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Three new ring B-seco limonoids, ciliatonoids A-C (1-3), were isolated from Toona ciliate and structurally characterized by spectroscopic data, X-ray crystallography, and electronic circular dichroism analysis. Ciliatonoids A and B feature an unprecedented limonoid architecture, while ciliatonoid C belongs to a rare class of limonoids. Biological evaluation showed that compound 3 exhibited modest activities against the tested tumor cell lines.

This study was designed to evaluate the diagnostic value of common inflammatory markers with regard to fever of unknown origin (FUO). We investigated 383 patients who were hospitalized with FUO at the Henan Province People's hospital between January 2009 and June 2015. Of all the cases, infectious diseases accounted for 33.9%, neoplasms for 21.1%, collagen vascular diseases for 25.1%, miscellaneous diseases for 4.7%, and no diagnosis for 15.1%. Patients in the neoplasm group were older than those in the infectious disease, collagen vascular disease, and miscellaneous disease groups (p = 0.006, p < 0.0001, and p = 0.001, respectively). The duration of fever before admission of patients in the neoplasm and collagen vascular disease group was longer than that of patients in the infectious disease group (p = 0.002 and p = 0.007, respectively). The diagnostic time after admission of patients from the neoplasm and collagen vascular disease groups was longer than that for patients from the infectious disease group (both p < 0.0001). Serum ferritin levels of patients in the infectious disease group were lower than those of patients in the neoplasm and collagen vascular disease groups (p = 0.029 and p = 0.032, respectively), while serum procalcitonin (PCT) levels in the infectious disease group was higher than that in the neoplasm and collagen vascular disease groups (p = 0.016 and p = 0.007, respectively). Therefore, FUO remains a clinical problem in China and serum ferritin and PCT may be useful in discriminating infectious from non-infectious causes (neoplasms and collagen vascular diseases) in patients with FUO.

OBJECTIVE: This study aimed to assess risk factors for mother-to-child transmission (MTCT) of hepatitis B virus (HBV) after immunoprophylaxis. METHODS: Risk factors for MTCT were assessed using a multivariate logistic regression model. PATIENTS: We enrolled 256 mother-child pairs with positive maternal hepatitis B surface antigens (HBsAg) between January 2010 and June 2013. All children received passive-active immunization after birth. The children were tested for HBsAg at birth and 6-12 months and/or 1-3 years of age. RESULTS: Among 256 children, 10 (3.9%) developed HBV infection, all of whom were born to hepatitis B e antigen (HBeAg)-positive mothers with a high HBV DNA level (median, 7.36; range, 6.75-8.00 log10 IU/mL). A total of 20 mothers received antiviral treatment during pregnancy. The maternal viral load decreased from an average of 7.16 to 3.08 log10 IU/mL (p

Summary: Glucose-stimulated insulin secretion from islet β cells is mediated by KATP channels. However, the role of non-KATP K+ channels in insulin secretion is largely unknown. Here, we show that a non-KATP K+ channel, KCNH6, plays a key role in insulin secretion and glucose hemostasis in humans and mice. KCNH6 p.P235L heterozygous mutation co-separated with diabetes in a four-generation pedigree. Kcnh6 knockout (KO) or Kcnh6 p.P235L knockin (KI) mice had a phenotype characterized by changing from hypoglycemia with hyperinsulinemia to hyperglycemia with insulin deficiency. Islets from the young KO mice had increased intracellular calcium concentration and increased insulin secretion. However, islets from the adult KO mice not only had increased intracellular calcium levels but also had remarkable ER stress and apoptosis, associated with loss of β cell mass and decreased insulin secretion. Therefore, dysfunction of KCNH6 causes overstimulation of insulin secretion in the short term and β cell failure in the long term. : Yang et al. show that KCNH6 plays a key role in insulin secretion and glucose hemostasis in humans and mice. Dysfunction of KCNH6 results in a hyperinsulinemia phenotype in the short term and hypoinsulinemia and diabetes in the long term. Keywords: maturity-onset diabetes of the young, MODY, monogenic diabetes, type 2 diabetes, islet, insulin secretion, KCNH6, KCNH2, KATP, Cas9

