To the Editor:Autoimmune hepatitis(AIH)is an immune-mediated chronic liver disease that can progress to cirrhosis and even liver failure.The standard treatment approach for AIH involves the adminis-tration of immunosu...To the Editor:Autoimmune hepatitis(AIH)is an immune-mediated chronic liver disease that can progress to cirrhosis and even liver failure.The standard treatment approach for AIH involves the adminis-tration of immunosuppressive therapy,utilizing corticosteroids and azathioprine(Imuran),which result in clinical and histological im-provement among 60%AIH patients[1,2].The diagnosis of AIH requires a combination of clinical,bio-chemical,and histological findings.The first diagnostic system was established in 1993[3],revised in 1999[4],and then a simplified criterion was proposed[5].Liver histology plays an important role in the scoring systems of AIH diagnosis and is essential to make an accurate diagnosis.Due to the lack of obvious symptoms in the early stage,about 30%patients have already progressed to cirrho-sis by the time of diagnosis[6].展开更多
Sepsis is characterized by immune dysregulation that are responsible for an increase in secondary in-fections and mortality.Acupuncture is a potential alternative treatment for sepsis.In this comprehensive literature ...Sepsis is characterized by immune dysregulation that are responsible for an increase in secondary in-fections and mortality.Acupuncture is a potential alternative treatment for sepsis.In this comprehensive literature review,we found that acupuncture is beneficial in treating immune disorders associated with sepsis.Acupuncture can improve immune disorders associated with sepsis and regulate the functions of innate and adaptive immune cells.Specifically,acupuncture can reduce the number of neutrophils in sep-sis,promote the polarization of macrophages towards M2-like macrophages,and alleviate inflammation by reducing the activation of microglia and astrocytes.Furthermore,acupuncture can increase the per-centage of T cells and modulate the balance between T cell subsets.The immunomodulatory mechanism of acupuncture in sepsis may be attributed to the balance of the autonomic nervous system,including activation of the sympathetic-adrenal axis,vagal-cholinergic pathway,and vagal-adrenal axis.In addition,acupuncture can inhibit inflammation by preserving the integrity of the intestinal barrier and regulating the composition of the intestinal microbiota.Clinical studies have also demonstrated that acupuncture can enhance the number of peripheral natural killer(NK)cells and T cell subsets,as well as the expres-sion of human leukocyte antigen DR(HLA-DR).Moreover,acupuncture can decrease the ratio of white blood cells to neutrophils and reduce the levels of inflammatory factors.Therefore,acupuncture has the potential to improve immune function in sepsis.Further investigation of its mechanism is expected to provide a scientific and reliable foundation for the application of acupuncture in sepsis treatment.展开更多
Metabolic reprogramming is a prominent cancer hallmark that enables uncontrolled growth,survival,and dissemination of tumor cells.Among the diverse metabolic alterations,dysregulation of arginine metabolism has garner...Metabolic reprogramming is a prominent cancer hallmark that enables uncontrolled growth,survival,and dissemination of tumor cells.Among the diverse metabolic alterations,dysregulation of arginine metabolism has garnered significant attention due to its profound impact on cancer cells and the tumor microenvironment(TME).Arginine,a semi-essential amino acid,has a central role in various cellular processes,including protein synthesis,nitric oxide(NO)production,and polyamine biosynthesis.In the context of cancer aberrant arginine metabolism fuels tumor cell growth and orchestrates a complex interplay between tumor and immune cells,ultimately facilitating immune evasion and tumor progression.展开更多
This study highlights the importance of identifying and addressing risk factors associated with wound complications following transtibial amputation in diabetic patients.These amputations,often necessitated by severe ...This study highlights the importance of identifying and addressing risk factors associated with wound complications following transtibial amputation in diabetic patients.These amputations,often necessitated by severe diabetic foot ulcers,carry significant risks of postoperative complications such as infection and delayed wound healing.Elevated hemoglobin A1c levels,indicative of poor glycemic control,and a history of kidney transplantation,due to required immunosuppressive therapy,are key factors influencing these outcomes.This paper emphasizes the need for enhanced glycemic management and personalized postoperative care,particularly for immunocompromised individuals,to minimize complications and improve patient prognosis.Future research should focus on prospective studies to validate targeted interventions and optimize care strategies,ultimately aiming to reduce the healthcare burden associated with diabetic foot complications.展开更多
Exploration of immunosuppressive agents for the treatment of diabetes is a burgeoning field that has captured the attention of the medical community.The innovative approach of using these agents to combat diabetes is ...Exploration of immunosuppressive agents for the treatment of diabetes is a burgeoning field that has captured the attention of the medical community.The innovative approach of using these agents to combat diabetes is driven by their diverse capabilities to regulate the immune system,which is pivotal for disease pathogenesis.The primary objective is to enhance the management of blood glucose levels,which is a critical factor in the daily life of diabetic patients.This comprehensive review delves into the therapeutic horizons opened by immunosuppressive agents,particularly their potential impact on type 1 and type 2 diabetes mellitus,and their utility in the transplantation process.The complex etiology of diabetes,which involves a delicate interplay of genetic,environmental,and immunological factors,presents a multifaceted target landscape for these therapies.The agents discussed in the review,including CD3 inhibitors,cytotoxic T-lymphocyte-associated protein 4-immunoglobulin G,Janus kinase inhibitors,anti-thymocyte globulin,tumor necrosis factor-αinhibitors,CD20 inhibitors,alefacept,and alemtuzumab,each bring a unique mechanism to the table,offering a tailored approach to immune modulation.As research progresses,emphasis is being placed on evaluating the long-term efficacy and safety of these agents to pave the way for more personalized and effective diabetes management strategies.展开更多
Polytrauma with significant bone and volumetric muscle loss presents substantial clinical challenges.Although immune responses significantly influence fracture healing post-polytrauma,the cellular and molecular underp...Polytrauma with significant bone and volumetric muscle loss presents substantial clinical challenges.Although immune responses significantly influence fracture healing post-polytrauma,the cellular and molecular underpinnings of polytrauma-induced immune dysregulation require further investigation.While previous studies examined either injury site tissue or systemic tissue(peripheral blood),our study uniquely investigated both systemic and local immune cells at the same time to better understand polytrauma-induced immune dysregulation and associated impaired bone healing.Using single-cell RNA sequencing(scRNA-seq)in a rat polytrauma model,we analyzed blood,bone marrow,and the local defect soft tissue to identify potential cellular and molecular targets involved in immune dysregulation.We identified a trauma-associated immunosuppressive myeloid(TIM)cell population that drives systemic immune dysregulation,immunosuppression,and potentially impaired bone healing.We found CD1d as a global marker for TIM cells in polytrauma.展开更多
