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Metastasis is the leading cause of cancer-related deaths and myeloid cells are critical in the metastatic microenvironment. Here, we explore the implications of reprogramming pre-metastatic niche myeloid cells by inducing trained immunity with whole beta-glucan particle (WGP). WGP-trained macrophages had increased responsiveness not only to lipopolysaccharide but also to tumor-derived factors. WGP in vivo treatment led to a trained immunity phenotype in lung interstitial macrophages, resulting in inhibition of tumor metastasis and survival prolongation in multiple mouse models of metastasis. WGP-induced trained immunity is mediated by the metabolite sphingosine-1-phosphate. Adoptive transfer of WGP-trained bone marrow-derived macrophages reduced tumor lung metastasis. Blockade of sphingosine-1-phosphate synthesis and mitochondrial fission abrogated WGP-induced trained immunity and its inhibition of lung metastases. WGP also induced trained immunity in human monocytes, resulting in antitumor activity. Our study identifies the metabolic sphingolipid-mitochondrial fission pathway for WGP-induced trained immunity and control over metastasis.
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Neoplasias Pulmonares , beta-Glucanas , Animais , Camundongos , Humanos , Imunidade Treinada , Macrófagos , Lisofosfolipídeos/metabolismo , Monócitos , Neoplasias Pulmonares/patologia , beta-Glucanas/metabolismo , beta-Glucanas/farmacologia , Microambiente TumoralRESUMO
Mitoxantrone (MX) is an effective treatment for breast cancer; however, high efflux of MX that is accomplished by breast cancer resistance protein (BCRP) leads to acquired multidrug resistance (MDR), reducing MX's therapeutic efficacy in breast cancer. Non-muscle myosin IIA (NMIIA) and its heavy phosphorylation at S1943 have been revealed to play key roles in tumor metastasis and progression, including in breast cancer; however, their molecular function in BCRP-mediated MDR in breast cancer remains unknown. In this study, we revealed that the expression of NMIIA heavy chain phosphorylation at S1943 was downregulated in BCRP-overexpressing breast cancer MCF-7/MX cells, and stable expression of NMIIA-S1943A mutant increased BCRP expression and promoted the resistance of MCF-7/MX cells to MX. Meanwhile, NMIIA S1943 phosphorylation induced by epidermal growth factor (EGF) was accompanied by the downregulation of BCRP in MCF-7/MX cells. Furthermore, stable expression of NMIIA-S1943A in MCF-7/MX cells resulted in upregulation of N-cadherin and the accumulation of ß-catenin on the cell surface, which inhibited the nucleus translocation of ß-catenin and Wnt/ß-catenin-based proliferative signaling. EGF stimulation of MCF-7/MX cells showed the downregulation of N-cadherin and ß-catenin. Our results suggest that decreased NMIIA heavy phosphorylation at S1943 increases BCRP expression and promotes MX resistance in breast cancer cells via upregulating N-cadherin expression.
Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Neoplasias da Mama , Caderinas , Resistencia a Medicamentos Antineoplásicos , Mitoxantrona , Proteínas de Neoplasias , Regulação para Cima , Humanos , Mitoxantrona/farmacologia , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Neoplasias da Mama/tratamento farmacológico , Proteínas de Neoplasias/metabolismo , Proteínas de Neoplasias/genética , Fosforilação , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Regulação para Cima/efeitos dos fármacos , Caderinas/metabolismo , Caderinas/genética , Células MCF-7 , Antineoplásicos/farmacologia , Cadeias Pesadas de Miosina/metabolismo , Cadeias Pesadas de Miosina/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacosRESUMO
An embedded obstacle-type micromixer-concentration gradient generator based on capillary self-driven is proposed and studied. Herringbone structure (HS) for mixing and palisade-shape small channels at the outlet are designed in the device (named HS). Simulation and experimentation are done to study the liquid mixing efficiency in the small channels and concentration gradient at the outlet, and the experimental results agree with the simulation results. For three cases of liquid dripping (sequential, reverse, and delayed drippings), mixing analysis shows that the mixing efficiency increases along both mixing channel and palisade length, and is high in the middle small channel of the palisade-shape area and low on both sides. An obvious concentration gradient at the outlet can form compared with the device without the palisade-shape area. Finally, water pH value detection is done as one of the applications of HS. This study can provide guidance for the application of HS in biochemical detection, cell research, drug screening, etc. based on the capillary-driven effect.
