RESUMEN
The prevalence of obesity in contemporary society has brought attention to how serious it is all around the world. Obesity, a proinflammatory condition defined by hypertrophied adipocytes and immune cells that reside in adipose tissue, is characterized by elevated circulating levels of proinflammatory cytokines. The pro-inflammatory mediators trigger a number of inflammatory pathways and affect the phosphorylation of a number of insulin-signaling pathways in peripheral tissues. In this work, we pointed the outcome of the leaves of Carica papaya (C. papaya) on the inflammatory molecules by in vivo and in silico analysis in order to prove its mechanisms of action. Adipocytokines, antioxidant enzymes, gene and protein expression of pro-inflammatory signaling molecules (mTOR, TNF-α, IL-1ß, IL-6 and IKKß) by q-RT-PCR and immunohistochemistry, as well as histopathological analysis, in adipose tissues were carried out. C. papaya reinstated the levels of adipocytokines, antioxidant enzymes and mRNA levels of mTOR, TNF-α, IL-1ß, IL-6 and IKKß in the adipose tissues of type 2 diabetic rats. Molecular docking and dynamics simulation studies revealed that caffeic acid, transferulic acid and quercetin had the top hit rates against IKKß, TNF-α, IL-6, IL-1ß, and mTOR. This study concludes that C. papaya put back the altered effects in fatty tissue of type 2 diabetic rats by restoring the adipocytokines and the gene expression.
RESUMEN
ß-sitosterol (SIT), the most abundant bioactive component of vegetable oil and other plants, is a highly potent antidiabetic drug. Our previous studies show that SIT controls hyperglycemia and insulin resistance by activating insulin receptor and glucose transporter 4 (GLUT-4) in the adipocytes of obesity induced type 2 diabetic rats. The current research was undertaken to investigate if SIT could also exert its antidiabetic effects by circumventing adipocyte induced inflammation, a key driving factor for insulin resistance in obese individuals. Effective dose of SIT (20 mg/kg b.wt) was administered orally for 30 days to high fat diet and sucrose induced type-2 diabetic rats. Metformin, the conventionally used antidiabetic drug was used as a positive control. Interestingly, SIT treatment restores the elevated serum levels of proinflammatory cytokines including leptin, resistin, tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) to normalcy and increases anti-inflammatory adipocytokines including adiponectin in type 2 diabetic rats. Furthermore, SIT decreases sterol regulatory element binding protein-1c (SREBP-1c) and enhances Peroxisome Proliferator-activated receptor-γ (PPAR-γ) gene expression in adipocytes of diabetic rats. The gene and protein expression of c-Jun-N-terminal kinase-1 (JNK1), inhibitor of nuclear factor kappa-B kinase subunit beta (IKKß) and nuclear factor kappa B (NF-κB) were also significantly attenuated in SIT treated groups. More importantly, SIT acts very effectively as metformin to circumvent inflammation and insulin resistance in diabetic rats. Our results clearly show that SIT inhibits obesity induced insulin resistance by ameliorating the inflammatory events in the adipose tissue through the downregulation of IKKß/NF-κB and c-Jun-N-terminal kinase (JNK) signaling pathway.
Asunto(s)
Adipocitos/metabolismo , Diabetes Mellitus Tipo 2/complicaciones , Regulación hacia Abajo , Quinasa I-kappa B/metabolismo , Inflamación/tratamiento farmacológico , Resistencia a la Insulina , Obesidad/complicaciones , Sitoesteroles/uso terapéutico , Adipocitos/efectos de los fármacos , Adipoquinas/sangre , Tejido Adiposo/efectos de los fármacos , Tejido Adiposo/metabolismo , Tejido Adiposo/patología , Animales , Peso Corporal/efectos de los fármacos , Citocinas/sangre , Citocinas/genética , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patología , Dieta Alta en Grasa , Regulación hacia Abajo/efectos de los fármacos , Conducta Alimentaria , Inflamación/sangre , Inflamación/metabolismo , Inflamación/patología , Mediadores de Inflamación/metabolismo , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Masculino , Simulación del Acoplamiento Molecular , FN-kappa B/metabolismo , Obesidad/sangre , PPAR gamma/genética , PPAR gamma/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas , Sitoesteroles/farmacología , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/metabolismo , Sacarosa , Regulación hacia Arriba/efectos de los fármacos , Regulación hacia Arriba/genéticaRESUMEN
Breast cancer is a well-known complex disease. The availability of different screening approaches and booming phytochemical drug synthesis can contribute towards breast cancer treatment. Hence, we document the molecular docking analysis of triterpenoids from Cassia fistula with breast cancer targets.
