Bosnian Journal of Basic Medical Sciences (BJBMS)
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Hepatoprotective effect of taxifolin on cyclophosphamide-induced oxidative stress, inflammation, and apoptosis in mice: Involvement of Nrf2/HO-1 signaling
Get PDFTaxifolin (TA) is a natural flavonoid found in many foods and medicinal plants with well-documented antioxidant and anti-inflammatory properties. Cyclophosphamide (CP) is an effective antineoplastic and immunosuppressive agent; however, it is associated with numerous adverse events, including hepatotoxicity. Herein, we aimed to investigate the potential protective effects of TA using a mouse model of CP-induced hepatotoxicity. Mice were co-treated with TA (25 and 50 mg/kg, orally) and CP (30 mg/kg, i.p.) for 10 consecutive days and sacrificed 24 hours later. CP induced increased transaminases (ALT and AST), alkaline phosphatase (ALP), and lactate dehydrogenase (LDH) paralleled with pronounced histopathological alterations in the liver. Moreover, hepatic tissues of CP-injected mice showed increased malondialdehyde (MDA), protein carbonyl, and nitric oxide (NO) levels, accompanied by decreased antioxidant defenses (glutathione [GSH], superoxide dismutase [SOD], and catalase [CAT]). Livers of CP-injected mice also showed increased inflammatory response (nuclear transcription factor kappa-B [NF-κB] p65 activation, increased levels of proinflammatory cytokines tumor necrosis factor alpha [TNF-α], interleukin 1 beta [IL-1β], and IL-6) and apoptosis (decreased Bcl-2 and increased Bax and caspase-3 expression levels). Remarkably, TA ameliorated markers of liver injury and histological damage in CP-injected mice. TA treatment also attenuated numerous markers of oxidative stress, inflammation, and apoptosis in the liver of CP-injected mice. This was accompanied by increased nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase 1 (HO-1) expression in the liver tissues of CP-injected mice. Taken together, this study indicates that TA may represent a promising new avenue to prevent/treat CP-induced hepatotoxicity and perhaps other liver diseases associated with oxidative stress and inflammation
Validation of Doi’s weighted average glucose as a measure of post-load glucose excursion for clinical use
Get PDFIn this study, we examined the performance of a novel index of glucose excursion (Doi’s weighted average glucose [dwAG]) in relation to the conventional measure of area under the oral glucose tolerance test (A-GTT) and the homeostatic model assessment for insulin sensitivity (HOMA-S) and pancreatic beta cell function (HOMA-B). A cross-sectional comparison of the new index was conducted using 66 oral glucose tolerance tests (GTTs) performed at different follow-up times among 27 participants who had undergone surgical subcutaneous fat removal (SSFR). Comparisons across categories were made using box plots and the Kruskal-Wallis one-way ANOVA on ranks. Passing-Bablok regression was used to compare the dwAG against the conventional A-GTT. The Passing-Bablok regression model suggested a cutoff for normality for the A-GTT of 15.14 mmol/L·2h-1 compared to the dwAG’s suggested threshold of 6.8 mmol/L. For every 1 mmol/L·2h-1 increase in A-GTT, the dwAG value increased by 0.473 mmol/L. The glucose area under the curve correlated well with the four defined dwAG categories, with at least one of the categories having a different median A-GTT value (KW Chi2 = 52.8 [df = 3], P < 0.001). The HOMA-S tertiles were also associated with significantly different levels of glucose excursion measured through both the dwAG value (KW Chi2 = 11.4 [df = 2], P = 0.003) and A-GTT measure (KW Chi2 = 13.1 [df = 2], P = 0.001). It is concluded that the dwAG value and categories serve as a simple and accurate tool that can be used for interpreting glucose homeostasis across clinical settings.
