BIOCHEMICAL PHARMACOLOGY
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2020
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IF 4.96
Qi Zhao,Ping Tang,Ting Zhang,Jian-Feng Huang,Xue-Rong Xiao,Wei-Feng Zhu,Frank J. Gonzalez,Fei Li
Celastrol , derived from the roots of the Tripterygium Wilfordi , has attracted interest for its potential anti-inflammatory and lipid-lowering activities. In the present study, the protective effect of celastrol on carbon tetrachloride (CCl 4 )-induced acute liver injury was investigated. Celastrol improved the increased transaminase activity, inflammation, and oxidative stress induced by CCl 4 , resulting in improved metabolic disorders found in mice with liver injury. Dual-luciferase reporter assays and primary hepatocyte studies demonstrated that the peroxisome proliferator-activated receptor α (PPARα) signaling mediated the protective effect of celastrol, which was not observed in Ppara -null mice, and co-treatment of wild-type mice with the PPARα antagonist GW6471. Mechanistically, PPARα deficiency potentiated CCl 4 -induced liver injury through a deoxycholic acid (DCA)-EGR1-inflammatory factor axis. These data demonstrate a novel role for celastrol in protection against acute liver injury through modulating PPARα signaling.
研究领域:
药理学
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肝脏病学
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分子生物学
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DOI
PubMed
高影响因子
JOURNAL OF PROTEOME RESEARCH
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2018
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IF 3.95
Xiao-Nan Yang,Xue-Mei Liu,Jian-He Fang,Xu Zhu,Xiu-Wei Yang,Xue-Rong Xiao,Jian-Feng Huang,Frank J. Gonzalez,Fei Li
Nutmeg is a Traditional Chinese Medicine used to treat gastrointestinal diseases. Some reports have indicated that nutmeg has hepatoprotective activity. In this study, a thioacetamide (TAA)-induced acute liver injury model in mice was used to explore the mechanism of the protective effects of nutmeg extract (NME), including its major bioactive component myrislignan. The results indicated that NME could effectively protect TAA-induced liver damage as assessed by recovery of increased serumtransaminases, decrease in hepatic oxidative stress, and lower hepatic inflammation. Metabolomics analysis further revealed that treatment with NME led to the recovery of a series of lipids including lysophosphatidylcholines that were decreased and a lowering of acylcarnitines that were increased in mouse plasma and liver after TAA exposure. Gene expression analysis demonstrated that the hepatoprotective effect of NME was achieved by modulation of the peroxisome proliferator-activated receptor alpha (PPARα) as well as the decrease in oxidative stress. NME could not protect from TAA-induced liver injury in Ppara-null mice, suggesting that its protective effect was dependent on PPARα. Myrislignan, a representative neolignan in nutmeg, showed potent protective activity against TAA-induced liver toxicity. These data demonstrate that nutmeg alleviates TAA-induced liver injury through the modulation of PPARα and that the lignan compounds in nutmeg such as myrislignan partly contributed to this action.
研究领域:
药理学
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肝病学
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中药
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分子生物学
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DOI
PubMed
高影响因子
Acta Pharmaceutica Sinica B
·
2024
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IF 14.7
Shicheng Fan,Yue Gao,Pengfei Zhao,Guomin Xie,Yanying Zhou,Xiao Yang,Xuan Li,Shuaishuai Zhang,Frank J. Gonzalez,Aijuan Qu,Min Huang,Huichang Bi
Fenofibrate, a peroxisome proliferator-activated receptor α (PPAR α ) agonist, is widely prescribed for hyperlipidemia management. Recent studies also showed that it has therapeutic potential in various liver diseases. However, its effects on hepatomegaly and liver regeneration and the involved mechanisms remain unclear. Here, the study showed that fenofibrate significantly promoted liver enlargement and regeneration post-partial hepatectomy in mice, which was dependent on hepatocyte-expressed PPAR α . Yes-associated protein (YAP) is pivotal in manipulating liver growth and regeneration. We further identified that fenofibrate activated YAP signaling by suppressing its K48-linked ubiquitination, promoting its K63-linked ubiquitination, and enhancing the interaction and transcriptional activity of the YAP–TEAD complex. Pharmacological inhibition of YAP–TEAD interaction using verteporfin or suppression of YAP using AAV Yap shRNA in mice significantly attenuated fenofibrate-induced hepatomegaly. Other factors, such as MYC, KRT23, RAS, and RHOA, might also participate in fenofibrate-promoted hepatomegaly and liver regeneration. These studies demonstrate that fenofibrate-promoted liver enlargement and regeneration are PPAR α -dependent and partially through activating the YAP signaling, with clinical implications of fenofibrate as a novel therapeutic agent for promoting liver regeneration.
