Pub Date : 2024-09-25DOI: 10.1016/j.bcp.2024.116556
Ting Chen , Dacheng Bai , Changyong Gong , Yu Cao , Xiaoqing Yan , Renyi Peng
Diabetes induces a pro-aging state characterized by an increased abundance of senescent cells in various tissues, heightened chronic inflammation, reduced substance and energy metabolism, and a significant increase in intracellular reactive oxygen species (ROS) levels. This condition leads to mitochondrial dysfunction, including elevated oxidative stress, the accumulation of mitochondrial DNA (mtDNA) damage, mitophagy defects, dysregulation of mitochondrial dynamics, and abnormal energy metabolism. These dysfunctions result in intracellular calcium ion (Ca2+) homeostasis disorders, telomere shortening, immune cell damage, and exacerbated inflammation, accelerating the aging of diabetic cells or tissues. Hydrogen sulfide (H2S), a novel gaseous signaling molecule, plays a crucial role in maintaining mitochondrial function and mitigating the aging process in diabetic cells. This article systematically explores the specific mechanisms by which H2S regulates diabetes-induced mitochondrial dysfunction to delay cellular senescence, offering a promising new strategy for improving diabetes and its complications.
{"title":"Hydrogen sulfide mitigates mitochondrial dysfunction and cellular senescence in diabetic patients: Potential therapeutic applications","authors":"Ting Chen , Dacheng Bai , Changyong Gong , Yu Cao , Xiaoqing Yan , Renyi Peng","doi":"10.1016/j.bcp.2024.116556","DOIUrl":"10.1016/j.bcp.2024.116556","url":null,"abstract":"<div><div>Diabetes induces a pro-aging state characterized by an increased abundance of senescent cells in various tissues, heightened chronic inflammation, reduced substance and energy metabolism, and a significant increase in intracellular reactive oxygen species (ROS) levels. This condition leads to mitochondrial dysfunction, including elevated oxidative stress, the accumulation of mitochondrial DNA (mtDNA) damage, mitophagy defects, dysregulation of mitochondrial dynamics, and abnormal energy metabolism. These dysfunctions result in intracellular calcium ion (Ca<sup>2+</sup>) homeostasis disorders, telomere shortening, immune cell damage, and exacerbated inflammation, accelerating the aging of diabetic cells or tissues. Hydrogen sulfide (H<sub>2</sub>S), a novel gaseous signaling molecule, plays a crucial role in maintaining mitochondrial function and mitigating the aging process in diabetic cells. This article systematically explores the specific mechanisms by which H<sub>2</sub>S regulates diabetes-induced mitochondrial dysfunction to delay cellular senescence, offering a promising new strategy for improving diabetes and its complications.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"230 ","pages":"Article 116556"},"PeriodicalIF":5.3,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142340417","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-25DOI: 10.1016/j.bcp.2024.116554
Zhizhong Luo , Yuqing Liu , Xin Wang , Faxin Fan , Zhenzhen Yang , Duosheng Luo
The rapidly rising prevalence of metabolic diseases has turned them into an escalating global health concern. By producing or altering metabolic products, the gut microbiota plays a pivotal role in maintaining human health and influencing disease development. These metabolites originate from the host itself or the external environment. In the system of interactions between microbes and the host, tryptophan (Trp) plays a central role in metabolic processes. As the amino acid in the human body that must be obtained through dietary intake, it is crucial for various physiological functions. Trp can be metabolized in the gut into three main products: The gut microbiota regulates the transformation of 5-hydroxytryptamine (5-HT, serotonin), kynurenine (Kyn), and various indole derivatives. It has been revealed that a substantial correlation exists between alterations in Trp metabolism and the initiation and progression of metabolic disorders, including obesity, diabetes, non-alcoholic fatty liver disease, and atherosclerosis, but Trp metabolites have not been comprehensively reviewed in metabolic diseases. As such, this review summarizes and analyzes the latest research, emphasizing the importance of further studying Trp metabolism within the gut microbiota to understand and treat metabolic diseases. This carries potential significance for improving human health and may introduce new therapeutic strategies.
