RESUMEN
Antiviral innate immunity is the first line of defence against viruses. The interferon (IFN) signaling pathway, the DNA damage response (DDR), apoptosis, endoplasmic reticulum (ER) stress, and autophagy are involved in antiviral innate immunity. Viruses abrogate the antiviral immune response of cells to replication in various ways. Viral genes/proteins play a key role in evading antiviral innate immunity. Here, we will discuss the interference of viruses with antiviral innate immunity and the strategy for identifying viral gene/protein immune evasion.
Asunto(s)
Inmunidad Innata , Humanos , Proteínas Virales/inmunología , Proteínas Virales/genética , Virus/inmunología , Virus/genética , Evasión Inmune , Virosis/inmunología , Virosis/virología , Animales , Genes Virales , Autofagia/inmunología , Interacciones Huésped-Patógeno/inmunología , Transducción de Señal/inmunologíaRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Tackling phlegm and improving blood circulation is vital in the treatment of ischemic stroke (IS), culminating in the development of Zhongfeng Decoction (ZFD), a method grounded in this approach and serving as an effective therapy for IS. Nonetheless, the defensive mechanism of the ZFD in preventing cerebral ischemia-reperfusion damage remains ambiguous. AIM OF THE STUDY: Determine the active ingredients in ZFD that have neuroprotective effects, and identify its mechanism of action against IS. MATERIALS AND METHODS: A cerebral ischemia model in rats was developed, utilizing TTC, Nissl staining, and an oxidative stress kit to evaluate the neuroprotective impact of ZFD on this rat model. Following this, an amalgamation of LC-MS and network pharmacology techniques was employed to pinpoint potential active components, primary targets, and crucial action mechanisms of ZFD in treating IS. Finally, key targets and signaling pathways were detected using qRT-PCR, ELISA, Western blotting, electron microscopy, and other methods. RESULTS: Through LC-MS and network analysis, 15 active ingredients and 6 hub targets were identified from ZFD. Analysis of pathway enrichment revealed that ZFD predominantly engages in the AGE-RAGE signaling route. Kaempferol, quercetin, luteolin, baicalein, and nobiletin in ZFD are the main active ingredients for treating IS. In vivo validation showed that ZFD can improve nerve damage in cerebral ischemic rats, reduce the mRNA expression of IL6, SERPINE1, CCL2, and TGFB1 related to inflammation. Furthermore, we also confirmed that ZFD can inhibit the protein expression of AGEs, RAGE, p-IKBα/IKBα, p-NF-κB p65/NF-κB p65, reduce autophagy levels, and thus decrease neuronal apoptosis. CONCLUSIONS: The mechanism of action of ZFD in treating IS primarily includes inflammation suppression, oxidative stress response alleviation, post-stroke cell autophagy and apoptosis regulation, and potential mediation of the AGE-RAGE signaling pathway. This study elucidates how ZFD functions in treating IS, establishing a theoretical basis for its clinical application.
Asunto(s)
Autofagia , Medicamentos Herbarios Chinos , Fármacos Neuroprotectores , Ratas Sprague-Dawley , Daño por Reperfusión , Transducción de Señal , Animales , Daño por Reperfusión/tratamiento farmacológico , Daño por Reperfusión/metabolismo , Medicamentos Herbarios Chinos/farmacología , Transducción de Señal/efectos de los fármacos , Masculino , Autofagia/efectos de los fármacos , Ratas , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Receptor para Productos Finales de Glicación Avanzada/metabolismo , Isquemia Encefálica/tratamiento farmacológico , Estrés Oxidativo/efectos de los fármacos , Modelos Animales de Enfermedad , Productos Finales de Glicación Avanzada/metabolismoRESUMEN
Tumor vaccines have become a promising approach for cancer treatment by triggering antigen-specific responses against tumors. However, autophagy and immunosuppressive tumor microenvironment (TME) reduce antigen exposure and immunogenicity, which limit the effect of tumor vaccines. Here, we develop fucoidan (Fuc) based chlorin e6 (Ce6)-chloroquine (CQ) self-assembly hydrogels (CCFG) as in situ vaccines. Ce6 triggers immune response in situ by photodynamic therapy (PDT) induced immunogenic cell death (ICD) effect, which is further enhanced by macrophage polarization of Fuc and autophagy inhibition of CQ. In vivo studies show that CCFG effectively enhances antigen presentation under laser irradiation, which induces a powerful in situ vaccine effect and significantly inhibits tumor metastasis and recurrence. Our study provides a novel approach for enhancing tumor immunotherapy and inhibiting tumor recurrence and metastasis.
