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BackgroundThe four major RNA adenosine modifications, i.e., m6A, m1A, alternative polyadenylation, and adenosine-to-inosine RNA editing, are mediated mostly by the “writer” enzymes and constitute critical mechanisms of epigenetic regulation in immune response and tumorigenesis. However, the cross-talk and potential roles of these “writers” in the tumor microenvironment (TME), drug sensitivity, and immunotherapy remain unknown.MethodsWe systematically characterized mRNA expression and genetic alterations of 26 RNA modification “writers” in colorectal cancer (CRC), and evaluated their expression pattern in 1697 CRC samples from 8 datasets. We used an unsupervised clustering method to assign the samples into two patterns of expression of RNA modification “writers”. Subsequently, we constructed the RNA modification “writer” Score (WM_Score) model based on differentially expressed genes (DEGs) responsible for the RNA modification patterns to quantify the RNA modification-related subtypes of individual tumors. Furthermore, we performed association analysis for WM_Score and characteristics of TME, consensus molecular subtypes (CMSs), clinical features, transcriptional and post-transcriptional regulation, drug response, and the efficacy of immunotherapy.ResultsWe demonstrated that multi-layer alterations of RNA modification “writer” are associated with patient survival and TME cell-infiltrating characteristics. We identified two distinct RNA modification patterns, characterized by a high and a low WM_Score. The WM_Score-high group was associated with worse patient overall survival and with the infiltration of inhibitory immune cells, such as M2 macrophages, EMT activation, and metastasis, while the WM_Score-low group was associated with a survival advantage, apoptosis, and cell cycle signaling pathways. WM_Score correlated highly with the regulation of transcription and post-transcriptional events contributing to the development of CRC. In response to anti-cancer drugs, WM_Score highly negatively correlated (drug sensitive) with drugs which targeted oncogenic related pathways, such as MAPK, EGFR, and mTOR signaling pathways, positively correlated (drug resistance) with drugs which targeted in apoptosis and cell cycle. Importantly, the WM_Score was associated with the therapeutic efficacy of PD-L1 blockade, suggesting that the development of potential drugs targeting these “writers” to aid the clinical benefits of immunotherapy.ConclusionsOur study is the first to provide a comprehensive analysis of four RNA modifications in CRC. We revealed the potential function of these writers in TME, transcriptional and post-transcriptional events, and identified their therapeutic liability in targeted therapy and immunotherapy. This work highlights the cross-talk and potential clinical utility of RNA modification “writers” in cancer therapy.

Imbalance of macrophage polarization plays an indispensable role in acute lung injury (ALI), which is considered as a promising target. Matrix metalloproteinase-9 (MMP-9) is expressed in the macrophage, and has a pivotal role in secreting inflammatory cytokines. We reported that saquinavir (SQV), a first-generation human immunodeficiency virus-protease inhibitor, restricted exaggerated inflammatory response. However, whether MMP-9 could regulate macrophage polarization and inhibit by SQV is still unknown. We focused on the important role of macrophage polarization in CLP (cecal ligation puncture)-mediated ALI and determined the ability of SQV to maintain M2 over M1 phenotype partially through the inhibition of MMP-9. We also performed a limited clinical study to determine if MMP-9 is a biomarker of sepsis. Lipopolysaccharide (LPS) increased MMP-9 expression and recombinant MMP-9 (rMMP-9) exacerbated LPS-mediated M1 switching. Small interfering RNA to MMP-9 inhibited LPS-mediated M1 phenotype and SQV inhibition of this switching was reversed with rMMP-9, suggesting an important role for MMP-9 in mediating LPS-induced M1 phenotype. MMP-9 messenger RNA levels in peripheral blood mononuclear cells of these 14 patients correlated with their clinical assessment. There was a significant dose-dependent decrease in mortality and ALI after CLP with SQV. SQV significantly inhibited LPS-mediated M1 phenotype and increased M2 phenotype in cultured RAW 264.7 and primary murine bone marrow-derived macrophages as well as lung macrophages from CLP-treated mice. This study supports an important role for MMP-9 in macrophage phenotypic switching and suggests that SQV-mediated inhibition of MMP-9 may be involved in suppressing ALI during systemic sepsis.

