PHYTOMEDICINE
·
2020
·
IF 4.268
Ying Xie,Sen-Ling Feng,Chu-Tian Mai,Yan-Fang Zheng,Hui Wang,Zhong-Qiu Liu,Hua Zhou,Liang Liu
Background As dysregulation of immunometabolism plays a key role in the immunological diseases , dyslipidemia frequently observed in rheumatoid arthritis (RA) patients (60%) is associated with the disease activity and has been considered as the potential target of anti-inflammatory strategy. However, targeting of metabolic events to develop novel anti-inflammatory therapeutics are far from clear as well as the mechanism of dyslipidemia in RA. Purpose To explore the therapeutic potential and mechanisms of silybin again RA through the regulation of lipid metabolism . Methods Adjuvant-induced arthritis (AIA) rat model was used to examine the effects of silybin on modulating dysregulated lipid metabolism and arthritis. Metabolomics , docking technology, and biochemical methods such as western blots , qRT-PCR, immunofluorescence staining were performed to understanding the underlying mechanisms. Moreover, knock-down of LXRα and LXRα agonist were used on LO2 cell lines to understand the action of silybin. Results We are the first to demonstrate that silybin can ameliorate dyslipidemia and arthritis in AIA rats. Overexpression of LXRα and several key lipogenic enzymes regulated by LXRα, including lipoprotein lipase (LPL), cholesterol 7α and 27α hydroxylase (CYP7A, CYP27A), adipocyte fatty acid-binding protein (aP2/FABP4) and fatty acid translocase (CD36/FAT), were observed in AIA rats, which mostly accounted for dyslipidemia during arthritis development. Metabolomics, docking technology, and biochemical results indicated that anti-arthritis effects of silybin related to suppressing the up-regulated LXRα and abnormal lipid metabolism. Notably, activation of LXRα could potentiate cell inflammatory process induced by LPS through the regulation of NF-κB pathway, however, suppression of LXRα agonism by siRNA or silybin reduced the nuclear translocation of NF-κB as well as the induction of downstream cytokines, indicating LXRα agonism is the important factor for the arthritis development and could be a potential target. Conclusion The up-regulation of LXRα can activate lipogenesis enzymes to worsen the inflammatory process in AIA rats as well as the development of dyslipidemia, therefore, rectifying lipid disorder via suppression of LXRα agonism pertains the capacity of drug target, which enables to discover and develop new drugs to treat rheumatoid arthritis with dyslipidaemia.
研究领域:
免疫学
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药理学
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风湿病学
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代谢组学
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分子生物学
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DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
·
2025
·
IF 5.4
Youyun Liu,Junxi Liu,Rui Xu,Yonglei Yuan,Qiwen Sun,Susu Ding,Feifei Wang,Liping Qu
Ethnopharmacological relevance Ludwigia adscendens (L.) Hara ( L. adscendens ) is a Traditional Chinese Medicine (TCM), first mentioned in Sheng Cao Yao Xing Bei Yao ( Essential Guide to Raw Herbal Properties ). It clears heat, removes dampness, detoxifies, and reduces swelling. In TCM, it is prescribed for acne caused by dampness-heat accumulation. It is also used for cold, fever, sore throat, boils, dermatitis, and snake or dog bites. Research shows it has antioxidant, antibacterial, anti-inflammatory, and anti-lipoxygenase effects. However, studies on its impact on sebaceous gland function (a key factor in acne pathogenesis) are still limited. Aim of the study This study aims to investigate the effects of L. adscendens extract (LHE) on sebaceous gland function and its mechanisms. Materials and methods Active compounds in LHE were identified using high-performance liquid chromatography (HPLC). Its effects on lipid synthesis, sebocyte proliferation, and reactive oxygen species (ROS) were assessed in a 5α-dihydrotestosterone (DHT)-induced sebocyte model. Untargeted lipidomics was used to analyse sebum composition and detect LHE-induced changes. Anti-inflammatory and antioxidant activities were evaluated using zebrafish models and biochemical assays. Sebum-regulatory efficacy was measured to assess LHE's impact on sebum production. Results LHE showed strong biological activity by activating the PPARγ/LXRα/SREBP1 pathway, reducing lipid production, inhibiting sebocyte hyperproliferation, and delivering notable antioxidant and anti-inflammatory effects. Lipidomic analysis revealed that LHE effectively altered lipid composition, especially by lowering triglycerides (TG), diacylglycerols (DG), ceramides (Cer), and hexosyl-1-ceramides (Hex1Cer), with major changes observed in medium- and long-chain TG and phosphatidylethanolamine (PE) levels. Efficacy tests confirmed that LHE reduced sebum production and improved skin texture by shrinking pore size. Conclusions LHE improves sebaceous gland function by reducing lipid overproduction and hyperproliferation through the PPARγ/LXRα/SREBP1 pathway. It also enhances the lipid profile by lowering key lipid molecules like TGs and PEs. Moreover, LHE shows anti-inflammatory and antioxidant effects. These findings suggest its therapeutic potential for sebaceous gland-related conditions and reveal new insights into its mechanism in topical use.
