ACTA PHARMACOLOGICA SINICA
·
2023
·
IF 8.2
Li Yi-jie,Wu Rui-yu,Liu Run-ping,Wu Kai-yi,Ding Ming-ning,Sun Rong,Gu Yi-qing,Zhou Fei,Wu Jian-zhi,Zheng Qi,Duan Shu-ni,Li Rong-rong,Zhang Yin-hao,Li Fang-hong,Li Xiaojiaoyang
Obesity contributes to the progression of various chronic diseases, and shortens life expectancy. With abundant mitochondria, brown adipose tissue (BAT) dissipates energy through heat to limit weight gain and metabolic dysfunction in obesity. Our previous studies have shown that aurantio-obtusin (AO), a bioactive ingredient in Chinese traditional medicine Cassiae semen significantly improves hepatic lipid metabolism in a steatotic mouse model. In the current study we investigated the effects of AO on lipid metabolism in the BAT of diet-induced obesity mice and in oleic acid and palmitic acid (OAPA)-stimulated primary mature BAT adipocytes. Obese mice were established by feeding a HFHS diet for 4 weeks, and then administered AO (10 mg/kg, i.g.) for another 4 weeks. We showed that AO administration significantly increased the weight of BAT and accelerated energy expenditure to protect the weight increase in the obese mice. Using RNA sequencing and molecular biology analysis we found that AO significantly enhanced mitochondrial metabolism and UCP1 expression by activating PPARα both in vivo and in vitro in the primary BAT adipocytes. Interestingly, AO administration did not improve metabolic dysfunction in the liver and white adipose tissue of obese mice after interscapular BAT excision. We demonstrated that low temperature, a trigger of BAT thermogenesis, was not a decisive factor for AO to stimulate the growth and activation of BATs. This study uncovers a regulatory network of AO in activating BAT-dependent lipid consumption and brings up a new avenue for the pharmaceutical intervention in obesity and related comorbidities.
研究领域:
药理学
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代谢学
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内分泌学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
BIOSCIENCE BIOTECHNOLOGY AND BIOCHEMISTRY
·
2021
·Vol. 85
·期 4
·798-804
·
IF 2.043
Yang Yanfei,Li Yabin,Han Jinli,Wang Yanfen
Gastrodin has shown the potential as an anticonvulsant. Epilepsy is a neurological disease with significant effects in children. In the current study, the therapeutic potential of gastrodin in handling pediatric epilepsy was explored by focusing on the AMPK/PPARα pathway. Three-week-old Sprague–Dawley rats were subjected to lithium-pilocarpine method to induce epileptic symptoms and then administrated with gastrodin. The effects of gastrodin on rats were first assessed using electroencephalogram (EEG) recording, Racine classification, Morris water maze test, and histological staining. The levels of BDNF and NGF, and the activity of AMPK/PPARα were measured. Based on the results of EEG, behavior analyses, and histological staining, epileptic symptoms were significantly alleviated by gastrodin. Moreover, the administration of gastrodin also suppressed the levels of BDNF and NGF, and activated the AMPK/PPARα pathway. In conclusion, our results demonstrated that gastrodin contributed to the alleviation of pediatric epilepsy by activating AMPK/PPARα signaling transduction.