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Combat and care during CoVid-19 was non-trivial. Therefore, it is of interest to use the pharmacologically active plant component quercetin for the treatment of CoVid-19. Quercetin exhibits favourable ADMET values and abides by Lipinski's rule of five. When quercetin and remdesivir were positioned in relation to the CoVid-19 targets, quercetin exhibited a greater propensity for binding and H-bond interaction in their molecular interactions. Thus, the quercetin molecule can be used to manage CoVid-19.
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Regardless of socioeconomic or demographic background, the prevalence of type 2 diabetes mellitus, which affects more than half a billion people worldwide, has been steadily increasing over time. The health, emotional, sociological, and economic well-being of people would suffer if this number is not successfully handled. The liver is one of the key organs accountable for sustaining metabolic balance. Elevated levels of reactive oxygen species inhibit the recruitment and activation of IRS-1, IRS-2, and PI3K-Akt downstream signaling cascade. These signaling mechanisms reduce hepatic glucose absorption and glycogenesis while increasing hepatic glucose output and glycogenolysis. In our work, an analysis of the molecular mechanism of Carica papaya in mitigating hepatic insulin resistance in vivo and in silico was carried out. The gluconeogenic enzymes, glycolytic enzymes, hepatic glycogen tissue concentration, oxidative stress markers, enzymatic antioxidants, protein expression of IRS-2, PI3K, SREBP-1C, and GLUT-2 were evaluated in the liver tissues of high-fat-diet streptozotocin-induced type 2 diabetic rats using q-RT-PCR as well as immunohistochemistry and histopathology. Upon treatment, C. papaya restored the protein and gene expression in the liver. In the docking analysis, quercetin, kaempferol, caffeic acid, and p-coumaric acid present in the extract were found to have high binding affinities against IRS-2, PI3K, SREBP-1c, and GLUT-2, which may have contributed much to the antidiabetic property of C. papaya. Thus, C. papaya was capable of restoring the altered levels in the hepatic tissues of T2DM rats, reversing hepatic insulin resistance.
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It is of interest to develop effective drugs for diabetes mellitus. We document the molecular docking analysis data of tetra-cyclic-tri-terpenoids from Cassia fistula L. with targets for diabetes mellitus.
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Glyphosate, an endocrine disruptor, has an adverse impact on human health through food and also has the potential to produce reactive oxygen species (ROS), which can lead to metabolic diseases. Glyphosate consumption from food has been shown to have a substantial part in insulin resistance, making it a severe concern to those with type 2 diabetes (T2DM). However, minimal evidence exists on how glyphosate impacts insulin-mediated glucose oxidation in the liver. Hence the current study was performed to explore the potential of glyphosate toxicity on insulin signaling in the liver of experimental animals. For 16 weeks, male albino Wistar rats were given 50 mg, 100 mg and 250 mg/kg b. wt. of glyphosate orally. In the current study, glyphosate exposure group was linked to a rise in fasting sugar and insulin as well as a drop in serum testosterone. At the same time, in a dose dependent fashion, glyphosate exposure showed alternations in glucose metabolic enzymes. Glyphosate exposure resulted in a raise in H2O2 formation, LPO and a reduction in antioxidant levels those results in impact on membrane integrity and insulin receptor efficacy in the liver. It also registered a reduced levels of mRNA and protein expression of insulin receptor (IR), glucose transporter-2 (GLUT2) with concomitant increase in the production of proinflammatory factors such as JNK, IKKß, NFkB, IL-6, IL-1ß, and TNF-α as well as transcriptional factors like SREBP1c and PPAR-γ leading to pro-inflammation and cirrhosis in the liver which results in the development of insulin resistance and type 2 diabetes. Our present findings for the first time providing an evidence that exposure of glyphosate develops insulin resistance and type 2 diabetes by aggravating NFkB signaling pathway in liver.
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Despite rigorous endeavors, existing attempts to handle type 2 diabetes (T2DM) are still a long way off, as a substantial number of patients do not meet therapeutic targets. Insulin resistance in skeletal muscle is discerned as a forerunner in the pathogenesis of T2DM and can be detected years before its progress. Studies have revealed the antidiabetic properties of Carica papaya (C. papaya), but its molecular mechanism on insulin receptor substrate-1 (IRS-1)/Akt signaling mechanisms is not yet known. The present study aimed to evaluate the role of C. papaya on IRS1 and Akt in high-fat-diet-streptozotocin-induced type 2 diabetic rats and also to analyze the bioactive compounds of C. papaya against IRS-1 and Akt via in silico analysis. Ethanolic extract of the leaves of C. papaya (600 mg/kg of body weight) was given daily for 45 days postinduction of T2DM up to the end of the study. Gluconeogenic enzymes, glycolytic enzymes, gene expression, and immunohistochemical analysis of IRS-1 and Akt in skeletal muscle were evaluated. C. papaya treatment regulated the levels of gluconeogenic and glycolytic enzymes and the levels of IRS-1 and Akt in skeletal muscle of type 2 diabetic animals. In silico studies showed that trans-ferulic acid had the greatest hit rate against the protein targets IRS-1 and Akt. C. papaya restored the normoglycemic effect in diabetic skeletal muscle by accelerating the expression of IRS-1 and Akt.