研究领域:
药理学
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民族药理学
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皮肤科学
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分子生物学
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生物化学
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脂质代谢
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植物学
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DOI
PubMed
高影响因子
Cell Death & Disease
·
2023
·Vol. 14
·期 2
·1-17
·
IF 9
Chen Yulian,Jiang Huanguo,Zhan Zhikun,Lu Jindi,Gu Tanwei,Yu Ping,Liang Weimin,Zhang Xi,Liu Shuwen,Bi Huichang,Zhong Shilong,Tang Lan
Converting lipid disturbances in response to energy oversupply into healthy lipid homeostasis is a promising therapy to alleviate hepatosteatosis. Our clinical studies found that a further elevation of triglyceride (TG) in obese patients with the body mass index (BMI) greater than 28 was accompanied by a further reduction of phosphatidylethanolamine (PE). Shorter survival and poor prognosis were shown for the patients with high TG and low PE levels. Liver X receptor alpha ( LXRα ) knockout mice aggravated high-fat diet (HFD)-induced obesity and lipid disorders, making the TG enrichment and the PE decrease more pronounced according to the liver lipidomics analysis. The RNA-seq from mice liver exhibited that these metabolism disorders were attributed to the decline of Atgl (encoding the TG metabolism enzyme ATGL) and Ept1 (encoding the PE synthesis enzyme EPT1) expression. Mechanistic studies uncovered that LXRα activated the ATGL and EPT1 gene via direct binding to a LXR response element (LXRE) in the promoter. Moreover, both the supplement of PE in statin or fibrate therapy, and the LXRα inducer (oridonin) ameliorated cellular lipid deposition and lipotoxicity. Altogether, restoration of lipid homeostasis of TG and PE via the LXRα-ATGL/EPT1 axis may be a potential approach for the management of hepatosteatosis and metabolic syndrome.
