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Obesity is a risk factor for gastrointestinal malignancies and tumors. However, which factors either protect or predispose the gastrointestinal organs to high-fat diet (HFD)-induced neoplasia remains unclear. Here, we demonstrate that HFD impacts the stomach to a greater extent as compared to the colorectum, resulting in leptin receptor (LepR) signaling-mediated neoplasia in the tissues. HFD activated leptin signaling, which in turn, accelerates the pathogenesis in the gastric mucosa more than that in the colorectum along with ectopic TFF3 expression. Moreover, in the stomach, higher levels of phosphorylated epidermal growth factor receptor (EGFR) in addition to the activation of STAT3 and Akt were observed as compared to the colorectum. The mice with LepR deletion in the gastrointestinal epithelium exhibited a suppressed induction of leptin, TFF3, and phosphorylated EGFR in the stomach, whereas the levels in the colorectum were insignificant. In co-transfected COS-7 cells with LepR and EGFR plasmid DNA, leptin transactivated EGFR to accelerate TFF3 induction along with activation of STAT3, ERK1/2, Akt, and PI3K p85/p55. Furthermore, TFF3 could bind to EGFR but did not transactivate LepR. Leptin-induced TFF3 induction was markedly suppressed by inhibitors of PI3K (LY294002) and EGFR (Erlotinib). Together, these results suggest a novel role of LepR-mediated signaling in transactivating EGFR that leads to TFF3 expression via the PI3K-Akt pathway. Therefore, this study sheds light on the identification of potentially new therapeutic targets for the treatment of pre-cancerous symptoms in stomach and colorectum., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Obesity increases the risk for gastric cancers. However, the occurrence and mechanisms of precancerous atrophic gastritis induced by high-fat diet (HFD) remain unclear. Here, we show that HFD-associated lipotoxicity induces precancerous lesions that are accompanied by the disruption of organelle homeostasis, tissue integrity, and deregulated expression of stemness genes in the gastric epithelium mediated by leptin receptor (ObR) signaling. Following HFD feeding, ectopic fat accumulated and expression of LAMP2A in lysosome and COX IV in mitochondria increased in the gastric mucosa. HFD feeding also led to enhanced expression of activated-Notch1 and stem cell markers Lgr5, CD44, and EpCAM. In addition, HFD-fed mice showed intracellular β-catenin accumulation in the gastric mucosa with increased expression of its target genes, Nanog, Oct4, and c-Myc. These observations were abrogated in the leptin-deficient ob/ob mice and ObR-mutated db/db mice, indicating that these HFD-induced changes were responsible for effects downstream of the ObR. Consistent with this, the expression of the Class IA and III PI3Ks was increased following ObR activation in the gastric mucosa of HFD-fed mice. Together, these results suggest that HFD-induced lipotoxicity and deregulated organelle biosynthesis confer cancer stem cell-like properties to the gastric mucosa via signaling pathway mediated by leptin, PI3K and β-catenin., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Integrin αIIbβ3 plays key roles in platelet aggregation and subsequent thrombus formation. Hydrogen peroxide-inducible clone-5 (Hic-5), a member of the paxillin family, serves as a focal adhesion adaptor protein associated with αIIbβ3 at its cytoplasmic strand., Objectives: Hic-5 function in αIIbβ3 activation and subsequent platelet aggregation remains unknown. To address this question, platelets from Hic-5(-/-) mice were analyzed., Methods and Results: Hic-5(-/-) mice displayed a significant hemostatic defect and resistance to thromboembolism, which were explained in part by weaker thrombin-induced aggregation in Hic-5(-/-) platelets. Mechanistically, Hic-5(-/-) platelets showed limited activation of αIIbβ3 upon thrombin treatment. Morphological alteration in Hic-5(-/-) platelets after thrombin stimulation on fibrinogen plates was also limited. As a direct consequence, the quantity of actin co-immunoprecipitating with the activated αIIbβ3 was smaller in Hic-5(-/-) platelets than in wild-type platelets., Conclusion: We identified Hic-5 as a novel and specific regulatory factor for thrombin-induced αIIbβ3 activation and subsequent platelet aggregation in mice., (© 2012 International Society on Thrombosis and Haemostasis.)

Objective: Human salusin-alpha and -beta are two-related peptides processed from the same precursor, preprosalusin. Our previous in vitro studies have shown that human macrophage foam cell formation is stimulated by salusin-beta but suppressed by salusin-alpha. Thus we investigated the effects of salusin-alpha and -beta on atherosclerotic plaque formation in vivo in apolipoprotein E-deficient (ApoE-/-) mice., Methods: Saline (vehicle), salusin-alpha or -beta (0.6 nmol/kg/h) was continuously infused through osmotic mini-pumps into 13-week-old ApoE-/- mice for 8 weeks. Aortic atherosclerosis, oxidized LDL-induced cholesterol ester accumulation (foam cell formation), and its related gene expression in exudate peritoneal macrophages were determined., Results: After 4-week infusion of salusin-beta, atherosclerotic lesions were 2.6 times greater than vehicle controls, which paralleled 1.9-fold increase in foam cell formation and up-regulation of scavenger receptors (CD36, scavenger receptor class A) and acyl-CoA: cholesterol acyltransferase-1 (ACAT1). In contrast, salusin-alpha decreased serum total cholesterol levels by 15% and foam cell formation by 68% associated with ACAT1 down-regulation. After 8-week infusion of salusin-alpha, atherosclerotic lesions were significantly suppressed by 54% compared with vehicle controls., Conclusions: Our study provided the first evidence that salusin-beta accelerates the development of atherosclerotic lesions associated with up-regulation of scavenger receptors and ACAT1 in ApoE-/- mice. Whilst, salusin-alpha exerts anti-atherosclerotic effects by suppressing serum total cholesterol levels and ACAT1 expression., (Copyright 2010 Elsevier Ireland Ltd. All rights reserved.)

