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Thrombosis Research Nov 2023In a healthy individual, the lifespan of most platelets is tightly regulated by intrinsic, or mitochondrial, apoptosis. This is a special form of programmed cell death... (Review)
Review
In a healthy individual, the lifespan of most platelets is tightly regulated by intrinsic, or mitochondrial, apoptosis. This is a special form of programmed cell death governed by the BCL-2 family of proteins, where the prosurvival protein BCL-X maintains platelet viability by restraining the prodeath proteins BAK and BAX. Restriction of platelet lifespan by activation of BAK and BAX mediated intrinsic apoptosis is essential to maintain a functional, haemostatically reactive platelet population. This review focuses on the molecular regulation of intrinsic apoptosis in platelets, reviews conditions linked to enhanced platelet death, discusses ex vivo storage of platelets and describes caveats associated with the assessment of platelet apoptosis.
Topics: Humans; bcl-2-Associated X Protein; Blood Platelets; Apoptosis; bcl-X Protein
PubMed: 36739256
DOI: 10.1016/j.thromres.2022.11.024 -
Cell Death & Disease Nov 2023The mechanism underlying acute kidney injury (AKI) and AKI-to-Chronic kidney disease (CKD) transition remains unclear, but mitochondrial dysfunction may be a key driving...
The mechanism underlying acute kidney injury (AKI) and AKI-to-Chronic kidney disease (CKD) transition remains unclear, but mitochondrial dysfunction may be a key driving factor. Literature reports suggest that dual-specificity phosphatase 1 (DUSP1) plays a critical role in maintaining mitochondrial function and structural integrity. In this study, ischemic Acute Kidney Injury (AKI) and post-ischemic fibrosis models were established by clamping the renal pedicle with different reperfusion times. To investigate the role of DUSP1, constitutional Dusp1 knockout mice and tubular-specific Sting knockout mice were used. Mitochondrial damage was assessed through electron microscopy observation, measurements of mitochondrial membrane potential, mtDNA release, and BAX translocation. We found that Dusp1 expression was significantly upregulated in human transplant kidney tissue and mouse AKI tissue. Dusp1 gene deletion exacerbated acute ischemic injury, post-ischemic renal fibrosis, and tubular mitochondrial dysfunction in mice. Mechanistically, DUSP1 could directly bind to JNK, and DUSP1 deficiency could lead to aberrant phosphorylation of JNK and BAX mitochondria translocation. BAX translocation promoted mitochondrial DNA (mtDNA) leakage and activated the cGAS-STING pathway. Inhibition of JNK or BAX could inhibit mtDNA leakage. Furthermore, STING knockout or JNK inhibition could significantly mitigate the adverse effects of DUSP1 deficiency in ischemic AKI model. Collectively, our findings suggest that DUSP1 is a regulator for the protective response during AKI. DUSP1 protects against AKI by preventing BAX-induced mtDNA leakage and blocking excessive activation of the cGAS-STING signaling axis through JNK dephosphorylation.
Topics: Animals; Humans; Mice; Acute Kidney Injury; bcl-2-Associated X Protein; DNA, Mitochondrial; Dual Specificity Phosphatase 1; Kidney; Mice, Knockout; Mitochondria; Nucleotidyltransferases; Reperfusion Injury
PubMed: 37935658
DOI: 10.1038/s41419-023-06247-4 -
Biomedicine & Pharmacotherapy =... Sep 2023Cardiac hypertrophy is frequently associated with ventricular dysfunction and heart failure. Paeoniflorin, has been widely used to treat cardiovascular...
