Causal relationship between gut microbiota and childhood obesity: A Mendelian randomization study and case-control study.

BACKGROUND: Gut microbiota and obesity are deeply interconnected. However, the causality in the relationship between these factors remains unclear. Therefore, this study aimed to elucidate the genetic relationship between gut microbiota and childhood obesity. METHODS: Genetic summary statistics for the gut microbiota were obtained from the MiBioGen consortium. Genome-wide association studies (GWAS) summary data for childhood obesity were obtained from North American, Australian, and European collaborative genome-wide meta-analyses. Mendelian randomization (MR) analyses were performed using the inverse variance weighting method. 16 children with obesity and 16 without obesity were included for clinical observation, and their weight, body mass index, blood lipid levels, and gut microbiology were assessed. Paired t-test was the primary method of data analysis, and statistical significance was set at P < 0.05. RESULTS: MR identified 16 causal relationships between the gut microbiome and childhood obesity. In the case-control study, we found that five gut microorganisms differed between children with and without obesity, whereas three gut microorganisms changed after weight loss in children with obesity. CONCLUSION: Our study provides new insights into the genetic mechanisms underlying gut microbiota and childhood obesity. TRIAL REGISTRATION NUMBER: ChiCTR2300072179. NAME OF REGISTRY: Change of intestinal flora and plasma metabolome in obese children and their weight loss intervention: a randomized controlled tria URL OF REGISTRY: https://www.chictr.org.cn/showproj.html. DATE OF REGISTRATION: 2023-06-06. DATE OF ENROLMENT OF THE FIRST PARTICIPANT TO THE TRIAL: 2023-06-07.

Serum stromal cell-derived factor-1 concentrations are increased and associated with nonalcoholic fatty liver disease in children with obesity.

INTRODUCTION: Stromal cell-derived factor-1 (SDF-1) is a newly discovered small molecule adipocytokine, and research has shown that it is closely related to the occurrence and development of obesity. However, there are currently few research reports on SDF-1 in childhood obesity and nonalcoholic fatty liver disease (NAFLD), and this study aims to explore the relationship between SDF-1 and obesity related indicators in obese children. METHODS: Serum SDF-1 concentrations were measured using enzyme-linked immunosorbent assay (ELISA). Clinical and biochemical data were collected, such as body mass index (BMI), waist and hip circumference, blood pressure, liver enzymes, cholesterol, and fasting insulin. Children with NAFLD or not were evaluated through Color Doppler Ultrasound. RESULTS: Serum SDF-1 concentrations were significantly higher in obese subjects than in non-obese subjects (P < 0.05), and were elevated in the NAFLD obese subjects than in the non-NAFLD obese subjects (P < 0.05). SDF-1 was positively correlated with BMI, waist-to-hip ratio, systolic blood pressure, body fat percentage (BFP), basal metabolic rate (BMR), alanine transaminase (ALT), aspartate transaminase (AST), glutyltranspeptidase (GT), and homoeostasis model of HOMA-IR, independent of their uric acid (UA), total cholesterol (TC), triglycerides (TG), high-density lipoprotein (HDL), low-density lipoprotein (LDL), very-low-density lipoprotein (VLDL), gender and age. BFP and BMR were associated with the serum SDF-1 concentrations in multivariable linear regression analysis. CONCLUSION: These results suggest that SDF-1 levels are elevated in obese children and are associated with NAFLD, indicating that SDF-1 may play a role in the development of childhood obesity and metabolic disorders.

A Comprehensive Study on the Association between Plasma NOV/CCN3 Levels and Insulin Resistance in Childhood Obesity.

