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

The C-565T Polymorphism (rs2422493) of the ATP-binding Cassette Transporter A1 Gene Contributes to the Development and Severity of Coronary Artery Disease in an Iranian Population

Objectives: ATP-binding cassette transporter A1 (ABCA1) plays a pivotal role in reverse cholesterol transport from peripheral tissues back to the liver. Abnormalities in ABCA1 function may lead to dyslipidemia and coronary artery disease (CAD). We investigated the role of C-565T (rs2422493) promoter polymorphism of ABCA1 gene in the development and severity of CAD in an Iranian subpopulation. Methods: Our study population consisted of 110 angiographically-confirmed CAD patients and 110 matched controls. The severity of CAD was expressed based on the number of stenotic vessels. Genotyping of C-565T promoter polymorphism was performed using the polymerase chain reaction followed by restriction fragments length polymorphism analysis methods. Lipid profile was determined by routine colorimetric methods. Results: The distribution of ABCA1 C-565T genotypes (p = 0.035) and alleles (p = 0.017) was significantly different between the CAD and control groups. In univariate analysis (with genotype CC as reference), the TT genotype was significantly associated with an increased risk of CAD (odds ratio = 3.83; 95% confidence interval: 1.29–11.30, p = 0.014), but the CT genotype was not (p = 0.321). A multiple binary logistic regression analysis revealed that smoking, hypertension, triglyceride, cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and ABCA1 C-565T dominant genotype were significant and independent risk factors for CAD development (p 0.050). Conclusions: Our study indicated that ABCA1 C-565T polymorphism is a significant risk factor for development and severity of CAD in our population

Cardioprotective effects of mebudipine in a rat model of doxorubicin-induced heart failure

Background: Mebudipine, a dihydropyridine calcium-channel blocker (CCB), shows greater time- and voltage-dependent inhibitory effects than nifedipine. Its significant negative chronotropic effects without having considerable negative inotropic properties may make it a suitable candidate for the pharmacotherapy of heart failure (HF). This study aimed to investigate the possible beneficial action of mebudipine in a rat model of HF. Methods: The present study carried out in the Department of Pharmacology at the Iran University of Medical Sciences during the years of 2009-2011. An experimental model of HF was induced in male Wistar rats using doxorubicin (DOX). The rats were divided into five groups with seven animals in each group: normal control group, DOX-induced HF control groups, and treatment groups. The animals were administered DOX for 15 days. A consistent deterioration occurred after a four-week rest period. The animals were then treated with intraperitoneal mebudipine (0.5 mg/kg) and intraperitoneal amlodipine (0.35 mg/kg), as well as an equal volume of distilled water for 15 days. The plasma levels of big endothelin-1 (BET-1), creatine kinase-myocardial band (CKMB), lactate dehydrogenase (LDH), aspartate aminotransferase (AST), and alanine aminotransferase (ALT), as well as the clinical status (heart rate and blood pressure), were assessed before and after treatment. Statistical analysis was performed with SPSS software using parametric and nonparametric ANOVA. Results: Mebudipine and amlodipine reversed the increased plasma BET-1 values in the treated animals when compared with the HF control group (0.103 and 0.112 vs 0.231 pg/ mL, respectively). The increased plasma levels of AST, ALT, CK-MB, and LDH were also reversed in the HF animals that received mebudipine or amlodipine. Conclusion: The administration of mebudipine to HF animals, akin to amlodipine, palliated the clinical and biochemical signs of the disease in the present study. The abstract was presented in the Iranian Congress of Physiology and Pharmacology as a poster and published in the Scientific Information Database as a supplement (2015; Vol 22)

The capability of nonlinear optical characteristics as a predictor for cellular uptake of nanoparticles and cell damage

