Novel heterozygous variants in the EP300 gene cause Rubinstein-Taybi syndrome 2: Reports from two Chinese children.

BACKGROUND: Rubinstein-Taybi syndrome (RSTS) is a rare autosomal-dominant genetic disease caused by variants of CREBBP (RSTS1) or EP300 (RSTS2) gene. RSTS2 is much less common, with less than 200 reported cases worldwide to date. More reports are still needed to increase the understanding of its clinical manifestations and genetic characteristics. METHODS: The clinical data of two children with RSTS2 were analyzed retrospectively, and their clinical manifestations, auxiliary examinations, and mutational spectrum were summarized. Liquid chromatography-tandem mass spectrometer (LC-MS/MS) technology was used to detect the levels of steroid hormones if possible. RESULTS: After analyzing the clinical and genetic characteristics of two boys with RSTS2 (0.7 and 10.4 years old, respectively) admitted in our hospital, we identified two novel heterozygous variants in the EP300 exon 22 (c.3750C > A, p. Cys1250*, pathogenic; c.1889A > G, p. Tyr630Cys, likely pathogenic), which could account for their phenotype. In addition to common clinical manifestations such as special facial features, microcephaly, growth retardation, intellectual disability, speech delay, congenital heart defect, recurrent respiratory infections, and immunodeficiency, we found one of them had a rare feature of adrenal insufficiency, and LC-MS/MS detection showed an overall decrease in steroid hormones. CONCLUSION: In our study, we identified two novel variants in the EP300 exon 22, and for the first time, we reported a case of RSTS2 associated with adrenal insufficiency, which will enrich the clinical and mutational spectrum of this syndrome.

Case Report: Glycogen Storage Disease Type Ia in a Chinese Child Treated With Growth Hormone.

Background: Glycogen storage disease type Ia is a rare metabolic disorder that leads to excessive glycogen and fat accumulation in organs, characterized by hepatomegaly, hypoglycemia, lactic acidemia, hyperlipidemia, hyperuricemia, puberty delay, and growth retardation. Here, we report on a patient with glycogen storage disease type Ia treated with growth hormone. Case Presentation: A 10-year-old boy had growth retardation for 6 years, and was admitted to clarify the cause of his short stature. We found that his bone age was 5.5 years, significantly lower than his physical age, while his serum IGF-1 and IGFBP-3 were 23.30 and 1620.0 ng/mL, respectively, both lower than normal. His medical history revealed that he had suffered from steatohepatitis, hyperlipidemia, and hypoglycemia since he was 11 months of age. Whole exome sequencing (WES) showed compound heterozygous mutations in exons 2 and 5 of the glucose-6-phosphatase (G6PC) gene on chromosome 17: c.G248A (p.R83H) and c.G648T (p.L216L). The patient was finally diagnosed with GSD Ia. After growth hormone (GH) treatment and corn starch therapy for 14 months, his height significantly increased (by 13 cm). The serum IGF-1 level increased to the normal range but his lipid levels and liver function did not significantly increase. Conclusion: We describe a young patient with a compound heterozygous G6PC variant in a Chinese family; his height increased significantly after growth hormone and corn starch interventions. This case emphasizes that WES is essential for early diagnosis, and that growth hormone treatment may increase the height of patients with GSD Ia safely.

Xq26.3-q27.1 duplication including SOX3 gene in a Chinese boy with hypopituitarism: case report and two years treatment follow up.

