Spinal cord injury involves non-reversible damage to the central nervous system that is characterized by limited regenerative capacity and secondary inflammatory damage.The expression of the C-C motif chemokine ligand...Spinal cord injury involves non-reversible damage to the central nervous system that is characterized by limited regenerative capacity and secondary inflammatory damage.The expression of the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis exhibits significant differences before and after injury.Recent studies have revealed that the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis is closely associated with secondary inflammatory responses and the recruitment of immune cells following spinal cord injury,suggesting that this axis is a novel target and regulatory control point for treatment.This review comprehensively examines the therapeutic strategies targeting the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis,along with the regenerative and repair mechanisms linking the axis to spinal cord injury.Additionally,we summarize the upstream and downstream inflammatory signaling pathways associated with spinal cord injury and the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis.This review primarily elaborates on therapeutic strategies that target the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis and the latest progress of research on antagonistic drugs,along with the approaches used to exploit new therapeutic targets within the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis and the development of targeted drugs.Nevertheless,there are presently no clinical studies relating to spinal cord injury that are focusing on the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis.This review aims to provide new ideas and therapeutic strategies for the future treatment of spinal cord injury.展开更多
BACKGROUND The diagnosis of inflammatory bowel disease(IBD)involves clinical,endoscopic,and radiologic evaluation.Endoscopic procedures,particularly in pediatrics,require general anesthesia and carry potential risks.A...BACKGROUND The diagnosis of inflammatory bowel disease(IBD)involves clinical,endoscopic,and radiologic evaluation.Endoscopic procedures,particularly in pediatrics,require general anesthesia and carry potential risks.AIM To investigate whether serum biomarkers can differentiate between pediatric patients with and without IBD.Secondary objectives included identifying biomarkers that distinguish Crohn’s disease(CD)from ulcerative colitis(UC)and assessing their predictive value for progression to biologic therapy.METHODS Pediatric patients undergoing diagnostic colonoscopy at British Columbia Children’s Hospital between December 2017 and June 2022 were enrolled.Blood samples were collected at colonoscopy,and demographic clinical data,laboratory,and histopathologic evaluation were obtained.An exploratory screen of 50 biomarkers was undertaken in a subset of patients(54 IBD,41 controls)using LegendplexTM flow cytometry kits to identify candidates.A refined panel of 12 serum biomarkers was subsequently selected and a supervised learning model was developed to classify patients.RESULTS The study included 246 pediatric patients,who had a median age of 13.03 years and were 37.4%female(103 CD,52 UC,91 controls).In univariate analyses,C-X-C motif chemokine ligand 9(CXCL9)was the only biomarker significantly elevated in IBD vs controls(P<0.001).A multivariable model achieved an area under the receiver operating characteristic of 0.861 for distinguishing IBD from controls.Interleukin 8(IL-8)emerged as a key biomarker alongside CXCL9 and IL-22 in the model.The random forest model identified CXCL9 with the greatest diagnostic accuracy(area under the curve[AUC]=0.81),followed by IL8 and IL22(AUC=0.737 and 0.68,respectively).CXCL9 and IL-18 showed higher levels in CD(P=0.016),whereas CXCL1 levels predicted progression to biologic therapy within 1 year(P=0.039).However,the model did not effectively predict disease subclassification or progression to biologic therapy.CONCLUSION Serum biomarkers,particularly CXCL9,IL-8,and IL-22,can aid in the diagnosis of pediatric IBD.CXCL9 and IL18 were found to be significant predictors of CD,and CXCL1 differed between patients requiring biologic therapy vs those who did not.展开更多
Chronic pain,frequently comorbid with neuropsychiatric disorders,significantly impairs patients’quality of life and functional capacity.Accumulating evidence implicates the chemokine CCL2 and its receptor CCR2 as key...Chronic pain,frequently comorbid with neuropsychiatric disorders,significantly impairs patients’quality of life and functional capacity.Accumulating evidence implicates the chemokine CCL2 and its receptor CCR2 as key players in chronic pain pathogenesis.This review examines the regulatory mechanisms of the CCL2/CCR2 axis in chronic pain processing at three hierarchical levels:(1)Peripheral Sensitization:CCL2/CCR2 modulates TRPV1,Nav1.8,and HCN2 channels to increase neuronal excitability and CGRP signaling and calcium-dependent exocytosis in peripheral nociceptors to transmit pain.(2)Spinal Cord Central Sensitization:CCL2/CCR2 contributes to NMDAR-dependent plasticity,glial activation,GABAergic disinhibition,and opioid receptor desensitization.(3)Supraspinal Central Networks:CCL2/CCR2 signaling axis mediates the comorbidity mechanisms of pain with anxiety and cognitive impairment within brain regions,including the ACC,CeA,NAc,and hippocampus,and it also increases pain sensitization through the descending facilitation system.Current CCL2/CCR2-targeted therapeutic strategies and their development status are discussed,highlighting novel avenues for chronic pain management.展开更多
BACKGROUND C-X-C chemokine receptor type 5(CXCR5)^(+)CD8^(+)T cells represent a unique immune subset with dual roles,functioning as cytotoxic cells in persistent viral infections while promoting B cell responses.Despi...BACKGROUND C-X-C chemokine receptor type 5(CXCR5)^(+)CD8^(+)T cells represent a unique immune subset with dual roles,functioning as cytotoxic cells in persistent viral infections while promoting B cell responses.Despite their importance,the specific role of CXCR5^(+)CD8^(+)T cells in chronic hepatitis B(CHB),particularly during interferon-alpha(IFN-α)treatment,is not fully understood.This study aims to elucidate the relationship between CXCR5^(+)CD8^(+)T cells and sustained serologic response(SR)in patients undergoing 48 weeks of pegylated IFN-α(peg-IFN-α)treatment for CHB.AIM To elucidate the relationship between CXCR5^(+)CD8^(+)T cells and sustained SR in patients undergoing 48 weeks of peg-IFN-αtreatment for CHB.METHODS This study enrolled 60 patients with hepatitis Be antigen(HBeAg)-positive CHB undergoing 48 weeks of peg-IFN-αtreatment.Participants were assessed for eligibility based on criteria such as persistent HBsAg-positive status for at least six months,HBeAb-negative,hepatitis B virus DNA levels exceeding 2×10^(4) copies/mL,and alanine aminotransferase(ALT)levels between 2 and 10 times the upper limit of normal.Blood samples were collected at baseline and at weeks 12,24,48,and a 24-week treatment-free follow-up(week 72)to measure serum interleukin(IL)-21 concentration via ELISA and to analyze CXCR5 and programmed death-ligand 1(PD-L1)expression on CD8^(+)T cells by flow cytometry,CXCR5 is a chemokine receptor that directs immune cells to specific tissues,while PD-L1 is a protein that regulates immune responses by inhibiting T cell activity.RESULTS Patients with CHB exhibited significantly lower levels of circulating CXCR5^(+)CD8^(+)T cells compared to healthy controls(P<0.01).Notably,CXCR5^(+)CD8^(+)T cells were prominently expressed in patients who achieved sustained SR compared to non-SR(NSR).A significant correlation was observed between CXCR5 and PD-L1 expression(r=-0.189,P=0.002).However,there was no significant correlation between serum IL-21 levels and CXCR5+CD8+lymphocytes(r=-0.03,P=0.625)or serum ALT levels(r=0.026,P=0.678).CONCLUSION The enhanced expression of CXCR5^(+)CD8^(+)T cells in patients achieving HBeAg seroconversion during IFN-αtreatment suggests that these cells play a crucial role in antiviral immune responses against hepatitis B.This study highlights the potential of CXCR5^(+)CD8^(+)T cells as immune regulators in CHB,which may inform future therapeutic strategies to optimize antiviral treatments.展开更多
Ethanol(EtOH)is a common trigger for gastric mucosal diseases,and mitigating oxidative stress is essential for attenuating gastric mucosal damage.Capsaicin(CAP)has been identified as a potential agent to counteract ox...Ethanol(EtOH)is a common trigger for gastric mucosal diseases,and mitigating oxidative stress is essential for attenuating gastric mucosal damage.Capsaicin(CAP)has been identified as a potential agent to counteract oxidative damage in the gastric mucosa;however,its precise mechanism remains unclear.This study demonstrates that CAP alleviates EtOH-induced gastric mucosal injuries through two primary pathways:by suppressing the chemokine receptor 4(CCR4)/Src/p47phox axis,thereby reducing oxidative stress,and by inhibiting the phosphorylation and nuclear translocation of nuclear factor-κB p65(NF-κB)p65,resulting in diminished inflammatory responses.These findings elucidate the mechanistic pathways of CAP and provide a theoretical foundation for its potential therapeutic application in the treatment of gastric mucosal injuries.展开更多
