Exosomal Dynamics and Brain Redox Imbalance: Implications in Alzheimer's Disease Pathology and Diagnosis.

Oxidative burden plays a central role in Alzheimer's disease (AD) pathology, fostering protein aggregation, inflammation, mitochondrial impairment, and cellular dysfunction that collectively lead to neuronal injury. The role of exosomes in propagating the pathology of neurodegenerative diseases including AD is now well established. However, recent studies have also shown that exosomes are crucial responders to oxidative stress in different tissues. Thus, this offers new insights and mechanistic links within the complex pathogenesis of AD through the involvement of oxidative stress and exosomes. Several studies have indicated that exosomes, acting as intracellular communicators, disseminate oxidatively modified contents from one cell to another, propagating the pathology of AD. Another emerging aspect is the exosome-mediated inhibition of ferroptosis in multiple tissues under different conditions which may have a role in neurodegenerative diseases as well. Apart from their involvement in the pathogenesis of AD, exosomes enter the bloodstream serving as novel noninvasive biomarkers for AD; some of the exosome contents also reflect the cerebral oxidative stress in this disease condition. This review highlights the intricate interplay between oxidative stress and exosome dynamics and underscores the potential of exosomes as a novel tool in AD diagnosis.

Association of Vitamin D Status With Metabolic Syndrome and Its Individual Risk Factors: A Cross-Sectional Study.

Background Vitamin D deficiency has been associated with metabolic syndrome and its related outcomes, including type 2 diabetes mellitus, cardiovascular disease, myocardial infarction, and stroke. However, studies in Indian populations have provided conflicting results. Methods This single-center cross-sectional study was conducted in a tertiary care hospital in north India to determine the prevalence of vitamin D deficiency in patients with metabolic syndrome and to study the correlations of individual components of metabolic syndrome with 25 hydroxy vitamin D levels. The study included 235 patients aged between 30 to 70 years who met the criteria for metabolic syndrome. Patients with diabetes, hypothyroidism, Cushing's, and other disorders affecting vitamin D status, on supplements of vitamin D or anti-dyslipidaemic drugs were excluded. Information regarding socio-demographic characteristics, medical history, and anthropometric measurements were collected. Blood samples were collected to assess vitamin D levels. Results The prevalence of vitamin D deficiency (<20 ng/ml) was 76% among the study population. There was a significant negative correlation between vitamin D levels and diastolic blood pressure (Spearman's rho: -0.134, 95% CI: -0.82,-0.260, p=0.040), fasting blood glucose (Spearman's rho: -0.142, 95% CI: -0.101,-0.269, p=0.029), A weak correlation was also found between vitamin D3 levels and total cholesterol (Spearman's rho: -0.246, 95% CI: -0.119,-0.367, p<0.001), triglyceride levels (Spearman's rho: -0.246, 95% CI: -0.118,-0.370, p<0.001) and low-density lipoprotein (LDL) levels (Spearman's rho: -0.229, 95% CI: -0.102,-0.351, p<0.001). Conclusion The study findings suggest that vitamin D deficiency is prevalent among patients with metabolic syndrome in north India. There is a significant negative correlation between vitamin D levels and some components of metabolic syndrome. This highlights the need for further research to understand the underlying mechanisms and potential benefits of vitamin D supplementation in this population. Identification of high-risk individuals for hypovitaminosis D can aid in streamlining treatment guidelines and preventing unnecessary prescription of investigations in developing countries.

Genetic Variations in IL-1ß, TNF-α, and TGF-ß Associated with the Severity of Chronic Cervical Spondylitis in Patients.

