Phosphatidylcholine-hydrolyzing phospholipase C （PC-PLC） catalyzes the hydrolysis of phosphatidylcholine （PC） to generate phosphocholine and diacylglycerol （DAG）. PC-PLC has a long tradition in animal signal tra...Phosphatidylcholine-hydrolyzing phospholipase C （PC-PLC） catalyzes the hydrolysis of phosphatidylcholine （PC） to generate phosphocholine and diacylglycerol （DAG）. PC-PLC has a long tradition in animal signal transduction to generate DAG as a second messenger besides the classical phosphatidylinositol splitting phospholipase C （PI-PLC）. Based on amino acid sequence similarity to bacterial PC-PLC, six putative PC-PLC genes （NPC1 to NPC6） were identified in the Arabidopsis genome. RT-PCR analysis revealed overlapping expression pattern of NPC genes in root, stem, leaf, flower, and silique. In auxin-treated PNPc3：GUS and PNPc4：GUS seedlings, strong increase of GUS activity was visible in roots, leaves, and shoots and, to a weaker extent, in brassinolide-treated （BL） seedlings. PNPc4：GUS seedlings also responded to cytokinin with increased GUS activity in young leaves. Compared to wild-type, T-DNA insertional knockouts npc3 and npc4 showed shorter primary roots and lower lateral root density at low BL concentrations but increased lateral root densities in response to exogenous 0.05-1.0 I^M BL BL-induced expression of TCH4 and LRX2, which are involved in cell expansion, was impaired but not impaired in repression of CPD, a BL biosynthesis gene, in BL-treated npc3 and npc4. These observations suggest NPC3 and NPC4 are important in BL-mediated signaling in root growth. When treated with 0.1 I^M BL, DAG accumulation was observed in tobacco BY-2 cell cultures labeled with fluorescent PC as early as 15 min after application. We hypothesize that at least one PC-PLC is a plant signaling enzyme in BL signal transduction and, as shown earlier, in elicitor signal transduction.展开更多
BACKGROUND The objective of the current study was to elucidate the clinical mechanism through which phospholipase D2(PLD2)exerted a regulatory effect on neutrophil migra-tion,thereby alleviating the progression of acu...BACKGROUND The objective of the current study was to elucidate the clinical mechanism through which phospholipase D2(PLD2)exerted a regulatory effect on neutrophil migra-tion,thereby alleviating the progression of acute pancreatitis.AIM To elucidate the clinical mechanism through which PLD2 exerted a regulatory effect on neutrophil migration,thereby alleviating the progression of acute pan-creatitis.METHODS The study involved 90 patients diagnosed with acute pancreatitis,admitted to our hospital between March 2020 and November 2022.A retrospective analysis was conducted,categorizing patients based on Ranson score severity into mild(n=25),moderate(n=30),and severe(n=35)groups.Relevant data was collected for each group.Western blot analysis assessed PLD2 protein expression in patient serum.Real-time reverse transcription polymerase chain reaction was used to evaluate the mRNA expression of chemokine receptors associated with neutrophil migration.Serum levels of inflammatory factors in patients were detected using enzyme-linked immunosorbent assay.Transwell migration tests were conducted to compare migration of neutrophils across groups and analyze the influence of PLD2 on neutrophil migration.RESULTS Overall data analysis did not find significant differences between patient groups(P>0.05).The expression of PLD2 protein in the severe group was lower than that in the moderate and mild groups(P<0.05).The expression level of PLD2 in the moderate group was also lower than that in the mild group(P<0.05).The severity of acute pancreatitis is negatively correlated with PLD2 expression(r=-0.75,P=0.002).The mRNA levels of C-X-C chemokine receptor type 1,C-X-C chemokine receptor type 2,C-C chemokine receptor type 2,and C-C chemokine receptor type 5 in the severe group are significantly higher than those in the moderate and mild groups(P<0.05),and the expression levels in the moderate group are also higher than those in the mild group(P<0.05).The levels of C-reactive protein,tumor necrosis factor-α,interleukin-1β,and interleukin-6 in the severe group were higher than those in the moderate and mild groups(P<0.05),and the levels in the moderate group were also higher than those in the mild group(P<0.05).The number of migrating neutrophils in the severe group was higher than that in the moderate and mild groups(P<0.05),and the moderate group was also higher than the mild group(P<0.05).In addition,the number of migrating neutrophils in the mild group combined with PLD2 inhibitor was higher than that in the mild group(P<0.05),and the number of migrating neutrophils in the moderate group combined with PLD2 inhibitor was higher than that in the moderate group(P<0.05).The number of migrating neutrophils in the severe group+PLD2 inhibitor group was significantly higher than that in the severe group(P<0.05),indicating that PLD2 inhibitors significantly stimulated neutrophil migration.CONCLUSION PLD2 exerted a crucial regulatory role in the pathological progression of acute pancreatitis.Its protein expression varied among patients based on the severity of the disease,and a negative correlation existed between PLD2 expression and disease severity.Additionally,PLD2 appeared to impede acute pancreatitis progression by limiting neutrophil migration.展开更多
