Iram Murtaza

miR-23a functions downstream of NFATc3 to regulate cardiac hypertrophy

Cardiac hypertrophy is accompanied by maladaptive cardiac remodeling, which leads to heart failure or sudden death. MicroRNAs (miRNAs) are a class of small, noncoding RNAs that mediate posttranscriptional gene silencing. Recent studies show that miRNAs are involved in the pathogenesis of hypertrophy, but their signaling regulations remain to be understood. Here, we report that miR-23a is a pro-hypertrophic miRNA, and its expression is regulated by the transcription factor, nuclear factor of activated T cells (NFATc3). The results showed that miR-23a expression was up-regulated upon treatment with the hypertrophic stimuli including isoproterenol and aldosterone. Knockdown of miR-23a could attenuate hypertrophy, suggesting that miR-23a is able to convey the hypertrophic signal. In exploring the molecular mechanism by which miR-23a is up-regulated, we identified that NFATc3 could directly activate miR-23a expression through the transcriptional machinery. The muscle specific ring finger protein 1, an anti-hypertrophic protein, was identified to be a target of miR-23a. Its translation could be suppressed by miR-23a. Our data provide a model in which the miRNA expression is regulated by the hypertrophic transcriptional factor.

Down-regulation of catalase and oxidative modification of protein kinase CK2 lead to the failure of apoptosis repressor with caspase recruitment domain to inhibit cardiomyocyte hypertrophy.

Cardiac hypertrophy is regulated by a complex interplay of pro- and anti-hypertrophic factors. Here, we report a novel anti-hypertrophic pathway composed of catalase, protein kinase CK2 (CK2), and apoptosis repressor with caspase recruitment domain (ARC). Our results showed that ARC phosphorylation levels, CK2 activity, and catalase expression levels were decreased in the hearts of the angiotensinogen transgenic mice and in cardiomyocytes treated with the hypertrophic stimuli, including phenylephrine, tumor necrosis factor-α, and angiotensin II. To understand the role of ARC in hypertrophy, we observed that enforced expression of ARC could inhibit hypertrophy. Knockdown of endogenous ARC or inhibition of its phosphorylation could sensitize cardiomyocytes to undergoing hypertrophy. The phosphorylatable, but not the nonphosphorylatable, ARC could inhibit hypertrophy. Thus, ARC is able to inhibit hypertrophy in a phosphorylation-dependent manner. In exploring the molecular mechanism by which CK2 activity is reduced, we found that CK2 was carbonylated in angiotensinogen transgenic mice and in cardiomyocytes treated with the hypertrophic stimuli. The decrease in catalase expression led to an elevated level of reactive oxygen species. The latter oxidatively modified CK2, resulting in its carbonylation. CK2 lost its catalytic activity upon carbonylation. ARC is phosphorylated by CK2, and ARC phosphorylation levels were reduced as a consequence of the decrease of CK2 activity. To understand the molecular mechanism by which ARC inhibits hypertrophy, we observed that ARC could inhibit the activation of mitochondrial permeability transition. These results suggest that catalase, CK2, and ARC constitute an anti-hypertrophic pathway in the heart.

miR-761 regulates the mitochondrial network by targeting mitochondrial fission factor

Mitochondria are dynamic organelles that constantly undergo fission and fusion. The balance between fission and fusion determines the fate of the cell. In this study, we show that mitochondrial fission factor (MFF) is upregulated upon hydrogen peroxide treatment or ischemia/reperfusion (I/R) injury. Knockdown of MFF attenuated hydrogen peroxide- and I/R injury-induced cardiomyocyte apoptosis and myocardial infarction. We found that MFF is a direct target of miR-761, and miR-761 inhibits mitochondrial fission and cardiomyocyte apoptosis by repressing MFF. This study reveals a novel model of mitochondrial fission regulation, which is composed of miR-761 and MFF. Modulation of their levels may provide a new approach for tackling apoptosis and myocardial infarction.

