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.

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.

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.

Maternal exposure to bisphenol S induces neuropeptide signaling dysfunction and oxidative stress in the brain, and abnormal social behaviors in zebrafish (Danio rerio) offspring.

Recent studies show that bisphenol S (BPS) induces multiple adverse effects in exposed organisms; however, the maternal effects of BPS exposure remain poorly understood. Here, we expose adult female zebrafish to environmentally relevant concentrations of BPS (0, 1, 10, 30 µg/L) and 1 µg/L of 17-ß-estradiol (E2) as a positive control for 60 days. Females were then paired with BPS-unexposed males and their offspring were raised in control water for 6 months. Maternal exposure to BPS was found to alter social behavior and anxiety response in a dose-specific manner in male offspring. Group preferences and social cohesion were significantly reduced by maternal exposure to 1 and 10 µg/L BPS, respectively. Additionally, maternal exposure to 1 and 30 µg/L BPS and E2 decreased offspring stress responses during the novel tank test. The impaired social behavior was associated with elevated arginine-vasotocin (AVT) level as well as with the altered expression of genes involved in AVT signaling pathway (AVT, avpr1aa) and enzymatic antioxidant genes (cat and Mn-sod) in the brain. Collectively, these results suggest that maternal exposure to environmentally relevant concentrations of BPS alters social behavior in zebrafish offspring, which is likely mediated by oxidative stress and disruption of neuropeptide signaling pathways in the brain.

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.

In Vitro Phytochemical Screening, Cytotoxicity Studies of Curcuma longa Extracts with Isolation and Characterisation of Their Isolated Compounds.

The Curcuma longa plant is endowed with multiple traditional and therapeutic utilities and is here explored for its phytochemical constituents and cytotoxic potential. Turmeric rhizomes were extracted from three different solvents and screened for the presence of different phytochemical constituents, observation of which indicated that the polar solvents favoured extraction of greater versatile phytochemical constituents. These extracts were investigated for their cytotoxic potential by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay on three different of cell lines including SCC-29B (oral cancer cell line), DU-145 (prostate cancer cell line) and the Vero cell line (healthy cell line/non-cancerous cell line). This assay was performed by taking three extracts from isolated curcuminoids and a pure bioactive compound bisdemethoxycurcumin (BD). Bisdemethoxycurcumin was isolated from curcuminoids and purified by column and thin-layer chromatography, and its structural characterisation was performed with different spectroscopic techniques such as FTIR, NMR (1H Proton and 13C Carbon-NMR) and LC-MS. Amongst the extracts, the ethanolic extracts exhibited stronger cytotoxic potential against the oral cancer cell line (SCC-29B) with an IC50value of 11.27 µg/mL, and that this was too low of a cytotoxicity against the Vero cell line. Although, curcuminoids have also shown a comparable cytotoxic potential against SCC-29B (IC50 value 16.79 µg/mL), it was not as potent against the ethanolic extract, and it was even found to be cytotoxic against healthy cell lines at a very low dose. While considering the isolated compound, bisdemethoxycurcumin, it also possessed a cytotoxic potential against the prostate cancer cell line (DU-145) (IC50 value of 93.28 µg/mL), but was quite safe for the healthy cell line in comparison to doxorubicin.

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.

Applications of Adductomics in Chemically Induced Adverse Outcomes and Major Emphasis on DNA Adductomics: A Pathbreaking Tool in Biomedical Research.

Adductomics novel and emerging discipline in the toxicological research emphasizes on adducts formed by reactive chemical agents with biological molecules in living organisms. Development in analytical methods propelled the application and utility of adductomics in interdisciplinary sciences. This review endeavors to add a new dimension where comprehensive insights into diverse applications of adductomics in addressing some of society's pressing challenges are provided. Also focuses on diverse applications of adductomics include: forecasting risk of chronic diseases triggered by reactive agents and predicting carcinogenesis induced by tobacco smoking; assessing chemical agents' toxicity and supplementing genotoxicity studies; designing personalized medication and precision treatment in cancer chemotherapy; appraising environmental quality or extent of pollution using biological systems; crafting tools and techniques for diagnosis of diseases and detecting food contaminants; furnishing exposure profile of the individual to electrophiles; and assisting regulatory agencies in risk assessment of reactive chemical agents. Characterizing adducts that are present in extremely low concentrations is an exigent task and more over absence of dedicated database to identify adducts is further exacerbating the problem of adduct diagnosis. In addition, there is scope of improvement in sample preparation methods and data processing software and algorithms for accurate assessment of adducts.

Pulmonary fibrotic response to inhalation of ZnO nanoparticles and toluene co-exposure through directed flow nose only exposure chamber.

