Impacts of oxidative stress and anti-oxidants on the development, pathogenesis, and therapy of sickle cell disease: A comprehensive review.

Sickle cell disease (SCD) is the most severe monogenic hemoglobinopathy caused by a single genetic mutation that leads to repeated polymerization and depolymerization of hemoglobin resulting in intravascular hemolysis, cell adhesion, vascular occlusion, and ischemia-reperfusion injury. Hemolysis causes oxidative damage indirectly by generating reactive oxygen species through various pathophysiological mechanisms, which include hemoglobin autoxidation, endothelial nitric oxide synthase uncoupling, reduced nitric oxide bioavailability, and elevated levels of asymmetric dimethylarginine. Red blood cells have a built-in anti-oxidant system that includes enzymes like sodium dismutase, catalase, and glutathione peroxidase, along with free radical scavenging molecules, such as vitamin C, vitamin E, and glutathione, which help them to fight oxidative damage. However, these anti-oxidants may not be sufficient to prevent the effects of oxidative stress in SCD patients. Therefore, in line with a recent FDA request that the focus to be placed on the development of innovative therapies for SCD that address the root cause of the disease, there is a need for therapies that target oxidative stress and restore redox balance in SCD patients. This review summarizes the current state of knowledge regarding the role of oxidative stress in SCD and the potential benefits of anti-oxidant therapies. It also discusses the challenges and limitations of these therapies and suggests future directions for research and development.

Advances in biomedical applications of vitamin D for VDR targeted management of obesity and cancer.

BACKGROUND: 1,25(OH)2D3 is a fat-soluble vitamin, involved in regulating Ca2+ homeostasis in the body. Its storage in adipose tissue depends on the fat content of the body. Obesity is the result of abnormal lipid deposition due to the prolonged positive energy balance and increases the risk of several cancer types. Furthermore, it has been associated with vitamin D deficiency and defined as a low 25(OH)2D3 blood level. In addition, 1,25(OH)2D3 plays vital roles in Ca2+-Pi and glucose metabolism in the adipocytes of obese individuals and regulates the expressions of adipogenesis-associated genes in mature adipocytes. SCOPE AND APPROACH: The present contribution focused on the VDR mediated mechanisms interconnecting the obese condition and cancer proliferation due to 1,25(OH)2D3-deficiency in humans. This contribution also summarizes the identification and development of molecular targets for VDR-targeted drug discovery. KEY FINDINGS AND CONCLUSIONS: Several studies have revealed that cancer development in a background of 1,25(OH)2D3 deficient obesity involves the VDR gene. Moreover, 1,25(OH)2D3 is also known to influence several cellular processes, including differentiation, proliferation, and adhesion. The multifaceted physiology of obesity has improved our understanding of the cancer therapeutic targets. However, currently available anti-cancer drugs are notorious for their side effects, which have raised safety issues. Thus, there is interest in developing 1,25(OH)2D3-based therapies without any side effects.

Tailored nutritional interventions: A precision approach to managing gestational diabetes mellitus.

Gestational diabetes mellitus (GDM) is a risk to maternal-fetal health due to uncertain diagnostic criteria and treatment options. Luo's study demonstrated the efficacy of customized nutritional therapies in controlling GDM. Tailored strategies led to significant body weight loss, improved glucolipid metabolism, and fewer prenatal and newborn problems. This holistic approach, which emphasizes the notion of 'chrononutrition', takes into account optimal meal timing that is in sync with circadian rhythms, as well as enhanced sleep hygiene. Implementing tailored dietary therapy, managing meal timing, and ensuring appropriate sleep may improve results for women with GDM, opening up a possible avenue for multi-center trials.

Recent advances and future perspectives in the therapeutics of prostate cancer.

Prostate cancer (PC) is one of the most common cancers in males and the fifth leading reason of death. Age, ethnicity, family history, and genetic defects are major factors that determine the aggressiveness and lethality of PC. The African population is at the highest risk of developing high-grade PC. It can be challenging to distinguish between low-risk and high-risk patients due to the slow progression of PC. Prostate-specific antigen (PSA) is a revolutionary discovery for the identification of PC. However, it has led to an increase in over diagnosis and over treatment of PC in the past few decades. Even if modifications are made to the standard PSA testing, the specificity has not been found to be significant. Our understanding of PC genetics and proteomics has improved due to advances in different fields. New serum, urine, and tissue biomarkers, such as PC antigen 3 (PCA3), have led to various new diagnostic tests, such as the prostate health index, 4K score, and PCA3. These tests significantly reduce the number of unnecessary and repeat biopsies performed. Chemotherapy, radiotherapy, and prostatectomy are standard treatment options. However, newer novel hormone therapy drugs with a better response have been identified. Androgen deprivation and hormonal therapy are evolving as new and better options for managing hormone-sensitive and castration-resistant PC. This review aimed to highlight and discuss epidemiology, various risk factors, and developments in PC diagnosis and treatment regimens.

