Glyphosate Exposure Associated with Human Neurodegenerative Disorders: A Scoping Review

Chemically engineered agricultural products such as pesticides, insecticides, and herbicides, although used considerably for both industrialized and personal agricultural use, have recently been associated with a number of serious human health disorders. This rapid literature review aims to accumulate and analyze research from the last ten years, focusing specifically on the effects of exposure to glyphosate-based herbicide products such as Roundup as associated with the formation of various neurological disorders. Specifically, this review focuses on laboratory research using animal models or human cell cultures as well as human population-based epidemiological studies. It associates exposure to glyphosate or glyphosate-based products with the formation or exacerbation of neurological disorders such as Parkinson’s disease, Alzheimer’s disease, seizures, and autism spectrum disorder. In addition, it examines the correlation between the gut-brain axis, exposure to glyphosate, and neurodegeneration.

Decoding degeneration:the implementation of machine learning for clinical detection of neurodegenerative disorders

Machine learning represents a growing subfield of artificial intelligence with much promise in the diagnosis,treatment,and tracking of complex conditions,including neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases.While no definitive methods of diagnosis or treatment exist for either disease,researchers have implemented machine learning algorithms with neuroimaging and motion-tracking technology to analyze pathologically relevant symptoms and biomarkers.Deep learning algorithms such as neural networks and complex combined architectures have proven capable of tracking disease-linked changes in brain structure and physiology as well as patient motor and cognitive symptoms and responses to treatment.However,such techniques require further development aimed at improving transparency,adaptability,and reproducibility.In this review,we provide an overview of existing neuroimaging technologies and supervised and unsupervised machine learning techniques with their current applications in the context of Alzheimer’s and Parkinson’s diseases.

Mesenchymal stem cells-based therapy as a potential treatment in neurodegenerative disorders: is the escape from senescence an answer?

Aging is the most prominent risk factor contributing to the development of neurodegenerative disorders. In the United States, over 35 million of elderly people suffer from age-related diseases. Aging impairs the self-repair ability of neuronal cells, which undergo progressive deterioration. Once initiated, this process hampers the already limited regenerative power of the central nervous system, making the search for new therapeutic strategies particularly difficult in elderly affected patients. So far, mesenchymal stem cells have proven to be a viable option to ameliorate certain aspects of neurodegeneration, as they possess high proliferative rate and differentiate in vitro into multiple lineages. However, accumulating data have demonstrated that during longterm culture, mesenchymal stem cells undergo spontaneous transformation. Transformed mesenchymal stem cells show typical features of senescence, including the progressive shortening of telomers, which results in cell loss and, as a consequence, hampered regenerative potential. These evidences, in line with those observed in mesenchymal stem cells isolated from old donors, suggest that senescence may represent a limit to mesenchymal stem cells exploitation in therapy, prompting scholars to either find alternative sources of pluripotent cells or to arrest the age-re- lated transformation. In the present review, we summarize findings from recent literature, and critically discuss some of the major hurdles encountered in the search of appropriate sources of mesenchymal stem cells, as well as benefits arising from their use in neurodegenerative diseases. Finally, we provide some insights that may aid in the development of strategies to arrest or, at least, delay the aging of mesenchymal stem cells to improve their therapeutic potential.

Is glial heme oxygenase-1 suppression in neurodegenerative disorders permissive for neural repair?

＇Core＇ neuropathology of degenerative central nervous system （CNS） disorders The common human neurodegenerative disorders （Alzheimer＇s disease （AD）, Parkinson＇s disease （PD）, amyotrophic lateral sclerosis, etc.） vary with respect to risk factors, ages of onset, sex predilections, neuraxial regions affected, hallmark cellular inclusions, behavioral and neurological symptoms, and responses to treatment. Despite these differences, there appears to be a set of ＇core＇ neuropathological features shared among these and related entities. Common to these conditions are 1） pathological deposition of non-transferrin bound iron, 2） oxidative stress and associated protein, lipid and nucleic acid modifications, 3） mitochondrial membrane damage and bioenergetic failure, and 4） macroautophagy in the affected neural tissues.