Cardiac hypertrophy is frequently associated with ventricular dysfunction and heart failure. Paeoniflorin, has been widely used to treat cardiovascular dysfunction-related diseases. However, the underlying mechanism has been unclear. Here, we investigated the potential inhibitory effects and mechanism of paeoniflorin on oxidative stress of cardiac hypertrophy induced by angiotensin II (AngII) in vitro. Using MTS assay, qRT-PCR, WGA staining assay, and western blot, different dosages (50-400 μM) of paeoniflorin were utilized to examine the antihypertrophy effects on H9c2 cells. Western blot examination revealed the presence of apoptosis-related proteins Bax, Bcl2, and Cytc, antioxidative stress-related proteins Nrf2, HO-1, SOD, and CAT, and mitophagy-related proteins PINK1 and Parkin. qRT-PCR was used to detect the mRNA expression of Bax, Bcl2, Nrf2, and HO-1. TUNEL, caspase3/9 enzyme viability, and MDA, T-AOC, and superoxide levels were all evaluated using commercial kits.The fluorescent probes DCFH-DA and JC-1 were employed to measure cellular ROS and MMP levels. Nrf2 siRNA was utilized to investigate Nrf2's role in paeoniflorin-treated cardiac hypertrophy. Paeoniflorin dramatically reduced cell section area (CSA) and hypertrophic marker (ANP, BNP) expression while inhibiting oxidative stress by modulating ROS and MDA, CAT, SOD, and T-AOC levels. Furthermore, in AngII-induced cardiomyocyte hypertrophy, paeoniflorin restores H9c2 apoptosis by restoring Bax, Bcl-2 Cyt-C, Caspase 3, and Caspase 9 levels. Paeoniflorin also restored Nrf2/HO-1 and PINK1/Parkin expression, and its anti-AngII activities were mediated by Nrf2, which was regulated by Nrf2 knockdown. In conclusion, Our data confirm that paeoniflorin alleviates cardiac hypertrophy through modulating oxidative stress and Nrf2 signaling pathway in vitro.
Topics: Animals; Rats; Angiotensin II; Apoptosis; Apoptosis Regulatory Proteins; bcl-2-Associated X Protein; Cardiomegaly; Myocytes, Cardiac; NF-E2-Related Factor 2; Oxidative Stress; Protein Kinases; Proto-Oncogene Proteins c-bcl-2; Rats, Sprague-Dawley; Reactive Oxygen Species; Signal Transduction; Superoxide Dismutase
PubMed: 37542855
DOI: 10.1016/j.biopha.2023.115253 -
Apoptosis : An International Journal on... Oct 2023Mitochondrial dysfunction and necroptosis are closely associated, and play vital roles in the medical strategy of multiple cardiovascular diseases. However, their...
Comprehensive analysis of mitochondrial dysfunction and necroptosis in intracranial aneurysms from the perspective of predictive, preventative, and personalized medicine.
Mitochondrial dysfunction and necroptosis are closely associated, and play vital roles in the medical strategy of multiple cardiovascular diseases. However, their implications in intracranial aneurysms (IAs) remain unclear. In this study, we aimed to explore whether mitochondrial dysfunction and necroptosis could be identified as valuable starting points for predictive, preventive, and personalized medicine for IAs. The transcriptional profiles of 75 IAs and 37 control samples were collected from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs), weighted gene co-expression network analysis, and least absolute shrinkage and selection operator (LASSO) regression were used to screen key genes. The ssGSEA algorithm was performed to establish phenotype scores. The correlation between mitochondrial dysfunction and necroptosis was evaluated using functional enrichment crossover, phenotype score correlation, immune infiltration, and interaction network construction. The IA diagnostic values of key genes were identified using machine learning. Finally, we performed the single-cell sequencing (scRNA-seq) analysis to explore mitochondrial dysfunction and necroptosis at the cellular level. In total, 42 IA-mitochondrial DEGs and 15 IA-necroptosis DEGs were identified. Screening revealed seven key genes invovled in mitochondrial dysfunction (KMO, HADH, BAX, AADAT, SDSL, PYCR1, and MAOA) and five genes involved in necroptosis (IL1B, CAMK2G, STAT1, NLRP3, and BAX). Machine learning confirmed the high diagnostic value of these key genes for IA. The IA samples showed higher expression of mitochondrial dysfunction and necroptosis. Mitochondrial dysfunction and necroptosis exhibited a close association. Furthermore, scRNA-seq indicated that mitochondrial dysfunction and necroptosis were preferentially up-regulated in monocytes/macrophages and vascular smooth muscle cells (VSMCs) within IA lesions. In conclusion, mitochondria-induced necroptosis was involved in IA formation, and was mainly up-regulated in monocytes/macrophages and VSMCs within IA lesions. Mitochondria-induced necroptosis may be a novel potential target for diagnosis, prevention, and treatment of IA.
