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BACKGROUND: Immune checkpoint blockade (ICB) therapy can be effective against clear cell renal cell carcinoma (ccRCC), but many patients show no benefit. Tumor-derived pericytes (TDPs) may promote tumor progression by influencing T cells and are an immunotherapy target; however, they may comprise functionally distinct subtypes. We aimed to identify markers of tumor-promoting TDPs and develop TDP-targeting strategies to enhance ICB therapy effectiveness against ccRCC. METHODS: We analyzed the relationship between endosialin (EN) expression and cytotoxic T-lymphocyte (CTL) infiltration in ccRCC tumor samples using flow cytometry and in a ccRCC-bearing mice inhibited for EN via knockout or antibody-mediated blockade. The function of ENhigh TDPs in CTL infiltration and tumor progression was analyzed using RNA-sequencing (RNA-seq) data from ccRCC tissue-derived TDPs and single-cell RNA-seq (scRNA-seq) data from an online database. The role of EN in TDP proliferation and migration and in CTL infiltration was examined in vitro. Finally, we examined the anti-tumor effect of combined anti-EN and anti-programmed death 1 (PD-1) antibodies in ccRCC-bearing mice. RESULTS: High EN expression was associated with low CTL infiltration in ccRCC tissues, and inhibition of EN significantly increased CTL infiltration in ccRCC-bearing mice. RNA-seq and scRNA-seq analyses indicated that high EN expression represented the TDP activation state. EN promoted TDP proliferation and migration and impeded CTL infiltration in vitro. Finally, combined treatment with anti-EN and anti-PD-1 antibodies synergistically enhanced anti-tumor efficacy. CONCLUSION: ENhigh TDPs are in an activated state and inhibit CTL infiltration into ccRCC tissues. Combined treatment with anti-EN and anti-PD-1 antibodies may improve ICB therapy effectiveness against ccRCC.
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Carcinoma de Células Renais , Neoplasias Renais , Animais , Camundongos , Linfócitos T CD8-Positivos , Proteínas de Ligação a DNA/metabolismo , Pericitos/metabolismo , Pericitos/patologia , Microambiente TumoralRESUMO
BACKGROUND: Osteosarcoma (OS) is the most common malignant bone tumor with a high incidence in children and adolescents. Frequent tumor metastasis and high postoperative recurrence are the most common challenges in OS. However, detailed mechanism is largely unknown. METHODS: We examined the expression of CD248 in OS tissue microarrays by immunohistochemistry (IHC) staining. We studied the biological function of CD248 in cell proliferation, invasion and migration of OS cells by CCK8 assay, transwell and wound healing assay. We also studied its function in the metastasis of OS in vivo. At last, we explored the potential mechanism how CD248 promotes OS metastasis by using RNA-seq, western blot, immunofluorescence staining and co-immunoprecipitation using CD248 knockdown OS cells. RESULTS: CD248 was highly expressed in OS tissues and its high expression was correlated with pulmonary metastasis of OS. Knockdown of CD248 in OS cells significantly inhibited cell migration, invasion and metastasis, while had no obvious effect on cell proliferation. Lung metastasis in nude mice was significantly inhibited when CD248 was knocked down. Mechanistically, we found that CD248 could promote the interaction between ITGB1 and extracellular matrix (ECM) proteins like CYR61 and FN, which activated the FAK-paxillin pathway to promote the formation of focal adhesion and metastasis of OS. CONCLUSION: Our data showed that high CD248 expression is correlated with the metastatic potential of OS. CD248 may promote migration and metastasis through enhancing the interaction between ITGB1 and certain ECM proteins. Therefore, CD248 is a potential marker for diagnosis and effective target for the treatment of metastatic OS.
