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
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
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
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
Recent studies have revealed that lipid droplets accumulate in neurons after brain injury and evoke lipotoxicity,damaging the neurons.However,how lipids are metabolized by spinal cord neurons after spinal cord injury ...Recent studies have revealed that lipid droplets accumulate in neurons after brain injury and evoke lipotoxicity,damaging the neurons.However,how lipids are metabolized by spinal cord neurons after spinal cord injury remains unclear.Herein,we investigated lipid metabolism by spinal cord neurons after spinal cord injury and identified lipid-lowering compounds to treat spinal cord injury.We found that lipid droplets accumulated in perilesional spinal cord neurons after spinal cord injury in mice.Lipid droplet accumulation could be induced by myelin debris in HT22 cells.Myelin debris degradation by phospholipase led to massive free fatty acid production,which increased lipid droplet synthesis,β-oxidation,and oxidative phosphorylation.Excessive oxidative phosphorylation increased reactive oxygen species generation,which led to increased lipid peroxidation and HT22 cell apoptosis.Bromocriptine was identified as a lipid-lowering compound that inhibited phosphorylation of cytosolic phospholipase A2 by reducing the phosphorylation of extracellular signal-regulated kinases 1/2 in the mitogen-activated protein kinase pathway,thereby inhibiting myelin debris degradation by cytosolic phospholipase A2 and alleviating lipid droplet accumulation in myelin debris-treated HT22 cells.Motor function,lipid droplet accumulation in spinal cord neurons and neuronal survival were all improved in bromocriptine-treated mice after spinal cord injury.The results suggest that bromocriptine can protect neurons from lipotoxic damage after spinal cord injury via the extracellular signal-regulated kinases 1/2-cytosolic phospholipase A2 pathway.展开更多
Phospholipase A2 (PLA2) is the key enzyme to the venom from Deinagkistrodon acutus which is one of the highly venomous snakes in China. In addition to being a catalyst for the hydrolysis of phospholipases A2 from snak...Phospholipase A2 (PLA2) is the key enzyme to the venom from Deinagkistrodon acutus which is one of the highly venomous snakes in China. In addition to being a catalyst for the hydrolysis of phospholipases A2 from snake venom, its well known that it possesses a broad spectrum of pharmacological activities, such as myotoxicity, neurotoxicity, cardiotoxicity, and hemolytic, anticoagulant and antiplatelet activities. However, snakebites are not efficiently treated by conventional serum therapy. Acute wounds can still cause poisoning and death. In order to find effective inhibitors of Deinagkistrodon venom acid phospholipase A2 (dPLA2), we obtained 385 compounds in 9 Chinese herbs from the TCMSP. These compounds were further performed to virtual screen using in silico tools like ADMET analysis, molecular docking and molecular dynamics (MD) simulation. After Pharmacokinetics analysis, we found 7 candidate compounds. Besides, analysis of small molecule interactions with dPLA2 confirmed that the amino acid residues HIS47 and GLY29 are key targets. Because they bind not only to the natural substrate phosphatidylcholine and compounds known for having inhibitory functions, but also for combining with potential antidote molecules in Chinese herbal medicine. This study is the first to report experience with virtual screening for possible inhibitor of dPLA2, such as the interaction spatial structure, binding energy and binding interaction analysis, these experiences not only provide reference for further experimental research, but also have a guideline for the study of drug molecular mechanism of action.展开更多
BACKGROUND Patatin like phospholipase domain containing 8(PNPLA8)has been shown to play a significant role in various cancer entities.Previous studies have focused on its roles as an antioxidant and in lipid peroxidat...BACKGROUND Patatin like phospholipase domain containing 8(PNPLA8)has been shown to play a significant role in various cancer entities.Previous studies have focused on its roles as an antioxidant and in lipid peroxidation.However,the role of PNPLA8 in colorectal cancer(CRC)progression is unclear.AIM To explore the prognostic effects of PNPLA8 expression in CRC.METHODS A retrospective cohort containing 751 consecutive CRC patients was enrolled.PNPLA8 expression in tumor samples was evaluated by immunohistochemistry staining and semi-quantitated with immunoreactive scores.CRC patients were divided into high and low PNPLA8 expression groups based on the