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BACKGROUND: Sepsis-associated encephalopathy (SAE) is a common and severe complication of sepsis. While several studies have reported the proteomic alteration in plasma, urine, heart, etc. of sepsis, few research focused on the brain tissue. This study aims at discovering the differentially abundant proteins in the brains of septic rats to identify biomarkers of SAE. METHODS: The Prague-Dawley rats were randomly divided into sepsis (n = 6) or sham (n = 6) groups, and then the whole brain tissue was dissected at 24 h after surgery for further protein identification by Quantitative iTRAQ LC-MS/MS Proteomics. Ingenuity pathway analysis, Gene ontology knowledgebase, and STRING database are used to explore the biological significance of proteins with altered concentration. RESULTS: Among the total of 3163 proteins identified in the brain tissue, 57 were increased while 38 were decreased in the sepsis group compared to the sham group. Bioinformatic analyses suggest that the differentially abundant proteins are highly related to cellular microtubule metabolism, energy production, nucleic acid metabolism, neurological disease, etc. Additionally, acute phase response signaling was possibly activated and PI3K/AKT signaling was suppressed during sepsis. An interaction network established by IPA revealed that Akt1, Gc-globulin, and ApoA1 were the core proteins. The increase of Gc-globulin and the decrease of Akt1 and ApoA1 were confirmed by Western blot. CONCLUSION: Based on the multifunction of these proteins in several brain diseases, we first propose that Gc-globulin, ApoA1, PI3K/AKT pathway, and acute phase response proteins (hemopexin and cluster of alpha-2-macroglobulin) could be potential candidates for the diagnosis and treatment of SAE. These results may provide new insights into the pathologic mechanism of SAE, yet further research is required to explore the functional implications and clinical applications of the differentially abundant proteins in the brains of sepsis group.
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Globulinas , Proteómica , Encefalopatía Asociada a la Sepsis , Animales , Ratas , Reacción de Fase Aguda/metabolismo , Biomarcadores/metabolismo , Cromatografía Liquida , Fosfatidilinositol 3-Quinasas/metabolismo , Proteómica/métodos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Sepsis/complicaciones , Encefalopatía Asociada a la Sepsis/diagnóstico , Encefalopatía Asociada a la Sepsis/metabolismo , Espectrometría de Masas en TándemRESUMEN
Intracerebral hemorrhage (ICH) is a devastating subtype of stroke characterized by high mortality and morbidity rates with no effective treatment. TGF-ß/ALK-5 signaling is reported to participated in the regulation of blood-brain barrier (BBB) integrity in the inflammation pain model, the effects of transforming growth factor (TGF)-ß1 and the potential mechanisms on BBB after ICH have not been fully elucidated. Herein, we have demonstrated that peripheral administration of TGF-ß1 reduces brain edema and ameliorated BBB injury after ICH. Consistent with previous results, TGF-ß1 is shown to promote activation of anti-inflammatory microglia and reduce the inflammatory response after ICH. Furthermore, TGF-ß1 administration improves long-term outcomes after ICH. Our data suggest that TGF-ß1 may be a promising therapeutic agent for ICH.
