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(1) Vildagliptin improves high glucose-induced endothelial mitochondrial dysfunction via inhibiting mitochondrial fission.[TOP]

Pubmed ID :30444033
Publication Date : //
The dipeptidyl peptidase 4 inhibitor vildagliptin (VLD), a widely used anti-diabetic drug, exerts favourable effects on vascular endothelium in diabetes. We determined for the first time the improving effects of VLD on mitochondrial dysfunction in diabetic mice and human umbilical vein endothelial cells (HUVECs) cultured under hyperglycaemic conditions, and further explored the mechanism behind the anti-diabetic activity. Mitochondrial ROS (mtROS) production was detected by fluorescent microscope and flow cytometry. Mitochondrial DNA damage and ATP synthesis were analysed by real time PCR and ATPlite assay, respectively. Mitochondrial network stained with MitoTracker Red to identify mitochondrial fragmentation was visualized under confocal microscopy. The expression levels of dynamin-related proteins (Drp1 and Fis1) were determined by immunoblotting. We found that VLD significantly reduced mtROS production and mitochondrial DNA damage, but enhanced ATP synthesis in endothelium under diabetic conditions. Moreover, VLD reduced the expression of Drp1 and Fis1, blocked Drp1 translocation into mitochondria, and blunted mitochondrial fragmentation induced by hyperglycaemia. As a result, mitochondrial dysfunction was alleviated and mitochondrial morphology was restored by VLD. Additionally, VLD promoted the phosphorylation of AMPK and its target acetyl-CoA carboxylase in the setting of high glucose, and AMPK activation led to a decreased expression and activation of Drp1. In conclusion, VLD improves endothelial mitochondrial dysfunction in diabetes, possibly through inhibiting Drp1-mediated mitochondrial fission in an AMPK-dependent manner.

Authors : Liu Hengdao, Xiang Hong, Zhao Shaoli, Sang Haiqiang, Lv Fenghua, Chen Ruifang, Shu Zhihao, Chen Alex F, Chen Shuhua, Lu Hongwei,

(2) Analysis of the Correlation between the Myocardial Expression of DPP-4 and the Clinical Parameters of Patients with Heart Failure.[TOP]

Pubmed ID :30369565
Publication Date : //
Dipeptidyl peptidase-4 (DPP-4) inhibitors are widely used as antidiabetic drugs. We recently reported that DPP-4 inhibition has beneficial effects on heart failure (HF) mice model. Furthermore, we confirmed that myocardial DPP-4 activity was significantly increased in HF mice compared with non-HF mice. The aim of this study was to investigate the level of myocardial CD26 (DPP-4) expression and its association to clinical parameters in HF patients.Endomyocardial biopsy (EMB) specimens (n = 33) were obtained from HF patients who were admitted to Chiba University Hospital from June 2006 to July 2012. EMB specimens were fixed in formaldehyde and stained with Masson's trichrome staining or with anti-CD26 antibody. Patients were divided into the high CD26 density (CD26-H) or low CD26 density groups (CD26-L). DPP-4 density was compared with blood brain natriuretic peptide (BNP) level and echocardiographic parameters at one year after EMB. Although there were no significant differences in echocardiographic parameters between the CD26-H group and CD26-L group, blood BNP levels were higher in the CD26-H group than in the CD26-L group at one year after EMB. Multivariate regression analysis showed that CD26 density was also an independent determinant of blood BNP levels at one year after EMB.The level of myocardial CD26 expression might be a predictive marker of prognosis in patients with HF.

