RESUMO
Immunotherapy of PD-L1/PD-1 blockage elicited impressive clinical benefits for cancer treatment. However, the relative low response and therapy resistance highlight the need to better understand the molecular regulation of PD-L1 in tumors. Here, we report that PD-L1 is a target of UFMylation. UFMylation of PD-L1 destabilizes PD-L1 by synergizing its ubiquitination. Inhibition of PD-L1 UFMylation via silencing of UFL1 or Ubiquitin-fold modifier 1 (UFM1), or the defective UFMylation of PD-L1, stabilizes the PD-L1 in multiple human and murine cancer cells, and undermines antitumor immunity in vitro and mice, respectively. Clinically, UFL1 expression was decreased in multiple cancers and lower expression of UFL1 negatively correlated with the response of anti-PD1 therapy in melanoma patients. Moreover, we identified a covalent inhibitor of UFSP2 that promoted the UFMylation activity and contributed to the combination therapy with PD-1 blockade. Our findings identified a previously unrecognized regulator of PD-L1 and highlighted UFMylation as a potential therapeutic target.
Assuntos
Antígeno B7-H1 , Melanoma , Humanos , Animais , Camundongos , Evasão Tumoral , Receptor de Morte Celular Programada 1/genética , Ubiquitinação , Cisteína EndopeptidasesRESUMO
APE1 is an essential gene involved in DNA damage repair, the redox regulation of transcriptional factors (TFs) and RNA processing. APE1 overexpression is common in cancers and correlates with poor patient survival. Stress granules (SGs) are phase-separated cytoplasmic assemblies that cells form in response to environmental stresses. Precise regulation of SGs is pivotal to cell survival, whereas their dysregulation is increasingly linked to diseases. Whether APE1 engages in modulating SG dynamics is worthy of investigation. In this study, we demonstrate that APE1 colocalizes with SGs and promotes their formation. Through phosphoproteome profiling, we discover that APE1 significantly alters the phosphorylation landscape of ovarian cancer cells, particularly the phosphoprofile of SG proteins. Notably, APE1 promotes the phosphorylation of Y-Box binding protein 1 (YBX1) at S174 and S176, leading to enhanced SG formation and cell survival. Moreover, expression of the phosphomutant YBX1 S174/176E mimicking hyperphosphorylation in APE1-knockdown cells recovered the impaired SG formation. These findings shed light on the functional importance of APE1 in SG regulation and highlight the importance of YBX1 phosphorylation in SG dynamics.
Assuntos
DNA Liase (Sítios Apurínicos ou Apirimidínicos) , Neoplasias Ovarianas , Grânulos de Estresse , Proteína 1 de Ligação a Y-Box , Feminino , Humanos , Endodesoxirribonucleases , Neoplasias Ovarianas/genética , Fosforilação , Grânulos de Estresse/metabolismo , Proteína 1 de Ligação a Y-Box/genética , DNA Liase (Sítios Apurínicos ou Apirimidínicos)/metabolismoRESUMO
BACKGROUND: Hepatic ischemia-reperfusion injury (IRI) in donation after cardiac death (DCD) donors is a major determinant of transplantation success. Endoplasmic reticulum (ER) stress plays a key role in hepatic IRI, with potential involvement of the Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) pathway and the antiapoptotic protein hematopoietic-lineage substrate-1-associated protein X-1 (HAX1). In this study, we aimed to investigate the effects of hypothermic oxygenated perfusion (HOPE), an organ preservation modality, on ER stress and apoptosis during hepatic IRI in a DCD rat model. METHODS: To investigate whether HOPE could improve IRI in DCD livers, levels of different related proteins were examined by western blotting and quantitative real-time polymerase chain reaction. Further expression analyses, immunohistochemical analyses, immunofluorescence staining, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining, and transmission electron microscopy were conducted to analyze the effects of HOPE on ER stress and apoptosis. To clarify the role of the JAK2/STAT3 pathway and HAX1 in this process, AG490 inhibitor, JAX1 plasmid transfection, co-immunoprecipitation (CO-IP), and flow cytometry analyses were conducted. RESULTS: HOPE reduced liver injury and inflammation while alleviating ER stress and apoptosis in the DCD rat model. Mechanistically, HOPE inhibited unfolded protein responses by activating the JAK2/STAT3 pathway, thus reducing ER stress and apoptosis. Moreover, the activated JAK2/STAT3 pathway upregulated HAX1, promoting the interaction between HAX1 and SERCA2b to maintain ER calcium homeostasis. Upregulated HAX1 also modulated ER stress and apoptosis by inhibiting the inositol-requiring enzyme 1 (IRE1) pathway. CONCLUSIONS: JAK2/STAT3-mediated upregulation of HAX1 during HOPE alleviates hepatic ER stress and apoptosis, indicating the JAK2/STAT3/HAX1 pathway as a potential target for IRI management during DCD liver transplantation.
