RESUMO
Osteoarthritis (OA) is a chronic joint disease characterized by the degeneration, destruction, and excessive ossification of articular cartilage. The prevalence of OA is rising annually, concomitant with the aging global population and increasing rates of obesity. This condition imposes a substantial and escalating burden on individual health, healthcare systems, and broader social and economic frameworks. The etiology of OA is multifaceted and not fully understood. Current research suggests that the death of chondrocytes, encompassing mechanisms such as cellular apoptosis, pyroptosis, autophagy, ferroptosis and cuproptosis, contributes to both the initiation and progression of the disease. These cell death pathways not only diminish the population of chondrocytes but also exacerbate joint damage through the induction of inflammation and other deleterious processes. This paper delineates the morphological characteristics associated with various modes of cell death and summarizes current research results on the molecular mechanisms of different cell death patterns in OA. The objective is to review the advancements in understanding chondrocyte cell death in OA, thereby offering novel insights for potential clinical interventions.
Assuntos
Morte Celular , Condrócitos , Progressão da Doença , Osteoartrite , Condrócitos/patologia , Humanos , Osteoartrite/patologia , Osteoartrite/terapia , Morte Celular/fisiologia , Apoptose/fisiologia , Cartilagem Articular/patologia , Autofagia/fisiologia , Animais , Piroptose/fisiologia , Ferroptose/fisiologiaRESUMO
Autophagy, the major lysosomal pathway for degrading damaged or obsolete constituents, protects neurons by eliminating toxic organelles and peptides, restoring nutrient and energy homeostasis, and inhibiting apoptosis. These functions are especially vital in neurons, which are postmitotic and must survive for many decades while confronting mounting challenges of cell aging. Autophagy failure, especially related to the declining lysosomal ("phagy") functions, heightens the neuron's vulnerability to genetic and environmental factors underlying Alzheimer's disease (AD) and other late-age onset neurodegenerative diseases. Components of the global autophagy-lysosomal pathway and the closely integrated endolysosomal system are increasingly implicated as primary targets of these disorders. In AD, an imbalance between heightened autophagy induction and diminished lysosomal function in highly vulnerable pyramidal neuron populations yields an intracellular lysosomal build-up of undegraded substrates, including APP-ßCTF, an inhibitor of lysosomal acidification, and membrane-damaging Aß peptide. In the most compromised of these neurons, ß-amyloid accumulates intraneuronally in plaque-like aggregates that become extracellular senile plaques when these neurons die, reflecting an "inside-out" origin of amyloid plaques seen in human AD brain and in mouse models of AD pathology. In this review, the author describes the importance of lysosomal-dependent neuronal cell death in AD associated with uniquely extreme autophagy pathology (PANTHOS) which is described as triggered by lysosomal membrane permeability during the earliest "intraneuronal" stage of AD. Effectors of other cell death cascades, notably calcium-activated calpains and protein kinases, contribute to lysosomal injury that induces leakage of cathepsins and activation of additional death cascades. Subsequent events in AD, such as microglial invasion and neuroinflammation, induce further cytotoxicity. In major neurodegenerative disease models, neuronal death and ensuing neuropathologies are substantially remediable by reversing underlying primary lysosomal deficits, thus implicating lysosomal failure and autophagy dysfunction as primary triggers of lysosomal-dependent cell death and AD pathogenesis and as promising therapeutic targets.
