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International Journal of Biological... 2024Radiotherapy (RT) stands as the primary treatment for tumors, but it inevitably causes damage to normal cells. Consequently, radiation injury is a crucial consideration... (Review)
Review
Radiotherapy (RT) stands as the primary treatment for tumors, but it inevitably causes damage to normal cells. Consequently, radiation injury is a crucial consideration for radiation oncologists during therapy planning. Cell death including apoptosis, autophagy, pyroptosis, ferroptosis, and necroptosis play significant roles in tumor treatment. While previous studies elucidated the induction of apoptosis and autophagy by ionizing radiation (IR), recent attention has shifted to pyroptosis, ferroptosis, and necroptosis, revealing their effects induced by IR. This review aims to summarize the strategies employed by IR, either alone or in combination therapy, to induce pyroptosis, ferroptosis, and necroptosis in radiation injury. Furthermore, we explore their effects and molecular pathways, shedding light on their roles in radiation injury. Finally, we summarize the regulative agents for these three types of cell death and their mechanisms. In summary, optimizing radiation dose, dose rate, and combined treatment plans to minimize radiation damage and enhance the killing effect of RT is a key focus.
Topics: Humans; Pyroptosis; Ferroptosis; Necroptosis; Radiation Injuries; Apoptosis
PubMed: 38481804
DOI: 10.7150/ijbs.91112 -
Drug Delivery Dec 2023Human struggle against the deadly disease conditions is continued since ages. The contribution of science and technology in fighting against these diseases cannot be... (Review)
Review
Human struggle against the deadly disease conditions is continued since ages. The contribution of science and technology in fighting against these diseases cannot be ignored exclusively due to the invention of novel procedure and products, extending their size ranges from micro to nano. Recently nanotechnology has been gaining more consideration for its ability to diagnose and treat different cancers. Different nanoparticles have been used to evade the issues related with conservative anticancer delivery systems, including their nonspecificity, adverse effects and burst release. These nanocarriers including, solid lipid nanoparticles (SLNs), liposomes, nano lipid carriers (NLCs), nano micelles, nanocomposites, polymeric and magnetic nanocarriers, have brought revolutions in antitumor drug delivery. Nanocarriers improved the therapeutic efficacy of anticancer drugs with better accumulation at the specific site with sustained release, improved bioavailability and apoptosis of the cancer cells while bypassing the normal cells. In this review, the cancer targeting techniques and surface modification on nanoparticles are discussed briefly with possible challenges and opportunities. It can be concluded that understanding the role of nanomedicine in tumor treatment is significant, and therefore, the modern progressions in this arena is essential to be considered for a prosperous today and an affluent future of tumor patients.
Topics: Humans; Drug Delivery Systems; Neoplasms; Micelles; Apoptosis; Biological Availability
PubMed: 36866455
DOI: 10.1080/10717544.2023.2183815 -
International Journal of Molecular... Aug 2023Diabetic retinopathy (DR) is a major complication of diabetes and a leading cause of blindness worldwide. DR was recently defined as a neurovascular disease associated... (Review)
Review
Diabetic retinopathy (DR) is a major complication of diabetes and a leading cause of blindness worldwide. DR was recently defined as a neurovascular disease associated with tissue-specific neurovascular impairment of the retina in patients with diabetes. Neurovascular cell death is the main cause of neurovascular impairment in DR. Thus, neurovascular cell protection is a potential therapy for preventing the progression of DR. Growing evidence indicates that a variety of cell death pathways, such as apoptosis, necroptosis, ferroptosis, and pyroptosis, are associated with neurovascular cell death in DR. These forms of regulated cell death may serve as therapeutic targets for ameliorating the pathogenesis of DR. This review focuses on these cell death mechanisms and describes potential therapies for the treatment of DR that protect against neurovascular cell death.
