Genetic insights into bladder cancer: the impact of SIRT1 gene polymorphism.

Bladder cancer (BC) has shown a significant global health concern with distinct pathological, genetic, and epigenetic characteristics. Its prevalence is influenced by various risk factors, including age, gender, and genetic predisposition. This study investigates the association between BC and the Sirtuin 1 (SIRT1) gene polymorphism rs369274325 in the Turkish population. Genomic DNA was isolated from peripheral blood samples and genotyping of rs369274325 polymorphism in SIRT 1 was investigated in 200 individuals (in 100 Turkish bladder cancer patients and 100 healthy individuals as the control group.) by real-time PCR. Demographic information, smoking and alcohol consumption status was analyzed by statistical analysis. Statistical analysis was performed by Pearson's Chi-square test. Smoking and alcohol consumption were significantly higher in BC patients compared to controls (p < 0.00018 and p < 0.0001, respectively). The genotypic distribution of SIRT1 rs369274325 did not show a significant difference between BC patients and controls (p = 0.5550). BC, influenced by genetic and environmental factors, has been linked to various gene mutations. SIRT1, involved in diverse physiological processes, is proposed to play a role in BC. However, our study did not find a significant association between SIRT1 rs369274325 polymorphism and BC in the Turkish population.

Unraveling the blood microbiome: novel insights into inflammasome responses in Crohn's disease.

OBJECTIVE: Crohn's disease (CD), an inflammatory bowel disease with unknown etiology, is influenced by genetic, environmental, and immunological factors. This study aimed to analyze the blood microbiome and inflammasome responses, emphasizing NLRP3 protein expression and IL-1ß and IL-18 plasma levels, between Crohn's patients and healthy subjects. METHODS: A total of 40 volunteers were included in this study. The 16S rRNA technique was used to sequence the V3-V4 regions of the blood sample. NLRP3 protein levels in plasma were ascertained through Western Blot, and IL-1ß and IL-18 plasma profiles were examined using ELISA. RESULTS: Analysis highlighted five unique phyla in patients' plasma, emphasizing the role of the blood microbiome in CD. Compared to controls, Crohn's patients exhibited elevated NLRP3 protein expression. Plasma IL-1ß levels were diminished in patients (P = 0.0041), whereas IL-18 levels were comparably higher (P = 0.8209). In patients with CD, the presence of Staphylococcus sciuri in blood samples highlights its potential role in the disease's onset. The study also underscored the interplay between dietary habits, specifically increased meat consumption, and the progression of CD. CONCLUSION: Our pioneering research discerns the variations in the blood microbiome and inflammasome responses between Crohn's patients and healthy individuals. Significant microbiome alterations and the detection of the Staphylococcus sciuri pathogen in Crohn's patients were notable. The pronounced NLRP3 protein in patients suggests its potential as a diagnostic biomarker. Future explorations into IL-1ß and IL-18 pathways promise to unveil innovative insights into CD.

Adoptive T-cell therapies to overcome T cell-dependent immune dysregulations in COVID-19.

Coronavirus disease 2019 (COVID-19) pandemic has been an important global interest that affected millions of people, and it requires a deep investigation of the disease immunology for developing further therapeutic applications. Adoptive T cell therapy promises to address T cell-dependent immune dysregulation in COVID-19 patients by the generation of specific T cell clones against virus-specific antigens. Additionally, targeting B cell-dependent protection through COVID-19 vaccines, which have been developed in the recent year, possessed sufficient prevention for spreading the virus, since the cases and deaths related to COVID-19 tend to decrease after the vaccination. However, adoptive cell therapies are now encouraging scientists to deal with pathological challenges like inadequate T cell-dependent immune response or lymphopenia, since they are the most frequent outcome of severe infection, especially in immunocompromized patients. In this review, the current knowledge of immunopathology of COVID-19 was aimed to be highlighted along with the T cell responses against SARS-CoV-2 to comprise a basis for therapeutics. Moreover, current therapeutics and treatment strategies for COVID-19 were discussed to evaluate possible agents. Furthermore, the use of adoptive T cell therapy representing an emerging therapeutic approach was purposed to be presented comprehensively against SARS-CoV-2 infection. Even though further studies are needed to fully understand T cell response against SARS-CoV-2 in order to develop therapies to provide long term and efficient protection, adoptive cell therapies now meet the demand for a large population of people who suffer immunocompromization, considering the previous usage of the technique for different infectious diseases.

The Prophylactic Effects of Metoprolol, Diltiazem, and Pilocarpine on Hypoglycemia-Induced Prolongation of QT Interval.

