Reproductive and Developmental Effects of Sex-Specific Chronic Exposure to Dietary Arsenic in Zebrafish (Danio rerio).

The present study investigated the reproductive and developmental effects of sex-specific chronic exposure to dietary arsenic in zebrafish. Adult zebrafish (Danio rerio) were exposed to environmentally realistic doses of arsenic via diet [0 (control; no added arsenic), 30 (low), 60 (medium), and 100 (high) µg/g dry weight, as arsenite] for 90 days. Following exposure, arsenic-exposed females from each dietary treatment were mated with control males, and similarly, arsenic-exposed males from each dietary treatment were mated with control females. In females, arsenic exposure resulted in a dose-dependent decrease in reproductive performance (fecundity, fertilization success, and hatching success). Moreover, a dose-dependent increase in developmental toxicity (larval deformities and larval mortality) was observed with maternal exposure to arsenic. In contrast, in males, arsenic exposure also induced similar reproductive and developmental toxicity; however, the adverse effects were mainly evident only in the medium and high dietary arsenic treatment groups. We also examined the sex-specific effects of dietary arsenic exposure on the expression of genes that regulate the hypothalamus-pituitary-gonadal-liver (HPG-L) axis in fish. The gene expression results indicated the downregulation of HPG-L axis genes in females irrespective of the arsenic treatment dose; however, the reduced expression of HPG-L axis genes in males was recorded only in the medium and high arsenic treatment groups. These observations suggest that chronic arsenic exposure in either females or males causes reproductive and developmental toxicity in zebrafish. However, these toxic effects are markedly higher in females than in males. Our results also suggest that arsenic can act as an endocrine disruptor and mediate reproductive and developmental toxicity by disrupting the HPG-L axis in zebrafish.

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.

Arsenic Exposure and Amyloid Precursor Protein Processing: A Focus on Alzheimer's Disease.

BACKGROUND: Arsenic is present in above permissible safe limits in groundwater, soil, and food, in various areas of the world. This is increasing exposure to humankind and affecting health in various ways. Alternation in cognition is one among them. Epidemiological research has reflected the impact of arsenic exposure on children in the form of diminished cognition. AIMS: Considering this fact, the present study reviewed the impact of arsenic on amyloid precursor protein, which is known to cause one of the commonest cognitive disorders such as Alzheimer's disease. METHODS: The present study reviews the arsenic role in the generation of amyloid-beta from its precursor that leads to Alzheimer's disease through the published article from Pubmed and Scopus. DESCRIPTION: According to the findings, regular, long-term exposure to arsenic beginning in infancy changes numerous arsenic level-regulating regions in the rat brain, which are related to cognitive impairments. Arsenic also affects the BBB clearance route by increasing RAGE expression. Arsenic triggers the proamyloidogenic pathway by increasing APP expression and subsequently, its processing by ß-secretase and presenilin. Arsenic also affects mitochondrial dynamics, DNA repair pathway and epigenetic changes. The mechanism behind all these changes is explained in the present review article. CONCLUSION: A raised level of arsenic exposure affects the amyloid precursor protein, a factor for the early precipitation of Alzheimer's disease.

Examining the subchronic (28-day) effects of aqueous Cd-BaP co-exposure on detoxification capacity and cardiac function in adult zebrafish (Danio rerio).

The present study aimed to examine the effects of environmentally relevant concentrations of cadmium (Cd) and Benzo[a]Pyrene (BaP) in the adult zebrafish (Danio rerio). To this end, fish were exposed to either 1 or 10 µg/L Cd or 0.1 or 1 µg/L BaP in isolation, or a co-exposure containing a mixture of the two toxicants. Our results showed extensive modulation of the expression of key antioxidant genes (GPx, SOD1, catalase), detoxifying genes (MT1, MT2, CYP1A1) and a stress biomarker (HSP70) differing between control, single toxicant groups and co-exposure groups. We additionally carried out histopathological analysis of the gills, liver, and hearts of exposed animals, noting no differences in tissue necrosis or apoptosis. Finally, we carried out ultrasonographic analysis of cardiac function, noting a significant decrease of E-wave peak velocity and end diastolic volume in exposed fish. This in turn was accompanied by a decrease in stroke volume and ejection fraction, but not cardiac output in co-exposed fish. The present study is the first to demonstrate that a subchronic aqueous exposure to a Cd-BaP mixture can extensively modulate detoxification capacity and cardiac function in adult zebrafish in a tissue-specific manner.