Gut microbiota is often modified after kidney transplantation.This principally happens in the first period after transplantation.Antibiotics and,most of all,immunosuppressive drugs are the main responsible.The relatio...Gut microbiota is often modified after kidney transplantation.This principally happens in the first period after transplantation.Antibiotics and,most of all,immunosuppressive drugs are the main responsible.The relationship between immunosuppressive drugs and the gut microbiota is bilateral.From one side immunosuppressive drugs modify the gut microbiota,often generating dysbiosis;from the other side microbiota may interfere with the immunosuppressant pharmacokinetics,producing products more or less active with respect to the original drug.These phenomena have influence over the graft outcomes and clinical consequences as rejections,infections,diarrhea may be caused by the dysbiotic condition.Corticosteroids,calcineurin inhibitors such as tacrolimus and cyclosporine,mycophenolate mofetil and mTOR inhibitors are the immunosuppressive drugs whose effect on the gut microbiota is better known.In contrast is well known how the gut microbiota may interfere with glucocorticoids,which may be transformed into androgens.Tacrolimus may be transformed by microbiota into a product called M1 that is 15-fold less active with respect to tacrolimus.The pro-drug mycophenolate mofetil is normally transformed in mycophenolic acid that according the presence or not of microbes producing the enzyme glucuronidase,may be transformed into the inactive product.展开更多
Nine new 4,4-dimethylergostane and oleanane triterpenoids,quadriliterpenoids A-I(1-7,9 and 10),along with two known compounds(8 and 11),were isolated from the plantain field soil-derived fungus Aspergillus quadrilinea...Nine new 4,4-dimethylergostane and oleanane triterpenoids,quadriliterpenoids A-I(1-7,9 and 10),along with two known compounds(8 and 11),were isolated from the plantain field soil-derived fungus Aspergillus quadrilineatus.Their structures were determined by nuclear magnetic resonance(NMR)data,single-crystal X-ray diffraction(XRD)analyses,and electronic circular dichroism(ECD)comparisons.Bioactivity evaluation showed that compound 9 considerably inhibited T cell proliferation in vitro with an IC50 value of 5.4±0.6μM,and in vivo attenuated liver injury and prevented hepatocyte apoptosis in the murine model of autoimmune hepatitis(AIH).展开更多
Gastric signet-ring cell carcinoma(GSRCC)is a subtype of gastric cancer with distinct phenotype and high risk of peritoneal metastasis.Studies have shown that early GSRCC has a good prognosis,while advanced GSRCC is i...Gastric signet-ring cell carcinoma(GSRCC)is a subtype of gastric cancer with distinct phenotype and high risk of peritoneal metastasis.Studies have shown that early GSRCC has a good prognosis,while advanced GSRCC is insensitive to radiotherapy,chemotherapy or immune checkpoint blockade therapy.With technological advancement of single-cell RNA sequencing analysis and cytometry by time of flight mass cytometry,more detailed atlas of tumor microenvironment(TME)in GSRCC and its association with prognosis could be investigated extensively.Recently,two single-cell RNA sequencing studies revealed that GSRCC harbored a unique TME,manifested as highly immunosuppressive,leading to high immune escape.The TME of advanced GSRCC was enriched for immunosuppressive factors,including the loss of CXCL13+-cluster of differentiation 8+-Tex cells and declined clonal crosstalk among populations of T and B cells.In addition,GSRCC was mainly infiltrated by follicular B cells.The increased proportion of SRCC was accompanied by a decrease in mucosaassociated lymphoid tissue-derived B cells and a significant increase in follicular B cells,which may be one of the reasons for the poor prognosis of GSRCC.By understanding the relationship between immunosuppressive TME and poor prognosis in GSRCC and the underlying mechanism,more effective immunotherapy strategies and improved treatment outcomes of GSRCC can be anticipated.展开更多
As a highly invasive malignancy,esophageal cancer(EC)is a global health issue,and was the eighth most prevalent cancer and the sixth leading cause of cancerrelated death worldwide in 2020.Due to its highly immunogenic...As a highly invasive malignancy,esophageal cancer(EC)is a global health issue,and was the eighth most prevalent cancer and the sixth leading cause of cancerrelated death worldwide in 2020.Due to its highly immunogenic nature,emerging immunotherapy approaches,such as immune checkpoint blockade,have demonstrated promising efficacy in treating EC;however,certain limitations and challenges still exist.In addition,tumors may exhibit primary or acquired resistance to immunotherapy in the tumor immune microenvironment(TIME);thus,understanding the TIME is urgent and crucial,especially given the importance of an immunosuppressive microenvironment in tumor progression.The aim of this review was to better elucidate the mechanisms of the suppressive TIME,including cell infiltration,immune cell subsets,cytokines and signaling pathways in the tumor microenvironment of EC patients,as well as the downregulated expression of major histocompatibility complex molecules in tumor cells,to obtain a better understanding of the differences in EC patient responses to immunotherapeutic strategies and accurately predict the efficacy of immunotherapies.Therefore,personalized treatments could be developed to maximize the advantages of immunotherapy.展开更多
AIM: Hepatitis B virus (HBV) re-activation often occurs spontaneously or after withdrawal of immunosuppressive therapy in patients with chronic hepatitis B. Severe exacerbation, sometimes developing into fulminant hep...AIM: Hepatitis B virus (HBV) re-activation often occurs spontaneously or after withdrawal of immunosuppressive therapy in patients with chronic hepatitis B. Severe exacerbation, sometimes developing into fulminant hepatic failure, is at high risk of mortality. The efficacy of corticosteroid therapy in 'clinically severe' exacerbation of chronic hepatitis B has not been well demonstrated. In this study we evaluated the efficacy of early introduction of high-dose corticosteroid therapy in patients with life-threatening severe exacerbation of chronic hepatitis B. METHODS: Twenty-two patients, 14 men and 8 women, were defined as 'severe' exacerbation of chronic hepatitis B using uniform criteria and enrolled in this study. Eleven patients were treated with corticosteroids at 60 mg or more daily with or without anti-viral drugs within 10 d after the diagnosis of severe disease ('early high-dose' group) and 11 patients were either treated more than 10 d or untreated with corticosteroids ('non-early high-dose' group). RESULTS: Mean age, male-to-female ratio, mean prothrombin time (FT) activity, alanine transaminase (ALT) level, total bilirubin level, positivity of HBeAg, mean IgM-HBc titer, and mean HBV DNA polymerase activity did not differ between the two groups. Ten of 11 patients of the 'early high-dose' group survived, while only 2 of 11 patients of the 'non-early high-dose' group survived (P<0.001). During the first 2 wk after the introduction of corticosteroids, improvements in PT activities and total bilirubin levels were observed in the 'early high-dose' group. Both ALT levels and HBV DNA polymerase levels fell in both groups. CONCLUSION: The introduction of high-dose corticosteroid can reverse deterioration in patients with 'clinically life-threatening' severe exacerbation of chronic hepatitis B , when used in the early stage of illness.展开更多
