Role of heavy metals (copper (Cu), arsenic (As), cadmium (Cd), iron (Fe) and lithium (Li)) induced neurotoxicity.

Parkinson's disease (PD) is a neurodegenerative condition characterized by the dopamine (DA) neuronal loss in the substantia nigra. PD impairs motor controls symptoms such as tremor, rigidity, bradykinesia and postural imbalance gradually along with non-motor problems such as olfactory dysfunction, constipation, sleeping disorder. Though surplus of factors and mechanisms have been recognized, the precise PD etiopathogenesis is not yet implied. Reports suggest that various environmental factors play a crucial role in the causality of the PD cases. Epidemiological studies have reported that heavy metals has a role in causing defects in substantia nigra region of brain in PD. Though the reason is unknown, exposure to heavy metals is reported to be an underlying factor in PD development. Metals are classified as either essential or non-essential, and they have a role in physiological processes such protein modification, electron transport, oxygen transport, redox reactions, and cell adhesion. Excessive metal levels cause oxidative stress, protein misfolding, mitochondrial malfunction, autophagy dysregulation, and apoptosis, among other things. In this review, we check out the link between heavy metals like copper (Cu), arsenic (As), cadmium (Cd), iron (Fe), and lithium (Li) in neurodegeneration, and how it impacts the pathological conditions of PD. In conclusion, increase or decrease in heavy metals involve in regulation of neuronal functions that have an impact on neurodegeneration process. Through this review, we suggest that more research is needed in this stream to bring more novel approaches for either disease modelling or therapeutics.

Leber's hereditary optic neuropathy: Current approaches and future perspectives on Mesenchymal stem cell-mediated rescue.

Leber's Hereditary Optic Neuropathy (LHON) is an inherited optic nerve disorder. It is a mitochondrially inherited disease due to point mutation in the MT-ND1, MT-ND4, and MT-ND6 genes of mitochondrial DNA (mtDNA) coding for complex I subunit proteins. These mutations affect the assembly of the mitochondrial complex I and hence the electron transport chain leading to mitochondrial dysfunction and oxidative damage. Optic nerve cells like retinal ganglion cells (RGCs) are more sensitive to mitochondrial loss and oxidative damage which results in the progressive degeneration of RGCs at the axonal region of the optic nerve leading to bilateral vision loss. Currently, gene therapy using Adeno-associated viral vector (AAV) is widely studied for the therapeutics application in LHON. Our review highlights the application of cell-based therapy for LHON. Mesenchymal stem cells (MSCs) are known to rescue cells from the pre-apoptotic stage by transferring healthy mitochondria through tunneling nanotubes (TNT) for cellular oxidative function. Empowering the transfer of healthy mitochondria using MSCs may replace the mitochondria with pathogenic mutation and possibly benefit the cells from progressive damage. This review discusses the ongoing research in LHON and mitochondrial transfer mechanisms to explore its scope in inherited optic neuropathy.

Dysfunction in Mitochondrial Electron Transport Chain Complex I, Pyruvate Dehydrogenase Activity, and Mutations in ND1 and ND4 Gene in Autism Spectrum Disorder Subjects from Tamil Nadu Population, India.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterised by impaired social interaction and behavioural abnormalities. Growing evidence proved that impairment in mitochondrial functions could inhibit energy production and may contribute to the onset of ASD. Genetic variants in the genes of mitochondrial DNA (mtDNA) could interrupt the normal energy metabolism and production in the brain which lead to a wide range of structural and functional changes in the brain resulting in ASD. The present study aims to compare the activities of mitochondrial electron transport chain (ETC) complex I, pyruvate dehydrogenase (PDH) and specific mitochondrial DNA gene (MT-ND1 and MT-ND4) variants associated with ASD subjects in the Tamil Nadu population. Mutational analysis revealed that most mutations in ASD subjects showed synonymous type followed by missense in both the ND1 and ND4 genes. Interestingly, we found that the complex I and PDH dysfunctions may have a role in ASD compared to the controls (p ≤ 0.0001). Hence, the results of the present study suggest that mitochondrial dysfunction, specifically the complex I genes, may play a major role in the onset of ASD, concluding that further research on mitochondrial genes are mandatory to unravel the mechanism behind ASD pathogenesis.

