Environmentally Relevant Concentrations of Tetrabromobisphenol A Exposure Impends Neurovascular Formation through Perturbing Mitochondrial Metabolism in Zebrafish Embryos and Human Primary Endothelial Cells.

Tetrabromobisphenol A (TBBPA), the most extensively utilized brominated flame retardant, has raised growing concerns regarding its environmental and health risks. Neurovascular formation is essential for metabolically supporting neuronal networks. However, previous studies primarily concerned the neuronal injuries of TBBPA, its impact on the neurovascularture, and molecular mechanism, which are yet to be elucidated. In this study, 5, 30, 100, 300 µg/L of TBBPA were administered to Tg (fli1a: eGFP) zebrafish larvae at 2-72 h postfertilization (hpf). The findings revealed that TBBPA impaired cerebral and ocular angiogenesis in zebrafish. Metabolomics analysis showed that TBBPA-treated neuroendothelial cells exhibited disruption of the TCA cycle and the Warburg effect pathway. TBBPA induced a significant reduction in glycolysis and mitochondrial ATP production rates, accompanied by mitochondrial fragmentation and an increase in mitochondrial reactive oxygen species (mitoROS) production in neuroendothelial cells. The supplementation of alpha-ketoglutaric acid, a key metabolite of the TCA cycle, mitigated TBBPA-induced mitochondrial damage, reduced mitoROS production, and restored angiogenesis in zebrafish larvae. Our results suggested that TBBPA exposure impeded neurovascular injury via mitochondrial metabolic perturbation mediated by mitoROS signaling, providing novel insight into the neurovascular toxicity and mode of action of TBBPA.

Association between the soluble receptor for advanced glycation end products and diabetes mellitus: systematic review and meta-analysis.

BACKGROUND AND AIMS: In both type 1 diabetes (T1DM) and type 2 diabetes (T2DM), previous studies have yielded inconsistent findings regarding whether the levels of the soluble receptor for advanced glycation end products (sRAGE) are significantly altered. This meta-analysis aims to systematically evaluate the changes of sRAGE levels in patients with T1DM and T2DM. METHODS: PubMed, Embase, and Web of Science were systematically searched from inception until April 2024. We included studies reporting sRAGE levels in individuals with T1DM or T2DM, using non-diabetic healthy individuals as the control group. A random-effects model was applied to conduct a meta-analysis of effect measures (means and SDs). RESULTS: 49 datasets from 32 studies, involving 4948 subjects, met the inclusion criteria. A random-effects model meta-analysis showed that sRAGE levels in T1DM subjects (SMD 0.45, CI: 0.16-0.73, P = 0.002) and T2DM subjects with complications (SMD 1.59, CI: 0.77-2.41, P = 0.0001) were significantly higher than those in the control groups. No statistically significant change in sRAGE levels was observed in T2DM subjects without complications (SMD 0.01, CI: -0.61-0.64, P = 0.97). A decrease in sRAGE levels was observed in subjects with newly diagnosed T2DM (SMD-0.40, CI: -0.71- -0.09, P = 0.01). CONCLUSION: This meta-analysis indicated that sRAGE levels increased in T1DM patients and T2DM patients with complications, while they decreased in newly diagnosed T2DM patients. No significant difference was observed in T2DM patients without complications. Clearly, changes in sRAGE levels in patients with T1DM or T2DM are not uniform, but depend on the different types and stages of the disease. PROSPERO REGISTRATION NUMBER: CRD42024521252.

A single-cell survey unveils cellular heterogeneity and sensitive responses in mouse cortices induced by oral exposure to triphenyl phosphate.

Triphenyl phosphate (TPhP) is a non-halogenated organophosphorus flame retardant, and there is a higher exposure risk in children. TPhP has been found to be neurotoxic upon developmental exposure, yet the specific mechanism remains unclear. To characterize the cellular responses underlying TPhP-induced developmental neurotoxicity, we administered TPhP (0.5, 5 or 50 mg/kg/day) to neonatal mice from postnatal day 10 (P10)-P70. A total of 17,229 cells and 26,338 genes were identified in cortical samples from control and low-dose (the internal doses of metabolite DPhP comparable to human exposure level) groups using single-cell RNA sequencing (scRNA-seq). TPhP exposure led to heterogeneous transcriptional alterations and intercellular crosstalk among neurons, neural stem/progenitor cells (NSPCs), endothelial cells, and immunocytes. Deprivation of NSPCs, loss of mature neurons, and concomitant neuroinflammation mediated by extrinsic and intrinsic immunocytes were found in TPhP-exposed cortices. In addition, we observed blood-brain barrier destruction prior to the anxiety/depression-like neurobehavioral changes. These results reveal the distinctive cellular processes in TPhP's neurodevelopmental toxicity and uncover that the impeded neurogenesis, disrupted vascular barrier, and concomitant neuroinflammation are the sensitive responses to TPhP exposure. Our study paves the way for the application of scRNA-seq in toxicity assessments for emerging neurotoxic pollutants.

