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[Display omitted] • TBI induced increased expression of TREM1 in microglia. • TREM1 inhibitor LP17 could alleviate neuroinflammation after TBI. • LP17 could reduce neuronal apoptosis and ameliorate nerve dysfunction after TBI. • Inhibtion TREM1 by LP17 could block the ERK/cPLA2 signalling pathway after TBI. The neuroinflammatory response promotes secondary brain injury after traumatic brain injury (TBI). Triggering receptor expressed on myeloid cells 1 (TREM1) is a key regulator of inflammation. However, the role of TREM1 in TBI is poorly studied. The purpose of this study was to investigate the role of TREM1 in TBI and the possible underlying mechanism. We found that the protein expression of TREM1 significantly increased after TBI in rats, and the TREM1 protein localized to microglia. Inhibition of the TREM1 protein with LP17 significantly blocked ERK phosphorylation and reduced cytoplasmic phospholipase A2 (cPLA2) protein expression and phosphorylation. In addition, LP17-mediated TREM1 inhibition significantly reduced the protein expression of iNOS and increased the protein expression of Arg1. Moreover, after TREM1 was inhibited, the secretion of the proinflammatory factors TNF-α and IL-1β was significantly reduced, while the secretion of the anti-inflammatory factors IL-4 and IL-10 was significantly increased. Additionally, inhibition of TREM1 by LP17 significantly reduced neuronal apoptosis and ameliorated nerve dysfunction in TBI model rats. In conclusion, our findings suggest that TREM1 enhances neuroinflammation and promotes neuronal apoptosis after TBI, and these effects may be partly mediated via the ERK/cPLA2 signalling pathway. [ABSTRACT FROM AUTHOR]

Background: The association of lipoprotein-associated phospholipase A2 (Lp-PLA2) with various cardiovascular events has been well-established. However, the exploration of its potential involvement in Chronic obstructive pulmonary disease (COPD) is currently limited. Therefore, our study aims to examine the relationship between Lp-PLA2 and pulmonary conditions, including emphysema, obstructive ventilatory dysfunction as well as small airway dysfunction, to provide further evidence of a possible association with COPD development. Methods: Using data from the Southwest Hospital Health Management Center, spanning January 2013 to July 2024, we analyze relationship of serum Lp-PLA2 levels with diffuse pulmonary emphysema and pulmonary functions. In univariate analysis, group differences were assessed with t-tests for numerical variables and Chi-square tests for categorical data. Variables found to be statistically significant (two-sided P < 0.05) in univariate analysis were subsequently included as covariates in multivariate analysis, performed using a binary logistic regression model. Odds ratios and 95% confidence intervals were calculated to assess the differences. Results: We established 2 case-control populations: the Imaging population (1056 subjects, mean age 57.666 ± 8.700 years old, 89.9% male) selected from 24,670 initial records, and the Pulmonary Function population (279 subjects, mean age 52.082 ± 11.473 years old, 71.4% male) selected from 1868 initial records. Univariate analysis revealed that serum Lp-PLA2 levels were significantly higher in patients with diffuse pulmonary emphysema, obstructive ventilatory dysfunction as well as small airway dysfunction compared to those without (454.682 ± 141.382U/L vs. 423.330 ± 140.658U/L, P < 0.001; 475.059 ± 157.181U/L vs. 420.824 ± 142.119U/L, P = 0.006; 475.31 ± 148.980U/L vs. 439.036 ± 157.977U/L, P = 0.049, respectively). Multivariate analysis further showed higher Lp-PLA2 levels were associated with increased risks of diffuse pulmonary emphysema, obstructive ventilatory dysfunction as well as small airway dysfunction. Using Lp-PLA2 ≤ 300 U/L as reference, odds ratios for the aforementioned conditions showed a gradually increasing trend with every 100U/L increase in Lp-PLA2 levels. Conclusions: Our preliminary study suggests that Lp-PLA2 is independently associated with diffuse pulmonary emphysema, obstructive ventilatory dysfunction as well as small airway dysfunction, which are commonly seen in COPD development. These findings indicated a possible association between Lp-PLA2 and COPD, though further validation is needed in a large cohort of COPD patients. [ABSTRACT FROM AUTHOR]

Background: Hypothyroidism (HT) affects millions worldwide and can lead to various lipid disorders. The metabolic complexity and the influence of toxic elements in autoimmune and non-autoimmune HT subtypes are not fully understood. This study aimed to investigate the relationships between plasma lipidome, toxic elements, and clinical classifications of HT in unexposed individuals. Methods: Samples were collected from 120 adults assigned to a study group with Hashimoto's disease and non-autoimmune HT, and a healthy control group. Quantification of 145 pre-defined lipids was performed by using triple quadrupole tandem mass spectrometry (TQ MS/MS) in multiple reactions monitoring (MRM) mode via positive electrospray ionization (ESI). Levels of toxic elements were determined using inductively coupled plasma mass spectrometry (ICP-MS). Results: Significant associations between altered levels of several components of the plasma lipidome and Al, Cd, Ni, As, and Pb with HT were found. We show metabolic differences in lysophosphatidylcholines (LPC) and phosphatidylcholines (PC) between HT and controls, with distinct predicted activation patterns for lysolecithin acyltransferase and phospholipase A2. Conclusions: There are significant changes in the lipidome profiles of healthy subjects compared to euthyroid HT patients treated with L-thyroxine, which are related to the type of hypothyroidism and non-occupational exposure to toxic elements. [ABSTRACT FROM AUTHOR]

Snakebite envenomation is a serious health concern in tropical regions, resulting in high mortality. The World Health Organization (WHO) has declared it a neglected tropical disease and is working on strategies to reduce mortality. Russell's viper (Daboia russelii) is one of the most abundant venomous snakes found across Southeast Asia. Proteomic analysis of Russell's viper venom has demonstrated variation, with phospholipase A2 (PLA2) being the most abundant toxin across geographic boundaries. PLA2, a major constituent of the low-molecular-weight fraction of snake venom, hydrolyses phospholipids at the sn-2 position, releasing arachidonic acid and lysophospholipids. They are reported to cause various pharmacological effects, including hemolysis, anticoagulation, neurotoxicity, myotoxicity, and oedema. Though administration of antivenoms (ASV) is the primary treatment for envenomation, it has many drawbacks. Besides causing hypersensitivity reactions and life-threatening anaphylaxis, treatment with ASV is further complicated due to its inability to neutralize low-molecular-weight toxins. Thus, there is a greater need to produce next-generation antivenoms that can target specific toxins in the venom. In this review, we explored the classification of Russell's viper and the variation in its proteomic profile across Southeast Asia to date. In addition, we have also summarized the mechanism of action of PLA2 and discussed various isoforms of PLA2 found across different regions with their respective pharmacological effects. Finally, the drawbacks of commercially available antivenoms and the molecules investigated for inhibiting the low-molecular-weight toxin, PLA2 are discussed. [ABSTRACT FROM AUTHOR]

Background: As an initial treatment for primary membranous nephropathy (PMN), there remains a significant proportion of patients for whom rituximab is not fully effective. Here, we aimed to assess the effectiveness and safety of obinutuzumab as initial treatment in patients with PMN. Methods: In this observational case series, patients diagnosed with PMN and treated with obinutuzumab as initial treatment were included. Treatment response was assessed by 24‐h urine total protein (24 h UTP) and serum albumin, and immunologic remission was assessed by phospholipase A2 receptor (PLA2R) antibodies. Results: Twelve patients with PMN receiving obinutuzumab as initial treatment were included. Over 6 months, a statistically significant reduction in 24 h UTP levels (p = 0.003) and an increase in serum albumin levels were observed (p < 0.001). By the 6‐month follow‐up, two patients (16.7%) achieved complete remission, eight (66.6%) reached partial remission, and two (16.7%) showed no remission. Immunological remission was observed in 44.4% of evaluable patients (n = 9) after 3 months, increasing to 100% (6/6) at 6 months. Except for cases 1, 2, and 3, the total B cell counts in the remaining patients fell to less than 5 cells/μL before the administration of the second dose of obinutuzumab, including seven patients with counts as low as 0 cells/μL. Mild to moderate treatment‐related adverse events (TRAEs) were reported in 58.3% (7/12) of the patients. No serious TRAEs were reported. Conclusions: Obinutuzumab demonstrates promising potential as an initial treatment for PMN, with good effectiveness and a manageable safety profile. Further large‐scale prospective studies are needed to confirm these findings. [ABSTRACT FROM AUTHOR]

