IL-17A promotes Helicobacter pylori-induced gastric carcinogenesis via interactions with IL-17RC.

BACKGROUND: Gastric cancer (GC) is a common malignancy worldwide, with a major attribution to Helicobacter pylori. Interleukin (IL)-17A has been reported to be up-regulated in serum and tumor of GC patients, but the precise mechanisms underlying its involvement in gastric tumorigenesis are yet to be established. Here, we investigated the roles of IL-17A in the pathogenesis of H. pylori-induced GC. METHODS: GC was induced in IL-17A knockout (KO) and wild-type (WT) mice via N-methyl-N-nitrosourea (MNU) treatment and H. pylori infection. At 50 weeks after treatment, gastric tissues were examined by histopathology, immunohistochemistry, and immunoblot analyses. In vitro experiments on the human GC cell lines were additionally performed to elucidate the underlying mechanisms. RESULTS: Deletion of IL-17A suppressed MNU and H. pylori-induced gastric tumor development accompanied by a decrease in gastric epithelial cell growth, oxidative stress, and expression of gastric epithelial stem cells markers. In AGS cells, recombinant human IL-17A (rhIL-17A) inhibited apoptosis and G1/S phase transition arrest while promoting reactive oxygen species production, sphere formation ability of cancer stem cells (CSC), and expression of stemness-related genes. In addition, rhIL-17A induced expression of IL-17RC, leading to NF-κB activation and increased NADPH oxidase 1 (NOX1) levels. Inhibition of NOX1 with GKT136901 attenuated rhIL-17A-mediated elevation of GC cell growth, ROS generation, and CSC stemness. Clinically, IL-17RC expressions were significantly upregulated in human GC compared with normal gastric tissues. CONCLUSION: Our results suggest that IL-17A promotes gastric carcinogenesis, in part, by regulating IL-17RC/NF-κB/NOX1 pathway, supporting its potential as a target in human GC therapy.

Alpha-1,3-galactosyltransferase-deficient miniature pigs produced by serial cloning using neonatal skin fibroblasts with loss of heterozygosity.

OBJECTIVE: Production of alpha-1,3-galactosyltransferase (αGT)-deficient pigs is essential to overcome xenograft rejection in pig-to-human xenotransplantation. However, the production of such pigs requires a great deal of cost, time, and labor. Heterozygous αGT knockout pigs should be bred at least for two generations to ultimately obtain homozygote progenies. The present study was conducted to produce αGT-deficient miniature pigs in much reduced time using mitotic recombination in neonatal ear skin fibroblasts. METHODS: Miniature pig fibroblasts were transfected with αGT gene-targeting vector. Resulting gene-targeted fibroblasts were used for nuclear transfer (NT) to produce heterozygous αGT gene-targeted piglets. Fibroblasts isolated from ear skin biopsies of these piglets were cultured for 6 to 8 passages to induce loss of heterozygosity (LOH) and treated with biotin-conjugated IB4 that binds to galactose-α-1,3-galactose, an epitope produced by αGT. Using magnetic activated cell sorting, cells with monoallelic disruption of αGT were removed. Remaining cells with LOH carrying biallelic disruption of αGT were used for the second round NT to produce homozygous αGT gene-targeted piglets. RESULTS: Monoallelic mutation of αGT gene was confirmed by polymerase chain reaction in fibroblasts. Using these cells as nuclear donors, three heterozygous αGT gene-targeted piglets were produced by NT. Fibroblasts were collected from ear skin biopsies of these piglets, and homozygosity was induced by LOH. The second round NT using these fibroblasts resulted in production of three homozygous αGT knockout piglets. CONCLUSION: The present study demonstrates that the time required for the production of αGT-deficient miniature pigs could be reduced significantly by postnatal skin biopsies and subsequent selection of mitotic recombinants. Such procedure may be beneficial for the production of homozygote knockout animals, especially in species, such as pigs, that require a substantial length of time for breeding.

Targeted disruption of Ataxia-telangiectasia mutated gene in miniature pigs by somatic cell nuclear transfer.

Ataxia telangiectasia (A-T) is a recessive autosomal disorder associated with pleiotropic phenotypes, including progressive cerebellar degeneration, gonad atrophy, and growth retardation. Even though A-T is known to be caused by the mutations in the Ataxia telangiectasia mutated (ATM) gene, the correlation between abnormal cellular physiology caused by ATM mutations and the multiple symptoms of A-T disease has not been clearly determined. None of the existing ATM mouse models properly reflects the extent to which neurological degeneration occurs in human. In an attempt to provide a large animal model for A-T, we produced gene-targeted pigs with mutations in the ATM gene by somatic cell nuclear transfer. The disrupted allele in the ATM gene of cloned piglets was confirmed via PCR and Southern blot analysis. The ATM gene-targeted pigs generated in the present study may provide an alternative to the current mouse model for the study of mechanisms underlying A-T disorder and for the development of new therapies.