Asunto(s)
Autofagia , Vacunas contra el Cáncer , Clorofilidas , Cloroquina , Hidrogeles , Inmunoterapia , Macrófagos , Fotoquimioterapia , Polisacáridos , Porfirinas , Animales , Polisacáridos/farmacología , Polisacáridos/química , Ratones , Vacunas contra el Cáncer/farmacología , Vacunas contra el Cáncer/inmunología , Porfirinas/química , Porfirinas/farmacología , Porfirinas/uso terapéutico , Autofagia/efectos de los fármacos , Hidrogeles/química , Hidrogeles/farmacología , Inmunoterapia/métodos , Fotoquimioterapia/métodos , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Cloroquina/farmacología , Ratones Endogámicos C57BL , Microambiente Tumoral/efectos de los fármacos , Células RAW 264.7 , Línea Celular Tumoral , Humanos , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/uso terapéutico , Ratones Endogámicos BALB C , FemeninoRESUMEN
OBJECTIVE: To study the biological role and related mechanism of autophagy in acute lung injury (ALI) of hemorrhagic shock mice. METHODS: According to random number table method, wild-type male C57BL/6 mice were divided into control group, ALI group, rapamycin group and 3-methyladenine (3-MA) group, with 8 mice in each group. Light chain 3 (LC3) gene knockout mice with C57BL/6 background were divided into LC3 knockout group and LC3 knockout+ALI group, with 8 mice in each group. Control group, ALI group, LC3 knockout group, LC3 knockout+ALI group were intraperitoneally injected with 2 mL/kg normal saline, rapamycin group was intraperitoneally injected with 3 mg/kg autophagy activator rapamycin, 3-MA group was intraperitoneally injected with 15 mg/kg autophagy inhibitor 3-MA, all of which were given for 3 consecutive days. 2 hours after the last administration, the hemorrhagic shock induced ALI model was established. 24 hours after modeling, the lung index was calculated. Hematoxylin-eosin (HE) staining was used to observe the pathological changes of lung tissue and lung injury score was performed. The expressions of autophagy genes LC3- II/LC3- I and Beclin-1 in lung tissue were detected by Western blotting. The contents of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and malondialdehyde (MDA) in lung tissue were detected according to the steps of the kit. RESULTS: Compared with the control group, the lung tissue structure was destroyed and exudation increased, lung index, lung injury score, the expressions of LC3- II/LC3- I, Beclin-1, and the contents of TNF-α, IL-6 and MDA in lung tissue significantly increased in the ALI group. Compared with the ALI group, the structural damage and exudation of lung tissue were reduced in the rapamycin group, lung index, lung injury score and the contents of TNF-α, IL-6 and MDA in lung tissue decreased, while the expressions of LC3- II/LC3- I and Beclin-1 in lung tissue increased [lung index: (7.56±0.39)% vs. (9.12±0.59)%, lung injury score: 3.04±0.58 vs. 9.32±2.14, TNF-α (ng/mg): 1.85±0.32 vs. 3.51±0.62, IL-6 (ng/mg): 1.61±0.32 vs. 2.52±0.44, MDA (nmol/mg): 1.03±0.16 vs. 1.88±0.24, LC3- II/LC3- I: 1.21±0.12 vs. 0.39±0.05, Beclin-1/ß-actin: 1.10±0.12 vs. 0.58±0.06, all P < 0.05], while lung tissue structure damage was aggravated and exudation was further increased in the 3-MA group, lung index, lung injury score and the contents of TNF-α, IL-6 and MDA in lung tissue increased, the expressions of LC3- II/LC3- I and Beclin-1 in lung tissue decreased [lung index: (10.44±0.62)% vs. (9.12±0.59)%, lung injury score: 11.59±2.28 vs. 9.32±2.14, TNF-α (ng/mg): 4.77±0.71 vs. 3.51±0.62, IL-6 (ng/mg): 3.44±0.52 vs. 2.52±0.44, MDA (nmol/mg): 2.71±0.42 vs. 1.88±0.24, LC3- II/LC3- I: 0.25±0.04 vs. 0.39±0.05, Beclin-1/ß-actin: 0.21±0.03 vs. 0.58±0.06, all P < 0.05]. Lung index, lung injury score and the contents of TNF-α, IL-6 and MDA in lung tissue of LC3 knockout ALI mice were higher than those of wild-type ALI mice [lung index: (10.44±0.75)% vs. (9.12±0.59)%, lung injury score: 12.41±2.86 vs. 9.32±2.14, TNF-α (ng/mg): 4.85±0.72 vs. 3.51±0.62, IL-6 (ng/mg): 3.28±0.51 vs. 2.52±0.44, MDA (nmol/mg): 2.75±0.41 vs. 1.88±0.24, all P < 0.05]. CONCLUSIONS: Autophagy plays a protective role in ALI of hemorrhagic shock mice, and the related molecular mechanism is the inhibition of inflammatory response and oxidative stress response.
