Wei et al reported a comprehensive single-cell transcriptomic analysis of the small intestine during early acute pancreatitis(AP)and identified activated mast cells and their secretion of CCL5 as pivotal factors drivi...Wei et al reported a comprehensive single-cell transcriptomic analysis of the small intestine during early acute pancreatitis(AP)and identified activated mast cells and their secretion of CCL5 as pivotal factors driving gut barrier dysfunction.By integrating scRNA-seq with in vitro and in vivo functional assays,this study advances our understanding of the cellular and molecular events underlying AP-associated intestinal injury.In this commentary,I highlight the methodological innovations employed in the study,contextualize its findings in the literature,and propose directions for future research.As an avid researcher in single-cell sequen-cing,I approached this letter with a spirit of academic inquiry and welcome any further discussion or corrections that may enhance my understanding.展开更多
Objective The present study evaluated the effects of deep acupuncture at Weizhong acupoint(BL40)on bladder function and brain activity in a rat model of overactive bladder(OAB),and investigated the possible mechanisms...Objective The present study evaluated the effects of deep acupuncture at Weizhong acupoint(BL40)on bladder function and brain activity in a rat model of overactive bladder(OAB),and investigated the possible mechanisms around the acupuncture area that initiate the effects of acupuncture.Methods Adult female Sprague-Dawley rats were randomly divided into six groups,comprising a control group,model group,group treated with deep acupuncture at BL40,group treated with shallow acupuncture at BL40,group treated with acupuncture at non-acupoint next to BL40,and group treated with acupuncture at Xuanzhong(GB39).Urodynamic evaluation was used to observe the urination,and functional magnetic resonance imaging was used to observe the brain activation.The mechanism of acupuncture at BL40 in regulating bladder function was explored by toluidine blue staining and enzyme-linked immunosorbent assay,and the mechanism was verified by stabilizing mast cells(MCs)or blocking tibial nerve.Results Deep acupuncture at BL40 significantly increased the intercontraction interval in OAB rats and enhanced the mean amplitude of low frequency fluctuation of primary motor cortex(M1),periaquaductal gray matter(PAG),and pontine micturition center(PMC).It also increased the zero-lag functional connectivity between M1 and PAG and between PAG and PMC.Shallow acupuncture at BL40 and acupuncture at non-acupoint or GB39 had no effect on these indexes.Further studies suggested that deep acupuncture at BL40 increased the number and degranulation rate of MCs as well as the contents of 5-hydroxytryptamine,substance P,and histamine in the tissues around BL40.Blocking the tibial nerve by lidocaine injection or inhibiting MC degranulation by sodium cromoglycate injection obstructed the effects of acupuncture on restoring urinary function and modulating brain activation in OAB rats.Conclusion Deep acupuncture at BL40 may be more effective for inhibiting OAB by promoting degranulation of MCs around the acupoint and stimulating tibial nerve,thereby regulating the activation of the brain area that controls the lower urinary tract.展开更多
BACKGROUND Intestinal barrier dysfunction is a prevalent and varied manifestation of acute pancreatitis(AP).Molecular mechanisms underlying the early intestinal barrier in AP remain poorly understood.AIM To explore th...BACKGROUND Intestinal barrier dysfunction is a prevalent and varied manifestation of acute pancreatitis(AP).Molecular mechanisms underlying the early intestinal barrier in AP remain poorly understood.AIM To explore the biological processes and mechanisms of intestinal injury associated with AP,and to find potential targets for early prevention or treatment of intestinal barrier injury.METHODS This study utilized single-cell RNA sequencing of the small intestine,alongside in vitro and in vivo experiments,to examine intestinal barrier function homeostasis during the early stages of AP and explore involved biological processes and potential mechanisms.RESULTS Seventeen major cell types and 33232 cells were identified across all samples,including normal,AP1(4x caerulein injections,animals sacrificed 2 h after the last injection),and AP2(8x caerulein injections,animals sacrificed 4 h after the last injection).An average of 980 genes per cell was found in the normal intestine,compared to 927 in the AP1 intestine and 1382 in the AP2 intestine.B cells,dendritic cells,mast cells(MCs),and monocytes in AP1 and AP2 showed reduced numbers compared to the normal intestine.Enterocytes,brush cells,enteroendocrine cells,and goblet cells maintained numbers similar to the normal intestine,while cytotoxic T cells and natural killer(NK)cells increased.Enterocytes in early AP exhibited elevated programmed cell death and intestinal barrier dysfunction but retained absorption capabilities.Cytotoxic T cells and NK cells showed enhanced pathogen-fighting abilities.Activated MCs,secreted chemokine(C-C motif)ligand 5(CCL5),promoted neutrophil and macrophage infiltration and contributed to barrier dysfunction.CONCLUSION These findings enrich our understanding of biological processes and mechanisms in AP-associated intestinal injury,suggesting that CCL5 from MCs is a potential target for addressing dysfunction.展开更多