Chronic cervical spondylitis (CCS), a degenerative disorder of the spine, is known for causing disability among old and young people. Single-nucleotide polymorphisms (SNPs) in various cytokine genes have demonstrated an impactful association with several inflammatory disorders. In the present study, we have investigated the SNPs and allelic distribution of the three most prevalent cytokines genes, IL-1ß (-511C/T), TNF-α (-308G/A), and TGF-ß (-509C/T), along with serum levels of these cytokines in 252 subjects. SNPs were analyzed using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), and digested fragments were separated and visualized using agarose gel electrophoresis and Native Polyacrylamide gel electrophoresis (PAGE). The serum cytokine levels were analyzed with a flow cytometer using a customized multiplex bead-based assay. It was observed that these SNPs did not reflect the susceptibility to CCS but were associated with susceptibility to CCS. We found a significant association between the C/C and G/G genotypes and the C and G alleles of IL-1ß and TNF-α, respectively, suggesting a lower risk of CCS. The frequency distribution of risk alleles (-511T) and (-308A) were simultaneously higher in CCS compared to the control, reflecting the susceptibility to CCS. TGF-ß showed a significant association with disease susceptibility, along with a significant correlation between age and the chronicity of CCS. The serum cytokine levels were significantly different in CCS and controls.

Assessment of Vitamin D Levels and Other Bone Related Biochemical Markers in Healthy Adults in Rural Population of Uttarakhand, India.

Despite being close to equator and receiving sufficient sun rays, evidences revealed that Indians have severe deficiency of vitamin D (vit D) ranging from 41 to 100% in different geographical locations. Therefore, in this study levels of 25(OH)D (physiologically measurable form) along with other bone metabolism associated biochemical markers were determined in serum sample of 300 apparently healthy study subjects (rural) from Doiwala block of Dehradun district in the state of Uttarakhand. Demographic data was also obtained based on a structured questionnaire to establish an association between 25(OH)D levels and various dietary and socio-cultural factors. Results demonstrated that of all study subjects, 197 (65%) had 25(OH)D levels below < 12 ng/mL (deficient) and 65 (21%) had 25(OH)D levels between 12 and 20 ng/mL (insufficient) with all other markers falling within respectively established reference ranges. Further, in univariate analysis, gender, occupation (indoor and outdoor), education were independently associated with vitamin D status. Additionally, parathyroid hormone associated significantly with gender and occupation, while calcium associated significantly with gender, occupation and education. Lastly, regression analysis revealed that gender and occupation independently associated with vitamin D status of subjects. In conclusion, apparently healthy subjects showed considerable vitamin D deficiency thereby generating an urgent need for formulating and implementing better government policies for enrichment of vitamin D levels among rural adults of Uttarakhand in future. Supplementary Information: The online version contains supplementary material available at 10.1007/s12291-022-01048-6.

Correlation of serum SARS-CoV-2 IgM and IgG serology and clinical outcomes in COVID-19 patients: Experience from a tertiary care centre.

BACKGROUND: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus has become a pandemic for the last 2 years. Inflammatory response to the virus leads to organ dysfunction and death. Predicting the severity of inflammatory response helps in managing critical patients using serology tests IgG and IgM. AIM: To investigate the correlation of the serology (IgM and IgG) with reverse transcriptase polymerase chain reaction (RT-PCR) status, disease severity [mild to critical], intensive care unit (ICU) admission, septic shock, acute kidney injury, and in-hospital mortality. METHODS: We conducted a longitudinal study to correlate serum SARS-CoV-2 immunoglobulin M (IgM) and immunoglobulin G (IgG) serology with clinical outcomes in coronavirus disease 2019 (COVID-19) patients. We analyzed patient data from March to December 2020 for those who were admitted at All India Institute of Medical Sciences Rishikesh. Clinical and laboratory data of these patients were collected from the e-hospital portal and analyzed. A correlation was seen with clinical outcomes and was assessed using MS Excel 2010 and SPSS software. RESULTS: Out of 494 patients, the mean age of patients was 48.95 ± 16.40 years and there were more male patients in the study (66.0%). The patients were classified as mild-moderate 328 (67.1%), severe 131 (26.8%), and critical 30 (6.1%). The mean duration from symptom onset to serology testing was 19.87 ± 30.53 d. In-hospital mortality was observed in 25.1% of patients. The seropositivity rate (i.e., either IgG or IgM > 10 AU) was 50%. IgM levels (AU/mL) (W = 33428.000, P ≤ 0.001) and IgG levels (AU/mL) (W = 39256.500, P ≤ 0.001), with the median IgM/ IgG levels (AU/mL), were highest in the RT-PCR-Positive group compared to RT-PCR-Negative clinical COVID-19. There was no significant difference between the two groups in terms of all other clinical outcomes (disease severity, septic shock, ICU admission, mechanical ventilation, and mortality). CONCLUSION: The study showed that serology levels are high in RT-PCR positive group compared to clinical COVID-19. However, serology cannot be useful for the prediction of disease outcomes. The study also highlights the importance of doing serology at a particular time as antibody titers vary with the duration of the disease. In week intervals there was a significant correlation between clinical outcomes and serology on week 3.

