In this editorial,we focus specifically on the mechanisms by which pancreatic inflammation affects pancreatic cancer.Cancer of the pancreas remains one of the deadliest cancer types.The highest incidence and mortality...In this editorial,we focus specifically on the mechanisms by which pancreatic inflammation affects pancreatic cancer.Cancer of the pancreas remains one of the deadliest cancer types.The highest incidence and mortality rates of pancreatic cancer are found in developed countries.Trends of pancreatic cancer incidence and mortality vary considerably worldwide.A better understanding of the etiology and identification of the risk factors is essential for the primary prevention of this disease.Pancreatic tumors are characterized by a complex microenvironment that orchestrates metabolic alterations and supports a milieu of interactions among various cell types within this niche.In this editorial,we highlight the foundational studies that have driven our understanding of these processes.In our experimental center,we have carefully studied the mechanisms of that link pancreatic inflammation and pancreatic cancer.We focused on the role of mast cells(MCs).MCs contain pro-angiogenic factors,including tryptase,that are associated with increased angiogenesis in various tumors.In this editorial,we address the role of MCs in angiogenesis in both pancreatic ductal adenocarcinoma tissue and adjacent normal tissue.The assessment includes the density of c-Kit receptor-positive MCs,the density of tryptase-positive MCs,the area of tryptasepositive MCs,and angiogenesis in terms of microvascularization density.展开更多
Probiotics have great potential in regulating intestinal pain.In this study,the effects of Lactobacillus plantarum AR495 on the visceral sensitivity and gut microbiota of irritable bowel syndrome(IBS)rats were studied...Probiotics have great potential in regulating intestinal pain.In this study,the effects of Lactobacillus plantarum AR495 on the visceral sensitivity and gut microbiota of irritable bowel syndrome(IBS)rats were studied.The results showed that tryptase released after mast cell activation and degranulation plays a key role in visceral pain,and L.plantarum AR495 reduced the stimulation of colonic mast cells and the expression of protease-activated receptor 2(PAR2)and TRPV1 in dorsal root ganglia.Research further showed that supplementation with L.plantarum AR495 increased the level of short-chain fatty acids(SCFAs)and enhanced the barrier function of the colon.In addition,the microbiota analysis of the colon indicated that L.plantarum AR495 promoted the proliferation of Bifidobacterium and inhibited the proliferation of Lachnospiraceae,which alleviated the imbalance of the intestinal microbiota caused by IBS to a certain extent.In total,L.plantarum AR495 might reduce visceral sensitivity through the Mast cell-PAR2-TRPV1 signaling pathway by maintaining the homeostasis of the intestinal barrier.展开更多
BACKGROUND Mast cell leukemia(MCL),a subtype of systemic mastocytosis(SM),is an extremely rare clinical entity characterized by a very poor prognosis.Chemotherapy,tyrosine kinase inhibitors,and allogeneic hematopoieti...BACKGROUND Mast cell leukemia(MCL),a subtype of systemic mastocytosis(SM),is an extremely rare clinical entity characterized by a very poor prognosis.Chemotherapy,tyrosine kinase inhibitors,and allogeneic hematopoietic cell transplantation are the only treatment options,but they cannot provide the desired outcomes in most cases of MCL.However,other types of SM can be successfully treated.The disease has no specific manifestation,but gastroenterological symptoms are present in most cases.CASE SUMMARY The authors,hereby,report a case of a 46-year-old female patient diagnosed with MCL-the rarest subtype of SM.The patient presented to the gastroenterology clinic with multiple,various,and unspecific gastroenterological symptoms.Concomitance of skin lesions significantly contributed to a relatively prompt diagnosis.The serum tryptase level was extremely high and bone the marrow aspirate showed an infiltration of atypical mast cells.The disease was rapidly progressive and primary refractory to chemotherapy and the patient succumbed to the illness about a month after the initiation of treatment.CONCLUSION Despite its“hematological nature”,MCL,in most cases presents dominantly with unspecific gastroenterological symptoms.Thus,a high disease awareness among physicians other than hematologists is necessary to improve treatment outcomes.Serum tryptase level,due to its non-invasive nature and easy access,may serve as an initial step to estimate the probability of mastocytosis.展开更多
Mast cells are a subtype of white blood cells and are involved in the immune system.These cells contain many chemical substances called mediators,which are involved in the allergic response.The fact that mast cells pl...Mast cells are a subtype of white blood cells and are involved in the immune system.These cells contain many chemical substances called mediators,which are involved in the allergic response.The fact that mast cells play a role in many events that require urgent intervention,especially anaphylaxis,has led to a more detailed study of these cells.The diseases also caused by dysfunctions of mast cells have been examined in many circumstances.For instance,mast cell activation syndrome is known as an augmented number of cells due to decreased cell death,resulting in clinical symptoms affecting many systems.The main common symptoms include flushing,hypotension,urticaria,angioedema,headache,vomiting and diarrhea.Although the underlying mechanism is not yet clearly known,we aim to review the literature in a broad perspective and bring together the existing knowledge in the light of the literature due to the diversity of its involvement in the body and the fact that it is a little known syndrome.展开更多