Asunto(s)
Lesión Pulmonar Aguda , Autofagia , Interleucina-6 , Ratones Endogámicos C57BL , Ratones Noqueados , Choque Hemorrágico , Factor de Necrosis Tumoral alfa , Animales , Lesión Pulmonar Aguda/metabolismo , Masculino , Choque Hemorrágico/metabolismo , Choque Hemorrágico/complicaciones , Ratones , Interleucina-6/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Modelos Animales de Enfermedad , Pulmón/metabolismo , Pulmón/patología , Proteínas Asociadas a Microtúbulos/metabolismoRESUMEN
BACKGROUND: Drug-induced liver injury (DILI) is gradually becoming a common global problem that causes acute liver failure, especially in acute hepatic damage caused by acetaminophen (APAP). Paeoniflorin (PF) has a wide range of therapeutic effects to alleviate a variety of hepatic diseases. However, the relationship between them is still poorly investigated in current studies. PURPOSE: This work aimed to explore the protective effects of PF on APAP-induced hepatic damage and researched the potential molecular mechanisms. METHODS: C57BL/6J male mice were injected with APAP to establish DILI model and were given PF for five consecutive days for treatment. Aiming to clarify the pharmacological effects, the molecular mechanisms of PF in APAP-induced DILI was elucidated by high-throughput and other techniques. RESULTS: The results demonstrated that serum levels of ALP, γ-GT, AST, TBIL, and ALT were decreased in APAP mice by the preventive effects of PF. Moreover, PF notably alleviated hepatic tissue inflammation and edema. Meanwhile, the results of TUNEL staining and related apoptotic factors coincided with the results of transcriptomics, suggesting that PF inhibited hepatocyte apoptosis by regulated MAPK signaling. Besides, PF also acted on reactive oxygen species (ROS) to regulate the oxidative stress for recovery the damaged mitochondria. More importantly, transmission electron microscopy showed the generation of autophagosomes after PF treatment, and PF was also downregulated mTOR and upregulated the expression of autophagy markers such as ATG5, ATG7, and BECN1 at the mRNA level and LC3, p62, ATG5, and ATG7 at the protein level, implying that the process by which PF exerted its effects was accompanied by the occurrence of autophagy. In addition, combinined with molecular dynamics simulations and western blotting of MAPK, the results suggested p38 as a direct target for PF on APAP. Specifically, PF-activated autophagy through the downregulation of MAPK/mTOR signaling, which in turn reduced APAP injury. CONCLUSIONS: Paeoniflorin mitigated liver injury by activating autophagy to suppress oxidative stress and apoptosis via the MAPK/mTOR signaling pathway. Taken together, our findings elucidate the role and mechanism of paeoniflorin in DILI, which is expected to provide a new therapeutic strategy for the development of paeoniflorin.
Asunto(s)
Acetaminofén , Autofagia , Enfermedad Hepática Inducida por Sustancias y Drogas , Glucósidos , Hepatocitos , Ratones Endogámicos C57BL , Monoterpenos , Serina-Treonina Quinasas TOR , Animales , Autofagia/efectos de los fármacos , Glucósidos/farmacología , Serina-Treonina Quinasas TOR/metabolismo , Monoterpenos/farmacología , Masculino , Hepatocitos/metabolismo , Hepatocitos/efectos de los fármacos , Ratones , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/tratamiento farmacológico , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Acetaminofén/efectos adversos , Transducción de Señal/efectos de los fármacos , Apoptosis/efectos de los fármacos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Sustancias Protectoras/farmacología , Especies Reactivas de Oxígeno/metabolismo , Estrés Oxidativo/efectos de los fármacosRESUMEN
Implant-associated infection (IAI) is a prevalent and potentially fatal complication of orthopaedic surgery. Boosting antibacterial immunity, particularly the macrophage-mediated response, presents a promising therapeutic approach for managing persistent infections. In this study, we successfully isolated and purified a homogeneous and neutral water-soluble polysaccharide, designated as AM-1, from the edible fungus Agaricus blazei Murrill. Structure analysis revealed that AM-1 (Mw = 3.87 kDa) was a low-molecular-weight glucan characterized by a primary chain of â4)-α-D-Glcp-(1 â and side chains that were linked at the O-6 and O-3 positions. In vivo assays showed that AM-1 effectively attenuated the progression of infection and mitigated infectious bone destruction in IAI mouse models. Mechanistically, AM-1 promotes intracellular autophagy-lysosomal biogenesis by inducing the nuclear translocation of transcription factor EB, finally enhancing the bactericidal capabilities and immune-modulatory functions of macrophages. These findings demonstrate that AM-1 significantly alleviates the progression of challenging IAIs as a presurgical immunoenhancer. Our research introduces a novel therapeutic strategy that employs natural polysaccharides to combat refractory infections.
Asunto(s)
Agaricus , Glucanos , Macrófagos , Animales , Ratones , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Macrófagos/inmunología , Agaricus/química , Glucanos/química , Glucanos/farmacología , Células RAW 264.7 , Antibacterianos/farmacología , Antibacterianos/química , Infecciones Relacionadas con Prótesis/tratamiento farmacológico , Peso Molecular , Ratones Endogámicos C57BL , Autofagia/efectos de los fármacos , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-HéliceRESUMEN
Epigenetic modifications to DNA and chromatin control oncogenic and tumor-suppressive mechanisms in melanoma. Ezh2, the catalytic component of the Polycomb Repressive Complex 2 (PRC2), which mediates methylation of lysine 27 on histone 3 (H3K27me3), can regulate both melanoma initiation and progression. We previously found that mutant Ezh2Y641F interacts with the immune regulator Stat3 and together they affect anti-tumor immunity. However, given the numerous downstream targets and pathways affected by Ezh2, many mechanisms that determine its oncogenic activity remain largely unexplored. Using genetically engineered mouse models, we further investigated the role of pathways downstream of Ezh2 in melanoma carcinogenesis and identified significant enrichment in several autophagy signatures, along with increased expression of autophagy regulators, such as Atg7. In this study, we investigated the effect of Atg7 on melanoma growth and tumor immunity within the context of a wild-type or Ezh2Y641F epigenetic state. We found that the Atg7 locus is controlled by multiple Ezh2 and Stat3 binding sites, Atg7 expression is dependent on Stat3 expression, and that deletion of Atg7 slows down melanoma cell growth in vivo, but not in vitro. Atg7 deletion also results in increased CD8 + T cells in Ezh2Y641F melanomas and reduced myelosuppressive cell infiltration in the tumor microenvironment, particularly in Ezh2WT melanomas, suggesting a strong immune system contribution in the role of Atg7 in melanoma progression. These findings highlight the complex interplay between genetic mutations, epigenetic regulators, and autophagy in shaping tumor immunity in melanoma.
