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BACKGROUND AND AIMS: The efficacy and safety of early sacubitril/valsartan (Sac/Val) initiation after acute heart failure (AHF) has not been demonstrated outside North America. The present study aimed to evaluate the effect of in-hospital Sac/Val therapy initiation after an AHF episode on N-terminal pro-B-type natriuretic peptide (NT-proBNP) level in Japanese patients. METHODS: This was an investigator-initiated, multicentre, prospective, randomized, open-label, blinded-endpoint pragmatic trial. After haemodynamic stabilization within 7 days after hospitalization, eligible inpatients were allocated to switch from angiotensin-converting enzyme inhibitor or angiotensin receptor blocker to Sac/Val (Sac/Val group) or to continue angiotensin-converting enzyme inhibitor or angiotensin receptor blocker (control group). The primary efficacy endpoint was the 8-week proportional change in geometric means of NT-proBNP levels. RESULTS: A total of 400 patients were equally randomized, and 376 (median age 75 years, 31.9% women, de novo heart failure rate 55.6%, and median left ventricular ejection fraction 37%) were analysed. The per cent changes in NT-proBNP level geometric means at Weeks 4/8 were -35%/-45% (Sac/Val group) and -18%/-32% (control group), and their group ratio (Sac/Val vs. control) was 0.80 (95% confidence interval 0.68-0.94; P = .008) at Week 4 and 0.81 (95% confidence interval 0.68-0.95; P = .012) at Week 8, respectively. In the pre-specified subgroup analyses, the effects of Sac/Val were confined to patients with a left ventricular ejection fraction < 40% and were more evident in those in sinus rhythm and taking mineralocorticoid receptor antagonists. No adverse safety signal was evident. CONCLUSIONS: In-hospital Sac/Val therapy initiation in addition to contemporary recommended therapy triggered a greater NT-proBNP level reduction in Japanese patients hospitalized for AHF. These findings may expand the evidence on Sac/Val therapy in this clinical situation outside North America. CLINICAL TRIAL REGISTRATION: ClinicalTrial.gov (NCT05164653) and Japan Registry of Clinical Trials (jRCTs021210046).
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Gold nano-rods, rod-shaped gold nanoparticles, act as contrast agents for in vivo bioimaging, drug delivery vehicles and thermal converters for photothermal therapy. Pro-inflammatory cytokines play critical roles in the development of heart failure. We examined the delivery of GNRs into the failing heart of a transgenic (TG) mouse model of inflammatory cardiomyopathy with the cardiac-specific overexpression of TNF-α. We modified GNRs with polyethylene glycol (PEG) to avoid cytotoxicity and reduce the rapid clearance of nanoparticles from blood. PEG-modified GNRs (4.5 mM as gold atoms, 200 µL) were administered intravenously to TG (n = 7) and wild-type (WT) mice (n = 5). These were killed 24 h later, and the heart, lung, liver, kidney and spleen were excised. A quantitative analysis of gold was performed using inductively coupled plasma mass or optical emission spectrometry. The amount of gold (ng) in the TG heart (3.24 ± 1.56 ng/mg heart weight) was significantly greater than that in the WT heart (1.01 ± 0.19; p < 0.05). No significant differences were observed among the other organs of TG and WT mice. The amount of gold in the TG heart was significantly and positively correlated with the ratio of the ventricular weight to body weight, which is known to be an index of ventricular hypertrophy. In conclusion, PEG-modified GNRs accumulated in the inflammatory TG heart in proportion with the severity of ventricular hypertrophy.
