m 6A RNA Methylation Decreases Atherosclerotic Vulnerable Plaque Through Inducing T Cells

ABSTRACT Introduction: Knockdown of fat mass and obesity-associated gene (FTO) can induce N6-methyladenosine (m 6A) ribonucleic acid (RNA) methylation. The objective of this study was to explore the effect of m 6A RNA methylation on atherosclerotic vulnerable plaque by FTO knockdown. Methods: A total of 50 New Zealand white rabbits were randomly divided into pure high-fat group, sham operation group, vulnerable plaque group, empty load group, and FTO knockdown group (10 rabbits/group). Results: Flow cytometry showed that helper T (Th) cells in the FTO knockdown group accounted for a significantly higher proportion of lymphocytes than in the vulnerable plaque group and empty load group (P<0.05). Th cells were screened by cell flow. The level of m 6A RNA methylation in the FTO knockdown group was significantly higher than in the vulnerable plaque group and empty load group (P<0.05). The levels of total cholesterol, triglyceride, and low-density lipoprotein C were higher at the 12th week than at the 1st week, but the high-density lipoprotein C level was lower at the 12th week than at the 1st week. At the 12th week, the interleukin-7 level was significantly lower in the adeno-associated virus-9 (AVV9)-FTO short hairpin RNA group than in the control and AVV9-green fluorescent protein groups (P<0.001). Conclusion: After successfully establishing a vascular parkinsonism rabbit model, m 6A RNA methylation can decrease Th cells and vulnerable atherosclerotic plaques.

Alkaptonuria with IgA nephropathy: a case report and literature review / 中华肾脏病杂志

The paper reports a rare case of alkaptonuria (AKU) with IgA nephropathy, and analyzes its clinical manifestations, imaging findings, pathological features, gene diagnosis and treatment process, so as to provide reference for the diagnosis and treatment of the disease. The clinical symptoms of the patient were mainly black urine, microscopic hematuria and proteinuria. Renal pathology showed mild mesangial hyperplasia IgA nephropathy, and renal tubular epithelial cytochrome deposition. Genetic analysis indicated that a pathogenic mutation was detected on the AKU-related homogentisate 1, 2-dioxygenase gene possibly associated with the phenotype of the patient. Genetic testing and renal pathology were effective methods to make a definite diagnosis for the case.

Insight into strigolactone hormone functions in plant parasitic weeds: a regulatory perspective

The strigolactones (SLs) are plants hormones that have multiple functions in architecture and development. The roles of SLs in shoot branching and stem secondary growth of autotrophic plants are established. SL is also involved in the interaction between root parasitic plants and their host plants. SLs are exudates by the root of the host plant in search of a fungal partner for symbiotic association, while parasitic plants utilize this facility to detect the host root. The first formed tubercle of Philapanhche, whose germinations are driven by host-derived SLs, exudates parasitic derived SLs (PSLs) and could encourages germination of the adjacent parasitic seeds, resulting in parasite cluster formation. The existence of aboveground spikes in clusters suggests an intriguing approach for increasing parasite population by amplifying PSLs, which result in massive parasitic seed germination. PSLs probably have a role in the increased branching of Broomrapes opposing the host plant, resulting in the parasites' clustered appearance aboveground. This review highlights the distinct roles of SLs and PSLs, and their potential role in host-parasitic interaction.

Indoleamine-2,3-dioxygenase-related anti-inflammatory effects of 3-aminobenzamide and infliximab in experimental colitis

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.

Highly penetrable nanoparticles co-loading doxorubicin and IDO1 siRNA enhance tumor immunotherapy / 药学学报

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.

Research progress on the role of IDO signaling pathway in radiotherapy for non-small cell lung cancer / 中华放射肿瘤学杂志

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.

The functions and mechanisms of kynurenine pathway in cognitive dysfunction / 中国医师杂志

Tryptophan (TRP) is an essential amino-acid and the precursor of many signaling molecules. Under the catalysis of indoleamine 2, 3-dioxygenase, kynurenine pathway can form its metabolites uroquinolinic acid and quinolinic acid, which is the main channel of TRP metabolism.Through different mechanisms in N-methyl-D-aspartate receptor, they participate in nervous modulation, affect cognitive processes and play an important role in many central nervous system diseases development. Kynurenine pathway is different under physiological and pathological conditions. In addition, there are many rate-limiting enzymes in the kynurenine pathway, which can interfere kynurenine pathway. This article reviews the relationship between tryptophan/kynurenine pathway and cognitive dysfunction.

