Type 2 diabetes mellitus(T2DM)is a lifelong condition and a threat to human health.Thorough understanding of its pathogenesis is acutely needed in order to devise innovative,preventative,and potentially curative pharm...Type 2 diabetes mellitus(T2DM)is a lifelong condition and a threat to human health.Thorough understanding of its pathogenesis is acutely needed in order to devise innovative,preventative,and potentially curative pharmacological interventions.MicroRNAs(miRNA),are small,non-coding,one-stranded RNA molecules,that can target and silence around 60%of all human genes through translational repression.MiR-155 is an ancient,evolutionarily well-conserved miRNA,with distinct expression profiles and multifunctionality,and a target repertoire of over 241 genes involved in numerous physiological and pathological processes including hematopoietic lineage differentiation,immunity,inflammation,viral infections,cancer,cardiovascular conditions,and particularly diabetes mellitus.MiR-155 Levels are progressively reduced in aging,obesity,sarcopenia,and T2DM.Thus,the loss of coordinated repression of multiple miR-155 targets acting as negative regulators,such as C/EBPβ,HDAC4,and SOCS1 impacts insulin signaling,deteriorating glucose homeostasis,and causing insulin resistance(IR).Moreover,deranged regulation of the renin angiotensin aldosterone system(RAAS)through loss of Angiotensin II Type 1 receptor downregulation,and negated repression of ETS-1,results in unopposed detrimental Angiotensin II effects,further promoting IR.Finally,loss of BACH1 and SOCS1 repression abolishes cytoprotective,anti-oxidant,anti-apoptotic,and anti-inflam matory cellular pathways,and promotesβ-cell loss.In contrast to RAAS inhibitor treatments that further decrease already reduced miR-155 Levels,strategies to increase an ailing miR-155 production in T2DM,e.g.,the use of metformin,mineralocorticoid receptor blockers(spironolactone,eplerenone,finerenone),and verapamil,alone or in various combinations,represent current treatment options.In the future,direct tissue delivery of miRNA analogs is likely.展开更多
Angiotensin Ⅱ (ANGⅡ) plays an important role in the pathogenesis of atherosclerosis by inducing proliferation of vascular smooth muscle cells (VSMCs).In our study,we observed the effects of valsartan on proliferatio...Angiotensin Ⅱ (ANGⅡ) plays an important role in the pathogenesis of atherosclerosis by inducing proliferation of vascular smooth muscle cells (VSMCs).In our study,we observed the effects of valsartan on proliferation of cultured VSMCs treated with or without ANGⅡ by cell counting and methyl thiazolyl tetrazolium (MTT) assay,and detected the expression of mitofusin 2 (Mfn2),a newly discovered cell proliferation inhibitor and a related cell proliferation signaling pathway pro-tein by Western blotting.ANGⅡ at a concentration of 10-6 mol/L significantly stimulated VSMCs proliferation,down-regulated the expression of Mfn2 and upregulated the expression of Raf and ERK1/2.Valsartan inhibited such effects of ANGⅡ at concentrations of 10-5 and 10-6 mol/L,but not at 10-7 mol/L.Valsartan had no significant effect on the proliferation of untreated VSMCs.These results suggest that valsartan inhibits ANGⅡ-induced proliferation of VSMCs in vitro via Mfn2-Ras-Raf-ERK/MAPK signaling pathway.展开更多
The emergence of coronavirus disease-2019 induced by a newly identified bcoronavirus, namely severe acute respiratory syndrome coronavirus 2(SARSCoV-2) has constituted a public health emergency. Even though it was con...The emergence of coronavirus disease-2019 induced by a newly identified bcoronavirus, namely severe acute respiratory syndrome coronavirus 2(SARSCoV-2) has constituted a public health emergency. Even though it was considered a zoonotic disease, the virus has also spread among humans via respiratory secretions. The expression and distribution of angiotensin converting enzyme type 2(ACE2) in various human organs might also show other possible infection routes. High ACE2 ribonucleic acid expression has been identified in the gastrointestinal tract(GI) indicating its importance as a possible infection pathway of SARS-CoV-2. ACE2 induces viral entry into the host and most importantly has been found to be associated with the function of the gut. Its deficiency has been implicated in several pathologies such as colorectal inflammation. The renin-angiotensin system(RAS) is an essential regulatory cascade operating both at a local tissue level and at the systemic or circulatory level. The RAS may be important in the pathogenesis of chronic liver disease and is associated with the up-regulation of ACE2. Thus, the aim of this review is firstly, the analysis of some important general and genome characteristics of SARS-CoV-2 and secondly, and most importantly, to focus on the utility of ACE2 receptors in both SARS-CoV-2 replication and pathogenesis, especially in the GI tract.展开更多