Osteoarthritis(OA) and intervertebral disc degeneration(IVDD) are degenerative musculoskeletal disorders characterized by degeneration of cartilaginous tissues and inflammation. While inflammation is implicated in the...Osteoarthritis(OA) and intervertebral disc degeneration(IVDD) are degenerative musculoskeletal disorders characterized by degeneration of cartilaginous tissues and inflammation. While inflammation is implicated in the pathogenesis of OA and IVDD, and cytosolic phospholipase A2(cPLA2) is a key mediator of inflammation, direct evidence linking cPLA2 to chondrocyte homeostasis and cartilage degeneration is lacking. This study aims to investigate the role of cPLA2 in chondrocytes and its contribution to the development of cartilage degenerative conditions such as OA and IVDD. Here, single-cell RNA sequencing was used to examine cPLA2 expression in chondrocytes. To explore its importance in chondrocytes and OA/IVDD, various cell-based assays and genetically modified mouse models with age-related and surgically induced OA/IVDD were employed. Furthermore, the therapeutic potential of fexofenadine, an over-the-counter drug recently identified as a cPLA2 inhibitor, was explored in these models. cPLA2 is predominantly expressed in prehypertrophic chondrocytes, characterized by elevated levels of cartilage degeneration markers and senescence-related genes. Genetic deletion and pharmacological inhibition of cPLA2 reduced inflammation induced catabolic activity and senescence in chondrocytes, as well as cartilage degeneration in various OA and IVDD models. This study identifies cPLA2 as a pivotal driver of cartilage degeneration and senescence in OA and IVDD, highlighting its potential as a dual-action therapeutic target that suppresses both inflammation and senescence to preserve cartilage integrity. These findings position cPLA2as a promising candidate for developing disease-modifying therapies for cartilage degenerative conditions such as OA and IVDD.展开更多
In this editorial,we critically evaluate the recent article by Niu et al,which ex-plores the potential of phospholipase D2(PLD2)as a biomarker for stratifying disease severity in acute pancreatitis(AP).AP is a clinica...In this editorial,we critically evaluate the recent article by Niu et al,which ex-plores the potential of phospholipase D2(PLD2)as a biomarker for stratifying disease severity in acute pancreatitis(AP).AP is a clinically heterogeneous inflam-matory condition that requires reliable biomarkers for early and accurate classi-fication of disease severity.PLD2,an essential regulator of neutrophil migration and inflammatory responses,has emerged as a promising candidate.Although current biomarkers such as C-reactive protein and procalcitonin provide general indications of inflammation,they lack specificity regarding the molecular mechanisms underlying AP progression.Recent studies,including the research conducted by Niu et al,suggest an inverse correlation between PLD2 expression and AP severity,offering both diagnostic insights and mechanistic understanding.This editorial critically evaluates the role of PLD2 as a biomarker in the broader context of AP research.Evidence indicates that decreased levels of PLD2 are associated with increased neutrophil chemotaxis and cytokine release,con-tributing to pancreatic and systemic inflammation.However,several challenges remain,including the need for large-scale validation and functional studies to establish causation,and standardization of measurement protocols.Additionally,further investigation into the temporal dynamics of PLD2 expression and its variability across diverse populations is warranted.Looking ahead,PLD2 holds the potential to revolutionize AP management by integrating molecular diagnostics with precision medicine.The utilization of large-scale multi-omics approaches and advancements in diagnostic platforms could position PLD2 as a fundamental biomarker for early diagnosis,prognosis,and potentially therapeutic targeting.While promising,it is crucial to conduct critical evaluations and rigorous validations of PLD2’s role to ensure its efficacy in improving patient outcomes.展开更多
Acute pancreatitis(AP)remains a clinical challenge due to its heterogeneous presentation and potential for rapid progression to severe disease.In their editorial,Wang et al highlight phospholipase D2(PLD2)as a novel c...Acute pancreatitis(AP)remains a clinical challenge due to its heterogeneous presentation and potential for rapid progression to severe disease.In their editorial,Wang et al highlight phospholipase D2(PLD2)as a novel candidate biomarker,proposing its involvement in key inflammatory pathways and its inverse correlation with disease severity.While this represents a promising improvement in precision diagnostics,significant gaps remain that require further investigation.Specifically,the functional role of PLD2 in the molecular cascade of AP is not yet fully understood.Questions still remain,such as:Is the observed downregulation of PLD2 a causal factor or an epiphenomenon?Does PLD2 modulation offer a tangible therapeutic benefit beyond a mere correlation?These questions highlight the necessity of mechanistic in vivo studies to validate the role and therapeutic potential of PLD2.Furthermore,interindividual variability in inflammatory responses raises concerns regarding PLD2’s predictive consistency across genetically diverse populations.The temporal dynamics of PLD2 expression in AP also remain unclear;establishing whether its variations precede clinical deterioration is essential for its use in early risk stratification,integrating multiomics research(proteomics,metabolomics,transcriptomics,and lipidomics),which can clarify the biological interactions and regulatory pathways of PLD2 under complex mechanisms.Likewise,well-designed,multicenter,prospective studies will be essential in determining its true clinical value.The research by Wang et al initiates an intriguing direction in the quest for AP biomarkers,but further research is required before PLD2 can be established as a clinically applicable tool.Additional efforts are required to close this gap and define whether its role transcends a mere association in order for it to become a therapeutic target.展开更多