Mast cells(MCs)under stress conditions contribute to the development of irritable bowel syndrome(IBS),yet their precise mechanisms in IBS remain unclear.AIM To investigate the role of MC-derived thymosinβ4(Tβ4)in st...Mast cells(MCs)under stress conditions contribute to the development of irritable bowel syndrome(IBS),yet their precise mechanisms in IBS remain unclear.AIM To investigate the role of MC-derived thymosinβ4(Tβ4)in stress-induced intestinal barrier dysfunction.METHODS The colonic mucus Tβ4 levels in IBS patients were determined and their effects on the epithelial barrier were assessed in vitro and in vivo.Specifically,rats genetically deficient in Tβ4(Tβ4^(-/-))or mice deficient in MCs(Kit^(w-sh/w-sh))were used to observe the effects of reintroducing Tβ4 or wild-type peritoneal MCs(wt-PMCs)into these animals.Additionally,the regulatory mechanism underlying Tβ4 secretion in MCs was investigated.RESULTS We demonstrated that high levels of Tβ4 in IBS mucus and intestinal MCs mediate stress-associated disruptive changes to the epithelial barrier.Moreover,Tβ4 treatment of wild-type or MC-deficient Kit^(w-sh/w-sh)mice caused a reduction in tight junction proteins and the interleukin 22 receptor A1(IL22RA1)/Reg3γcascade,but an increase in myosin light chain kinase.Furthermore,Tβ4^(-/-)rats were resistant to stress,though reintroduction of Tβ4 or wt-PMCs restored stress or corticotropin-releasing hormone(CRH)-induced barrier disturbance.Consistently,Tβ4 release from MCs was dependent on the CRH receptor 1,but not degranulation.The effect of Tβ4 was accompanied by IL22RA1/Janus kinase 1(JAK1)/signal transducer and activation of transcription 3(STAT3)pathway inhibition,suggesting a mechanism for physical and immune barrier suppression.CONCLUSION Collectively,these results suggest that Tβ4,which is abundant in IBS mucus and the secretome of MCs,plays a crucial role in the pathogenesis of IBS via IL22RA1/JAK1/STAT3 signaling,with potential implications for diagnostic and therapeutic targeting.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
With numerous applications coilable masts in high-precision astronomical observations,such as X-ray source observations,it is important to investigate mast stiffness.To date,there have been many studies on the bending...With numerous applications coilable masts in high-precision astronomical observations,such as X-ray source observations,it is important to investigate mast stiffness.To date,there have been many studies on the bending stiffness of coilable masts,but few studies on their torsional stiffness,especially regarding the nonlinear characteristics of torsional stiffness of coilable masts under large torsional deformation.In this paper,a nonlinear analysis method is presented to examine the torsional stiffness of coilable masts with triangular sections.Based on the second-order bending buckling hypothesis of battens under large torsion deformation,the nonlinear relationship between torsional torque and torsional angle is obtained by analyzing torsional deformation and force of coilable masts.This method is used to analyze the torsional stiffness nonlinearity of a certain type of coilable mast which will be used in a practical application in the future and the results are verified by simulation and testing.The comparison results show that the error is within the acceptable range,which proves the effectiveness of the proposed method.展开更多
SARS-CoV-2 infection-induced hyper-inflammation is a key pathogenic factor of COVID-19.Our research,along with others',has demonstrated that mast cells(MCs)play a vital role in the initiation of hyper-inflammation...SARS-CoV-2 infection-induced hyper-inflammation is a key pathogenic factor of COVID-19.Our research,along with others',has demonstrated that mast cells(MCs)play a vital role in the initiation of hyper-inflammation caused by SARS-CoV-2.In previous study,we observed that SARS-CoV-2 infection induced the accumulation of MCs in the peri-bronchus and bronchioalveolar-duct junction in humanized mice.Additionally,we found that MC degranulation triggered by the spike protein resulted in inflammation in alveolar epithelial cells and capillary endothelial cells,leading to subsequent lung injury.The trachea and bronchus are the routes for SARS-CoV-2 transmission after virus inhalation,and inflammation in these regions could promote viral spread.MCs are widely distributed throughout the respiratory tract.Thus,in this study,we investigated the role of MCs and their degranulation in the development of inflammation in tracheal-bronchial epithelium.Histological analyses showed the accumulation and degranulation of MCs in the peri-trachea of humanized mice infected with SARS-CoV-2.MC degranulation caused lesions in trachea,and the formation of papillary hyperplasia was observed.Through transcriptome analysis in bronchial epithelial cells,we found that MC degranulation significantly altered multiple cellular signaling,particularly,leading to upregulated immune responses and inflammation.The administration of ebastine or loratadine effectively suppressed the induction of inflammatory factors in bronchial epithelial cells and alleviated tracheal injury in mice.Taken together,our findings confirm the essential role of MC degranulation in SARS-CoV-2-induced hyper-inflammation and the subsequent tissue lesions.Furthermore,our results support the use of ebastine or loratadine to inhibit SARS-CoV-2-triggered degranulation,thereby preventing tissue damage caused by hyper-inflammation.展开更多
