Association of Serum Complement C3 Levels with Severity and Mortality in COVID 19.

The severe acute respiratory distress syndrome-associated coronavirus-2 infection can activate innate and adaptive immune responses which may lead to harmful tissue damage, both locally and systemically. C3, a member of complement system of serum proteins, is a major component of innate immune and inflammatory responses. This study is aimed to assess serum C3 as a marker of COVID-19 severity and a predictor of disease progression. A total of 150 COVID-19 patients, confirmed by RT-PCR, and 50 healthy controls were recruited. Serum C3 levels were determined by using direct colorimetric method. Median levels of serum C3 in total cases and controls were 157.8 and 165.7 mg/dL respectively. Serum C3 although not significantly decreased, they were lower in cases when compared to controls. Similarly, significant differences were found between the groups, with severe group (140.6 mg/dL) having low levels of serum C3 protein when compared to mild (161.0 mg/dL) and moderate group (167.1 mg/dL). Interestingly, during hospitalization, significant difference between baseline (admission) and follow-up (discharge) was observed only in patients with moderate disease. Based on our results, lower levels of C3, with an increase in IL-6 and d-dimer levels, are associated with higher odds of mortality. Therefore, we would like to emphasize that measuring serum C3 levels along with other inflammatory markers might give an added advantage in early identification of patients who are prone to having a severe disease course and can help in a more effective follow-up of disease progression. Supplementary Information: The online version contains supplementary material available at 10.1007/s12291-023-01148-x.

Genetic and Epigenetic Basis of Drug-Induced Liver Injury.

Drug-induced liver injury (DILI) is a rare but severe adverse drug reaction seen in pharmacotherapy and a major cause of postmarketing drug withdrawals. Advances in genome-wide studies indicate that genetic and epigenetic diversity can lead to inter-individual differences in drug response and toxicity. It is necessary to identify how the genetic variations, in the presence of environmental factors, can contribute to development and progression of DILI. Studies on microRNA, histone modification, DNA methylation, and single nucleotide polymorphisms related to DILI were retrieved from databases and were analyzed for the current research and updated to develop this narrative review. We have compiled some of the major genetic, epigenetic, and pharmacogenetic factors leading to DILI. Many validated genetic risk factors of DILI, such as variants of drug-metabolizing enzymes, HLA alleles, and some transporters were identified. In conclusion, these studies provide useful information in risk alleles identification and on implementation of personalized medicine.

Epigenetics regulation of prostate cancer: Biomarker and therapeutic potential.

Prostate cancer (CaP) is the second leading cause of cancer death and displays a broad range of clinical behavior from relatively indolent to aggressive metastatic disease. The etiology of most cases of CaP is not understood completely, which makes it imperative to search for the molecular basis of CaP and markers for early diagnosis. Epigenetic modifications, including changes in DNA methylation patterns, histone modifications, miRNAs, and lncRNAs are key drivers of prostate tumorigenesis. These epigenetic defects might be due to deregulated expression of the epigenetic machinery, affecting the expression of several important genes like GSTP1, RASSF1, CDKN2, RARRES1, IGFBP3, RARB, TMPRSS2-ERG, ITGB4, AOX1, HHEX, WT1, HSPE, PLAU, FOXA1, ASC, GPX3, EZH2, LSD1, etc. In this review, we highlighted the most important epigenetic gene alterations and their variations as a diagnostic marker and target for therapeutic intervention of CaP in the future. Characterization of epigenetic changes involved in CaP is obscure and adequate validation studies are still required to corroborate the present results that would be the impending future of transforming basic research settings into clinical practice.

Association of circulatory Klotho levels and its expression with miRNA- 339 in patients with schizophrenia.

Schizophrenia is one of the major neuropsychiatric disorders affecting 1% of the population worldwide. Neuroinflammation, neurodevelopment, and oxidative stress are some of the crucial factors that can contribute to the pathogenesis of Schizophrenia. Klotho gene is an antiaging gene whose dysregulated expression can lead to Schizophrenia and aging-like symptoms in patients. Klotho gene expression is regulated by miRNA- 339, which might lead to expression changes of the klotho gene in schizophrenia patients. This study aimed to determine the Role of miRNA- 339-5p in the Regulation of Klotho Gene Expression and its Circulatory Levels in Schizophrenia. In this study total of 60 cases, schizophrenia patients and 30 healthy controls were recruited, and written informed consent was obtained from all the study subjects. The klotho gene and miRNA - 339-5p expressions were done using a reverse transcription polymerase chain reaction. And relative fold change expression was calculated by Livaak's method, that is 2^-double delta ct. It was found that the klotho gene is around 2.08 times upregulated as compared to healthy control, and miRNA- 339-5p was downregulated and showed an inverse relationship. The present study is the first to evaluate the klotho gene expression and correlate it with miRNA- 339-5p. Further confirmation of the results study should be planned with a large sample size and with drug naïve patients.

