PRDX6 alleviates lipopolysaccharide-induced inflammation and ferroptosis in periodontitis.

OBJECTIVE: Periodontitis is a progressive and inflammatory oral disease and results in the damage of the supporting tissues of teeth. Peroxiredoxin 6 (PRDX6) is an antioxidant enzyme identified as a regulator in ferroptosis. This study aimed to investigate whether PRDX6 could protect human gingival fibroblasts (HGFs) from lipopolysaccharide (LPS)-induced inflammation and its mechanisms. MATERIAL AND METHODS: Both inflamed and non-inflamed human gingival tissues were collected to assess the expression of PRDX6 and nuclear factor erythropoietin 2-related factor 2 (NRF2) by Immunohistochemistry and Western blotting. Furthermore, the molecular mechanisms of PRDX6 have been clarified in PRDX6 silenced cells. The inflammatory cytokines in HGFs were measured by RT-qPCR and ELISA. The lipid hydroperoxide (LOOH) was detected by C11-BODIPY. RESULTS: The expression of PRDX6 and NRF2 were decreased in gingival tissues of severe periodontitis patients. The increased LPS-induced LOOH and inflammatory cytokines were found in PRDX6 knockdown HGFs. Besides, the inhibition of ferroptosis or PRDX6 phospholipase A2 activity (PLA2) alleviated LPS-induced inflammatory cytokines and LOOH. However, inhibiting NRF2 signalling upregulated those in HGFs. CONCLUSIONS: Therefore, this study provided a new mechanistic insight that PRDX6, regulated by the NRF2 signalling, alleviates LPS-induced inflammation and ferroptosis in human gingival fibroblasts.

Comparison of insulin lispro mix 25 with insulin lispro mix 50 as an insulin starter in Asian patients with type 2 diabetes: a phase 4, open-label, randomized trial (CLASSIFY study).

BACKGROUND: Lispro Mix 25% insulin lispro/75% insulin lispro protamine (LM25) and Lispro Mix 50% insulin lispro/50% insulin lispro protamine (LM50) were compared as starter insulins in East Asian patients with type 2 diabetes. METHODS: Phase 4, open-label, randomized trial conducted in China, Japan, Korea, and Turkey. Subjects received twice-daily LM25 (n = 207) or LM50 (n = 196) for 26 weeks. The primary outcome was the HbA1c change from baseline. RESULTS: The least squares mean changes from baseline in HbA1c are -1.52% and -1.69% for LM25 and LM50, respectively, and the least squares mean difference [95% CI] is 0.17% [-0.01, 0.35]. More subjects in the LM50 group than in the LM25 group achieved HbA1c targets of <7.0% (59.7% versus 45.9%, respectively; p = 0.007). LM50 was more effective than LM25 in reducing postprandial glucose after the morning (mean difference in change from baseline, 0.56 mmol/L; p = 0.038) and evening (1.11 mmol/L; p < 0.001) meals. The reduction in fasting blood glucose was significantly greater (p = 0.046) in the LM25 group (LS mean [95% CI] change from baseline: -2.37 mmol/L [-2.68, -2.06]) than in the LM50 group (-1.99 mmol/L [-2.30, -1.68]). LM50 was more effective than LM25 in reducing HbA1c in subjects with baseline HbA1c , postprandial glucose, or carbohydrate intake levels greater than the median levels. Hypoglycemia rates and weight gain were similar between groups. CONCLUSIONS: LM25 and LM50 were noninferior to each other in improving glycemic control in Asian patients with type 2 diabetes. In addition, LM50 was more efficacious than LM25 with respect to the percentage of subjects reaching target HbA1c levels. Copyright © 2016 John Wiley & Sons, Ltd.

Effectiveness of different waist circumference cut-off values in predicting metabolic syndrome prevalence and risk factors in adults in China.

OBJECTIVE: To study the effectiveness of waist circumference cut-off values in predicting the prevalence of metabolic syndrome (MetS) and risk factors in adults in China. METHODS: A cross-sectional survey was condcuted in 14 provinces (autonomous region, municipality) in China. A total of 47,325 adults aged⋝20 years were selected by multistage stratified sampling, and questionnaire survey and physical and clinical examination were conducted among them. MetS was defined according to the International Diabetes Federation (IDF) criteria and modified IDF criteria. RESULTS: The age-standardized prevalence of MetS was 24.2% (22.1% in men and 25.8% in women) and 19.5% (22.1% in men and 18.0% in women) according to the IDF criteria and modified IDF criteria respectively. The age-standardized prevalence of pre-MetS was 8.1% (8.6% in men and 7.8% in women) according to the modified IDF criteria. The prevalence of MetS was higher in urban residents than rural residents and in northern China residents than in southern China residents. The prevalence of central obesity was about 30% in both men and women according to the ethnicity-specific cut-off values of waist circumference for central obesity (90 cm for men and 85 cm for women). Multivariate regression analysis revealed no significant difference in risk factors between the two MetS definitions. CONCLUSION: Using both the modified IDF criteria and ethnicity-specific cut-off values of waist circumference can provide more useful information about the prevalence of MetS in China. Conclusion Using both the modified IDF criteria and ethnicity-specific cut-off values of waist circumference can provide more useful information about the prevalence of MetS in China.

