Structural insights into the interactions of repositioning and known drugs for Alzheimer's disease with hen egg white lysozyme by MM-GBSA.

Six drugs (dapsone, diltiazem, timolol, rosiglitazone, mesalazine, and milnacipran) that were predicted by network-based polypharmacology approaches as potential anti-Alzheimer's drugs, have been subjected in this study for in silico and in vitro evaluation to check their potential against protein fibrillation, which is a causative factor for multiple diseases such as Alzheimer's disease, Parkinson's disease, Huntington disease, cardiac myopathy, type-II diabetes mellitus and many others. Molecular docking and thereafter molecular dynamics (MD) simulations revealed that diltiazem, rosiglitazone, and milnacipran interact with the binding residues such as Asp52, Glu35, Trp62, and Asp101, which lie within the fibrillating region of HEWL. The MM-GBSA analysis revealed -7.86, -5.05, and -10.29 kcal/mol as the binding energy of diltiazem, rosiglitazone, and milnacipran. The RMSD and RMSF calculations revealed significant stabilities of these ligands within the binding pocket of HEWL. While compared with two reported ligands inhibiting HEWL fibrillation, milnacipran depicted almost similar binding potential with one of the known ligands (Ligand binding affinity -10.66 kcal/mol) of HEWL. Furthermore, secondary structure analyses revealed notable inhibition of the secondary structural changes with our candidate ligand; especially regarding retention of the 3/10 α-helix both by DSSP simulation, Circular dichroism, and FESEM-based microscopic image analyses. Taking further into experimental validation, all three ligands inhibited fibrillation in HEWL in simulated conditions as revealed by blue shift in Congo red assay and later expressing percentage inhibition in ThioflavinT assay as well. However, dose-dependent kinetics revealed that the antifibrillatory effects of drugs are more pronounced at low protein concentrations.Communicated by Ramaswamy H. Sarma.

An Integrated Dynamic Closed Loop Simulation Platform for Elbow Flexion Augmentation Using an Upper Limb Exosuit Model.

Wearable robotic devices are designed to assist, enhance or restore human muscle performance. Understanding how a wearable robotic device changes human biomechanics through complex interaction is important to guide its proper design, parametric optimization and functional success. The present work develops a human-machine-interaction simulation platform for closed loop dynamic analysis with feedback control and to study the effect of soft-robotic wearables on human physiology. The proposed simulation platform incorporates Computed Muscle Control (CMC) algorithm and is implemented using the MATLAB -OpenSim interface. The framework is generic and will allow incorporation of any advanced control strategy for the wearable devices. As a demonstration, a Gravity Compensation (GC) controller has been implemented on the wearable device and the resulting decrease in the joint moments, muscle activations and metabolic costs during a simple repetitive load lifting task with two different speeds is investigated.

Toxicological impacts of nanopolystyrene on zebrafish oocyte with insight into the mechanism of action: An expression-based analysis.

Many studies have investigated the negative impacts of microplastics on teleost fishes with very little or no evidence of their mechanism of action. This scenario entreats us to investigate the toxicities of nanopolystyrene in zebrafish oocyte with emphasis on the mechanism of action. In the present study, the cellular levels of mRNA transcripts of different genetic markers (such as: sod, gpx, nrf2, inos, ucp2, and atp6 (redox-sensitive markers); nfkß, tnfα, il-10, ikß, gdf9, and bmp15 (immune markers); gadd45, rad51, p53 and bcl2 (DNA damage and apoptotic)) have been quantified by real-time PCR after 6 h of incubation of isolated oocyte with different doses of nanopolystyrene viz. P0 (control i.e. no polystyrene in culture medium), P1 (100 ng/ml), and P2 (400 ng/ml). Results showed that both the treatment concentrations of nanopolystyrene induce oxidative stress with % DPPH = 30.75, 31.61, and 32.43% for P0, P1, and P2, respectively. Increase in oxidative stress in oocytes with increasing doses of nanopolystyrene was also observed in TBARS assay with MDA content 0.12 and 0.21 µM for P1 and P2, respectively as compaired to the control 0.08 µM. This increased oxidative stress can regulate the expression pattern (upregulation/downregulation) of selected genes leading to different toxic effects like - oxidative stress, immunotoxicity, and apoptosis in oocytes, which suggests the impairment of reproductive functions by nanopolystyrene.

Toxic effects of cyanotoxins in teleost fish: A comprehensive review.

