AGING CELL
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2021
·Vol. 20
·期 3
·e13319
·
IF 9.304
Gang Du,Zhiming Liu,Zihua Yu,Zhangpeng Zhuo,Yuedan Zhu,Juanyu Zhou,Yang Li,Haiyang Chen
As they age, adult stem cells become more prone to functional decline, which is responsible for aging-associated tissue degeneration and diseases. One goal of aging research is to identify drugs that can repair age-associated tissue degeneration. Multiple organ development-related signaling pathways have recently been demonstrated to have functions in tissue homeostasis and aging process. Therefore, in this study, we tested several chemicals that are essential for organ development to assess their ability to delay intestinal stem cell (ISC) aging and promote gut function in adult Drosophila . We found that taurine, a free amino acid that supports neurological development and tissue metabolism in humans, represses ISC hyperproliferation and restrains the intestinal functional decline seen in aged animals. We found that taurine represses age-associated ISC hyperproliferation through a mechanism that eliminated endoplasmic reticulum (ER) stress by upregulation of the target genes of unfolded protein response in the ER (UPR ER ) and inhibiting the c-Jun N-terminal kinase (JNK) signaling. Our findings show that taurine plays a critical role in delaying the aging process in stem cells and suggest that it may be used as a natural compound for the treatment of age-associated, or damage-induced intestinal dysfunction in humans.
研究领域:
衰老研究
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干细胞生物学
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分子遗传学
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DOI
PubMed
高影响因子
CARBOHYDRATE POLYMERS
·
2020
·
IF 7.182
Wei Xu,Sijia Fang,Yong Wang,Xiaoqing Chi,Xiaodan Ma,Tao Zhang,Songhua Hu
The present study was to investigate the molecular mechanism underlying lymphocyte activation by total polysaccharides from Atractylodis macrocephalae (RAMPtp). The results showed that RAMPtp significantly promoted the secretions of cytokines (IFN-γ, IL-1α, IL-21, IFN-α, CCL4, CXCL9 and CXCL10), increased the proportions of CD4 + and CD8 + subpopulations, and enhanced the expressions of c-JUN, NFAT4, STAT1 and STAT3. microRNA sequencing identified 67 differentially expressed miRNAs (DEMs) in RAMPtp-stimulated SMLN lymphocytes, including 55 up-regulated and 12 down-regulated. GO and KEGG enrichment analyses of the predicted DEMs-targeted genes indicated that they were associated with immune system pathways, including PI3K-Akt, MAPKs, Jak-STAT and Calcium signaling pathways, which were confirmed by western blot and pathway inhibition assays. RAMPtp was further observed to favor immunostimulatory effect on both T and B lymphocytes via binding to TCR and membrane Ig individually. These findings might explain the immunomodulatory mechanism of RAMPtp in ameliorating the bovine intramammary infection.
研究领域:
免疫学
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分子生物学
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兽医学
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药理学
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DOI
PubMed
高影响因子
Natural Product Communications
·
2022
·
IF 1.496
Qiyi Wang,Xiaotong Duan,Shan Li,Huaqing Lai,Weina Cheng,Jingwen Ao,Jianyong Zhang,Cancan Duan
Objective: The study aimed to analyze the core active compounds and the potential mechanism of Shuganning injection (SGNI) through network pharmacology with biological experiments. Methods: Active compounds and targets of SGNI were screened from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) and Targetnet database, whereas the liver disease-related targets were identified through the Genecards and Online Mendelian Inheritance in Man databases. The “compound-target” and “protein-protein interaction” networks construction, core target identification, and pathway enrichment were then performed. Finally, the exploration of the mechanism of action for SGNI against acetaminophen (APAP)-induced liver injury in the HepaRG cells and validation of three identified protein targets was also carried out through western blot assay, including tumor protein p53 (p53, TP53), transcription factor Jun (Jun), and Caspase 3 (CASP3). Results: The result showed that a total of 312 active compounds of SGNI and 408 liver disease-related targets, as well as 131 core targets were revealed through databases, such as prostaglandin G/H synthase 1, prostaglandin G/H synthase 2, and nuclear factor NF-kappa B (NF-kB) p65 subunit (RELA). The core targets of SGNI were involved in regulating hepatitis B signaling pathway, NF-kB signaling pathway, Toll-like receptor signaling pathway, and tumor necrosis factor (TNF) signaling pathway. Moreover, results of molecular docking in this study indicated that chlorogenic acid, geniposide, baicalin, indirubin, and ganoderic acid A could act on RELA, JUN, TP53, TNF, CASP3, Caspase 8 (CASP8) and nuclear factor NF-kB p105 subunit (NFKB1). Similarly, results of western blot revealed that SGNI reduced the expression of p53, Jun, and Caspase 3 proteins in HepaRG cells as compared with the APAP group (P < 0.01 or P < 0.05). Conclusion: The present study verified the therapeutic effects and mechanism of SGNI on liver diseases and pointed out new directions for further research.