Mast cells(MC)are found perivascularly in all tissues and may function as the sentinel immune cells sensing danger and then acting as the master conductor to orchestrate responses aimed at restoring homeostasis.Yet,MC...Mast cells(MC)are found perivascularly in all tissues and may function as the sentinel immune cells sensing danger and then acting as the master conductor to orchestrate responses aimed at restoring homeostasis.Yet,MC are best known for their critical role in allergic,but also inflammatory and other neuroimmune conditions.MC are stimulated by allergens,but also by many other environmental,neuroimmune,pathogenic and stress triggers.Stimulation of MC is called“activation”and is associated with the release of numerous neurohormonal,proinflammatory,tissue remodeling and vasoactive mediators via different secretory mechanisms,some of which do not involve the release of histamine and tryptase.However,mast cell activation and the subsequent responses may become excessive either because of persistent stimulation or dysregulation.Clinical and experimental evidence indicates that MC may be regulated by innate molecules,some derived from MC,themselves.However,discovery of such innate,natural,inhibitors has not been a priority even though they would substantially change the treatment of mast cell activation disorders(MCADs)since drugs that are available or under development focus on inducing MC apoptosis.Development of effective inhibitors of MC activation would require access to MC from healthy and MCAD subjects,preferably identical twins,that would allow differential investigation of the respective transcriptome.展开更多
Allergic inflammation is closely related to the activation of mast cells(MCs),which is regulated by its intracellular Ca^(2+) plevel,but the intake and effects of the intracellular Ca^(2+) premain unclear.The Ca^(2+) ...Allergic inflammation is closely related to the activation of mast cells(MCs),which is regulated by its intracellular Ca^(2+) plevel,but the intake and effects of the intracellular Ca^(2+) premain unclear.The Ca^(2+) pinflux is controlled by members of Ca^(2+) pchannels,among which calcium voltage-gated channel subunit alpha1 C(CaV1.2)is the most robust.This study aimed to reveal the role and underlying mechanism of MC CaV1.2 in allergic inflammation.We found that CaV1.2 participated in MC activation and allergic inflammation.Nimodipine(Nim),as a strong CaV1.2-specific antagonist,ameliorated allergic inflammation in mice.Further,CaV1.2 activation in MC was triggered by phosphatizing at its Ser1928 through protein kinase C(PKC),which calcium/calmodulin-dependent protein kinase II(CaMKII)catalyzed.Overexpression or knockdown of MC CaV1.2 influenced MC activation.Importantly,CaV1.2 expression in MC had detrimental effects,while its deficiency ameliorated allergic pulmonary inflammation.Results provide novel insights into CaV1.2 function and a potential drug target for controlling allergic inflammation.展开更多
Objective:Injury can lead to long-term changes that increase the sensitivity of afferent nerve endings to subsequent stimulation and pain can transition from acute to chronic.This phenomenon is known as hyperalgesic p...Objective:Injury can lead to long-term changes that increase the sensitivity of afferent nerve endings to subsequent stimulation and pain can transition from acute to chronic.This phenomenon is known as hyperalgesic priming(HP).This study aimed to understand the mechanisms underlying the effect of electroacupuncture(EA)on HP and optimize acupoint selection for EA to prevent pain transition.Methods:A rat HP model was established using sequential intraplantar injections of carrageenan(Cg)and prostaglandin E2(PGE2).The pain thresholds were measured using von Frey filaments.EA on bilateral Zusanli(ST36)and Kunlun(BL60)was used to prevent pain transition.The number of mast cells in the ipsilateral hindpaw skin was determined using toluidine blue or fluorescencelabeled avidin staining.The protein expression levels of protein kinase C epsilon(PKCε)in the lumbar dorsal root ganglions(DRGs)were detected by western blotting 24 h after PGE2 injection.Serial pharmacological experiments were conducted to evaluate the relationship between mast cells and pain transition.Finally,EA on the bilateral ST36 and Chongyang(ST42)or a novel combination(ST36 and ST42 on the ipsilateral side,and ST36 and BL60 on the contralateral side)was used to prevent pain transition.Results:Although EA applied to ST36 and BL60 alleviated acute pain induced by Cg injection,it failed to prevent the pain transition caused by PGE2 injection.Mast cell accumulation in the ipsilateral