Copper: From enigma to therapeutic target for neurological disorder.

Neurological disorders (NDs) have a negative impact on the lives of individuals. There could be two explanations for this: unclear aetiology and lack of effective therapy. However, research in the past few years has revealed the role of bio-metals dyshomeostasis in NDs. The imbalance in copper (Cu) concentration may be one of the main causative factors in NDs. In this review, we have discussed the role of Cu in NDs, especially Alzheimer's disease (AD), including the molecular mechanisms involved in Cu-associated NDs like oxidative stress, neuroinflammation, and protein misfolding. We have also summarized the recent Cu-targeting approaches and highlighted the in vitro and in vivo studies recently being reported on the subject. Based on the earlier published reports, it could be speculated that the Cu targeting strategy might be an interesting and potential therapeutic approach for NDs. Various difficulties must be overcome to develop safe and efficient Cu-targeting medications for NDs.

Incidence of Morphological Defects in Sperm of Mice Exposed to Hospital Effluent.

Hospital effluents are loaded with drugs, radioactive elements, pathogens, etc. Effluents from treatment plants at source sites may get mixed up with potable water, leading to numerous detrimental/toxic effects. In this study, efforts were made to investigate the toxic effects of one such effluent from a local hospital on the reproductive characteristics of mice when orally administered daily for 60 consecutive days. We primarily focused on the changes in the morphology of the sperm and its geometric morphometrics, i.e., sperm head length and width, area, and perimeter, measured using ImageJ software. The incidence of sperm defects was recorded, and variations in the morphometrics were analyzed by one-way ANOVA using Tukey's post hoc test. A physico-chemical characterization of the water samples was also performed to assess the basic water quality. In summary, the study revealed the critical role of treated water in inducing different abnormalities in sperm, such as the absence of a head, bent necks, abnormal neck attachment, highly coiled tails, and missing tails. Significant differences (p < 0.01 **, p < 0.001 ***) in the morphometrics of spermatozoa with banana heads, hammer heads, missing heads, pin heads, and missing hooks were noted compared to corresponding controls. It could thus be concluded that treated hospital effluent is still inadequately clean and contains significant amounts of toxicants that might be detrimental to sperm quality.

Melatonin ameliorates chronic copper-induced lung injury.

Copper (Cu) is an important trace element required for several biological processes. The use of copper is increasing gradually in several applications. Previous studies suggest that excess levels of copper are attributed to induce oxidative stress and inflammation, mediating tissue damage. Inline, melatonin the hormone of darkness has been reported to exhibit various therapeutic effects including strong free radical scavenging properties and anti-inflammatory effects. However, its effects against pulmonary injury promoted by copper are not explored and remain unclear so far. Therefore, the present study was aimed to investigate the protective effect of melatonin against copper-induced lung damage. Female Sprague Dawley (SD) rats were exposed to 250 ppm of copper in drinking water for 16 weeks and treated with melatonin (i.p.) 5 and 10 mg/kg from the week (13-16th). The extent of tissue damage was assessed by tissue oxidative stress parameters, metal estimation and histological analysis. Copper-challenged rats showed altered oxidative stress variables. In addition, metal analysis revealed increased copper accumulation in the lungs and histological staining results further indicated severe tissue injury and inflammatory cell infiltration in copper-exposed rats. To this side, treatment with melatonin showed antioxidant and anti-inflammatory activities evidenced by reduced oxidative stress, tissue inflammation and collagen deposition as compared to copper-exposed animals. Moreover, spectral findings suggested melatonin treatment modulated the frequency sift, as compared to copper-challenged animals. Altogether, the present results suggest that melatonin might play a potential role in preventing copper-induced lung aberrations via inhibiting the ROS-mediated oxidative stress and inflammation.

Alpha Lipoic Acid and Monoisoamyl-DMSA Combined Treatment Ameliorates Copper-Induced Neurobehavioral Deficits, Oxidative Stress, and Inflammation.