Topics: Humans; Diabetic Retinopathy; Cell Death; Apoptosis; Retina; Pyroptosis; Diabetes Mellitus
PubMed: 37629100
DOI: 10.3390/ijms241612919 -
Current Opinion in Cell Biology Feb 2024Cellular stress plays a pivotal role in the onset of numerous human diseases. Consequently, the removal of dysfunctional cells, which undergo excessive stress-induced... (Review)
Review
Cellular stress plays a pivotal role in the onset of numerous human diseases. Consequently, the removal of dysfunctional cells, which undergo excessive stress-induced damage via various cell death pathways, including apoptosis, is essential for maintaining organ integrity and function. The evolutionarily conserved family of cysteine-aspartic-proteases, known as caspases, has been a key player in orchestrating apoptosis. However, recent research has unveiled the capability of these enzymes to govern fundamental cellular processes without triggering cell death. Remarkably, some of these non-lethal functions of caspases may contribute to restoring cellular equilibrium in stressed cells. This manuscript discusses how caspases can function as cellular stress managers and their potential impact on human health and disease. Additionally, it sheds light on the limitations of caspase-based therapies, given our still incomplete understanding of the biology of these enzymes, particularly in non-apoptotic contexts.
Topics: Humans; Caspases; Apoptosis; Cell Death
PubMed: 38215516
DOI: 10.1016/j.ceb.2023.102314 -
International Journal of Biological... 2023Pyroptosis is a form of cell death that is characterized by the destruction of the cell, and it has implications in both the immune system and cancer immunotherapy. The... (Review)
Review
Pyroptosis is a form of cell death that is characterized by the destruction of the cell, and it has implications in both the immune system and cancer immunotherapy. The gasdermin family is responsible for the activation of pyroptosis, which involves the formation of pores in the cellular membrane that permit the discharge of inflammatory factors. The inflammasome response is a powerful mechanism that helps to eliminate bacteria and cancer cells when cellular damage occurs. As tumor cells become more resilient to apoptosis, other treatments for cancer are becoming more popular. It is essential to gain a thorough understanding of pyroptosis in order to use it in cancer treatment, considering the intricate association between pyroptosis and the immune system's defensive reaction against tumors. This review offers an overview of the mechanisms of pyroptosis, the relationship between the gasdermin family and pyroptosis, and the interplay between pyroptosis and anti-tumor immunity. In addition, the potential implications of pyroptosis in cancer immunotherapy are discussed. Additionally, we explore future research possibilities and introduce a novel approach to tumor treatment.
Topics: Pyroptosis; Gasdermins; Apoptosis; Cell Death; Immunotherapy
PubMed: 37705746
DOI: 10.7150/ijbs.86855 -
Journal of Hepatology Feb 2024Hepatocyte apoptosis, a well-defined form of cell death in non-alcoholic steatohepatitis (NASH), is considered the primary cause of liver inflammation and fibrosis....
BACKGROUND & AIMS
Hepatocyte apoptosis, a well-defined form of cell death in non-alcoholic steatohepatitis (NASH), is considered the primary cause of liver inflammation and fibrosis. However, the mechanisms underlying the regulation of hepatocyte apoptosis in NASH remain largely unclear. We explored the anti-apoptotic effect of hepatocyte CD1d in NASH.
METHODS
Hepatocyte CD1d expression was analyzed in patients with NASH and mouse models. Hepatocyte-specific gene overexpression or knockdown and anti-CD1d crosslinking were used to investigate the anti-apoptotic effect of hepatocyte CD1d on lipotoxicity-, Fas-, and concanavalin (ConA)-mediated liver injuries. A high-fat diet, a methionine-choline-deficient diet, a Fas agonist, and ConA were used to induce lipotoxic and/or apoptotic liver injuries. Palmitic acid was used to mimic lipotoxicity-induced apoptosis in vitro.
