Atf3-mediated metabolic reprogramming in hepatic macrophage orchestrates metabolic dysfunction-associated steatohepatitis.

Metabolic dysfunction-associated steatohepatitis (MASH) is regulated by complex interplay between the macrophages and surrounding cells in the liver. Here, we show that Atf3 regulates glucose-fatty acid cycle in macrophages attenuates hepatocyte steatosis, and fibrogenesis in hepatic stellate cells (HSCs). Overexpression of Atf3 in macrophages protects against the development of MASH in Western diet-fed mice, whereas Atf3 ablation has the opposite effect. Mechanistically, Atf3 improves the reduction of fatty acid oxidation induced by glucose via forkhead box O1 (FoxO1) and Cd36. Atf3 inhibits FoxO1 activity via blocking Hdac1-mediated FoxO1 deacetylation at K242, K245, and K262 and increases Zdhhc4/5-mediated CD36 palmitoylation at C3, C7, C464, and C466; furthermore, macrophage Atf3 decreases hepatocytes lipogenesis and HSCs activation via retinol binding protein 4 (Rbp4). Anti-Rbp4 can prevent MASH progression that is induced by Atf3 deficiency in macrophages. This study identifies Atf3 as a regulator of glucose-fatty acid cycle. Targeting macrophage Atf3 or Rbp4 may be a plausible therapeutic strategy for MASH.

The Prevalence and Risk Analysis of Cerebral Palsy and Other Neuro-Psychological Comorbidities in Children with Low Birth Weight in Taiwan: A Nationwide Population-Based Cohort Study.

Background: This study evaluated early childhood comorbidities of cerebral palsy (CP) in low birth weight (LBW) children and assessed the impact of maternal bio-psychosocial factors on CP risk in preterm infants of varying birth weights (BWs). Methods: Data from 15,181 preterm infants (2009-2013) and 151,810 controls were analyzed using Taiwan's National Health Insurance Research Database. CP prevalence and LBW-associated comorbidities were examined, and odds ratios (ORs) were calculated. Results: This study confirmed increasing prematurity and LBW rates in Taiwan, with LBW infants showing higher CP prevalence. Significant maternal risk factors included age extremes (<20 and >40 years). LBW infants exhibited higher risks for respiratory, circulatory, nervous system, and psycho-developmental comorbidities compared with controls, with the lowest BW having even higher ORs. Maternal factors such as family income, the number of hospital admissions, and length of hospital stay were remarkably correlated with BW and subsequent complications. Each additional gestational week crucially reduced the risk of complications in premature infants. Conclusions: LBW infants are at a higher risk for CP and various comorbidities, with maternal bio-psychosocial factors playing a critical role. Addressing these factors in prenatal care and interventions is essential to improve outcomes for premature infants.

Krüppel-like factor 10 protects against metabolic dysfunction-associated steatohepatitis by regulating HNF4α-mediated metabolic pathways.

BACKGROUND: Krüppel-like factor 10 (KLF10), a zinc finger transcription factor, plays a pivotal role in modulating TGF-ß-mediated cellular processes such as growth, apoptosis, and differentiation. Recent studies have implicated KLF10 in regulating lipid metabolism and glucose homeostasis. This study aimed to elucidate the precise role of hepatic KLF10 in developing metabolic dysfunction-associated steatohepatitis (MASH) in diet-induced obese mice. METHODS: We investigated hepatic KLF10 expression under metabolic stress and the effects of overexpression or ablation of hepatic KLF10 on MASH development and lipidemia. We also determined whether hepatocyte nuclear factor 4α (HNF4α) mediated the metabolic effects of KLF10. RESULTS: Hepatic KLF10 was downregulated in MASH patients and genetically or diet-induced obese mice. AAV8-mediated overexpression of KLF10 in hepatocytes prevented Western diet-induced hypercholesterolemia and steatohepatitis, whereas inactivation of hepatocyte KLF10 aggravated Western diet-induced steatohepatitis. Mechanistically, KLF10 reduced hepatic triglyceride and free fatty acid levels by inducing lipolysis and fatty acid oxidation and inhibiting lipogenesis, and reducing hepatic cholesterol levels by promoting bile acid synthesis. KLF10 highly induced HNF4α expression by directly binding to its promoter. The beneficial effect of KLF10 on MASH development was abolished in mice lacking hepatocyte HNF4α. In addition, the inactivation of KLF10 in hepatic stellate cells exacerbated Western diet-induced liver fibrosis by activating the TGF-ß/SMAD2/3 pathway. CONCLUSIONS: Our data collectively suggest that the transcription factor KLF10 plays a hepatoprotective role in MASH development by inducing HNF4α. Targeting hepatic KLF10 may offer a promising strategy for treating MASH.

