Chronic Unpredictable Mild Stress (CUMS) is a well-established model for inducing behavioral, cognitive, neurochemical, and metabolic impairments associated with neurobehavioral alterations. This stud Show more
Chronic Unpredictable Mild Stress (CUMS) is a well-established model for inducing behavioral, cognitive, neurochemical, and metabolic impairments associated with neurobehavioral alterations. This study assessed the neuroprotective, antidepressant, and metabolic regulatory effects of Lonafarnib, a selective farnesyltransferase inhibitor, in mice subjected to chronic unpredictable mild stress (CUMS) for 28 days. The in silico docking analysis revealed encouraging binding energies of Lonafarnib with AChE (- 11.58 kcal/mol), CRF1 (- 10.94 kcal/mol), BDNF (- 5.99 kcal/mol), 5HT1A (- 10.48 kcal/mol), and 5HT2A (- 10.77 kcal/mol). This suggests a potential structural compatibility with cholinergic, serotonergic, neurotrophic, and stress-related proteins as preliminary results which requires experimental validation. The in -vivo study of Lonafarnib (20 or 40 mg/kg, i.p.) were effective in preventing the neurobehavioral alterations in CUMS mice. As, the behavioral evaluations demonstrated that CUMS resulted in anxiety-like behaviors, depressive-like behaviors, and cognitive impairments (p < 0.0001), all of which were significantly alleviated by Lonafarnib, particularly at a dosage of 40 mg/kg. The administration of Lonafarnib resulted in significant improvements in behavioral performance, a reduction in oxidative and inflammatory markers (IL-6, TNF-α), stabilization of HPA-axis related parameters, normalization of corticosterone, glucose, and lipid profiles, along with an increase in BDNF levels. Histological findings also indicated the preservation of neuronal structure within the hippocampus. In conclusion, these findings suggest that Lonafarnib may offer protective advantages against neurobehavioral and metabolic dysfunction caused by CUMS. However, a comprehensive mechanistic validation of prenylation-dependent signaling pathways is essential for further investigation. Show less
Alzheimer's disease (AD) is the prime cause of 65-80% of dementia cases and is caused by plaque and tangle deposition in the brain neurons leading to brain cell degeneration. β-secretase (BACE-1) is a Show more
Alzheimer's disease (AD) is the prime cause of 65-80% of dementia cases and is caused by plaque and tangle deposition in the brain neurons leading to brain cell degeneration. β-secretase (BACE-1) is a key enzyme responsible for depositing extracellular plaques made of β-amyloid protein. Therefore, efforts are being applied to develop novel BACE-1 enzyme inhibitors to halt plaque build-up. In our study, we analyzed some Elenbecestat analogues (a BACE-1 inhibitor currently in clinical trials) using a structure-based drug design and scaffold morphing approach to achieve a superior therapeutic profile, followed by in silico studies, including molecular docking and pharmacokinetics methodologies. Among all the designed compounds, SB306 and SB12 showed good interactions with the catalytic dyad motifs (Asp228 and Asp32) of the BACE-1 enzyme with drug-likeliness properties and a high degree of thermodynamic stability confirmed by the molecular dynamic and stability of the simulated system indicating the inhibitory nature of the SB306 and SB12 on BACE 1. Show less
DUSP6 phosphatase serves as a negative regulator of MAPK kinases involved in numerous cellular processes. BCI has been identified as a potential allosteric inhibitor with anticancer activity. Our stud Show more
DUSP6 phosphatase serves as a negative regulator of MAPK kinases involved in numerous cellular processes. BCI has been identified as a potential allosteric inhibitor with anticancer activity. Our study was designed to test the anticancer properties of BCI in colon cancer cells, to characterize the effect of this compound on chemotherapeutics such as irinotecan and oxaliplatin activity, and to identify potential molecular targets for this inhibitor. BCI cytotoxicity, proapoptotic activity, and cell cycle distribution were investigated in vitro on three colon cancer cell lines (DLD1, HT-29, and Caco-2). In silico investigation was prepared to assess BCI drug-likeness and identify potential molecular targets. The exposure of colorectal cancer cells with BCI resulted in antitumor effects associated with cell cycle arrest and induction of apoptosis. BCI exhibited strong cytotoxicity on DLD1, HT-29, and Caco-2 cells. BCI showed no significant interaction with irinotecan, but strongly attenuated the anticancer activity of oxaliplatin when administered together. Analysis of synergy potential further confirmed the antagonistic interaction between these two compounds. In silico investigation indicated CDK5 as a potential new target of BCI. Our studies point to the anticancer potential of BCI but note the need for a precise mechanism of action. Show less