RESULTS
We identified a dramatic decrease in CD1d expression in hepatocytes of patients with NASH and mouse models. Hepatocyte-specific CD1d overexpression and knockdown experiments collectively demonstrated that hepatocyte CD1d protected against hepatocyte apoptosis and alleviated hepatic inflammation and injuries in NASH mice. Furthermore, decreased JAK2-STAT3 signaling was observed in NASH patient livers. Mechanistically, anti-CD1d crosslinking on hepatocytes induced tyrosine phosphorylation of the CD1d cytoplasmic tail, leading to the recruitment and phosphorylation of JAK2. Phosphorylated JAK2 activated STAT3 and subsequently reduced apoptosis in hepatocytes, which was associated with an increase in anti-apoptotic effectors (Bcl-xL and Mcl-1) and a decrease in pro-apoptotic effectors (cleaved-caspase 3/7). Moreover, anti-CD1d crosslinking effectively protected against Fas- or ConA-mediated hepatocyte apoptosis and liver injury in mice.
CONCLUSIONS
Our study uncovered a previously unrecognized anti-apoptotic CD1d-JAK2-STAT3 axis in hepatocytes that conferred hepatoprotection and highlighted the potential of hepatocyte CD1d-directed therapy for liver injury and fibrosis in NASH, as well as in other liver diseases associated with hepatocyte apoptosis.
IMPACT AND IMPLICATIONS
Excessive and/or sustained hepatocyte apoptosis is critical in driving liver inflammation and injury. The mechanisms underlying the regulation of hepatocyte apoptosis in non-alcoholic steatohepatitis (NASH) remain largely unclear. Here, we found that CD1d expression in hepatocytes substantially decreases and negatively correlates with the severity of liver injury in patients with NASH. We further revealed a previously unrecognized anti-apoptotic CD1d-JAK2-STAT3 signaling axis in hepatocytes, which confers significant protection against liver injury in NASH and acute liver diseases. Thus, hepatocyte CD1d-targeted therapy could be a promising strategy to manipulate liver injury in both NASH and other hepatocyte apoptosis-related liver diseases.
Topics: Animals; Humans; Mice; Apoptosis; Concanavalin A; Disease Models, Animal; Hepatocytes; Inflammation; Non-alcoholic Fatty Liver Disease
PubMed: 38438948
DOI: 10.1016/j.jhep.2023.10.025 -
Journal of Experimental & Clinical... Jun 2024PANoptosis represents a novel type of programmed cell death (PCD) with distinctive features that incorporate elements of pyroptosis, apoptosis, and necroptosis.... (Review)
Review
PANoptosis represents a novel type of programmed cell death (PCD) with distinctive features that incorporate elements of pyroptosis, apoptosis, and necroptosis. PANoptosis is governed by a newly discovered cytoplasmic multimeric protein complex known as the PANoptosome. Unlike each of these PCD types individually, PANoptosis is still in the early stages of research and warrants further exploration of its specific regulatory mechanisms and primary targets. In this review, we provide a brief overview of the conceptual framework and molecular components of PANoptosis. In addition, we highlight recent advances in the understanding of the molecular mechanisms and therapeutic applications of PANoptosis. By elucidating the complex crosstalk between pyroptosis, apoptosis and necroptosis and summarizing the functional consequences of PANoptosis with a special focus on the tumor immune microenvironment, this review aims to provide a theoretical basis for the potential application of PANoptosis in cancer therapy.
Topics: Humans; Neoplasms; Cell Death; Necroptosis; Tumor Microenvironment; Animals; Pyroptosis; Apoptosis
PubMed: 38877579
DOI: 10.1186/s13046-024-03089-6 -
Science Advances Mar 2024Deregulated centrosome numbers are frequently found in human cancer and can promote malignancies in model organisms. Current research aims to clarify if extra...