Assuntos
Simulação por ComputadorRESUMO
2,4-dichlorophenol (2,4-DCP), 2,5-DCP, 2,4,5-trichlorophenol (2,4,5-TCP), 2,4,6-TCP, and ortho-phenylphenol (OPP) are widely present in the environment. However, their associations with risk and prognosis of diabetes and prediabetes remains unclear. We investigated the associations of these five phenols with the risk of diabetes and prediabetes, and with all-cause and cardiovascular disease (CVD) mortality, in adults with diabetes or prediabetes (n=6419). Information on diabetes and prediabetes indicators, and mortality data was collected from the National Health and Nutrition Examination Survey. Logistic and Cox regression models were used to explore the associations of the five phenols with risk and prognosis of diabetes and prediabetes. Participants in the highest urinary 2,4-DCP and 2,5-DCP tertiles had higher odds of diabetes [adjusted odds ratio (aOR), 1.34, 95â¯% confidence interval (CI): 1.10, 1.62; aOR, 1.29, 95â¯% CI: 1.07, 1.56, respectively] than those in the lowest tertiles. Participants with urinary OPP concentrations above the limit of detection (LOD), but below median had an aOR of 1.25 (95â¯% CI: 1.08, 1.46) for prediabetes compared to those with concentrations below the LOD. In adults with diabetes, the highest 2,4-DCP and 2,5-DCP tertiles were associated with all-cause mortality [adjusted hazard ratio (aHR), 1.49; 95â¯% CI: 1.08, 2.06; aHR, 1.49; 95â¯% CI: 1.08, 2.05, respectively] and CVD mortality (aHR, 2.58; 95 % CI: 1.33, 4.97; aHR, 1.96; 95â¯% CI: 1.06, 3.60, respectively) compared with the lowest tertiles. Compared with 2,4,5-TCP concentrations below the LOD, those above median were associated with all-cause mortality (aHR: 1.75; 95â¯% CI: 1.24, 2.48) and CVD mortality (aHR: 2.34; 95â¯% CI: 1.19, 4.63) in adults with prediabetes. Furthermore, the associations between these phenols and mortality were strengthened in some subgroups. Environmental exposure to 2,4-DCP, 2,5-DCP, 2,4,5-TCP, and OPP increases the risk or adverse prognosis of diabetes or prediabetes in adults in the US. Further studies are required to confirm these findings.
Assuntos
Clorofenóis , Diabetes Mellitus , Poluentes Ambientais , Estado Pré-Diabético , Humanos , Clorofenóis/urina , Masculino , Estado Pré-Diabético/urina , Estado Pré-Diabético/epidemiologia , Estado Pré-Diabético/induzido quimicamente , Feminino , Pessoa de Meia-Idade , Diabetes Mellitus/epidemiologia , Adulto , Poluentes Ambientais/urina , Fenóis/urina , Prognóstico , Inquéritos Nutricionais , Idoso , Doenças Cardiovasculares/mortalidade , Doenças Cardiovasculares/epidemiologia , Exposição Ambiental/estatística & dados numéricos , Exposição Ambiental/efeitos adversosRESUMO
A middle-aged woman presented to our hospital with a chief complaint of a mass on the left shoulder for 1 year. The initial lump was small with no pain or tenderness, and the patient had not sought medical attention for numbness in the left shoulder. Clinical examination showed a mass on the left shoulder measuring 11 × 8 × 3 cm approximately with no apparent skin damage or ecchymosis. No limitations in left shoulder joint movements were observed, and the patient exhibited normal movement of the left elbow joint, wrist joint, and metacarpophalangeal joint. Moreover, the left radial artery was palpable.
