RESUMO
BACKGROUND: Tumor-associated macrophages (TAM), a major component of the tumor microenvironment, play key roles in tumor formation and progression; however, mechanisms underlying TAM-induced tumor progression are complex and not well known. We previously reported that tumor cell-derived angiopoietin-like protein 2 (ANGPTL2) functions as a tumor promoter in some cancer contexts. METHODS: We examined ANGPTL2 expression in paraffin-embedded tumor samples from resected specimens of 221 patients with esophageal cancer. Patients were subdivided into four groups based on immunohistochemistry scores described above: ANGPTL2-low/TAM-low, ANGPTL2-low/TAM-high, ANGPTL2-high/TAM-low, and ANGPTL2-high/TAM-high groups. Gene expression datasets of esophageal cancer cell lines were obtained from the cancer cell line encyclopedia public database. RESULTS: In this study, we demonstrate that TAM infiltration is associated with poor prognosis in patients with esophageal cancer whose tumor cells show relatively higher ANGPTL2 expression levels; however, TAM infiltration did not affect prognosis in patients with ANGPTL2-low-expressing esophageal cancer, suggesting that ANGPTL2 expression in esophageal cancer cells is required for TAM-induced tumor progression. Our analysis of public datasets indicates a potential positive correlation of ANGPTL2 expression levels with that of transforming growth factor (TGF)-ß, a TAM-activating factor, in esophageal cancer cell lines. CONCLUSION: We conclude that ANGPTL2 signaling in tumor cells supports TAM-induced tumor progression and contributes to poor prognosis in patients with esophageal cancer. These findings overall provide novel insight into pro-tumor ANGPTL2 functions and illustrate the essential role of cancer cell/TAM crosstalk in cancer progression.
RESUMO
Use of immune checkpoint inhibitors (ICIs) as cancer immunotherapy has advanced rapidly in the clinic. We recently reported that tumor stroma-derived angiopoietin-like protein 2 (ANGPTL2) has tumor suppressive activity by enhancing dendritic cell-mediated CD8+ T cell anti-tumor immune responses. However, a direct impact of ANGPTL2 on ICI anti-tumor effect remains unclear. Here, we use a murine syngeneic model to show that host ANGPTL2 facilitates CD8+ T cell cross-priming and contributes to anti-tumor responses to ICIs in this context. Importantly, our analysis of public datasets indicated that ANGPTL2 expression is associated with positive responses to ICI therapy by human melanoma patients. We conclude that ANGPTL2-mediated stromal cell crosstalk facilitates anti-tumor immunity and ICI responsiveness. These findings overall provide novel insight into ANGPTL2 anti-tumor function and regulation of ICI-induced anti-tumor immunity.
Assuntos
Proteína 2 Semelhante a Angiopoietina , Inibidores de Checkpoint Imunológico , Animais , Camundongos , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Humanos , Proteínas Semelhantes a Angiopoietina/metabolismo , Proteínas Semelhantes a Angiopoietina/genética , Células Estromais/metabolismo , Células Estromais/imunologia , Camundongos Endogâmicos C57BL , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Microambiente Tumoral/imunologia , Linhagem Celular Tumoral , Feminino , Melanoma/tratamento farmacológico , Melanoma/imunologia , Melanoma/metabolismo , Melanoma/genéticaRESUMO
The Dja2 knockout (Dja2-/- ) mice had respiratory distress, and >60% died within 2 days after birth. The surviving adult Dja2-/- mice were infertile and the lungs of Dja2-/- mice showed several abnormalities, including the processing defect of prosurfactant protein C in the alveolar epithelial type II cells and the accumulation of glycolipids in enlarged alveolar macrophages. The luminal pH of acidic organelles in Dja2-/- cells was shifted to pH 5.37-5.45. This deviated pH was immediately restored to control levels (pH 4.56-4.65) by the addition of a diuretic, ethyl isopropyl amiloride (EIPA). Although the role of DJA2 in maintaining the pH homeostasis of lysosome-related organelles is currently obscure, this rapid and remarkable pH resilience is best explained by an EIPA-sensitive proton efflux machinery that is disorganized and overactivated due to the loss of Dja2.