INTRODUCTION: Childhood obesity is a global health problem that is associated with various metabolic complications, such as insulin resistance, type 2 diabetes, dyslipidemia, and cardiovascular diseases. The mechanisms underlying the development of insulin resistance in childhood obesity are not fully understood. Nephroblastoma overexpressed gene (NOV), also known as CCN3, is a member of the CCN family of matricellular proteins that modulate cell proliferation, differentiation, adhesion, migration, and survival. Previous studies have shown that NOV/CCN3 is involved in glucose metabolism and insulin signaling in various tissues and cell types. However, the role of NOV/CCN3 in childhood obesity and insulin resistance remains unclear. METHODS: In this study, we aimed to investigate the association between plasma NOV/CCN3 levels and insulin resistance in 58 obese and 43 non-obese children aged 6-12 years. We measured plasma NOV/CCN3 levels by enzyme-linked immunosorbent assay (ELISA), and assessed insulin resistance by homeostasis model assessment of insulin resistance (HOMA-IR). We also collected clinical and biochemical data, such as body mass index (BMI), waist circumference (WC), blood pressure (BP), fasting glucose (FG), fasting insulin (FI), lipid profile, and inflammatory markers. RESULTS: We found that plasma NOV/CCN3 levels were significantly higher in obese children than in non-obese children (P<0.001), and positively correlated with BMI (r=0.42, P<0.001), WC (r=0.38, P<0.001), BP (r=0.35, P<0.001), FG (r=0.31, P<0.001), FI (r=0.45, P<0.001), HOMA-IR (r=0.48, P<0.001), triglycerides (r=0.28, P<0.001), low-density lipoprotein cholesterol (LDL-C) (r=0.26, P<0.001), and C-reactive protein (CRP) (r=0.32, P<0.001). Multiple linear regression analysis revealed that plasma NOV/CCN3 levels were independently associated with HOMA-IR after adjusting for age, sex, BMI, WC, BP, FG, FI, lipid profile, and CRP (ß=0.36, P<0.001). CONCLUSION: These results suggest that plasma NOV/CCN3 levels are elevated in childhood obesity and are associated with insulin resistance, indicating that NOV/CCN3 may play a role in the pathogenesis of metabolic disorders in obese children.

Lifestyle Improvements and Vitamin D Supplementation Play an Important Role in the Prevention of Childhood Diabetes.

Objective: This study was to investigate the characteristics of insulin secretion and the 25-hydroxyvitamin D3 (25(OH)D3) levels in children with obesity. Methods: A retrospective analysis was conducted among children who underwent health checkups in the pediatric healthcare department of our hospital from January 2018 to January 2021, and they were divided into a normal group and an obese group according to their BMI. The insulin secretion and the 25(OH)D3 levels of the two groups of children were compared. A total of 721 children were included in the study, including 591 in the normal group and 130 in the obese group, with an obesity rate of 18.03%. Results: The blood glucose of the normal group was 4.55 ± 1.75 mmol/L, and the 2 h PG was 7.51 ± 2.11 mmol/L; in the obesity group, they were 6.03 ± 2.16 mmol/L and 8.92 ± 3.24 mmol/L, respectively. The FPG and 2 h PG in the obese group were significantly higher than those in the normal group (all P < 0.05). The incidence of IFG/IGT in the normal group was 5.24% (31/591), and the incidence of DM was 3.71% (22/591); the incidence of IFG/IGT in the obese group was 14.62% (19/130), and the incidence of DM was 13.08% (17/130). The incidences of IFG/IGT and DM in the obese group were significantly higher than those in the normal group (P < 0.05). The FINS of the children in the normal group was 18.46 ± 3.15 µU/mL, and the HOMA-IR was 2.64 ± 0.62; the above indicators in the obese group were 19.11 ± 4.72 µU/mL and 3.01 ± 0.83, respectively. The FINS and HOMA-IR in the obese group were significantly higher than those in the normal group (P < 0.05). The serum 25(OH)D3 level in the normal group was 28.15 ± 5.27 ng/mL, of which 556 cases were normal in 25(OH)D3 and 35 cases were deficient in 25(OH)D3. The serum 25(OH)D3 level in the obese group was 24.35 ± 4.51 ng/mL, of which 112 cases were normal in 25(OH)D3 and 18 cases were deficient in 25(OH)D3. The level of serum 25(OH)D3 in the normal group was significantly higher than that in the normal group, and the ratio of 25(OH)D3 deficiency was significantly lower than that in the normal group (P < 0.05). Conclusions: The blood glucose level of childhood obesity was significantly increased, the incidence of abnormal glucose metabolism and diabetes was significantly increased, and the level of 25(OH) vitamin D3 was significantly decreased. Lifestyle improvements and vitamin D supplementation play an important role in the prevention of childhood diabetes. Because the major causes of childhood obesity are excessive caloric intake and lack of exercise, the most effective and direct measures to prevent obesity are a reasonable lifestyle, reasonable eating habits, and moderate exercise. Although genetics are critical, there is no reliable way to eliminate obesity genes in the human body. Therefore, the role of obesity genes is required to be ultimately eliminated by reduced caloric intake and increased physical activity.

