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Aim: To synthesize and evaluate the fused heterocyclic imidazopyridine 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 an anticonvulsant drugs are recommended for the treatment of OP poisoning. Unfortunately, the drawback of the existing reactivator is that owing to the permanent charge present on the pyridinium makes them inefficient to cross the blood-brain barrier (BBB) and reactivate OP-inhibited central nervous system (CNS) acetylcholinesterase. Therefore, there is a need of 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. Method: The reactivators were synthesized in three steps and characterized using various spectroscopic techniques. Molecular docking study was performed on 2WHP and 3ZLV PDB using Autodock tool. The acid dissociation constant (pKa) of oximes was calculated experimentally and drug-likeness properties of the oximes were calculated In silico using mole inspiration and Swiss ADME software. The binding of oximes with bovine serum albumin (BSA) was also investigated by UV-Vis spectrophotometer. The reactivation potential of the oximes was determined by in vitro enzymatic assay. Result: in-silico study inferred that synthesized molecules fulfilled the parameters that required for a successful CNS drug candidate. Further, 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 static quenching of intrinsic fluorescence of BSA by oxime. The binding constant value and number of binding sites were found 0.24 mol-1 and 1 respectively. Conclusion: The results of study concluded that this scaffold could be used for further designing of more efficient uncharged reactivators.

Autophagy is defined as a process in which cell undergo sequential sequestration of degraded protein and damaged organelles for maintenance of cellular hemostasis. Autophagy is regulated by complex mammalian target of rapamycin complex 1 (m-TORC) pathway, and its types depends on nature phagocytized material. Interaction of autophagic signaling pathway with nanocarriers causes autophagy inhibition and cell death. The role different classes of nanomaterials in autophagy perturbation, both regulation and inhibition in in-vitro and animal models were studied. These nanocarriers have application in anticancer delivery agents to cancer cells. Due to retention of NPs in mitochondria and endoplasmic reticulum induces stress and up-regulates autophagy sequences. This co-localization of NPs in organelles lead to cancer cell death due to autophagy inhibition. The review covers autophagy regulation pathways and NPs mediated autophagy modulation in combination with chemotherapeutics has been explored for cancer therapy with their toxicity concerns.

Purpose: In this study, a novel D-α-tocopheryl polyethylene glycol succinate (TPGS) modified bovine serum albumin (BSA) nanoparticles (NPs) were developed for delivery of Anastrozole (ANZ) which is optimized by Box-Behnken design (BBD). Fabricated TPGS-ANZ-BSA NPs were evaluated for their physicochemical and drug release characteristics. Methods: TPGS-ANZ-BSA NPs were prepared by desolvation thermal gelation method and the effects of critical process parameter (CPP) which are BSA amount, TPGS concentration and stirring speed on the critical quality attributes (CQA) such as % drug loading (%DL) and particle size were studied using BBD. TPGS-ANZ-BSA NPs were characterized using different spectroscopic techniques including UV-Visible and FTIR is used to confirm the entrapment of ANZ in BSA. DSC and PXRD revealed the amorphization of ANZ in the TPGS-ANZ-BSA NPs after freeze drying. Scanning electron microscopy (SEM) analysis was performed for the surface morphology analyses NPs. In vitro release studies were performed at pH 5.5 and pH 7.4 for 48h to mimic tumour microenvironment. Results: The BBD optimized TPGS-ANZ-BSA NPs showed 107 nm particle size with %DL 8.5± 0.5%. The spectroscopic and thermal characterizations revealed the successful encapsulation of ANZ inside the NPs. The TPGS-ANZ-BSA NPs were found to exhibit burst release at pH 5.5 and sustained release at pH 7.4. The short-term stability displayed no significant changes in physical properties TPGS-ANZ-BSA NPs at room temperature for a period one month. Conclusion: The BBD optimized TPGS-ANZ-BSA nanoparticles showed enhanced physiochemical properties for ANZ and potential candidates for anticancer agent drugs delivery.

Tungsten (W) and its compounds have emerged as a relatively new area of environmental health concern in the last decade. Tungsten is environmentally benign due to its increasing use in armour-piercing munitions and as a replacement for lead in other ammunition. It has also been identified in various hazardous waste sites and therefore been proposed for inclusion in the Environmental Protection Agency National Priorities List. The major objective of this study was to evaluate the therapeutic efficacy of orally administered monoisoamyl 2, 3-dimercaptosuccinic acid (MiADMSA) against tungstate induced oxidative injury in blood, liver and kidneys of male Wistar rats. MiADMSA, a thiol chelator has gained wide recognition recently as a future chelating drug of choice specifically for arsenic and was chosen for this study as tungstate ions too have an affinity toward the -SH group thus, being less bioavailable in the body. We determined the effects of MiADMSA (50 mg/kg, p.o.) against sodium tungstate (500 ppm in drinking water, daily for 28 days) induced biochemical changes indicative of oxidative stress in blood, and other soft tissues of of male Wistar rats. Tungsten exposure led to an increased levels of Reactive Oxygen Species (ROS) in liver, kidney, spleen and blood accompanied also by an increase in TBARS levels. The GSH: GSSG ratio also showed a decrease on sodium tungstate intoxication. Treatment with MiADMSA restored most of the sodium tungstate-induced alterations in the biomarkers suggestive of oxidative stress. These preliminary results led us to conclude that sub-acute exposure to tungstate-induced oxidative stress could be effectively reduced by the administration of MiADMSA and thus might be a promising antidote for studying in detail its efficacy in reducing body tungstate burden and its excretion post tungstate exposure.