Pancreatitis is one of the largest contributors to increased healthcare costs.It is widely accepted that exposure of acinar cells to injurious agents leads to necrosis and pancreatic enzyme activation.Inappropriate ac...Pancreatitis is one of the largest contributors to increased healthcare costs.It is widely accepted that exposure of acinar cells to injurious agents leads to necrosis and pancreatic enzyme activation.Inappropriate activation of trypsinogen in the pancreas is related to infiltration of leukocytes recruited by chemokines,which directly leads to acinar cell damage,and indirectly to a strong systemic inflammatory response.Otherwise,chemokines exert pleiotropic effects by recruiting immune cells during inflammation,immune surveillance,and directing cells to target organs in homeostasis.Here,we give a brief introduction to the basic molecular and cellular sources of chemokines,and focus on their pleiotropic functions in acute pancreatitis,chronic pancreatitis,autoimmune pancreatitis,and pancreatic cancer.Understanding the interaction between these processes is helpful for devising therapeutic strategies for pancreatitis.展开更多
Background:The incidence of spontaneously ruptured hepatocellular carcinoma(srHCC)has been shown to significantly elevate mortality rates.However,the precise mechanisms underlying srHCC remain poorly understood.Method...Background:The incidence of spontaneously ruptured hepatocellular carcinoma(srHCC)has been shown to significantly elevate mortality rates.However,the precise mechanisms underlying srHCC remain poorly understood.Methods:Analysis was conducted on the data of 198 hepatocellular carcinoma(HCC)patients to inves-tigate the factors contributing to srHCC.The clinical data of 33 transcriptome HCC patients were served for verification.An in-depth transcriptome analysis was conducted to investigate the distinctions between 26 cases of srHCC and 35 cases of non-ruptured hepatocellular carcinoma(nrHCC).Weighted Gene Co-expression Network Analysis(WGCNA)tool was utilized to develop a gene co-expression network.Gene ontology(GO)and Kyoto encyclopedia of genes and genomes(KEGG)pathways enrichment,and protein-protein interaction(PPI)network were carried out.The corresponding samples for spontaneously rup-tured hepatocellular carcinoma tissue(srHCC-T)and ruptured hepatocellular carcinoma paracancerous tissue(srHCC-P)were selected for verification.Transcriptional data were validated through reverse tran-scription quantitative polymerase chain reaction(RT-qPCR).Immunofluorescence(IF),immunohistochem-istry(IHC)and Western blot were used to detect the protein expression.Results:Our results showed that white blood cell(WBC)and monocyte levels were significant inde-pendent risk factors for srHCC(P<0.05).There was a strong association between the srHCC-T and the expression of cell cycle-related genes BUB1B and macrophage function-related gene MACRO.Furthermore,chemokines and the PI3K/AKT signaling pathway play a crucial role in regulating the cell cycle process through a complex network of interactions,ultimately impacting the occurrence of srHCC.Conclusions:Our study confirms that chemokines and the PI3K/AKT signaling pathway mediate the occur-rence of HCC rupture by regulating the cell cycle.We provide a theoretical basis for the clinical treatment of srHCC.展开更多
Acute high-altitude(HA)illnesses(AHAIs),including acute mountain sickness(AMS),HA cerebral edema(HACE),and HA pulmonary edema(HAPE),represent significant health challenges for individuals rapidly ascending to high alt...Acute high-altitude(HA)illnesses(AHAIs),including acute mountain sickness(AMS),HA cerebral edema(HACE),and HA pulmonary edema(HAPE),represent significant health challenges for individuals rapidly ascending to high altitudes.Cytokines(interleukins(ILs))and chemokines,which are involved in inflammatory and immunological responses,regulate the response of the body to hypoxic stress.Their dysregulation can contribute to the clinical symptoms of AMS,HACE,and HAPE by increasing vascular permeability,causing edema and damaging tissue.AHAIs elevate the levels of pro-inflammatory cytokines and chemokines,such as IL-17,tumor necrosis factorα(TNF-α),IL-1,IL-6,C-X-C motif chemokine ligand(CXCL)10,CXCL8,C-C motif ligand 2(CCL2),and CCL3,exacerbating symptoms.Thus,this review focuses on the cytokines and chemokines involved in AHAIs and the molecular mechanisms that extend beyond these cytokines and chemokines in clinical and preclinical contexts.Identifying these mediators and pathways helps researchers design drugs that reduce symptoms,slow disease progression,and enhance outcomes.Cytokines and chemokines have complex functions in these disorders and may serve as prospective therapeutic targets.Finally,we discuss treatment possibilities for AHAIs(drugs,exercise,and other inhibitors).This knowledge will help us to protect and improve the health of individuals at high altitudes.展开更多
BACKGROUND Sarcosine dehydrogenase(SARDH)and C-X-C motif chemokine ligand 1(CXCL1)have been identified as potential tumor regulators,with growing evidence linking them to cancer progression.However,their specific role...BACKGROUND Sarcosine dehydrogenase(SARDH)and C-X-C motif chemokine ligand 1(CXCL1)have been identified as potential tumor regulators,with growing evidence linking them to cancer progression.However,their specific roles,regulatory mechanisms,and influence on key signaling pathways remain unclear.AIM To investigate the regulatory mechanisms of SARDH and CXCL1 in cancer cells and their impact on key signaling pathways.METHODS Real-time quantitative polymerase chain reaction and western blot analyses were used to assess the expression levels of SARDH and CXCL1 and their effects on protein kinase B(Akt)and extracellular signal-regulated kinase(ERK)signaling pathways.Gene overexpression was induced using an expression vector,while gene silencing was achieved using short hairpin RNA and small interfering RNA.CCK-8,migration,and invasion assays were used to evaluate the impact of gene suppression and overexpression on cancer cell proliferation,migration,and invasion.RESULTS SARDH silencing significantly enhanced cancer cell proliferation,whereas its overexpression suppressed proliferation in the early stages of the experiment.CXCL1 silencing reduced cancer cell migration and invasion.SARDH overexpression inhibited cell migration,invasion,and adhesion while increasing apoptosis.Conversely,SARDH silencing reversed these effects.Furthermore,simultaneous silencing of SARDH and CXCL1 strongly activated the Akt and ERK signaling pathways,indicating the potential role of these pathways in regulating cellular functions influenced by these genes.CONCLUSION This study revealed that SARDH and CXCL1 regulate cancer cell growth,migration,and invasion through Akt and ERK signaling pathways,highlighting their potential as therapeutic targets for cancer treatment.展开更多
AIM： To evaluate and compare the expression profiles of CXCL12 （SDF-1）, CCL19 （MIP-3β）, CCL20 （MIP-3a） and CCL21 （6Ckine, Exodus2） and their receptors on RNA and protein levels in hepatocellular carcinoma （...AIM： To evaluate and compare the expression profiles of CXCL12 （SDF-1）, CCL19 （MIP-3β）, CCL20 （MIP-3a） and CCL21 （6Ckine, Exodus2） and their receptors on RNA and protein levels in hepatocellular carcinoma （HCC） versus colorectal liver metastases （CRLM） and to elucidate their impact on the carcinogenesis and progression of malignant liver diseases. METHODS： Chemokine expression was analyzed by RT-PCR and ELISA in 11 cases of HCC specimens and in 23 cases of CRLM and corresponding adjacent nontumorous liver tissues, respectively. Expressions of their receptors CXCR4, CCR6 and CCR7 were analyzed by RT- PCR and Western blot analysis in the same cases of HCC and CRLM. RESULTS： Significant up-regulation for CCL20/CCR6 was detected in both cancer types. Moreover, CCL20 demonstrated significant overexpression in CRLM in relation to the HCC tissues. Being significantly up-regulated only in CRLM, CXCR4 displayed an aberrant expression pattern with respect to the HCC tissues. CONCLUSION： Correlation of CXCR4 expression with CRLM suggests CXCR4 as a potential predictive factor for CRLM. High level expression of CCL20 and its receptor CCR6 in HCC and CRLM with marked up-regulation of CCL20 in CRLM in relation to HCC tissues indicates involvement of the CCL20/CCR6 ligand-receptor pair in the carcinogenesis and progression of hepatic malignancies.展开更多
