👤 Rekha M M

Epilepsy is a debilitating neurological disorder that impacts approximately 50 million people worldwide. The treatment of epilepsy with antiepileptic drugs has not achieved effective seizure management and thus requires new therapeutic options. This study investigated the catechins' affect on epilepsy-related molecular targets using a computational method that combined network pharmacology, molecular docking, and molecular dynamics (MDs) simulation. We fetched 84 catechins-related and 5356 disease-associated targets from various databases, yielding 31 common targets. The protein-protein interaction (PPI) network of 31 common targets identified 10 hub genes, including ALB, INS, brain-derived neurotrophic factor (BDNF), PTGS2, tumor necrosis factor (TNF), IL1B, FOS, IL6, LEP, and FGF2. Further, the functional enrichment analysis revealed that these common targets have a high prevalence in multiple pathways and gene ontology functions. Furthermore, "compound-target" and "compound-gene-pathway" networks were constructed and analyzed. Network pharmacology data show TNF, IL1B, and IL6 could influence epilepsy treatment by regulating several pathways. The Cresset Flare Pro+ docking study unveiled that the lead catechin, epigallocatechin gallate (EGCG), exhibited the highest Lead Finder (LF) dG scores of -10.2, -9.40, and -8.15 kcal/mol against TNF, IL6, and IL1B, respectively. The electrostatic complementarity and Molecular Mechanics with Generalized Born and surface area (MMGBSA) results supported the docking results. Further, the stability of EGCG-bound complexes was analyzed using a 300 ns MD simulation. The principal component analysis yielded promising results for the EGCG-2AZ5 and EGCG-1ALU complexes collective motion. These findings provide computational evidence suggesting that EGCG has a promising scaffold for designing multi-target molecules that could modulate epilepsy, meriting further experimental validation. Show less

Phthalates are well-known emerging contaminants in the environment and food packaging, posing serious risks to human health as endocrine disruptors with significant neurotoxic potential. Epidemiological and experimental evidence have linked early-life phthalate exposure to neurodevelopmental disorders, including attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). However, the precise molecular mechanisms responsible for these associations remain poorly understood. This study aimed to comprehensively investigate the putative toxic targets and molecular pathways underlying phthalate-induced ADHD and ASD through integrated network toxicology and molecular docking approaches. Targets related to phthalates, ADHD, and ASD were extracted from various databases, yielding 21 potential targets associated with ADHD and ASD, which are common to the studied phthalates. Network analysis highlighted BDNF and ESR1 as the top two core targets. Functional enrichment analyses demonstrated that the core targets are involved in multiple pathways. Furthermore, the GEO database was queried to identify differentially expressed genes (DEGs) and gene modules through Weighted Gene Co-expression Network Analysis (WGCNA) using the R package. Moreover, molecular docking demonstrated high binding affinity between phthalates and core targets, with di(2-ethylhexyl) phthalate with BDNF and diisononyl phthalate with ESR1, emphasizing the potential role of phthalate exposure in neurodevelopmental disorders. The stability of these complexes was demonstrated through molecular dynamics simulations, which confirmed their binding interactions remained constant throughout the simulation. Our findings contribute to a deeper understanding of the intricate molecular mechanisms of phthalate-induced neurotoxicity, offering a valuable foundation for the development of future therapeutic strategies to mitigate their adverse effects on neurodevelopment. Show less

Alzheimer's disease is a progressive, irreversible, neurodegenerative disease, i.e., characterized by the presence of amyloid plaques, hyperphosphorylated tau protein (hyper p-tau), neural damage, etc. β-amyloid precursor protein cleavage enzyme 1 (BACE-1) inhibition is a promising avenue for slowing AD progression. In a rate-limiting step, BACE-1 cleaves the amyloid precursor protein (APP) into soluble amyloid precursor protein β (sAPPβ) and a membrane-bound C-terminal fragment called C99. γ-secretase processes C99, resulting in neurotoxic amyloid β (Aβ). Selective and potent BACE-1 inhibitors offer promising therapeutic avenues for Alzheimer's disease. While BACE-1 inhibitors have shown significant assurance as potential treatments for Alzheimer's disease, many early compounds struggled to advance clinically due to poor brain penetration, limited selectivity, and unwanted side effects. Over the last two decades, substantial progress has been made in the development of BACE-1 inhibitors, leading to the emergence of diverse structural frameworks such as aminohydontoins, dihydropyridines, pyrimidines, and iminohydantoins, and fused heterocycles. This review provides an in-depth analysis of the synthetic strategies employed. It emphasizes the structure-activity relationship (SAR) trends that have guided their optimization and the crystal structure of the enzyme used in the inhibition study. Show less

