scholarly journals The Role of the Key Effector of Necroptotic Cell Death, MLKL, in Mouse Models of Disease

Biomolecules ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 803
Author(s):  
Emma C. Tovey Crutchfield ◽  
Sarah E. Garnish ◽  
Joanne M. Hildebrand
Keyword(s):  
Cell Death ◽  
Mouse Models ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Sterile Inflammation ◽  
Murine Models ◽  
Genetic Deletion ◽  
Models Of Disease ◽  
Terminal Effector

Necroptosis is an inflammatory form of lytic programmed cell death that is thought to have evolved to defend against pathogens. Genetic deletion of the terminal effector protein—MLKL—shows no overt phenotype in the C57BL/6 mouse strain under conventional laboratory housing conditions. Small molecules that inhibit necroptosis by targeting the kinase activity of RIPK1, one of the main upstream conduits to MLKL activation, have shown promise in several murine models of non-infectious disease and in phase II human clinical trials. This has triggered in excess of one billion dollars (USD) in investment into the emerging class of necroptosis blocking drugs, and the potential utility of targeting the terminal effector is being closely scrutinised. Here we review murine models of disease, both genetic deletion and mutation, that investigate the role of MLKL. We summarize a series of examples from several broad disease categories including ischemia reperfusion injury, sterile inflammation, pathogen infection and hematological stress. Elucidating MLKL’s contribution to mouse models of disease is an important first step to identify human indications that stand to benefit most from MLKL-targeted drug therapies.

scholarly journals Up-regulation of MicroRNA-21 Mediates Isoflurane-induced Protection of Cardiomyocytes

2015 ◽  
Vol 122 (4) ◽  
pp. 795-805 ◽  
Author(s):  
Jessica M. Olson ◽  
Yasheng Yan ◽  
Xiaowen Bai ◽  
Zhi-Dong Ge ◽  
Mingyu Liang ◽  
...  
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Messenger Rna ◽  
Functional Role ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Cell Death Protein

Abstract Background: Anesthetic cardioprotection reduces myocardial infarct size after ischemia–reperfusion injury. Currently, the role of microRNA in this process remains unknown. MicroRNAs are short, noncoding nucleotide sequences that negatively regulate gene expression through degradation or suppression of messenger RNA. In this study, the authors uncovered the functional role of microRNA-21 (miR-21) up-regulation after anesthetic exposure. Methods: MicroRNA and messenger RNA expression changes were analyzed by quantitative real-time polymerase chain reaction in cardiomyocytes after exposure to isoflurane. Lactate dehydrogenase release assay and propidium iodide staining were conducted after inhibition of miR-21. miR-21 target expression was analyzed by Western blot. The functional role of miR-21 was confirmed in vivo in both wild-type and miR-21 knockout mice. Results: Isoflurane induces an acute up-regulation of miR-21 in both in vivo and in vitro rat models (n = 6, 247.8 ± 27.5% and 258.5 ± 9.0%), which mediates protection to cardiomyocytes through down-regulation of programmed cell death protein 4 messenger RNA (n = 3, 82.0 ± 4.9% of control group). This protective effect was confirmed by knockdown of miR-21 and programmed cell death protein 4 in vitro. In addition, the protective effect of isoflurane was abolished in miR-21 knockout mice in vivo, with no significant decrease in infarct size compared with nonexposed controls (n = 8, 62.3 ± 4.6% and 56.2 ± 3.2%). Conclusions: The authors demonstrate for the first time that isoflurane mediates protection of cardiomyocytes against oxidative stress via an miR-21/programmed cell death protein 4 pathway. These results reveal a novel mechanism by which the damage done by ischemia/reperfusion injury may be decreased.

scholarly journals Polycystin-2 is upregulated in fibrotic kidneys and inhibition of plycystin-2 by triptolide attenuates renal fibrosis

2021 ◽  
Author(s):  
Ming Wu ◽  
Yanzhe Wang ◽  
Yin Jing ◽  
Juanyan Lin ◽  
Dongping Chen ◽  
...  
Keyword(s):  
Mouse Models ◽  
Direct Effect ◽  
Renal Fibrosis ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Inhibitory Effect ◽  
Dependent Manner ◽  
Hk2 Cells ◽  
Cyst Growth

