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BACKGROUND: Chronic obstructive pulmonary disease (COPD) contributes to the incidence and prognosis of lung cancer. The presence of COPD significantly increases the risk of lung squamous cell carcinoma (LSCC). COPD may promote an immunosuppressive microenvironment in LSCC by regulating the expression of immune-inhibitory factors in T cells, although the mechanisms remain unclear. In this study, we aimed to decipher the tumour microenvironment signature for LSCC with COPD at a single-cell level. METHODS: We performed single-cell RNA sequencing on tumour tissues from LSCC with or without COPD, then investigated the features of the immune and tumour cells. We employed multiple techniques, including multispectral imaging, flow cytometry, tissue microarray analysis, survival analysis, co-culture systems and in vitro and in vivo treatment experiments, to validate the findings obtained from single-cell analyses. RESULTS: LSCC with COPD showed increased proportions of tumour-associated macrophages (TAMs) and higher levels of CD8+ T cell exhaustion molecules, which contributed to an immunosuppressive microenvironment. Further analysis revealed a critical cluster of CD74+ tumour cells that expressed both epithelial and immune cell signatures, exhibited a stronger capacity for tumorigenesis and predicted worse overall survival. Notably, migration inhibitory factor (MIF) secreted by TAMs from LSCC with COPD may promote the activation of CD74. MIF-CD74 may interact with CD8+ T cells and impair their anti-tumour activity by regulating the PI3K-STAT3-programmed cell death-1 ligand 1 signalling pathway, facilitating tumour proliferation and immune evasion. CONCLUSIONS: Our comprehensive picture of the tumour ecosystem in LSCC with COPD provides deeper insights into relevant immune evasion mechanisms and potential targets for immunotherapy. HIGHLIGHT: Our results demonstrated higher proportions of tumour-associated macrophages (TAMs) and higher levels of exhaustion molecules in CD8+ T cells in the microenvironment of LSCC with COPD. CD74+tumour cells were associated with poor disease prognosis. Migration inhibitory factor (MIF)-CD74 may interact with CD8+ T cells and impair their anti-tumour activity by regulating the PI3K-STAT3-PD-L1 signalling pathway, facilitating immune evasion.
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Neoplasias Pulmonares , Doença Pulmonar Obstrutiva Crônica , Análise da Expressão Gênica de Célula Única , Humanos , Antígenos de Diferenciação de Linfócitos B/genética , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/imunologia , Carcinoma de Células Escamosas/patologia , Evasão da Resposta Imune/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Doença Pulmonar Obstrutiva Crônica/genética , Doença Pulmonar Obstrutiva Crônica/imunologia , Análise da Expressão Gênica de Célula Única/métodos , Microambiente Tumoral/genética , Microambiente Tumoral/imunologiaRESUMO
The effects of adipocyterich microenvironment (ARM) on chemoresistance have garnered increasing interest. Ovarian cancer (OVCA) is a representative adipocyterich associated cancer. In the present study, epithelial OVCA (EOC) was used to investigate the influence of ARM on chemoresistance with the aim of identifying novel targets and developing novel strategies to reduce chemoresistance. Bioinformatics analysis was used to explore the effects of ARMassociated mechanisms contributing to chemoresistance and treated EOC cells, primarily OVCAR3 cells, with human adipose tissue extracts (HATES) from the peritumoral adipose tissue of patients were used to mimic ARM in vitro. Specifically, the peroxisome proliferatoractivated receptor γ (PPARγ) antagonist GW9662 and the ABC transporter G family member 2 (ABCG2) inhibitor KO143, were used to determine the underlying mechanisms. Next, the effect of HATES on the expression of PPARγ and ABCG2 in OVCAR3 cells treated with cisplatin (DDP) and paclitaxel (PTX) was determined. Additionally, the association between PPARγ, ABCG2 and chemoresistance in EOC specimens was assessed. To evaluate the effect of inhibiting PPARγ, using DDP, a nude mouse model injected with OVCAR3shPPARγ cells and a C57BL/6 model injected with ID8 cells treated with GW9662 were established. Finally, the factors within ARM that contributed to the mechanism were determined. It was found that HATES promoted chemoresistance by increasing ABCG2 expression via PPARγ. Expression of PPARγ/ABCG2 was related to chemoresistance in EOC clinical specimens. GW9662 or knockdown of PPARγ improved the efficacy of chemotherapy in mice. Finally, angiogenin and oleic acid played key roles in HATES in the upregulation of PPARγ. The present study showed that the introduction of ARMeducated PPARγ attenuated chemoresistance in EOC, highlighting a potentially novel therapeutic adjuvant to chemotherapy and shedding light on a means of improving the efficacy of chemotherapy from the perspective of ARM.