Krüppel-like factor 5 associates with melamine-cyanurate crystal-induced nephritis in rats.

BACKGROUND: Melamine and cyanuric acid (M/CA), when orally administered together to rats, can induce crystal formation within renal tubules and cause acute kidney injury. METHODS: To investigate the pathomechanism of crystal-induced nephritis, melamine and/or cyanuric acid were administered to 3-week-old (young) and 8-week-old (adult) rats, respectively. RESULTS: Crystal formation, blood urea nitrogen elevation, tubular cell injury and macrophage infiltration were noted in rats fed with M/CA, but not in rats fed with vehicle, melamine or CA alone. These parameters were significantly higher in young rats than those in adult rats fed with M/CA 200 mg/kg body weight (BW) for 3 days. Krüppel-like factor 5 (KLF5) was expressed on distal tubule cells, especially when crystals deposited within the lumens. Both mRNA and protein levels were higher in young rats than those in adult rats fed with M/CA (200 mg/kg BW). KLF5 expression has been shown to modulate renal tissue cytokine production, and we found that proinflammatory cytokines like monocyte chemoattractant protein-1 and interlukin-6 were increased in kidney tissues of young rats fed with M/CA for 3 days. In contrast, interlukin-10, an anti-inflammatory cytokine, was upregulated in kidneys of adult rats fed with M/CA for 3 days. CONCLUSIONS: Crystals are prone to deposition in distal tubules of young rats fed with M/CA. M/CA Crystal-related nephritis might be induced by the KLF5 expression, which modulated macrophage recruitment and proinflammatory cytokine production, subsequently leading to renal tubular injury and interstitial inflammation.

Glycemic control among patients in China with type 2 diabetes mellitus receiving oral drugs or injectables.

BACKGROUND: The prevalence of type 2 diabetes mellitus (T2DM) is increasing rapidly among Chinese adults, and limited data are available on T2DM management and the status of glycemic control in China. We assessed the efficacy of oral antidiabetes drugs (OADs), glucagon-like peptide-1 (GLP-1) receptor agonists, and insulin for treatment of T2DM across multiple regions in China. METHODS: This was a multicenter, cross-sectional survey of outpatients conducted in 606 hospitals across China. Data from all the patients were collected between April and June, 2011. RESULTS: A total of 238,639 patients were included in the survey. Eligible patients were treated with either OADs alone (n=157,212 [65.88%]), OADs plus insulin (n=80,973 [33.93%]), or OADs plus GLP-1 receptor agonists (n=454 [0.19%]). The OAD monotherapy, OAD + insulin, and OAD + GLP-1 receptor agonist groups had mean glycosylated hemoglobin (HbA1c) levels (±SD) of 7.67% (±1.58%), 8.21% (±1.91%), and 7.80% (±1.76%), respectively. Among those three groups, 34.63%, 26.21%, and 36.12% met the goal of HbA1c <7.0%, respectively. Mean HbA1c and achievement of A1c <7.0% was related to the duration of T2DM. CONCLUSIONS: Less than one third of the patients had achieved the goal of HbA1c <7.0%. Glycemic control decreased and insulin use increased with the duration of diabetes.

Prevalence of cardiovascular disease risk factor in the Chinese population: the 2007-2008 China National Diabetes and Metabolic Disorders Study.