Assuntos
Lisossomos , Prótons , Animais , Camundongos , Transporte Biológico , Concentração de Íons de Hidrogênio , Lisossomos/metabolismo , Macrófagos Alveolares , Camundongos Endogâmicos C57BLRESUMO
Previously, we reported that an ANGPTL3 vaccine is a hopeful therapeutic option against dyslipidemia. In our current study, we assess durability and booster effects of that vaccine over a period representing a mouse's lifespan. The vaccine remained effective for over one year, and booster vaccination maintained suppression of circulating triglyceride levels thereafter without major adverse effects on lungs, kidneys, or liver, suggesting vaccine efficacy and safety.
RESUMO
Acetaminophen (APAP) overdoses can cause severe liver injury. In this study, the protective effect of fasudil against APAP-induced liver injury was investigated. APAP (400 mg/kg) was administered to male C57BL/6J mice to induce liver injury, and fasudil (20 or 40 mg/kg) was injected 30 min before APAP administration. Fasudil markedly suppressed APAP-induced elevation in serum transaminase activity and hepatic necrosis and significantly reduced an increase in nitrotyrosine and DNA fragmentation. However, fasudil did not affect cytochrome P450 2E1 expression, N-acetyl-p-benzoquinone imine production or c-jun N-terminal kinase activation. In contrast, fasudil significantly inhibited an APAP-induced increase in expression of the transcription factor C/EBP homologous protein (CHOP) in the liver, accompanied by transcriptional suppression of ER stress-related molecules such as Ero1α, Atf4 and Grp78. These findings indicate that suppression of CHOP expression by fasudil exhibits a remarkable protective effect against APAP liver injury by regulating ER stress. We suggest that fasudil is a promising therapeutic candidate for treating APAP-induced liver injury.
Assuntos
Doença Hepática Crônica Induzida por Substâncias e Drogas , Doença Hepática Induzida por Substâncias e Drogas , Camundongos , Masculino , Animais , Acetaminofen/efeitos adversos , Doença Hepática Crônica Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Camundongos Endogâmicos C57BL , Fígado/metabolismoRESUMO
Use of immune checkpoint inhibitors (ICIs) as cancer immunotherapy advances rapidly in the clinic. Despite their therapeutic benefits, ICIs can cause clinically significant immune-related adverse events (irAEs), including myocarditis. However, the cellular and molecular mechanisms regulating irAE remain unclear. Here, we investigate the function of Angiopoietin-like protein 2 (ANGPTL2), a potential inflammatory mediator, in a mouse model of ICI-related autoimmune myocarditis. ANGPTL2 deficiency attenuates autoimmune inflammation in these mice, an outcome associated with decreased numbers of T cells and macrophages. We also show that cardiac fibroblasts express abundant ANGPTL2. Importantly, cardiac myofibroblast-derived ANGPTL2 enhances expression of chemoattractants via the NF-κB pathway, accelerating T cell recruitment into heart tissues. Our findings suggest an immunostimulatory function for ANGPTL2 in the context of ICI-related autoimmune inflammation and highlight the pathophysiological significance of ANGPTL2-mediated cardiac myofibroblast/immune cell crosstalk in enhancing autoimmune responses. These findings overall provide insight into mechanisms regulating irAEs.
Assuntos
Proteína 2 Semelhante a Angiopoietina , Inibidores de Checkpoint Imunológico , Miocardite , Animais , Camundongos , Coração , Inibidores de Checkpoint Imunológico/efeitos adversos , Inflamação , Miocardite/induzido quimicamenteRESUMO
Loss or downregulation of major histocompatibility complex class I (MHC-I) contributes to tumor immune evasion. We previously demonstrated that angiopoietin-like protein 2 (ANGPTL2) promotes tumor progression using a Xp11.2 translocation renal cell carcinoma (tRCC) mouse model. However, molecular mechanisms underlying ANGPTL2 tumor-promoting activity in the tRCC model remained unclear. Here, we report that ANGPTL2 deficiency in renal tubular epithelial cells slows tumor progression in the tRCC mouse model and promotes activated CD8+ T-cell infiltration of kidney tissues. We also found that Angptl2-deficient tumor cells show enhanced interferon γ-induced expression of MHC-I and increased susceptibility to CD8+ T-cell-mediated anti-tumor immune responses. Moreover, we provide evidence that the ANGPTL2-α5ß1 integrin pathway accelerates polycomb repressive complex 2-mediated repression of MHC-I expression in tumor cells. These findings suggest that ANGPTL2 signaling in tumor cells contributes to tumor immune evasion and that suppressing that signaling in tumor cells could serve as a potential strategy to facilitate tumor elimination by T-cell-mediated anti-tumor immunity.
Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Animais , Camundongos , Proteína 2 Semelhante a Angiopoietina , Proteínas Semelhantes a Angiopoietina/genética , Proteínas Semelhantes a Angiopoietina/metabolismo , Evasão Tumoral/genética , Repressão Epigenética , Antígenos de Histocompatibilidade Classe I/genética , Carcinoma de Células Renais/genética , Modelos Animais de DoençasRESUMO
Interleukin-7 (IL-7) is a cytokine critical for the development and maintenance of group 2 innate lymphoid cells (ILC2s). ILC2s are resident in peripheral tissues such as the intestine and lung. However, whether IL-7 produced in the lung plays a role in the maintenance and function of lung ILC2s during airway inflammation remains unknown. IL-7 was expressed in bronchoalveolar epithelial cells and lymphatic endothelial cells (LECs). To investigate the role of local IL-7 in lung ILC2s, we generated two types of IL-7 conditional knockout (IL-7cKO) mice: Sftpc-Cre (SPC-Cre) IL-7cKO mice specific for bronchial epithelial cells and type 2 alveolar epithelial cells and Lyve1-Cre IL-7cKO mice specific for LECs. In steady state, ILC2s were located near airway epithelia, although lung ILC2s were unchanged in the two lines of IL-7cKO mice. In papain-induced airway inflammation dependent on innate immunity, lung ILC2s localized near bronchia via CCR4 expression, and eosinophil infiltration and type 2 cytokine production were reduced in SPC-Cre IL-7cKO mice. In contrast, in house dust mite (HDM)-induced airway inflammation dependent on adaptive immunity, lung ILC2s localized near lymphatic vessels via their CCR2 expression 2 weeks after the last challenge. Furthermore, lung ILC2s were decreased in Lyve1-Cre IL-7cKO mice in the HDM-induced inflammation because of decreased cell survival and proliferation. Finally, administration of anti-IL-7 antibody attenuated papain-induced inflammation by suppressing the activation of ILC2s. Thus, this study demonstrates that IL-7 produced by bronchoalveolar epithelial cells and LECs differentially controls the activation and maintenance of lung ILC2s, where they are localized in airway inflammation.
Assuntos
Imunidade Inata , Interleucina-7 , Camundongos , Animais , Células Endoteliais/metabolismo , Papaína , Linfócitos , Pulmão , Imunidade Adaptativa , Inflamação , Citocinas/metabolismo , Interleucina-33RESUMO
BACKGROUND: The ability to predict secondary cardiovascular events could improve health of patients undergoing statin treatment. Circulating ANGPTL8 (angiopoietin-like protein 8) levels, which positively correlate with proatherosclerotic lipid profiles, activate the pivotal proatherosclerotic factor ANGPTL3. Here, we assessed potential association between circulating ANGPTL8 levels and risk of secondary cardiovascular events in statin-treated patients. METHODS: We conducted a biomarker study with a case-cohort design, using samples from a 2018 randomized control trial known as randomized evaluation of high-dose (4 mg/day) or low-dose (1 mg/day) lipid-lowering therapy with pitavastatin in coronary artery disease (REAL-CAD [Randomized Evaluation of Aggressive or Moderate Lipid-Lowering Therapy With Pitavastatin in Coronary Artery Disease])." From that study's full analysis set (n=12 413), we selected 2250 patients with stable coronary artery disease (582 with the primary outcome, 1745 randomly chosen, and 77 overlapping subjects). A composite end point including cardiovascular-related death, nonfatal myocardial infarction, nonfatal ischemic stroke, or unstable angina requiring emergent admission was set as a primary end point. Circulating ANGPTL8 levels were measured at baseline and 6 months after randomization. RESULTS: Over a 6-month period, ANGPTL8 level changes significantly decreased in the high-dose pitavastatin group, which showed 19% risk reduction of secondary cardiovascular events compared with the low-dose group in the REAL-CAD [Randomized Evaluation of Aggressive or Moderate Lipid-Lowering Therapy With Pitavastatin in Coronary Artery Disease] study. In the highest quartiles, relative increases in ANGPTL8 levels were significantly associated with increased risk for secondary cardiovascular events, after adjustment for several cardiovascular disease risk factors and pitavastatin treatment (hazard ratio in Q4, 1.67 [95% CI, 1.17-2.39). Subgroup analyses showed relatively strong relationships between relative ANGPTL8 increases and secondary cardiovascular events in the high-dose pitavastatin group (hazard ratio in Q4, 2.07 [95% CI, 1.21-3.55]) and in the low ANGPTL8 group at baseline (166 Assuntos
