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Annual Review of Cell and Developmental... Oct 2018Balancing cell death and survival is essential for normal development and homeostasis and for preventing diseases, especially cancer. Conventional cell death pathways... (Review)
Review
Balancing cell death and survival is essential for normal development and homeostasis and for preventing diseases, especially cancer. Conventional cell death pathways include apoptosis, a form of programmed cell death controlled by a well-defined biochemical pathway, and necrosis, the lysis of acutely injured cells. New types of regulated cell death include necroptosis, pyroptosis, ferroptosis, phagoptosis, and entosis. Autophagy can promote survival or can cause death. Newly described processes of anastasis and resuscitation show that, remarkably, cells can recover from the brink of apoptosis or necroptosis. Important new work shows that epithelia achieve homeostasis by extruding excess cells, which then die by anoikis due to loss of survival signals. This mechanically regulated process both maintains barrier function as cells die and matches rates of proliferation and death. In this review, we describe these unconventional ways in which cells have evolved to die or survive, as well as the contributions that these processes make to homeostasis and cancer.
Topics: Anoikis; Apoptosis; Autophagy; Cell Proliferation; Entosis; Homeostasis; Humans; Necrosis; Neoplasms; Pyroptosis; Signal Transduction
PubMed: 30089222
DOI: 10.1146/annurev-cellbio-100616-060748 -
Proceedings (Baylor University. Medical... Apr 2018The have a significant role in mythology, religion, folklore, and literature. In the 1800s, the word was used to describe reanimated corpses in the Caribbean who often...
The have a significant role in mythology, religion, folklore, and literature. In the 1800s, the word was used to describe reanimated corpses in the Caribbean who often worked on plantations doing long, arduous field work. The movie was released in 1932 and exploited this folklore, but it ignored the fact that zombies represent one outcome in Vodou religious beliefs regarding death and the migration of spirits following death. The interest in zombies eventually led to sociological and medical investigations into zombification. Wade Davis reported that powders used by malevolent priests contained tetrodotoxin, which could cause the neurologic changes underlying the zombie phenotype. Recent clinical studies have indicated that synthetic cannabinoids and synthetic cathinones can cause bizarre zombie-like behavior. According to Haitian folklore, zombies can develop when reanimate someone who suddenly died from an acute illness or who was purposely poisoned. Recent studies in molecular biology suggest that the sequence of programmed cell death can be reversed when the stressor is removed and that cells, tissues, and bodies (at least in flies) can recover. These scientific studies would support the remote possibility that the near dead might recover under certain circumstances but have residual neuropsychological dysfunction. Alternatively, the could maintain control of their victims using drugs with properties similar to those of synthetic cannabinoids. The concept of zombification needs to be considered in the context of culture, religion, and science.
PubMed: 29706835
DOI: 10.1080/08998280.2018.1441216 -
Cancers Jun 2022Colorectal cancer (CRC) is one of the leading causes of death worldwide. The 5-year survival rate is 90% for patients with early CRC, 70% for patients with locally... (Review)
Review
Colorectal cancer (CRC) is one of the leading causes of death worldwide. The 5-year survival rate is 90% for patients with early CRC, 70% for patients with locally advanced CRC, and 15% for patients with metastatic CRC (mCRC). In fact, most CRC patients are at an advanced stage at the time of diagnosis. Although chemotherapy, molecularly targeted therapy and immunotherapy have significantly improved patient survival, some patients are initially insensitive to these drugs or initially sensitive but quickly become insensitive, and the emergence of such primary and secondary drug resistance is a significant clinical challenge. The most direct cause of resistance is the aberrant anti-tumor drug metabolism, transportation or target. With more in-depth research, it is found that cell death pathways, carcinogenic signals, compensation feedback loop signal pathways and tumor immune microenvironment also play essential roles in the drug resistance mechanism. Here, we assess the current major mechanisms of CRC resistance and describe potential therapeutic interventions.