BACKGROUND: SOX3 is essential for pituitary development normally at the earliest stages of development. In humans, variants of SOX3 can cause X-linked hypopituitarism with various clinical manifestations, with or without mental retardation. CASE PRESENTATION: We present an 8-year-old Chinese patient with congenital hypopituitarism who had a 6.180 Mb duplication on Xq26.3q27.1 including SOX3, F9, and eight other contiguous genes. The main complains of the boy was short stature. His height was 90.1 cm (- 5.87SDS), weight 11.5 kg (- 5.25SDS). He developed growth hormone (GH) deficiency, cryptorchidism and low thyroid function. Pituitary magnetic resonance imaging revealed the pituitary dysplasia. After diagnosis, levothyroxine was given for one month first, and the thyroid function basically returned to normal, but the growth situation did not improve at all. Then recombinant human GH was given, his height, growth rate and height SDS were improved significantly in the 2 years follow-up. The level of height SDS improved from - 5.87 SDS before treatment to - 3.27 SDS after the first year of treatment and - 1.78 SDS after the second years of treatment. Gonadal function and long-term prognosis of the patient still need further observation and follow-up. CONCLUSIONS: This is the first case of Chinese male patient with multiple hypophysis dysfunction caused by SOX3 duplication, which will expand the range of phenotypes observed in patients with duplication of SOX3.

Clinical applications of genetic analysis and liquid chromatography tandem-mass spectrometry in rare types of congenital adrenal hyperplasia.

BACKGROUND: Our study aims to summarize the clinical characteristics of rare types of congenital adrenal hyperplasia (CAH) other than 21-hydroxylase deficiency (21-OHD), and to explore the clinical applications of genetic analysis and liquid chromatography tandem-mass spectrometry (LC-MS/MS) in rare CAH. METHODS: We retrospectively analysed the clinical data of 5 rare cases of CAH admitted to our hospital and summarized their clinical manifestations, auxiliary examinations, diagnosis and mutational spectrum. RESULTS: After gene sequencing, complex heterozygous variants were detected in all patients (2 cases were lipoid congenital adrenal hyperplasia (LCAH), 11ß-hydroxylase deficiency (11ß-OHD), 3ß-hydroxysteroid dehydrogenase deficiency (3ß-HSD deficiency) and P450 oxidoreductase deficiency (PORD) each accounted for 1 case), which were consistent with their clinical manifestations. Among them, 4 novel variants were detected, including c.650 + 2 T > A of the StAR gene, c.1145 T > C (p. L382P) of the CYP11B1 gene, c.1622C > T (p. A541V) and c.1804C > T (p. Q602 *) of the POR gene. The LC-MS/MS results for steroid hormones in patients were also consistent with their genetic variants: 2 patients with LCAH showed a decrease in all steroid hormones; 11ß-OHD patient showed a significant increase in 11-deoxycortisol and 11-deoxycorticosterone; patient with 3ß-HSD deficiency showed a significant increase in DHEA; and PORD patient was mainly characterized by elevated 17OHP, progesterone and impaired synthesis of androgen levels. CONCLUSIONS: The clinical manifestations and classification of CAH are complicated, and there are cases of missed diagnosis or misdiagnosis. It's necessary to combine the analysis of clinical manifestations and auxiliary examinations for diagnosis; if necessary, LC-MS/MS analysis of steroid hormones or gene sequencing is recommended for confirming diagnosis and typing.

Analysis of the Screening Results for Congenital Adrenal Hyperplasia Involving 7.85 Million Newborns in China: A Systematic Review and Meta-Analysis.

Background: Congenital adrenal hyperplasia (CAH) is a group of congenital genetic diseases caused by defective steroidogenesis. Our study aims to systematically analyze the screening results for CAH in Chinese newborns. Methods: Studies were searched from PubMed, Web of Science, Cochrane library and some Chinese databases up to September, 2020. Meta-analysis was performed after quality assessment and data extraction. Results: After a review of 2 694 articles, we included 41 studies enrolling 7 853 756 newborns. In our study, we found that the incidence of CAH in China was 0.43‱ [95% confidence intervals(CI), (0.39‱, 0.48‱)], or 1/23 024 [95%CI, (1/25 757,1/20 815)]. 27 studies were included for analysis of the screening positive rate, which gave a rate of 0.66% [95%CI, (0.54%, 0.78%)]. As for the recall rate of positive cases, 17 studies were included and showed that the recall rate reached 86.17% [95%CI, (82.70%, 89.64%)]. Among the CAH patients, the ratio of males to females was 1.92:1 (119:62), and the ratio of salt wasting (SW) to simple virilization (SV) type was 3.25:1 (104:32). The average 17-hydroxyprogesterone (17-OHP) value of CAH was 393.40 ± 291.85 nmol/L (Range 33-1 300 nmol/L); there was no significant difference between male and female patients (437.17 ± 297.27 nmol/L v.s. 322.25 ± 293.04 nmol/L, P=0.16), but a significant difference was found between SW and SV patients (483.29 ± 330.07 nmol/L v.s. 73.80 ± 7.83nmol/L, P=0.04). Conclusion: We systematically analyzed the current situation of neonatal CAH screening in China, which will deepen our understanding for future CAH screening and early diagnosis.