{"title":"Exploring tryptophan metabolism: The transition from disturbed balance to diagnostic and therapeutic potential in metabolic diseases","authors":"Zhizhong Luo , Yuqing Liu , Xin Wang , Faxin Fan , Zhenzhen Yang , Duosheng Luo","doi":"10.1016/j.bcp.2024.116554","DOIUrl":"10.1016/j.bcp.2024.116554","url":null,"abstract":"<div><div>The rapidly rising prevalence of metabolic diseases has turned them into an escalating global health concern. By producing or altering metabolic products, the gut microbiota plays a pivotal role in maintaining human health and influencing disease development. These metabolites originate from the host itself or the external environment. In the system of interactions between microbes and the host, tryptophan (Trp) plays a central role in metabolic processes. As the amino acid in the human body that must be obtained through dietary intake, it is crucial for various physiological functions. Trp can be metabolized in the gut into three main products: The gut microbiota regulates the transformation of 5-hydroxytryptamine (5-HT, serotonin), kynurenine (Kyn), and various indole derivatives. It has been revealed that a substantial correlation exists between alterations in Trp metabolism and the initiation and progression of metabolic disorders, including obesity, diabetes, non-alcoholic fatty liver disease, and atherosclerosis, but Trp metabolites have not been comprehensively reviewed in metabolic diseases. As such, this review summarizes and analyzes the latest research, emphasizing the importance of further studying Trp metabolism within the gut microbiota to understand and treat metabolic diseases. This carries potential significance for improving human health and may introduce new therapeutic strategies.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"230 ","pages":"Article 116554"},"PeriodicalIF":5.3,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142340414","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-25DOI: 10.1016/j.bcp.2024.116555
Aldana Magalí Gola , María Bucci-Muñoz , Juan Pablo Rigalli , María Paula Ceballos , María Laura Ruiz
The insulin-like growth factor-2 mRNA-binding protein 1 (IGF2BP1), a member of a conserved family of single-stranded RNA-binding proteins (IGF2BP1-3), is expressed in a broad range of fetal tissues, placenta and more than sixteen cancer types but only in a limited number of normal adult tissues. IGF2BP1is required for the transport from nucleus to cytoplasm of certain mRNAs that play essential roles in embryogenesis, carcinogenesis, and multidrug resistance (MDR), by affecting their stability, translation, or localization. The purpose of this review is to gather and present information on MDR mechanisms in cancer and the significance of IGF2BP1 in this context. Within this review, we will provide an overview of IGF2BP1, including its tissue distribution, expression, molecular targets in the context of tumorigenesis and its inhibitors. Our main focus will be on elucidating the interplay between IGF2BP1 and MDR, particularly with regard to chemoresistance mediated by ABC transporters.
