Estrogen altered visceromotor reflex and P2X3 mRNA expression in a rat model of colitis

P2X₃ and P2X_2/3 receptors are expressed in peripheral tissues and dorsal root ganglia (DRG) and participate in peripheral pain. However, the mechanisms underlying P2X receptor-mediated nociception at different ovarial hormone levels has not been examined. In this study, 24 female rats were randomly divided into sham-operated (sham), ovariectomized (OVX), estrogen-treated, and estrogen–progesterone-treated groups with colitis. In each group, the visceromotor reflex (VMR) to colorectal distension was tested and the DRG were harvested for a real-time PCR analysis of P2X₃ and P2X₂ receptor mRNA. In OVX rats with colitis we found that the VMR to colorectal distension and P2X₃ receptor mRNA in DRG were both significantly decreased. Estrogen replacement reversed the decrease. However, neither the VMR nor the P2X₃ mRNA level in DRG from OVX colitis rats was reversed by the complex of estrogen and progesterone. Patch-clamp recording showed that in colitis rats, estradiol rapidly potentiated the sustained and transient currents evoked by ATP to 336 ± 49% and 122 ± 12% of controls, respectively, in a subpopulation of DRG neurons, which were blocked by ICI 182, 780, an antagonist of the estrogen receptor. Whereas progesterone rapidly inhibited the transient currents induced by ATP to 67 ± 10% of control and had no effect on the sustained currents evoked by the same agonist. These results indicate that P2X₃ receptors are likely to be an important contributor to the altered colonic functions in colitis rats, where the underlying mechanisms are closely related to endogenous estrogen modulation.     

Mechanisms of Weight Loss After Sleeve Gastrectomy and Adjustable Gastric Banding: Far More Than Just Restriction

Obesity has reached global epidemic proportions in recent decades. Bariatric surgery is currently accepted as most effective in alleviating morbid obesity and related disorders. Sleeve gastrectomy (SG) and adjustable gastric banding (AGB) have gained popularity since the beginning of this century because of their efficacy, safety, and simplicity. SG, in particular, has emerged as the most popular bariatric procedure because of its simpler concept and shorter operative time compared with gastric bypass. Caloric restriction, however, cannot account for the sustained weight loss and improved glucose metabolism seen following SG and AGB. Other mechanisms, including changes in gastrointestinal hormone secretion, rearrangement of hypothalamic and vagal control, alteration in energy expenditure, and re‐regulation of bile acid metabolism and the intestinal flora environment, are thought to contribute to the postoperative benefits. This review focuses on clinical and experimental literature addressing the potential mechanisms for SG and AGB procedures in human and animal models. Understanding such mechanisms can provide important insight into how current gastric restrictive procedures work and how future treatments of obesity, both surgical and nonsurgical, can be developed.     

A selectivity study of sodium‐dependent glucose cotransporter 2/sodium‐dependent glucose cotransporter 1 inhibitors by molecular modeling

Sodium‐dependent glucose cotransporters (SGLTs) play an important role in glucose reabsorption in the kidney and have been identified as promising targets to treat diabetes. Because of the side effects like glucose and galactose malabsorption by targeting SGLT1, highly selective SGLT2 inhibitors are more promising in the treatment of diabetes. To understand the mechanism of selectivity, we conducted selectivity‐based three‐dimensional quantitative structure–activity relationship studies to highlight the structure requirements for highly selective SGLT2 inhibitors. The best comparative molecular field analysis and comparative molecular similarity indices analysis models showed the noncross‐validated coefficient (r²) of 0.967 and 0.943, respectively. The predicted correlation coefficients (r²_pred) of 0.974 and 0.938 validated the reliability and predictability of these models. Besides, homology models of SGLT2 and SGLT1 were also constructed to investigate the selective mechanism from structure‐based perspective. Molecular dynamics simulation and binding free energy calculation were performed on the systems of a potent and selective compound interacting with SGLT2 and SGLT1 to compare the different binding modes. The simulation results showed that the stretch of the methylthio group on Met241 had an essential effect on the different binding modes between SGLT1 and SGLT2, which was consistent with the three‐dimensional quantitative structure–activity relationship analysis. Hydrogen bond analysis and binding free energy calculation revealed that SGLT2 binding complex was more stable and favorable than SGLT1 complex, which was highly correlated with the experimental results. Our obtained results give useful information for the investigation of the inhibitors' selectivity between SGLT2 and SGLT1 and will help for further development of highly selective SGLT2 inhibitors. Copyright © 2015 John Wiley & Sons, Ltd.     