Clinical analysis and long-term treatment monitoring of 3 patients with glycogen storage disease type Ib.

BACKGROUND: To investigate the clinical and genetic characteristics of patients with glycogen storage disease type Ib (GSD Ib). CASE PRESENTATION: This report retrospectively analyzed the clinical data of 3 patients with GSD Ib admitted into our hospital, and summarized their onset characteristics, clinical manifestations, related examinations and treatment as well as mutational spectrum. After gene sequencing, the diagnosis of GSD Ib was confirmed in all 3 patients. Five variants of SLC37A4 gene were detected, of which c. 572C > T was the common variant and c. 680G > A was a novel variant. The 3 cases of GSD Ib were mainly affected by liver enlargement, growth retardation, etc., and all had a history of repeated infections. At the onset, patients mainly manifested as mildly elevated alanine-aminotransferase (ALT), accompanied by decreased absolute neutrophil count (ANC), hypertriglyceridemia, and metabolic disorders (hypoglycemia, hyperlactic acidemia, metabolic acidosis, etc.). After long-term treatment by oral uncooked cornstarch, the abnormal liver enzymes gradually returned to normal, and metabolic abnormalities were basically controlled most of the time. With increasing age, ANC of 2 patients decreased progressively, whereas the times of infections was reduced. CONCLUSIONS: We reported 3 cases with GSD Ib and a novel SLC37A4 variant. The possibility of GSD type Ib should be kept on alert when a patient suffers recurrent infections, accompanied by hepatomegaly, elevated liver enzymes, hypoglycemia, dyslipidemia, and metabolic disorders.

Intrauterine inflammation induced white matter injury protection by fibrinogen-like protein 2 deficiency in perinatal mice.

BACKGROUND: White matter injury (WMI) induced by intrauterine inflammation can cause adverse neurological outcomes. Fibrinogen-like protein 2 (FGL2)/fibroleukin is an important trigger of inflammatory responses and is involved in some cerebral diseases. However, the role of FGL2 in intrauterine inflammation-induced WMI remains unclear. METHODS: Lipopolysaccharide (LPS) was intraperitoneally injected into wild-type and FGL2 knockout mice to induce intrauterine inflammation. Body weight and brain weight of offspring were monitored. Major basic protein (MBP) expression was evaluated to demonstrate the myelination of offspring. To investigate the regulatory mechanism of FGL2, cytokine expression, microglial polarization, and the activation of mitogen-activated protein kinase (MAPK) signaling pathway in the offspring were analyzed. RESULTS: Upon LPS exposure, FGL2 knockout offspring showed a significant increase in body weight loss. MBP reduction induced by LPS was prevented in FGL2 knockout offspring. Expression levels of proinflammatory cytokines interleukin-1ß (IL-1ß) and tumor necrosis factor-α, and M1 marker CD86 were suppressed, while the expression levels of anti-inflammatory cytokines IL-10 and M2 marker CD206 were increased. FGL2 deficiency significantly inhibited the phosphorylation of p38MAPK and c-Jun N-terminal kinase (JNK) protein. CONCLUSIONS: FGL2 deficiency can ameliorate WMI induced by intrauterine inflammation, reducing inflammatory cascade and improving hypomyelination, through the regulation of microglial polarization and MAPK signaling pathways. IMPACT: Intrauterine inflammation induces WMI leading to severe neurological sequelae. FGL2 plays an important role in the progression of WMI induced by intrauterine inflammation. FGL2 deficiency can protect against WMI by inhibiting p38 MAPK and JNK phosphorylation, regulating microglia polarization, and reducing inflammation response. FGL2 could be a novel molecular target for protecting against WMI induced by intrauterine inflammation.

