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Early apoptosis of grafted islets is one of the main factors affecting the efficacy of islet transplantation. The combined transplantation of islet cells and bone marrow mesenchymal stem cells (BMSCs) can significantly improve the survival rate of grafted islets. Transcription factor insulin gene enhancer binding protein 1 (ISL1) is shown to promote the angiogenesis of grafted islets and the paracrine function of mesenchymal stem cells during the co-transplantation, yet the regulatory mechanism remains unclear. By using ISL1-overexpressing BMSCs and the subtherapeutic doses of islets for co-transplantation, we managed to reduce the apoptosis and improve the survival rate of the grafts. Our metabolomics and proteomics data suggested that ISL1 upregulates aniline (ANLN) and Inhibin beta A chain (INHBA), and stimulated the release of caffeine in the BMSCs. We then demonstrated that the upregulation of ANLN and INHBA was achieved by the binding of ISL1 to the promoter regions of the two genes. In addition, ISL1 could also promote BMSCs to release exosomes with high expression of ANLN, secrete INHBA and caffeine, and reduce streptozocin (STZ)-induced islets apoptosis. Thus, our study provides mechanical insight into the islet/BMSCs co-transplantation and paves the foundation for using conditioned medium to mimic the ISL1-overexpressing BMSCs co-transplantation.
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Exossomos , Insulinas , Ilhotas Pancreáticas , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , Compostos de Anilina/metabolismo , Apoptose/genética , Cafeína/metabolismo , Cafeína/farmacologia , Meios de Cultivo Condicionados , Subunidades beta de Inibinas , Insulinas/metabolismo , Ilhotas Pancreáticas/metabolismo , Células-Tronco Mesenquimais/metabolismo , Estreptozocina/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
Revascularization of the islet transplant is a crucial step that defines the success rate of patient recovery. Bone marrow-derived mesenchymal stem cells (BMSCs) have been reported to promote revascularization; however, the underlying cellular mechanism remains unclear. Moreover, our liquid chromatography-tandem mass spectrometry results showed that BMSCs could promote the expression of insulin gene enhancer binding protein-1 (ISL1) in islets. ISL1 is involved in islets proliferation and plays a potential regulatory role in the revascularization of islets. This study identifies the ISL1 protein as a potential modulator in BMSCs-mediated revascularization of islet grafts. We demonstrated that the survival rate and insulin secretion of islets were increased in the presence of BMSCs, indicating that BMSCs promote islet revascularization in a coculture system and rat diabetes model. Interestingly, we also observed that the presence of BMSCs led to an increase in ISL1 and vascular endothelial growth factor A (VEGFA) expression in both islets and the INS-1 rat insulinoma cell line. In silico protein structure modeling indicated that ISL1 is a transcription factor that has four binding sites with VEGFA mRNA. Further results showed that overexpression of ISL1 increased both the abundance of VEGFA transcripts and protein accumulation, while inhibition of ISL1 decreased the abundance of VEGFA. Using a ChIP-qPCR assay, we demonstrated that direct molecular interactions between ISL1 and VEGFA occur in INS-1 cells. Together, these findings reveal that BMSCs promote the expression of ISL1 in islets and lead to an increase in VEGFA in islet grafts. Hence, ISL1 is a potential target to induce early revascularization in islet transplantation.
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Transplante das Ilhotas Pancreáticas , Ilhotas Pancreáticas , Células-Tronco Mesenquimais , Animais , Medula Óssea/metabolismo , Humanos , Ilhotas Pancreáticas/metabolismo , Transplante das Ilhotas Pancreáticas/métodos , Células-Tronco Mesenquimais/metabolismo , Ratos , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
Beneficial effects of metformin on cancer risk and mortality have been proved by epidemiological and clinical studies, thus attracting research interest in elucidating the underlying mechanisms. Recently, tumour-associated macrophages (TAMs) appeared to be implicated in metformin-induced antitumour activities. However, how metformin inhibits TAMs-induced tumour progression remains ill-defined. Here, we report that metformin-induced antitumour and anti-angiogenic activities were not or only partially contributed by its direct inhibition of functions of tumour and endothelial cells. By skewing TAM polarization from M2- to M1-like phenotype, metformin inhibited both tumour growth and angiogenesis. Depletion of TAMs by clodronate liposomes eliminated M2-TAMs-induced angiogenic promotion, while also abrogating M1-TAMs-mediated anti-angiogenesis, thus promoting angiogenesis in tumours from metformin treatment mice. Further in vitro experiments using TAMs-conditioned medium and a coculture system were performed, which demonstrated an inhibitory effect of metformin on endothelial sprouting and tumour cell proliferation promoted by M2-polarized RAW264.7 macrophages. Based on these results, metformin-induced inhibition of tumour growth and angiogenesis is greatly contributed by skewing of TAMs polarization in microenvironment, thus offering therapeutic opportunities for metformin in cancer treatment.
