RESUMO
Pyroptosis, a lytic form of cell death mediated by the gasdermin family, is characterized by cell swelling and membrane rupture. Inducing pyroptosis in cancer cells can enhance antitumor immune responses and is a promising strategy for cancer therapy. However, excessive pyroptosis may trigger the development of inflammatory diseases due to immoderate and continuous inflammatory reactions. Nanomaterials and nanobiotechnology, renowned for their unique advantages and diverse structures, have garnered increasing attention owing to their potential to induce pyroptosis in diseases such as cancer. A nano-delivery system for drug-induced pyroptosis in cancer cells can overcome the limitations of small molecules. Furthermore, nanomedicines can directly induce and manipulate pyroptosis. This review summarizes and discusses the latest advancements in nanoparticle-based treatments with pyroptosis among inflammatory diseases and cancer, focusing on their functions and mechanisms and providing valuable insights into selecting nanodrugs for pyroptosis. However, the clinical application of these strategies still faces challenges owing to a limited understanding of nanobiological interactions. Finally, future perspectives on the emerging field of pyroptotic nanomaterials are presented.
Assuntos
Inflamação , Nanopartículas , Neoplasias , Piroptose , Piroptose/efeitos dos fármacos , Humanos , Neoplasias/tratamento farmacológico , Nanopartículas/química , Animais , Inflamação/tratamento farmacológico , Nanomedicina/métodos , Sistemas de Liberação de Medicamentos/métodos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêuticoRESUMO
BACKGROUND: Pulmonary sequestration (PS) is a rare congenital lower airway malformation. This study presents the clinical and imaging features and surgical outcomes of PS in adults, and compare the safety and feasibility of minimally invasive surgery versus open thoracotomy for PS. METHODS: Adult patients with PS treated at our center from July 2011 to September 2021 were included. Information regarding the patient demographics, clinical and CT features, arterial supply and venous drainage, and surgical outcomes were collected. RESULTS: Ninety seven patients were included. The most common CT findings were mass lesions (50.5%) and cystic lesions (20.6%). The vast majority of the lesions (96 out of 97) were located close to the spine in the lower lobes (left vs. right: 3.6 vs. 1). Arterial supply was mainly provided by the thoracic aorta (87.4%) and abdominal aorta (10.5%). Intralobar and extralobar PS accounted for 90.7% and 9.3% of the patients, respectively. Three (4.5%) patients who underwent minimally invasive surgery were converted to open thoracotomy due to dense adhesions. Though no significant differences regarding operative time (P = 0.133), the minimally invasive surgery group was significantly better than the open thoracotomy group regarding intraoperative blood loss (P = 0.001), drainage volume (P = 0.004), postoperative hospital days (P = 0.017) and duration of chest drainage (P = 0.001). There were no cases of perioperative mortality. Only four (4.1%) patients developed postoperative complications, and no significant difference existed between the two groups. CONCLUSION: Our study revealed PS can present with a variety of different clinical and radiologic manifestations. Clinicians should consider the possibility of PS when diagnosing a lesion in the lower lobes close to the spine. Moreover, minimally invasive surgery is a safe and effective treatment modality for the treatment of PS in an experienced center.
Assuntos
Sequestro Broncopulmonar , Humanos , Adulto , Sequestro Broncopulmonar/diagnóstico por imagem , Sequestro Broncopulmonar/cirurgia , Sequestro Broncopulmonar/complicações , Estudos Retrospectivos , Tomografia Computadorizada por Raios X , Pulmão/patologia , Resultado do TratamentoRESUMO
Previous studies have shown that the tumor necrosis factor-α (TNF-α) levels in serum and bone tissues formed in avascular necrosis of femoral head (ANFH) patients were higher than those of normal individuals, indicating TNF-α might play a role in the pathogenesis of ANFH. However, the underlying mechanisms remain unclear. Hematoxylin and eosin staining was performed to show the pathological changes of ANFH bone tissues. TNF-α expression in normal and ANFH tissues was examined by quantitative real-time polymerase chain reaction and western blot analyses. Osteoblast autophagy and apoptosis, as well as signaling pathways activation, were measured by their corresponding marker proteins. Osteoblast proliferation, autophagy, and apoptosis were evaluated using cell counting kit-8, transmission electron microscopy, and flow cytometry. The structures of bone tissues of ANFH were obviously damaged. TNF-α expression was significantly upregulated in ANFH bone tissues compared to normal tissues. Autophagy and apoptosis were remarkably promoted, and p38 mitogen-activated protein kinase (MAPK)/nuclear factor-κB (NF-κB) signaling pathways were markedly activated in ANFH. Suppression of the p38 MAPK/NF-κB pathway significantly attenuated the TNF-α-induced autophagy, however, enhanced the TNF-α-induced apoptosis in osteoblasts. Increased TNF-α in ANFH regulated osteoblast autophagy and apoptosis by p38 MAPK/NF-κB signaling pathways, blocking the pathway by inhibitors exacerbated TNF-α-induced apoptosis through impairing autophagy flux.