OBJECTIVE:To determine whether moxibustion had an anti-inflammatory effect on rheumatoid arthritis(RA)by regulating Annexin 1 expression and interfering with the phospholipaseA2 signaling pathway.METHODS:Thirty male S...OBJECTIVE:To determine whether moxibustion had an anti-inflammatory effect on rheumatoid arthritis(RA)by regulating Annexin 1 expression and interfering with the phospholipaseA2 signaling pathway.METHODS:Thirty male Sprague-Dawley rats were randomly categorized into five groups(six rats per group):blank control(CON)group,RA model(RA)group,moxibustion(MOX)group,Annexin 1 lentiviral intervention(RNAi-Anxa1)group,and Annexin 1 lentiviral intervention+moxibustion(RNAi-Anxa1+MOX)group.The rats in the RNAi-Anxa1 and the RNAi-Anxa1+MOX groups were injected with the lentiviral vector-mediated RNAi-Anxa1 into the rat foot pad.An experimental RA rat model was established by injecting Freund's complete adjuvant(FCA)into the RA,MOX,RNAi-Anxa1,and RNAi-Anxa1+MOX groups.Rats in the MOX and RNAiAnxa1+MOX groups received moxibustion treatment.After modeling,using moxibustion“Shenshu(BL23)”and“Zusanli(ST36)”,each point is 5 times,bilateral alternating,once a day,6 times for a course of treatment,between the courses of rest for a one day.A total of three treatment courses were conducted.Both bilateral pad thicknesses were measured using Vernier calipers on experimental days 1,7,14,21,and 28.The expression of cPLA2αsignaling in the synovium of diseased joints was observed using Western blot.The pathology of the rat ankle synovium was observed using hematoxylineosin(HE)staining.Interleukin(IL)-1β,IL-10,prostaglandin E2(PGE2),and leukotriene B4(LTB4)were detected using enzyme-linked immunosorbent assay.RESULTS:Moxibustion increased the levels of Annexin 1 and decreased the inflammatory response in rats with RA.After increasing the expression of Annexin 1,the phosphorylated expression of cPLA2αwas inhibited,the serum levels of IL-1β,PGE2,and LTB4 decreased,and the level of IL-10 increased.In moxibustion treated RA rats after the Annexin 1 lentiviral intervention,the serum levels of IL-1β,PGE2,LTB4,and IL-10 were almost unchanged.CONCLUSION:Moxibustion enhanced the negative regulation of the cPLA2αsignaling pathway,increased the synovial Annexin 1 expression,inhibited the cPLA2αsignaling pathway,indirectly inhibited the expression of downstream inflammatory factors,and played a role in reducing inflammation.展开更多
研究背景力学门控性离子通道（mechanogated ion channels）,又称为力学敏感性离子通道（mechanosensitive ion channels,MSIC）,是心肌细胞的力学感受器之一。MSIC在心脏受到力学超负荷后电生理改变过程中起主要作用,可能是心肌细胞肥...研究背景力学门控性离子通道（mechanogated ion channels）,又称为力学敏感性离子通道（mechanosensitive ion channels,MSIC）,是心肌细胞的力学感受器之一。MSIC在心脏受到力学超负荷后电生理改变过程中起主要作用,可能是心肌细胞肥大过程中,力学负荷与蛋白质合成之间信号传导的一条重要通路。瞬时感受器电位（Transient receptor potential,TRP）离子通道C亚族（TRPC）蛋白TRPC1、C6对于心肌细胞适应生物力学刺激很重要,其表达上调会导致病理性心肌肥大及心衰<sup>[1-3]</sup>。TRPC通道不仅可被G蛋白耦联受体下游的磷脂酶C（phospholipase C,PLC）、二脂酰甘油（diacylglycerol,DAG）等信号分子继发激活,TRPC1、C6等可能还是力学敏感的离子通道,展开更多
Objective To survey changes and the significance of phospholipase A_2(PLA_2) on brain tissue of SD rat in acute pancreatitis.Methods With retrograde injection of 3% taurocholate sodium into pancreatic and biliary duct...Objective To survey changes and the significance of phospholipase A_2(PLA_2) on brain tissue of SD rat in acute pancreatitis.Methods With retrograde injection of 3% taurocholate sodium into pancreatic and biliary duct,rat model of severe acute pancreatitis(SAP) was made,and it included four groups: the control group,the sham-operation group, the SAP group and the PLA_2 inhibitor-treated group of SAP.Serum amylases,PLA_2 and PLA_2 in brain tissue were measured and the brain tissue changes were observed.Results There were no significant difference in serum amylases, PLA_2 and PLA_2 in brain tissue between the sham-operation and the control groups;the levels of serum amylases,PLA_2 and PLA_2 in brain tissue in the SAP group were higher than those in the control.In the SAP group expansion and hemorrhage of meninges,intracephalic arteriolar hyperemia,in meninges and cephalic-parenchyma infiltration of inflammatory cells and interval broaden were observed,significant differences were found between two groups.Compared with the SAP group,the level of serum amylase,PLA_2 and PLA_2 in brain tissue were reduced significantly in the treatment group of SAP.Pathological damages in the treatment group were significantly reduced when compared with the SAP group.Conclusion PLA_2 might play an important role in brain tissue damages in severe acute pancreatitis.展开更多
Atherosclerosis manifests itself clinically at advanced stages when plaques undergo hemorrhage and/or rupture with superimposed thrombosis, thus abruptly stopping blood supply. Identification of markers of plaque dest...Atherosclerosis manifests itself clinically at advanced stages when plaques undergo hemorrhage and/or rupture with superimposed thrombosis, thus abruptly stopping blood supply. Identification of markers of plaque destabilization at a pre-clinical stage is, therefore, a major goal of cardiovascular research. Promising results along this line were provided by studies investigating the lipoprotein-associated phospholipase A2(Lp-PLA2), a member of phospholipase A2 proteins family that plays a key role in the metabolism of pro-inflammatory phospholipids, as oxidized low-density lipoproteins, and in the generation of pro-atherogenic metabolites, including lysophosphatidylcholine and oxidized free fatty acids. We herein review the experimental and clinical studies supporting use of Lp-PLA2 activity for predicting cardiovascular events. To his end we considered not only Lp-PLA2 activity and mass, but also Lp-PLA2 gene variations and their association with incident coronary artery disease, stroke, and cardiovascular mortality. Based on these evidences the major scientific societies have included in their guidelines the measurement of Lp-PLA2 activity among the biomarkers that are useful in risk stratification of adult asymptomatic patients at intermediate cardiovascular risk. The results of two recently published major clinical trials with the LpPLA2 inhibitor darapladib, which seem to challenge the pathogenic role of Lp-PLA2, will also be discussed.展开更多
