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The development of effective tumor vaccines is an important direction in the field of cancer prevention/immunotherapy. Efficient antigen delivery is essential for inducing effective antitumor responses for tumor vaccines. Lumazine synthase (BLS) from Brucella spp. is a decameric protein with delivery and adjuvant properties, but its application in tumor vaccines is limited. Here, we developed an antigen delivery platform by combining a BLS asymmetric assembly and the Plug-and-Display system of SpyCatcher/SpyTag. An asymmetric assembly system consisting of BLSke and BLSdr was developed to equally assemble two molecules. Then, the MHC-I-restricted ovalbumin peptide (OVA(257-264) SIINFEKL) was conjugated with BLSke, and a cell-penetrating peptide (CPP) KALA was conjugated with BLSdr using the SpyCatcher/SpyTag system. KALA modification enhanced internalization of OVA peptides by DCs as well as promoted the maturation of DCs and the cross-presentation of SIINFEKL. Moreover, the immunotherapy of a KALA-modified vaccine suppressed tumor growth and enhanced CD8+ T cell responses in E.G7-OVA tumor-bearing mice. In the prophylactic model, KALA-modified vaccination showed the most significant protective effect and significantly prolonged the survival period of tumor challenged mice. In conclusion, the asymmetric assembly platform equally assembles two proteins or peptides, avoiding their spatial or functional interference. This asymmetric assembly and Plug-and-Display technology provide a universal platform for rapid development of personalized tumor vaccines.
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Vacunas contra el Cáncer , Péptidos de Penetración Celular , Neoplasias , Animales , Ratones , Vacunas contra el Cáncer/uso terapéutico , Autoantígenos/metabolismo , Linfocitos T CD8-positivos , Adyuvantes Inmunológicos/metabolismo , Antígenos de Histocompatibilidad Clase I/metabolismo , Ovalbúmina , Neoplasias/metabolismo , Péptidos de Penetración Celular/química , Ratones Endogámicos C57BL , Células DendríticasRESUMEN
Vaccination can prevent and control animal brucellosis. Currently, live attenuated vaccines are extensively used to prevent Brucella infection. However, traditional vaccines such as live attenuated vaccines are associated with biological safety risks for both humans and animals. The bacterial ghost (BG) is a new form of vaccine with great prospects. However, bacterial cells cannot be completely inactivated by biological lysis, conferring a safety risk associated with the vaccine. In this study, we developed a Brucella abortus A19 bacterial ghost (A19BG) through a double inactivation strategy with sequential biological lysis and hydrogen peroxide treatment. This strategy resulted in 100% inactivation of Brucella, such that viable bacterial cells were not detected even at an ultrahigh concentration of 1010 colony-forming units/mL. Furthermore, A19BG had a typical BG morphology and good genetic stability. Moreover, it did not induce adverse reactions in guinea pigs. The levels of antibodies, interferon-γ, interleukin-4, and CD4+ T cells in guinea pigs inoculated with the A19BG vaccine were similar to those inoculated with the existing A19 vaccine. Immunization with A19BG conferred a similar level of protection with that of A19 against Brucella melitensis M28 in both guinea pigs and cattle. In conclusion, the combination of biological lysis and H2O2-mediated inactivation is a safe and effective strategy that can serve as a reference for the preparation of BG vaccines.
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Vacuna contra la Brucelosis , Brucella melitensis , Brucelosis , Animales , Anticuerpos Antibacterianos , Brucella abortus , Brucelosis/prevención & control , Bovinos , Cobayas , Peróxido de Hidrógeno , Ratones , Ratones Endogámicos BALB C , VacunaciónRESUMEN
BACKGROUND: Brucella spp. is an important zoonotic pathogen responsible for brucellosis in humans and animals. Brucella abortus A19 strain is a widespread vaccine in China. However, it has a drawback of residual virulence in animals and humans. METHODS: In this study, the BALB/c mice were inoculated with either 100 µL PBS(control group, C group), 109 CFU/mL inactivated B. abortus A19 strain (I group), 105 CFU/mL (low-dose group, L group) 106 CFU/mL live B. abortus A19 strain (high-dose group, H group), or 105 CFU/mL live B. abortus A19 strain combined with 109 CFU/mL inactivated B. abortus A19 strain (LI group). Mice were challenged with B. abortus strain 2308 at 7 week post vaccination. Subsequently, the immune and protective efficacy of the vaccines were evaluated by measuring splenic bacterial burden, spleen weight, serum IgG, interferon-gamma (IFN-γ), interleukin-4 (IL-4) percentage of CD4 + and CD8 + T cells of mice via bacterial isolation, weighing, ELISA and flow cytometry, respectively. RESULTS: The splenic bacterial burden and spleen weight of the mice in group LI were mostly equivalent to the mice of group H. Moreover, Brucella-specific serum IgG, IFN-γ, IL-4, and the percentage of CD4+ and CD8+ T cells of the LI group mice were similar to those of the H group. In the subsequent challenge test, both vaccines conferred protective immunity to wild-type (WT) 2308 strain. In addition, the levels of IL-4 and IFN-γ, CD4+ and CD8+ T cells in these mice were similar to those of the mice in the H group. CONCLUSIONS: Combined immunization with low dose live vaccine and inactivated vaccine allowed to reduce the live B. abortus A19 vaccine, dose with an equivalent protection of the high-dose live vaccine.