hind paw was observed 7 days after Cg injection.Furthermore,mast cell degranulation may be responsible for PKCεactivation in the DRG,a marker of pain transition.EA significantly decreased the number of mast cells in the skin of the ipsilateral hind paw when applied at ST36 and ST42,but not when applied at ST36 and BL60.Furthermore,EA employed to ST36 and ST42 significantly reversed long-term hyperalgesia induced by PGE2 injection,even when administered before injection.However,EA did not alleviate acute pain caused by Cg injection.By using a novel acupoint combination,EA simultaneously alleviated acute pain and prevented pain transition.Conclusions:Our study suggests that mast cells play a critical role in both HP and the transition from acute to chronic pain,whereas EA can prevent pain transition by decreasing the number of mast cells in the local tissue.展开更多
Objective:To investigate whether cardiac mast cells(MCs)participate in pressure overload-induced myocardial hypertrophy through the regulation of transient receptor potential vanilloid 4(TRPV4).Methods:Pressure overlo...Objective:To investigate whether cardiac mast cells(MCs)participate in pressure overload-induced myocardial hypertrophy through the regulation of transient receptor potential vanilloid 4(TRPV4).Methods:Pressure overload-induced myocardial hypertrophy was induced via abdominal aortic constriction(AAC).Myocardial hypertrophy was evaluated by measuring the heart weight index(HW/BW),lung weight index(LW/BW),ratio of heart weight to tibia length(HW/TL),ratio of lung weight to tibia length(LW/TL),and cross-sectional area of myocardial cells.qRT-PCR was used to detect the mRNA expression of TRPV4.Western blotting was used to detect the protein expression of TRPV4,mast cell tryptase,myosin heavy chain beta(β-MHC),calcineurin A(CnA),and nuclear factor of activated T-cell c3(NFATc3).ELISA was used to measure the levels of brain natriuretic peptide(BNP)and histamine.Fluo4 AM was used to detect the calcium signal in H9c2 myocardial cells.Results:Compared with those of the sham rats,the myocardial mast cells,tryptase,HW/BW,LW/BW,HW/TL,and LW/TL,the cross-sectional area of the myocardial cells,and the expression ofβ-MHC,TRPV4,CnA,and NFATc3 in the myocardial tissue and the serum BNP of the AAC-treated rats increased significantly,whereas the MC stabilizer cromolyn sodium(CS)reversed these indicators.In H9c2 cardiomyocytes,treatment with histamine and the TRPV4 agonist GSK1016790A upregulated the expression of TRPV4,β-MHC,BNP,CnA and NFATc3 and increased calcium ion influx,whereas these effects were inhibited by the H2 receptor inhibitor famotidine and the TRPV4 inhibitor HC067047.Conclusion:Cardiac MCs participate in pressure overload-induced myocardial hypertrophy through the upregulation of TRPV4 via its mediator histamine,and the Ca^(2+)/CnA/NFATc3 signaling pathway is involved in this process.展开更多
Carnoy′s fluid and neutral buffered formalin(NBF)have been proved to be good fixatives for preservation of mast cells in pig,cattle and sheep except NBF blocked staining of most porcine mast cells,especially thos...Carnoy′s fluid and neutral buffered formalin(NBF)have been proved to be good fixatives for preservation of mast cells in pig,cattle and sheep except NBF blocked staining of most porcine mast cells,especially those located in intestinal mucosa(MMC)and in thymus medulla(TMMC). Both toluidine blue and Alcian blue were the excellent stains generally,but Alcian blue stained more porcine mast cells than did toluidine blue( P <0 01). Staining with toluidine blue of a wide pH range(from 0 1 to 7 0)showed that porcine mast cells were not very pH dependent,but the dye at pH 0 5 seemed to have the strongest affinity for all mast cells in pigs and it was also suitable for bovine and ovine mast cell staining. In the three species,unlike in rodents,the Alcian blue method did not distinguish between mast cells in the intestinal mucosa(MMC)and those in the connective tissue of the intestinal submucosa,tongue and skin(CTMC). Porcine CTMC,but not MMC,fluoresced strongly when stained with berberine sulphate or with a mixture of berberine sulphate and acridine orange. It suggested that porcine CTMC contained heparin proteoglycan.展开更多
基金Supported by the Top-level Talents Support Program of Yangzhou University“Lv Yang Jin Feng”Outstanding Doctor of YangzhouNatural Science Foundation of Jiangsu Province,No.BK20240907。
文摘Wei et al reported a comprehensive single-cell transcriptomic analysis of the small intestine during early acute pancreatitis(AP)and identified activated mast cells and their secretion of CCL5 as pivotal factors driving gut barrier dysfunction.By integrating scRNA-seq with in vitro and in vivo functional assays,this study advances our understanding of the cellular and molecular events underlying AP-associated intestinal injury.In this commentary,I highlight the methodological innovations employed in the study,contextualize its findings in the literature,and propose directions for future research.As an avid researcher in single-cell sequen-cing,I approached this letter with a spirit of academic inquiry and welcome any further discussion or corrections that may enhance my understanding.
