scholarly journals Imatinib protects against human beta-cell death via inhibition of mitochondrial respiration and activation of AMPK

2021 ◽  
Author(s):  
Andris Elksnis ◽  
Tomas A Schiffer ◽  
Fredrik Palm ◽  
Yun Wang ◽  
Jing Cen ◽  
...  
Keyword(s):  
Cell Death ◽  
Tyrosine Kinase ◽  
Beta Cell ◽  
Mitochondrial Respiration ◽  
Kinase Inhibitor ◽  
Direct Interaction ◽  
Ampk Activation ◽  
Beta Cell Death ◽  
Compound C

The protein tyrosine kinase inhibitor imatinib is used in the treatment of various malignancies, but may also promote beneficial effects in the treatment of diabetes. The aim of the present investigation was to characterize the mechanisms by which imatinib protects insulin producing cells. Treatment of NOD mice with imatinib resulted in increased beta-cell AMPK phosphorylation. Imatinib activated AMPK also in vitro, resulting in decreased ribosomal protein S6 phosphorylation and protection against IAPP-aggregation, TXNIP upregulation and beta-cell death. AICAR mimicked and compound C counteracted the effect of imatinib on beta-cell survival. Imatinib-induced AMPK activation was preceded by reduced glucose/pyruvate-dependent respiration, increased glycolysis rates, and a lowered ATP/AMP ratio. Imatinib augmented the fractional oxidation of fatty acids/malate, possibly via a direct interaction with the beta-oxidation enzyme ECHS1. In non-beta cells, imatinib reduced respiratory chain complex I and II-mediated respiration and ACC phosphorylation, suggesting that mitochondrial effects of imatinib are not beta-cell specific. In conclusion, tyrosine kinase inhibitors modestly inhibit mitochondrial respiration, leading to AMPK activation and TXNIP downregulation, which in turn protects against beta-cell death.

In vitro profiling of endocrine cell death using UCHL1 and GAD65 as soluble biomarkers

2016 ◽  
Author(s):  
Benedicte Brackeva ◽  
Sarah Roels ◽  
Geert Stangé ◽  
Gamze Ates ◽  
Olivier R. Costa ◽  
...  
Keyword(s):  
Cell Death ◽  
Beta Cell ◽  
Beta Cells ◽  
Islet Transplantation ◽  
High Sensitivity ◽  
Low Grade ◽  
Variable Degree ◽  
Beta Cell Death

AbstractBACKGROUNDPancreatic islet grafts are cultured in vitro prior to transplantation and this is associated to a variable degree of beta cell loss. Optimization of culture conditions is currently hampered by the lack of a specific and sensitive in vitro indicator of beta cell death.METHODSWe developed a high-sensitivity duplex bead-based immunoassay for two protein-type biomarkers of beta cell destruction, GAD65 and UCHL1, and investigated its proficiency for in vitro toxicity profiling on rodent and human beta cells, as compared to a semi-automatic and manual image-based assessment of beta cell death, and in vivo after intraportal islet transplantation.RESULTSBoth GAD65 and UCHL1 were discharged by necrotic and apoptotic beta cells proportionate to the number of dead beta cells as counted by microscopic methods. In vitro, UCHL1 was superior to GAD65, in terms of biomarker stability providing more sensitive detection of low grade beta cell death. In vivo, however, GAD65 was consistently detected after islet transplantation while UCHL1 remained undetectable.CONCLUSIONThe use of soluble biomarkers represents a fast, selective and sensitive method for beta cell toxicity profiling in vitro. UCHL1 is superior to GAD65 in vitro but not in vivo.

scholarly journals Deletion of protein kinase Cδ in mice modulates stability of inflammatory genes and protects against cytokine-stimulated beta cell death in vitro and in vivo

Diabetologia ◽  
2010 ◽  
Vol 54 (2) ◽  
pp. 380-389 ◽  
Author(s):  
J. Cantley ◽  
E. Boslem ◽  
D. R. Laybutt ◽  
D. V. Cordery ◽  
G. Pearson ◽  
...  
Keyword(s):  
Cell Death ◽  
Protein Kinase ◽  
Beta Cell ◽  
Beta Cell Death ◽  
Inflammatory Genes ◽  
Protein Kinase Cδ

scholarly journals Regulation of forkhead box O1 (FOXO1) by protein kinase B and glucocorticoids: different mechanisms of induction of beta cell death in vitro

Diabetologia ◽  
2013 ◽  
Vol 56 (7) ◽  
pp. 1587-1595 ◽  
Author(s):  
G. Kaiser ◽  
F. Gerst ◽  
D. Michael ◽  
S. Berchtold ◽  
B. Friedrich ◽  
...  
Keyword(s):  
Cell Death ◽  
Protein Kinase ◽  
Beta Cell ◽  
Protein Kinase B ◽  
Beta Cell Death ◽  
Forkhead Box

