Antimicrobial mexicanolide limonoids from the seeds of Khaya senegalensis.

Three new mexicanolide limonoids were obtained from the 90% ethanol extract of the seeds of Khaya senegalensis. Their structures were elucidated as senegalenines A-C (1-3) by analysing their 1D/2D NMR and MS spectroscopic analysis. In addition, the isolated limonoids were tested in vitro for antimicrobial potentials against 5 pathogenic microorganisms. Consequently, compounds 1-3 exhibited antimicrobial activity against the tested Gram negative bacteria at the minimum inhibitory concentration values less than 40 µg/ml.

A Slug-dependent mechanism is responsible for tumor suppression of p53-stabilizing compound CP-31398 in p53-mutated endometrial carcinoma.

Mutation in the tumor suppressor gene p53 is the most frequent molecular defect in endometrial carcinoma (EC). Recently, CP-31398, a p53-stabilizing compound, has been indicated to possess the ability to alter the expression of non-p53 target genes in addition to p53 downstream genes in tumor cells. Herein, we explore the alternative mechanisms underlying the restoration of EC tumor suppressor function in mutant p53 by CP-31398. A p53-mutated EC cell was constructed in AN3CA cells with restored or partial loss of Slug using lentiviral vectors, followed by treatment with 25 µM CP-31398. A p53-independent mechanism of CP-31398 was confirmed by the interaction between mouse double minute 2 homolog (MDM2) and Slug AN3CA cells treated with IWR-1 (inhibitor of Wnt response 1). Furthermore, the AN3CA cells were treated with short hairpin RNA against Slug, Wnt-specific activators (LiCl) or inhibitors (XAV-939) followed by CP-31398 treatment. Moreover, AN3CA cell proliferation and apoptosis were examined. A tumorigenicity assay was conducted in nude mice. CP-31398 could promote the apoptosis of p53-mutated EC cells, while Slug reversed this effect. Slug ubiquitination was found to occur via binding of Slug to MDM2 in AN3CA cells. We found that CP-31398 increased the GSK-3ß, p-Slug, Puma, Wtp53, and Bax expressions whereas Wnt, Mtp-53, Slug, Bcl-2, and Ki-67 expressions were decreased. However, these findings were reversed following the activation of the Wnt pathway and overexpression of Slug. Finally, the in vivo experimental evidence confirmed that CP-31398 with depleted Slug suppressed tumor growth by downregulating the Slug. Collectively, CP-31398-regulated Slug downregulation represses the p53-mutated EC via the p53/Wnt/Puma pathway.

Research on the application of inertially stabilized platform in the dynamic measurement of cold atomic gravimeter.

Dynamic gravity field measurement based on the cold atom absolute gravity measurement system has important applications in geological exploration, gravity field mapping and other fields. The inertial stabilized platform is the key component of the dynamic cold atom absolute gravity measurement system, which can isolate the interference of carrier angle motion and keep the atomic gravimeter probe in the horizontal attitude during the measurement process. In this paper, according to the dynamic measurement requirements of atomic gravimeter, a high-precision two-axis inertial stabilized platform system is designed. The relationship between attitude angle and gravity measurement error is analyzed, and the stability of the system is enhanced by lead-lag method. Then the static vertical vibration power spectrum of the platform is measured to consider its influence on dynamic gravity measurement. Finally, a dynamic gravity test experiment was conducted in the Yellow Sea to verify the attitude control accuracy of the platform, and the attitude data of the platform under different heading were evaluated. The attitude standard deviation of the platform was better than 4 × 10-5 rad, and the absolute gravity standard deviation of the linear round-trip measurement reached 1.49 mGal. The experimental data show that the inertial stabilized platform can meet the dynamic measurement requirements of the cold atom gravimeter.

Nano Sized Hydroxyapatite-Polylactic Acid-Vancomycin in Alleviation of Chronic Osteomyelitis.