Copper (Cu), being an essential trace metal, plays several roles in biological processes, though exposure to Cu can be potentially toxic to the brain and a few other soft organs. In the present study, we investigated the effects of the combined administration of monoisoamyl 2, 3-dimercaptosuccinic acid (MiADMSA), which is a new chelator, and alpha lipoic acid (ALA) and an antioxidant that is made naturally in the body and is also found in foods, against Cu-induced oxidative stress in rats. Rats were exposed to 20 mg/kg copper sulfate for 16 weeks once a day via the oral route. After 16 weeks of exposure, animals were divided into different sub-groups. Group I was divided into three subgroups: Group IA, control; Group IB, MiADMSA (75 mg/kg, oral); Group IC, ALA (75 mg/kg, oral), while Group II was divided into four subgroups: Group IIA, Cu pre-exposed; Group IIB, Cu+ MiADMSA; Group IIC, Cu+ ALA; Group IID, Cu+ ALA+ MiADMSA. Exposure to Cu led to significant neurobehavioral abnormalities; treatment with MiADMSA, and in particular MiADMSA + ALA, significantly ameliorated the neurobehavioral parameters and restored the memory deficits in rats. Oxidative stress variables (ROS, nitrite, TBARS, SOD, catalase) and inflammatory markers (TNF-α, and IL-1ß), which were altered on Cu exposed rats, also responded favorably to ALA+ MiADMSA combined treatment. Thus, combined administration of MiADMSA and ALA might be a better treatment strategy than monotherapy with MiADMSA or ALA against Cu-induced neurotoxicity, particularly in reducing oxidative stress, neurobehavioral abnormalities, and inflammatory markers.

Synthesis, Molecular Docking, BSA, and In Vitro Reactivation Study of Imidazopyridine Oximes Against Paraoxon Inhibited Acetylcholinesterase.

AIM: To synthesize and evaluate the fused heterocyclic imidazo[1,2-a]pyridine based oxime as a reactivator against paraoxon inhibited acetylcholinesterase. BACKGROUND: Organophosphorus compounds (OPs) include parathion, malathion, chlorpyrifos, monocrotophos, and diazinon, which are commonly used in agriculture for enhancing agricultural productivity via killing crop-damaging pests. However, people may get exposed to OPs pesticides unintentionally/intentionally via ingestion, inhalation, or dermal. The current treatment regimen includes reactivator such as mono or bis-pyridinium oximes along with anticholinergic and anticonvulsant drugs that are recommended for the treatment of OP poisoning. Unfortunately, the drawback of the existing reactivator is the permanent charge present on the pyridinium, making them inefficient to cross the blood-brain barrier (BBB) and reactivate OP-inhibited central nervous system (CNS) acetylcholinesterase. Therefore, there is a need of a reactivator that could cross the BBB and reactivate the OP inhibited acetylcholinesterase. OBJECTIVE: The objectives of the study were synthesis, molecular docking, BSA binding, and in-vitro estimation of oximes of various substituted imidazo [1,2-a]pyridine against paraoxon inhibited acetylcholinesterase. METHODS: The reactivators were synthesized in three steps and characterized using various spectroscopic techniques. The molecular docking study was performed on 2WHP and 3ZLV PDB using the Glide-XP software. The acid dissociation constant (pKa) of oximes was calculated experimentally, and the drug-likeness properties of the oximes were calculated in silico using Molinspiration and Swiss ADME software. The binding of oximes with bovine serum albumin (BSA) was also investigated using a Fluorescence spectrophotometer. The reactivation potential of the oximes was determined by in vitro enzymatic assay. RESULTS: The In-silico study inferred that the synthesized molecules fulfilled the parameters required for a successful CNS drug candidate. Furthermore, in-vitro enzymatic assay indicated reasonable reactivation potential of the oximes against paraoxon-inhibited AChE. The binding of oximes with bovine serum albumin (BSA) revealed that there was a static quenching of intrinsic fluorescence of BSA by the oxime. The binding constant value and number of binding sites were found to be 0.24 x 104 mol-1 and 1, respectively. CONCLUSION: The results of the study concluded that this scaffold could be used for further designing of more efficient uncharged reactivators.

Stimuli-responsive Polymeric Nanosystems for Therapeutic Applications.

BACKGROUND: Recent studies have been reported emerging polymeric nanoparticles as a promising particulate carrier system for controlled and targeted drug delivery. Stimuli-responsive nanocarriers have shown characteristics, such as high drug uptake at specific sites or targeted cells with an advantage of no drug leakage. These stimuli-responsive polymeric systems are used to functionalize nanocarriers, such as dendrimers, metallic nanoparticles, polymeric nanoparticles, liposomal nanoparticles, and quantum dots. OBJECTIVE: The study reviews the potential of smart stimuli-responsive carriers for therapeutic application and their behavior in external or internal stimuli, like pH, temperature, redox, light, and magnetic field. These stimuli- responsive drug delivery systems exhibit different drug release patterns in in vitro and in vivo studies. Stimuli- responsive nanocarriers are useful for both hydrophilic and hydrophobic drugs and release them on applied stimulus. This review highlights the recent development in the physical properties of polymeric materials and their application in stimuli-responsive specific drug delivery. CONCLUSION: The stimuli (smart, intelligent, programmable) drug delivery systems provide site-specific drug delivery with potential therapy for cancer, neurodegenerative, and lifestyle disorders. The stimuli-responsive- based nanocarriers are developing at a fast pace, and there is a huge demand for biocompatible and biodegradable responsive polymers for effective and safe delivery.