Asunto(s)
Carica , Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Resistencia a la Insulina , Animales , Carica/metabolismo , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Dieta Alta en Grasa/efectos adversos , Hipoglucemiantes/farmacología , Insulina/metabolismo , Proteínas Sustrato del Receptor de Insulina/metabolismo , Resistencia a la Insulina/fisiología , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas , EstreptozocinaRESUMEN
In the management of type 2 diabetes, oral antidiabetic drugs have several side effects, which in turn have led the pharmaceutical industry to search for good therapeutic, non-toxic and reliable drugs. Carica papaya (C. papaya) is one of several plants in nature that have been found to possess anti-diabetic properties. Despite studies being focused on the antidiabetic activity of C. papaya, the molecular mechanism against high fat diet induced insulin resistance is yet to be identified. The role of C. papaya was evaluated on insulin signaling molecules, such as the insulin receptor (IR) and glucose transporter-4 (GLUT4) in high fat, diet-streptozotocin induced type 2 diabetic rats, and analyzed the bioactive compounds of C. papaya against IR and GLUT4 via molecular docking and dynamics. The ethanolic extract of C. papaya leaves (600 mg/kg of body weight) was given daily to male wistar rats for 45 days and we observed the various biochemical parameters, gene expression analysis and histopathology of skeletal muscle. Molecular docking and dynamics were undertaken to understand the bioactive compounds with the greatest hit rate. C. papaya treatment was able to control blood glucose levels, the lipid profile and serum insulin, but it facilitated tissue antioxidant enzymes and IR and GLUT4 levels. The in-silico study showed that kaempferol, quercitin and transferulic acid were the top three ligands with the greatest hit rate against the protein targets. Our preliminary findings, for the first time, showed that C. papaya reinstates the glycemic effect in the diabetic skeletal muscle by accelerating the expression of IR and GLUT4.
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Cissampelos pareira Linn. is a climbing herb known in Indian traditional medicine as laghupatha. It belongs to the Menispermaceae family. The enzyme glycogen phosphorylase (GP) is a promising target for the treatment of type-2 diabetes (T2DM). A variety of natural product inhibitors with both pharmaceutical and nutraceutical potential have been reported in the search for powerful, selective and drug-like GP inhibitors that could lead to hypoglycemic medicines. Therefore, it is of interest to document the molecular docking analysis data of glycogen phosphorylase with compounds from Cissampelos pareira Linn. We report the optimal binding features of 4 compounds namely Trans-N-feruloyltyramine, Coclaurine, Magnoflorine, and Curine with the target protein for further consideration in the context of T2DM.
RESUMEN
In our previous study, we have shown that ß-sitosterol (SIT) enhances glycemic control by increasing the activation of insulin receptor (IR) and glucose transporter 4 (GLUT4) proteins in adipose tissue. However, the possible role of SIT on the regulation of post-receptor insulin signal transduction is not known. Hence, the study was aimed to assess the effects of SIT on IRS-1/Akt mediated insulin signaling molecules in high-fat diet and sucrose induced type-2 diabetic rats. An oral effective dose of SIT (20 mg/kg b.wt) was given for 30 days to high fat-fed type-2 diabetic rats to find out whether SIT regulates IRS-1/Akt pathway of insulin signaling. The results showed that SIT attenuated the insulin receptor substrate-1 serine phosphorylation (p-IRS-1Ser636) (P = 0.0003). However, it up-regulated the mRNA expression of IR (P = 0.0036) and post-receptor insulin signaling molecules such as IRS-1 (P < 0.0001), ß-arrestin-2 (P < 0.0058), Akt (P = 0.0008), AS160 (P = 0.0030) and GLUT4 (P < 0.0001) with a concomitant increase in the levels of IRS-1(P < 0.0001), p-IRS1-1Tyr632 (P = 0.0014), Akt (P < 0.0001), p-AktSer473/Thr308 (P = 0.0006; P < 0.0001), AS160 and p-AS160Thr642 (P < 0.0001) compared with type-2 diabetic rats. In Silico analysis was also performed and it showed that SIT possesses the greater binding affinity with ß-arrestin-2, c-Src, and IRS-1 as well as Akt proteins and proved to attenuate insulin resistance as this study coincides with in vivo findings. Our present study clearly shows that SIT attenuates high fat diet-induced detrimental changes in adipose tissue. Therefore, it is concluded from the present findings that, SIT could be used as potential therapeutic phytomedicine for the management of type-2 diabetes.