Background-Ischemic heart disease is the greatest cause of death in Western countries. The deleterious effects of cardiac ischemia are ameliorated by ischemic preconditioning (IPC), in which transient ischemia protects against subsequent severe ischemia/reperfusion injury. IPC activates multiple signaling pathways, including the reperfusion injury salvage kinase pathway (mainly PI3K-Akt-glycogen synthase kinase-3␤ [GSK3␤] and ERK1/2) and the survivor activating factor enhancement pathway involving activation of the JAK-STAT3 axis. Nevertheless, the fundamental mechanism underlying IPC is poorly understood. Methods and Results-In the present study, we define MG53, a muscle-specific TRIM-family protein, as a crucial component of cardiac IPC machinery. Ischemia/reperfusion or hypoxia/oxidative stress applied to perfused mouse hearts or neonatal rat cardiomyocytes, respectively, causes downregulation of MG53, and IPC can prevent ischemia/ reperfusion-induced decrease in MG53 expression. MG53 deficiency increases myocardial vulnerability to ischemia/ reperfusion injury and abolishes IPC protection. Overexpression of MG53 attenuates whereas knockdown of MG53 enhances hypoxia-and H 2 O 2 -induced cardiomyocyte death. The cardiac protective effects of MG53 are attributable to MG53-dependent interaction of caveolin-3 with phosphatidylinositol 3 kinase and subsequent activation of the reperfusion injury salvage kinase pathway without altering the survivor activating factor enhancement pathway. Conclusions-These results establish MG53 as a primary component of the cardiac IPC response, thus identifying a potentially important novel therapeutic target for the treatment of ischemic heart disease. (Circulation. 2010;121:2565-2574.)Key Words: hypoxia Ⅲ ischemia Ⅲ myocardial infarction Ⅲ myocytes Ⅲ stress I schemic heart disease remains the greatest cause of mortality in Western countries and the predicted leading source of mortality worldwide by 2020. 1 Blockage of heart blood flow leads to myocardial ischemia. Persistent ischemia causes myocardial infarctions, resulting in profound myocyte death, irreversible myocardial damage, and a permanent loss of contractile mass. Timely reperfusion of ischemic heart is the only way to preserve cardiac cell viability. However, reperfusion can trigger further damage to the myocardium (ie, ischemia/reperfusion [IR] injury) via reactive oxygen species-induced oxidative stress, calcium overload, or calpain activation. [2][3][4] Both ischemic injury and subsequent IR injury after restoration of blood flow represent important therapeutic targets. Editorial on p 2547 Clinical Perspective on p 2574Interventional approaches against IR injury have centered on the study of ischemic preconditioning (IPC), in which nonlethal ischemic stress to the heart (IPC) protects against subsequent lethal IR injury in the heart. 5-7 IPC is the most powerful intrinsic cellular mechanism to protect the heart as well as other organs, such as brain, liver, and kidney, from IR injury. 8 -11 A variety of signaling mo...

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BackgroundPancreatic carcinoma (PC) is one of the most aggressive cancers affecting human health. It is essential to identify candidate biomarkers for the diagnosis and prognosis of PC. The present study aimed to investigate the diagnosis and prognosis biomarkers of PC.MethodsDifferentially expressed genes (DEGs) were identified from the mRNA expression profiles of GSE62452, GSE28735 and GSE16515. Functional analysis and the protein-protein interaction network analysis was performed to explore the biological function of the identified DEGs. Diagnosis markers for PC were identified using ROC curve analysis. Prognosis markers were identified via survival analysis of TCGA data. The protein expression pattern of the identified genes was verified in clinical tissue samples. A retrospective clinical study was performed to evaluate the correlation between the expression of candidate proteins and survival time of patients. Moreover, comprehensive analysis of the combination of multiple genes/proteins for the prognosis prediction of PC was performed using both TCGA data and clinical data. In vitro studies were undertaken to elaborate the potential roles of these biomarkers in clonability and invasion of PC cells.FindingsIn total, 389 DEGs were identified. These genes were mainly associated with pancreatic secretion, protein digestion and absorption, cytochrome P450 drug metabolism, and energy metabolism pathway. The top 10 genes were filtered out following Fisher's exact test. ROC curve analysis demonstrated that TMPRSS4, SERPINB5, SLC6A14, SCEL, and TNS4 could be used as biomarkers for the diagnosis of PC. Survival analysis of TCGA data and clinical data suggested that TMC7, TMPRSS4, SCEL, SLC2A1, CENPF, SERPINB5 and SLC6A14 can be potential biomarkers for the prognosis of PC. Comprehensive analysis show that a combination of identified genes/proteins can predict the prognosis of PC. Mechanistically, the identified genes attributes to clonability and invasiveness of PC cells.InterpretationWe synthesized several sets of public data and preliminarily clarified pathways and functions of PC. Candidate molecular markers were identified for diagnosis and prognosis prediction of PC including a novel gene, TMC7. Moreover, we found that the combination of TMC7, TMPRSS4, SCEL, SLC2A1, CENPF, SERPINB5 and SLC6A14 can serve as a promising indicator of the prognosis of PC patients. The candidate proteins may attribute to clonability and invasiveness of PC cells. This research provides a novel insight into molecular mechanisms as well as diagnostic and prognostic markers of PC.Fund [No. 81602646 & 81802339], [No. 2016A030310254] and [No. 2016M600648].

