RESUMO
Airway remodeling is a cardinal feature of asthma, associated with increased airway smooth muscle (ASM) cell mass and upregulation of extracellular matrix deposition. Exaggerated ASM cell migration contributes to excessive ASM mass. Previously, we demonstrated the alleviating role of Kp (kisspeptin) receptor (KISS1R) activation by Kp-10 in mitogen (PDGF [platelet-derived growth factor])-induced human ASM cell proliferation in vitro and airway remodeling in vivo in a mouse model of asthma. Here, we examined the mechanisms by which KISS1R activation regulates mitogen-induced ASM cell migration. KISS1R activation using Kp-10 significantly inhibited PDGF-induced ASM cell migration, further confirmed using KISS1R shRNA. Furthermore, KISS1R activation modulated F/G actin dynamics and the expression of promigration proteins like CDC42 (cell division control protein 42) and cofilin. Mechanistically, we observed reduced ASM RhoA-GTPAse with KISS1R activation. The antimigratory effect of KISS1R was abolished by PKA (protein kinase A)-inhibitory peptide. Conversely, KISS1R activation significantly increased cAMP and phosphorylation of CREB (cAMP-response element binding protein) in PDGF-exposed ASM cells. Overall, these results highlight the alleviating properties of Kp-10 in the context of airway remodeling.
Assuntos
Movimento Celular , Kisspeptinas , Miócitos de Músculo Liso , Fator de Crescimento Derivado de Plaquetas , Receptores de Kisspeptina-1 , Transdução de Sinais , Proteína rhoA de Ligação ao GTP , Humanos , Movimento Celular/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/efeitos dos fármacos , Kisspeptinas/metabolismo , Fator de Crescimento Derivado de Plaquetas/metabolismo , Fator de Crescimento Derivado de Plaquetas/farmacologia , Receptores de Kisspeptina-1/metabolismo , Receptores de Kisspeptina-1/genética , Proteína rhoA de Ligação ao GTP/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Proteína cdc42 de Ligação ao GTP/metabolismo , Remodelação das Vias Aéreas , AMP Cíclico/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Células Cultivadas , Fatores de Despolimerização de Actina/metabolismo , Actinas/metabolismo , Proliferação de CélulasRESUMO
Airway smooth muscle cell (ASM) is renowned for its involvement in airway hyperresponsiveness through impaired ASM relaxation and bronchoconstriction in asthma, which poses a significant challenge in the field. Recent studies have explored different targets in ASM to alleviate airway hyperresponsiveness, however, a sizeable portion of patients with asthma still experience poor control. In our study, we explored protein phosphatase 2 A (PP2A) in ASM as it has been reported to regulate cellular contractility by controlling intracellular calcium ([Ca2+]i), ion channels, and respective regulatory proteins. We obtained human ASM cells and lung tissues from healthy and patients with asthma and evaluated PP2A expression using RNA-Seq data, immunofluorescence, and immunoblotting. We further investigated the functional importance of PP2A by determining its role in bronchoconstriction using mouse bronchus and human ASM cell [Ca2+]i regulation. We found robust expression of PP2A isoforms in human ASM cells with PP2Aα being highly expressed. Interestingly, PP2Aα was significantly downregulated in asthmatic tissue and human ASM cells exposed to proinflammatory cytokines. Functionally, FTY720 (PP2A agonist) inhibited acetylcholine- or methacholine-induced bronchial contraction in mouse bronchus and further potentiated isoproterenol-induced bronchial relaxation. Mechanistically, FTY720 inhibited histamine-evoked [Ca2+]i response and myosin light chain (MLC) phosphorylation in the presence of interleukin-13 (IL-13) in human ASM cells. To conclude, we for the first time established PP2A signaling in ASM, which can be further explored to develop novel therapeutics to alleviate airway hyperresponsiveness in asthma.NEW & NOTEWORTHY This novel study deciphered the expression and function of protein phosphatase 2Aα (PP2Aα) in airway smooth muscle (ASM) during asthma and/or inflammation. We showed robust expression of PP2Aα in human ASM while its downregulation in asthmatic ASM. Similarly, we demonstrated reduced PP2Aα expression in ASM exposed to proinflammatory cytokines. PP2Aα activation inhibited bronchoconstriction of isolated mouse bronchi. In addition, we unveiled that PP2Aα activation inhibits the intracellular calcium release and myosin light chain phosphorylation in human ASM.