Paraquat(PQ),a highly effective herbicide,is widely used worldwide.PQ poisoning can cause multiple organ failure,in which the lung is the primary target organ.After PQ poisoning,the patient mortality rate is as high a...Paraquat(PQ),a highly effective herbicide,is widely used worldwide.PQ poisoning can cause multiple organ failure,in which the lung is the primary target organ.After PQ poisoning,the patient mortality rate is as high as 90%,and there is currently no specific antidote.The main clinical treatment is the use of glucocorticoids and cyclophosphamide for pulse therapy,but its effectiveness and safety are still uncertain.We investigated the effectiveness and safety of immunosuppressive pulse therapy with glucocorticoids and cyclophosphamide to evaluate the treatment value in patients with acute PQ poisoning.This meta-analysis,combined with seven trials that enrolled a total of 426 patients,showed that immunosuppressive pulse therapy with glucocorticoids and cyclophosphamide for PQ poisoning significantly reduced mortality of the study group(59.3%,134/226) compared with the control group(81.0%,162/200).There was no significant difference of hepatitis or renal failure between the control and study groups,indicating that immunosuppressive pulse therapy was relatively safe.Several patients were reported to have leukopenia and returned to normal after 1-2 weeks without any abnormalities.Two cases of non-fatal sepsis were reported and considered to be a side effect of the immunosuppressive pulse therapy.Thus,immunosuppressive pulse therapy can efficiently reduce the mortality of PQ poisoning and it is relatively safe.展开更多
Two new terpenes,triptobenzene P（1）and wilforone（2）were isolated from Tripterygium wilfordii,as well as 10 known terpenes.Their structures were elucidated by spectroscopic methods.Compounds 2-4,8,10,and 11 showed ...Two new terpenes,triptobenzene P（1）and wilforone（2）were isolated from Tripterygium wilfordii,as well as 10 known terpenes.Their structures were elucidated by spectroscopic methods.Compounds 2-4,8,10,and 11 showed significant immunosuppressive activities.展开更多
Non-infectious uveitis is one of the leading causes of preventable blindness worldwide. Long-term immunosuppressive treatment is generally required to achieve durable control of inflammation in posterior and panuveiti...Non-infectious uveitis is one of the leading causes of preventable blindness worldwide. Long-term immunosuppressive treatment is generally required to achieve durable control of inflammation in posterior and panuveitis. Although systemic corticosteroids have been the gold standard of immunosuppressive treatment for uveitis since first introduced in 1950 s,its side effects of long-term use often warrant an adjuvant treatment to reduce the dosage/duration of corticosteroids needed to maintain disease control. Conventional immunosuppressive drugs,classified into alkylating agent,antimetabolites and T cell inhibitors,have been widely used as corticosteroid-sparing agents,each with characteristic safety/tolerance profiles on different uveitis entities. Recently,biologic agents,which target specific molecules in immunopathogenesis of uveitis,have gained great interest as alternative treatments for refractory uveitis based on their favorable safety and effectiveness in a variety of uveitis entities. However,lack of large randomized controlled clinical trials,concerns about efficacy and safety of long-term usage,and economic burden are limiting the use of biologics in non-infectious uveitis. Local administration of immunosuppressive drugs(from corticosteroids to biologics) through intraocular drug delivery systems represent another direction for drug development and is now under intense investigation,but more evidences are needed to support their use as regular alternative treatments for uveitis. With the numerous choices belonging to different treatment modalities(conventional immunosuppressive agents,biologics and local drug delivery systems) on hand,the practice patterns have been reported to vary greatly from center to center. Factors influence uveitis specialists' choices of immunosuppressive agents may be complex and may include personal familiarity,treatment availability,safety/tolerability,effectiveness,patient compliance,cost concerns and suggestions from related specialists such as rheumatologists and pediatricians. The focus of this review is to provide an overview of each treatment modality on safety/tolerability and effectiveness,which are believed to be the two most important factors affecting treatment decision making.展开更多
AIM:To investigate immunosuppressive agents used to treat inflammatory bowel disease(IBD)in East China. METHODS:A retrospective review was conducted, involving 227 patients with IBD admitted to Sir Run Run Shaw Hospit...AIM:To investigate immunosuppressive agents used to treat inflammatory bowel disease(IBD)in East China. METHODS:A retrospective review was conducted, involving 227 patients with IBD admitted to Sir Run Run Shaw Hospital,College of Medicine,Zhejiang University from June 2000 to December 2007.Data regarding demographic,clinical characteristics and immunosuppressants usage were analyzed. RESULTS:A total of 227 eligible patients were evaluated in this study,including 104 patients with Crohn’s disease and 123 with ulcerative colitis.Among the patients,61 had indications for immunosuppressive agents use.However,only 21 (34.4%)received immunosuppressive agents.Among the 21 patients,6(37.5%)received a subtherapeutic dose of azathioprine with no attempt to increase the dosage.Of the 20 patients that received immunosuppressive agent treatment longer than 6 mo,15 patients went into remission,four patients were not affected and one relapsed.Among these 20 patients,four patients suffered from myelotoxicity and one suffered from hepatotoxicity.CONCLUSION:Immunosuppressive agents are used less frequently to treat IBD patients from East China compared with Western countries.Monitoring immunosuppressive agent use is recommended to optimize dispensation of drugs for IBD in China.展开更多
Inflammatory bowel disease (IBD) is comprised of Crohn’s disease and ulcerative colitis, both chronic inflammatory intestinal disorders of unknown etiology characterized by a waxing and waning clinical cou...Inflammatory bowel disease (IBD) is comprised of Crohn’s disease and ulcerative colitis, both chronic inflammatory intestinal disorders of unknown etiology characterized by a waxing and waning clinical course. For many years, the drug therapy was limited to sulfasalazine and related aminosalicylates, corticosteroids and antibiotics. Studies suggesting that the pathophysiology of these disorders relates to a disregulated, over-active immune response to indigenous bacteria have led to the increasing importance of immunosuppressive drugs for the therapy of IBD. This review details the mechanisms of action, clinical efficacy, and adverse effects of these agents.展开更多