{"title":"Role of the RNA binding protein IGF2BP1 in cancer multidrug resistance","authors":"Aldana Magalí Gola , María Bucci-Muñoz , Juan Pablo Rigalli , María Paula Ceballos , María Laura Ruiz","doi":"10.1016/j.bcp.2024.116555","DOIUrl":"10.1016/j.bcp.2024.116555","url":null,"abstract":"<div><div>The insulin-like growth factor-2 mRNA-binding protein 1 (IGF2BP1), a member of a conserved family of single-stranded RNA-binding proteins (IGF2BP1-3), is expressed in a broad range of fetal tissues, placenta and more than sixteen cancer types but only in a limited number of normal adult tissues. IGF2BP1is required for the transport from nucleus to cytoplasm of certain mRNAs that play essential roles in embryogenesis, carcinogenesis, and multidrug resistance (MDR), by affecting their stability, translation, or localization. The purpose of this review is to gather and present information on MDR mechanisms in cancer and the significance of IGF2BP1 in this context. Within this review, we will provide an overview of IGF2BP1, including its tissue distribution, expression, molecular targets in the context of tumorigenesis and its inhibitors. Our main focus will be on elucidating the interplay between IGF2BP1 and MDR, particularly with regard to chemoresistance mediated by ABC transporters.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"230 ","pages":"Article 116555"},"PeriodicalIF":5.3,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142340415","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-25DOI: 10.1016/j.bcp.2024.116558
Gia Cac Chau , Ji Eun Lim , Kyeongwon Moon , In Su Kim , Sung Hee Um
Indole derivatives exhibit a broad spectrum of beneficial effects, encompassing anti-inflammatory, antiviral, antimalarial, anti-diabetic, antioxidant, anti-hepatitis, and antidepressant properties. Here, we describe the potentiation of insulin secretion in pancreatic islets and INS-1 cells through methyl 2-(2-ethoxy-1-hydroxy-2-oxoethyl)-1-(pyrimidine-2-yl)-1H-indole-3-carboxylate (HI 129), a novel indole derivative. Treatment with HI 129 led to notably decreased ADP/ATP ratios in pancreatic islets and INS-1 cells compared to those in the vehicle-treated controls, indicating a shift in cellular ATP production. Moreover, the augmentation of insulin secretion by HI 129 was closely correlated with its ability to enhance the mitochondrial membrane potential and respiration, partly by reducing the phosphorylation levels of AMP-activated protein kinase (AMPK). Mechanistically, HI 129 enhanced the association between AMPK and β-arrestin-1, critical molecules for glucose-induced insulin secretion. Furthermore, β-arrestin-1 depletion attenuated the effect of HI 129 on glucose-induced insulin secretion, suggesting that HI 129 potentiates insulin secretion via β-arrestin-1/AMPK signaling. These results collectively underscore the potential of HI 129 in enhancing insulin secretion as a novel candidate for improving glucose homeostasis in type 2 diabetes.
吲哚衍生物具有广泛的有益作用,包括抗炎、抗病毒、抗疟、抗糖尿病、抗氧化、抗肝炎和抗抑郁等特性。在这里,我们描述了新型吲哚衍生物 2-(2-乙氧基-1-羟基-2-氧代乙基)-1-(嘧啶-2-基)-1H-吲哚-3-羧酸甲酯(HI 129)对胰岛和 INS-1 细胞胰岛素分泌的增效作用。用 HI 129 治疗后,胰岛和 INS-1 细胞中的 ADP/ATP 比率与用药物治疗的对照组相比明显下降,这表明细胞 ATP 的产生发生了变化。此外,HI 129 对胰岛素分泌的促进作用与它增强线粒体膜电位和呼吸的能力密切相关,部分原因是它降低了 AMP 激活蛋白激酶(AMPK)的磷酸化水平。从机制上讲,HI 129 增强了 AMPK 与β-arrestin-1(葡萄糖诱导胰岛素分泌的关键分子)之间的关联。此外,β-arrestin-1 的耗竭减弱了 HI 129 对葡萄糖诱导的胰岛素分泌的影响,这表明 HI 129 可通过 β-arrestin-1/AMPK 信号转导增强胰岛素分泌。这些结果共同强调了 HI 129 在增强胰岛素分泌方面的潜力,是改善 2 型糖尿病患者血糖稳态的新型候选药物。
{"title":"The stimulatory effect of HI 129, a novel indole derivative, on glucose-induced insulin secretion","authors":"Gia Cac Chau , Ji Eun Lim , Kyeongwon Moon , In Su Kim , Sung Hee Um","doi":"10.1016/j.bcp.2024.116558","DOIUrl":"10.1016/j.bcp.2024.116558","url":null,"abstract":"<div><div>Indole derivatives exhibit a broad spectrum of beneficial effects, encompassing anti-inflammatory, antiviral, antimalarial, anti-diabetic, antioxidant, anti-hepatitis, and antidepressant properties. Here, we describe the potentiation of insulin secretion in pancreatic islets and INS-1 cells through methyl 2-(2-ethoxy-1-hydroxy-2-oxoethyl)-1-(pyrimidine-2-yl)-1<em>H</em>-indole-3-carboxylate (HI 129), a novel indole derivative. Treatment with HI 129 led to notably decreased ADP/ATP ratios in pancreatic islets and INS-1 cells compared to those in the vehicle-treated controls, indicating a shift in cellular ATP production. Moreover, the augmentation of insulin secretion by HI 129 was closely correlated with its ability to enhance the mitochondrial membrane potential and respiration, partly by reducing the phosphorylation levels of AMP-activated protein kinase (AMPK). Mechanistically, HI 129 enhanced the association between AMPK and β-arrestin-1, critical molecules for glucose-induced insulin secretion. Furthermore, β-arrestin-1 depletion attenuated the effect of HI 129 on glucose-induced insulin secretion, suggesting that HI 129 potentiates insulin secretion via β-arrestin-1/AMPK signaling. These results collectively underscore the potential of HI 129 in enhancing insulin secretion as a novel candidate for improving glucose homeostasis in type 2 diabetes.