Background: Vancomycin (VAN) is effective in inhibiting inflammatory reactions in chronic osteomyelitis (CO), while nano-hydroxyapatite (nHA) can effectively address the poor biocompatibility and high brittleness of ordinary HA and better repair bone defects. Therefore, the efficacy of nHA combined with VAN for CO with bone defects deserves further discussion. Objective: To explore the effect of VAN, which is loaded in the nanodelivery system formed by nHA and polylactic acid (PLA), in CO therapy. Methods: The stability of nHA-PLA-VAN in PBS solution at different temperatures and its effect on VAN's half-life were determined in the physicochemical property test. Immunofluorescence (IF) determined the stability and permeability of Cy3-coupled nHA-PLA-VAN in bone marrow of B6/J mice. The cultured osteoblasts were further divided into control, polyethyleneimine (PEI), and nHA-PLA groups to observe their differences in cell proliferation, mineralization, and migration capacities. And a CO mouse model was constructed to detect the anti-CO effect of nHA-PLA-VAN. Results: nHA-PLA-VAN nanocomposites maintained good stability in different acidic solutions, favoring their long-term preservation in vitro. nHA-PLA extended VAN's half-life by 6-times. In the permeation test, nHA-PLA-VAN showed significantly higher permeation efficiency than PEI, enabling it to effectively transport VAN to bone marrow tissue, thus better inhibiting bacterial activity and reducing CD4, CD8, CD19, and CD20 expression in the lesion area of CO mice. In the osteoblast experiment, nHA-PLA more effectively maintained osteoblast viability and promoted proliferation and migration, thus better repairing defective bone tissue. In the CO mouse model, nHA-PLA-VAN better inhibited inflammatory reactions, such as congestion and edema in the focus, and increased the number and thickness of bone trabeculae. Furthermore, max load, elastic load, and rigidity coefficient of the bone defect area were recovered to a great extent. Conclusion: nHA-PLA-VAN may be a better choice for future treatment of CO.

Mass drug administration in response to vivax malaria resurgence in Anhui Province of Huanghuai Plain, China.

This article summarizes the background, specific conditions, main measures, steps and effects of the implementation of Mass Drug Administration (MDA) to control the local P. vivax malaria epidemic in Anhui Province in central China. Distributing medicines to the designated population quickly controlled the local epidemic of P. vivax. Implementing MDA to control P. vivax ensured the correct selection of medicines, clarification of the targeted population for receipt of medicines, and assurance of a high rate of compliance through government support and health education. These results provide a reference for countries and regions experiencing similar events and planning to implement MDA in malaria control.

Penfluridol triggers mitochondrial-mediated apoptosis and suppresses glycolysis in colorectal cancer cells through down-regulating hexokinase-2.

Penfluridol, a commonly used antipsychotic agent in a clinical setting, exhibits potential anticancer properties against various human malignancies. Here, we investigated the effect of penfluridol on the biological behavior of colorectal cancer (CRC) cells. Cell viability and clonogenic potential were detected by the cell counting kit-8 and colony formation assay. The cell apoptosis and cell cycle distribution were quantified through flow cytometry. Caspase-3 activity, glucose consumption, lactate production, and intracellular ATP levels were evaluated using the corresponding commercial detection kits. The protein levels of related genes were detected through western blotting. Mitochondrial membrane potential was detected using JC-1 staining. A CRC xenograft tumor model was used to validate the antitumor activity of penfluridol in vivo. Penfluridol reduced cell survival and promoted apoptotic cell death effectively through the mitochondria-mediated intrinsic pathway in a dose-dependent manner. Furthermore, the process of glycolysis in HCT-116 and HT-29 cells was inhibited upon penfluridol treatment, as evidenced by the decrease in glucose consumption, lactate production, and intracellular ATP levels. Further mechanistic studies revealed that penfluridol influenced cell apoptosis and glycolysis in CRC cells by downregulating hexokinase-2 (HK-2). The proapoptotic effect and glycolytic inhibition-induced by penfluridol were effectively reversed by HK-2 overexpression. Consistent with in vitro results, penfluridol could also suppress tumor growth and trigger apoptosis in vivo. Penfluridol triggers mitochondrial-mediated apoptosis and induces glycolysis inhibition via modulating HK-2 in CRC and provides a theoretical basis to support penfluridol as a repurposed drug for CRC patients.

