Publications by authors named "Jun Nakayama"

197 Publications

Effects of orally administered Euglena gracilis and its reserve polysaccharide, paramylon, on gastric dysplasia in A4gnt knockout mice.

Sci Rep 2021 Jul 1;11(1):13640. Epub 2021 Jul 1.

Laboratory of Veterinary Public Health, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1, Yayoi, Bunkyo-ku, Tokyo, 113-8657, Japan.

Euglena gracilis is widely utilized as food or supplement to promote human and animal health, as it contains rich nutrients. In this study, we administered spray-dried powder of E. gracilis and paramylon, β-glucan stored in E. gracilis cells, to A4gnt knockout (KO) mice. A4gnt KO mice are a mutant mouse model that spontaneously develops gastric cancer through hyperplasia-dysplasia-adenocarcinoma sequence in the antrum of the stomach, and we observed the effects of E. gracilis and paramylon on the early involvements of A4gnt KO mice. Male and female 10-week-old A4gnt KO mice and their age-matched wildtype C57BL/6J mice were orally administered with 50 mg of E. gracilis or paramylon suspended in saline or saline as a control. After 3-week administration, animals were euthanatized and the stomach was examined histopathologically and immunohistochemically. Gene expression patterns of the stomach, which have been reported to be altered with A4gnt KO, and IgA concentration in small intestine were also analyzed with real-time PCR and ELISA, respectively. Administration of Euglena significantly reduced the number of stimulated CD3-positive T-lymphocytes in pyloric mucosa of A4gnt KO mice and tend to reduce polymorphonuclear leukocytes infiltration. Euglena administration further downregulated the expression of Il11 and Cxcl1 of A4gnt KO mice. Euglena administration also affected IgA concentration in small intestinal contents of A4gnt KO mice. Paramylon administration reduced the number of CD3-positive lymphocytes in pyloric mucosa of A4gnt KO mice, and downregulated the expressions of Il11 and Ccl2 of A4gnt KO mice. Although we found no significant effects on gross and microscopic signs of gastric dysplasia and cell proliferation, the present study suggests that the administration of Euglena and paramylon may ameliorate the early involvements of A4gnt mice through the effects on inflammatory reactions in the gastric mucosa. The cancer-preventing effects should be studied with long-term experiments until actual gastric cancer formation.
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http://dx.doi.org/10.1038/s41598-021-92013-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8249615PMC
July 2021

CNKSR1 serves as a scaffold to activate an EGFR phosphatase via exclusive interaction with RhoB-GTP.

Life Sci Alliance 2021 Sep 29;4(9). Epub 2021 Jun 29.

Department of Biochemistry and Molecular Genetics, Ehime University Graduate School of Medicine, Toon, Japan

Epidermal growth factor receptor (EGFR) and human EGFR 2 (HER2) phosphorylation drives HER2-positive breast cancer cell proliferation. Enforced activation of phosphatases for those receptors could be a therapeutic option for HER2-positive breast cancers. Here, we report that degradation of an endosomal small GTPase, RhoB, by the ubiquitin ligase complex cullin-3 (CUL3)/KCTD10 is essential for both EGFR and HER2 phosphorylation in HER2-positive breast cancer cells. Using human protein arrays produced in a wheat cell-free protein synthesis system, RhoB-GTP, and protein tyrosine phosphatase receptor type H (PTPRH) were identified as interacting proteins of connector enhancer of kinase suppressor of Ras1 (CNKSR1). Mechanistically, constitutive degradation of RhoB, which is mediated by the CUL3/KCTD10 E3 complex, enabled CNKSR1 to interact with PTPRH at the plasma membrane resulting in inactivation of EGFR phosphatase activity. Depletion of CUL3 or KCTD10 led to the accumulation of RhoB-GTP at the plasma membrane followed by its interaction with CNKSR1, which released activated PTPRH from CNKSR1. This study suggests a mechanism of PTPRH activation through the exclusive binding of RhoB-GTP to CNKSR1.
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http://dx.doi.org/10.26508/lsa.202101095DOI Listing
September 2021

Cholestenone functions as an antibiotic against by inhibiting biosynthesis of the cell wall component CGL.

Proc Natl Acad Sci U S A 2021 Apr;118(16)

Department of Molecular Pathology, Shinshu University School of Medicine, Asahi 3-1-1, Matsumoto 390-8621, Japan;

, a pathogen responsible for gastric cancer, contains a unique glycolipid, cholesteryl-α-D-glucopyranoside (CGL), in its cell wall. Moreover, -glycans having α1,4-linked -acetylglucosamine residues (αGlcNAc) are secreted from gland mucous cells of gastric mucosa. Previously, we demonstrated that CGL is critical for survival and that αGlcNAc serves as antibiotic against by inhibiting CGL biosynthesis. In this study, we tested whether a cholesterol analog, cholest-4-en 3-one (cholestenone), exhibits antibacterial activity against in vitro and in vivo. When the standard strain ATCC 43504 was cultured in the presence of cholestenone, microbial growth was significantly suppressed dose-dependently relative to microbes cultured with cholesterol, and cholestenone inhibitory effects were not altered by the presence of cholesterol. Morphologically, cholestenone-treated exhibited coccoid forms. We obtained comparable results when we examined the clarithromycin-resistant strain "2460." We also show that biosynthesis of CGL and its derivatives cholesteryl-6--tetradecanoyl-α-D-glucopyranoside and cholesteryl-6--phosphatidyl-α-D-glucopyranoside in is remarkably inhibited in cultures containing cholestenone. Lastly, we asked whether orally administered cholestenone eradicated strain SS1 in C57BL/6 mice. Strikingly, mice fed a cholestenone-containing diet showed significant eradication of from the gastric mucosa compared with mice fed a control diet. These results overall strongly suggest that cholestenone could serve as an oral medicine to treat patients infected with , including antimicrobial-resistant strains.
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http://dx.doi.org/10.1073/pnas.2016469118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8072394PMC
April 2021

How to Select Firefly Luciferin Analogues for In Vivo Imaging.

Int J Mol Sci 2021 Feb 12;22(4). Epub 2021 Feb 12.

School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Tokyo 192-0392, Japan.