Genotypic and clinical analysis of 49 Chinese children with hepatic glycogen storage diseases.

BACKGROUND: Glycogen storage disease (GSD) is a relatively rare inborn metabolic disorder, our study aims to investigate the genotypic and clinical feature of hepatic GSDs in China. METHODS: The clinical and genotypic data of 49 patients with hepatic GSDs were collected retrospectively and analyzed. RESULTS: After gene sequencing, 49 patients were diagnosed as GSDs, including GSD Ia (24 cases), GSD IIIa (11 cases), GSD IXa (8 cases), GSD VI (3 cases) and GSD Ib (3 cases). About 45 gene variants of G6PC, AGL, PHKA2, PYGL, and SLC37A4 were detected; among which, 22 variants were unreported previously. c.648G>T (p. Leu216Leu) of G6PC exon 5 is the most common variant for GSD Ia patients (20/24,83.33%）, splice variant c.1735+1G>T of AGL exon 13 is relatively common among GSD IIIa, while novel variant accounts for the majority of GSD IXa and GSD VI patients. As for clinical features, there was no significant difference in the onset age among group GSD Ia, GSD IIIa, and GSD IXa, but the age at diagnosis and average disease duration from diagnosis of GSD Ia were significantly higher than GSD IIIa and GSD IXa. Body weight of GSD patients was basically normal, but growth retardation was relatively common among them, especially for GSD Ia patients; and renomegaly was only found in GSD Ia. Besides, serum cholesterol, triglyceride, lactic acid, and uric acid in GSD Ia were significantly higher than those with GSD IIIa and IXa (p < 0.05); but ALT, AST, CK, and LDH of GSD III and GSD IXa were significantly higher when compared to GSD Ia (p < 0.05). CONCLUSIONS: All hepatic GSDs patients share similarity in clinical and biochemical spectrum, but delayed diagnosis and biochemical metabolic abnormalities were common in GSD Ia. For family with GSD proband, pedigree analysis and genetic testing is strongly recommended.

Genetic analysis and long-term treatment monitoring of 11 children with glycogen storage disease type IIIa.

Objectives To investigate the clinical and genetic characteristics of children with glycogen storage disease type IIIa (GSD IIIa) and to explore the muscle involvement and manifestations of GSD IIIa patients. Methods The clinical data of 11 patients with GSD IIIa diagnosed by genetic testing from 2003 to 2019 were retrospectively analyzed. Results Twenty variants of AGL gene were detected in 11 patients, eight of which were novel variants. Before treatment, the height was significantly backward. All patients had hepatomegaly. Abnormal biochemical indicators were mainly manifested as significantly increased serum liver and muscle enzymes, accompanied by hypertriglyceridemia, hypoglycemia, hyperlactacidemia, slightly elevated pyruvic acid, and metabolic acidosis. After treatment, the height and liver size of the patients were significantly improved. At the same time, alanine aminotransferase (ALT), aspartate aminotransferase (AST), triglyceride (TG), lactic acid and pyruvic acid in children were significantly decreased, while creatine kinase (CK) was significantly increased. During follow-up monitoring, six patients developed ventricular hypertrophy. Lactate dehydrogenase (LDH) (691.67 ± 545.27 vs. 362.20 ± 98.66), lactic acid (3.18 ± 3.05 vs. 1.10 ± 0.40), and pyruvic acid (64.30 ± 39.69 vs. 32.06 ± 4.61) were significantly increased in patients with ventricular hypertrophy compared with those without ventricular hypertrophy. Conclusions In clinical cases of upper respiratory tract infection or gastrointestinal symptoms accompanied by hypoglycemia, dyslipidemia, metabolites disorders, elevated serum liver, and muscle enzymes, the possibility of GSD IIIa should be vigilant. During treatment monitoring, if lactic acid, pyruvic acid, LDH, and CK rise, it indicates that the disease is not well controlled and there is the possibility of cardiac hypertrophy.

