Mini Reviews in Medicinal Chemistry - Volume 12, Issue 11, 2012

In the search of the sleep substance, many studies have been addressed for different hormones, responsible for sleep-wake cycle regulation. In this article we mentioned the participation of steroid hormones, besides its role regulating sexual behavior, they influence importantly in the sleep process. One of the clearest relationships are that estrogen and progesterone have, that causing changes in sleep patterns associated with the hormonal cycles of women throughout life, from puberty to menopause and specific periods such as pregnancy and the menstrual cycle, including being responsible for some sleep disorders such as hypersomnia and insomnia. Another studied hormone is cortisol, a hormone released in stressful situations, when an individual must react to an extraordinary demand that threatens their survival, but also known as the hormone of awakening because the release peak occurs in the morning, although this may be altered in some sleep disorders like insomnia and mood disorders. Furthermore neurosteroids such as pregnanolone, allopregnanolone and pregnenolone are involved in the generation of slow wave sleep, the effect has been demonstrated in experimental animal studies. Thus we see that the sleep and the endocrine system saved a bidirectional relationship in which depends on each other to regulate different physiological processes including sleep.

The Acquired Immunodeficiency Syndrome (AIDS) constitutes the main infectious cause of death in adults worldwide. Epidemiological data suggest the existence of differences in viral load and CD4+ T lymphocytes cell counts related to gender. Women have more favorable clinical and viro-immunological patterns than men in early infection, although once established the infection these patterns are reversed. Increasing evidence shows that estradiol (E) and progesterone (P) participate in the regulation of several infections, such as that produced by human immunodeficiency virus (HIV). Several functions of these hormones involve the interaction with their intracellular receptors (ER and PR, respectively). During infection, E and P not only exert their action upon the immune system, but also directly act on the virus. Effects of E and P depend on their concentration or the phase of HIV infection but in general terms, they could exert a protective role against HIV infection.

Progesterone and estradiol participate in the regulation of many pulmonary functions, for example progesterone mediates the fall of alveolar carbon dioxide tension observed in the luteal phase of the menstrual cycle and during pregnancy in humans, when progesterone levels are high. The treatment with estradiol diminishes vasoconstriction and hypoxia. Progesterone and estradiol in addition to participating in non-pathological functions such as vasodilation and lung maturation, also have influence on pathologies as asthma, cystic diseases and cancer. Therefore this review will provide an overview of the action and effects of these hormones in lung, their mechanism of action through their intracellular receptors and their influence over asthma, cystic lung diseases and cancer.

Herein we discuss the effects of hormones on reproduction, but with a focus on the ripples that emanate from the main effects. That is, the role of hormones in reproductive events is both well-known and well accepted; less studied and understood are effects that appear to be ancillary to the primary objectives of the hormonal effects, which support, complement and extend their primary effects. We present evidence for how the hormonal stimulation of pregnancy constructs the maternal brain; makes it more efficient; enhances cognition; regulates stress responsiveness; modifies sensory systems (we discuss mainly olfaction); neurogenesis; and learning. Thus, steroid and other hormones and neuropeptides restructure the nervous system, particularly of females, to produce and regulate maternal behavior as well as behaviors and physiological systems that contribute to and support what is arguably the primary function of the hormones: survival and effective nurturance of the female's metabolic and genetic investment.

During the helminth infections, the immune system tends to be modulated by host's sex hormones. Actually, many studies show the reciprocal relationship between sex steroids, the immune system and the elimination or establishment of helminth parasites. Is well known that innate immune response determines the type of adaptive immune response, so the effects in the innate immune response by hormones may affect subsequent adaptive immunity. The sex steroids as estrogens, progesterone and testosterone regulate growth, differentiation, survival and function of many cell types that could be involved in process like homeostasis and immunity, but also have a direct effect on the helminthes, that may probably be mediated by specific receptors on these parasites. Sex steroids, parasites and immunity are closely connected, and their interconnection is involved in the maintenance of elimination or establishment of helminthes in an immunocompetent host. For that reason, understanding the action’s mechanisms of sex steroids on immune cells and its direct effect on helminth parasites is important for further progress in the development of novel therapies for chronic helminth diseases associated to immune dysregulation. In this review, we will describe the effects of sex steroids on the immune response during helminth infections as well as the direct effect in these parasites, and the possible implications of these effects on the incidence of several helminth infections.

