■ Abstract Apoptosis is a genetically programmed, morphologically distinct form of cell death that can be triggered by a variety of physiological and pathological stimuli. Studies performed over the past 10 years have demonstrated that proteases play critical roles in initiation and execution of this process. The caspases, a family of cysteine-dependent aspartate-directed proteases, are prominent among the death proteases. Caspases are synthesized as relatively inactive zymogens that become activated by scaffold-mediated transactivation or by cleavage via upstream proteases in an intracellular cascade. Regulation of caspase activation and activity occurs at several different levels: ( a) Zymogen gene transcription is regulated; ( b) antiapoptotic members of the Bcl-2 family and other cellular polypeptides block proximity-induced activation of certain procaspases; and ( c) certain cellular inhibitor of apoptosis proteins (cIAPs) can bind to and inhibit active caspases. Once activated, caspases cleave a variety of intracellular polypeptides, including major structural elements of the cytoplasm and nucleus, components of the DNA repair machinery, and a number of protein kinases. Collectively, these scissions disrupt survival pathways and disassemble important architectural components of the cell, contributing to the stereotypic morphological and biochemical changes that characterize apoptotic cell death.

Mammalian caspases: structure ,a ctivation ,s ubstrates, and functions during apoptosis

Fetal nutrition and cardiovascular disease in adult life

Consensus on women's health aspects of polycystic ovary syndrome (PCOS): The Amsterdam ESHRE/ASRM-Sponsored 3rd PCOS Consensus Workshop Group

The insulin-like growth factors (IGFs) are mitogens that play a pivotal role in regulating cell proliferation, differentiation, and apoptosis. The effects of IGFs are mediated through the IGF-I receptor, which is also involved in cell transformation induced by tumor virus proteins and oncogene products. Six IGF-binding proteins (IGFBPs) can inhibit or enhance the actions of IGFs. These opposing effects are determined by the structures of the binding proteins. The effects of IGFBPs on IGFs are regulated in part by IGFBP proteases. Laboratory studies have shown that IGFs exert strong mitogenic and antiapoptotic actions on various cancer cells. IGFs also act synergistically with other mitogenic growth factors and steroids and antagonize the effect of antiproliferative molecules on cancer growth. The role of IGFs in cancer is supported by epidemiologic studies, which have found that high levels of circulating IGF-I and low levels of IGFBP-3 are associated with increased risk of several common cancers, including those of the prostate, breast, colorectum, and lung. Evidence further suggests that certain lifestyles, such as one involving a high-energy diet, may increase IGF-I levels, a finding that is supported by animal experiments indicating that IGFs may abolish the inhibitory effect of energy restriction on cancer growth. Further investigation of the role of IGFs in linking high energy intake, increased cell proliferation, suppression of apoptosis, and increased cancer risk may provide new insights into the etiology of cancer and lead to new strategies for cancer prevention.

/pdf/role-of-the-insulin-like-growth-factor-family-in-cancer-550yl3popq.pdf

Role of the insulin-like growth factor family in cancer development and progression

Measuring gene expression in individual cells is crucial for understanding the gene regulatory network controlling human embryonic development. Here we apply single-cell RNA sequencing (RNA-Seq) analysis to 124 individual cells from human preimplantation embryos and human embryonic stem cells (hESCs) at different passages. The number of maternally expressed genes detected in our data set is 22,687, including 8,701 long noncoding RNAs (lncRNAs), which represents a significant increase from 9,735 maternal genes detected previously by cDNA microarray. We discovered 2,733 novel lncRNAs, many of which are expressed in specific developmental stages. To address the long-standing question whether gene expression signatures of human epiblast (EPI) and in vitro hESCs are the same, we found that EPI cells and primary hESC outgrowth have dramatically different transcriptomes, with 1,498 genes showing differential expression between them. This work provides a comprehensive framework of the transcriptome landscapes of human early embryos and hESCs.

