Triterpenoids of Rhus chinensis Supressed Colorectal Cancer Progress by Enhancing Antitumor Immunity and CD8 + T Cells Tumor Infiltration.

The absence of CD8+ T cells in the tumor center has become a major obstacle in the immunotherapy of colorectal cancer. Therefore, new therapeutic strategies are urgently needed to promote the accumulation of CD8+ T cells in the tumor center. Previous studies have shown that triterpenoid of Rhus chinensis (TER) is involved in the proliferation and apoptosis of colorectal cancer cells, and can regulate their immune activity, but its mechanism needs to be further elucidated. In this study, the antitumor effect and adaptive immune response of TER on tumor-bearing mice were evaluated and compared with 5-fluorouracil. The results showed that TER could significantly inhibit tumor growth and prolong the survival time of tumor-bearing mice. The In Vivo studies have shown that TER can not only enhance antitumor immunity and promote the accumulation of CD8 + T cells to tumor sites, but also inhibit tumor progression by regulating the expression of PD-1 and PD-L1 and significantly reducing the mortality of mice. Our study demonstrated for the first time that TER has oncolytic effect, and recruited adaptive immune cells to enhance the efficacy of anti-PD-1/PD-L1 in colorectal cancer, which provides a potential therapeutic target for combined immunotherapy of colorectal cancer.

Eudragit S100 prepared pH-responsive liposomes-loaded betulinic acid against colorectal cancer in vitro and in vivo.

This study aimed to develop polymer Eudragit S100 for preparing pH-responsive liposomes-loaded betulinic acid (pH-BA-LP) to improve the therapeutic index of chemotherapy for colorectal cancer. BA-loaded liposomes were coated with Eudragit S100 by a thin film dispersion and easily scalable pH-driven method. The prepared liposomes were evaluated for size, surface morphology, entrapment efficiency, stability, in vitro drug release, and antitumor activity. In particular, pH-BA-LP showed advantages such as lower size (<100 nm), encapsulation efficiency of 90%, high stability, and stably cumulative release. By detecting the antitumor effects of pH-BA-LP in vivo, it showed that the tumor proliferation and cell migration were significantly inhibited in colorectal cancer. The pH-BA-LP also inhibited tumor growth via the regulation of Akt/TLR-mediated signalling and significantly down-regulated the expression of NFAT1 and NFAT4 proteins. It was found that pH-BA-LP can increase NK cells and CD3+ cells in tumor tissues, and the proportion of CD8+ cells in CD3+ cells was also increased, which proved that pH-BA-LP can play an antitumor effect by enhancing the autoimmunity level in tumor-bearing mice. The positive infiltration rates of CD8 and CD68 were increased and CD163 was relatively decreased by using pH-BA-LP, which proved that pH-BA-LP can regulate the immune infiltration levels in tumor-bearing mice. Therefore, the present work provides an effective method to prepare pH-responsive polymer-coated liposomes for colonic delivery with biologically active compounds.

The relationship between patterns of insulin secretion and risks of gestational diabetes mellitus.

OBJECTIVE: To evaluate patterns of insulin secretion in pregnancy and analyze the association between insulin patterns and risks of gestational diabetes mellitus (GDM). METHODS: A prospective study was conducted to collect and analyze pregnant women's materials from January 2015 to December 2018. Pregnant women were grouped according to results of 75-g oral glucose tolerance test at 24-28 weeks of pregnancy: normal glucose tolerance (NGT) and GDM. Insulin secretion patterns were based on the time of peak(s) and shape of insulin secretion curve. The relationship between insulin secretion patterns and pregnant outcomes was analyzed. RESULTS: A total of 2432 pregnant women met the inclusion criteria during the study period. Among them, 737 (30.3%) women were grouped as GDM and 1695 (69.7%) as NGT. Type I insulin secretion represented the early phase of insulin secretion (peak time at 30 or 60 minutes), while type II represented the delayed peak of insulin secretion (peak time at 120 or 180 minutes). Logistic regression analysis showed that type II insulin secretion was a risk factor of pre-eclampsia, large-for-gestational-age, and neonatal hypoglycemia. CONCLUSION: The delayed insulin peak is a useful marker for risk of GDM and adverse pregnant outcomes in women with GDM.

