Efficacy and safety of oral semaglutide vs sitagliptin in a predominantly Chinese population with type 2 diabetes uncontrolled with metformin: PIONEER 12, a double-blind, Phase IIIa, randomised trial.

AIMS/HYPOTHESIS: The aim of this study was to assess the efficacy and safety of oral semaglutide vs sitagliptin in a predominantly Chinese population with type 2 diabetes inadequately controlled with metformin treatment. METHODS: The Peptide Innovation for Early Diabetes Treatment (PIONEER) 12 trial was a randomised, double-dummy, active-controlled, parallel-group, Phase IIIa trial conducted over 26 weeks at 90 sites across the China region (including mainland China, Taiwan and Hong Kong) and five other countries. Adults aged ≥18 years (≥20 years in Taiwan) with a diagnosis of type 2 diabetes, HbA1c between 53 and 91 mmol/mol (inclusive) and treated with a stable daily dose of metformin were eligible for inclusion. Participants were randomised (1:1:1:1) using a web-based randomisation system to either once-daily oral semaglutide (3 mg, 7 mg or 14 mg) or once-daily oral sitagliptin 100 mg. Treatment allocation was masked to both participants and investigators. Randomisation was stratified according to whether participants were from the China region or elsewhere. The primary endpoint was change in HbA1c from baseline to week 26. The confirmatory secondary endpoint was change in body weight (kg) from baseline to week 26. All randomised participants were included in the full analysis set (FAS). All participants exposed to at least one dose of trial product were included in the safety analysis (SAS). RESULTS: Of 1839 participants screened, 1441 were randomly assigned to oral semaglutide 3 mg (n=361), 7 mg (n=360), 14 mg (n=361) or sitagliptin 100 mg (n=359) and included in the FAS. A total of 1438 participants were included in the SAS. In total, 75.2% of participants were from the China region. A total of 1372 (95.2%) participants completed the trial and 130 participants prematurely discontinued treatment (8.3%, 8.6% and 15.0% for oral semaglutide 3 mg, 7 mg and 14 mg, respectively; 4.2% for sitagliptin 100 mg). Significantly greater reductions in HbA1c from baseline to week 26 were reported for all doses of oral semaglutide vs sitagliptin 100 mg. For oral semaglutide 3 mg, 7 mg and 14 mg vs sitagliptin 100 mg, the estimated treatment differences (ETDs [95% CI]) were -2 (-4, -1) mmol/mol, -8 (-9, -6) mmol/mol and -11 (-12, -9) mmol/mol, respectively. The corresponding ETDs (95% CI) in percentage points vs sitagliptin 100 mg were -0.2 (-0.3, -0.1), -0.7 (-0.8, -0.6) and -1.0 (-1.1, -0.8), respectively. Reductions in body weight were significantly greater for all doses of oral semaglutide vs sitagliptin 100 mg (ETD [95% CI] -0.9 [-1.4, -0.4] kg, -2.3 [-2.8, -1.8] kg and -3.3 [-3.8, -2.8] kg for 3 mg, 7 mg and 14 mg, respectively). In the subpopulation of participants from the China region (75.2% of trial participants), reductions in HbA1c and body weight from baseline to week 26 were similar to those seen in the overall population. The most frequent adverse events in the semaglutide treatment arms were gastrointestinal, although these were mostly transient and mild/moderate in severity. CONCLUSIONS/INTERPRETATION: Significantly greater reductions in both HbA1c and body weight over 26 weeks were seen with oral semaglutide 3 mg, 7 mg and 14 mg than with sitagliptin 100 mg in a predominantly Chinese population with type 2 diabetes inadequately controlled with metformin treatment. Oral semaglutide was generally well tolerated, with a safety profile consistent with that seen in the global PIONEER trials. TRIAL REGISTRATION: ClinicalTrials.gov NCT04017832. FUNDING: This trial was funded by Novo Nordisk A/S, Søborg, Denmark.

Tirzepatide for Weight Reduction in Chinese Adults With Obesity: The SURMOUNT-CN Randomized Clinical Trial.

