:  Cell Signal. 2023 Jul ;107:110667. Epub 2023 Apr 5. PMID: 37023996 Abstract Title:  Quercetin modulates signal transductions and targets non-coding RNAs against cancer development. Abstract:  In recent decades, various investigations have indicated that natural compounds have great potential in the prevention and treatment of different chronic disorders including different types of cancer. As a bioactive flavonoid, Quercetin (Qu) is a dietary ingredient enjoying high pharmacological values and health-promoting effects due to its antioxidant and anti-inflammatory characterization. Conclusive in vitro and in vivo evidence has revealed that Qu has great potential in cancer prevention and development. Qu exerts its anticancer influences by altering various cellular processes such as apoptosis, autophagy, angiogenesis, metastasis, cell cycle, and proliferation. In this way, Qu by targeting numerous signaling pathways as well as non-coding RNAs regulates several cellular mechanisms to suppress cancer occurrence and promotion. This review aimed to summarize the impact of Qu on the molecular pathways and non-coding RNAs in modulating various cancer-associated cellular mechanisms.

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PMID:  Eur Rev Med Pharmacol Sci. 2023 Mar ;27(6):2580-2590. PMID: 37013776 Abstract Title:  Quercetin downregulates the expression of IL15 in cancer cells through DNA methylation. Abstract:  OBJECTIVE: This study aimed to investigate the effect of quercetin on cellular immunity (via IL15 expression) against cancer and to elucidate its regulatory mechanism.MATERIALS AND METHODS: HeLa cells and A549 cells were cultured in vitro and were divided into control (DMSO treated) and experimental groups (treated with different concentrations of quercetin). Transcript levels of IL15 and DNA methyltransferase (DNMTS) were measured using quantitative reverse transcription polymerase chain reaction (qRT-PCR). Genomic DNA was extracted, treated with bisulfite, and the promoter region of IL15 was cloned. Finally, Sanger sequencing was used to detect the degree of promoter methylation.RESULTS: Following quercetin treatment, the expression of IL15 was significantly downregulated in HeLa and A549 cells. The methylation level of IL15 promoter in HeLa cells was about twice that of the control group, and the methylation level of IL15 promoter in A549 cells was about three times that of the control group.CONCLUSIONS: Quercetin inhibits cancer cell proliferation while downregulating IL15 expression, and this regulation is achieved by increasing the methylation of the IL15 promoter.

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PMID:  Front Biosci (Landmark Ed). 2023 Mar 2 ;28(3):42. PMID: 37005755 Abstract Title:  Protective Effects of Querectin against MPP-Induced Dopaminergic Neurons Injury via the Nrf2 Signaling Pathway. Abstract:  BACKGROUND: Parkinson's disease (PD) is a common selective and progressive neurodegenerative disorder of nigrostriatal dopaminergic (DA) neurons. Quercetin is a bioflavonoid with antioxidant, anti-inflammatory, anti-aging and anti-cancer properties. However, the exact mechanism by which quercetin exerts its protective effect on DAergic neurons remains unclear.PURPOSE: To investigate the underlying molecular mechanism of quercetin's protective effect on DA neurons using 1-methyl-4-phenylpyridinium (MPP+)-induced PD ferroptosis model.METHODS: MPP+ was used to induce cytotoxicity in SH-SY5Y/primary neurons. Cell viability and apoptosis were assessed by CCK-8 assay and flow cytometry. The expression levels of ferroptosis-related proteins (NCOA4, SLC7A11, Nrf2, and GPX4) were determined by Western blotting. Malondialdehyde (MDA), iron, and GPX4 levels were assesed using corresponding assay kits. Lipid peroxidation was assessed by C11-BODIPY staining.RESULTS: In the MPP+-induced ferroptosis model of SH-SY5Y cells, the expressions of SLC7A11 and GPX4 were inhibited, and the expression of NCOA4 protein was increased, causing the overproduction of MDA and lipid peroxidation. Quercetin can reduce the above changes caused by MPP+, that is, reduce the protein expression of NCOA4 in SH-SY5Y cells, increase SLC7A11 and GPX4 partially inhibited by MPP+, and reduce MDA overproduction and lipid peroxidation to protect DA neurons. Nrf2 inhibitor ML385 could inhibit quercetin-induced increase of GPX4 and SLC7A11 protein expression, indicating that the protective effect of quercetin was mediated through Nrf2.CONCLUSIONS: The results of this study suggest that quercetin regulates ferroptosis through Nrf2-dependent signaling pathways, thereby inhibiting MPP+-induced neurotoxicity in SH-SY5Y/primary neurons.

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PMID:  Curr Pharm Des. 2023 ;29(11):883-891. PMID: 37005541 Abstract Title:  and Molecular Docking Analysis of Quercetin as an Anti-inflammatory and Antioxidant. Abstract:  INTRODUCTION: Quercetin (3,3',4',5,7-pentahydroxyflavone) is a dietary flavonoid with good antioxidant and anti-inflammatory properties.AIMS: The present study aims to determine these effects in peripheral blood mononuclear cells (PBMCs) evoked by lipopolysaccharides (LPS).METHODS: The mRNA expression and protein secretion of inflammatory mediators were evaluated by enzyme- linked immunosorbent assay (ELISA) and quantitative real-time polymerase chain reaction (PCR), respectively. Western blotting was utilized for assessing p65-NF-B phosphorylation. Ransod kits evaluated the glutathione peroxidase (GPx) and superoxide dismutase (SOD) activity in the cell lysates. Ultimately, the molecular docking approach was performed to investigate the biological activity of Quercetin against NF-B pathway proteins and antioxidant enzymes.RESULTS: The findings revealed that quercetin significantly attenuated the expression and secretion of inflammatory mediators and p65-NF-B phosphorylation in LPS-induced PBMCs. Additionally, quercetin dose-dependently improved the activities of SOD and GPx enzymes and decreased LPS-mediated oxidative stress in PBMCs. Moreover, quercetin has a considerable binding affinity to IKb, the core element of the NF-B pathway and the antioxidant enzyme SOD.CONCLUSION: The data show that quercetin plays a vital role in ameliorating inflammation and oxidative stress caused by LPS in PBMCs.

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PMID:  Pharmaceutics. 2023 Mar 16 ;15(3). Epub 2023 Mar 16. PMID: 36986827 Abstract Title:  Quercetin and Its Nano-Formulations for Brain Tumor Therapy-Current Developments and Future Perspectives for Paediatric Studies. Abstract:  The development of efficient treatments for tumors affecting the central nervous system (CNS) remains an open challenge. Particularly, gliomas are the most malignant and lethal form of brain tumors in adults, causing death in patients just over 6 months after diagnosis without treatment. The current treatment protocol consists of surgery, followed using synthetic drugs and radiation. However, the efficacy of these protocols is associated with side effects, poor prognosis and with a median survival of fewer than two years. Recently, many studies were focused on applying plant-derived products to manage various diseases, including brain cancers. Quercetin is a bioactive compound derived from various fruits and vegetables (asparagus, apples, berries, cherries, onions and red leaf lettuce). Numerous in vivo and in vitro studies highlighted that quercetin through multitargeted molecular mechanisms (apoptosis, necrosis, anti-proliferative activity and suppression of tumor invasion and migration) effectively reduces the progression of tumor cells. This review aims to summarize current developments and recent advances of quercetin's anticancer potential in brain tumors. Since all reported studies demonstrating the anti-cancer potential of quercetin were conducted using adult models, it is suggested to expand further research in the field of paediatrics. This could offer new perspectives on brain cancer treatment for paediatric patients.

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PMID:  Int J Mol Sci. 2023 Mar 15 ;24(6). Epub 2023 Mar 15. PMID: 36982678 Abstract Title:  Quercetin and Its Fermented Extract as a Potential Inhibitor of Bisphenol A-Exposed HT-29 Colon Cancer Cells' Viability. Abstract:  Bisphenol A (BPA) promotes colon cancer by altering the physiological functions of hormones. Quercetin (Q) can regulate signaling pathways through hormone receptors, inhibiting cancer cells. The antiproliferative effects of Q and its fermented extract (FEQ, obtained by Q gastrointestinal digestion and in vitro colonic fermentation) were analyzed in HT-29 cells exposed to BPA. Polyphenols were quantified in FEQ by HPLC and their antioxidant capacity by DPPH and ORAC. Q and 3,4-dihydroxyphenylacetic acid (DOPAC) were quantified in FEQ. Q and FEQ exhibited antioxidant capacity. Cell viability with Q+BPA and FEQ+BPA was 60% and 50%, respectively; less than 20% of dead cells were associated with the necrosis process (LDH). Treatments with Q and Q+BPA induced cell cycle arrest in the G0/G1 phase, and FEQ and FEQ+BPA in the S phase. Compared with other treatments, Q positively modulatedandgenes. Using a gene microarray of thepathway, Q, Q+BPA, FEQ and FEQ+BPA positively modulated genes involved in apoptosis and cell cycle arrest; bisphenol inhibited the expression of pro-apoptotic and cell cycle repressor genes. In silico analyses demonstrated the binding affinity of Q>BPA>DOPAC molecules for ERand ER. Further studies are needed to understand the role of disruptors in colon cancer.

