Apoptosis signal-regulating kinase 1 plays a pivotal role in angiotensin II-induced cardiac hypertrophy and remodeling

Multiple lines of evidence establish that angiotensin II (Ang II) induces not only hypertension but also directly contributes to cardiac diseases. Apoptosis signal-regulating kinase 1 (ASK1), one of mitogen-activated protein kinase kinase kinases, plays a key role in stress-induced cellular responses. However, nothing is known about the role of ASK1 in cardiac hypertrophy and remodeling in vivo. In this study, by using mice deficient in ASK1 (ASK1-/- mice), we investigated the role of ASK1 in cardiac hypertrophy and remodeling induced by Ang II. Left ventricular (LV) ASK1 was activated by Ang II infusion in wild-type mice, which was mediated by angiotensin II type 1 receptor and superoxide. Although Ang II-induced hypertensive effect was comparable to wild-type and ASK1-/- mice, LV ASK1 activation by Ang II was not detectable in ASK1-/- mice, and p38 and c-Jun N-terminal kinase (JNK) activation was lesser in ASK-/- mice than in wild-type mice. Elevation of blood pressure by continuous Ang II infusion was comparable between ASK1-/- and wild-type mice. However, Ang II-induced cardiac hypertrophy and remodeling, including cardiomyocyte hypertrophy, cardiac hypertrophy-related mRNA upregulation, cardiomyocyte apoptosis, interstitial fibrosis, coronary arterial remodeling, and collagen gene upregulation, was significantly attenuated in ASK1-/- mice compared with wild-type mice. These results provided the first in vivo evidence that ASK1 is the critical signaling molecule for Ang II-induced cardiac hypertrophy and remodeling. Thus, ASK1 is proposed to be a potential therapeutic target for cardiac diseases.     

In vivo klotho gene transfer ameliorates angiotensin II-induced renal damage

The klotho gene, originally identified by insertional mutagenesis in mice, suppresses the expression of multiple aging-associated phenotypes. This gene is predominantly expressed in the kidney. Recent studies have shown that expression of renal klotho gene is regulated in animal models of metabolic diseases and in humans with chronic renal failure. However, little is known about the mechanisms and the physiological relevance of the regulation of the expression of the klotho gene in the kidney in some diseased conditions. In the present study, we first investigated the role of angiotensin II in the regulation of renal klotho gene expression. Long-term infusion of angiotensin II downregulated renal klotho gene expression at both the mRNA and protein levels. This angiotensin II-induced renal klotho downregulation was an angiotensin type 1 receptor-dependent but pressor-independent event. Adenovirus harboring mouse klotho gene (ad-klotho, 3.3x10(10) plaque forming units) was also intravenously administered immediately before starting angiotensin II infusion in some rats. This resulted in a robust induction of Klotho protein in the liver at day 4, which was still detectable 14 days after the gene transfer. Ad-klotho gene transfer, but not ad-lacZ gene transfer, caused an improvement of creatinine clearance, decrease in urinary protein excretion, and amelioration of histologically demonstrated tubulointerstitial damage induced by angiotensin II administration. Our data suggest that downregulation of the renal klotho gene may have an aggravative role in the development of renal damage induced by angiotensin II, and that induction of the klotho gene may have therapeutic possibilities in treating angiotensin II-induced end organ damage.     

Oncostatin M is a potential agent for the treatment of obesity and related metabolic disorders: a study in mice

Aims/hypothesis

Obesity and insulin resistance are closely associated with adipose tissue dysfunction caused by the abnormal recruitment of inflammatory cells, including macrophages. Oncostatin M (OSM), a member of the IL-6 family of cytokines, plays important roles in a variety of biological functions including the regulation of inflammatory responses. In previous reports, we have demonstrated that mice deficient in the OSM receptor β subunit show obesity, adipose tissue inflammation, insulin resistance and hepatic steatosis, all of which are exacerbated by feeding the mice a high-fat diet. These results prompted us to test the therapeutic effects of OSM on obesity-induced metabolic disorders using mouse models of obesity.

Methods

In diet-induced obese and ob/ob mice, metabolic variables were assessed physiologically, histologically and biochemically after the intraperitoneal injection of recombinant mouse OSM twice a day for 1 week.

Results

Treatment with OSM improved obesity, adipose tissue inflammation, insulin resistance and hepatic steatosis in both mouse models. Although OSM reduced food intake, such therapeutic effects of OSM were observed even under pair-feeding conditions. Functionally, OSM directly changed the phenotype of adipose tissue macrophages from M1 type (inflammatory) to M2 type (anti-inflammatory). In the liver, OSM suppressed the expression of genes related to fatty acid synthesis and increased the expression of genes related to fatty acid oxidation. Furthermore, OSM decreased lipid absorption and increased the expression of active glucagon-like peptide-1 in the intestine.

Conclusions/interpretation

We showed that OSM is a novel candidate to act as a powerful therapeutic agent for the treatment of obesity-induced metabolic disorders.