研究领域:
药理学
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分子生物学
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网络分析
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肝病研究
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DOI
高影响因子
METABOLISM-CLINICAL AND EXPERIMENTAL
·
2025
·
IF 11.9
Long Xu,Xinyan Wu,Luosha Long,Suchun Li,Meiying Huang,Meng Li,Pinning Feng,Moshe Levi,Wei Chen,Lei Wang,Chunling Li,Weidong Wang
Epithelial sodium channel (ENaC), located in the collecting duct principal cells of the kidney, is responsible for the reabsorption of sodium and plays a critical role in the regulation of extracellular fluid volume and consequently blood pressure. The G protein-coupled bile acid receptor (TGR5) is a membrane receptor mediating effects of bile acid and is implicated in kidney diseases. The current study aims to investigate whether TGR5 activation in the kidney regulated ENaC expression and potential mechanism. Lithocholic acid (LCA), a TGR5 agonist, markedly decreased systolic blood pressure induced by DOCA-salt in mice, which was associated with decreased ENaC expression in the kidney. DOCA-salt treatment increased renal expression of histone H3 lysine 4 trimethylation (H3K4me3) and decreased expression of lysine-specific demethylase 5A (KDM5A), a lysine demethylase, which was markedly reversed by LCA. TGR5 knockout caused further increased systolic blood pressure and ENaC expression in mice with DOCA-salt in association with increased H3K4me3 and decreased KDM5A. In immortalized mouse cortical collecting duct (mpkCCD) cells LCA markedly inhibited aldosterone-induced ENaC-mediated current. LCA treatment or TGR5 overexpression markedly inhibited ENaC and H3K4me3 protein expression in association with decreased KDM5A in mpkCCD cells treated with either aldosterone or angiotensin II. Inhibition or knockdown of KDM5A in mpkCCD cells prevented LCA-induced downregulation of ENaC expression by promoting H3K4me3 on the ENaC transcription start site. LCA upregulated KDM5A expression was likely through JNK/c-Jun signal pathway. In conclusion, LCA decreased blood pressure and ENaC protein expression in the kidney of mice with DOCA-salt, likely through activating TGR5 and upregulating KDM5A-induced H3K4me3 demethylation in ENaC promoter region.
研究领域:
肾病学
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分子生物学
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药理学
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DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2023
·
IF 5.6
La Yan,Juanyu Zhou,Lu Yuan,Jinbao Ye,Xudong Zhao,Gang Ren,Haiyang Chen
Inflammatory bowel diseases (IBDs) are characterized by chronic relapsing intestinal inflammation that causes digestive system dysfunction. For years, researchers have been working to find more effective and safer therapeutic strategies to treat these diseases. Silibinin (SIL), a flavonoid compound extracted from the seeds of milk thistle plants, possesses multiple biological activities and is traditionally applied to treat liver diseases. SIL is also widely used in the treatment of a variety of inflammatory diseases attributed to its excellent antioxidant and anti-inflammatory effects. However, the efficacy of SIL against IBDs and its mechanisms remain unclear. In this study, using Drosophila melanogaster as a model organism, we found that SIL can effectively relieve intestinal inflammation caused by dextran sulfate sodium (DSS). Our results suggested that SIL supplementation can inhibit the overproliferation of intestinal stem cells (ISCs) induced by DSS, protect intestinal barrier function, acid-base balance, and intestinal excretion function, reduce intestinal reactive oxygen species (ROS) levels and inflammatory stress, and extend the lifespan of Drosophila . Furthermore, our study demonstrated that SIL ameliorates intestinal inflammation via modulating the c-Jun N-terminal kinase (JNK) signaling pathway in Drosophila . Our research aims to provide new insight into the treatment of IBDs.