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"230 ","pages":"Article 116558"},"PeriodicalIF":5.3,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142340416","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-24DOI: 10.1016/j.bcp.2024.116559
Xiaotong Wang , Xin Li , Xu Zhang , Xuekun Wang , Jie Yang , Guoyun Liu
The latest global cancer data statistics report shows that cancer poses a serious threat to human life and health; The number of new cancer and death cases worldwide is severe. Molecular hybridization is considered an effective strategy for developing new anti-cancer drugs. Curcumin (Cur) is a natural active compound containing Michael receptors that target thioredoxin reductase (TrxR). Fluorouracil (5-FU) is the first anti-metabolic drug synthesized based on certain assumptions for tumor treatment, acting on thymidylate synthase (TS). This study synthesized a series of novel hybrid derivatives of Cur and 5-FU, and evaluated their anti-tumor cell proliferation effects. Several compounds with good cytotoxic activity against tumor cells were discovered; and they exhibited high selectivity towards A549 cells, compared to normal THLE cells. Among them, the hybrid derivative F-4 has the best anti-proliferative activity in tumor cells. F-4 can target TrxR, increase reactive oxygen species levels in tumor cells, and lead to tumor cell apoptosis, which may be related to the Michael receptor structure in the chemical structure of F-4; F-4 can also target TS, leading to cell cycle arrest in G0/G1 phase, which may be related to the 5-FU structure in the chemical structure of F-4. Moreover, F-4 can effectively exert anti-tumor activity in mice, significantly reduce tumor volume and weight, and has low toxic side effects. These results indicate that Cur-5-FU hybrid derivative F-4 is a novel lead compound with in vivo anti-tumor activity and minimal side effects, which deserves further investigation.
{"title":"Design, synthesis and biological evaluation of novel curcumin-fluorouracil hybrids as potential anti-cancer agents","authors":"Xiaotong Wang , Xin Li , Xu Zhang , Xuekun Wang , Jie Yang , Guoyun Liu","doi":"10.1016/j.bcp.2024.116559","DOIUrl":"10.1016/j.bcp.2024.116559","url":null,"abstract":"<div><div>The latest global cancer data statistics report shows that cancer poses a serious threat to human life and health; The number of new cancer and death cases worldwide is severe. Molecular hybridization is considered an effective strategy for developing new anti-cancer drugs. Curcumin (Cur) is a natural active compound containing Michael receptors that target thioredoxin reductase (TrxR). Fluorouracil (5-FU) is the first anti-metabolic drug synthesized based on certain assumptions for tumor treatment, acting on thymidylate synthase (TS). This study synthesized a series of novel hybrid derivatives of Cur and 5-FU, and evaluated their anti-tumor cell proliferation effects. Several compounds with good cytotoxic activity against tumor cells were discovered; and they exhibited high selectivity towards A549 cells, compared to normal THLE cells. Among them, the hybrid derivative <strong>F-4</strong> has the best anti-proliferative activity in tumor cells. <strong>F-4</strong> can target TrxR, increase reactive oxygen species levels in tumor cells, and lead to tumor cell apoptosis, which may be related to the Michael receptor structure in the chemical structure of <strong>F-4</strong>; <strong>F-4</strong> can also target TS, leading to cell cycle arrest in G0/G1 phase, which may be related to the 5-FU structure in the chemical structure of <strong>F-4</strong>. Moreover, <strong>F-4</strong> can effectively exert anti-tumor activity in mice, significantly reduce tumor volume and weight, and has low toxic side effects. These results indicate that Cur-5-FU hybrid derivative <strong>F-4</strong> is a novel lead compound with <em>in vivo</em> anti-tumor activity and minimal side effects, which deserves further investigation.