基金supported by grants from the Shanghai Science and Technology Commission(No.21ZR1461000)Shanghai Municipal Health Commission(No.ZY[2021–2023]−0204).
文摘Objective The present study evaluated the effects of deep acupuncture at Weizhong acupoint(BL40)on bladder function and brain activity in a rat model of overactive bladder(OAB),and investigated the possible mechanisms around the acupuncture area that initiate the effects of acupuncture.Methods Adult female Sprague-Dawley rats were randomly divided into six groups,comprising a control group,model group,group treated with deep acupuncture at BL40,group treated with shallow acupuncture at BL40,group treated with acupuncture at non-acupoint next to BL40,and group treated with acupuncture at Xuanzhong(GB39).Urodynamic evaluation was used to observe the urination,and functional magnetic resonance imaging was used to observe the brain activation.The mechanism of acupuncture at BL40 in regulating bladder function was explored by toluidine blue staining and enzyme-linked immunosorbent assay,and the mechanism was verified by stabilizing mast cells(MCs)or blocking tibial nerve.Results Deep acupuncture at BL40 significantly increased the intercontraction interval in OAB rats and enhanced the mean amplitude of low frequency fluctuation of primary motor cortex(M1),periaquaductal gray matter(PAG),and pontine micturition center(PMC).It also increased the zero-lag functional connectivity between M1 and PAG and between PAG and PMC.Shallow acupuncture at BL40 and acupuncture at non-acupoint or GB39 had no effect on these indexes.Further studies suggested that deep acupuncture at BL40 increased the number and degranulation rate of MCs as well as the contents of 5-hydroxytryptamine,substance P,and histamine in the tissues around BL40.Blocking the tibial nerve by lidocaine injection or inhibiting MC degranulation by sodium cromoglycate injection obstructed the effects of acupuncture on restoring urinary function and modulating brain activation in OAB rats.Conclusion Deep acupuncture at BL40 may be more effective for inhibiting OAB by promoting degranulation of MCs around the acupoint and stimulating tibial nerve,thereby regulating the activation of the brain area that controls the lower urinary tract.
基金Supported by National Natural Science Foundation of China,No.82300739Hunan Provincial Natural Science Foundation,No.2023JJ40821Changsha Natural Science Foundation,No.kq2208308.
文摘BACKGROUND Intestinal barrier dysfunction is a prevalent and varied manifestation of acute pancreatitis(AP).Molecular mechanisms underlying the early intestinal barrier in AP remain poorly understood.AIM To explore the biological processes and mechanisms of intestinal injury associated with AP,and to find potential targets for early prevention or treatment of intestinal barrier injury.METHODS This study utilized single-cell RNA sequencing of the small intestine,alongside in vitro and in vivo experiments,to examine intestinal barrier function homeostasis during the early stages of AP and explore involved biological processes and potential mechanisms.RESULTS Seventeen major cell types and 33232 cells were identified across all samples,including normal,AP1(4x caerulein injections,animals sacrificed 2 h after the last injection),and AP2(8x caerulein injections,animals sacrificed 4 h after the last injection).An average of 980 genes per cell was found in the normal intestine,compared to 927 in the AP1 intestine and 1382 in the AP2 intestine.B cells,dendritic cells,mast cells(MCs),and monocytes in AP1 and AP2 showed reduced numbers compared to the normal intestine.Enterocytes,brush cells,enteroendocrine cells,and goblet cells maintained numbers similar to the normal intestine,while cytotoxic T cells and natural killer(NK)cells increased.Enterocytes in early AP exhibited elevated programmed cell death and intestinal barrier dysfunction but retained absorption capabilities.Cytotoxic T cells and NK cells showed enhanced pathogen-fighting abilities.Activated MCs,secreted chemokine(C-C motif)ligand 5(CCL5),promoted neutrophil and macrophage infiltration and contributed to barrier dysfunction.CONCLUSION These findings enrich our understanding of biological processes and mechanisms in AP-associated intestinal injury,suggesting that CCL5 from MCs is a potential target for addressing dysfunction.