Authors : Kobara Yuka, Hasegawa Hiroshi, Hirose Masanori, Takano Hiroyuki, Kobayashi Yoshio,

(3) Silver Fir (Abies alba) Extracts Inhibit Enzymes Involved in Blood Glucose Management and Protect against Oxidative Stress in High Glucose Environment.[TOP]

Pubmed ID :30361961
Publication Date : //
The diet rich in fruits and vegetables reduces the risk of metabolic syndrome, including diabetes development by various mechanisms of action, mainly due to the presence of polyphenolic compounds. Extracts from different conifer species are known to be a rich source of various polyphenols. In the present study we elucidated the in vitro mechanism of anti-diabetic activity of silver fir (Abies alba) wood and bark extracts and compared their activity to non-coniferous sweet chestnut wood extract and standardized maritime pine bark extract. Extracts and lignans were tested for their inhibitory activity of enzymes involved in the regulation of blood glucose in vitro. The ability of extracts to protect against oxidative stress in high glucose environment was tested on mouse myoblast cell line. Silver fir wood and bark extracts were shown to be effective inhibitors of α-glucosidase, α-amylase and dipeptidyl peptidase 4, three enzymes involved in the regulation of blood glucose levels. Coniferous extracts also showed protection against oxidative stress generated in high glucose environment. Lignans, particularly pinoresinol diglucoside, isolariciresinol and secolariciresinol were shown to be important contributors of antihyperglycemic activity through inhibition of dipeptidyl peptidase 4. This corroborates previously published in vivo results on blood glucose level obtained with silver fir wood extract and supports the use of silver fir wood and bark extracts as food supplements or functional foods in borderline diabetes.

Authors : Lunder Mojca, Roškar Irena, Hošek Jan, Štrukelj Borut,

(4) Targeting CD26 suppresses proliferation of malignant mesothelioma cell via downmodulation of ubiquitin-specific protease 22.[TOP]

Pubmed ID :30197002
Publication Date : //
Malignant pleural mesothelioma (MPM) is an aggressive malignancy arising from mesothelial lining of pleura. It is associated with a poor prognosis, partly due to the lack of a precise understanding of the molecular mechanisms associated with its malignant behavior. In the present study, we expanded on our previous studies on cell cycle control of MPM cells by targeting CD26 molecule with humanized anti-CD26 monoclonal antibody (HuCD26mAb), focusing particularly on ubiquitin-specific protease 22 (USP22). We showed that USP22 protein expression is detected in clinical specimens of MPM and that USP22 knockdown, as well as CD26 knockdown, significantly inhibits the growth and proliferation of MPM cells in vitro and in vivo. Moreover, depletion of both USP22 and CD26 suppresses MPM cell proliferation even more profoundly. Furthermore, expression levels of USP22 correlate with those of CD26. HuCD26mAb treatment induces a decrease in USP22 level through its interaction with the CD26 molecule, leading to increased levels of ubiquitinated histone H2A and p21. By demonstrating a CD26-related linkage with USP22 in MPM cell inhibition induced by HuCD26mAb, our present study hence characterizes USP22 as a novel target molecule while concurrently suggesting a new therapeutic strategy for MPM.

Authors : Okamoto Toshihiro, Yamazaki Hiroto, Hatano Ryo, Yamada Taketo, Kaneko Yutaro, Xu C Wilson, Dang Nam H, Ohnuma Kei, Morimoto Chikao,

(5) DPP4 inhibition by sitagliptin attenuates LPS-induced lung injury in mice.[TOP]

Pubmed ID :30188745
Publication Date : //
Acute respiratory distress syndrome (ARDS) is a severe clinical condition marked by acute respiratory failure and dysregulated inflammation. Pulmonary vascular endothelial cells (PVECs) function as an important pro-inflammatory source in ARDS, suggesting that modulation of inflammatory events at the endothelial level may have a therapeutic benefit. Dipeptidyl peptidase-4 (DPP4) inhibitors, widely used for the treatment of diabetes mellitus, have been reported to have possible anti-inflammatory effects. However, the potential anti-inflammatory effects of DPP4 inhibition on PVEC function and ARDS pathophysiology are unknown. Therefore, we evaluated the effects of sitagliptin, a DPP4 inhibitor in wide clinical use, on LPS-induced lung injury in mice and in human lung ECs in vitro. In vivo, sitagliptin reduced serum DPP4 activity, bronchoalveolar lavage protein concentration, cell number, and proinflammatory cytokine levels after LPS and alleviated histological findings of lung injury. LPS decreased the expression levels of CD26/DPP4 on pulmonary epithelial cells and PVECs isolated from mouse lungs, and the effect was partially reversed by sitagliptin. In vitro, human lung microvascular ECs (HLMVECs) expressed higher levels of CD26/DPP4 than human pulmonary arterial ECs. LPS induced the release of TNFα, IL-6, and IL-8 by HLMVECs that were inhibited by sitagliptin. LPS promoted the proliferation of HLMVECs, and sitagliptin suppressed this response. However, sitagliptin failed to reverse LPS-induced permeability in cultured ECs or lung epithelial cells in vitro. In summary, sitagliptin attenuates LPS-induced lung injury in mice and exerts anti-inflammatory effects on HLMVECs. These novel observations indicate DPP4 inhibitors may have potential as therapeutic drugs for ARDS.