Circulating betatrophin/ANGPTL8 levels correlate with body fat distribution in individuals with normal glucose tolerance but not those with glucose disorders.

BACKGROUND: The relationship between betatrophin/ANGPTL8 and obesity has been investigated using body mass index (BMI); however, since BMI reflects overall adiposity rather than body fat distribution, it remains unclear whether fat deposition in different areas of the body affects betatrophin expression. Here, we investigated the correlation between circulating betatrophin levels and body fat distribution in patients with different glucose tolerance. METHODS: We performed a cross-sectional study in 128 participants with impaired glucose tolerance (IGT; n = 64) or normal glucose tolerance (NGT; n = 64). Circulating betatrophin levels were detected by enzyme-linked immunosorbent assay (ELISA). Body fat distribution (subcutaneous, visceral, and limb fat) was measured by magnetic resonance imaging (MRI) and a body fat meter. RESULTS: After controlling for age, sex, and BMI, betatrophin was correlated positively with visceral adipose tissue-to-subcutaneous adipose tissue ratio (VAT/SAT ratio; r = 0.339, p = 0.009) and negatively with body fat ratio (BFR; r = - 0.275, p = 0.035), left lower limb fat ratio (LLR; r = - 0.330, p = 0.011), and right lower limb fat ratio (RLR; r = - 0.288, p = 0.027) in the NGT group, with these correlations remaining after controlling for triglycerides. VAT/SAT ratio (standardized ß = 0.419, p = 0.001) was independently associated with serum betatrophin levels; however, betatrophin was not associated with body fat distribution variables in the IGT group. CONCLUSIONS: Circulating betatrophin levels correlated positively with VAT/SAT ratio and negatively with lower limb fat, but not with subcutaneous or upper limb fat, in individuals with normal glucose tolerance. Thus, betatrophin may be a potential biomarker for body fat distribution in individuals without glucose disorders.

Neonatal exposure to organophosphorus flame retardant TDCPP elicits neurotoxicity in mouse hippocampus via microglia-mediated inflammation in vivo and in vitro.

Tris(1,3-dichloro-2-propyl) phosphate (TDCPP) is a phosphorus-based flame retardant common in consumer goods and baby products. Concerns have been raised about TDCPP exposure and neurodevelopmental toxicity. However, the mechanism and early response for TDCPP-induced neurotoxicity are poorly understood. This study investigates the role of microglia-mediated neuroinflammation in TDCPP-induced neurotoxicity in mice and primary cells. TDCPP was administered to C57BL/6 pups (0, 5, or 50 mg/kg/day) via an oral gavage from postnatal days 10-38 (28 days). The results showed that TDCPP exposure for 28 days altered the gene expression of neuronal markers Tubb3, Nefh, and Nes, and led to apoptosis in the hippocampus. The mRNA levels of pro-inflammatory factors Il-1ß, Tnfα and Ccl2 dose dependently increased in the hippocampus at both 24 h and 28 days following exposure, accompanied by microglia activation characterized by an amoeboid-like phenotype. In in vitro studies using the primary microglia isolated from neonatal mice, exposure to TDCPP (0-100 µM) for 24 h resulted in cellular activation. It also increased the expression of genes responsible for inflammatory responses including surface markers and pro-inflammatory cytokines. These changes occurred in a dose-dependent fashion. Neurite outgrowth of primary mouse hippocampal neurons was inhibited by treatment with the conditioned medium harvested from microglia exposed to TDCPP. These results reveal that neonatal exposure to TDCPP induces neuronal damage through microglia-mediated inflammation. This provides insight into the mechanism of TDCPP's neurodevelopmental toxicity, and suggests that microglial cell is a sensitive responder for OPFRs exposure.

Decreased circulating dipeptidyl peptidase-4 activity after short-term intensive insulin therapy predicts clinical outcomes in patients with newly diagnosed type 2 diabetes.