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Vacuna contra la Brucelosis , Animales , Linfocitos T CD8-positivos , Inmunización/veterinaria , Ratones , Vacunación/veterinaria , Vacunas de Productos InactivadosRESUMEN
Sympathetic stimulated-cardiac fibrosis imposes great significance on both disease progression and survival in the pathogenesis of many cardiovascular diseases. However, there are few effective therapies targeting it clinically. The cardioprotective effect of aldehyde dehydrogenase 2 (ALDH2) has been explored in many pathological conditions, whether it can exert benefit effects on chronic sympathetic stimulus-induced cardiac fibrosis remains unclear. In this study, we determined to explore the role of ALDH2 on isoproterenol (ISO)-induced cardiac fibroblasts (CF) proliferation and cardiac fibrosis. It was found that ALDH2 enzymatic activity was impaired in ISO-induced HCF proliferation and Aldh2 deficiency promoted mouse CF proliferation. Alda-1, an ALDH2 activator, exerted obvious suppressive effect on ISO-induced HCF proliferation, together with the induction of cell cycle arrest at G0/G1 phase and decreased expression of cyclin E1 and cyclin-dependent kinase 2 (CDK2). Mechanistically, the inhibitory role of Alda-1 on HCF proliferation was achieved by decreasing mitochondrial reactive oxygen species (ROS) production, which was partially reversed by rotenone, an inducer of ROS. In addition, wild-type mice treated with Alda-1 manifested with reduced fibrosis and better cardiac function after ISO pump. In summary, Alda-1 alleviates sympathetic excitation-induced cardiac fibrosis via decreasing mitochondrial ROS accumulation, highlighting ALDH2 activity as a promising drug target of cardiac fibrosis.
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Aldehído Deshidrogenasa Mitocondrial/metabolismo , Cardiomiopatías/patología , Aldehído Deshidrogenasa Mitocondrial/antagonistas & inhibidores , Aldehído Deshidrogenasa Mitocondrial/genética , Animales , Benzamidas/farmacología , Benzodioxoles/farmacología , Cardiomiopatías/inducido químicamente , Cardiomiopatías/enzimología , Cardiotónicos/farmacología , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Electrocardiografía , Fibroblastos/patología , Fibrosis , Ventrículos Cardíacos/patología , Humanos , Isoproterenol/toxicidad , Masculino , Ratones Endogámicos C57BL , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Pathological stimulus-triggered differentiation of cardiac fibroblasts plays a major role in the development of myocardial fibrosis. Aldehyde dehydrogenase 2 (ALDH2) was reported to exert a protective role in cardiovascular disease, and whether ALDH2 is involved in cardiac fibroblast differentiation remains unclear. In this study, we used transforming growth factor-ß1 (TGF-ß1) to induce the differentiation of human cardiac fibroblasts (HCFs) and adopted ALDH2 activator Alda-1 to verify the influence of ALDH2 on HCF differentiation. Results showed that ALDH2 activity was obviously impaired when treating HCFs with TGF-ß1. Activation of ALDH2 with Alda-1 inhibited the transformation of HCFs into myofibroblasts, demonstrated by the decreased smooth muscle actin (α-actin) and periostin expression, reduced HCF-derived myofibroblast proliferation, collagen production, and contractility. Moreover, application of Smad2/3 inhibitor alleviated TGF-ß1-induced HCF differentiation and improved ALDH2 activity, which was reversed by the application of ALDH2 inhibitor daidzin. Finally, Alda-1-induced HCF alterations alleviated neonatal rat cardiomyocyte hypertrophy, supported by the immunostaining of α-actin. To summarize, activation of ALDH2 enzymatic activity inhibited the differentiation of cardiac fibroblasts via the TGF-ß1/Smad signaling pathway, which might be a promising strategy to relieve myocardial fibrosis of various causes.
