No abstract

BackgroundAutism spectrum disorder (ASD) is characterized by impairments in social communication and restricted or repetitive behaviors or interests. ASD is now diagnosed in more than one out of 100 children and is biased towards males by a ratio of at least 4:1. Many possible explanations and potential causative factors have been reported, such as genetics, sex, and environmental factors, although the detailed mechanisms of ASD remain unclear.MethodsThe dams were exposed through oral contraceptives to either vehicle control (VEH) alone, levonorgestrel (LNG) alone, ethinyl estradiol (EE) alone, or a combination of LNG/EE for 21 days during their pregnancy. The subsequent 10-week-old offspring were used for autism-like behavior testing, and the limbic tissues were isolated for analysis. In another experimental group, 8-week-old male offspring were treated by infusion of ERβ overexpression/knockdown lentivirus in the amygdala, and the offspring were analyzed after 2 weeks.ResultsWe show that prenatal exposure of either LNG alone or a LNG/EE combination, but not EE alone, results in suppression of ERβ (estrogen receptor β) and its target genes in the amygdala with autism-like behavior in male offspring, while there is a much smaller effect on female offspring. However, we find that there is no effect on the hippocampus and hypothalamus. Further investigation shows that ERβ suppression is due to LNG-mediated altered methylation on the ERβ promoter and results in tissue damage with oxidative stress and the dysfunction of mitochondria and fatty acid metabolism, which subsequently triggers autism-like behavior. Overexpression of ERβ in the amygdala completely restores LNG-induced ERβ suppression and autism-like behaviors in offspring, while ERβ knockdown mimics this effect, indicating that ERβ expression in the amygdala plays an important role in autism-like behavior development.ConclusionsWe conclude that prenatal levonorgestrel exposure induces autism-like behavior in offspring through ERβ suppression in the amygdala. To our knowledge, this is the first time the potential effect of oral contraceptives on the contribution of autism-like behavior in offspring has been discovered.Electronic supplementary materialThe online version of this article (doi:10.1186/s13229-017-0159-3) contains supplementary material, which is available to authorized users.

BackgroundSchistosomiasis is a parasitic disease infecting more than 200 million people in the world. Although chemotherapy targeting on killing schistosomes is one of the main strategies in the disease control, there are few effective ways of dealing with liver fibrosis caused by the parasite infection in the chronic and advanced stages of schistosomiasis. For this reason, new strategies and prospective drugs, which exert antifibrotic effects, are urgently required.Methods and FindingsThe antifibrotic effects of praziquantel were assessed in the murine models of schistosomiasis japonica. Murine fibrosis models were established by cutaneous infection with 14±2 Schistosoma japonicum cercariae. Then, the mice of both chronic (8 weeks post-infection) and advanced (15 weeks post-infection) schistosomiasis were treated by gavage of praziquantel (250 mg/kg, once daily for 3 days) to eliminate worms, and followed by praziquantel anti-fibrosis treatment (300 mg/kg, twice daily for 30 days). The fibrosis-related parameters assessed were areas of collagen deposition, content of hydroxyproline and mRNA expressions of Col1α1, Col3α1, α-SMA, TGF-β, MMP9, TIMP1, IL-4, IL-10, IL-13 and IFN-γ of liver. Spleen weight index, alanine aminotransferase activity and liver portal venous pressure were also measured. The results showed that anti-fibrosis treatment improved liver fibrosis, splenomegaly, hepatic function, as well as liver portal hypertension. In order to confirm the anti-fibrotic properties of praziquantel, we established a CCL4-induced model and revealed that CCL4-induced liver fibrosis was inhibited by PZQ treatment for 30 days. Furthermore, we analyzed the effects of praziquantel on mouse primary hepatic stellate cells (HSCs). It is indicated that mRNA expressions of Col1α1, Col3α1, α-SMA, TGF-β, MMP9 and TIMP1 of HSCs were all inhibited after praziquantel anti-parasite treatments.ConclusionsThe significant amelioration of hepatic fibrosis by praziquantel treatment validates it as a promising drug of anti-fibrosis and offers potential of a new chemotherapy for hepatic fibrosis resulting from schistosomiasis.

BackgroundEmerging studies have investigated the association between different anthropometric indices with diabetes risk but the results were inconsistent. The aims of the study were to examine the associations of different anthropometric indices with incident diabetes risk and whether novel anthropometric indices improve diabetes prediction beyond traditional indices among elderly Chinese.MethodsNine thousand nine hundred sixty-two elderly individuals (age ≥ 60 years old) derived from the prospective Dongfeng-Tongji cohort were included. Hazard ratio (HR) and corresponding 95% confidence interval (CI) were evaluated by Cox proportional hazard model to examine the associations between traditional anthropometric indices (body mass index [BMI], waist circumference [WC], waist-to-height ratio [WHtR]), novel anthropometric indices (visceral adiposity index [VAI], a body shape index [ABSI], body roundness index [BRI]) and diabetes risk. Receiver operating characteristic (ROC) curve and area under curve (AUC) were applied to compare the novel anthropometric indices with the traditional indices in diabetes prediction.ResultsDuring mean 4.6 years of follow-up, 614 incident cases of type 2 diabetes (T2D) were identified. Significant positive associations were detected between BMI, WC, WHtR, VAI and BRI and incident T2D risk. For ABSI, no significant association was observed in either men or women. BMI was the strongest predictor in diabetes in men (AUC = 0.655) comparable with the other anthropometric indices (P < 0.05). Similar as men, BMI was the strongest predictor (AUC = 0.635) in women. Except for WC, the AUC of BMI was larger than WHtR, VAI, and BRI. In contrast, ABSI was not a good predictor in either men (AUC = 0.507) or women (AUC = 0.503).ConclusionsIn elderly Chinese, BMI, WC, WHtR, VAI and BRI were positively associated with incident T2D risk. Among them, BMI was the strongest predictor in both men and women.Electronic supplementary materialThe online version of this article (10.1186/s12877-018-0912-2) contains supplementary material, which is available to authorized users.

OBJECTIVE Insulin resistance is a powerful risk factor for Type 2 diabetes and a constellation of chronic diseases, and is most commonly associated with obesity. We examined if factors other than obesity are more substantial predictors of insulin sensitivity under baseline, non-stimulated conditions. DESIGN AND METHODS Metabolic assessment was performed in healthy dogs (n=90). Whole-body sensitivity from euglycemic clamps (SICLAMP) was the primary outcome variable, and was measured independently by IVGTT (n=36). Adiposity was measured by MRI (n=90), and glucose-stimulated insulin response was measured from hyperglycemic clamp or IVGTT (n=86 and 36, respectively). RESULTS SICLAMP was highly variable (5.9 to 75.9 dl/min per kg per μU/ml). Despite narrow range of body weight (mean, 28.7±0.3 kg), adiposity varied ∼8-fold and was inversely correlated with SICLAMP (p<0.025). SICLAMP was negatively associated with fasting insulin, but most strongly associated with insulin clearance. Clearance was the dominant factor associated with sensitivity (r=0.53, p<0.00001), whether calculated from clamp or IVGTT. CONCLUSIONS These data suggest that insulin clearance contributes substantially to insulin sensitivity, and may be pivotal in understanding the pathogenesis of insulin resistance. We propose that hyperinsulinemia due to reduction in insulin clearance is responsible for insulin resistance secondary to changes in body weight.