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Anilidas , Neoplasias Ovarianas , Animais , Feminino , Humanos , Camundongos , Adipócitos/metabolismo , Apoptose , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Carcinoma Epitelial do Ovário/tratamento farmacológico , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/genética , Camundongos Endogâmicos C57BL , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , PPAR gama/genética , PPAR gama/metabolismo , Microambiente Tumoral , Regulação para CimaRESUMO
Triple-negative breast cancer (TNBC) is a heterogeneous subtype of breast cancer. Anti-PD-1/PD-L1 treatment for advanced TNBC is still limited to PD-L1-positive patients. Ataxia telangiectasia mutated (ATM) is a switch molecule for homologous recombination and repair. In this study, we found a significant negative correlation between ATM and PD-L1 in 4 TNBC clinical specimens by single-cell RNA sequencing (scRNA-seq), which was confirmed by immunochemical staining in 86 TNBC specimens. We then established ATM knockdown TNBC stable cell lines to perform in vitro studies and animal experiments, proving the negative regulation of PD-L1 by ATM via suppression of tumor necrosis factor-alpha (TNF-α), which was confirmed by cytokine array analysis of TNBC cell line and analysis of clinical specimens. We further found that ATM inhibits TNF-α via inactivating JNK/c-Jun by scRNA-seq, Western blot and luciferase reporter assays. Finally, we identified a negative correlation between changes in phospho-ATMS1981 and PD-L1 levels in TNBC post- and pre-neoadjuvant therapy. This study reveals a novel mechanism by which ATM negatively regulates PD-L1 by downregulating JNK/c-Jun/TNF-α in TNBC, shedding light on the wide application of immune checkpoint blockade therapy for treating multi-line-resistant TNBC.
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Ataxia Telangiectasia , Neoplasias de Mama Triplo Negativas , Animais , Humanos , Proteínas Mutadas de Ataxia Telangiectasia/genética , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Antígeno B7-H1/metabolismo , Citocinas/metabolismo , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Intermedin (IMD) is a member of the calcitonin gene-related peptide (CGRP)/calcitonin (CT) superfamily, and it is expressed extensively throughout the body. The typical receptors for IMD are complexes composed of calcitonin receptor-like receptor (CLR) and receptor activity-modifying protein (RAMP), which leads to a biased activation towards Gαs. As a diagnostic and prognostic biomarker, IMD regulates the initiation and metastasis of multiple tumors. Additionally, IMD functions as a proangiogenic factor that can restrain excessive vascular budding and facilitate the expansion of blood vessel lumen, ultimately resulting in the fusion of blood vessels. IMD has protective roles in various diseases, including ischemia-reperfusion injury, metabolic disease, cardiovascular diseases and inflammatory diseases. This review systematically elucidates IMD's expression, structure, related receptors and signal pathway, as well as its comprehensive functions in the context of acute kidney injury, obesity, diabetes, heart failure and sepsis. However, the precise formation process of IMD short peptides in vivo and their downstream signaling pathway have not been fully elucidated yet. Further in-depth studies are need to translate IMD research into clinical applications.
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The SEVEN IN Absentia (SINA), a typical member of the RING E3 ligase family, plays a crucial role in plant growth, development and response to abiotic stress. However, its biological functions in oil crops are still unknown. Previously, we reported that overexpression of AtSINA2 in Arabidopsis positively regulated the drought tolerance of transgenic plants. In this work, we demonstrate that ectopic expression of AtSINA2 in soybean improved the shoot growth, grain yield, drought tolerance and seed oil content in transgenic plants. Compared to wild type, transgenic soybean produced greater shoot biomass and grain yield, and showed improved seed oil and drought tolerance. Physiological analyses exhibited that the increased drought tolerance of transgenic plants was accompanied with a higher chlorophyll content, and a lower malondialdehyde accumulation and water loss during drought stress. Further transcriptomic analyses revealed that the expressions of genes related to plant growth, flowering and stress response were up- or down-regulated in transgenic soybean under both normal and drought stress conditions. Our findings imply that AtSINA2 improved both agricultural production and drought tolerance, and it can be used as a candidate gene for the genetic engineering of new soybean cultivars with improved grain yield and drought resistance.
