Arsenic toxicity: sources, pathophysiology and mechanism.

Background: Arsenic is a naturally occurring element that poses a significant threat to human health due to its widespread presence in the environment, affecting millions worldwide. Sources of arsenic exposure are diverse, stemming from mining activities, manufacturing processes, and natural geological formations. Arsenic manifests in both organic and inorganic forms, with trivalent meta-arsenite (As3+) and pentavalent arsenate (As5+) being the most common inorganic forms. The trivalent state, in particular, holds toxicological significance due to its potent interactions with sulfur-containing proteins. Objective: The primary objective of this review is to consolidate current knowledge on arsenic toxicity, addressing its sources, chemical forms, and the diverse pathways through which it affects human health. It also focuses on the impact of arsenic toxicity on various organs and systems, as well as potential molecular and cellular mechanisms involved in arsenic-induced pathogenesis. Methods: A systematic literature review was conducted, encompassing studies from diverse fields such as environmental science, toxicology, and epidemiology. Key databases like PubMed, Scopus, Google Scholar, and Science Direct were searched using predetermined criteria to select relevant articles, with a focus on recent research and comprehensive reviews to unravel the toxicological manifestations of arsenic, employing various animal models to discern the underlying mechanisms of arsenic toxicity. Results: The review outlines the multifaceted aspects of arsenic toxicity, including its association with chronic diseases such as cancer, cardiovascular disorders, and neurotoxicity. The emphasis is placed on elucidating the role of oxidative stress, genotoxicity, and epigenetic modifications in arsenic-induced cellular damage. Additionally, the impact of arsenic on vulnerable populations and potential interventions are discussed. Conclusions: Arsenic toxicity represents a complex and pervasive public health issue with far-reaching implications. Understanding the diverse pathways through which arsenic exerts its toxic effects is crucial to developing effective mitigation strategies and interventions. Further research is needed to fill gaps in our understanding of arsenic toxicity and to inform public health policies aimed at minimising exposure.Arsenic toxicity is a crucial public health problem influencing millions of people around the world. The possible sources of arsenic toxicity includes mining, manufacturing processes and natural geological sources. Arsenic exists in organic as well as in inorganic forms. Trivalent meta-arsenite (As3+) and pentavalent arsenate (As5+) are two most common inorganic forms of arsenic. Trivalent oxidation state is toxicologically more potent due to its potential to interact with sulfur containing proteins. Humans are exposed to arsenic in many ways such as environment and consumption of arsenic containing foods. Drinking of arsenic-contaminated groundwater is an unavoidable source of poisoning, especially in India, Bangladesh, China, and some Central and South American countries. Plenty of research has been carried out on toxicological manifestation of arsenic in different animal models to identify the actual mechanism of aresenic toxicity. Therefore, we have made an effort to summarize the toxicology of arsenic, its pathophysiological impacts on various organs and its molecular mechanism of action.

Pesticide Toxicity Associated with Infertility.

Pesticides have benefited mankind in many ways like agriculture, industrial and health sectors. On the other hand, conversely their deleterious effects in both, humans and animals are also alarming. Pesticides including organophosphates, organochlorines, carbamates, pyrethrins and pyrethroids are found sufficiently in the environment resulting in everyday human exposure. This is of a huge concern because most of the pesticides are known to target all the physiological functions of both humans and animals. Indeed, reproduction, being one of the most important physiological processes, that is affected by the daily exposure to pesticides and leading to infertility issues. The present study summarizes the exposure of men and women to certain pesticides resulting in different infertility concerns like sperm abnormalities, decreased fertility, abnormal sperm count and motility, testicular atrophy, ovarian dysfunction, spontaneous abortions, disruption of hypothalamic-pituitary-gonadal axis, etc. So, this article will be helpful in perceiving the mechanism of reproductive toxicity of different pesticides and their management before any alarm of danger.

CRISPR/Cas9 system: a reliable and facile genome editing tool in modern biology.