cut-off va-lues,which were calculated by X-tile software.The prognostic value of PNPLA8 was identified using univariate and multivariate Cox regression analysis.The over-all survival(OS)rates of CRC patients in the study cohort were compared with Kaplan-Meier analysis and Log-rank test.RESULTS PNPLA8 expression was significantly associated with distant metastases in our cohort(P=0.048).CRC patients with high PNPLA8 expression indicated poor OS(median OS=35.3,P=0.005).CRC patients with a higher PNPLA8 expression at either stage I and II or stage III and IV had statistically significant shorter OS.For patients with left-sided colon and rectal cancer,the survival curves of two PN-PLA8-expression groups showed statistically significant differences.Multivariate analysis also confirmed that high PNPLA8 expression was an independent prog-nostic factor for overall survival(hazard ratio HR=1.328,95%CI:1.016-1.734,P=0.038).展开更多
In the face of increasingly serious environmental pollution,the health of human lung tissues is also facing serious threats.Mogroside IIE(M2E)is the main metabolite of sweetening agents mogrosides from the anti-tussiv...In the face of increasingly serious environmental pollution,the health of human lung tissues is also facing serious threats.Mogroside IIE(M2E)is the main metabolite of sweetening agents mogrosides from the anti-tussive Chinese herbal Siraitia grosvenori.The study elucidated the anti-inflammatory action and molecular mechanism of M2E against acute lung injury(ALI).A lipopolysaccharide(LPS)-induced ALI model was established in mice and MH-S cells were employed to explore the protective mechanism of M2E through the western blotting,co-immunoprecipitation,and quantitative real time-PCR analysis.The results indicated that M2E alleviated LPS-induced lung injury through restraining the activation of secreted phospholipase A2 type IIA(Pla2g2a)-epidermal growth factor receptor(EGFR).The interaction of Pla2g2a and EGFR was identified by co-immunoprecipitation.In addition,M2E protected ALI induced with LPS against inflammatory and damage which were significantly dependent upon the downregulation of AKT and m TOR via the inhibition of Pla2g2a-EGFR.Pla2g2a may represent a potential target for M2E in the improvement of LPS-induced lung injury,which may represent a promising strategy to treat ALI.展开更多
Chagas disease (CD) affects 21 countries in the Americas and is caused by the parasite Trypanosoma cruzi. A key molecule involved in CD is lysophosphatidylcholine (LPC), which has been studied in various contexts: in ...Chagas disease (CD) affects 21 countries in the Americas and is caused by the parasite Trypanosoma cruzi. A key molecule involved in CD is lysophosphatidylcholine (LPC), which has been studied in various contexts: in the saliva of insect vectors, during the establishment of infection in the vertebrate host, and for the parasite itself. This lipid can be produced by the action of phospholipases A2 (PLA2), enzymes that catalyze the hydrolysis of phospholipids releasing fatty acids and lysophospholipids, such as LPC. This study investigates LPC levels and PLA2 activities in the plasma of CD patients and compares these levels with those in healthy individuals and patients with idiopathic dilated cardiomyopathy (IDCM). Plasma from 64 CD patients, 54 healthy individuals, and 16 IDCM patients were analyzed. LPC levels and the activity of two types of phospholipase A2: secreted (sPLA2) and lipoprotein-associated (Lp-PLA2) were measured. LPC levels and sPLA2 activity were similar between CD patients and the control groups. However, there were notable differences in LPC levels and sPLA2 activity between subgroups of CD patients and IDCM patients. This study is the first to identify LPC in patients with CD across various stages of the disease. It also offers new insights into the biochemical changes observed in the plasma of patients with IDCM.展开更多
BACKGROUND Genetic factors of chronic intestinal ulcers are increasingly garnering attention.We present a case of chronic intestinal ulcers and bleeding associated with mu-tations of the activin A receptor type II-lik...BACKGROUND Genetic factors of chronic intestinal ulcers are increasingly garnering attention.We present a case of chronic intestinal ulcers and bleeding associated with mu-tations of the activin A receptor type II-like 1(ACVRL1)and phospholipase A2 group IVA(PLA2G4A)genes and review the available relevant literature.CASE SUMMARY A 20-year-old man was admitted to our center with a 6-year history of recurrent abdominal pain,diarrhea,and dark stools.At the onset 6 years ago,the patient had received treatment at a local hospital for abdominal pain persisting for 7 d,under the diagnosis of diffuse peritonitis,acute gangrenous appendicitis