Identifying celiac disease-related chemicals by transcriptome-wide association study and chemical-gene interaction analyses.

Celiac disease (CeD) is one of the most common intestinal inflammatory diseases, and its incidence and prevalence have increased over time. CeD affects multiple organs and systems in the body, and environmental factors play a key role in its complex pathogenesis. Although gluten exposure is known to be the causative agent, many unknown environmental factors can trigger or exacerbate CeD. In this study, we investigated the influence of genetic and environmental factors on CeD. Data from a CeD genome-wide association study that included 12,041 CeD cases and 12,228 controls were used to conduct a transcriptome-wide association study (TWAS) using FUSION software. Gene expression reference data were obtained for the small intestine, whole blood, peripheral blood, and lymphocytes. We performed Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses using the significant genes identified by the TWAS and conducted a protein-protein interaction network analysis based on the STRING database to detect the function of TWAS-identified genes for CeD. We also performed a chemical-related gene set enrichment analysis (CGSEA) using the TWAS-identified genes to test the relationships between chemicals and CeD. The TWAS identified 8,692 genes, including 101 significant genes (p adjusted < 0.05). The CGSEA identified 2,559 chemicals, including 178 chemicals that were significantly correlated with CeD. This study performed a TWAS (for genetic factors) and CGSEA (for environmental factors) and identified several CeD-associated genes and chemicals. The findings expand our understanding of the genetic and environmental factors related to immune-mediated diseases.

Inhibition of USP15 ameliorates high-glucose-induced oxidative stress and inflammatory injury in podocytes through regulation of the Keap1/Nrf2 signaling.

Ubiquitin-specific peptidase 15 (USP15) is implicated in the pathogenesis of numerous diseases. However, whether USP15 plays a role in diabetic nephropathy remains undetermined. This project was designed to determine the potential role of USP15 in mediating high glucose (HG)-induced podocyte injury, a key event in the pathogenesis of diabetic nephropathy. We found that USP15 levels were elevated in podocytes after HG stimulation. Inhibition of USP15 led to decreases in HG-evoked apoptosis, oxidative stress, and inflammation in podocytes. Further investigation showed that inhibition of USP15 enhanced the activation of NF-E2-related factor 2 (Nrf2) and expression of Nrf2 target genes in HG-simulated podocytes. Moreover, depletion of Kelch-like ECH-associated protein 1 (Keap1) diminished the regulatory effect of USP15 inhibition on Nrf2 activation. In addition, Nrf2 suppression reversed USP15-inhibition-induced protective effects in HG-injured podocytes. Taken together, these data indicate that USP15 inhibition protects podocytes from HG-induced injury by enhancing Nrf2 activation via Keap1.

Comparison of Two Ultrasound-guided Plane Blocks for Pain and Postoperative Opioid Requirement in Lumbar Spine Fusion Surgery: A Prospective, Randomized, and Controlled Clinical Trial.