Gastric cancer is the fourth most common cancer,and the second-highest cause of cancer-related deaths worldwide.Despite extensive research to identify novel diagnostic and therapeutic agents,patients with advanced gas...Gastric cancer is the fourth most common cancer,and the second-highest cause of cancer-related deaths worldwide.Despite extensive research to identify novel diagnostic and therapeutic agents,patients with advanced gastric cancer suffer from a poor quality of life and poor prognosis,and treatment is dependent mainly on conventional cytotoxic chemotherapy.To improve the quality of life and survival of gastric cancer patients,a better understanding of the underlying molecular pathologies,and their application towards the development of novel targeted therapies,is urgently needed.Chemokines are a group of small proteins associated with cytoskeletal rearrangements,the directional migration of several cell types during development and physiology,and the host immune response via interactions with G-protein coupled receptors.There is also growing evidence to suggest that chemokines not only play a role in the immune system,but are also involved in the development and progression of tumors.In gastric cancer,CXC chemokines and chemokine receptors regulate the trafficking of cells in and out of the tumor microenvironment.CXC chemokines and their receptors can also directly influence tumorigenesis by modulating tumor transformation,survival,growth,invasion and metastasis,as well as indirectly by regulating angiogenesis,and tumor-leukocyte interactions.In this review,we will focus on the roles of CXC chemokines and their receptors in the development,progression,and metastasis of gastric tumors,and discuss their therapeutic potential for gastric cancer.展开更多
Chemokines produced in the liver during hepatitis C virus(HCV) infection induce migration of activated T cells from the periphery to infected parenchyma.The milieu of chemokines secreted by infected hepatocytes is pre...Chemokines produced in the liver during hepatitis C virus(HCV) infection induce migration of activated T cells from the periphery to infected parenchyma.The milieu of chemokines secreted by infected hepatocytes is predominantly associated with the T-helper cell/Tc1 T cell(Th1/Tc1) response.These chemokines consist of CCL3(macrophage inflammatory protein-1α;MIP-1α),CCL4(MIP-1β),CCL5(regulated on activation normal T cell expressed and secreted;RANTES),CXCL10(interferon-γ-inducible protein-10;IP-10),CXCL11(interferon-inducible T-cell α chemoattractant;I-TAC),and CXCL9(monokine induced by interferon γ;Mig) and they recruit T cells expressing either CCR5 or CXCR3 chemokine receptors.Intrahepatic and peripheral blood levels of these chemokines are increased during chronic hepatitis C.The interaction between chemokines and their receptors is essential in recruiting HCV-specific T cells to control the infection.When the adaptive immune response fails in this task,non-specific T cells without the capacity to control the infection are also recruited to the liver,and these are ultimately responsible for the persistent hepatic damage.The modulation of chemokine receptor expression and chemokine secretion could be a viral escape mechanism to avoid specific T cell migration to the liver during the early phase of infection,and to maintain liver viability during the chronic phase,by impairing non-specific T cell migration.Some chemokines and their receptors correlate with liver damage,and CXCL10(IP-10) and CXCR3 levels have shown a clinical utility as predictors of treatment response outcome.The regulation of chemokines and their receptors could be a future potential therapeutic target to decrease liver inflammation and to increase specific T cell migration to the infected liver.展开更多
Chemokines belong to a superfamily of small, cytokinelike proteins, which induce multiple physiological functions, particularly cytoskeletal rearrangement and compartment-specific migration through their interaction w...Chemokines belong to a superfamily of small, cytokinelike proteins, which induce multiple physiological functions, particularly cytoskeletal rearrangement and compartment-specific migration through their interaction with G-protein-coupled receptors. Chemokines and their receptors have been widely acknowledged as essential and selective mediators in leukocyte migration in inflammatory response. It is now established that the chemokine/chemokine receptor system is also used by cancer cells to direct lymphatic and haematogenous spreading and additionally has an impact on the site of metastatic growth of different tumours. In recent years an increasing number of studies have drawn attention to CC-chemokine cysteine motif chemokine ligand 20(CCL20) and its physiological sole receptor CCR6 to play a role in the onset, development and metastatic spread of various gastrointestinal cancer entities. Among various cancer types CCR6 was also demonstrated to be significantly overexpressed in colorectal cancer(CRC) and stimulation by its physiological ligand CCL20 has been reported to promote CRC cell proliferation and migration in vitro. Further, the CCL20/CCR6 system apparently plays a role in the organ-selective liver metastasis of CRC. Here we review the literature on expression patterns of CCL20 and CCR6 and their physiological interactions as well as the currently presumed role of CCL20 and CCR6 in the formation of CRC and the development of liver metastasis, providing a potential basis for novel treatment strategies.展开更多
The chemokine system consists of four different subclasses with over 50 chemokines and 19 receptors. Their functions in the immune system have been well elucidated and research during the last decades unveils their ne...The chemokine system consists of four different subclasses with over 50 chemokines and 19 receptors. Their functions in the immune system have been well elucidated and research during the last decades unveils their new roles in hepatocellular carcinoma(HCC). The chemokines and their receptors in the microenvironment influence the development of HCCby several aspects including:inflammation,effects on immune cells,angiogenesis,and direct effects on HCC cells. Regarding these aspects,pre-clinical research by targeting the chemokine system has yielded promising data,and these findings bring us new clues in the chemokine-based therapies for HCC.展开更多
Spinal cord injury causes accumulation of a large number of leukocytes at the lesion site where they contribute to excessive inflammation.Overproduced chemokines are responsible for the migratory process of the leukoc...Spinal cord injury causes accumulation of a large number of leukocytes at the lesion site where they contribute to excessive inflammation.Overproduced chemokines are responsible for the migratory process of the leukocytes,but the regulatory mechanism underlying the production of chemokines from resident cells of the spinal cord has not been fully elucidated.We examined the protein levels of macrophage migration inhibitory factor and chemokine C-C motif chemokine ligand 2 in a spinal cord contusion model at different time points following spinal cord injury.The elevation of macrophage migration inhibitory factor at the lesion site coincided with the increase of chemokine C-C motif chemokine ligand 2 abundance in astrocytes.Stimulation of primary cultured astrocytes with different concentrations of macrophage migration inhibitory factor recombinant protein induced chemokine C-C motif chemokine ligand 2 production from the cells,and the macrophage migration inhibitory factor inhibitor 4-iodo-6-phenylpyrimidine attenuated the stimulatory effect.Further investigation into the underlying mechanism on macrophage migration inhibitory factor-mediated astrocytic production of chemokine C-C motif chemokine ligand 2 revealed that macrophage migration inhibitory factor activated intracellular JNK signaling through binding with CD74 receptor.Administration of the macrophage migration inhibitory factor inhibitor 4-iodo-6-phenylpyrimidine following spinal cord injury resulted in the reduction of chemokine C-C motif chemokine ligand 2-recruited microglia/macrophages at the lesion site and remarkably improved the hindlimb locomotor function of rats.Our results have provided insights into the functions of astrocyte-activated chemokines in the recruitment of leukocytes and may be beneficial to develop interventions targeting chemokine C-C motif chemokine ligand 2 for neuroinflammation after spinal cord injury.展开更多
Objective To determine the levels of CC chemokine ligand 5 (CCL5) in serum and synovial fluid (SF) from patients with rheumatoid arthritis (RA) and their relations with disease activity and medication. Methods CCL5 in...Objective To determine the levels of CC chemokine ligand 5 (CCL5) in serum and synovial fluid (SF) from patients with rheumatoid arthritis (RA) and their relations with disease activity and medication. Methods CCL5 in serum and SF was quantified by enzyme-linked immunosorbent assay (ELISA) in 28 RA patients and 21 osteoarthritis (OA) patients. In RA patients, the correlations of CCL5 levels in serum and SF with disease activity were analyzed. Meanwhile, the serum CCL5 levels among RA patients treated with disease-modifying antirheumatic drugs (DMARDs), Tripterygium Glucosides, and other Chinese herbs without disease-modifying effects were also compared. Results CCL5 levels in both serum and SF of RA patients were significantly higher than those of OA patients (P<0.05). Moreover, the level of CCL5 was higher in SF than that in serum of RA patients (P<0.01). Serum CCL5 level was correlated significantly with the number of swollen joints (r=0.3329, P<0.05), erythrocyte sedimentation rate (r=0.4001, P<0.05), and C reactive protein (r=0.3735, P<0.01). In addition, the level of CCL5 had a trend of lower in patients treated with DMARDs or Tripterygium Glucosides than those treated with other Chinese herbs, although the difference was not significant among those patients due to the small number of patients in each group. Conclusions In RA patients, the expression of CCL5 increases and correlates with some clinical and laboratory parameters of RA, which indicate that CCL5 plays an important role in RA and may serve as a useful marker of disease activity. DMARDs and Tripterygium Glucosides might exert their clinical effects through reducing CCL5 production in RA.展开更多