LINC00540 promotes sorafenib resistance and functions as a ceRNA for miR-4677-3p to regulate AKR1C2 in hepatocellular carcinoma.

Sorafenib resistance is one of the main causes of poor prognosis in patients with advanced hepatocellular carcinoma (HCC). Long noncoding RNAs (lncRNAs) function as suppressors or oncogenic factors during tumor progression and drug resistance. Here, to identify therapeutic targets for HCC, the biological mechanisms of abnormally expressed lncRNAs were examined in sorafenib-resistant HCC cells. Specifically, we established sorafenib-resistant HCC cell lines (Huh7-S and SMMC7721-S), which displayed an epithelial-mesenchymal transition (EMT) phenotype. Transcriptome sequencing (RNA-Seq) was performed to established differential lncRNA expression profiles for sorafenib-resistant cells. Through this analysis, we identified LINC00540 as significantly up-regulated in sorafenib-resistant cells and a candidate lncRNA for further mechanistic investigation. Functionally, LINC00540 knockdown promoted sorafenib sensitivity and suppressed migration, invasion, EMT and the activation of PI3K/AKT signaling pathway in sorafenib-resistant HCC cells, whereas overexpression of LINC00540 resulted in the opposite effects in parental cells. LINC00540 functions as a competing endogenous RNA (ceRNA) by competitively binding to miR-4677-3p , thereby promoting AKR1C2 expression. This is the first study that demonstrates a role for LINC00540 in enhancing sorafenib resistance, migration and invasion of HCC cells through the LINC00540/miR-4677-3p/AKR1C2 axis, suggesting that LINC00540 may represent a potential therapeutic target and prognosis biomarker for HCC.

Hepatic FOXA3 overexpression prevents Western diet-induced obesity and MASH through TGR5.

Forkhead transcription factor 3 (FOXA3) has been shown to regulate metabolism and development. Hepatic FOXA3 is reduced in obesity and fatty liver disease. However, the role of hepatic FOXA3 in regulating obesity or steatohepatitis remains to be investigated. In this work, C57BL/6 mice were i.v. injected with AAV8-ALB-FOXA3 or the control virus. The mice were then fed a chow or Western diet for 16 weeks. The role of hepatic FOXA3 in energy metabolism and steatohepatitis was investigated. Plasma bile acid composition and the role of Takeda G protein-coupled receptor 5 (TGR5) in mediating the metabolic effects of FOXA3 were determined. Overexpression of hepatic FOXA3 reduced hepatic steatosis in chow-fed mice and attenuated Western diet-induced obesity and steatohepatitis. FOXA3 induced lipolysis and inhibited hepatic genes involved in bile acid uptake, resulting in elevated plasma bile acids. The beneficial effects of hepatic FOXA3 overexpression on Western diet-induced obesity and steatohepatitis were abolished in Tgr5-/- mice. Our data demonstrate that overexpression of hepatic FOXA3 prevents Western diet-induced obesity and steatohepatitis via activation of TGR5.

Effect of surface modification on the distribution of magnetic nanorings in hepatocellular carcinoma and immune cells.