INTRODUCTION: The erector spinae plane (ESP) block and thoracolumbar interfascial plane (TLIP) block were two novel plane blocks. The purpose of this study was to investigate TLIP block and ESP block on the effect of analgesic and opioid consumption in lumbar spine fusion surgery in the perioperative period. METHODS: Three hundred and four patients who suffered lumbar spine fusion were included and randomly divided into three groups: a control group (n = 102), an ESP block group (n = 100), and a TLIP block group (n = 102). We recorded the numerical rating scale (NRS) pain at movement and static during the postoperative 48 h, opioid consumption, additional analgesic requirement, frequency of patient-controlled analgesia (PCA) compressions, Bruggemann Comfort Scale (BCS) score, side effects, duration of hospital stay, and the life quality score (LQS) after operation at 6 months. RESULTS: The patients in the ESP block group have better analgesia during 12-48 h postoperative time at static state, a lower frequency of PCA compressions at 24-48 h after surgery, and the opioid consumption in the PCA (sufentanil) were less than those in the TLIP block group (P < 0.05). However, the BCS and LQS scores were no different between the two plane block groups after surgery at 6 months. There was no difference in hospital stay and the incidence of side effect among the three groups. CONCLUSIONS: Our results found that patients who suffered ESP block have better analgesic effects and less pain scores in static states and less frequency of PCA compression and opioid analgesic consumption compared with those that suffered TLIP block. TRIAL REGISTRATION: ChiCTR1800019639.

Blood coagulation factor VIII D1241E polymorphism leads to a weak malectin interaction and reduction of factor VIII posttranslational modification and secretion.

Blood coagulation factor VIII (FVIII) is a key cofactor in regulation of blood coagulation. This study investigated the mechanism by which FVIII is translated and transported into the endoplasmic reticulum (ER) and processed in the Golgi apparatus before secretion using an in vitro cell model. HEK-293T cells were transfected with vectors carrying wild-type (WT) FVIII or polymorphic FVIII D1241E for coexpression with ER lectins and treatment with tunicamycin (an N-linked glycosylation inhibitor), 1-deoxynojirimycin (an alpha-glucosidase inhibitor), endoglycosidase H, or MG132 (Cbz-Leu-Leu-leucinal; a proteasome inhibitor). The data showed that the minor allele of FVIII D1241E was able to reduce FVIII secretion into the conditioned medium but maintain a normal level of procoagulation ability, although both FVIII WT and the minor allele of FVIII D1241E showed similar levels of transcription and translation capacities. Functionally, the D1241E polymorphism led to a reduced level of FVIII in the Golgi apparatus because of its reduced association with malectin, which interacts with newly synthesized glycoproteins in the ER for FVIII folding and trafficking, leading to degradation of the minor allele of FVIII D1241E in the cytosol. This study demonstrated that malectin is important for regulation of the FVIII posttranslational process and that the minor allele of FVIII D1241E had a reduced association with malectin but an increased capacity for proteasomal FVIII degradation. These data imply the role of the ER quality control in future recombinant FVIII development.

Knockdown of CTRP6 inhibits high glucose-induced oxidative stress, inflammation and extracellular matrix accumulation in mesangial cells through regulating the Akt/NF-κB pathway.

