RESUMO
PURPOSE: This phase I trial is to determine the recommended dose of the TAS-102, irinotecan plus bevacizumab regimen and assess its safety and efficacy in patients with metastatic colorectal cancer refractory to fluoropyrimidine and oxaliplatin treatment. METHODS: A 3 + 3 designed dose escalation was performed. Patients were administered TAS-102 (30-35 mg/m2 twice daily on days 1-5) and irinotecan (150-165 mg/m2 on day 1) combined with a fixed dose of bevacizumab (5 mg/kg on day 1) every two weeks. The primary endpoint was the determination of the recommended phase II dose. RESULTS: Eighteen patients were enrolled: 6 at the Level 1 (TAS-102 30 mg/m2 twice daily, irinotecan 150 mg/m2 plus bevacizumab 5 mg/kg), six at the Level 2 (TAS-102 35 mg/m2 twice daily, irinotecan 150 mg/m2 plus bevacizumab 5 mg/kg), and six at the Level 3 (TAS-102 30 mg/m2 twice daily, irinotecan 165 mg/m2 plus bevacizumab 5 mg/kg). Five dose-limiting toxicities occurred: one observed at Level 1 (thrombocytopenia), two at Level 2 (neutropenia and diarrhea), and two at Level 3 (fatigue and neutropenia). The RP2D was established as TAS-102 30 mg/m2 twice daily and irinotecan 150 mg/m2 plus bevacizumab 5 mg/kg. The most frequent grade 3/4 treatment-related adverse events were neutropenia (33.3%), diarrhea (16.7%), and thrombocytopenia (11.1%). No treatment-related death occurred. Two patients (11.1%) experienced partial responses and 14 (77.8%) had stable disease. CONCLUSION: The regimen of TAS-102, irinotecan, and bevacizumab is tolerable with antitumor activity for metastatic colorectal cancer patients refractory to first-line fluoropyrimidines and oxaliplatin treatment.
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Protocolos de Quimioterapia Combinada Antineoplásica , Bevacizumab , Neoplasias Colorretais , Combinação de Medicamentos , Irinotecano , Pirrolidinas , Timina , Trifluridina , Uracila , Humanos , Timina/administração & dosagem , Trifluridina/administração & dosagem , Trifluridina/uso terapêutico , Trifluridina/efeitos adversos , Bevacizumab/administração & dosagem , Bevacizumab/efeitos adversos , Bevacizumab/uso terapêutico , Masculino , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Feminino , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Pessoa de Meia-Idade , Pirrolidinas/administração & dosagem , Pirrolidinas/efeitos adversos , Pirrolidinas/uso terapêutico , Idoso , Irinotecano/administração & dosagem , Irinotecano/efeitos adversos , Irinotecano/uso terapêutico , Uracila/análogos & derivados , Uracila/administração & dosagem , Uracila/uso terapêutico , Uracila/efeitos adversos , Adulto , Metástase NeoplásicaRESUMO
By directly harming cancer cells, radiotherapy (RT) is a crucial therapeutic approach for the treatment of cancers. However, the efficacy of RT is reduced by the limited accumulation and short retention time of the radiosensitizer in the tumor. Herein, we developed hypoxia-triggered in situ aggregation of nanogapped gold nanospheres (AuNNP@PAA/NIC NPs) within the tumor, resulting in second near-infrared window (NIR-II) photoacoustic (PA) imaging and enhanced radiosensitization. AuNNP@PAA/NIC NPs demonstrated increased accumulation and retention in hypoxic tumors, mainly due to the hypoxia-triggered aggregation. After aggregation of AuNNP@PAA/NIC NPs, the absorption of the system extended from visible light to NIR-II light owing to the plasmon coupling effects between adjacent nanoparticles. Compared to the normoxic tumor, the PA intensity at 1200 nm in the hypoxic tumor increased from 0.42 to 1.88 at 24 h postintravenous injection of AuNNP@PAA/NIC NPs, leading to an increase of 4.5 times. This indicated that the hypoxic microenvironment in the tumor successfully triggered the in situ aggregation of AuNNP@PAA/NIC NPs. The in vivo radiotherapeutic effect demonstrated that this hypoxia-triggered in situ aggregation of radiosensitizers significantly enhanced radiosensitization and thus resulted in superior cancer radiotherapeutic outcomes.