研究领域:
药理学
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肝脏生物学
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分子生物学
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DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
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2025
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IF 8.5
Haotian Zhang,Xiaoying Chen,Hua Rong,Baojia Chen,Junfeng Guang,Qing Pan,Xiaobo Wen,Lijun Ning
Unlike predictability in mammals, the responses of PPARα activation treatment in fish varies between different fish species. Existing results indicated that the varied effects may result from fish feeding habits difference within their varied dietary protein content, while the exact mechanism remains obscure. In this study, we conducted an in vivo 8-week trial of low protein 30 % (LP) or high protein 38 % (HP) diet fed tilapia (8.83 ± 0.02 g) supplemented with or without fenofibrate and in vitro 24-h of BCAA (leucine, valine and isoleucine) treated primary cell trial, aiming to reveal the unknown mechanism. The in vivo results showed that, in LP group, fenofibrate significantly increased serum levels of TG, glucose, AST, ALT, MDA and liver TG ( P < 0.05), while decreased liver, muscle and serum BCAA, liver mitochondria quantity, glucose tolerance ( P < 0.05). Moreover, fenofibrate notably lifted the hepatic bckdha , bckdhb , mff , fis , fas and pparγ expression ( P < 0.05), while decreased genes expression of pgc1α , tfam , parkin , pink , foxo3a, sod2, cat , ir and irs ( P < 0.05). No great impact was found in aco , cyp4a3 and cytb ( P > 0.05). In HP group, fenofibrate improved lipid and glucose metabolism along with unaltered BCAA, increased expression of aco , cytb , cpt1a , pparβ , foxo3a , sod2 , nrf1 , mfn1 and fis ( P < 0.05). In vitro findings revealed that the PGC1α and PPARα could be activated by BCAA, particular for leucine ( P < 0.05). Taken together, we conclude that: 1) increased lipid deposition, lipid peroxidation, liver damage and glucose intolerance in fenofibrate-LP group could be ascribed to decreased BCAA and done through PGC1α/FOXO3, PGC1α/MQC regulation; 2) improved lipid-lowering and glucose tolerance in fenofibrate-HP group would be attributed to the enhanced PGC1α/MQC, organelles proliferation and fatty acid β-oxidation.
研究领域:
分子生物学
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营养学
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代谢组学
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产品关联
DOI
PubMed
高影响因子
FITOTERAPIA
·
2025
·
IF 2.6
Weijian Qu,Yi Lan,Zhuoqing Cheng,Han Yuan,Honghong Zhan,Xiaozhong Lan,Zhihua Liao,Guowei Wang,Min Chen
Diabetic kidney disease (DKD) is a common complication in patients with diabetes, and glycolipid metabolism disorders are an important cause of DKD. The root of Oxybaphus himalaicus (Edgew.) Heimerl is a traditional Tibetan medicine commonly used to treat kidney-related diseases. Nevertheless, contemporary pharmacological investigations into O. himalaicus , especially those associated with the treatment of renal disorders, remain scarce. The objective of this research was to explore the pharmaceutical impacts and mechanisms of action of O. himalaicus in the treatment of DKD. The active fraction and potential pharmacological effects of O. himalaicus were determined through network pharmacology. Then, in vivo and in vitro efficacy and mechanism studies were conducted through streptozotocin-induced DKD mice and high glucose-induced HK-2 cells. Network pharmacology research speculated the ethyl acetate (EA) fraction as the main active component of O. himalaicus for treating DKD. In vivo and in vitro experiments showed that EA reduces renal lipotoxicity by upregulating PPARα pathway proteins, enhancing fatty acid oxidation (FAO), and downregulating inflammatory factors such as TNF-α and IL-6. Molecular docking studies revealed that the active components of EA with a high affinity for PPARα are mainly rotenoid compounds. EA mitigates DKD through the activation of PPARα, which serves to augment FAO, abate lipid accumulation, and impede the expression of inflammatory factors. Among these, rotenoids may be the main active components that exert pharmacological effects.