Genome engineering has always been a versatile technique in biological research and medicine, with several applications. In the last several years, the discovery of Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-Cas9 technology has swept the scientific community and revolutionised the speed of modern biology, heralding a new era of disease detection and rapid biotechnology discoveries. It enables successful gene editing by producing targeted double-strand breaks in virtually any organism or cell type. So, this review presents a comprehensive knowledge about the mechanism and structure of Cas9-mediated RNA-guided DNA targeting and cleavage. In addition, genome editing via CRISPR-Cas9 technology in various animals which are being used as models in scientific research including Non-Human Primates Pigs, Dogs, Zebra, fish and Drosophila has been discussed in this review. This review also aims to understand the applications, serious concerns and future perspective of CRISPR/Cas9-mediated genome editing.

Evidences of the radiofrequency exposure on the antioxidant status, potentially contributing to the inflammatory response and demyelination in rat brain.

Present study exhibited the oxidative potential of microwave radiation (MWR) leading to the neurodegeneration in rats. Wistar rats were exposed at 2100 MHz frequency for 4 h/day, 5 days/week/3 months. Animals were exposed at an estimated specific absorption rate (0.453 W/kg) and power density (8.237 µW/m2). After exposure irradiated group was compared with control group. Results indicated that microwave exposure significantly increased the levels of serological triglycerides and cholesterol. Oxidative stress is observed through alteration of glutathione homeostasis followed by activated inflammatory response further confirmed by pro and anti-inflammatory cytokines in the exposed group. Histopathological assessments and electron microscopic observation confirmed a significant change in the myelination pattern and cellular organelles in the brain of exposed animals. Taking everything into account it can be concluded that chronic exposure of 2100-MHz frequency caused oxidative stress, which leads to neural damage and demyelination and may affect neural communication.

Mechanisms and treatment strategies of organophosphate pesticide induced neurotoxicity in humans: A critical appraisal.

Organophosphates (OPs) are commonly used pesticides worldwide. Humans are exposed to OPs via different routes viz., the respiratory tract, gastrointestinal tract, and dermal integuments. OPs induce neuropathy by either phosphorylating acetyl cholinesterase or neuropathy target esterase, or by binding specifically to nicotinic or muscarinic receptors of nervous system. Other than neurobehavioral effects in humans, OPs cause cholinergic crisis, intermediate syndrome, OP-induced delayed neuropathy, and Chronic organophosphate-induced neuropsychiatric disorders in time and dosage dependent manner. Biomonitoring of OP markers from body fluids minimizes or measures the severity of the impact, allowing for timely control of the exposure. The standard treatments for OPs poisoning which avoid secondary organ damage are atropine administration, acetylcholine esterase restoration therapy with oximes, and general intensive care. This review summarizes the toxic manifestation data available on humans and discusses potential therapeutic modalities, with the aim to highlight the importance of increasing awareness about its potential risk and reevaluation of exposure level.

Drug Resistance Mechanism of M46I-Mutation-Induced Saquinavir Resistance in HIV-1 Protease Using Molecular Dynamics Simulation and Binding Energy Calculation.

Drug-resistance-associated mutation in essential proteins of the viral life cycle is a major concern in anti-retroviral therapy. M46I, a non-active site mutation in HIV-1 protease has been clinically associated with saquinavir resistance in HIV patients. A 100 ns molecular dynamics (MD) simulation and MM-PBSA calculations were performed to study the molecular mechanism of M46I-mutation-based saquinavir resistance. In order to acquire deeper insight into the drug-resistance mechanism, the flap curling, closed/semi-open/open conformations, and active site compactness were studied. The M46I mutation significantly affects the energetics and conformational stability of HIV-1 protease in terms of RMSD, RMSF, Rg, SASA, and hydrogen formation potential. This mutation significantly decreased van der Waals interaction and binding free energy (∆G) in the M46I-saquinavir complex and induced inward flap curling and a wider opening of the flaps for most of the MD simulation period. The predominant open conformation was reduced, but inward flap curling/active site compactness was increased in the presence of saquinavir in M46I HIV-1 protease. In conclusion, the M46I mutation induced structural dynamics changes that weaken the protease grip on saquinavir without distorting the active site of the protein. The produced information may be utilized for the discovery of inhibitor(s) against drug-resistant HIV-1 protease.

Protective efficacy of rutin against acrylamide-induced oxidative stress, biochemical alterations and histopathological lesions in rats.

