Hirotsugu Noguchi

Peroxiredoxin 4 Protects Against Nonalcoholic Steatohepatitis and Type 2 Diabetes in a Nongenetic Mouse Model

AIMS Consumption of a high-fructose diet (HFrD) can induce the development of a metabolic syndrome, manifesting as nonalcoholic steatohepatitis (NASH) and/or type 2 diabetes mellitus (T2DM), via a process in which oxidative stress plays a critical role. Peroxiredoxin 4 (PRDX4) is a unique and only known secretory member of the PRDX antioxidant family. However, its putative roles in the development of NASH and/or T2DM have not been investigated. RESULTS To elucidate the functions of PRDX4 in a metabolic syndrome, we established a nongenetic mouse model of T2DM by feeding mice a HFrD after injecting a relatively low dose of streptozotocin. Compared with wild-type (WT), human PRDX4 transgenic (Tg) mice exhibited significant improvements in insulin resistance, characterized by a lower glucose and insulin concentration and faster responses in glucose tolerance tests. The liver of Tg also showed less severe vesicular steatosis, inflammation, and fibrosis, along with lower lipid concentrations, lower levels of oxidative stress markers, more decreased expression of hepatic aminotransferase, and more reduced stellate cell activation than those in the WT liver, reminiscent of human early NASH. Hepatocyte apoptosis was also significantly repressed in Tg mice. By contrast, serum adiponectin levels and hepatic adiponectin receptor expression were significantly lower in WT mice, consistent with greater insulin resistance in the peripheral liver tissue compared with Tg mice. INNOVATION AND CONCLUSION Our data for the first time show that PRDX4 may protect against NASH, T2DM, and the metabolic syndrome by ameliorating oxidative stress-induced injury.

Apoptosis Signal–Regulating Kinase 1 Deficiency Attenuates Vascular Injury–Induced Neointimal Hyperplasia by Suppressing Apoptosis in Smooth Muscle Cells

Apoptosis signal-regulating kinase 1 (ASK1) is a mitogen-activated protein kinase kinase kinase that plays a crucial role in stress-induced apoptosis. Recently, we have reported that suppressed macrophage apoptosis in ASK1 and apolipoprotein E double-knockout mice accelerates atheromatous plaques in the hyperlipidemia-induced atherosclerotic model. However, the pathogenic role of smooth muscle cell (SMC) apoptosis in atherosclerosis still remains unclear. We investigated neointimal remodeling in ligated carotid arteries of ASK1-deficient mice (ASK1(-/-)) for 3 weeks. ASK1(-/-) mice had significantly more suppressed intimal formation, inversely manifesting as potential anti-atherogenic aspects of ASK1 deficiency, characterized by fewer SMCs and less collagen synthesis; and fewer apoptotic SMCs, infiltrating T lymphocytes, and microvessels, associated with decreased apoptosis of luminal endothelial cells, compared with those of wild-type mice. Injured arteries of ASK1(-/-) mice also showed significantly down-regulated expression of pro-apoptotic markers, adhesion molecules, and pro-inflammatory signaling factors. Moreover, tumor necrosis factor-α-induced apoptosis was markedly suppressed in cultured aortic SMCs from ASK1(-/-) mice. These findings suggest that ASK1 accelerates mechanical injury-induced vascular remodeling with activated SMC migration via increased neovascularization and/or enhanced SMC and endothelial cell apoptosis. ASK1 expression, especially in the SMCs, might be crucial, and reciprocally responsible for various pro-atherogenic functions, and SMC apoptosis seems to be detrimental in this model.

Depletion of apoptosis signal-regulating kinase 1 prevents bile duct ligation-induced necroinflammation and subsequent peribiliary fibrosis

Apoptosis signal-regulating kinase 1 (ASK1), also known as mitogen-activated protein kinase kinase kinase (MAP3K), is ubiquitously expressed and situated in an important upstream position of many signal transduction pathways. ASK1 plays a pivotal role in stressor-induced cell survival and inflammatory reactions. To ascertain the regulatory functions of ASK1 in bile duct ligation (BDL)-induced liver injury, we examined the net effects of ASK1 depletion on hepatic necroinflammation and/or fibrosis. We subjected C57BL/6 wild-type (WT) or ASK1-deficient (ASK1(-/-)) mice to sham or BDL surgery for 14 days. In day 3 BDL animals, ASK1(-/-) mice had significantly fewer bile infarcts along with more reduced interlobular or portal inflammatory infiltrate of various immune cells, including neutrophils, compared with WT mice in which ASK1 expression was markedly activated. Morphologically apoptotic hepatocytes or cholangiocytes were negligible in both the sham and BDL animals. In contrast, ASK1(-/-) mice had significantly less proliferating activity of not only hepatocytes but also large cholangiocytes than WT mice. Day 14 BDL ASK1(-/-) mice manifested potential antifibrogenic aspects of ASK1 deficiency, characterized by significantly fewer activated peribiliary fibrogenic cells and peribiliary fibrosis. These observations indicate that ASK1-mediated hepatic necroinflammation and proliferation, but not apoptosis, are closely linked to liver fibrosis and fibrogenesis. A specific ASK1 pathway blocker or inhibitor might offer a therapeutic strategy against human cholestatic diseases.