Assuntos
DNA/genética , Regulação da Expressão Gênica , Ouro/análise , Insuficiência Cardíaca/metabolismo , Nanopartículas Metálicas/análise , Miocárdio/química , Fator de Necrose Tumoral alfa/genética , Animais , Modelos Animais de Doenças , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/patologia , Ventrículos do Coração/química , Ventrículos do Coração/patologia , Masculino , Camundongos , Camundongos Transgênicos , Miocárdio/metabolismo , Miocárdio/patologia , Reação em Cadeia da Polimerase , Fator de Necrose Tumoral alfa/biossínteseRESUMO
Paramyxoviral RNAs are synthesized by a viral RNA-dependent RNA polymerase (RdRp) consisting of the large (L) protein and its cofactor phosphoprotein (P protein). The L protein is a multifunctional protein that catalyzes RNA synthesis, mRNA capping, and mRNA polyadenylation. Growing evidence shows that the stability of several paramyxovirus L proteins is regulated by heat shock protein 90 (Hsp90). In this study, we demonstrated that Hsp90 activity was important for mumps virus (MuV) replication. The Hsp90 activity was required for L-protein stability and activity because an Hsp90-specific inhibitor, 17-allylamino-17-demethoxygeldanamycin (17-AAG), destabilized the MuV L protein and suppressed viral RNA synthesis. However, once the L protein formed a mature polymerase complex with the P protein, Hsp90 activity was no longer required for the stability and activity of the L protein. When the Hsp90 activity was inhibited, the MuV L protein was degraded through the CHIP (C terminus of Hsp70-interacting protein)-mediated proteasomal pathway. High concentrations of 17-AAG showed strong cytotoxicity to certain cell types, but combined use of an Hsp70 inhibitor, VER155008, potentiated degradation of the L protein, allowing a sufficient reduction of 17-AAG concentration to block MuV replication with minimum cytotoxicity. Regulation of the L protein by Hsp90 and Hsp70 chaperones was also demonstrated for another paramyxovirus, the measles virus. Collectively, our data show that the Hsp90/Hsp70 chaperone machinery assists in the maturation of the paramyxovirus L protein and thereby in the formation of a mature RdRp complex and efficient viral replication.IMPORTANCE Heat shock protein 90 (Hsp90) is nearly universally required for viral protein homeostasis. Here, we report that Hsp90 activity is required for efficient propagation of mumps virus (MuV). Hsp90 functions in the maintenance of the catalytic subunit of viral polymerase, the large (L) protein, prior to formation of a mature polymerase complex with the polymerase cofactor of L, phosphoprotein. Hsp70 collaborates with Hsp90 to regulate biogenesis of the MuV L protein. The functions of these chaperones on the viral polymerase may be common among paramyxoviruses because the L protein of measles virus is also similarly regulated. Our data provide important insights into the molecular mechanisms of paramyxovirus polymerase maturation as well as a basis for the development of novel antiviral drugs.
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Proteínas de Choque Térmico HSP90/metabolismo , Interações Hospedeiro-Patógeno , Vírus da Caxumba/fisiologia , RNA Polimerase Dependente de RNA/metabolismo , Replicação Viral , Animais , Linhagem Celular , Chlorocebus aethiops , Células Epiteliais/virologia , Humanos , Vírus do Sarampo/fisiologia , Estabilidade Proteica , ProteóliseRESUMO
We recently reported that the early initiation of tolvaptan in congestive heart failure shortened the hospital stay and reduced the rate of in-hospital death. However, whether or not these results apply to elderly patients with congestive heart failure is unclear. We performed a sub-analysis of our previous study. Among the 102 patients in that study, we retrospectively analyzed the elderly patients >75 years of age treated with tolvaptan. First, we analyzed the efficacy of early tolvaptan use in these patients. We then compared the efficacy and the safety of all tolvaptan use between elderly and younger patients. There were no significant differences in the baseline clinical parameters between the early- and late-tolvaptan-use elderly patients, except for the serum blood nitrogen urea. However, the early use of tolvaptan was also associated with the earlier initiation of ambulatory cardiac rehabilitation, a shorter hospital stay, and a lower rate of in-hospital death in elderly congestive heart failure patients. Furthermore, there were no significant differences in the occurrence of worsening renal failure and hypernatremia. The early use of tolvaptan in elderly patients was also associated with a shorter hospital stay and reduced mortality. We also confirmed the safety of tolvaptan in elderly patients. It might, therefore, be beneficial to consider administering tolvaptan early in elderly patients with heart failure, just as in younger patients.
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Benzazepinas/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Antagonistas dos Receptores de Hormônios Antidiuréticos/uso terapêutico , Feminino , Seguimentos , Insuficiência Cardíaca/mortalidade , Humanos , Hiponatremia , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida/tendências , Fatores de Tempo , Tolvaptan , Resultado do TratamentoRESUMO
Recently, a new paramyxovirus closely related to human mumps virus (MuV) was detected in bats. We generated recombinant MuVs carrying either or both of the fusion and hemagglutinin-neuraminidase bat virus glycoproteins. These viruses showed replication kinetics similar to human MuV in cultured cells and were neutralized efficiently by serum from healthy humans.