Therapeutic Potential of Tumour Necrosis Factor-alpha Antagonists in Patients with Chronic Heart Failure

OBJECTIVES Elevated levels of tumour necrosis factor alpha (TNF-alpha) are associated with the development of heart failure. TNF-alpha antagonists, etanercept (ETA) and infliximab (INF) have been used for treating different clinical conditions. Anti-TNF-alpha therapy did not show favourable results in patients with chronic heart failure (CHF). This review analyses the reasons for anti-TNF-alpha therapy failure in CHF patients; potential approaches for improved clinical outcome are also addressed. DESIGN AND METHODS Data analysis from clinical trials of CHF patients treated with ETA and INF. RESULTS In heart failure patients, ETA and INF therapy did not lead to improved clinical outcomes and high doses of INF were associated with worsening of cardiac events. This contrasts with the observation that these agents are associated with reduced cardiac events when used in patients with inflammatory diseases such as rheumatoid arthritis (RA). CONCLUSIONS Treatment of CHF patients with TNF-alpha antagonists did not show encouraging results. There is a need for the development of better treatment strategies for CHF. Perhaps, tailored anti-TNF-alpha therapy in relation to the TNF-alpha genotype of CHF patients and targeting of the cytokine gene expression via signalling pathway inhibitors may have useful clinical implications.

Cardiac hypertrophy is negatively regulated by miR-541

Heart failure is a leading cause of death in aging population. Cardiac hypertrophy is an adaptive reaction of the heart against cardiac overloading, but continuous cardiac hypertrophy is able to induce heart failure. We found that the level of miR-541 was decreased in angiotensin II (Ang-II) treated cardiomyocytes. Enforced expression of miR-541 resulted in a reduced hypertrophic phenotype upon Ang-II treatment in cellular models. In addition, we generated miR-541 transgenic mice that exhibited a reduced hypertrophic response upon Ang-II treatment. Furthermore, we found miR-541 is the target of microphthalmia-associated transcription factor (MITF) in the hypertrophic pathway and MITF can negatively regulate the expression of miR-541 at the transcriptional levels. MITFce/ce mice exhibited a reduced hypertrophic phenotype upon Ang-II treatment. Knockdown of MITF also results in a reduction of hypertrophic responses after Ang-II treatment. Knockdown of miR-541 can block the antihypertrophic effect of MITF knockdown in cardiomyocytes upon Ang-II treatment. This indicates that the effect of MITF on cardiac hypertrophy relies on the regulation of miR-541. Our present study reveals a novel cardiac hypertrophy regulating pathway that was composed of miR-541 and MITF. Modulation of their levels may provide a new approach for tackling cardiac hypertrophy.

Extracellular vesicles in ovarian cancer: applications to tumor biology, immunotherapy and biomarker discovery

ABSTRACT In recent years there has been tremendous interest in both the basic biology and applications of extracellular vesicles (EVs) in translational cancer research. This includes a better understanding of their biogenesis and mechanisms of selective cargo packaging, their precise roles in horizontal communication, and their application as non-invasive biomarkers. The rapid advances in next-generation omics technologies are the driving forces for these discoveries. In this review, the authors focus on recent results of EV research in ovarian cancer. A deeper understanding of ovarian cancer-derived EVs, the types of cargo molecules and their biological roles in cancer growth, metastases and drug resistance, could have significant impact on the discovery of novel biomarkers and innovative therapeutics. Insights into the role of EVs in immune regulation could lead to novel approaches built on EV-based immunotherapy.

Tumor Necrosis Factor-Alpha Gene Promoter Region Polymorphism and the Risk of Coronary Heart Disease

Background. Tumor necrosis factor-alpha (TNF-α) gene polymorphisms have been implicated in the manifestation of atherosclerosis. Controversy exists regarding the link between the cytokines variant genotype and CHD among different ethnic groups. There have been fewer studies on the TNF-α gene −1031T>C and −863C>A polymorphisms in relation to CHD. Therefore, the current study was designed to investigate the association of the TNF-α gene −1031T>C and −863C>A polymorphisms with CHD in a Pakistani population. Methods. Patients with CHD (n = 310) and healthy individuals (n = 310) were enrolled in this study. Genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Results. A significant difference was observed in the −863C>A polymorphism between patients with CHD and control subjects (P < 0.0001). CHD risk was positively associated with the variant allele −863A (P < 0.0001) in the study subjects. There was no significant link between the −1031T>C polymorphism and CHD risk in the study population. Haplotypes A-T and A-C of the TNF-alpha gene loci at −863 and −1031 showed higher frequency in the patient group compared with controls (P < 0.05). Conclusion. The TNF-α  −863C>A gene polymorphism was associated with the pathogenesis of CHD while the −1031T>C polymorphism did not show any link with the disease in a Pakistani population.