Assuntos
Asma , Broncoconstrição , Regulação para Baixo , Miócitos de Músculo Liso , Proteína Fosfatase 2 , Asma/metabolismo , Asma/patologia , Humanos , Proteína Fosfatase 2/metabolismo , Proteína Fosfatase 2/genética , Animais , Camundongos , Regulação para Baixo/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Miócitos de Músculo Liso/efeitos dos fármacos , Broncoconstrição/efeitos dos fármacos , Músculo Liso/metabolismo , Músculo Liso/patologia , Músculo Liso/efeitos dos fármacos , Masculino , Brônquios/patologia , Brônquios/metabolismo , Brônquios/efeitos dos fármacos , Cálcio/metabolismo , Feminino , Camundongos Endogâmicos C57BLRESUMO
BACKGROUND: Diabetic cardiomyopathy (DCM) is an age-related disease, and its progression is accompanied by hyperglycaemia, cardiac dysfunction, and myocardial structural and functional abnormalities. Cissus quadrangularis, a traditional medicinal plant, contains polyphenols, flavonoids, phytosterols, carbohydrates and ascorbic acid. It is used to treat osteoporosis, asthma, haemorrhoids and menstrual disorders.Objective: In the current research, we have investigated the effect of ethanolic extract of C. quadrangularis (EECQ) against a high-fat diet (HFD)/streptozotocin-induced DCM by estimating cardiac biomarkers, inflammatory markers and Reactive oxygen species (ROS) production. MATERIAL AND METHODS: Rats were fed with an HFD for 12 weeks, followed by single-shot low-dose streptozotocin (35 mg/kg; i.p.). The treatment was performed by EECQ (200 mg/kg/day, orally) for six weeks. RESULTS: The extract EECQ improves glucose, insulin tolerance tests and hypercholesteremia. DCM is characterized by cardiac dysfunction, cardiac biomarkers CKMB and LDH, which were attenuated by the EECQ treatment. The hypertrophic biomarker ANP, BNP expression and cardiomyocyte surface area were decreased by EECQ. Moreover, EECQ also alleviated the biomarkers Angiotensin II and renin level. EECQ also reduced oxidative stress, ROS production and cardiac inflammation. CONCLUSIONS: Thus, these findings suggested that EECQ could be used as a possible therapeutic regiment to treat DCM.
Cissus quadrangularis ameliorates hyperglycaemia, hyperinsulinemia and hyperlipidaemia.Cissus quadrangularis mitigates cardiac dysfunction.Cissus quadrangularis decreases RAAS activation, thereby down-regulates ANP, BNP expression.Cissus quadrangularis alleviates ROS propagated oxidative stress and apoptosis.
Assuntos
Cissus , Diabetes Mellitus , Cardiomiopatias Diabéticas , Ratos , Animais , Cissus/química , Estreptozocina/farmacologia , Cardiomiopatias Diabéticas/tratamento farmacológico , Espécies Reativas de Oxigênio , Sistema Renina-Angiotensina , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Estresse Oxidativo , Inflamação/tratamento farmacológico , Etanol/farmacologia , Diabetes Mellitus/tratamento farmacológicoRESUMO
BACKGROUND: Endothelial dysfunction is related to the reduced bioavailability of nitric oxide (NO) and plays a significant role in developing hypertension. The intake of a diet rich in antioxidants decreases the threat of hypertension. Cissus quadrangularis possesses antioxidant, anti-inflammatory, and hypocholesterolemic activities. However, to date, no studies have been performed to explore this plant's antihypertensive and vasorelaxant activity. Herein, we investigated the chronic effect of C. quadrangularis on blood pressure as well as vascular function in hypertensive rats. METHODS: Male spontaneously hypertensive rats (SHR) were randomly divided into two groups. Normotensive Wistar rats were taken as the control group. The treatment was done using ethanolic extract of C. quadrangularis (EECQ) at a dose of 200 mg/kg. RESULTS: The administration of EECQ for six weeks reduced the systolic blood pressure, mean arterial blood pressure, and heart rate. It also alleviated the cardiac and renal hypertrophy indices. Supplementation of EECQ improved the endothelium-dependent aortic vasodilation induced by acetylcholine. It restored the NO level and endothelial NO synthase expression in the aorta. Subsequently, the extract alleviates the oxidative stress and inflammatory markers in SHR rats. CONCLUSION: Thus, in the present study, the chronic treatment of EECQ to genetically hypertensive rats improved endothelium-dependent relaxation in addition to its antihypertensive effect by eNOS activation and inhibition of ROS production, inflammation.
