Metabolic control in cancer cells.

An important hallmark of cancer cells is a profound change in metabolism. Indeed, most tumor cells are characterized by higher rates of glycolysis, lactate production, and biosynthesis of lipids and other macromolecules. Our group, among others, has previously demonstrated a close relationship between metabolic responses and proliferative stimuli, showing that cell cycle regulators have a major role in the control of metabolism. Changes in this coordinated response might lead to abnormal metabolic changes during tumor development and cancer progression. In this paper we review the dual role of cell cycle regulators in the control of both proliferation and metabolism in normal and in cancer cells. We show participation of the E2F1-CDK4 axis in the modulation of oxidative metabolism, in the positive regulation of lipid synthesis, and the regulation glycolysis. These three metabolic pathways are, interestingly fundamental in providing synthetic processes, energy production and cell signaling events, which are crucial factors for cancer cell survival.

Hormonal control of spermatogenesis in men: therapeutic aspects in hypogonadotropic hypogonadism.

During the first two trimesters of intrauterine life, fetal sex steroid production is driven by maternal human chorionic gonadotropin (hCG). The HPG axis is activated around the third trimester and remains active for the first 6-months of neonatal life. This so-called mini-puberty is a developmental window that has profound effects on future potential for fertility. In early puberty, GnRH secretion is reactivated first at night and then night and day. Pulsatile GnRH stimulates both LH and FSH, which induce maturation of the seminiferous tubules and Leydig cells. Congenital hypogonadotropic hypogonadism (CHH) results from GnRH deficiency. Men with CHH lack the mini-pubertal and pubertal periods of Sertoli Cell proliferation and thus present with prepubertal testes (<4mL) and low inhibin serum levels --reflecting diminished SC numbers. To induce full maturation of the testes, GnRH-deficient patients can be treated with either pulsatile GnRH, hCG or combined gonadotropin therapy (FSH+hCG). Fertility outcomes with each of these regimens are highly variable. Recently, a randomized, open label treatment study (n=13) addressed the question of whether a sequential treatment with FSH alone prior to LH and FSH (via GnRH pump) could enhance fertility outcomes. All men receiving the sequential treatment developed sperm in the ejaculate, whereas 2/6 men in the other group remained azoospermic. A large, multicenter clinical trial is needed to definitively prove the optimal treatment approach for severe CHH.

Steroidogenesis of the testis - new genes and pathways

Defects of androgen biosynthesis cause 46,XY disorder of sexual development (DSD). All steroids are produced from cholesterol and the early steps of steroidogenesis are common to mineralocorticoid, glucocorticoid and sex steroid production. Genetic mutations in enzymes and proteins supporting the early biosynthesis pathways cause adrenal insufficiency (AI), DSD and gonadal insufficiency. The classic androgen biosynthesis defects with AI are lipoid CAH, CYP11A1 and HSD3B2 deficiencies. Deficiency of CYP17A1 rarely causes AI, and HSD17B3 or SRD5A2 deficiencies only cause 46,XY DSD and gonadal insufficiency. All androgen biosynthesis depends on 17,20 lyase activity of CYP17A1 which is supported by P450 oxidoreductase (POR) and cytochrome b5 (CYB5). Therefore 46,XY DSD with apparent 17,20 lyase deficiency may be due to mutations in CYP17A1, POR or CYB5. Illustrated by patients harboring mutations in SRD5A2, normal development of the male external genitalia depends largely on dihydrotestosterone (DHT) which is converted from circulating testicular testosterone (T) through SRD5A2 in the genital skin. In the classic androgen biosynthetic pathway, T is produced from DHEA and androstenedione/-diol in the testis. However, recently found mutations in AKR1C2/4 genes in undervirilized 46,XY individuals have established a role for a novel, alternative, backdoor pathway for fetal testicular DHT synthesis. In this pathway, which has been first elucidated for the tammar wallaby pouch young, 17-hydroxyprogesterone is converted directly to DHT by 5α-3α reductive steps without going through the androgens of the classic pathway. Enzymes AKR1C2/4 catalyse the critical 3αHSD reductive reaction which feeds 17OH-DHP into the backdoor pathway. In conclusion, androgen production in the fetal testis seems to utilize two pathways but their exact interplay remains to be elucidated.

Contribution to the ethnobotanical study of antidiabetic medicinal plants of the Central Middle Atlas region (Morocco)

An ethnobotanical survey of medicinal plants was carried out in the Central Middle Atlas in the years 2013 and 2014 to establish the catalog of medicinal plants used in traditional medicine in the treatment of diabetes. Thus, 1560 people were interviewed, using questionnaires. The latter enabled us to gather information on traditional healing practices of the local population including scientific name, French name, vernacular name, plant parts used , therapeutic indications , revenues and mode of administration. The results show that 76 medicinal species were inventoried in the study area. These plant species are included into 67 genus and 40 families. The most represented families are: Lamiaceae (12 species), Asteraceae and Brassicaceae species with 14 each. Of 76 medicinal species found in the region, four species are reported for the first time in the traditional treatment of diabetes in Morocco. They are Pistacia atlantica, Ptychotis verticillata, Anacyclus pyrethrum, Alyssum spinosum, Cistus albidus, Juniperus thurifera, Ephedra nebrodensis, Thymus algeriensis, Th. munbyanus, Th. zygis, Abelmoschus esculentus, Fraxinus augustifolia, Sorghum vulgare and, Eriobotrya japonica. The leaves are the most used organs (38%). The decoction is the dominant mode of preparation (50%) and administration is mostly for oral use (97%).