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Tumores de Células Gigantes , Ombro , Pessoa de Meia-Idade , Feminino , Humanos , Tumores de Células Gigantes/diagnóstico por imagem , Tumores de Células Gigantes/patologia , Ultrassonografia , Articulação do Punho , Tendões/diagnóstico por imagemRESUMO
BACKGROUND: Diabetic peripheral neuropathy (DPN) is a major complication of diabetes. This study aimed to investigate the therapeutic effects and molecular mechanisms of Compound Qiying Granules (CQYG) for DPN. METHODS: Rats and RSC96 cells of DPN models were established to evaluate the therapeutic effects of CQYG. Then the morphology and apoptotic changes of sciatic nerves were detected. Further, tandem mass tag based quantitative proteomics technology was used to identify differentially expressed proteins (DEPs) and the underlying molecular mechanisms. Protein expression of key signaling pathways was also detected. RESULTS: CQYG treatment significantly improved blood glucose and oxidative stress levels, and further reduced nerve fiber myelination lesions, denervation, and apoptosis in DPN rats. Further, 2176 DEPs were found in CQYG treated DPN rats. Enrichment analysis showed that protein processing in the endoplasmic reticulum (ER), and apoptosis were all inhibited after CQYG treatment. Next, CQYG treatment reduced inflammatory factor expression, mitochondrial damage, and apoptosis in RSC96 cells which induced by high glucose. Transmission electron microscopy results found that CQYG treatment improved the morphology of nerve myelin, mitochondria, and ER. CQYG treatment decreased ER stress and apoptosis pathway proteins that were highly expressed in DPN models. In addition, we also predicted the potential targets of CQYG in DEPs. CONCLUSIONS: CQYG exerts neuroprotective effects in experimental diabetic neuropathy through anti-ER stress and anti-apoptosis.
Assuntos
Diabetes Mellitus , Neuropatias Diabéticas , Ratos , Animais , Neuropatias Diabéticas/tratamento farmacológico , Neuropatias Diabéticas/patologia , Ratos Sprague-Dawley , Estresse do Retículo Endoplasmático/fisiologia , Bainha de Mielina , Transdução de Sinais , Nervo IsquiáticoRESUMO
Droplet transport occurs frequently in nature and has a wide range of applications. We studied the droplet motion in a lyophilic axially varying geometry-gradient tube (AVGGT). The motion of the AVGGT in two directionsâfrom the large opening side (L) to the small opening side (S) and from S to Lâwas theoretically and experimentally analyzed. The droplet dynamic behaviors, such as the self-transport behavior and the droplet stuck behavior, are explored from the view points of mechanics and energy. We found that the surface tension force of a three-phase contact line can be either a driving or an impeding force depending on the various droplet geometries in different AVGGTs. An important contributing factor to the self-transport behavior of a droplet moving from L to S in an AVGGT is the bridge liquid force caused by negative pressure inside the droplet, which is always pointing in the direction of S. As a result of experiments, we investigated the relationship between droplet motion and correlated parameters. The theoretical model based on the simplified Navier-Stokes equation was developed to explain the corresponding mechanism of the droplet motion. Additionally, dimensional analysis was carried out for the droplet stuck behavior of a droplet moving from S to L in an AVGGT to investigate the relationship between the droplet stopping location and the correlated parameters and thus obtain the required geometry for the droplet stopping location.
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A sensitive and selective molecularly imprinted polymer (MIP) sensor was developed for the determination of amyloid-ß (1-42) (Aß42). The glassy carbon electrode (GCE) was successively modified with electrochemical reduction graphene oxide (ERG) and poly(thionine-methylene blue) (PTH-MB). The MIPs were synthesized by electropolymerization with Aß42 as a template and o-phenylenediamine (o-PD) and hydroquinone (HQ) as functional monomers. Cyclic voltammetry (CV), electrochemical impedance spectroscopy (EIS), chronoamperometry (CC), and differential pulse voltammetry (DPV) were used to study the preparation process of the MIP sensor. The preparation conditions of the sensor were investigated in detail. In optimal experimental conditions, the response current of the sensor was linear in the range of 0.12-10 µg mL-1 with a detection limit of 0.018 ng mL-1. The MIP-based sensor successfully detected Aß42 in commercial fetal bovine serum (cFBS) and artificial cerebrospinal fluid (aCSF).
