ABSTRACT
Activators of peroxisome proliferator-activated receptor-γ (PPARγ agonists) are therapeutically promising candidates against insulin resistance and hyperglycemia. Synthetic PPARγ agonists are known to effectively enhance insulin sensitivity, but these are also associated with adverse side-effects and rising cost of treatment. Therefore, natural PPARγ targeting ligands are desirable alternatives for the management of insulin resistance associated with type 2 diabetes. Phloretin (PT) and Phloridzin (PZ) are predominant apple phenolics, which are recognized for their various pharmacological functions. The present study assessed the potential of PT and PZ in enhancing insulin sensitivity and glucose uptake by inhibiting Cdk5 activation and corresponding PPARγ phosphorylation in differentiated 3T3L1 cells. In silico docking and subsequent validation using 3T3L1 cells revealed that PT and PZ not only block the ser273 site of PPARγ but also inhibit the activation of Cdk5 itself, thereby, indicating their potent PPARγ regulatory attributes. Corroborating this, application of PT and PZ significantly enhanced the accumulation of cellular triglycerides as well as expression of insulin-sensitizing genes in adipocytes ultimately resulting in improved glucose uptake. Taken together, the present study reports that PT and PZ inhibit Cdk5 activation, which could be directly influencing the apparent PPARγ inhibition at ser273, ultimately resulting in improved insulin sensitivity and glucose uptake.
Subject(s)
Cyclin-Dependent Kinase 5/antagonists & inhibitors , Glucose/metabolism , Insulin Resistance , PPAR gamma/antagonists & inhibitors , Phloretin/pharmacology , Phlorhizin/pharmacology , Protein Interaction Domains and Motifs/drug effects , 3T3-L1 Cells , Adipocytes/cytology , Adipocytes/drug effects , Adipocytes/metabolism , Animals , Cell Differentiation , Cyclin-Dependent Kinase 5/metabolism , Mice , PPAR gamma/metabolism , PhosphorylationABSTRACT
Background The research delves into the intricate relationship between periodontal health and specific blood biomarkers in pregnant women during their second trimester. It specifically focuses on the levels of interleukin-6 (IL-6), lactate dehydrogenase (LDH), and C-reactive protein (CRP) in those suffering from chronic periodontitis compared to healthy controls. Methodology A detailed approach was taken involving 60 pregnant women categorized into two groups based on the presence or absence of chronic periodontitis. Out of 60 pregnant women, 30 had chronic periodontitis, while the other 30 served as controls selected from the regular patient population of the college. The study utilized blood sample analysis and advanced statistical tools for data analysis, ensuring precise and reliable results. Levels of IL-6, LDH, and CRP in those suffering from chronic periodontitis compared to healthy controls were checked. Results The findings revealed a notable variance in IL-6, LDH, and CRP levels between the two groups. Women with chronic periodontitis exhibited significantly higher levels of these biomarkers. The statistical analysis reinforced the validity of these differences, highlighting their significance. Conclusions The study underscored a clear link between higher levels of IL-6, LDH, and CRP and the presence of chronic periodontitis in pregnant women. These biomarkers emerge as potential indicators for early detection and monitoring of periodontal health in this demographic.
ABSTRACT
Any contamination in potable water leads to high risk on human health. Hence, it is inevitable to characterize water quality and assess temporal change with reference to human health. In this paper, nineteen water quality parameters from 50 sources of drinking water supply operated by state agency Uttarakhand Jal Sansthan (UJS) were analysed. The water samples were collected for pre-monsoon (May) and post-monsoon (November) seasons for the year 2010, 2011, 2018 and 2019. Multivariate analysis such as Pearson's correlation coefficient (r), K-mean, hierarchical clustering and principle component analysis (PCA) were applied to examine the drinking water quality at source sites. The strength of correlation among the parameters is reduced over the time. Cluster analysis provides six major hydro-chemical clusters in the study region. Clusters were compact during 2010-2011 and converted to overlapping structure in later period. The size of clusters was change from two clusters to six clusters during 2018-2019. These hydro-chemical clusters were examined through PCA and established six major hydro-chemical components of water quality. The physico-chemical parameters, namely, pH, alkalinity, TH, TDS, Na, K, Ca, Mg, Cl and SO4, were in PC-1, the heavy metals in PC-3, turbidity in PC-4, TC in PC-5 and PC-6 is combination of turbidity, NO3 and TC, whereas PC-2 was a mix of pH and Na and K salts. Study highlighted that the water quality has changed over the time due to runoff of plant debris, erosion, agricultural fertilizer, development activities and local geology hosts. Each PCs was mapped with associated human health issues. Result reveals that structures and pattern of PCs indicate several human health diseases over the later period with seasonal effects.
