Midbrain organoids for Parkinson's disease (PD) - A powerful tool to understand the disease pathogenesis.

Brain Organiods (BOs) are a promising technique for researching disease progression in the human brain. These organoids, which are produced from human induced pluripotent stem cells (HiPSCs), can construct themselves into structured frameworks. In the context of Parkinson's disease (PD), recent advancements have been made in the development of Midbrain organoids (MBOs) models that consider key pathophysiological mechanisms such as alpha-synuclein (α-Syn), Lewy bodies, dopamine loss, and microglia activation. However, there are limitations to the current use of BOs in disease modelling and drug discovery, such as the lack of vascularization, long-term differentiation, and absence of glial cells. To address these limitations, researchers have proposed the use of spinning bioreactors to improve oxygen and nutrient perfusion. Modelling PD utilising modern experimental in vitro models is a valuable tool for studying disease mechanisms and elucidating previously unknown features of PD. In this paper, we exclusively review the unique methods available for cultivating MBOs using a pumping system that mimics the circulatory system. This mechanism may aid in delivering the required amount of oxygen and nutrients to all areas of the organoids, preventing cell death, and allowing for long-term culture and using co-culturing techniques for developing glial cell in BOs. Furthermore, we emphasise some of the significant discoveries about the BOs and the potential challenges of using BOs will be discussed.

Artificial intelligence and machine learning algorithms in the detection of heavy metals in water and wastewater: Methodological and ethical challenges.

Heavy metals (HMs) enter waterbodies through various means, which, when exceeding a threshold limit, cause toxic effects both on the environment and in humans upon entering their systems. Recent times have seen an increase in such HM influx incident rates. This requires an instant response in this regard to review the challenges in the available classical methods for HM detection and removal. As well as provide an opportunity to explore the applications of artificial intelligence (AI) and machine learning (ML) for the identification and further redemption of water and wastewater from the HMs. This review of research focuses on such applications in conjunction with the available in-silico models producing worldwide data for HM levels. Furthermore, the effect of HMs on various disease progressions has been provided, along with a brief account of prediction models analysing the health impact of HM intoxication. Also discussing the ethical and other challenges associated with the use of AI and ML in this field is the futuristic approach intended to follow, opening a wide scope of possibilities for improvement in wastewater treatment methodologies.

Does gut brain axis has an impact on Parkinson's disease (PD)?

Parkinson's Disease (PD) is becoming a growing global concern by being the second most prevalent disease next to Alzheimer's Disease (AD). Henceforth new exploration is needed in search of new aspects towards the disease mechanism and origin. Evidence from recent studies has clearly stated the role of Gut Microbiota (GM) in the maintenance of the brain and as a root cause of various diseases and disorders including other neurological conditions. In the case of PD, with an unknown etiology, the GM is said to have a larger impact on the disease pathophysiology. Although GM and its metabolites are crucial for maintaining the normal physiology of the host, it is an undeniable fact that there is an influence of GM in the pathophysiology of PD. As such the Enteroendocrine Cells (EECs) in the epithelium of the intestine are one of the significant regulators of the gut-brain axis and act as a communication mediator between the gut and the brain. The communication is established via the molecules of neuroendocrine which are said to have a crucial part in neurological diseases such as AD, PD, and other psychiatry-related disorders. This review is focused on understanding the proper role of GM and EECs in PD. Here, we also focus on some of the metabolites and compounds that can interact with the PD genes causing various dysfunctions in the cell and facilitating the disease conditions using bioinformatical tools. Various mechanisms concerning EECs and PD, their identification, the latest studies, and available current therapies have also been discussed.

Association of Biochemical Parameters and Screening for Mutations in the MCU Gene in Alzheimer's Disease Patients.

The most prevalent form of dementia, Alzheimer's disease (AD) is a chronic illness that is on the rise among the geriatric population. Even though research into its biochemical, genetic, and cytogenetic pathways has advanced, its aetiology is still unclear and complex. In this study, we recruited sixty-eight participants diagnosed with AD where the cytogenetic, biochemical parameters and genetic mutations were analysed. Our results revealed chromosomal aberrations such as aneuploidies in the peripheral blood of Alzheimer's disease patients. Biochemical parameters revealed no statistical significance in the study though a pattern could be observed in the serum levels. Further few novel mutations at the c.21 C > T, c.56G > A were observed in the MCU gene of mitochondrial calcium uniporter. All these findings reveal the need for a larger cohort study to gain a better and more detailed understanding of the aetiology of Alzheimer's disease.