AIM: To evaluate vascular endothelial growth factor(VEGF) and tryptase in hepatocellular cancer(HCC)before and after trans-arterial chemoembolization(TACE).METHODS: VEGF and tryptase serum concentrations were assessed...AIM: To evaluate vascular endothelial growth factor(VEGF) and tryptase in hepatocellular cancer(HCC)before and after trans-arterial chemoembolization(TACE).METHODS: VEGF and tryptase serum concentrations were assessed from 71 unresectable HCC patients before and after hepatic TACE performed by binding DC-Beads?to doxorubicin. VEGF levels were examined for each serum sample using the Quantikine Human VEGF-enzyme-linked immuno-absorbent assay(ELISA),whereas tryptase serum concentrations were assessed for each serum sample by means of fluoro-enzyme immunoassay(FEIA) using the Uni-CAP100 tool.Differences between serum VEGF and tryptase values before and after TACE were evaluated using Student t test. Person's correlation was used to assess the degree of association between the two variables.RESULTS: VEGF levels and serum tryptase in HCCpatients before TACE had a mean value and standard deviation(SD) of 114.31 ± 79.58 pg/mL and 8.13± 3.61 μg/L, respectively. The mean levels and SD of VEGF levels and serum tryptase in HCC patients after TACE were 238.14 ± 109.41 pg/mL and 4.02 ±3.03 μg/L. The changes between the mean values of concentration of VEGF and tryptase before treatment and after treatment was statistically significant(P <0.000231 and P < 0.00124, by Wilcoxon-Mann-Whitney respectively). A significant correlation between VEGF levels before and after TACE and between tryptase levels before and after TACE was demonstrated(r =0.68, P = 0.003; r = 0.84, P = 0.000 respectively).CONCLUSION: Our pilot results suggest that the higher serum VEGF levels and the lower tryptase levels following TACE may be potential biomarkers changing in response to therapy.展开更多
AIM To determine the functional role of mi R-490-5p in mast cell proliferation and apoptosis,and in the mast cell tryptase/PAR-2 signal pathway.METHODS The 3rd generation of lentivirus vector systems containing enhanc...AIM To determine the functional role of mi R-490-5p in mast cell proliferation and apoptosis,and in the mast cell tryptase/PAR-2 signal pathway.METHODS The 3rd generation of lentivirus vector systems containing enhanced green fluorescent protein(EGFP)(Ruisai Inc.,Shanghai,China),which acts as a reporter gene was used to construct the mmu-mi R-490-5p lentivirus expression vector p EGFP-antagomi R-490-5p,and the lentivirus vector p EGFP-negative was used as a negative control.The stably transfected mast cell line p815 was then constructed.GFP positive cells were successfully transfected cells.We determined the expression of mi R-490-5p in p815 mast cells before and after transfection using quantitative real-time PCR(q RT-PCR).In addition,after transduction with the lentivirus vectors,the role of mi R-490-5p in mast cell proliferation and apoptosis was investigated using the CCK-8 assay and flow cytometry,respectively.The m RNA levels of tryptase and PAR-2 were detected by q RT-PCR and the protein levels were detected by Western blot.RESULTS The inhibition of mi R-490-5p expression promoted apoptosis and inhibited proliferation of p815 mast cells.The m RNA levels of tryptase and PAR-2 were significantly increased after transfection comparedwith the control group,tryptase(P=0.721,normal vs null;P=0.001,si RNA vs normal;P=0.002,si RNA vs null)and PAR-2(P=0.027,si RNA vs null;P=0.353,normal vs null;P=0.105,si RNA vs normal).The protein levels of tryptase and PAR2 were slightly higher in the si RNA group than those in the control group,but the difference was not statistically significant(P>0.05).CONCLUSION mi R-490-5p plays a vital role in the pathogenesis of irritable bowel syndrome by affecting mast cell proliferation and apoptosis;with down-regulation of mi R-490-5p,the m RNA level of mast cell tryptase and PAR-2 increased,and the protein level increased,but the difference was not statistically significant.展开更多
Mast cells (MCs), located ubiquitously near blood vessels, are descended from CD34<sup>+</sup> hematopoietic stem cells. Initially, although their role has been well defined in hypersensitivity reactions, ...Mast cells (MCs), located ubiquitously near blood vessels, are descended from CD34<sup>+</sup> hematopoietic stem cells. Initially, although their role has been well defined in hypersensitivity reactions, the discovery of their sharing in both innate and adaptive immunity has allowed to redefine their crucial interplay on the regulatory function between inflammatory and tumor cells through the release of mediators granule-associated (mainly tryptase and vascular endothelial growth factor). In particular, in several animal and human malignancies it has been well demonstrated that activated c-Kit receptor (c-KitR) and tryptase (an agonist of the proteinase-activated receptor-2) take pivotal part in tumor angiogenesis after the MCs activation, contributing to tumor cells invasion and metastasis. In this review, we focused on crucial MCs density (MCD) role in colorectal cancer (CRC) development and progression angiogenesis-mediated; then, we will analyze the principal studies that have focused on MCD as possible prognostic factor. Finally, we will consider a possible role of MCD as novel therapeutic target mainly by c-KitR tyrosine kinase inhibitors (imatinib, masitinib) and tryptase inhibitors (gabexate and nafamostat mesylate) with the aim to prevent CRC progression.展开更多
AIM: To investigate the expression of mast cell tryptase and carboxypeptidase A in drug-related fatal anaphylaxis.METHODS: The expression of mast cell tryptase and carboxypeptidase A in 15 autopsy cases of drugrelated...AIM: To investigate the expression of mast cell tryptase and carboxypeptidase A in drug-related fatal anaphylaxis.METHODS: The expression of mast cell tryptase and carboxypeptidase A in 15 autopsy cases of drugrelated fatal anaphylaxis and 20 normal autopsy cases were detected. First, the expression of mast cell tryptase was determined in stomach, jejunum, lung, heart, and larynx by immunofluorescence. Different tissues were removed and fixed in paraformaldehyde solution, then paraffin sections were prepared for immunofluorescence. Using specific mast cell tryptase and carboxypeptidase A antibodies, the expression of tryptase and carboxypeptidase A in gastroenterology tract and other tissues were observed using fluorescent microscopy. The postmortem serum and pericardial fluid were collected from drug-related fatal anaphylaxis and normal autopsy cases. The level of mast cell tryptase and carboxypeptidase A in postmortem serum and pericardial fluid were measured using fluor enzyme linked immunosorbent assay(FEIA) and enzyme linked immunosorbent assay(ELISA) assay. The expression of mast cell tryptase and carboxypeptidase A was analyzed in