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Edema Encefálico , Accidente Cerebrovascular , Ratones , Animales , Barrera Hematoencefálica/metabolismo , Factor de Crecimiento Transformador beta1/metabolismo , Hemorragia Cerebral/tratamiento farmacológico , Hemorragia Cerebral/metabolismo , Transducción de Señal , Accidente Cerebrovascular/metabolismo , Edema Encefálico/tratamiento farmacológico , Edema Encefálico/metabolismoRESUMEN
BACKGROUND: Neuroinflammation is a crucial factor in the development of secondary brain injury after intracerebral hemorrhage (ICH). Irisin is a newly identified myokine that confers strong neuroprotective effects in experimental ischemic stroke. However, whether this myokine can exert neuroprotection effects after ICH remains unknown. This study aimed to investigate the impact of irisin treatment on neuroinflammation and neuronal apoptosis and the underlying mechanism involving integrin αVß5/AMPK pathway after ICH. METHODS: Two hundred and eighty-five adult (8-week-old) male C57BL/6 mice were randomly assigned to sham and ICH surgery groups. ICH was induced via intrastriatal injection of autologous blood. Irisin was administered intranasally at 30 min after ICH. To elucidate the underlying mechanism, cilengitide (a selective integrin αVß5 inhibitor) and dorsomorphin (a selective phosphorylated AMPK inhibitor) were administered before irisin treatment. The short- and long-term neurobehavior tests, brain edema, quantitative-PCR, western blotting, Fluoro-Jade C, TUNEL, and immunofluorescence staining were performed to assess the neurofunctional outcome at the level of molecular, cell, histology, and function. RESULTS: Endogenous irisin and its receptor, integrin αVß5, were increased, peaked at 24 h after ICH. irisin post-treatment improved both short- and long-term neurological functions, reduced brain edema after ICH. Interestingly, integrin αVß5 was mainly located in the microglia after ICH, and irisin post-treatment inhibited microglia/macrophage pro-inflammatory polarization and promoted anti-inflammatory polarization. Moreover, irisin treatment inhibited neutrophil infiltration and suppressed neuronal apoptotic cell death in perihematomal areas after ICH. Mechanistically, irisin post-treatment significantly increased the expression of integrin αVß5, p-AMPK and Bcl-2, and decreased the expression of IL-1ß, TNF-α, MPO, and Bax following ICH. The neuroprotective effects of irisin were abolished by both integrin αVß5 inhibitor cilengitide and AMPK inhibitor dorsomorphin. CONCLUSIONS: This study demonstrated that irisin post-treatment ameliorated neurological deficits, reduced brain edema, and ameliorated neuroinflammation and neuronal apoptosis, at least in part, through the integrin αVß5/AMPK signaling pathway after ICH. Thus, irisin post-treatment may provide a promising therapeutic approach for the early management of ICH.
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Hemorragia Cerebral , Fibronectinas , Enfermedades Neuroinflamatorias , Fármacos Neuroprotectores , Transducción de Señal , Proteínas Quinasas Activadas por AMP/metabolismo , Animales , Apoptosis , Edema Encefálico/tratamiento farmacológico , Edema Encefálico/etiología , Hemorragia Cerebral/complicaciones , Hemorragia Cerebral/tratamiento farmacológico , Hemorragia Cerebral/patología , Fibronectinas/farmacología , Masculino , Ratones , Ratones Endogámicos C57BL , Fármacos Neuroprotectores/farmacología , Receptores de Vitronectina/metabolismoRESUMEN
Disorders mainly caused by ischemia-reperfusion (I/R), including stroke and myocardial infarction, is linked to debilitating health conditions and death. Recent research indicates that microRNAs (miRNAs) mediate the process of ischemic pathology. This study investigated the effects of miR-145-5p in regulating myocardial ischemic injury. The I/R models were established in rat cardiomyocytes H9C2 and rats. Western blot analysis and quantitative polymerase chain reaction was performed to analyze protein expression. Annexin V-FITC/PI staining was conducted to evaluate cell apoptosis. The application of miR-145-5p mimics and inhibitor revealed that miR-145-5p promoted apoptosis in cardiomyocytes. Furthermore, we found that miR-145-5p directly inhibited dual specificity phosphatase 6 (DUSP6) by luciferase reporter assay. The results indicated that DUSP6 was beneficial against I/R injury through inhibiting c-Jun N-terminal kinase pathways. In conclusion, the essential roles of miR-145-5p and DUSP6 in I/R provide a novel therapeutic target to develop future intervention strategies.