Kidney-Replenishing Herb Induces SOCS-3 Expression via ERK/MAPK Pathway and Improves Growth of the First-Trimester Human Trophoblast Cells.

Kidney-replenishing herb is a traditional medicine formula in China which has been widely used for clinical treatment of recurrent miscarriage. Our previous study showed that Kidney-replenishing herb could promote proliferation and inhibit apoptosis of the human first-trimester trophoblasts. In the present study, we further explored the potential mechanism and signal pathway of Kidney-replenishing herb on human trophoblast cells. Our research showed that Kidney-replenishing herb stimulated proliferation and reduced apoptosis of human trophoblast cells in vitro, and this appeared to be positive correlation with SOCS-3 transcription, suggesting that Kidney-replenishing herb regulated biological functions of human trophoblast cells by inducing SCOS-3 expression. Furthermore, the Kidney-replenishing herb treatment stimulated the phosphorylation of ERK1/2, and blocking the signaling pathway by mitogen-activated protein MAPK (MEK) inhibitor, U0126, inhibited Kidney-replenishing herb-induced SOCS-3 transcription, depressed proliferation, and promoted apoptosis of human trophoblasts. Kidney-replenishing herbs still induced ERK1/2 phosphorylation after SOCS-3 siRNA silence. Overexpression of SOCS-3 stimulated the proliferation of trophoblast. These findings suggest that SOCS-3 expression is induced by Kidney-replenishing herbs via activation of MAPK pathways, and this may possibly be involved in promoting human trophoblast cells growth which is contributed to embryo development.

RelB/NF-κB links cell cycle transition and apoptosis to endometrioid adenocarcinoma tumorigenesis.

Dysfunction of nuclear factor-κB (NF-κB) signaling has been causally associated with numerous human malignancies. Although the NF-κB family of genes has been implicated in endometrial carcinogenesis, information regarding the involvement of central regulators of NF-κB signaling in human endometrial cancer (EC) is limited. Here, we investigated the specific roles of canonical and noncanonical NF-κB signaling in endometrial tumorigenesis. We found that NF-κB RelB protein, but not RelA, displayed high expression in EC samples and cell lines, with predominant elevation in endometrioid adenocarcinoma (EEC). Moreover, tumor cell-intrinsic RelB was responsible for the abundant levels of c-Myc, cyclin D1, Bcl-2 and Bcl-xL, which are key regulators of cell cycle transition, apoptosis and proliferation in EEC. In contrast, p27 expression was enhanced by RelB depletion. Thus, increased RelB in human EC is associated with enhanced EEC cell growth, leading to endometrial cell tumorigenicity. Our results reveal that regulatory RelB in noncanonical NF-κB signaling may serve as a therapeutic target to block EC initiation.

Association between glycemic control and birthweight with glycated albumin in Chinese women with gestational diabetes mellitus.

AIMS/INTRODUCTION: To assess glycated albumin (GA) as a potential glycemic index in managing gestational diabetes mellitus (GDM). MATERIALS AND METHODS: Eligible pregnant women were divided into the GDM group with abnormal result on a 75-g oral glucose tolerance test (OGTT) and the control (normal) group. GA measurements, Pearson's correlation analysis, multiple logistic regression and receiver operating characteristic curve analysis were obtained at the follow-up examination of participants in the two groups. RESULTS: A total of 2,118 women were assigned to the GDM group (n = 639) and control group (n = 1,479). The mean level of serum GA in GDM group was significantly greater than that in the control group at both 24-28 and 36-38 weeks of gestation (P < 0.05). The area under the receiver operating characteristic curve for GA defining good glycemic control in GDM was 0.874 (95% confidence interval 0.811-0.938). The cut-off point for the GA levels derived from the receiver operating characteristic curve was 11.60%, which had sensitivity and specificity for detecting a poor glycemic status of 75.93% and 86.36%, respectively. The risk of birthweight ≥3,500 g and macrosomia increased significantly with GA levels ≥13.00% at 24-28 weeks and ≥12.00% at 36-38 weeks of gestation. CONCLUSIONS: GA might be an appropriate and conveniently measured index that can detect poor glycemic control and predict birthweights in GDM women.

