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Panax notoginseng saponins (PNS), the primary medicinal ingredient of Panax notoginseng, mitigates cerebral ischemia-reperfusion injury (CIRI) by inhibiting inflammation, regulating oxidative stress, promoting angiogenesis, and improving microcirculation. Moreover, PNS activates nuclear factor erythroid 2-related factor 2 (Nrf2), which is known to inhibit ferroptosis and reduce inflammation in the rat brain. However, the molecular regulatory roles of PNS in CIRI-induced ferroptosis remain unclear. In this study, we aimed to investigate the effects of PNS on ferroptosis and inflammation in CIRI. We induced ferroptosis in SH-SY5Y cells via erastin stimulation and oxygen glucose deprivation/re-oxygenation (OGD/R) in vitro. Furthermore, we determined the effect of PNS treatment in a rat model of middle cerebral artery occlusion/reperfusion and assessed the underlying mechanism. We also analyzed the changes in the expression of ferroptosis-related proteins and inflammatory factors in the established rat model. OGD/R led to an increase in the levels of ferroptosis markers in SH-SY5Y cells, which were reduced by PNS treatment. In the rat model, combined treatment with an Nrf2 agonist, Nrf2 inhibitor, and PNS-Nrf2 inhibitor confirmed that PNS promotes Nrf2 nuclear localization and reduces ferroptosis and inflammatory responses, thereby mitigating brain injury. Mechanistically, PNS treatment facilitated Nrf2 activation, thereby regulating the expression of iron overload and lipid peroxidation-related proteins and the activities of anti-oxidant enzymes. This cascade inhibited ferroptosis and mitigated CIRI. Altogether, these results suggest that the ferroptosis-mediated activation of Nrf2 by PNS reduces inflammation and is a promising therapeutic approach for CIRI.
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Ferroptose , Fator 2 Relacionado a NF-E2 , Panax notoginseng , Ratos Sprague-Dawley , Traumatismo por Reperfusão , Saponinas , Animais , Fator 2 Relacionado a NF-E2/metabolismo , Ferroptose/efeitos dos fármacos , Panax notoginseng/química , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/metabolismo , Saponinas/farmacologia , Masculino , Ratos , Humanos , Modelos Animais de Doenças , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/metabolismo , FitoterapiaRESUMO
Daurisoline (DS) is an isoquinoline alkaloid that exerts anticancer activities in various cancer cells. However, the underlying mechanisms through which DS affects the survival of breast cancer cells remain poorly understood. Therefore, the present study was undertaken to investigate the potential anticancer effect of DS on breast cancer cells and reveal the mechanism underlying the enhanced tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis by DS. Cell counting kit-8 (CCK-8) and 5-ethynyl-2-deoxyuridine (EdU) assay were used to evaluate the ability of cell proliferation. Flow cytometry was selected to examine the cell cycle distribution. TUNEL assay was used to detect the cell apoptosis. The protein expression was measured by Western blot analysis. DS was found to reduce the cell viability and suppress the proliferation of MCF-7 and MDA-MB-231 cells by causing G1 phase cell cycle arrest. DS could trigger apoptosis by promoting the cleavage of caspase-8 and PARP. The phosphorylation of ERK, JNK, and p38MAPK was upregulated clearly following DS treatment. Notably, SP600125 (JNK inhibitor) pretreatment significantly abrogated DS-induced PARP cleavage. DS inactivated Akt/mTOR and Wnt/ß-catenin signaling pathway and upregulated the expression of ER stress-related proteins. Additionally, DS amplified TRAIL-caused viability reduction and apoptosis in breast cancer cells. Mechanismly, DS upregulated the protein level of DR4 and DR5, and knockdown of DR5 attenuated the cotreatment-induced cleavage of PARP. Inhibition of JNK could block DS-induced upregulation of DR5. This study provides valuable insights into the mechanisms of DS inhibiting cell proliferation, triggering apoptosis, and enhancing TRAIL sensitivity of breast cancer cells.
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PURPOSE: The purpose of this research was to investigate the efficacy of the CT-based peritoneal cancer index (PCI) to predict the overall survival of patients with peritoneal metastasis in gastric cancer (GCPM) after two cycles of chemotherapy. METHODS: This retrospective study registered 112 individuals with peritoneal metastasis in gastric cancer in our hospital. Abdominal and pelvic enhanced CT before and after chemotherapy was independently analyzed by two radiologists. The PCI of peritoneal metastasis in gastric cancer was evaluated according to the Sugarbaker classification, considering the size and distribution of the lesions using CT. Then we evaluated the prognostic performance of PCI based on CT, clinical characteristics, and imaging findings for survival analysis using multivariate Cox proportional hazard regression. RESULTS: The PCI change ratio based on CT after treatment (ΔPCI), therapy lines, and change in grade of ascites were independent factors that were associated with overall survival (OS). The area under the curve (AUC) value of ΔPCI for predicting OS with 0.773 was higher than that of RECIST 1.1 with 0.661 (P < 0.05). Patients with ΔPCI less than -15% had significantly longer OS. CONCLUSION: CT analysis after chemotherapy could predict OS in patients with GCPM. The CT-PCI change ratio could contribute to the determination of an appropriate strategy for gastric cancer patients with peritoneal metastasis.