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BACKGROUND: Invasive aspergillosis is a complication in immunocompromised patients and commonly detected in patients with hematological malignancies, which mostly affect the lungs. Because of its high iodine content, rich blood supply and capsule, the thyroid is considered to be less prone to microbial invasion thus most infectious thyroiditis cases are caused by bacteria. However, a few case reports have described thyroid gland aspergilloses, most of which were due to disseminated invasive aspergillosis. CASE PRESENTATION: We first report a case of thyroid gland and subcutaneous labium majus aspergillosis in a Chinese patient who received long-term glucocorticoid treatment for systemic lupus erythematosus (SLE) and lupus nephritis, and then we reviewed 36 articles describing similar aspergillus infections in 41 patients. CONCLUSION: We included 29 cases of diagnosed aspergillus thyroiditis and analyzed clinical findings, treatments and outcomes to provide clinical information for diagnosis and prognosis of thyroiditis caused by Aspergillus fumigatus.
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Absceso/diagnóstico , Aspergilosis/diagnóstico , Aspergillus fumigatus/aislamiento & purificación , Dermatomicosis/diagnóstico , Perineo/microbiología , Tiroiditis Supurativa/diagnóstico , Absceso/tratamiento farmacológico , Absceso/microbiología , Antifúngicos/uso terapéutico , Aspergilosis/complicaciones , Aspergilosis/tratamiento farmacológico , Dermatomicosis/complicaciones , Dermatomicosis/tratamiento farmacológico , Dermatomicosis/microbiología , Femenino , Humanos , Huésped Inmunocomprometido , Infecciones Fúngicas Invasoras/complicaciones , Infecciones Fúngicas Invasoras/diagnóstico , Infecciones Fúngicas Invasoras/tratamiento farmacológico , Lupus Eritematoso Sistémico/complicaciones , Lupus Eritematoso Sistémico/tratamiento farmacológico , Lupus Eritematoso Sistémico/microbiología , Persona de Mediana Edad , Perineo/patología , Succión , Tiroiditis Supurativa/tratamiento farmacológico , Tiroiditis Supurativa/microbiología , Tiroiditis Supurativa/cirugía , Voriconazol/uso terapéuticoRESUMEN
Gastrointestinal stromal tumor (GIST) is the most common mesenchymal original tumor in gastrointestinal (GI) tract and is considered to have varying malignant potential. With the advancement of computer science, radiomics technology and deep learning had been applied in medical researches. It's vital to construct a more accurate and reliable multimodal predictive model for recurrence-free survival (RFS) aiding for clinical decision-making. A total of 254 patients underwent surgery and pathologically diagnosed with GIST in The First Hospital of China Medical University from 2019 to 2022 were included in the study. Preoperative contrast enhanced computerized tomography (CE-CT) and hematoxylin/eosin (H&E) stained whole slide images (WSI) were acquired for analysis. In the present study, we constructed a sum of 11 models while the multimodal model (average C-index of 0.917 on validation set in 10-fold cross validation) performed the best on external validation cohort with an average C-index of 0.864. The multimodal model also reached statistical significance when validated in the external validation cohort (n = 42) with a p-value of 0.0088 which pertained to the recurrence-free survival (RFS) comparison between the high and low groups using the optimal threshold on the predictive score. We also explored the biological significance of radiomics and pathomics features by visualization and quantitative analysis. In the present study, we constructed a multimodal model predicting RFS of GIST which was prior over unimodal models. We also proposed hypothesis on the correlation between morphology of tumor cell and prognosis.
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Sepsis is a leading cause of intensive care unit admission and death worldwide. Most surviving patients show acute or chronic mental disorders, which are known as sepsis-associated encephalopathy (SAE). Although accumulating studies in the past two decades focused on the pathogenesis of SAE, a systematic review of retrospective studies which exclusively focuses on the inflammatory mechanisms of SAE has been lacking yet. This review summarizes the recent advance in the field of neuroinflammation and sheds light on the activation of microglia in SAE. Activation of microglia predominates neuroinflammation. As the gene expression profile changes, microglia show heterogeneous characterizations throughout all stages of SAE. Here, we summarize the systemic inflammation following sepsis and also the relationship of microglial diversity and neuroinflammation. Moreover, a collection of neuroinflammation-related dysfunction has also been reviewed to illustrate the possible mechanisms for SAE. In addition, promising pharmacological or non-pharmacological therapeutic strategies, especially those which target neuroinflammation or microglia, are also concluded in the final part of this review. Collectively, clarification of the vital relationship between neuroinflammation and SAE-related mental disorders would significantly improve our understanding of the pathophysiological mechanisms in SAE and therefore provide potential targets for therapies of SAE aimed at inhibiting neuroinflammation.