Assuntos
Cissus , Hipertensão , Animais , Cissus/metabolismo , Endotélio Vascular/metabolismo , Hipertensão/tratamento farmacológico , Hipertensão/metabolismo , Masculino , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Estresse Oxidativo , Extratos Vegetais/farmacologia , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Ratos Wistar , VasodilataçãoRESUMO
Hesperidin possesses myriads of pharmacological benefits, including anti-inflammatory and antioxidant properties. Herein, we speculated that the described pharmacological benefits of hesperidin might be due to its potentiating action on SIRT1; thereby, inhibition of NOX4. We developed diabetic neuropathy in Sprague-Dawley rats by feeding them a high-fat diet (HFD) for 12 weeks. We checked the effect of hesperidin on the level of oxidative stress, inflammatory markers, NOX4, and SIRT1 by biochemical analysis, histopathology, immunoblotting, immunocytochemistry, and real-time qPCR in HFD-fed rats and Palmitate encountered rat glial C6 cells. Hesperidin administration improved mechanical, thermal allodynia, and glucose homeostasis. There was a decrease in oxidative stress and inflammation and an enhanced level of antioxidant enzymes. Besides, the expression of NOX4 was down-regulated, while SIRT1 was upregulated. Interestingly, hesperidin treatment protected them from oxidative and inflammatory damage by upregulating SIRT1 and inhibiting NOX4 expression.
Assuntos
Diabetes Mellitus , Neuropatias Diabéticas , Hesperidina , Ratos , Animais , Antioxidantes/metabolismo , Hesperidina/farmacologia , Sirtuína 1/metabolismo , Neuropatias Diabéticas/tratamento farmacológico , Ratos Sprague-Dawley , Estresse Oxidativo , Inflamação/tratamento farmacológico , Dieta Hiperlipídica/efeitos adversos , NADPH Oxidase 4/genéticaRESUMO
Hepatic steatosis is an important mstetabolic complication in women encountering postmenopausal phase of life. Pancreastatin (PST), has previously been investigated in diabetic and insulin resistant rodents. The present study highlighted the role of PST in ovariectomized rats. Female SD rats were ovariectomized and subsequently fed high fructose diet for 12 weeks. PST inhibitor peptide was intraperitoneally administered for 14 days and further examined for insulin resistance, glucose intolerance development, body mass composition, lipid profile detection and hepatic fibrosis. Gut microbial alterations has also been investigated. Results showed development of glucose intolerance in high fructose fed ovariectomized rats with reduced level of reproductive hormones including estradiol and progesterone. Enhanced lipid production was detected in these rats as they showed increased triglycerides, lipid accumulation in liver tissue (determined by HE staining, Oil Red O staining, Nile Red staining). Sirius Red and Masson's trichome analysis depicted positive results for fibrosis development. We also found gut microbiota alterations in fecal samples of these rats. Furthermore, PST inhibition decreased the expression of hepatic Fetuin B and resumed gut microbial diversity. PST deregulates hepatic lipid metabolism which leads to altered expression of Fetuin B in liver and gut dysbiosis in postmenopausal rats.
Assuntos
Intolerância à Glucose , Metabolismo dos Lipídeos , Animais , Feminino , Humanos , Ratos , Dieta Hiperlipídica , Fetuína-B/metabolismo , Frutose/metabolismo , Lipídeos , Fígado/metabolismo , Ratos Sprague-DawleyRESUMO
Recent studies have focused on exploring the efficacy of Cissus quadrangularis extract (EECQ) against various metabolic disorders involving the liver as the prime target organ, suggesting a considerable threat of hepatotoxicity in the person encountering it. Consequently, the current study was aimed to unravel the mutagenic, cytotoxic, mitochondrial dysfunction, apoptotic activity in HepG2 cells, and acute toxicity of EECQ. MTT, SRB, trypan blue dye exclusion, and lactate dehydrogenase (LDH) assay were performed in HepG2 cell lines to determine the cytotoxicity of the extract. The mutagenic potential was determined by the Ames test using various strains of Salmonella typhimurium. Acute toxicity was done at a dose of 2000 mg/kg in Sprague Dawley rats. MTT and SRB cytotoxicity assays demonstrated dose-dependent cytotoxicity of extract. The three highest noncytotoxic doses from the above assay, investigated by trypan blue dye exclusion and LDH assay, did not reveal cytotoxicity. Besides, mitochondrial dysfunction was determined by measuring cellular and mitochondrial ROS, ATP, NAD, mitochondrial membrane potential, Bax/Bcl2 ratio, mitochondrial and cytoplasmic cytochrome c, and apoptosis-inducing factor, were found to be equivalent in both extract exposed and unexposed cells. Moreover, the apoptotic cell morphology and the expression of pro-apoptotic mRNAs and proteins were equivalent in both the group. In acute toxicity, EECQ in rats did not cause any significant change in body weight, liver index, and liver function test. All-encompassing, the present study unraveled that EECQ is not mutagenic, cytotoxic, nor apoptotic in human hepatic cells, as well as neither acute toxicity.