Utility of IL-6 in the Diagnosis, Treatment and Prognosis of COVID-19 Patients: A Longitudinal Study.

COVID-19 has caused devastating effects worldwide ever since its origin in December 2019. IL-6 is one of the chief markers used in the management of COVID-19. We conducted a longitudinal study to investigate the role of IL-6 in diagnosis, treatment, and prognosis of COVID-19-related cytokine storm. Patients with COVID-19 who were admitted at AIIMS Rishikesh from March to December 2020 were included in the study. Patients with no baseline IL-6 value at admission and for whom clinical data were not available were excluded. Clinical and laboratory data of these patients were collected from the e-hospital portal and entered in an excel sheet. Correlation was seen with other inflammatory markers and outcomes were assessed using MS Excel 2010 and SPSS software. A total of 131 patients were included in the study. Of these, 74.8% were males, with mean age 55.03 ± 13.57 years, and mean duration from symptom onset being 6.69 ± 6.3 days. A total of 82.4% had WHO severe category COVID-19, with 46.56% having severe hypoxia at presentation and 61.8% of them having some comorbidity. Spearman rank correlation coefficient of IL-6 with D-dimer was 0.203, with LDH was -0.005, with ferritin was 0.3, and with uric acid was 0.123. A total of 11 patients received Tocilizumab at a mean duration from symptom onset of 18.09 days, and 100% mortality was observed. Deaths were reported more in the group with IL-6 ≥ 40 pg/mL (57.1% vs. 40.2%, p = 0.06). ICU admissions and ventilator requirement were higher in the IL-6 ≥ 40 pg/mL group (95.9% vs. 91.4%, p = 0.32 and 55.1% vs. 37.8%, p = 0.05). The study showed that IL-6 can be used as a possible "thrombotic cytokine marker". Higher values of IL-6 (≥40 pg/mL) are associated with more deaths, ICU admissions, and ventilator requirement.

An Insight Into the Association of Sclerostin With Insulin Sensitivity and Glycemic Parameters in Male Indian Prediabetic and Diabetic Population.

Background Type 2 diabetes (T2D) is increasing day by day and creating a huge financial and social burden on the Indian population. Insulin resistance results in hyperglycemia, a condition that eventually causes prediabetes and Type 2 diabetes. The etiopathogenesis of T2D is still not clearly defined. Wnt signaling pathway is involved in pancreas development, islet function, insulin production, and secretion. Recent studies show that sclerostin, a Wnt signaling inhibitor, is associated with diabetes. The sclerostin level is altered as a function of race and ethnicity. However, no study has been conducted to observe the sclerostin level in prediabetic and diabetic individuals in the Indian population. Objectives The main objectives of the study are: to determine whether sclerostin is associated with glycemic parameters, serum insulin levels, insulin resistance/ sensitivity, beta-cell function, and adipose tissue insulin resistance (Adipo-IR). Methods This observational study was carried out at a tertiary care hospital, in Rishikesh, Uttarakhand, India. Individuals with T2D and prediabetes and healthy references were included in this study. Sclerostin and free fatty acids (FFA) were measured with the enzyme-linked immunosorbent assay (ELISA), and blood sugar, insulin, and glycated haemoglobin (HbA1c) were measured by the hexokinase, chemiluminescent, and chromatography methods, respectively. Messenger RNA (mRNA) was quantified by real-time polymerase chain reaction (PCR) using the SYBR Green protocol. Adipo-IR, homeostasis model assessment-estimated insulin resistance (HOMA-IR), homeostasis model assessment of ß-cell function (HOMA-B), quantitative insulin sensitivity check index (QUICKI), and single point insulin sensitivity estimator (SPISE) indices were calculated. Results A total of 171 study participants were enrolled in type 2 diabetes, prediabetes, and controls groups, having 57 each in the group. There was a gradual increase in sclerostin levels from healthy [242.12(158.44)] to prediabetes [256.06(299.65)] and diabetes [465.76 (735.71)] with a significant (<0.001) difference from healthy reference. Sclerostin showed a significant positive correlation with fasting blood sugar (r=0.200; p=0.009), HbA1c (r=0.394; p<0.001) and free fatty acids (r=0.205; p=0.007) in total study participants. The SPISE index showed a significant positive correlation (r=0.269, p=0.043) in the prediabetic group. SOST, GLUT4, and insulin receptor (IR) mRNA expression all corroborate with the glycemic status. Conclusion Significantly higher expression of sclerostin (both protein and gene) in newly diagnosed T2D and prediabetes male patients, as well as significant association with SPISE index, suggest that sclerostin might be an indicator of pathophysiology related to insulin resistance, which is a characteristic feature of diabetes mellitus. However, the identification of causal relationships would warrant a large-scale prospective cohort study.