Hepatocellular carcinoma(HCC) is the fourth cause of cancer related mortality, and its incidence is rapidly increasing. Viral hepatitis, alcohol abuse, and exposure to hepatotoxins are major risk factors, but nonalcoh...Hepatocellular carcinoma(HCC) is the fourth cause of cancer related mortality, and its incidence is rapidly increasing. Viral hepatitis, alcohol abuse, and exposure to hepatotoxins are major risk factors, but nonalcoholic fatty liver disease(NAFLD) associated with obesity, insulin resistance, and type 2 diabetes, is an increasingly recognized trigger, especially in developed countries. Older age, severity of insulin resistance and diabetes, and iron overload have been reported to predispose to HCC in this context. Remarkably, HCCs have been reported in non-cirrhotic livers in a higher proportion of cases in NAFLD patients than in other etiologies. Inherited factors have also been implicated to explain the different individual susceptibility to develop HCC, and their role seems magnified in fatty liver, where only a minority of affected subjects progresses to cancer. In particular, the common I148 M variant of the PNPLA3 gene influencing hepatic lipid metabolism influences HCC risk independently of its effect on the progression of liver fibrosis. Recently, rare loss-of-function mutations in Apolipoprotein B resulting in very low density lipoproteins hepatic retention and in Telomerase reverse transcriptase influencing cellular senescence have also been linked to HCC in NAFLD. Indeed, hepatic stellate cells senescence has been suggested to bridge tissue aging with alterations of the intestinal microbiota in the pathogenesis of obesity-related HCC. A deeper understanding of the mechanisms mediating hepatic carcinogenesis during insulin resistance, and the identification of its genetic determinants will hopefully provide new diagnostic and therapeutic tools.展开更多
AIM:To explore the relationship between gastric and intestinal microcirculatory impairment and inflammatory mediators released in rats with acute necrotizing pancreatitis (ANP). METHODS: A total of 64 rats were random...AIM:To explore the relationship between gastric and intestinal microcirculatory impairment and inflammatory mediators released in rats with acute necrotizing pancreatitis (ANP). METHODS: A total of 64 rats were randomized into control group and ANP group. ANP model was induced by injection of 5% sodium taurocholate under the pancreatic membrane. Radioactive biomicrosphere technique was used to measure the gastric and intestinal tissue blood flow at 2 and 12 h after the induction of ANP, meanwhile serum phospholipase A2 (PLA2) activities and interleukin-1β levels were determined. Pathologic changes in pancreas, gastric and intestinal mucosae were studied. RESULTS: The gastric blood flow in ANP group (0.62±0.06 and 0.35±0.05) mL/(min·g) was significantly lower than that in control group (0.86±0.11 and 0.85±0.06) mL/(min·g) (P<0.01) at 2 and 12 h after induction of ANP. The intestinal blood flow in ANP group (0.80±0.07 and 0.50±0.06) mlV(min·g) was significantly lower than that in control group (1.56±0.18 and 1.61±0.11) mL/(min·g) (P<0.01). Serum PLA2 activities (94.29±9.96 and 103.71± 14.40) U/L and IL-1β levels (0.78±0.13 and 0.83±0.20)μg/L in ANP group were higher than those in control group (65.27±10.52 and 66.63±9.81) U/L, (0.32±0.06 and 0.33±0.07)μg/L (P<0.01). At 2 and 12 h after introduction of the model, typical pathologic changes were found in ANP. Compared with control group, the gastric and intestinal mucosal pathologic changes were aggravated significantly (P<0.01) at 12 h after induction of ANP. Gastric and intestinal mucosal necrosis, multiple ulcer and hemorrhage occurred. CONCLUSION: Decrease of gastric and intestinal blood flow and increase of inflammatory mediators occur simultaneously early in ANP, both of them are important pathogenic factors for gastric and intestinal mucosal injury in ANP.展开更多
BACKGROUND: Pancreatic encephalopathy (PE) is a serious complication of severe acute pancreatitis (SAP). In recent years, more and more PE cases have been reported worldwide, and the onset PE in the early stage was re...BACKGROUND: Pancreatic encephalopathy (PE) is a serious complication of severe acute pancreatitis (SAP). In recent years, more and more PE cases have been reported worldwide, and the onset PE in the early stage was regarded as a poor prognosis sign of SAP, but the pathogenesis of PE in SAP still has not been clarified in the past decade. The purpose of this review is to elucidate the possible pathogenesis of PE in SAP. DATA SOURCES: The English-language literature concerning PE in this review came from the Database of MEDLINE (period of 1991-2005), and the keywords of severe acute pancreatitis and pancreatic encephalopathy were used in the searching. RESULTS: Many factors were involved in the pathogenesis of PE in SAP. Pancreatin activation, excessive release of cytokines and oxygen free radicals, microcirculation abnormalities of hemodynamic disturbance, ET-1/NO ratio, hypoxemia, bacterial infection, water and electrolyte imbalance, and vitamin B1 deficiency participated in the development of PE in SAP. CONCLUSIONS: The pathogenesis of PE in SAP has not yet been fully understood. The development of PE in SAP may be a multi-factor process. To find out the possible inducing factor is essential to the clinical management of PE in SAP.展开更多
文摘Phosphatidylcholine-hydrolyzing phospholipase C （PC-PLC） catalyzes the hydrolysis of phosphatidylcholine （PC） to generate phosphocholine and diacylglycerol （DAG）. PC-PLC has a long tradition in animal signal transduction to generate DAG as a second messenger besides the classical phosphatidylinositol splitting phospholipase C （PI-PLC）. Based on amino acid sequence similarity to bacterial PC-PLC, six putative PC-PLC genes （NPC1 to NPC6） were identified in the Arabidopsis genome. RT-PCR analysis revealed overlapping expression pattern of NPC genes in root, stem, leaf, flower, and silique. In auxin-treated PNPc3：GUS and PNPc4：GUS seedlings, strong increase of GUS activity was visible in roots, leaves, and shoots and, to a weaker extent, in brassinolide-treated （BL） seedlings. PNPc4：GUS seedlings also responded to cytokinin with increased GUS activity in young leaves. Compared to wild-type, T-DNA insertional knockouts npc3 and npc4 showed shorter primary roots and lower lateral root density at low BL concentrations but increased lateral root densities in response to exogenous 0.05-1.0 I^M BL BL-induced expression of TCH4 and LRX2, which are involved in cell expansion, was impaired but not impaired in repression of CPD, a BL biosynthesis gene, in BL-treated npc3 and npc4. These observations suggest NPC3 and NPC4 are important in BL-mediated signaling in root growth. When treated with 0.1 I^M BL, DAG accumulation was observed in tobacco BY-2 cell cultures labeled with fluorescent PC as early as 15 min after application. We hypothesize that at least one PC-PLC is a plant signaling enzyme in BL signal transduction and, as shown earlier, in elicitor signal transduction.