The roles of trimethylamine-N-oxide in atherosclerosis and its potential therapeutic aspect: A literature review
Get PDFCurrent research supports the evidence that the gut microbiome (GM), which consist of gut microbiota and their biologically active metabolites, is associated with atherosclerosis development. Trimethylamine-N-oxide (TMAO), a metabolite produced by the GM through trimethylamine (TMA) oxidation, significantly enhances the formation and vulnerability of atherosclerotic plaques. TMAO promotes inflammation and oxidative stress in endothelial cells, leading to vascular dysfunction and plaque formation. Dimethyl-1-butanol (DMB), iodomethylcholine (IMC) and fluoromethylcholine (FMC) have been recognized for their ability to reduce plasma TMAO by inhibiting trimethylamine lyase, a bacterial enzyme involved in the choline cleavage anaerobic process, thus reducing TMA formation. Conversely, indole-3-carbinol (I3C) and trigonelline inhibit TMA oxidation by inhibiting flavin-containing monooxygenase-3 (FMO3), resulting in reduced plasma TMAO. The combined use of inhibitors of choline trimethylamine lyase and flavin-containing monooxygenase-3 could provide novel therapeutic strategies for cardiovascular disease prevention by stabilizing existing atherosclerotic plaques. This review aims to present the current evidence of the roles of TMA/TMAO in atherosclerosis as well as its potential therapeutic prevention aspects
Analysis of GPR126 polymorphisms and their relationship with scoliosis in Marfan syndrome and Marfan-like syndrome in Mexican patients
Get PDFMarfan syndrome (MFS) is an inherited connective tissue disorder. As the spinal growth depends on delicate balance of forces, conditions that affect musculoskeletal matrix often lead to spinal deformities. A large cross-sectional study revealed a 63% prevalence of scoliosis among patients with MFS. Multi-ethnic genome-wide association studies and analyses of human genetic mutations showed that variations and mutations of G protein-coupled receptor 126 (GPR126)locus are associated with multiple skeletal defects, including shorter stature and adolescent idiopathic scoliosis. The study included 54 patients with MFS and 196 control patients. The DNA was extracted from peripheral blood using the saline expulsion method and single nucleotide polymorphism (SNP) determination was carried out using TaqMan probes. Allelic discrimination was performed by RT-qPCR. Significant differences in genotype frequencies were found for SNP rs6570507 in relation to MFS and sex (recessive model, OR 2.46, 95% CI 1.03 -5.87; P = 0.03) and rs7755109 (overdominant model, OR 0.39, 95% CI 0.16-0.91; P = 0.03). The most significant association was found in SNP rs7755109, where the frequency of genotype AG was significantly different between MFS patients with scoliosis and those without (OR 5.68, 95% CI 1.09-29.48; P=0.04). This study, for the first time, examined the genetic association of SNP GPR126 with the risk of scoliosis in patients with connective tissue diseases. The study revealed that SNP rs7755109 is associated with the presence of scoliosis in Mexican patients with MFS
Acquired atresia of the external auditory canal and canaloplasty with Thiersch graft reconstruction: Outcomes and complications
Get PDFAcquired atresia of the external auditory canal (EAC) is a rare disease characterized by otorrhea and progressive hearing loss. Clinically, it is differentiated into two stages: the wet stage and the dry stage. The dry stage does not respond to pharmacological treatment and has to be treated surgically. One surgical option is canaloplasty of the EAC with Thiersch graft reconstruction. This study aimed to report the follow-up outcomes (otomicroscopic signs and pure tone audiometry [PTA]) in patients with acquired atresia treated with this technique. Eighteen adult patients surgically treated for acquired atresia of the EAC between 2010 and 2020 were enrolled. All underwent canaloplasty with Thiersch graft reconstruction by one senior surgeon. Otomicroscopy and PTA results were evaluated before and after surgery. Postsurgical follow-up was performed at 1-3-6-12 months and then annually. Presurgical otomicroscopic examination revealed stenosis that occluded more than 75% of the