D-004 ameliorates phenylephrine-induced urodynamic changes and increased prostate and bladder oxidative stress in rats

Background

Lower urinary tract symptoms (LUTS) in patients with benign prostatic hyperplasia (BPH) mainly depend on alpha1-adrenoreceptors (α₁-ADR) stimulation, but a link with oxidative stress (OS) is also involved. D-004, a lipid extract of Roystonea regia fruits, antagonizes ADR-induced responses and produces antioxidant effects. The objective of this study was to investigate whether D-004 produce antioxidant effects in rats with phenylephrine (PHE)-induced urodynamic changes.

Methods

Rats were randomized into eight groups (ten rats/group): a negative vehicle control and seven groups injected with PHE: a positive control, three treated with D-004 (200, 400 and 800 mg/kg) and three others with tamsulosin (0.4 mg/kg), grape seed extract (GSE) (250 mg/kg) and vitamin E (VE) (250 mg/kg), respectively.

Results

Effects on urinary total volume (UTV), volume voided per micturition (VM), malondialdehyde (MDA) and carbonyl groups (CG) concentrations in prostate and bladder homogenates were study outcomes. While VM and UTV lowered significantly in the positive control as compared to the negative control group, the opposite occurred with prostate and bladder MDA and CG values. D-004 (200-800 mg/kg) increased significantly both VM and UTV, lowered significantly MDA in prostate and bladder homogenates, and reduced GC levels only in the prostate. Tamsulosin increased significantly VM and UTV, but unchanged oxidative variables. GSE and VE unchanged the UTV, whereas VE, not GSE, modestly but significantly attenuated the PHE-induced decrease of VM.

Conclusions

Single oral administration of D-004 (200-800 mg/kg) was the only treatment that ameliorated the urodynamic changes and reduced increased oxidative variables in the prostate of rats with PHE-induced prostate hyperplasia.     

Delayed Gastric Emptying After Sleeve Gastrectomy Is Associated with Poor Weight Loss

Obesity Surgery - Intermediate to long-term weight regain is a major challenge following sleeve gastrectomy (SG). Physiological changes that mediate the extent of weight loss remain unclear. We...     

Partial redirection of transgenic human growth hormone secretion from rat salivary glands

Regulated secretory pathway proteins, when delivered as transgenes to salivary glands, are secreted predominantly into saliva. This is not useful for those proteins whose therapeutic function is required systemically, for example, human growth hormone (hGH). One strategy to improve the efficiency of hGH secretion into the bloodstream involves manipulation of existing sorting signals. The C terminus of hGH is highly conserved and contains a domain similar to the regulated pathway sorting domain of pro-opiomelanocortin (POMC). We hypothesized that, similar to POMC, mutation of this domain would divert hGH secretion from the regulated to the constitutive pathway, which in salivary glands leads to the bloodstream. Several mutations were made in the C terminus of the hGH cDNA and tested in vitro. One biologically active mutant containing E174A and E186A substitutions, and with an included C-terminal extension, was studied in greater detail. Compared with wild-type hGH, we found that this mutant hGH accumulated in the Golgi/trans-Golgi network and showed increased basal secretion in AtT20 cells, a model endocrine cell line. Importantly, in vivo, the mutant hGH displayed a relative increase in the proportion of constitutive pathway secretion seen from rat salivary glands, with a significantly lower saliva-versus-serum secretion ratio (p=0.03). Although this mutant is unlikely to be therapeutically beneficial, these results suggest that the final destination of a transgenic secretory protein may be controlled by reengineering its sorting determinants.     