Neurodegenerative disorders can arise as a result of amyloid-β production and misfolding of its protein. The complex anatomy of the brain and the unresolved mechanics of the central nervous system hinder drug delivery; the brain is sheathed in a highly protective blood–brain barrier, a tightly packed layer of endothelial cells that restrict the entry of certain substances into the brain. Nanotechnology has achieved success in delivery to the brain, with preclinical assessments showing an acceptable concentration of active drugs in the therapeutic range, and nanoparticles can be fabricated to inhibit amyloid and enhance the delivery of the therapeutic molecule. This review focuses on the interactions of nanoparticles with amyloid-β aggregates and provides an assessment of their theranostic potential.

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.

New chemical agents that could combat increasing antibiotic resistance are urgently needed. In this mini-review, an old but highly relevant RNA sequence which is crucial for the continuation of bacterial life-cycle is covered. Some of the most significant advances of the last decade in sensing and targeting the bacterial rRNA A-site: a well-validated binding site of proverbially known aminoglycoside antibiotics are described. Some of the major advances in direct sensing of the bacterial decoding side (A-site) are described and also new fluorescent molecules that are capable of detecting lead compounds through high-throughput assays by displacement of fluorescent probe molecules are highlighted. Lastly, some of the recently discovered non-aminoglycoside small molecule binders of bacterial rRNA A-site as a new class of molecules that could provide future scaffolds and molecules for developing new antibacterial agents have been discussed.

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.

Nanodiamonds (ND) belong to the nano-carbon family, which involves several synthesis, post-synthesis methods, and other modifications for ND preparation. NDs have played vital role both inside and outside of medicine in recent years. The study of NDs has stated in early 1960s, NDs are smaller particles with a size of about 4-5 nm with confined size distribution, large-scale synthesis at lower costs relying on the carbon explosives ignition, apparent surface functional design along with bio-conjugation and extreme biocompatibility. It has been predicted that the ND's magnetic characteristics will contribute to the up-growth of various therapeutic promoters for delivery vehicles, diagnostic probes, gene therapy, tissue scaffolds, anti-bacterial and anti-viral treatments, and devices like nano-robots. Furthermore, the wide applications of biotechnology have displayed the potential usage of NDs in certain bioanalytical needs like fluorescent bio labeling through fluorescent and protein purification of proteins. In this current review, the determination of ND's design, property, classes, constancy, organization, surface modification, biocompatibility, and its applications in the biomedical field have penned. The usage of ND as anti-neoplastic agents and in other health related formulations have displayed exceptional results for future growth. Additionally, NDs provide other functionalities such as production of biodegradable surgical devices of bone, the assassination of drug resistant microbes and viruses, tissue engineering scaffolds, and aids in the delivery of genetic matter into the nucleus of cells.

Organophosphorus Compounds (OPCs) are used as pesticides to control pest, as chemical weapons in military conflict and unfortunately in the terrorist attack. These compounds are irreversible inhibitors of acetylcholinesterase, resulting in the accumulation of acetylcholine that leads to severe health complications which may be ended with the death of the victim. Current antidotes used for reactivation of organophosphorus inhibited acetylcholinesterase (OP-AChE) are not able to cross the blood-brain barrier efficiently, therefore being incapable to reactivate OP-AChE of the central nervous system. Due to limitations with current antidotes, there is an urgent need for new effective antidotes that could be included in the treatment regimen of OP poisoning. In this direction, comprehensive work has been done to improve the permeability of existing antidotes using a variety of strategies that include synthesis of oxime bonded to peripheral site binding moiety via an alkyl, aryl, or heteroatom-containing linker, synthesis of sugar oximes, and prodrug of 2-PAM, incorporating fluorine and chlorine in the structure of charged oximes. Other classes of compounds such as the mannich base, N-substituted hydroxyimino acetamide, alkylating agents, have been investigated for reactivation of OP-AChE. This review comprises the development of various classes of reactivators with the aim of either enhancing blood-brain permeability of existing antidotes or discovering a new class of reactivators.

Highly stable pine oil-loaded nanoemulsions were evaluated for nutraceutical and storage stability applications. Pine oil-loaded nanoemulsion preparation was done with pine oil as the oily phase and additionally with different ratios of the non-ionic surfactant (Tween 80) and cosurfactant (ethanol) in an aqueous solution using the isothermal low-energy or spontaneous emulsification method. A transparent and stable nanoemulsion was obtained with a combination of pine oil (5 wt %), surfactant mixture (35 wt %), and water quantity sufficient (qs) by the isothermal low-energy method. The mean droplet size and ζ-potential of the fabricated nanoemulsion were ≈14 nm and -3.4 mV, respectively. The size of the transparent nanoemulsion increased to ∼45 nm and showed turbidity at 60 °C. Microrheological investigation highlighted the gel-sol-gel conversion in the presence of applied angular frequency at 25 °C. The loss modulus shifted to lower frequency at 60 °C in comparison to other temperatures. The anticholinesterase (AChE) inhibition activity of the pine oil-loaded nanoemulsion suggested a possible therapeutic value, and at 0.10% concentration of the nanoemulsion, the AChE inhibition activity was ≈95.72 ± 5.59%. These studies have important implications in fabrication and optimization of a nanoemulsion as a delivery system for combating reminiscence in Alzheimer's disease and application in the nutraceutical-based industry. This isothermal low-energy method offers an advantage of preparing an edible oil delivery system using simple and rapid operational parameters.