研究领域:
分子生物学
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代谢学
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肝病学
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药理学
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产品关联
DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2024
·
IF 6.7
Yinhuang Gao,Peng Zhao,Chunyan Wang,Keren Fang,Yueqing Pan,Yan Zhang,Zhishuo Miao,Meirong Wang,Minlong Wei,Wei Zou,Menghua Liu,Kang Peng
Background Chronic cerebral hypoperfusion (CCH) has been confirmed as one of the pathogenesis underlying vascular cognitive impairment. A series of pathological changes, including inflammation, oxidative stress, and apoptosis, are involved in this pathophysiology and contribute to cognitive impairment and neuropathological alterations. The traditional Chinese medicine (TCM) of Buqi Huoxue Tongnao (BQHXTN) prescription possesses a remarkable clinical efficacy for treating patients with CCH, but still lacks a scientific foundation for its pharmacological mechanisms. Purpose To investigate the role and underlying mechanism of the effects of BQHXTN on CCH both in vitro and in vivo . Methods In this study, we established a two-vessel occlusion (2-VO) induced CCH model in Sprague-Dawley rats, an oxygen-glucose deprivation model in BV2 cells, and a steatosis cell model in L02 cells to reveal the underlying mechanisms of BQHXTN by behavioral test, histopathological analysis and the detection of pro-inflammatory cytokine, apoptotic factors and reactive oxide species. Donepezil hydrochloride and Buyang Huanwu decoction were used as positive drugs. Results Compared with the 2-VO group, BQHXTN treatment at three doses significantly enhanced the memory and learning abilities in the Y-maze and novel object recognition tests. The hematoxylin-eosin staining indicated that BQHXTN protected against hippocampal injury induced by CCH. Of note, in both in vivo and in vitro experiments, BQHXTN prominently inhibited the production of IL-1β, TNF-α, cleaved-caspase 3, and iNOS by regulating the PI3K/AKT pathway, consequently exerting anti-inflammatory, anti-apoptotic, and antioxidant effects. Moreover, it provided the first initial evidence that BQHXTN treatment mitigated dyslipidemia by increasing the LXRα/CYP7A1 expression, thereby delaying the neuropathological process. Conclusion In summary, these findings firstly revealed the pharmacodynamics and mechanism of BQHXTN, that is, BQHXTN could alleviate cognitive impairment, neuropathological alterations and dyslipidemia in CCH rats by activating PI3K/AKT and LXRα/CYP7A1 signaling pathways, as well as providing a TCM treatment strategy for CCH.
研究领域:
神经科学
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药理学
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中医
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病理生理学
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DOI
PubMed
高影响因子
Nature Communications
·
2026
·Vol. 17
·期 1
·2821
·
IF 18.1
Xiao Hai-Tao,Song Peng,Jin Jing,Wang Yong-Dan,Xu Yin-Yue,Wu He,Shao Xue-Xue,Gan Qi-Feng,He Jian,Wen Yan-Rong,Zhu Jing,Chen Bao-Yi,Zhou Ping,Lai Li-Na,Yang Hua,Li Ping,Zheng Zu-Guo
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a global health concern that affects nearly one-quarter of the world’s population. General control non-repressed protein 5 (GCN5), a histone acetyltransferase (HAT), has been implicated in the progression of several diseases, but its role in MASLD remains unclear. Here, we provide the experimental evidence that progressive human and male murine MASLD is driven by GCN5, but not by p300/CREB binding protein associated factor (PCAF) activation. Hepatocyte-specific GCN5 overexpression accelerates MASLD progression, whereas its ablation alleviates disease severity. Moreover, pharmacological inhibition of GCN5 with CPTH2 protects against MASLD. Metabolomics and RNA-seq analyses demonstrate that GCN5 promotes de novo lipogenesis (DNL) by upregulating SREBP1c-mediated transcription of lipogenic genes. Mechanistically, GCN5 acetylates histone H3 at the SREBP1c promoter, enhancing transcription through its intrinsic acetyltransferase activity. Our findings further identify GCN5 as a key regulator of LXRα-induced SREBP1c expression, suggesting that targeting GCN5 may selectively inhibit SREBP1c-driven DNL without impairing LXRα-mediated reverse cholesterol transport (RCT). Notably, combined treatment with the Liver X Receptor (LXR) agonist T0901317 and CPTH2 synergistically reduced lipid accumulation in vitro and in vivo, highlighting a promising therapeutic strategy for MASLD.