C1qTNF-related protein 6 (CTRP6) is a member of the CTRP family and exerts a key role in the progression of diabetes mellitus. However, the role of CTRP6 in diabetic nephropathy remains unknown. The present study was designed to examine the roles of CTRP6 in diabetic nephropathy and explore the potential molecular mechanisms. Our results showed that the expression level of CTRP6 was significantly increased in high glucose (HG)-stimulated glomerular mesangial cells (MCs). The following loss/gain-of-function assays demonstrated that CTRP6 knockdown significantly inhibited HG-induced reactive oxygen species (ROS) production in MCs. CTRP6 knockdown caused significant decreases in tumour necrosis factor-α (TNF-α), interleukin (IL)-1ß and IL-6 production levels in HG-induced MCs. Moreover, knockdown of CTRP6 inhibited HG-stimulated extracellular matrix (ECM) accumulation in MCs characterized by decreased expression and production levels of fibronectin (FN) and collagen IV (Col IV). Furthermore, CTRP6 knockdown suppressed HG-induced the activation of Akt/NF-κB pathway in MCs, while overexpression of CTRP6 exhibited the opposite effects. Treatment with LY294002, an inhibitor of Akt, reversed the induction effects of CTRP6 overexpression on ROS production, inflammation and ECM accumulation in MCs. In conclusion, these findings demonstrated that CTRP6 knockdown inhibits HG-induced ROS production, inflammation and ECM accumulation in MCs, which were mediated by the inactivation of the Akt/NF-κB pathway. The roles of CTRP6 in diabetic nephropathy provided evidence for its therapeutic potential for the treatment of diabetic nephropathy.

Effects of birth weight on body composition and overweight/obesity at early school age.

OBJECTIVES: The prevalence of childhood obesity has increased substantially. We aimed to characterize the effect of birth weight on body composition and overweight/obesity at early school age. STUDY DESIGN: A total of 1669 children with available birth records from a double-blind cluster-randomized controlled trial exploring micronutrient supplementation during pregnancy were included. Data regarding school-aged body composition, social-demographic factors and health behaviours were prospectively collected. RESULT: s: The study population consisted of 1004 boys and 665 girls aged between 7 and 10 years. The prevalence of overweight/obesity (>85th age-sex-specific percentiles) was 7.4% for boys and 5.0% for girls. Generalized estimating equation models were used to account for the cluster nature of the data. A significant upward trend across quintiles of birth weight was observed for fat mass index (boys: P for trend 0.002; girls: P for trend <0.001), fat-free mass index (boys: P for trend <0.001; girls: P for trend <0.001), and percentage of body fat (boys: P for trend 0.003; girls: P for trend <0.001). A birth weight in the higher three quintiles could increase the risk ratios [RRs (95% CI) third quintile: 2.88, (1.13, 7.32); fourth quintile: 2.40, (0.87, 6.66); top quintile: 2.31, (0.92, 5.80)] of overweight/obesity at early school age compared with the RRs of the reference group (the second quintile of birth weight) among boys. CONCLUSIONS: Higher birth weight could increase the risk of being overweight/obese among 7- to 10-year-old boys in rural western China. Sex differences in this association need to be considered when planning interventions. RESEARCH REGISTRATION: This trial was registered at www.isrctn.com with the identifier ISRCTN08850194.

Correction: PID1 alters the antilipolytic action of insulin and increases lipolysis via inhibition of AKT/PKA pathway activation.

[This corrects the article DOI: 10.1371/journal.pone.0214606.].

PID1 alters the antilipolytic action of insulin and increases lipolysis via inhibition of AKT/PKA pathway activation.

PURPOSE: The aim of this study was to investigate the effect of phosphotyrosine interaction domain containing 1 (PID1) on the insulin-induced activation of the AKT (protein kinase B)/protein kinase A (PKA)/hormone-sensitive lipase (HSL) pathway and lipolysis. METHODS: Sprague-Dawley rats were fed either chow or a high-fat diet (HFD). The levels of insulin, glycerol, free fatty acids (FFAs) and PID1 mRNA expression were measured in the 2 groups. Furthermore, we examined the role of PID1 in the regulation of the AKT/PKA/HSL cascade and lipolysis in the 3T3-L1 cell line. RESULTS: Adipose tissue from HFD rats exhibited elevated PID1 expression, which showed a positive correlation with insulin levels and lipolysis. In 3T3-L1 adipocytes, we found that the antilipolytic effect of insulin is mediated by AKT and that phosphorylated AKT results in the promotion of PDE3B expression, the dephosphorylation of PKA and HSL and the suppression of glycerol release. However, overexpression of PID1 and treatment with 1 µM isoproterenol and 100 nM insulin for 24 h resulted in an increased release of glycerol and a noticeable inhibition of AKT phosphorylation, PDE3B expression and the phosphorylation of PKA/HSL in 3T3-L1 cells. In contrast, knockdown of PID1 and treatment with the above reagents inhibited lipolysis and activated the phosphorylation of AKT, which resulted in the dephosphorylation of PKA and HSL. CONCLUSIONS: Our findings indicate that PID1 in adipose tissue increases lipolysis by altering the antilipolytic action of insulin. This suggests that PID1 may represent a new therapeutic target to ameliorate adipocyte lipolysis and hence improve insulin sensitivity.

