Development of Midbrain Dopaminergic Neurons and the Advantage of Using hiPSCs as a Model System to Study Parkinson's Disease.

Midbrain dopaminergic (mDA) neurons are significantly impaired in patients inflicted with Parkinson's disease (PD), subsequently affecting a variety of motor functions. There are four pathways through which dopamine elicits its function, namely, nigrostriatal, mesolimbic, mesocortical and tuberoinfundibular dopamine pathways. SHH and Wnt signalling pathways in association with favourable expression of a variety of genes, promotes the development and differentiation of mDA neurons in the brain. However, there is a knowledge gap regarding the complex signalling pathways involved in development of mDA neurons. hiPSC models have been acclaimed to be effective in generating complex disease phenotypes. These models mimic the microenvironment found in vivo thus ensuring maximum reliability. Further, a variety of therapeutic compounds can be screened using hiPSCs since they can be used to generate neurons that could carry an array of mutations associated with both familial and sporadic PD. Thus, culturing hiPSCs to study gene expression and dysregulation of cellular processes associated with PD can be useful in developing targeted therapies that will be a step towards halting disease progression.

Mitochondria-Endoplasmic Reticulum Contact Sites (MERCS): A New Axis in Neuronal Degeneration and Regeneration.

Mitochondria-Endoplasmic Reticulum Contact Sites (MERCS) are dynamic structures whose physiological interaction is vital to direct life and death of the cell. A bevy of tethering proteins, mitofusin-1/2 (Mfn-1/2), glucose-regulated protein-75 (Grp-75), voltage-dependent anion channel-1 (VDAC1), and dynamic-related protein-1 (Drp1), plays an integral role in establishing and regulating this intricate intracellular communication. Dysregulation of this interplay leads to various neurodegenerative disorders, like Alzheimer's disease (AD), Parkinson's disease (PD), stroke, traumatic brain injury (TBI), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD). Although there is an absence of a well-defined molecular background that dictates the pathway of MERCS, adequate exploration has resulted in preliminary data that suggests its cardinal role in neuroregeneration. The juxtaposition of mitochondria and ER has a critical function in cell senescence, thus regulating regeneration. Axonal regeneration and brain tissue regeneration, using reactive astrocytes, are studied most extensively. Overexpression of Grp-75 promoted axonal regeneration post a nerve injury. Attempts have been made to exploit MERCS as potential therapeutic drug targets for enhancing neuroregeneration and impeding neurodegeneration. Novel strategies have been developed to aid the delivery of mitochondria into the neuronal cell body, which in turn establishes a network with the presiding ER resulting in contact site formation. The fascinating aspect of this mechanism is that despite the lack of inherent regenerative capacity in neurons, it can be induced by modifying MERCS.

Prospects of microRNAs as therapeutic biomarkers in non-small cell lung cancer.

Lung Cancer, the second most common cancer worldwide, remains the leading cause of cancer-related deaths, contemporarily. More than 85% of identified lung cancer cases are comprised of non-small-cell lung carcinoma (NSCLC). Despite the best advancements in the realm of NSCLC therapy, the five-year survival period of NSCLC patients remains unchanged. Underlying complex molecular heterogeneity, delay in early detection resulting in progression of the disease to its advanced stage and acquired resistance of NSCLC cells during therapy have posed additional challenges for circumventing the discrepancies in treatment strategy. microRNAs (miRNAs) are a class of non-coding RNAs, identified as molecules playing an indispensable role in tumorigenesis & progression and metastasis of several cancers, including NSCLC, either by possessing tumor suppressor or by oncogenic functions. As observed across several studies, miRNA dysregulation has been recognised as a causative mechanism behind NSCLC tumorigenesis. In this review, we discuss the role of miRNAs in NSCLC tumor progression caused by their dysregulation, thereby stating their potential therapeutic application in NSCLC as therapeutic biomarkers. We have also highlighted the recent findings of some of the most widely studied tumor suppressor (miR-486, miR-7 miR-34), and oncogene miRNAs (miR-21, miR-224, miR-135b) that can be further explored for its therapeutic potentialities in the management of NSCLC.

Role of tissue markers associated with tumor microenvironment in the progression and immune suppression of oral squamous cell carcinoma.

