Carica Papaya Reduces High Fat Diet and Streptozotocin-Induced Development of Inflammation in Adipocyte via IL-1ß/IL-6/TNF-α Mediated Signaling Mechanisms in Type-2 Diabetic Rats.

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.

A Comprehensive Review on Therapeutic Perspectives of Phytosterols in Insulin Resistance: A Mechanistic Approach.

Natural products in the form of functional foods have become increasingly popular due to their protective effects against life-threatening diseases, low risk of adverse effects, affordability, and accessibility. Plant components such as phytosterol, in particular, have drawn a lot of press recently due to a link between their consumption and a modest incidence of global problems, such as Type 2 Diabetes mellitus (T2DM), cancer, and cardiovascular disease. In the management of diet-related metabolic diseases, such as T2DM and cardiovascular disorders, these plant-based functional foods and nutritional supplements have unquestionably led the market in terms of cost-effectiveness, therapeutic efficacy, and safety. Diabetes mellitus is a metabolic disorder categoriszed by high blood sugar and insulin resistance, which influence major metabolic organs, such as the liver, adipose tissue, and skeletal muscle. These chronic hyperglycemia fallouts result in decreased glucose consumption by body cells, increased fat mobilisation from fat storage cells, and protein depletion in human tissues, keeping the tissues in a state of crisis. In addition, functional foods such as phytosterols improve the body's healing process from these crises by promoting a proper physiological metabolism and cellular activities. They are plant-derived steroid molecules having structure and function similar to cholesterol, which is found in vegetables, grains, nuts, olive oil, wood pulp, legumes, cereals, and leaves, and are abundant in nature, along with phytosterol derivatives. The most copious phytosterols seen in the human diet are sitosterol, stigmasterol, and campesterol, which can be found in free form, as fatty acid/cinnamic acid esters or as glycosides processed by pancreatic enzymes. Accumulating evidence reveals that phytosterols and diets enriched with them can control glucose and lipid metabolism, as well as insulin resistance. Despite this, few studies on the advantages of sterol control in diabetes care have been published. As a basis, the primary objective of this review is to convey extensive updated information on the possibility of managing diabetes and associated complications with sterol-rich foods in molecular aspects.

Influence of Pterostilbene on Gene Expression in Liver Cancer: An In Silico Analysis.

Background Liver cancer, in particular, is a serious threat to global health and has few viable treatments. One natural molecule that shows potential in cancer therapy is pterostilbene, especially for hepatocellular carcinoma (HCC). The molecular details of pterostilbene's interactions with liver cancer are uncovered in this study using an in silico method. Methodology This study determines the differentially expressed genes (DEGs) in HCC and the way pterostilbene affects them using data from Gene Expression Omnibus (GEO) datasets. To identify the intricate linkages and possible treatment targets, network pharmacology, protein-protein interaction (PPI) analysis, and pathway enrichment investigations were performed. Results The study revealed complex relationships between pterostilbene and liver cancer, identified important DEGs in HCC, and showed enriched pathways. Pterostilbene shows promise as a target for therapeutic approaches in HCC due to its modulation of important signaling pathways. Conclusions This work offers an extensive knowledge of pterostilbene's potential in liver cancer, despite intrinsic computational limitations. In addition to the importance of experimental validation, the pathways and DEGs that have been found provide insightful information for future investigation, highlighting the ongoing research that is necessary to create targeted therapeutics for HCC.

Analysing the Anticancer Properties of Pterostilbene Through Absorption, Distribution, Metabolism, and Excretion (ADME) and Molecular Docking Studies.