Assuntos
Necrose da Cabeça do Fêmur/fisiopatologia , Cabeça do Fêmur/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Adulto , Animais , Apoptose/fisiologia , Autofagia/fisiologia , Feminino , Necrose da Cabeça do Fêmur/metabolismo , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Camundongos , Pessoa de Meia-Idade , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NF-kappa B/metabolismo , Osteoblastos/metabolismo , Transdução de Sinais/genética , Fator de Necrose Tumoral alfa/fisiologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
Nucleolin is a multifunctional phosphoprotein and is involved in protecting from myocardial ischemia/reperfusion (I/R) injury. The function of nucleolin is regulated by posttranslational modifications, including phosphorylation and glycosylation. To study whether phosphorylation of nucleolin (P-nucleolin) was involved in the protection from myocardial I/R injury. We investigated the expression pattern of P-nucleolin (Thr-76 and 84) in hearts subjected to I/R injury, or rat cardiac myoblast cells (H9C2) subjected to hydrogen peroxide (H 2 O 2 ). The results showed that the expression of P-nucleolin and the ratio of P-nucleolin/nucleolin were significantly increased both in vivo and in vitro. Mutant nucleolin was obtained by site directed mutagenesis in vitro: threonine at 76 and 84 was replaced by alanine, and we found that the protective effect of nucleolin on apoptosis induced by oxidative stress was dependent on its phosphorylation at 76 and 84 in H9C2 cells. Furthermore, the cardio-protective roles of P-nucleolin (Thr-76 and 84) in H9C2 cardiomyocytes, were attributable to the upregulation of microRNA (miR)-21. Further analysis found that P-nucleolin (Thr-76 and 84) could bind to miR-21, and P-nucleolin colocalized with argonaute 2 (Ago2) in cytoplasm and could interact with Ago2 in a RNA-independent manner under cell oxidative stress. The current study revealed that P-nucleolin (Thr-76 and 84) increased in I/R injury myocardium, P-nucleolin was indispensable to upregulate miR-21 and inhibited apoptosis induced by H 2 O 2 in H9C2 cardiomyocytes. These findings provided new insight into the molecular mechanisms of nucleolin in myocardial I/R injury and oxidative stress cells.
Assuntos
Apoptose , MicroRNAs/metabolismo , Traumatismo por Reperfusão Miocárdica/metabolismo , Miócitos Cardíacos/metabolismo , Estresse Oxidativo , Fosfoproteínas/metabolismo , Proteínas de Ligação a RNA/metabolismo , Animais , Apoptose/efeitos dos fármacos , Proteínas Argonautas/metabolismo , Linhagem Celular , Modelos Animais de Doenças , Peróxido de Hidrogênio/toxicidade , Masculino , Camundongos Endogâmicos BALB C , MicroRNAs/genética , Mutação , Traumatismo por Reperfusão Miocárdica/genética , Traumatismo por Reperfusão Miocárdica/patologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/patologia , Estresse Oxidativo/efeitos dos fármacos , Fosfoproteínas/genética , Fosforilação , Proteínas de Ligação a RNA/genética , Ratos , Transdução de Sinais , Regulação para Cima , NucleolinaRESUMO
Gymnemic acid I (GA I) is a bioactive component of Gymnema sylvestre. It is an Indian traditional medicinal herb which has antidiabetic effect. However, the molecular mechanism is remaining to be elucidated. Here, we showed that high glucose promoted the rate of apoptosis, GA I decreased the apoptosis under the high glucose stress. Our further study explored that GA I increased the number of autophagosome and the ratio of light chain 3-I (LC3-I)/LC3-II in MIN-6 cells under the normal or high glucose stress by the methods of western blot analysis and immunofluorescence. It induced autophagy flux and inhibited the phosphorylation of mammalian target of rapamycin (mTOR) and ribosomal protein S6 kinase ß-1 (p70 S6K/S6K1), which is a substrate of mTOR. GA I decreased the rate of apoptosis and the activity of caspase-3 under the high glucose stress. The inhibition of apoptosis and caspase-3 activity by GA I were increased after treating with autophagy inhibitor in mouse islet ß cells MIN-6. Our data suggested that GA I-induced autophagy protected MIN-6 cells from apoptosis under high glucose stress via inhibition the phosphorylation activity of mTOR.
