EUROPEAN JOURNAL OF PHARMACOLOGY
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2022
·
IF 5.195
Huizhen Sun,Anyong Zhang,Yanchun Gong,Wei Sun,Baiyi Yan,Shuihong Lei,Li-Hua Yao
Diabetes mellitus (DM) has recently become one of the major diseases that have received attention. Cordycepin (molecular formula: C 10 H 13 N 5 O 3 ), is one of the major bioactive components of Cordyceps militaris , decreases blood glucose levels. In this study, the effect and mechanism of cordycepin in normal and oxidative-damaged INS-1 cells were explored by using cell and molecular biology methods. Results showed that cordycepin could enhance insulin synthesis and secretion. The mechanism is possibly related to the elevated ATP content induced membrane depolarisation and increased Ca 2+ concentration. At the genetic level, cordycepin upregulated the mRNA level of insulin, pancreatic duodenal homeobox factor-1 (PDX-1) and glucose transporter 1 (GLUT1). At the protein level, cordycepin promoted the expression of PDX-1, GLUT1, serine threonine kinase (Akt) and phosphorylated Akt (P-Akt). These effects may also contribute to the enhancement of insulin synthesis and secretion. Further analysis revealed that cordycepin protected against H 2 O 2 -induced damage on INS-1 cells and improved their viability and insulin synthesis/secretion. This effect should be attributed to the reduced intracellular reactive oxygen species (ROS), enhanced mitochondrial membrane potential (MMP), increased activity of superoxide dismutase (SOD) and upregulated genetic and protein expression of catalase (CAT), PDX-1, GLUT1 and P-Akt. In conclusion, cordycepin promotes insulin synthesis and secretion in normal islet β cells and improves this function in oxidative-damaged islet β cells. Given that islet β cells are vulnerable to oxidative stress , the improving effect of cordycepin on the antioxidant capacity and insulin synthesis/secretion of INS-1 cells may be an important mechanism for its hypoglycaemic effect.
研究领域:
药理学
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内分泌学
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细胞生物学
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分子生物学
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糖尿病研究
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产品关联
DOI
PubMed
高影响因子
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS
·
2023
·
IF 3.9
Qingqing Du,Xiaoyun Wu,Kai Ma,Weiwei Liu,Panwen Liu,Toshihiko Hayashi,Kazunori Mizuno,Shunji Hattori,Hitomi Fujisaki,Takashi Ikejima
Type 2 diabetes (T2DM) is induced by the abundance of glucose and lipids , which causes glucolipotoxicity to the pancreatic β-cells. Silibinin is a natural flavonoid possessing the regulatory activity on insulin production and therapeutic activity in diabetic mice; however, its effect on glucolipotoxicity is not fully explained. This in vitro study investigates the effects of silibinin on palmitic acid (PA) and high glucose (HG)-induced cell loss and ferroptosis of rat insulinoma INS-1 cells. In the cells treated with PA and HG, expressions of glucose transporter 4 (Glut4) and carnitine acyltransferase I (CPT1) for β-oxidation of fatty acids are reduced. Mitochondria are the metabolic organelles for glucose and fatty acids. The mitochondrial membrane potential (MMP) and ATP production were decreased, while the ROS level was elevated in the cells treated with PA and HG, indicating an induction of mitochondrial disorder . Cell loss was partially rescued by ferroptosis inhibition, suggesting an involvement of ferroptosis in the cells treated with PA and HG. More importantly, the increases in total iron, lipid ROS, MDA and COX-2, and the decrease in ferroptosis inhibitory molecules GSH, GPX4 and FSP1 appeared in the cells treated with PA and HG, confirming the occurrence of ferroptosis. Moreover, PINK1/parkin-mediated mitophagy , a vital process for selective elimination of damaged mitochondria, was blocked. Interestingly, silibinin rescued the mitochondria, restricted the ferroptosis and restored the mitophagy. By using the pharmacological stimulator and inhibitor of mitophagy, and si-RNA transfection to silence PINK1 expression, silibinin's protective effect against ferroptosis caused by PA and HG treatment was found to depend on mitophagy. Collectively, our current study reveals the new mechanisms for the protection of silibinin against the injury of INS-1 cells treated with PA and HG, elucidates the participation of ferroptosis in glucolipotoxicity, highlighting the involvement of mitophagy in defense against ferroptotic cell death.