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Proteínas de Arabidopsis , Arabidopsis , Arabidopsis/metabolismo , Glycine max/fisiologia , Resistência à Seca , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Grão Comestível/metabolismo , Plantas Geneticamente Modificadas/metabolismo , Secas , Óleos de Plantas/metabolismo , Estresse Fisiológico/genética , Regulação da Expressão Gênica de Plantas , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismoRESUMO
Glutathione S-transferases (GSTs) play an essential role in plant cell detoxification and secondary metabolism. However, their accurate functions in the growth and response to abiotic stress in woody plants are still largely unknown. In this work, a Phi class Glutathione S-transferase encoding gene PtGSTF1 was isolated from poplar (P. trichocarpa), and its biological functions in the regulation of biomass production and salt tolerance were investigated in transgenic poplar. PtGSTF1 was ubiquitously expressed in various tissues and organs, with a predominant expression in leaves and inducible expression by salt stress. Transgenic poplar overexpressing PtGSTF1 showed improved shoot growth, wood formation and improved salt tolerance, consistent with the increased xylem cell number and size under normal condition, and the optimized Na+ and K+ homeostasis and strengthened reactive oxygen species scavenging during salt stress. Further transcriptome analyses demonstrated that the expressions of genes related to hydrolase, cell wall modification, ion homeostasis and ROS scavenging were up- or down-regulated in transgenic plants. Our findings imply that PtGSTF1 improves both biomass production and salt tolerance through regulating hydrolase activity, cell wall modification, ion homeostasis and ROS scavenging in transgenic poplar, and that it can be considered as a useful gene candidate for the genetic breeding of new tree varieties with improved growth under salt stress conditions.
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Populus , Tolerância ao Sal , Biomassa , Proliferação de Células , Regulação da Expressão Gênica de Plantas , Glutationa/metabolismo , Glutationa Transferase/genética , Glutationa Transferase/metabolismo , Homeostase , Hidrolases/metabolismo , Melhoramento Vegetal , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Plantas Geneticamente Modificadas/genética , Populus/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Tolerância ao Sal/genética , Xilema/metabolismoRESUMO
A type VI secretion system (T6SS) gene cluster has been reported in Acidovorax citrulli. Research on the activation conditions, functions, and the interactions between key elements in A. citrulli T6SS is lacking. Hcp (Hemolysin co-regulated protein) is both a structural protein and a secretion protein of T6SS, which makes it a special element. The aims of this study were to determine the role of Hcp and its activated conditions to reveal the functions of T6SS. In virulence and colonization assays of hcp deletion mutant strain Δhcp, tssm (type VI secretion system membrane subunit) deletion mutant strain Δtssm and double mutant ΔhcpΔtssm, population growth was affected but not virulence after injection of cotyledons and seed-to-seedling transmission on watermelon. The population growth of Δhcp and Δtssm were lower than A. citrulli wild type strain Aac5 of A. citrulli group II at early stage but higher at a later stage. Deletion of hcp also affected growth ability in different culture media, and the decline stage of Δhcp was delayed in KB medium. Biofilm formation ability of Δhcp, Δtssm and ΔhcpΔtssm was lower than Aac5 with competition by prey bacteria but higher in KB and M9-Fe3+ medium. Deletion of hcp reduced the competition and survival ability of Aac5. Based on the results of Western blotting and qRT-PCR analyses, Hcp is activated by cell density, competition, ferric irons, and the host plant. The expression levels of genes related to bacterial secretion systems, protein export, and several other pathways, were significantly changed in the Δhcp mutant compared to Aac5 when T6SS was activated at high cell density. Based on transcriptome data, we found that a few candidate effectors need further identification. The phenotypes, activated conditions and transcriptome data all supported the conclusion that although there is only one T6SS gene cluster present in the A. citrulli group II strain Aac5, it related to multiple biological processes, including colonization, growth ability, competition and biofilm formation.
