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PMID:  Food Funct. 2023 May 22 ;14(10):4456-4469. Epub 2023 May 22. PMID: 37066493 Abstract Title:  -Sitosterol protects against food allergic response in BALB/c mice by regulating the intestinal barrier function and reconstructing the gut microbiota structure. Abstract:  This study investigated whether-sitosterol has anti-allergic activity and explored its potential mechanism, using ovalbumin (OVA) allergic mouse model. Results indicated that supplementation with-sitosterol at 5-20 mg kgdayfor 7 weeks alleviated allergic symptoms and intestinal inflammation, and reduced serum OVA-specific immunoglobulin (Ig) E, IgG and histamine levels in sensitized mice.-Sitosterol enhanced physical and biochemical barrier in the intestinal epithelium by upregulating tight junction proteins (claudin-1, occludin, and ZO-1) expression and promoting the secretion of regenerating islet-derived protein IIIand secretory IgA in mucous layer. Furthermore,-sitosterol administration increased the levels of interleukin 10 and transforming growth factor-secreted by regulatory T cells, while reducing T helper 2 cell associated factor levels in intestinal lamina propria. Additionally, the alpha and beta diversity analysis revealed that the structure and diversity of the intestinal flora in the-sitosterol group tended to be normalized compared with the model group, and the number of biomarkers was reduced from 32 to 7. Moreover, the altered composition of gut microbiota in allergic mice was also reversed by-sitosterol supplementation, characterized by an increase in abundance ofandand a decrease in abundance of. Consequently,-sitosterol may prevent FA by ameliorating intestinal barrier function and remodeling the gut microbiota.

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PMID:  Food Funct. 2023 May 11 ;14(9):4117-4128. Epub 2023 May 11. PMID: 37039861 Abstract Title:  Marginal zinc deficiency alters the heart proteome of rats. Abstract:  Zinc deficiency is closely related to cardiovascular diseases (CVDs), but the effects of marginal zinc deficiency (MZD) after birth on the heart are unknown. In this study, 4-week-old male rats were fed a low zinc diet (10 mg kg, 1/3 recommended nutrient intake, RNI) for 8 weeks. Echocardiography and histopathology were performed to assess the functional and morphological alterations of the heart. High-throughput proteomics was used to study the effects of MZD on cardiac protein expression. We found that MZD reduced food intake, body weight, serum zinc, and heart weight; however, the coefficient, zinc concentration, function, and histopathology of the heart were not changed. The heart proteome was altered in the marginal zinc-deficient diet group (MZG), compared with the normal zinc diet group (NZG). A total of 310 differentially expressed proteins (

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PMID:  Food Funct. 2023 May 11 ;14(9):4129-4142. Epub 2023 May 11. PMID: 37042256 Abstract Title:  attenuates Coxsackievirus B3-induced pancreatitis through the BAX/BCL2/CASP3 signaling pathway. Abstract:  is a lactic acid bacterium widely used in food production. Coxsackievirus B3 (CVB3) is an important human pathogen associated with acute pancreatitis development, and no antiviral therapeutics or vaccines are approved to treat or prevent its infection. However, whethercould inhibit CVB3 infection remains unclear. Here,FLPL05 showed antiviral activity against CVB3 infectionand. Pretreatment withFLPL05 reduced serum amylase levels, CVB3 viral load in the pancreas, serum pro-inflammatory cytokine levels, and macrophage infiltration in CVB3-infected mice. In mice,FLPL05 inhibited CVB3-induced pancreas apoptosisthe B cell leukemia/lymphoma 2 (BCL2)/BCL2-associated X protein (BAX)/caspase-3 (CASP3) signaling pathway. Furthermore,FLPL05 reduced CVB3 replication, protected cells from the cytopathic effect of CVB3 infection, and inhibited cell apoptosis. Moreover,FLPL05's exopolysaccharide (EPS) had activity against CVB3, reducing the CVB3 titer and improving cell activity. Therefore,FLPL05 pretreatment improved CVB3-induced pancreatitis by partially reversing pancreatitis, which might be associated with EPS. Consequently,FLPL05 could be a potential probiotic with antiviral activity against CVB3.

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PMID:  Food Funct. 2023 Apr 24 ;14(8):3526-3537. Epub 2023 Apr 24. PMID: 37014333 Abstract Title:  Peptides from Antarctic krill () ameliorate acute liver injury in mice induced by carbon tetrachlorideactivating the Nrf2/HO-1 pathway. Abstract:  This study aimed to evaluate the hepatoprotective effects of peptides from Antarctic krill (AKP) on carbon tetrachloride (CCl)-induced acute liver injury (ALI) in mice and the underlying molecular mechanisms. ICR mice were pretreated with AKP (500 mg kg, i.g.) and silybin (30 mg kg, i.g.) for 15 days before CCl(0.25 mL per kg BW, i.p.) injection. To assess hepatocellular damage and molecular indices, the serum and liver tissue were evaluated at harvest. The results showed that AKP pretreatment remarkably attenuated CCl-induced liver injury, which was identified by the decrease in serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST), alleviation of hepatocyte necrosis, and inhibition of the levels of the pro-inflammatory factors TNF-and IL-1compared to those for silymarin. AKP pretreatment also enhanced the redox balance by reducing the concentrations of MDA and 8-iso-PG and increasing the activities of SOD, GSH and GSH-PX in the liver of mice. In addition, AKP upregulated oxidative stress-related mRNA expressions of Nrf2, Keap1, HO-1, and NQO1 and further activated the protein expression on the Nrf2/HO-1 singling pathway. In summary, AKP might be a promising hepatoprotective nutraceutical against ALI and its underlying mechanisms are associated with activation of the Nrf2/HO-1 pathway.

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PMID:  Biomedicines. 2023 Apr 1 ;11(4). Epub 2023 Apr 1. PMID: 37189686 Abstract Title:  Suppressive Effects ofon Depression through Regulating the Gut Microbiota and Metabolites in C57BL/6J Mice Induced by Ampicillin. Abstract:  Depression is a medical and social problem. Multiple metabolites and neuroinflammation regulate it. Modifying the gut microbiota with probiotics to reduce depression through the gut-brain axis is a potential treatment strategy. In this study, three anti-depressive potentials ofspp. (LAB), includingGMNL-74,GMNL-185 andGMNL-141, which combined to produce low dosage LAB (1.610CFU/mouse, LABL) and high dosage LAB (4.810CFU/mouse, LABH), were administered to C57BL/6 mice induced depression by ampicillin (Amp). A behavioral test of depression, 16S ribosomal RNA gene amplicon sequencing, bioinformatic analysis, and short-chain fatty acid (SCFA) content measurement were executed to investigate the gut microbiota composition, activation of nutrient metabolism pathways, levels of inflammatory factors, gut-derived 5-HT biosynthesis genes, and SCFA levels in C57BL/6 mice. Results showed that after mice were induced by Amp, both LAB groups recovered from depressive behaviors, decreased the abundance of, and increased the abundance ofandin the mouse ileum. The prediction of metabolism pathways of microbes revealed the activation of arginine and proline metabolism, cyanoamino acid metabolism, and nicotinate and nicotinamide metabolism were increased, and fatty acid synthesis was decreased in both LAB groups. The LABH groups showed increased levels of acetic acid, propanoic acid, and iso-butyric acid and decreased butyric acid levels in the cecum. LABH treatment increased claudin-5 and reduced IL-6 mRNA expression. Both LAB groups also reduced monoamine oxidase, and the LABH group increased vascular endothelial growth factor mRNA expression. These results showed that the composite of three LAB exerts antidepressant effects by regulating the gut microbiota and modifying the levels of depression-related metabolites in C57BL/6J Amp-treated mice.

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PMID:  Food Funct. 2023 May 11 ;14(9):3982-3993. Epub 2023 May 11. PMID: 36971096 Abstract Title:  ZJ316 alleviates ulcerative colitis by inhibiting inflammation and regulating short-chain fatty acid levels and the gut microbiota in a mouse model. Abstract:  Ulcerative colitis is an inflammatory bowel disease that is mainly related to gut microbiota dysbiosis.ZJ316 (ZJ316) has been proved to regulate the gut microbiota. However, more evidence is needed for the intestinal effects of ZJ316. Colitis was induceddissolved 2.5% DSS in drinking water for 7 days in 8-week-old BALB/c mice, which were then fed with ZJ316 (110CFU mL) for 35 days. After ZJ316 intervention, the dextran sulfate sodium salt (DSS)-induced colitis symptoms were remarkably alleviated, including recovery of body weight and colon weight and effective inhibition of the expression of pro-inflammatory cytokines. Results based on 16S rRNA gene sequencing indicated that the structure of the gut microbiota in ZJ316 supplementation was markedly altered by upregulating the percentage ofwhile reducing the percentage of. Furthermore, the colon contained more short-chain fatty acids (SCFAs) and butyrate-producing genera, such as,, and. Spearman correlation analysis indicated that SCFAs, especially butyric acid, were positively associated withandOur study suggested that ZJ316 could be used to relieve ulcerative colitis (UC) as dietary therapeutics.

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PMID:  Food Funct. 2023 Apr 24 ;14(8):3701-3711. Epub 2023 Apr 24. PMID: 36974730 Abstract Title:  The effect of ginger () supplementation on clinical, biochemical, and anthropometric parameters in patients with multiple sclerosis: a double-blind randomized controlled trial. Abstract:  : different lines of evidence have shown that ginger administration may be beneficial for patients with multiple sclerosis (MS). Therefore, we aimed to investigate the effect of ginger supplementation on disability, physical and psychological quality of life (QoL), body mass index (BMI), neurofilament light chain (NfL), interlukin-17 (IL-17), matrix metalloproteinase-9 (MMP-9), and neutrophil to lymphocyte ratio (NLR) in patients with relapsing-remitting MS.: this was a 12 week double-blind parallel randomized placebo-controlled trial with a 3 week run-in period. The treatment (= 26) and control (= 26) groups received 500 mg ginger and placebo (corn) supplements 3 times daily, respectively. Disability was evaluated using the Expanded Disability Status Scale (EDSS). QoL was rated using the Multiple Sclerosis Impact Scale (MSIS-29). BMI was calculated by dividing weight by height squared. Serum levels of NfL, IL-17, and MMP-9 were measured using the enzyme-linked immunosorbent assay. NLR was determined using a Sysmex XP-300automated hematology analyzer. All outcomes were assessed before and after the intervention and analyzed using the intention-to-treat principle.: in comparison with placebo, ginger supplementation caused a significant reduction in the EDSS (-0.540.580.080.23,

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PMID:  J Parasit Dis. 2023 Jun ;47(2):329-339. Epub 2023 Mar 25. PMID: 37193490 Abstract Title:  The potential therapeutic effect ofandextracts versus Nitazoxanide drug against experimentally induced cryptosporidiosis in laboratory mice. Abstract:  In this study, the potential anti-cryptosporidial effect of(black seeds) and(ginger) alcoholic extracts versus Nitazoxanide (NTZ) medication was investigated in immunosuppressed (IS) laboratory mice. Parasitological, histopathological studies were used to assess their therapeutic efficacy. Serum level and tissue expression percentage of IFN-was also used. Nigella extract succeeded to reduce the mean oocyst counts in the feces of immunosuppressed mice followed by NTZ. Ginger-treated ones showed the lowest reduction percentage.showed the best results in terms of restoring the normal architecture of ileal epithelium in histopathological sections stained with H&E. NTZ treatment sub-groups showed mild improvement, followed by ginger-treated mice, which showed a slight improvement in small intestine microenvironment. A significant substantial rise in serum and intestinal tissue IFN-cytokine levels were recorded in Nigella subgroups compared to those of NTZ and ginger respectively. According to our findingsoutperformed Nitazoxanide in terms of anti-cryptosporidial effectiveness and regeneration characteristics revealing a promising medication. When compared to the commonly used Nitazoxanide medication or Nigella extracts, the outcomes of ginger extract were suboptimal.