     

Usefulness of Ultrasonography for Diagnosis of Small Bowel Tumors: A Comparison Between Ultrasonography and Endoscopic Modalities

Ultrasonography is a standard, noninvasive modality used to evaluate patients with gastrointestinal diseases. This study assessed the usefulness of ultrasonography in the detection of small bowel tumors.This study enrolled 558 consecutive patients (295 males, 263 females; mean age 71.1 years) who underwent ultrasonography before capsule endoscopy and/or balloon-assisted endoscopy. Ultrasonographic detection of small bowel tumors was compared with detection by capsule endoscopy and/or balloon-assisted endoscopy. In addition, factors affecting small bowel tumor detection by ultrasonography and clinical characteristics of patients with small bowel tumors undetected by ultrasonography were evaluated.Ninety-seven tumors (52 benign, 45 malignant) detected by capsule endoscopy and/or balloon-assisted endoscopy were retrospectively analyzed. The sensitivity and specificity of ultrasonography in the detection of small bowel tumors were 50.5% (47/93) and 100% (465/465), respectively. If we restricted patients to those with a tumor >20 mm in size, its detection ratio would become higher (91.7%): the ratio of submucosal tumor >20 mm in size was 85.7% (6/7) and that of partial and circumferential ulcerative tumors >20 mm in size was 96.9% (31/32), respectively. Small bowel tumors detected by ultrasonography (mean 33.2 mm) were significantly larger than those undetected by ultrasonography (mean 8.7 mm). The percentage of small bowel tumors located in the ileum detected by ultrasonography (70.6%) was significantly higher than those undetected by ultrasonography (29.4%). Of the 46 small bowel tumors undetected by ultrasonography, 42 (91.3%) were benign tumors with good clinical prognosis.Ultrasonography is a useful modality for detecting larger small bowel tumors and ulcerative lesions. Ultrasonography should be considered a first-line modality for patients suspected of having small bowel tumors, because most small bowel tumors undetected by ultrasonography were benign tumors with good clinical prognosis.     

Intravenous cyclophosphamide therapy in a case with refractory thrombotic microangiopathic hemolytic anemia and SLE

The case of a 27-year-old woman who simultaneously presented with SLE and severe refractory thrombotic microangiopathic hemolytic anemia (TMHA) is reported. She had extremely high levels of platelet-associated IgG (PAIgG), and her TMHA was refractory to plasma exchange and corticosteroid therapy. However, the TMHA was effectively controlled by i.v. cyclophosphamide therapy. ITP and TTP are generally considered distinct diseases; however, TMHA may occur secondary to platelet aggregation via autoimmune mechanisms in certain cases. Immunosuppressive therapy at an early stage of the disease may be beneficial in refractory cases of TMHA with autoimmune features.     

Gene therapy with SOCS1 for gastric cancer induces G2/M arrest and has an antitumour effect on peritoneal carcinomatosis

Background:

Suppressor of cytokine signaling1 (SOCS1) is a negative regulator of various cytokines. Recently, it was investigated as a therapeutic target in various cancers. However, the observed antitumour effects of SOCS1 cannot not be fully explained without taking inhibition of proliferation signalling into account. Our aim was to discover a new mechanism of antitumour effects of SOCS1 for gastric cancer (GC).

Methods:

We analysed the mechanism of antitumour effect of SOCS1 in vitro. In addition, we evaluated antitumour effect for GC using a xenograft peritoneal carcinomatosis mouse model in preclinical setting.

Results:

We confirmed that SOCS1 suppressed proliferation in four out of five GC cell lines. SOCS1 appeared to block proliferation by a new mechanism that involves cell cycle regulation at the G2/M checkpoint. We showed that SOCS1 influenced cell cycle-associated molecules through its interaction with ataxia telangiectasia and Rad3-related protein. The significant difference in therapeutic effects was noted in terms of the post-treatment weight and total photon count of the intra-abdominal tumours.

Conclusion:

Forced expression of SOCS1 revealed a heretofore-unknown mechanism for regulating the cell cycle and may represent a novel therapeutic approach for the treatment of peritoneal carcinomatosis of GC.     

Novel function of Oncostatin M as a potent tumour‐promoting agent in lung

Oncostatin M is a leukocyte product that has been reported to have anti‐proliferative effects directly on melanoma and other cancer cell lines in vitro. However, its function(s) in cancers in vivo appears complex and its roles in cancer growth in lungs are unknown. Here, we show that OSM promotes marked growth of tumour cells in mouse lungs. Local pulmonary administration of adenovirus vector expressing mouse OSM (AdOSM) induced >13‐fold increase in lung tumour burden of ectopically delivered B16‐F10 melanoma cells in C57BL/6 mice. AdOSM caused increases in tumour size (14 days post‐challenge), whereas control vector (Addel70) did not. AdOSM had no such action in C57BL/6 mice deficient in the OSM receptor beta chain (OSMRβ?/?), indicating that these effects required OSMRβ expression on non‐tumour cells in the recipient mice. AdOSM induced elevated levels of chemokines and inflammatory cells in the bronchoalveolar lavage (BAL) fluid, elevated arginase‐1 mRNA levels (60‐fold), and increased arginase‐1+immunostaining macrophage numbers in lungs. Adherent BAL cells collected from AdOSM‐treated mice expressed elevated arginase‐1 activity. In contrast to AdOSM‐induced effects, pulmonary over‐expression of IL‐1β (AdIL‐1β) induced neutrophil accumulation and iNOS mRNA, but did not modulate tumour burden. AdOSM also increased lung tumour load (>50‐fold) upon ectopic administration of Lewis lung carcinoma (LLC) cells in vivo. However, in vitro, neither recombinant OSM nor AdOSM infection stimulated B16‐F10 or LLC cell growth directly. We conclude that pulmonary over‐expression of OSM promotes tumour growth, and does so through altering the local lung environment with accumulation of M2 macrophages.