Objective: To examine expressions of chemokine receptor CXCR4 and its ligand CXCL12 in primary focus and lymphogenous metastasis of salivary adenoid cystic carcinoma (ACC) with lung metastasis. Methods: Using immunohi...Objective: To examine expressions of chemokine receptor CXCR4 and its ligand CXCL12 in primary focus and lymphogenous metastasis of salivary adenoid cystic carcinoma (ACC) with lung metastasis. Methods: Using immunohistochemical hypersensitivity catalyzed signal amplification (CSA), expressions of chemokine receptor CXCR4 and ligand CXCL12 were detected in tissue specimens from 20 cases of primary cancer focus and lymphogenous metastasis of salivary adenoid cystic carcinoma, of which 7 cases were associated with lung metastasis and 3 with lympogenous metastasis. Twenty cases of tongue carcinoma (including 10 cases with lymphogenous metastasis) and 15 cases of mucoepidermoid carcinoma (including 5 cases with lymphogenous metastasis) were used as the malignant control group;and salivary mixed tumor (n=10), tongue leukoceratosis (n=10) and cervical lymph node reactive hyperplasia (n=10) were used as the benign control group. Results: Expression of CXCR4 in the tissues and lymph metastases of oral and maxillofacial salivary ACC, mucoepidermoid carcinoma and tongue carcinoma was significantly higher than that of the benign control group (P<0.05); expression of CXCR4 in the primary focus of ACC was significantly higher than that of the malignant control group; and expression of CXCR4 in the ACC with lung metastasis was 87.1% (6/7), significantly higher than that without lung metastasis(P<0.01). There was evident positive expression of CXCL12 in endotheliocytes of microvessels within cancer and paracancer tissues and significantly high expression of CXCL12 in lymphogenous metastasis(P<0.05). Conclusion: Chemokine receptor CXCR4 and its ligand CXCL12 may be associated with local invasion and lymphogenous metastasis of oral and maxillofacial cancer, especially with lung metastasis of salivary ACC.展开更多
BACKGROUND Leukocytes,such as T cells and macrophages,play an important role in tumorigenesis.CC chemokine ligand(CCL)4,which is produced by lymphocytes and macrophages,has been found to be expressed in the mucosa of ...BACKGROUND Leukocytes,such as T cells and macrophages,play an important role in tumorigenesis.CC chemokine ligand(CCL)4,which is produced by lymphocytes and macrophages,has been found to be expressed in the mucosa of the gastrointestinal tract and is a potent chemoattractant for various leukocytes.AIM To examine CCL4 expression and its genetic polymorphism rs10491121 in patients with colorectal cancer(CRC)and evaluate their prognostic significance.METHODS Luminex technology was used to determine CCL4 Levels in CRC tissue(n=98),compared with paired normal tissue,and in plasma from patients with CRC(n=103),compared with healthy controls(n=97).Included patients had undergone surgical resection for primary colorectal adenocarcinomas between 1996 and 2019 at the Department of Surgery,Ryhov County Hospital,Jönköping,Sweden.Reverse transcription quantitative PCR was used to investigate the CCL4 gene expression in CRC tissue(n=101).Paired normal tissue and TaqMan single nucleotide polymorphism assays were used for the CCL4 rs10491121 polymorphism in 610 CRC patients and 409 healthy controls.RESULTS The CCL4 protein and messenger RNA expression levels were higher in CRC tissue than in normal paired tissue(90%,P<0.001 and 45%,P<0.05,respectively).CRC tissue from patients with localized disease had 2.8-fold higher protein expression levels than that from patients with disseminated disease.Low CCL4 protein expression levels in CRC tissue were associated with a 30%lower cancer-specific survival rate in patients(P<0.01).The level of plasma CCL4 was 11%higher in CRC patients than in healthy controls(P<0.05)and was positively correlated(r=0.56,P<0.01)with the CCL4 protein level in CRC tissue.The analysis of CCL4 gene polymorphism rs10491121 showed a difference(P<0.05)between localized disease and disseminated disease in the right colon,with a dominance of allele A in localized disease.Moreover,the rate of the A allele was higher among CRC patients with mucinous cancer than among those with nonmucinous cancer.CONCLUSION The present study indicates that the CRC tissue levels of CCL4 and CCL4 gene polymorphism rs10491121,particularly in the right colon,are associated with clinical outcome in CRC patients.展开更多
Summary: In order to explore the possible role of CC chemokine ligand 20 (CCL20) and its receptor CC chemokine receptor 6 (CCR6) in the pathogenesis of psoriasis, the expression levels of mRNA of them in psoriatic les...Summary: In order to explore the possible role of CC chemokine ligand 20 (CCL20) and its receptor CC chemokine receptor 6 (CCR6) in the pathogenesis of psoriasis, the expression levels of mRNA of them in psoriatic lesions were investigated. The skin biopsies were collected from skin lesions in 35 cases of psoriasis vulgaris and 18 normal controls. RT-PCR was used to semi-quantitatively analyze the mRNA expression of CCL20 and CCR6 in the psoriatic lesions and the normal skin tissues. The results showed that the mRNA of CCL20 and CCR6 was present in every specimen. The expression levels of CCL20 mRNA in skin lesions were 1.1397±0.0521, which were greatly higher than those in normal controls (0.8681±0.0308) (P<0.001). The expression levels of CCR6 mRNA in skin lesions were 1.1103±0.0538, significantly higher than in the controls (0.9131±0.0433, P<0.001). These findings indicate that up-regulated expression of CCL20 and CCR6 mRNA might be related to the pathogenesis of psoriasis.展开更多
The difficulty of early diagnosis,high tumor heterogeneity,and high recurrence and metastasis rates lead to an unsatisfactory treatment status for hepatocellular carcinoma(HCC).HCC is a typical inflammation-driven tum...The difficulty of early diagnosis,high tumor heterogeneity,and high recurrence and metastasis rates lead to an unsatisfactory treatment status for hepatocellular carcinoma(HCC).HCC is a typical inflammation-driven tumor.Chronic inflammation allows nascent tumors to escape immunosurveillance.Chemokines are small,soluble,secreted proteins that can regulate the activation and trafficking of immune cells during inflammation.Several studies have shown that various chemokines with overarching functions disrupt the immune microenvironment during the initiation and progression of HCC.The dysregulated chemokine network in HCC contributes to multiple malignant processes,including angiogenesis,tumor proliferation,migration,invasion,tumor low response,and resistance to immune therapy.Here,we summarize the current studies focusing on the role of chemokines and their receptors in the HCC immune microenvironment,highlighting potential translational therapeutic uses for modulating the chemokine system in HCC.展开更多
基金supported by the National Natural Science Foundation of China(Key Program),No.11932013the National Natural Science Foundation of China(General Program),No.82272255+2 种基金Armed Police Force High-Level Science and Technology Personnel ProjectThe Armed Police Force Focuses on Supporting Scientific and Technological Innovation TeamsKey Project of Tianjin Science and Technology Plan,No.20JCZDJC00570(all to XC)。
文摘Spinal cord injury involves non-reversible damage to the central nervous system that is characterized by limited regenerative capacity and secondary inflammatory damage.The expression of the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis exhibits significant differences before and after injury.Recent studies have revealed that the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis is closely associated with secondary inflammatory responses and the recruitment of immune cells following spinal cord injury,suggesting that this axis is a novel target and regulatory control point for treatment.This review comprehensively examines the therapeutic strategies targeting the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis,along with the regenerative and repair mechanisms linking the axis to spinal cord injury.Additionally,we summarize the upstream and downstream inflammatory signaling pathways associated with spinal cord injury and the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis.This review primarily elaborates on therapeutic strategies that target the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis and the latest progress of research on antagonistic drugs,along with the approaches used to exploit new therapeutic targets within the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis and the development of targeted drugs.Nevertheless,there are presently no clinical studies relating to spinal cord injury that are focusing on the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis.This review aims to provide new ideas and therapeutic strategies for the future treatment of spinal cord injury.
