Bisphenol-F and Bisphenol-S (BPF and BPS) Impair the Stemness of Neural Stem Cells and Neuronal Fate Decision in the Hippocampus Leading to Cognitive Dysfunctions.

Neurogenesis occurs throughout life in the hippocampus of the brain, and many environmental toxicants inhibit neural stem cell (NSC) function and neuronal generation. Bisphenol-A (BPA), an endocrine disrupter used for surface coating of plastic products causes injury in the developing and adult brain; thus, many countries have banned its usage in plastic consumer products. BPA analogs/alternatives such as bisphenol-F (BPF) and bisphenol-S (BPS) may also cause neurotoxicity; however, their effects on neurogenesis are still not known. We studied the effects of BPF and BPS exposure from gestational day 6 to postnatal day 21 on neurogenesis. We found that exposure to non-cytotoxic concentrations of BPF and BPS significantly decreased the number/size of neurospheres, BrdU+ (proliferating NSC marker) and MAP-2+ (neuronal marker) cells and GFAP+ astrocytes in the hippocampus NSC culture, suggesting reduced NSC stemness and self-renewal and neuronal differentiation and increased gliogenesis. These analogs also reduced the number of BrdU/Sox-2+, BrdU/Dcx+, and BrdU/NeuN+ co-labeled cells in the hippocampus of the rat brain, suggesting decreased NSC proliferation and impaired maturation of newborn neurons. BPF and BPS treatment increases BrdU/cleaved caspase-3+ cells and Bax-2 and cleaved caspase protein levels, leading to increased apoptosis in hippocampal NSCs. Transmission electron microscopy studies suggest that BPF and BPS also caused degeneration of neuronal myelin sheath, altered mitochondrial morphology, and reduced number of synapses in the hippocampus leading to altered cognitive functions. These results suggest that BPF and BPS exposure decreased the NSC pool, inhibited neurogenesis, induced apoptosis of NSCs, caused myelin degeneration/synapse degeneration, and impaired learning and memory in rats.

Ecological and Health Risk Assessment of Heavy Metals Bioaccumulation in Ganges Fish Near Varanasi, India.

Heavy metal contamination in river Ganga is one of the factors for deterioration in its water quality and also adds to human health risks. We designed our study to achieve a holistic approach by not only estimating the concentration of heavy metals (lead, manganese, chromium, and cadmium) in the river water at different sites based on human anthropogenic activities but also in the fishes residing in the same sites that are collected for human consumption on daily basis. We found that Ganga River in Varanasi is highly loaded with metals (PLI = 6.698). Mean concentration in water was 1.29 mg/L for Pb, 1.325 mg/L for Mn, 0.169 mg/L for Cr, and 0.161 mg/L for Cd, which were above the permissible limits stated by Environment Protection Agency (EPA) in drinking water. Fish, including exotic and invasive species, were collected from the wild and were processed for the presence of these metals in their tissues. Degree of heavy metal concentration followed liver > gills > muscles. The highest accumulation of Pb was observed in Carpio (Cyprinus carpio) liver (8.86 µg/g) and lowest in Baikari (Clupisoma garua) muscles (0.07 µg/g). Total target hazard quotient (THQ) value, i.e., hazard index (HI) showed values in following sequence: Cyprinus carpio > Oreochromis niloticus > Channa gachua > Johnius coitor > Mastacembelus armatus > Mystus tengara > Clupisoma garua. Maximum HI value was recorded in C. carpio, which is highly consumed fish by humans, hence, may be harmful to them.

Bisphenol-A (BPA) Impairs Hippocampal Neurogenesis via Inhibiting Regulation of the Ubiquitin Proteasomal System.