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Neoplasias Ósseas , Neoplasias Pulmonares , Osteossarcoma , Animais , Camundongos , Antígenos CD , Antígenos de Neoplasias , Neoplasias Ósseas/genética , Neoplasias Ósseas/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/secundário , Camundongos Nus , Osteossarcoma/genética , Osteossarcoma/patologia , Paxilina/genética , Paxilina/metabolismo , Integrina beta1/metabolismoRESUMO
Myofibroblasts, or activated fibroblasts, play a critical role in the process of renal fibrosis. Targeting myofibroblasts to inhibit their activation or induce specific cell death has been considered to be an effective strategy to attenuate renal fibrosis. However, specific biomarkers for myofibroblasts are needed to ensure the efficacy of these strategies. Here, we verified that CD248 was mainly expressed in myofibroblasts in patients with chronic kidney disease, which was inversely correlated with renal function. The same result was also confirmed in renal fibrotic mice induced by unilateral ureteral obstruction and aristolochic acid nephropathy. By using an antibody-drug conjugate (ADC) named IgG78-DM1, in which maytansinoid (DM1) was linked to a fully human antibody IgG78 through an uncleavable SMCC linker, we demonstrated that it could effectively bind with and kill CD248+ fibroblasts in vitro and alleviate renal fibrosis in mice models. Besides, we confirmed that IgG78-DM1 had qualified biosafety in vivo. Our results confirmed that CD248 can be used as a specific marker for myofibroblasts, and specific killing of CD248+ myofibroblasts by IgG78-DM1 has excellent anti-fibrotic effect in renal fibrotic mice. Our study expanded the application of ADC and provided a novel strategy for the treatment of renal fibrosis.
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Antígenos CD/metabolismo , Antígenos de Neoplasias/metabolismo , Sistemas de Liberação de Medicamentos , Imunoconjugados/farmacologia , Maitansina/farmacologia , Miofibroblastos/metabolismo , Insuficiência Renal Crônica , Animais , Fibrose , Masculino , Camundongos , Insuficiência Renal Crônica/tratamento farmacológico , Insuficiência Renal Crônica/metabolismoRESUMO
Acquired thrombotic thrombocytopenic purpura (aTTP) is a fatal hematologic disease. Despite the currently high standards of care, some patients who develop refractory or recurrent disease still have a poor prognosis. Although N-acetylcysteine (NAC) is recommended for the treatment of aTTP, its use in aTTP treatment is still controversial. We aimed to evaluate the association of NAC with mortality in patients with aTTP. This was a retrospective cohort study of patients with aTTP with in-hospital mortality as the primary outcome and time to platelet recovery and neurological recovery as secondary outcomes. We used multifactorial COX regression analysis to check for an association of NAC with mortality. Moreover, we performed a sensitivity analysis check the stability of our results. Finally, 89 patients with aTTP were enrolled. After adjusting for potential confounders, we found NAC to be associated with 75% lower in-hospital mortality (HR = 0.25, 95% CI = 0.1-0.64). The results of sensitivity analyses performed remained stable as the risk of in-hospital mortality in patients reduced in patients with comorbid neurological symptoms (HR = 0.23, 95% CI = 0.06-0.89). However, NAC use did not affect the time to platelet recovery (HR = 1.19, 95% CI = 0.57-2.5) or neurological recovery (HR = 0.32, 95% CI = 0.08-1.25) in patients with aTTP. NAC treatment reduces in-hospital mortality in patients with aTTP but does not shorten the time to platelet recovery or neurological recovery.
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Púrpura Trombocitopênica Trombótica , Humanos , Adulto , Púrpura Trombocitopênica Trombótica/diagnóstico , Acetilcisteína/uso terapêutico , Estudos Retrospectivos , Estudos de Coortes , Mortalidade Hospitalar , Troca PlasmáticaRESUMO
BACKGROUND: Chronic liver injury induces pathological repair, resulting in fibrosis, during which hepatic stellate cells (HSCs) are activated and transform into myofibroblasts. CD248 is mainly expressed on myofibroblasts and was considered as a promising target to treat fibrosis. The primary aim of this study was to generate a CD248 specific antibody-drug conjugate (ADC) and evaluate its therapeutic efficacy for liver fibrosis and its safety in vivo. METHODS: CD248 expression was examined in patients with liver cirrhosis and in mice with CCl4-induced liver fibrosis. The ADC IgG78-DM1, which targets CD248, was prepared and its bioactivity on activated primary HSCs was studied. The anti-fibrotic effects of IgG78-DM1 on liver fibrosis were evaluated in CCl4-induced mice. The reproductive safety and biosafety of IgG78-DM1 were also evaluated in vivo. RESULTS: CD248 expression was upregulated in patients with liver cirrhosis and in CCl4-induced mice, and was mainly expressed on alpha smooth muscle actin (α-SMA)+ myofibroblasts. IgG78-DM1 was successfully generated, which could effectively bind with and kill CD248+ activated HSCs in vitro and inhibit liver fibrosis in vivo. In addition, IgG78-DM1 was demonstrated to have qualified biosafety and reproductive safety in vivo. CONCLUSIONS: Our study demonstrated that CD248 could be an ideal target for myofibroblasts in liver fibrosis, and CD248-targeting IgG78-DM1 had excellent anti-fibrotic effects in mice with liver fibrosis. Our study provided a novel strategy to treat liver fibrosis and expanded the application of ADCs beyond tumors.
