Relevance of Autophagy Induction by Gastrointestinal Hormones: Focus on the Incretin-Based Drug Target and Glucagon

The biology of autophagy in health and disease conditions has been intensively analyzed for decades. Several potential interventions can induce autophagy in preclinical research; however, none of these interventions are ready for translation to clinical practice yet. The topic of the current review is the molecular regulation of autophagy by glucagon, glucagon-like peptide (GLP)-1 and the GLP-1-degrading enzyme dipeptidyl peptidase-4 (DPP-4). Glucagon is a well-known polypeptide that induces autophagy. In contrast, GLP-1 has been shown to inhibit glucagon secretion; GLP-1 also has been related to the induction of autophagy. DPP-4 inhibitors can induce autophagy in a GLP-1–dependent manner, but other diverse effects could be relevant. Here, we analyze the distinct molecular regulation of autophagy by glucagon, GLP-1, and DPP-4 inhibitors. Additionally, the potential contribution to autophagy by glucagon and GLP-1 after bariatric surgery is discussed

「学科間プロジェクト」のカリキュラム開発に関する実践的研究/「有馬温泉ゆけむり大学」を事例として

本研究では、「有馬温泉ゆけむり大学」を実践的なデザイン教育の場として研究を行った。すなわち、「学科間プロジェクト」の教育的効果を再考するために、本イベントの「Tシャツ」、「チラシ」デザイン、及び有志学生による「神戸芸工大雑貨屋さん」、「浴衣DEファッションショー」を開催した。その他イベントとして、「有馬温泉クリスマスツリープロジェクト」のワークショップ、「有馬節分会」の「チラシ」デザインを行った。また、武蔵野美術大学・群馬県立女子大学・立命館アジア太平洋大学に出向き、聞き取り調査を行った。研究の結果、「有馬温泉ゆけむり大学」に参加した学生は、他の学科及び学年を超えた交流の機会ができた。また、特に大阪音楽大学・近畿大学・武庫川女子大学の学生たち及び有馬温泉のスタッフとも交流ができたことは、大変貴重な経験となり、様々な教育効果が期待できる。したがって、「学科間プロジェクト」のカリキュラム開発のための基礎資料を得ることができた。In this studies, we studied that the "Arima Onsen Yukemuri University" was for design practical education. That is, in order to rethink the educational effect of "Interdepartmental Project", of this event "T-shirt", "Flyer" design, and by volunteer students "Kobe Design University Zakkaya san", "Yukata DE Fashion show" were held. As other events, workshop of "Arima Onsen Christmas tree project" , "Flyer" design for "Arima Setsubun E".In addition, visited to Musashino Art University, Gunma Prefectural Women\u27s University, Ritsumeikan Asia Pacific University, which were investigated.Results of the studies, students who participated in the "Arima Onsen Yukemuri University" was able opportunity of exchange beyond the school year and other departments. In addition, it becomes a very valuable experience, that the staff of Arima Onsen and students of Osaka College of Music, Kinki University, Mukogawa Women\u27s University also could exchange in particular can be expected to be teaching a variety of effects. Therefore, it was possible to obtain the basic data for curriculum development "Interdepartmental Project"

Linagliptin ameliorated cardiac fibrosis and restored cardiomyocyte structure in diabetic mice associated with the suppression of necroptosis

ABSTRACT Aims/Introduction Linagliptin is a selective dipeptidyl peptidase (DPP)‐4 inhibitor capable of successfully regulating blood glucose levels. The cardiovascular protective effects of several DPP‐4 inhibitors have been shown in preclinical studies; however, the detailed influence of DPP‐4 inhibitors on diabetic pathological alterations in cardiac tissue has not yet been elucidated. Materials and Methods We combined laboratory‐based experiments and bioinformatics techniques to identify suitable candidate targets with significant biological pathways. Mice with streptozotocin‐induced insulin deficiency diabetic model were utilized for in vivo experiments. Mice were euthanized at 24 weeks after the induction of diabetes; linagliptin intervention was carried out for 4 weeks before euthanasia. Microarray analysis of heart samples was carried out. Results Mice with streptozotocin‐induced diabetes, but not control mice, showed cardiac fibrosis with an endothelial–mesenchymal transition program, and myocardial fiber and sarcomere disruption; linagliptin alleviated these diabetes‐associated pathological alterations without altering blood glucose levels. Bioinformatics analysis utilizing a microarray dataset identified 10 hub genes that were confirmed to have human disease relevance by Gene Expression Omnibus analysis. Among these hub genes, we focused on the Sox9–necroptosis axis as a therapeutic target in diabetic hearts. Indeed, diabetic mice showed the induction of necroptosis‐associated genes and the phosphorylation of RIP3 and mixed lineage kinase domain‐like protein. Conclusions Linagliptin showed excellent heart protection in mice with streptozotocin‐induced diabetes associated with alterations in human disease‐relevant hub genes. Further investigation is required to determine why DPP‐4 inhibitors do not show similar superior organ‐protective effects in the clinical setting