Assuntos
Autofagia , Lisossomos , Doenças Neurodegenerativas , Neurônios , Humanos , Animais , Lisossomos/metabolismo , Lisossomos/patologia , Neurônios/patologia , Neurônios/metabolismo , Doenças Neurodegenerativas/patologia , Doenças Neurodegenerativas/metabolismo , Autofagia/fisiologia , Morte Celular/fisiologiaRESUMO
Purpose: Retinal detachment (RD) leads to photoreceptor (PR) hypoxia due to separation from the retinal pigment epithelium (RPE). Hypoxia stabilizes retinal hypoxia-inducible factor 1-alpha (HIF1α), crucial for PR survival during RD. This study explores the regulatory role of HIF1α in PR cell survival pathways during RD. Methods: Experimental RD was created in C57BL/6J and HIF1αΔrod mice by injecting 1% hyaluronic acid into the subretinal space. The 661W photoreceptor cells were exposed to hypoxic conditions. Markers of endoplasmic reticulum stress (ERS), mitophagy, and accumulation of polyubiquinated proteins were evaluated using RT-PCR and western blot analyses. Cell death of PR cells was quantified using trypan blue exclusion assay and TUNEL staining. Retinal cell death was assessed using a DNA fragmentation assay. Results: In C57BL/6J mice and 661W cells, there were increases in HIF1α protein levels: 2.2-fold after RD (P = 0.04) and threefold after hypoxia (P = 0.057). Both the in vivo and in vitro RD models showed increased protein expression of ERS markers (including BIP, CHOP, and IRE1α), mitophagy markers (Parkin, PINK, and FUNDC1), and polyubiquitinated proteins. In 661W cells, hypoxia resulted in a loss of mitochondrial membrane potential, an increase in mitochondrial reactive oxygen species, and a decrease in intracellular adenosine triphosphate levels. Lack of HIF1α in rods blocked the upregulation of mitophagy markers after RD. Conclusions: RD results in the activation of ERS, mitophagy, mitochondrial dysfunction, and accumulation of polyubiquitinated proteins. Results suggest a role for HIF1α in activation of the mitophagy pathway after RD, which may serve to protect the PR cells.
Assuntos
Western Blotting , Modelos Animais de Doenças , Estresse do Retículo Endoplasmático , Subunidade alfa do Fator 1 Induzível por Hipóxia , Mitocôndrias , Descolamento Retiniano , Animais , Camundongos , Apoptose/fisiologia , Morte Celular/fisiologia , Sobrevivência Celular/fisiologia , Estresse do Retículo Endoplasmático/fisiologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Marcação In Situ das Extremidades Cortadas , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , Mitofagia/fisiologia , Células Fotorreceptoras de Vertebrados/metabolismo , Células Fotorreceptoras de Vertebrados/patologia , Descolamento Retiniano/metabolismo , Descolamento Retiniano/patologia , Epitélio Pigmentado da Retina/metabolismo , Epitélio Pigmentado da Retina/patologiaRESUMO
BACKGROUND: Copper is an essential trace element for biological systems, as it plays a critical role in the activity of various enzymes and metabolic processes. However, the dysregulation of copper homeostasis is closely associated with the onset and progression of numerous diseases. In recent years, copper-induced cell death, a novel form of cellular demise, has garnered significant attention. This process is characterized by the abnormal accumulation of intracellular copper ions, leading to cellular dysfunction and eventual cell death. Copper toxicity occurs through the interaction of copper with acylated enzymes in the tricarboxylic acid (TCA) cycle. This interaction results in subsequent protein aggregation, causing proteotoxic stress and ultimately resulting in cell death. Despite the promise of these findings, the detailed mechanisms and broader implications of cuproptosis remain underexplored. Therefore, our study aimed to investigate the role of copper in cell death and autophagy, focusing on the molecular mechanisms of cuproptosis. We also aimed to discuss recent advancements in copper-related research across various diseases and tumors, providing insights for future studies and potential therapeutic applications. MAIN BODY: This review delves into the biological significance of copper metabolism and the molecular mechanisms underlying copper-induced cell death. Furthermore, we discuss the role of copper toxicity in the pathogenesis of various diseases, emphasizing recent advancements in the field of oncology. Additionally, we explore the therapeutic potential of targeting copper toxicity. CONCLUSION: The study highlights the need for further research to explore alternative pathways of copper-induced cell death, detailed mechanisms of cuproptosis, and biomarkers for copper poisoning. Future research should focus on exploring the molecular mechanisms of cuproptosis, developing new therapeutic strategies, and verifying their safety and efficacy in clinical trials.
Assuntos
Cobre , Humanos , Cobre/metabolismo , Cobre/toxicidade , Animais , Morte Celular/efeitos dos fármacos , Morte Celular/fisiologia , Autofagia/fisiologia , Autofagia/efeitos dos fármacosRESUMO
Norovirus infection is characterised by a rapid onset of disease and the development of debilitating symptoms including projectile vomiting and diffuse diarrhoea. Vaccines and antivirals are sorely lacking and developments in these areas are hampered by the lack of an adequate cell culture system to investigate human norovirus replication and pathogenesis. Herein, we describe how the model norovirus, Mouse norovirus (MNV), produces a viral protein, NS3, with the functional capacity to attenuate host protein translation which invokes the activation of cell death via apoptosis. We show that this function of NS3 is conserved between human and mouse viruses and map the protein domain attributable to this function. Our study highlights a critical viral protein that mediates crucial activities during replication, potentially identifying NS3 as a worthy target for antiviral drug development.