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Imunoconjugados , Miofibroblastos , Animais , Antígenos CD/metabolismo , Antígenos de Neoplasias/efeitos adversos , Antígenos de Neoplasias/metabolismo , Fibrose , Células Estreladas do Fígado/metabolismo , Humanos , Imunoconjugados/efeitos adversos , Imunoconjugados/metabolismo , Fígado/metabolismo , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/metabolismo , Camundongos , Miofibroblastos/metabolismoRESUMO
Pathogen-induced host immune responses reduce the efficacy of pathogens used to control pests. However, compared to the well-deciphered immunity system of Drosophila melanogaster, the immunity system of agricultural pests is largely unconfirmed through functional analysis. Beginning to unveil mechanisms of transcription regulation of immune genes in the Asian corn borer, Ostrinia furnacalis, we cloned the complementary DNA (cDNA) of a transcription factor Relish by rapid amplification of cDNA ends. The 3164 bp cDNA, designated Of-Relish, encodes a 956-residue protein. Bioinformatic analysis showed that Of-Relish had a Rel homology domain, a predicted cleavage site between Q409 and L410 , six ankyrin repeats, and a death domain. The response of Of-Relish expression to the Gram-negative bacteria Pseudomonas aeruginosa was sooner and stronger than to the Gram-positive Micrococcus luteus. The antimicrobial peptide genes Attacin and Gloverin had similar expression patterns in response to the infections. Knockdown of Of-Relish led to a decrease in Attacin and Gloverin messenger RNA levels, suggesting that Attacin and Gloverin were regulated by Of-Relish. Together, the results suggested that Of-Relish is a key component of the IMD pathway in O. furnacalis, involved in defense against P. aeruginosa through activation of Attacin and Gloverin.
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Regulação da Expressão Gênica , Mariposas/imunologia , Proteínas Citotóxicas Formadoras de Poros/metabolismo , Fatores de Transcrição/genética , Animais , Proteínas de Drosophila/genética , Genes de Insetos , Imunidade/genética , Proteínas de Insetos/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Mariposas/genéticaRESUMO
PURPOSE: Acute kidney injury (AKI) is a common complication of sepsis and has high mortality. The 2017 Acute Disease Quality Initiative (AQDI) workgroup proposed new definitions for AKI - transient AKI and persistent AKI; however, very little is known about the effect of transient and persistent septic AKI on short-term mortality among critically ill patients with sepsis. The purpose of this study was to assess the impact of persistent AKI on mortality and to evaluate whether serum hepcidin can predict the occurrence of persistent AKI in critically ill patients with sepsis. MATERIALS AND METHODS: This prospective observational study was performed in a general hospital mixed surgical-medical ICU in Pudong, China. Consecutive adults with sepsis admitted to the ICU with absence of chronic kidney disease, renal transplant, and AKI were included. AKI was defined according to the KDIGO criteria and classified as transient (< 48-hour duration) or persistent (48-hour duration). Blood samples were obtained within 6 hours from when AKI was diagnosed. RESULTS: A total of 90 patients with sepsis or septic shock were included in the analysis. 44 (48.89%) patients developed AKI during ICU stay: 20 (45.45%) had transient and 24 (54.55%) had persistent AKI. Persistent AKI has a higher mortality than transient AKI (66.7 vs. 30.0%, p = 0.002). Persistent AKI and sequential organ failure assessment (SOFA) scores were an independent predictor of 60-day mortality. Patients with persistent AKI had higher concentrations of serum creatinine (SCr) and hepcidin than transient AKI patients when AKI was diagnosed. Logistic regression indicated that serum hepcidin was an independent predictor of persistent AKI in septic patients, with a fairly predictive value (AUC 0.71, 95% CI: 0.47 - 0.87; p = 0.02). CONCLUSION: Persistent AKI was associated with increased 60-day mortality compared with transient AKI in septic patients. The serum hepcidin levels measured when AKI was diagnosed have a fair predictive value to predict the occurrence of persistent AKI in septic patients.
