Chinese Journal of Integrative Medicine
·
2025
·
IF 2.5
Liu Shu-yan,Zhang Xiao-wei,Gao Gai,Liu Chang-xin,Chen Hui,Fu Zhong-xue,Xu Jiang-yan,Wang Zhen-zhen,Zhang Zhen-qiang,Xie Zhi-shen
Objective To investigate the therapeutic potential of pseudolaric acid B (PAB) on non-alcoholic fatty liver disease (NAFLD) and its underlying molecular mechanism in vitro and in vivo . Methods Eight-week-old male C57BL/6J mice ( n =32) were fed either a normal chow diet (NCD) or a high-fat diet (HFD) for 8 weeks. The HFD mice were divided into 3 groups according to a simple random method, including HFD, PAB low-dose [10 mg/(kg·d), PAB-L], and PAB high-dose [20 mg/(kg·d), PAB-H] groups. After 8 weeks of treatment, glucose metabolism and insulin resistance were assessed by oral glucose tolerance test (OGTT) and insulin tolerance test (ITT). Biochemical assays were used to measure the serum and cellular levels of total cholesterol (TC), triglycerides (TG), aspartate aminotransferase (AST), alanine aminotransferase (ALT), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C). White adipose tissue (WAT), brown adipose tissue (BAT) and liver tissue were subjected to hematoxylin and eosin (H&E) staining or Oil Red O staining to observe the alterations in adipose tissue and liver injury. PharmMapper and DisGeNet were used to predict the NAFLD-related PAB targets. Peroxisome proliferator-activated receptor alpha (PPARα) pathway involvement was suggested by Kyoto Encyclopedia of Genes and Genomes (KEGG) and search tool Retrieval of Interacting Genes (STRING) analyses. Luciferase reporter assay, cellular thermal shift assay (CETSA), and drug affinity responsive target stability assay (DARTS) were conducted to confirm direct binding of PAB with PPARα. Molecular dynamics simulations were applied to further validate target engagement. RT-qPCR and Western blot were performed to assess the downstream genes and proteins expression, and validated by PPARα inhibitor MK886. Results PAB significantly reduced serum TC, TG, LDL-C, AST, and ALT levels, and increased HDL-C level in HFD mice ( P <0.01). Target prediction analysis indicated a significant correlation between PAB and PPARα pathway. PAB direct target binding with PPARα was confirmed through luciferase reporter assay, CETSA, and DARTS ( P <0.05 or P <0.01). The target engagement between PAB and PPARα protein was further confirmed by molecular dynamics simulations and the top 3 amino acid residues, LEU321, MET355, and PHE273 showed the most significant changes in mutational energy. Subsequently, PAB upregulated the genes expressions involved in lipid metabolism and mitochondrial biogenesis downstream of PPARα ( P <0.05 or P <0.01). Significantly, the PPARα inhibitor MK886 effectively reversed the lipid-lowering and PPARα activation properties of PAB ( P <0.05 or P <0.01). Conclusion PAB mitigates lipid accumulation, ameliorates liver damage, and improves mitochondrial biogenesis by binding with PPARα, thus presenting a potential candidate for pharmaceutical development in the treatment of NAFLD.
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Pharmaceutics
·
2022
·Vol. 14
·期 11
·2534
·
IF 6.525
Bo Wei,Yuanfang Li,Meiying Ao,Wenxiang Shao,Kun Wang,Tong Rong,Yun Zhou,Yong Chen
Previously, we found that exogenous ganglioside GM3 had an antiatherosclerotic efficacy and that its antiatherosclerotic efficacy could be enhanced by reconstituted high-density lipoprotein (rHDL). In this study, we hypothesized that GM3-functionalized rHDL (i.e., GM3-rHDL) as a nanocarrier can promote the efficacy of traditional antiatherosclerotic drugs (e.g., statins). To test this hypothesis, lovastatin (LT) was used as a representative of statins, and LT-loaded GM3-rHDL nanoparticle (LT-GM3-rHDL or[email protected]; a mean size of ~142 nm) and multiple controls (e.g., GM3-rHDL without LT, LT-loaded rHDL or LT-rHDL, and other