Background: Phospholipase A2 (PLA2) is a large family of enzymes involved in the inflammatory process that catalyzes the hydrolysis of membrane phospholipids, leading to the production of free fatty acids and lysophospholipids, starting the arachidonic acid cascade. Their expression has been related to the behavior of several cancers. Our objective is to search for PLA2 expression in prostate cancer (PCa) tissue that correlates with prognosis and survival. Methods: Using qRT-PCR, we analyzed the expression levels of PLA2G1B, PLA2G2A, PLA2G2D, PLA2G4A, PLA2G4B, PLA2G4C, PLA2G4D, PLA2G4E, PLA2G4F, PLA2G6, PLA2G7, PLA2G16, PNPLA1, and PNPLA2 in PCa tissue from 108 patients submitted to radical prostatectomy, followed by a mean time of 163 months. Results: All PLA2 was overexpressed in PCa compared to normal tissue. Interestingly, higher expression of some PLA2 was related to favorable prognostic factors: lower levels of PSA (PLA2G2A, PLA2G4D), lower rates of lymph node metastasis (PLA2G16 and PLA2G1B), and organ-confined disease (PLA2G4A). Most importantly, PLAG4B was independently related to longer disease-free survival. Conclusion: This is the first study exploring comprehensively the expression levels of PLA2 in PCa, showing that the higher expression of some PLA2 should be used as biomarkers of good prognosis and longer disease-free survival. [ABSTRACT FROM AUTHOR]

Plant‐based meat is projected to address world‐wide meat shortage and supply–demand imbalances, potentially promoting the growth of sustainable diet choices. Soybean is a key ingredient to produce this alternative food, but the off‐flavours that naturally occur in soy can hinder its widespread acceptance among consumers. This review extensively elaborates on the primary compounds responsible for off‐flavours, their formation mechanisms, and removal techniques. Lipoxygenase oxidation–reduction, oleosins removal, adjustment extrusion conditions, and β‐cyclodextrin treatment were discussed. Fermentation mechanisms, solvent extraction, enzymes hydrolysis, flavouring, and controlling storage conditions were summarised. The most crucial, safe, and effective techniques were enzyme restriction, β‐cyclodextrin treatment in conjugation with phospholipase A2, and modification of the extrusion condition. The reviews provide a systematic summary of the development and prevention methods for the undesirable flavour of soy protein isolate and soy‐based meat products. [ABSTRACT FROM AUTHOR]

Secondary lymphoedema is one of the common complications after lymph node dissection for gynecologic malignancies and breast cancer. In this study, the relationship between PLA2 and postoperative lymphoedema in cancer at the molecular level has been explored through transcriptomics and metabolomic assays. Transcriptome sequencing technology, as well as metabolomic assays, were utilized to explore the expression of PLA2 in lymphoedema patients, and search for potential pathways in the pathogenesis and exacerbation mechanism of lymphoedema. The effect of sPLA2 on human lymphatic endothelial cells was investigated by culturing human lymphatic endothelial cells. Secretory phospholipases A2 (sPLA2) showed high expression levels in lymphoedema tissues, however, cytoplasmic phospholipases A2 (cPLA2), showed low expression in lymphoedema, as demonstrated by RT-qPCR. By culturing human lymphatic vascular endothelial cells, the study found that sPLA2 causes HLEC vacuolization and has an inhibitory effect on HLEC proliferation and migration. By detecting sPLA2 in the serum of lymphoedema patients and analyzing clinical data, it was found that sPLA2 was positively correlated with the severity of lymphoedema. Secretory Phospholipase A2 (sPLA2) is highly expressed in lymphoedema tissue, damages lymphatic vessel endothelial cells, is strongly associated with disease severity, and can be used as a potential predictor of disease severity. Abbreviations: PLA2: Phospholipase A2; DEGs: differentially expressed genes; DMP: differential metabolic production [ABSTRACT FROM AUTHOR]

This study was performed on Micropterus salmoides to determine growth-linked gene and single nucleotide polymorphism (SNP) markers under carbohydrate diet and varying temperature through RNA-seq and whole-genome re-sequencing. The results showed that growth-related genes were primarily enriched in the fat digestion and absorption signaling pathway, playing a role in lipid transport and metabolism. Fatty acid binding protein 6, bile salt-activated lipase-like, lysophosphatidylcholine acyltransferase 2, phospholipase A2, minor isoenzyme-like, and phospholipase A2, group IB (pancreas) were identified as the crucial genes. The differentially expressed genes between high and low temperatures were enriched in the pentose phosphate pathway, with carbohydrate transport and metabolism were most affected by temperature. Major facilitator superfamily domain containing 10, phosphogluconate dehydrogenase, fructose-1,6-bisphosphatase 1a, and spinster homolog 3 transcript variant X1(spns3) were the shared genes affected by temperature. From all the common genes, 10 growth-associated SNP markers were identified. The TT genotype at rs7781 was associated with lower body weight, while AA genotype at rs31434173 and CC genotype at rs31435313 showed positive correlation with body weight. Analogously, the GG genotype at rs31436887 and AA genotype at rs31438769 also found to characterize better growth performance. At low temperature, individuals with the AA genotype at rs11506587 and rs31435313 exhibited the slowest growth. For the genotypes labeled with rs11510589, the GG individual grew faster than the AA individual, whereas the opposite phenomenon occurred in these genotypes when labeled with rs11511314. The genotypes at rs32970704 and rs32967921 showed no growth correlation. The AA genotype at rs31435313 in spns3 had the slowest growth under a carbohydrate-rich diet regardless of the temperature. Our study presents candidate genes and SNP markers associated with growth influenced by carbohydrate and temperature, providing basis for the development of M. salmoides strain that better accepts carbohydrate diets at varying temperature. [ABSTRACT FROM AUTHOR]

Background: In mouse models of atherosclerosis, knockout of the PLA2G2A gene has been shown to reduce the volume of atherosclerotic plaques. Clinical trials have demonstrated the potential of using the sPLA2 inhibitor Varespladib in combination with statins to reduce lipid levels. However, this approach has not yielded the expected results in reducing the risk of cardiovascular events. Therefore, it is necessary to further investigate the mechanisms of PLA2G2A. Methods: Single-cell transcriptome data from two sets of carotid plaques, combined with clinical patient information. were used to describe the expression characteristics of PLA2G2A in carotid plaques at different stages. In order to explore the mechanisms of PLA2G2A, we conducted enrichment analysis, cell–cell communication analysis and single-cell regulatory network inference and clustering analyses. We validated the above findings at the cellular level. Results: Our findings indicate that PLA2G2A is primarily expressed in vascular fibroblasts and shows significant cell interactions with macrophages in the early-stage, especially in complement and inflammation-related pathways. We also found that serum sPLA2 levels have stronger diagnostic value in patients with mild carotid artery stenosis. Subsequent comparisons of single-cell transcriptomic data from early and late-stage carotid artery plaques corroborated these findings and predicted transcription factors that might regulate the progression of early carotid atherosclerosis (CA) and the expression of PLA2G2A. Conclusions: Our study discovered and validated that PLA2G2A is highly expressed by vascular fibroblasts and promotes plaque progression through the activation of macrophage complement and coagulation cascade pathways in the early-stage of CA. [ABSTRACT FROM AUTHOR]

Abstract\nKEY POLICY HIGHLIGHTSMetformin is known for its antioxidant properties and ability to ameliorate metabolic dysfunction-associated fatty liver disease (MAFLD) and is the focus of this study. Lipoprotein-associated phospholipase A2 (Lp-PLA2) is linked to MAFLD risk. This study investigated the effects of metformin on ferroptosis in free fatty acid (FFA)-treated Huh7 hepatoma cells and its association with MAFLD risk. Using Western blot, immunofluorescence, and ELISA, this study revealed that FFA treatment led to increased intracellular fat and iron accumulation, heightened Lp-PLA2 expression, reduced levels of the cysteine transporter SLC7A11 and glutathione peroxidase 4 (GPX4), altered glutathione (GSH)/oxidized glutathione (GSSG) ratios, generation of reactive oxygen species (ROS), and initiation of lipid peroxidation, which ultimately resulted in cell ferroptosis. Importantly, metformin reversed FFA-induced iron accumulation, and this effect was attenuated by ferrostatin-1 but enhanced by erastin, RSL3, and si-GPX4. Additionally, metformin activated antioxidant and antiapoptotic mechanisms, which reduced lipid peroxidation and suppressed Lp-PLA2 expression in FFA-treated Huh7 cells. In conclusion, our findings indicate that metformin may protect against MAFLD by inhibiting iron accumulation and Lp-PLA2 expression through the ROS, ferroptosis, and apoptosis signaling pathways. This study highlights potential therapeutic strategies for managing MAFLD-related risks and emphasizes the diverse roles of metformin in maintaining hepatocyte balance.Metformin lowered Lp-PLA2 levels in human Huh7 hepatoma cells.Both fatty acid and iron metabolism improved after metformin treatment.Metformin alleviated oxidative stress, apoptosis, lipid peroxidation and ferroptosis.Metformin lowered Lp-PLA2 levels in human Huh7 hepatoma cells.Both fatty acid and iron metabolism improved after metformin treatment.Metformin alleviated oxidative stress, apoptosis, lipid peroxidation and ferroptosis. [ABSTRACT FROM AUTHOR]