Crystalline solid dispersion of lurasidone hydrochloride (LH) was made with various polar and non-polar small molecules to overcome the poor aqueous solubility issue. LH-Glutathione (GSH) solid dispersion in 1:1 ratio was prepared by co-grinding method and characterized by using differential scanning calorimetry (DSC), powder X-ray diffraction, Fourier transform infrared spectroscopy (FTIR) and Raman spectroscopy. GSH acts as antioxidant and reported for anti-schizophrenic activity may provide synergistic action with LH or reduce the side effects. LH in LH-GSH solid dispersion (SD) has shown improvement in solubility by 7.9 folds than plain drug which translated in terms of improved dissolution rate by two-folds. The in vitro dissolution results showed maximum dissolution rate with LH-GSH SD (97.85 ± 2.40%) compared to plain drug (50.5 ± 3.02%) at 15 min (t15 min, %) and thus, satisfying criteria of immediate release dosage form. DSC and FTIR data confirmed the stability of LH-GSH SD for 3 months at accelerated stability condition (40 ± 2°C and 75 ± 5% RH). The prepared LH-GSH SD can be used as a tool to target dual problems that is, enhanced physicochemical properties along with possible management of disorder which could be due to synergism with co-administered GSH. This approach is thought to be efficiently providing the relief to the psychological patients.

Despite the availability of sufficient data on the effects of individual metal exposure on living organisms, a critical knowledge gap still exists in predicting effects of multi-metals particularly on the pituitary-testicular axis. Thus, the aim of the present study was to check the effects of individual or combined (binary and ternary) exposure to aluminum, copper, and zinc on (i) sperm and testosterone levels (ii) oxidative stress and (iii) structural changes in testis of male Wistar rats. Animals were exposed to aluminum, copper, and zinc either individually (20

Introduction: copper dyshomeostasis has long been linked with several neurodegenerative disorders. The binding of Cu with amyloid beta and other neuronal proteins in the brain leads to the generation of oxidative stress, which eventually causes neurotoxicity. Method: the present study was aimed at elucidating the efficacy of monoisoamyl 2,3-dimercaptosuccinic acid (MiADMSA) and d-penicillamine (DPA) (0.3 mEq kg−1, oral administration for 2 weeks) against Cu(ii)-induced (20 mg kg−1, oral administration for 16 weeks) neurotoxicity in Sprague-Dawley (SD) rats. Results: we observed that the MiADMSA treatment modulated the altered oxidative and nitrosative stress parameters, antioxidant enzymes, and acetylcholinesterase (AChE) activity. Significant improvements were noticed in the neurobehavioral parameters except for the memory parameter. We also observed moderate improvement of memory impairment in the rats treated with MiADMSA and DPA post Cu(ii) exposure, as assessed by a passive avoidance test. Disease progression involves multiple factors and results in the up-regulation of intra and extracellular proteins such as amyloid beta and tau proteins; the expressions of these proteins were significantly reduced by the treatment proposed in our study, and these results were confirmed by ELISA and qRT-PCR. The expression of caspase-3 was higher in Cu(ii)-exposed rats, whereas it was lower in the MiADMSA-treated group. The proposed treatment reduced the copper-induced histological changes in the cortex and hippocampus regions of the brain. Conclusion: it can be summarised from the present study that MiADMSA is effective in reducing Cu(ii)-induced oxido-nitrosative stress, antioxidant defense enzymes, neurobehavioral changes, neuronal markers, apoptotic markers, and their genetic expressions. We conclude that chelation therapy using MiADMSA might be a promising approach for the treatment of copper-induced neurotoxicity.

Nitrogen-containing heterocycles are one of the most common structural motifs in approximately 80% of the marketed drugs. Of these, benzimidazoles analogues are known to elicit a wide spectrum of pharmaceutical activities such as anticancer, antibacterial, antiparasitic, antiviral, antifungal as well as chemosensor effect. Based on the benzimidazole core fused heterocyclic compounds, crescent-shaped bisbenzimidazoles were developed which provided an early breakthrough in the sequence-specific DNA recognition. Over the years, a number of functional variations in the bisbenzimidazole core have led to the emergence of their unique properties and established them as versatile ligands against several classes of pathogens. The present review provides an overview of diverse pharmacological activities of the bisbenzimidazole analogues in the past decade with a brief account of its development through the years.

Arsenic considered as one of the most hazardous chemical while arsenic poisoning is also one of the serious medical issues worldwide. Long term arsenic exposure is associated with bone degeneration. The exact mechanism involving arsenic induced bone degeneration remains unclear but, plentiful literature suggested that oxidative/nitrosative stress caused by generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) is one of the leading causes.Various treatment strategies are available for bone degeneration however, the suitable treatment for arsenic induced bone degeneration still lacks. In the current investigation, we evaluated the efficacy of chelation against arsenic induced bone degeneration in experimental rats. Male Sprague Dawley rats were exposed to sodium arsenite and dimethylarsinic acid (DMA) (50 ppm) for 18 weeks. After arsenic exposure, animals were treated with Monoisoamyl dimercaptosuccinic acid (MiADMSA) for three course of treatment (50 mg/kg, p.o., once daily for 5 days) with an interval of one week between two courses of treatment. MiADMSA minimizes the bone degeneration through reduction of oxidative stress (Reactive Oxygen Species, Reactive Nitrogen Species, and thiobarbituric reactive substances), alteration of antioxidant status (rGSH, Superoxide dismutase, Catalase) which led to the depletion in the levels of inflammatory markers like TNFα and IL-1β and alteration in the bone remodelling biomarkers like ALP, RANKL, and Runx2. It can be concluded from this study that MiADMSA could be an effective therapeutic strategy against arsenic induced bone degeneration and the possible mechanism could be the chelation of arsenic accompanied by the reduction in oxidative stress and inflammation.