Assuntos
Infecções por Caliciviridae , Macrófagos , Norovirus , Norovirus/fisiologia , Animais , Camundongos , Infecções por Caliciviridae/virologia , Macrófagos/virologia , Macrófagos/metabolismo , Humanos , Biossíntese de Proteínas , Replicação Viral/fisiologia , Morte Celular/fisiologia , Proteínas não Estruturais Virais/metabolismo , Proteínas não Estruturais Virais/genética , ApoptoseRESUMO
The Ribosomal S6 Kinase (RSK) family of serine/threonine kinases function as key downstream effectors of the MAPK signaling cascade. In the nervous system, RSK signaling plays crucial roles in neuronal development and contributes to activity-dependent neuronal plasticity. This study examined the role of RSK signaling in cell viability during neuronal development and in neuroprotection in the mature nervous system. Using neuronal cell-culture-based profiling, we found that suppressing RSK signaling led to significant cell death in developing primary neuronal cultures. To this end, treatment with the RSK inhibitors BiD1870 or SL0101 on the first day of culturing resulted in over 80% cell death. In contrast, more mature cultures showed attenuated cell death upon RSK inhibition. Inhibition of RSK signaling during early neuronal development also disrupted neurite outgrowth and cell growth. In maturing hippocampal explant cultures, treatment with BiD1870 had minimal effects on cell viability, but led to a striking augmentation of NMDA-induced cell death. Finally, we used the endothelin 1 (ET-1) model of ischemia to examine the neuroprotective effects of RSK signaling in the mature hippocampus in vivo. Notably, in the absence of RSK inhibition, the granule cell layer (GCL) was resistant to the effects of ET-1; However, disruption of RSK signaling (via the microinjection of BiD1870) prior to ET-1 injection triggered cell death within the GCL, thus indicating a neuroprotective role for RSK signaling in the mature nervous system. Together these data reveal distinct, developmentally-defined, roles for RSK signaling in the nervous system.
Assuntos
Morte Celular , Sobrevivência Celular , Neurônios , Proteínas Quinases S6 Ribossômicas , Transdução de Sinais , Animais , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Morte Celular/efeitos dos fármacos , Morte Celular/fisiologia , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Proteínas Quinases S6 Ribossômicas/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Células Cultivadas , Endotelina-1/farmacologia , Endotelina-1/metabolismo , N-Metilaspartato/farmacologia , Ratos Sprague-Dawley , Ratos , Neurogênese/fisiologia , Neurogênese/efeitos dos fármacos , PteridinasRESUMO
Subarachnoid hemorrhage due to rupture of intracranial aneurysms has a poor outcome, making this disease being the social problem. Inflammation evoked by the increase in intracranial pressure and the clot in the subarachnoid space after the onset of SAH exacerbates neuronal death and vasospasm, resulting in the poor outcome and severe aftereffects. Here, FROUNT mediates CCR2 and CCR5 signaling as an intracellular molecule binding to these chemoattractant receptors which facilitate the migration of inflammatory cells, such as macrophages, in situ to trigger inflammation there. Animal model of subarachnoid hemorrhage was established in rats through intrathecal injection of autologous blood. The effect of the FROUNT inhibitor, disulfiram, on survival rate, neuronal death in hippocampus or vasospasm was then examined. The intrathecal administration of disulfiram significantly suppressed the infiltration of CD68-positive macrophages and myeloperoxidase-positive neutrophils toward the clot in the cistern in situ. In this condition, disulfiram ameliorated the death of animals after the onset of subarachnoid hemorrhage in rats. In addition, disulfiram suppressed both the two major events after subarachnoid hemorrhage, the neuronal death in hippocampus and vasospasm. The pharmacological inhibition of CCR2 and CCR5 signaling by disulfiram could thus be the therapeutic strategy to improve the outcome of subarachnoid hemorrhage.
