The Anti-Ischemic Effects of PIK3IP1 in Reducing the Likelihood of Cardiac Cell Death are Mediated Through its Interactions with the ETA-PI3Kγ-AKT Axis

Abstract Oxidative stress, caused by the accumulation of reactive oxygen species (ROS) during acute myocardial infarction (AMI), is one of the main factors leading to myocardial cell damage and programmed cell death. Phosphatidylinositol-3-kinase -AKT (PI3K-AKT) signaling is essential for regulating cell proliferation, differentiation, and apoptosis. Phosphoinositide-3-kinase (PI3K)-interacting protein 1 (PIK3IP1) is an intrinsic inhibitor of PI3K in various tissues, but its functional role during AMI remains unknown. In this study, the anti-ischemic role of PIK3IP1 in an in vitro AMI setting was evaluated using H9c2 cells. The MTT assay demonstrated that cell viability decreased significantly with treatment of H2O2 (200 -500 µM). The TUNEL assay results revealed substantial cellular apoptosis following treatment with 200 µM H2O2. Under the same conditions, the expression levels of hypoxia-inducible factor (HIF-1α), endothelin-1 (ET-1), bcl-2-like protein 4 (BAX), and cleaved caspase–3, were elevated, whereas those of PIK3IP1 and Bcl-2 decreased significantly. PIK3IP1 overexpression inhibited H2O2-induced, and PI3K-mediated, apoptosis; however, PIK3IP1 knockdown reversed this effect, suggesting that PIK3IP1 functions as an anti-apoptotic molecule. To identify both the upstream and downstream molecules associated with PIK3IP1, ET-1 receptor type-specific antagonists (BQ-123 and BQ-788) and PI3K subtype-specific antagonists (LY294002 and IPI-549) were used to determine the participating isoforms. Co-immunoprecipitation was performed to identify the binding partners of PIK3IP1. Our results demonstrated that ROS-induced cardiac cell death may occur through the ETA-PI3Kγ-AKT axis, and that PIK3IP1 inhibits binding with both ETA and PI3Kγ. Taken together, these findings reveal that PIK3IP1 plays an anti-ischemic role by reducing the likelihood of programmed cell death via interacting with the ETA-PI3Kr-AKT axis.

Download Full-text

RIP1/RIP3/MLKL-mediated necroptosis contributes to vinblastine-induced myocardial damage

Molecular and Cellular Biochemistry ◽

10.1007/s11010-020-03985-3 ◽

2020 ◽

Author(s):

Huiling Zhou ◽

Lijun Liu ◽

Xiaolong Ma ◽

Jian Wang ◽

Jinfu Yang ◽

...

Keyword(s):

Ventricular Myocytes ◽

Cell Damage ◽

Animal Experiments ◽

Myocardial Damage ◽

Myocardial Cell ◽

Neonatal Rat ◽

H9c2 Cells ◽

Interacting Protein

AbstractVinblastine (VBL) has been considered as a first-line anti-tumor drug for many years. However, vinblastine-caused myocardial damage has been continually reported. The underlying molecular mechanism of the myocardial damage remains unknown. Here, we show that vinblastine induces myocardial damage and necroptosis is involved in the vinblastine-induced myocardial damage both in vitro and in vivo. The results of WST-8 and flow cytometry analysis show that vinblastine causes damage to H9c2 cells, and the results of animal experiments show that vinblastine causes myocardial cell damage. The necrosome components, receptor-interacting protein 1 (RIP1) receptor-interacting protein 3 (RIP3), are significantly increased in vinblastine-treated H9c2 cells, primary neonatal rat ventricular myocytes and rat heart tissues. And the downstream substrate of RIP3, mixed lineage kinase domain like protein (MLKL) was also increased. Pre-treatment with necroptosis inhibitors partially inhibits the necrosome components and MLKL levels and alleviates vinblastine-induced myocardial injury both in vitro and in vivo. This study indicates that necroptosis participated in vinblastine-evoked myocardial cell death partially, which would be a potential target for relieving the chemotherapy-related myocardial damage.

Download Full-text

Small molecule-mediated up-regulation of microRNA targeting a key cell death modulator BNIP3 improves cardiac function following ischemic injury

Scientific Reports ◽

10.1038/srep23472 ◽

2016 ◽

Vol 6 (1) ◽

Cited By ~ 9

Author(s):

Se-Yeon Lee ◽

Seahyoung Lee ◽

Eunhyun Choi ◽

Onju Ham ◽

Chang Youn Lee ◽

...