with perforation,adhesive intestinal obstruction,and pelvic abscess.The surgical treat-ment included exploratory laparotomy,appendectomy,intestinal adhesiolysis,and pelvic abscess removal.The patient’s condition improved and he was dis-charged.However,the recurrent episodes of abdominal pain and passage of black stools started again one year after discharge.On the basis of these features and results of subsequent colonoscopy,the clinical diagnosis was established as in-flammatory bowel disease(IBD).Accordingly,aminosalicylic acid,immunotherapy,and related symptomatic treatment were administered,but the symptoms of the patient did not improve significantly.Further investigations revealed mutations in the ACVRL1 and PLA2G4A genes.ACVRL1 and PLA2G4A are involved in angiogenesis and coagulation,respectively.This suggests that the chronic intestinal ulcers and bleeding in this case may be linked to mutations in the ACVRL1 and PLA2G4A genes.Oral Kangfuxin liquid was administered to promote healing of the intestinal mucosa and effectively manage clinical symptoms.CONCLUSION Mutations in the ACVRL1 and PLA2G4A genes may be one of the causes of chronic intestinal ulcers and bleeding in IBD.Orally administered Kangfuxin liquid may have therapeutic potential.展开更多
Objective: In folk and TCM clinical medicine, Chinese herbal medicine is used to treat snakebite and has good curative effect, but its active ingredients and mechanism are still unclear. In this study, virtual screeni...Objective: In folk and TCM clinical medicine, Chinese herbal medicine is used to treat snakebite and has good curative effect, but its active ingredients and mechanism are still unclear. In this study, virtual screening and mechanism analysis of effective components from 6 Chinese herbs to inhibit phospholipase A2 of Deinagkistrodon acutus (dPLA2) venom were conducted. Methods: With advanced computing software AutoDock, Pymol and GROMACS, the molecules selected from the Chinese herbal Medicine Chemical Composition databas6e (TCMSP) were docked with the dPLA2 from the protein database (PDB). Further molecular dynamics simulation was used to evaluate the molecular binding stability. Results: Four potential dPLA2-inhibiting molecules were screened: lobelanidine, lobeline, norlobelanine and pratensein, by analyzing the spatial structure, binding energy and binding interaction of small molecular-dPLA2 complexes, as well as the RMSD and RMSF of molecular dynamics simulation. Conclusion: To our knowledge, this is the first report of lobeline has an inhibitory effect on dPLA2, and lobelanidine, as a precursor of lobeline, has a stronger inhibitory effect. According to the docking results, it is speculated that the mechanism of action of the four molecules is to form stable interactions with calcium ions and amino acid residues on the calcium ion binding ring in dPLA2. Moreover, these small molecules compete with phosphatidylcholine (the natural substrate of dPLA2) to bind dPLA2 and have a higher affinity than phosphatidylcholine, resulting in inhibition of dPLA2 activity.展开更多
Phospholipase A1(PLA1)is a kind of specific phospholipid hydrolase widely used in food,medical,textile.However,limitations in its expression and enzymatic activity have prompted the investigation of the phospholipase-...Phospholipase A1(PLA1)is a kind of specific phospholipid hydrolase widely used in food,medical,textile.However,limitations in its expression and enzymatic activity have prompted the investigation of the phospholipase-assisting protein PlaS.In this study,we elucidate the role of PlaS in enhancing the expression and activity of PlaA1 through N-terminal truncation.Our research demonstrates that truncating the N-terminal region of PlaS effectively overcomes its inhibitory effect on host cells,resulting in improved cell growth and increased protein solubility of the protein.The yeast two-hybrid assay confirms the interaction between PlaA1 and N-terminal truncated PlaS(ΔN27 PlaS),highlighting their binding capabilities.Furthermore,in vitro studies using Biacore analysis reveal a concentration-dependent and specific binding between PlaA1 andΔN27 PlaS,exhibiting high affinity.Molecular docking analysis provides insights into the hydrogen bond interactions betweenΔN27 PlaS and PlaA1,identifying key amino acid residues crucial for their binding.Finally,the enzyme activity of PLA1 was boost to 8.4 U/mL by orthogonal test.Study significantly contributes to the understanding of the interaction mechanism between PlaS and PlaA1,offering potential strategies for enhancing PlaA1 activity through protein engineering approaches.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
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 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.