基金Supported by the Lutsky Family Foundation and AdMare Bioinnovations(previously known as the Genome BC CDRD Development Fund).
文摘BACKGROUND The diagnosis of inflammatory bowel disease(IBD)involves clinical,endoscopic,and radiologic evaluation.Endoscopic procedures,particularly in pediatrics,require general anesthesia and carry potential risks.AIM To investigate whether serum biomarkers can differentiate between pediatric patients with and without IBD.Secondary objectives included identifying biomarkers that distinguish Crohn’s disease(CD)from ulcerative colitis(UC)and assessing their predictive value for progression to biologic therapy.METHODS Pediatric patients undergoing diagnostic colonoscopy at British Columbia Children’s Hospital between December 2017 and June 2022 were enrolled.Blood samples were collected at colonoscopy,and demographic clinical data,laboratory,and histopathologic evaluation were obtained.An exploratory screen of 50 biomarkers was undertaken in a subset of patients(54 IBD,41 controls)using LegendplexTM flow cytometry kits to identify candidates.A refined panel of 12 serum biomarkers was subsequently selected and a supervised learning model was developed to classify patients.RESULTS The study included 246 pediatric patients,who had a median age of 13.03 years and were 37.4%female(103 CD,52 UC,91 controls).In univariate analyses,C-X-C motif chemokine ligand 9(CXCL9)was the only biomarker significantly elevated in IBD vs controls(P<0.001).A multivariable model achieved an area under the receiver operating characteristic of 0.861 for distinguishing IBD from controls.Interleukin 8(IL-8)emerged as a key biomarker alongside CXCL9 and IL-22 in the model.The random forest model identified CXCL9 with the greatest diagnostic accuracy(area under the curve[AUC]=0.81),followed by IL8 and IL22(AUC=0.737 and 0.68,respectively).CXCL9 and IL-18 showed higher levels in CD(P=0.016),whereas CXCL1 levels predicted progression to biologic therapy within 1 year(P=0.039).However,the model did not effectively predict disease subclassification or progression to biologic therapy.CONCLUSION Serum biomarkers,particularly CXCL9,IL-8,and IL-22,can aid in the diagnosis of pediatric IBD.CXCL9 and IL18 were found to be significant predictors of CD,and CXCL1 differed between patients requiring biologic therapy vs those who did not.
基金supported by grants from the Ministry of Science and Technology of China(2021ZD0203205 and 2021ZD0203104)the National Natural Science Foundation of China(82371225,82171212,82571386,82330036 and 82221001)+2 种基金National Key Research and Development Program of China(2024YFC2510102)the Excellent Youth Science Foundation of Shaanxi Province(2025JC-JCQN-103)Shaanxi Province Sanqin Talent Program.
文摘Chronic pain,frequently comorbid with neuropsychiatric disorders,significantly impairs patients’quality of life and functional capacity.Accumulating evidence implicates the chemokine CCL2 and its receptor CCR2 as key players in chronic pain pathogenesis.This review examines the regulatory mechanisms of the CCL2/CCR2 axis in chronic pain processing at three hierarchical levels:(1)Peripheral Sensitization:CCL2/CCR2 modulates TRPV1,Nav1.8,and HCN2 channels to increase neuronal excitability and CGRP signaling and calcium-dependent exocytosis in peripheral nociceptors to transmit pain.(2)Spinal Cord Central Sensitization:CCL2/CCR2 contributes to NMDAR-dependent plasticity,glial activation,GABAergic disinhibition,and opioid receptor desensitization.(3)Supraspinal Central Networks:CCL2/CCR2 signaling axis mediates the comorbidity mechanisms of pain with anxiety and cognitive impairment within brain regions,including the ACC,CeA,NAc,and hippocampus,and it also increases pain sensitization through the descending facilitation system.Current CCL2/CCR2-targeted therapeutic strategies and their development status are discussed,highlighting novel avenues for chronic pain management.
基金Supported by Changsha Science and Technology Program,No.kq2022397Natural Science Foundation of Hunan Province(Departmental Joint Fund),No.2023JJ60440+2 种基金Research Program of Health Commission of Hunan Province,No.202303088786Clinical Medical Research Center for Viral Hepatitis of Hunan Province,No.2023SK4009the Scientific Research Program of FuRong Laboratory,No.2023SK2108.
文摘BACKGROUND C-X-C chemokine receptor type 5(CXCR5)^(+)CD8^(+)T cells represent a unique immune subset with dual roles,functioning as cytotoxic cells in persistent viral infections while promoting B cell responses.Despite their importance,the specific role of CXCR5^(+)CD8^(+)T cells in chronic hepatitis B(CHB),particularly during interferon-alpha(IFN-α)treatment,is not fully understood.This study aims to elucidate the relationship between CXCR5^(+)CD8^(+)T cells and sustained serologic response(SR)in patients undergoing 48 weeks of pegylated IFN-α(peg-IFN-α)treatment for CHB.AIM To elucidate the relationship between CXCR5^(+)CD8^(+)T cells and sustained SR in patients undergoing 48 weeks of peg-IFN-αtreatment for CHB.METHODS This study enrolled 60 patients with hepatitis Be antigen(HBeAg)-positive CHB undergoing 48 weeks of peg-IFN-αtreatment.Participants were assessed for eligibility based on criteria such as persistent HBsAg-positive status for at least six months,HBeAb-negative,hepatitis B virus DNA levels exceeding 2×10^(4) copies/mL,and alanine aminotransferase(ALT)levels between 2 and 10 times the upper limit of normal.Blood samples were collected at baseline and at weeks 12,24,48,and a 24-week treatment-free follow-up(week 72)to measure serum interleukin(IL)-21 concentration via ELISA and to analyze CXCR5 and programmed death-ligand 1(PD-L1)expression on CD8^(+)T cells by flow cytometry,CXCR5 is a chemokine receptor that directs immune cells to specific tissues,while PD-L1 is a protein that regulates immune responses by inhibiting T cell activity.RESULTS Patients with CHB exhibited significantly lower levels of circulating CXCR5^(+)CD8^(+)T cells compared to healthy controls(P<0.01).Notably,CXCR5^(+)CD8^(+)T cells were prominently expressed in patients who achieved sustained SR compared to non-SR(NSR).A significant correlation was observed between CXCR5 and PD-L1 expression(r=-0.189,P=0.002).However,there was no significant correlation between serum IL-21 levels and CXCR5+CD8+lymphocytes(r=-0.03,P=0.625)or serum ALT levels(r=0.026,P=0.678).CONCLUSION The enhanced expression of CXCR5^(+)CD8^(+)T cells in patients achieving HBeAg seroconversion during IFN-αtreatment suggests that these cells play a crucial role in antiviral immune responses against hepatitis B.This study highlights the potential of CXCR5^(+)CD8^(+)T cells as immune regulators in CHB,which may inform future therapeutic strategies to optimize antiviral treatments.
