Arun Parashar

Background and Objectives: Neurodegenerative diseases are characterized by degeneration or progressive loss/death of neurons in specific areas of the brain, often worsened by cigarette smoke through oxidative stress and inflammation. Cordyceps militaris (C. militaris) exhibits antioxidant and anti-inflammatory properties, suggesting potential neuroprotective effects. This study evaluated the protective role of C. militaris hot water extract (CMWE) against cigarette smoke extract-induced neurodegeneration in zebrafish. Methods: Neurodegeneration was induced in zebrafish using cigarette smoke extract, and CMWE was administered at 1 mg/L and 4 mg/L. Behavioral performance was assessed using Y-maze, inhibitory avoidance, and novel tank tests. LC-MS was employed to identify CMWE constituents, while antioxidant activity was evaluated by the DPPH assay. Histological analysis of the periventricular grey zone (PGZ) of the optic tectum was performed to assess neuronal integrity. Results: Cigarette smoke exposure led to aimless exploration, impaired memory retention, and increased bottom-dwelling behavior. CMWE improved behavioral outcomes, with 4 mg/L showing greater efficacy than 1 mg/L. LC-MS revealed bioactive compounds including cordycepin, adenosine, ergothioneine, D-mannitol, and vitamins. The DPPH assay confirmed strong antioxidant activity. Histological evaluation showed reduced pyknotic neuronal density in CMWE-treated groups compared with diseased controls, indicating anti-inflammatory effects. Conclusions: CMWE mitigated cigarette smoke-induced behavioral and histological hallmarks of neurodegeneration in zebrafish, likely via synergistic antioxidant and anti-inflammatory mechanisms. These findings support the potential of C. militaris as a natural product-based therapeutic candidate for neurodegenerative disorders, warranting further studies on its individual constituents and mechanisms of action.

Type 2 diabetes mellitus (T2DM) is a systemic metabolic disorder increasingly implicated in central nervous system (CNS) dysfunction, yet the molecular substrates underlying diabetes-induced dopaminergic (DAergic) dysregulation remain poorly defined. This study evaluated region-specific alterations in DAergic neurotransmission within the hippocampus, striatum, and prefrontal cortex, and their association with social behavioral deficits in diabetic mice. According to the weight and age of the animal, two groups were designated as the control group and the diabetes group. The control group was designated as group 1, and the diabetic group was designated as group 2. In group 2, diabetes was caused by injecting 50 mg/kg of streptozotocin for five consecutive days in them. The behavioural tests were performed after eight weeks of inducing diabetes. On the 60th day, from the striatum, hippocampus, and cortex, total RNA was taken out after the dissection. Real-time polymerase chain reaction was used to carry out expression analysis. STZ-induced diabetic mice showed normal sociability and social novelty preference but exhibited a marked decline in social recognition memory, indicating selective impairment of long-term social cognition. Region-specific dysregulation of dopaminergic signaling was evident, particularly in the striatum and cortex. These transcriptional alterations likely represent compensatory neuroadaptive mechanisms responding to oxidative and neuronal stress induced by diabetes, suggesting that T2DM-driven dopaminergic imbalance contributes to cognitive and neurobehavioral dysfunction. T2DM induces differential dysregulation of dopaminergic signaling across cortical and subcortical regions, contributing to selective deficits in social cognition. These findings highlight potential therapeutic targets for mitigating diabetes-associated neurobehavioral dysfunction. Graphical Abstract

Gastrointestinal perforation (GIP) is a rare and potentially fatal adverse event of antineoplastic therapy. GIP is a rare but serious complication in oncology patients, often leading to significant morbidity and mortality. In general oncology patients, the incidence of GIP ranged from 0.5 to 1.9%. A meta-analysis of six clinical trials with 4579 patients reported an incidence of 1.0%. Among mCRC patients, the incidence varied between 0.5 and 2.4%, with geographic differences—1.5% in the USA and 2.4% in Australia. For metastatic melanoma patients, the incidence of GIP ranged from 0.4 to 0.67%, with U.S. rates of 0.57% and 0.67% and a lower rate of 0.40% reported in Germany. The findings suggest that the risk of GIP varies significantly across oncology populations and treatment regimens, with higher risks noted in metastatic cancer patients undergoing therapies such as VEGF inhibitors or immune checkpoint inhibitors. These data highlight the need for careful monitoring and early intervention in high-risk populations to reduce the impact of GIP on patient outcomes. This systematic review aims to summarize the incidence of GIP in general oncology, metastatic colorectal cancer (mCRC), and metastatic melanoma (MM) populations. A literature search was conducted in Embase and Medline databases from January 1, 2011 to August 30, 2017, identifying relevant studies on GIP incidence.