Bioluminescence reactions are widely applied in optical in vivo imaging in the life science and medical fields. Such reactions produce light upon the oxidation of a luciferin (substrate) catalyzed by a luciferase (enzyme), and this bioluminescence enables the quantification of tumor cells and gene expression in animal models. Many researchers have developed single-color or multicolor bioluminescence systems based on artificial luciferin analogues and/or luciferase mutants, for application in vivo bioluminescence imaging (BLI). In the current review, we focus on the characteristics of firefly BLI technology and discuss the development of luciferin analogues for high-resolution in vivo BLI. In addition, we discuss the novel luciferin analogues TokeOni and seMpai, which show potential as high-sensitivity in vivo BLI reagents.
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http://dx.doi.org/10.3390/ijms22041848DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7918177PMC
February 2021

The In Vivo Selection Method in Breast Cancer Metastasis.

Int J Mol Sci 2021 Feb 14;22(4). Epub 2021 Feb 14.

Department of Life Science and Medical Bioscience, School of Advanced Science and Engineering, Waseda University, Tokyo 162-8480, Japan.

Metastasis is a complex event in cancer progression and causes most deaths from cancer. Repeated transplantation of metastatic cancer cells derived from transplanted murine organs can be used to select the population of highly metastatic cancer cells; this method is called as in vivo selection. The in vivo selection method and highly metastatic cancer cell lines have contributed to reveal the molecular mechanisms of cancer metastasis. Here, we present an overview of the methodology for the in vivo selection method. Recent comparative analysis of the transplantation methods for metastasis have revealed the divergence of metastasis gene signatures. Even cancer cells that metastasize to the same organ show various metastatic cascades and gene expression patterns by changing the transplantation method for the in vivo selection. These findings suggest that the selection of metastasis models for the study of metastasis gene signatures has the potential to influence research results. The study of novel gene signatures that are identified from novel highly metastatic cell lines and patient-derived xenografts (PDXs) will be helpful for understanding the novel mechanisms of metastasis.
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http://dx.doi.org/10.3390/ijms22041886DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7918415PMC
February 2021

Carbonic anhydrase 13 suppresses bone metastasis in breast cancer.

Cancer Treat Res Commun 2021 9;27:100332. Epub 2021 Feb 9.

Department of Biochemistry, The Jikei University School of Medicine, 3-25-8 Nishi-shinbashi, Minato-ku, Tokyo 105-8461, Japan. Electronic address:

Metastatic progression is the leading cause of mortality in breast cancer. However, molecular mechanisms that govern this process remain unclear. In this study, we found that carbonic anhydrase 13 (CA13) plays a potential role in suppressing bone metastasis. iRFP713-labeled iCSCL-10A (iRFP-iCSCL-10A) breast cancer cells, which exhibit the hallmarks of cancer stem cells, exerted the ability of bone metastasis in hind legs after 5-week injections, whereas no metastasis was observed in control iRFP713-labeled MCF-10A (iRFP-MCF10A) cells. Transcriptome analysis indicated that the expression of several genes, including metabolism-related CA13, was reduced in bone metastatic iRFP-iCSCL-10A cells. In vitro and in vivo analyses demonstrated that overexpression of CA13 in iRFP-iCSCL-10A cells suppressed migration, invasion, and bone metastasis, together with the reduction of VEGF-A and M-CSF expression. Furthermore, we found that breast cancer patients with a low CA13 expression had significantly shorter overall survival and disease-free survival rates compared to those with higher CA13 expression. These findings suggest that CA13 may act as a novel prognostic biomarker and would be a therapeutic candidate for the prevention of bone metastasis in breast cancer.
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http://dx.doi.org/10.1016/j.ctarc.2021.100332DOI Listing
February 2021

High Sensitivity In Vivo Imaging of Cancer Metastasis Using a Near-Infrared Luciferin Analogue seMpai.

Int J Mol Sci 2020 Oct 24;21(21). Epub 2020 Oct 24.

Department of Engineering Science, Graduate School of Informatics and Engineering, The University of Electro-Communications, Tokyo 182-8585, Japan.

Bioluminescence imaging (BLI) is useful to monitor cell movement and gene expression in live animals. However, D-luciferin has a short wavelength (560 nm) which is absorbed by tissues and the use of near-infrared (NIR) luciferin analogues enable high sensitivity in vivo BLI. The AkaLumine-AkaLuc BLI system (Aka-BLI) can detect resolution at the single-cell level; however, it has a clear hepatic background signal. Here, to enable the highly sensitive detection of bioluminescence from the surrounding liver tissues, we focused on seMpai (CHNOS) which has been synthesized as a luciferin analogue and has high luminescent abilities as same as AkaLumine. We demonstrated that seMpai BLI could detect micro-signals near the liver without any background signal. The solution of seMpai was neutral; therefore, seMpai imaging did not cause any adverse effect in mice. seMpai enabled a highly sensitive in vivo BLI as compared to previous techniques. Our findings suggest that the development of a novel mutated luciferase against seMpai may enable a highly sensitive BLI at the single-cell level without any background signal. Novel seMpai BLI system can be used for in vivo imaging in the fields of life sciences and medicine.
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http://dx.doi.org/10.3390/ijms21217896DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7660630PMC
October 2020

Dietary Restriction Suppresses Steatosis-Associated Hepatic Tumorigenesis in Hepatitis C Virus Core Gene Transgenic Mice.

Liver Cancer 2020 Sep 10;9(5):529-548. Epub 2020 Jul 10.

Department of Metabolic Regulation, Shinshu University School of Medicine, Matsumoto, Japan.

Background And Aims: Dietary restriction (DR) is a preventive strategy for obesity, metabolic syndrome, cardiovascular disease, and diabetes. Although an interconnection between obesity, metabolic syndrome, fatty liver, and hepatocellular carcinoma has been documented, the mechanism and impact of DR on steatosis-derived hepatocarcinogenesis are not fully understood. This study aimed to evaluate whether DR can prevent hepatic tumorigenesis.

Methods: Male hepatitis C virus core gene transgenic (HCVcpTg) mice that develop spontaneous age-dependent insulin resistance, hepatic steatosis, and ensuing liver tumor development without apparent hepatic fibrosis, were fed with either a control diet ad libitum (control group) or 70% of the same control diet (DR group) for 15 months, and liver phenotypes were investigated.