基金supported by the High-level Talent Research Start-up Project Funding of Henan Academy of Sciences (No.252028037)。
文摘Ethanol(EtOH)is a common trigger for gastric mucosal diseases,and mitigating oxidative stress is essential for attenuating gastric mucosal damage.Capsaicin(CAP)has been identified as a potential agent to counteract oxidative damage in the gastric mucosa;however,its precise mechanism remains unclear.This study demonstrates that CAP alleviates EtOH-induced gastric mucosal injuries through two primary pathways:by suppressing the chemokine receptor 4(CCR4)/Src/p47phox axis,thereby reducing oxidative stress,and by inhibiting the phosphorylation and nuclear translocation of nuclear factor-κB p65(NF-κB)p65,resulting in diminished inflammatory responses.These findings elucidate the mechanistic pathways of CAP and provide a theoretical foundation for its potential therapeutic application in the treatment of gastric mucosal injuries.
基金Supported by Sichuan Provincial Geriatric Health Development Center and the Sichuan Gerontological Society,No.24SCLN0138。
文摘Pancreatitis is one of the largest contributors to increased healthcare costs.It is widely accepted that exposure of acinar cells to injurious agents leads to necrosis and pancreatic enzyme activation.Inappropriate activation of trypsinogen in the pancreas is related to infiltration of leukocytes recruited by chemokines,which directly leads to acinar cell damage,and indirectly to a strong systemic inflammatory response.Otherwise,chemokines exert pleiotropic effects by recruiting immune cells during inflammation,immune surveillance,and directing cells to target organs in homeostasis.Here,we give a brief introduction to the basic molecular and cellular sources of chemokines,and focus on their pleiotropic functions in acute pancreatitis,chronic pancreatitis,autoimmune pancreatitis,and pancreatic cancer.Understanding the interaction between these processes is helpful for devising therapeutic strategies for pancreatitis.
基金supported by grants from the National Natu-ral Science Foundation of China(52072005 and 51872279).
文摘Background:The incidence of spontaneously ruptured hepatocellular carcinoma(srHCC)has been shown to significantly elevate mortality rates.However,the precise mechanisms underlying srHCC remain poorly understood.Methods:Analysis was conducted on the data of 198 hepatocellular carcinoma(HCC)patients to inves-tigate the factors contributing to srHCC.The clinical data of 33 transcriptome HCC patients were served for verification.An in-depth transcriptome analysis was conducted to investigate the distinctions between 26 cases of srHCC and 35 cases of non-ruptured hepatocellular carcinoma(nrHCC).Weighted Gene Co-expression Network Analysis(WGCNA)tool was utilized to develop a gene co-expression network.Gene ontology(GO)and Kyoto encyclopedia of genes and genomes(KEGG)pathways enrichment,and protein-protein interaction(PPI)network were carried out.The corresponding samples for spontaneously rup-tured hepatocellular carcinoma tissue(srHCC-T)and ruptured hepatocellular carcinoma paracancerous tissue(srHCC-P)were selected for verification.Transcriptional data were validated through reverse tran-scription quantitative polymerase chain reaction(RT-qPCR).Immunofluorescence(IF),immunohistochem-istry(IHC)and Western blot were used to detect the protein expression.Results:Our results showed that white blood cell(WBC)and monocyte levels were significant inde-pendent risk factors for srHCC(P<0.05).There was a strong association between the srHCC-T and the expression of cell cycle-related genes BUB1B and macrophage function-related gene MACRO.Furthermore,chemokines and the PI3K/AKT signaling pathway play a crucial role in regulating the cell cycle process through a complex network of interactions,ultimately impacting the occurrence of srHCC.Conclusions:Our study confirms that chemokines and the PI3K/AKT signaling pathway mediate the occur-rence of HCC rupture by regulating the cell cycle.We provide a theoretical basis for the clinical treatment of srHCC.
基金supported by the National Natural Science Foundation of China(Grant Nos.:32070671 and 32270690)supported by West China Hospital and Sichuan University,China。
文摘Acute high-altitude(HA)illnesses(AHAIs),including acute mountain sickness(AMS),HA cerebral edema(HACE),and HA pulmonary edema(HAPE),represent significant health challenges for individuals rapidly ascending to high altitudes.Cytokines(interleukins(ILs))and chemokines,which are involved in inflammatory and immunological responses,regulate the response of the body to hypoxic stress.Their dysregulation can contribute to the clinical symptoms of AMS,HACE,and HAPE by increasing vascular permeability,causing edema and damaging tissue.AHAIs elevate the levels of pro-inflammatory cytokines and chemokines,such as IL-17,tumor necrosis factorα(TNF-α),IL-1,IL-6,C-X-C motif chemokine ligand(CXCL)10,CXCL8,C-C motif ligand 2(CCL2),and CCL3,exacerbating symptoms.Thus,this review focuses on the cytokines and chemokines involved in AHAIs and the molecular mechanisms that extend beyond these cytokines and chemokines in clinical and preclinical contexts.Identifying these mediators and pathways helps researchers design drugs that reduce symptoms,slow disease progression,and enhance outcomes.Cytokines and chemokines have complex functions in these disorders and may serve as prospective therapeutic targets.Finally,we discuss treatment possibilities for AHAIs(drugs,exercise,and other inhibitors).This knowledge will help us to protect and improve the health of individuals at high altitudes.
基金Supported by the Qingpu Science and Technology Commission Project,No.QKY2022-13.
文摘BACKGROUND Sarcosine dehydrogenase(SARDH)and C-X-C motif chemokine ligand 1(CXCL1)have been identified as potential tumor regulators,with growing evidence linking them to cancer progression.However,their specific roles,regulatory mechanisms,and influence on key signaling pathways remain unclear.AIM To investigate the regulatory mechanisms of SARDH and CXCL1 in cancer cells and their impact on key signaling pathways.METHODS Real-time quantitative polymerase chain reaction and western blot analyses were used to assess the expression levels of SARDH and CXCL1 and their effects on protein kinase B(Akt)and extracellular signal-regulated kinase(ERK)signaling pathways.Gene overexpression was induced using an expression vector,while gene silencing was achieved using short hairpin RNA and small interfering RNA.CCK-8,migration,and invasion assays were used to evaluate the impact of gene suppression and overexpression on cancer cell proliferation,migration,and invasion.RESULTS SARDH silencing significantly enhanced cancer cell proliferation,whereas its overexpression suppressed proliferation in the early stages of the experiment.CXCL1 silencing reduced cancer cell migration and invasion.SARDH overexpression inhibited cell migration,invasion,and adhesion while increasing apoptosis.Conversely,SARDH silencing reversed these effects.Furthermore,simultaneous silencing of SARDH and CXCL1 strongly activated the Akt and ERK signaling pathways,indicating the potential role of these pathways in regulating cellular functions influenced by these genes.CONCLUSION This study revealed that SARDH and CXCL1 regulate cancer cell growth,migration,and invasion through Akt and ERK signaling pathways,highlighting their potential as therapeutic targets for cancer treatment.