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Aldehído Deshidrogenasa Mitocondrial/metabolismo , Benzamidas/farmacología , Benzodioxoles/farmacología , Plasticidad de la Célula/efectos de los fármacos , Activadores de Enzimas/farmacología , Ventrículos Cardíacos/efectos de los fármacos , Miofibroblastos/efectos de los fármacos , Proteína Smad2/metabolismo , Proteína smad3/metabolismo , Factor de Crecimiento Transformador beta1/farmacología , Animales , Animales Recién Nacidos , Cardiomegalia/enzimología , Cardiomegalia/patología , Cardiomegalia/prevención & control , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Colágeno/metabolismo , Activación Enzimática , Fibrosis , Ventrículos Cardíacos/enzimología , Ventrículos Cardíacos/patología , Humanos , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/enzimología , Miocitos Cardíacos/patología , Miofibroblastos/enzimología , Miofibroblastos/patología , Comunicación Paracrina , Fenotipo , Fosforilación , Ratas , Transducción de SeñalRESUMEN
Feline herpesvirus type 1 (FHV-1) is a highly contagious pathogen of domestic cats and other members of the family Felidae. Point-of-care diagnosis of persistent infection in cats is essential for control of its spread. A recombinase polymerase amplification (RPA) assay (RPA-LFD-FHV) combined with a lateral flow dipstrip (LFD) was developed that uses human body heat for incubation. Sensitivity was evaluated by testing a serial dilution of a control plasmid, and specificity was evaluated by testing related viruses. Swab samples from cats with suspected infection were tested by RPA-LFD-FHV, and the results were compared to those obtained by PCR to evaluate its clinical performance. The RPA-FLD-FHV assay was carried out successfully within 20 min, using body heat for incubation. The RPA-FLD-FHV had a detection limit of 103 copies of the FHV-1 gD gene, which was lower than that of PCR, which was 104 copies. The assay could detect templates of FHV-1 but not those of other feline and canine viruses. Viruses in boiled samples could be efficiently detected by the RPA-FLD-FHV. Thirty-one out of the 80 samples were positive by the RPA-FLD-FHV assay, whereas only 27 were positive by PCR. DNA sequencing confirmed that the four samples that were positive by RPA-FLD-FHV but negative by PCR were indeed positive. These results indicate that RPA-FLD-FHV is applicable for clinical use. The RPA-FLD-FHV assay is a simple, rapid, and reliable method for point-of-care diagnosis of FHV-1 infection.
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Enfermedades de los Gatos/virología , Herpesviridae/clasificación , Herpesviridae/aislamiento & purificación , Sistemas de Atención de Punto , Animales , Enfermedades de los Gatos/diagnóstico , Gatos , Reacción en Cadena de la Polimerasa/veterinaria , Sensibilidad y Especificidad , VaricellovirusRESUMEN
BACKGROUND: Glaesserella parasuis (G. parasuis) is an influential pathogen of the pig, which induces high morbidity and mortality in naive pig populations in the pig industry. Accurate and rapid detection of the agent is important for disease control. In this study, a simple recombinase polymerase amplification (RPA) with a Lateral flow (LF) strip (RPA-LF-GPS) was developed to detect G. parasuis. RESULTS: The RPA-LF-GPS can specifically detect G. parasuis a limit of 100 CFU from other common related pathogens causing arthritis in the pig. The RPA-LF-GPS assay can use boiled synovial fluid samples as a template with the same sensitivity as other DNA extraction methods. In the detection of clinic positive synovial fluid sample, RPA-LF-GPS is equally sensitive (98.1%) compared with that of PCR (90.4%) (P > 0.05). The whole procedure of the RPA-LF-GPS assay could be finished in 1 hour without professional equipment. CONCLUSIONS: RPA-LF-GPS assay is a rapid and simple method for point-of-care diagnostic testing for G. parasuis infection.