drug-related fatal anaphylaxis cases and compared to normal autopsy cases.RESULTS: The expression of carboxypeptidase A was less in the gastroenterology tract and other tissues from anaphylaxis-related death cadavers than normal controls. Immunofluorescence revealed that tryptase expression was significantly increased in multiple organs, especially the gastrointestinal tract, from anaphylaxis-related death cadavers compared to normal autopsy cases(46.67 ± 11.11 vs 4.88 ± 1.56 in stomach, 48.89 ± 11.02 vs 5.21 ± 1.34 in jejunum, 33.72 ± 5.76 vs 1.30 ± 1.02 in lung, 40.08 ± 7.56 vs 1.67 ± 1.03 in larynx, 7.11 ± 5.67 vs 1.10 ± 0.77 in heart, P < 0.05). Tryptase levels, as measured with FEIA, were significantly increased in both sera(43.50 ± 0.48 μg/L vs 5.40 ± 0.36 μg/L, P < 0.05) and pericardial fluid(28.64 ± 0.32 μg/L vs 4.60 ± 0.48 μg/L, P < 0.05) from the anaphylaxis group in comparison with the control group. As measured by ELISA, the concentration of carboxypeptidase A was also increased more than 2-fold in the anaphylaxis group compared to control(8.99 ± 3.91 ng/m L vs 3.25 ± 2.30 ng/m L in serum, 4.34 ± 2.41 ng/m L vs 1.43 ± 0.58 ng/m L in pericardial fluid, P < 0.05).CONCLUSION: Detection of both mast cell tryptase and carboxypeptidase A could improve the forensic identification of drug-related fatal anaphylaxis.展开更多
Objective： To explore the effects of down-regulated tryptase expression in mast cells on the synthesis and release of interleukin-6 （IL-6） and tumor necrosis factor-alpha （TNF-α） of vascular endothelial cells. M...Objective： To explore the effects of down-regulated tryptase expression in mast cells on the synthesis and release of interleukin-6 （IL-6） and tumor necrosis factor-alpha （TNF-α） of vascular endothelial cells. Methods： Tryptase-siRNA （small-interfering RNA） vector was constructed to inhibit tryptase expression in P815 cells. The medium of P815 cells treated by the tryptase-siRNA （RNAi-P815 group） or pure vector （P815 group） was collected and used to culture bEnd.3 cells. The messenger RNAs （mRNAs） of IL-6 and TNF-α in bEnd.3 cells and their protein levels in the medium were measured by reverse transcription polymerase chain reaction （RT-PCR） and enzyme-linked immunosorbent assay （ELISA）, respectively. Results： IL-6 and TNF-α mRNAs in bEnd.3 cells cultured in RNAi-P815-conditioned medium decreased significantly compared to those in P815-conditioned medium. Consistently, lL-6 and TNF-α protein levels in the medium of bEnd.3 of RNAi-P815 group were lower than those of P815 group. Conclusion： Reduced tryptase expression significantly inhibited the synthesis and release of IL-6 and TNF-α in vascular endothelial cells. RNA interference targeting tryptase expression may be a new anti-inflammatory strategy for vascular diseases.展开更多
As recognition of mast cell(MC) involvement in a range of chronic inflammatory disorders has increased, diagnosticians' suspicions of MC activation disease(MCAD) in their chronically mysteriously inflamed patients...As recognition of mast cell(MC) involvement in a range of chronic inflammatory disorders has increased, diagnosticians' suspicions of MC activation disease(MCAD) in their chronically mysteriously inflamed patients have similarly increased. It is now understood that the various forms of systemic mastocytosis- diseases of inappropriate activation and proliferation of MCs seemingly driven by a small set of rare, usually constitutively activating mutations in assorted MC regulatory elements-comprise merely the tip of the MCAD iceberg, whereas the far larger and far more clinically heterogeneous(and thus more difficult to recognize) bulk of the iceberg consists of assorted forms of MC activation syndrome(MCAS) which manifest little to no abnormal MC proliferation and may originate from a far more heterogeneous set of MC mutations. It is reasonable to suspect MCAD when symptoms and signs of MC activation are present and no other diagnosis better accounting for the full range of findings is present. Initial laboratory assessment should include not only routine blood counts and serum chemistries but also a serum total tryptase level, which helps direct further evaluation for mastocytosis vs MCAS. Appropriate tissue examinations are needed to diagnose mastocytosis, while elevated levels of relatively specific mast cell mediators are sought to support diagnosis of MCAS. Whether assessing for mastocytosis or MCAS, testing is fraught with potential pitfalls which can easily yield false negatives leading to erroneous rejection of diagnostic consideration of MCAD in spite of a clinical history highly consistent with MCAD. Efforts at accurate diagnosis of MCAD are worthwhile, as many patients then respond well to appropriately directed therapeutic efforts.展开更多
Objective:To explore the effect of 1,25-dihydroxyvitamin D3 on the mast cell tryptase(MCT) in asthmatic guinea pigs.Methods:A total of 60 male or female healthy guinea pigs were randomly divided into control group(gro...Objective:To explore the effect of 1,25-dihydroxyvitamin D3 on the mast cell tryptase(MCT) in asthmatic guinea pigs.Methods:A total of 60 male or female healthy guinea pigs were randomly divided into control group(group A),asthmatic group(group B).and 1,25-dihydroxyvitamin D3 group(group C),with 20 cases in each group.To establish asthmatic guinea pig models,1ml peanut oil was tilled into stomach in the morning in group A and group B.and 1 ml peanut oil with 1,25-dihydroxyvitamin D3 was filled into stomach in group C.Airway resistance(Re) of asthmatic guinea pigs was detected,and the bronchoalveolar lavage fluid(BALF) cells were counted.Lung tissue with HE and MCT immunohistochemical staining were used to observe the pathological changes in lung tissue and the distribution of MCT.Results:After injection of different concentration of acetylcholine chloride,the Re in group B and group C were increased significantly compared with group A(P<0.05):compared with group B.the Re in group C were decreased significantly(t=-5.385.-5.761.-6.184.-13.574.P<0.05):the total number of BALF cells and eosinophils were increased significantly in group B and C(t=19.618.9.598.10.854.5.388.P<0.05);compared with group B.the total number of BALF cells and eosinophils in group C was decreased significantly(t=-5.555.-5.392.P<0.05):the number of tryptase positive cells in group B was increased significantly than that in group A(t=21.312,P<0.05),and in addition to the alveolar septum and submucosa,the cells were also distributed around blood vessels and outside the cells:the number of tryptase positive cells in group C was decreased significantly compared with group B.and the difference was statistically significant(t=5.043.P<0.05).Conclusions:After the asthmatic guinea pigs arc treated with 1,25-dihydroxyvitamin D3,their BALF.Re.infiltration degree of inflammatory cells in the trachea and lung tissue and airway inflammatory reaction are reduced significantly.1,25-dihydroxyvitamin D3 has a certain inhibiting effect on the activation of mast cells and the release of MCT granules.展开更多
