Oral arsenite exposure induces inflammation and apoptosis in pulmonary tissue: acute and chronic evaluation in young and adult mice.

Inorganic arsenic is a well-known environmental toxicant, and exposure to this metalloid is strongly linked with severe and extensive toxic effects in various organs including the lungs. In the present study, we aimed to investigate the acute and chronic effects of arsenite exposure on pulmonary tissue in young and adult mice. In brief, young and adult female Balb/C mice were exposed to 3 and 30 ppm arsenite daily via drinking water for 30 and 90 days. Subsequently, the animals were sacrificed and various histological and immunohistochemistry (IHC) analyses were performed using lung tissues. Our findings showed arsenite was found to cause dose-dependent pathological changes such as thickening of the alveolar septum, inflammatory cell infiltrations and lung fibrosis in young and adult mice. In addition, arsenite exposure significantly increased the expression of inflammatory markers NF-κB and TNF-α, indicating that arsenite-exposed mice suffered from severe lung inflammation. Moreover, the IHC analysis of fibrotic proteins demonstrated an increased expression of TGF-ß1, α-SMA, vimentin and collagen-I in the arsenite-exposed mice compared to the control mice. This was accompanied by apoptosis, which was indicated by the upregulated expression of caspase-3 in arsenite-exposed mice compared to the control. Adult mice were generally found to be more prone to arsenite toxicity during chronic exposure relative to their younger counterparts. Overall, our findings suggest that arsenite in drinking water may induce dose-dependent and age-dependent structural and functional impairment in the lungs through elevating inflammation and fibrotic proteins.

Pyrazolo[1,5-a]pyrimidine as a Prominent Framework for Tropomyosin Receptor Kinase (Trk) Inhibitors-Synthetic Strategies and SAR Insights.

Tropomyosin receptor kinases (Trks) are transmembrane receptor tyrosine kinases named TrkA, TrkB, and TrkC and encoded by the NTRK1, NTRK2, and NTRK3 genes, respectively. These kinases have attracted significant attention and represent a promising therapeutic target for solid tumor treatment due to their vital role in cellular signaling pathways. First-generation TRK inhibitors, i.e., Larotrectinib sulfate and Entrectinib, received clinical approval in 2018 and 2019, respectively. However, the use of these inhibitors was significantly limited because of the development of resistance due to mutations. Fortunately, the second-generation Trk inhibitor Repotrectinib (TPX-0005) was approved by the FDA in November 2023, while Selitrectinib (Loxo-195) has provided an effective solution to this issue. Another macrocycle-based analog, along with many other TRK inhibitors, is currently in clinical trials. Two of the three marketed drugs for NTRK fusion cancers feature a pyrazolo[1,5-a] pyrimidine nucleus, prompting medicinal chemists to develop numerous novel pyrazolopyrimidine-based molecules to enhance clinical applications. This article focuses on a comprehensive review of chronological synthetic developments and the structure-activity relationships (SAR) of pyrazolo[1,5-a]pyrimidine derivatives as Trk inhibitors. This article will also provide comprehensive knowledge and future directions to the researchers working in the field of medicinal chemistry by facilitating the structural modification of pyrazolo [1,5-a]pyrimidine derivatives to synthesize more effective novel chemotherapeutics as TRK inhibitors.

Neuroprotective effect of taxifolin against aluminum chloride-induced dementia and pathological alterations in the brain of rats: possible involvement of toll-like receptor 4.