Doenças Cardiovasculares
, Doença da Artéria Coronariana
, Inibidores de Hidroximetilglutaril-CoA Redutases
, Infarto do Miocárdio
, Hormônios Peptídicos
, Humanos
, Proteína 3 Semelhante a Angiopoietina
, Proteína 8 Semelhante a Angiopoietina
, Doenças Cardiovasculares/sangue
, Doenças Cardiovasculares/induzido quimicamente
, Doenças Cardiovasculares/diagnóstico
, Doenças Cardiovasculares/epidemiologia
, Doença da Artéria Coronariana/sangue
, Doença da Artéria Coronariana/tratamento farmacológico
, Doença da Artéria Coronariana/epidemiologia
, População do Leste Asiático
, Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos
, Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico
, Lipídeos
, Infarto do Miocárdio/tratamento farmacológico
, Resultado do Tratamento
RESUMO
In mammalian mitochondria, translation of the AUA codon is supported by 5-formylcytidine (f5C) modification in the mitochondrial methionine tRNA anticodon. The 5-formylation is initiated by NSUN3 methylase. Human NSUN3 mutations are associated with mitochondrial diseases. Here we show that Nsun3 is essential for embryonic development in mice with whole-body Nsun3 knockout embryos dying between E10.5 and E12.5. To determine the functions of NSUN3 in adult tissue, we generated heart-specific Nsun3 knockout (Nsun3HKO) mice. Nsun3HKO heart mitochondria were enlarged and contained fragmented cristae. Nsun3HKO resulted in enhanced heart contraction and age-associated mild heart enlargement. In the Nsun3HKO hearts, mitochondrial mRNAs that encode respiratory complex subunits were not down regulated, but the enzymatic activities of the respiratory complexes decreased, especially in older mice. Our study emphasizes that mitochondrial tRNA anticodon modification is essential for mammalian embryonic development and shows that tissue-specific loss of a single mitochondrial tRNA modification can induce tissue aberration that worsens in later adulthood.
Assuntos
Anticódon , RNA de Transferência de Metionina , Humanos , Animais , Camundongos , Adulto , RNA de Transferência de Metionina/genética , Códon , Mitocôndrias/genética , Mamíferos/genética , Metiltransferases/genéticaRESUMO
BACKGROUND: Evaluating patients' risk for acute kidney injury (AKI) is crucial for positive outcomes following cardiac surgery. Our aims were first to select candidate risk factors from pre- or intra-operative real-world parameters collected from routine medical care and then evaluate potential associations between those parameters and risk of onset of post-operative cardiac surgery-associated AKI (CSA-AKI). METHOD: We conducted two cohort studies in Japan. The first was a single-center prospective cohort study (n = 145) to assess potential association between 115 clinical parameters collected from routine medical care and CSA-AKI (≥ Stage1) risk in the population of patients undergoing cardiac surgery involving cardiopulmonary bypass (CPB). To select candidate risk factors, we employed random forest analysis and applied survival analyses to evaluate association strength. In a second retrospective cohort study, we targeted patients undergoing cardiac surgery with CPB (n = 619) and evaluated potential positive associations between CSA-AKI incidence and risk factors suggested by the first cohort study. RESULTS: Variable selection analysis revealed that parameters in clinical categories such as circulating inflammatory cells, CPB-related parameters, ventilation, or aging were potential CSA-AKI risk factors. Survival analyses revealed that increased counts of pre-operative circulating monocytes and neutrophils were associated with CSA-AKI incidence. Finally, in the second cohort study, we found that increased pre-operative circulating monocyte counts were associated with increased CSA-AKI incidence. CONCLUSIONS: Circulating monocyte counts in the pre-operative state are associated with increased risk of CSA-AKI development. This finding may be useful in stratifying patients for risk of developing CSA-AKI in routine clinical practice.