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Neoplasias Peritoneais , Neoplasias Gástricas , Tomografia Computadorizada por Raios X , Humanos , Neoplasias Gástricas/patologia , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/diagnóstico por imagem , Neoplasias Peritoneais/secundário , Neoplasias Peritoneais/mortalidade , Neoplasias Peritoneais/tratamento farmacológico , Neoplasias Peritoneais/diagnóstico por imagem , Feminino , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Tomografia Computadorizada por Raios X/métodos , Idoso , Prognóstico , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
BACKGROUND: This study assessed the performance of early contrast-enhanced magnetic resonance (ECE-MR) in the detecting of complete tumor response (ypT0) in patients with esophageal squamous cell carcinoma following neoadjuvant therapy. PATIENTS AND METHODS: Preoperative MR images of consecutive patients who underwent neoadjuvant therapy and surgical resection were reviewed retrospectively. The accuracy of ECE-MR and T2WI+DWI was evaluated by comparing the findings with pathological results. Receiver operating characteristic curve analysis was used to assess the diagnostic performance, and DeLong method was applied to compare the areas under the curves (AUC). Chi-squared analysis was conducted to explore the difference in pathological changes. RESULTS: A total of 198 patients (mean age 62.6 ± 7.8 years, 166 men) with 201 lesions were included. The AUC of ECE-MR was 0.85 (95% CI 0.79-0.90) for diagnosing ypT1-4, which was significantly higher than that of T2WI+DWI (AUC 0.69, 95% CI 0.63-0.76, p < 0.001). The diagnostic performance of both T2WI+DWI and ECE-MR improved with increasing tumor stage. The AUCs of ECE-MRI were higher in ypT1 and ypT2 tumors than T2WI+DWI. Degree 2-3 tumor-infiltrating lymphocytes and neutrophils were commonly seen in ypT0 tumors misdiagnosed by ECE-MR. CONCLUSIONS: Visual evaluation of ECE-MR is a promising diagnostic protocol for the detection of complete tumor response, especially for differentiation with early stage tumors. The accurate diagnosis of complete tumor response after neoadjuvant therapy using imaging modalities is of important significance for clinical decision-making for patients with esophageal squamous cell carcinoma. It is hoped that early contrast-enhanced MR will provide supportive advice for the development of individualized treatment options for patients.
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Meios de Contraste , Neoplasias Esofágicas , Imageamento por Ressonância Magnética , Terapia Neoadjuvante , Humanos , Masculino , Feminino , Estudos Retrospectivos , Pessoa de Meia-Idade , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/terapia , Neoplasias Esofágicas/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Seguimentos , Esofagectomia , Carcinoma de Células Escamosas do Esôfago/terapia , Carcinoma de Células Escamosas do Esôfago/patologia , Prognóstico , Idoso , Curva ROCAssuntos
Ácido Glicirrízico , Fotoquimioterapia , Mancha Vinho do Porto , Humanos , Fotoquimioterapia/efeitos adversos , Fotoquimioterapia/métodos , Mancha Vinho do Porto/tratamento farmacológico , Bandagens , Feminino , Fármacos Fotossensibilizantes/efeitos adversos , Fármacos Fotossensibilizantes/administração & dosagem , Pele/efeitos dos fármacos , Pele/patologia , Pele/efeitos da radiação , Ácido Aminolevulínico/efeitos adversos , AdultoRESUMO
Recent studies have shown that nucleophagy can mitigate DNA damage by selectively degrading nuclear components protruding from the nucleus. However, little is known about the role of nucleophagy in neurons after spinal cord injury (SCI). Western blot analysis and immunofluorescence were performed to evaluate the nucleophagy after nuclear DNA damage and leakage in SCI neurons in vivo and NSC34 expression in primary neurons cultured with oxygen-glucose deprivation (OGD) in vitro, as well as the interaction and colocalization of autophagy protein LC3 with nuclear lamina protein Lamin B1. The effect of UBC9, a Small ubiquitin-related modifier (SUMO) E2 ligase, on Lamin B1 SUMOylation and nucleophagy was examined by siRNA transfection or 2-D08 (a small-molecule inhibitor of UBC9), immunoprecipitation, and immunofluorescence. In SCI and OGD injured NSC34 or primary cultured neurons, neuronal nuclear DNA damage induced the SUMOylation of Lamin B1, which was required by the nuclear Lamina accumulation of UBC9. Furthermore, LC3/Atg8, an autophagy-related protein, directly bound to SUMOylated Lamin B1, and delivered Lamin B1 to the lysosome. Knockdown or suppression of UBC9 with siRNA or 2-D08 inhibited SUMOylation of Lamin B1 and subsequent nucleophagy and protected against neuronal death. Upon neuronal DNA damage and leakage after SCI, SUMOylation of Lamin B1 is induced by nuclear Lamina accumulation of UBC9. Furthermore, it promotes LC3-Lamin B1 interaction to trigger nucleophagy that protects against neuronal DNA damage.