Aluminum (Al) overexposure damages various organ systems, especially the nervous system. Regularly administered aluminum chloride (AlCl3) to rats causes dementia and pathophysiological alterations linked to Alzheimer's disease (AD). Taxifolin's neuroprotective effects against AlCl3-induced neurotoxicity in vitro and in vivo studies were studied. Taxifolin (0.1, 0.3, 1, 3, and 10 µM) was tested against AlCl3 (5 mM)-induced neurotoxicity in C6 and SH-SY5Y cells using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) and lactate dehydrogenase (LDH) assays. Additionally, neural morphology was examined by confocal microscopy. Additionally, taxifolin's mode of binding with the co-receptor of toll-like receptor 4 (TLR4), human myeloid differentiation-2 (hMD-2) was investigated. AlCl3 (25 mg/kg/d, i.p.) was administered to rats for 14 d, and from the eighth day, taxifolin (1, 2, and 5 mg/kg/d, i.p.) was given along with AlCl3. This study assessed memory impairment using the Morris water maze, plus maze, and pole tests. This study also performed measurement of oxidant (malondialdehyde [MDA] and nitrite), antioxidant (reduced glutathione), and inflammatory (myeloperoxidase [MPO] activity, TLR4 expression) parameters in rats' brain in addition to histopathology. The docking score for taxifolin with hMD-2 was found to be -4.38 kcal/mol. Taxifolin treatment reduced the neurotoxicity brought on by AlCl3 in both C6 and SH-SY5Y cells. Treatment with 10 µM taxifolin restored AlCl3-induced altered cell morphology. AlCl3 administration caused memory loss, oxidative stress, inflammation (increased MPO activity and TLR4 expression), and brain atrophy. Taxifolin treatment significantly improved the AlCl3-induced memory impairment. Taxifolin treatment also mitigated the histopathological and neurochemical consequences of repeated AlCl3 administration in rats. Thus, taxifolin may protect the brain against AD.

Convenient One-Pot Synthesis of Kynurenic Acid Ethyl Ester and Exploration to Direct Synthesis of Neuroprotective Kynurenic Acid and Amide Derivatives.

Kynurenic acid (KYNA) is an endogenous molecule, which is a non-selective antagonist of ionotropic glutamate receptors and has been found to have neuroprotective activity. A supplement of KYNA may be applicable for the treatment of neurodegenerative disease, but it does not cross the blood-brain barrier due to its polar nature. Therefore, its different esters and amide derivatives were explored as a prodrug, which can cross blood-brain barrier and transform into KYNA in situ. However, many esters and amide derivatives of KYNA are synthesized via coupling reaction or multi-step synthesis using different organic or metallic catalysts. Herein, we developed a novel one-pot, catalyst-free, convenient synthesis of KYNA ethyl esters using aniline and diethyl acetylene dicarboxylate in DMF under heating. We also explored the synthesis of KYNA and KYNA amide derivative in a simple manner with overall good yields via hydrolysis and condensation, respectively.

Artificial intelligence and machine learning disciplines with the potential to improve the nanotoxicology and nanomedicine fields: a comprehensive review.

The use of nanomaterials in medicine depends largely on nanotoxicological evaluation in order to ensure safe application on living organisms. Artificial intelligence (AI) and machine learning (MI) can be used to analyze and interpret large amounts of data in the field of toxicology, such as data from toxicological databases and high-content image-based screening data. Physiologically based pharmacokinetic (PBPK) models and nano-quantitative structure-activity relationship (QSAR) models can be used to predict the behavior and toxic effects of nanomaterials, respectively. PBPK and Nano-QSAR are prominent ML tool for harmful event analysis that is used to understand the mechanisms by which chemical compounds can cause toxic effects, while toxicogenomics is the study of the genetic basis of toxic responses in living organisms. Despite the potential of these methods, there are still many challenges and uncertainties that need to be addressed in the field. In this review, we provide an overview of artificial intelligence (AI) and machine learning (ML) techniques in nanomedicine and nanotoxicology to better understand the potential toxic effects of these materials at the nanoscale.

Posttranscriptional regulation of Nrf2 through miRNAs and their role in Alzheimer's disease.