Results: DR significantly reduced the number and volume of liver tumors. DR attenuated hepatic oxidative and endoplasmic reticulum stress and markedly suppressed nuclear factor-κB, signal transducer and activator of transcription 3 (STAT3) and STAT5, and phosphorylation of extracellular signal-regulated kinase, leading to downregulation of several pro-oncogenic mediators, such as cyclin D1. Serum insulin and insulin-like growth factor 1 levels, as well as hepatic expression of insulin receptor substrate 1/2, phosphatidylinositol-3 kinase, and serine/threonine-protein kinase AKT, were downregulated by DR. A transcriptome analysis revealed that STAT3 signaling and lipogenesis were the most suppressed hepatocarcinogenic pathways affected by DR. Additionally, DR stimulated autophagy and p62/sequestosome 1 degradation, enhanced phosphorylation of AMP-activated protein kinase α, increased fibroblast growth factor 21 expression, and attenuated expression of senescence-associated secretory phenotypes.

Conclusion: DR suppressed steatosis-associated hepatic tumorigenesis in HCVcpTg mice, mainly due to attenuation of pathways involved in inflammation, cellular stress, cell proliferation, insulin signaling, and senescence. These findings support the notion that persistent 30% reduction of daily food intake is beneficial for preventing steatosis-associated hepatocarcinogenesis caused by HCV core protein.
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http://dx.doi.org/10.1159/000508308DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7548900PMC
September 2020

Decreased alpha-1,4-linked N-acetylglucosamine glycosylation in biliary tract cancer progression from biliary intraepithelial neoplasia to invasive adenocarcinoma.

Cancer Sci 2020 Dec 23;111(12):4629-4635. Epub 2020 Oct 23.

Department of Molecular Pathology, Shinshu University School of Medicine, Matsumoto, Japan.

Biliary tract cancer (BTC) is typically lethal due to the difficulty of early stage diagnosis. Thus, novel biomarkers of BTC precursors are necessary. Biliary intraepithelial neoplasia (BilIN) is a major precursor of BTC and is classified as low or high grade based on cell atypia. In normal gastric mucosa, gastric gland mucin-specific O-glycans are unique in having α1,4-linked N-acetylglucosamine (αGlcNAc) attached to MUC6. Previously, we reported that αGlcNAc functions as a tumor suppressor of differentiated-type gastric adenocarcinoma and that decreased αGlcNAc glycosylation on MUC6 in gastric, pancreatic, and uterine cervical neoplasms occurs in cancer as well as in their precursor lesions. However, αGlcNAc and MUC6 expression patterns in biliary tract neoplasms have remained unclear. Here, we analyzed MUC5AC, MUC6, and αGlcNAc expression status in 51 BTC cases and compared the expression of each with progression from low-grade BilIN to invasive adenocarcinoma (IAC). The frequency of αGlcNAc-positive and MUC6-positive lesions decreased with tumor progression. When we compared each marker's expression level with tumor progression, we found that the MUC6 expression score in IAC was significantly lower than in low-grade or high-grade BilIN (P < 0.001 or P < 0.01, respectively). However, the αGlcNAc expression score was low irrespective of histological grade, and also lower than that of MUC6 across all histological grades (P < 0.001 for low-grade and high-grade BilIN, and P < 0.01 for IAC). These results suggest that decreased expression of αGlcNAc relative to MUC6 marks the initiation of BTC progression.
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http://dx.doi.org/10.1111/cas.14677DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7734011PMC
December 2020

A saturated fatty acid-rich diet enhances hepatic lipogenesis and tumorigenesis in HCV core gene transgenic mice.

J Nutr Biochem 2020 11 3;85:108460. Epub 2020 Jul 3.

Department of Metabolic Regulation, Shinshu University School of Medicine, Matsumoto, Japan; Research Center for Social Systems, Shinshu University, Matsumoto, Japan. Electronic address:

Previous studies suggested that high consumption of saturated fatty acid (SFA) is a risk factor for liver cancer. However, it remains unclear how dietary SFA affects liver tumorigenesis. This study aimed to investigate the impact of a SFA-rich diet on hepatic tumorigenesis using hepatitis C virus core gene transgenic (HCVcpTg) mice that spontaneously developed hepatic steatosis and tumors with aging. Male HCVcpTg mice were treated for 15 months with a purified control diet or SFA-rich diet prepared by replacing soybean oil in the control diet with hydrogenated coconut oil, and phenotypic changes were assessed. In this special diet, almost all dietary fatty acids were SFA. Long-term feeding of SFA-rich diet to HCVcpTg mice increased hepatic steatosis, liver dysfunction, and the prevalence of liver tumors, likely due to stimulation of de novo lipogenesis, activation of the pro-inflammatory and pro-oncogenic transcription factor nuclear factor-kappa B (NF-κB), enhanced c-Jun N-terminal kinase/activator protein 1 (JNK/AP-1) signaling and induction of the oncogenes cyclin D1 and p62/sequestosome 1. The SFA-rich diet did not affect liver fibrosis or autophagy. Collectively, long-term SFA-rich diet consumption promoted hepatic tumorigenesis mainly through activation of lipogenesis, NF-κB, and JNK/AP-1 signaling. We therefore propose that HCV-infected patients should avoid excessive intake of SFA-rich foods to prevent liver cancer.
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http://dx.doi.org/10.1016/j.jnutbio.2020.108460DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7756930PMC
November 2020

Overcoming the blood-brain barrier by Annexin A1-binding peptide to target brain tumours.

Br J Cancer 2020 11 14;123(11):1633-1643. Epub 2020 Sep 14.

Cancer Center, Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, CA, 92037, USA.

Background: Annexin A1 is expressed specifically on the tumour vasculature surface. Intravenously injected IF7 targets tumour vasculature via annexin A1. We tested the hypothesis that IF7 overcomes the blood-brain barrier and that the intravenously injected IF7C(RR)-SN38 eradicates brain tumours in the mouse.