Inhibition of Dipeptidyl Peptidase-4 Activates Autophagy to Promote Survival of Breast Cancer Cells via the mTOR/HIF-1α Pathway

Autophagy plays a complex role in breast cancer cell survival, metastasis, and chemotherapeutic resistance. Dipeptidyl peptidase (DPP)-4, a therapeutic target for type 2 diabetes mellitus, is also involved in autophagic flux. The potential influence of DPP-4 suppression on cancer biology remains unknown. Here, we report that DPP-4 deficiency promotes breast cancer cell survival via the induction of autophagy by the C-X-C motif chemokine 12 (CXCL12)/C-X-C receptor 4 (CXCR4)/mammalian target of rapamycin (mTOR)/hypoxia inducible factor (HIF)-1α axis. DPP-4 knockdown and DPP-4 inhibitor KR62436 (KR) treatment both increased the levels of LC3II and HIF-1α in cultured human breast and mouse mammary cancer cells. The KR-induced autophagic phenotype in cancer cells was inhibited by treatment with the CXCR4 inhibitor AMD3100 and rapamycin. HIF-1α knockdown also suppressed breast cancer autophagy induced by KR. The autophagy inhibitor 3-methyladenine significantly blocked the KR-mediated suppression of cleaved caspase-3 levels and apoptosis in breast cancer cell lines. Finally, we found that the metformin-induced apoptosis of DPP-4-deficient 4T1 mammary cancer cells was associated with the suppression of autophagy. Our findings identify a novel role for DPP-4 inhibition in the promotion of breast cancer survival by inducing CXCL12/CXCR4/mTOR/HIF-1α axis-dependent autophagy. Metformin is a potential drug that counteracts the breast cancer cell survival system

Deficiency in Dipeptidyl Peptidase-4 Promotes Chemoresistance Through the CXCL12/CXCR4/mTOR/TGFβ Signaling Pathway in Breast Cancer Cells

Dipeptidyl peptidase (DPP)-4, a molecular target of DPP-4 inhibitors, which are type 2 diabetes drugs, is expressed in a variety of cell types, tissues and organs. DPP-4 has been shown to be involved in cancer biology, and we have recently shown that a DPP-4 inhibitor promoted the epithelial mesenchymal transition (EMT) in breast cancer cells. The EMT is known to associate with chemotherapy resistance via the induction of ATP-binding cassette (ABC) transporters in cancer cells. Here, we demonstrated that deficiency in DPP-4 promoted chemotherapy resistance via the CXCL12/CXCR4/mTOR axis, activating the TGFβ signaling pathway via the expression of ABC transporters. DPP-4 inhibition enhanced ABC transporters in vivo and in vitro. Doxorubicin (DOX) further induced ABC transporters in DPP-4-deficient 4T1 cells, and the induction of ABC transporters was suppressed by either the CXCR4 inhibitor AMD3100, the mTOR inhibitor rapamycin or a neutralizing TGFβ (1, 2 and 3) antibody(N-TGFβ). Knockdown of snail, an EMT-inducible transcription factor, suppressed ABC transporter levels in DOX-treated DPP-4-deficient 4T1 cells. In an allograft mouse model, however, the effects of DOX in either primary tumor or metastasis were not statistically different between control and DPP-4-kd 4T1. Taken together, our findings suggest that DPP-4 inhibitors potentiate chemotherapy resistance via the induction of ABC transporters by the CXCL12/CXCR4/mTOR/TGFβ signaling pathway in breast cancer cells