Lake sediment records the evolution process of the interaction between human and nature. It is important to master the lacustrine sedimentation rate for the ecological environment assessment of catchment. A 60-cm sediment core was collected in the Da River Reservoir during 2019 to analyze radionuclides (

Prostaglandin E2 (PGE2) is a lipid mediator derived from the fatty acid arachidonic acid. As an essential inflammatory factor, PGE2 has a critical impact on immune regulation through the prostanoid E (EP) receptor pathway. T cells, including CD4+ and CD8+ T cell subsets, play crucial roles in the adaptive immune response. Previous studies have shown that PGE2 is involved in regulating CD4+ T cell differentiation and inflammatory cytokine production via the EP receptor pathway, thereby affecting the development of diseases mediated by CD4+ T cells. In this review, we summarize the signaling pathway of PGE2 and describe the relationship between PGE2 and T cell differentiation. Hence, this review may provide important evidence for immune therapies and may even promote the development of biomedicines.

In the last few decades, the eutrophication of lakes has been a serious issue in the middle and lower reaches of the Yangtze River watershed. To explore the relationship between lake systems and anthropogenic activities, sediments were collected from the Shuanglong reservoir in the Dianchi watershed in Southwest China. Total nitrogen (TN), total phosphorus (TP), total organic carbon (TOC), and the carbon isotopic ratio (δ13C) were analyzed in sediment cores to reconstruct the effects of natural succession and human activities on the past lacustrine environmental conditions. A reliable chronology of the sediment core was established by using the 210Pb dating technique, which indicated that the age span of the 70-cm sediment core is from the years 1871 to 2011. Above – 31 cm depth in the core, TN, TP, TOC, C/N, and δ13C increased significantly, indicating that eutrophication has occurred since the 1980s. By combining the indicators of δ13C and C/N, it was shown that terrestrial and lacustrine components were the main sources of organic matter (OM) in the reservoir, which was mostly controlled by terrestrial C3 plants and algae. Since the 1980s, increased sewage discharge, fish aquaculture, fertilizer application, population, and economic strength have sped up the eutrophication process, and the eutrophication was further intensified in 2001.

BACKGROUND HSP60-related immunological activities are found in normal-pressure glaucoma (NPG) patients, in whom an elevated intraocular pressure (IOP) found in primary open-angle glaucoma (POAG) is not observed. HSP60 was found in POAG and NPG patients, while anti-HSP60 level was mainly found to be higher in NPG patients. The purpose of this study was to compare the percentages of Th cells and levels of related cytokines, attempting to provide evidence to explain this discrepancy. MATERIAL AND METHODS Blood samples from POAG, NPG, and normal control (NC) groups were collected and peripheral blood monocytes were isolated and cultured with or without the stimulation of HSP60. Flow cytometry and enzyme-linked immunosorbent assay were used to assess the percentages of Th1, Th2, Th17, and Treg cells, as well as HSP60 antibody levels and related cytokine levels, before and after culture. RESULTS Significantly higher titers of anti-HSP60 were observed only in NPG patients. Comparable Th1 and Th2 cell frequencies, IL-4 level, and IFN-γ level were found in POAG and NPG patients, while higher Treg cell frequency was only found in POAG patients. After culturing with HSP60, increased Th2 frequencies and decreased Th1 frequencies were observed in the POAG, NPG, and NC groups, while increased Treg frequency was only identified in the POAG and NC groups. CONCLUSIONS Different Th cell patterns were observed among POAG, NPG, and NC groups. Lack of induction of Treg cells and imbalance of the pro-inflammatory and anti-inflammatory response patterns of Th cells exist in some NPG patients.

Rheumatoid arthritis (RA) is a common autoimmune disease with unknown etiology and pathogenesis. Although major therapeutic advances have been made in recent years, there is no cure for the disease. Current medications mainly reduce inflammation in order to relieve pain and slow joint damage, but many have potentially serious side effects. Therefore, to find specific biomarkers will benefit both RA patients to find relief from the disease and physicians to monitor the disease development. A number of biomarkers have been discovered and used clinically, and others are still under investigation. The autoantibodies, which are widely used in diagnosis and prognosis, novel biomarkers, which reflect clinical disease activity, and newly found biomarkers and pathogenic-related cytokines are discussed in this review.

