PHARMACEUTICAL BIOLOGY
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2020
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IF 2.971
Yucheng Li,Baoying Wang,Jiduo Shen,Ming Bai,Erping Xu
Context Berberine is an alkaloid that possesses various pharmacologic effects.Objective To explore the mechanism of berberine to improve insulin sensitivity in fructose-fed mice.Materials and methods Sixty male ICR mice were randomly divided into 6 groups (10 mice in each group): control, fructose, pioglitazone (10 mg/kg) and berberine (50, 100, and 200 mg/kg). Except for the control group, the mice received 20% fructose drinking for 10 weeks. Pioglitazone and berberine were orally administered once daily during the last 4 weeks. The insulin sensitivity was evaluated using an oral glucose tolerance test (OGTT). The serum levels of fasting glucose and insulin, blood lipids, and hormones were determined. The hepatic AMP and ATP contents were detected using high performance liquid chromatography (HPLC) analysis, and the protein expression was examined by immunoblotting.Results Berberine significantly reversed the insulin resistance induced by fructose, including lowering fasting insulin levels (from 113.9 to 67.4) and area under the curve (AUC) during OGTT (from 1310 to 1073), decreasing serum leptin (from 0.28 to 0.13) and increasing serum adiponectin levels (from 1.50 to 2.80). Moreover, berberine enhanced the phosphorylation levels of protein kinase B (PKB/AKT; 2.27-fold) and glycogen synthase kinase-3β (GSK3β; 2.56-fold), and increased hepatic glycogen content (from 0.19 to 1.65). Furthermore, berberine upregulated the protein expression of peroxisome proliferator activated receptor gamma coactivator 1α (PGC1α; 2.61-fold), phospho-AMP-activated protein kinase (p-AMPK; 1.35-fold) and phospho-liver kinase B1 (p-LKB1; 1.41-fold), whereas it decreased the AMP/ATP ratio (from 4.25 to 1.82).Conclusion The present study demonstrated the protective effects of berberine against insulin resistance induced by fructose. Our findings may provide an experimental basis for the application of berberine in the treatment of insulin resistance.
研究领域:
药理学
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代谢紊乱
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分子生物学
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DOI
PubMed
高影响因子
PHARMACOLOGICAL RESEARCH
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2019
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IF 5.574
Jin Wen,Bin Xu,Yuchao Sun,Mengqiao Lian,Yanli Li,Yuan Lin,Dapeng Chen,Yunpeng Diao,Marwan Almoiliqy,Li Wang
Intestinal ischemia-reperfusion (I/R) injury is a common pathological process with high clinical morbidity and mortality. Paeoniflorin , a monoterpene glucoside, is found to have diverse health beneficial effects including autophagy modulation, anti-inflammatory, anti-apoptotic, and anti-oxidative effects. Based on our pre-experiments, we proposed that paeoniflorin could ameliorate intestinal I/R injury and restore autophagy through activating LKB1/AMPK signal pathway. Our proposal was verified using rat intestinal I/R model in vivo and intestinal epithelial cell line (IEC-6 cells) hypoxia/reoxygenation (H/R) model in vitro. Our results showed that paeoniflorin pretreatment exerted protective effects in rat intestinal I/R injury by reducing intestinal morphological damage, inflammation, oxidative stress, and apoptosis . Paeoniflorin restored H/R-impaired autophagy flux by up-regulating autophagy-related protein p62/SQSTM1 degradation, LC3II and beclin-1 expression, and autophagosomes synthesis without significantly affecting control IEC-6 cells. Paeoniflorin pretreatment significantly activated LKB1/AMPK signaling pathway by reversing the decreased LKB1 and AMPK phosphorylation without affecting total LKB1 both in vivo and in vitro . LKB1 knockdown reduced AMPK phosphorylation, suppressed LC3II and Beclin-1 level, and decreased the degradation of SQSTM/p62, and the knockdown weakened the effects of paeoniflorin in restoring the impaired autophagy flux in H/R injured IEC-6 cells, suggesting that paeoniflorin mitigated the intestinal I/R-impaired autophagy flux by activating LKB1/AMPK signaling pathway. Our study may provide valuable information for further studies.