Authors : Kawasaki Takeshi, Chen Weiguo, Htwe Yu Maw, Tatsumi Koichiro, Dudek Steven M,

(6) A Human DPP4-Knockin Mouse's Susceptibility to Infection by Authentic and Pseudotyped MERS-CoV.[TOP]

Pubmed ID :30142928
Publication Date : //
Infection by the Middle East respiratory syndrome coronavirus (MERS-CoV) causes respiratory illness and has a high mortality rate (~35%). The requirement for the virus to be manipulated in a biosafety level three (BSL-3) facility has impeded development of urgently-needed antiviral agents. Here, we established anovel mouse model by inserting human dipeptidyl peptidase 4 (hDPP4) into the Rosa26 locus using CRISPR/Cas9, resulting in global expression of the transgene in a genetically stable mouse line. The mice were highly susceptible to infection by MERS-CoV clinical strain hCoV-EMC, which induced severe diffuse pulmonary disease in the animals, and could also be infected by an optimized pseudotyped MERS-CoV. Administration of the neutralizing monoclonal antibodies, H111-1 and m336, as well as a fusion inhibitor peptide, HR2P-M2, protected mice from challenge with authentic and pseudotyped MERS-CoV. These results confirmed that the hDPP4-knockin mouse is a novel model for studies of MERS-CoV pathogenesis and anti-MERS-CoV antiviral agents in BSL-3 and BSL-2facilities, respectively.

Authors : Fan Changfa, Wu Xi, Liu Qiang, Li Qianqian, Liu Susu, Lu Jianjun, Yang Yanwei, Cao Yuan, Huang Weijin, Liang Chunnan, Ying Tianlei, Jiang Shibo, Wang Youchun,

(7) Anti-angiogenic effects of the DPP-4 inhibitor linagliptin via inhibition of VEGFR signalling in the mouse model of oxygen-induced retinopathy.[TOP]

Pubmed ID :30097694
Publication Date : //
Linagliptin has protective effects on the retinal neurovascular unit but, in proliferative retinopathy, dipeptidyl peptidase 4 (DPP-4) inhibition could be detrimental. The aim of this study was to assess the effect of linagliptin on ischaemia-induced neovascularisation of the retina.

Authors : Kolibabka Matthias, Dietrich Nadine, Klein Thomas, Hammes Hans-Peter,

(8) Design, synthesis and biological evaluation of novel pyrimidinedione derivatives as DPP-4 inhibitors.[TOP]

Pubmed ID :29773502
Publication Date : //
A series of novel pyrimidinedione derivatives were designed and evaluated for in vitro dipeptidyl peptidase-4 (DPP-4) inhibitory activity and in vivo anti-hyperglycemic efficacy. Among them, the representative compounds 11, 15 and 16 showed excellent inhibitory activity of DPP-4 with IC values of 64.47 nM, 188.7 nM and 65.36 nM, respectively. Further studies revealed that compound 11 was potent in vivo hypoglycemic effect. The structure-activity relationships of these pyrimidinedione derivatives had been discussed, which would be useful for developing novel DPP-4 inhibitors as treating type 2 diabetes.