Importance: Obesity has become a global public health concern and China has the largest number of affected people worldwide. Objective: To assess the efficacy and safety of treatment with tirzepatide for weight reduction in Chinese adults with obesity or overweight and weight-related comorbidities. Design, Setting, and Participants: This randomized, double-blind, placebo-controlled, phase 3 clinical trial conducted at 29 centers in China from September 2021 to December 2022 included Chinese adults (aged ≥18 years) with a body mass index (BMI) greater than or equal to 28 or greater than or equal to 24 and at least 1 weight-related comorbidity, excluding diabetes. Interventions: Participants were randomly assigned (1:1:1) to receive once-weekly, subcutaneous 10-mg (n = 70) or 15-mg (n = 71) tirzepatide or placebo (n = 69), plus a lifestyle intervention, for 52 weeks. Main Outcomes and Measures: Co-primary end points were the percent change in body weight from baseline and weight reduction of at least 5% at week 52. Efficacy and safety analyses were performed on an intention-to-treat population. Results: Of 210 randomized participants (103 [49.0%] female; mean [SD] age, 36.1 [9.1] years; body weight, 91.8 [16.0] kg; BMI, 32.3 [3.8]), 201 (95.7%) completed the trial. The mean change in body weight at week 52 was -13.6% (95% CI, -15.8% to -11.4%) with tirzepatide 10 mg, -17.5% (95% CI, -19.7% to -15.3%) with tirzepatide 15 mg, and -2.3% with placebo (difference between 10 mg and placebo, -11.3% [95% CI, -14.3% to -8.3%; P < .001]; difference between 15 mg and placebo, -15.1% [95% CI, -18.2% to -12.1%; P < .001]). The percentage of participants achieving body weight reductions of 5% or greater was 87.7% with tirzepatide 10 mg, 85.8% with tirzepatide 15 mg, and 29.3% with placebo (P < .001 for comparisons with placebo). The most frequent treatment-emergent adverse events with tirzepatide were gastrointestinal. Most were mild to moderate in severity, with few events leading to treatment discontinuation (<5%). Conclusions and Relevance: In Chinese adults with obesity or overweight, once-weekly treatment with tirzepatide 10 mg or 15 mg resulted in statistically significant and clinically meaningful weight reduction with an acceptable safety profile. Trial Registration: ClinicalTrials.gov Identifier: NCT05024032.

A phase III randomized, double-blind, placebo-controlled trial of the denosumab biosimilar QL1206 in postmenopausal Chinese women with osteoporosis and high fracture risk.

The current study evaluated the efficacy and safety of a denosumab biosimilar, QL1206 (60 mg), compared to placebo in postmenopausal Chinese women with osteoporosis and high fracture risk. At 31 study centers in China, a total of 455 postmenopausal women with osteoporosis and high fracture risk were randomly assigned to receive QL1206 (60 mg subcutaneously every 6 months) or placebo. From baseline to the 12-month follow-up, the participants who received QL1206 showed significantly increased bone mineral density (BMD) values (mean difference and 95% CI) in the lumbar spine: 4.780% (3.880%, 5.681%), total hip :3.930% (3.136%, 4.725%), femoral neck 2.733% (1.877%, 3.589%) and trochanter: 4.058% (2.791%, 5.325%) compared with the participants who received the placebo. In addition, QL1206 injection significantly decreased the serum levels of C-terminal crosslinked telopeptides of type 1 collagen (CTX): -77.352% (-87.080%, -66.844%), and N-terminal procollagen of type l collagen (P1NP): -50.867% (-57.184%, -45.217%) compared with the placebo over the period from baseline to 12 months. No new or unexpected adverse events were observed. We concluded that compared with placebo, QL1206 effectively increased the BMD of the lumbar spine, total hip, femoral neck and trochanter in postmenopausal Chinese women with osteoporosis and rapidly decreased bone turnover markers. This study demonstrated that QL1206 has beneficial effects on postmenopausal Chinese women with osteoporosis and high fracture risk.

ENSMUST00000147869 regulates proliferation and fibrosis of mesangial cells in diabetic nephropathy by interacting with Hspa9.

Our previous study showed that ENSMUST00000147869 was abnormally low expressed in the early stage of diabetic nephropathy (DN). ENSMUST00000147869 could inhibit the fibrosis and proliferation of mouse mesangial cells (MMCs), but the mechanism is still unclear. This study aims to explore the specific mechanism underline ENSMUST00000147869 regulates the proliferation and fibrosis of MMCs in DN. Nucleocytoplasmic fractionation was applied to define the location of ENSMUST00000147869 in MMCs. RNA-protein pulldown, RNA immunoprecipitation and mass spectrometry were used to identify upregulated Hspa9 directly interacting with ENSMUST00000147869. SiRNA and lentivirus packaging were used to clarify the role of Hspa9 downregulated by ENSMUST00000147869 in promoting proliferation and fibrosis in MMCs. CHX and MG132 were used to clarify the regulatory role of ENSMUST00000147869 to Hspa9. Immunoprecipitation confirmed the binding of Hspa9 and HMGB1. HSPA9 was a direct binding protein of ENSMUST00000147869, and ENSMUST00000147869 could inhibit proliferation and fibrosis of MMCs by down-regulating HSPA9 through ubiquitination process. HMGB1 was the downstream binding protein of Hspa9, and ENSMUST00000147869 could inhibit the interaction between Hspa9 and HMGB1. Our data showed that ENSMUST00000147869 regulates Hspa9 through the ubiquitin proteasome pathway and inhibits the binding of Hspa9 and HMGB1. The ENSMUST00000147869/Hspa9/HMGB1 axis may act as a diagnostic molecular marker and an effective therapeutic target for DN.

