JOURNAL OF ETHNOPHARMACOLOGY
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2025
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IF 5.4
Zhaolin Sun,Yuhua Wei,Shuangyi Ma,Yuchen Xu,Yuna Zhang,Changxian Li,Jinghan Zhang,Feifei Duan,Jianwei Jiao,Xiuying Duan
Ethnopharmacological relevance Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent liver disease worldwide, primarily caused by poor lifestyle choices and dietary habits. Caulis Bambusae In Taenias , commonly known as Zhuru in Chinese, is a traditional Chinese medicinal material from the Bambusoideae family, frequently used for liver detoxification, liver protection, and lowering lipids. Aim of the study The study aimed to reveal the protective effects and underlying mechanisms of Zhuru extracts (EZR) in treating MASLD. Methods High performance liquid chromatography, liquid chromatography-tandem mass spectrometry, and fourier infrared spectroscopy were used to identify the components of EZR. We utilized oleic acid-treated HepG2/LO2 cells as in vitro models and zebrafish on high-fat diets (HFD) as animal models, and conducted network pharmacology, RNA sequencing, and biological assays, including confocal fluorescence, commercial kits, western blotting, and quantitative PCR, to investigate the lipid-lowering effect of EZR and its underlying mechanisms. Results EZR alleviated lipid accumulation in both in vitro and in vivo models. Analyses through network pharmacology and RNA sequencing revealed that the lipid-lowering properties of EZR were associated with pathways related to lipid biosynthesis, antioxidant functions, and anti-inflammatory mechanisms. Subsequent experimental validation confirmed that EZR decreased the expression levels of FASN, ACC1, HMGCR, ACLY, and LDLR. Additional findings indicated that EZR inhibited mTORC1 activation, leading to the suppression of SREBP1 and SREBP2, thereby mitigating lipid accumulation. Furthermore, EZR was found to downregulate oxidative stress and the levels of inflammatory cytokines. Conclusions EZR demonstrated the ability to lower lipid levels and alleviate HFD-induced MASLD. This is achieved by inhibiting mTORC1/SREBPs-related lipid biosynthesis and reducing oxidative stress and inflammation.
研究领域:
药理学
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肝脏疾病
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产品关联
DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
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2016
·
IF 5.091
Zu-Guo Zheng,Ya-Ping Zhou,Xin Zhang,Pyone Myat Thu,Zhi-Shen Xie,Chong Lu,Tao Pang,Bin Xue,Da-Qian Xu,Yan Chen,Xiao-Wei Chen,Hui-Jun Li,Xiaojun Xu
SREBPs play important roles in the regulation of lipid metabolism, and are closely related to the occurrence and development of many metabolic diseases . Small molecular inhibitors of SERBPs are important tools in developing efficient treatment of metabolic diseases. However, there are no listing drug targeting SREBPs. Therefore, there is an urgent need to develop highly specific small molecules that inhibit SREBPs. In this study, using a hepatocyte-based high-throughput screening, we identified anhydroicaritin (AHI) as a novel inhibitor of SREBPs. HepG2, HL-7702, and human primary hepatocytes were used to verify the effects of AHI. We explored the mechanism by which AHI blocks the binding of SCAP/SREBPs complex with Sec23α/24D via regulating LKB1/AMPK/mTOR pathway. AHI reduced liver cell lipid level by preventing de novo lipogenesis. In diet induced obese mice , AHI ameliorated obesity, insulin resistance, fatty accumulation in liver and hyperlipemia . In conclusion, AHI improves diet-induced obesity and alleviates insulin resistance by suppressing SREBPs maturation which is dependent on LKB1/AMPK/mTOR pathway. Thus, AHI can serve as a leading compound for pharmacological control of metabolic diseases.
研究领域:
药理学
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代谢学
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分子生物学
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内分泌学
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产品关联
DOI
PubMed
高影响因子
Acta Pharmaceutica Sinica B
·
2021
·
IF 11.614
Ping-Ting Xiao,Zhi-Shen Xie,Yu-Jia Kuang,Shi-Yu Liu,Chun Zeng,Ping Li,E-Hu Liu
The mammalian target of rapamycin (mTOR)-sterol regulatory element-binding proteins (SREBPs) signaling promotes lipogenesis. However, mTOR inhibitors also displayed a significant side effect of hyperlipidemia. Thus, it is essential to develop mTOR-specific inhibitors to inhibit lipogenesis. Here, we screened the endogenous inhibitors of mTOR, and identified that FKBP38 as a vital regulator of lipid metabolism. FKBP38 decreased the lipid content in vitro and in vivo via suppression of the mTOR/P70S6K/SREBPs pathway. 3,5,6,7,8,3ʹ,4ʹ-Heptamethoxyflavone (HMF), a citrus flavonoid, was found to target FKBP38 to suppress the mTOR/P70S6K/SREBPs pathway, reduce lipid level, and potently ameliorate hyperlipidemia and insulin resistance in high fat diet (HFD)-fed mice. Our findings suggest that pharmacological intervention by targeting FKBP38 to suppress mTOR/P70S6K/SREBPs pathway is a potential therapeutic strategy for hyperlipidemia, and HMF could be a leading compound for development of anti-hyperlipidemia drugs.