Background: This study aims to investigate the changes in circulating dipeptidyl peptidase-4 (DPP-4) activity following short-term intensive insulin therapy (SIIT) in newly diagnosed type 2 diabetes (T2D) patients and to assess its potential in predicting long-term remission. Methods: Ninety-five patients underwent SIIT for 2-3 weeks to attain and sustain near-normal glycemia. Insulin was then discontinued, and patients were followed for a year to evaluate glycemic outcomes. Biochemical tests, serum DPP-4 activity, and mixed meal tolerance tests were conducted at baseline, post-SIIT, and the 3-month follow-up. Results: DPP-4 activity decreased from 44.08 ± 9.58 to 40.53 ± 8.83 nmol/min/mL after SIIT (P<0.001). After three months post-SIIT, DPP-4 activity remained stable in the remission group (39.63 ± 8.53 nmol/L) but increased in the non-remission group (42.34 ± 6.64 nmol/L). This resulted in a more pronounced decrease in DPP-4 activity from baseline in the remission group (-3.39 ± 8.90 vs. -1.10 ± 8.95, P = 0.035). Logistic regression analyses showed that patients with greater DPP-4 activity reduction had a higher likelihood of 1-year remission (70% vs. 51.1%, OR: 7.939 [1.829, 34.467], P = 0.006 in the fully adjusted model). A non-linear relationship between △DPP-4 and 1-year remission rate was observed, with a clear threshold and saturation effect. Conclusion: Circulating DPP-4 activity significantly decreases after SIIT. The change in circulating DPP-4 activity during the 3-month post-treatment phase has the potential to predict long-term remission.

Development of an Automated Morphometric Approach to Assess Vascular Outcomes following Exposure to Environmental Chemicals in Zebrafish.

BACKGROUND: Disruptions in vascular formation attributable to chemical insults is a pivotal risk factor or potential etiology of developmental defects and various disease settings. Among the thousands of chemicals threatening human health, the highly concerning groups prevalent in the environment and detected in biological monitoring in the general population ought to be prioritized because of their high exposure risks. However, the impacts of a large number of environmental chemicals on vasculature are far from understood. The angioarchitecture complexity and technical limitations make it challenging to analyze the entire vasculature efficiently and identify subtle changes through a high-throughput in vivo assay. OBJECTIVES: We aimed to develop an automated morphometric approach for the vascular profile and assess the vascular morphology of health-concerning environmental chemicals. METHODS: High-resolution images of the entire vasculature in Tg(fli1a:eGFP) zebrafish were collected using a high-content imaging platform. We established a deep learning-based quantitative framework, ECA-ResXUnet, combined with MATLAB to segment the vascular networks and extract features. Vessel scores based on the rates of morphological changes were calculated to rank vascular toxicity. Potential biomarkers were identified by vessel-endothelium-gene-disease integrative analysis. RESULTS: Whole-trunk blood vessels and the cerebral vasculature in larvae exposed to 150 representative chemicals were automatically segmented as comparable to human-level accuracy, with sensitivity and specificity of 95.56% and 95.81%, respectively. Chemical treatments led to heterogeneous vascular patterns manifested by 31 architecture indexes, and the common cardinal vein (CCV) was the most affected vessel. The antipsychotic medicine haloperidol, flame retardant 2,2-bis(chloromethyl)trimethylenebis[bis(2-chloroethyl) phosphate], and tert-butylphenyl diphenyl phosphate ranked as the top three in vessel scores. Pesticides accounted for the largest group, with a vessel score of ≥1, characterized by a remarkable inhibition of subintestinal venous plexus and delayed development of CCV. Multiple-concentration evaluation of nine per- and polyfluoroalkyl substances (PFAS) indicated a low-concentration effect on vascular impairment and a positive association between carbon chain length and benchmark concentration. Target vessel-directed single-cell RNA sequencing of fli1a+ cells from larvae treated with λ-cyhalothrin, perfluorohexanesulfonic acid, or benzylbutyl phthalate, along with vessel-endothelium-gene-disease integrative analysis, uncovered potential associations with vascular disorders and identified biomarker candidates. DISCUSSION: This study provides a novel paradigm for phenotype-driven screenings of vascular-disrupting chemicals by converging morphological and transcriptomic profiles at a high-resolution level, serving as a powerful tool for large-scale toxicity tests. Our approach and the high-quality morphometric data facilitate the precise evaluation of vascular effects caused by environmental chemicals. https://doi.org/10.1289/EHP13214.

Intense simplified strategy for newly diagnosed type 2 diabetes in patients with severe hyperglycaemia: multicentre, open label, randomised trial.