AIMS: Cardiovascular disease (CVD) is now the most prevalent and debilitating disease affecting the Chinese population. The goal of the present manuscript was to analyse cardiovascular risk factors and the prevalence of non-fatal CVDs from data gathered from the 2007-2008 China National Diabetes and Metabolic Disorders Study. METHODS AND RESULTS: A nationally representative sample of 46 239 adults, 20 years of age or older, was randomly recruited using a multistage stratified design method. Lifestyle factors, diagnosis of CVD, stroke, diabetes, and family history of each subject were collected, and an oral glucose tolerance test or a standard meal test was performed. Various non-fatal CVDs were reported by the subjects. SUDAAN software was used to perform all weighted statistical analyses, with P < 0.05 considered statistically significant. The prevalence of coronary heart disease, stroke, and CVDs was 0.74, 1.07, and 1.78% in males; and 0.51, 0.60, and 1.10% in females, respectively. The presence of CVDs increased with age in both males and females. The prevalence of being overweight or obese, hypertension, dyslipidaemia, or hyperglycaemia was 36.67, 30.09, 67.43, and 26.69% in males; and 29.77, 24.79, 63.98, and 23.62% in females, respectively. In the total sample of 46 239 patients, the prevalence of one subject having 1, 2, 3, or ≥4 of the 5 defined risk factors (i.e. smoking, overweight or obese, hypertension, dyslipidaemia, or hyperglycaemia) was 31.17, 27.38, 17.76, and 10.19%, respectively. Following adjustment for gender and age, the odds ratio of CVDs for those who had 1, 2, 3, or ≥4 risk factors was 2.36, 4.24, 4.88, and 7.22, respectively, when compared with patients with no risk factors. CONCLUSION: Morbidity attributed to the five defined cardiovascular risk factors was high in the Chinese population, with multiple risk factors present in the same individual. Therefore, reasonable prevention strategies should be designed to attenuate the rapid rise in cardiovascular morbidity.

[The safety and effectiveness of once daily detemir in patients with type 2 diabetes previously failing oral agents: the Chinese cohort from SOLVE(TM) observational study].

OBJECTIVE: Study of Once-daily LeVEmir(®) (SOLVE(TM)) was a 24-week international observational study to evaluate the safety and effectiveness of initiating once-daily insulin detemir (Levemir) as add-on therapy in patients with type 2 diabetes mellitus (T2DM) who failed treatment of oral anti-diabetic drugs (OAD). METHODS: The present study was derived from the data of Chinese cohort. A total of 3272 patients with T2DM failing OAD were enrolled in the study. Determir were prescribed to the patients by the decision of the physician. Clinical data were collected at baseline, week 12 and week 24 to evaluate the safety and effectiveness of detemir. RESULTS: The age of the patients was (56.2 ± 10.8) years with a diabetes duration of (7.1 ± 5.2) years. Their BMI was (25.3 ± 3.3) kg/m(2). No patient experienced any major or nocturnal hypoglycaemic event during the study. After 24 weeks of treatment, the glycosylated hemoglobin A1c (HbA1c) decreased from (8.33 ± 1.69)% to (7.16 ± 1.18)% with a mean change of -1.17%, the fasting plasma glucose decreased from (9.52 ± 2.59) mmol/L to (6.84 ± 1.42) mmol/L with a mean change of -2.7 mmol/L, and the 7-point blood glucose profile improved overall. Totally 49.1% of patients achieved HbA1c < 7%. The mean body weight decreased by 0.15 kg. CONCLUSIONS: Insulin detemir administered once daily as add-on therapy in patients with T2DM failing OAD regimen significantly reduces the risk of major hypoglycemia, improves glycemic control, increases the percentage of patients achieving treatment target with neutral effect on body weight.

Postprandial glucagon-like peptide 1 secretion is associated with urinary albumin excretion in newly diagnosed type 2 diabetes patients.

BACKGROUND: Microalbuminuria is an early and informative marker of diabetic nephropathy. Our study found that microalbuminuria developed in patients with newly diagnosed type 2 diabetes mellitus (T2DM). AIM: To investigate the association between glucagon-like peptide 1 (GLP-1) and microalbuminuria in newly diagnosed T2DM patients. METHODS: In total, 760 patients were recruited for this cross-sectional study. The GLP-1 levels during a standard meal test and urinary albumin-creatinine ratio (UACR) were determined. RESULTS: Patients with microalbuminuria exhibited lower GLP-1 levels at 30 min and 120 min during a standard meal test than patients with normal albuminuria (30 min GLP-1, 16.7 ± 13.3 pmol vs 19.9 ± 15.6 pmol, P = 0.007; 120 min GLP-1, 16.0 ± 14.1 pmol vs 18.4 ± 13.8 pmol, P = 0.037). The corresponding area under the curve for active GLP-1 (AUCGLP-1) was also lower in microalbuminuria patients (2257, 1585 to 3506 vs 2896, 1763 to 4726, pmol × min, P = 0.003). Postprandial GLP-1 levels at 30 min and 120 min and AUCGLP-1 were negatively correlated with the UACR (r = 0.159, r = 0.132, r = 0.206, respectively, P < 0.001). The prevalence of microalbuminuria in patients with newly diagnosed T2DM was 21.7%, which decreased with increasing quartiles of AUCGLP-1 levels (27.4%, 25.3%, 18.9% and 15.8%). After logistic regression analysis adjusted for sex, age, hemoglobin A1c, body mass index, systolic blood pressure, estimated glomerular filtration rate, homeostasis model assessment of insulin resistance, AUCglucose and AUCglucagon, patients in quartile 4 of the AUCGLP-1 presented a lower risk of microalbuminuria compared with the patients in quartile 1 (odds ratio = 0.547, 95% confidence interval: 0.325-0.920, P = 0.01). A consistent association was also found between 30 min GLP-1 or 120 min GLP-1 and microalbuminuria. CONCLUSION: Postprandial GLP-1 levels were independently associated with microalbuminuria in newly diagnosed Chinese T2DM patients.