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Nanopartículas Metálicas , Nanopartículas , Neoplasias , Técnicas Fotoacústicas , Radiossensibilizantes , Humanos , Ouro , Técnicas Fotoacústicas/métodos , Neoplasias/diagnóstico por imagem , Neoplasias/radioterapia , Neoplasias/patologia , Radiossensibilizantes/farmacologia , Hipóxia , Linhagem Celular Tumoral , Microambiente TumoralRESUMO
The cardiac glycoside digoxin was identified as a potent suppressor of pyruvate kinase isoform 2-hypoxia-inducible factor-α (PKM2-HIF-1α) pathway activation in liver injury mouse models via intraperitoneal injection. We have assessed the therapeutic effects of digoxin to reduce nonalcoholic steatohepatitis (NASH) by the clinically relevant oral route in mice and analyzed the cellular basis for this effect with differential involvement of liver cell subsets. C57BL/6J male mice were placed on a high-fat diet (HFD) for 10 wk and started concurrently with the gavage of digoxin (2.5, 0.5, 0.125 mg/kg twice a week) for 5 wk. Digoxin significantly reduced HFD-induced hepatic damage, steatosis, and liver inflammation across a wide dosage range. The lowest dose of digoxin (0.125 mg/kg) showed significant protective effects against liver injury and sterile inflammation. Consistently, digoxin attenuated HIF-1α sustained NLRP3 inflammasome activation in macrophages. We have reported for the first time that PKM2 is upregulated in hepatocytes with hepatic steatosis, and digoxin directly improved hepatocyte mitochondrial dysfunction and steatosis. Mechanistically, digoxin directly bound to PKM2 and inhibited PKM2 targeting HIF-1α transactivation without affecting PKM2 enzyme activation. Thus, oral digoxin showed potential to therapeutically inhibit liver injury in NASH through the regulation of PKM2-HIF-1α pathway activation with involvement of multiple cell types. Because of the large clinical experience with oral digoxin, this may have significant clinical applicability in human NASH.NEW & NOTEWORTHY This study is the first to assess the therapeutic efficacy of oral digoxin on nonalcoholic steatohepatitis (NASH) in a high-fat diet (HFD) mouse model and to determine the divergent of cell type-specific effects. Oral digoxin reduced liver damage, steatosis, and inflammation in HFD mice. Digoxin attenuated hypoxia-inducible factor (HIF)-1α axis-sustained inflammasome activity in macrophages and hepatic oxidative stress response in hepatocytes via the regulation of PKM2-HIF-1α axis pathway activation. Oral digoxin may have significant clinical applicability in human NASH.
Assuntos
Digoxina/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Hepatócitos/enzimologia , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Piruvato Quinase/antagonistas & inibidores , Ativação Transcricional/efeitos dos fármacos , Animais , Linhagem Celular , Dieta Hiperlipídica , Hepatite/patologia , Hepatócitos/efeitos dos fármacos , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Estresse Oxidativo/efeitos dos fármacos , Piruvato Quinase/metabolismoRESUMO
Purpose: Immunotherapy has demonstrated durable clinical responses in various cancers by disinhibiting the immune system, largely attributed to the success of immune-checkpoint blockade. However, there are still subsets of patients across multiple cancers not showing robust responses to these agents and one significant barrier to their efficacy may be the recruitment of myeloid-derived suppressor cells (MDSCs) into the tumor microenvironment. In this study, we demonstrated that functional inhibition of MDSCs with (3 R)-5,6,7-trihydroxy-3-isopropyl-3-methylisochroman-1-one (TIMO), a potent PI3Kδ/γ inhibitor, enhanced the therapeutic efficacy of anti-PD1 antibody in the tumor model.Materials and methods: A syngeneic ovarian tumor model was established. MDSCs from the peripheral blood and tumor parenchyma were analyzed by flow cytometry. Proliferation and killing effects of T-lymphocytes were measured. IFNγ production was measured by ELISA assay. qPCR and western blot were used to detect the gene and protein expression. Furthermore, the therapeutic effects of TIMO combined with anti-PD1 antibody were assessed by the tumor model.Results: Our data demonstrated that inhibition of granulocytic myeloid-derived suppressor cells (G-MDSCs) function with TIMO could overcome MDSCs-mediated immunosuppression and promote antigen-specific T-lymphocyte responses, resulting in the restoration of cytotoxic T cell-mediated tumor control. We further demonstrated that TIMO and anti-PD1 combination therapy promoted tumor growth control in a syngeneic ovarian tumor model.Conclusions: Our results provided proof of concept for a new combination strategy involving the use of a selective inhibitor of PI3Kδ/γ to inhibit the function of MDSCs to enhance tumor responses to immune checkpoint blocking antibodies.