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Angiomotin (Amot) is a newly discovered, multifunctional protein that is involved in cell migration and angiogenesis. However, the role of its isoform, AmotP130, in the regulation of cytoskeleton and metastasis of breast cancer, is unclear. The aim of this study was to investigate the role of AmotP130 in the reorganization of the actin cytoskeleton and the changes of morphology in breast cancer cells through the Rho pathway that influences the invasion and migration of cells. The results suggested that AmotP130 suppressed the invasion ability through remodelling the cytoskeleton of breast cancer cells, including the actin fibre organization and focal adhesion protein turnover. Global transcriptome changes in breast cancer cells following knockdown of AmotP130 identified pathways related with the cytoskeleton and cell motility that involved the Rho GTPase family. From database analyses, changes in the Rho GTPase family of proteins were identified as possible prognostic factors in patients with breast cancer. We have been suggested that AmotP130 suppressed the invasion ability through remodelling of the cytoskeleton of breast cancer cells, involving regulation of the Rho pathway. The cytoskeleton-related pathway components may provide novel, clinically therapeutic targets for breast cancer treatment.
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Actinas/genética , Neoplasias da Mama/genética , Peptídeos e Proteínas de Sinalização Intercelular/genética , Proteínas de Membrana/genética , Proteínas rho de Ligação ao GTP/genética , Angiomotinas , Neoplasias da Mama/patologia , Adesão Celular/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Citoesqueleto/genética , Feminino , Adesões Focais/genética , Adesões Focais/patologia , Regulação Neoplásica da Expressão Gênica , Humanos , Proteínas dos Microfilamentos , Isoformas de Proteínas/genética , Transdução de Sinais , Proteína rhoA de Ligação ao GTP/genéticaRESUMO
Substantial data from preclinical studies have revealed the biphasic effects of statins on cardiovascular angiogenesis. Although some have reported the anti-angiogenic potential of statins in malignant tumors, the underlying mechanism remains poorly understood. The aim of this study is to elucidate the mechanism by which simvastatin, a member of the statin family, inhibits tumor angiogenesis. Simvastatin significantly suppressed tumor cell-conditioned medium-induced angiogenic promotion in vitro, and resulted in dose-dependent anti-angiogenesis in vivo. Further genetic silencing of hypoxia-inducible factor-1α (HIF-1α) reduced vascular endothelial growth factor and fibroblast growth factor-2 expressions in 4T1 cells and correspondingly ameliorated HUVEC proliferation facilitated by tumor cell-conditioned medium. Additionally, simvastatin induced angiogenic inhibition through a mechanism of post-transcriptional downregulation of HIF-1α by increasing the phosphorylation level of AMP kinase. These results were further validated by the fact that 5-aminoimidazole-4-carboxamide ribonucleotide reduced HIF-1α protein levels and ameliorated the angiogenic ability of endothelial cells in vitro and in vivo. Critically, inhibition of AMPK phosphorylation by compound C almost completely abrogated simvastatin-induced anti-angiogenesis, which was accompanied by the reduction of protein levels of HIF-1α and its downstream pro-angiogenic factors. These findings reveal the mechanism by which simvastatin induces tumor anti-angiogenesis, and therefore identifies the target that explains the beneficial effects of statins on malignant tumors.
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Proteínas Quinases Ativadas por AMP/fisiologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/fisiologia , Neovascularização Patológica/prevenção & controle , Sinvastatina/farmacologia , Proteínas Quinases Ativadas por AMP/antagonistas & inibidores , Animais , Linhagem Celular Tumoral , Proliferação de Células , Relação Dose-Resposta a Droga , Ativação Enzimática/efeitos dos fármacos , Feminino , Fator 2 de Crescimento de Fibroblastos/análise , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/antagonistas & inibidores , Camundongos , Camundongos Endogâmicos BALB C , Fator A de Crescimento do Endotélio Vascular/análiseRESUMO
Pleural effusion (PE), a tumor-proximal body fluid, may be a promising source for biomarker discovery in human cancers. Because a variety of pathological conditions can lead to PE, characterization of the relative PE proteomic profiles from different types of PEs would accelerate discovery of potential PE biomarkers specifically used to diagnose pulmonary disorders. Using quantitative proteomic approaches, we identified 772 nonredundant proteins from six types of exudative PEs, including three malignant PEs (MPE, from lung, breast, and gastric cancers), one lung cancer paramalignant PE, and two benign diseases (tuberculosis and pneumonia). Spectral counting was utilized to semiquantify PE protein levels. Principal component analysis, hierarchical clustering, and Gene Ontology of cellular process analyses revealed differential levels and functional profiling of proteins in each type of PE. We identified 30 candidate proteins with twofold higher levels (q<0.05) in lung cancer MPEs than in the two benign PEs. Three potential markers, MET, DPP4, and PTPRF, were further verified by ELISA using 345 PE samples. The protein levels of these potential biomarkers were significantly higher in lung cancer MPE than in benign diseases or lung cancer paramalignant PE. The area under the receiver-operator characteristic curve for three combined biomarkers in discriminating lung cancer MPE from benign diseases was 0.903. We also observed that the PE protein levels were more clearly discriminated in effusions in which the cytological examination was positive and that they would be useful in rescuing the false negative of cytological examination in diagnosis of nonsmall cell lung cancer-MPE. Western blotting analysis further demonstrated that MET overexpression in lung cancer cells would contribute to the elevation of soluble MET in MPE. Our results collectively demonstrate the utility of label-free quantitative proteomic approaches in establishing differential PE proteomes and provide a new database of proteins that can be used to facilitate identification of pulmonary disorder-related biomarkers.