The ubiquitin-proteasome system (UPS) controls protein homeostasis to maintain cell functionality and survival. Neurogenesis relies on proteasome function, and a defective proteasome system during brain development leads to neurological disorders. An endocrine-disrupting xenoestrogen bisphenol-A (BPA) used in plastic products adversely affects human health and causes neurotoxicity. Previously, we reported that BPA reduces neural stem cells (NSCs) proliferation and differentiation, impairs myelination and mitochondrial protein import, and causes excessive mitochondrial fragmentation leading to cognitive impairments in rats. Herein, we examined the effect(s) of prenatal BPA exposure on UPS functions during NSCs proliferation and differentiation in the hippocampus. Rats were orally treated with 40 µg/kg body weight BPA during day 6 gestation to day 21 postnatal. BPA significantly reduced proteasome activity in a cellular extract of NSCs. Immunocytochemistry exhibited a significant reduction of 20S proteasome/Nestin+ and PSMB5/Nestin+ cells in NSCs culture. BPA decreased 20S/Tuj1+ and PSMB5/Tuj1+ cells, indicating disrupted UPS during neuronal differentiation. BPA reduced the expression of UPS genes, 20S, and PSMB5 protein levels and proteasome activity in the hippocampus. It significantly reduced overall protein synthesis by the loss of Nissl substances in the hippocampus. Pharmacological activation of UPS by a bioactive triterpenoid 18α-glycyrrhetinic acid (18α GA) caused increased proteasome activities, significantly increased neurosphere size and number, and enhanced NSCs proliferation in BPA exposed culture, while proteasome inhibition by MG132 further aggravates BPA-mediated effects. In silico studies demonstrated that BPA strongly binds to catalytic sites of UPS genes (PSMB5, TRIM11, Parkin, and PSMD4) which may result in UPS inactivation. These results suggest that BPA significantly reduces NSCs proliferation by impairing UPS, and UPS activation by 18α GA could suppress BPA-mediated neurotoxicity and exerts neuroprotection.

Bisphenol-A Mediated Impaired DRP1-GFER Axis and Cognition Restored by PGC-1α Upregulation Through Nicotinamide in the Rat Brain Hippocampus.

The regulatory network of mitochondrial biogenesis and dynamics is vital for mitochondrial functions and cellular homeostasis. Any impairment in the mitochondrial network leads to neurodegenerative disorders. Our earlier studies suggest that environmental toxicant Bisphenol-A (BPA) exposure reduces neurogenesis by abnormal mitochondrial dynamics and mitochondrial biogenesis through impairment of mitochondrial fission factor dynamin-related protein (DRP1) and mitochondrial import protein GFER, which leads to demyelination, neurodegeneration, and cognitive deficits in the rats. In the present study, we found that chronic BPA exposure reduces PGC-1α levels (master regulator of mitochondrial biogenesis), alters mitochondrial localization of DRP1 and GFER, and reduces the number of PGC-1α/NeuN+ and PGC-1α/ß-tubulin+ neurons in the rat hippocampus, suggesting reduced PGC-1α-mediated neurogenesis. Nicotinamide significantly increased PGC-1α protein levels, PGC-1α/NeuN+ co-labeled cells in BPA-treated rat hippocampus and PGC-1α/ß-tubulin+ co-labeled cells in neuron culture derived from hippocampal neural stem cells. Interestingly, PGC-1α upregulation by nicotinamide also resulted in increased GFER levels and restored mitochondrial localization of GFER (increased GFER/TOMM20 co-labeled cells) in vitro and in vivo following BPA treatment. Nicotinamide also reduced DRP1 levels and prevented DRP1 mitochondrial localization in BPA-treated neuronal cultures and hippocampus, suggesting reduced mitochondrial fission. This resulted in reduced cytochrome c levels in neuronal culture and reduced hippocampal neurodegeneration (reduced caspase-3/NeuN+ co-labeled neurons) following nicotinamide treatment in BPA-treated group. Consequently, activation of PGC-1α by nicotinamide restored BPA-mediated cognitive deficits in rats. Results suggest that the treatment of nicotinamide has therapeutic potential and rescues BPA-mediated neuronal death and cognitive deficits by upregulating the PGC-1α and GFER-DRP1 link, thus balancing mitochondrial homeostasis.

Corrigendum to "Possible Role for Bacteriophages in the Treatment of SARS-CoV-2 Infection".

[This corrects the article DOI: 10.1155/2020/8844963.].

Polyphenols and Stem Cells for Neuroregeneration in Parkinson's Disease and Amyotrophic Lateral Sclerosis.

