Evidence for Bell-Shaped Dose-Response Emetic Effects of Temsirolimus and Analogs: The Broad-Spectrum Antiemetic Efficacy of a Large Dose of Temsirolimus Against Diverse Emetogens in the Least Shrew ().

Temsirolimus is a prodrug form of sirolimus (rapamycin). With its analogs (everolimus, ridaforolimus, and rapamycin), it forms a group of anticancer agents that block the activity of one of the two mammalian targets of rapamycin (mTOR) complexes, mTORC1. We investigated the emetic potential of varying doses (0, 0.

Signal transduction pathways involved in dopamine D receptor-evoked emesis in the least shrew (Cryptotis parva).

With its five receptor subtypes (D), dopamine is implicated in a myriad of neurological illnesses. Dopamine D receptor-based agonist therapy evokes nausea and vomiting. The signaling mechanisms by which dopamine D receptors evoke vomiting remains unknown.

Dopamine receptors in emesis: Molecular mechanisms and potential therapeutic function.

Dopamine is a member of the catecholamine family and is associated with multiple physiological functions. Together with its five receptor subtypes, dopamine is closely linked to neurological disorders such as schizophrenia, Parkinson's disease, depression, attention deficit-hyperactivity, and restless leg syndrome. Unfortunately, several dopamine receptor-based agonists used to treat some of these diseases cause nausea and vomiting as impending side-effects.

Δ-THC and related cannabinoids suppress substance P- induced neurokinin NK-receptor-mediated vomiting via activation of cannabinoid CB receptor.

Δ-THC suppresses cisplatin-induced vomiting through activation of cannabinoid CB receptors. Cisplatin-evoked emesis is predominantly due to release of serotonin and substance P (SP) in the gut and the brainstem which subsequently stimulate their corresponding 5-HT-and neurokinin NK-receptors to induce vomiting. Δ-THC can inhibit vomiting caused either by the serotonin precursor 5-HTP, or the 5-HT receptor selective agonist, 2-methyserotonin.

Phosphaplatin Anti-tumor Effect Enhanced by Liposomes Partly an Up-regulation of PEDF in Breast Cancer.

Background/aim: Phosphaplatin platinum (IV) (RRD4) complex has exceptional antitumor properties. The aim of this study was to investigate the effects and the mechanism of action of free and liposome-encapsulated RRD4 in breast cancer.

Materials And Methods: Liposome-encapsulated RRD4 prepared by thin-film dehydration: hydration and free RRD4 were tested in vivo and in vitro against 4T1 breast cancer cells.

Insights into the anti-angiogenic properties of phosphaplatins.

Phosphaplatins are platinum-based antitumor compounds that, unlike other clinically utilized platinum drugs (i.e. cisplatin, carboplatin, and oxaliplatin), appear to target proteins rather than DNA.

Altered cytokine network in gestational diabetes mellitus affects maternal insulin and placental-fetal development.

Pregnancy is characterized by an altered inflammatory profile, compared to the non-pregnant state with an adequate balance between pro-and anti-inflammatory cytokines needed for normal development. Cytokines are small secreted proteins expressed mainly in immunocompetent cells in the reproductive system. From early developmental stages onward, the secretory activity of placenta cells clearly contributes to increase local as well as systemic levels of cytokines.

Correlation between Gene Variants, Signaling Pathways, and Efficacy of Chemotherapy Drugs against Colon Cancers.

Efficacies, toxicities, and resistance mechanisms of chemotherapy drugs, such as oxaliplatin and 5-fluorouracil (5-FU), vary widely among various categories and subcategories of colon cancers. By understanding the differences in the drug efficacy and resistance at the level of protein-protein networks, we identified the correlation between the drug activity of oxaliplatin/5-FU and gene variations from the US National Cancer Institute-60 human cancer cell lines. The activity of either of these drugs is correlated with specific amino acid variant(s) of KRAS and other genes from the signaling pathways of colon cancer progression.

Anti-tumor effects of pigment epithelium-derived factor (PEDF): implication for cancer therapy. A mini-review.

Pigment epithelium-derived factor (PEDF) is a secreted glycoprotein and a non-inhibitory member of the serine protease inhibitor (serpin) family. It is widely expressed in human fetal and adult tissues but its expression decreases with age and in malignant tissues. The main anti-cancer activities of PEDF derive from its dual effects, either indirectly on the tumor microenvironment (indirect antitumor action) or directly on the tumor itself (direct antitumor influence).