研究领域:
药理学
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免疫学
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分子生物学
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胃肠病学
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DOI
PubMed
高影响因子
Frontiers in Immunology
·
2024
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IF 5.7
Zhuwei Liang,Chao Zhang,Xiaoyu Liu,Kaiyue Yang,Zhile Xiong,Bingshao Liang,Jialiang Mai,Xiaojun Xiao,Jie Liu,Pingchang Yang,Damo Xu,Zhenwen Zhou
Background: Milk allergy commonly occurs in children, mainly caused by bovine-derived casein (CAS) protein. Neutrophil-activating protein (NAP) of Helicobacter pylori plays an immunomodulatory role with potential to suppress Th2-type immune responses. Bacillus subtilis (B. subtilis) spores are commonly used as oral vectors for drug delivery.Objective: To investigate whether recombinantly expressed NAP on B. subtilis spores could be an effective treatment for CAS allergy in mouse.Methods: After CAS sensitization, mice were orally administered B. subtilis spores expressing recombinant NAP for 6 weeks. Allergic symptoms and parameters were evaluated after CAS challenge oral gavage, including allergic inflammation, splenic cytokines, and serum-specific antibodies. Protein levels of Toll-like receptor 2 (TLR2) and c-JUN in the jejunum tissue were measured by western blot. Bone marrow-derived macrophages (BMDMs) were stimulated with inactivated NAP spores to measure the influence on cytokine profiles in vitro.Results: NAP recombinant spore treatment significantly reduced allergic symptoms and intestinal inflammation. Interleukin-12 and interferon-gamma levels increased, whereas serum CAS-specific IgG1 and IgE levels decreased. TLR2 and c-JUN expression levels were elevated in the jejunal tissue. Inactivated NAP spores polarized BMDMs to the M1 phenotype and enhanced cytokine expression, which were inhibited by a TLR2 neutralizing antibody.Conclusion: NAP offers a new strategy in the treatment of CAS allergy by inhibiting the Th2 response, while eliciting macrophages to promote Th1 immune responses.
研究领域:
免疫学
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过敏
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微生物学
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分子生物学
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DOI
PubMed
高影响因子
ACTA PHARMACOLOGICA SINICA
·
2021
·Vol. 43
·期 1
·133-145
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IF 6.15
Shen Dai-fei,Cheng He,Cai Bo-zhi,Cai Wen-feng,Wang Bin,Zhu Qing,Wu Yue-bin,Liu Man,Chen Run-ji,Gao Fen-fei,Zhang Yan-mei,Niu Yong-dong,Shi Gang-gang
N -n-Butyl haloperidol iodide (F 2 ) is a novel compound that has antiproliferative and antifibrogenic activities. In this study we investigated the therapeutic potential of F 2 against liver fibrosis in mice and the underlying mechanisms. Two widely used mouse models of fibrosis was established in mice by injection of either carbon tetrachloride (CCl 4 ) or thioacetamide (TAA). The mice received F 2 (0.75, 1.5 or 3 mg·kg −1 ·d −1 , ip) for 4 weeks of fibrosis induction. We showed that F 2 administration dose-dependently ameliorated CCl 4 - or TAA-induced liver fibrosis, evidenced by significant decreases in collagen deposition and c-Jun, TGF-β receptor II (TGFBR2), α-smooth muscle actin (α-SMA), and collagen I expression in the liver. In transforming growth factor beta 1 (TGF-β1)-stimulated LX-2 cells (a human hepatic stellate cell line) and primary mouse hepatic stellate cells, treatment with F 2 (0.1, 1, 10 μM) concentration-dependently inhibited the expression of α-SMA, and collagen I. In LX-2 cells, F 2 inhibited TGF-β/Smad signaling through reducing the levels of TGFBR2; pretreatment with LY2109761 (TGF-β signaling inhibitor) or SP600125 (c-Jun signaling inhibitor) markedly inhibited TGF-β1-induced induction of α-SMA and collagen I. Knockdown of c-Jun decreased TGF-β signaling genes, including TGFBR2 levels. We revealed that c-Jun was bound to the TGFBR2 promoter, whereas F 2 suppressed the binding of c-Jun to the TGFBR2 promoter to restrain TGF-β signaling and inhibit α-SMA and collagen I upregulation. In conclusion, the therapeutic benefit of F 2 against liver fibrosis results from inhibition of c-Jun expression to reduce TGFBR2 and concomitant reduction of the responsiveness of hepatic stellate cells to TGF-β1. F 2 may thus be a potentially new effective pharmacotherapy for human liver fibrosis.