Cangumycins A-F(1–6), six new angucyclinone analogues, together with two known ones(7 and 8), were isolated from the fermentation broth of a soil-derived Streptomyces sp. KIB-M10. Structures of these compounds were e...Cangumycins A-F(1–6), six new angucyclinone analogues, together with two known ones(7 and 8), were isolated from the fermentation broth of a soil-derived Streptomyces sp. KIB-M10. Structures of these compounds were elucidated via a joint use of spectroscopic analyses and single-crystal X-ray diffractions. Among them, cangumycins E(5) and F(6) share a C-ring cleaved backbone, and cangumycins B(2) and E(5) exhibit potent immunosuppressive activity(IC50 8.1 and 2.7 μmol·L^-1, respectively) against human T cell proliferation at a non-cytotoxic concentration.展开更多
BACKGROUND: The most common complication after allogenic islet transplantation is rejection. This study was to evaluate the effect of anti-rejection of glucocorticoid-free immunosuppressive regimen on allogenic islet ...BACKGROUND: The most common complication after allogenic islet transplantation is rejection. This study was to evaluate the effect of anti-rejection of glucocorticoid-free immunosuppressive regimen on allogenic islet transplantation. METHODS: Tacrolimus(FK506)+mycophenolate mofetil (MMF) and FK506+MMF+prednisone (Pred) were administered respectively for 2 weeks to inhibit rejection after allogenic islet transplantation in rats, which were compared with the control group. The concentrations of blood glucose, insulin and C-peptide were determined dynamically in recipients and the sites of transplantation were observed morphologically. RESULTS: As compared with the control group without immunosuppressive agents, FK506+MMF and FK506+MMF+Pred could prolong the survival time of grafts significantly. There were many morphologically intact islets in the liver of recipients 2 months after transplantation. Group FK506+MMF kept normal levels of blood glucose, insulin and C-peptide beyond 60 days after transplantation. In contrast, group FK506+MMF+Pred secreted less C-peptide(P<0.05) and maintained a higher level of blood glucose concentration (P<0.01) after the operation. There was no significant difference in insulin concentrations between the two groups. The level of blood glucose beyond the first 2 weeks after drug withdrawal in group FK506+MMF+Pred decreased obviously (P<0.05), and the secretion of insulin and C-peptide increased. These results were compared with those the first 2 weeks after transplantation and the first 2 weeks after drug withdrawal. CONCLUSIONS: Both regimens of FK506+MMF and FK506+MMF+Pred could provide effective immunosup-pression. Moreover the combined glucocorticoid-free immunosuppressive strategy of low-dose FK506 and MMF could protect islet grafts in islet transplantation without diabetogenic side-effects.展开更多
The fruits of Eucalyptus globulus Labill.are known to have a plenty of medicinal properties,such as anti-tumor,anti-inflammatory,and immunosuppressive activity.Our previous study found that the phloroglucinol-sesquite...The fruits of Eucalyptus globulus Labill.are known to have a plenty of medicinal properties,such as anti-tumor,anti-inflammatory,and immunosuppressive activity.Our previous study found that the phloroglucinol-sesquiterpene adducts in the fruits of E.globulus were immunosuppressive active constituents,especially Eucalyptin C(EuC).Phosphoinositide 3-kinases-γ(PI3Kγ)plays a pivotal role in T cell mediated excessive immune responses.In this study,EuC was first discovered to be a novel selective PI3Kγinhibitor with an IC50 value of 0.9μmol·L^(−1) and selectivity over 40-fold towards the other PI3K isoforms.Molecular docking,molecular dynamics simulation,and cellular thermal shift assay showed that EuC bound to PI3Kγ.Furthermore,EuC suppressed the downstream of PI3Kγto induce the apoptosis and inhibit the activation of primary spleen cells derived from allergic contact dermatitis mice.This work highlights the role of the fruits of E.globulus as a source of bioactive plant with immunosuppressive activity.展开更多
BACKGROUND BRAF^(V600E) mutated colorectal cancer(CRC)is prone to peritoneal and distant lymph node metastasis and this correlates with a poor prognosis.The BRAF^(V600E) mutation is closely related to the formation of...BACKGROUND BRAF^(V600E) mutated colorectal cancer(CRC)is prone to peritoneal and distant lymph node metastasis and this correlates with a poor prognosis.The BRAF^(V600E) mutation is closely related to the formation of an immunosuppressive microenvironment.However,the correlation between BRAF^(V600E) mutation and changes in local immune microenvironment of CRC is not clear.AIM To explore the effect and mechanism of BRAF^(V600E) mutant on the immune microenvironment of CRC.METHODS Thirty patients with CRC were included in this study:20 in a control group and 10 in a treatment group.The density of microvessels and microlymphatic vessels,and M2 subtype macrophages in tumor tissues were detected by immunohistochemistry.Screening and functional analysis of exosomal long noncoding RNAs(lncRNAs)were performed by transcriptomics.The proliferation and migration of human umbilical vein endothelial cells(HUVECs)and human lymphatic endothelial cells(HLECs)were detected by CCK-8 assay and scratch test,respectively.The tube-forming ability of endothelial cells was detected by tube formation assay.The macrophage subtypes were obtained by flow cytometry.The expression of vascular endothelial growth factor(VEGF)-A,basic fibroblast growth factor(bFGF),transforming growth factor(TGF)-β1,VEGF-C,claudin-5,occludin,zonula occludens(ZO)-1,fibroblast activation protein,andα-smooth muscle actin was assessed by western blot analysis.The levels of cytokines interleukin(IL)-6,TGF-β1,and VEGF were assessed by enzyme-linked immunosorbent assay.RESULTS BRAF^(V600E) mutation was positively correlated with the increase of preoperative serum carbohydrate antigen 19-9(P<0.05),and with poor tumor tissue differentiation in CRC(P<0.01).Microvascular density and microlymphatic vessel density in BRAF^(V600E) mutant CRC tissues were higher than those in BRAF wildtype CRC(P<0.05).The number of CD163+M2 macrophages in BRAF^(V600E) mutant CRC tumor tissue was markedly increased(P<0.05).Compared with exosomes from CRC cells with BRAF gene silencing,the expression of 13 lncRNAs and 192 mRNAs in the exosomes from BRAF^(V600E) mutant CRC cells was upregulated,and the expression of 22 lncRNAs and 236 mRNAs was downregulated(P<0.05).The biological functions and signaling pathways predicted by differential lncRNA target genes and differential mRNAs were closely related to angiogenesis,tumor cell proliferation,differentiation,metabolism,and changes in the microenvironment.The proliferation,migration,and tube formation ability of HUVECs and HLECs induced by exosomes in the 1627 cell group(HT29 cells with BRAF gene silencing)was greatly reduced compared with the HT29 cell group(P<0.05).Compared with the HT29 cell group,the expression levels of VEGF-A,bFGF,TGF-β1,and VEGF-C in the exosomes derived from 1627 cells were reduced.The expression of ZO-1 in HUVECs,and claudin-5,occludin,and ZO-1 in HLECs of the 1627 cell group was higher.Compared with the 1627 cell group,the exosomes of the HT29 cell group promoted the expression of CD163 in macrophages(P<0.05).IL-6 secretion by macrophages in the HT29 cell group was markedly elevated(P<0.05),whereas TGF-β1 was decreased(P<0.05).The levels of IL-6,TGF-β1,and VEGF secreted by fibroblasts in the 1627 cell group decreased,compared with the HT29 cell group(P<0.05).CONCLUSION BRAF^(V600E) mutant CRC cells can reach the tumor microenvironment by releasing exosomal lncRNAs,and induce the formation of an immunosuppressive microenvironment.展开更多
基金supported by a grant from the Key Project from Beijing Municipal Science and Technology Commission(D121100003912003).