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PMID:  Int J Mol Sci. 2023 Mar 14 ;24(6). Epub 2023 Mar 14. PMID: 36982615 Abstract Title:  Quercetin Reprograms Immunometabolism of Macrophages via the SIRT1/PGC-1Signaling Pathway to Ameliorate Lipopolysaccharide-Induced Oxidative Damage. Abstract:  The redox system is closely related to changes in cellular metabolism. Regulating immune cell metabolism and preventing abnormal activation by adding antioxidants may become an effective treatment for oxidative stress and inflammation-related diseases. Quercetin is a naturally sourced flavonoid with anti-inflammatory and antioxidant activities. However, whether quercetin can inhibit LPS-induced oxidative stress in inflammatory macrophages by affecting immunometabolism has been rarely reported. Therefore, the present study combined cell biology and molecular biology methods to investigate the antioxidant effect and mechanism of quercetin in LPS-induced inflammatory macrophages at the RNA and protein levels. Firstly, quercetin was found to attenuate the effect of LPS on macrophage proliferation and reduce LPS-induced cell proliferation and pseudopodia formation by inhibiting cell differentiation, as measured by cell activity and proliferation. Subsequently, through the detection of intracellular reactive oxygen species (ROS) levels, mRNA expression of pro-inflammatory factors and antioxidant enzyme activity, it was found that quercetin can improve the antioxidant enzyme activity of inflammatory macrophages and inhibit their ROS production and overexpression of inflammatory factors. In addition, the results of mitochondrial morphology and mitochondrial function assays showed that quercetin could upregulate the mitochondrial membrane potential, ATP production and ATP synthase content decrease induced by LPS, and reverse the mitochondrial morphology damage to a certain extent. Finally, Western blotting analysis demonstrated that quercetin significantly upregulated the protein expressions of SIRT1 and PGC-1, that were inhibited by LPS. And the inhibitory effects of quercetin on LPS-induced ROS production in macrophages and the protective effects on mitochondrial morphology and membrane potential were significantly decreased by the addition of SIRT1 inhibitors. These results suggested that quercetin reprograms the mitochondria metabolism of macrophages through the SIRT1/PGC-1signaling pathway, thereby exerting its effect of alleviating LPS-induced oxidative stress damage.

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PMID:  Toxics. 2023 Mar 1 ;11(3). Epub 2023 Mar 1. PMID: 36977005 Abstract Title:  Hypoglycemic Potential ofin Liver Is Mediated through IRS-2/PI3K/SREBP-1c/GLUT2 Signaling in High-Fat-Diet-Induced Type-2 Diabetic Male Rats. Abstract:  Regardless of socioeconomic or demographic background, the prevalence of type 2 diabetes mellitus, which affects more than half a billion people worldwide, has been steadily increasing over time. The health, emotional, sociological, and economic well-being of people would suffer if this number is not successfully handled. The liver is one of the key organs accountable for sustaining metabolic balance. Elevated levels of reactive oxygen species inhibit the recruitment and activation of IRS-1, IRS-2, and PI3K-Akt downstream signaling cascade. These signaling mechanisms reduce hepatic glucose absorption and glycogenesis while increasing hepatic glucose output and glycogenolysis. In our work, an analysis of the molecular mechanism ofin mitigating hepatic insulin resistance in vivo and in silico was carried out. The gluconeogenic enzymes, glycolytic enzymes, hepatic glycogen tissue concentration, oxidative stress markers, enzymatic antioxidants, protein expression of IRS-2, PI3K, SREBP-1C, and GLUT-2 were evaluated in the liver tissues of high-fat-diet streptozotocin-induced type 2 diabetic rats using q-RT-PCR as well as immunohistochemistry and histopathology. Upon treatment,restored the protein and gene expression in the liver. In the docking analysis, quercetin, kaempferol, caffeic acid, and p-coumaric acid present in the extract were found to have high binding affinities against IRS-2, PI3K, SREBP-1c, and GLUT-2, which may have contributed much to the antidiabetic property of. Thus,was capable of restoring the altered levels in the hepatic tissues of T2DM rats, reversing hepatic insulin resistance.

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PMID:  Appl Biochem Biotechnol. 2023 Mar 29. Epub 2023 Mar 29. PMID: 36988843 Abstract Title:  Discovery of Potential Phytochemicals from Carica papaya Targeting BRCA-1 in Breast Cancer Treatment. Abstract:  The BRCA1 and BRCA2 are genes that encode a protein that ensures the integrity of DNA and prevents the unregulated cells from proliferating. Mutations in the sequence of these genes are associated with the birth of inherited breast cancers. The research for possible human breast cancer treatment remains a vital step in the drug development process. In this study, in silico investigations involving a computational method for the discovery of active phytochemicals from Carica papaya against the BRCA-1 gene were carried out. The in silico studies for these phytochemicals datasets as BRCA-1 breast cancer therapeutic agents showed promising results through pharmacokinetics and pharmacodynamics studies. The Carica papaya compounds were found to follow the rule of five and have good bioavailability. The ADMET and drug-likeness screening score of the identified ligands also recognized their potential as a promising drug candidate against BRCA-1 while the DFT also confirm better biological and chemical reactivity of Carica papaya compounds with excellent intra-molecular charge transfer between electron donor and electron acceptor site. The results of the molecular docking provided useful information on possible target-lead interactions, demonstrating that the newly developed leads showed a high affinity for BRCA-1 targets and might be investigated for further research.

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PMID:  Asian Pac J Cancer Prev. 2023 Feb 1 ;24(2):581-586. Epub 2023 Feb 1. PMID: 36853308 Abstract Title:  Cytotoxic Activity of the Ethyl Acetate Extract of Iraqi Carica papaya Leaves in Breast and Lung Cancer Cell Lines. Abstract:  UNLABELLED: The aim of this study was to evaluate the cytotoxic effect of the ethyl acetate fraction of Iraqi Carica papaya (C. papaya) in breast and lung cancer cell lines, MCF-7 and A549, respectively.METHODS: The ethyl acetate extract of Iraqi C. papaya leaves was prepared and tested for its phytochemical constitution. The 3-(4,5-dimethylthiazoline-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was performed in breast (MCF-7) and lung (A549) cells lines that were treated with different concentrations of ethyl acetate extract (3.125,6.25,12.5, 25, 50, and 100g/ml). After 72 hrs of treatment, cell viability was evaluated.RESULTS: The ethyl acetate extract of C. papaya showed considerable cytotoxic activity in the MCF-7 and A549 cell lines. The activity was dose-dependent; The half-maximum inhibitory concentration (IC50) values were 22.74g/ml and 8.674g/ml in the MCF-7 and A549 cell lines, respectively.CONCLUSION: The ethyl acetate fraction of Iraqi C. papaya leaves has potential anticancer activity in lung and breast cancer.

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Newly-obtained documents reveal.

Originally published on www.reclaimthenet.org by Cindy Harper

In a sharp spotlight on the interplay between national security and individual privacy, newly disclosed documents have unveiled that the Department of Homeland Security (DHS) entered into a contract with the University of Alabama at Birmingham (UAB) in 2018 to develop a project, dubbed "Night Fury," designed to analyze and assign "risk scores" to social media accounts.

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PMID:  Front Pharmacol. 2023 ;14:1092475. Epub 2023 Mar 24. PMID: 37033627 Abstract Title:  Astragaloside IV alleviates 1-deoxysphinganine-induced mitochondrial dysfunction during the progression of chronic kidney disease through p62-Nrf2 antioxidant pathway. Abstract:  Chronic kidney disease (CKD) can lead to significant elevation of 1-deoxysphingolipids (1-deoxySL). The increase of 1-deoxySL in turn can result in mitochondrial damage and oxidative stress, which can cause further progression of CKD.This study assessed the therapeutic effect of Astragaloside IV (AST) against 1-deoxySL-induced cytotoxicityand in rats with CKD. HK-2 cells were exposed to 1-deoxysphinganine (doxSA) or doxSA + AST. doxSA-induced mitochondrial dysfunction and oxidative stress were evaluated by immunostaining, real-time PCR, oxidative stress sensor, and transmission electron microscopy. The potential effects of AST on kidney damage were evaluated in a rat 5/6 nephrectomy (5/6 Nx) model of CKD.The findings ofexperiments showed that doxSA induced mitochondrial damage, oxidative stress, and apoptosis. AST markedly reduced the level of mitochondrial reactive oxygen species, lowered apoptosis, and improved mitochondrial function. In addition, exposure to AST significantly induced the phosphorylation of p62 and the nuclear translocation of Nrf2 as well as its downstream anti-oxidant genes. p62 knock-down fully abolished Nrf2 nuclear translocation in cells after AST treatment. However, p62 knock-down did not affect TBHQ-induced Nrf2 nuclear translocation, indicating that AST can ameliorate doxSA-induced oxidative stress through modulation of p62 phosphorylation and Nrf2 nuclear translocation.The findings indicate that AST can activate Nrf2 antioxidant pathway in a p62 dependent manner. The anti-oxidative stress effect and the further mitochondrial protective effect of AST represent a promising therapeutic strategy for the progression of CKD.

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PMID:  Free Radic Biol Med. 2023 Jul ;203:45-57. Epub 2023 Apr 6. PMID: 37030337 Abstract Title:  Astragaloside IV attenuates podocyte apoptosis through ameliorating mitochondrial dysfunction by up-regulated Nrf2-ARE/TFAM signaling in diabetic kidney disease. Abstract:  Defective antioxidant system as well as mitochondrial dysfunction contributes to the pathogenesis and progression of diabetic kidney disease (DKD). Nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated signaling is the central defensive mechanism against oxidative stress and therefore pharmacological activation of Nrf2 is a promising therapeutic strategy. In this study, using molecular docking we found that Astragaloside IV (AS-IV), an active ingredient from traditional formula of Huangqi decoction (HQD), exerted a higher potential to promote Nrf2 escape from Keap1-Nrf2 interaction via competitively bind to amino acid sites in Keap1. When podocyte exposed to high glucose (HG) stimulation, mitochondrial morphological alterations and podocyte apoptosis were presented and accompanied by Nrf2 and mitochondrial transcription factor A (TFAM) downregulation. Mechanistically, HG promoted a decrease in mitochondria-specific electron transport chain (ETC) complexes, ATP synthesis and mtDNA content as well as increased ROS production. Conversely, all these mitochondrial defects were dramatically alleviated by AS-IV, but suppression of Nrf2 with inhibitor or siRNA and TFAM siRNA simultaneously alleviated the AS-IV efficacy. Moreover, experimental diabetic mice exhibited significant renal injury as well as mitochondrial disorder, corresponding with the decreased expression of Nrf2 and TFAM. On the contrary, AS-IV reversed the abnormality and the Nrf2 and TFAM expression were also restored. Taken together, the present findings demonstrate the improvement of AS-IV on mitochondrial function, thereby resistance to oxidative stress-induced diabetic kidney injury and podocyte apoptosis, and the process is closely associated with activation of Nrf2-ARE/TFAM signaling.

