Shyam Sunder Sharma

This study presents a novel triazole‐based compound as a highly promising therapeutic agent against Alzheimer's disease (AD), specifically targeting amyloid beta (A β ) toxicity in neuronal cells. Using a comprehensive blend of advanced spectroscopy, microscopy, and mass spectrometry techniques, we demonstrate that this compound effectively inhibits A β peptide oligomerization, a well‐established primary driver of AD pathology. Crucially, high‐resolution mass spectrometry reveals the compound's selective affinity for distinct, highly toxic oligomeric populations, particularly tetramers and pentamers. These specific intermediate structures are abundant during the A β misfolding pathway and play a pivotal role in driving severe neurodegeneration. By disrupting the formation of these early‐stage toxic structures, the compound neutralizes their detrimental effects, limits amyloid accumulation, and actively promotes overall neuronal health. Furthermore, comprehensive molecular modeling analysis identifies acetylcholinesterase (AChE) as the primary macromolecular target for the observed drug action, suggesting a powerful multifaceted mechanism. By successfully mitigating A β ‐induced neurodegeneration and targeting AChE, this research underscores the immense potential of triazole‐based scaffolds in AD drug discovery. Ultimately, these findings highlight the therapeutic value of selectively halting A β oligomerization, offering molecular insights that pave the way for innovative, disease‐modifying treatments.

Introduction: Transient Receptor Potential (TRP) channels have gained worldwide attention for their expression and distribution in multiple human organs. Among these TRPs, Transient Receptor Potential Vanilloid (TRPV) channels play diverse physiological roles in the brain, and changes in their expression contribute to central nervous system (CNS) diseases. In a previous druggable-genome α-synuclein modifier screen, a member of the TRPV family, TRPV2, emerged as a Tier 3 ion-channel candidate, meeting directionality and conflict-score criteria, though with limited shRNA-level support. However, based on this preliminary data and the known role of TRPV2 in Ca ²⁺ entry and cellular stress responses, we decided to investigate its role in detail using experimental PD models. Methods: In the present investigation, 6-hydroxydopamine (6-OHDA) was used in vivo (Sprague Dawley rats) and in vitro (SH-SY5Y cells) to induce Parkinson’s disease (PD), and its effect on TRPV2 expression was investigated. The study further involved measuring behavioral parameters using the rotarod, open field, apomorphine, and cylinder tests. Results: 6-OHDA administration induced excessive reactive oxygen species (ROS) production and increased expression of TRPV2 channels. This is also accompanied by increased intracellular calcium influx and reduces cell viability. However, Tranilast, a TRPV2 antagonist, exhibited promising neuroprotective effects in the 6-OHDA PD model by restoring tyrosine hydroxylase levels, reducing oxidative stress, and improving motor function. Also, it diminished the intracellular Ca ²⁺ influx and reduced ROS levels in the 6-OHDA-treated SH-SY5Y cells. Conclusion: Overall, our results suggest that TRPV2 levels are elevated in PD, and targeting TRPV2 could be a potential therapeutic approach in the future.

Cognitive impairment represents the most prevalent complication of neurological diseases (NDs), which significantly affects the quality of life in affected patients. Current treatments primarily target neurotransmitter imbalances but do not act on the key pathological events such as Ca ²⁺ dyshomeostasis, oxidative stress, microglia activation, mitochondrial dysfunction and neuroinflammation that occur in the brain of patients with NDs. Therefore, existing treatments fail to stop the progressive cognitive decline in these diseases. Thus, there is a critical need for literature which covers the potential novel therapeutic targets along with their modulators for the effective treatment of cognitive impairment associated with NDs. Recently, transient receptor potential (TRP) channels have emerged as key regulators of these pathological events implicated in ND‐associated cognitive impairment. Many preclinical studies have demonstrated that pharmacological modulation of specific TRP channels can improve cognitive function in animal models of NDs. However, clinical translation of TRP channel modulators is still constrained due to a lack of subtype specificity, limited clinical data and difficulties in drug delivery across the blood–brain barrier (BBB). In the present review, we have discussed the structural diversity of TRP channels, their role in regulating synaptic plasticity and cognitive function, and their potential as pharmacological targets for the treatment of cognitive impairment, which can provide a direction for future research in this field.