Role of Klotho Protein in Neuropsychiatric Disorders: A Narrative Review.

Neuropsychiatric disorders are comprised of diseases having both the neurological and psychiatric manifestations. The increasing burden of the disease on the population worldwide makes it necessary to adopt measures to decrease the prevalence. The Klotho is a single pass transmembrane protein that decreases with age, has been associated with various pathological diseases, like reduced bone mineral density, cardiac problems and cognitive impairment. However, multiple studies have explored its role in different neuropsychiatric disorders. A comprehensive search was undertaken in the Pubmed database for articles with the keywords "Klotho" and "neuropsychiatric disorders". The available literature, based on the above search strategy, has been compiled in this brief narrative review to describe the emerging role of Klotho in various neuropsychiatric disorders. The Klotho levels were decreased in various neuropsychiatric disorders except for bipolar disorder. A suppressed Klotho protein levels induced oxidative stress and incited pro-inflammatory conditions significantly contributing to the pathophysiology of neuropsychiatric disorder. The increasing evidence of altered Klotho protein levels in cognition-decrement-related disorders warrants its consideration as a biomarker in various neuropsychiatric diseases. However, further evidence is required to understand its role as a therapeutic target.

Acute kidney injury in COVID 19 - an update on pathophysiology and management modalities.

Acute kidney injury (AKI), characterised by fluid imbalance and overload, is prevalent in severe disease phenotypes of coronavirus disease 2019 (COVID-19). The elderly immunocompromised patients with pre-existing comorbidities being more risk-prone to severe COVID-19, the importance of early diagnosis and intervention in AKI is imperative. Histopathological examination of COVID-19 patients with AKI reveals viral invasion of the renal parenchyma and evidence of AKI. The definitive treatment for AKI includes renal replacement therapy and renal transplant. Immunosuppressant regimens and its interactions with COVID-19 have to be further explored to devise effective treatment strategies in COVID-19 transplant patients. Other supportive strategies for AKI patients include hemodynamic monitoring and maintenance of fluid balance. Antiviral drugs should be meticulously monitored in the management of these high-risk patients. We have focussed on the development of renal injury provoked by the SARS-CoV-2, the varying clinical characteristics, and employment of different management strategies, including renal replacement therapy, alongside the emerging cytokine lowering approaches.

Comparative Analysis of Serum Zinc, Copper and Magnesium Level and Their Relations in Association with Severity and Mortality in SARS-CoV-2 Patients.

The deficiencies of trace elements and infectious diseases often coexist and exhibit complex interactions. Several trace elements such as zinc (Zn), copper (Cu) and magnesium (Mg) have immunomodulatory functions and thus influence the susceptibility to the course and outcome of a variety of viral infections. So, this present study was aimed to study relations of trace metals in association with severity and mortality in SARS-CoV-2 patients. A total of 150 individuals infected with COVID-19 and 50 healthy individuals were recruited. Cases were divided based on severity (mild, moderate and severe) and outcome (discharged or deceased). Serum Zn, Mg and Cu levels were analysed by direct colourimetric method. Both serum Cu and Zn levels were significantly decreased in cases when compared to those in controls (p < 0.005 and p < 0.0001). Serum magnesium levels although not significant were found to be slightly decreased in controls. On comparing the trace elements between the deceased and discharged cases, a significant difference was found between serum copper and zinc levels, but for magnesium, both groups have similar levels. The receiver operating characteristic (ROC) curve results indicate that a serum Cu/Zn ratio along with the age of patient provides some reliable information on COVID-19 course and survival odds by yielding an AUC of 95.1% with a sensitivity of 93.8% and specificity of 89.8%. Therefore, we would like to emphasize that measuring the serum copper and zinc along with their ratio can be used as routine investigations for COVID-19 patients in proper identification and management of severe cases in upcoming new waves of COVID-19.

Comparative Study of Calculated LDL-Cholesterol Levels with the Direct Assay in Patients with Hypothyroidism.