The increasing use of Zinc Oxide nanoparticles (ZnONPs) in paint industry is not supplemented with adequate toxicology data. This report focuses on the fibrogenic toxicity caused due to co-exposure of ZnONPs and toluene in male Wistar rats, exposed for 28 days, through directed flow nose only exposure chamber. The rats were grouped as air control, toluene control (200 ppm), zinc oxide control (10 mg/m(3)), low dose co-exposed (5 mg/m(3) ZnO and 200 ppm of toluene) and high dose co-exposed (10 mg/m(3) of ZnO and 200 ppm of toluene). Our study demonstrates that co-exposure of ZnONPs and toluene (as in paint industry), even at their respective permissible exposure level (5 mg/m(3) for ZnO and 200 ppm for toluene) have the potential to produce a progressive inflammatory and fibrotic response in the alveolar tissues of the lungs. We observed a significant increase in inflammatory markers in BAL fluid and elevated malondialdehyde (MDA) levels with lower levels of intracellular reduced glutathione (GSH) in lungs of rats of co-exposed group. Significant increase in the levels of pro-inflammatory mediators (IL-6, Ikßα, Cox-II, p-NF-κB) in lung tissues also indicated pulmonary damage. To best of our knowledge this is the first study which highlights the toxicity of co-exposed ZnO NPs and toluene.

Modulation of histone deacetylase attenuates naloxone-precipitated opioid withdrawal syndrome.

The present study has been designed to investigate the effect of selective inhibitors of histone deacetylase and/or N-acetyl-Asp-Glu-Val-Asp-al (Ac-DEVD-CHO), a selective interleukin-1ß converting enzyme inhibitor, on the development of naloxone-induced opioid withdrawal syndrome both in vitro and in vivo and the effect of histone deacetylase inhibition on histone H3 acetylation in brain. Sub-acute morphine administration followed by a single injection of naloxone (8 mg/kg, i.p.) was used to precipitate opioid withdrawal syndrome in mice. Behavioral observations were made immediately after naloxone treatment. Withdrawal syndrome was quantitatively assessed in terms of withdrawal severity score and frequency of jumping, rearing, fore paw licking and circling. Separately naloxone-induced contraction in morphine-dependent isolated rat ileum was employed as an in vitro model. An isobolographic study design was employed to assess potential synergistic activity between trichostatin A and Ac-DEVD-CHO. Brain histone acetylation status was examined by western blotting. Injection of naloxone precipitated a severe form of abstinence syndrome in morphine-dependent mice along with strong contracture in isolated rat ileum. Administration of tributyrin (1.5, 3 and 6 g/kg, p.o.), trichostatin A (0.3, 1.0 and 3.0 mg/kg, p.o.) and Ac-DEVD-CHO (0.3, 1.0 and 3.0 mg/kg, p.o.) markedly and dose dependently attenuated naloxone-induced morphine withdrawal syndrome in vivo as well as in vitro in rat ileum. Trichostatin A was also observed to exert a synergistic interaction with Ac-DEVD-CHO. Western blot analysis revealed that multiple administration with the effective dose of tributyrin or trichostatin A in the in vivo experiments induced hyperacetylation of histone H3 in the mouse brain. Thus, it is proposed that histone deacetylase activation linked mechanism might be involved in the development of opioid dependence and the precipitation of its withdrawal syndrome.

Cytarabine induced cerebellar neuronal damage in juvenile rat: correlating neurobehavioral performance with cellular and genetic alterations.

Cytosine arabinoside (Ara-C), a pyrimidine analogue induces cerebellar dysfunction and behavioral abnormalities. Although many in vitro experiments have been conducted in the past demonstrating the lethal potential of Ara-C to cerebellar neurons, there is a paucity of literature available regarding the effects of Ara-C on the cellular and genetic material of cerebellum and its subsequent influence on the neurobehavioral performance in vivo. Rats were treated with Ara-C at the dose levels 50, 100 and 200mg/kg/day for 5 and 14 days by intraperitoneal (i.p.) route. Endpoints of the evaluation included food and water intake, body and organ weight, behavioral parameters, histopathology, oxidative stress, DNA damage, apoptosis, expression of p53, caspase-3 and calbindin D-28K (calbindin) as well as histone acetylation and methylation. Ara-C treatment for 14 days significantly decreased the food and water intake, body weight gain and brain weight in rat as compared to the control. Alterations in various behavioral parameters were observed, indicating the impaired cerebellar function. Further, cellular abnormalities in the cerebellum such as Purkinje cell misalignment and granule cell cytotoxicity were observed. Positive correlation was observed between Ara-C induced disturbance in the motor performance and the Purkinje cell loss in rat cerebellum. Moreover, Ara-C treatment significantly increased the oxidative stress, DNA damage, TUNEL positive cells, p53 and caspase-3 positive cells in the rat cerebellum. Unlike short-term treatment, long-term Ara-C treatment significantly reduced calbindin expression in the cerebellum. Apart from this, 14 days Ara-C treatment led to significant alterations in the histone acetylation and methylation in the cerebellum, while in 5 days treatment no such alterations were observed. Present results indicated that Ara-C, by inducing oxidative stress mediated DNA damage, executes neuronal apoptosis which is accompanied by an increase in the p53 and caspase-3, but decrease in the calbindin expression.