Magnetic nanomaterial-mediated magnetic hyperthermia is a localized heating treatment modality that has been applied to treat aggressive cancer in clinics. In addition to being taken up by tumor cells to function in cancer therapy, magnetic nanomaterials can also be internalized by immune cells in the tumor microenvironment, which may contribute to regulating the anti-tumor immune effects. However, there exists little studies on the distribution of magnetic nanomaterials in different types of cells within tumor tissue. Herein, ferrimagnetic vortex-domain iron oxide nanorings (FVIOs) with or without the liver-cancer-targeting peptide SP94 have been successfully synthesized as a model system to investigate the effect of surface modification of FVIOs (with or without SP94) on the distribution of tumor cells and different immune cells in hepatocellular carcinoma (HCC) microenvironment of a mouse. The distribution ratio of FVIO-SP94s in tumor cells was 1.3 times more than that of FVIOs. Immune cells in the liver tumor microenvironment took up fewer FVIO-SP94s than FVIOs. In addition, myeloid cells were found to be much more amenable than lymphoid cells in terms of their ability to phagocytose nanoparticles. Specifically, the distributions of FVIOs/FVIO-SP94s in tumor-associated macrophages, dendritic cells, and myeloid-derived suppressor cells were 13.8%/12%, 3.7%/0.9%, and 6.3%/1.2%, respectively. While the distributions of FVIOs/FVIO-SP94s in T cells, B cells, and natural killer cells were 5.5%/0.7%, 3.0%/0.7%, and 0.4%/0.3%, respectively. The results described in this article enhance our understanding of the distribution of nanomaterials in the tumor microenvironment and provide a strategy for rational design of magnetic hyperthermia agents that can effectively regulate anti-tumor immune effects.

NADP+-dependent isocitrate dehydrogenase as a novel target for altering carbon flux to lipid accumulation and enhancing antioxidant capacity in Tetradesmus obliquus.

Regulatory complexities in lipogenesis hinder the harmonization of metabolic carbon precursors towards lipid synthesis. Exploring regulatory complexities in lipogenesis, this study identifies NADP+-dependent isocitrate dehydrogenase (IDH) in Tetradesmus obliquus as a key factor. Overexpression IDH in strains ToIDH-1 and ToIDH-2 resulted in a 1.69 and 1.64-fold increase in neutral lipids, respectively, compared to the wild type, with lipid yield reaching 234.56 and 227.17 mg/L. Notably, despite slower growth, the cellular biomass augmented to 790.67 mg/L. Metabolite analysis indicated a shift in carbon precursors from protein to lipid and carbohydrate synthesis. Morphological observations revealed increases in the volume and number of lipid droplets, alongside a change in the fatty acid profile favoring monounsaturated and saturated fatty acids. Furthermore, IDH overexpression enhanced NADPH production and antioxidant activity, thereby further boosting lipid accumulation when combined with salt stress. This study suggests a pathway for improved lipogenesis and algal growth via metabolic engineering.

A Significant Association between Type 1 Diabetes and Helicobacter pylori Infection: A Meta-Analysis Study.

Background and Objectives: Type 1 diabetes mellitus (T1DM) is a chronic and serious condition that is characterized by inadequate pancreatic-ß-cells' insulin production. The connection between T1DM and Helicobacter pylori infection remains uncertain. This study aimed to conduct a systematic meta-analysis to examine the association between H. pylori infection, hemoglobin A1c levels, and the development of T1DM. Materials and Methods: The initial search identified 451 articles on the association between H. pylori infection and T1DM. Among them, 12 articles had 2797 participants who met the inclusion criteria for an advanced meta-analysis. Results: A significant association was observed between H. pylori infection and T1DM (OR 1.77, 95% CI 1.47-2.12, p < 0.0001), with heterogeneity: Tau2 = 0.47; Chi2 = 57.07, df = 11 (p < 0.0001); I2 = 81%. Subgroup analysis showed that H. pylori infection was significantly associated with a longer duration of T1DM and higher hemoglobin A1c levels (p < 0.001 for both) but not with age at T1DM diagnosis (p = 0.306). Conclusions: These findings contribute to the understanding of the association between H. pylori infection and T1DM and highlight the potential role of H. pylori in influencing the duration and glycemic control of diabetes. Therefore, pediatric patients who have longstanding T1DM and poor glycemic control should be screened for H. pylori infection.

Adipocyte retinoic acid receptor α prevents obesity and steatohepatitis by regulating energy expenditure and lipogenesis.

