The microbiome and rheumatic heart disease: current knowledge and future perspectives.

Rheumatic heart disease (RHD) is a cardiovascular disease caused by an autoimmune response to group A Streptococcus (GAS) infection resulting in the damage of heart valves. RHD is the most commonly acquired heart disease among children and young adults with a global burden of over 40 million cases accounting for 306,000 deaths annually. Inflammation in the heart valves caused due to molecular mimicry between the GAS antigens and host cardiac proteins is facilitated by cytokines, cross-reactive antibodies and CD4+ T cells. The complex interaction between genetic and environmental factors linked with erratic events leads to the loss of immunological tolerance and autoimmunity in RHD. Despite extensive research on the etiopathogenesis of RHD, the precise mechanism underpinning the initiation of acute rheumatic fever (ARF) to the progression of RHD still remains elusive. Mounting evidences support the contribution of the human microbiome in the development of several immune-mediated diseases including rheumatoid arthritis, juvenile idiopathic arthritis, Kawasaki disease, inflammatory bowel disease and type 1 diabetes. The microbiome and their metabolites could play a crucial role in the integrity of the epithelial barrier, development of the immune system, inflammation and differentiation of T cell subsets. Consequently, microbiome dysbiosis might result in autoimmunity by molecular mimicry, epitope spreading and bystander activation. This review discusses various aspects of the interaction between the microbiome and the immune system in order to reveal causative links relating dysbiosis and autoimmune diseases with special emphasis on RHD.

Molecular docking analysis of bioactive compounds from Plectranthus amboinicus with glucokinase.

Natural remedies from medicinal plants are known to be effective and reliable appropriate medicine for illnesses. The current research examined Plectranthus amboinicus' anti diabetic property by docking the bioactive compounds of certain target proteins. We document the molecular docking analysis of bioactive compounds from Plectranthus amboinicus with protein Glucokinase. Molecular docking experiments were carried out in PyRx software. Results of these docking experiments showed that most of the compounds showed very strong interaction with the target protein Glucokinase. Based on the scoring parameters we have selected best four compounds (Rutin, Salvianolic acid, Luteolin and Salvigenin) which showed very good docking score and hydrogen bond interaction for diabetics.

Molecular docking analysis of metformin analogues with GSK-3ß.

We report the molecular docking analysis of four analogues of metformin [1-Carbamimidoyl-1,2-dimethylguanidine hydrochloride, Metformin hydrochloride, N1,N1-Dimethyl-N5-methylbiguanide hydrochloride, and N1,N1,N5,N5-Tetrakis (methyl-biguanide hydrochloride] with GSK3.

Molecular docking analysis of flavonoids with aldose reductase.

Diabetes mellitus is a group of metabolic disorders that has risen to become the third most common cause in humans in recent years. The development of new bioactive substances from natural sources is a relatively new area. Flavonoids are believed to have a variety of beneficial properties in nature, including anti-inflammatory, antimicrobial, anticancer, antioxidant, neuroprotective, and anti-HIV properties. 15 naturally occurring flavonoids docked with the selected target aldose reductase. We report the optimal binding of Acumitin, Agathisflavone, Agehoustin B, and alpha-Toxicarol with aldose reductase for further consideration in drug discovery for T2DM.

Molecular docking analysis of bioactive compounds from Cissampelos pareira with PPAR gamma.

We document the Molecular docking analysis of bioactive compounds from Cissampelos pareira with PPAR gamma for further consideration in drug discovery for T2DM.

Thyroid-Stimulating Hormone Favors Runx2-Mediated Matrix Mineralization in HOS and SaOS2 Cells: An In Vitro and In Silico Approach.

Osteoporosis is a skeletal disease that is both systemic and silent characterized by an unbalanced activity of bone remodeling leading to bone loss. Rising evidences demonstrate that thyroid stimulating hormone (TSH) has an important role in the regulation on the metabolism of bone. However, TSH regulation on human osteoblast essential transcriptional factors has not been identified. Current study examined the role of TSH on human osteoblastic Runx2 expression and their functional genes by in vitro and in slico analysis. Human osteoblast like (HOS and SaoS-2) cells were cultured with DMEM and treated with hTSH at the concentration of 0.01 ng/mL and 10 ng/mL. After treatment, osteoblastic Runx2 and IGF-1R beta expression were studied using RT-PCR and western blot analysis. TSH treatment induced osteoblastic essential transcriptional factor, Runx2 in HOS and SaOS2 cells on 48 h duration and elevated the expression of IGF-IR ß gene and Protein in SaoS-2 cells. TSH also promotes Runx2 responsive genes such as ALP, Collagen and osteocalcin in SaOS2 cells on day 2 to day 14 of 10 ng/mL of treatment and favors' matrix mineralization matrix in these cells. In addition, TSH facilitated human osteoblastic cells to mineralize their matrix confirmed by day 21 of alizarin red calcium staining. In silico study was performed to check CREB and ELK1 interaction with Runx2. Results of in silico analysis showed that TSH mediated signalling molecules such as CREB and ELK1 showed interaction with Runx2 which involve in osteobalstic gene expression and differentiation. Present findings confirm that TSH promotes Runx2 expression, osteoblastic responsive genes and bone matrix formation.