研究领域:
药理学
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代谢学
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脂质生物学
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药物发现
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
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2022
·
IF 5.195
Zhishen Xie,Er-wen Li,Gai Gao,Yueyue Du,Mengyao Wang,Hui Wang,Pan Wang,Yonghui Qiao,Yunfang Su,Jiangyan Xu,Xiaowei Zhang,Zhenqiang Zhang
Ethnopharmacological relevance Zexie Tang (ZXT), only two consists with Alismatis Rhizoma (AR) and Atractylodes macrocephala Rhizoma (AM), a classical Chinese medicine formula from Synopsis of the Golden Chamber with a history of 2000 years. Clinical observation in recent years has found that ZXT has excellent lipid-lowering effect. Aim of the study : To explore the potential mechanism of ZXT ameliorates hyperlipidemia based on FKBP38/mTOR/SREBPs pathway. Materials and methods WD-induced hyperlipidemia mice and oleic acid induced cell lipid accumulation model were used to investigate pharmacodynamic . The effect of ZXT on the transcriptional activity of SREBPs was detected by reporter gene assay. Proteins and downstream genes of mTOR/SREBPs pathway were detected in vivo and in vitro . Combined with network pharmacology and HPLC-Q-TOF/MS, the active ingredients were screened and identified. The interaction between active compounds of ZXT and FKBP38 protein were analyzed by docking analysis. Results ZXT decreased TC, TG and LDL-c levels in blood of WD-induced hyperlipidemia mouse model, and improved insulin resistance in vivo . ZXT also reduced TC, TG and lipid accumulation in cells line, and inhibited SREBPs luciferase activity, protein and its target genes expression such as FASN , HMGCR , etc. Meanwhile, ZXT inhibited protein expression levels of p-mTOR, p-S6K, etc in vitro and in vivo . Combined with network pharmacology and HPLC-Q-TOF/MS, 16 active ingredients were screened and identified. Docking results showed that active compounds of ZXT binding to FKBP38 and formed hydrogen bond . Conclusion Our findings highlighted that ZXT ameliorates hyperlipidemia, in which FKBP/mTOR/SREBPs pathway might be the potential regulatory mechanism.
研究领域:
药理学
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分子生物学
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中医药
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产品关联
DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2023
·
IF 7.9
Gai Gao,Jie Zhao,Jing Ding,Shuyan Liu,Yanyan Shen,Changxin Liu,Huifen Ma,Yu Fu,Jiangyan Xu,Yiran Sun,Xiaowei Zhang,Zhenqiang Zhang,Zhishen Xie
Background The occurrence of hyperlipidemia is significantly influenced by lipid synthesis, which is regulated by sterol regulatory element binding proteins (SREBPs), thus the development of drugs that inhibit lipid synthesis has become a popular treatment strategy for hyperlipidemia. Alisol B (ALB), a triterpenoid compound extracted from Alisma , has been reported to ameliorate NASH and slow obesity. However, the effect of ALB on hyperlipidemia and mechanism are unclear. Purpose To examine the therapeutic impact of ALB on hyperlipidemia whether it inhibits SREBPs to reduce lipid synthesis. Study Design HepG2, HL7702 cells, and C57BL/6J were used to explore the effect of ALB on hyperlipidemia and the molecular mechanism in vivo and in vitro . Methods Hyperlipidemia models were established using western diet (WD)-fed mice in vivo and oleic acid (OA)-induced hepatocytes in vitro . Western blot, real-time PCR and other biological methods verified that ALB regulated AMPK/mTOR/SREBPs to inhibit lipid synthesis. Cellular thermal shift assay (CETSA), molecular dynamics (MD), and ultrafiltration-LC/MS analysis were used to evaluate the binding of ALB to VDAC1. Results ALB decreased TC, TG, LDL-c, and increased HDL-c in blood, thereby ameliorating liver damage. Gene set enrichment analysis (GSEA) indicated that ALB inhibited the biosynthesis of cholesterol and fatty acids. Consistently, ALB inhibited the protein expression of n-SREBPs and downstream genes. Mechanistically, the impact of ALB on SREBPs was dependent on the regulation of AMPK/mTOR, thereby impeding the transportation of SREBPs from endoplasmic reticulum to Golgi apparatus. Further investigations indicated that the activation of AMPK by ALB was independent on traditional CAMKK2 and LKB1. Instead, ALB resulted in a decrease in ATP levels and an increase in the ratios of ADP/ATP and AMP/ATP. CETSA, MD, and ultrafiltration-LC/MS analysis indicated that ALB interacted with VDAC1. Molecular docking revealed that ALB directly bound to VDAC1 by forming hydrogen bonds at the amino acid sites S196 and H184 in the ATP-binding region. Importantly, the thermal stabilization of ALB on VDAC1 was compromised when VDAC1 was mutated at S196 and H184, suggesting that these amino acids played a crucial role in the interaction. Conclusion Our findings reveal that VDAC1 serves as the target of ALB, leading to the inhibition of lipid synthesis, presents potential target and candidate drugs for hyperlipidemia.
