Adenosine, a critical molecule regulating cellular function both inside and outside cells, is controlled by two human adenosine deaminases: ADA1 and ADA2. While ADA1 primarily resides in the cytoplasm, ADA2 can be transported to lysosomes within cells or secreted outside the cell. Patients with ADA2 deficiency (DADA2) often suffer from systemic vasculitis due to elevated levels of TNF-α in their blood. Monocytes from DADA2 patients exhibit excessive TNF-α secretion and differentiate into pro-inflammatory M1-type macrophages. Our findings demonstrate that ADA2 localizes to endolysosomes within macrophages, and its intracellular concentration decreases in cells secreting TNF-α. This suggests that ADA2 may function as a lysosomal adenosine deaminase, regulating TNF-α expression by the cells. Interestingly, pneumonia patients exhibit higher ADA2 concentrations in their bronchoalveolar lavage (BAL), correlating with elevated pro-inflammatory cytokine levels. Conversely, cord blood has low ADA2 levels, creating a more immunosuppressive environment. Additionally, secreted ADA2 can bind to apoptotic cells, activating immune cells by reducing extracellular adenosine levels. These findings imply that ADA2 release from monocytes during inflammation, triggered by growth factors, may be crucial for cell activation. Targeting intracellular and extracellular ADA2 activities could pave the way for novel therapies in inflammatory and autoimmune disorders.
Humans ; Adenosine Deaminase/deficiency* ; Monocytes/cytology* ; Cell Differentiation ; Intercellular Signaling Peptides and Proteins/metabolism* ; Tumor Necrosis Factor-alpha/metabolism* ; Biomarkers/metabolism* ; Macrophages/metabolism* ; Pneumonia/metabolism*

OBJECTIVES: Peripheral whole blood cell counts have been used as prognostic indicators for various cancers, but their predictive value in nasopharyngeal carcinoma remain unclear. This study aims to evaluate the prognostic significance of the pretreatment hemoglobin×lymphocyte/monocyte ratio (HLMR) in non-recurrent, non-metastatic NPC patients undergoing definitive radiotherapy. METHODS: Clinical and follow-up data from 805 NPC patients who completed definitive radiotherapy or chemoradiotherapy were retrospectively analyzed. Pretreatment hemoglobin, lymphocyte count, and monocyte count were collected to calculate HLMR. Receiver operating characteristic (ROC) curves were used to determine the optimal cut-off value of HLMR. Patients were then classified into high and low HLMR groups. The association between HLMR and clinicopathological characteristic was assessed using chi-square tests. Independent prognostic factors for overall survival (OS) and progression-free survival (PFS) were identified using Cox proportional hazards models. A nomogram was constructed based on the independent predictors to estimate patient survival rates, and internal validation was performed using a validation cohort. RESULTS: The ROC curve identified 605.5 as the optimal HLMR cut-off value for predicting 5-year survival. Multivariate Cox regression analysis revealed that T stage (HR=1.886, 95% CI 1.331 to 2.673, P<0.001), N stage (HR=2.021, 95% CI 1.267 to 3.225, P=0.003), Eastern Cooperative Oncology Group (ECOG) score (HR=3.991, 95% CI 1.257 to 12.677, P=0.019), concurrent chemoradiotherapy regimen (HR=0.338, 95% CI 0.156 to 0.731, P=0.006), and HLMR (HR=0.648, 95% CI 0.460 to 0.912, P=0.013) were independent prognostic factors for OS. A nomogram including T stage, N stage, and HLMR in the training cohort was constructed to predict 3-, 5-, and 7-year OS, with a C-index of 0.713. The area under the curves for predicting 3-, 5-, and 7-year OS were 0.744, 0.665, and 0.682, respectively. Calibration curves showed good agreement between predicted and observed survival rates. The above results were further confirmed in the validation cohort. CONCLUSIONS Pretreatment HLMR may serve as a promising prognostic biomarker for patients with nasopharyngeal carcinoma.
Humans ; Nasopharyngeal Carcinoma/mortality* ; Prognosis ; Hemoglobins/analysis* ; Nasopharyngeal Neoplasms/pathology* ; Monocytes/cytology* ; Female ; Male ; Retrospective Studies ; Middle Aged ; Adult ; Aged ; Nomograms ; Chemoradiotherapy ; ROC Curve

