Spexin ameliorated obesity-related metabolic disorders through promoting white adipose browning mediated by JAK2-STAT3 pathway.

BACKGROUND: Spexin, a 14 amino acid peptide, has been reported to regulate obesity and its associated complications. However, little is known about the underlying molecular mechanism. Therefore, this study aimed to investigate the effects of spexin on obesity and explore the detailed molecular mechanisms in vivo and in vitro. METHODS: Male C57BL/6J mice were fed a high-fat diet (HFD) for 12 weeks to induce obesity, and mice fed a standard fat diet were used as controls. Then, these mice were treated with SPX or Vehicle by intraperitoneal injection for an additional 12 weeks, respectively. The metabolic profile, fat-browning specific markers and mitochondrial contents were detected. In vitro, 3T3-L1 cells were used to investigate the molecular mechanisms. RESULTS: After 12 weeks of treatment, SPX significantly decreased body weight, serum lipid levels, and improved insulin sensitivity in HFD-induced obese mice. Moreover, SPX was found to promote oxygen consumption in HFD mice, and it increased mitochondrial content as well as the expression of brown-specific markers in white adipose tissue (WAT) of HFD mice. These results were consistent with the increase in mitochondrial content and the expression of brown-specific markers in 3T3-L1 mature adipocytes. Of note, the spexin-mediated beneficial pro-browning actions were abolished by the JAK2/STAT3 pathway antagonists in mature 3T3-L1 cells. CONCLUSIONS: These data indicate that spexin ameliorates obesity-induced metabolic disorders by improving WAT browning via activation of the JAK2/STAT3 signaling pathway. Therefore, SPX may serve as a new therapeutic candidate for treating obesity.

A novel model for predicting intravenous immunoglobulin-resistance in Kawasaki disease: a large cohort study.

Background: Predicting intravenous immunoglobulin (IVIG)-resistant Kawasaki disease (KD) can aid early treatment and prevent coronary artery lesions. A clinically consistent predictive model was developed for IVIG resistance in KD. Methods: In this retrospective cohort study of children diagnosed with KD from January 1, 2016 to December 31, 2021, a scoring system was constructed. A prospective model validation was performed using the dataset of children with KD diagnosed from January 1 to June 2022. The least absolute shrinkage and selection operator (LASSO) regression analysis optimally selected baseline variables. Multivariate logistic regression incorporated predictors from the LASSO regression analysis to construct the model. Using selected variables, a nomogram was developed. The calibration plot, area under the receiver operating characteristic curve (AUC), and clinical impact curve (CIC) were used to evaluate model performance. Results: Of 1975, 1,259 children (1,177 IVIG-sensitive and 82 IVIG-resistant KD) were included in the training set. Lymphocyte percentage; C-reactive protein/albumin ratio (CAR); and aspartate aminotransferase, sodium, and total bilirubin levels, were risk factors for IVIG resistance. The training set AUC was 0.825 (sensitivity, 0.723; specificity, 0.744). CIC indicated good clinical application of the nomogram. Conclusion: The nomogram can well predict IVIG resistance in KD. CAR was an important marker in predicting IVIG resistance in Kawasaki disease.

Prediction Model Risk-of-Bias Assessment Tool for coronary artery lesions in Kawasaki disease.

Objective: To review and critically appraise articles on prediction models for coronary artery lesions (CALs) in Kawasaki disease included in PubMed, Embase, and Web of Science databases from January 1, 1980, to December 23, 2021. Materials and methods: Study screening, data extraction, and quality assessment were performed by two independent reviewers, with a statistics expert resolving discrepancies. Articles that developed or validated a prediction model for CALs in Kawasaki disease were included. The Critical Appraisal and Data Extraction for Systematic Reviews of Prediction Modeling Studies checklist was used to extract data from different articles, and Prediction Model Risk-of-Bias Assessment Tool (PROBAST) was used to assess the bias risk in different prediction models. We screened 19 studies from a pool of 881 articles. Results: The studies included 73-5,151 patients. In most studies, univariable logistic regression was used to develop prediction models. In two studies, external data were used to validate the developing model. The most commonly included predictors were C-reactive protein (CRP) level, male sex, and fever duration. All studies had a high bias risk, mostly because of small sample size, improper handling of missing data, and inappropriate descriptions of model performance and the evaluation model. Conclusion: The prediction models were suitable for the subjects included in the studies, but were poorly effective in other populations. The phenomenon may partly be due to the bias risk in prediction models. Future models should address these problems and PROBAST should be used to guide study design.

Nomogram to predict risk of resistance to intravenous immunoglobulin in children hospitalized with Kawasaki disease in Eastern China.