文摘BACKGROUND The objective of the current study was to elucidate the clinical mechanism through which phospholipase D2(PLD2)exerted a regulatory effect on neutrophil migra-tion,thereby alleviating the progression of acute pancreatitis.AIM To elucidate the clinical mechanism through which PLD2 exerted a regulatory effect on neutrophil migration,thereby alleviating the progression of acute pan-creatitis.METHODS The study involved 90 patients diagnosed with acute pancreatitis,admitted to our hospital between March 2020 and November 2022.A retrospective analysis was conducted,categorizing patients based on Ranson score severity into mild(n=25),moderate(n=30),and severe(n=35)groups.Relevant data was collected for each group.Western blot analysis assessed PLD2 protein expression in patient serum.Real-time reverse transcription polymerase chain reaction was used to evaluate the mRNA expression of chemokine receptors associated with neutrophil migration.Serum levels of inflammatory factors in patients were detected using enzyme-linked immunosorbent assay.Transwell migration tests were conducted to compare migration of neutrophils across groups and analyze the influence of PLD2 on neutrophil migration.RESULTS Overall data analysis did not find significant differences between patient groups(P>0.05).The expression of PLD2 protein in the severe group was lower than that in the moderate and mild groups(P<0.05).The expression level of PLD2 in the moderate group was also lower than that in the mild group(P<0.05).The severity of acute pancreatitis is negatively correlated with PLD2 expression(r=-0.75,P=0.002).The mRNA levels of C-X-C chemokine receptor type 1,C-X-C chemokine receptor type 2,C-C chemokine receptor type 2,and C-C chemokine receptor type 5 in the severe group are significantly higher than those in the moderate and mild groups(P<0.05),and the expression levels in the moderate group are also higher than those in the mild group(P<0.05).The levels of C-reactive protein,tumor necrosis factor-α,interleukin-1β,and interleukin-6 in the severe group were higher than those in the moderate and mild groups(P<0.05),and the levels in the moderate group were also higher than those in the mild group(P<0.05).The number of migrating neutrophils in the severe group was higher than that in the moderate and mild groups(P<0.05),and the moderate group was also higher than the mild group(P<0.05).In addition,the number of migrating neutrophils in the mild group combined with PLD2 inhibitor was higher than that in the mild group(P<0.05),and the number of migrating neutrophils in the moderate group combined with PLD2 inhibitor was higher than that in the moderate group(P<0.05).The number of migrating neutrophils in the severe group+PLD2 inhibitor group was significantly higher than that in the severe group(P<0.05),indicating that PLD2 inhibitors significantly stimulated neutrophil migration.CONCLUSION PLD2 exerted a crucial regulatory role in the pathological progression of acute pancreatitis.Its protein expression varied among patients based on the severity of the disease,and a negative correlation existed between PLD2 expression and disease severity.Additionally,PLD2 appeared to impede acute pancreatitis progression by limiting neutrophil migration.
基金supported partly by NIH research grants R01AR078035, R01AR062207,R01AR076900 and R01NS070328。
文摘Osteoarthritis(OA) and intervertebral disc degeneration(IVDD) are degenerative musculoskeletal disorders characterized by degeneration of cartilaginous tissues and inflammation. While inflammation is implicated in the pathogenesis of OA and IVDD, and cytosolic phospholipase A2(cPLA2) is a key mediator of inflammation, direct evidence linking cPLA2 to chondrocyte homeostasis and cartilage degeneration is lacking. This study aims to investigate the role of cPLA2 in chondrocytes and its contribution to the development of cartilage degenerative conditions such as OA and IVDD. Here, single-cell RNA sequencing was used to examine cPLA2 expression in chondrocytes. To explore its importance in chondrocytes and OA/IVDD, various cell-based assays and genetically modified mouse models with age-related and surgically induced OA/IVDD were employed. Furthermore, the therapeutic potential of fexofenadine, an over-the-counter drug recently identified as a cPLA2 inhibitor, was explored in these models. cPLA2 is predominantly expressed in prehypertrophic chondrocytes, characterized by elevated levels of cartilage degeneration markers and senescence-related genes. Genetic deletion and pharmacological inhibition of cPLA2 reduced inflammation induced catabolic activity and senescence in chondrocytes, as well as cartilage degeneration in various OA and IVDD models. This study identifies cPLA2 as a pivotal driver of cartilage degeneration and senescence in OA and IVDD, highlighting its potential as a dual-action therapeutic target that suppresses both inflammation and senescence to preserve cartilage integrity. These findings position cPLA2as a promising candidate for developing disease-modifying therapies for cartilage degenerative conditions such as OA and IVDD.