Assuntos
Autofagia , Citoproteção , Glucose/toxicidade , Células Secretoras de Insulina/patologia , Saponinas/farmacologia , Serina-Treonina Quinases TOR/metabolismo , Triterpenos/farmacologia , Animais , Linhagem Celular Tumoral , Citoproteção/efeitos dos fármacos , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Camundongos , Fosforilação/efeitos dos fármacos , Saponinas/química , Triterpenos/químicaRESUMO
Nucleolin is a multifunctional protein and participates in many important biological processes. Our previous study found that nucleolin protects the heart against myocardial ischemia-reperfusion injury. In this study, we aimed to investigate the role of nucleolin in doxorubicin (DOX)-induced cardiotoxicity. The expression pattern of nucleolin in hearts subjected to DOX injury was investigated, and we found that administration of DOX induced nucleolin expression significantly in vivo and in vitro. Gene transfection and RNA interference approaches were used in cardiomyocytes to investigate the function of nucleolin. Nucleolin overexpression protects cardiomyocytes against DOX-induced injury. Nucleolin-ablated cardiomyocytes become susceptible to the injury induced by DOX. The hearts of cardiac-myocyte-specific nucleolin transgenic mice are more resistant to DOX injury. Furthermore, nucleolin upregulates microRNA(miRNA)-21 expression in vivo and in vitro, and the miRNA-21 inhibitor negates the protective effect of nucleolin against injury induced by DOX. These results have demonstrated that nucleolin is involved in the regulation of DOX-induced cardiac injury and dysfunction via the regulation of miRNA-21 expression, and may be a novel therapeutic target for DOX-induced cardiotoxicity.
Assuntos
Cardiotoxicidade/genética , Cardiotoxicidade/prevenção & controle , Doxorrubicina/efeitos adversos , MicroRNAs/genética , Fosfoproteínas/metabolismo , Substâncias Protetoras/metabolismo , Proteínas de Ligação a RNA/metabolismo , Regulação para Cima , Animais , Cardiotoxicidade/patologia , Morte Celular/efeitos dos fármacos , Masculino , Camundongos Transgênicos , MicroRNAs/metabolismo , Miocárdio/metabolismo , Miocárdio/patologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Especificidade de Órgãos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , NucleolinaRESUMO
Organosulfur compounds (OSCs) are the bioactive components of garlic. Some OSCs have apoptotic or autophagy-inducing effects. Autophagy plays roles in both cytoprotection and apoptosis-related cell death, and the interaction between autophagy and apoptosis is important in the modulation of immune responses. The mechanism of an OSC-mediated effect via the interaction of autophagy and apoptosis is unknown. In this study, the effects of five OSC compounds on autophagy in the macrophage cell line RAW264.7 and primary macrophages were investigated. We found that S-allylcysteine (SAC), diallyl disulde (DADS) and diallyl tetrasulfide (DTS) treatment increased the number of autophagosomes of RAW264.7 cells, inhibited the phosphorylation of ribosomal protein S6 kinase beta-1 (p70S6K/S6K1) which is a substrate of mammalian target of rapamycin (mTOR), and significantly enhanced autophagy flux. The induction of autophagy by SAC, DADS and DTS was inhibited by stably knocking down the expression of autophagy-related gene 5 (ATG5) with short hairpin RNA (shRNA). Further experiments confirmed that SAC, DADS and DTS also induced apoptosis in RAW264.7 cells. The induction of apoptosis and Caspase 3 activity by SAC, DADS and DTS were increased by stably knocking down of ATG5 expression with shRNA in RAW264.7 cells or treating with 5 mM 3-MA in primary macrophages. Our results suggest that SAC, DADS and DTS induce both autophagy and apoptosis. The autophagy induction protects macrophages from apoptosis by inhibiting mTOR phosphorylation activity to maintain the mass of immune cells.
Assuntos
Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Compostos Orgânicos/farmacologia , Compostos de Enxofre/farmacologia , Serina-Treonina Quinases TOR/metabolismo , Compostos Alílicos/farmacologia , Animais , Autofagossomos/efeitos dos fármacos , Autofagossomos/metabolismo , Células Cultivadas , Cisteína/análogos & derivados , Cisteína/farmacologia , Dissulfetos/farmacologia , Alho/química , Macrófagos/citologia , Macrófagos/metabolismo , Camundongos , Fosforilação/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Células RAW 264.7 , Sulfetos/farmacologiaRESUMO
Our recent studies have indicated that nucleolin, as a multifunctional RNA-binding protein, exerts protective effects in the myocardial cells and endothelial cells under the condition of oxidative stress. However, the function of nucleolin and its potential mechanism in macrophage-derived foam cell formation remain largely unexplored. ApoE-/- mice were fed with a high-fat diet (HFD) for 10-24 weeks. Protein expression was measured by western blotting or immunofluorescence, and gene expression at the mRNA level was detected by qRT-PCR. The level of lipid in macrophages was examined by Oil Red O staining, high-performance liquid chromatography (HPLC) and NBD-cholesterol. Actinomycin D (Act D) was used to determine the stability of ABCA1 mRNA in macrophages. The interaction of nucleolin with ABCA1 mRNA was assessed using co-immunoprecipitation (co-IP). The aortas advanced plaques demonstrated significantly lower levels of nucleolin protein compared with early plaques in ApoE-/- mice, in which the macrophage foam cells occupied main body. Nucleolin expression at the mRNA and protein levels in RAW264.7 macrophages was significantly reduced by oxidized low-density lipoprotein (oxLDL) in a dose- and time-dependent manner. Furthermore, nucleolin overexpression markedly attenuated lipid accumulation in oxLDL-challenged macrophages through increasing cholesterol efflux. In addition, nucleolin overexpression significantly increased the expression of ATP-binding cassette transporter A1 (ABCA1) at the mRNA and protein levels without affecting expressions of scavenger receptors (SR)-A, SR-B1, CD36 and ATP-binding cassette transporter G1 (ABCG1) at the mRNA level. Moreover, nucleolin overexpression increased the stability of ABCA1 mRNA in macrophages, whereas nucleolin ablation abrogated the oxLDL-induced up-regulation of ABCA1. The up-regulation of ABCA1 by nucleolin resulted from its protein-RNA interaction. Our data suggested that nucleolin inhibited foam cell formation through enhancing stability of ABCA1 mRNA and subsequently increasing cholesterol efflux.