Association Study Between Kynurenine 3-Monooxygenase (KMO) Gene and Parkinson's Disease Patients.

The influence of various risk factors such as aging, intricate cellular molecular processes, and lifestyle factors like smoking, alcohol consumption, caffeine intake, and occupational factors has received increased focus in relation to the risk and development of Parkinson's disease (PD). Limited research has been conducted on the assessment of lifestyle impact on kynurenine 3-monooxygenase (KMO) gene in PD. A total of 164 subjects, including 82 PD cases and 82 healthy individuals, were recruited based on specific inclusion and exclusion criteria. The severity of PD and clinical assessment were evaluated using the Unified Parkinson's Disease Rating Scale (UPDRS) and Hoehn and Yahr (HY) scaling. Sanger sequencing was performed to analyse the KMO gene in the recruited subjects, and case-control studies were conducted. The UPDRS assessment revealed significant impairments in smell, tremors, walking, and posture instability in the late-onset PD cohorts. The HY scaling indicated a higher proportion of late-onset cohorts in stage 2. Moreover, both alcoholic and non-alcoholic groups showed significantly increased levels of 3-HK in late-onset PD. Gene analysis identified missense variants at position g.241593373 T > A (rs752312199) and intronic variants at positions g.241592623A > G (rs640718), g.241592800C > A (rs990388262), g.241592802A > C (rs1350160268), g.241592808 T > C (rs1478255936), and g.241592812G > T (rs948928931). The alterations in the KMO gene were found to influence the levels of kynurenic acid (KYNA) and 3-hydroxykynurenine (3-HK). Genomic analysis revealed a high prevalence of missense mutations in the late-onset PD groups, leading to a decline in 3-HK levels in patients. This leads to the reduction of the progression of disease in late-onset groups which shows that this mutation may lead to the protective effect on the PD subjects. This study suggests the use of KYNA and 3-HK as potential biomarkers in analysing the progression of disease. This study is limited by its small sample size. To overcome this limitation, a larger study involving in greater number of participants is needed to thoroughly investigate the KMO gene and KP metabolites, to enhance our understanding of Parkinson's disease progression, and to enhance diagnostic capabilities.

A cooperativity between virus and bacteria during respiratory infections.

Respiratory tract infections remain the leading cause of morbidity and mortality worldwide. The burden is further increased by polymicrobial infection or viral and bacterial co-infection, often exacerbating the existing condition. Way back in 1918, high morbidity due to secondary pneumonia caused by bacterial infection was known, and a similar phenomenon was observed during the recent COVID-19 pandemic in which secondary bacterial infection worsens the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) condition. It has been observed that viruses paved the way for subsequent bacterial infection; similarly, bacteria have also been found to aid in viral infection. Viruses elevate bacterial infection by impairing the host's immune response, disrupting epithelial barrier integrity, expression of surface receptors and adhesion proteins, direct binding of virus to bacteria, altering nutritional immunity, and effecting the bacterial biofilm. Similarly, the bacteria enhance viral infection by altering the host's immune response, up-regulation of adhesion proteins, and activation of viral proteins. During co-infection, respiratory bacterial and viral pathogens were found to adapt and co-exist in the airways of their survival and to benefit from each other, i.e., there is a cooperative existence between the two. This review comprehensively reviews the mechanisms involved in the synergistic/cooperativity relationship between viruses and bacteria and their interaction in clinically relevant respiratory infections.

Assessment of tRNAThr and tRNAGln Variants and Mitochondrial Functionality in Parkinson's Disease (PD) Patients of Tamil Nadu Population.

Parkinson's disease (PD) is speculated with genetic and environmental factors. At molecular level, the mitochondrial impact is stated to be one of the causative reasons for PD. In this study, we investigated the mitochondrial membrane potential (MMP), reactive oxygen species (ROS) and adenosine triphosphate (ATP) levels along with mitochondrial tRNA alterations among three age categories of PD. By determining the genetic and organellar functionality using molecular techniques, the ROS levels were reported to be high with decreased MMP and ATP in the late-onset age group than in other two age categories. Likewise, the tRNA significancy in tRNAThr and tRNAGln was noticed with C4335T and G15927A mutations in late-onset and early-onset PD groups respectively. Therefore, from the findings, ageing has shown a disruption in tRNA metabolism leading to critical functioning of ATP synthesis and MMP, causing oxidative stress in PD patients. These physiological outcomes show that ageing has a keen role in the divergence of mitochondrial function, thereby proving a correlation with ageing and maintenance of mitochondrial homeostasis in PD.

