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Endoplasmic reticulum (ER) stress initiates the unfolded protein response (UPR) and is decisive for tumor cell growth and tumor microenvironment (TME) maintenance. Tumor cells persistently undergo ER stress and could transmit it to the neighboring macrophages and surroundings. Tumor infiltrating macrophages can also adapt to the microenvironment variations to fulfill their highly energy-demanding and biological functions via ER stress. However, whether the different macrophage populations differentially sense ER stress and transmit ER stress to surrounding tumor cells has not yet been elucidated. Here, we aimed to investigate the role of transmissible ER stress, a novel regulator of intercellular communication in the TME. Murine bone marrow-derived macrophage (BMDM) can be polarized toward distinct functional endpoints termed classical (M1) and alternative (M2) activation, and their polarization status has been shown to be tightly correlated with their functional significance. We showed that tumor cells could receive the transmissible ER stress from two differentially polarized macrophage populations with different extent of ER stress activation. The proinflammatory M1-like macrophages respond to ER stress with less extent, however they could transmit more ER stress to tumor cells. Moreover, by analyzing the secreted components of two ER-stressed macrophage populations, we identified certain damage-associated molecular patterns (DAMPs), including S100A8 and S100A9, which are dominantly secreted by M1-like macrophages could lead to significant recipient tumor cells death in synergy with transferred ER stress.
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Neoplasias , Microambiente Tumoral , Animales , Estrés del Retículo Endoplásmico , Macrófagos/metabolismo , Ratones , Neoplasias/patología , Respuesta de Proteína DesplegadaRESUMEN
The effect of ratio and consecutive number of hydrophobic residues in the repeating unit of protein chains was investigated by MD simulation. The modified off-lattice HNP model was applied in this study. The protein chains constituted by different HNP ratios or different numbers of consecutively hydrophobic residues with the same chain length were simulated under a broad temperature range. We concluded that the proteins with higher ratio or larger number of sequentially hydrophobic residues present more orientated and compact structure under a certain low temperature. It is attributed to the lower non-bonded potential energy between H-H residual pairs, especially more hydrophobic residues in a procession among the protein chain. Considering the microscopic structure of the protein, more residue contacts are achieved with the proteins with higher ratios and sequential H residues under the low temperature. Meanwhile, with the ratio and consecutive number of H residues increasing, the distribution of stem length showed a transition from exponential decline to unimodal and even multiple peaks, indicating the specific ordered structure formed. These results provide an insight into 3D structural properties of proteins from their residue sequences, which has a primary structure at molecular level and, ultimately, a practical possibility of applying in biotechnological applications.
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Proteínas , Proteínas/química , Interacciones Hidrofóbicas e Hidrofílicas , Simulación por ComputadorRESUMEN
JAK/STAT and NFκB signalling pathways play essential roles in regulating inflammatory responses, which are important pathogenic factors of various serious immune-related diseases, and function individually or synergistically. To find prodrugs that can treat inflammation, we performed a preliminary high-throughput screening of 18 840 small molecular compounds and identified scaffold compound L971 which significantly inhibited JAK/STAT and NFκB driven luciferase activities. L971 could inhibit the constitutive and stimuli-dependent activation of STAT1, STAT3 and IκBα and could significantly down-regulate the proinflammatory gene expression in mouse peritoneal macrophages stimulated by LPS. Gene expression profiles upon L971 treatment were determined using high-throughput RNA sequencing, and significant differentially up-regulated and down-regulated genes were identified by DESeq analysis. The bioinformatic studies confirmed the anti-inflammatory effects of L971. Finally, L971 anti-inflammatory character was further verified in LPS-induced sepsis shock mouse model in vivo. Taken together, these data indicated that L971 could down-regulate both JAK/STAT and NFκB signalling activities and has the potential to treat inflammatory diseases such as sepsis shock.