Mutations of WD repeat domain 62 (WDR62) lead to autosomal recessive primary microcephaly (MCPH), and down-regulation of WDR62 expression causes the loss of neural progenitor cells (NPCs). However, how WDR62 is regulated and hence controls neurogenesis and brain size remains elusive. Here, we demonstrate that mitogen-activated protein kinase kinase kinase 3 (MEKK3) forms a complex with WDR62 to promote c-Jun N-terminal kinase (JNK) signaling synergistically in the control of neurogenesis. The deletion of Mekk3, Wdr62, or Jnk1 resulted in phenocopied defects, including premature NPC differentiation. We further showed that WDR62 protein is positively regulated by MEKK3 and JNK1 in the developing brain and that the defects of wdr62 deficiency can be rescued by the transgenic expression of JNK1. Meanwhile, WDR62 is also negatively regulated by T1053 phosphorylation, leading to the recruitment of F-box and WD repeat domain-containing protein 7 (FBW7) and proteasomal degradation. Our findings demonstrate that the coordinated reciprocal and bidirectional regulation among MEKK3, FBW7, WDR62, and JNK1, is required for fine-tuned JNK signaling for the control of balanced NPC self-renewal and differentiation during cortical development., Author summary Microcephaly is a neural developmental disorder characterized by significantly reduced brain size and variable intellectual disability. WD repeat domain 62 (WDR62) was identified as the second most common gene for autosomal recessive primary microcephaly (MCPH) in human. Here, we studied the underlying regulatory mechanism of WDR62 and the impact on generation of new neurons. We show that mitogen-activated protein kinase kinase kinase 3 (Mekk3), Wdr62, and c-Jun N-terminal kinase 1 (Jnk1) knockout (KO) mice have defects in the generation and maturation of neurons. We demonstrate that WDR62 stability is positively regulated by a mitogen-activated protein kinase kinase kinase (MAPKKK), MEKK3, but negatively regulated by the E3 ligase, F-box and WD repeat domain-containing protein 7 (FBW7). These positive and negative factors calibrate the strength of the activity of the JNK signaling pathway, which controls self-renewal and differentiation of neural progenitor cells (NPCs) during brain development. This finding improves our understanding of the molecular pathogenesis of MCPH.

PURPOSE: To assess the effects of dexmedetomidine on the duration of sensory and motor block, postoperative analgesia, hypotension, bradycardia, and side effects in patients undergoing spinal anesthesia. METHODS: Two researchers searched MEDLINE, EMBASE, and the Cochrane controlled trial register independently for randomized controlled trials comparing dexmedetomidine with a placebo without any language restrictions. RESULTS: A total of 412 patients from eight trials were included in this study. The results revealed that dexmedetomidine was statistically significant in prolonging the duration of sensory block (mean difference, MD = 73.55; 95% CI, [55.69, 91.40] P

Oral lichen planus (OLP) is a T cell-mediated chronic inflammatory mucosal disease, and CD4(+)CD25(+) regulatory T cells (Tregs) are considered involved in the pathogenesis of OLP. In this study, to investigate whether there are intrinsic factors that might cause functional changes in Tregs in this disease, we evaluated the frequency of Tregs in peripheral blood and oral lesions and the expression levels of function-related transcription factors, forkhead/winged-helix transcription factor box P3 (FOXP3), transforming growth factor β (TGF-β), interleukin 10 (IL-10), and TGF-β receptors (TβRI and TβRII) mRNAs in Tregs of patients with oral lichen planus (OLP). We also investigated the frequency of pro-inflammatory cytokines (IFN-γ and IL-17A) producing Foxp3(+) regulatory cells. Increased proportions of Tregs were found in OLP patients. The expression of FOXP3 on mRNA and protein level was elevated in the Tregs of OLP. The expression of TGF-β was lower both on the mRNA and serum level, whereas the expression of IL-10 showed no significant difference between the OLP patients and normal controls. The percentages of CD4(+)FOXP3(+)IL-17(+) T cells were significantly higher than that of normal controls, whereas the percentages of CD4(+)FOXP3(+)IFN-γ(+) T cells did not differ significantly. Furthermore, impaired suppressive function of CD4(+)CD25(+) T cells was demonstrated in OLP patients by in vitro proliferation assay. These data indicate that Tregs in OLP are frequently expanded but functionally deficient. This could explain, at least in part, why the increased Tregs in OLP fail to control the pathogenesis and development of this autoimmune disease.