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.
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.
基金supported by the National Natural Science Foundation of China,Nos.82071376(to ZC)and 82001471(to CJ)the Natural Science Foundation of Shanghai,No.20ZR1410500(to ZC).
文摘Recent studies have revealed that lipid droplets accumulate in neurons after brain injury and evoke lipotoxicity,damaging the neurons.However,how lipids are metabolized by spinal cord neurons after spinal cord injury remains unclear.Herein,we investigated lipid metabolism by spinal cord neurons after spinal cord injury and identified lipid-lowering compounds to treat spinal cord injury.We found that lipid droplets accumulated in perilesional spinal cord neurons after spinal cord injury in mice.Lipid droplet accumulation could be induced by myelin debris in HT22 cells.Myelin debris degradation by phospholipase led to massive free fatty acid production,which increased lipid droplet synthesis,β-oxidation,and oxidative phosphorylation.Excessive oxidative phosphorylation increased reactive oxygen species generation,which led to increased lipid peroxidation and HT22 cell apoptosis.Bromocriptine was identified as a lipid-lowering compound that inhibited phosphorylation of cytosolic phospholipase A2 by reducing the phosphorylation of extracellular signal-regulated kinases 1/2 in the mitogen-activated protein kinase pathway,thereby inhibiting myelin debris degradation by cytosolic phospholipase A2 and alleviating lipid droplet accumulation in myelin debris-treated HT22 cells.Motor function,lipid droplet accumulation in spinal cord neurons and neuronal survival were all improved in bromocriptine-treated mice after spinal cord injury.The results suggest that bromocriptine can protect neurons from lipotoxic damage after spinal cord injury via the extracellular signal-regulated kinases 1/2-cytosolic phospholipase A2 pathway.
文摘Phospholipase A2 (PLA2) is the key enzyme to the venom from Deinagkistrodon acutus which is one of the highly venomous snakes in China. In addition to being a catalyst for the hydrolysis of phospholipases A2 from snake venom, its well known that it possesses a broad spectrum of pharmacological activities, such as myotoxicity, neurotoxicity, cardiotoxicity, and hemolytic, anticoagulant and antiplatelet activities. However, snakebites are not efficiently treated by conventional serum therapy. Acute wounds can still cause poisoning and death. In order to find effective inhibitors of Deinagkistrodon venom acid phospholipase A2 (dPLA2), we obtained 385 compounds in 9 Chinese herbs from the TCMSP. These compounds were further performed to virtual screen using in silico tools like ADMET analysis, molecular docking and molecular dynamics (MD) simulation. After Pharmacokinetics analysis, we found 7 candidate compounds. Besides, analysis of small molecule interactions with dPLA2 confirmed that the amino acid residues HIS47 and GLY29 are key targets. Because they bind not only to the natural substrate phosphatidylcholine and compounds known for having inhibitory functions, but also for combining with potential antidote molecules in Chinese herbal medicine. This study is the first to report experience with virtual screening for possible inhibitor of dPLA2, such as the interaction spatial structure, binding energy and binding interaction analysis, these experiences not only provide reference for further experimental research, but also have a guideline for the study of drug molecular mechanism of action.
基金This study was approved by the Clinical Research Ethics Committee of Zhongshan Hospital,Fudan University.
文摘BACKGROUND Patatin like phospholipase domain containing 8(PNPLA8)has been shown to play a significant role in various cancer entities.Previous studies have focused on its roles as an antioxidant and in lipid peroxidation.However,the role of PNPLA8 in colorectal cancer(CRC)progression is unclear.AIM To explore the prognostic effects of PNPLA8 expression in CRC.METHODS A retrospective cohort containing 751 consecutive CRC patients was enrolled.PNPLA8 expression in tumor samples was evaluated by immunohistochemistry staining and semi-quantitated with immunoreactive scores.CRC patients were divided into high and low PNPLA8 expression groups based on the cut-off va-lues,which were calculated by X-tile software.The prognostic value of PNPLA8 was identified using univariate and multivariate Cox regression analysis.The over-all survival(OS)rates of CRC patients in the study cohort were compared with Kaplan-Meier analysis and Log-rank test.RESULTS PNPLA8 expression was significantly associated with distant metastases in our cohort(P=0.048).CRC patients with high PNPLA8 expression indicated poor OS(median OS=35.3,P=0.005).CRC patients with a higher PNPLA8 expression at either stage I and II or stage III and IV had statistically significant shorter OS.For patients with left-sided colon and rectal cancer,the survival curves of two PN-PLA8-expression groups showed statistically significant differences.Multivariate analysis also confirmed that high PNPLA8 expression was an independent prog-nostic factor for overall survival(hazard ratio HR=1.328,95%CI:1.016-1.734,P=0.038).
