■ 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

The mechanistic target of rapamycin (mTOR) coordinates eukaryotic cell growth and metabolism with environmental inputs, including nutrients and growth factors. Extensive research over the past two decades has established a central role for mTOR in regulating many fundamental cell processes, from protein synthesis to autophagy, and deregulated mTOR signaling is implicated in the progression of cancer and diabetes, as well as the aging process. Here, we review recent advances in our understanding of mTOR function, regulation, and importance in mammalian physiology. We also highlight how the mTOR signaling network contributes to human disease and discuss the current and future prospects for therapeutically targeting mTOR in the clinic.

mTOR Signaling in Growth, Metabolism, and Disease

Malignant cells are known to have accelerated metabolism, high glucose requirements, and increased glucose uptake. Transport of glucose across the plasma membrane of mammalian cells is the first rate-limiting step for glucose metabolism and is mediated by facilitative glucose transporter (GLUT) proteins. Increased glucose transport in malignant cells has been associated with increased and deregulated expression of glucose transporter proteins, with overexpression of GLUT1 and/or GLUT3 a characteristic feature. Oncogenic transformation of cultured mammalian cells causes a rapid increase of glucose transport and GLUT1 expression via interaction with GLUT1 promoter enhancer elements. In human studies, high levels of GLUT1 expression in tumors have been associated with poor survival. Studies indicate that glucose transport in breast cancer is not fully explained by GLUT1 or GLUT3 expression, suggesting involvement of another glucose transporter. Recently, a novel glucose transporter protein, GLUT12, has been found in breast and prostate cancers. In human breast and prostate tumors and cultured cells, GLUT12 is located intracellularly and at the cell surface. Trafficking of GLUT12 to the plasma membrane could therefore contribute to glucose uptake. Several factors have been implicated in the regulation of glucose transporter expression in breast cancer. Hypoxia can increase GLUT1 levels and glucose uptake. Estradiol and epidermal growth factor, both of which can play a role in breast cancer cell growth, increase glucose consumption. Estradiol and epidermal growth factor also increase GLUT12 protein levels in cultured breast cancer cells. Targeting GLUT12 could provide novel methods for detection and treatment of breast and prostate cancer.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/jcp.20166

Molecular and cellular regulation of glucose transporter (GLUT) proteins in cancer

The steep rise of type 2 diabetes mellitus (T2DM) and associated complications go along with mounting evidence of clinically important sex and gender differences. T2DM is more frequently diagnosed at lower age and body mass index in men; however, the most prominent risk factor, which is obesity, is more common in women. Generally, large sex-ratio differences across countries are observed. Diversities in biology, culture, lifestyle, environment, and socioeconomic status impact differences between males and females in predisposition, development, and clinical presentation. Genetic effects and epigenetic mechanisms, nutritional factors and sedentary lifestyle affect risk and complications differently in both sexes. Furthermore, sex hormones have a great impact on energy metabolism, body composition, vascular function, and inflammatory responses. Thus, endocrine imbalances relate to unfavorable cardiometabolic traits, observable in women with androgen excess or men with hypogonadism. Both biological and psychosocial factors are responsible for sex and gender differences in diabetes risk and outcome. Overall, psychosocial stress appears to have greater impact on women rather than on men. In addition, women have greater increases of cardiovascular risk, myocardial infarction, and stroke mortality than men, compared with nondiabetic subjects. However, when dialysis therapy is initiated, mortality is comparable in both males and females. Diabetes appears to attenuate the protective effect of the female sex in the development of cardiac diseases and nephropathy. Endocrine and behavioral factors are involved in gender inequalities and affect the outcome. More research regarding sex-dimorphic pathophysiological mechanisms of T2DM and its complications could contribute to more personalized diabetes care in the future and would thus promote more awareness in terms of sex- and gender-specific risk factors.

/pdf/sex-and-gender-differences-in-risk-pathophysiology-and-1p8mzg4br6.pdf

Sex and Gender Differences in Risk, Pathophysiology and Complications of Type 2 Diabetes Mellitus.