基金Supported by the National Natural Science Foundation of China,No.81270465the Sichuan Science and Technology Program,No.2024NSFSC0631,No.2023JDRC0088,and No.MZGC20240097+4 种基金the Basic Research Cultivation Support Program of Fundamental Research Funds for the Central Universities,No.2682023ZTPY071the Baiqiuen Public Welfare Foundation Program,No.BCF-LX-XH-20221014-12the Third People’s Hospital of Chengdu Clinical Research Program,No.CSY-YN-01-2023-012the Yibin Science and Technology Program,No.2021ZYY009and the Chengdu Medical Research Project Foundation,No.2022284.
文摘Mast cells(MCs)under stress conditions contribute to the development of irritable bowel syndrome(IBS),yet their precise mechanisms in IBS remain unclear.AIM To investigate the role of MC-derived thymosinβ4(Tβ4)in stress-induced intestinal barrier dysfunction.METHODS The colonic mucus Tβ4 levels in IBS patients were determined and their effects on the epithelial barrier were assessed in vitro and in vivo.Specifically,rats genetically deficient in Tβ4(Tβ4^(-/-))or mice deficient in MCs(Kit^(w-sh/w-sh))were used to observe the effects of reintroducing Tβ4 or wild-type peritoneal MCs(wt-PMCs)into these animals.Additionally,the regulatory mechanism underlying Tβ4 secretion in MCs was investigated.RESULTS We demonstrated that high levels of Tβ4 in IBS mucus and intestinal MCs mediate stress-associated disruptive changes to the epithelial barrier.Moreover,Tβ4 treatment of wild-type or MC-deficient Kit^(w-sh/w-sh)mice caused a reduction in tight junction proteins and the interleukin 22 receptor A1(IL22RA1)/Reg3γcascade,but an increase in myosin light chain kinase.Furthermore,Tβ4^(-/-)rats were resistant to stress,though reintroduction of Tβ4 or wt-PMCs restored stress or corticotropin-releasing hormone(CRH)-induced barrier disturbance.Consistently,Tβ4 release from MCs was dependent on the CRH receptor 1,but not degranulation.The effect of Tβ4 was accompanied by IL22RA1/Janus kinase 1(JAK1)/signal transducer and activation of transcription 3(STAT3)pathway inhibition,suggesting a mechanism for physical and immune barrier suppression.CONCLUSION Collectively,these results suggest that Tβ4,which is abundant in IBS mucus and the secretome of MCs,plays a crucial role in the pathogenesis of IBS via IL22RA1/JAK1/STAT3 signaling,with potential implications for diagnostic and therapeutic targeting.
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.
文摘With numerous applications coilable masts in high-precision astronomical observations,such as X-ray source observations,it is important to investigate mast stiffness.To date,there have been many studies on the bending stiffness of coilable masts,but few studies on their torsional stiffness,especially regarding the nonlinear characteristics of torsional stiffness of coilable masts under large torsional deformation.In this paper,a nonlinear analysis method is presented to examine the torsional stiffness of coilable masts with triangular sections.Based on the second-order bending buckling hypothesis of battens under large torsion deformation,the nonlinear relationship between torsional torque and torsional angle is obtained by analyzing torsional deformation and force of coilable masts.This method is used to analyze the torsional stiffness nonlinearity of a certain type of coilable mast which will be used in a practical application in the future and the results are verified by simulation and testing.The comparison results show that the error is within the acceptable range,which proves the effectiveness of the proposed method.
基金supported by the National Natural Science Foundation of China(82172242)the Natural Science Foundation of Guangdong(2022A1515012053)+2 种基金National Key Research and Development Program of China(2022YFC2303700,2021YFE0113000)Yunnan Key Research and Development Program(202103AC100005)the State key Laboratory of Respiratory Disease,Guangzhou,China(SKLRD-OP202207).
