Jigna Shah

Parkinson’s disease (PD) is a chronic neurodegenerative disorder marked by the gradual loss of dopaminergic neurons. Mitochondrial impairment, neuroinflammation, oxidative stress, and abnormal aggregation of α-synuclein are the most prominent features of the pathology. Current therapeutic approaches lack disease-modifying abilities and render only symptomatic relief. It has been observed that increased risk of PD is somehow linked to type 2 diabetes mellitus, and these pathologies share some common signaling cascades. Hence, repurposing hypoglycemic agents targeting specific molecular signaling pathways that mediate α-synuclein aggregation and neuroinflammation can be an effective disease-modifying strategy for PD treatment. This study investigated the neuroprotective potential of the DPP-4 inhibitor, vildagliptin, in a mouse model of chemically induced PD. In silico analyses, including molecular docking as well as molecular dynamics simulation, demonstrate good binding affinity as well as stable interaction of vildagliptin with PI3K (4YKN) and NLRP3 (7ALV) proteins in comparison to other DPP-4 inhibitors (sitagliptin, saxagliptin, linagliptin, and alogliptin). In in vivo studies, it was observed that vildagliptin improved motor coordination, muscle strength, and cognitive abilities. Biochemical assays show a reduction in MDA and restoration of GSH, indicating alleviation of oxidative stress. Moreover, at the molecular level, vildagliptin upregulated neuroprotective markers like PI3K, AKT, CREB, BDNF, and TH and downregulated pathological and inflammatory markers like NLRP3, IL-1β, caspase-1, gasdermin D, and α-syn. Histopathological and immunohistochemistry studies also demonstrate preservation of dopaminergic neurons. These findings collectively suggest that vildagliptin rendered neuroprotection by PI3K/AKT activation and inhibition of NLRP3-mediated neuroinflammation and apoptosis. In conclusion, we can say that vildagliptin possesses definitive neuroprotective potential as a disease-modifying therapy that warrants further clinical exploration.

Alzheimer’s disease widely affects millions of people worldwide, accounting for 60% of dementia cases. Clinically classified by the presence of cognition impairment, pathophysiological representation includes deposited senile plaques, neurofibrillary tangles, and neuroinflammation. The pathogenesis of Alzheimer’s disease (AD) remains multifaceted and is governed by multiple hypotheses. However, it undeniably involves amyloid-β (Aβ) accumulation and hyperphosphorylated tau (p-tau) pathology as the crucial events in disease initiation. Substantial evidence has correlated Vitamin D₃ as a vital supplementation for the prevention of dementia and delays the progression of AD. The presence of localized Vitamin D receptors (VDR) in the brain and their capacity to convert absorbed Vitamin D to its active form have established a robust link between Vitamin D₃ and Alzheimer’s disease. The current study aims to explore the role of Vitamin D₃ on specific parameters related to Alzheimer’s disease in the Streptozotocin ICV-induced sporadic AD rat model. The study protocol included a single bilateral ICV STZ intrahippocampal injection to induce AD, followed by 21 days of treatment with two different doses of Vitamin D₃ or Calcitriol (1alpha,25-dihydroxyvitamin D₃)i.e., 2.5 μg/kg and 5.0 μg/kg. Results demonstrated that Vitamin D₃ attenuates AD-specific parameters of amyloid plaque (Aβ_1-40 and Aβ_1-42), p-tau, and BACE-1. Moreover, a significant increase in the levels of both neprilysin (NEP) and insulin-degrading enzyme (IDE) was observed, both of which play a crucial role in the clearance of senile plaques. Vitamin D₃ treatment also demonstrated a significant improvement in cognitive performance, along with attenuation of neuroinflammatory and oxidative stress parameters. Conclusively, optimal levels of Vitamin D₃ impart neuroprotection in AD by attenuating production and increasing clearance of amyloid proteins.

Alzheimer’s Disease (AD), a leading cause of dementia, is a known neurodegenerative disorder. Affecting millions of people worldwide, AD pathogenesis involves diverse risk factors such as lifestyle, environmental, and metabolic conditions that accelerate sporadic AD. Very recently, backed with substantial evidence, herpes simplex virus-1 (HSV-1) has been recognized as a potential causative factor that may play a pivotal role in sporadic AD. Latent virus is estimated to activate key underlying pathways, preferably Aβ and p-tau, to cause AD. Additionally, Antivirals such as Valacyclovir have emerged to impart a potential neuroprotective role in AD. Present research aimed to explore the neuroprotective role and mechanism of Valacyclovir in the streptozotocin-induced Alzheimer’s disease model in rats. A single dose of 3 mg/kg ICV (intracerebroventricular) Streptozotocin (STZ) was administered to induce AD in rats. Two doses of Valacyclovir, i.e., 100 mg/kg and 150 mg/kg were evaluated with Donepezil 5 mg/kg as standard. Post 21 days of treatment, Valacyclovir demonstrated dose-dependent improvement in neurobehavioral parameters. Further, AD-specific parameters i.e. Aβ1-40 and Aβ1-42, p-tau, and BACE-1 were significantly (p < 0.001) reduced with parallel reduction in inflammatory (p < 0.001) and oxidative stress markers. Additionally, Valacyclovir also increased the levels of amyloid clearance enzymes i.e., neprilysin (NEP) (p < 0.001) and insulin-degrading enzyme (IDE) (p < 0.001). Results suggest promising neuroprotective action of valacyclovir via reducing Aβ-amyloid protein, p-Tau, BACE-1, as well as demonstrating anti-inflammatory and antioxidant activity. Graphical Abstract