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Antineoplásicos Imunológicos/farmacologia , Cromanos/farmacologia , Classe I de Fosfatidilinositol 3-Quinases , Classe Ib de Fosfatidilinositol 3-Quinase/imunologia , Imunoterapia , Células Supressoras Mieloides/imunologia , Proteínas de Neoplasias/antagonistas & inibidores , Neoplasias Experimentais , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Microambiente Tumoral , Animais , Linhagem Celular Tumoral , Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Classe I de Fosfatidilinositol 3-Quinases/imunologia , Feminino , Camundongos , Células Supressoras Mieloides/patologia , Proteínas de Neoplasias/imunologia , Neoplasias Experimentais/imunologia , Neoplasias Experimentais/patologia , Neoplasias Experimentais/terapia , Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/terapia , Receptor de Morte Celular Programada 1/imunologia , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologiaRESUMO
BACKGROUND/AIMS: Aberrant localization and over-expression of Ezrin have been reported to be implicated in cervical cancer (CC). Aberrant promoter methylation of some gene families may serve as potential diagnostic biomarkers for CC. In this study, we explored the correlation of promoter methylation of the Ezrin gene with the incidence and prognosis of CC. METHODS: Cervical tissues from a total of 483 patients with CC were collected from the China-Japan Union Hospital of Jilin University. Samples were assigned into four groups accordingly to pathological diagnosis, namely the control group, the cervical intraepithelial neoplasia (CIN) I group, the CIN II-III group and the CC group. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) was performed to detect the mRNA expression of Ezrin. Methylation-specific polymerase chain reaction (MSP) was used to detect the promoter methylation of the Ezrin gene. The Kaplan-Meier product-limit method and the log-rank analysis were used for survival analysis, the Cox regression analysis for the prognostic factors for CC, and the logistic regression analysis for the risk factors for the occurrence of CC. RESULTS: The methylation rate of the Ezrin gene was correspondingly increased from the control, the CIN I, the CIN II-III to the CC groups. Over-expressed mRNA of Ezrin was determined in CC tissues. The mRNA expression of Ezrin was correlated with tumor size, lymphatic metastasis, pathological grade and clinical stage (FIGO). The risk factors for the occurrence of CC were the number of abortions and the promoter methylation of the Ezrin gene. Poor prognosis of CC correlated to lymphatic metastasis, higher pathological grade, higher FIGO stage and positive Ezrin promoter methylation. CONCLUSION: These findings indicate that promoter methylation of the Ezrin gene may play a crucial role in carcinogenesis, progression and prognosis of CC.
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Proteínas do Citoesqueleto/genética , Metilação de DNA , Neoplasias do Colo do Útero/patologia , Adulto , China/epidemiologia , Proteínas do Citoesqueleto/metabolismo , Feminino , Humanos , Incidência , Estimativa de Kaplan-Meier , Metástase Linfática , Ciclo Menstrual , Pessoa de Meia-Idade , Gradação de Tumores , Prognóstico , Regiões Promotoras Genéticas , Modelos de Riscos Proporcionais , Fatores de Risco , Neoplasias do Colo do Útero/epidemiologia , Neoplasias do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/mortalidadeRESUMO
Increasing evidence has demonstrated the involvement of dysregulated long non-coding RNAs (lncRNAs) in chemoresistance acting as potential oncogenes or tumor suppressors in various cancers. Nevertheless, the profound molecular mechanisms of lncRNAs in ovarian cancer (OC) chemoresistance is not well elucidated. The objective of this work was to investigate the role and molecular mechanisms of urothelial carcinoma associated 1 (UCA1) in paclitaxel (PTX) resistance in OC. Our results indicated that UCA1 was significantly up-regulated in PTX-resistant OC cells (SKOV3/PTX and HeyA-8/PTX) compared with their parental cells (SKOV3 and HeyA-8). Functionally, UCA1 knockdown sensitized SKOV3/PTX and HeyA-8/PTX cells to PTX through enhancing PTX-induced apoptosis. Mechanistically, UCA1 silencing induced PTX sensitivity of SKOV3/PTX and HeyA-8/PTX cells by de-repressing ABCB1 through sponging miR-129. Collectively, our study elaborated a novel UCA1/miR-129/ABCB1 regulatory axis underlying PTX resistance of OC cells, providing a potential therapeutic target for OC.