Role of Telomeres and Telomerase in Parkinson's Disease-A New Theranostics?

Parkinson's disease (PD) is a complex condition that is significantly influenced by oxidative stress and inflammation. It is also suggested that telomere shortening (TS) is regulated by oxidative stress which leads to various diseases including age-related neurodegenerative diseases like PD. Thus, it is anticipated that PD would result in TS of peripheral blood mononuclear cells (PBMCs). Telomeres protect the ends of eukaryotic chromosomes preserving them against fusion and destruction. The TS is a normal process because DNA polymerase is unable to replicate the linear ends of the DNA due to end replication complications and telomerase activity in various cell types counteracts this process. PD is usually observed in the aged population and progresses over time therefore, disparities among telomere length in PBMCs of PD patients are recorded and it is still a question whether it has any useful role. Here, the likelihood of telomere attrition in PD and its implications concerning microglia activation, ageing, oxidative stress, and the significance of telomerase activators are addressed. Also, the possibility of telomeres and telomerase as a diagnostic and therapeutic biomarker in PD is discussed.

Plausible Role of Mitochondrial DNA Copy Number in Neurodegeneration-a Need for Therapeutic Approach in Parkinson's Disease (PD).

Parkinson's disease (PD) is an advancing age-associated progressive brain disorder which has various diverse factors, among them mitochondrial dysfunction involves in dopaminergic (DA) degeneration. Aging causes a rise in mitochondrial abnormalities which leads to structural and functional modifications in neuronal activity and cell death in PD. This ends in deterioration of mitochondrial function, mitochondrial alterations, mitochondrial DNA copy number (mtDNA CN) and oxidative phosphorylation (OXPHOS) capacity. mtDNA levels or mtDNA CN in PD have reported that mtDNA depletion would be a predisposing factor in PD pathogenesis. To maintain the mtDNA levels, therapeutic approaches have been focused on mitochondrial biogenesis in PD. The depletion of mtDNA levels in PD can be influenced by autophagic dysregulation, apoptosis, neuroinflammation, oxidative stress, sirtuins, and calcium homeostasis. The current review describes the regulation of mtDNA levels and discusses the plausible molecular pathways in mtDNA CN depletion in PD pathogenesis. We conclude by suggesting further research on mtDNA depletion which might show a promising effect in predicting and diagnosing PD.

Advantages of mesenchymal stem cell over the other stem cells.

A stem cell is a particular group of cells that has the extraordinary potential to convert within the body into particular cell types. They are used to regenerate tissues and cells in the body that have been damaged or destroyed by the disease. Stem cells come in three different varieties: adult stem cells, embryonic stem cells and induced pluripotent stem cells (iPSCs). Embryonic stem cells have a high chance of immune rejection and also have ethical dilemmas and iPSCs have genetic instability. Adult stem cells are difficult to analyze and extract for research since they are frequently insufficient in native tissues. However, mesenchymal stem cells (MSC) one of the categories of adult stem cells are stromal cells with a variety of potentials that can differentiate into a wide range of cell types. MSCs can be transplanted into a variety of people without worrying about rejection because they have demonstrated the ability to prevent an adverse reaction from the immune system. These transplants have powerful anti-inflammatory and immunosuppressive effects and greatly enhance the body's inherent healing capacity. While MSCs do not offer treatment for illnesses, the idea behind them is to enable the body to recover sufficiently for a protracted reduction in symptoms. In many cases, this is sufficient to significantly enhance the patient's well-being. Inspite of several advantages some potential long-term concerns connected to MSC therapy are maldifferentiation, immunosuppression and cancerous tumor growth. In this review, we will compare the mesenchymal stem cells with other stem cells with respect to the source of origin, their properties and therapeutic applications, and discuss the MSC's disadvantages.

Untangle the mystery behind DS-associated AD - Is APP the main protagonist?