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Fenômenos Biológicos , Sistemas de Secreção Tipo VI , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Biofilmes , Comamonadaceae , Ferro , Sistemas de Secreção Tipo VI/genética , Sistemas de Secreção Tipo VI/metabolismoRESUMO
Understanding immune cell phenotypes in the tumor microenvironment (TME) is essential for explaining and predicting progression of non-small cell lung cancer (NSCLC) and its response to immunotherapy. Here we describe the single-cell transcriptomics of CD45+ immune cells from tumors, normal tissues and blood of NSCLC patients. We identified three clusters of immune cells exerting immunosuppressive effects: CD8+ T cells with exhausted phenotype, tumor-associated macrophages (TAMs) with a pro-inflammatory M2 phenotype, and regulatory B cells (B regs) with tumor-promoting characteristics. We identified genes that may be mediating T cell phenotypes, including the transcription factors ONECUT2 and ETV4 in exhausted CD8+ T cells, TIGIT and CTL4 high expression in regulatory T cells. Our results highlight the heterogeneity of CD45+ immune cells in the TME and provide testable hypotheses about the cell types and genes that define the TME.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Linfócitos T CD8-Positivos , Proteínas de Homeodomínio/genética , Humanos , Fatores de Transcrição/genética , Transcriptoma , Microambiente Tumoral/genéticaRESUMO
Compared with other types of breast cancer, triple-negative breast cancer (TNBC) has the characteristics of rapid progression, a lack of specific molecular targets for treatment and a poor prognosis. However, based on previously published studies, TGF-ß1 and survivin are potentially meaningful for the prognosis of patients with TNBC. The present study was therefore designed to measure and compare the expression of transforming growth factor-ß1 (TGF-ß1) and survivin in tissue samples of TNBC and non-TNBC patients in order to evaluate their ability as prognostic indicators. In total, 90 TNBC and 52 non-TNBC tissue specimens were selected, following which immunohistochemistry was used to detect the expression of TGF-ß1 and survivin in the cancer tissues. Subsequently, the potential association between the expression levels of these two proteins and the clinicopathological variables was analyzed. The expression levels of TGF-ß1 and survivin in TNBC tissues were found to be significantly higher compared with those in the non-TNBC tissues. In addition, the results of the present study demonstrated that TGF-ß1 expression was positively associated with survivin expression in the TNBC samples, but no significant correlation was found between TGF-ß1 and survivin expression in the non-TNBC samples. Kaplan-Meier (K-M) analysis was performed to assess the levels of TGF-ß1 and survivin in regard to patient survival, and univariate and multivariate Cox analyses of TGF-ß1 and survivin protein expression were performed to analyze the overall survival (OS) and progression-free survival (PFS) rates of patients with TNBC and non-TNBC. Although multivariate Cox analysis demonstrated that neither TGF-ß1 or survivin were independent prognostic predictors of TNBC or non-TNBC, results of the K-M curve revealed that patients with TNBC with TGF-ß1- and survivin-positive breast cancer exhibited shorter OS and PFS times. Multivariate Cox analysis demonstrated that in patients with TNBC, the combined expression of TGF-ß1 and survivin may yield additional prognostic information, compared with patients with non-TNBC.