Assuntos
Resistencia a Medicamentos Antineoplásicos/genética , MicroRNAs/genética , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Paclitaxel/uso terapêutico , RNA Longo não Codificante/metabolismo , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Sequência de Bases , Linhagem Celular Tumoral , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/genética , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Humanos , MicroRNAs/metabolismo , Paclitaxel/farmacologia , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genéticaRESUMO
Polycystic ovary syndrome (PCOS) is a common disease associated with high androgen and infertility. The gut microbiota plays an important role in metabolic diseases including obesity, hyperglycemia, and fatty liver. Although the gut microbiota has been associated with PCOS, little is known about the gut microbial structure and function in individuals with PCOS from Northeast China. In this study, 17 PCOS individuals and 17 age-matched healthy individuals were recruited for community structure and function analysis of the gut microbiota. The results showed that PCOS individuals have reduced diversity and richness of the gut microbiota compared with healthy individuals. Beta diversity analysis showed that the community structure of the gut microbiota of individuals with PCOS was significantly separated from healthy individuals. At the phylum level, PCOS individuals have reduced Firmicutes and Bacteroidota and increased Actinobacteriota and Proteobacteria compared with healthy individuals. At the family and genus levels, the composition of the gut microbiota between PCOS patients and healthy individuals was also significantly different. In addition, PICRUSt2 showed that individuals with PCOS have different microbial functions in the gut compared with healthy individuals. We finally confirmed that Bifidobacterium was enriched in the fecal samples of PCOS patients, while other 11 genera including Bacteroides, UCG_002, Eubacterium__coprostanoligenes_group_unclassified, Dialister, Firmicutes_unclassified, Ruminococcus, Alistipes, Christensenellaceae_R_7_group, Clostridia_UCG_014_unclassified, Roseburia, and Lachnospiraceae_unclassified were depleted compared with healthy individuals. These results indicate that individuals with PCOS have altered community structure and functions of the gut microbiota, which suggests that targeting the gut microbiota might be a potential strategy for PCOS intervention. IMPORTANCE: Gut microbiota plays a critical role in the development of PCOS. There is a complex and close interaction between PCOS and gut microbiota. The relationship between the pathogenesis and pathophysiological processes of PCOS and the structure and function of the gut microbiota needs further investigation.
Assuntos
Bactérias , Disbiose , Fezes , Microbioma Gastrointestinal , Síndrome do Ovário Policístico , Humanos , Síndrome do Ovário Policístico/microbiologia , Feminino , Fezes/microbiologia , Adulto , Disbiose/microbiologia , Bactérias/classificação , Bactérias/isolamento & purificação , Bactérias/genética , Adulto Jovem , China , RNA Ribossômico 16S/genéticaRESUMO
OBJECTIVE: To investigate the effects and mechanisms of Erbanxiao solution in inhibiting tumor angiogenesis. METHODS: We observed the effects and mechanisms of Chinese medicines on inhibiting tumor angiogenesis and studied the theories and results of treatment. Sixty patients with lung cancer were randomized into two groups (n = 30). Patients in the control group were given compound Kushen injection, and patients in the treatment group were given Erbanxiao solution. The effect of Erbanxiao solution on vascular endothelium growth factor (VEGF), basic fibroblast growth factor (bFGF), and tumor necrosis factor-alpha (TNF-alpha) was observed. RESULTS: The effective rate of the treatment group was 60% while the control group was 36%. There was a significant difference between the two groups (P < 0.05). VEGF, bFGF, and TNF-alpha levels of the two groups were significantly different before and after treatment (P < 0.01). These Traditional Chinese Medicines significantly inhibited tumor angiogenesis, possibly by changing levels of VEGF, bFGF, and TNF-alpha. CONCLUSION: It is necessary to further explore the potential of Traditional Chinese Medicine in the treatment of angiogenesis in tumor patients.
Assuntos
Inibidores da Angiogênese/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Medicamentos de Ervas Chinesas/administração & dosagem , Neoplasias Pulmonares/tratamento farmacológico , Idoso , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Feminino , Fator 2 de Crescimento de Fibroblastos/genética , Fator 2 de Crescimento de Fibroblastos/metabolismo , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Masculino , Pessoa de Meia-Idade , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
Endometritis is an inflammatory condition that affects the endometrium; it is induced by bacterial infection and often leads to infertility and repeated abortions. Farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily that mediates a variety of inflammatory diseases. In the present study, we determined the protective effects of FXR on lipopolysaccharide (LPS)-induced endometritis in mice and the underlying mechanisms. The results showed that LPS administration reduced the expression of FXR in the uterus, and treatment with the FXR agonist GW4064 and fexaramine significantly alleviated the endometritis induced by LPS. In addition, compared with wild-type (WT) mice, FXR-knockout mice had more severe inflammatory responses in their uteri after LPS treatment. Moreover, ferroptosis was increased during LPS-induced endometritis, as shown by increased levels of malondialdehyde (MDA) and iron, and decreased levels of superoxide dismutase (SOD), glutathione (GSH), GXP4 and SLC7A11. In addition, inhibition of ferroptosis by treatment with ferrostation-1 (Fer-1) and liproxstatin (Lip-1) alleviated LPS-induced endometritis. Additionally, FXR-knockout mice were used to determine the relationship between FXR and ferroptosis. The results showed that knockout of FXR induced ferroptosis, and an FXR agonist inhibited LPS-induced ferroptosis. Finally, the regulatory effects of obeticholic acid (OCA) on FXR/ferroptosis and endometritis were assessed. The results showed that treatment with OCA increased the expression of FXR, decreased the levels of ferroptosis, and inhibited the endometritis induced by LPS. In conclusion, the results showed that activation of FXR can alleviate LPS-induced endometritis by inhibiting ferroptosis, and FXR may be a potential therapeutic target for treating endometritis.