Acrylamide is a well-known neurotoxicant and carcinogen. Apart from industrial exposure, acrylamide is also found in different food products. The present study deals with in vivo experiment to test the protective effect of rutin against acrylamide induced toxicity in rats. The study was carried out on female rats with exposure of acrylamide at the dose of 38.27 mg/kg body weight, orally for 10 days followed by the therapy of rutin (05, 10, 20 and 40 mg/kg orally), for three consecutive days. All animals were sacrificed after 24 h of last treatment and various biochemical parameters in blood and tissue were investigated. Histopathology of liver, kidney and brain was also done. On administration of acrylamide for 10 days, neurotoxicity was observed in terms of decreased acetylcholinesterase activity and oxidative stress was observed in terms of increased lipid peroxidation, declined level of reduced glutathione, antioxidant enzymes (superoxide dismutase and catalase) in liver, kidney and brain. Acrylamide exposure increased the activities of serum transaminases, lipid profile, bilirubin, urea, uric acid and creatinine in serum indicating damage. Our experimental results conclude that rutin showed remarkable protection against oxidative DNA damage induced by acrylamide, which may be due to its antioxidant potential.

Oxidative Stress in Human Pathology and Aging: Molecular Mechanisms and Perspectives.

Reactive oxygen and nitrogen species (RONS) are generated through various endogenous and exogenous processes; however, they are neutralized by enzymatic and non-enzymatic antioxidants. An imbalance between the generation and neutralization of oxidants results in the progression to oxidative stress (OS), which in turn gives rise to various diseases, disorders and aging. The characteristics of aging include the progressive loss of function in tissues and organs. The theory of aging explains that age-related functional losses are due to accumulation of reactive oxygen species (ROS), their subsequent damages and tissue deformities. Moreover, the diseases and disorders caused by OS include cardiovascular diseases [CVDs], chronic obstructive pulmonary disease, chronic kidney disease, neurodegenerative diseases and cancer. OS, induced by ROS, is neutralized by different enzymatic and non-enzymatic antioxidants and prevents cells, tissues and organs from damage. However, prolonged OS decreases the content of antioxidant status of cells by reducing the activities of reductants and antioxidative enzymes and gives rise to different pathological conditions. Therefore, the aim of the present review is to discuss the mechanism of ROS-induced OS signaling and their age-associated complications mediated through their toxic manifestations in order to devise effective preventive and curative natural therapeutic remedies.

Acetaminophen-induced renal toxicity: preventive effect of silver nanoparticles.

Present study was planned to investigate the ameliorative effect of silver nanoparticles (AgNPs) on acetaminophen-induced nephrotoxicity. Our results demonstrate that therapy of AgNPs at three different doses (50, 100 and 150 µg/kg once only) prevented the acetaminophen (2 g/kg once only) induced acute renal toxicity. AgNPs treated animals also show less intensity in the histological alterations in kidneys and corroborating the results of analysis of serum urea and creatinine. In addition, AgNPs therapy prevented the acetaminophen-induced oxidative stress, which was confirmed by the alleviated lipid peroxidation, enhanced renal reduced glutathione content and restored enzymatic activities of superoxide dismutase, catalase and adenosine triphosphatase in kidney. Thus, our results demonstrate a possible protective potential of AgNPs on renal toxicity induced by acetaminophen. This study will definitely lead to the development of therapeutic drug against nephrotoxicity, after further clinical and preclinical studies.

Silver nanoparticles protect acetaminophen induced acute hepatotoxicity: A biochemical and histopathological approach.

The present study was premeditated to demonstrate the hepatoprotective effect of silver nanoparticles (AgNPs). Rats were treated with three different doses of AgNPs (50, 100 and 150 µg/kg, p.o.) after Acetaminophen (APAP; 2 g/kg, p.o. once only) intoxication. Treatment with AgNPs recouped the levels of serum aspartate amino transaminase (AST), alanine amino transaminase (ALT), lactate dehydrogenase (LDH), alkaline phosphatase (ALP), bilirubin, triglyceride (TG) and cholesterol in dose dependent manner. Significant reduction in lipid peroxidation (LPO) and restoration of reduced glutathione (GSH) was found in liver in AgNPs treated animals. Alleviated activities of adenosine triphosphatase (ATPase), glucose-6- phosphatase (G6Pase) and antioxidant enzymes viz. superoxide dismutase (SOD) and catalase (CAT) due to APAP induced toxicity in liver were recovered by the treatment of AgNPs. Improvement in histoarchitecture of liver was also consistent with biochemical observations. The results revealed that AgNPs showed significant dose-dependent protection against APAP induced hepatocellular injury.