Neuroprotective potential of saroglitazar in 6-OHDA induced Parkinson's disease in rats.

Parkinson's disease (PD) is a neurodegenerative disorder that affects 2%-3% of the population worldwide. Clinical presentation of PD includes motor and non-motor symptoms. The interplay between pathogenic factors such as increased oxidative stress, neuroinflammation, mitochondrial dysfunction and apoptosis are responsible for neurodegeneration in PD. Intrastriatal administration of 6-hydroxy dopamine (6-OHDA) in rat brain provoked oxidative and nitrosative stress by decreasing endogenous antioxidants such as superoxide dismutase, catalase, glutathione, glutathione peroxidase and glutathione reductase. Consequently, interleukin-6, tumour necrosis-α, interferon-γ and cyclooxygenase-2 mediated neuroinflammation leads to mitochondrial dysfunction, involving inhibition of complex-II and IV activities, followed by apoptosis and degeneration of striatal dopaminergic neurons. Degeneration of dopaminergic neurons resulted in reduced dopamine turnover, consequently induced behavioural abnormalities in rats. Activation of peroxisome proliferator-activated receptors (PPARs) have protective role in PD by modulating response of antioxidant enzymes, neuroinflammation and apoptosis in various animal models of PD. Saroglitazar (SG) being dual PPAR-α/γ agonist activates both PPAR-α and PPAR-γ receptors and provide neuroprotection by reducing oxidative stress, neuroinflammation, mitochondrial dysfunction and apoptosis of dopaminergic cells in 6-OHDA induced PD in rats. Thereby, SG restored striatal histopathological damage and dopamine concentration in rat striatum, and behavioural alterations in rats. Thus, SG proved neuroprotective effects in rat model of PD. Potential benefits of SG in rat model of PD advocates to consider it for further preclinical and clinical evaluation.

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.

Mitochondrial Dysfunction: A Cellular and Molecular Hub in Pathology of Metabolic Diseases and Infection.

Mitochondria are semiautonomous doubly membraned intracellular components of cells. The organelle comprises of an external membrane, followed by coiled structures within the membrane called cristae, which are further surrounded by the matrix spaces followed by the space between the external and internal membrane of the organelle. A typical eukaryotic cell contains thousands of mitochondria within it, which make up 25% of the cytoplasm present in the cell. The organelle acts as a common point for the metabolism of glucose, lipids, and glutamine. Mitochondria chiefly regulate oxidative phosphorylation-mediated aerobic respiration and the TCA cycle and generate energy in the form of ATP to fulfil the cellular energy needs. The organelle possesses a unique supercoiled doubly stranded mitochondrial DNA (mtDNA) which encodes several proteins, including rRNA and tRNA crucial for the transport of electrons, oxidative phosphorylation, and initiating genetic repair processors. Defects in the components of mitochondria act as the principal factor for several chronic cellular diseases. The dysfunction of mitochondria can cause a malfunction in the TCA cycle and cause the leakage of the electron respiratory chain, leading to an increase in reactive oxygen species and the signaling of aberrant oncogenic and tumor suppressor proteins, which further alter the pathways involved in metabolism, disrupt redox balance, and induce endurance towards apoptosis and several treatments which play a major role in developing several chronic metabolic conditions. The current review presents the knowledge on the aspects of mitochondrial dysfunction and its role in cancer, diabetes mellitus, infections, and obesity.

Geraniol protects hippocampal CA1 neurons and improves functional outcomes in global model of stroke in rats.

Geraniol (GE), an acyclic monoterpene, is a chief constituent of essential oils of herbs and fruits. It possesses diverse pharmacological actions like antioxidant, anti-inflammatory, anti-apoptotic, and anti-parkinson. However, its neuroprotective potential in stroke is yet to be explored at large. The present study evaluated the neuroprotective potential of GE against the global model of cerebral ischemia/reperfusion (I/R)-injury in rats. Bilateral common carotid artery (BCCA) occlusion for 30 min followed by 7 days of reperfusion caused varied biochemical/enzymatic alterations viz. increase in levels of lipid peroxidation (LPO), nitric oxide (NO), xanthine oxidase (XO), and decrease in the levels of cerebroprotectives like superoxide dismutase (SOD), catalase (CAT), total thiols, and glutathione (GSH). GE-pretreatment markedly reversed these changes and restored the levels of protective enzymatic and non-enzymatic antioxidants near to normal compared to I/R group. Besides, GE treatment showed marked improvement in anxiety-related behavior and neuronal deficits in animals subjected to I/R injury. Moreover, 2,3,5-triphenyl tetrazolium chloride (TTC)-stained rat brain coronal sections and histopathological studies revealed neuronal protection against I/R-injury, as evidenced by a reduction in infarct area (%) and an increase in hippocampal CA1 neuronal density in the GE-treated groups. The results of this study revealed that GE exhibited potential neuroprotective activity by reducing oxidative stress and infarction area, and protecting hippocampal CA1 neurons against I/R-injury in the global stroke model in rats.

