Biology subjects

Ravichandiran, V.

Publications and source records attributed to Ravichandiran, V..

3 recordsLinked to original sources

bioRxiv2026

Dehydrozingerone mitigates energy deficits and cognitive impairments induced by cranial irradiation

Radiotherapy is widely used in the management of brain tumors; however, it is often associated with delayed adverse effects, including cognitive decline and depression-like behavior. These effects are thought to arise, in part, from suppressed hippocampal neurogenesis, altered neuronal architecture, and microglial dysfunction. Despite this, the precise mechanisms underlying irradiation-induced cognitive deficits, as well as effective therapeutic interventions, remain poorly understood. In the present study, six-month-old male mice were subjected to a single 9 Gy dose of cranial irradiation, followed by behavioral assessments several weeks post-exposure. We observed that cranial irradiation significantly impaired hippocampal-, prefrontal cortex-, and cortical-dependent memory functions. Notably, treatment with dehydrozingerone (DH), a curcumin analog (50 mg/kg, oral administration for two weeks), markedly prevented these cognitive deficits. At the molecular level, irradiation disrupted the activity of key enzymes involved in the tricarboxylic acid (TCA) cycle and the glutamate-glutamine/GABA cycle, both of which were restored following DH treatment. Furthermore, irradiation induced dysregulation of genes and proteins associated with glycolysis (Atp2b1, mt-Nd2, mt-Atp6), mitochondrial energetics (mt-Atp8, mt-Cytb), glucose transport (Slc4a5), insulin resistance (Etnppl), lipid metabolism (Pla2g3, Plin4), and inflammation (Ighg2c), all of which were significantly normalized by DH. Importantly, DH also prevented irradiation-induced loss of cell-type-specific glucose transporter expression, including GLUT3 in neurons and GLUT5 in microglia. In conclusion, our findings suggest that DH is a promising therapeutic candidate for mitigating irradiation-induced energy deficits and cognitive impairments, likely through modulation of metabolic and mitochondrial pathways.

neuroscience↗

bioRxiv2025

Epoxyazadiradione ameliorates Parkinson's disease by upregulating heat shock factor 1 and protein degradation pathways in mice.

Parkinsons disease (PD) is a major debilitating health concern for millions of the elderly population all over the world. This progressive neurodegenerative disorder also poses a severe mental and financial burden to caregivers and society. Despite a major thrust on research for therapy development, no significant progress has been made; only temporary management options are currently available. To this end, we have reported azadiradione (AZD), a triterpenoid that we isolated from neem seed extract using a cell-based assay. AZD showed high efficacy in ameliorating protein aggregation-induced pathology and symptoms in fruit flies and mice. Current evidence suggests that AZD functions through activating the transcriptional function of heat shock factor 1 (HSF1), a master regulator of protein quality control pathways, without modulating the cellular redox balance. To better understand the pharmacophore of AZD, a triterpenoid in its observed function, we have analysed various structural derivatives, focusing on their HSF1-activating function in vitro and their efficacies in ameliorating protein aggregation-induced toxicities in cell and mouse models. Our analyses, based on real-time PCR, immunoblots, fluorescent anisotropy, and a mouse model of MPTP-induced PD, highlighted Epoxy-azadiradione (Epoxy) as being as efficient as AZD in in vivo functional tests, albeit activating the promoter binding activity of HSF1 with at least two-fold higher efficacy in vitro. Notably, similar to AZD, Epoxy did not induce cellular redox imbalance. We also incorporated molecular docking analyses involving the published crystal structure of the DNA-binding domain of HSF1 bound to its DNA recognition element to study molecular dynamics-based energy estimation. The analysis revealed a higher energy stability of the epoxy-bound complexes, as indicated by a significant decrease in binding free energy ({Delta}G) estimated from an ensemble of intermediate docked complex structures.

pharmacology and toxicology↗

bioRxiv2023

A mechanistic study on the tolerance of PAM distal end mismatch by SpCas9

CRISPR-Cas9 is the newest technology available for targeted genome editing. It is very efficient and cheap compared to other genome editing techniques. However, its therapeutic application is limited due to its off-target activity. To have a better understanding of this off-target effect, we concentrated our efforts on its mismatch-prone PAM distal end. Current off-target prediction algorithms use RNA-DNA complementation derived energy as a major factor in predicting off-target effect. RNA-DNA complementation derived energy drives Cas9 conformational change, which in turn drives its functional activity. In the case of lower RNA-DNA complementarity, a partial conformational change occurs resulting in a slower reaction rate and partial activity. However, extensive mismatches are often tolerated despite lower complementation derived energy available from RNA: DNA duplex formation. Thus, the off-target activity of Cas9 depends directly on the nature of mismatches which in turn result in deviation of the active site of the enzyme due to structural instability in the duplex strand. In order to test the hypothesis, we have designed an array of mismatched target sites and performed in vitro and cell line-based experiments to assess the effects of PAM distal mismatches in Cas9 activity. For further mechanistic validation, Molecular dynamics simulation was performed and it revealed that certain mismatch mutations induced pronounced conformational instability within the RNA-DNA duplex, leading to elevated root mean square deviation (RMSD) values. We found that, target sites having mismatches in the 18th to 16th position upstream of the PAM showed no to little activity.

genomics↗