Bioelemental patterns in the cerebrospinal fluid as potential biomarkers for neurodegenerative disorders

Neurodegenerative disorders like Parkinson＇s disease （PD） or atypi- cal Parkinsonian syndromes including the different synucleinopa- thies and tauopathies are an important burden for patients, rela- tives, care providers and incur mounting costs for the health care system in our aging society.

MSCs derived extracellular vesicles as a therapeutic paragon for neurodegenerative disorders:A viewpoint

Neurodegenerative disorders are a vicious woe to the public health and wellness.Uncertainty in their underlying causes,lack of effective biomarkers for their early detection,existence of only supportive therapy,and their ever rising incidence creates an unmatched need for targeted therapies.Mesenchymal Stem Cells(MSCs)have found to be promising candidates for regenerative and remedial therapy in neurodegenerative disorders,however several biological risks and practical issues impede in their translational utility.Deriving from MSCs are certain Extracellular Vesicles(EVs),which aid in the paracrine action of MSCs and have lately gained the scientific interest for their implacability in diverse set ups.Their cargo is of utmost importance and is being explored in various different diseases like heart diseases,neuronal diseases,respiratory diseases and hepatic diseases.They thereby hold the position of a likely prospective remedial candidate for therapy against neurodegenerative disorders.

Paracrine factors for neurodegenerative disorders:special emphasis on Parkinson's disease

The progressive loss of dopaminergic neurons in the ventral mesencephalon is the main pathological hallmark of Parkinson’s disease（PD）.Drugs currently available only alleviate the principal symptomatic motor-related disturbances and their benefit is counteracted by side effects in the long time.

New insights into the functions of Ptd Ins(3,5)P_2 in the pathogenisis of neurodegenerative disorders

The membrane trafficking systems in brain play an important role in the regulation of neuronal processes,such as morphology,neuronal survival and synaptic plasticity.It has been suggested that the phosphatidylinositols（PIs）located on endolysosomal membranes play a key role in controlling this trafficking systems.

The Role of Glutamate Dehydrogenase Activity in Development of Neurodegenerative Disorders

The specific role of Glutamate dehydrogenase (GLDH) in the brain is not yet clear, but it is an important enzyme in protein degradation as well as a metabolism regulator of glutamate as a neurotransmitter. The enzyme probably provides crucial protection for postsynaptic membranes against the neurotoxic effects of glutamate neurotransmitters. In men, GLDH activity declines almost evenly through the ages;in women, it declines faster in the first five decades. In the years of menopause, GLDH activity declines slower. The diminished GLDH activities in leukocytes and in the brain vary considerably, but they are parallel with the progress of neurodegenerative diseases. The GLDH activity is partly deficient in the brain, particularly in the leukocytes of patients with heterogeneous neurological disorders and degeneration of multiple neuronal systems. We found a statistically significant difference of GLDH activity in the cerebrospinal fluid in patients with neurological diseases and unexpected in patients with degenerative and inflammatory disorders. The decrease in GLDH activity in the cerebrospinal fluid of patients with neurodegenerative disorders may be one of the reasons for the neuro-excito-toxic glutamate effect. Defining the GLDH activity in leukocytes is at the moment the sole experimental method. The second one could be the measurement in cerebrospinal fluid. The results suggest a possibility to regulate glutamate level in human brain through activation of GLDH.

Neuron Foundry Mach 8:A Concept of Multi-modal Neurosupportive Energy Therapy Device for Treating Neurodegenerative Disorders

The prevalence of neurodegenerative disorders is rising as the population ages,and many ailments,such as depression,Parkinson’s disease,Alzheimer’s disease,autism spectrum disorder,and multiple sclerosis,have intricate underlying mechanisms that are still poorly understood.The Neuron Foundry Mach 8 is a multi-modal neuro-supportive energy therapy device designed to treat neurodegenerative disorders through daily sessions.This device proposes to deliver safe and controlled energy therapy through multiple therapeutic pathways,including stimulating brain mitochondrial energy,supporting homeostasis within the brain’s immune system,increasing melatonin production within neuronal mitochondria,and triggering cellular communication through the brain’s white matter.By combining these unique energy-based treatments,this device holds promising potential for slowing,stopping,reversing,or at least reducing the effects of neurodegenerative diseases.