Assuntos
Cissus , Ratos , Humanos , Animais , Mutagênicos , Azul Tripano/farmacologia , Extratos Vegetais/toxicidade , Ratos Sprague-Dawley , Etanol , MitocôndriasRESUMO
Insulin resistance (IR) is a significant complication in menopausal women, which predisposes them to cardiovascular disorder, obesity, and diabetes. Cissus quadrangularis is a polyphenolic plant rich in nutrients and is used as an edible vegetable in Nigeria. Previously, we investigated that C. quadrangularis extract (EECQ) treatment ameliorates IR, hyperlipidemia, and overweight in diabetic rats. Accordingly, in the current study, we further evaluated the adiponectin mimetic activity of EECQ in peri-/post-menopausal rats. Perimenopause was induced by High-fat diet/4-vinylcyclohexenediepoxide/(HFD-VCD), while postmenopause was by HFD/bilateral ovariectomy (HFD-OVX). Both the menopausal rats demonstrated an abnormal level of sex hormones, IR, hyperlipidemia, increased fat mass, and abnormal weight gain. Nevertheless, EECQ treated group revealed protection from these untoward complications. Furthermore, the docking score of major constituents of EECQ on adiponectin receptor 1 (AdipoR1) depicted a strong binding affinity, which was comparable to the ligand adipoRon. Besides, AdipoR1 expression determined by RT-PCR, Western blotting, and immunohistochemistry was downregulated in peri-/post-menopausal rats. Similarly, the expression of AdipoR1 downstream marker APPL1 and insulin sensitivity markers, including IRS1, Akt1, and GLUT4, were also dysregulated in menopausal rats. However, EECQ treated rats manifested restoration of normal expression of APPL1, IRS1, Akt1, and GLUT4 by upregulating AdipoR1. Altogether, the current study promulgated the adiponectin mimetic activity of EECQ, which is substantial to mitigate IR in menopausal conditions.
Assuntos
Cissus , Diabetes Mellitus Experimental , Resistência à Insulina , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Adiponectina/metabolismo , Animais , Diabetes Mellitus Experimental/metabolismo , Resistência à Insulina/fisiologia , Proteínas do Tecido Nervoso/metabolismo , Extratos Vegetais/farmacologia , Pós-Menopausa , Ratos , Receptores de Adiponectina/metabolismoRESUMO
OBJECTIVES: Hyperglycemia-induced SIRT1, DNMT1, SODs, as well as oxidative stress, play a pivotal role in the progression of diabetic nephropathy. Cissus quadrangularis, holds antioxidant and hypoglycemic activity; however, a direct link between its activity and prevention of diabetic nephropathy has not been ascertained yet. Accordingly, we aimed to delineate the protective effect of ethanolic extract of Cissus quadrangularis (EECQ) against high-fat diet/streptozotocin (HFD/STZ) induced diabetic nephropathy rats. METHODS: The control group was fed with a normal chow diet. Rats kept on an HFD for 12 weeks with a single low dose of STZ manifested the features of diabetic nephropathy. The treatment was done by the oral administration of EECQ (200 mg/kg) for six weeks (six rats in each group). KEY FINDINGS: Treatment with EECQ demonstrated substantial attenuation of elevated insulin resistance, lipid profile and creatinine level. Additionally, EECQ restored albuminuria, glomerular filtration rate and creatinine clearance in diabetic nephropathy rats. Furthermore, HFD consumption in rats culminated in reduced SIRT1 and enhanced DNMT1 expression, nonetheless, rescued by EECQ. Moreover, EECQ augmented the SOD 1 and 3 levels, thereby safeguarded from oxidative damage and renal inflammation. Besides, treatment protected from renal fibrosis by downregulating TGFß, Smad2/3 and col1/3 expression in diseased rats. CONCLUSIONS: Thus, based on the above findings, we conclude that EECQ shows a protective effect against diabetic nephropathy.