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The Wnt/ß-catenin signaling pathway plays an important role in tissue homeostasis, and its malignant activation is closely related to the occurrence and development of many cancers, especially colorectal cancer with adenomatous polyposis coli (APC) and CTNNB1 mutations. By applying a TCF/lymphoid-enhancing factor (LEF) luciferase reporter system, the high-throughput screening of 18 840 small-molecule compounds was performed. A novel scaffold compound, C644-0303, was identified as a Wnt/ß-catenin signaling inhibitor and exhibited antitumor efficacy. It inhibited both constitutive and ligand activated Wnt signals and its downstream gene expression. Functional studies showed that C644-0303 causes cell cycle arrest, induces apoptosis, and inhibits cancer cell migration. Moreover, transcription factor array indicated that C644-0303 could suppress various tumor-promoting transcription factor activities in addition to Wnt/ß-catenin. Finally, C644-0303 suppressed tumor spheroidization in a 3-dimensional cell culture model and inhibited xenograft tumor growth in mice. In conclusion, we report a novel structural small molecular inhibitor targeting the Wnt/ß-catenin signaling pathway that has therapeutic potential for colorectal cancer treatment.
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Poliposis Adenomatosa del Colon/tratamiento farmacológico , Antineoplásicos/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Vía de Señalización Wnt/efectos de los fármacos , Poliposis Adenomatosa del Colon/genética , Poliposis Adenomatosa del Colon/patología , Animales , Apoptosis/efectos de los fármacos , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Descubrimiento de Drogas , Femenino , Células HCT116 , Células HT29 , Humanos , Luciferasas , Células MCF-7 , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Terapia Molecular Dirigida/métodos , Esferoides Celulares/efectos de los fármacos , Factores de Transcripción TCF , Factores de Transcripción/antagonistas & inhibidores , Ensayos Antitumor por Modelo de Xenoinjerto , beta Catenina/genéticaRESUMEN
OBJECTIVE: This study aimed to study the relationship between air pollution and stroke (especially emergency stroke) in different regions and determine which air pollutant is the most significantly associated with stroke. METHODS: The number of patients with emergency stroke, air pollutant data and related meteorological indicators were collected from December 2013 to May 2018 for large comprehensive hospitals in Chongqing. The generalized additive model was used to analyse the relationship between air pollution and emergency stroke. RESULTS: After analysis and adjusting for meteorological indicators and day-of-the-week effects, in the one-pollutant model, every 10 µg/m3 increase in ozone(O3) was associated with a 2.482% (95% CI 1.044%, 3.919%) change in emergency strokes within lag0. For males, every 10 µg/m3 increase of O3 contributed to a 0.77% percent greater change compared with females. For the group younger than 60 years, we observed a 1.14% increase in risk with every 10 µg/m3 increase in O3. The group with pre-existing hypertension had a 0.26% higher risk than the group with no pre-existing hypertension with every 10 µg/m3 increase in O3. In two-pollutant model, when O3 was combined with a 10 µg/m3 increase of NO2, it increased the most significant risk of emergency stroke by 0.22%. CONCLUSION: These findings suggest that short-term exposure to O3 within 0 days is associated with emergency outpatient strokes, and younger people (age < 60 years) males and people with hypertension are more sensitive than older people, females and people without pre-existing hypertension.