Progress of tryptophan and its metabolites in pathogenesis of allergic asthma / 国际儿科学杂志

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.

Genome-wide identification of CsCCD gene family in tea plant (Camellia sinensis) and expression analysis of the oolong tea processing with supplementary LED light / 生物工程学报

Carotenoid cleavage dioxygenase (CCD) family is important for production of volatile aromatic compounds and synthesis of plant hormones. To explore the biological functions and gene expression patterns of CsCCD gene family in tea plant, genome-wide identification of CsCCD gene family was performed. The gene structures, conserved motifs, chromosome locations, protein physicochemical properties, evolutionary characteristics, interaction network and cis-acting regulatory elements were predicted and analyzed. Real time-quantitative reverse transcription PCR (RT-qPCR) was used to detect the relative expression level of CsCCD gene family members under different leaf positions and light treatments during processing. A total of 11 CsCCD gene family members, each containing exons ranging from 1 to 11 and introns ranging from 0 to 10, were identified. The average number of amino acids and molecular weight were 519 aa and 57 643.35 Da, respectively. Phylogenetic analysis showed the CsCCD gene family was clustered into 5 major groups (CCD1, CCD4, CCD7, CCD8 and NCED). The CsCCD gene family mainly contained stress response elements, hormone response elements, light response elements and multi-factor response elements, and light response elements was the most abundant (142 elements). Expression analysis showed that the expression levels of CsCCD1 and CsCCD4 in elder leaves were higher than those in younger leaves and stems. With the increase of turning over times, the expression levels of CsCCD1 and CsCCD4 decreased, while supplementary LED light strongly promoted their expression levels in the early stage. The expression level of NCED in younger leaves was higher than that in elder leaves and stems on average, and the expression trend varied in the process of turning over. NCED3 first increased and then decreased, with an expression level 15 times higher than that in fresh leaves. In the late stage of turning over, supplementary LED light significantly promoted its gene expression. In conclusion, CsCCD gene family member expressions were regulated by mechanical force and light. These understandings may help to optimize tea processing techniques and improve tea quality.

Indoleamine 2, 3-dioxygenase: An important medium with the role of a double-edged sword in various liver diseases / 临床肝胆病杂志

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.

Anti-tumor activity and mechanisms of IDO1 inhibitor in combined treatment with temozolomide on human glioma cell lines / 药学学报

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.

Transcriptome-wide identification and expression analysis of 2-ODD gene family in Salvia apiana Jepson / 药学学报

2-Oxoglutarate/Fe(II)-dependent dioxygenases (2-ODD) play an important role in plant primary and secondary metabolism. Based on the high-throughput sequencing platform Illumina NovaSeq 6000, the transcriptome of Salvia apiana Jepson was sequenced, and the obtained reads were de novo assembled. A total of 38 534 unigenes were obtained from the transcriptome. The assembled unigenes were annotated and 29 982 unigenes were given functional annotations. The 2-ODD genes were identified from the assembled S. apiana transcriptome database by bioinformatics methods, and the genes were analyzed, including the homology of the sequences, physicochemical characteristics, signal peptides, transmembrane domains, subcellular localization, secondary structure and tertiary structure, etc. The evolutionary relationships and the expression patterns of the identified 2-ODD genes were also analyzed. 39 full-length 2-ODD genes were identified from the transcriptome of S. apiana. The average length of these 2-ODD encoding proteins was 320 amino acids, the molecular weight was about 36.00 kDa, and most of them were hydrophilic proteins. Phylogenetic analysis divided these 2-ODD genes into several subfamilies. Gene expression analysis indicated that the 2-ODD genes were expressed in different parts of S. apiana, and the expression level of most genes was much higher in roots than that in leaves. This study can lay a foundation for further study of 2-ODD genes in S. apiana.

Jujuboside A inhibits oxidative stress damage and enhances immunomodulatory capacity of human umbilical cord mesenchymal stem cells through up-regulating IDO expression / 中国天然药物

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.

