Mitochondrial dysfunction and mitochondrial DNA mutations in atherosclerotic complications in diabetes

Mitochondrial DNA(mtDNA) is particularly prone to oxidation due to the lack of histones and a deficient mismatch repair system.This explains an increased mutation rate of mtDNA that results in heteroplasmy,e.g.,the coexistence of the mutant and wild-type mtDNA molecules within the same mitochondrion.In diabetes mellitus,glycotoxicity,advanced oxidative stress,collagen cross-linking,and accumulation of lipid peroxides in foam macrophage cells and arterial wall cells may significantly decrease the mutation threshold required for mitochondrial dysfunction,which in turn further contributes to the oxidative damage of the diabetic vascular wall,endothelial dysfunc-tion,and atherosclerosis.

Clinical correlations between chronic hepatitis C infection and decreasing bone mass density after treatment with interferon-alpha

Objective: To compare the bone mass density in chronic hepatitis patients before and after interferon-a treatment.Methods: A total of 70 patients with chronic hepatitis C were treated with interferon-a and were evaluated. The treatment dosage was three million IU three times a week for one year. All the patients underwent bone mass density detection at lumbar spine and femoral neck before and after the interferon-a treatment. All the necessary information such as age,sex, and laboratory test, history of occurrence of fractures, lifestyle, and menopause status was collected by interviewers face-to-face from participants at the research visit. Smoking was categorized by whether participants were nonsmokers or smokers. Menopause was designated if there had been complete cessation of menses for more than 12 months. All statistical analyses were performed by SPSS version 14(SPSS, Inc., Chicago, IL, USA).Results: Among 70 patients, 52% were male, 48% were female and the mean age was(57.0 ± 9.6) years(range: 24–79). Twenty-nine percent of the patients had a history of smoking. The mean body mass index was(24.4 ± 3.6) kg/m^2(range: 18.4–35.3). Of the70 cases, 21 had high fibrosis-4. The prevalence of overall fracture history was 2.9%(two patients).Conclusions: Chronic hepatitis C virus infection did increase the risk of development of metabolic bone disease in this cohort. Indeed, greater reduction of bone mass density occurs in advanced liver fibrosis. The bone loss in earlier stages of chronic hepatitis C infection is likely to result from increased bone reduction rather than decreased bone formation. Overall, these observations suggest an important role for chronic hepatitis C virus infection in increased bone turnover in osteodystrophy pathogenesis.

Single intravenous injection of CoQ₁₀reduces infarct size in a rat model of ischemia and reperfusion injury

Maintenance of mitochondrial activity and antioxidant features of coenzyme Q10 (CoQ10) could be an effective background for treatment of acute myocardial ischemia. Dietary uptake of CoQ10 is limited to only a few percent. In urgent cases, parenteral administration of CoQ10 could provide fast increase of its plasma and myocardial levels. The aim was to evaluate whether a single intravenous (i.v.) injection of solubilized CoQ10 before ischemia/reperfusion (IR) could lead to replenishment of its myocardial levels and limits subsequent myocardial IR injury. Methods: 30 min prior to coronary artery occlusion rats received i.v. solubilized CoQ10 (30 mg/kg) or saline (1 ml/kg). After 30 min of ischemia and 120 min of reperfusion, infarct zone of left ventricle (LV) and quantity of CoQ10 in LV were determined. Cardiac rhythm was monitored through the whole experiment. Results: At the beginning of reperfusion, arrhythmias were recorded in 8 (from 9) in saline and 2 (from 9) in CoQ10-treated rats. Arrhythmias in CoQ10-treated rats arose later (40 ± 8 sec) and had less duration (26 ± 14 sec);14 ± 13 sec and 52 ± 17 sec in saline treated rats respectively. At the end of reperfusion CoQ10 treated rats revealed: 2 fold higher CoQ10 content in LV (p 10 were accompanied by less infarct size (r = ﹣0.77, p i.v. injection of CoQ10 effectively increased its myocardial levels and protected heart against IR injury by diminishing the size of the irreversibly damaged myocardium, decreasing frequency and duration of arrhythmias. The infarct zone inversely correlated with the quantity of CoQ10 in LV.

Association of the level of heteroplasmy of the 15059G>A mutation in the MT-CYB mitochondrial gene with essential hypertension

AIM: To examine whether the heteroplasmy level for 15059G】A mutation in the mitochondrial genome might be associated with essential hypertension. METHODS: This cross-sectional study involved 196 unrelated participants randomly selected from general population (90 males and 106 females) who underwent a regular medical check-up at the Institute for Ath-erosclerosis Research (Moscow, Russia). One hundred and twenty of them (61%) had essential hypertension, and 76 (39%) were apparently healthy normotensive persons. The level of heteroplasmy for 15059G】A mutation occurring in the coding region of cytochrome b gene (MT-CYB) of mtDNA isolated from the blood leukocytes, was quantified using DNA pyrosequencing method. RESULTS: The 15059G】A heteroplasmy level ranged between 4% and 83%, with a median level of 31%. Between the upper and lower quartiles of 15059G】A heteroplasmy distribution, significant differences were observed for patients’ age, systolic blood pressure, and triglyceride levels. 15059G】A heteroplasmy correlated both with age (r = 0.331, P 【 0.001) and the presence of hypertension (r = 0.228, P = 0.002). Regression analysis revealed that the age explains 12% variability of 15059G】A heteroplasmy, and hypertension independently explains more 5% variability. The 15059G】A heteroplasmy exceeding 31% was found to be significantly associated with a higher risk of essential hypertension (odds ratio 2.76; P (Fisher) 0.019]. The study participants with high 15059G】A heteroplasmy level were found to have significantly higher age (P 【 0.001) and the prevalence of essential hypertension (P = 0.033), as compared to those with low 15059G】A heteroplasmy level. These observations suggested a positive correlation between the level of 15059G】A heteroplasmy and essential hypertension. CONCLUSION: This study provides the evidence of association of mtDNA 15059G】A mutation heteroplasmy with essential hypertension.