Assuntos
Dissulfiram , Ratos Sprague-Dawley , Hemorragia Subaracnóidea , Animais , Dissulfiram/farmacologia , Hemorragia Subaracnóidea/tratamento farmacológico , Hemorragia Subaracnóidea/metabolismo , Masculino , Vasoespasmo Intracraniano/tratamento farmacológico , Vasoespasmo Intracraniano/metabolismo , Receptores CCR2/metabolismo , Receptores CCR2/antagonistas & inibidores , Modelos Animais de Doenças , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Receptores CCR5/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Ratos , Prognóstico , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Morte Celular/efeitos dos fármacos , Morte Celular/fisiologia , Antígenos de Diferenciação Mielomonocítica/metabolismoRESUMO
Osteoarthritis (OA) is the most common degenerative joint disease. Multiple tissues are altered during the development of OA, resulting in joint pain and permanent damage to the osteoarticular joints. Current research has demonstrated that non-apoptotic cell death plays a crucial role in OA. With the continuous development of targeted therapies, non-apoptotic cell death has shown great potential in the prevention and treatment of OA. We systematically reviewed research progress on the role of non-apoptotic cell death in the pathogenesis, development, and outcome of OA, including autophagy, pyroptosis, ferroptosis, necroptosis, immunogenic cell death, and parthanatos. This article reviews the mechanism of non-apoptotic cell death in OA and provides a theoretical basis for the identification of new targets for OA treatment.
Assuntos
Autofagia , Morte Celular , Osteoartrite , Osteoartrite/patologia , Humanos , Animais , Morte Celular/fisiologia , Autofagia/fisiologia , Piroptose/fisiologia , Ferroptose/fisiologia , Necroptose , ApoptoseRESUMO
Microglia are crucial for maintaining brain health and neuron function. Here, we report that microglia establish connections with neurons using tunneling nanotubes (TNTs) in both physiological and pathological conditions. These TNTs facilitate the rapid exchange of organelles, vesicles, and proteins. In neurodegenerative diseases like Parkinson's and Alzheimer's disease, toxic aggregates of alpha-synuclein (α-syn) and tau accumulate within neurons. Our research demonstrates that microglia use TNTs to extract neurons from these aggregates, restoring neuronal health. Additionally, microglia share their healthy mitochondria with burdened neurons, reducing oxidative stress and normalizing gene expression. Disrupting mitochondrial function with antimycin A before TNT formation eliminates this neuroprotection. Moreover, co-culturing neurons with microglia and promoting TNT formation rescues suppressed neuronal activity caused by α-syn or tau aggregates. Notably, TNT-mediated aggregate transfer is compromised in microglia carrying Lrrk22(Gly2019Ser) or Trem2(T66M) and (R47H) mutations, suggesting a role in the pathology of these gene variants in neurodegenerative diseases.
Assuntos
Microglia , Neurônios , alfa-Sinucleína , Proteínas tau , Microglia/metabolismo , Microglia/efeitos dos fármacos , Animais , Neurônios/metabolismo , Neurônios/efeitos dos fármacos , Proteínas tau/metabolismo , Proteínas tau/genética , alfa-Sinucleína/metabolismo , alfa-Sinucleína/genética , Técnicas de Cocultura , Camundongos , Mitocôndrias/metabolismo , Mitocôndrias/efeitos dos fármacos , Humanos , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/genética , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/metabolismo , Morte Celular/efeitos dos fármacos , Morte Celular/fisiologia , Nanotubos , Células Cultivadas , Comunicação Celular/fisiologia , Comunicação Celular/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Estruturas da Membrana CelularRESUMO
This review summarizes recent progress in our current understanding of the mechanisms underlying the cell death pathways in bryophytes, focusing on conserved pathways and particularities in comparison to angiosperms. Regulated cell death (RCD) plays key roles during essential processes along the plant life cycle. It is part of specific developmental programmes and maintains homeostasis of the organism in response to unfavourable environments. Bryophytes could provide valuable models to study developmental RCD processes as well as those triggered by biotic and abiotic stresses. Some pathways analogous to those present in angiosperms occur in the gametophytic haploid generation of bryophytes, allowing direct genetic studies. In this review, we focus on such RCD programmes, identifying core conserved mechanisms and raising new key questions to analyse RCD from an evolutionary perspective.