Asunto(s)
Proteína 7 Relacionada con la Autofagia , Proteína Potenciadora del Homólogo Zeste 2 , Factor de Transcripción STAT3 , Animales , Factor de Transcripción STAT3/metabolismo , Ratones , Proteína Potenciadora del Homólogo Zeste 2/metabolismo , Proteína Potenciadora del Homólogo Zeste 2/genética , Proteína 7 Relacionada con la Autofagia/genética , Proteína 7 Relacionada con la Autofagia/metabolismo , Melanoma Experimental/inmunología , Melanoma Experimental/patología , Melanoma Experimental/genética , Melanoma Experimental/metabolismo , Microambiente Tumoral/inmunología , Ratones Endogámicos C57BL , Regulación Neoplásica de la Expresión Génica , Melanoma/inmunología , Melanoma/metabolismo , Melanoma/genética , Melanoma/patología , Epigénesis Genética , Línea Celular Tumoral , Humanos , Autofagia/inmunología , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismoRESUMEN
Sleep and circadian rhythm dysfunctions are common clinical features of Alzheimer's disease (AD). Increasing evidence suggests that in addition to being a symptom, sleep disturbances can also drive the progression of neurodegeneration. Protein aggregation is a pathological hallmark of AD; however, the molecular pathways behind how sleep affects protein homeostasis remain elusive. Here we demonstrate that sleep modulation influences proteostasis and the progression of neurodegeneration in Drosophila models of tauopathy. We show that sleep deprivation enhanced Tau aggregational toxicity resulting in exacerbated synaptic degeneration. In contrast, sleep induction using gaboxadol led to reduced toxic Tau accumulation in neurons as a result of modulated autophagic flux and enhanced clearance of ubiquitinated Tau, suggesting altered protein processing and clearance that resulted in improved synaptic integrity and function. These findings highlight the complex relationship between sleep and regulation of protein homeostasis and the neuroprotective potential of sleep-enhancing therapeutics to slow the progression or delay the onset of neurodegeneration.
Asunto(s)
Enfermedad de Alzheimer , Autofagia , Modelos Animales de Enfermedad , Proteostasis , Sueño , Proteínas tau , Animales , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Sueño/fisiología , Proteínas tau/metabolismo , Proteínas de Drosophila/metabolismo , Proteínas de Drosophila/genética , Neuronas/metabolismo , Drosophila melanogaster/metabolismo , Humanos , Drosophila , Privación de Sueño/metabolismo , Privación de Sueño/fisiopatología , Tauopatías/metabolismo , Tauopatías/patología , Tauopatías/etiologíaRESUMEN
Lysosomes are acidic organelles involved in crucial intracellular functions, including the degradation of organelles and protein, membrane repair, phagocytosis, endocytosis, and nutrient sensing. Given these key roles of lysosomes, maintaining their homeostasis is essential for cell viability. Thus, to preserve lysosome integrity and functionality, cells have developed a complex intracellular system, called lysosome quality control (LQC). Several stressors may affect the integrity of lysosomes, causing Lysosomal membrane permeabilization (LMP), in which membrane rupture results in the leakage of luminal hydrolase enzymes into the cytosol. After sensing the damage, LQC either activates lysosome repair, or induces the degradation of the ruptured lysosomes through autophagy. In addition, LQC stimulates the de novo biogenesis of functional lysosomes and lysosome exocytosis. Alterations in LQC give rise to deleterious consequences for cellular homeostasis. Specifically, the persistence of impaired lysosomes or the malfunctioning of lysosomal processes leads to cellular toxicity and death, thereby contributing to the pathogenesis of different disorders, including neurodegenerative diseases (NDs). Recently, several pieces of evidence have underlined the importance of the role of lysosomes in NDs. In this review, we describe the elements of the LQC system, how they cooperate to maintain lysosome homeostasis, and their implication in the pathogenesis of different NDs.