Botanical and Chemical Fingerprinting of Medicinal Roots of Justicia gendarussa Burm f.

BACKGROUND: Justicia gendarussa Burm f. of family Acanthaceae is medicinally important herb used in the treatment of inflammatory disorders, asthma, hepatic injuries, pathogenic infection and also shows antiproliferative activity against various cancer cell lines. MATERIALS AND METHODS: Pharmacognostical evaluation (macro-microscopy, physicochemical analysis and preliminary phytochemical analysis), high-performance thin layer chromatography (HPTLC) fingerprinting and chemical profiling by gas chromatography-mass spectrometry (GCMS) of dried roots of J. gendarussa were done according to quality standard procedures. RESULTS: Microscopic analysis revealed the compact arrangement of cells in cork region and thin-walled cortex beneath epidermis. Parenchymatous cells with xylem vessel were observed in the roots of J. gendarussa. Physicochemical studies revealed loss on drying (10.474%), total ash (2.990%), acid-insoluble ash (0.099%), water-soluble ash (1.528%), alcohol-soluble extractive value (0.564%) and water-soluble extractive value (4.11%) of the raw drug. Preliminary phytochemical analysis of ethanolic extract of J. gendarussa showed the presence of alkaloid, steroid, flavonoid, phenol, carbohydrate, saponin and quinone. Rf, color of the spots and densitometric scan were recorded by HPTLC fingerprinting using toluene: ethyl acetate: formic acid (5.0:4.0:1.0). On photodocumentation, six spots were visualized under 254 nm, nine spots under 360 nm and six spots at 620 nm. Identification of components in ethanolic extract of J. gendarussa was done by GC-MS. GC-MS results in the presence of oleic acid, 9,12-octadecadienoic acid, 6,9,12-octadecatrienoic acid and estra-1, 3,5 (10)-trein-17-ß-ol in ethanolic extract of J. gendarussa. CONCLUSION: These specific identities will be useful in identification and authentication of the raw drug in dried form. SUMMARY: Transverse section and powder of dried roots of Justicia gendarussa were examined microscopically. Microscopic observations showed the presence of well-developed cork and cortex. Presence of xylem vessels and parenchymatic rays were observed in transverse section. Parenchymatous cell and sclereids with vessel elements were found in powder microscopyPhysicochemical studies revealed loss on drying (10.474%), total ash (2.990%), acid-insoluble ash (0.099%), water-soluble ash (1.528%), alcohol-soluble extract (0.564%) and water-soluble extract (4.11%)Preliminary phytochemical analysis of ethanolic extract of J. gendarussa showed the presence of alkaloid, steroid, flavonoid, phenol, carbohydrate, saponin and quinoneHigh-performance thin layer chromatography fingerprinting showed different peaks at different wavelengthChemical profiling of medicinal roots of J. gendarussa by gas chromatography. mass spectrometry revealed the presence of oleic acid, 9,12.octadecadienoic acid, 6,9,12-octadecatrienoic acid and estra-1,3,5 (10)-trein-17-ß-ol as bioactive compound. Abbreviations Used: TLC: Thin layer chromatography; HPTLC: High performance thin layer chromatography; GCMS: Gas chromatography-mass specrtometry; QSIMP: Quality standard of indian medicinal plant; LOD: Loss on drying; TA: Total ash; AIA: Acid insoluble ash; WSA: Water soluble ash; ASE: Alcohol soluble extractive; WSE: Water soluble extractive.

Gold nanoparticles ameliorate acetaminophen induced hepato-renal injury in rats.

