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The epithelial cell adhesion molecule (EpCAM) is a single transmembrane protein on the cell surface. Given its strong expression on epithelial cells and epithelial cell-derived tumors, EpCAM has been identified as a biomarker for circulating tumor cells (CTCs) and exosomes and a target for cancer therapy. As a cell adhesion molecule, EpCAM has a crystal structure that indicates that it forms a cis-dimer first and then probably a trans-tetramer to mediate intercellular adhesion. Through regulated intramembrane proteolysis (RIP), EpCAM and its proteolytic fragments are also able to regulate multiple signaling pathways, Wnt signaling in particular. Although great progress has been made, increasingly more findings have revealed the context-specific expression and function patterns of EpCAM and their regulation processes, which necessitates further studies to determine the structure, function, and expression of EpCAM under both physiological and pathological conditions, broadening its application in basic and translational cancer research. [ABSTRACT FROM AUTHOR]

Objective: Diabetes is one of the most distinct comorbidities of COVID-19. Here, we describe the clinical characteristics of and outcomes in patients with diabetes in whom COVID-19 was confirmed or clinically diagnosed (with typical features on lung imaging and symptoms) and their association with glucose-lowering or blood pressure-lowering medications.Research Design and Methods: In this retrospective study involving 904 patients with COVID-19 (136 with diabetes, mostly type 2 diabetes), clinical and laboratory characteristics were collected and compared between the group with diabetes and the group without diabetes, and between groups taking different medications. Logistic regression was used to explore risk factors associated with mortality or poor prognosis.Results: The proportion of comorbid diabetes is similar between cases of confirmed and of clinically diagnosed COVID-19. Risk factors for higher mortality of patients with diabetes and COVID-19 were older age (adjusted odds ratio [aOR] 1.09 [95% CI 1.04, 1.15] per year increase; P = 0.001) and elevated C-reactive protein (aOR 1.12 [95% CI 1.00, 1.24]; P = 0.043). Insulin usage (aOR 3.58 [95% CI 1.37, 9.35]; P = 0.009) was associated with poor prognosis. Clinical outcomes of those who use an ACE inhibitor (ACEI) or angiotensin II type-I receptor blocker (ARB) were comparable with those of patients who do not use ACEI/ARB among COVID-19 patients with diabetes and hypertension.Conclusions: C-reactive protein may help to identify patients with diabetes who are at greater risk of dying during hospitalization. Older patients with diabetes were prone to death related to COVID-19. Attention needs to be paid to patients with diabetes and COVID-19 who use insulin. ACEI/ARB use showed no significant impact on patients with diabetes and hypertension who have COVID-19. [ABSTRACT FROM AUTHOR]