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This study aimed to realize the automatic diagnosis of fatty degeneration of uterine fibroids. In this study, the traditional nonlocal means (NLM) algorithm was improved by changing the Euclidean distance and introducing a cosine function and applied to the ultrasonic imaging intelligent diagnosis of patients with fatty degeneration of uterine fibroids. Then, the noise reduction effect of the improved NLM algorithm was evaluated based on several indicators, such as peak signal-to-noise ratio (PSNR), mean square error (MSE), contrast-to-noise ratio (CNR), figure of merit (FOM), and structural similarity (SSIM). The accuracy, sensitivity, specificity, and F1 score were adopted to evaluate the improved NLM algorithm for diagnosing fatty degeneration of uterine fibroids, and the Perona-Malik (PM) algorithm and NLM algorithm were used for comparative analysis. The results showed that after the ultrasound images of patients with uterine fibroids were denoised using the improved NLM algorithm, the PSNR, MSE, CNR, FOM, and SSIM were obviously better than the same indicators of the image processed with the PM algorithm and the NLM algorithm, and the differences were statistically significant (P < 0.05). The diagnosis results of patients with fatty degeneration of uterine fibroids found that there was only one patient with missed diagnosis after the ultrasound image was processed with NLM algorithm, and there was no statistical difference between the improved NLM algorithm and the assisted diagnosis accuracy of the pathological examination results (P > 0.05). The average noise reduction time of the PM algorithm, NLM algorithm, and the improved NLM algorithm was 16.38 ± 4.33 s, 18.01 ± 5.14 s, and 23.81 ± 4.62 s, respectively. The diagnosis rate before improvement was 75.0%, the diagnosis accuracy rate for PM was 79.69%, and that after improvement was 85.94%. In summary, the improved NLM algorithm showed a good noise reduction effect on ultrasound images of patients with uterine fibroids, could improve the diagnosis accuracy of fatty degeneration of uterine fibroids, and could assist clinicians in the ultrasound imaging diagnosis of patients with uterine fibroids.
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Leiomioma , Algoritmos , Humanos , Leiomioma/diagnóstico por imagem , UltrassonografiaRESUMO
BACKGROUND: Cigarette smoking constitutes a major lifestyle risk factor for osteoporosis and hip fracture. It is reported to impair the outcome of many clinical procedures, such as wound infection treatment and fracture healing. Importantly, although several studies have already demonstrated the negative correlation between cigarette consume and impaired bone homeostasis, there is still a poor understanding of how does smoking affect bone health, due to the lack of an adequately designed animal model. Our goal was to determine that cigarette smoke exposure impairs the dynamic bone remodeling process through induction of bone resorption and inhibition of bone formation. METHODS: We developed cigarette smoke exposure protocols exposing mice to environmental smoking for 10 days or 3 months to determine acute and chronic smoke exposure effects. We used these models, to demonstrate the effect of smoking exposure on the cellular and molecular changes of bone remodeling and correlate these early alterations with subsequent bone structure changes measured by microCT and pQCT. We examined the bone phenotype alterations in vivo and ex vivo in the acute and chronic smoke exposure mice by measuring bone mineral density and bone histomorphometry. Further, we measured osteoclast and osteoblast differentiation gene expression levels in each group. The function changes of osteoclast or osteoblast were evaluated. RESULTS: Smoke exposure caused a significant imbalance between bone resorption and bone formation. A 10-day exposure to cigarette smoke sufficiently and effectively induced osteoclast activity, leading to the inhibition of osteoblast differentiation, although it did not immediately alter bone structure as demonstrated in mice exposed to smoke for 3 months. Cigarette smoke exposure also induced DNA-binding activity of nuclear factor kappaB (NFκB) in osteoclasts, which subsequently gave rise to changes in bone remodeling-related gene expression. CONCLUSIONS: Our findings suggest that smoke exposure induces RANKL activation-mediated by NFκB, which could be a "smoke sensor" for bone remodeling.
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NF-kappa B , Fumar , Animais , Remodelação Óssea , Inflamação , Camundongos , Fumaça , Fumar/efeitos adversosRESUMO
The drug resistance of cancer cells has become one of the biggest obstacles of effective anticancer treatments. Adipocytes produce plenty of cytokines (also known as adipokines), which remarkably affect the drug resistance exhibited by cancer cells. Different adipokines (leptin, visfatin, resistin, adiponectin, Interleukin 6, and tumor necrosis factor α) can induce drug resistance in different cancer cells by various functional mechanisms. This phenomenon is of great interest in pharmacological anti-cancer studies since it indicates that in the cancers with adipocyte-rich microenvironment, all adipokines join together to assist cancer cells to survive by facilitating drug resistance. Studies on adipokines contribute to the development of novel pharmacological strategies for cancer therapy if their roles and molecular targets are better understood. The review will elucidate the roles and the underlying mechanisms of adipokines in drug resistance, which may be of great significance for revealing new strategies for cancer treatment.