Organophosphorus (OP) compounds are typically a broad class of compounds that possess various uses such as insecticides, pesticides, etc. One of the most evil utilizations of these compounds is as chemical warfare agents, which pose a greater threat than biological weapons because of their ease of access. OP compounds are highly toxic compounds that cause irreversible inhibition of enzyme acetylcholinesterase, which is essential for hydrolysis of neurotransmitter acetylcholine, leading to series of neurological disorders and even death. Due to the extensive use of these organophosphorus compounds in agriculture, there is an increase in the environmental burden of these toxic chemicals, with severe environmental consequences. Hence, the rapid and sensitive, selective, real-time detection of OP compounds is very much required in terms of environmental protection, health, and survival. Several techniques have been developed over a few decades to easily detect them, but still, numerous challenges and problems remain to be solved. Major advancement has been observed in the development of sensors using the spectroscopic technique over recent years because of the advantages offered over other techniques, which we focus on in the presented review.

We evaluated the neuro-, immuno-, and male reproductive toxicity of zinc oxide nanoparticles (ZnO NPs) alone and in combination with lead acetate. We also studied the therapeutic role of α-lipoic acid postexposure. Lead (10 mg/kg, body weight), ZnO NPs (100 mg/kg, bwt) alone, and their combination were administered orally in Wistar rats for 28 days, followed by the administration of α-lipoic acid (15 mg/kg, bwt) for the next 15 days. Our results demonstrated protective effects of α-lipoic acid on lead and ZnO NP–induced biochemical alterations in neurological, immunological, and male reproductive organs in rats. The altered levels of blood δ-aminolevulinic acid dehydratase (ALAD), immunoglobulins (IgA, IgG, IgM, and IgE), interleukins (IL-1β, IL-4, and IL-6), caspase-3, and tumor necrosis factor (TNF-α) were attenuated by lipoic acid treatment. Lead and ZnO NP–induced oxidative stress was decreased by lipoic acid treatment, while a moderate recovery in the normal histoarchitecture of the brain section (cortex and hippocampus) and testes further confirmed the neuro- and male reproductive toxicity of lead and ZnO NPs. We also observed a significant decrease in the blood metal content in the animals treated with lipoic acid compared to the lead-administered group, indicating the moderate chelating property of lipoic acid. It may thus be concluded that lipoic acid might be a promising protective agent against lead and ZnO NP–induced alterations in the neurological, immunological, and reproductive parameters.

Background: Presently arsenicosis is considered as dangerous health issues including cancer. Urinary bladder is one of the common target organs for developing carcinogenesis by arsenic exposure due to accumulation of arsenic toxic metabolites in bladder. The mechanism involving urinary bladder carcinogenesis is still mysterious. Although there are multiple studies revealed about oxidative/nitosative stress, which plays main role for carcinogenesis, but no study evaluated the associated factor that linked with it as early sign to identify bladder carcinogenesis using a rat model. This study thus will be useful in predicting early sign for arsenic exposed urinary bladder carcinogenesis. Objective: We evaluated 8-Hydroxy-2-deoxyguanosine (8-OHdG) and Matrix Metalloproteinases-9 (MMP-9), which may be the possible associated factors along with oxidative/nitrosative stress as early sign for developing urinary bladder carcinogenesis upon arsenic and its metabolites exposure. Methods: Male Sprague Dawley rats were exposed to 25 ppm of sodium arsenite and its metabolite Dimethylarsinic Acid (DMA) via drinking water for a period of 16 weeks. The carcinogenic potentials were evaluated using various biochemical parameters indicative of oxidative/ nitrosative stress, ELISA of 8-OHdG as biomarker of oxidative/nitrosative stress induced DNA damage, which acts as a bridge between DNA damage and carcinogenesis. We also determined MMP-9 as potential pro-oncogenic biomarker associated with DNA damage. Results: High accumulation of arsenic was noted in tissues accompanied by a significant alteration of oxidative/nitrosative variables in liver and urinary bladder like significant changes in positive predictor of 8-OHdG and MMP-9 both in serum as well as urinary bladder tissue in animals exposed to arsenic and its metabolites. Conclusion: Early sign of urinary bladder carcinogenesis evaluated possibly by co-linking between oxidative/ nitrosative stress, 8-OHdG, MMP-9 and metal accumulation.

Copper (Cu), one of the essential transition metal acts as a prosthetic group for variety of proteins and metalloenzymes. However, it may be hazardous when administered in excess. Copper induced memory impairment and progression of neurodegenerative diseases have not yet been fully elucidated. The aim of the present study was to investigate the effect of exposure to copper sulphate (10mg/kg and 20mg/kg body weight, daily for 16 weeks) on brain copper concentration, few biochemical parameters indicative of oxidative stress and on different neurobehavioral functions in male Sprague Dawley rats. Copper-administered animals showed significant increase in brain copper concentration and a depleted Ceruloplasmin level. Different neurobehavioral studies revealed impaired memory and motor coordination in copper exposed rat. Spontaneous locomotors activity and depression symptoms were also noted in copper intoxicated rats. 8-hydroxy-2' -deoxyguanosine (8-OHdG) level, one of the predominant forms of free radical-induced oxidative lesions, and has been widely used as a biomarker for oxidative stress, increased in copper treated group. Copper induced oxidative stress in the brain was also evident from the increased lipid per oxidation (LPO) and nitrite level, depletion of reduced glutathione (GSH), and reduced activities of the antioxidant enzymes such as superoxide dismutase (SOD), and catalase. The present study thus suggests a significant correlation between copper induced oxidative stress and changes in neurobehavioral function in rats. The changes were more pronounced in animals exposed to a higher dose of copper (20mg/kg) than the lower dose.