Antisense therapy:a potential breakthrough in the treatment of neurodegenerative diseases

Neurodegenerative diseases are a group of disorders characterized by the progressive degeneration of neurons in the central or peripheral nervous system.Currently,there is no cure for neurodegenerative diseases and this means a heavy burden for patients and the health system worldwide.Therefore,it is necessary to find new therapeutic approaches,and antisense therapies offer this possibility,having the great advantage of not modifying cellular genome and potentially being safer.Many preclinical and clinical studies aim to test the safety and effectiveness of antisense therapies in the treatment of neurodegenerative diseases.The objective of this review is to summarize the recent advances in the development of these new technologies to treat the most common neurodegenerative diseases,with a focus on those antisense therapies that have already received the approval of the U.S.Food and Drug Administration.

A global online study of haematopoietic stem cell transplantation in multiple sclerosis and other neurodegenerative disorders

Background:The objective of this study was to understand the uptake of hemopoietic stem cell transplantation(HSCT)in neuroimmunological disorders like multiple sclerosis(MS).Method:An independent University affiliated research organization conducted a global online survey of people having had HSCT,examining demographics,treatment protocol,and effectiveness.Results:Of 271 participants,useful data were available in 223;women aged 35–54 accounted for 73.5%.Most had a household income greater than US$50,000,and the majority of participants were from Australia and the United States.Nearly 94.6%of people suffer from MS.Most had their treatment in Russia(38.7%)and 78.1%had nonmyeloablative transplants.Nearly half of the participants spent between US$50,000 to US$74,999.There were 54.5%of neurologists who did not support their patients having HSCT.Around 85.5%of participants believed HSCT helped them manage their disease from weeks to years after transplantation,and treatment was recommended by 9.5%of participants.The average reduction in Expanded Disability Status Score after transplantation was 1.2(95%CI:0.97–1.41;N=197;p<0.01;t:10.7,df:196).Conclusion:Participants were supportive of HSCT despite the costs and would recommend it to others.The data suggest some benefit in minimizing disability in MS and provides justification for large randomized controlled trials.

Emergence of taurine as a therapeutic agent for neurological disorders

Taurine is a sulfur-containing,semi-essential amino acid that occurs naturally in the body.It alternates between inflammation and oxidative stress-mediated injury in various disease models.As part of its limiting functions,taurine also modulates endoplasmic reticulum stress,Ca^(2+)homeostasis,and neuronal activity at the molecular level.Taurine effectively protects against a number of neurological disorders,including stro ke,epilepsy,cerebral ischemia,memory dysfunction,and spinal cord injury.Although various therapies are available,effective management of these disorders remains a global challenge.Approximately 30 million people are affected worldwide.The design of taurine fo rmation co uld lead to potential drugs/supplements for the health maintenance and treatment of central nervous system disorders.The general neuroprotective effects of taurine and the various possible underlying mechanisms are discussed in this review.This article is a good resource for understanding the general effects of taurine on various diseases.Given the strong evidence for the neuropharmacological efficacy of taurine in various experimental paradigms,it is concluded that this molecule should be considered and further investigated as a potential candidate for neurotherapeutics,with emphasis on mechanism and clinical studies to determine efficacy.

Targeting TrkB–PSD-95 coupling to mitigate neurological disorders

Tropomyosin receptor kinase B(TrkB)signaling plays a pivotal role in dendritic growth and dendritic spine formation to promote learning and memory.The activity-dependent release of brain-derived neurotrophic factor at synapses binds to pre-or postsynaptic TrkB resulting in the strengthening of synapses,reflected by long-term potentiation.Postsynaptically,the association of postsynaptic density protein-95 with TrkB enhances phospholipase Cγ-Ca^(2+)/calmodulin-dependent protein kinaseⅡand phosphatidylinositol 3-kinase-mechanistic target of rapamycin signaling required for long-term potentiation.In this review,we discuss TrkB-postsynaptic density protein-95 coupling as a promising strategy to magnify brain-derived neurotrophic factor signaling towards the development of novel therapeutics for specific neurological disorders.A reduction of TrkB signaling has been observed in neurodegenerative disorders,such as Alzheimer's disease and Huntington's disease,and enhancement of postsynaptic density protein-95 association with TrkB signaling could mitigate the observed deficiency of neuronal connectivity in schizophrenia and depression.Treatment with brain-derived neurotrophic factor is problematic,due to poor pharmacokinetics,low brain penetration,and side effects resulting from activation of the p75 neurotrophin receptor or the truncated TrkB.T1 isoform.Although TrkB agonists and antibodies that activate TrkB are being intensively investigated,they cannot distinguish the multiple human TrkB splicing isoforms or cell type-specific functions.Targeting TrkB–postsynaptic density protein-95 coupling provides an alternative approach to specifically boost TrkB signaling at localized synaptic sites versus global stimulation that risks many adverse side effects.