PubMed: 35740594
DOI: 10.3390/cancers14122928 -
Bioactive Materials Sep 2023A long-standing paucity of effective therapies results in the poor outcomes of triple-negative breast cancer brain metastases. Immunotherapy has made progress in the...
A long-standing paucity of effective therapies results in the poor outcomes of triple-negative breast cancer brain metastases. Immunotherapy has made progress in the treatment of tumors, but limited by the non-immunogenicity of tumors and strong immunosuppressive environment, patients with TNBC brain metastases have not yet benefited from immunotherapy. Dual immunoregulatory strategies with enhanced immune activation and reversal of the immunosuppressive microenvironment provide new therapeutic options for patients. Here, we propose a cocktail-like therapeutic strategy of microenvironment regulation-chemotherapy-immune synergistic sensitization and construct reduction-sensitive immune microenvironment regulation nanomaterials (SIL@T). SIL@T modified with targeting peptide penetrates the BBB and is subsequently internalized into metastatic breast cancer cells, releasing silybin and oxaliplatin responsively in the cells. SIL@T preferentially accumulates at the metastatic site and can significantly prolong the survival period of model animals. Mechanistic studies have shown that SIL@T can effectively induce immunogenic cell death of metastatic cells, activate immune responses and increase infiltration of CD8 T cells. Meanwhile, the activation of STAT3 in the metastatic foci is attenuated and the immunosuppressive microenvironment is reversed. This study demonstrates that SIL@T with dual immunomodulatory functions provides a promising immune synergistic therapy strategy for breast cancer brain metastases.
PubMed: 37159612
DOI: 10.1016/j.bioactmat.2023.04.021 -
Current Opinion in Virology Oct 2019HIV cure is impeded by the persistence of a strenuous reservoir of latent but replication competent infected cells, which remain unsusceptible to c-ART and unrecognized... (Review)
Review
HIV cure is impeded by the persistence of a strenuous reservoir of latent but replication competent infected cells, which remain unsusceptible to c-ART and unrecognized by the immune system for elimination. Ongoing progress in understanding the molecular mechanisms that control HIV transcription and latency has led to the development of strategies to either permanently inactivate the latent HIV infected reservoir of cells or to stimulate the virus to emerge out of latency, coupled to either induction of death in the infected reactivated cell or its clearance by the immune system. This review focuses on the currently explored and non-exclusive pharmacological strategies and their molecular targets that 1. stimulate reversal of HIV latency in infected cells by targeting distinct steps in the HIV-1 gene expression cycle, 2. exploit mechanisms that promote cell death and apoptosis to render the infected cell harboring reactivated virus more susceptible to death and/or elimination by the immune system, and 3. permanently inactivate any remaining latently infected cells such that c-ART can be safely discontinued.
Topics: Anti-HIV Agents; CD4-Positive T-Lymphocytes; CpG Islands; DNA Methylation; Drug Development; Gene Expression Regulation, Viral; HIV Infections; HIV Long Terminal Repeat; HIV-1; Humans; Transcriptional Activation; Viral Load; Virus Activation; Virus Latency; Virus Replication
PubMed: 31323521
DOI: 10.1016/j.coviro.2019.06.001 -
Frontiers in Cell and Developmental... 2019Mechanoreciprocity refers to a cell's ability to maintain tensional homeostasis in response to various types of forces. Physical forces are continually being exerted... (Review)
Review
Mechanoreciprocity refers to a cell's ability to maintain tensional homeostasis in response to various types of forces. Physical forces are continually being exerted upon cells of various tissue types, even those considered static, such as the brain. Through mechanoreceptors, cells sense and subsequently respond to these stimuli. These forces and their respective cellular responses are prevalent in regulating everything from embryogenic tissue-specific differentiation, programmed cell death, and disease progression, the last of which being the subject of extensive attention. Abnormal mechanical remodeling of cells can provide clues as to the pathological status of tissues. This becomes particularly important in cancer cells, where cellular stiffness has been recently accepted as a novel biomarker for cancer metastasis. Several studies have also elucidated the importance of cell stiffness in cancer metastasis, with data highlighting that a reversal of tumor stiffness has the capacity to revert the metastatic properties of cancer. In this review, we summarize our current understanding of extracellular matrix (ECM) homeostasis, which plays a prominent role in tissue mechanics. We also describe pathological disruption of the ECM, and the subsequent implications toward cancer and cancer metastasis. In addition, we highlight the most novel approaches toward understanding the mechanisms which generate pathogenic cell stiffness and provide potential new strategies which have the capacity to advance our understanding of one of human-kinds' most clinically significant medical pathologies. These new strategies include video-based techniques for structural dynamics, which have shown great potential for identifying full-field, high-resolution modal properties, in this case, as a novel application.