Tryptophan 2,3-dioxygenase 2 controls M2 macrophages polarization to promote esophageal squamous cell carcinoma progression

Tryptophan 2,3-dioxygnease 2 (TDO2) is specific for metabolizing tryptophan to kynurenine (KYN), which plays a critical role in mediating immune escape of cancer. Although accumulating evidence demonstrates that TDO2 overexpression is implicated in the development and progression of multiple cancers, its tumor-promoting role in esophageal squamous cell carcinoma (ESCC) remains unclear. Here, we observed that TDO2 was overexpressed in ESCC tissues and correlated significantly with lymph node metastasis, advanced clinical stage, and unfavorable prognosis. Functional experiments showed that TDO2 promoted tumor cell proliferation, migration, and colony formation, which could be prevented by inhibition of TDO2 and aryl hydrocarbon receptor (AHR). Further experimentation demonstrated that TDO2 could promote the tumor growth of KYSE150 tumor-bearing model, tumor burden of C57BL/6 mice with ESCC induced by 4-NQO, enhance the expression of phosphorylated AKT, with subsequent phosphorylation of GSK3

Advances in research on inhibitors based on targets: IDO1 and TDO / 药学学报

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.

Research progress on indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors / 药学学报

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.

Myricetin inhibits interferon-γ-induced programmed death ligand-1 and indoleamine 2, 3-dioxygenase 1 expression in lung cancer cells / 中国药理学与毒理学杂志

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.

Role of long noncoding RNA AC073046.25 in regulation of systemic lupus erythematosus susceptibility gene TET3 expression / 上海交通大学学报（医学版）

Objective: To investigate the regulatory effect of long noncoding RNA (lncRNA) AC073046.25 on the expression of Tet methylcytosine dioxygenase 3 (TET3) in monocytes, and analyze the feasibility of AC073046.25 as a biomarker for the diagnosis of systemic lupus erythematosus (SLE). Methods: The cell specificity and function of AC073046.25 were predicted by epigenetic modification and cytoplasm/nuclear location experiment. In U-937 cells, antisense oligonucleotide (ASO) was used to knock down AC073046.25. The effect of ASO knockdown on TET3 expression was analyzed by quantitative real-time PCR. Monocytes from healthy volunteers (n=32) and SLE patients (n=46) were collected. The correlation between AC073046.25 and TET3 expression was analyzed by Pearson coefficient. Healthy volunteers were included in the healthy control group, and the SLE patients were divided into SLE-inactive group and SLE-active group according to the systemic lupus erythematosus disease activity index (SLEDAI). The differences of AC073046.25 and TET3 expression in healthy control group and different disease activity groups were compared by unpaired bilateral student's t test. Results: The epigenetic modification and cytoplasm/nuclear location experiment showed that AC073046.25 may be involved in the regulation of TET3 expression in monocytes. In U-937 cells, after ASO knocked down AC073046.25, TET3 expression level decreased (both P=0.002 in ASO groups). Correlation analysis showed that AC073046.25 expression was positively correlated with TET3 expression in primary monocytes (r=0.650, P=0.000). Unpaired bilateral student's t test showed that the expression level of AC073046.25 in the SLE-active group was lower than that in the healthy control group (P=0.002) and the SLE-inactive group (P=0.000). Conclusion: In monocytes, AC073046.25 can regulate the expression of TET3, and its expression is significantly decreased in monocytes derived from disease active SLE patients, which implicating that AC073046.25 can be thought as a biomarker for SLE disease activity diagnosis.

Progress of researches on the involvement of indoleamine 2, 3-dioxygenase in regulation of parasite-host immune interactions / 中国血吸虫病防治杂志

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.

Research progress of epigenetic regulation of vascular diseases / 中国胸心血管外科临床杂志

@#Epigenetics refers to heritable changes in gene expression independent of DNA nucleotide sequence itself, and the main mechanisms include DNA methylation, histone modifications, noncoding RNAs, and so on. Vascular disease is a chronic disease regulated by the interaction between environmental and genetic factors. In recent years, more and more studies have confirmed that epigenetic regulation plays an important role in the occurrence and development of vascular diseases. This article reviews recent advances in epigenetics in vascular disease.