A dual nociceptin and mu opioid receptor agonist exhibited robust antinociceptive effect with decreased side effects.

The compelling demand of a consummate analgesic medication without addiction is rising due to the clinical mistreatment. Additionally, the series of severe untoward effects usually deterred the utilization while coping with serious pain. As a possible turning point, we revealed that compound 14 is a dual agonist of mu opioid receptor (MOR) and nociceptin-orphanin FQ opioid peptide (NOP) receptor in this study. More importantly, compound 14 achieves pain relieving at very small doses, meanwhile, reduces several unwanted side effects such as constipation, reward, tolerance and withdrawal effects. Here, we evaluated the antinociception and side effects of this novel compound from wild type and humanized mice to further develop a safer prescription analgesic drug.

Association of SLC22A1, SLC22A2, SLC47A1, and SLC47A2 Polymorphisms with Metformin Efficacy in Type 2 Diabetic Patients.

Response to metformin, first-line therapy for type 2 diabetes mellitus (T2DM), exists interindividual variation. Considering that transporters belonging to the solute carrier (SLC) superfamily are determinants of metformin pharmacokinetics, we evaluated the effects of promoter variants in organic cation transporter 1 (OCT1) (SLC22A1 rs628031), OCT2 (SLC22A2 rs316019), multidrug and toxin extrusion protein 1 (MATE1) (SLC47A1 rs2289669), and MATE2 (SLC47A2 rs12943590) on the variation in metformin response. The glucose-lowering effects and improvement of insulin resistance of metformin were assessed in newly diagnosed, treatment-naive type 2 diabetic patients of Han nationality in Chaoshan China (n = 93) receiving metformin. Fasting plasma glucose (FPG), fasting insulin (FINS), glycated hemoglobin A1 (HbA1C), homeostasis model assessment-insulin sensitivity (HOMA-IS), and homeostasis model assessment-insulin resistance (HOMA-IR) were the main metformin efficacy measurements. There were significant correlations between both SLC47A1 rs2289669 and SLC47A2 rs12943590 and the efficacy of metformin in individuals with T2DM. In normal weight T2DM patients, significant associations between the AA and GG genotypes of the rs2289669 variant of SLC47A1 and a greater reduction in FINS and HOMA-IR were detected. A significant correlation was observed between the AG genotype of the rs12943590 polymorphism of SLC47A2 and a greater reduction in HOMA-IR. Gene-environment interaction analysis showed that in the FINS interaction model, the second-order of dose30_g-SLC47A2 rs12943590 was statistically significant. The variants of SLC47A1 rs2289669 and SLC47A2 rs12943590 could be predictors of insulin resistance in type 2 diabetic patients treated with metformin. The second-order interaction of dose30_g-SLC47A2 rs12943590 may have a significant effect on FINS in patients with T2DM on metformin treatment. These findings suggest that promoter variants of SLC47A1 and SLC47A2 are important determinants of metformin transport and response in type 2 diabetes mellitus.

Association of SLC22A1 rs622342 and ATM rs11212617 polymorphisms with metformin efficacy in patients with type 2 diabetes.

Metformin is the first-choice oral anti-hyperglycemic drug for type 2 diabetes mellitus (T2DM) patients. There are controversies about the association of SLC22A1 rs622342, which was not reported in the Chinese population, and ataxia-telangiectasia mutated (ATM) rs11212617 polymorphisms with metformin efficacy in T2DM. Our study was to investigate the effects of the two single nucleotide polymorphisms on the efficacy of metformin in T2DM of Han nationality in Chaoshan China. After enrollment, 82 newly diagnosed T2DM patients went on 2-month metformin monotherapy. According to BMI before treatment, the patients were divided into a normal weight group (≥18.5 and <25 kg/m2) and an overweight group (BMI ≥ 25 and <30 kg/m2). T-test, Pearson χ2 test, and regression analysis, which adjusted for age, BMI, sex, the dose of metformin, education, tea drink, smoking, and sweet, were used to evaluate the effects of rs622342 and rs11212617 on several variables, such as fasting plasma glucose (FPG). Compared with the AA or CC genotype, patients with AC genotype of rs622342 achieved greater reduction in Δ60FPG and Δ(60-30)FPG (P = 0.00820, 0.00089, respectively). For 11212617, the reduction in Δ30FPG and Δ60FPG was significantly different among patients with the AC genotype (P = 0.00026, 0.00820, respectively). Our results indicated that common variants of SLC22A1 rs622342 and ATM rs11212617 were associated with the efficacy of metformin in T2DM of Han nationality in Chaoshan China.

