Association Study of the ATP - Binding Cassette Transporter A1 (ABCA1) Rs2230806 Genetic Variation with Lipid Profile and Coronary Artery Disease Risk in an Iranian Population

BACKGROUND: ATP - binding cassette transporter A1 (ABCA1) plays essential roles in the biogenesis of high -density lipoprotein - cholesterol. Variations in the ABCA1 gene may influence the risk of coronary artery disease (CAD).AIM: Present study aimed to investigate the association of rs2230806 (R219K) polymorphism of ABCA1 gene with the development and severity of CAD in an Iranian population.MATERIALS AND METHODS: Our study population consisted of 100 patients with angiographically confirmed CAD and 100 controls. The genotyping of R219K mutation of ABCA1 gene was determined by PCR - RFLP method. Lipid profile was determined using routine colourimetric assays. Statistical analysis was done by SPSS - 16.RESULTS: The genotypic (P = 0.024) and allelic (P = 0.001) distribution of the ABCA1 R219K polymorphism were significantly different between the two groups. In a univariate analysis (with genotype RR as the reference), the RK genotype (OR = 0.46, 95%CI = 0.25-0.86, P = 0.020) and KK genotype (OR = 0.27, 95%CI = 0.11 – 0.66, P = 0.005) was significantly associated with a decreased risk of CAD. A multiple logistic regression analysis revealed that smoking (0.008), diabetes (P = 0.023), triglyceride (P = 0.001), HDL - cholesterol (P = 0.002) and ABCA1 KK genotype (P = 0.009) were significantly and independently associated with the risk of CAD. The association between different genotypes of R219K polymorphism with lipid profile was not significant in both groups (P > 0.05). The R219K polymorphism was significantly associated with severity of CAD (P < 0.05).CONCLUSION: The carriage of K allele of ABCA1 R219K polymorphism has a protective effect on CAD risk and correlates with a decreased severity of CAD. This protective effect seems to be mediated independently of plasma lipid levels

Amelioration effects of vitamin E, melatonin, L-carnitine, and atorvastatin, on destructive effects of busulfan in the testes of male rats: A gene expression evaluation

According to toxicity of various types of cancer treatments on different kind of cells with high division activities such as germ cells, antioxidants may protect these cells in testes against the toxic effects of the chemotherapeutic drugs. For this purpose, 24 h after busulfan treatment, 30 adult male wistar-rats were divided to six groups. Intra-peritoneally administrations of normal saline in control group and DMSO (as a busulfan solvent) in DMSO group were performed daily for 6 weeks beside the treatment contain vitamin E (Vit-E group), L-carnitine and melatonin (LM group), atorvastatin and melatonin (AM group), atorvastatin, L-carnitine, and melatonin (ALM group). After decapitation and removal of the testes, molecular evaluations were performed by the relative abundance measurement of DAZL, Bcl2, and Casp3 transcripts. The results of this study exhibited high level of expression of DAZL in Vit-E treated rats compared to control counterparts (P<0.01). The expression level of Bcl2 is significantly down-regulated in LM (P<0.008), and ALM groups (P<0.001), and the relative abundance of Casp3 transcripts was significantly lower in AM (P<0.001) and ALM (P<0.007) than that of control group. As well as, there was significant high expression of this gene in Vit E-treated rats compared to the rats of control group. In conclusion, busulfan destructive effects were moderated with Vit-E administration through regulation of the expression of DAZL. The other antioxidants used in different combinations had not amelioration effects on spermatogenesis in busulfan-induced male rats, though the positive effects of some of these antioxidants on apoptosis reduction. Keywords: Rat, Busulfan, Vitamin E, Melatonin, L-carnitine, Atorvastatin, DAZL, Bcl2, Casp

Activity of meropenem-vaborbactam against different beta-lactamase producing Klebsiella pneumoniae and Escherichia coli isolates in Iran