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PMID:  Phytomedicine. 2023 Jun ;114:154795. Epub 2023 Mar 29. PMID: 37030053 Abstract Title:  Astragaloside IV targets PRDX6, inhibits the activation of RAC subunit in NADPH oxidase 2 for oxidative damage. Abstract:  BACKGROUND: Radix Astragali Mongolici, as a traditional Chinese medicine, is widely used in the treatment of qi deficiency, viral or bacterial infection, inflammation and cancer. Astragaloside IV (AST), a key active compound in Radix Astragali Mongolici, has been shown to reduce disease progression by inhibiting oxidative stress and inflammation. However, the specific target and mechanism of action of AST in improving oxidative stress are still unclear.PURPOSE: This study aims to explore the target and mechanism of AST to improve oxidative stress, and to explain the biological process of oxidative stress.METHODS: AST functional probes were designed to capture target proteins and combined with protein spectrum to analyze target proteins. Small molecule and protein interaction technologies were used to verify the mode of action, while computer dynamics simulation technology was used to analyze the site of interaction with the target protein. The pharmacological activity of AST in improving oxidative stress was evaluated in a mouse model of acute lung injury induced by LPS. Additionally, pharmacological and serial molecular biological approaches were used to explore the underlying mechanism of action.RESULTS: AST inhibits PLA2 activity in PRDX6 by targeting the PLA2 catalytic triad pocket. This binding alters the conformation and structural stability of PRDX6 and interferes with the interaction between PRDX6 and RAC, hindering the activation of the RAC-GDI heterodimer. Inactivation of RAC prevents NOX2 maturation, attenuates superoxide anion production, and improves oxidative stress damage.CONCLUSION: The findings of this research indicate that AST impedes PLA2 activity by acting on the catalytic triad of PRDX6. This, in turn, disrupts the interaction between PRDX6 and RAC, thereby hindering the maturation of NOX2 and diminishing the oxidative stress damage.

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PMID:  Acta Cir Bras. 2023 ;38:e380723. Epub 2023 Mar 24. PMID: 36995819 Abstract Title:  Astragaloside IV alleviates stroke-triggered early brain injury by modulating neuroinflammation and ferroptosis via the Nrf2/HO-1 signaling pathway. Abstract:  PURPOSE: Stroke is an acute cerebrovascular disease. Astragaloside IV (AS-IV) is an active ingredient extracted from Astragalus membranaceus with an established therapeutic effect on central nervous system diseases. This study examined the neuroprotective properties and possible mechanisms of AS-IV in stroke-triggered early brain injury (EBI) in a rat transient middle cerebral artery occlusion (MCAO) model.METHODS: The neurological scores and brain water content were analyzed. 2,3,5-triphenyl tetrazolium chloride (TTC) staining was utilized to determine the infarct volume, neuroinflammatory cytokine levels, and ferroptosis-related genes and proteins, and neuronal damage and molecular mechanisms were evaluated by terminal deoxynucleotidyl transferase dutp nick-end labeling (TUNEL) staining, western blotting, and real-time polymerase chain reaction.RESULTS: AS-IV administration decreased the infarct volume, brain edema, neurological deficits, and inflammatory cytokines TNF-, interleukin-1(IL-1), IL-6, and NF-B, increased the levels of SLC7A11 and glutathione peroxidase 4 (GPX4), decreased lipid reactive oxygen species (ROS) levels, and prevented neuronal ferroptosis. Meanwhile, AS-IV triggered the Nrf2/HO-1 signaling pathway and alleviated ferroptosis due to the induction of stroke.CONCLUSIONS: Hence, the findings of this research illustrate that AS-IV administration can improve delayed ischemic neurological deficits and decrease neuronal death by modulating nuroinflammation and ferroptosis via the Nrf2/HO-1 signaling pathway.

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PMID:  Biotechnol Genet Eng Rev. 2023 Mar 27:1-18. Epub 2023 Mar 27. PMID: 36971224 Abstract Title:  Astragaloside IV induces the protective effect of bone marrow mesenchymal stem cells derived exosomes in acute myocardial infarction by inducing angiogenesis and inhibiting apoptosis. Abstract:  Bone marrow mesenchymal stem cells (BMECs)-derived exosomes (MSC-Exo) can improve acute myocardial infarction (AMI). Astragaloside IV (AS-IV) has also been reported to have cardioprotective pharmacological effects. However, it is not entirely clear whether AS-IV can improve AMI by inducing MSC-Exo. BMSCs and MSC-Exo were isolated and identified, and we also established the AMI rat model and the OGD/R model with H9c2 cells. After MSC-Exo or AS-IV-mediated MSC-Exo treatment, cell angiogenesis, migration, and apoptosis were evaluated by tube formation, wound healing, and TUNEL staining. The cardiac function of the rats was measured by echocardiography. The pathological changes and collagen deposition in rats were also assessed with Masson and Sirius red staining. The levels of-SMA, CD31 and inflammatory factors were determined by immunohistochemistry and enzyme-linked immunosorbent assay (ELISA)., AS-IV-mediated MSC-Exo can significantly enhance the angiogenesis and migration of H9c2 cells induced by OGD/R, and significantly reduce their apoptosis., AS-IV-mediated MSC-Exo can improve the cardiac function of rats, and attenuate pathological damage and collagen deposition in AMI model rats. In addition, AS-IV-mediated MSC-Exo can also promote angiogenesis and reduce inflammatory factors in rats with AMI. AS-IV-stimulated MSC-Exo can improve myocardial contractile function, myocardial fibrosis and angiogenesis, reduce inflammatory factors and induce apoptosis in rats after AMI.

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PMID:  Nutrients. 2023 Mar 10 ;15(6). Epub 2023 Mar 10. PMID: 36986081 Abstract Title:  Palmitoylethanolamide in the Treatment of Chronic Pain: A Systematic Review and Meta-Analysis of Double-Blind Randomized Controlled Trials. Abstract:  Chronic pain is a major source of morbidity for which there are limited effective treatments. Palmitoylethanolamide (PEA), a naturally occurring fatty acid amide, has demonstrated utility in the treatment of neuropathic and inflammatory pain. Emerging reports have supported a possible role for its use in the treatment of chronic pain, although this remains controversial. We undertook a systematic review and meta-analysis to examine the efficacy of PEA as an analgesic agent for chronic pain. A systematic literature search was performed, using the databases MEDLINE and Web of Science, to identify double-blind randomized controlled trials comparing PEA to placebo or active comparators in the treatment of chronic pain. All articles were independently screened by two reviewers. The primary outcome was pain intensity scores, for which a meta-analysis was undertaken using a random effects statistical model. Secondary outcomes including quality of life, functional status, and side effects are represented in a narrative synthesis. Our literature search identified 253 unique articles, of which 11 were ultimately included in the narrative synthesis and meta-analysis. Collectively, these articles described a combined sample size of 774 patients. PEA was found to reduce pain scores relative to comparators in a pooled estimate, with a standard mean difference of 1.68 (95% CI 1.05 to 2.31,= 0.00001). Several studies reported additional benefits of PEA for quality of life and functional status, and no major side effects were attributed to PEA in any study. The results of this systematic review and meta-analysis suggest that PEA is an effective and well-tolerated treatment for chronic pain. Further study is warranted to determine the optimal dosing and administration parameters of PEA for analgesic effects in the context of chronic pain.

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PMID:  Neuropsychologia. 2023 Jun 6 ;184:108544. Epub 2023 Mar 21. PMID: 36948452 Abstract Title:  Acetaminophen changes Mu rhythm power related to pain empathy. Abstract:  Empathy is an intricate ability that entails the subjective feeling and understanding of emotions someone else may be experiencing. Acetaminophen, the active ingredient found in Tylenol, is among the most common pain medications consumed. There is new evidence, however, that suggests this common analgesic may also dampen empathic processes. However, no previous study has investigated the effect acetaminophen may have on pain empathy or mu power during a pain empathy task. Therefore, participants were randomly assigned to either an experimental (acetaminophen) or control (sugar) group in a double-blinded experimental research design aimed to measure mu power, using EEG, and behavioral responses to painful and non-painful images. Participants in the experimental group were administered 1000 mg of acetaminophen, and it was verified that participants were unaware of their group assignment. We found that mu suppression was greater in the acetaminophen group, which was strongest at electrode C3. Additionally, mu power differences between painful and non-painful images were related to trait empathy, and mu power during the painful images were positively correlated with empathy scores. Results from this study suggest that in addition to reducing physical pain, acetaminophen may also change the neural response when perceiving others in pain. The implications of these findings could possibly lead to changes in how we prescribe and administer this common drug.