The nuclear factor erythroid-derived 2-related factor 2 (NFE2L2/Nrf2) is a pivotal facilitator of cytoprotective responses against the oxidative/electrophilic insults. Upon activation, Nrf2 induces transcription of a wide range of cytoprotective genes having antioxidant response element (ARE) in their promoter region. Dysfunction in Nrf2 signaling has been linked to the pathogenesis of AD and several studies have suggested that boosting Nrf2 expression/activity by genetic or pharmacological approaches is beneficial in AD. Among the diverse mechanisms that regulate the Nrf2 signaling, miRNAs-mediated regulation of Nrf2 has gained much attention in recent years. Several miRNAs have been reported to directly repress the post-transcriptional expression of Nrf2 and thereby negatively regulate the Nrf2-dependent cellular cytoprotective response in AD. Moreover, several Nrf2 targeting miRNAs are misregulated in AD brains. This review is focused on the role of misregulated miRNAs that directly target Nrf2, in AD pathophysiology. Here, alongside a general description of functional interactions between miRNAs and Nrf2, we have reviewed the evidence indicating the possible role of these miRNAs in AD pathogenesis.

Potential therapeutic applications of phytoconstituents as immunomodulators: Pre-clinical and clinical evidences.

Autoimmune and infectious diseases are the major public health issues and have gained great attention in the last few years for the search of new agents with therapeutic benefits on the host immune functions. In recent years, natural products (NPs) have been studied broadly for their multi-targeted activities under pathological conditions. Interestingly, several attempts have been made to outline the immunomodulatory properties of NPs. Research on in-vitro and in-vivo models have shown the immunomodulatory activity of NPs, is due to their antiinflammatory property, induction of phagocytosis and immune cells stimulation activity. Moreover, studies on humans have suggested that phytomedicines reduce inflammation and could provide appropriate benefits either in single form or complex combinations with other agents preventing disease progression, subsequently enhancing the efficacy of treatment to combat multiple malignancies. However, the exact mechanism of immunomodulation is far from clear, warranting more detailed investigations on their effectiveness. Nevertheless, the reduction of inflammatory cascades is considered as a prime protective mechanism in a number of inflammation regulated autoimmune diseases. Altogether, this review will discuss the biological activities of plant-derived secondary metabolites, such as polyphenols, alkaloids, saponins, polysaccharides and so forth, against various diseases and their potential use as an immunomodulatory agent under pathological conditions.

Molecular Mechanism of Arsenic-Induced Neurotoxicity including Neuronal Dysfunctions.

Arsenic is a key environmental toxicant having significant impacts on human health. Millions of people in developing countries such as Bangladesh, Mexico, Taiwan, and India are affected by arsenic contamination through groundwater. Environmental contamination of arsenic leads to leads to various types of cancers, coronary and neurological ailments in human. There are several sources of arsenic exposure such as drinking water, diet, wood preservatives, smoking, air and cosmetics, while, drinking water is the most explored route. Inorganic arsenic exhibits higher levels of toxicity compared its organic forms. Exposure to inorganic arsenic is known to cause major neurological effects such as cytotoxicity, chromosomal aberration, damage to cellular DNA and genotoxicity. On the other hand, long-term exposure to arsenic may cause neurobehavioral effects in the juvenile stage, which may have detrimental effects in the later stages of life. Thus, it is important to understand the toxicology and underlying molecular mechanism of arsenic which will help to mitigate its detrimental effects. The present review focuses on the epidemiology, and the toxic mechanisms responsible for arsenic induced neurobehavioral diseases, including strategies for its management from water, community and household premises. The review also provides a critical analysis of epigenetic and transgenerational modifications, mitochondrial oxidative stress, molecular mechanisms of arsenic-induced oxidative stress, and neuronal dysfunction.

Protective effects of Tinospora cordifolia miers extract against hepatic and neurobehavioral deficits in thioacetamide-induced hepatic encephalopathy in rats via modulating hyperammonemia and glial cell activation.

