RESUMO
BACKGROUND: Antiangiogenic therapy has increasingly become an important strategy for the treatment of colorectal cancer. Recent studies have shown that the tumour microenvironment (TME) promotes tumour angiogenesis. Bufalin is an active antitumour compound whose efficacy has been indicated by previous studies. However, there are very few studies on the antiangiogenic effects of bufalin. METHODS: Herein, human umbilical vein endothelial cell (HUVEC) tube formation, migration and adhesion tests were used to assess angiogenesis in vitro. Western blotting and quantitative PCR were used to detect relevant protein levels and mRNA expression levels. A subcutaneous xenograft tumour model and a hepatic metastasis model were established in mice to investigate the influence of bufalin on angiogenesis mediated by the TME in vivo. RESULTS: We found that angiogenesis mediated by cells in the TME was significantly inhibited in the presence of bufalin. The results demonstrated that the proangiogenic genes in HUVECs, such as VEGF, PDGFA, E-selectin and P-selectin, were downregulated by bufalin and that this downregulation was mediated by inhibition of the STAT3 pathway. Overexpression of STAT3 reversed the inhibitory effects of bufalin on angiogenesis. Furthermore, there was little reduction in angiogenesis when bufalin directly acted on the cells in the tumour microenvironment. CONCLUSION: Our findings demonstrate that bufalin suppresses tumour microenvironment-mediated angiogenesis by inhibiting the STAT3 signalling pathway in vascular endothelial cells, revealing that bufalin may be used as a new antiangiogenic adjuvant therapy medicine to treat colorectal cancer.
Assuntos
Neoplasias Hepáticas , Microambiente Tumoral , Inibidores da Angiogênese/farmacologia , Animais , Bufanolídeos , Movimento Celular , Proliferação de Células , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Camundongos , Camundongos Nus , Neovascularização Patológica/tratamento farmacológico , Fator de Transcrição STAT3/metabolismoRESUMO
Cancer-associated fibroblasts (CAFs), a phenotypically and functionally heterogeneous stromal cell, are one of the most important components of the tumour microenvironment. Previous studies have consolidated it as a promising target against cancer. However, variable therapeutic efficacy-both protumor and antitumor effects have been observed not least owing to the strong heterogeneity of CAFs. Over the past 10 years, advances in single-cell RNA sequencing (scRNA-seq) technologies had a dramatic effect on biomedical research, enabling the analysis of single cell transcriptomes with unprecedented resolution and throughput. Specifically, scRNA-seq facilitates our understanding of the complexity and heterogeneity of diverse CAF subtypes. In this review, we discuss the up-to-date knowledge about CAF heterogeneity with a focus on scRNA-seq perspective to investigate the emerging strategies for integrating multimodal single-cell platforms. Furthermore, we summarized the clinical application of scRNA-seq on CAF research. We believe that the comprehensive understanding of the heterogeneity of CAFs form different visions will generate innovative solutions to cancer therapy and achieve clinical applications.
Assuntos
Fibroblastos Associados a Câncer , Neoplasias , Análise de Sequência de RNA , Análise de Célula Única , Microambiente Tumoral , Humanos , Fibroblastos Associados a Câncer/metabolismo , Fibroblastos Associados a Câncer/patologia , Análise de Célula Única/métodos , Análise de Sequência de RNA/métodos , Neoplasias/genética , Neoplasias/patologia , Animais , Heterogeneidade Genética , Transcriptoma/genéticaRESUMO
The small intestine exhibits remarkable sensitivity to ionizing radiation (IR), which significantly hampers the effectiveness of radiotherapy in the treatment of abdominal and pelvic tumors. Unfortunately, no effective medications are available to treat radiation-induced intestinal damage (RIID). Fraxin (7-hydroxy-6-methoxycoumarin 8-glucoside), is a coumarin derivative extracted from the Chinese herb Cortex Fraxini. Several studies have underscored the anti-inflammatory, antibacterial, antioxidant, and immunomodulatory properties of fraxin. However, the efficacy of fraxin at preventing or mitigating RIID remains unclear. Thus, the present study aimed to investigate the protective effects of fraxin against RIID in vitro and in vivo and to elucidate the underlying mechanisms. The study findings revealed that fraxin markedly ameliorated intestinal injuries induced by 13 Gy whole abdominal irradiation (WAI), which was accompanied by a significant increase in the population of Lgr5+ intestinal stem cells (ISCs) and Ki67+ progeny. Furthermore, fraxin mitigated WAI-induced intestinal barrier damage, and reduced oxidative stress and intestinal inflammation in mice. Transcriptome sequencing of fraxin-treated mice revealed upregulation of IL-22, a pleiotropic cytokine involved in regulating the function of intestinal epithelial cells. Moreover, in both human intestinal epithelial cells and ex vivo cultured mouse intestinal organoids, fraxin effectively ameliorated IR-induced damage by promoting the expression of IL-22. The radioprotective effects of fraxin were partially negated in the presence of an IL-22-neutralizing antibody. In summary, fraxin is demonstrated to possess the ability to alleviate RIID and maintain intestinal homeostasis, suggesting that fraxin might serve as a strategy for mitigating accidental radiation exposure- or radiotherapy-induced RIID.