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PMID:  Neurochem Res. 2023 Sep ;48(9):2826-2834. Epub 2023 May 6. PMID: 37148458 Abstract Title:  Effects of Curcumin on Axon Growth and Myelin Sheath Formation in an In Vitro Model. Abstract:  Although the beneficial effects of curcumin, extracted from rhizomes of the ginger family genus Curcuma, on the repair and regeneration of nerves have been evaluated in vitro, there are few studies concerning its effects on axon myelination. Here, we used pheochromocytoma cells as an in vitro model of peripheral nerves. Pheochromocytoma cells were cultured alone or cocultured with Schwann cells and treated with increasing concentrations of curcumin. Cell growth was observed, and the expression levels of growth-associated protein 43 (GAP-43), microtubule-associated protein 2 (MAP-2), myelin basic protein (MBP), myelin protein zero (MPZ), Krox-20, and octamer binding factor 6 (Oct-6) were quantified. We found a significant increase in expression of all six proteins following curcumin treatment, with a corresponding increase in the levels of MBP, MPZ, Krox-20, and Oct-6 mRNA. Upregulation was greater with increasing curcumin concentration, showing a concentration-dependent effect. The results suggested that curcumin can promote the growth of axons by upregulating the expression of GAP-43 and MAP-2, stimulate synthesis and secretion of myelin-related proteins, and facilitate formation of the myelin sheath in axons by upregulating the expression of Krox-20 and Oct-6. Therefore, curcumin could be widely applied in future strategies for the treatment of nerve injuries.

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PMID:  Photochem Photobiol Sci. 2023 Apr 19. Epub 2023 Apr 19. PMID: 37076760 Abstract Title:  Protective effect and mechanism research of Phyllanthus emblica Linn. fruit extract on UV-induced photodamage in keratinocytes. Abstract:  Ultraviolet (UV) irradiation causes acute and chronic cutaneous effects that may result in photodamage and photoaging. Epidermis keratinocytes, as the closest surface of skin, are susceptible to damage from UV rays. Phyllanthus emblica Linn. fruit (PE) extract, as a medicine and food dual-use plant, contains high levels of polyphenols and possesses multiple pharmacological properties. The present study investigated common and different molecular mechanisms and signaling pathway activations of UVA and UVB stimulated cell damage and photoprotective effect of PE extract against UVA and UVB by Methyl Thiazolyl Tetrazolium (MTT) method, Elisa assay, flow cytometry, differentially expressed genes analysis and western blot analysis. The results showed that UVA exposure (10 J/cm) reduced HaCaT cell viability significantly, increased the apoptosis rate, elevated intracellular reactive oxygen species level and reduced antioxidant enzyme activities. And UVA irradiation could inhibit the ERK/TGF-/Smad signaling pathway to downregulate collagen I, collagen III and elastin expressions, resulting in the photoaging of skin cells. We also found UVB exposure (30 mJ/cm) caused HaCaT cell damage, promoted apoptosis, increased ROS production and induced the release of proinflammatory cytokines (IL-1, IL-6 and PGE2). Further, in HaCaT cells, UVB ray was able to induce the activation of apoptosis markers (cleaved PARP1 and cleaved caspase3) through the MAPK/AP-1 signaling pathway using western blot analysis. Pre-treatment of PE extract prevented the UVA and UVB induced photoaging and injury in HaCaT cells through activation of ERK/TGF-/Smad pathway and inhibition of MAPK/AP-1 pathway, respectively. Therefore, PE extract has the potential to be used as an oral and topical preparation against skin aging and injury induced by UVA and UVB.

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PMID:  Food Funct. 2023 Apr 24 ;14(8):3406-3422. Epub 2023 Apr 24. PMID: 36974511 Abstract Title:  Meta-analysis of randomized controlled trials of the effects of probiotics in Parkinson's disease. Abstract:  : Patients with Parkinson's disease (PD) demonstrate intestinal dysbiosis and substantial gastrointestinal dysfunction. Preliminary evidence suggests that probiotics may have a positive effect on the motor and non-motor symptoms of PD. However, the effectiveness of probiotics in treating PD remains unclear. Therefore, a randomized controlled trial (RCT) was performed to examine the efficacy of oral probiotics in PD treatment.: PubMed, Web of Science, Cochrane Library, EMBASE, Clinical Trials, and Google Scholar were searched for relevant RCTs published until January 28, 2023. Meta-analyses have examined the effects of probiotics on motor and non-motor symptom parameters in RCTs. Inverse-variance random or fixed effects were used to pool data. The Grading of Recommendations Assessment, Development, and Evaluations was used to examine the quality of evidence for outcomes of the meta-analysis.: Nine eligible RCTs (= 663) were included in this meta-analysis. In the meta-analysis, probiotic treatment significantly improved motor symptoms (UPDRS-III scores: standardized mean difference [SMD] = -0.28, 95% confidence interval [CI], -0.49 to -0.07,= 7%), constipation and constipation-related quality of life (Bristol scores: SMD = 0.54; 95% CI, 0.35 to 0.73,= 0%; bowel movement scores: SMD = 0.83; 95% CI, 0.59 to 1.07,= 43%; CSBMs: SMD = 0.56; 95% CI, 0.30 to 0.82,= 0%; PAC-QCL scores: SMD = -0.84; 95% CI, -1.08 to -0.60,= 0%), and anxiety and depression parameters (HAMA scores: SMD = -0.35; 95% CI, -0.60 to -0.10,= 0%; HADM-17 scores: SMD = -0.33; 95% CI, -0.59 to -0.08,= 0%). In addition, probiotic supplements significantly reduced the use of laxatives (SMD = -0.27; 95% CI, -0.53 to -0.01,= 15%) and increased GSH levels in the serum of PD patients (SMD = 0.52; 95% CI, 0.14 to 0.90,= 0%). The certainty of evidence was graded as very low for UPDRS-III, PAC-QCL, CSBMs, HAMA, HADM-17 and Bristol scores and low for bowel movement scores. Two of the nine RCTs reported that probiotics may cause abdominal bloating at low rates on consuming probiotics, which suggests that we should pay attention to the occurrence of adverse events during the consumption of probiotics in future studies.: Oral probiotic consumption significantly improved motor symptoms, gastrointestinal dysfunction, anxiety, and depression in patients with PD. Notably, oral probiotics also reduced the use of laxatives and increased GSH levels in the serum of patients with PD. In future studies, more high-quality evidence from large-scale RCTs is needed to determine the exact effects of probiotic treatment on PD....

PMID:  Exp Ther Med. 2023 Jun ;25(6):265. Epub 2023 Apr 20. PMID: 37206558 Abstract Title:  Sulforaphane alleviates lung ischemiareperfusion injury through activating Nrf2/HO1 signaling. Abstract:  Oxidative stress and inflammation are both involved in the pathogenesis of lung ischemia-reperfusion (I/R) injury. Sulforaphane (SFN) is a natural product with cytoprotective, anti-inflammatory, and antioxidant properties. The present study hypothesized that SFN may protect against lung I/R injury via the regulation of antioxidant and anti-inflammatory-related pathways. A rat model of lung I/R injury was established, and rats were randomly divided into 3 groups: Sham group, I/R group, and SFN group. It was shown that SFN protected against a pathological inflammatory response via inhibition of neutrophil accumulation and in the reduction of the serum levels of the pro-inflammatory cytokines, IL-6, IL-1, and TNF-. SFN treatment also significantly inhibited lung reactive oxygen species production, decreased the levels of 8-OH-dG and malondialdehyde, and reversed the decrease in the antioxidant activities of the enzymes catalase, superoxide dismutase, and glutathione peroxidase in the lungs of the I/R treated rats. In addition, SFN ameliorated I/R-induced lung apoptosis in rats by suppressing Bax and cleaved caspase-3 levels and increased Bcl-2 expression. Furthermore, SFN treatment activated an Nrf2-related antioxidant pathway, as indicated by the increased nuclear transfer of Nrf2 and the downstream HO-1 and NADPH quinone oxidoreductase-1. In conclusion, these findings suggested that SFN protected against I/R-induced lung lesions in rats via activation of the Nrf2/HO-1 pathway and the accompanied anti-inflammatory and anti-apoptotic effects.

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PMID:  Biomedicines. 2023 Mar 23 ;11(4). Epub 2023 Mar 23. PMID: 37189614 Abstract Title:  Sulforaphane-Induced Cell Mitotic Delay and Inhibited Cell Proliferation via Regulating CDK5R1 Upregulation in Breast Cancer Cell Lines. Abstract:  Our research has revealed that sulforaphane (SFN) has chemopreventive properties and could be used in chemotherapy treatments. Further investigation is needed to understand the mechanisms behind sulforaphane's (SFN) antitumor activity in breast adenocarcinoma, as observed in our studies. This research looked into the effects of SFN on mitosis delay and cell cycle progression in MDA-MB-231 and ZR-75-1 cells, two types of triple-negative breast cancer adenocarcinoma.The proliferation of the cancer cells after SFN exposure was evaluated using MTT assay, DNA content and cell cycle arrest induction by flow cytometry, and expressions of cdc25c, CDK1, cyclin B1 and CDK5R1 were assessed through qRT-PCR and Western blot analysis. SFN was found to inhibit the growth of cancer cells. The accumulation of G2/M-phase cells in SFN-treated cells was attributed to CDK5R1. The disruption of the CDC2/cyclin B1 complex suggested that SFN may have antitumor effects on established breast adenocarcinoma cells. Our findings suggest that, in addition to its chemopreventive properties, SFN could be used as an anticancer agent for breast cancer, as it was found to inhibit growth and induce apoptosis of cancer cells.

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PMID:  Food Sci Nutr. 2023 May ;11(5):2277-2287. Epub 2023 Mar 31. PMID: 37181316 Abstract Title:  Effects of sulforaphane on breast cancer based on metabolome and microbiome. Abstract:  Sulforaphane (SFN) is a promising phytochemical with a wide range of antitumor activities. A comprehensive understanding of the effects of SFN on breast cancer based on the metabolome and microbiome is limited. Thus, we treated MCF-7 cell-transplanted nude mice with 50mg/kg SFN. SFN inhibits breast cancer cell proliferation. SFN increased the levels of sulfate-related metabolites and glutathione-related metabolites and decreased tryptophan metabolites and methyl-purine metabolites in urinary metabolic profile. SFN indirectly affected the activation of aryl hydrocarbon receptor by tryptophan metabolism. The ratio of SAM to methionine was decreased by SFN while the global DNA methylation was downregulated in tumor tissue. SFN decreased the sulfate-reducing bacterium, which is related to reduced methylation capacity, and increased the genusrelated to tryptophan metabolites with antitumor activities. In conclusion, we provide a perspective on the metabolome and microbiome to elucidate the antitumor activities of SFN.

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PMID:  Food Funct. 2023 Apr 3 ;14(7):3259-3268. Epub 2023 Apr 3. PMID: 36928268 Abstract Title:  F40-4 ameliorates hyperuricemia by modulating the gut microbiota and alleviating inflammation in mice. Abstract:  Hyperuricemia (HUA) is a systemic disease characterized by a disorder of purine metabolism and an abnormal increase in the serum level of uric acid (UA). Probiotics can exert potential therapeutic benefits against some metabolic diseases by regulating the intestinal microbiota.F40-4 with UA-lowering activity of 87.40% was screened using purine as the target. The UA-lowering activity ofF40-4 was further explored in a mouse model of HUA.F40-4 could downregulate serum levels of UA, blood urea nitrogen, creatinine, and xanthine oxidase by 40.84%, 11.61%, 57.66%, and 41.79%, respectively.F40-4 restored organ damage, and adjusted enzyme activity and transporter expression to promote the metabolic level of UA. In addition,F40-4 could reshape the gut microbiota and suppress inflammation to ameliorate HUA. An increment in intestinal UA excretion was documented. These findings suggest thatF40-4 might serve as a potential probiotic for the prevention and treatment of HUA.

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PMID:  Food Funct. 2023 Mar 20 ;14(6):2668-2683. Epub 2023 Mar 20. PMID: 36883322 Abstract Title:  Oolong tea of different years protects high-fat diet-fed mice against obesity by regulating lipid metabolism and modulating the gut microbiota. Abstract:  Long-term stored oolong tea has recently attracted considerable attention concerning its salutary effect. In this study, the anti-obesity effect of different years' oolong tea on high-fat diet-fed mice was compared. Wuyi rock tea of 2001, 2011, and 2020 were chosen to be the representative samples of oolong tea. The results showed that eight-week administration of 2001 Wuyi rock tea (WRT01), 2011 Wuyi rock tea (WRT11), and 2020 Wuyi rock tea (WRT20) extracts (400 mg per kg per d) significantly decreased the body weight and attenuated the obesity in high-fat diet-fed mice. 2001 and 2011 Wuyi rock teas reduced obesity mainly through regulating lipid metabolism and activating the AMPK/SREBP-1 pathway, downregulating the expression of SREBP-1, FAS, and ACC and upregulating CPT-1a expression; while the 2011 and 2020 Wuyi rock teas by moderating the gut microbiota dysbiosis, reshaping the gut microbiota, and promoting the growth of beneficial bacteria, especially. 2011 Wuyi rock tea was proven to be more effective in reducing body weight gain and liver oxidative stress than the others. Collectively, all three Wuyi rock teas of different years alleviated high-fat diet-induced obesity by regulating lipid metabolism and modulating gut microbiota, whereas the emphasis of their internal mechanism is different with different storage ages.

