Melatonin improves insulin resistance and hepatic steatosis through attenuation of alpha‐2‐HS‐glycoprotein

Melatonin plays an important role in regulating circadian rhythms. It also acts as a potent antioxidant and regulates glucose and lipid metabolism, although the exact action mechanism is not clear. The α2‐HS‐glycoprotein gene (AHSG) and its protein, fetuin‐A (FETUA), are one of the hepatokines and are known to be associated with insulin resistance and type 2 diabetes. The aim of this study was to determine whether melatonin improves hepatic insulin resistance and hepatic steatosis in a FETUA‐dependent manner. In HepG2 cells treated with 300 μmol/L of palmitic acid, phosphorylated AKT expression decreased, and FETUA expression increased, but this effect was inhibited by treatment with 10 μmol/L of melatonin. However, melatonin did not improve insulin resistance in FETUA‐overexpressing cells, indicating that improvement in insulin resistance by melatonin was dependent on downregulation of FETUA. Moreover, melatonin decreased palmitic acid‐induced ER stress markers, CHOP, Bip, ATF‐6, XBP‐1, ATF‐4, and PERK. In addition, in the high‐fat diet (HFD) mice, oral treatment with 100 mg/kg/day melatonin for 10 weeks reduced body weight gain to one‐third of that of the HFD group and hepatic steatosis. Insulin sensitivity and glucose intolerance improved with the upregulation of muscle p‐AKT protein expression. FETUA expression and ER stress markers in the liver and serum of HFD mice were decreased by melatonin treatment. In conclusion, melatonin can improve hepatic insulin resistance and hepatic steatosis through reduction in ER stress and the resultant AHSG expression.     

The Burden of Iron Deficiency in Heart Failure: Therapeutic Approach

Heart failure (HF) is highlighted by its burdening symptom-limited exercise capacity and recurrent hospitalizations. Despite substantial advances regarding disease-modifying drugs in HF with reduced ejection fraction, additional therapeutic strategies to improve quality of life are invaluable. Currently, iron deficiency (ID) is overwhelmingly recognized in over 30% to 50% of patients with stable chronic HF, which worsens prognosis. The established pathophysiological mechanisms of progressive HF may be intertwined with increasing myocardial iron scarcity, wherein one begets the other. Most importantly, ID constitutes a novel target for symptom relief in carefully selected patients. In this regard, intravenous iron may be a safe and efficacious intervention, potentially reducing HF hospitalizations. We discuss the evidence and gaps in knowledge concerning iron therapy in HF and propose a practical, comprehensive, clinically oriented algorithm for timely adequate iron replenishment in different clinical scenarios. Finally, we further debate imperative decision-making before intervention and the drawbacks of such a strategy.     

Predictive capacity of different bioelectrical impedance analysis devices,with and without protocol,in the evaluation of adolescents

Objectivethis study was performed to determine the predictive capacity of four different bioelectrical impedance analysis (BIA) devices in the assessment of adolescents, with and without a protocol.Methodsa cross-sectional study was performed with 215 adolescents aged 10 to 14 years, of both genders, evaluated through anthropometry and body composition by dual energy X-ray absorptiometry (DXA) and by four different BIA devices, with and without a protocol. The following tests were used: Kolmogorov-Smirnov's, chi-squared, Student's t or Mann-Whitney's, Kruskal-Wallis's, Wilcoxon's, and kappa index. The ROC curves were constructed and the sensitivity, specificity, and positive and negative predictive values were calculated.Resultsof the 215 adolescents, 44.2% had excessive body fat. The tetrapolar BIA device equipped with eight tactile electrodes showed more sensitivity and results that were closer to those obtained by DXA (area under the ROC curve [AUC] = 0.964 with protocol and AUC = 0.973 without protocol, p < 0.001), as well as greater agreement (k = 0.67 with protocol and k = 0.63 without protocol, p < 0.001). The evaluation without protocol was similar to that by DXA in most investigated situations (p > 0.05).ConclusionBIA is capable of predicting alterations in adolescents’ body composition. When it is impossible to perform the assessment with a protocol, its results may be useful in population studies.     

DNA methylation patterns of genes related to immune response in the different clinical forms of oral lichen planus

Background

The oral lichen planus is a chronic inflammatory disease. Although its aetiology is not well understood, the role of T lymphocytes in its inflammatory events is recognised. Identifying the epigenetic mechanisms involved in the pathogenesis of this immune‐mediated condition is fundamental for understanding the inflammatory reaction that occurs in the disease. The purpose of this work was to evaluate the methylation pattern of 21 immune response‐related genes in the different clinical forms of oral lichen planus.

Methods

A cross‐sectional study was performed to analyse the DNA methylation patterns in three distinct groups of oral lichen planus: (i) reticular/plaque lesions; (ii) erosive lesions; (iii) normal oral mucosa (control group). After DNA extraction from biopsies, the samples were submitted to digestions by methylation‐sensitive and methylation‐dependent enzymes and double digestion. The relative percentage of methylated DNA for each gene was provided using real‐time polymerase chain reaction arrays.