Asunto(s)
Lisosomas , Enfermedades Neurodegenerativas , Lisosomas/metabolismo , Humanos , Enfermedades Neurodegenerativas/metabolismo , Animales , Homeostasis , AutofagiaRESUMEN
OBJECTIVE: Hepatocellular carcinoma (HCC) poses a significant challenge to global health. Its pathophysiology involves interconnected processes, including cell proliferation, autophagy, and macrophage polarization. However, the role of Absent in Melanoma 2 (AIM2) in HCC remains elusive. METHODS: The expression of AIM2 in Huh-7 and Hep3B cell lines was manipulated and cell proliferation, autophagy, apoptosis, and migration/invasion, together with the polarization of M2 macrophages, were evaluated. The markers of autophagy pathway, LC3B, Beclin-1, and P62, underwent examination through Western blot analysis. An autophagy inhibitor, 3-MA, was used to measured the role of autophagy in HCC. Finally, the effect of AIM2 overexpression on HCC was further evaluated using a subcutaneous tumor model in nude mice. RESULTS: Our results established that AIM2 overexpression inhibits HCC cell proliferation, migration, and invasion while promoting apoptosis and autophagy. Conversely, knockdown of AIM2 engendered opposite effects. AIM2 overexpression was correlated with reduced M2 macrophage polarization. The autophagy inhibitor substantiated AIM2's role in autophagy and identified its downstream impact on cell proliferation, migration, invasion, and macrophage polarization. In the in vivo model, overexpression of AIM2 led to the inhibition of HCC tumor growth. CONCLUSION: The findings underscore AIM2's crucial function in modulating major biological processes in HCC, pointing to its potential as a therapeutic target. This study inaugurally demonstrated that AIM2 activates autophagy and influences macrophage polarization, playing a role in liver cancer progression.
Asunto(s)
Autofagia , Carcinoma Hepatocelular , Movimiento Celular , Proliferación Celular , Neoplasias Hepáticas , Macrófagos , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/inmunología , Autofagia/genética , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/inmunología , Animales , Humanos , Ratones , Macrófagos/metabolismo , Macrófagos/inmunología , Línea Celular Tumoral , Movimiento Celular/genética , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Apoptosis/genética , Ratones Desnudos , Ensayos Antitumor por Modelo de Xenoinjerto , Activación de Macrófagos/genéticaRESUMEN
Porcine reproductive and respiratory syndrome virus (PRRSV), a significant pathogen affecting the swine industry globally, has been shown to manipulate host cell processes, including autophagy, to facilitate its replication and survival within the host. Autophagy, an intracellular degradation process crucial for maintaining cellular homeostasis, can be hijacked by viruses for their own benefit. During PRRSV infection, autophagy plays a complex role, both as a defense mechanism of the host and as a tool exploited by the virus. This review explores the current understanding of the molecular mechanisms underlying autophagy induction under PRRSV infection, its impact on virus replication, and the potential implications for viral pathogenesis and antiviral strategies. By synthesizing the latest research findings, this article aims to enhance our understanding of the intricate relationship between autophagy and PRRSV, paving the way for novel therapeutic approaches against this swine pathogen.
Asunto(s)
Autofagia , Interacciones Huésped-Patógeno , Síndrome Respiratorio y de la Reproducción Porcina , Virus del Síndrome Respiratorio y Reproductivo Porcino , Replicación Viral , Animales , Virus del Síndrome Respiratorio y Reproductivo Porcino/fisiología , Virus del Síndrome Respiratorio y Reproductivo Porcino/patogenicidad , Porcinos , Síndrome Respiratorio y de la Reproducción Porcina/virología , Síndrome Respiratorio y de la Reproducción Porcina/patologíaRESUMEN
Alzheimer's disease (AD) is a common neurodegenerative disease with the main manifestations of progressive cognitive dysfunction,behavioral disorders,and gradual decline of living ability.The etiology of AD is complex,and the pathogenesis of this disease remains controversial.Calcium signaling plays an important role in regulating neuronal activities,including neurotransmitter release,synaptic plasticity,memory storage,and neuronal apoptosis.Increasing studies have shown that neuronal calcium dyshomeostasis is a major pathological factor in the occurrence and development of AD.This article reviews the role and research progress in intracellular calcium dyshomeostasis in AD,including the relationship between calcium homeostasis and amyloid ß,the role of calcium/calmodulin-dependent protein kinases in tau phosphorylation,calcium signaling pathways,the relationship between calcium homeostasis and mitochondrial function,autophagy,and neuroinflammation.