Hydrogen sulfide,nitric oxide,and neurodegenerative disorders

Hydrogen Sulfide(H_(2)S)and Nitric Oxide(NO)have become recognized as important gaseous signaling molecules with enormous pharmacological effects,therapeutic value,and central physiological roles.NO is one of the most important regulators of the pathophysiological condition in central nervous system(CNS).It is critical in the various functioning of the brain;however,beyond certain concentration/level,it is toxic.H_(2)S was regarded as toxic gas with the smell like rotten egg.But,it is now regarded as emerging neuroprotectant and neuromodulator.Recently,the use of donors and inhibitors of these signaling molecules have helped us to identify their accurate and precise biological effects.The most abundant neurotransmitter of CNS(glutamate)is the initiator of the reaction that forms NO,and H_(2)S is highly expressed in brain.These molecules are shedding light on the pathogenesis of various neurological disorders.This review is mainly focused on the importance of H_(2)S and NO for normal functioning of CNS.

Glucose 6 phosphatase dehydrogenase (G6PD) and neurodegenerative disorders:Mapping diagnostic and therapeutic opportunities

Glucose 6 phosphate dehydrogenase(G6PD)is a key and rate limiting enzyme in the pentose phosphate pathway(PPP).The physiological significance of enzyme is providing reduced energy to specific cells like erythrocyte by maintaining co-enzyme nicotinamide adenine dinucleotide phosphate(NADPH).There are preponderance research findings that demonstrate the enzyme(G6PD)role in the energy balance,and it is associated with bloodrelated diseases and disorders,primarily the anemia resulted from G6PD deficiency.The Xlinked genetic deficiency of G6PD and associated non-immune hemolytic anemia have been studied widely across the globe.Recent advancement in biology,more precisely neuroscience has revealed that G6PD is centrally involved in many neurological and neurodegenerative disorders.The neuroprotective role of the enzyme(G6PD)has also been established,as well as the potential of G6PD in oxidative damage and the Reactive Oxygen Species(ROS)produced in cerebral ischemia.Though G6PD deficiency remains a global health issue,however,a paradigm shift in research focusing the potential of the enzyme in neurological and neurodegenerative disorders will surely open a new avenue in diagnostics and enzyme therapeutics.Here,in this study,more emphasis was made on exploring the role of G6PD in neurological and inflammatory disorders as well as non-immune hemolytic anemia,thus providing diagnostic and therapeutic opportunities.

The lymphatic system:a therapeutic target for central nervous system disorders

The lymphatic vasculature forms an organized network that covers the whole body and is involved in fluid homeostasis,metabolite clearance,and immune surveillance.The recent identification of functional lymphatic vessels in the meninges of the brain and the spinal cord has provided novel insights into neurophysiology.They emerge as major pathways for fluid exchange.The abundance of immune cells in lymphatic vessels and meninges also suggests that lymphatic vessels are actively involved in neuroimmunity.The lymphatic system,through its role in the clearance of neurotoxic proteins,autoimmune cell infiltration,and the transmission of pro-inflammatory signals,participates in the pathogenesis of a variety of neurological disorders,including neurodegenerative and neuroinflammatory diseases and traumatic injury.Vascular endothelial growth factor C is the master regulator of lymphangiogenesis,a process that is critical for the maintenance of central nervous system homeostasis.In this review,we summarize current knowledge and recent advances relating to the anatomical features and immunological functions of the lymphatic system of the central nervous system and highlight its potential as a therapeutic target for neurological disorders and central nervous system repair.