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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DOI
PubMed
高影响因子
MOLECULAR MEDICINE
·
2025
·Vol. 31
·期 1
·1-20
·
IF 6.4
Peng Shuaijun,Su Pan,Liu Liming,Li Zibo,Liu Yuan,Tian Lei,Bai Ming,Xu Erping,Li Yucheng
Background The dysregulation of neuroinflammation triggered by imbalance of microglia M1/M2 polarization is a key pathogenic factor and closely associated with occurrence of depression. Formononetin (FMN), a natural non-steroidal isoflavonoid, has been confirmed to exhibit remarkable anti-inflammatory efficacy, but the impact of FMN on depression and the underlying antidepressant mechanisms are still not fully understood. This study aimed to investigate whether the antidepressant effect of FMN is involved in modulating microglia polarization, and if so, what are the underlying mechanisms.Methods Lipopolysaccharide (LPS)-induced depressive mice were used to study antidepressant mechanisms of FMN. Microglia cell line BV2 stimulated by LPS was employed to investigate pharmacological mechanisms of FMN. Effects of FMN on neuronal damage were detected by H&E, Nissl and Golgi staining. The efficacy of FMN were evaluated by immunostaining and western blots in vivo and vitro. In addition, molecular docking, luciferase reporter assay, cellular thermal shift assay (CETSA) and drug affinity responsive target stability (DARTS) were used to confirm the direct target of FMN.Results Our results showed that FMN significantly reverses depression-like behaviors, alleviates neuroinflammation and neuronal damage, rebalances M1/M2 polarization, inhibits NLRP3 inflammasome and enhances microglial autophagy level in prefrontal cortex of LPS-induced depressive mice. In vitro assays, results unraveled that autophagy inhibitor chloroquine (CQ) blocks effects of FMN on inhibiting NLRP3 inflammasome and rebalancing M1/M2 polarization. Moreover, PPARα is identified as a direct target of FMN and FMN can activate PPARα-mediated autophagy. Furtherly, combination PPARα agonist (WY14643) with FMN had no significant additive effects on inhibiting NLRP3 inflammasome and rebalancing M1/M2 polarization, whereas PPARα antagonist (GW6471) abrogated these pharmacologic effects of FMN in BV2. Importantly, GW6471 exhibited similar pharmacologic effects to abolish antidepressant effect of FMN in LPS-induced depressive mice.Conclusion Our study firstly demonstrated that FMN can rebalance microglia M1/M2 polarization and inhibit NLRP3 inflammasome, with the involvement of activating PPARα-mediated autophagy to ameliorate depression-like behaviors, which provides a novel view to elucidate antidepressant mechanisms of FMN and also offers a potential therapeutic target for depression.
研究领域:
神经科学
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药理学
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免疫学
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产品关联
DOI
PubMed
高影响因子
BIOMEDICINE & PHARMACOTHERAPY
·
2022
·
IF 7.419
Mengyang Wang,Wu Luo,Tianxiang Yu,Shiqi Liang,Jinfeng Sun,Yi Zhang,Xue Han,Xiaohong Long,Guang Liang,Gao Li
Heart failure is a fairly common outcome of hypertension. Recent studies have highlighted the key role of the non-hemodynamic activity of angiotensin II (Ang II) in hypertensive heart failure via inducing cardiac inflammation. Drugs that disrupt Ang II-induced cardiac inflammation may have clinical utility in the treatment of hypertensive heart failure. A naturally occurring compound, corynoline, exhibit anti-inflammatory activities in other systems. C57BL/6 mice were injected with Ang II via a micro-osmotic pump for four weeks to develop hypertensive heart failure. The mice were treated with corynoline by gavage for two weeks. RNA-sequencing analysis was performed to explore the potential mechanism of corynoline. We found that corynoline could inhibit inflammation, myocardial fibrosis, and hypertrophy to prevent heart dysfunction, without the alteration of blood pressure. RNA-sequencing analysis indicates that the PPARα pathway is involved Ang II-induced cardiac fibrosis and cardiac remodeling. Corynoline reversed Ang II-induced PPARα inhibition both in vitro and in vivo. We further found that corynoline increases the interaction between PPARα and P65 to inhibit the NF-κB pro-inflammatory pathway in H9c2 cells. Our studies show that corynoline relieves Ang II-induced hypertensive heart failure by increasing the interaction between PPARα and P65 to inhibit the NF-κB pathway.
