Genetic Polymorphisms of Gene Methionine Synthase Reductase (MTRR) and Risk of Urinary Bladder Cancer.

Methionine synthase reductase (MTRR) gene involved in the signaling for production of enzyme called methionine synthase reductase that use for the synthesis of methionine, which further used in DNA replication and repair. Genetic variation in MTRR gene may alter the susceptibility of developing urinary bladder cancer. The present study undertaken to identify the contribution of genetic polymorphisms in the MTRR gene on the selected polymorphic sites including c.66A>G and c.524C>T towards urinary bladder cancer risk. Direct-DNA sequencing method was applied for the observation of genotyping distribution of MTRR c.66A>G and c.524C>T polymorphisms in 232 histopathological confirmed cases of transitional cell carcinoma (TCC) of urinary bladder cancer and 250 age-, sex- and ethnicity-matched cancer free controls. With significant difference (p = 0.05) of genotype analysis further corresponding Odds ratio (OR) and 95% confidence interval (CI) were calculated. Multivariable logistic regression analysis was applied for adjusting significant confounder variables. Haploview software (version 4.2) was used to perform pairwise Linkage Disequilibrium (LD) analysis. Age (p = 0.01), Habit of smoking (p = 0.05), tobacco consumption (p = 0.001) and diet (p = 0.02) were significantly differed between cases and controls. Both the MTRR substitution showed higher risk of developing urinary bladder cancer (p = <0.001), although this effect alters in multivariable logistic regression analysis in a protective association for both the substitution. No LD observed between the c.66A>G and c.524C>T substitutions. In conclusion, MTRR c.66A>G and c.524C>T substitutions showed a joint effect with the other associated risk factors. Further studies with a greater number of subjects of different ethnicity and polymorphisms are recommended for the better understanding urinary bladder cancer etiology and to screen the population who are at higher risk of developing urinary bladder cancer.

Extracellular vesicles in neurodegenerative diseases: A systematic review.

Introduction: Extracellular vesicles (EVs) are known to have a significant role in the central nervous system (CNS) and neurodegenerative disease. Methods: PubMed, Scopus, ISI Web of Science, EMBASE, and Google Scholar were used to identify published articles about EV modifications (2012 to Feb 2022). Results: In total, 1,435 published papers were identified among the searched articles, with 1,128 non-duplicate publications being identified. Following the screening of titles and abstracts, 214 publications were excluded; following the full-text screening of 93 published articles, another 33 publications were excluded. The remaining 60 studies were considered. The kappa statistic of 0.868 indicated that the raters were highly reliable. Furthermore, the inter-reliability and intra-reliability coefficients were found to be 0.931 and 0.908, respectively, indicating strong reliability and consistency between the eligible studies identified by the raters. A total of 27 relevant studies demonstrated the role of EVs as therapeutic and diagnostic biomarkers in neurodegenerative diseases. Of note, 19 and 14 studies, respectively, found EVs to be pioneering in diagnostic and therapeutic roles. Discussion: EVs play an important role in the central nervous system (CNS), aiding in cell-to-cell communication and serving as a diagnostic marker and therapeutic target in a variety of neurodegenerative diseases. EVs are the home of several proteins [including-synuclein (-syn) and tau proteins], lipids, and genetic materials such as DNA and RNA. The presence of novel miRNAs in EVs suggests biomarkers for the diagnosis and screening of neurodegenerative disorders. Furthermore, EVs play an important role in the pathogenesis of such disorders. This systematic review discussed the current state of EVs' role in neurological diseases, as well as some preclinical studies on the therapeutic and diagnostic potential of EVs.

Role of the circulatory interleukin-6 in the pathogenesis of gliomas: A systematic review.