Efficacy and Safety of Dulaglutide by Baseline HbA1c in Chinese Patients with Type 2 Diabetes: A Post Hoc Analysis.

INTRODUCTION: To evaluate the efficacy and safety of dulaglutide 0.75 and 1.5 mg in patients with type 2 diabetes mellitus (T2DM) by baseline glycated hemoglobin (HbA1c) < 8.5% or ≥ 8.5% after 26 weeks of treatment. METHODS: Assessment of the Weekly AdministRation of dulaglutide in Diabetes (AWARD) China 1 (CHN1) study (NCT01644500, n = 556) included patients on dulaglutide vs. glimepiride who were treatment naïve or on monotherapy but discontinued therapy. AWARD-CHN2 (NCT01648582, n = 591) patients were on dulaglutide vs. insulin glargine and continued on metformin and/or sulfonylurea. Mean daily dose of glimepiride and insulin glargine was 2.51 mg and 21.0 IU, respectively. Post hoc analyses were conducted based on mixed-model repeated measures using a modified intent-to-treat analysis set with only the Chinese population. Change from baseline in HbA1c and body weight was analyzed by individual study. RESULTS: In the two studies, 70.1% of patients in AWARD-CHN1 and 59.7% in AWARD-CHN2 had baseline HbA1c < 8.5% (mean HbA1c 7.4% and 7.6%, respectively) and 29.9% in AWARD-CHN1 and 40.3% in AWARD-CHN2 had baseline HbA1c ≥ 8.5% (mean HbA1c 9.2% and 9.4%, respectively). In AWARD-CHN1, the HbA1c reductions at 26 weeks with baseline HbA1c < 8.5% and ≥ 8.5%, respectively, were dulaglutide 1.5 mg: - 1.1% and - 2.2%; dulaglutide 0.75 mg: - 0.9% and - 2.0%; glimepiride: - 0.7% and - 1.4%. In AWARD-CHN2, the HbA1c reductions at 26 weeks with baseline HbA1c < 8.5% and ≥ 8.5%, respectively, were dulaglutide 1.5 mg: - 1.2% and - 2.3%; dulaglutide 0.75 mg: - 1.0% and - 1.7%; and insulin glargine: - 0.6% and - 1.7%. Irrespective of baseline HbA1c, body weight decreased with both dulaglutide doses and increased with either glimepiride or insulin glargine at 26 weeks. Dulaglutide demonstrated low incidence of hypoglycemia in both doses in the two trials. Hypoglycemia incidence was generally lower in patients with baseline HbA1c ≥ 8.5%. CONCLUSIONS: Dulaglutide demonstrated significantly greater HbA1c reduction with weight loss and lower risk of hypoglycemia compared with active comparators in Chinese patients with T2DM irrespective of baseline HbA1c, with much greater HbA1c reductions in patients with a higher baseline HbA1c. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT01644500 and NCT01648582.

Search for clinical predictors of good glycemic control in patients starting or intensifying oral hypoglycemic pharmacological therapy: A multicenter prospective cohort study.

AIMS: Our aim was to search for clinical predictors of good glycemic control in patients starting or intensifying oral hypoglycemic pharmacological therapy. METHODS: A multicenter, prospective cohort of 499 diabetic subjects was enrolled in this study: patients with newly diagnosed diabetes (NDM group) or poor glycemic control with oral antidiabetic drugs (OADs) (PDM group). All subjects then started or intensified OADs therapy and followed up for 91 days. Glycemic control was determined according to HbA1c at day 91 with HbA1c <7% considered good. RESULTS: The proportions of patients with good glycemic control after follow up for 91 days were 66.9% and 34.8% in NDM group and PDM group respectively. Logistic regression analysis showed that the change in GA at 28 days was the only predictor of good glycemic control in NDM patients (OR = 1.630, 95% CI 1.300-2.044, P < 0.001). In PDM patients, changes in GA at 28 days, CPI, baseline HbA1c, diabetic duration, and BMI were all independent predictors of good glycemic control (All P < 0.05). CONCLUSIONS: GA decline is a good predictor of future success in newly diagnosed patients. In patients intensifying therapy, beside GA decline, other individualized clinical characteristics should also be considered.