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Autofagia , Dano ao DNA , Lamina Tipo B , Neurônios , Traumatismos da Medula Espinal , Sumoilação , Enzimas de Conjugação de Ubiquitina , Animais , Camundongos , Núcleo Celular/metabolismo , Lamina Tipo B/metabolismo , Lamina Tipo B/genética , Neurônios/metabolismo , Neurônios/patologia , Traumatismos da Medula Espinal/metabolismo , Traumatismos da Medula Espinal/genética , Traumatismos da Medula Espinal/patologia , Enzimas de Conjugação de Ubiquitina/metabolismo , Enzimas de Conjugação de Ubiquitina/genética , Camundongos Endogâmicos C57BL , Linhagem Celular TumoralRESUMO
6-methoxydihydrosanguinarine (6-MS), a natural benzophenanthridine alkaloid extracted from Macleaya cordata (Willd.) R. Br, has shown to trigger apoptotic cell death in cancer cells. However, the exact mechanisms involved have not yet been clarified. The current study reveals the underlying mechanisms of 6-MS-induced cytotoxicity in hepatocellular carcinoma (HCC) cells and investigates whether 6-MS sensitizes TNF-related apoptosis inducing ligand (TRAIL)-induced apoptosis. 6-MS was shown to suppress cell proliferation and trigger cell cycle arrest, DNA damage, and apoptosis in HCC cells. Mechanisms analysis indicated that 6-MS promoted reactive oxygen species (ROS) generation, JNK activation, and inhibits EGFR/Akt signaling pathway. DNA damage and apoptosis induced by 6-MS were reversed following N-acetyl-l-cysteine (NAC) treatment. The enhancement of PARP cleavage caused by 6-MS was abrogated by pretreatment with JNK inhibitor SP600125. Furthermore, 6-MS enhanced TRAIL-mediated HCC cells apoptosis by upregulating the cell surface receptor DR5 expression. Pretreatment with NAC attenuated 6-MS-upregulated DR5 protein expression and alleviated cotreatment-induced viability reduction, cleavage of caspase-8, caspase-9, and PARP. Overall, our results suggest that 6-MS exerts cytotoxicity by modulating ROS generation, EGFR/Akt signaling, and JNK activation in HCC cells. 6-MS potentiates TRAIL-induced apoptosis through upregulation of DR5 via ROS generation. The combination of 6-MS with TRAIL may be a promising strategy and warrants further investigation.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/patologia , Benzofenantridinas/farmacologia , Benzofenantridinas/uso terapêutico , Neoplasias Hepáticas/patologia , Regulação para Cima , Espécies Reativas de Oxigênio/metabolismo , Linhagem Celular Tumoral , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ligante Indutor de Apoptose Relacionado a TNF/farmacologia , Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Apoptose , Receptores ErbB/genéticaRESUMO
OBJECTIVE: To evaluate and compare the efficacy of different mind-body therapies (MBTs) for sleep disturbance in patients with early-stage cancer. METHODS: Randomised controlled trials that included patients (aged ≥18 years) with early stage cancer who underwent MBTs (mindfulness, hypnosis, relaxation, yoga, and qigong) were searched in the CINAHL via the EBSCO Host, Cochrane Library, Embase, MEDLINE, PsycINFO, PubMed, and Scopus databases, from the date of database inception to October 2022. The outcomes were subjective sleep disturbance and objective sleep efficiency. Network meta-analysis (NMA) and comparative effects ranking were performed using STATA (v14.0; STATACorp, College Station, TX, USA). RESULTS: Forty-seven studies investigating five MBTs were included in the NMA. For cancer patients receiving active treatment, mindfulness demonstrated the largest effect size in reducing subjective sleep disturbance (standardised mean difference [SMD]: 0.85; 95% confidence intervals [CI]: 0.20-1.50; Grading of Recommendations Assessment, Development, and Evaluation assessment: moderate), and had the highest cumulative probability compared to usual care or waitlist. For cancer patients who had completed active treatment, qigong demonstrated the largest effect size in reducing subjective sleep disturbance (SMD: 0.99; 95% CI: 0.35-1.63; GRADE: low), followed by hypnosis (SMD: 0.87; 95% CI: 0.32-1.42; GRADE: moderate), and mindfulness (SMD: 0.42; 95% CI: 0.24-0.59; GRADE: moderate). Qigong also demonstrated the largest effect size in improving objective sleep efficiency (weighted mean differences: 10.76; 95% CI: 2.01-19.50; GRADE: low); however, the effect of qigong was tested in only one study in this NMA. Among the eight different treatment conditions, cognitive behavioral therapy (CBT) showed the highest cumulative probability (surface under the cumulative ranking curve: 96.3%) in reducing subjective sleep disturbance and the second highest cumulative probability (SUCRA: 83.3%) in improving objective sleep efficiency. CONCLUSION: There is no evidence supporting the use of MBTs to replace or be comparable to CBT. Mindfulness can be recommended as an optional treatment for reducing sleep disturbance in patients with early-stage cancer. Some support was observed for qigong and hypnosis in reducing sleep disturbances in patients with early-stage cancer who had completed active treatment. More rigorous trials are warranted to confirm whether different forms of MBTs have different effects on sleep in patients with cancer.