Asunto(s)
Enfermedad de Alzheimer , Calcio , Homeostasis , Enfermedad de Alzheimer/metabolismo , Humanos , Calcio/metabolismo , Péptidos beta-Amiloides/metabolismo , Señalización del Calcio/fisiología , Mitocondrias/metabolismo , Proteínas tau/metabolismo , Autofagia/fisiología , Animales , Proteínas Quinasas Dependientes de Calcio-Calmodulina/metabolismo , Neuronas/metabolismo , FosforilaciónRESUMEN
OBJECTIVE: To investigate the protective effects of an anti-inflammatory mixture on acute lung injury (ALI) induced by sepsis in rats, as well as its possible mechanisms. METHODS: A total of 40 Sprague-Dawley (SD) rats were randomly divided into the sham group, septic ALI model group (model group), 3-methyladenine (3-MA) control group, and anti-inflammatory mixture pretreatment group, with 10 rats in each group. Cecal ligation and perforation (CLP) was performed to reproduce a septic ALI model. The rats in the sham group only underwent opening and closing the abdomen without perforation and ligation. Both groups were given saline gavage and intraperitoneal injection for 3 consecutive days before surgery. The 3-MA control group was given intraperitoneal injection of saline and autophagy inhibitor 3-MA 15 mg/kg for 3 consecutive days before modeling. The anti-inflammatory mixture pretreatment group was given 8.8 mL/kg of anti-inflammatory mixture by gavage [the composition of anti-inflammatory mixture: rhubarb 15 g (after the next), coptis chinensis 15 g, baical skullcap root 12 g, magnoliae cortex 12 g, dahurian patrinia herb 30 g] and saline intraperitoneal injection for 3 consecutive days before modeling. The rats in each group were anesthetized 24 hours after surgery and died due to abdominal aortic blood collection. Enzyme-linked immunosorbent assay (ELISA) was used to detect the levels of serum inflammatory cytokines interleukins (IL-1ß and IL-6). Lung tissue was taken and then the bronchoalveolar lavage fluid (BALF) was collected, and the levels of IL-1ß and IL-6 were detected by ELISA. Lung wet/dry weight (W/D) ratio was measured. After hematoxylin-eosin (HE) staining, the histopathological changes of the lungs were observed under light microscopy. Western blotting was used to detect the expression of autophagy markers microtubule-associated protein 1 light chain 3- II/I (LC3- II/I) and Beclin-1 protein in lung tissue. Autophagosomes in lung tissue were observed with transmission electron microscopy. RESULTS: Compared with the sham group, the rats in the model group exhibited severe destruction of lung tissue structure, with significant infiltration of inflammatory cells, the lung W/D ratio and the levels of IL-1ß and IL-6 in serum and BALF were significantly increased, the expressions of LC3- II/I and Beclin-1 protein were down-regulated, the autophagosomes were more. The rats in the 3-MA control group exhibited more severe lung tissue injury as compared with the model group, the lung W/D ratio and the levels of inflammatory cytokines in serum and BALF were further increased, the expressions of LC3- II/I and Beclin-1 protein still showed a decrease tendency as compared with the sham group, and the autophagosomes were less than that in the model group. Compared with the model group, the anti-inflammatory mixture pretreatment group showed milder lung tissue injury with a minimal amount of inflammatory cell infiltration, the lung W/D ratio was significantly reduced (7.07±1.02 vs. 11.33±1.85, P < 0.05), the levels of IL-1ß and IL-6 in both serum and BALF were significantly decreased [IL-1ß (ng/L): 26.04±3.86 vs. 40.83±5.46 in serum, 17.75±2.02 vs. 26.86±4.32 in BALF; IL-6 (ng/L): 91.28±10.15 vs. 129.44±13.05 in serum, 76.06±7.51 vs. 120.91±7.47 in BALF, all P < 0.05], and the ratio of LC3- II/I and Beclin-1 protein expression were significantly increased [LC3- II/I ratio: 1.23±0.02 vs. 0.60±0.02, Beclin-1 protein (Beclin-1/GAPDH): 2.37±0.33 vs. 0.62±0.05, both P < 0.05]. Furthermore, an increase in the number of autophagosomes was observed. CONCLUSIONS: The anti-inflammatory mixture improves lung injury in rats with sepsis induced by CLP and reduce inflammation levels, potentially through upregulation of Beclin-1-mediated autophagy.
Asunto(s)
Lesión Pulmonar Aguda , Autofagia , Beclina-1 , Ratas Sprague-Dawley , Sepsis , Animales , Lesión Pulmonar Aguda/etiología , Lesión Pulmonar Aguda/metabolismo , Ratas , Sepsis/complicaciones , Sepsis/metabolismo , Sepsis/tratamiento farmacológico , Autofagia/efectos de los fármacos , Masculino , Beclina-1/metabolismo , Antiinflamatorios/farmacología , Proteínas Reguladoras de la Apoptosis/metabolismo , Interleucina-1beta/metabolismo , Pulmón/patología , Pulmón/metabolismo , Interleucina-6/metabolismo , Modelos Animales de EnfermedadRESUMEN
Autophagy plays a crucial role in cancer cell survival by facilitating the elimination of detrimental cellular components and the recycling of nutrients. Understanding the molecular regulation of autophagy is critical for developing interventional approaches for cancer therapy. In this study, we report that migfilin, a focal adhesion protein, plays a novel role in promoting autophagy by increasing autophagosome-lysosome fusion. We found that migfilin is associated with SNAP29 and Vamp8, thereby facilitating Stx17-SNAP29-Vamp8 SNARE complex assembly. Depletion of migfilin disrupted the formation of the SNAP29-mediated SNARE complex, which consequently blocked the autophagosome-lysosome fusion, ultimately suppressing cancer cell growth. Restoration of the SNARE complex formation rescued migfilin-deficiency-induced autophagic flux defects. Finally, we found depletion of migfilin inhibited cancer cell proliferation. SNARE complex reassembly successfully reversed migfilin-deficiency-induced inhibition of cancer cell growth. Taken together, our study uncovers a new function of migfilin as an autophagy-regulatory protein and suggests that targeting the migfilin-SNARE assembly could provide a promising therapeutic approach to alleviate cancer progression.