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Adipocinas/metabolismo , Antineoplásicos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Neoplasias/tratamento farmacológico , Animais , Humanos , Neoplasias/metabolismo , Neoplasias/patologia , Transdução de SinaisRESUMO
The inflammatory milieu in tumor modulates the resistance to the conventional antitumoral therapies. Interleukin-6 (IL-6), a pleiotropic pro-inflammatory cytokine and a crucial mediator of tumor development, has been targeted as a therapeutic strategy to overcome chemoresistance in the treatment of tumors. The protein levels and nuclear translocation of HIFs (hypoxia-inducible factors), such as HIF-1α, are linked to the drug resistance of tumor cells. However, whether IL-6 promotes the nuclear translocation of HIF-1α and the related mechanism remain to be investigated. We applied two ovarian cancer (OvCa) cell lines, A2780 cells and SKOV3 cells for the in vivo and in vitro studies. We found that IL-6 up-regulates the HIF-1α expression via the signal transducer and activator of transcription 3 (STAT3) signaling under hypoxia in either endogenous or exogenous way, and then we proved that IL-6 enhances the transcriptional activity of HIF-1α via the STAT3 signaling. Further mechanism research revealed that IL-6 promotes the nuclear translocation of HIF-1α through the STAT3 signaling under hypoxia. Proliferation assay and apoptosis assay were applied and proved that IL-6 enhances the chemoresistance of OvCa cells against cisplatin through the upregulation of HIF-1α via the STAT3 signaling in vitro. The In vivo studies confirmed the effect of IL-6 in increasing the chemoresistance of OvCa cells against cisplatin through the IL-6/STAT3/HIF-1α loop in the animal models. Our data elucidates the explicit mechanism of IL-6/STAT3/HIF-1α loop in OvCa and also provides new insights into the development of different approaches for the inflammation-induced and hypoxia-induced resistance in tumor therapies.
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Resistencia a Medicamentos Antineoplásicos/fisiologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Interleucina-6/efeitos adversos , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Animais , Apoptose/efeitos dos fármacos , Hipóxia Celular/fisiologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cisplatino/farmacologia , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Interleucina-6/genética , Interleucina-6/metabolismo , Camundongos Nus , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Regulação para CimaRESUMO
The present study examined SMAD family member 4 (Smad4), SMAD family member 2 (Smad2) and phosphorylated (p-)Smad2 expression in biopsy specimens from patients with invasive breast ductal carcinoma, in order to assess their abilities as prognostic markers. A total of 126 tissue samples were selected, and the expression of Smad2, p-Smad2 and Smad4 in carcinoma tissues was detected by immunostaining, and the association between protein expression and clinicopathological variables was analyzed. Smad4 expression was negatively correlated with human epidermal growth factor receptor 2 in carcinoma tissues, and Smad4 expression was consistent with that of p-Smad2. Although multivariate analysis revealed that Smad2, p-Smad2 and Smad4 were not independent predictors, Kaplan-Meier curves demonstrated that Smad4 positivity was correlated with a longer overall survival (OS) and progression-free survival (PFS) time. However, upon analysis of combined markers, there was a significant difference between the p-Smad2/Smad4 co-positive and co-negative patients; the latter tended to exhibit a shorter OS and PFS time, and multivariate analysis revealed that the combined expression of p-Smad2 and Smad4 may be used as an independent prognostic factor. These results suggested that the assessment of p-Smad2 and Smad4 protein expression in breast ductal carcinoma biopsy specimens may provide additional prognostic information.
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Pro-inflammatory cytokines are crucial mediators of cancer development, representing potential targets for cancer therapy. The molecular mechanism of a vital pro-inflammatory cytokine, IL-17A, in cancer progression and its potential use in therapy through influencing fatty acid (FA) metabolism, especially FA uptake of cancer cells, remains unknown. In the present study, we used IL-17A and ovarian cancer (OvCa), a representative of both obesity-related and inflammation-related cancers, to explore the interactions among IL-17A, cancer cells and adipocytes (which can provide FAs). We found that in the presence of palmitic acid (PA), IL-17A could directly increase the cellular uptake of PA, leading to the proliferation of OvCa cells via the IL-17A/IL-17RA/p-STAT3/FABP4 axis rather than via CD36. Moreover, in vivo experiments using an orthotopic implantation model in IL-17A-deficient mice demonstrated that endogenous IL-17A could fuel OvCa growth and metastasis with increased expression of FABP4 and p-STAT3. Furthermore, analysis of clinical specimens supported the above findings. Our data not only provide useful insights into the clinical intervention of the growth and metastasis of the tumors (such as OvCa) that are prone to growth and metastasis in an adipocyte-rich microenvironment (ARM) but also provides new insights into the roles of IL-17A in tumor progression and immunomodulatory therapy of OvCa.
