RESUMO
Efferocytosis is a crucial process whereby phagocytes engulf and eliminate apoptotic cells (ACs). This intricate process can be categorized into four steps: (1) ACs release "find me" signals to attract phagocytes, (2) phagocytosis is directed by "eat me" signals emitted by ACs, (3) phagocytes engulf and internalize ACs, and (4) degradation of ACs occurs. Maintaining immune homeostasis heavily relies on the efficient clearance of ACs, which eliminates self-antigens and facilitates the generation of anti-inflammatory and immunosuppressive signals that maintain immune tolerance. However, any disruptions occurring at any of the efferocytosis steps during apoptosis can lead to a diminished efficacy in removing apoptotic cells. Factors contributing to this inefficiency encompass dysregulation in the release and recognition of "find me" or "eat me" signals, defects in phagocyte surface receptors, bridging molecules, and other signaling pathways. The inadequate clearance of ACs can result in their rupture and subsequent release of self-antigens, thereby promoting immune responses and precipitating the onset of autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, type 1 diabetes, and multiple sclerosis. A comprehensive understanding of the efferocytosis process and its implications can provide valuable insights for developing novel therapeutic strategies that target this process to prevent or treat autoimmune diseases.
RESUMO
Age-related diseases have become more common with the advancing age of the worldwide population. Such diseases involve multiple organs, with tissue degeneration and cellular apoptosis. To date, there is a general lack of effective drugs for treatment of most age-related diseases and there is therefore an urgent need to identify novel drug targets for improved treatment. Acid-sensing ion channel 1a (ASIC1a) is a degenerin/epithelial sodium channel family member, which is activated in an acidic environment to regulate pathophysiological processes such as acidosis, inflammation, hypoxia, and ischemia. A large body of evidence suggests that ASIC1a plays an important role in the development of age-related diseases (e.g., stroke, rheumatoid arthritis, Huntington's disease, and Parkinson's disease.). Herein we present: 1) a review of ASIC1a channel properties, distribution, and physiological function; 2) a summary of the pharmacological properties of ASIC1a; 3) and a consideration of ASIC1a as a potential therapeutic target for treatment of age-related disease.
Assuntos
Acidose , Acidente Vascular Cerebral , Humanos , Canais Iônicos Sensíveis a Ácido/farmacologia , Canais Iônicos Sensíveis a Ácido/fisiologia , Apoptose , EnvelhecimentoRESUMO
Rheumatoid arthritis (RA) is a common autoimmune disease characterized by chronic inflammation. Immune dysfunction is an essential mechanism in the pathogenesis of RA and directly linked to synovial inflammation and cartilage/bone destruction. Intermediate conductance Ca2+-activated K+ channel (KCa3.1) is considered a significant regulator of proliferation, differentiation, and migration of immune cells by mediating Ca2+ signal transduction. Earlier studies have demonstrated abnormal activation of KCa3.1 in the peripheral blood and articular synovium of RA patients. Moreover, knockout of KCa3.1 reduced the severity of synovial inflammation and cartilage damage to a significant extent in a mouse collagen antibody-induced arthritis (CAIA) model. Accumulating evidence implicates KCa3.1 as a potential therapeutic target for RA. Here, we provide an overview of the KCa3.1 channel and its pharmacological properties, discuss the significance of KCa3.1 in immune cells and feasibility as a drug target for modulating the immune balance, and highlight its emerging role in pathological progression of RA.
Assuntos
Artrite Experimental , Artrite Reumatoide , Camundongos , Animais , Membrana Sinovial , Artrite Experimental/patologia , Inflamação , Modelos Animais de Doenças , ColágenoRESUMO
Rheumatoid arthritis is a common autoimmune disease that results from the deposition of antibodies-autoantigens in the joints, leading to long-lasting inflammation. The main features of RA include cartilage damage, synovial invasion and flare-ups of intra-articular inflammation, and these pathological processes significantly reduce patients' quality of life. To date, there is still no drug target that can act in rheumatoid arthritis. Therefore, the search for novel drug targets has become urgent. Due to their unique physicochemical properties, calcium ions play an important role in all cellular activities and the body has evolved a rigorous calcium signaling system. Calcium-permeable channels, as the main operators of calcium signaling, are widely distributed in cell membranes, endoplasmic reticulum membranes and mitochondrial membranes, and mediate the efflux and entry of Ca2+. Over the last century, more and more calcium-permeable channels have been identified in human cells, and the role of this large family of calcium-permeable channels in rheumatoid arthritis has gradually become clear. In this review, we briefly introduce the major calcium-permeable channels involved in the pathogenesis of RA (e.g., acid-sensitive ion channel (ASIC), transient receptor potential (TRP) channel and P2X receptor) and explain the specific roles and mechanisms of these calcium-permeable channels in the pathogenesis of RA, providing more comprehensive ideas and targets for the treatment of RA.
