Lysosomal cholesterol overload in macrophages promotes liver fibrosis in a mouse model of NASH.

Accumulation of lipotoxic lipids, such as free cholesterol, induces hepatocyte death and subsequent inflammation and fibrosis in the pathogenesis of nonalcoholic steatohepatitis (NASH). However, the underlying mechanisms remain unclear. We have previously reported that hepatocyte death locally induces phenotypic changes in the macrophages surrounding the corpse and remnant lipids, thereby promoting liver fibrosis in a murine model of NASH.

Dietary Supplementation With Eicosapentaenoic Acid Inhibits Plasma Cell Differentiation and Attenuates Lupus Autoimmunity.

Accumulating evidence suggests that cholesterol accumulation in leukocytes is causally associated with the development of autoimmune diseases. However, the mechanism by which fatty acid composition influences autoimmune responses remains unclear. To determine whether the fatty acid composition of diet modulates leukocyte function and the development of systemic lupus erythematosus, we examined the effect of eicosapentaenoic acid (EPA) on the pathology of lupus in drug-induced and spontaneous mouse models.

Macrophages rely on extracellular serine to suppress aberrant cytokine production.

A growing body of evidence indicates that cellular metabolism is involved in immune cell functions, including cytokine production. Serine is a nutritionally non-essential amino acid that can be generated by de novo synthesis and conversion from glycine. Serine contributes to various cellular responses, but the role in inflammatory responses remains poorly understood.

Upregulation of cancer-associated gene expression in activated fibroblasts in a mouse model of non-alcoholic steatohepatitis.

Non-alcoholic steatohepatitis (NASH), characterized by chronic inflammation and fibrosis, is predicted to be the leading cause of cirrhosis and hepatocellular carcinoma (HCC) in the next decade. Although recent evidence suggests the importance of fibrosis as the strongest determinant of HCC development, the molecular mechanisms underlying NASH-induced carcinogenesis still remain unclear. Here we performed RNA sequencing analysis to compare gene expression profiles of activated fibroblasts prepared from two distinct liver fibrosis models: carbon tetrachloride-induced fibrosis as a model without obesity and HCC and genetically obese melanocortin 4 receptor-deficient (MC4R-KO) mice fed Western diet, which develop steatosis, NASH, and eventually HCC.

Obeticholic acid protects against hepatocyte death and liver fibrosis in a murine model of nonalcoholic steatohepatitis.

Accumulating evidence has suggested that farnesoid X receptor (FXR) agonists, such as obeticholic acid (OCA) are therapeutically useful for non-alcoholic steatohepatitis (NASH). However, it is still unclear how FXR agonists protect against NASH and which cell type is the main target of FXR agonists. In this study, we examined the effects of OCA on the development of NASH using melanocortin 4 receptor-deficient (MC4R-KO) mice that progressively developed hepatic steatosis and NASH on Western diet (WD).

CD11c+ resident macrophages drive hepatocyte death-triggered liver fibrosis in a murine model of nonalcoholic steatohepatitis.

Although recent evidence has pointed to the role of organ- and pathogenesis-specific macrophage subsets, it is still unclear which subsets are critically involved in the pathogenesis of nonalcoholic steatohepatitis (NASH). Using melanocortin-4 receptor-deficient (MC4R-KO) mice fed Western diet (WD), which exhibit liver phenotypes similar to those of human NASH, we found a histological structure, termed hepatic crown-like structure (hCLS), in which CD11c+ macrophages surround dead/dying hepatocytes, a prominent feature of NASH. Here, we demonstrate that hCLS-constituting macrophages could be a novel macrophage subset that drives hepatocyte death-triggered liver fibrosis.

Synthetic "smart gel" provides glucose-responsive insulin delivery in diabetic mice.

