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 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.

scholarly journals Integrin α10, a Novel Therapeutic Target in Glioblastoma, Regulates Cell Migration, Proliferation, and Survival

Cancers ◽  
2019 ◽  
Vol 11 (4) ◽  
pp. 587 ◽  
Author(s):  
Matilda Munksgaard Thorén ◽  
Katarzyna Chmielarska Masoumi ◽  
Cecilia Krona ◽  
Xiaoli Huang ◽  
Soumi Kundu ◽  
...  
Keyword(s):  
Cell Death ◽  
Therapeutic Target ◽  
Functional Role ◽  
Treatment Strategies ◽  
Antibody Drug Conjugate ◽  
Potential Therapeutic Target ◽  
Sphere Formation

New, effective treatment strategies for glioblastomas (GBMs), the most malignant and invasive brain tumors in adults, are highly needed. In this study, we investigated the potential of integrin α10β1 as a therapeutic target in GBMs. Expression levels and the role of integrin α10β1 were studied in patient-derived GBM tissues and cell lines. The effect of an antibody–drug conjugate (ADC), an integrin α10 antibody conjugated to saporin, on GBM cells and in a xenograft mouse model was studied. We found that integrin α10β1 was strongly expressed in both GBM tissues and cells, whereas morphologically unaffected brain tissues showed only minor expression. Partial or no overlap was seen with integrins α3, α6, and α7, known to be expressed in GBM. Further analysis of a subpopulation of GBM cells selected for high integrin α10 expression demonstrated increased proliferation and sphere formation. Additionally, siRNA-mediated knockdown of integrin α10 in GBM cells led to decreased migration and increased cell death. Furthermore, the ADC reduced viability and sphere formation of GBM cells and induced cell death both in vitro and in vivo. Our results demonstrate that integrin α10β1 has a functional role in GBM cells and is a novel, potential therapeutic target for the treatment of GBM.

scholarly journals STIM1/Orai1-mediated SOCE: current perspectives and potential roles in cardiac function and pathology

2013 ◽  
Vol 305 (4) ◽  
pp. H446-H458 ◽  
Author(s):  
Helen E. Collins ◽  
Xiaoyuan Zhu-Mauldin ◽  
Richard B. Marchase ◽  
John C. Chatham
Keyword(s):  
Cardiac Function ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Molecular Regulation ◽  
Cardiomyocyte Hypertrophy ◽  
Substantial Evidence ◽  
Contraction Coupling

Store-operated Ca2+ entry (SOCE) is critical for Ca2+ signaling in nonexcitable cells; however, its role in the regulation of cardiomyocyte Ca2+ homeostasis has only recently been investigated. The increased understanding of the role of stromal interaction molecule 1 (STIM1) in regulating SOCE combined with recent studies demonstrating the presence of STIM1 in cardiomyocytes provides support that this pathway co-exists in the heart with the more widely recognized Ca2+ handling pathways associated with excitation-contraction coupling. There is now substantial evidence that STIM1-mediated SOCE plays a key role in mediating cardiomyocyte hypertrophy, both in vitro and in vivo, and there is growing support for the contribution of SOCE to Ca2+ overload associated with ischemia/reperfusion injury. Here, we provide an overview of our current understanding of the molecular regulation of SOCE and discuss the evidence supporting the role of STIM1/Orai1-mediated SOCE in regulating cardiomyocyte function.

scholarly journals cGAS-mediated autophagy protects the liver from ischemia-reperfusion injury independently of STING

2018 ◽  
Vol 314 (6) ◽  
pp. G655-G667 ◽  
Author(s):  
Zhao Lei ◽  
Meihong Deng ◽  
Zhongjie Yi ◽  
Qian Sun ◽  
Richard A. Shapiro ◽  
...  
Keyword(s):  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Adenosine Monophosphate ◽  
Cyclic Guanosine Monophosphate ◽  
Protective Role ◽  
Guanosine Monophosphate ◽  
Independent Manner

