摘要
Objective To investigate the expression of indoleamine 2,3-dioxygenase 1(IDO1)and kynure-ninase(KYNU)in oral squamous cell carcinoma(OSCC)and their relationship with pathological features and prognosis.Methods A total of 98 OSCC patients admitted to the hospital from January 2018 to June 2020 were enrolled in the study.OSCC tissue samples and corresponding adjacent tissue samples were collected.Im-munohistochemical method was used to detect the expression of IDO1 and KYNU in tissues.The relationship between IDO1 and KYNU expression and the clinicopathological characteristics of OSCC patients was ana-lyzed.Multivariate Cox regression analysis was used to analyze the factors affecting the prognosis of OSCC pa-tients.Results The positive expression rates of IDO1 and KYNU in OSCC tissues were higher than those in adjacent tissues(P＜0.05).The positive expression rates of IDO1 and KYNU in patients with poor differenti-ation,depth of invasion(DOI)＞5 mm,lymph node metastasis,and clinical stage Ⅲ-Ⅳ were higher than those in patients with medium or high differentiation,DOI＜5 mm,no lymph node metastasis,and clinical stage Ⅰ-Ⅱ,respectively(P＜0.05).The 3-year overall survival rates of OSCC patients with medium or high differentiation,DOI＜5 mm,no lymph node metastasis,clinical stage Ⅰ-Ⅱ,negative expression of IDO1,and negative expression of KYNU were higher than those of OSCC patients with low differentiation,DOI＞5 mm,lymph node metastasis,clinical stage Ⅲ-Ⅳ,positive expression of IDO1,and positive expression of KYNU,respectively(P＜0.05).Multivariate Cox regression analysis showed that DOI＞5 mm(HR=3.225,95％CI:1.496-6.954),positive expression of IDO1(HR=3.714,95％CI:1.941-7.105),positive expression of KYNU(HR=4.150,95％CI:1.887-9.124)were the influencing factors of the prognosis of OSCC patients(P＜0.05).Conclusion IDO1 and KYNU are highly expressed in cancer tissues of OSCC patients,which are closely related to the DOI,clinical stage,and differentiation degree of OSCC.IDO1 and KYNU are hopeful to be used as markers to assist in evaluating the prognosis of patients.
摘要
Objective:To explore the changes in serum indoleamine 2, 3-dioxygenase (IDO) and kynurenic acid (KYNA) levels in preterm infants diagnosed with bronchopulmonary dysplasia (BPD).Methods:A nested case-control study was conducted. The inclusion criteria covered premature infants with less than 32 weeks of gestational age within 24 h post-birth, from December 1, 2021, to December 31, 2022, at Children's Hospital of Soochow University. Those diagnosed with BPD were allocated to the BPD group ( n=35). Non-BPD preterm infants matching the BPD cases in terms of gestational age (within one week difference) and birth weight (within a 150 g difference) were selected in a 1∶1 ratio for the control group ( n=35). Serum levels of IDO and KYNA were measured on days 1, 7, 14, and 28 postnatally. Differences in serum IDO and KYNA levels were analyzed between the BPD and control groups and among infants with mild BPD versus moderate-to-severe BPD. The association between serum IDO and KYNA levels with the severity of BPD was also assessed. Statistical analysis was conducted using independent samples t-tests and Spearman's correlation analysis. Results:Elevated levels of serum IDO on days 7, 14, and 28 postnatally [(60.68±9.37) vs. (50.66±10.46), (57.81±11.07) vs. (44.45±8.20), and (50.62±10.77) vs. (41.31±7.74) pg/ml; t=4.21, 5.73, and 4.15, respectively] as well as increased serum KYNA levels on days 14 and 28 [(439.31±41.22) vs. (368.99±68.79), (376.97±45.74) vs. (325.50±60.07) μmol/L; t=5.18 and 4.03, respectively] were observed in the BPD group compared to the control group, with all differences being statistically significant (all P<0.05). Furthermore, positive correlations were observed between serum IDO levels and BPD severity on the 7th, 14th, and 28th days ( r=0.546, 0.495, and 0.502, all P<0.05), as well as between serum KYNA levels and BPD severity on the 14th and 28th days ( r=0.536 and 0.458, both P<0.05). Conclusion:Elevated serum levels of IDO and KYNA in infants with BPD suggest these metabolites may play a role in the pathogenesis and progression of BPD.