研究领域:
糖尿病
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细胞生物学
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药理学
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生物化学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2016
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IF 2.937
Ramachandran Vinayagam,Baojun Xu
Background and objective Daphnetin (7, 8-dihydroxycoumarin), a natural coumarin compound, is known to exhibit antioxidant and anti-inflammatrory effects. However, the underlying mechanisms of its anti-apoptotic and antidiabetic effects yet not been examined. Therefore, the present work studied the anti-apoptotic and anti-diabetic effects of daphnetin by in vitro experiments. Methods The rat insulinoma (INS-1) cells were pre-treated with daphnetin at different concentrations (1, 10, 20 and 40 µM) for 24 h followed by exposition to streptozotocin (STZ) (3 mM) for 12 h. Effects of daphnetin and STZ on INS-1 cells were determined by MTT assay, glucose stimulated insulin secretion (GSIS) assay, lipid peroxidation, antioxidant status (SOD, CAT, GPx, and GST) Apoptosis staining (DAPI, Hoechst 33342, AO/EB and ROS) was performed by fluorescence microscopy, and Bcl-2, Bax and NF-κB protein expression was detected by Western blotting. Results MTT assay indicated that the viability of INS-1 cells was significantly reduced with exposure to STZ for 12 h as compared to control cells, while pre-treated with daphnetin for 24 h resulted in a significant improvement of cell viability. The effects daphnetin treatment in INS-1 cells on insulin secretion was tested and results showed that the pre-treatment of daphnetin could improve GSIS. Further, daphnetin pre-treatment significantly reduced the levels of lipid peroxidation markers and also improved antioxidant enzymes’ activities in STZ-induced INS-1 cells. Western blotting assay revealed that daphnetin could suppress apoptosis through up-regulation of anti-apoptotic Bcl-2 protein expression and the down-regulation of pro-apoptotic Bax and nuclear factor NF-κB protein levels. Conclusion The results showed that daphnetin might be used in treating diabetes due to its insulin stimulating property and subsequent regulation of apoptotic pathway.
研究领域:
药理学
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内分泌学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
Genes & Genomics
·
2022
·Vol. 44
·期 7
·867-878
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IF 2.164
Li Mo,She Jiang,Ma Louyan,Ma Li,Ma Xiaorui,Zhai Jiajia
Background Destruction of pancreatic beta cells is the most typical characteristic of diabetes. Objective We aimed to evaluate the effect of berberine (BBR), a bioactive isoquinoline derivative alkaloid, on beta cell injury. Methods Rodent pancreatic beta cell line INS-1 was treated with 0.5 mM palmitate (PA) for 24 h to establish an in vitro beta cell injury model. Results BBR at 5 µM promoted cell viability, inhibited cell apoptosis and enhanced insulin secretion in PA-induced INS-1 cells. BBR treatment also suppressed PA-induced oxidative stress in INS-1 cells, as evidenced by the decreased ROS production and increased activities of antioxidant enzymes. In addition, suppressed ATP production and reduced mitochondrial membrane potential were restored by BBR in PA-treated INS-1 cells. It was further determined that BBR affected the expressions of mitophagy-associated proteins, suggesting that BBR promoted mitophagy in PA-exposed INS-1 cells. Meanwhile, we found that BBR facilitated nuclear expression and DNA-binding activity of Nrf2, an antioxidative protein that can regulate mitophagy. Finally, a rescue experiment was performed and the results demonstrated that the effect of BBR on cell viability, apoptosis and mitochondrial function in PA-induced INS-1 cells were cancelled by PINK1 knockdown. Conclusions BBR protects islet β cells from PA-induced injury, and this protective effect may be achieved by regulating mitophagy. The present study may provide a novel therapeutic strategy for β cell injury in diabetes mellitus.