Epitope spreading is a critical mechanism driving the progression of autoimmune glomerulonephritis. This phenomenon, where immune responses broaden from a single epitope to encompass additional targets, contributes to the complexity and severity of diseases such as membranous nephropathy (MN), lupus nephritis (LN), and ANCA-associated vasculitis (AAV). In MN, intramolecular spreading within the phospholipase A2 receptor correlates with a worse prognosis, while LN exemplifies both intra- and intermolecular spreading, exacerbating renal involvement. Similarly, ANCA reactivity in AAV highlights the destructive potential of epitope diversification. Understanding these immunological cascades reveals therapeutic opportunities—targeting early epitope spreading could curb disease progression. Despite promising insights, the clinical utility of epitope spreading as a prognostic tool remains debated. This review provides a complete overview of the current evidence, exploring the dual-edged nature of epitope spreading, the intricate immune mechanisms behind it, and its therapeutic implications. By elucidating these dynamics, we aim to pave the way for more precise, targeted interventions in autoimmune glomerular diseases. [ABSTRACT FROM AUTHOR]

The discovery of the target antigen M-type phospholipase A2 receptor (PLA2R) with the possibility to detect anti-PLA2R antibodies in serum as well as the identification of several other antigens, overall accounting for almost all cases of membranous nephropathy, paved the way to a revolutionary change in the classification of membranous nephropathy. Serum anti-PLA2R autoantibody titers have been found to be highly specific diagnostic and prognostic biomarkers. Therefore, a positive test for anti-PLA2R serology in patients who present with nephrotic syndrome, normal kidney function, and no evidence of another process to account for proteinuria is believed to suffice to make a diagnosis of primary membranous nephropathy, thus removing the need for a renal biopsy. While technological advances will likely allow this proposal to prevail in the near future, the reasons why renal biopsy could still remain a critical tool for the management of membranous nephropathy in real life are discussed. [ABSTRACT FROM AUTHOR]

Salmonella Typhi, the cause of typhoid fever, is a bacterial pathogen of substantial global importance. Typhoid toxin is a secreted AB-type toxin that is a key S. Typhi virulence factor encoded within a 5-gene genetic islet. Four genes in this islet have well-defined roles in typhoid toxin biology; however, the function of the fifth gene is unknown. Here, we investigate the function of this gene, which we name ttaP. We show that ttaP is cotranscribed with the typhoid toxin subunit cdtB, and we perform genomic analyses that indicate that TtaP is very highly conserved in typhoid toxin islets found in diverse salmonellae. We show that TtaP is a distant homolog of group XIV secreted phospholipase A2 (PLA2) enzymes, and experimentally demonstrate that TtaP is a bona fide PLA2. Sequence and structural analyses indicate that TtaP differs substantially from characterized PLA2s, and thus represents a novel class of PLA2. Secretion assays revealed that TtaP is neither cosecreted with typhoid toxin, nor is it required for toxin secretion. Although TtaP is a phospholipase that remains associated with the S. Typhi cell, assays that probed for altered cell envelope integrity failed to identify any differences between WT S. Typhi and a ttaP deletion strain. Collectively, this study identifies a biochemical activity for the lone uncharacterized typhoid toxin islet gene and lays the groundwork for exploring how this gene factors into S. Typhi pathogenesis. This study further identifies a novel class of PLA2, enzymes that have a wide range of industrial applications. [ABSTRACT FROM AUTHOR]

Honeybee venom (apitoxin), composed of bioactive components such as melittin, apamin, and phospholipase A2, has been used in traditional medicine for centuries. Modern research explores its potential therapeutic applications for various diseases. Clinical studies and preclinical research have demonstrated its efficacy in treating conditions like rheumatoid arthritis, osteoarthritis, neurological disorders, and cancer. Despite its therapeutic potential, bee venom carries risks, including allergic reactions. Advances in synthetic venom production offer promising alternatives for broader and safer clinical applications. While more large-scale clinical trials are needed to confirm its efficacy and safety, honeybee venom remains a compelling candidate for novel treatments across a wide range of diseases. [ABSTRACT FROM AUTHOR]

Background: Neoadjuvant chemoradiotherapy (nCRT) stands as a pivotal therapeutic approach for locally advanced rectal cancer (LARC), yet the absence of a reliable biomarker to forecast its efficacy remains a challenge. Thus, this study aimed to assess whether the proteomic compositions of small extracellular vesicles (sEVs) might offer predictive insights into nCRT response among patients with LARC, while also delving into the proteomic alterations within sEVs post nCRT. Methods: Plasma samples were obtained from LARC patients both pre- and post-nCRT. Plasma-derived sEVs were isolated utilizing the TIO2-based method, followed by LC-MS/MS-based proteomic analysis. Subsequently, pathway enrichment analysis was performed to the Differentially Expressed Proteins (DEPs). Additionally, ROC curves were generated to evaluate the predictive potential of sEV proteins in determining nCRT response. Public databases were interrogated to identify sEV protein-associated genes that are correlated with the response to nCRT in LARC. Results: A total of 16 patients were enrolled. Among them, 8 patients achieved a pathological complete response (good responders, GR), while the remaining 8 did not achieve a complete response (poor responders, PR). Our analysis of pretreatment plasma-derived sEVs revealed 67 significantly up-regulated DEPs and 9 significantly down-regulated DEPs. Notably, PROC (AUC: 0.922), F7 (AUC: 0.953) and AZU1 (AUC: 0.906) demonstrated high AUC values and significant differences (P value < 0.05) in discriminating between GR and PR patients. Furthermore, a signature consisting of 5 sEV protein-associated genes (S100A6, ENO1, MIF, PRDX6 and MYL6) was capable of predicting the response to nCRT, yielding an AUC of 0.621(95% CI: 0.454–0.788). Besides, this 5-sEV protein-associated gene signature enabled stratification of patients into low- and high-risk group, with the low-risk group demonstrating a longer overall survival in the testing set (P = 0.048). Moreover, our investigation identified 11 significantly up-regulated DEPs and 31 significantly down-regulated DEPs when comparing pre- and post-nCRT proteomic profiles. GO analysis unveiled enrichment in the regulation of phospholipase A2 activity. Conclusions: Differential expression of sEV proteins distinguishes between GR and PR patients and holds promise as predictive markers for nCRT response and prognosis in patients with LARC. Furthermore, our findings highlight substantial alterations in sEV protein composition following nCRT. [ABSTRACT FROM AUTHOR]

AbstractVesicular nanocarriers like niosomes and liposomes are widely researched for controlled drug delivery systems, with niosomes emerging as promising alternatives due to their higher stability and ease of manufacturing. This study aimed to develop and characterize a niosomal formulation for the encapsulation and sustained release of temozolomide (TMZ), a model lipophilic drug, and to compare the stability of niosomes and liposomes, with a particular focus on the behavior of their lipid bilayers. Niosomes were prepared using the thin-film hydration method, composed of Span 60 (Sorbitan monostearate), cholesterol, and soy lecithin in varying molar ratios. The study investigated critical properties such as drug loading capacity, release kinetics, and resistance to enzymatic degradation. The optimized formulation was analyzed for drug entrapment efficiency and stability against phospholipase A2 (PLA2) degradation. The optimized niosomal formulation, with a 4:2:1 molar ratio of Span 60: cholesterol, achieved a high TMZ entrapment efficiency of 73.23 ± 1.02% and demonstrated sustained drug release over 24 hours. In comparison, liposomes released their TMZ payload within 4 hours upon exposure to PLA2, while the niosomes maintained their release profile, indicating superior stability. Spectroscopic and thermal analysis confirmed successful drug encapsulation with no component incompatibilities. [ABSTRACT FROM AUTHOR]