研究领域:
药理学
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分子生物学
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生物化学
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细胞生物学
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代谢
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产品关联
DOI
PubMed
高影响因子
Chinese Journal of Natural Medicines
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2016
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IF 1.382
Zhi-Shen XIE,Ling-Jun ZHONG,Xiao-Meng WAN,Meng-Ning LI,Hua YANG,Ping LI,Xiao-Jun XU
As a culinary and medicinal herb, rosemary is widely used. The present work aimed to investigate the effects of rosemary extracts on metabolic diseases and the underlying mechanisms of action. Liver cells stably expressing SREBP reporter were used to evaluate the inhibitory effects of different fractions of rosemary extracts on SREBP activity. The obese mice induced by Western-type diet were orally administered with rosemary extracts or vehicle for 7 weeks, the plasma and tissue lipids were analyzed. SREBPs and their target genes were measured by quantitative RT-PCR. We demonstrated that the petroleum ether sub-fraction of rosemary extracts (PER) exhibited the best activity in regulating lipid metabolism by inhibiting SREBPs, while water and n -BuOH sub-fraction showed the SREBPs agonist-effect. After PER treatment, there was a significant reduction of total SREBPs in liver cells. PER not only decreased SREBPs nuclear abundance, but also inhibited their activity, resulting in decreased expression of SREBP-1c and SREBP-2 target genes in vitro and in vivo . Inhibiting SREBPs by PER decreased the total triglycerides and cholesterol contents of the liver cells. In the mice fed with Western-type diet, PER treatment decreased TG, TC, ALT, glucose, and insulin in blood, and improved glucose tolerance and insulin sensitivity. Furthermore, PER treatment also decreased lipid contents in liver, brown adipose tissue, and white adipose tissue. Our results from the present study suggested that petroleum ether fraction of rosemary extracts exhibited the best potential of improving lipid metabolism by inhibiting SREBPs activity.
研究领域:
药理学
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代谢学
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营养学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Cell Reports Medicine
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2024
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IF 11.7
Weize Zhu,Ying Hong,Zhaowei Tong,Xiaofang He,Yan Li,Hao Wang,Xinxin Gao,Pengtao Song,Xianshan Zhang,Xiaochang Wu,Zhenhua Tan,Wenjin Huang,Zekun Liu,Yiyang Bao,Junli Ma,Ningning Zheng,Cen Xie,Xisong Ke,Wen Zhou,Wei Jia,Mingxiao Li,Jing Zhong,Lili Sheng,Houkai Li
Metabolic (dysfunction)-associated steatohepatitis (MASH) is the advanced stage of metabolic (dysfunction)-associated fatty liver disease (MAFLD) lacking approved clinical drugs. Adenosine A1 receptor (A 1 R), belonging to the G-protein-coupled receptors (GPCRs) superfamily, is mainly distributed in the central nervous system and major peripheral organs with wide-ranging physiological functions; however, the exact role of hepatic A 1 R in MAFLD remains unclear. Here, we report that liver-specific depletion of A 1 R aggravates while overexpression attenuates diet-induced metabolic-associated fatty liver (MAFL)/MASH in mice. Mechanistically, activation of hepatic A 1 R promotes the competitive binding of sterol-regulatory element binding protein (SREBP) cleavage-activating protein (SCAP) to sequestosome 1 (SQSTM1), rather than protein kinase A (PKA) leading to SCAP degradation in lysosomes. Reduced SCAP hinders SREBP1c/2 maturation and thus suppresses de novo lipogenesis and inflammation. Higher hepatic A 1 R expression is observed in patients with MAFL/MASH and high-fat diet (HFD)-fed mice, which is supposed to be a physiologically adaptive response because A 1 R agonists attenuate MAFL/MASH in an A 1 R-dependent manner. These results highlight that hepatic A 1 R is a potential target for MAFL/MASH therapy.