Background Insulin-induced hypoglycemia has been demonstrated to prolong the corrected QT (QTc) interval. Prolongation of the QTc interval, especially in diabetic patients using insulin, can cause fatal ventricular arrhythmias. The aim of this study was to evaluate the effects of metoprolol, diltiazem, and pilocarpine on hypoglycemia-induced QTc prolongation. Methods Thirty male rats were randomly distributed into the following five groups: Group 1 (1 mL/kg saline, n=6), Group 2 (40 U/kg crystalline insulin + saline, n=6), Group 3 (40 U/kg crystalline insulin + 1 mg/kg metoprolol, n=6), Group 4 (40 U/kg crystalline insulin + 0.8 mg/kg pilocarpine, n=6), and Group 5 (40 U/kg crystalline insulin + 2 mg/kg diltiazem, n=6). Three hours after insulin injection, the blood glucose level was measured in all groups. Blood glucose <40 mg/dl was defined as hypoglycemia. Electrocardiograms (ECG) were taken in lead I (DI), and QTc was calculated by using Bazett's formula. Results Group 2 (insulin + saline) showed that it had a significantly prolonged QTc interval as compared to the control group (p<0.0001). However, treatments of the rats with metoprolol, pilocarpine, and diltiazem significantly prevented prolongation of the QTc interval as compared to the insulin + saline group (p<0.005, p<0.005, and p<0.01, respectively). Conclusion The findings of the present study demonstrated the efficacy of metoprolol, pilocarpine, and diltiazem in the prevention of hypoglycemia-induced QTc prolongation in male rats.

Determination of B- and T- cell epitopes for Helicobacter pylori cagPAI: An in silico approach.

BACKGROUND/AIMS: Helicobacter pylori is classified as a gram-negative bacteria and can cause significant diseases, including gastric cancer, mucosa-associated lymphoid tumor, peptic ulcer, and chronic gastritis. Recent studies have shown that some autoimmune diseases are also associated with H. pylori. In the past decades, polymorphisms of certain genes of H. pylori, mechanisms and strains of H. pylori, and new therapeutic approaches have continued to be defined. Bioinformatic tools continue to be used in drug design and vaccine design. This study aimed to investigate the cag pathogenicity island (cagPAI) of H. pylori using an in silico approach, which could contribute to vaccine studies. MATERIALS AND METHODS: The pathogenicity island of H. pylori was obtained from GenBank and analyzed with ClustalW software. Structures of cag Virb11 (Hp0525) and an inhibitory protein (Hp1451) were obtained, and codon optimization and secondary and tertiary structure prediction for the cagPAI of H. pylori were analyzed using Garnier-Osguthorpe-Rabson IV secondary structure prediction method and self-optimized prediction method with alignment software. The BcePred prediction server was used to distinguish linear B-cell epitopes, and prediction of T-cell was obtained with NetCTL and MHCPred. RESULTS: According to the physicochemical parameters, the cagPAI of H. pylori was analyzed and found to be stable, and 2 B-cell epitopes of cagPAI of H. pylori and 2 T-cell epitopes of cagPAI were found in this study. CONCLUSION: B- and T-cell epitopes that we have identified can induce both humoral and cellular immune responses. Thus, these epitopes have a potential for vaccine studies. Consequently, this in silico analysis should be combined with other pieces of evidence, including experimental data, to assign function.

Polymorphisms in Toll-like receptors 1, 2, 5, and 10 are associated with predisposition to Helicobacter pylori infection.

OBJECTIVE: Toll-like receptors (TLRs) are significant receptors to the innate immune system which symbolizes a family of pattern recognition receptors. We aimed to investigate associations between rs4833095 polymorphism of TLR1, rs3804099 polymorphism of TLR2, rs5744174 polymorphism of TLR5, and rs10004195 polymorphism of TLR10 in dyspeptic individuals with Helicobacter pylori infection. METHODS: Genomic DNA was isolated and genotyping of rs4833095 polymorphism in TLR1, rs3804099 polymorphism in TLR2, rs5744174 polymorphism in TLR5, and rs10004195 polymorphism in TLR10 were investigated in 400 individuals (205 in dyspeptic individuals with H. pylori-positive subjects and 195 dyspeptic individuals with H. pylori-negative subjects) by real-time PCR. Statistical analysis was performed by Pearson's Chi-square test. RESULTS: According to our study; rs4833095 polymorphism in TLR1 C allele, rs3804099 polymorphism in TLR2 C allele, rs5744174 polymorphism in TLR5 C allele, and rs10004195 polymorphism in TLR10 A allele increased the risk of H. pylori infection [odds ratio (OR), 2.01; 95% confidence interval (CI), 1.39-3.16; OR, 1.78; 95% CI, 1.19-2.6; OR, 1.87; 95% CI, 1.25-2.78; OR, 2.66; 95% CI, 1.72-4.099, respectively]. CONCLUSION: This is the first study that investigates TLRs in H. pylori infection in Turkey. Our findings may support the hypothesis that polymorphisms in certain TLRs may cause a genetic predisposition to H. pylori-related gastric problems.

mRNA Expression Profile of SFKs and Involvement of SFKs in the Regulation of LPS-Induced Erk1/2 Signaling in PBMCs of Active BD Patients.