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Sepsis is a condition characterized by organ dysfunction resulting from the systemic inflammatory response triggered by an infection. Excessive inflammation and immunosuppression are intertwined, and severe cases may even develop into multiple organ failure. Studies have shown that indoleamine 2,3-dioxygenase 1-mediated tryptophan metabolism is involved in the occurrence and development of sepsis, and elevated plasma kynurenine levels and Kyn/Trp ratios are early indicators of sepsis development. In this paper, we provide a comprehensive summary of the role of IDO1 in the acute inflammatory phase of sepsis, late immunosuppression, and organ damage. This includes its regulation of inflammatory state, immune cell function, blood pressure, and other aspects. Additionally, we analyze preclinical studies on targeted IDO1 drugs. An in-depth understanding and study of IDO may help to understand the pathogenesis and clinical significance of sepsis and multiple organ damage from a new perspective and provide new research ideas for exploring its prevention and treatment methods.
摘要
Objective:To investigate whether indoleamine 2, 3-dioxygenase-1 (IDO1) is involved in Neisseria gonorrhoeae ( Ng) infection and its immunomodulatory role in Ng infection. Methods:Human peripheral blood mononuclear cells were induced to differentiate into DC in vitro. The phenotype of DC was identified. The expression of IDO1 was detected by Western blot. The expression of IDO1 at mRNA level in the secretions of Ng-positive patients was detected. Changes in Treg and myeloid-derived suppressor cell (MDSC) in the anticoagulant whole blood of Ng-positive patients were detected by flow cytometry. Results:Ng could induce human DCs to produce IDO1, which depended on the activity of Ng. The expression of IDO1 in the genital tract secretions of Ng-positive patients was significantly higher than that in healthy people. Besides, the proportions of MDSC and Treg in the peripheral blood of patients with Ng infection were higher than those in healthy people. Based on literature review, it was suggested that Treg could induce the expression of IDO1 +, and IDO1 +, in turn, together with MDSC, promoted the differentiation of new Treg, which inhibited the proliferation of CD4 + T cells and was involved in immune tolerance. Conclusions:Understanding the immune regulatory network of "IDO1-CD4 + T cells-immune microenvironment" in the immune microenvironment would provide new targets or thoughts for the immunotherapy of gonorrhea, so as to better use immunotherapy to prevent and control the occurrence and development of gonorrhea.
摘要
SUMMARY OBJECTIVE: This study aimed to investigate the presence of indoleamine-2,3-dioxygenase and bacterial translocation after the administration of 3-aminobenzamide and infliximab in the TNBS model of rat colitis. METHODS: The study group was divided into five categories as follows: group 1: (control), group 2: colitis+saline, group 3: colitis+3-aminobenzamide, group 4: colitis+infliximab, and group 5: colitis+3-aminobenzamide+infliximab. Intestinal mesenteric cultures were incubated on specific agar media plates under aerobic and anaerobic conditions, bacterial translocation was evaluated and assessed as colony-forming units per gram of tissue. Colonic tissue samples were evaluated by Western blotting method to detect the presence of indoleamine-2,3-dioxygenase. RESULTS: The results obtained were as follows: group 1: normal gut flora; group 2: eight of nine samples had bacterial translocation, of which six of them had positive indoleamine-2,3-dioxygenase protein; group 3: five of nine samples had bacterial translocation, of which seven of them had positive indoleamine-2,3-dioxygenase; group 4: three of nine samples had bacterial translocation, of which seven of them had positive indoleamine-2,3-dioxygenase; and group 5: only one sample had exact indoleamine-2,3-dioxygenase protein. CONCLUSION: Altered expression of indoleamine-2,3-dioxygenase results in a lower bacterial translocation via infliximab compared with 3-aminobenzamide treatment. Combined treatments emphasized different approaches for the new molecules related to indoleamine-2,3-dioxygenase.