Aim The aim of this study is to examine the possible therapeutic effect of pterostilbene (PTS), a chemical present in grapes and blueberries, in the treatment of liver cancer by analysing its interactions with important proteins linked to the wingless/integrated (Wnt) signaling system. Objective Using computational techniques like molecular docking and absorption, distribution, metabolism, and excretion (ADME) studies, this research focuses on examining the pharmacokinetics and molecular interactions of PTS with proteins such as vimentin (Vim), glycogen synthase kinase 3 beta (GSK3-ß), epithelial cadherin (E-cadherin), interleukin-6 (IL-6), interleukin-1 beta (IL-1ß), c-Jun N-terminal kinase (JNK), and Wnt, all of which are connected to the Wnt signaling pathway in liver cancer. Methods The study includes the synthesis of proteins and ligands, ADME investigations for PTS, and AutoDock Vina molecular docking simulations to evaluate binding affinities and interactions. PTS is obtained from PubChem, while protein structures are obtained from the Protein Data Bank. Results Strong binding affinities between PTS and essential proteins in the Wnt signaling cascade are shown by molecular docking, which also highlights noteworthy hydrogen bonds, hydrophobic interactions, and electrostatic contacts. According to an ADME study, PTS has advantageous pharmacokinetic properties, such as moderate solubility, membrane permeability, and a minimal chance of drug interactions. Conclusion The extensive study highlights PTS's potential as a viable treatment option for liver cancer. The study promotes its investigation in cutting-edge liver cancer therapy approaches and urges more investigation into the molecular mechanisms, underpinning its anticancer properties. This paper sheds important light on the role of natural chemicals in cancer therapy and emphasizes the need for computational methods in drug discovery.

Comparative In Vitro and In Silico Analyses of Phytochemicals From Butea monosperma for Wound-Healing Potential in Human Cells.

Aim The objective of this study is to investigate the phytochemicals present in Butea monosperma and assess their potential for healing wounds using a computational comparative method. Materials and methods The phytochemical substances derived from B. monosperma were examined using a phytochemical test, Fourier-transform infrared (FTIR) spectroscopy, and gas chromatography-mass spectroscopy (GCMS). The chemical structures of these substances were investigated in silico using computational techniques to predict their wound-healing capacity. The molecular docking tests evaluate the binding strengths of the phytochemicals to specific proteins that play a major role in wound-healing mechanisms. The pharmacokinetic features of the substances were evaluated by analyzing their ADMET (absorption, distribution, metabolism, excretion, and toxicity) profiles. Results The computer analysis found several phytochemicals from B. monosperma that bind strongly to the proteins for wound healing: compounds such as hexanoic acid, 2,7-dimethyloct-7-en-5-yn-4-yl ester, 1,3,5-pentanetriol, 3-methyl-, and 2-butyne-1,4-diol. The ADMET analysis indicated favorable pharmacokinetic properties for the majority of the identified compounds, with low predicted toxicity. Conclusion Based on the in silico analysis, the phytochemicals in B. monosperma possess significant potential for use in wound-healing applications. These findings required additional in vitro and in vivo studies to confirm the effectiveness and safety of these drugs for improving wound healing. This study emphasizes the potential of B. monosperma as a source of innovative medicinal substances for wound care.

Molecular Docking and Absorption, Distribution, Metabolism, and Excretion (ADME) Analysis: Examining the Binding Modes and Affinities of Myricetin With Insulin Receptor, Glycogen Synthase Kinase, and Glucokinase.