研究领域:
药理学
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肝病学
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细胞生物学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Journal of Orthopaedic Surgery and Research
·
2022
·Vol. 17
·期 1
·1-8
·
IF 2.677
Zhang Bin-Fei,Song Wei,Wang Jun,Wen Peng-Fei,Zhang Yu-Min
Objectives The lung injury is often secondary to severe trauma. In the model of crush syndrome, there may be secondary lung injury. We hypothesize that high-mobility group box 1 (HMGB1), released from muscle tissue, mediates the apoptosis of alveolar epithelial cells (AEC) via HMGB1/Receptor of advanced glycation end-products (RAGE)/c-Jun N-terminal kinase (JNK) pathway. The study aimed to investigate how HMGB1 mediated the apoptosis of AEC in the rat model. Methods Seventy-five SD male rats were randomly divided into five groups: CS, CS + vehicle, CS + Ethyl pyruvate (EP), CS + FPS-ZM1 group, and CS + SP600125 groups. When the rats CS model were completed after 24 h, the rats were sacrificed. We collected the serum and the whole lung tissues. Inflammatory cytokines were measured in serum samples. Western blot and RT-qPCR were used to quantify the protein and mRNA. Lastly, apoptotic cells were detected by TUNEL. We used SPSS 25.0 for statistical analyses. Results Nine rats died during the experiments. Dead rats were excluded from further analysis. Compared to the CS group, levels of HMGB1 and inflammatory cytokines in serum were downregulated in CS + EP, CS + FPS-ZM1, and CS + SP600125 groups. Western blot and RT-qPCR analysis revealed a significant downregulation of HMGB1, RAGE, and phosphorylated-JNK in CS + EP, CS + FPS-ZM1, and CS + SP600125 groups, compared with the CS groups, excluding total-JNK mRNA. Apoptosis of AEC was used TUNEL to assess. We found the TUNEL-positive cells were downregulated in CS + EP, CS + FPS-ZM1, and CS + SP600125 groups. Conclusion The remote lung injury begins early after crush injuries. The HMGB1/RAGE/JNK signaling axis is an attractive target to abrogate the apoptosis of AEC after crush injuries.
研究领域:
病理生理学
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肺医学
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创伤外科
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分子生物学
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DOI
PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2015
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IF 2.912
Chuanyang Su,Xiaomin Xia,Qiong Shi,Xiufang Song,Juanli Fu,Congxue Xiao,Hongjun Chen,Bin Lu,Zhiyin Sun,Shanmei Wu,Siyu Yang,Xuegang Li,Xiaoli Ye,Erqun Song,Yang Song
Neohesperidin dihydrochalcone (NHDC), a sweetener derived from citrus, belongs to the family of bycyclic flavonoids dihydrochalcones. NHDC has been reported to act against CCl4-induced hepatic injury, but its mechanism is still unclear. We first discovered that NHDC showed a strong ability to scavenge free radicals. In addition, NHDC induces the phase II antioxidant enzymes heme oxygenase 1 (HO-1) and NAD(P)H/quinone oxidoreductase 1 (NQO1) through the activation of the nuclear factor (erythroid-derived 2)-like 2 (Nrf2)/antioxidant response element (ARE) signaling. Further assays demonstrated that NHDC induces accumulation of Nrf2 in the nucleus and augmented Nrf2-ARE binding activity. Moreover, NHDC inhibits the ubiquitination of Nrf2 and suggests the modification of Kelch-like ECH-associated protein 1 (Keap1) and the disruption of the Keap1/Nrf2 complex. c-Jun N-terminal kinase (JNK) and p38 but not extracellular signal-regulated protein kinase (ERK) phosphorylations were up-regulated by NHDC treatment. Taken together, NHDC showed its protective antioxidant effect against CCl4-induced oxidative damage via the direct free radical scavenging and indirect Nrf2/ARE signaling pathway.
研究领域:
药理学
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毒理学
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分子生物学
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DOI
PubMed
高影响因子
NUTRITION RESEARCH
·
2015
·
IF 2.472
Qian Wang,Shuang-ting Wang,Xin Yang,Pan-pan You,Wen Zhang
Myricetin (MyR), a naturally occurring flavonol widely distributed in fruits, vegetables, and medicinal plants , has anticancer, anti-inflammatory, antihyperlipidaemic , and antiobesity activities. In the present study, we hypothesized that the antiobesity property of MyR is mediated via suppression of differentiation of preadipocytes into adipocytes and promotion of lipolysis of mature adipocytes, which effectively decrease the intracellular triglyceride concentration of adipocytes. Accordingly, the aim of this work was to investigate the effects of MyR on adipocyte differentiation and lipolysis in differentiated 3 T3-L1 adipocytes. Our results showed that MyR inhibited differentiation of 3 T3-L1 preadipocytes in a concentration-dependent manner. Myricetin downregulated the mRNA and protein levels of CCAAT/enhancer-binding protein α and peroxisome proliferator-activated receptor γ , both of which are major adipogenic transcription factors. Furthermore, the mRNA levels of other adipogenesis-related transcription factors, namely, CCAAT/enhancer-binding protein β , sterin regulatory element binding protein 1-c, peroxisome proliferator-activated receptor γ coactivator–1, adipocyte protein 2 , lipoprotein lipase and glucose transporter 4 , were also reduced by MyR treatment. Moreover, MyR significantly inhibited the phosphorylation of extracellular signal–regulated kinase, Jun N-terminal kinase, and p38 during the differentiation process. On the other hand, MyR induced a dose-dependent increase in glycerol release in fully differentiated adipocytes, indicating its stimulatory effect on adipocyte lipolysis. Furthermore, MyR downregulated mRNA level of perilipin A and enhanced the phosphorylation level of extracellular signal–regulated kinase, Jun N-terminal kinase, and p38 during lipolysis. Taken together, these findings indicate that MyR exerts antiobesity activity in adipocytes.
