Physiological and pharmacological modulation of BAX

Spitz, Adam Z.; Gavathiotis, Evripidis

doi:10.1016/j.tips.2021.11.001

Cited by 143 publications

(67 citation statements)

References 85 publications

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“…Among them, three genes, namely, Bax, Zbp1, and Pycard, overlapped among these three sets of genes, indicating that they may play key roles in the crosstalk among these PCD pathways. The protein encoded by the Bax gene belongs to the BCL2 protein family and is regarded as the fundamental effector of the intrinsic apoptotic pathway ( Spitz and Gavathiotis, 2022 ). Numerous studies have indicated that Bax-dependent initiation and activation of subsequent apoptotic pathways play critical roles in ischemic brain injury ( Li et al, 2021 ; Tu and Hu, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Identification of programmed cell death-related gene signature and associated regulatory axis in cerebral ischemia/reperfusion injury

Shu

Wei

et al. 2022

Front. Genet.

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Background: Numerous studies have suggested that programmed cell death (PCD) pathways play vital roles in cerebral ischemia/reperfusion (I/R) injury. However, the specific mechanisms underlying cell death during cerebral I/R injury have yet to be completely clarified. There is thus a need to identify the PCD-related gene signatures and the associated regulatory axes in cerebral I/R injury, which should provide novel therapeutic targets against cerebral I/R injury.Methods: We analyzed transcriptome signatures of brain tissue samples from mice subjected to middle cerebral artery occlusion/reperfusion (MCAO/R) and matched controls, and identified differentially expressed genes related to the three types of PCD(apoptosis, pyroptosis, and necroptosis). We next performed functional enrichment analysis and constructed PCD-related competing endogenous RNA (ceRNA) regulatory networks. We also conducted hub gene analysis to identify hub nodes and key regulatory axes.Results: Fifteen PCD-related genes were identified. Functional enrichment analysis showed that they were particularly associated with corresponding PCD-related biological processes, inflammatory response, and reactive oxygen species metabolic processes. The apoptosis-related ceRNA regulatory network was constructed, which included 24 long noncoding RNAs (lncRNAs), 41 microRNAs (miRNAs), and 4 messenger RNAs (mRNAs); the necroptosis-related ceRNA regulatory network included 16 lncRNAs, 20 miRNAs, and 6 mRNAs; and the pyroptosis-related ceRNA regulatory network included 15 lncRNAs, 18 miRNAs, and 6 mRNAs. Hub gene analysis identified hub nodes in each PCD-related ceRNA regulatory network and seven key regulatory axes in total, namely, lncRNA Malat1/miR-181a-5p/Mapt, lncRNA Malat1/miR-181b-5p/Mapt, lncRNA Neat1/miR-181a-5p/Mapt, and lncRNA Neat1/miR-181b-5p/Mapt for the apoptosis-related ceRNA regulatory network; lncRNA Neat1/miR-181a-5p/Tnf for the necroptosis-related ceRNA regulatory network; lncRNA Malat1/miR-181c-5p/Tnf for the pyroptosis-related ceRNA regulatory network; and lncRNAMalat1/miR-181a-5p for both necroptosis-related and pyroptosis-related ceRNA regulatory networks.Conclusion: The results of this study supported the hypothesis that these PCD pathways (apoptosis, necroptosis, pyroptosis, and PANoptosis) and crosstalk among them might be involved in ischemic stroke and that the key nodes and regulatory axes identified in this study might play vital roles in regulating the above processes. This may offer new insights into the potential mechanisms underlying cell death during cerebral I/R injury and provide new therapeutic targets for neuroprotection.

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Section: Discussionmentioning

confidence: 99%

Identification of programmed cell death-related gene signature and associated regulatory axis in cerebral ischemia/reperfusion injury

Shu

Wei

et al. 2022

Front. Genet.

