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The role of intra-ovarian factors in the regulation of follicular death and survival, and management of ovarian lifespan
No full textLiving organisms are characterized by their ability to reproduce. History has witnessed the importance given by human societies to the process of procreation. Nevertheless, the people of yore were not capable of comprehending the intricate processes underlying such an important function and attributed it to divine intervention. While fertility and procreation formed the very basis of the dogmas of early life, failure to conceive was perceived as the ultimate curse. Light was thrown on the science of reproductive processes during the sixteenth century. With time, our knowledge has managed to permeate profoundly to understand the process of reproduction, but infertility continues to remain a major and painful life crisis that provides lifelong scarring with significant psychological, economic, demographic and medical effects. The inability to conceive strikes out at the very base of human identity, rapidly plummeting the couple downhill emotional turmoil; needless to say however, the women are subjected to more emotional damage than their male counterparts. Despite all the breakthroughs in the empowerment of women, a woman is still considered incomplete if she cannot become a mother. In humans, reproduction is much the same as for other mammals where they employ in-vivo fertilization that depends on the integrated action of hormones, the nervous system, and the reproductive system. It involves production and maturation of male and female gametes by the gonads, fertilization of the oocyte by spermatozoa, implantation in the uterus, and beginning of a new life. For the woman this demands regular and reliable ovarian cycles centrally featured by ovarian follicle development leading to ovulation in concert with production of estrogen and progesterone under the chief controlling influence of pulsatile gonadotropin secretion from pituitary. For both sexes, the gonads, ovaries in female and testes in male, serve the gametogenic and key endocrine functions, while the hypothalamo-pituitary unit governs the whole process. Diseases interfering with any of these components adversely affect the ability of a couple to conceive. Infertility can be defined as a failure to become pregnant in a period of 12 months for patients under the age of 35 and failure to conceive in a 6 month period for the over 35 age group. Causes of infertility can be found in about 90% of the cases, but despite extensive investigations, about 10% of couples will never know why they cannot conceive.Male or female infertility each accounts for about 30% to 40% of cases. Other cases are due to a combination of male and female factors or to unknown causes. Over the past several decades, demographic and socioeconomic trends have resulted in an increase in the absolute number of women seeking pregnancy in their late 30’s and early to mid 40’s. Compared to other major organ systems the female reproductive system ages to the point of failure at a relatively young age. Although the average age of menopause is 51, peak efficiency in the female reproductive system occurs in the early 20’s with a steady decline thereafter. There is a gradual loss of fertility as a function of female age with the rate of decline in fertility becoming more dramatic after the age of 35. This decline in fertility occurs in spite of the fact that women generally maintain regular, ovulatory menstrual cycles well into the fifth decade. A significant number of women in the advance age group seek evaluation and treatment for infertility. The general consensus is that the ovarian aging is accompanied not only by remarkable decline in the ovarian follicle pool but also by an increase in low-quality oocytes that are not competent enough for fertilization and further development. There are several lines of evidence documenting that oocyte quality determines its fertilization and subsequent development potential, and abnormalities of the oocyte act as the predominant cause of age-associated infertility. Clinical research over the last three decades almost exclusively concentrated on the ovarian hyperstimulation and in vitro fertilization. A number of recent documents raised suspicion over the classical concept of ‘oocyte aging’. Indirect evidence are there to support the view that the so called ‘aged oocytes’ collected from ‘aged ovary’ may be rendered fertile if cultured in ‘suitable’ conditions. This forms the basis of the present dissertation that endeavors understanding the ovarian milieu with respect to size of follicular reserve that, in fact, differentiates the ‘healthy’ and ‘aged’ ovary. The objective is to identify the missing link between declining follicular reserve and loss of oocyte quality, which may perhaps open a new frontier in the management of infertility
Regio- and Stereoselective Synthesis of a Library of Bioactive Dispiro-Oxindolo/Acenaphthoquino Andrographolides via 1 ,3- Dipolar Cycloaddition Reaction Under Microwave Irradiation
No full textDispiro-pyrrolidino/pyrrolizidino fused oxindoles/acenaphthoquinones have
been derived from andrographolide via azomethine ylide cycloaddition to the conjugated double-bond under microwave (MW) irradiation. The reactions are chemo-, stereo-, and regioselective in nature. Change in amino acid from sarcosine/N-benzyl glycine to L-proline changes the regiochemistry. A representative library of 40 compounds along with in vitro anticancer evaluation is reported
pEapfefricient Synthesis of Imidazole-Fused Benzodiazepines Using Palladium- Catalyzed Intramolecular C–N Bond Formation Reaction
No full textAn efficient three-step synthetic route to imidazolefused
benzodiazepines from imidazole-2-carbaldehyde is described.