Ferroptosis is a newly identified regulated form of cell death, which is thought to play a major role in neurodegenerative diseases. In this review, we discuss recent studies elucidating the molecular mechanisms involved in the regulation and execution of ferroptotic cell death and also its role in the brain. Ferroptosis is regulated mainly via iron homeostasis, glutathione metabolism, and lipid peroxidation. Ferroptotic cell death and pro-ferroptotic factors are correlated with the etiopathogenesis of Parkinson's disease (PD) and Alzheimer's disease (AD). Ferroptosis and etiological factors act synergistically in PD and AD pathogenesis. Furthermore, several preclinical and clinical studies targeting ferroptosis in PD and AD have also shown positive results. Evidence of ferroptosis in the brain thus gives new insights into understanding neurodegenerative diseases. Ferroptosis studies in the brain are still in their infancy, but the existing pieces of evidence suggest a strong correlation between ferroptotic cell death and neurodegenerative diseases. Thus, ferroptosis might be a promising target for treating neurodegenerative diseases.

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.

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.

The treatment of central nervous system (CNS) disorders remains a challenge due to the limited access of drug molecules across the blood-brain barrier (BBB). The BBB is the major hurdle for the delivery of therapeutics to brain, which leads to lesser brain drug concentrations, poor patient compliance, and failure of therapy. Nose-to-brain drug delivery provides a myriad of healthcare advances for the management of systemic, local, as well as CNS disorders due to suitable physiological conditions such as highly vascularized mucosa, large surface area, and porous endothelial membrane. The route involves trigeminal or olfactory nerve pathways, which commence in the brain and ends in the nasal cavity at the respiratory epithelium. The route also emerged as a reliable technique to bypass the BBB and avoiding the hepatic first-pass metabolism for the treatment of conditions like Alzheimer’s disease (AD), Prion’s disease (PrD), and other neuroailments. Noninvasive site-specific delivery makes this route more attractive for the direct delivery of small-drug molecule, proteins, and peptides to the brain. Emphasis is given on the prospective role of nanotechnology-based drug delivery through the nose-to-brain route for neurodegenerative diseases and other neuroailments. In particular, different nanoparticulate and nanovesicular carriers, as well as nanocrystals and nanogels, are analyzed for their in vivo therapeutic efficacy based on their physicochemical properties and composition. Nanotechnological advancements for neuroprotection and neuronal tissue regeneration are also analyzed. This chapter concludes highlighting the therapy of different neurodegenerative diseases and neuroailments by a nanocarrier-mediated drug delivery via the nose-to-brain route.

Lifestyle changes have affected the health of many individuals, majority being in industrialized nations compared to developing nations. Epithelial and mucosal permeability potentially mediates and influences immune tolerance to residing local microbiome. Lifestyle changes and dietary habits affect the local microbiome and finally lead to immunological imbalances. Diet which has great impact on microbiome of human intestines is associated with inflammation at local site and enhances the permeability of pro-inflammatory lymphocytes and cytokines into systemic circulation and leads to spread of various inflammatory mediators to distant joints. Recently, clinical trials which reported an administration of Lactobacillus casei 01 to rheumatoid arthritis patients have significantly reduced level of inflammatory cytokines and alleviation of symptoms. This chapter will emphasize on literature related to relationship of intestinal microbiome with arthritis progression and role of probiotics in management of rheumatoid arthritis.

Monoisoamyl 2,3-dimercaptosuccinic acid (MiADMSA), a lipophilic chelator has been evaluated for its potential use as an antidote in arsenic poisoning. The pharmacokinetics and pharmacodynamics properties of a drug could be understood via study its mechanism of interaction with bovine serum albumin protein (BSA). Therefore, the interaction between MiADMSA with BSA was investigated using various spectroscopic techniques and computational methods. Linear quenching of BSA intrinsic fluorescence intensity with the increasing concentration of MiADMSA was observed in the fluorescence study. Furthermore, synchronous results revealed that MiADMSA slightly changed the conformation of BSA. The binding constant value of the BSA-MiADMSA complex was found 1.60 × 104 M−1 at 298 K. The value of thermodynamic parameters ΔG, ΔH, and ΔS described that the process is spontaneous, endothermic, and hydrophobic forces are involved in the interaction of MiADMSA with BSA. Competitive site marker experiments showed that MiADMSA binds to site-II of BSA. Conformational changes of BSA with the interaction of MiADMSA were apparent by CD, UV–Visible, FT-IR, and 3D fluorescence spectroscopy. To strengthen the experimental findings we have also performed a theoretical study on the BSA-MiADMSA complex. Two sites were identified with docking score of − 6.642 kcal/mol at site IIa and − 3.80 kcal/mol for site IIb via molecular docking study. Molecular dynamics simulation study inferred the stability of the BSA-MiADMSA complex which was analyzed in a long simulation run. The experimental and computational studies have shown the effective binding of MiADMSA with BSA which is essential for the transportation and elimination of a drug from the body.

Background A simple, rapid and accurate reverse phase RP-HPLC method for the validation of antitubercular drug bedaquiline fumarate (BQF) was developed. The stability and forced degradation behaviour of bedaquiline fumarate (BQF) in official dissolution media (0.01 N HCl) and methanol were assessed. Results The method provided linear responses within the concentration range which varies from 10 to 100 μg/mL with LOD values of 2.6 μg/mL and LOQ of 7.9 μg/mL. Mean percent recovery varied between 97.46 and 103.82% and precise mean RSD of 0.31% (repeatability) and 0.48% (intermediate precision). The method was validated for other parameters like specificity, system suitability and robustness. Potential degradation of the BQF when exposed to direct sunlight in official dissolution media was 90.75% and in methanolic stock solution was 91.98%. Acid-alkali degradation study showed 86.59% loss of BQF in 0.5 N NaOH, and in acidic environment (0.5 N HCl), there was 6.15% loss. Thermal degradation of BQF was 70.11% loss in official dissolution media at 80 °C. No significant change in drug concentrations was noted when exposed and protected from normal daylight at room temperature and at 2–8 °C temperature. Conclusion The developed method has significant applicability for the qualitative and quantitative determination of BQF in different pharmaceutical formulations in the official dissolution media in routine quality control analysis.