Mucormycosis: An opportunistic pathogen during COVID-19.

The pandemic of coronavirus disease 2019 (COVID-19) still remains on an upsurge trend. The second wave of this disease has led to panic in many countries, including India and some parts of the world suffering from the third wave. As there are no proper treatment options or remedies available for this deadly infection, supportive care equipment's such as oxygen cylinders, ventilators and heavy use of steroids play a vital role in the management of COVID-19. In the midst of this pandemic, the COVID-19 patients are acquiring secondary infections such as mucormycosis also known as black fungus disease. Mucormycosis is a serious, but rare opportunistic fungal infection that spreads rapidly, and hence prompt diagnosis and treatment are necessary to avoid high rate of mortality and morbidity rates. Mucormycosis is caused by the inhalation of its filamentous (hyphal form) fungi especially in the patients who are immunosuppressed. Recent studies have documented alarming number of COVID-19 patients with mucormycosis infection. Most of these patients had diabetes and were administered steroids for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection and were consequently more prone to mucormycosis. Hence, the present review emphasizes mucormycosis and its related conditions, its mechanism in normal and COVID-19 affected individuals, influencing factors and challenges to overcome this black mold infection. Early identification and further investigation of this fungus will significantly reduce the severity of the disease and mortality rate in COVID-19 affected patients.

COVID-19 and olfactory dysfunction: A possible associative approach towards neurodegenerative diseases.

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the agent of novel coronavirus 2019 (COVID-19), has kept the globe in disquiets due to its severe life-threatening conditions. The most common symptoms of COVID-19 are fever, sore throat, and shortness of breath. According to the anecdotal reports from the health care workers, it has been suggested that the virus could reach the brain and can cause anosmia, hyposmia, hypogeusia, and hypopsia. Once the SARS-CoV-2 has entered the central nervous system (CNS), it can either exit in an inactive form in the tissues or may lead to neuroinflammation. Here, we aim to discuss the chronic infection of the olfactory bulb region of the brain by SARS-CoV-2 and how this could affect the nearby residing neurons in the host. We further review the probable cellular mechanism and activation of the microglia 1 phenotype possibly leading to various neurodegenerative disorders. In conclusion, SARS-CoV-2 might probably infect the olfactory bulb neuron enervating the nasal epithelium accessing the CNS and might cause neurodegenerative diseases in the future.

Immunomodulatory effect of mesenchymal stem cells and mesenchymal stem-cell-derived exosomes for COVID-19 treatment.

The world has witnessed unimaginable damage from the coronavirus disease-19 (COVID-19) pandemic. Because the pandemic is growing rapidly, it is important to consider diverse treatment options to effectively treat people worldwide. Since the immune system is at the hub of the infection, it is essential to regulate the dynamic balance in order to prevent the overexaggerated immune responses that subsequently result in multiorgan damage. The use of stem cells as treatment options has gained tremendous momentum in the past decade. The revolutionary measures in science have brought to the world mesenchymal stem cells (MSCs) and MSC-derived exosomes (MSC-Exo) as therapeutic opportunities for various diseases. The MSCs and MSCExos have immunomodulatory functions; they can be used as therapy to strike a balance in the immune cells of patients with COVID-19. In this review, we discuss the basics of the cytokine storm in COVID-19, MSCs, and MSC-derived exosomes and the potential and stem-cell-based ongoing clinical trials for COVID-19. [BMB Reports 2020; 53(8): 400-412].

Follow-up studies in COVID-19 recovered patients - is it mandatory?