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Anticorpos Antivirais/sangue , Vírus da Caxumba/genética , Caxumba/imunologia , Caxumba/veterinária , Vírus Reordenados/imunologia , Proteínas Virais de Fusão/imunologia , Adolescente , Adulto , Animais , Linhagem Celular , Quirópteros , Chlorocebus aethiops , Cricetulus , República Democrática do Congo/epidemiologia , Feminino , Expressão Gênica , Proteína HN/genética , Proteína HN/imunologia , Especificidade de Hospedeiro , Humanos , Soros Imunes/química , Soros Imunes/farmacologia , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Caxumba/epidemiologia , Caxumba/virologia , Vírus da Caxumba/crescimento & desenvolvimento , Vírus da Caxumba/isolamento & purificação , Testes de Neutralização , Vírus Reordenados/genética , Células Vero , Proteínas Virais de Fusão/antagonistas & inibidores , Proteínas Virais de Fusão/genéticaRESUMO
UNLABELLED: Mumps virus (MuV) is an airborne virus that causes a systemic infection in patients. In vivo, the epithelium is a major replication site of MuV, and thus, the mode of MuV infection of epithelial cells is a subject of interest. Our data in the present study showed that MuV entered polarized epithelial cells via both the apical and basolateral surfaces, while progeny viruses were predominantly released from the apical surface. In polarized cells, intracellular transport of viral ribonucleoprotein (vRNP) complexes was dependent on Rab11-positive endosomes, and vRNP complexes were transported to the apical membrane. Expression of a dominant negative form of Rab11 (Rab11S25N) reduced the progeny virus release in polarized cells but not in nonpolarized cells. Although in this way these effects were correlated with cell polarity, Rab11S25N did not modulate the direction of virus release from the apical surface. Therefore, our data suggested that Rab11 is not a regulator of selective apical release of MuV, although it acts as an activator of virus release from polarized epithelial cells. In addition, our data and previous studies on Sendai virus, respiratory syncytial virus, and measles virus suggested that selective apical release from epithelial cells is used by many paramyxoviruses, even though they cause either a systemic infection or a local respiratory infection. IMPORTANCE: Mumps virus (MuV) is the etiological agent of mumps and causes a systemic infection. However, the precise mechanism by which MuV breaks through the epithelial barriers and achieves a systemic infection remains unclear. In the present study, we show that the entry of MuV is bipolar, while the release is predominantly from the apical surface in polarized epithelial cells. In addition, the release of progeny virus was facilitated by a Rab11-positive recycling endosome and microtubule network. Our data provide important insights into the mechanism of transmission and pathogenesis of MuV.
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Endossomos/virologia , Células Epiteliais/virologia , Vírus da Caxumba/fisiologia , Liberação de Vírus/fisiologia , Proteínas rab de Ligação ao GTP/metabolismo , Animais , Chlorocebus aethiops , Cães , Endossomos/metabolismo , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Humanos , Immunoblotting , Microscopia de Fluorescência , Plasmídeos/genéticaRESUMO
UNLABELLED: Mumps virus (MuV) infection induces formation of cytoplasmic inclusion bodies (IBs). Growing evidence indicates that IBs are the sites where RNA viruses synthesize their viral RNA. However, in the case of MuV infection, little is known about the viral and cellular compositions and biological functions of the IBs. In this study, pulldown purification and N-terminal amino acid sequencing revealed that stress-inducible heat shock protein 70 (Hsp72) was a binding partner of MuV phosphoprotein (P protein), which was an essential component of the IB formation. Immunofluorescence and immunoblotting analyses revealed that Hsp72 was colocalized with the P protein in the IBs, and its expression was increased during MuV infection. Knockdown of Hsp72 using small interfering RNAs (siRNAs) had little, if any, effect on viral propagation in cultured cells. Knockdown of Hsp72 caused accumulation of ubiquitinated P protein and delayed P protein degradation. These results show that Hsp72 is recruited to IBs and regulates the degradation of MuV P protein through the ubiquitin-proteasome pathway. IMPORTANCE: Formation of cytoplasmic inclusion bodies (IBs) is a common characteristic feature in mononegavirus infections. IBs are considered to be the sites of viral RNA replication and transcription. However, there have been few studies focused on host factors recruited to the IBs and their biological functions. Here, we identified stress-inducible heat shock protein 70 (Hsp72) as the first cellular partner of mumps virus (MuV) phosphoprotein (P protein), which is an essential component of the IBs and is involved in viral RNA replication/transcription. We found that the Hsp72 mobilized to the IBs promoted degradation of the MuV P protein through the ubiquitin-proteasome pathway. Our data provide new insight into the role played by IBs in mononegavirus infection.