研究领域:
肝病学
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药理学
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代谢性疾病
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分子生物学
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细胞信号传导
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DOI
高影响因子
PHYTOTHERAPY RESEARCH
·
2021
·Vol. 35
·期 7
·3898-3915
·
IF 5.882
Li Zhang,Sheng-Ye Yang,Feng-Rong Qi-Li,Xiao-Xiao Liu,Wei-Tao Zhang,Chao Peng,Ping Wu,Ping Li,Pingping Li,Xiaojun Xu
Isoliquiritigenin (ISO) is a flavonoid extracted from the root of licorice, which serves various biological and pharmacological functions including antiinflammatory, antioxidation, liver protection, and heart protection. However, the mechanism of its action remains elusive and the direct target proteins of ISO have not been identified so far. Through cell-based screening, we identified ISO as a potent lipid-lowering compound. ISO treatment successfully ameliorated fatty acid-induced cellular lipid accumulation and improved nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) by increasing PPARα-dependent lipid oxidation and decreasing SREBPs-dependent lipid synthesis. Both these signaling required the activation of SIRT1. Knockdown of SIRT1 resulted in the reversal of ISO beneficiary effects suggesting that the lipid-lowering activity of ISO was regulated by SIRT1 expression. To identify the direct target of ISO, limited proteolysis combined with mass spectrometry (LiP-SMap) strategy was applied and IQGAP2 was identified as the direct target for ISO in regulating lipid homeostasis. In the presence of ISO, both mRNA and protein levels of SIRT1 were increased; however, this effect was abolished by blocking IQGAP2 expression using siRNA. To explore how IQGAP2 regulated the expression level of SIRT1, proteome profiler human phospho-kinase array kit was used to reveal possible phosphorylated kinases and signaling nodes that ISO affected. We found that through phosphorylation of CREB, ISO transduced signals from IQGAP2 to upregulate SIRT1 expression. Thus, we not only demonstrated the molecular basis of ISO in regulating lipid metabolism but also exhibited for the first time a novel IQGAP2-CREB-SIRT1 axis in treating NAFLD/NASH.
研究领域:
药理学
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分子生物学
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肝病学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
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2026
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IF 15
Yu Su,Haobo Wen,Ke Hu,Cuiping Wen,Ping Wang,Lulu Zhao,Gang Zou,Wei Jiang,Yaxi Chen,Yunfei Zhao,Qiu Li
The multifaceted pathogenesis and multi-cellular involvement of diabetic nephropathy (DN) stand in stark contrast to the inadequacy of conventional single-target therapeutic strategies. This disparity underscores the urgent need for novel drugs with comprehensive targeting capabilities. Herein, the SREBP cleavage-activating protein/sterol regulatory element-binding proteins (SCAP/SREBPs) pathway was identified as a central driver in DN, where its activation in key renal parenchymal cells promotes lipid metabolic disorders and inflammation, thereby exacerbating renal injury. Guided by this discovery, we screened a 245-member nanoparticle library comprising SCAP inhibitors self-assembled with chitosan, and identified chitosan-lycorine nanoparticles (CLNPs) as the optimal candidate. Owing to its efficient intestinal absorption and significant accumulation in mesangial and proximal tubular epithelial cells, oral CLNPs strongly alleviated renal injury in a murine model of DN by counteracting lipid accumulation and inflammation, consistent with SCAP/SREBPs pathway inhibition. Critically, CLNPs prevented hepatotoxicity from free lycorine, which reduced mortality and enabled safer prolonged therapy. Together, our findings demonstrate the viability of CLNPs for DN, thereby offering a generalizable strategy for combating complex diseases through a single combinatorial agent that counters multiple co-existing pathological injuries.
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产品关联
DOI
PubMed
高影响因子
Journal of Functional Foods
·
2017
·
IF 3.144
Zhishen Xie,Xiaomeng Wan,Lingjun Zhong,Hua Yang,Ping Li,Xiaojun Xu
Carnosic acid (CA), from rosemary, a food additive used for long history in western countries, reduces triglyceride, cholesterol and glucose levels. However, the detailed mechanisms contributing to these effects remain unclear. Here we investigate the potential mechanism of how CA regulates lipid metabolism. Using reporter cell lines, we found CA inhibited SREBPs activity, using radioactive isotope labeling, we found CA impeded de novo lipid synthesis, using gene silencing and inhibitors, we investigated the possible mechanism of how CA affects SREBPs stability. In hepatocytes, CA reduces the nuclear abundance of SREBPs and downregulates their target genes, thereby inhibiting the de novo biosynthesis of both fatty acids and cholesterol. Furthermore, in western type diet-induced obese mice, CA alleviates hyperlipidemia, fatty liver and insulin resistance by suppressing SREBPs target gene expression in the liver. Our results indicate that CA promotes the degradation of mature form of SREBPs via the 26S proteasome. To our knowledge, this study is the first to describe a small molecule that strongly reduces mature SREBPs.