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Biomarcadores Tumorais/metabolismo , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Neoplasias Pulmonares/metabolismo , Proteínas de Neoplasias/metabolismo , Derrame Pleural/metabolismo , Proteômica/métodos , Área Sob a Curva , Western Blotting , Linhagem Celular Tumoral , Análise por Conglomerados , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Cavidade Pleural/metabolismo , Cavidade Pleural/patologia , Derrame Pleural/diagnóstico , Neoplasias Pleurais/secundário , Análise de Componente Principal , Proteínas Proto-Oncogênicas c-met/metabolismo , Reprodutibilidade dos TestesRESUMO
Karyopherin alpha 2 (KPNA2) is overexpressed in various human cancers and is associated with cancer invasiveness and poor prognosis. Herein, to understand the essential role of KPNA2 protein complexes in cancer progression, we applied stable isotope labeling with amino acids in cell culture (SILAC)-based quantitative proteomic strategy combined with immunoprecipitation (IP) to investigate the differential KPNA2 protein complexes in lung adenocarcinoma cell lines with different invasiveness potentials. We found that 64 KPNA2-interaction proteins displayed a 2-fold difference in abundance between CL1-5 (high invasiveness) and CL1-0 (low invasiveness) cells. Pathway map analysis revealed that the formation of complexes containing KPNA2 and cytoskeleton-remodeling-related proteins, including actin, beta tubulin, tubulin heterodimers, vimentin, keratin 8, keratin 18, and plectin, was associated with cancer invasiveness. IP demonstrated that the levels of KPNA2-vimentin-pErk complexes were significantly higher in CL1-5 cells than in CL1-0 cells. The KPNA2-vimentin-pErk complex was also up-regulated in the advanced stage compared with the early-stage lung adenocarcinoma tissues. Importantly, the levels of pErk as well as cell migration ability were significantly reduced in KPNA2-knockdown cells; however, migration was restored by treatment with pErk phosphatase inhibitors. Collectively, our results demonstrate the usefulness of a SILAC-based proteomic strategy for identifying invasiveness-associated KPNA2 protein complexes and provide new insight into the KPNA2-mediated modulation of cell migration.
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Movimento Celular/fisiologia , Neoplasias Pulmonares/metabolismo , Complexos Multiproteicos/metabolismo , Invasividade Neoplásica/fisiopatologia , Transdução de Sinais/fisiologia , alfa Carioferinas/metabolismo , Movimento Celular/genética , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Humanos , Fosforilação , Proteômica/métodos , Transdução de Sinais/genética , Vimentina/metabolismo , alfa Carioferinas/fisiologiaRESUMO
The aim of this study was to assess the correlation between gut microbial taxonomy and various ovarian responses to controlled ovarian stimulation. A total of 22 IVF cycles with a follicle-to-oocyte index (FOI) < 0.5 and 25 IVF cycles with FOI ≥ 0.5 were included in this study. Baseline demographic characteristics were compared between the two groups. Metagenomic sequencing was performed to analyze fecal microbial community profiles. Mice were used to evaluate the effect of Bifidobacterium_longum on ovarian response to stimulation. Compared with FOI < 0.5 group, women in group with FOI ≥ 0.5 had significant more oocytes retrieved (p < 0.01). Prevotella_copri, Bateroides_vulgatus, Escherichia_coli and Bateroides_stercoris were more abundant in FOI < 0.5 group while Bifidobacterium_longum, Faecalibacterium_prausnitzii, Ruminococcus_gnavus and Bifidobacterium_pseudocatenula were more abundant in FOI ≥ 0.5 group. After adjusting for women's age and BMI, Pearson correlation analysis indicated alteration of gut microbiome was related with serum E2, FSH, number of oocytes retrieved and clinical pregnancy rate. Animal study showed ovarian response will be improved after Bifidobacterium_longum applied. An increased abundance of Bacteroidetes and Prevotella copri, as well as a decreased abundance of Bifidobacterium longum, have been found to be associated with poor ovarian responsiveness. Changes in gut microbiomes have been observed to be correlated with certain clinical characteristics. The potential enhancement of ovarian response may be facilitated by the integration of Bifidobacterium longum.
