SARS-CoV-2 Infection to Premature Neuronal Aging and Neurodegenerative Diseases: Is there any Connection with Hypoxia?

The pandemic of coronavirus disease-2019 (COVID-19), caused by SARS-CoV-2, has become a global concern as it leads to a spectrum of mild to severe symptoms and increases death tolls around the world. Severe COVID-19 results in acute respiratory distress syndrome, hypoxia, and multi- organ dysfunction. However, the long-term effects of post-COVID-19 infection are still unknown. Based on the emerging evidence, there is a high possibility that COVID-19 infection accelerates premature neuronal aging and increases the risk of age-related neurodegenerative diseases in mild to severely infected patients during the post-COVID period. Several studies correlate COVID-19 infection with neuronal effects, though the mechanism through which they contribute to the aggravation of neuroinflammation and neurodegeneration is still under investigation. SARS-CoV-2 predominantly targets pulmonary tissues and interferes with gas exchange, leading to systemic hypoxia. The neurons in the brain require a constant supply of oxygen for their proper functioning, suggesting that they are more vulnerable to any alteration in oxygen saturation level that results in neuronal injury with or without neuroinflammation. We hypothesize that hypoxia is one of the major clinical manifestations of severe SARS-CoV-2 infection; it directly or indirectly contributes to premature neuronal aging, neuroinflammation, and neurodegeneration by altering the expression of various genes responsible for the survival of the cells. This review focuses on the interplay between COVID-19 infection, hypoxia, premature neuronal aging, and neurodegenerative diseases and provides a novel insight into the molecular mechanisms of neurodegeneration.

Emerging Role of Long Noncoding RNAs in Regulating Inflammasome-Mediated Neurodegeneration in Parkinson's Disease.

Parkinson's disease (PD) is one of the complex neurodegenerative disorders, primarily characterized by motor deficits, including bradykinesia, tremor, rigidity, and postural instability. The underlying pathophysiology involves the progressive loss of dopaminergic neurons within the substantia nigra pars compacta, leading to dopamine depletion in the basal ganglia circuitry. While motor symptoms are hallmark features of PD, emerging research highlights a wide range of non-motor symptoms, including cognitive impairments, mood disturbances, and autonomic dysfunctions. Inflammasome activation is pivotal in inducing neuroinflammation and promoting disease onset, progression, and severity of PD. Several studies have shown that long noncoding RNAs (lncRNAs) modulate inflammasomes in the pathogenesis of neurodegenerative diseases. Dysregulation of lncRNAs is linked to aberrant gene expression and cellular processes in neurodegeneration, causing the activation of inflammasomes that contribute to neuroinflammation and neurodegeneration. Inflammasomes are cytosolic proteins that form complexes upon activation, inducing inflammation and neuronal cell death. This review explores the significance of lncRNAs in regulating inflammasomes in PD, primarily focusing on specific lncRNAs such as nuclear paraspeckle assembly transcript 1 (NEATNEAT1), X-inactive specific transcript (XIST), growth arrest-specific 5 (GAS5), and HOX transcript antisense RNA (HOTAIR), which have been shown to activate or inhibit the NLRP3 inflammasome and induce the release of proinflammatory cytokines. Moreover, some lncRNAs mediate inflammasome activation through miRNA interactions. Understanding the roles of lncRNAs in inflammasome regulation provides new therapeutic targets for controlling neuroinflammation and reducing the progression of neurodegeneration. Identifying lncRNA-mediated regulatory pathways paves the way for novel therapies in the battle against these devastating neurodegenerative disorders.

Mitochondrial Toxicant-Induced Neuronal Apoptosis in Parkinson's Disease: What We Know so Far.