Assuntos
Impressão Molecular , Polímeros , Polímeros/química , Hidroquinonas , Impressão Molecular/métodos , Técnicas Eletroquímicas/métodos , Polímeros Molecularmente Impressos , Eletrodos , Limite de DetecçãoRESUMO
The signal transducer and activator of transcription 3 (STAT3), which regulates multiple oncogenic processes, has been found to be constitutively activated in lymphoma, suggesting its potential as a therapeutic target. Here, we constructed an anti-CD19-N-(4-carboxycyclohexylmethyl) maleimide N-hydroxysuccinimide ester (SMCC)-protamine (CSP)-STAT3 small interfering RNA (siRNA) conjugate and demonstrated that the CSP-STAT3 siRNA conjugate could specifically bind to normal B cells and A20 lymphoma cells in vitro. It decreased the STAT3 expression in B cell lymphoma cell lines (A20, SU-DHL-2 and OCI-Ly3), resulting in reduced proliferation of lymphoma cells featured with lower S-phase and higher apoptosis. Using an A20 transplantable lymphoma model, we found that the CSP-STAT3 siRNA conjugate significantly inhibited tumor growth and weight. Ki-67, p-STAT3, STAT3, and serum IL-6 levels were all significantly reduced in A20-bearing mice treated with CSP-STAT3 siRNA. These findings indicate that specifically targeting STAT3 siRNA to B cell lymphoma cell lines can significantly decrease STAT3 activity and inhibit tumor progression in vitro and in vivo, suggesting its potential utilization for cancer treatment.
Assuntos
Linfoma de Células B , Fator de Transcrição STAT3 , Animais , Camundongos , Proteínas Adaptadoras de Transdução de Sinal , Anticorpos , Linfócitos B , Linfoma de Células B/genética , Linfoma de Células B/terapia , RNA Interferente Pequeno/genética , Fator de Transcrição STAT3/genéticaRESUMO
KEY MESSAGE: qGSN5, a novel quantitative trait locus coordinating grain size and grain number in rice, was fine-mapped to an 85.60-kb region. GS3 may be a suppressor of qGSN5. Grain size and grain number are two factors that directly determine rice grain yield; however, the underlying genetic mechanisms are complicated and remain largely unclear. In this study, a chromosome segment substitution line (CSSL), CSSL28, which showed increased grain size and decreased grain number per panicle, was identified in a set of CSSLs derived from a cross between 93-11 (recipient) and Nipponbare (donor). Four substitution segments were identified in CSSL28, and the substitution segment located on chromosome 5 was responsible for the phenotypes of CSSL28. Thus, we defined this quantitative trait locus (QTL) as grain size and grain number 5 (qGSN5). Cytological and quantitative PCR analysis showed that qGSN5 regulates the development of the spikelet hull by affecting cell proliferation. Genetic analysis showed that qGSN5 is a semi-dominant locus regulating grain size and grain number. Through map-based cloning and overlapping substitution segment analysis, qGSN5 was finally delimited to an 85.60-kb region. Based on sequence and quantitative PCR analysis, Os05g47510, which encodes a P-type pentatricopeptide repeat protein, is the most likely candidate gene for qGSN5. Pyramiding analysis showed that the effect of qGSN5 was significantly lower in the presence of a functional GS3 gene, indicating that GS3 may be a suppressor of qGSN5. In addition, we found that qGSN5 could improve the grain shape of hybrid rice. Together, our results lay the foundation for cloning a novel QTL coordinating grain size and grain number in rice and provide a good genetic material for long-grain hybrid rice breeding.