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Injúria Renal Aguda/etiologia , Hepcidinas/sangue , Sepse/mortalidade , Injúria Renal Aguda/sangue , Idoso , Idoso de 80 Anos ou mais , Estado Terminal , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Sepse/sangue , Sepse/complicaçõesRESUMO
BACKGROUND Sepsis is an organ dysfunction characterized by systemic inflammatory response. Micro(mi)ribonucleic acids take part in the regulation of the inflammatory response in many conditions. However, the role and mechanism of miR-106a and anoctamin 1 (ANO1) in the inflammatory response in sepsis remain largely unknown. MATERIAL AND METHODS The serum samples were collected from 31 sepsis patients and healthy volunteers. Lipopolysaccharide (LPS)-treated RAW264.7 cells were used for the study in vitro. The inflammatory response was investigated via interleukin-6 and tumor necrosis factor-alpha levels using quantitative real-time polymerase chain reaction (qRT-PCR) and enzyme-linked immunosorbent assay. The expression abundances of miR-106a and ANO1 were detected via qRT-PCR or western blot. The target association between miR-106a and ANO1 was explored using dual-luciferase reporter analysis. RESULTS The inflammatory response was trigged in sepsis and LPS-treated RAW264.7 cells. miR-106a expression was enhanced and ANO1 declined in sepsis and LPS-treated RAW264.7 cells. Overexpression of ANO1 suppressed the inflammatory response and knockdown of ANO1 promoted the inflammatory response in RAW264.7 cells. ANO1 was directly targeted via miR-106a, and miR-106a reversed ANO1-mediated inflammatory inhibition in LPS-treated RAW264.7 cells. CONCLUSIONS MiR-106a regulated LPS-induced inflammatory response by targeting ANO1 in RAW264.7 cells, indicating the potential value of miR-106a for treatment of inflammatory diseases, including sepsis.
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Anoctamina-1/metabolismo , Lipopolissacarídeos/toxicidade , Macrófagos/metabolismo , MicroRNAs/metabolismo , Proteínas de Neoplasias/metabolismo , Adulto , Animais , Feminino , Humanos , Inflamação/induzido quimicamente , Inflamação/metabolismo , Inflamação/patologia , Macrófagos/patologia , Masculino , Camundongos , Pessoa de Meia-Idade , Células RAW 264.7RESUMO
BACKGROUND/AIMS: Acute pancreatitis (AP) is an inflammatory disease characterized by acinar cell damage and inflammation of the pancreas with infiltration of leukocytes, predominantly neutrophils. We investigated whether neutrophil depletion protects against experimental AP induced by L-arginine. METHODS: AP was induced in C57BL/6 mice via two intraperitoneal L-arginine (4 g/kg) injections. Mice were pretreated with 250 and 100 µg anti-Gr-1 antibody via intraperitoneal injection at 24 and 4 h, respectively, before L-arginine challenge for neutrophil depletion. At 48 and 72 h after injection, the severity of AP was determined with the aid of biochemical and histological analyses. Amylase and MPO activity was detected using specific assay kits. The plasma cytokines levels were detected using ELISA. RESULTS: Neutrophil depletion resulted in significantly reduced plasma amylase levels in pancreas, myeloperoxidase (MPO) activity in pancreas and lung, reactive oxygen species (ROS) generation and cell apoptosis, and decreased circulating neutrophil, tissue damage as well as expression levels of nuclear factor NF-κB. CONCLUSION: Neutrophil depletion is capable of reducing tissue damage of pancreas and lung in mice with acute pancreatitis.