Parkinson's disease (PD) and Amyotrophic lateral sclerosis (ALS) are neurological disorders pathologically characterized by chronic degeneration of dopaminergic neurons and motor neurons, respectively. There is still no cure or effective treatment against the disease progression and most of the treatments are symptomatic. The present review offers an overview of the different factors involved in the pathogenesis of these diseases. Subsequently, we focused on the recent advanced studies of dietary polyphenols and stem cell therapies, which have made it possible to slow down the progression of neurodegeneration. To date, stem cells and different polyphenols have been used for the directional induction of neural stem cells into dopaminergic neurons and motor neurons. We have also discussed their involvement in the modulation of different signal transduction pathways and growth factor levels in various in vivo and in vitro studies. Likewise stem cells, polyphenols also exhibit the potential of neuroprotection by their anti-apoptotic, anti-inflammatory, and anti-oxidant properties regulating the growth factors levels and molecular signaling events. Overall this review provides a detailed insight into recent strategies that promise the use of polyphenol with stem cell therapy for the possible treatment of PD and ALS.

Bisphenol-A inhibits mitochondrial biogenesis via impairment of GFER mediated mitochondrial protein import in the rat brain hippocampus.

Mitochondrial biogenesis relies on different protein import machinery, as mitochondrial proteins are imported from the cytosol. The mitochondrial intermembrane space assembly (MIA) pathway consists of GFER/ALR and CHCHD4/Mia40, responsible for importing proteins and their oxidative folding inside the mitochondria. The MIA pathway plays an essential role in complex IV (COX IV) biogenesis via importing copper chaperone COX17, associated with the respiratory chain. BPA, an environmental toxicant, found in consumable plastics, causes neurotoxicity via impairment in mitochondrial dynamics, neurogenesis, and cognitive functions. We studied the levels of key regulatory proteins of mitochondrial import pathways and mitochondrial biogenesis after BPA exposure in the rat hippocampus. BPA caused a significant reduction in the levels of mitochondrial biogenesis proteins (PGC1α, and TFAM) and mitochondrial import protein (GFER). Immunohistochemical analysis showed reduced co-localization of NeuN with GFER, PGC-1α, and TFAM suggesting impaired mitochondrial biogenesis and protein import. BPA exposure resulted in damaged mitochondria with distorted cristae in neurons and caused a significant reduction in GFER localization inside IMS as depicted by immunogold electron microscopy. The reduced levels of GFER resulted in defective COX17 import. The translocation of cytochrome c into the cytosol and increased cleaved caspase-3 levels triggered apoptosis due to BPA toxicity. Overall, our study implicates GFER as a potential target for impaired mitochondrial protein machinery, biogenesis, and apoptosis against BPA neurotoxicity in the rat hippocampus.

Brain Organoids: Tiny Mirrors of Human Neurodevelopment and Neurological Disorders.

Unravelling the complexity of the human brain is a challenging task. Nowadays, modern neurobiologists have developed 3D model systems called "brain organoids" to overcome the technical challenges in understanding human brain development and the limitations of animal models to study neurological diseases. Certainly like most model systems in neuroscience, brain organoids too have limitations, as these minuscule brains lack the complex neuronal circuitry required to begin the operational tasks of human brain. However, researchers are hopeful that future endeavors with these 3D brain tissues could provide mechanistic insights into the generation of circuit complexity as well as reproducible creation of different regions of the human brain. Herein, we have presented the contemporary state of brain organoids with special emphasis on their mode of generation and their utility in modelling neurological disorders, drug discovery, and clinical trials.

Cypermethrin Impairs Hippocampal Neurogenesis and Cognitive Functions by Altering Neural Fate Decisions in the Rat Brain.