Breast cancer remains the most prevalent cancer among women and a significant cause of mortality, partly due to treatment resistance and adverse effects. Sorafenib, a tyrosine kinase inhibitor, and Pioglitazone, a PPAR-γ agonist, exhibit anti-cancer properties. This study explores improved anti-cancer effects of combination of Sorafenib and Pioglitazone for breast cancer treatment. Protein-ligand molecular docking was performed to identify interactions of both drugs with various proteins. Cytotoxic effects of Sorafenib and Pioglitazone, individually and in combination, were evaluated on MCF-7 cells using MTT assay. DMBA-induced breast cancer model in female Sprague-Dawley rats assessed tumor volume, survival rates, oxidative stress markers, cytokines, tumor markers, and histopathology. Rats were divided into six groups, including control, individual treatments, combination therapy, and a doxorubicin standard group. Sorafenib demonstrated dose-dependent cytotoxicity. Pioglitazone exhibited limited cytotoxic effects when used alone but showed significant cytotoxicity when combined with Sorafenib. Combination therapy resulted in reduced tumor volume, enhanced survival rates, and restored body weight in DMBA-induced treatment animals. It significantly lowered oxidative stress parameters and pro-inflammatory cytokines, including IL-6, IL-1β, and TNF-α, as well as phosphorylated Akt levels. It inhibited tumor angiogenic markers VEGFR2 and VEGFR3 and promoted tumor suppressor p53 levels. Histopathological analysis confirms a reduction in tumor cell invasion and inflammation. The combination of Sorafenib and Pioglitazone exhibited enhanced anti-cancer effects by suppressing oxidative stress, inflammatory markers, pAkt, VEGF2, and VEGF3, as well as upregulating p53 levels, highlighting the promising potential of this combination for breast cancer treatment.

Parkinson's disease (PD) is one of the most common progressive neurodegenerative pathologies that leads to dopaminergic deficiency and motor manifestations. Alpha-synuclein aggregation is a characteristic hallmark of PD pathogenesis. These aggregates facilitate the formation of Lewy bodies and degeneration. The epidemiological evidence demonstrates a definitive association of diabetes with PD risk. Considering this, many antidiabetic agents such as GLP-1 agonists and DPP-4 inhibitors are being explored as alternative PD therapeutics. This study evaluated the neuroprotective effect of the DPP-4 inhibitor sitagliptin mediated by the PI3K/AKT and Nrf2 pathways in PD models. In silico studies were conducted to determine the binding affinity, stability, and ADMET properties of DPP-4 inhibitors with target proteins. Sitagliptin (15 mg/kg p.o.) was administered in rotenone (30 mg/kg p.o. for 28 days)-induced and MPTP/P (25 mg/kg i.p. MPTP and 100 mg/kg probenecid i.p. twice a week for 5 weeks)-induced PD mouse (C57/BL6) models. Neurobehavioral assessments were carried out throughout the study. Biochemical (GSH, MDA), molecular estimations (AKT, Nrf2, PI3K, GSK-3β, GLP1, CREB, BDNF, NF-κB, alpha-synuclein), histopathological studies, and immunohistochemistry were carried out at the end of the study. The in silico studies demonstrate better binding, stability, and ADMET profile of sitagliptin with both target proteins. Sitagliptin restored cognitive and motor deficits in both rotenone- and MPTP/P-induced mouse models. There was upregulation of PI3K, AKT, Nrf2, CREB, and BDNF levels and downregulation of GSK-3β, NF-κB, and alpha-synuclein levels in both models after treatment with sitagliptin. However, GLP1 levels were not significantly restored, indicating a GLP1-independent mechanism. It also restored histopathological alterations and TH+ neuronal loss induced by rotenone and MPTP/P. These findings demonstrate that sitagliptin exhibits neuroprotective action mediated by upregulation of the PI3K/AKT and Nrf2 pathways in rotenone and MPTP/P mouse models of PD.

Parkinson's disease (PD) is an age-related progressive disorder that leads to dopaminergic loss and subsequent motor dysfunction. Current therapies mainly deal with symptomatic effects, and hence, therapies targeting progressive neurodegeneration need to developed. In this study, tirzepatide, a coagonist of glucagon like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptors, exhibited a neuroprotective effect in preliminary studies. This study aims to evaluate the effect of tirzepatide, in comparison with exendin-4, in a rat model of PD. The effect of tirzepatide (50 and 100 nmol/kg, s.c.) and exendin-4 (8 μg/kg, s.c.) on behavioral functions, oxidative markers, inflammatory markers, dopamine level, and alpha-synuclein expression were studied against a rotenone (2 mg/kg)-induced toxicity model in rats. Tirzepatide prevented rotenone-induced motor deficits. Additionally, it significantly inhibited the rotenone-induced increase in proinflammatory cytokines TNF-α and IL-6. Furthermore, it upregulated striatal dopamine levels. It alleviated oxidative stress and alpha-synuclein aggregation. Both doses of tirzepatide exert neuroprotective effects in a PD rat model. Furthermore, the effect is dose-dependent, and a 100 nmol/kg dose of tirzepatide was found to be more effective.