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Genes de Plantas , Oryza/genética , Locos de Características Quantitativas , Sementes/genética , Mapeamento Cromossômico , Cromossomos de Plantas , Grão Comestível/genética , Estudos de Associação Genética , Fenótipo , Sementes/anatomia & histologiaRESUMO
Primary or acquired drug resistance accounts for the failure of chemotherapy and cancer recurrence in esophageal squamous cell carcinoma (ESCC). However, the aberrant mechanisms driving drug resistance are not fully understood in ESCC. In our previous study, FAT Atypical Cadherin 1 (FAT1) was found to inhibit the epithelial-mesenchymal transition (EMT) process in ESCC. EMT plays a critical role in the development of drug resistance in multiple cancer types. Besides, it equips cancer cells with cancer stem cell (CSC)-like characters that also are associated with chemotherapy resistance. Whether FAT1 regulates the stemness or drug resistance of ESCC cells is worth being explored. Here we found that FAT1 was downregulated in ESCC spheres and negatively correlated with stemness-associated markers including ALDH1A1 and KLF4. Knocking down FAT1 enhanced the sphere-forming ability, resistance to cisplatin and drug efflux of ESCC cells. Additionally, FAT1 knockdown upregulated the expression of drug resistance-related gene ABCC3. Furtherly, we found FAT1 knockdown induced the translocation of ß-catenin into nucleus and enhanced its transcriptional activity. The result of ChIP showed that ß-catenin was enriched in ABCC3 promoter. Furthermore, ß-catenin promoted expression of ABCC3. In conclusion, FAT1 knockdown might enhance the stemness and ABCC3-related cisplatin resistance of ESCC cells via Wnt/ß-catenin signaling pathway. FAT1 and its downstream gene ABCC3 might be potential targets for overcoming chemoresistance in ESCC.
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Caderinas , Resistencia a Medicamentos Antineoplásicos , Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Células-Tronco Neoplásicas , Humanos , beta Catenina/metabolismo , Caderinas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Cisplatino/farmacologia , Regulação para Baixo , Transição Epitelial-Mesenquimal , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/metabolismo , Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Carcinoma de Células Escamosas do Esôfago/genética , Regulação Neoplásica da Expressão GênicaRESUMO
Xu et al. recently demonstrated that cryptochrome 4 (CRY4) protein, as a light-dependent magnetic receptor, can sense geomagnetic fields to guide night-migratory songbirds' navigation and evolution by the formation of composite radical pairs and electron transport. We aim to comment on CRY4 through radical pairs and electron transport for magnetic sensitive in night-migratory songbirds' migration and evolution. Additionally, we find that the role of magnetic fields is deeply concerning to the scientific community and very enlightening for the diagnosis and treatment of cancer and vascular disease. We believe that this commentary makes a significant contribution to the literature because it elaborates on the importance of the geomagnetic field to night-migratory songbirds and extends the diagnostic and therapeutic value to cancer and vascular disease.
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Neoplasias , Aves Canoras , Doenças Vasculares , Migração Animal , Animais , Criptocromos/metabolismo , Campos Magnéticos , Aves Canoras/metabolismoRESUMO
Regulation of myeloid-derived suppressor cells (MDSC) by ongoing inflammation following repeated chemotherapy remain elusive. In this study, we show that a multidose clinical regimen of gemcitabine (GEM) treatment enhances the immunosuppressive function of monocytic MDSC (M-MDSC), although tumor development is delayed in E0771 tumor-bearing mice. Accordingly, effector IFN-γ-producing CD4 and CD8 T cells are significantly decreased in the tumor microenvironment (TME) of GEM-treated mice. The conditioned medium of GEM-treated tumor cells enhances differentiation of mouse bone marrow cells and human PBMC into immunosuppressive M-MDSC. Cytokine profiling of GEM-treated tumor cells identifies GM-CSF as one of the most differentially expressed cytokines. Blockade or knockdown of GM-CSF can partially reduce immunosuppression of Ly6Chigh cells induced by GEM-conditioned medium. Knockdown of GM-CSF in tumor cells also delays tumor progression with decreased accumulation of M-MDSC in the TME. Mechanistically, enhanced production of reactive oxygen species and activation of NF-κB are observed in GEM-treated tumor cells. Treatment with the mitochondrial-targeted antioxidant and inhibitor of NF-κB signaling can abrogate GEM-induced hyperexpression of GM-CSF in E0771 cells. In addition, the phagocytic clearance of apoptotic tumor cells (efferocytosis) enhances the immunosuppressive function of bone marrow Ly6Chigh myeloid cells. Further, GEM treatment results in metabolic changes in residual tumor cells, leading to the resistance to T cell-mediated killing. Together, our results define an undesired effect of repeated GEM treatment promoting immunosuppression in TME via upregulation of GM-CSF and efferocytosis as well as deregulation of lipid metabolism in residual tumor cells.