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Arginina/farmacologia , Neutrófilos/metabolismo , Neutrófilos/fisiologia , Pancreatite/induzido quimicamente , Pancreatite/fisiopatologia , Doença Aguda , Amilases/metabolismo , Animais , Apoptose/efeitos dos fármacos , Citocinas/metabolismo , Modelos Animais de Doenças , Pulmão/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Pâncreas/metabolismo , Pâncreas/fisiopatologia , Pancreatite/metabolismo , Peroxidase/metabolismo , Espécies Reativas de Oxigênio/metabolismoRESUMO
Systolic dysfunction has been observed following isolated moderate-severe traumatic brain injury (Ims-TBI). However, early risk factors for the development of systolic dysfunction after Ims-TBI and their impact on the prognosis of patients with Ims-TBI have not been thoroughly investigated. A prospective observational study among patients aged 16 to 65 years without cardiac comorbidities who sustained Ims-TBI (Glasgow Coma Scale [GCS] score ≤12) was conducted. Systolic dysfunction was defined as left ventricular ejection fraction <50% or apparent regional wall motion abnormality assessed by transthoracic echocardiography within 24 hours after admission. The primary endpoint was the incidence of systolic dysfunction after Ims-TBI. The secondary endpoint was survival on discharge. Clinical data and outcomes were assessed within 24 hours after admission or during hospitalization. About 23 of 123 patients (18.7%) developed systolic dysfunction after Ims-TBI. Higher admission heart rate (odds ratios [ORs]: 1.05, 95% confidence interval [CI]: 1.02-1.08; Pâ =â .002), lower admission GCS score (OR: 0.77, 95% CI: 0.61-0.96; Pâ =â .022), and higher admission serum high-sensitivity cardiac troponin T (Hs-cTnT) (OR: 1.14, 95% CI: 1.06-1.22; Pâ <â .001) were independently associated with systolic dysfunction among patients with Ims-TBI. A combination of heart rate, GCS score, and serum Hs-cTnT level on admission improved the predictive performance for systolic dysfunction (area under curveâ =â 0.85). Duration of mechanical ventilation, intensive care unit length of stay, and in-hospital mortality of patients with systolic dysfunction was higher than that of patients with normal systolic function (Pâ <â .05). Lower GCS (OR: 0.66, 95% CI: 0.45-0.82; Pâ =â .001), lower admission oxygen saturation (OR: 0.82, 95% CI: 0.69-0.98; Pâ =â .025), and the development of systolic dysfunction (OR: 4.85, 95% CI: 1.36-17.22; Pâ =â .015) were independent risk factors for in-hospital mortality in patients with Ims-TBI. Heart rate, GCS, and serum Hs-cTnT level on admission were independent early risk factors for systolic dysfunction in patients with Ims-TBI. The combination of these 3 parameters can better predict the occurrence of systolic dysfunction.
Assuntos
Lesões Encefálicas Traumáticas , Humanos , Feminino , Masculino , Adulto , Pessoa de Meia-Idade , Fatores de Risco , Estudos Prospectivos , Lesões Encefálicas Traumáticas/complicações , Lesões Encefálicas Traumáticas/mortalidade , Adulto Jovem , Adolescente , Disfunção Ventricular Esquerda/etiologia , Disfunção Ventricular Esquerda/epidemiologia , Disfunção Ventricular Esquerda/fisiopatologia , Idoso , Escala de Coma de Glasgow , Ecocardiografia , Prognóstico , Troponina T/sangue , Frequência Cardíaca/fisiologia , SístoleRESUMO
Endosialin, also known as tumor endothelial marker 1 (TEM1) or CD248, is a single transmembrane glycoprotein with a C-type lectin-like domain. Endosialin is mainly expressed in the stroma, especially in cancer-associated fibroblasts and pericytes, in most solid tumors. Endosialin is also expressed in tumor cells of most sarcomas. Endosialin can promote tumor progression through different mechanisms, such as promoting tumor cell proliferation, adhesion and migration, stimulating tumor angiogenesis, and inducing an immunosuppressive tumor microenvironment. Thus, it is considered an ideal target for cancer treatment. Several endosialin-targeted antibodies and therapeutic strategies have been developed and have shown preliminary antitumor effects. Here, we reviewed the endosialin expression pattern in different cancer types, discussed the mechanisms by which endosialin promotes tumor progression, and summarized current therapeutic strategies targeting endosialin.