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"230 ","pages":"Article 116559"},"PeriodicalIF":5.3,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142340413","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Microglia, a widely dispersed cohort of immune cells in the retina, are intricately involved in a diverse range of pivotal biological processes, including inflammation, vascular development, complement activation, antigen presentation, and phagocytosis. Within the retinal milieu, microglia are crucial for the clearance of dead cells and cellular debris, release of anti-inflammatory agents, and orchestration of vascular network remodeling to maintain homeostasis. In addition, microglia are key mediators of neuroinflammation. Triggered by oxidative stress, elevated intraocular pressure, genetic anomalies, and immune dysregulation, microglia release numerous inflammatory cytokines, contributing to the pathogenesis of various retinal disorders. Recent studies on the ontogeny and broad functions of microglia in the retina have elucidated their characteristics during retinal development, homeostasis, and disease. Furthermore, therapeutic strategies that target microglia and their effector cytokines have been developed and shown positive results for some retinal diseases. Therefore, we systematically review the microglial ontogeny in the retina, elucidate their dual roles in retinal homeostasis and disease pathogenesis, and demonstrate microglia-based targeted therapeutic strategies for retinal diseases.
{"title":"Microglia in retinal diseases: From pathogenesis towards therapeutic strategies","authors":"Ruihan Xiao , Xi Huang , Sheng Gao , Jianan Duan , Yun Zhang , Meixia Zhang","doi":"10.1016/j.bcp.2024.116550","DOIUrl":"10.1016/j.bcp.2024.116550","url":null,"abstract":"<div><div>Microglia, a widely dispersed cohort of immune cells in the retina, are intricately involved in a diverse range of pivotal biological processes, including inflammation, vascular development, complement activation, antigen presentation, and phagocytosis. Within the retinal milieu, microglia are crucial for the clearance of dead cells and cellular debris, release of anti-inflammatory agents, and orchestration of vascular network remodeling to maintain homeostasis. In addition, microglia are key mediators of neuroinflammation. Triggered by oxidative stress, elevated intraocular pressure, genetic anomalies, and immune dysregulation, microglia release numerous inflammatory cytokines, contributing to the pathogenesis of various retinal disorders. Recent studies on the ontogeny and broad functions of microglia in the retina have elucidated their characteristics during retinal development, homeostasis, and disease. Furthermore, therapeutic strategies that target microglia and their effector cytokines have been developed and shown positive results for some retinal diseases. Therefore, we systematically review the microglial ontogeny in the retina, elucidate their dual roles in retinal homeostasis and disease pathogenesis, and demonstrate microglia-based targeted therapeutic strategies for retinal diseases.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"230 ","pages":"Article 116550"},"PeriodicalIF":5.3,"publicationDate":"2024-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142279985","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Mitochondrial dysfunction is associated with hyperglycemic conditions and insulin resistance leading to cellular damage and apoptosis of cardiomyocytes in diabetic cardiomyopathy. The dysregulation of glucagon-like peptide-1 (GLP-1) receptor and mammalian target of rapamycin (mTOR) is linked to cardiomyopathies and myocardial dysfunctions mediated by hyperglycemia. However, the involvements of mTOR for GLP-1 receptor-mediated cardioprotection against high glucose (HG)-induced mitochondrial disturbances are not clearly identified. The present study demonstrated that HG-induced cellular stress and mitochondrial damage resulted in impaired ATP production and oxidative defense markers such as catalase and SOD2, along with a reduction in survival markers such as Bcl-2 and p-Akt, while an increased expression of pro-apoptotic marker Bax was observed in H9c2 cardiomyoblasts. In addition, the autophagic marker LC3-II was considerably reduced, together with the disruption of autophagy regulators (p-mTOR and p-AMPKα) under the