Application of intramolecular Buchwald–Hartwig cycloamination
reaction in the final step is shown to be a convenient
method for the synthesis of fused seven-membered diazacycles. The
reactions proceeded smoothly with both aliphatic and aromatic
amines.
Key words: palladium, catalysis, amination, cyclization, benzodiazepin
Understanding the Molecular Mechanisms of Wnt/B -Catenin Signalling in Cancer
No full textIn spite of significant advancements in diagnosis and treatment, cancer is still a big threat to society. This is the second most common disease for maximum deaths in the world and it accounts for about 7% deaths in India. Prostate cancer is the most common cancer in males in
western countries and breast cancer is the most prevalent cancer in women in India. It has long been appreciated that multiple signaling pathways coexist within the cell during cancer development. Many examples have been presented in which these pathways can influence each other’s behaviour through crosstalk. The puzzle that remains for researchers is to determine the extent and relevance of such crosstalk during cancer development as well as progression.
Wnt/�-catenin and EGFR pathways are important in cancer development and often aberrantly activated in human cancers. However, it is very important to understand the
mechanism responsible for their activation and the relation between them. This study reveals an interesting mechanism of EGFR expression by transcriptionally active �-catenin in GSK3� inactivated prostate cancer cells that eventually leads to its enhanced proliferation and survival.
Expressions of �-catenin and EGFR are elevated in various cancers specifically in prostate cancer (PCa) cells, DU145. When GSK3� is inactivated in these cells, �-catenin gets stabilized, phosphorylated at Ser552 by PKA, accumulates in the nucleus and regulates the expression of its target genes that include EGFR. Chromatin Immunoprecipitation (ChIP) and promoter analysis revealed that the EGFR promoter gets occupied by transcriptionally active �-catenin
when elevated in GSK3� inactivated cells. This phenomenon not only leads to increased expression of EGFR but also initiates the activation of its downstream molecules such as
ERK1/2 and Stat3. P68 is overexpressed in cancers which has been implicated in a variety of processes, including rearrangement of RNA secondary structures, RNA splicing, gene transcription and tumor development. We found that �-catenin directly induce transcription of the p68 promoter
or indirectly through oncogenic protein c-Myc in human as well as mouse cancer cells. The p68 promoter contains putative consensus sequences of TCF4 and c-Myc. TCF4 putative site isn critical for activation by �-catenin as analyzed by promoter analysis using luciferase assay.
Moreover we have found that �-catenin and TCF4 occupies the p68 promoter. Here we have also analyzed positive feedback regulation of TCF4 expression by p68. These consequences of
�-catenin/TCF4 mediated p68 expression plays a crucial role in enhanced migratory and invasive potential of triple negative breast cancer cells MDA-MB-231 and mouse aggressive
4T1cells. These findings strongly indicate that Wnt signaling plays an important role in cancer progression by upregulating p68 and EGFR expression which consequently leads to tumor progression
In-Silico Studies for Designing Potential Anti -alzheimer�s Disease Drug Candidates using Integrated Approaches
No full textMore than one hundred years ago, a small group of psychiatrists described the abnormal protein deposits in the brain that define the most common neurodegenerative diseases. Over the past 30 years, it has become clear that the proteins forming the deposits are central to the
disease process. Aging is a major risk factor for neurodegenerative disorders, such as Alzheimer’s disease (AD) and Parkinson disease (PD). Among these, Alzheimer’s disease is the most common cause of dementia and has emerged as the most prevalent form of late-life
mental failure in humans. AD was first described by the German psychiatrist and neuropathologist Alois Alzheimer [1] in 1906 from whom it takes its name. He reported the
existence of two abnormal structures, senile plaques and neurofibrillary tangles, in the brain of his patient, a woman referred to as Auguste D. The symptoms, observed in his patient, exemplified several cardinal features of the disorder that is observed in AD patients even today, viz., progressive memory impairment, disordered cognitive function, altered behaviour including paranoia, delusions, and loss of social appropriateness, and a progressive decline in language function [2]. AD is a devastating and ultimately fatal neurodegenerative disease,
characterized by progressive cognitive and memory deterioration that leads to difficulty in carrying out everyday activities