Improved glycaemic control and weight benefit with iGlarLixi versus insulin glargine 100 U/mL in Chinese people with type 2 diabetes advancing their therapy from basal insulin plus oral antihyperglycaemic drugs: Results from the LixiLan-L-CN randomized controlled trial.

AIMS: To evaluate the efficacy and safety of iGlarLixi compared with iGlar in Chinese adults with type 2 diabetes advancing therapy from basal insulin ± oral antihyperglycaemic drugs. MATERIALS AND METHODS: LixiLan-L-CN (NCT03798080) was a 30-week randomized, active-controlled, open-label, parallel-group, multicentre study. Participants were randomized 1:1 to iGlarLixi or iGlar. The primary objective was to show the superiority of iGlarLixi over iGlar in glycated haemoglobin (HbA1c) change from baseline to Week 30. RESULTS: In total, 426 participants were randomized to iGlarLixi (n = 212) or iGlar (n = 214). Mean age was 58 years, 67% had a body mass index ≥24 kg/m2 , corresponding to overweight/obesity, and the mean diabetes duration was 12.3 years. From mean baseline HbA1c of 8.1% in both groups, greater decreases were seen with iGlarLixi versus iGlar [least squares mean difference: -0.7 (95% confidence interval: -0.9, -0.6)%; p < .0001] to final HbA1c of 6.7% and 7.4%, respectively. HbA1c <7.0% achievement was greater with iGlarLixi (63.3%) versus iGlar (29.9%; p < .0001). Mean body weight decreased with iGlarLixi and increased with iGlar [least squares mean difference: -0.9 (95% confidence interval: -1.4, -0.5) kg; p = .0001]. Hypoglycaemia incidence was similar between groups. Few gastrointestinal adverse events occurred (rated mild/moderate) with a slightly higher incidence with iGlarLixi than iGlar. CONCLUSIONS: iGlarLixi provided better glycaemic control and facilitated more participants to reach glycaemic targets alongside beneficial effects on body weight, no additional risk of hypoglycaemia, and few gastrointestinal AEs, supporting iGlarLixi use as an efficacious and well tolerated therapy option in Chinese people with long-standing T2D advancing therapy from basal insulin.

DUAL II China: Superior HbA1c reductions and weight loss with insulin degludec/liraglutide (IDegLira) versus insulin degludec in a randomized trial of Chinese people with type 2 diabetes inadequately controlled on basal insulin.

AIM: To assess the efficacy and safety of insulin degludec/liraglutide (IDegLira) versus insulin degludec (degludec) in Chinese people with type 2 diabetes (T2D) treated with basal insulin. MATERIALS AND METHODS: In DUAL II China, a randomized, double-blinded, multicentre, treat-to-target trial, Chinese adults with T2D and HbA1c of 7.5% or more on basal insulin and metformin, with or without other oral antidiabetic drugs (OADs), were randomized 2:1 to 26 weeks of treatment with either IDegLira (max. dose 50 U degludec/1.8 mg liraglutide) or degludec (max. 50 U/day), respectively, combined with metformin. At 26 weeks, superiority of IDegLira over degludec was assessed for change in HbA1c (primary endpoint), and body weight and number of severe or blood glucose (BG)-confirmed hypoglycaemic episodes (confirmatory secondary endpoints). RESULTS: Overall, 453 participants were randomized to IDegLira (n = 302) or degludec (n = 151). Superiority was confirmed for IDegLira over degludec in HbA1c change (-1.9% vs. -1.0%, respectively, estimated treatment difference [ETD] [95% confidence interval]: -0.92% [-1.09; -0.75], P < .0001), body weight change (-0.7 vs. +0.4 kg, respectively, ETD [95% CI]: -1.08 kg [-1.63; -0.52], P = .0002) and severe or BG-confirmed hypoglycaemia (estimated rate ratio [95% CI]: 0.53 [0.30; 0.94], P = .0297). The odds of achieving HbA1c less than 7.0% without hypoglycaemia and/or weight gain were greater with IDegLira than degludec (P < .0001 for all). Daily insulin dose at 26 weeks was lower for IDegLira (34.3 U) than degludec (37.4 U) (P = .0014). No unexpected safety signals were observed. CONCLUSIONS: IDegLira may be an efficacious and well-tolerated treatment intensification option for Chinese people with T2D uncontrolled on basal insulin and OADs.