OBJECTIVE: The adipose tissue-liver axis is a major regulator of the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Retinoic acid signaling plays an important role in development and metabolism. However, little is known about the role of adipose retinoic acid signaling in the development of obesity-associated NAFLD. In this work, the aim was to investigate whether and how retinoic acid receptor alpha (RARα) regulated the development of obesity and NAFLD. METHODS: RARα expression in adipose tissue of db/db or ob/ob mice was determined. Rarαfl/fl mice and adipocyte-specific Rarα-/- (RarαAdi-/- ) mice were fed a chow diet for 1 year or high-fat diet (HFD) for 20 weeks. Primary adipocytes and primary hepatocytes were co-cultured. Metabolic regulation and inflammatory response were characterized. RESULTS: RARα expression was reduced in adipose tissue of db/db or ob/ob mice. RarαAdi-/- mice had increased obesity and steatohepatitis (NASH) when fed a chow diet or HFD. Loss of adipocyte RARα induced lipogenesis and inflammation in adipose tissue and the liver and reduced thermogenesis. In the co-culture studies, loss of RARα in adipocytes induced inflammatory and lipogenic programs in hepatocytes. CONCLUSIONS: The data demonstrate that RARα in adipocytes prevents obesity and NASH via inhibiting lipogenesis and inflammation and inducing energy expenditure.

Single-cell transcriptomics reveals ferrimagnetic vortex iron oxide nanoring-mediated mild magnetic hyperthermia exerts antitumor effects by alleviating macrophage suppression in breast cancer.

The potential of Ferrimagnetic vortex iron oxide nanoring-mediated mild magnetic hyperthermia (FVIO-MHT) in solid tumor therapy has been demonstrated. However, the impact of FVIO-MHT on the tumor microenvironment (TME) remains unclear. This study utilized single-cell transcriptome sequencing to examine the alterations in the TME in response to FVIO-MHT in breast cancer. The results revealed the cellular composition within the tumor microenvironment (TME) was primarily modified due to a decrease in tumor cells and an increased infiltration of myeloid cells. Subsequently, an enhancement in active oxygen (ROS) metabolism was observed, indicating oxidative damage to tumor cells. Interestingly, FVIO-MHT reprogrammed the macrophages' phenotypes, as evidenced by alterations in the transcriptome characteristics associated with both classic and alternative activated phenotypes. And an elevated level of ROS generation and oxidative phosphorylation suggested that activated phagocytosis and inflammation occurred in macrophages. Additionally, cell-cell communication analysis revealed that FVIO-MHT attenuated the suppression between tumor cells and macrophages by inhibiting phagocytic checkpoint and macrophage migration inhibitory factor signaling pathways. Inhibition of B2m, an anti-phagocytosis checkpoint, could promote macrophage-mediated phagocytosis and significantly inhibit tumor growth. These data emphasize FVIO-MHT may promote the antitumor capabilities of macrophages by alleviating the suppression between tumor cells and macrophages.

Development of an automated Raman system and use of principal component analysis to classify real and counterfeit liquors.

We developed an automated Raman measurement platform for the customized design of various solution containers. We used the software LabVIEW to integrate the entire automatic measurement process. By designing an intuitive human-machine interface, the user only needs to input a few setting parameters and can efficiently operate the machine in automation mode for an array of solutions containing real or counterfeit liquors such as kaoliang liquor, vodka, rum, gin, rice wine, ethanol, and methanol. In this study, data from various alcoholic beverage solutions were subjected to principal component analysis (PCA) to distinguish from the low-concentration counterfeit liquors (methanol <50 g L-1). Moreover, several brands of liquors with the same alcohol concentration were successfully classified into different groups based on a combination of Raman spectroscopy and PCA analysis.

Hepatocytic lipocalin-2 controls HDL metabolism and atherosclerosis via Nedd4-1-SR-BI axis in mice.

High-density lipoprotein (HDL) metabolism is regulated by complex interplay between the scavenger receptor group B type 1 (SR-BI) and multiple signaling molecules in the liver. Here, we show that lipocalin-2 (Lcn2) is a key regulator of hepatic SR-BI, HDL metabolism, and atherosclerosis. Overexpression of human Lcn2 in hepatocytes attenuates the development of atherosclerosis via SR-BI in western-diet-fed Ldlr-/- mice, whereas hepatocyte-specific ablation of Lcn2 has the opposite effect. Mechanistically, hepatocyte Lcn2 improves HDL metabolism and alleviates atherogenesis by blocking Nedd4-1-mediated SR-BI ubiquitination at K500 and K508. The Lcn2-improved HDL metabolism is abolished in mice with hepatocyte-specific Nedd4-1 or SR-BI deletion and in SR-BI (K500A/K508A) mutation mice. This study identifies a regulatory axis from Lcn2 to HDL via blocking Nedd4-1-mediated SR-BI ubiquitination and demonstrates that hepatocyte Lcn2 may be a promising target to improve HDL metabolism to treat atherosclerotic cardiovascular diseases.