Assuntos
Briófitas , Briófitas/genética , Briófitas/fisiologia , Briófitas/crescimento & desenvolvimento , Morte Celular/fisiologia , Regulação da Expressão Gênica de Plantas , Transdução de Sinais , Modelos Biológicos , Morte Celular Regulada/fisiologia , Morte Celular Regulada/genética , Magnoliopsida/genética , Magnoliopsida/fisiologia , Magnoliopsida/crescimento & desenvolvimentoRESUMO
Hepatic encephalopathy (HE) is a neurological complication arising from acute liver failure with poor prognosis and high mortality; the underlying cellular mechanisms are still wanting. We previously found that neuronal death caused by mitochondrial dysfunction in rostral ventrolateral medulla (RVLM), which leads to baroreflex dysregulation, is related to high fatality in an animal model of HE. Lipocalin-2 (Lcn2) is a secreted glycoprotein mainly released by astrocytes in the brain. We noted the presence of Lcn2 receptor (Lcn2R) in RVLM neurons and a parallel increase of Lcn2 gene in astrocytes purified from RVLM during experimental HE. Therefore, our guiding hypothesis is that Lcn2 secreted by reactive astrocytes in RVLM may underpin high fatality during HE by eliciting bioenergetic failure-induced neuronal death in this neural substrate. In this study, we first established the role of astrocyte-secreted Lcn2 in a liver toxin model of HE induced by azoxymethane (100 µg/g, ip) in C57BL/6 mice, followed by mechanistic studies in primary astrocyte and neuron cultures prepared from postnatal day 1 mouse pups. In animal study, immunoneutralization of Lcn2 reduced apoptotic cell death in RVLM, reversed defunct baroreflex-mediated vasomotor tone and prolonged survival during experimental HE. In our primary cell culture experiments, Lcn2 produced by cultured astrocytes and released into the astrocyte-conditioned medium significantly reduced cell viability of cultured neurons. Recombinant Lcn2 protein reduced cell viability, mitochondrial ATP (mitoATP) production, and pyruvate dehydrogenase (PDH) activity but enhanced the expression of pyruvate dehydrogenase kinase (PDK) 1, PDK3 and phospho-PDHA1 (inactive PDH) through MAPK/ERK pathway in cultured neurons, with all cellular actions reversed by Lcn2R knockdown. Our results suggest that astrocyte-secreted Lcn2 upregulates PDKs through MAPK/ERK pathway, which leads to reduced PDH activity and mitoATP production; the reinforced neuronal death in RVLM is causally related to baroreflex dysregulation that underlies high fatality associated with HE.
Assuntos
Astrócitos , Morte Celular , Modelos Animais de Doenças , Encefalopatia Hepática , Lipocalina-2 , Camundongos Endogâmicos C57BL , Neurônios , Animais , Astrócitos/metabolismo , Astrócitos/patologia , Lipocalina-2/metabolismo , Encefalopatia Hepática/metabolismo , Encefalopatia Hepática/patologia , Neurônios/metabolismo , Neurônios/patologia , Camundongos , Morte Celular/fisiologia , Masculino , Metabolismo Energético/fisiologia , Metabolismo Energético/efeitos dos fármacos , Células CultivadasRESUMO
Regulated cell death (RCD) pathways, such as pyroptosis, apoptosis, and necroptosis, are essential for maintaining the body's balance, defending against pathogens, and eliminating abnormal cells that could lead to diseases like cancer. Although these pathways operate through distinct mechanisms, recent genetic and pharmacological studies have shown that they can interact and influence each other. The concept of "PANoptosis" has emerged, highlighting the interplay between pyroptosis, apoptosis, and necroptosis, especially during cellular responses to infections. This article provides a concise overview of PANoptosis and its molecular mechanisms, exploring its implications in various diseases. The review focuses on the extensive interactions among different RCD pathways, emphasizing the role of PANoptosis in infections, cytokine storms, inflammatory diseases, and cancer. Understanding PANoptosis is crucial for developing novel treatments for conditions involving infections, sterile inflammations, and cancer.