Silencing of Long Non-coding RNA ENST00000606790.1 Inhibits the Malignant Behaviors of Papillary Thyroid Carcinoma through the PI3K/AKT Pathway.

PURPOSE: This study aimed to investigate the role and mechanism of lncRNA ENST00000606790.1 (ENST) in promoting the progression of papillary thyroid carcinoma (PTC). METHODS: The expression of ENST in human PTC and normal para-cancerous thyroid (NPTC) tissues or cell lines was determined by RT-qPCR. Cell growth was determined by CCK8 assay. Cell colony formation was determined by cell colony formation assay. Cell cycle analysis was performed by staining cells with PI (Propidium Iodide). Cell invasion was assessed by transwell assay. Protein expression was examined by western-blot. siRNA was constructed to inhibit the expression of ENST. 740-Y-P was used to activate PI3K. The correlation between ENST expression and clinical outcomes was analyzed. RESULTS: ENST was significantly up-regulated in PTC tissues or PTC cell lines (PTC and IHH4 cell lines), compared to NPTC tissues or normal cell lines, respectively. High expression of ENST was strongly correlated to lymph node metastasis and tumor size at diagnosis. Silencing of ENST significantly inhibited cell growth and colony formation, arrested the cell cycle at G2/M phase, upregulated the expression of CHK1, downregulated the expression of CDC25C, and inhibited cell invasion. Silencing of ENST significantly down-regulated the expression of PI3K, p-PI3K, AKT, and p-AKT in IHH4 cells. Furthermore, treatment with the PI3K activator  740-Y-P partially abolished the effect of silencing of ENST on PTC cells. CONCLUSIONS: Overall, our results demonstrated that ENST can promote PTC progression by activating the PI3K/AKT signaling pathway, suggesting that ENST can serve as a potential biomarker and new therapeutic target for patients with PTC.

Effects of active localization and vascular preservation of inferior parathyroid glands in central neck dissection for papillary thyroid carcinoma.

BACKGROUND: The purpose of present study is to assess the effects of active localization and vascular preservation of inferior parathyroid glands in central neck dissection (CND) for papillary thyroid carcinoma (PTC). METHODS: A classification of IPGs according to their location and vascular features was developed, and, based on this classification, a CND procedure was designed, and IPGs and their vascular were actively localized and strategically preserved. A total of 197 patients with PTC who underwent a total thyroidectomy and concomitant CND were enrolled. Eighty-nine patients with traditional meticulous fascia dissection were allocated to group A, and 108 patients with active location and vascular preservation of IPGs were allocated to group B. Those with inferior parathyroid glands auto-transplantation in each group were assigned as group At (18) and group Bt (12). Variables including serum intact parathyroid hormone (PTH), total calcium, the incidence of transient, and permanent hypoparathyroidism were studied. RESULTS: Compared with group A, serum intact PTH (P < 0.001) and total calcium levels (P < 0.05) in group B significantly improved on the first postoperative day, and the incidence of transient hypoparathyroidism significantly dropped in group B (P < 0.001). A total of 170 patients in the two groups had complete follow-up data. The incidence of permanent hypoparathyroidism significantly decreased in group B, from 8.8% to 1.0% (P = 0.017). However, there were no significant differences in all variables between group Bt and group At. CONCLUSION: Active location and vascular preservation of inferior parathyroid glands effectively protected the function of IPGs in CND for PTC.

LncRNA ENST00000539653 acts as an oncogenic factor via MAPK signalling in papillary thyroid cancer.

BACKGROUND: Papillary thyroid cancer (PTC) is the most frequent type of thyroid malignancy. In this study, we investigated the mechanisms whereby long non-coding RNAs (lncRNAs) are associated with PTC pathogenesis. METHODS: Microarray analysis was used to determine differentially expressed lncRNAs between paired PTC tissues and normal adjacent thyroid tissues. Quantitative RT-PCR was used for validation in 86 PTC cases. Small interfering RNA (siRNA) transfection assays were then performed to assess how a novel lncRNA affected key proliferation and cell death pathways in IHH4 PTC cells. RESULTS: We identified 1878 differentially expressed lncRNAs versus matched control samples (fold change ≥2.0, P < 0.05), of which 429 were upregulated and 1449 were downregulated. ENST00000539653.1 (ENS-653), one of the top hits in this microarray, was selected for further study. Higher ENS-653 expression was observed in PTC tissue samples versus adjacent normal tissues, and was associated with a larger tumor size and a more advanced clinical stage. In the Cancer Genome Atlas (TCGA) PTC cohort, higher ENS-653 expression was correlated with more frequent BRAF (V600E) mutation and poorer disease-free survival. Furthermore, ENS-653 downregulation reduced the proliferation of PTC cells and led to G1-S arrest, but had no impact on apoptosis. ENS-653 downregulation also inactivated ERK1/2 and ERK5, causing partial MAPK cascade suppression. CONCLUSION: ENS-653 exhibits oncogenic properties in PTC, and could be a diagnostic and/or prognostic PTC biomarker, in addition to possibly being a future target for therapy.