A novel deletion variant in TRAPPC2 causes spondyloepiphyseal dysplasia tarda in a five-generation Chinese family.

BACKGROUND: Spondyloepiphyseal dysplasia tarda (SEDT) is a rare X-linked recessive inherited osteochondrodysplasia caused by mutations in the TRAPPC2 gene. It is clinically characterized by disproportionate short stature and early onset of degenerative osteoarthritis. Clinical diagnosis can be challenging due to the late-onset of the disease and lack of systemic metabolic abnomalites. Genetic diagnosis is critical in both early diagnosis and management of the disease. Here we reported a five-generation Chinese SEDT family and described the novel molecular findings. METHODS: Detailed family history and clinical data were collected. Genomic DNA was extracted from venous blood samples of family members. The exons of genes known to be associated with skeletal disorders were captured and deep sequenced. Variants were annotated by ANNOVAR and associated with multiple databases. Putative variants were confirmed by Sanger sequencing. The identified variant was classified according to the American College of Medical Genetics (ACMG) criteria. RESULTS: The proband was a 27-year-old Chinese male who presented with short-trunk short stature and joint pain. His radiographs showed platyspondyly with posterior humping, narrow hip-joint surfaces, and pelvic osteosclerosis. A pedigree analysis of 5 generations with 6 affected males revealed an X-linked recessive mode of inheritance. Affected males were diagnosed as SEDT according to the clinical and radiological features. Next-generation sequencing identified a novel variant of c.216_217del in the exon 4 of TRAPPC2 gene in the proband and other affected males. This variant resulted in the shift of reading frame and early termination of protein translation (p.S73Gfs*15). The mother and maternal female relatives of the proband were heterozygous carriers of the same variant, while no variations were detected in this gene of his father and other unaffected males. Based on the ACMG criteria, the novel c.216_217del variant of the TRAPPC2 gene was the pathogenic variant of this SEDT family. CONCLUSION: In this study we identified the novel pathogenic variant of of c.216_217del in the gene of TRAPPC2 in this five-generation Chinese SEDT family. Our findings expand the clinical and molecular spectrum of SEDT and helps the genetic diagnosis of SEDT patients.

Novel truncating variant of PPM1D penultimate exon in a Chinese patient with Jansen-de Vries syndrome.

BACKGROUND: Jansen-de Vries syndrome is a rare autosomal dominant neurodevelopmental disorder caused by pathogenic variants in the last and penultimate exons of the PPM1D gene. It is characterized by delayed psychomotor development, intellectual disability with speech delay, behavioral abnormalities, and dysmorphic features. Up to date, only 17 affected patients have been reported worldwide (no report in Chinese). METHODS: Here, we analyzed the clinical data and genetic test results of a Chinese patient with Jansen-de Vries syndrome admitted in our hospital in May 2019. RESULTS: We report a 9-month-old boy carrying a pathogenic variant (c.1254_1255del, p.(V419Qfs*14)) in PPM1D exon 5, which can account for his phenotype. Most of his clinical features overlap with the reported phenotype, such as growth retardation, feeding difficulties, constipation, congenital abnormalities (such as atrial septal defect, ventricular septal defect, and patent ductus arteriosus), small hands and feet with broad forehead, low-set posteriorly rotated ears, wide mouth with thin upper lip and pointed chin; however, he also presented with additional features like hepatomegaly and left inguinal hernia. CONCLUSION: This is the first published case of Jansen-de Vries syndrome in Chinese population, which will help us to enrich the clinical spectrum of this syndrome.

Decreased Circulating Levels of Asprosin in Obese Children.