OBJECTIVE: To evaluate whether the intense simplified strategy, which comprises short term intensive insulin therapy (SIIT) followed by subsequent oral antihyperglycaemic regimens, could improve long term glycaemic outcomes in patients with newly diagnosed type 2 diabetes mellitus and severe hyperglycaemia. DESIGN: Multicentre, open label, randomised trial. SETTING: 15 hospitals in China between December 2017 and December 2020. PARTICIPANTS: 412 patients with newly diagnosed type 2 diabetes and significant hyperglycaemia (HbA1c ≥8.5%). INTERVENTIONS: All randomised participants initially received SIIT for 2-3 weeks, followed by linagliptin 5 mg/day, metformin 1000 mg/day, combination linagliptin plus metformin, or lifestyle modification alone (control) for 48 weeks. MAIN OUTCOME MEASURES: The primary outcome was the percentage of participants achieving HbA1c <7.0% at week 48 after SIIT. Secondary outcomes included glycaemic control, ß cell function, and variations in insulin sensitivity. RESULTS: 412 participants were randomised. At baseline, the mean age was 46.8 (standard deviation 11.2) years, mean body mass index was 25.8 (2.9), and mean HbA1c was 11.0% (1.9%). At week 48, 80% (78/97), 72% (63/88), and 73% (69/95) of patients in the linagliptin plus metformin, linagliptin, and metformin groups, respectively, achieved HbA1c <7.0%, compared with 60% (56/93) in the control group (P=0.02 overall; P=0.003 for linagliptin plus metformin versus control; P=0.12 for linagliptin versus control; P=0.09 for metformin versus control). Additionally, 70% (68/97), 68% (60/88), and 68% (65/95) of patients in the linagliptin plus metformin, linagliptin, and metformin group, respectively, achieved HbA1c <6.5% compared with 48% (45/93) in the control group (P=0.005 overall; P=0.005 for linagliptin plus metformin versus control; P=0.01 for linagliptin versus control; P=0.008 for metformin versus control; all were significant after adjustment for multiple comparisons). Thus, compared with the control group, participants in the linagliptin plus metformin group were more likely to achieve HbA1c <7.0% at week 48 (odds ratio 2.78, 95% confidence interval 1.37 to 5.65; P=0.005). Moreover, the linagliptin plus metformin group showed the most significant improvement in fasting plasma glucose and ß cell function indices. All treatments were well tolerated. CONCLUSIONS: The intense simplified strategy using subsequent oral therapies post-SIIT, especially the linagliptin plus metformin combination, sustainably improved glycaemic control and ß cell function in patients with newly diagnosed type 2 diabetes mellitus and severe hyperglycaemia. This approach offers a promising direction for decision making in the clinical management of type 2 diabetes mellitus. TRIAL REGISTRATION: ClinicalTrials.gov NCT03194945.

Evaluating the role of time in range as a glycemic target during short-term intensive insulin therapy in patients with newly diagnosed type 2 diabetes.

BACKGROUND: Tight glycemic control during short-term intensive insulin therapy (SIIT) is critical for inducing diabetes remission in patients with newly diagnosed type 2 diabetes (T2D). This work aimed to investigate the role of time in range (TIR) during SIIT as a novel glycemic target by predicting clinical outcomes. METHODS: SIIT was given to 116 patients with newly diagnosed T2D, with daily eight-point capillary glucose monitored. Glycemic targets (fasting/premeal glucose, 3.9-6.0 mmol/L; 2 h postprandial blood glucose, 3.9-7.8 mmol/L) were achieved and maintained for 2 weeks. TIRPIR was calculated as the percentage of glucose points within these glycemic targets during the maintenance period and was compared to TIR3.9-7.8mmol/L and TIR3.9-10.0mmol/L . Acute insulin response (AIR), HOMA-IR, HOMA-B, and disposition index (DI) were measured. Patients were followed up for 1 year to observe clinical outcomes. RESULTS: TIRPIR , TIR3.9-7.8mmol/L , and TIR3.9-10.0mmol/L were 67.2 ± 11.2%, 80.8 ± 9.2%, and 90.1 ± 6.2%, respectively. After SIIT, ß-cell function and insulin sensitivity improved remarkably, and the 1-year remission rate was 55.2%. △AIR and △DI were positively correlated with all the TIR values, whereas only TIRPIR was correlated with △HOMA-IR (r = -0.22, p = 0.03). Higher TIRPIR but not TIR3.9-7.8mmol/L or TIR3.9-10.0mmol/L was robustly associated with diabetes remission; patients in the lower TIRPIR tertile had an elevated risk of hyperglycemia relapse (hazard ratio 3.4, 95% confidence interval 1.6-7.2， p = .001). Only those with TIRPIR ≥ 65% had a one-year remission rate of over 60%. CONCLUSIONS: These findings advocate TIRPIR ≥ 65% as a novel glycemic target during SIIT for clinical decision-making.