Differential activations of PKC/PKA related to microvasculopathy in diabetic GK rats.

Microvasculopathy is the most serious and predictable threat to the health of diabetic patients, which often results in end-stage renal disease, blindness, and limb amputations. Up to the present, the underlying mechanisms have remained elusive. Here, it was found that the differential activations of PKC/PKA were involved in diabetic microvasculopathy in diabetic GK rats. By real-time PCR, Western blot, immunohistochemistry, and enzyme activity assay, upregulation of PKC was prominent in kidney but was not significant in liver and brain. The expression and activity of PKA were lowered in kidney but comparable in brain and liver during diabetic nephropathy. Furthermore, the generation of reactive oxygen species, production of nitric oxide, and expression of inducible nitric oxide synthase induced by advanced glycation end products were inhibited by PKCß inhibitor LY-333531 or a PKA agonist in rat glomerular microvascular endothelial cells. Finally, albuminuria was significantly lowered by a PKA agonist and boosted by a PKA antagonist. It suggested that the differential activations of PKC/PKA related to microvasculopathy in diabetes and that activation of PKA may protect the diabetic microvasculature.

[The baseline characteristics of patients with type 2 diabetes initiating insulin detemir : the Chinese cohort from the SOLVE(TM) study].

OBJECTIVE: To characterize the baseline status of Chinese diabetic patients based on data derived from Chinese cohort from SOLVE(TM) study. METHODS: Patients with type 2 diabetes initiating basal insulin detemir at the decision of the physician were eligible for the study. Data on demographics, medical history, glycemic profile and treatment regimen at baseline were collected by physicians. RESULTS: A total of 3272 patients [female 42%, male 58%, mean age (56.2 ± 10.8) years] were included in the study. Their BMI was (25.3 ± 3.3) kg/m(2). The duration of diabetes was 4.0 (0.1 - 27.0) years, and the duration of treatment with oral antidiabetic drugs (OADs) was 3.0 (0.0 - 20.2) years. The proportions of subjects with diabetic macro- and micro-vascular complications were 15.8% (515 cases) and 27.1% (866 cases), respectively. The hemoglobin A1c (HbA1c) at baseline was (8.33 ± 1.70)%, and the fasting blood glucose (FPG) was (9.5 ± 2.6) mmol/L. CONCLUSIONS: A large proportion of patients with type 2 diabetes remain in poor glycemic control, and the prevalence of diabetic complications is high, which requires optimal therapeutic strategy for the patients with suboptimal glycemic control.

[Analysis of medication with hypertension by different glucose tolerance status].

OBJECTIVE: To analyze the combination of hypertension and the use of antihypertensive drugs by different glucose tolerance status. METHODS: Matched case-control design was used to sample the subjects from the population for the prevalence of diabetes mellitus and metabolism syndrome from 2007 to 2008. There were 3 groups including normal glucose tolerance (NGT, n = 2124), impaired glucose regulation (IGR, n = 2162) and diabetes (DM, n = 2470). The matched factors were location, age and gender. All subjects were interviewed to describe the hypertension and antihypertensive drugs of these conditions. RESULTS: After adjusting for age, gender and location, the combination of hypertension in IGR and DM groups was higher than NGT (28.3%, 40.2% and 19.9%) and OR was 1.29 (1.08 - 1.53) and 1.99 (1.67 - 2.37) respectively. The percent of treatment, prescription compliance and the surveillance of hypertension in total subjects were 48.6%, 79.3% and 62.5%. And no difference was observed among 3 groups. The proportion of calcium channel blocker of DM groups was higher than NGT group. The uses of angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II receptor blocker (ARB) showed no difference among 3 groups. CONCLUSIONS: The combination of hypertension is higher in IGR and DM groups than that in NGT group. And the treatment rate of hypertension remains low. ACEI and ARB are under-utilized in IGR and DM groups.

[Ageing related changes of insulin secretion and insulin sensitivity among normal glucose tolerance individuals in China].