Besides their effects on reproduction, estrogens exert neuroprotective effects for brain diseases. Thus, estrogens ameliorate the negative aspects of aging and age-associated diseases in the nervous system, including hypertension. Within the brain, the hippocampus is sensitive to the effects of hypertension, as exemplified in a genetic model, the spontaneously hypertensive rat (SHR). In the dentate gyrus of the hippocampus, SHR present decreased neurogenesis, astrogliosis, low expression of brain derived neurotrophic factor (BDNF), decreased number of neurons in the hilus and increased basal levels of the estrogen-synthesizing enzyme aromatase, with respect to the Wistar Kyoto (WKY) normotensive strain. In the hypothalamus, SHR show increased expression of the hypertensinogenic peptide arginine vasopressin (AVP) and its V1b receptor. From the therapeutic point of view, it was highly rewarding that estradiol treatment decreased blood pressure and attenuated brain abnormalities of SHR, rendering hypertension a suitable model to test estrogen neuroprotection. When estradiol treatment was given for 2 weeks, SHR normalized their faulty brain parameters. This was shown by the enhancement of neurogenesis in the dentate gyrus, according to increased bromodeoxyuridine incorporation and doublecortin labeling, decreased reactive astrogliosis, increased BDNF mRNA and protein expression in the dentate gyrus, increased neuronal number in the hilus of the dentate gyrus and a further hyperexpression of aromatase. The presence of estradiol receptors in hippocampus and hypothalamus suggests the possibility of direct effects of estradiol on brain cells. Successful neuroprotection produced by estradiol in hypertensive rats should encourage the treatment with non-feminizing estrogens and estrogen receptor modulators for age-associated diseases.

The rat posterodorsal medial amygdala (MePD) expresses receptors for gonadal hormones and integrates sex steroid-sensitive subcortical networks. Male-female differences are found in the morphology, connectivity, and local neuropil structure of MePD. For example, dendritic spine density is sexually-dimorphic and changes with the estrous cycle and following gonadal hormones manipulations. Due to its connectivity, the MePD may affect emotionally-loaded social behaviors, according to a former Newman's seminal proposition. Unilateral fiber-sparing ibotenic acid damage of the MePD does not impair male sexual behavior. However, microinjecting glutamate and histamine into the right MePD facilitates ejaculation. Further, MePD-lesioned rats are not different from normal rats in anxiety-like behavior as evaluated by the elevated plus maze test or innate fear test induced by a live cat. In another study, an adapted model for inducing aggressive behavior in rats by a brief period of restraint prior to the resident-intruder paradigm was used to study Fosimmunoreactivity in the MePD. Following stressful stimulation (restraint) or the restraint and fight condition, but not after aggression alone, Fos-immunoreactivity was detected in the MePD. Microinjecting the inhibitory neuropeptide somatostatin into the right MePD notably reduces fighting behavior without affecting locomotion. Overall, these data indicate that sex steroids and local neurochemical stimulatory/inhibitory transmitters modulate the MePD and reinforce the idea that this area is a node for modulating social behavior neural networks.

Appetite is the desire to satisfy the need to consume food, felt as hunger. It is regulated by the balance of food intake and energy expenditure via signals between the brain, the digestive tract and the adipose tissue. Males and females vary in terms of eating behavior as well as the way the body fat is stored. Energy balance and body fat distribution are part of the sexual dimorphism in many mammalian species including human beings. These sex dissimilarities could be related to the different sex steroid hormone profile in each sex. Gonadal steroid hormones play an important role in the regulation of food intake and energy homeostasis. Human epidemiological and experimental animal studies have shown that estradiol has a key role in the control of food intake and energy balance. Estradiol has long been known to inhibit feeding in animals. There are important changes in food intake patterns during the estrous cycle, with a reduction of food intake around the time of ovulation, when estradiol presents its highest levels. Men have less total fat and more central fat distribution which carries a much greater risk for metabolic disorders while women have more total fat and more gluteal/femoral subcutaneous fat distribution. Men and postmenopausal women accumulate more fat in the intraabdominal depot. This review is focused on the mechanism by which sex steroids affect feeding behavior and fat distribution.