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Proteínas de Choque Térmico HSP72/metabolismo , Vírus da Caxumba/metabolismo , Caxumba/enzimologia , Fosfoproteínas/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Ubiquitinas/metabolismo , Proteínas Virais/metabolismo , Proteínas de Choque Térmico HSP72/genética , Humanos , Corpos de Inclusão Viral/metabolismo , Corpos de Inclusão Viral/virologia , Caxumba/genética , Caxumba/virologia , Vírus da Caxumba/genética , Fosfoproteínas/genética , Ligação Proteica , Proteólise , Proteínas Virais/genéticaRESUMO
The host protease TMPRSS2 plays an essential role in proteolytic activation of the influenza A virus (IAV) hemagglutinin (HA) protein possessing a monobasic cleavage site. However, after passages in TMPRSS2 knockout mice, an H3N2 subtype IAV began to undergo cleavage activation of HA, showing high virulence in the mice due to the loss of an oligosaccharide at position 8 in the HA stalk region. Thus, the H3N2 IAV acquired cleavability by an alternative HA activation mechanism/protease(s).
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Glicoproteínas de Hemaglutininação de Vírus da Influenza/metabolismo , Vírus da Influenza A Subtipo H3N2/genética , Vírus da Influenza A Subtipo H3N2/fisiologia , Oligossacarídeos/metabolismo , Processamento de Proteína Pós-Traducional , Serina Endopeptidases/deficiência , Animais , Glicoproteínas de Hemaglutininação de Vírus da Influenza/genética , Vírus da Influenza A Subtipo H3N2/crescimento & desenvolvimento , Camundongos Knockout , Oligossacarídeos/genética , Virulência , Internalização do VírusRESUMO
Tolvaptan is an oral antagonist of arginine vasopressin receptor 2 that has been approved in Japan to reduce congestive symptoms in patients with heart failure refractory to loop diuretics. However, it is unknown whether the early use of tolvaptan results in better clinical outcomes. We retrospectively analyzed 102 consecutive patients with decompensated heart failure treated with tolvaptan at our hospital. A given patient was defined as a responder when the maximum urine volume was greater than 150 % of that observed before tolvaptan use. A logistic regression analysis revealed that the early use of tolvaptan (within 3 days after admission) was an independent factor associated with tolvaptan responsiveness. There were no significant differences in the baseline clinical parameters between the early and late tolvaptan use groups. However, the early use of tolvaptan was associated with higher tolvaptan responsiveness, a shorter duration of carperitide infusion, earlier initiation of ambulatory cardiac rehabilitation, shorter hospital stay, lower rate of in-hospital death. The early use of tolvaptan was associated with a shorter hospital stay and reduced mortality in our retrospective cohort. It might therefore be beneficial to consider administering tolvaptan earlier in patients with heart failure.
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Antagonistas dos Receptores de Hormônios Antidiuréticos/uso terapêutico , Benzazepinas/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/mortalidade , Mortalidade Hospitalar , Tempo de Internação , Idoso , Idoso de 80 Anos ou mais , Antagonistas dos Receptores de Hormônios Antidiuréticos/administração & dosagem , Benzazepinas/administração & dosagem , Intervenção Médica Precoce , Feminino , Hemodinâmica , Humanos , Japão , Testes de Função Renal , Modelos Lineares , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Curva ROC , Estudos Retrospectivos , TolvaptanRESUMO
Epithelial-mesenchymal transition (EMT) has an essential role in organogenesis and contributes to a host of pathologies, including carcinogenesis. Hypoxia (low oxygen supply) aids tumor metastasis in part by promoting EMT in cancer cells. The underlying mechanism whereby hypoxia orchestrates EMT remains poorly defined. Here we report that SIRT1, a multifaceted player in tumorigenesis, opposed ovarian cancer metastasis in vitro and in vivo by impeding EMT. Hypoxic stress downregulated the expression of SIRT1, primarily at the transcriptional level, by reducing the occupancy of the transcriptional activator Sp1 on the proximal promoter of the SIRT1 gene in a SUMOylation-dependent manner. Further analysis revealed that the SUMO E3 ligase PIASy (also known as PIAS4) was induced by hypoxia and prevented Sp1 from binding to the SIRT1 promoter. Conversely, knockdown of PIASy by small interfering RNA (siRNA) restored Sp1 binding and SIRT1 expression in cancer cells challenged with hypobaric hypoxia, reversed cancer cell EMT, and attenuated metastasis in vivo in nude mice. Importantly, analysis of human ovarian tumor specimens indicated that PIASy expression was positively, whereas SIRT1 expression was inversely, correlated with cancer aggressiveness. In summary, our work has identified a new pathway that links downregulation of SIRT1 to hypoxia-induced EMT in ovarian cancer cells and, as such, sheds light on the development of novel anti-tumor therapeutics.