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DOI
PubMed
高影响因子
Chinese Medicine
·
2026
·Vol. 21
·期 1
·223
·
IF 7.4
Liang Hui-Mei,Xu Yin-Yue,Miao Kun,Xiao Hai-Tao,Wang Yong-Dan,Jin Jing,Wu He,Chen Bao-Yi,Xu Li-Jun,Zhu Jiang-Ping,Lai Li-Na,Zheng Zu-Guo
Background Astragaloside IV (AS-IV), a bioactive saponin from Astragalus membranaceus, shows promise for treating metabolic dysfunction-associated steatotic liver disease (MASLD), though its mechanisms remain unclear. Purpose This study aimed to elucidate how AS-IV alleviates hepatic steatosis, specifically investigating its epigenetic regulation of lipogenesis. Methods Using high-fat diet-fed mice and lipids-loaded hepatocytes, we assessed AS-IV's effects through SREBP-1c overexpression, histone acetylation analysis, and GCN5 rescue experiments. Results AS-IV significantly reduced hepatic steatosis by suppressing SREBP-1c-mediated de novo lipogenesis. Mechanistically, it inhibited histone acetyltransferase GCN5, decreasing H3K9/H3K14 acetylation at the SREBP-1c promoter and attenuating LXRα-driven transcription. GCN5 overexpression reversed AS-IV's suppression of SREBP-1c and lipid accumulation. Conclusion AS-IV uniquely downregulates GCN5 expression at the transcriptional level, exerting epigenetic regulation to disrupts lipogenic programming, This represents a novel multi-target approach against MASLD that connects natural product pharmacology with epigenetic modulation.
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DOI
高影响因子
BASIC & CLINICAL PHARMACOLOGY & TOXICOLOGY
·
2025
·Vol. 136
·期 6
·e70045
·
IF 3.3
Dong Yan,Yuanwei Fu,Jie Mei,Junhong Wang,Ayijiang Jiamaliding,Ying Liu,Zanmei Zhao,Qingbian Ma
Phosgene, used in large‐scale industrial production, is highly toxic and irritant. Accidental exposure can lead to varying degrees of injuries, with severe cases potentially resulting in acute lung injury or acute respiratory distress syndrome, resulting in a mortality rate of 40%–50%. The indirect damages of phosgene (inflammation and oxidative stress) are considered important factors in phosgene‐induced acute lung injury (P‐ALI). The expression of Liver X Receptor α (LXRα) significantly reduces during periods of inflammation. LXRs were initially discovered to be highly expressed in the liver, whereas LXRs are expressed in immune cells and vascular endothelial cells, playing a significant role in anti‐inflammatory and antioxidant responses. LXRα may have pulmonary protection in P‐ALI. However, evidence to verify this association is still lacking. In this study, rats were divided into six groups to explore the potential role of LXRα in P‐ALI. This study found that GW3965 effectively activated LXRα, upregulated its expression and downregulated the levels of proinflammatory cytokines, inhibited malondialdehyde activity while enhancing superoxide dismutase activity, suppressed apoptosis and ameliorated the pathological processes of P‐ALI, ultimately exerting pulmonary protection in P‐ALI. Further validation revealed that the pulmonary protective effect of LXRα may be associated with the PI3K/Akt and NF‐kB signalling pathways.
研究领域:
药理学
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呼吸病学
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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 ETHNOPHARMACOLOGY
·
2024
·
IF 4.8
Ranyi Luo,Yinhao Zhang,Hong Wang,Bing Xu,Jiaorong Qu,Shuwen Duan,Runping Liu,Jia Liu,Shuo Li,Xiaojiaoyang Li