Arsenic causing gallbladder cancer disease in Bihar.

In recent times Gallbladder cancer (GBC) incidences increased many folds in India and are being reported from arsenic hotspots identified in Bihar. The study aims to establish association between arsenic exposure and gallbladder carcinogenesis. In the present study, n = 200 were control volunteers and n = 152 confirmed gallbladder cancer cases. The studied GBC patient's biological samples-gallbladder tissue, gallbladder stone, bile, blood and hair samples were collected for arsenic estimation. Moreover, n = 512 gallbladder cancer patients blood samples were also evaluated for the presence of arsenic to understand exposure level in the population. A significantly high arsenic concentration (p < 0.05) was detected in the blood samples with maximum concentration 389 µg/L in GBC cases in comparison to control. Similarly, in the gallbladder cancer patients, there was significantly high arsenic concentration observed in gallbladder tissue with highest concentration of 2166 µg/kg, in gallbladder stones 635 µg/kg, in bile samples 483 µg/L and in hair samples 6980 µg/kg respectively. Moreover, the n = 512 gallbladder cancer patient's blood samples study revealed very significant arsenic concentration in the population of Bihar with maximum arsenic concentration as 746 µg/L. The raised arsenic concentration in the gallbladder cancer patients' biological samples-gallbladder tissue, gallbladder stone, bile, blood, and hair samples was significantly very high in the arsenic exposed area. The study denotes that the gallbladder disease burden is very high in the arsenic exposed area of Bihar. The findings do provide a strong link between arsenic contamination and increased gallbladder carcinogenesis.

Lung fibrosis: Post-COVID-19 complications and evidences.

BACKGROUND: COVID 19, a lethal viral outbreak that devastated lives and the economy across the globe witnessed non-compensable respiratory illnesses in patients. As been evaluated in reports, patients receiving long-term treatment are more prone to acquire Pulmonary Fibrosis (PF). Repetitive damage and repair of alveolar tissues increase oxidative stress, inflammation and elevated production of fibrotic proteins ultimately disrupting normal lung physiology skewing the balance towards the fibrotic milieu. AIM: In the present work, we have discussed several important pathways which are involved in post-COVID PF. Further, we have also highlighted the rationale for the use of antifibrotic agents for post-COVID PF to decrease the burden and improve pulmonary functions in COVID-19 patients. CONCLUSION: Based on the available literature and recent incidences, it is crucial to monitor COVID-19 patients over a period of time to rule out the possibility of residual effects. There is a need for concrete evidence to deeply understand the mechanisms responsible for PF in COVID-19 patients.

Melatonin Attenuates Extracellular Matrix Accumulation and Cardiac Injury Manifested by Copper.

Copper-induced cardiac injury is not widely reported in spite of its ability to cause oxidative damage and tissue injury. Structural and morphological changes in the cardiac tissue are triggered via oxidative stress and inflammatory responses following copper exposure. The varied and unavoidable exposure of copper through contaminated food and water warrants a safe and effective agent against its harmful effects. Since the heart is highly sensitive to changes in the redox balance, the present study was undertaken to examine the protective effects of melatonin against copper-induced cardiac injury. Sprague Dawley (SD) rats were exposed to 100 ppm of elemental copper via drinking water for 4 months. The cardiac tissue was evaluated for various biochemical, histological, and protein expression studies. Animals exposed to copper exhibited induced oxidative stress and cardiac injury compared to normal control. To this end, we found that melatonin treatment ameliorated copper-induced alterations in tissue oxidative variables like ROS, nitrate, MDA, and GSH. In addition, histological examinations unravelled decreased cardiac muscle dilation, atrophy, and cardiomyopathy in melatonin-treated rats. Furthermore, melatonin-treated rats were associated with reduced tissue copper levels, collagen deposition, α-SMA, and increased HO-1 expression as compared to rats exposed exclusively to copper. Moreover, the levels of NF-κB and cardiac markers such as CK-MB, cTnI, and cTnT were found to be decreased in the melatonin-treated animals. Altogether, melatonin-triggered increase in antioxidant capacity resulting in reduced aggregation of ECM components demonstrates the therapeutic potential of melatonin in the treatment of cardiac injury and tissue fibrosis.