AIM:To validate methods for determining mast cell density,extracellular major basic protein content,and presence of fibrosis in esophageal eosinophilia.METHODS:Twenty specimens with > 20 eosinophils/high-power fiel...AIM:To validate methods for determining mast cell density,extracellular major basic protein content,and presence of fibrosis in esophageal eosinophilia.METHODS:Twenty specimens with > 20 eosinophils/high-power field(hpf) classified as high eosinophil density(HE) and 20 specimens with < 5 eosinophils/hpf classified as low esophageal density(LE) were identified.All 40 specimens underwent immunohistochemical staining and trichrome staining.Mast cell density,extracellular major basic protein(MBP) density,and presence of subepithelial fibrosis were assessed in a standardized manner.All specimens were evaluated by two separate observers and by a single observer on two separate occasions to evaluate reproducibility of the methods.RESULTS:A strong inter-observer correlation was noted for both peak and mean mast cell counts(r = 0.725,P < 0.0001 and r = 0.823,P < 0.0001).A strong intraobserver correlation also was noted for both peak and mean mast cell counts(r = 0.752,P < 0.0001 and r =0.878,P < 0.0001).A very strong inter-observer correlation was noted for both peak(τ = 0.867,P < 0.0001)and mean extracellular MBP densities(r = 0.925,P <0.0001).A very strong intra-observer correlation was noted for both peak(τ = 0.875;P < 0.0001) and mean extracellular MBP densities(r = 0.956,P < 0.0001).Excellent inter-rater reliability was found for fibrosis(κ= 0.887).Mast cell and MBP densities,as well as presence of fibrosis,were significantly increased in HE vs LE.The HE group had significantly higher intraepithelial mast cell peak(29.35 ± 21.61 vs 12.45 ± 8.26,P =0.002) and mean(19.84 ± 15.81 vs 6.35 ± 4.5,P =0.001) densities than the LE group.The HE group had significantly higher peak extracellular MBP(2.35 ± 0.67vs 0.45 ± 0.61,P < 0.001) and mean extracellular MBP(1.95 ± 0.76 vs 0.20 ± 0.29,P < 0.0001) densities than the LE group.Seventy-three percent of patients with HE(11/15) had fibrosis,whereas only 10% of patients with LE(1/10) had fibrosis(P < 0.01).MBP performed the best in predicting classification of HE vs LE,with mean MBP demonstrating 100% sensitivity and95% specificity at the optimal cut point.CONCLUSION:This study provides methodology and proof-of-concept for future evaluation of these biomarkers for differentiating esophageal eosinophilic diseases such as reflux esophagitis and eosinophilic esophagitis.展开更多
Systemic mastocytosis (SM) is a heterogeneous disease of the bone marrow characterized by abnormal growth, accumulation and activation of clonal mast cells (MCs). We report a case of SM with multiorgan involvement. A ...Systemic mastocytosis (SM) is a heterogeneous disease of the bone marrow characterized by abnormal growth, accumulation and activation of clonal mast cells (MCs). We report a case of SM with multiorgan involvement. A 30-year-old man presented with diarrhea, flushing, maculopapular rash with itching and weight loss. The upper and lower gastrointestinal endoscopies showed macroscopic involvement of stomach and duodenum; mucosal samples from stomach, duodenum, colon and distal ileum showed mucosal inf iltration by large, spindleshaped MCs with abnormal surface molecule expression (CD2 and CD25), a picture fully consistent with SM, according to the World Health Organization diagnostic criteria. A computed tomography scan showed diffuse lymphadenopathy, hepatosplenomegaly and diffuse small bowel involvement. Bone marrow aspirate and biopsy were diagnostic for SM; serum tryptase levels were increased (209 ng/mL, normal values < 20 ng/mL). The conclusive diagnosis was smouldering SM. There wereno therapeutic indications except for treatment of symptoms. The patient was strictly followed up because of the risk of aggressive evolution.展开更多
In some cases of fatalities involving opioid use,the concentrations of detected opioids are not in the toxic range.Immune reactions can be triggered by opioid use,suggesting that immune response may be a factor in the...In some cases of fatalities involving opioid use,the concentrations of detected opioids are not in the toxic range.Immune reactions can be triggered by opioid use,suggesting that immune response may be a factor in these cases.Autopsy cases from 2002–2012 were reviewed.Persons with physical,microscopic or serum evidence of allergic reactions and opioid use at autopsy were compared to persons who used opioids but had no such signs.Overall,49 persons were identified who had used opioids,of which five had evidence of immune response.A medical history of asthma was significantly more common in persons with signs of immune response(P=0.0244)and fatality(P=0.0085)compared to normals.A history of asthma is suggestive of susceptibility to immunologic reactions to opioids,and correlates strongly with the cause of death.展开更多