hyperglycemic state. Furthermore, there was a dysregulated expression of several indicators related to mitochondrial homeostasis, including MFN2, p-DRP1, FIS1, MCU, UCP3, and Parkin. Remarkably, treatment with either exendin-4 (GLP-1 receptor agonist) or rapamycin (mTOR inhibitor) significantly inhibited HG-induced mitochondrial damage while co-treatment of exendin-4 and rapamycin completely reversed all mitochondrial abnormalities. Antagonism of GLP-1 receptors using exendin-(9–39) abolished these cardioprotective effects of exendin-4 and rapamycin under HG conditions. In addition, exendin-4 attenuated HG-induced phosphorylation of mTOR, and this inhibitory effect was antagonized by exendin-(9–39), indicating the regulation of mTOR by GLP-1 receptor. Therefore, improvement of mitochondrial dysfunction by stimulating the GLP-1 receptor/AMPK/Akt pathway and inhibiting mTOR signaling could ameliorate cardiac abnormalities caused by hyperglycemic conditions.
{"title":"Exendin-4 exhibits cardioprotective effects against high glucose-induced mitochondrial abnormalities: Potential role of GLP-1 receptor and mTOR signaling","authors":"Warisara Parichatikanond , Sudhir Pandey , Supachoke Mangmool","doi":"10.1016/j.bcp.2024.116552","DOIUrl":"10.1016/j.bcp.2024.116552","url":null,"abstract":"<div><div>Mitochondrial dysfunction is associated with hyperglycemic conditions and insulin resistance leading to cellular damage and apoptosis of cardiomyocytes in diabetic cardiomyopathy. The dysregulation of glucagon-like peptide-1 (GLP-1) receptor and mammalian target of rapamycin (mTOR) is linked to cardiomyopathies and myocardial dysfunctions mediated by hyperglycemia. However, the involvements of mTOR for GLP-1 receptor-mediated cardioprotection against high glucose (HG)-induced mitochondrial disturbances are not clearly identified. The present study demonstrated that HG-induced cellular stress and mitochondrial damage resulted in impaired ATP production and oxidative defense markers such as catalase and SOD2, along with a reduction in survival markers such as Bcl-2 and p-Akt, while an increased expression of pro-apoptotic marker Bax was observed in H9c2 cardiomyoblasts. In addition, the autophagic marker LC3-II was considerably reduced, together with the disruption of autophagy regulators (p-mTOR and p-AMPKα) under the hyperglycemic state. Furthermore, there was a dysregulated expression of several indicators related to mitochondrial homeostasis, including MFN2, p-DRP1, FIS1, MCU, UCP3, and Parkin. Remarkably, treatment with either exendin-4 (GLP-1 receptor agonist) or rapamycin (mTOR inhibitor) significantly inhibited HG-induced mitochondrial damage while co-treatment of exendin-4 and rapamycin completely reversed all mitochondrial abnormalities. Antagonism of GLP-1 receptors using exendin-(9–39) abolished these cardioprotective effects of exendin-4 and rapamycin under HG conditions. In addition, exendin-4 attenuated HG-induced phosphorylation of mTOR, and this inhibitory effect was antagonized by exendin-(9–39), indicating the regulation of mTOR by GLP-1 receptor. Therefore, improvement of mitochondrial dysfunction by stimulating the GLP-1 receptor/AMPK/Akt pathway and inhibiting mTOR signaling could ameliorate cardiac abnormalities caused by hyperglycemic conditions.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"229 ","pages":"Article 116552"},"PeriodicalIF":5.3,"publicationDate":"2024-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142279980","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-20DOI: 10.1016/j.bcp.2024.116551
Yan-Ting Wang , Lan-Tian Liu , Bo Hou , Chun-Meng Yao , Xu-Fang Wang , Bin Lu
With the abuse of antibiotics, multidrug resistant strains continue to emerge and spread rapidly. Therefore, there is an urgent need to develop new antimicrobial drugs. As a highly conserved cell division protein in bacteria, filamenting temperature-sensitive mutant Z (FtsZ) has been identified as a potential antimicrobial target. This paper reviews the structure, function, and action mechanism of FtsZ and a variety of natural and synthetic compounds targeting FtsZ, including 3-MBA derivatives, taxane derivatives, cinnamaldehyde, curcumin, quinoline and quinazoline derivatives, aromatic compounds, purpurin, and totarol. From these studies, FtsZ has a clear supporting role in the field of antimicrobial drug discovery. The urgent need and interest of antibacterial drugs will contribute to the discovery of new clinical drugs targeting FtsZ.