Contemporary Comprehensive Review on Arsenic-Induced Male Reproductive Toxicity and Mechanisms of Phytonutrient Intervention.

Arsenic (As) is a poisonous metalloid that is toxic to both humans and animals. Drinking water contamination has been linked to the development of cancer (skin, lung, urinary bladder, and liver), as well as other disorders such as diabetes and cardiovascular, gastrointestinal, neurological, and developmental damage. According to epidemiological studies, As contributes to male infertility, sexual dysfunction, poor sperm quality, and developmental consequences such as low birth weight, spontaneous abortion, and small for gestational age (SGA). Arsenic exposure negatively affected male reproductive systems by lowering testicular and accessory organ weights, and sperm counts, increasing sperm abnormalities and causing apoptotic cell death in Leydig and Sertoli cells, which resulted in decreased testosterone synthesis. Furthermore, during male reproductive toxicity, several molecular signalling pathways, such as apoptosis, inflammation, and autophagy are involved. Phytonutrient intervention in arsenic-induced male reproductive toxicity in various species has received a lot of attention over the years. The current review provides an in-depth summary of the available literature on arsenic-induced male toxicity, as well as therapeutic approaches and future directions.

Targeting Nanotechnology and Nutraceuticals in Obesity: An Updated Approach.

HYPOTHESIS: This review article represents a brief layout of the risk factors and pathophysiology responsible for obesity, customary treatment strategies, and nanotechnology-based nutraceutical for the therapeutics of obesity. EXPERIMENTS: An exhaustive search of the literature was done for this purpose, using Google Scholar, PubMed, and ScienceDirect databases. A literature study was conducted using publications published in peer-reviewed journals between 2000 and 2022. FINDINGS: This was revealed that risk factors responsible for obesity were genetic abnormalities and environmental and socio-economic factors. Several research articles published between 2000 and 2022 were based on phytoconstituents-based nanoformulation for obesity therapeutics and, therefore, have been systematically compiled in this review. Various nutraceuticals like Garcinia cambogia, quercetin, resveratrol, capsaicin, Capsicum, Curcuma longa, Camella Sinensis, Zingiber officinalis, Citrus aurantium, Aegle marmelos, Coffea canephora, Asparagus officinalis, Gardenia jasminoides, Catha edulis, Clusia nemroisa, Rosmarinus officinalis, Cirsium setidens, Betula platyphylla, Tripterygium wilfordi possessing anti-obesity actions are discussed in this review along with their patents, clinical trials as well as their nanoformulation available. CONCLUSION: This review illustrates that nanotechnology has a great propensity to impart a promising role in delivering phytochemicals and nutraceuticals in managing obesity conditions and other related disorders.

CRISPR/Cas9 gene editing: New hope for Alzheimer's disease therapeutics.

BACKGROUND: Alzheimer's disease (AD) is an insidious, irreversible, and progressive neurodegenerative health condition manifesting as cognitive deficits and amyloid beta (Aß) plaques and neurofibrillary tangles. Approximately 50 million individuals are affected by AD, and the number is rapidly increasing globally. This review explores the role of CRISPR/Cas9 gene editing in the management of AD and its clinical manifestations. AIM OF REVIEW: This review aims to provide a deep insight into the recent progress in CRISPR/Cas9-mediated genome editing and its use against neurodegenerative disorders, specifically AD. However, we have referred to its use against parkinsons's disease (PD), Huntington's disease (HD), and other human diseases, as is one of the most promising and emerging technologies for disease treatment. KEY SCIENTIFIC CONCEPTS OF REVIEW: The pathophysiology of AD is known to be linked with gene mutations, that is, presenilin (PSEN) and amyloid beta precursor protein (APP). However, clinical trials focused at the genetic level could not meet the desired efficiency. The CRISPR/Cas9 genome editing tool is one of the most powerful technologies for correcting inconsistent genetic signatures and now extensively used for AD management. It has significant potential for the correction of undesired gene mutations associated with AD. This technology has allowed the development of empirical AD models, therapeutic lines, and diagnostic approaches for better understanding the nervous system, from in vitro to in vivo models.