Aim By using molecular docking analysis (MDA) to examine its interactions with important regulatory proteins linked to diabetes, such as glycogen synthase kinase 3 beta (GSK3ß), insulin receptor (IR), and glucose kinase (GCK), this study seeks to explore the therapeutic potential of myricetin, a naturally occurring flavonoid. Objective The main goal is to determine potential effects on insulin signalling, GSK3ß activity, and glucose metabolism by evaluating the binding affinities of myricetin with GCK, IR, and GSK3ß through MDA. In order to assess the drug affinity of myricetin, the study also intends to perform absorption, distribution, metabolism, and excretion (ADME) studies. Materials and methods To model the interaction between myricetin and the target proteins (GCK, IR, and GSK3ß), we used molecular docking analysis with computational tools. ADME studies were also included in the study to evaluate drug affinity. Identification of binding sites, essential residues, and interaction stability were all part of the structural analysis. Results As evidence of possible interactions with these regulatory proteins, myricetin showed positive binding affinities with GCK, IR, and GSK3ß. Strong interactions with important ligand recognition residues were seen in the docking into IR, indicating a potential impact on insulin signalling. Moreover, a strong binding affinity for GCK indicated potential effects on the metabolism of glucose. Studies using ADME confirmed the high drug affinity of myricetin. Conclusion This work sheds light on the multi-target potential of myricetin in the regulation of diabetes. It appears that it has the ability to influence glucose metabolism, suppress GSK3ß activity, and regulate insulin signalling based on its interactions with IR, GSK3ß, and GCK. Although these computational results show promise, more experimental work is necessary to confirm and fully understand the precise mechanisms that underlie myricetin's effects on the regulation of diabetes.

Glyphosate potentiates insulin resistance in skeletal muscle through the modulation of IRS-1/PI3K/Akt mediated mechanisms: An in vivo and in silico analysis.

Herbicides have been linked to a higher risk of developing diabetes. Certain herbicides also operate as environmental toxins. Glyphosate is a popular and extremely effective herbicide for weed control in grain crops that inhibits the shikimate pathway. It has been shown to negatively influence endocrine function. Few studies have demonstrated that glyphosate exposure results in hyperglycemic and insulin resistance; but the molecular mechanism underlying the diabetogenic potential of glyphosate on skeletal muscle, a primary organ that includes insulin-mediated glucose disposal, is unknown. In this study, we aimed to evaluate the impact of glyphosate on the detrimental changes in the insulin metabolic signaling in the gastrocnemius muscle. In vivo results showed that glyphosate exposure caused hyperglycemia, dyslipidemia, increased glycosylated hemoglobin (HbA1c), liver function, kidney function profile, and oxidative stress markers in a dose-dependent fashion. Conversely, hemoglobin and antioxidant enzymes were significantly reduced in glyphosate-induced animals indicating its toxicity is linked to induce insulin resistance. The histopathology of the gastrocnemius muscle and RT-PCR analysis of insulin signaling molecules revealed glyphosate-induced alteration in the expression of IR, IRS-1, PI3K, Akt, ß-arrestin-2, and GLUT4 mRNA. Lastly, molecular docking and dynamics simulations confirmed that glyphosate showed a high binding affinity with target molecules such as Akt, IRS-1, c-Src, ß-arrestin-2, PI3K, and GLUT4. The current work provides experimental proof that glyphosate exposure has a deleterious effect on the IRS-1/PI3K/Akt signaling pathways, which in turn causes the skeletal muscle to become insulin resistant and eventually develop type 2 diabetes mellitus.

Piperine modulates IR/Akt/GLUT4 pathways to mitigate insulin resistance: Evidence from animal and computational studies.

The global prevalence of diabetes mellitus is rising, especially in India. Medicinal herbs, whether used alone or in combination with conventional medicines, have shown promise in managing diabetes and improving overall well-being. Piperine (PIP), a major bioactive compound found in pepper, is gaining attention for its beneficial properties. This study aimed to assess whether PIP could alleviate diabetes by targeting insulin pathway-related molecules in the adipose tissue of rats on a high-fat diet (HFD). After 60 days on the HFD, rats received PIP at a dose of 40 mg/kg body weight for one month. The results showed that PIP significantly improved metabolic indicators, antioxidant enzymes, and carbohydrate metabolic enzymes. It also regulated the mRNA and protein expression of insulin signaling, which had been disrupted by the diet and sucrose intake. Molecular docking analysis also revealed strong binding of PIP to key diabetes-related regulatory proteins, including Akt (-6.2 kcal/mol), IR (-7.02 kcal/mol), IRS-1 (-6.86 kcal/mol), GLUT4 (-6.24 kcal/mol), AS160 (-6.28 kcal/mol), and ß-arrestin (-6.01 kcal/mol). Hence, PIP may influence the regulation of glucose metabolism through effective interactions with these proteins, thereby controlling blood sugar levels due to its potent antilipidemic and antioxidant properties. In conclusion, our study provides in vivo experimental evidence against the HFD-induced T2DM model for the first time, making PIP a potential natural remedy to enhance the quality of life for diabetic patients and aid in their management.