研究领域:
药理学
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病理生理学
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细胞生物学
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DOI
PubMed
高影响因子
PHARMAZIE
·
2018
·Vol. 73
·期 10
·594-597
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IF 1.016
Wu Bo,Chen Xi,Zhou Ying,Hu Pingjun,Wu Dan,Zheng Guodong,Cai Yi
Background: Andrographolide (Andro) belongs to the main bioactive ingredients of Andrographis paniculata. Many studies have shown that andro has a variety of pharmacological activities such as anti-inflammatory, anti-bacterial, anti-virus, anti-oxidant, immune regulation
and liver protective effects. Moreover andro has been reported to have anticancer activity in multiple types of cancer, including gastric cancer, breast cancer, lung cancer and so on. However, there is no report about the effect of andro on the human NPC cell line C666-1 and the molecular
mechanisms of andro-mediated apoptosis in C666-1 cells remain to be clarified. Methods: Cell proliferation was measured by a CCK8 assay, cell apoptosis rate was evaluated by flow cytometric analysis, and the protein expression of LKB1/AMPK signaling pathways was detected by Western
blotting. Results: Treatment with andro inhibited cell proliferation and induced apoptosis of C666-1 cells. Moreover, andro could activate LKB1-AMPK signaling. We also demonstrated that Ca2+/calmodulin-dependent protein kinase kinaseβ (CaMKKβ) was not involved in
the regulation of andro on AMPK activation in C666-1 Cells. Conclusions: Andro suppressed proliferation and induced apoptosis of C666-1 cells through regulating the LKB1/AMPK/mTOR signal pathway.
研究领域:
肿瘤学
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药理学
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细胞生物学
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分子生物学
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DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
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2023
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IF 5
Ling Yang,Linzi Li,Qian Lu,Lingfeng Li,Chun Xie,Fakun Jiang,Hongbing Li,Ai Zhao,Qian Wang,Wenyong Xiong
As a global epidemic disease, obesity causes dysfunction of glucose and lipid metabolism leading to persistently high morbidity and mortality. Given the difficulty to achieve and maintain weight loss through controlling diet and physical exercise, pharmacotherapy is considered an effective treatment for obesity. This investigation revealed that alisol B, a triterpene monomer isolated from the classical Chinese medicine Alisma orientale (Sam.) Juzep, functioned in suppressing adipogenesis and reducing the mass of subcutaneous adipose tissue, resulting in the reduction of weight gain, and improvements of hyperglycemia, hyperlipidemia, and insulin resistance in HFD-induced obese mice. In consistent to the results, alisol B also significantly inhibited adipocyte differentiation and maturation in vitro . Furthermore, our data revealed that the effects of alisol B on adipogenesis were mediated by LKB1-AMPK signaling pathway. In total, alisol B could be a potential lead compound which contributes to the improvement of obesity-related metabolic disorders.