Diffuse large B-cell lymphoma presenting with neurolymphomatosis and intravascular lymphoma: a unique autopsy case with diverse neurological symptoms

A 78-year-old Japanese male noticed a difficulty in the beginning of standing up, followed by 7a progressive numbness of extremities with pain, Bell’s palsy, dysarthria, and difficulty in swallowing. A clinician had suspected cancer of unknown primary origin, accompanied by the diverse and elusive neurological symptoms, likely presenting as painful mononeuropathy simplex and cranial neuropathy. He developed dysbasia over weeks and died 1 month after the symptom onset. At autopsy, an ill-defined large and soft tumor mass in the right lobe of the liver with direct invasion into the right adrenal gland was observed. The left adrenal gland or right iliopsoas muscle was also involved. Microscopic findings showed a monotonous proliferation of medium-sized to large atypical lymphoid cells, which were diffusely positive for CD20 in immunohistochemistry, consistent with diffuse large B-cell lymphoma (DLBL). Furthermore, the lymphoma cells aggressively infiltrated endoneurial and subperineurial spaces not only in the peripheral nerves and plexuses, but partly in the spinal nerve roots, and intravascular spaces in various tissues. Therefore, systemic lymphoma (DLBL) complicated with neurolymphomatosis (NL) and intravascular lymphoma (IVL) was diagnosed. Very early diagnosis and treatment are necessary for the NL patients with poor prognosis.Virtual slidesThe virtual slides for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/5862472377020448.

Overexpression of Peroxiredoxin 4 Affects Intestinal Function in a Dietary Mouse Model of Nonalcoholic Fatty Liver Disease

Background Accumulating evidence has shown that methionine- and choline-deficient high fat (MCD+HF) diet induces the development of nonalcoholic fatty liver disease (NAFLD), in which elevated reactive oxygen species play a crucial role. We have reported that peroxiredoxin 4 (PRDX4), a unique secretory member of the PRDX antioxidant family, protects against NAFLD progression. However, the detailed mechanism and potential effects on the intestinal function still remain unclear. Methods & Results Two weeks after feeding mice a MCD+HF diet, the livers of human PRDX4 transgenic (Tg) mice exhibited significant suppression in the development of NAFLD compared with wild-type (WT) mice. The serum thiobarbituric acid reactive substances levels were significantly lower in Tg mice. In contrast, the Tg small intestine with PRDX4 overexpression showed more suppressed shortening of total length and villi height, and more accumulation of lipid in the jejunum, along with lower levels of dihydroethidium binding. The enterocytes exhibited fewer apoptotic but more proliferating cells, and inflammation was reduced in the mucosa. Furthermore, the small intestine of Tg mice had significantly higher expression of cholesterol absorption-regulatory factors, including liver X receptor-α, but lower expression of microsomal triglyceride-transfer protein. Conclusion Our present data provide the first evidence of the beneficial effects of PRDX4 on intestinal function in the reduction of the severity of NAFLD, by ameliorating oxidative stress-induced local and systemic injury. We can suggest that both liver and intestine are spared, to some degree, by the antioxidant properties of PRDX4.

Benign cutaneous plexiform hybrid tumor of perineurioma and cellular neurothekeoma arising from the nose

Very recently, Requena et al. have demonstrated the detailed clinicopathological features of 9 cases of a benign cutaneous plexiform nerve sheath tumor with hybrid characteristics of perineurioma and cellular neurothekeoma, given the name as a benign cutaneous plexiform hybrid tumor of perineurioma and cellular neurothekeoma, all of which were peculiarly located on the lips. Herein we described the first case of that arising from the nose, but not the lip, representing a histological hybridoma of perineurioma and cellular neurothekeoma after thorough consideration especially with its immunohistochemical profile.