Methylated ZNF582: a therapeutic target in oral cancer.

Tweetable abstract Zinc finger proteins control the transcription of downstream genes that are implicated in migration, invasion, cell death and proliferation. More mechanistic research on ZNF582 is needed to ascertain how this protein's methylation regulates the inflammatory pathway in oral cancer.

Views on high-fat diet linked insulin resistance.

Insulin resistance is linked to impaired cell metabolism and survival in the peripheral tissues, as well as increased oxidative stress and activated inflammatory responses. Chronic High fat diet insulin resistant to exposure results in liver damage, impaired glucose homeostasis, hyperinsulinemia, late pancreatic-cell failure to generate insulin due to cell exhaustion, and subsequent hyperglycaemia, all of which are hallmarks of Type 2 Diabetes Mellitus (T2DM). Therefore, it is of intrest to document a short review on the impact of a high-fat diet with insulin resistance.

Diosgenin inhibits ER stress-induced inflammation in aorta via iRhom2/TACE mediated signaling in experimental diabetic rats: An in vivo and in silico approach.

Hyperglycemia, hyperlipidemia, and atherosclerotic lesions may cause inflammation, which leads to chemokine production and changes in vascular responses. Hyperglycemia can impair normal protein folding by producing reactive oxygen species (ROS) and interacting with various signaling molecules, resulting in the activation of ER stress responses, that stimulates NF-kB, which regulates the expression of numerous genes involved in inflammation and vascular remodeling. Our previous studies have shown that diosgenin has a protective effect against streptozotocin (STZ) - induced oxidative damage in rat aorta. However, the therapeutic role of diosgenin on iRhom2/TACE signaling which has primarily been linked to the endoplasmic reticulum (ER)-stress induced inflammation is unknown. Diosgenin was administered (40 mg/kg b. wt, orally, for 4 weeks) to STZ-induced male albino rats. Fasting plasma glucose, blood pressure, nitrite level, lipid profile, and lipoprotein were assessed. Serum insulin and pro-inflammatory markers were analyzed using ELISA, mRNA and protein expression of iRhom2/TACE signaling molecules were analyzed using RT-PCR and western blotting analysis respectively. In silico study was also performed to find out the possible binding affinity of diosgenin with the ER stress signaling molecules. Through regulation of the iRhom2/TACE signaling molecules, diosgenin lowered dyslipidemia, hypertension, and pro-inflammatory cytokines (TNF-α, IL-1, IL-6, and IL-4) in the aorta of STZ induced diabetic rats. Results of molecular docking analysis also confirmed the potential binding interaction with iRhom2/TACE and TNF- α. These in silico and in vivo results indicated that a change in lipid profile and hypertension led to diabetes-related inflammation by promoting ER stress and, as a result, accelerating the aorta by generating proinflammatory cytokines and lipid deposition. This study concludes that diosgenin attenuates ER stress-induced inflammation in diabetic rat aorta by modulating the expression of pro-inflammatory, iRhom2/TACE mediated mechanism and hence diosgenin can be a therapeutic drug for the treatment of diabetes-induced inflammation.

A comprehensive review on high -fat diet-induced diabetes mellitus: an epigenetic view.