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Transição Epitelial-Mesenquimal/genética , Neoplasias Ovarianas/metabolismo , Proteínas Inibidoras de STAT Ativados/metabolismo , Sirtuína 1/metabolismo , Fator de Transcrição Sp1/metabolismo , Animais , Hipóxia Celular , Linhagem Celular Tumoral , Transformação Celular Neoplásica , Feminino , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Nus , Metástase Neoplásica/genética , Proteínas de Ligação a Poli-ADP-Ribose , Regiões Promotoras Genéticas , Ligação Proteica/genética , Proteínas Inibidoras de STAT Ativados/genética , Interferência de RNA , RNA Interferente Pequeno , Sirtuína 1/biossíntese , Sirtuína 1/genética , Sumoilação/genética , Transcrição GênicaRESUMO
UNLABELLED: Proteolytic cleavage of the hemagglutinin (HA) protein is essential for influenza A virus (IAV) to acquire infectivity. This process is mediated by a host cell protease(s) in vivo. The type II transmembrane serine protease TMPRSS2 is expressed in the respiratory tract and is capable of activating a variety of respiratory viruses, including low-pathogenic (LP) IAVs possessing a single arginine residue at the cleavage site. Here we show that TMPRSS2 plays an essential role in the proteolytic activation of LP IAVs, including a recently emerged H7N9 subtype, in vivo. We generated TMPRSS2 knockout (KO) mice. The TMPRSS2 KO mice showed normal reproduction, development, and growth phenotypes. In TMPRSS2 KO mice infected with LP IAVs, cleavage of HA was severely impaired, and consequently, the majority of LP IAV progeny particles failed to gain infectivity, while the viruses were fully activated proteolytically in TMPRSS2+/+ wild-type (WT) mice. Accordingly, in contrast to WT mice, TMPRSS2 KO mice were highly tolerant of challenge infection by LP IAVs (H1N1, H3N2, and H7N9) with ≥1,000 50% lethal doses (LD50) for WT mice. On the other hand, a high-pathogenic H5N1 subtype IAV possessing a multibasic cleavage site was successfully activated in the lungs of TMPRSS2 KO mice and killed these mice, as observed for WT mice. Our results demonstrate that recently emerged H7N9 as well as seasonal IAVs mainly use the specific protease TMPRSS2 for HA cleavage in vivo and, thus, that TMPRSS2 expression is essential for IAV replication in vivo. IMPORTANCE: Influenza A virus (IAV) is a leading pathogen that infects and kills many humans every year. We clarified that the infectivity and pathogenicity of IAVs, including a recently emerged H7N9 subtype, are determined primarily by a host protease, TMPRSS2. Our data showed that TMPRSS2 is the key host protease that activates IAVs in vivo through proteolytic cleavage of their HA proteins. Hence, TMPRSS2 is a good target for the development of anti-IAV drugs. Such drugs could also be effective for many other respiratory viruses, including the recently emerged Middle East respiratory syndrome (MERS) coronavirus, because they are also activated by TMPRSS2 in vitro. Consequently, the present paper could have a large impact on the battle against respiratory virus infections and contribute greatly to human health.
Assuntos
Interações Hospedeiro-Patógeno , Subtipo H7N9 do Vírus da Influenza A/fisiologia , Serina Endopeptidases/metabolismo , Replicação Viral , Animais , Modelos Animais de Doenças , Feminino , Glicoproteínas de Hemaglutininação de Vírus da Influenza/metabolismo , Vírus da Influenza A Subtipo H1N1/fisiologia , Vírus da Influenza A Subtipo H3N2/fisiologia , Virus da Influenza A Subtipo H5N1/fisiologia , Dose Letal Mediana , Pulmão/virologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Infecções por Orthomyxoviridae/patologia , Infecções por Orthomyxoviridae/virologia , Serina Endopeptidases/deficiência , Análise de SobrevidaRESUMO
BACKGROUND: Recombinant human soluble thrombomodulin (rTM) protects against disseminated intravascular coagulopathy by inhibiting coagulation, inflammation, and apoptosis. This study tests the hypothesis that rTM is hepatoprotective after extensive hepatectomy (Hx) and investigates the mechanisms underlying this effect. MATERIALS AND METHODS: Experiment 1: rats (15 per group) were injected with rTM (1.0 or 2.0 mg/kg) or saline just before 95% Hx and their 7-d survival assessed. Experiment 2: rats were assigned to either a treated (2.0 mg/kg rTM just before Hx) or control group (n = 5 per group). Five rats per group were euthanized immediately after surgery, and at 1, 3, 6, 12, and 24 h postoperatively; serum and liver remnant samples were collected for biochemical and histologic analysis, as well as reverse-transcription polymerase chain reaction and Western blotting. RESULTS: All saline-injected rats died within 52 h of Hx, whereas injection of 2.0 mg/kg rTM prolonged survival (P = 0.003). rTM increased the number of Ki67-positive cells and reduced the number of terminal deoxynucleotidyl transferase dUTP nick-end labeling-positive cells. The number of myeloperoxidase-positive cells and the expression of high-mobility group box 1 protein did not differ. Reverse-transcription polymerase chain reaction revealed that rTM significantly enhanced protease-activated receptor-1 and sphingosine kinase 1 messenger RNA expression and significantly reduced plasminogen activator inhibitor-1 and Bax messenger RNA expression. Immunohistochemistry and Western blotting demonstrated that protease-activated receptor-1 expression 24 h after Hx was significantly higher in rTM-treated than in control rats. CONCLUSIONS: rTM may improve survival after extensive Hx by inhibiting apoptosis and promoting liver regeneration.