Metabolic reprogramming, a key mechanism regulating the growth and recurrence of hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), still lacks effective clinical strategies for its integration into the precise screening of primary liver cancer. This study utilized ultra-high-performance liquid chromatography with quadrupole time-of-flight mass spectrometry to conduct a comprehensive, non-targeted metabolomics analysis, revealing significant upregulation of lipid metabolites such as phosphatidylcholine and lysophosphatidylcholine in patients with HCC and CCA, particularly within the glycerophospholipid metabolic pathway. Hematoxylin and eosin and immunohistochemical staining demonstrated marked upregulation of phospholipase A2 in tumor tissues, further emphasizing the potential of lipid metabolism as a therapeutic target and its important part in the course of cancer. This work provides a new viewpoint for addressing the clinical challenges associated with HCC and CCA, laying the groundwork for the broad application of early diagnosis and personalized treatment strategies, and ultimately aiming to provide tailored and precise therapeutic options for patients. [ABSTRACT FROM AUTHOR]

Background and Aim: This study aimed to clarify whether several single‐nucleotide polymorphisms (SNPs)‐related chronic pancreatitis such as carboxypeptidase A1 (CPA1), carboxypeptidase B1 (CPB1), Gamma‐glutamyltransferase 1 (GGT1), G‐protein‐coupled receptor Class C Group 6 Member A (GPRC6A), and serine protease inhibitor, Kazal type 1 (SPINK‐1) genotypes were associated with clinical characteristics of patients with intraductal papillary mucinous neoplasm (IPMN) and worrisome features of IPMN. Methods: We enrolled 100 patients with IPMN and 116 patients as a control. Serum p‐amylase, lipase, trypsin, phospholipase A2 (PLA2), and elastase‐1 levels were measured. An Olympus EUS (GF‐UCT 260) was used to perform endosonography in 100 patients with IPMN. Total EUS score was evaluated using endosonography. DNA was isolated from the duodenal tissue using a commercial system and polymerase chain reaction (PCR) was performed on 7500 Fast PCR System. Results: There were no associations between glucose tolerances, lipid levels and genotypes of CPA1, GGT1, GPRC6A, and SPINK‐1 in patients with IPMN. CPA1 genotype was significantly associated with the pathophysiology of IPMN. Then, GGT1 genotype was also significantly associated with EUS total score and the size of cyst more than 20 mm and more than 30 mm as one of worrisome features of IPMN. Conclusion: Genotypes of carboxypeptidase A1 and gamma‐glutamyltransferase 1 may be useful tools for the diagnosis and the predictor of worrisome features of IPMN. [ABSTRACT FROM AUTHOR]

Background: Growing evidence suggests the type of periodontal treatment could differentially influence the reduction of key cardiovascular risk mediators in periodontitis patients. This randomized, controlled clinical trial compared the impact of minimally invasive non‐surgical therapy (MINST) with quadrant‐wise subgingival instrumentation (Q‐SI) on C‐reactive protein (CRP) together with lipoprotein‐associated phospholipase A2 (Lp‐PLA2) levels, and clinical periodontal outcomes in patients with periodontitis. Moreover, it was evaluated if baseline CRP levels impacted the efficacy of non‐surgical periodontal therapy protocols. Methods: Forty‐two periodontitis patients were enrolled and randomly treated by means of MINST (n = 21) or Q‐SI (n = 21). The outcomes assessed were serum CRP and Lp‐PLA2, and periodontal parameters (probing depth [PD], clinical attachment level [CAL], full‐mouth bleeding score [FMBS]), at baseline and at follow‐ups at 1, 3, and 6 months and at 1 year after treatment. Results: At 1 year, MINST significantly reduced, among others, mean PD (p = 0.007), mean CAL (p = 0.007), the number of pockets >4 mm (p = 0.011) and ≥6 mm (p = 0.005), and FMBS (p = 0.048) compared to Q‐SI. Generalized multivariate analysis evidenced that high baseline CRP (p = 0.039) and FMBS (p = 0.046) levels, together with MINST treatment (p = 0.007) were significant predictors of PD reduction at 1‐year follow‐up. Moreover, the Jonckheere–Terpstra test showed that patients with high baseline CRP levels gained more benefits from MINST treatment at 1‐year follow‐up than they did from Q‐SI. Conclusion: Patients receiving MINST showed a greater reduction in CRP levels than patients with Q‐SI after 1 year of follow‐up. Moreover, patients with high baseline levels of CRP and Lp‐PLA2 gained more benefits from the MINST approach at 1‐year follow‐up. [ABSTRACT FROM AUTHOR]

Objective: To investigate the application value of dual-source CT cerebral perfusion imaging combined with serum ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1) and lipoprotein-associated phospholipase A2(Lp-PLA2) in the diagnosis and poor prognosis prediction of patients with acute cerebral infarction (ACI). Methods: 151 ACI patients admitted to Hulunbuir People's Hospital from February 2021 to March 2023 were selected as ACI group and 109 healthy volunteers as control group. According to the National Institutes of Health Stroke Scale (NIHSS), ACI patients were divided into mild group (52 cases), moderate group (53 cases), severe group (46 cases); and according to the Modified Rankin Score Scale (mRS), ACI patients were divided into poor prognosis group (37 cases) and good prognosis group (114 cases). All subjects were underwent dual-source CT cerebral perfusion imaging to obtain relevant parameters of cerebral blood flow (CBF), cerebral blood volume (CBV), mean transit time (MTT), and time to peak (TTP), and serum UCH-L1 and Lp-PLA2 levels were detected. The value of dual-source CT cerebral perfusion imaging parameters combine with serum UCH-L1 and Lp-PLA2 in the diagnosis of ACI and predicted the prognosis of ACI patients were analyzed by receiver operating characteristic (ROC) curve. Results: CBF and CBV in ACI group were lower than those in control group(P<0.05), MTT and TTP in ACI group were longer than those in control group (P < 0.05) serum UCH-L1 and Lp-PLA2 levels in ACI group were higher than those in con- trol group (P < 0.05) CBF and CBV in severe group were lower than those in moderate group and mild group(P<0.05), MTT and TTP in severe group were longer than those in moderate group and mild group(P<0.05), and serum UCH-L1 and Lp-PLA2 levels in severe group were higher than those in moderate group and mild group (P < 0.05) CBF and CBV in moderate group were lower than those in mild group (P < 0.05) MTT and TTP in moderate group were longer than those in mild group(P<0.05), and serum UCH-L1 and Lp-PLA2 levels in moderate group were higher than those in mild group (P < 0.05) . CBF and CBV in poor prognosis group were lower than those in good prognosis group (P < 0.05) MTT and TTP in poor prognosis group were longer than those in good prognosis group (P < 0.05) and serum UCH-L1 and Lp-PLA2 levels in poor prognosis group were higher than those in good prognosis group (P < 0.05) ROC curve analysis showed that: the area under the curve of combine dual-source CT cerebral perfusion imaging parameters and serum UCH-L1 and Lp-PLA2 in the diagnosis of ACI and the prediction of poor prognosis of ACI were 0.898 and 0.892, respectively, which were higher than those of single index diagnosis and prediction. Conclusion: In ACI patients, dual-source CT cerebral perfusion imaging parameters CBF and CBV decrease, MTT and TTP prolonged, serum UCH-L1 and Lp-PLA2 levels increase, which are relate to the aggravation of ACI nerve defect and poor prognosis. The combination of dual-source CT cerebral perfusion imaging parameters and serum UCH-L1 and Lp-pLA2 has high value in the diagnosis and prognosis analysis of ACI. [ABSTRACT FROM AUTHOR]

Background: Low albumin level is a risk factor for thromboembolic events in patients with NS (nephrotic syndrome). However, little is known about the proportion and characteristics of patients with NS who experience thromboembolic events with relatively high albumin levels (≥ 25 g/L). Therefore, we explored the features of this specific group of patients. Methods: This study included all hospitalized patients in our center for the past 10 years who had diagnoses of NS and relevant thromboembolic events. We divided them into 2 groups based on their serum albumin level when the thromboembolic event occurred. The clinical data were analyzed with SPSS software. Results: There were 312 patients enrolled in our study. Eighty-four (26.9%) of them had relatively high albumin levels (≥ 25 g/L). Patients with NS with high albumin levels had significantly lower levels of 24-h proteinuria (P < 0.01) and a higher rate of autoimmune disease (P = 0.03) than the low-albumin group. Membranous nephropathy (MN) was the most frequent pathological type of NS in patients with thromboembolic events, regardless of their albumin level. There were significantly fewer patients with anti-PLA2R (M-type phospholipase A2 receptor)-positive MN in the high-albumin group than in the low-albumin group (P < 0.01). Conclusions: Our study found that there was still a high risk for patients with NS and relatively high albumin levels to develop thromboembolic events. [ABSTRACT FROM AUTHOR]