Parkinson's disease (PD) is one of the most common progressive neurodegenerative diseases caused by the loss of dopamine-producing neuronal cells in the region of substantia nigra pars compacta of the brain. During biological aging, neuronal cells slowly undergo degeneration, but the rate of cell death increases tremendously under some pathological conditions, leading to irreversible neurodegenerative diseases. By the time symptoms of PD usually appear, more than 50 to 60% of neuronal cells have already been destroyed. PD symptoms often start with tremors, followed by slow movement, stiffness, and postural imbalance. The etiology of PD is still unknown; however, besides genetics, several factors contribute to neurodegenerative disease, including exposure to pesticides, environmental chemicals, solvents, and heavy metals. Postmortem brain tissues of patients with PD show mitochondrial abnormalities, including dysfunction of the electron transport chain. Most chemicals present in our environment have been shown to target the mitochondria; remarkably, patients with PD show a mild deficiency in NADH dehydrogenase activity, signifying a possible link between PD and mitochondrial dysfunction. Inhibition of electron transport complexes generates free radicals that further attack the macromolecules leading to neuropathological conditions. Apart from that, oxidative stress also causes neuroinflammation-mediated neurodegeneration due to the activation of microglial cells. However, the mechanism that causes mitochondrial dysfunction, especially the electron transport chain, in the pathogenesis of PD remains unclear. This review discusses the recent updates and explains the possible mechanisms of mitochondrial toxicant-induced neuroinflammation and neurodegeneration in PD.

Bisphenol A-Induced Endocrine Dysfunction and its Associated Metabolic Disorders.

Bisphenol A (BPA) is an endocrine-disrupting chemical widely present in many consumer goods that poses a significant threat to our health upon exposure. Humans are exposed to BPA, which directly or indirectly causes endocrine dysfunctions that lead to metabolic disorders like obesity, fatty liver diseases, insulin resistance, polycystic ovarian syndrome, and other endocrine- related imbalances. The duration, quantity, and period of exposure to BPA, especially during the critical stage of development, determine its impact on reproductive and non-reproductive health. Because of its endocrine-disrupting effects, the European Chemical Agency has added BPA to the candidate list of chemicals of very serious concern. Due to its estrogenic properties and structural similarities with thyroid hormones, BPA disrupts the endocrine system at different levels. It interacts with estrogen receptors at the molecular level and acts as an antagonist or agonist via an estrogen receptor-dependent signaling pathway. In particular, BPA binds to G-protein coupled receptors and estrogen receptors, activating signaling pathways that influence cellular apoptosis, proliferation, differentiation, and inflammation. BPA acts as an obesogen that promotes adipogenesis and correlates with increased lipid accumulation and elevated expression of adipogenic markers. As a metabolic and endocrine disruptor, BPA impairs cellular homeostasis by increasing oxidative mediators and decreasing antioxidant enzymes, resulting in mitochondrial dysfunction. Due to its endocrine-disrupting properties, BPA exposure induces endocrine dysfunctions, causing metabolic syndrome. This review article gives recent development and novel insights into the cellular and molecular mechanisms of BPA-induced endocrine dysfunctions and their associated metabolic disorders.

An Insight into the Molecular Mechanism of Mitochondrial Toxicant-induced Neuronal Apoptosis in Parkinson's Disease.

Parkinson's disease (PD) is one of the most common progressive neurodegenerative disorders affecting approximately 1% of the world's population at the age of 50 and above. Majority of PD cases are sporadic and show symptoms after the age of 60 and above. At that time, most of the dopaminergic neurons in the region of substantia nigra pars compacta have been degenerated. Although in past decades, discoveries of genetic mutations linked to PD have significantly impacted our current understanding of the pathogenesis of this devastating disorder, it is likely that the environment also plays a critical role in the etiology of sporadic PD. Recent epidemiological and experimental studies indicate that exposure to environmental agents, including a number of agricultural and industrial chemicals, may contribute to the pathogenesis of several neurodegenerative disorders, including PD. Furthermore, there is a strong correlation between mitochondrial dysfunction and several forms of neurodegenerative disorders, including Alzheimer's disease (AD), Huntington's disease (HD), Amyotrophic lateral sclerosis (ALS) and PD. Interestingly, substantia nigra of patients with PD has been shown to have a mild deficiency in mitochondrial respiratory electron transport chain NADH dehydrogenase (Complex I) activity. This review discusses the role of mitochondrial toxicants in the selective degeneration of dopaminergic neurons targeting the electron transport system that leads to Parkinsonism.

In-vitro anti-Mycobacterium tuberculosis effect of Eugenol.