Safety Event Outcomes and Glycemic Control with a Hybrid Closed-Loop System Used by Chinese Adolescents and Adults with Type 1 Diabetes Mellitus.

Background: While evidence supports glycemic control benefits for individuals with type 1 diabetes mellitus (T1DM) using hybrid closed-loop (HCL) systems, HCL automated insulin delivery therapy in China has not been assessed. This study evaluated safety events and effectiveness during HCL system use by Chinese adolescents and adults with T1DM. Methods: Sixty-two participants (n = 12 adolescents with a mean ± standard deviation [SD] of 15.5 ± 1.1 years and n = 50 adults [mean ± SD of 37.6 ± 11.1 years]) with T1DM and baseline A1C of 7.1% ± 1.0% underwent a run-in period (∼2 weeks) using open-loop Manual Mode (sensor-augmented pump) insulin delivery with the MiniMed™ 770G system with the Guardian™ Sensor (3) glucose sensor, followed by a study period (4 weeks) with HCL Auto Mode enabled. Analyses compared continuous glucose monitoring data and insulin delivered during the run-in versus study period (Wilcoxon signed-rank test or t-test). Safety events included rates of severe hypoglycemia and diabetic ketoacidosis (DKA). Results: Compared to baseline run-in, overall Auto Mode use increased time in range (TIR, 70-180 mg/dL) from 75.3% to 80.9% (P < 0.001) and reduced time below range (TBR, <70 mg/dL) from 4.7% to 2.2% (P < 0.001). Subgroup analysis demonstrated that participants (n = 29) with baseline A1C <7.0% had TBR that reduced from 5.6% to 2.0%, while participants (n = 21) with baseline A1C ≥7.5% had time above range (TAR, >180 mg/dL) that reduced from 31.6% to 20.8%. Auto Mode use also increased the percentage achieving combined recommendations for time at sensor glucose ranges (i.e., TIR of >70%, TBR of <4% and TAR of <25%) from 24.2% at baseline to 77.4% at study end. Total daily insulin dose reduced from 42.8 ± 19.8 to 40.7 ± 18.9 U (P = 0.013). There were no severe hypoglycemic, DKA, or serious adverse events. Conclusions: Chinese adolescents and adults, some of whom met target A1C at baseline, safely achieved significantly improved glycemia with 1 month of MiniMed 770G system use when compared to open-loop insulin delivery. ClinicalTrials.gov ID: NCT04663295.

Early intensive insulin therapy attenuates the p38 pathway in the renal cortex and indices of nephropathy in diabetic rats.

In this rodent study, we compared the effects of early versus late intensive insulin therapy on diabetic nephropathy and potential causal mechanisms. Diabetes was induced in rats by high-fat diet and low-dose streptozotocin. Intensive insulin therapy was initiated in the early intensive insulin therapy groups as soon as diabetes was confirmed and lasted for 8 (8wEI group) and 16 weeks (16wEI group). In the late insulin therapy group (LI group), intensive insulin treatment was initiated 8 weeks later and lasted for 8 weeks. Age-matched diabetic rats (8wDM group and 16wDM group) and non-diabetic rats (8wNC group and 16wNC group) served as controls. Histological analysis, real-time PCR, and western blot were performed in renal cortex specimens. Glomerular hypertrophy and mesangial matrix expansion were prominent in the 16wDM and LI groups while the EI groups remained normal and similar to the 16wNC group. Western blots revealed that p38 MAPK activities in the EI groups decreased significantly, whereas the level in the LI group was markedly higher than the 16wEI group, and not different from the DM groups. Activities of MKK3/6, CREB and MKP-1 proteins as well as CREB and MKP-1 mRNA showed a similar pattern. Therefore, we concluded that early intensive insulin treatment and attainment of good glycemic control counteracted some renal molecular pathways associated with epigenetic metabolic memory to minimize risk of diabetic nephropathy. However, late insulin therapy did not abrogate the increased renal cortical p38 MAPK pathway activation in diabetic rats and led to glomerular hypertrophy and extracellular matrix expansion.

Hippocampal proteomic analysis reveals the disturbance of synaptogenesis and neurotransmission induced by developmental exposure to organophosphate flame retardant triphenyl phosphate.