Single-Point Insulin Sensitivity Estimator (SPISE) as a Feasible Marker of Insulin Resistance in Adult Metabolic Syndrome: Evaluated in a Hospital Based Cross-Sectional Pilot Study at Tertiary Care Centre of Uttarakhand.

Insulin resistance (IR) plays an important role as a major determinant of Metabolic syndrome (MetS). Various methods are available for measuring insulin resistance but they are laborious, time-consuming, and costly. Therefore various surrogate markers and indices have been devised to simplify and improve the determination of insulin resistance. Recently, a new index, single point insulin sensitivity estimator (SPISE) was proposed in the European population and was found comparable to the gold standard test (hyperinsulinemic euglycemic glucose clamp).This study was planned to evaluate whether SPISE could be a useful potential low-cost indicator for predicting MetS with IR patients in Indian population. Eighty-three participants from outpatient care of AIIMS Rishikesh were evaluated after informed consent. They were divided into Metabolic syndrome (n = 56) and Non Metabolic Syndrome(n = 27), using South Asian Modified National Cholesterol Education Program- ATP-III criteria for metabolic syndrome. SPISE index, HOMA-IR, Insulin Resistance Index, Triglycerides to high-density lipoproteins cholesterol ratio (TG/HDL-C) were calculated for all the subjects. Receiver operating characteristic (ROC) curve was plotted to assess discriminatory ability of SPISE, HOMA-IR, TG/HDL-C ratio, IRI and hs-CRP to differentiate between IR(Metabolic syndrome) and non-IR (Non-Metabolic syndrome) subjects. SPISE has greater area under curve with better sensitivity and specificity compared to HOMA-IR, IRI, TG/HDL-C ratio and hs CRP. So, SPISE has better predictive ability than HOMA-IR, IRI, TG/HDL-C ratio and hs CRP to discriminate IR from non-IR cases. SPISE could be a useful potential low-cost indicator with high sensitivity and specificity for predicting IR in MetS patients.

Involvement of Cdkal1 in the etiology of type 2 diabetes mellitus and microvascular diabetic complications: a review.

Diabetes Mellitus, being a polygenic disorder, have a set of risk genes involved in the onset of the insulin resistance, obesity and impaired insulin synthesis. Recent genome wide association studies (GWAS) shows the intimacy of CDK5 regulatory subunit Associated protein 1-Like 1 (Cdkal1) with the pathophysiology of the diabetes mellitus and its complications, although the exact molecular relation is still unknown. In this short review, we have summarized all the diverse biological roles of Cdkal1 in relation to the onset of diabetes mellitus. Variations in the Cdkal1 transcript are responsible for the accumulation of misfolded insulin and thus generating oxidative and ER stress in the pancreatic ß-cells, leading to their destruction. Recent studies have shown that Cdkal1 has an intrinsic thiomethyl transferase activity, which is essential for proper posttranslational processing of pre-proinsulin to produce mature insulin. Moreover, Cdkal1 has also been claimed as an endogenous inhibitor of cdk5, which prevents the cdk5-induced interruption in insulin synthesis through PDX1 translocation from nucleus to cytosol. Recent clinical studies have identified the risk single nucleotide polymorphisms (SNPs) of Cdkal1 as one of the root causes for the onset of diabetic complications. To the best of our knowledge, it is the first comprehensive review which elaborates most of the potential Cdkal1-dependent molecular mechanisms studied yet. In this review, we present a compiled and concise summary about all the diverse roles of Cdkal1 in the context of type 2 diabetes mellitus and its associated complications. This review will be helpful to target Cdkal1 as a potential option for the management of type 2 diabetes mellitus in future.