基金Supported by National Natural Sciences Foundation of China,No.82301700Liaoning Province Natural Science Foundation Project,No.2024-MS-157+2 种基金Youth Talent Cultivation Fund Key Project of Dalian Medical UniversityScientific Research Projects from Wuhan Municipal Health Commission,No.WX23Z26Science and Technology of Liaoning Province,No.2023-MS-266.
文摘In this editorial,we critically evaluate the recent article by Niu et al,which ex-plores the potential of phospholipase D2(PLD2)as a biomarker for stratifying disease severity in acute pancreatitis(AP).AP is a clinically heterogeneous inflam-matory condition that requires reliable biomarkers for early and accurate classi-fication of disease severity.PLD2,an essential regulator of neutrophil migration and inflammatory responses,has emerged as a promising candidate.Although current biomarkers such as C-reactive protein and procalcitonin provide general indications of inflammation,they lack specificity regarding the molecular mechanisms underlying AP progression.Recent studies,including the research conducted by Niu et al,suggest an inverse correlation between PLD2 expression and AP severity,offering both diagnostic insights and mechanistic understanding.This editorial critically evaluates the role of PLD2 as a biomarker in the broader context of AP research.Evidence indicates that decreased levels of PLD2 are associated with increased neutrophil chemotaxis and cytokine release,con-tributing to pancreatic and systemic inflammation.However,several challenges remain,including the need for large-scale validation and functional studies to establish causation,and standardization of measurement protocols.Additionally,further investigation into the temporal dynamics of PLD2 expression and its variability across diverse populations is warranted.Looking ahead,PLD2 holds the potential to revolutionize AP management by integrating molecular diagnostics with precision medicine.The utilization of large-scale multi-omics approaches and advancements in diagnostic platforms could position PLD2 as a fundamental biomarker for early diagnosis,prognosis,and potentially therapeutic targeting.While promising,it is crucial to conduct critical evaluations and rigorous validations of PLD2’s role to ensure its efficacy in improving patient outcomes.
基金Supported by Mexican Association of Gastroenterology 2023 for the scholarship warded.
文摘Acute pancreatitis(AP)remains a clinical challenge due to its heterogeneous presentation and potential for rapid progression to severe disease.In their editorial,Wang et al highlight phospholipase D2(PLD2)as a novel candidate biomarker,proposing its involvement in key inflammatory pathways and its inverse correlation with disease severity.While this represents a promising improvement in precision diagnostics,significant gaps remain that require further investigation.Specifically,the functional role of PLD2 in the molecular cascade of AP is not yet fully understood.Questions still remain,such as:Is the observed downregulation of PLD2 a causal factor or an epiphenomenon?Does PLD2 modulation offer a tangible therapeutic benefit beyond a mere correlation?These questions highlight the necessity of mechanistic in vivo studies to validate the role and therapeutic potential of PLD2.Furthermore,interindividual variability in inflammatory responses raises concerns regarding PLD2’s predictive consistency across genetically diverse populations.The temporal dynamics of PLD2 expression in AP also remain unclear;establishing whether its variations precede clinical deterioration is essential for its use in early risk stratification,integrating multiomics research(proteomics,metabolomics,transcriptomics,and lipidomics),which can clarify the biological interactions and regulatory pathways of PLD2 under complex mechanisms.Likewise,well-designed,multicenter,prospective studies will be essential in determining its true clinical value.The research by Wang et al initiates an intriguing direction in the quest for AP biomarkers,but further research is required before PLD2 can be established as a clinically applicable tool.Additional efforts are required to close this gap and define whether its role transcends a mere association in order for it to become a therapeutic target.