Lipoprotein (a) [Lp(a)] levels are closely related to the development of ischemic heart disease in international studies; however, the impact on the severity of coronary and cardiac involvement in our country has not been described. High levels of Lp(a) are associated with greater involvement of coronary disease and ventricular function compromise. Cross-sectional study among patients with ischemic heart disease admitted to a cardiac intensive care unit after acute coronary syndrome (ACS) or after coronary angioplasty for chronic coronary syndrome. Lipid profile and Lp(a) measurements were performed within the first 24 hours of admission, and echocardiogram with left ventricular ejection fraction (LVEF) measurement was performed within 5 days of admission. The magnitude of coronary disease (number of coronary arteries severely affected) and LVEF were evaluated in patients distributed according to Lp(a) levels considering a cut-off of 30 mg/dL and 50 mg/dL. One hundred and eighteen subjects were recruited, aged 65.9±20.2 years, 74.6% men, and 75% with ACS. Sixty patients (50.8%) were taking statins. Left anterior descending artery involvement was observed in 78.8%, with mean LVEF 49.9±17.5%, LDL 95.6±43.4 mg/dL (LDL >70 mg/dL in 69.4%), non-HDL 120.4±49.1 mg/dL, and Lp(a) 40.5±38.6 mg/dL. Lp(a) levels >30 mg/dL were detected in 42.3% and >50 mg/ dL in 27.9% of subjects. Lp(a) >30 mg/dL was associated with LVEF <40% (OR 2.6, p= 0.02), and values >50 mg/dL were related to LVEF <40% (OR 3.7, p= 0.03) and significant disease of 2 or more coronary arteries (OR 2.4, p= 0.04). Multivariate logistic regression analysis showed that Lp(a) levels >50 mg/dL were related to a higher risk of LVEF <40% (OR 3.8, p<0.01) and multivessel coronary disease (OR 2.8, p= 0.03). In patients with established coronary heart disease, elevated Lp(a) levels are associated with a greater severity of coronary involvement and a lower LVEF. Show less

The leading factor contributing to patient mortality is the local invasion and metastasis of tumors, which are influenced by the malignant progression of tumor cells. The epithelial-mesenchymal transition (EMT) is key to understanding malignancy development. EMT is a critical regulatory mechanism for differentiating cell populations initially observed during the neural crest and embryonic gastrulation formation. This process is closely associated with tumor metastasis in cancer and is also related to the maintenance of cancer stem cells. Flavonoids, known for their antioxidant properties, have been widely studied for their anticancer potential to protect plants from harmful environmental conditions. They have attracted considerable attention and have been the focus of numerous experimental and epidemiological studies to evaluate their potential in cancer treatment. In vitro and in vivo research has demonstrated that flavonoids can significantly impact cancer-related EMT. They may inhibit the EMT process by reducing the levels of Twist1, N-cadherin, ZEB1, integrins, SNAI1/2, CD44, MMPs, and vimentin while increasing E-cadherin levels and targeting the PI3K/AKT, NF-κB p65, and JAK2/STAT3 signaling pathways. In order to suppress the transcription of the E-cadherin promoter, several Zn-finger transcription factors, such as SNAI2, ZEB1, and ZEB2, and basic helix-loop-helix (bHLH) factors, such as Twist, may directly bind to its E-boxes. Overall, clinical cancer research should integrate the anticancer properties of flavonoids, which address all phases of carcinogenesis, including EMT, to improve the prospects for targeted cancer therapies in patients suffering from aggressive forms of tumors. Show less