Relationship between Serum Total Testosterone Concentration and Metabolic Syndrome in Premenopausal Obese Women.

BACKGROUND: Men with low testosterone levels are at an increased risk of developing metabolic syndrome, irrespective of age or obesity. However, the relationship between metabolic syndrome and testosterone levels in women remains unclear. We compared the total testosterone concentrations between premenopausal obese women with and without metabolic syndrome and identified the factors affecting these concentrations. METHODS: A single-center retrospective analysis was conducted using the medical records of 580 premenopausal women with obesity. The diagnostic criteria for metabolic syndrome were established using the National Cholesterol Education Program Adult Treatment Panel III guidelines. RESULTS: The mean±standard deviation age, weight, and body mass index were 38.8±8.4 years, 78.0±11.8 kg, and 30.0±4.1 kg/m2, respectively. The mean total testosterone concentration was lower in the metabolic syndrome group than in the non-metabolic syndrome group (n=385 vs. n=195; 0.22±0.10 ng/mL vs. 0.24±0.11 ng/mL; P<0.001). In a model adjusted for age, body mass index, skeletal muscle mass, body fat mass, and body fat percentage, the odds ratio for metabolic syndrome with respect to the total testosterone level was 0.128 (P=0.028). Testosterone concentration was negatively correlated with age (r=-0.334), systolic blood pressure (r=-0.084), and triglyceride concentration (r=-0.093) but positively correlated with weight (r=0.144), body mass index (r=0.140), waist circumference (r=0.133), body fat mass (r=0.167), and body fat percentage (r=0.167). Stepwise regression analysis revealed that age (ß=-0.004, P<0.001), body mass index (ß=0.003, P=0.004), and high-density lipoprotein cholesterol concentration (ß=0.001, P=0.019) were independently associated with total testosterone concentration (adjusted R2=12.6%). CONCLUSION: Metabolic syndrome and obesity may be independently associated with testosterone levels in premenopausal women with obesity.

Improving Mechanical and Corrosion Properties of 6061 Al Alloys via Differential Speed Rolling and Plasma Electrolytic Oxidation.

This study explores the combined potential of severe plastic deformation (SPD) via differential speed rolling (DSR) and plasma electrolytic oxidation (PEO) to enhance the material performance of 6061 Al alloys. To this end, DSR was carried out at a roll-speed-ratio of 1:4 to obtain ~75% total thickness reduction and a final microstructure of <1 µm. The rest of the samples were annealed to obtain various grain sizes of ~1, ~25, and ~55 µm. Through DSR, the hardness of the material increased from ~64 to ~102 HV. Different grain sizes altered the plasma behavior which further influence the growth of the coating layer, where the fine grain size produced a compact structure beneficial for corrosion protection. This synergy offers tailored materials ideal for high-performance applications across diverse industries, combining enhanced bulk properties from DSR with optimized surface attributes from PEO.

TXNIP in liver sinusoidal endothelial cells ameliorates alcohol-associated liver disease via nitric oxide production.

Dysregulation of liver sinusoidal endothelial cell (LSEC) differentiation and function has been reported in alcohol-associated liver disease (ALD). Impaired nitric oxide (NO) production stimulates LSEC capillarization and dysfunction; however, the mechanism underlying NO production remains unclear. Here, we investigated the role of thioredoxin-interacting protein (TXNIP), an important regulator of redox homeostasis, in endothelial cell NO production and its subsequent effects on ALD progression. We found that hepatic TXNIP expression was upregulated in patients with ALD and in ethanol diet-fed mice with high expression in LSECs. Endothelial cell-specific Txnip deficiency (TxnipΔEC) in mice exacerbated alcohol-induced liver injury, inflammation, fibrosis, and hepatocellular carcinoma development. Deletion of Txnip in LSECs led to sinusoidal capillarization, downregulation of NO production, and increased release of proinflammatory cytokines and adhesion molecules, whereas TXNIP overexpression had the opposite effects. Mechanistically, TXNIP interacted with transforming growth factor ß-activated kinase 1 (TAK1) and subsequently suppressed the TAK1 pathway. Inhibition of TAK1 activation restored NO production and decreased the levels of proinflammatory cytokines, thereby, blocking liver injury and inflammation in TxnipΔEC mice. Our findings indicate that upregulated TXNIP expression in LSECs serves a protective role in ameliorating ALD. Enhancing TXNIP expression could, therefore, be a potential therapeutic approach for ALD.