Crosslink between mutations in mitochondrial genes and brain disorders:implications for mitochondrial-targeted therapeutic interventions

At the present,association of mitochondrial dysfunction and progression of neurological disorders has gained significant attention.Defects in mitochondrial network dynamics,point mutations,deletions,and interaction of pathogenomic proteins with mitochondria are some of the possible underlying mechanisms involved in these neurological disorders.Mitochondrial genetics,defects in mitochondrial oxidative phosphorylation machinery,and reactive oxygen species production might share common crosstalk in the progression of these neurological disorders.It is of significant interests to explore and develop therapeutic strategies aimed at correcting mitochondrial abnormalities.This review provided insights on mitochondrial dysfunction/mutations involved in the progression of Alzheimer’s disease,Huntington’s disease,and epilepsy with a special focus on Parkinson’s disease pathology.Along with the deleterious effects of mitochondrial mutations in aforesaid neurological disorders,this paper unraveled the available therapeutic strategy,specifically aiming to improve mitochondrial dysfunction,drugs targeting mitochondrial proteins,gene therapies aimed at correcting mutant mtDNA,peptide-based approaches,and lipophilic cations.

Potential role and therapeutic implications of glutathione peroxidase 4 in the treatment of Alzheimer's disease

Alzheimer's disease is an age-related neurodegenerative disorder with a complex and incompletely understood pathogenesis. Despite extensive research, a cure for Alzheimer's disease has not yet been found. Oxidative stress mediates excessive oxidative responses, and its involvement in Alzheimer's disease pathogenesis as a primary or secondary pathological event is widely accepted. As a member of the selenium-containing antioxidant enzyme family, glutathione peroxidase 4 reduces esterified phospholipid hydroperoxides to maintain cellular redox homeostasis. With the discovery of ferroptosis, the central role of glutathione peroxidase 4 in anti-lipid peroxidation in several diseases, including Alzheimer's disease, has received widespread attention. Increasing evidence suggests that glutathione peroxidase 4 expression is inhibited in the Alzheimer's disease brain, resulting in oxidative stress, inflammation, ferroptosis, and apoptosis, which are closely associated with pathological damage in Alzheimer's disease. Several therapeutic approaches, such as small molecule drugs, natural plant products, and non-pharmacological treatments, ameliorate pathological damage and cognitive function in Alzheimer's disease by promoting glutathione peroxidase 4 expression and enhancing glutathione peroxidase 4 activity. Therefore, glutathione peroxidase 4 upregulation may be a promising strategy for the treatment of Alzheimer's disease. This review provides an overview of the gene structure, biological functions, and regulatory mechanisms of glutathione peroxidase 4, a discussion on the important role of glutathione peroxidase 4 in pathological events closely related to Alzheimer's disease, and a summary of the advances in small-molecule drugs, natural plant products, and non-pharmacological therapies targeting glutathione peroxidase 4 for the treatment of Alzheimer's disease. Most prior studies on this subject used animal models, and relevant clinical studies are lacking. Future clinical trials are required to validate the therapeutic effects of strategies targeting glutathione peroxidase 4 in the treatment of Alzheimer's disease.

Role of copper in central nervous system physiology and pathology

Copper is a transition metal and an essential element for the organism,as alterations in its homeostasis leading to metal accumulation or deficiency have pathological effects in several organs,including the central nervous system.Central copper dysregulations have been evidenced in two genetic disorders characterized by mutations in the copper-ATPases ATP7A and ATP7B,Menkes disease and Wilson’s disease,respectively,and also in multifactorial neurological disorders such as Alzheimer’s disease,Parkinson’s disease,amyotrophic lateral sclerosis,and multiple sclerosis.This review summarizes current knowledge about the role of copper in central nervous system physiology and pathology,reports about unbalances in copper levels and/or distribution under disease,describes relevant animal models for human disorders where copper metabolism genes are dysregulated,and discusses relevant therapeutic approaches modulating copper availability.Overall,alterations in copper metabolism may contribute to the etiology of central nervous system disorders and represent relevant therapeutic targets to restore tissue homeostasis.