Assuntos
Transportador 1 de Cassete de Ligação de ATP/genética , Aterosclerose/genética , Hiperlipidemias/genética , Lipoproteínas LDL/farmacologia , Fosfoproteínas/genética , RNA Mensageiro/genética , Proteínas de Ligação a RNA/genética , Transportador 1 de Cassete de Ligação de ATP/metabolismo , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Apolipoproteínas E/deficiência , Apolipoproteínas E/genética , Aterosclerose/etiologia , Aterosclerose/metabolismo , Aterosclerose/patologia , Transporte Biológico/efeitos dos fármacos , Antígenos CD36/genética , Antígenos CD36/metabolismo , Diferenciação Celular , Linhagem Celular , Colesterol/metabolismo , Dieta Hiperlipídica , Relação Dose-Resposta a Droga , Células Espumosas/efeitos dos fármacos , Células Espumosas/metabolismo , Células Espumosas/patologia , Regulação da Expressão Gênica , Hiperlipidemias/etiologia , Hiperlipidemias/metabolismo , Hiperlipidemias/patologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Camundongos , Camundongos Knockout , Fosfoproteínas/metabolismo , Estabilidade de RNA , RNA Mensageiro/metabolismo , Proteínas de Ligação a RNA/metabolismo , Receptores Depuradores Classe A/genética , Receptores Depuradores Classe A/metabolismo , Receptores Depuradores Classe B/genética , Receptores Depuradores Classe B/metabolismo , Transdução de Sinais , NucleolinaRESUMO
Denatured dermis, a part of dermis in burned skin, has the ability to restore its normal morphology and functions after their surrounding microenvironment is improved. However, the cellular and molecular mechanisms by which the denatured dermis could improve wound healing are still unclear. This study aimed to investigate the role of nucleolin during the recovery of heat-denatured human dermal fibroblasts. Nucleolin mRNA and protein expression were significantly increased time-dependently during the recovery of heat-denatured human dermal fibroblasts (52 °C, 30 seconds). Heat-denaturation promoted a time-dependent cell proliferation, migration, chemotaxis, and scratched wound healing during the recovery of human dermal fibroblasts. These effects were prevented by knockdown of nucleolin expression with small interference RNA (siRNA), whereas overexpression of nucleolin enhanced cell proliferation, migration, and chemotaxis of human dermal fibroblasts with heat-denaturation. In addition, the expression of transforming growth factor-beta 1(TGF-ß1) was significantly increased during the recovery of heat-denatured dermis and human dermal fibroblasts. TGF-ß1 expression was up-regulated by nucleolin in human dermal fibroblasts. The results suggest that nucleolin expression is up-regulated, and play an important role in promoting cell proliferation, migration, and chemotaxis of human dermal fibroblasts during the recovery of heat-denatured dermis with a mechanism probably related to TGF-ß1.
Assuntos
Queimaduras/fisiopatologia , Quimiotaxia/efeitos dos fármacos , Derme/fisiopatologia , Fibroblastos/metabolismo , Fosfoproteínas/farmacologia , Proteínas de Ligação a RNA/farmacologia , Fator de Crescimento Transformador beta1/metabolismo , Cicatrização , Western Blotting , Movimento Celular , Proliferação de Células , Células Cultivadas , Derme/lesões , Derme/metabolismo , Fibroblastos/citologia , Regulação da Expressão Gênica , Temperatura Alta , Humanos , RNA Mensageiro , Regulação para Cima , NucleolinaRESUMO
Doxorubicin (DOX) is an anthracycline drug with a wide spectrum of antineoplastic activities. However, it causes cardiac cytotoxicity, and this limits its clinical applications. MicroRNA-21 (miR-21) plays a vital role in regulating cell proliferation and apoptosis. While miR-21 is preferentially expressed in adult cardiomyocytes and involved in cardiac development and heart disease, little is known regarding its biological functions in responding to DOX-induced cardiac cytotoxicity. In this study, the effects of DOX on mouse cardiac function and the expression of miR-21 were examined in both mouse heart tissues and rat H9C2 cardiomyocytes. The results showed that the cardiac functions were more aggravated in chronic DOX injury mice compared with acute DOX-injury mice; DOX treatment significantly increased miR-21 expression in both mouse heart tissue and H9C2 cells. Over-expression of miR-21 attenuated DOX-induced apoptosis in cardiamyocytes whereas knocking down its expression increased DOX-induced apoptosis. These gain- and loss- of function experiments showed that B cell translocation gene 2 (BTG2) was a target of miR-21. The expression of BTG2 was significantly decreased both in myocardium and H9C2 cells treated with DOX. The present study has revealed that miR-21 protects mouse myocardium and H9C2 cells against DOX-induced cardiotoxicity probably by targeting BTG2.