Asunto(s)
Autofagia , Moléculas de Adhesión Celular , Proliferación Celular , Lisosomas , Proteínas Qb-SNARE , Proteínas Qc-SNARE , Proteínas R-SNARE , Humanos , Proteínas R-SNARE/metabolismo , Proteínas R-SNARE/genética , Proteínas Qb-SNARE/metabolismo , Proteínas Qb-SNARE/genética , Proteínas Qc-SNARE/metabolismo , Proteínas Qc-SNARE/genética , Lisosomas/metabolismo , Moléculas de Adhesión Celular/metabolismo , Moléculas de Adhesión Celular/genética , Autofagosomas/metabolismo , Células HeLa , Línea Celular Tumoral , Unión Proteica , Proteínas SNARE/metabolismo , Proteínas SNARE/genética , Fusión de Membrana , Proteínas Qa-SNARERESUMEN
Autophagy is a cellular homeostatic mechanism characterized by cyclic degradation. It plays an essential role in maintaining cellular quality and survival by eliminating dysfunctional cellular components. This process is pivotal in various pathophysiological processes. Benign prostatic hyperplasia (BPH) is a common urological disorder in middle-aged and elderly men. It frequently presents as lower urinary tract symptoms due to an increase in epithelial and stromal cells surrounding the prostatic urethra. The precise pathogenesis of BPH is complex. In recent years, research on autophagy in BPH has gained significant momentum, with accumulating evidence indicating its crucial role in the onset and progression of the disease. This review aims to outline the various roles of autophagy in BPH and elucidate potential therapeutic strategies targeting autophagy for managing BPH.
Asunto(s)
Autofagia , Hiperplasia Prostática , Hiperplasia Prostática/terapia , Humanos , Masculino , Autofagia/fisiologíaRESUMEN
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.
Asunto(s)
Cobre , Humanos , Cobre/metabolismo , Cobre/toxicidad , Animales , Muerte Celular/efectos de los fármacos , Muerte Celular/fisiología , Autofagia/fisiología , Autofagia/efectos de los fármacosRESUMEN
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by motor neuron degeneration. Dysregulation of long non-coding RNAs (lncRNAs) has been implicated in ALS pathogenesis but their roles remain unclear. Previous studies found lnc-ABCA12-3 was downregulated in ALS patients. We aim to characterize the expression and function of lnc-ABCA12-3 in ALS and explore its mechanisms of action. Lnc-ABCA12-3 expression was analyzed in PBMCs from ALS patients and correlated with clinical outcomes. Effect of modulating lnc-ABCA12-3 expression was assessed in cell models using assays of apoptosis, protein homeostasis and pathway analysis. RNA pull-down and interaction studies were performed to identify lnc-ABCA12-3 binding partners. Lnc-ABCA12-3 was downregulated in ALS patients, correlating with faster progression and shorter survival. Overexpression of lnc-ABAC12-3 conferred protection against oxidative stress-induced apoptosis, while knockdown lnc-ABCA12-3 enhanced cell death. Lnc-ABCA12-3 maintained protein quality control pathways, including ubiquitination, autophagy and stress granule formation, by regulating the ubiquitin shuttle protein UBQLN1. This study identified lnc-ABCA12-3 as a novel regulatory lncRNA implicated in ALS pathogenesis by modulating cellular survival and stress responses through interactions with UBQLN1, influencing disease progression. Lnc-ABCA12-3 may influence ALS through regulating protein homeostasis pathways.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales , Esclerosis Amiotrófica Lateral , Apoptosis , Proteínas Relacionadas con la Autofagia , Regulación hacia Abajo , ARN Largo no Codificante , Esclerosis Amiotrófica Lateral/genética , Esclerosis Amiotrófica Lateral/metabolismo , Esclerosis Amiotrófica Lateral/patología , Humanos , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Proteínas Relacionadas con la Autofagia/genética , Proteínas Relacionadas con la Autofagia/metabolismo , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Apoptosis/genética , Femenino , Proteostasis , Masculino , Persona de Mediana Edad , Autofagia/genética , Estrés Oxidativo , Regulación de la Expresión GénicaRESUMEN
BACKGROUND: Fibrosis with unrelieved chronic inflammation is an important pathological change in keloids. Mitochondrial autophagy plays a crucial role in reducing inflammation and inhibiting fibrosis. Adipose stem cell-derived exosomes, a product of adipose stem cell paracrine secretion, have pharmacological effects, such as anti-inflammatory and antiapoptotic effects, and mediate autophagy. Therefore, this study aims to investigate the function and mechanism of adipose stem cell exosomes in the treatment of keloids. METHOD: We isolated adipose stem cell exosomes under normoxic and hypoxic condition to detect their effects on keloid fibroblast proliferation, migration, and collagen synthesis. Meanwhile, 740YPDGFR (PI3K/AKT activator) was applied to detect the changes in autophagic flow levels and mitochondrial morphology and function in keloid fibroblasts. We constructed a human keloid mouse model by transplanting human keloid tissues into six-week-old (20-22 g; female) BALB/c nude mice, meanwhile, we applied adipose stem cell exosomes to treat the mouse model and observed the retention and effect of ADSC exosomes in vivo. RESULTS: ADSC exosomes can inhibit the PI3K/AKT/mTOR signaling pathway. The exosomes of ADSCs decreased the inflammatory level of KFs, enhanced the interaction between P62 and LC3, and restored the mitochondrial membrane potential. In the human keloid mouse model, ADSC exosomes can exist stably, promote mitochondrial autophagy in keloid tissue, improve mitochondrial morphology, reduce inflammatory reaction and fibrosis. Meanwhile, At the same time, the exosomes derived from hypoxic adipose stem cells have played a more effective role in both in vitro and in vivo experiments. CONCLUSIONS: Adipose stem cell exosomes inhibited the PI3K/AKT/mTOR pathway, activated mitochondrial autophagy, and alleviated keloid scars.