研究领域:
药理学
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细胞生物学
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糖尿病
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Endocrine Connections
·
2019
·Vol. 8
·期 1
·8-19
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IF 2.474
Shan Wu,Jianjun Zhou,Jing Guo,Zhan Hua,Jianchen Li,Zai Wang
Angiogenesis has a pivotal role in the growth and metastasis of pancreatic neuroendocrine tumors (PNETs). Apatinib inhibits angiogenesis as a highly selective KDR inhibitor and has been used to treat advanced gastric cancer and malignancies in clinical settings. However, the efficacy of apatinib in PNETs remains unclear. The aim of this study was to compare the antitumor efficacy of apatinib with that of the standard PNET drug sunitinib in our subcutaneous and liver metastasis models of insulinoma and non-functional PNET. Our results revealed that apatinib had a generally comparable or even superior antitumor effect to that of sunitinib on primary PNET, and it inhibited angiogenesis without directly causing tumor cell cytotoxicity. Apatinib inhibited the tumor in a dose-dependent manner, and the high dose was well tolerated in mice. We also found that the apatinib efficacy in liver metastasis models was cell-type (disease) selective. Although apatinib efficiently inhibited INR1G9-represented non-functional PNET liver metastasis, it led to the emergence of a hypoxic area in the INS-1-represented insulinoma and promoted liver metastasis. Our study demonstrated that apatinib has promise for clinical applications in certain malignant PNETs, and the application of anti-angiogenesis drugs to benign insulinomas may require careful consideration. Angiogenesis has a pivotal role in the growth and metastasis of pancreatic neuroendocrine tumors (PNETs). Apatinib inhibits angiogenesis as a highly selective KDR inhibitor and has been used to treat advanced gastric cancer and malignancies in clinical settings. However, the efficacy of apatinib in PNETs remains unclear. The aim of this study was to compare the antitumor efficacy of apatinib with that of the standard PNET drug sunitinib in our subcutaneous and liver metastasis models of insulinoma and non-functional PNET. Our results revealed that apatinib had a generally comparable or even superior antitumor effect to that of sunitinib on primary PNET, and it inhibited angiogenesis without directly causing tumor cell cytotoxicity. Apatinib inhibited the tumor in a dose-dependent manner, and the high dose was well tolerated in mice. We also found that the apatinib efficacy in liver metastasis models was cell-type (disease) selective. Although apatinib efficiently inhibited INR1G9-represented non-functional PNET liver metastasis, it led to the emergence of a hypoxic area in the INS-1-represented insulinoma and promoted liver metastasis. Our study demonstrated that apatinib has promise for clinical applications in certain malignant PNETs, and the application of anti-angiogenesis drugs to benign insulinomas may require careful consideration.
研究领域:
肿瘤学
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药理学
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分子生物学
✓ 已验证
DOI
PubMed
高影响因子
BIOMEDICINE & PHARMACOTHERAPY
·
2023
·
IF 7.5
Baiyi Yan,Yanchun Gong,Wei Meng,Huizhen Sun,Wenxi Li,Kaizhi Ding,Caixia Dang,Xiaofei Gao,Wei Sun,Chunhua Yuan,Songhua Wang,Li-Hua Yao
Type 2 diabetes mellitus (T2DM) is a common and multiple endocrine metabolic disease. When pancreatic β cell in case of dysfunction, the synthesis and secretion of insulin are reduced. This study is to explore the effect of cordycepin (the molecular formula C 10 H 13 N 5 O 3 ), a natural adenosine isolated from Cordyceps militaris , on high glucose/lipid-induced glucotoxicity and lipotoxicity in INS-1 cells. Our results showed that cordycepin improved cell viability, improved cell energy metabolism and promoted insulin synthesis and secretion. The mechanism may be related to that cordycepin reduces intracellular reactive oxygen species (ROS), increases ATP content in cells, causes membrane depolarization and balances the steady state of Ca 2+ concentration, cordycepin inhibits cell apoptosis, which may be related to the downregulation of proteins level of c-Jun N-terminal kinases (JNK) phosphorylation, cytochrome c (Cyt-c), Cleaved Capase-3, the mRNA level of JNK, Cyt-c, Capase-3 and upregulation of proteins/mRNA level of pancreatic and duodenal homeobox factor-1 (PDX-1). These results suggest that cordycepin can inhibit cell apoptosis and protect cell number by downregulating ROS/JNK mitochondrial apoptosis pathway under high glucose/lipid environment, thereby improving the function of pancreatic islet cells, providing a theoretical basis for the related research on the prevention and control of cordycepin on T2DM.