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Hepatectomia/efeitos adversos , Falência Hepática/prevenção & controle , Regeneração Hepática/efeitos dos fármacos , Complicações Pós-Operatórias/prevenção & controle , Trombomodulina/uso terapêutico , Alanina Transaminase/sangue , Animais , Apoptose/efeitos dos fármacos , Western Blotting , Avaliação Pré-Clínica de Medicamentos , Hepatectomia/mortalidade , Hepatócitos/efeitos dos fármacos , Imuno-Histoquímica , Falência Hepática/etiologia , Masculino , Complicações Pós-Operatórias/etiologia , Ratos Wistar , Receptor PAR-1/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase ReversaAssuntos
Neuropatias Amiloides Familiares , Pré-Albumina , Idoso , Difosfatos , Humanos , CintilografiaRESUMO
Sinus of Valsalva aneurysm (SVA) is a rare cardiac anomaly that commonly originates from the right or noncoronary sinuses and rarely from the left sinus. SVA is usually diagnosed in the setting of clinical sequelae of a rupture. We herein report a case of an unruptured left SVA presenting as acute myocardial infarction. A 54-year-old woman with a history of radical operation for patent ductus arteriosus in childhood was transferred to our hospital. An electrocardiogram indicated extensive myocardial ischemia with ST elevation. Urgent coronary angiography was performed but was unable to identify the left coronary artery. Subsequent aortography and computed tomography revealed a large SVA originating from the left sinus and compressing the left coronary artery. The patient died after approximately one month of intensive care, including mechanical circulatory support and coronary artery bypass grafting. Autopsy confirmed that the left main coronary trunk was stretched and compressed by the SVA and revealed unexpected atherosclerosis in the left anterior descending artery. Although a left SVA is an extremely rare anomaly, it occasionally provokes fatal myocardial infarction. Since an SVA might hinder performing percutaneous coronary intervention, cardiac surgery should be considered when myocardial ischemia is recognized. Learning objective: We herein report a case of an unruptured left sinus of Valsalva aneurysm (SVA) with acute myocardial infarction. Urgent percutaneous coronary intervention (PCI) was unsuccessful, as the left coronary artery was compressed by the SVA. The patient died after intensive care, including coronary artery bypass grafting (CABG). SVA, especially from the left sinus, is extremely rare but occasionally provokes myocardial infarction by compressing the coronary arteries. Because SVA might hinder PCI, CABG should be considered when myocardial ischemia is recognized.
RESUMO
Nonylphenolpolyethoxylates (NPEOs) are non-ionic surfactants widely used for industrial and household purposes. In actual environments, NPEOs can be biodegraded, but the products are reported to be more persistent and toxic than the parent compounds. NPEOs are also exposed to sunlight and degraded. Studies on the photodegradation of NPEOs have focused mainly on chemical changes after exposure to light. Toxic changes of photodegraded products correlating to the chemical changes are not completely understood. In this study, we examined the genotoxicity of UVB-irradiated NPEOs having ethylene oxide units 15 and 70 in a human breast adenocarcinoma cell line, MCF-7, based on the phosphorylation of histone H2AX (γ-H2AX), a sensitive marker for DNA damage. We clarified that UVB irradiation drastically changed the genotoxic potential of NPEOs: NPEO(15)'s ability to generate γ-H2AX was significantly reduced, whereas non-genotoxic NPEO(70) became able to generate γ-H2AX. Flow cytometric analysis showed that the γ-H2AX generated by UVB-irradiated NPEO(70)was produced independent of cell cycle phases. In addition, its production involved the activation of ATM or DNA-PK, a general signalling pathway in response to DNA double strand breaks. High-performance liquid chromatography analysis indicated that the formation of NPEO intermediates with a short side-chain like NPEO(15) was the cause of the γ-H2AX generation. This study suggests the importance of taking the genotoxicity of photodegraded intermediates into consideration when conducting risk assessments of environmental pollutants.