Assuntos
Injúria Renal Aguda , Procedimentos Cirúrgicos Cardíacos , Humanos , Estudos de Coortes , Monócitos , Estudos Retrospectivos , Estudos Prospectivos , Ponte Cardiopulmonar/efeitos adversos , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Injúria Renal Aguda/diagnóstico , Injúria Renal Aguda/epidemiologia , Injúria Renal Aguda/etiologia , Fatores de Risco , Complicações Pós-Operatórias/epidemiologiaRESUMO
Brown adipose tissue plays a central role in the regulation of the energy balance by expending energy to produce heat. NAD+-dependent deacylase sirtuins have widely been recognized as positive regulators of brown adipose tissue thermogenesis. However, here we reveal that SIRT7, one of seven mammalian sirtuins, suppresses energy expenditure and thermogenesis by regulating brown adipose tissue functions. Whole-body and brown adipose tissue-specific Sirt7 knockout mice have higher body temperature and energy expenditure. SIRT7 deficiency increases the protein level of UCP1, a key regulator of brown adipose tissue thermogenesis. Mechanistically, we found that SIRT7 deacetylates insulin-like growth factor 2 mRNA-binding protein 2, an RNA-binding protein that inhibits the translation of Ucp1 mRNA, thereby enhancing its inhibitory action on Ucp1. Furthermore, SIRT7 attenuates the expression of batokine genes, such as fibroblast growth factor 21. In conclusion, we propose that SIRT7 serves as an energy-saving factor by suppressing brown adipose tissue functions.
Assuntos
Tecido Adiposo Marrom , Sirtuínas , Camundongos , Animais , Tecido Adiposo Marrom/metabolismo , Termogênese/genética , Proteína Desacopladora 1/genética , Proteína Desacopladora 1/metabolismo , Metabolismo Energético/fisiologia , Camundongos Knockout , RNA Mensageiro/metabolismo , Mamíferos/genética , Sirtuínas/genética , Sirtuínas/metabolismoRESUMO
Sirtuins (SIRT1-7 in mammals) are evolutionarily conserved nicotinamide adenine dinucleotide-dependent lysine deacetylases/deacylases that regulate fundamental biological processes including aging. In this study, we reveal that male Sirt7 knockout (KO) mice exhibited an extension of mean and maximum lifespan and a delay in the age-associated mortality rate. In addition, aged male Sirt7 KO mice displayed better glucose tolerance with improved insulin sensitivity compared with wild-type (WT) mice. Fibroblast growth factor 21 (FGF21) enhances insulin sensitivity and extends lifespan when it is overexpressed. Serum levels of FGF21 were markedly decreased with aging in WT mice. In contrast, this decrease was suppressed in Sirt7 KO mice, and the serum FGF21 levels of aged male Sirt7 KO mice were higher than those of WT mice. Activating transcription factor 4 (ATF4) stimulates Fgf21 transcription, and the hepatic levels of Atf4 mRNA were increased in aged male Sirt7 KO mice compared with WT mice. Our findings indicate that the loss of SIRT7 extends lifespan and improves glucose metabolism in male mice. High serum FGF21 levels might be involved in the beneficial effect of SIRT7 deficiency.
Assuntos
Intolerância à Glucose , Resistência à Insulina , Sirtuínas , Camundongos , Masculino , Animais , Longevidade , Resistência à Insulina/genética , Envelhecimento , Camundongos Knockout , Mamíferos , Sirtuínas/genéticaRESUMO
Invariant natural killer T (iNKT) cells are a group of innate-like T lymphocytes that recognize lipid antigens. They are supposed to be tissue resident and important for systemic and local immune regulation. To investigate the heterogeneity of iNKT cells, we recharacterized iNKT cells in the thymus and peripheral tissues. iNKT cells in the thymus were divided into three subpopulations by the expression of the natural killer cell receptor CD244 and the chemokine receptor CXCR6 and designated as C0 (CD244-CXCR6-), C1 (CD244-CXCR6+), or C2 (CD244+CXCR6+) iNKT cells. The development and maturation of C2 iNKT cells from C0 iNKT cells strictly depended on IL-15 produced by thymic epithelial cells. C2 iNKT cells expressed high levels of IFN-γ and granzymes and exhibited more NK cell-like features, whereas C1 iNKT cells showed more T cell-like characteristics. C2 iNKT cells were influenced by the microbiome and aging and suppressed the expression of the autoimmune regulator AIRE in the thymus. In peripheral tissues, C2 iNKT cells were circulating that were distinct from conventional tissue-resident C1 iNKT cells. Functionally, C2 iNKT cells protected mice from the tumor metastasis of melanoma cells by enhancing antitumor immunity and promoted antiviral immune responses against influenza virus infection. Furthermore, we identified human CD244+CXCR6+ iNKT cells with high cytotoxic properties as a counterpart of mouse C2 iNKT cells. Thus, this study reveals a circulating subset of iNKT cells with NK cell-like properties distinct from conventional tissue-resident iNKT cells.