Neurogenesis is a developmental process that involves fine-tuned coordination between self-renewal, proliferation, and differentiation of neural stem cells (NSCs) into neurons. However, early-life assault with environmental toxicants interferes with the regular function of genes, proteins, and other molecules that build brain architecture resulting in attenuated neurogenesis. Cypermethrin is a class II synthetic pyrethroid pesticide extensively used in agriculture, veterinary, and residential applications due to its low mammalian toxicity, high bio-efficacy, and enhanced stability. Despite reports on cypermethrin-mediated behavioral and biochemical alterations, till now, no study implicates whether cypermethrin exposure has any effect on neurogenesis. Therefore, the present study was undertaken to comprehend the effects of cypermethrin treatment on embryonic and adult neurogenesis. We found that cypermethrin exposure led to a considerable decrease in the BrdU/Sox-2+, BrdU/Dcx+, and BrdU/NeuN+ co-labeled cells indicating that cypermethrin treatment decreases NSC proliferation and generation of mature and functional neurons. On the contrary, the generation of BrdU/S100ß+ glial cells was increased resulting in neurogliogenesis imbalance in the hippocampus. Further, cypermethrin treatment also led to an increased number of BrdU/cleaved caspase-3+ and Fluoro-Jade B+ cells suggesting an induction of apoptosis in NSCs and increased degeneration of neurons in the hippocampus. Overall, these results explicate that cypermethrin exposure not only reduces the NSC pool but also disturbs the neuron-astrocyte ratio and potentiates neurodegeneration in the hippocampus, leading to cognitive dysfunctions in rats.

Nanomedicine against Alzheimer's and Parkinson's Disease.

Alzheimer's and Parkinson's are the two most rampant neurodegenerative disorders worldwide. Existing treatments have a limited effect on the pathophysiology but are unable to fully arrest the progression of the disease. This is due to the inability of these therapeutic molecules to efficiently cross the blood-brain barrier. We discuss how nanotechnology has enabled researchers to develop novel and efficient nano-therapeutics against these diseases. The development of nanotized drug delivery systems has permitted an efficient, site-targeted, and controlled release of drugs in the brain, thereby presenting a revolutionary therapeutic approach. Nanoparticles are also being thoroughly studied and exploited for their role in the efficient and precise diagnosis of neurodegenerative conditions. We summarize the role of different nano-carriers and RNAi-conjugated nanoparticle-based therapeutics for their efficacy in pre-clinical studies. We also discuss the challenges underlying the use of nanomedicine with a focus on their route of administration, concentration, metabolism, and any toxic effects for successful therapeutics in these diseases.

Mitochondrial Protein Import Dysfunction in Pathogenesis of Neurodegenerative Diseases.

Mitochondria play an essential role in maintaining energy homeostasis and cellular survival. In the brain, higher ATP production is required by mature neurons for communication. Most of the mitochondrial proteins transcribe in the nucleus and import in mitochondria through different pathways of the mitochondrial protein import machinery. This machinery plays a crucial role in determining mitochondrial morphology and functions through mitochondrial biogenesis. Failure of this machinery and any alterations during mitochondrial biogenesis underlies neurodegeneration resulting in Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and Parkinson's disease (PD) etc. Current knowledge has revealed the different pathways of mitochondrial protein import machinery such as translocase of the outer mitochondrial membrane complex, the presequence pathway, carrier pathway, ß-barrel pathway, and mitochondrial import and assembly machinery etc. In this review, we have discussed the recent studies regarding protein import machinery, beyond the well-known effects of increased oxidative stress and bioenergetics dysfunctions. We have elucidated in detail how these types of machinery help to import and locate the precursor proteins to their specific location inside the mitochondria and play a major role in mitochondrial biogenesis. We further discuss their involvement in mitochondrial dysfunctioning and the induction of toxic aggregates in neurodegenerative diseases like AD and PD. The review supports the importance of import machinery in neuronal functions and its association with toxic aggregated proteins in mitochondrial impairment, suggesting a critical role in fostering and maintaining neurodegeneration and therapeutic response.

Fast kinetics of environmentally induced α-synuclein aggregation mediated by structural alteration in NAC region and result in structure dependent cytotoxicity.