Assuntos
Cissus , Diabetes Mellitus Experimental/metabolismo , Nefropatias Diabéticas/metabolismo , Rim/efeitos dos fármacos , Extratos Vegetais/farmacologia , Proteínas Repressoras/metabolismo , Sirtuína 1/metabolismo , Albuminúria , Animais , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Creatinina/sangue , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/patologia , Nefropatias Diabéticas/prevenção & controle , Dieta Hiperlipídica , Taxa de Filtração Glomerular , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Inflamação , Resistência à Insulina , Rim/metabolismo , Rim/patologia , Lipídeos/sangue , Masculino , Estresse Oxidativo/efeitos dos fármacos , Fitoterapia , Extratos Vegetais/uso terapêutico , Ratos Sprague-Dawley , Proteínas Smad Reguladas por Receptor/metabolismo , Superóxido Dismutase/metabolismo , Fator de Crescimento Transformador beta/metabolismoRESUMO
AIMS: Pancreastatin (PST) is a crucial bioactive peptide derived from chromogranin A (CHGA) proprotein that exhibits an anti-insulin effect on adipocytes. Herein, we investigated the effects of PST on brown adipose tissues (BAT) and white adipose tissue (WAT) in connection with uncoupling protein-1 (UCP-1) regulated energy expenditure in high fructose diet (HFrD) fed and vinylcyclohexenediepoxide (VCD) induced perimenopausal rats. MATERIAL AND METHODS: We administered VCD in rats for 17 consecutive days and fed HFrd for 12 weeks. After 12 weeks estradiol and progesterone levels were detected. Furthermore, detection of glucose tolerance, insulin sensitivity, and body composition revealed impaired glucose homeostasis and enhanced PST levels. Effects of enhanced PST on UCP-1 level in BAT and WAT of perimenopausal rats were further investigated. KEY FINDINGS: Reduced serum estradiol, progesterone, and attenuated insulin response confirmed perimenopausal model development. Furthermore, enhanced PST serum level and its increased expression in BAT and WAT downregulated the UCP-1 expression. Subsequently, impaired ATP level, NADP/NADPH ratio, citrate synthase activity, enhanced mitochondrial reactive oxygen species (ROS) generation and perturbed mitochondrial membrane potential, further exacerbated mitochondrial dysfunction, cellular ROS production, and promoted apoptosis. Interestingly, PST inhibition by PST inhibitor peptide-8 (PSTi8) displayed a favorable impact on UCP-1 and energy expenditure. SIGNIFICANCE: The aforementioned outcomes indicated the substantial role of PST in altering the UCP-1 expression and associated energy homeostasis. Hence our results corroborate novel avenues to unravel the quest deciphering PST's role in energy homeostasis and its association with perimenopause.
Assuntos
Tecido Adiposo Marrom/efeitos dos fármacos , Tecido Adiposo Branco/efeitos dos fármacos , Cromogranina A/farmacologia , Metabolismo Energético , Frutose/administração & dosagem , Regulação da Expressão Gênica/efeitos dos fármacos , Proteína Desacopladora 1/metabolismo , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/metabolismo , Animais , Feminino , Resistência à Insulina , Menopausa , Ratos , Ratos Sprague-Dawley , Edulcorantes/administração & dosagem , Proteína Desacopladora 1/genéticaRESUMO
Recent findings suggest that the accumulation of misfolded aggregates of islet amyloid peptide (IAPP) plays an essential role in pancreatic damage and type 2 diabetes (T2D). Pancreastatin (PST), a chromogranin derived peptide, instigates insulin resistance (IR) and promotes T2D. Here, we aimed to investigate whether PST induces IAPP aggregation in the pancreas, liver, and skeletal muscles. Foremost, we unraveled kinetics of fibril formation by ThT kinetic assay, ANS binding, turbidity, and far UV-CD. Subsequently, we checked the microarchitecture of fibril by TEM. Moreover, the PST action on IAPP expression was examined by immunocytochemistry, immunohistochemistry, western blotting, and real-time PCR. The outcome of spectral analysis and TEM demonstrated the fibril formation in the alone IAPP group but not in the alone PST; however, PST with IAPP produced stronger fibril. Moreover, PST was found to stimulate IAPP aggregation and expression more prominently in PANC1 and HepG2 cells, and pancreas and liver tissues than in L6 and skeletal muscle. Subsequently, pancreastatin inhibitor manifested a decline in the extent of the IAPP fibril formation and its expression. To conclude, PST upon combination induces the aggregation of IAPP in the pancreas, liver, and skeletal muscle, which may have the potential to generate IR and cause T2D.