Assuntos
Inflamação , Necroptose , Neoplasias , Piroptose , Humanos , Inflamação/patologia , Inflamação/tratamento farmacológico , Inflamação/imunologia , Animais , Necroptose/efeitos dos fármacos , Necroptose/fisiologia , Piroptose/efeitos dos fármacos , Piroptose/fisiologia , Neoplasias/patologia , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Neoplasias/metabolismo , Apoptose/efeitos dos fármacos , Morte Celular/fisiologia , Morte Celular Regulada/efeitos dos fármacos , Infecções/patologia , Infecções/imunologiaRESUMO
Glutamate excitotoxicity is involved in retinal ganglion cell (RGC) death in various retinal degenerative diseases, including ischemia-reperfusion injury and glaucoma. Excitotoxic RGC death is caused by both direct damage to RGCs and indirect damage through neuroinflammation of retinal glial cells. Omidenepag (OMD), a novel E prostanoid receptor 2 (EP2) agonist, is a recently approved intraocular pressure-lowering drug. The second messenger of EP2 is cyclic adenosine monophosphate (cAMP), which activates protein kinase A (PKA) and exchange protein directly activated by cAMP (Epac). In this study, we investigated the neuroprotective effects of OMD on excitotoxic RGC death by focusing on differences in cAMP downstream signaling from the perspective of glia-neuron interactions. We established a glutamate excitotoxicity model in vitro and NMDA intravitreal injection model in vivo. In vitro, rat primary RGCs were used in an RGC survival rate assay. MG5 cells (mouse microglial cell line) and A1 cells (astrocyte cell line) were used for immunocytochemistry and Western blotting to evaluate the expressions of COX-1/2, PKA, Epac1/2, pCREB, cleaved caspase-3, inflammatory cytokines, and neurotrophic factors. Mouse retinal specimens underwent hematoxylin and eosin staining, flat-mounted retina examination, and immunohistochemistry. OMD significantly suppressed excitotoxic RGC death, cleaved caspase-3 expression, and activated glia both in vitro and in vivo. Moreover, it inhibited Epac1 and inflammatory cytokine expression and promoted COX-2, pCREB, and neurotrophic factor expression. OMD may have neuroprotective effects through inhibition of the Epac pathway and promotion of the COX-2-EP2-cAMP-PKA pathway by modulating glia-neuron interaction.
Assuntos
Proteínas Quinases Dependentes de AMP Cíclico , AMP Cíclico , Ciclo-Oxigenase 2 , Neuroglia , Fármacos Neuroprotetores , Células Ganglionares da Retina , Animais , Células Ganglionares da Retina/efeitos dos fármacos , Células Ganglionares da Retina/metabolismo , Fármacos Neuroprotetores/farmacologia , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Ciclo-Oxigenase 2/metabolismo , AMP Cíclico/metabolismo , Camundongos , Neuroglia/efeitos dos fármacos , Neuroglia/metabolismo , Receptores de Prostaglandina E Subtipo EP2/metabolismo , Receptores de Prostaglandina E Subtipo EP2/antagonistas & inibidores , Receptores de Prostaglandina E Subtipo EP2/agonistas , Morte Celular/efeitos dos fármacos , Morte Celular/fisiologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Ratos Sprague-Dawley , Ratos , Ácido Glutâmico/metabolismo , Ácido Glutâmico/toxicidade , Camundongos Endogâmicos C57BL , Masculino , N-Metilaspartato/farmacologia , N-Metilaspartato/toxicidade , Neurônios/efeitos dos fármacos , Neurônios/metabolismoRESUMO
ß-Cell death contributes to ß-cell loss and insulin insufficiency in type 1 diabetes (T1D), and this ß-cell demise has been attributed to apoptosis and necrosis. Apoptosis has been viewed as the lone form of programmed ß-cell death, and evidence indicates that ß-cells also undergo necrosis, regarded as an unregulated or accidental form of cell demise. More recently, studies in non-islet cell types have identified and characterized novel forms of cell death that are biochemically and morphologically distinct from apoptosis and necrosis. Several of these mechanisms of cell death have been categorized as forms of regulated necrosis and linked to inflammation and disease pathogenesis. In this review, we revisit discoveries of ß-cell death in humans with diabetes and describe studies characterizing ß-cell apoptosis and necrosis. We explore literature on mechanisms of regulated necrosis including necroptosis, ferroptosis and pyroptosis, review emerging literature on the significance of these mechanisms in ß-cells, and discuss experimental approaches to differentiate between various mechanisms of ß-cell death. Our review of the literature leads us to conclude that more detailed experimental characterization of the mechanisms of ß-cell death is warranted, along with studies to better understand the impact of various forms of ß-cell demise on islet inflammation and ß-cell autoimmunity in pathophysiologically relevant models. Such studies will provide insight into the mechanisms of ß-cell loss in T1D and may shed light on new therapeutic approaches to protect ß-cells in this disease.