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Microbioma Gastrointestinal , Metagenômica , Indução da Ovulação , Feminino , Animais , Humanos , Metagenômica/métodos , Adulto , Camundongos , Indução da Ovulação/métodos , Ovário/microbiologia , Gravidez , Fezes/microbiologia , Fertilização in vitro/métodosRESUMO
Background: As a highly prevalent malignancy among women worldwide, breast cancer, remains a critical public health issue necessitating the development of novel therapeutics and biomarkers. Kruppel Like Factor 2 (KLF2), a member of the Kruppel family of transcription factors, has been implicated in various types of cancer due to its diminished expression; however, the potential implications of KLF2 expression in relation to breast cancer progression, prognosis, and therapy remain unclear. Methods: The present study employed the Tumor Immune Estimation Resource (TIMER) and The Human Protein Atlas databases to investigate the expression pattern of KLF2 in pan-cancer. The relationship between KLF2 expression and clinical features or immune infiltration of The Cancer Genome Atlas (TCGA) breast cancer samples was evaluated using Breast Cancer Integrative Platform (BCIP) and TIMER. The expression levels of KLF2 in breast cancer were validated via immunohistochemical staining analysis. Gene Set Enrichment Analysis (GSEA) to study the KLF2-related gene ontology. STRING database was employed to construct a protein-protein interaction (PPI) network of KLF2 in relation to vascular endothelial growth factor A (VEGFA) and hypoxia-inducible factor 1α (HIF1α). The expression of KLF2 following diverse breast cancer therapies was analyzed in the Gene Expression Omnibus (GEO) databases. The expression of KLF2 following treatment with simvastatin was validated via immunofluorescence and western blotting. Results: Our study reveals that KLF2 displays significantly reduced expression in cancerous tissues compared to non-cancerous controls. Patients with low KLF2 expression levels exhibited poor prognosis across multiple cancer types. KLF2 expression levels were found to be reduced in advanced cancer stages and grades, while positively correlated with the expression of estrogen receptor (ER), progesterone receptor (PR), and tumor size in breast cancer. KLF2 expression is associated with diverse immune infiltration cells, and may impact the breast tumor immune microenvironment by regulating dendritic cell activation. Additionally, we observed a negative correlation between KLF2 expression levels and angiogenesis, as well as the expression of VEGFA and HIF1α. Notably, the anticancer drug simvastatin could induce KLF2 expression in both breast cancer. Conclusion: Based on our observations, KLF2 has potential as a diagnostic, prognostic, and therapeutic biomarker for breast cancer.
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The development of chemoresistance which results in a poor prognosis often renders current treatments for colorectal cancer (CRC). In this study, we identified reduced microvessel density (MVD) and vascular immaturity resulting from endothelial apoptosis as therapeutic targets for overcoming chemoresistance. We focused on the effect of metformin on MVD, vascular maturity, and endothelial apoptosis of CRCs with a non-angiogenic phenotype, and further investigated its effect in overcoming chemoresistance. In situ transplanted cancer models were established to compare MVD, endothelial apoptosis and vascular maturity, and function in tumors from metformin- and vehicle-treated mice. An in vitro co-culture system was used to observe the effects of metformin on tumor cell-induced endothelial apoptosis. Transcriptome sequencing was performed for genetic screening. Non-angiogenic CRC developed independently of angiogenesis and was characterized by vascular leakage, immaturity, reduced MVD, and non-hypoxia. This phenomenon had also been observed in human CRC. Furthermore, non-angiogenic CRCs showed a worse response to chemotherapeutic drugs in vivo than in vitro. By suppressing endothelial apoptosis, metformin sensitized non-angiogenic CRCs to chemo-drugs via elevation of MVD and improvement of vascular maturity. Further results showed that endothelial apoptosis was induced by tumor cells via activation of caspase signaling, which was abrogated by metformin administration. These findings provide pre-clinical evidence for the involvement of endothelial apoptosis and subsequent vascular immaturity in the chemoresistance of non-angiogenic CRC. By suppressing endothelial apoptosis, metformin restores vascular maturity and function and sensitizes CRC to chemotherapeutic drugs via a vascular mechanism.