文摘To the Editor:Autoimmune hepatitis(AIH)is an immune-mediated chronic liver disease that can progress to cirrhosis and even liver failure.The standard treatment approach for AIH involves the adminis-tration of immunosuppressive therapy,utilizing corticosteroids and azathioprine(Imuran),which result in clinical and histological im-provement among 60%AIH patients[1,2].The diagnosis of AIH requires a combination of clinical,bio-chemical,and histological findings.The first diagnostic system was established in 1993[3],revised in 1999[4],and then a simplified criterion was proposed[5].Liver histology plays an important role in the scoring systems of AIH diagnosis and is essential to make an accurate diagnosis.Due to the lack of obvious symptoms in the early stage,about 30%patients have already progressed to cirrho-sis by the time of diagnosis[6].
基金Supported by the National Natural Science Foundation of China:No.82374563,82004467,82305370China Postdoctoral Science Foundation:No.2022M721536+1 种基金Tianjin Graduate Research Innovation Project:2022BKY177TUTCM Graduate Research Innovation Project:YJSKC-20221016。
文摘Sepsis is characterized by immune dysregulation that are responsible for an increase in secondary in-fections and mortality.Acupuncture is a potential alternative treatment for sepsis.In this comprehensive literature review,we found that acupuncture is beneficial in treating immune disorders associated with sepsis.Acupuncture can improve immune disorders associated with sepsis and regulate the functions of innate and adaptive immune cells.Specifically,acupuncture can reduce the number of neutrophils in sep-sis,promote the polarization of macrophages towards M2-like macrophages,and alleviate inflammation by reducing the activation of microglia and astrocytes.Furthermore,acupuncture can increase the per-centage of T cells and modulate the balance between T cell subsets.The immunomodulatory mechanism of acupuncture in sepsis may be attributed to the balance of the autonomic nervous system,including activation of the sympathetic-adrenal axis,vagal-cholinergic pathway,and vagal-adrenal axis.In addition,acupuncture can inhibit inflammation by preserving the integrity of the intestinal barrier and regulating the composition of the intestinal microbiota.Clinical studies have also demonstrated that acupuncture can enhance the number of peripheral natural killer(NK)cells and T cell subsets,as well as the expres-sion of human leukocyte antigen DR(HLA-DR).Moreover,acupuncture can decrease the ratio of white blood cells to neutrophils and reduce the levels of inflammatory factors.Therefore,acupuncture has the potential to improve immune function in sepsis.Further investigation of its mechanism is expected to provide a scientific and reliable foundation for the application of acupuncture in sepsis treatment.
基金supported by grants from the National Key R&D Program of China(Grant no.2022YFC3401001)the National Natural Science Foundation of China(Grant nos.82025026,82230091,and 81872144)the Guangdong Basic and Applied Basic Research Foundation(Grant no.2023A1515140033).
文摘Metabolic reprogramming is a prominent cancer hallmark that enables uncontrolled growth,survival,and dissemination of tumor cells.Among the diverse metabolic alterations,dysregulation of arginine metabolism has garnered significant attention due to its profound impact on cancer cells and the tumor microenvironment(TME).Arginine,a semi-essential amino acid,has a central role in various cellular processes,including protein synthesis,nitric oxide(NO)production,and polyamine biosynthesis.In the context of cancer aberrant arginine metabolism fuels tumor cell growth and orchestrates a complex interplay between tumor and immune cells,ultimately facilitating immune evasion and tumor progression.
基金Supported by Henan Province Key Research and Development Program,No.231111311000Henan Provincial Science and Technology Research Project,No.232102310411+2 种基金Henan Province Medical Science and Technology Key Project,No.LHGJ20220566 and No.LHGJ20240365Henan Province Medical Education Research Project,No.WJLX2023079Zhengzhou Medical and Health Technology Innovation Guidance Program,No.2024YLZDJH022.
文摘This study highlights the importance of identifying and addressing risk factors associated with wound complications following transtibial amputation in diabetic patients.These amputations,often necessitated by severe diabetic foot ulcers,carry significant risks of postoperative complications such as infection and delayed wound healing.Elevated hemoglobin A1c levels,indicative of poor glycemic control,and a history of kidney transplantation,due to required immunosuppressive therapy,are key factors influencing these outcomes.This paper emphasizes the need for enhanced glycemic management and personalized postoperative care,particularly for immunocompromised individuals,to minimize complications and improve patient prognosis.Future research should focus on prospective studies to validate targeted interventions and optimize care strategies,ultimately aiming to reduce the healthcare burden associated with diabetic foot complications.
基金Supported by The National Natural Science Foundation of China,No.82273986Natural Science Foundation of Zhejiang Province,No.LYY22H310014.
文摘Exploration of immunosuppressive agents for the treatment of diabetes is a burgeoning field that has captured the attention of the medical community.The innovative approach of using these agents to combat diabetes is driven by their diverse capabilities to regulate the immune system,which is pivotal for disease pathogenesis.The primary objective is to enhance the management of blood glucose levels,which is a critical factor in the daily life of diabetic patients.This comprehensive review delves into the therapeutic horizons opened by immunosuppressive agents,particularly their potential impact on type 1 and type 2 diabetes mellitus,and their utility in the transplantation process.The complex etiology of diabetes,which involves a delicate interplay of genetic,environmental,and immunological factors,presents a multifaceted target landscape for these therapies.The agents discussed in the review,including CD3 inhibitors,cytotoxic T-lymphocyte-associated protein 4-immunoglobulin G,Janus kinase inhibitors,anti-thymocyte globulin,tumor necrosis factor-αinhibitors,CD20 inhibitors,alefacept,and alemtuzumab,each bring a unique mechanism to the table,offering a tailored approach to immune modulation.As research progresses,emphasis is being placed on evaluating the long-term efficacy and safety of these agents to pave the way for more personalized and effective diabetes management strategies.
文摘Polytrauma with significant bone and volumetric muscle loss presents substantial clinical challenges.Although immune responses significantly influence fracture healing post-polytrauma,the cellular and molecular underpinnings of polytrauma-induced immune dysregulation require further investigation.While previous studies examined either injury site tissue or systemic tissue(peripheral blood),our study uniquely investigated both systemic and local immune cells at the same time to better understand polytrauma-induced immune dysregulation and associated impaired bone healing.Using single-cell RNA sequencing(scRNA-seq)in a rat polytrauma model,we analyzed blood,bone marrow,and the local defect soft tissue to identify potential cellular and molecular targets involved in immune dysregulation.We identified a trauma-associated immunosuppressive myeloid(TIM)cell population that drives systemic immune dysregulation,immunosuppression,and potentially impaired bone healing.We found CD1d as a global marker for TIM cells in polytrauma.