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PMID:  Anal Cell Pathol (Amst). 2023 ;2023:1714884. Epub 2023 Apr 4. PMID: 37056637 Abstract Title:  Comparative Effect of the Active Substance of Thyme with N-Acetyl Cysteine on Hematological Parameters and Histopathological Changes of Bone Marrow and Liver in Rat Models of Acetaminophen Toxicity. Abstract:  Acetaminophen has always been at the center of attention as a non-steroidal anti-inflammatory drug, which is generally associated with the serious side effects on liver and the hematological parameters. This study aimed to compare the effect of N-acetyl cysteine (NAC) and thyme extract on rat models of acetaminophen-induced toxicity. The present experimental study was conducted on 48 Wistar rats randomized into six groups, including the control group (no treatment); the Ac group (470 mg/kg of acetaminophen); the Ac+100Ex, Ac+200Ex, and Ac+400Ex groups (acetaminophen+thyme extract at doses of 100, 200, 400mg/kg); and Ac+NA group (acetaminophen+NAC). After weighing, a blood sample was taken from heart at the end of the period. The measured parameters were hematological, liver biochemical, and oxidative stress profiles. A part of the liver tissue was also fixed for the pathological examinations. The bone marrow was aspirated to check for cellular changes as well. The lowest mean of the final weight and liver weight to body weight ratio was observed in the Ac group. Weight loss was compensated in Ac+NA and Ac+200Ex groups (= 0.035). White blood cell (WBC), red blood cell (RBC), Hemoglobin (Hgb), and Hematocrit (HCT) in Ac and Ac+400Ex groups showed significant differences from those of the other test groups (

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PMID:  Front Pharmacol. 2023 ;14:1122632. Epub 2023 Mar 27. PMID: 37050900 Abstract Title:  Acetaminophen-induced liver injury: Molecular mechanism and treatments from natural products. Abstract:  Acetaminophen (APAP) is a widely used analgesic and antipyretic over-the-counter medicine worldwide. Hepatotoxicity caused by APAP overdose is one of the leading causes of acute liver failure (ALF) in the US and in some parts of Europe, limiting its clinical application. Excessive APAP metabolism depletes glutathione and increases N-acetyl-p-benzoquinoneimide (NAPQI) levels, leading to oxidative stress, DNA damage, and cell necrosis in the liver, which in turn leads to liver damage. Studies have shown that natural products such as polyphenols, terpenes, anthraquinones, and sulforaphane can activate the hepatocyte antioxidant defense system with Nrf2 as the core player, reduce oxidative stress damage, and protect the liver. As the key enzyme metabolizing APAP into NAPQI, cytochrome P450 enzymes are also considered to be intriguing target for the treatment of APAP-induced liver injury. Here, we systematically review the hepatoprotective activity and molecular mechanisms of the natural products that are found to counteract the hepatotoxicity caused by APAP, providing reference information for future preclinical and clinical trials of such natural products.

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PMID:  J Agric Food Chem. 2023 Apr 26 ;71(16):6314-6325. Epub 2023 Apr 14. PMID: 37057839 Abstract Title:  Using Inflammatory Biological Age To Evaluate the Preventing Aging Effect of a Polyphenol-Probiotic-Enhanced Dietary Pattern in Adults Aged 50 Years and Older. Abstract:  A high-compliance dietary intervention was conducted for 2 weeks in adults aged 50 years and older to investigate the preventing aging effects of a polyphenol-probiotic-enhanced diet (P-diet) by using inflammatory biological age (IBA). Following the P-diet, levels of interleukin-6 (IL-6), IL-10, and C-reactive protein were reduced. These effects were accompanied by a significant increase in the richness ofandand decrease in, as well as an increase in butyrate and acetate and decrease in lysine, uracil, and valine. We optimized a model by a back propagation artificial neural network to evaluate the degree of aging, with anof 0.68. After the P-diet intervention, IBA was younger than chronological age and the inflammatory aging potential (age) was observably reduced by 90.12%, with change inage having a direct negative association with. Overall, P-diet may alleviate chronic low-grade inflammation and thus prevent the procession of inflammatory aging.

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PMID:  Food Nutr Res. 2023 ;67. Epub 2023 Mar 24. PMID: 37056702 Abstract Title:  LP45 inhibits the RANKL/OPG signaling pathway and prevents glucocorticoid-induced osteoporosis. Abstract:  OBJECTIVE: To examine the potential effect of the probiotic strainLP45 on osteoporosis and to explore the involved molecular mechanisms.METHODS: A rat model of glucocorticoid-induced osteoporosis (GIO) was established, which was also orally administered with increasing doses of LP45 for 8 weeks. After the termination of the 8-week treatment, the tibia and femur bones of rats were analyzed for bone histomorphometry, bone mineral content (BMC), and bone mineral density (BMD). Femoral biomechanics were assessed. In addition, levels of osteocalcin, tartrate-resistant acid phosphatase 5 (TRAP5), osteoprotegerin (OPG), and receptor activator of nuclear factor kappa-B ligand (RANKL) in the serum and bone marrow were also measured using ELISA, Western blot, and real time-polymerase chain reaction.RESULTS: GIO caused obvious defects in tibia and femur bone structures, in terms of tissue/bone volume, trabecular separation, trabecular thickness, and trabecular number, which could be rescued by LP45 dose dependently. The GIO-induced reductions in BMC, BMD, osteoblast surfaces per bone surface (BS), as well as elevated osteoclast surface per BS were largely restored by LP45 administration dose-dependently. LP45 also increased femoral biomechanics of GIO rats. Importantly, LP45 dose-dependently restored the changes of osteocalcin, TRAP5, OPG, and RANKL in the serum as well as bone marrow of GIO rats.CONCLUSION: Oral LP45 administration could significantly prevent bone defects in GIO rats, suggesting its potential as a dietary supplement with beneficial effects against osteoporosis, which might involve the RANKL/OPG signaling pathway.

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PMID:  J Cell Physiol. 2023 Jun ;238(6):1336-1353. Epub 2023 Apr 13. PMID: 37052047 Abstract Title:  Lactobacillus plantarum postbiotics trigger AMPK-dependent autophagy to suppress Salmonella intracellular infection and NLRP3 inflammasome activation. Abstract:  We previously found that Lactobacillus plantarum (LP)-derived postbiotics protected animals against Salmonella infection, but the molecular mechanism remains obscure. This study clarified the mechanisms from the perspective of autophagy. Intestinal porcine epithelial cells (IPEC-J2) were pretreated with LP-derived postbiotics (the culture supernatant, LPC; or heat-killed bacteria, LPB), and then challenged with Salmonella enterica Typhimurium (ST). Results showed that LP postbiotics markedly triggered autophagy under ST infection, as indicated by the increased LC3 and Beclin1 and the decreased p62 levels. Meanwhile, LP postbiotics (particularly LPC) exhibited a strong capacity of inhibiting ST adhesion, invasion and replication. Pretreatment with the autophagy inhibitor 3-methyladenine (3-MA) led to a significant decrease of autophagy and the aggravated infection, indicating the importance of autophagy in LP postbiotics-mediated Salmonella elimination. LP postbiotics (especially LPB) significantly suppressed ST-induced inflammation by modulating inflammatory cytokines (the increased interleukin (IL)-4 and IL-10, and decreased tumor necrosis factor-(TNF), IL-1, IL-6 and IL-18). Furthermore, LP postbiotics inhibited NOD-like receptor protein 3 (NLRP3) inflammasome activation, as evidenced by the decreased levels of NLRP3, Caspase-1 and apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC). Deficits in autophagy resulted in an increase of inflammatory response and inflammasome activation. Finally, we found that both LPC and LPB triggered AMP-activated protein kinase (AMPK) signaling pathway to induce autophagy, and this was further confirmed by AMPK RNA interference. The intracellular infection and NLRP3 inflammasome were aggravated after AMPK knockdown. In summary, LP postbiotics trigger AMPK-mediated autophagy to suppress Salmonella intracellular infection and NLRP3 inflammasome in IPEC-J2 cells. Our findings highlight the effectiveness of postbiotics, and provide a new strategy for preventing Salmonella infection.

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PMID:  Nutrients. 2023 Apr 1 ;15(7). Epub 2023 Apr 1. PMID: 37049578 Abstract Title:  CCFM405 against Rotenone-Induced Parkinson's Disease Mice via Regulating Gut Microbiota and Branched-Chain Amino Acids Biosynthesis. Abstract:  Recent studies have demonstrated that disturbances in the gut microbiota and microbiota -derived metabolites contribute to the pathogenesis of Parkinson's disease (PD), suggesting that probiotic treatments that restore them may delay disease progression. This study aimed to examine the attenuating efficacy ofCCFM405 and the potential mechanisms in mice with rotenone-induced PD. Our results indicate thatCCFM405 ameliorated rotenone-induced motor deficits and constipation, decreased dopaminergic neuronal death, reduced intestinal inflammation and neuroinflammation, and raised dopamine levels, 5-HT, and associated metabolites in the striatal region of the brain in mice with PD. Sequencing of 16S rRNA from fecal microbiota revealed thatCCFM405 normalized the gut bacterial composition in mice with PD, as evidenced by the increased relative abundance of the following genus,,, and, and decreased relative abundance of,,, and. The PICRUSt-predicted gut microbiota function revealed thatCCFM405 enhanced the biosynthesis of amino acid pathways, particularly valine, leucine, and isoleucine (branched-chain amino acids, BCAAs). A non-metabolomic analysis of the serum and feces showed thatCCFM405 markedly increased the levels of BCAAs. Pathway enrichment analysis based on the KEGG database further suggested thatCCFM405 supplementation can promote BCAAs biosynthesis. Collectively,CCFM405 can help to prevent rotenone-induced PD by modulating the gut microbiota-metabolite axis. BCAAs may play a dominant role inCCFM405-associated neuroprotection in PD mice. This probiotic could be utilized as a potential food supplement in the management of PD.