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PMID:  Molecules. 2022 Nov 6 ;27(21). Epub 2022 Nov 6. PMID: 36364431 Abstract Title:  Green Tea Catechins Attenuate Neurodegenerative Diseases and Cognitive Deficits. Abstract:  Neurodegenerative diseases exert an overwhelming socioeconomic burden all around the globe. They are mainly characterized by modified protein accumulation that might trigger various biological responses, including oxidative stress, inflammation, regulation of signaling pathways, and excitotoxicity. These disorders have been widely studied during the last decade in the hopes of developing symptom-oriented therapeutics. However, no definitive cure has yet been discovered. Tea is one of the world's most popular beverages. The same plant,(L.).O. Kuntze, is used to make green, black, and oolong teas. Green tea has been most thoroughly studied because of its anti-cancer, anti-obesity, antidiabetic, anti-inflammatory, and neuroprotective properties. The beneficial effect of consumption of tea on neurodegenerative disorders has been reported in several human interventional and observational studies. The polyphenolic compounds found in green tea, known as catechins, have been demonstrated to have many therapeutic effects. They can help in preventing and, somehow, treating neurodegenerative diseases. Catechins show anti-inflammatory as well as antioxidant effects via blocking cytokines' excessive production and inflammatory pathways, as well as chelating metal ions and free radical scavenging. They may inhibit tau protein phosphorylation, amyloid beta aggregation, and release of apoptotic proteins. They can also lower alpha-synuclein levels and boost dopamine levels. All these factors have the potential to affect neurodegenerative disorders. This review will examine catechins' neuroprotective effects by highlighting their biological, pharmacological, antioxidant, and metal chelation abilities, with a focus on their ability to activate diverse cellular pathways in the brain. This review also points out the mechanisms of catechins in various neurodegenerative and cognitive diseases, including Alzheimer's, Parkinson's, multiple sclerosis, and cognitive deficit.

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PMID:  Food Funct. 2023 Mar 20 ;14(6):2857-2869. Epub 2023 Mar 20. PMID: 36880662 Abstract Title:  Natural isoflavone formononetin inhibits IgE-mediated mast cell activation and allergic inflammation by increasing IgE receptor degradation. Abstract:  Immunoglobulin (Ig)E-associated mast cell (MC) activation triggers pro-inflammatory signals that underlie type I allergic diseases. Here, we examined the effects of the natural isoflavone formononetin (FNT) on IgE-mediated MC activation and associated mechanisms of high-affinity IgE receptor (FcRI) signal inhibition. The effects of FNT on the mRNA expression of inflammatory factors, release of histamine and-hexosaminidase (-hex), and expression of signaling proteins and ubiquitin (Ub)-specific proteases (USPs) were analyzed in two sensitized/stimulated MC lines. FcRI-USP interactions were detected by co-immunoprecipitation (IP). FNT dose-dependently inhibited-hex activity, histamine release, and inflammatory cytokine expression in FcRI-activated MCs. FNT suppressed IgE-induced NF-B and MAPK activity in MCs. The oral administration of FNT attenuated passive cutaneous anaphylaxis (PCA) reactions and ovalbumin (OVA)-induced active systemic anaphylaxis (ASA) reactions in mice. FNT reduced the FcRIchain expression,increased proteasome-mediated degradation, and induced FcRIubiquitination by inhibiting USP5 and/or USP13. FNT and USP inhibition may be useful for suppressing IgE-mediated allergic diseases.

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PMID:  Phytother Res. 2023 Jun ;37(6):2693-2737. Epub 2023 May 17. PMID: 37195042 Abstract Title:  Molecular mechanisms underlying the potential neuroprotective effects of Trifolium pratense and its phytoestrogen-isoflavones in neurodegenerative disorders. Abstract:  Neurodegenerative disorders are heterogeneous, debilitating, and incurable groups of brain disorders that have common features including progressive degeneration of the structure and function of the nervous system. Phytoestogenic-isoflavones have been identified as active compounds that can modulate different molecular signaling pathways related to the nervous system. The main aim is to shed the light on the molecular mechanisms followed by phytoestrogen-isoflavones profound in the Trifolium pratense and discuss the latest pharmacological findings in the treatment of neurodegenerative disorders. Data were collected using different databases. The search terms used included "Phytoestrogens," "Isoflavones," "neurodegenerative disorders," "Neuronal plasticity," etc., and combinations of these keywords. As a result, this review article mainly demonstrates the potential neuroprotective properties of phystoestrogen-isoflavones present in the Trifolium pratense (Red clover), particularly in neurodegenerative disorders. Phytochemical studies have shown that Trifolium pratense mainly includes more than 30 isoflavone compounds. Among them, phytoestrogen-isoflavones, such as biochanin A, daidzein, formononetin, genistein (Gen), etc.,are characterized by potent neuroprotective properties against different neurodegenerative disorders. There are preclinical and clinical scientific evidence on their mechanisms of action involve molecular interaction with estrogenic receptors, anti-inflammatory, anti-oxidative, antiapoptotic, autophagic inducing, and so on. phytoestrogen-isoflavones are the major bioactive components in the Trifolium pratense that exhibit therapeutic efficacy in the case of neurodegenerative disorders. This review provides detailed molecular mechanisms targeted by phytoestrogen-isoflavones and experimental key findings for the clinical use of prescriptions containing Trifolium pratense-derived isoflavones for the treatment of neurodegenerative disorders.

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PMID:  Immunol Invest. 2023 Nov ;52(4):399-414. Epub 2023 Mar 28. PMID: 36975047 Abstract Title:  Formononetin Inhibits Microglial Inflammatory Response and Contributes to Spinal Cord Injury Repair by Targeting the EGFR/MAPK Pathway. Abstract:  Zhenbao Pill contains many Chinese herbal medicinal ingredients and has been proven to have therapeutic effects on the repair of spinal cord injury (SCI). This study attempts to investigate the role of formononetin (FMN), an ingredient of Zhenbao Pill, in regulating neuroinflammation after SCI and the underlying mechanism. Primary microglia isolated from the spinal cord of newborn rats and human microglial clone 3 (HMC3) cells were stimulated with IL-1followed by FMN incubation. The cell viability and inflammatory cytokine levels were detected. The target of FMN was predicted and screened using databases. By silencing or overexpression of epidermal growth factor receptor (EGFR), the anti-neuroinflammatory effect of FMN was assessed in vitro. In vivo, FMN was intraperitoneally injected into rats after SCI followed by the neurological function and histopathology examination. The isolated microglia were in high purity, and the different concentrations of FMN incubation had no toxic effects on primary microglia and HMC3 cells. FMN reduced the inflammatory cytokine levels (TNF-and IL-6) in a concentration-dependent manner. EGFR silencing or FMN incubation decreased p-EGFR and p-p38 levels and down-regulated inflammatory cytokine levels in IL-1-stimulated cells or supernatants. Nevertheless, the effects of FMN on microglial inflammation were reversed by EGFR overexpression. In vivo, FMN treatment improved the neuromotor function, repaired tissue injury, and inhibited EGFR/p38MAPK phosphorylation. Formononetin inhibits microglial inflammatory response and contributes to SCI repair via the EGFR/p38MAPK signaling pathway.

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PMID:  Phytother Res. 2023 Apr 1. Epub 2023 Apr 1. PMID: 37002905 Abstract Title:  Formononetin improves the inflammatory response and bone destruction in knee joint lesions by regulating the NF-kB and MAPK signaling pathways. Abstract:  Formononetin (FMN) is a phytoestrogen that belongs to the isoflavone family. It has antioxidant and anti-inflammatory effects, as well as, many other biological activities. Existing evidence has aroused interest in its ability to protect against osteoarthritis (OA) and promote bone remodeling. To date, research on this topic has not been thorough and many issues remain controversial. Therefore, the purpose of our study was to explore the protective effect of FMN against knee injury and clarify the possible molecular mechanisms. We found that FMN inhibited osteoclast formation induced by receptor activator of NF-B ligand (RANKL). Inhibition of the phosphorylation and nuclear translocation of p65 in the NF-B signaling pathway plays a role in this effect. Similarly, during the inflammatory response of primary knee cartilage cells activated by IL-1, FMN inhibited the NF-B signaling pathway and the phosphorylation of the ERK and JNK proteins in the MAPK signaling pathway to suppress the inflammatory response. In addition, in vivo experiments showed that both low- and high-dose FMN had a clear protective effect against knee injury in the DMM (destabilization of the medial meniscus) model, and the therapeutic effect of high-dose FMN was stronger. In conclusion, these studies provide evidence of the protective effect of FMN against knee injury.

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PMID:  Life Sci. 2023 Feb 15 ;315:121331. Epub 2022 Dec 29. PMID: 36586573 Abstract Title:  Formononetin ameliorates ferroptosis-associated fibrosis in renal tubular epithelial cells and in mice with chronic kidney disease by suppressing the Smad3/ATF3/SLC7A11 signaling. Abstract:  AIMS: Chronic kidney disease (CKD) is characterized by interstitial fibrosis, while limited treatment drugs are available. Ferroptosis is a newly identified process that can trigger tubular atrophy and fibrosis. The aim of this study is to investigate the effects of formononetin (FN), a bioflavonoid, on ferroptosis and renal fibrosis.MAIN METHODS: In vivo experiments, unilateral ureteral obstruction (UUO)- and folic acid (FA, 250 mg/kg)-induced CKD models were constructed in C57BL/6 mice of 6-8 weeks old, followed by the administration with 40 mg/kg/day FN by gavage. For in vitro experiments, ferroptosis was induced with RSL3 or erastin in primary mouse renal tubular epithelial cells (TECs), followed by the addition of indicated concentrations of FN. Then, the levels of ferroptosis and fibrosis were analyzed. The translocation of Smad3, ATF3, and Nrf2 from the cytoplasm to the nucleus was checked by western blotting. The interaction of Smad3 and ATF3 was detected by Co-immunoprecipitation.KEY FINDINGS: FN dramatically ameliorated tubular injury along with reduced expression of the profibrotic genes including-SMA, Col1a1, and fibronectin in both two CKD mouse models and RSL3/erastin-treated TECs. Furthermore, FN administration also significantly suppressed ferroptosis, as evidenced by increased expression of SLC7A11 and GPX4, and decreased levels of 4-HNE. In mechanism, FN disrupted the interaction between Smad3 and ATF3, resulting in the blocking of their translocation from the cytoplasm to the nucleus. In addition, FN also promoted the separation of the Nrf2/Keap1 complex and enhanced Nrf2 nuclear accumulation.SIGNIFICANCE: FN alleviates CKD by impeding ferroptosis-associated fibrosis by suppressing the Smad3/ATF3/SLC7A11 signaling and could serve as a candidate therapeutic drug for CKD.

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PMID:  Microbiol Spectr. 2023 Jun 15 ;11(3):e0052623. Epub 2023 May 16. PMID: 37191530 Abstract Title:  Perillaldehyde Functions as a Potential Antifungal Agent by Triggering Metacaspase-Independent Apoptosis in Botrytis cinerea. Abstract:  Botrytis cinerea, the causal agent of gray mold, is an important plant pathogen causing preharvest and postharvest diseases. Due to the extensive use of commercial fungicides, fungicide-resistant strains have emerged. Natural compounds with antifungal properties are widely present in various kinds of organisms. Perillaldehyde (PA), derived from the plant species Perilla frutescens, is generally recognized as a potent antimicrobial substance and to be safe to humans and the environment. In this study, we demonstrated that PA could significantly inhibit the mycelial growth of B. cinerea and reduced its pathogenicity on tomato leaves. We also found that PA had a significant protective effect on tomato, grape, and strawberry. The antifungal mechanism of PA was investigated by measuring the reactive oxygen species (ROS) accumulation, the intracellular Calevel, the mitochondrial membrane potential, DNA fragmentation, and phosphatidylserine exposure. Further analyses revealed that PA promoted protein ubiquitination and induced autophagic activities and then triggered protein degradation. When the two metacaspase genes,and, were knocked out from, all mutants did not exhibit reduced sensitivity to PA. These findings demonstrated that PA could induce metacaspase-independent apoptosis in. Based on our results, we proposed that PA could be used as an effective control agent for gray mold management.Botrytis cinerea causes gray mold disease, is considered one of the most important dangerous pathogens worldwide, and leads to severe economic losses worldwide. Due to the lack of resistant varieties of, gray mold control has mainly relied on application of synthetic fungicides. However, long-term and extensive use of synthetic fungicides has increased fungicide resistance inand is harmful to humans and the environment. In this study, we found that perillaldehyde has a significant protective effect on tomato, grape, and strawberry. We further characterized the antifungal mechanism of PA on. Our results indicated that PA induced apoptosis that was independent of metacaspase function.