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Contaminantes Atmosféricos/efectos adversos , Contaminación del Aire/efectos adversos , Exposición a Riesgos Ambientales/efectos adversos , Hipertensión/epidemiología , Ozono/efectos adversos , Accidente Cerebrovascular/epidemiología , Contaminantes Atmosféricos/análisis , Contaminación del Aire/análisis , China/epidemiología , Servicio de Urgencia en Hospital , Exposición a Riesgos Ambientales/análisis , Femenino , Humanos , Masculino , Persona de Mediana Edad , Dióxido de Nitrógeno/análisis , Ozono/análisis , Material Particulado/análisis , Dióxido de Azufre/análisis , Temperatura , VientoRESUMEN
The Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway plays a vital role in immunity, cell division, cell death and tumor formation. Disrupted JAK-STAT signaling may lead to various diseases, especially cancer and immune disorders. Because of its importance, this signaling pathway has received significant attention from the pharmaceutical and biotechnology industries as a therapeutic target for drug design. However, few JAK or STATs inhibitors have been developed for cancer treatment. We used an in vitro STAT3 luciferase reporter assay to find novel inhibitors that could effectively block the JAK-STAT pathway. In our study, we screened 16,081 drug-like chemicals and found that atopaxar hydrobromide (AHB) is a specific inhibitor of JAK-STAT3 signaling. Our results suggest that AHB not only blocks constitutively activated and cytokine-induced STAT3 phosphorylation but also inhibits JAK1 and JAK2 phosphorylation. Moreover, AHB induces G1 phase cell cycle arrest, which stops cancer cell growth and induces apoptosis. AHB also inhibited tumor cell growth in vivo. In conclusion, AHB is a potential inhibitor that could be developed as a JAK-STAT pathway drug.
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Antineoplásicos/farmacología , Iminas/farmacología , Janus Quinasa 1/antagonistas & inhibidores , Janus Quinasa 2/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Piridinas/farmacología , Factor de Transcripción STAT3/antagonistas & inhibidores , Animales , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Citocinas/farmacología , Humanos , Janus Quinasa 1/metabolismo , Janus Quinasa 2/metabolismo , Ratones Endogámicos BALB C , Ratones Desnudos , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Fosforilación/efectos de los fármacos , Factor de Transcripción STAT3/metabolismoRESUMEN
The Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) signaling pathway plays central roles in cancer cell growth and survival. Drug repurposing strategies have provided a valuable approach for developing antitumor drugs. Zelnorm (tegaserod maleate) was originally designed as an agonist of 5-hydroxytryptamine 4 receptor (5-HT4R) and approved by the FDA for treating irritable bowel syndrome with constipation (IBS-C). Through the use of a high-throughput drug screening system, Zelnorm was identified as a JAK/STAT3 signaling inhibitor. Moreover, the inhibition of STAT3 phosphorylation by Zelnorm was independent of its original target 5-HT4R. Zelnorm could cause G1 cell cycle arrest, induce cell apoptosis and inhibit the growth of a variety of cancer cells. The present study identifies Zelnorm as a novel JAK/STAT3 signaling inhibitor and reveals a new clinical application of Zelnorm upon market reintroduction.
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Antineoplásicos/uso terapéutico , Indoles/uso terapéutico , Quinasas Janus/antagonistas & inhibidores , Neoplasias/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Factor de Transcripción STAT3/antagonistas & inhibidores , Agonistas del Receptor de Serotonina 5-HT4/uso terapéutico , Animales , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Puntos de Control de la Fase G1 del Ciclo Celular/efectos de los fármacos , Humanos , Indoles/farmacología , Quinasas Janus/metabolismo , Ratones Desnudos , Neoplasias/genética , Neoplasias/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Receptores de Serotonina 5-HT4/genética , Factor de Transcripción STAT3/metabolismo , Agonistas del Receptor de Serotonina 5-HT4/farmacología , Transducción de Señal/efectos de los fármacosRESUMEN
Activation of transcription factor STAT3 is involved in cell proliferation, differentiation, and cell survival. Constitutive activation of STAT3 pathway has been associated with the oncogenesis of various types of cancers. It has been reported that STAT3 plays a key role in the G1 to S phase cell cycle transition induced by the cytokine receptor subunit gp130, through the upregulation of cyclins D1, D2, D3, A, and Cdc25A and the concomitant downregulation of p21 and p27. However, its role in mediating G2-M phase transition has not been studied. The cyclin B1/Cdc2 complex is widely accepted as the trigger of mitosis in all organisms and is believed to be necessary for progression through S phase and keep active during the G2-M transition and progression. In the present study, we found that activation of STAT3 stimulates cyclin B1 and Cdc2 expressions. Deletion and site-directed mutations on cyclin B1 and Cdc2 promoters indicated that E2F element mediates the upregulation of these two promoters in a STAT3-dependent manner. The findings reported here demonstrated that STAT3 participates in modulating G2-M phase checkpoint by regulating gene expressions of cyclin B1 and Cdc2 via E2F.