Mast cells are emerging as players in the communication between peripheral nerve endings and cells of the immune system.However,it is not clear the mechanism by which mast cells communicate with peripheral nerves.We p...Mast cells are emerging as players in the communication between peripheral nerve endings and cells of the immune system.However,it is not clear the mechanism by which mast cells communicate with peripheral nerves.We previously found that mast cells located within healing tendons can express glutamate receptors,raising the possibility that mast cells may be sensitive to glutamate signaling.To evaluate this hypothesis,we stimulated primary mast cells with glutamate and showed that glutamate induced the profound upregulation of a panel of glutamate receptors of both the ionotropic type(NMDAR1,NMDAR2A,and NMDAR2B)and the metabotropic type(mGluR2 and mGluR7)at both the mRNA and protein levels.The binding of glutamate to glutamate receptors on the mast cell surface was confirmed.Further,glutamate had extensive effects on gene expression in the mast cells,including the upregulation of proinflammatory components such as IL-6 and CCL2.Glutamate also induced the upregulation of transcription factors,including Egr2,Egr3 and,in particular,FosB.The extensive induction of FosB was confirmed by immunofluorescence assessment.Glutamate receptor antagonists abrogated the responses of the mast cells to glutamate,supporting the supposition of a functional glutamate–glutamate receptor axis in mast cells.Finally,we provide in vivo evidence supporting a functional glutamate–glutamate receptor axis in the mast cells of injured tendons.Together,these findings establish glutamate as an effector of mast cell function,thereby introducing a novel principle for how cells in the immune system can communicate with nerve cells.展开更多
文摘In this editorial,we focus specifically on the mechanisms by which pancreatic inflammation affects pancreatic cancer.Cancer of the pancreas remains one of the deadliest cancer types.The highest incidence and mortality rates of pancreatic cancer are found in developed countries.Trends of pancreatic cancer incidence and mortality vary considerably worldwide.A better understanding of the etiology and identification of the risk factors is essential for the primary prevention of this disease.Pancreatic tumors are characterized by a complex microenvironment that orchestrates metabolic alterations and supports a milieu of interactions among various cell types within this niche.In this editorial,we highlight the foundational studies that have driven our understanding of these processes.In our experimental center,we have carefully studied the mechanisms of that link pancreatic inflammation and pancreatic cancer.We focused on the role of mast cells(MCs).MCs contain pro-angiogenic factors,including tryptase,that are associated with increased angiogenesis in various tumors.In this editorial,we address the role of MCs in angiogenesis in both pancreatic ductal adenocarcinoma tissue and adjacent normal tissue.The assessment includes the density of c-Kit receptor-positive MCs,the density of tryptase-positive MCs,the area of tryptasepositive MCs,and angiogenesis in terms of microvascularization density.
基金supported by the shanghai agriculture applied technology development program(2019-02-08-00-07-F01152)the national science fund for distinguished young scholars(32025029)+1 种基金the shanghai engineering research center of food microbiology program(19DZ2281100)the national key R&D program of china(2018YFC1604305)。
文摘Probiotics have great potential in regulating intestinal pain.In this study,the effects of Lactobacillus plantarum AR495 on the visceral sensitivity and gut microbiota of irritable bowel syndrome(IBS)rats were studied.The results showed that tryptase released after mast cell activation and degranulation plays a key role in visceral pain,and L.plantarum AR495 reduced the stimulation of colonic mast cells and the expression of protease-activated receptor 2(PAR2)and TRPV1 in dorsal root ganglia.Research further showed that supplementation with L.plantarum AR495 increased the level of short-chain fatty acids(SCFAs)and enhanced the barrier function of the colon.In addition,the microbiota analysis of the colon indicated that L.plantarum AR495 promoted the proliferation of Bifidobacterium and inhibited the proliferation of Lachnospiraceae,which alleviated the imbalance of the intestinal microbiota caused by IBS to a certain extent.In total,L.plantarum AR495 might reduce visceral sensitivity through the Mast cell-PAR2-TRPV1 signaling pathway by maintaining the homeostasis of the intestinal barrier.
文摘BACKGROUND Mast cell leukemia(MCL),a subtype of systemic mastocytosis(SM),is an extremely rare clinical entity characterized by a very poor prognosis.Chemotherapy,tyrosine kinase inhibitors,and allogeneic hematopoietic cell transplantation are the only treatment options,but they cannot provide the desired outcomes in most cases of MCL.However,other types of SM can be successfully treated.The disease has no specific manifestation,but gastroenterological symptoms are present in most cases.CASE SUMMARY The authors,hereby,report a case of a 46-year-old female patient diagnosed with MCL-the rarest subtype of SM.The patient presented to the gastroenterology clinic with multiple,various,and unspecific gastroenterological symptoms.Concomitance of skin lesions significantly contributed to a relatively prompt diagnosis.The serum tryptase level was extremely high and bone the marrow aspirate showed an infiltration of atypical mast cells.The disease was rapidly progressive and primary refractory to chemotherapy and the patient succumbed to the illness about a month after the initiation of treatment.CONCLUSION Despite its“hematological nature”,MCL,in most cases presents dominantly with unspecific gastroenterological symptoms.Thus,a high disease awareness among physicians other than hematologists is necessary to improve treatment outcomes.Serum tryptase level,due to its non-invasive nature and easy access,may serve as an initial step to estimate the probability of mastocytosis.
文摘Mast cells are a subtype of white blood cells and are involved in the immune system.These cells contain many chemical substances called mediators,which are involved in the allergic response.The fact that mast cells play a role in many events that require urgent intervention,especially anaphylaxis,has led to a more detailed study of these cells.The diseases also caused by dysfunctions of mast cells have been examined in many circumstances.For instance,mast cell activation syndrome is known as an augmented number of cells due to decreased cell death,resulting in clinical symptoms affecting many systems.The main common symptoms include flushing,hypotension,urticaria,angioedema,headache,vomiting and diarrhea.Although the underlying mechanism is not yet clearly known,we aim to review the literature in a broad perspective and bring together the existing knowledge in the light of the literature due to the diversity of its involvement in the body and the fact that it is a little known syndrome.