Assuntos
Apoptose , Morte Celular , Diabetes Mellitus Tipo 1 , Células Secretoras de Insulina , Necrose , Humanos , Células Secretoras de Insulina/patologia , Células Secretoras de Insulina/fisiologia , Diabetes Mellitus Tipo 1/patologia , Diabetes Mellitus Tipo 1/imunologia , Animais , Morte Celular/fisiologia , Apoptose/fisiologia , Necroptose/fisiologia , Piroptose/fisiologia , Ferroptose/fisiologiaRESUMO
Understanding the dynamics of acute HIV infection can offer valuable insights into the early stages of viral behavior, potentially helping uncover various aspects of HIV pathogenesis. The standard viral dynamics model explains HIV viral dynamics during acute infection reasonably well. However, the model makes simplifying assumptions, neglecting some aspects of HIV infection. For instance, in the standard model, target cells are infected by a single HIV virion. Yet, cellular multiplicity of infection (MOI) may have considerable effects in pathogenesis and viral evolution. Further, when using the standard model, we take constant infected cell death rates, simplifying the dynamic immune responses. Here, we use four models-1) the standard viral dynamics model, 2) an alternate model incorporating cellular MOI, 3) a model assuming density-dependent death rate of infected cells and 4) a model combining (2) and (3)-to investigate acute infection dynamics in 43 people living with HIV very early after HIV exposure. We find that all models qualitatively describe the data, but none of the tested models is by itself the best to capture different kinds of heterogeneity. Instead, different models describe differing features of the dynamics more accurately. For example, while the standard viral dynamics model may be the most parsimonious across study participants by the corrected Akaike Information Criterion (AICc), we find that viral peaks are better explained by a model allowing for cellular MOI, using a linear regression analysis as analyzed by R2. These results suggest that heterogeneity in within-host viral dynamics cannot be captured by a single model. Depending on the specific aspect of interest, a corresponding model should be employed.
Assuntos
Morte Celular , Infecções por HIV , Modelos Biológicos , Infecções por HIV/virologia , Infecções por HIV/fisiopatologia , Humanos , Morte Celular/fisiologia , HIV-1/fisiologia , HIV-1/patogenicidade , Biologia Computacional , Carga Viral , Masculino , Adulto , Doença Aguda , FemininoRESUMO
Ferroptosis is a lipid peroxidation-driven and iron-dependent form of programmed cell death, which is involved in a variety of physical processes and multiple diseases. Numerous reports have demonstrated that ferroptosis is closely related to the pathophysiological processes of Mycobacterium tuberculosis (M. tuberculosis) infection and is characterized by the accumulation of excess lipid peroxides on the cell membrane. In this study, the various functions of ferroptosis, and the therapeutic strategies and diagnostic biomarkers of tuberculosis, were summarized. Notably, this review provides insights into the molecular mechanisms and functions of M. tuberculosis-induced ferroptosis, suggesting potential future therapeutic and diagnostic markers for tuberculosis.
Assuntos
Ferroptose , Mycobacterium tuberculosis , Tuberculose , Ferroptose/fisiologia , Humanos , Mycobacterium tuberculosis/patogenicidade , Tuberculose/microbiologia , Tuberculose/patologia , Tuberculose/metabolismo , Animais , Peroxidação de Lipídeos , Morte Celular/fisiologia , Ferro/metabolismo , Biomarcadores/metabolismoRESUMO
Preparing acute brain slices produces trauma that mimics severe penetrating brain injury. In neonatal acute brain slices, the spatiotemporal characteristics of trauma-induced calcium dynamics in neurons and its effect on network activity are relatively unknown. Using multiphoton laser scanning microscopy of the somatosensory neocortex in acute neonatal mouse brain slices (P8-12), we simultaneously imaged neuronal Ca2+ dynamics (GCaMP6s) and cytotoxicity (propidium iodide or PI) to determine the relationship between cytotoxic Ca2+ loaded neurons (GCaMP-filled) and cell viability at different depths and incubation times. PI+ cells and GCaMP-filled neurons were abundant at the surface of the slices, with an exponential decrease with depth. Regions with high PI+ cells correlated with elevated neuronal and neuropil Ca2+ The number of PI+ cells and GCaMP-filled neurons increased with prolonged incubation. GCaMP-filled neurons did not participate in stimulus-evoked or seizure-evoked network activity. Significantly, the superficial tissue, with a higher degree of trauma-induced injury, showed attenuated seizure-related neuronal Ca2+ responses. Calpain inhibition prevented the increase in PI+ cells and GCaMP-filled neurons in the deep tissue and during prolonged incubation times. Isoform-specific pharmacological inhibition implicated calpain-2 as a significant contributor to trauma-induced injury in acute slices. Our results show a calpain-mediated spatiotemporal relationship between cell death and aberrant neuronal Ca2+ load in acute neonatal brain slices. Also, we demonstrate that neurons in acute brain slices exhibit altered physiology depending on the degree of trauma-induced injury. Blocking calpains may be a therapeutic option to prevent acute neuronal death during traumatic brain injury in the young brain.