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Terapia Cognitivo-Comportamental , Hipnose , Neoplasias , Yoga , Humanos , Adolescente , Adulto , Metanálise em Rede , Neoplasias/complicações , Neoplasias/terapiaRESUMO
Noise pollution has become one of the important social hazards that endanger the auditory system of residents, causing noise-induced hearing loss (NIHL). Oxidative stress has a significant role in the pathogenesis of NIHL, in which the silent information regulator 1(SIRT1)/proliferator-activated receptor-gamma coactivator 1α (PGC-1α) signaling pathway is closely engaged. Ginsenoside Rd (GSRd), a main monomer extract from ginseng plants, has been confirmed to suppress oxidative stress. Therefore, the hypothesis that GSRd may attenuate noise-induced cochlear hair cell loss seemed promising. Forty-eight male guinea pigs were randomly divided into four groups: control, noise exposure, GSRd treatment (30 mg/kg Rd for 10d + noise), and experimental control (30 mg/kg glycerol + noise). The experimental groups received military helicopter noise exposure at 115 dB (A) for 4 h daily for five consecutive days. Hair cell damage was evaluated by using inner ear basilar membrane preparation and scanning electron microscopy. Terminal dUTP nick end labeling (TUNEL) and immunofluorescence staining were conducted. Changes in the SIRT1/PGC-1α signaling pathway and other apoptosis-related markers in the cochleae, as well as oxidative stress parameters, were used as readouts. Loss of outer hair cells, more disordered cilia, prominent apoptosis, and elevated free radical levels were observed in the experimental groups. GSRd treatment markedly mitigated hearing threshold shifts, ameliorated outer hair cell loss and lodging or loss of cilia, and improved apoptosis through decreasing Bcl-2 associated X protein (Bax) expression and increasing Bcl-2 expression. In addition, GSRd alleviated the noise-induced cochlear redox injury by upregulating superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) levels, decreasing malondialdehyde (MDA) levels, and enhancing the activity of SIRT1 and PGC-1α messenger ribonucleic acid (mRNA) and protein expression. In conclusion, GSRd can improve structural and oxidative damage to the cochleae caused by noise. The underlying mechanisms may be associated with the SIRT1/PGC-1α signaling pathway.
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Aviação , Perda Auditiva Provocada por Ruído , Animais , Cobaias , Células Ciliadas Auditivas/metabolismo , Células Ciliadas Auditivas/patologia , Ruído , Estresse Oxidativo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Sirtuína 1/metabolismoRESUMO
INTRODUCTION: Type 1 diabetes (T1D) is a multifactorial autoimmune disease. Broad knowledge about the genetics, epidemiology and clinical management of T1D has been achieved, but understandings about the cell varieties in the bone marrow during T1D remain limited. OBJECTIVES: We aimed to present a profile of the bone marrow cells and reveal the relationship of bone marrow and osteopenia in streptozotocin (STZ)-induced T1D mice. METHODS: The whole bone marrow cells from the femurs and tibias of healthy (group C) and STZ-induced T1D mice (group D) were collected for single-cell RNA sequencing analysis. Single-cell flow cytometry and immunohistochemistry were performed to confirm the proportional changes among bone marrow neutrophils (BM-neutrophils) (Cxcr2+, Ly6g+) and B lymphocytes (Cd19+). X-ray and micro-CT were performed to detect bone mineral density. The correlation between the ratio of BM-neutrophils/B lymphocytes and osteopenia in STZ-induced T1D mice was analyzed by nonparametric Spearman correlation analysis. RESULTS: The bone marrow cells in groups C and D were divided into 12 clusters, and 249 differentially expressed genes were found. The diversity of CD45+ immune cells between groups C and D were greatly affected: the proportion of BM-neutrophils showed a significant increase while the proportion of B lymphocytes in group D showed a significant decrease. X-ray and micro-CT analyses confirmed that osteopenia occurred in group D mice. In addition, the results of single-cell flow cytometry and correlation analysis showed that the ratio of BM-neutrophils/B lymphocytes negatively correlated with osteopenia in STZ-induced T1D mice. CONCLUSION: A single-cell RNA sequencing analysis revealed the profile and heterogeneity of bone marrow immune cells in STZ-induced T1D mice for the first time. The ratio of BM-neutrophils/B lymphocytes negatively correlated with osteopenia in STZ-induced T1D mice, which may enhance understanding for treating T1D and preventing T1D-induced osteopenia.