Key points: Diabetic kidney disease (DKD) is a major complication of diabetes. We found that UTX (ubiquitously transcribed tetratricopeptide repeat on chromosome X, also known as KDM6A), a histone demethylase, was upregulated in the renal mesangial and tubular cells of diabetic mice and DKD patients.In cultured renal mesangial and tubular cells, UTX overexpression promoted palmitic acid‐induced elevation of inflammation and DNA damage, whereas UTX knockdown or GSK‐J4 treatment showed the opposite effects.We found that UTX demethylase activity‐dependently regulated the transcription of inflammatory genes and apoptosis; moreover, UTX bound with p53 and p53‐dependently exacerbated DNA damage.Administration of GSK‐J4, an H3K27 demethylase inhibitor, ameliorated the diabetes‐induced renal abnormalities in db/db mice, an animal model of type 2 diabetes.These results revealed the possible mechanisms underlying the regulation of histone methylation in DKD and suggest UTX as a potential therapeutic target for DKD. Diabetic kidney disease (DKD) is a microvascular complication of diabetes and the leading cause of end‐stage kidney disease worldwide without effective therapy available. UTX (ubiquitously transcribed tetratricopeptide repeat on chromosome X, also known as KDM6A), a histone demethylase that removes the di‐ and tri‐methyl groups from histone H3K27, plays important biological roles in gene activation, cell fate control and life span regulation in Caenorhabditis elegans. In the present study, we report upregulated UTX in the kidneys of diabetic mice and DKD patients. Administration of GSK‐J4, an H3K27 demethylase inhibitor, ameliorated the diabetes‐induced renal dysfunction, abnormal morphology, inflammation, apoptosis and DNA damage in db/db mice, comprising an animal model of type 2 diabetes. In cultured renal mesanglial and tubular cells, UTX overexpression promoted palmitic acid induced elevation of inflammation and DNA damage, whereas UTX knockdown or GSK‐J4 treatment showed the opposite effects. Mechanistically, we found that UTX demethylase activity‐dependently regulated the transcription of inflammatory genes; moreover, UTX bound with p53 and p53‐dependently exacerbated DNA damage. Collectively, our results suggest UTX as a potential therapeutic target for DKD. Key points: Diabetic kidney disease (DKD) is a major complication of diabetes. We found that UTX (ubiquitously transcribed tetratricopeptide repeat on chromosome X, also known as KDM6A), a histone demethylase, was upregulated in the renal mesangial and tubular cells of diabetic mice and DKD patients.In cultured renal mesangial and tubular cells, UTX overexpression promoted palmitic acid‐induced elevation of inflammation and DNA damage, whereas UTX knockdown or GSK‐J4 treatment showed the opposite effects.We found that UTX demethylase activity‐dependently regulated the transcription of inflammatory genes and apoptosis; moreover, UTX bound with p53 and p53‐dependently exacerbated DNA damage.Administration of GSK‐J4, an H3K27 demethylase inhibitor, ameliorated the diabetes‐induced renal abnormalities in db/db mice, an animal model of type 2 diabetes.These results revealed the possible mechanisms underlying the regulation of histone methylation in DKD and suggest UTX as a potential therapeutic target for DKD. [ABSTRACT FROM AUTHOR]

Acetaminophen (APAP) overdose is a major cause of acute liver failure, while the underlying mechanisms of APAP hepatotoxicity are not fully understood. Recently, emerging evidence suggests that epigenetic enzymes play roles in APAP-induced liver injury. Here, we found that Utx (ubiquitously transcribed tetratricopeptide repeat, X chromosome, also known as KDM6A), a X-linked histone demethylase which removes the di- and tri-methyl groups from histone H3K27, was markedly induced in the liver of APAP-overdosed female mice. Hepatic deletion of Utx suppressed APAP overdose-induced hepatotoxicity in female but not male mice. RNA-sequencing analysis suggested that Utx deficiency in female mice upregulated antitoxic phase II conjugating enzymes, including sulfotransferase family 2 A member 1 (Sult2a1), thus reduces the amount of toxic APAP metabolites in injured liver; while Utx deficiency also alleviated ER stress through downregulating transcription of ER stress genes including Atf4 , Atf3 , and Chop. Mechanistically, Utx promoted transcription of ER stress related genes in a demethylase activity-dependent manner, while repressed Sult2a1 expression through mediating H3K27ac levels independent of its demethylase activity. Moreover, overexpression of Sult2a1 in the liver of female mice rescued APAP-overdose induced liver injury. Together, our results indicated a novel UTX-Sult2a1 axis for the prevention or treatment of APAP-induced liver injury. [Display omitted] • Utx is induced in the liver of female mouse upon APAP overdose. • Loss of Utx suppresses APAP-induced liver injury in female but not male mouse. • Utx gender-specifically regulates antitoxic phase II conjugating enzyme Sult2a1. • Utx demethylase-dependently induces ER stress and represses Sult2a1 independently. • Overexpression of Sult2a1 rescues APAP-induced hepatotoxicity in female mouse. [ABSTRACT FROM AUTHOR]

The migration, dedifferentiation, and proliferation of vascular smooth muscle cells (VSMCs) are responsible for intimal hyperplasia, but the mechanism of this process has not been elucidated. WD repeat domain 1 (WDR1) promotes actin-depolymerizing factor (ADF)/cofilin-mediated depolymerization of actin filaments (F-actin). The role of WDR1 in neointima formation and progression is still unknown. A model of intimal thickening was constructed by ligating the left common carotid artery in Wdr1 deletion mice, and H&E staining showed that Wdr1 deficiency significantly inhibits neointima formation. We also report that STAT3 promotes the proliferation and migration of VSMCs by directly promoting WDR1 transcription. Mechanistically, we clarified that WDR1 promotes the proliferation and migration of VSMCs and neointima formation is regulated by the activation of the JAK2/STAT3/WDR1 axis.