Assuntos
Artrite Reumatoide , Canais de Potencial de Receptor Transitório , Humanos , Canais de Cálcio/metabolismo , Cálcio/metabolismo , Qualidade de Vida , Artrite Reumatoide/patologia , Canais de Potencial de Receptor Transitório/metabolismo , Inflamação , AutoantígenosRESUMO
TRPM (transient receptor potential melastatin) 7, a member of the TRPM subfamily, is a nonselective cation channel located on the cell membrane that regulates mammalian cell intracellular Mg2+ balance. TRPM7 is widely expressed in vivo and is characterized by a unique domain structure comprised of cation channel and protein kinase. TRPM7 primarily controls the cellular influx of Mg2+ and Ca2+. As such TRPM7 plays an important role in the physiological processes of cell proliferation, adhesion, migration, and differentiation, as well as phenotypic transformation. Changes in TRPM7 expression and activity are directly related to diseases such as tissue fibrosis, vascular injury, as well as the occurrence and development of tumors. The structure and function of TRPM7 has been previously described, but regulation of TRPM7 has been limited to Mg2+ and laboratory pharmacological compounds. Hence, in this review, we summarized the endogenous and exogenous regulation of TRPM7, clarified its internal regulatory mechanisms and molecular signaling pathways, and emphasized the regulation of TRPM7 activity as an important target for disease treatment.
Assuntos
Neoplasias , Canais de Cátion TRPM , Animais , Proliferação de Células , Mamíferos/metabolismo , Neoplasias/patologia , Proteínas Quinases/metabolismo , Transdução de Sinais/fisiologia , Canais de Cátion TRPM/metabolismoRESUMO
Osteoarthritis (OA) is a common and debilitating chronic joint disease, which is characterized by degeneration of articular cartilage and the aging of chondrocytes. Acid-sensitive ion channel 1a (ASIC1a) is a proton-activated cationic channel abundant in chondrocytes, which senses and regulates joint cavity pH. Our previous study demonstrated that ASIC1a was involved in acid-induced rat articular chondrocyte senescence, but the mechanistic basis remained unclear. In this study, we explored the mechanism of ASIC1a in chondrocyte senescence and OA. The results showed that senescence-related-ß-galactosidase, senescence-related markers (p53 and p21) and the autophagy-related protein Beclin-1 were found to be increased, but Lamin B1 was found to be reduced with acid (pH 6.0) treatment. These effects were inhibited by ASIC1a-specific blocker psalmotoxin-1 or ASIC1a-short hairpin RNA respectively in chondrocytes. Moreover, Silencing of Lamin B1 enhanced ASIC1a-mediated chondrocyte senescence, this effect was reversed by overexpression of Lamin B1, indicating that Lamin B1 was involved in ASIC1a-mediated chondrocyte senescence. Further, blockade of ASIC1a inhibits acid-induced autophagosomes and Beclin-1 protein expression, suggesting that ASIC1a is involved in acid-induced chondrocyte autophagy. Blocking autophagy with chloroquine inhibited Beclin-1 and increased Lamin B1 in acid-induced chondrocyte senescence. We further demonstrated that ASIC1a-mediated reduction of Lamin B1 expression was caused by autophagy pathway-dependent protein degradation. Finally, blocking ASIC1a protected cartilage tissue, restored Lamin B1 levels and inhibited chondrocyte senescence in a rat OA model. In summary, these findings suggest that ASIC1a may promote Lamin B1 degradation to mediate osteoarthritis chondrocyte senescence through the autophagy pathway.