Association of KCNQ1 polymorphisms with gliclazide efficacy in Chinese type 2 diabetic patients.

OBJECTIVES: To investigate the effects of KCNQ1 polymorphisms on the efficacy of gliclazide in type 2 diabetic patients. MATERIALS AND METHODS: A total of 443 newly diagnosed type 2 diabetic patients were included in this study. After enrollment, patients went on an 8-week gliclazide monotherapy. Fasting plasma glucose (FPG) was measured before and after the treatment. Life-style information was collected by weekly follow-up. Genotyping of the two single-nucleotide polymorphisms was performed using the single base primer extension method. T-test, one-way analysis of variance, and Pearson χ-test were used to evaluate the effects of rs2237892 and rs2237897 on the FPG reduction and treatment success rate. RESULTS: After 8 weeks of gliclazide therapy, the FPG decreased significantly from 10.9±2.8 to 7.4±2.2 mmol/l (P<0.001). Compared with the CC genotype, patients with CT or TT genotypes of rs2237897 achieved greater reduction in FPG (3.9±2.6 vs. 3.2±2.4 mmol/l, P=0.003; 33.9±19.0 vs. 27.7±17.4%, P<0.001) and a higher rate of treatment success (74.1 vs. 65.2%, P=0.042 for criterion 1; 61.1 vs. 44.5%, P<0.001 for criterion 2, respectively), whereas no significant difference was found in the FPG reduction and treatment success rate among different genotypes of rs2237892. CONCLUSION: Our results indicated that a common variant of KCNQ1, rs2237897, was associated with the efficacy of gliclazide after 8-week monotherapy in Chinese newly diagnosed type 2 diabetic patients. The FPG reduction and treatment success rate were significantly higher in carriers of CT and TT genotypes.

Correlation between myeloid-derived suppressor cells and S100A8/A9 in tumor and autoimmune diseases.

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of cells that constitute an important component of immune regulatory system. Two calcium-binding proteins S100A8 and S100A9 act as important mediators in acute and chronic inflammation. In recent years, many researchers have found that MDSCs and S100A8/A9 operated with one another through a positive feedback loop to promote tumor development and metastasis. However, the correlation between MDSCs and S100A8/A9 in autoimmune diseases (AIDs) remains unknown. In this review, we discussed the co-operation of MDSCs and S100A8/A9 in tumor environment, and also, the role of these two components in AIDs.

A phase 3, multicenter, randomized, allopurinol-controlled study assessing the safety and efficacy of oral febuxostat in Chinese gout patients with hyperuricemia.

AIM: To compare the efficiency and safety of febuxostat with those of allopurinol in Chinese patients with gout and hyperuricemia. METHODS: The trial which was conducted at 13 centers in China during 2011-2013 included a 2-week run-in and a 24-week treatment period. A total of 504 eligible participants with gout and with serum urate ≥ 480 µmol/L were randomly assigned 1 : 1 : 1 to febuxostat 40 mg/day, febuxostat 80 mg/day and allopurinol 300 mg/day groups. The primary efficacy endpoint was the percentage of subjects whose last three serum urate levels were < 360 µmol/L. RESULTS: The primary efficacy endpoint was reached by 33.5% of subjects taking febuxostat 80 mg/day, 22.5% of those taking febuxostat 40 mg/day and 17.0% of those taking allopurinol 300 mg/day (P < 0.001 for the comparison between febuxostat 80 mg/day and allopurinol 300 mg/day groups; P = 0.216 for the comparison between febuxostat 40 mg/day and allopurinol 300 mg/day groups). The incidence of gout flare was relatively high in each group during the first 8 weeks and gradually decreased thereafter. There was no statistically significant difference between the three groups (P > 0.05). The incidence of adverse events was similar in the three treatment groups. The most frequent treatment-related adverse events were liver function test abnormalities. CONCLUSIONS: Febuxostat 80 mg/day had superior urate-lowering efficacy to that of febuxostat 40 mg/day or allopurinol 300 mg/day, which was comparable in Chinese gout patients with hyperuricemia. Febuxostat, at a daily dose of 40 or 80 mg, was safe and well tolerated.