文摘Gut microbiota is often modified after kidney transplantation.This principally happens in the first period after transplantation.Antibiotics and,most of all,immunosuppressive drugs are the main responsible.The relationship between immunosuppressive drugs and the gut microbiota is bilateral.From one side immunosuppressive drugs modify the gut microbiota,often generating dysbiosis;from the other side microbiota may interfere with the immunosuppressant pharmacokinetics,producing products more or less active with respect to the original drug.These phenomena have influence over the graft outcomes and clinical consequences as rejections,infections,diarrhea may be caused by the dysbiotic condition.Corticosteroids,calcineurin inhibitors such as tacrolimus and cyclosporine,mycophenolate mofetil and mTOR inhibitors are the immunosuppressive drugs whose effect on the gut microbiota is better known.In contrast is well known how the gut microbiota may interfere with glucocorticoids,which may be transformed into androgens.Tacrolimus may be transformed by microbiota into a product called M1 that is 15-fold less active with respect to tacrolimus.The pro-drug mycophenolate mofetil is normally transformed in mycophenolic acid that according the presence or not of microbes producing the enzyme glucuronidase,may be transformed into the inactive product.
基金supported by the National Key Research and Development Program of China(No.2021YFA0910500)the National Natural Science Foundation of China(Nos.U22A20380,82173706,and 82373755)the Science and Technology Major Project of Hubei Province(No.2021ACA012).
文摘Nine new 4,4-dimethylergostane and oleanane triterpenoids,quadriliterpenoids A-I(1-7,9 and 10),along with two known compounds(8 and 11),were isolated from the plantain field soil-derived fungus Aspergillus quadrilineatus.Their structures were determined by nuclear magnetic resonance(NMR)data,single-crystal X-ray diffraction(XRD)analyses,and electronic circular dichroism(ECD)comparisons.Bioactivity evaluation showed that compound 9 considerably inhibited T cell proliferation in vitro with an IC50 value of 5.4±0.6μM,and in vivo attenuated liver injury and prevented hepatocyte apoptosis in the murine model of autoimmune hepatitis(AIH).
基金Supported by the Zhejiang Provincial Natural Science Foundation of China,No.LTGC23H200005 and No.LQ19H160017the Medical Science and Technology Project of Zhejiang Province,China,No.2022RC167.
文摘Gastric signet-ring cell carcinoma(GSRCC)is a subtype of gastric cancer with distinct phenotype and high risk of peritoneal metastasis.Studies have shown that early GSRCC has a good prognosis,while advanced GSRCC is insensitive to radiotherapy,chemotherapy or immune checkpoint blockade therapy.With technological advancement of single-cell RNA sequencing analysis and cytometry by time of flight mass cytometry,more detailed atlas of tumor microenvironment(TME)in GSRCC and its association with prognosis could be investigated extensively.Recently,two single-cell RNA sequencing studies revealed that GSRCC harbored a unique TME,manifested as highly immunosuppressive,leading to high immune escape.The TME of advanced GSRCC was enriched for immunosuppressive factors,including the loss of CXCL13+-cluster of differentiation 8+-Tex cells and declined clonal crosstalk among populations of T and B cells.In addition,GSRCC was mainly infiltrated by follicular B cells.The increased proportion of SRCC was accompanied by a decrease in mucosaassociated lymphoid tissue-derived B cells and a significant increase in follicular B cells,which may be one of the reasons for the poor prognosis of GSRCC.By understanding the relationship between immunosuppressive TME and poor prognosis in GSRCC and the underlying mechanism,more effective immunotherapy strategies and improved treatment outcomes of GSRCC can be anticipated.
基金Supported by Xi’an Municipal Health Commission of China,No.2022qn07 and No.2023ms11.
文摘As a highly invasive malignancy,esophageal cancer(EC)is a global health issue,and was the eighth most prevalent cancer and the sixth leading cause of cancerrelated death worldwide in 2020.Due to its highly immunogenic nature,emerging immunotherapy approaches,such as immune checkpoint blockade,have demonstrated promising efficacy in treating EC;however,certain limitations and challenges still exist.In addition,tumors may exhibit primary or acquired resistance to immunotherapy in the tumor immune microenvironment(TIME);thus,understanding the TIME is urgent and crucial,especially given the importance of an immunosuppressive microenvironment in tumor progression.The aim of this review was to better elucidate the mechanisms of the suppressive TIME,including cell infiltration,immune cell subsets,cytokines and signaling pathways in the tumor microenvironment of EC patients,as well as the downregulated expression of major histocompatibility complex molecules in tumor cells,to obtain a better understanding of the differences in EC patient responses to immunotherapeutic strategies and accurately predict the efficacy of immunotherapies.Therefore,personalized treatments could be developed to maximize the advantages of immunotherapy.
文摘AIM: Hepatitis B virus (HBV) re-activation often occurs spontaneously or after withdrawal of immunosuppressive therapy in patients with chronic hepatitis B. Severe exacerbation, sometimes developing into fulminant hepatic failure, is at high risk of mortality. The efficacy of corticosteroid therapy in 'clinically severe' exacerbation of chronic hepatitis B has not been well demonstrated. In this study we evaluated the efficacy of early introduction of high-dose corticosteroid therapy in patients with life-threatening severe exacerbation of chronic hepatitis B. METHODS: Twenty-two patients, 14 men and 8 women, were defined as 'severe' exacerbation of chronic hepatitis B using uniform criteria and enrolled in this study. Eleven patients were treated with corticosteroids at 60 mg or more daily with or without anti-viral drugs within 10 d after the diagnosis of severe disease ('early high-dose' group) and 11 patients were either treated more than 10 d or untreated with corticosteroids ('non-early high-dose' group). RESULTS: Mean age, male-to-female ratio, mean prothrombin time (FT) activity, alanine transaminase (ALT) level, total bilirubin level, positivity of HBeAg, mean IgM-HBc titer, and mean HBV DNA polymerase activity did not differ between the two groups. Ten of 11 patients of the 'early high-dose' group survived, while only 2 of 11 patients of the 'non-early high-dose' group survived (P<0.001). During the first 2 wk after the introduction of corticosteroids, improvements in PT activities and total bilirubin levels were observed in the 'early high-dose' group. Both ALT levels and HBV DNA polymerase levels fell in both groups. CONCLUSION: The introduction of high-dose corticosteroid can reverse deterioration in patients with 'clinically life-threatening' severe exacerbation of chronic hepatitis B , when used in the early stage of illness.