Mutations in PKD2 gene, which encodes polycystin-2, cause autosomal polycystic kidney disease (ADPKD). Development of ADPKD is associated with progression of renal fibrosis. Whether renal fibrosis in ADPKD is a direct effect of polycystin-2 mutation or a consequence of cyst growth induced tubular obstruction is currently unknown. Polycystin-2 has been identified as a direct target of triptolide, and we used triptolide as a probe to study the role of polycystin-2 in renal fibrosis. To study the expression of polycystin-2, we established unilateral ureteral obstruction (UUO), unilateral ischemia-reperfusion injury (UIRI) and aristolochic acid nephropathy mouse models. Here we showed that polycystin-2 is up-regulated in these three mouse models and tightly correlated with the expression of collagen-I in a time dependent manner. Treatment with triptolide inhibited the expression of polycystin-2 and pro-fibrotic markers in UUO and UIRI models. Moreover, triptolide dose-dependently inhibited the expression of polycystin-2 and pro-fibrotic markers in rat renal fibroblasts or in TGF-β stimulated human renal epithelial (HK2) cells. Knockdown of PKD2 reduced the expression of pro-fibrotic markers in TGF-β stimulated or unstimulated HK2 cells. Finally, we showed that knockdown of PKD2 attenuated the inhibitory effect of triptolide on the expression of pro-fibrotic markers in TGF-β stimulated HK2 cells. In conclusion, polycystin-2 is a pro-fibrotic protein suggesting that renal fibrosis in ADPKD kidneys is not a direct effect of PKD2 mutation.

scholarly journals C-type lectin Mincle mediates cell death–triggered inflammation in acute kidney injury

2020 ◽  
Vol 217 (11) ◽  
Author(s):  
Miyako Tanaka ◽  
Marie Saka-Tanaka ◽  
Kozue Ochi ◽  
Kumiko Fujieda ◽  
Yuki Sugiura ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Cell Death ◽  
Free Cholesterol ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Sterile Inflammation ◽  
Renal Tubular Cell ◽  
Renal Tubules ◽  
Underlying Mechanisms

Accumulating evidence indicates that cell death triggers sterile inflammation and that impaired clearance of dead cells causes nonresolving inflammation; however, the underlying mechanisms are still unclear. Here, we show that macrophage-inducible C-type lectin (Mincle) senses renal tubular cell death to induce sustained inflammation after acute kidney injury in mice. Mincle-deficient mice were protected against tissue damage and subsequent atrophy of the kidney after ischemia–reperfusion injury. Using lipophilic extract from the injured kidney, we identified β-glucosylceramide as an endogenous Mincle ligand. Notably, free cholesterol markedly enhanced the agonistic effect of β-glucosylceramide on Mincle. Moreover, β-glucosylceramide and free cholesterol accumulated in dead renal tubules in proximity to Mincle-expressing macrophages, where Mincle was supposed to inhibit clearance of dead cells and increase proinflammatory cytokine production. This study demonstrates that β-glucosylceramide in combination with free cholesterol acts on Mincle as an endogenous ligand to induce cell death–triggered, sustained inflammation after acute kidney injury.

scholarly journals Ferroptosis and its facet in Cancer therapy

2021 ◽  
Vol 6 (1) ◽  
pp. 10-15
Author(s):  
Shreya Shreshtha
Keyword(s):  
Cell Death ◽  
Cell Therapy ◽  
Cancer Cell ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Death Process ◽  
Cell Organelles ◽  
Clinical Role ◽  
Cell Death Process

Ferroptosis is a regulated process impelled by iron-dependent lipid peroxidation. It is a new type of cell destruction processes including apoptosis, autophagy and necrosis. It demonstrates mainly the contraction of mitochondria and expansion of mitochondrial membrane density which does not lead to any alteration in morphology. Due to the malfunctioning of ferroptosis several disorders arise which includes damage of one or more nerve which leads to numbness and muscle weakness whereas ischemia reperfusion injury, acute kidney failure and cancer also occurs. Also, ferroptosis is induced in large number of cancer cells through series of small molecules which helps in to bringing out this process. In scientific research and medicine many findings contribute in the chance of defeating cancer by genetic or pharmacological interference with ferroptosis cell death which is appealing for various researches. There are multiple pathways and cell organelles which plays a role in ferroptosis regulation. Ongoing studies on ferroptosis have demonstrated its role in humans though its mechanism is not yet clear. Recently, various studies have encouraged the role of this newly emerged cell death process and also showed some effective usage in the treatment of cancer. Here, we review the mitochondrial aspect of ferroptosis as well as discuss on the role of ferroptosis in Cancer cell therapy. We will also aim on the future scope of ferroptosis in the treatment of Cancer as well as discuss about the problems related to its clinical role which may trigger the cancer cell therapy.