Objective To investigate the clinical value of preoperative lymphocyte-to-monocyte ratio(LMR)in evaluating the prognosis of patients with stage T1 non-muscle invasive bladder cancer(NMIBC).Methods A total of 215 patients with stage T1 NMIBC who underwent transurethral resection of bladder tumor were enrolled.Clinical data were collected.Patients were followed up and their disease-free survival(DFS)and overall survival(OS)were recorded.The receiver operating characteristic(ROC)curve of preoperative LMR in detecting patient prognosis was used to determine the optimal cut-off value for LMR.Patients were divided into low LMR group(LMR <3.86,=77)and high LMR group(LMR ≥ 3.86,=138).Kaplan-Meier survival curves were explored to compare cumulative DFS and OS rates in patients with different LMR levels,and COX proportional hazards regression model was used to analyze factors associated with DFS and OS.Results All these 215 patients with T1 stage NMIBC were followed up for 2-92 months,and the DFS rate was 59.07% and OS rate was 65.12%.Kaplan-Meier curves showed that the cumulative DFS rate(=4.784,=0.029)and cumulative OS rate(=7.146, =0.008)in the low LMR group were significantly lower than those in the high LMR group.Tumor size ≥ 3 cm(=1.398,95% :1.042-1.875,=0.025),pathological grade G3(=1.266,95% :1.026-1.563,=0.028),and LMR ≥ 3.86(=2.347,95% :1.080-5.101,=0.031)were independent factors associated with DFS in patients with stage T NMIBC.In addition,tumor size ≥ 3 cm(=1.228,95% :1.015-1.484,=0.034),pathological grade G3(=1.366,95% :1.017-1.834,=0.038),and LMR<3.86(=2.008,95% :1.052-3.832,=0.035)were independent factors associated with OS in patients with T1 stage NMIBC. Conclusion Preoperative LMR is an independent factor associated with patients' prognosis in T1 stage NIMBC.Patients with low LMR tend to have higher risk of NMIBC progression and death.
Disease-Free Survival ; Humans ; Lymphocytes ; cytology ; Monocytes ; cytology ; Prognosis ; Retrospective Studies ; Survival Rate ; Urinary Bladder Neoplasms ; diagnosis ; pathology

Dendritic cells (DCs) are important immune cells linking innate and adaptive immune responses. DCs encounter various self and non-self antigens present in the environment and induce different types of antigen specific adaptive immune responses. DCs can be classified into lymphoid tissue-resident DCs, migratory DCs, non-lymphoid resident DCs, and monocyte derived DCs (moDCs). Recent work has also established that DCs consist of developmentally and functionally distinct subsets that differentially regulate T lymphocyte function. The development of different DC subsets has been found to be regulated by a network of different cytokines and transcriptional factors. Moreover, the response of DC is tightly regulated to maintain the homeostasis of immune system. MicroRNAs (miRNAs) are an important class of cellular regulators that modulate gene expression and thereby influence cell fate and function. In the immune system, miRNAs act at checkpoints during hematopoietic development and cell subset differentiation, they modulate effector cell function, and are implicated in the maintenance of homeostasis. DCs are also regulated by miRNAs. In the past decade, much progress has been made to understand the role of miRNAs in regulating the development and function of DCs. In this review, we summarize the origin and distribution of different mouse DC subsets in both lymphoid and non-lymphoid tissues. The DC subsets identified in human are also described. Recent progress on the function of miRNAs in the development and activation of DCs and their functional relevance to autoimmune diseases are discussed.
Animals ; Autoimmune Diseases ; immunology ; Cell Differentiation ; immunology ; Dendritic Cells ; cytology ; immunology ; Humans ; MicroRNAs ; immunology ; Monocytes ; cytology ; immunology ; T-Lymphocytes ; cytology ; immunology

OBJECTIVETo investigate the effect of inhibiting and activating Wnt signalling pathway on monocyte differentiation of HL-60 cells induced with a new steroidal drug NSC67657 and its possible mechamism.

METHODSThe HL-60 cells were treated with 5, 10 and 20 µmol/L XAV-939 (inhibitor of Wnt signalling pathway) for 3 days, and with 10, 20 and 30 mmol/L LiCl (activator of Wnt signalling pathway) for 1 day; the expression levels of down-stream genes and proteins of Wnt signolling pathway were detected by RT-PCR and Western blot, respectively; the expression of cell surface differentiation antigen CD14 and early apoptosis of HL-60 cells was detected by flow cytometry, moreover the most suitable concentration of Wnt inhibitor and activator for HL-60 cells was determined. Then the HL-60 cells with inhibited and activated Wnt pathway were treated with NSC67657 of 10 µmol/L for 3 days; the expression levels of CD14 and down-stream target proteins of Wnt signalling pathway in blank control (culture mediam) group, simple NSC67657-treated group, NSC67657 combined with inhibitor group and NSC67657 combined activator group were compared and analyzed.