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Infecciones por Haemophilus/veterinaria , Haemophilus parasuis , Recombinasas/metabolismo , Enfermedades de los Porcinos/microbiología , Líquido Sinovial/microbiología , Animales , Infecciones por Haemophilus/microbiología , Técnicas de Amplificación de Ácido Nucleico/veterinaria , Reacción en Cadena de la Polimerasa/veterinaria , Recombinasas/química , Recombinasas/genética , Sensibilidad y Especificidad , Porcinos , Enfermedades de los Porcinos/diagnósticoRESUMEN
BACKGROUND/AIMS: Consumption of a high-fat (HF) diet exacerbates metabolic cardiomyopathy through lipotoxic mechanisms. In this study, we explored the role of aldehyde dehydrogenase-2 (ALDH2) in myocardial damage induced by a HF diet. METHODS: Wild-type C57 BL/6J mice were fed a HF diet or control diet for 16 weeks. ALDH2 overexpression was achieved by injecting a lentiviral ALDH2 expression vector into the left ventricle. RESULTS: Consumption of a HF diet induced metabolic syndrome and myocardial remodeling, and these deleterious effects were attenuated by ALDH2 overexpression. In addition, ALDH2 overexpression attenuated the cellular apoptosis and insulin resistance associated with a HF diet. Mechanistically, ALDH2 overexpression inhibited the expression of c-Jun N-terminal kinase (JNK)-1, activated protein 1 (AP-1), insulin receptor substrate 1 (IRS-1), 4- hydroxynonenal, caspase 3, transforming growth factor ß1, and collagen I and III, and enhanced Akt phosphorylation. CONCLUSION: ALDH2 may effectively attenuate myocardial remodeling and contractile defects induced by a HF diet through the regulation of the JNK/AP-1 and IRS-1/Akt signaling pathways. Our study demonstrates that ALDH2 plays an essential role in protecting cardiac function from lipotoxic cardiomyopathy.
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Aldehído Deshidrogenasa Mitocondrial/metabolismo , Dieta Alta en Grasa , Miocardio/metabolismo , Aldehído Deshidrogenasa Mitocondrial/genética , Animales , Apoptosis , Proteínas Sustrato del Receptor de Insulina/metabolismo , Resistencia a la Insulina , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Potencial de la Membrana Mitocondrial , Síndrome Metabólico/etiología , Ratones , Ratones Endogámicos C57BL , Mitocondrias/metabolismo , Contracción Miocárdica , Miocardio/patología , Estrés Oxidativo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal , Factor de Transcripción AP-1/metabolismo , Remodelación VentricularRESUMEN
Cyclophosphamide (CY) is a widely used chemotherapeutic agent that is associated with severe side effects, such as hepatotoxicity and nephrotoxicity. However, the extent, mechanisms and potential prevention and treatment strategies of CY-induced acute hepatotoxicity and nephrotoxicity are largely unknown. In this study, we determined the existence and extent of CY-induced acute hepatotoxicity and nephrotoxicity, and demonstrated the effect of ALDH2 on CY-induced acute tissue toxicity and related mechanisms. Adult male C57BL/6J (wide-type, WT) and ALDH2-/- (KO) mice were divided into four groups: WT, WT + CY, KO + CY and WT + CY + Alda-1. Biochemical analysis showed that plasma ALT was increased by 35.8% in KO + CY group and decreased by 21.1% in WT + CY + Alda-1 group compared to WT + CY group (P < 0.05, respectively). However, there was no significant difference among WT, WT + CY and KO + CY groups regarding plasma renal marker enzymes, including blood urea nitrogen (BUN), creatinine and cystatin C (CysC). Levels of reactive oxygen species (ROS) and toxic aldehydes (acrolein, 4-hydroxynonenol and malondialdehyde) were increased significantly in KO + CY group and decreased significantly in WT + CY + Alda-1 group compared to WT + CY group (Pâ¯<â¯0.05, respectively). These findings demonstrate that CY could induce acute hepatotoxicity without nephrotoxicity, and ALDH2 plays a protective role in CY-induced acute hepatotoxicity. The underlying mechanisms are associated with attenuating oxidative stress and detoxifying reactive aldehydes.
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Aldehído Deshidrogenasa Mitocondrial/genética , Enfermedad Hepática Inducida por Sustancias y Drogas/genética , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Ciclofosfamida/toxicidad , Riñón/enzimología , Hígado/enzimología , Acroleína/metabolismo , Alanina Transaminasa/sangre , Aldehído Deshidrogenasa Mitocondrial/deficiencia , Aldehídos/metabolismo , Animales , Aspartato Aminotransferasas/sangre , Nitrógeno de la Urea Sanguínea , Enfermedad Hepática Inducida por Sustancias y Drogas/enzimología , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Creatinina/sangre , Cistatina C/sangre , Regulación de la Expresión Génica , Riñón/patología , L-Lactato Deshidrogenasa/sangre , Hígado/patología , Masculino , Malondialdehído/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Estrés Oxidativo , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Visceral adipose tissue-derived serine protease inhibitor (vaspin), as a secretory adipokine, was reported to exert a protective role on insulin resistance. Recent studies showed that serum vaspin level was downregulated in patients with coronary artery disease. However, whether vaspin exerted specific effects on myocardial injury remains unknown. In this study, we determined to explore the role of vaspin overexpression in myocardial ischaemia/reperfusion (I/R) injury and the underlying mechanisms. Our results showed that the systemic delivery of adeno-associated virus-vaspin to mice reduced myocardial infarct size and apoptosis, and improved cardiac function after reperfusion, accompanied with upregulated autophagic flux and restored lysosomal function in the ischaemic heart. Blockage of the autophagic flux with choroquine mitigated the protection of vaspin on myocardial I/R injury. Moreover, we testified that administration of exogenous recombinant human vaspin on cultured cardiomyocytes suppressed hypoxia/reoxygenation-induced apoptosis, through the AMPK-mTOR-upregulated autophagic flux. Overall, we verified that vaspin functions as an adipokine which can alleviate I/R injury in the heart by suppressing myocardial apoptosis through AMPK-mTOR-dependent activation of autophagic flux, and then provided a potential breakthrough in the treatment of myocardial I/R injury and other ischaemic diseases.