Topics: Humans; Precision Medicine; Intracranial Aneurysm; Necroptosis; bcl-2-Associated X Protein; Apoptosis
PubMed: 37410216
DOI: 10.1007/s10495-023-01865-x -
Nature Communications Dec 2023The BCL-2 family protein BAX is a major regulator of physiological and pathological cell death. BAX predominantly resides in the cytosol in a quiescent state and upon...
The BCL-2 family protein BAX is a major regulator of physiological and pathological cell death. BAX predominantly resides in the cytosol in a quiescent state and upon stress, it undergoes conformational activation and mitochondrial translocation leading to mitochondrial outer membrane permeabilization, a critical event in apoptosis execution. Previous studies reported two inactive conformations of cytosolic BAX, a monomer and a dimer, however, it remains unclear how they regulate BAX. Here we show that, surprisingly, cancer cell lines express cytosolic inactive BAX dimers and/or monomers. Expression of inactive dimers, results in reduced BAX activation, translocation and apoptosis upon pro-apoptotic drug treatments. Using the inactive BAX dimer structure and a pharmacophore-based drug screen, we identify a small-molecule modulator, BDM19 that binds and activates cytosolic BAX dimers and prompts cells to apoptosis either alone or in combination with BCL-2/BCL-XL inhibitor Navitoclax. Our findings underscore the role of the cytosolic inactive BAX dimer in resistance to apoptosis and demonstrate a strategy to potentiate BAX-mediated apoptosis.
Topics: bcl-2-Associated X Protein; Cytosol; Apoptosis; Biological Transport; Antineoplastic Agents; Proto-Oncogene Proteins c-bcl-2; bcl-X Protein
PubMed: 38104127
DOI: 10.1038/s41467-023-44084-3 -
The Journal of Clinical Investigation Jul 2023Targeted therapies such as venetoclax (VEN) (Bcl-2 inhibitor) have revolutionized the treatment of chronic lymphocytic leukemia (CLL). We previously reported that...
Targeted therapies such as venetoclax (VEN) (Bcl-2 inhibitor) have revolutionized the treatment of chronic lymphocytic leukemia (CLL). We previously reported that persister CLL cells in treated patients overexpress multiple antiapoptotic proteins and display resistance to proapoptotic agents. Here, we demonstrated that multidrug-resistant CLL cells in vivo exhibited apoptosis restriction at a pre-mitochondrial level due to insufficient activation of the Bax and Bak (Bax/Bak) proteins. Co-immunoprecipitation analyses with selective BH domain antagonists revealed that the pleiotropic proapoptotic protein (Bim) was prevented from activating Bax/Bak by "switching" interactions to other upregulated antiapoptotic proteins (Mcl-1, Bcl-xL, Bcl-2). Hence, treatments that bypass Bax/Bak restriction are required to deplete these resistant cells in patients. Protein phosphatase 2A (PP2A) contributes to oncogenesis and treatment resistance. We observed that small-molecule activator of PP2A (SMAP) induced cytotoxicity in multiple cancer cell lines and CLL samples, including multidrug-resistant leukemia and lymphoma cells. The SMAP (DT-061) activated apoptosis in multidrug-resistant CLL cells through induction of mitochondrial permeability transition pores, independent of Bax/Bak. DT-061 inhibited the growth of wild-type and Bax/Bak double-knockout, multidrug-resistant CLL cells in a xenograft mouse model. Collectively, we discovered multidrug-resistant CLL cells in patients and validated a pharmacologically tractable pathway to deplete this reservoir.