Background Hypothyroidism is one among the many factors that predisposes one to coronary artery disease. As low-density lipoprotein-cholesterol (LDL-C) is associated with cardiovascular risk, calculated LDL-C should have good accuracy with minimal bias. Hypothyroidism alters the lipid composition of lipoproteins by the secretion of triglyceride-rich lipoproteins, which affects the calculation of LDL-C. The present study aimed to compare 13 different formulae for the calculation of LDL-C including the newly derived Martin's formula by direct assay in patients of hypothyroidism. Method In this analytical cross-sectional study, a total of 105 patients with laboratory evidence of hypothyroidism, from January to June 2019, were studied, and blood samples were subjected for lipid profile analysis at central biochemistry laboratory. Calculated LDL-C was assessed by different formulae. Result We observed that calculated LDL-C by Friedewald's, Cordova's, Anandaraja's, Hattori's, and Chen's formulae has bias less than ± 5 compared with direct LDL-C, with Anandaraja's formula having the lowest bias (2.744) and Cordova's formula having lowest bias percentage (-1.077) among them. According to the Bland-Altman plots, the bias in Friedewald's and Anandraja's were equally distributed below and above the reference line of direct LDL-C. Conclusion This is the first study comparing different formulae for LDL-C calculation in patients with hypothyroidism. Anandaraja's formula was as equally effective as Friedewald's formula when used as an alternative cost-effective tool to evaluate LDL-C in hypothyroid patients. The recently proposed Martin's formula for calculated LDL-C had a higher bias when compared with Friedewald's and Anandaraja's formulae in patients with hypothyroidism.

Urinary Screening in Asymptomatic Indian Children: A Cross Sectional Epidemiological Study.

Background and aims: Early detection and management of renal abnormalities in children can reduce the progression of paediatric chronic kidney disease. Currently, data on the prevalence of routine abnormal urinary parameters are scarce in Indian population. This study aims to identify the prevalence of asymptomatic kidney diseases in Indian school children and the population who may benefit from routine urinary screening tests for timely identification and intervention of asymptomatic renal diseases. Materials and methods: A total of 1675 children from a North Indian, multiethnic population aged 5-19 years were screened for hematuria and proteinuria by dipstick test from a midstream, clean urine specimen. The children who tested positive had their urine tested further for microscopy. The incidences of proteinuria and hematuria were also separately checked in hypertensive children. Results: 76 children had urinary abnormalities with the prevalence of isolated haematuria in 1.9%, isolated proteinuria in 0.35% and glycosuria in 0.06%. When these children were followed with urine microscopy, 44 were observed to have abnormal findings. Of these, 4.5% children had proteinuria, 34% had isolated hematuria, and 47.7% had isolated WBCs. The prevalence for proteinuria was 0.60% and the prevalence for hematuria was 2.99% (in upper decile of SBP) in hypertensive children, both of which were more than the prevalence in otherwise healthy children. Conclusion: Urine screening is a non-invasive, inexpensive test for early detection of occult renal diseases. A large-scale study with follow-up of children with urinary abnormalities will further establish the benefit, if any, of a national paediatric urine screening programme.

A National Survey of the Prevalence of Anemia and Obesity in Indian School Children.

Background: In India, the socioeconomic shift in the past few decades has led to a sedentary lifestyle with poor dietary habits, leading to an increased incidence of overweight and obesity in children. Furthermore, obesity and anemia share some common links. Objectives: In this study, we have prevalence of anemia and obesity in Indian schoolchildren. Methods: The study was carried out on 1675 children and adolescent participants aged 6-18 years for the prevalence of obesity and anemia. Height, weight, waist and hip circumference were taken. Hemoglobin levels was measured for each participant. Results: Males and females differed in height (p = 0.007), waist circumference (p = 0.019), waist-to-hip ratio (p < 0.001) and hemoglobin levels (p < 0.001). A total of 294 girls (44.4%) and 283 boys (29.7%) were anemic. There were significant differences between BMI within age groups for both boys (p < 0.001) and girls (p < 0.001). The highest percentage of anemia was observed in the 12-14 years age group in girls (54.2%) and 15-18 years-old boys (54.2%). Among the obese children, 28.2% were anemic, while 29.3% of overweight children were anemic (Pearson's chi-squared = 7.68, p = 0.020). Conclusion: This study sheds light on the prevalence of obesity and anemia in Indian schoolchildren and adolescents, while also suggesting an association between the two conditions. Nutritional counselling as well as lifestyle modification should be advocated in school curricula to make an early impact.

Association of iron-related biomarkers with severity and mortality in COVID-19 patients.