ETHNOPHARMACOLOGICAL RELEVANCE: Tinospora cordifolia (TC) a potential medicinal herb, has been ethnobotanically used as an eco-friendly supplement to manage various diseases, including cerebral fever. Earlier studies have shown that TC exhibits diverse beneficial effects, including hepatoprotective and neuroprotective effects. However, the effects of TC remain unexplored in animal models of encephalopathy including hepatic encephalopathy (HE). AIM OF THE STUDY: To evaluate the effects of TC stem extract against thioacetamide (TAA)-induced behavioural and molecular alterations in HE rats. METHODS AND MATERIALS: The extract was preliminarily screened through phytochemical and HR-LC/MS analysis. Animals were pre-treated with TC extract at doses 30 and 100 mg/kg, orally. Following 7 days of TC pre-treatment, HE was induced by administering TAA (300 mg/kg, i. p. thrice). Behavioural assessments were performed after 56 h of TAA first dose. The animals were then sacrificed to assess biochemical parameters in serum, liver and brain. Liver tissue was used for immunoblotting and histological studies to evaluate inflammatory and fibrotic signalling. Moreover, brain tissue was used to evaluate brain edema, activation of glial cells (GFAP, IBA-1) and NF-κB/NLRP3 downstream signalling via immunoblotting and immunohistochemical analysis in cortex and hippocampus. RESULTS: The pre-treatment with TC extract effective mitigated TAA-induced behavioural alterations, lowered serum LFT (AST, ALT, ALP, bilirubin) and oxidative stress markers in liver and brain. TC treatment significantly modulated hyperammonemia, cerebral edema and preserved the integrity of BBB proteins in HE animals. TC treatment attenuated TAA-induced histological changes, tissue inflammation (pNF-κB (p65), TNF-α, NLRP3) and fibrosis (collagen, α-SMA) in liver. In addition, immunoblotting analysis revealed TC pre-treatment inhibited fibrotic proteins such as vimentin, TGF-ß1 and pSmad2/3 in the liver. Our study further showed that TC treatment downregulated the expression of MAPK/NF-κB inflammatory signalling, as well as GFAP and IBA-1 (glial cell markers) in cortex and hippocampus of TAA-intoxicated rats. Additionally, TC-treated animals exhibited reduced expression of caspase3/9 and BAX induced by TAA. CONCLUSION: This study revealed promising insights on the protective effects of TC against HE. The findings clearly demonstrated that the significant inhibition of MAPK/NF-κB signalling and glial cell activation could be responsible for the observed beneficial effects of TC in TAA-induced HE rats.

Virtual screening of acetylcholinesterase inhibitors through pharmacophore-based 3D-QSAR modeling, ADMET, molecular docking, and MD simulation studies.

Alzheimer's disease (AD) is a leading cause of dementia in elderly patients. The pathophysiology of AD includes various pathways, such as the degradation of acetylcholine, amyloid-beta deposition, neurofibrillary tangle formation, and neuroinflammation. Many studies showed that targeting acetylcholinesterase enzyme (AChE) to improve acetylcholine can be an effective option to treat AD. In the current work, we employed a 3D QSAR-based approach to generate a pharmacophore to screen a chemical library of compounds that may inhibit AChE. Data from experimental studies were collected and used for the generation of pharmacophores. More than 1 million compounds were screened, and further drug-like properties were determined via in-silico ADMET studies. Techniques like molecular docking and molecular dynamics simulation were performed to analyze the binding of novel AChE inhibitors. A novel AChE inhibitor ligand-1 was identified as best with a docking score of -13.560 kcal/mol with RMSD of 1.71 Å during a 100 ns MD run. Further biological studies can give an insight into the potential of ligand-1 as a therapeutic agent for AD. Supplementary Information: The online version contains supplementary material available at 10.1007/s40203-024-00189-1.

Identifying potential neuroprotective polyphenols targeting endoplasmic reticulum stress through an in silico approach.