Assuntos
Janus Quinase 2 , Fator de Transcrição STAT3 , Animais , Ratos , Fígado , Estresse do Retículo Endoplasmático , PerfusãoRESUMO
Metformin is widely used to treat hyperglycemia. However, metformin treatment may induce intrahepatic cholestasis and liver injury in a few patients with type II diabetes through an unknown mechanism. Here we show that metformin decreases SIRT1 protein levels in primary hepatocytes and liver. Both metformin-treated wild-type C57 mice and hepatic SIRT1-mutant mice had increased hepatic and serum bile acid levels. However, metformin failed to change systemic bile acid levels in hepatic SIRT1-mutant mice. Molecular mechanism study indicates that SIRT1 directly interacts with and deacetylates Foxa2 to inhibit its transcriptional activity on expression of genes involved in bile acids synthesis and transport. Hepatic SIRT1 mutation elevates Foxa2 acetylation levels, which promotes Foxa2 binding to and activating genes involved in bile acids metabolism, impairing hepatic and systemic bile acid homeostasis. Our data clearly suggest that hepatic SIRT1 mediates metformin effects on systemic bile acid metabolism and modulation of SIRT1 activity in liver may be an attractive approach for treatment of bile acid-related diseases such as cholestasis.
Assuntos
Ácidos e Sais Biliares/metabolismo , Colestase Intra-Hepática/genética , Fator 3-beta Nuclear de Hepatócito/genética , Hipoglicemiantes/efeitos adversos , Metformina/efeitos adversos , Sirtuína 1/genética , Acetilação , Animais , Colestase Intra-Hepática/induzido quimicamente , Colestase Intra-Hepática/metabolismo , Colestase Intra-Hepática/patologia , Regulação da Expressão Gênica , Células Hep G2 , Fator 3-beta Nuclear de Hepatócito/metabolismo , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Hepatócitos/patologia , Homeostase/efeitos dos fármacos , Homeostase/genética , Humanos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos , Camundongos Transgênicos , Mutação , Cultura Primária de Células , Transdução de Sinais , Sirtuína 1/antagonistas & inibidores , Sirtuína 1/metabolismoRESUMO
AIM/HYPOTHESIS: Hepatic forkhead box q1 (FOXQ1) expression levels are regulated by nutritional and pathophysiological status. In this study we investigated the role of FOXQ1 in the regulation of hepatic gluconeogenesis. METHODS: We used multiple mouse and cell models to study the role of FOXQ1 in regulating expression of gluconeogenic genes, and cellular and hepatic glucose production. RESULTS: Expression of hepatic FOXQ1 was regulated by fasting in normal mice and was dysregulated in diabetic mice. Overexpression of FOXQ1 in primary hepatocytes inhibited expression of gluconeogenic genes and decreased cellular glucose output. Hepatic FOXQ1 rescue in db/db and high-fat diet-induced obese mice markedly decreased blood glucose level and improved glucose intolerance. In contrast, wild-type C57 mice with hepatic FOXQ1 deficiency displayed increased blood glucose levels and impaired glucose tolerance. Interestingly, studies into molecular mechanisms indicated that FOXQ1 interacts with FOXO1, thereby blocking FOXO1 activity on hepatic gluconeogenesis, preventing it from directly binding to insulin response elements mapped in the promoter region of gluconeogenic genes. CONCLUSIONS/INTERPRETATION: FOXQ1 is a novel factor involved in regulating hepatic gluconeogenesis, and the decreased FOXQ1 expression in liver may contribute to the development of type 2 diabetes.