Head and neck cancers (HNC) continues to dominate major cancers contributing to  mortality worldwide. Squamous cell carcinoma is the major type of HNC. Oral Squamous Cell Carcinoma grouped under HNC is a malignant tumor occurring in the oral cavity. The primary risk factors of OSCC are tobacco, alcohol consumption, etc. This review focuses on modulations, mechanisms, growth and differentiation of oral squamous cell carcinoma. Cancer cell surrounds itself with a group of elements forming a favorable environment known as tumor microenvironment (TME). It consists of numerous cells which includes immune cells, blood cells and acellular components that are responsible for the progression, immunosuppression, metastasis and angiogenesis of cancer. This review highlights the most important tissue biomarkers (mTOR, CAF, FOXp3, CD163, CD33, CD34) that are associated with TME cells. mTOR remains as the primary regulator responsible in cancer and its importance towards immune-suppression is highlighted. Tumor-associated macrophages associated with cancer development and its relationship with immunomodulatory mechanism and Tregs, which are potential blockers of immune response and its mechanism and aberrations are discussed. Cancer-associated fibroblasts that are a part of TME and their role in evading the immune response and myeloid derived suppressor cells that have slight control over the immune response and their mechanism in the tumor progression is further explained. These markers have been emphasised as therapeutic targets and are currently in different stages of clinical trials.

Decoding the mechanism of vascular morphogenesis to explore future prospects in targeted tumor therapy.

The growth and formation of blood vessels is an undeniably fundamental biological process crucial to controlling overall development of an organism. This phenomenon consists of two separate processes, commencing with vasculogenesis, which refers to the process of blood vessel formation strictly in embryonic stages, via de novo endothelial cell synthesis. Angiogenesis continues the formation of the vascular network via sprouting and splitting. Tumor growth is dependent on the growth and supply of blood vessels around the tumor mass. Extracellular matrix (ECM) molecules can promote angiogenesis by establishing a vascular network and sequestering pro-angiogenic growth factors. Although the methods by which tumor-associated fibroblasts (which differ in phenotype from normal fibroblasts) influence angiogenesis are unknown, they are thought to be a major source of growth factors and cytokines that attract endothelial cells. Chemokines and growth factors (sourced from macrophages and neutrophils) are also regulators of angiogenesis. When considered as a whole, the tumor microenvironment is a heterogenous and dynamic mass of tissue, composed of a plethora of cell types and an ECM that can fundamentally control the pathological angiogenic switch. Angiogenesis is involved in numerous diseases, and understanding the various mechanisms surrounding this phenomenon is key to finding cures.

Plastic particles in medicine: A systematic review of exposure and effects to human health.

Single-use plastics (SUPs) have become an essential constituent of our daily life. It is being exploited in numerous pharmaceutical and healthcare applications. Despite their advantages and widespread use in the pharma and medical sectors, the potential clinical problems of plastics, especially the release of micro-nanoplastics (MNPs) and additives from medical plastics (e.g. bags, containers, and administrative sets) and sorption of drugs remain understudied. Certainly, the MNPs are multifaceted stressors that cause detrimental effects to the ecosystem and human health. The origin and persistence of MNPs in pharmaceutical products, their administration to humans, endurance and possible health implication, translocation, and excretion have not been reviewed in detail. The prime focus of this article is to conduct a systematic review on the leaching of MNPs and additives from pharmaceutical containers/administrative sets and their interaction with the pharmaceutical constituents. This review also explores the primary and secondary routes of MNPs entry from healthcare plastic products and their potential health hazards to humans. Furthermore, the fate of plastic waste generated in hospitals, their disposal, and associated MNPs release to the environment, along with preventive, and alternative measures are discussed herein.

Mechanisms contributing to adverse outcomes of COVID-19 in obesity.

A growing amount of epidemiological data from multiple countries indicate an increased prevalence of obesity, more importantly central obesity, among hospitalized subjects with COVID-19. This suggests that obesity is a major factor contributing to adverse outcome of the disease. As it is a metabolic disorder with dysregulated immune and endocrine function, it is logical that dysfunctional metabolism contributes to the mechanisms behind obesity being a risk factor for adverse outcome in COVID-19. Emerging data suggest that in obese subjects, (a) the molecular mechanisms of viral entry and spread mediated through ACE2 receptor, a multifunctional host cell protein which links to cellular homeostasis mechanisms, are affected. This includes perturbation of the physiological renin-angiotensin system pathway causing pro-inflammatory and pro-thrombotic challenges (b) existent metabolic overload and ER stress-induced UPR pathway make obese subjects vulnerable to severe COVID-19, (c) host cell response is altered involving reprogramming of metabolism and epigenetic mechanisms involving microRNAs in line with changes in obesity, and (d) adiposopathy with altered endocrine, adipokine, and cytokine profile contributes to altered immune cell metabolism, systemic inflammation, and vascular endothelial dysfunction, exacerbating COVID-19 pathology. In this review, we have examined the available literature on the underlying mechanisms contributing to obesity being a risk for adverse outcome in COVID-19.