Cardiac Cachexia: Unaddressed Aspect in Cancer Patients.

Tumor-derived cachectic factors such as proinflammatory cytokines and neuromodulators not only affect skeletal muscle but also affect other organs, including the heart, in the form of cardiac muscle atrophy, fibrosis, and eventual cardiac dysfunction, resulting in poor quality of life and reduced survival. This article reviews the holistic approaches of existing diagnostic, pathophysiological, and multimodal therapeutic interventions targeting the molecular mechanisms that are responsible for cancer-induced cardiac cachexia. The major drivers of cardiac muscle wasting in cancer patients are autophagy activation by the cytokine-NFkB, TGF ß-SMAD3, and angiotensin II-SOCE-STIM-Ca2+ pathways. A lack of diagnostic markers and standard treatment protocols hinder the early diagnosis of cardiac dysfunction and the initiation of preventive measures. However, some novel therapeutic strategies, including the use of Withaferin A, have shown promising results in experimental models, but Withaferin A's effectiveness in human remains to be verified. The combined efforts of cardiologists and oncologists would help to identify cost effective and feasible solutions to restore cardiac function and to increase the survival potential of cancer patients.

Overview of follicle stimulating hormone and its receptors in reproduction and in stem cells and cancer stem cells.

Follicle stimulating hormone (FSH) and its receptor (FSHR) have been reported to be responsible for several physiological functions and cancers. The responsiveness of stem cells and cancer stem cells towards the FSH-FSHR system make the function of FSH and its receptors more interesting in the context of cancer biology. This review is comprised of comprehensive information on FSH-FSHR signaling in normal physiology, gonadal stem cells, cancer cells, and potential options of utilizing FSH-FSHR system as an anti-cancer therapeutic target.

Antiviral Combination Clinically Better Than Standard Therapy in Severe but Not in Non-Severe COVID-19.

PURPOSE: Definitive antiviral treatment is not available for COVID-19 infection, with the exception of remdesivir, which still evokes many doubts. Various monotherapy or combination therapies with antivirals or other agents have been tried. The present study aims to evaluate the therapeutic potential of hydroxychloroquine and lopinavir-ritonavir in combination with ribavirin in mild-severe COVID-19. PATIENTS AND METHODS: A single-center, open-label, parallel-arm, stratified randomized controlled trial evaluated the therapeutic potential of combination antiviral therapies. Enrolled patients in the severe category were randomized into three groups: (A) standard treatment, (B) hydroxychloroquine+ribavirin+standard treatment, or (C) lopinavir+ritonavir+ribavirin+standard treatment; while the non-severe category comprised two groups: (A) standard treatment or (B) hydroxychloroquine+ribavirin. Combination antivirals were given for 10 days and followed for 28 days. The primary endpoints were safety, symptomatic and laboratory recovery of organ dysfunctions, and time to SARS-CoV-2 RT-PCR negative report. RESULTS: In total, 111 patients were randomized: 24, 23, and 24 in severe categories A, B, and C, respectively, and 20 in each of the non-severe groups. Two patients receiving ribavirin experienced drug induced liver injury, and another developed QT prolongation after hydroxychloroquine. In the severe category, 47.6%, 55%, and 30.09% in A, B, and C groups, respectively, showed symptomatic recovery, compared to 93.3% and 86.7% in A and B groups, respectively, in the non-severe category at 72 hours (P>0.05). CONCLUSION: Though the results failed to show statistical superiority of the antiviral combination therapies to that of the standard therapy in both the severe and non-severe categories in symptomatic adult patients of COVID-19 due to very small sized trial, clinically hydroxychloroquine+ribavirin therapy is showing better recovery by 7.4% than standard therapy in the former category. However, results do indicate the benefit of standard therapy in the non-severe category by 6.6%. Furthermore, the dose of ribavirin needs to be reconsidered in the Indian population.

