Tale of Viruses in Male Infertility.

Male infertility is a condition where the males either become sterile or critically infertile. The World Health Organisation assessed that approximately 9% of the couple have fertility issues where the contribution of the male partner was estimated to be 50%. There are several factors that can amalgamate to give rise to male infertility. Among them are lifestyle factors, genetic factors and as well as several environmental factors. The causes of male infertility may be acquired, congenital or sometimes idiopathic. All these factors adversely affect the spermatogenesis process as well as they impart serious threats to male genital organs thus resulting in infertility. Viruses are submicroscopic pathogenic agents that rely on host for their replication and survival. They enter the host cell, hijack the host cell machinery to aid their own replication and exit the cell for a new round of infection. With the growing abundance of different types of viruses and the havoc they have stirred in the form of pandemics, it is very essential to decipher their route of entry inside the human body and understand their diverse functional roles in order to combat them. In this chapter, we will review how viruses invade the male genital system thus in turn leading to detrimental consequence on male fertility. We will discuss the tropism of various viruses in the male genital organs and explore their sexual transmissibility. This chapter will summarise the functional and mechanistic approaches employed by the viruses in inducing oxidative stress inside spermatozoa thus leading to male infertility. Moreover, we will also highlight the various antiviral therapies that have been studied so far in order to ameliorate viral infection in order to combat the harmful consequences leading to male infertility.

YAP1 induces hyperglycemic stress-mediated cardiac hypertrophy and fibrosis in an AKT-FOXM1 dependent signaling pathway.

Cardiac disease is one of the most common complications associated with diabetes. Cardiac hypertrophy and fibrosis often lead to structural and functional abnormalities leading to risks of heart failure. Several regulatory molecules related to major signaling pathways have been found to overexpress in different tissues during diabetes which show very low level of expression in non-diabetic condition. YAP1 and FOXM1 are recently being reported to play important role in various hypertrophic and fibrotic disorders. But, very limited information is still known regarding their roles in cardiomyopathies especially in the context of diabetes and hyperglycemic stress. YAP1 is known to be associated with AKT- GSK3ß signaling that is one of the important regulatory pathways in glucose and lipid metabolism. On the other hand, the expression of FOXM1 has been found to be significantly upregulated in adult lung tissue with induction of fibrosis but little is known about their role in cardiac diseases. In our study, YAP1 and FOXM1 have been found to overexpress in cardiac tissue under hyperglycemic condition leading to cardiomyocyte hypertrophy and increased fibrotic response. Further YAP1 inhibition has resulted in a reduced expression of FOXM1 pointing to a possible association of YAP1 and FOXM1 in high glucose-stressed cardiomyocyte. As mechanism we have found that YAP1 undergoes reduced ser127 phosphorylation as well as extensive O-GlcNAcylation mediated activation under hyperglycemia. Upregulated YAP1 further acts through increased AKT phosphorylation causing inhibition of GSK3ß that in turn results in increased FOXM1 expression, leading to cardiomyocyte hypertrophy and fibrosis.

Induction of cardiomyocyte calcification is dependent on FoxO1/NFATc3/Runx2 signaling.

Cardiovascular disorders (CAVDs) being a major concern over the past several years due to the huge number of morbidity and mortality worldwide, a number of studies have been done on the various aspects of cardiac problems. One of the various CAVDs is cardiovascular calcification. A number of investigations and research work have been done previously on the molecular mechanism of vascular and heart valve calcification but the mechanism of myocardial and cardiomyocyte calcification has remained uninvestigated. A number of case studies have shown the presence of calcific deposits in the myocardial/ventricular region of the heart in fetal condition as well as in individuals of different ages but no detailed studies have been done yet. In this study, we have mainly investigated the role of Forkhead box transcription factor FoxO1 and nuclear factor of activated T-cells NFATc3 in cardiomyocyte calcification. Our studies in H9c2 cardiomyocytes show that calcific deposition in cardiomyocytes does not occur in 15 d but upon osteogenic induction for 1 mo where FoxO1 expression gets reduced thereby increasing the expression of its downstream target NFATc3, thus increasing the expression of the osteogenic marker Runx2. Detailed studies on the molecular mechanism of cardiomyocyte calcification will help in finding out therapeutic strategies in the treatment of cardiac calcification.

Unfolded protein response during cardiovascular disorders: a tilt towards pro-survival and cellular homeostasis.