Authors : Li Ning, Wang Li-Jun, Jiang Bo, Guo Shu-Ju, Li Xiang-Qian, Chen Xue-Chun, Luo Jiao, Li Chao, Wang Yi, Shi Da-Yong,

(9) A novel role for CD26/dipeptidyl peptidase IV as a therapeutic target.[TOP]

Pubmed ID :29772527
Publication Date : //
CD26 is a 110 kDa surface glycoprotein with intrinsic dipeptidyl peptidase IV activity that is expressed on numerous cell types and has a multitude of biological functions. The role of CD26 in immune regulation has been extensively characterized, with recent findings elucidating its linkage with signaling pathways and structures involved in T-lymphocyte activation as well as antigen presenting cell-T-cell interaction. In this paper, we will review emerging data on CD26-mediated immune regulation suggesting that CD26 may be an appropriate therapeutic target for the treatment of selected immune disorders as well as Middle East respiratory syndrome coronavirus. Moreover, we have had a long-standing interest in the role of CD26 in cancer biology and its suitability as a novel therapeutic target in selected neoplasms. We reported robust data on the anti-tumor activity of anti-CD26 monoclonal antibody in mouse xenograft models. We herein review significant novel findings and the early clinical development of a CD26-targeted therapy in selected immune disorders and cancers, advances that can lead to a more hopeful future for patients with these intractable diseases.

Authors : Ohnuma Kei, Hatano Ryo, Komiya Eriko, Otsuka Haruna, Itoh Takumi, Iwao Noriaki, Kaneko Yutaro, Yamada Taketo, Dang Nam H, Morimoto Chikao,

(10) Phenotyping and Target Expression Profiling of CD34/CD38 and CD34/CD38 Stem- and Progenitor cells in Acute Lymphoblastic Leukemia.[TOP]

Pubmed ID :29772458
Publication Date : //
Leukemic stem cells (LSCs) are an emerging target of curative anti-leukemia therapy. In acute lymphoblastic leukemia (ALL), LSCs frequently express CD34 and often lack CD38. However, little is known about markers and targets expressed in ALL LSCs. We have examined marker- and target expression profiles in CD34/CD38 LSCs in patients with Ph ALL (n = 22) and Ph ALL (n = 27) by multi-color flow cytometry and qPCR. ALL LSCs expressed CD19 (B4), CD44 (Pgp-1), CD123 (IL-3RA), and CD184 (CXCR4) in all patients tested. Moreover, in various subgroups of patients, LSCs also displayed CD20 (MS4A1) (10/41 = 24%), CD22 (12/20 = 60%), CD33 (Siglec-3) (20/48 = 42%), CD52 (CAMPATH-1) (17/40 = 43%), IL-1RAP (13/29 = 45%), and/or CD135 (FLT3) (4/20 = 20%). CD25 (IL-2RA) and CD26 (DPPIV) were expressed on LSCs in Ph ALL exhibiting BCR/ABL1, whereas in Ph ALL with BCR/ABL1, LSCs variably expressed CD25 but did not express CD26. In Ph ALL, CD34/CD38 LSCs expressed IL-1RAP in 6/18 patients (33%), but did not express CD25 or CD26. Normal stem cells stained negative for CD25, CD26 and IL-1RAP, and expressed only low amounts of CD52. In xenotransplantation experiments, CD34/CD38 and CD34/CD38 cells engrafted NSG mice after 12-20 weeks, and targeting with antibodies against CD33 and CD52 resulted in reduced engraftment. Together, LSCs in Ph and Ph ALL display unique marker- and target expression profiles. In Ph ALL with BCR/ABL1, the LSC-phenotype closely resembles the marker-profile of CD34/CD38 LSCs in chronic myeloid leukemia, confirming the close biologic relationship of these neoplasms. Targeting of LSCs with specific antibodies or related immunotherapies may facilitate LSC eradication in ALL.

Authors : Blatt Katharina, Menzl Ingeborg, Eisenwort Gregor, Cerny-Reiterer Sabine, Herrmann Harald, Herndlhofer Susanne, Stefanzl Gabriele, Sadovnik Irina, Berger Daniela, Keller Alexandra, Hauswirth Alexander, Hoermann Gregor, Willmann Michael, Rülicke Thomas, Sill Heinz, Sperr Wolfgang R, Mannhalter Christine, Melo Junia V, Jäger Ulrich, Sexl Veronika, Valent Peter,