A small molecule chemical chaperone optimizes its unfolded state contraction and denaturant like properties
No full textProtein aggregation is believed to occur through the formation of misfolded conformations. It is expected
that, in order to minimize aggregation, an effective small molecule chaperone would destabilize these
intermediates. To study the mechanism of a chemical chaperone, we have designed a series of mutant
proteins in which a tryptophan residue experiences different local environments and solvent exposures. We
show that these mutants correspond to a series of conformationally altered proteins with varying degree of
misfolding stress and aggregation propensities. Using arginine as a model small molecule, we show that a
combination of unfolded state contraction and denaturant like properties results in selective targeting and
destabilization of the partially folded proteins. In comparison, the effect of arginine towards the folded like
control mutant, which is not aggregation prone, is significantly less. Other small molecules, lacking either of
the above two properties, do not offer any specificity towards the misfolded proteins
A feed-forward loop involving Trib3, Akt and FoxO mediates death of NGF-deprived neurons
No full textThe mechanisms governing neuron death following NGF deprivation are incompletely understood. Here, we show that Trib3, a protein induced by NGF withdrawal, has a key role in such death via a loop involving the survival kinase Akt and FoxO transcription factors. Trib3 overexpression is sufficient to induce neuron death, and silencing of endogenous Trib3 strongly protects from death when NGF is withdrawn. Mechanism studies reveal that Trib3 interferes with phosphorylation/activity of Akt and contributes to Akt inactivation after NGF deprivation. FoxO1a, a direct Akt substrate, is dephosphorylated upon NGF withdrawal and consequently undergoes nuclear translocation and activates pro-apoptotic genes. We find that Trib3 is required
for FoxO1a dephosphorylation and nuclear translocation after NGF deprivation. Conversely, Trib3 induction requires FoxO transcription factors, which show enhanced occupancy of the Trib3 promoter region following NGF withdrawal. Collectively, these findings support a mechanism in which NGF deprivation, Akt dephosphorylation/inactivation, FoxO dephosphorylation/ activation and Trib3 induction are linked in a self-amplifying feed-forward loop that culminates in neuron deat
Epigenetic Modifications of DAPK and p16 Genes Contribute to Arsenic-Induced Skin Lesions and Nondermatological Health Effects
No full textOver 26 million people in West Bengal, India, are exposed to
very high levels of arsenic through drinking water, leading to several deleterious endpoints including cancers. To elucidate the role of promoter methylation in arsenic-induced dermatological and nondermatological health effects, methylation status of p16 and DAPK genes was determined. A case-control study was conducted involving 72 individuals with arsenic-induced skin lesions (cases) and 50 individuals without skin lesions (controls), having similar arsenic exposure through drinking water.Methylation status was determined by bisulfite conversion of genomic DNA and methylation-specific PCR. Expression of the
genes was determined by real-time PCR and Western blot analysis. Associations between the promoter methylation status and nondermatological health effects were determined from epidemiological survey data. Significant hypermethylation was found in the promoters of both DAPK and p16 genes in the cases compared with the controls resulting in downregulation of both the genes in the cases. There was a 3.4-fold decrease in the expression
of death-associated protein kinase and 2.2-fold decrease in
gene expression of p16 in the cases compared to the controls, the lowest expression being in the cancer tissues. Promoter hypermethylation of the genes was also associated with higher risk of developing arsenic-induced skin lesions, peripheral neuropathy, ocular and respiratory diseases. This study for the first time makes an attempt to correlate epigenetic modifications of the tumor suppressor genes with dermatological and nondermatological health outcomes in a population chronically exposed to arseni
An Unusual Diastereoselective Pictet–Spengler Reaction: Synthesis of Novel Tetrahydro-β-Carboline Glycosides
No full textAn unusual kinetic approach to the Pictet–Spengler reaction
was investigated, in which L- or D-tryptophan methyl ester
reacted with aldehydes of 1,2-O-cyclohexylidene-3-allyloxy-α-Dxylofuranose,
yielding exclusively the cis or trans diastereomer of
tetrahydro-β-carboline glycoside, respectively, with complete
stereocontro