The hepatitis B virus(HBV) polymerase rtA181T mutation is selected during long-term antiviral therapy. As the polymerase gene completely overlaps with the envelope (S) gene, HBV rtA181T mutation also carries sW172 mutations. In this study, we investigated whether there were biological differences between rtA181T/sW172* (coding truncated HBsAg) and rtA181T/sW172L (coding substituted HBsAg) mutants. In cell experiments, a slight decline of viral replication was observed in both two mutants as compared to wild-type strains, but the levels of supernatant HBsAg and HBV DNA in rtA181T/sW172* were significantly lower than those in rtA181T/sW172L transfected cells. In animal experiments, we were amazed to find that viral replication in rtA181T/sW172* mutant increased and maintained significantly longer than that in rtA181T/sW172L mutant, while no significant difference was observed between rtA181T/sW172L and wild-type strains. Compared with wild-type strains, there were intracellular accumulations of HBsAg and HBcAg in rtA181/sW172* but none in rtA181/sW172L mutant strains. Importantly, we also found that truncated HBsAg could increase the activity of HBV core promoter, but substituted HBsAg could not. In summary, the characteristics of above two rtA181T mutants mentioned above were significantly different, and it is necessary and important for us to distinguish sW172* truncated mutation from sW172L substituted mutation.

There is a widespread interest in defining factors and mechanisms that stimulate proliferation of pancreatic islet β-cells. Pregnancy is a special period when the pancreatic islet displays a highly reproducible physiological proliferation. However, the molecular mechanism of β-cell proliferation during pregnancy is unclear. Here, we used cDNA expression array to explore gene expression profiles of islet at various stages of pregnancy in rats. Differentially expressed genes related to islet proliferation were screened by bioinformatics methods, and further verified by real-time PCR, RT-PCR, and Western blotting. Compared with control group, expressions of hundreds of genes were changed during pregnancy. The differentially expressed genes related to islet proliferation were mainly distributed in three groups: genes involved in transcription regulator activity, genes involved in apoptosis or tumor, and genes for Wnt signaling pathway. Among these genes, expressions of Nupr1, Atf3, Btg2, β-catenin, and c-Myc mRNA were up-regulated during pregnancy. A prominent expression of Nupr1 and Atf3 protein was observed in islets on day 10.5 of pregnancy, i.e., with earlier time phases than proliferation peak. Moreover, we found that prolactin (PRL) can increase the proliferation of β-cell in vitro, which is accompanied by up-regulation of Atf3 and Nupr1, indicating that they may play a crucial role in PRL-induced pancreatic β-cell growth. In conclusion, our results suggest that the transcription factor Nupr1, Atf3, and Wnt pathway may play an important role in adaptive proliferation of pancreatic islets during pregnancy in rats.

Hirschsprung disease (HSCR) is a complex congenital disorder characterized by intestinal obstructions caused by the absence of the intestinal ganglion cells of the nerve plexuses in variable lengths of the digestive tract. This study investigated a possible role of the RET proto-oncogene in sporadic HSCR patients in the Han Chinese population. Our results indicated that rs1800858, rs1800860, rs1800863, and rs2075912, located in exons 2, 7, 15, and intron 19 of RET, are strongly associated with the disease (P < 0.01), with rs1800860 and rs1800863 playing a protective role in the pathogenesis of HSCR in the Chinese population. We also showed that the haplotype consisting of four SNPs is significantly associated with HSCR. We did not find a significant difference in the CA-repeat in intron 5 of RET between cases and controls. Our study provided further evidence that the RET gene is involved in the susceptibility to HSCR in the Han Chinese population.

Staphylococcal enterotoxin C injection is established as a clinical therapy for delayed healing or disunion of bone fractures. In the present study, the effects of staphylococcal enterotoxin C injection in combination with ascorbic acid (SEC-AA) on the differentiation of bone marrow-derived mesenchymal stem cells (MSCs) and their influences on the mineralization of osteoblasts were investigated. SEC-AA treatment induced increased levels of alkaline phosphatase activity in MSCs and increased numbers of alizarin red-stained calcified nodules, indicating enhanced differentiation of MSCs into osteoblasts. The findings demonstrated that SEC-AA promoted the differentiation of MSCs into osteoblasts and accelerated the cytopoiesis of osteoblasts. Our data provide a cytological model for bone fracture therapy aimed at shortening the time required for healing and improving the clinical outcome, and also provide a theoretical basis for inducible differentiation of MSCs, mineralization of osteoblasts and reconstruction of bone tissues.