Results

Hypermethylation of the STAT5A gene was observed only in the control group (59.0%). A higher hypermethylation of the ELANE gene was found in reticular/plaque lesions (72.1%) compared to the erosive lesions (50.0%).

Conclusion

Our results show variations in the methylation profile of immune response‐related genes, according to the clinical type of oral lichen planus after comparing with the normal oral mucosa. Further studies are necessary to validate these findings using gene expression analysis.     

Updates in biological therapies for knee injuries: menisci

The preservation of meniscal tissue is paramount for long-term joint function, especially in younger patients who are athletically active. Many studies have reported encouraging results following the repair of meniscus tears, including both simple longitudinal tears located in the periphery and complex multiplanar tears that extend into the central third avascular region. However, most types of meniscal lesions are managed with a partial meniscectomy. Options to restore the meniscus range from an allograft transplantation to the use of synthetic and biological technologies. Recent studies have demonstrated good long-term outcomes with meniscal allograft transplantation, although the indications and techniques continue to evolve, and the long-term chondroprotective potential of this approach has yet to be determined. Several synthetic implants, most of which are approved in the European market, have shown some promise for replacing part of or the entire meniscus, including collagen meniscal implants, hydrogels, and polymer scaffolds. Currently, there is no ideal implant generated by means of tissue engineering. However, meniscus tissue engineering is a fast developing field that promises to develop an implant that mimics the histologic and biomechanical properties of a native meniscus.     

Serum proinflammatory cytokines and nutritional status in pediatric chronic liver disease

AIM: To evaluate the nutritional status and its association with proinflammatory cytokines in children with chronic liver disease.METHODS: We performed a cross-sectional study with 43 children and adolescents, aged 0 to 17 years, diagnosed with chronic liver disease. All patients regularly attended the Pediatric Hepatology Unit and were under nutritional follow up. The exclusion criteria were fever from any etiology at the time of enrollment, inborn errors of the metabolism and any chronic illness. The severity of liver disease was assessed by Child-Pugh, Model for End-stage Liver Disease(MELD) and Pediatric End Stage Liver Disease(PELD) scores. Anthropometric parameters were height/age, body mass index/age and triceps skinfold/age according to World Health Organization standards. The cutoff points for nutritional status were risk of malnutrition(Z-score -1.00) and malnutrition(Z-score -2.00). Interleukin-1β(IL-1β), IL-6 and tumor necrosis factor-α levels were assessed by commercial ELISA kits. For multivariate analysis, linear regression was applied to assess the association between cytokine levels, disease severity and nutritional status. RESULTS: The median(25th-75 th centile) age of the study population was 60(17-116)-mo-old, and 53.5% were female. Biliary atresia was the main cause of chronic liver disease(72%). With respect to Child-Pugh score, cirrhotic patients were distributed as follows: 57.1% Child-Pugh A, a mild presentation of the disease, 34.3% Child-Pugh B, a moderate stage of cirrhosis and 8.6% Child-Pugh C, were considered severe cases. PELD and MELD scores were only above the cutoff point in 5 cases. IL-6 values were increased in patients at nutritional risk(34.9%) compared with those who were well-nourished [7.12(0.58-34.23) pg/m L vs 1.63(0.53-3.43) pg/m L; P = 0.02], correlating inversely with triceps skinfold-for-age z-score(rs =-0.61; P 0.001). IL-6 levels were associated with liver disease severity assessed by Child-Pugh score(P = 0.001). This association remained significant after adjusting for nutritional status in a linear regression model. CONCLUSION: High IL-6 levels were found in children with chronic liver disease at nutritional risk. Inflammatory activity may be related to nutritional status deterioration in these patients.     

Nuclear localization of epidermal growth factor receptor (EGFR) in ameloblastomas

Background: Ameloblastoma is a locally invasive neoplasm often associated with morbidity and facial deformities, showing increased Epidermal Growth Factor Receptor (EGFR) expression. Inhibition of EGFR was suggested as a treatment option for a subset of ameloblastomas. However, there are resistance mechanisms that impair anti-EGFR therapies. One important resistance mechanism for EGFR-inhibition is the EGFR nuclear localization, which activates genes responsible for its mitogenic effects, such as Cyclin D1.Methods: We assessed EGFR nuclear localization in encapsulated (unicystic, n = 3) and infiltrative (multicystic, n = 11) ameloblastomas and its colocalization with Cyclin D1 by using anti-EGFR and anti-lamin B1 double labeling immunofluorescence analyzed by confocal microscopy. Oral inflammatory fibrous hyperplasia and oral squamous cell carcinoma samples were used for comparison.Results: Twelve cases of ameloblastoma exhibited nuclear EGFR colocalization with lamin B1. This positive staining was mainly observed in the ameloblast-like cells. The EGFR nuclear localization was also observed in control samples. In addition, nuclear EGFR colocalized with Cyclin D1 in ameloblastomas.Conclusions: Nuclear EGFR occurs in ameloblastomas in association with Cyclin D1 expression, which is important in terms of tumor biology clarification and raises a concern about anti-EGFR treatment resistance in ameloblastomas.