Assuntos
Diabetes Mellitus Experimental/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Animais , Glicemia/metabolismo , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/patologia , Dieta Hiperlipídica/efeitos adversos , Jejum/sangue , Fatores de Transcrição Forkhead/genética , Gluconeogênese/genética , Gluconeogênese/fisiologia , Intolerância à Glucose , Hepatócitos/metabolismo , Insulina/metabolismo , Fígado , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos ObesosRESUMO
Dysregulation of hepatic gluconeogenesis contributes to the pathogenesis of diabetes, yet the detailed molecular mechanisms remain to be fully elucidated. Here we show that FOXP1, a transcriptional repressor, plays a key role in the regulation of systemic glucose homeostasis. Hepatic expression levels of FOXP1 are decreased in diabetic mice. Modest hepatic overexpression of FOXP1 in mice inhibited the expression of gluconeogenic genes, such as peroxisome proliferators-activated receptor γ coactivator-1α (PGC-1α), phosphoenolpyruvate carboxykinase (PEPCK), and glucose-6-phosphatase (G6PC), leading to a decrease in hepatic glucose production and fasting blood glucose levels in normal mice and different mouse models of diabetes, including db/db diabetic and high-fat diet-induced obese mice. FOXP1 physically interacted with FOXO1 in vivo and competed with FOXO1 for binding to the insulin response element in the promoter region of gluconeogenic genes, thereby interfering expression of these genes. These results identify a previously unrecognized role for FOXP1 in the transcriptional control of hepatic glucose homeostasis.
Assuntos
Fatores de Transcrição Forkhead/metabolismo , Gluconeogênese , Glucose/metabolismo , Homeostase , Fígado/metabolismo , Proteínas Repressoras/metabolismo , Animais , Diabetes Mellitus/genética , Diabetes Mellitus/metabolismo , Gorduras na Dieta/efeitos adversos , Gorduras na Dieta/farmacologia , Fatores de Transcrição Forkhead/genética , Glucose/genética , Masculino , Camundongos , Camundongos Obesos , Obesidade/induzido quimicamente , Obesidade/genética , Obesidade/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Fosfoenolpiruvato Carboxiquinase (GTP) , Proteínas Repressoras/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
We investigated mechanisms of pancreatic cancer metastasis and defined the biological role of miR-29c in pancreatic cancer metastasis. After two rounds of cell selection in vivo, pancreatic cancer cells with various metastatic potentials derived from spontaneous liver metastases were used as a model of pancreatic cancer to determine the role of miR-29c in pancreatic cancer metastasis. Pancreatic cancer samples were analyzed for miRNA-29c expression, and these levels were associated with survival between groups. miR-29c suppresses cell migration and invasion by targeting the MMP2 3'UTR. Overexpression of miR-29c suppresses pancreatic cancer liver metastasis in a nude mouse orthotopic implantation model. miR-29c expression was associated with metastasis and pancreatic cancer patient survival. miR-29c plays an important role in mediating pancreatic cancer metastasis to the liver by targeting MMP2. Therefore, miR-29c may serve as a novel marker of pancreatic cancer metastasis and possibly as a therapeutic target to treat pancreatic cancer liver metastasis.