Influencing Factors for Sleep Quality Among Shift-working Nurses: A Cross-Sectional Study in China Using 3-factor Pittsburgh Sleep Quality Index.

PURPOSE: The aim of this study was to identify influencing factors for sleep quality among shift-working nurses based on a three-factor scoring model that included sleep efficacy, sleep quality and daily dysfunction. METHODS: A cross-sectional survey of 513 nurses in a hospital in Shanghai, China, was conducted using a self-reported questionnaire. Sleep quality was measured by the Pittsburgh Sleep Quality Index (PSQI). Data were analyzed based on the three-factor PSQI model: Factor 1, sleep efficacy; Factor 2, sleep quality; Factor 3, daily disturbances. RESULTS: After adjusting for age, marital status, and having children, multivariate logistic regression analysis showed that participants who had previous shift work experience which was at least 6 months ago, or were currently performing shift work were significantly more likely to have poor sleep quality (PSQI > 5) than those who had never done shift work (adjusted odds ratios of 3.943 and 3.975, respectively, both p < .001). Mean scores of the three individual factors increased significantly among nurses currently performing shift work compared with those who had never done shift work (Factor 1, ß = 0.61, p < .001; Factor 2, ß = 1.86, p < .001; Factor 3, ß = 0.45, p = .002). Mean scores of Factor 2 and Factor 3 increased significantly among nurses with previous shift work experience compared with those who had never done shift work (Factor 2, ß = 1.15, p = .003; Factor 3, ß = 0.52, p = .005). CONCLUSIONS: Performing current shift work and performing shift work previously were significantly associated with poor sleep quality. An appropriate arrangement and intervention strategies are needed in Chinese hospitals in order to improve sleep quality among shift-working nurses.

Association of serum 25-hydroxyvitamin D with insulin resistance and ß-cell function in a healthy Chinese female population.

AIM: To assess associations of the serum level of 25-hydroxyvitamin D with insulin resistance and ß-cell function in a healthy Chinese female population. METHODS: This cross-sectional study included 1382 female participants free of type 2 diabetes who were recruited in Shanghai. Blood samples were collected within a winter season and the serum levels of 25-hydroxyvitamin D, fasting plasma glucose and insulin, and other biochemical parameters were determined. Insulin resistance and ß-cell function were assessed using the homeostasis model assessments of insulin resistance (HOMA-IR) and ß-cell function (HOMA-B), respectively. RESULTS: Multiple linear regression analyses adjusted for age, parathyroid hormone, Ca(2+) and BMI revealed that independent inverse associations existed between the serum level of 25-hydroxyvitamin D and HOMA-IR (P<0.001) and between the serum level of 25-hydroxyvitamin D and HOMA-B (P=0.001). CONCLUSION: Serum vitamin D level is significantly and independently associated with insulin resistance and ß-cell function in a healthy Chinese female population.

Increased mean glucose levels in patients with polycystic ovary syndrome and hyperandrogenemia as determined by continuous glucose monitoring.