We have examined factors concerned with the maintenance of uterine quiescence during pregnancy and the onset of uterine activity at term in an animal model, the sheep, and in primate species. We suggest that in both species the fetus exerts a critical role in the processes leading to birth, and that activation of the fetal hypothalamic-pituitary-adrenal axis is a central mechanism by which the fetal influence on gestation length is exerted. Increased cortisol output from the fetal adrenal gland is a common characteristic across animal species. In primates, there is, in addition, increased output of estrogen precursor from the adrenal in late gestation. The end result, however, in primates and in sheep is similar: an increase in estrogen production from the placenta and intrauterine tissues. We have revised the pathway by which endocrine events associated with parturition in the sheep come about and suggest that fetal cortisol directly affects placental PGHS expression. In human pregnancy we suggest that cortisol increases PGHS expression, activity, and PG output in human fetal membranes in a similar manner. Simultaneously, cortisol contributes to decreases in PG metabolism and to a feed-forward loop involving elevation of CRH production from intrauterine tissues. In human pregnancy, there is no systemic withdrawal of progesterone in late gestation. We have argued that high circulating progesterone concentrations are required to effect regionalization of uterine activity, with predominantly relaxation in the lower uterine segment, allowing contractions in the fundal region to precipitate delivery. This new information, arising from basic and clinical studies, should further the development of new methods of diagnosing the patient at risk of preterm labor, and the use of scientifically based strategies specifically for the management of this condition, which will improve the health of the newborn.

/pdf/endocrine-and-paracrine-regulation-of-birth-at-term-and-4igz1kdkru.pdf

Endocrine and paracrine regulation of birth at term and preterm

This paper describes the development of a computer-facilitated learning package that integrates the various stages of A Woman’s Reproductive Life Cycle integrating reproductive and endocrine physiology. A holistic yet modular approach has been taken with the design of the package and the modules follow the developmental journey of a woman throughout her major reproductive life stages from birth to menopause incorporating puberty, menstrual cycles, contraception and pregnancy. The overall development approaches are described as a part of the package design. Students are presented with a single case study and follow the reproductive and endocrine changes that take place in this woman over time. A core component of the package is a graphical simulation tool, which has been developed to encourage exploration and understanding of the complex mechanisms involved in hormonal regulation of the menstrual cycle.

A woman's reproductive lifecycle: a developmental journey

Continued breastfeeding attenuates maternal and infant risks associated with gestational diabetes mellitus (GDM), which may be more difficult after a GDM pregnancy, with reports of delayed secretory activation and reduced milk production. The total 24 h milk production cycle is not routinely measured; therefore, it is unclear whether reported low milk production is actual or perceived. We aimed to describe early lactation outcomes and 24 h milk production in women with GDM. Women with GDM-complicated pregnancies recorded early feeding practices. The 24 h cycle of milk production was measured at 3 weeks by weighing infants pre- and post-breastfeeds, as well as breast expression volumes. Electronic scales sensitive to 2 g were used. Low 24 h milk production was classified as &lt;600 mL. For women with GDM (n = 40), the median time to the initiation of breastfeeding was 55 min, and delayed secretory activation (n = 24, 60%) was common. Most women achieved frequent milk removal (&ge;8 &times; 24 h) in the first 24 h after birth (n = 27, 68%) was at one week (n = 38, 95%) and three weeks postpartum (n = 36, 90%). However, median 24 h milk production was 639 mL (range 100&ndash;1220 mL), with low milk production measured in n = 16 (40%, range 100&ndash;592 mL). Conclusions: Delayed secretory activation and low milk production are more common in women with GDM despite regular milk removal from the breast, suggesting that altered endocrine pathways inherent to GDM may be implicated. 

/pdf/early-lactation-outcomes-after-pregnancies-complicated-by-3w3bgqzp.pdf

Early Lactation Outcomes after Pregnancies Complicated by Gestational Diabetes

Low female birth weight and advanced maternal age program alterations in next

https://www.mdpi.com/2504-3900/84/1/9/pdf?version=1676880180

Mary E. Wlodek

Papers

A woman's reproductive lifecycle: a developmental journey

Early Lactation Outcomes after Pregnancies Complicated by Gestational Diabetes

Low female birth weight and advanced maternal age program alterations in next

The Importance of Human Milk Fatty Acids in Infant Growth and Development—Concentration vs. Relative Abundance vs. Intake

Pregnant biglycan knockout mice have altered cardiorenal adaptations and a shorter gestational length, but do not develop a pre-eclamptic phenotype.