Single-cell RNA-Seq profiling of human preimplantation embryos and embryonic stem cells

BACKGROUND: Polycystic ovary syndrome (PCOS) is the commonest cause of anovulatory infertility and menstrual cycle abnormalities, but the factors responsible for failure to select a dominant follicle remain unclear. METHOD: Source is authors’ own studies and search of the relevant literature. RESULTS: Arrest of antral follicle growth is associated with an abnormal endocrine environment involving hypersecretion of luteinizing hormone and insulin (and perhaps hyperandrogenism). The net effect is secondary suppression of FSH, which leads to inhibition of maturation of otherwise healthy follicles in the cohort. There is, however, emerging evidence for an intrinsic abnormality of folliculogenesis in PCOS that affects the very earliest, gonadotrophin independent, stages of follicle development. There is an increased density of small pre-antral follicles and an increased proportion of early growing follicles. These abnormalities in anovulatory PCOS are further defined by abnormal granulosa cell proliferation and disparate growth of oocyte and surrounding granulosa cells. This suggests that the normal ‘dialogue’ between oocyte and granulosa cells in these early growing follicles is altered. There is evidence that abnormal, local (follicle-to-follicle) signal

/pdf/follicle-dynamics-and-anovulation-in-polycystic-ovary-1x0fn3xmig.pdf

Follicle dynamics and anovulation in polycystic ovary syndrome

Formation and early development of follicles in the polycystic ovary.

Cell death is a widespread feature in the blastocysts of many mammals. Isolated cells in both the inner cell mass and the trophectoderm undergo cell death. These dying cells appear morphologically to be undergoing apoptosis. In mouse blastocysts, a wave of cell death is seen in vivo, suggesting that it plays an important role in normal development. However, cell death is increased under suboptimal culture conditions. There is evidence that levels of cell death are regulated by ‘survival’ factors produced both by the embryo itself and by the maternal reproductive tract. The role of cell death in development is unknown, but could involve the elimination of abnormal cells, or a sublineage of cells with an inappropriate developmental potential. Work in other systems has demonstrated that cell death is regulated by the activity of apoptosis genes. Whether these genes are implicated in blastocyst cell death, and the reasons for apoptosis in the early embryo, remain to be determined.

/pdf/cell-death-in-the-mammalian-blastocyst-31930kgeow.pdf

Cell death in the mammalian blastocyst.

There is increasing evidence that even before implantation, human development is regulated by embryonically and maternally derived growth factors. Studies in other mammalian species have shown that growth factors and their receptors are expressed by the preimplantation embryo and the reproductive tract. Furthermore, a number of growth factors have been shown to affect rate of embryo development, the proportion of embryos developing to the blastocyst stage, blastocyst cell number, metabolism and apoptosis. Growth factor ligands and receptors are also expressed in human embryos and the maternal reproductive tract, and supplementation of culture medium with exogenous growth factors affects cell fate, development and metabolism of human embryos in vitro. Autocrine, paracrine and endocrine pathways that may operate within the embryo and between the embryo and the reproductive tract before implantation are proposed.

/pdf/growth-factor-expression-and-function-in-the-human-and-mouse-19p7n3i5r0.pdf

Growth factor expression and function in the human and mouse preimplantation embryo.

Preimplantation human embryos are characterized by various degrees of cytoplasmic fragmentation, and a high incidence of developmental arrest before the blastocyst stage. This review examines the current morphological and biochemical evidence that apoptosis plays a role in early human development and embryonic loss. Embryos examined 24 h or more after arrest often show characteristic features of apoptosis including cytoplasmic, nuclear and DNA fragmentation. In contrast, embryos of good morphology that appear to be developing normally show no evidence of apoptosis before compaction. However, at the morula and blastocyst stages, scattered cells with fragmented nuclei and DNA characteristic of cells undergoing apoptosis are common features. Apoptosis may result from suboptimal culture conditions, or may be involved in the elimination of abnormal cells. However, the causes, role and regulation of apoptosis in the human preimplantation embryo remain to be determined.

/pdf/apoptosis-in-the-human-embryo-1gec5dqjgl.pdf

Kate Hardy

Papers

Follicle dynamics and anovulation in polycystic ovary syndrome

Formation and early development of follicles in the polycystic ovary.

Cell death in the mammalian blastocyst.

Growth factor expression and function in the human and mouse preimplantation embryo.

Apoptosis in the human embryo.