Gout results from a metabolic disorder characterized by increased uric acid (UA) levels or hyperuricemia (HUA). UA is a metabolic waste product generated throughout the body and collected in the blood. UA metabolism predominantly occurs in the liver, kidney, and intestine, with the liver being the most significant as it converts purines into UA. About ~70% of UA is excreted via the kidney, while ~30% is via the intestine. UA excretion from the kidney has been extensively studied, while that from the intestine has been overlooked. As the intestine is responsible for one-third of UA excretion, researchers investigated whether or not the microbes residing in the gut, known as the human gut microbiota (GM), are involved in UA excretion. GM is now evidently responsible for UA excretion and lowering effects. As our understanding of the effects of gut microbiomes on health grows, GM has emerged as a new promising target for HUA interventions. Moreover, gut dysbiosis is also associated with gout. Furthermore, some prebiotics (polysaccharides, and polyphenols) and probiotics (Bifidobacteria and Lactobacilli) have UA-lowering effects, which provides a new promising dimension for gout therapeutic intervention research. GM interventions like probiotics, prebiotics, synbiotics, phenols, polysaccharides, washed microbiota transplantation (WMT), and Fecal Microbiota Transplantation (FMT) reduced HUA by either increasing excretion or lowering UA levels. In this review, we explore the possible involvement of GM in UA metabolism and excretion and possible involvement in gout pathophysiology.

Acetylcholinesterase (AChE) is one of the key enzyme targets that have been used clinically for the management of Alzheimer’s Disorder (AD). Numerous reports in the literature predict and demonstrate in-vitro, and in-silico anticholinergic activity of herbal molecules, however, majority of them failed to find clinical application. To address these issues, we developed a 2D-QSAR model that could efficiently predict the AChE inhibitory activity of herbal molecules along with predicting their potential to cross the blood-brain-barrier (BBB) to exert their beneficial effects during AD. Virtual screening of the herbal molecules was performed and amentoflavone, asiaticoside, astaxanthin, bahouside, biapigenin, glycyrrhizin, hyperforin, hypericin, and tocopherol were predicted as the most promising herbal molecules for inhibiting AChE. Results were validated through molecular docking, atomistic molecular dynamics simulations and Molecular mechanics-Poisson Boltzmann surface area (MM-PBSA) studies against human AChE (PDB ID: 4EY7). To determine whether or not these molecules can cross BBB to inhibit AChE within the central nervous system (CNS) for being beneficial for the management of AD, we determined a CNS Multi-parameter Optimization (MPO) score, which was found in the range of 1 to 3.76. Overall, the best results were observed for amentoflavone and our results demonstrated a PIC₅₀ value of 7.377 nM, molecular docking score of −11.5 kcal/mol, and CNS MPO score of 3.76. In conclusion, we successfully developed a reliable and efficient 2D-QSAR model and predicted amentoflavone to be the most promising molecule that could inhibit human AChE enzyme within the CNS and could prove beneficial for the management of AD. Communicated by Ramaswamy H. Sarma

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Cardiovascular diseases (CVD) are the leading cause of mortality, morbidity, and “sudden death” globally. Environmental and lifestyle factors play important roles in CVD susceptibility, but the link between environmental factors and genetics is not fully established. Epigenetic influence during CVDs is becoming more evident as its direct involvement has been reported. The discovery of epigenetic mechanisms, such as DNA methylation and histone modification, suggested that external factors could alter gene expression to modulate human health. These external factors also influence our gut microbiota (GM), which participates in multiple metabolic processes in our body. Evidence suggests a high association of GM with CVDs. Although the exact mechanism remains unclear, the influence of GM over the epigenetic mechanisms could be one potential pathway in CVD etiology. Both epigenetics and GM are dynamic processes and vary with age and environment. Changes in the composition of GM have been found to underlie the pathogenesis of metabolic diseases via modulating epigenetic changes in the form of DNA methylation, histone modifications, and regulation of non-coding RNAs. Several metabolites produced by the GM, including short-chain fatty acids, folates, biotin, and trimethylamine-N-oxide, have the potential to regulate epigenetics, apart from playing a vital role in normal physiological processes. The role of GM and epigenetics in CVDs are promising areas of research, and important insights in the field of early diagnosis and therapeutic approaches might appear soon.

Acetylcholinesterase (AChE) is one of the key enzyme targets that have been used clinically for the management of Alzheimer’s Disorder (AD). Numerous reports in the literature predict and demonstrate in-vitro , and in-silico anticholinergic activity of synthetic and herbal molecules, however, the majority of them failed to reproduce the results in preclinical or clinical settings. To address these issues, we developed a 2D-QSAR model that could not only efficiently predict the AChE inhibitory activity of herbal molecules but also predicted their potential to cross BBB to exert their beneficial effects during AD. Applying this model, virtual screening of the herbal molecules was performed and amentoflavone, asiaticoside, astaxanthin, bahouside, biapigenin, glycyrrhizin, hyperforin, hypericin, and tocopherol were predicted as the most promising herbal molecules for inhibiting AChE. Results were validated through molecular docking studies against human AChE (PDB ID: 4EY7). To determine whether or not these molecules can cross BBB to inhibit AChE within the CNS for being beneficial for the management of AD, we determined a CNS PPO score, which was found in the range of 1 to 3.76. Overall, the best results were observed for amentoflavone and our results demonstrated a PIC ₅₀ value of 7.377 nM, molecular docking score of −11.5 kcal/mol, and CNS MPO score of 3.76. In conclusion, we successfully developed a reliable and efficient 2D-QSAR model and predicted amentoflavone to be the most promising molecule that could inhibit human AChE enzyme within the CNS and could prove beneficial for the management of AD.