Chronic low-grade inflammation characterized by adipose tissue macrophage accumulation and abnormal cytokine production is a key feature of obesity and type 2 diabetes. Adipose-tissue-derived monocyte chemoattractant protein (MCP)-1, induced by cytokines, has been shown to play an essential role in the early events during macrophage infiltration into adipose tissue. In this study we investigated the effects of resveratrol upon both tumor necrosis factor (TNF)-a-induced MCP-1 gene expression and its underlying signaling pathways in 3T3-L1 adipoctyes. Resveratrol was found to inhibit TNF-a-induced MCP-1 secretion and gene transcription, as well as promoter activity, which based on down-regulation of TNF-a-induced MCP-1 transcription. Nuclear factor (NF)-jB was determined to play a major role in the TNF-a-induced MCP-1 expression. Further analysis showed that resveratrol inhibited DNA binding activity of the NF-jB complex and subsequently suppressed NF-jB transcriptional activity in TNF-a-stimulated cells. Finally, the inhibition of MCP-1 may represent a novel mechanism of resveratrol in preventing obesity-related pathologies. 2008 Elsevier Inc. All rights reserved.

Aim: To investigate the activity and expression of neutral ceramidase (N-CDase) in the insulin-secreting cell line INS-1 and its role in the cellular response to cytokines. Methods: HPLC, Western blotting, and quantitative real-time PCR were performed to detect the activity and expression of N-CDase in INS-1 cells treated with a cytokine mixture (5 ng/mL interleukin-1β, 10 ng/mL TNF-α, and 50 ng/mL interferon-γ). The expression and activity of N-CDase in the INS-1 cells were specifically inhibited using N-CDase-siRNA transfection. Annexin V-fluorescein-isothiocyanate/propidium iodide flow cytometry was used to assess apoptosis in the INS-1 cells. Results: The INS-1 cells exhibited some basal N-CDase activity, and cytokines induced a time-dependent delay in the activation of N-CDase. As a result, the activation of N-CDase was first detectable at 8 h after stimulation. It peaked at 16 h and remained elevated at 24 h. Cytokines also upregulated the mRNA and protein expression of N-CDase in the INS-1 cells. Furthermore, when N-CDase activity was inhibited by RNA interference, cytokine-induced apoptosis in the INS-1 cells was markedly increased. Conclusion: The N-CDase pathway is active in INS-1 cells, and the chronic activation of N-CDase is involved in the pathological response of β-cells to cytokines, potentially providing protection against cytokine toxicity.

Objective To investigate the effects of gene therapy with IL-10 on PTg-induced proliferation of splenocytes and Th1 cytokine production from PTg-stimulated splenocytes. Methods EAT rats were divided into four groups: group A (PBS+PLL), group B (pORF+PLL), group C (pORFmIL10+PLL), and group D (pORFmIL10+MEM). The substances mixed with lipofectamine were injected into the thyroid tissues of rats on the 18th dday after immunization. The rats were sacrificed at the 8th week. In vitro proliferative responses to ConA and different concentration of PTg were measured by culturing 4×105 splenocytes pulsed with 18.5KBq of [ 3 H] thymidine for the final 12h and then harvested for liquid scintillation counting. In vitro splenocytes were cultured with PTg (25 mg/L). Th1 cytokine IFN-γ, TNF-α and IL-2 were detected by ELISA. Results The proliferative response to PTg was suppressed in group C, compared with that of group A and B ( P P P P Conclusion IL-10 gene transmission in thyroid tissues could inhibit PTg specific proliferation of splenocytes from EAT rats and the secretion of Th1 cytokines from PTg-stimulated splenocytes.

Fourteen new diterpenoids including clerodane (1–12), labdane (13), and norlabdane (14) types, as well as nine known analogues were isolated from the aerial parts of Croton laui. Their structures were established on the basis of spectroscopic analysis, and that of crotonolide H (11) was confirmed by single-crystal X-ray crystallography. Crotonolide A (1) exhibited moderate cytotoxicity against two tumor cell lines, HL-60 (human premyelocytic leukemia, IC50 9.42 μM) and P-388 (murine leukemia, IC50 7.45 μM), and crotonolide G (10) displayed significant antibacterial activity against a panel of Gram-positive bacteria.