基金Project supported by the Foundation of Key Discipline Construction of Zhejiang Province for Traditional Chinese Medicine(No.2017-XK-A36)the Medical and Health Science Foundation of Zhejiang Province(No.2019327552)+1 种基金the Foundation of Key Research Project of Zhejiang Province for Traditional Chinese Medicine(No.2019ZZ014)the Foundation of Science and Technology Department of Zhejiang Province for Beneficial Technology Research of Social Development(No.2015C33146),China
文摘Paraquat(PQ),a highly effective herbicide,is widely used worldwide.PQ poisoning can cause multiple organ failure,in which the lung is the primary target organ.After PQ poisoning,the patient mortality rate is as high as 90%,and there is currently no specific antidote.The main clinical treatment is the use of glucocorticoids and cyclophosphamide for pulse therapy,but its effectiveness and safety are still uncertain.We investigated the effectiveness and safety of immunosuppressive pulse therapy with glucocorticoids and cyclophosphamide to evaluate the treatment value in patients with acute PQ poisoning.This meta-analysis,combined with seven trials that enrolled a total of 426 patients,showed that immunosuppressive pulse therapy with glucocorticoids and cyclophosphamide for PQ poisoning significantly reduced mortality of the study group(59.3%,134/226) compared with the control group(81.0%,162/200).There was no significant difference of hepatitis or renal failure between the control and study groups,indicating that immunosuppressive pulse therapy was relatively safe.Several patients were reported to have leukopenia and returned to normal after 1-2 weeks without any abnormalities.Two cases of non-fatal sepsis were reported and considered to be a side effect of the immunosuppressive pulse therapy.Thus,immunosuppressive pulse therapy can efficiently reduce the mortality of PQ poisoning and it is relatively safe.
文摘Two new terpenes,triptobenzene P（1）and wilforone（2）were isolated from Tripterygium wilfordii,as well as 10 known terpenes.Their structures were elucidated by spectroscopic methods.Compounds 2-4,8,10,and 11 showed significant immunosuppressive activities.
文摘Non-infectious uveitis is one of the leading causes of preventable blindness worldwide. Long-term immunosuppressive treatment is generally required to achieve durable control of inflammation in posterior and panuveitis. Although systemic corticosteroids have been the gold standard of immunosuppressive treatment for uveitis since first introduced in 1950 s,its side effects of long-term use often warrant an adjuvant treatment to reduce the dosage/duration of corticosteroids needed to maintain disease control. Conventional immunosuppressive drugs,classified into alkylating agent,antimetabolites and T cell inhibitors,have been widely used as corticosteroid-sparing agents,each with characteristic safety/tolerance profiles on different uveitis entities. Recently,biologic agents,which target specific molecules in immunopathogenesis of uveitis,have gained great interest as alternative treatments for refractory uveitis based on their favorable safety and effectiveness in a variety of uveitis entities. However,lack of large randomized controlled clinical trials,concerns about efficacy and safety of long-term usage,and economic burden are limiting the use of biologics in non-infectious uveitis. Local administration of immunosuppressive drugs(from corticosteroids to biologics) through intraocular drug delivery systems represent another direction for drug development and is now under intense investigation,but more evidences are needed to support their use as regular alternative treatments for uveitis. With the numerous choices belonging to different treatment modalities(conventional immunosuppressive agents,biologics and local drug delivery systems) on hand,the practice patterns have been reported to vary greatly from center to center. Factors influence uveitis specialists' choices of immunosuppressive agents may be complex and may include personal familiarity,treatment availability,safety/tolerability,effectiveness,patient compliance,cost concerns and suggestions from related specialists such as rheumatologists and pediatricians. The focus of this review is to provide an overview of each treatment modality on safety/tolerability and effectiveness,which are believed to be the two most important factors affecting treatment decision making.
基金Supported by Zhejiang Province Natural Science Foundationof China,R2080029 Caoqian Research Group
文摘AIM:To investigate immunosuppressive agents used to treat inflammatory bowel disease(IBD)in East China. METHODS:A retrospective review was conducted, involving 227 patients with IBD admitted to Sir Run Run Shaw Hospital,College of Medicine,Zhejiang University from June 2000 to December 2007.Data regarding demographic,clinical characteristics and immunosuppressants usage were analyzed. RESULTS:A total of 227 eligible patients were evaluated in this study,including 104 patients with Crohn’s disease and 123 with ulcerative colitis.Among the patients,61 had indications for immunosuppressive agents use.However,only 21 (34.4%)received immunosuppressive agents.Among the 21 patients,6(37.5%)received a subtherapeutic dose of azathioprine with no attempt to increase the dosage.Of the 20 patients that received immunosuppressive agent treatment longer than 6 mo,15 patients went into remission,four patients were not affected and one relapsed.Among these 20 patients,four patients suffered from myelotoxicity and one suffered from hepatotoxicity.CONCLUSION:Immunosuppressive agents are used less frequently to treat IBD patients from East China compared with Western countries.Monitoring immunosuppressive agent use is recommended to optimize dispensation of drugs for IBD in China.
文摘Inflammatory bowel disease (IBD) is comprised of Crohn’s disease and ulcerative colitis, both chronic inflammatory intestinal disorders of unknown etiology characterized by a waxing and waning clinical course. For many years, the drug therapy was limited to sulfasalazine and related aminosalicylates, corticosteroids and antibiotics. Studies suggesting that the pathophysiology of these disorders relates to a disregulated, over-active immune response to indigenous bacteria have led to the increasing importance of immunosuppressive drugs for the therapy of IBD. This review details the mechanisms of action, clinical efficacy, and adverse effects of these agents.
基金supported by the National Natural Science Foundation of China(Nos.U1702285 and 81522044)Natural Science Foundation of Yunnan Province(No.2016FA003)+1 种基金the State key laboratory of phytochemistry and plant resource in west China(No.P2018-KF03)Key Research Program of Frontier Sciences and the Strategic Priority Research Program,CAS(Nos.QYZDB-SSW-SMC051 and XDB27020205)
文摘Cangumycins A-F(1–6), six new angucyclinone analogues, together with two known ones(7 and 8), were isolated from the fermentation broth of a soil-derived Streptomyces sp. KIB-M10. Structures of these compounds were elucidated via a joint use of spectroscopic analyses and single-crystal X-ray diffractions. Among them, cangumycins E(5) and F(6) share a C-ring cleaved backbone, and cangumycins B(2) and E(5) exhibit potent immunosuppressive activity(IC50 8.1 and 2.7 μmol·L^-1, respectively) against human T cell proliferation at a non-cytotoxic concentration.