The role of NF-κB in breast cancer initiation, growth, metastasis, and resistance to chemotherapy.

Breast cancer (BC) is the second most fatal disease and is the prime cause of cancer allied female deaths. BC is caused by aberrant tumor suppressor genes and oncogenes regulated by transcription factors (TFs) like NF-κB. NF-κB is a pro-inflammatory TF that crucially alters the expressions of various genes associated with inflammation, cell progression, metastasis, and apoptosis and modulates a network of genes that underlie tumorigenesis. Herein, we focus on NF-κB signaling pathways, its regulators, and the rationale for targeting NF-κB. This review also includes TFs that maintain NF-κB crosstalk and their roles in promoting angiogenesis and metastasis. In addition, we discuss the importance of combination therapies, resistance to treatment, and potential novel therapeutic strategies including nanomedicine that targets NF-κB.

Emerging perspectives on RNA virus-mediated infections: from pathogenesis to therapeutic interventions.

RNA viruses continue to pose significant threats to global public health, necessitating a profound understanding of their pathogenic mechanisms and the development of effective therapeutic interventions. This manuscript provides a comprehensive overview of emerging perspectives on RNA virus-mediated infections, spanning from the intricate intricacies of viral pathogenesis to the forefront of innovative therapeutic strategies. A critical exploration of antiviral drugs sets the stage, highlighting the diverse classes of compounds that target various stages of the viral life cycle, underscoring the ongoing efforts to combat viral infections. Central to this discussion is the exploration of RNA-based therapeutics, with a spotlight on messenger RNA (mRNA)-based approaches that have revolutionized the landscape of antiviral interventions. Furthermore, the manuscript delves into the intricate world of delivery systems, exploring inno-vative technologies designed to enhance the efficiency and safety of mRNA vaccines. By analyzing the challenges and advancements in delivery mechanisms, this review offers a roadmap for future research and development in this critical area. Beyond conventional infectious diseases, the document explores the expanding applications of mRNA vaccines, including their promising roles in cancer immunotherapy and personalized medicine approaches. This manuscript serves as a valuable resource for researchers, clinicians, and policymakers alike, offering a nuanced perspective on RNA virus pathogenesis and the cutting-edge therapeutic interventions. By synthesizing the latest advancements and challenges, this review contributes significantly to the ongoing discourse in the field, driving the development of novel strategies to combat RNA virus-mediated infections effectively.

NOS3 gene intron 4 a/b polymorphism is associated with ESRD in autosomal dominant polycystic kidney disease patients / O polimorfismo intron 4 a/b do gene NOS3 está associado à DRET em pacientes com doença renal policística autossômica dominante

Abstract Introduction: Endothelial nitric oxide synthase (eNOS) genes have been implicated in renal hemodynamics as potent regulators of vascular tone and blood pressure. It has been linked to a reduction in plasma nitric oxide levels. Several studies have recently been conducted to investigate the role of NOS3 gene polymorphisms and end-stage renal disease (ESRD). However, the results are still unclear and the mechanisms are not fully defined. As a result, we conducted a meta-analysis to examine the relationship between NOS3 gene polymorphism and ESRD in autosomal polycystic kidney disease (ADPKD) patients. Methods: To assess the relationship between NOS3 gene polymorphism and ESRD, relevant studies published between September 2002 and December 2020 were retrieved from the PubMed (Medline), EMBASE, Google Scholar, and Web of Science databases. The pooled odds ratio (OR) and 95 % confidence interval (CI) were calculated using a fixed-effect model. To assess the heterogeneity of studies, we used Cochrane's Q test and the Higgins and Thompson I2 statistics. Results: Our meta-analysis of 13 studies showed that the presence of the two NOS3 gene polymorphisms significantly increased ESRD risk in ADPKD patients with 4a/b gene polymorphism (aa+ab vs. bb: OR=1.95, 95% CI=1.24-3.09, p=0.004). In addition, no significant association was found between the NOS3 894G>T (Glu298Asp) polymorphism and the risk of ESRD in ADPKD patients (GT+TT vs. GG: OR=1.21, 95% CI=0.93-1.58, p=0.157). There was no evidence of publication bias. Conclusions: The findings of the current meta-analysis suggest that NOS3 intron 4a/b polymorphism plays a vital role in the increasing risk of ESRD in ADPKD patients.