The phenomenon of eutrophication leads to the global occurrence of algal blooms. Cyanotoxins as produced by many cyanobacterial species can lead to detrimental effects to the biome due to their stability and potential biomagnification along food webs. Therefore, understanding of the potential risks these toxins pose to the most susceptible organisms is an important prerequisite for ecological risks assessment of cyanobacteria blooms. Fishes are an important component of aquatic ecosystems that are prone to direct exposure to cyanotoxins. However, relatively few investigations have focused on measuring the toxic potentials of cyanotoxins in teleost fishes. This review comprehensively describes the major toxicological impacts (such as hepatotoxicity, neurotoxicity, immune toxicity, reproductive toxicity and cytogenotoxicity) of commonly occurring cyanotoxins in teleost fishes. The present work encompasses recent research progresses with special emphasis on the basic molecular mechanisms by which different cyanotoxins impose their toxicities in teleost fishes. The major research areas, which need to be focused on in future scientific investigations, have also been highlighted. Protein kinase inhibition, transcriptional dysregulation, disruption of redox homeostasis and the induction of apoptotic pathways appear to be the key drivers of the toxicological effects of cyanotoxins in fish. Analyses also showed that the impacts of cyanotoxins on specific reproductive processes are relatively less described in teleosts in comparison to mammalian systems. In fact, as compared to other toxicological effects of cyanotoxins, their reproductive toxicity (such as impacts on oocyte development, maturation and their hormonal regulation) is poorly understood in fish, and thus requires further studies. Furthermore, additonal studies characterizing the molecular mechanisms responsible for the cellular uptake of cyanotoxins need to be investigated.

Interaction of plastic particles with heavy metals and the resulting toxicological impacts: a review.

Interactions of plastic particles with different organic/inorganic pollutants including heavy metals impact their ecotoxicological potential, and proper understanding in this regard is important for their ecological risk assessment. However, many studies have reported the interactions between micro-/nanoplastics (MNPs) and heavy metals (HMs), but the most prevalent interactive forces and factors monitoring their interactions are still not clear. So, the present review represents the mechanisms of interactions with special emphasis on major interactive forces and biophysicochemical and environmental factors influencing trace element's adsorption onto the surface of MNPs. Electrostatic interaction and pore-filling mechanism can best explain the HMs adsorption to MNPs. A number of biophysicochemical factors (such as biofilm, size, crystallinity, and surface charge) and environmental factors (such as pH, salt, and temperature) act together for mediating interactions and ecotoxicities of MNPs and HMs in the real environment. From a toxicological point of view, the synergistic mode of action may be more active in animals, whereas the antagonistic activity may be prevalent in plants. Besides polymer density, biofilm formation and agglomeration property of MNPs can control the vertical distribution of MNPs along the water column. Finally, the ecotoxicological potential of MNPs in the natural environment can be considered as a function of spatiotemporal variation in abiotic (including MNPs and heavy metals) and biotic components. This review will be helpful in the detail understanding of ecotoxicological risk assessment of MNPs in relation to their interaction with heavy metals.

Co-occurrence of co-contaminants: Cyanotoxins and microplastics, in soil system and their health impacts on plant - A comprehensive review.

Cyanotoxins (CTX) and micro/nanoplastics (M/NP) are ubiquitously distributed in every environmental compartment. But the distribution, abundance and associated ecological risks of CTX are still poorly understood in soil system. On the other hand, M/NP could serve as vectors for persistent organic/inorganic pollutants in the natural environment through the sorption of pollutants onto them. Thus, co-occurrence of CTX and M/NP in soils suggests the sorption of CTX onto M/NP. So, major aim of this review is to understand the relevance of CTX and M/NP in soils as co-contaminants, possible interactions between them and ecological risks of CTX in terms of phytotoxicity. In this study, we comprehensively discuss different sources and fate of CTX and the sorption of CTX onto M/NP in soil system, considering the partition coefficient of different phases of soil and mass balance. Phytotoxicity of CTX, CTX mixture and co-contaminants has also been discussed with insights on the mechanism of action. This study indicates the need for the evaluation of sorption between co-contaminants, especially CTX and M/NP, and their phytotoxicity assessment using environmentally relevant concentrations.

Functional interplay between plastic polymers and microbes: a comprehensive review.

