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Gastric mucins serve as a protective barrier on the stomach's surface, protecting from external stimuli including gastric acid and gut microbiota. Their composition typically changes in response to the metaplastic sequence triggered by Helicobacter pylori infection. This alteration in gastric mucins is also observed in cases of gastric cancer, although the precise connection between mucin expressions and gastric carcinogenesis remains uncertain. This review first introduces the relationship between mucin expressions and gastric metaplasia or cancer observed in humans and mice. Additionally, we discuss potential pathogenic mechanisms of how aberrant mucins and their glycans affect gastric carcinogenesis. Finally, we summarize challenges to target tumor‐specific glycans by utilizing lectin‐drug conjugates that can bind to specific glycans. Understanding the correlation and mechanism between these mucin expressions and gastric carcinogenesis could pave the way for new strategies in gastric cancer treatment. [ABSTRACT FROM AUTHOR]

During fasting, induction of hepatic gluconeogenesis is crucial to ensure proper energy homeostasis (1). Such induction is dysregulated in type 2 diabetes, resulting in the development of fasting hyperglycemia (2). [...]

Mutations in the coactivator CREB-binding protein (CBP) are a major cause of the human skeletal dysplasia Rubinstein-Taybi syndrome (RTS); however, the mechanism by which these mutations affect skeletal mineralization and patterning is unknown. Here, we report the identification of 3-phosphoinositide-dependent kinase 1 (PDK1) as a key regulator of CBP activity and demonstrate that its functions map to both osteoprogenitor cells and mature osteoblasts. In osteoblasts, PDK1 activated the CREB/CBP complex, which in turn controlled runt-related transcription factor 2 (RUNX2) activation and expression of bone morphogenetic protein 2 (BMP2). These pathways also operated in vivo, as evidenced by recapitulation of RTS spectrum phenotypes with osteoblast-specific Pdk1 deletion in mice [(Pdk1.sup.osx] mice) and by the genetic interactions observed in mice heterozygous for both osteoblast-specific Pdk1 deletion and either Runx2 or Creb deletion. Finally, treatment of [Pdk1.sup.osx] and [Cbp.sup.+/-] embryos with BMPs in utero partially reversed their skeletal anomalies at birth. These findings illustrate the in vivo function of the PDK1-AKT-CREB/CBP pathway in bone formation and provide proof of principle for in utero growth factor supplementation as a potential therapy for skeletal dysplasias., Introduction Rubinstein-Taybi syndrome (RTS) was first described in 1963 as a condition characterized by impaired intellectual function, broad thumbs and halluces, craniofacial dysmorphism, and frequent fractures (1), (2). Characteristic craniofacial [...]

A study uses fine-mapping techniques of SNPs in a region of chromosome 21q and identifies potassium inwardly-rectifying channel, subfamily J, member 15 (KCNJ15) as a previously unreported susceptibility gene in Asian patients with type 2 diabetes mellitus (T2DM). It also shows that the KCNJ15 gene is expressed in human pancreatic beta cells, and demonstrates that a synonymous variant in KCNJ15 is significantly associated in T2DM among Asians.

Pancreatic β cell failure is thought to underlie the progression from glucose intolerance to overt diabetes, and ER stress is implicated in such β cell dysfunction. We have now shown that the transcription factor CCAAT/enhancer-binding protein β (C/EBPβ) accumulated in the islets of diabetic animal models as a result of ER stress before the onset of hyperglycemia. Transgenic overexpression of C/EBPβ specifically in β cells of mice reduced β cell mass and lowered plasma insulin levels, resulting in the development of diabetes. Conversely, genetic ablation of C/EBPβ in the β cells of mouse models of diabetes, including Akita mice, which harbor a heterozygous mutation in Ins2 ([Ins2.sup.[WT/C96Y]]), and leptin receptor-deficient ([Lepr.sup.[-/-]]) mice, resulted in an increase in β cell mass and ameliorated hyperglycemia. The accumulation of C/EBPβ in pancreatic β cells reduced the abundance of the molecular chaperone glucose-regulated protein of 78 kDa (GRP78) as a result of suppression of the transactivation activity of the transcription factor ATF6α, thereby increasing the vulnerability of these cells to excess ER stress. Our results thus indicate that the accumulation of C/EBPβ in pancreatic β cells contributes to β cell failure in mice by enhancing susceptibility to ER stress., Introduction The prevalence of type 2 diabetes is increasing rapidly in many industrialized nations, with the total number of people with this condition projected to reach 300 million worldwide by [...]

The 3-phosphoinositide-dependent kinase-1 (PDK1) plays an important role in the regulation of cellular responses in multiple organs by mediating the phosphoinositide 3-kinase (PI3-K) signaling pathway through activating AGC kinases. Here we defined the role of PDK1 in controlling cardiac homeostasis. Cardiac expression of PDK1 was significantly decreased in murine models of heart failure. Tamoxifen-inducible and heart-specific disruption of Pdkl in adult mice caused severe and lethal heart failure, which was associated with apoptotic death of cardiomyocytes and [[beta].sub.1]-adrenergic receptor (AR) down-regulation. Overexpression of Bcl-2 protein prevented cardiomyocyte apoptosis and improved cardiac function. In addition, PDK1-deficient hearts showed enhanced activity of PI3-K[gamma], leading to robust [[beta].sub.1]-AR internalization by forming complex with [beta]-AR kinase 1 ([beta]ARK1). Interference of [beta]ARK1/PI3-K[gamma], complex formation by transgenic overexpression of phosphoinositide kinase domain normalized [[beta].sub.1]-AR trafficking and improved cardiac function. Taken together, these results suggest that PDK1 plays a critical role in cardiac homeostasis in vivo by serving as a dual effector for cell survival and [beta]-adrenergic response. AGC kinase | apoptosis | heart failure | receptor internalization