The endoplasmic reticulum (ER) is essential in many cellular processes, including protein processing, lipid metabolism, and calcium storage. Dysregulation of ER function has been linked with neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, etc. The primary pathological alteration explicated in the diseases is the accumulation of misfolded proteins in the neuronal cells. ER stress-associated activation of PERK-mediated pro-apoptotic cell death leads to neurodegeneration. In this study, we have primarily screened the potential polyphenols evidenced for neuroprotective activity. The 24 polyphenols were selected to explore their binding affinity towards various proteins of ER cascade such as pPERK (phospho-PERK), EIF2 (Eukaryotic Initiation Factor 2), and ATF4 (Activating Transcription Factor 4). On the basis of binding affinity, four phytopolyphenols were further selected for in-silico ADMET and molecular dynamic simulation. Among them curcumin found to be the most promising and serve as a potential hit against all three targets of ER cascade. The selected proteins' active site has demonstrated high stability of curcumin binding according to molecular dynamics findings. Though curcumin exhibited a significant hit in interaction with targets but needs to be further improved in drug-ability criteria. Thus, seventy derivatives of curcumin scaffold (from the published literature) were also screened with improve in druggability criteria, which showed good interaction with unfolded protein response related targets. The new scaffolds serve considerable potential to be developed as novel polyphenolic lead for neurodegenerative disorders.Communicated by Ramaswamy H. Sarma.

PPARs (Peroxisome Proliferator-activated Receptors) and Their Agonists in Alzheimer's Disease.

Alzheimer's disease (AD) is a neurodegenerative disease leading to dementia because of complex phathomechanisms like amyloid ß (Aß) aggregation, tau aggregates, and neurofibrillary tangles. Peroxisome proliferator-activated receptor (PPAR) agonists have been reported recently with neuroprotective and anti-inflammatory properties. PPARs belong to the superfamily of nuclear hormone receptors and function as ligand-activated transcription factors. These have emerged as crucial players in the pathogenesis of AD. This review presented the potential of PPARs and their agonists in treating neurodegenerative diseases like AD. PPARs regulate the expression of specific genes vital for synaptic function and neurotransmitter release. PPAR agonists play a critical role in increasing the clearance of Aß peptides by lowdensity lipoprotein receptor-related protein 1 (LRP1) in the microvascular endothelial cells of the human brain. Studies have shown that PPAR agonists reduce the level of APoE-mRNA, contributing to the accumulation of Aß plaques and up-regulation of PPAR. A knockout of miR-128 has been found to inhibit AD-like cognitive decline, amyloid precursor protein (APP) amyloidogenic processing, and inflammatory responses in AD. PPARs are involved in the pathomechanism of AD, and therefore, PPAR agonists could be viable options for controlling the neurodegenerative symptoms and may be useful in treating AD.

Tricompartmental Microcarriers with Controlled Release for Efficient Management of Parkinson's Disease.

Parkinson's is a progressive neurodegenerative disease of the nervous system. It has no cure, but its symptoms can be managed by supplying dopamine artificially to the brain.This work aims to engineer tricompartmental polymeric microcarriers by electrohydrodynamic cojetting technique to encapsulate three PD (Parkinson's disease) drugs incorporated with high encapsulation efficiency (∼100%) in a single carrier at a fixed drug ratio of 4:1:8 (Levodopa (LD): Carbidopa(CD): Entacapone (ENT)). Upon oral administration, the drug ratio needs to be maintained during subsequent release from microparticles to enhance the bioavailability of primary drug LD. This presents a notable challenge, as the three drugs vary in their aqueous solubility (LD > CD > ENT). The equilibrium of therapeutic release was achieved using a combination of FDA-approved polymers (PLA, PLGA, PCL, and PEG) and the disc shape of particles. In vitro studies demonstrated the simultaneous release of all the three therapeutics in a sustained and controlled manner. Additionally, pharmacodynamics and pharmacokinetics studies in Parkinson's disease rats induced by rotenone showed a remarkable improvement in PD conditions for the microparticles-fed rats, thereby showing a great promise toward efficient management of PD.

Safety and Efficacy of Calcitonin Gene-related Peptide Receptor Antagonists and Selective Serotonin Receptor Agonist in the Management of Migraine: A Systematic Review and Meta-analysis.