Epidemiological studies have linked intrauterine growth retardation (IUGR) to the metabolic diseases, consisting of insulin resistance, type 2 diabetes, obesity and coronary artery disease, during adult life. To determine the internal relationship between IUGR and islet β cell function and insulin sensitivity, we established the IUGR model by maternal nutrition restriction during mid- to late-gestation. Glucose tolerance test and insulin tolerance test (ITT) in vivo and glucose stimulated insulin secretion (GSIS) test in vitro were performed at different stages in IUGR and normal groups. Body weight, pancreas weight and pancreas/body weight of IUGR rats were much lower than those in normal group before 3 weeks of age. While the growth of IUGR rats accelerated after 3 weeks, pancreas weight and pancreas/body weight remained lower till 15 weeks of age. In the newborns, the fasting glucose and insulin levels of IUGR rats were both lower than those of controls, whereas glucose levels at 120 and 180 min after glucose load were significantly higher in IUGR group. Between 3 and 15 weeks of age, both the fasting glucose and insulin levels were elevated and the glucose tolerance was impaired with time in IUGR rats. At age 15 weeks, the area under curve of insulin (AUCi) after glucose load in IUGR rats elevated markedly. Meanwhile, the stimulating index of islets in IUGR group during GSIS test at age 15 weeks was significantly lower than that of controls. ITT showed no significant difference in two groups before 7 weeks of age. However, in 15-week-old IUGR rats, there was a markedly blunted glycemic response to insulin load compared with normal group. These findings demonstrate that IUGR rats had both impaired pancreatic development and deteriorated glucose tolerance and insulin sensitivity, which would be the internal causes why they were prone to develop type 2 diabetes.

Hypothyroidism is often related with increased blood pressure, yet, gender-specific associations between subclinical hypothyroidism (SCH) and hypertension have not been previously assessed. We conducted a large-scale, cross-sectional study from six districts of Jiangsu Province to investigate the association of SCH and blood pressure in female and male adults. In the studied population, 4725 participants (3034 women and 1691 men) aged 20-60 years were included. The prevalence of hypertension was significantly higher in males as compared to females (37.34% vs. 27.39%, P 0.05), while the prevalence of SCH was much higher in women (9.36% vs. 5.32%, P 0.05). Furthermore, the hypertension rate was significantly higher in female SCH group compared to euthyroid (EUT) group(P 0.05), while no significant differences were observed between the two groups in male participants(P 0.05). After adjusting for age and body mass index (BMI), SCH was an independent predictor for increased SBP (OR = 1.47, 95%CI 1.08-1.99, P = 0.015) and elevated pulse pressure (OR = 1.45, 95%CI 1.05-1.99, P = 0.024) in females, and serum thyroid stimulating hormone (TSH) was significantly higher in female hypertensive group as compared to normotensive group (2.09 vs. 1.92 mIU/l, P = 0.0004). In male participants, SCH was not independently correlated with blood pressure, and no significant difference in TSH levels between hypertensive and normotensive groups was observed (1.74 vs. 1.66 mIU/l, P = 0.12). We concluded that SCH is an independent predictor of increased SBP and pulse pressure in females. Thus, thyroid function may influence blood pressure to a greater extent in females compared to males.

The relationship between subclinical thyroid dysfunction and blood pressure has been controversial and received unsufficient attention. Thus, we performed a cross-sectional study conducted among 6,992 inhabitants from six districts of Jiangsu Province to investigate the association of subclinical thyroid dysfunction with blood pressure in China. The data from 6,583 subjects (4,115 women and 2,468 men) were included and divided into three groups: euthyroidism (n = 5669, 86.11%), subclinical hyperthyroidism (n = 108, 1.65%), and subclinical hypothyroidism (n = 806, 12.24%). In the groups with subclinical hypothyroidism and hyperthyroidism, systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse pressure were not significantly different from those in the groups with euthyroidism after being adjusted for age, sex, BMI, and smoking status (P0.05). More extensively, the SBP and DBP in the group of subclinical hypothyroidism with lower level of TSH (TSH 4.51-10.00 mIU/l, SCH(1)) were significantly higher than those of participants with euthyroidism (P0.05). Multivariable logistic analysis revealed that subclinical hypothyroidism with lower TSH (TSH 4.51-10.00 mIU/l) was an independent risk factor for increased SBP (OR = 1.28, 95% CI 1.03-1.59, P = 0.028). Similar results could not be found between groups of euthyroid and subclinical hypothyroid with higher level of TSH (TSH10 mIU/l, SCH(2)). Further subdivision of the euthyroid group on the basis of a TSH cut-off of 2.5 mIU/l, revealed still no significant difference in blood pressure after adjustment regardless of whether the TSH levels were in the lower reference (TSH 0.40-2.50 mIU/l, n = 4093) or in the upper reference ranges (TSH 2.51-4.50 mIU/l, n = 1576) (P0.05). We concluded that subclinical thyroid dysfunction was not associated with blood pressure. Neither subclinical hyperthyroidism nor subclinical hypothyroidism independently predicted increased blood pressure.