Methods: (1) A dual-tumour model was generated by inoculating luciferase-expressing melanoma B16 cell line, B16-Luc, into the brain and under the skin of syngeneic C57BL/6 mice. IF7C(RR)-SN38 was injected intravenously daily at 7.0 μmoles/kg and growth of tumours was assessed by chemiluminescence using an IVIS imager. A similar dual-tumour model was generated with the C6-Luc line in immunocompromised SCID mice. (2) IF7C(RR)-SN38 formulated with 10% Solutol HS15 was injected intravenously daily at 2.5 μmoles/kg into two brain tumour mouse models: B16-Luc cells in C57BL/6 mice, and C6-Luc cells in nude mice.

Results: (1) Daily IF7C(RR)-SN38 injection suppressed tumour growth regardless of cell lines or mouse strains. (2) Daily injection of Solutol-formulated IF7C(RR)-SN38 led into complete disappearance of B16-Luc brain tumour in C57BL/6 mice, whereas this did not occur in C6-Luc in nude mice.

Conclusions: IF7C(RR)-SN38 crosses the blood-brain barrier and suppresses growth of brain tumours in mouse models. Solutol HS15-formulated IF7C(RR)-SN38 may have promoted an antitumour immune response.
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http://dx.doi.org/10.1038/s41416-020-01066-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686308PMC
November 2020

Proliferative Classification of Intracranially Injected HER2-positive Breast Cancer Cell Lines.

Cancers (Basel) 2020 Jul 6;12(7). Epub 2020 Jul 6.

Department of Life Science and Medical Bioscience, School of Advanced Science and Engineering, Waseda University, TWIns 2-2 Wakamatsu-cho, Shinjuku-ku, Tokyo 162-8480, Japan.

HER2 is overexpressed in 25-30% of breast cancers, and approximately 30% of HER2-positive breast cancers metastasize to the brain. Although the incidence of brain metastasis in HER2-positive breast cancer is high, previous studies have been mainly based on cell lines of the triple-negative subtype, and the molecular mechanisms of brain metastasis in HER2-positive breast cancer are unclear. In the present study, we performed intracranial injection using nine HER2-positive breast cancer cell lines to evaluate their proliferative activity in brain tissue. Our results show that UACC-893 and MDA-MB-453 cells rapidly proliferated in the brain parenchyma, while the other seven cell lines moderately or slowly proliferated. Among these nine cell lines, the proliferative activity in brain tissue was not correlated with either the HER2 level or the HER2 phosphorylation status. To extract signature genes associated with brain colonization, we conducted microarray analysis and found that these two cell lines shared 138 gene expression patterns. Moreover, some of these genes were correlated with poor prognosis in HER2-positive breast cancer patients. Our findings might be helpful for further studying brain metastasis in HER2-positive breast cancer.
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http://dx.doi.org/10.3390/cancers12071811DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408688PMC
July 2020

Systematic investigation of the skin in Chst14-/- mice: A model for skin fragility in musculocontractural Ehlers-Danlos syndrome caused by CHST14 variants (mcEDS-CHST14).

Glycobiology 2021 Feb;31(2):137-150

Laboratory of Veterinary Anatomy, School of Veterinary Medicine, Rakuno Gakuen University, Ebetsu, Hokkaido 069-8501, Japan.

Loss-of-function variants in CHST14 cause a dermatan 4-O-sulfotransferase deficiency named musculocontractural Ehlers-Danlos syndrome-CHST14 (mcEDS-CHST14), resulting in complete depletion of the dermatan sulfate moiety of decorin glycosaminoglycan (GAG) chains, which is replaced by chondroitin sulfate. Recently, we uncovered structural alteration of GAG chains in the skin of patients with mcEDS-CHST14. Here, we conducted the first systematic investigation of Chst14 gene-deleted homozygote (Chst14-/-) mice. We used skin samples of wild-type (Chst14+/+) and Chst14-/- mice. Mechanical fragility of the skin was measured with a tensile test. Pathology was observed using light microscopy, decorin immunohistochemistry and electron microscopy (EM) including cupromeronic blue (CB) staining. Quantification of chondroitin sulfate and dermatan sulfate was performed using enzymatic digestion followed by anion-exchange HPLC. In Chst14-/- mice, skin tensile strength was significantly decreased compared with that in Chst14+/+ mice. EM showed that collagen fibrils were oriented in various directions to form disorganized collagen fibers in the reticular layer. Through EM-based CB staining, rod-shaped linear GAG chains were found to be attached at one end to collagen fibrils and protruded outside of the fibrils, in contrast to them being round and wrapping the collagen fibrils in Chst14+/+ mice. A very low level of dermatan sulfate disaccharides was detected in the skin of Chst14-/- mice by anion-exchange chromatography. Chst14-/- mice, exhibiting similar abnormalities in the GAG structure of decorin and collagen networks in the skin, could be a reasonable model for skin fragility of patients with mcEDS-CHST14, shedding light on the role of dermatan sulfate in maintaining skin strength.
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http://dx.doi.org/10.1093/glycob/cwaa058DOI Listing
February 2021

Diffuse MIST1 expression and decreased α1,4-linked N-acetylglucosamine (αGlcNAc) glycosylation on MUC6 are distinct hallmarks for gastric neoplasms showing oxyntic gland differentiation.

Histopathology 2020 Sep 5;77(3):413-422. Epub 2020 Aug 5.

Department of Molecular Pathology, Shinshu University School of Medicine, Matsumoto, Japan.

Aims: Gastric neoplasms showing oxyntic gland differentiation (GAOGs) constitute a gastric neoplasm subtype that shows low atypia, thus similar to non-neoplastic gastric oxyntic glands. Therefore, their diagnosis in biopsy specimens is difficult. GAOGs were first described in 2007, and introduced in the latest World Health Organization classification book as gastric adenocarcinoma of the fundic gland type (GA-FG) and oxyntic gland adenoma. Previously, we assessed α1,4-linked N-acetylglucosamine (αGlcNAc) residues attached to the MUC6 scaffold in gastric neoplasms, and observed decreased αGlcNAc glycosylation in both differentiated-type gastric cancer and high-grade pyloric gland adenoma (PGA), a gastric cancer precursor. GA-FG and PGA often harbour the same mutations. However, the αGlcNAc status in GAOGs remained unknown. To elucidate αGlcNAc expression in GAOGs, we performed the study.