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OBJECTIVE: To identify whether the time interval from insemination to ovulation (I-O interval) affects outcome after intrauterine insemination with donor sperm (IUI-D). METHODS: A retrospective study was conducted in a public assisted reproductive medicine center between January, 2014 and December, 2016 in Xi'an, China. The data were collected from the medical records and generalized estimating equations (GEEs) were used to evaluate the effects of various variables on IUI outcome. RESULTS: A total of 2091 IUI-D cycles from 1165 couples were included in this study. Multiple predictors were identified for (live birth rate) LBR. The I-O interval was the predictor for LBR. An I-O interval ≥19 h significantly decreased CPR (odds ratio [OR], 95% confidence interval [CI]: 0.29, 0.17-0.48) and LBR (OR, 95% CI: 0.32, 0.19-0.55). The presence of at least two follicles ≥18 mm on ovulation day significantly increased the LBR (OR, 95%CI: 1.27, 1.01-1.60). Women aged 35 years and older had a significantly decreased LBR (OR, 95% CI: 0.61, 0.38-0.98). CONCLUSION: The I-O interval, a new prognostic factor, in combination with the woman's age and number of mature follicles, can predict the outcome after IUI-D. IUI-D is best performed within 19 h of I-O interval for a higher probability of clinical pregnancy and live birth.
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Inseminação , Ovulação , Feminino , Humanos , Inseminação Artificial , Masculino , Indução da Ovulação , Gravidez , Taxa de Gravidez , Estudos Retrospectivos , EspermatozoidesRESUMO
Immune checkpoint inhibitors (ICIs) have encouraged a paradigm shift in the clinical management of patients with cancer. Despite the dramatically improved tumor response and patient prognosis, ICIs have been associated with ICI-related myocarditis, which has a high fatality rate. Cardiac imaging plays a critical role in the assessment of cardiac injury. Echocardiography, cardiac magnetic resonance imaging, and targeted tracer-based cardiac molecular imaging techniques alone or in combination reflect pathophysiology and depict different aspects of lesions at different clinical stages, i.e., they have potentially complementary value. Imaging techniques for identifying ICI-induced cardiotoxicity at the early stage may reduce the incidence of adverse cardiovascular events. Particularly in planned ICI therapy among patients with cancer, improved monitoring approaches to identify patients who are at the highest risk of ICI-related myocarditis may help in refining clinical decisions, allowing treatment to be more accurately targeted toward patients who are most likely to benefit. In this study, we systematically reviewed the studies on cardiac imaging techniques for assessing ICI-induced cardiotoxicity. We elaborated about the potential applications of cardiac imaging techniques for the optimized management of patients with ICI-related myocarditis, including risk stratification, diagnosis, and prognosis.
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OBJECTIVE: To observe the effect of electroacupuncture (EA) on the pyrolysis of dopaminergic neurons in rats with Parkinson's disease (PD), so as to explore its underlying molecular mechanism. METHODS: Male SD rats were randomly divided into the sham operation, model, EA, MCC950 and EA+MCC950 groups, with 12 rats in each group. The PD rat model was established by two-point injection of 6-OHDA. Rats in the MCC950 group were injected with MCC950 at the dose of 10 mg/kg, once a day; for rats of EA group, EA was applied to "Taichong" (LR3) and "Fengfu"(GV16) for 30 min, once a day; rats in the EA+ MCC950 group were given MCC950 injection and EA once a day. All above interventions were performed for 2 weeks. After the intervention, the behavioral changes of rats were observed using rotating induction experiment, rotating rod experiment and open field experiment; the positive expressions of dopaminergic neuronal markers tyrosine hydroxylase (TH) and α-Synuclein (α-Syn) in substantia nigra striatum were detected by immunohistochemistry; the damage of dopaminergic neurons in substantia nigra striatum was observed after HE staining; immunopositive coexpression of brain nucleotide-binding oligomerization domain like receptor protein 3 (NLRP3), Caspase-1 and ionized calcium binding adapter1 (Iba-1) were detected by immunofluorescence double staining; the levels of interleukin (IL)-1ß and IL-18 in brain tissues were detected by ELISA; the protein expression levels of NLRP3, Cleaved Caspase-1 and apoptosis-associated speck-like protein containing a CARD (ASC) in the substantia nigra striatum were detected by Western blot. RESULTS: Compared with the sham operation group, the number of rotations of rotating induction experiment, the residence time in the central area of open field experiment, the positive expression of α-Syn, the positive co-expressions of NLRP3/Iba-1 and Caspase-1/Iba-1, the contents of IL-1ß and IL-18 in brain tissues, and the protein expression levels of NLRP3, ASC and Cleaved Caspase-1 in substantia nigra striatum were significantly increased (P<0.05), while the drop latency of rotating rod experiment, the rearing times and the total distance of open field experiment, and the positive expression of TH in substantia nigra striatum were significantly decreased (P<0.05) in the model group. Compared with the model group, the above mentioned markers were reversed in EA, MCC950 and EA+MCC950 groups (P<0.05), and the improvement of the EA+MCC950 group was more obvious than those of the MCC950 and EA groups. In the model group, the neurons were disorderly arranged, the number of neurons was reduced, the cytoplasm was swollen, and some of them were vacuolar degeneration; while the degree of neuronal arrangement disorder, cytoplasmic swelling and the vacuolar degeneration were reduced in varying degrees in the MCC950, EA and EA+MCC950 groups. CONCLUSION: The ameliorative effect of EA on dopaminergic neuron damage in PD rats may be related to its effects in inhibiting NLRP3/Caspase-1 mediated neuronal pyrosis.