White adipocytes are unique in that they contain large unilocular lipid droplets that occupy most of the cytoplasm. To identify genes involved in the maintenance of mature adipocytes, we expressed dominant-negative PPAR[gamma] in 3T3-L1 cells and performed a microarray screen. The fat-specific protein of 27 kDa (FSP27) was strongly downregulated in this context. FSP27 expression correlated with induction of differentiation in cultured preadipocytes, and the protein localized to lipid droplets in murine white adipocytes in vivo. Ablation of FSP27 in mice resulted in the formation of multilocular lipid droplets in these cells. Furthermore, FSP27-deficient mice were protected from diet-induced obesity and insulin resistance and displayed an increased metabolic rate due to increased mitochondrial biogenesis in white adipose tissue (WAT). Depletion of FSP27 by siRNA in murine cultured white adipocytes resulted in the formation of numerous small lipid droplets, increased lipolysis, and decreased triacylglycerol storage, while expression of FSP27 in COS cells promoted the formation of large lipid droplets. Our results suggest that FSP27 contributes to efficient energy storage in WAT by promoting the formation of unilocular lipid droplets, thereby restricting lipolysis. In addition, we found that the nature of lipid accumulation in WAT appears to be associated with maintenance of energy balance and insulin sensitivity., Introduction Obesity is associated with various complications such as insulin resistance, type 2 diabetes, dyslipidemia, and atherosclerosis (1), (2). It results from an imbalance between energy intake and energy expenditure [...]

Insulin receptor substrate (IRS)-1 and IRS-2 have dominant roles in the action of insulin (1), but other substrates of the insulin receptor kinase, such as Gabl, c-Cbl, SH2-B and APS, are also of physiological relevance (2-5). Although the protein downstream of tyrosine kinases-1 (Dok1) is known to function as a multisite adapter molecule in insulin signaling (6-8), its role in energy homeostasis has remained unclear. Here we show that Dok1 regulates adiposity. Expression of Dok1 in white adipose tissue was markedly increased in mice fed a high-fat diet, whereas adipocytes lacking this adapter were smaller and showed a reduced hypertrophic response to this dietary manipulation. Dok1-deficient mice were leaner and showed improved glucose tolerance and insulin sensitivity compared with wild-type mice. Embryonic fibroblasts from Dok1-deficient mice were impaired in adipogenic differentiation, and this defect was accompanied by an increased activity of the protein kinase ERK and a consequent increase in the phosphorylation of peroxisome proliferator-activated receptor (PPAR)-[gamma] on Ser112. Mutation of this negative regulatory site for the transactivation activity of PPAR-[gamma] blocked development of the lean phenotype caused by Dok1 ablation. These results indicate that Dok1 promotes adipocyte hypertrophy by counteracting the inhibitory effect of ERK on PPAR-[gamma] and may thus confer predisposition to diet-induced obesity., We and others have shown that tyrosine-phosphorylated Dok1 binds and recruits p120 Ras GTPase-activating protein (rasGAP) as well as the adapter protein Nck, thereby regulating mitogenic signaling mediated by Ras [...]

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.cell.2007.04.028 Byline: Yasuhiro Takashima (1)(3), Takumi Era (1), Kazuki Nakao (2), Saki Kondo (4), Masato Kasuga (3), Austin G. Smith (5), Shin-Ichi Nishikawa (1) Keywords: STEMCELL Abstract: Mesenchymal stem cells (MSCs) are defined as cells that undergo sustained in vitro growth and are able to give rise to multiple mesenchymal lineages. Although MSCs are already used in regenerative medicine little is known about their in vivo behavior and developmental derivation. Here, we show that the earliest wave of MSC in the embryonic trunk is generated from Sox1.sup.+ neuroepithelium but not from mesoderm. Using lineage marking by direct gfp knock-in and Cre-recombinase mediated lineage tracing, we provide evidence that Sox1.sup.+ neuroepithelium gives rise to MSCs in part through a neural crest intermediate stage. This pathway can be distinguished from the pathway through which Sox1.sup.+ cells give rise to oligodendrocytes by expression of PDGFR[beta] and A2B5. MSC recruitment from this pathway, however, is transient and is replaced by MSCs from unknown sources. We conclude that MSC can be defined as a definite in vivo entity recruited from multiple developmental origins. Author Affiliation: (1) Laboratory for Stem Cell Biology, Riken Center for Developmental Biology, 2-2-3 Minatojima-minamimachi, Chuo-ku, Kobe, 650-0047, Japan (2) Laboratory for Animal Resources and Genetic Engineering, Riken Center for Developmental Biology, 2-2-3 Minatojima-minamimachi, Chuo-ku, Kobe, 650-0047, Japan (3) Department of Clinical Molecular Medicine, Division of Diabetes and Digestive and Kidney Diseases, Kobe University Graduate School of Medicine, 7-5-1 Kusunokimachi, Chuo-ku, Kobe, 650-0017, Japan (4) Laboratory of Molecular Genetics, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan (5) Institute for Stem Cell Biology, University of Cambridge, Cambridge, CB2, 1QT, UK Article History: Received 14 September 2006; Revised 16 February 2007; Accepted 9 April 2007 Article Note: (miscellaneous) Published: June 28, 2007

It is now well accepted that diabetes mellitus is one of the main threats to human health in the twenty-first century. The total number of people with diabetes worldwide was [...]