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Antígenos Ly/imunologia , Antimetabólitos Antineoplásicos/farmacologia , Desoxicitidina/análogos & derivados , Imunossupressores/farmacologia , Células Mieloides/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos , Animais , Antimetabólitos Antineoplásicos/administração & dosagem , Apoptose/efeitos dos fármacos , Apoptose/imunologia , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/imunologia , Proliferação de Células/efeitos dos fármacos , Desoxicitidina/administração & dosagem , Desoxicitidina/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Imunossupressores/administração & dosagem , Injeções Intraperitoneais , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Células Mieloides/imunologia , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/imunologia , Neoplasias Experimentais/patologia , Células Tumorais Cultivadas , GencitabinaRESUMO
Mitochondria regulate intracellular metabolism and are also involved in intercellular transfer in vitro and in vivo, thereby affecting the function of adjacent cells. Mitochondria can also be transferred to various differentiated cells to improve their respiratory function, ATP production, as well as protect damaged cells from apoptosis. Both in vivo and in vitro, mitochondria can be transferred from one cell to another to regulate cellular metabolism under physiological or pathophysiological conditions, referred to as "mitochondrial translocation". Mitochondrial translocation is associated in various situations such as repairing damaged cells, promoting cancer progression and enhancing chemoresistance. Platelets contain mitochondria that promote energy metabolism and various growth factors, thus playing an important role in pathophysiological processes such as thrombosis, hemostasis, inflammation and wound healing. Current studies suggest that mesenchymal stem cells (MSCs) can communicate with their microenvironment through bidirectional alternation of mitochondria to improve their wound healing capacity. Platelets or platelet-containing preparations such as platelet-rich plasma (PRP) can stimulate the proliferation and pro-angiogenic properties of MSCs under oxidative stress to enhance their survival. Recent studies by Levoux et al. have shown that activated platelet-derived mitochondria have the respiratory capacity to translocate to MSCs and stimulate the pro-angiogenic properties of MSCs through metabolic reprogramming, thereby promoting angiogenesis and wound healing. The mechanism of mitochondrial internalization of cells and energy metabolism is a new example of mitochondrial translocation altering somatic cell behavior and viability. Therefore, we aim to comment the mechanisms of platelet mitochondrial translocation and metabolic reprogramming of MSCs, suggesting that platelets or platelet-containing preparations such as platelet-rich plasma (PRP) may provide a practical guide for tissue injury treatment.
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Plaquetas/metabolismo , Células-Tronco Mesenquimais/metabolismo , Mitocôndrias/metabolismo , Cicatrização/fisiologia , Diferenciação Celular , HumanosRESUMO
Overexpression of breast cancer resistance protein (BCRP) plays a crucial role in the acquired multidrug resistance (MDR) in breast cancer. The elucidation of molecular events that confer BCRP-mediated MDR is of major therapeutic importance in breast cancer. Epithelial cell adhesion molecule (EpCAM) has been implicated in tumor progression and drug resistance in various types of cancers, including breast cancer. However, the role of EpCAM in BCRP-mediated MDR in breast cancer remains unknown. In the present study, we revealed that EpCAM expression was upregulated in BCRP-overexpressing breast cancer MCF-7/MX cells, and EpCAM knockdown using siRNA reduced BCRP expression and increased the sensitivity of MCF-7/MX cells to mitoxantrone (MX). The epithelial-mesenchymal transition (EMT) promoted BCRP-mediated MDR in breast cancer cells, and EpCAM knockdown partially suppressed EMT progression in MCF-7/MX cells. In addition, Wnt/ß-catenin signaling was activated in MCF-7/MX cells, and the inhibition of this signaling attenuated EpCAM and BCRP expression and partially reversed EMT. Together, this study illustrates that EpCAM upregulation by Wnt/ß-catenin signaling induces partial EMT to promote BCRP-mediated MDR resistance in breast cancer cells. EpCAM may be a potential therapeutic target for overcoming BCRP-mediated resistance in human breast cancer.