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Doenças Ósseas Metabólicas , Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 1 , Camundongos , Animais , Estreptozocina , Medula Óssea , Análise de Sequência de RNARESUMO
This study aimed to explore the role of mitochondrial DNA copy number (mtDNAcn) in the risk, glucocorticoid (GC) effectiveness, and prognosis of systemic lupus erythematosus (SLE) and its interactions with environmental factors and tumor necrosis factor receptor-associated protein 1 (TRAP1) genetic polymorphisms. We first conducted a case-control study of 1198 subjects (595 SLE patients and 603 healthy controls). Subsequently, we followed up with patients to assess the effectiveness of GC treatment and the prognosis of SLE. Real-time fluorescent quantitative PCR (qPCR) was used to quantify mtDNAcn. Associations were estimated using logistic regression, and prognosis analysis was performed using Kaplan-Meier analysis and Cox proportional hazards models. Interactions on multiplicative and additive scales were also evaluated. Individuals with low mtDNAcn had an increased risk of SLE (P < 0.001). Low mtDNAcn was associated with poor GC effectiveness in patients with spicy food consumption or with arthritis (P < 0.05). mtDNAcn was significantly related to the prognosis of SLE in the drinking subgroup (P = 0.018). Furthermore, we found significant interactions between mtDNAcn and environmental factors/TRAP1 genetic polymorphisms on the risk, GC effectiveness, and prognosis of SLE. Our data suggest that low mtDNAcn is associated with an increased risk of SLE. Alteration of mtDNAcn may be associated with GC effectiveness and prognosis in certain subgroups of SLE. The interactions between mtDNAcn, environmental factors, and TRAP1 gene polymorphisms may jointly affect the risk, GC effectiveness, and prognosis of SLE.
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DNA Mitocondrial , Lúpus Eritematoso Sistêmico , Humanos , DNA Mitocondrial/genética , Glucocorticoides/uso terapêutico , Variações do Número de Cópias de DNA , Estudos de Casos e Controles , Lúpus Eritematoso Sistêmico/diagnóstico , Lúpus Eritematoso Sistêmico/genética , Prognóstico , Proteínas de Choque Térmico HSP90RESUMO
Despite tremendous progress made in the diagnosis and managements, head and neck squamous cell carcinoma (HNSC) remains a global medical dilemma with dismal clinical prognosis and high mortality. Gene NT5E encodes the ecto-5'-nucleotidase (CD73), which facilitates the formation of immunosuppressive tumor microenvironment (TME) permissive for tumor progression in various malignancies. Nevertheless, the cell subsets NT5E expressed on and the potential function of NT5E in the TME of HNSC remain virgin lands in HNSC. In this study, we comprehensively performed integrated prognostic analysis and elucidated that NT5E was an independent prognostic indicator for HNSC, for which a high NT5E level predicted poor overall survival (OS), disease-specific survival (DSS) and progression-free interval (PFI) in HNSC patients (p<0.05). Enrichment analyses revealed the close correlation between NT5E and ECM remodeling, and the latent function of NT5E may involve in epithelial-to-mesenchymal transition (EMT) and metastasis during HNSC progression. HNSC-related immune infiltration analysis and single-cell type analysis demonstrated that NT5E expression was significantly positively associated with cancer-associated fibroblasts (CAFs) in HNSC (p<0.01). NT5E-related TME analysis revealed that NT5E-high group are characterized by low neoantigen loads (NAL, p<0.001) and tumor mutation burden (TMB, p<0.01), indicating high-NT5E-expression HNSC patients may be recalcitrant to immunotherapy. In-situ multicolor immunofluorescence staining was later conducted and the results further verified our findings. Taken together, NT5E could be a novel biomarker in HNSC. Predominantly expressed on CAFs, the upregulation of NT5E might predict an immunosuppressive TME for HNSC patients who may benefit little from immunotherapy. Targeting CAFs with high NT5E expression might be a novel therapeutic strategy for HNSC patients.