Determining the optimal fasting glucose target for patients with type 2 diabetes: Results of the multicentre, open-label, randomized-controlled FPG GOAL trial.

The optimal fasting blood glucose (FBG) target of achieving HbA1c less than 7.0% in type 2 diabetes (T2D) patients remains controversial. This open-label trial randomized (1:3:3) 947 adults with uncontrolled T2D (HbA1c >7% to ≤10.5%) who were using one to three oral antidiabetic drugs to achieve an FBG target of 3.9 < FBG ≤5.6 mmol/L (Group 1), 3.9 < FBG ≤6.1 mmol/L (Group 2) or of 3.9 < FBG ≤7.0 mmol/L (Group 3). Targets were achieved using a pre-defined insulin glargine 100 U/mL titration scheme. The primary endpoint was proportion of patients achieving HbA1c <7.0% at 24 weeks. At 24 weeks, 44.4%, 46.1% and 37.7% of patients achieved HbA1c <7.0% in Groups 1, 2 and 3, respectively (P = 0.017; Group 2 vs Group 3). Alert hypoglycaemia (glucose ≤3.9 mmol/L) was significantly more frequent in Group 1 than in Group 3 (38.9 vs 23.3%; P < 0.001) but was not in Group 2 vs Group 3 (27.5% vs 23.3%; P = 0.177). Clinically important hypoglycaemia (glucose ≤3.0 mmol/L) was reported in 4.8%, 2.0% and 3.8% of patients in Groups 1, 2 and 3, respectively. In conclusion, the optimal FBG target for most Chinese patients with T2D appears to be 3.9-6.1 mmol/L.

Research on the spectral phase correction method for the atmospheric detection in open space.

During the atmospheric detection process in open space, the excessive phase noise is introduced into the signal, due to the atmospheric turbulence, which causes the intensity and phase fluctuation. In the previous study, a spectral data processing method based on the co-frequency and dual-wave has been used to reduce the influence of the scintillation noise from the atmospheric turbulence in open space, while the influence of the phase noise remains to be solved. So the wavelength modulated signal is theoretically analyzed at first. On studying the relationship between the dual-waves in one cycle to eliminate the phase fluctuation and reduce the phase fluctuation caused by the atmospheric turbulence, a new method of the spectral phase correction for the open space atmospheric detection has been proposed. An atmospheric detection experiment on the phase correction in the open space based on co-frequency and dual-wave has been carried out. The results show that the maximum fluctuation of the spectral signal processed with this method is 1.06%, while the power spectral density fluctuation is suppressed below 50Hz, and the Allan analysis result is 8.8 × 10-8(1s). Compared with the traditional concentration inversion method using 2f-wavelength modulation and the classical light intensity elimination, the proposed phase correction method can effectively reduce the fluctuation of random noise caused by the short-term atmospheric turbulence and the laser flashing to improve the stability of the concentration measurement, which has practical engineering value.

Association of thyroid nodules with adiposity: a community-based cross-sectional study in China.

BACKGROUND: The association between thyroid nodules and adiposity remains controversial. We performed a cross-sectional, community-based study to examine whether thyroid nodules are associated with overweight and obesity, as defined with body mass index (BMI) and waist circumference. METHODS: The study included 1482 subjects (≥20 years of age; residing in Nanjing, China) receiving questionnaire interview, anthropometric measurements, laboratory tests and thyroid ultrasonography in 2009-2010. Overweight and obesity were defined as BMI ≥24 and ≥28 kg/m2, respectively. Central obesity was defined as waist circumference at ≥90 cm in men and ≥80 cm in women. A sensitivity analysis was conducted using the American Diabetes Association (ADA) criteria for overweight and obesity (BMI ≥ 23 and ≥25 kg/m2). RESULTS: Thyroid nodules were identified in 12.6% of the subjects. A greater proportion of the subjects with thyroid nodules had a BMI at ≥24 kg/m2 (51.9% vs. 40.5% in those without thyroid nodules, P = 0.003) and central obesity (43.3% vs. 24.2%, P < 0.001). After adjustment for other confounders, central obesity was still associated with significantly elevated risk of thyroid nodules (OR 1.62, 95%CI 1.14-2.28), whereas obesity/overweight based on BMI was not in both the main analysis and sensitivity analysis with the alternative criteria. In the subgroup analysis, BMI ≥24 kg/m2 (OR 1.61, 95%CI 1.01-2.54), as well as BMI ≥25 kg/m2 (OR 1.95, 95%CI 1.14-3.34), was significantly associated with higher risk of thyroid nodules among women. Using the ADA criteria, overweight and obesity were associated with thyroid nodules (OR 5.59, 95%CI 1.39-22.51 and 5.15, 95%CI 1.30-20.37) in thyroid-stimulating hormone (TSH) > 4.2 mIU/L subgroup. Central obesity correlated with higher risk of thyroid nodules regardless of age (< 50 years: OR 1.87, 95%CI 1.05-3.32: ≥50 years: OR 1.54, 95%CI 1.00-2.37) and in the following subgroups: men (OR 1.91, 95%CI 1.14-3.20), TSH > 4.2 mIU/L (OR 3.05, 95%CI 1.01-9.22), and urine iodine ≥200 µg/L (OR 1.79, 95%CI 1.14-2.81). CONCLUSION: Waist circumference is superior to BMI for assessing risk of thyroid nodules in Chinese subjects.