Assuntos
Neoplasias Hepáticas/secundário , Metaloproteinase 2 da Matriz/genética , MicroRNAs/genética , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Animais , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Fígado/patologia , Masculino , Metaloproteinase 2 da Matriz/biossíntese , Camundongos , Camundongos Nus , MicroRNAs/biossíntese , Pessoa de Meia-Idade , Invasividade Neoplásica/genética , Pâncreas/patologiaRESUMO
In the present world chitin is used enormously in various fields, such as biopharmaceuticals, medical and clinical bioproducts, food packaging, etc. However, its development has been curbed by the impaired performance and cumbersome dissolution process when chitin materials are dissolved and regenerated by physical or chemical methods. To further obtain the regenerated chitin fiber material with improved performance, silk fibroin was introduced into the chitin matrix material, and chitin/silk fibroin biocompatible composite fibers were obtained by formic acid/calcium chloride/ethanol ternary system and top-down wet spinning technology. The produced composite fibers outperformed previously reported chitin-silk composites in terms of the tensile strength (160 MPa) and failure strain (25%). The fibers also performed good cell compatibility and strong cellular affinity for non-toxicity. The cell viabilities of the fibers were about 20% greater than those of silk fiber after three days of co-culture with NIH-3T3. Furthermore, no hemolysis occurs in the presence of chitin/silk fibers, demonstrating their superior hemocompatibility. The fibers had a hemolysis index as low as 1%, which is far lower than the acceptable level of 5%. The material offers prospective opportunities for biomaterial applications in anticoagulation, absorbable surgical sutures, etc.
Assuntos
Fibroínas , Fibroínas/química , Quitina , Estudos Prospectivos , Seda/química , Materiais Biocompatíveis/farmacologiaRESUMO
Liver and kidney failure can lead to extensive accumulation of toxic metabolites in the blood and tissues, such as bilirubin, blood ammonia, endotoxins, cytokines, creatinine, uric acid, and urea, which aggravate the progression of the disease. Hemoperfusion can effectively adsorb and remove toxins from the blood and treat liver and kidney failure. However, the adsorption efficiency and safety of traditional hemoperfusion adsorbents are not ideal. Thus, it is urgent to develop adsorbents with good blood compatibility, as well as high adsorption and strong selective capacities, to fulfill the clinical needs. In recent years, new hemoperfusion adsorbents with improved adsorption performance and good blood compatibility have been developed. This review classifies and summarizes the recent research progress in hemoperfusion adsorbents for common blood toxins (bilirubin, blood ammonia, endotoxins, cytokines, creatinine, uric acid, and urea) produced by liver and kidney failure. The composition and structure of various toxin adsorbents, toxin adsorption performance, biocompatibility, blood safety, and the adsorption mechanisms of toxins are discussed. Based on a summary of recent studies, feasible strategies have been explored for designing and preparing hemoperfusion adsorbents to fulfill future development requirements. The trends and clinical application prospects of various toxin adsorbents are also discussed.
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Postoperative peritoneal adhesions are common complications caused by abdominal and pelvic surgery, which seriously impact the quality of life of patients and impose additional financial burdens. Using of biomedical materials as physical barriers to completely isolate the traumatic organ and injured tissue is an optimal strategy for preventing postoperative adhesions. However, the limited efficacy and difficulties in the complete degradation or integration of biomedical materials with living tissues restrict the application of these materials. In this study, novel chitin-based crosslinked hydrogels with appropriate mechanical properties and flexibilities were developed using a facile and green strategy. The developed hydrogels simultaneously exhibited excellent biocompatibilities and resistance to nonspecific protein adsorption and NIH/3T3 fibroblast adhesion. Furthermore, these hydrogels were biodegradable and could be completely integrated into the native extracellular matrix. The chitin-based crosslinked hydrogels also effectively inhibited postoperative peritoneal adhesions in rat models of adhesion and recurrence. Therefore, these novel chitin-based crosslinked hydrogels are excellent candidate physical barriers for the efficient prevention of postoperative peritoneal adhesions and provide a new anti-adhesion strategy for biomedical applications.