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PMID:  Molecules. 2023 Apr 12 ;28(8). Epub 2023 Apr 12. PMID: 37110648 Abstract Title:  An Ethanol Extract ofLeaves Suppresses Adrenergic Agonist-Induced Metastatic Ability of Cancer Cells by Inhibiting Src-Mediated EMT. Abstract:  Previous studies have indicated that the adrenergic receptor signaling pathway plays a fundamental role in chronic stress-induced cancer metastasis. In this study, we investigated whether an ethanol extract ofleaves (EPF) traditionally used to treat stress-related symptoms by moving Qi could regulate the adrenergic agonist-induced metastatic ability of cancer cells. Our results show that adrenergic agonists including norepinephrine (NE), epinephrine (E), and isoproterenol (ISO) increased migration and invasion of MDA-MB-231 human breast cancer cells and Hep3B human hepatocellular carcinoma cells. However, such increases were completely abrogated by EPF treatment. E/NE induced downregulation of E-cadherin and upregulation of N-cadherin, Snail, and Slug. Such effects were clearly reversed by pretreatment with EPF, suggesting that the antimetastatic activity of EPF could be related to epithelial-mesenchymal transition (EMT) regulation. EPF suppressed E/NE-stimulated Src phosphorylation. Inhibition of Src kinase activity with dasatinib completely suppressed the E/NE-induced EMT process. Transfecting MDA-MB-231 cells with constitutively activated Src (SrcY527F) diminished the antimigration effect of EPF. Taken together, our results demonstrate that EPF can suppress the adrenergic agonist-promoted metastatic ability of cancer cells by inhibiting Src-mediated EMT. This study provides basic evidence supporting the probable use of EPF to prevent metastasis in cancer patients, especially those under chronic stress.

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PMID:  Front Pharmacol. 2023 ;14:1114410. Epub 2023 Mar 14. PMID: 36998613 Abstract Title:  Efficacy of(L.) Britton var.extract on mild knee joint pain: A randomized controlled trial. Abstract:  This study aimed to evaluate the clinical efficacy and safety of PE extracts developed for the purpose of relieving pain and improving knee joint function on semi-healthy people with mild knee joint pain.A randomized, double-blind, two-arm, single-center, placebo-controlled clinical trial was conducted. Individuals with knee joint pain and a visual analogue scale (VAS) score

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PMID:  Front Pharmacol. 2023 ;14:1044576. Epub 2023 Apr 18. PMID: 37144216 Abstract Title:  Lycium barbarum polysaccharide alleviates dextran sodium sulfate-induced inflammatory bowel disease by regulating M1/M2 macrophage polarization via the STAT1 and STAT6 pathways. Abstract:  Disruption of colonic homeostasis caused by aberrant M1/M2 macrophage polarization contributes to the development of inflammatory bowel disease (IBD). Lycium barbarum polysaccharide (LBP) is the primary active constituent of traditional Chinese herbal, which has been widely demonstrated to have important functions in regulating immune activity and anti-inflammatory. Thus, LBP may protect against IBD. To test this hypothesis, the DSS-induced colitis model was established in mice, then the mice were treated with LBP. The results indicated that LBP attenuated the weight loss, colon shortening, disease activity index (DAI), and histopathological scores of colon tissues in colitis mice, suggesting that LBP could protect against IBD. Besides, LBP decreased the number of M1 macrophages and the protein level of Nitric oxide synthase 2(NOS2) as a marker of M1 macrophages and enhanced the number of M2 macrophages and the protein level of Arginase 1(Arg-1) as a marker of M2 macrophages in colon tissues from mice with colitis, suggesting that LBP may protect against IBD by regulating macrophage polarization. Next, the mechanistic studies in RAW264.7 cells showed that LBP inhibited M1-like phenotype by inhibiting the phosphorylation of STAT1, and promoted M2-like phenotype by promoting the phosphorylation of STAT6. Finally, immunofluorescence double-staining results of colon tissues showed that LBP regulated STAT1 and STAT6 pathways. The results in the study demonstrated that LBP could protect against IBD by regulating macrophage polarization through the STAT1 and STAT6 pathways.

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PMID:  Free Radic Biol Med. 2023 Aug 1 ;204:84-94. Epub 2023 Apr 28. PMID: 37119863 Abstract Title:  Lycium barbarum polysaccharide-glycoprotein ameliorates ionizing radiation-induced epithelial injury by regulating oxidative stress and ferroptosis via the Nrf2 pathway. Abstract:  Radiation-induced oral mucositis (RIOM) is considered to be the most common acute side effect of radiation therapy and occurs during intentional or accidental radiation exposure. Antioxidant synthesis agents have been reported to protect against or alleviate the development of mucositis, but the resulting side effects of chemical synthesis agents limit their use in clinical practice. Lycium barbarum polysaccharide-glycoprotein (LBP), a polysaccharide extract of the Lycium barbarum fruit, has superior antioxidant capacity and biosafety and is a potential option for radiation prevention and treatment. Here, we aimed to investigate whether LBP conferred radioprotection against ionizing radiation-induced oral mucosal damage. We found that LBP exerted radioprotective effects in irradiated HaCaT cells, improving cell viability, stabilizing mitochondrial membrane potential, and decreasing cell death. LBP pretreatment reduced oxidative stress and ferroptosis in radioactivity-damaged cells by activating the transcription factor Nrf2 and promoting its downstream targets, such as HO-1, NQO1, SLC7A11, and FTH1. Knockdown of Nrf2 eliminated the protective effects of LBP, implying the essential role of Nrf2 in LBP activity. Additionally, the topical application of LBP thermosensitive hydrogel on rat mucosa resulted in a significant decrease in ulcer size in the irradiated group, suggesting that LBP oral mucoadhesive gel may be a potential tool for the treatment of irradiation. In conclusion, we demonstrated that LBP attenuates ionizing radiation-induced oral mucosa injury by reducing oxidative stress and inhibiting ferroptosis via the Nrf2 signaling pathway. LBP may be a promising medical countermeasure against RIOM.

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PMID:  Foods. 2023 Apr 11 ;12(8). Epub 2023 Apr 11. PMID: 37107413 Abstract Title:  Oligosaccharides Alleviate Hepatic Steatosis by Modulating Gut Microbiota in C57BL/6J Mice Fed a High-Fat Diet. Abstract:  High-fat diets (HFD) can promote the development of hepatic steatosis by altering the structure and composition of gut flora. In this study, the potential therapeutic mechanism ofoligosaccharide (LBO) against hepatic steatosis was investigated by analyzing the changes in the intestinal flora and metabolites in mice. Mice on an HFD were administered LBO by gavage once daily for a continuous period of eight weeks. Compared with the HFD group, the levels of triglyceride (TG), alanine aminotransferase (ALT) in the serum, and hepatic TG were significantly reduced in the LBO group, and liver lipid accumulation was obviously improved. In addition, LBO could regulate the HFD-induced alteration of intestinal flora. The HFD increased the proportion of,, and. LBO increased the proportion of,, and. LBO also altered the fecal metabolic profile. Significantly different metabolites between LBO and the HFD, such as taurochenodeoxycholate, taurocholate, fluvastatin, and kynurenic acid, were related to the cholesterol metabolism, bile acid metabolism, and tryptophan metabolic pathways. In light of the above, LBO can alleviate HFD-induced NAFLD by modulating the components of the intestinal flora and fecal metabolites.

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PMID:  Food Funct. 2023 Mar 20 ;14(6):2768-2780. Epub 2023 Mar 20. PMID: 36857703 Abstract Title:  Cherry juice alleviates high-fat diet-induced obesity in C57BL/6J mice by resolving gut microbiota dysbiosis and regulating microRNA. Abstract:  Cherry is a nutrient-rich food that is good for health. This study demonstrated the inhibitory action of dietary cherry juice on high-fat diet (HFD)-induced obesity in mice. Cherry juice intervention significantly decreased body weight, fat contents, and blood lipid levels in obese mice. The overproduction of proinflammatory cytokines was suppressed by dietary cherry juice, which was accompanied by the elevation of tight junction proteins to maintain intestinal barrier. Moreover, dietary cherry juice restored the decreased production of short-chain fatty acids (SCFAs) by regulating the composition and abundance of gut microbiota. In addition, dietary cherry juice also suppressed the expression of some microRNAs associated with obesity such as miR-200c-3p, miR-125a-5p, miR-132-3p, and miR-223-3p and target proteins related with microRNAs in the inguinal or epididymal white tissue in the obese mice. These results offer a fresh perspective on cherry juice's role in the prevention of obesity caused by the HFD.

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PMID:  Drug Deliv Transl Res. 2023 May 6. Epub 2023 May 6. PMID: 37149557 Abstract Title:  Preparation, characterization, and evaluation of the antitumor effect of kaempferol nanosuspensions. Abstract:  Kaempferol (KAE) is a naturally occurring flavonoid compound with antitumor activity. However, the low aqueous solubility, poor chemical stability, and suboptimal bioavailability greatly restrict its clinical application in cancer therapy. To address the aforementioned limitations and augment the antitumor efficacy of KAE, we developed a kaempferol nanosuspensions (KAE-NSps) utilizing D--tocopherol polyethylene glycol 1000 succinate (TPGS) as a stabilizing agent, screened the optimal preparation process, and conducted a comprehensive investigation of their fundamental properties as well as the antitumor effects in the study. The findings indicated that the particle size was 186.62.6 nm of the TPGS-KAE-NSps optimized, the shape of which was fusiform under the transmission electron microscope. The 2% (w/v) glucose was used as the cryoprotectant for TPGS-KAE-NSps, whose drug loading content was 70.312.11%, and the solubility was prominently improved compared to KAE. The stability and biocompatibility of TPGS-KAE-NSps were favorable and had a certain sustained release effect. Moreover, TPGS-KAE-NSps clearly seen to be taken in the cytoplasm exhibited a stronger cytotoxicity and suppression of cell migration, along with increased intracellular ROS production and higher apoptosis rates compared to KAE in vitro cell experiments. In addition, TPGS-KAE-NSps had a longer duration of action in mice, significantly improved bioavailability, and showed a stronger inhibition of tumor growth (the tumor inhibition rate of high dose intravenous injection group was 68.91.46%) than KAE with no obvious toxicity in 4T1 tumor-bearing mice. Overall, TPGS-KAE-NSps prepared notably improved the defect and the antitumor effects of KAE, making it a promising nanodrug delivery system for KAE with potential applications as a clinical antitumor drug.

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PMID:  Med Res Rev. 2023 May 5. Epub 2023 May 5. PMID: 37147865 Abstract Title:  The role of flavonoids in the regulation of epithelial-mesenchymal transition in cancer: A review on targeting signaling pathways and metastasis. Abstract:  One of the hallmarks of cancer is metastasis, a process that entails the spread of cancer cells to distant regions in the body, culminating in tumor formation in secondary organs. Importantly, the proinflammatory environment surrounding cancer cells further contributes to cancer cell transformation and extracellular matrix destruction. During metastasis, front-rear polarity and emergence of migratory and invasive features are manifestations of epithelial-mesenchymal transition (EMT). A variety of transcription factors (TFs) are implicated in the execution of EMT, the most prominent belonging to the Snail Family Transcriptional Repressor (SNAI) and Zinc Finger E-Box Binding Homeobox (ZEB) families of TFs. These TFs are regulated by interaction with specific microRNAs (miRNAs), as miR34 and miR200. Among the several secondary metabolites produced in plants, flavonoids constitute a major group of bioactive molecules, with several described effects including antioxidant, antiinflammatory, antidiabetic, antiobesogenic, and anticancer effects. This review scrutinizes the modulatory role of flavonoids on the activity of SNAI/ZEB TFs and on their regulatory miRNAs, miR-34, and miR-200. The modulatory role of flavonoids can attenuate mesenchymal features and stimulate epithelial features, thereby inhibiting and reversing EMT. Moreover, this modulation is concomitant with the attenuation of signaling pathways involved in diverse processes as cell proliferation, cell growth, cell cycle progression, apoptosis inhibition, morphogenesis, cell fate, cell migration, cell polarity, and wound healing. The antimetastatic potential of these versatile compounds is emerging and represents an opportunity for the synthesis of more specific and potent agents.