Amyloid precursor protein profusion in Trisomy 21, also called Down Syndrome (DS), is rooted in the genetic determination of Alzheimer's disease (AD). With the recent development in patient care, the life expectancy of DS patients has gradually increased, leading to the high prospect of AD development, consequently leading to the development of plaques of amyloid proteins and neurofibrillary tangles made of tau by the fourth decade of the patient leading to dementia. The altered gene expression resulted in cellular dysfunction due to impairment of autophagy, mitochondrial and lysosomal dysfunction, and copy number variation controlled by the additional genes in Trisomy 21. The cognitive impairment and mechanistic insights underlying DS-AD conditions have been reviewed in this article. Some recent findings regarding biomarkers and therapeutics of DS-AD conditions were highlighted in this review.

Type 2 Diabetes (T2DM) and Parkinson's Disease (PD): a Mechanistic Approach.

Growing evidence suggest that there is a connection between Parkinson's disease (PD) and insulin dysregulation in the brain, whilst the connection between PD and type 2 diabetes mellitus (T2DM) is still up for debate. Insulin is widely recognised to play a crucial role in neuronal survival and brain function; any changes in insulin metabolism and signalling in the central nervous system (CNS) can lead to the development of various brain disorders. There is accumulating evidence linking T2DM to PD and other neurodegenerative diseases. In fact, they have a lot in common patho-physiologically, including insulin dysregulation, oxidative stress resulting in mitochondrial dysfunction, microglial activation, and inflammation. As a result, initial research should focus on the role of insulin and its molecular mechanism in order to develop therapeutic outcomes. In this current review, we will look into the link between T2DM and PD, the function of insulin in the brain, and studies related to impact of insulin in causing T2DM and PD. Further, we have also highlighted the role of various insulin signalling pathway in both T2DM and PD. We have also suggested that T2DM-targeting pharmacological strategies as potential therapeutic approach for individuals with cognitive impairment, and we have demonstrated the effectiveness of T2DM-prescribed drugs through current PD treatment trials. In conclusion, this investigation would fill a research gap in T2DM-associated Parkinson's disease (PD) with a potential therapy option.

A review of chromium (Cr) epigenetic toxicity and health hazards.

Carcinogenic metals affect a variety of cellular processes, causing oxidative stress and cancer. The widespread distribution of these metals caused by industrial, residential, agricultural, medical, and technical activities raises concern for adverse environmental and human health effects. Of these metals, chromium (Cr) and its derivatives, including Cr(VI)-induced, are of a public health concern as they cause DNA epigenetic alterations resulting in heritable changes in gene expression. Here, we review and discuss the role of Cr(VI) in epigenetic changes, including DNA methylation, histone modifications, micro-RNA changes, biomarkers of exposure and toxicity, and highlight prevention and intervention strategies to protect susceptible populations from exposure and adverse occupational health effects. Cr(VI) is a ubiquitous toxin linked to cardiovascular, developmental, neurological, and endocrine diseases as well as immunologic disorders and a high number of cancer types in humans following inhalation and skin contact. Cr alters DNA methylation levels as well as global and gene-specific histone posttranslational modifications, emphasizing the importance of considering epigenetics as a possible mechanism underlying Cr(VI) toxicity and cell-transforming ability. Our review shows that determining the levels of Cr(VI) in occupational workers is a crucial first step in shielding health problems, including cancer and other disorders. More clinical and preventative measures are therefore needed to better understand the toxicity and safeguard employees against cancer.

Concurrent Assessment of Oxidative Stress and MT-ATP6 Gene Profiling to Facilitate Diagnosis of Autism Spectrum Disorder (ASD) in Tamil Nadu Population.