研究领域:
心脏病学
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药理学
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分子生物学
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炎症研究
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产品关联
DOI
PubMed
高影响因子
CHEMICO-BIOLOGICAL INTERACTIONS
·
2024
·
IF 4.7
Huilin Li,Yanying Zhou,Chenghui Cai,Hangfei Liang,Xuan Li,Min Huang,Shicheng Fan,Huichang Bi
Fenofibrate is a clinically prescribed drug for treating hypertriglyceridemia, which is also a classic peroxisome proliferator activated receptor α (PPARα) agonist. We previously reported that fenofibrate induced liver enlargement in adult mice partially through yes-associated protein (YAP) signaling pathway. However, the effects of fenofibrate on liver enlargement and the YAP signaling pathway in aging mice remain unclear. In this study, D-galactose-induced aging mice, naturally aging mice and senescence accelerated mice P8 (SAMP8) were used to investigate the effects of aging on fenofibrate-induced liver enlargement and YAP signaling activation. The results showed that fenofibrate-induced liver enlargement in aging mice was consistent with that of adult mice. The effect of fenofibrate on hepatocyte enlargement around the central vein (CV) area and hepatocyte proliferation around the portal vein (PV) area was comparable between adult and aging mice. There was no significant difference in the upregulation of PPARα downstream proteins between the two groups following fenofibrate treatment. Fenofibrate treatment also increased the expression of proliferation-related proteins and activated the YAP signaling pathway to a similar degree in both groups. In summary, these results demonstrated that the fenofibrate-induced liver enlargement and activation of the YAP pathway are consistent between adult and aging mice, indicating that the effect of fenofibrate on promoting liver enlargement and its activation of the PPARα and YAP pathway were independent of aging. These findings provide a new perspective for the clinical use of fenofibrate in elderly patients and provide a new insight for role of PPARα in liver enlargement.
研究领域:
药理学
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老年学
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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
BIOCHEMICAL PHARMACOLOGY
·
2025
·
IF 5.6
Shuaibing Liu,Jinxin Miao,Hang Li,Guangbo Ge,Quanjun Yang,Songfeng Zhao,Cheng Guo
Primary sclerosing cholangitis (PSC) is a chronic liver disease characterized by bile duct inflammation and fibrosis, ultimately leading to liver dysfunction. The role of peroxisome proliferator-activated receptor α (pparα) in regulating hepatic drug-metabolizing enzymes, including cytochrome P450s (P450s) and UDP-glucuronosyltransferases (UGTs), in PSC remains insufficiently understood. In this study, wild-type and pparα −/− Syrian hamsters were used to establish a PSC model, aiming to investigate the effects of pparα on the expression and activity of P450 and UGT enzymes. Sequential windowed acquisition of all theoretical fragment ions profiling and multiple reaction monitoring mass spectrometry with high resolution assays revealed a significant downregulation of CYP2C27 and CYP2D20 in pparα−/− hamsters. Enzymatic kinetic assays demonstrated reduced activity for several enzymes, including CYP1A2 (involved in the metabolism of acetaminophen), CYP2C family (responsible for 4′-hydroxy diclofenac formation), CYP2D family (involved in dextrorphan production), CYP2E1 (involved in 6-hydroxy chlorzoxazone production), and UGTs (responsible for chenodeoxycholic acid 24-acyl-β-D-glucuronide and mycophenolic acid glucuronide formation). These reductions suggest impaired drug metabolism and an increased risk of drug-drug interactions in conditions of reduced pparα function. In contrast, enzymes such as the CYP2B family, CYP3A family, and UGTs involved in N-Acetyl serotonin β-D-glucuronide formation retained their activity, indicating selective pathway preservation in pparα −/− hamsters. These findings highlight the selective regulatory roles of pparα on certain drug-metabolizing enzymes, providing important insights into metabolic regulation in pparα-deficient states.