BACKGROUND: Circulating asprosin is a newly discovered adipokine that triggers the release of hepatic glucose stores and increases appetite. Asprosin levels are elevated in adult obese men as well as in mice, and reductions in asprosin protect against the hyperinsulinism associated with metabolic syndrome in mice with diet-induced obesity, which indicates a potential therapeutic role of asprosin in obesity and type 2 diabetes. OBJECTIVES: Few data on asprosin in children are available, which is why this study aimed to assess concentrations of fasting asprosin, as well as its relationship to parameters of glucose and lipid metabolism, in children. METHODS: Data on clinical and metabolic parameters were collected from 40 healthy normal-weight and 47 obese children. Circulating asprosin levels were measured using an ELISA. RESULTS: The concentrations of fasting asprosin were lower in the obese children (9.24 ± 4.11 ng/mL) than in the normal-weight controls (12.33 ± 4.18 ng/mL, p < 0.001). When comparing the two groups by sex, both the boys and the girls showed similar trends. In within-group comparison, the asprosin levels were lower in boys than in girls only in the obese group (8.13 ± 4.10 vs. 10.61 ± 3.78 ng/mL, p = 0.013) but not in the control group. Interestingly, asprosin was correlated with ALT after adjusting for age and sex in all participants; in boys, asprosin was correlated with BMI, HOMA-IR, insulin, and HDL after adjusting for age. CONCLUSIONS: Concentrations of asprosin were significantly lower in obese children than in normal-weight children, and there was a gender difference in asprosin concentration. Our results suggest a complex role for asprosin in energy metabolism.

Characterization of Wnt1-inducible Signaling Pathway Protein-1 in Obese Children and Adolescents.

Wnt1-inducible signaling pathway protein-1 (WISP1), a member of the CCN family, is increasingly being recognized as a potential target for obesity and type 2 diabetes mellitus. Recent studies have shown that WISP1 can regulate low-grade inflammation in obese mice, and circulating WISP1 levels are associated with obesity and type 2 diabetes mellitus in adults. Herein, we measured serum WISP1 levels in obese youth and explored its relationships with pro-inflammatory cytokine interleukin 18 (IL-18) and other metabolic indexes. Totally, 44 normal-weight and 44 obese children and adolescents were enrolled. Physical and laboratory data were recorded, and then serum levels of WISP1 and IL-18 were determined by enzyme-linked immunosorbent assays. Results showed that serum levels of WISP1 were significantly higher in obese children and adolescents than in normal-weight healthy controls (1735.44±15.29 vs. 1364.08±18.69 pg/mL). WISP1 levels were significantly positively correlated with body mass index (BMI) and BMI z-score (r=0.392, P=0.008; r=0.474, P=0.001, respectively) in obese group; circulating IL-18 was increased in obese individuals (1229.06±29.42 vs. 295.87±13.30 pg/mL). Circulating WISP1 levels were significantly correlated with IL-18 (r=0.542, P<0.001), adiponectin (r=0.585, P<0.001) and leptin (r=0.592, P<0.001). The multivariate stepwise regression analysis showed that higher IL-18 levels represented the main determinant of increased WISP1 levels after adjusting for BMI, waist circumference, fasting insulin, homeostatic model assessment of insulin resistance (HOMA-IR) and HbA1c in obese individuals (ß=0.542, P=0.000). WISP1 can be involved in glucose/lipid metabolism in obese youth, which may be modulated by IL-18. Increased WISP1 levels may be a risk factor of obesity and insulin resistance, and WISP1 has a potential therapeutic effect on insulin resistance in obese children and adolescents.