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“…FOS, a gene critical for monocyte and macrophage function, showed that SIRT3-mediated inhibition of FOS through histone H3 deacetylation prevents cardiac fibrosis and inflammation [ 65 ]. BAX is a key protein in mitochondria that regulates cell death; the physiological function of BAX ensures tissue homeostasis; dysregulation of BAX leads to aberrant cell death [ 66 ]. Studies have shown that inhibition of the BAX expression can reduce myocardial apoptosis after ischemia reperfusion [ 67 , 68 ].…”

Section: Discussionmentioning

confidence: 99%

Integrated Gut-Heart Axis and Network Pharmacology to Reveal the Mechanisms of the Huoxue Wentong Formula Against Myocardial Ischemia

Lin

Wang

Hua

et al. 2022

Evidence-Based Complementary and Alternative Medicine

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Background. Myocardial ischemia (MI) is a major public health problem with high mortality and morbidity worldwide. Huoxue Wentong formula (HX), a traditional Chinese medicine (TCM) formula, exhibits unambiguous effects on treating MI and preventing cardiovascular diseases. However, the molecular mechanism of the therapeutic effects of HX on MI remains largely unknown. Objective. This study combined microbiology, metabolomics, and network pharmacology to explore the relationship between the gut microbiota and its metabolites in MI rats and the efficacy of HX. Methods. First, the MI rat model was established by ligation of left anterior descending. Echocardiography, Masson’s staining, and hematoxylin and eosin staining were used to evaluate the effect of HX on MI. Then, fecal metabolomics and 16S rRNA sequencing were used to obtain the microbial and metabolic characteristics of HX on MI. After that, network pharmacology was used to predict the target and action pathway of HX in treating MI. Finally, the relationship between fecal metabolites and target was explored through bioinformatics. Results. HX can improve the cardiac function and ameliorated myocardial fibrosis in MI rats. Moreover, HX can affect the gut microbiota community and metabolites of MI rats, especially Bacteroides, Deferribacteres, Ruminococcus_sp._zagget7, Acidobacteria, daidzein, L-lactic acid, and malate. Network pharmacology found that HX can function through tumor necrosis factor (TNF), tumor protein p53 (TP53), interleukin 6 (IL6), vascular endothelial growth factor A (VEGFA), fos proto-oncogene (FOS), bcl2-associated X (BAX), myeloperoxidase (MPO), PI3K-Akt signaling pathways, and HIF-1 signaling pathway. The mechanism study showed that the anti-MI effect of HX was related to valine, leucine, and isoleucine biosynthesis, fatty acid biosynthesis, and arachidonic acid metabolism. Conclusion. This study demonstrates that HX treated MI rats in a multitarget and multipathway manner. Its mechanism is related to the change of gut microbiota and the regulation of valine, leucine and isoleucine biosynthesis, fatty acid biosynthesis, and arachidonic acid metabolism.

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“…55 Finally, modulators and direct activators of BAX have shown promising pre-clinical results. 56 Studies in AML cell lines and primary samples have shown efficacy in overcoming apoptosis resistance and growth suppression without toxicity to normal cells. 57…”

Section: Abhishek Maiti Et Almentioning

confidence: 99%

SOHO State of the Art Updates and Next Questions | Beyond BCL-2 Inhibition in Acute Myeloid Leukemia: Other Approaches to Leverage the Apoptotic Pathway

Maiti

Carter

Andreeff

et al. 2022

Clinical Lymphoma Myeloma and Leukemia

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Physiological and pharmacological modulation of BAX

Cited by 143 publications

References 85 publications

Identification of programmed cell death-related gene signature and associated regulatory axis in cerebral ischemia/reperfusion injury

Identification of programmed cell death-related gene signature and associated regulatory axis in cerebral ischemia/reperfusion injury

Integrated Gut-Heart Axis and Network Pharmacology to Reveal the Mechanisms of the Huoxue Wentong Formula Against Myocardial Ischemia

SOHO State of the Art Updates and Next Questions | Beyond BCL-2 Inhibition in Acute Myeloid Leukemia: Other Approaches to Leverage the Apoptotic Pathway

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