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Adipoquinas/genética , Autofagia , Vectores Genéticos/uso terapéutico , Daño por Reperfusión Miocárdica/genética , Daño por Reperfusión Miocárdica/terapia , Serpinas/genética , Regulación hacia Arriba , Adipoquinas/metabolismo , Animales , Apoptosis , Línea Celular , Técnicas de Transferencia de Gen , Terapia Genética , Vectores Genéticos/genética , Humanos , Lisosomas/genética , Lisosomas/metabolismo , Lisosomas/patología , Masculino , Ratones Endogámicos C57BL , Daño por Reperfusión Miocárdica/metabolismo , Daño por Reperfusión Miocárdica/patología , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Ratas , Proteínas Recombinantes/farmacología , Serpinas/metabolismo , Serpinas/farmacología , Transducción de SeñalRESUMEN
OBJECTIVE: To explore the effect of peptide extract from scorpion venom (PESV) to multidrug resistance (MDR) of leukemic stem cell (LSC) in vivo. METHODS: K562/A02 cells were cultured and collected in the logarithmic phase. K562/A02 stem cells were screened using immunomagnetic beads for reserve. K562/A02 LSC was injected to 5 of 40 BABL/c nude mice for preparing subcutaneous tumor. The rest 35 nude mice were then randomly divided into 7 groups, i.e., the normal control group, the model group, the Adriamycin (ADM) group, the PESV group, the ADM +high dose PESV group, the ADM + middle dose PESV group, the ADM +low dose PESV group, 5 in each group. Tumor tissue was embedded in all groups except the normal control group. One milliliter normal saline was peritoneally injected to mice in the model group after modeling, once per day. ADM 0. 05 mg was peritoneally injected to mice in the ADM group, once per other day. PESV 2 µg was peritoneally injected to mice in the PESV group, once per day. Mice in 3 ADM + PESV groups were peritoneally injected with ADM 0. 05 mg (once per other day) plus PESV (5, 2, and 1 µg respectively, once per day). All medication lasted for 14 days. P-glycoprotein (P-gp) was detected using flow cytometry. Breast cancer resistance protein (BCRP) and mRNA expression of multidrug resistance 1 (MDR1) were measured using RT-PCR. Aldehyde dehydrogenase 1 (ALDH1) was detected using immunohistochemistry. Phosphoinositide 3-kinase (PI3K) was detected using Western blot. NF-κB content was detected using ELISA. RESULTS: CD34 + CD38-ratio was 31.5% and IC50 was (60.33 ± 10. 68) µg/mL before K562/A02 cells were screened with immunomagnetic beads, while they were 92. 8% and (58. 33 ±9. 72) µg/mL after screen. The tumor formation rate was 100% in modeling mice. Compared with the model group, no statistical difference of each index occurred in the ADM group (P <0. 05). There was statistical difference in BCRP, MDR1 mRNA, or NF-κB factor between the model group and the PESV group (P <0. 05). The expression level of P-gp obviously decreased and the protein expression of P13K was down-regulated in 3 ADM + PESV groups (P <0. 05); mRNA expression of BCRP decreased and mRNA ex- pression of MDR1 obviously increased in the ADM + high dose PESV group and the ADM + middle dose PESV group, with statistical difference (P <0. 05). Protein expression of P13K was down-regulated in the ADM+ high dose PESV group, with statistical difference (P <0. 05). P-gp value, BCRP mRNA expression, MDR1 mRNA expression, PI3K, and NF-κB factor were all obviously down-regulated in the ADM +high dose PESV group, as compared with the ADM group and the PESV group respectively (P <0. 05). There was no statistical difference in ALDH1 positive rate among all groups (P >0. 05). Conclusion PESV combined ADM could down-regulate expression levels of P-gp, BCRP, MDR1, P13K, and NF-κB, strengthen the sensitivity of K562/A02 LSC to ADM in vivo, and reverse MDR of LSC.