Hepatocyte Sirtuin 6 Protects against Atherosclerosis and Steatohepatitis by Regulating Lipid Homeostasis.

Histone deacetylase Sirtuin 6 (SIRT6) regulates many biological processes. SIRT6 is known to regulate hepatic lipid metabolism and inhibit the development of nonalcoholic fatty liver disease (NAFLD). We aimed to investigate the role of hepatocyte SIRT6 in the development of atherosclerosis and further characterize the mechanism underlying SIRT6's effect on NAFLD. Ldlr-/- mice overexpressing or lacking hepatocyte SIRT6 were fed a Western diet for 16 weeks. The role of hepatic SIRT6 in the development of nonalcoholic steatohepatitis (NASH), atherosclerosis, and obesity was investigated. We also investigated whether p53 participates in the pathogenesis of NAFLD in mice overexpressing hepatic SIRT6. Our data show that loss of hepatocyte SIRT6 aggravated the development of NAFLD, atherosclerosis, and obesity in Ldlr-/- mice, whereas adeno-associated virus (AAV)-mediated overexpression of human SIRT6 in the liver had opposite effects. Mechanistically, hepatocyte SIRT6 likely inhibited the development of NAFLD by inhibiting lipogenesis, lipid droplet formation, and p53 signaling. Hepatocyte SIRT6 also likely inhibited the development of atherosclerosis by inhibiting intestinal lipid absorption and hepatic VLDL secretion. Hepatic SIRT6 also increased energy expenditure. In conclusion, our data indicate that hepatocyte SIRT6 protects against atherosclerosis, NAFLD, and obesity by regulating lipid metabolism in the liver and intestine.

Activating transcription factor 3, glucolipid metabolism, and metabolic diseases.

Lipids and glucose exert many essential physiological functions, such as providing raw materials or energy for cellular biosynthesis, regulating cell signal transduction, and maintaining a constant body temperature. Dysregulation of lipid and glucose metabolism can lead to glucolipid metabolic disorders linked to various metabolic diseases, such as obesity, diabetes, and cardiovascular disease. Therefore, intervention in glucolipid metabolism is a key therapeutic strategy for the treatment of metabolic diseases. Activating transcription factor 3 (ATF3) is a transcription factor that acts as a hub of the cellular adaptive-response network and plays a pivotal role in the regulation of inflammation, apoptosis, DNA repair, and oncogenesis. Emerging evidence has illustrated the vital roles of ATF3 in glucolipid metabolism. ATF3 inhibits intestinal lipid absorption, enhances hepatic triglyceride hydrolysis and fatty acid oxidation, promotes macrophage reverse cholesterol transport, and attenuates the progression of western diet-induced nonalcoholic fatty liver disease and atherosclerosis. In addition to its role in lipid metabolism, ATF3 has also been identified as an important regulator of glucose metabolism. Here, we summarize the recent advances in the understanding of ATF3, mainly focusing on its role in glucose and lipid metabolism and potential therapeutic implications.

Prenatal dexamethasone exposure induces anxiety- and depressive-like behavior of male offspring rats through intrauterine programming of the activation of NRG1-ErbB4 signaling in hippocampal PV interneurons.