Evidence for Necroptosis as a Mechanism of Islet Amyloid–Induced Beta-Cell Death

Diabetes ◽  
2018 ◽  
Vol 67 (Supplement 1) ◽  
pp. 82-OR
Author(s):  
ANDREW T. TEMPLIN ◽  
MEGHAN F. HOGAN ◽  
NATHALIE ESSER ◽  
SAKENEH ZRAIKA ◽  
REBECCA L. HULL ◽  
...  
Keyword(s):  
Cell Death ◽  
Beta Cell ◽  
Islet Amyloid ◽  
Beta Cell Death

Apoptosis is the mode of beta-cell death responsible for the development of IDDM in the nonobese diabetic (NOD) mouse

Diabetes ◽  
1997 ◽  
Vol 46 (5) ◽  
pp. 750-757 ◽  
Author(s):  
B. A. O'Brien ◽  
B. V. Harmon ◽  
D. P. Cameron ◽  
D. J. Allan
Keyword(s):  
Cell Death ◽  
Beta Cell ◽  
Nod Mouse ◽  
Beta Cell Death ◽  
Nonobese Diabetic

scholarly journals Targeting USP47 overcomes tyrosine kinase inhibitor resistance and eradicates leukemia stem/progenitor cells in chronic myelogenous leukemia

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Hu Lei ◽  
Han-Zhang Xu ◽  
Hui-Zhuang Shan ◽  
Meng Liu ◽  
Ying Lu ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Progenitor Cells ◽  
Chronic Myelogenous Leukemia ◽  
Drug Targets ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Myelogenous Leukemia ◽  
Tki Resistance

AbstractIdentifying novel drug targets to overcome resistance to tyrosine kinase inhibitors (TKIs) and eradicating leukemia stem/progenitor cells are required for the treatment of chronic myelogenous leukemia (CML). Here, we show that ubiquitin-specific peptidase 47 (USP47) is a potential target to overcome TKI resistance. Functional analysis shows that USP47 knockdown represses proliferation of CML cells sensitive or resistant to imatinib in vitro and in vivo. The knockout of Usp47 significantly inhibits BCR-ABL and BCR-ABLT315I-induced CML in mice with the reduction of Lin−Sca1+c-Kit+ CML stem/progenitor cells. Mechanistic studies show that stabilizing Y-box binding protein 1 contributes to USP47-mediated DNA damage repair in CML cells. Inhibiting USP47 by P22077 exerts cytotoxicity to CML cells with or without TKI resistance in vitro and in vivo. Moreover, P22077 eliminates leukemia stem/progenitor cells in CML mice. Together, targeting USP47 is a promising strategy to overcome TKI resistance and eradicate leukemia stem/progenitor cells in CML.

Perinatal exposure to silver nanoparticles reprograms immunometabolism and promotes pancreatic beta-cell death and kidney damage in mice

2021 ◽  
pp. 1-25
Author(s):  
Ratnakar Tiwari ◽  
Radha Dutt Singh ◽  
Monika Binwal ◽  
Anurag Kumar Srivastav ◽  
Neha Singh ◽  
...  
Keyword(s):  
Silver Nanoparticles ◽  
Cell Death ◽  
Beta Cell ◽  
Pancreatic Beta Cell ◽  
Kidney Damage ◽  
Perinatal Exposure ◽  
Beta Cell Death

scholarly journals Integrin α6 mediates the drug resistance of acute lymphoblastic B-cell leukemia

Blood ◽  
2020 ◽  
Vol 136 (2) ◽  
pp. 210-223 ◽  
Author(s):  
Eun Ji Gang ◽  
Hye Na Kim ◽  
Yao-Te Hsieh ◽  
Yongsheng Ruan ◽  
Heather A. Ogana ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Tyrosine Kinase ◽  
B Cell ◽  
Kinase Inhibitor ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Underlying Mechanism ◽  
Conditional Knockout

Abstract Resistance to multimodal chemotherapy continues to limit the prognosis of acute lymphoblastic leukemia (ALL). This occurs in part through a process called adhesion-mediated drug resistance, which depends on ALL cell adhesion to the stroma through adhesion molecules, including integrins. Integrin α6 has been implicated in minimal residual disease in ALL and in the migration of ALL cells to the central nervous system. However, it has not been evaluated in the context of chemotherapeutic resistance. Here, we show that the anti-human α6-blocking Ab P5G10 induces apoptosis in primary ALL cells in vitro and sensitizes primary ALL cells to chemotherapy or tyrosine kinase inhibition in vitro and in vivo. We further analyzed the underlying mechanism of α6-associated apoptosis using a conditional knockout model of α6 in murine BCR-ABL1+ B-cell ALL cells and showed that α6-deficient ALL cells underwent apoptosis. In vivo deletion of α6 in combination with tyrosine kinase inhibitor (TKI) treatment was more effective in eradicating ALL than treatment with a TKI (nilotinib) alone. Proteomic analysis revealed that α6 deletion in murine ALL was associated with changes in Src signaling, including the upregulation of phosphorylated Lyn (pTyr507) and Fyn (pTyr530). Thus, our data support α6 as a novel therapeutic target for ALL.

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