Glycemic control and comprehensive metabolic risk factors control in older adults with type 2 diabetes.

BACKGROUND: Older adults with type 2 diabetes are prone to multiple metabolic abnormalities. However, data from these patients on comprehensive metabolic risk factors control are limited. METHODS: The present study included 2736 older adults aged 60 to 90 years with type 2 diabetes from 114 hospitals across 22 provinces in China. Metabolic abnormalities, including hypertension, dyslipidemia, hyperuricemia, and obesity, were recorded. Comprehensive metabolic risk factors control included the control of hemoglobin A1c (HbA1c) level, blood pressure, serum lipids level, serum uric acid level, and body mass index. The target glycemic control was defined as HbA1c <7%. RESULTS: The proportion of older adults who achieved the HbA1c target was 23.0%. The glycemic control rate increased with the number of metabolic abnormalities increased. The patients who had all four metabolic abnormalities had 4.05 times (95% confidence interval: 2.16, 7.61) the odd to meet glycemic target than those with none of metabolic abnormalities. However, only 4.6% of patients met the targets for all 5 metabolic risk factors. The comprehensive rate of all 5 factors in control decreased from 13.4% to 0% with the number of metabolic abnormalities increased. CONCLUSION: The glycemic control rate and the comprehensive metabolic risk factors control rate were 23.0% and 4.6%, respectively. As the number of metabolic abnormalities increased, the number of risk factor targets achieved decreased. Our findings suggest that a strategy for comprehensive control is urgently needed in older adults with type 2 diabetes, especially in those with co-existing metabolic abnormalities.

The impact of insulin pump therapy to oxidative stress in patients with diabetic nephropathy.

BACKGROUND: The oxidative stress resulting from increased production of ROS plays a crucial role in the development of diabetic complications. We aim to explore the relationships between oxidative stress, diabetic nephropathy (DN) and short-term insulin pump intensive therapy (insulin therapy). METHODS: Levels of 8-hydroxy-deoxyguanosine (8-OHdG), 3-nitrotyrosine (3-NT), glutathione (GSH), superoxide dismutase (SOD) and Interleukin-6 (IL-6) were estimated before and after 2 weeks of insulin therapy in normal group (NC) and type 2 diabetic (DM) with normal albuminuria (NA), microalbuminuria (MA) and clinical albuminuria (CA). RESULTS: In DM group, levels of 8-OHdG and 3-NT were higher than those in NC group (P < 0.05); GSH and SOD were lower (P < 0.05). And their levels changed with urine albumin-creatinine ratio (P < 0.05). After insulin therapy, these derangements were significantly ameliorated and the changes in NA and MA groups were more significant than CA group (P < 0.05). Correlation analysis showed glycated hemoglobin, the course of disease, the HOME-IR and fasting plasma glucose were positively correlated with 8-OHdG and 3-NT, but negatively correlated with GSH and SOD. CONCLUSIONS: The oxidative stress gradually increased with the magnitude of DN, and insulin pump intensive therapy can significantly ameliorate the derangements in the early stage of DN. Trial registration NCT03174821.

RNAi­mediated downregulation of asparaginase­like protein 1 inhibits growth and promotes apoptosis of human cervical cancer line SiHa.

Asparaginase like 1 (ASRGL1) protein belongs to the N­terminal nucleophile group, cleaving the isoaspartyl­dipeptides and L­asparagine by adding water. It tends to be overexpressed in cancerous tumors including ovarian cancer and breast tumors. The present study assessed the potential ability of ASRGL1 as a molecular target in gene­based cervical cancer treatment. The protein expression level of ASRGL1 was determined in paraffin­embedded tumor specimen by immunohistochemistry. Additionally, in order to assess the activity of ASRGL1 during the process of cervical cancer cell multiplication, ASRGL1­short hairpin (sh) RNA­expressing lentivirus was established, which was used to infect SiHa cells. The Cellomics ArrayScan VT1 Reader identified the influence of downregulation on SiHa caused by RNA interference­intervened ASRGL1. Flow cytometric analysis was also performed to evaluate the influence. The cyclin dependent kinase (CDK2), cyclin A2, B­cell lymphoma 2 (Bcl­2) and Bcl­2­associated X protein (Bax) expression levels were assessed by western blot analysis. ASRGL1 was observed to be overexpressed in cervical cancer tissues when compared with the adjacent normal tissues. The knockdown of ASRGL1 in SiHa by ASRGL1­shRNA lentivirus infection significantly inhibited cell growth and enhanced cellular apoptosis; the cells were also captured during the S phase. The knockdown of ASRGL1 expression led to the increased expression of Bax and decreased expression of Bcl­2, CDK2 and cyclin A2. In conclusion, ASRGL1 was closely associated with growth and apoptosis in cervical cancer. Therefore, ASRGL1 may be a novel, potentially effective anti­cervical cancer therapy.