Current methods for determining the cellular effects of a treatment modality need expensive materials and much time to provide a researcher with results. The aim of this study was to evaluate the potential of nonlinear optical characteristics of cancer cells using Z-scan technique to monitor the level of cellular uptake and cell damage caused by a nanotechnology based treatment modality. Two nanocomplexes were synthesized and characterized. The first one was made of alginate hydrogel co-loaded with cisplatin and gold nanoparticles (AuNPs) named as ACA nanocomplex. The second one, named as AA nanocomplex, was the same as ACA, but without cisplatin and this AA nanocomplex was considered as the control for ACA. Different groups of CT26 mouse colon cancer cell line received various treatments of cisplatin, ACA, and AA nanocomplexes and then the samples were prepared for Z-scan studies. The MTT assay was used to evaluate the cytotoxicity induced by different treatment modalities. Transmission electron microscopy (TEM) and inductively coupled plasma-mass spectrometry (ICP-MS) were used for qualitative and quantitative assessments of the level of AuNPs cellular uptake. The trend of nonlinear optical properties changes for treated cells was in agreement with MTT, TEM and ICP-MS results. Z-scan technique was able to successfully indicate the occurrence of cell damage. It was also capable to determine the intensity of cell damage induced by ACA nanocomplex in comparison to free cisplatin. Furthermore, Z-scan results showed that it was able to discriminate the differences of optical properties of the cells incubated with ACA nanocomplex for various incubation times. Nonlinear optical characteristics of a cell may be considered as a reliable indicator to predict the level of cellular effects induced by a nanotechnology based treatment modality. The protocol suggested in this article does not waste materials, not take much time to provide the results, and it is inexpensive technique

Gold nanoparticles promote a multimodal synergistic cancer therapy strategy by co-delivery of thermo-chemo-radio therapy

Multimodal cancer therapy has become a new trend in clinical oncology due to potential generation of synergistic therapeutic effects. Herein, we propose a multifunctional nanoplatform comprising alginate hydrogel co-loaded with cisplatin and gold nanoparticles (abbreviated as ACA) for triple combination of photothermal therapy, chemotherapy and radiotherapy (thermo-chemo-radio therapy). The therapeutic potential of ACA was assessed in combination with 532 nm laser and 6 MV X-ray against KB human mouth epidermal carcinoma cells. The results demonstrated that tri-modal thermo-chemo-radio therapy using ACA induced a superior anticancer efficacy than mono- or bi-modality treatments. The intracellular reactive oxygen species (ROS) level in KB cells treated with tri-modal therapy was increased by 4.4-fold compared to untreated cells. The gene expression analysis demonstrated the up-regulation of Box pro-apoptotic factor (by 4.5-fold) and the down-regulation of Bcl-2 anti-apoptotic factor (by 0.3-fold). The massive cell injury and the appearance of morphological characteristics of apoptosis were also evident in the micrograph of KB cells caused by thermo-chemo-radio therapy. Therefore, ACA nanocomplex can be offered as a promising platform to combine photothermal therapy, chemotherapy and radiotherapy, thereby affording an opportunity for combating chemo- and radio-resistant tumors

Triple combination of heat, drug and radiation using alginate hydrogel co-loaded with gold nanoparticles and cisplatin for locally synergistic cancer therapy

Although multimodal cancer therapy has shown superior antitumor efficacy in comparison to individual therapy due to the potential generation of synergistic interactions among the treatments, its clinical usage is highly hampered by systemic dose-limiting toxicities. Herein, we developed a multi-responsive nanocomplex constructed from alginate hydrogel co-loaded with cisplatin and gold nanoparticles (AuNPs) (abbreviated as ACA) to combine chemotherapy, radiotherapy (RT) and photothermal therapy. The nanocomplex markedly improved the efficiency of drug delivery where ACA resulted in noticeably higher tumor growth inhibition than free cisplatin. The tumor treated with ACA showed an increased heating rate upon 532 nm laser irradiation, indicating the photothermal conversion ability of the nanocomplex. While RT alone resulted in slight tumor growth inhibition, thermo-chemo therapy, chemoradiation therapy and thermo-radio therapy using ACA dramatically slowed down the rate of tumor growth. Upon 532 nm laser and 6 MV X-ray, the nanocomplex could enable a trimodal thermo-chemo-radio therapy that yielded complete tumor regression with no evidence of relapse during the 90-days follow up period. The results of this study demonstrated that the incorporation of AuNPs and cisplatin into alginate hydrogel network can effectively combine chemotherapy, RT and photothermal therapy to achieve a locally synergistic cancer therapy. (C) 2020 Elsevier B.V. All rights reserved