研究领域:
内分泌学
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代谢学
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药理学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
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2022
·
IF 8.025
Yanna Pan,Shilin Yuan,Yilong Teng,Zeng Zhang,Yanming He,Ying Zhang,Haohui Liang,Xiao Wu,Jiaqi Li,Hongjie Yang,Ping Zhou
Oxidative stress is one of the major factors in induction of pancreatic β-cell apoptosis and diabetes. Here, we investigated systematically the roles of a proteoglycan (namely, FYGL ) from Ganoderma lucidum in protection and repair of pancreatic β-cells against oxidative stress-induced injury and apoptosis on molecular, cellular and animal basis. FYGL in vitro had antioxidant activity in terms of scavenging of free radicals and reduction power. FYGL improved cells viability, insulin secretion, redox indicator expressions, and mitochondrial membrane potential in H 2 O 2 -induced INS-1 cell via regulating the activations of apoptosis-related mitogen-activated protein kinases (MAPK) and nuclear factor kappa B (NF-κB) pathways as well as the insulin secretion-related pathway. Thrillingly in vivo , FYGL repaired the injured pancreas, reduced the pancreatic β-cells apoptosis, and improved insulin secretion because of regulating the balance of oxidation-reduction, therefore well managed blood glucose in db/db diabetic mice. These results demonstrated that FYGL is promising to be used as a novel natural remedy for protection of pancreatic β-cells against oxidative stress in diabetes treatment.
研究领域:
药理学
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糖尿病
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细胞生物学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Scientific Reports
·
2017
·Vol. 7
·期 1
·1-11
·
IF 4.259
Ma Jie,Li Huan,Hu Xiangnan,Yang Lu,Chen Qi,Hu Congli,Chen Zhihao,Tian Xiaoyan,Yang Yang,Luo Ying,Gan Run,Yang Junqing
Dipeptidyl peptidase IV (DPP-IV) inhibitor has been expected to be a new class of anti-diabetic agent. The present study was designed to characterize the pharmacological profiles of CMD-05, a novel DPP-IV inhibitor discovered in our laboratory, in vitro and in vivo . The IC 50 of CMD-05 on DPP-IV inhibitory activity was approximately 12 nM while vildagliptin was 3.5 nM in vitro . In diabetes rat model established by high fat diet/low dose streptozotocin, CMD-05 inhibited DPP-IV activity, significantly improved glucose tolerance, increased GLP-1 and insulin levels in plasma. Long-term administration of CMD-05 decreased HbA1c and TG levels and improved the islet function without significantly effect on body weight. Furthermore, CMD-05 reduced INS-1 cell apoptosis and increased GLP-1 secretion in NCI-H716. After oral administration, CMD-05 reached peak concentration at 30 min with half-life of 288 minutes and the inhibitory rate of DPP-IV greater than 50% lasted for 15 h. In fasted normal rats, CMD-05 didn’t cause significant hypoglycemia. CMD-05 had a lower cytotoxicity than vildagliptin in vitro and its maximum tolerance dose in mice is beyond 2000 mg/kg. These results indicated that CMD-05 has similar activity with vildagliptin in vivo and has a much longer half-life and lower cytotoxicity than vildagliptin.
研究领域:
药理学
·
内分泌学
·
糖尿病研究
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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