Topics: Humans; Animals; Mice; bcl-2-Associated X Protein; Leukemia, Lymphocytic, Chronic, B-Cell; Protein Phosphatase 2; Myeloid Cell Leukemia Sequence 1 Protein; Proto-Oncogene Proteins c-bcl-2; Apoptosis; Apoptosis Regulatory Proteins; Drug Resistance, Multiple
PubMed: 37166997
DOI: 10.1172/JCI155938 -
Cell Death & Disease Jul 2023Small molecule direct BAK activators can potentially be used for the development of anti-cancer drugs or as tools to study BAK activation. The thrombopoietin receptor...
Small molecule direct BAK activators can potentially be used for the development of anti-cancer drugs or as tools to study BAK activation. The thrombopoietin receptor agonist eltrombopag (Eltro) inhibits BAX activation and BAX-mediated apoptosis. Here we report that, in contrast to its function as a BAX inhibitor, Eltro directly binds BAK but induces its activation in vitro. Moreover, Eltro induces or sensitizes BAK-dependent cell death in mouse embryonic fibroblasts (MEFs) and Jurkat cells. Chemical shift perturbation analysis by NMR indicates that Eltro binds to the BAK α4/α6/α7 groove to initiate BAK activation. Further molecular docking by HADDOCK suggests that several BAK residues, including R156, F157, and H164, play an important role in the interaction with Eltro. The introduction of an R156E mutation in the BAK α4/α6/α7 groove not only decreases Eltro binding and Eltro-induced BAK activation in vitro but also diminishes Eltro-induced apoptosis. Thus, our data suggest that Eltro directly induces BAK activation and BAK-dependent apoptosis, providing a starting point for the future development of more potent and selective direct BAK activators.
Topics: Animals; Mice; Molecular Docking Simulation; bcl-2-Associated X Protein; Fibroblasts; Apoptosis
PubMed: 37393297
DOI: 10.1038/s41419-023-05918-6 -
International Journal of Molecular... Mar 2024Breast cancer is the second leading contributor to the age-standardized mortality rate, for both sexes and all ages worldwide. In Europe and the United States, it is the... (Review)
Review
Breast cancer is the second leading contributor to the age-standardized mortality rate, for both sexes and all ages worldwide. In Europe and the United States, it is the second leading cause of mortality, with an incidence rate of about 2.6 million cases per year. Noscapine, a well-known alkaloid used as a cough suppressant, demonstrated anti-tumor effects by triggering apoptosis in various cancer cell lines and has the potential to become another ally against breast, ovarian, colon, and gastric cancer, among other types of malignancy. Apoptosis plays a crucial role in the treatment of cancer. Noscapine affected , , , , and gene and protein expression in the MCF-7 and MDA-MB-231 cell lines. Gene expression was higher in tumor than in normal tissue, including the BAX expression levels in lung, ovary, endometrium, colon, stomach, and glioblastoma patients; BCL2L1 expression in endometrium, colon, and stomach patients; CASP8 gene expression levels in lung, endometrium, colon, stomach, and glioblastoma patients; RELA in colon, stomach, and glioblastoma patients; and NFKBIA in glioblastoma patients. It can be concluded that noscapine affected genes and proteins related to apoptosis in cancer cell lines and several types of cancer patients.
Topics: Male; Female; Humans; Noscapine; bcl-2-Associated X Protein; Glioblastoma; Apoptosis; Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation
PubMed: 38542508
DOI: 10.3390/ijms25063536 -
Endocrine Aug 2023CHCHD2 is an antiapoptotic mitochondrial protein acting through the BCL2/BAX pathway in various cancers. However, data on the regulatory role of CHCHD2 in adrenal...