We evaluated the activity of meropenem-vaborbactam against different beta-lactamase producing Klebsiella pneumoniae and Escherichia coli isolates. In our study antibiotic susceptibility testing, double disk synergy test, modified Hodge test were applied. Detection of ESBL, AmpC, and carbapenemase genes was performed by PCR. Multilocus sequence typing (MLST) analysis was done on OXA-48 producing K. pneumoniae strains. Our results showed that among E. coli and K. pneumoniae isolates, 41.1% and 40% of strains produced ESBL, respectively. Additionally, the prevalence of AmpC producing K. pneumoniae and E. coli was 4% and 45.5%, respectively. Altogether 64.2% of K. pneumoniae strains and one E. coli isolate produced carbapenemase. Among OXA-48 producing K. pneumoniae strains ST3500 and ST2528 were detected by MLST. Based on the phenotypic results of this study, vaborbactam was an effective inhibitor on the third-generation cephalosporin-resistant isolates (P < 0.0001). Mer-openem-vaborbactam combination had the highest efficacy on KPC producing strains, and it had limited activity on isolates producing OXA-48 type beta-lactamases, whereas no effect was observed on NDM-1 producing isolates. Our study provided valuable information regarding the vaborbactam inhibitory effect on b-lactamase-producing strains

Activity of meropenem-vaborbactam against different beta-lactamase producing Klebsiella pneumoniae and Escherichia coli isolates in Iran

We evaluated the activity of meropenem-vaborbactam against different beta-lactamase producing Klebsiella pneumoniae and Escherichia coli isolates. In our study antibiotic susceptibility testing, double disk synergy test, modified Hodge test were applied. Detection of ESBL, AmpC, and carbapenemase genes was performed by PCR. Multilocus sequence typing (MLST) analysis was done on OXA-48 producing K. pneumoniae strains. Our results showed that among E. coli and K. pneumoniae isolates, 41.1% and 40% of strains produced ESBL, respectively. Additionally, the prevalence of AmpC producing K. pneumoniae and E. coli was 4% and 45.5%, respectively. Altogether 64.2% of K. pneumoniae strains and one E. coli isolate produced carbapenemase. Among OXA-48 producing K. pneumoniae strains ST3500 and ST2528 were detected by MLST. Based on the phenotypic results of this study, vaborbactam was an effective inhibitor on the thirdgeneration cephalosporin-resistant isolates (P < 0.0001). Meropenem-vaborbactam combination had the highest efficacy on KPC producing strains, and it had limited activity on isolates producing OXA-48 type beta-lactamases, whereas no effect was observed on NDM-1 producing isolates. Our study provided valuable information regarding the vaborbactam inhibitory effect on β-lactamaseproducing strains

Enhancing the Therapeutic Efficacy of Daunorubicin and Mitoxantrone with Bavachinin, Candidone, and Tephrosin

The capability of flavonoids in sensitizing cancer cells was demonstrated in numerous works to chemotherapy and converse multidrug resistance by modulating efflux pumps and apoptosis mechanisms. Three flavonoids, namely, bavachinin, tephrosin, and candidone, have been recently introduced to cancer treatment research presenting various activities, such as antibacterial, immunomodulatory, cell death, and anticancer. Less information exists regarding the therapeutic significance of these flavonoids in cancer treatment, especially in overcoming multidrug resistance (MDR). Here, we tempted to investigate the potency of these agents in reversing MDR by analyzing their effects as chemosensitizers on cell cytotoxicity, P-gp and ABCG2 protein expression levels, and their function on two multidrug-resistant cell lines, P-gp-overexpressing human gastric adenocarcinoma cell line (EPG85.257RDB) and ABCG2-overexpressing human epithelial breast cancer cell line (MCF7/MX). The inhibitory concentration of 10% (IC10) of bavachinin, tephrosin, and candidone in EPG85.257RDB cells was 1588.7 ± 202.2, 264.8 ± 86.15, and 1338.6 ± 114.11 nM, respectively. Moreover, these values in MCF7/MX cell were 2406.4 ± 257.63, 38.8 ± 4.28, and 27.9 ± 5.59 nM, respectively. Expression levels of ABCG2 and P-gp were not significantly downregulated by these flavonoids. Maximum levels of daunorubicin and mitoxantrone accumulations and minimum rates of drug efflux in both cell lines were detected 48 hrs posttreatment with tephrosin and bavachinin, respectively. Chemosensitization to mitoxantrone and daunorubicin treatments was, respectively, achieved in MCF7/MX and EPG85.257RDB cells in response to IC10 of bavachinin and tephrosin, independently. These effects did not follow time-dependent manner, and each flavonoid had its cell-dependent patterns. Overall, bavachinin, tephrosin, and candidone showed potency to sensitize MDR cells to daunorubicin and mitoxantrone and could be considered as attractive MDR modulators for cancer treatment. However, their action was time and cell specific