A series of multi-target natural product-pyridoxine based derivatives were designed, synthesized, characterized and evaluated as anti-Alzheimer agents. In vitro testing revealed the multi-functional properties of compounds such as inhibition of acetylcholinesterase (AChE), antioxidant and metal chelation. Among the series, 5i derivative was found most potent AChE inhibitor, possess antioxidant potential and chelating metal ions. Further binding interaction of 5i with AChE was studied using molecular docking, showed interaction with both PAS and CAS site of AChE. In silico predictions were also performed to predict toxicity and ADME properties of the molecule 5i and found within drug likeness range. Therefore, 5i could be a promising multi-functional compound that can be used for further development of novel drug for Alzheimer disease.

Tungsten (W) toxicity has been identified as one of the major health concerns in the last decade. It has been identified in few hazardous waste sites and proposed for inclusion in the Environmental Protection Agency National Priorities List. The purpose of this study was to provide biochemical basis for understanding the tungstate induced interference in different organs and blood. Male Wistar rats were exposed to the concentration of 50, 100 and 200 ppm of tungstate in drinking water for 120 days. The hematological profiling was done after 15, 30 and 120 days. The biochemical estimation of oxidative stress parameters and histopathology of different organs were performed after 120 days. Significant reduction in the WBC and RBC counts, and hemoglobin levels was observed after exposure to 200 ppm of tungstate for 120 days. Significant alterations were observed in oxidative stress markers, being more pronounced in the liver and spleen. This was consistent with elevated number of apoptotic cells in spleen, and high tungstate concentration in blood, liver and spleen. Hence, we can conclude that the free radical induced oxidative stress which alters the antioxidant response are the possible mechanisms behind tungstate toxicity as we observed alterations in hematological parameters, histopathological observations, number of apoptotic cells, and bio-distribution of W. The study provides useful data for assessing the need to conduct health checkup in individuals living near hazardous waste sites or other sites associated with W exposure. Also, it provides information for assessing the potential health risks associated with tungstate toxicity.

When safe and adequate exposure of an essential trace element is exceeded it becomes potentially toxic. Fluoride is one classic example of such a double edged sword which both plays a fundamental role in the normal growth and development of the body for example the consumption of levels between 0.5-1.0 ppm via drinking water is beneficial for prevention of dental caries but its excessive consumption leads to development of fluorosis. PURPOSE OF REVIEW: The abundance of fluorine in the environment as well as in drinking water sources are the major contributors to fluorosis. It is a serious public health concern as it is a noteworthy medical problem in 24 nations including India yet the threat of fluorosis has not been rooted out. The review focuses on recent findings related to skeletal fluorosis and role of oxidative stress in its development. The fluoride mitigation strategies adopted in recent years are also discussed. RECENT FINDINGS BASED ON CASE STUDIES: Recent findings revealed that consumption of fluoride at concentrations of 1.5 ppm is majorly responsible for skeletal fluorosis. The sampling from rural areas showed that 80% villages are having fluoride concentrations more than the WHO permissible limits and people residing in such areas are affected by the skeletal fluorosis and also in the regions of Africa and Asia endemic fluorosis have been accounted in the majority of the region affecting approximately 100 million people. Various mitigation programmes and strategies have been conducted all over the world using defluoridation. Fluorosis is a slow and progressive malady affecting our body and a serious concern to be taken into consideration and to be dealt with effectively. The fluoride toxicity although reversible, is a slow process and the side effects lack treatment options. The treatment options available are either not approachable or affordable in the rural areas commonly suffering from the fluoride toxicity. No specific treatments are available to date to treat skeletal fluorosis affectively; therefore, prevention is one of most safest and best approach to fight fluorosis. The current review lays emphasis on the skeletal fluorosis and its prevalence in recent years. It also includes the recent findings as well as the current strategies related to combat skeletal fluorosis and provides findings that might be helpful to promote the research in the field of effective treatment for fluorosis as well as development of easy and affordable methods of fluoride removal from water.

More than 180 pathogens have been explored or employed as biological weapons that pose a potential threat to military, civilian population, and crops. Biological warfare (BW) agents include bacteria, fungi, viruses, and toxins that affect human beings, animals, and plants, and can be used in bioterrorist activity and biological warfare attacks. They are characterized by low detectable quality, high effectiveness, adequate reach ability, and comparative ease of delivery. It can be delivered by unconventional methods like aerosol sprays, water and food contamination, or by covert injection. In perspective on their hidden movement, easy transportation, and complicated detection, they are readily adaptable for terrorist operations or to gain political advantage. BW agents are a serious concern nowadays due to emerging bioterrorist incidents all over the world. Although various treatment strategies have been developed in recent years to treat or neutralize such kinds of biological warfare agents, these are not enough for a complete cure. In this chapter, we review the various biological warfare agents, their possible mode of transmission, and treatment strategies that be adopted during biological and bioterrorist activity. The present chapter also highlights specific antibiotics, antivirals, vaccines, and monoclonal antibodies that may be effective against the particular disease-causing organisms.