Intervention of childhood and adolescents obesity in Shantou city.

OBJECTIVES: The purpose of this study was to evaluate the effects of multicomponent school based intervention constituted of diet modification, regular exercise and psychosocial consultation on body status in overweight and obese children and adolescents. And to come up with an appropriate intervention protocol for controlling children and adolescents obesity in Shantou city. METHODS: Two schools were randomised to intervention group and control group respectively. A total of 41 students enrolled were diagnosed as overweight or obese. Twenty-six students of the intervention group completed the one-year intervention programme consisted of diet modification, regular exercise and psychological consultation except two of them were transferred to another school. The differences of BMI, anthropometric measures, metabolic profile and the scores of questionnaire and the scale were compared to evaluate the effects of the intervention programme. RESULTS: After one-year intervention, it observed in the intervention group that BMI-Z score, WHR and WHtR had significant improvements, and there was a nonsignificant trend (P=0.053) for a decrease in BMI-P. Fasting plasma glucose, cholesterol (CH) and low-density-lipoprotein cholesterol (LDL-C) levels in the intervention group showed nonsignificant trend for a decrease (PFPG=0.084, PCH=0.057, PLDLC=0.098), compared with a significant increase of triglycerides (TG) and LDL-C levels in the control group (PTG=0.041, PLDL-C=0.038). There were some positive dietary, physical activity, or sedentary behaviour changes found in the students of the intervention group as the scores of the questionnaire got significant improvement (P=0.04). CONCLUSIONS: Our one-year multicomponent school-based intervention programme did have positive effects to some extents on health state and lifestyle behaviour of overweight and obese children and adolescents, which indicated that it is feasible and important to implement such a school-based intervention programme in Shantou city.

Expression and distribution of S-100, CD83, and costimulatory molecules (CD80 and CD86) in tissues of thyroid papillary carcinoma.

A higher expression of S-100 in tissue of thyroid papillary carcinoma (TPC) vs. thyroid follicular adenoma (TFA) (p < .001) was observed as well as a higher expression of CD83 in the peri-cancerous tissues vs. TFA (p < .001), oppositely, CD83 was negative in the cancerous net. TPC showed greater decreases in levels of CD80 and CD86 than did the TFA. These findings suggest that impaired immune function, absence of CD83-positive mature and activated dendritic cells in cancer nodules may have a role in the pathogenesis of TPC. The low expression of CD80 and CD86 in TPC may help them evade the immune system.

In vitro antigen-specific cytotoxic T cell response against esophageal carcinoma cells induced by HPV18E7-transfected dendritic cells.

Human Papillomavirus (HPV)-associated esophageal carcinoma (EC) is a high incidence tumor worldwide. Dendritic cell (DC)-based tumor vaccine is considered an alternative therapy to treat EC. Here we developed a DC-based vaccine by transfecting cord blood CD34+ stem cell-derived DC with HPV18E7 gene, observed its biological characteristics and the antigen-specific T-cell cytotoxicity on EC cells induced by HPV18E7-DC in vitro. Our results showed that 1) HPV18E7 gene transfer did not change the typical morphology of mature DC, 2) the representative phenotypes of mature DC (CD80, CD86, and CD83) were highly expressed in HPV18E7- DC (81.6%, 80.5%, and 86.6%, respectively), 3) the expression level of 18E7 protein in HPV18E7-DC was 47.5%, and 4) the specific cytotoxicity against EC cells was significantly higher than that in controls (p<0.01). This study indicates the possibility of a DC-based immunotherapy in HPV-associated EC.

Changes of serum and urine neutrophil gelatinase-associated lipocalin in type-2 diabetic patients with nephropathy: one year observational follow-up study.