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Lesiones Encefálicas , Encefalopatía Asociada a la Sepsis , Sepsis , Humanos , Microglía/metabolismo , Enfermedades Neuroinflamatorias , Estudios Retrospectivos , Sepsis/metabolismo , Encefalopatía Asociada a la Sepsis/metabolismo , Lesiones Encefálicas/metabolismoRESUMEN
Diabetes mellitus (DM) is a chronic metabolic disorder characterized by hyperglycemia resulting from insulin secretion defects or insulin resistance. The global incidence of DM has been gradually increasing due to improvements in living standards and changes in dietary habits, making it a major non-communicable disease that poses a significant threat to human health and life. The pathogenesis of DM remains incompletely understood till now, and current pharmacotherapeutic interventions are largely inadequate, resulting in relapses and severe adverse reactions. Although DM is not explicitly mentioned in traditional Chinese medicine (TCM) theory and clinical practice, it is often classified as "Xiaoke" due to similarities in etiology, pathogenesis, and symptoms. With its overall regulation, multiple targets, and personalized medication approach, TCM treatment can effectively alleviate the clinical manifestations of DM and prevent or treat its complications. Furthermore, TCM exhibits desirable therapeutic effects with minimal side effects and a favorable safety profile. This paper provides a comprehensive comparison and contrast of Xiaoke and DM by examining the involvement of TCM in their etiology, pathogenesis, treatment guidelines, and other relevant aspects based on classical literature and research reports. The current TCM experimental research on the treatment of DM by lowering blood glucose levels also be generalized. This innovative focus not only illuminates the role of TCM in DM treatment, but also underscores the potential of TCM in DM management.
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BACKGROUND: Male genitourinary abscess is one of the serious complications of urinary tract infections (UTIs). There were few researches on the clinical and pathogenic characteristics of male genitourinary abscess. PATIENTS AND METHODS: A retrospective observational study was conducted between January 2004 and April 2019. Male patients with genitourinary abscess originated from urinary tract, including sites of scrotum, testis, epididymis, spermatic cord, and prostate, were enrolled. Clinical and microbial records were collected and analyzed, and antimicrobial susceptibility testings were performed according to CLSI standard. Whole-genome sequencing was applied to detect the ß-lactamase genes and virulence genes, as well as to determine the multilocus-sequence typing (MLST) of the collected Klebsiella pneumoniae (K. pneumoniae) isolates. RESULTS: A total of 22 male patients were included. The main clinical symptoms were fever (86.4%), scrotal swelling (68.2%), local skin warmth (59.1%) and ulceration (45.5%). Urinary irritation was often presented in prostate involved abscess. Ultrasound features had a 94.7% positive rate. Surgical treatment, including abscess drainage, was helpful to the prognosis. No matter where the specimens obtained from, including blood, urine or pus, multidrug-resistant K. pneumoniae was the dominant (11 cases, 50.0%) microorganism in positive cultures. Nine of eleven K. pneumoniae isolates had been preserved and recovered. As for MLST typing, all the nine available isolates of K. pneumoniae belonged to the ST11 type and characterized with bla KPC-2 carbapenemase gene. Virulence genes rmpA2, ybtS, kfuC, wzi, aerobactin genes (iucABCD and iutA) and type 3 fimbriae genes (mrkAD) were identified in all the K. pneumoniae isolates. CONCLUSION: It seemed that more patients under 35 years old were vulnerable to genitourinary abscess. There was an increasing trend that multidrug-resistant K. pneumoniae isolates with multiple virulence genes were involved in male genitourinary abscess. Prompt and proper antibiotic use, combined with adequate drainage of the abscess, was important to prognosis.