EAC in all patients, and preoperative PTA showed conductive hearing loss in 89% of patients. However, postsurgical otomicroscopic examination showed that 94% of patients had a normal EAC diameter after one year, and only one patient had anterior blunting and recurrent atresia. In addition, postsurgical PTA evidenced a normal range in 89% of patients after one year. In conclusion, acquired atresia of the EAC is a troublesome disease usually associated with hearing loss. Therefore, treatment is chosen to resolve its symptoms. The results demonstrate evidence that canaloplasty with Thirsch graft may be a suitable surgical method considering the lower incidence of recurrence and the excellent hearing outcomes
Association of triglyceride/high-density lipoprotein cholesterol ratio with subclinical inflammation and 10-year cardiovascular disease risk as determined by Framingham risk scores in Korean male smokers
Get PDFVarious risk factors and the multifactorial pathophysiology of cardiovascular disease (CVD) have been studied. We focused on the interaction between insulin resistance and inflammatory processes. Thus, we analyzed the association of triglyceride/high-density lipoprotein cholesterol (TG/HDL) ratio with subclinical inflammation and CVD risk in male smokers. We retrospectively reviewed medical records from the Health Promotion Center of Severance Hospital in Korea between 2015 and 2017. Subjects were currently smoking men aged 30 to 59, with leukocyte counts within the normal range, for a total of 1,566. We grouped participants into four groups using the median TG/HDL ratio and the median leukocyte count. The odds ratio (OR) of high Framingham 10-year CVD risk (≥10%) was calculated using multiple logistic regression. The median Framingham 10-year CVD risk increased significantly from Group 1 (low leukocyte count, low TG/HDL ratio) to Group 4 (high leukocyte count, high TG/HDL ratio). The OR for Group 4 was 2.46 compared with Group 1 after adjusting for various CVD risk factors. In subgroup analysis, the OR of the highest leukocyte group was 1.57 compared to the lowest leukocyte group after adjusting for other variables. In conclusion, TG/HDL ratio and subclinical inflammation were positively related to CVD risk in Korean male smokers
Interleukin-37 suppresses the cytotoxicity of hepatitis B virus peptides-induced CD8+ T cells in patients with acute hepatitis B
Get PDFInterleukin-37 (IL-37) is a newly identified anti-inflammatory cytokine, owning immunosuppressive activity in infectious diseases. The aim of this study was to investigate the regulatory function of IL-37 on CD8+ T cells during hepatitis B virus (HBV) infection. Eighteen acute hepatitis B (AHB) patients, thirty-nine chronic hepatitis B (CHB) patients, and twenty controls were enrolled. IL-37 concentration was measured by ELISA. IL-37 receptor subunits expressions on CD8+ T cells were assessed by flow cytometry. Purified CD8+ T cells were stimulated with HBV peptides and recombinant IL-37. Perforin and granzyme B secretion was investigated by ELISPOT. Programmed death-1 (PD-1) and cytotoxic T-lymphocyte associated protein-4 (CTLA-4) mRNA expressions were semi-quantified by real-time PCR. CD8+ T cell cytotoxicity was assessed in direct contact and indirect contact coculture with HepG2.2.15 cells. Plasma IL-37 level was down-regulated and negatively correlated with aminotransferase levels in AHB patients. There were no significant differences of IL-37 receptor subunits among AHB patients, CHB patients, and controls. Exogenous IL-37 stimulation suppressed HBV peptides-induced perforin and granzyme B secretion by CD8+ T cells in AHB patients, but not in CHB patients. Exogenous IL-37 stimulation did not affect proinflammatory cytokines secretion as well as PD-1/CTLA-4 mRNA expressions in CD8+ T cells in AHB and CHB patients. Exogenous IL-37 stimulation dampened HBV peptide-induced CD8+ T cell cytotoxicity in a cell-to-cell contact manner. The current data indicated that acute HBV infection might induce down-regulation of IL-37, which might be associated with enhanced CD8+ T cell cytotoxicity and liver damage
Is hepatic resection always a better choice than radiofrequency ablation for solitary hepatocellular carcinoma regardless of age and tumor size?