BACKGROUND: Recently, US Food and Drug Administration (FDA) has approved calcitonin gene-related peptide receptor antagonists (rimegepant, and ubrogepant), and selective serotonin receptor agonists (lasmiditan) in the management of migraine. However, the exact safety and efficacy profile of these drugs is unclear so far. METHODS: The study's primary objective was to determine the exact safety and efficacy profile. The overall estimate was calculated in terms of risk ratios using a suitable model. The subgroup analysis was also performed to check the effect of individual drugs on the outcome, whereas sensitivity analysis was performed to check the effects of outliers on the outcome. All the analyses were performed using Rev Man 5. The drugs have shown significant improvement in efficacy parameters (pain freedom, most bothersome symptoms, phonophobia, nausea, and photophobia). RESULTS: The subgroup analysis results have shown significant improvement in all efficacy parameters in the rimegepant and ubrogepant groups. The effect of ubrogepant on safety parameters was found to be non-significant, indicating a better safety profile of ubrogepant than lasmiditan. CONCLUSION: The sensitivity analysis results have shown no effect of outliers on the efficacy parameters. Based on the available evidence, recently approved drugs are effective in the treatment of migraine, however, associated with few adverse drug reactions.

Metabolomics in Depression: What We Learn from Preclinical and Clinical Evidences.

Depression is one of the predominant common mental illnesses that affects millions of people of all ages worldwide. Random mood changes, loss of interest in routine activities, and prevalent unpleasant senses often characterize this common depreciated mental illness. Subjects with depressive disorders have a likelihood of developing cardiovascular complications, diabesity, and stroke. The exact genesis and pathogenesis of this disease are still questionable. A significant proportion of subjects with clinical depression display inadequate response to antidepressant therapies. Hence, clinicians often face challenges in predicting the treatment response. Emerging reports have indicated the association of depression with metabolic alterations. Metabolomics is one of the promising approaches that can offer fresh perspectives into the diagnosis, treatment, and prognosis of depression at the metabolic level. Despite numerous studies exploring metabolite profiles post-pharmacological interventions, a quantitative understanding of consistently altered metabolites is not yet established. The article gives a brief discussion on different biomarkers in depression and the degree to which biomarkers can improve treatment outcomes. In this review article, we have systemically reviewed the role of metabolomics in depression along with current challenges and future perspectives.

An insight into crosstalk among multiple signalling pathways contributing to the pathophysiology of PTSD and depressive disorders.

Post-traumatic stress disorder (PTSD) and depressive disorders represent two significant mental health challenges with substantial global prevalence. These are debilitating conditions characterized by persistent, often comorbid, symptoms that severely impact an individual's quality of life. Both PTSD and depressive disorders are often precipitated by exposure to traumatic events or chronic stress. The profound impact of PTSD and depressive disorders on individuals and society necessitates a comprehensive exploration of their shared and distinct pathophysiological features. Although the activation of the stress system is essential for maintaining homeostasis, the ability to recover from it after diminishing the threat stimulus is also equally important. However, little is known about the main reasons for individuals' differential susceptibility to external stressful stimuli. The solution to this question can be found by delving into the interplay of stress with the cognitive and emotional processing of traumatic incidents at the molecular level. Evidence suggests that dysregulation in these signalling cascades may contribute to the persistence and severity of PTSD and depressive symptoms. The treatment strategies available for this disorder are antidepressants, which have shown good efficiency in normalizing symptom severity; however, their efficacy is limited in most individuals. This calls for the exploration and development of innovative medications to address the treatment of PTSD. This review delves into the intricate crosstalk among multiple signalling pathways implicated in the development and manifestation of these mental health conditions. By unravelling the complexities of crosstalk among multiple signalling pathways, this review aims to contribute to the broader knowledge base, providing insights that could inform the development of targeted interventions for individuals grappling with the challenges of PTSD and depressive disorders.

Futuristic Alzheimer's therapy: acoustic-stimulated piezoelectric nanospheres for amyloid reduction.