Assuntos
Cumarínicos , Intestinos , Camundongos , Humanos , Animais , Cumarínicos/farmacologia , Cumarínicos/uso terapêutico , Antioxidantes , Radiação IonizanteRESUMO
The cystine/glutamate antiporter SLC7A11, as the key regulator of ferroptosis, functions to transport cystine for glutathione biosynthesis and antioxidant defense. Accumulating evidence has shown that SLC7A11 is overexpressed in multiple human cancers and promotes tumor growth and progression. However, the exact mechanism underlying this key protein remains unclear. In this study, we confirmed that SLC7A11 is S-palmitoylated in glioblastoma, and this modification is required for SLC7A11 protein stability. Moreover, we revealed that ZDHHC8, a member of the protein palmitoyl transferases (PATs), catalyzes S-palmitoylation of SLC7A11 at Cys327, thereby decreasing the ubiquitination level of SLC7A11. Furthermore, AMPKα1 directly phosphorylates ZDHHC8 at S299, strengthening the interaction between ZDHHC8 and SLC7A11, leading to SLC7A11 S-palmitoylation and deubiquitination. Functional investigations showed that ZDHHC8 knockdown impairs glioblastoma (GBM) cell survival via promoting intracellular ferroptosis events, which could be largely rescued by ectopic expression of SLC7A11. Clinically, ZDHHC8 expression positively correlates with SLC7A11 and AMPKα1 expression in clinical glioma specimens. This study underscores that ZDHHC8-mediated SLC7A11 S-palmitoylation is critical for ferroptosis resistance during GBM tumorigenesis, indicating a novel treatment strategy for GBM.
Assuntos
Ferroptose , Glioblastoma , Humanos , Sistema y+ de Transporte de Aminoácidos/genética , Sistema y+ de Transporte de Aminoácidos/metabolismo , Linhagem Celular Tumoral , Cistina/metabolismo , Glioblastoma/metabolismo , Lipoilação , FosforilaçãoRESUMO
The intestine is prone to radiation damage in patients undergoing radiotherapy for pelvic tumors. However, there are currently no effective drugs available for the prevention or treatment of radiation-induced enteropathy (RIE). In this study, we aimed at investigating the impact of indole-3-carboxaldehyde (I3A) derived from the intestinal microbiota on RIE. Intestinal organoids were isolated and cultivated for screening radioprotective tryptophan metabolites. A RIE model was established using 13 Gy whole-abdominal irradiation in male C57BL/6J mice. After oral administration of I3A, its radioprotective ability was assessed through the observation of survival rates, clinical scores, and pathological analysis. Intestinal stem cell survival and changes in the intestinal barrier were observed through immunofluorescence and immunohistochemistry. Subsequently, the radioprotective mechanisms of I3A was investigated through 16S rRNA and transcriptome sequencing, respectively. Finally, human colon cancer cells and organoids were cultured to assess the influence of I3A on tumor radiotherapy. I3A exhibited the most potent radioprotective effect on intestinal organoids. Oral administration of I3A treatment significantly increased the survival rate in irradiated mice, improved clinical and histological scores, mitigated mucosal damage, enhanced the proliferation and differentiation of Lgr5+ intestinal stem cells, and maintained intestinal barrier integrity. Furthermore, I3A enhanced the abundance of probiotics, and activated the AhR/IL-10/Wnt signaling pathway to promote intestinal epithelial proliferation. As a crucial tryptophan metabolite, I3A promotes intestinal epithelial cell proliferation through the AhR/IL-10/Wnt signaling pathway and upregulates the abundance of probiotics to treat RIE. Microbiota-derived I3A demonstrates potential clinical application value for the treatment of RIE.