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Airway epithelial damage, increased Th2 inflammatory response, and impaired immune regulatory T cell function are important mechanisms for the development of asthma.Indoleamine 2, 3-dioxygenase(IDO) is induced by LPS and IFN-γ, which regulates the differentiation of naive T cells into CD4 + CD25 + regulatory T cells(Treg)and induces immune tolerance.It can inhibit eosinophilic airway inflammation.Decreased IDO activity may promote the development of asthma.Tryptophan metabolites act on AhR receptors to promote the production of IL-22 and enhance the integrity of the epithelium and its resistance to infection.The Th17/Treg balance induced by specific immunotherapy could be altered, and Treg cell proliferation was observed.Tryptophan metabolites can reduce airway inflammation and inflammatory cytokine infiltration.D-tryptophan can promote the diversity of intestinal flora, increase the number of Treg in lung and colon, reduce Th2 reaction, and reduce airway hyperresponsiveness.Tryptophan and its metabolites, IDO and D-tryptophan play an important role in the occurrence, development and specific immunotherapy of asthma.
摘要
Indoleamine 2, 3-dioxygenase (IDO) is one of the rate-limiting enzymes that degrade tryptophan (Trp) into kynurenine (Kyn). Inflammatory factor IFN-γ mediates tumor′s immune escape by activating the IDO signaling pathway, upregulating theKyn/Trp (K/T ratio) and suppressing the activity of both CD 8+T and regulatory T cells. Radiotherapy plays a major role in treating non-small cell lung cancer. It not only bi-directionally regulates immune response of the host, but also collaborates with immunosuppressive agents to kill tumors. Meanwhile, immune status of the host can affect the therapeutic effect of radiotherapy. In recent years, studies have shown that IDO activity levels change before and after radiotherapy and is related to clinical prognosis. Nevertheless, relevant mechanism remains unclear. This article aims to elucidate the application of IDO signaling pathway in radiotherapy for non-small cell lung cancer.
摘要
Impaired immunomodulatory capacity and oxidative stress are the key factors limiting the effectiveness of mesenchymal stem cell transplantation therapy. The present study was aimed to investigate the effects of jujuboside A (JuA) on the protective effect and immunomodulatory capacity of human umbilical cord mesenchymal stem cells (hUC-MSCs). Hydrogen peroxide was used to establish an oxidative damage model of hUC-MSCs, while PBMCs isolated from rats were used to evaluate the effect of JuA pre-treatment on the immunomodulatory capacity of hUC-MSCs. Furthermore, Hoechst 33258 staining, lactate dehydrogenase test, measurement of malondialdehyde, Western blot, high-performance liquid chromatography; and flow cytometry were performed. Our results indicated that JuA (25 μmol·L-1) promoted the proliferation of hUC-MSCs, but did not affect the differentiating capability of these cells. JuA pre-treatment inhibited apoptosis, prevented oxidative damage, and up-regulated the protein expression of nuclear factor-erythroid factor 2-related factor 2 and heme oxygenase 1 in hUC-MSCs in which oxidative stress was induced with H2O2. In addition, JuA pre-treatment enhanced the inhibitory effect of hUC-MSCs against abnormally activated PBMCs, which was related to stimulation of the expression and activity of indoleamine 2,3-dioxygenase. In conclusion, our results demonstrate that JuA pre-treatment can enhance the survival and immunomodulatory ability through pathways related to oxidative stress, providing a new option for the improvement of hUC-MSCs in the clinical setting.
Subject(s)
Animals , Humans , Rats , Cell Differentiation , Hydrogen Peroxide/metabolism , Mesenchymal Stem Cells , Oxidative Stress , Saponins , Umbilical Cord/metabolism摘要
We analyzed the anticancer effect and mechanism of the novel indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor NLG-919 combined with temozolomide (TMZ) on human glioma cell lines. The anti-tumor activity of NLG-919 and temozolomide after single and combined treatments was detected by MTT assay. Colony formation assay, invasion assay and migration assays were used to detect the effects of NLG-919 and temozolomide alone or in combination on proliferation, invasion and migration of human glioma cells. A flow cytometry assay was used to detect cell apoptosis, cell cycle arrest, reactive oxygen species (ROS) production and mitochondrial membrane potential damage (JC-1). An immunofluorescence assay was used to detect the expression level of IDO1 and HPLC was used to detect the expression level of L-kynurenine (Kyn) to explore the anti-tumor mechanism of NLG-919 and temozolomide. The results show that NLG-919 had a weak in vitro inhibitory effect compared to that of temozolomide. The IC50 of NLG-919 on U251 cells and U87 after 72 h was 26.9 and 30.7 μmol·L-1, respectively. However, when NLG-919 was used in combination with temozolomide, its anti-glioma activity was significantly increased. Compared with the single treatment, the combination treatment had a potent ability to inhibit proliferation, invasion and migration of glioma cells. Combination treatment improved the capacity of temozolomide to induce cell cycle arrest and inhibit the growth of glioma cells. NLG-919 significantly down-regulated the expression and activity of IDO1 in glioma cells, and the inhibitory effect was improved after combination with temozolomide, and effectively blocked the production of Kyn through the metabolism of L-tryptophan (Trp). In conclusion, the IDO1 inhibitor NLG-919 and temozolomide showed synergistic effects in the anticancer therapy of human glioma cell lines.