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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产品关联
DOI
PubMed
高影响因子
BIOORGANIC CHEMISTRY
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2026
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IF 5.1
Yongsheng Fang,Han Liu,Fakun Jiang,Qian Lu,Bangrui Huang,Chuanjun Mao,Qian Long,Qixin Zhou,Xiaodong Yang,Jun Cao,Wenyong Xiong
Hepatic steatosis is a chronic progressive condition that leads to multiple severe liver disorders. However, current therapeutic options are limited for available drugs. Screening active natural products for curing hepatic steatosis provide novel chemical scaffolds for drug development and chemical probes to reveal novel mechanisms in the development of hepatic steatosis. Here, we established an in vitro cell model for measuring hepatic lipid content and screened a series of euphorane-type diterpenoids to identify active diterpenoids for decreasing hepatic lipids. Interestingly, among these diterpenoids, euphorbia factor L3 (EFL3) exhibited the most pronounced inhibition activity for lipid amount, both in cultured hepatocytes and in HFD-induced mice with hepatic steatosis. Mechanistic studies demonstrated that EFL3 activated the LKB1-AMPK signaling pathway in hepatocytes, leading to downregulation of the lipogenic factors SREBP-1c, ACC1, and FASN, and leading to upregulation of fatty acid oxidation-related proteins SIRT1, PGC-1α, PPARα, and CPT1A. These changes improved cellular lipid metabolism and ultimately ameliorated hepatic steatosis in mice. In summary, this study supports the key role of LKB1-AMPK pathway in regulation of hepatic steatosis and reveals that EFL3 could be considered as a novel compound for drug development against hepatic steatosis.
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PubMed
高影响因子
VETERINARY RESEARCH
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2023
·Vol. 54
·期 1
·1-12
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IF 4.4
Fu Shaodong,Wang Zhenglei,Han Xiangan,Xu Yuanyuan,Miao Jinfeng
Macrophages play a pivotal role in the inflammatory response to the zoonotic pathogen E. coli, responsible for causing enteric infections. While considerable research has been conducted to comprehend the pathogenesis of this disease, scant attention devoted to host-derived H2S. Herein, we reported that E. coli infection enhanced the expression of CSE in macrophages, accompanied by a significantly increased inflammatory response. This process may be mediated by the involvement of excessive autophagy. Inhibition of AMPK or autophagy with pharmacological inhibitors could alleviate the inflammation. Additionally, cell model showed that the mRNA expression of classic inflammatory factors (Il-1β, Il-6), macrophage polarization markers (iNOS, Arg1) and ROS production was significantly down-regulated after employing CSE specific inhibitor PAG. And PAG is capable of inhibiting excessive autophagy through the LKB1-AMPK-ULK1 axis. Interestingly, exogenous H2S could suppress inflammation response. Our study emphasizes the importance of CSE in regulating the macrophage-mediated response to E. coli. Increased CSE in macrophages leads to excessive inflammation, which should be considered a new target for drug development to treat intestinal infection.
研究领域:
免疫学
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微生物学
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药理学
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DOI
PubMed
高影响因子
Nutrients
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2018
·Vol. 10
·期 8
·1024
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IF 4.196
Yu-Cheng Li,Jing-Yi Qiao,Bao-Ying Wang,Ming Bai,Ji-Duo Shen,Yong-Xian Cheng
The present study aimed to evaluate the effects of paeoniflorin on insulin resistance and hepatic steatosis induced by fructose. Male Sprague-Dawley rats were fed 20% fructose drink for eight weeks. The insulin sensitivity, serum lipid profiles, and hepatic lipids contents were measured. The results showed that paeoniflorin significantly decreased serum insulin and glucagon levels, improved insulin sensitivity and serum lipids profiles, and alleviated hepatic steatosis in fructose-fed rats. Moreover, paeoniflorin enhanced the phosphorylation level of AMP-activated protein kinase (AMPK) and protein kinase B (PKB/AKT) and inhibited the phosphorylation of acetyl coenzyme A carboxylase (ACC)1 in liver. Paeoniflorin also increased the hepatic carnitine palmitoyltransferase (CPT)-1 mRNA and