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Adipócitos/imunologia , Interleucina-17/metabolismo , Neoplasias Ovarianas/imunologia , Ácido Palmítico/metabolismo , Adipócitos/metabolismo , Animais , Antígenos CD36/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Modelos Animais de Doenças , Progressão da Doença , Proteínas de Ligação a Ácido Graxo/metabolismo , Feminino , Humanos , Interleucina-17/genética , Interleucina-17/imunologia , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Neoplasias Ovarianas/patologia , Ovário/patologia , Fosforilação , Receptores de Interleucina-17/metabolismo , Proteínas Recombinantes/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Microambiente Tumoral/imunologiaRESUMO
Ankylosing spondylitis (AS) is a high disability and greatly destructive disease. In this study, we preliminarily studied the function and mechanism of bilobalide (BIL) on interleukin (IL)-17-induced inflammatory injury in ATDC5 cells. CCK-8 and migration assays were used to detect the functions of IL-7, BIL, and microRNA (miR)-125a on cell viability and migration. The miR-125a level was changed by transfection, and tested by real-time quantitative polymerase chain reaction. Additionally, Western blot tested the levels of inflammatory factors (IL-6 and tumor necrosis factor-α), matrix metalloproteinases (MMPs), and pathway-related proteins. Moreover, the enzyme-linked immunosorbent assay also was used to detect inflammatory factor levels. IL-7 was used to construct an inflammatory injury model in ATDC5 cells. Based on this, BIL inhibited IL-17-induced cell viability, migration, and expressions of inflammatory factors and MMPs. Furthermore, we found BIL negatively regulated miR-125a, and the miR-125a mimic could partly reverse the effects of BIL on IL-17-injury. Finally, we showed that BIL inhibited the c-Jun N-terminal kinase (JNK) and nuclear factor kappa B (NF-κB) pathways, and the miR-125a mimic had the opposite effect. BIL inhibited IL-17-induced inflammatory injury in ATDC5 cells by downregulation of miR-125a via JNK and NF-κB signaling pathways.
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Ciclopentanos/farmacologia , Regulação para Baixo/efeitos dos fármacos , Furanos/farmacologia , Ginkgolídeos/farmacologia , Inflamação/induzido quimicamente , Interleucina-17/farmacologia , MicroRNAs/metabolismo , Extratos Vegetais/farmacologia , Animais , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Ginkgo biloba , Proteínas Quinases JNK Ativadas por Mitógeno/antagonistas & inibidores , Metaloproteinases da Matriz/metabolismo , Camundongos , MicroRNAs/química , MicroRNAs/genética , Mimetismo Molecular , NF-kappa B/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Espondilite Anquilosante/metabolismo , TransfecçãoRESUMO
BACKGROUND: This study aimed to assess the efficacy of water-filtered infrared A (wIRA) in sacroiliitis in male patients with ankylosing spondylitis (AS) and the effect of wIRA therapy on serum vascular endothelial growth factor (VEGF). METHODS: One hundred twenty male AS patients with active sacroiliitis were randomly divided into wIRA group and control group. wIRA treatment was performed twice daily for 5 consecutive days with 24-h interval before switching the treatment (crossover design). Bath ankylosing spondylitis disease activity index (BASDAI) scores, pain visual analogue scale (VAS), and morning stiffness VAS were recorded prior to and after each treatment period. Additionally, C-reactive protein (CRP), serum VEGF, and resistance index (RI) of sacroiliac joints detected by ultrasonography were recorded at baseline and after the first and second treatment period, respectively. The efficacy was examined by using repeated measures analysis of variance (ANOVA). RESULTS: BASDAI, pain VAS, and morning stiffness VAS scores decreased significantly (P < 0.001) after wIRA treatment and no-wIRA treatment (control group), and the difference between the two groups was significant (P < 0.001). CRP declined and RI increased during the wIRA treatment as compared with the no-wIRA treatment (P < 0.001). The increase in RI was associated with improvement of pain VAS scores (P = 0.018), while serum VEGF was unaffected by the treatment. CONCLUSIONS: wIRA treatment achieved symptom and pain relief for AS patients with active sacroiliitis. wIRA treatment also improved RI revealed by ultrasonography, and this effect was associated with improved pain VAS scores.