Assuntos
Endometrite , Ferroptose , Humanos , Gravidez , Feminino , Animais , Camundongos , Endometrite/induzido quimicamente , Endometrite/tratamento farmacológico , Lipopolissacarídeos/farmacologia , Endométrio , Camundongos Knockout , Camundongos Endogâmicos C57BLRESUMO
Polycystic ovary syndrome (PCOS) is a serious disease characterized by high androgen, insulin resistance (IR), hyperglycemia, and obesity, leading to infertility. The gut mycobiota has been reported to evolve in metabolic diseases including obesity, hyperglycemia, and fatty liver. However, little is known about the gut mycobiota and PCOS. In the current study, we recruited 17 PCOS patients and 17 age-matched healthy controls for community structure and functional analysis of the gut mycobiota. The results showed that PCOS patients have reduced diversity and richness of the gut microbiota compared with healthy controls. ß-Diversity analysis showed that the community structure of the gut microbiota of patients with PCOS was significantly different from healthy controls. At the phylum level, PCOS patients have reduced Basidiomycota and increased Ascomycota compared with healthy controls. At the family level, the higher relative abundance of Saccharomycetaceae and lower Trichosporonaceae and Ascomycota_unclassified were detected in PCOS patients than in healthy controls. At the genus level, different microbial compositions were also observed between PCOS patients and healthy controls. In addition, PICRUSt2 showed that patients with PCOS have different microbial functions in the gut compared with healthy controls. LEfSe indicated that Saccharomyces and Lentinula were enriched in the fecal samples of PCOS patients, while Aspergillus was depleted compared with healthy controls. Our finding indicates that PCOS patients have different community structures and functions of the gut mycobiota, which provides new insight into PCOS pathogenesis and intervention. IMPORTANCE It was found that intestinal fungi as well as serum metabolites in PCOS patients were significantly different from those in healthy subjects. However, no studies have been done to show exactly which fungus interacts with which bacteria in humans or which fungus acts alone. As fungal research progresses, it will be possible to fill this gap.
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Phototheranostics integrating optical imaging and phototherapy has attracted extensive attention. Achieving nanophototherapeutics with near infrared (NIR)-light synchronously triggered photodynamic therapy (PDT) and photothermal therapy (PTT) is challenging. Herein, we develop a multifunctional theranostic nanoplatform prepared from the co-assembly of NIR boron dipyrromethene (BODIPY) with a cooperative D-π-A structure of a thiophene-BODIPY core and benzene-diethylamino, and a choline phosphate lipid. The as-fabricated nanoparticles (DBNPs) exhibited desirable NIR absorption, uniform spherical morphology and good colloidal stability. The elaborate molecular design and supramolecular assembly endowed DBNPs with desirable PDT and PTT activities. Upon 808 nm laser irradiation, the DBNPs efficiently generated active singlet oxygen and regional hyperpyrexia, with a photothermal conversion efficiency of 37.6%. The excellent PDT and PTT performance of DBNPs boosted the potent in vitro and in vivo anti-tumor effects. In addition, these nanoparticles manifested their good capability of NIR fluorescence imaging of tumors. Overall, the DBNPs provide a paradigm for delivering hydrophobic phototherapy molecules with phospholipids for enhanced tumor treatment and imaging.
Assuntos
Nanopartículas , Neoplasias , Humanos , Boro , Fosforilcolina , Nanopartículas/química , Neoplasias/diagnóstico por imagem , Neoplasias/tratamento farmacológico , Imagem Óptica , LipídeosRESUMO
Endometritis, inflammation of the endometrium, is a major cause of subfertility in women. Selenomethionine (SeMet)is known to exert anti-inflammatory activity. We aimed to verify the protective roles of SeMet on Escherichia coli (E.coli)-induced endometritis. The extent of uterus damage was assessed by detecting histopathology and inflammatory mediators. The results revealed that SeMet significantly prevented E.coli-induced endometritis by attenuating uterine histopathology and inflammatory cytokine production. E.coli-induced MPO activity and MDA content were inhibited by SeMey. E.coli-induced ZO-1 and occludin were upregulated by SeMet. E.coli-induced necroptosis was also inhibited by SeMet. Additionally, E.coli-induced NF-κB activation was alleviated by SeMet. PPAR-γ expression was upregulated by SeMet. Notably, the protective effects of SeMet on endometritis were abolished by a PPAR-γ inhibitor. In conclusion, SeMet inhibits E.coli-induced endometritis by attenuating inflammation and necroptosis, which is mediated by the PPAR-γ/NF-κB signaling pathway.