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5'-Nucleotidase , Fibroblastos Associados a Câncer , Proteínas Ligadas por GPI , Neoplasias de Cabeça e Pescoço , Carcinoma de Células Escamosas de Cabeça e Pescoço , Microambiente Tumoral , 5'-Nucleotidase/genética , 5'-Nucleotidase/imunologia , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/imunologia , Fibroblastos Associados a Câncer/imunologia , Proteínas Ligadas por GPI/genética , Proteínas Ligadas por GPI/imunologia , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/imunologia , Humanos , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/imunologia , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia , Regulação para CimaRESUMO
PURPOSE We aimed to develop models for predicting overall survival (OS) and progression-free survival (PFS) of patients with primary hepatocellular carcinoma (HCC). METHODS Clinicopathological characteristics and laboratory information of patients were collected. We retrospectively analyzed presurgical data of 216 patients with primary HCC. The random forest and least absolute shrinkage and selection operator regression models were used to select features. We established prognostic models for predicting OS and PFS of primary liver cancer using ultrasonic imaging as well as clinical and pathological features. Accuracy of the models was evaluated using area under the curve, C index, and calibration curves, whereas their clinical application value was assessed using decision curve analysis. RESULTS Models for predicting OS and PFS were established based on ultrasonic imaging accessible features. The models showed excellent accuracy and prognosis prediction of OS and PFS in patients with primary HCC. CONCLUSION The established models based on factors such as aspartate aminotransferase platelet ratio index, Child-Turcotte-Pugh grade, tumor grade, hepatitis B virus-DNA, the intensity of ultrasound enhancement at the portal stage, lymphocyte/monocyte ratio, portal hypertension, gender, stage, the beginning time of ultrasonic contrast, and the total grade of ultrasonic enhancement can effectively predict OS and PFS of primary HCC.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Carcinoma Hepatocelular/diagnóstico por imagem , Carcinoma Hepatocelular/patologia , Humanos , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/patologia , Prognóstico , Intervalo Livre de Progressão , Estudos Retrospectivos , UltrassonografiaRESUMO
Port-wine stains (PWSs) are a congenital capillary malformed disorder and are caused by a number of somatic mutations that disrupt vascular development. However, the underlying genetic mutations in the pathogenesis of PWS have not yet been fully elucidated. To understand PWS genetic variations and investigate novel genetic mutations, we extracted genomic DNA from four sporadic PWS patients and then performed whole-genome sequencing (WGS). Using Sorting Intolerant from Tolerant (SIFT), PolyPhen2, Mutation Assessor, MetaSVM to identify candidate genetic mutations and whole-exome sequencing (WES) to confirm the identified variants. We found a previously reported G protein subunit alpha q (GNAQ) mutation c.548G > A, p.Arg183Gln in one case, whereas no such mutation was found in the other three samples. Moreover, six novel somatic mutations in three genes, including KCNJ12, SLC25A5, POTEE, were found in these four samples. Importantly, WES also verified the KCNJ12 (c.433G > A, p.Gly145Ser) and SLC25A5 (c.413G > A, p.Arg138His) mutations in other five sporadic PWS patients, with the frequency of 60% (3 of 5) and 40% (2 of 5), respectively. Thus, we reveal in this study two novel somatic mutations, KCNJ12 and SLC25A5, in the sporadic PWS patients for the first time. These findings highlight the genetic polymorphism of PWS and provide potential clinical prediction targets for this disease.
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INTRODUCTION: Mitochondrial transfer is a new cell-to-cell communication manner. Whether the mitochondrial transfer is also involved in the macrophage infiltration-induced cardiac injury is unclear. OBJECTIVES: This study aimed to determine whether macrophage mitochondria can be transferred to cardiomyocytes, and to investigate its possible role and mechanism. METHODS: Mitochondrial transfer between macrophages and cardiomyocytes was detected using immunofluorescence staining and flow cytometry. Cellular metabolites were analyzed using LC-MS technique. Differentially expressed mRNAs were identified using RNA-seq technique. RESULTS: (1) After cardiomyocytes were cultured with macrophage-conditioned medium (COND + group), macrophage-derived mitochondria have been found in cardiomyocytes, which could be blocked by dynasore (an inhibitor of clathrin-mediated endocytosis). (2) Compared with control (CM) group, there were 545 altered metabolites found in COND + group, most of which were lipids and lipid-like molecules. The altered metabolites were mainly enriched in the ß-oxidation of fatty acids and glutathione metabolism. And there were 4824 differentially expressed mRNAs, which were highly enriched in processes like lipid metabolism-associated pathway. (3) Both RNA-seq and qRT-PCR results found that ferroptosis-related mRNAs such as Ptgs2 and Acsl4 increased, and Gpx4 mRNA decreased in COND + group (P < 0.05 vs CM group). (4) The levels of cellular free Fe2+ and mitochondrial lipid peroxidation were increased; while GSH/GSSG ratio, mitochondrial aspect ratio, mitochondrial membrane potential, and ATP production were decreased in cardiomyocytes of COND + group (P < 0.05 vs CM group). All the above phenomena could be blocked by a ferroptosis inhibitor ferrostatin-1 (P < 0.05). CONCLUSION: Macrophages could transfer mitochondria to cardiomyocytes. Macrophage-derived mitochondria were internalized into cardiomyocytes through clathrin- and/or lipid raft-mediated endocytosis. Uptake of exogenous macrophage mitochondria induced cardiomyocyte injury via triggering ferroptosis.