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Resistencia a Múltiples Medicamentos , Resistencia a Antineoplásicos , Leucemia Eritroblástica Aguda , Venenos de Escorpión , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Animales , Doxorrubicina , Humanos , Células K562 , Leucemia Eritroblástica Aguda/patología , Ratones , Ratones Desnudos , Péptidos , Fosfatidilinositol 3-Quinasas , Venenos de Escorpión/farmacología , Células MadreRESUMEN
Although hyperglycemia is common in patients with acute myocardial infarction (MI), the underlying mechanisms are largely unknown. Insulin signaling plays a key role in the regulation of glucose homeostasis. In this study, we test the hypothesis that rapid alteration of insulin signaling pathways could be a potential contributor to acute hyperglycemia after MI. Male rats were used to produce MI by ligation of the left anterior descending coronary artery. Plasma glucose and insulin levels were significantly higher in MI rats than those in controls. Insulin-stimulated tyrosine phosphorylation of insulin receptor substrate 1 (IRS1) was reduced significantly in the liver tissue of MI rats compared with controls, followed by decreased attachment of phosphatidylinositol 3-kinase (PI3K) p85 subunit with IRS1 and Akt phosphorylation. However, insulin-stimulated signaling was not altered significantly in skeletal muscle after MI. The relative mRNA levels of phosphoenolpyruvate carboxykinase (PEPCK) and G6Pase were slightly higher in the liver tissue of MI rats than those in controls. Rosiglitazone (ROSI) markedly restored hepatic insulin signaling, inhibited gluconeogenesis and reduced plasma glucose levels in MI rats. Insulin resistance develops rapidly in liver but not skeletal muscle after MI, which contributes to acute hyperglycemia. Therapy aimed at potentiating hepatic insulin signaling may be beneficial for MI-induced hyperglycemia.
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Hiperglucemia/etiología , Hiperglucemia/metabolismo , Resistencia a la Insulina , Hígado/metabolismo , Infarto del Miocardio/complicaciones , Animales , Glucemia/efectos de los fármacos , Gluconeogénesis , Insulina/sangre , Insulina/metabolismo , Masculino , Músculo Esquelético/metabolismo , Infarto del Miocardio/patología , Ratas , Receptor de Insulina/metabolismo , Rosiglitazona , Transducción de Señal , Tiazolidinedionas/farmacología , Factor de Necrosis Tumoral alfa/sangreRESUMEN
Objectives: Aplastic anemia (AA) is one of the immune-mediated bone marrow failure disorders caused by multiple factors, including the inability of CD4 + CD25 + regulatory T cells (Tregs) to negatively regulate cytotoxic T lymphocytes (CTLs). Dioscin is a natural steroid saponin that has a similar structure to steroid hormones. The purpose of this study is to look into the effect of Dioscin on the functions of CD4 + CD25+ Tregs in the AA mouse model and explore its underlying mechanism.Methods: To begin with, bone marrow failure was induced through total body irradiation and allogeneic lymphocyte infusion using male Balb/c mice. After 14 consecutive days of Dioscin orally administrated, the AA mouse model was tested for complete blood counts, HE Staining of the femur, Foxp3, IL-10 and TGF-ß. Then CD4 + CD25+ Tregs were isolated from splenic lymphocytes of the AA mouse model, Tregs and the biomarkers and cytokines of Tregs were measured after 24 h of Dioscin intervention treatment in vitro.Results: Dioscin promotes the expression of Foxp3, IL-10, IL-35 and TGF-ß, indicating its Tregs-promoting properties. Mechanistically, the administration of Dioscin resulted in the alteration of CD152, CD357, Perforin and CD73 on the surface of Tregs, and restored the expression of Foxp3.Conclusion: Dioscin markedly attenuated bone marrow failure, and promoted Tregs differentiation, suggesting the maintenance of theimmune balance effect of Dioscin. Dioscin attenuates pancytopenia and bone marrow failure via its Tregs promotion properties.