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Eletroacupuntura , Doença de Parkinson , Masculino , Animais , Ratos , Caspase 1/genética , Neurônios Dopaminérgicos , Piroptose , Ratos Sprague-Dawley , Doença de Parkinson/genética , Doença de Parkinson/terapia , Interleucina-18 , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Tirosina 3-Mono-OxigenaseRESUMO
OBJECTIVE: To compare the effects of felodipine combined irbesartan regimen with that of felodipine combined metoprolol regimen on the sexual function in male hypertensive patients. METHOD: One hundred and twenty-three male hypertensive patients (age 25 to 60) were randomly assigned to felodipine (5 mg/d) plus irbesartan (150 mg/d, n = 64) group and felodipine (5 mg/d) plus metoprolol (47.5 mg/d, n = 59) group. Dosage of felodipine were doubled after 4 weeks if the blood pressure were > or = 140/ 90 mm Hg (1 mm Hg = 0.133 kPa). At the baseline and post 24th week treatment, sexual function of patients was assessed by the International Index of Erectile Function (IIEF) Questionaire. Serum testosterone (T), sex hormone binding globulin (SHBG), 4-hydroxynonenal (HNE), 8-hydroxy-2'-deoxyguanosine (8-OHdG) and Malonaldehyde (MDA) were measured by Radioimmunoassay (RIA), ELISA and TBA respectively. RESULTS: Total prevalence of erectile dysfunction (ED), T, SHBG and HNE were similar between pre- and post-treatment in two groups (P > 0.05). On the other hand, the scores of the mild ED and sexual desire (SD) were improved and both serum 8-OHdG and MDA in patients with ED decreased [(146.02 +/- 60.54) ng/L vs. (139.89 +/- 62.03) ng/L, P = 0.048 and (6.59 +/- 1.75) micromol/L vs. (5.51 +/- 1.65) micromol/L, P = 0.039] in Felodipine plus Irbesartan group. CONCLUSION: The results suggested that Felodipine + Irbesartan regimen may be superior to Felodipine + metoprolol regimen for male hypertensive patients with mild ED.
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Anti-Hipertensivos/uso terapêutico , Compostos de Bifenilo/uso terapêutico , Disfunção Erétil/induzido quimicamente , Hipertensão/tratamento farmacológico , Metoprolol/uso terapêutico , Ereção Peniana/efeitos dos fármacos , Tetrazóis/uso terapêutico , Adulto , Anti-Hipertensivos/administração & dosagem , Compostos de Bifenilo/administração & dosagem , Quimioterapia Combinada , Disfunção Erétil/fisiopatologia , Humanos , Hipertensão/fisiopatologia , Irbesartana , Masculino , Metoprolol/administração & dosagem , Pessoa de Meia-Idade , Tetrazóis/administração & dosagemRESUMO
Mitochondria, independent double-membrane organelles, are intracellular power plants that feed most eukaryotic cells with the ATP produced via the oxidative phosphorylation (OXPHOS). Consistently, cytochrome c oxidase (COX) catalyzes the electron transfer chain's final step. Electrons are transferred from reduced cytochrome c to molecular oxygen and play an indispensable role in oxidative phosphorylation of cells. Cytochrome c oxidase subunit 6c (COX6C) is encoded by the nuclear genome in the ribosome after translation and is transported to mitochondria via different pathways, and eventually forms the COX complex. In recent years, many studies have shown the abnormal level of COX6C in familial hypercholesterolemia, chronic kidney disease, diabetes, breast cancer, prostate cancer, uterine leiomyoma, follicular thyroid cancer, melanoma tissues, and other conditions. Its underlying mechanism may be related to the cellular oxidative phosphorylation pathway in tissue injury disease. Here reviews the varied function of COX6C in non-tumor and tumor diseases.
