bims-miptne 2024-03-31 papers

Mol Biol Rep. 2024 Mar 29. 51(1): 473

Cellular and molecular mechanisms of cell damage and cell death in ischemia-reperfusion injury in organ transplantation.

George J Dugbartey.

Ischemia-reperfusion injury (IRI) is a critical pathological condition in which cell death plays a major contributory role, and negatively impacts post-transplant outcomes. At the cellular level, hypoxia due to ischemia disturbs cellular metabolism and decreases cellular bioenergetics through dysfunction of mitochondrial electron transport chain, causing a switch from cellular respiration to anaerobic metabolism, and subsequent cascades of events that lead to increased intracellular concentrations of Na+, H+ and Ca2+ and consequently cellular edema. Restoration of blood supply after ischemia provides oxygen to the ischemic tissue in excess of its requirement, resulting in over-production of reactive oxygen species (ROS), which overwhelms the cells' antioxidant defence system, and thereby causing oxidative damage in addition to activating pro-inflammatory pathways to cause cell death. Moderate ischemia and reperfusion may result in cell dysfunction, which may not lead to cell death due to activation of recovery systems to control ROS production and to ensure cell survival. However, prolonged and severe ischemia and reperfusion induce cell death by apoptosis, mitoptosis, necrosis, necroptosis, autophagy, mitophagy, mitochondrial permeability transition (MPT)-driven necrosis, ferroptosis, pyroptosis, cuproptosis and parthanoptosis. This review discusses cellular and molecular mechanisms of these various forms of cell death in the context of organ transplantation, and their inhibition, which holds clinical promise in the quest to prevent IRI and improve allograft quality and function for a long-term success of organ transplantation.

Keywords: Apoptosis; Autophagy; Ferroptosis; Ischemia–reperfusion injury (IRI); Necroptosis; Necrosis; Organ transplantation; Parthanoptosis; Pyroptosis

DOI: https://doi.org/10.1007/s11033-024-09261-7

Biochim Biophys Acta Mol Cell Res. 2024 Mar 21. pii: S0167-4889(24)00056-9. [Epub ahead of print] 119713

Recent advances in canonical versus non-canonical Ca2+-signaling-related anti-apoptotic Bcl-2 functions and prospects for cancer treatment.

Claire Cauwelier, Ian de Ridder, Geert Bultynck.

Cell fate is tightly controlled by a continuous balance between cell survival and cell death inducing mechanisms. B-cell lymphoma 2 (Bcl-2)-family members, composed of effectors and regulators, not only control apoptosis at the level of the mitochondria but also by impacting the intracellular Ca2+ homeostasis and dynamics. On the one hand, anti-apoptotic protein Bcl-2, prevents mitochondrial outer membrane permeabilization (MOMP) by scaffolding and neutralizing proapoptotic Bcl-2-family members via its hydrophobic cleft (region composed of BH-domain 1-3). On the other hand, Bcl-2 suppress pro-apoptotic Ca2+ signals by binding and inhibiting IP3 receptors via its BH4 domain, which is structurally exiled from the hydrophobic cleft by a flexible loop region (FLR). As such, Bcl-2 prevents excessive Ca2+ transfer from ER to mitochondria. Whereas regulation of both pathways requires different functional regions of Bcl-2, both seem to be connected in cancers that overexpress Bcl-2 in a life-promoting dependent manner. Here we discuss the anti-apoptotic canonical and non-canonical role, via calcium signaling, of Bcl-2 in health and cancer and evolving from this the proposed anti-cancer therapies with their shortcomings. We also argue how some cancers, with the major focus on diffuse large B-cell lymphoma (DLBCL) are difficult to treat, although theoretically prime marked for Bcl-2-targeting therapeutics. Further work is needed to understand the non-canonical functions of Bcl-2 also at organelles beyond the mitochondria, the interaction partners outside the Bcl-2 family as well as their ability to target or exploit these functions as therapeutic strategies in diseases.

Keywords: Anti-apoptotic proteins; Calcium signaling; Endoplasmic reticulum; IP3 receptors; Mitochondria

DOI: https://doi.org/10.1016/j.bbamcr.2024.119713

Pharmaceutics. 2024 Mar 18. pii: 416. [Epub ahead of print]16(3):

Preparation of Nanoparticles Loaded with Membrane-Impermeable Peptide AC3-I and Its Protective Effect on Myocardial Ischemia and Reperfusion.

Yi Liu, Yingyi Niu, Wenjie Zhang, Kaikai Wang, Tianqing Liu, Weizhong Zhu.