Analysis of polymorphisms and haplotypes in genes associated with vascular tone,hypertension and oxidative stress in Mexican-Mestizo women with severe preeclampsia

ObjectiveSeveral studies have reported the association of genes related to vascular tone, hypertension, oxidative stress and preeclampsia. We investigated the possible association among three polymorphisms in eNOS (as well their haplotypes): one of MTHFR, one of GSTP1 and one of AGT, with severe preeclampsia in Mexican-Mestizo women.MethodsTwo hundred thirty women with severe preeclampsia and 350 control subjects were genotyped; for rs2070744 and rs1799983 of eNOS, rs1801133 of MTHFR, rs1695 of GSTP1 and rs699 of AGT we used real-time PCR allelic discrimination and for VNTR of eNOS, PCR. Allele frequency differences were assessed by χ². Logistic regression was used to test for associations and for haplotype frequencies using Haploview 4.2.ResultsGenotypic and allelic distribution of the polymorphisms was similar between cases and controls; likewise, haplotype frequencies of the three polymorphisms of eNOS did not differ significantly.ConclusionsTo our knowledge, this is the first time that these polymorphisms have been analyzed together and exclusively in women with severe preeclampsia. However, we did not find an association between polymorphisms of eNOS, MTHFR, GSTP1 and AGT with severe preeclampsia in our population. Additionally, we observed differences in the distribution of the alleles and genotypes of these polymorphisms in our population in comparison to those described in other ethnic groups.     

Pediatric and adult H3 K27M-mutant diffuse midline glioma treated with the selective DRD2 antagonist ONC201

Journal of Neuro-Oncology - Smoking is agreed to be a major health risk factor, but it is debated whether it has an influence on perioperative adverse events (AEs) in elective cranial tumor...     

Protective effects of D-002 on experimentally induced gastroesophageal reflux in rats

AIM:To investigate the effects of beeswax alcohols(D-002)on the esophageal damage induced by gastroesophageal reflux(GER)in rats.METHODS:Sixty male rats were randomized into six groups(10 rats/group):a negative control and five groups with experimentally induced GER:a positive vehicle control,three treated with D-002(25,100 and 200mg/kg,respectively),and one with omeprazole 10 mg/kg.All treatments were given by gastric gavage.One hour after dosing,GER was produced by simultaneous ligation of the pyloric end and the forestomach.Esophageal lesions index(ELI),gastric secretion volume and acidity,and esophageal malondialdehyde(MDA)and sulfhydryl(SH)group concentrations were measured.Statistical significance was considered at P<0.05.RESULTS:As compared to the negative control,the positive control group exhibited increased ELI(5.2±0.33 vs 0±0,P=0.0003),gastric secretion volume(2.69±0.09 vs 0.1±0.0,P=0.0003)and acidity(238±19.37 vs 120.0±5.77,P=0.001),and esophageal concentrations of MDA(2.56±0.1 vs 1.76±0.28,P=0.001)and SH groups(1.02±0.05 vs 0.56±0.08,P=0.0003).D-002(25,100 and 200 mg/kg)reduced ELI(3.36±0.31,2.90±0.46 and 2.8±0.23,respectively)vs the positive control(5.2±0.33)(P=0.004;P=0.002;P=0.001,respectively).There were no significant changes in acidity with D-002 treatment,and only the highest dose reduced the volume of the gastric secretion(1.92±0.25)vs the positive control(2.69±0.09,P=0.013).D-002(25,100 and 200 mg/kg)lowered the esophageal MDA(2.05±0.16,1.98±0.22and 1.93±0.22,respectively)(P=0.01;P=0.03;P=0.03,respectively)and SH group concentration(0.87±0.06,0.79±0.08 and 0.77±0.06,respectively)(P=0.04;P=0.04;P=0.02)vs the positive control(2.56±0.10 and 1.02±0.05,respectively).Omeprazole decreased ELI(2.54±0.47),gastric secretion volume(1.97±0.14)and acidity(158.5±22.79),esophageal MDA(1.87±0.13)and SH group(0.72±0.05)concentrations vs the positive control(P=0.002;P=0.001;P=0.02;P=0.003;P=0.002,respectively).CONCLUSION:Acute oral administration of D-002 decreased macroscopic esophageal lesions and oxidative stress in rats with experimentally induced GER,without modifying gastric secretion acidity.     