Ethnopharmacological relevance Hepatic ischemia/reperfusion injury (HIRI) is a common occurrence during or after liver surgery, representing a major cause for postoperative complications or increased morbidity and mortality in liver diseases. Rehmanniae Radix Praeparata (RRP) is a traditional Chinese medicine frequently used and has garnered extensive attention for its therapeutic potential treating cardiovascular and hepatic ailments. Recent studies have indicated the possibility of RRP in regulating lipid accumulation and apoptosis in hepatocytes. Aim of the study This study aimed to investigate the specific mechanisms by which RRP may impede the progression of HIRI through the regulation of lipid metabolism. Materials and methods High-performance liquid chromatography (HPLC) was used to identify the major components of RRP water extract. C57BL/6J mice were orally given RRP at doses of 2.5 g/kg, 5 g/kg, and 10 g/kg for a duration of 7 days before undergoing HIRI surgery. Furthermore, we established a lipid-loaded in vitro model by exposing hepatocytes to oleic acid and palmitic acid (OAPA). The anti-HIRI effect of RRP was determined through transcriptomics and various molecular biology experiments. Results After identifying active ingredients in RRP, we observed that RRP exerted lipid-lowering and hepatoprotective effects on HIRI mice and OAPA-treated hepatocytes. RRP activated AMP-activated protein kinase (AMPK) and inhibited mammalian target of rapamycin (mTOR), which further on the one hand, inhibited the cleavage and activation of sterol regulatory element binding protein 2 (SREBP2) by limiting the movement of SREBPs cleavage-activating protein (SCAP)-SREBP2 complex with the help of endoplasmic reticulum lipid raft-associated protein 1 (ERLIN1) and insulin-induced gene 1 (INSIG1), and on the other hand, promoted liver X receptor α (LXRα) nuclear transportation and subsequent cholesterol efflux. Meanwhile, the anti-lipotoxic effect of RRP can be partly reversed by an LXRα inhibitor but largely blocked by the application of compound C, an AMPK inhibitor. Conclusion Our study elucidated that RRP served as a potential AMPK activator to alleviate HIRI by blocking SREBP2 activation and cholesterol synthesis, while also activating LXRα to facilitate cholesterol efflux. These findings shed new light on the potential therapeutic use of RRP for improving HIRI.
研究领域:
药理学
·
肝病学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
CHEMICAL & PHARMACEUTICAL BULLETIN
·
2015
·Vol. 63
·期 8
·628-635
·
IF 1.164
Siyun Nian,Xia Gan,Xiangduan Tan,Zhenpeng Yu,Panfeng Wang,Xing Chen,Guoping Wang
Fourteen novel compounds were prepared and their antagonistic activities against liver X receptors (LXR) α/β were tested in vitro. Compound 26 had an IC50 value of 6.4 µM against LXRα and an IC50 value of 5.6 µM against LXRβ. Docking studies and the results of structure–activity relationships support the further development of this chemical series as LXRα/β antagonists.
研究领域:
药理学
·
分子生物学
✓ 已验证
DOI
高影响因子
Food & Function
·
2020
·Vol. 11
·期 8
·7217-7230
·
IF 4.171
Konglong Feng,Xiaoai Zhu,Guo Liu,Qixin Kan,Tong Chen,Yunjiao Chen,Yong Cao
Citrus peel essential oil (CPEO) contains abundant volatile compounds and exhibits fragrance properties and beneficial pharmacological effects on humans. Herein, we aimed to investigate the effects of CPEO on the prevention of hypercholesterolemia and hepatic steatosis in high-fat diet-fed rats and identify its possible regulatory mechanisms in lipid metabolism by combining lipidomics with gene expression analysis. CPEO at effective supplementation levels of 0.5% and 0.75% significantly ameliorated hypercholesterolemia and hepatic steatosis, including decreased serum total cholesterol (TC), low-density lipoprotein cholesterol (LDL-c), hepatic TC and triglyceride (TG) levels, and hepatic lipid droplet accumulation. Lipidomics analysis revealed that the total levels of fatty acid (FFA), TG and cholesteryl ester (CE) classes in the liver tissue were remarkably decreased after 0.75% CPEO supplementation some of which (3 TGs and 4 CEs) might emerge as potential lipid biomarkers in response to the effects of CPEO. Furthermore, these lipidomics findings were associated with downregulation of lipogenesis-related genes SREBP-1c, ACC and FAS and upregulation of bile acid biosynthesis-related genes LXRα, CYP7A1 and CYP27A1 in the liver. This study indicated that CPEO could effectively prevent hypercholesterolemia and hepatic steatosis, possibly because of its mediation of lipid and cholesterol homeostasis by altering liver lipid metabolites and regulating lipid metabolism-related genes.