Escalated production of plastic, their worldwide distribution and persistent nature finally results into their environmental accumulation causing severe threats to the ecological environment and biotic health. Thus, development of suitable measurements for environmental remediation of plastic may be an urgent issue in this plastic age. Some recent reviews have categorized the microbial species able to degrade different plastic polymers and the different factors effecting bio-degradation of plastic are poorly understood. This review comprehensively discusses bio-degradation of traditional and biodegradable plastic polymers both in natural and biological environment (gut microbes and fungi) to understand different factors regulating their degradation, and also shows how degradation of plastic polymers under abiotic factors influence subsequent biological degradation. Different physicochemical modifications like - breaking large polymers into small fragments by pre-treatment, functional groups enrichment, identifying potent microbial species (consortia) and engineering microbial enzymes might be crucial for bio-degradations of plastic. Effects of micro/nanoplastic and other chemical intermediates, formed during the bio-degradation of plastic, on species composition, abundance, growth, metabolism and enzymatic systems of microbes involved in the bio-degradation of plastic should be determined in future research.

Critical analysis of biophysicochemical parameters for qualitative improvement of phytogenic nanoparticles.

Conventional chemical approaches for synthesizing nanoparticles (NPs) may restrict their applicability as they are not eco-friendly, energetically efficient and often involve toxic reducing/capping agents; but phytonanotechnology enabled the synthesis of safe, inexpensive, highly biocompatible NPs. In this regard, thorough understanding of green components and the modulatory effects of different reaction conditions on the physicochemical parameters of green synthesized NPs would be a prerequisite, which is not depicted elsewhere. This review critically analyzes the relevant reaction conditions from their mechanistic viewpoints in plant-based synthesis of NPs arising fundamental issues which need to be determined carefully. The size, stability and surface chemistry of phytogenic NPs may be fabricated as a function of multiple interconnected reaction parameters and the plant species used. The therapeutic potential of phytogenic NPs may depend on the plant species used; and so the meticulous understanding of physicochemical parameters and the family wise shorting of elite plant species may potentially benefit the theranostic future of plant-based NPs.

Functions of interleukin-6 in ovulation of female climbing perch, Anabas testudineus.

In mammals, interleukin 6 (IL-6) has an important function during ovulation, however, the functions of IL-6 in fish have not been elucidated. In the present study, there was quantification of de novo synthesis of ovarian IL-6 and tumor necrosis factor-alpha (TNFα) in control and hCG-treated fish and results were compared with those from an in vitro study where there was evaluation of the regulatory functions of gonadotropins and TNFα of IL-6 secretions. Relatively greater concentrations of ovarian IL-6 at the post-GVBD (post-germinal vesicle breakdown) stage indicates IL-6 modulates ovulatory processes. The hCG-induced increase in relative abundance of IL-6 (in vitro) mRNA transcript and secretion from the ovary were attenuated when there was administration of the inhibitor of TNFα secreting enzyme, TAPI-I, which indicates TNFα modulates IL-6 secretion. Treatments with IL-6 induced a marked increase in ovulation rate in vitro when there was induction of activating matrix metalloproteinase (MMP). Furthermore, treatment with IL-6 resulted in production of prostaglandin as indicated by the IL-6 induced increase in the abundance of ptgs2 mRNA transcript in the ovary of Anabas testudineus. Furthermore, results indicate the source of IL-6 in the ovary is the granulosa cells with secretion of IL-6 being induced by the additions of hCG and TNFα in the medium. There was also an IL-6-induced increase in abundance of receptors (IL-6 Rα and gp130) to which it binds indicating IL-6 autoregulates this population of receptors. Results from this study, for the first time, elucidate the reproductive functions of IL-6 in a teleost fish.

Cytogenotoxic potential of a hazardous material, polystyrene microparticles on Allium cepa L.

Plastic pollution represents a global concern for the biodiversity conservation, ecosystem and public health. The polystyrene is one of the dominant pollutants in both terrestrial and aquatic ecosystem. This work measured the hazardous nature of 100 nm micropolystyrene (MPS) using 25, 50, 100, 200, and 400 mg/L concentrations in terms of oxidative stress, morphotoxicity and cytogenotoxicity in Allium cepa. The results were compared with the positive control (PC) (400 mg/L chlorpyrifos). MPS significantly (p < 0.05) reduced the root length while induced the production of hydroxyl, superoxide radicals with a concomitant increase in DPPH scavenging activity and lipid peroxidation as compared to the negative control. The significant decrease in mitotic index with respect to the negative control (MI: 23.855 ±â€¯5.336 %; lowest MI: 3.88 ±â€¯1.042 %) showed the cytotoxic nature of MPS. Genotoxicity was assessed by various chromosomal and nuclear aberrations. The highest 3.029 ±â€¯0.403 % (PC: 3.09 ±â€¯0.535 %) chromosomal abnormality index and 2.31 ±â€¯0.338 % (PC: 1.178 ±â€¯0.095 %) nuclear abnormality index were observed. MPS down-regulated the expression of plant CDKA encoding gene: cdc2, an important cell cycle regulator. The overall results indicated that MPS could induce cytogenotoxicity through the exacerbation of ROS production and inhibition of cdc2.