Rituximab occasionally induces reactivation of hepatitis C virus (HCV) in patients with resolved HCV infection, sometimes with fatal consequences. As rituximab has become one of the first-line therapies for the treatment of phospholipase A2 receptor (PLA2R)-associated membranous nephropathy (MN) and is more widely used, there is a lack of studies reporting the effectiveness and safety of rituximab in patients with PLA2R-associated MN and resolved HCV infection. A single-center retrospective study was conducted on PLA2R-associated membranous nephropathy (MN) patients who were HCVAb positive but HCV-RNA negative and treated with rituximab. A total of 598 adult patients with PLA2R-associated MN who underwent rituximab therapy were screened. General clinical information, including gender, age, pathological data, and previous treatment plans, was collected from medical records. Routine blood tests, liver and kidney function assessments, blood lipid profiles, 24-h urine protein levels, anti-PLA2R antibody titers, circulating B-cell counts, and HCV viral loads were measured at the time of rituximab infusion and repeated at intervals of 1–3 months post-rituximab administration. A total of 8 patients were enrolled, with a median follow-up period of 19.00 (range: 16.00–25.25) months. Among the 8 patients, 5 were male, and the mean age was 50.13 ± 4.29 years. Histological findings indicated that tubuloreticular inclusions, mesangial deposits, intramembranous deposits, and subendothelial deposits were not observed in any of the 8 patients. The overall 1-year remission rate for these patients was 75%, accompanied by a significant reduction in proteinuria. Additionally, blood albumin levels increased significantly, and renal function remained stable. No increase in HCV viral load and stable liver function tests were observed throughout the entire follow-up period. This study suggested that on the basis of successful eradication of HCV virus with antiviral drugs, rituximab can effectively induce clinical remission of patients with PLA2R associated MN and resolved HCV infection, and does not lead to a significant increase in HCV virus load. However, this finding is based on a very small sample size and should be confirmed in larger clinical trials. [ABSTRACT FROM AUTHOR]

Membranous nephropathy (MN) is an antibody-mediated autoimmune disease and the most common cause of nephrotic syndrome in adults. The discovery of phospholipase A2 receptor 1 (PLA2R1) as the first target antigen in patients with MN 15 years ago has led to a paradigm shift in the pathobiological understanding of this disease. Autoantibodies against PLA2R1 as well as thrombospondin type-1 domain-containing 7A, the second identified antigen in adults, were shown to be disease-causing and act through local activation of the complement system, primarily via the classical and lectin pathways. These findings indicate that both plasma cells, the main source of antibodies and autoantibodies, as well as the complement system, the main pathogenic effector mechanism in MN, are rational and pathogenesis-based treatment targets in MN. This review summarizes pathomechanistic and clinical evidence for and against plasma cell– and complement-targeted treatments in MN. [ABSTRACT FROM AUTHOR]

Background: The relationship between ischemic stroke (IS) and lipoprotein-associated phospholipase A2 (Lp-PLA2) activity is still unclear, and there is a dearth of stratified research on the relationship between Lp-PLA2 activity and different IS subtypes. Therefore, Mendelian randomization (MR) was used in this study to examine the relationship between genetically proxied Lp-PLA2 activity and the risks of IS and its subtypes. Methods: Based on information from a meta-analysis of genome-wide association studies, which included 13,664 European people, five single nucleotide polymorphisms related to Lp-PLA2 activity were chosen as instrumental variables. Summary statistics information about the MEGESTROKE consortium with the European group (40,585 cases and 406,111 controls) include any IS (AIS; n = 34,217), large-artery stroke (LAS; n = 4,373), cardioembolic stroke (CES; n = 7,193), and small-vessel stroke (SVS; n = 5,386). In order to determine the causal relationships between Lp-PLA2 activity and IS as well as its subtypes, the inverse-variance-weighted (IVW) approach was chosen as the primary analysis. Significant estimates were then tested by sensitivity analysis to rule out heterogeneity and pleiotropy. Results: IVW showed that Lp-PLA2 activity was causally associated with LAS (odds ratio = 3.25, 95% confidence interval = 1.65–6.41, p = 0.0007) but not with other subtypes of stroke. Sensitivity analysis for causal estimates between Lp-PLA2 activity and LAS showed no significant heterogeneity or pleiotropy. Conclusions: These MR analyses support a causal effect of Lp-PLA2 activity on LAS but not on AIS, CES, or SVS, which suggests that serum Lp-PLA2 activity might be a biomarker for prediction of LAS. [ABSTRACT FROM AUTHOR]

The widespread geographical distribution of Russell's vipers (Daboia spp.) is associated with marked variations in the clinical outcomes of envenoming by species from different countries. This is likely to be due to differences in the quantity and potency of key toxins and, potentially, the presence or absence of some toxins in venoms across the geographical spectrum. In this study, we aimed to isolate and pharmacologically characterise the major neurotoxic components of D. siamensis venoms from Thailand and Java (Indonesia) and explore the efficacy of antivenom and a PLA2 inhibitor, Varespladib, against the neuromuscular activity. These data will provide insights into the link between venom components and likely clinical outcomes, as well as potential treatment strategies. Venoms were fractionated using RP-HPLC and the in vitro activity of isolated toxins assessed using the chick biventer cervicis nerve-muscle preparation. Two major PLA2 fractions (i.e., fractions 8 and 10) were isolated from each venom. Fraction 8 from both venoms produced pre-synaptic neurotoxicity and myotoxicity, whereas fraction 10 from both venoms was weakly neurotoxic. The removal of the two fractions from each venom abolished the in vitro neurotoxicity, and partially abolished myotoxicity, of the whole venom. A combination of the two fractions from each venom produced neurotoxic activity that was equivalent to the respective whole venom (10 µg/mL), but the myotoxic effects were not additive. The in vitro neurotoxicity of fraction 8 (100 nM) from each venom was prevented by the pre-administration of Thai Russell's viper monovalent antivenom (2× recommended concentration) or preincubation with Varespladib (100 nM). Additionally, the neurotoxicity produced by a combination of the two fractions was partially reversed by the addition of Varespladib (100–300 nM) 60 min after the fractions. The present study demonstrates that the in vitro skeletal muscle effects of Thai and Javanese D. siamensis venoms are primarily due to key PLA2 toxins in each venom. [ABSTRACT FROM AUTHOR]

Apitoxin therapy (BVT—bee venom therapy) is an emerging complementary treatment utilizing bee venom for various medical conditions. This review explores the potential and therapeutic mechanisms of bee venom, focusing on its chemical composition and the methods for its extraction and purification to enhance safety while maintaining bioactivity. Bee venom contains amphipathic peptides such as melittin and apamin, enzymes like phospholipase A2, and bioamines including histamine and catecholamines, contributing to its pleiotropic effects. The therapeutic applications of bee venom span anti-inflammatory, analgesic, antimicrobial, antiviral, neuroprotective, anti-arthritic, and anti-cancer activities. Clinical and laboratory studies have demonstrated its efficacy in treating chronic and autoimmune diseases, pain management, and improving quality of life. The immunogenic properties of bee venom necessitate ongoing research to mitigate allergic reactions, ensuring its safe and effective use in medical practice. This review summarizes the current state of research on bee venom therapy, highlighting its potential benefits and future research directions. [ABSTRACT FROM AUTHOR]