RESULTS20 µmol/L XAV-939 and 20 mmol/L LiCl could effectively inhibit and activate Wnt signalling pathway of HL-60 cells respectively, could significantly down- and up-regulate the expression of cyclinD1, TCF1 and c-Jun genes (P < 0.05) and proteins (P < 0.05); moreover, the number of CD10(+) HL-60 cells in these conditions was below 1%, no early apoptosis of HL-60 cells was found. In the simple NSC67657-treated groups, the expression of cyclinD1, TCF1 and c-Jun proteins was down-regulated (P < 0.05), and the percentage of CD14(+) HL-60 cells accounted for 62.13 ± 9.44; after the HL-60 cells were treated with XAV-939, the NSC67657 could more significantly down-regulate the expression of cyclinD1, TCF1 and c-Jun proteins and the percentage of CD14(+) HL-60 cell accounted for 84.17 ± 5.39%, as compared with simple NSC67657-treated group; as compared with blank controls group, the expression of cyclinD1, TCF1 and c-Jun proteins was more obviously down-regulated and the percentage of CD14(+) HL-60 cells decreased to 33.99 ± 8.37% in NSC67657 combined LiC1 streated group, but which were higher than those in simple NSC67657-treated group (P < 0.05).

CONCLUSION20 µmol/L XAV-939 and 20 mmol/L LiCl as effective inhabitor and activator of Wnt signalling pathway respectively can significantly down- and up-regulate the expression of Wnt down-stream pathway target genes and proteins. The influence of XAV-939 and LiC1 on differentiation of HL-60 cells induced by NSC67657 suggests that Wnt signalling pathway plays a key role in monocyte differentiction of HL-60 cells induced by NSC67657.

Apoptosis ; Cell Differentiation ; Cyclin D1 ; metabolism ; Flow Cytometry ; HL-60 Cells ; Hepatocyte Nuclear Factor 1-alpha ; metabolism ; Humans ; Lipopolysaccharide Receptors ; metabolism ; Mesylates ; pharmacology ; Monocytes ; cytology ; Proto-Oncogene Proteins c-jun ; metabolism ; Steroids ; pharmacology ; Wnt Signaling Pathway

OBJECTIVETo explore the molecular basis for a CD36 deficiency individual and distribution of CD36 gene mutation in Guangxi population.

METHODSA female individual was studied. CD36 phenotype was detected by monoclonal antibody immobilization of platelet antigens assay (MAIPA) and flow cytometry (FCM). The coding regions of the CD36 gene were sequenced. A DNA-based polymerase chain reaction-sequence specific primer (PCR-SSP) assay was used to verify the identified mutation. Cell lines expressing the mutant and wild-type CD36[CD36(MT) and CD36(WT)] were established, with the expression of CD36 determined by Western blotting. The distribution of CD36 gene mutation was investigated among 1010 unrelated individuals with the PCR-SSP assay.

RESULTSBoth MAIPA and FCM assays showed that the patient had type II CD36 deficiency. DNA sequencing showed that she has carried a heterozygous mutation T538C (Trp180Arg) in the exon 6 of CD36. Sequencing of cDNA clone confirmed that there was a nucleotide substitution at position 538 (538T>C). Western blotting also confirmed that the CD36 did not express on the CD36(MT) cell line that expressed the 538C mutant, but did express on the CD36(WT) cell line. The novel CD36 mutation T538C was further verified with 100% concordance of genotyping results by DNA-based PCR-SSP assay and 1010 unrelated individuals. No CD36 538C allele was detected among the 1010 individuals.

CONCLUSIONThis study has identified a novel CD36 mutation T538C(Trp180Arg)(GenBank: HM217022.1), and established a genotyping method for the novel sequence-specific primer PCR. The novel mutation is rare in Guangxi and can cause type II CD36 deficiency.