The endocannabinoid system comprises the cannabinoid receptors type 1 (CB1) and type 2 (CB2), their endogenous ligands (endocannabinoids) and the whole apparatus appointed of their synthesis and degradation. Recent studies investigated the possibility that drugs targeting the endocannabinoid system might be used to retard or block cancer growth. CB1, CB2 and metabolic enzymes of endocannabinoids, function in the context of lipid rafts, specialized membrane microdomains enriched in cholesterol, sphingolipids and glycosphingolipids which may be important in modulating signal transduction. Here, we analysed the role of lipid rafts/caveolae in the intracellular signaling and trafficking of cannabinoid receptor agonist in cancer cells. Perturbation of lipid rafts/caveolae may in fact represent a useful tool for the development of a novel therapy for endocannabinoids-related diseases, such as cancer. Also, we report the more recent developments of endocannabinoids in cancer drug discovery.

Multidrug resistance (MDR) against groups of therapeutic drugs emerged to a central problem in the treatment of various diseases, i.e. cancer and infectious diseases like HIV or malaria. ABC transporters namely P-glycoprotein (P-gp) and various multidrug resistance associated proteins (MRPs) mainly contribute to the MDR phenomenon in cancer treatment and HIV therapy. Their cellular expression in respective cells like cancer cells lowers the intracellular drug concentrations and thus reasons the cellular resistance. The induction of such efflux pumps occurs during the therapy with drugs which will be affected by the MDR phenomenon as a consequence of the induction. In this review studies which report such drugs-caused inductions will be viewed. The review will cover the literature of recent years and attract attention to this important question in drug resistance. Finally, the discussion will suggest possible strategies to overcome the problem, i. e. by using non-inducing drugs.

Telomerase is a ribonucleoprotein complex that elongates telomeric DNA and appears to play an important part in the cellular immortalization of cancers. In the screening of potent inhibitors of human telomerase, several inhibitors have been discovered from natural and chemical sources. Some compounds potently inhibit the activity of human telomerase. Rubromycins and fatty acids such as β-rubromycin and oleic acid, respectively, were found to be inhibitors of human telomerase. The IC50 values of β-rubromycin and oleic acid were 8.60 and 8.78 μM, respectively. A kinetic study revealed that these compounds competitively inhibited the activity of telomerase with respect to the substrate of the primer and dNTP. The energy-minimized three-dimensional structure of β-rubromycin and oleic acid was calculated and designed. The V-shaped curve and molecule length of 18.7-20.3 Å in these compound structures were suggested to be important for telomerase inhibition. The three-dimensional structure of the active site of telomerase (i.e., the binding site of the primer and dNTP substrate) might have a “pocket” that could “join” these compounds. These results appear to suggest a potential structure for the development of more potent inhibitors of human telomerase.

Designing antagonists to anti-apoptotic proteins of Bcl-2 family has become an important strategy in cancer chemotherapy. Using experimental techniques and computational methods, a few numbers of lead inhibitors to the antiapoptotic proteins have been reported in the literature and a few of them are under clinical trials. In this review, the lead inhibitors designed using in silico methodologies are exclusively covered, systematically organized and critically evaluated. An orchestrated in silico strategy for screening and identifying efficient antagonists to the anti-apoptotic proteins has also been brought into fore.

As a natural antioxidant resource, traditional Chinese medicine (TCM) has been paid much more attentions than before. The studies on its antioxidative activity have also increased dramatically in recent years. Abundant studies on TCM show that some TCM can increase body's activity of antioxidant enzymes, enhance body's ability of scavenging free radicals and decrease the generation of lipid peroxide (LPO) and malondialdehyde (MDA) in the body etc. The action mechanism of TCM is closely related to its active constituents, including polysaccharides, quinines, flavonoids, saponins, alkaloids, terpenes, phenolic acids compounds and tannins etc. Through referring to related reports on TCM, in the last 20 years, this paper reviews literatures involved in antioxidation research on TCM. Antioxidative mechanism, functional property and application prospect of some active constituents with antioxidation in TCM are discussed.