Heme oxygenase-1 enhances autophagy in podocytes as a protective mechanism against high glucose-induced apoptosis.

Injury and loss of podocytes play vital roles in diabetic nephropathy progression. Emerging evidence suggests autophagy, which is induced by multiple stressors including hyperglycemia, plays a protective role. Meanwhile, heme oxygenase-1 (HO-1) possesses powerful anti-apoptotic properties. Therefore, we investigated the impact of autophagy on podocyte apoptosis under diabetic conditions and its association with HO-1. Mouse podocytes were cultured in vitro; apoptosis was detected by flow cytometry. Transmission electron microscopy and biochemical autophagic flux assays were used to measure the autophagy markers microtubule-associated protein 1 light chain 3-II (LC3-II) and beclin-1. LC3-II and beclin-1 expression peaked 12-24h after exposing podocytes to high glucose. Inhibition of autophagy with 3-methyladenine or Beclin-1 siRNAs or Atg 5 siRNAs sensitized cells to apoptosis, suggesting autophagy is a survival mechanism. HO-1 inactivation inhibited autophagy, which aggravated podocyte injury in vitro. Hemin-induced autophagy also protected podocytes from hyperglycemia in vitro and was abrogated by HO-1 siRNA. Adenosine monophosphate-activated protein kinase phosphorylation was higher in hemin-treated and lower in HO-1 siRNA-treated podocytes. Suppression of AMPK activity reversed HO-1-mediated Beclin-1 upregulation and autophagy, indicating HO-1-mediated autophagy is AMPK dependent. These findings suggest HO-1 induction and regulation of autophagy are potential therapeutic targets for diabetic nephropathy.

An rs13293512 polymorphism in the promoter of let-7 is associated with a reduced risk of ischemic stroke.

The expression of let-7 family members was differentiated in ischemic stroke (IS), functioning as an important regulating molecular in the pathophysiology of stroke. We hypothesized that genetic polymorphism in the promoters of let-7 family may be associated with the risk of IS. To test this hypothesis, we investigated the association of the rs10877887 and rs13293512 in the promoters of let-7 family with the susceptibility to IS. A hospital-based case-control study was performed. The rs10877887 genotype was determined by using a polymerase chain reaction-restriction fragment length polymorphism assay, and the rs13293512 genotype was determined by using a TaqMan assay. We found that the rs13293512CC genotype was associated with a reduced risk of IS (CC vs. TT: adjusted OR = 0.43, 95 % CI 0.26-0.71; dominant model: adjusted OR = 0.70, 95 % CI 0.49-0.98; recessive model: adjusted OR = 0.45, 95 % CI, 0.28-0.73). Stratification analysis showed that the rs10877887TT carriers had a higher level of total cholesterol compared to rs10877887TC/CC carriers (P = 0.03). Combined analysis showed that the rs10877887TC/CC and rs13293512TC/CC genotypes had a reduced risk of IS risk (adjusted OR = 0.58, 95 % CI 0.36-0.95). Our findings suggest that the rs13293512 polymorphism may be a protective factor for the development of IS.

Serum bile acid and unsaturated fatty acid profiles of non-alcoholic fatty liver disease in type 2 diabetic patients.