Evaluation of imatinib mesylate(Gleevec) on KAI1/CD82 gene expression in breast cancer MCF-7 cells using quantitative real-time PCR

Objective: To evaluate the effect of imatinib mesylate on cell viability, anti cancer effect through modulation of KAI1/CD82 gene expression in breast cancer MCF-7 cell line.Methods: The effects of imatinib mesylate on cell viability in MCF-7 cell line were assessed using MTT assay and IC_(50) value was determined. GAPDH and KAI1/CD82 were selected as reference and target genes, respectively. Quantitative real time PCR technique was applied for investigation of KAI1/CD82 gene expression in human breast cancer MCF-7 cells. Subsequently, the quantity of KAI1 compared to GAPDH gene expressions were analyzed using the formula; 2^(-DDCt).Results: Imatinib was showed to have a dose-dependent inhibitory effect on the viability of MCF-7 cells. CD82/GAPDH gene expression ratios were 1.322 ± 0.030(P > 0.05),2.052 ± 0.200(P < 0.05), 2.151 ± 0.270(P < 0.05) for 10, 20 and 40 mmol/L of imatinib concentrations.Conclusions: Based on the present data, imatinib mesylate might modulate metastasis by up-regulating KAI1/CD82 gene expression in human breast MCF-7 cancer cell line.

Leishmaniosis phytotherapy: Review of plants used in Iranian traditional medicine on leishmaniasis

Many native plants in traditional medicine have been used for the treatment of cutaneous leishmaniasis and the recent clinical trials have proven the efficacy of some of them. Researches conducted on these plants have shown that garlic, shallots, wormwood, yarrow, walnuts, thyme, henna plant, mimosa, aloe, wood betony, medlar, periwinkle, yeah, savory, black beans, etc. are ef ective on cutaneous leishmania. Synthetic agents in Iranian market have some disadvantages such as high cost and side ef ects and are painful in injections. Given the ef ectiveness of these plants, they can be a source of natural and safe compounds for the treatment of Leishmania. Therefore, more clinical researches should be done to determine the ef ectiveness and safety of these medicinal plants, their active ingredients and their possible toxic substances which can lead to the production of ef ective and safe drugs for leishmaniasis. It also might be an ef ective way to prepare herbal ointment on wound healing.

Hyaluronidase Proof for Endothelial Glycocalyx as Partaker of Microcirculation Disturbances

Covalent modification of bovine testicular hyaluronidase with chondroitin sulphate led to changes in the pattern of glycation of native and modified enzyme in its reaction with neutral saccharides and N-acetylhexosamines. Thus, mono- and di-saccharides inactivated the native hyaluronidase to a greater extent than the chondroitin sulfate-modified enzyme. N-acetylhexosamine, on the opposite, inactivated the modified hyaluronidase to a greater extent than the native one. These properties made it possible to use native and modified hyaluronidase as an informative research system for in vivo measurement of the predominant type of saccharide agents in the circulation. The proposed approach was experimentally substantiated by obtained results of the study on these interactions of hyaluronidase derivatives with hyaluronan fragments and their mixture. In a model of post-ischemic perfusion of the rat limb, the effect of hyaluronidase derivatives and their components on restoration of the microcirculation were tracked using laser Doppler flowmetry. Native hyaluronidase accelerated the restoration of initial level of microcirculation, but modified enzyme was markedly inhibited by glycocalyx degradation products. N-acetylhexosamine was positioned at the reducing terminal of these products as a natural label for these glycocalyx fragments. These and other data obtained under various experimental conditions supported the participation of endothelial glycocalyx in microcirculation disturbances.

Chemotactic signaling in mesenchymal cells compared to amoeboid cells

Cell chemotaxis plays a pivotal role in normal development,inflammatory response,injury repair and tissue regeneration in all organisms.It is also a critical contributor to cancer metastasis,altered angiogenesis and neurite growth in disease.The molecular mechanisms regulating chemotaxis are currently being identified and key components may be pertinent therapeutic targets.Although these components appear to be mostly common in various cells,there are important differences in chemotactic signaling networks and signal processing that result in the distinct chemotactic behavior of mesenchymal cells compared to much better studied amoeboid blood cells.These differences are not necessarily predetermined based on cell type,but are rather chosen and exploited by cells to modify their chemotactic behavior based on physical constraints and/or environmental conditions.This results in a specific type of chemotactic migration in mesenchymal cells that can be selectively targeted in disease.Here,we compare the chemotactic behavior,signaling and motility of mesenchymal and amoeboid cells.We suggest that the current model of chemotaxis is applicable for small amoeboid cells but needs to be reconsidered for large mesenchymal cells.We focus on new candidate regulatory molecules and feedback mechanisms that may account for mesenchymal cell type-specific chemotaxis.