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PMID:  Int J Mol Sci. 2023 Apr 5 ;24(7). Epub 2023 Apr 5. PMID: 37047769 Abstract Title:  Neuroprotective Effects ofPS128 in a Mouse Model of Parkinson's Disease: The Role of Gut Microbiota and MicroRNAs. Abstract:  Parkinson's disease (PD) is a neurodegenerative disease characterized by motor deficits and marked neuroinflammation in various brain regions. The pathophysiology of PD is complex and mounting evidence has suggested an association with the dysregulation of microRNAs (miRNAs) and gut dysbiosis. Using a rotenone-induced PD mouse model, we observed that administration ofPS128 (PS128) significantly improved motor deficits in PD-like mice, accompanied by an increased level of dopamine, reduced dopaminergic neuron loss, reduced microglial activation, reduced levels of inflammatory factors, and enhanced expression of neurotrophic factor in the brain. Notably, the inflammation-related expression of miR-155-5p was significantly upregulated in the proximal colon, midbrain, and striatum of PD-like mice. PS128 reduced the level of miR-155-5p, whereas it increased the expression of suppressor of cytokine signaling 1 (SOCS1), a direct target of miR-155-5p and a critical inhibitor of the inflammatory response in the brain. Alteration of the fecal microbiota in PD-like mice was partially restored by PS128 administration. Among them,,_6,, andwere statistically correlated with the improvement of rotenone-induced motor deficits and the expression of miR-155-5p and SOCS1. Our findings suggested that PS128 ameliorates motor deficits and exerts neuroprotective effects by regulating the gut microbiota and miR-155-5p/SOCS1 pathway in rotenone-induced PD-like mice.

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PMID:  Front Immunol. 2023 ;14:1158137. Epub 2023 Mar 23. PMID: 37033942 Abstract Title:  PsychobioticJYLP-326 relieves anxiety, depression, and insomnia symptoms in test anxious collegemodulating the gut microbiota and its metabolism. Abstract:  INTRODUCTION: Test anxiety is a common issue among college students, which can affect their physical and psychological health. However, effective interventions or therapeutic strategies are still lacking. This study aims to evaluate the potential effects ofJYLP-326 on test anxious college students.METHODS: Sixty anxious students were enrolled and randomly allocated to the placebo group and the probiotic group. Both groups were instructed to take placebo and JYLP-326 products twice per day for three weeks, respectively. Thirty unanxious students with no treatments were assigned to a regular control group. The anxiety, depression, and insomnia questionnaires were used to measure students' mental states at the baseline and the end of this study. 16S rRNA sequencing and untargeted metabolomics were performed to analyze the changes in the gut microbiota and fecal metabolism.RESULTS: The questionnaire results suggested that JYLP-326 administration could relieve the symptoms of anxiety, depression, and insomnia in test anxious students. The gut microbiomes of the placebo group showed a significantly greater diversity index than the control group (p

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PMID:  Life Sci. 2023 Jun 1 ;322:121664. Epub 2023 Apr 5. PMID: 37023957 Abstract Title:  Sulforaphane exhibits potent renoprotective effects in preclinical models of kidney diseases: A systematic review and meta-analysis. Abstract:  AIMS: Sulforaphane (SFN), a naturally occurring isothiocyanate found in cruciferous vegetables, has received extensive attention as a natural activator of the Nrf2/Keap1 cytoprotective pathway. In this review, a meta-analysis and systematic review of the renoprotective effects of SFN were performed in various preclinical models of kidney diseases.MAIN METHODS: The primary outcome was the impact of SFN on renal function biomarkers (uremia, creatininemia, proteinuria or creatinine clearance) and secondary outcomes were kidney lesion histological indices/kidney injury molecular biomarkers. The effects of SFN were evaluated according to the standardized mean differences (SMDs). A random-effects model was applied to estimate the overall summary effect.KEY FINDINGS: Twenty-five articles (out of 209 studies) were selected from the literature. SFN administration significantly increased creatinine clearance (SMD +1.88 95 % CI: [1.09; 2.68], P 

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PMID:  Biomed Pharmacother. 2023 May ;161:114490. Epub 2023 Mar 15. PMID: 36931031 Abstract Title:  Anticancer effect and safety of doxorubicin and nutraceutical sulforaphane liposomal formulation in triple-negative breast cancer (TNBC) animal model. Abstract:  Female breast cancer is the most deadly cancer in women worldwide. The triple-negative breast cancer subtype therapies, due to the lack of specific drug targets, are still based on systemic chemotherapy with doxorubicin, which is burdened with severe adverse effects. To enhance therapeutic success and protect against systemic toxicity, drug carriers or combination therapy are being developed. Thus, an innovative liposomal formulation containing doxorubicin and the main nutraceutical, sulforaphane, has been developed. The anticancer efficacy and safety of the proposed liposomal formulation was evaluated in vivo, in a 4T1 mouse model of triple-negative breast cancer, and the mechanism of action was determined in vitro, using triple-negative breast cancer MDA-MB-231 and non-tumorigenic breast MCF-10A cell line. The elaborated drug carriers were shown to efficiently deliver both compounds into the cancer cell and direct doxorubicin to the cell nucleus. Incorporation of sulforaphane resulted in a twofold inhibition of tumor growth and the potential of up to a fourfold reduction in doxorubicin concentration due to the synergistic interaction between the two compounds. Sulforaphane was shown to increase the accumulation of doxorubicin in the nuclei of cancer cells, accompanied by inhibition of mitosis, without affecting the reactive oxygen species status of the cell. In normal cells, an antagonistic effect resulting in less cytotoxicity was observed. In vivo results showed that sulforaphane incorporation yielded not only cardioprotective, but also nephro- and hepatoprotective effects. The results of the research revealed the prospects of applying sulforaphane as a component of liposomal doxorubicin in triple-negative breast cancer chemotherapy.

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PMID:  Ecotoxicol Environ Saf. 2023 Apr 1 ;254:114747. Epub 2023 Mar 10. PMID: 36907095 Abstract Title:  Sulforaphane suppresses paraquat-induced oxidative damage in bovine in vitro-matured oocytes through Nrf2 transduction pathway. Abstract:  Sulforaphane (SFN), a bioactive phytocompound extracted from cruciferous plants, has received increasing attention due to its vital cytoprotective role in eliminating oxidative free radical through activation of nuclear factor erythroid 2-related factor (Nrf2)-mediated signal transduction pathway. This study aims at a better insight into the protective benefit of SFN in attenuating paraquat (PQ)-caused impairment in bovine in vitro-matured oocytes and the possible mechanisms involved therein. Results showed that addition of 1 M SFN during oocyte maturation obtained higher proportions of matured oocytes and in vitro-fertilized embryos. SFN application attenuated the toxicological effects of PQ on bovine oocytes, as manifested by enhanced extending capability of cumulus cell and increased extrusion proportion of first polar body. Following incubation with SFN, oocytes exposed to PQ exhibited reduced intracellular ROS and lipid accumulation levels, and elevated T-SOD and GSH contents. SFN also effectively inhibited PQ-mediated increase in BAX and CASPASE-3 protein expressions. Besides, SFN promoted the transcription of NRF2 and its downstream antioxidative-related genes GCLC, GCLM, HO-1, NQO-1, and TXN1 in a PQ-exposed environment, indicating that SFN prevents PQ-caused cytotoxicity through activation of Nrf2 signal transduction pathway. The mechanisms underlying the role of SFN against PQ-induced injury included the inhibition of TXNIP protein and restoration of the global O-GlcNAc level. Collectively, these findings provide novel evidence for the protective role of SFN in alleviating PQ-caused injury, and suggest that SFN application may be an efficacious intervention strategy against PQ cytotoxicity.

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PMID:  Adv Mind Body Med. 2023 Spring;37(2):5-8. PMID: 37315227 Abstract Title:  Effect of a Single Yoga Asana on Blood Glucose Levels in Type 2 Diabetes Mellitus: A Self-Controlled Study. Abstract:  CONTEXT: Diabetes is a metabolic disorder characterized by high blood sugar levels. Yoga has been shown to have positive effects on blood sugar levels in diabetes patients. However, there is limited research on the effects of specific yoga poses on blood sugar levels in patients with type 2 diabetes (T2DM).OBJECTIVE: This study aimed to evaluate the effect of a single yoga asana, Ardha Matsyendrasana, on random blood glucose (RBG) levels in patients with T2DM. Specifically, we aimed to investigate whether a 15-minute practice of Ardha Matsyendrasana could reduce RBG levels in patients with T2DM.DESIGN: This study employed a self-controlled design to evaluate the effect of Ardha Matsyendrasana on blood glucose levels in patients with type 2 diabetes mellitus.PARTICIPANTS: 100 patients with type 2 diabetes mellitus (T2DM) were recruited for this study.INTERVENTIONS: All participants underwent two sessions: a control session (CS) and an asana session (AS), each lasting 15 minutes. During the CS, participants rested in a sitting pose, while during the AS, they practiced Ardha Matsyendrasana. The order of the sessions was randomized, with half the participants undergoing the CS on day 1, the AS on day 2, and the other half undergoing the sessions in reverse order.OUTCOME MEASURES: We measured participants' random blood glucose (RBG) levels immediately before and after each intervention.STATISTICAL ANALYSIS: The statistical package for the compare RBG levels before and after each intervention.RESULTS: The study demonstrated a significant reduction in random blood glucose (RBG) levels in the Ardha Matsyendrasana session compared to the control session. This trend was observed in both males and females with T2DM.CONCLUSIONS: A single session of Ardha Matsyendrasana for 15 minutes can effectively reduce blood glucose levels in patients with T2DM. However, further studies are required to determine the long-term effects of this asana on glycemic control.