文摘AIM： To evaluate and compare the expression profiles of CXCL12 （SDF-1）, CCL19 （MIP-3β）, CCL20 （MIP-3a） and CCL21 （6Ckine, Exodus2） and their receptors on RNA and protein levels in hepatocellular carcinoma （HCC） versus colorectal liver metastases （CRLM） and to elucidate their impact on the carcinogenesis and progression of malignant liver diseases. METHODS： Chemokine expression was analyzed by RT-PCR and ELISA in 11 cases of HCC specimens and in 23 cases of CRLM and corresponding adjacent nontumorous liver tissues, respectively. Expressions of their receptors CXCR4, CCR6 and CCR7 were analyzed by RT- PCR and Western blot analysis in the same cases of HCC and CRLM. RESULTS： Significant up-regulation for CCL20/CCR6 was detected in both cancer types. Moreover, CCL20 demonstrated significant overexpression in CRLM in relation to the HCC tissues. Being significantly up-regulated only in CRLM, CXCR4 displayed an aberrant expression pattern with respect to the HCC tissues. CONCLUSION： Correlation of CXCR4 expression with CRLM suggests CXCR4 as a potential predictive factor for CRLM. High level expression of CCL20 and its receptor CCR6 in HCC and CRLM with marked up-regulation of CCL20 in CRLM in relation to HCC tissues indicates involvement of the CCL20/CCR6 ligand-receptor pair in the carcinogenesis and progression of hepatic malignancies.
基金Supported by Basic Science Research Program through the National Research of Korea(NRF)funded by the Ministry of Education,Science and Technology,NRF-2009-0076540,NRF-2009-0067256
文摘Gastric cancer is the fourth most common cancer,and the second-highest cause of cancer-related deaths worldwide.Despite extensive research to identify novel diagnostic and therapeutic agents,patients with advanced gastric cancer suffer from a poor quality of life and poor prognosis,and treatment is dependent mainly on conventional cytotoxic chemotherapy.To improve the quality of life and survival of gastric cancer patients,a better understanding of the underlying molecular pathologies,and their application towards the development of novel targeted therapies,is urgently needed.Chemokines are a group of small proteins associated with cytoskeletal rearrangements,the directional migration of several cell types during development and physiology,and the host immune response via interactions with G-protein coupled receptors.There is also growing evidence to suggest that chemokines not only play a role in the immune system,but are also involved in the development and progression of tumors.In gastric cancer,CXC chemokines and chemokine receptors regulate the trafficking of cells in and out of the tumor microenvironment.CXC chemokines and their receptors can also directly influence tumorigenesis by modulating tumor transformation,survival,growth,invasion and metastasis,as well as indirectly by regulating angiogenesis,and tumor-leukocyte interactions.In this review,we will focus on the roles of CXC chemokines and their receptors in the development,progression,and metastasis of gastric tumors,and discuss their therapeutic potential for gastric cancer.
基金Supported by Grants from "Fiscam" J.C.C.M (Ayuda paraproyectos de investigación en saludPI-2007/32)+7 种基金"AsociaciónCastellana de Aparato Digestivo" (Beca ACADACAD/06)"Fundación de Investigación Médica Mutua Madrilea"(Beca Ayudas a la Investigación FMMM2548/2008),Spainsupported by a research grantfrom "Fiscam" J.C.C.M ("Perfeccionamiento y movilidad deinvestigadores" MOV-2007_JI/18), Spainsupported by a research grant from "Instituto de SaludCarlos Ⅲ" (Contrato de apoyo a la investigación en el SNS"CA07/00157),Spain
文摘Chemokines produced in the liver during hepatitis C virus(HCV) infection induce migration of activated T cells from the periphery to infected parenchyma.The milieu of chemokines secreted by infected hepatocytes is predominantly associated with the T-helper cell/Tc1 T cell(Th1/Tc1) response.These chemokines consist of CCL3(macrophage inflammatory protein-1α;MIP-1α),CCL4(MIP-1β),CCL5(regulated on activation normal T cell expressed and secreted;RANTES),CXCL10(interferon-γ-inducible protein-10;IP-10),CXCL11(interferon-inducible T-cell α chemoattractant;I-TAC),and CXCL9(monokine induced by interferon γ;Mig) and they recruit T cells expressing either CCR5 or CXCR3 chemokine receptors.Intrahepatic and peripheral blood levels of these chemokines are increased during chronic hepatitis C.The interaction between chemokines and their receptors is essential in recruiting HCV-specific T cells to control the infection.When the adaptive immune response fails in this task,non-specific T cells without the capacity to control the infection are also recruited to the liver,and these are ultimately responsible for the persistent hepatic damage.The modulation of chemokine receptor expression and chemokine secretion could be a viral escape mechanism to avoid specific T cell migration to the liver during the early phase of infection,and to maintain liver viability during the chronic phase,by impairing non-specific T cell migration.Some chemokines and their receptors correlate with liver damage,and CXCL10(IP-10) and CXCR3 levels have shown a clinical utility as predictors of treatment response outcome.The regulation of chemokines and their receptors could be a future potential therapeutic target to decrease liver inflammation and to increase specific T cell migration to the infected liver.
文摘Chemokines belong to a superfamily of small, cytokinelike proteins, which induce multiple physiological functions, particularly cytoskeletal rearrangement and compartment-specific migration through their interaction with G-protein-coupled receptors. Chemokines and their receptors have been widely acknowledged as essential and selective mediators in leukocyte migration in inflammatory response. It is now established that the chemokine/chemokine receptor system is also used by cancer cells to direct lymphatic and haematogenous spreading and additionally has an impact on the site of metastatic growth of different tumours. In recent years an increasing number of studies have drawn attention to CC-chemokine cysteine motif chemokine ligand 20(CCL20) and its physiological sole receptor CCR6 to play a role in the onset, development and metastatic spread of various gastrointestinal cancer entities. Among various cancer types CCR6 was also demonstrated to be significantly overexpressed in colorectal cancer(CRC) and stimulation by its physiological ligand CCL20 has been reported to promote CRC cell proliferation and migration in vitro. Further, the CCL20/CCR6 system apparently plays a role in the organ-selective liver metastasis of CRC. Here we review the literature on expression patterns of CCL20 and CCR6 and their physiological interactions as well as the currently presumed role of CCL20 and CCR6 in the formation of CRC and the development of liver metastasis, providing a potential basis for novel treatment strategies.
基金Supported by National Science Foundation of China,No.31471147
文摘The chemokine system consists of four different subclasses with over 50 chemokines and 19 receptors. Their functions in the immune system have been well elucidated and research during the last decades unveils their new roles in hepatocellular carcinoma(HCC). The chemokines and their receptors in the microenvironment influence the development of HCCby several aspects including:inflammation,effects on immune cells,angiogenesis,and direct effects on HCC cells. Regarding these aspects,pre-clinical research by targeting the chemokine system has yielded promising data,and these findings bring us new clues in the chemokine-based therapies for HCC.
基金supported by the China Postdoctoral Science Foundation,No.2020M681689(to YMH)the Basic Scientific Research Projects of Nantong,Nos.JC2020015(to HX)and JC2020041(to YMH)。
文摘Spinal cord injury causes accumulation of a large number of leukocytes at the lesion site where they contribute to excessive inflammation.Overproduced chemokines are responsible for the migratory process of the leukocytes,but the regulatory mechanism underlying the production of chemokines from resident cells of the spinal cord has not been fully elucidated.We examined the protein levels of macrophage migration inhibitory factor and chemokine C-C motif chemokine ligand 2 in a spinal cord contusion model at different time points following spinal cord injury.The elevation of macrophage migration inhibitory factor at the lesion site coincided with the increase of chemokine C-C motif chemokine ligand 2 abundance in astrocytes.Stimulation of primary cultured astrocytes with different concentrations of macrophage migration inhibitory factor recombinant protein induced chemokine C-C motif chemokine ligand 2 production from the cells,and the macrophage migration inhibitory factor inhibitor 4-iodo-6-phenylpyrimidine attenuated the stimulatory effect.Further investigation into the underlying mechanism on macrophage migration inhibitory factor-mediated astrocytic production of chemokine C-C motif chemokine ligand 2 revealed that macrophage migration inhibitory factor activated intracellular JNK signaling through binding with CD74 receptor.Administration of the macrophage migration inhibitory factor inhibitor 4-iodo-6-phenylpyrimidine following spinal cord injury resulted in the reduction of chemokine C-C motif chemokine ligand 2-recruited microglia/macrophages at the lesion site and remarkably improved the hindlimb locomotor function of rats.Our results have provided insights into the functions of astrocyte-activated chemokines in the recruitment of leukocytes and may be beneficial to develop interventions targeting chemokine C-C motif chemokine ligand 2 for neuroinflammation after spinal cord injury.