研究领域:
肝脏病学
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分子药理学
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药物代谢
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毒理学
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代谢调控
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实验动物模型
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转录调控
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产品关联
DOI
PubMed
高影响因子
BIOMEDICINE & PHARMACOTHERAPY
·
2024
·
IF 6.9
Yan Xie,Yimin Jin,Jianhui Wen,Guiping Li,Xue Huai,Yueyang Duan,Fuyong Ni,Juan Fu,Ming Li,Liang Li,Ming Yan,Liang Cao,Wei Xiao,Hao Yang,Zhen-zhong Wang
Non-alcoholic fatty liver disease (NAFLD), particularly advanced non-alcoholic steatohepatitis (NASH), leads to irreversible liver damage. This study investigated the therapeutic effects and potential mechanism of a novel extract from traditional Chinese medicine Alisma orientale (Sam.) Juzep (AE) on free fatty acid (FFA)-induced HepG2 cell model and high-fat diet (HFD) + carbon tetrachloride (CCl 4 )-induced mouse model of NASH. C57BL/6 J mice were fed a HFD for 10 weeks. Subsequently, the mice were injected with CCl 4 to induce NASH and simultaneously treated with AE at daily doses of 50, 100, and 200 mg/kg for 4 weeks. At the end of the treatment, animals were fasted for 12 h and then sacrificed. Blood samples and liver tissues were collected for analysis. Lipid profiles, oxidative stress, and histopathology were examined. Additionally, a polymerase chain reaction (PCR) array was used to predict the molecular targets and potential mechanisms involved, which were further validated in vivo and in vitro . The results demonstrated that AE reversed liver damage (plasma levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), hepatocyte ballooning, hepatic steatosis, and NAS score), the accumulation of hepatic lipids (TG and TC), and oxidative stress (MDA and GSH). PCR array analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis revealed that AE protects against NASH by regulating the adipocytokine signaling pathway and influencing nuclear receptors such as PPARα. Furthermore, AE increased the expression of peroxisome proliferator-activated receptor gamma coactivator-1α (PPARGC1α) and reversed the decreased expression of PPARα in NASH mice. Moreover, in HepG2 cells, AE reduced FFA-induced lipid accumulation and oxidative stress, which was dependent on PPARα up-regulation. Overall, our findings suggest that AE may serve as a potential therapeutic approach for NASH by inhibiting lipid accumulation and reducing oxidative stress specifically through the PPARα pathway.
研究领域:
药理学
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肝病学
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分子生物学
·
传统中药
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF OBESITY
·
2024
·
IF 4.2
Yan Zheng,Luo Jia,Wang Ying,Yang Jie,Su Mingli,Jiang Lei,Yang Julin,Dai Manyun,Liu Aiming
Background As the second most risky environmental pollution, noise imposes threats to human health. Exposure to high-intensity noise causes hearing impairment, psychotic disorders, endocrine modifications. The relationship among low-intensity noise, obesity and lipid-regulating nuclear factor PPARα is not yet clear. Methods In this study, male wild-type (WT) and Pparα -null (KO) mice on a high-fat diet (HFD) were exposed to 75 dB noise for 12 weeks to explore the effect of low-intensity noise on obesity development and the role of PPARα. 3T3-L1 cells were treated with dexamethasone (DEX) and sodium oleate (OA) to verify the down-stream effect of hypothalamic-pituitary-adrenal (HPA) axis activation on the adipose tissues. Results The average body weight gain (BWG) of WT mice on HFD exposed to noise was inhibited, which was not observed in KO mice. The mass and adipocyte size of adipose tissues accounted for the above difference of BWG tendency. In WT mice on HFD, the adrenocorticotropic hormone level was increased by the noise challenge. The aggravation of fatty liver by noise exposure occurred in both mouse lines, and the transport of hepatic redundant lipid to adipose tissues were similar. The lipid metabolism in adipose tissue driven by HPA axis accorded with the BWG inhibition in vivo, validated in 3T3-L1 adipogenic stem cells. Conclusion Chronic exposure to low-intensity noise aggravated fatty liver in both WT and KO mice. BWG inhibition was observed only in WT mice, which covered up the aggravation of fatty liver by noise exposure. PPARα mediates the activation of HPA axis by noise exposure in mice on HFD. Elevated adrenocorticotropic hormone (ACTH) promoted lipid metabolism in adipocytes, which contributed to the disassociation of BWG and fatty liver development in male WT mice. Summary of PPARα suppresses noise-induced body weight gain in mice on high-fat-diet. Chronic exposure to low-intensity noise exposure inhibited BWG by PPARα-dependent activation of the HPA axis.