Yes-associated protein 1 is widely expressed in human brain tumors and promotes glioblastoma growth

The hippo pathway and its downstream mediator yes-associated protein 1 (YAP1) regulate mammalian organ size in part through modulating progenitor cell numbers. YAP1 has also been implicated as an oncogene in multiple human cancers. Currently, little is known about the expression of YAP1 either in normal human brain tissue or in central nervous system neoplasms. We used immunohistochemistry to evaluate nuclear YAP1 expression in the fetal and normal adult human brains and in 264 brain tumors. YAP1 was expressed in fetal and adult brain regions known to harbor neural progenitor cells, but there was little YAP1 immunoreactivity in the adult cerebral cortex. YAP1 protein was also readily detected in the nuclei of human brain tumors. In medulloblastoma, the expression varied between histologic subtypes and was most prominent in nodular/desmoplastic tumors. In gliomas, it was frequently expressed in infiltrating astrocytomas and oligodendrogliomas but rarely in pilocytic astrocytomas. Using a loss-of-function approach, we show that YAP1 promoted growth of glioblastoma cell lines in vitro. High levels of YAP1 messenger RNA expression were associated with aggressive molecular subsets of glioblastoma and with a nonsignificant trend toward reduced mean survival in human astrocytoma patients. These findings suggest that YAP1 may play an important role in normal human brain development and that it could represent a new target in human brain tumors.     

Translation, adaptation, and validation of the Stanford Hypnotic Clinical Scale in Puerto Rico

The only hypnotizability scale that has been translated and validated for the Puerto Rican population is the Barber Suggestibility Scale (BSS). In this article, the Stanford Hypnotic Clinical Scale (SHCS) was translated and validated for this population. The translated SHCS ("Escala Stanford de Hipnosis Clinica" [ESHC]) was administered individually to 100 Puerto Rican college students. There were no significant differences found between the norms of the original SHCS samples and the Spanish version of the SHCS. Both samples showed similar distributions. The Spanish version's internal reliability as well as the item discrimination index were adequate. The authors conclude that the ESHC is an adequate instrument to measure hypnotizability in the Puerto Rican population.     

LIN28A facilitates the transformation of human neural stem cells and promotes glioblastoma tumorigenesis through a pro-invasive genetic program

The cellular reprogramming factor LIN28A promotes tumorigenicity in cancers arising outside the central nervous system, but its role in brain tumors is unknown. We detected LIN28A protein in a subset of human gliomas observed higher expression in glioblastoma (GBM) than in lower grade tumors. Knockdown of LIN28A using lentiviral shRNA in GBM cell lines inhibited their invasion, growth and clonogenicity. Expression of LIN28A in GBM cell lines increased the number and size of orthotopic xenograft tumors. LIN28A expression also enhanced the invasiveness of GBM cells in vitro and in vivo. Increasing LIN28A was associated with down-regulation of tumor suppressing microRNAs let-7b and let-7g and up-regulation of the chromatin modifying protein HMGA2. The increase in tumor cell aggressiveness in vivo and in vitro was accompanied by an upregulation of pro-invasive gene expression, including SNAI1. To further investigate the oncogenic potential of LIN28A, we infected hNSC with lentiviruses encoding LIN28A together with dominant negative R248W-TP53, constitutively active KRAS and hTERT. Resulting subclones proliferated at an increased rate and formed invasive GBM-like tumors in orthotopic xenografts in immunodeficient mice. Similar to LIN28A-transduced GBM neurosphere lines, hNSC-derived tumor cells showed increased expression of HMGA2. Taken together, these data suggest a role for LIN28A in high grade gliomas and illustrate an HMGA2-associated, pro-invasive program that can be activated in GBM by LIN28A-mediated suppression of let-7 microRNAs.