BACKGROUND: Glioma is the most common primary tumor in the brain originating from glial cells. In spite of extensive research, the overall survival rate is not enhanced. A number of published articles observed differentially circulating levels of cytokines in glioma. Interleukin-6 (IL-6) protein coded by IL-6 gene is regulated by the immune system and it has been found to have a significant role in progression and apoptosis resistance of glioma. AIM: To review the role of circulatory IL-6 in the development and progression of glioma and its utility as a biomarker. METHODS: Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines were applied to filter the relevant studies based on inclusion and exclusion criteria. We used a combination of keywords and the Reference Citation Analysis (RCA) tool to search the potential studies and performed data extraction from selected studies. RESULTS: The published results were inconsistent; however, most studies showed a significantly higher IL-6 level in glioma cases as compared to controls. Comparative IL-6 level among the different grades of glioma showed a higher level with low-grade gliomas and lower level with high-grade gliomas. CONCLUSION: IL-6 level significantly differed between cases and controls, and among different cancer stages, which shows its potential as a diagnostic and prognostic marker.

Newer Horizon of Mesenchymal Stem Cell-Based Therapy in the Management of SARS-CoV-2-Associated Mucormycosis: A Safe Hope for Future Medicine.

SARS-CoV-2-infected patients are reported to show immunocompromised behavior that gives rise to a wide variety of complications due to impaired innate immune response, cytokine storm, and thrombo-inflammation. Prolonged use of steroids, diabetes mellitus, and diabetic ketoacidosis (DKA) are some of the factors responsible for the growth of Mucorales in such immunocompromised patients and, thus, can lead to a life-threatening condition referred to as mucormycosis. Therefore, an early diagnosis and cell-based management cosis is the need of the hour to help affected patients overcome this severe condition. In addition, extended exposure to antifungal drugs/therapeutics is found to initiate hormonal and neurological complications. More recently, mesenchymal stem cells (MSCs) have been used to exhibit immunomodulatory function and proven to be beneficial in a clinical cell-based regenerative approach. The immunomodulation ability of MSCs in mucormycosis patient boosts the immunity by the release of chemotactic proteins. MSC-based therapy in mucormycosis along with the combination of short-term antifungal drugs can be utilized as a prospective approach for mucormycosis treatment with promising outcomes. However, preclinical and in mucormyIn mucormycosis, the hyphae of clinical trials are needed to establish the precise mechanism of MSCs in mucormycosis treatment.

Mesenchymal Stromal Cell-Derived Tailored Exosomes Treat Bacteria-Associated Diabetes Foot Ulcers: A Customized Approach From Bench to Bed.

Exosomes are nano-vesicles of endosomal origin inherited with characteristics of drug delivery and cargo loading. Exosomes offer a diverse range of opportunities that can be exploited in the treatment of various diseases post-functionalization. This membrane engineering is recently being used in the management of bacteria-associated diabetic foot ulcers (DFUs). Diabetes mellitus (DM) is among the most crippling disease of society with a large share of its imposing economic burden. DM in a chronic state is associated with the development of micro- and macrovascular complications. DFU is among the diabetic microvascular complications with the consequent occurrence of diabetic peripheral neuropathy. Mesenchymal stromal cell (MSC)-derived exosomes post-tailoring hold promise to accelerate the diabetic wound repair in DFU associated with bacterial inhabitant. These exosomes promote the antibacterial properties with regenerative activity by loading bioactive molecules like growth factors, nucleic acids, and proteins, and non-bioactive substances like antibiotics. Functionalization of MSC-derived exosomes is mediated by various physical, chemical, and biological processes that effectively load the desired cargo into the exosomes for targeted delivery at specific bacterial DFUs and wound. The present study focused on the application of the cargo-loaded exosomes in the treatment of DFU and also emphasizes the different approaches for loading the desired cargo/drug inside exosomes. However, more studies and clinical trials are needed in the domain to explore this membrane engineering.

Mesenchymal Stem Cell-Derived Exosomes Exhibit Promising Potential for Treating SARS-CoV-2-Infected Patients.