文摘SARS-CoV-2 infection-induced hyper-inflammation is a key pathogenic factor of COVID-19.Our research,along with others',has demonstrated that mast cells(MCs)play a vital role in the initiation of hyper-inflammation caused by SARS-CoV-2.In previous study,we observed that SARS-CoV-2 infection induced the accumulation of MCs in the peri-bronchus and bronchioalveolar-duct junction in humanized mice.Additionally,we found that MC degranulation triggered by the spike protein resulted in inflammation in alveolar epithelial cells and capillary endothelial cells,leading to subsequent lung injury.The trachea and bronchus are the routes for SARS-CoV-2 transmission after virus inhalation,and inflammation in these regions could promote viral spread.MCs are widely distributed throughout the respiratory tract.Thus,in this study,we investigated the role of MCs and their degranulation in the development of inflammation in tracheal-bronchial epithelium.Histological analyses showed the accumulation and degranulation of MCs in the peri-trachea of humanized mice infected with SARS-CoV-2.MC degranulation caused lesions in trachea,and the formation of papillary hyperplasia was observed.Through transcriptome analysis in bronchial epithelial cells,we found that MC degranulation significantly altered multiple cellular signaling,particularly,leading to upregulated immune responses and inflammation.The administration of ebastine or loratadine effectively suppressed the induction of inflammatory factors in bronchial epithelial cells and alleviated tracheal injury in mice.Taken together,our findings confirm the essential role of MC degranulation in SARS-CoV-2-induced hyper-inflammation and the subsequent tissue lesions.Furthermore,our results support the use of ebastine or loratadine to inhibit SARS-CoV-2-triggered degranulation,thereby preventing tissue damage caused by hyper-inflammation.
文摘Mast cells(MC)are found perivascularly in all tissues and may function as the sentinel immune cells sensing danger and then acting as the master conductor to orchestrate responses aimed at restoring homeostasis.Yet,MC are best known for their critical role in allergic,but also inflammatory and other neuroimmune conditions.MC are stimulated by allergens,but also by many other environmental,neuroimmune,pathogenic and stress triggers.Stimulation of MC is called“activation”and is associated with the release of numerous neurohormonal,proinflammatory,tissue remodeling and vasoactive mediators via different secretory mechanisms,some of which do not involve the release of histamine and tryptase.However,mast cell activation and the subsequent responses may become excessive either because of persistent stimulation or dysregulation.Clinical and experimental evidence indicates that MC may be regulated by innate molecules,some derived from MC,themselves.However,discovery of such innate,natural,inhibitors has not been a priority even though they would substantially change the treatment of mast cell activation disorders(MCADs)since drugs that are available or under development focus on inducing MC apoptosis.Development of effective inhibitors of MC activation would require access to MC from healthy and MCAD subjects,preferably identical twins,that would allow differential investigation of the respective transcriptome.
基金funded by National Natural Science Foundation of China(Grant Nos.:81930096 and 82274063).
文摘Allergic inflammation is closely related to the activation of mast cells(MCs),which is regulated by its intracellular Ca^(2+) plevel,but the intake and effects of the intracellular Ca^(2+) premain unclear.The Ca^(2+) pinflux is controlled by members of Ca^(2+) pchannels,among which calcium voltage-gated channel subunit alpha1 C(CaV1.2)is the most robust.This study aimed to reveal the role and underlying mechanism of MC CaV1.2 in allergic inflammation.We found that CaV1.2 participated in MC activation and allergic inflammation.Nimodipine(Nim),as a strong CaV1.2-specific antagonist,ameliorated allergic inflammation in mice.Further,CaV1.2 activation in MC was triggered by phosphatizing at its Ser1928 through protein kinase C(PKC),which calcium/calmodulin-dependent protein kinase II(CaMKII)catalyzed.Overexpression or knockdown of MC CaV1.2 influenced MC activation.Importantly,CaV1.2 expression in MC had detrimental effects,while its deficiency ameliorated allergic pulmonary inflammation.Results provide novel insights into CaV1.2 function and a potential drug target for controlling allergic inflammation.
基金the Zhejiang Provincial Natural Science Fund of China(LY24H270003)the National Natural Science Fund of China(82174490,82374561)+1 种基金the Zhejiang Medical and Health Science and Technology Program(2021RC098)the Research Project of Zhejiang Chinese Medical University(2022JKZKTS44).