Keyword(s):

Cell Death ◽

Small Molecule ◽

Heart Function ◽

Ischemia Reperfusion ◽

Target Prediction ◽

Cardiac Cell ◽

Interacting Protein ◽

Genetic Ablation

Abstract Genetic ablation of BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3), an essential regulator of cardiac cell death, is an effective way to prevent cardiac cell death triggered by pathologic conditions. However, currently there exists no known means, such as inhibitors, to down-regulate BNIP3 in mature heart. Here, we report that a small molecule inducer of microRNA-182 (miR-182) suppressed ischemia/reperfusion (I/R)-induced cardiac cell death by down-regulating BNIP3. We first selected miR-182 as a potent BNIP3-targeting miRNA based on miRNA-target prediction databases and empirical data. The subsequent screening of small molecules for inducing miR-182 expression identified Kenpaullone as a hit compound. Both exogenous miR-182 and Kenpaullone significantly suppressed hypoxia-induced cardiomyocyte death in vitro. To investigate the effect of changing substituents of Kenpaullone on miR-182 expression, we synthesized 9 derivatives of Kenpaullone. Among these derivatives, compound 5 showed significantly improved ability to induce miR-182 expression. The results of the in vivo study showed that compound 5 significantly improved heart function following I/R-injury in rats. Our study provides strong evidence that the small molecule-mediated up-regulation of miRNAs is a viable strategy to down-regulate target proteins with no known chemical inhibitor and that compound 5 may have potential to prevent I/R-inflicted cardiac cell death.

Download Full-text

The role of programmed cell death ligand-1/ programmed cell death-1 (PD-L1/PD-1) in HPV-induced cervical cancer and potential for their use in blockade therapy

Current Medicinal Chemistry ◽

10.2174/0929867327666200128105459 ◽

2020 ◽

Vol 27 ◽

Cited By ~ 1

Author(s):

Lifang Zhang ◽

Yu Zhao ◽

Quanmei Tu ◽

Xiangyang Xue ◽

Xueqiong Zhu ◽

...

Keyword(s):

Cervical Cancer ◽

Cell Death ◽

Programmed Cell Death ◽

Immune Escape ◽

Hypoxia Inducible Factor ◽

Hpv Infection ◽

Advanced Cervical Cancer ◽

Cervical Carcinogenesis ◽

Programmed Cell Death 1

Background: Cervical cancer induced by infection with human papillomavirus (HPV) remains a leading cause of mortality for women worldwide although preventive vaccines and early diagnosis have reduced morbidity and mortality. Advanced cervical cancer can only be treated with either chemotherapy or radiotherapy but outcomes are poor. The median survival for advanced cervical cancer patients is only 16.8 months. Methods: We undertook a structural search of peer-reviewed published studies based on 1). Characteristics of programmed cell death ligand-1/programmed cell death-1(PD-L1/PD-1) expression in cervical cancer and upstream regulatory signals of PD-L1/PD-1 expression, 2). The role of the PD-L1/PD-1 axis in cervical carcinogenesis induced by HPV infection and 3). Whether the PD-L1/PD-1 axis has emerged as a potential target for cervical cancer therapies. Results: One hundred and twenty-six published papers were included in the review, demonstrating that expression of PD-L1/PD-1 is associated with HPV-caused cancer, especially with HPV 16 and 18 which account for approximately 70% of cervical cancer cases. HPV E5/E6/E7 oncogenes activate multiple signaling pathways including PI3K/AKT, MAPK, hypoxia-inducible factor 1α, STAT3/NF-kB and MicroRNAs, which regulate PD-L1/PD-1 axis to promote HPV-induced cervical carcinogenesis. The PD-L1/PD-1 axis plays a crucial role in immune escape of cervical cancer through inhibition of host immune response. creating an "immune-privileged" site for initial viral infection and subsequent adaptive immune resistance, which provides a rationale for therapeutic blockade of this axis in HPV-positive cancers. Currently, Phase I/II clinical trials evaluating the effects of PD-L1/PD-1 targeted therapies are in progress for cervical carcinoma, which provide an important opportunity for the application of anti-PD-L1/anti-PD-1 antibodies in cervical cancer treatment. Conclusion: Recent research developments have led to an entirely new class of drugs using antibodies against the PD-L1/PD-1 thus promoting the body’s immune system to fight the cancer. The expression and roles of the PD-L1/ PD-1 axis in the progression of cervical cancer provide great potential for using PD-L1/PD-1 antibodies as a targeted cancer therapy.