PURPOSE: It is well known that inhibition of Ca2+/calmodulin-dependent protein kinase II (CaMKII) provides cardiac protection in cases of myocardial ischemia-reperfusion injury. However, there are currently no cytoplasm-impermeable drugs that target CaMKII. The aim of this study was to develop curcumin albumin nanoparticles (HSA-CCM NPs) containing AC3-I and investigate their protective effects on hypoxia-reoxygenation (H/R)-induced injuries in adult rat cardiomyocytes and ischemia-reperfusion (I/R) injuries in isolated rat hearts.
METHODS: HSA-CCM NPs were synthesized using β-ME methods, while the membrane-impermeable peptide AC3-I was covalently linked via a disulfide bond to synthesize AC3-I@HSA-CCM NPs (AC3-I@NPs). Nanoparticle stability and drug release were characterized. To assess the cardiomyocyte uptake of AC3-I@NPs, AC3-I@NPs were incubated with cardiomyocytes under normoxia and hypoxia, respectively. The cardioprotective effect of AC3-I@NPs was determined by using a lactate dehydrogenase kit (LDH) and PI/Hoechst staining. The phosphorylation of phospholamban (p-PLB) was detected by Western blotting in hypoxia-reoxygenation and electric field stimulation models. To further investigate the protective role of AC3-I@NPs against myocardial ischemia-reperfusion injury, we collected coronary effluents and measured creatine kinase (CK) and LDH release in Langendorff rat hearts.
RESULTS: AC3-I@NPs were successfully prepared and characterized. Both HSA-CCM NPs and AC3-I@NPs were taken up by cardiomyocytes. AC3-I@NPs protected cardiomyocytes from injury caused by hypoxia-reoxygenation, as demonstrated by decreased cardiomyocyte death and LDH release. AC3-I@NPs reduced p-PLB levels evoked by hypoxia-reoxygenation and electrical field stimulation in adult rat cardiac myocytes. AC3-I@NPs decreased the release of LDH and CK from coronary effluents.
CONCLUSIONS: AC3-I@NPs showed protective effects against myocardial injuries induced by hypoxia-reoxygenation in cardiomyocytes and ischemia-reperfusion in isolated hearts.

Keywords: AC3-I; CaMKII; cardiomyocytes; ischemia–reperfusion injury; nanoparticle

DOI: https://doi.org/10.3390/pharmaceutics16030416

Evol Lett. 2024 Apr;8(2): 267-282

Intrinsic apoptosis is evolutionarily divergent among metazoans.

Gabriel Krasovec, Helen R Horkan, Éric Quéinnec, Jean-Philippe Chambon.

Apoptosis is regulated cell death that depends on caspases. A specific initiator caspase is involved upstream of each apoptotic signaling pathway. Characterized in nematode, fly, and mammals, intrinsic apoptosis is considered to be ancestral, conserved among animals, and depends on shared initiators: caspase-9, Apaf-1 and Bcl-2. However, the biochemical role of mitochondria, the pivotal function of cytochrome c and the modality of caspase activation remain highly heterogeneous and hide profound molecular divergence among apoptotic pathways in animals. Uncovering the phylogenetic history of apoptotic actors, especially caspases, is crucial to shed light on the evolutionary history of intrinsic apoptosis. Here, we demonstrate with phylogenetic analyses that caspase-9, the fundamental key of intrinsic apoptosis, is deuterostome-specific, while caspase-2 is ancestral to bilaterians. Our analysis of Bcl-2 and Apaf-1 confirms heterogeneity in functional organization of apoptotic pathways in animals. Our results support emergence of distinct intrinsic apoptotic pathways during metazoan evolution.

Keywords: cell death evolution; initiator caspases; intrinsic apoptosis; phylogeny

DOI: https://doi.org/10.1093/evlett/qrad057

Int J Mol Sci. 2024 Mar 12. pii: 3228. [Epub ahead of print]25(6):

Cellular Dynamics of Fas-Associated Death Domain in the Regulation of Cancer and Inflammation.

Kishu Ranjan, Chandramani Pathak.

Fas-associated death domain (FADD) is an adaptor protein that predominantly transduces the apoptosis signal from the death receptor (DR) to activate caspases, leading to the initiation of apoptotic signaling and the coordinated removal of damaged, infected, or unwanted cells. In addition to its apoptotic functions, FADD is involved in signaling pathways related to autophagy, cell proliferation, necroptosis, and cellular senescence, indicating its versatile role in cell survival and proliferation. The subcellular localization and intracellular expression of FADD play a crucial role in determining its functional outcomes, thereby highlighting the importance of spatiotemporal mechanisms and regulation. Furthermore, FADD has emerged as a key regulator of inflammatory signaling, contributing to immune responses and cellular homeostasis. This review provides a comprehensive summary and analysis of the cellular dynamics of FADD in regulating programmed cell death and inflammation through distinct molecular mechanisms associated with various signaling pathways.

Keywords: FADD; NF-κB; RIP kinases; apoptosis; autophagy; cancer; inflammation; therapy

DOI: https://doi.org/10.3390/ijms25063228

Environ Sci Pollut Res Int. 2024 Mar 25.

Ochratoxin A (OTA) causes intestinal aging damage through the NLRP3 signaling pathway mediated by calcium overload and oxidative stress.

Guoxia Wang, Shuai Zhang, Hainan Lan, Xin Zheng.

Ochratoxin A (OTA) is a widespread environmental toxin that poses a serious threat to human and animal health. OTA has been shown to cause cellular and tissue damage and is a global public health problem. However, the effects of OTA on gastrointestinal aging have not been reported. The aim of this study was to investigate the effects of OTA on intestinal aging in vitro and in vivo. In vitro experiments showed that OTA induced cellular inflammation through calcium overload and oxidative stress, significantly up-regulated the expression of P16, P21, and P53 proteins, markedly increased senescence-associated β-galactosidase activity (SA-β-gal) positive cells, and obviously decreased the expression of proliferating cell nuclear antigen (PCNA) proteins, which led to intestinal cell senescence. Meanwhile, we found that treatment with β-carotene ameliorated OTA-induced intestinal cell senescence. Consistent with the results of the in vitro experiments, in vivo studies showed that the intestinal aging of mice fed OTA was significantly higher than that of the control group. In conclusion, OTA may induce intestinal aging through calcium overload, oxidative stress and inflammation. This study lays a foundation for further research on the toxicological effects of OTA.

Keywords: IEC6 cells; Inflammation, Oxidative stress; Intestinal aging; Ochratoxin A; β-carotene

DOI: https://doi.org/10.1007/s11356-024-32696-1