基金Supported by A research grant from the"Alleanza Contro il Cancro"project(partly),the Italian National Health Institute and the Italian Ministry of Health
文摘AIM: To evaluate vascular endothelial growth factor(VEGF) and tryptase in hepatocellular cancer(HCC)before and after trans-arterial chemoembolization(TACE).METHODS: VEGF and tryptase serum concentrations were assessed from 71 unresectable HCC patients before and after hepatic TACE performed by binding DC-Beads?to doxorubicin. VEGF levels were examined for each serum sample using the Quantikine Human VEGF-enzyme-linked immuno-absorbent assay(ELISA),whereas tryptase serum concentrations were assessed for each serum sample by means of fluoro-enzyme immunoassay(FEIA) using the Uni-CAP100 tool.Differences between serum VEGF and tryptase values before and after TACE were evaluated using Student t test. Person's correlation was used to assess the degree of association between the two variables.RESULTS: VEGF levels and serum tryptase in HCCpatients before TACE had a mean value and standard deviation(SD) of 114.31 ± 79.58 pg/mL and 8.13± 3.61 μg/L, respectively. The mean levels and SD of VEGF levels and serum tryptase in HCC patients after TACE were 238.14 ± 109.41 pg/mL and 4.02 ±3.03 μg/L. The changes between the mean values of concentration of VEGF and tryptase before treatment and after treatment was statistically significant(P <0.000231 and P < 0.00124, by Wilcoxon-Mann-Whitney respectively). A significant correlation between VEGF levels before and after TACE and between tryptase levels before and after TACE was demonstrated(r =0.68, P = 0.003; r = 0.84, P = 0.000 respectively).CONCLUSION: Our pilot results suggest that the higher serum VEGF levels and the lower tryptase levels following TACE may be potential biomarkers changing in response to therapy.
基金the National Natural Science Foundation of China,No.81160053(to Zhang FC)
文摘AIM To determine the functional role of mi R-490-5p in mast cell proliferation and apoptosis,and in the mast cell tryptase/PAR-2 signal pathway.METHODS The 3rd generation of lentivirus vector systems containing enhanced green fluorescent protein(EGFP)(Ruisai Inc.,Shanghai,China),which acts as a reporter gene was used to construct the mmu-mi R-490-5p lentivirus expression vector p EGFP-antagomi R-490-5p,and the lentivirus vector p EGFP-negative was used as a negative control.The stably transfected mast cell line p815 was then constructed.GFP positive cells were successfully transfected cells.We determined the expression of mi R-490-5p in p815 mast cells before and after transfection using quantitative real-time PCR(q RT-PCR).In addition,after transduction with the lentivirus vectors,the role of mi R-490-5p in mast cell proliferation and apoptosis was investigated using the CCK-8 assay and flow cytometry,respectively.The m RNA levels of tryptase and PAR-2 were detected by q RT-PCR and the protein levels were detected by Western blot.RESULTS The inhibition of mi R-490-5p expression promoted apoptosis and inhibited proliferation of p815 mast cells.The m RNA levels of tryptase and PAR-2 were significantly increased after transfection comparedwith the control group,tryptase(P=0.721,normal vs null;P=0.001,si RNA vs normal;P=0.002,si RNA vs null)and PAR-2(P=0.027,si RNA vs null;P=0.353,normal vs null;P=0.105,si RNA vs normal).The protein levels of tryptase and PAR2 were slightly higher in the si RNA group than those in the control group,but the difference was not statistically significant(P>0.05).CONCLUSION mi R-490-5p plays a vital role in the pathogenesis of irritable bowel syndrome by affecting mast cell proliferation and apoptosis;with down-regulation of mi R-490-5p,the m RNA level of mast cell tryptase and PAR-2 increased,and the protein level increased,but the difference was not statistically significant.
文摘Mast cells (MCs), located ubiquitously near blood vessels, are descended from CD34<sup>+</sup> hematopoietic stem cells. Initially, although their role has been well defined in hypersensitivity reactions, the discovery of their sharing in both innate and adaptive immunity has allowed to redefine their crucial interplay on the regulatory function between inflammatory and tumor cells through the release of mediators granule-associated (mainly tryptase and vascular endothelial growth factor). In particular, in several animal and human malignancies it has been well demonstrated that activated c-Kit receptor (c-KitR) and tryptase (an agonist of the proteinase-activated receptor-2) take pivotal part in tumor angiogenesis after the MCs activation, contributing to tumor cells invasion and metastasis. In this review, we focused on crucial MCs density (MCD) role in colorectal cancer (CRC) development and progression angiogenesis-mediated; then, we will analyze the principal studies that have focused on MCD as possible prognostic factor. Finally, we will consider a possible role of MCD as novel therapeutic target mainly by c-KitR tyrosine kinase inhibitors (imatinib, masitinib) and tryptase inhibitors (gabexate and nafamostat mesylate) with the aim to prevent CRC progression.