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Clinical studies have shown that dexmedetomidine (DEX) reduces mortality and inflammation in patients with sepsis, and ameliorates cognitive decline in both postoperative and critical care patients. This study aims to explain the neuroprotective effects provided by DEX in mice with cecal ligation and puncture (CLP)-induced polymicrobial sepsis. Mice were treated with DEX intraperitoneally three times every two hours after CLP. The survival rate, body weight, and clinical scores were recorded each day. Morris water maze (MWM) and fear conditioning tests were used to evaluate cognitive function. Blood brain barrier (BBB) permeability, hippocampal inflammation, hippocampal neural apoptosis, and T helper (Th) cell subgroups were assessed. Furthermore, Atipamezole was used to verify that the potential neuroprotective effects in the sepsis-associated encephalopathy (SAE) were mediated by DEX. Compared with the Sham group, CLP mice showed significant cognitive impairment, BBB interruption, excessive neuroinflammation, and neuronal apoptosis. These detrimental effects of CLP were attenuated by DEX. Furthermore, we found that DEX corrects peripheral Th1/Th2/Th17 shift and reduces proinflammatory cytokines in the hippocampus. Additionally, atipamezole prevented DEX's protective effect. Taken together, DEX alleviates cognitive impairments by reducing blood-brain barrier interruption and neuroinflammation by regulating Th1/Th2/Th17 polarization.
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Barrera Hematoencefálica/metabolismo , Animales , Ciego/metabolismo , Disfunción Cognitiva/tratamiento farmacológico , Citocinas/metabolismo , Dexmedetomidina/uso terapéutico , Hipocampo/efectos de los fármacos , Inflamación/tratamiento farmacológico , Masculino , Ratones , Enfermedades Neuroinflamatorias , Fármacos Neuroprotectores/uso terapéutico , Sepsis/tratamiento farmacológico , Células Th17/metabolismoRESUMEN
BACKGROUND: Albumin has been regarded as a potent antioxidant with free radical scavenging activities. Oxidative stress and neuronal apoptosis are responsible for its highly damaging effects on brain injury after intracerebral hemorrhage (ICH). Here, the present study investigated the neuroprotective effect of albumin against early brain injury after ICH and the potential underlying mechanisms. METHODS: Adult male Sprague-Dawley rats were subjected to intrastriatal injection of autologous blood to induce ICH. Human serum albumin was given by intravenous injection 1 h after ICH. U0126, an inhibitor of extracellular signal-regulated kinase (ERK1/2), and ML385, an inhibitor of nuclear factor-E2-related factor 2 (Nrf2), were intraperitoneally administered 1 h before ICH induction. Short- and long-term neurobehavioral tests, western blotting, immunofluorescence staining, oxidative stress evaluations, and apoptosis measurements were performed. RESULTS: Endogenous expression of albumin (peaked at 5 days) and heme oxygenase 1 (HO-1, peaked at 24 h) was increased after ICH compared with the sham group. Albumin and HO-1 were colocalized with neurons. Compared with vehicle, albumin treatment significantly improved short- and long-term neurobehavioral deficits and reduced oxidative stress and neuronal death at 72 h after ICH. Moreover, albumin treatment significantly promoted the phosphorylation of ERK1/2; increased the expression of Nrf2, HO-1, and Bcl-2; and downregulated the expression of Romo1 and Bax. U0126 and ML385 abolished the treatment effects of albumin on behavior and protein levels after ICH. CONCLUSIONS: Albumin attenuated oxidative stress-related neuronal death may in part via the ERK/Nrf2/HO-1 signaling pathway after ICH in rats. Our study suggests that albumin may be a novel therapeutic method to ameliorate brain injury after ICH.