nanoparticles) were prepared. By using two different microsphere-based methods, the presences of apolipoprotein A-I (apoA-I) and/or GM3 in nanoparticles and the apoA-I-mediated macrophage-targeting ability of apoA-I/rHDL-containing nanoparticles were verified in vitro. Moreover, LT-GM3-rHDL nanoparticle had a slowly sustained LT release in vitro and the strongest inhibitory effect on the foam cell formation of macrophages (a key event of atherogenesis). After single administration of rHDL-based nanoparticles, a higher LT concentration was detected shortly in the atherosclerotic plaques of apoE−/−mice than non-rHDL-based nanoparticles, suggesting the in vivo plaque-targeting ability of apoA-I/rHDL-containing nanoparticles. Finally, among all nanoparticles LT-GM3-rHDL induced the largest decreases in the contents of blood lipids and in the areas of atherosclerotic plaques at various aortic locations in apoE−/−mice fed a high-fat diet for 12 weeks, supporting that LT-GM3-rHDL has the best in vivo antiatherosclerotic efficacy among the tested nanoparticles. Our data imply that GM3-functionalized rHDL (i.e., GM3-rHDL) can be utilized as a novel nanocarrier to enhance the efficacy of traditional antiatherosclerotic drugs (e.g., statins).Keywords:ganglioside GM3;atherosclerosis;reconstituted high-density lipoprotein (rHDL);lovastatin (LT);drug delivery system;statins;ApoA-I
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JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2022
·
IF 5.895
Bei Yan,Lei Chen,Yanhui Wang,Jiacheng Zhang,Hui Zhao,Qinglian Hua,Shengjie Pei,Zihang Yue,Hui Liang,Huaqi Zhang
In this work, the protective effect of apple polyphenol extract (APE) on hepatic steatosis was investigated. Thirty-two C57BL/6J mice were assigned randomly to control group, hepatic steatosis group, lovastatin group, and APE group. After 8 weeks of intervention, APE supplementation markedly decreased the body weight gain, liver weight, liver index, epididymal adipose weight, epididymal adipose index, serum, and hepatic lipid levels. Hematoxylin and eosin staining revealed that APE supplementation alleviated histopathological changes of hepatic steatosis. Western blot revealed that APE downregulated the protein levels of GRP78, IRE1α, p-IRE1α, XBP1, PERK, p-PERK, p-eIF2α, ATF6, PPAR-γ, SREBP-1c, FAS, and ACC1. In conclusion, this study found that APE inhibited IRE1α-XBP1, PERK-eIF2α, and ATF6 signaling pathways to alleviate endoplasmic reticulum stress, thereby improving HFD-induced hepatic steatosis.
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JOURNAL OF FOOD AND DRUG ANALYSIS
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2022
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IF 6.157
Ping-Ting Xiao,Yu-Jia Kuang,Shi-Yu Liu,Zhi-Shen Xie,Jin-Hua Hao,E-Hu Liu
Since the combinatorial components responsible for the antihyperlipidemic activity of Citrus reticulata ‘Chachi’ (CRC) peels remains unclear, we herein developed a bioactive equivalence oriented feedback screening method to discover the bioactive equivalent combinatorial components (BECCs) from CRC peels. Using palmitic acid (PA)-stimulated hepatocyte model, a combination of 5 polymethoxyflavones (PMFs) including tangeretin, sinensetin, nobiletin, 5,7,8,4′-tetramethoxyflavone and 3,5,6,7,8,3′,4′-heptamethoxyflavone was identified to be responsible for the antihyperlipidemic effect of CRC peels. Via evaluation of combination effect by combination index (CI), these 5 PMFs were found to take effect via a synergistic mode. Our data indicated that the antihyperlipidemic mechanism of PMF combination was associated with the inhibition of fatty acid and cholesterol synthesis, and inflammation. Also, the PMF combination exhibited robust antihyperlipidemic effects in HFD-fed rats in vivo . Our study offers evidence-based data to uncover the pharmacological effect of CRC peels.