Glycated albumin is superior to glycated hemoglobin for glycemic control assessment at an early stage of diabetes treatment: A multicenter, prospective study.

AIMS: This study was to determine whether serum glycated albumin (GA) was a better indicator of glycemic control than hemoglobin A1c (HbA1c) when starting a new treatment regimen for type 2 diabetes. METHODS: Newly diagnosed type 2 diabetes patients, or patients who had poor glycemic control with oral hypoglycemic agents, were enrolled at 10 hospitals in Beijing. Serum GA, HbA1c, fasting blood glucose (FBG), and C-peptide were assayed on Days 0, 14, 28, and 91 after treatment. RESULTS: Four hundred ninety-nine patients were enrolled. Mean FBG, GA and HbA1c decreased significantly in patients at Days 14, 28, and 91. In patients with improved glycemic control, the reduction of GA and HbA1c levels was 10.5±13.3% vs. 5.1±5.4% on Day 14, 16.0±13.4% vs. 9.0±7.0% on Day 28, and 18.0±16.7% vs. 18.3±9.4% on Day 91, respectively, compared with baseline values. Changes in GA on Day 14, 28 and 91 were all closely correlated with changes in HbA1c on Day 91. Change in GA on Day 14 was correlated with treatment effectiveness evaluated by HbA1c on Day 91. CONCLUSIONS: GA may be a useful marker for assessing glycemic control at an early stage of new diabetes treatment and assist in guiding adjustments to treatment and therapy.

Efficacy of structured education in patients with type 2 diabetes mellitus receiving insulin treatment.

BACKGROUND: The aim of the present study was to assess the efficacy of structured education in insulin-treated type 2 diabetes mellitus (T2DM) patients. METHODS: In a 16-week open-label randomized controlled study, 1511 T2DM patients with inadequate responses to two or more oral antidiabetic drugs (OADs) for >3 months (HbA1c >7.5%) were randomized (1:1) to either an education group (structured diabetes education plus insulin therapy) or a control group (usual care plus insulin therapy). Both groups discontinued previous OADs (except biguanides and α-glucosidase inhibitors) and started twice daily injections of 30% soluble-70% isophane recombinant insulin. The primary endpoint was the change in HbA1c from baseline. Efficacy and safety data were analyzed for within- and between-group differences. RESULTS: Of the initial 1511 patients, 1289 completed the study (643 in the control group; 646 in the education group). At the end of the study, significant reductions in HbA1c versus baseline were evident in both groups, but the reduction was greater in the education group (2.16% vs. 2.08%; P < 0.05). A higher proportion of patients in the education group achieved target HbA1c levels <7% (43.81% vs. 36.86%; P < 0.05) and ≤6.5% (28.48% vs. 22.71%; P < 0.05). In addition, patients in the education group showed greater increments in scores and improvement in the Morisky Medication Adherence Scale (P < 0.05). The overall incidence of hypoglycemic events was similar in the two groups. CONCLUSIONS: Structured education can promote the ability of patients to self-manage and their compliance with medications, thereby achieving better outcomes.

Efficacy and safety of glimepiride as initial treatment in Chinese patients with Type 2 diabetes mellitus.