We initiated the present work to explore whether neutrophil gelatinase-associated lipocalin (NGAL) could be used to predict the progression of diabetic nephropathy in type-2 diabetic patients. Seventy-four type-2 diabetic patients were divided into normo-, micro- and macro-albuminuria groups according to their 24 h-urinary albumin excreting rate. Serum and urine NGAL, and other clinical parameters were detected. Patients were followed and measurements were repeated 1 year later. An increased tendency of urine NGAL and a decreased tendency of serum NGAL were detected, from normo-albuminuria group to macro-albuminuria group. Serum NGAL was found to rise after follow-up. Moreover, urine NGAL was found to be correlated positively with cystatin C, urea nitrogen, and serum creatinine (SCr), and inversely with glomerular filtration rate (GFR), while serum NGAL correlated negatively with cystatin C and urea nitrogen, at both baseline and follow-up levels. The results indicate that NGAL correlates closely with renal function. Both serum and urine NGAL are sensitive for predicting the progression of type-2 diabetic nephropathy but they may change differently. Serum NGAL may be more useful in early detection and urine NGAL may be more meaningful in renal function assessment.

Heterogeneity in mitotic activity and telomere length implies an important role of young islets in the maintenance of islet mass in the adult pancreas.

Understanding the mechanisms of beta-cell dynamics in postnatal animals is central to cure diabetes. A major obstacle in evaluating the status of pancreatic cells is the lack of surface markers. Here we performed quantitative measurements of two internal markers to follow the developmental history of islets. One marker, cell-cycle activity, was established by measuring expression of Ki67 and the incorporation of 5-bromodeoxyuridine. The other marker, the aging process, was delineated by the determination of telomere length. Moreover, islet neogenesis, possibly from ductal precursors, was monitored by pancreatic duct labeling with an enhanced green fluorescence protein (EGFP) transgene. We found that islets from younger animals, on average, expressed higher Ki67 transcripts, displayed elevated 5-bromodeoxyuridine incorporation, and had longer telomeres. However, significant heterogeneity of these parameters was observed among islets from the same mouse. In contrast, the levels of proinsulin-1 transcripts in islets of different ages did not change significantly. Moreover, mitotic activities correlated significantly with telomere lengths of individual islets. Lastly, after 5.5 d pancreatic duct labeling, a few EGFP-positive islets could be identified in neonatal but not from adult pancreases. Compared with unlabeled control islets, EGFP-positive islets had higher mitotic activities and longer telomeres. The results suggest that islets are born at different time points during the embryonic and neonatal stages and imply that young islets might play an important role in the maintenance of islet mass in the adult pancreas.

Study on immune function of dendritic cells in patients with esophageal carcinoma.

AIM: To investigate the immune function of dendritic cells from both peripheral blood and operated tissues of esophageal carcinoma patients in order to find the relationship between the immune function of dendritic cells and the pathogenesis of esophageal carcinoma. METHODS: The expression of CD83, CD80, and CD86 on the surface of dendritic cells cultured from the peripheral blood of patients was detected compared with that from health donors using flow cytometry. The ability of dendritic cells to induce T lymphocyte proliferation was evaluated by a liquid scintillation counter. The expression of CD80, CD86, CD83, and S-100 proteins was assessed in esophageal carcinoma tissues using immunohistochemical method. RESULTS: Compared with those from healthy donors, dendritic cells cultured from the peripheral blood of patients expressed lower CD80 and CD86. Furthermore, the ability of dendritic cells in patients to induce T lymphocyte proliferation was significantly lower than that of the control group. Compared with the control group, the positive expression ratio and frequencies of CD80, CD86, and S-100 in esophageal carcinoma tissues were significantly down regulated. The expression of CD83 was up-regulated in the pericancerous tissues, but no expression was found in the cancerous nodules. CONCLUSION: The impaired immune function and the decreased number of dendritic cells cause pathogenesis and progression of esophageal carcinoma.

Analysis of the expression of Fas, FasL and Bcl-2 in the pathogenesis of autoimmune thyroid disorders.