{"title":"Recent advances in studies on FtsZ inhibitors","authors":"Yan-Ting Wang , Lan-Tian Liu , Bo Hou , Chun-Meng Yao , Xu-Fang Wang , Bin Lu","doi":"10.1016/j.bcp.2024.116551","DOIUrl":"10.1016/j.bcp.2024.116551","url":null,"abstract":"<div><div>With the abuse of antibiotics, multidrug resistant strains continue to emerge and spread rapidly. Therefore, there is an urgent need to develop new antimicrobial drugs. As a highly conserved cell division protein in bacteria, filamenting temperature-sensitive mutant Z (FtsZ) has been identified as a potential antimicrobial target. This paper reviews the structure, function, and action mechanism of FtsZ and a variety of natural and synthetic compounds targeting FtsZ, including 3-MBA derivatives, taxane derivatives, cinnamaldehyde, curcumin, quinoline and quinazoline derivatives, aromatic compounds, purpurin, and totarol. From these studies, FtsZ has a clear supporting role in the field of antimicrobial drug discovery. The urgent need and interest of antibacterial drugs will contribute to the discovery of new clinical drugs targeting FtsZ.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"230 ","pages":"Article 116551"},"PeriodicalIF":5.3,"publicationDate":"2024-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142279986","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-19DOI: 10.1016/j.bcp.2024.116549
Yaoyuan Tong , Xiaoru Wang , Ruonan Li , Xiangyu Xu , Mengge Dai , Nan Wang , Boyi Fan , Siqi Feng , Ting Ma
As the first discovered histone demethylase, LSD1 plays a vital role in maintaining pathological processes such as cancer, infection, and immune diseases. Based on previous researches, LSD1 is highly expressed in sorts of tumor cells such as acute myeloid leukemia, non-small cell lung cancer, prostate cancer, breast cancer and gastric cancer, etc. Therefore, targeting LSD1 is a prospective strategy for tumor treatment. Cancer stem cells could preserve self-renewal, cell proliferation, cell migration and malignant phenotype. So, the reduction of tumor cell stemness can effectively inhibit the growth of tumor cells, which may be a new strategy for the treatment of cancers. Up to now, there exist many researches confirming the significant role of LSD1 in regulating the stemness characteristics such as embryonic stem cells differentiation. Many reports show that inhibition of LSD1 effectively decreases the property of cancer cell stemness. However, there lacks a detailed review about the relationship between LSD1 and cancer cell stemness. Herein, in this review, we summarized the mechanisms how LSD1 regulates cell stemness comprehensively. In addition, some related inhibitors targeting LSD1 to reduce the proliferation characteristics of cancer stem cells are also described.