With the advancements in technology, the ways of killing and terrorizing people changed from metallurgical weapons to microbial bombs containing bacteria or viruses. The practice of bioweapons is not new; it started in antiquity, before germ theory of disease came into force. Being cheap and easy to handle, they are considered as “poor man’s weapons.” Viruses as bioweapons have been used since the 16th century and they have been classified as potential biothreat agents by CDC. Although viruses like smallpox and hemorrhagic fever viruses had been a threat for society since ancient times, Nipah virus, Hantaviruses, and Ebola virus are considered to be emerging viral threats. High dissemination and transmission rate of viruses, lack of efficient diagnostic techniques, and availability of limited therapeutics make them the primary bioweapon of choice for terrorist groups or the military services. High risk of disruption of healthcare system of population and socioeconomic impact of viral attacks demands public health care programs and intensive research for development of sensitive diagnostic techniques and effective therapeutics. The current chapter focuses on various viral agents employed as bioweapons throughout history or having potential to be used in the future, signs for identification of viral bioterrorism, diagnostic techniques, and future perspectives of viruses as biothreat agents.

As per changing times, terrorism using infectious bacteria as a weapon is considered to be increasing, which is a great challenge for the survival of human beings in the near future. Dreadful events such as the Black Death and anthrax outbreaks remind us of the terrible intensity of bacterial biothreat agents. Although we are advanced and much concerned in the field of bacteriology in the era of modern microbiology, we are still only in the initial stages, in terms of following ethics humanely, and strengthening the implementation of protocols regarding protection from terrorist activities. This chapter discusses bacterial biological warfare agents, various evidences of bacterial bioattacks in the past, advances in the establishment of biological warfare programs from antiquity, through the Middle Ages, to the Modern and contemporary periods, early detection techniques for identifying the evidence of attacks, and socioeconomic impacts of bacterial warfare agents.

Since ancient times, the use of hazardous materials, bacteria, viruses, and toxins as weapons at some stages in war has been well documented. These agents can cause large numbers of causalities both to the military as well as civilian populations and are difficult to manage. Chlorine was first used as a chemical weapon during World War I in 1915 by German military forces at Ypres, Belgium. Military use of chemical and biological warfare agents in time of war demonstrated their level of toxic effect on living beings, i.e., they lead to mass destruction, and occasions where these toxic agents had been used against civilians by terrorists highlighted that these agents could be a danger to whole world community. Preparedness against biological agents prompted research about the type of diseases caused by them, trained persons who can tackle the situation at the time of incidence, better diagnostic tools, and improved public health systems. The menace that occurs due to the use of these agents in war or terrorism can be lessened with the accessibility of better detection technologies. This chapter gives insight about the history of biological warfare agents, classification of biological warfare agents, and also the detection systems available/in process of development to detect them.

Genome information and subsets of genes in the genome of each biological warfare agent have started to be revealed with the help of modern genome sequencing technology. This information will be helpful for the detection of bio-threat or even unknown threats. Unfortunately, this information can also be misused for the creation of new types of biological warfare agents, which will be difficult to detect and treat, and used for the production of bio-weapons. This chapter summarizes genomic information of potential biological warfare agents including bacteria, viruses, and toxins, and their application in biodefense.

Starting from the practice of bio-warfare to surveys of any epidemiological studies, identification of the origin and causes of any outbreaks is a challenging task for any scientific and health care professionals. For this, advanced biochemical and molecular detection techniques are highly necessary and, to get the best biochemical and molecular results, proper methods of collection, storage, and transportation of samples are of the highest importance. It is likely that in every attack site or epidemic area, there will be a lack of availability of resources/equipment/competent technical staff; hence, offsite analysis of samples is necessary in these situations. Thousands of samples are currently being collected in many ongoing projects/studies. Even new proposed projects will result in more collection, storage, and transportation of biological specimens. For better understanding of the mechanisms of toxicity, evaluating the causal relationship between specific hazards and biological effects, accurately assessing the risk of exposure, differentiating between groups of higher or lower susceptibility, and providing solid scientific support to policy makers toward intervention strategies, the way of collection, storage, and transportation of samples play vital roles. Hence the purpose of this chapter is to discuss the challenges and potential pitfalls of biological sample collection, storage, and transportation for offsite analysis.

Background Tuberculosis (TB) is a deadly infectious disease caused by the pathogen Mycobacterium tuberculosis (Mtb). Approximately, 1.8 and 1.3 million people are infected and die, from TB each year as estimated by the World Health Organization. Due to increase in the incidence of drug-resistant strains of Mtb, there is an urgent need to accelerate research which focuses on the development of new drugs with novel mechanism of action that can treat both drugsensitive and resistant TB infections. Objective The purpose of this review study was to describe vitamins as drug target that can be explored to develop new anti tubercular drugs that can treat both drug-sensitive and resistant TB infections. Method The methodological approaches include literature review which is performed in the databases like PubMed, Web of Science, Scopus, Springer and Science Direct, etc. On the basis of evaluation of literature sources, the review was complied. Results This review study demonstrated that vitamins biosynthesis pathway could be used in the development of novel drug targets. Further sequencing of the Mtb genome facilitated research in target identification and validation that make possible the discovery of novel anti-TB agent with new mechanisms of action. Several compounds were identified, which target vitamin biosynthesis pathway /enzymes. Some other new targets were also identified and can be explored for the identification of novel structural moiety. Conclusion Further exploration of these compounds which have been identified to target these vitamins related novel target pathways /molecules could led to the development of antitubercular drug which can be used in the treatment of drug sensitive and resistant TB.