The novel coronavirus severe acute respiratory syndrome-CoV-2 (SARS-CoV-2) is responsible for COVID-19 infection. The COVID-19 pandemic represents one of the worst global threats in the 21st century since World War II. This pandemic has led to a worldwide economic recession and crisis due to lockdown. Biomedical researchers, pharmaceutical companies, and premier institutes throughout the world are claiming that new clinical trials are in progress. During the severe phase of this disease, mechanical ventilators are used to assist in the management of outcomes; however, their use can lead to the development of pneumonia. In this context, mesenchymal stem cell (MSC)-derived exosomes can serve as an immunomodulation treatment for COVID-19 patients. Exosomes possess anti-inflammatory, pro-angiogenic, and immunomodulatory properties that can be explored in an effort to improve the outcomes of SARS-CoV-2-infected patients. Currently, only one ongoing clinical trial (NCT04276987) is specifically exploring the use of MSC-derived exosomes as a therapy to treat SARS-CoV-2-associated pneumonia. The purpose of this review is to provide insights of using exosomes derived from mesenchymal stem cells in management of the co-morbidities associated with SARS-CoV-2-infected persons in direction of improving their health outcome. There is limited knowledge of using exosomes in SARS-CoV-2; the clinicians and researchers should exploit exosomes as therapeutic regime.

Significance of Vitamin D on the Susceptibility of Gestational Diabetes Mellitus - A Meta-Analysis.

Vitamin D plays an important role in glucose tolerance by stimulating insulin secretion and evidences suggest a contradictory result on the association between vitamin D status and risk of developing gestational diabetes mellitus (GDM). The present updated meta-analysis has been undertaken to find out the joined effect of vitamin D status on the risk of effect GDM considering previously published articles. Data were collected through literature search using electronic databases to retrieve relevant published research articles using various combinations of the following keywords, "vitamin D," "vitamin D deficiency," "cholecalciferol," "25-hydroxyvitamin D," "25(OH) D," "gestational diabetes mellitus," and "GDM." A total of 36 studies including 7,596 GDM cases and 23,377 non-GDM controls were involved in this study. Overall, pooled meta-analysis showed that pregnant women diagnosed with GDM have 18% higher risk of GDM risk when compared with controls [odds ratio (OR) = 1.18, 95% confidence interval (CI) 1.10-1.25; P = 0.00] with high heterogeneity (I2 = 73.29). The mean difference was also significantly different between cases and controls (OR = -0.18, 95% CI - 0.22 to - 0.14; P = 0.00). Subgroup analysis showed significant results with age more than 30 years, Asian and European regions, and case-control, cross-sectional, and nested case-control study design. Low concentration of vitamin D is associated with the development of GDM. Although in future more studies especially systematically designed clinical trials based on vitamin D supplementation with large sample size on different population are needed to elucidate the exact concentration of vitamin D during pregnancy as well as before and after pregnancy.

Use of flow cytometry in forensic medicine: Current scenario and future prospects.

Several methodologies are being used on different biological, physical and chemical indicators to determine the postmortem interval (PMI); however, most of them are not completely accurate. Flow cytometry is an emerging technology widely used for single cell analysis in the field of clinical pathology. Studies on flow cytometry and its application in the field of forensic medicine were retrieved from systematic web searched of different databases including "MEDLINE", "ScienceDirect", "PubMed" and "Google Scholar" using keywords forensic science; forensic medicine; forensic investigation; flow cytometry; DNA; postmortem interval; vitreous humour with the last search performed in January 2018. A total of 43 publications have been reviewed, and out of them 22 studies met our criteria and have been cited in this article. A handful of studies have evaluated the application of flow cytometry in forensic medicine for estimation of the PMI and identification of the perpetrator of sexual assault cases. Flow cytometry is also useful for quantifying the ABH antigens in red blood cells as well as in other human samples that can be further used for personal identification. In conclusion, flow cytometry is more sensitive, faster and easy compared to the other methods of investigation, thus making it a preferred method. However, a large numbers of studies with the application of flow cytometry on different cases of death are required to establish a universally accepted rate of DNA degradation to avoid errors in judgment.