Assuntos
Cromogranina A/farmacologia , Diabetes Mellitus Tipo 2/etiologia , Polipeptídeo Amiloide das Ilhotas Pancreáticas/metabolismo , Fígado/metabolismo , Pâncreas/metabolismo , Agregação Patológica de Proteínas/metabolismo , Amiloide/metabolismo , Animais , Células Hep G2 , Humanos , Polipeptídeo Amiloide das Ilhotas Pancreáticas/genética , Fígado/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Pâncreas/efeitos dos fármacos , Agregação Patológica de Proteínas/patologia , Dobramento de ProteínaRESUMO
AIMS: Mitochondrial dysfunction is among the key factors for the advancement of hepatic steatosis to NAFLD and NASH. Pancreastatin (PST: human ChgA250-301) is a dysglycemic hormone, previously reported to promote steatosis and inflammation in various animal models of metabolic disorders. Recently, we observed PST deregulates energy expenditure and mitochondrial functioning in perimenopausal rats. In the current study, we aimed to decipher the role of PST instigated altered mitochondrial functioning in hepatic steatosis. MAIN METHODS: The HepG2 cells were PST exposed and the Chga gene was knocked down using siRNA and lipofectamine. Parallelly, type 2 diabetes (T2D) was developed in C57BL/6 mice by HFD feeding and administered PST inhibitor (PSTi8). KEY FINDINGS: The PST exposed cells and HFD fed mice depicted: enhanced CHGA expression detected by IF/IHC, WB, and ELISA; dysregulated cellular ROS, mitochondrial ROS, oxygen consumption rate, mitochondrial membrane potential, ATP level, and NADP/NADP ratio; enhanced apoptosis determined by MTT, TUNEL, Annexin-V FITC, and WB of Bax/bcl2 and caspase 3; hepatic lipid accumulation upon Nile Red, Oil Red O, H&E staining, and the expression of SREBP-1c, FAS, ACC, and SCD; inflammation based on expression and circulatory level of IL6, IL-1ß, and TNF-α. However, Chga knocked down HepG2 cells and PSTi8 treated mice unveiled protection from all the above abnormalities. SIGNIFICANCE: Collectively, the aforementioned data suggested the alteration in mitochondrial function induced by PST is responsible for hepatic steatosis in T2D.
Assuntos
Cromogranina A/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Fígado Gorduroso/metabolismo , Mitocôndrias Hepáticas/metabolismo , Animais , Peso Corporal , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 2/patologia , Dieta Hiperlipídica , Células Hep G2 , Humanos , Inflamação/metabolismo , Inflamação/patologia , Metabolismo dos Lipídeos , Masculino , Camundongos Endogâmicos C57BLRESUMO
BACKGROUND & OBJECTIVE: Significant health and social burdens have been created by the growth of metabolic disorders like type 2 diabetes mellitus (T2DM), atherosclerosis, and non-alcoholic steatohepatitis, worldwide. The number of the affected population is as yet rising, and it is assessed that until 2030, 4-5 million individuals will acquire diabetes. A blend of environmental, genetic, epigenetic, and other factors, such as diet, are accountable for the initiation and progression of metabolic disorders. Several researches have shown strong relevance of adiponectin gene and metabolic disorders. In this review, the potential influence of epigenetic mechanisms of adiponectin gene "ADIPOQ" on increasing the risk of developing metabolic disorders and their potential in treating this major disorder are discussed. RESULTS & CONCLUSION: Various studies have postulated that a series of factors such as maternal High fat diet (HFD), oxidative stress, pro-inflammatory mediators, sleep fragmentation throughout lifetime, from gestation to old age, could accumulate epigenetic marks, including histone remodeling, DNA methylation, and microRNAs (miRNAs) that, in turn, alter the expression of ADIPOQ gene and result in hypoadiponectinemia which precipitates insulin resistance (IR) that in turn might induce or accelerate the onset and development of metabolic disorder. A better understanding of global patterns of epigenetic modifications and further their alterations in metabolic disorders will bestow better treatment strategies design.