Asunto(s)
Autofagia , Exosomas , Queloide , Mitocondrias , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Transducción de Señal , Serina-Treonina Quinasas TOR , Queloide/metabolismo , Queloide/terapia , Queloide/patología , Exosomas/metabolismo , Exosomas/trasplante , Animales , Serina-Treonina Quinasas TOR/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Humanos , Fosfatidilinositol 3-Quinasas/metabolismo , Ratones , Mitocondrias/metabolismo , Femenino , Ratones Endogámicos BALB C , Ratones Desnudos , Tejido Adiposo/metabolismo , Tejido Adiposo/citología , Células Madre/metabolismo , Células Madre/citología , Proliferación Celular , Fibroblastos/metabolismoRESUMEN
OBJECTIVE: This study aimed to reveal the role and mechanism of MG-132 in delaying hyperlipidemia-induced senescence of vascular smooth muscle cells (VSMCs). METHODS: Immunohistochemistry and hematoxylin-eosin staining confirmed the therapeutic effect of MG-132 on arterial senescence in vivo and its possible mechanism. Subsequently, VSMCs were treated with sodium palmitate (PA), an activator (Recilisib) or an inhibitor (Pictilisib) to activate or inhibit PI3K, and CCK-8 and EdU staining, wound healing assays, Transwell cell migration assays, autophagy staining assays, reactive oxygen species assays, senescence-associated ß-galactosidase staining, and Western blotting were performed to determine the molecular mechanism by which MG-132 inhibits VSMC senescence. Validation of the interaction between MG-132 and PI3K using molecular docking. RESULTS: Increased expression of p-PI3K, a key protein of the autophagy regulatory system, and decreased expression of the autophagy-associated proteins Beclin 1 and ULK1 were observed in the aortas of C57BL/6J mice fed a high-fat diet (HFD), and autophagy was inhibited in aortic smooth muscle. MG-132 inhibits atherosclerosis by activating autophagy in VSMCs to counteract PA-induced cell proliferation, migration, oxidative stress, and senescence, thereby inhibiting VSMC senescence in the aorta. This process is achieved through the PI3K/AKT/mTOR signaling pathway. CONCLUSION: MG-132 activates autophagy by inhibiting the PI3K/AKT/mTOR pathway, thereby inhibiting palmitate-induced proliferation, migration, and oxidative stress in vascular smooth muscle cells and suppressing their senescence.
Asunto(s)
Autofagia , Senescencia Celular , Leupeptinas , Músculo Liso Vascular , Miocitos del Músculo Liso , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Transducción de Señal , Serina-Treonina Quinasas TOR , Autofagia/efectos de los fármacos , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/citología , Serina-Treonina Quinasas TOR/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Animales , Senescencia Celular/efectos de los fármacos , Humanos , Fosfatidilinositol 3-Quinasas/metabolismo , Ratones , Transducción de Señal/efectos de los fármacos , Miocitos del Músculo Liso/efectos de los fármacos , Miocitos del Músculo Liso/metabolismo , Leupeptinas/farmacología , Masculino , Ratones Endogámicos C57BL , Ácido Palmítico/farmacología , Proliferación Celular/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Dieta Alta en Grasa/efectos adversosRESUMEN
Glioblastoma multiforme (GBM) is a malignant tumour with a poor prognosis. Therefore, potential treatment strategies and novel therapeutic targets have gained increased attention. Our data showed that the ethanol extract of Vanilla planifolia stem (VAS) significantly decreased the viability and the colony formation of GBM cells. Moreover, VAS induced the cleavage of MAP1LC3, a marker of autophagy. Further RNA-seq and bioinformatic analysis revealed 4248 differentially expressed genes (DEGs) between VAS-treated GBM cells and the control cells. Protein-protein interactions between DEGs with fold changes less than -3 and more than 5 were further analysed, and we found that 16 and 9 hub DEGs, respectively, were correlated with other DEGs. Further qPCR experiments confirmed that 14 hub DEGs was significantly downregulated and 9 hub DEGs was significantly upregulated. In addition, another significantly downregulated DEG, p21-activated kinase 6 (PAK6), was correlated with the overall survival of GBM patients. Further validation experiments confirmed that VAS significantly reduced the mRNA and protein expression of PAK6, which led to the abolition of cell viability and colony formation. These findings demonstrated that VAS reduced cell viability, suppressed colony formation and induced autophagy and revealed PAK6 and other DEGs as potential therapeutic targets for GBM treatment.