Objective The main purpose of this study was to investigate whether the folliculo stellate cells (FSC) respond to angiotensin(Ang)Ⅱ by increasing intracellular free Ca 2+ concentration ([Ca 2+ ]i),and where the origi...Objective The main purpose of this study was to investigate whether the folliculo stellate cells (FSC) respond to angiotensin(Ang)Ⅱ by increasing intracellular free Ca 2+ concentration ([Ca 2+ ]i),and where the origin of Ca 2+ mobilization is if that has occurred.Methods Pituitary cells in primary culture were prepared from male Wister rats(250g) by a conventional method and cultured in MEM supplemented with 4% normal rat serum.After 2 days in culutre,cells were loaded with 1 μmol/L fura PE3/AM for 1 h and subjected to a Ca 2+ imaging experiment with Quanti Cell 700 system.Excitation wavelengths of 340 and 380 nm were selected by means of a computer controlled filterwheel.Results The [Ca 2+ ]i of FSC in the rat anterior pituitary was elevated by Ang Ⅱ.The elevation of [Ca 2+ ]i of FSC induced by 0.1,1.0,10 and 100 nmol/L Ang Ⅱ was (56.33±6.18)( ±s ),(117.07±36.07),(175.59±40.01) and (216.02±11.52) nmol/L,respectively.The increase of [Ca 2+ ]i of FSC induced by 100 nmol/L Ang Ⅱ was not influenced by the medium without Ca 2+ (0Ca),but significantly suppressed by thapsigargin(TG),an inhibitor of ATPase.The rate of responsive FSC to Ang Ⅱ (100 nmol/L) was 61.84% which was obviously higher than that of pituitary endocrine cells(43.49%).Conclusion The present experiment demonstrates that the FSC in the rat anterior pituitary responds to Ang Ⅱ by increasing [Ca 2+ ]i,which raises the possibility that Ang Ⅱ released from either lactotrophs or gonadotrophs affects FSC through paracrine mechanism.The elevation of [Ca 2+ ]i induced by Ang Ⅱ presents a dosage dependent relation, and is possibly because of the release of Ca 2+ from an intracellular Ca 2+ pool(s).Fashions of Ca 2+ release are relative to the concentration of Ang Ⅱ.The results indicate that Ang Ⅱ functions as a paracrine factor among pituitary cells including FSC.展开更多
Background: Breast cancer is the most common type of cancer among women. Diagnosed and treated timely, patients may have good prognostics. In Brazil, in 2012, the estimate of new cases was 52,680 and the number of reg...Background: Breast cancer is the most common type of cancer among women. Diagnosed and treated timely, patients may have good prognostics. In Brazil, in 2012, the estimate of new cases was 52,680 and the number of registered deaths in 2012 was 12,852. The Renin-Angiotensin System (RAS) is known for its role in arterial hypertension and in other cardiovascular diseases. Angiotensin-Converting Enzyme 2 (ACE2) is the key to Ang-(1-7) formation, and counterbalances the ACE1/AngII/AGTR1 axis actions. RAS components have complex interactions with different tissues and their actions are not restricted to the cardiovascular system. Recently, the RAS has been associated with different types of cancers and in particular with gynecological cancers. Objectives: Our aim is to investigate possible associations between allelic distribution of two genetic polymorphisms in the AGTR2 receptor with ACEs 1 and 2 plasma levels among women with breast cancer. Patients and Methods: Patients with breast cancer were genotyped for two polymorphisms of the AGTR2 (T1247G and A5235G). Genotyping assays (TaqMan) were performed with genomic DNA extracted from blood cells. ACEs plasma level measurements were conducted in women from the breast-cancer group (N = 53). ACEs were measured in the plasma of these patients using ELISA kits. Results: SNPs genotype distribution is correlated with ACEs plasma levels. ACEs plasma levels are also correlated with clinical variables and ACE2 high levels are associated with better prognostics. Conclusions: Changes in circulating levels of ECA1/AngII ECA2/ Ang-(1-7) determine the magnitude of the inflammatory response that an individual can trigger and the variation in ACE 1 and 2 plasma level measurements in the blood of breast cancer patients suggests an association with the process of mammary carcinogenesis. Thus, the RAS may be associated with the process of mammary carcinogenesis by both genotypic variations of RAS components and by circulating levels of ACEs.展开更多