OBJECTIVE: To explore the aging-related changes of insulin secretion and insulin sensitivity among normal glucose tolerance (NGT) individuals in China. METHODS: A total of 34 293 individuals were recruited. All of them were described as NGT by 75 g oral glucose tolerance test (75 g OGTT) according to the diagnostic criterion of WHO, 1999. HOMA-ß, ΔI(30)/ΔG(30), InsAuc30/GluAuc30, InsAuc120/GluAuc120 were calculated to estimate insulin secretion; HOMA-IR and Matsuda index measured to estimate insulin sensitivity; Disposition index: DI(30) and DI(120) were used to estimate ß-cell function. RESULTS: HOMA-ß, ΔI(30)/ΔG(30), InsAuc30/GluAuc30 and InsAuc120/GluAuc120 were all lower in the elder group then the younger group (P trend < 0.05). The mean HOMA-ß dropped from 192 ± 16 (20 - 29 years) to 115 ± 7 (70 or elder) among men and from 162 ± 8 (20 - 29 years) to 120 ± 12 (70 or elder) among women. The mean ΔI(30)/ΔG(30) dropped from 20.0 ± 2.0 (20 - 29 years) to 8.6 ± 0.6 (70 or elder) among men and from 22.4 ± 1.6 (20 - 29 years) to 12.5 ± 1.7 (70 or elder) among women. The above index were negatively correlated with age in univariate linear regression (P < 0.05), the results among men and overall still existed after adjusted for BMI and waist circumference in multivariate linear regression, while the relation between HOMA-ß and age disappeared among women. Matsuda Index was positively correlated with age (ß = 0.02, P = 0.001) and HOMA-IR were negatively correlated with age (ß = -0.01, P = 0.001) among men even after adjusted for BMI and waist circumference and the above correlation between Matsuda Index/HOMA-IR and ageing was not significant until adjusted for BMI and waist circumference in multivariate linear regression. Among women HOMA-IR (ß = -0.01, P = 0.000), Matsuda index (ß = 0.03, P = 0.000). DI(30) and DI(120) were negatively correlated with age in both univariate and multivariate linear regression. CONCLUSIONS: The basal, postchallenge insulin secretion and postchallenge islet compensatory function decreases with ageing, while insulin sensitivity does not deteriorate with ageing and its related change of body composition and weight gain.

[Efficacy of tianmaixiaoke tablets in the treatment of newly diagnosed type 2 diabetes mellitus in China].

OBJECTIVE: To explore the efficacy and influencing factors of chromium picolinate (tianmaixiaoke tablet) in the treatment of newly diagnosed type 2 diabetes mellitus in China. METHODS: A total of 84 outpatients with newly diagnosed type 2 diabetes mellitus visiting 4 hospitals in Beijing were randomly divided into two equal groups: study group receiving tianmaixiaoke tablet 240 mg bid for 24 weeks (n = 42) and control group sitagliptin 100 mg qd for 24 weeks (n = 42). The levels of fasting plasma glucose (FPG), plasma glucose 2 h after meal (PG2 h) and glycated hemoglobin (HbA1c) were detected before and 24 weeks after treatment. The serum levels of chromium and insulin were detected. RESULTS: Study was completed in 76 patients. The serum level of chromium was significantly lower in the diabetes group than in the normal group at baseline ((56 ± 28) µg/L vs (112 ± 21) µg/L, P = 0.00). At 24 weeks after treatment, the levels of HbA1c, FPG and PG2 h decreased while the serum level of chromium increased significantly in both groups. There were 11 patients with changed HbA1c from baseline (ΔHbA1c) ≥ 1% in the study group. At 24 weeks after treatment, HbA1c decreased by 1.61% (from 8.38% ± 0.72% to 6.77% ± 0.62%) and serum level of chromium increased by 35.14 µg/L in the ΔHbA1c ≥ 1% group with a low baseline serum level of chromium ((36.2 ± 18.0) µg/L). Both study group and control group were divided into three subgroups according to baseline serum level of chromium. ΔHbA1c reduced with the increase in baseline serum level of chromium in study group, while in control group, ΔHbA1c was unrelated with baseline serum level of chromium. At 24 weeks after treatment, insulin resistance index (HOMA-IR) reduced, ß cell function index (HOMA-ß) and insulinogenic index (IGI) increased in both groups. Multiple linear regression showed that the variables significantly associated with ΔHbA1c were baseline HbA1c and the baseline serum level of chromium. CONCLUSIONS: Chromium is commonly deficient in the newly diagnosed type 2 diabetics in China. HbA1c decreases and serum chromium increases significantly after chromium supplementation in the patients with a low baseline serum level of chromium.