Characterization of fibroblast growth factor 1 in obese children and adolescents

Background: Fibroblast growth factor 1 (FGF1) can regulate glucose and lipid metabolism in obese mice. Serum FGF1 has increased in type 2 diabetes mellitus adults and correlated with BMI. This study aimed to indicate conventional weight loss effects on FGF1 in obese children and adolescents. Materials and Methods: Clinical and metabolic parameters of 88 lean and obese individuals (ages 5­15 years) and 39 obese individuals followed with 6 months of lifestyle intervention were collected. Serum FGF1 levels were detected through enzyme-linked immunosorbent assays. Results: FGF1 levels were increased in obese individuals. Serum FGF1 levels were significantly correlated with BMI and waist circumferences (r = 0.377, P = 0.012; r = 0.301, P = 0.047, respectively). Multivariate stepwise linear regression analyses showed that FGF1 levels were significantly correlated with HbA1c and HOMA-IR (ß = 0.371, P = 0.008; ß = 0.323, P = 0.021, respectively). Weight loss (2.3 ± 0.1 kg) was accompanied by a significant reduction of circulating FGF1 levels (7.2 ± 0.4 pg/mL). Changes in FGF1 were significantly correlated with changes in fasting glucose, HOMA-IR and low-density lipoprotein cholesterol (ß = 0.277, P = 0.020; ß = 0.474, P < 0.001; ß = 0.320, P = 0.008, respectively). Conclusion: FGF1 levels were increased in obese individuals. Serum FGF1 levels were significantly correlated with BMI and waist circumferences (r = 0.377, P = 0.012; r = 0.301, P = 0.047, respectively). Multivariate stepwise linear regression analyses showed that FGF1 levels were significantly correlated with HbA1c and HOMA-IR (ß = 0.371, P = 0.008; ß = 0.323, P = 0.021, respectively). Weight loss (2.3 ± 0.1 kg) was accompanied by a significant reduction of circulating FGF1 levels (7.2 ± 0.4 pg/mL). Changes in FGF1 were significantly correlated with changes in fasting glucose, HOMA-IR and low-density lipoprotein cholesterol (ß = 0.277, P = 0.020; ß = 0.474, P < 0.001; ß = 0.320, P = 0.008, respectively).

Circulating MOTS-c levels are decreased in obese male children and adolescents and associated with insulin resistance.

BACKGROUND AND AIMS: A novel bioactive peptide, mitochondrial-derived peptide (MOTS-c), has recently attracted attention as a potential prevention or therapeutic option for obesity and type 2 diabetes mellitus (T2DM). MOTS-c profiles have not yet been reported in human obesity and T2DM. We aimed to determine circulating MOTS-c levels in obesity and explore the association between MOTS-c levels and various metabolic parameters. METHODS: In this case-control study, 40 obese children and adolescents (27 males) and 57 controls (40 males) were recruited in the Hubei Province of China in 2017. Circulating MOTS-c levels were measured, clinical data (eg, glucose, insulin, and lipid profile) were recorded, and anthropometric measurements were performed. Finally, we investigated correlations between MOTS-c levels and related variables. RESULTS: MOTS-c levels were significantly decreased in the obese group compared with the control group (472.61 ±22.83 vs 561.64 ±19.19 ng/mL, P <.01). After classification by sex, MOTS-c levels were significantly decreased in obese male children and adolescents compared to their counterparts (465.26 ±24.53 vs 584.07 ±21.18 ng/mL, P <.001), while they were comparable between the obese and healthy female subjects (487.89 ±49.77 vs 508.85 ±38.76 ng/mL, P >.05). Further, MOTS-c levels were negatively correlated with body mass index (BMI), BMI SD score, waist circumference, waist-to-hip ratio, fasting insulin level, homeostasis model assessment of insulin resistance (HOMA-IR), and glycated hemoglobin (HbA1c) in the male cohort. CONCLUSIONS: Circulating MOTS-c levels were decreased in obese male children and adolescents and correlated with markers of insulin resistance and obesity.

CO suppresses prostate cancer cell growth by directly targeting LKB1/AMPK/mTOR pathway in vitro and in vivo.