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Proteína Quinasa CDC2/genética , Ciclina B1/genética , Factores de Transcripción E2F/fisiología , Factor de Transcripción STAT3/fisiología , División Celular , Células Cultivadas , Fase G2 , Regulación de la Expresión Génica , Humanos , Regiones Promotoras Genéticas , Regulación hacia ArribaRESUMEN
c-Met is a transmembrane receptor tyrosine kinase and an important therapeutic target for anticancer drugs. In this study, we designed a small library containing 300 BISAs molecules that consisted of carbohydrates, amino acids, isothiourea, tetramethylthiourea, guanidine and heterocyclic groups and screened c-Met targeting compounds using docking and MM/GBSA. Guided by virtual screening, we synthesised a series of novel compounds and their activity on inhibition of the autophosphorylation of c-Met and its downstream signalling pathway proteins were evaluated. We found a panel of benzisoselenazolones (BISAs) obtained by introducing isothiourea, tetramethylthiourea and heterocyclic groups into the C-ring of Ebselen, including 7a, 7b, 8a, 8b and 12c (with IC50 values of less than 20 µM in MET gene amplified lung cancer cell line EBC-1), exhibited more potent antitumour activity than Ebselen by cell growth assay combined with in vitro biochemical assays. In addition, we also tested the antitumour activity of three cancer cell lines without MET gene amplification/activation, including DLD1, MDA-MB-231 and A549. The neuroblastoma SK-N-SH cells with HGF overexpression which activates MET signalling are sensitive to MET inhibitors. The results reveal that our compounds may be nonspecific multitarget kinase inhibitors, just like type-II small molecule inhibitors. Western blot analysis showed that these inhibitors inhibited autophosphorylation of c-MET, and its downstream signalling pathways, such as PI3K/AKT and MARK/ERK. Results suggest that bensoisoselenones can be used as a scaffold for the design of c-Met inhibiting drug leads, and this study opens up new possibilities for future antitumour drug design.
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Antineoplásicos/síntesis química , Ciclodextrinas/química , Inhibidores de Proteínas Quinasas/síntesis química , Proteínas Proto-Oncogénicas c-met/antagonistas & inhibidores , Transducción de Señal , Antineoplásicos/farmacología , Sitios de Unión , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Humanos , Simulación del Acoplamiento Molecular , Unión Proteica , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas c-met/química , Proteínas Proto-Oncogénicas c-met/metabolismoRESUMEN
STAT1 and STAT3 are two important members of the STAT (signal transducers and activators of transcription) protein family and play opposing roles in regulating cancer cell growth. Suppressing STAT3 and/or enhancing STAT1 signaling are considered to be attractive anticancer strategies. Cucurbitacin I (CuI) isolated from the cucurbitacin family was reported to be an inhibitor of STAT3 signaling and a disruptor of actin cytoskeleton. In this study we investigated the function and mechanisms of CuI in regulating STAT signaling in human cancer cells in vitro. CuI (0.1-10 mmol/L) dose-dependently inhibited the phosphorylation of STAT3, and enhanced the phosphorylation of STAT1 in lung adenocarcinoma A549 cells possibly through disrupting actin filaments. We further demonstrated that actin filaments physically associated with JAK2 and STAT3 in A549 cells and regulated their phosphorylation through two signaling complexes, the IL-6 receptor complex and the focal adhesion complex. Actin filaments also interacted with STAT1 in A549 cells and regulated its dephosphorylation. Taken together, this study reveals the molecular mechanisms of CuI in the regulation of STAT signaling and in a possible inhibition of human cancer cell growth. More importantly, this study uncovers a novel role of actin and actin-associated signaling complexes in regulating STAT signaling.