Modern lifestyle, genetics, nutritional overload through high-fat diet attributed prevalence and diabetes outcomes with various complications primarily due to obesity in which energy-dense diets frequently affect metabolic health. One possible issue usually associated with elevated chronic fat intake is insulin resistance, and hyperglycemia constitutes an important function in altering the carbohydrates and lipids metabolism. Similarly, in assessing human susceptibility to weight gain and obesity, genetic variations play a central role, contributing to keen interest in identifying the possible role of epigenetics as a mediator of gene-environmental interactions influencing the production of type 2 diabetes mellitus and its related concerns. Epigenetic modifications associated with the acceptance of a sedentary lifestyle and environmental stress factors in response to energy intake and expenditure imbalances complement genetic alterations and lead to the production and advancement of metabolic disorders such as diabetes and obesity. Methylation of DNA, histone modifications, and increases in the expression of non-coding RNAs can result in reduced transcriptional activity of key ß-cell genes thus creating insulin resistance. Epigenetics contribute to changes in the expression of the underlying insulin resistance and insufficiency gene networks, along with low-grade obesity-related inflammation, increased ROS generation, and DNA damage in multiorgans. This review focused on epigenetic mechanisms and metabolic regulations associated with high-fat diet (HFD)-induced diabetes mellitus.

Impact of Glyphosate on the Development of Insulin Resistance in Experimental Diabetic Rats: Role of NFκB Signalling Pathways.

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.

Beta-Sitosterol Facilitates GLUT4 Vesicle Fusion on the Plasma Membrane via the Activation of Rab/IRAP/Munc 18 Signaling Pathways in Diabetic Gastrocnemius Muscle of Adult Male Rats.

Nutritional overload in the form of high-fat and nonglycolysis sugar intake contributes towards the accelerated creation of reactive oxygen species (ROS), hyperglycemia, and dyslipidemia. Glucose absorption and its subsequent oxidation processes in fat and muscle tissues alter as a consequence of these modifications. Insulin resistance (IR) caused glucose transporter 4 (GLUT4) translocation to encounter a challenge that manifested itself as changes in glycolytic pathways and insulin signaling. We previously found that beta (ß)-sitosterol reduces IR in fat tissue via IRS-1/PI3K/Akt facilitated signaling due to its hypolipidemic and hypoglycemic activity. The intention of this research was to see whether the phytosterol ß-sitosterol can aid in the translocation of GLUT4 in rats fed on high-fat diet (HFD) and sucrose by promoting Rab/IRAP/Munc 18 signaling molecules. The rats were labeled into four groups, namely control rats, HFD and sucrose-induced diabetic control rats, HFD and sucrose-induced diabetic rats given oral dose of 20 mg/kg body wt./day of ß-sitosterol treatment for 30 days, and HFD and sucrose-induced diabetic animals given oral administration of 50 mg/kg body wt./day metformin for 30 days. Diabetic rats administered with ß-sitosterol and normalized the titers of blood glucose, serum insulin, serum testosterone, and the status of insulin tolerance and oral glucose tolerance. In comparison with the control group, ß-sitosterol effectively regulated both glycolytic and gluconeogenesis enzymes. Furthermore, qRT-PCR analysis of the mRNA levels of key regulatory genes such as SNAP23, VAMP-2, syntaxin-4, IRAP, vimentin, and SPARC revealed that ß-sitosterol significantly regulated the mRNA levels of the above genes in diabetic gastrocnemius muscle. Protein expression analysis of Rab10, IRAP, vimentin, and GLUT4 demonstrated that ß-sitosterol had a positive effect on these proteins, resulting in effective GLUT4 translocation in skeletal muscle. According to the findings, ß-sitosterol reduced HFD and sucrose-induced IR and augmented GLUT4 translocation in gastrocnemius muscle through insulin signaling modulation via Rab/IRAP/Munc 18 and glucose metabolic enzymes. The present work is the first of its kind to show that ß-sitosterol facilitates GLUT4 vesicle fusion on the plasma membrane via Rab/IRAP/Munc 18 signaling molecules in gastrocnemius muscle.