Assuntos
Canais Iônicos Sensíveis a Ácido , Senescência Celular , Condrócitos , Lamina Tipo B , Osteoartrite , Canais Iônicos Sensíveis a Ácido/genética , Canais Iônicos Sensíveis a Ácido/metabolismo , Animais , Proteína Beclina-1/metabolismo , Cartilagem Articular/metabolismo , Condrócitos/citologia , Lamina Tipo B/metabolismo , Osteoartrite/genética , Osteoartrite/metabolismo , Ratos , Ratos Sprague-DawleyRESUMO
An autoimmune disease is an inappropriate response to one's tissues due to a break in immune tolerance and exposure to self-antigens. It often leads to structural and functional damage to organs and systemic disorders. To date, there are no effective interventions to prevent the progression of autoimmune diseases. Hence, there is an urgent need for new treatment targets. TRPM7 is an enzyme-coupled, transient receptor ion channel of the subfamily M that plays a vital role in pathologic and physiologic conditions. While TRPM7 is constitutively activated under certain conditions, it can regulate cell migration, polarization, proliferation and cytokine secretion. However, a growing body of evidence highlights the critical role of TRPM7 in autoimmune diseases, including rheumatoid arthritis, multiple sclerosis and diabetes. Herein, we present (a) a review of the channel kinase properties of TRPM7 and its pharmacological properties, (b) discuss the role of TRPM7 in immune cells (neutrophils, macrophages, lymphocytes and mast cells) and its upstream immunoreactive substances, and (c) highlight TRPM7 as a potential therapeutic target for autoimmune diseases.
Assuntos
Doenças Autoimunes/etiologia , Doenças Autoimunes/metabolismo , Autoimunidade , Imunomodulação , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Canais de Cátion TRPM/genética , Canais de Cátion TRPM/metabolismo , Animais , Doenças Autoimunes/diagnóstico , Doenças Autoimunes/terapia , Biomarcadores , Suscetibilidade a Doenças , Desenvolvimento de Medicamentos , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Sistema Imunitário/citologia , Sistema Imunitário/efeitos dos fármacos , Sistema Imunitário/imunologia , Sistema Imunitário/metabolismo , Imunomodulação/efeitos dos fármacos , Ativação do Canal Iônico/efeitos dos fármacos , Especificidade de Órgãos/efeitos dos fármacos , Especificidade de Órgãos/genética , Especificidade de Órgãos/imunologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/química , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-Atividade , Canais de Cátion TRPM/químicaRESUMO
PURPOSE: To explore the feasibility of applying bilateral free expanded scapular flaps to treat extensive cervicomandibular scar in children and adolescents. METHODS: This study reviewed 7 children and adolescent patients who received bilateral expanded scapular flaps to treat extensive cervicomandibular scars in the Pediatric Plastic Surgery Ward from August 2018 to December 2020. The scars in all patients involved neck, mandible, and anterior chest. The cervical scars involved the anterior neck and one or both sides of the lateral neck, and there were varying degrees of cervical dysfunction and mandibular dysplasia. The operation was completed into two stages. In the first stage, the expanded circumflex scapular artery perforator flaps were designed on both sides of the back and soft tissue expanders were implanted. The expansion process lasted for 6-14 months. In the second stage, the scar tissue was removed and contracture was released, and the expanded flaps were harvested. The cervical wound was repaired with free flap transplantation by anastomosing the facial artery and vein with the circumflex scapular artery and vein. The donor sites were closed directly. RESULTS: In this series of 7 patients, one patient had poorly healed incision after the expander was implanted. One expanded flap ruptured before the second-stage surgery, which was successfully treated by secondary surgery. One patient had expansion problem due to the blockage of the internally placed injection bottle, which was treated by placing the injection bottle externally. One patient developed a small area of ischemic necrosis at the distal end of the flap after transplantation, which was treated conservatively with dressing change. The postoperative follow-up was 6 months to 2 years. The cervico-mandibular angle restored to normal range, the cervical extension, flexion, and rotation were significantly improved. Two patients underwent flap thinning and scar releasing. CONCLUSIONS: The route of the circumflex scapular artery is constant. Bilateral expanded scapular flap transplantation can be used to repair extensive cervicomandibular scar in children and adolescent patients. The flap donor site is concealed and secondary damage is minimal.