Seasonal ovarian development in relation to the gonadotropins, steroids, aromatase and steroidogenic factor 1 (SF-1) in the banded gourami, Trichogaster fasciata.

The endocrine regulation of gonadal development and annual variation of key sex steroids is the basic knowledge to understand the reproductive cycle of teleost fish. Present study was aimed to investigate the levels of gonadotropins in relation to the follicular development and plasma steroids during the reproductive cycle of female Trichogaster fasciata. Female fish were sampled and ovarian development is described histologically throughout the year in relation to the seasonal variations of gonadosomatic index (GSI); follicle stimulating hormone (FSH) and luteinizing hormone (LH); three key steroids for folliculogenesis and maturation i.e. testosterone (T), 17ß-estradiol (E2) and 17α20ßdihydroxy4pregnen3one (17,20ß-P). Relatively higher level of FSH was observed till the ovary reaches in late vitellogenic stage confirms that FSH regulates the early folliculogenesis of the ovary, whereas LH peak was observed in the postvitellogenic stage, which indicates that maturation and ovulation were controlled by LH. Seasonal steroid profiles show that both T and E2 reach its maximum level prior to the 17,20ß-P which attain its peak value in the month of August. Thus, single peak values of LH and 17,20ß-P coinciding with GSI peak, clearly indicates that T. fasciata breeds only once in a year. Furthermore, to elucidate the molecular basis of the reproductive cycle, this study analyzes the other key factors of ovarian function such as cyp19a1a gene expression, aromatase activity and SF-1 localization throughout the year. cyp19a1a gene expression and the aromatase activity were highest in vitellogenic stages indicate that relatively higher E2 production in this stage is regulated by FSH. Immunohistochemical localizations of aromatase and SF-1 in the cellular layer of oocytes demonstrated that aromatase is FSH-dependent and SF-1 could be regulated by both FSH and LH as relatively higher amount of aromatase was localized in the vitellogenic stage oocytes than the postvitellogenic and post germinal vesicle breakdown (post-GVBD) stages; whereas, high amount of SF-1 was observed in vitellogenic, postvitellogenic and post-GVBD stages. These data regarding the reproductive endocrinology of T. fasciata may be useful to understand the interaction between gonadotropins, steroids, aromatase and SF-1 in teleost fishes and may contribute to restoration of the ecologically important fish through artificial reproduction.

Molecular mechanism of mercury-induced reproductive impairments in banded gourami, Trichogaster fasciata.

Mercury is one of the key pollutants responsible for the degradation of natural aquatic ecosystems. Among the different forms of mercury that exist in the environment, mercuric chloride (HgCl2) is the dominant pollutant for freshwater environments as it is used as an ingredient in antiseptics, disinfectants and preservatives, insecticides, batteries and in metallurgical and photographic operations. Pollutant may exert their action on organisms or populations by affecting their normal endocrine function as well as reproduction. Thus, the present study tried to understand the effect of mercuric chloride (HgCl2) on reproductive function and to decipher the molecular mechanism of Hg-induced reproductive impairments of female Trichogaster fasciata. Both in vivo and in vitro experiments were performed by using ecologically relevant doses of HgCl2 and the resulting effects on follicular development, steroidogenic potentiality, aromatase activity, aromatase gene expression and steroidogenic factor-1 (SF-1) expression pattern were analysed. In vivo exposure to HgCl2 caused reproductive impairments as shown by the inhibitory role of HgCl2 on follicular development, steroid biosynthesis and SF-1 activity. In vitro experiments revealed that aromatase activity, steroidogenesis, aromatase and SF-1 expression were blocked by HgCl2. The results obtained from this study contribute to understand the molecular mechanism of HgCl2-induced reproductive impairment of T. fasciata.