Assuntos
Adiponectina/genética , Adiponectina/metabolismo , Epigênese Genética/fisiologia , Doenças Metabólicas/genética , Doenças Metabólicas/metabolismo , Animais , Metilação de DNA/fisiologia , Dieta Hiperlipídica/efeitos adversos , Feminino , Humanos , Resistência à Insulina/fisiologia , MicroRNAs/genética , MicroRNAs/metabolismo , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/genética , Efeitos Tardios da Exposição Pré-Natal/metabolismoRESUMO
AIMS: Recent findings have instituted the role of hyperglycemia-related AGE/RAGE and NF-κB in instigating reactive oxygen species (ROS) mediated mitochondrial dysfunction and apoptosis of hepatocyte, which leads to steatohepatitis. Naringin, a flavanone glycoside found to possess myriads of pharmacological benefits along with its antioxidant and anti-inflammatory properties. Consequently, we aimed to decipher the effect of naringin on RAGE/NF-κB mediated mitochondrial apoptosis in type 2 diabetes mellitus (T2DM)-induced steatohepatitis. MAIN METHODS: Hepatic HepG2 cells were cultured in palmitic acid medium with and without naringin. Lipid content was examined by Oil Red O and Nile Red staining. Cellular apoptosis was determined by Annexin V-FITC/PI staining. An experimental T2DM-induced steatohepatitis was developed in Sprague Dawley rats by high-fat diet (HFD) for 12 weeks. The naringin was administrated orally at a dose of 100 mg/kg, daily for eight weeks. Glucose and insulin tolerance test was performed. Liver sections were stained by hematoxylin-eosin and picrosirius red. The mRNA and protein expression of RAGE and NF-κB were determined by qPCR, Immunofluorescence, and Immunoblotting. Mitochondrial membrane potential (MMP), cellular and mitochondrial ROS were measured by FACS. KEY FINDINGS: Palmitic acid encountered HepG2 cells and HFD fed rats exhibited hyperlipidemia, insulin resistance, abnormal aminotransferases, steatosis, and fibrosis. Besides, the level of AGEs, RAGE, NF-κB, and oxidative stress were exacerbated. Moreover, MMP, cellular and mitochondrial ROS were altered in diabetic rats. Nevertheless, the naringin treatment ameliorated the steatohepatitis by improving the levels of aforementioned parameters. SIGNIFICANCE: Collectively, these findings suggested anti-steatohepatitis potential of naringin in diabetics.
Assuntos
Antioxidantes/uso terapêutico , Apoptose/efeitos dos fármacos , Diabetes Mellitus Tipo 2/complicações , Fígado Gorduroso/tratamento farmacológico , Flavanonas/uso terapêutico , Mitocôndrias/efeitos dos fármacos , NF-kappa B/metabolismo , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Animais , Diabetes Mellitus Experimental/complicações , Fígado Gorduroso/etiologia , Fígado Gorduroso/patologia , Imunofluorescência , Teste de Tolerância a Glucose , Células Hep G2/efeitos dos fármacos , Humanos , Insulina/sangue , Fígado/patologia , Masculino , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Reação em Cadeia da Polimerase em Tempo RealRESUMO
BACKGROUND: AdipoRon is the first synthetic analog of endogenous adiponectin, an adipose tissue-derived hormone. AdipoRon possesses pharmacological properties similar to adiponectin and its ability to bind and activate the adipoR1 and adipoR2 receptors makes it a suitable candidate for the treatment of a multitude of disorders. OBJECTIVE: In the present review, an attempt was made to compile and discuss the efficacy of adipoRon against various disorders. RESULTS: AdipoRon is a drug that acts not only in metabolic diseases but in other conditions unrelated to energy metabolism. It is well- reported that adipoRon exhibits strong anti-obesity, anti-diabetic, anticancer, anti-depressant, anti-ischemic, anti-hypertrophic properties and also improves conditions like post-traumatic stress disorder, anxiety, and systemic sclerosis. CONCLUSION: A lot is known about its effects in experimental systems, but the translation of this knowledge to the clinic requires studies which, for many of the potential target conditions, have yet to be carried out. The beneficial effects of AdipoRon in novel clinical conditions will suggest an underlying pathophysiological role of adiponectin and its receptors in previously unsuspected settings.