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Antígenos de Neoplasias , Neoplasias , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neovascularização Patológica/patologia , Pericitos/metabolismo , Microambiente Tumoral , Antígenos CD/metabolismoRESUMO
Adipose tissue encompasses various types, including White Adipose Tissue (WAT), Brown Adipose Tissue (BAT), and beige adipose tissue, each having distinct roles in energy storage and thermogenesis. Vitamin D (VD), a fat-soluble vitamin, maintains a complex interplay with adipose tissue, exerting significant effects through its receptor (VDR) on the normal development and functioning of adipocytes. The VDR and associated metabolic enzymes are widely expressed in the adipocytes of both rodents and humans, and they partake in the regulation of fat metabolism and functionality through various pathways. These encompass adipocyte differentiation, adipogenesis, inflammatory responses, and adipokine synthesis and secretion. This review primarily appraises the role and mechanisms of VD in different adipocyte differentiation, lipid formation, and inflammatory responses, concentrating on the pivotal role of the VD/VDR pathway in adipogenesis. This insight furnishes new perspectives for the development of micronutrient-related intervention strategies in the prevention and treatment of obesity.
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Adipogenia , Vitamina D , Humanos , Vitamina D/metabolismo , Tecido Adiposo/metabolismo , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/metabolismo , Obesidade/metabolismo , Vitaminas/metabolismo , TermogêneseRESUMO
BACKGROUND: This study aimed to elucidate the effect and underlying molecular mechanisms of SZ168 (Podoplanin (PDPN) monoclonal antibody) on lipopolysaccharide (LPS)-induced acute lung injury (ALI) mice and LPS-induced MH-S cells. METHODS: The survival rate was calculated by recording the death of mice in each group. Enzyme linked immunosorbent assay (ELISA) was used to detect the levels of interleukin (IL)- 6 and tumor necrosis factor-alpha (TNF-α) in blood and bronchoalveolar lavage fluid (BALF) of mice. Hematoxylin-eosin (H&E) staining were performed to evaluate the pathological changes in pulmonary tissues. Additionally, the phagocytosis of cells was tested by flow cytometry, and the expression levels of caveolin-1 (CAV-1) and Occludin proteins in lung tissue and the expression of nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) pathway-related proteins in MH-S cells were determined by western blot. RESULTS: SZ168 significantly improved the survival rate of ALI mice. Briefly speaking, SZ168 protected pulmonary vascular permeability, reduced the level of pro-inflammatory cytokines, improved the pathological changes of lung tissue, reduced the infiltration of inflammatory cells, increased CAV-1 and Occludin protein expression, and then effectively relieved lung injury. In addition, SZ168 could significantly reduce the phagocytic ability of LPS-induced MH-S cells and inhibit the expression of hospho-extracellular regulated protein kinases (p-ERK), Phospho-Jun N-terminal kinase (p-JNK), Phospho-NF-κB p65 (p-p65) and Phospho-IkappaB-alpha (p-IκBα). CONCLUSION: SZ168 can treat ALI by inhibiting the activation of NF-κB and MAPK signaling pathways and restoring tight junction protein expression.