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Molecular Cancer
·
2022
·Vol. 21
·期 1
·1-17
·
IF 41.444
Pan Zhenzhen,Wang Kai,Wang Xiniao,Jia Zhirong,Yang Yuqi,Duan Yalei,Huang Lianzhan,Wu Zhuo-Xun,Zhang Jian-ye,Ding Xuansheng
Background The use of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) brings remarkable benefits for the survival of patients with advanced NSCLC harboring EGFR mutations. Unfortunately, acquired resistance seems to be inevitable and limits the application of EGFR-TKIs in clinical practice. This study reported a common molecular mechanism sustaining resistance and potential treatment options to overcome EGFR-TKIs resistance.Methods EGFR-TKIs resistant NSCLC cells were established and confirmed by MTT assay. Cholesterol content was detected and the promotional function of cholesterol on NSCLC growth was determined in vivo. Then, we identified ERRα expression as the downstream factor of cholesterol-mediated drug resistance. To dissect the regulatory mechanism, we conducted experiments, including immunofluorescence, co-immunoprecipitation, luciferase reporter assay and chromatin immunoprecipitation assay.Results Long-term exposure to EGFR-TKIs generate drug resistance with the characteristic of cholesterol accumulation in lipid rafts, which promotes EGFR and Src to interact and lead EGFR/Src/Erk signaling reactivation-mediated SP1 nuclear translocation and ERRα re-expression. Further investigation identifies ERRα as a target gene of SP1. Functionally, re-expression of ERRα sustains cell proliferation by regulating ROS detoxification process. Lovastatin, a drug used to decrease cholesterol level, and XCT790, an inverse agonist of ERRα, overcome gefitinib and osimertinib resistance both in vitro and in vivo.Conclusion sOur study indicates that cholesterol/EGFR/Src/Erk/SP1 axis-induced ERRα re-expression promotes survival of gefitinib and osimertinib-resistant cancer cells. Besides, we demonstrate the potential of lowing cholesterol and downregulation of ERRα as effective adjuvant treatment of NSCLC.
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JOURNAL OF ETHNOPHARMACOLOGY
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2022
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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.
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Drug Design Development and Therapy
·
2022
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IF 4.319
Qing Sun,Li Li,Quan Zhou
Purpose Wuzhi capsule (WZ) is a proprietary Chinese medicine prepared from the ethanolic extract of Schisandra sphenanthera that is commonly used to treat liver injury. Statins are widely used in patients with hyperlipidemia, coronary heart disease, metabolic syndrome, type 2 diabetes mellitus, and nonalcoholic fatty liver disease. Co-administration of statins with WZ is possible in clinical practice. WZ has obvious inhibitory effects on the bioavailability of atorvastatin and simvastatin; however, the drug–herb interactions between WZ and rosuvastatin have not been addressed. We explored the effects of WZ on the pharmacokinetics of rosuvastatin in Sprague-Dawley rats to promote a rational use of statins.Methods Eighteen male rats were randomly and evenly divided into three groups: control group (gavage feeding of rosuvastatin 10 mg·kg−1), single dose group (gavage feeding of a single dose of WZ 150 mg·kg−1 followed by rosuvastatin 10 mg·kg−1) and multiple doses group (gavage feeding of WZ 150 mg·kg−1 for 7 days followed by rosuvastatin 10 mg·kg−1 on the seventh day). Plasma samples were collected at different times before and after rosuvastatin administration. The other 18 female rats were tested the same way as the male rats. All samples were analyzed by a validated LC-MS/MS method, and the pharmacokinetic parameters were calculated using a non-compartmental model.Results In both male and female rats, there were no statistically significant differences in rosuvastatin pharmacokinetic parameters between the control group, the single dose group, and the multi-dose group.Conclusion Acute or long-term intake of WZ had no obvious effect on the pharmacokinetics of rosuvastatin, and therefore rosuvastatin could be used as an alternative to atorvastatin and simvastatin when WZ is clinically required in conjunction with statins. An appropriate pharmacodynamic study is needed to encourage the safe use of this combination.
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Journal of Materials Chemistry B
·
2021
·Vol. 10
·期 4
·607-624
·
IF 6.331
Andy Wijaya,Yi Wang,Dan Tang,Yuan Zhong,Boyan Liu,Meng Yan,Quhui Jiu,Wei Wu,Guixue Wang
Nitric oxide (NO) is an exceptional endogenous biological gas that mediates and regulates physiological and pathological processes in the human body. However, its synthesis process is impaired during athero-progression and formation. Hence, a strategy to boost NO production and target endothelial nitric oxide synthase (eNOS) is crucial and intriguing in atherosclerosis (AS) management. Herein, we prepare L-arginine (LA) and lovastatin (LV) co-loaded PLGA nanomedicine to achieve sustainable release for enhancing NO production. The utilization of LA reveals that LA has dual contributions, acting as a NO donor and enhancing the solubility of LV by stabilizing PLGA NPs. PLGA-LA/LV demonstrated its potential to boost NO in vitro and in vivo confirmed using DAF-FM DA, augment eNOS and p-eNOS mRNA and protein levels, and suppress the ki67 proliferation marker in VSMCs; in addition, it lowers the total cholesterol level of blood plasma in C57BL/6 mice. Moreover, PLGA can protect the compound delivered and enhance the bioavailability to reach and get released in the blood circulation after oral administration. Collectively, our results endow a safe and efficient nanomedicine outcome, specifically with potential for AS management.