Cross-sectional pilot study about the liver enzymes profile in type 2 diabetic patients from an Algerian west region: Wilaya of Mostaganem.

Aims: The magnitude of abnormal liver enzymes profile in type 2 diabetic patients is unknown in Algerian west region even though it counts among liver diseases considered as an important cause of death in type 2 diabetes. The main objective is to assess the prevalence of elevated liver enzymes levels among patients with type 2 diabetes from Algerian west region and to determine associated risk factors.

Materials And Methods: A descriptive cross sectional study was performed on 180 type 2 diabetic patients in whom anthropometric and biochemical parameters were determined.

Absence of Activation of DNA Repair Genes and Excellent Efficacy of Phosphaplatins against Human Ovarian Cancers: Implications To Treat Resistant Cancers.

Phosphaplatins, platinum(II) and platinum(IV) complexes coordinated to a pyrophosphate moiety, exhibit excellent antitumor activities against a variety of cancers. To determine whether phosphaplatins trigger resistance to treatment by engaging DNA damage repair genes, a yeast genome-wide fitness assay was used. Treatment of yeast cells with pyrodach-2 (D2) or pyrodach-4 (D4) revealed no particular sensitivity to nucleotide excision repair, homologous recombination repair, or postreplication repair when compared with platin control compounds.

HSP27 knockdown produces synergistic induction of apoptosis by HSP90 and kinase inhibitors in glioblastoma multiforme.

Background/aim: The heat-shock proteins HSP27 and HSP90 perpetuate the malignant nature of glioblastoma multiforme (GBM) and offer promise as targets for novel cancer therapeutics. The present study sought to define synergistic antitumor benefits of concurrent HSP27-knockdown and the HSP90 inhibitor, 17-N-allylamino-17-demethoxygeldanamycin (17-AAG) or, comparatively, the non-selective kinase inhibitor, staurosporine, in GBM cells.

Materials And Methods: Dose-response relations were determined for 17-AAG and staurosporine in three GBM cell lines.

Gestational diabetes mellitus alters apoptotic and inflammatory gene expression of trophobasts from human term placenta.

Aim: Increased placental growth secondary to reduced apoptosis may contribute to the development of macrosomia in GDM pregnancies. We hypothesize that reduced apoptosis in GDM placentas is caused by dysregulation of apoptosis related genes from death receptors or mitochondrial pathway or both to enhance placental growth in GDM pregnancies.

Methods: Newborn and placental weights from women with no pregnancy complications (controls; N=5), or with GDM (N=5) were recorded.

Neurotrophic factor expression in expandable cell populations from brain samples in living patients with Parkinson's disease.

Cell-based therapies offer promise for patients with Parkinson's disease (PD); however, durable and effective transplantation substrates need to be defined. This study characterized the feasibility and growth properties of primary cultures established from small-volume brain biopsies taken during deep brain stimulation (DBS) surgery in patients with PD. The lineage and expression of neurotrophic factors with known beneficial actions in PD-affected brain circuitry were also evaluated.

Placental-mediated increased cytokine response to lipopolysaccharides: a potential mechanism for enhanced inflammation susceptibility of the preterm fetus.

Background: Cerebral palsy is a nonprogressive motor impairment syndrome that has no effective cure. The etiology of most cases of cerebral palsy remains unknown; however, recent epidemiologic data have demonstrated an association between fetal neurologic injury and infection/inflammation. Maternal infection/inflammation may be associated with the induction of placental cytokines that could result in increased fetal proinflammatory cytokine exposure, and development of neonatal neurologic injury.

Intermittent fasting modulation of the diabetic syndrome in streptozotocin-injected rats.

This study investigates the effects of intermittent overnight fasting in streptozotocin-induced diabetic rats (STZ rats). Over 30 days, groups of 5-6 control or STZ rats were allowed free food access, starved overnight, or exposed to a restricted food supply comparable to that ingested by the intermittently fasting animals. Intermittent fasting improved glucose tolerance, increased plasma insulin, and lowered Homeostatis Model Assessment index.

Altered mitochondrial apoptotic pathway in placentas from undernourished rat gestations.

Maternal undernutrition (MUN) during pregnancy results in intrauterine growth-restricted (IUGR) fetuses and small placentas. Although reduced fetal nutrient supply has been presumed to be etiologic in IUGR, MUN-induced placental dysfunction may occur prior to detectable fetal growth restriction. Placental growth impairment may result from apoptosis signaled by mitochondria in response to reduced energy substrate.