Assuntos
Antineoplásicos/efeitos adversos , Apoptose , Doxorrubicina/efeitos adversos , Proteínas Imediatamente Precoces/metabolismo , MicroRNAs/metabolismo , Miócitos Cardíacos/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Animais , Linhagem Celular , Células Cultivadas , Proteínas Imediatamente Precoces/genética , Camundongos , MicroRNAs/genética , Miócitos Cardíacos/efeitos dos fármacos , Ratos , Proteínas Supressoras de Tumor/genéticaRESUMO
Sepsis, a systemic inflammatory response to infection, is the major cause of death in intensive care units (ICUs). The mortality rate of sepsis remains high even though the treatment and understanding of sepsis both continue to improve. Sinomenine (SIN) is a natural alkaloid extracted from Chinese medicinal plant Sinomenium acutum, and its hydrochloride salt (Sinomenine hydrochloride, SIN-HCl) is widely used to treat rheumatoid arthritis (RA). However, its role in sepsis remains unclear. In the present study, we investigated the role of SIN-HCl in sepsis induced by cecal ligation and puncture (CLP) in BALB/c mice and the corresponding mechanism. SIN-HCl treatment improved the survival of BALB/c mice that were subjected to CLP and reduced multiple organ dysfunction and the release of systemic inflammatory mediators. Autophagy activities were examined using Western blotting. The results showed that CLP-induced autophagy was elevated, and SIN-HCl treatment further strengthened the autophagy activity. Autophagy blocker 3-methyladenine (3-MA) was used to investigate the mechanism of SIN-HCl in vitro. Autophagy activities were determined by examining the autophagosome formation, which was shown as microtubule-associated protein light chain 3 (LC3) puncta with green immunofluorescence. SIN-HCl reduced lipopolysaccharide (LPS)-induced inflammatory cytokine release and increased autophagy in peritoneal macrophages (PM). 3-MA significantly decreased autophagosome formation induced by LPS and SIN-HCl. The decrease of inflammatory cytokines caused by SIN-HCl was partially aggravated by 3-MA treatment. Taken together, our results indicated that SIN-HCl could improve survival, reduce organ damage, and attenuate the release of inflammatory cytokines induced by CLP, at least in part through regulating autophagy activities.
Assuntos
Autofagia/efeitos dos fármacos , Morfinanos/farmacologia , Sepse/tratamento farmacológico , Adenina/análogos & derivados , Adenina/farmacologia , Animais , Ceco/cirurgia , Linhagem Celular , Citocinas/metabolismo , Modelos Animais de Doenças , Rim/patologia , Lipopolissacarídeos/toxicidade , Fígado/patologia , Pulmão/patologia , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Proteínas Associadas aos Microtúbulos/metabolismo , Morfinanos/química , Morfinanos/uso terapêutico , Sepse/etiologia , Sepse/mortalidade , Taxa de SobrevidaRESUMO
OBJECTIVE: To investigate the nucleolus expression in the diabetic cardiomyopathy. METHODS: The rats were divided into a control group and a type II diabetic cardiomyopathy group (model group). In the model group, rats were fed with high-fat and high-sugar food (rats were intravenously injected with 60 mg/kg chain urea with cephalosporins in the 5th and 6th weeks in mice). The level of blood glucose was determined at the end of 8th week and the level of fasting blood glucose was examined at the end of 20th week. The ratio of the heart mass and body mass was calculated, and the pathological changes in myocardial morphology were observed. The immunohistochemical method and Western blot were used to detect the expression level of myocardial nucleolin. RESULTS: The level of fasting blood glucose was significantly increased in the diabetic model group than that in the control group (P<0.05). Rats in the model group were found hypertrophic cardic cells, with fracture, dissolusion, and disordered arrangement. Immunohistochemical staining and Western blot showed the protein levels of myocardial nucleolin in the model group were obviously higher than those in the control group (P<0.05). CONCLUSION: Nucleolin may play a role in the pathogenesis and development of the diabetic cardiomyopathy.