scholarly journals Autophagy Dynamics and Modulation in a Rat Model of Renal Ischemia-Reperfusion Injury

2020 ◽  
Vol 21 (19) ◽  
pp. 7185
Author(s):  
Jean-Paul Decuypere ◽  
Shawn Hutchinson ◽  
Diethard Monbaliu ◽  
Wim Martinet ◽  
Jacques Pirenne ◽  
...  
Keyword(s):  
Cell Death ◽  
Rat Model ◽  
Renal Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Mammalian Target Of Rapamycin ◽  
Treatment Strategies ◽  
Kidney Injury ◽  
Renal Ischemia

Renal ischemia-reperfusion (IR) injury leading to cell death is a major cause of acute kidney injury, contributing to morbidity and mortality. Autophagy counteracts cell death by removing damaged macromolecules and organelles, making it an interesting anchor point for treatment strategies. However, autophagy is also suggested to enhance cell death when the ischemic burden is too strong. To investigate whether the role of autophagy depends on the severity of ischemic stress, we analyzed the dynamics of autophagy and apoptosis in an IR rat model with mild (45 min) or severe (60 min) renal ischemia. Following mild IR, renal injury was associated with reduced autophagy, enhanced mammalian target of rapamycin (mTOR) activity, and apoptosis. Severe IR, on the other hand, was associated with a higher autophagic activity, independent of mTOR, and without affecting apoptosis. Autophagy stimulation by trehalose injected 24 and 48 h prior to onset of severe ischemia did not reduce renal injury markers nor function, but reduced apoptosis and restored tubular dilation 7 days post reperfusion. This suggests that trehalose-dependent autophagy stimulation enhances tissue repair following an IR injury. Our data show that autophagy dynamics are strongly dependent on the severity of IR and that trehalose shows the potential to trigger autophagy-dependent repair processes following renal IR injury.

scholarly journals microRNA-377 Signaling Modulates Anticancer Drug-Induced Cardiotoxicity in Mice

2021 ◽  
Vol 8 ◽  
Author(s):  
John Henderson ◽  
Praveen K. Dubey ◽  
Mallikarjun Patil ◽  
Sarojini Singh ◽  
Shubham Dubey ◽  
...  
Keyword(s):  
Cell Death ◽  
Rna Sequencing ◽  
Molecular Mechanisms ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Drug Induced ◽  
Chemotherapy Agent

Doxorubicin (DOX, an anthracycline) is a widely used chemotherapy agent against various forms of cancer; however, it is also known to induce dose-dependent cardiotoxicity leading to adverse complications. Investigating the underlying molecular mechanisms and strategies to limit DOX-induced cardiotoxicity might have potential clinical implications. Our previous study has shown that expression of microRNA-377 (miR-377) increases in cardiomyocytes (CMs) after cardiac ischemia-reperfusion injury in mice, but its specific role in DOX-induced cardiotoxicity has not been elucidated. In the present study, we investigated the effect of anti-miR-377 on DOX-induced cardiac cell death, remodeling, and dysfunction. We evaluated the role of miR-377 in CM apoptosis, its target analysis by RNA sequencing, and we tested the effect of AAV9-anti-miR-377 on DOX-induced cardiotoxicity and mortality. DOX administration in mice increases miR-377 expression in the myocardium. miR-377 inhibition in cardiomyocyte cell line protects against DOX-induced cell death and oxidative stress. Furthermore, RNA sequencing and Gene Ontology (GO) analysis revealed alterations in a number of cell death/survival genes. Intriguingly, we observed accelerated mortality and enhanced myocardial remodeling in the mice pretreated with AAV9-anti-miR-377 followed by DOX administration as compared to the AAV9-scrambled-control-pretreated mice. Taken together, our data suggest that in vitro miR-377 inhibition protects against DOX-induced cardiomyocyte cell death. On the contrary, in vivo administration of AAV9-anti-miR-377 increases mortality in DOX-treated mice.

1843: Role of Cxcr2 in Renal Ischemia/Reperfusion Injury

2004 ◽  
Vol 171 (4S) ◽  
pp. 487-487
Author(s):  
Motoo Araki ◽  
Masayoshi Miura ◽  
Hiromi Kumon ◽  
John Belperio ◽  
Robert Strieter ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Renal Ischemia ◽  
Renal Ischemia Reperfusion Injury
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