基金Grants from the National Natural Science Foundation of China:Study on the Immune Mechanism of Macrophages 1/Macrophages 2 Polarization of Macrophages Treated with Moxibustion"Strengthening the Body and Expelling Pathogenic Qi"for"Struggle Between Healthy Qi and Pathogenic Qi"in Rheumatoid Arthritis(No.81973959)the National Key R&D Program of China:a Comparative Study of Moxibustion at Zusanli(ST36)on the Polarization of Knee Synovial Macrophage in Kneeosteoar-thritis and Rheumatoid Arthritis Rat Models(No.2019YFC1709001)+2 种基金the National Natural Science Foundation of China:Study on the Regulatory Mechanism of the"Immune-Inflammation"Molecular Signal of the Nucleotide—Binding Oligomerization Domain,Leucine rich Repeat and Pyrin domain containing Proteins 3 Inflammasome Treated by Moxibustion for Rheumatoid Arthritis(No.81774435)the Foundation of Chengdu University of Traditional Chinese Medicine:Study on the Mechanism of"Macrophage Migration Inhibitory Factor-Target Protein-Glucocorticoid-Inflammation"in Moxibustion Treatment and Anti-inflammatory Effect of Rheumatoid Arthritis(No.QNXZ2018034)the Science and Technology Innovation Seedling Project of Sichuan Province:Exploring the Effector Mechanism of Moxibustion Treatment in the Experimental Rheumatoid Arthritis Model based on the Macrophage Macrophages 1 Polarization Signaling Pathway Toll-like Receptors 4-Maximum Tolerated Dose 88-Nuclear Factor-Kappa B and its Regulatory Molecule T Cell Immunoglobulin and Mucin Domain-containing Protein 3(No.2022037)。
文摘OBJECTIVE:To determine whether moxibustion had an anti-inflammatory effect on rheumatoid arthritis(RA)by regulating Annexin 1 expression and interfering with the phospholipaseA2 signaling pathway.METHODS:Thirty male Sprague-Dawley rats were randomly categorized into five groups(six rats per group):blank control(CON)group,RA model(RA)group,moxibustion(MOX)group,Annexin 1 lentiviral intervention(RNAi-Anxa1)group,and Annexin 1 lentiviral intervention+moxibustion(RNAi-Anxa1+MOX)group.The rats in the RNAi-Anxa1 and the RNAi-Anxa1+MOX groups were injected with the lentiviral vector-mediated RNAi-Anxa1 into the rat foot pad.An experimental RA rat model was established by injecting Freund's complete adjuvant(FCA)into the RA,MOX,RNAi-Anxa1,and RNAi-Anxa1+MOX groups.Rats in the MOX and RNAiAnxa1+MOX groups received moxibustion treatment.After modeling,using moxibustion“Shenshu(BL23)”and“Zusanli(ST36)”,each point is 5 times,bilateral alternating,once a day,6 times for a course of treatment,between the courses of rest for a one day.A total of three treatment courses were conducted.Both bilateral pad thicknesses were measured using Vernier calipers on experimental days 1,7,14,21,and 28.The expression of cPLA2αsignaling in the synovium of diseased joints was observed using Western blot.The pathology of the rat ankle synovium was observed using hematoxylineosin(HE)staining.Interleukin(IL)-1β,IL-10,prostaglandin E2(PGE2),and leukotriene B4(LTB4)were detected using enzyme-linked immunosorbent assay.RESULTS:Moxibustion increased the levels of Annexin 1 and decreased the inflammatory response in rats with RA.After increasing the expression of Annexin 1,the phosphorylated expression of cPLA2αwas inhibited,the serum levels of IL-1β,PGE2,and LTB4 decreased,and the level of IL-10 increased.In moxibustion treated RA rats after the Annexin 1 lentiviral intervention,the serum levels of IL-1β,PGE2,LTB4,and IL-10 were almost unchanged.CONCLUSION:Moxibustion enhanced the negative regulation of the cPLA2αsignaling pathway,increased the synovial Annexin 1 expression,inhibited the cPLA2αsignaling pathway,indirectly inhibited the expression of downstream inflammatory factors,and played a role in reducing inflammation.
文摘研究背景力学门控性离子通道（mechanogated ion channels）,又称为力学敏感性离子通道（mechanosensitive ion channels,MSIC）,是心肌细胞的力学感受器之一。MSIC在心脏受到力学超负荷后电生理改变过程中起主要作用,可能是心肌细胞肥大过程中,力学负荷与蛋白质合成之间信号传导的一条重要通路。瞬时感受器电位（Transient receptor potential,TRP）离子通道C亚族（TRPC）蛋白TRPC1、C6对于心肌细胞适应生物力学刺激很重要,其表达上调会导致病理性心肌肥大及心衰<sup>[1-3]</sup>。TRPC通道不仅可被G蛋白耦联受体下游的磷脂酶C（phospholipase C,PLC）、二脂酰甘油（diacylglycerol,DAG）等信号分子继发激活,TRPC1、C6等可能还是力学敏感的离子通道,
文摘Objective To survey changes and the significance of phospholipase A_2(PLA_2) on brain tissue of SD rat in acute pancreatitis.Methods With retrograde injection of 3% taurocholate sodium into pancreatic and biliary duct,rat model of severe acute pancreatitis(SAP) was made,and it included four groups: the control group,the sham-operation group, the SAP group and the PLA_2 inhibitor-treated group of SAP.Serum amylases,PLA_2 and PLA_2 in brain tissue were measured and the brain tissue changes were observed.Results There were no significant difference in serum amylases, PLA_2 and PLA_2 in brain tissue between the sham-operation and the control groups;the levels of serum amylases,PLA_2 and PLA_2 in brain tissue in the SAP group were higher than those in the control.In the SAP group expansion and hemorrhage of meninges,intracephalic arteriolar hyperemia,in meninges and cephalic-parenchyma infiltration of inflammatory cells and interval broaden were observed,significant differences were found between two groups.Compared with the SAP group,the level of serum amylase,PLA_2 and PLA_2 in brain tissue were reduced significantly in the treatment group of SAP.Pathological damages in the treatment group were significantly reduced when compared with the SAP group.Conclusion PLA_2 might play an important role in brain tissue damages in severe acute pancreatitis.
基金Supported by FORICA(the FOundation for Advanced Research in Hypertension and Cardiovascular diseases,www.forica.it)
文摘Atherosclerosis manifests itself clinically at advanced stages when plaques undergo hemorrhage and/or rupture with superimposed thrombosis, thus abruptly stopping blood supply. Identification of markers of plaque destabilization at a pre-clinical stage is, therefore, a major goal of cardiovascular research. Promising results along this line were provided by studies investigating the lipoprotein-associated phospholipase A2(Lp-PLA2), a member of phospholipase A2 proteins family that plays a key role in the metabolism of pro-inflammatory phospholipids, as oxidized low-density lipoproteins, and in the generation of pro-atherogenic metabolites, including lysophosphatidylcholine and oxidized free fatty acids. We herein review the experimental and clinical studies supporting use of Lp-PLA2 activity for predicting cardiovascular events. To his end we considered not only Lp-PLA2 activity and mass, but also Lp-PLA2 gene variations and their association with incident coronary artery disease, stroke, and cardiovascular mortality. Based on these evidences the major scientific societies have included in their guidelines the measurement of Lp-PLA2 activity among the biomarkers that are useful in risk stratification of adult asymptomatic patients at intermediate cardiovascular risk. The results of two recently published major clinical trials with the LpPLA2 inhibitor darapladib, which seem to challenge the pathogenic role of Lp-PLA2, will also be discussed.