The erratic antibiotic susceptibility patterns of bacterial pathogens causing urinary tract infections.

Increasing trend of antibiotic resistance and expression of Extended Spectrum Beta Lactamases (ESBLs) are serious threats for public health as they render the treatment ineffective. Present study was designed to elucidate the antibiotic-susceptibility patterns of ESBL and non-ESBL producing E. coli and K. pneumoniae causing urinary tract infections so that the ineffective antibiotics could be removed from the line of treatment. The bacterial isolates obtained from the urine of patients visiting a tertiary health care facility were cultured for strain identification using API20E. Antimicrobial susceptibility and ESBL detection were done by Kirby-bauer diffusion technique. Almost 53.4 % isolates of E. coli and 24.5 % isolates of K. pneumoniae were found to be ESBL producers. The ESBL producing bacteria were found to be more resistant towards various antibiotics. The most effective drugs against E. coli ESBL isolates were imipenem (99.54 %), ampicillin-sulbactam (97.48 %), piperacillin-tazobactam (96.86 %), fosfomycin (94.51 %), amikacin (92.26 %) and nitrofurantoin (90.68 %). The most effective drugs against K. pneumoniae ESBL isolates were imipenem (97.62 %), piperacillin-tazobactam (95.35 %), ampicillin-sulbactam (90.48 %) and amikacin (88.37 %). The antibiotics having the highest resistance, particularly by the ESBL producers were amoxicillin clavulanic acid, sulphamethoxalzole/ trimethoprim, cefuroxime, cefpirome, ceftriaxone and ciprofloxacin. Most of the isolates showed multi drug resistance (MDR). High frequency of ESBL producing E. coli and K. pneumoniae were observed as compared to previous data. Penicillins, cephalosporins and some representatives of fluoroquinolones were least effective against the common UTIs and are recommended to be removed from the line of treatment.

Radical scavenging propensity of Cu(2+), Fe(3+) complexes of flavonoids and in-vivo radical scavenging by Fe(3+)-primuletin.

Cu2+ and Fe3+ complexes of three flavonoids (morin or mo, quercetin or quer and primuletin or prim) were synthesized with the objective of improving antioxidant capacities of flavonoids. The radical scavenging activities of pure flavonoids and their metal complexes were assayed to monitor their tendencies towards sequestering of radicals at physiological conditions. The scavenger potencies of metal-flavonoid complexes were significantly higher than those of the parent flavonoids. Further, influence of the solvent polarity on the radical capturing by flavonoids and their metal complexes was in favor for the polar solvent. Fe3+-prim displayed its radical scavenging ability via up gradation of CAT and SOD activities in in-vivo antioxidant assays.

Effect of maternal iodine supplementation on thyroid function and birth outcome in goiter endemic areas

Abstract Objective: The study was undertaken to examine the clinical and endocrine parameters of thyroid in a total of 460 pregnant women belonging to non-goiter areas (group 1; n = 156) and endemic areas without (group 2; n = 154) and with iodine supplementation (group 3; n = 150), and their respective newborns. Methods: Women of group 3 with visible goiter were administered two capsules of iodized oil orally each containing 200 mg of iodine, from weeks 6--8 of pregnancy. Blood samples were obtained from all groups during each trimester, at parturition (umbilical cord blood) and after delivery. Serum triiodothyronine (T3), thyroxine (T4) and thyroid stimulating hormone (TSH) levels were measured by specific enzyme immunoassays. Results: In group 2, serum T4 concentrations were low while T3 and TSH levels were high which showed hypothyroidism in the women of endemic areas. Goiter size decreased in most of the subjects who received a single dose of iodized oil and resulted in increase in serum concentrations of thyroid hormones; whereas, TSH levels decreased. Iodine supplementation also resulted in raised T4 and low TSH levels in the cord blood of neonates. During the course of study, two abortions, three still births and one cretin were reported in group 2; none was reported in group 3; and one still birth was reported in group 1. Conclusions: The oral administration of a single dose of iodized oil is capable of correcting iodine deficiency both clinically and endocrinologically in mothers and neonates. Iodine supplementation has the potential to positively impact the birth weight of newborns.