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Anemia Aplásica , Diosgenina , Diosgenina/análogos & derivados , Animales , Ratones , Masculino , Humanos , Linfocitos T Reguladores , Interleucina-10/metabolismo , Interleucina-10/farmacología , Diosgenina/farmacología , Diosgenina/uso terapéutico , Diosgenina/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Factor de Crecimiento Transformador beta/farmacología , Factores de Transcripción ForkheadRESUMEN
Macroautophagy, the mainly regulated form of autophagy, maintains the cellular homeostasis and degrades the transported cargoes. It is initiated by the protein kinase complex regulating by two signals pathway Mammalian target of rapamycin complex 1 (mTORC1)-Adenosine 5' monophosphate activated protein kinase (AMPK)-Unc 51 like kinase 1(ULK1) and ULK1-PI3K- phosphatidylinositol 3-phosphate (PI3P). Currently, autolysosomes are accumulated during the aging process of CD8+T cells in vitro and may participate in inducing death sensitization of senescent cells. The main mechanism of aplastic anemia, a hyperimmune disease, is the T cells subsets imbalance such as CD8+T cells abnormal activation and hyperfunction. Therefore, the role of autophagy in the CD8+T cells and supposed whether some immunosuppress drugs induced the cells autophagic death to treat the hyperimmune diseases were focused. It was decided found that the acetyltransferase p300 obviously increased in the aplastic anemia patients and was related with the severity of disease. Previous studies have reported that canonical autophagy is regulated by the mTORC1-p300 axis. p300 is a critical bridge in the p300-VPS34 axis mediated non-canonical autophagy. There is the deficiency of autophagy and acetylation in the CD8+T cells. The expression of p300 also decreased notably after the immunosuppressive drugs therapy. Our findings provide a framework for understanding how immunosuppressive drugs effect on the AA autophagy deficiency mechanism and proved that immunosuppressive drugs negatively regulated the function of CD8+T cells by p300-mediated canonical autophagy pathway and non-canonical autophagy pathway.
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Cardiac arrest is a leading cause of death globally. Only 25.8% of in-hospital and 33.5% of out-of-hospital individuals who achieve spontaneous circulation following cardiac arrest survive to leave the hospital. Respiratory failure and acute coronary syndrome are the two most common etiologies of cardiac arrest. Effort has been made to improve the outcomes of individuals resuscitated from cardiac arrest. Magnesium is an ion that is critical to the function of all cells and organs. It is often overlooked in everyday clinical practice. At present, there have only been a small number of reviews discussing the role of magnesium in cardiac arrest. In this review, for the first time, we provide a comprehensive overview of magnesium research in cardiac arrest focusing on the effects of magnesium on the occurrence and prognosis of cardiac arrest, as well as in the two main diseases causing cardiac arrest, respiratory failure and acute coronary syndrome. The current findings support the view that magnesium disorder is associated with increased risk of cardiac arrest as well as respiratory failure and acute coronary syndrome.
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In this study, we evaluated the effectiveness and safety of bisoprolol, metoprolol, carvedilol, and nebivolol in the treatment of chronic heart failure. The results demonstrated that bisoprolol improved the prognosis of chronic heart failure in comparison with carvedilol, and carvedilol exerted similar effects as metoprolol succinate and nebivolol and better effect than metoprolol tartrate (evidence levels: bisoprolol > carvedilol = metoprolol succinate = nebivolol > metoprolol tartrate; " > " means "prior to").
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Postmenopausal osteoporosis is one of the most prevalent skeletal disorders in women and is featured by the imbalance between intraosseous vascularization and bone metabolism. In this study, a pH-responsive shell-core structured micro/nano-hydrogel microspheres loaded with polyhedral oligomeric silsesquioxane (POSS) using gas microfluidics and ionic cross-linking technology are developed. This micro/nano-hydrogel microsphere system (PDAP@Alg/Cs) can achieve oral delivery, intragastric protection, intestinal slow/controlled release, active targeting to bone tissue, and thus negatively affecting intraosseous angiogenesis and osteoclastogenesis. According to biodistribution data, PDAP@Alg/Cs can successfully enhance drug intestinal absorption and bioavailability through intestine adhesion and bone targeting after oral administration. In vitro and in vivo experiments reveal that PDAP@Alg/Cs promoted type H vessel formation and inhibited bone resorption, effectively mitigating bone loss by activating HIF-1α/VEGF signaling pathway and promoting heme oxygenase-1 (HO-1) expression. In conclusion, this novel oral micro/nano-hydrogel microsphere system can simultaneously accelerate intraosseous vascularization and decrease bone resorption, offering a brand-new approach to prevent postmenopausal osteoporosis.