摘要
Indoleamine 2, 3-dioxygenase (IDO) is an important immunoregulatory enzyme, which can degrade the level of the mammalian essential amino acid tryptophan (TRP), catalyze the initiation and rate-limiting steps through the kynurenine pathway, and produce a variety of metabolites to participate in the immune response. On the one hand, IDO plays an immunosuppressive role in microenvironment and thus leads to infection and immune escape of tumor cells; on the other hand, IDO also exerts an inhibitory effect on the pathogens such as bacteria and parasites and thus protects the body from the harm of pathogens to a certain extent. Therefore, IDO is considered an important medium with the role of a double-edged sword in the development and progression of various liver diseases. This article reviews the latest research advances in IDO in viral hepatitis, liver fibrosis, liver cirrhosis, liver cancer, and hepatic echinococcosis.
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There are two serious obstacles to tumor immunotherapy. Firstly, the immune response of the tumor is seriously reduced due to immunosuppressive tumor microenvironment (ITM) and low immunogenicity of tumor. The second obstacle is the dense and complex heterogeneous structures, which seriously prevent the nanoparticles (NPs) from penetrating deeper into tumor tissue. Immunogenic cell death (ICD) induced by doxorubicin (DOX) is an effective method to enhance tumor immune activity. However, interferon-γ (IFN-γ) secreted by cytotoxic T lymphocytes (CTL) after ICD induction would increase the expression of indoleamine 2,3-dioxygenase 1 (IDO1) and enhance ITM. IDO1 siRNA would reduce the expression of IDO1 protein, regulate the tumor immunosuppressive microenvironment and regulate ITM, so as to enhance the ICD effect of DOX. In this paper, a novel charge conversional, particle size reduction and highly penetrable NPs based on a pH sensitive copolymer poly(ethylene glycol)-poly-L-lysine-2,3-dimethylmaleic anhydride (mPEG-PLL-DMA, PLD) and polyamidoamine (PAMAM) dendrimers to achieve deep delivery of tumor tissue. DOX and IDO1 siRNA were encapsulated to achieve efficient tumor immunotherapy. Preparation and cell level experiments showed that PLD material had significant pH sensitivity. Results of 3D tumor penetrable experiment in vitro showed that adding the pH sensitive material PLD significantly improved the permeability of the preparation. In addition, 4T1 tumor model was established for BALB/c mice and all animal experiments were displayed in according with the requirements of the Animal Experiment Ethics Committee of Shenyang Pharmaceutical University. The results of in vivo efficacy experiments and tissue experiments evaluated that IDO1 siRNA significantly improved the ICD effect owing to DOX, so as to significantly inhibit tumor growth.