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Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/biossíntese , Neoplasias da Mama/metabolismo , Resistência a Múltiplos Medicamentos/fisiologia , Resistencia a Medicamentos Antineoplásicos/fisiologia , Molécula de Adesão da Célula Epitelial/biossíntese , Transição Epitelial-Mesenquimal/fisiologia , Proteínas de Neoplasias/biossíntese , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Antineoplásicos/farmacologia , Neoplasias da Mama/genética , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Relação Dose-Resposta a Droga , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Molécula de Adesão da Célula Epitelial/antagonistas & inibidores , Molécula de Adesão da Célula Epitelial/genética , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Feminino , Humanos , Células MCF-7 , Mitoxantrona/farmacologia , Proteínas de Neoplasias/genética , RNA Interferente Pequeno/administração & dosagemRESUMO
Inflammation as a host's excessive immune response to stimulation, is involved in the development of numerous diseases. To discover novel anti-inflammatory agents and based on our previous synthetic work on marine natural product Chrysamide B, it and a series of derivatives were synthesized and evaluated for their anti-inflammatory activity on inhibition of LPS-induced NO production. Then the preliminary structure-activity relationships were conducted. Among them, Chrysamide B is the most potent anti-inflammatory agent with low cytotoxicity and strong inhibition on the production of NO (IC50 = 0.010 µM) and the activity of iNOS (IC50 = 0.082 µM) in LPS-stimulated RAW 264.7 cells. Primary studies suggested that the mechanism of action may be that it interfered the formation of active dimeric iNOS but not affected transcription and translation. Furthermore, its good performance of anti-inflammatory effect on LPS-induced multiple inflammatory cytokines production, carrageenan-induced paw edema, and endotoxin-induced septic mice, was observed. We believe that these findings would provide an idea for the further modification and research of these analogs in the future.
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Amidas/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Compostos Bicíclicos com Pontes/farmacologia , Descoberta de Drogas , Inflamação/tratamento farmacológico , Óxido Nítrico/antagonistas & inibidores , Doença Aguda , Amidas/síntese química , Amidas/química , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Compostos Bicíclicos com Pontes/síntese química , Compostos Bicíclicos com Pontes/química , Carragenina , Relação Dose-Resposta a Droga , Edema/induzido quimicamente , Edema/tratamento farmacológico , Inflamação/metabolismo , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Camundongos , Estrutura Molecular , Óxido Nítrico/biossíntese , Células RAW 264.7 , Relação Estrutura-AtividadeRESUMO
BACKGROUND: Posthepatectomy liver failure (PHLF) is one of the major complications of liver resection that causes perioperative mortality. Accurate preoperative assessment of PHLF is of great significance to reduce the complication rate after hepatectomy and improve the survival rate. METHODS: A retrospective study of patients who received hepatectomy from January 2016 to October 2019 at Tang Du Hospital was performed. The area under the receiver operating characteristic (ROC) curve was used to compare the predictive effects of various scoring models on PHLF. RESULTS: The area under the ROC curve of platelet-albumin-bilirubin (PALBI) score, new platelet-albumin-bilirubin (I-PALBI) score, ALBI score, and MELD score was, respectively, 0.647, 0.772, 0.677, and 0.686 (p < 0.01). The I-PALBI score was significantly better than the other scores. CONCLUSIONS: I-PALBI score can be used as a predictive score of PHLF, and its prediction accuracy is better than other scoring systems.