Assuntos
Quitina , Hidrogéis , Ratos , Animais , Quitina/farmacologia , Quitina/uso terapêutico , Hidrogéis/farmacologia , Qualidade de Vida , Peritônio/patologia , Materiais Biocompatíveis/farmacologia , Materiais Biocompatíveis/uso terapêutico , Aderências Teciduais/prevenção & controleRESUMO
Obstructive jaundice is a common clinical symptom generally caused by bile duct stones, inflammatory hyperplasia, and tumors. It is characterized by hyperbilirubinemia and may trigger a variety of complications such as hypotension, kidney injury, endotoxemia, multiple organ dysfunction syndrome, and even death (Pavlidis and Pavlidis, 2018; Liu et al., 2021). Relieving bile duct obstruction and providing adequate drainage have been considered as the most effective therapies for obstructive jaundice. However, it has not yet been established whether it is beneficial to treat affected patients by pre-operative biliary drainage (Blacker et al., 2021). Moreover, the pathophysiological changes or mechanisms associated with the reversal of organ function following the relief of bile-duct obstruction are unclear (Huang et al., 2004). Therefore, it is necessary to establish an experimental model of reversible obstructive jaundice to simulate biliary drainage in clinical practice.
Assuntos
Icterícia Obstrutiva , Animais , Ratos , Icterícia Obstrutiva/etiologia , Icterícia Obstrutiva/cirurgia , Modelos Animais de DoençasRESUMO
Natural polymer hydrogels are widely used in various aspects of biomedical engineering, such as wound repair, owing to their abundance and biosafety. However, the low strength and the lack of function restricted their development and application scope. Herein, we fabricated novel multifunctional chitin/PEGDE-tannic acid (CPT) hydrogels through chemical- and physical-crosslinking strategies, using chitin as the base material, polyethylene glycol diglycidyl ether (PEGDE) and tannic acid (TA) as crosslinking agents, and 90 % ethanol as the regenerative bath. CPT hydrogels maintained a stable three-dimensional porous structure with suitable water contents and excellent biocompatibility. The mechanical properties of hydrogels were greatly improved (tensile stress up to 5.43 ± 1.14 MPa). Moreover, CPT hydrogels had good antibacterial, antioxidant, and hemostatic activities and could substantially promote wound healing in a rat model of full-thickness skin defect by regulating inflammatory responses and promoting collagen deposition and blood vessel formation. Therefore, this work provides a useful strategy to fabricate novel multifunctional CPT hydrogels with excellent mechanical, antibacterial, antioxidant, hemostatic, and biocompatible properties. CPT hydrogels could be promising candidates for wound healing.
Assuntos
Hemostáticos , Ratos , Animais , Hemostáticos/farmacologia , Antioxidantes/farmacologia , Antioxidantes/química , Hidrogéis/farmacologia , Hidrogéis/química , Cicatrização/fisiologia , Antibacterianos/farmacologia , Antibacterianos/química , Quitina/farmacologiaRESUMO
Infections caused by bacteria have long constituted a major threat to human health and the economy. Therefore, there is an urgent need to design broad-spectrum antibacterial materials possessing good biocompatibility to treat such infections. Herein, inspired by the good biocompatibility of chitin and antibacterial properties of imidazolium salts, a polysaccharide-based material, imidazolium salt chitin (IMSC), was homogeneously prepared using a facile method with epichlorohydrin as a chemical crosslinker to combine chitin with imidazole to enhance Staphylococcus aureus (S. aureus)-infected wound healing. The characteristics, antimicrobial properties, and biosafety of IMSC were evaluated. The results demonstrated successful grafting of imidazole onto chitin. Furthermore, IMSC exhibited good water solubility, broad-spectrum antimicrobial activity, hemocompatibility, and biocompatibility. Moreover, IMSC enabled complete healing of S. aureus-infected wound in Sprague-Dawley rats within 15 days of application, thus demonstrating that IMSC could reduce wound inflammation and remarkably accelerate wound healing owing to its efficient antibacterial activity and ability to promote collagen deposition in and around the wound area. Therefore, this study provides a promising and potential therapeutic strategy for infected wound healing by synthesizing a water-soluble and broad-spectrum antimicrobial material exhibiting good biocompatibility.
