Increased PHLPP1 expression through ERK-4E-BP1 signaling axis drives nicotine induced oxidative stress related damage of cardiomyocytes.

Nicotine, a key constituent of tobacco/electronic cigarettes causes cardiovascular injury and mortality. Nicotine is known to induce oxidative stress and mitochondrial dysfunction in cardiomyocytes leading to cell death. However, the underlying mechanisms remain unclear. Pleckstrin homology domain leucine-rich repeat protein phosphatase (PHLPP) is a member of metal-dependent protein phosphatase (PPM) family and is known to dephosphorylate several AGC family kinases and thereby regulate a diverse set of cellular functions including cell growth, survival, and death. Our lab has previously demonstrated that PHLPP1 removal reduced cardiomyocyte death and cardiac dysfunction following injury. Here, we present a novel finding that nicotine exposure significantly increased PHLPP1 protein expression in the adolescent rodent heart. Building upon our in vivo finding, we determined the mechanism of PHLPP1 expression in cardiomyocytes. Nicotine significantly increased PHLPP1 protein expression without altering PHLPP2 in cardiomyocytes. In cardiomyocytes, nicotine significantly increased NADPH oxidase 4 (NOX4), which coincided with increased reactive oxygen species (ROS) and increased cardiomyocyte apoptosis which were dependent on PHLPP1 expression. PHLPP1 expression was both necessary and sufficient for nicotine induced mitochondrial dysfunction. Mechanistically, nicotine activated extracellular signal-regulated protein kinases (ERK1/2) and subsequent eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) to increase PHLPP1 protein expression. Inhibition of protein synthesis with cycloheximide (CHX) and 4EGI-1 abolished nicotine induced PHLPP1 protein expression. Moreover, inhibition of ERK1/2 activity by U0126 significantly blocked nicotine induced PHLPP1 expression. Overall, this study reveals a novel mechanism by which nicotine regulates PHLPP1 expression through ERK-4E-BP1 signaling axis to drive cardiomyocyte injury.

Arsenic and human health effects: A review.

Arsenic (As) is ubiquitous in nature and humans being exposed to arsenic via atmospheric air, ground water and food sources are certain. Major sources of arsenic contamination could be either through geological or via anthropogenic activities. In physiological individuals, organ system is described as group of organs that transact collectively and associate with other systems for conventional body functions. Arsenic has been associated with persuading a variety of complications in body organ systems: integumentary, nervous, respiratory, cardiovascular, hematopoietic, immune, endocrine, hepatic, renal, reproductive system and development. In this review, we outline the effects of arsenic on the human body with a main focus on assorted organ systems with respective disease conditions. Additionally, underlying mechanisms of disease development in each organ system due to arsenic have also been explored. Strikingly, arsenic has been able to induce epigenetic changes (in utero) and genetic mutations (a leading cause of cancer) in the body. Occurrence of various arsenic induced health effects involving emerging areas such as epigenetics and cancer along with their respective mechanisms are also briefly discussed.

Functional significance of long non-coding RNAs in breast cancer.

Most of the genome is transcribed to transcripts of no protein-coding potential. However, these transcripts do not represent transcriptional 'noise', rather they play an important role in cellular metabolism and development. Non-coding transcripts of 200 bases to 100 kb length are termed as long non-coding RNAs, majority of which are yet to be characterised thoroughly. Long non-coding RNAs (lncRNAs) play a significant role in cellular process ranging from transcriptional to post-transcriptional regulation. In this review, we highlight the recent efforts to characterise the major functions of lncRNAs in breast cancer. lncRNA expression is altered in several cancer types. Further, the aberrant regulation of lncRNAs promotes tumour development as they are involved in several cancer-associated pathways.

KATP channels are up-regulated with increasing age in human myometrium.

It is well established that ageing is associated with decrease in myometrial efficiency and higher incidence of labour complications. In myometrium, the presence of ATP-sensitive K+ (KATP) channels has been detected and they could be a factor in regulating uterine quiescence in pregnancy and contractions during labour. Here, we have examined a possibility of ageing-mediated regulation of KATP channels in the human myometrium. Myometrial samples were taken from non-pregnant women undergoing hysterectomy (n=34) and from women undergoing caesarean section in late pregnancy (n=36). Real time RT-PCR revealed that mRNAs of all known KATP channel subunits were present in the human myometrium. In non-pregnant myometrium, ageing up-regulated SUR2B/Kir6.1, subunits forming KATP channels in this tissue, without affecting the expression of other channel subunits. In the late pregnant myometrium, the level of subunits that do not form functional KATP channels was not affected by age within 20-41 age range. However, uterine SUR2B and Kir6.1 were up-regulated in parturient over 35 years. An ageing-induced increase in those channel subunits was confirmed by Western blotting. Thus, this study suggests that KATP channels are up-regulated with increasing age in human myometrium. This may help explain, at least partially, increased rate of birth complications in women aged over 35 years.