研究领域:
药理学
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代谢
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分子生物学
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营养学
✓ 已验证
DOI
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
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2025
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IF 5.4
Yu-Jia Kuang,Qian-Qian Chen,Jin-hua Hao,Yang Lin,Ping-Ting Xiao,E-Hu Liu
Ethnopharmacological relevance Atherosclerosis is a pathological condition characterized by the accumulation of lipid-rich lesions within the endothelial layer, and it remains a significant contributor to global morbidity and mortality. Typhae Pollen (TP) has been extensively used in the treatment of blood stasis. However, the potential protective effects and underlying mechanisms of TP in atherosclerosis remain poorly understood. Aim of the study To explore the protective effects and mechanisms of Typhae Pollen extract (TPEX) on atherosclerosis. Materials and methods We established atherosclerosis models in ApoE -/- mice using high-fat diet (HFD), with continuous oral administration of TPEX at specified doses and intervals in vivo . To explore the underlying mechanisms of TPEX, we employed integrated network pharmacology and transcriptome analysis. In vitro , palmitic acid and H 2 O 2 induced primary hepatic cells lipid accumulation and endothelial cells dysfunction model were employed to investigate the potential mechanisms of TPEX using western blot, immunofluorescence, nuclear/cytoplasmic proteins isolation techniques. Results TPEX improved aortic lipid deposition and arterial injury, alleviated hyperlipidemia, and reduced liver damage in HFD-induced ApoE -/- mice. Mechanistically, TPEX mitigated endothelial cell senescence through the p53/p21 signaling pathway, suppressed inflammation by inhibiting the translocation of p65 into the nucleus, and alleviated oxidative stress by preventing the nuclear translocation of NRF2 and modulating the NRF2/HO-1 pathway. Furthermore, TPEX reduced inflammation and regulated lipid metabolism via the NOD signaling pathway and the SREBPs signaling pathway in the liver. Conclusion TPEX alleviates atherosclerosis by regulating endothelial dysfunction, hepatic lipid metabolism, and inflammatory processes. These findings provide new insights into the protective role of TPEX in atherosclerosis, especially regarding endothelial dysfunction and hepatic lipid metabolism.
研究领域:
药理学
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心血管医学
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分子生物学
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民族药理学
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生物信息学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2018
·
IF 3.61
Zhisheng Xie,Lingjun Zhong,Yanrao Wu,Xiaomeng Wan,Hua Yang,Xiaojun Xu,Ping Li
Background Diabetic nephropathy (DN), one of the most serious complications of diabetes , is the leading cause of morbidity and mortality of end-stage renal disease. Our previous research found that carnosic acid (CA) or rosemary extract can effectively improve glucose and lipid metabolism disorder by inhibiting SREBPs . Purpose In this study, we aimed to explore the therapeutic effects of CA on the DN. Methods The mice glomerular mesangial cells (mGMCs) were used to evaluate the anti-oxidative and anti-inflammation effects of CA under high glucose (HG) condition. Furthermore, db/db mice and streptozotocin (STZ)-induced diabetic mice were used to investigate the effects of CA against DN in vivo . Results The results showed that CA activated Nrf2, inhibited NF-κB pathway and regulated related downstream genes in mGMC under HG condition. A 14-week treatment of mice with CA reduced water uptake and urine volume, attenuated diabetes-induced albuminuria , increased urine creatinine , and subsequently improved the glomerular sclerosis and mesangial expansion in db/db mice. Similarly, a 20-week oral administration of CA improved kidney damage in STZ-induced diabetic mice. In addition, CA inhibited the expression of profibrotic factors, such as TGF-β1, fibronectin and E-cadherin. Compared to irbesartan , CA exerted better glucose lowering effect, and in kidney, CA was more potent to reduce fibronectin and E-cadherin expression. In all the animal experiment, CA did not lead to abnormal damages to other tissues. Conclusion These findings suggest that CA is a safe compound which exerts the protective effects on diabetes-induced kidney complications.
研究领域:
药理学
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内分泌学
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肾病学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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