BACKGROUND/OBJECTIVES: Mycobacterium tuberculosis, the causative agent of tuberculosis has developed resistance to most of the available antimicrobials. Therefore research on the detection of new antimicrobials against Mycobacterium tuberculosis is needed urgently. Essential oils extracted from plants have been shown to have anti-Mycobacterium tuberculosis effect in in-vitro experiments. Essential oil contains many chemicals and any one or more than one chemical may have the anti-Mycobacterium tuberculosis effect. Eugenol is one such chemical in the essential oil and the anti-Mycobacterium tuberculosis effect of eugenol is investigated. METHODS: The anti-Mycobacterium tuberculosis effect of eugenol was evaluated against H37Rv and twelve clinical isolates of Mycobacterium tuberculosis in the BD BACTEC MGIT instrument using different volumes of eugenol. RESULTS: H37Rv and all the twelve clinical isolates of Mycobacterium tuberculosis were inhibited by eugenol. The minimal inhibitory concentration of H37Rv was 2.5 µl (2.67 mg) and those of the clinical isolates of Mycobacterium tuberculosis ranged from to 2.5 µl (2.67 mg) to 10 µl (10.68 mg). CONCLUSION: Eugenol has anti-Mycobacterium tuberculosis effect in the in-vitro BD BACTEC MGIT method.

Role of Long Non-coding RNAs in the Pathogenesis of Alzheimer's and Parkinson's Diseases.

Neurodegenerative diseases are a diverse group of diseases that are now one of the leading causes of morbidity in the elderly population. These diseases include Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), Amyotrophic Lateral Sclerosis (ALS), etc. Although these diseases have a common characteristic feature of progressive neuronal loss from various parts of the brain, they differ in the clinical symptoms and risk factors, leading to the development and progression of the diseases. AD is a neurological condition that leads to dementia and cognitive decline due to neuronal cell death in the brain, whereas PD is a movement disorder affecting neuro-motor function and develops due to the death of the dopaminergic neurons in the brain, resulting in decreased dopamine levels. Currently, the only treatment available for these neurodegenerative diseases involves reducing the rate of progression of neuronal loss. This necessitates the development of efficient early biomarkers and effective therapies for these diseases. Long non-coding RNAs (LncRNAs) belong to a large family of non-coding transcripts with a minimum length of 200 nucleotides. They are implied to be involved in the development of the brain, a variety of diseases, and epigenetic, transcriptional, and posttranscriptional levels of gene regulation. Aberrant expression of lncRNAs in the CNS is considered to play a major role in the development and progression of AD and PD, two of the most leading causes of morbidity among elderly populations. In this mini-review, we discuss the role of various long non-coding RNAs in neurodegenerative diseases, such as Alzheimer's and Parkinson's disease, which can further be studied for the development of potential biomarkers and therapeutic targets for various neurodegenerative diseases.

Inflammasome Signaling in the Aging Brain and Age-Related Neurodegenerative Diseases.

Inflammasomes are intracellular protein complexes, members of the innate immune system, and their activation and regulation play an essential role in maintaining homeostatic conditions against exogenous and endogenous stimuli. Inflammasomes occur as cytosolic proteins and assemble into a complex during the recognition of pathogen-associated or danger-associated molecular patterns by pattern-recognition receptors in host cells. The formation of the inflammasome complex elicits signaling molecules of proinflammatory cytokines such as interleukin-1ß and interleukin 18 via activation of caspase-1 in the canonical inflammasome pathway whereas caspase-11 in the case of a mouse and caspase-4 and caspase-5 in the case of humans in the non-canonical inflammasome pathway, resulting in pyroptotic or inflammatory cell death which ultimately leads to neuroinflammation and neurodegenerative diseases. Inflammasome activation, particularly in microglial cells and macrophages, has been linked to aging as well as age-related neurodegenerative diseases. The accumulation of abnormal/ misfolded proteins acts as a ligand for inflammasome activation in neurodegenerative diseases. Although recent studies have revealed the inflammasomes' functionality in both in vitro and in vivo models, many inflammasome signaling cascade activations during biological aging, neuroinflammation, and neurodegeneration are still ambiguous. In this review, we comprehensively unveil the cellular and molecular mechanisms of inflammasome activation during neuronal aging and age-related neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, prion disease, and amyotrophic lateral sclerosis.