Assuntos
Células T Matadoras Naturais , Camundongos , Humanos , Animais , Células T Matadoras Naturais/metabolismo , Células T Matadoras Naturais/patologia , Interleucina-15 , Antivirais , Granzimas , Receptores de Células Matadoras Naturais , Receptores de Quimiocinas/metabolismo , LipídeosRESUMO
Uncontrolled proliferation of intestinal epithelial cells caused by mutations in genes of the WNT/ß-catenin pathway is associated with development of intestinal cancers. We previously reported that intestinal stromal cell-derived angiopoietin-like protein 2 (ANGPTL2) controls epithelial regeneration and intestinal immune responses. However, the role of tumor cell-derived ANGPTL2 in intestinal tumorigenesis remained unclear. Here, we show that tumor cell-derived ANGPTL2 promotes ß-catenin-driven intestinal tumorigenesis. ANGPTL2 deficiency suppressed intestinal tumor development in an experimental mouse model of sporadic colon cancer. We also found that increased ANGPTL2 expression in colorectal cancer (CRC) cells augments ß-catenin pathway signaling and promotes tumor cell proliferation. Relevant to mechanism, our findings suggest that tumor cell-derived ANGPTL2 upregulates expression of OB-cadherin, which then interacts with ß-catenin, blocking destruction complex-independent proteasomal degradation of ß-catenin proteins. Moreover, our observations support a model whereby ANGPTL2-induced OB-cadherin expression in CRC cells is accompanied by decreased cell surface integrin α5ß1 expression. These findings overall provide novel insight into mechanisms of ß-catenin-driven intestinal tumorigenesis.
Assuntos
Neoplasias Colorretais , Neoplasias Intestinais , Proteína 2 Semelhante a Angiopoietina , Proteínas Semelhantes a Angiopoietina/genética , Animais , Carcinogênese/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Transformação Celular Neoplásica/metabolismo , Neoplasias Colorretais/patologia , Regulação Neoplásica da Expressão Gênica , Neoplasias Intestinais/genética , Camundongos , Via de Sinalização Wnt/genética , beta Catenina/metabolismoRESUMO
Renal cell carcinoma with Xp11.2 translocation involving the TFE3 gene (TFE3-RCC) is a recently identified subset of RCC with unique morphology and clinical presentation. The chimeric PRCC-TFE3 protein produced by Xp11.2 translocation has been shown to transcriptionally activate its downstream target genes that play important roles in carcinogenesis and tumor development of TFE3-RCC. However, the underlying molecular mechanisms remain poorly understood. Here we show that in TFE3-RCC cells, PRCC-TFE3 controls heme oxygenase 1 (HMOX1) expression to confer chemoresistance. Inhibition of HMOX1 sensitized the PRCC-TFE3 expressing cells to genotoxic reagents. We screened for a novel chlorambucil-polyamide conjugate (Chb) to target PRCC-TFE3-dependent transcription, and identified Chb16 as a PRCC-TFE3-dependent transcriptional inhibitor of HMOX1 expression. Treatment of the patient-derived cancer cells with Chb16 exhibited senescence and growth arrest, and increased sensitivity of the TFE3-RCC cells to the genotoxic reagent etoposide. Thus, our data showed that the TFE3-RCC cells acquired chemoresistance through HMOX1 expression and that inhibition of HMOX1 by Chb16 may be an effective therapeutic strategy for TFE3-RCC.
Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/metabolismo , Clorambucila/farmacologia , Cromossomos Humanos X , Resistencia a Medicamentos Antineoplásicos/genética , Humanos , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/genética , Neoplasias Renais/metabolismo , Nylons , Translocação GenéticaRESUMO
Aging is an important medical and social problem. Excessive angiopoietin-like protein (ANGPTL)-2 signaling causes chronic tissue inflammation, promoting development and progression of aging-related diseases. Moreover, circulating ANGPTL2 levels reportedly predict the risk of some aging-related diseases and subsequent death. However, there are, as yet, no reports of whether circulating ANGPTL2 levels predict vital prognosis in younger-old, community-dwelling populations. This study investigated associations between plasma ANGPTL2 levels and all-cause and specific-cause mortality in this population. The case-cohort study was abstracted from an ongoing, age-specific prospective cohort study: the New Integrated Suburban Seniority Investigation Project. This project enrolled 3 073 participants aged 64 years at the beginning of the investigation from 1996 through 2005. A subcohort of 714 randomly sampled participants plus 387 cases representing deceased participants followed through 2015 underwent survival analysis. Plasma ANGPTL2 concentrations were positively associated with >80% and 100% higher risk of all-cause mortality and cancer mortality, respectively, after adjustment for gender, smoking, alcohol consumption, walking time, sleep duration, caloric intake, medical status, disease history, BMI, and triglyceride, creatinine, uric acid, and high sensitivity C-reactive protein levels. A more robust association between ANGPTL2 levels and all-cause and cancer mortality was seen in participants with either frailties or with lifestyles of heavier drinking or current smoking. Elevated plasma ANGPTL2 levels are associated with high all-cause and cancer mortality in a community-dwelling sample of younger-old adults. These findings expand our knowledge of human aging and associated diseases.
Assuntos
Proteína 2 Semelhante a Angiopoietina , Neoplasias , Proteínas Semelhantes a Angiopoietina , Estudos de Coortes , Humanos , Inflamação , Japão/epidemiologia , Estudos ProspectivosRESUMO
Background: Patients with cardiogenic shock due to acute myocardial infarction (AMI) can rapidly undergo veno-arterial extracorporeal membrane oxygenation (VA-ECMO) therapy to recover cardiac output and decrease mortality. However, the clinical indicators predictive of mortality in these patients remain unknown. MethodsâandâResults: We conducted a single-center retrospective cohort study targeting AMI patients undergoing VA-ECMO. All 63 patients undergoing VA-ECMO for AMI at the Japanese Red Cross Kumamoto Hospital between January 1, 2010 and June 30, 2020 were enrolled. An exploratory analysis was conducted using a survival tree model and variables selected in a univariate Cox proportional hazard model. The median survival time from the start of VA-ECMO was 6.3 days, and 77.8% (n=49) of patients died. Survival analysis divided patients into 3 groups based on 2 parameters at the initial medical examination: Group 1, patients with neither hyperglycemia (blood glucose ≥213 mg/dL) nor thrombocytopenia (platelets ≤145,100/µL); Group 2, patients with hyperglycemia; and Group 3, patients with hyperglycemia plus thrombocytopenia. Relative to Group 1, the risk of in-hospital mortality was significantly increased in Group 2 (hazard ratio [HR] 2.25; 95% confidence interval [CI] 1.13-4.46), and that risk further increased in Group 3 (HR 7.60; 95% CI 3.21-17.95). Conclusions: Hyperglycemia plus thrombocytopenia on initial medical examination combinatorially increase the risk of mortality in patients with cardiogenic shock due to AMI undergoing VA-ECMO.
RESUMO
Dyslipidemia is a risk factor for cardiovascular disease (CVD), a major cause of death worldwide. Angiopoietin-like protein 3 (ANGPTL3), recognized as a new therapeutic target for dyslipidemia, regulates the metabolism of low-density lipoprotein-cholesterol (LDL-C) and triglycerides. Here, we design 3 epitopes (E1-E3) for use in development of a peptide vaccine targeting ANGPTL3 and estimate effects of each on obesity-associated dyslipidemia in B6.Cg-Lepob /J (ob/ob) mice. Vaccination with the E3 (32EPKSRFAMLD41) peptide significantly reduces circulating levels of triglycerides, LDL-C, and small dense (sd)-LDL-C in ob/ob mice and decreases obese-induced fatty liver. Moreover, E3 vaccination does not induce cytotoxicity in ob/ob mice. Interestingly, the effect of E3 vaccination on dyslipidemia attenuates development of atherosclerosis in B6.KOR/StmSlc-Apoeshl mice fed a high-cholesterol diet, which represent a model of severe familial hypercholesterolemia (FH) caused by ApoE loss of function. Taken together, ANGPTL3 vaccination could be an effective therapeutic strategy against dyslipidemia and associated diseases.