Consumption of arsenic contaminated water causes serious skin disease and cancer in a significant number of exposed people. Chelating agents, consider an expensive therapy, are employed in the treatment of arsenic intoxication. There are reports which suggest that the poorest suffer the most from arsenicosis. This may be due to improper diet intake, consist of low protein and micronutrients which increase the vulnerability to arsenic-related disorders. Several human studies demonstrated the associations between malnourishment and the development of arsenic-caused skin lesions, skin cancer and cardiovascular effects. Thus, there is an urgent need of implementation of mitigation strategies for improving the health of exposed populations. Nutrition enhances the detoxification process so food rich in vitamins, protein, antioxidants help in its detoxification process. Methylation is the detoxification process which takes place via S-adenosylmethionine (SAM). It is a methyl group donor and it derived its methyl group from diet. Nutritional intervention thus may appear as a practical and inexpensive approach. Nutrition provides protection from toxic effect of arsenic by two ways (i) methylation of As (ii) antioxidants which provides protection against free radical species. The governments and NGOs may run awareness programmes in arsenic affected area regarding prevention and alternate therapy which can decrease the susceptibility of the exposed population. They could also help in distributing cheaper, high protein diets particularly to the masses who cannot afford such foods. Thus, to prevent arsenicosis alternate therapy and proper nutrition could be the important strategy for alleviating its toxic effects. This mini review provides an insight on the importance of nutrition in preventing adverse effect cause by arsenic to suffer population.

Neurodegenerative diseases are heterogenous group of diseases arises in the diverse segments of brain such as hippocampus, cerebellum, and brain stem due to protein accumulation, gene mutations, synaptic loss, mitochondrial dysfunction in neuronal cell. Neuronal disorders including Alzheimer's disease (AD), Parkinson's disease (PD), and Prion's disease, caused by combination with multiple factors. Contrast reagents are proficient to access the damaged cells or tissues to crossing blood brain barrier (BBB). All these creates troublesome for the contrasting agents for detection of impairments in the brain. BBB is limits entry of threpaeutic agent in brain there evolved a field in the nanotechnology known as nanotheranostics where both diagnostic and therapeutic effects were achieved. The semiconductor nanocrystals called quantum dots (QDs) are the efficient drug delivery systems accomplishing the objective of theranostic activity. The quantum dots are the zero-dimensional nanostructures with particle size of 2–10 nm, intermediary between bulk semiconductors and discrete molecules owing outstanding optical and electrochemical properties due to their characteristics like luminescence, photostability, electronic properties, high excitation capacity, size tunable emission etc. These features preserve their applicability in the diagnostics, bioimaging, biosensing and therapeutics etc. The QDs show their efficiency in diagnosing and treating the neurodegenerative diseases as they are capable of crossing BBB and biocompatible with the neuronal cells with low cytotoxicity. This article provides the knowledge of quantum dots, their preparation processes and their theranostic activity over the neurodegenerative diseases.

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.

Arsenic, a ubiquitous metalloid, is naturally present in the lithosphere (Earth’s crusts, soil, rock, etc.), hydrosphere (surface water, aquifers, deep wells, etc.), atmosphere, and biosphere. In South Asia, Some studies reported that GSH contamination in groundwater in the Ganga- Brahmaputra fluvial plains in India and Padma-Meghna fluvial plains in Bangladesh has been found to have a huge impact on human health, and its consequences have been reported as the world’s biggest natural groundwater calamities. After entering into the body, it is distributed in a large number of organs including the lungs, liver, kidney, and skin. The clinical manifestations of arsenic poisoning are myriad, and the correct diagnosis depends largely on awareness of the problem. It is very difficult to diagnose early symptoms of arsenicosis because such non-specific symptoms may also be present in many other diseases. Medicine used for remedy of arsenicosis has been found to be unsatisfactory by repeated application and experience. The number of chelating drugs has been used for the treatment of arsenic poisoning. Some of them have been found to be effective during acute poisoning; however, there is still no safe and effective antidote available for treating chronic arsenicosis. Few natural and herbal extracts too have been attempted with limited success. This chapter reviews some of the fundamentals of arsenic toxicity and also summarizes currently available remedial measures.

Alzheimer's disease (AD), a complex neurodegenerative disorder causing multiple cellular changes including impaired cholinergic system, beta-amyloid (βA) 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.

Approximately 40 % drugs in the market are having poor aqueous solubility related problems and 70 % molecules in discovery pipeline are being practically insoluble in water. Nanocrystals is a prominent tool to solve the issue related to poor aqueous solubility and helps in improving the bioavailability of many drugs as reported in the literature. Nanocrystals can be prepared by top down methods, bottom up methods and combination methods. Many patented products such as Nanocrystals®, DissoCubes®, NANOEDGE® and SmartCrystals ®, etc., are available, which are based on these three preparation methodologies. The particle size reduction resulted into unstable nanocrystalline system and the phenomenon of Ostawald ripening occurs. This instability issue could be resolved by using an appropriate stabilizers or combination of stabilizers. The nanosuspensions could be transformed to the solid state to prevent particle aggregation in liquid state by employing various unit operations such as lyophilisation, spray drying, granulation and pelletisation. These techniques are well known for their scalability and continuous nanocrystal formation advantages. Nanocrystals can be characterized by using scanning electron microscopy, transmission electron microscopy, atomic force microscopy, differential scanning calorimetry, fourier transform infrared spectroscopy, powdered x- ray diffraction and photon correlation spectroscopy. The downscaling of nanocrystals will enable rapid optimization of nanosuspension formulation in parallel screening design of preclinical developmental stage drug moieties. One of the most acceptable advantages of nanocrystals is their wide range of applicability such as oral delivery, ophthalmic delivery, pulmonary delivery, transdermal delivery, intravenous delivery and targeting (brain and tumor targeting). The enhancement in market value of nanocrystals as well as the amount of nanocrystal products in the market is gaining attention to be used as an approach in order to get commercial benefits.