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Lesão Pulmonar Aguda , NF-kappa B , Camundongos , Animais , NF-kappa B/metabolismo , Lipopolissacarídeos/toxicidade , Lipopolissacarídeos/metabolismo , Ocludina/metabolismo , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/tratamento farmacológico , Pulmão , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Studies have indicated that neuronal mitochondrial injury may be involved in the brain injury caused by intracerebral hemorrhage (ICH). Syntaphilin (SNPH) is associated with mitochondrial anchoring and Armadillo repeat-containing X-linked protein 1 (Armcx1) is linked to mitochondrial transport. This study aimed to analyze the contribution of SNPH and Armcx1 to the neuronal damage resulting from ICH. Primary cultured neuron cells were exposed to oxygenated hemoglobin to replicate the effects of ICH stimulation, while a mouse model of ICH was established by injecting autoblood into the basal ganglia. Specific SNPH knockout or Armcx1 overexpression in neurons is achieved by stereolocalization injection of adeno-associated virus vectors carrying hsyn specific promoters. First, it was confirmed that there is a correlation between SNPH/Armcx1 and ICH pathology, as evidenced by the rise of SNPH and the decrease of Armcx1 in neurons exposed to ICH both in vitro and in vivo. Second, our research revealed the protective effects of SNPH knockdown and Armcx1 overexpression on brain cell death around the hematoma in mice. In addition, the efficacy of SNPH knockdown and Armcx1 overexpression in improving neurobehavioral deficits was also demonstrated in mouse ICH model. Thus, moderate adjusting the levels of SNPH and Armcx1 may be an effective way to improve the outcome of ICH.
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Lesões Encefálicas , Neurônios , Animais , Camundongos , Encéfalo/metabolismo , Lesões Encefálicas/metabolismo , Hemorragia Cerebral/metabolismo , Neurônios/metabolismoRESUMO
BACKGROUND: Angiomyolipoma (AML), the most common benign tumor of the kidney, is usually composed of dysmorphic blood vessels, smooth muscle, and mature adipose tissue. To our knowledge, AML with cystic degeneration has rarely been documented. Cystic degeneration, hemorrhage, and a lack of fat bring great challenges to the diagnosis. CASE SUMMARY: A 60-year-old man with hypertension presented with a 5-year history of cystic mass in his left kidney. He fell 2 mo ago. A preoperative computed tomography (CT) scan showed a mixed-density cystic lesion without macroscopic fat density, the size of which had increased compared with before, probably due to hemorrhage caused by a trauma. Radical nephrectomy was performed. Histopathological studies revealed that the lesion mainly consisted of tortuous, ectatic, and thick-walled blood vessels, mature adipose tissue, and smooth muscle-like spindle cells arranged around the abnormal blood vessels. The tumor cells exhibited positivity for human melanoma black-45, Melan-A, smooth muscle actin, calponin, S-100, and neuron-specific enolase, rather than estrogen receptor, progesterone receptor, CD68, and cytokeratin. The Ki-67 labeling index was less than 5%. The final diagnosis was a fat-poor renal AML (RAML) with prominent cystic degeneration. CONCLUSION: When confronting a large renal cystic mass, RAML should be included in the differential diagnosis.
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Matrix metalloproteinases (MMPs) are crucial for tissue remodeling and immune responses in insects, yet it remains unclear how MMPs affect the various immune processes against pathogenic infections and whether the responses vary among insects. In this study, we used the lepidopteran pest Ostrinia furnacalis larvae to address these questions by examining the changes of immune-related gene expression and antimicrobial activity after the knockdown of MMP14 and bacterial infections. We identified MMP14 in O. furnacalis using the rapid amplification of complementary DNA ends (RACE), and found that it was conserved and belonged to the MMP1 subfamily. Our functional investigations revealed that MMP14 is an infection-responsive gene, and its knockdown reduces phenoloxidase (PO) activity and Cecropin expression, while the expressions of Lysozyme, Attacin, Gloverin, and Moricin are enhanced after MMP14 knockdown. Further PO and lysozyme activity determinations showed consistent results with gene expression of these immune-related genes. Finally, the knockdown of MMP14 decreased larvae survival to bacterial infections. Taken together, our data indicate that MMP14 selectively regulates the immune responses, and is required to defend against bacterial infections in O. furnacalis larvae. Conserved MMPs may serve as a potential target for pest control using a combination of double-stranded RNA and bacterial infection.