Anakinra, a human recombinant IL-1 receptor antagonist, is approved for the treatment of RA. In this study, 12 patients received the placebo plus MTX treatment, 38 patients received Anakinra combined with MTX treatment. Compared with the placebo plus MTX group, serum levels of IL-17, IFN-γ, IL-21 and IL-1β significantly decreased, the percentages of Th17 cells and Th1 cells were lower and the percentage of Treg cells was higher after receiving Anakinra combined with MTX treatment. The observed regulatory immune responses collectively correlated with clinical improvement in treated patients. A substantial response, ACR 20 at 24 w were consistent with those at 12 w, 16 w and 20 w, and was accompanied by a marked improvement in RA related laboratory parameters. The study reveals that the combination of Anakinra and MTX is safe and well tolerated, which induces regulatory immune responses and significantly provides greater clinical benefit than the placebo plus MTX group.

IL-21 is a type I cytokine that like IL-2, IL-4, IL-7, IL-9, and IL-15 uses the common gamma chain of cytokine receptor. IL-21 has been shown to regulate the function of T cells, B cells, natural killer cells, and dendritic cells in immune responses. Although activated CD4(+) T cells produce IL-21, recent data suggest that novel subsets of effector T cells are the major producers in immune responses. In this study, we show that IL-21 expression correlates with the presence of Th17 cells in synovial fluid (SF) and peripheral blood in rheumatoid arthritis patients. Human CCR6+ CD4(+) T cells produce high levels of both IL-21 and IL-17. Similar to mouse T cells, IL-21 auto-regulates its own production in human CD4(+) T cells. IL-21 potently enhances Th17 proliferation and suppresses Foxp3 expression, leading to the expression of RORC. IL-21 is therefore an autocrine cytokine that regulates human Th17 cells in rheumatoid arthritis, and serves as a good target for treating this autoimmune disease.

Objective. To expand upon the role of iguratimod (T-614) in the treatment of rheumatoid arthritis (RA), we investigated whether the Th1, Th17, follicular helper T cells (Tfh), and regulatory T cells (Treg) imbalance could be reversed by iguratimod and the clinical implications of this reversal.Methods. In this trial, 74 patients were randomized into iguratimod-treated (group A) and control (broup B) group for a 24-week treatment period. In the subsequent 28 weeks, both groups were given iguratimod. Frequencies of Th1, Th17, Tfh, and Treg were quantified using flow cytometry, and serum cytokines were detected by enzyme-linked immunosorbent assay. mRNA expression of cytokines and transcriptional factor were quantified by RT-PCR. The composite Disease Activity Score, erythrocyte sedimentation rate, and C-reactive protein were assessed at each visit.Result. The clinical scores demonstrated effective suppression of disease after treatment with iguratimod. In addition, iguratimod downregulated Th1, Th17-type response and upregulated Treg. Furthermore, the levels of Th1, Th17, and Tfh associated inflammatory cytokines and transcription factors were reduced after treatment with iguratimod, while the levels of Treg associated cytokines and transcription factors were increased.

Objective The most recent systematic review and meta-analysis comparing the analgesic efficacy and side effects of paravertebral and epidural blockade for thoracotomy was published in 2006. Nine well-designed randomized trials with controversial results have been published since then. The present report constitutes an updated meta-analysis of this issue. Summary of Background Thoracotomy is a major surgical procedure and is associated with severe postoperative pain. Epidural analgesia is the gold standard for post-thoracotomy pain management, but has its limitations and contraindications, and paravertebral blockade is increasingly popular. However, it has not been decided whether the analgesic effect of the two methods is comparable, or whether paravertebral blockade leads to a lower incidence of adverse side effects after thoracotomy. Methods Two reviewers independently searched the databases PubMed, EMBASE, and the Cochrane Library (last performed on 1 February, 2013) for reports of studies comparing post-thoracotomy epidural analgesia and paravertebral blockade. The same individuals independently extracted data from the appropriate studies. Result Eighteen trials involving 777 patients were included in the current analysis. There was no significant difference in pain scores between paravertebral blockade and epidural analgesia at 4–8, 24, 48 hours, and the rates of pulmonary complications and morphine usage during the first 24 hours were also similar. However, paravertebral blockade was better than epidural analgesia in reducing the incidence of urinary retention (p