With the spread of organophosphorus flame retardants (OPFRs), the environmental and health risks they induce are attracting attention. Triphenyl phosphate (TPHP) is a popular alternative to brominated flame retardant and halogenated OPFRs. Neurodevelopmental toxicity is TPHP's primary adverse effect, whereas the biomarkers and the modes of action have yet to be elucidated. In the present study, 0.5, 5, and 50 mg/kg of TPHP were orally administered to mice from postnatal day 10 (P10) to P70. The behavioral tests showed a compromised learning and memory capability. Proteomic analysis of the hippocampus exposed to 0.5 or 50 mg/kg of TPHP identified 531 differentially expressed proteins that were mainly involved in axon guidance, synaptic function, neurotransmitter transport, exocytosis, and energy metabolism. Immunoblot and immunofluorescence analysis showed that exposure to TPHP reduced the protein levels of TUBB3 and SYP in the synapses of hippocampal neurons. TPHP exposure also downregulated the gene expression of neurotransmitter receptors including Grins, Htr1α, and Adra1α in a dose-dependent fashion. Moreover, the calcium-dependent synaptic exocytosis governed by synaptic vesicle proteins STX1A and SYT1 was inhibited in the TPHP-treated hippocampus. Our results reveal that TPHP exposure causes abnormal learning and memory behaviors by disturbing synaptogenesis and neurotransmission.

Dermatopontin inhibits papillary thyroid cancer cell proliferation through MYC repression.

Dermatopontin (DPT), a noncollagenous extracellular matrix component, has been illustrated to regulate cellular proliferation and invasiveness in several types of neoplasms. Nevertheless, the biological functions of DPT in cell proliferation, especially papillary thyroid cancer (PTC) cell proliferation, remain unknown, as do the mechanisms underlying its effects. In this study, we detected low DPT expression in PTC, which was related to higher T classifications. Ectopic DPT expression impeded cell proliferation both in vitro and in vivo. Furthermore, we illustrated that DPT down-regulated MYC, which in turn targeted CDK4, CDK6 and p21, through the ERK pathway. These results suggest that DPT regulates CDK4, CDK6 and p21, through MEK-ERK-MYC signaling to repress PTC proliferation.

Developmental exposure to BDE-99 hinders cerebrovascular growth and disturbs vascular barrier formation in zebrafish larvae.

Polybrominated diphenyl ethers (PBDEs) are distributed throughout the environment. Despite a moratorium on their use, concentrations of PBDEs in the atmosphere and in residential environments remain high due to their persistence. The environmental health risks remain concerning and one of the major adverse effects is neurodevelopmental toxicity. However, the early response and effects of PBDEs exposure on the developing brain remain unknown. In the present study, we investigated the impacts of 2,2',4,4',5-pentabrominated diphenyl ether (BDE-99) on vascular growth and vascular barrier function with an emphasis on cerebral blood vessels, in the early life stages, using a zebrafish model. No general toxicity was observed in exposing zebrafish larvae to 0-0.5 µM BDE-99 at 72 hpf. BDE-99 exposure resulted in neither general toxicity nor pronounced developmental impairment in somatic blood vessels, including intersegmental vessels (ISV) and common cardinal veins (CCV). Meanwhile, both 0.05 µM and 0.5 µM of BDE-99 reduced cerebrovascular density as well as down-regulation of VEGFA and VEGFR2 in the head. In addition, BDE-99 exposure increased vascular leakage, both in cerebral and truncal vasculature at 72 hpf. The accentuated vascular permeability was observed in the head. The mRNA levels of genes encoding tight junction molecules decreased in the BDE-99-exposed larvae, and more robust reductions in Cldn5, Zo1 and Jam were detected in the head than in the trunk. Moreover, proinflammatory factors including TNF-α, IL-1ß and ICAM-1 were induced, and the expression of neurodevelopment-related genes was suppressed in the head following BDE-99 exposure. Taken together, these results reveal that developmental exposure to BDE-99 impedes cerebrovascular growth and disturbs vascular barrier formation. The cerebral vasculature in developing zebrafish, a more sensitive target for BDE-99, may be a promising tool for the assessment of the early neurodevelopmental effects due to PBDEs exposure.

Angiopoietin-like protein 8/betatrophin correlates with hepatocellular lipid content independent of insulin resistance in non-alcoholic fatty liver disease patients.