Gut Microbiota and Alzheimer's Disease: Experimental Evidence and Clinical Reality.

Alzheimer's disease (AD) is characterized by progressive death of neuronal cells in the regions of the brain concerned with memory and cognition, and is the major cause of dementia in the elderly population. Various molecular mechanisms, metabolic risk factors and environmental triggers contributing to the genesis and progression of AD are under intense investigations. The present review has dealt with the impact of a highly discussed topic of gut microbiota affecting the neurodegeneration in the AD brain. A detailed description of the composition of gut bacterial flora and its interaction with the host has been presented, followed by an analysis of key concepts of bidirectional communication between gut microbiota and the brain. The substantial experimental evidence of gut microbiota affecting the neurodegenerative process in experimental AD models has been described next in this review, and finally, the limitations of such experimental studies vis-avis the actual disease and the paucity of clinical data on this topic have also been mentioned.

Ovarian Cancer Stem Cells: Characterization and Role in Tumorigenesis.

Ovarian cancer is a heterogenous disease with variable clinicopathological and molecular mechanisms being responsible for tumorigenesis. Despite substantial technological improvement, lack of early diagnosis contributes to its highest mortality. Ovarian cancer is considered to be the most lethal female gynaecological cancer across the world. Conventional treatment modules with platinum- and Taxane-based chemotherapy can cause an initial satisfactory improvement in ovarian cancer patients. However, approximately 75-80% patients of advanced stage ovarian cancer, experience relapse and nearly 40% have overall poor survival rate. It has been observed that a subpopulation of cells referred as cancer stem cells (CSCs), having self renewal property, escape the conventional chemotherapy because of their quiescent nature. Later, these CSCs following its interaction with microenvironment and release of various inflammatory cytokines, chemokines and matrix metalloproteinases, induce invasion and propagation to distant organs of the body mainly peritoneal cavity. These CSCs can be enriched by their specific surface markers such as CD44, CD117, CD133 and intracellular enzyme such as aldehyde dehydrogenase. This tumorigenicity is further aggravated by the epithelial to mesenchymal transition of CSCs and neovascularisation via epigenetic reprogramming and over-expression of various signalling cascades such as Wnt/ß-catenin, NOTCH, Hedgehog, etc. to name a few. Hence, a comprehensive understanding of various cellular events involving interaction between cancer cells and cancer stem cells as well as its surrounding micro environmental components would be of unmet need to achieve the ultimate goal of better management of ovarian cancer patients. This chapter deals with the impact of ovarian cancer stem cells in tumorigenesis which would help in the implementation of basic research into the clinical field in the form of translational research in order to reduce the morbidity and mortality in ovarian cancer patients through amelioration of diagnosis and impoverishment of therapeutic resistance.

Application of Stem Cell Therapy for Infertility.

Infertility creates an immense impact on the psychosocial wellbeing of affected couples, leading to poor quality of life. Infertility is now considered to be a global health issue affecting approximately 15% of couples worldwide. It may arise from factors related to the male (30%), including varicocele, undescended testes, testicular cancer, and azoospermia; the female (30%), including premature ovarian failure and uterine disorders; or both partners (30%). With the recent advancement in assisted reproduction technology (ART), many affected couples (80%) could find a solution. However, a substantial number of couples cannot conceive even after ART. Stem cells are now increasingly being investigated as promising alternative therapeutics in translational research of regenerative medicine. Tremendous headway has been made to understand the biology and function of stem cells. Considering the minimum ethical concern and easily available abundant resources, extensive research is being conducted on induced pluripotent stem cells (iPSCs) and mesenchymal stem cells (MSC) for their potential application in reproductive medicine, especially in cases of infertility resulting from azoospermia and premature ovarian insufficiency. However, most of these investigations have been carried out in animal models. Evolutionary divergence observed in pluripotency among animals and humans requires caution when extrapolating the data obtained from murine models to safely apply them to clinical applications in humans. Hence, more clinical trials based on larger populations need to be carried out to investigate the relevance of stem cell therapy, including its safety and efficacy, in translational infertility medicine.