Assuntos
Histonas/metabolismo , Tensoativos/efeitos da radiação , Tensoativos/toxicidade , Raios Ultravioleta , Biomarcadores/metabolismo , Linhagem Celular Tumoral , Cromatografia Líquida de Alta Pressão , Dano ao DNA/efeitos dos fármacos , Feminino , Citometria de Fluxo , Humanos , Testes de Mutagenicidade/métodos , Fosforilação , Espécies Reativas de Oxigênio/metabolismo , Tensoativos/químicaRESUMO
Adult T-cell leukemia/lymphoma (ATLL) is a mature peripheral T-cell neoplasm caused by human T-cell leukemia virus type I (HTLV-1) infection. Besides the oncogenic property, HTLV-1 causes HTLV-1-associated myelopathy/tropical spastic paraparesis and certain inflammatory diseases via a complex host immune response to latent virus infection. Cardiac involvement of ATLL is rare, with the majority of cases being disclosed in postmortem autopsy in patients with advanced subtypes. We herein report the case of a 64-year-old female patient with indolent chronic ATLL with severe mitral regurgitation. Although the condition of ATLL was stable, dyspnea on exertion gradually progressed over the course of three years and echocardiography revealed marked thickening of the mitral valve. Finally, the patient experienced hemodynamic collapse with atrial fibrillation and underwent surgical valve replacement. The removed mitral valve was grossly edematous and swollen. A histological examination revealed a granulomatous reaction mimicking the active phase of rheumatic valvulitis, with the infiltration of ATLL cells that were immunohistochemically positive for CD3, CD4, FoxP3, HLA-DRα, and CCR4. The postoperative course was uneventful, with the exception that Sjögren's syndrome was noted. The history of rheumatic fever was unclear, and such unique valvular pathology was presumably related to autoimmune mechanisms associated with HTLV-1 infection. Learning objective: We report a case of chronic adult T-cell leukemia/lymphoma (ATLL) with isolated valvular infiltration with a unique histology of granulomatous reaction. Human T-cell leukemia virus type I infection may accelerate autoimmune reactions and cardiac inflammation, irrespective of indolent clinical subtype. Among ATLL cases, possible progression of valvular insufficiency and heart failure in patients with cardiac symptoms should be carefully evaluated.
RESUMO
The protein inhibitor of activated STAT (PIAS) family proteins regulates innate immune responses by controlling transcription induced by Toll-like receptor, RIG-I-like receptor signaling, and JAK/STAT pathways. Here, we show that PIASy negatively regulates type I interferon (IFN) transcription. Virus infection led to enhanced type I IFN induction in PIASy null cells, and conversely PIASy overexpression reduced IFN transcription. A mutation in the LXXLL motif of the SAP domain abolished inhibition of IFN-stimulated gene expression but did not affect virus or Toll-like receptor/RIG-I-like receptor-stimulated IFN transcription, indicating that PIASy employs distinct mechanisms to inhibit virus-induced and IFN-stimulated transcription. SUMO E3 activity was not required for PIASy inhibition of IFN transcription; however, PIASy relied on the SUMO modification mechanism to inhibit IFN transcription, because the activity of the SUMO-interacting motif was required for inhibition, and knockdown of SUMO E2 enzyme UBC9 decreased inhibitory activity of PIASy. Our results demonstrate that PIASy negatively regulates both IFN transcription and IFN-stimulated gene expression through multiple mechanisms utilizing the function of different domains.
Assuntos
Regulação da Expressão Gênica/fisiologia , Interferon gama/biossíntese , Proteínas Inibidoras de STAT Ativados/metabolismo , Transdução de Sinais/fisiologia , Transcrição Gênica/fisiologia , Motivos de Aminoácidos , Animais , Humanos , Interferon gama/genética , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Knockout , Mutação , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Proteínas Inibidoras de STAT Ativados/genética , Estrutura Terciária de Proteína , Receptores de Superfície Celular , Proteína SUMO-1/genética , Proteína SUMO-1/metabolismo , Sumoilação/fisiologia , Enzimas de Conjugação de Ubiquitina/genética , Enzimas de Conjugação de Ubiquitina/metabolismoRESUMO
Heart failure (HF) has been recognized as a hypercoagulable state. However, the natural anticoagulation systems in the failing heart have not been studied. Recent experimental and clinical data have indicated that not only the thrombomodulin (TM)/protein C (PC) pathway but also the protein S (PS)/tissue factor pathway inhibitor (TFPI) system function as potent natural anticoagulants. To investigate the balance between procoagulant and anticoagulant activities in the failing heart, we measured the cardiac expression of tissue factor (TF), type 1 plasminogen activator inhibitor (PAI-1), TM, PC, PS, and TFPI by RT-PCR and/or Western blot analysis in male transgenic (TG) mice with heart-specific overexpression of TNF-α. Both procoagulant (TF and PAI-1) and anticoagulant (PS and TFPI) factors were upregulated in the myocardium of 24-wk-old TG (end-stage HF) but not in that of 4-wk-old TG (early decompensated HF) compared with the wild-type mice. Both factors were also upregulated in the infarcted myocardium at 3 days after coronary ligation in the wild-type mice. The expression of TM was downregulated in the TG heart, and PC was not detected in the hearts. The transcript levels of PS orphan receptors, Mer and Tyro3, but not Axl, were significantly upregulated in the TG heart. Double immunohistochemical staining revealed that myocardial infiltrating CD3-positive T cells may produce PS in the TG myocardium. In conclusion, the PS/TFPI was upregulated in the myocardium of a different etiological model of HF, thus suggesting a role for the PS/TFPI system in the protection of the failing heart under both inflammatory and hypercoagulable states.