The novel Coronavirus disease 2019 (COVID-19) is an illness caused due to Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). The World Health Organization (WHO) has declared this outbreak a global health emergency and as on April 24, 2020, it has spread to 213 countries, with 25,91,015 confirmed cases and 742,855 cases have been recovered from COVID-19. In this dreadful situation our team has already published an article in the Science of the Total Environment, which elaborates the various aspects of the SARS-CoV-2 infection. In this situation, it is imperative to understand the possible outcome of COVID-19 recovered patients and determine if they have any other detrimental illnesses by longitudinal analysis to safeguard their life in future. It is necessary to follow-up these recovered patients and performs comprehensive assessments for detection and appropriate management towards their psychological, physical, and social realm. This urges us to suggest that it is highly important to provide counselling, moral support as well as a few recommended guidelines to the recovered patients and society to restore to normalcy. Epidemiological, clinical and immunological studies from COVID-19 recovered patients are particularly important to understand the disease and to prepare better for potential outbreaks in the future. Longitudinal studies on a larger cohort would help us to understand the in-depth prognosis as well as the pathogenesis of COVID-19. Also, follow-up studies will help us provide more information for the development of vaccines and drugs for these kinds of pandemics in the future. Hence, we recommend more studies are required to unravel the possible mechanism of COVID-19 infection and the after-effects of it to understand the characteristics of the virus and to develop the necessary precautionary measures to prevent it.

Does retina play a role in Parkinson's Disease?

Visual disorder is one of the non-motor symptoms found in Parkinson's disease (PD). It can be easily identified in the early stages even before the spread of pathological conditions to the brain parts. Studies have revealed that loss of dopamine (DA) cells in retinal layers is a prime cause for both retinal disturbance and pathological conditions of PD. This reduction of DA in retina is due to the aggregation of phosphorylated α-synuclein (aSyn) in the intra-retinal region, which eventually results in visual impairment in PD. Until now, very limited studies have been focused on the mechanism of aSyn influence and DA depletion as a cause for both retinal layer dysfunction and PD. Thus, more research is warranted to provide the missing connection between the exact role of DA and aSyn as a risk factor for visual problems in PD. Hence, the current review's focus is on the function and effects of DA degeneration in retinal cells of PD. Further, we suggest that iron plays a major role in regulating the aggregation of aSyn in the DA cells of retina and brain in PD. The study finds that the unidentified pathophysiological role of retinal degeneration in PD is an essential biomarker that needs further investigation to use it as a novel therapy in treating retinal dysfunctions in PD.

New insight into NANOG: A novel therapeutic target for ovarian cancer (OC).

Cancer incidence, metastasis, drug resistance and recurrence are still the critical issues of oncological diseases especially Ovarian cancer (OC). It has been suggested that drug resistance and disease relapse are the main causes for the aggressive nature of OC. There is an immediate need to develop novel strategies to understand the mechanism to overcome chemoresistance. Nanog has been found to regulate stemness like cells inside the cancer cells that are termed as Cancer Stem Cells (CSCs). These cells show high self-renewal capacity with a peculiar potential in tumour initiation, heterogeneity, progression, metastasis, recurrence, radiotherapy and multi drug resistance. Recent studies have demonstrated that Nanog, a key transcription factor for pluripotency, has been playing a major role in chemoresistance. In this review, we address the functions of Nanog in both normal and cancer cells, how Nanog is involved in OC tumorigenesis and chemoresistance. This review also highlights the methods that are used for targeting Nanog as a remedy for treating OC. Thus, through this review, we predict that these concepts will open new avenues of research in ovarian cancer stem cells, and would propose Nanog as a target to improve the outcome of chemotherapy.

Targeting phosphoinositide-3-kinase pathway in biliary tract cancers: A remedial route?

Biliary tract cancers (BTC) are aggressive tumours with a low survival rate. At the advent of the genomic era, various genetic mutations in cell signalling pathways have been incriminated in carcinogenesis. Genomic analysis studies have connected main components of the phosphoinositide-3-kinase (PI3K) signalling pathway to BTC. PI3K pathway playing a central role in cell signalling and being deregulated in various tumours has been studied as a target for chemotherapy. Novel compounds have also been identified in preclinical trials that specifically target the PI3K pathway in BTCs, but these studies have not accelerated to clinical use. These novel compounds can be examined in upcoming studies to validate them as potential therapeutic agents, as further research is required to combat the growing need for adjuvant chemotherapy to successfully battle this tumour type. Furthermore, these molecules could also be used along with gemcitabine, cisplatin and 5-fluorouracil to improve sensitivity of the tumour tissue to chemotherapy. This review focuses on the basics of PI3K signalling, genetic alterations of this pathway in BTCs and current advancement in targeting this pathway in BTCs. It emphasizes the need for gene-based drug screening in BTC. It may reveal various novel targets and drugs for amelioration of survival in patients with BTC and serve as a stepping stone for further research.