Assuntos
Endometrite , Feminino , Humanos , Endometrite/prevenção & controle , Endometrite/induzido quimicamente , Endometrite/metabolismo , NF-kappa B/metabolismo , Selenometionina/efeitos adversos , PPAR gama , Escherichia coli/metabolismo , Necroptose , Inflamação/prevenção & controle , LipopolissacarídeosRESUMO
Endometriosis is a common gynecological disease, that often leads to pain and infertility. At present, the specific pathogenesis of endometriosis has not been clarified, but it may be closely related to an imbalance of sex hormones in the body, ectopic hyperplasia stimulated by immune inflammation, and invasion and escape based on tumor characteristics. Gut microbiota is associated with many inflammatory diseases. With the further study of the gut microbiota, people are paying increasing attention to its relationship with endometriosis. Studies have shown that there is an association between the gut microbiota and endometriosis. The specific ways and mechanisms by which the gut microbiota participates in endometriosis may involve estrogen, immune inflammation, and tumor characteristics, among others. Therefore, in the future, regulating gut microbiota disorders in various ways can help in the treatment of endometriosis patients. This study reviewed the research on the gut microbiota and endometriosis in order to provide ideas for clinical diagnosis and treatment.
Assuntos
Microbioma Gastrointestinal , Feminino , Humanos , Inflamação , Estrogênios , HiperplasiaRESUMO
Diabetic encephalopathy (DE) is one of the main chronic complications of diabetes, and is characterized by cognitive defects. MicroRNAs (miRNAs/miRs) are widely involved in the development of diabetesrelated complications. The present study evaluated the role of miR130b in DE and investigated its mechanisms of action. PC12 cells and hippocampal cells were exposed to a high glucose environment to induce cell injuries to mimic the in vitro model of DE. Cells were transfected with miR130b mimic, miR130b inhibitor and small interfering RNA (si)phosphatase and tensin homolog (PTEN) to evaluate the protective effect of the miR130b/PTEN axis against oxidative stress in high glucosestimulated cells involving Akt activity. Furthermore, the effect of agomir130b was also assessed on rats with DE. The expression of miR130b was reduced in the DE models in vivo and in vitro. The administration of miR130b mimic increased the viability of high glucosestimulated cells, prevented apoptosis, increased the activity of superoxide dismutase (SOD), decreased the malondialdehyde (MDA) content, activated Akt protein levels and inhibited the mitochondriamediated apoptotic pathway. The administration of miR130b inhibitor exerted opposite effects, while siPTEN reversed the effects of miR130b inhibitor. In vivo, the administration of agomir130b attenuated cognitive disorders and neuronal damage, increased SOD activity, reduced the MDA content, activated Akt protein levels and inhibited the mitochondriamediated apoptosis pathway in rats with DE. On the whole, these results suggest that miR130b activates the PI3K/Akt signaling pathway to exert protective effects against oxidative stress injury via the regulation of PTEN in rats with DE.
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Encefalopatias/metabolismo , Complicações do Diabetes/metabolismo , Diabetes Mellitus Experimental/metabolismo , MicroRNAs/metabolismo , Estresse Oxidativo , PTEN Fosfo-Hidrolase/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Animais , Encefalopatias/genética , Complicações do Diabetes/genética , Diabetes Mellitus Experimental/genética , Masculino , MicroRNAs/genética , Células PC12 , PTEN Fosfo-Hidrolase/genética , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas c-akt/genética , Ratos , Ratos WistarRESUMO
OBJECTIVES: Ultrasound-guided core biopsy (UGCB) for supraclavicular lymph nodes (SLNs) represents an attractive procedure to obtain tissues for lung cancer confirmation. The aim of the present study is to evaluate the performance of UGCB driven by FDG-avid SLNs, as performed by nuclear medicine physicians, in patients with suspected lung cancer. METHODS: Institutional database in our hospital was searched for eligible patients between September 2019 and March 2021. A 3-12 MHz linear probe was used to guide the biopsy process and to ensure that the needle tip was being directed at the metabolically active area that had been indicated by side-by-side PET/CT images. Diagnostic yield, malignancy rate, molecular testing results, and complications were reviewed. RESULTS: Among the 54 patients included in this study, definite pathological diagnosis from UGCB specimens was achieved in 53 patients, reaching a diagnostic yield of 98.1% (53/54) and a malignancy rate of 96.2% (51/53). Among the 50 patients confirmed as lung cancer, thirty-eight were spared from further invasive procedures which had been planned. Molecular analyses were adequately performed on all the 38 specimens obtained from non-small cell lung cancer (NSCLS). The positive rate was 36.8% (14/38) for epidermal growth receptor (EGFR) mutation and 31.6% (12/38) for anaplastic lymphoma kinase (ALK) translocation. 28.9% (11/38) of the patients had a tumor proportion score (TPS) ≥ 50% for PD-L1 expression. No complication was observed and the average biopsy time was 15 min. CONCLUSIONS: Nuclear medicine physicians-performed UGCB driven by FDG-avid SLNs in suspected lung cancer patients could produce a high performance in terms of diagnostic yield, malignancy rate, and molecular analysis, which may obliviate more invasive interventional procedures and lead to fast decisions on subsequent management.