PubMed: 31637239
DOI: 10.3389/fcell.2019.00199 -
Pharmaceutics Mar 2023Retinal neurodegeneration is considered an early event in the pathogenesis of several ocular diseases, such as diabetic retinopathy, age-related macular degeneration,... (Review)
Review
Retinal neurodegeneration is considered an early event in the pathogenesis of several ocular diseases, such as diabetic retinopathy, age-related macular degeneration, and glaucoma. At present, there is no definitive treatment to prevent the progression or reversal of vision loss caused by photoreceptor degeneration and the death of retinal ganglion cells. Neuroprotective approaches are being developed to increase the life expectancy of neurons by maintaining their shape/function and thus prevent the loss of vision and blindness. A successful neuroprotective approach could prolong patients' vision functioning and quality of life. Conventional pharmaceutical technologies have been investigated for delivering ocular medications; however, the distinctive structural characteristics of the eye and the physiological ocular barriers restrict the efficient delivery of drugs. Recent developments in bio-adhesive in situ gelling systems and nanotechnology-based targeted/sustained drug delivery systems are receiving a lot of attention. This review summarizes the putative mechanism, pharmacokinetics, and mode of administration of neuroprotective drugs used to treat ocular disorders. Additionally, this review focuses on cutting-edge nanocarriers that demonstrated promising results in treating ocular neurodegenerative diseases.
PubMed: 36986699
DOI: 10.3390/pharmaceutics15030837 -
Journal of Pineal Research Aug 2022Efficient cell-to-cell communication is essential for tissue development, homeostasis, and the maintenance of cellular functions after injury. Tunneling nanotubes (TNTs)... (Review)
Review
Efficient cell-to-cell communication is essential for tissue development, homeostasis, and the maintenance of cellular functions after injury. Tunneling nanotubes (TNTs) have emerged as a new important method of cell-to-cell communication. TNTs are primarily established between stressed and unstressed cells and can transport a variety of cellular components. Mitochondria are important trafficked entities through TNTs. Transcellular mitochondria transfer permits the incorporation of healthy mitochondria into the endogenous network of recipient cells, changing the bioenergetic profile and other functional properties of the recipient and may allow the recipient cells to recuperate from apoptotic processes and return to a normal operating state. Mesenchymal cells (MSCs) can form TNTs and transfer mitochondria and other constituents to target cells. This occurs under both physiological and pathological conditions, leading to changes in cellular energy metabolism and functions. This review summarizes the newly described capacity of melatonin to improve mitochondrial fusion/fission dynamics and promote TNT formation. This new evidence suggests that melatonin's protective effects could be attributed to its ability to prevent mitochondrial damage in injured cells, reduce senescence, and promote anastasis, a natural cell recovery phenomenon that rescues cells from the brink of death. The modulation of these new routes of intercellular communication by melatonin could play a key role in increasing the therapeutic potential of MSCs.
Topics: Cell Communication; Cell Membrane Structures; Melatonin; Mesenchymal Stem Cells; Nanotubes
PubMed: 35419879
DOI: 10.1111/jpi.12800 -
Nature Medicine Jul 2020Common germline variants of the APOE gene are major risk modifiers of neurodegenerative and atherosclerotic diseases, but their effect on cancer outcome is poorly...