研究领域:
环境健康
·
内分泌学
·
营养学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Pharmaceuticals
·
2025
·Vol. 18
·期 8
·1109
·
IF 4.8
Lingxin Zhuo,Mingxuan Ma,Jiayi Zhang,Jiayu Zhou,Yuqi Zheng,Aiyin Liang,Qingqing Sun,Jia Liu,Wenting Liao
Background/Objectives: Sepsis-induced cardiomyopathy (SIC) is a serious clinical disorder with a high death rate. Qifu decoction (QFD) is a renowned traditional Chinese medicine with documented pharmacological actions, such as anti-inflammatory, anti-oxidant and anti-apoptosis activities, and it has good therapeutic effects on cardiovascular diseases. This study aimed to reveal the cardioprotective effects and underlying mechanisms of QFD against SIC.Methods: Electrocardiography, histopathological examination, and biochemical indicator determination were carried out to investigate the cardioprotective effects of QFD in the treatment of LPS-induced SIC mice. Metabolomics and network pharmacology strategies were employed to preliminarily analyze and predict the mechanisms of QFD against SIC. Molecular docking and Western blot were further applied to validate the core targets and potential pathways for the treatment of SIC in in vitro and in vivo models.Results: It was found that QFD considerably enhanced cardiac function; attenuated myocardial injury; and reduced the serum levels of LDH, CK-MB, IL-1β, and TNF-α by 28.7%, 32.3%, 38.6%, and 36.7%, respectively. Metabolomic analysis showed that QFD could regulate seven metabolic pathways, namely, glutathione metabolism; alanine, aspartate, and glutamate metabolism; arachidonic acid metabolism; glycerophospholipid metabolism; purine metabolism; sphingolipid metabolism; and fatty acid metabolism. Network pharmacology suggested that the anti-SIC effect of QFD may be mediated through the TNF, toll-like receptor, NOD-like receptor, NF-κB, and PPAR signaling pathways. Additionally, 26 core targets were obtained. Molecular docking revealed that active ingredients such as formononetin, kaempferol, quercetin, and (R)-norcoclaurine in QFD had a high affinity for binding to PPARα and TLR4. Further Western blot validation indicated that QFD could regulate the protein levels of NLRP3, TLR4, NF-κB, IL-6, TNF-α, COX2, sPLA2, PPARα, CPT1B, and CPT2.Conclusions: This study demonstrates that QFD can alleviate SIC by suppressing the TLR4/NF-κB/NLRP3 inflammatory pathway and modulating impaired FAO through the activation of the PPARα/CPT pathway, highlighting QFD as a promising candidate drug for SIC treatment.
研究领域:
心脏病学
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药理学
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中医学
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分子生物学
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免疫学
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代谢组学
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网络药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
PESTICIDE BIOCHEMISTRY AND PHYSIOLOGY
·
2025
·
IF 4
Hao Wu,Tong Xu,Naixi Yang,Shiwen Xu
Microplastics (MPs) and Emamectin Benzoate (EMB) were identified as hazardous environmental pollutants, frequently coexisting in aquatic ecosystems, posing potential risk in the immune system of human and animal. However, the hazards of concurrent exposed to MPs and EMB on the carp spleen, and the specific mechanisms remain unclear. Here, we employed MPs and EMB-exposed carp models, and cultured splenocytes in vitro, to demonstrate that PPARα signals suppression underlay MPs and EMB-induced carp spleen injury, based on transcriptomics and lipomics analysis. This suppression exacerbated the buildup of polyunsaturated fatty acid (PUFA), and promoted ACSL4 expression, resulting in increased lipid peroxidation. Further studies found that the accumulation of lipid peroxides predominantly occurred in the mitochondria, which evoked mitochondrial homeostasis imbalance and compromised mitochondrial function, thereby initiating ferroptosis. Additionally, enhancing PPARα signaling, inhibiting ACSL4, or scavenging mitochondrial ROS was favor of mitigating accumulation of lipid peroxides, reducing mitochondrial damage and inhibiting ferroptosis. Notably, MPs and EMB co-exposure caused more severe damage than single exposure. These findings uncovered a potential mechanism, involving PPARα signaling inhibition by MPs and EMB co-exposure, which evoked lipid remodeling and increased ACSL4, to drive ferroptosis and carp splenic injury. This study highlighted the potential hazards to the aquaculture environments where co-exposure of MPs and EMB and provided reference for environmental toxicology research and the sustainable development of the aquaculture industry.