Get PDFIn this study, we aimed to compare survival outcomes after receiving radiofrequency ablation (RFA) and hepatic resection (HR) for solitary hepatocellular carcinoma (HCC) with stratification by tumor size and age. A retrospective cohort was obtained from the Surveillance, Epidemiology, and End Results (SEER) database from 2004 to 2015. Patients were grouped by tumor size (0-2, 2-5, and > 5 cm) and age (>65 and ≤65). Overall survival (OS) and disease-specific survival (DSS) were assessed. For patients >65 with tumors measuring 0-2 and 2-5 cm, the HR group had better OS and DSS compared with the RFA group. For patients >65 with tumors > 5 cm, OS and DSS did not differ significantly between the RFA and HR groups (p = 0.262 and p = 0.129, respectively). For patients ≤65, the HR group had better OS and DSS compared with the RFA group regardless of tumor size. For patients with resectable solitary HCC, regardless of age, HR is the better choice not only for tumors ≤ 2 cm, but also for tumors 2-5 cm. For resectable solitary HCC with tumors ＞5 cm, HR is the better choice for patients ≤65 but for patients >65, the issue of treatment choice needs to be further studied
Increased co-expression of TIM-3 with TIGIT or 2B4 on CD8+ T cells is associated with poor prognosis in locally advanced nasopharyngeal carcinoma
Get PDFThe use of immune checkpoint inhibitors in malignant tumors improves patient outcomes. Because single-agent immune checkpoint blockade has a low objective response rate, it is meaningful to explore combined blockade of immune checkpoint receptors. We aimed to investigate the co-expression of TIM-3 with TIGIT or 2B4 on peripheral blood CD8+ T cells from patients with locally advanced nasopharyngeal carcinoma. The correlation between co-expression level and clinical characteristics and prognosis was studied to provide a basis for immunotherapy for nasopharyngeal carcinoma. Flow cytometry was used to detect TIM-3/TIGIT and TIM-3/2B4 co-expression on CD8+ T cells. The differences in co-expression between patients and healthy controls were analyzed. The correlation between co-expression of TIM-3/TIGIT or TIM-3/2B4 and the patient clinical characteristics and prognosis was examined. Also, the correlation between the TIM-3/TIGIT or 2B4 co-expression and other common inhibitory receptors was analyzed. We further validated our results using mRNA data from the Gene Expression Omnibus (GEO) database. TIM-3/TIGIT and TIM-3/2B4 co-expression was upregulated on peripheral blood CD8+ T cells from patients with nasopharyngeal carcinoma. They were both correlated with poor prognosis. There was a correlation between TIM-3/TIGIT co-expression and patient age and pathological stage, whereas TIM-3/2B4 co-expression correlated with age and sex. CD8+ T cells with elevated mRNA levels of TIM3/TIGIT and TIM3/2B4 also showed increased expression of multiple inhibitory receptors, indicating T cell exhaustion in locally advanced nasopharyngeal carcinoma. TIM-3/TIGIT or TIM-3/2B4 can be used as potential targets for combination immunotherapy in locally advanced nasopharyngeal carcinoma
The role of Rapsyn in neuromuscular junction and congenital myasthenic syndrome
Get PDFRapsyn, an intracellular scaffolding protein associated with the postsynaptic membranes in the neuromuscular junction (NMJ), is critical for nicotinic acetylcholine receptor clustering and maintenance. Therefore, Rapsyn is essential to the NMJ formation and maintenance, and Rapsyn mutant is one of the reasons causing the pathogenies of congenital myasthenic syndrome (CMS). In addition, there is little research on Rapsyn in the central nervous system (CNS). In this review, the role of Rapsyn in the NMJ formation and the mutation of Rapsyn leading to CMS will be reviewed separately and sequentially. Finally, the potential function of Rapsyn is prospected