The degeneration of neurons due to the accumulation of misfolded amyloid aggregates in the central nervous system (CNS) is a fundamental neuropathology of Alzheimer's disease (AD). It is believed that dislodging/clearing these amyloid aggregates from the neuronal tissues could lead to a potential cure for AD. In the present work, we explored biocompatible polydopamine-coated piezoelectric polyvinylidene fluoride (DPVDF) nanospheres as acoustic stimulus-triggered anti-fibrillating and anti-amyloid agents. The nanospheres were tested against two model amyloidogenic peptides, including the reductionist model-based amyloidogenic dipeptide, diphenylalanine, and the amyloid polypeptide, amyloid beta (Aß42). Our results revealed that DPVDF nanospheres could effectively disassemble the model peptide-derived amyloid fibrils under suitable acoustic stimulation. In vitro studies also showed that the stimulus activated DPVDF nanospheres could efficiently alleviate the neurotoxicity of FF fibrils as exemplified in neuroblastoma, SHSY5Y, cells. Studies carried out in animal models further validated that the nanospheres could dislodge amyloid aggregates in vivo and also help the animals regain their cognitive behavior. Thus, these acoustic stimuli-activated nanospheres could serve as a novel class of disease-modifying nanomaterials for non-invasive electro-chemotherapy of Alzheimer's disease.

Age-dependent assessment of selenium nanoparticles: biodistribution and toxicity study in young and adult rats.

Aim: To study the biodistribution and toxicology of selenium nanoparticles (SeNPs) versus their bulk counterpart in young and adult male rats in a 28-day study. Methods: SeNPs were synthesized and conjugated with indocyanine green to assess comparative biodistribution by in vivo imaging and further characterized by transmission electron microscopy, Fourier transform infrared, scanning electron microscopy/energy dispersive x-ray spectroscopy, UV and ζ-analysis. The toxicity of bulk selenium was evaluated relative to its nano form by hematology indices, redox, inflammatory markers and histopathology. Results: Indocyanine green-conjugated nanoparticles showed preferential accumulation in the liver, followed by testis and kidney. The protective effect of SeNPs was more significantly observed in young livers than in adults compared with the bulk counterpart. Conclusion: Age-dependent monitoring and diagnosis of toxicity may need different biomarkers of selenium and may also provide better understanding of SeNPs as therapeutics.

Selenium is an essential element in the body. Its bioactive properties can protect against neurological conditions, diabetes, cancer and other chronic disorders. However, selenium in various biological forms (bulk) can be toxic. Selenium nanoparticles (SeNPs) have unique properties which might prevent this toxicity, providing a potential alternative for selenium supplementation and therapy. However, more studies are needed to see where SeNPs localize in the body, as well as comparing their toxicology with conventional forms of selenium in different age groups. We synthesized and characterized SeNPs of 70­90 nm, then injected them into young and adult rats to see where they distributed in the body. This was compared with rats injected with bulk selenium. SeNPs showed preferential accumulation in the liver, followed by the testes and kidneys. Next, the toxicity profiles of SeNPs and bulk selenium were established by measuring a series of health markers in the liver. It was found that the protection against toxicity provided by SeNPs was more significant in younger rats. Our results demonstrate that the same dose may behave differently in different age groups and that bulk selenium induces different toxicities in young and adult rats compared with SeNPs, highlighting the importance of different indicators of health for the monitoring of selenium-related toxicity when designing selenium-based therapeutics.

Tinospora cordifolia Miers enhances the immune response in mice immunized with JEV-vaccine: A network pharmacology and experimental approach.