This project explored the influence of loss of heterozygosity (LOH) and microsatellite instability (MSI) of locus D8S277 to PINX1 expression of gastric cancer in Chinese people. LOH and MSI of locus D8S277 in 90 paraffin-embedded gastric carcinoma specimens were detected by polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP). Envision immunohistochemistry was used to assess the expression of PINX1. The frequency of LOH was higher in cases with lymph node metastasis than those without (18.57 vs. 0.00%, P

Hirschsprung’s disease (HSCR) is a congenital disorder characterized by intestinal obstructions due to the absence of enteric ganglia along variable lengths of the intestinal tract. RET coding mutations have been found in approximately 50% of familial cases, but they only explain a minority of sporadic cases. Here, we report our investigation of a possible role of RET non-coding mutations in sporadic HSCR patients. The haplotypes of seven single nucleotide polymorphisms (SNPs), all located in a region 4 kb upstream of the gene through to 23 kb of intron 1, and one SNP in exon 2 were constructed in 125 Han Chinese patients with sporadic HSCR and in 148 Han Chinese controls. Our results indicated that eight SNPs were significantly associated with HSCR (P < 0.0001). The C allele of rs2505535 would appear to represent a protecting allele for the Chinese population. One single haplotype composed of these eight markers was present in 59.6% of patients, versus 18.1% of controls. Based on our results, we conclude that non-coding mutations in RET have important roles in the development of HSCR. The unknown functional disease variant(s), with a dosage-dependent effect in HSCR, is likely to be located in the 5′-region of the RET gene.

AIM: To study the capacity of bone marrow mesenchymal stem cells (BM-MSCs) trans-differentiating into islet-like cells and to observe the effect of portal vein transplantation of islet-like cells in the treatment of streptozotocin-induced diabetic rat. METHODS: BM-MSCs were isolated from SD rats and induced to differentiate into islet-like cells under defined conditions. Differentiation was evaluated with electron microscopy, RT-PCR, immunofluorescence and flow cytometry. Insulin release after glucose challenge was tested with ELISA. Then allogeneic islet-like cells were transplanted into diabetic rats via portal vein. Blood glucose levels were monitored and islet hormones were detected in the liver and pancreas of the recipient by immunohistochemistry. RESULTS: BM-MSCs were spheroid adherent monolayers with high CD90, CD29 and very low CD45 expression. Typical islet-like cells clusters were formed after induction. Electron microscopy revealed that secretory granules were densely packed within the cytoplasm of the differentiated cells. The spheroid cells expressed islet related genes and hormones. The insulin-positive cells accounted for 19.8% and mean fluorescence intensity increased by 2.6 fold after induction. The cells secreted a small amount of insulin that was increased 1.5 fold after glucose challenge. After transplantation, islet-like cells could locate in the liver expressing islet hormones and lower the glucose levels of diabetic rats during d 6 to d 20. CONCLUSION: Rat BM-MSCs could be transdiffe-rentiated into islet-like cells in vitro. Portal vein transplantation of islet-like cells could alleviate the hyperglycemia of diabetic rats.

ObjectiveThis study investigated and compared the clinical thinking ability of undergraduate nursing students of different grades, and searched for influencing factors of clinical thinking ability of nursing undergraduate students.MethodsThe convenience sampling method was used to select the Subject of the study. In total, 180 third-year, fourth-year, and fifth-year nursing undergraduate students were enrolled in this study. A self-designed scale of clinical thinking ability was used to collect the data. SPSS17.0 was used to analyze the data.ResultsThe average scores of clinical thinking ability of undergraduate nursing students were 68.14 ± 9.13. in addition, 71.1% of the students have a higher level of clinical thinking ability, and only 7.2% of the students have the best level. The ANOVA test showed that the fourth-year students had the highest scores (72.96 ± 8.64), and the third-year students had the lowest scores (62.35 ± 8.09), which indicated a significant difference in the scores of the three groups (F = 26.79, P