The endoplasmic reticulum (ER) is an organelle that orchestrates the production and proper assembly of an extensive types of secretory and membrane proteins. Endoplasmic reticulum stress is conventionally related to prolonged disruption in the protein folding machinery resulting in the accumulation of unfolded proteins in the ER. This disruption is often manifested due to oxidative stress, Ca2+ leakage, iron imbalance, disease conditions which in turn hampers the cellular homeostasis and induces cellular apoptosis. A mild ER stress is often reverted back to normal. However, cells retaliate to acute ER stress by activating the unfolded protein response (UPR) which comprises three signaling pathways, Activating transcription factor 6 (ATF6), inositol requiring enzyme 1 alpha (IRE1α), and protein kinase RNA-activated-like ER kinase (PERK). The UPR response participates in both protective and pro-apoptotic responses and not much is known about the mechanistic aspects of the switch from pro-survival to pro-apoptosis. When ER stress outpaces UPR response then cell apoptosis prevails which often leads to the development of various diseases including cardiomyopathies. Therefore, it is important to identify molecules that modulate the UPR that may serve as promising tools towards effective treatment of cardiovascular diseases. In this review, we elucidated the latest advances in construing the contribution imparted by the three arms of UPR to combat the adverse environment in the ER to restore cellular homeostasis during cardiomyopathies. We also summarized the various therapeutic agents that plays crucial role in tilting the UPR response towards pro-survival.

Supramolecular Dipeptide-Based Near-Infrared Fluorescent Nanotubes for Cellular Mitochondria Targeted Imaging and Early Apoptosis.

Herein, we have designed and synthesized unsymmetrical visible Cy-3 and near-infrared (NIR) Cy-5 chromophores anchoring mitochondria targeting functional group conjugated with a Phe-Phe dipeptide by a microwave-assisted Fmoc solid phase peptide synthesis method on Wang resin. These dipeptide-based Cy-3-TPP/FF as well as Cy-5-TPP/FF molecules self-assemble to form fluorescent nanotubes in solution, and it has been confirmed by TEM, SEM, and AFM. The Cy-3-TPP/FF and Cy-5-TPP/FF molecules in solution exhibit narrow excitation as well as emission bands in the visible and NIR region, respectively. These lipophilic cationic fluorescent peptide molecules spontaneously and selectively accumulate inside the mitochondria of human carcinoma cells that have been experimentally validated by live cell confocal laser scanning microscopy and display a high Pearson's correlation coefficient in a colocalization assay. Live cell multicolor confocal imaging using the NIR Cy-5-TPP/FF in combination with other organelle specific dye is also accomplished. Moreover, these lipophilic dipeptide-based cationic molecules reach the critical aggregation concentration inside the mitochondria because of the extremely negative inner mitochondrial membrane potential [(ΔΨm)cancer ≈ -220 mV] and form supramolecular nanotubes which are accountable for malignant mitochondria targeted early apoptosis. The early apoptosis is arrested using Cy-5-TPP/FF and confirmed by annexin V-FITC/PI apoptosis detection assay.

Oleic Acid Protects from Arsenic-Induced Cardiac Hypertrophy via AMPK/FoxO/NFATc3 Pathway.

Arsenic toxicity is one of the major environmental problems causing various diseases, cardiovascular disorders is one of them. Several epidemiological studies have shown that arsenic causes cardiac hypertrophy but the detailed molecular mechanism is to be studied yet. This study is designed to determine the molecules involved in the augmentation of arsenic-induced cardiac hypertrophy. Furthermore, the effects of oleic acid on arsenic-induced hypertrophy and cardiac injury have also been investigated. Our results show that arsenic induces cardiac hypertrophy both in vivo in mice and in vitro in rat H9c2 cardiomyocytes. Moreover, arsenic results in decreased activity of AMPK and FoxO1 along with increased NFATc3 expression, a known cardiac hypertrophy inducer. In addition, activation of AMPK and FoxO1 results in reduced NFATc3 expression causing attenuation of arsenic-induced cardiac hypertrophy in H9c2 cells. Interestingly, we have observed that oleic acid helps in ameliorating cardiac hypertrophy in arsenic-exposed mice. Our studies on protection from arsenic-induced cardiac hypertrophy by oleic acid in H9c2 cells shows that oleic acid activates AMPK along with increased nuclear FoxO1 localization, thereby reducing NFATc3 expression and attenuating cardiomyocyte hypertrophy. This study will help in finding out new avenues in treating arsenic-induced cardiac hypertrophy.

Primary transitional cell carcinoma of the fallopian tube in a premenopausal woman: A case report and review of literature.

Transitional carcinomas are extremely rare in the fallopian tube. A 41-year-old premenopausal lady presented with colicky abdominal pain and was found to have a left-sided pelvic mass on examination. In view of the elevated CA-125 and imaging findings suggestive of ovarian mass, she underwent staging laparotomy. Pathological examination confirmed a primary transitional cell carcinoma of the left fallopian tube. Review of available literature suggested that the primary transitional cell carcinoma is probably less aggressive compared to classical adenocarcinoma of the fallopian tube, and it has to be distinguished from the recently recognized entity, parafallopian tube transitional cell carcinoma.