PD-L1 expression in papillary renal cell carcinoma

BackgroundThe immune escape or tolerance of cancer cells is considered to be closely involved in cancer progression. Programmed death-1 (PD-1) is an inhibitory receptor expressed on activating T cells, and several types of cancer cells were found to express PD-1 ligand 1 (PD-L1) and ligand 2 (PD-L2).MethodsIn the present study, we investigated PD-L1/2 expression in papillary renal cell carcinoma (pRCC).ResultWe found PD-L1 expression in 29 of 102 cases, but no PD-L2 expression was seen. PD-L1 expression was not significantly correlated with any clinicopathological factor, including progression-free survival and overall survival. The frequency of PD-L1-positive cases was higher in type 2 (36%) than in type 1 (22%) pRCC; however, there was no significant difference in the percentages of score 0 cases (p value = 0.084 in Chi-square test). The frequency of high PD-L1 expression cases was higher in type 2 (23%) than in type 1 (11%), and the frequency of high PD-L1 expression cases was higher in grade 3/4 (21%) than in grade 1/2 (13%). However, no significant association was found between PD-L1 expression and all clinicopathological factors in pRCC.ConclusionHigh expression of PD-L1 in cancer cells was potentially associated to highly histological grade of malignancy in pRCC. The evaluation of the PD-L1 protein might still be useful for predicting the efficacy of anti-cancer immunotherapy using immuno-checkpoint inhibitors, however, not be useful for predicting the clinical prognosis.

Methotrexate-related Primary Hepatic Lymphoma in a Patient with Rheumatoid Arthritis

A 56-year-old woman with rheumatoid arthritis treated with methotrexate (MTX) was admitted to our hospital due to multiple liver tumors. Contrast-enhanced computed tomography (CT) revealed multiple hypovascular masses, and 18F-fluorodeoxyglucose positron emission tomography CT showed diffuse abnormal accumulation in the liver only. We therefore made a diagnosis of MTX-related primary hepatic lymphoma (MTX-PHL) exhibiting features of diffuse large B-cell lymphoma. Although MTX has been reported to increase the risk of lymphoproliferative disorders, MTX-PHL has not been reported previously. The present case is the first case in which MTX appears to have been involved in the development of PHL.

The combination of strong immunohistochemical mtTFA expression and a high survivin index predicts a shorter disease-specific survival in pancreatic ductal adenocarcinoma.

Mitochondrial transcription factor A (mtTFA) plays a crucial role in both the transcription and maintenance of mitochondrial DNA. A high expression of mtTFA has been demonstrated in several solid tumors, and is closely associated with cancer cell survival/apoptosis and growth. However, its expression pattern in pancreatic ductal adenocarcinoma (PAC) remains to be elucidated. Additionally, our groups have recently revealed that a subset of apoptosis-related genes is strongly regulated by mtTFA, and that two putative mtTFA binding sites are present in the promoter region of the survivin gene, which is a member of the inhibitor-of-apoptosis protein family. We therefore investigated the correlation of the immunohistochemical mtTFA expression and the survivin index with various clinicopathological variables and the prognosis, using 70 paraffin-embedded tumor samples from patients with surgically-resected PAC. The mtTFA expression or survivin index was considered to be strong or high when ≥30% or 10% of the PAC cells showed positive staining, respectively. Strong mtTFA expression and/or a high survivin index was revealed to have a significant relationship to a pathologically high tumor grading and advanced tumor stage. Moreover, mtTFA showed significantly high co-expression with survivin. Univariate and multivariate analyses demonstrated that both the strong mtTFA expression and high survivin index groups had significantly shorter survival rates, especially within the first two years postoperatively. The combination of strong mtTFA expression and a high survivin index may predict a poor prognosis in patients with PAC, and these new biomarkers might offer useful information for the early clinical management.

Basaloid carcinoma of the lung associated with central cavitation: a unique surgical case focusing on cytological and immunohistochemical findings

A history of an increase in pulmonary mass was presented in the right upper lobe of a 72-year-old male. The bronchial brushing cytology specimens contained many sheet-like or three-dimensional clusters of malignant cells having small to medium-sized, uniform oval to round, and hyperchromatic nuclei, inconspicuous nucleoli, and scanty cytoplasm, admixed with mitotic figures. A coarsely granular chromatin pattern was predominantly noted. We first interpreted it as suspicious of malignancy, such as atypical carcinoid. A right upper lobectomy was performed, and gross examination revealed a centrally cavity-formed tumor lesion, containing asymmetrically thinned wall and looking grayish to whitish, partly adjacent to the bronchiolar wall. On microscopic examination, the tumor was predominantly composed of a solid proliferation of atypical epithelial cells without apparent glandular or squamous differentiation, often arranged in an alveolar growth pattern with peripheral palisading. Immunohistochemically, these atypical cells are negative for all three neuroendocrine markers and thyroid transcription factor 1, whereas positive for 34βE12, p63 and S-100 protein. Therefore, we finally made a diagnosis of basaloid carcinoma with cavity formation. We should be aware that, owing to its characteristic features, cytopathologists might be able to raise basaloid carcinoma of the lung as one of differential diagnoses, based on careful cytological examination.Virtual slidesThe virtual slide(s) for this article can be found here: http://www.dianosticpathology.diagnomx.eu/vs/1519986488570234