Resumo Introdução: Genes da óxido nítrico sintase endotelial (eNOS) têm sido implicados na hemodinâmica renal como potentes reguladores do tônus vascular e pressão arterial. Tem sido vinculado a uma redução nos níveis plasmáticos de óxido nítrico. Realizou-se recentemente vários estudos para investigar o papel de polimorfismos do gene NOS3 e doença renal em estágio terminal (DRET). Entretanto, os resultados ainda não são claros e os mecanismos não estão totalmente definidos. Como resultado, realizamos meta-análise para examinar a relação entre polimorfismo do gene NOS3 e DRET em pacientes com doença renal policística autossômica dominante (DRPAD). Métodos: Para avaliar a relação entre polimorfismo do gene NOS3 e DRET, recuperou-se estudos relevantes publicados entre Setembro-2002 e Dezembro-2020 dos bancos de dados PubMed (Medline), EMBASE, Google Scholar, Web of Science. Calculamos odds ratio (OR) e intervalo de confiança (IC) de 95% utilizando modelo de efeitos fixos. Para avaliar a heterogeneidade dos estudos, utilizamos teste Q de Cochrane e estatísticas I2 de Higgins e Thompson. Resultados: Nossa meta-análise de 13 estudos mostrou que a presença dos dois polimorfismos do gene NOS3 aumentou significativamente o risco de DRET em pacientes com DRPAD com polimorfismo do gene 4a/b (aa+ab vs. bb: OR=1,95; IC 95%=1,24-3,09; p=0,004). Ademais, não encontramos associação significativa entre polimorfismo 894G>T NOS3 (Glu298Asp) e risco de DRET em pacientes com DRPAD (GT+TT vs. GG: OR=1,21; IC 95%=0,93-1,58; p=0,157). Não houve evidência de viés de publicação. Conclusões: Achados da meta-análise atual sugerem que o polimorfismo intron 4a/b do NOS3 desempenha papel vital no aumento do risco de DRET em pacientes com DRPAD.

NOS3 gene intron 4 a/b polymorphism is associated with ESRD in autosomal dominant polycystic kidney disease patients.

INTRODUCTION: Endothelial nitric oxide synthase (eNOS) genes have been implicated in renal hemodynamics as potent regulators of vascular tone and blood pressure. It has been linked to a reduction in plasma nitric oxide levels. Several studies have recently been conducted to investigate the role of NOS3 gene polymorphisms and end-stage renal disease (ESRD). However, the results are still unclear and the mechanisms are not fully defined. As a result, we conducted a meta-analysis to examine the relationship between NOS3 gene polymorphism and ESRD in autosomal polycystic kidney disease (ADPKD) patients. METHODS: To assess the relationship between NOS3 gene polymorphism and ESRD, relevant studies published between September 2002 and December 2020 were retrieved from the PubMed (Medline), EMBASE, Google Scholar, and Web of Science databases. The pooled odds ratio (OR) and 95 % confidence interval (CI) were calculated using a fixed-effect model. To assess the heterogeneity of studies, we used Cochrane's Q test and the Higgins and Thompson I2 statistics. RESULTS: Our meta-analysis of 13 studies showed that the presence of the two NOS3 gene polymorphisms significantly increased ESRD risk in ADPKD patients with 4a/b gene polymorphism (aa+ab vs. bb: OR=1.95, 95% CI=1.24-3.09, p=0.004). In addition, no significant association was found between the NOS3 894G>T (Glu298Asp) polymorphism and the risk of ESRD in ADPKD patients (GT+TT vs. GG: OR=1.21, 95% CI=0.93-1.58, p=0.157). There was no evidence of publication bias. CONCLUSIONS: The findings of the current meta-analysis suggest that NOS3 intron 4a/b polymorphism plays a vital role in the increasing risk of ESRD in ADPKD patients.

SARS-CoV-2 infection in people with pre-existing liver disease: Further research is warranted.

Patients with severe liver disease who have been infected with severe acute respiratory syndrome coronavirus-2 (coronavirus disease 2019) frequently develop acute respiratory distress syndrome and multiple organ failure, with a high mortality rate, as a result of the hyper-proinflammatory state known as the cytokine storm. Clinicians must recognize cytokine storms earlier to avoid intensive care admission and multi-organ damage, a critical life-threatening condition with prognostic and therapeutic implications.