BACKGROUND: The understanding of bile acid (BA) and unsaturated fatty acid (UFA) profiles, as well as their dysregulation, remains elusive in individuals with type 2 diabetes mellitus (T2DM) coexisting with non-alcoholic fatty liver disease (NAFLD). Investigating these metabolites could offer valuable insights into the pathophy-siology of NAFLD in T2DM. AIM: To identify potential metabolite biomarkers capable of distinguishing between NAFLD and T2DM. METHODS: A training model was developed involving 399 participants, comprising 113 healthy controls (HCs), 134 individuals with T2DM without NAFLD, and 152 individuals with T2DM and NAFLD. External validation encompassed 172 participants. NAFLD patients were divided based on liver fibrosis scores. The analytical approach employed univariate testing, orthogonal partial least squares-discriminant analysis, logistic regression, receiver operating characteristic curve analysis, and decision curve analysis to pinpoint and assess the diagnostic value of serum biomarkers. RESULTS: Compared to HCs, both T2DM and NAFLD groups exhibited diminished levels of specific BAs. In UFAs, particular acids exhibited a positive correlation with NAFLD risk in T2DM, while the ω-6:ω-3 UFA ratio demonstrated a negative correlation. Levels of α-linolenic acid and γ-linolenic acid were linked to significant liver fibrosis in NAFLD. The validation cohort substantiated the predictive efficacy of these biomarkers for assessing NAFLD risk in T2DM patients. CONCLUSION: This study underscores the connection between altered BA and UFA profiles and the presence of NAFLD in individuals with T2DM, proposing their potential as biomarkers in the pathogenesis of NAFLD.

FFAs and adipokine-mediated regulation of hsa-miR-143 expression in human adipocytes.

Accumulating evidence suggests that microRNAs (miRNAs) play an important role in regulating the pathways in adipose tissue that control processes such as adipogenesis, insulin resistance, and inflammation. MiR-143 is a well-characterized miRNA involved in adipogenesis and may be involved in regulating insulin resistance. Free fatty acids (FFAs) and adipokines, such as tumor necrosis factor-α (TNF-α), leptin, resistin, and interleukin-6 (IL-6), have already been identified as main regulators of obesity and insulin sensitivity. Therefore, we studied the effects of these inflammatory cytokines on the expression of miR-143. FFAs, resistin, and leptin downregulated miR-143 expression in human adipocytes, whereas TNF-α and IL-6 had little effect on miR-143 expression. These results suggest that the expression of miR-143 is affected by a variety of factors that are related to insulin sensitivity. Therefore, miR-143 may be an important mediator in the development of obesity-related insulin resistance.

[Retrospective analysis of patients with thrombocytopenia after patent ductus arteriosus interventional occlusion].

OBJECTIVE: To explore the risk factors of patent ductus arteriosus (PDA) patients with thrombocytopenia after PDA interventional occlusion. METHODS: Thrombocytopenia occurred in 14 out of 350 patients underwent PDA occlusion. Age, gender, body weight, PDA size, occluder size, mean pulmonary arterial pressure, the dose of heparin, the manufacturer of occluder, residual shunt after operation were analyzed. The recovery time of different grades of thrombocytopenia was observed. RESULTS: Multivariate logistic regression showed that the PDA size (OR = 2.238, P < 0.05), the dose of heparin (OR = 3.247, P < 0.05), residual shunt after operation (OR = 1.912, P < 0.01) were the independent risk factors of thrombocytopenia after PDA occlusion. The recovery time of mild thrombocytopenia was (7 ± 2) days without treatment. The recovery time of moderate thrombocytopenia was (12 ± 4) days with glucocorticoids treatment. The recovery time of severe thrombocytopenia was (21 ± 7) days with platelet transfusion. CONCLUSIONS: The occluder size, dose of heparin, residual shunt are the independent risk factors of thrombocytopenia after PDA interventional occlusion. Recover time of thrombocytopenia after PDA interventional occlusion is closely related to the severity of thrombocytopenia.

Prevalence and Influencing Factors of Mixed Dentition Malocclusion in Children Aged 6-12 Years in Jinzhou, China.

PURPOSE: To investigate the prevalence, clinical manifestations and related risk factors of malocclusion in schoolchildren of Jinzhou City, China. MATERIALS AND METHODS: A total of 2162 children aged 6-12 years were randomly selected from various districts of Jinzhou. Conventional clinical examination was performed by stomatologists, and the results were described based on different clinical manifestations of malocclusion and individual normal occlusion. Further, a questionnaire survey completed by children's parents or guardians provided the demographic data, lifestyle, and oral habits. The distribution of individual normal occlusion and malocclusion was documented in percentage, and Pearson's Χ2 was used for two-factor analysis. The data were statistically analysed using SPSS software (version 25.0) with a significance level of α = 0.05. RESULTS: A total of 1129 boys and 1033 girls were included in this study, i.e. 52.2% and 47.8% of the total number of children, respectively. The prevalence of malocclusion in children aged 6-12 years old in Jinzhou was 67.9%, of which crowded dentition was the most common form, with a prevalence of 71.8%, followed by deep overbite, anterior crossbite, dental spacing, deep overjet, anterior edge-to-edge occlusion, and anterior open bite. In the logistic regression model, the results showed that BMI index had little effect on the occurrence of malocclusion (p > 0.05), while dental caries, bad oral habits, retained primary teeth, and a low labial frenum were all related to the occurrence of malocclusion (p < 0.05). Moreover, the higher frequency and duration of bad oral habits were associated with a higher likelihood of malocclusion. CONCLUSIONS: The prevalence of malocclusion in children aged 6-12 years in Jinzhou is high. In addition, bad oral habits (such as lip biting, tongue thrusting, biting/gnawing objects, unilateral chin supporting, and unilateral mastication) and other related risk factors (such as dental caries, mouth breathing, retention of primary teeth, and low labial frenum, etc) were associated with malocclusion.