Assuntos
Anti-Infecciosos , Infecção dos Ferimentos , Ratos , Animais , Humanos , Staphylococcus aureus , Ratos Sprague-Dawley , Escherichia coli , Cicatrização , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Antibacterianos/química , Quitina/farmacologia , Quitina/uso terapêutico , Quitina/química , Cloreto de Sódio , Água/química , Infecção dos Ferimentos/tratamento farmacológicoRESUMO
Objective: Ischemia-reperfusion injury (IRI) is an important cause of delayed functional recovery after transplantation. This study is aimed at investigating the molecular mechanism of ALDH2 in a kidney ischemia-reperfusion model based on RNA-seq. Methods: We performed kidney ischemia-reperfusion in ALDH2-/- and WT mice and evaluated kidney function and morphology using SCr, HE staining, TUNEL staining, and TEM. We used RNA-seq to compare mRNA expression in ALDH2-/- and WT mice after IR, and then, we verified the related molecular pathways by PCR and western blotting. In addition, activators and inhibitors of ALDH2 were used to alter the activity of ALDH2. Finally, we established a model of hypoxia and reoxygenation in HK-2 cells and clarified the role of ALDH2 in IR by interfering with ALDH2 and using an NF-κB inhibitor. Results: After kidney ischemia-reperfusion, the SCr value increased significantly, kidney tubular epithelial cells were damaged, and the apoptosis rate increased. In the microstructure, mitochondria were swollen and deformed, and ALDH2 deficiency aggravated these changes. The NF-κB pathway and IL-17 pathway were significantly enriched in ALDH2-/- mice compared with WT mice according to KEGG enrichment analysis of the RNA-seq data. The PCR results showed that the mRNA expression levels of IκBα and IL-17B, C, D, E, and F were significantly higher than those in the WT-IR group. Western blot verification results showed that ALHD2 knockdown resulted in increased phosphorylation of IκBα, increased phosphorylation of NF-κB, and increased expression of IL-17C. When we used ALDH2 agonists, the number of lesions and the expression levels of the corresponding proteins were reduced. Knockdown of ALDH2 in HK-2 cells resulted in a higher proportion of apoptotic cells after hypoxia and reoxygenation, but inhibiting the phosphorylation of NF-κB prevented the increase in apoptosis and reduced the protein expression level of IL-17C. Conclusion: ALDH2 deficiency can lead to the aggravation of kidney ischemia-reperfusion injury. RNA-seq analysis and validation by PCR and western blotting revealed that this effect may be due to the promotion of IκBα/NF-κB p65 phosphorylation during ischemia-reperfusion caused by ALDH2 deficiency, which then leads to an increase in inflammatory factors, including IL-17C. Thus, cell death is promoted, and kidney IRI is eventually aggravated. We link ALDH2 deficiency with inflammation, revealing a new idea for ALDH2-related research.
Assuntos
Aldeído-Desidrogenase Mitocondrial , Rim , Traumatismo por Reperfusão , Animais , Camundongos , Aldeído-Desidrogenase Mitocondrial/genética , Hipóxia , Interleucina-17 , NF-kappa B , Inibidor de NF-kappaB alfa , RNA MensageiroRESUMO
Combining immune checkpoint therapy (ICT) and targeted therapy holds great promises for broad and long-lasting anti-cancer therapies. However, combining ICT with anti-PI3K inhibitors have been challenging because the multifaceted effects of PI3K on both cancer cells and immune cells within the tumor microenvironment. Here we find that intermittent but not daily dosing of a PI3Kα/ß/δ inhibitor, BAY1082439, on Pten-null prostate cancer models could overcome ICT resistance and unleash CD8+ T cell-dependent anti-tumor immunity in vivo. Mechanistically, BAY1082439 converts cancer cell-intrinsic immune-suppression to immune-stimulation by promoting IFNα/IFNγ pathway activation, ß2-microglubin expression and CXCL10/CCL5 secretion. With its preferential regulatory T cell inhibition activity, BAY1082439 promotes clonal expansion of tumor-associated CD8+ T cells, most likely via tertiary lymphoid structures. Once primed, tumors remain T cell-inflamed, become responsive to anti-PD-1 therapy and have durable therapeutic effect. Our data suggest that intermittent PI3K inhibition can alleviate Pten-null cancer cell-intrinsic immunosuppressive activity and turn "cold" tumors into T cell-inflamed ones, paving the way for successful ICT.