TNF-α Upregulates IKKε Expression via the Lin28B/let-7a Pathway to Induce Catecholamine Resistance in Adipocytes.

OBJECTIVE: Overexpression of inhibitor of nuclear factor kappa-B kinase subunit epsilon (IKKε) contributes to blunted catecholamine-induced lipolysis. Tumor necrosis factor α (TNF-α) upregulates adipose IKKε expression to inhibit stimulated lipolysis, which can be reversed by IKKε inhibitors. This study investigated adipose IKKε expression in children with and without obesity and potential involvement of the Lin28B/let-7a axis in posttranscriptional regulation of TNF-α-stimulated IKKε in adipocytes. METHODS: Adipose IKKε was detected in children both with and without obesity. The effects of TNF-α on IKKε expression of adipocytes were investigated. Inhibitor and mimics of microRNA let-7a or short interfering RNA of protein lin-28 homolog B (Lin28B) were used to determine the effect of the Lin28B/let-7a axis on TNF-α-mediated IKKε upregulation. Reporter assays were performed to confirm that let-7a targets the IKKε gene. RESULTS: Adipose IKKε expression in children with obesity was upregulated to a greater extent than that in children without obesity and was positively correlated with BMI. TNF-α increased IKKε expression through activation of Lin28B/let-7a and then inhibited isoproterenol-stimulated lipolysis in adipocytes. Blocking the Lin28B /let-7a axis rescued inhibition of isoproterenol-stimulated lipolysis produced by TNF-α by inhibiting IKKε expression. Reporter assays confirmed that IKKε is a target of let-7a. CONCLUSIONS: Adipose IKKε expression in children with obesity is substantially elevated and positively correlated with BMI. TNF-α induces catecholamine resistance via activation of the Lin28B/let-7a/IKKε pathway.

Integrated analysis of long noncoding RNA and mRNA expression profile in children with obesity by microarray analysis.

Long noncoding RNAs (lncRNAs) have an important role in adipose tissue function and energy metabolism homeostasis, and abnormalities may lead to obesity. To investigate whether lncRNAs are involved in childhood obesity, we investigated the differential expression profile of lncRNAs in obese children compared with non-obese children. A total number of 1268 differentially expressed lncRNAs and 1085 differentially expressed mRNAs were identified. Gene Ontology (GO) and pathway analysis revealed that these lncRNAs were involved in varied biological processes, including the inflammatory response, lipid metabolic process, osteoclast differentiation and fatty acid metabolism. In addition, the lncRNA-mRNA co-expression network and the protein-protein interaction (PPI) network were constructed to identify hub regulatory lncRNAs and genes based on the microarray expression profiles. This study for the first time identifies an expression profile of differentially expressed lncRNAs in obese children and indicated hub lncRNA RP11-20G13.3 attenuated adipogenesis of preadipocytes, which is conducive to the search for new diagnostic and therapeutic strategies of childhood obesity.

IL-10/STAT3 is reduced in childhood obesity with hypertriglyceridemia and is related to triglyceride level in diet-induced obese rats.