Assuntos
Animais Recém-Nascidos , Cálcio , Calpaína , Morte Celular , Neurônios , Animais , Calpaína/metabolismo , Morte Celular/fisiologia , Neurônios/metabolismo , Cálcio/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Feminino , Masculino , Neocórtex/metabolismoRESUMO
Gamma aminobutyric acid (GABA) is a critical inhibitory neurotransmitter in the central nervous system that plays a vital role in modulating neuronal excitability. Dysregulation of GABAergic signaling, particularly involving the cotransporters NKCC1 and KCC2, has been implicated in various pathologies, including epilepsy, schizophrenia, autism spectrum disorder, Down syndrome, and ischemia. NKCC1 facilitates chloride influx, whereas KCC2 mediates chloride efflux via potassium gradient. Altered expression and function of these cotransporters have been associated with excitotoxicity, inflammation, and cellular death in ischemic events characterized by reduced cerebral blood flow, leading to compromised tissue metabolism and subsequent cell death. NKCC1 inhibition has emerged as a potential therapeutic approach to attenuate intracellular chloride accumulation and mitigate neuronal damage during ischemic events. Similarly, targeting KCC2, which regulates chloride efflux, holds promise for improving outcomes and reducing neuronal damage under ischemic conditions. This review emphasizes the critical roles of GABA, NKCC1, and KCC2 in ischemic pathologies and their potential as therapeutic targets. Inhibiting or modulating the activity of these cotransporters represents a promising strategy for reducing neuronal damage, preventing excitotoxicity, and improving neurological outcomes following ischemic events. Furthermore, exploring the interactions between natural compounds and NKCC1/KCC2 provides additional avenues for potential therapeutic interventions for ischemic injury.
Assuntos
Isquemia Encefálica , Morte Celular , Cotransportadores de K e Cl- , Membro 2 da Família 12 de Carreador de Soluto , Simportadores , Ácido gama-Aminobutírico , Animais , Humanos , Ácido gama-Aminobutírico/metabolismo , Simportadores/metabolismo , Membro 2 da Família 12 de Carreador de Soluto/metabolismo , Morte Celular/fisiologia , Morte Celular/efeitos dos fármacos , Isquemia Encefálica/metabolismo , Isquemia Encefálica/tratamento farmacológicoRESUMO
Most projection neurons, including retinal ganglion cells (RGCs), undergo cell death after axotomy proximal to the cell body. Specific RGC subtypes, such as ON-OFF direction selective RGCs (ooDSGCs) are particularly vulnerable, whereas intrinsically photosensitive RGCs (ipRGCs) exhibit resilience to axonal injury. Through the application of RNA sequencing and fluorescent in situ hybridization, we show that the expression of chloride intracellular channel protein 1 and 4 (Clic1 and Clic4) are highly increased in the ooDSGCs after axonal injury. Toward determining a gene's role in RGCs, we optimized the utility and efficacy of adenovirus associated virus (AAV)-retro expressing short hairpin RNA (shRNA). Injection of AAV2-retro into the superior colliculus results in efficient shRNA expression in RGCs. Incorporating histone H2B gene fused with mGreenLantern results in bright nuclear reporter expression, thereby enhancing single RGC identification and cell quantitation in live retinas. Lastly, we demonstrate that AAV2-retro mediated knockdown of both Clic1 and Clic4 promotes RGC survival after injury. Our findings establish an integrated use of AAV2-retro-shRNA and real-time fundus imaging and reveal CLICs' contribution to RGC death.