OBJECTIVE: Women with polycystic ovary syndrome are at risk of developing type 2 diabetes mellitus. This study aimed to evaluate the influence of hyperandrogenemia on glucose metabolism in polycystic ovarian syndrome patients. DESIGN: Cohort study. SETTING: Reproductive Endocrinology Clinic of the Shanghai Sixth People's Hospital. SAMPLE: Fifty-three patients were recruited from June 2008 to December 2009, including 28 women with hyperandrogenism and 25 without hyperandrogenemia. METHODS: Anthropometric parameters, including weight, height, body mass index and waist-to-hip ratio, as well as sex hormones, were measured. An oral glucose tolerance test, including fasting and two hour glucose and insulin levels, was recorded. Insulin resistance was evaluated by homeostatic model assessment of insulin resistance, and patients underwent continuous glucose monitoring. MAIN OUTCOME MEASURES: Mean blood glucose level, mean amplitude of glycemic excursion, frequency of glycemic excursion and the percentage of time of hypoglycemia and hyperglycemia during a 48 h period. RESULTS: No differences in age, body mass index, waist-to-hip ratio, fasting and two hour glucose and insulin concentrations were observed between the groups. The hyperandrogenism group had higher levels of luteinizing hormone and dehydroepiandrosterone sulfate (p < 0.05). However, continuous glucose monitoring showed that the minimal blood glucose and mean blood glucose were significantly higher in hyperandrogenemia group (p = 0.004). The percentage of time for hypoglycemia (≤70 mg/dL) was higher in the hyperandrogenemia group (p = 0.002). CONCLUSIONS: Polycystic ovarian syndrome patients with hyperandrogenemia had an increased mean glucose value, which may place them at increased risk for developing type 2 diabetes.

Dehydroepiandrosterone indirectly inhibits human osteoclastic resorption via activating osteoblastic viability by the MAPK pathway.

BACKGROUND: Dehydroepiandrosterone (DHEA) is widely known for its beneficial effect on postmenopausal osteoporosis, although the underlying mechanisms remain mainly unclear. In this study, we tried to determine the activation of mitogen-activated protein kinase signal pathways during DHEA treatment and the indirect role of osteoblasts (OBs) on osteoclasts under the DHEA treatment of postmenopausal osteoporosis. METHODS: Primary human OBs and osteoclast-like cells were cultured and, we pretreated OBs with or without U0126 (a highly selective inhibitor of both MEK1 and MEK2). The OBs were treated with DHEA. We then tested the effects of DHEA on human osteoblastic viability, osteoprotegerin production and the expression of phosphor-ERK1/2 (extracellular signal-regulated kinase). In the presence or absence of OBs, the function of osteoclastic resorption upon DHEA treatment was calculated. RESULTS: DHEA promoted the human osteoblastic proliferation and inhibited the osteoblastic apoptosis within the concentration range of 10(-8) - 10(-6) mol/L (P < 0.05, P < 0.01, respectively). Within the effective concentration range, the expression of phosphor-ERK1/2 and osteoprotegerin was increased by DHEA and blocked by U0126. In the presence of OBs, DHEA could significantly decrease the number and the area of bone resorption lacuna (P < 0.05 and P < 0.01, respectively). Without OBs, however, the effects of DHEA on the bone resorption lacuna were almost completely abolished. CONCLUSIONS: DHEA could indirectly inhibit the human osteoclastic resorption through promoting the osteoblastic viability and osteoprotegerin production, which is mediated by mitogen-activated protein kinases signal pathway involving the phosphor-ERK1/2.

[Selective ERß action of dehydroepiandrosterone for osteoblast cell line].