Methods And Results: We assessed the expression of αGlcNAc; the mucin markers MUC6, MUC5AC, and MUC2; the gastric gland cell markers MIST1, pepsinogen 1 (PG1), H/K-ATPase and chromogranin-A (CGA); and the proliferation marker Ki67 in 13 GAOG lesions. All 13 (100%) were MUC6-positive, whereas 10 (76.2%) were αGlcNAc-negative. Moreover, all 13 (100%) were MIST1- and PG1-positive, three (23.1%) were MUC5AC-positive, four (30.8%) were H/K-ATPase-positive, and one (7.7%) was CGA-positive.

Conclusions: GAOGs frequently lost αGlcNAc residues on MUC6, but expressed the gastric gland progenitor marker MIST1 and aberrantly expressed various types of gastric gland cell lineage marker, suggestive of immature differentiation to gastric gland cells. Thus, diffuse MIST1 positivity and decreased αGlcNAc glycosylation on MUC6-positive cells could serve as important biomarkers for the histopathological diagnosis of GAOG.
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http://dx.doi.org/10.1111/his.14165DOI Listing
September 2020

Polyunsaturated fatty acid deficiency affects sulfatides and other sulfated glycans in lysosomes through autophagy-mediated degradation.

FASEB J 2020 07 5;34(7):9594-9614. Epub 2020 Jun 5.

Department of Metabolic Regulation, Shinshu University School of Medicine, Matsumoto, Japan.

Metabolic changes in sulfatides and other sulfated glycans have been related to various diseases, including Alzheimer's disease (AD). However, the importance of polyunsaturated fatty acids (PUFA) in sulfated lysosomal substrate metabolism and its related disorders is currently unknown. We investigated the effects of deficiency or supplementation of PUFA on the metabolism of sulfatides and sulfated glycosaminoglycans (sGAGs) in sulfatide-rich organs (brain and kidney) of mice. A PUFA-deficient diet for over 5 weeks significantly reduced the sulfatide expression by increasing the sulfatide degradative enzymes arylsulfatase A and galactosylceramidase in brain and kidney. This sulfatide degradation was clearly associated with the activation of autophagy and lysosomal hyperfunction, the former of which was induced by suppression of the Erk/mTOR pathway. A PUFA-deficient diet also activated the degradation of sGAGs in the brain and kidney and that of amyloid precursor proteins in the brain, indicating an involvement in general lysosomal function and the early developmental process of AD. PUFA supplementation prevented all of the above abnormalities. Taken together, a PUFA deficiency might lead to sulfatide and sGAG degradation associated with autophagy activation and general lysosomal hyperfunction and play a role in many types of disease development, suggesting a possible benefit of prophylactic PUFA supplementation.
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http://dx.doi.org/10.1096/fj.202000030RRDOI Listing
July 2020

Clinical Characteristics and In Vitro Analysis of Variants Causing Late-Onset Progressive Hearing Loss.

Genes (Basel) 2020 03 4;11(3). Epub 2020 Mar 4.

Department of Otorhinolaryngology, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan.

is known as a genetic cause of autosomal dominant and autosomal recessive inherited hearing loss. In this study, to clarify the frequency and clinical characteristics of hearing loss caused by gene mutations, a large-scale genetic analysis of Japanese patients with hearing loss was performed. By means of massively parallel DNA sequencing (MPS) using next-generation sequencing for 8074 Japanese families, we found 27 variants in 33 families, 22 of which are novel. In total, 2.40% of autosomal dominant sensorineural hearing loss (ADSNHL) in families in this study (32 out of 1336) was found to be caused by mutations. The present study clarified that most cases showed juvenile-onset progressive hearing loss and their hearing deteriorated markedly after 40 years of age. The estimated hearing deterioration was found to be 0.57 dB per year; when restricted to change after 40 years of age, the deterioration speed was accelerated to 1.07 dB per year. To obtain supportive evidence for pathogenicity, variants identified in the patients were introduced to cDNA by site-directed mutagenesis and overexpressed in epithelial cells. They were then assessed for their effects on espin1-induced microvilli formation. Cells with wildtype myosin 6 and espin1 co-expressed created long microvilli, while co-expression with mutant constructs resulted in severely shortened microvilli. In conclusion, the present data clearly showed that is one of the genes to keep in mind with regard to ADSNHL, and the molecular characteristics of the identified gene variants suggest that a possible pathology seems to result from malformed stereocilia of the cochlear hair cells.
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http://dx.doi.org/10.3390/genes11030273DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7140843PMC
March 2020

Generation of Rat Monoclonal Antibodies Specific for Human Stromal Cell-Derived Factor-2.

Monoclon Antib Immunodiagn Immunother 2020 Feb 9;39(1):23-26. Epub 2020 Jan 9.

Department of Life Science and Medical BioScience, School of Advanced Science and Engineering, Waseda University, Tokyo, Japan.

Stromal cell-derived factor-2 (SDF-2) is reportedly involved in multiple endoplasmic reticulum (ER) functions, including the misfolded protein catabolic process, protein glycosylation, and ER protein quality control. However, the precise molecular and cellular functions of SDF-2 remain unknown. Previously, we discovered that SDF-2 mediates acquired resistance to oxaliplatin in human gastric cancer cells. In this study, we have generated SDF-2-specific monoclonal antibodies (mAbs), using the rat medial iliac lymph node method, as a tool to explore novel mechanisms of oxaliplatin resistance. The antibodies detected endogenous human SDF-2 in immunoblotting analyses. In addition, immunoprecipitation analyses revealed the availability of these antibodies for human SDF-2. Thus, these mAbs will be available to elucidate molecular and cellular functions of SDF-2 in cancer cells.
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http://dx.doi.org/10.1089/mab.2019.0043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7044778PMC
February 2020

[Inverted Variant of Urothelial Carcinoma of the Urinary Bladder : A Case Report].

Hinyokika Kiyo 2019 Nov;65(11):463-467

The Department of Molecular Pathology, Shinshu University School of Medicine.