Association of HLA-DRB1 Alleles with Rheumatic Fever and Rheumatic Heart Disease: A Meta-analysis.

BACKGROUND: Rheumatic fever (RF) and its sequel rheumatic heart disease (RHD) is an autoimmune disease caused by an abnormal host immune response to group A streptococcus (GAS) infection. The HLA class II molecules are entailed in immune-mediated infectious, inflammatory, and autoimmune diseases including RHD. However, HLA class II genes are reported to be associated with RF/RHD across different populations with a very little consistency. OBJECTIVE: The aim of the study is to investigate the association between HLA class II genes and RF/RHD by meta-analysis. METHODS: A comprehensive literature search was conducted to identify all relevant case-control studies published before December 31, 2019. The data were extracted using standardized form and pooled odds ratio (OR) with 95% confidence interval (CI) are calculated to assess the strength of the association between HLA class II genes and RF/RHD. RESULTS: Thirteen studies for HLA-DRB1 alleles (1065 patients and 1691 controls) and eight studies for HLA-DQB1 alleles (644 patients and 1088 controls) were finally included. The meta-analysis showed a significantly higher frequency of HLA-DRB1*07 allele (OR = 1.68, P < .0001) in RF/RHD patients when compared to controls, while the frequency of HLA-DRB1*15 allele (OR = 0.60, P = .03) was significantly lower in RF/RHD patients than in controls. However, there were no significant differences in the frequency of HLA-DQB1 alleles between RF/RHD patients and controls. CONCLUSIONS: The results of the meta-analysis suggest that the differential presentation of autoimmune peptides by HLA-DRB1*07 (susceptible) and HLA-DRB1*15 (protective) alleles with different affinities may play a crucial role in the pathogenesis of RF/RHD.

Beta-sitosterol attenuates insulin resistance in adipose tissue via IRS-1/Akt mediated insulin signaling in high fat diet and sucrose induced type-2 diabetic rats.

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.

Molecular docking analysis of compounds from Justica adhatoda L with the MUC1 oncoprotein.

The MUC1 oncoprotein is known to be linked with different types of cancer. Therefore, it is of interest to document the molecular docking analysis of compounds from Justica adhatoda L with the MUC1 oncoprotein. We report the structure based molecular binding features compounds such as amrinone, ethambutol, pyrazinamide and vasicoline the MUC1 oncoprotein for further consideration in drug discovery.

Effect of statins with α-tricalcium phosphate on proliferation, differentiation, and mineralization of human dental pulp cells.

INTRODUCTION: The aim of this study was to investigate the combined effect of statin and α-tricalcium phosphate (α-TCP) on odontoblastic differentiation of human dental pulp cells and to compare them with mineral trioxide aggregate (MTA). METHODS: Experimental cements were prepared with TCP containing simvastatin and atorvastatin. Cell proliferation, cell adherence on a dentin disc, alkaline phosphatase (ALP) activity, expression of osteogenic/odontoblastic markers, and mineralization of the human dental pulp cells on experimental cement and MTA were assessed. RESULTS: The cell growth and ALP activity of TCP containing simvastatin-treated cells was greater than MTA-treated cells. The mineralization and messenger RNA expression of markers (ie, dentin sialophosphoprotein, dentin matrix protein 1, bone morphogenetic protein 2, ALP, and osteonectin) of TCP containing simvastatin- and TCP containing atorvastatin-treated cells were comparable with MTA-treated cells. The enhanced cell proliferation and similar level of ALP of TCP-treated cells compared with the control indicate that α-TCP is an effective osteoconductive material. The differentiation effect observed in TCP containing simvastatin- and TCP containing atorvastatin-treated cells is attributed to the effect of statin. CONCLUSIONS: The results suggest that α-TCP can be used for local delivery of statin as a pulp capping material to accelerate reparative dentin formation.

Cissus quadrangularis augments IGF system components in human osteoblast like SaOS-2 cells.

Osteoporosis is a public health problem which is associated with significant morbidity and mortality. Growth factors are produced locally in the bone and control cellular events such as induction of bone growth. Signaling through the Insulin-like growth factor (IGF)-I receptor (IGF-IR) by locally synthesized IGF - I or IGF-II in osteoblast is considered crucial for normal development and for bone remodeling. Traditional use of Cissus quadrangularis (C. quadrangularis) in the treatment of bone disorders have been documented, however its regulatory effects on IGF system components remain largely unknown. The present study is employed to delineate the effects of ethanolic extract of C. quadrangularis on the regulation of IGF system components in human osteoblast like SaOS-2 cells. RT-PCR analysis revealed an increase in the mRNA expression of IGF-I, IGF-II, IGF-IR in cells treated with C. quadrangularis when compared with control cells. The mRNA expression of IGF binding protein-3 (IGFBP-3) did not differ significantly between control and C. quadrangularis treated cells. Immunoradiometric analysis revealed increased levels of IGF-I, IGF-II and IGFBP-3 in the conditioned medium of C. quadrangularis treated cultures when compared with control. Western blotting analysis revealed increase in protein levels of IGF-IR in cells treated with C. quadrangularis. These results indicate positive regulation of C. quadrangularis on the IGF system components of human osteoblast like SaOS-2 cells.