Aggregation of α-synuclein (α-syn) is associated with the manifestation of various pathogenic synucleinopathies, including Parkinson's disease attributed to both genetic and environmental stress factors. The initial events triggering α-syn aggregation and disease initiation due to environmental stress factors are still largely unknown. Here, to understand the mechanism of misfolding and aggregation initiation, we induced α-syn aggregation with rotenone, an established chemical inducer of PD like symptoms. We found that rotenone accelerates the formation of structurally distinct oligomers and fibrils that act as templates and increase the formation of conformers capable of spreading to the neighboring neuronal cells. Molecular dynamics simulations and NMR studies revealed the involvement of NAC region and formation of helical conformations resulting in structural variations in oligomers and fibrils. These structural variations affect the cytotoxic potential of oligomers and fibrils, where, the beta sheet rich oligomers and fibrils alter the membrane potential of neuronal cells and lead to early apoptosis. Our results describe the initial mechanistic events in pathogenic protein aggregation, where initial structural alterations in response to external stress factors dictate the toxicity of resulting conformers. This information will further provide insights in the understanding of protein aggregation, disease progression and pathogenesis.

Possible Role for Bacteriophages in the Treatment of SARS-CoV-2 Infection.

An outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first reported in Wuhan City, China, in December 2019. Since then, the outbreak has grown into a global pandemic, and neither a vaccine nor a treatment for the disease, termed coronavirus disease 2019 (COVID-19), is currently available. The slow translational progress in the field of research suggests that a large number of studies are urgently required. In this context, this review explores the impact of bacteriophages on SARS-CoV-2, especially concerning phage therapy (PT). Bacteriophages are viruses that infect and kill bacterial cells. Several studies have confirmed that in addition to their antibacterial abilities, bacteriophages also show antiviral and antifungal properties. It has also been shown that PT is effective for building immunity against viral pathogens by reducing the activation of NF kappa B; additionally, phages produce the antiviral protein phagicin. The Ganges river in India, which originates from the Himalayan range, is known to harbor a large number of bacteriophages, which are released into the river gradually by the melting permafrost. Water from this river has traditionally been considered a therapeutic agent for several diseases. In this review, we hypothesize that the Ganges river may play a therapeutic role in the treatment of COVID-19.

Notch pathway up-regulation via curcumin mitigates bisphenol-A (BPA) induced alterations in hippocampal oligodendrogenesis.

CNS myelination process involves proliferation and differentiation of oligodendrocyte progenitor cells (OPCs). Defective myelination causes onset of neurological disorders. Bisphenol-A (BPA), a component of plastic items, exerts adverse effects on human health. Our previous studies indicated that BPA impairs neurogenesis and myelination process stimulating cognitive dysfunctions. But, the underlying mechanism(s) of BPA induced de-myelination and probable neuroprotection by curcumin remains elusive. We found that curcumin protected BPA mediated adverse effects on oligosphere growth kinetics. Curcumin significantly improved proliferation and differentiation of OPCs upon BPA exposure both in-vitro and in-vivo. Curcumin enhanced the mRNA expression and protein levels of myelination markers in BPA treated rat hippocampus. Curcumin improved myelination potential via increasing ß-III tubulin-/MBP+ cells (neuron-oligodendrocyte co-culture) and augmented fluoromyelin intensity and neurofilament/MBP+ neurons in vivo. In silico docking studies suggested Notch pathway genes (Notch-1, Hes-1 and Mib-1) as potential targets of BPA and curcumin. Curcumin reversed BPA mediated myelination inhibition via increasing the Notch pathway gene expression. Genetic and pharmacological Notch pathway inhibition by DAPT and Notch-1 siRNA exhibited decreased curcumin mediated neuroprotection. Curcumin improved BPA mediated myelin sheath degeneration and neurobehavioral impairments. Altogether, results suggest that curcumin protected BPA induced de-myelination and behavioural deficits through Notch pathway activation.

Correction to: Neuroprotective Role of Novel Triazine Derivatives by Activating Wnt/ß Catenin Signaling Pathway in Rodent Models of Alzheimer's Disease.

The original version of this article unfortunately contained mistakes in figures.

Correction to: Inhibitory Effects of Bisphenol-A on Neural Stem Cells Proliferation and Differentiation in the Rat Brain Are Dependent on Wnt/ß-Catenin Pathway.

The original version of this article unfortunately contained a mistake.