RESUMO
Macrophages are the most abundant cells in tumor stroma and their polarization within tumor microenvironment exert the key roles in tumorigenesis. Astragaloside IV is a natural extract from traditional Chinese herbal Radix Astragali, and fulfills pleiotropic function in several cancers. Nevertheless, its function in ovarian cancer microenvironment remains elusive. In the present research, astragaloside IV exhibited little cytotoxicity within a certain dose range in THP-1 cells. Moreover, astragaloside IV suppressed the ratio of CD14+CD206+ cells in IL-4/IL-13-treated THP-1 macrophages and transcripts of M2 macrophage markers (including CD206, CCL24, PPARγ, Arg-1, IL-10), indicating the inhibitory effects of astragaloside IV on IL-4/IL-13-induced macrophage M2 polarization. Intriguingly, astragaloside IV antagonized M2 macrophages coculture-evoked cell proliferation, invasion and migration in ovarian cancer cells. During this process, administration with astragaloside IV restrained the high expression of high-mobility group box1 (HMGB1) and TLR4 in macrophages co-cultured with ovarian cancer cells, concomitant with decreases in release of M2 marker TGF-ß, MMP-9 and IL-10. Moreover, targeting the HMGB1 signaling reversed M2 macrophages-induced ovarian cancer cell proliferation, invasion and migration. Noticeably, exogenous HMGB1 overturned the inhibitory efficacy of astragaloside IV against macrophage M2 polarization-evoked malignant potential in ovarian cancer cells. Together, these findings suggest that astragaloside IV may protect against M2 macrophages-evoked malignancy in ovarian cancer cells by suppressing the HMGB1-TLR4 signaling. Therefore, astragaloside may alleviate the progression of ovarian cancer by regulating macrophage M2 polarization within tumor microenvironment, implying a promising therapeutic strategy against ovarian cancer.
Assuntos
Polaridade Celular/efeitos dos fármacos , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Neoplasias Ovarianas/patologia , Saponinas/farmacologia , Triterpenos/farmacologia , Movimento Celular/efeitos dos fármacos , Polaridade Celular/imunologia , Progressão da Doença , Feminino , Proteína HMGB1/metabolismo , Humanos , Macrófagos/fisiologia , Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/metabolismo , Fenótipo , Transdução de Sinais/efeitos dos fármacos , Células THP-1 , Receptor 4 Toll-Like/metabolismo , Células Tumorais Cultivadas , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologiaRESUMO
Emerging evidences have indicated that abnormal expression of microRNAs (miRNAs) contributed to carcinogenesis of ovarian cancer. However, the molecular mechanism of many aberrant expressed miRNAs was not known. Here, we discovered that miR-1224-5p was a downregulated miRNA in ovarian cancer via bioinformatic analysis and RT-qPCR. It was found that upregulation of miR-1224-5p inhibited cell proliferation and invasion ability of ovarian cancer cells. SND1, a well-characterized oncogene, was predicted as a target gene of miR-1224-5p. The western blotting, dual luciferase reporter assay, RNA-binding protein immunoprecipitation assay, and RT-qPCR demonstrated SND1 as a target gene of miR-1224-5p in ovarian cancer. MiR-1224-5p inhibited the expression of mesenchymal markers and increased the expression of epithelial markers in ovarian cancer cells via targeting SND1, indicating miR-1224-5p was involved in epithelial mesenchymal transition. The rescue assay manifested that miR-1224-5p-regulated cell proliferation and invasion mainly rely on downregulation of SND1 in ovarian cancer cells. In conclusion, our study revealed a direct regulatory association between miR-1224-5p and SND1 and their involvement in ovarian carcinogenesis.