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Resorción Ósea , Osteoporosis Posmenopáusica , Femenino , Humanos , Hidrogeles , Microesferas , Distribución Tisular , HuesosRESUMEN
Purpose: The prevalence of benign prostatic hyperplasia (BPH) in the general Chinese adult male population has risen sharply over the past few decades. Increasing evidence suggests that inflammation plays an important role in the pathogenesis of BPH. To better understand the role of inflammation in the pathogenesis of BPH, we can use the neutrophil-to-lymphocyte ratio (NLR) because it is a simple and effective marker of inflammation and immunity. This study aims to prospectively investigate the association between NLR levels and the prevalence of BPH in a general Chinese adult male population. Patients and Methods: This study included a total of 15,783 male participants free from BPH at baseline. NLR was measured according to the complete blood count. BPH was defined as total prostate volume (TPV) ≥30 mL, and TPV was determined by transabdominal ultrasonography. Multivariable Cox proportional hazards models were fitted to calculate hazards ratios (HRs) and corresponding 95% confidence intervals (CIs) for BPH risk with NLR levels. Results: During a median follow-up of 2.7 years, 5078 BPH cases were documented. After adjusting for age, body mass index, smoking, alcohol, education, occupation, income, physical activity, total energy intake, personal and family history of disease, and inflammation markers, the multivariable-adjusted HRs of BPH were 1.00 (reference), 1.08 (95% CIs 0.99, 1.17), 1.10 (95% CIs1.02, 1.19), and 1.12 (95% CIs1.03, 1.21), respectively, for participants with NLR in the first, second, third, and fourth quartiles (P for trend <0.01). Conclusion: Higher NLR levels were associated with a higher risk of BPH in Chinese adult male population. Our findings support the notion that NLR levels may be an important target for BPH prevention and intervention.
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Purpose: This study aimed to prospectively investigate the association between mean platelet volume (MPV) levels and risk of benign prostatic hyperplasia (BPH) in a general Chinese adult male population, and assessed this association in metabolic syndrome (MetS) patients. Patients and methods: This study included a total of 14,923 male participants free from BPH at baseline. MPV was measured by the method of laser-based flow cytometric impedance according to the complete blood sample. BPH was defined as total prostate volume (TPV) ≥ 30 mL, TPV was determined by transabdominal ultrasonography. Multivariable Cox proportional hazards models were fitted to calculate hazards ratios (HRs) and corresponding 95% confidence intervals (CIs) for BPH risk with NLR levels. Results: During a median follow-up of 2.7 years, 4848 BPH cases were documented in total male participants, and 1787 BPH cases were documented in MetS participants. After adjusting for age, body mass index, smoking, alcohol and personal and family history of disease, the multivariable-adjusted HRs of BPH were 1.00 (reference), 1.03 (95% CIs 0.96, 1.11), 1.00 (95% CIs 0.92, 1.08) and 0.98 (95% CIs 0.90, 1.06), respectively, for participants with MPV in the 1st, 2nd, 3rd and 4th quartiles (P for trend = 0.47). In MetS patients, the multivariable-adjusted HRs of BPH were 1.00 (reference), 1.03 (95% CIs 0.90, 1.16), 0.99 (95% CIs 0.87, 1.14) and 1.01 (95% CIs 0.89, 1.15) (P for trend= 0.98), respectively. Conclusion: A non-significant association was observed between MPV levels and risk of BPH, and no association in this association in MetS patients. Our findings support the notion that MPV levels may not be a target for BPH prevention and intervention.
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Heart failure (HF) is one of the leading causes of morbidity and mortality worldwide. Sacubitril/valsartan, an angiotensin receptor-neprilysin inhibitor, has been approved for the treatment of HF. At present, there have been few systematic and detailed reviews discussing the efficacy and safety of sacubitril/valsartan in HF. In this review, we first introduced the pharmacological mechanisms of sacubitril/valsartan, including the reduction in the degradation of natriuretic peptides in the natriuretic peptide system and inhibition of the renin-angiotensin system. Then, we summarized the efficacy of sacubitril/valsartan in HF patients with reduced ejection fraction (HFrEF) or preserved ejection fraction (HFpEF) including the reduction in risks of mortality and hospitalization, reversal of cardiac remodeling, regulation of biomarkers of HF, improvement of the quality of life, antiarrhythmia, improving renal dysfunction and regulation of metabolism. Finally, we discussed the safety and tolerability of sacubitril/valsartan in the treatment of HFrEF or HFpEF. Compared with ACEIs/ARBs or placebo, sacubitril/valsartan showed good safety and tolerability, although the risk of hypotension might be high. In conclusion, the overwhelming majority of studies show that sacubitril/valsartan is effective and safe in the treatment of HFrEF patients but that it has little benefit in HFpEF patients. Sacubitril/valsartan will probably be a promising anti-HF drug in the near future.