Stabilization of Cx43 mRNA via RNA-binding protein HuR regulated by polyamines enhances intestinal epithelial barrier function.

Gut barrier dysfunction occurs commonly in patients with critical disorders, leading to the translocation of luminal toxic substances and bacteria to the bloodstream. Connexin 43 (Cx43) acts as a gap junction protein and is crucial for intercellular communication and the diffusion of nutrients. The levels of cellular Cx43 are tightly regulated by multiple factors, including polyamines, but the exact mechanism underlying the control of Cx43 expression remains largely unknown. The RNA-binding protein HuR regulates the stability and translation of target mRNAs and is involved in many aspects of intestinal epithelial pathobiology. Here we show that HuR directly bound to Cx43 mRNA via its 3'-untranslated region in intestinal epithelial cells (IECs) and this interaction enhanced Cx43 expression by stabilizing Cx43 mRNA. Depletion of cellular polyamines inhibited the [HuR/Cx43 mRNA] complex and decreased the level of Cx43 protein by destabilizing its mRNA, but these changes were prevented by ectopic overexpression of HuR. Polyamine depletion caused intestinal epithelial barrier dysfunction, which was reversed by ectopic Cx43 overexpression. Moreover, overexpression of checkpoint kinase 2 in polyamine-deficient cells increased the [HuR/Cx43 mRNA] complex, elevated Cx43 levels, and promoted barrier function. These findings indicate that Cx43 mRNA is a novel target of HuR in IECs and that polyamines regulate Cx43 mRNA stability via HuR, thus playing a critical role in the maintenance of intestinal epithelial barrier function.NEW & NOTEWORTHY The current study shows that polyamines stabilize the Cx43 mRNA via HuR, thus enhancing the function of the Cx43-mediated gap junction. These findings suggest that induced Cx43 by HuR plays a critical role in the process by which polyamines regulate intestinal epithelial barrier.

The triglyceride-to-high density lipoprotein cholesterol ratio in overweight Korean children and adolescents.

PURPOSE: The triglyceride-to-high-density lipoprotein cholesterol (TG/HDL-C) ratio has recently been reported as a biomarker of cardiometabolic risk in obese children and adolescents. The purpose of this study is to describe the TG/HDL-C ratio and related factors in overweight and normal weight Korean children and to evaluate whether the high TG/HDL-C ratio is associated with insulin resistance in overweight children and adolescents. METHODS: Data from 255 overweight (aged 8.7±2.0 years) and 514 normal weight (aged 8.9±1.8 years) children and adolescents were evaluated. Glucose, insulin, total cholesterol (TC), HDL-C and TG levels were measured after overnight fasting, and the TG/HDL-C ratio, non-HDL-C and the homeostasis model assessment of insulin resistance (HOMA-IR) were calculated. RESULTS: The TG/HDL-C ratio was higher in overweight group compared to normal weight group (P<0.001). Among overweight children and adolescents, alanine aminotransferase (P=0.018), non-HDL-C (P<0.001), and HOMA-IR (P=0.004) were different between the TG/HDL-C ratio tertile groups. The prevalence of elevated HOMA-IR was increased with increasing TG/HDL-C ratio tertiles (P for trend=0.003). On regression analysis adjusted for age and sex, the BMI (ß=0.402, P=0.001) and TG/HDL-C ratio (ß=0.251, P=0.014) were independently associated with HOMA-IR (adjusted R2=0.324). The TG/HDL-C ratio of 2.0 or more showed higher sensitivity (55.6%) and specificity (72.9%), when compared to TC (≥200 mg/dL), non-HDL-C (≥145 mg/dL), and LDL-C (≥130 mg/dL) for identifying overweight children with elevated HOMA-IR. CONCLUSIONS: The TG/HDL-C ratio is independently associated with insulin resistance in overweight children and adolescents, and it can be useful in identifying those at higher cardiometabolic risk.

Diurnal variation of gonadotropin levels in girls with early stages of puberty.

PURPOSE: Pubertal gonadotropin secretion shows circadian pattern and the luteinizing hormone (LH) levels tend to rise in later stages of puberty in girls. We studied the usefulness of basal LH in the evaluation of central precocious puberty with emphasis on the influence of sampling time. METHODS: Medical records of 334 girls that underwent gonadotropin-releasing hormone stimulation test (GnRHST) were reviewed. Auxological and laboratory data were compared between those with early morning (EM, before 10 AM) and late morning/afternoon (LM/A, after 10 AM) basal samples. RESULTS: Among those in sexual maturity rating (SMR) 2, EM samples showed higher basal LH (P=0.004) compare to LM/A samples, whereas those in SMR 3 showed no difference in LH levels between EM and LM/A samples. Among girls with pubertal response, EM group showed higher basal LH (P=0.031) and follicular stimulating hormone (P=0.008) than LM/A group. The EM basal LH was more closely related with the peak stimulated LH than the LM/A basal LH did (rs=0.871 vs. rs=0.524). The optimal basal LH cutoffs to predict a pubertal response to GnRHST were 0.11 IU/L with a sensitivity of 66.7% and a specificity of 78.7% in EM group, and 0.07 IU/L with a sensitivity of 60.0% and a specificity of 78.9% in LM/A group, respectively. CONCLUSIONS: In girls with early stages of puberty, EM basal LH is a more sensitive screening tool than the LM/A basal LH. Diurnal variation should be considered in evaluating children with precocious puberty.

Delayed diagnosis of 22q11 deletion syndrome due to late onset hypocalcemia in a 11-year-old girl with imperforated anus.

Neonatal hypocalcemia and congenital heart defects has been known as the first clinical manifestation of the chromosome 22q11.2 deletion syndrome (22q11DS). However, because of its wide clinical spectrum, diagnosis of 22q11DS can be delayed in children without classic symptoms. We report the case of a girl with the history of imperforate anus but without neonatal hypocalcemia or major cardiac anomaly, who was diagnosed for 22q11DS at the age of 11 after the onset of overt hypocalcemia. She was born uneventfully from phenotypically normal Korean parents. Imperforate anus and partial cleft palate were found at birth, which were surgically repaired thereafter. There was no history of neonatal hypocalcemia, and karyotyping by GTG banding was normal. At the age of 11, hypocalcemia (serum calcium, 5.0 mg/dL) and decreased parathyroid hormone level (10.8 pg/mL) was noted when she visited our Emergency Department for fever and vomiting. The 22q11DS was suspected because of her mild mental retardation and velopharyngeal insufficiency, and a microdeletion on chromosome 22q11.2 was confirmed by fluorescence in situ hybridization. The 22q11DS should be considered in the differential diagnosis of hypocalcemia at any age because of its wide clinical spectrum.