Disease Burden Due to Herpes Zoster among Population Aged ≥50 Years Old in China: A Community Based Retrospective Survey

ObjectiveTo understand the disease burden due to Herpes Zoster (HZ) among people aged ≥50 years old in China and provide baseline data for future similar studies, and provide evidence for development of herpes zoster vaccination strategy.MethodsRetrospective cohort study was conducted in 4 townships and one community. A questionnaire was used to collect information on incidence and cost of HZ among people aged ≥ 50 years old.ResultsThe cumulative incidence rate was 22.6/1,000 among people aged ≥ 50 years old. The average annual incidence rate of HZ was 3.43/1,000 among people aged ≥ 50 years old in 2010–2012. Cumulative incidence and average annual incidence rate increased with age: the cumulative incidence of HZ among people aged ≥ 80 years old was 3.34 times of that among 50- years old (52.3/1000vs15.7/1,000); average annual incidence rate rises from 2.66/1,000 among 50- years old to 8.55/1,000 among 80- year old. Cumulative incidence and average annual incidence rate for females were higher than that for males (cumulative incidence, 26.5/1000vs18.7/1,000; annual incidence rate, 3.95/1000vs2.89/1,000). Cumulative incidence and average annual incidence rate in urban were higher than in rural (cumulative incidence, 39.5/1000vs 17.2/1,000; annual incidence rate, 7.65/1000vs2.06/1,000). The hospitalization rate of HZ was 4.53%. And with the increase of age, the rate has an increasing trend. HZ costs 945,709.5 RMB in total, corresponding to 840.6 RMB per patient with a median cost of 385 RMB (interquartile range 171.7–795.6). Factors associated with cost included the first onset year, area, whether hospitalized and whether sequelae left.ConclusionIncidence rate, complications, hospitalization rate and average cost of HZ increase with age. We recommend that the HZ vaccinations should target people aged ≥50 years old if Zoster vaccine is licensed in China.     

Association of TRB3 Q84R polymorphism with polycystic ovary syndrome in Chinese women

Background  

Tribbles 3 (TRB3) affects insulin signalling by inhibiting insulin-stimulated Akt phosphorylation and subsequent activation. A single nucleotide polymorphism located in the second extron of the human TRB3 gene is thought to be associated with insulin resistance. The latter is a core abnormality in PCOS independent of obesity. The present study was designed to clarify the relationships of TRB3 Q84R polymorphism with PCOS in a Chinese women group.     

Synthesis and evaluation of some steroidal oximes as cytotoxic agents: Structure/activity studies (II)

Hydroximinosteroids isolated from marine sponges display a variety of biological functions including cytotoxicity and anti-virus. In this study, we synthesized a series of hydroximinosteroid derivatives with a different functional group on the ring A or B and various side chains at position 17, and analyzed the cytotoxicity of these compounds against sk-Hep-1, H-292, PC-3 and Hey-1B cancer cells. Our results revealed that although a cholesterol-type side chain at position 17 is required for the biological activity of the compounds as we previously confirmed, elimination of the 4,5-double bond augmented the cytotoxic activity for the steroidal oximes. In addition, the presence of a hydroxy on 3- or 6-position of the steroidal nucleus resulted in a remarkable increase of cytotoxic activity. Our findings present more evidence showing the relationship between the chemical structure and biological function.     

Diversity of the superfamily of phloem lectins (phloem protein 2) in angiosperms

Phloem protein 2 (PP2) is one of the most abundant and enigmatic proteins in the phloem sap. Although thought to be associated with structural P-protein, PP2 is translocated in the assimilate stream where its lectin activity or RNA-binding properties can exert effects over long distances. Analyzing the diversity of these proteins in vascular plants led to the identification of PP2-like genes in species from 17 angiosperm and gymnosperm genera. This wide distribution of PP2 genes in the plant kingdom indicates that they are ancient and common in vascular plants. Their presence in cereals and gymnosperms, both of which lack structural P-protein, also supports a wider role for these proteins. Within this superfamily, PP2 proteins have considerable size polymorphism. This is attributable to variability in the length of the amino terminus that extends from a highly conserved domain. The conserved PP2 domain was identified in the proteins encoded by six genes from several cucurbits, celery (Apium graveolens), and Arabidopsis that are specifically expressed in the sieve element-companion cell complex. The acquisition of additional modular domains in the amino-terminal extensions of other PP2-like proteins could reflect divergence from its phloem function.     

The association of idiopathic recurrent early pregnancy loss with polymorphisms in folic acid metabolism-related genes

The aim of this study was to investigate the association between polymorphisms in folic acid metabolism-related genes and idiopathic recurrent early pregnancy loss (REPL). A prospective case–control study was performed on a cohort of 82 REPL patients and 166 healthy controls. Genotyping of methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C was assessed by applying polymerase chain reaction for amplification followed by DNA sequencing, for methionine synthase reductase A66G, solute carrier family 19, member 1 (SLC19A1) G80A and C696T, and genotyping was done by utilizing the Sequenom MassARRAY system. The results revealed a significant association between MTHFR A1298C polymorphism and idiopathic REPL. Haplotype analysis indicated that the MTHFR 677C-MTHFR 1298C allele combination was associated with REPL (P < 0.001). The MTHFR 677C-MTHFR 1298A and SLC19A1 80G-SLC19A1 696C allele combinations had lower frequencies in patients with REPL, but with P > 0.05 (P = 0.093 and P = 0.084, respectively).