Abnormalities of methyl-CpG binding protein 2 (Mecp2) cause neurological disorders with metabolic dysfunction; however, its role in adipose tissues remains unclear. Here, we report upregulated Mecp2 in white adipose tissues (WAT) of obese humans, as well as in obese mice and during in vitro adipogenesis. Normal chow-fed adipocyte-specific Mecp2 knockout mice ( Mecp2 Adi KO mice) showed a lean phenotype, with downregulated lipogenic genes and upregulated thermogenic genes that were identified using RNA sequencing. Consistently, the deficiency of Mecp2 in adipocytes protected mice from high-fat diet (HFD)-induced obesity and inhibited in vitro adipogenesis. Furthermore, Mecp2 Adi KO mice showed increased browning under different stimuli, including cold treatment. Mechanistically, Mecp2 bound to the promoter of secretory leukocyte protease inhibitor ( Slpi ) and negatively regulated its expression. Knockdown of Slpi in inguinal WAT of Mecp2 Adi KO mice prevented cold-induced browning. Moreover, recombinant SLPI treatment reduced the HFD-induced obesity via enhancing browning. Together, our results suggest a novel non-central nervous system function of Mecp2 in obesity by suppressing browning, at least partially, through regulating adipokine Slpi., (© 2019 by the American Diabetes Association.)

Scope: The number of people with diabetes is increasing rapidly in the world. In the present study, the hypoglycemic activity and potential mechanism of ergosterol (ERG), a phytosterol derived from the edible mushroom Pleurotus ostreatus are investigated in vitro and in vivo., Methods and Results: ERG is isolated from Pleurotus ostreatus and identified by NMR spectra. The effects of ERG on the glucose uptake, glucose transporter 4 (GLUT4) translocation, GLUT4 expression, and the phosphorylation of AMPK, Akt and PKC in L6 cells are evaluated. ERG enhances glucose uptake and displays a GLUT4 translocation activity with up-regulating GLUT4 expression and phosphorylation of Akt and PKC in L6 cells. In vivo, antidiabetic activity of ERG is examined. The phosphorylation of Akt and PKC in different tissues from KK-A y mice is assessed. ERG significantly improves insulin resistance and blood lipid indices while reducing fasting blood glucose levels and protecting pancreas and liver in the mice. Moreover, the phosphorylation of Akt and PKC is increased in different tissues., Conclusion: The results suggest that ERG may be a potential hypoglycemic agent for the treatment of T2DM with the probable mechanism of stimulating GLUT4 translocation and expression modulated by the PI3K/Akt pathway and PKC pathway., (© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: Chloroquine, a bitter tastant, inhibits Ca 2+ signaling, resulting in suppression of B cell activation; however, the inhibitory mechanism remains unclear., Results: In this study, thapsigargin (TG), but not caffeine, induced sustained intracellular Ca 2+ increases in mouse splenic primary B lymphocytes, which were markedly inhibited by chloroquine. Under Ca 2+ -free conditions, TG elicited transient Ca 2+ increases, which additionally elevated upon the restoration of 2 mM Ca 2+ . The former were from release of intracellular Ca 2+ store and the latter from Ca 2+ influx. TG-induced release was inhibited by 2-APB (an inhibitor of inositol-3-phosphate receptors, IP 3 Rs) and chloroquine, and TG-caused influx was inhibited by pyrazole (Pyr3, an inhibitor of transient receptor potential C3 (TRPC3) and stromal interaction molecule (STIM)/Orai channels) and chloroquine. Moreover, chloroquine also blocked Ca 2+ increases induced by the engagement of B cell receptor (BCR) with anti-IgM., Conclusions: These results indicate that chloroquine inhibits Ca 2+ elevations in splenic B cells through inhibiting Ca 2+ permeable IP 3 R and TRPC3 and/or STIM/Orai channels. These findings suggest that chloroquine would be a potent immunosuppressant.