基金the National Natural Science Foundation(81773982,82003937)Youth Academic leaders of the Qinglan Project in Jiangsu province for financial support。
文摘In the face of increasingly serious environmental pollution,the health of human lung tissues is also facing serious threats.Mogroside IIE(M2E)is the main metabolite of sweetening agents mogrosides from the anti-tussive Chinese herbal Siraitia grosvenori.The study elucidated the anti-inflammatory action and molecular mechanism of M2E against acute lung injury(ALI).A lipopolysaccharide(LPS)-induced ALI model was established in mice and MH-S cells were employed to explore the protective mechanism of M2E through the western blotting,co-immunoprecipitation,and quantitative real time-PCR analysis.The results indicated that M2E alleviated LPS-induced lung injury through restraining the activation of secreted phospholipase A2 type IIA(Pla2g2a)-epidermal growth factor receptor(EGFR).The interaction of Pla2g2a and EGFR was identified by co-immunoprecipitation.In addition,M2E protected ALI induced with LPS against inflammatory and damage which were significantly dependent upon the downregulation of AKT and m TOR via the inhibition of Pla2g2a-EGFR.Pla2g2a may represent a potential target for M2E in the improvement of LPS-induced lung injury,which may represent a promising strategy to treat ALI.
文摘Chagas disease (CD) affects 21 countries in the Americas and is caused by the parasite Trypanosoma cruzi. A key molecule involved in CD is lysophosphatidylcholine (LPC), which has been studied in various contexts: in the saliva of insect vectors, during the establishment of infection in the vertebrate host, and for the parasite itself. This lipid can be produced by the action of phospholipases A2 (PLA2), enzymes that catalyze the hydrolysis of phospholipids releasing fatty acids and lysophospholipids, such as LPC. This study investigates LPC levels and PLA2 activities in the plasma of CD patients and compares these levels with those in healthy individuals and patients with idiopathic dilated cardiomyopathy (IDCM). Plasma from 64 CD patients, 54 healthy individuals, and 16 IDCM patients were analyzed. LPC levels and the activity of two types of phospholipase A2: secreted (sPLA2) and lipoprotein-associated (Lp-PLA2) were measured. LPC levels and sPLA2 activity were similar between CD patients and the control groups. However, there were notable differences in LPC levels and sPLA2 activity between subgroups of CD patients and IDCM patients. This study is the first to identify LPC in patients with CD across various stages of the disease. It also offers new insights into the biochemical changes observed in the plasma of patients with IDCM.
基金Supported by the Science and Technology Research Foundation of Guizhou Province,No.QKHJC-ZK[2022]YB642Science and Technology Research Foundation of Hubei Province,No.2022BCE030+2 种基金Science and Technology Research Foundation of Zunyi City,No.ZSKH-HZ(2022)344Research Project on Traditional Chinese Medicine and Ethnic Medicine Science and Technology of Guizhou Provincial Administration of Traditional Chinese Medicine,No.QZYY-2023-021Science and Technology Research Foundation of Bijie City,No.BKH[2022]8.