AIMS/INTRODUCTION: To explore angiopoietin-like protein 8 (ANGPTL-8) levels, and its association with hepatocellular lipid content (HCL) and insulin resistance in patients with different extents of non-alcoholic fatty liver disease (NAFLD). MATERIALS AND METHODS: In 48 adults were recruited, of which 12 had no NAFLD (HCL < 5.5%; group 1), 18 had mild NAFLD (5.5% ≤ HCL < 10.0%; group 2) and 18 had moderate-to-severe NAFLD (HCL ≥ 10.0%; group 3). The peripheral insulin sensitivity of all participants was monitored by a hyperinsulinemic-euglycemic clamp (M value), as well as the magnetic resonance image of HCL. Serum ANGPTL-8, blood glucose levels and lipid profiles were also recorded in the study. RESULTS: Group 3 had a worse metabolic profile, and had the highest ANGPTL-8 level (1,129 ± 351 pg/mL vs 742 ± 252 pg/mL, 765 ± 301 pg/mL, P = 0.001) compared with those in group 1 and group 2. In all metabolic profiles, HCL positively correlated the strongest with ANGPTL-8 (r = 0.436, P = 0.042). Multivariate stepwise linear regression analysis showed ANGPTL-8 and alanine aminotransferase were independent determinants of HCL (P = 0.002, P < 0.001, respectively), and these two indexes explained 67.4% of the variation of HCL (P < 0.001). CONCLUSIONS: ANGPTL-8 was positively correlated with hepatocellular lipid content independent of obesity and insulin resistance, indicating that ANGPTL-8 might be a new and important important predictor of the severity of NAFLD.

CITED1 promotes proliferation of papillary thyroid cancer cells via the regulation of p21 and p27.

BACKGROUND: It has been reported that CBP/p300-Interacting Transactivator with glutamic acid [E]/aspartic acid [D]-rich C-terminal domain 1 (CITED1) is overexpressed in papillary thyroid cancer (PTC). However, the functional significance and underlying mechanisms of CITED1 in PTC are largely unknown. METHODS: The Cancer Genome Atlas dataset and real-time PCR were used to determine the expression of CITED1 in PTC. The role of CITED1 in PTC cell proliferation was determined conducted using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), colony formation, 5-ethynyl-2'-deoxyuridine (EdU) incorporation, and flow cytometry assays in vitro, and a subcutaneous xenotransplantation tumor model in nude mice was established to analyze tumor growth in vivo. We studied the potential mechanisms underlying the contribution of CITED1 to PTC proliferation using western blotting and luciferase assays. RESULTS: We found that CITED1 was highly expressed in PTC. In vitro and in vivo experiments demonstrated that CITED1 was involved in PTC cell proliferation and tumorigenesis. Then, gain- and loss-of-function experiments revealed that CITED1 decreased the expression of p21 and p27, and thereby increased the phosphorylation of pRb as well as E2F1 transcriptional activity. CONCLUSIONS: Our results suggest that CITED1 is overexpressed in PTC and that CITED1 promotes the proliferation of PTC cells via the regulation of p21 and p27, which indicates that CITED1 might be a potential therapeutic target in the treatment of PTC.

Lower mean blood glucose during short-term intensive insulin therapy is associated with long-term glycemic remission in patients with newly diagnosed type 2 diabetes: Evidence-based recommendations for standardization.

AIMS/INTRODUCTION: Optimal glycemic targets during short-term intensive insulin therapy in patients with newly diagnosed type 2 diabetes are not standardized. The present study was carried out to determine the optimal glycemic targets during therapy by analyzing the impacts of glucose levels on therapeutic outcomes. MATERIALS AND METHODS: A total of 95 individuals with newly diagnosed type 2 diabetes were enrolled. Short-term intensive insulin therapy was carried out using an insulin pump to achieve and maintain glycemic targets (fasting blood glucose ≤6.0 mmol/L, 2-h postprandial blood glucose ≤7.8 mmol/L) for 14 days, with daily eight-point capillary blood glucose profiles recorded. Patients were followed up for 1 year after discharge. RESULTS: In most participants, the mean blood glucose and glycemic excursion parameters during the therapy were controlled within the normal range. Mean blood glucose was independently associated with amelioration of acute insulin response (r = -0.25, P = 0.015) and 1-year remission (odds ratio 0.12, 95% confidence interval 0.034-0.426), but negatively associated with more level 1 hypoglycemia (r = -0.34, P = 0.001), although major hypoglycemia was rare. Among mean blood glucose tertiles, patients in the middle (68.7%) and lower (75.0%) tertiles had a higher 1-year remission rate compared with the upper tertile (32.3%, both P < 0.001), whereas only the middle tertile did not have increased hypoglycemia compared with the upper tertile (8.1 ± 5.4 vs 7.2 ± 3.9 events/person, P = 0.48). CONCLUSIONS: Stricter glycemic control during short-term intensive insulin therapy produced more remission despite self-manageable hypoglycemia. Based on glycemic parameters in the middle mean tertile, we propose new glycemic targets that are approximately 0.4 mmol/L lower than current the targets, as long-term benefit outweighs short-term risks.