BACKGROUND: Nutritional deficiency is associated with weaken immune system and increased susceptibility to infection. Among other nutrients, several trace elements have been shown to regulate immune responses. Iron is one of the most abundant trace elements present in our body, which is required in various biological processes. Iron has an immunomodulatory function and thus influence the susceptibility to the course and outcome of a variety of viral infections. So, this present study was aimed to study relations of different iron-related biomarkers in association to severity and mortality in SARS-CoV-2 patients. MATERIALS AND METHODS: A total of 150 individuals infected with COVID-19 and 50 healthy individuals were recruited. Cases were divided based on severity (mild, moderate, and severe) and outcome (discharged or deceased). Serum iron, TIBC, ferritin, transferrin, transferrin saturation levels were analyzed by the direct colourimetric method. RESULTS: In cases the median levels of serum iron, TIBC, transferrin, transferrin saturation and ferritin are 29 µg/dL, 132.53 µg/dL, 106.3 mg/dL, 17.74 % and 702.9 ng/dL respectively. Similarly, in controls the median levels of serum iron, TIBC, transferrin, transferrin saturation and ferritin are 53 µg/dL, 391.88 µg/dL, 313.51 mg/dL, 12.81 % and 13.52 ng/dL respectively. On comparing the cases with the controls, a significant lower level of iron, TIBC, and transferrin were found in the cases along with the significant higher levels of ferritin and transferrin saturation. On comparing the Receiver operating characteristic (ROC) curves of Iron, Ferritin, Transferrin, Transferrin sat % and TIBC in relation to survival in COVID-19 patients it was found that iron, followed by transferrin and ferritin has the highest area under the curve (AUC) with 74 %, 63 % and 61 % respectively. Further, in pairwise analysis of ROC curve, a significant difference was found between the Iron-transferrin (p < 0.01), iron-TIBC (p < 0.001) and transferrin-ferritin (P < 0.01). The multiple regression model based on Iron and transferrin outperformed any other combination of variables via stepwise AIC selection with an AUC of 98.2 %. The cutoff point according to Youden's J index is characterized with a sensitivity of 98 % and a specificity of 96.8 %, indicating that iron along with transferrin can be a useful marker that may contribute to a better assessment of survival chances in COVID-19. CONCLUSION: Our study demonstrated a significantly decreased levels of iron, TIBC, & transferrin and a significantly increased levels of ferritin and transferrin saturation in COVID-19 patients when compared with controls. Further, Iron and transferrin were observed to be a good predictor of mortality in patients with COVID-19. From the above analysis we confirm that iron-related biomarkers play an important role in the development of oxidative stress and further lead to activation of the cytokine storm. So, continuous monitoring of these parameters could be helpful in the early detection of individuals developing the severe disease and can be used to decrease mortality in upcoming new waves of COVID-19.

Assessment of DHEAS, cortisol, and DHEAS/cortisol ratio in patients with COVID-19: a pilot study.

PURPOSE: Dehydroepiandrosterone sulfate (DHEAS) is observed to be decreased in sepsis and inflammatory conditions. In the present study, we assessed the levels of DHEAS and cortisol and the DHEAS/cortisol ratio and their association with inflammatory markers in patients with COVID-19. METHODS: The study recruited 76 RT-PCR-positive COVID-19-positive patients and 79 healthy controls. The blood samples were collected and were analyzed for cortisol and DHEAS. RESULTS: We observed decreased levels of DHEAS and DHEAS/cortisol ratio and increased levels of cortisol in cases when compared with controls. DHEAS and DHEAS/cortisol ratio showed a decreasing trend with the increase in disease severity. CONCLUSION: The present study is the first of its kind comparing DHEAS levels and DHEAS/cortisol ratio in COVID-19 patients and control subjects. DHEAS, with its inhibitory effect on IL6 and activation of Tregs, may play a crucial role in immune defense mechanisms against COVID-19.

Klotho: A Possible Role in the Pathophysiology of Nephrotic Syndrome.

Klotho, encoded by the klotho gene, is associated with phosphate homeostasis. Klotho acts as a co-receptor for FGF23 for binding to its receptors. With FGF23, klotho regulates the systemic mineral homeostasis by regulation of vitamin D and parathyroid hormone. The anti-inflammatory, antifibrotic and antioxidant properties of klotho give it a cardinal role in the development of various renal diseases. The protective effect of klotho has been evident in different types of nephropathy, including diabetic nephropathy, cyclosporine A-induced nephropathy, Calcineurin inhibitors-induced nephropathy, and renal ischemic-reperfusion injury. Nephrotic syndrome is distinguished by hypoproteinemia, proteinuria, and hypercholesterolemia as a result of the aberration of the glomerular filtration barrier. The various factors and pathways associated with the pathophysiology of the nephrotic syndrome have similarities with other types of nephropathy. Despite these similarities, the role of klotho in the pathology of nephrotic syndrome remains still unexplored. This minireview builds the case for the possible role of klotho in nephrotic syndrome. The review explores the possible pathways where klotho can play a major role by identifying the similarities in the pathophysiology of nephrotic syndrome and other types of nephropathy.