研究领域:
环境毒理学
·
水产养殖学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
·
2024
·
IF 4.2
Yi Chu,Sisi Gui,Yazhen Zheng,Jingwu Zhao,Yaxiang Zhao,Yingying Li,Xiaodong Chen
Non-alcoholic fatty liver disease (NAFLD) is closely associated with the body's energy metabolism. A potential strategy to regulate energy metabolism, combat obesity, and reduce NAFLD is by enhancing adipocyte thermogenesis and increasing energy expenditure. In this study, our objective was to examine the effects of phenolic extracts derived from Magnolia officinalis on the regulation of NAFLD. Specifically, we investigated the impact of Magnolol or Honokiol treatment on high-fat diet (HFD)-induced obese C57BL6/J male mice. Firstly, we monitored energy metabolism, dissected tissues, and analyzed tissue sections. Additionally, we conducted experiments on HepG2 and primary adipocytes to gain insights into the roles of Magnolol or Honokiol. To further understand the effects of these compounds on related signaling pathways and marker genes, we performed molecular docking, dual-luciferase assays, and interfered with target genes. Our findings revealed that Magnolol or Honokiol activate the peroxisome proliferator activated receptor alpha (PPARα) signaling pathway, leading to the alleviation of NAFLD. This activation promotes fatty acid oxidation, reduces lipogenesis, and enhances the expression and secretion of FGF21. Notably, Fibroblast growth factor 21 (FGF21), secreted by the liver, plays a crucial role in improving communication between the liver and adipocytes while also promoting the browning of adipose tissue. Additionally, Magnolol or Honokiol activate the peroxisome proliferator activated receptor gamma (PPARγ) signaling pathway, resulting in increased uncoupling protein 1 (UCP1) expression, heightened heat production in adipose tissue, and anti-obesity. Therefore, Magnolol or Honokiol alleviate NAFLD, promote adipose tissue browning and resist obesity through dual activation of PPARα/γ.
研究领域:
药理学
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代谢
·
分子生物学
·
营养学
✓ 已验证
DOI
PubMed
高影响因子
JOURNAL OF CELLULAR PHYSIOLOGY
·
2020
·Vol. 236
·期 3
·1889-1902
·
IF 5.546
Wenhui Yao,Kai Wang,Xiniao Wang,Xinran Li,Jieyan Dong,Yusheng Zhang,Xuansheng Ding
Icariin (ICA), as a flavonoid glycoside, is associated with the improvement of vascular complications in diabetes. However, its protective mechanisms remain to be well-established. Here, we tested the hypothesis that ICA attenuates vascular endothelial dysfunction by inhibiting endoplasmic reticulum (ER) stress in type 1 diabetes. In streptozotocin-induced diabetic rats, ICA positively affected acetylcholine-induced vasodilation and phenylephrine-induced vasoconstriction in aortas. ICA treatment significantly attenuated ER stress in diabetic rats and high-glucose induced human umbilical vein endothelial cells. Incubation with ICA in vitro attenuated vascular reactivity in diabetic rats, which was blocked by the ER stress inducer, and peroxisome proliferator-activated receptor α (PPARα), sirtuin1 (Sirt1), or AMP-activated protein kinase-α (AMPKα) inhibitors. Western blot showed that ICA activated the PPARα/Sirt1/AMPKα pathway, which contributed to reducing ER stress and activating endothelial nitric oxide synthase in vivo and vitro. Our results implicate that ICA normalizes ER stress to attenuate endothelial dysfunction by the regulation of the PPARα/Sirt1/AMPKα pathway.
研究领域:
药理学
·
糖尿病
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心血管疾病
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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）