Overexpression of hepatocyte growth factor/scatter factor promotes vascularization and granulation tissue formation in vivo

AbstractThe effect of hepatocyte growth factor/scatter factor (HGF/SF) during wound healing in the skin was investigated, using HGF/SF-overexpressing transgenic mouse model. Histological analysis of HGF/SF transgenic mouse excisional wound sites revealed increased granulation tissue with marked vascularization. Northern blot analysis demonstrated that, relative to control, vascular endothelial growth factor (VEGF) expression in transgenic skin was significantly higher at baseline and was robustly up-regulated during wound healing. Elevated levels of VEGF protein were detected immunohistochemically, predominantly in endothelial cells and fibroblasts within the granulation tissue of HGF/SF transgenic skin. Serum levels of VEGF were also elevated in HGF/SF transgenic mice. Thus, results from our study suggest that HGF/SF has a significant effect on vascularization and granulation tissue formation during wound healing in vivo, involving with induction of VEGF

Involvement of SIK3 in Glucose and Lipid Homeostasis in Mice

Salt-inducible kinase 3 (SIK3), an AMP-activated protein kinase-related kinase, is induced in the murine liver after the consumption of a diet rich in fat, sucrose, and cholesterol. To examine whether SIK3 can modulate glucose and lipid metabolism in the liver, we analyzed phenotypes of SIK3-deficent mice. Sik3−/− mice have a malnourished the phenotype (i.e., lipodystrophy, hypolipidemia, hypoglycemia, and hyper-insulin sensitivity) accompanied by cholestasis and cholelithiasis. The hypoglycemic and hyper-insulin-sensitive phenotypes may be due to reduced energy storage, which is represented by the low expression levels of mRNA for components of the fatty acid synthesis pathways in the liver. The biliary disorders in Sik3−/− mice are associated with the dysregulation of gene expression programs that respond to nutritional stresses and are probably regulated by nuclear receptors. Retinoic acid plays a role in cholesterol and bile acid homeostasis, wheras ALDH1a which produces retinoic acid, is expressed at low levels in Sik3−/− mice. Lipid metabolism disorders in Sik3−/− mice are ameliorated by the treatment with 9-cis-retinoic acid. In conclusion, SIK3 is a novel energy regulator that modulates cholesterol and bile acid metabolism by coupling with retinoid metabolism, and may alter the size of energy storage in mice

Adenomyoma of the small intestine

Adenomyoma of the gastrointestinal tract is a rare benign tumor-like lesion. The small intestine is the second most frequent location, usually in the periampullary area, but the lesion also occurs in the jejunum and ileum. While adenomyoma of the Vaterian system is primarily diagnosed in adults, more than half of reported cases of jejunal and ileal adenomyoma have been diagnosed in pediatric patients. Adenomyoma of the periampullary area usually presents with biliary obstruction or abdominal pain, whereas jejunal and ileal adenomyoma usually presents with intussusception or is incidentally discovered during surgery or autopsy. Since endoscopic and radiological examination yields uncharacteristic findings, histopathological evaluation is important in adenomyoma diagnosis. Pathologically, adenomyoma consists of glandular structures of various sizes and interlacing smooth muscle bundles that surround the glandular elements. The pathogenesis of adenomyoma is generally considered to be either a form of hamartoma or a pancreatic heterotopia. Although limited resection is considered the most effective treatment, pancreaticoduodenectomy is often performed when the lesion occurs in the periampullary area due to preoperative misdiagnosis as a carcinoma. It is, therefore, important that clinicians and pathologists maintain current knowledge of the disease to avoid inaccurate diagnosis, which could lead to unnecessary surgery

Pediatric nonalcoholic fatty liver disease: Overview with emphasis on histology

Nonalcoholic fatty liver disease (NAFLD) is a disease in which excessive fat accumulates in the liver of a patient without a history of alcohol abuse. This disease includes simple steatosis and nonalcoholic steatohepatitis (NASH). NAFLD/NASH is recognized as a hepatic manifestation of metabolic syndrome. In recent years, pediatric NAFLD has increased in line with the increased prevalence of pediatric obesity. The estimated prevalence of pediatric NAFLD is 2.6%-9.6%, and it is associated with sex, age, and ethnicity. With regard to the pathogenesis of NAFLD, the “two-hit” hypothesis is widely accepted and oxidative stress is thought to play an important role in the second hit. Although clinical symptoms, laboratory data, and imaging findings are important, liver biopsy is regarded as the gold standard for the diagnosis of NAFLD/NASH. In addition, liver biopsy is essential for assessing the degree of necro-inflammatory change and fibrosis in NASH. Two different types of steatohepatitis (type 1 and type 2 NASH) have been reported, with type 2 NASH being present in as many as 51% of pediatric NAFLD patients. However, we and others have observed that type 1 and 2 patterns commonly overlap. Although pharmacotherapy has been studied in clinical trials, lifestyle modification by diet and exercise remains the mainstay of treatment for NAFLD/NASH