Although previous studies have attempted to create "electronics-free" insulin delivery systems using glucose oxidase and sugar-binding lectins as a glucose-sensing mechanism, no successful clinical translation has hitherto been made. These protein-based materials are intolerant of long-term use and storage because of their denaturing and/or cytotoxic properties. We provide a solution by designing a protein-free and totally synthetic material-based approach.

The H3K9 methyltransferase Setdb1 regulates TLR4-mediated inflammatory responses in macrophages.

Proinflammatory cytokine production in macrophages involves multiple regulatory mechanisms, which are affected by environmental and intrinsic stress. In particular, accumulating evidence has suggested epigenetic control of macrophage differentiation and function mainly in vitro. SET domain, bifurcated 1 (Setdb1, also known as Eset) is a histone 3 lysine 9 (H3K9)-specific methyltransferase and is essential for early development of embryos.

Macrophage-inducible C-type lectin underlies obesity-induced adipose tissue fibrosis.

In obesity, a paracrine loop between adipocytes and macrophages augments chronic inflammation of adipose tissue, thereby inducing systemic insulin resistance and ectopic lipid accumulation. Obese adipose tissue contains a unique histological structure termed crown-like structure (CLS), where adipocyte-macrophage crosstalk is known to occur in close proximity. Here we show that Macrophage-inducible C-type lectin (Mincle), a pathogen sensor for Mycobacterium tuberculosis, is localized to macrophages in CLS, the number of which correlates with the extent of interstitial fibrosis.

Activating transcription factor 4 links metabolic stress to interleukin-6 expression in macrophages.

Chronic inflammation is a molecular element of the metabolic syndrome and type 2 diabetes. Saturated fatty acids (SFAs) are considered to be an important proinflammatory factor. However, it is still incompletely understood how SFAs induce proinflammatory cytokine expression.

Increased expression of macrophage-inducible C-type lectin in adipose tissue of obese mice and humans.

Objective: We have provided evidence that saturated fatty acids, which are released from adipocytes via macrophage-induced adipocyte lipolysis, serve as a naturally occurring ligand for the Toll-like receptor (TLR) 4 complex in macrophages, thereby aggravating obesity-induced adipose tissue inflammation. The aim of this study was to identify the molecule(s) activated in adipose tissue macrophages in obesity.

Research Design And Methods: We performed a cDNA microarray analysis of coculture of 3T3-L1 adipocytes and RAW264 macrophages.

Activating transcription factor 3 constitutes a negative feedback mechanism that attenuates saturated Fatty acid/toll-like receptor 4 signaling and macrophage activation in obese adipose tissue.

Obese adipose tissue is markedly infiltrated by macrophages, suggesting that they may participate in the inflammatory pathways that are activated in obese adipose tissue. Evidence has suggested that saturated fatty acids released via adipocyte lipolysis serve as a naturally occurring ligand that stimulates Toll-like receptor (TLR)4 signaling, thereby inducing the inflammatory responses in macrophages in obese adipose tissue. Through a combination of cDNA microarray analyses of saturated fatty acid-stimulated macrophages in vitro and obese adipose tissue in vivo, here we identified activating transcription factor (ATF)3, a member of the ATF/cAMP response element-binding protein family of basic leucine zipper-type transcription factors, as a target gene of saturated fatty acids/TLR4 signaling in macrophages in obese adipose tissue.

Fluvastatin accelerates re-endothelialization impaired by local sirolimus treatment.

Sirolimus-eluting stent reduces restenosis after percutaneous coronary intervention. However, accumulating evidence suggests that sirolimus potentially affects re-endothelialization, leading to late thrombosis. Statins have protective effects on endothelium.

The mental health of Korean immigrants in São Paulo, Brazil.

This study investigated the frequency of lifetime mental disorders among Korean immigrants in the city of São Paulo, Brazil. Snowball sampling with multiple focuses was used to recruit Korean immigrants older than 18 years and living in São Paulo. A total of 324 Korean immigrants were selected and their mental status was evaluated using a structured interview, namely the Portuguese or the Korean version of the Composite International Diagnostic Interview 2.