基金Supported by the National Natural Science Foundation of ChinaNo.81172905+1 种基金Shanxi Province Science Foundation for YouthsNo.2012021032-2
文摘AIM: To investigate the expression of mast cell tryptase and carboxypeptidase A in drug-related fatal anaphylaxis.METHODS: The expression of mast cell tryptase and carboxypeptidase A in 15 autopsy cases of drugrelated fatal anaphylaxis and 20 normal autopsy cases were detected. First, the expression of mast cell tryptase was determined in stomach, jejunum, lung, heart, and larynx by immunofluorescence. Different tissues were removed and fixed in paraformaldehyde solution, then paraffin sections were prepared for immunofluorescence. Using specific mast cell tryptase and carboxypeptidase A antibodies, the expression of tryptase and carboxypeptidase A in gastroenterology tract and other tissues were observed using fluorescent microscopy. The postmortem serum and pericardial fluid were collected from drug-related fatal anaphylaxis and normal autopsy cases. The level of mast cell tryptase and carboxypeptidase A in postmortem serum and pericardial fluid were measured using fluor enzyme linked immunosorbent assay(FEIA) and enzyme linked immunosorbent assay(ELISA) assay. The expression of mast cell tryptase and carboxypeptidase A was analyzed in drug-related fatal anaphylaxis cases and compared to normal autopsy cases.RESULTS: The expression of carboxypeptidase A was less in the gastroenterology tract and other tissues from anaphylaxis-related death cadavers than normal controls. Immunofluorescence revealed that tryptase expression was significantly increased in multiple organs, especially the gastrointestinal tract, from anaphylaxis-related death cadavers compared to normal autopsy cases(46.67 ± 11.11 vs 4.88 ± 1.56 in stomach, 48.89 ± 11.02 vs 5.21 ± 1.34 in jejunum, 33.72 ± 5.76 vs 1.30 ± 1.02 in lung, 40.08 ± 7.56 vs 1.67 ± 1.03 in larynx, 7.11 ± 5.67 vs 1.10 ± 0.77 in heart, P < 0.05). Tryptase levels, as measured with FEIA, were significantly increased in both sera(43.50 ± 0.48 μg/L vs 5.40 ± 0.36 μg/L, P < 0.05) and pericardial fluid(28.64 ± 0.32 μg/L vs 4.60 ± 0.48 μg/L, P < 0.05) from the anaphylaxis group in comparison with the control group. As measured by ELISA, the concentration of carboxypeptidase A was also increased more than 2-fold in the anaphylaxis group compared to control(8.99 ± 3.91 ng/m L vs 3.25 ± 2.30 ng/m L in serum, 4.34 ± 2.41 ng/m L vs 1.43 ± 0.58 ng/m L in pericardial fluid, P < 0.05).CONCLUSION: Detection of both mast cell tryptase and carboxypeptidase A could improve the forensic identification of drug-related fatal anaphylaxis.
基金Project (No. 30470689) supported by the National Natural ScienceFoundation of China
文摘Objective： To explore the effects of down-regulated tryptase expression in mast cells on the synthesis and release of interleukin-6 （IL-6） and tumor necrosis factor-alpha （TNF-α） of vascular endothelial cells. Methods： Tryptase-siRNA （small-interfering RNA） vector was constructed to inhibit tryptase expression in P815 cells. The medium of P815 cells treated by the tryptase-siRNA （RNAi-P815 group） or pure vector （P815 group） was collected and used to culture bEnd.3 cells. The messenger RNAs （mRNAs） of IL-6 and TNF-α in bEnd.3 cells and their protein levels in the medium were measured by reverse transcription polymerase chain reaction （RT-PCR） and enzyme-linked immunosorbent assay （ELISA）, respectively. Results： IL-6 and TNF-α mRNAs in bEnd.3 cells cultured in RNAi-P815-conditioned medium decreased significantly compared to those in P815-conditioned medium. Consistently, lL-6 and TNF-α protein levels in the medium of bEnd.3 of RNAi-P815 group were lower than those of P815 group. Conclusion： Reduced tryptase expression significantly inhibited the synthesis and release of IL-6 and TNF-α in vascular endothelial cells. RNA interference targeting tryptase expression may be a new anti-inflammatory strategy for vascular diseases.
文摘As recognition of mast cell(MC) involvement in a range of chronic inflammatory disorders has increased, diagnosticians' suspicions of MC activation disease(MCAD) in their chronically mysteriously inflamed patients have similarly increased. It is now understood that the various forms of systemic mastocytosis- diseases of inappropriate activation and proliferation of MCs seemingly driven by a small set of rare, usually constitutively activating mutations in assorted MC regulatory elements-comprise merely the tip of the MCAD iceberg, whereas the far larger and far more clinically heterogeneous(and thus more difficult to recognize) bulk of the iceberg consists of assorted forms of MC activation syndrome(MCAS) which manifest little to no abnormal MC proliferation and may originate from a far more heterogeneous set of MC mutations. It is reasonable to suspect MCAD when symptoms and signs of MC activation are present and no other diagnosis better accounting for the full range of findings is present. Initial laboratory assessment should include not only routine blood counts and serum chemistries but also a serum total tryptase level, which helps direct further evaluation for mastocytosis vs MCAS. Appropriate tissue examinations are needed to diagnose mastocytosis, while elevated levels of relatively specific mast cell mediators are sought to support diagnosis of MCAS. Whether assessing for mastocytosis or MCAS, testing is fraught with potential pitfalls which can easily yield false negatives leading to erroneous rejection of diagnostic consideration of MCAD in spite of a clinical history highly consistent with MCAD. Efforts at accurate diagnosis of MCAD are worthwhile, as many patients then respond well to appropriately directed therapeutic efforts.
基金supported by Natural Science Foundation of Guangdong Province:gd291823
文摘Objective:To explore the effect of 1,25-dihydroxyvitamin D3 on the mast cell tryptase(MCT) in asthmatic guinea pigs.Methods:A total of 60 male or female healthy guinea pigs were randomly divided into control group(group A),asthmatic group(group B).and 1,25-dihydroxyvitamin D3 group(group C),with 20 cases in each group.To establish asthmatic guinea pig models,1ml peanut oil was tilled into stomach in the morning in group A and group B.and 1 ml peanut oil with 1,25-dihydroxyvitamin D3 was filled into stomach in group C.Airway resistance(Re) of asthmatic guinea pigs was detected,and the bronchoalveolar lavage fluid(BALF) cells were counted.Lung tissue with HE and MCT immunohistochemical staining were used to observe the pathological changes in lung tissue and the distribution of MCT.Results:After injection of different concentration of acetylcholine chloride,the Re in group B and group C were increased significantly compared with group A(P<0.05):compared with group B.the Re in group C were decreased significantly(t=-5.385.-5.761.-6.184.-13.574.P<0.05):the total number of BALF cells and eosinophils were increased significantly in group B and C(t=19.618.9.598.10.854.5.388.P<0.05);compared with group B.the total number of BALF cells and eosinophils in group C was decreased significantly(t=-5.555.-5.392.P<0.05):the number of tryptase positive cells in group B was increased significantly than that in group A(t=21.312,P<0.05),and in addition to the alveolar septum and submucosa,the cells were also distributed around blood vessels and outside the cells:the number of tryptase positive cells in group C was decreased significantly compared with group B.and the difference was statistically significant(t=5.043.P<0.05).Conclusions:After the asthmatic guinea pigs arc treated with 1,25-dihydroxyvitamin D3,their BALF.Re.infiltration degree of inflammatory cells in the trachea and lung tissue and airway inflammatory reaction are reduced significantly.1,25-dihydroxyvitamin D3 has a certain inhibiting effect on the activation of mast cells and the release of MCT granules.