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PMID:  Adv Mind Body Med. 2023 Spring;37(2):24-31. PMID: 37315229 Abstract Title:  Yoga Practice Facilitates Prefrontal Oxygenation and Working Memory in Type 2 Diabetes Mellitus Patients: A Pilot Study. Abstract:  BACKGROUND: Type 2 diabetes mellitus (T2DM) is associated with cognitive decline. Lifestyle behaviors such as yoga practices play a significant role in preventing cognitive decline.PURPOSE: The goal of this study was to assess the effect of yoga intervention on working memory and prefrontal cortex (PFC) oxygenation in T2DM patients.METHODS: Twenty T2DM participants, aged between 40 and 60 years, volunteered for a 6-week study. Participants were randomized into a yoga practice (n = 10) and a waitlist control group (n = 10). The n-back task was administered to evaluate working memory before and after the intervention. While performing the working memory task, PFC oxygenation was monitored using functional near-infrared spectroscopy.RESULTS: The yoga group showed a significant improvement in working memory performance. The accuracy improved in 1-back (mean difference of 4.73%, 95% CI[0.69,8.77], P = .026) and 2-back (8.0%, 95% CI[1.89,14.1], P = .016) task conditions. The reaction time improved in 0-back (mean difference of -79.07 milliseconds, 95% CI[-128.3,-29.8]), 1-back (mean difference of -119.17 milliseconds, 95% CI[-217.5,-20.8] ) and 2-back (-76.06 milliseconds, 95% CI[-148.8,-3.3]) task conditions. In the yoga group, at post-intervention, higher oxygenation was observed during 0-back and 1-back task conditions (Beta coefficient mean difference of 211.3, 95% CI[2.8, 420.0], P = .048 and 80.5, 95% CI [3.7,157.2], P = .042 respectively) in the left PFC region compared to the pre-intervention values. The control group showed no significant change in working memory performance and PFC oxygenation.CONCLUSIONS: The study suggests that yoga practice may improve working memory performance and facilitate higher PFC oxygenation in T2DM patients. Further studies with a larger sample and a longer intervention period are required to strengthen the findings.

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PMID:  Trop Doct. 2023 Jun 15:494755231180633. Epub 2023 Jun 15. PMID: 37321800 Abstract Title:  Physical and psychological impact of yoga therapy in improving heart failure. Abstract:  Effective therapy for patients with chronic cardiac failure (CCF) entails significant lifestyle modifications as well as often complex pharmaceutical regimes to alleviate symptoms, which, however, do not actually cure many patients. The gradual loss of cardiac function is impeded but not halted by such complicated pharmacological therapy, which primarily includes angiotensin-converting enzyme inhibitors, beta-blockers and diuretics, and sometimes digoxin, aspirin, warfarin, and anti-arrhythmic agents. Patients may be advised to track their weight and modify their diuretic prescription accordingly to avoid fluid overload or dehydration as part of the treatment plan. Non-pharmacologic treatment options are routinely integrated to improve the management of somatic complaints. Yoga and specialized breathing exercises seem to help CCF patients improve their cardiorespiratory and autonomic system function, and also their quality of life. We present the evidence.

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PMID:  Int J Yoga Therap. 2023 Jan 1 ;33(2023). PMID: 37327384 Abstract Title:  Efficacy of Yoga Nidra on Depression, Anxiety, and Insomnia in Frontline COVID-19 Healthcare Workers: A Pilot Randomized Controlled Trial. Abstract:  The COVID-19 pandemic has led to a surge of mental health disturbances and the subsequent use of various mind-body therapies. Although evidence supports the benefits of yoga for mental health in a variety of disease states, information on its effects among healthcare workers during the COVID-19 epidemic is scarce. Therefore, this study evaluated and compared the efficacy of relaxation to music and yoga nidra on the mental health of frontline healthcare workers during the pandemic. This open-label randomized trial was conducted at a Level III COVID-19 care center. In the Relaxation-to-Music Group, participants received deep relaxation music, whereas those in the Yoga Nidra Group performed yoga nidra practices; both interventions were delivered through a YouTube platform and were to be done daily for 30 minutes during the healthcare workers' 2-week duty periods. The primary outcomes were measured using scores of the Patient Health Questionnaire (PHQ)-9, Generalized Anxiety Disorder (GAD)-7 scale, and Insomnia Severity Index (ISI) at the end of the duty period. A total of 79 healthcare workers were randomly divided into two groups: (1) Relaxation-to-Music (n = 40) and (2) Yoga Nidra (n = 39). Demographics; clinical characteristics; and PHQ-9, GAD-7, and ISI scores of the two groups were comparable at baseline. In the Yoga Nidra Group, PHQ-9 scores decreased significantly (5.174.25 to 3.032.40, p = 0.002) compared to the Relaxation-to-Music Group (5.684.73 to 4.342.90, p = 0.064). Similarly, GAD-7 scores decreased significantly in the Yoga Nidra Group (4.933.27 to 2.332.56, p

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PMID:  Holist Nurs Pract. 2023 Jul-Aug 01;37(4):E59-E68. PMID: 37335153 Abstract Title:  The Effects of Yoga and Stabilization Exercises in Patients With Chronic Low Back Pain: A Randomized Crossover Study. Abstract:  This study aimed to assess the effectiveness of yoga and stabilization exercises in patients with chronic low back pain. Thirty-five female patients were randomly assigned to the stabilization exercise group or the yoga group. Outcome measures were the visual analog scale (VAS), Oswestry Disability Index (ODI) and Back Performance Scale (BPS), 6-minute walk test (6MWT), Fear-Avoidance Beliefs Questionnaire (FABQ), and Pittsburgh Sleep Quality Index (PSQI). The scores of the VAS, ODI, BPS, 6MWT, and PSQI improved significantly after both interventions (P

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PMID:  Brain Behav. 2023 Jun 21:e3108. Epub 2023 Jun 21. PMID: 37340873 Abstract Title:  The impact of humor therapy on people suffering from depression or anxiety: An integrative literature review. Abstract:  OBJECTIVES: To identify and synthesize existing research on the effectiveness and feasibility of multiform humor therapy on people suffering from depression or anxiety, with the hope of benefiting future research.METHODS: An integrative literature review of quantitative, qualitative, and mixed studies was performed. The PubMed, Cochrane Library, Web of Science, Embase, and CINAHL databases were searched up to March 2022. Two independent reviewers conducted each stage of the review process, by assessing eligibility using preferred reporting items for systematic review and meta-analyses (PRISMA) and quality appraisal using the Mixed Methods Appraisal Tool, and data extraction.RESULTS: In this integrative review, 29 papers were included, containing 2964 participants across a diverse range of studies, including quantitative, qualitative, and mixed methods. The articles were from the United States, Australia, Italy, Turkey, South Korea, Iran, Israel, China, and Germany. The findings indicated that most of the subjects thought humor therapy was effective in improving depression and anxiety while a few participants considered the effect insignificant. However, more high-quality studies will be needed to confirm these conclusions.DISCUSSION: This review collated and summarized findings from studies examining the impact of humor therapy (medical clowns, laughter therapy/yoga) on people with depression or anxiety, including children undergoing surgery or anesthesia, older people in nursing homes, patients with Parkinson's disease, cancer, mental illness, and undergoing dialysis, retired women, and college students. The results from this review may help inform future research, policy, and practice in humor therapy to improve people's symptoms of depression and anxiety.IMPACT: This systematic review objectively evaluated the effect of humor therapy on depression and anxiety. As a simple and feasible complementary alternative therapy, humor therapy may provide a favorable alternative for clinicians, nurses, and patients in the future.

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PMID:  Int Immunopharmacol. 2023 Jun ;119:110236. Epub 2023 May 5. PMID: 37148772 Abstract Title:  Vinpocetine mitigates DMH-induce pre-neoplastic colon damage in rats through inhibition of pro-inflammatory cytokines. Abstract:  Colorectal cancer (CRC) is currently recognized as the third most prevalent cancer worldwide. Vinpocetine is a synthetic derivative of the vinca alkaloid vincamine. It has been found effective in ameliorating the growth and progression of cancerous cells. However, its pharmacological effect on colon damage remains elusive. Hence, in this study, we have shown the role of vinpocetine in DMH-induced colon carcinogenesis. At first, male albino Wistar rats were administered with DMH consistently for four weeks to induce pre-neoplastic colon damage. Afterward, animals were treated with vinpocetine (4.2 and 8.4 mg/kg/day p.o.) for 15 days. Serum samples were collected to assess the physiological parameters, including ELISA and NMR metabolomics. Colon from all the groups was collected and processed separately for histopathology and western blot analysis. Vinpocetine attenuated the altered plasma parameters; lipid profile and showed anti-proliferative action as evidenced by suppressed COX-2 stimulation and decreased levels of IL-1, IL-2, IL-6, and IL-10. Vinpocetine is significantly effective in preventing CRC which may be associated with its anti-inflammatory and antioxidant potential. Accordingly, vinpocetine could serve as a potential anticancer agent for CRC treatment and thus be considered for future clinical and therapeutic research.