Assuntos
Microbioma Gastrointestinal , Indóis , Camundongos Endogâmicos C57BL , Probióticos , Receptores de Hidrocarboneto Arílico , Via de Sinalização Wnt , Animais , Camundongos , Microbioma Gastrointestinal/efeitos dos fármacos , Masculino , Humanos , Probióticos/administração & dosagem , Probióticos/farmacologia , Receptores de Hidrocarboneto Arílico/metabolismo , Indóis/metabolismo , Indóis/farmacologia , Protetores contra Radiação/farmacologia , Organoides/metabolismo , Lesões por Radiação/metabolismo , Lesões por Radiação/prevenção & controle , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Mucosa Intestinal/efeitos da radiação , Intestinos/microbiologia , Intestinos/efeitos da radiação , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genéticaRESUMO
PURPOSE: Radiation-induced intestinal injury (RIII) commonly occur during abdominal-pelvic cancer radiation therapy; however, no effective prophylactic or therapeutic agents are available to manage RIII currently. This study aimed to clarify the potential of probiotic consortium supplementation in alleviating RIII. METHODS AND MATERIALS: Male C57BL/6J mice were orally administered a probiotic mixture comprising Bifidobacterium longum BL21, Lactobacillus paracasei LC86, and Lactobacillus plantarum Lp90 for 30 days before exposure to 13 Gy of whole abdominal irradiation. The survival rates, clinical scores, and histologic changes in the intestines of mice were assessed. The impacts of probiotic consortium treatment on intestinal stem cell proliferation, differentiation, and epithelial barrier function; oxidative stress; and inflammatory cytokines were evaluated. A comprehensive examination of the gut microbiota composition was conducted through 16S rRNA sequencing, while changes in metabolites were identified using liquid chromatography-mass spectrometry. RESULTS: The probiotic consortium alleviated RIII, as reflected by increased survival rates, improved clinical scores, and mitigated mucosal injury. The probiotic consortium treatment exhibited enhanced therapeutic effects at the histologic level compared with individual probiotic strains, although there was no corresponding improvement in survival rates and colon length. Moreover, the probiotic consortium stimulated intestinal stem cell proliferation and differentiation, enhanced the integrity of the intestinal epithelial barrier, and regulated redox imbalance and inflammatory responses in irradiated mice. Notably, the treatment induced a restructuring of the gut microbiota composition, particularly enriching short-chain fatty acid-producing bacteria. Metabolomic analysis revealed distinctive metabolic changes associated with the probiotic consortium, including elevated levels of anti-inflammatory and antiradiation metabolites. CONCLUSIONS: The probiotic consortium attenuated RIII by modulating the gut microbiota and metabolites, improving inflammatory symptoms, and regulating oxidative stress. These findings provide new insights into the maintenance of intestinal health with probiotic consortium supplementation and will facilitate the development of probiotic-based therapeutic strategies for RIII in clinical practice.