Download Full-text

In vitro antioxidant treatment recovers proliferative responses of anergic CD4+ lymphocytes from human immunodeficiency virus-infected individuals

Blood ◽

10.1182/blood.v87.11.4746.bloodjournal87114746 ◽

1996 ◽

Vol 87 (11) ◽

pp. 4746-4753 ◽

Cited By ~ 30

Author(s):

A Cayota ◽

F Vuillier ◽

G Gonzalez ◽

G Dighiero

Keyword(s):

Human Immunodeficiency Virus ◽

Cell Death ◽

Programmed Cell Death ◽

Redox Status ◽

Therapeutic Strategies ◽

Antioxidant Treatment ◽

Immunodeficiency Virus ◽

Cd4 Lymphocytes ◽

Cellular Thiol

Oxidative stress has been proposed to be involved in the immunologic defeat observed in effector calls of the immune system as well as in lymphocyte cell death and viral replication in human immunodeficiency virus (HIV)-infected patients. Because thiol-containing antioxidants such as N-acetyl-L-cysteine have been shown to have beneficial effects on CD4+ lymphocyte survival and to inhibit programmed cell death and HIV-1 replication, they may play a role in therapeutic strategies of this disease. In this work we have studied the cellular thiol levels and the affect of in vitro antioxidant treatment of purified CD4+ lymphocytes from HIV-infected patients, and correlated these parameters to proliferative responses and programmed cell death. We show that CD4+ lymphocytes from HIV-infected patients display impaired proliferative responses and a significant decrease in cellular thiol levels, indicating a disturbed redox status. Interestingly, antioxidant treatment succeeded to restore defective proliferative responses to CD3- mediated activation in 8 of 11 patients (high antioxidant responders). In contrast to high responders, patients failing to respond to antioxidant treatment (low antioxidant responders), were characterized by an abnormal ratio of apoptotic cells, which was not affected by N- acetyl-L-cysteine and/or 2-beta-mercaptoethanol preincubation. These results demonstrate for the first time that antioxidant treatment is able to revert the impaired proliferative activity of CD4 cells from HIV-infected patients and could help designing therapeutic strategies with antioxidant drugs. However, this action is not observed in cells undergoing programmed cell death.

Download Full-text

Programmed cell death 1 forms negative costimulatory microclusters that directly inhibit T cell receptor signaling by recruiting phosphatase SHP2

Journal of Experimental Medicine ◽

10.1084/jem.20112741 ◽

2012 ◽

Vol 209 (6) ◽

pp. 1201-1217 ◽

Cited By ~ 442

Author(s):

Tadashi Yokosuka ◽

Masako Takamatsu ◽

Wakana Kobayashi-Imanishi ◽

Akiko Hashimoto-Tane ◽

Miyuki Azuma ◽

...

Keyword(s):

Cell Death ◽

T Cell ◽

Programmed Cell Death ◽

T Cell Activation ◽

Cell Activation ◽

Tyrosine Phosphatase ◽

Cell Receptor ◽

Programmed Cell Death 1

Programmed cell death 1 (PD-1) is a negative costimulatory receptor critical for the suppression of T cell activation in vitro and in vivo. Single cell imaging elucidated a molecular mechanism of PD-1–mediated suppression. PD-1 becomes clustered with T cell receptors (TCRs) upon binding to its ligand PD-L1 and is transiently associated with the phosphatase SHP2 (Src homology 2 domain–containing tyrosine phosphatase 2). These negative costimulatory microclusters induce the dephosphorylation of the proximal TCR signaling molecules. This results in the suppression of T cell activation and blockade of the TCR-induced stop signal. In addition to PD-1 clustering, PD-1–TCR colocalization within microclusters is required for efficient PD-1–mediated suppression. This inhibitory mechanism also functions in PD-1hi T cells generated in vivo and can be overridden by a neutralizing anti–PD-L1 antibody. Therefore, PD-1 microcluster formation is important for regulation of T cell activation.

Download Full-text

OCT4&SOX2-specific cytotoxic T lymphocytes plus programmed cell death protein 1 inhibitor presented with synergistic effect on killing lung cancer stem-like cells in vitro and treating drug-resistant lung cancer mice in vivo

Journal of Cellular Physiology ◽

10.1002/jcp.27423 ◽

2018 ◽

Vol 234 (5) ◽

pp. 6758-6768 ◽

Cited By ~ 4

Author(s):

Xueyan Zhang ◽

Fang Hu ◽

Changhui Li ◽

Xiaoxuan Zheng ◽

Bo Zhang ◽

...

Keyword(s):

Lung Cancer ◽

Cell Death ◽

T Lymphocytes ◽

Programmed Cell Death ◽

Synergistic Effect ◽

Cytotoxic T Lymphocytes ◽

Drug Resistant ◽

Cell Death Protein

Download Full-text

Phosphorylation of the mitochondrial triphosphate tunnel metalloenzyme TTM1 regulates programmed cell death in senescence

10.1101/2020.10.06.328278 ◽

2020 ◽

Author(s):

Purva Karia ◽

Keiko Yoshioka ◽

Wolfgang Moeder

Keyword(s):