Valuable effects of gold particles have been reported and used in complementary medicine for decades. The aim of this study was to evaluate the therapeutic efficacy of gold nanoparticles (AuNPs) against acetaminophen (APAP) induced toxicity. Albino rats were administered APAP at a dose of 2g/kg p.o. once only. After 24h of APAP intoxication, animals were treated with three different doses of AuNPs (50µg/kg, 100µg/kg, 150µg/kg) orally or silymarin at a dose of 50mg/kg p.o., once only. Animals of all the groups were sacrificed after 24h of last treatment. APAP administered group showed a significant rise in the AST, ALT, SALP, LDH, cholesterol, bilirubin, albumin, urea and creatinine in serum which indicated the hepato-renal damage. A significantly enhanced LPO and a depleted level of GSH were observed in APAP intoxicated rats. Declined activities of SOD and Catalase, after acetaminophen exposure indicated oxidative stress in liver and kidney. The activities of ATPase and glucose-6-Phosphatase were significantly inhibited after APAP administration. AuNPs treatment reversed all variables significantly towards normal level and was found nontoxic. Thus it is concluded that gold nanoparticles played a beneficial role in reducing acetaminophen induced toxicity and can be used in the development of drug against hepatic as well as renal diseases, after further preclinical and clinical studies.

Therapeutic potential of quercetin against acrylamide induced toxicity in rats.

Acrylamide (AA) is found in foods containing carbohydrates and proteins, where it is formed during the heating process. It is classified as neurotoxic and probably carcinogenic to humans. The present investigation was aimed to determine the lethal Dose (LD50) of AA and to evaluate the protective effects of quercetin (QE) against AA induced adverse effects in rats. For the determination of LD50, AA was administered orally at four different doses (46.4mg/kg, 100mg/kg, 215mg/kg and 464mg/kg) to experimental animals for seven days. After 7days LD50 of AA was determined using graphical method of Miller and Tainter. Then AA was administered at 1/3rd dose of LD50 (38.27mgkg-1 body weight; p.o. for 10 days) followed by the therapy of QE (5, 10, 20 and 40mg kg-1 orally), for 3 consecutive days for the determination of protective effect of QE against AA. The estimated LD50 of AA was 114.81mg/kg with 95% confidence interval. Exposure to AA 1/3rd dose of LD50 for 10days induced neurotoxicity which was confirmed by decreased acetylcholinesterase (AChE) activity. AA substantially increased lipid peroxidation (LPO), decreased the level of reduced glutathione (GSH) and antioxidant enzymes (SOD and CAT) in liver, kidney and brain. It also increased the activities of serum transaminases, urea, uric acid, creatinine, lipid profile, bilirubin in serum. Treatment with QE restored tissue and serological indices concomitantly towards normal levels. These results revealed that QE is able to significantly alleviate the toxicity induced by AA in rats.

Therapeutic Efficacy of Nigella Sativa Linn. against Antituberculosis Drug-Induced Hepatic Injury in Wistar Rats.

Antituberculosis drug (ATD)-induced hepatotoxicity is a major impediment for the effective treatment of tuberculosis (TB). All first-line anti-TB medications have adverse effects that interrupt the successful completion of TB treatment. This investigation focuses on the evaluation of the protective role of Nigella sativa (NS) against liver injury caused by ATDs. Female rats were treated with ATDs for 8 weeks (3 d/wk) followed by NS for 8 weeks (3 d/wk). The antioxidant activity of NS was estimated with a 1,1-diphenyl-2-picrylhydrazyl (DPPH) assay and by analyzing total phenolic contents. Qualitative characterization of active compounds of the plant was done by high-performance liquid chromotography (HPLC). ATD-induced adverse effects were associated with sharp elevation in levels of serum transaminases, albumin, cholesterol, urea, uric acid, creatinine, and blood urea nitrogen (BUN). ATDs significantly increased lipid peroxidation (LPO) and decreased enzyme activities (superoxide dismutase [SOD], catalase [CAT], adenosine triphosphatase [ATPase], and glucose-6-phosphatase [G6Pase]) in liver, indicating oxidative stress. Conjoint treatment with NS could reverse the serological biochemistry and inhibit oxidative stress by suppressing LPO and augmenting antioxidant enzyme activity toward that of the control. Histological studies support the above biochemical findings. Results indicate that NS exerts excellent hepatoprotective abilities and can be used as a supplement to improve patient adherence and reduce interruptions in treatment due to ATD-related liver injury.