protein expression and decreased the mRNA expression of sterol regulatory element-binding protein (SREBP)1c, stearyl coenzyme A decarboxylase (SCD)-1 and fatty acid synthetase (FAS). Furthermore, we found that paeoniflorin significantly increased the heptatic protein expression of tumor suppressor serine/threonine kinase (LKB)1 but not Ca2+/CaM-dependent protein kinase kinase (CaMKK)β. These results suggest that the protective effects of paeoniflorin might be involved in the activation of LKB1/AMPK and insulin signaling, which resulted in the inhibition of lipogenesis, as well as the activation of β-oxidation and glycogenesis, thus ameliorated the insulin resistance and hepatic steatosis. The present study may provide evidence for the beneficial effects of paeoniflorin in the treatment of insulin resistance and non-alcoholic fatty liver.Keywords:insulin resistance;hepatic steatosis;paeoniflorin;AMPK
研究领域:
药理学
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代谢
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肝病学
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DOI
PubMed
高影响因子
MOLECULES
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2023
·Vol. 28
·期 21
·7307
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IF 4.6
Yecheng Lei,Xiao Lei,Anqi Zhu,Shijie Xie,Tiantian Zhang,Chuo Wang,Anning Song,Xiaoming Wang,Guangwen Shu,Xukun Deng
Acetaminophen (APAP)-induced liver injury is a common hepatic disease resulting from drug abuse. Few targeted treatments are available clinically nowadays. The flower bud ofRosa rugosahas a wide range of biological activities. However, it is unclear whether it alleviates liver injury caused by APAP. Here, we prepared an ethanol extract ofRosa rugosa(ERS) and analyzed its chemical profile. Furthermore, we revealed that ERS significantly ameliorated APAP-induced apoptosis and ferroptosis in AML-12 hepatocytes and dampened APAP-mediated cytotoxicity. In AML-12 cells, ERS elevated Sirt1 expression, boosted the LKB1/AMPK/Nrf2 axis, and thereby crippled APAP-induced intracellular oxidative stress. Both EX527 and NAM, which are chemically unrelated inhibitors of Sirt1, blocked ERS-induced activation of LKB1/AMPK/Nrf2 signaling. The protection of ERS against APAP-triggered toxicity in AML-12 cells was subsequently abolished. As expression of LKB1 was knocked down, ERS still upregulated Sirt1 but failed to activate AMPK/Nrf2 cascade or suppress cytotoxicity provoked by APAP. Results of in vivo experiments showed that ERS attenuated APAP-caused hepatocyte apoptosis and ferroptosis and improved liver injury and inflammation. Consistently, ERS boosted Sirt1 expression, increased phosphorylations of LKB1 and AMPK, and promoted Nrf2 nuclear translocation in the livers of APAP-intoxicated mice. Hepatic transcriptions of HO-1 and GCLC, which are downstream antioxidant genes of Nrf2, were also significantly increased in response to ERS. Our results collectively indicated that ERS effectively attenuates APAP-induced liver injury by activating LKB1/AMPK/Nrf2 cascade. Upregulated expression of Sirt1 plays a crucial role in ERS-mediated activation of LKB1.Keywords:extract ofRosa rugosa;acetaminophen;liver injury;Sirt1;Nrf2
研究领域:
药理学
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肝脏病学
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植物化学
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产品关联
DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
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2016
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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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DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
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2026
·
IF 6.8
Yi Feng,Xiaoyu Liu,Xinyi Zhang,Yongzhi Sun,Kexin Ren,Xuemei Qian,Wenjing Sun,Ji Li,Bo Yu