Dexamethasone is a commonly used synthetic glucocorticoid in the clinic. As a compound that can cross the placental barrier to promote fetal lung maturation, dexamethasone is extensively used in pregnant women at risk of premature delivery. However, the use of glucocorticoids during pregnancy increases the risk of neurodevelopmental disorders. In the present study, we observed anxiety- and depressive-like behavior changes and hyperexcitability of hippocampal neurons in adult rat offspring with previous prenatal dexamethasone exposure (PDE); the observed changes were related to in utero damage of parvalbumin interneurons. A programmed change in neuregulin 1 (NRG1)-Erb-b2 receptor tyrosine kinase 4 (ErbB4) signaling was the key to the damage of parvalbumin interneurons in the hippocampus of PDE offspring. Anxiety- and depressive-like behavior, NRG1-ErbB4 signaling activation, and damage of parvalbumin interneurons in PDE offspring were aggravated after chronic stress. The intervention of NRG1-ErbB4 signaling contributed to the improvement in dexamethasone-mediated injury to parvalbumin interneurons. These results suggested that PDE might cause anxiety- and depressive-like behavior changes in male rat offspring through the programmed activation of NRG1-ErbB4 signaling, resulting in damage to parvalbumin interneurons and hyperactivity of the hippocampus. Intrauterine programming of neuregulin 1 (NRG1)-Erb-b2 receptor tyrosine kinase 4 (ERBB4) overactivation by dexamethasone mediates anxiety- and depressive-like behavior in male rat offspring.

Retinoic Acid Receptor Alpha (RARα) in Macrophages Protects from Diet-Induced Atherosclerosis in Mice.

Retinoic acid signaling plays an important role in regulating lipid metabolism and inflammation. However, the role of retinoic acid receptor alpha (RARα) in atherosclerosis remains to be determined. In the current study, we investigated the role of macrophage RARα in the development of atherosclerosis. Macrophages isolated from myeloid-specific Rarα-/- (RarαMac-/-) mice showed increased lipid accumulation and inflammation and reduced cholesterol efflux compared to Rarαfl/fl (control) mice. All-trans retinoic acid (AtRA) induced ATP-binding cassette subfamily A member 1 (Abca1) and Abcg1 expression and cholesterol efflux in both RarαMac-/- mice and Rarαfl/fl mice. In Ldlr-/- mice, myeloid ablation of RARα significantly reduced macrophage Abca1 and Abcg1 expression and cholesterol efflux, induced inflammatory genes, and aggravated Western diet-induced atherosclerosis. Our data demonstrate that macrophage RARα protects against atherosclerosis, likely via inducing cholesterol efflux and inhibiting inflammation.

Hepatic retinoic acid receptor alpha mediates all-trans retinoic acid's effect on diet-induced hepatosteatosis.

All-trans retinoic acid (AtRA) is an active metabolite of vitamin A that influences many biological processes in development, differentiation, and metabolism. AtRA functions through activation of retinoid acid receptors (RARs). AtRA is shown to ameliorate hepatic steatosis, but the underlying mechanism is not well understood. In this study, we investigated the role of hepatocyte RAR alpha (RARα) in mediating the effect of AtRA on hepatosteatosis in mice. Hepatocyte-specific Rarα-/- (L-Rarα-/- ) mice and their control mice were fed a chow diet, high-fat diet (HFD), or a high-fat/cholesterol/fructose (HFCF) diet. Some of the mice were also treated with AtRA. Loss of hepatocyte RARα-induced hepatosteatosis in chow-fed aged mice and HFD-fed mice. AtRA prevented and reversed HFCF diet-induced obesity and hepatosteatosis in the control mice but not in L-Rarα-/- mice. Furthermore, AtRA reduced hepatocyte fatty acid uptake and lipid droplet formation, dependent on hepatocyte RARα. Our data suggest that hepatocyte RARα plays an important role in preventing hepatosteatosis and mediates AtRA's effects on diet-induced hepatosteatosis.

A novel approach to button battery removal in a two-and-half year-old patient's esophagus after ingestion: a case report.

BACKGROUND: Accidental swallowing of a foreign body occurs more frequently in children than in adults. Among these cases, button battery impaction in the esophagus may cause severe complications. While prevention is always ideal, if button battery impaction is suspected, immediate diagnosis and retrieval are important. CASE PRESENTATION: We introduce a novel method for retrieval of a button battery after ingestion by a 2.5-year-old child. When the patient arrived at our center, the battery was incarcerated in the upper esophagus. The battery could not be removed, despite the use of several methods such as alligator forceps under endoscopy and net retrieval. We decided to use a novel method that combined endoscopic balloon extraction and forceps retrieval. This resulted in a push-and-pull effect, creating synergy and easy removal of the battery. There were no long term complications based on the follow-up endoscopy examination. CONCLUSIONS: This new procedure was very effective for removing the esophageal foreign body. When button battery in esophagus was too tight to be removed by the traditional retrieval methods, this procedure was suggested to use. It could be performed at medical institutions. If it fails or esophageal perforation (iatrogenic or spontaneous) occurs, pediatric surgeons could take over immediately.