Base Sequence ; Blood Platelet Disorders ; genetics ; Blood Platelets ; cytology ; metabolism ; Blotting, Western ; CD36 Antigens ; genetics ; metabolism ; Cells, Cultured ; DNA Mutational Analysis ; DNA Primers ; genetics ; Exons ; genetics ; Female ; Flow Cytometry ; Fluorescent Antibody Technique ; Genetic Diseases, Inborn ; genetics ; Genotype ; Genotyping Techniques ; methods ; Humans ; Middle Aged ; Monocytes ; cytology ; metabolism ; Mutation, Missense ; Polymerase Chain Reaction ; methods

OBJECTIVETo analyze the effect of dexamethason (Dex) on blast composition in patients with myelodysplastic syndrome (MDS) and investigate its significance in diagnosis of MDS.

METHODSThe flow cytometry (FCM) was used to detect the blast rate and the expression of its antigens in 30 cases of MDS (10 cases were treated with Dex as DX group and 20 cases were treated without Dex as control group).

RESULTSThe difference of the CD34(+) cell number detected by FCM was not statistically significant between DX group and control group (P > 0.05); The rate of BM B cell precursors (BCP CD34(+)/CD19(+)/CD10(+) cells) increased in DX group significantly, and BM CD117(+) cells in CD34(+) cells was decreased significantly as compared with control group (P < 0.001). The expression of antigens between granulocyte and monocyte was not significantly different (P > 0.05).

CONCLUSIONThe dexamethasone can increase the rate of BCP significantly and decreased the rate of BM CD117(+) cells in CD34(+) cells significantly. There is significant influence on the blast composition in MDS patients after dexamethasone treatment and without significant influence on the other phenotypcs.

Antigens, CD34 ; metabolism ; Dexamethasone ; therapeutic use ; Flow Cytometry ; Granulocytes ; cytology ; Humans ; Monocytes ; cytology ; Myelodysplastic Syndromes ; drug therapy ; Precursor Cells, B-Lymphoid ; cytology ; Proto-Oncogene Proteins c-kit ; metabolism

Infection of schistosomiasis japonica may eventually lead to liver fibrosis, and no effective antifibrotic therapies are available but liver transplantation. Hedgehog (HH) signaling pathway has been involved in the process and is a promising target for treating liver fibrosis. This study aimed to explore the effects of pentoxifylline (PTX) on liver fibrosis induced by schistosoma japonicum infection by inhibiting the HH signaling pathway. Phorbol12-myristate13-acetate (PMA) was used to induce human acute mononuclear leukemia cells THP-1 to differentiate into macrophages. The THP-1-derived macrophages were stimulated by soluble egg antigen (SEA), and the culture supernatants were collected for detection of activation of macrophages. Cell Counting Kit-8 (CCK-8) was used to detect the cytotoxicity of the culture supernatant and PTX on the LX-2 cells. The LX-2 cells were administered with activated culture supernatant from macrophages and(or) PTX to detect the transforming growth factor-β gene expression. The mRNA expression of shh and gli-1, key parts in HH signaling pathway, was detected. The mRNA expression of shh and gli-1 was increased in LX-2 cells treated with activated macrophages-derived culture supernatant, suggesting HH signaling pathway may play a key role in the activation process of hepatic stellate cells (HSCs). The expression of these genes decreased in LX-2 cells co-cultured with both activated macrophages-derived culture supernatant and PTX, indicating PTX could suppress the activation process of HSCs. In conclusion, these data provide evidence that PTX prevents liver fibrogenesis in vitro by the suppression of HH signaling pathway.
Animals ; Antigens, Helminth ; isolation & purification ; pharmacology ; Cell Culture Techniques ; Cell Differentiation ; drug effects ; Cell Line ; Culture Media, Conditioned ; chemistry ; pharmacology ; Gene Expression Regulation ; Hedgehog Proteins ; agonists ; antagonists & inhibitors ; genetics ; immunology ; Hepatic Stellate Cells ; cytology ; drug effects ; metabolism ; Humans ; Liver Cirrhosis ; metabolism ; parasitology ; prevention & control ; Macrophage Activation ; drug effects ; Macrophages ; cytology ; drug effects ; immunology ; Models, Biological ; Monocytes ; cytology ; drug effects ; metabolism ; Pentoxifylline ; pharmacology ; Phosphodiesterase Inhibitors ; pharmacology ; RNA, Messenger ; genetics ; immunology ; Schistosoma japonicum ; chemistry ; Signal Transduction ; Tetradecanoylphorbol Acetate ; pharmacology ; Zinc Finger Protein GLI1 ; genetics ; immunology ; Zygote ; chemistry

OBJECTIVETo investigate whether I-tetrahydropalmatine (I-THP), an alkaloid mainly present in Corydalis family, could ameliorate early vascular inflammatory responses in atherosclerotic processes.