Development and validation of a risk assessment model for prediabetes in China national diabetes survey.

BACKGROUND: Prediabetes risk assessment models derived from large sample sizes are scarce. AIM: To establish a robust assessment model for prediabetes and to validate the model in different populations. METHODS: The China National Diabetes and Metabolic Disorders Study (CNDMDS) collected information from 47325 participants aged at least 20 years across China from 2007 to 2008. The Thyroid Disorders, Iodine Status and Diabetes Epidemiological Survey (TIDE) study collected data from 66108 participants aged at least 18 years across China from 2015 to 2017. A logistic model with stepwise selection was performed to identify significant risk factors for prediabetes and was internally validated by bootstrapping in the CNDMDS. External validations were performed in diverse populations, including populations of Hispanic (Mexican American, other Hispanic) and non-Hispanic (White, Black and Asian) participants in the National Health and Nutrition Examination Survey (NHANES) in the United States and 66108 participants in the TIDE study in China. C statistics and calibration plots were adopted to evaluate the model's discrimination and calibration performance. RESULTS: A set of easily measured indicators (age, education, family history of diabetes, waist circumference, body mass index, and systolic blood pressure) were selected as significant risk factors. A risk assessment model was established for prediabetes with a C statistic of 0.6998 (95%CI: 0.6933 to 0.7063) and a calibration slope of 1.0002. When externally validated in the NHANES and TIDE studies, the model showed increased C statistics in Mexican American, other Hispanic, Non-Hispanic Black, Asian and Chinese populations but a slightly decreased C statistic in non-Hispanic White individuals. Applying the risk assessment model to the TIDE population, we obtained a C statistic of 0.7308 (95%CI: 0.7260 to 0.7357) and a calibration slope of 1.1137. A risk score was derived to assess prediabetes. Individuals with scores ≥ 7 points were at high risk of prediabetes, with a sensitivity of 60.19% and specificity of 67.59%. CONCLUSION: An easy-to-use assessment model for prediabetes was established and was internally and externally validated in different populations. The model had a satisfactory performance and could screen individuals with a high risk of prediabetes.

[The protection of islet ß-cells in db/db mice by combination pioglitazone and glucagon like peptide-1 treatment].

OBJECTIVES: To evaluate the effect of combination of liraglutide, a glucagon-like peptide-1 analogue and pioglitazone, an insulin sensitizer, on diabetic db/db mice. METHODS: Thirty-five 8-week old male db/db mice were divided into control group (n = 8), pioglitazone group (n = 9), liraglutide group (n = 9) and combined therapeutic group (n = 9), which was given normal saline 0.1 ml, 2/d, pioglitazone 24 mg×kg(-1)×d(-1) (feed contained 0.02% pioglitazone) + normal saline 0.1 ml, 2/d, liraglutide 300 mg/kg, 2/d, and pioglitazone 20 mg×kg(-1)×d(-1) (feed contained 0.02% pioglitazone) + liraglutide 300 mg/kg, 2/d, respectively. Liraglutide were given at 8:00 and 16:00 via subcutaneous injection after having been diluted with sterilized normal saline. Effect on glucose, lipid metabolism and islet ß-cell preservation were assessed after 4 weeks. Oneway ANOVA was adopted for statistical analysis. RESULTS: Combination therapy displayed promising anti-hyperglycemic [glycosylated hemoglobin A1c: (4.5 ± 0.6)% vs. (7.3 ± 0.4)%, P < 0.001]. Glucose tolerance were improved assessed by area under curve (AUC) of glucose by intraperitoneal glucose tolerance test (IPGTT) [(1814 ± 91) mmol×min×L(-1) vs. (4042 ± 183) mmol×min×L(-1), P < 0.001]; insulin release response to glucose were also preserved as AUC of insulin by IPGTT was higher [(1639 ± 372) µg×min×L(-1) vs.(834 ± 201) µg×min×L(-1)]. Combination therapy also reduced circulated free fatty acids and TG [(202.0 ± 20.4) µmol/L vs. (272.5 ± 21.7) µmol/L, (0.81 ± 0.28) mmol/L vs. (1.35 ± 0.21) mmol/L], and increased plasma adiponectin [(16.7 ± 2.0) mg/L vs. (10.2 ± 1.8) mg/L]. All P value < 0.05. Islet immunohistochemistry showed that combination therapy significantly increased insulin positive area were [(59.5 ± 1.5)% vs. (22.4 ± 1.5)%] and ratio of Brdu positive ß-cells was three folds than vehicle-treated mice [(2.4 ± 0.5)% vs. (0.8 ± 0.3)%], both greater than each single treatment. Combined therapy significantly improved islet ß cell/α cell distribution, which led to islet recovery. CONCLUSIONS: Combined therapy improves glucose and lipid metabolism, preserves islet ß-cell function and stimulates ß-cell proliferation, greater than either liraglutide or pioglitazone treatment alone.