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Albuminas/metabolismo , Bilirrubina/metabolismo , Hepatectomia , Falência Hepática/sangue , Falência Hepática/cirurgia , Plaquetas/patologia , Feminino , Humanos , Falência Hepática/etiologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Curva ROC , Estudos Retrospectivos , Taxa de Sobrevida , Resultado do TratamentoRESUMO
The role of the mTOR signaling pathway in different myeloid cell subsets is poorly understood in the context of tumor development. In this study, myeloid cell-specific Raptor knockout (KO) mice were used to determine the roles of mechanistic target of rapamycin complex 1 (mTORC1) in regulating macrophage function from Lewis lung carcinoma (LLC) s.c. tumors and lung tumor metastasis. We found no difference in tumor growth between conditional Raptor KO and control mice in the s.c. tumor models, although depletion of mTORC1 decreased the immunosuppressive function of tumor-associated macrophages (TAM). Despite the decreased immunosuppressive activity of TAM, M1-like TAM differentiation was impaired in the s.c. tumor microenvironment of mTORC1 conditional Raptor KO mice due to downregulated CD115 expression on macrophages. In addition, TNF-α production by mTORC1-deficient myeloid cells was also decreased in the s.c. LLC tumors. On the contrary, disruption of mTORC1 in myeloid cells promoted lung cancer metastasis. Accordingly, immunosuppressive interstitial macrophages/metastasis-associated macrophages (CD11b+F4/80high) were accumulated in the lungs of Raptor KO mice in the LLC lung metastasis model, leading to decreased Th1 responses. Taken together, our results demonstrate that differential tumor microenvironment dictates the immunological outcomes of myeloid cells, with mTORC1 disruption leading to different tumor growth phenotypes.
Assuntos
Neoplasias Pulmonares/imunologia , Alvo Mecanístico do Complexo 1 de Rapamicina/imunologia , Células Mieloides/imunologia , Microambiente Tumoral/imunologia , Animais , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Knockout , Camundongos TransgênicosRESUMO
Carbon quantum dots (CQDs) are drawing tremendous attention due to their unique photoluminescence property and fascinating functions. Herein, we prepared novel CQDs functionalized with amino acids (AA-CQDs) by a one-pot hydrothermal method for selective detection of Al3+ ions and fluorescence imaging. The prepared AA-CQDs exhibit a novel triple-excitation and single-colour emission for fluorescent property. In addition, the AA-CQDs have a high absolute quantum yield (24.23%) and quantum lifetime (13.29 ns). Moreover, the AA-CQDs exhibit high selectivity and sensitivity for Al3+ by fluorescence enhancement. In pH 7.4 PBS solution, there was a good linear relation between the fluorescence intensity and the concentration of Al3+ in the range of 1-20 µmol L-1; the limit of detection (3σ) was only 0.32 µmol L-1. Furthermore, an AA-CQD probe was also utilized for detection of Al3+ in living cells based on excellent biocompatibility and endocytosis. Based on the concentration of Al3+ ions in cells and apoptosis data, there will be a quick reflect of apoptosis induced by aluminium ions via the fluorescence intensity of the AA-CQD probe. This work will set the stage for developing novel CQD-based biosensors in cell research.
Assuntos
Alumínio/análise , Aminoácidos/química , Carbono/química , Pontos Quânticos/química , Espectrometria de Fluorescência/métodos , Células A549 , Humanos , Limite de Detecção , Microscopia de Força Atômica , Microscopia Eletrônica de TransmissãoRESUMO
Marine natural products derived from special or extreme environment provide an important source for the development of anti-tumor drugs due to their special skeletons and functional groups. In this study, based on our previous work on the total synthesis and structure revision of the novel marine natural product Chrysamide B, a group of its derivatives were designed, synthesized, and subsequently of which the anti-cancer activity, structure-activity relationships and cellular mechanism were explored for the first time. Compared with Chrysamide B, better anti-cancer performance of some derivatives against five human cancer cell lines (SGC-7901, MGC-803, HepG2, HCT-116, MCF-7) was observed, especially for compound b-9 on MGC-803 and SGC-7901 cells with the IC 50 values of 7.88 ± 0.81 and 10.08 ± 1.08 µM, respectively. Subsequently, cellular mechanism study suggested that compound b-9 treatment could inhibit the cellular proliferation, reduce the migration and invasion ability of cells, and induce mitochondrial-dependent apoptosis in gastric cancer MGC-803 and SGC-7901 cells. Furthermore, the mitochondrial-dependent apoptosis induced by compound b-9 is related with the JAK2/STAT3/Bcl-2 signaling pathway. To conclude, our results offer a new structure for the discovery of anti-tumor lead compounds from marine natural products.