Obesity in Children and Adolescents: 2022 Update of Clinical Practice Guidelines for Obesity by the Korean Society for the Study of Obesity.

The prevalence of obesity in children and adolescents has been gradually increasing in recent years and has become a major health problem. Childhood obesity can readily progress to adult obesity. It is associated with obesity-related comorbidities, such as type 2 diabetes mellitus, hypertension, obstructive sleep apnea, non-alcoholic fatty liver disease, and the risk factor for cardiovascular disease. It is important to make an accurate assessment of overweight and obesity in children and adolescents with consideration of growth and development. Childhood obesity can then be prevented and treated using an appropriate treatment goal and safe and effective treatment strategies. This article summarizes the clinical practice guidelines for obesity in children and adolescents that are included in the 8th edition of the Clinical Practice Guidelines for Obesity of the Korean Society for the Study of Obesity.

Impact of biologic agents on body weight and obesity-related disorders in patients with psoriasis: A nationwide population-based cohort study.

OBJECTIVE: This large-scale population-based study aimed to analyze the effects of biologic agents on body weight and obesity-related disorders in patients with psoriasis for 10 years (January 2010 to December 2019), using the customized database provided by the Korean National Health Insurance Service. METHODS: The demographic data and health charts of 620,885 psoriasis patients, divided into three groups according to their treatment modalities (biologics, non-biologic systemic agents, and other agents), were analyzed. RESULTS: Patients with severe psoriasis who were prescribed biologic agents had a higher rate of comorbidities, such as diabetes, dyslipidemia, fatty liver, increased body weight, body mass index, and waist circumference than those in the other treatment groups. We found that the use of biologic agents was a significant independent risk factor for gaining weight after correcting for age, sex, initial weight, total prescription period, duration between the weight measurements before and after psoriasis treatment, exercise, smoking, drinking and presence of comorbidities. In contrast, the use of non-biologic systemic agents was not a significant independent risk factor for weight change. Gender-stratified regression analysis found that biologics were an independent variable affecting weight change for men, but not for women. CONCLUSIONS: Patients with severe psoriasis who are prescribed biologic agents tend to have a higher body weight and a higher prevalence of obesity-related disorders than those in other treatment groups. Caution must be exercised when using biologics, as they may cause additional weight gain, especially in men.

Effect of Ultrasonic Frequency on Structure and Corrosion Properties of Coating Formed on Magnesium Alloy via Plasma Electrolytic Oxidation.

This study explores the application of ultrasonic vibration during plasma electrolytic oxidation (PEO) to enhance the corrosion resistance of magnesium (Mg) alloy. To this end, three different ultrasonic frequencies of 0, 40, and 135 kHz were utilized during PEO. In the presence of ultrasonic waves, the formation of a uniform and dense oxide layer on Mg alloys is facilitated. This is achieved through plasma softening, acoustic streaming, and improved mass transport for successful deposition and continuous reforming of the oxide layer. The oxide layer exhibits superior protective properties against corrosive environments due to the increase in compactness. Increasing ultrasonic frequency from 40 to 135 kHz, however, suppresses the optimum growth of the oxide layer due to the occurrence of super-soft plasma swarms, which results in a low coating thickness. The integration of ultrasonic vibration with PEO presents a promising avenue for practical implementation in industries seeking to enhance the corrosion protection of Mg alloys, manipulating microstructures and composition.

Diagnosis of Obesity: 2022 Update of Clinical Practice Guidelines for Obesity by the Korean Society for the Study of Obesity.

The prevalence of obesity has consistently increased worldwide, and many obesity-related diseases are emerging as major health problems. Body mass index (BMI) is used to define obesity and is highly correlated with body fat mass. Moreover, obesity-related morbidities increase linearly with the increase in BMI. The Korean Society for the Study of Obesity defined overweight as a BMI ≥23 kg/m2 and obesity as a BMI ≥25 kg/m2, based on a significant increase in obesity-related diseases. A waist circumference of ≥90 cm in men and ≥85 cm in women are defined as abdominal obesity, which is also correlated with obesity-related diseases. These diagnostic criteria are the same as in the previous version; however, the updated guidelines put greater emphasis on the use of morbidity as the basis for obesity and abdominal obesity diagnoses. These new guidelines will help to identify and manage high-risk groups for obesity-related comorbidities among Korean adults.