Assuntos
Anticorpos Neutralizantes/farmacologia , Antineoplásicos Imunológicos/farmacologia , Classe I de Fosfatidilinositol 3-Quinases/genética , Inibidores de Checkpoint Imunológico/farmacologia , PTEN Fosfo-Hidrolase/genética , Receptor de Morte Celular Programada 1/genética , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Animais , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Quimiocina CCL5/genética , Quimiocina CCL5/imunologia , Quimiocina CXCL10/genética , Quimiocina CXCL10/imunologia , Classe I de Fosfatidilinositol 3-Quinases/imunologia , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Resistencia a Medicamentos Antineoplásicos/imunologia , Regulação Neoplásica da Expressão Gênica , Humanos , Interferon-alfa/genética , Interferon-alfa/imunologia , Interferon gama/genética , Interferon gama/imunologia , Masculino , Camundongos , Camundongos Knockout , PTEN Fosfo-Hidrolase/deficiência , PTEN Fosfo-Hidrolase/imunologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Próstata/efeitos dos fármacos , Próstata/metabolismo , Próstata/patologia , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/metabolismo , Neoplasias de Próstata Resistentes à Castração/patologia , Transdução de Sinais , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia , Microglobulina beta-2/genética , Microglobulina beta-2/imunologiaRESUMO
Extra bilirubin in the blood can provoke serious illness in patients with severe liver disease. Hemoperfusion is an effective method to remove the extra bilirubin, but its application is limited by the low adsorption efficiency and poor biocompatibility of available adsorbent materials. In this study, chitin/ordered mesoporous carbon CMK3 (Ch/CMK3) microspheres are successfully prepared. Results of characterization experiments indicated that these composite microspheres possess a multilayered porous nanofibrous structure with an extremely large specific surface area (300.19 m2 g-1 ) and large pore size. Notably, the Ch/CMK3 microspheres demonstrated a high bilirubin adsorption capacity (228.19 mg g-1 ) in phosphate buffer solution (PBS), and an outstanding bilirubin removal ratio (76.78% ± 4.40%) in the plasma of rabbits with hyperbilirubinemia without affecting the protein components. More importantly, the Ch/CMK3 microspheres showed no effect on other blood components, no cytotoxicity, and no systemic toxicity to mice. Cell co-culture experiments revealed that the microspheres can provide a 3-dimensional (3D) space to promote cell adhesion, proliferation, and nutrient exchange. These Ch/CMK3 microspheres featuring a strong ability for bilirubin adsorption and good biocompatibility can be a promising candidate in biomedical applications such as hemoperfusion, cell microcarrier, and 3D tissue engineering.
Assuntos
Bilirrubina , Quitina , Adsorção , Animais , Carbono/farmacologia , Quitina/química , Quitina/farmacologia , Humanos , Camundongos , Microesferas , Porosidade , CoelhosRESUMO
The rectangular magnetoelectric (ME) composites of Metglas/PZT and Terfenol-D/PZT are prepared, and the effects of a magnetostrictive layer's material characteristics on the magnetoimpedance of ME composite are discussed and experimentally investigated. The theoretical analyses show that the impedance is not only dependent on Young's modulus and the magnetostrictive strain of magnetostrictive material but is also influenced by its relative permeability. Compared with Terfenol-D, Metglas possesses significantly higher magnetic permeability and larger magnetostrictive strain at quite low Hdc due to the small saturation field, resulting in the larger magnetoimpedance ratio. The experimental results demonstrate that the maximum magnetoimpedance ratios (i.e., ΔZ/Z) of Metglas/PZT composite are about 605.24% and 239.98% at the antiresonance and resonance, respectively. Specifically, the maximum ΔZ/Z of Metglas/PZT is 8.6 times as high as that of Terfenol-D/PZT at the antiresonance. Such results provide the fundamental guidance in the design and fabrication of novel multifunction devices based on the magnetoimpedance effect of ME composites.