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.

Dose-dependent hepatic toxicity and oxidative stress on exposure to nano and bulk selenium in mice.

Selenium is an essential mineral naturally found in soil, water, and some of the food and is required as essential elements in human and animal body. Se supplementation is required especially for those having Se deficiency. Food supplement of selenium has several forms such as selenocysteine, selenite, selenomethionine, and selenate. Recently, Se supplement as selenium nanoparticles (SeNPs) has gained worldwide attention due to its bioactivities and properties. In the present study, we determined the potential hepatotoxicity of nano and bulk selenium using low and high doses in mice. Twenty-five Swiss albino mice (n=5) were randomly divided into 5 groups and treated orally for 28 days: Group 1: sterile saline (0.9%) as a control; Group 2: sodium selenite (1mg/kg); Group 3: sodium selenite (4mg/kg); Group 4: selenium nanoparticles (1mg/kg); and Group 5: selenium nanoparticles (4mg/kg). Administration of nano-selenium (70-90 nm) led to an increase in the activities of serum transaminases (ALT and AST), while no significant effects were noted on biochemical variables indicative of changes in heme synthesis pathway and oxidative stress like blood δ-aminolevulinic acid dehydratase (δ-ALAD), hepatic reactive oxygen species (ROS), catalase activity, superoxide dismutase (SOD), malondialdehyde assay (MDA), reduced glutathione (GSH) and oxidized glutathione (GSSG), glutathione peroxidase (GPx) compared to controls, and a high dose of sodium selenite. Our results suggest that nano-selenium at low dose (1mg/kg) exhibited antioxidant effects in the liver compared to the high dose (4mg/kg) of SeNPs and sodium selenite (1 and 4 mg/kg). The data from the present study might be useful for pharmacologists and toxicologists in providing future directions while designing selenium-based therapeutic strategies.

Positive and Negative Regulation of Ferroptosis and Its Role in Maintaining Metabolic and Redox Homeostasis.

Ferroptosis is a recently recognized regulated form of cell death characterized by accumulation of lipid-based reactive oxygen species (ROS), particularly lipid hydroperoxides and loss of activity of the lipid repair enzyme glutathione peroxidase 4 (GPX4). This iron-dependent form of cell death is morphologically, biochemically, and also genetically discrete from other regulated cell death processes, which include autophagy, apoptosis, necrosis, and necroptosis. Ferroptosis is defined by three hallmarks, defined as the loss of lipid peroxide repair capacity by GPX4, the bioavailability of redox-active iron, and oxidation of polyunsaturated fatty acid- (PUFA-) containing phospholipids. Experimentally, it can be induced by many compounds (e.g., erastin, Ras-selective lethal small-molecule 3, and buthionine sulfoximine) and also can be pharmacologically inhibited by iron chelators (e.g., deferoxamine and deferoxamine mesylate) and lipid peroxidation inhibitors (e.g., ferrostatin and liproxstatin). The sensitivity of a cell towards ferroptotic cell death is tightly associated with the metabolism of amino acid, iron, and polyunsaturated fatty acid metabolism, and also with the biosynthesis of glutathione, phospholipids, NADPH, and coenzyme Q10. Ferroptosis sensitivity is also governed by many regulatory proteins, which also link ferroptosis to the function of key tumour suppressor pathways. In this review, we highlight the discovery of ferroptosis, the mechanism of ferroptosis regulation, and its association with other cellular metabolic processes.

Nanotechnology in Wastewater Management: A New Paradigm Towards Wastewater Treatment.