研究领域:
药理学
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内分泌学
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肾脏病学
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产品关联
DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2023
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IF 7.9
Zhi-shen Xie,Jian-ping Zhao,Li-min Wu,Shuang Chu,Zheng-hao Cui,Yi-ran Sun,Hui Wang,Hui-fen Ma,Dong-rui Ma,Pan Wang,Xiao-wei Zhang,Zhen-qiang Zhang
Background Autophagic flux is coordinated by a network of master regulatory genes, which centered on transcription factor EB (TFEB). The disorders of autophagic flux are closely associated with Alzheimer's disease (AD), and thus restoring autophagic flux to degrade pathogenic proteins has become a hot therapeutic strategy. Hederagenin (HD), a triterpene compound, isolated from a variety food such as Matoa (Pometia pinnata) Fruit, Medicago sativa, Medicago polymorpha L. Previous studies have shown that HD has the neuroprotective effect. However, the effect of HD on AD and underlying mechanisms are unclear. Purpose To determine the effect of HD on AD and whether it promotes autophagy to reduce AD symptoms. Study Design BV2 cells , C. elegans and APP/PS1 transgenic mice were used to explore the alleviative effect of HD on AD and the molecular mechanism in vivo and in vitro . Methods The APP/PS1 transgenic mice at 10 months were randomized into 5 groups ( n = 10 in each group) and orally administrated with either vehicle (0.5% CMC Na), WY14643 (10 mg/kg/d), low-dose of HD (25 mg/kg/d), high-dose of HD (50 mg/kg/d) or MK-886 (10 mg/kg/d) + HD (50 mg/kg/d) for consecutive 2 months. The behavioral experiments including morris water maze test, object recognition test and Y maze test were performed. The effects of HD on Aβ deposition and alleviates Aβ pathology in transgenic C. elegans were operated using paralysis assay and fluorescence staining assay. The roles of HD in promoting PPARα/TFEB-dependent autophagy were investigated using the BV2 cells via western blot analysis, real-time quantitative PCR (RT-qPCR), molecular docking, molecular dynamic (MD) simulation, electron microscope assay and immunofluorescence. Results In this study, we found that HD upregulated mRNA and protein level of TFEB and increased the distribution of TFEB in the nucleus, and the expressions of its target genes. HD also promoted the expressions of LC3BII/LC3BI, LAMP2, etc. , and promoted autophagy and the degradation of Aβ. HD reduced Aβ deposition in the head area of C. elegans and Aβ-induced paralysis. HD improved cognitive impairment and pathological changes in APP/PS1 mice by promoting autophagy and activating TFEB. And our results also showed that HD could strongly target PPARα. More importantly, these effects were reversed by treatment of MK-886, a selective PPARα antagonist. Conclusion Our present findings demonstrated that HD attenuated the pathology of AD through inducing autophagy and the underlying mechanism associated with PPARα/TFEB pathway.