BACKGROUND: Behcet's Disease (BD) is a multisystemic inflammatory disorder affecting large vessels, lungs joints, gastrointestinal and neurological systems. The pathogenesis of BD remains poorly understood. Identifying the key signaling pathway is crucial for a complete understanding of the pathogenesis of BD. OBJECTIVE: The aim of this study was to determine mRNA expression level of Src family kinases (SFKs) members and their involvement in lipopolysaccharide (LPS)-induced mitogen-activated protein kinases (MAPKs) regulation in peripheral blood mononuclear cells (PBMCs) of active BD patients. METHODS: Twenty- five active BD patients and twenty-five healthy controls were included in the study. PBMCs were isolated from total blood by density gradient centrifugation. The mRNA expression levels of SFKs members were measured by real-time quantitative PCR (RT-qPCR). The effect of SFKs activity on LPS-induced activation MAPKs (Erk1/2, p38 and JNK) was examined by Western blot. RESULTS: The mRNA expression levels of Hck, Src, Lyn, Yes and Fyn were found to be slightly decreased in active BD patients compared to the control subjects, but a slight change in mRNA level of SFKs members did not impact on protein levels and protein activity. LPS-induced Erk1/2 phosphorylation was significantly increased in the absence of SFKs activity in active BD patients. However, inhibition of SFKs activity had no effect on LPS-induced phosphorylation of p38 and JNK in both controls and active BD patients. CONCLUSION: SFKs downregulate LPS-induced Erk1/2 phosphorylation in PBMCs of active BD patients.

Pharmacological Inactivation of Src Family Kinases Inhibits LPS-Induced TNF-α Production in PBMC of Patients with Behçet's Disease.

Behçet's disease (BD) is a multisystemic chronic inflammatory disease characterized by relapsing oral and genital ulcers, uveitis, and skin lesions. The pathogenesis of BD is still unknown. Aberrant production of some cytokines/chemokines plays an important role in the pathogenesis of various inflammatory diseases. Revealing a key signaling regulatory mechanism involved in proinflammatory cytokines/chemokines production is critical for understanding of the pathogenesis of BD. The aim of this study was to determine the role of Src family kinases (SFKs) in production of some LPS-induced proinflammatory cytokines/chemokines in peripheral blood mononuclear cells (PBMC) of active BD patients. Chemical inhibition of SFKs activity impaired LPS-induced TNF-α production in PBMC of active BD patients, suggesting that modulating SFKs activity may be a potential target for BD treatment.

The prophylactic effects of folic acid and vitamin E against valproic acid during fetal thymus development: an ultrastructural study / Los efectos profilácticos del ácido fólico y la vitamina E contra el ácido valproico durante el desarrollo fetal del timo: un estudio ultraestructural

To evaluate histopathologic differences in the thymus of Wistar Albino rat fetuses prenatally exposed to valproic acid (VPA), folic acid (FA) and vitamin E (Vit-E). VPA (400 mg/kg), FA (400 mcg/kg) and Vit -E (250 mg/kg) were administered to rats on each of gestation days 8, 9 and 10. The fetuses (n:24) were divided into four groups: control, VPA, VPA+Vit-E and VPA+FA groups. On the 20th day of gestation, all pregnant rats were sacrificed and the fetuses were extracted. Thin sections from thymus of live fetuses were stained with uranyl acetate-lead citrate and were examined under transmission electron microscope. The histopathological findings of control group was normal. In VPA group, it showed extensive degenerative changes by VPA were on all tissue compartments when compared to controls. In VPA-FA group, vacuoles, mitochondrial cristalysis and swelling were decreased in cytoplasm. In VPA-Vit-E group, lipid storage and vacuolization were observed. Mitochondrial cristalysis decreased. Our aim in the present study is to analyze histopathological changes which may occur in a high risk experimental model after giving of VPA. In addition, protective roles of the administration of FA and Vit-E are assessed.

Se realizó este estudio para evaluar las diferencias histopatológicas en el timo de fetos de ratas Wistar Albinas expuestas prenatalmente a ácido valproico (VPA), ácido fólico (AF) y vitamina E (Vit-E). VPA (400 mg/kg), FA (400 mcg/kg) y vitamina E (250mg/kg) administradas a ratas en los días 8, 9 y 10 de gestación. Los fetos (n=24) fueron divididos en cuatro grupos: control, APV, APV + vitamina E y VPA + FA. En el día 20 de gestación, todas las ratas preñadas fueron sacrificadas y los fetos fueron extraídos. Se obtuvieron secciones delgadas del timo de los fetos y se tiñeron con citrato de uranilo - acetato de plomo, siendo examinados al microscopio electrónico de transmisión. Los hallazgos histopatológicos del grupo control fueron normales. En el grupo VPA, se observaron cambios degenerativos en todos los compartimentos de tejido en comparación con los controles. En el grupo VPA+FA, las vacuolas, cristalisis mitocondrial e inflamación se redujeron en el citoplasma. En grupo VPA + Vitamina E, se observó el almacenamiento de lípidos y vacuolización. La cristalisis mitocondrial disminuyó. El estudio permitió analizar los cambios histopatológicos que pueden ocurrir en un modelo experimental de alto riesgo después de la administración de VPA, además, las funciones de protección por la administración de AF y vitamina E.