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Citoesqueleto de Actina/metabolismo , Factor de Transcripción STAT1/metabolismo , Factor de Transcripción STAT3/metabolismo , Transducción de Señal , Triterpenos/farmacología , Línea Celular Tumoral , Relación Dosis-Respuesta a Droga , Humanos , Janus Quinasa 2/metabolismo , Fosforilación/efectos de los fármacosRESUMEN
Checkpoint blockades have emerged as a frontline approach in cancer management, designed to enhance the adaptive immune response against tumors. However, its clinical efficacy is limited to a narrow range of tumor types, which necessitates the exploration of novel strategies that target another main branch of the immune system. One such potential strategy is the therapeutic modulation of pattern recognition receptors (PRRs) pathways in innate immune cells, which have shown promise in tumor eradication. Previously, a ß-1,3/1,6-glucan with high purity from Durvillaea antarctica (BG136) was reported by our group to exhibit pan-antitumor effects. In the current study, we systemically studied the antitumor activity of BG136 in combination with anti-PD1 antibody in MC38 syngeneic tumor model in vivo. Integrated transcriptomic and metabolomic analyses suggested that BG136 enhances the antitumor immunity of anti-PD1 antibody by reprogramming the tumor microenvironment to become more proinflammatory. In addition, an increase in innate and adaptive immune cell infiltration and activation, enhanced lipid metabolism, and a decreased in ascorbate and aldarate metabolism were also found. These findings provide mechanistic insights that support the potent antitumor efficacy of BG136 when combined with immune checkpoint inhibitor antibodies.
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Background and Aims: Syntaxin 5 (STX5) is a member of the syntaxin or target-soluble SNAP receptor (t-SNARE) family and plays a critical role in autophagy. However, its function and molecular mechanism in tumor cell migration are still unknown. The role of STX5 in influencing hepatocellular carcinoma (HCC) is an important topic in our research. Methods: By using quantitative reverse transcription polymerase chain reaction (qPCR), western blotting, and immunohistochemical analysis of RNA and protein in tissues, we comprehensively evaluated data sets from public databases and clinical patient cohorts for STX5. The correlation of STX5 expression with the clinicopathological characteristics of HCC patients were assessed. In addition, we predicted signal pathways from differentially expressed genes (DEGs) and the Cancer Genome Atlas (TCGA) databases, and confirmed the prediction using integrated transcriptome and RNA-seq. We further investigated the underlying mechanisms of STX5 in the migration and adhesion of HCC cells both in vitro and in vivo. Results: In the TCGA dataset and our patient cohort, STX5 levels were significantly higher in HCC tissues than in adjacent normal liver tissues. At the same time, high expression of STX5 predicted worse prognosis in patients with liver cancer. High expression of STX5 indicates the decrease of adhesion and the increase of migration of HCC cells, and the conversion of epithelial-mesenchymal transition (EMT) in vitro via PI3K/mTOR pathway activation. Conversely, when Sirolimus, a phosphoinositide 3-kinase (PI3K)/AKT/mechanistic target of rapamycin (mTOR) inhibitor acts on cells simultaneously, STX5 overexpression-mediated enhancement of HCC metastasis is reversed. Double-negative regulation of STX5 and mTOR further enhanced the inhibitory effect of STX5 on HCC metastasis. In vivo, STX5 knockdown inhibited the metastasis of HCC cells. Conclusions: Our study demonstrates a novel research result that STX5 promotes HCC metastasis through PI3K/mTOR pathway. We believe that combined inhibition of STX5 and mTOR is a potential treatment for effectively prolonging patient survival and inhibiting HCC metastasis.