研究领域:
神经科学
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药理学
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分子生物学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
·
2025
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IF 5.4
Zhuoqing Cheng,Honghong Zhan,Han Yuan,Nan Wang,Yi Lan,Weijian Qu,Xiaozhong Lan,Zhihua Liao,Guowei Wang,Min Chen
Ethnopharmacological relevance The roots of Oxybaphus himalaicus Edgew. is a traditional Tibetan herbal medicine with kidney reinforcing and tonifying effects, which is commonly applied to treat nephritis. Boeravinone C has been identified as one of the primary constituents of O. himalaicus. However, the potential renal protective effects of boeravinone C remains unclear. Aim of the study This research aimed to investigate the protective effects of boeravinone C on diabetic kidney disease and the underlying mechanisms. Materials and methods Streptozotocin (100 mg/kg) was intraperitoneally injected to induce DKD in mice. High glucose (50 mM)-induced HK-2 cells were utilized to investigate the mechanisms of boeravinone C against tubular injuries in vitro . Anti-DKD activity was assessed by measuring reactive oxygen species (ROS) levels, analyzing apoptosis through flow cytometry, and evaluating inflammation, apoptosis, and FAO-related proteins via Western blotting. Additionally, serum biochemical assays, as well as histopathological and immunohistochemical analyses of kidney tissues, were performed to explore the pharmacological effects of boeravinone C. Results In vivo , boeravinone C administered significantly reduced the creatinine (CRE), blood urea nitrogen (BUN), triglycerides (TG), total cholesterol (TC), and low-density lipoprotein cholesterol (LDL-C) levels in serum of DKD mice. In vitro , boeravinone C significantly restored the apoptosis induced by HG in HK-2 cells, which is further validated by an upregulation of the apoptosis-inhibiting protein Bcl-2, along with a decreased expression of the apoptosis-promoting proteins Bax and caspase-3. Mechanistically, boeravinone C reversed HG-induced downregulation of peroxisome proliferator-activated receptor α (PPARα) expression. As a transcription factor, elevated expression of PPARα led to upregulation of CPT1A and ACOX1, which then enhanced fatty acid oxidation (FAO) to reduce lipid accumulation in HK-2 cells. Furthermore, boeravinone C-mediated high expression of PPARα sequestered p65 subunit of NF-κB in the cytoplasm, leading to reduced expression of proinflammatory cytokines such as iNOS, TNF-α and IL-6. To verify that the therapeutic effects of boeravinone C in diabetic kidney disease (DKD) are mediated via PPARα activation, we developed a PPARα knockdown HK-2 cell line. Our findings revealed that PPARα downregulation modified biological effects of boeravinone C, especially regarding fatty acid metabolism and the inflammatory response, with significant repercussions on apoptosis. Conclusion This study demonstrates that the major component boeravinone C from O. himalaicus promotes the fatty acid oxidation and suppresses inflammatory response by upregulating PPARα expression, thereby reducing apoptosis in HG-induced renal tubule cells. Consequently, boeravinone C restores tubular function in DKD mice. Collectively, this study provides a pharmacological basis for utilizing of O. himalaicus in treating DKD.
研究领域:
民族药理学
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分子生物学
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肾脏病学
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产品关联
DOI
PubMed
高影响因子
CHEMICO-BIOLOGICAL INTERACTIONS
·
2024
·
IF 4.7
Shulin Wang,Xuan Zhang,Yanhong Hou,Yuliang Zhang,Jiamin Chen,Shuhan Gao,Huiying Duan,Shaoju Gu,Shanshan Yu,Yi Cai
The Sirtuins family, formally known as the Silent Information Regulator Factors, constitutes a highly conserved group of histone deacetylases. Recent studies have illuminated SIRT6's role in doxorubicin (DOX)-induced oxidative stress and apoptosis within myocardial cells. Nevertheless, the extent of SIRT6's impact on DOX-triggered myocardial cell aging and damage remains uncertain, with the associated mechanisms yet to be fully understood. In our research, we examined the influence of SIRT6 on DOX-induced cardiomyocyte senescence using β-galactosidase and γ-H2AX staining. Additionally, we gauged the mRNA expression of senescence-associated genes, namely p16, p21, and p53, through Real-time PCR. Employing ELISA assay kits, MDA, and total SOD activity assay kits, we measured inflammatory factors TNF-α, IL-6, and IL-1β, alongside oxidative stress-related indicators. The results unequivocally indicated that SIRT6 overexpression robustly inhibited DOX-induced cardiomyocyte senescence. Furthermore, we established that SIRT6 overexpression suppressed the inflammatory response and oxidative stress induced by DOX in cardiomyocytes. Conversely, silencing SIRT6 exacerbated DOX-induced cardiomyocyte injury. Our investigations further unveiled that SIRT6 upregulated the expression of genes CD36, CPT1, LCAD, MCAD associated with fatty acid oxidation through its interaction with PPARα, thereby exerting anti-aging effects. In vivo , the overexpression of SIRT6 was observed to restore DOX-induced declines in EF and FS to normal levels in mice. Echocardiography and HE staining revealed the restoration of cardiomyocyte alignment, affording protection against DOX-induced myocardial senescence and injury. The findings from this study suggest that SIRT6 holds significant promise as a therapeutic target for mitigating DOX-induced cardiomyopathy.