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Apoptosis/efectos de los fármacos , Hemorragia Cerebral/patología , Hemo-Oxigenasa 1/metabolismo , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Factor 2 Relacionado con NF-E2/metabolismo , Neuronas/patología , Estrés Oxidativo/efectos de los fármacos , Albúmina Sérica Humana/farmacología , Animales , Hemorragia Cerebral/metabolismo , Humanos , Masculino , Memoria/efectos de los fármacos , Actividad Motora/efectos de los fármacos , Degeneración Nerviosa/patología , Degeneración Nerviosa/fisiopatología , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacos , Factores de TiempoRESUMEN
BACKGROUND: Survivors of sepsis must often endure significant cognitive and behavioral impairments after discharge, but research on the relevant mechanisms and interventions remains lacking. TGR5, a member of the class A GPCR family, plays an important role in many physiological processes, and recent studies have shown that agonists of TGR5 show neuroprotective effects in a variety of neurological disorders. To date, no studies have assessed the effects of TGR5 on neuroinflammatory, cognitive, or behavioral changes in sepsis models. METHODS: A total of 267 eight-week-old male Sprague-Dawley rats were used in this study. Sepsis was induced via cecal ligation and puncture (CLP). All animals received volume resuscitation. The rats were given TGR5 CRISPR oligonucleotide intracerebroventricularly 48 h before CLP surgery. INT-777 was administered intranasally 1 h after CLP, and the cAMP inhibitor, SQ22536, was administered intracerebroventricularly 1 h after CLP. Survival rate, bodyweight change, and clinical scores were assessed, and neurobehavioral tests, western blot, and immunofluorescence staining were performed. The cognitive function of rats was measured using the Morris water maze during 15-20 days after CLP. RESULTS: The expression of TGR5 in the rat hippocampus was upregulated, and peaked at 3 days after CLP. The survival rate of rats after CLP was less than 50%, and the growth rate, in terms of weight, was significantly decreased. While INT-777 treatment did not improve these changes, the treatment did reduce the clinical scores of rats at 24 h after CLP. On day 15 and later, the surviving mice completed a series of behavioral tests. CLP rats showed spatial and memory deficits and anxiety-like behaviors, but INT-777 treatment significantly improved these effects. Mechanistically, immunofluorescence analysis showed that INT-777 treatment reduced the number of microglia in the hippocampus, neutrophilic infiltration, and the expression of inflammatory factors after CLP in rats. Moreover, INT-777 treatment significantly increased the expression of TGR5, cAMP, p-PKA, and p-CREB, but downregulated the expression of IL-1ß, IL-6, and TNF-α. CRISPR-mediated TGR5 knockdown and SQ22536 treatment abolished the neuroprotective effects of TGR5 activation after CLP. CONCLUSION: This study demonstrates that INT-777 treatment reduced neuroinflammation and microglial cell activation, but improved cognitive impairment in the experimental sepsis rats. TGR5 has translational potential as a therapeutic target to improve neurological outcomes in sepsis survivors.
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Ácidos Cólicos/uso terapéutico , Encefalitis/tratamiento farmacológico , Nootrópicos/uso terapéutico , Receptores Acoplados a Proteínas G/agonistas , Sepsis/tratamiento farmacológico , Transducción de Señal/efectos de los fármacos , Adenina/análogos & derivados , Adenina/farmacología , Animales , Ansiedad/psicología , Disfunción Cognitiva/tratamiento farmacológico , Disfunción Cognitiva/etiología , Disfunción Cognitiva/psicología , AMP Cíclico/antagonistas & inhibidores , Proteína de Unión a Elemento de Respuesta al AMP Cíclico , Proteínas Quinasas Dependientes de AMP Cíclico , Citocinas/biosíntesis , Encefalitis/patología , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Sepsis/complicaciones , Sepsis/psicología , Análisis de SupervivenciaRESUMEN