Assuntos
Diabetes Mellitus Experimental/metabolismo , Cardiomiopatias Diabéticas/metabolismo , Fosfoproteínas/metabolismo , Proteínas de Ligação a RNA/metabolismo , Animais , Glicemia , Miocárdio/patologia , Ratos , NucleolinaRESUMO
Background: Breast and thyroid cancer are increasingly prevalent, but it remains unclear whether the observed associations are due to heightened medical surveillance or intrinsic etiological factors. Observational studies are vulnerable to residual confounding, reverse causality, and bias, which can compromise causal inference. In this study, we employed a two-sample Mendelian randomization (MR) analysis to establish a causal link between breast cancer and heightened thyroid cancer risk. Methods: We obtained the single nucleotide polymorphisms (SNPs) associated with breast cancer from a genome-wide association study (GWAS) conducted by the Breast Cancer Association Consortium (BCAC). The FinnGen consortium's latest and largest accessible GWAS thyroid cancer data at the summary level. We performed four MR analyses, including the inverse-variance-weighted (IVW), weighted median, MR-Egger regression, and weighted mode, to evaluate the potential causal connection between genetically predicted breast cancer and higher risk for thyroid cancer. Sensitivity analysis, heterogeneity and pleiotropy tests were used to ensure the reliability of our findings. Results: Our study revealed causal relationship between genetically predicted breast cancer and thyroid cancer (IVW method, odds ratio (OR) = 1.135, 95% confidence interval (CI): 1.006 to 1.279, P = 0.038). However, there was no causal association between genetically predicted triple-negative breast cancer and thyroid cancer (OR = 0.817, 95% CI: 0.610 to 1.095, P = 0.177). There was no directional pleiotropy or horizontal pleiotropy in the present study. Conclusion: This two-sample MR study supports a causal link between ER-positive breast cancer and heightened the risk of thyroid cancer. Our analysis did not reveal a direct correlation between triple-negative breast cancer and thyroid cancer.
Assuntos
Neoplasias da Glândula Tireoide , Neoplasias de Mama Triplo Negativas , Humanos , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Reprodutibilidade dos Testes , Neoplasias da Glândula Tireoide/epidemiologia , Neoplasias da Glândula Tireoide/genéticaRESUMO
Autophagy plays an important role in endotoxemic mice, and heat shock factor 1 (HSF1) plays a crucial protective role in endotoxemic mice. However, the protective mechanisms of HSF1 are poorly understood. In this text, bioinformatics analysis, chromatin immunoprecipitation, and electrophoresis mobility shift assay were employed to investigate the underlying mechanisms. The results showed that the release of inflammatory cytokines increased and autophagy decreased significantly in Hsf1-/- endotoxemic mice compared with those in Hsf1+/+ endotoxemic mice. HSF1 could directly bind to the noncoding promoter region of the autophagy-related gene 10 (Atg10). The expression of ATG10 and the ratio of LC3-II/LC3-I were obviously decreased in LPS-treated Hsf1-/- peritoneal macrophages (PM) versus those in LPS-treated Hsf1+/+ PM. Overexpression of HSF1 increased the level of the ATG10 protein and enhanced the ratio of LC3-II/LC3-I in RAW264.7 cells. In contrast, silencing of HSF1 decreased the expression of ATG10 and markedly lowered the ratio of LC3-II/LC3-I. In a cotransfected cell experiment, the upregulation of autophagy by overexpression HSF1 was reversed by small interfering RNA (siRNA)-ATG10. Compared with the overexpression HSF1, the release of inflammatory cytokines induced by lipopolysaccharide (LPS) was decreased in pcDNA3.1-HSF1 with siRNA-ATG10 cotransfected RAW264.7 cells. On the other hand, the decrease of autophagy by siRNA-HSF1 was compensated by overexpression of ATG10. Compared with siRNA-HSF1, the release of inflammatory cytokines induced by LPS was increased in siRNA-HSF1 with pcDNA3.1-ATG10 cotransfected RAW264.7 cells. These results presented a novel mechanism that HSF1 attenuated the release of inflammatory cytokines induced by LPS through transcriptional regulation of Atg10. Targeting of HSF1-Atg10-autophagy might be an attractive strategy in endotoxemia therapeutics. IMPORTANCE HSF1 plays an important protective role in endotoxemic mice. However, the protective mechanisms of HSF1 are poorly understood. In the present study, we demonstrated that HSF1 upregulated ATG10 through specifically binding Atg10 promoter's noncoding region in LPS-treated PM and RAW264.7 cells. By depletion of HSF1, the expression of ATG10 was significantly decreased, leading to aggravate releasing of inflammatory cytokines in LPS-treated RAW264.7 cells. These findings provided a new mechanism of HSF1 in endotoxemic mice.