文摘Hepatocellular carcinoma(HCC) is the fourth cause of cancer related mortality, and its incidence is rapidly increasing. Viral hepatitis, alcohol abuse, and exposure to hepatotoxins are major risk factors, but nonalcoholic fatty liver disease(NAFLD) associated with obesity, insulin resistance, and type 2 diabetes, is an increasingly recognized trigger, especially in developed countries. Older age, severity of insulin resistance and diabetes, and iron overload have been reported to predispose to HCC in this context. Remarkably, HCCs have been reported in non-cirrhotic livers in a higher proportion of cases in NAFLD patients than in other etiologies. Inherited factors have also been implicated to explain the different individual susceptibility to develop HCC, and their role seems magnified in fatty liver, where only a minority of affected subjects progresses to cancer. In particular, the common I148 M variant of the PNPLA3 gene influencing hepatic lipid metabolism influences HCC risk independently of its effect on the progression of liver fibrosis. Recently, rare loss-of-function mutations in Apolipoprotein B resulting in very low density lipoproteins hepatic retention and in Telomerase reverse transcriptase influencing cellular senescence have also been linked to HCC in NAFLD. Indeed, hepatic stellate cells senescence has been suggested to bridge tissue aging with alterations of the intestinal microbiota in the pathogenesis of obesity-related HCC. A deeper understanding of the mechanisms mediating hepatic carcinogenesis during insulin resistance, and the identification of its genetic determinants will hopefully provide new diagnostic and therapeutic tools.
基金Supported by the Traditional Chinese Medicine Administration Bureau Foundation of Jiangsu Province,No.9965the Applied Basic Research Program of Science and Technology Commission Foundation of Jiangsu Province,No.BJ2000327
文摘AIM:To explore the relationship between gastric and intestinal microcirculatory impairment and inflammatory mediators released in rats with acute necrotizing pancreatitis (ANP). METHODS: A total of 64 rats were randomized into control group and ANP group. ANP model was induced by injection of 5% sodium taurocholate under the pancreatic membrane. Radioactive biomicrosphere technique was used to measure the gastric and intestinal tissue blood flow at 2 and 12 h after the induction of ANP, meanwhile serum phospholipase A2 (PLA2) activities and interleukin-1β levels were determined. Pathologic changes in pancreas, gastric and intestinal mucosae were studied. RESULTS: The gastric blood flow in ANP group (0.62±0.06 and 0.35±0.05) mL/(min·g) was significantly lower than that in control group (0.86±0.11 and 0.85±0.06) mL/(min·g) (P<0.01) at 2 and 12 h after induction of ANP. The intestinal blood flow in ANP group (0.80±0.07 and 0.50±0.06) mlV(min·g) was significantly lower than that in control group (1.56±0.18 and 1.61±0.11) mL/(min·g) (P<0.01). Serum PLA2 activities (94.29±9.96 and 103.71± 14.40) U/L and IL-1β levels (0.78±0.13 and 0.83±0.20)μg/L in ANP group were higher than those in control group (65.27±10.52 and 66.63±9.81) U/L, (0.32±0.06 and 0.33±0.07)μg/L (P<0.01). At 2 and 12 h after introduction of the model, typical pathologic changes were found in ANP. Compared with control group, the gastric and intestinal mucosal pathologic changes were aggravated significantly (P<0.01) at 12 h after induction of ANP. Gastric and intestinal mucosal necrosis, multiple ulcer and hemorrhage occurred. CONCLUSION: Decrease of gastric and intestinal blood flow and increase of inflammatory mediators occur simultaneously early in ANP, both of them are important pathogenic factors for gastric and intestinal mucosal injury in ANP.
基金This work was supported by grants from the Technology Foundation of Traditional Chinese Medicine Science of Zhejiang Province (No.2003C130 No.2004C142)+4 种基金the Foundation of Medical Sciences and Technology of Zhejiang Province (No.2003B134)the Grave Foundation for Technological Development of Hangzhou (2003123B19)the Intensive Foundation for Technology of Hangzhou (No.2004Z006)the Foundation for Medical Sciences and Technology of Hangzhou (No.2003A004)the Foundation for Technology of Hangzhou (No.2005224).
文摘BACKGROUND: Pancreatic encephalopathy (PE) is a serious complication of severe acute pancreatitis (SAP). In recent years, more and more PE cases have been reported worldwide, and the onset PE in the early stage was regarded as a poor prognosis sign of SAP, but the pathogenesis of PE in SAP still has not been clarified in the past decade. The purpose of this review is to elucidate the possible pathogenesis of PE in SAP. DATA SOURCES: The English-language literature concerning PE in this review came from the Database of MEDLINE (period of 1991-2005), and the keywords of severe acute pancreatitis and pancreatic encephalopathy were used in the searching. RESULTS: Many factors were involved in the pathogenesis of PE in SAP. Pancreatin activation, excessive release of cytokines and oxygen free radicals, microcirculation abnormalities of hemodynamic disturbance, ET-1/NO ratio, hypoxemia, bacterial infection, water and electrolyte imbalance, and vitamin B1 deficiency participated in the development of PE in SAP. CONCLUSIONS: The pathogenesis of PE in SAP has not yet been fully understood. The development of PE in SAP may be a multi-factor process. To find out the possible inducing factor is essential to the clinical management of PE in SAP.