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OBJECTIVES: This study aimed to investigate the effect and mechanism of hypoxia on pancreatic cancer (PC) cell dedifferentiation and tumorigenic potential. METHODS: Inhibition of hypoxia-inducible factor 1α (HIF-1α) and overexpression of Notch1 in PC HS766T cell lines were by lentiviral transfection. The expression of stem cell-specific markers C-X-C motif chemokine receptor 4, CD44, and Nestin was detected by immunofluorescence and Western blot assays. Cell invasion capacity was examined by Transwell assay. Tumorigenic potential was measured in an in situ tumor transplantation experiment. The expression of HIF-1α, Notch signals, and apoptosis signals was examined by Western blot assay. RESULTS: Hypoxia promoted PC cells to dedifferentiate into stem-like cells by upregulating HIF-1α and activating Notch signals. Silencing of HIF-1α significantly repressed cell dedifferentiation and invasion, whereas overexpression of Notch1 reversed the effect of HIF-1α repression. In situ tumor transplantation experiment further confirmed that hypoxia promoted tumorigenic ability through upregulating HIF-1α. Moreover, the expression of HIF-1α and Notch1 was significantly increased in human PC tissues, and high expression of HIF-1α was correlated with poor survival rate. CONCLUSIONS: Hypoxia promoted PC cell dedifferentiation to stem-like cell phenotypes with high tumorigenic potential by activating HIF-1α/Notch signaling pathway, indicating a novel role in regulating PC progression.
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Desdiferenciação Celular , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Células-Tronco Neoplásicas/metabolismo , Neoplasias Pancreáticas/metabolismo , Receptor Notch1/metabolismo , Hipóxia Tumoral , Idoso , Animais , Linhagem Celular Tumoral , Movimento Celular , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Masculino , Camundongos Nus , Invasividade Neoplásica , Células-Tronco Neoplásicas/patologia , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Fenótipo , Receptor Notch1/genética , Transdução de SinaisRESUMO
Metastasis is the main culprit of the great majority of cancerrelated deaths. However, the complicated process of the invasion-metastasis cascade remains the least understood aspect of cancer biology. Telomerase plays a pivotal role in bypassing cellular senescence and sustaining the cancer progression by maintaining telomere homeostasis and genomic integrity. Telomerase reverse transcriptase (TERT) exerts a series of fundamental functions that are independent of its enzymatic cellular activity, including proliferation, inflammation, epithelia-mesenchymal transition (EMT), angiogenesis, DNA repair, and gene expression. Accumulating evidence indicates that TERT may facilitate most steps of the invasion-metastasis cascade. In this review, we summarize important advances that have revealed some of the mechanisms by which TERT facilitates tumor metastasis, providing an update on the non-canonical functions of telomerase beyond telomere maintaining. [BMB Reports 2020; 53(9): 458-465].
Assuntos
Neoplasias/genética , Animais , Humanos , TelomeraseRESUMO
Brain metastasis, the most lethal form of melanoma and carcinoma, is the consequence of favorable interactions between the invading cancer cells and the brain cells. Peroxisome proliferator-activated receptor γ (PPARγ) has ambiguous functions in cancer development, and its relevance in advanced brain metastasis remains unclear. Here, we demonstrate that astrocytes, the unique brain glial cells, activate PPARγ in brain metastatic cancer cells. PPARγ activation enhances cell proliferation and metastatic outgrowth in the brain. Mechanistically, astrocytes have a high content of polyunsaturated fatty acids that act as "donors" of PPARγ activators to the invading cancer cells. In clinical samples, PPARγ signaling is significantly higher in brain metastatic lesions. Notably, systemic administration of PPARγ antagonists significantly reduces brain metastatic burden in vivo. Our study clarifies a prometastatic role for PPARγ signaling in cancer metastasis in the lipid-rich brain microenvironment and argues for the use of PPARγ blockade to treat brain metastasis. SIGNIFICANCE: Brain-tropic cancer cells take advantage of the lipid-rich brain microenvironment to facilitate their proliferation by activating PPARγ signaling. This protumor effect of PPARγ in advanced brain metastases is in contrast to its antitumor function in carcinogenesis and early metastatic steps, indicating that PPARγ has diverse functions at different stages of cancer development.This article is highlighted in the In This Issue feature, p. 1631.