摘要
OBJECTIVE Programmed death ligand-1 (PD-L1) and indoleamine 2, 3-dioxygenase 1 (IDO1) are immune checkpoints which can be induced by interferon-γ(IFN-γ) in the tumor microenvironment, leading to immune escape of tumors. Myricetin (MY) is a flavonoid distributed in many edible and medicinal plants. The aim of this study is to clarify the effect and the mechanism of MY on inhibiting IFN-γ-induced PD-L1 and IDO1 in lung cancer cells. METHODS Expressions of PD-L1 and major histocompatibility complex-I (MHC-I) were evaluated by flow cytometry and Western blotting, and the expression of IDO1 was measured by Western blotting. qRT-PCR was used to detect their mRNA levels. The function of T cells was evaluated using a co-culture system consist of lung cancer cells and the Jurkat-PD-1 T cell line that overexpressing PD-1. Molecular docking analysis, Western blotting and immunofluorescence were used for mechanism study. RESULTS MY potently inhibited IFN-γ-induced PD-L1 and IDO1 expression in human lung cancer cells, while didn't show obvious effect on the expression of MHC-I. In addition, MY restored the survival, proliferation, CD69 expression and interleukin-2 (IL-2) secretion of Jurkat-PD-1 T cells suppressed by IFN-γ-treated lung cancer cells in the co-culture system. Mechanistically, IFN-γ up-regulated PD-L1 and IDO1 at the transcriptional level through the JAK-STAT-IRF1 axis, which was targeted and inhibited by MY. CONCLUSION Our research revealed a new insight into the anti-tumor effects of MY which inhibited IFN-γ-induced PD-L1 and IDO1 expression, supporting the potential of MY in anti-tumor immunotherapy.
摘要
Indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO) catalyze the initial and rate limiting step in the catabolism of tryptophan, which is related to tumor immune tolerance and poor prognosis in patients. In this regard, two enzymes have become important therapeutic targets for tumor immunotherapy. So far, nine IDO1 inhibitors and three IDO1/TDO dual inhibitors have entered clinical trials. This review summarizes the research progress of IDO1 inhibitors, TDO inhibitors and IDO1/TDO dual inhibitors from the perspective of medicinal chemistry.
摘要
Indoleamine 2,3-dioxygenase 1 (IDO1) is the rate-limiting enzyme in the degradation of tryptophan to kynurenine. IDO1 is highly expressed in some tumor tissues. IDO1 can deplete tryptophan in tumor microenvironment, inhibit T cell function, and mediate the immune escape of tumor cells. Thus, IDO1 is considered a potential target of tumor immunotherapy. Currently, there are several IDO1 inhibitors in clinical research studies. The mechanism of IDO1-mediated tumor immune escape and the structure of IDO1 inhibitors are summarized in this review.
摘要
Aim To study the effect of resveratrol on the metabolism of tryptophan to kynurenine in human liver microsomes.Methods High performance liquid chromatography-tandem mass spectrometry ( LC-MS/ MS) was used to detect the concentration of tryptophan and kynurenine in the microsome incubation system, and the incubation time, tryptophan concentration, and microsomal protein concentration were investigated respectively.The optimal tryptophan incubation system obtained above was used to explore the effect of resveratrol on the kynurenine pathway.Results The optimal incubation time of tryptophan in human liver mi-crosomes in vitro was 90 min,the concentration of tryptophan and liver microsomal protein was 8 mg • L"1 and 1 g • L"1, respectively.The enzyme reaction rate constant Km was 95.91 ±22.29 jxmol • L'1, and the maximum reaction rate V
摘要
Indoleamine 2, 3-dioxygenase (IDO) is an important immunoregulatory enzyme, which mediates immune effects by depleting tryptophan and producing multiple metabolites. Recently, the studies on the immune function of IDO have been mostly restricted in tumors and autoimmune diseases. Nevertheless, there are few studies pertaining to the role of IDO in parasitic diseases, notably in parasite-host immune interactions. This review mainly describes IDO-mediated immunoregulatory effects and its regulation of parasite-host interactions, so as to provide insights into the development of immune intervention schemes against parasitic diseases.
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RESUMEN En las gestantes obesas se han observado complicaciones, incluyendo prevalencia de abortos espontáneos y preeclampsia. Se ha propuesto que en parte estas complicaciones podrían explicarse por el ambiente inflamatorio que predomina en la obesidad. La enzima indolami-na-2,3-dioxigenasa 1 (IDO1) es inducida por la citoquina pro-inflamatoria IFN-y, por lo que se ha sugerido un incremento en su expresión en pacientes obesos. IDO1 desempeña funciones claves durante el embarazo, entre las que se encuentra el establecimiento de la tolerancia materno-fetal, la placentación y la regulación del flujo sanguíneo en la placenta. Hasta el momento los estudios que evalúan la expresión de IDO1 en la gestación en condiciones de obesidad son escasos. Por lo tanto, en esta revisión se propuso explorar las implicaciones derivadas de la alteración en la expresión de esta enzima en gestantes obesas. Según la evidencia disponible en la literatura, es posible que en gestantes obesas se presente un aumento en la expresión y la actividad de IDO1. Estas modificaciones podrían tener efectos deletéreos sobre la gestación y estar relacionada con las complicaciones que se observan en gestantes obesas.