研究领域:
心脏病学
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分子生物学
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药理学
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产品关联
DOI
PubMed
高影响因子
TOXICOLOGY LETTERS
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2017
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IF 3.858
Jie Zhang,Tiezhu Li,Tuoyi Wang,Tianzhu Guan,Hansong Yu,Zhuolin Li,Yongzhi Wang,Yongjun Wang,Tiehua Zhang
The binding of bisphenol A (BPA) and its halogenated derivatives (halogenated BPAs) to mouse peroxisome proliferator-activated receptor α ligand binding domain (mPPARα-LBD) was examined by a combination of in vitro investigation and in silico simulation. Fluorescence polarization (FP) assay showed that halogenated BPAs could bind to mPPARα-LBD* as the affinity ligands. The calculated electrostatic potential (ESP) illustrated the different charge distributions of halogenated BPAs with altered halogenation patterns. As electron-attracting substituents, halogens decrease the positive electrostatic potential and thereby have a significant influence on the electrostatic interactions of halogenated BPAs with mPPARα-LBD*. The docking results elucidated that hydrophobic and hydrogen-bonding interactions may also contribute to stabilize the binding of the halogenated BPAs to their receptor molecule. Comparison of the calculated binding energies with the experimentally determined affinities yielded a good correlation (R 2 = 0.6659) that could provide a rational basis for designing environmentally benign chemicals with reduced toxicities. This work can potentially be used for preliminary screening of halogenated BPAs.
研究领域:
环境科学
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毒理学
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生物化学
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DOI
PubMed
高影响因子
CHEMICO-BIOLOGICAL INTERACTIONS
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2022
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IF 5.168
Xueyun Liu,Man Hu,Chen Ye,Lihong Liao,Chang Ding,Lijuan Sun,Jichao Liang,Yong Chen
It is well known that the excessive accumulation of lipid in hepatocytes is one of the important causes of non-alcoholic fatty liver disease (NAFLD). The purpose of this study was to explore the effects of isosilybin on lipid metabolism in free fatty acids (FFAs) or TO901317-induced HepG2 cells. Cells were treated with FFAs (oleic acid: palmitic acid , 2:1) or TO901317 to induce steatosis in vitro. Intracellular triglyceride (TG) content was quantified using commercial assay kits. The mRNA and protein expression of genes involved in fatty acid uptake, synthesis and oxidation were analyzed by RT-qPCR and western blotting . Selected biological pathways regulated by isosilybin treatment were determined by GO and KEGG analysis. The results showed that isosilybin significantly reduced TG levels in FFAs- and TO901317-induced HepG2 cells. Further studies showed that isosilybin treatment decreased the mRNA and protein expression of lipid synthesis genes Srebp-1c, Pnpla3, Acc and Fas , as well as the mRNA expression of fatty acid uptake gene CD36, whereas increased the mRNA levels of lipid oxidation genes Pparα, Acox1 and Cpt1α, as well as the mRNA expression of lipid export gene Mttp, in FFAs-induced HepG2 cells. Moreover, TO901317 was employed to induce endogenous lipid synthesis and steatosis, and the expression of Srebp-1c and its target genes in TO901317-induced hepatocytes was basically similar to that in FFAs-induced hepatocytes following isosilybin treatment. We also observed the increased level of phosphorylated AMP kinase (AMPK) after isosilybin treatment, while this effect was reversed after further treatment with AMPK inhibitor , compound C. The results of GO and KEGG analysis indicated that the pathways of fatty acid and TG metabolism were regulated by isosilybin. Interestingly, we found that treatment with the diastereoisomer A of isosilybin increased TG level, while exposure to the diastereoisomer B of isosilybin decreased TG level in FFAs-induced HepG2 cells. The above results suggest that isosilybin can inhibit lipid synthesis and activate lipid oxidation through AMPK signaling pathway, thereby improving steatosis of hepatocytes, and isosilybin B is the basis of its active substance.