Bee venom (BV) and its components, secretory phospholipase A2 (sPLA2) and Apis cerana secapin-1 (AcSecapin-1), have potential effects on wound healing. This study aims to evaluate impact of BV, sPLA2, and AcSecapin-1 on full-thickness wound healing in male Wistar Albino rats over a 7-day period. Various morphometric (body weight, wound contraction), biochemical (hydroxyproline, oleic acid, IL-8, TGF-β1, redox parameters), and histopathological markers (reepithelialization, inflammatory cells, angiogenesis, fibroblast activation, and collagen density) were assessed. Treatment with sPLA2 and AcSecapin-1 increased oleic acid levels. IL-8 levels increased with sPLA2 treatment, and TGF-β1 levels increased with AcSecapin-1 treatment. BV and its components led to a decrease in FRAP levels. Additionally, BV treatment resulted in reduced angiogenesis, and both BV and sPLA2 treatments reduced inflammatory cells. All groups exhibited wound contraction without delay or regression. sPLA2 and AcSecapin-1 induced alterations in the wound healing milieu, without systemic changes. The treatment groups, except for the AcSecapin-1 group, showed an anti-inflammatory effect, identified by reduced inflammatory cell accumulation. Only the BV treatment suppressed angiogenesis. In conclusion, BV, sPLA2, and AcSecapin-1 demonstrate distinct effects on wound healing, with BV showing notable anti-inflammatory and anti-angiogenic properties, while sPLA2 and AcSecapin-1 influenced cytokine and oleic acid levels. [ABSTRACT FROM AUTHOR]

Phospholipase A2 (PLA2) is a superfamily of phospholipase enzymes that dock at the water/oil interface of phospholipid assemblies, hydrolyzing the ester bond at the sn-2 position. The enzymatic activity of these enzymes differs based on the nature of the substrate, its supramolecular assemblies (micelle, liposomes), and their composition, reflecting the interfacial nature of the PLA2s and requiring assays able to directly quantify this interaction of the enzyme(s) with these supramolecular assemblies. We developed and optimized a simple, universal assay method employing the pH-sensitive indicator dye bromothymol blue (BTB), in which different POPC (3-palmitoyl-2-oleoyl-sn-glycero-1-phosphocholine) self-assemblies (liposomes or mixed micelles with Triton X-100 at different molar ratios) were used to assess the enzymatic activity. We used this assay to perform a comparative analysis of PLA2 kinetics on these supramolecular assemblies and to determine the kinetic parameters of PLA2 isozymes IB and IIA for each supramolecular POPC assembly. This assay is suitable for assessing the inhibition of PLA2s with great accuracy using UV-VIS spectrophotometry, being thus amenable for screening of PLA2 enzymes and their substrates and inhibitors in conditions very similar to physiologic ones. [ABSTRACT FROM AUTHOR]

Sepsis is caused by a dysregulated host response to an infection that leads to cascading cell death and eventually organ failure. In this study, the role of inflammatory response serum secretory phospholipase A2 (sPLA2) and albumin in sepsis was investigated by determining the activities of the two proteins in serial serum samples collected on different days from patients with sepsis after enrollment in the permissive underfeeding versus standard enteral feeding protocols in an intensive care unit. Serum sPLA2 and albumin showed an inverse relationship with increasing sPLA2 activity and decreasing albumin membrane-binding activity in patients with evolving complications of sepsis. The activities of sPLA2 and albumin returned to normal values more rapidly in the permissive underfeeding group than in the standard enteral feeding group. The inverse sPLA2–albumin activity relationship suggests a complex interplay between these two proteins and a regulatory mechanism underlying cell membrane phospholipid homeostasis in sepsis. The decreased albumin–membrane binding activity in patients' serum was due to its fatty acid-binding sites occupied by pre-bound fatty acids that might alter albumin's structure, binding capacities, and essential functions. The sPLA2–albumin dual serum assays may be useful in determining whether nutritional intervention effectively supports the more rapid recovery of appropriate immune responses in critically ill patients with sepsis. [ABSTRACT FROM AUTHOR]

There is abundant evidence that parasitoids manipulate their hosts by envenomation to support the development and survival of their progeny before oviposition. However, the specific mechanism underlying host nutritional manipulation remains largely unclear. To gain a more comprehensive insight into the effects induced by the gregarious ectoparasitoid Iseropus kuwanae (Hymenoptera: Ichneumonidae) on the greater wax moth Galleria mellonella (Lepidoptera: Pyralidae) larvae, we sequenced the transcriptome of both non‐envenomed and envenomed G. mellonella larvae, specifically targeting genes related to lipid metabolism. The present study revealed that 202 differentially expressed genes (DEGs) were identified and 9 DEGs were involved in lipid metabolism. The expression levels of these 9 DEGs relied on envenomation and the duration post‐envenomation. Further, envenomation by I. kuwanae induced an increase in triglyceride (TG) level in the hemolymph of G. mellonella larvae. Furthermore, silencing GmPLA2 in G. mellonella larvae 24 h post‐envenomation significantly decreased the content of 4 unsaturated fatty acids and TG levels in the hemolymph. The content of linoleic acid and α‐linoleic acid were significantly decreased and the content of oleic acid was significantly increased by exogenous supplement of arachidonic acid. Meanwhile, the reduction in host lipid levels impairs the growth and development of wasp offspring. The present study provides valuable knowledge about the molecular mechanism of the nutritional interaction between parasitoids and their hosts and sheds light on the coevolution between parasitoids and host insects. [ABSTRACT FROM AUTHOR]

There is evidence to suggest that M‐type phospholipase A2 (PLA2R) antibodies activate the mannose‐binding lectin (MBL) cascade, resulting in glomerular damage and proteinuria in patients with primary membranous nephropathy (PMN). Furthermore, there are few reports indicating that aberrant MBL activation is associated with endothelial dysfunction and accelerated atherosclerosis. While PMN is a common cause of adult nephrotic syndrome, and patients are at increased risk of cardiovascular disease (CVD), there is a lack of research that explores the factors that contribute to this condition. This study aims to determine the MBL levels in PMN and their relation to the clinical activity and endothelial dysfunction in PMN. The MBL levels of 22 biopsy‐confirmed PMN patients were assessed at baseline and after 6 months of immunosuppressive therapy. In order to evaluate endothelial dysfunction in PMN patients, flow‐mediated vasodilation (FMD) was measured at baseline and after treatment. A total of 22 healthy controls were included in this study to measure MBL levels and FMD. A significant difference was observed between MBL levels in PMN patients and healthy controls (p <.01). MBL levels decreased significantly after immunosuppressive therapy (p =.04). The baseline MBL levels and FMD levels exhibited a strong correlation (Spearman correlation coefficient [ρ] = 0.51: p =.01). In conclusion, the study signals the activation of the MBL cascade and its association with endothelial dysfunction in PMN patients. [ABSTRACT FROM AUTHOR]

It is urgent to explore factors affecting immunotherapy efficacy to benefit non‐small cell lung cancer (NSCLC) patient survival. Bioinformatics predicted genes associated with programmed cell death ligand 1 (PD‐L1) expression and analysed phospholipase A2 group IID (PLA2G2D) expression in NSCLC. BODIPY 493/503 dye staining and kits detected lipids, triglycerides, and phospholipids in H1299 cells, respectively. Extracellular vesicles (EVs) were extracted for morphology and size assessment using electron microscopy. Western blot assayed CD9, CD63, HSP90, EVs‐PD‐L1, PD‐L1, and PLA2G2D expression. CCK‐8, LDH, and ELISA tested proliferation and toxicity of CD8+ T cells, interleukin‐2, and interferon‐gamma secretion, respectively. PLA2G2D, PD‐L1, and Ki67 expression was detected by immunohistochemistry. Immunofluorescence assayed PLA2G2D localisation and CD8+ T cell content. Flow cytometry assessed PD‐L1 and CD8 expression. In NSCLC, upregulated EVs‐PD‐L1 and clinical characteristics showed a strong correlation. H1299 cells with overexpression PD‐L1 significantly reduced proliferation, toxicity of CD8+ T cells, and interleukin‐2 and interferon‐gamma levels. Bioinformatics revealed positive correlations between PLA2G2D and overexpressed PD‐L1. PLA2G2D was expressed in macrophages and dendritic cells in NSCLC tissue. Overexpression PLA2G2D (oe‐PLA2G2D) increased lipids, triglycerides, and phospholipids contents in H1299 cells. oe‐PLA2G2D significantly reduced proliferation, toxicity of CD8+ T cells, and interleukin‐2 and interferon‐gamma levels. si‐PD‐L1 restored inhibition of oe‐PLA2G2D on CD8+ T cells. oe‐PLA2G2D significantly increased mice tumour volume and weight, upregulated expression of blood EVs‐PD‐L1 and tissue PD‐L1, PLA2G2D, Ki67, and decreased CD8+ T cell content. PLA2G2D facilitated immune escape in NSCLC by regulating CD8+ T cell immune function by upregulating EVs‐PD‐L1. [ABSTRACT FROM AUTHOR]