Assuntos
Contratura , Retalho Perfurante , Procedimentos de Cirurgia Plástica , Adolescente , Criança , Cicatriz/cirurgia , Contratura/cirurgia , Humanos , Transplante de Pele , Resultado do TratamentoRESUMO
Articular cartilage damage with subsequent impairment of joint function is a common feature of articular diseases, in particular, rheumatoid arthritis and osteoarthritis. While articular cartilage injury mediated by chondrocyte apoptosis is a known major pathological feature of arthritis, the specific mechanisms remain unclear at present. Transient receptor potential melastatin-like seven channel (TRPM7) is reported to play an important regulatory role in apoptosis. This study focused on the effects of TRPM7 on arthritic chondrocyte injury and its underlying mechanisms of action. Sodium nitroprusside (SNP)-induced rat primary chondrocyte apoptosis and rat adjuvant arthritis (AA) were used as in vitro and in vivo models, respectively. Blockage of TRPM7 with 2-APB or specific siRNA resulted in increased chondrocyte viability and reduced toxicity of SNP. Moreover, treatment with 2-APB enhanced the Bcl-2/Bax ratio and reduced cleaved PARP and IL-6, MMP-13 and ADAMTS-5 expression in SNP-treated chondrocytes. Activation of Indian Hedgehog with purmorphamine reversed the protective effects of 2-APB on SNP-induced chondrocyte apoptosis. Blockage of TRPM7 with 2-APB relieved the clinical signs of AA in the rat model and reduced the arthritis score and paw swelling. Similar to findings in SNP-treated chondrocytes, 2-APB treatment increased the Bcl-2/Bax ratio and suppressed cleaved PARP, IL-6, MMP-13, ADAMTS-5, TRPM7, and Indian hedgehog expression in articular cartilage of AA rats. Our collective findings suggest that blockade of TRPM7 could effectively reduce chondrocyte apoptosis and articular cartilage damage in rats with adjuvant arthritis through regulation of the Indian Hedgehog signaling pathway.
RESUMO
Rapid increase in aging populations is an urgent problem because older adults are more likely to suffer from disabilities and age-related diseases (ARDs), burdening healthcare systems and society in general. ARDs are characterized by the progressive deterioration of tissues and organs over time, eventually leading to tissue and organ failure. To date, there are no effective interventions to prevent the progression of ARDs. Hence, there is an urgent need for new treatment strategies. Ferroptosis, an iron-dependent cell death, is linked to normal development and homeostasis. Accumulating evidence, however, has highlighted crucial roles for ferroptosis in ARDs, including neurodegenerative and cardiovascular diseases. In this review, we a) summarize initiation, regulatory mechanisms, and molecular signaling pathways involved in ferroptosis, b) discuss the direct and indirect involvement of the activation and/or inhibition of ferroptosis in the pathogenesis of some important diseases, and c) highlight therapeutic targets relevant for ARDs.
Assuntos
Envelhecimento/patologia , Doenças Cardiovasculares/tratamento farmacológico , Diabetes Mellitus/tratamento farmacológico , Ferroptose/efeitos dos fármacos , Doenças Neurodegenerativas/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/efeitos dos fármacos , Animais , Doenças Cardiovasculares/patologia , Linhagem Celular Tumoral , Diabetes Mellitus/patologia , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Ferroptose/fisiologia , Humanos , Ferro/metabolismo , Doenças Neurodegenerativas/patologia , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Doença Pulmonar Obstrutiva Crônica/patologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologiaRESUMO
The pyroptosis is a causative agent of rheumatoid arthritis, a systemic autoimmune disease merged with degenerative articular cartilage. Nevertheless, the precise mechanism of extracellular acidosis on chondrocyte pyroptosis is largely unclear. Acid-sensing ion channels (ASICs) belong to an extracellular H+ -activated cation channel family. Accumulating evidence has highlighted activation of ASICs induced by extracellular acidosis upregulate calpain and calcineurin expression in arthritis. In the present study, to investigate the expression and the role of acid-sensing ion channel 1a (ASIC1a), calpain, calcineurin, and NLRP3 inflammasome proteins in regulating acid-induced articular chondrocyte pyroptosis, primary rat articular chondrocytes were subjected to different pH, different time, and different treatments with or without ASIC1a, calpain-2, and calcineurin, respectively. Initially, the research results showed that extracellular acidosis-induced the protein expression of ASIC1a in a pH- and time-dependent manner, and the messenger RNA and protein expressions of calpain, calcineurin, NLRP3, apoptosis-associated speck-like protein, and caspase-1 were significantly increased in a time-dependent manner. Furthermore, the inhibition of ASIC1a, calpain-2, or calcineurin, respectively, could decrease the cell death accompanied with the decreased interleukin-1ß level, and the decreased expression of ASIC1a, calpain-2, calcineurin, and NLRP3 inflammasome proteins. Taken together, these results indicated the activation of ASIC1a induced by extracellular acidosis could trigger pyroptosis of rat articular chondrocytes, the mechanism of which might partly be involved with the activation of calpain-2/calcineurin pathway.