METHODSFluorescently labeled monocytes were co-incubated with human umbilical vein endothelial cells (HUVECs), which were pretreated with I-THP and then simulated with tumor necrosis factor (TNF)-α in absence of I-THP to determine if I-THP could reduce thecytokine-induced adhesion of monocytes to HUVECs. Then I-THP were further studied the underlying mechanisms through observing the transcriptional and translational level of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) and the nuclear translocation of nuclear factor (NF)-κ B in HUVECs.

RESULTSL-THP could block TNF-α-induced adhesion of monocytes to HUVECs and could significantly inhibited the expression of ICAM-1 and VCAM-1 on cell surface by 31% and 36% at 30 μ mol/L. L-THP pretreatment could also markedly reduce transcriptional and translational level of VCAM-1 as well as mildly reduce the total protein and mRNA expression levels of ICAM-1. Furthermore, I-THP attenuated TNF-α-stimulated NF-κ B nuclear translocation.

CONCLUSIONThese results provide evidences supporting that I-THP could be a promising compound in the prevention and treatment of the early vascular inflammatory reaction in atherosclerosis by inhibiting monocyte adhesion to vascular endothelial cell through downregulating ICAM-1 and VCAM-1 in vascular endothelial cell based on suppressing NF-κ B.

Berberine Alkaloids ; pharmacology ; Cell Adhesion ; drug effects ; Cell Nucleus ; drug effects ; metabolism ; Down-Regulation ; drug effects ; Human Umbilical Vein Endothelial Cells ; cytology ; drug effects ; metabolism ; Humans ; Intercellular Adhesion Molecule-1 ; genetics ; metabolism ; Monocytes ; cytology ; drug effects ; metabolism ; NF-kappa B ; metabolism ; Protein Transport ; drug effects ; RNA, Messenger ; genetics ; metabolism ; Signal Transduction ; drug effects ; Transcription Factor RelA ; metabolism ; Tumor Necrosis Factor-alpha ; pharmacology ; Vascular Cell Adhesion Molecule-1 ; genetics ; metabolism

OBJECTIVETo study the mechanism underlying the inhibitory effect of Qingluo Tongbi Granule (, QTG) on osteoclast differentiation in rheumatoid arthritis in rats.

METHODSFibroblast and monocyte co-culture were used to induce osteoclast differentiation in adjuvant-induced arthritic (AIA) rats. Serum containing QTG was prepared and added to the osteoclasts, and activation of the tumor necrosis factor receptor-associated factor 6/mitogen-activated protein kinase/nuclear factor of activated T cells, cytoplasmic1 (TRAF6/MAPK/NFATc1) pathways was examined.

RESULTSThe induced osteoclasts were multinucleated and stained positive for tartrate-resistant acid phosphatase (TRAP) staining. Serum containing QTG at 14.4, 7.2 or 3.6 g/kg inhibited the activation of TRAF6, extracellular regulated protein kinase (ERK)1/2, c-Jun N-terminal kinase (JNK) and p38 and decreased the percentage of cells with nuclear NFATc1 in a dose-dependent manner, the high and middle doses exhibited clear inhibitory activity (P<0.01 and P<0.05, respectively). After the addition of MAPK inhibitors, the NFATc1 expression showed no significant difference compared with the control group (P>0.05).

CONCLUSIONSSerum containing QTG could generally inhibit the TRAF6/MAPK pathways and possibly inhibit the NFATc1 pathway. In addition, QTG may regulate other signaling pathways that are related to osteoclast differentiation and maturation.

Adjuvants, Immunologic ; adverse effects ; Animals ; Arthritis, Experimental ; pathology ; Cell Differentiation ; drug effects ; Cells, Cultured ; Coculture Techniques ; Down-Regulation ; drug effects ; Drugs, Chinese Herbal ; pharmacology ; Fibroblasts ; pathology ; Male ; Monocytes ; pathology ; Osteoclasts ; cytology ; drug effects ; physiology ; Rats ; Rats, Sprague-Dawley ; Synovial Membrane ; pathology