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OBJECTIVE: To compare the effects between felodipine plus irbesartan and felodipine plus metoprolol regimen on blood pressure and the sexual function in young and middle-aged hypertensive women. METHODS: In this prospective, randomized, parallelized, controlled and fixed combined therapy trial, 99 female patients (aged 18 to 60) with grade 1 and grade 2 hypertension (BP ≥ 140/90 mm Hg and < 179/109 mm Hg, 1 mm Hg = 0.133 kPa) were assigned to felodipine 5 mg q.d + irbesartan 150 mg q.d (F + I group, n = 49) and felodipine 5 mg q.d + metoprolol 47.5 mg q.d (F + M group, n = 50) group. Target blood pressure was < 140/90 mm Hg. The female sexual function index (FSFI) questionnaire, levels of serum estradiol and testosterone were assessed. Female sexual dysfunction was defined as a FSFI score of less than 25.5. Patients were followed up for 24 weeks. RESULTS: The rate of achieving blood pressure goal between 2 groups was similar at the 4th, 8th, 12th and 24th weeks respectively (42.9% vs. 62.0% at 4th week, 89.8% vs. 90.0% at 8th week, 93.9% vs. 94.0% at 12th week, 98.0% vs. 96.0% at 24th week, P > 0.05). Compared to baseline, scores for the items related to "desire" and "arousal" were significantly improved (P < 0.05), the level of the serum estradiol was significantly elevated [(50.3 ± 37.4) pg/L vs. (54.4 ± 10.8) pg/L before menopause, (18.4 ± 2.9) pg/L vs. (20.2 ± 3.1)pg/L after menopause, P < 0.05] and the level of the serum testosterone was significantly decreased [(722.8 ± 277.1) ng/L vs. (650.0 ± 156.0) ng/L before menopause, (841.2 ± 279.3) ng/L vs. (761.9 ± 197.8) ng/L after menopause, P < 0.05] in the F + I group, while scores for the items related to "sexual desire" and "lubrication" were statistically reduced (P < 0.01), the concentration of the serum estradiol was significantly reduced [(57.4 ± 9.7) pg/L vs. (51.1 ± 12.1) pg/L before menopause, (19.8 ± 2.3) pg/L vs. (17.8 ± 3.3) pg/L after menopause, P < 0.01] and the level of the serum testosterone was significantly increased [(775.6 ± 217.8) ng/L vs. (886.0 ± 186.4) ng/L before menopause, (812.5 ± 311.3) ng/L vs. (914.4 ± 300.2) ng/L after menopause, P < 0.01] in the F + M group. FSFI score was negatively correlated with age and systolic blood pressure levels. CONCLUSION: felodipine plus irbesartan or metoprolol for 24 weeks equally reduced blood pressure and the former regimen is superior to the latter on sexual function improvement in this patient cohort.
Assuntos
Anti-Hipertensivos/uso terapêutico , Felodipino/farmacologia , Hipertensão/tratamento farmacológico , Disfunções Sexuais Fisiológicas , Adolescente , Adulto , Compostos de Bifenilo/farmacologia , Compostos de Bifenilo/uso terapêutico , Felodipino/uso terapêutico , Feminino , Humanos , Irbesartana , Metoprolol/farmacologia , Metoprolol/uso terapêutico , Pessoa de Meia-Idade , Estudos Prospectivos , Tetrazóis/farmacologia , Tetrazóis/uso terapêutico , Adulto JovemRESUMO
Soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins are a large protein complex that is involved in the membrane fusion in vesicle trafficking, cell growth, cytokinesis, membrane repair, and synaptic transmission. As one of the SNARE proteins, SEC22B functions in membrane fusion of vesicle trafficking between the endoplasmic reticulum and the Golgi apparatus, antigen cross-presentation, secretory autophagy, and other biological processes. However, apart from not being SNARE proteins, there is little knowledge known about its two homologs (SEC22A and SEC22C). SEC22B alterations have been reported in many human diseases, especially, many mutations of SEC22B in human cancers have been detected. In this review, we will introduce the specific functions of SEC22B, and summarize the researches about SEC22B in human cancers and other diseases. These findings have laid the foundation for further studies to clarify the exact mechanism of SEC22B in the pathological process and to seek new therapeutic targets and better treatment strategies.