Assuntos
Microbioma Gastrointestinal , Homeostase , Mucosa Intestinal , Camundongos Endogâmicos C57BL , Probióticos , Animais , Probióticos/farmacologia , Probióticos/uso terapêutico , Masculino , Camundongos , Mucosa Intestinal/microbiologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/efeitos da radiação , Mucosa Intestinal/patologia , Microbioma Gastrointestinal/efeitos dos fármacos , Lesões por Radiação/prevenção & controle , Lesões por Radiação/patologia , Proliferação de Células/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Intestinos/microbiologia , Diferenciação Celular/efeitos dos fármacos , Lesões Experimentais por Radiação/prevenção & controle , Lesões Experimentais por Radiação/patologia , Lesões Experimentais por Radiação/metabolismo , Células-Tronco , Citocinas/metabolismoRESUMO
The selenium-containing enzyme GPX4 moonlights as a central regulator of ferroptosis, an iron-dependent, nonapoptotic form of regulated cell death caused by lipid peroxidation. Yet, little is known about the mechanisms underlying the regulation of its post-transcriptional modifications. Here, we identify the tripartite motif-containing protein TRIM26 as an E3 ubiquitin ligase of GPX4. TRIM26 directly interacts with GPX4 through its Ring domain and catalyzes the ubiquitination of GPX4 at K107 and K117, which promotes the switch in polyubiquitination of GPX4 from K48 to K63, thus enhancing GPX4 protein stability. Moreover, PLK1-mediated S127 phosphorylation of TRIM26 enhances the interaction between TRIM26 and GPX4. Inhibition of TRIM26 phosphorylation causes a reduction in GPX4 K63-linked polyubiquitination and diminishes GPX4 protein levels in tumor cells. Further investigation revealed that TRIM26 is overexpressed in glioma cells. TRIM26 silencing dramatically impedes ferroptosis resistance and tumorigenesis in glioma in vivo and in vitro. Clinically, TRIM26 expression shows a direct correlation with GPX4 and PLK1 levels in glioma samples and is associated with poor outcome in patients with glioma. Collectively, these findings define the role of GPX4 K63-linked polyubiquitination in ferroptosis and suggest a potential strategy for glioma treatment.
Assuntos
Ferroptose , Glioma , Humanos , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinação , Glioma/genética , Proteínas com Motivo Tripartido/genética , Proteínas com Motivo Tripartido/metabolismoRESUMO
The transient receptor potential (TRP) protein superfamily is a special group of cation channels expressed in different cell types and signaling pathways. In this review, we focus on TRPA1 (transient receptor potential ankyrin 1), an ion channel in this family that exists in the cell membrane and shows a different function from other TRP channels. TRPA1 usually has a special activation effect that can induce cation ions, especially calcium ions, to flow into activated cells. In this paper, we review the role of TRPA1 in fibroblasts. To clarify the relationship between fibroblasts and TRPA1, we have also paid special attention to the interactions between TRPA1 and inflammatory factors leading to fibroblast activation. TRPA1 has different functions in the fibrosis process in different organs, and there have also been interesting discussions of the mechanism of TRPA1 in fibroblasts. Therefore, this review aims to describe the function of TRP channels in controlling fibrosis through fibroblasts in different organ inflammatory and immune-mediated diseases. We attempt to prove that TRPA1 is a target for fibrosis. In fact, some clinical trials have already proven that TRPA1 is a potential adjuvant therapy for treating fibrosis.
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OBJECTIVE: This meta-analysis with trial sequential analysis (TSA) compared the clinical efficacy of extracorporeal cardiopulmonary resuscitation (ECPR) with conventional CPR (CCPR) for adult patients who experienced in-hospital cardiac arrest (IHCA) or out-of-hospital CA (OHCA). METHODS: A literature search was used to identify eligible publications (up to 30 July 2018) from PubMed, the Cochrane Library, the ISI Web of Knowledge, and Embase. Two investigators independently conducted the literature search, study selection, data extraction, and quality evaluation. Meta-analysis and TSA were used to analyze each outcome, and the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) was used to evaluate the level of evidence. The primary outcome was 30-day survival, and the secondary outcomes were 30-day neurologic outcome, 3-6 months' survival, 3-6 months' neurological outcome, 1-year survival, and 1-year neurological outcome. RESULTS: We identified 13 eligible observational studies for the final analysis. Pooled analyses showed that ECPR was associated with a significantly better 30-day survival (RR = 1.60, 95% CI = 1.25-2.06) and 30-day neurologic outcome (RR = 2.69, 95% CI = 1.63-4.46), and TSA confirmed these results. However, subgroup analysis of patients with OHCA indicated that ECPR and CCPR had similar effects on 30-day survival (RR = 1.18, 95% CI = 0.71-1.97), which was not confirmed by TSA. Analysis of OHCA patients indicated that ECPR provided a better 30-day neurological outcome (RR = 3.93, 95% CI = 1.00-15.50), but TSA did not support these results. Analysis of IHCA patients indicated that ECPR was associated with a better 30-day survival (RR 1.90, 95% CI 1.43-2.52) and 30-day neurologic outcome (RR 2.02, 95% CI 1.21-3.39), and TSA supported these results. Other subgroup analyses showed that the results were generally consistent, regardless of nation, propensity score matching, presumed etiology, whether the CA was witnessed or not, and study quality. CONCLUSIONS: Relative to CCPR, ECPR improved the survival and neurological outcome of patients who had IHCA. Compared to IHCA patients, TSA could not confirm better survival and neurologic outcome of ECPR in OHCA patients, suggesting that further studies are needed. TRIAL REGISTRATION: This trial was registered with PROSPERO (CRD42018100513) on 17 July 2018.