文摘Type 2 diabetes mellitus(T2DM)is a lifelong condition and a threat to human health.Thorough understanding of its pathogenesis is acutely needed in order to devise innovative,preventative,and potentially curative pharmacological interventions.MicroRNAs(miRNA),are small,non-coding,one-stranded RNA molecules,that can target and silence around 60%of all human genes through translational repression.MiR-155 is an ancient,evolutionarily well-conserved miRNA,with distinct expression profiles and multifunctionality,and a target repertoire of over 241 genes involved in numerous physiological and pathological processes including hematopoietic lineage differentiation,immunity,inflammation,viral infections,cancer,cardiovascular conditions,and particularly diabetes mellitus.MiR-155 Levels are progressively reduced in aging,obesity,sarcopenia,and T2DM.Thus,the loss of coordinated repression of multiple miR-155 targets acting as negative regulators,such as C/EBPβ,HDAC4,and SOCS1 impacts insulin signaling,deteriorating glucose homeostasis,and causing insulin resistance(IR).Moreover,deranged regulation of the renin angiotensin aldosterone system(RAAS)through loss of Angiotensin II Type 1 receptor downregulation,and negated repression of ETS-1,results in unopposed detrimental Angiotensin II effects,further promoting IR.Finally,loss of BACH1 and SOCS1 repression abolishes cytoprotective,anti-oxidant,anti-apoptotic,and anti-inflam matory cellular pathways,and promotesβ-cell loss.In contrast to RAAS inhibitor treatments that further decrease already reduced miR-155 Levels,strategies to increase an ailing miR-155 production in T2DM,e.g.,the use of metformin,mineralocorticoid receptor blockers(spironolactone,eplerenone,finerenone),and verapamil,alone or in various combinations,represent current treatment options.In the future,direct tissue delivery of miRNA analogs is likely.
基金supported by grants from the National Natural Science Foundation of China (No. 30872714 and No.30971244)
文摘Angiotensin Ⅱ (ANGⅡ) plays an important role in the pathogenesis of atherosclerosis by inducing proliferation of vascular smooth muscle cells (VSMCs).In our study,we observed the effects of valsartan on proliferation of cultured VSMCs treated with or without ANGⅡ by cell counting and methyl thiazolyl tetrazolium (MTT) assay,and detected the expression of mitofusin 2 (Mfn2),a newly discovered cell proliferation inhibitor and a related cell proliferation signaling pathway pro-tein by Western blotting.ANGⅡ at a concentration of 10-6 mol/L significantly stimulated VSMCs proliferation,down-regulated the expression of Mfn2 and upregulated the expression of Raf and ERK1/2.Valsartan inhibited such effects of ANGⅡ at concentrations of 10-5 and 10-6 mol/L,but not at 10-7 mol/L.Valsartan had no significant effect on the proliferation of untreated VSMCs.These results suggest that valsartan inhibits ANGⅡ-induced proliferation of VSMCs in vitro via Mfn2-Ras-Raf-ERK/MAPK signaling pathway.
文摘The emergence of coronavirus disease-2019 induced by a newly identified bcoronavirus, namely severe acute respiratory syndrome coronavirus 2(SARSCoV-2) has constituted a public health emergency. Even though it was considered a zoonotic disease, the virus has also spread among humans via respiratory secretions. The expression and distribution of angiotensin converting enzyme type 2(ACE2) in various human organs might also show other possible infection routes. High ACE2 ribonucleic acid expression has been identified in the gastrointestinal tract(GI) indicating its importance as a possible infection pathway of SARS-CoV-2. ACE2 induces viral entry into the host and most importantly has been found to be associated with the function of the gut. Its deficiency has been implicated in several pathologies such as colorectal inflammation. The renin-angiotensin system(RAS) is an essential regulatory cascade operating both at a local tissue level and at the systemic or circulatory level. The RAS may be important in the pathogenesis of chronic liver disease and is associated with the up-regulation of ACE2. Thus, the aim of this review is firstly, the analysis of some important general and genome characteristics of SARS-CoV-2 and secondly, and most importantly, to focus on the utility of ACE2 receptors in both SARS-CoV-2 replication and pathogenesis, especially in the GI tract.