Assuntos
Doença/genética , Transporte Proteico/fisiologia , Proteínas R-SNARE/genética , HumanosRESUMO
Placental growth factor (PlGF) related signaling pathway has been shown to have close relationship with the progression of cancers. Metformin has been reported to have an inhibitory effect on PlGF expression in a breast cancer model. However, little is known about whether the anti-neoplastic activity of metformin is contributed by its inhibitory effect on PlGF expression. Protein, mRNA and secretion levels of PlGF were tested and the proliferation of cancer cells was determined. After treatment of metformin, BALB/c mice bearing 4T1 tumors were sacrificed and immunohistochemistry staining of the tumor sections was obtained. Baseline expression of autocrine PlGF varied between different breast cancer cell lines, while the expression of vascular endothelial growth factor receptor-1 (VEGFR-1) was comparable between cell lines. Other clinical data showed that the expression of PlGF other than VEGFR-1 had a prognostic value for patients with breast cancers. Metformin significantly decreased the secretion and mRNA levels of PlGF, which greatly contributed to its inhibitory effect on the proliferation of breast cancer cells with high P1GF expression. The unresponsiveness of tumor cells with low PlGF expression to genetic silencing was reversed by the supplementation of exogenous PlGF. Systemic metformin administration apparently inhibited the in vivo growth of 4T1 carcinoma, which was accompanied by the repolarization of macrophages from M2 to M1. These findings indicated that both autocrine and paracrine PlGF signaling and macrophage repolarization are involved in the progression of breast cancer, which could be targeted by metformin.
Assuntos
Antineoplásicos/farmacologia , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Proteínas de Membrana/metabolismo , Metformina/farmacologia , Transdução de Sinais/efeitos dos fármacos , Comunicação Autócrina/efeitos dos fármacos , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Proteínas de Membrana/genética , Prognóstico , RNA Mensageiro/genética , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: Vascular maturity and functionality are closely associated with tumor progression and chemosensitivity. The antidiabetic agent metformin has shown its ability to inhibit tumor angiogenesis in metastatic breast cancer models. However, it remains unclear if or how metformin remodels the abnormal vasculature of metastatic breast cancer, while inhibiting angiogenesis. METHODS: Metastatic breast cancer models were constructed to compare microvessel density (MVD), vascular maturity and function, lung metastasis and chemosensitivity in metformin-treated or untreated mice. Protein array assay and transcriptome sequencing were performed for genetic screening. Lentiviral shRNA-PDGF-B transfection was used for observing the contribution of PDGF-B knockdown to metformin's vascular effects. RESULTS: Metastatic breast cancers were characterized by an excessively angiogenic, immature and morphologically abnormal vasculature. Compared to control, metformin significantly reduced MVD, leakage and hypoxia, and increased vascular mural cells coverage and perfusion, namely, "vessel normalization". Metformin at human blood concentrations had no direct effect on the migration and proliferation of cancer cells. Based on that, reduced lung metastasis of the primary tumor and improved chemosensitization by metformin were assumed to be mediated via metformin's vascular effects. Further results of genetic screening and in vivo experiments showed that the downregulation of platelet-derived growth factor B (PDGF-B) greatly contributed to the metformin-induced vessel normalization. CONCLUSIONS: These findings provide pre-clinical evidences for the vascular mechanism of metformin-induced metastasis inhibition and the chemosensitization of metastatic breast cancers.
Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Metformina/farmacologia , Neovascularização Patológica/genética , Proteínas Proto-Oncogênicas c-sis/genética , Animais , Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/mortalidade , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Modelos Animais de Doenças , Progressão da Doença , Feminino , Perfilação da Expressão Gênica , Humanos , Camundongos , Modelos Biológicos , Estadiamento de Neoplasias , Neovascularização Patológica/tratamento farmacológico , Prognóstico , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The anti-diabetic metformin has been demonstrated to be effective in suppression of tumor progression via multiple mechanisms, in which angiogenic inhibition is involved. Hypoxia is a common feather of malignant tumor and promotes angiogenesis via induction of pro-angiogenic factors. However, the effect of metformin on tumor hypoxia and the association with angiogenic inhibition are still unclear. In the current study, we investigated the effects of metformin on both tumor blood perfusion and hypoxia-induced excessive angiogenesis. In the tumor region adjacent to necrosis, aberrantly excessive angiogenesis resulted from hypoperfusion-induced intense hypoxia and greatly contributed to the high average levels of both microvessel density and vascular branch density. Metformin administration increased the percentage of lectin-perfused vessels and reduced hypoxyprobe-positive area. This metformin-induced amelioration of hypoxia was accompanied by a significant reduction in expressions of both HIF-1α and angiogenesis-associated factors (AAFs). Consequently, inhibited excessive angiogenesis in hypoxic peri-necrotic region was observed in metformin-treated tumor. Further stable knockdown of HIF-1α abrogated hypoxia-induced AAFs in vitro and reduced both microvessel density and area of fitc-conjugated dextran that leaked outside the vascular lumen. Taken together, metformin ameliorated tumor hypoxia and restrained HIF-1α-induced expressions of AAFs through elevating tumor blood perfusion, thus suppressing the excessive tumor angiogenesis.