Clean and safe water is a fundamental human need for multi-faceted development of society and a thriving economy. Brisk rises in populations, expanding industrialization, urbanization and extensive agriculture practices have resulted in the generation of wastewater which have not only made the water dirty or polluted, but also deadly. Millions of people die every year due to diseases communicated through consumption of water contaminated by deleterious pathogens. Although various methods for wastewater treatment have been explored in the last few decades but their use is restrained by many limitations including use of chemicals, formation of disinfection by-products (DBPs), time consumption and expensiveness. Nanotechnology, manipulation of matter at a molecular or an atomic level to craft new structures, devices and systems having superior electronic, optical, magnetic, conductive and mechanical properties, is emerging as a promising technology, which has demonstrated remarkable feats in various fields including wastewater treatment. Nanomaterials encompass a high surface to volume ratio, a high sensitivity and reactivity, a high adsorption capacity, and ease of functionalization which makes them suitable for application in wastewater treatment. In this article we have reviewed the techniques being developed for wastewater treatment using nanotechnology based on adsorption and biosorption, nanofiltration, photocatalysis, disinfection and sensing technology. Furthermore, this review also highlights the fate of the nanomaterials in wastewater treatment as well as risks associated with their use.

3D Printing in Development of Nanomedicines.

Three-dimensional (3D) printing is gaining numerous advances in manufacturing approaches both at macro- and nanoscales. Three-dimensional printing is being explored for various biomedical applications and fabrication of nanomedicines using additive manufacturing techniques, and shows promising potential in fulfilling the need for patient-centric personalized treatment. Initial reports attributed this to availability of novel natural biomaterials and precisely engineered polymeric materials, which could be fabricated into exclusive 3D printed nanomaterials for various biomedical applications as nanomedicines. Nanomedicine is defined as the application of nanotechnology in designing nanomaterials for different medicinal applications, including diagnosis, treatment, monitoring, prevention, and control of diseases. Nanomedicine is also showing great impact in the design and development of precision medicine. In contrast to the "one-size-fits-all" criterion of the conventional medicine system, personalized or precision medicines consider the differences in various traits, including pharmacokinetics and genetics of different patients, which have shown improved results over conventional treatment. In the last few years, much literature has been published on the application of 3D printing for the fabrication of nanomedicine. This article deals with progress made in the development and design of tailor-made nanomedicine using 3D printing technology.

Heavy Metal-Induced Cerebral Small Vessel Disease: Insights into Molecular Mechanisms and Possible Reversal Strategies.

Heavy metals are considered a continuous threat to humanity, as they cannot be eradicated. Prolonged exposure to heavy metals/metalloids in humans has been associated with several health risks, including neurodegeneration, vascular dysfunction, metabolic disorders, cancer, etc. Small blood vessels are highly vulnerable to heavy metals as they are directly exposed to the blood circulatory system, which has comparatively higher concentration of heavy metals than other organs. Cerebral small vessel disease (CSVD) is an umbrella term used to describe various pathological processes that affect the cerebral small blood vessels and is accepted as a primary contributor in associated disorders, such as dementia, cognitive disabilities, mood disorder, and ischemic, as well as a hemorrhagic stroke. In this review, we discuss the possible implication of heavy metals/metalloid exposure in CSVD and its associated disorders based on in-vitro, preclinical, and clinical evidences. We briefly discuss the CSVD, prevalence, epidemiology, and risk factors for development such as genetic, traditional, and environmental factors. Toxic effects of specific heavy metal/metalloid intoxication (As, Cd, Pb, Hg, and Cu) in the small vessel associated endothelium and vascular dysfunction too have been reviewed. An attempt has been made to highlight the possible molecular mechanism involved in the pathophysiology, such as oxidative stress, inflammatory pathway, matrix metalloproteinases (MMPs) expression, and amyloid angiopathy in the CSVD and related disorders. Finally, we discussed the role of cellular antioxidant defense enzymes to neutralize the toxic effect, and also highlighted the potential reversal strategies to combat heavy metal-induced vascular changes. In conclusion, heavy metals in small vessels are strongly associated with the development as well as the progression of CSVD. Chelation therapy may be an effective strategy to reduce the toxic metal load and the associated complications.

Natural products and their derivatives as multifunctional ligands against Alzheimer's disease.

Alzheimer's disease (AD), a complex neurodegenerative disorder causing multiple cellular changes including impaired cholinergic system, beta-amyloid (ßA) aggregation, tau hyperphosphorylation, metal dyshomeostasis, neuroinflammation, and many other pathways are involved in the pathogenesis of the disease. However, the exact cause of the disease is not known. Natural products such as flavonoids, alkaloids, resveratrol, and curcumin have multifunctional properties, and have drawn the attention of the researchers because these molecules are capable of interacting concurrently with the multiple targets of AD. Therefore, natural products and their derivatives with proven efficacy could be used in the management of the neurodegenerative disorders. This review focuses on the natural product based multitarget directed ligands like tacrine-coumarin, tacrine-huperzine A, harmine-isoxazoline, berberine-thiophenyl, galantamine-indole, pyridoxine-resveratrol, donepezil-curcumin and their mode of action.