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PMID:  J Health Popul Nutr. 2023 May 5 ;42(1):39. Epub 2023 May 5. PMID: 37147659 Abstract Title:  Inflammatory biomarkers in overweight and obese Iranian women are associated with polyphenol intake. Abstract:  BACKGROUND: The evidence shows that obesity is associated with chronic inflammation in obese subjects. Polyphenols are a complex group of plant secondary metabolites that may play a role in reducing the risk of obesity and obesity-related diseases. Given the scarcity of evidence on the association between inflammatory markers and dietary polyphenols intake in overweight/obese Iranian women, the current study aims to investigate this link.METHOD: The present cross-sectional study was conducted on 391 overweight and obese Iranian women aged 18-48 years (body mass index (BMI)25 kg/m). A 147-item food frequency questionnaire (FFQ) was used to assess dietary intake, as well as anthropometric indices including weight, height, waist circumference (WC), and hip circumference (HC) and biochemistry parameters including triglyceride (TG), total cholesterol (Chole), low-density lipoprotein cholesterol (LDL-c), high-density lipoprotein cholesterol (HDL-c), serum glutamic pyruvic transaminase (SGPT), serum glutamic-oxaloacetic transaminase (SGOT), galactin-3 (Gal-3), monocyte chemoattractant protein-1 (MCP-1), transforming growth factor beta (TGF-), interleukin-1 beta (IL_1), plasminogen activator inhibitor-1 (PA-I), serum leptin concentrations, and C-reactive protein of high sensitivity (hs-CRP) in all participants. The inflammatory markers were assessed using the enzyme-linked immunosorbent assay (ELISA).RESULT: The findings revealed a significant negative association between flavonoids intake and MCP-1 (P=0.024), lignans intake and MCP-1 (P=0.017), and Gal-3 (P=0.032). These significant associations were observed between other polyphenols intake and IL_1(P=0.014). There was also a significant positive association between other polyphenol intake and TGF-(P=0.008) and between phenolic acid intake and TGF-(P=0.014).CONCLUSION: Our findings suggest that a high polyphenol intake may help individuals to reduce systemic inflammation. Further large studies involving participants of different ages and genders are highly warranted.

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n/a PMID:  Biomed Pharmacother. 2023 Jul ;163:114795. Epub 2023 May 3. PMID: 37146415 Abstract Title:  Nobiletin alleviates myocardial ischemia-reperfusion injury via ferroptosis in rats with type-2 diabetes mellitus. Abstract:  Susceptibility to myocardial ischemia-reperfusion (IR) injury in type-2 diabetes (T2DM) remains disputed, although studies have reported that ferroptosis is associated with myocardial IR injury. Nobiletin, a flavonoid isolated from citrus peels, is an antioxidant that possesses anti-inflammatory and anti-diabetic activities. However, it remains unknown whether nobiletin has any protective effects on susceptibility to myocardial IR injury during T2DM in rats via ferroptosis. To investigate the effects and underlying mechanisms of nobiletin on myocardial IR injury during T2DM, we induced myocardial IR model in rats at T2DM onset vs mature disease. We also established a high-fat high-glucose (HFHG) and hypoxia-reoxygenation (H/R) model in H9c2 cells to imitate abnormal glycolipid metabolism during T2DM. Myocardial injury, oxidative stress and ferroptosis towards myocardial IR in rats with mature T2DM but not at T2DM onset were increased. These changes were restored under treatment with ferrostain-1 or nobiletin. Both ferrostain-1 and nobiletin decreased the expression of ferroptosis-related proteins including Acyl-CoA synthetase long chain family member 4 (ACSL4) and nuclear receptor coactivator 4 (NCOA4) but not glutathione peroxidase 4 (GPX4) in rats with mature T2DM and cells with HFHG and H/R injury. Nobiletin strengthened the effect of si-ACSL4 on inhibiting ACSL4 expression, and also inhibited the effect of Erastin or oe-ACSL4 on increasing ACSL4 expression. Taken together, our data indicates that ferroptosis involves in susceptibility to myocardial IR injury in rats during T2DM. Nobiletin has therapeutic potential for alleviating myocardial IR injury associated with ACSL4- and NCOA4-related ferroptosis.

PMID:  Front Endocrinol (Lausanne). 2023 ;14:1148954. Epub 2023 Apr 17. PMID: 37143734 Abstract Title:  Naringenin and-carotene convert human white adipocytes to a beige phenotype and elevate hormone- stimulated lipolysis. Abstract:  INTRODUCTION: Naringenin, a peroxisome proliferator-activated receptor (PPAR) activator found in citrus fruits, upregulates markers of thermogenesis and insulin sensitivity in human adipose tissue. Our pharmacokinetics clinical trial demonstrated that naringenin is safe and bioavailable, and our case report showed that naringenin causes weight loss and improves insulin sensitivity. PPARs form heterodimers with retinoic-X-receptors (RXRs) at promoter elements of target genes. Retinoic acid is an RXR ligand metabolized from dietary carotenoids. The carotenoid-carotene reduces adiposity and insulin resistance in clinical trials. Our goal was to examine if carotenoids strengthen the beneficial effects of naringenin on human adipocyte metabolism.METHODS: Human preadipocytes from donors with obesity were differentiated in culture and treated with 8M naringenin + 2M-carotene (NRBC) for seven days. Candidate genes involved in thermogenesis and glucose metabolism were measured as well as hormone-stimulated lipolysis.RESULTS: We found that-carotene acts synergistically with naringenin to boost UCP1 and glucose metabolism genes including GLUT4 and adiponectin, compared to naringenin alone. Protein levels of PPAR, PPARand PPAR-coactivator-1, key modulators of thermogenesis and insulin sensitivity, were also upregulated after treatment with NRBC. Transcriptome sequencing was conducted and the bioinformatics analyses of the data revealed that NRBC induced enzymes for several non-UCP1 pathways for energy expenditure including triglyceride cycling, creatine kinases, and Peptidase M20 Domain Containing 1 (PM20D1). A comprehensive analysis of changes in receptor expression showed that NRBC upregulated eight receptors that have been linked to lipolysis or thermogenesis including the1-adrenergic receptor and the parathyroid hormone receptor. NRBC increased levels of triglyceride lipases and agonist-stimulated lipolysis in adipocytes. We observed that expression of RXR, an isoform of unknown function, was induced ten-fold after treatment with NRBC. We show that RXRis a coactivator bound to the immunoprecipitated PPARprotein complex from white and beige human adipocytes.DISCUSSION: There is a need for obesity treatments that can be administered long-term without side effects. NRBC increases the abundance and lipolytic response of multiple receptors for hormones released after exercise and cold exposure. Lipolysis provides the fuel for thermogenesis, and these observations suggest that NRBC has therapeutic potential.

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PMID:  Acta Cir Bras. 2023 ;38:e380823. Epub 2023 May 1. PMID: 37132753 Abstract Title:  Naringenin attenuates cerebral ischemia/reperfusion injury by inhibiting oxidative stress and inflammatory response via the activation of SIRT1/FOXO1 signaling pathway in vitro. Abstract:  PURPOSE: To explore the protection of naringenin against oxygen-glucose deprivation/reperfusion (OGD/R)-induced HT22 cell injury, a cell model of cerebral ischemia/reperfusion (I/R) injury in vitro, focusing on SIRT1/FOXO1 signaling pathway.METHODS: Cytotoxicity, apoptosis, reactive oxygen species (ROS) generation, malondialdehyde (MDA) content, 4-hydroxynonenoic acid (4-HNE) level, superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase (CAT) activities were measured by commercial kits. Inflammatory cytokines levels were determined by enzyme-linked immunosorbent assay (ELISA). The protein expressions were monitored by Western blot analysis.RESULTS: Naringenin significantly ameliorated OGD/R-induced cytotoxicity and apoptosis in HT22 cells. Meanwhile, naringenin promoted SIRT1 and FOXO1 protein expressions in OGD/R-subjected HT22 cells. In addition, naringenin attenuated OGD/R-induced cytotoxicity, apoptosis, oxidative stress (the increased ROS, MDA and 4-HNE levels, and the decreased SOD, GSH-Px and CAT activities) and inflammatory response (the increased tumor necrosis factor-, interleukin [IL]-1, and IL-6 levels and the decreased IL-10 level), which were blocked by the inhibition of the SIRT1/FOXO1 signaling pathway induced by SIRT1-siRNA transfection.CONCLUSIONS: Naringenin protected HT22 cells against OGD/R injury depending on its antioxidant and anti-inflammatory activities via promoting the SIRT1/FOXO1 signaling pathway.

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PMID:  J Mol Struct. 2023 Sep 5 ;1287:135642. Epub 2023 Apr 26. PMID: 37131962 Abstract Title:  Targeting the vital non-structural proteins (NSP12, NSP7, NSP8 and NSP3) from SARS-CoV-2 and inhibition of RNA polymerase by natural bioactive compound naringenin as a promising drug candidate against COVID-19. Abstract:  The prevalence of SARS-CoV-2-induced respiratory infections is now a major challenge worldwide. There is currently no specific antiviral drug to prevent or treat this disease. Infection with COVID-19 seriously needs to find effective therapeutic agents. In the present study, naringenin, as a potential inhibitor candidate for RNA Polymerase SARS-CoV-2 was compared with remdesivir (FDA-approved drug) and GS-441,524 (Derivative of the drug remdesivir) by screening with wild-type and mutant SARS-CoV-2 NSP12 (NSP7-NSP8) and NSP3 interfaces, then complexes were simulated by molecular dynamics (MD) simulations to gain their stabilities. The docking results displayedscores of -3.45 kcal/mol and -4.32 kcal/mol against NSP12 and NSP3, respectively. Our results showed that naringenin hadG values more negative than theG values of Remdesivir (RDV) and GS-441,524. Hence, naringenin was considered to be a potential inhibitor. Also, the number of hydrogen bonds of naringenin with NSP3 and later NSP12 are more than Remdesivir and its derivative. In this research, Mean root mean square deviation (RMSD) values of NSP3 and NSP12with naringenin ligand (5.551.58 nm to 3.450.56 nm and 0.2380.01 to 0.2420.021 nm, respectively showed stability in the presence of ligand. The root mean square fluctuations (RMSF) values of NSP3 and NSP12 amino acid units in the presence of naringenin in were 1.5  0.31 nm and 0.1180.058, respectively. Pharmacokinetic properties and prediction of absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties of naringenin and RDV showed thatthese two compounds had no potential cytotoxicity.

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PMID:  Drug Chem Toxicol. 2023 Apr 19:1-9. Epub 2023 Apr 19. PMID: 37073537 Abstract Title:  Naringenin blocks hepatic cadmium accumulation and suppresses cadmium-induced hepatotoxicity via amelioration of oxidative inflammatory signaling and apoptosis in rats. Abstract:  Liver is one of the targets of cadmium (Cd) bioaccumulation for hepatic damage and pathologies via oxidative inflammation and apoptosis. The current study explored whether the citrus flavonoid naringenin (NAR) could prevent hepatic accumulation of Cd and Cd hepatotoxicity in a rat model. Rats in group 1 received normal saline; group 2 received NAR (50mg/kg body weight); group 3 received CdCl(5mg/kg body weight); group 4 received NAR+CdCl, for four consecutive weeks. Assays related to markers of oxidative stress, inflammation, and apoptosis were carried out using liver homogenate. Blood and liver sample analyses revealed significant elevation of blood and hepatic Cd levels coupled with prominent increases in alkaline phosphatase (ALP), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) activities, whereas the albumin and total protein levels were decreased considerably. Hepatic superoxide dismutase (SOD), catalase (CAT), glutathione peroxide (GPx) activities diminished significantly compared to control followed by marked increases in malondialdehyde (MDA) levels, and dysregulation in caspase and cytokine (TNF-, IL-6, IL-4, IL-10) levels. However, it was found that in the rats administered NAR+Cd, the levels of Cd, hepatic enzymes, MDA, TNF-, IL-6, and caspases-3/-9 were prominently reduced compared to the Cd group. The hepatic SOD, CAT, GPx, IL-4, IL-10, albumin, and total protein were markedly elevated along with alleviated hepatic histopathological abrasions. Taken together therefore, NAR is a potential flavonoid for blocking hepatic Cd bioaccumulation and consequent inhibition of Cd-induced oxidative inflammation and apoptotic effects on the liver of rats.