A 69-year-old male complained of gross hematuria. Cystoscopy revealed a papillary pedunculated tumor. The tumor was approximately 4 cm in length, and mimicked an inverted papilloma with a small stalk and smooth surface, located on the bladder trigone. Transurethral resection of the bladder tumor was performed, and the tumor was resected en bloc. Histopathological examination revealed thick and irregular epithelial cords. Immunohistochemically, Ki-67 labeling index was 5%, p40 and CK7 were positive, and CK20 was negative. Then, this tumor was diagnosed as inverted variant of urothelial carcinoma. Even when gross appearance is compatible with inverted papilloma, pathological and immunohistochemical examinations are essential for accurate diagnosis of inverted bladder tumor. No recurrence was observed by cystoscopy 13 months after the resection.
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http://dx.doi.org/10.14989/ActaUrolJap_65_11_463DOI Listing
November 2019

Tumor-suppressing potential of stingless bee propolis in in vitro and in vivo models of differentiated-type gastric adenocarcinoma.

Sci Rep 2019 12 23;9(1):19635. Epub 2019 Dec 23.

Laboratory of Biomedical Science, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1, Yayoi, Bunkyo-ku, Tokyo, 113-8657, Japan.

The protective property of propolis across a wide spectrum of diseases has long been realized, yet the anti-tumor efficacy of this bioactive substance from Philippine stingless bees has remained poorly understood. Here, we showed the tumor-suppressing potential of crude ethanolic extract of Philippine stingless bee propolis (EEP) in in vitro models of gastric cancer highlighting the first indication of remarkable subtype specificity towards differentiated-type human gastric cancer cell lines but not the diffuse-type. Mechanistically, this involved the profound modulation of several cell cycle related gene transcripts, which correlated with the prominent cell cycle arrest at the G0/G1 phase. To reinforce our data, a unique differentiated-type gastric cancer model, A4gnt KO mice, together with age-matched 60 week-old C57BL/6 J mice were randomly assigned to treatment groups receiving distilled water or EEP for 30 consecutive days. EEP treatment induced significant regression of gross and histological lesions of gastric pyloric tumors that consistently corresponded with specific transcriptional regulation of cell cycle components. Also, the considerable p21 protein expression coupled with a marked reduction in rapidly dividing BrdU-labeled S-phase cells unequivocally supported our observation. Altogether, these findings support the role of Philippine stingless bee propolis as a promising adjunct treatment option in differentiated-type gastric cancer.
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http://dx.doi.org/10.1038/s41598-019-55465-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6928070PMC
December 2019

Establishment and characterization of highly osteolytic luminal breast cancer cell lines by intracaudal arterial injection.

Genes Cells 2020 Feb 17;25(2):111-123. Epub 2020 Jan 17.

Department of Life Science and Medical Bioscience, School of Advanced Science and Engineering, Waseda University, Tokyo, Japan.

Bone is one of the most common metastatic sites of breast cancer, and bone metastasis profoundly affects the quality of life of breast cancer patients. Bone metastasis is commonly observed among all the subtypes of breast cancer; however, its molecular mechanism has been analyzed only in triple-negative subtype of breast cancer (TNBC). To characterize the molecular mechanisms of bone metastasis of luminal breast cancer, we established a bone-metastatic model of the MCF7, luminal breast cancer cell line, with enhanced osteolytic activity by intracaudal arterial injection (CAI). Pathological analysis of the established cell lines revealed that they exhibited fierce osteolytic ability by promoting osteoclast differentiation and activity. The signature genes extracted from highly osteolytic MCF7 cell lines were differed from those of bone-metastatic TNBC cell lines. Our results suggest that unique mechanisms of osteolysis in bone-metastatic lesions of luminal breast cancer. In addition, several up-regulated genes in MCF7-BM (Bone Metastasis) 02 cell lines correlated with poor prognosis with luminal breast cancer patients. Our findings support further study on the bone-metastatic mechanisms of luminal breast cancer.
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http://dx.doi.org/10.1111/gtc.12743DOI Listing
February 2020

Cecal Tumorigenesis in Aryl Hydrocarbon Receptor-Deficient Mice Depends on Cecum-Specific Mitogen-Activated Protein Kinase Pathway Activation and Inflammation.

Am J Pathol 2020 02 14;190(2):453-468. Epub 2019 Nov 14.

Department of Molecular Pathology, Shinshu University School of Medicine, Matsumoto, Japan.

The aryl hydrocarbon receptor (AhR) is a transcription factor known as a dioxin receptor. Recently, Ahr mice were revealed to develop cecal tumors with inflammation and Wnt/β-catenin pathway activation. However, whether β-catenin degradation is AhR dependent remains unclear. To determine whether other signaling pathways function in Ahr cecal tumorigenesis, we investigated histologic characteristics of the tumors and cytokine/chemokine production in tumors and Ahr peritoneal macrophages. AhR expression was also assessed in human colorectal carcinomas. Of the 28 Ahr mice, 10 developed cecal lesions by 50 weeks of age, an incidence significantly lower than previously reported. Cecal lesions of Ahr mice developed from serrated hyperplasia to adenoma/dysplasia-like neoplasia with enhanced proliferation. Macrophage and neutrophil infiltration into the lesions was also observed early in serrated hyperplasia, although adjacent mucosa was devoid of inflammation. Il1b, Il6, Ccl2, and Cxcl5 were up-regulated at lesion sites, whereas only IL-6 production increased in Ahr peritoneal macrophages after lipopolysaccharide + ATP stimulation. Neither Myc (alias c-myc) up-regulation nor β-catenin nuclear translocation was observed, unlike previously reported. Interestingly, enhanced phosphorylation of extracellular signal-regulated kinase, Src, and epidermal growth factor receptor and Amphiregulin up-regulation at Ahr lesion sites were detected. In human serrated lesions, however, AhR expression in epithelial cells was up-regulated despite morphologic similarity to Ahr cecal lesions. Our results suggest novel mechanisms underlying Ahr cecal tumorigenesis, depending primarily on cecum-specific mitogen-activated protein kinase pathway activation and inflammation.
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http://dx.doi.org/10.1016/j.ajpath.2019.10.005DOI Listing
February 2020

αGlcNAc and its catalyst α4GnT are diagnostic and prognostic markers in uterine cervical tumor, gastric type.

Sci Rep 2019 09 10;9(1):13043. Epub 2019 Sep 10.

Department of Molecular Pathology, Shinshu University School of Medicine, Matsumoto, 390-8621, Japan.