Tumor necrosis factor (TNF) plays important roles in host defense and in preventing tumor formation by acting via its receptors, TNFR1 and TNFR2, functions of which are less understood. To this end, we have been isolating TNF receptor-selective mutants using phage display technique. However, generation of a phage library with large repertoire (>10(8)) is impeded by the limited transformation efficiency of Escherichia coli. Therefore, it is currently difficult to create a mutant library containing amino acid substitutions in more than seven residues. To overcome this problem, here we have used two different TNF mutant libraries, each containing random substitutions at six selected amino acid residues, and utilized a gene shuffling method to construct a randomized mutant library containing substitutions at 12 different amino acid residues of TNF. Consequently, using this library, we identified TNF mutants with greater receptor-selectivity and enhanced receptor-specific bioactivity than the existing mutants.

Six calves, aged between 55 days and 15 months, were presented between September and November 2006 with neurological signs including limb weakness and circling. Microscopical examination of the brain and spinal cord revealed the presence of non-suppurative encephalitis in all animals. Perivascular cuffing of lymphocytes and macrophages and diffuse gliosis was prominent in the cerebrum and degeneration and/or necrosis of neurons with vacuolation of the neuropil was present in the brainstem. Neuronal necrosis and neuronophagia were noted in the ventral horn of the spinal cord. The distribution of the lesions was closely related to the clinical signs displayed by each calf. Five calves presenting with astasia with low head carriage or torticollis had lesions throughout the central nervous system (CNS). The oldest calf displayed astasia caused by weakness of the "hindlimb" one word and had lesions largely restricted to the caudal spinal cord. Akabane virus (AKAV) antigens were detected immunohistochemically within neurons and axons in lesional tissue. Virus was not isolated from CNS tissue but the AKAV S gene was detected in this tissue from five calves by reverse transcriptase polymerase chain reaction (RT-PCR). It is suggested that AKAV infection is likely to have occurred during the early life period in the calves of this study.

Objective: The aim of this study was to compare the clinical efficacy of new caries detecting dye Caries Check Blue (CCB) with Caries Check (CC) and Caries Detector (CD) using a laser fluorescence device (DIAGNOdent)., Method: Primary and permanent teeth with dentin caries were stained with polypropylene glycol (MW=300) based new caries detecting dyes CCB, CC, or propylene glycol (MW=76) based CD. In the CCB and CC groups, stained dentin was completely removed. In the CD groups, pink-stained dentin was retained according to the manufacturers' instructions. Cavities before and after caries removal were measured with the DIAGNOdent. Data were analyzed using ANOVA and Fisher's PLSD multiple comparison test at alpha=0.05. Regression analyses were performed between DIAGNOdent readings and scores obtained from the clinical parameters., Results: The DIAGNOdent readings after caries removal were: primary-CCB (13.2+/-10.4), primary-CC (14.3+/-16.7), primary-CD (9.0+/-5.2), permanent-CCB (22.7+/-13.4), permanent-CC (10.6+/-6.8) and permanent-CD (9.7+/-9.0). Significant differences were identified between the permanent-CCB and all other groups. Correlation coefficients between DIAGNOdent readings and clinical parameters were low., Conclusions: When dentin stained with Caries Check Blue or Caries Check was completely removed, the DIAGNOdent readings were higher than those recorded when palely-stained pink dentin was retained with the Caries Detector, with significant difference observed for the permanent-CCB group. Caries Check Blue may be used clinically to avoid excessive removal of caries-affected or sound dentin in permanent teeth but not in primary teeth.

It is well known that cadmium (Cd) causes renal dysfunction such as increase of beta(2)-microglobulin excretion into urine. Although Cd in rice seems to be one of the largest sources of total Cd intake in Japan, there are very few studies that have epidemiologically clarified the relationship between Cd concentration in rice (Cd-R) and renal dysfunction, because such studies are basically ecological studies, in which confounding factors are difficult to take into consideration. To derive safety levels for foodstuff from Cd-R, it is essential to evaluate the effect of confounding factors. Thus, we investigated the dose-response relationship between renal dysfunction and not only Cd-R but also confounding factors, and we tried to determine whether Cd-R is an adequate indicator of "dose" in the dose-response relationship between Cd intake and renal dysfunction. In 1971, Cd-R data were obtained from rice samples collected by the Environment Agency, Government of Japan in the Fuchu area of Toyama Prefecture, which is known as a place where many itai-itai disease patients were found, and medical data were collected during 1979-1984 by Toyama Prefecture. First, the dose-response relationship between Cd-R and renal dysfunction was analyzed using the data from the Fuchu area. Second, to investigate the effect of confounding factors, analysis using the data from both the Fuchu area and an unpolluted area with environmental factors different from those of the Fuchu area was performed. The results showed that the cause of renal dysfunction could not be explained by Cd-R alone, and confounding factors were not negligible. Although it is difficult to clarify precisely the confounding factors from the available data, it is concluded that deriving a safety level for foodstuffs using only the Cd-R level as a reference is not appropriate., (Copyright 2000 Academic Press.)