OBJECTIVE: We aimed to develop a nomogram to predict risk of resistance to intravenous immunoglobulin (IVIG) in children with Kawasaki disease in eastern China. METHODS: We retrospectively analysed the data of children with Kawasaki disease who received IVIG during hospitalisation at Soochow University Affiliated Children's Hospital. IVIG resistance was defined as recrudescent or persistent fever ≥36 h after the end of the IVIG infusion. Baseline variables were analysed using least absolute shrinkage and selection operator (LASSO) to identify the predictors of IVIG resistance, which were then used to construct a predictive nomogram. Calibration curve and area under the receiver operating characteristic curve (AUC) were used to evaluate the performance of the model. The predictive nomogram was validated on test sets of external data and prospective data. RESULTS: Between January 2015 and December 2020, 1293 Kawasaki disease patients were hospitalized in Soochow University Affiliated Children's Hospital. Among them, 72 (5.57%) showed IVIG resistance. LASSO identified haemoglobin, percentage of neutrophils, C-reactive protein level, platelet count, serum albumin, serum sodium, serum alkaline phosphatase, coronary artery damage, and complete Kawasaki disease as risk factors for IVIG resistance. The nomogram constructed using these factors showed satisfactory discriminatory power (AUC, 0.75), and sensitivity (0.74) and specificity (0.64). In the external data and prospective data, the AUC was 0.66 and 0.83, respectively, the sensitivity was 0.86 and 1, respectively, and the specificity was 0.49 and 0.60, respectively. CONCLUSIONS: The predictive nomogram constructed using nine factors associated with IVIG resistance in children with Kawasaki disease could be a useful tool for identifying patients likely to show IVIG resistance. This nomogram may help reduce the risk of coronary artery lesions.Key MessagesNone of the IVIG resistance scoring systems has shown consistently good performance in previous studies. Tools to predict the risk of IVIG resistance in eastern China are lacking.In our series, haemoglobin level, percentage of neutrophils, platelet count, coronary artery damage, incomplete Kawasaki disease, and CRP, serum albumin, serum sodium, and serum alkaline phosphatase levels were risk factors of IVIG resistance in hospitalized children in the eastern China cities of Suzhou and Fuzhou.We propose an easy-to-use nomogram to predict the risk factors of IVIG resistance in hospitalized children.

[Effects of HPGA suppression on predicted adult height in girls with central precocious puberty].

OBJECTIVE: To study the relationship between the suppression of the hypothalamic-pituitary-gonadal axis (HPGA) and the predicted adult height (PAH) in girls with central precocious puberty (CPP) during the treatment with gonadotropin-releasing hormone analogue (GnRHa), in order to provide guidance for individualized GnRHa dose adjustment in clinical practice. METHODS: The clinical data of 75 CPP girls were collected, and then height, bone age (BA), uterine and ovarian volumes, and peak luteinizing hormone (LH), peak follicle-stimulating hormone (FSH), and estradiol (E2) levels were recorded at different time points of GnRHa treatment. PAH at each time point was calculated. PAH improvement (ΔPAH=PAH-target height) and its relationship with the degree of HPGA suppression were analyzed. Threshold effect analysis was applied to determine the best HPGA suppression range forΔPAH. RESULTS: After GnRHa treatment, PAHs were improved markedly compared with the data in the early stage of treatment. ΔPAH showed a negative correlation with ΔBA. At 24 months of treatment, ΔPAH was also negatively correlated with LH. Uterine volume controlled between 2.3 and 3.0 mL, LH level controlled below 0.8 IU/L, and FSH controlled below 2.4 IU/L could slow down the growth of BA and improve PAH. CONCLUSIONS: GnRHa treatment can improve the PAH of CPP girls. Selection of an appropriate therapeutic dose for GnRHa to control uterine volume, LH and FSH levels within certain ranges can slow down the growth of BA and improve PAH.

Lateral ventricle injection of orexin-A ameliorates central precocious puberty in rat via inhibiting the expression of MEG3.

BACKGROUND: Central precocious puberty (CPP) is characterized as increasing gonadotropin-releasing hormone (GnRH) release. Orexin-A has also been shown to affect GnRH release. However, there are few reports about the effect of orexin A on the treatment of CPP. METHODS: After establishing the precocious puberty model, the rats were divided into four groups: normal control, precocious puberty rats, precocious puberty rats treated with normal saline and precocious puberty rats treated with orexin-A. The vaginal opening time, second estrus cycle, ovarian index and uterus index of rats in each group were detected. qRT-PCR was performed to examine the expression of MEG3 and kisspeptin in rats. HT22 cells were transfected with pcDNA-MEG3 to detect the expression of Kisspeptin. RESULTS: In this study, we found that orexin-A not only delayed the day of vaginal opening and regular estrus cycle days but also decreased the ovarian index and uterus index in rats with CPP. In addition, orexin-A reversed the up-regulation of MEG3 and kisspeptin in rats with CPP. In HT22 cells, the mRNA and protein level of kisspeptin were enhanced by pcDNA-MEG3. CONCLUSION: Our results suggest that orexin-A ameliorates central precocious puberty in rat and MEG3 might be involved in this effect, suggesting that MEG3 might be a novel target in treating central precocious puberty.