Liver ischemia-reperfusion (I/R) injury occurs through induction of oxidative stress and release of damage-associated molecular patterns (DAMPs), including cytosolic DNA released from dysfunctional mitochondria or from the nucleus. Cyclic guanosine monophosphate–adenosine monophosphate (cGAMP) synthase (cGAS) is a cytosolic DNA sensor known to trigger stimulator of interferon genes (STING) and downstream type 1 interferon (IFN-I) pathways, which are pivotal innate immune system responses to pathogen. However, little is known about the role of cGAS/STING in liver I/R injury. We subjected C57BL/6 (WT), cGAS knockout (cGAS−/−), and STING-deficient (STINGgt/gt) mice to warm liver I/R injury and that found cGAS−/− mice had significantly increased liver injury compared with WT or STINGgt/gt mice, suggesting a protective effect of cGAS independent of STING. Liver I/R upregulated cGAS in vivo and also in vitro in hepatocytes subjected to anoxia/reoxygenation (A/R). We confirmed a previously published finding that hepatocytes do not express STING under normoxic conditions or after A/R. Hepatocytes and liver from cGAS−/− mice had increased cell death and reduced induction of autophagy under hypoxic conditions as well as increased apoptosis. Protection could be restored in cGAS−/− hepatocytes by overexpression of cGAS or by pretreatment of mice with autophagy inducer rapamycin. Our findings indicate a novel protective role for cGAS in the regulation of autophagy during liver I/R injury that occurs independently of STING. NEW & NOTEWORTHY Our studies are the first to document the important role of cGAS in the acute setting of sterile injury induced by I/R. Specifically, we provide evidence that cGAS protects liver from I/R injury in a STING-independent manner.

scholarly journals Smad3-Targeted Therapy Protects against Cisplatin-Induced AKI by Attenuating Programmed Cell Death and Inflammation via a NOX4-Dependent Mechanism

2021 ◽  
pp. 1-19
Author(s):  
Qin Yang ◽  
Li Gao ◽  
Xiao-wei Hu ◽  
Jia-nan Wang ◽  
Yao Zhang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Targeted Therapy ◽  
Programmed Cell Death ◽  
Functional Role ◽  
Transforming Growth Factor ◽  
Kidney Injury ◽  
Nadph Oxidase 4

<b><i>Background:</i></b> Transforming growth factor-β (TGF-β)/Smad signaling is the central mediator in renal fibrosis, yet its functional role in acute kidney injury (AKI) is not fully understood. Recent evidence showed that TGF-β/Smad3 may be involved in the pathogenesis of AKI, but its functional role and mechanism of action in cisplatin-induced AKI are unclear. <b><i>Objectives:</i></b> Demonstrating that Smad3 may play certain roles in cisplatin nephropathy due to its potential effect on programmed cell death and inflammation. <b><i>Methods:</i></b> Here, we established a cisplatin-induced AKI mouse model with Smad3 knockout mice and created stable in vitro models with Smad3 knockdown tubular epithelial cells. In addition, we tested the potential of Smad3-targeted therapy using 2 in vivo protocols – lentivirus-mediated Smad3 silencing in vivo and use of naringenin, a monomer used in traditional Chinese medicine and a natural inhibitor of Smad3. <b><i>Results:</i></b> Disruption of Smad3 attenuated cisplatin-induced kidney injury, inflammation, and NADPH oxidase 4-dependent oxidative stress. We found that Smad3-targeted therapy protected against loss of renal function and alleviated apoptosis, RIPK-mediated necroptosis, renal inflammation, and oxidative stress in cisplatin nephropathy. <b><i>Conclusions:</i></b> These findings show that Smad3 promotes cisplatin-induced AKI and Smad3-targeted therapy protects against this pathological process. These findings have substantial clinical relevance, as they suggest a therapeutic target for AKI.

scholarly journals Inhibition of Neuronal Necroptosis Mediated by RIPK1 Provides Neuroprotective Effects on Hypoxia and Ischemia In Vitro and In Vivo