Recent progress in glomerular immune complex and complement-mediated diseases have refined diagnostic categories and informed mechanistic understanding of disease development in pediatric patients. Herein, we discuss selected advances in 3 categories. First, membranous nephropathy antigens are increasingly utilized to characterize disease in pediatric patients and include phospholipase A2 receptor (PLA2R), Semaphorin 3B (Sema3B), neural epidermal growth factor-like 1 (NELL1), and protocadherin FAT1, as well as the lupus membranous-associated antigens exostosin 1/2 (EXT1/2), neural cell adhesion molecule 1 (NCAM1), and transforming growth factor beta receptor 3 (TGFBR3). Second, we examine advances in techniques for paraffin and light chain immunofluorescence (IF), including the former's function as a salvage technique and their necessity for diagnosis in adolescent cases of membranous-like glomerulopathy with masked IgG kappa deposits (MGMID) and proliferative glomerulonephritis with monotypic Ig deposits (PGNMID), respectively. Finally, progress in understanding the roles of complement in pediatric glomerular disease is reviewed, with specific attention to overlapping clinical, histologic, and genetic or functional alternative complement pathway (AP) abnormalities among C3 glomerulopathy (C3G), infection-related and post-infectious GN, "atypical" post-infectious GN, immune complex mediated membranoproliferative glomerulonephritis (IC-MPGN), and atypical hemolytic uremic syndrome (aHUS). [ABSTRACT FROM AUTHOR]

Abstract Background The association of lipoprotein-associated phospholipase A2 (Lp-PLA2) with various cardiovascular events has been well-established. However, the exploration of its potential involvement in Chronic obstructive pulmonary disease (COPD) is currently limited. Therefore, our study aims to examine the relationship between Lp-PLA2 and pulmonary conditions, including emphysema, obstructive ventilatory dysfunction as well as small airway dysfunction, to provide further evidence of a possible association with COPD development. Methods Using data from the Southwest Hospital Health Management Center, spanning January 2013 to July 2024, we analyze relationship of serum Lp-PLA2 levels with diffuse pulmonary emphysema and pulmonary functions. In univariate analysis, group differences were assessed with t-tests for numerical variables and Chi-square tests for categorical data. Variables found to be statistically significant (two-sided P

Abstract Background In mouse models of atherosclerosis, knockout of the PLA2G2A gene has been shown to reduce the volume of atherosclerotic plaques. Clinical trials have demonstrated the potential of using the sPLA2 inhibitor Varespladib in combination with statins to reduce lipid levels. However, this approach has not yielded the expected results in reducing the risk of cardiovascular events. Therefore, it is necessary to further investigate the mechanisms of PLA2G2A. Methods Single-cell transcriptome data from two sets of carotid plaques, combined with clinical patient information. were used to describe the expression characteristics of PLA2G2A in carotid plaques at different stages. In order to explore the mechanisms of PLA2G2A, we conducted enrichment analysis, cell–cell communication analysis and single-cell regulatory network inference and clustering analyses. We validated the above findings at the cellular level. Results Our findings indicate that PLA2G2A is primarily expressed in vascular fibroblasts and shows significant cell interactions with macrophages in the early-stage, especially in complement and inflammation-related pathways. We also found that serum sPLA2 levels have stronger diagnostic value in patients with mild carotid artery stenosis. Subsequent comparisons of single-cell transcriptomic data from early and late-stage carotid artery plaques corroborated these findings and predicted transcription factors that might regulate the progression of early carotid atherosclerosis (CA) and the expression of PLA2G2A. Conclusions Our study discovered and validated that PLA2G2A is highly expressed by vascular fibroblasts and promotes plaque progression through the activation of macrophage complement and coagulation cascade pathways in the early-stage of CA.

Abstract Metabolic reprogramming, a key mechanism regulating the growth and recurrence of hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), still lacks effective clinical strategies for its integration into the precise screening of primary liver cancer. This study utilized ultra-high-performance liquid chromatography with quadrupole time-of-flight mass spectrometry to conduct a comprehensive, non-targeted metabolomics analysis, revealing significant upregulation of lipid metabolites such as phosphatidylcholine and lysophosphatidylcholine in patients with HCC and CCA, particularly within the glycerophospholipid metabolic pathway. Hematoxylin and eosin and immunohistochemical staining demonstrated marked upregulation of phospholipase A2 in tumor tissues, further emphasizing the potential of lipid metabolism as a therapeutic target and its important part in the course of cancer. This work provides a new viewpoint for addressing the clinical challenges associated with HCC and CCA, laying the groundwork for the broad application of early diagnosis and personalized treatment strategies, and ultimately aiming to provide tailored and precise therapeutic options for patients.

Background Hypertension is a common chronic non-communicable disease in clinical practice, and its prevalence is on the rise globally due to population aging and changes in human lifestyles. Prolonged high blood pressure can lead to damage to various target organs such as the heart, brain, kidneys, and retina, severely threatening human health and being a major cause of global disease burden. The left ventricle, as the primary target of end-organ damage, its structural changes are also the pathological basis for the development of many cardiovascular diseases. Objective This study aims to explore the relationship between the atherogenic index of plasma (AIP) and serum lipoprotein-associated phospholipase A2 (Lp-PLA2) levels and left ventricular hypertrophy (LVH) in patients with primary hypertension. Methods A total of 167 patients with primary hypertension who visited the Department of Cardiovascular Medicine at the Second Affiliated Hospital of Zhengzhou University from October 2021 to June 2023 were enrolled in this study. Baseline data of the patients were collected, and fasting venous blood biochemical markers were measured. Echocardiograms were conducted within 24 hours of admission to calculate left ventricular mass (LVM) and left ventricular mass index (LVMI). Patients were divided into non-left ventricular hypertrophy (NLVH) group (87 patients) and LVH group (80 patients) based on LVMI. Pearson correlation test and Spearman rank correlation analysis were used to investigate the correlation between serum Lp-PLA2 level, AIP and echocardiographic parameters. Multivariate Logistic regression analysis was used to explore the influencing factors of LVH in hypertensive patients. Receiver operating characteristic (ROC) curve was plotted to explore the diagnostic value of serum Lp-PLA2 level and AIP in hypertensive patients with LVH, and the area under ROC curve (AUC) was calculated. Results Patients in the LVH group had higher age, duration of hypertension, levels of N-terminal pro B-type natriuretic peptide (NT-proBNP), high-sensitivity C-reactive protein (hs-CRP), left ventricular posterior wall thickness (LVWPT), interventricular septal thickness (IVST), left ventricular end-diastolic diameter (LVEDd), left atrial end-systolic diameter (LAESd), Lp-PLA2 levels, AIP, LVM, and LVMI compared to the NLVH group (P

The M-type phospholipase A2 receptor (PLA2R)-associated primary membranous nephropathy (PMN) is an immune-related disease in adults with increasing morbidity and variable treatment response, in which inflammation may contribute to the multifactorial immunopathogenesis. The relationship between fibrinogen-albumin ratio (FAR), serving as a novel inflammatory biomarker, and PMN is still unclear. Therefore, this study aims to clarify the association between FAR and disease activity and therapy response of PMN. 110 biopsy-proven phospholipase A2 receptor (PLA2R) -associated PMN participants with nephrotic syndrome from January 2017 to December 2021 were recruited in the First Affiliated Hospital of Nanjing Medical University. The independent risk factors of non-remission (NR) and the predictive ability of FAR were explored by Cox regression and receiver-operating characteristic (ROC) curve analysis. According to the optimal cutoff value, study patients were categorized into the low-FAR group (≤the cutoff value) and the high-FAR group (>the cutoff value). Spearman's correlations were used to examine the associations between FAR and baseline clinicopathological characteristics. Kaplan-Meier method was used to assess the effects of FAR on remission. In the entire study cohort, 78 (70.9%) patients reached complete or partial remission (CR or PR). The optimal cutoff value of FAR for predicting the remission outcome (CR + PR) was 0.233. The Kaplan-Meier survival analysis demonstrated that the high-FAR group (>0.233) had a significantly lower probability to achieve CR or PR compared to the low-FAR group (≤0.233) (Log Rank test, p = 0.021). Higher levels of FAR were identified as an independent risk factor for NR, and the high-FAR group was associated with a 2.27 times higher likelihood of NR than the low-FAR group (HR 2.27, 95% CI 1.01, 5.13, p = 0.048). These relationships remained robust with further analysis among calcineurin inhibitors (CNIs)-receivers. In the multivariate Cox regression model, the incidence of NR was 4.00 times higher in the high-FAR group than in the low-FAR group (HR 4.00, 95% CI 1.41, 11.31, p = 0.009). Moreover, ROC analysis revealed the predictive value of FAR for CR or PR with a 0.738 area under curve (AUC), and the AUC of anti-PLA2R Ab was 0.675. When combining FAR and anti-PLA2R Ab, the AUC was boosted to 0.766. FAR was significantly correlated with proteinuria and anti-PLA2R Ab in PMN. As an independent risk factor for NR, FAR might serve as a potential inflammation-based prognostic tool for identifying cases with poor treatment response, and the best predictive cutoff value for outcomes was 0.233. [ABSTRACT FROM AUTHOR]