研究领域:
营养学
·
分子生物学
·
药理学
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产品关联
DOI
PubMed
高影响因子
ACTA PHARMACOLOGICA SINICA
·
2026
·
IF 10.4
Jiang Huan-guo,Zhan Zhi-kun,Tian Ling-min,Chen Yu-lian,Cai Mei-qun,Ge Guang-bo,Chen Xin,Wei Chuan-liang,Tang Lan
Carboxylesterases CES1 and CES2 are the pivotal hepatic enzymes involved in triglyceride (TG) hydrolysis and prodrug metabolism, yet their expression and activity are suppressed in metabolic dysfunction-associated steatotic liver disease (MASLD). Liver X receptor alpha (LXRα) is known to play a crucial role in maintaining the constitutive expression of CES1 in human liver cells. Oridonin (ORI) is a diterpene derived from a traditional Chinese herb that possesses antitumor, anti-inflammatory, and antimicrobial activities. We previously demonstrated that ORI, as a natural LXRα agonist, activated the LXRα-ATGL/EPT1 pathway, correcting the TG/phosphatidylethanolamine (PE) lipid imbalance induced by obesity and thereby improving MASLD. Here, we investigated the regulatory role of LXRα on CES1/CES2 expression in MASLD liver and elucidated the underlying molecular mechanisms of ORI’s lipid-lowering effects. A high-fat diet (HFD)-induced steatosis model was established in mice. The mice were treated with ORI (100 mg·kg − 1 ·d − 1 , i.g.) from the 16th to the 24th week. RNA-seq analysis in MASLD patients demonstrated that LXRα is a key transcriptional regulator of CES1 and CES2. LXRα knockout (LXRα − / − ) mice exhibited aggravated HFD-induced steatosis and impaired metabolic conversion of the CES1/CES2 substrates, oseltamivir and irinotecan. This deficiency resulted in a corresponding increase in their drug exposure (AUC) by 154.5% and 26.2%, respectively. Mechanistically, LXRα directly bound to liver X receptor response elements (LXREs) in the promoter regions of CES1 (−183/−165 bp) and CES2 (−1870/−1852 bp) to drive transcription in HepG2 cells. Furthermore, ORI (2.5, 5, 10 μM) dose-dependently restored CES1/CES2 expression and activity, reducing lipid accumulation. Silencing of CES1 or CES2 abolished ORI’s lipid-lowering effect, confirming their essential roles. These findings establish the LXRα-CES1/CES2 pathway as a pivotal node integrating hepatic lipid homeostasis and drug metabolism, positioning ORI as a promising therapeutic agent for MASLD.
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PubMed
高影响因子
TOXICOLOGY LETTERS
·
2024
·
IF 2.9
Yifei Shen,Jie Liu,Bingyi Yao,Yuanjin Zhang,Shengbo Huang,Chenmeizi Liang,Junze Huang,Yu Tang,Xin Wang
Non-alcoholic fatty liver disease (NAFLD) is one of the most common liver diseases, which can cause serious complications and gradually increase the mortality rate. However, the effects of NAFLD on drug-metabolizing enzymes and transporters remain unclear, which may cause some confusion regarding patient medication. In this study, a NAFLD rat model was constructed by feeding rats with methionine and choline deficiency diets for 6 weeks, and the mRNA and protein levels of drug-metabolizing enzymes and transporter were analyzed by real-time fluorescent quantitative PCR and Western blot, respectively. The activity of drug-metabolizing enzymes was detected by cocktail methods. In the NAFLD rat model, the mRNA expression of phase I enzymes, phase II enzymes, and transporters decreased. At the protein level, only CYP1A1, CYP1B1, CYP2C11, and CYP2J3 presented a decrease. In addition, the activities of CYP1A2, CYP2B1, CYP2C11, CYP2D1, CYP3A2, UGT1A1, UGT1A3, UGT1A6, and UGT1A9 decreased. These changes may be caused by the alteration of FXR, HNF4α, LXRα, LXRβ, PXR, and RXR. In conclusion, NAFLD changes the expression and activity of hepatic drug-metabolizing enzymes and transporters in rats, which may affect drug metabolism and pharmacokinetics. In clinical medication, drug monitoring should be strengthened to avoid potential risks.
研究领域:
药理学
·
肝病学
·
分子生物学
✓ 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）