This is the first report of geraniin alleviating visceral adipose tissue expansion. • Geraniin promotes lipid metabolic remodeling in visceral adipose tissue. • This is the first in vivo study of geraniin activating cAMP-LKB1-AMPK signaling. • β-adrenergic receptors contributes to geraniin-induced lipid metabolic remodeling. • This study provides a new insight on the anti-obesity potential of natural tannin. Ethnopharmacological relevance Geranium ( Geranium wilfordii Maxim.) has traditionally been used as a folk medicine in East Asia and Europe. Geraniin, the major bioactive constituent of geranium, has been reported to ameliorate dyslipidemia and insulin resistance, but its effects against adipose metabolic dysfunction remain unclear. Aim of the study To investigate the protective effects of geraniin against pathological visceral adipose tissue (VAT) expansion in high-fat diet-fed (HFD-fed) mice and to elucidate the underlying mechanisms. Methods Adipose tissue content was detected using micro-CT. Adipocyte morphology and macrophage infiltration in VAT were evaluated by HE staining and immunohistochemistry. Target gene and protein expression were analyzed by qPCR, Western blot, and immunofluorescence staining. Circulating free fatty acid (FFA) profiles were quantified using GC-MS. Results Geraniin markedly attenuated body weight gain and pathological VAT expansion in HFD-fed mice without affecting food intake. Geraniin reduced adipocyte hypertrophy and inflammatory responses in VAT. Mechanistically, geraniin suppressed the SREBP-1/FAS-associated lipogenic program while enhancing PGC-1α/ATGL-associated lipolytic program. These metabolic changes were accompanied by increased cAMP level and enhanced LKB1 and AMPK phosphorylation. Importantly, propranolol reversed geraniin-induced cAMP accumulation and LKB1-AMPK activation, as well as lipid metabolic remodeling in VAT. Consistent findings were observed in 3T3-L1 adipocytes. In addition, geraniin partially normalized circulating FFA profiles, particularly by reducing palmitic acid levels. Conclusion Geraniin alleviated pathological VAT expansion in HFD-fed mice through lipid metabolic remodeling. Our findings suggest that β-adrenergic receptor (ADRB)-associated signaling and downstream cAMP-LKB1-AMPK activation may contribute to the protective effects of geraniin, supporting its therapeutic potential for abdominal obesity and related metabolic disorders. Download: Download high-res image (280KB) Download: Download full-size image
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DOI
PubMed
高影响因子
PHYTOMEDICINE
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2023
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IF 7.9
Yi Cai,Shisheng Jiang,Chaoming Huang,Ao Shen,Xuan Zhang,Wanling Yang,Yichuan Xiao,Shuhan Gao,Rong Du,Guodong Zheng,Tingdong Yan,Chunpeng (Craig) Wan
Background The conserved sirtuin protein sirtuin 3 (SIRT3) is a vital protective protein for cardiac hypertrophy. Inhibition of SIRT3 accelerated the development of heart hypertrophy. On the other hand, myocardial hypertrophy was prevented by overexpressing SIRT3. SIRT3 has been proposed as a potential therapeutic target for managing or averting heart hypertrophy. Baicalin, a flavonoid extracted from the Scutellaria baicalensis plant, has anti-cardiovascular properties, including protection against cardiac hypertrophy. However, the molecular mechanism of the anti-hypertrophic effect of baicalin is not well known. Purpose In this study, we aim to investigate the effect of baicalin on cardiac hypertrophy and explored its underlying molecular mechanisms. Study-design/methods Abdominal aortic constriction (AAC)-induced mouse cardiac hypertrophy and angiotensin II (Ang II)-induced cardiomyocyte hypertrophy models were established. After baicalin treatment, cardiac hypertrophy was monitored by detecting the expression of hypertrophic genes and cell surface area. Echocardiogram was performed to check the heart function in vivo . Moreover, the protein expression of the SIRT3-dependent pathway was detected by Western blotting. Results In this work, we demonstrated that baicalin might suppress the cell surface area and the expression of the Ang II -induced myosin heavy chain β (β-MHC), brain natriuretic polypeptide (BNP), and atrial natriuretic factor (ANF). Additionally, it reduced the AAC rats' hypertrophic impact. We also found that baicalin prevents cardiac hypertrophy by regulating SIRT3/LKB1/AMPK signaling pathway. Moreover, we showed that baicalin upregulated the SIRT3 protein expression by inhibiting proteasome and by the activation of 20 S proteasome subunit beta type-5 (PSMB5). Conclusion These results offer the first proof that baicalin inhibits cardiac hypertrophy due to its effect on the SIRT3-dependent signaling pathway, indicating its potential for treating cardiac hypertrophy and heart failure. The present study provides a preliminary experimental basis for the clinical application of baicalin and baicalin-like compounds.
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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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）