Dexamethasone may affect the occurrence of parenteral nutrition-associated cholestasis in preterm neonates.

Introduction: Glucocorticoids are currently used for the co-therapeutic management of autoimmune hepatitis and some cholestatic diseases. Thus far, we do not know the efficacy of glucocorticoids in the treatment of parenteral nutrition-associated cholestasis. We aimed to analyze whether the administration of late postnatal dexamethasone for treating bronchopulmonary dysplasia influence the occurrence of parenteral nutrition-associated cholestasis in preterm neonates. Methods: A retrospective study was conducted for 78 preterm neonates without major anomalies (gestational age was <30 weeks, and birthweight was ≤1000 g) hospitalized in a neonatal unit. Total and direct serum bilirubin levels were measured about every two weeks for all neonates. Data including the administration of dexamethasone, intravenous nutrition, and enteral feeding were collected by at least three audits. Results: A total of 15 preterm neonates were diagnosed with parenteral nutrition-associated cholestasis, and after stopping parenteral nutrition, the direct bilirubin value decreased to the normal level for no longer than 150 days. The prolonged duration of parenteral nutrition was a risk factor, and late postnatal dexamethasone treatment was a protective factor in reducing the incidence of parenteral nutrition-associated cholestasis. Conclusion: Dexamethasone treatment may reduce the occurrence of parenteral nutrition-associated cholestasis in preterm neonates.

Evaluation of the diagnostic value of gastric juice aspirate culture for early-onset sepsis in newborns 28-35 weeks' gestation.

The aim of the study was to discuss the diagnostic value of gastric aspirate culture of early-onset sepsis in premature neonates. A retrospective study was conducted for 600 premature neonates of predisposing high-risk factors (gestation age from 28 to 35 weeks) hospitalized in neonatal unit of the First Affiliated Hospital of Wenzhou Medical University. The culture of gastric aspirate was performed within 24 h after birth. The sepsis group and nonsepsis group were divided by diagnosis given by 3 neonatologists. The specificity of gastric aspirate on diagnosis of sepsis was analyzed. The positive rate of gastric aspirate culture in sepsis group was higher than nonsepsis group (P < 0.05). The incidence of sepsis (P < 0.05) and positive rate of gastric aspirate culture (P < 0.05) were higher after vaginal delivery. Escherichia coli were the dominant bacteria after vaginal delivery. For premature neonates born vaginally, gastric aspirate culture may have diagnostic value for sepsis.

Sex Differences in Progression of Diabetic Cardiomyopathy in OVE26 Type 1 Diabetic Mice.

OVE26 mice are a widely used transgenic model of early-onset type 1 diabetes. These mice overexpress calmodulin in their pancreatic ß cells, develop severe diabetes within the first weeks of life, and progress to severe diabetic complications including diabetic nephropathy and diabetic cardiomyopathy (DCM). To date, diabetic nephropathy in OVE26 mice has been well explored, leaving the progression of DCM and the gender impact in this type 1 diabetes model still unrevealed. In our study, male and female OVE26 mice and age-matched nondiabetic FVB mice were examined at 4, 12, 24, and 36 weeks for their cardiac function, body weight, blood glucose, and heart weight/tibia length ratio. Further, histopathological examination and Western blot analysis for the key markers demonstrate that DCM appears at 24 weeks OVE26 mice, initiating with cardiac senescence, followed by fibrosis and then cardiac dysfunction. Mitochondrial respiration function analysis showed no indication of dysfunction in OVE26 mice at 24 weeks of age in both genders. In addition, no significant difference for the pathogenic progression was observed between OVE26 and FVB mice in both males and females. In conclusion, this study suggests cardiac senescence and fibrosis, which may be amended by sex differences, play key roles in the progression of DCM in OVE26 mice. The comprehensive characterization of diabetic cardiomyopathy progression and the sex difference impact in OVE26 mice provides a basis for future study on DCM using OVE26 mice.

Diabetic­induced alterations in hepatic glucose and lipid metabolism: The role of type 1 and type 2 diabetes mellitus (Review).

Diabetes mellitus (DM) is a growing health concern in society. Type 1 and type 2 DM are the two main types of diabetes; both types are chronic diseases that affect glucose metabolism in the body and the impaired regulation of glucose and lipid metabolism promotes the development and progression of DM. During the physiological metabolism process, the liver serves a unique role in glucose and lipid metabolism. The present article aimed to review the association between DM and glucose metabolism in the liver and discuss the changes of the following hepatic glucose fluxes: Gluconeogenesis, glucose/glucose 6­phosphate cycling, glycogenolysis, glycogenesis and the pentose phosphate pathway. Moreover, the incidence of fatty liver in DM was also investigated.

Sex differences in progression of diabetic nephropathy in OVE26 type 1 diabetic mice.

AIMS: OVE26 mice (FVB background), genetically overexpressing calmodulin in pancreatic beta cells, develop early onset type 1 diabetes, leading to progressive diabetic nephropathy (DN), with features of established human DN. The role of gender in characteristics of renal lesions has remained unexplored. METHODS: Male and female OVE26 mice were compared to age and sex matched wild-type, nondiabetic FVB mice at ages of 4, 12, 24 and 36 weeks. Nephropathy was examined by measuring urine albumin-to-creatinine ratio, histopathology, expression of pathological markers and immunochemistry in the same cohort of mice. RESULTS: Progression of diabetic kidney disease was evident first in the OVE26 glomerulus, initially as mesangial matrix expansion at 4 weeks followed by loss of podocytes, glomerular volume expansion and severe albuminuria at 12 weeks. Tubule dilation and initiation of interstitial fibrosis did not become significant until 24 weeks. T-lymphocyte infiltration into the renal parenchyma appeared at 36 weeks. OVE26 female mice developed more advanced DN than male OVE26 mice, such as more severe albuminuria, greater podocyte loss, additional fibrosis and significantly more inflammatory cell infiltration. The female OVE26 mice had lowest level of plasma estradiol in all 36 weeks old mice, as well as renal estrogen receptors. CONCLUSIONS: This demonstration of the role of gender, combined with the detailed characterization of DN progression illustrates the value of OVE26 mice for understanding gender effects on DN and provides the basis for researchers to better select the age and sex of OVE26 mice in future studies of type 1 DN. RESEARCH IN CONTEXT: What is already known about this subject? What is the key question? What are the new findings? How might this impact on clinical practice in the foreseeable future?