Assuntos
Citocinas , Lipopolissacarídeos , Camundongos , Animais , Citocinas/metabolismo , Fatores de Transcrição de Choque Térmico/genética , Fatores de Transcrição de Choque Térmico/metabolismo , Regulação da Expressão Gênica , RNA Interferente PequenoRESUMO
Background: Hypermethylated in Cancer 1 (HIC1) was originally confirmed as a tumor suppressor and has been found to be hypermethylated in human cancers. Although growing evidence has supported the critical roles of HIC1 in cancer initiation and development, its roles in tumor immune microenvironment and immunotherapy are still unclear, and no comprehensive pan-cancer analysis of HIC1 has been conducted. Methods: HIC1 expression in pan-cancer, and differential HIC1 expression between tumor and normal samples were investigated. Immunohistochemistry (IHC) was employed to validate HIC1 expression in different cancers by our clinical cohorts, including lung cancer, sarcoma (SARC), breast cancer, and kidney renal clear cell carcinoma (KIRC). The prognostic value of HIC1 was illustrated by Kaplan-Meier curves and univariate Cox analysis, followed by the genetic alteration analysis of HIC1 in pan-cancer. Gene Set Enrichment Analysis (GSEA) was conducted to illustrate the signaling pathways and biological functions of HIC1. The correlations between HIC1 and tumor mutation burden (TMB), microsatellite instability (MSI), and the immunotherapy efficacy of PD-1/PD-L1 inhibitors were analyzed by Spearman correlation analysis. Drug sensitivity analysis of HIC1 was performed by extracting data from the CellMiner™ database. Results: HIC1 expression was abnormally expressed in most cancers, and remarkable associations between HIC1 expression and prognostic outcomes of patients in pan-cancer were detected. HIC1 was significantly correlated with T cells, macrophages, and mast cell infiltration in different cancers. Moreover, GSEA revealed that HIC1 was significantly involved in immune-related biological functions and signaling pathways. There was a close relationship of HIC1 with TMB and MSI in different cancers. Furthermore, the most exciting finding was that HIC1 expression was significantly correlated with the response to PD-1/PD-L1 inhibitors in cancer treatment. We also found that HIC1 was significantly correlated with the sensitivity of several anti-cancer drugs, such as axitinib, batracylin, and nelarabine. Finally, our clinical cohorts further validated the expression pattern of HIC1 in cancers. Conclusions: Our investigation provided an integrative understanding of the clinicopathological significance and functional roles of HIC1 in pan-cancer. Our findings suggested that HIC1 can function as a potential biomarker for predicting the prognosis, immunotherapy efficacy, and drug sensitivity with immunological activity in cancers.
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Carcinoma de Células Renais , Ferroptose , Neoplasias Renais , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Receptor de Morte Celular Programada 1/genética , Prognóstico , Microambiente Tumoral/genética , Fatores de Transcrição Kruppel-LikeRESUMO
We reported a case of primary central nervous system lymphoma (PCNSL) coexistent with glial fibrillary acidic protein (GFAP) astrocytopathy, and discussed the problems needing attention in the diagnosis and differential diagnosis of GFAP astrocytopathy. Our patient was a 51-year-old female who presented with somnolence for a month, and memory declination for 10 days. Brain magnetic resonance imaging (MRI) demonstrated multiple abnormal enhancement lesions in bilateral basal ganglia and around the third ventricle, as well as transient T2-weighted hyper-intensity lesions at the splenium of the corpus callosum during the course of the disease. The cerebrospinal fluid (CSF) was positive for anti-GFAP antibodies by antigen-transfected HEK293 cell-based assay (indirect immunofluorescence assay). She was initially diagnosed with autoimmune GFAP astrocytopathy. After treatment with corticosteroids for about 2 months, she displayed poor response and even worsened clinical manifestations when the dose of prednisone reduced to 45 mg. Stereotactic brain biopsy was adopted and the diagnosis of large B-cell lymphoma, non-germinal center type was established on pathological examination. The results of brain biopsy also showed perivascular inflammation and CD8+ T cell infiltration, which also accorded with GFAP astrocytopathy. After chemotherapy with rituximab and methotrexate, the patient showed clinical and radiological improvement significantly. Our findings suggest that positivity of GFAP antibody calls for cautious interpretation. Cancer screening appropriate for age, sex, and risk factors is recommended for GFAP antibody-positive patients, especially for patients with atypical clinical and radiologic manifestations.
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Background: Evidence of osimertinib as neoadjuvant therapy for resectable non-small cell lung cancer (NSCLC) are currently lacking. This case series study aimed to assess the safety and feasibility of neoadjuvant osimertinib therapy followed by surgery for resectable NSCLC. Materials and methods: Patients with resectable NSCLC with epidermal growth factor receptor (EGFR) mutation who received osimertinib as neoadjuvant therapy followed by surgery at our center were included. Demographic features, radiologic and pathological assessment of response, surgery-related details and complications, toxicity profiles, and prognostic outcomes were extracted. Results: A total of 13 patients were included in this study. The median age at the time of surgical resection was 57 years (interquartile range: 52-64 years), and eight (61.5%) patients were female. The objective response rate (ORR) was 69.2% (9/13), and the complete resection rate was 100%. The rates of pathologic downstaging and lymph node downstaging were 100% (13/13) and 66.7% (6/9), respectively. There were no perioperative deaths and only three (23.1%) patients had postoperative complications. Seven (53.8%) and 13 (100%) patients experienced grade 1 treatment-related adverse reactions and laboratory abnormalities, respectively. No patients experienced drug withdrawal or surgical delays due to the adverse events. No patients showed grade 2 or worse toxicity profiles. One patient was lost to follow-up. The other 12 patients were alive and free of disease recurrence with a median follow-up time of 9.5 months. Conclusion: Neoadjuvant osimertinib therapy seemed to be safe and feasible for resectable EGFR-mutated NSCLC. Future large prospective studies are warranted to confirm whether osimertinib as neoadjuvant therapy outperforms standard tyrosine kinase inhibitors (TKIs) or chemotherapy for resectable EGFR-mutated NSCLC.