CircRNAs: Insights into Gastric Cancer.

BACKGROUND: Gastric cancer (GC) is recorded as the fifth most common cancer globally. The classic resemblance of early symptoms of chronic gastritis including nausea, dysphagia, and dyspepsia with GC is the current challenge limiting the early diagnosis of GC. The current diagnostic procedures of GC are limited due to their invasive nature. This directs the research question toward alternative approaches, specifically at the molecular level. Recent advances in molecular regulation of cancer suggest the prominence of circular RNAs (circRNAs) in the multistep process of tumourigenesis. SUMMARY: CircRNAs are a class of non-coding RNAs, abundant in eukaryotes, with key roles in regulating genes and miRNAs as well as the alteration of processes involved in pathological conditions. Research studies have demonstrated the participation of circRNAs in the initiation and progression of tumours. This review provides a comprehensive insight into the potential of circRNAs as disease biomarkers for the early detection and treatment of GC. KEY MESSAGES: This study is an amalgamation of the implications and future prospects of circRNAs for the detection and potential treatment of GC.

Marginalizing health: employing an equity and intersectionality frame / Marginalizando a saúde: empregando uma abordagem de equidade e interseccionalidade

ABSTRACT The understanding that the drivers of inequities are multiple and intersecting is critical for health policy formulation and implementation. An intersectionality analysis reveals these relationships and allows a nuanced grasp of how health inequities are framed and understood. Using global statistics and other examples, the paper argues the significance of an intersectionality analysis in unravelling the disproportionate impact of inequity and the implications for the health and lives of persons experiencing these multiple discriminations. Attention to this, challenges the assumption of homogeneity and helps to visibilize lived realities. A few examples of acts of resistance are cited by the authors that have attempted to amplify the voices and knowledge of those whose realities are otherwise invisibilized by prevailing inequities, policies and discourses. 'Marginalizing' health thus implies an intersectional understanding of inequity as well as challenging and changing prevailing socio-political structures.

RESUMO O entendimento de que os fatores motivadores das desigualdades são múltiplos e se cruzam é fundamental para a formulação e para a implementação de políticas de saúde. Uma análise de interseccionalidade revela essas relações e permite uma compreensão diferenciada de como as iniquidades em saúde são estruturadas e compreendidas. Usando estatísticas globais e outros exemplos, o artigo argumenta a importância de uma análise de interseccionalidade para desvendar o impacto desproporcional da desigualdade e as implicações para a saúde e a vida das pessoas que sofrem essas múltiplas discriminações. Essa abordagem desafia o pressuposto de homogeneidade e ajuda a visibilizar as realidades vividas. Alguns exemplos de atos de resistência são citados pelos autores que tentaram ampliar as vozes e o conhecimento daqueles cujas realidades são, de outro modo, invisibilizadas pelas iniquidades, políticas e discursos predominantes. A 'marginalização' da saúde implica, portanto, um entendimento interseccional da desigualdade, assim como em enfrentar e mudar as estruturas sociopolíticas predominantes.

'Marginalizing' health: employing an equity and intersectionality frame / 'Marginalizando' a saúde: empregando uma abordagem de equidade e interseccionalidade

ABSTRACT The understanding that the drivers of inequities are multiple and intersecting is critical for health policy formulation and implementation. An intersectionality analysis reveals these relationships and allows a nuanced grasp of how health inequities are framed and understood. Using global statistics and other examples, the paper argues the significance of an intersectionality analysis in unravelling the disproportionate impact of inequity and the implications for the health and lives of persons experiencing these multiple discriminations. Attention to this, challenges the assumption of homogeneity and helps to visibilize lived realities. A few examples of acts of resistance are cited by the authors that have attempted to amplify the voices and knowledge of those whose realities are otherwise invisibilized by prevailing inequities, policies and discourses. 'Marginalizing' health thus implies an intersectional understanding of inequity as well as challenging and changing prevailing socio-political structures.