Assuntos
Canais Iônicos Sensíveis a Ácido/fisiologia , Artrite Experimental , Calcineurina/metabolismo , Calpaína/metabolismo , Condrócitos , Piroptose , Animais , Artrite Experimental/mortalidade , Artrite Experimental/patologia , Células Cultivadas , Condrócitos/metabolismo , Condrócitos/patologia , Masculino , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Ratos , Ratos Sprague-DawleyRESUMO
Nerve growth factor (NGF) is a neurotrophic factor that is thought to have a broad role in the nervous system and tumors, and has recently been described as a mediator of inflammation. It is not clear whether or not NGF participates in apoptosis of articular chondrocytes. In this study, we determined if NGF affects ASIC1a expression and NF-κB P65 activation in rat chondrocytes, and measured the effectiveness of NGF on apoptotic protein expression in acid-induced chondrocytes. NGF was shown to up-regulate the level of ASIC1a in a dose- and time-dependent fashion. Simultaneously, NGF activated NF-κB P65 in chondrocytes. Additionally, the elevated ASIC1a expression induced by NGF was eliminated by the NF-κB inhibitor (PDTC) in chondrocytes. Moreover, NGF reduced cell viability and induced LDH release under the premise of acid-induced articular chondrocytes. Furthermore, NGF could enhance cleaved-caspase 9 and cleaved-PARP expression in acid-pretreated chondrocytes, and which could be inhibited by using psalmotoxin 1(PcTX1) or PDTC. Together, these results indicated that NGF may up-regulate ASIC1a expression through the NF-κB signaling pathway, and further promote acid-induced apoptosis of chondrocytes.
RESUMO
Epidemiological evidence suggests that the etiology and pathogenesis of rheumatoid arthritis (RA) are closely associated with estrogen metabolism and deficiency. Estrogen protects against articular damage. Estradiol replacement therapy ameliorates local inflammation and knee joint swelling in ovariectomized models of RA. The mechanistic basis for the protective role of 17ß-estradiol (17ß-E2) is poorly understood. Acid-sensing ion channel 1a (ASIC1a), a sodium-permeable channel, plays a pivotal role in acid-induced articular chondrocyte injury. The aims of this study were to evaluate the role of 17ß-E2 in acid-induced chondrocyte injury and to determine the effect of 17ß-E2 on the level and activity of ASIC1a protein. Results showed that pretreatment with 17ß-E2 attenuated acid-induced damage, suppressed apoptosis, and restored mitochondrial function. Further, 17ß-E2 was shown to reduce protein levels of ASIC1a through the ERα receptor, to protect chondrocytes from acid-induced apoptosis, and to induce ASIC1a protein degradation through the autophagy-lysosomal pathway. Taken together, these results show that the use of 17ß-E2 may be a novel strategy for the treatment of RA by reducing cartilage destruction through down-regulation of ASIC1a protein levels.
Assuntos
Canais Iônicos Sensíveis a Ácido/metabolismo , Apoptose/efeitos dos fármacos , Cartilagem Articular/patologia , Condrócitos/patologia , Estradiol/farmacologia , Animais , Autofagia/efeitos dos fármacos , Condrócitos/efeitos dos fármacos , Condrócitos/metabolismo , Receptor alfa de Estrogênio/metabolismo , Lisossomos/efeitos dos fármacos , Lisossomos/metabolismo , Masculino , Proteólise/efeitos dos fármacos , Ratos Sprague-DawleyRESUMO
Tissue acidosis is a common feature of brain ischemia which causes neuronal injury. Activation of acid-sensing ion channel 1a (ASIC1a) plays an important role in acidosis-mediated neurotoxicity. Acute ethanol administration has been shown to provide neuroprotective effects during ischemic stroke, but the precise mechanisms have yet to be determined. In this study, we investigated the effect of ethanol on the activity/expression of ASIC1a channels and acidosis-induced neurotoxicity. We showed that acute treatment of neuronal cells with ethanol for more than 3 h could reduce ASIC1a protein expression, ASIC currents, and acid-induced [Ca2+]i elevation. We further demonstrated that ethanol-induced reduction of ASIC1a expression is mediated by autophagy-lysosome pathway (ALP)-dependent protein degradation. Finally, we showed that ethanol protected neuronal cells against acidosis-induced cytotoxicity, which effect was mimicked by autophagy activator rapamycin and abolished by autophagy inhibitor CQ. Together, these results indicate that moderate acute ethanol exposure can promote autophagy-lysosome pathway-dependent ASIC1a protein degradation and protect against acidosis-induced neurotoxicity.