Lactose is the main carbohydrate in human and mammalian milk. Lactose requires enzymatic hydrolysis by lactase into D-glucose and D-galactose before it can be absorbed. Term infants express sufficient lactase to digest about one liter of breast milk daily. Physiological lactose malabsorption in infancy confers beneficial prebiotic effects, including the establishment of Bifidobacterium-rich fecal microbiota. In many populations, lactase levels decline after weaning (lactase non-persistence; LNP). LNP affects about 70% of the world’s population and is the physiological basis for primary lactose intolerance (LI). Persistence of lactase beyond infancy is linked to several single nucleotide polymorphisms in the lactase gene promoter region on chromosome 2. Primary LI generally does not manifest clinically before 5 years of age. LI in young children is typically caused by underlying gut conditions, such as viral gastroenteritis, giardiasis, cow’s milk enteropathy, celiac disease or Crohn’s disease. Therefore, LI in childhood is mostly transient and improves with resolution of the underlying pathology. There is ongoing confusion between LI and cow’s milk allergy (CMA) which still leads to misdiagnosis and inappropriate dietary management. In addition, perceived LI may cause unnecessary milk restriction and adverse nutritional outcomes. The treatment of LI involves the reduction, but not complete elimination, of lactose-containing foods. By contrast, breastfed infants with suspected CMA should undergo a trial of a strict cow’s milk protein-free maternal elimination diet. If the infant is not breastfed, an extensively hydrolyzed or amino acid-based formula and strict cow’s milk avoidance are the standard treatment for CMA. The majority of infants with CMA can tolerate lactose, except when an enteropathy with secondary lactase deficiency is present.

Aberrant expression of microRNA (miR)-1 has been observed in many human malignancies. However, the function and underlying mechanism of miR-1 remains elusive. To address the specific role of miR-1 in tumor glycolysis using the gain- or loss-of-function studies. Metabolic studies combined with gene expression analysis were performed in vitro and in vivo. We demonstrated aberrant expression of miR-1 in aerobic glycolysis, the Warburg effect, in cancer cells. MiR-1 suppressed aerobic glycolysis and tumor cell proliferation via inactivation of Smad3 and targeting HIF-1α, leading to reduce HK2 and MCT4 expression, which illustrated a novel pathway to mediate aerobic glycolysis in cancer cells. Overexpression of miR-1 mimics significantly decreased tumor glycolysis, including lactate production and glucose uptake, and cell proliferation, and these effects were reversed by ectopic expression of Smad3. Importantly, endogenous Smad3 regulated and interacted with HIF-1α, resulting in increasing activity of Smad3, and this interaction was dramatically abolished by addition of miR-1. We further demonstrated that Smad3 was central to the effects of miR-1 in colorectal cancer cells, establishing a previously unappreciated mechanism by which the miR-1/Smad3/HIF-1α axis facilitates the Warburg effect to promote cancer progression in vitro and in vivo. The results indicate that miR-1 may have an essential role as a tumor suppressor, suggesting its potential role in molecular therapy of patients with advanced colorectal cancer.