ABSTRACT Women who have an obese body mass index are more likely to experience pregnancy complications, including spontaneous abortion and preeclampsia. It has been suggested that these complications are at least in part related to the pro-inflamatory environment that predominates in obesity. Indoleamine-2,3-dioxygenase 1 is an enzyme induced downstream IFN-y signalling, hence it has been suggested that it increases its expression and activity in obese patients. IDO1 exerts multiple functions in pregnancy, including its contribution to materno-fetal tolerance, placentation and regulation of placental blood flow. The evidence about IDO1 in pregnant obese women is scarce. Therefore, herein the implications of an overexpression of IDO1 in pregnant obese patients were explored. The evidence available at the moment suggests that it is possible that IDO1 increases its expression and activity in pregnant obese women contributing to the complications observed on these patients.
摘要
Objective To investigate the antidepressant effects of Chaihu Shugan Powder(CSP) on depressive rats induced by reserpine and its influences on the kynurenine (KYN),indoleamine 2,3-dioxyge-nase(IDO),interleukin-6(IL-6) and tumor necrosis factor-α( TNF-α). Methods Forty rats with similar behavior results were divide into 4 groups randomly,including Control group(Con),Model group(Res),Flu- oxetine group(Res+Flu) and Chaihu Shugan Powder group(CSP). The depressive rat model was established by intraperitoneal injection reserpine. The rats in Res+Flu group were administered with fluoxetine by intrap-eritoneal and rats in Res+CSP group were administered with CSP by intraperitoneal. After 14 days,the be-havior of rats was measured and then the rats were executed and sampled. The content of tryptophan and kynurenine in raphe nuclei tissue were detected. The mRNA expression level of IDO,IL-6,TNF-α in raphe nuclei tissue were detected. Results ( 1) Compared with Con group (( 81. 81 ± 36. 13) s, ( 83. 51 ± 5. 34)%), the swimming immobility time((150. 50±31. 45)s) in Res group increased(t=68. 7, P<0. 05) and the sucrose perference (59. 73±11. 30)%) in Res group decreased(t=23. 8,P<0. 05). Compared with Res group, the swimming immobility time in Res+Flu group((114. 90± 14. 29) s) and Res+CSP group ((111. 7±11. 34)s) decreased(t=35. 6,35. 8,both P<0. 05). Compared with Res group, the sucrose pref-erence in Res+Flu group((78. 21±10. 07)%) increased(t=18. 3, P<0. 05). (2)Compared with Con group (KYN/TRP:(0. 023±0. 016),IDO mRNA:(1. 00±0. 05),IL-6 mRNA:(1. 00±0. 58),TNF-α mRNA:(1. 00±0. 32)), the activity of IDO(KYN/TRP(0. 039±0. 003)) and the mRNA levels of IDO mRNA(3. 63± 0. 31),IL-6 mRNA(2. 36±0. 23),TNF-α mRNA( 3. 56± 0. 14) of Raphe Nuclei tissue in Res group were significantly increased (t=21. 2,12. 9,38. 3,19. 7,all P<0. 05). Compared with Res group, the activity of IDO(KYN/TRP(0. 030±0. 013)),the mRNA expression levels of IDO mRNA( 1. 56±0. 36),IL-6 mRNA (1. 62±0. 16),TNF-α mRNA(2. 64±0. 20)of Raphe Nuclei tissue in Res+Flu group were significantly de-creased(t=38. 8,15. 8,12. 8,26. 4,all P<0. 05). And compared with Res group,the activity of IDO( KYN/TRP(0. 028±0. 021)) ,the mRNA expression level of IDO mRNA( 1. 33± 0. 29),IL-6 mRNA(1. 36± 0. 34),TNF-α mRNA(1. 93±0. 21)of raphe nuclei tissue in Res+CSP group were also significantly decreased (t=23. 21,17. 3,19. 8,29. 8,all P<0. 05). Compared with Res+Flu group,the level of IDO mRNA and in-flammatory factors' mRNA in Res+CSP group were significantly decreased(t=18. 3,20. 8,31. 5,all P<0. 05). Conclusion Chaihu Shugan Powder has antidepressant effect,and the mechanism is related with de-creasing the inflammatory factors,inhibiting IDO activation and decreasing the IDO mRNA.