Baseline red blood cell distribution width predicts long-term glycemic remission in patients with type 2 diabetes.

AIMS: We explored whether red blood cell distribution width (RDW), a routinely checked item of complete blood cell counts, was an indicator of long-term euglycemia remission in patients with type 2 diabetes after short-term continuous subcutaneous insulin infusion (CSII). METHODS: We analyzed the original data of patients enrolled in three randomized control trials from 2002 to 2014. CSII was administered to drug-naїve patients with newly diagnosed type 2 diabetes to achieve and maintain euglycemia for 2weeks. RESULTS: A total of 185 patients were involved and 98 patients (52.97%) who achieved and maintained euglycemia for at least 12months were classified as the remission group, and the others as the non-remission group. Patients in remission group had a relatively lower value for baseline RDW (38.82±2.76vs 39.89±2.78fL, p=0.017) compared with those in non-remission group. A graded decrease of remission rate (67.50%, 55.00%, 53.66% and 30.77% for Quartile 1 to Quartile 4 respectively, P<0.05) was observed with the increasing of RDWs. The risk of hyperglycemic relapse was significantly increased for those in the highest quartile compared with the lowest (hazard ratio=2.68; 95% CI, 1.38-5.22). Those who achieved euglycemia within 7days or obtained a better fasting glucose after therapy had preferable remission rates. CONCLUSIONS: Patients with lower baseline RDWs are more likely to maintain a one-year euglycemia remission after short-term CSII. A faster normalization of glucose during treatment and a lower fasting glucose after therapy are correlated with a long-term glucose control.

Ectopic Fat Deposition on Insulin Sensitivity: Correlation of Hepatocellular Lipid Content and M Value.

Purpose. This study aimed to explore the relationship among insulin sensitivity and ectopic fat depots in participants with different glucose status. Methods. Fifty-nine men and women were enrolled in this study: 29 with normal glucose tolerance (NGT), 17 with impaired glucose tolerance (IGT), and 13 with type 2 diabetes mellitus (T2DM). All participants underwent a hyperinsulinemic-euglycemic clamp to assess the insulin sensitivity index (M value) and magnetic resonance imaging to measure the hepatocellular lipid content (HCL), skeletal muscle fat content including intramyocellular lipid (IMCL) and extramyocellular lipid (EMCL) of tibialis anterior (ta), and soleus muscle (sol). Results. The M value of NGT group was higher than those of IGT and T2DM groups (P = 0.001). Participants with T2DM had the highest HCL and IMCL (ta) compared with those in NGT and IGT groups (P = 0.001). The M value had an inverse relationship with HCL (r = -0.789, P = 0.001), IMCL (sol) (r = -0.427, P = 0.002), and IMCL (ta) (r = -0.419, P = 0.002). Stepwise linear regression analysis showed that HCL (standardized ß = -0.416; P = 0.001) had an independent relationship with M value. Conclusions. Hepatocellular lipid content deposition happens earlier than skeletal muscle fat deposition. HCL is an independent risk factor for insulin resistance and may be used to evaluate the risk of developing T2DM as a noninvasive marker of insulin sensitivity index.

Effects of Liraglutide Combined with Short-Term Continuous Subcutaneous Insulin Infusion on Glycemic Control and Beta Cell Function in Patients with Newly Diagnosed Type 2 Diabetes Mellitus: A Pilot Study.

The objective of this paper is to investigate the effects of liraglutide in combination with short-term continuous subcutaneous insulin infusion (CSII) therapy on glycemic control and beta cell function in patients with newly diagnosed type 2 diabetes mellitus (T2DM). Thirty-nine eligible newly diagnosed T2DM patients were recruited and randomized to receive either of two therapies: short-term CSII alone (CSII alone group) or CSII in combination with liraglutide (CSII + Lira group) for 12 weeks. Blood glucose control, homeostasis model assessment (HOMA) indices, and acute insulin response (AIR) were compared between the two groups. The patients in CSII + Lira group achieved euglycemia with equivalent insulin dosage in shorter time (1 (0) versus 2 (3) days, P = 0.039). HbA1c at the end of study was comparable between two groups (6.3 ± 0.7% versus 6.0 ± 0.5%, for CSII alone group and CSII + Lira group, resp., P = 0.325). The increment of AIR was higher in CSII + Lira group (177.58 (351.57) µU · min/mL versus 58.15 (51.30) µU · min/mL, P < 0.001). However, after stopping liraglutide, its effect on beta cell function disappeared completely. Liraglutide combined with short-term CSII was effective in further improving beta cell function, but the beneficial effects did not sustain after suspension of the therapy.