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Macrophages play a critical role in the inflammatory response and tumor development. Macrophages are primarily divided into pro-inflammatory M1-like and anti-inflammatory M2-like macrophages based on their activation status and functions. In vitro macrophage models could be derived from mouse bone marrow cells stimulated with two types of differentiation factors: GM-CSF (GM-BMDMs) and M-CSF (M-BMDMs), to represent M1- and M2-like macrophages, respectively. Since macrophage differentiation requires coordinated metabolic reprogramming and transcriptional rewiring in order to fulfill their distinct roles, we combined both transcriptome and metabolome analysis, coupled with experimental validation, to gain insight into the metabolic status of GM- and M-BMDMs. The data revealed higher levels of the tricarboxylic acid cycle (TCA cycle), oxidative phosphorylation (OXPHOS), fatty acid oxidation (FAO), and urea and ornithine production from arginine in GM-BMDMs, and a preference for glycolysis, fatty acid storage, bile acid metabolism, and citrulline and nitric oxide (NO) production from arginine in M-BMDMs. Correlation analysis with the proteomic data showed high consistency in the mRNA and protein levels of metabolic genes. Similar results were also obtained when compared to RNA-seq data of human monocyte derived macrophages from the GEO database. Furthermore, canonical macrophage functions such as inflammatory response and phagocytosis were tightly associated with the representative metabolic pathways. In the current study, we identified the core metabolites, metabolic genes, and functional terms of the two distinct mouse macrophage populations. We also distinguished the metabolic influences of the differentiation factors GM-CSF and M-CSF, and wish to provide valuable information for in vitro macrophage studies.
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Factor Estimulante de Colonias de Granulocitos y Macrófagos , Factor Estimulante de Colonias de Macrófagos , Humanos , Animales , Ratones , Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Factor Estimulante de Colonias de Macrófagos/metabolismo , Transcriptoma , Proteómica , Diferenciación Celular , Macrófagos/metabolismo , Arginina/metabolismo , Ácidos Grasos/metabolismoRESUMEN
The JAK/STAT and NFκB signaling pathways are two major inflammatory signaling pathways that are usually activated simultaneously in the body's inflammatory response to bacterial or viral infections. Hyperactivation of these two prominent signaling pathways is associated with various immune-related diseases and mortality, pointing to an urgent need for drug development targeting JAK/STAT and/or NFκB signaling. In this study, we screened 18,840 compounds using our well-established dual STAT-NFκB driven luciferase reporter based high-throughput screening system and identified a bioactive compound C498-0670, which inhibits both JAK/STAT and NFκB signaling. C498-0670 inhibits the activation of STATs and p-IKKα/ß in both the immortalized cell lines and primary peritoneal macrophages, while suppressing the expression of LPS-induced inflammatory mediators in vitro. In addition, the overall anti-inflammatory effects of C498-0670 were investigated using transcriptome sequencing and bioinformatics approaches. C498-0670 was predicted to alleviate sepsis/septic shock by disease/function analysis using IPA software, which was further verified in the LPS-induced mouse sepsis model in vivo. C498 reduced LPS-induced liver and kidney damage, myeloid cell infiltration, and pro-inflammatory cytokine and chemokine production in vivo. Furthermore, the SPR-HPLC-MS-based target fishing approach was used to identify the putative drug targets, and the high affinities of JAK2 (JAK/STAT signaling), NFKBIA (NFκB signaling), and IL-1ß, NLRP1b (inflammasome signaling) for C498-0670 were verified by molecular docking approach. These results suggest that C498-0670 can be used as a dual-target inhibitor of JAK/STAT and NFκB signaling pathways for the treatment of various inflammatory diseases, especially septic shock.