Nicotine use in patients with schizophrenia evaluated by the Fagerström Tolerance Questionnaire: a descriptive analysis from a Brazilian sample.

Objective: This is a descriptive study to determine smoking prevalence rates in a convenience sample of patients with schizophrenia and to describe clinical/demographic variables for nicotine use in this population.

Method: Patients with schizophrenia were consecutively invited to answer a standard clinical/demographic questionnaire and a questionnaire on smoking habits (Fagerstrom Tolerance Questionnaire).

Results: Eighty-three patients were interviewed.

Attention in schizophrenia and in epileptic psychosis.

The adaptive behavior of human beings is usually supported by rapid monitoring of outstanding events in the environment. Some investigators have suggested that a primary attention deficit might trigger symptoms of schizophrenia. In addition, researchers have long discussed the relationship between schizophrenia and the schizophrenia-like psychosis of epilepsy (SLPE).

Atorvastatin attenuates transplant-associated coronary arteriosclerosis in a murine model of cardiac transplantation.

Accelerated coronary arteriosclerosis remains a major problem for the long-term survival of cardiac transplant recipients. However, the pathogenesis of transplant vasculopathy is poorly understood and there is no effective therapy. HMG-CoA reductase inhibitors, or statins, are widely prescribed to lower plasma cholesterol level.

How do experts recognize schizophrenia: the role of the disorganization symptom.

Objective: Research on clinical reasoning has been useful in developing expert systems. These tools are based on Artificial Intelligence techniques which assist the physician in the diagnosis of complex diseases. The development of these systems is based on a cognitive model extracted through the identification of the clinical reasoning patterns applied by experts within the clinical decision-making context.

Decision support system for the diagnosis of schizophrenia disorders.

Clinical decision support systems are useful tools for assisting physicians to diagnose complex illnesses. Schizophrenia is a complex, heterogeneous and incapacitating mental disorder that should be detected as early as possible to avoid a most serious outcome. These artificial intelligence systems might be useful in the early detection of schizophrenia disorder.

The role of circulating precursors in vascular repair and lesion formation.

The accumulation of smooth muscle cells (SMCs) plays a principal role in atherogenesis, post-angioplasty restenosis and transplantation-associated vasculopathy. Therefore, much effort has been expended in targeting the migration and proliferation of medial smooth muscle cells to prevent occlusive vascular remodeling. Recent evidence suggests that bone marrow-derived circulating precursors can also give rise to endothelial cells and smooth muscle cells that contribute to vascular repair, remodeling, and lesion formation under physiological and pathological conditions.

Ayahuasca in adolescence: a neuropsychological assessment.

The purpose of the study was to evaluate neuropsychologically adolescents who use ayahuasca in a religious context. A battery of neuropsychological tests was administered to adolescents who use ayahuasca. These subjects were compared to a matched control group of adolescents who did not use ayahuasca.

Effect of deuterium oxide on contraction characteristics and ATPase activity in glycerinated single rabbit skeletal muscle fibers.

We studied the effect of deuterium oxide (D(2)O) on contraction characteristics and ATPase activity of single glycerinated muscle fibers of rabbit psoas. D(2)O increased the maximum isometric force P(0) by about 20%, while the force versus stiffness relation did not change appreciably. The maximum shortening velocity under zero load V(max) did not change appreciably in D(2)O, so that the force-velocity (P-V) curve was scaled depending on the value of P(0).

[Endoscopic surgery for gynecologic malignancy--less invasive, more radical].

The development of endoscopic equipment and surgical skills make more complicated procedures possible laparoscopically. The application of these techniques to oncologic surgery, which used to be basically the most invasive procedure, has become an important issue when considering patient well-being. For cervical and endometrial cancer we can perform a simple hysterectomy, type II or a type II radical hysterectomy as well as a pelvic and para-aortic lymphadenectomy.