The role of non-coding RNAs in drug resistance of oral squamous cell carcinoma and therapeutic potential.

Oral squamous cell carcinoma (OSCC), the eighth most prevalent cancer in the world, arises from the interaction of multiple factors including tobacco, alcohol consumption, and betel quid. Chemotherapeutic agents such as cisplatin, 5-fluorouracil, and paclitaxel have now become the first-line options for OSCC patients. Nevertheless, most OSCC patients eventually acquire drug resistance, leading to poor prognosis. With the discovery and identification of non-coding RNAs (ncRNAs), the functions of dysregulated ncRNAs in OSCC development and drug resistance are gradually being widely recognized. The mechanisms of drug resistance of OSCC are intricate and involve drug efflux, epithelial-mesenchymal transition, DNA damage repair, and autophagy. At present, strategies to explore the reversal of drug resistance of OSCC need to be urgently developed. Nano-delivery and self-cellular drug delivery platforms are considered as effective strategies to overcome drug resistance due to their tumor targeting, controlled release, and consistent pharmacokinetic profiles. In particular, the combined application of new technologies (including CRISPR systems) opened up new horizons for the treatment of drug resistance of OSCC. Hence, this review explored emerging regulatory functions of ncRNAs in drug resistance of OSCC, elucidated multiple ncRNA-meditated mechanisms of drug resistance of OSCC, and discussed the potential value of drug delivery platforms using nanoparticles and self-cells as carriers in drug resistance of OSCC.

Gordian Knot: Gastrointestinal lesions caused by three highly pathogenic coronaviruses from SARS-CoV and MERS-CoV to SARS-CoV-2.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the pathogen of 2019 novel coronavirus disease (COVID-19), is currently spreading around the world. The WHO declared on January 31 that the outbreak of SARS-CoV-2 was a public health emergency. SARS-Cov-2 is a member of highly pathogenic coronavirus group that also consists of severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East Respiratory Syndrome Coronavirus (MERS-CoV). Although respiratory tract lesions were regarded as main manifestation of SARS-Cov-2 infection, gastrointestinal lesions were also reported. Similarly, patients with SARS-CoV and MERS-CoV were also observed. Common gastrointestinal symptoms of patients mainly included diarrhea, vomiting and abdominal pain. Gastrointestinal lesions could be used as basis for early diagnosis of patients, and at the same time, controlling gastrointestinal lesions better facilitated to cut off the route of fecal-oral transmission. Hence, this review summarizes the characteristics and mechanism of gastrointestinal lesions caused by three highly pathogenic human coronavirus infections including SARS-CoV, MERS-CoV, as well as SARS-CoV-2. Furthermore, it is expected to gain experience from gastrointestinal lesions caused by SARS-CoV and MERS-CoV infections in order to be able to better relieve SARS-CoV-2 epidemic. Targetin gut microbiota to regulate the process of SARS-CoV-2 infection should be a concern. Especially, the application of nanotechnology may provide help for further controlling COVID-19.

[Effects of fenofibrate on the expression of peroxisome proliferator-activated-gamma coactivator-1α in skeletal muscle of rats infused with intralipid].

OBJECTIVE: To observe the effects of fenofibrate on the expression of peroxisome proliferator-activated (PPAR)-gamma coactivator-1α (PGC-1α) in skeletal muscle of rats with insulin resistance (IR) induced by elevated plasma free fatty acid (FFA) levels. METHODS: Male Sprague-Dawley (SD) rats were randomly divided into three groups: control group (Con, infused with saline), lipid infusion group (FFA) and fenofibrate treatment plus lipid infusion group (F-FFA). Plasma glucose, insulin and FFA were measured. Glucose infusion rate (GIR) was used to evaluate the insulin sensitivity by euglycemic-hyperinsulinemic clamp. The gene expression of PGC-1α in skeletal muscle was determined by real-time polymerase chain reaction (PCR). RESULTS: Compared with the control group, the levels of plasma FFA and insulin were elevated significantly in rats infused with lipid, but they decreased significantly in rats pretreated with fenofibrate then infused with lipid [FFA, Con: 0.46 (0.08 - 0.72) mmol/L, FFA: 1.45(0.87-1.70) mmol/L, F-FFA: 0.54 (0.06 - 0.84) mmol/L, all P < 0.01; Insulin, Con: (6.56 ± 0.78) µIU/ml, FFA: (10.54 ± 0.86) µIU/ml, F-FFA: (6.69 ± 0.84) µIU/ml, all P < 0.01]. In addition, the plasma glucose levels did not change markedly after lipid infusion; GIR was significantly reduced by 55.6% in lipid infusion group, but fenofibrate-pretreatment increased glucose infusion rate (GIR) [Con: (25.13 ± 2.10) mg×kg(-1)×min(-1), FFA: (10.16 ± 0.75) mg×kg(-1)×min(-1), F-FFA: (21.72 ± 2.89) mg×kg(-1)×min(-1), all P < 0.01]; the mRNA expression of PGC-1α decreased by about 71% in lipid infusion group but fenofibrate increased the gene expression by about 150% as compared with FFA group (all P < 0.01). CONCLUSION: The elevation of plasma FFA levels may induce IR, and it also decreases the mRNA expression of PGC-1α in skeletal muscle. And fenofibrate pretreatment reverses these changes.