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BACKGROUND: Nucleolin has multiple functions within cell survival and proliferation pathways. Our previous studies have revealed that nucleolin can significantly reduce myocardial ischemia-reperfusion injury by promoting myocardial angiogenesis and reducing myocardial apoptosis. In this study, we attempted to determine the role of nucleolin in myocardial infarction (MI) injury recovery and the underlying mechanism. METHODS: Male BALB/c mice aged 6-8 weeks were used to set up MI models by ligating the left anterior descending coronary artery. Nucleolin expression in the heart was downregulated by intramyocardial injection of a lentiviral vector expressing nucleolin-specific small interfering RNA. Macrophage infiltration and polarization were measured by real-time polymerase chain reaction, flow cytometry, and immunofluorescence. Cytokines were detected by enzyme-linked immunosorbent assay. RESULTS: Nucleolin expression in myocardium after MI induction decreased a lot at early phase and elevated at late phase. Nucleolin knockdown impaired heart systolic and diastolic functions and decreased the survival rate after MI. Macrophage infiltration increased in the myocardium after MI. Most macrophages belonged to the M1 phenotype at early phase (2 days) and the M2 phenotype increased greatly at late phase after MI. Nucleolin knockdown in the myocardium led to a decrease in M2 macrophage polarization with no effect on macrophage infiltration after MI. Furthermore, Notch3 and STAT6, key regulators of M2 macrophage polarization, were upregulated by nucleolin in RAW 264.7 macrophages. CONCLUSIONS: Lack of nucleolin impaired heart function during recovery after MI by reducing M2 macrophage polarization. This finding probably points to a new therapeutic option for ischemic heart disease.
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Citocinas/metabolismo , Ativação de Macrófagos/fisiologia , Infarto do Miocárdio/fisiopatologia , Fosfoproteínas/metabolismo , Proteínas de Ligação a RNA/metabolismo , Animais , Masculino , Camundongos Endogâmicos BALB C , NucleolinaRESUMO
Shikonin (SHI) is an anti-inflammatory agent extracted from natural herbs. It is still unknown whether SHI ameliorates lipopolysaccharide (LPS)-induced cardiac dysfunction. This study aims to explore the protective effects of SHI on LPS-induced myocardial injury and its mechanism. The LPS-induced cardiac dysfunction mouse model was employed to investigate the protective effects of SHI. In the present study, we found that SHI treatment improved the survival rate and cardiac function and remarkably ameliorated the release of inflammatory cytokines and macrophage infiltration in heart tissue of LPS-treated mice. SHI also reduced lactate dehydrogenase (LDH) and cardiac troponin (cTn) release, cell inflammation, and apoptosis in LPS plus adenosine triphosphate (ATP)-treated H9c2 cells. In addition, SHI significantly upregulated silent information regulator 1 (SIRT1) expression and suppressed the upregulation of NOD-like receptor protein 3 (NLRP3), cleaved caspase-1, and caspase-1 activity in heart tissues induced by LPS. Meanwhile, we got the same results in LPS plus ATP-treated H9c2 cells in vitro. Further, SIRT1 inhibitor or siRNA partially blocked SHI-mediated upregulation of SIRT1 expression and downregulation of NLRP3, cleaved caspase-1, and caspase-1 activity in heart tissues induced by LPS. Therefore, we conclude that SHI ameliorates LPS-induced cardiac dysfunction by inhibiting SIRT1-dependent activation of NLRP3 inflammasomes and might be a promising therapeutic strategy for the treatment of LPS-induced cardiac dysfunction.
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OBJECTIVE: To explore the prognostic value of the expression of genes encoding structural maintenance of chromosomes (SMCs) in human sarcoma. RESULTS: We found that the levels of SMC1A, SMC2, SMC3, SMC4, SMC5 and SMC6 mRNA were all higher in most tumors compared to normal tissues, and especially in sarcoma. According to the Cancer Cell Line Encyclopedia (CCLE), SMC1A, SMC2, SMC3, SMC4, SMC5 and SMC6 are also highly expressed in sarcoma cell lines. Results of Gene Expression Profiling Interactive Analysis (GEPIA) indicated that high expression of SMC1A was significantly related to poor overall survival (OS) (p<0.05) and disease-free survival (DFS) in sarcoma (p<0.05). Additionally, strong expression of SMC2 was significantly related to poor OS in sarcoma (p<0.05). In contrast, SMC3, SMC4, SMC5, and SMC6 expression had no significant impact on OS or DFS in sarcoma. CONCLUSIONS: Expression of SMC family members is significantly different in sarcoma relative to normal tissues, and SMC1A and SMC2 may be useful as prognostic biomarkers. METHODS: We performed a detailed comparison of cancer and normal tissues regarding the expression levels of mRNA for SMC family members in various cancers including sarcoma through ONCOMINE and GEPIA (Gene Expression Profile Interactive Analysis) databases.