Frontiers in Pharmacology
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2026
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IF 5.4
Mengjie Gu,Yingxue Si,Kaizhi Luo,Chong Zhang,Tingting Xiong,Zhizhen Huang,Yijia Han,Xiaoli Zheng,Zejun Wang
Introduction Pancreatic cancer is a highly aggressive malignancy with a poor prognosis, largely owing to chemoresistance and frequent recurrence following gemcitabine-based therapy. This study investigated whether vortioxetine, a multimodal serotonin (5-HT) modulator, could enhance the antitumor efficacy of gemcitabine and explored the underlying molecular mechanisms. Methods The effects of vortioxetine alone and in combination with gemcitabine were evaluated in pancreatic cancer cells and xenograft models. Cell proliferation, apoptosis, migration, invasion, and epithelial-mesenchymal transition (EMT) were assessed using functional assays and relevant molecular markers. RNA sequencing was performed to identify potential molecular targets of vortioxetine, followed by molecular docking, thermal stability assays, and gene knockdown experiments for mechanistic validation. Results Vortioxetine significantly enhanced the inhibitory effects of gemcitabine on pancreatic cancer cell proliferation in vitro and tumor growth in xenograft models. The combination treatment markedly promoted apoptosis, as indicated by increased levels of cleaved poly(ADP-ribose) polymerase (PARP) and cleaved caspase-3. It also suppressed cancer cell migration and invasion and reversed EMT-related changes, as demonstrated by the upregulation of E-cadherin and downregulation of N-cadherin and Snail. RNA sequencing identified monoamine oxidase B (MAOB; EC 1.4.3.4) as a potential molecular target associated with vortioxetine treatment, which was further supported by molecular docking and thermal stability assays. Moreover, MAOB knockdown phenocopied the effects of vortioxetine by enhancing gemcitabine sensitivity and suppressing EMT-associated phenotypes. Discussion Vortioxetine potentiates the antitumor efficacy of gemcitabine against pancreatic cancer, with its effects associated with reduced MAOB expression, enhanced apoptosis, and suppression of EMT. These findings support further investigation of vortioxetine combined with gemcitabine as a potential therapeutic strategy for overcoming chemoresistance in pancreatic cancer.
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DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
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2023
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IF 5.4
Jin-Han Yang,Tong-Chen Bai,Lu-Li Shi,Bo Hou,Ran Tang,Rong-Ping Zhang,Xing-Long Chen
Ethnopharmacological relevance The buds of Vaccinium dunalianum Wight are used as folk medicine in the Yi settlement of the Yunnan Province, China. It has long been used as herbal tea in the local area owing to its effects of lowering blood lipids and body weight. However, there are only a few studies on its antihyperlipidemic effects, effective substances and mechanisms, especially its effectiveness in diet-induced hyperlipidemia . Aim of the study This study aimed to elucidate the therapeutic effects, pharmacodynamic material bases, and mechanisms of V. dunalianum buds on diet-induced hyperlipidemia. Materials and methods A high-fat diet-induced hyperlipidemic Sprague-Dawley (SD) rat model was established. Rats were gavaged with different doses of aqueous extract of V. dunalianum (VDW) for 8 weeks and their sera and organ samples were collected. The antihyperlipidemic effect of VDW on SD rats was evaluated based on the biochemical indices and histopathological outcomes. Liquid chromatography–mass spectrometry(LC-MS) was used to determine the main components in VDW, which were separated and purified using sequential chromatographic methods. Their chemical structures were determined using high-resolution electrospray ionization mass spectroscopy and nuclear magnetic resonance spectroscopy. 6′- O -caffeoyl-arbutin, as the principal component of VDW, was also evaluated for its antihyperlipidemic activity using an approach similar to that used for VDW. Lastly, the potential targets of VDW and 6′- O -caffeoyl-arbutin in lowering blood lipids were screened out using network pharmacology , and the selected targets were docked with arbutin derivatives. The expression of target proteins was determined using western blotting to illustrate the antihyperlipidemic mechanisms of VDW and 6′- O -caffeoyl-arbutin. Results VDW reduced triglyceride , total cholesterol, low-density lipoprotein, alanine transaminase , and aspartate transaminase levels in the serum of modeled rats, and increased high-density lipoprotein levels. There was an improvement in steatoses, and lipid droplet accumulation decreased in vivo after VDW intervention. LC-MS revealed that VDW mainly contained arbutin and chlorogenic acid derivatives. Sixteen compounds were isolated and identified. 6′- O -caffeoyl-arbutin was the main compound of VDW (>21.67%) that showed obvious antihyperlipidemic effect with low hepatic damage at different doses. PTGS2, ADH1C , and MAOB were screened out using network pharmacology and they showed strong correlations with arbutin derivative through molecular docking. Results from WB showed that VDW and 6′- O -caffeoyl-arbutin could reduce blood lipid levels by reducing the protein expression of PTGS2, ADH1C, and MAOB. Conclusions 6′- O -caffeoyl-arbutin was the main component of V. dunalianum buds. VDW and 6′- O -caffeoyl-arbutin could regulate blood lipid levels in the high-fat diet-induced rat model of hyperlipidemia without damaging their vital organs. Furthermore, they could regulate the expression of PTGS2, ADH1C, and MAOB proteins and play a role in lowering blood lipids. The findings of this study lay a foundation for the further development of V. dunalianum and 6′- O -caffeoyl-arbutin as health supplements or drugs for the management of hyperlipidemia.
研究领域:
药理学
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民族药理学
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生物化学
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分子生物学
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网络药理学
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产品关联
DOI
PubMed
高影响因子
BIOMEDICINE & PHARMACOTHERAPY
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2023
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IF 7.5
Lei Qian,Hu Xu,Ruqiang Yuan,Weijing Yun,Yufang Ma
Formononetin, an isoflavone compound, has been extensively researched due to its various biological activities, including a potent protective effect on the cardiovascular system. However, the impact of formononetin on cardiac fibrosis has not been investigated. In this study, C57BL/6 mice were used to establish cardiac fibrosis animal models by subcutaneous injecting of isoproterenol (ISO) and formononetin was orally administrated. The results showed that formononetin reversed ISO-induced heart stiffness revealed by early-to-atrial wave ratio (E/A ratio). Masson staining, western blot, immunohistochemistry and real-time PCR exhibited that the cardiac fibrosis and fibrosis-related proteins (collage III, fibronectin, TGF-β1, α-SMA, and vimentin) and genes ( Col1a1 , Col3a1 , Acta2 and Tgfb1 ) induced by ISO were significantly suppressed by formononetin. Furthermore, by combining metabolomics and network pharmacology, we found three important targets ( ALDH2 , HADH , and MAOB ), which are associated with mitochondrial function, were involved in the beneficial effect of formononetin. Further validation revealed that these three genes were more abundance in cardiomyocyte than in cardiac fibroblast. The mRNA expression of ALDH2 and HADH were decreased, while MOAB was increased in cardiomyocyte upon ISO treatment and these phenomena were reversed by formononetin. In addition, we investigated mitochondrial membrane potential and ROS production in cardiomyocytes, the results showed that formononetin effectively improved mitochondrial dysfunction induced by ISO. In summary, we demonstrated that formononetin via regulating the expressions of ALDH2 , HADH, and MAOB in cardiomyocyte to improve mitochondrial dysfunction and alleviate β-adrenergic activation cardiac fibrosis.
研究领域:
药理学
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心脏病学
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分子生物学
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细胞生物学
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代谢组学
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网络药理学
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产品关联
DOI
PubMed
高影响因子
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