Functional polymorphisms in the IL6 gene promoter and the risk of urinary bladder cancer in India.

BACKGROUND: Interleukin-6 is a multifunctional cytokine, which plays a key role in tumor proliferation and differentiation. Variations in its gene (IL6) sequence may affect the risk of developing various cancers, including urinary bladder cancer. The present study was done to find the association of functional polymorphisms in the IL6 promoter with urinary bladder cancer. MATERIALS AND METHODS: Single nucleotide polymorphisms were genotyped in histologically confirmed 232 cases of urinary bladder cancer and 250 healthy controls. The controls subjects were matched to the cases by age, sex, and ethnicity. Genotyping of the polymorphisms (-174G>C; -572G>C, -596A>G) was undertaken by direct DNA sequencing. The level of association between the genotypes and urinary bladder cancer risk was estimated by odds ratios and 95% confidence intervals generated by applying the chi-square test. Linkage disequilibrium (LD) between SNPs and haplotype analysis were performed using Haploview software. RESULT: Significantly higher number of smokers (p=0.047), tobacco chewers (p=<0.001) and those with non-vegetarian food habits (p=0.016) were seen in the case group. The distribution of genotypes at -174G>C locus differed significantly between cases and controls and the variant genotypes GC+CC were significantly rarer in the cases (p=0.00073; OR=0.52 95% CI 0.35-0.75). Variant genotypes (GC+CC) were more common in grade I than grade III tumors (p=0.032), further suggesting a protective effect. No LD was found between the SNPs; however, the frequency of haplotype AGC was significantly lesser in the cases than controls (p=0.0103), suggesting a protective effect. Genotype distribution at the other two loci (-572G>C and -596A>G) did not show association with bladder cancer. CONCLUSIONS: IL6 (-174G>C) substitution confers significant protection against the risk of urinary bladder cancer in the study population, while other substitutions in this gene (-572G>C and -596A>G) do not affect the risk. In general, there is a lack of studies on the cytokine gene polymorphisms in urinary bladder cancer.

c.29C>T polymorphism in the transforming growth factor-ß1 (TGFB1) gene correlates with increased risk of urinary bladder cancer.

TGF-ß1 is a pleiotropic cytokine, which plays a dual role in tumor development. In the early stages, it inhibits the growth of tumor while in the late stages of carcinoma, it promotes tumor growth. The purpose of this study was to analyze the distribution of the TGFB1 gene polymorphisms between cases and controls so as to assess their correlation with bladder cancer risk. This study included 237 cases of urinary bladder cancer and 290 age matched controls from the same ethnic background. Three polymorphisms in the TGFB1 gene, c.29C>T (rs-1800470), c.74G>C (rs-1800471) and +140A>G (rs-13447341), were analyzed by direct DNA sequencing. Statistical analyses revealed no significant differences in the demographical data, except that the frequencies of smokers and non-vegetarians were higher in the cases. Eighty percent of the bladder cancer patients had superficial transitional cell carcinoma, and 53.16% and 26.31% of the patients were in grade I and grade II, respectively. We found that c.29C>T substitution increased the risk of bladder cancer significantly and recessive model of analysis was the best fitted model (p=0.004; OR=1.72 95% CI 1.18-2.50). A significantly higher risk in the recessive form was also suggested by co-dominant analysis showing that the homozygous form (TT) was a significant risk factor in comparison to CC and CT genotypes. The other two polymorphisms, c.74G>C (p=0.18, OR=0.67 95% CI 0.37-1.21) and +140A>G (p=0.416, OR=0.77 95% CI 0.41-1.45) did not affect the risk of urinary bladder cancer. In conclusion, we found that the TGFB1 c.29C>T substitution increases the risk of bladder cancer significantly while c.74G>C and +140A>G polymorphisms do not affect the risk.