Gender differences in the relationship between alcohol consumption and gastric cancer risk are uncertain and not well-delineated.

The role of alcoholic and other beverage consumption in the etiology of gastric cancer is unknown. Several studies have summarized and established a significant association between heavy alcohol consumption and gastric cancer risk, but evidence on alcohol-related cancer risk is conflicting.

Association of hypercoagulation with severe acute respiratory syndrome coronavirus 2 infection

The coronavirus disease 2019 (COVID-19) pandemic has emerged as a major threat to all healthcare systems across the globe, and it was declared a public health emergency of international concern by the World Health Organization (WHO). The novel coronavirus affects the respiratory system, producing symptoms such as fever, cough, dyspnea, and pneumonia. The association between COVID-19 and coagulation has been previously reported. Due to several inflammatory changes that occur in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections such as alterations in the levels of clotting factors, platelet activation leads to thrombus formation in coronary and cerebral vessels, leading to myocardial infarction and cerebrovascular accidents, respectively.Unfortunately, the progression of hypercoagulability in COVID-19 is rapid in patients with and without comorbidities. Hence, the proper monitoring of thrombotic complications in patients with COVID-19 is essential to avoid further complications. The implementation of guidelines for antithrombotic treatments based on the presentation of the disease is recommended. This review discusses the symptoms and mechanisms of upregulated coagulation in patients with COVID-19.

Association of hypercoagulation with severe acute respiratory syndrome coronavirus 2 infection

The coronavirus disease 2019 (COVID-19) pandemic has emerged as a major threat to all healthcare systems across the globe, and it was declared a public health emergency of international concern by the World Health Organization (WHO). The novel coronavirus affects the respiratory system, producing symptoms such as fever, cough, dyspnea, and pneumonia. The association between COVID-19 and coagulation has been previously reported. Due to several inflammatory changes that occur in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections such as alterations in the levels of clotting factors, platelet activation leads to thrombus formation in coronary and cerebral vessels, leading to myocardial infarction and cerebrovascular accidents, respectively.Unfortunately, the progression of hypercoagulability in COVID-19 is rapid in patients with and without comorbidities. Hence, the proper monitoring of thrombotic complications in patients with COVID-19 is essential to avoid further complications. The implementation of guidelines for antithrombotic treatments based on the presentation of the disease is recommended. This review discusses the symptoms and mechanisms of upregulated coagulation in patients with COVID-19.

Analysis of microsatellite polymorphisms in South Indian patients with non syndromic cleft lip and palate.

Non syndromic cleft lip and/or palate (NSCLP) is a complex congenital anomaly with varying incidence among patients of different geographical origins. Multiple contributing factors are known to trigger the cleft formation. There are several genes involved in the aetiology of NSCLP and they are different in different populations. The genetic components of clefts that underlie the susceptibility to respond to the environment still remain unclear. In this study, five microsatellite polymorphisms from five candidate genes were employed to analyze the association between these genes and NSCLP in 83 patients and 90 controls. Genotyping was performed by separating and visualizing the fluorescently-labeled polymerase chain reaction (PCR) products. The association of the five microsatellite polymorphisms with NSCLP was tested by using the CLUMP v1.9 program that uses the Monte Carlo method. The genotypic distribution is in Hardy-Weinberg equilibrium in the control group for only the MSX1 and DLX3 genes. The RARA microsatellite was significantly associated with NSCLP. Our results suggest that the RARA gene is involved in pathogenesis of cleft lip and palate in South Indians.

Current concepts in genetics of nonsyndromic clefts.

Nonsyndromic cleft lip and palate is a complex genetic disorder with variable phenotype, largely attributed to the interactions of the environment and multiple genes, each potentially having certain effects. Numerous genes have been reported in studies demonstrating associations and/or linkage of the cleft lip and palate phenotypes to alleles of microsatellite markers and single nucleotide polymorphisms within specific genes that regulate transcription factors, growth factors, cell signalling and detoxification metabolisms. Although the studies reporting these observations are compelling, most of them lack statistical power. This review compiles the evidence that supports linkage and associations to the various genetic loci and candidate genes. Whereas significant progress has been made in the field of cleft lip and palate genetics in the past decade, the role of the genes and genetic variations within the numerous candidate genes that have been found to associate with the expression of the orofacial cleft phenotype remain to be determined.