Cardiovascular diseases (CVDs) are the leading cause of death among non-communicable diseases globally. Myocardial infarction (MI) is one of the most significant CVDs resulting from acute or chronic myocardial ischemia, which can lead to irreversible damage. Despite the substantial burden posed by these conditions, specific treatments remain limited to symptomatic management. ApoEFrag has been shown to be protective in the CNS. However, the cardioprotective potential of ApoE-mimetic has not been investigated. Thus, this study investigates the cardioprotective potential of ApoEFrag, a novel ApoE-mimetic peptide, in an acute MI model in rats. MI was induced in rats through two doses of isoproterenol (100 mg/kg via subcutaneous injection) administered 24 h apart. ApoEFrag was given at doses of 0.5 and 1 mg/kg to ISO-treated rats. Following treatment, we measured electrocardiogram (ECG) changes and arterial and ventricular pressure functions using the PV-loop system. Plasma and heart samples were collected for biochemical assessments, including plasma injury markers, hypertrophic index parameters, inflammatory markers, gene/protein expression analysis, and histopathological studies. ISO-induced MI resulted in alterations in ECG patterns, ventricular dysfunction, increased fibrosis, and elevated hypertrophic index parameters. Additionally, ISO administration led to increased inflammatory markers and oxidative stress levels, which were reversed by the ApoEFrag treatment. Furthermore, ApoEFrag significantly ameliorated cardiac injury, inflammation, hypertrophic index parameters, ECG alterations, ventricular dysfunction, and cardiac fibrosis in ISO-induced MI models. Notably, ApoEFrag also improved mitochondrial health. This study suggests that ApoEFrag has significant cardioprotective potential in an acute myocardial infarction model.

INTRODUCTION: Chronic sympathetic stress contributes significantly to the cardiac hypertrophy (CH) development. Currently, several pharmacological agents and surgical options are available for the treatment of CH. However, available treatment options are associated with side effects and surgical complications. The published reports indicated the PKM2 substantial role in numerous illnesses. Furthermore, the effect of shikonin (SK), a nonselective PKM2 inhibitor, on PKM2/c-Myc/PTBP1/HIF-1α signaling in the CH model has never been explored. Thus, in this study, we explore the effect of SK on the PKM2-mediated c-Myc/PTBP1/HIF-1α signaling pathway in isoproterenol (ISO)-induced CH. MATERIALS AND METHODS: The preclinical rat model of pathological CH was developed by subcutaneous (s.c.) administration of ISO (5 mg/kg/day) over 14 days. ISO-treated rats were orally received SK (2 and 4 mg/kg/day) for a period of 14 days. After all treatment completion, animals were anesthetized for electrocardiogram (ECG), blood pressure, and ventricular function recording. Afterward, animal blood samples were isolated, and then animals were sacrificed for further molecular and histopathology studies. RESULTS: Fourteen days treatment of SK showed significant improvement in ECG, fibrosis, inflammation, and cardiac function. Moreover, PKM2, PTBP1, c-Myc, and HIF-1α expressions were upregulated, while PKM1 expression was downregulated in ISO-treated rats, which was reversed by SK treatment in ISO-induced CH rats. CONCLUSION: Thus, our results demonstrated that SK modulates the PKM2/c-Myc/PTBP1/HIF-1α pathway mediated by PKM2 inhibition, which might be responsible for SK-mediated cardioprotection in ISO-induced CH.

Background: Glutamate has been implicated in the pathophysiology of central nervous system diseases, including stroke. Purpose: In this study, the neuroprotective potential of the newly synthesised thyrotropin-releasing hormone (TRH) analogue [Pyr- l -(2,5-dibromo)-His- l -ProNH ₂ ; NP-2376] against glutamate-induced injury model were investigated. Methods: Cortical neurons isolated from neonatal rats were used to evaluate the effects of the NP-2376. Cortical neurons were pre-treated with NP-2376 (6, 12 and 24 h) prior to glutamate (15 mM) exposure. Cell viability was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and neutral red uptake (NRU) assay, and oxidative stress by chloromethyl-2,7-dichlorodihydrofluorescein diacetate (DCFH-DA) and glutathione assays. Results: NP-2376 protected against glutamate-induced cortical neuron death and oxidative stress in a dose-dependent manner. Conclusions: This study demonstrates the neuroprotective potential of TRH analogue NP-2376 against glutamate-induced toxicity, which is attributed to a decrease in oxidative stress.

Alpha‐synuclein pathology is a characteristic feature of Parkinson's disease (PD) and related synucleinopathies. As a result, reducing alpha‐synuclein pathology is one of the mechanisms being looked at for the development of newer agents which target these diseases. In the present study, we investigated the potential of HC070, a transient receptor potential canonical 5 (TRPC5) channel inhibitor in reducing alpha‐synuclein pathology in PD. TRPC5 channels are activated in response to oxidative stress and mediators of apoptosis (calpain), the processes are also closely linked to alpha‐synuclein toxicity. Using exposure of alpha synuclein‐preformed fibrils to the Sprague Dawley rats and SH‐SY5Y cells, we induced PD in in vitro and in vivo model systems. It was followed by the estimation of behavioural deficits, molecular parameters and biochemical estimations. Results of our experiments revealed that animals treated intraperitoneally with HC070 exhibited reduced alpha‐synuclein levels accompanied by improvement in tyrosine hydroxylase levels, mitochondrial health and reduction in oxidative stress and calpain signalling. Furthermore, HC070 administration also caused a reduction in the TRPC5 levels along with improvement seen in motor and cognitive deficits. Similar protection was observed with HC070 in SH‐SY5Y cells exposed to alpha‐synuclein PFF. Overall, our study demonstrates the novel role of inhibition of TRPC5 channels in the reversal of alpha‐synuclein toxicity and associated PD pathology.