Interleukin-17F (IL-17F), produced by Th17 cells and other immune cells, is a member of IL-17 cytokine family with highest homology to IL-17A. IL-17F has been shown to have multiple functions in inflammatory responses. While IL-17A plays important roles in cancer development, the function of IL-17F in tumorigenesis has not yet been elucidated. In the current study, we found that IL-17F is expressed in normal human colonic epithelial cells, but this expression is greatly decreased in colon cancer tissues. To examine the roles of IL-17F in colon cancer, we have used IL-17F over-expressing colon cancer cell lines and IL-17F-deficient mice. Our data showed decreased tumor growth of IL-17F-transfected HCT116 cells comparing to mock transfectants when transplanted in nude mice. Conversely, there were increased colonic tumor numbers and tumor areas in Il-17f(-/-) mice than those from wild-type controls after colon cancer induction. These results indicate that IL-17F plays an inhibitory role in colon tumorigenesis in vivo. In IL-17F over-expressing tumors, there was no significant change in leukocyte infiltration; instead, we found decreased VEGF levels and CD31(+) cells. While the VEGF levels were increased in the colon tissues of Il-17f(-/-) mice with colon cancer. Together, our findings demonstrate a protective role for IL-17F in colon cancer development, possibly via inhibiting tumor angiogenesis.

Objective Osteopontin (OPN) that is aberrantly produced in rheumatoid synovium is thought to play an important role in rheumatoid arthritis (RA). This study was undertaken to investigate the role of OPN in the differentiation and accumulation of Th17 cells in rheumatoid synovium. Methods Peripheral blood mononuclear cells and purified CD4+ T cells derived from patients with RA or healthy controls were used to test the effect of OPN in vitro. Cytokine expression was determined by enzyme-linked immunosorbent assay and quantitative polymerase chain reaction. Intracellular staining and flow cytometry were used to detect the percentages of Th17 cells and OPN receptors. Signaling and molecular events were analyzed by immunoblotting and chromatin immunoprecipitation. Results The levels of OPN correlated significantly with interleukin-17 (IL-17) production and the frequency of Th17 cells in the synovial fluid (SF) of RA patients. Endogenous OPN produced in RA SF was responsible for markedly increased production of IL-17 in T cells, which was blocked by OPN antibody. The effect of OPN in Th17 differentiation was mediated through a mechanism independent of the IL-6/STAT-3 pathway or other cytokines and specifically involved the OPN receptors CD44 and CD29 and the transcription factor retinoic acid–related orphan receptor (ROR). Furthermore, OPN was found to induce H3 acetylation of the IL17A gene promoter, mainly through the CD44 binding domain in CD4+ T cells, allowing the interaction of the IL17A gene locus with ROR. Conclusion This study reveals new evidence of the critical role of OPN in Th17 differentiation in rheumatoid synovitis.

IFN-beta currently serves as one of the major treatments for MS. Its anti-inflammatory mechanism has been reported as involving a shift in cytokine balance from Th1 to Th2 in the T-cell response against elements of the myelin sheath. In addition to the Th1 and Th2 groups, two other important pro-inflammatory cytokines, IL-17 and osteopontin (OPN), are believed to play important roles in CNS inflammation in the pathogenesis of MS. In this study, we examined the potential effects of IFN-beta on the regulation of OPN and IL-17 in MS patients. We found that IFN-beta used in vitro at 0.5-3 ng/mL significantly inhibited the production of OPN in primary T cells derived from PBMC. The inhibition of OPN was determined to occur at the CD4(+) T-cell level. In addition, IFN-beta inhibited the production of IL-17 and IL-21 in CD4(+) T cells. It has been described that IFN-beta suppresses IL-17 production through the inhibition of a monocytic cytokine, the intracellular translational isoform of OPN. Our further investigation demonstrated that IFN-beta also acted directly on the CD4(+) T cells to regulate OPN and IL-17 expression through the type I IFN receptor-mediated activation of STAT1 and suppression of STAT3 activity. Administration of IFN-beta to EAE mice ameliorated the disease severity. Furthermore, spinal cord infiltration of OPN(+) and IL-17(+) cells decreased in IFN-beta-treated EAE mice along with decreases in serum levels of OPN and IL-21. Importantly, decreased OPN production by IFN-beta treatment contributes to the reduced migratory activity of T cells. Taken together, the results from both in vitro and in vivo experiments indicate that IFN-beta treatment can down-regulate the OPN and IL-17 production in MS. This study provides new insights into the mechanism of action of IFN-beta in the treatment of MS.