Association of Serum Bile Acid and Unsaturated Fatty Acid Profiles with the Risk of Diabetic Retinopathy in Type 2 Diabetic Patients.

Aim: We aimed to identify the ability of serum bile acids (BAs) and unsaturated fatty acids (UFAs) profiles to predict the development of diabetic retinopathy (DR) in type 2 diabetes mellitus (T2DM) patients. Methods: We first used univariate and multivariate analysis to compare 15 serum BA and 11 UFA levels in healthy control (HC) group (n = 82), T2DM patients with DR (n = 58) and T2DM patients without DR (n = 60). Forty T2DM patients were considered for validation. Then, the receiver operating characteristic curve (ROC) and decision curve analysis were used to assess the diagnostic value and clinical benefit of serum biomarkers alone, clinical variables alone or in combination, and the area under the curve (AUC), integrated discrimination improvement (IDI), and net reclassification improvement (NRI) were used to further assess whether the addition of biomarkers significantly improved the predictive ability of the model. Results: Orthogonal partial least squares-discriminant analysis (OPLS-DA) of serum BAs and UFAs separated the three cohorts including HC, T2DM patients with or without DR. The difference in serum BA and UFA profiles of T2DM patients with or without DR was mainly manifested in the three metabolites of taurolithocholic acid (TLCA), tauroursodeoxycholic acid (TUDCA) and arachidonic acid (AA). Together, they had an AUC of 0.785 (0.918 for validation cohort) for predicting DR in T2DM patients. After adjusting for numerous confounding factors, TLCA, TUDCA, and AA were independent predictors that differentiated T2DM with or without DR. The results of AUC, IDI, and NRI demonstrated that adding these three biomarkers to a model with clinical variables statistically increased their predictive value and were replicated in our independent validation cohort. Conclusion: These findings highlight the association of three metabolites, TLCA, TUDCA and AA, with DR and may indicate their potential value in the pathogenesis of DR.

Fecal microbiota transplantation ameliorates type 2 diabetes via metabolic remodeling of the gut microbiota in db/db mice.

INTRODUCTION: Gut microbiome (GM) deregulation has been implicated in major conditions such as obesity and type 2 diabetes (T2DM). Our previous prospective study indicated that fecal microbiota transplantation (FMT) successfully improved patients with T2DM. We hypothesized that FMT may be a potential therapeutic method for T2DM, but its precise mechanisms in T2DM remains to be elucidated. RESEARCH DESIGN AND METHODS: Eight db/m mice were FMT donors and control mice, and 16 genetically diabetic db/db mice were equally divided into two groups (db/db+phosphate-buffered saline (PBS) group, db/db+FMT group). The db/db+FMT group was administered fresh fecal suspension (0.2 mL/mice) daily for 4 weeks. Analysis of the GM and serum metabolome was carried out by 16S ribosomal RNA sequencing and liquid chromatogram-mass spectrometry, respectively. Effects of FMT on the gut barrier and pancreas were assessed using protein assays, messenger RNA, immunohistology and clinical indicators testing. RESULTS: Our results showed that FMT treatment of db/db mice relieves a series of clinical indicators, including fasting plasma glucose, serum insulin and oral glucose tolerance test among others. Compared with non-diabetic control mice, db/db+PBS mice exhibited decreased abundance of Ruminococaceae, Porphyromonadaceae and increased abundance of Rikenellaceae and Lactobacillaceae. FMT treatment reversed this effect on the microbiome. Eleven metabolites were changed between the db/db+PBS and db/db+FMT groups. Correlation analysis showed that the structural changes of the GM were correlated with host metabolite levels. We further showed that FMT treatment of db/db mice improved intestinal barrier function, reduced inflammation and caused an alteration in the number of circulating immune cells. CONCLUSIONS: FMT-mediated changes in the GM, serum metabolites, intestinal epithelial barrier, inflammation and circulating immune cells play an important role in the efficacy of FMT on T2DM disease progression.