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PMID:  Environ Toxicol. 2023 Jun ;38(6):1405-1419. Epub 2023 Mar 29. PMID: 36988289 Abstract Title:  Naringenin facilitates M2 macrophage polarization after myocardial ischemia-reperfusion by promoting nuclear translocation of transcription factor EB and inhibiting the NLRP3 inflammasome pathway. Abstract:  Myocardial ischemia-reperfusion injury (MIRI) remains an unsolved puzzle in medical circles. Naringenin (NAR) is a flavonoid with cardioprotective potential. The purpose of this article was to discuss the protective mechanism of NAR in MIRI by regulating macrophage polarization. The MIRI mouse model was established and perfused with NAR before surgery. In the in vitro experiment, macrophages RAW264.7 were treated with lipopolysaccharide to induce M1 polarization after pretreatment with NAR. Rescue experiments were carried out to validate the functions of transcription factor EB (TFEB), the NLR pyrin domain containing 3 (NLRP3) inflammasome, and autophagy in macrophage polarization. NAR reduced histopathological injury and infarction of myocardial tissues in MIRI mice, inhibited M1 polarization and promoted M2 polarization of macrophages, diminished levels of pro-inflammatory factors, and augmented levels of anti-inflammatory factors. NAR facilitated TFEB nuclear translocation and inhibited the NLRP3 inflammasome pathway. Silencing TFEB or Nigericin partly nullified the effect of NAR on macrophage polarization. NAR increased autophagosome formation, autophagy flux, and autophagy level. Autophagy inhibitor 3-methyladenine partly invalidated the inhibition of NAR on the NLRP3 inflammasome pathway. In animal experiments, NAR protected MIRI mice through the TFEB-autophagy-NLRP3 inflammasome pathway. Collectively, NAR inhibited NLRP3 inflammasome activation and facilitated M2 macrophage polarization by stimulating TFEB nuclear translocation, thus protecting against MIRI.

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PMID:  J Agric Food Chem. 2023 May 17 ;71(19):7312-7323. Epub 2023 May 4. PMID: 37139957 Abstract Title:  Nobiletin Ameliorates Nonalcoholic Fatty Liver Disease by Regulating Gut Microbiota and Myristoleic Acid Metabolism. Abstract:  Disturbance of the gut microbiota plays a critical role in the development of nonalcoholic fatty liver disease (NAFLD). Increasing evidence supports that natural products may serve as prebiotics to regulate the gut microbiota in the treatment of NAFLD. In the present study, the effect of nobiletin, a naturally occurring polymethoxyflavone, on NAFLD was evaluated, and metabolomics, 16S rRNA gene sequencing, and transcriptomics analysis were performed to determine the underlying mechanism of nobiletin, and the key bacteria and metabolites screened were confirmed by in vivo experiment. Nobiletin treatment could significantly reduce lipid accumulation in high-fat/high-sucrose diet-fed mice. 16S rRNA analysis demonstrated that nobiletin could reverse the dysbiosis of gut microbiota in NAFLD mice and nobiletin could regulate myristoleic acid metabolism, as revealed by untargeted metabolomics analysis. Treatment with the bacteria,, or the metabolite myristoleic acid displayed a protective effect on liver lipid accumulation under metabolic stress. These results indicated that nobiletin might target gut microbiota and myristoleic acid metabolism to ameliorate NAFLD.

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PMID:  J Nutr Biochem. 2023 Aug ;118:109353. Epub 2023 Apr 27. PMID: 37116815 Abstract Title:  A lipidomic study: Nobiletin ameliorates hepatic steatosis through regulation of lipid alternation. Abstract:  Hepatic lipidome has been given emphasis for years since hepatic steatosis is the most remarkable character of nonalcoholic fatty liver diseases, an increasingly serious health issue worldwide. Nobiletin (NOB), one of the citrus flavonoids, exerted outstanding effect on lipid metabolism disorder. However, the underlying mechanism of NOB exerting effect on hepatic lipid alternation remains unclear. In this study, the animal model was built by feeding APOEmice with high fat diet (HFD). The results of Oil Red O-stained liver section and the biochemical assay of lipid parameters confirmed the protective effect of NOB on hepatic steatosis and global lipid metabolism disorder in APOEmice. The hepatic lipidomic study revealed a total of 958 lipids significantly altered by HFD and a total of 86, 116, 212 lipid metabolites changed by L-NOB (50 mg/kg/d NOB), M-NOB (100 mg/kg/d NOB) and H-NOB (200 mg/kg/d NOB) respectively. In the further screening analysis, an amount of 60 lipids were identified as the potential lipid markers of NOB treatment, most of which belonged to glycerophospholipids lipid categories and exhibited obvious correlation with each other and the lipid parameters related to hepatic steatosis. Taken together, our data demonstrated that glycerophospholipids metabolism played an indispensable role in the progression of hepatic steatosis and the protective effect of NOB. Besides, the modulation towards genes involved in lipid synthesis was observed after NOB administration in this study. These finding illustrated the antihepatic steatosis effect of NOB based on altering hepatic lipidome, particularly the glycerophospholipids metabolism, and provided a new insight in the pathogenesis of hepatic steatosis.

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PMID:  Nutrients. 2023 Apr 7 ;15(8). Epub 2023 Apr 7. PMID: 37111020 Abstract Title:  Nobiletin Improves D-Galactose-Induced Aging Mice Skeletal Muscle Atrophy by Regulating Protein Homeostasis. Abstract:  Sarcopenia, a decrease in skeletal muscle mass and function caused by aging, impairs mobility, raises the risk of fractures, diabetes, and other illnesses, and severely affects a senior's quality of life. Nobiletin (Nob), polymethoxyl flavonoid, has various biological effects, such as anti-diabetic, anti-atherogenic, anti-inflammatory, anti-oxidative, and anti-tumor properties. In this investigation, we hypothesized that Nob potentially regulates protein homeostasis to prevent and treat sarcopenia. To investigate whether Nob could block skeletal muscle atrophy and elucidate its underlying molecular mechanism, we used the D-galactose-induced (D-gal-induced) C57BL/6J mice for 10 weeks to establish a skeletal muscle atrophy model. The findings demonstrated that Nob increased body weight, hindlimb muscle mass, lean mass and improved the function of skeletal muscle in D-gal-induced aging mice. Nob improved myofiber sizes and increased skeletal muscle main proteins composition in D-gal-induced aging mice. Notably, Nob activated mTOR/Akt signaling to increase protein synthesis and inhibited FOXO3a-MAFbx/MuRF1 pathway and inflammatory cytokines, thereby reducing protein degradation in D-gal-induced aging mice. In conclusion, Nob attenuated D-gal-induced skeletal muscle atrophy. It is a promising candidate for preventing and treating age-associated atrophy of skeletal muscles.

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PMID:  Life Sci. 2023 Jul 15 ;325:121749. Epub 2023 May 2. PMID: 37142089 Abstract Title:  Role of NF-B/ICAM-1, JAK/STAT-3, and apoptosis signaling in the anticancer effect of tangeretin against urethane-induced lung cancer in BALB/c mice. Abstract:  Lung carcinoma is one of the most prevalent and deadly neoplasia worldwide. Numerous synthetic medications have been used in the treatment of cancer. However, there are several drawbacks, such as side effects and inefficiency. The current study focused on the potential anti-cancer effectiveness of tangeretin, an antioxidant flavonoid, on lung cancer induced experimentally in BALB/c mice and explored the involvement of NF-B/ICAM-1, JAK/STAT-3, and caspase-3 signaling in its anti-cancer effect. BALB/c mice were injected with urethane (1.5 mg/kg) twice; on the first day and on the 60day of the experiment, then treated with 200 mg/kg tangeretin orally once daily for the last 4 weeks of the experiment. Compared with urethane group, tangeretin normalized oxidative stress markers; MDA, GSH, and SOD activity. Moreover, it had an anti-inflammatory effect by decreasing lung MPO activity, ICAM-1, IL-6, NF-B, and TNF-expressions. Interestingly, tangeretin decreased cancer metastasis by reducing p-JAK, JAK, p-STAT-3, and STAT-3 protein expression levels. Furthermore, it increased the apoptotic marker, caspase-3, indicating enhanced apoptosis of cancer cells. Finally, histopathology confirmed the anti-cancer effect of tangeretin. In conclusion, tangeretin could have a promising effect in counteracting lung cancer via modulation of NF-B/ICAM-1, JAK/STAT-3, and caspase-3 signaling.

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PMID:  Molecules. 2023 Mar 12 ;28(6). Epub 2023 Mar 12. PMID: 36985541 Abstract Title:  Nobiletin Intake Attenuates Hepatic Lipid Profiling and Oxidative Stress in HFD-Induced Nonalcoholic-Fatty-Liver-Disease Mice. Abstract:  Nobiletin (NOB) is a naturally occurring compound, commonly found in citrus peel, that shows hepatoprotective and lipid-reducing effects. However, the lipid biomarkers and the potential improvement mechanisms have not been adequately explored. Therefore, we investigated the ameliorative effect and the molecular mechanism of NOB on NAFLD induced by a high-fat diet in mice. The results showed that supplementation with NOB over 12 weeks markedly improved glucose tolerance, serum lipid profiles, inflammatory factors, hepatic steatosis, and oxidative stress. These beneficial effects were mainly related to reduced levels of potential lipid biomarkers including free fatty acids, diacylglycerols, triacylglycerols, and cholesteryl esters according to hepatic lipidomic analysis. Twenty lipids, including DGs and phosphatidylcholines, were identified as potential lipid biomarkers. Furthermore, RT-qPCR and Western blot analysis indicated that NOB inhibited the expression of lipogenesis-related factors such as SREBP-1c, SCD-1, and FAS, and upregulated the expression of lipid oxidation (PPAR) and well as antioxidation-related factors (Nucl-Nrf2, NQO1, HO-1, and GCLC), indicating that NOB intake may reduce lipid biosynthesis and increase lipid consumption to improve hepatic steatosis and oxidative stress. This study is beneficial for understanding the ameliorative effects of NOB on NAFLD.

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PMID:  Inflammopharmacology. 2023 Jun ;31(3):1373-1386. Epub 2023 Mar 22. PMID: 36947298 Abstract Title:  Suppressing NLRP3 activation and PI3K/AKT/mTOR signaling ameliorates amiodarone-induced pulmonary fibrosis in rats: a possible protective role of nobiletin. Abstract:  Amiodarone (AMD), a medicine used to treat life-threatening arrhythmias, is frequently linked to pulmonary fibrosis (PF). Despite the involvement of NLRP3 inflammasome and PI3K/Akt/mTOR axis in fibrosis modulation and development, their significance in the etiology of AMD-induced PF remains uncertain. Nobiletin (NOB), a citrus flavonoid, has recently gained attention for its ability to reduce fibrotic processes in a variety of organs through inhibiting NLRP3-associated inflammation and suppressing PI3K/AKT/mTOR fibrotic pathway. Therefore, this research aimed to investigate the possible beneficial impact of NOB against AMD-induced PF, taking into account the roles of NLRP3 and PI3K/AKT/mTOR axis in its pathogenesis. Twenty-four rats were randomly specified into Vehicle; NOB 20 mg/kg; AMD 30 mg/kg, and NOB+AMD. All treatments were administered orally once a day for 4 weeks. The lung oxidant/antioxidant status, as well as the expression of inflammatory and fibrotic markers were all assessed. The results revealed that NOB, by improving Nrf2/HO-1 pathway, could reduce ROS production and NLRP3 activation, which in turn hindered IL-1release, prohibited TGF-1-related PI3K/AKT/mTOR cascade, suppressed-SMA expression, and impeded collagen deposition. These findings point to a novel strategy by which NOB may alleviate the AMD-prompted NLRP3 inflammatory responses and associated PF through blocking PI3K/AKT/mTOR signaling.