To investigate the expression of apoptosis-related protein (Fas, FasL, and Bcl-2) in the pathogenesis of autoimmune thyroid disorders (ATDs), immunohistochemical staining was performed on 20 Hashimoto's thyroiditis (HT), 20 Graves' disease (GD), and 20 thyroid follicular adenoma (TFA, as control). All the cases expressed Fas, mainly on the cell surface and cytoplasm. FasL was found in 17 cases of the TFA. Bcl-2 was detected in 15 cases of HT, 19 of GD and 17 of TFA. In TFA, a moderate Fas expression and a minimal or no FasL expression was detected on follicular cells. In HT, the follicles adjacent to infiltrating lymphocytes showed increased levels of Fas and FasL expression. A weaker staining of Fas and FasL was exhibited on infiltrating lymphocytes than on thyrocytes. In a comparison of GD with HT, thyrocytes and lymphocytes showed similar Fas staining, but for FasL the staining was rather weaker in HT. The expression of Bcl-2 was nearly identical in GD and TFA, but much weaker on the follicular cells in vicinity of lymphocytes and on the lymphocytes located in germinal centers of HT tissues. The expression of Fas, FasL, Bcl-2 in Hashimoto's thyroiditis and Graves' disease were almost same. FasL strong expression and Bcl-2 weak expression on the follicles in HT may induce apoptosis. These results provided evidence for expression of Fas, FasL and Bcl-2 in the pathogenesis of autoimmune thyroid disease. The lymphocytes seem not to be directly engaged in the process via their own FasL, but they may provide some cytokines that, in turn, upregulate Fas and/or FasL expression to induce apoptosis.

The expression and distribution of S-100 protein and CD 83 in thyroid tissues of autoimmune thyroid diseases.

To investigate the expression and distribution of S-100 protein and CD 83 in the thyroid tissues of autoimmune thyroid diseases (ATDs), and to study the role of the dendritic cells in the pathogenesis of ATDs, immunohistochemical staining was used on pathological tissues of 20 patients with Hashimoto's thyroiditis (HT) and 20 patients with Graves' disease (GD) to check the expression and distribution of S-100 protein and CD 83. Compared with control group (20 cases of thyroid follicular adenoma, TFA), the higher expressions of S-100 in HT (139.38+/-5.92 vs 59.47+/-11.69) and GD (119.42+/-14.48 vs 59.47+/-11.69) were observed respectively (p<0.001). The increased positive expressions of CD 83 which is known as a marker of mature and activated DCs in HT (22.58+/-13.96 vs 5.19+/-8.08) and GD (29.92 +/-14.43 vs 5.19+/-8.08) were also found respectively (p<0.001). Serum TPO antibody (TPO-Ab, 67.3+/-11.6%) and Tg antibody (Tg-Ab, 59.8+/-10.1%) in HT were higher than those in GD (28.4+/-5.7%, 23.1+/-4.9%) and TFA (6.1+/-3.4%, 7.2 +/-4.6%) (p<0.01). Serum TR-Ab in GD (16.3+/-5.6 U/L) was higher than those in HT (4.8+/- 2.3 U/L) and TFA (2.5+/-1.2 U/L) (p<0.01). Our findings suggest that the high expression of DCs' markers may be related to the pathogenesis of HT and GD. The upregulation of both the number and the matured functions of DCs, may lead to present more antigens and to produce more auto-antibodies (such as Tg-Ab and TPO-Ab in HT, TR-Ab in GD), which may be involved in pathogenesis of the autoimmune thyroid diseases.

Event-related potentials P300 in type 2 diabetes mellitus.

OBJECTIVE: To investigate event-related potentials (ERP) P(300) in patients with type 2 diabetes mellitus (DM) for early detection of the abnormalities in cognitive function and studying the related factors. METHODS: With the assistance of Nicolet Vinking IV equipment, ERP (P(300)) were tested in 30 type 2 diabetic patients and 30 healthy subjects matched for age, gender, and education background, and the the results were analyzed statistically. The relationships of each ERP parameter with glucose hemoglobin (GHb) and blood lipid levels and renal function were analyzed. RESULTS: No significant difference was found in P(300) latencies in the control group irrespective of the gender and education (P > 0.05), while the latencies were significantly prolonged (P < 0.01) and the amplitudes decreased (P < 0.05) in diabetic patients. It was found that P(300) correlated with glucose hemoglobin (GHb) and blood lipid levels (P < 0.05). CONCLUSION: ERP test is useful for early detection of cognition dysfunction in DM cases, helping to timely identify diabetic patients with potential dementia.