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PMID:  J Pharm Pharmacol. 2023 May 25. Epub 2023 May 25. PMID: 37229596 Abstract Title:  Effect of vinpocetine alone and in combination with enalapril in experimental model of diabetic cardiomyopathy in rats: possible involvement of PDE-1/TGF-/ Smad 2/3 signalling pathways. Abstract:  OBJECTIVE: Diabetic cardiomyopathy (DC) is one of the severe secondary complications of diabetes mellitus in humans. Vinpocetine is an alkaloid having pleiotropic pharmacological effects. The present study is designed to investigate the effect of vinpocetine in DC in rats.METHODS: Rats were fed a high-fat diet for nine weeks along with single dose of streptozotocin after the second week to induce DC. The haemodynamic evaluation was performed to assess the functional status of rats using the Biopac system. Cardiac echocardiography, biochemical, oxidative stress parameters and inflammatory cytokine level were analysed in addition to haematoxylin-eosin and Masson's trichome staining to study histological changes, cardiomyocyte diameter and fibrosis, respectively. Phosphodiesterase-1 (PDE-1), transforming growth factor-(TGF-) and p-Smad 2/3 expression in cardiac tissues were quantified using western blot/RT-PCR.KEY FINDING: Vinpocetine treatment and its combination with enalapril decreased the glucose levels compared to diabetic rats. Vinpocetine improved the echocardiographic parameters and cardiac functional status of rats. Vinpocetine decreased the cardiac biochemical parameters, oxidative stress, inflammatory cytokine levels, cardiomyocyte diameter and fibrosis in rats. Interestingly, expressions of PDE-1, TGF-and p-Smad 2/3 were ameliorated by vinpocetine alone and in combination with enalapril.CONCLUSIONS: Vinpocetine is a well-known inhibitor of PDE-1 and the protective effect of vinpocetine in DC is exerted by inhibition of PDE-1 and subsequent inhibition of the expression of TGF-/Smad 2/3.

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PMID:  Neuroscience. 2023 Jun 7. Epub 2023 Jun 7. PMID: 37290685 Abstract Title:  Neuroprotective Effects of Vinpocetine Against Ischemia-Reperfusion Injury Via Inhibiting NLRP3 Inflammasome Signaling Pathway. Abstract:  Ischemic stroke is one of the main causes of serious disability and death worldwide. NLRP3 inflammasome is an intracellular pattern recognition receptor composed of polyprotein complex, which participates in mediating a series of inflammatory responses and is considered as a potential target for the treatment of ischemic stroke. Vinpocetine, a derivative of vincamine, has been widely used in the prevention and treatment of ischemic stroke. However, the therapeutic mechanism of vinpocetine is not clear, and its effect on NLRP3 inflammasome remains to be determined. In this study, we used the mouse model of transient middle cerebral artery occlusion (tMCAO) to simulate the occurrence of ischemic stroke. Different doses of vinpocetine (5, 10, 15mg/kg/d) were injected intraperitoneally for 3days after ischemia-reperfusion in mice. The effects of different doses of vinpocetine on the degree of ischemia-reperfusion injury in mice were observed by TTC staining and modified neurological severity score scale, and the optimal dose was determined. Then, based on this optimal dose, we observed the effects of vinpocetine on apoptosis, microglial proliferation and NLRP3 inflammasome. In addition, we compared the effects of vinpocetine and MCC950 (a specific inhibitor of NLRP3 inflammasome) on NLRP3 inflammasome. Our results show that vinpocetine can effectively reduce the infarct volume and promote the recovery of behavioral function in stroke mice, and the maximal beneficial effects were observed at the dose of 10mg/kg/d. Vinpocetine can effectively inhibit the apoptosis of peri-infarct neurons, promote the expression of Bcl-2, inhibit the expression of Bax and Cleaved Caspase-3, and reduce the proliferation of peri-infarct microglia. In addition, vinpocetine, like MCC950, can reduce the expression of NLRP3 inflammasome. Therefore, vinpocetine can effectively alleviate the ischemia-reperfusion injury in mice, and the inhibition of NLRP3 inflammasome may be an important therapeutic mechanism of vinpocetine.

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PMID:  Metab Brain Dis. 2023 Jun 19. Epub 2023 Jun 19. PMID: 37335452 Abstract Title:  New insights on the potential effect of vinpocetine in Parkinson's disease: one of the neglected warden and baffling topics. Abstract:  Vinpocetine (VPN) is an ethyl apovincaminate that has anti-inflammatory and antioxidant effects by inhibiting the expression of nuclear factor kappa B (NF-B) and phosphodiesterase enzyme 1 (PDE-1). VPN is used in the management of stroke, dementia, and other neurodegenerative brain diseases. VPN may be effective in treating Parkinson's disease (PD). Therefore, this review aimed to clarify the mechanistic role of VPN in the management of PD. VPN has protective and restorative effects against neuronal injury by reducing neuroinflammation, and improvement of synaptic plasticity and cerebral blood flow. VPN protects dopaminergic neurons by reducing oxidative stress, lipid peroxidation, glutamate neurotoxicity, and regulation of Caoverloads. VPN can alleviate PD neuropathology through its anti-inflammatory, antioxidant, antiapoptotic and neurogenic effects. VPN through inhibition of PDE1 improves cyclic adenosine monophosphate (cAMP)/cyclic guanosine monophosphate (cGMP) signaling in the dopaminergic neurons of the substantia nigra (SN). VPN improves PD neuropathology through PDE1 inhibition with a subsequent increase of the cAMP/cGMP signaling pathway. Therefore, increasing cAMP leads to antioxidant effects, while augmentation of cGMP by VPN leads to anti-inflammatory effects which reduced neurotoxicity and development of motor severity in PD. In conclusion, this review indicated that VPN could be effective in the management of PD.

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PMID:  Crit Rev Food Sci Nutr. 2023 Jun 19:1-27. Epub 2023 Jun 19. PMID: 37335106 Abstract Title:  Crosstalk between dietary pomegranate and gut microbiota: evidence of health benefits. Abstract:  Gut microbiota (GM) is an invisible organ that plays an important role in human health. Increasing evidence suggests that polyphenols in pomegranate (punicalagin, PU) could serve as prebiotics to modulate the composition and function of GM. In turn, GM transform PU into bioactive metabolites such as ellagic acid (EA) and urolithin (Uro). In this review, the interplay between pomegranate and GM is thoroughly described by unveiling a dialog in which both actors seem to affect each other's roles. In a first dialog, the influence of bioactive compounds from pomegranate on GM is described. The second act shows how the GM biotransform pomegranate phenolics into Uro. Finally, the health benefits of Uro and that related molecular mechanism are summarized and discussed. Intake of pomegranate promotes beneficial bacteria in GM (e.g.spp.,spp.) while reducing the growth of harmful bacteria (e.g.group,)., andspp., among others, biotransform PU and EA into Uro. Uro contributes to strengthening intestinal barrier and reducing inflammatory processes. Yet, Uro production varies greatly among individuals and depend on GM composition. Uro-producing bacteria and precise metabolic pathways need to be further elucidated therefore contributing to personalized and precision nutrition.

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PMID:  J Biomol Struct Dyn. 2023 May 30:1-14. Epub 2023 May 30. PMID: 37254310 Abstract Title:  In silico molecular study of hepatitis B virus X protein as a therapeutic target. Abstract:  The Hepatitis B virus is a leading cause of liver cirrhosis and hepatocellular carcinoma. HBx viral protein is considered a contributor to pathogenesis and hepatocarcinogenesis. This study aimed to screen the effect of some antiviral compounds to target HBx protein for inhibition of its function. Here, molecular docking, molcular dynsmic simulation, MM/GBSA and T-SNE methods were applied to study the complex stability and to cluster the conformations that generated in the simulation. Among the 179 compounds screened in this study, three antiviral agents (SC75741, Punicalagin, and Ledipasvir) exhibited the lowest docking energy and best interaction. Among these compounds, SC75741 was identified as a potent inhibitor of HBx that showed the best and most stable interaction during molecular dynamic simulation, and blocking a region near to HBx helix resides (aa 88-100) that is associated with cell invasion. The analysis of relative binding free energy through MM/GBSA for molecular dynamic simulation results revealed binding energy -9.9kcal/mol for SC75741, -11kcal/mol for Punicalagin, and -10.1kcal/mol for Ledipasvir. These results elucidate the possible use of these compounds in the research for targeting HBx.Communicated by Ramaswamy H. Sarma.

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PMID:  Int J Mol Sci. 2023 May 9 ;24(10). Epub 2023 May 9. PMID: 37239823 Abstract Title:  The Role of Punicalagin and Its Metabolites in Atherosclerosis and Risk Factors Associated with the Disease. Abstract:  Atherosclerotic cardiovascular disease (ACVD) is the leading cause of death worldwide. Although current therapies, such as statins, have led to a marked reduction in morbidity and mortality from ACVD, they are associated with considerable residual risk for the disease together with various adverse side effects. Natural compounds are generally well-tolerated; a major recent goal has been to harness their full potential in the prevention and treatment of ACVD, either alone or together with existing pharmacotherapies. Punicalagin (PC) is the main polyphenol present in pomegranates and pomegranate juice and demonstrates many beneficial actions, including anti-inflammatory, antioxidant, and anti-atherogenic properties. The objective of this review is to inform on our current understanding of the pathogenesis of ACVD and the potential mechanisms underlying the beneficial actions of PC and its metabolites in the disease, including the attenuation of dyslipidemia, oxidative stress, endothelial cell dysfunction, foam cell formation, and inflammation mediated by cytokines and immune cells together with the regulation of proliferation and migration of vascular smooth muscle cells. Some of the anti-inflammatory and antioxidant properties of PC and its metabolites are due to their strong radical-scavenging activities. PC and its metabolites also inhibit the risk factors of atherosclerosis, including hyperlipidemia, diabetes mellitus, inflammation, hypertension, obesity, and non-alcoholic fatty liver disease. Despite the promising findings that have emerged from numerous in vitro, in vivo, and clinical studies, deeper mechanistic insights and large clinical trials are required to harness the full potential of PC and its metabolites in the prevention and treatment of ACVD.