PURPOSE
CHCHD2 is an antiapoptotic mitochondrial protein acting through the BCL2/BAX pathway in various cancers. However, data on the regulatory role of CHCHD2 in adrenal tumourigenesis are scarce.
METHODS
We studied the expression of CHCHD2, BCL2, and BAX in human adrenocortical tissues and SW13 cells. mRNA and protein levels were analyzed through qPCR and immunoblotting, respectively, in 16 benign adrenocortical neoplasms (BANs), along with their adjacent normal adrenal tissues (controls), and 10 adrenocortical carcinomas (ACCs). BCL2/BAX mRNA expression was also analyzed in SW13 cells after CHCHD2 silencing. MTS, flow cytometry and scratch assays were performed to assess cell viability, apoptosis, and invasion, respectively.
RESULTS
BCL2 and CHCHCD2 mRNA and protein expression was increased in BANs compared to normal adrenal tissues whereas BAX was decreased. BAX and CHCHD2 mRNA and protein levels were significantly downregulated and upregulated, respectively, in ACCs compared with either BANs or controls. Expression of the studied genes was not different among cortisol-secreting and nonfunctional ACAs. No significant association was found between genes' expression and other established prognostic markers of ACCs patients. In vitro analysis showed that CHCHD2 silencing resulted in reduced cell viability and invasion as well as increased SW13 cells apoptosis.
CONCLUSIONS
CHCHD2 expression seems to be implicated in adrenal tumourigenesis and its absence resulted to increased apoptosis in vitro. However, the exact mechanism of action and particularly its association with the BAX/BCL2 pathway needs to be further studied and evaluate whether it could be a protentional therapeutic target.
Topics: Humans; Adrenal Cortex Neoplasms; bcl-2-Associated X Protein; Adrenocortical Carcinoma; RNA, Messenger; Carcinogenesis; Cell Transformation, Neoplastic; Apoptosis; DNA-Binding Proteins; Transcription Factors
PubMed: 37221428
DOI: 10.1007/s12020-023-03393-9 -
Redox Report : Communications in Free... Dec 2024Acrylamide is a toxic substance formed in some foods that require high-temperature cooking processes and has been implicated as a gonadotoxic agent. Zinc, on the other...
BACKGROUND
Acrylamide is a toxic substance formed in some foods that require high-temperature cooking processes and has been implicated as a gonadotoxic agent. Zinc, on the other hand, is a known antioxidant with fertility-enhancing properties. Hence, this study was designed to explore the possible ameliorative effect of zinc in acrylamide-induced gonadotoxicity.
METHODS
Twenty-four male Wistar rats were randomized into control, acrylamide (10 mg/kg of acrylamide), acrylamide + 1 mg/kg of zinc, and acrylamide + 3 mg/kg of zinc. The administration was via the oral route and lasted for 56 days.
RESULTS
Zinc treatment ameliorated acrylamide-impaired sperm quality, normal testicular histoarchitecture, and hormonal balance, which was accompanied by increased testicular malondialdehyde and interleukin-1β and decreased testicular superoxide dismutase (SOD) and catalase (CAT). Furthermore, zinc prevented acrylamide-induced downregulation of testicular nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), and B-cell lymphoma 2 (BCl2) expression and upregulation of testicular nuclear factor kappa B (NF-κB) and bcl-2-like protein 4 (bax) expression.
CONCLUSION
In conclusion, zinc may protect against acrylamide-induced testicular toxicity, mediated by its antioxidant, anti-inflammatory, and antiapoptotic effects.
Topics: Animals; Male; Rats; Acrylamide; Antioxidants; Apoptosis; bcl-2-Associated X Protein; Heme Oxygenase-1; NF-E2-Related Factor 2; NF-kappa B; Oxidative Stress; Proto-Oncogene Proteins c-bcl-2; Rats, Wistar; Semen; Signal Transduction; Zinc
PubMed: 38629506
DOI: 10.1080/13510002.2024.2341537