Hepatic functional and pathological changes of type 1 diabetic mice in growing and maturation time.

To detect the changes in the liver function in both male and female OVE26 mice from young to adults for better understanding of type 1 diabetes-induced hepatic changes, OVE26 mice and wild-type FVB mice were raised in the same environment without any intervention, and then killed at 4, 12, 24 and 36 weeks for examining liver's general properties, including pathogenic and molecular changes. The influence of diabetes on the bodyweight of male and female mice was different. Both male and female OVE26 mice did not obtain serious liver injury or non-alcoholic fatty liver disease, manifested by mild elevation of plasma alanine transaminase, and less liver lipid content along with significantly suppressed lipid synthesis. Uncontrolled diabetes also did not cause hepatic glycogen accumulation in OVE26 mice after 4 weeks. Oxidative stress test showed no change in lipid peroxidation, but increased protein oxidation. Changed endoplasmic reticulum stress and apoptosis along with increased antioxidant capacity was observed in OVE26 mice. In conclusion, uncontrolled type 1 diabetes did not cause hepatic lipid deposition most likely because of reduced lipids synthesis in response to insulin deficiency. Enhanced antioxidant capacity might not only prevent the occurrence of severe acute liver injury but also the self-renewal, leading to liver dysfunction.

HDAC3 inhibition in diabetic mice may activate Nrf2 preventing diabetes-induced liver damage and FGF21 synthesis and secretion leading to aortic protection.

Vascular complications are common pathologies associated with type 1 diabetes. In recent years, histone deacetylation enzyme (HDAC) inhibitors have been shown to be successful in preventing atherosclerosis. To investigate the mechanism for HDAC3 inhibition in preventing diabetic aortic pathologies, male OVE26 type 1 diabetic mice and age-matched wild-type (FVB) mice were given the HDAC3-specific inhibitor RGFP-966 or vehicle for 3 mo. These mice were then euthanized immediately or maintained for an additional 3 mo without treatment. Levels of aortic inflammation and fibrosis and plasma and fibroblast growth factor 21 (FGF21) levels were determined. Because the liver is the major organ for FGF21 synthesis in diabetic animals, the effects of HDAC3 inhibition on hepatic FGF21 synthesis were examined. Additionally, hepatic miR-200a and kelch-like ECH-associated protein 1 (Keap1) expression and nuclear factor erythroid 2-related factor 2 (Nrf2) nuclear translocation were measured. HDAC3 inhibition significantly reduced aortic fibrosis and inflammation in OVE26 mice at both 3 and 6 mo. Plasma FGF21 levels were significantly higher in RGFP-966-treated OVE26 mice compared with vehicle-treated mice at both time points. It also significantly reduced hepatic pathologies associated with diabetes, accompanied by increased FGF21 mRNA and protein expression. HDAC3 inhibition also increased miR-200a expression, reduced Keap1 protein levels, and increased Nrf2 nuclear translocation with an upregulation of antioxidant gene and FGF21 transcription. Our results support a model where HDAC3 inhibition may promote Nrf2 activity by increasing miR-200a expression with a concomitant decrease in Keap1 to preserve hepatic FGF21 synthesis. The preservation of hepatic FGF21 synthesis ultimately leads to a reduction in diabetes-induced aorta pathologies.

Exacerbation of diabetic cardiac hypertrophy in OVE26 mice by angiotensin II is associated with JNK/c-Jun/miR-221-mediated autophagy inhibition.

Both diabetes and angiotensin II (Ang II) excess trigger cardiac remodeling and dysfunction, and diabetic cardiomyopathy. We hypothesized that cardiac hypertrophy associated with the development of diabetic cardiomyopathy is worsened by increased Ang II. Male type 1 diabetic OVE26 and wild-type mice were given Ang II (sc., 1.15 mg/kg, twice a day) for 14 days. Diabetes-induced cardiac dysfunction and hypertrophy was exacerbated by Ang II treatment as determined by echocardiography, wheat germ agglutinin staining and atrial natriuretic peptide. Ang II treatment dramatically exacerbated diabetes-caused decreased LC3-II, a marker of autophagy, and increased p62, an indicator of cytosolic protein clearance. Ang II treatment also augmented diabetes-associated increased phosphorylated levels of c-Jun, JNK, mTOR, and miR-221, and decreased of p27 expression, a direct target of miR-221. Chromatin immunoprecipitation assay showed that Ang II elevated c-Jun binding to the promoter of miR-221 in diabetic mice. These results suggest that Ang II accelerates cardiac hypertrophy in the early stage of murine diabetes, probably through activation of the JKN/c-Jun/miR-221 axis and inhibition of downstream autophagy. Therefore, inhibition of Ang II or miR-221 in diabetic individuals may be a potential approach for delaying the onset and/or reducing the severity of diabetic cardiomyopathy.