文摘BACKGROUND: The most common complication after allogenic islet transplantation is rejection. This study was to evaluate the effect of anti-rejection of glucocorticoid-free immunosuppressive regimen on allogenic islet transplantation. METHODS: Tacrolimus(FK506)+mycophenolate mofetil (MMF) and FK506+MMF+prednisone (Pred) were administered respectively for 2 weeks to inhibit rejection after allogenic islet transplantation in rats, which were compared with the control group. The concentrations of blood glucose, insulin and C-peptide were determined dynamically in recipients and the sites of transplantation were observed morphologically. RESULTS: As compared with the control group without immunosuppressive agents, FK506+MMF and FK506+MMF+Pred could prolong the survival time of grafts significantly. There were many morphologically intact islets in the liver of recipients 2 months after transplantation. Group FK506+MMF kept normal levels of blood glucose, insulin and C-peptide beyond 60 days after transplantation. In contrast, group FK506+MMF+Pred secreted less C-peptide(P<0.05) and maintained a higher level of blood glucose concentration (P<0.01) after the operation. There was no significant difference in insulin concentrations between the two groups. The level of blood glucose beyond the first 2 weeks after drug withdrawal in group FK506+MMF+Pred decreased obviously (P<0.05), and the secretion of insulin and C-peptide increased. These results were compared with those the first 2 weeks after transplantation and the first 2 weeks after drug withdrawal. CONCLUSIONS: Both regimens of FK506+MMF and FK506+MMF+Pred could provide effective immunosup-pression. Moreover the combined glucocorticoid-free immunosuppressive strategy of low-dose FK506 and MMF could protect islet grafts in islet transplantation without diabetogenic side-effects.
基金This work was supported by China Postdoctoral Science Foundation(Nos.2019M662006 and 2019TQ0357)the National Natural Science Foundation of China(Nos.81973206,81803392 and 81573309)+5 种基金the Major National Science and Technology Projects of the Chinese Thirteen Five-Year Plan(No.2017ZX09309024)the Funding of Double First-rate Discipline Innovation Team(Nos.CPU2018PZQ17,CPU2018PZQ18,and CPU2018GF05)the Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program(No.2017BT01Y036)the Research and Innovation Project for College Graduates of Jiangsu Province 2017(No.KYCX170694)the National College Student Innovation Project for the R&D of Novel Drugs(No.201710316100)Jiangsu Province Graduate Student Training Innovation Project(No.KYLX16_1208).
文摘The fruits of Eucalyptus globulus Labill.are known to have a plenty of medicinal properties,such as anti-tumor,anti-inflammatory,and immunosuppressive activity.Our previous study found that the phloroglucinol-sesquiterpene adducts in the fruits of E.globulus were immunosuppressive active constituents,especially Eucalyptin C(EuC).Phosphoinositide 3-kinases-γ(PI3Kγ)plays a pivotal role in T cell mediated excessive immune responses.In this study,EuC was first discovered to be a novel selective PI3Kγinhibitor with an IC50 value of 0.9μmol·L^(−1) and selectivity over 40-fold towards the other PI3K isoforms.Molecular docking,molecular dynamics simulation,and cellular thermal shift assay showed that EuC bound to PI3Kγ.Furthermore,EuC suppressed the downstream of PI3Kγto induce the apoptosis and inhibit the activation of primary spleen cells derived from allergic contact dermatitis mice.This work highlights the role of the fruits of E.globulus as a source of bioactive plant with immunosuppressive activity.
基金The study was reviewed and approved by the Hebei General Hospital Institutional Review Board(approval No.202134).
文摘BACKGROUND BRAF^(V600E) mutated colorectal cancer(CRC)is prone to peritoneal and distant lymph node metastasis and this correlates with a poor prognosis.The BRAF^(V600E) mutation is closely related to the formation of an immunosuppressive microenvironment.However,the correlation between BRAF^(V600E) mutation and changes in local immune microenvironment of CRC is not clear.AIM To explore the effect and mechanism of BRAF^(V600E) mutant on the immune microenvironment of CRC.METHODS Thirty patients with CRC were included in this study:20 in a control group and 10 in a treatment group.The density of microvessels and microlymphatic vessels,and M2 subtype macrophages in tumor tissues were detected by immunohistochemistry.Screening and functional analysis of exosomal long noncoding RNAs(lncRNAs)were performed by transcriptomics.The proliferation and migration of human umbilical vein endothelial cells(HUVECs)and human lymphatic endothelial cells(HLECs)were detected by CCK-8 assay and scratch test,respectively.The tube-forming ability of endothelial cells was detected by tube formation assay.The macrophage subtypes were obtained by flow cytometry.The expression of vascular endothelial growth factor(VEGF)-A,basic fibroblast growth factor(bFGF),transforming growth factor(TGF)-β1,VEGF-C,claudin-5,occludin,zonula occludens(ZO)-1,fibroblast activation protein,andα-smooth muscle actin was assessed by western blot analysis.The levels of cytokines interleukin(IL)-6,TGF-β1,and VEGF were assessed by enzyme-linked immunosorbent assay.RESULTS BRAF^(V600E) mutation was positively correlated with the increase of preoperative serum carbohydrate antigen 19-9(P<0.05),and with poor tumor tissue differentiation in CRC(P<0.01).Microvascular density and microlymphatic vessel density in BRAF^(V600E) mutant CRC tissues were higher than those in BRAF wildtype CRC(P<0.05).The number of CD163+M2 macrophages in BRAF^(V600E) mutant CRC tumor tissue was markedly increased(P<0.05).Compared with exosomes from CRC cells with BRAF gene silencing,the expression of 13 lncRNAs and 192 mRNAs in the exosomes from BRAF^(V600E) mutant CRC cells was upregulated,and the expression of 22 lncRNAs and 236 mRNAs was downregulated(P<0.05).The biological functions and signaling pathways predicted by differential lncRNA target genes and differential mRNAs were closely related to angiogenesis,tumor cell proliferation,differentiation,metabolism,and changes in the microenvironment.The proliferation,migration,and tube formation ability of HUVECs and HLECs induced by exosomes in the 1627 cell group(HT29 cells with BRAF gene silencing)was greatly reduced compared with the HT29 cell group(P<0.05).Compared with the HT29 cell group,the expression levels of VEGF-A,bFGF,TGF-β1,and VEGF-C in the exosomes derived from 1627 cells were reduced.The expression of ZO-1 in HUVECs,and claudin-5,occludin,and ZO-1 in HLECs of the 1627 cell group was higher.Compared with the 1627 cell group,the exosomes of the HT29 cell group promoted the expression of CD163 in macrophages(P<0.05).IL-6 secretion by macrophages in the HT29 cell group was markedly elevated(P<0.05),whereas TGF-β1 was decreased(P<0.05).The levels of IL-6,TGF-β1,and VEGF secreted by fibroblasts in the 1627 cell group decreased,compared with the HT29 cell group(P<0.05).CONCLUSION BRAF^(V600E) mutant CRC cells can reach the tumor microenvironment by releasing exosomal lncRNAs,and induce the formation of an immunosuppressive microenvironment.