Common germline variants of the APOE gene are major risk modifiers of neurodegenerative and atherosclerotic diseases, but their effect on cancer outcome is poorly defined. Here we report that, in a reversal of their effect on Alzheimer's disease, the APOE4 and APOE2 variants confer favorable and poor outcomes in melanoma, respectively. Mice expressing the human APOE4 allele exhibited reduced melanoma progression and metastasis relative to APOE2 mice. APOE4 mice exhibited enhanced anti-tumor immune activation relative to APOE2 mice, and T cell depletion experiments showed that the effect of APOE genotype on melanoma progression was mediated by altered anti-tumor immunity. Consistently, patients with melanoma carrying the APOE4 variant experienced improved survival in comparison to carriers of APOE2. Notably, APOE4 mice also showed improved outcomes under PD1 immune checkpoint blockade relative to APOE2 mice, and patients carrying APOE4 experienced improved anti-PD1 immunotherapy survival after progression on frontline regimens. Finally, enhancing APOE expression via pharmacologic activation of liver X receptors, previously shown to boost anti-tumor immunity, exhibited therapeutic efficacy in APOE4 mice but not in APOE2 mice. These findings demonstrate that pre-existing hereditary genetics can impact progression and survival outcomes of a future malignancy and warrant prospective investigation of APOE genotype as a biomarker for melanoma outcome and therapeutic response.
Topics: Animals; Apolipoprotein E2; Apolipoprotein E3; Apolipoprotein E4; Brain; Disease Progression; Disease-Free Survival; Female; Genotype; Germ-Line Mutation; Humans; Melanoma; Mice; Mice, Transgenic; Programmed Cell Death 1 Receptor
PubMed: 32451497
DOI: 10.1038/s41591-020-0879-3 -
Cellular and Molecular Gastroenterology... 2023Alterations in mitochondrial morphology and function and increased oxidative stresses in hepatocytes are well established in nonalcoholic fatty liver disease (NAFLD)....
BACKGROUND & AIMS
Alterations in mitochondrial morphology and function and increased oxidative stresses in hepatocytes are well established in nonalcoholic fatty liver disease (NAFLD). Patients can undergo lifestyle changes, especially in earlier NAFLD stages, to reverse disease-induced phenotypes on a gross level. Yet, little is known about whether mitochondrial function and injuries recover upon reversal. Thus, we elucidated this question and interplays between the cytoskeletal network and mitochondria in the development and reversal of steatosis.
METHODS
We cultured primary human hepatocytes stably for 2 weeks and used free fatty acid supplementation to induce steatosis over 7 days and reversed steatosis by free fatty acid withdrawal over the next 7 days. We assessed cytoskeletal and mitochondrial morphologies using immunocytochemistry and confocal microscopy. We evaluated mitochondrial respiration and function via the Seahorse analyzer, in which we fully optimized reagent dosing specifically for human hepatocytes.
RESULTS
During early steatosis, intracellular lipid droplets displaced microtubules altering mitochondrial distribution, and disrupted the F-actin network, leading to loss of bile canaliculi in steatotic hepatocytes. Basal mitochondrial respiration, maximum respiratory capacity, and resistance to HO-induced cell death also increased as an adaptative response. Upon reversal of steatosis, F-actin and bile canaliculi were restored in hepatocytes. Nevertheless, we observed an increase in elongated mitochondrial branches accompanied by decreases in α-tubulin expression, mitochondrial proton leak, and susceptibility to HO-induced cell death.
CONCLUSIONS
Despite the restoration of cytoskeletons morphologically upon reversal of steatosis, the mitochondria in hepatocytes were impaired owing to early adaptative respiratory increase. Hepatocytes thus were highly predisposed to HO-induced cell death. These results indicate the persistence of potential health risks for recovering NAFLD patients.
Topics: Humans; Non-alcoholic Fatty Liver Disease; Fatty Acids, Nonesterified; Actins; Hydrogen Peroxide; Hepatocytes; Mitochondria; Cytoskeleton; Microtubules
PubMed: 37085137
DOI: 10.1016/j.jcmgh.2023.04.003