Assuntos
Proliferação de Células/genética , Endonucleases/genética , Endonucleases/metabolismo , MicroRNAs/fisiologia , Invasividade Neoplásica/genética , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Transição Epitelial-Mesenquimal/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , HumanosRESUMO
PURPOSE: To investigate the regulation mechanism of long non-coding RNA (lncRNA) plasmocytoma variant translocation 1 (PVT1) in ovarian cancer (OC). METHODS: The levels of PVT1, microRNA (miR)-543, serpin peptidase inhibitor-clade I (neuroserpin)-member 1 (SERPINI1) in OC tissues and OVCAR-3, A2780, TOV-112D of OC cell lines were detected by quantitative real-time PCR (qRT-PCR) and Western Blot (WB). Cell proliferation, migration, invasion, apoptosis and the regulatory relationship between genes and target genes were analyzed by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), Transwell, flow cytometry and dual luciferase reporter (DLR). The OC patients were followed up for 5 years to analyze the relationship between PVT1 and 5-year overall survival (OS). RESULTS: In contrast with miR-543, PVT1 and SERPINI1 were highly expressed in OC tissues and cell lines, and high levels of PVT1 were significantly associated with lower 5-year OS of patients. Down-regulating PVT1 not only inhibited the malignant proliferation, migration and invasion of OC cells, but promoted cell apoptosis. PVT1 regulated miR-543 in a targeted manner, and its overexpression could attenuate the anticancer effect of miR-543 on OC cells. In addition, miR-543 also directly targeted SERPINI1, and miR-543 knockdown weakened the inhibitory effect of down-regulated SERPINI1 on OC progression. Furthermore, we found that PVT1 acted as a competitive endogenous RNA to sponge miR-543, thereby regulating the expression of SERPINI1. CONCLUSION: PVT1 can mediate the molecular mechanism of OC by miR-543/SERPINI1 axis regulatory network, which is a new therapeutic direction for OC.
Assuntos
MicroRNAs/metabolismo , Neuropeptídeos/metabolismo , Neoplasias Ovarianas/metabolismo , RNA Longo não Codificante/metabolismo , Serpinas/metabolismo , Adulto , Apoptose , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , MicroRNAs/genética , Pessoa de Meia-Idade , Invasividade Neoplásica , Neuropeptídeos/genética , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/patologia , Prognóstico , RNA Longo não Codificante/genética , Serpinas/genética , Transdução de Sinais , NeuroserpinaRESUMO
Interleukin-5 (IL-5) involves in the development of airway inflammation and hyperresponsiveness through activation of eosinophils. Thus, inhibition of IL-5 expression seems to be an attractive approach for asthma therapy. In this study, an antisense IL-5 gene transferred by recombinant adeno-associated virus (asIL-5) was constructed to transfect murine allergic asthma model. Our results showed that asIL-5 efficiently inhibited the IL-5 mRNA expression and significantly attenuated the inflammation in lung tissues. Significant decreasing of eosinophils and inflammatory cells were found in peripheral blood and bronchoalveolar lavage fluid (BALF). In addition, significant inhibition of airway hyperresponsiveness (AHR) was also found in the mice treated with asIL-5. These observations demonstrate that antisense oligonucleotid against IL-5 delivered by adeno-associated virus system is possibly an efficacious therapeutic strategy for allergic asthma and other eosinophil-related disorders.
Assuntos
Asma/terapia , Movimento Celular/imunologia , Eosinófilos/imunologia , Interleucina-5/antagonistas & inibidores , Oligodesoxirribonucleotídeos Antissenso , Animais , Asma/genética , Asma/imunologia , Dependovirus , Modelos Animais de Doenças , Humanos , Interleucina-5/genética , Interleucina-5/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Transdução GenéticaRESUMO
Interleukin-5 (IL-5) accompanies the development of airway inflammation and hyperresponsiveness through the activation of eosinophils. Therefore, interference of IL-5 expression in lung tissue seems to be an accepted approach in asthma therapy. In this study, we designed a small interfering RNA (siRNA) to inhibit the expression of IL-5. The siRNAs against IL-5 were constructed in a lentivirus expressing system, and 1.5x10(6) IFU (inclusion-forming unit) lentiviruses were administered intratracheally to ovalbumin (OVA)-sensitized murine asthmatic models. Our results show that lentivirus-delivered siRNA against IL-5 efficiently inhibited the IL-5 messenger ribonucleic acid (mRNA) expression and significantly attenuated the inflammation in lung tissue. Significant decrease of eosinophils and inflammatory cells were found in peripheral blood, bronchoalveolar lavage fluid (BALF), and lung tissue. In addition, significant inhibition of airway hyperresponsiveness (AHR) was found in the mice treated with siRNA against IL-5. These observations demonstrate that siRNA delivered by means of the lentivirus system is possibly an efficacious therapeutic approach for asthma.