OBJECTIVE: To investigate the selective mechanism of dehydroepiandrosterone (DHEA) for osteoblast via ERß. METHODS: High expression of ERß in hMG63-ERß group (infected with pWPT-ERß), gene silencing of ERß in hMG63-shERß group (infected with pLVTHM-GFP/ERß-shRNA) and hMG63 group (control) were cultured and treated with 1×10(-7) mol/L DHEA, with or without U0126 and etoposide. The proliferation and apoptosis of hMG63 were evaluated by flow cytometry. The mRNA level of estrogen receptor subtype was detected by reverse transcription-PCR. RESULTS: The expression of ERß in hMG63-ERß group and hMG63-shERß group were increased 7.39 times and decreased 17% compared with that in hMG63 group (control). DHEA could increase ERß expression in hMG63 in each group, however, it did not influence the expression of ERα mRNA. When the level of ERß was high, DHEA could accelerate the proliferation [proliferation index were (81.6 ± 7.6)% in hMG63-ERß, (75.0 ± 5.3)% in hMG63, P < 0.05] and inhibit the apoptosis [apoptosis rate were (12.2 ± 1.6)% in hMG63-ERß, (14.6 ± 1.5)% in hMG63, P < 0.01], which was blocked by U0126 [proliferation index were (33.2 ± 2.0)% in hMG63-ERß, (41.2 ± 2.4)% in hMG63, apoptosis rate were (40.5 ± 4.3)% in hMG63-ERß, (43.3 ± 4.1)% in hMG63, all P < 0.05]. When the expression of ERß was silenced, DHEA could not inhibit the apoptosis of hMG63 anymore. CONCLUSION: DHEA selectively act on osteoblasts via the dominant expression of ERß.

[Insulin release and daily glucose change in polycystic ovary syndrome women with normal glucose tolerance].

OBJECTIVE: To evaluate the characteristics of daily glucose change, insulin sensitivity, and insulin release in polycystic ovary syndrome (PCOS) women with normal glucose tolerance. METHODS: Oral glucose tolerance test (OGTT) with 75 g glucose was conducted on 20 PCOS women with normal glucose tolerance and 20 age-matched healthy women with normal menstruation. Before the glucose uptake and 30, 60, and 120 min after samples of venous blood were collected to detect the blood glucose and insulin. Continuous glucose monitoring system (CGMS) was used to monitor the glucose concentration of subcutaneous interstitial fluid so as to reflect the blood glucose level. Mean blood glucose level (MBG) and its standard deviation (SDBG), mean amplitude of glycemic excursion (MAGE), peak level of postprandial plasma glucose as well as its peaking time during a 48-hour period CGMS were calculated. Stumvoll first-phase and second-phase (1st PH and 2nd PH) insulin release during OGTT were evaluated by Stumvoll formula, whereas baseline insulin release by HOMA-B. Insulin sensitivity index (ISI) was evaluated by Cederholm formula. RESULTS: (1) The 1-hour and 3-hour plasma glucose levels during OGTT of the PCOS group were higher than those of the control group (P < 0.01 and P < 0.05 respectively). The fasting insulin level and insulin levels 30, 60, 120, and 180 min after the glucose uptake during OGTT of the PCOS group were all significantly higher than those of the control group (all P < 0.01). (2) The daily MBG, SDBG, and MAGE of the PCOS group were (5.43 +/- 0.44), (0.66 +/- 0.24), and (1.46 +/- 0.47) mmol/L respectively, all similar to those of the control group [(5.3 +/- 0.5), (0.67 +/- 0.27), and (1.7 +/- 0.7) mmol/L respectively, all P > 0.05]. The peaking time of post-breakfast plasma glucose level of the PCOS group was (40 +/- 18) min, significantly longer than that of the control group [(30 +/- 10) min, P < 0.05]. (3) The ISI of the PCOS group was 64 (59 - 81), significantly lower than that of the control group [95 (78 - 102), P < 0.01]. The Stumvoll 1st PH and 2nd PH insulin release levels of the PCOS group were 1779 (1411 - 2194) mU/L and 440 (361 - 545) mU/L respectively, both significantly higher than those of the control group [1217 (1056 - 1477) and 320 (283 - 375) mU/L respectively, P < 0.01 and P < 0.05]. CONCLUSION: With normal glucose tolerance, the PCOS women show (1) a backwardly-shifted peak of glucose -stimulated insulin secretion, (2) an abnormal mode of daily glucose change characterized by a delayed peak of post-breakfast plasma glucose level, and (3) significant decrease of peripheral insulin sensitivity with compensated increase of insulin secretion.