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PMID:  Biomed Res Int. 2023 ;2023:6407588. Epub 2023 Jan 23. PMID: 36726839 Abstract Title:  The Effect ofon Non-Small-Cell Lung Cancer: A Research Based on Network and Experimental Pharmacology. Abstract:  PURPOSE: To screen the main active components ofthrough a network pharmacology approach, construct a component-disease target network, explore its molecular mechanism for the treatment of non-small-cell lung cancer (NSCLC), and validate it experimentally.METHODS: The active ingredients inand the targets ofand NSCLC were collected through the Traditional Chinese Medicine Systematic Pharmacology Database and Analysis Platform (TCMSP), GeneCards, and OMIM databases. The protein interaction network was constructed using the STRING database, and the component-disease relationship network graph was analyzed using Cytoscape 3.9.1. The Metascape database can be used for GO and KEGG enrichment analyses. The Kaplan-Meier plotter was applied for overall survival analysis of key targets ofin the treatment of NSCLC. Real-time PCR (RT-PCR) and Western blotting were used to determine the mRNA and protein levels of key targets offor the treatment of NSCLC.RESULTS: Five active ingredients ofwere screened, and 54 potential targets for the treatment of NSCLC were found, of which the key ingredient was nobiletin and the key targets are TP53, CXCL8, ESR1, PPAR-, and MMP9. GO and KEGG enrichment analyses indicated that the mechanism of nobiletin in treating NSCLC may be related to the regulation of cancer signaling pathway, phosphatidylinositol-3 kinase (PI3K)/protein kinase B (Akt) signaling pathway, lipid and atherosclerosis signaling pathway, and neurodegenerative signaling pathway. The experimental results showed that nobiletin could inhibit the proliferation of NSCLC cells and upregulate the levels of P53 and PPAR-and suppress the expression of MMP9 (

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PMID:  Phytomedicine. 2023 Jul ;115:154842. Epub 2023 Apr 28. PMID: 37148713 Abstract Title:  Berberine activates PPARand promotes gut microbiota-derived butyric acid to suppress hepatocellular carcinoma. Abstract:  BACKGROUND: Peroxisome proliferator-activated receptors (PPARs) are a family of ligand-inducible transcription factors that govern various essential metabolic activities in the liver and other organs. Recently, berberine (BBR) has been characterized as a modulator of PPARs; however, the matter of whether PPARs are involved in the inhibitory effect of BBR on hepatocellular carcinoma (HCC) is not well understood.PURPOSE: This study aimed to investigate the role of PPARs in the suppressive effect of BBR on HCC and to elucidate the relative mechanism.METHODS: We studied the role of PPARs in the anti-HCC effects of BBR both in vitro and in vivo. The mechanism whereby BBR regulated PPARs was studied using real-time PCR, immunoblotting, immunostaining, luciferase, and a chromatin immunoprecipitation coupled PCR assay. Additionally, we used adeno-associated virus (AAV)-mediated gene knockdown to address the effect of BBR more effectively.RESULTS: We demonstrated that PPARplayed an active role in the anti-HCC effect of BBR, rather than PPARor PPAR. Following a PPAR-dependent manner, BBR increased BAX, cleaved Caspase 3, and decreased BCL2 expression to trigger apoptotic death, thereby suppressing HCC development both in vitro and in vivo. It was noted that the interactions between PPARand the apoptotic pathway resulted from the BBR-induced upregulation of the PPARtranscriptional function; that is, the BBR-induced activation of PPARcould mediate the binding with the promoters of apoptotic genes such as Caspase 3, BAX, and BCL2. Moreover, gut microbiota also contributed to the suppressive effect of BBR on HCC. We found that BBR treatment restored the dysregulated gut microbiota induced by the liver tumor burden, and a functional gut microbial metabolite, butyric acid (BA), acted as a messenger in the gut microbiota-liver axis. Unlike BBR, the effects of BA suppressing HCC and activating PPARwere not potent. However, BA was able to enhance the efficacy of BBR by reducing PPARdegradation through a mechanism to inhibit the proteasome ubiquitin system. Additionally, we found that the anti-HCC effect of BBR or a combination of BBR and BA was much weaker in mice with AAV-mediated PPARknockdown than those in the control mice, suggesting the critical role of PPAR.CONCLUSION: In summary, this study is the first to report that a liver-gut microbiota-PPARtrilogy contributes to the anti-HCC effect of BBR. BBR not only directly activated PPARto trigger apoptotic death but also promoted gut microbiota-derived BA production, which could reduce PPARdegradation to enhance the efficacy o...

PMID:  Front Pharmacol. 2023 ;14:1148611. Epub 2023 Apr 18. PMID: 37144221 Abstract Title:  Berberine stimulates lysosomal AMPK independent of PEN2 and maintains cellular AMPK activity through inhibiting the dephosphorylation regulator UHRF1. Abstract:  AMPK is the key regulatory kinase mediating the effect of berberine (BBR) and metformin on metabolic improvement. The present study investigated the mechanism of BBR on AMPK activation at low doses, which was different from that of metformin.Lysosomes were isolated, and AMPK activity assay was performed. PEN2, AXIN1 and UHRF1 were investigated through gain/loss of function approaches, including overexpression, RNA interfering and CRISPR/Cas9-mediated gene knockout. Immunoprecipitation was utilized for detecting the interaction of UHRF1 and AMPK1 after BBR treatment.BBR activated lysosomal AMPK, but weaker than metformin. AXIN1 mediated BBR's effect on lysosomal AMPK activation, while PEN2 did not. BBR, but not metformin, decreased UHRF1 expression by promoting its degradation. BBR reduced the interaction between UHRF1 and AMPK1. And overexpression of UHRF1 abolished the effect of BBR on AMPK activation.BBR activated lysosomal AMPK as dependent on AXIN1, but not PEN2. BBR maintained cellular AMPK activity by reducing UHRF1 expression and its interaction with AMPK1. The mode of action of BBR was different from that of metformin on AMPK activation.

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PMID:  Arch Esp Urol. 2023 Mar ;76(2):152-160. PMID: 37139621 Abstract Title:  Berberine Affects the Proliferation, Migration, Invasion, Cell Cycle, and Apoptosis of Bladder Cancer Cells T24 and 5637 by Down-Regulating the HER2/PI3K/AKT Signaling Pathway. Abstract:  OBJECTIVE: To assess the anticancer effect, target, and mechanism of berberine on bladder cancer.METHODS: Bladder cancer T24 and 5637 cells were treated with different concentrations of berberine. Then, cell proliferation was assessed by cell counting kit-8 (CCK8) measure, cell migration and invasion were assessed by transwell method, cell cycle and apoptosis were assessed by flow cytometry, and the expression of human epidermal growth factor receptor-2/PhosphoInositide-3 Kinase/AKT Serine/Threonine Kinase (HER2/PI3K/AKT) proteins were assessed by Western blot. Berberine molecular docking and HER2 target were performed using the AutoDock Tools 1.5.6. Finally, HER2 inhibitors CP-724714 and berberine were used independently or in combination to detect AKT and P-AKT protein downstream changes by Western blot.RESULTS: Berberine inhibited the proliferation of T24 and 5637 bladder cancer cells in a concentration-dependent and time-dependent manner. Berberine can significantly inhibit the migration, invasion, and cell cycle progression of T24 and 5637 bladder cancer cells, promote their apoptosis, and down-regulate the expression of HER2/PI3K/AKT proteins. Berberine showed good docking with HER2 molecular target and had a similar and synergistic effect with HER2 inhibitor in T24 and 5637 bladder cancer cells.CONCLUSIONS: Berberine inhibited the proliferation, migration, invasion, and cell cycle progression of T24 and 5637 bladder cancer cells and promoted their apoptosis by down-regulating HER2/PI3K/AKT signaling pathway.

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PMID:  Acta Pharm Sin B. 2023 Apr ;13(4):1537-1553. Epub 2022 Dec 20. PMID: 37139409 Abstract Title:  Berberine ameliorates chronic kidney disease through inhibiting the production of gut-derived uremic toxins in the gut microbiota. Abstract:  At present, clinical interventions for chronic kidney disease are very limited, and most patients rely on dialysis to sustain their lives for a long time. However, studies on the gut-kidney axis have shown that the gut microbiota is a potentially effective target for correcting or controlling chronic kidney disease. This study showed that berberine, a natural drug with low oral availability, significantly ameliorated chronic kidney disease by altering the composition of the gut microbiota and inhibiting the production of gut-derived uremic toxins, including-cresol. Furthermore, berberine reduced the content of-cresol sulfate in plasma mainly by lowering the abundance ofand inhibiting the tyrosine--cresol pathway of the intestinal flora. Meanwhile, berberine increased the butyric acid producing bacteria and the butyric acid content in feces, while decreased the renal toxic trimethylamine-oxide. These findings suggest that berberine may be a therapeutic drug with significant potential to ameliorate chronic kidney disease through the gut-kidney axis.

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PMID:  Emerg Microbes Infect. 2023 Dec ;12(1):2195020. PMID: 36951188 Abstract Title:  Berbamine suppresses intestinal SARS-CoV-2 infection via a BNIP3-dependent autophagy blockade. Abstract:  SARS-CoV-2, the causative virus of COVID-19, continues to threaten global public health. COVID-19 is a multi-organ disease, causing not only respiratory distress, but also extrapulmonary manifestations, including gastrointestinal symptoms with SARS-CoV-2 RNA shedding in stool long after respiratory clearance. Despite global vaccination and existing antiviral treatments, variants of concern are still emerging and circulating. Of note, new Omicron BA.5 sublineages both increasingly evade neutralizing antibodies and demonstrate an increased preference for entry via the endocytic entry route. Alternative to direct-acting antivirals, host-directed therapies interfere with host mechanisms hijacked by viruses, and enhance cell-mediated resistance with a reduced likelihood of drug resistance development. Here, we demonstrate that the autophagy-blocking therapeutic berbamine dihydrochloride robustly prevents SARS-CoV-2 acquisition by human intestinal epithelial cells via an autophagy-mediated BNIP3 mechanism. Strikingly, berbamine dihydrochloride exhibited pan-antiviral activity against Omicron subvariants BA.2 and BA.5 at nanomolar potency, providing a proof of concept for the potential for targeting autophagy machinery to thwart infection of current circulating SARS-CoV-2 subvariants. Furthermore, we show that autophagy-blocking therapies limited virus-induced damage to intestinal barrier function, affirming the therapeutic relevance of autophagy manipulation to avert the intestinal permeability associated with acute COVID-19 and post-COVID-19 syndrome. Our findings underscore that SARS-CoV-2 exploits host autophagy machinery for intestinal dissemination and indicate that repurposed autophagy-based antivirals represent a pertinent therapeutic option to boost protection and ameliorate disease pathogenesis against current and future SARS-CoV-2 variants of concern.

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PMID:  Environ Int. 2023 May ;175:107949. Epub 2023 Apr 25. PMID: 37126915 Abstract Title:  Bisphenol P exposure in C57BL/6 mice caused gut microbiota dysbiosis and induced intestinal barrier disruption via LPS/TLR4/NF-B signaling pathway. Abstract:  Despite being one of the most world's widely used and mass-produced compounds, bisphenol A (BPA) has a wide range of toxic effects. Bisphenol P (BPP), an alternative to BPA, has been detected in many foods. The effects of BPP dietary exposure on gut microbiota and the intestinal barrier were unclear. We designed three batches of animal experiments: The first studied mice were exposed to BPP (30 g/kg BW/day) for nine weeks and found that they gained weight and developed dysbiosis of the gut microbiota. The second, using typical human exposure levels (L, 0.3 g/kg BW/day BPP) and higher concentrations (M, 30 g/kg BW/day BPP; H, 3000 g/kg BW/day BPP), caused gut microbiota dysbiosis in mice, activated the Lipopolysaccharide (LPS) /TLR4/NF-B signaling pathway, triggered an inflammatory response, increased intestinal permeability, and promoted bacterial translocation leading to intestinal barrier disruption. The third treatment used a combination of antibiotics and alleviated intestinal inflammation and injury. This study demonstrated the mechanism of injury and concentration effects of intestinal damage caused by BPP exposure, providing reference data for BPP use and control and yielding new insights for human disease prevention.

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PMID:  Toxicol Ind Health. 2023 Jun ;39(6):325-335. Epub 2023 Apr 25. PMID: 37122122 Abstract Title:  Exposure to bisphenol A induces neurotoxicity associated with synaptic and cytoskeletal dysfunction in neuro-2a cells. Abstract:  Bisphenol A (BPA) has been reported to injure the developing and adult brain. However, the underlying mechanism still remains elusive. This study used neuro-2a cells as a cellular model to investigate the neurotoxic effects of BPA. Microtubule-associated protein 2 (MAP2) and tau protein maintain microtubule normal function and promote the normal development of the nervous system. Synaptophysin (SYP) and drebrin (Dbn) proteins are involved in regulating synaptic plasticity. Cells were exposed to the minimum essential medium (MEM), 0.01% (v/v) DMSO, and 150 M BPA for 12, 24, or 36 h. Morphological analysis revealed that the cells in the BPA-treated groups shrank and collapsed compared with those in the control groups. CCK-8 and lactate dehydrogenase assay (LDH) assays showed that the mortality of neuro-2a cells increased as the BPA treatment time was prolonged. Ultrastructural analysis further revealed that cells demonstrated nucleolar swelling, dissolution of nuclear and mitochondrial membranes, and partial mitochondrial condensation following exposure to BPA. BPA also decreased the relative protein expression levels of MAP2, tau, and Dbn. Interestingly, the relative protein expression levels of SYP increased. These results indicated that BPA inhibited the proliferation and disrupted cytoskeleton and synaptic integrity of neuro-2a cells.