Cervical adenocarcinoma, gastric type (GAS) is not associated with human papilloma virus (HPV) infection. GAS patients prognoses are significantly worse compared with cervical adenocarcinoma associated with HPV infection, as their tumors exhibit resistance to conventional chemotherapy and radiotherapy. GAS is often associated with lobular endocervical glandular hyperplasia (LEGH), which is regarded as a precursor to GAS in the latest WHO classification. Recently, we reported that a decrease in expression of terminal α1,4-linked N-acetylglucosamine (αGlcNAc) relative to that of MUC6 was already apparent in atypical LEGH in the LEGH-GAS sequence. Here, we analyzed expression of α1,4-N-acetylglucosaminyltransferase (α4GnT), the sole enzyme catalyzing αGlcNAc biosynthesis, and that of αGlcNAc and MUC6 in cases representing non-neoplastic endocervical gland (NNEG) (11 cases), LEGH (26 cases) and GAS (12 cases). α4GnT protein was detected in a "dot-like" pattern, indicating localization in the Golgi apparatus in all 26 LEGH cases and 5 of 12 GAS cases. α4GnT- and αGlcNAc-positive cells largely overlapped, suggesting that α4GnT gene expression regulates αGlcNAc biosynthesis. Interestingly, all NNEG cases were negative for α4GnT and αGlcNAc expression, but 7 of 11 NNEG and all LEGH cases were MUC6-positive. In GAS cases, patients whose tumors were α4GnT- and αGlcNAc-positive had more favorable prognosis than others. Multivariate analysis revealed that positive expressions of α4GnT and αGlcNAc were independent prognostic indicators. These results indicate that α4GnT and αGlcNAc could serve as useful markers not only to distinguish LEGH from NNEG but to evaluate prognoses of GAS patients.
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http://dx.doi.org/10.1038/s41598-019-49376-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6737144PMC
September 2019

Comprehensive analysis of syndromic hearing loss patients in Japan.

Sci Rep 2019 08 19;9(1):11976. Epub 2019 Aug 19.

Department of Otorhinolaryngology - Head and Neck Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan.

More than 400 syndromes associated with hearing loss and other symptoms have been described, corresponding to 30% of cases of hereditary hearing loss. In this study we aimed to clarify the mutation spectrum of syndromic hearing loss patients in Japan by using next-generation sequencing analysis with a multiple syndromic targeted resequencing panel (36 target genes). We analyzed single nucleotide variants, small insertions, deletions and copy number variations in the target genes. We enrolled 140 patients with any of 14 syndromes (BOR syndrome, Waardenburg syndrome, osteogenesis imperfecta, spondyloepiphyseal dysplasia congenita, Stickler syndrome, CHARGE syndrome, Jervell and Lange-Nielsen syndrome, Pendred syndrome, Klippel-Feil syndrome, Alport syndrome, Norrie disease, Treacher-Collins syndrome, Perrault syndrome and auditory neuropathy with optic atrophy) and identified the causative variants in 56% of the patients. This analysis could identify the causative variants in syndromic hearing loss patients in a short time with a high diagnostic rate. In addition, it was useful for the analysis of the cases who only partially fulfilled the diagnostic criteria.
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http://dx.doi.org/10.1038/s41598-019-47141-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6700179PMC
August 2019

A trans-fatty acid-rich diet promotes liver tumorigenesis in HCV core gene transgenic mice.

Carcinogenesis 2020 04;41(2):159-170

Department of Metabolic Regulation, Shinshu University School of Medicine, Matsumoto, Japan.

Excess consumption of trans-fatty acid (TFA), an unsaturated fatty acid containing trans double bonds, is a major risk factor for cardiovascular disease and metabolic syndrome. However, little is known about the link between TFA and hepatocellular carcinoma (HCC) despite it being a frequent form of cancer in humans. In this study, the impact of excessive dietary TFA on hepatic tumorigenesis was assessed using hepatitis C virus (HCV) core gene transgenic mice that spontaneously developed HCC. Male transgenic mice were treated for 5 months with either a control diet or an isocaloric TFA-rich diet that replaced the majority of soybean oil with shortening. The prevalence of liver tumors was significantly higher in TFA-rich diet-fed transgenic mice compared with control diet-fed transgenic mice. The TFA-rich diet significantly increased the expression of pro-inflammatory cytokines, as well as oxidative and endoplasmic reticulum stress, and activated nuclear factor-kappa B (NF-κB) and nuclear factor erythroid 2-related factor 2 (NRF2), leading to high p62/sequestosome 1 (SQSTM1) expression. Furthermore, the TFA diet activated extracellular signal-regulated kinase (ERK) and stimulated the Wnt/β-catenin signaling pathway, synergistically upregulating cyclin D1 and c-Myc, driving cell proliferation. Excess TFA intake also promoted fibrogenesis and ductular reaction, presumably contributing to accelerated liver tumorigenesis. In conclusion, these results demonstrate that a TFA-rich diet promotes hepatic tumorigenesis, mainly due to persistent activation of NF-κB and NRF2-p62/SQSTM1 signaling, ERK and Wnt/β-catenin pathways and fibrogenesis. Therefore, HCV-infected patients should avoid a TFA-rich diet to prevent liver tumor development.
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http://dx.doi.org/10.1093/carcin/bgz132DOI Listing
April 2020

Cullin-3/KCTD10 complex is essential for K27-polyubiquitination of EIF3D in human hepatocellular carcinoma HepG2 cells.

Biochem Biophys Res Commun 2019 09 5;516(4):1116-1122. Epub 2019 Jul 5.

Division of Cell Growth and Tumor Regulation, Proteo-Science Center, Ehime University, Shitsukawa, Toon, Ehime, 791-0295, Japan; Department of Biochemistry and Molecular Genetics, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, 791-0295, Japan. Electronic address:

Eukaryotic translation initiation factor 3 subunit D (EIF3D) binds to the 5'-cap of specific mRNAs, initiating their translation into polypeptides. From a pathological standpoint, EIF3D has been observed to be essential for cell growth in various cancer types, and cancer patients with high EIF3D mRNA levels exhibit poor prognosis, indicating involvement of EIF3D in oncogenesis. In this study, we found, by mass spectrometry, that Cullin-3 (CUL3)/KCTD10 ubiquitin (Ub) ligase forms a complex with EIF3D. We also demonstrated that EIF3D is K27-polyubiquitinated at the lysine 153 and 275 residues in a KCTD10-dependent manner in human hepatocellular carcinoma HepG2 cells. Similar to other cancers, high expression of EIF3D significantly correlated with poor prognosis in hepatocellular carcinoma patients, and depletion of EIF3D drastically suppressed HepG2 cell proliferation. These results indicate that EIF3D is a novel substrate of CUL3/KCTD10 Ub ligase and suggest involvement of K27-polyubiquitinated EIF3D in the development of hepatocellular carcinoma.
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http://dx.doi.org/10.1016/j.bbrc.2019.07.010DOI Listing
September 2019

Analysis of Knockout Mice Reveals an Essential Role for Gastric Sulfomucins in Preventing Gastritis Cystica Profunda.