研究领域:
分子生物学
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细胞生物学
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药理学
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代谢紊乱
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产品关联
DOI
PubMed
高影响因子
Nature Communications
·
2023
·Vol. 14
·期 1
·1-18
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IF 16.6
Zhong Jing,He Xiaofang,Gao Xinxin,Liu Qiaohong,Zhao Yu,Hong Ying,Zhu Weize,Yan Juan,Li Yifan,Li Yan,Zheng Ningning,Bao Yiyang,Wang Hao,Ma Junli,Huang Wenjin,Liu Zekun,Lyu Yuanzhi,Ke Xisong,Jia Wei,Xie Cen,Hu Yiyang,Sheng Lili,Li Houkai
Nonalcoholic fatty liver disease (NAFLD) is usually characterized with disrupted bile acid (BA) homeostasis. However, the exact role of certain BA in NAFLD is poorly understood. Here we show levels of serum hyodeoxycholic acid (HDCA) decrease in both NAFLD patients and mice, as well as in liver and intestinal contents of NAFLD mice compared to their healthy counterparts. Serum HDCA is also inversely correlated with NAFLD severity. Dietary HDCA supplementation ameliorates diet-induced NAFLD in male wild type mice by activating fatty acid oxidation in hepatic peroxisome proliferator-activated receptor α (PPARα)-dependent way because the anti-NAFLD effect of HDCA is abolished in hepatocyte-specific Pparα knockout mice. Mechanistically, HDCA facilitates nuclear localization of PPARα by directly interacting with RAN protein. This interaction disrupts the formation of RAN/CRM1/PPARα nucleus-cytoplasm shuttling heterotrimer. Our results demonstrate the therapeutic potential of HDCA for NAFLD and provide new insights of BAs on regulating fatty acid metabolism.
研究领域:
肝病学
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分子生物学
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代谢
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS
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2025
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IF 3.3
Qinghua Fu,Peng Wang,Weilin Li,Zhenhua Cai,Shiji Zhao,Weidong Ling,Mingxun Li,Xiaochuan Tang,Ziyi Song
Obesity poses a significant risk for metabolic disorders, such as insulin resistance and metabolic-associated fatty liver disease (MAFLD), yet effective treatments remain limited. Cell Death-Inducing DNA Fragmentation Factor-α-Like Effector C (CIDEC), a lipid droplet membrane protein, facilitates lipid droplet fusion and is crucial for adipose tissue expansion, making it a key target for obesity and related metabolic diseases. However, previous research revealed that complete genetic deletion of Cidec in adipose tissues, while reducing fat accumulation, induced severe insulin resistance in high-fat diet (HFD)-fed mice, potentially due to ectopic fat storage in the liver. Given that complete knockout is an extreme approach, partial inhibition holds greater clinical relevance. Therefore, this study aimed to investigate the effects of partial inhibition of CIDEC in adipose tissues on fat accumulation and insulin sensitivity in mice. Using the Cre-LoxP system, we generated adipose Cidec haploinsufficient mice. Under a standard diet, these mice exhibited normal body weight, fat accumulation, and insulin sensitivity. Notably, under HFD conditions, mice with partial Cidec deficiency showed reduced fat accumulation in adipose tissues while hepatic fat accumulation remained unchanged, accompanied by improved insulin sensitivity and increased energy expenditure. Mechanistically, we found partial Cidec deficiency activated thermogenic program in adipocytes in vivo and in vitro through the ATGL-PPARα pathway. In conclusion, adipose CIDEC partial inhibition attenuates HFD-induced obesity and insulin resistance by enhancing ATGL-PPARα-mediated energy expenditure, establishing this approach as a promising therapeutic strategy for obesity and related metabolic diseases.
研究领域:
生物学
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医学
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代谢疾病
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）