Assuntos
Insuficiência Cardíaca/metabolismo , Lipoproteínas/metabolismo , Miocárdio/metabolismo , Proteína S/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Regulação para Cima/fisiologia , Animais , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Transgênicos , Miocárdio/patologia , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Proteína C/metabolismo , RNA Mensageiro/metabolismo , Trombomodulina/metabolismo , Tromboplastina/metabolismo , Fator de Necrose Tumoral alfa/genéticaRESUMO
Nonylphenol polyethoxylates (NPEOs) are non-ionic surfactants widely used for industrial and household purposes. Since biodegraded short chain NPEOs were reported to elicit estrogenic activity in organisms, numerous studies have been carried out to assess the endocrine-disrupting potential of NPEOs; however, the genotoxicity of the compounds is not fully known, let alone the relationship between the genotoxic potential and number of ethylene oxide (EO) units of NPEOs. In this study, we examined the genotoxicity of NPEO(n) having various EO units (n=0, 5, 10, 15, 20, 30, 40 and 70) in a human breast adenocarcinoma cell line, MCF-7, based on the phosphorylation of histone H2AX (γ-H2AX), recently regarded as a sensitive marker for DNA damage. We clarified that NPEOs have the ability to form γ-H2AX via activation of ATM or DNA-PK, a general signaling pathway in response to DSBs, and this ability was strongly dependent on the number of EO units, that is, NPEO(0-15) having smaller numbers of EO units more readily generated γ-H2AX. Flow cytometric analysis revealed that the generation of γ-H2AX was independent of cell cycle phases. Although the mechanism by which the NPEOs generated γ-H2AX was not able to be elucidated in the present study, it was clear that the involvement of reactive oxygen species and apoptotic DNA fragmentation were not causal factors. The generation of γ-H2AX means the formation of DSBs, the worst type of DNA damage. The results indicated that attention should be paid to degradated short chain NPEOs and their genotoxicity.
Assuntos
Apoptose/efeitos dos fármacos , Quebras de DNA de Cadeia Dupla , Etilenoglicóis/toxicidade , Histonas/metabolismo , Mutagênicos/toxicidade , Ciclo Celular , Linhagem Celular Tumoral , Etilenoglicóis/química , Óxido de Etileno , Feminino , Humanos , Fosforilação , Espécies Reativas de OxigênioRESUMO
Background: Ventricular premature complexes (VPCs) occasionally originate from the aortic sinus of Valsalva. Because the anterior part of the left coronary cusp (LCC) and right coronary cusp (RCC) are connected through the ventricular musculature at their bases, VPCs are more common in the LCC and the RCC than in the non-coronary cusp (NCC). We herein report a case in which VPCs were successfully ablated from the NCC, which is considered rare. Case summary: A 30-year-old woman was admitted to our hospital for the ablation of VPCs, which comprised 43% of the total heart beats. The clinical VPCs had an inferior axis and left bundle branch block morphology with a precordial transition between V4 and V5. Three-dimensional mapping of the target VPCs indicated that the earliest activation site was RCC. After radiofrequency (RF) energy application at the RCC, VPCs were temporally suppressed but recurred after 24â min. Remapping of the recurrent VPCs revealed that the earliest activation site shifted from the RCC to the His region. To avoid the risk of atrioventricular block, RF energy was applied from the NCC, which resulted in successful elimination of the VPCs without any complications. Discussion: The present case suggests that RF energy application from the NCC may be a safe and effective option for the ablation of VPCs with the earliest activation at the RCC and His region.