Global burden of 288 causes of death and life expectancy decomposition in 204 countries and territories and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

BACKGROUND Regular, detailed reporting on population health by underlying cause of death is fundamental for public health decision making. Cause-specific estimates of mortality and the subsequent effects on life expectancy worldwide are valuable metrics to gauge progress in reducing mortality rates. These estimates are particularly important following large-scale mortality spikes, such as the COVID-19 pandemic. When systematically analysed, mortality rates and life expectancy allow comparisons of the consequences of causes of death globally and over time, providing a nuanced understanding of the effect of these causes on global populations. METHODS The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 cause-of-death analysis estimated mortality and years of life lost (YLLs) from 288 causes of death by age-sex-location-year in 204 countries and territories and 811 subnational locations for each year from 1990 until 2021. The analysis used 56 604 data sources, including data from vital registration and verbal autopsy as well as surveys, censuses, surveillance systems, and cancer registries, among others. As with previous GBD rounds, cause-specific death rates for most causes were estimated using the Cause of Death Ensemble model-a modelling tool developed for GBD to assess the out-of-sample predictive validity of different statistical models and covariate permutations and combine those results to produce cause-specific mortality estimates-with alternative strategies adapted to model causes with insufficient data, substantial changes in reporting over the study period, or unusual epidemiology. YLLs were computed as the product of the number of deaths for each cause-age-sex-location-year and the standard life expectancy at each age. As part of the modelling process, uncertainty intervals (UIs) were generated using the 2·5th and 97·5th percentiles from a 1000-draw distribution for each metric. We decomposed life expectancy by cause of death, location, and year to show cause-specific effects on life expectancy from 1990 to 2021. We also used the coefficient of variation and the fraction of population affected by 90% of deaths to highlight concentrations of mortality. Findings are reported in counts and age-standardised rates. Methodological improvements for cause-of-death estimates in GBD 2021 include the expansion of under-5-years age group to include four new age groups, enhanced methods to account for stochastic variation of sparse data, and the inclusion of COVID-19 and other pandemic-related mortality-which includes excess mortality associated with the pandemic, excluding COVID-19, lower respiratory infections, measles, malaria, and pertussis. For this analysis, 199 new country-years of vital registration cause-of-death data, 5 country-years of surveillance data, 21 country-years of verbal autopsy data, and 94 country-years of other data types were added to those used in previous GBD rounds. FINDINGS The leading causes of age-standardised deaths globally were the same in 2019 as they were in 1990; in descending order, these were, ischaemic heart disease, stroke, chronic obstructive pulmonary disease, and lower respiratory infections. In 2021, however, COVID-19 replaced stroke as the second-leading age-standardised cause of death, with 94·0 deaths (95% UI 89·2-100·0) per 100 000 population. The COVID-19 pandemic shifted the rankings of the leading five causes, lowering stroke to the third-leading and chronic obstructive pulmonary disease to the fourth-leading position. In 2021, the highest age-standardised death rates from COVID-19 occurred in sub-Saharan Africa (271·0 deaths [250·1-290·7] per 100 000 population) and Latin America and the Caribbean (195·4 deaths [182·1-211·4] per 100 000 population). The lowest age-standardised death rates from COVID-19 were in the high-income super-region (48·1 deaths [47·4-48·8] per 100 000 population) and southeast Asia, east Asia, and Oceania (23·2 deaths [16·3-37·2] per 100 000 population). Globally, life expectancy steadily improved between 1990 and 2019 for 18 of the 22 investigated causes. Decomposition of global and regional life expectancy showed the positive effect that reductions in deaths from enteric infections, lower respiratory infections, stroke, and neonatal deaths, among others have contributed to improved survival over the study period. However, a net reduction of 1·6 years occurred in global life expectancy between 2019 and 2021, primarily due to increased death rates from COVID-19 and other pandemic-related mortality. Life expectancy was highly variable between super-regions over the study period, with southeast Asia, east Asia, and Oceania gaining 8·3 years (6·7-9·9) overall, while having the smallest reduction in life expectancy due to COVID-19 (0·4 years). The largest reduction in life expectancy due to COVID-19 occurred in Latin America and the Caribbean (3·6 years). Additionally, 53 of the 288 causes of death were highly concentrated in locations with less than 50% of the global population as of 2021, and these causes of death became progressively more concentrated since 1990, when only 44 causes showed this pattern. The concentration phenomenon is discussed heuristically with respect to enteric and lower respiratory infections, malaria, HIV/AIDS, neonatal disorders, tuberculosis, and measles. INTERPRETATION Long-standing gains in life expectancy and reductions in many of the leading causes of death have been disrupted by the COVID-19 pandemic, the adverse effects of which were spread unevenly among populations. Despite the pandemic, there has been continued progress in combatting several notable causes of death, leading to improved global life expectancy over the study period. Each of the seven GBD super-regions showed an overall improvement from 1990 and 2021, obscuring the negative effect in the years of the pandemic. Additionally, our findings regarding regional variation in causes of death driving increases in life expectancy hold clear policy utility. Analyses of shifting mortality trends reveal that several causes, once widespread globally, are now increasingly concentrated geographically. These changes in mortality concentration, alongside further investigation of changing risks, interventions, and relevant policy, present an important opportunity to deepen our understanding of mortality-reduction strategies. Examining patterns in mortality concentration might reveal areas where successful public health interventions have been implemented. Translating these successes to locations where certain causes of death remain entrenched can inform policies that work to improve life expectancy for people everywhere. FUNDING Bill & Melinda Gates Foundation