Subject(s)
Drinking Water , Metals, Heavy , Water Pollutants, Chemical , Drinking Water/analysis , Environmental Monitoring , Fertilizers/analysis , Humans , Metals, Heavy/analysis , Rivers/chemistry , Salts/analysis , Water Pollutants, Chemical/analysis , Water QualityABSTRACT
BACKGROUND: Therapeutic failure and drug resistance are common sequelae to insulin resistance associated with type 2 diabetes mellitus (T2DM). Consequently, there is an unmet need of alternative strategies to overcome insulin resistance associated complications. PURPOSE: To demonstrate whether Kutkin (KT), iridoid glycoside enriched fraction of Picrorhiza kurroa extract (PKE) has potential to increase the insulin sensitivity vis à vis glucose uptake in differentiated adipocytes. METHODS: Molecular interaction of KT phytoconstituents, picroside-I (P-I) & picroside- II (P-II) with peroxisome proliferator-activated receptor gamma (PPARγ), phosphatidylinositol 3-kinase (PI3K) and protein kinase B (Akt) were analyzed in silico. Cellular viability and adipogenesis were determined by following 3-(4, 5-Dimethylthiazol-2-Yl)-2, 5-Diphenyltetrazolium bromide (MTT) assay and Oil Red-O staining. Further, ELISA kit based triglycerides and diacylglycerol-O-Acyltransferase-1 (DGAT1) were assessed in differentiated adipocytes. ELISA based determination were performed to check the levels of adiponectin and tumor necrosis factor alpha (TNF-α). However, Flow cytometry and immunofluorescence based assays were employed to measure the glucose uptake and glucose transporter 4 (glut4) expression in differentiated adipocytes, respectively. Further to explore the targeted signaling axis, mRNA expression levels of PPARγ, CCAAT/enhancer binding protein α (CEBPα), and glut4 were determined using qRT-PCR and insulin receptor substrate-1 (IRS-1), Insulin receptor substrate-2 (IRS-2), PI3K/Akt, AS160, glut4 followed by protein validation using immunoblotting in differentiated adipocytes. RESULTS: In silico analysis revealed the binding affinities of major constituents of KT (P-I& P-II) with PPARγ/PI3K/Akt. The enhanced intracellular accumulation of triglycerides with concomitant activation of PPARγ and C/EBPα in KT treated differentiated adipocytes indicates augmentation of adipogenesis in a concentration-dependent manner. Additionally, at cellular level, KT upregulated the expression of DAGT1, and decreases fatty acid synthase (FAS), and lipoprotein lipase (LPL), further affirmed improvement in lipid milieu. It was also observed that KT upregulated the levels of adiponectin and reduced TNFα expression, thus improving the secretory functions of adipocytes along with enhanced insulin sensitivity. Furthermore, KT significantly promoted insulin mediated glucose uptake by increasing glut4 translocation to the membrane via PI3/Akt signaling cascade. The results were further validated using PI3K specific inhibitor, wortmannin and findings revealed that KT treatment significantly enhanced the expression and activation of p-PI3K/PI3K and p-Akt/Akt even in case of treatment with PI3K inhibitor wortmannin alone and co-treatment with KT in differentiated adipocytes and affirmed that KT as activator of PI3K/Akt axis in the presence of inhibitor as well. CONCLUSION: Collectively, KT fraction of PKE showed anti-diabetic effects by enhancing glucose uptake in differentiated adipocytes via activation of PI3K/Akt signaling cascade. Therefore, KT may be used as a promising novel natural therapeutic agent for managing T2DMand to the best of our knowledge, this is the first report, showing the efficacy and potential molecular mechanism of KT in enhancing insulin sensitivity and glucose uptake in differentiated adipocytes.
Subject(s)
Diabetes Mellitus, Type 2 , Insulin Resistance , Picrorhiza , 3T3-L1 Cells , Adipocytes , Adiponectin/metabolism , Animals , CCAAT-Enhancer-Binding Protein-alpha/metabolism , Cinnamates , Diabetes Mellitus, Type 2/drug therapy , Glucose/metabolism , Glucose Transporter Type 4/metabolism , Glycosides , Iridoid Glycosides/pharmacology , Mice , PPAR gamma/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Triglycerides/metabolism , Vanillic Acid , Wortmannin/pharmacologyABSTRACT
Background: Long-acting reversible contraceptives (LARC), a highly effective class of contraceptives, has a limited uptake by few couples due to lack of awareness, unavailability, and myths surrounding their application and side effects. Aims: This study was undertaken to understand and to clear myths of LARC among patients as well as to assess the knowledge, attitudes, practices, and preference. Materials and Methods: A hospital-based cross-sectional study using a semistructured questionnaire was conducted in the out-patient Department of Obstetrics and Gynecology, in a tertiary level hospital in Eastern India. A total of 600 women responded to the structured validated questionnaire. Results: High prevalence of teenage marriages (64%), teenage pregnancies (44%), and unwanted pregnancy (41%) was noted among responders. The knowledge scores were low in 66.7%, moderate in 26.66%, and only 6.66% had high level >80% scores in the 15 questions about LARC methods. While 41% had a positive attitude to future use of LARC, a majority (59%) had a strong negative attitude due to many myths of genital tract infections, discharges, and cancer, changed menstrual bleeding patterns, delayed conception after discontinuation, and altered sexual functions. Out of those with a positive attitude, 21% of women had a preference for intrauterine devices, 19.5% of women for injectables, and only 0.5% of women preferred contraceptive implants. 24.5% of women had used LARC in their lifetime but a meager 5% were currently using them. Conclusions: The study shows that there is a huge unmet need for spacing contraceptive methods as childbearing spacing is not maintained. There were lack of correct knowledge and awareness, and numerous myths surrounding LARC methods.