Narrative on Hydrogen Therapy and its Clinical Applications: Safety and Efficacy.

Molecular hydrogen proved itself as a novel therapeutic candidate and has been thriving from the beginning with its potential clinical significance, higher affinity, and cellular integrity and permeability. Hydrogen Therapy (HT) has gained scientists' attention with the proven clinical ability to attenuate chronic inflammation, diminish oxidative stress, restrict apoptosis, minimize cellular injury, and refine tissue functioning. Therapeutic Implementation of H2 for disease prevention and treatment is a newly emerging field with limited knowledge available on formulations, tissue-specific effects, efficacy, and safety. This article will discuss HT's therapeutic potential for its efficacy and safety in cardiovascular, respiratory, hematological, metabolic, infectious, and neurodegenerative disorders. In addition to this, the molecular mechanisms and nanotechnological implications of hydrogen therapy will be discussed in detail. Finally, the article will provide insight into advancements and automation, future perspectives, and recommendations. There is a need to study and conduct higher-scale trials targeting personalized treatments under molecular and genetic vitals.

Targeting endoplasmic reticulum stress using natural products in neurological disorders.

The primary aim of this review is to summarize the literature on natural products that are effective in the treatment of various neurological disorders by targeting endoplasmic reticulum stress (ERS). Various electronic databases such as SCOPUS, PubMed, Web of Science, and Google Scholar were searched for relevant publications. ERS has been implicated in the pathogenesis of numerous neurological disorders such as cerebral ischemia, Parkinson's disease, and Alzheimer's disease. Several natural products targeting ERS signalling pathways provide therapeutic options for neurological diseases, and in this review, the potential neuroprotective properties of these products are discussed.

The Conundrum of the PFOA human half-life, an international collaboration.

The Steering Committee of the Alliance for Risk Assessment (ARA) opened a call for scientists interested in resolving what appeared to be a conundrum in estimating of the half-life of perfluorooctanoate (PFOA) in humans. An Advisory Committee was formed from nominations received and a subsequent invitation led to the development of three small independent working groups to review appropriate information and attempt a resolution. Initial findings were shared among these groups and a conclusion developed from the ensuing discussions. Many human observational studies have estimated the PFOA half-life. Most of these studies note the likely occurrence of unmonitored PFOA exposures, which could inflate values of the estimated PFOA half-life. Also, few of these studies estimated the half-life of PFOA isomers, the branched chains of which likely have shorter half-lives. This could deflate values of the estimated linear PFOA half-life. Fortunately, several studies informed both of these potential problems. The majority opinion of this international collaboration is that the studies striking the best balance in addressing some of these uncertainties indicate the likely central tendency of the human PFOA half-life is less than 2 years. The single best value appears to be the geometric mean (GM) of 1.3 years (Zhang et al., 2013, Table 3), based on a GM = 1.7 years in young females (n = 20) and GM = 1.2 years in males of all ages and older females (n = 66). However, a combined median value from Zhang et al. (2013) of 1.8 years also adds value to this range of central tendency. While the Collaboration found this study to be the least encumbered with unmonitored PFOA exposures and branched isomers, more studies of similar design would be valuable. Also valuable would be clarification around background exposures in other existing studies in case adjustments to half-life estimates are attempted.

Biotechnological Innovations from Ocean: Transpiring Role of Marine Drugs in Management of Chronic Disorders.

Marine drugs are abundant in number, comprise of a diverse range of structures with corresponding mechanisms of action, and hold promise for the discovery of new and better treatment approaches for the management of several chronic diseases. There are huge reserves of natural marine biological compounds, as 70 percent of the Earth is covered with oceans, indicating a diversity of chemical entities on the planet. The marine ecosystems are a rich source of bioactive products and have been explored for lead drug molecules that have proven to be novel therapeutic targets. Over the last 70 years, many structurally diverse drug products and their secondary metabolites have been isolated from marine sources. The drugs obtained from marine sources have displayed an exceptional potential in the management of a wide array of diseases, ranging from acute to chronic conditions. A beneficial role of marine drugs in human health has been recently proposed. The current review highlights various marine drugs and their compounds and role in the management of chronic diseases such as cancer, diabetes, neurodegenerative diseases, and cardiovascular disorders, which has led to the development of new drug treatment approaches.