Assuntos
Reanimação Cardiopulmonar/métodos , Parada Cardíaca/terapia , Parada Cardíaca Extra-Hospitalar/terapia , Idoso , Oxigenação por Membrana Extracorpórea , Feminino , Parada Cardíaca/mortalidade , Parada Cardíaca/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Observacionais como Assunto , Parada Cardíaca Extra-Hospitalar/mortalidade , Parada Cardíaca Extra-Hospitalar/fisiopatologia , Fatores de Tempo , Resultado do TratamentoRESUMO
RATIONALE: We report a man with amyopathic dermatomyositis (ADM) complicated by severe interstitial lung disease (ILD) received extracorporeal membrane oxygenation (ECMO) in combination with double filtration plasmapheresis (DFPP). This is the first report of the utility of ECMO in combination with DFPP in ADM related ILD in adults. PATIENT CONCERNS: A 48-year-old man who was previously healthy had a 2-month history of cough and shortness of breath, which aggravated in 5 days. DIAGNOSES: Amyopathic dermatomyositis and complicated by severe interstitial lung disease. INTERVENTIONS: ECMO was giving when the patient suffered acute respiratory failure. Though corticosteroids was giving, primary disease was still developing with relapses of spontaneous pneumomediastinum and pneumothorax. Then, DFPP treatment was initiated. OUTCOME: After the treatments above, the patient's clinical condition improved with the reduction of bilateral interstitial infiltrates and improvement of lung compliance. Unfortunately, he discontinued the treatment because of the financial problem. LESSONS: When get a rapid progressive interstitial lung disease for no apparent reason, amyopathic dermatomyositis should be considered, especially with suspected skin lesions. ECMO, in combination with DFPP, should be considered as a supportive therapy and initiated early in patients in acute respiratory failure secondary to ADM-ILD. Prompt initiation of DFPP in dermatomyositis patients with ILD might help reduce the occurrence of spontaneous pneumomediastinum or pneumothorax.
Assuntos
Dermatomiosite/complicações , Oxigenação por Membrana Extracorpórea/métodos , Doenças Pulmonares Intersticiais/terapia , Plasmaferese/métodos , Terapia Combinada , Dermatomiosite/terapia , Glucocorticoides/uso terapêutico , Humanos , Doenças Pulmonares Intersticiais/etiologia , Masculino , Enfisema Mediastínico/etiologia , Enfisema Mediastínico/terapia , Pessoa de Meia-Idade , Pneumotórax/etiologia , Pneumotórax/terapiaRESUMO
OBJECTIVE: Sepsis-induced cardiomyopathy is a reversible myocardial dysfunction due to sepsis, which may be severe enough to complicate cardiogenic shock, and without effective drug and with high mortality during the acute phase. A case of sepsis-induced cardiomyopathy complicated with cardiogenic shock was treated in the intensive care unit (ICU) of Shunde Hospital Southern Medical University. A 37 years old female patient was admitted because she had suffered repeated fever for 5 days, chest tightness and abdominal pain for 3 days. At the same time, there were severe cardiac depression and abdominal infection, which could be explained by the monismtheory of sepsis cardiomyopathy.The cardiogenic shock patient was not improved after antibiotic therapy and hemodynamic support, extracorporeal membrane oxygenation (ECMO) support was prescribed. The circulation failure was smoothly got through with ECMO and was transfer from ICU to ordinary ward. Computed tomographic angiography (CTA) of abdominal aorta and colonoscopy indicated lesions of small intestine. The diagnosis of infection and bleeding in ileum diverticulum was confirmed during the operation and the lesions was removed. She recovered and was discharged 1 week after operation. Through the case review, we aim to improve the awareness of sepsis-induced cardiomyopathy and the value of ECMO support in cardiogenic shock.