Deregulated centrosome numbers are frequently found in human cancer and can promote malignancies in model organisms. Current research aims to clarify if extra centrosomes are cause or consequence of malignant transformation, and if their biogenesis can be targeted for therapy. Here, we show that oncogene-driven blood cancer is inert to genetic manipulation of centrosome numbers, whereas the formation of DNA damage-induced malignancies is delayed. We provide first evidence that this unexpected phenomenon is connected to extra centrosomes eliciting a pro-death signal engaging the apoptotic machinery. Apoptosis induction requires the PIDDosome multi-protein complex, as it can be abrogated by loss of any of its three components, , , or . BCL2 overexpression equally blocks cell death, documenting for the first time induction of mitochondrial apoptosis downstream of extra centrosomes. Our findings demonstrate context-dependent effects of centrosome amplification during transformation and ask to adjust current belief that extra centrosomes are intrinsically pro-tumorigenic.
Topics: Humans; Centrosome; Apoptosis; Neoplasms; Cell Transformation, Neoplastic; DNA Damage
PubMed: 38552015
DOI: 10.1126/sciadv.adk0564 -
Frontiers in Bioscience (Landmark... Jan 2024Metabolic dysfunction-associated steatotic liver disease (MASLD) has a global prevalence of 25% and is a leading cause of cirrhosis and hepatocellular carcinoma. The... (Review)
Review
Metabolic dysfunction-associated steatotic liver disease (MASLD) has a global prevalence of 25% and is a leading cause of cirrhosis and hepatocellular carcinoma. The prevalence of MASLD has been increasing, mirroring the global increase in diabetes and metabolic syndrome. MASLD is a chronic and progressive condition characterized by inflammation, oxidative stress, insulin resistance, and disruptions in lipid metabolism. Programmed cell death (PCD) plays a pivotal role in determining the pathological aspects of MASLD, including liver inflammation, fibrosis, and even the potential for malignant transformation. PCD is a dominant process that is fundamental for eukaryotic growth and serves as a regulatory factor in MASLD. PCD encompasses various pathways, including autophagy, ferroptosis, apoptosis, and pyroptosis. These PCD pathways can be activated at different stages of MASLD. The key effector molecules involved in these processes are central focal points in the development of therapeutic interventions for MASLD. Here, we comprehensively review the idea that targeted the modulation of the PCD pathway may be an effective approach for the prevention and/or treatment of MASLD.
Topics: Humans; Pyroptosis; Ferroptosis; Apoptosis; Metabolic Diseases; Autophagy; Carcinoma, Hepatocellular; Fatty Liver; Inflammation; Liver Neoplasms
PubMed: 38287834
DOI: 10.31083/j.fbl2901030 -
ELife Dec 2023Apoptosis and clearance of apoptotic cells via efferocytosis are evolutionarily conserved processes that drive tissue repair. However, the mechanisms by which...
Apoptosis and clearance of apoptotic cells via efferocytosis are evolutionarily conserved processes that drive tissue repair. However, the mechanisms by which recognition and clearance of apoptotic cells regulate repair are not fully understood. Here, we use single-cell RNA sequencing to provide a map of the cellular dynamics during early inflammation in mouse skin wounds. We find that apoptotic pathways and efferocytosis receptors are elevated in fibroblasts and immune cells, including resident Lyve1 macrophages, during inflammation. Interestingly, human diabetic foot wounds upregulate mRNAs for efferocytosis pathway genes and display altered efferocytosis signaling via the receptor and its ligand . During early inflammation in mouse wounds, we detect upregulation of Axl in dendritic cells and fibroblasts via TLR3-independent mechanisms. Inhibition studies in vivo in mice reveal that Axl signaling is required for wound repair but is dispensable for efferocytosis. By contrast, inhibition of another efferocytosis receptor, Timd4, in mouse wounds decreases efferocytosis and abrogates wound repair. These data highlight the distinct mechanisms by which apoptotic cell detection coordinates tissue repair and provides potential therapeutic targets for chronic wounds in diabetic patients.
Topics: Humans; Animals; Mice; Apoptosis; Efferocytosis; Fibroblasts; Inflammation; Inhibition, Psychological
PubMed: 38127424
DOI: 10.7554/eLife.86269