Cell Death ◽

Programmed Cell Death ◽

Map Kinases ◽

Mitochondrial Protein ◽

Mitochondrial Outer Membrane ◽

Mitogen Activated Protein ◽

Animal Growth ◽

Triphosphate Tunnel Metalloenzyme

ABSTRACTThe role of mitochondria in programmed cell death (PCD) during animal growth and development is well documented, but much less is known for plants. We previously showed that the Arabidopsis thaliana triphosphate tunnel metalloenzyme (TTM) proteins TTM1 and TTM2 are tail-anchored proteins that localize in the mitochondrial outer membrane and participate in PCD during senescence and immunity, respectively. Here, we show that TTM1 is specifically involved in senescence induced by abscisic acid (ABA). Moreover, phosphorylation of TTM1 by multiple mitogen-activated protein kinases (MAPKs) regulates its function and turnover. A combination of proteomics and in vitro kinase assays revealed three major phosphorylation sites of TTM1 (S10, S437, and S490), which are phosphorylated upon perception of senescence cues such as ABA and prolonged darkness. S437 is phosphorylated by the MAP kinases MPK3 and MPK4, and S437 phosphorylation is essential for TTM1 function in senescence. These MPKs, together with three additional MAP kinases (MPK1, MPK7, and MPK6), phosphorylate S10 and S490, marking TTM1 for protein turnover, which likely prevents uncontrolled cell death. Taken together, our results show that multiple MPKs regulate the function and turnover of the mitochondrial protein TTM1 during senescence-related PCD, revealing a novel link between mitochondria and PCD.SummaryEmail addresses: [email protected]

Download Full-text

The Importance of Exosomal PD-L1 in Cancer Progression and Its Potential as a Therapeutic Target

Cells ◽

10.3390/cells10113247 ◽

2021 ◽

Vol 10 (11) ◽

pp. 3247

Author(s):

Lingxiao Ye ◽

Zhengxin Zhu ◽

Xiaochuan Chen ◽

Haoran Zhang ◽

Jiaqi Huang ◽

...

Keyword(s):

Drug Resistance ◽

Cell Death ◽

Programmed Cell Death ◽

Cancer Progression ◽

T Cell Activation ◽

Cell Activation ◽

Immune Escape ◽

Tumor Treatment

Binding of programmed cell death ligand 1 (PD-L1) to its receptor programmed cell death protein 1 (PD-1) can lead to the inactivation of cytotoxic T lymphocytes, which is one of the mechanisms for immune escape of tumors. Immunotherapy based on this mechanism has been applied in clinic with some remaining issues such as drug resistance. Exosomal PD-L1 derived from tumor cells is considered to play a key role in mediating drug resistance. Here, the effects of various tumor-derived exosomes and tumor-derived exosomal PD-L1 on tumor progression are summarized and discussed. Researchers have found that high expression of exosomal PD-L1 can inhibit T cell activation in in vitro experiments, but the function of exosomal PD-L1 in vivo remains controversial. In addition, the circulating exosomal PD-L1 has high potential to act as an indicator to evaluate the clinical effect. Moreover, therapeutic strategy targeting exosomal PD-L1 is discussed, such as inhibiting the biogenesis or secretion of exosomes. Besides, some specific methods based on the strategy of inhibiting exosomes are concluded. Further study of exosomal PD-L1 may provide an effective and safe approach for tumor treatment, and targeting exosomal PD-L1 by inhibiting exosomes may be a potential method for tumor treatment.

Download Full-text

RIPK1 Is Cleaved by 3C Protease of Rhinovirus A and B Strains and Minor and Major Groups

Viruses ◽

10.3390/v13122402 ◽

2021 ◽

Vol 13 (12) ◽

pp. 2402

Author(s):

Sarah N. Croft ◽

Erin J. Walker ◽

Reena Ghildyal

Keyword(s):

Cell Death ◽

Protein Kinase ◽

Programmed Cell Death ◽

Protease Inhibitor ◽

Phylogenetic Groups ◽

Viral Protease ◽

Interacting Protein ◽

3C Protease ◽

Survival Pathways ◽

Integral Role

Rhinoviruses (RV), like many other viruses, modulate programmed cell death to their own advantage. The viral protease, 3C has an integral role in the modulation, and we have shown that RVA-16 3C protease cleaves Receptor-interacting protein kinase-1 (RIPK1), a key host factor that modulates various cell death and cell survival pathways. In the current study, we have investigated whether this cleavage is conserved across selected RV strains. RIPK1 was cleaved in cells infected with strains representing diversity across phylogenetic groups (A and B) and receptor usage (major and minor groups). The cleavage was abrogated in the presence of the specific 3C protease inhibitor, Rupintrivir. Interestingly, there appears to be involvement of another protease (maybe 2A protease) in RIPK1 cleavage in strains belonging to genotype B. Our data show that 3C protease from diverse RV strains cleaves RIPK1, highlighting the importance of the cleavage to the RV lifecycle.

Download Full-text