2022 ◽  
Vol 23 (2) ◽  
pp. 735
Author(s):  
Elena V. Mitroshina ◽  
Maria M. Loginova ◽  
Roman S. Yarkov ◽  
Mark D. Urazov ◽  
Maria O. Novozhilova ◽  
...  
Keyword(s):  
Cell Death ◽  
Ischemia Reperfusion Injury ◽  
Pathological Condition ◽  
Ischemia Reperfusion ◽  
Laboratory Animals ◽  
Bioelectrical Activity ◽  
Electrode Arrays ◽  
Ischemic Brain

Ischemic brain injury is a widespread pathological condition, the main components of which are a deficiency of oxygen and energy substrates. In recent years, a number of new forms of cell death, including necroptosis, have been described. In necroptosis, a cascade of interactions between the kinases RIPK1 and RIPK3 and the MLKL protein leads to the formation of a specialized death complex called the necrosome, which triggers MLKL-mediated destruction of the cell membrane and necroptotic cell death. Necroptosis probably plays an important role in the development of ischemia/reperfusion injury and can be considered as a potential target for finding methods to correct the disruption of neural networks in ischemic damage. In the present study, we demonstrated that blockade of RIPK1 kinase by Necrostatin-1 preserved the viability of cells in primary hippocampal cultures in an in vitro model of glucose deprivation. The effect of RIPK1 blockade on the bioelectrical and metabolic calcium activity of neuron-glial networks in vitro using calcium imaging and multi-electrode arrays was assessed for the first time. RIPK1 blockade was shown to partially preserve both calcium and bioelectric activity of neuron-glial networks under ischemic factors. However, it should be noted that RIPK1 blockade does not preserve the network parameters of the collective calcium dynamics of neuron-glial networks, despite the maintenance of network bioelectrical activity (the number of bursts and the number of spikes in the bursts). To confirm the data obtained in vitro, we studied the effect of RIPK1 blockade on the resistance of small laboratory animals to in vivo modeling of hypoxia and cerebral ischemia. The use of Necrostatin-1 increases the survival rate of C57BL mice in modeling both acute hypobaric hypoxia and ischemic brain damage.

scholarly journals MiR-298 Exacerbates Ischemia/Reperfusion Injury Following Ischemic Stroke by Targeting Act1

2018 ◽  
Vol 48 (2) ◽  
pp. 528-539 ◽  
Author(s):  
Hongxue Sun ◽  
Di Zhong ◽  
Cheng Wang ◽  
Yilei Sun ◽  
Jiaying Zhao ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Artery Occlusion ◽  
Neurological Deficits ◽  
Luciferase Assay ◽  
Regulatory Relationship

Background/Aims: This study investigated the role of the microRNA miR-298 and its target Act1 in ischemic stroke. Methods: Cell viability was assessed with the 3-(4,5-dimethythiazol-2- yl)-2,5-diphenyl tetrazolium bromide assay. Apoptotic cells were detected by flow cytometry, and mRNA and protein expression were assessed by quantitative real-time PCR and western blotting, respectively. The regulatory relationship between miR-298 and Act1 was evaluated with the luciferase assay. To clarify the role of Act1 following ischemic stroke, the transcript was knocked down by short interfering RNA. The in vitro findings were validated in a mouse model of middle cerebral artery occlusion by administration of miR-298 mimic. Results: Act1 was upregulated whereas miR-298 was downregulated in ischemic stroke. miR-298 overexpression by transfection of a mimic suppressed Act1 protein levels in vitro and in vivo, and the luciferase assay showed that miR-298 directly binds to the 3’ untranslated region of the Act1 transcript. miR-298 overexpression enhanced cell apoptosis and autophagy and exacerbated ischemic infarction and neurological deficits, effects that were exerted via negative regulation of Act1/c-Jun N-terminal kinase (JNK)/nuclear factor (NF)-κB signaling and downstream autophagy pathways. Conclusions: Upregulation of miR-298 following ischemic stroke promotes brain injury in vitro and vivo by inhibiting the Act1/JNK/NF-κB signaling cascade and the downstream autophagy pathway. Therapeutic strategies that target miR-298 could be beneficial for the treatment of ischemic stroke.

scholarly journals Critical Roles of Calpastatin in Ischemia/Reperfusion Injury in Aged Livers

Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1863
Author(s):  
Joseph Flores-Toro ◽  
Sung-Kook Chun ◽  
Jun-Kyu Shin ◽  
Joan Campbell ◽  
Melissa Lichtenberger ◽  
...  
Keyword(s):  
Cell Death ◽  
Mitochondrial Permeability Transition ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Age Groups ◽  
Permeability Transition ◽  
Mitochondrial Morphology ◽  
Human And Mouse

Ischemia/reperfusion (I/R) injury unavoidably occurs during hepatic resection and transplantation. Aged livers poorly tolerate I/R during surgical treatment. Although livers have a powerful endogenous inhibitor of calpains, calpastatin (CAST), I/R activates calpains, leading to impaired autophagy, mitochondrial dysfunction, and hepatocyte death. It is unknown how I/R in aged livers affects CAST. Human and mouse liver biopsies at different ages were collected during in vivo I/R. Hepatocytes were isolated from 3-month- (young) and 26-month-old (aged) mice, and challenged with short in vitro simulated I/R. Cell death, protein expression, autophagy, and mitochondrial permeability transition (MPT) between the two age groups were compared. Adenoviral vector was used to overexpress CAST. Significant cell death was observed only in reperfused aged hepatocytes. Before the commencement of ischemia, CAST expression in aged human and mouse livers and mouse hepatocytes was markedly greater than that in young counterparts. However, reperfusion substantially decreased CAST in aged human and mouse livers. In hepatocytes, reperfusion rapidly depleted aged cells of CAST, cleaved autophagy-related protein 5 (ATG5), and induced defective autophagy and MPT onset, all of which were blocked by CAST overexpression. Furthermore, mitochondrial morphology was shifted toward an elongated shape with CAST overexpression. In conclusion, CAST in aged livers is intrinsically short-lived and lost after short I/R. CAST depletion contributes to age-dependent liver injury after I/R.

scholarly journals PGC-1α Protects against Hepatic Ischemia Reperfusion Injury by Activating PPARα and PPARγ and Regulating ROS Production

2021 ◽  
Vol 2021 ◽  
pp. 1-19
Author(s):  
Chaoqun Wang ◽  
Zihao Li ◽  
Baolei Zhao ◽  
Yaohua Wu ◽  
Yao Fu ◽  
...  
Keyword(s):  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Peroxisome Proliferator ◽  
Hepatic Ischemia ◽  
Peroxisome Proliferator Activated Receptors ◽  
Hepatic Ischemia Reperfusion ◽  
Serum Aminotransferases

Peroxisome proliferator-activated receptors (PPARs) α and γ have been shown to be protective in hepatic ischemia/reperfusion (I/R) injury. However, the precise role of PPARγ coactivator-1α (PGC-1α), which can coactivate both of these receptors, in hepatic I/R injury, remains largely unknown. This study was designed to test our hypothesis that PGC-1α is protective during hepatic I/R injury in vitro and in vivo. Our results show that endogenous PGC-1α is basally expressed in normal livers and is moderately increased by I/R. Ectopic PGC-1α protects against hepatic I/R and hepatocyte anoxia/reoxygenation (A/R) injuries, whereas knockdown of endogenous PGC-1α aggravates such injuries, as evidenced by assessment of the levels of serum aminotransferases and inflammatory cytokines, necrosis, apoptosis, cell viability, and histological examination. The EMSA assay shows that the activation of PPARα and PPARγ is increased or decreased by the overexpression or knockdown of PGC-1α, respectively, during hepatic I/R and hepatocyte A/R injuries. In addition, the administration of specific antagonists of either PPARα (MK886) or PPARγ (GW9662) can effectively decrease the protective effect of PGC-1α against hepatic I/R and hepatocyte A/R injuries. We also demonstrate an important regulatory role of PGC-1α in reactive oxygen species (ROS) metabolism during hepatic I/R, which is correlated with the induction of ROS-detoxifying enzymes and is also dependent on the activations of PPARα and PPARγ. These data demonstrate that PGC-1α protects against hepatic I/R injury, mainly by regulating the activation of PPARα and PPARγ. Thus, PGC-1α may be a promising therapeutic target for the protection of the liver against I/R injury.

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