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PMID:  Zhongguo Zhong Yao Za Zhi. 2023 Apr ;48(7):1751-1759. PMID: 37282949 Abstract Title:  [Punicalagin inhibits hepatic lipid deposition in obese mice via AMPK/ACC pathway]. Abstract:  Hepatic lipid deposition is one of the basic manifestations of obesity, and nowadays pharmacological treatment is the most important tool. Punicalagin(PU), a polyphenol derived from pomegranate peel, is a potential anti-obesity substance. In this study, 60 C57BL/6J mice were randomly divided into a normal group and a model group. After establishing a model of simple obesity with a high-fat diet for 12 weeks, the successfully established rat models of obesity were then regrouped into a model group, an orlistat group, a PU low-dose group, a PU medium-dose group, and a PU high-dose group. The normal group was kept on routine diet and other groups continued to feed the high-fat diet. The body weight and food intake were measured and recorded weekly. After 8 weeks, the levels of the four lipids in the serum of each group of mice were determined by an automatic biochemical instrument. Oral glucose tole-rance and intraperitoneal insulin sensitivity were tested. Hemoxylin-eosin(HE) staining was applied to observe the hepatic and adipose tissues. The mRNA expression levels of peroxisome proliferators-activated receptor(PPAR) and C/EBPwere determined by real-time quantitative polymerase chain reaction(Q-PCR), and the mRNA and protein expression levels of adenosine 5'-monophosphate-activated protein kinase(AMPK), anterior cingulate cortex(ACC), and carnitine palmitoyltransferase 1A(CPT1A) were determined by Western blot. Finally, the body mass, Lee's index, serum total glyceride(TG), serum total cholesterol(TC), and low-density lipoprotein cholesterol(LDL-C) levels were significantly higher and high-density lipoprotein cholesterol(HDL-C) levels were significantly lower in the model group as compared with the normal group. The fat deposition in the liver was significantly increased. The mRNA expression levels of hepatic PPARand C/EBPand the protein expression level of ACC were increased, while the mRNA and protein expression levels of CPT-1(CPT1A) and AMPK were decreased. After PU treatment, the above indexes of obese mice were reversed. In conclusion, PU can decrease the body weight of obese mice and control their food intake. It also plays a role in the regulation of lipid metabolism and glycometabolism metabolism, which can significantly improve hepatic fat deposition. Mechanistically, PU may regulate liver lipid deposition in obese mice by down-regulating lipid synthesis and up-regulating lipolysis through activation of the AMPK/ACC pathway.

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PMID:  J Nat Med. 2023 Jun 12. Epub 2023 Jun 12. PMID: 37306932 Abstract Title:  Punicalagin alleviates the hyperproliferation of keratinocytes in psoriasis through inhibiting SKP2 expression. Abstract:  Psoriasis is a chronic inflammatory skin disorder characterized by abnormal keratinocytes proliferation and multiple immune cells infiltration in the dermis and epidermis. Although most psoriasis-related researches have been concentrated on the interleukin-23 (IL-23)/interleukin-17 (IL-17) axis, new data suggest that keratinocytes also play a pivotal role in psoriasis. Previously, we found that punicalagin (PUN), a bioactive ellagitannin extracted from Pericarpium Granati (the pericarpium of Punica granatum L.), exerts a therapeutic effect on psoriasis. However, the underlying mechanism, especially its potential modulatory effect on keratinocytes, remains obscure. Our study aims to reveal the potential regulatory effect and its underlying cellular mechanism of PUN on the hyperproliferation of keratinocytes. We used tumor necrosis factor(TNF-), IL-17A and interleukin-6 (IL-6) to induce abnormal proliferation of HaCaT cells (Human Keratinocytes Cells) in vitro. Then, we evaluated the effects of PUN through MTT assay, EdU staining and cell cycle detection. Finally, we explored the underlying cellular mechanisms of PUN via RNA-sequencing, WB in vitro and in vivo. Here, we found that PUN can directly and dose-dependently decrease TNF-, IL-17A and IL-6-induced abnormal proliferation of HaCaT cells in vitro. Mechanically, PUN suppresses the hyperproliferation of keratinocytes through repressing S-phase kinase-associated protein 2 (SKP2) expression in vitro and in vivo. Moreover, overexpression of SKP2 can partly abolish PUN-mediated inhibition of aberrantly proliferative keratinocytes. These results illustrate that PUN can reduce the severity of psoriasis through directly repressing SKP2-mediated abnormal proliferation of keratinocytes, which gives new insight into the therapeutic mechanism of PUN on psoriasis. Moreover, these findings imply that PUN might be a promising drug candidate for the treatment of psoriasis.

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PMID:  BMC Neurosci. 2023 Mar 16 ;24(1):20. Epub 2023 Mar 16. PMID: 36927298 Abstract Title:  Neuroprotective effects of vinpocetine, as a phosphodiesterase 1 inhibitor, on long-term potentiation in a rat model of Alzheimer's disease. Abstract:  BACKGROUND: Vinpocetine (Vin) is known as a phosphodiesterase 1 inhibitor (PDE1-I) drug with multilateral effects, including antioxidant and anti-inflammatory activity. In this research, we investigated the neuroprotective and therapeutic effects of Vin through hippocampal synaptic plasticity on a rat's model of Alzheimer's disease (AD) induced by an intracerebroventricular (ICV) injection of beta-amyloid (A).METHODS: Sixty adult male Wistar rats were randomly divided into six groups: 1. control, 2. sham, 3. A, 4. pretreatment (Vin+A): Vin (4 mg/kg, gavage) for 30 days and then, inducing an AD model by an ICV injection of A(1-42), 5. treatment (A+Vin): inducing an AD model and then receiving Vin for 30 days by gavage, and 7. pretreatment+treatment (Vin+A+Vin): receiving Vin by gavage for 30 days before and 30 days after the induction of an AD model. After these procedures, via stereotaxic surgery, the stimulating electrodes were placed at the perforant pathway (PP) and the recording electrodes were implanted in the dentate gyrus.RESULTS: Excitatory postsynaptic potential (EPSP) slope and population spike (PS) amplitude in the Agroup meaningfully diminished compared to the control group after the induction of long-term potentiation (LTP).CONCLUSIONS: Vin could significantly prevent the Aeffects on LTP. It can be concluded that pretreatment and treatment with Vin can be neuroprotective against harmful consequences of Aon hippocampal synaptic plasticity.

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PMID:  Iran J Basic Med Sci. 2023 Jan ;26(1):13-22. PMID: 36594060 Abstract Title:  Vinpocetine's immunomodulating, anti-oxidant, anti-inflammatory, ant-ifibrotic, and PDE inhibiting potencies ameliorate bleomycin-induced pulmonary fibrosis. Abstract:  OBJECTIVES: Pulmonary fibrosis (PF) is a global health problem with a high economic burden. Intratracheal administration of bleomycin is the best model that resembles the pathogenesis of PF in humans. Recently, vinpocetine proved to have neuroprotective, cardioprotective, hepatoprotective, anti-aging, and antifibrotic effects through its anti-oxidant, immunomodulating, and anti-inammatory activities. The present study investigated the antifibrotic potentiality of vinpocetine in a rat model of PF induced by intratracheal bleomycin administration.MATERIALS AND METHODS: PF induced by a single intratracheal instillation of 5 mg/kg bleomycin in nine-week-old Wister rats. Oral vinpocetine was used at doses of 5, 10, or 20 mg/kg to treat PF for 21 days immediately after the bleomycin instillation.RESULTS: Vinpocetine dose-dependently ameliorates PF induced by bleomycin administration since vinpocetine effectively restored the normal body weight gain rates, pulmonary architecture, and collagen fiber distribution and suppressed the elevated BALF cell count, lymphocytes and neutrophils percentage, BALF, IL-6, TNF-, and TGF-1 levels and LDH activity, lung tissue MDA level, PDE activity, hydroxyproline content, immunohistochemical expression of-SMA and CD68 positive macrophage, and fibrosis score. Meanwhile, it efficiently augmented the reduced BALF macrophage percentage, IL-10 level, lung tissue GSH level, CAT, and SOD activities.CONCLUSION: Vinpocetine may propose a new promising agent to manage PF.

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PMID:  Food Funct. 2023 Apr 3 ;14(7):3126-3138. Epub 2023 Apr 3. PMID: 36929898 Abstract Title:  Punicalagin protects against impaired skeletal muscle function in high-fat-diet-induced obese mice by regulating TET2. Abstract:  The function of skeletal muscles can be markedly hampered by obesity. Ten-eleven translocation 2 (TET2) is an important therapeutic target for ameliorating skeletal muscle dysfunction. Our previous study revealed that punicalagin (PUN) regulated TET2 in obese mice; however, whether PUN can prevent obesity-induced skeletal muscle dysfunction by regulating TET2 remains unclear. In the present study, 40 male C57BL/6J mice were divided into four groups (= 10 per group): the control (CON) group, the high-fat-diet (HFD, negative control) group, the resveratrol (positive control) group, and the PUN group. The ratio of gastrocnemius weight to body weight (0.00970.00160.00800.0011), the grip strength (120.04 g11.1098.89 g2.79), and the muscle fiber count (314.56 per visual field92.73236.44 per visual field50.58) in the PUN group were higher than those in the HFD group. Moreover, the levels of the TET2 protein, 5-hydroxymethylcytosine (5hmC), and 5-formylcytosine (5fC) in skeletal muscles were significantly lower in the HFD group than those in the CON group; these levels increased after PUN treatment. Compared with the HFD group, the phosphorylation level of AMP-activated protein kinase (AMPK)in the PUN group was higher, which effectively enhanced the stability of the TET2 protein. Besides, the ratio of (succinic acid + fumaric acid)/-ketoglutarate in the PUN group was lower than that in the HFD group (43.2112.4299.1937.07), and a lower ratio led to a higher demethylase activity of TET2 in the PUN group than in the HFD group. This study highlights that PUN supplementation protects against obesity-induced impairment of the skeletal muscle functionregulating the protein stability of TET2 and the enzymatic activity of TET2 demethylation.

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