摘要
BACKGROUND: Although Th2 immune activation is predominant in allergic diseases, neopterinlevels and indoleamine 2,3-dioxygenase (IDO)-1 activity (kynurenine:tryptophan ratio), which reflect Th1 immune activity, increase with interferon-gamma (IFN-γ) stimulation. We investigated neopterin, tryptophan, and kynurenine levels as biomarkersof the Th1 immune system activation and changes in IDO-1 activityin children with asthma, allergic rhinitis, and atopic dermatitis, as well as the relationship between these biomarkers and the total IgE level, age, and disease severity. METHODS: We divided 205 children (80 girls and 125 boys, four months to 17 years old) into four groups: controls, patients with asthma, patients with allergic rhinitis, and patients with atopic dermatitis. Peripheral venous blood samples were collected. Neopterin levels were determined by an enzyme immunoassay. Tryptophan and kynurenine levels were analyzed using HPLC. IDO-1 enzyme activity was calculated using tryptophan and kynurenine levels. IgE levels were measured. The Mann-Whitney U test, Kruskal-Wallis test, and Conover post-hoc method were used for statistical analysis. RESULTS: Neopterin, tryptophan, and kynurenine levels were higher and IgE levels and IDO-1 enzyme activity were lower in patients with asthma and allergic rhinitis than in controls (P < 0.05). Patients with atopic dermatitis showed higher neopterin, tryptophan, and kynurenine levels, higher IDO-1 activity, and lower IgE levels thancontrols (P < 0.05). CONCLUSIONS: The Th1/Th2 balance is disrupted in children with allergic diseases, concomitant with increased Th1-mediated immune response activation and reduced IgEproduction, which is promoted by Th2-type cytokines.
Subject(s)
Child , Female , Humans , Asthma , Biomarkers , Chromatography, High Pressure Liquid , Cytokines , Dermatitis, Atopic , Hypersensitivity , Immune System , Immunoenzyme Techniques , Immunoglobulin E , Indoleamine-Pyrrole 2,3,-Dioxygenase , Interferon-gamma , Kynurenine , Methods , Neopterin , Rhinitis, Allergic , Tryptophan摘要
PURPOSE: Breast cancer has become a major public health threat in the current society. Anthracycline doxorubicin (DOX) is a widely used drug in breast cancer chemotherapy. We aimed to investigate the immunogenic death of breast tumor cells caused by DOX, and detect the effects of combination of DOX and a small molecule inhibitor in tumor engrafted mouse model. METHODS: We used 4T1 breast cancer cells to examine the anthracycline DOX-mediated immunogenic death of breast tumor cells by assessing the calreticulin exposure and adenosine triphosphate and high mobility group box 1 release. Using 4T1 tumor cell-engrafted mouse model, we also detected the expression of indoleamine 2,3-dioxygenase (IDO) in tumor tissues after DOX treatment and further explored whether the specific small molecule IDO1 inhibitor NLG919 combined with DOX, can exhibit better therapeutic effects on breast cancer. RESULTS: DOX induced immunogenic cell death of murine breast cancer cells 4T1 as well as the upregulation of IDO1. We also found that treatment with NLG919 enhanced kynurenine inhibition in a dose-dependent manner. IDO1 inhibition reversed CD8+ T cell suppression mediated by IDO-expressing 4T1 murine breast cancer cells. Compared to the single agent or control, combination of DOX and NLG919 significantly inhibited the tumor growth, indicating that the 2 drugs exhibit synergistic effect. The combination therapy also increased the expression of transforming growth factor-β, while lowering the expressions of interleukin-12p70 and interferon-γ. CONCLUSION: Compared to single agent therapy, combination of NLG919 with DOX demonstrated better therapeutic effects in 4T1 murine breast tumor model. IDO inhibition by NLG919 enhanced the therapeutic efficacy of DOX in breast cancer, achieving synergistic effect.