Factors associated with improvement in waist-to-height ratio among newly diagnosed type 2 diabetes patients treated with acarbose or metformin: A randomized clinical trial study.

BACKGROUND: The waist-to-height ratio (WHtR) is a promising anthropometric measure used to evaluate cardiovascular risk in diabetes and metabolic syndrome patients. The metformin and acarbose in Chinese as the initial hypoglycaemic treatment trial demonstrated that acarbose and metformin reduced the WHtR after 24 wk of treatment. AIM: To investigate the factors associated with a decrease in the WHtR in newly diagnosed Chinese type 2 diabetes patients receiving acarbose or metformin monotherapy. METHODS: At 24 wk, 343 patients in the acarbose treatment and 333 patients in the metformin treatment were included in this analysis. On the basis of the reduction in the WHtR, these participants were divided into the following two groups: Low ΔWHtR group and high ΔWHtR group. Metabolic and related parameters associated with a high ΔWHtR were investigated using univariate and multivariate logistic regression analyses. RESULTS: A significant decrease in the WHtR was observed in both treatment groups (acarbose: -0.015, 95% confidence interval [CI]: -0.018 to -0.012, P < 0.001; metformin: -0.013, 95%CI: -0.016 to -0.010, P < 0.001). In both the acarbose and metformin groups, the WHtR of the women was more likely to be reduced than that of the men. In the acarbose group, a lower baseline area under the curve of glucagon-like peptide 1 (AUCGLP-1) was associated with a high ΔWHtR (odds ratio [OR] = 0.796, P < 0.001), while a higher baseline AUCGLP-1 was associated with a high ΔWHtR in the patients treated with metformin (OR = 1.133, P = 0.025). Regarding the changes from baseline, an increase in AUCGLP-1 was associated with a high ΔWHtR in the acarbose (OR = 1.121, P = 0.016) but not metformin group. A higher reduction in high-density lipoprotein cholesterol/non-high-density lipoprotein cholesterol was also associated with a high ΔWHtR in the acarbose arm (OR = 20.735, P = 0.001). In the metformin arm, a higher reduction in fasting plasma glucose (OR = 0.843, P = 0.039) and total cholesterol was associated with a high ΔWHtR (OR = 0.743, P = 0.013). CONCLUSION: A lower glucagon-like peptide 1 level and higher increase in glucagon-like peptide 1 are associated with a high reduction in the WHtR in newly diagnosed Chinese diabetes patients receiving treatment with acarbose.

Liquid biopsy in head and neck squamous cell carcinoma: circulating tumor cells, circulating tumor DNA, and exosomes.

Introduction: Head and neck squamous cell carcinoma (HNSCC) is one of the most common cancers worldwide. Due to a lack of reliable markers, HNSCC patients are usually diagnosed at a late stage, which will lead to a worse outcome. Therefore, it is critical to improve the clinical management of cancer patients. Nowadays, the development of liquid biopsy enables a minimally invasive manner to extract molecular information from HNSCCs. Thus, this review aims to outline the clinical value of liquid biopsy in early detection, real-time monitoring, and prognostic evaluation of HNSCC. Areas covered: This comprehensive review focused on the characteristics as well as clinical applications of three liquid biopsy markers (CTCs, ctDNA, and exosomes) in HNSCC. What is more, it is promising to incorporate machine learning and 3D organoid models in the liquid biopsy of HNSCC. Expert opinion: Liquid biopsy provides a noninvasive technique to reflect the inter and intra-lesional heterogeneity through the detection of tumor cells or materials released from the primary and secondary tumors. Recently, some evolving technologies have the potential to combine with liquid biopsy to improve clinical management of HNSCC patients.