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Infecções Bacterianas , Mariposas , Animais , Muramidase/genética , Muramidase/metabolismo , Metaloproteinase 14 da Matriz/genética , Metaloproteinase 14 da Matriz/metabolismo , Larva/microbiologia , ImunidadeRESUMO
Objective: As the frontoparietal network underlies recovery from coma, a limited frontoparietal montage was used, and the prognostic values of EEG features for comatose patients were assessed. Methods: Collected with a limited frontoparietal EEG montage, continuous EEG recordings of 81 comatose patients in ICU were used retrospectively. By the 60-day Glasgow outcome scale (GOS), the patients were dichotomized into favorable and unfavorable outcome groups. Temporal-, frequency-, and spatial-domain features were automatically extracted for comparison. Partial correlation analysis was applied to eliminate redundant factors, and multiple correspondence analysis was used to explore discrimination between groups. Prognostic characteristics were calculated to assess the performance of EEG feature-based predictors established by logistic regression. Analyses were performed on all-patients group, strokes subgroup, and traumatic brain injury (TBI) subgroup. Results: By analysis of all patients, raised burst suppression ratio (BSR), suppressed root mean square (RMS), raised power ratio of ß to α rhythm (ß/α), and suppressed phase-lag index between F3 and P4 (PLI [F3, P4]) were associated with unfavorable outcome, and yielded AUC of 0.790, 0.811, 0.722, and 0.844, respectively. For the strokes subgroup, the significant variables were BSR, RMS, θ/total, θ/δ, and PLI (F3, P4), while for the TBI subgroup, only PLI (F3, P4) was significant. BSR combined with PLI (F3, P4) gave the best predictor by cross-validation analysis in the all-patients group (AUC = 0.889, 95% CI: 0.819-0.960). Conclusion: Features extracted from limited frontoparietal montage EEG served as valuable coma prognostic tools, where PLI (F3, P4) was always significant. Combining PLI (F3, P4) with features in other domains may achieve better performance. Significance: A limited-montage EEG coupled with an automated algorithm is valuable for coma prognosis.
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The textured design of amorphous carbon (a-C) film can significantly improve the tribological performance and service life of moving mechanical components. However, its friction dependence on different texture shapes, especially under different load conditions, remains unclear. In particular, due to the lack of information regarding the friction interface, the underlying friction mechanism has still not been unveiled. Therefore, the effects of contact pressure and textured shapes on the tribological behavior of a-C films under dry friction conditions were comparatively studied in this work by reactive molecular dynamics simulation. The results show that under low contact pressure, the tribological property of a-C film is sensitive to the textured shape, and the system with a circular textured surface exhibits a lower friction coefficient than that with a rectangular textured surface, which is attributed to the small fraction of unsaturated bonds. However, the increase of contact pressure results in the serious reconstruction and passivation of the friction interface. On the one hand, this induces a growth rate of friction force that is much smaller than that of the normal load, which is followed by a significant decrease in the friction coefficient with contact pressure. On the other hand, the destruction or even disappearance of the textured structure occurs, weakening the difference in the friction coefficient caused by different textured shapes of the a-C surface. These results reveal the friction mechanism of textured a-C film and provide a new way to functionalize the a-C as a protective film for applications in hard disks, MEMS, and NEMS.
RESUMO
The combination of fluid lubricants and textured amorphous carbon (a-C) can provide an ultralow friction state, which can improve the reliability and service life of dynamic machinery. However, the coupling effects of the contact pressure and oil content on the friction-reducing efficiency is still lack of study, and the corresponding friction mechanism is also not fully understood, which cannot be achieved by experiment due to the limitation of in situ characterization. In this study, using the reactive molecular dynamics simulation, the insight into the evolution of interfacial structures induced by both contact pressures and oil contents on a-C surface was systematically investigated to explore the fundamental mechanism. In particular, the friction difference between textured and untextured a-C films was evaluated comparatively. Results indicate that the tribological performance strongly depends on the interfacial lubrication state, which is jointly determined by the oil content and contact pressure; the best operating condition to achieve ultralow friction coefficient (0.002) is obtained, and the evolution of friction coefficient with oil content and contact pressure is highly dominated by the lubricant mobility, cross-linking between mating a-C surfaces, or competition/synergy of the H stress state from the lubricant with interfacial passivation. Furthermore, the difference in friction reduction between textured and untextured systems is unveiled; with the increase of contact pressure, the role of texturing a-C surface in antifriction changes from positive to negative effect, which is related to the transformation of interfacial hybridized structure and anomalous flow of lubricant. These results can significantly enhance the understanding of composite lubrication systems through computation and also provide a roadmap for the R&D of the advanced lubrication system according to the working conditions.