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Journal of Functional Foods
·
2021
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IF 4.451
Hong Zhang,Shaoting Sang,Huimin Xu,Linghua Piao,Xiande Liu
Lovastatin is a statin produced by Monascus purpureous -fermented pu-erh tea, which is used in the treatment of cardiovascular diseases and prostate cancer. Bacteria-mediated cancer immunotherapy (BCI), which is an effective antitumor strategy compared with conventional immunotherapies, targets neutrophil infiltration associated with tumor recurrence and metastasis. In mouse colon cancer models, combination treatment with lovastatin and BCI suppressed tumor progression by extending the survival of tumor-colonizing bacteria. We used zebrafish live imaging to show that lovastatin decreases the recruitment of neutrophils to the inflammatory site by inducing neutrophil apoptosis via phosphorylation of ERK and AKT. The present findings suggest that the combination of BCI with lovastatin or fermented pu-erh tea is an effective approach compared with conventional cancer immunotherapy.
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JOURNAL OF FOOD BIOCHEMISTRY
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2021
·Vol. 45
·期 11
·e13976
·
IF 2.72
Longkai Shi,Emad Karrar,Xingguo Wang
Non-alcoholic fatty liver disease (NAFLD) is a chronic hepatopathy caused by disordered lipid metabolism in the liver. Sesamol, a phenolic compound derived from sesame oil, has been shown to inhibit obesity, hyperlipidemia, and atherosclerosis in previous investigations. However, the preventive effect of sesamol against hepatic steatosis and oxidative stress in NAFLD has not been well-studied. In this work, sesamol was observed to alleviate lipid accumulation and oxidative stress in high oleic acid (300 μM)/cholesterol (25 μM) induced HepG2 cells, thus indicating that sesamol was involved in regulating hepatic lipid metabolism and oxidative injury. Mechanism studies found that the activated peroxisome proliferator-activated receptors (PPAR) signaling pathway by sesamol intervention up-regulated gene and protein expressions related to fatty acid oxidation and cholesterol efflux and catabolism, thus accelerating lipid consumption and reducing intracellular lipid accumulation in the process of NAFLD. These data suggested that sesamol can effectively ameliorate hepatic steatosis and sesamol riched sesamol oil may be a potential agent for finding therapeutic strategies to treat the NAFLD. Practical applications Sesamol and sesamol-rich sesame oil have received much attention due to their performance on hepatic lipid regulation. The results of this study indicate that sesamol treatment could ameliorate hepatic steatosis by inhibiting lipid accumulation and oxidative stress, thus demonstrating that sesamol and sesame oil can be used for functional foods and nutraceutical applications in the future. In addition, the present work provides knowledge of the effects of sesamol on NAFLD and involved mechanisms, and further supplies nutritional guidelines for sesame oil consumption.
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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.
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NEUROCHEMISTRY INTERNATIONAL
·
2021
·
IF 3.921
Ying Xu,Yunxia Dong,Cong Wang,Qian Jiang,Haichao Chu,Yue Tian
As a general anesthetic widely used in surgical, sevoflurane has been shown to cause cognitive and memory deficits in the elderly. It's important to find out agents that can counteract sevoflurane-induced cognitive dysfunction. This study is aimed to investigate the effect of lovastatin on sevoflurane-induced cognitive impairment in aged rats and reveal the potential mechanisms. BV-2 cells, rat hippocampal neurons or male aged rats were exposed to 2% sevoflurane for 5 h. The cells were pretreated with 10 μM lovastatin. The rats were intraperitoneally injected with 5 mg/kg/day lovastatin for three days. The results showed that lovastatin enhanced exosomal IDE secretion from sevoflurane-exposed BV-2 cells and promoted Aβ degradation. Lovastatin treatment also inhibited the increased expressions of β-secretase 1 (BACE1) and γ-secretase in hippocampal neurons under sevoflurane exposure in vitro . In animal experiments, the discrimination index in novel object recognition test and percentage of spontaneous alternation in Y-maze test were significantly elevated after lovastatin administration. In addition, Aβ plaque area and contents of soluble Aβ 1-40 and Aβ 1-42 in the hippocampal tissues were decreased upon lovastatin treatment. Furthermore, lovastatin reversed sevoflurane-induced Aβ accumulation via up-regulating IDE expression, and down-regulating amyloid precursor protein (APP)-related protein expression (β-C-terminal fragment (CTF), BACE1 and γ-secretase). In conclusion, lovastatin alleviates sevoflurane-induced cognitive deficient in aged rats via promoting Aβ degradation and reducing Aβ production. Lovastatin may be beneficial in preventing anesthetic-induced cognitive impairment.
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