OBJECTIVE: To investigate the efficacy and safety of glimepiride as initial mono-therapy in type 2 diabetes patients in China. METHODS: This is a multi-center, open-label, single arm study. A total of 391 subjects were enrolled to receive glimepiride treatment for 16 weeks, the initiation dose was 1 mg/d, with titration to 2 mg/d and 4 mg/d according to the fasting blood glucose (FBG) level measured at each visit. The change in HbA1c, fasting plasma glucose (FPG), 2 h postprandial blood glucose (2hPPG), HOMA-IR, weight, waist circumference and the incidence of hypoglycemia were evaluated. An exploratory analysis was conducted to identify the potential population prone to achieve target glycemic control. RESULTS: HbA1c was reduced significantly from 8.6 ± 1.6% to 6.9 ± 0.9% (p < 0.001); 60.9% of the subjects achieved HbA1c <7% at study endpoint. The reduction in FPG and 2hPPG were 2.3 mmol/L and 4.4 mmol/L (p < 0.001) respectively. Insulin resistance was improved significantly with HOMA-IR decreasing from 2.5 ± 2.3 to 2.2 ± 1.9 (p = 0.009). The incidence of confirmed hypoglycemia (BG ≤ 3.9 mmol/L) was 3.1%. CONCLUSIONS: Glimepiride treatment as initial mono-therapy could effectively improve blood glucose control in type 2 diabetic patients, with a favorable safety profile. Lack of control group was the major limitation of this study. ClinicalTrial.gov identifier: NCT00908921.

Enteroenteroanastomosis near adjacent ileocecal valve in infants.

AIM: To investigate the feasibility and the effectiveness of ileoileostomy in the region adjacent to the ileocecal valve, which can retain the ileocecal valve in infants. METHODS: This is a retrospective review of 48 patients who underwent ileoileostomy in the region adjacent to the ileocecal valve (group 1) and 34 patients who underwent ileocecal resections and ileotransversanastomosis (group 2). Patients were monitored for the time to flatus, resumption of eating, length of hospital stay after surgery, serum total bile acid, vitamin B12 and postoperative complications. RESULTS: The time to flatus, time until resumption of eating and post-operative length of hospital stay showed no statistically significant differences between the two groups. Serum total bile acid and vitamin B12 were not significantly different between the two groups at post-operative day 1 and day 3, but were significantly decreased at 1 wk after operation in group 2. None of the patients died or suffered from stomal leak in these two groups. However, the incidence of diarrhea, intestinal infection, disturbance of acid-base balance and water-electrolytes in group 1 was lower than in group 2. CONCLUSION: Ileoileostomy in the region adjacent to the ileocecal valve is safe and results in fewer complications than ileotransversanastomosis in infants.

A randomized, open-label, multicentre study to evaluate plasma atherosclerotic biomarkers in patients with type 2 diabetes mellitus and arteriosclerosis obliterans when treated with Probucol and Cilostazol.

OBJECTIVES: To evaluate the plasma atherosclerotic biomarkers in patients with type 2 diabetes mellitus (T2DM) and arteriosclerosis obliteran (ASO) when treated with Probucol plus Cilostazol in combination and individually. METHODS: In this open-label study, patients aged 40-75 years were randomized to receive conventional therapy alone, or with Cilostazol 100 mg bid, or with Probucol 250 mg bid, or with both in combination. Endpoints included changes in plasma biomarker and safety at 12 weeks. RESULTS: Of the 200 randomized patients, 165 for per-protocol and 160 for the safety (QTc intervals) were set, respectively. Probucol significantly reduced total cholesterol (P < 0.001), low-density lipoprotein cholesterol (LDL-C), (P = 0.01), and high-density lipoprotein cholesterol (HDL-C) (P < 0.001) compared with conventional therapy. Cilostazol was effective in increasing HDL-C (P = 0.002) and reducing triglycerides levels (P < 0.01) compared with conventional therapy. A trend towards significance was observed for the difference between conventional therapy alone and Probucol plus Cilostazol group for the change in oxidized low-density lipoprotein (Ox-LDL, P = 0.065). No significant effects on the majority of the remaining biomarkers were found across the treatment groups. CONCLUSIONS: We have confirmed that Ox-LDL could be a possible plasma atherosclerotic biomarker among the evaluated biomarkers, which reflected the synergetic effect of Cilostazol plus Probucol in patients with T2DM and ASO shown previously in preclinical studies.