MicroRNAs (miRNAs) are involved in many pathological and biological processes, such as ischemia/reperfusion (I/R) injury by modulating gene expression. Increasing evidence indicates that miR-378a-3p might provide a potential cardioprotective effect against ischemic heart disease. Cell apoptosis is a crucial mechanism in I/R injury. As such, this study evaluated the protective effects and underlying mechanisms of action of miR-378a-3p on H9C2 cardiomyocyte apoptosis following I/R injury. We found that I/R-induced H9C2 cardiomyocytes exhibited a decrease in miR-378a-3p expression, while treatment with a miR-378a-3p mimic suppressed cell apoptosis, JNK1/2 activation, cleavage of PARP and caspase-3, and Bax/Bcl-2 ratio but increased DUSP1 expression, which subsequently inhibited JNK1/2 phosphorylation. TRIM55 was shown to be a target of miR-378a-3p and its downregulation inhibited the miR-378a-3p inhibitor-induced increase in cell apoptosis and JNK1/2 activation. TRIM55 inhibited DUSP1 protein expression through ubiquitination of DUSP1. Moreover, DUSP1 overexpression inhibited the TRIM55 overexpression-induced increase in cell apoptosis and JNK1/2 activation. The protective effect of miR-378a-3p was subsequently confirmed in a rat myocardial I/R model, as evidenced by a decrease in cardiomyocyte apoptosis of cardiomyocytes, TRIM55 expression, and JNK1/2 activation. Taken together, these results suggest that miR-378a-3p may protect against I/R-induced cardiomyocyte apoptosis via TRIM55/DUSP1/JNK signaling.
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Apoptosis/genética , MicroARNs , Proteínas Musculares/metabolismo , Miocitos Cardíacos , Daño por Reperfusión/metabolismo , Proteínas de Motivos Tripartitos/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Animales , Línea Celular , Fosfatasa 1 de Especificidad Dual/metabolismo , Sistema de Señalización de MAP Quinasas/genética , MicroARNs/genética , MicroARNs/metabolismo , Proteína Quinasa 8 Activada por Mitógenos/metabolismo , Proteínas Musculares/genética , Miocitos Cardíacos/citología , Miocitos Cardíacos/efectos de los fármacos , Ratas , Proteínas de Motivos Tripartitos/genética , Ubiquitina-Proteína Ligasas/genéticaRESUMEN
BACKGROUND: We conducted a real-world analysis of the effectiveness of different antibiotic regimens for bloodstream infections (BSIs) caused by carbapenem-resistant gram-negative bacilli (CR-GNB) in a Chinese population. METHODS: A retrospective observational study was conducted between January 2010 and December 2017. Patients with BSIs caused by CR-GNB confirmed by in vitro susceptibility tests were enrolled, and patient medical record data on antimicrobial agents and microbiological and clinical outcomes were extracted. RESULTS: A total of 175 individuals were included; 127 individuals (72.6%) received combination therapy (two or more antibiotics), while 48 individuals (27.4%) received monotherapy (single antibiotic). The all-cause 28-day mortality was 20.0%. Treatment success or presumed success rates were very similar between the monotherapy and combination therapy groups (58.3% versus 59.1%; P = 0.931). Combination therapy had a higher success rate trend than monotherapy in septic shock patients (40.7% versus 18.2%; P = 0.268). Improved therapeutic effects were observed in the active agent-containing group, although the differences were not significant. CONCLUSION: Combination therapy likely has better therapeutic effects on critical BSIs caused by CR-GNB than monotherapy. Choosing a proper active agent in an antimicrobial regime is relatively crucial to the ultimate treatment outcome.
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AIMS: Sepsis is a syndrome of inflammatory response induced by infection. Cellular adhesion molecules may involve in sepsis-induced myocardial dysfunction (SIMD) which is a major predictor of morbidity and mortality of sepsis. Here we studied the role of FAM46C in AC16 cells and c57 mice with lipopolysaccharides (LPS) treatment. MAIN METHODS: Real-time PCR and western blot were used to detect the expression level of relative genes and protein. Cell proliferation and apoptosis were evaluated. KEY FINDINGS: Interestingly, negative correlation between Toll-like receptor 4 (TLR4) and FAM46C in sepsis was observed. The overexpression of FAM46C reduced the apoptosis induced by LPS in AC16 cells. Inhibition of apoptosis contributed by FAM46C was mediated by adhesion molecule via blocking p38 and ERK/MAPK signaling pathway. Moreover, overexpression of Fam46c and inhibition of TLR4 by TAK-242 could attenuate apoptosis induced by LPS in vivo. SIGNIFICANCE: FAM46C played an important role in SIMD via inhibiting LPS-induced myocardial dysfunction by downregulating cellular adhesion molecules and inhibiting apoptosis. It was the first time to explore the role of FAM46C in SIMD in this study.