文摘AIM:To validate methods for determining mast cell density,extracellular major basic protein content,and presence of fibrosis in esophageal eosinophilia.METHODS:Twenty specimens with > 20 eosinophils/high-power field(hpf) classified as high eosinophil density(HE) and 20 specimens with < 5 eosinophils/hpf classified as low esophageal density(LE) were identified.All 40 specimens underwent immunohistochemical staining and trichrome staining.Mast cell density,extracellular major basic protein(MBP) density,and presence of subepithelial fibrosis were assessed in a standardized manner.All specimens were evaluated by two separate observers and by a single observer on two separate occasions to evaluate reproducibility of the methods.RESULTS:A strong inter-observer correlation was noted for both peak and mean mast cell counts(r = 0.725,P < 0.0001 and r = 0.823,P < 0.0001).A strong intraobserver correlation also was noted for both peak and mean mast cell counts(r = 0.752,P < 0.0001 and r =0.878,P < 0.0001).A very strong inter-observer correlation was noted for both peak(τ = 0.867,P < 0.0001)and mean extracellular MBP densities(r = 0.925,P <0.0001).A very strong intra-observer correlation was noted for both peak(τ = 0.875;P < 0.0001) and mean extracellular MBP densities(r = 0.956,P < 0.0001).Excellent inter-rater reliability was found for fibrosis(κ= 0.887).Mast cell and MBP densities,as well as presence of fibrosis,were significantly increased in HE vs LE.The HE group had significantly higher intraepithelial mast cell peak(29.35 ± 21.61 vs 12.45 ± 8.26,P =0.002) and mean(19.84 ± 15.81 vs 6.35 ± 4.5,P =0.001) densities than the LE group.The HE group had significantly higher peak extracellular MBP(2.35 ± 0.67vs 0.45 ± 0.61,P < 0.001) and mean extracellular MBP(1.95 ± 0.76 vs 0.20 ± 0.29,P < 0.0001) densities than the LE group.Seventy-three percent of patients with HE(11/15) had fibrosis,whereas only 10% of patients with LE(1/10) had fibrosis(P < 0.01).MBP performed the best in predicting classification of HE vs LE,with mean MBP demonstrating 100% sensitivity and95% specificity at the optimal cut point.CONCLUSION:This study provides methodology and proof-of-concept for future evaluation of these biomarkers for differentiating esophageal eosinophilic diseases such as reflux esophagitis and eosinophilic esophagitis.
文摘Systemic mastocytosis (SM) is a heterogeneous disease of the bone marrow characterized by abnormal growth, accumulation and activation of clonal mast cells (MCs). We report a case of SM with multiorgan involvement. A 30-year-old man presented with diarrhea, flushing, maculopapular rash with itching and weight loss. The upper and lower gastrointestinal endoscopies showed macroscopic involvement of stomach and duodenum; mucosal samples from stomach, duodenum, colon and distal ileum showed mucosal inf iltration by large, spindleshaped MCs with abnormal surface molecule expression (CD2 and CD25), a picture fully consistent with SM, according to the World Health Organization diagnostic criteria. A computed tomography scan showed diffuse lymphadenopathy, hepatosplenomegaly and diffuse small bowel involvement. Bone marrow aspirate and biopsy were diagnostic for SM; serum tryptase levels were increased (209 ng/mL, normal values < 20 ng/mL). The conclusive diagnosis was smouldering SM. There wereno therapeutic indications except for treatment of symptoms. The patient was strictly followed up because of the risk of aggressive evolution.
文摘In some cases of fatalities involving opioid use,the concentrations of detected opioids are not in the toxic range.Immune reactions can be triggered by opioid use,suggesting that immune response may be a factor in these cases.Autopsy cases from 2002–2012 were reviewed.Persons with physical,microscopic or serum evidence of allergic reactions and opioid use at autopsy were compared to persons who used opioids but had no such signs.Overall,49 persons were identified who had used opioids,of which five had evidence of immune response.A medical history of asthma was significantly more common in persons with signs of immune response(P=0.0244)and fatality(P=0.0085)compared to normals.A history of asthma is suggestive of susceptibility to immunologic reactions to opioids,and correlates strongly with the cause of death.
基金This study was funded by grants from AFA Forsakring(M.P.).
文摘Mast cells are emerging as players in the communication between peripheral nerve endings and cells of the immune system.However,it is not clear the mechanism by which mast cells communicate with peripheral nerves.We previously found that mast cells located within healing tendons can express glutamate receptors,raising the possibility that mast cells may be sensitive to glutamate signaling.To evaluate this hypothesis,we stimulated primary mast cells with glutamate and showed that glutamate induced the profound upregulation of a panel of glutamate receptors of both the ionotropic type(NMDAR1,NMDAR2A,and NMDAR2B)and the metabotropic type(mGluR2 and mGluR7)at both the mRNA and protein levels.The binding of glutamate to glutamate receptors on the mast cell surface was confirmed.Further,glutamate had extensive effects on gene expression in the mast cells,including the upregulation of proinflammatory components such as IL-6 and CCL2.Glutamate also induced the upregulation of transcription factors,including Egr2,Egr3 and,in particular,FosB.The extensive induction of FosB was confirmed by immunofluorescence assessment.Glutamate receptor antagonists abrogated the responses of the mast cells to glutamate,supporting the supposition of a functional glutamate–glutamate receptor axis in mast cells.Finally,we provide in vivo evidence supporting a functional glutamate–glutamate receptor axis in the mast cells of injured tendons.Together,these findings establish glutamate as an effector of mast cell function,thereby introducing a novel principle for how cells in the immune system can communicate with nerve cells.