Review on the mesenchymal stem cells and their potential application in regenerative medicine

Stem cells are unspecialized cells that are capable of self-renewal and differentiate into a variety of cell types. Indeed, stem cells are able to differentiate into functional specialized cells e.g. myocardiocyte, neurocyte, osteoblast, adipocyte, chondrocyte, etc. Among stem cells, mesenchymal stem cells (MSCs) have been considered by researchers on account of having differentiation ability into variety of cells with no risk of tumorogenicity and immune system stimulation. The aim of this article is reviewing of stem cell types, their sources, MSCs, their features and characteristics, their potential in regenerative medicine and their clinical application in medicine. Information have been gathered in the present review study in 2017, by referring to the following databases; PubMed, Science Direct, Ovid Databases, Scopus, Wiley and Springer. MSCs have an ability to differentiate into various cells e.g. osteoblast, adipocyte, myocardiocyte, chondrocyte, myoblast, neurocyte, neuroglia cells, myocyte, endothelial cells, isle cells, etc. Also, it seems that MSCs have been preferred in regenerative medicine because of having immunomodulatory properties and ability of secretion of various cytokines and growth factors. Development of human knowledge in the field of producing, proliferation and differentiation of stem cells, bring the hope of using these cells in treatment of neural lesion e.g. spinal cord injury, multiple sclerosis, Alzheimer, parkinsonism, etc. Keywords: Stem cell, Mesenchymal stem cell, Regenerative medicin