文摘BACKGROUND Genetic factors of chronic intestinal ulcers are increasingly garnering attention.We present a case of chronic intestinal ulcers and bleeding associated with mu-tations of the activin A receptor type II-like 1(ACVRL1)and phospholipase A2 group IVA(PLA2G4A)genes and review the available relevant literature.CASE SUMMARY A 20-year-old man was admitted to our center with a 6-year history of recurrent abdominal pain,diarrhea,and dark stools.At the onset 6 years ago,the patient had received treatment at a local hospital for abdominal pain persisting for 7 d,under the diagnosis of diffuse peritonitis,acute gangrenous appendicitis with perforation,adhesive intestinal obstruction,and pelvic abscess.The surgical treat-ment included exploratory laparotomy,appendectomy,intestinal adhesiolysis,and pelvic abscess removal.The patient’s condition improved and he was dis-charged.However,the recurrent episodes of abdominal pain and passage of black stools started again one year after discharge.On the basis of these features and results of subsequent colonoscopy,the clinical diagnosis was established as in-flammatory bowel disease(IBD).Accordingly,aminosalicylic acid,immunotherapy,and related symptomatic treatment were administered,but the symptoms of the patient did not improve significantly.Further investigations revealed mutations in the ACVRL1 and PLA2G4A genes.ACVRL1 and PLA2G4A are involved in angiogenesis and coagulation,respectively.This suggests that the chronic intestinal ulcers and bleeding in this case may be linked to mutations in the ACVRL1 and PLA2G4A genes.Oral Kangfuxin liquid was administered to promote healing of the intestinal mucosa and effectively manage clinical symptoms.CONCLUSION Mutations in the ACVRL1 and PLA2G4A genes may be one of the causes of chronic intestinal ulcers and bleeding in IBD.Orally administered Kangfuxin liquid may have therapeutic potential.
文摘Objective: In folk and TCM clinical medicine, Chinese herbal medicine is used to treat snakebite and has good curative effect, but its active ingredients and mechanism are still unclear. In this study, virtual screening and mechanism analysis of effective components from 6 Chinese herbs to inhibit phospholipase A2 of Deinagkistrodon acutus (dPLA2) venom were conducted. Methods: With advanced computing software AutoDock, Pymol and GROMACS, the molecules selected from the Chinese herbal Medicine Chemical Composition databas6e (TCMSP) were docked with the dPLA2 from the protein database (PDB). Further molecular dynamics simulation was used to evaluate the molecular binding stability. Results: Four potential dPLA2-inhibiting molecules were screened: lobelanidine, lobeline, norlobelanine and pratensein, by analyzing the spatial structure, binding energy and binding interaction of small molecular-dPLA2 complexes, as well as the RMSD and RMSF of molecular dynamics simulation. Conclusion: To our knowledge, this is the first report of lobeline has an inhibitory effect on dPLA2, and lobelanidine, as a precursor of lobeline, has a stronger inhibitory effect. According to the docking results, it is speculated that the mechanism of action of the four molecules is to form stable interactions with calcium ions and amino acid residues on the calcium ion binding ring in dPLA2. Moreover, these small molecules compete with phosphatidylcholine (the natural substrate of dPLA2) to bind dPLA2 and have a higher affinity than phosphatidylcholine, resulting in inhibition of dPLA2 activity.
基金financially supported by National Natural Science Foundations of China(No.31471615)Scientific Research Start-up Fund for Introduced Talents of Anhui Polytechnic University(2022YOO068)Natural Science Research Project of Colleges and Universities in Anhui Province(Grant 2022AH050971).
文摘Phospholipase A1(PLA1)is a kind of specific phospholipid hydrolase widely used in food,medical,textile.However,limitations in its expression and enzymatic activity have prompted the investigation of the phospholipase-assisting protein PlaS.In this study,we elucidate the role of PlaS in enhancing the expression and activity of PlaA1 through N-terminal truncation.Our research demonstrates that truncating the N-terminal region of PlaS effectively overcomes its inhibitory effect on host cells,resulting in improved cell growth and increased protein solubility of the protein.The yeast two-hybrid assay confirms the interaction between PlaA1 and N-terminal truncated PlaS(ΔN27 PlaS),highlighting their binding capabilities.Furthermore,in vitro studies using Biacore analysis reveal a concentration-dependent and specific binding between PlaA1 andΔN27 PlaS,exhibiting high affinity.Molecular docking analysis provides insights into the hydrogen bond interactions betweenΔN27 PlaS and PlaA1,identifying key amino acid residues crucial for their binding.Finally,the enzyme activity of PLA1 was boost to 8.4 U/mL by orthogonal test.Study significantly contributes to the understanding of the interaction mechanism between PlaS and PlaA1,offering potential strategies for enhancing PlaA1 activity through protein engineering approaches.
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,