研究领域:
药理学
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细胞生物学
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分子生物学
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营养学
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产品关联
DOI
PubMed
高影响因子
BIOSCIENCE BIOTECHNOLOGY AND BIOCHEMISTRY
·
2020
·Vol. 84
·期 12
·2491-2498
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IF 1.516
Liang Haohui,Pan Yanna,Teng Yilong,Yuan Shilin,Wu Xiao,Yang Hongjie,Zhou Ping
The pancreatic β-cell death or dysfunction induced by oxidative stress plays an important effect on the development and progression of diabetes mellitus. Based on our previous findings, a natural proteoglycan extracted from Ganoderma Lucidum, named FYGL, could treat T2DM in vivo. In this study, we investigated the effects of FYGL on STZ‐induced apoptosis of INS-1 cells and its underlying mechanisms. The results showed that FYGL significantly improved the cell viability and alleviated the apoptosis in STZ‐treated INS‐1 cells. Moreover, FYGL markedly decreased the intracellular ROS accumulation and NO release, and deactivated NF-κB, JNK, and p38 MAPK signaling pathways in STZ-induced INS-1 cells. Furthermore, FYGL improved the insulin secretion through inhibiting the activation of JNK and improving the expression of Pdx-1 in INS-1 cells damaged by STZ. These results indicated that FYGL could protect pancreatic β-cells against apoptosis and dysfunction, and be used as a promising pharmacological medicine for diabetes management.Abbreviations: T2DM: type 2 diabetes mellitus; FYGL: Fudan-Yueyang G. lucidum; ROS: reactive oxygen species; NO: reactive oxygen species; NF-κB: nuclear factor kappa beta; JNK: c-jun N-terminal kinase; MAPK: mitogen-activated protein kinase; Pdx-1: Pancreatic duodenal homeobox 1
研究领域:
药理学
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糖尿病
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细胞生物学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Food Bioscience
·
2025
·
IF 5.9
Ruoxin Chen,Jiahao Ren,Zhenlong Zhou,Wenjun Zhang,Jianyu Su
Gentiana rigescens Franch. extract have demonstrated various important bioactivities, however, their potential against photoaging has yet to be evaluated. This study explored the anti-photoaging effects of Gentiana rigescens Franch. root extract (GRFR) and stem (GRFS), along with their underlying mechanisms and bioactive components, using the UVB-induced zebrafish model. GRFS demonstrated superior anti-photoaging efficacy compared to GRFR. GRFS significantly alleviated UVB-induced tail fin damage, increasing the relative tail fin area from 31.23% to 80.92% (at 1mg/mL), and reducing ROS levels from 244.80% to 150.95%. It also inhibited lipid peroxidation, lowering malondialdehyde (MDA) levels from 202.87 nmol/g to 142.83 nmol/g. Furthermore, GRFS enhanced antioxidant enzyme activities, increasing superoxide dismutase (SOD) from 80.94 U/g to 104.06 U/g. Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS) indicated substantial distinctions in the composition and content of major constituents between GRFR and GFRS, which may explain the differences in their anti-photoaging activities. And then network pharmacology was used to investigate possible mechanisms of GFRS, which identified five potential targets including CTNNB1, ESR1, AKT1, JUN and EGFR, as well as three key active compounds including aspartyl-phenylalanine (Asp-Phe), N-acetyl-L-phenylalanine (N-Acetyl-L-Phe), and phenylalanyl-tyrosine (Phe-Tyr). Finally, the molecular docking revealed that Phe-Tyr exhibited the strongest binding affinity for AKT1 (-8.86 kcal/mol), indicating that it may be the most potent anti-photoaging compound in GFRS. These findings suggest that G . rigescens , with its potent anti-photoaging properties, offers superior protection against UVB-induced photoaging and holds promise as a natural therapeutic agent.
研究领域:
药理学
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植物学
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皮肤科学
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生物化学
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计算生物学
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天然产物研究
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生物技术
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产品关联
DOI
高影响因子
危险品化学品经营许可证（带存储）