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Ferroptose , Miócitos Cardíacos , Clatrina/metabolismo , Ferroptose/genética , Macrófagos/metabolismo , Mitocôndrias , Miócitos Cardíacos/metabolismoRESUMO
BACKGROUND AND AIMS: This updated meta-analysis aimed to further quantify the risk of endometrial, ovarian, and breast cancer in patients with polycystic ovary syndrome (PCOS), thus providing updated and more reliable estimates. METHODS AND RESULTS: We identified relevant articles by searching electronic databases of PubMed, Embase, Web of Science, and Chinese Biological Medical Literature (CBM) published up to March 20, 2021. The pooled effect estimates and their 95% confidence intervals (CIs) were calculated using the random-effect model or the fixed-effect model. A total of 26 eligible studies were included. We found that PCOS was significantly associated with endometrial cancer (odds ratios [OR]: 3.66, 95%CI: 2.05-6.54, P < 0.001), but not with ovarian or breast cancer (OR: 1.23, 95%CI: 0.99-1.53, P = 0.059; OR: 0.94, 95%CI: 0.78-1.14, P = 0.551, respectively). However, in subgroups of high-quality studies, cohort studies, younger women (54 years or less or premenopausal), and studies with unadjusted body mass index (BMI), PCOS patients had a significantly higher risk of ovarian cancer. CONCLUSION: These results indicated that PCOS is a significant risk factor for endometrial cancer independent of BMI, but not for breast cancer. PCOS may increase the risk of ovarian cancer in younger women.
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Neoplasias da Mama , Neoplasias do Endométrio , Neoplasias Ovarianas , Síndrome do Ovário Policístico , Neoplasias da Mama/complicações , Neoplasias da Mama/etiologia , Neoplasias do Endométrio/complicações , Neoplasias do Endométrio/etiologia , Feminino , Humanos , Neoplasias Ovarianas/epidemiologia , Neoplasias Ovarianas/etiologia , Síndrome do Ovário Policístico/complicações , Síndrome do Ovário Policístico/epidemiologia , Fatores de RiscoRESUMO
OBJECTIVE: The majority of giant cell tumors of bone (GCTB) occur in adult patients, especially between the ages of 20 and 40. This study aims to investigate the imaging features of GCTBs in pediatric patients and compare their characteristics with adult cases. METHODS: Fifty-seven cases of patients aged 18 years old or younger were retrospectively analyzed, accounting for 12.8% of GCTBs in the First Affiliated Hospital of Zhengzhou University from 2001 to 2019. One hundred twenty-six adult patients (19 years of age and older) with GCTB occurring in long tubular bones were also included in this study. The following clinical information was identified from the medical records: age, sex, and follow-up data. Imaging features were reviewed by two musculoskeletal radiologists. Patient characteristics and imaging features between the two groups were compared. RESULTS: A total of 57 patients (32 females, 25 males) were included in the study. The patients' ages ranged from 9 to 18 (median = 17 y). The majority of tumors occurred in tubular bones (n = 38, 66.7%) and the pelvis (n = 8, 14.0%). Imaging features were identified in GCTB cases occurring in the long tubular bones. Compared with adult GCTB patients, pediatric GCTB patients had a larger superior-inferior (SI) diameter (P = 0.005) and smaller left-to-right diameter/SI diameter ratio (P = 0.001). Epiphyseal involvement was relatively less common in pediatric patients with GCTBs than in adult patients (P = 0.009). The median age of patients without epiphyseal involvement was lower than the median age of patients with epiphyseal involvement (11 vs 17 y). CONCLUSION: GCTB in the pediatric age group is rare. This study has found that, in pediatric patients with GCTBs, the epiphysis is relatively less involved, and the tumor is more likely to grow longitudinally. These findings are helpful in the diagnosis of GCTBs in the pediatric population.
RESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Astragaloside IV (AST IV) is the active component of Astragalus membranaceus (Fisch.) Bunge, which regulates lipid and carbohydrate metabolism and improves insulin resistance. In this study, we investigated the effects of AST IV on insulin resistant cells and a non-alcoholic fatty liver disease (NAFLD) model induced by high-concentration insulin or oleic acid (OA) in HepG2 cells, as well as the associated regulatory markers. METHODS: First, the target of AST IV was predicted via pharmacophore model matching and molecular docking. Then, enzyme kinetics experiments were conducted in vitro to determine the effect of AST IV on the target protein. Next, AST IV's toxicity was tested on HepG2 cells in vitro, through an insulin resistance model and an NAFLD model, by high-concentration insulin or OA, respectively. To explore the effects of AST IV on insulin resistance and lipid metabolism, we detected the related indexes of glucose and lipid metabolism through commercially available kits. Relevant proteins were also detected by Western blot to provide future direction for study. RESULTS: Our preliminary results of pharmacophore model matching and molecular docking suggested that AST IV and protein tyrosine phosphatase 1B (PTP1B) can be well-combined through hydrogen bonding. Further, the enzyme kinetics experiment showed that AST IV was an effective and specific inhibitor to PTP1B. We found that the protein level of PTP1B in HepG2 cells was significantly increased after treating with high-concentration insulin or OA. Additionally, the intervention of AST IV significantly increased glucose consumption in an insulin resistance model and reduced the content of triglyceride (TG), total cholesterol (TC), and free fatty acid (FFA) in the NAFLD model. Moreover, the 2-N-(7-nitrobenze-2-oxa-1, 3 diazol-4-yl) (2-NBDG) uptake rate in the NAFLD model was also greatly improved. These results validated the effects of AST IV on improving insulin resistance and lipid accumulation. Furthermore, Western blot results illustrated that AST IV suppressed PTP1B and increased levels of phosphorylated insulin receptor (p-IR) and phosphorylated insulin receptor substrate-1 (p-IRS-1) in insulin-resistant HepG2 cells, while also decreasing protein levels of PTP1B and sterol element regulatory binding protein-1c (SREBP-1c) in the NAFLD model. CONCLUSION: This study demonstrated that AST IV inhibited PTP1B and effectively improved insulin resistance in insulin-resistant HepG2 cells and triglyceride accumulation in OA-treated HepG2 cells.
