■ 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

a sex-specific manner metabolic genes during postnatal cardiac development in Growth restriction in the rat alters expression of

The daily variation in human milk (HM) hormones and macronutrients is not well characterised and sample protocols are highly variable between studies. Method: During a 24 h period, the mothers (n = 10) hand-expressed small milk samples, immediately before and after each breastfeeding or expression from each breast. Test-weighing was used to determine the volume of HM consumed in each feed. Concentrations of leptin, adiponectin, insulin, fat, and glucose were measured by variable biochemical assays. A linear mixed model was fitted to eleven outcomes of leptin, adiponectin, insulin, fat, glucose (dose and concentration for each), and feed volume. The explanatory variables considered were a circadian cycle (cosine and sine terms), and for dose and concentration outcomes, an indicator variable for pre- or post-feed. The random effect was a circadian cycle (cosine and sine terms) for each mother. Results: The average infant intake of HM was 1060 mL/day (8 to 20 feeds/day). Pre- and post-feed differences were found in the concentrations of leptin, adiponectin, insulin, and fat (p &lt; 0.05). Significant circadian variation across the 24 h period was found in adiponectin concentration, insulin (both concentration and dose), fat dose, glucose (both concentration and dose), and milk volume. Conclusion: These results highlight the importance of establishing standardised and rigorous sampling protocols considering all levels of variations (within-feed or circadian) to provide a better determination of the impact of these components on infant health and development. 

/pdf/circadian-variation-of-human-milk-hormones-and-uzop5q17.pdf

Circadian Variation of Human Milk Hormones and Macronutrients: Implications for Sampling and Analysis Strategies

Objective: To evaluate whether characterization of maternal and foetoplacental factors beyond birthweight can enable early identification of children at risk of developing prehypertension/hypertension. Methods: We recruited 693 mother–offspring dyads from the GUSTO prospective mother–offspring cohort. Prehypertension/hypertension at age 6 years was identified using the simplified paediatric threshold of 110/70 mmHg. We evaluated the associations of pregnancy complications (gestational diabetes, excessive/inadequate gestational weight gain, hypertensive disorders of pregnancy), foetal growth deceleration (decline in foetal abdominal circumference at least 0.67 standard deviations between second and third trimesters), high foetoplacental vascular resistance (third trimester umbilical artery systolic-to-diastolic ratio ≥90th centile), preterm birth, small-for-gestational age and neonatal kidney volumes with risk of prehypertension/hypertension at age 6 years, after adjusting for sex, ethnicity, maternal education and prepregnancy BMI. Results: Pregnancy complications, small-for-gestational age, preterm birth, and low neonatal kidney volume were not associated with an increased risk of prehypertension/hypertension at age 6 years. In contrast, foetal growth deceleration was associated with a 72% higher risk [risk ratio (RR) = 1.72, 95% confidence interval (CI) 1.18–2.52]. High foetoplacental vascular resistance was associated with a 58% higher risk (RR = 1.58, 95% CI 0.96–2.62). Having both these characteristics, relative to having neither, was associated with over two-fold higher risk (RR = 2.55, 95% CI 1.26–5.16). Over 85% of the foetuses with either of these characteristics were born appropriate or large for gestational age. Conclusion: Foetal growth deceleration and high foetoplacental vascular resistance may be helpful in prioritizing high-risk children for regular blood pressure monitoring and preventive interventions, across the birthweight spectrum.

Associations of maternal and foetoplacental factors with prehypertension/hypertension in early childhood

lactation: comparing prenatal and postnatal exposure mothers consuming alcohol during pregnancy or Whole body insulin resistance in rat offspring of

The actions of relaxin are mediated by relaxin family peptide receptor 1 (Rxfp1). In pregnant mice, there is a decrease in myometrial Rxfp1 expression at term, coinciding with highest circulating relaxin. This down-regulation in Rxfp1 in reproductive tissues has not been investigated in other pregnant animals, nor are the regulatory mechanisms known. In this study, we examined Rxfp1 gene and protein expression in the non-pregnant (NP), pregnant and postpartum (PP) rat uterus. The potential effects of local conceptus-derived factors on Rxfp1 expression were then examined in unilaterally pregnant rats. Immunoreactive RXFP1 was predominantly detected in the circular smooth muscle layer in the myometrium and in the decidualized endometrium. Rxfp1 was expressed in the rat myometrium at similar levels to NP from early to mid gestation, with a significant reduction in expression at both the transcriptional and translational level in late gestation. In unilaterally pregnant rats, myometrial Rxfp1 was higher in the non-gravid compared to the gravid uterine horn, demonstrating a local negative influence of the fetal-placental unit on Rxfp1 expression. In summary, the down-regulation in myometrial Rxfp1 expression at the end of gestation in the rat is partially mediated by the fetalplacental unit and is indicative of a functional withdrawal of relaxin. This may represent a novel mechanism for the activation of spontaneous uterine contractions at labor in this species.

Title: Decreased Expression of the Rat Myometrial Relaxin Receptor (RXFP1) in Late Pregnancy is Partially Mediated by the Presence of the Conceptus Short title: Regulation of myometrial Rxfp1 expression

Mary E. Wlodek

Papers

a sex-specific manner metabolic genes during postnatal cardiac development in Growth restriction in the rat alters expression of

Circadian Variation of Human Milk Hormones and Macronutrients: Implications for Sampling and Analysis Strategies

Associations of maternal and foetoplacental factors with prehypertension/hypertension in early childhood

lactation: comparing prenatal and postnatal exposure mothers consuming alcohol during pregnancy or Whole body insulin resistance in rat offspring of

Title: Decreased Expression of the Rat Myometrial Relaxin Receptor (RXFP1) in Late Pregnancy is Partially Mediated by the Presence of the Conceptus Short title: Regulation of myometrial Rxfp1 expression