BACKGROUND: The prevalence of childhood obesity and obesity-related metabolic disorder such as dyslipidemia has sharply increased in the past few decades. Chronic low-grade inflammation is associated with the development of comorbidities and poor prognosis in obesity. This study aims to evaluate interleukin-10 (IL-10) in childhood obesity with hypertriglyceridemia. METHOD: We evaluated IL-10 and signal transducer and activator of transcription 3 (STAT3) mRNA expression in adipose tissue (AT) as well as serum IL-10 in 62 children of 3 groups and in high-fat diet (HFD) induced obese rat. Expression of IL-10 and STAT3 protein in AT of diet-induced obese rats were examined over feed period. RESULTS: Adipose IL-10 and STAT3 mRNA expression and serum IL-10 reduced in obese children with hypertriglyceridemia and in HFD obese rats. The protein expression of IL-10 and STAT3 decreased in AT of obese rats compared with the control rats at end time. Expression of IL-10 mRNA was negatively correlated to TG and LDL-C levels, and positively correlated to HDL-C, adiponectin and serum IL-10 levels. CONCLUSIONS: IL-10 expression and its downstream JAK-STAT pathway are down-regulated in obese children with hypertriglyceridemia and in HFD obese rats.

Serum complement factor 5a levels are associated with nonalcoholic fatty liver disease in obese children.

AIM: Nonalcoholic fatty liver disease (NAFLD) is a leading cause of progressive and chronic liver injury. Complement factor 5a (C5a) may be involved in many inflammation disorders. This study investigated levels of systemic C5a in patients with and without NAFLD and lean controls. METHODS: A cross-sectional study was conducted from July 2012 to June 2013 among 96 Chinese children, aged 6-17 years, recruited from the Pediatric Department of the Second Affiliated Hospital of Xi'an Jiao Tong University: 40 obese children with NAFLD, 31 obese children without NAFLD and 25 lean controls. Anthropometric parameters, clinical data and circulating C5a levels were measured. RESULTS: Obese children had higher serum concentrations of complement factor C5a compared with lean controls, especially in obese children with NAFLD. C5a was positively correlated with body mass index (BMI), waist circumference, diastolic blood pressure (BP), triglycerides and homoeostasis model of insulin resistance, independent of their body mass index standard deviations score and age. Of the well-known risk factors, C5a was a significant predictor of NAFLD in obese children. CONCLUSION: Serum C5a was elevated in obese children, especially in those with NAFLD and it may be proposed as a novel marker to predict advanced disease.

[Familial male-limited precocious puberty due to Asp578His mutations in the LHCGR gene: clinical characteristics and gene analysis in an infant].

The aim of the study was to provide a descriptive analysis of familial male-limited precocious puberty (FMPP), which is a rare inherited disease caused by heterozygous constitutively activating mutations of the luteinizing hormone/choriogonadotropin receptor gene (LHCGR). The patient was a ten-month-old boy, presenting with penile enlargement, pubic hair formation, and spontaneous erections. Based on the clinical manifestations and laboratory data, including sexual characteristics, serum testosterone levels, GnRH stimulation test, and bone age, this boy was diagnosed with peripheral precocious puberty. Subsequently the precocious puberty-related genes were analyzed by direct DNA sequencing of amplified PCR products from the patient and his parents. Genetic analysis revealed a novel heterozygous missense mutation c.1732G>C (Asp578His) of the LHCGR gene exon11 in the patient, which had never been reported. His parents had no mutations. After combined treatment with aromatase inhibitor letrozole and anti-androgen spironolactone for six months, the patient's symptoms were controlled. The findings in this study expand the mutation spectrum of the LHCGR gene, and provide molecular evidence for the etiologic diagnosis as well as for the genetic counseling and prenatal diagnosis in the family.

Selective Double Carbomagnesiation of Internal Alkynes Catalyzed by Iron-N-Heterocyclic Carbene Complexes: A Convenient Method to Highly Substituted 1,3-Dienyl Magnesium Reagents.