文摘Objective:Injury can lead to long-term changes that increase the sensitivity of afferent nerve endings to subsequent stimulation and pain can transition from acute to chronic.This phenomenon is known as hyperalgesic priming(HP).This study aimed to understand the mechanisms underlying the effect of electroacupuncture(EA)on HP and optimize acupoint selection for EA to prevent pain transition.Methods:A rat HP model was established using sequential intraplantar injections of carrageenan(Cg)and prostaglandin E2(PGE2).The pain thresholds were measured using von Frey filaments.EA on bilateral Zusanli(ST36)and Kunlun(BL60)was used to prevent pain transition.The number of mast cells in the ipsilateral hindpaw skin was determined using toluidine blue or fluorescencelabeled avidin staining.The protein expression levels of protein kinase C epsilon(PKCε)in the lumbar dorsal root ganglions(DRGs)were detected by western blotting 24 h after PGE2 injection.Serial pharmacological experiments were conducted to evaluate the relationship between mast cells and pain transition.Finally,EA on the bilateral ST36 and Chongyang(ST42)or a novel combination(ST36 and ST42 on the ipsilateral side,and ST36 and BL60 on the contralateral side)was used to prevent pain transition.Results:Although EA applied to ST36 and BL60 alleviated acute pain induced by Cg injection,it failed to prevent the pain transition caused by PGE2 injection.Mast cell accumulation in the ipsilateral hind paw was observed 7 days after Cg injection.Furthermore,mast cell degranulation may be responsible for PKCεactivation in the DRG,a marker of pain transition.EA significantly decreased the number of mast cells in the skin of the ipsilateral hind paw when applied at ST36 and ST42,but not when applied at ST36 and BL60.Furthermore,EA employed to ST36 and ST42 significantly reversed long-term hyperalgesia induced by PGE2 injection,even when administered before injection.However,EA did not alleviate acute pain caused by Cg injection.By using a novel acupoint combination,EA simultaneously alleviated acute pain and prevented pain transition.Conclusions:Our study suggests that mast cells play a critical role in both HP and the transition from acute to chronic pain,whereas EA can prevent pain transition by decreasing the number of mast cells in the local tissue.
基金supported by grants from the National Natural Science Foundation of China(No.30872716)the Natural Science Foundation of Hubei Province(No.2015CFB288).
文摘Objective:To investigate whether cardiac mast cells(MCs)participate in pressure overload-induced myocardial hypertrophy through the regulation of transient receptor potential vanilloid 4(TRPV4).Methods:Pressure overload-induced myocardial hypertrophy was induced via abdominal aortic constriction(AAC).Myocardial hypertrophy was evaluated by measuring the heart weight index(HW/BW),lung weight index(LW/BW),ratio of heart weight to tibia length(HW/TL),ratio of lung weight to tibia length(LW/TL),and cross-sectional area of myocardial cells.qRT-PCR was used to detect the mRNA expression of TRPV4.Western blotting was used to detect the protein expression of TRPV4,mast cell tryptase,myosin heavy chain beta(β-MHC),calcineurin A(CnA),and nuclear factor of activated T-cell c3(NFATc3).ELISA was used to measure the levels of brain natriuretic peptide(BNP)and histamine.Fluo4 AM was used to detect the calcium signal in H9c2 myocardial cells.Results:Compared with those of the sham rats,the myocardial mast cells,tryptase,HW/BW,LW/BW,HW/TL,and LW/TL,the cross-sectional area of the myocardial cells,and the expression ofβ-MHC,TRPV4,CnA,and NFATc3 in the myocardial tissue and the serum BNP of the AAC-treated rats increased significantly,whereas the MC stabilizer cromolyn sodium(CS)reversed these indicators.In H9c2 cardiomyocytes,treatment with histamine and the TRPV4 agonist GSK1016790A upregulated the expression of TRPV4,β-MHC,BNP,CnA and NFATc3 and increased calcium ion influx,whereas these effects were inhibited by the H2 receptor inhibitor famotidine and the TRPV4 inhibitor HC067047.Conclusion:Cardiac MCs participate in pressure overload-induced myocardial hypertrophy through the upregulation of TRPV4 via its mediator histamine,and the Ca^(2+)/CnA/NFATc3 signaling pathway is involved in this process.
文摘Carnoy′s fluid and neutral buffered formalin(NBF)have been proved to be good fixatives for preservation of mast cells in pig,cattle and sheep except NBF blocked staining of most porcine mast cells,especially those located in intestinal mucosa(MMC)and in thymus medulla(TMMC). Both toluidine blue and Alcian blue were the excellent stains generally,but Alcian blue stained more porcine mast cells than did toluidine blue( P <0 01). Staining with toluidine blue of a wide pH range(from 0 1 to 7 0)showed that porcine mast cells were not very pH dependent,but the dye at pH 0 5 seemed to have the strongest affinity for all mast cells in pigs and it was also suitable for bovine and ovine mast cell staining. In the three species,unlike in rodents,the Alcian blue method did not distinguish between mast cells in the intestinal mucosa(MMC)and those in the connective tissue of the intestinal submucosa,tongue and skin(CTMC). Porcine CTMC,but not MMC,fluoresced strongly when stained with berberine sulphate or with a mixture of berberine sulphate and acridine orange. It suggested that porcine CTMC contained heparin proteoglycan.