Altered placental development in undernourished rats: role of maternal glucocorticoids.

Maternal undernutrition (MUN) during pregnancy may lead to fetal intrauterine growth restriction (IUGR), which itself predisposes to adult risk of obesity, hypertension, and diabetes. IUGR may stem from insufficient maternal nutrient supply or reduced placental nutrient transfer. In addition, a critical role for maternal stress-induced glucocorticoids (GCs) has been suggested to contribute to both IUGR and the ensuing risk of adult metabolic syndrome.

Intermittent fasting modulation of the diabetic syndrome in sand rats. III. Post-mortem investigations.

The present report concerns several post-mortem variables examined in sand rats that were either maintained on a vegetal diet (control animals) or exposed first during a 20-day transition period to a mixed diet consisting of a fixed amount of a hypercaloric food and decreasing amounts of the vegetal food and then to a 30-day experimental period of exposure to the hypercaloric food. During the latter period, all animals were either given free access to food or fasting daily for 15 h, i.e.

Early compensatory adaptations in maternal undernourished pregnancies in rats: role of the aquaporins.

Objective: To investigate the effect of maternal undernutrition (MUN) during pregnancy on fetal and placental weight, amniotic fluid (AF) volume, AF osmolality and ion concentrations at gestational ages E16 and E20. We also quantified protein expression of water channels (aquaporins; AQPs).

Methods: Pregnant rat dams were fed an ad libitum diet (AdLib; n = 6) or were 50% MUN (n = 6) beginning at E10 of gestation.

Intermittent fasting modulation of the diabetic syndrome in sand rats. II. In vivo investigations.

This study deals with the effects of daily intermittent fasting for 15 h upon the development of diabetes in sand rats exposed to a hypercaloric diet. The same pattern of daily intermittent fasting was imposed on sand rats maintained on a purely vegetal diet (control animals). Over the last 30 days of the present experiments, non-fasting animals gained weight, whilst intermittently fasting sand rats lost weight.

Maternal undernutrition influences placental-fetal development.

Maternal nutrition during pregnancy has a pivotal role in the regulation of placental-fetal development and thereby affects the lifelong health and productivity of offspring. Suboptimal maternal nutrition yields low birth weight, with substantial effect on the short-term morbidity of the newborn. The placenta is the organ through which gases, nutrients, and wastes are exchanged between the maternal-fetal circulations.

Paradoxical increase in maternal plasma leptin levels in food-restricted gestation: contribution by placental and adipose tissue.

Maternal food restriction (FR) during pregnancy results in decreased body weight with increased plasma leptin. To address this paradox, we investigated the effects of FR during pregnancy on growth and leptin levels in maternal, placental, and fetal sites. From embryonic day E10, control pregnant rats received ad libitum (AdLib) food, whereas study rats were 50% FR.

AQP1 gene expression is upregulated by arginine vasopressin and cyclic AMP agonists in trophoblast cells.

Aquaporins (AQPs) are water channels that regulate water flow in many tissues. As AQP1 is a candidate to regulate placental fluid exchange, we sought to investigate the effect of arginine vasopressin (AVP) and cAMP agonists on AQP1 gene expression in first trimester-derived extravillous cytotrophoblasts (HTR-8/Svneo) and two highly proliferative carcinoma trophoblast-like cell lines but with a number of functional features of the syncytiotrophoblast namely; JAR and JEG-3 cells. Our data demonstrated that AVP (0.

Glyceryl trinitrate inhibits hypoxia/reoxygenation-induced apoptosis in the syncytiotrophoblast of the human placenta: therapeutic implications for preeclampsia.

Damage of the placenta resulting from ischemia-reperfusion is important to the pathophysiology of preeclampsia. Here we investigated whether low concentrations of glyceryl trinitrate (GTN), a nitric oxide mimetic with anti-apoptotic properties, inhibit hypoxia/reoxygenation-induced apoptosis in the syncytiotrophoblast of chorionic villous explants from human placentas. Compared with villi analyzed immediately after delivery or maintained under normoxic conditions, villi exposed to a 6-hour cycle of hypoxia/reoxygenation exhibited greater numbers of syncytiotrophoblasts with terminal dUTP nick-end labeling (TUNEL)-positive nuclei in the syncytiotrophoblast.