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Lipopolisacáridos , Choque Séptico , Ratones , Animales , Lipopolisacáridos/farmacología , Choque Séptico/inducido químicamente , Choque Séptico/tratamiento farmacológico , Simulación del Acoplamiento Molecular , Quinasas Janus/metabolismo , Transducción de Señal , FN-kappa B/metabolismoRESUMEN
Due to their broad functional plasticity, myeloid cells contribute to both liver injury and recovery during acetaminophen overdose-induced acute liver injury (APAP-ALI). A comprehensive understanding of cellular diversity and intercellular crosstalk is essential to elucidate the mechanisms and to develop therapeutic strategies for APAP-ALI treatment. Here, we identified the function of IFN-I in the myeloid compartment during APAP-ALI. Utilizing single-cell RNA sequencing, we characterized the cellular atlas and dynamic progression of liver CD11b+ cells post APAP-ALI in WT and STAT2 T403A mice, which was further validated by immunofluorescence staining, bulk RNA-seq, and functional experiments in vitro and in vivo. We identified IFN-I-dependent transcriptional programs in a three-way communication pathway that involved IFN-I synthesis in intermediate restorative macrophages, leading to CSF-1 production in aging neutrophils that ultimately enabled Trem2+ restorative macrophage maturation, contributing to efficient liver repair. Overall, we uncovered the heterogeneity of hepatic myeloid cells in APAP-ALI at single-cell resolution and the therapeutic potential of IFN-I in the treatment of APAP-ALI.
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Acetaminofén , Enfermedad Hepática Inducida por Sustancias y Drogas , Animales , Ratones , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Hígado/metabolismo , Neutrófilos/metabolismo , Macrófagos , Ratones Endogámicos C57BL , Glicoproteínas de Membrana/metabolismo , Receptores Inmunológicos/metabolismoRESUMEN
Phagocytosis is a cellular process maintaining tissue balance and plays an essential role in initiating the innate immune response. The process of phagocytosis was triggered by the binding of pathogen-associated molecular patterns (PAMP) with their cell surface receptors on the phagocytes. These receptors not only perform phagocytic functions, but also bridge the gap between extracellular and intracellular communication, leading to signal transduction and the production of inflammatory mediators, which are crucial for clearing the invading pathogens and maintaining cell homeostasis. For the past few years, the application of ß-glucan comes down to immunoregulation and anti-tumor territory. As a well-known PAMP, ß-glucan is one of the most abundant polysaccharides in nature. By binding to specific receptors on immune cells and activating intracellular signal transduction pathways, it causes phagocytosis and promotes the release of cytokines. Further retrieval and straightening out literature related to ß-glucan phagocytic receptors will help better elucidate their immunomodulatory functions. This review attempts to summarize physicochemical properties and specific processes involved in ß-glucan induced phagocytosis, its phagocytic receptors, and cascade events triggered by ß-glucan at the cellular and molecular levels.
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beta-Glucanos , Inmunidad Innata , Macrófagos/metabolismo , Fagocitos , Fagocitosis , beta-Glucanos/farmacologíaRESUMEN
Background: Metabolic syndrome (MetS) has been related to increased risks of a variety of cancers. However, the association between MetS and the risk of renal cell cancer (RCC) remains not fully determined. This meta-analysis was conducted to investigate whether MetS is independently associated with the risk of RCC in adults. Methods: Relevant observational studies were obtained by searching PubMed, Embase, Cochrane's Library, and Web of Science databases. Study characteristics and outcome data were extracted independently by two authors. The random-effect model was used for meta-analysis considering the possible influence of between-study heterogeneity. Predefined subgroup analyses were used to evaluate the possible influences of study characteristics on the outcome. Results: Eight studies involving 10,601,006 participants contributed to the meta-analysis. Results showed that MetS was independently associated with a higher risk of RCC in adult population (risk ratio [RR]: 1.62, 95% confidence interval [CI]: 1.41 to 1.87, p<0.001; I2 = 85%). Subgroup analyses showed consistent association in men (RR: 1.52, 95% CI: 1.23 to 1.89, p<0.001) and in women (RR: 1.71, 95% CI: 1.28 to 2.27, p<0.001), in Asians (RR: 1.51, 95% CI: 1.25 to 1.83, p<0.001) and in Caucasians (RR: 1.76, 95% CI: 1.46 to 2.12, p<0.001), and in community derived (RR: 1.56, 95% CI: 1.34 to 1.82, p<0.001) and non-community derived population (RR: 1.87, 95% CI: 1.71 to 2.04, p<0.001). Differences in study design or quality score also did not significantly affect the association (p for subgroup difference both >0.05). Conclusions: MetS may be independently associated with RCC in adult population.