Animal models of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis

Nonalcoholic fatty liver disease (NAFLD) is a condition in which excess fat accumulates in the liver of a patient without a history of alcohol abuse. Nonalcoholic steatohepatitis (NASH), a severe form of NAFLD, can progress to liver cirrhosis and hepatocellular carcinoma. NAFLD is regarded as a hepatic manifestation of metabolic syndrome and incidence has been increasing worldwide in line with the increased prevalence of obesity, type 2 diabetes, and hyperlipemia. Animal models of NAFLD/NASH give crucial information, not only in elucidating pathogenesis of NAFLD/NASH but also in examining therapeutic effects of various agents. An ideal model of NAFLD/NASH should correctly reflect both hepatic histopathology and pathophysiology of human NAFLD/NASH. Animal models of NAFLD/NASH are divided into genetic, dietary, and combination models. In this paper, we review commonly used animal models of NAFLD/NASH referring to their advantages and disadvantages

Plexiform angiomyxoid myofibroblastic tumor of the stomach

Plexiform angiomyxoid myofibroblastic tumor of the stomach is a unique mesenchymal tumor that we first described in 2007. The tumor is very rare, and to date, only 18 cases confirmed by immunohistochemistry have been reported in the literature. The patients’ ages ranged from 7 to 75 years (mean, 43 years), and the male-to-female ratio was approximately 1:1. Representative clinical symptoms are ulceration, associated upper gastrointestinal bleeding (hematemesis), and anemia. The tumors are located at the antrum in all cases, and grossly, the tumor is whitish to brownish or reddish, and forms a lobulated submucosal or transmural mass. Microscopically, the tumor is characterized by a plexiform growth pattern, the proliferation of cytologically bland spindle cells, and a myxoid stroma that is rich in small vessels and positive for Alcian blue stain. Immunohistochemically, the tumor cells are positive for α-smooth muscle actin and negative for KIT and CD34. Differential diagnoses include gastrointestinal stromal tumor and other mesenchymal tumors of the gastrointestinal tract. Some authors proposed that this tumor should be designated as “plexiform fibromyxoma”, but this designation might cause confusion. The tumor is probably benign and thus far, neither recurrence nor metastasis has been reported

Protein induced by vitamin K absence or antagonist II-producing gastric cancer

Protein induced by vitamin K absence or antagonist II (PIVKA-II) is a putative specific marker of hepatocellular carcinoma (HCC), but it may also be produced by a small number of gastric cancers. To date, 16 cases of PIVKA-II-producing gastric cancer have been reported, 2 of which were reported by us and all of which were identified in Japan. There are no symptoms specific to PIVKA-II-producing gastric cancer, and the representative clinical symptoms are general fatigue, appetite loss, and upper abdominal pain. Serum alpha-fetoprotein (AFP) levels are also increased in almost all cases. Liver metastasis is observed in approximately 80% of cases and portal vein tumor thrombus is observed in approximately 20% of cases. Differential diagnosis between metastatic liver tumor and HCC is often difficult. Grossly, almost all cases appear as advanced gastric cancer. Histologically, a hepatoid pattern is observed in many cases, in addition to a moderately to poorly differentiated adenocarcinoma component. The production of PIVKA-II and AFP is usually confirmed using immunohistochemical staining. Treatment and prognosis largely depends on the existence of liver metastasis, and the prognosis of patients with liver metastasis is very poor. PIVKA-II may be produced during the hepatocellularmetaplasia of the tumor cells

Artificial intelligence and deep learning: New tools for histopathological diagnosis of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis

Nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) is associated with metabolic syndrome and is rapidly increasing globally with the increased prevalence of obesity. Although noninvasive diagnosis of NAFLD/NASH has progressed, pathological evaluation of liver biopsy specimens remains the gold standard for diagnosing NAFLD/NASH. However, the pathological diagnosis of NAFLD/NASH relies on the subjective judgment of the pathologist, resulting in non-negligible interobserver variations. Artificial intelligence (AI) is an emerging tool in pathology to assist diagnoses with high objectivity and accuracy. An increasing number of studies have reported the usefulness of AI in the pathological diagnosis of NAFLD/NASH, and our group has already used it in animal experiments. In this minireview, we first outline the histopathological characteristics of NAFLD/NASH and the basics of AI. Subsequently, we introduce previous research on AI-based pathological diagnosis of NAFLD/NASH