J Histochem Cytochem 2019 10 27;67(10):759-770. Epub 2019 Jun 27.

Department of Molecular Pathology, Shinshu University School of Medicine, Shinshu University, Matsumoto, Japan.

Gastric adenocarcinoma cells secrete sulfomucins, but their role in gastric tumorigenesis remains unclear. To address that question, we generated / double-knockout (DKO) mice by crossing knockout (KO) mice, which spontaneously develop gastric adenocarcinoma, with KO mice, which are deficient in the sulfotransferase GlcNAc6ST-2. / DKO mice lack gastric sulfomucins but developed gastric adenocarcinoma. Unexpectedly, severe gastric erosion occurred in / DKO mice at as early as 3 weeks of age, and with aging these lesions were accompanied by gastritis cystica profunda (GCP). , and transcripts in gastric mucosa of 5-week-old / DKO mice exhibiting both hyperplasia and severe erosion were significantly upregulated relative to age-matched KO mice, which showed hyperplasia alone. However, upregulation of these genes disappeared in 50-week-old / DKO mice exhibiting high-grade dysplasia/adenocarcinoma and GCP. Moreover, and were downregulated in / DKO mice relative to age-matched KO mice exhibiting adenocarcinoma alone. These combined results indicate that the presence of sulfomucins prevents severe gastric erosion followed by GCP in KO mice by transiently regulating a set of inflammation-related genes, , and at 5 weeks of age, although sulfomucins were not directly associated with gastric cancer development.
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http://dx.doi.org/10.1369/0022155419860134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6764063PMC
October 2019

Cutting Edge: TAK1 Safeguards Macrophages against Proinflammatory Cell Death.

J Immunol 2019 08 26;203(4):783-788. Epub 2019 Jun 26.

Department of Molecular and Cellular Immunology, Shinshu University School of Medicine, Matsumoto, Nagano 390-8621, Japan.

TGF-β-activated kinase 1 (TAK1) is known to play vital roles for innate and adaptive immunity; however, little is known about its potential role in limiting biological responses such as inflammation. In this study, we report that macrophage TAK1 participates in negatively regulating inflammation by restraining proinflammatory cell death. Macrophages from TAK1-deficient mice underwent cell death in response to LPS and poly(I:C), which took place in a manner dependent on TLR/TRIF-induced active Caspase8-mediated cleavage of gasdermin D, known as an executioner of pyroptosis. Likewise, TNF-α induced Caspase8-dependent gasdermin D processing following cell death in TAK1-deficient macrophages. Importantly, we demonstrated that this type of proinflammatory macrophage death is linked to susceptibility to septic shock in mice lacking TAK1 in macrophages in a TNF-α-independent fashion. Taken together, our data revealed that TAK1 acts as a signaling checkpoint to protect macrophages from unique proinflammatory cell death, ensuring the maintenance of innate immune homeostasis.
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http://dx.doi.org/10.4049/jimmunol.1900202DOI Listing
August 2019

Correction to: A high-cholesterol diet promotes steatohepatitis and liver tumorigenesis in HCV core gene transgenic mice.

Arch Toxicol 2019 Jun;93(6):1727-1728

Department of Metabolic Regulation, Shinshu University School of Medicine, Matsumoto, 390-8621, Japan.

In the original publication of the article.
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http://dx.doi.org/10.1007/s00204-019-02491-wDOI Listing
June 2019

A high-cholesterol diet promotes steatohepatitis and liver tumorigenesis in HCV core gene transgenic mice.

Arch Toxicol 2019 06 19;93(6):1713-1725. Epub 2019 Apr 19.

Department of Metabolic Regulation, Shinshu University School of Medicine, Matsumoto, 390-8621, Japan.

Previous epidemiological studies have suggested a link between high-cholesterol intake and liver disease progression, including hepatocellular carcinoma (HCC). However, the precise mechanism of hepatotoxicity and hepatocarcinogenesis caused by excessive cholesterol consumption remains unclear. We aimed to investigate the impact of dietary cholesterol using hepatitis C virus core gene transgenic (HCVcpTg) mice, which spontaneously developed HCC with age. Male HCVcpTg mice were treated for 15 months with either a control diet or an isocaloric diet containing 1.5% cholesterol, and liver phenotypes and tumor-associated signaling pathways were evaluated. The high-cholesterol diet-fed HCVcpTg mice exhibited a significantly higher incidence of liver tumors compared with the control diet mice (100% vs. 41%, P < 0.001). The diet induced steatohepatitis with pericellular fibrosis and evoked higher mRNA expression of pro-inflammatory and pro-fibrotic mediators along with enhanced hepatocyte proliferation and greater oxidative and endoplasmic reticulum stress in the liver. Moreover, long-term consumption of cholesterol-rich diet activated nuclear factor-kappa B (NF-κB) and p62/sequestosome 1 (Sqstm1)-nuclear factor erythroid 2 (NRF2) axis, enhanced fibrogenesis, and consequently accelerated hepatic tumorigenesis. In conclusion, these results demonstrate that a high-cholesterol diet facilitates liver tumorigenesis by inducing steatohepatitis, promoting hepatocyte division, and up-regulating cellular stress and pro-inflammatory NF-κB and detoxifying p62/Sqstm1-NRF2 signals. Therefore, high dietary cholesterol should be avoided in HCV-infected patients to prevent development of steatohepatitis, liver fibrosis, and HCC.
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http://dx.doi.org/10.1007/s00204-019-02440-7DOI Listing
June 2019
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