RESUMO O entendimento de que os fatores motivadores das desigualdades são múltiplos e se cruzam é fundamental para a formulação e para a implementação de políticas de saúde. Uma análise de interseccionalidade revela essas relações e permite uma compreensão diferenciada de como as iniquidades em saúde são estruturadas e compreendidas. Usando estatísticas globais e outros exemplos, o artigo argumenta a importância de uma análise de interseccionalidade para desvendar o impacto desproporcional da desigualdade e as implicações para a saúde e a vida das pessoas que sofrem essas múltiplas discriminações. Essa abordagem desafia o pressuposto de homogeneidade e ajuda a visibilizar as realidades vividas. Alguns exemplos de atos de resistência são citados pelos autores que tentaram ampliar as vozes e o conhecimento daqueles cujas realidades são, de outro modo, invisibilizadas pelas iniquidades, políticas e discursos predominantes. A 'marginalização' da saúde implica, portanto, um entendimento interseccional da desigualdade, assim como em enfrentar e mudar as estruturas sociopolíticas predominantes.

Prenatal diagnosis: A connotation on genetic counseling being indispensable.

Prenatal testing and diagnosis are gaining a strong foothold in a progressively developing country like India, and an estimated boom in the market of noninvasive prenatal testing is predicted by the year 2024. Having said this, every technique needs an adequate amount of supplementation to increase its worth and that is where genetic counseling proves to be indispensable. Postdiagnosis, the women classified as high-risk individuals likely to give birth to infants inflicted with congenital and structural anomalies are appropriately counseled regarding the clinical aspects of the disease, life expectancy associated with the same, and the consequences associated with the decision to go ahead and conceive the child. Genetic counseling is majorly done for Down syndrome as the other aneuploidies have a highly reduced life expectancy. Although there are a variety of techniques available for testing various chromosomal anomalies, information regarding the appropriate time of the test and emphasis on pre- and posttest counseling is usually not supplied to primary physicians. A considerable amount of confusion dominates the decision of which test should be employed for testing of which anomaly as an array of rather efficient techniques has been identified. Furthermore, there is no nation-wide consensus of the timing and nature of these screening protocols. Moreover, ambiguous guidelines along with an impending lacuna in terms of awareness have led to India being at the backseat of the era that has ushered in tons of technological advancement in this field.

Health for all in an unequal world: Obligations of global bioethics.

The theme of the joint 14th World Congress of Bioethics and 7th National Bioethics Conference Congress "Health for all in an unequal world: Obligations of global bioethics" is of critical relevance in the present global context. Although the world is better off in terms of improved health status of people by many measures than before, there exist colossal gaps across and within populations. Much needs to be done to respond to the lack of access to healthcare, poor quality of living and working conditions, and deteriorating quality of overall environment which affects more adversely the already deprived. We take this opportunity to make a few observations about the current status of affairs on this front, and offer brief analytical insights into the complex origins of the global health scenario characterised by disparities. We revisit the original conception of bioethics and suggest that it is well placed to respond to the current global crisis of inexorably widening disparities in health and wealth, and that global bioethics has an obligation to engage with this crisis.

An idea whose time has come: Compensation for vaccine-related injuries and death in India.

This paper emphasises the urgent need for a compensation policy for those affected by adverse events following immunisation in India. In the absence of such a mechanism in the country, people claim compensation by taking recourse to tort law and have to face the ensuing uncertainty and challenges with regard to the award of compensation. The paper argues that people should be provided compensation in the event of death and serious adverse events following compulsory immunisation, irrespective of whether there is a causal association between the adverse event and the vaccine, on the basis of no fault compensation.

Bioactivity Studies of ß-Lactam Derived Polycyclic Fused Pyrroli-Dine/Pyrrolizidine Derivatives in Dentistry: In Vitro, In Vivo and In Silico Studies.

The antibacterial activity of ß-lactam derived polycyclic fused pyrrolidine/pyrrolizidine derivatives synthesized by 1, 3-dipolar cycloaddition reaction was evaluated against microbes involved in dental infection. Fifteen compounds were screened; among them compound 3 showed efficient antibacterial activity in an ex vivo dentinal tubule model and in vivo mice infectious model. In silico docking studies showed greater affinity to penicillin binding protein. Cell damage was observed under Scanning Electron Microscopy (SEM) which was further proved by Confocal Laser Scanning Microscope (CLSM) and quantified using Flow Cytometry by PI up-take. Compound 3 treated E. faecalis showed ROS generation and loss of membrane integrity was quantified by flow cytometry. Compound 3 was also found to be active against resistant E. faecalis strains isolated from failed root canal treatment cases. Further, compound 3 was found to be hemocompatible, not cytotoxic to normal mammalian NIH 3T3 cells and non mutagenic. It was concluded that ß-lactam compound 3 exhibited promising antibacterial activity against E. faecalis involved in root canal infections and the mechanism of action was deciphered. The results of this research can be further implicated in the development of potent antibacterial medicaments with applications in dentistry.