Programming changes of hippocampal miR-134-5p/SOX2 signal mediate the susceptibility to depression in prenatal dexamethasone-exposed female offspring.

Depression is a neuropsychiatric disorder and has intrauterine developmental origins. This study aimed to confirm the depression susceptibility in offspring rats induced by prenatal dexamethasone exposure (PDE) and to further explore the intrauterine programming mechanism. Wistar rats were injected with dexamethasone (0.2 mg/kg·d) subcutaneously during the gestational days 9-20 and part of the offspring was given chronic stress at postnatal weeks 10-12. Behavioral results showed that the adult PDE female offspring was susceptible to depression, accompanied by increased hippocampal miR-134-5p expression and decreased sex-determining region Y-box 2 (SOX2) expression, as well as disorders of neural progenitor cells proliferation and hippocampal neurogenesis. The PDE female fetal rats presented consistent changes with the adult offspring, accompanied by the upregulation of glucocorticoid receptor (GR) expression and decreased sirtuin 1 (SIRT1) expression. We further found that the H3K9ac level of the miR-134-5p promoter was significantly increased in the PDE fetal hippocampus, as well as in adult offspring before and after chronic stress. In vitro, the changes of GR/SIRT1/miR-134-5p/SOX2 signal by dexamethasone were consistent with in vivo experiments, which could be reversed by GR receptor antagonist, SIRT1 agonist, and miR-134-5p inhibitor. This study confirmed that PDE led to an increased expression level as well as H3K9ac level of miR-134-5p by activating the GR/SIRT1 pathway in the fetal hippocampus and then inhibited the SOX2 expression. The programming effect mediated by the abnormal epigenetic modification could last from intrauterine to adulthood, which constitutes the intrauterine programming mechanism leading to hippocampal neurogenesis disorders and depression susceptibility in female offspring. Intrauterine programming mechanism for the increased depressive susceptibility in adult female offspring by prenatal dexamethasone exposure (PDE). GR, glucocorticoid receptor; SIRT1, sirtuin 1; SOX2, sex-determining region Y-box 2; NPCs, neuroprogenitor cells; H3K9ac, histone 3 lysine 9 acetylation; GRE, glucocorticoid response element.

Drug-Induced Esophageal Ulcer in Adolescent Population: Experience at a Single Medical Center in Central Taiwan.

Background and Objectives: Drug-induced esophageal ulcer is caused by focal drug stimulation. It may occur in adults and children. Limited research is available in pediatric patients with drug-induced esophageal ulcer; therefore, we designed this study to determine the characteristics of this disease in this population. Materials and Methods: Thirty-two pediatric patients diagnosed with drug-induced esophageal ulcers from a hospital database of upper gastrointestinal tract endoscopies were included. After treatment, patients were followed for 2 months after upper gastrointestinal endoscopy. Results: Female patients were predominant (56.2%/43.8%). The mean age of patients was 15.6 years (median, 16 years; interquartile range, 2 years). Doxycycline was administered in most cases (56.3%); other drugs were dicloxacillin, amoxicillin, clindamycin, L-arginine, and nonsteroidal anti-inflammatory drugs. Doxycycline was associated with kissing ulcers. Esophageal ulcers induced by nonsteroidal anti-inflammatory drugs were more often associated with gastric or duodenal ulcers. The most common location was the middle-third of the esophagus (78.1%). Patients were treated with proton pump inhibitors, sucralfate, or H2-blockers. The mean duration for which symptoms lasted was 9.2 days. No esophageal stricture was found in 24 patients who were followed for 2 months after upper gastrointestinal endoscopy. Conclusions: The authors suggest informing patients to take medicine with enough water (approximately 100 mL) and enough time (15-30 min) before recumbency, especially high-risk drugs, such as doxycycline or nonsteroidal anti-inflammatory drugs.