Autism spectrum disorder (ASD) is a neurodevelopmental disability that causes social impairment, debilitated verbal or nonverbal conversation, and restricted/repeated behavior. Recent research reveals that mitochondrial dysfunction and oxidative stress might play a pivotal role in ASD condition. The goal of this case-control study was to investigate oxidative stress and related alterations in ASD patients. In addition, the impact of mitochondrial DNA (mtDNA) mutations, particularly MT-ATP6, and its link with oxidative stress in ASD was studied. We found that ASD patient's plasma had lower superoxide dismutase (SOD) and higher catalase (CAT) activity, resulting in lower SOD/CAT ratio. MT-ATP6 mutation analysis revealed that four variations, 8865 G>A, 8684 C>T, 8697 G>A, and 8836 A>G, have a frequency of more than 10% with missense and synonymous (silent) mutations. It was observed that abnormalities in mitochondrial complexes (I, III, V) are more common in ASD, and it may have resulted in MT-ATP6 changes or vice versa. In conclusion, our findings authenticate that oxidative stress and genetics both have an equal and potential role behind ASD and we recommend to conduct more such concurrent research to understand their unique mechanism for better diagnosis and therapeutic for ASD.

miRNA in Parkinson's disease: From pathogenesis to theranostic approaches.

Parkinson's disease (PD) is an age associated neurological disorder which is specified by cardinal motor symptoms such as tremor, stiffness, bradykinesia, postural instability, and non-motor symptoms. Dopaminergic neurons degradation in substantia nigra region and aggregation of αSyn are the classic signs of molecular defects noticed in PD pathogenesis. The discovery of microRNAs (miRNA) predicted to have a pivotal part in various processes regarding regularizing the cellular functions. Studies on dysregulation of miRNA in PD pathogenesis has recently gained the concern where our review unravels the role of miRNA expression in PD and its necessity in clinical validation for therapeutic development in PD. Here, we discussed how miRNA associated with ageing process in PD through molecular mechanistic approach of miRNAs on sirtuins, tumor necrosis factor-alpha and interleukin-6, dopamine loss, oxidative stress and autophagic dysregulation. Further we have also conferred the expression of miRNAs affected by SNCA gene expression, neuronal differentiation and its therapeutic potential with PD. In conclusion, we suggest more rigorous studies should be conducted on understanding the mechanisms and functions of miRNA in PD which will eventually lead to discovery of novel and promising therapeutics for PD.

The mechanism of action of non-coding RNAs in placental disorders.

Placental complication arises due to various risk factors occurring during the pregnancy period, leading to an increased morbidity rate. Placenta related disorders are one of primary reason for pregnancy related complications and the clinical incidences are seen to be on the rise. Most of the common disorders associated with placenta are pre-eclampsia, recurrent spontaneous abortions, intra-uterine growth restriction etc. Several studies have been done to understand the genetics and immunological attributes leading to the development of placenta associated complications. In the recent years, studies were able to establish and identify ncRNAs found specifically in foetal tissues such as the placenta. The aberrant expression patterns of ncRNA associated with placenta has been linked to disorders such as pre-eclampsia. Since ncRNA play a major role in regulating biological processes like trophoblast growth, migration and invasion, their aberrant expression could very well lead to complications like spontaneous pregnancy loss. This review article focuses on the association of ncRNAs - miRNAs, lncRNAs, CircRNAs in placenta associated complications as well as the different ncRNA based therapies. Deciphering the exact mechanism involved in the regulation and development of placenta through ncRNA will help in using it as a biomarker for early diagnosis. Understanding the therapeutic opportunities of ncRNAs in placental disorders will result in better treatment strategies.

Immunomodulatory Role of Thioredoxin Interacting Protein in Cancer's Impediments: Current Understanding and Therapeutic Implications.

Cancer, which killed ten million people in 2020, is expected to become the world's leading health problem and financial burden. Despite the development of effective therapeutic approaches, cancer-related deaths have increased by 25.4% in the last ten years. Current therapies promote apoptosis and oxidative stress DNA damage and inhibit inflammatory mediators and angiogenesis from providing temporary relief. Thioredoxin-binding protein (TXNIP) causes oxidative stress by inhibiting the function of the thioredoxin system. It is an important regulator of many redox-related signal transduction pathways in cells. In cancer cells, it functions as a tumor suppressor protein that inhibits cell proliferation. In addition, TXNIP levels in hemocytes increased after immune stimulation, suggesting that TXNIP plays an important role in immunity. Several studies have provided experimental evidence for the immune modulatory role of TXNIP in cancer impediments. TXNIP also has the potential to act against immune cells in cancer by mediating the JAK-STAT, MAPK, and PI3K/Akt pathways. To date, therapies targeting TXNIP in cancer are still under investigation. This review highlights the role of TXNIP in preventing cancer, as well as recent reports describing its functions in various immune cells, signaling pathways, and promoting action against cancer.