基金Present address:Departm ent of PhysiologyMedical College of Xi'an Jiaotong University+1 种基金Xi'an 710 0 6 1China
文摘Objective The main purpose of this study was to investigate whether the folliculo stellate cells (FSC) respond to angiotensin(Ang)Ⅱ by increasing intracellular free Ca 2+ concentration ([Ca 2+ ]i),and where the origin of Ca 2+ mobilization is if that has occurred.Methods Pituitary cells in primary culture were prepared from male Wister rats(250g) by a conventional method and cultured in MEM supplemented with 4% normal rat serum.After 2 days in culutre,cells were loaded with 1 μmol/L fura PE3/AM for 1 h and subjected to a Ca 2+ imaging experiment with Quanti Cell 700 system.Excitation wavelengths of 340 and 380 nm were selected by means of a computer controlled filterwheel.Results The [Ca 2+ ]i of FSC in the rat anterior pituitary was elevated by Ang Ⅱ.The elevation of [Ca 2+ ]i of FSC induced by 0.1,1.0,10 and 100 nmol/L Ang Ⅱ was (56.33±6.18)( ±s ),(117.07±36.07),(175.59±40.01) and (216.02±11.52) nmol/L,respectively.The increase of [Ca 2+ ]i of FSC induced by 100 nmol/L Ang Ⅱ was not influenced by the medium without Ca 2+ (0Ca),but significantly suppressed by thapsigargin(TG),an inhibitor of ATPase.The rate of responsive FSC to Ang Ⅱ (100 nmol/L) was 61.84% which was obviously higher than that of pituitary endocrine cells(43.49%).Conclusion The present experiment demonstrates that the FSC in the rat anterior pituitary responds to Ang Ⅱ by increasing [Ca 2+ ]i,which raises the possibility that Ang Ⅱ released from either lactotrophs or gonadotrophs affects FSC through paracrine mechanism.The elevation of [Ca 2+ ]i induced by Ang Ⅱ presents a dosage dependent relation, and is possibly because of the release of Ca 2+ from an intracellular Ca 2+ pool(s).Fashions of Ca 2+ release are relative to the concentration of Ang Ⅱ.The results indicate that Ang Ⅱ functions as a paracrine factor among pituitary cells including FSC.
文摘Background: Breast cancer is the most common type of cancer among women. Diagnosed and treated timely, patients may have good prognostics. In Brazil, in 2012, the estimate of new cases was 52,680 and the number of registered deaths in 2012 was 12,852. The Renin-Angiotensin System (RAS) is known for its role in arterial hypertension and in other cardiovascular diseases. Angiotensin-Converting Enzyme 2 (ACE2) is the key to Ang-(1-7) formation, and counterbalances the ACE1/AngII/AGTR1 axis actions. RAS components have complex interactions with different tissues and their actions are not restricted to the cardiovascular system. Recently, the RAS has been associated with different types of cancers and in particular with gynecological cancers. Objectives: Our aim is to investigate possible associations between allelic distribution of two genetic polymorphisms in the AGTR2 receptor with ACEs 1 and 2 plasma levels among women with breast cancer. Patients and Methods: Patients with breast cancer were genotyped for two polymorphisms of the AGTR2 (T1247G and A5235G). Genotyping assays (TaqMan) were performed with genomic DNA extracted from blood cells. ACEs plasma level measurements were conducted in women from the breast-cancer group (N = 53). ACEs were measured in the plasma of these patients using ELISA kits. Results: SNPs genotype distribution is correlated with ACEs plasma levels. ACEs plasma levels are also correlated with clinical variables and ACE2 high levels are associated with better prognostics. Conclusions: Changes in circulating levels of ECA1/AngII ECA2/ Ang-(1-7) determine the magnitude of the inflammatory response that an individual can trigger and the variation in ACE 1 and 2 plasma level measurements in the blood of breast cancer patients suggests an association with the process of mammary carcinogenesis. Thus, the RAS may be associated with the process of mammary carcinogenesis by both genotypic variations of RAS components and by circulating levels of ACEs.