基金Supported by a grant from the Department of Health of Sichuan province (010061)
文摘Objective To determine the levels of CC chemokine ligand 5 (CCL5) in serum and synovial fluid (SF) from patients with rheumatoid arthritis (RA) and their relations with disease activity and medication. Methods CCL5 in serum and SF was quantified by enzyme-linked immunosorbent assay (ELISA) in 28 RA patients and 21 osteoarthritis (OA) patients. In RA patients, the correlations of CCL5 levels in serum and SF with disease activity were analyzed. Meanwhile, the serum CCL5 levels among RA patients treated with disease-modifying antirheumatic drugs (DMARDs), Tripterygium Glucosides, and other Chinese herbs without disease-modifying effects were also compared. Results CCL5 levels in both serum and SF of RA patients were significantly higher than those of OA patients (P<0.05). Moreover, the level of CCL5 was higher in SF than that in serum of RA patients (P<0.01). Serum CCL5 level was correlated significantly with the number of swollen joints (r=0.3329, P<0.05), erythrocyte sedimentation rate (r=0.4001, P<0.05), and C reactive protein (r=0.3735, P<0.01). In addition, the level of CCL5 had a trend of lower in patients treated with DMARDs or Tripterygium Glucosides than those treated with other Chinese herbs, although the difference was not significant among those patients due to the small number of patients in each group. Conclusions In RA patients, the expression of CCL5 increases and correlates with some clinical and laboratory parameters of RA, which indicate that CCL5 plays an important role in RA and may serve as a useful marker of disease activity. DMARDs and Tripterygium Glucosides might exert their clinical effects through reducing CCL5 production in RA.
文摘Objective: To examine expressions of chemokine receptor CXCR4 and its ligand CXCL12 in primary focus and lymphogenous metastasis of salivary adenoid cystic carcinoma (ACC) with lung metastasis. Methods: Using immunohistochemical hypersensitivity catalyzed signal amplification (CSA), expressions of chemokine receptor CXCR4 and ligand CXCL12 were detected in tissue specimens from 20 cases of primary cancer focus and lymphogenous metastasis of salivary adenoid cystic carcinoma, of which 7 cases were associated with lung metastasis and 3 with lympogenous metastasis. Twenty cases of tongue carcinoma (including 10 cases with lymphogenous metastasis) and 15 cases of mucoepidermoid carcinoma (including 5 cases with lymphogenous metastasis) were used as the malignant control group;and salivary mixed tumor (n=10), tongue leukoceratosis (n=10) and cervical lymph node reactive hyperplasia (n=10) were used as the benign control group. Results: Expression of CXCR4 in the tissues and lymph metastases of oral and maxillofacial salivary ACC, mucoepidermoid carcinoma and tongue carcinoma was significantly higher than that of the benign control group (P<0.05); expression of CXCR4 in the primary focus of ACC was significantly higher than that of the malignant control group; and expression of CXCR4 in the ACC with lung metastasis was 87.1% (6/7), significantly higher than that without lung metastasis(P<0.01). There was evident positive expression of CXCL12 in endotheliocytes of microvessels within cancer and paracancer tissues and significantly high expression of CXCL12 in lymphogenous metastasis(P<0.05). Conclusion: Chemokine receptor CXCR4 and its ligand CXCL12 may be associated with local invasion and lymphogenous metastasis of oral and maxillofacial cancer, especially with lung metastasis of salivary ACC.
基金Medical Research Council of Southeast Sweden(FORSS)and Division of Medical Diagnostics(Futurum),Region Jönköping County,Sweden.
文摘BACKGROUND Leukocytes,such as T cells and macrophages,play an important role in tumorigenesis.CC chemokine ligand(CCL)4,which is produced by lymphocytes and macrophages,has been found to be expressed in the mucosa of the gastrointestinal tract and is a potent chemoattractant for various leukocytes.AIM To examine CCL4 expression and its genetic polymorphism rs10491121 in patients with colorectal cancer(CRC)and evaluate their prognostic significance.METHODS Luminex technology was used to determine CCL4 Levels in CRC tissue(n=98),compared with paired normal tissue,and in plasma from patients with CRC(n=103),compared with healthy controls(n=97).Included patients had undergone surgical resection for primary colorectal adenocarcinomas between 1996 and 2019 at the Department of Surgery,Ryhov County Hospital,Jönköping,Sweden.Reverse transcription quantitative PCR was used to investigate the CCL4 gene expression in CRC tissue(n=101).Paired normal tissue and TaqMan single nucleotide polymorphism assays were used for the CCL4 rs10491121 polymorphism in 610 CRC patients and 409 healthy controls.RESULTS The CCL4 protein and messenger RNA expression levels were higher in CRC tissue than in normal paired tissue(90%,P<0.001 and 45%,P<0.05,respectively).CRC tissue from patients with localized disease had 2.8-fold higher protein expression levels than that from patients with disseminated disease.Low CCL4 protein expression levels in CRC tissue were associated with a 30%lower cancer-specific survival rate in patients(P<0.01).The level of plasma CCL4 was 11%higher in CRC patients than in healthy controls(P<0.05)and was positively correlated(r=0.56,P<0.01)with the CCL4 protein level in CRC tissue.The analysis of CCL4 gene polymorphism rs10491121 showed a difference(P<0.05)between localized disease and disseminated disease in the right colon,with a dominance of allele A in localized disease.Moreover,the rate of the A allele was higher among CRC patients with mucinous cancer than among those with nonmucinous cancer.CONCLUSION The present study indicates that the CRC tissue levels of CCL4 and CCL4 gene polymorphism rs10491121,particularly in the right colon,are associated with clinical outcome in CRC patients.
文摘Summary: In order to explore the possible role of CC chemokine ligand 20 (CCL20) and its receptor CC chemokine receptor 6 (CCR6) in the pathogenesis of psoriasis, the expression levels of mRNA of them in psoriatic lesions were investigated. The skin biopsies were collected from skin lesions in 35 cases of psoriasis vulgaris and 18 normal controls. RT-PCR was used to semi-quantitatively analyze the mRNA expression of CCL20 and CCR6 in the psoriatic lesions and the normal skin tissues. The results showed that the mRNA of CCL20 and CCR6 was present in every specimen. The expression levels of CCL20 mRNA in skin lesions were 1.1397±0.0521, which were greatly higher than those in normal controls (0.8681±0.0308) (P<0.001). The expression levels of CCR6 mRNA in skin lesions were 1.1103±0.0538, significantly higher than in the controls (0.9131±0.0433, P<0.001). These findings indicate that up-regulated expression of CCL20 and CCR6 mRNA might be related to the pathogenesis of psoriasis.
基金Supported by grants from the National Natural Science Foundation of China(No.81871911[W.H.],No.81772623[L.X.],and No.81972237[L.X.])the National Key Research and Development Program of China(No.2018YFC1312103[L.X.]).
文摘The difficulty of early diagnosis,high tumor heterogeneity,and high recurrence and metastasis rates lead to an unsatisfactory treatment status for hepatocellular carcinoma(HCC).HCC is a typical inflammation-driven tumor.Chronic inflammation allows nascent tumors to escape immunosurveillance.Chemokines are small,soluble,secreted proteins that can regulate the activation and trafficking of immune cells during inflammation.Several studies have shown that various chemokines with overarching functions disrupt the immune microenvironment during the initiation and progression of HCC.The dysregulated chemokine network in HCC contributes to multiple malignant processes,including angiogenesis,tumor proliferation,migration,invasion,tumor low response,and resistance to immune therapy.Here,we summarize the current studies focusing on the role of chemokines and their receptors in the HCC immune microenvironment,highlighting potential translational therapeutic uses for modulating the chemokine system in HCC.
