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
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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PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
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2026
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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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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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DOI
PubMed
高影响因子
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