Controlled multicarbometalation of alkynes has been envisaged as an efficient synthetic method for dienyl and polyenyl metal reagents, but an effective catalyst enabling the transformation has remained elusive. Herein, we report that an iron(II)-N-heterocyclic carbene (NHC) complex (IEt2Me2)2FeCl2 (IEt2Me2 = 1,3-diethyl-4,5-dimethylimidazol-2-ylidene) can serve as a precatalyst for the double carbometalation of internal unsymmetrical alkynes with alkyl Grignard reagents, producing highly substituted 1,3-dienyl magnesium reagents with high regio- and stereoselectivity. Mechanistic studies suggest the involvement of low-coordinate organoiron(II)-NHC species as the in-cycle intermediates. The strong σ-donating nature of IEt2Me2 and its appropriate steric property are thought the key factors endowing the iron-NHC catalyst fine performance.

Four-Coordinate Iron(II) Diaryl Compounds with Monodentate N-Heterocyclic Carbene Ligation: Synthesis, Characterization, and Their Tetrahedral-Square Planar Isomerization in Solution.

The salt elimination reactions of (IPr2Me2)2FeCl2 (IPr2Me2 = 1,3-diisopropyl-4,5-dimethylimidazol-2-ylidene) with the corresponding aryl Grignard reagents afford [(IPr2Me2)2FeAr2] (Ar = Ph, 3; C6H4-p-Me, 4; C6H4-p-(t)Bu, 5; C6H3-3,5-(CF3)2, 6) in good yields. X-ray crystallographic studies revealed the presence of both tetrahedral and trans square planar isomers for 3 and 6 and the tetrahedral structures for 4 and 5. Magnetic susceptibility and (57)Fe Mössbauer spectrum measurements on the solid samples indicated the high-spin (S = 2) and intermediate-spin (S = 1) nature of the tetrahedral and square planar structures, respectively. Solution property studies, including solution magnetic susceptibility measurement, variable-temperature (1)H and (19)F NMR, and absorption spectroscopy, on 3-6, as well as an (57)Fe Mössbauer spectrum study on a frozen tetrahydrofuran solution of tetrahedral [(IPr2Me2)2(57)FePh2] suggest the coexistence of tetrahedral and trans square planar structures in solution phase. Density functional theory calculations on (IPr2Me2)2FePh2 disclosed that the tetrahedral and trans square planar isomers are close in energy and that the geometry isomerization can occur by spin-change-coupled geometric transformation on four-coordinate iron(II) center.

Three-coordinate cobalt(IV) and cobalt(V) imido complexes with N-heterocyclic carbene ligation: synthesis, structure, and their distinct reactivity in C-H bond amination.

The reaction of the cobalt(0) alkene complex [(IMes)Co(η(2):η(2)-dvtms)] (1) (IMes = 1,3-bis(1',3',5'-trimethylphenyl)imidazol-2-ylidene, dvtms = divinyltetramethyldisiloxane) with 2 equiv of DippN3 (Dipp = 2,6-diisopropylphenyl) afforded the cobalt(IV) imido complex [(IMes)Co(NDipp)2] (2), which could be oxidized by [Cp2Fe][BAr(F)4] (Ar(F) = 3,5-di(trifluoromethyl)phenyl) to give the cobalt(V) imido species [(IMes)Co(NDipp)2][BAr(F)4] (3). The molecular structures of all these complexes were established by single-crystal X-ray diffraction studies. Characterization data and theoretical calculations suggest ground spin states of S = (1)/2 and S = 0 for the cobalt(IV) and cobalt(V) species, respectively. When heated, the cobalt(IV) imido species was converted to a cobalt(II) diamido complex via an intramolecular C-H bond amination reaction, but the cobalt(V) species was stable under similar conditions. The different outcomes suggest that a high oxidation state does not guarantee C-H bond activation reactivity of late-transition-metal imido species.