Vitamin D and immuno-pathology of COVID-19: many interactions but uncertain therapeutic benefits.

Introduction: COVID-19 pandemic has caused huge loss of human lives and extensive socio-economic damages. The immuno-pathology of this disease is neither clearly understood nor there are effective drugs for severe cases of COVID-19. Repurposing of available drugs for the treatment of COVID-19 is imperative.Areas Covered: This review has gathered the evidence from PubMed, Google Scholar, WHO, and other reliable websites on COVID-19 and summarized the existing knowledge of the immuno-pathology of COVID-19. We elucidated how vitamin D through its diverse actions on immune effector cells, epithelial cells, or renin-angiotensin-aldosterone system could have a modulatory role on the pathogenic mechanisms of COVID-19. The epidemiological evidence associating vitamin D deficiency with the severity and incidence of COVID-19 is also presented. However, the evidence of clinical benefit to patients of COVID-19 from randomized controlled trials with vitamin D has not come as yet.Expert opinion: It is now established that fatality of COVID-19 is primarily determined by hyperactivation of the host's innate immune system in response to SARS-CoV-2 invasion, and thus the research on the immuno-modulatory and other roles of vitamin D against viral infections should be pursued vigorously. This would be also useful for future pandemics caused by other novel viruses.

Impact of serotonin transporter gene polymorphism on gut motility in patients with type 2 Diabetes mellitus.

BACKGROUND/AIMS: The pathogenesis of gastrointestinal (GI) symptoms in patients with type 2 diabetes mellitus (T2DM) is yet to be delineated clearly. Serotonin, a monoamine neurotransmitter, resides primarily in the gut and plays a vital role in GI system. However, no study has been documented the role of serotonin and serotonin transporter gene (SLC6A4) polymorphism in the development of GI symptoms in T2DM patients. METHODS: Three hundred diabetes patients attending diabetes clinic at Postgraduate Institute of Medical Education and Research, Chandigarh, and matched healthy controls were enrolled for this study. Plasma from collected blood sample was used for serotonin measurement by enzyme-linked immunosorbent assay method and buffy coat was used for isolation of DNA by phenol chloroform method. Serotonin transporter gene polymorphism was analyzed by polymerase chain reaction method. RESULTS: The frequency of short allele (S) and SS genotype was significantly higher in patients with T2DM than controls and was associated with increased risk of T2DM. The frequency of LS genotype showed an association with protection from the disease. Regarding GI symptoms, 78.2% of patients with constipation showed LL and LS genotypes, and 97.7% of patients with diarrhea had SS genotype. The patients without GI symptoms did not show any association of gut motility with genotype. Furthermore, serotonin was significantly higher in diabetic patients who belonged to SS genotype compared to LS or LL genotype and who presented with diarrhea. CONCLUSION: SS genotypes are prone to develop diarrhea because of faster gut motility resulting from higher serotonin levels as compared to LS and LL genotype in T2DM patients.

Review on COVID-19 Etiopathogenesis, Clinical Presentation and Treatment Available with Emphasis on ACE2.

In December 2019, Wuhan city in the Hubei province of China reported for the first time a cluster of patients infected with a novel coronavirus, since then there has been an outburst of this disease across the globe affecting millions of human inhabitants. Severe acute respiratory syndrome coronavirus type-2 (SARS-CoV-2), is a member of beta coronavirus family which upon exposure caused a highly infectious disease called novel coronavirus disease-2019 (COVID-19). COVID-19, a probably bat originated disease was declared by World Health Organization (WHO) as a global pandemic in March 2020. Since then, despite rigorous global containment and quarantine efforts, the disease has affected nearly 56,261,952 laboratory confirmed human population and caused deaths of over 1,349,506 lives worldwide. Virus passes in majority through respiratory droplets and then enters lung epithelial cells by binding to angiotensin converting enzyme 2 (ACE2) receptor and there it undergoes replication and targeting host cells causing severe pathogenesis. Majority of human population exposed to SARS-CoV-2 having fully functional immune system undergo asymptomatic infection while 5-10% are symptomatic and only 1-2% are critically affected and requires ventilation support. Older people or people with co-morbidities are severely affected by COVID-19. These categories of patients also display cytokine storm due to dysfunctional immune response which brutally destroys the affected organs and may lead to death in some. Real time PCR is still considered as standard method of diagnosis along with other serology, radiological and biochemical investigations. Till date, no specific validated medication is available for the treatment of COVID-19 patients. Thus, this review provides detailed knowledge about the different landscapes of disease incidence, etiopathogenesis, involvement of various organs, diagnostic criteria's and treatment guidelines followed for management of COVID-19 infection since its inception. In conclusion, extensive research to recognize novel pathways and their cross talk to combat this virus in precarious settings is our future positive hope.