BACKGROUND: Tinospora cordifolia Miers. (TC) (Giloya/Guduchi) is a native Indian herb, reported for its wide array of medicinal activities including immunomodulatory activity. However, the exact pharmacological mechanism of TC as an immunomodulatory agent remains unclear. Central to this, to the best of our knowledge, no study has explored the immunoadjuvant potential of TC in response to the Japanese encephalitis (JE) vaccines. PURPOSE: The study aims to explore the immunoadjuvant potential of TC ethanolic extract in response to the JE vaccine and illustrates its potential mechanism of immunomodulation using an integrated approach of network pharmacology and in-vivo experimental study. STUDY DESIGN AND METHODS: Initially, the extract was prepared and the components of TC were identified through high-resolution liquid chromatography mass spectrometry (HR-LC/MS). The compounds were then screened for network pharmacology analysis. Next, the drug and disease targets were identified and the network was constructed using Cytoscape 3.7.2 to obtain different signalling pathways of TC in JEV. We then evaluated the immunoadjuvant potential of TC ethanolic extract in mice immunized with inactivated JE vaccine (SA-14-14-2 strain). BALB/c mice were supplemented with TC extract (30 and 100 mg/kg, i.g.), daily for 56 days, marked with immunization on 28th day of the study, by JE vaccine. Blood was collected for flow cytometry and haematological analysis (total and differential cell counts). The surface expression of immune-cell markers (CD3+, CD4+, CD19+, CD11c+, CD40+) were evaluated on day 0 (pre-immunization), day 14 and 28 post-immunization. Additionally, inflammatory cytokines (IFN-γ+/IL-17A+) were evaluated post-14 and 28 days of immunization. RESULTS: The HR-LC/MS analysis identified the presence of glycosides, terpenoids, steroids and alkaloids in the TC extract. Through network analysis, 09 components and 166 targets were obtained, including pathways that involve toll-like receptor signalling, pattern-recognition receptor signalling, cytokine receptor and cytokine mediated signalling, etc. The in-vivo results showed that preconditioning with TC ethanolic extract significantly elevated the haematological variables (leucocyte count) as well as the surface expression of CD markers (B and T cell subsets) on day 0 (pre-immunization), day 14 and 28 post-immunization. Furthermore, preconditioning of TC demonstrated a dose-dependant augmentation of immune cells (CD3+, CD4+, CD19+, CD11c+) and inflammatory cytokines (IFN-γ+/IL-17A+) on day 14 and 28 post-immunization when compared to vaccine alone group. CONCLUSION: Results showed that preconditioning with TC extract before immunization might play a potential role in enhancing the cell-mediated as well as humoral immunity. Altogether, the combinatorial approach of network pharmacology and in-vivo animal experimentation demonstrated the immunoadjuvant potential of TC in response to JEV vaccine.

Chronic dietary exposure to arsenic at environmentally relevant concentrations impairs cognitive performance in adult zebrafish (Danio rerio) via oxidative stress and dopaminergic dysfunction.

The current study was designed to evaluate the effects of chronic dietary arsenic exposure on the cognitive performance of adult zebrafish and uncover probable pathways by which arsenic mediates such neurotoxic effects. Adult zebrafish were treated with 3 different dietary arsenic concentrations (30, 60, and 100 µg/g dry weight (dw), as arsenite) in addition to control for 60 days. A latent learning paradigm, which employs a complex maze, was used to assess the cognitive performance of fish. Our results demonstrated that dietary treatment with arsenic, especially at medium (60 µg/g dw) and high (100 µg/g dw) exposure dose levels, significantly impaired the performance of fish in various latent learning tasks evaluated in the present study. Concomitant with cognitive dysfunction, chronic dietary exposure to arsenic was also found to increase arsenic accumulation and dopamine levels, and induce oxidative stress (reduced thiol redox, increased lipid peroxidation and expression of antioxidant enzyme genes) in the brain of zebrafish in a dose-dependent manner. Dopaminergic system in the brain is known to play a critical role in regulating cognitive behaviours in fish, and our observations suggested that chronic dietary treatment with medium and high arsenic doses leads to significant alterations in the expression of genes involved in dopamine signaling (dopamine receptors), synthesis (thyroxine hydroxylase) and metabolism (monoamine oxidase) in the zebrafish brain. Moreover, we also recorded significant downregulation of genes such as the brain-derived neurotrophic factor (BDNF) and ectonucleotidases (entpd2_mg, entpd2_mq, and 5'-nucleotidase), which are critical for learning and memory functions, in the zebrafish brain following chronic dietary exposure to arsenic. Overall, the present study suggests that chronic environmentally relevant dietary exposure to arsenic can impair the cognitive performance in zebrafish, essentially by inducing oxidative stress and disrupting the dopaminergic neurotransmission in the brain.