Assuntos
Raios Infravermelhos/uso terapêutico , Sacroileíte/radioterapia , Espondilite Anquilosante/radioterapia , Fator A de Crescimento do Endotélio Vascular/sangue , Adulto , Proteína C-Reativa/metabolismo , Estudos Cross-Over , Humanos , Masculino , Pessoa de Meia-Idade , Medição da Dor/métodos , Amplitude de Movimento Articular , Articulação Sacroilíaca/diagnóstico por imagem , Articulação Sacroilíaca/fisiopatologia , Sacroileíte/sangue , Sacroileíte/diagnóstico por imagem , Sacroileíte/fisiopatologia , Índice de Gravidade de Doença , Espondilite Anquilosante/sangue , Espondilite Anquilosante/diagnóstico por imagem , Espondilite Anquilosante/fisiopatologia , Resultado do Tratamento , Ultrassonografia , Adulto JovemRESUMO
Adipose tissue has been considered as a crucial source of certain pro-inflammatory cytokines; conversely, these pro-inflammatory cytokines are involved in regulating the proliferation and apoptosis of adipocytes, promoting lipolysis, inhibiting lipid synthesis and decreasing blood lipids, etc. In recent decades, extensive studies have indicated that pro-inflammatory cytokines play important roles in the development of lipid metabolism of metabolic diseases, including obesity, atherosclerosis, steatohepatitis and hyperlipoproteinemia. However, the involved pro-inflammatory cytokines types and the underlying mechanisms remain largely unknown. The "re-discovery" of cancer as a metabolic disorder largely occurred in the last five years. Although pro-inflammatory cytokines have been intensively investigated in cancer research, there are very few studies about the roles of pro-inflammatory cytokines in the lipid metabolism of cancer. In the current review, we provide an overview of the progress that has been made in the roles of different pro-inflammatory cytokines in lipid metabolism of metabolic diseases including cancer.
Assuntos
Citocinas/metabolismo , Mediadores da Inflamação/metabolismo , Metabolismo dos Lipídeos , Doenças Metabólicas/etiologia , Doenças Metabólicas/metabolismo , Adipócitos/metabolismo , Animais , Aterosclerose/complicações , Aterosclerose/metabolismo , Suscetibilidade a Doenças , Ácidos Graxos/metabolismo , Humanos , Obesidade/complicações , Obesidade/metabolismoRESUMO
BACKGROUND: China is experiencing a sizeable rural-urban flow, which may influence the health of internal migrant youth deeply. Disadvantages in the city are highly likely to contribute to health issues among the young internal migrant population. The current qualitative study is to explore how internal migrant young people view the health issues they face, and the services and opportunities they could seek in their host community. METHODS: Data were collected from 90 internal migrant youth aged between 15 and 19 years old and 20 adult service providers who worked with them in a community of Shanghai, where the population of internal migrants was relatively large. Four types of qualitative research methods were used, including key informant interviews with adults, in-depth interviews with adolescents, a photovoice activity with adolescents and community mapping & focus group discussions with adolescents. Guided by the ecological systems framework and the acculturation theory, thematic analysis was conducted using ATLAS.Ti 7.0 software. RESULTS: While younger migrants had a limited understanding of health, elder migrant youths were more sensitive to societal and political factors related to their health. Mental health and health risk behaviors such as smoking, violence and premarital unsafe sex were thought as major health issues. Internal migrant youths rarely seek health information and services initiatively from formal sources. They believed their health concerns weren't as pressing as the pressure coming from the high cost of living, the experience of being unfairly treated and the lack of opportunities. Participants also cited lack of family and social support, lack of awareness and supportive policies to get access to community and public services as impacting health factors. CONCLUSIONS: The study's findings provide the insight to the social contexts which influence the health experience, health seeking behaviors, and city adaptation of young internal migrants in their host community. This research stresses the importance of understanding social networks and structural barriers faced by migrant youth in vulnerable environments. A multidimensional social support is essential for internal migrant youth facing present and potential health risks.