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Apoptosis , Cardiomiopatías/patología , Moléculas de Adhesión Celular/metabolismo , Miocitos Cardíacos/patología , Polinucleotido Adenililtransferasa/metabolismo , Proteínas/metabolismo , Sepsis/complicaciones , Animales , Cardiomiopatías/etiología , Cardiomiopatías/metabolismo , Estudios de Casos y Controles , Moléculas de Adhesión Celular/genética , Proliferación Celular , Humanos , Lipopolisacáridos/toxicidad , Sistema de Señalización de MAP Quinasas , Masculino , Ratones , Ratones Endogámicos C57BL , Miocitos Cardíacos/metabolismo , Nucleotidiltransferasas , Polinucleotido Adenililtransferasa/genética , Proteínas/genética , Sepsis/inducido químicamente , Transducción de Señal , Receptor Toll-Like 4/genética , Receptor Toll-Like 4/metabolismoRESUMEN
Monocytes serve an important role in systemic inï¬ammation. High mobility group box1 protein (HMGB1) promotes recruitment and suppresses apoptosis in monocytes through the receptor for advanced glycation end products/ nuclear factor (NF)κB and tolllike receptor 4/mitogenactivated protein kinase (MAPK)/extracellular signalregulated kinase (ERK) signaling pathways. Glycyrrhizin (GL), an effective component of licorice, weakens the proinflammatory effect of HMGB1. The present study investigated the effect of GL on the migration and apoptosis of monocytes associated with HMGB1 signaling. THP1 cells were used to evaluate the behavior of monocytes in response to GL treatment, and the downstream pathways were investigated. GL suppressed HMGB1induced monocyte migration and increased HMGB1inhibited monocyte apoptosis. GL inhibited the activation of the NFκB and MAPK/ERK signaling pathways induced by HMGB1 and decreased the expression of monocyte chemoattractant protein1 (MCP1) and myeloid cell leukemia 1 (Mcl1). Taken together, the results indicated that GL may suppress the migration of monocytes and induce apoptosis to reduce systemic inflammation by blocking downstream NFκB/MCP1 and MAPK/ERK/Mcl1 signaling pathways.
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Apoptosis/efectos de los fármacos , Ácido Glicirrínico/farmacología , Proteína HMGB1/metabolismo , Monocitos/efectos de los fármacos , Monocitos/metabolismo , Transducción de Señal/efectos de los fármacos , Línea Celular , Movimiento Celular/efectos de los fármacos , Quimiocina CCL2/metabolismo , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Humanos , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Monocitos/inmunología , FN-kappa B/metabolismoRESUMEN
Chromosomal translocations involving the mixed lineage leukemia (MLL) gene lead to the development of acute leukemias. Constitutive HOX gene activation by MLL fusion proteins is required for MLL-mediated leukemogenesis; however, the underlying mechanisms remain elusive. Here, we show that chromobox homolog 8 (CBX8), a Polycomb Group protein that interacts with MLL-AF9 and TIP60, is required for MLL-AF9-induced transcriptional activation and leukemogenesis. Conversely, both CBX8 ablation and specific disruption of the CBX8 interaction by point mutations in MLL-AF9 abrogate HOX gene upregulation and abolish MLL-AF9 leukemic transformation. Surprisingly, Cbx8-deficient mice are viable and display no apparent hematopoietic defects. Together, our findings demonstrate that CBX8 plays an essential role in MLL-AF9 transcriptional regulation and leukemogenesis.