Assuntos
Resistência à Insulina/fisiologia , Ácido Oleico/farmacologia , Proteína Tirosina Fosfatase não Receptora Tipo 1/antagonistas & inibidores , Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo , Saponinas/farmacologia , Triglicerídeos/metabolismo , Triterpenos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Relação Dose-Resposta a Droga , Medicamentos de Ervas Chinesas/farmacologia , Células Hep G2 , HumanosRESUMO
Oxidative stress and apoptosis are the key factors that limit the hypothermic preservation time of donor hearts to within 4-6 h. The aim of this study was to investigate whether the histone deacetylase 3 (HDAC3) inhibitor RGFP966 could protect against cardiac injury induced by prolonged hypothermic preservation. Rat hearts were hypothermically preserved in Celsior solution with or without RGFP966 for 12 h followed by 60 min of reperfusion. Hemodynamic parameters during reperfusion were evaluated. The expression and phosphorylation levels of mammalian STE20-like kinase-1 (Mst1) and Yes-associated protein (YAP) were determined by western blotting. Cell apoptosis was measured by the terminal deoxynucleotidyl-transferase (TdT)-mediated dUTP nick-end labeling (TUNEL) method. Addition of RGFP966 in Celsior solution significantly inhibited cardiac dysfunction induced by hypothermic preservation. RGFP966 inhibited the hypothermic preservation-induced increase of the phosphorylated (p)-Mst1/Mst1 and p-YAP/YAP ratios, prevented a reduction in total YAP protein expression, and increased the nuclear YAP protein level. Verteporfin (VP), a small molecular inhibitor of YAP-transcriptional enhanced associate domain (TEAD) interaction, partially abolished the protective effect of RGFP966 on cardiac function, and reduced lactate dehydrogenase activity and malondialdehyde content. RGFP966 increased superoxide dismutase, catalase, and glutathione peroxidase gene and protein expression, which was abolished by VP. RGFP966 inhibited hypothermic preservation-induced overexpression of B-cell lymphoma protein 2 (Bcl-2)-associated X (Bax) and cleaved caspase-3, increased Bcl-2 mRNA and protein expression, and reduced cardiomyocyte apoptosis. The antioxidant and anti-apoptotic effects of RGFP966 were cancelled by VP. The results suggest that supplementation of Celsior solution with RGFP966 attenuated prolonged hypothermic preservation-induced cardiac dysfunction. The mechanism may involve inhibition of oxidative stress and apoptosis via inactivation of the YAP pathway.
Assuntos
Acrilamidas/farmacologia , Criopreservação , Transplante de Coração/métodos , Inibidores de Histona Desacetilases/farmacologia , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Fenilenodiaminas/farmacologia , Animais , Apoptose/efeitos dos fármacos , Dissacarídeos/farmacologia , Eletrólitos/farmacologia , Glutamatos/farmacologia , Glutationa/farmacologia , Coração/efeitos dos fármacos , Coração/fisiologia , Fator de Crescimento de Hepatócito/antagonistas & inibidores , Histidina/farmacologia , Masculino , Manitol/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Proteínas de Sinalização YAPRESUMO
BACKGROUND: Fungal rhinosinusitis is an infectious and/or allergic disease caused by fungi in the sinus and nasal cavity. Due to the warm and humid climate in Guangxi Zhuang Autonomous Region, the incidence of fungal rhinosinusitis is higher than that in other provinces. However, its physiological mechanism is not yet clear. Not every patient colonized by fungi develops a fungal infection. To a large extent, the immune status of the patient determines the nature of fungal disease in the nasal passages. The pathologic process of progression from harmless fungal colonization to fungal rhinosinusitis is unclear and has not been reported. CASE SUMMURY: We report two patients, one who developed fungal rhinosinusitis 1.5 years after surgery performed to treat an inverted papilloma, and the other with a history of hypertension and cerebral infarction. Both patients recovered from their surgeries. An average time of 2.5 years elapsed from the development of maxillary sinus cysts to the development of fungal rhinosinusitis. CONCLUSION: According to these case reports, we speculate that the progression of fungal rhinosinusitis from harmless colonization to disease onset requires approximately one to three years and that the length of the process may be related to underlying diseases, surgical treatment, deficient autoimmune status, and abuse of hormone antibiotics and hormones. Additional data are needed to conduct relevant studies to appropriately prevent and treat fungal rhinosinusitis.