Physiological Relevance of Angiotensin Converting Enzyme 2 As a Metabolic Linker and Therapeutic Implication of Mesenchymal Stem Cells in COVID-19 and Hypertension.

Severe acute respiratory syndrome corona virus - 2 (SARS-CoV-2) is a single stranded RNA virus and responsible for infecting human being. In many cases the individual may remain asymptomatic. Some recently reported studies revealed that individuals of elderly age group and with pre-existing medical conditions such as hypertension, diabetes mellitus had severe consequences, even may lead to death. However, it is not clearly delineated whether hypertension itself or associated comorbidities or antihypertensive therapy contributes to the grave prognosis of COVID-19 infections. This review is aimed to decipher the exact mechanisms involved at molecular level from existing evidence and as reported. It has been reported that SARS-CoV-2 enters into the host cell through interaction between conserved residues of viral spike protein and angiotensin converting enzyme 2 (ACE2) receptor which is highly expressed in host's cardiac and pulmonary cells and finally transmembrane protease, serine-2 (TMPRSS2), helps in priming of the surface protein. Subsequently, symptom related to multi organ involvement is primarily contributed by cytokine storm. Although various clinical trials are being conducted on renin- angiotensin- system inhibitor, till to date there is no standard treatment protocol approved for critically ill COVID-19 positive cases with pre-existing hypertension. Recently, several studies are carried out to document the safety and efficacy outcome of mesenchymal stem cell transplantation based on its immunomodulatory and regenerative properties. Therefore, identification of future novel therapeutics in the form of mesenchymal stem cell either alone or in combination with pharmacological approach could be recommended for combating SARS-CoV-2 which might be dreadful to debilitating elderly people. Graphical Abstract.

Angiotensin-Converting Enzyme Gene Polymorphism Influences Gastrointestinal Motility in Type 2 Diabetes Mellitus.

Uncontrolled diabetes mellitus may affect any part of the gastrointestinal tract (GIT) and impact negatively the quality of life. Angiotensin-converting enzyme (ACE) gene polymorphism can have direct effect on circulating level of ACE which further modifies the degradation of substance P and thus may influence the gut motility. Hence, it could be hypothesised that ACE gene polymorphism would influence the gut motility. An observational analytical study was conducted at PGIMER, Chandigarh. 300 Type2 diabetes mellitus (T2DM) and 200 age and sex matched healthy individuals were enrolled. After taking written consent, 5 ml blood sample was collected for measurement of substance P by ELISA method and for ACE gene polymorphism (insertion[I]/deletion[D]) by polymerase chain reaction. Orocecal transit time (OCTT) was measured using non-invasive lactulose breath test. Out of 300 diabetic patients, 32.7%, 44% and 23.3% belonged to II, ID and DD genotypes, respectively. The frequency of D allele (OR = 1.39) and DD genotype (OR = 2.17) was significantly higher in patients than in controls and was associated with increased risk. Moreover, more number of diabetes patients with constipation (90%) belonged to DD genotype and their OCTT was significantly delayed (166.7 ± 7.3 min) as compared to ID (143.5 ± 4.2 min) or II (121.8 ± 4.9 min) genotype. From this study, it could be concluded that ACE gene polymorphism could be an important contributing factor to influence the gut motility and thus giving rise to the GI symptoms for T2DM patients.