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Non-alcohol-associated fatty liver/steatohepatitis (NAFL/NASH) has become the leading cause of liver disease worldwide. NASH, an advanced form of NAFL, can be progressive and more susceptible to developing cirrhosis and hepatocellular carcinoma. Currently, lifestyle interventions are the most essential and effective strategies for preventing and controlling NAFL without the development of fibrosis. While there are still limited appropriate drugs specifically to treat NAFL/NASH, growing progress is being seen in elucidating the pathogenesis and identifying therapeutic targets. In this review, we discussed recent developments in etiology and prospective therapeutic targets, as well as pharmacological candidates in pre/clinical trials and patents, with a focus on diabetes, hepatic lipid metabolism, inflammation, and fibrosis. Importantly, growing evidence elucidates that the disruption of the gut-liver axis and microbe-derived metabolites drive the pathogenesis of NAFL/NASH. Extracellular vesicles (EVs) act as a signaling mediator, resulting in lipid accumulation, macrophage and hepatic stellate cell activation, further promoting inflammation and liver fibrosis progression during the development of NAFL/NASH. Targeting gut microbiota or EVs may serve as new strategies for the treatment of NAFL/NASH. Finally, other mechanisms, such as cell therapy and genetic approaches, also have enormous therapeutic potential. Incorporating drugs with different mechanisms and personalized medicine may improve the efficacy to better benefit patients with NAFL/NASH.
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Neoplasias Hepáticas , Enfermedad del Hígado Graso no Alcohólico , Fibrosis , Humanos , Inflamación , Cirrosis Hepática , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/patología , Transducción de Señal/genéticaRESUMEN
Rheumatoid arthritis (RA) occurs in about 5 per 1,000 people and can lead to severe joint damage and disability. However, the knowledge of pathogenesis and treatment for RA remains limited. Here, we found that histone demethylase inhibitor GSK-J4 relieved collagen induced arthritis (CIA) symptom in experimental mice model, and the underlying mechanism is related to epigenetic transcriptional regulation in macrophages. The role of epigenetic regulation has been introduced in the process of macrophage polarization and the pathogenesis of inflammatory diseases. As a repressive epigenetic marker, tri-methylation of lysine 27 on histone H3 (H3K27me3) was shown to be important for transcriptional gene expression regulation. Here, we comprehensively analyzed H3K27me3 binding promoter and corresponding genes function by RNA sequencing in two differentially polarized macrophage populations. The results revealed that H3K27me3 binds on the promoter regions of multiple critical cytokine genes and suppressed their transcription, such as IL6, specifically in M-CSF derived macrophages but not GM-CSF derived counterparts. Our results may provide a new approach for the treatment of inflammatory and autoimmune disorders.
Asunto(s)
Artritis Reumatoide , Histonas , Animales , Epigénesis Genética , Histonas/metabolismo , Humanos , Interleucina-6/metabolismo , Histona Demetilasas con Dominio de Jumonji , Lisina/metabolismo , Macrófagos/metabolismo , RatonesRESUMEN
Diabetic retinopathy (DR) is a common complication and the leading cause of blindness in patients with type 2 diabetes. DR has been shown to be closely correlated with blood glucose levels and the duration of diabetes. However, the onset and progression of DR also display clinical heterogeneity. We applied whole-exome sequencing and RNA-seq approaches to study the gene mutation and transcription profiles in three groups of diabetic patients with extreme clinical phenotypes in DR onset, timing, and disease progression, aiming to identify genetic variants that may play roles in the pathogenesis of DR. We identified 23 putatively pathogenic genes, and ingenuity pathway analysis of these mutated genes reveals their functional association with glucose metabolism, diabetic complications, neural system activity, and dysregulated immune responses. In addition, ten potentially protective genes were also proposed. These findings shed light on the mechanisms underlying the pathogenesis of DR and may provide potential targets for developing new strategies to combat DR.