Nano drug delivery systems: a new paradigm for treating metal toxicity.

INTRODUCTION: The standard medical treatment for metal toxicity is chelation therapy. Chelating agents work by forming less toxic complexes with the toxic metal ions which are readily excreted from the body. These compounds, based on their hydrophilic/lipophilic property, can either remove toxic metal ions from extracellular sites or can penetrate the intracellular compartments to facilitate the removal of toxic metal ions. However, there are various disadvantages associated with this kind of therapy, notably, selectivity. Other problems and challenges are that the therapy regime is expensive, time consuming and has poor patient compliance. Two chelating agents, dimercaptosuccinic acid (DMSA) and dimercaptopropionicsulfonate (DMPS) have gained increased acceptance among clinicians, undoubtedly improving the management of metal intoxications. AREAS COVERED: The present review provides an insight into the conventional chelating agents, new chelators under development, and the new opportunities presented by the use of nanotherapy for the treatment of metal poisoning cases. EXPERT OPINION: Today's research should not only focus towards development of alternate chelators but also targeted therapy such as the nanotherapy.

Nanoencapsulation of DMSA monoester for better therapeutic efficacy of the chelating agent against arsenic toxicity.

AIMS: Exposure to toxic metals remains a widespread occupational and environmental problem in world. Chelation therapy is a mainstream treatment used to treat heavy metal poisoning. This paper describes the synthesis, characterization and therapeutic evaluation of monoisoamyl 2,3-dimercaptosuccinic acid (MiADMSA)-encapsulated polymeric nanoparticles as a detoxifying agent for arsenic poisoning. MATERIALS & METHODS: Polymeric nanoparticles entrapping the DMSA monoester, which can evade the reticulo-endothelial system and have a long circulation time in the blood, were prepared. Particle characterization was carried out by transmission electron microscopy and dynamic light scattering. An in vivo study was conducted to investigate the therapeutic efficacy of MiADMSA-encapsulated polymeric nanoparticles (nano- MiADMSA; 50 mg/kg orally for 5 days) and comparison drawn with bulk MiADMSA. Swiss albino mice exposed to sodium arsenite for 4 weeks were treated for 5 days to evaluate alterations in blood, brain, kidney and liver oxidative stress variables. The study also evaluated the histopathological changes in tissues and the chelating potential of the nanoformulation. RESULTS: Our results show that nano-MiADMSA have a narrow size distribution in the 50-nm range. We observed an enhanced chelating potential of nano-MiADMSA compared with bulk MiADMSA as evident in the reversal of biochemical changes indicative of oxidative stress and efficient removal of arsenic from the blood and tissues. Histopathological changes and urinary 8-OHdG levels also prove better therapeutic efficacy of the novel formulation for arsenic toxicity. CONCLUSION: The results from our study show better therapeutic efficacy of nano-MiADMSA in removing arsenic burden from the brain and liver.

Quenching action of monofunctional sulfur mustard on chlorophyll fluorescence: towards an ultrasensitive biosensor.

An ultrasensitive fluorimetric biosensor for the detection of chemical warfare agent sulfur mustard (SM) was developed using its monofunctional analogue. SM is a vesicant and a potent chemical threat owing to its direct toxic effects on eyes, lungs, skin and DNA. This work investigates the quenching action of the analyte on chlorophyll fluorescence as elucidated by nuclear magnetic resonance, Fourier transform infrared spectroscopy and mass spectrometry studies suggesting the electrophilic attack of carbonium ion on nitrogens of the porphyrin moiety of chlorophyll. The properties of immobilisation matrix were optimised and scanning electron microscope observations confirmed improvement in pore size of sol-gels by addition of 32 % (v/v) glycerol, a feature enabling enhanced sensitivity towards the analyte. Chlorophyll embedded sol-gel was treated with increasing concentrations of monofunctional SM and the corresponding drop in maximum fluorescence intensity as measured by emission at 673 nm was observed, which varied linearly and had a detection limit of 7.68 × 10(-16) M. The biosensor was found to be 6 orders of magnitude more sensitive than the glass microfibre-based disc biosensor previously reported by us.