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PMID:  Food Chem Toxicol. 2023 Jun ;176:113792. Epub 2023 Apr 18. PMID: 37080528 Abstract Title:  BPA exposure enhances the metastatic aggression of ovarian cancer through the ER/AKT/mTOR/HIF-1signaling axis. Abstract:  Long-term exposure to bisphenol A (BPA) in humans may promote ovarian cancer development. In present study, the mechanisms by which BPA mediates the aggression metastatic behavior of ovarian cancer were investigated in vitro/in vivo. The results showed that BPA (10 M) significantly promoted the proliferation, migration and invasion of human ovarian cancer cells (ES-2 and OVCAR-3 cells); moreover, it promoted ES-2 and OVCAR-3 cell glucose uptake, lactic acid release and intracellular ATP synthesis. After administration of 5 g/kg/day BPA, tumor volume was increased compared with that in control group. KEGG and GO enrichment analyses showed that the genes from ES-2 cell in 10 M BPA-treated group were enriched mainly in central carbon metabolism and PI3K-AKT signaling pathway. Then, qRTPCR and western blotting results showed that BPA (10 M) increased the mRNA and protein expression levels of glycolysis-related genes and mTOR, p-AKT HIF-1and ERin vitro/vivo; whereas this effect was reduced after treatment with the ERinhibitor methyl-piperidino-pyrazole. Furthermore, coimmunoprecipitation and mass spectrometry showed that BPA promoted the direct interaction of ERwith lactate dehydrogenase A. These results show that BPA directly promoted the proliferation, migration and invasion of ovarian cancer cells through the ER/AKT/mTOR/HIF-1signaling axis to enhance glycolysis.

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PMID:  Toxics. 2023 Apr 21 ;11(4). Epub 2023 Apr 21. PMID: 37112618 Abstract Title:  Protective Effects of a Red Grape Juice Extract against Bisphenol A-Induced Toxicity in Human Umbilical Vein Endothelial Cells. Abstract:  Human exposure to bisphenol A (BPA) occurs through the ingestion of contaminated food and water, thus leading to endothelial dysfunction, the first signal of atherosclerosis.L. (grape) juice is well known for its health-promoting properties, due to its numerous bioactive compounds among which are polyphenols. The aim of this study was to evaluate the protective effect of a red grape juice extract (RGJe) against the endothelial damage induced by BPA in human umbilical vein endothelial cells (HUVECs) as an in vitro model of endothelial dysfunction. Our results showed that RGJe treatment counteracted BPA-induced cell death and apoptosis in HUVECs, blocking caspase 3 and modulating p53, Bax, and Bcl-2. Moreover, RGJe demonstrated antioxidant properties in abiotic tests and in vitro, where it reduced BPA-induced reactive oxygen species as well as restored mitochondrial membrane potential, DNA integrity, and nitric oxide levels. Furthermore, RGJe reduced the increase of chemokines (IL-8, IL-1, and MCP-1) and adhesion molecules (VCAM-1, ICAM-1, and E-selectin), caused by BPA exposure, involved in the primary phase of atheromatous plaque formation. Overall, our results suggest that RGJe prevents BPA-induced vascular damage modulating specific intracellular mechanisms, along with protecting cells, owing to its antioxidant capability.

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PMID:  Toxics. 2023 Mar 31 ;11(4). Epub 2023 Mar 31. PMID: 37112567 Abstract Title:  Influence of Gut Microbiota on Metabolism of Bisphenol A, a Major Component of Polycarbonate Plastics. Abstract:  Bisphenol A (BPA) is a major component of polycarbonate plastics and epoxy resins. While many studies have investigated the effect BPA exposure has upon changes in gut microbial communities, the influence of gut microbiota on an organism's ability to metabolize BPA remains comparatively unexplored. To remedy this, in this study, Sprague Dawley rats were intermittently (i.e., at a 7-day interval) or continuously dosed with 500g BPA/kg bw/day for 28 days, via oral gavage. In the rats which underwent the 7-day interval BPA exposure, neither their metabolism of BPA nor their gut microbiota structure changed greatly with dosing time. In contrast, following continuous BPA exposure, the relative level ofandin the rats' guts significantly increased, and the alpha diversity of the rats' gut bacteria was greatly reduced. Meanwhile, the mean proportion of BPA sulfate to total BPA in rat blood was gradually decreased from 30 (on day 1) to 7.4% (by day 28). After 28 days of continuous exposure, the mean proportion of BPA glucuronide to total BPA in the rats' urine elevated from 70 to 81%, and in the rats' feces the mean proportion of BPA gradually decreased from 83 to 65%. Under continuous BPA exposure, the abundances of 27, 25, and 24 gut microbial genera were significantly correlated with the proportion of BPA or its metabolites in the rats' blood, urine, and feces, respectively. Overall, this study principally aimed to demonstrate that continuous BPA exposure disrupted the rats' gut microbiota communities, which in turn altered the rats' metabolism of BPA. These findings contribute to the better understanding of the metabolism of BPA in humans.

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PMID:  Int J Mol Sci. 2023 Apr 14 ;24(8). Epub 2023 Apr 14. PMID: 37108405 Abstract Title:  Protective Effects of Selenium Nanoparticles against Bisphenol A-Induced Toxicity in Porcine Intestinal Epithelial Cells. Abstract:  Bisphenol A (BPA) is widely used to harden plastics and polycarbonates and causes serious toxic effects in multiple organs, including the intestines. Selenium, as an essential nutrient element for humans and animals, exhibits a predominant effect in various physiological processes. Selenium nanoparticles have attracted more and more attention due to their outstanding biological activity and biosafety. We prepared chitosan-coated selenium nanoparticles (SeNPs) and further compared the protective effects, and investigated the underlying mechanism of SeNPs and inorganic selenium (NaSeO) on BPA-induced toxicity in porcine intestinal epithelial cells (IPEC-J2). The particle size, zeta potential, and microstructure of SeNPs were detected by using a nano-selenium particle size meter and a transmission electron microscope. IPEC-J2 cells were exposed to BPA alone or simultaneously exposed to BPA and SeNPs or NaSeO. The CCK8 assay was performed to screen the optimal concentration of BPA exposure and the optimal concentration of SeNPs and NaSeOtreatment. The apoptosis rate was detected by flow cytometry. Real-time PCR and Western blot methods were used to analyze the mRNA and protein expression of factors related to tight junctions, apoptosis, inflammatory responses and endoplasmic reticulum stress. Increased death and morphological damage were observed after BPA exposure, and these increases were attenuated by SeNPs and NaSeOtreatment. BPA exposure disturbed the tight junction function involved with decreased expression of tight junction protein Zonula occludens 1 (ZO-1), occludin, and claudin-1 proteins. Proinflammatory response mediated by the transcription factor nuclear factor-k-gene binding (NF-B), such as elevated levels of--,--,--,--, and tumor necrosis-(-expression was induced at 6 and 24 h after BPA exposure. BPA exposure also disturbed the oxidant/antioxidant status and led to oxidative stress. IPEC-J2 cell apoptosis was induced by BPA exposure, as indicated by increased BCL-2-associated X protein (Bax), caspase 3, caspase 8, and caspase 9 expression and decreased B-cell lymphoma-2 (Bcl-2) and Bcl-xl expression. BPA exposure activated the endoplasmic reticulum stress (ERS) mediated by the receptor protein kinase receptor-like endoplasmic reticulum kinase (PERK), Inositol requiring enzyme 1 (IRE1), and activating transcription factor 6 (ATF6). We found that treatment with SeNPs and NaSeOcan alleviate the intestinal damage caused by BPA. SeNPs were superior to NaSeOand counteracted BPA-induced tight junction function injury, proinflammatory response, oxidative stre...

PMID:  Sci Total Environ. 2023 Jul 20 ;883:163615. Epub 2023 Apr 25. PMID: 37105472 Abstract Title:  Induction of reproductive injury by bisphenol A and the protective effects of cyanidin-3-O-glucoside and protocatechuic acid in rats. Abstract:  Bisphenol A (BPA) has attracted growing attention as a well-known environmental pollutant due to its high risk of male reproductive toxicity. In this study, transcriptomics profiling combined with metabolomic techniques was applied to explore the intervention effects of BPA-induced male reproductive toxicity. We demonstrated that cyanidin-3-O-glucoside (C3G) and its main metabolite protocatechuic acid (PCA) significantly increased testosterone and luteinizing hormone (LH) levels in the serum of rats, and improved sperm quality. Furthermore, we identified and screened differentially expressed genes (DEGs) and metabolites (DMs) that functionally enriched in the steroidogenesis-related pathways. Next, the validated results found that C3G and PCA significantly up-regulated the gene expressions of Star, Cyp11a1, Cyp17a1, Cyp19a1, Cyp7a1, Hsd3b1, Hsd3b2, Hsd17b3, Scrab1, and Ass1 in testicular. In Leydig cells, C3G and PCA dramatically alleviated apoptosis, ROS accumulation, and cell cycle arrest caused by BPA. In addition, molecular docking and simulation results implied that C3G and PCA competitively with BPA bind to the estrogen receptorsand(ERand ER) and shared common key amino acids. The main interaction modes between small molecules and estrogen receptors included-stacking, salt bridges, hydrogen bonds, and hydrophobic interactions. Therefore, our study sheds light on C3G and PCA supplementation can protect male reproduction from BPA-induced injury.

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PMID:  Ecotoxicol Environ Saf. 2023 Jun 1 ;257:114946. Epub 2023 Apr 25. PMID: 37105096 Abstract Title:  In vivo effects of low dose prenatal bisphenol A exposure on adiposity in male and female ICR offspring. Abstract:  BACKGROUND: Bisphenol A (BPA) is known to exhibit endocrine disrupting activities and is associated with adiposity. We examined the obesogenic effect of prenatal BPA exposure in the present study.METHODS: Pregnant ICR mice were exposed to vehicle or BPA via the drinking water at a dose of 0.5 g/kgd throughout the gestation. Obesity-related indexes were investigated in the 12-wk-old offspring. Primary mouse embryonic fibroblasts (MEFs) collected from treated embryos were used to test effects of BPA on adipocyte differentiation.RESULTS: Offspring presented a significantly higher rate of weight gain than the control, with impaired insulin sensitivity and increased adipocyte size. Differentiation of MEFs from BPA-treated mice showed a higher propensity for the adipocyte commitment as well as up-regulation of genes enriched in lipid biosynthesis. TGF-signaling pathway was found to modulate obesogenic effect of BPA in MEF model, but estrogen signaling pathway had no effect.CONCLUSIONS: The present study provides strong evidence of the association between prenatal exposure to low dose of BPA and a significant increase in body weight in the offspring mice with a critical role played by TGF-signaling pathway. The potential interactions modulating the binding of BPA and TGF-that activate its obesogenic effects need to be examined.

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PMID:  Antioxidants (Basel). 2021 Apr 26 ;10(5). Epub 2021 Apr 26. PMID: 33926060 Abstract Title:  A Grape Juice Supplemented with Natural Grape Extracts Is Well Accepted by Consumers and Reduces Brain Oxidative Stress. Abstract:  Neurodegenerative diseases pose a major health problem for developed countries. Stress, which induces oxidation in the brain, has been identified as the main risk factor for these disorders. We have developed an antioxidant-enriched drink and have examined its protective properties against acute oxidative stress. We found that addition of red grape polyphenols and MecobalActiveto grape juice did not provoke changes in juice organoleptic characteristics, and that the pasteurization process did not greatly affect the levels of flavonoids and vitamin B12. Out of all combinations, grape juice with red grape polyphenols was selected by expert judges (28.6% selected it as their first choice). In vivo, oral administration of grape juice supplemented with red grape polyphenols exerted an antioxidant effect in the brain of stressed mice reducing two-fold the expression of genes involved in inflammation and oxidation mechanisms and increasing three-fold the expression of genes related to protection against oxidative stress. In addition, we found that this drink augmented antioxidant enzyme activity (17.8 vs. 8.2 nmol/mg), and prevented lipid peroxidation in the brain (49.7 vs. 96.5 nmol/mg). Therefore, we propose supporting the use of this drink by the general population as a new and global strategy for the prevention of neurodegeneration.

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