Multi-omics integration and interactomics reveals molecular networks and regulators of the beneficial effect of yoga and exercise.

Background: Yoga is a multifaceted spiritual tool that helps in maintaining health, peace of mind, and positive thoughts. In the context of asana, yoga is similar to physical exercise. This study aims to construct a molecular network to find hub genes that play important roles in physical exercise and yoga. Methodology: We combined differentially expressed genes (DEGs) in yoga and exercise using computational bioinformatics from publicly available gene expression omnibus (GEO) datasets and identified the codifferentially expressed mRNAs with GEO2R. The co-DEGs were divided into four different groups and each group was subjected to protein-protein interaction (PPI) network, pathways analysis, and gene ontology. Results: Our study identified immunological modulation as a dominant target of differential expression in yoga and exercise. Yoga predominantly modulated genes affecting the Th1 and NK cells, whereas Cytokines, Macrophage activation, and oxidative stress were affected by exercise. We also observed that while yoga regulated genes for two main physiological functions of the body, namely Circadian Rhythm (BHLHE40) and immunity (LBP, T-box transcription factor 21, CEACAM1), exercise-regulated genes involved in apoptosis (BAG3, protein kinase C alpha), angiogenesis, and cellular adhesion (EPH receptor A1). Conclusion: The dissimilarity in the genetic expression patterns in Yoga and exercise highlights the discrete effect of each in biological systems. The integration and convergences of multi-omics signals can provide deeper and comprehensive insights into the various biological mechanisms through which yoga and exercise exert their beneficial effects and opens up potential newer research areas.

Validation of a novel method for determination of low-density lipoprotein cholesterol levels in Indian patients with type 2 diabetes.

BACKGROUND AND AIMS: LDL-cholesterol (LDL-C), being the primary predictor of cardiovascular disease in Type 2 diabetes (T2D), is associated with cardiovascular risk stratification and requires to be estimated with better accuracy with minimal bias. Different formulae have been devised to calculate the LDL-C from the measured lipid profile parameters. METHODS: In this analytical cross-sectional study, a total of 150 patients with T2D were studied, and blood samples were subjected for lipid profile analysis at the Central Biochemistry laboratory. Different formulae assessed calculated LDL-C. RESULTS: We observed that all formulae, except Ahmadi, underestimated the LDL-C compared to direct assay. A significant difference was observed between all calculated LDL-C and directly measured LDL-C. On linear regression analysis, the newer formula Martin's has a better approximation with direct assay (slope: 0.9708) than Friedewald (slope: 0.9477). Similarly, Martin's formula exhibited lesser bias (-13.56) in calculating LDL-C in patients with T2D compared with Friedewald's formula. CONCLUSIONS: The study demonstrated that in patients with T2D, all formulae except Ahmadi significantly underestimated the LDL-C when compared with the direct assay. The newer Martin's formula appeared to more precisely calculate LDL-C in T2D when compared with the traditional Friedewald's formula.

MicroRNAs based regulation of cytokine regulating immune expressed genes and their transcription factors in COVID-19.

BACKGROUND: Coronavirus disease 2019 is characterized by the elevation of a broad spectrum of inflammatory mediators associated with poor disease outcomes. We aimed at an in-silico analysis of regulatory microRNA and their transcription factors (TF) for these inflammatory genes that may help to devise potential therapeutic strategies in the future. METHODS: The cytokine regulating immune-expressed genes (CRIEG) were sorted from literature and the GEO microarray dataset. Their co-differentially expressed miRNA and transcription factors were predicted from publicly available databases. Enrichment analysis was done through mienturnet, MiEAA, Gene Ontology, and pathways predicted by KEGG and Reactome pathways. Finally, the functional and regulatory features were analyzed and visualized through Cytoscape. RESULTS: Sixteen CRIEG were observed to have a significant protein-protein interaction network. The ontological analysis revealed significantly enriched pathways for biological processes, molecular functions, and cellular components. The search performed in the miRNA database yielded ten miRNAs that are significantly involved in regulating these genes and their transcription factors. CONCLUSION: An in-silico representation of a network involving miRNAs, CRIEGs, and TF, which take part in the inflammatory response in COVID-19, has been elucidated. Thus, these regulatory factors may have potentially critical roles in the inflammatory response in COVID-19 and may be explored further to develop targeted therapeutic strategies and mechanistic validation.