{"title":"LSD1 is a promising target to treat cancers by modulating cell stemness","authors":"Yaoyuan Tong , Xiaoru Wang , Ruonan Li , Xiangyu Xu , Mengge Dai , Nan Wang , Boyi Fan , Siqi Feng , Ting Ma","doi":"10.1016/j.bcp.2024.116549","DOIUrl":"10.1016/j.bcp.2024.116549","url":null,"abstract":"<div><div>As the first discovered histone demethylase, LSD1 plays a vital role in maintaining pathological processes such as cancer, infection, and immune diseases. Based on previous researches, LSD1 is highly expressed in sorts of tumor cells such as acute myeloid leukemia, non-small cell lung cancer, prostate cancer, breast cancer and gastric cancer, etc. Therefore, targeting LSD1 is a prospective strategy for tumor treatment. Cancer stem cells could preserve self-renewal, cell proliferation, cell migration and malignant phenotype. So, the reduction of tumor cell stemness can effectively inhibit the growth of tumor cells, which may be a new strategy for the treatment of cancers. Up to now, there exist many researches confirming the significant role of LSD1 in regulating the stemness characteristics such as embryonic stem cells differentiation. Many reports show that inhibition of LSD1 effectively decreases the property of cancer cell stemness. However, there lacks a detailed review about the relationship between LSD1 and cancer cell stemness. Herein, in this review, we summarized the mechanisms how LSD1 regulates cell stemness comprehensively. In addition, some related inhibitors targeting LSD1 to reduce the proliferation characteristics of cancer stem cells are also described.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"229 ","pages":"Article 116549"},"PeriodicalIF":5.3,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142279983","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-19DOI: 10.1016/j.bcp.2024.116543
Calvin Dunker , Laura Vinnenberg , Andreas Isaak , Elif Karabatak , Petra Hundehege , Thomas Budde , Kazuhiro Murakami , Anna Junker
The development of in vitro pharmacological assays relies on creating genetically modified cell lines that overexpress the target protein of interest. However, the choice of the host cell line can significantly impact the experimental outcomes. This study explores the functional characterization of P2X7 and P2X4 receptor modulators through cellular assays and advanced electrophysiological techniques. The influence of different host cell lines (HEK-293, HEK-293FT, and 1321N1) on the activity of reference agonists and antagonists targeting human and murine P2X4 and P2X7 receptors was systematically investigated, highlighting the significant impact of the host cell on experimental results. The 1321N1 cell line was identified as the preferred host cell line when investigating the human P2X4 receptor due to more consistent agonist activities, antagonist potencies, and a more stable assay signal window. Furthermore, a patch-clamp protocol that allows for the repetitive recording of ATP-mediated inward currents from isolated human CD4+ T-cells was established, revealing that both P2X7 and P2X4 receptors are crucial for immune cell regulation, positioning them as promising therapeutic targets for managing inflammatory disorders.
{"title":"Exploring P2X receptor activity: A journey from cellular impact to electrophysiological profiling","authors":"Calvin Dunker , Laura Vinnenberg , Andreas Isaak , Elif Karabatak , Petra Hundehege , Thomas Budde , Kazuhiro Murakami , Anna Junker","doi":"10.1016/j.bcp.2024.116543","DOIUrl":"10.1016/j.bcp.2024.116543","url":null,"abstract":"<div><div>The development of in vitro pharmacological assays relies on creating genetically modified cell lines that overexpress the target protein of interest. However, the choice of the host cell line can significantly impact the experimental outcomes. This study explores the functional characterization of P2X7 and P2X4 receptor modulators through cellular assays and advanced electrophysiological techniques. The influence of different host cell lines (HEK-293, HEK-293FT, and 1321N1) on the activity of reference agonists and antagonists targeting human and murine P2X4 and P2X7 receptors was systematically investigated, highlighting the significant impact of the host cell on experimental results. The 1321N1 cell line was identified as the preferred host cell line when investigating the human P2X4 receptor due to more consistent agonist activities, antagonist potencies, and a more stable assay signal window. Furthermore, a patch-clamp protocol that allows for the repetitive recording of ATP-mediated inward currents from isolated human CD4+ T-cells was established, revealing that both P2X7 and P2X4 receptors are crucial for immune cell regulation, positioning them as promising therapeutic targets for managing inflammatory disorders.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"229 ","pages":"Article 116543"},"PeriodicalIF":5.3,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142279981","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}