Assuntos
Canais Iônicos Sensíveis a Ácido/metabolismo , Acidose/complicações , Autofagia , Etanol/efeitos adversos , Lisossomos/metabolismo , Síndromes Neurotóxicas/etiologia , Síndromes Neurotóxicas/prevenção & controle , Proteólise , Animais , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Cálcio/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Ativação Enzimática/efeitos dos fármacos , Ativação do Canal Iônico/efeitos dos fármacos , Lisossomos/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Proteólise/efeitos dos fármacos , Canais de Sódio/metabolismoRESUMO
Necroptosis, a necrotic cell death pathway regulated by receptor interacting protein (RIP) 1 and 3, plays a key role in pathophysiological processes, including rheumatoid arthritis (RA). However, whether necroptosis is involved in RA articular cartilage damage processes remain unclear. The aim of present study was to investigate the dynamic changes in arthritic chondrocyte necroptosis and the effect of RIP1 inhibitor necrostatin-1 (Nec-1) and acid-sensing ion channels (ASICs) inhibitor amiloride on arthritic cartilage injury and acid-induced chondrocyte necroptosis. Our results demonstrated that the expression of RIP1, RIP3 and mixed lineage kinase domain-like protein phosphorylation (p-MLKL) were increased in adjuvant arthritis (AA) rat articular cartilage in vivo and acid-induced chondrocytes in vitro. High co-expression of ASIC1a and RIP1 showed in AA rat articular cartilage. Moreover, Nec-1 and amiloride could reduce articular cartilage damage and necroinflammation in AA rats. In addition, acid-induced increase in necroptosis markers RIP1/RIP3 were inhibited by Nec-1, ASIC1a-specific blocker psalmotoxin-1 (PcTx-1) or ASIC1a-short hairpin RNA respectively, which revealed that necroptosis is triggered in acid-induced chondrocytes and mediated by ASIC1a. These findings indicated that blocking ASIC1a-mediated chondrocyte necroptosis may provide potential therapeutic strategies for RA treatment.
Assuntos
Canais Iônicos Sensíveis a Ácido/metabolismo , Artrite Experimental/tratamento farmacológico , Condrócitos/efeitos dos fármacos , Imidazóis/farmacologia , Indóis/farmacologia , Canais Iônicos Sensíveis a Ácido/genética , Amilorida/farmacologia , Animais , Artrite Experimental/etiologia , Artrite Experimental/patologia , Cartilagem Articular/efeitos dos fármacos , Cartilagem Articular/patologia , Condrócitos/patologia , Masculino , Necrose/tratamento farmacológico , Peptídeos/farmacologia , Proteínas Serina-Treonina Quinases/metabolismo , Ratos Sprague-Dawley , Proteína Serina-Treonina Quinases de Interação com Receptores , Venenos de Aranha/farmacologiaRESUMO
4-Amino-2-Trifluoromethyl-Phenyl Retinate (ATPR), an all-trans retinoic acid (ATRA) derivative, possesses the ability to relief several carcinoma. Here, we explored the potential molecular mechanism of eukaryotic translation initiation factor 6 (eIF6) in ATPR-induced leukemia cell differentiation. Our research showed that ATPR could inhibit cell proliferation and promote cell differentiation in several leukemia cell lines. Besides, ATPR remarkably reduced the expression of eIF6 in vitro. Interestingly, the reduction of eIF6 contributed to restraining proliferation of K562â¯cells by inhibiting CyclinD1, C-myc and blocking cell cycle, as well as promoting differentiation of K562â¯cells by increasing the expression of C/EBPε, cell surface antigen CD11b and inducing renal-shrinkage of nuclear. Furthermore, the over-expression of eIF6 restrained the effects of ATPR on cell proliferation and maturation in K562â¯cells. In Addition, Notch1/CBF-1 signal activated by Chrysin could increase expression of eIF6 and restrain the differentiation in ATPR-induced K562â¯cells. Taken together, all above results indicated that ATPR induced differentiation of leukemia cells by decreasing eIF6 through Notch1/CBF-1 signal, which might exert an innovative treatment for leukemia.