BACKGROUND: CO is a freely diffusible gas that acts as a physiological mediator of many biological and cellular processes, which has been shown to possess anticancer effect in many kinds of cancers. However, the effect of CO on prostate cancer has not been demonstrated. Therefore, we analyzed the antitumor activities and related mechanisms of CO on prostate cancer in vitro and in vivo. METHODS: Cell viability of LNCaP and PC-3 cells after CORM-2 treatment was measured by CCK-8 assay, whereas the ATP production were detected by ATP detection assay. The early apoptosis induced by CO was evaluated by flow cytometry, and the expression level of apoptosis-related molecules (Caspases 3, 8, 9 and cleaved-Caspases 3, 8, 9) was detected using Western blot. Matrigel in vitro invasion assay was used to evaluate the effect of CO on cell invasion. We then evaluated the impact of CO on the expression of several key regulators involved in the LKB1 signaling pathway. At last, xenograft tumor in nude mice was used to further investigate the antitumor effect of CO in vivo. RESULTS: Our results showed that CO could significantly inhibit proliferation and invasion, and induce apoptosis in human prostate cancer cell lines. The expression of LKB1 could be up-regulated after CO treatment, and CO also could increase p-AMPK levels and decrease p-mTOR. Furthermore, LKB1 knockdown could weaken the effect of CO on prostate cancer cells. In vivo, CO treatment significantly suppressed tumor growth and induced apoptosis in xenografts tumor in nude mice. CONCLUSIONS: CO possesses striking anticancer effect in human prostate cancer cells in vitro and in vivo, which is largely mediated by LKB1-AMPK-mTOR axis.

Prevalence of vitamin D deficiency in girls with idiopathic central precocious puberty.

The relationship between vitamin D deficiency and idiopathic central precocious puberty (ICPP) has been recently documented. In this study, 280 girls diagnosed with ICPP and 188 normal puberty control girls of similar ages were enrolled and retrospectively studied. The ICPP group had significantly lower serum 25-hydroxyvitamin D (25[OH]D) levels than the control group. Furthermore, a nonlinear relationship was found between serum 25[OH]D and ICPP, and a cut-off point for serum 25[OH]D was found at 31.8 ng/ml for ICPP with and without adjusting the different confounding factors. Girls with serum 25[OH]D ≥ 31.8 ng/ml had a lower odds ratio (unadjusted: OR 0.36, 95% CI 0.15 to 0.83, P < 0.05; height and weight adjusted: OR 0.44, 95% CI 0.18 to 1.08, P = 0.072; BMI adjusted: OR 0.36, 95% CI 0.16 to 0.84, P < 0.05). The ICPP subjects with 25[OH]D deficiency had a higher body mass index (BMI) than the subjects from the two other subgroups. Correlation analysis showed that vitamin D level is correlated with BMI and some metabolic parameters in the ICPP group. Our study suggested that vitamin D status may be associated with ICPP risk and may have a threshold effect on ICPP.

Increased Cord Blood Betatrophin Levels in the Offspring of Mothers with Gestational Diabetes.

AIM: Exposing a fetus to hyperglycemia can increase the risk for later-life metabolic disorders. Betatrophin has been proposed as a key regulator of pancreatic beta cell proliferation and lipid regulation. Highly responsive to nutritional signals, serum betatrophin concentrations have been found to be altered by various physiological and pathological conditions. We hypothesized that betatrophin levels are increased in the cord blood in offspring exposed to intrauterine hyperglycemia. METHODS: This was a cross-sectional study including 54 mothers who underwent uncomplicated Cesarean delivery in a university hospital. Maternal gestational glucose concentration was determined at 24-48 weeks gestation after a 75-g OGTT. Cord blood and placental tissue was collected immediately post delivery. Metabolic parameters were determined in the Clinical Laboratory. Cord blood betatrophin levels were assayed using a commercially available ELISA kit. Placental mitochondrial content was determined by real-time PCR. RESULTS: Cord blood betatrophin levels were increased in the gestational diabetes mellitus (GDM) group compared with the normoglycemic group. Furthermore, betatrophin levels were positively correlated with maternal gestational 2h post-OGTT glucose, cord blood insulin, HOMA-IR, and inversely correlated with placental mitochondrial content. CONCLUSIONS: Cord blood betatrophin may function as a potential biomarker of maternal intrauterine hyperglycemia and fetal insulin resistance, which may presage for long-term metabolic impact of GDM on offspring.