Assuntos
Insulina/metabolismo , Piperidinas/farmacologia , Animais , Comportamento , Doença , Humanos , Piperidinas/uso terapêutico , Transdução de SinaisRESUMO
In the preceding study, we delineated that high-fat diet (HFD) consumption in mice increases the circulatory level of pancreastatin (PST), which additionally enhances the free fatty acid (FFA) concentration in circulation. Consequently, the aggravated FFA activates Fetuin-A, which facilitates hepatic lipid accumulation, insulin resistance (IR), and culminates in type 2 diabetes (T2D). Metformin (Met) is a widely known first-line drug for the treatment of T2D. We previously unveiled PSTi8, an inhibitor of PST, comprising antidiabetic property. Hence, we hypothesized that combination therapy of Met and PSTi8, at reduced therapeutic doses, would mitigate HFD-induced IR by inhibiting hepatic Fetuin-A in mice model of T2D. C57BL/6 mice were fed HFD for 12 weeks, followed by treatment with Met, PSTi8, and its combination for 10 days. Glucose and insulin tolerance tests were conducted. Circulatory levels of PST, Fetuin-A, and lipid markers were determined. Also, the mRNA and protein expression of Fetuin-A was assessed by qPCR, western blotting, and immunofluorescence. Moreover, the energy expenditure was measured by comprehensive laboratory animal monitoring system (CLAMS). Combination therapy displayed improved PST, Fetuin-A, and lipid profile in plasma. We also found reduced hepatic Fetuin-A, which reduced inhibitory phosphorylation of IRS and increased phosphorylation of AKT. Consequently, ameliorated hepatic lipogenesis, gluconeogenesis, and inflammation. Also, combination treatment attenuated Fetuin-A expression, lipid accumulation, and glucose production in palmitate-induced HepG2 cells. Altogether current study promulgates the beneficial effect of combination therapy of Met and PSTi8 (comparable to alone higher therapeutic doses) to ameliorate Fetuin-A activation, hepatic lipid accumulation, insulin resistance, and associated progressive pathophysiological alterations in T2D.
RESUMO
AIMS: Hepatic steatosis in women confronting menopause is the manifestation of substantial fructose consumption and forms a positive feedback loop to develop endoplasmic reticulum (ER) stress. Previously pancreastatin inhibitor peptide-8 (PSTi8) and Metformin (Met) combination effectively ameliorated hepatic lipid accumulation in high fructose diet (HFrD) fed diabetic mice models at reduced doses. Moreover, SIRT-1 plays a crucial role in the regulation of SREBP-1c. Hence we hypothesized that Met and PSTi8 in combination (at therapeutic lower doses) could mitigate hepatic steatosis linked ER stress by activating SIRT-1 and precluding SREBP-1c in HFrD fed 4-Vinylcyclohexenediepoxide (HVCD) induced perimenopausal rats. MAIN METHODS: HVCD rats were fed HFrD for 12 weeks, accompanied by 14 days of treatment with Met, PSTi8, and combination. We confirmed model establishment by estrus cycle study, estradiol level, and intraperitoneal glucose tolerance test. Plasma lipid profile and liver function were determined. Also, mRNA and protein expressions were examined. Moreover, distribution of SIRT-1 and SREBP-1c was detected in HepG2 cells by immunofluorescence staining. KEY FINDINGS: HVCD group displayed augmented insulin resistance (IR), lipogenesis, and ER stress in the liver. Combination therapy improved the estrus cyclicity, estradiol, and lipid profile of HVCD rats. Met and PSTi8 combination reduced hepatic SREBP-1c and triggered SIRT-1 expression in high fructose-induced insulin-resistant HepG2 cells; consequently, combination therapy attenuated ER stress. SIGNIFICANCE: Succinctly, present research promotes impetus concerning the remedial impact of Met with PSTi8 at lower therapeutic doses to ameliorate hepatic IR, steatosis, and associated ER stress by revamping the SIRT-1/SREBP-1c axis in perimenopausal rats.
RESUMO
In today's world, migraine is one of the most frequent disorders with an estimated world prevalence of 14.7% characterized by attacks of a severe headache making people enfeebled and imposing a big socioeconomic burden. The pathophysiology of a migraine is not completely understood however there are pieces of evidence that epigenetics performs a primary role in the pathophysiology of migraine. Here, in this review, we highlight current evidence for an epigenetic link with migraine in particular DNA methylation of numerous genes involved in migraine pathogenesis. Outcomes of various studies have explained the function of DNA methylation of a several migraine related genes such as RAMP1, CALCA, NOS1, ESR1, MTHFR and NR4A3 in migraine pathogenesis. Mentioned data suggested there exist a strong association of DNA methylation of migraine-related genes in migraine. Although we now have a general understanding of the role of epigenetic modifications of a numerous migraine associated genes in migraine pathogenesis, there are many areas of active research are of key relevance to medicine. Future studies into the complexities of epigenetic modifications will bring a new understanding of the mechanisms of migraine processes and open novel approaches towards therapeutic intervention.