Idiopathic membranous nephropathy (IMN) with deposits of phospholipase A2 receptor (PLA2R) antigen in glomerular tissue (GAg+) but no circulating serum PLA2R antibody (SAb−) has been reported. However, little is known about the clinicopathological characteristics and prognosis of this subtype. A total of 74 IMN patients with GAg + identified by kidney biopsy were enrolled in this study. We categorized patients into two groups based on the presence or absence of serum PLA2R antibody. Data on clinical features, pathological features, and outcomes were collected. Kaplan–Meier analysis of complete remission (CR) and partial remission (PR) comparing SAb−/GAg + and SAb+/GAg + patients. Cox proportional hazards models was used to examine factors associated with CR and PR. Among 74 IMN patients, 14 were SAb−/GAg+. Compared with SAb+/GAg + patients, SAb−/GAg + patients presented with higher levels of albumin, lower levels of cholesterol and low density lipoprotein cholesterol (all p <.01), but similar pathological manifestations of kidney biopsy. Multivariate logistic analyses indicated that low albumin (0.79 [95%CI: 0.66–0.95], p =.01) and high cholesterol (1.81 [95%CI: 1.02–3.19], p =.04) were correlated with seropositivity of PLA2R antibody. SAb−/GAg + patients exhibited a significantly higher probability of CR (p =.03) than patients who were SAb+/GAg+. However, no difference was found in the PR rate. Cox regression analyses showed that compared to SAb+/GAg + patients, SAb−/GAg + was more predictive of complete remission (4.28 [95%CI: 1.01–18.17], p =.04). IMN with PLA2R staining on kidney biopsy but without serum PLA2R antibody has milder clinical manifestations and a better prognosis. [ABSTRACT FROM AUTHOR]

Parvovirus B19 (B19V) is a human pathogen that is the causative agent of several diseases in infants and adults. Due to a lack of antivirals against this virus, treatment options are limited. The minor capsid protein of B19V has a unique N terminus, named VP1u, which is essential for infection. The VP1u encodes a receptor binding domain (RBD), necessary for host cell entry, and a phospholipase A2 (PLA2) domain, crucial for endosomal escape during cellular trafficking. Both domains are indispensable for infection, making the RBD a plausible drug target for inhibitors against B19V, as it is located on the exterior surface of the virus. To date, no experimental structural information has been available for the VP1u component for any Parvovirus. Here we report the backbone NMR resonance assignments for the RBD of B19V and demonstrate it forms a stable structure. The backbone chemical shifts are in good agreement with a structure predicted by AlphaFold, validating that the RBD contains three helices connected by tight turns. This RBD construct can now be used for further NMR studies, including assignment of full-length VP1u, determination of protein-protein interaction interfaces, and development of B19 antivirals specific to the RBD domain. [ABSTRACT FROM AUTHOR]

Introduction: Treatment of influenza A virus infections is currently limited to few direct acting antiviral substances. Repurposing other established pharmaceuticals as antivirals could aid in improving treatment options. Methods: This study investigates the antiviral properties of ProcCluster® and procaine hydrochloride, two derivatives of the local anesthetic procaine, in influenza A virus infection of A549, Calu-3 and MDCK cells. Results: Both substances inhibit replication in all three of these cell lines in multi-cycle experiments. However, cell line-dependent differences in the effects of the substances on viral RNA replication and subsequent protein synthesis, as well as release of progeny viruses in single-cycle experiments can be observed. Both ProcCluster® and procaine hydrochloride delay endosome fusion of the virus early in the replication cycle, possibly due to the alkaline nature of the active component procaine. In A549 and Calu-3 cells an additional effect of the substances can be observed at late stages in the first replication cycle. Interestingly, this effect is absent in MDCK cells. We demonstrate that ProcCluster® and procaine hydrochloride inhibit phospholipase A2 (PLA2) enzymes from A549 but not MDCK cells and confirm that specific inhibition of calcium independent PLA2 but not cytosolic PLA2 has antiviral effects. Discussion: We show that ProcCluster® and procaine hydrochloride inhibit influenza A virus infection at several stages of the replication cycle and have potential as antiviral substances. [ABSTRACT FROM AUTHOR]

The most characteristic feature of membranous nephropathy (MN) is the presence of subepithelial electron dense deposits and the consequential thickening of the glomerular basement membrane. There have been great advances in the understanding of the destiny of immune complexes in MN by the benefit of experimental models represented by Heymann nephritis. Subepithelial immune complexes are formed in situ by autoantibodies targeting native autoantigens or exogenous planted antigens such as the phospholipase A2 receptor (PLA2R) and cationic BSA respectively. The nascent immune complexes would not be pathogenic until they develop into immune deposits. Podocytes are the major source of autoantigens in idiopathic membranous nephropathy. They also participate in the modulation and removal of the immune complexes to a large extent. The balance between deposition and clearance is regulated by a wide range of factors such as the composition and physicochemical properties of the immune complexes and the complement system. Complement components such as C3 and C1q have been reported to be precipitated with the deposits whereas a complement regulatory protein CR1 expressed by podocytes is involved in the phagocytosis of immune complexes by podocytes. Podocytes regulate the dynamic change of immune complexes which is disturbed in membranous nephropathy. To elucidate the precise fate of the immune complexes is essential for developing more rational and novel therapies for membranous nephropathy. [ABSTRACT FROM AUTHOR]

Objective: To investigate the relationship between serum lipoprotein-associated phospholipase A2 (Lp-PLA2), neurotrophin-3 (NT-3) levels and rapid eye movement sleep behavior disorder (RBD) in patients with Parkinson’s disease (PD). Methods: 150 PD patients admitted to Zigong Hospital Affiliated to Southwest Medical University were selected as the PD group from January 2021 to December 2022, and at the same time, selected 55 healthy individuals who underwent physical examinations in our hospital as the control group. Enzyme linked immunosorbent assay (ELISA) was used to detect the serum levels of Lp-PLA2 and NT-3. The PD group was divided into RBD group and non RBD group based on the physical signs and RBD questionnaire Hong Kong version (RBDQ-HK) score. Univariate and multivariate logistic regression were used to analyze the influencing factors in PD patients concomitant with RBD, and the predictive efficacy of serum Lp-PLA2 and NT-3 in PD patients concomitant with RBD was analyzed by receiver operating characteristic curve (ROC) curve. Results: The serum Lp-PLA2 level in the control group was lower than that in the PD group (P＜0.05), and the serum NT-3 level was higher than that in the PD group (P＜0.05). The results of univariate analysis showed that the PD patients concomitant with RBD was associated with age, course of disease, and serum levels of Lp-PLA2 and NT-3 (P＜0.05). Multivariate logistic regression analysis showed that prolonged course of disease, elevated Lp-PLA2 levels were independent risk factors for PD with RBD, while elevated NT-3 levels were protective factors for PD concomitant with RBD (P＜0.05). The area under the curve (AUC) of serum Lp-PLA2, NT-3,and combined detection for predicting PD concomitant with RBD were 0.830, 0.766, and 0.866, respectively. Conclusion: Serum Lp-PLA2 and NT-3 are associated with PD patients concomitant with RBD. Elevated serum Lp-PLA2 is an independent risk factor, while elevated serum NT-3 is a protective factor. The combined detection of these two indicators has high predictive value for PD concomitant with RBD. [ABSTRACT FROM AUTHOR]

Neuropteran larvae are fierce predators that use venom to attack and feed on arthropod prey. Neuropterans have adapted to diverse and sometimes extreme habitats, suggesting their venom may have evolved accordingly, but the ecology and evolution of venom deployment in different families is poorly understood. We applied spatial transcriptomics, proteomics, morphological analysis, and bioassays to investigate the venom systems in the antlion Euroleon nostras and the lacewing Chrysoperla carnea, which occupy distinct niches. Although the venom system morphology was similar in both species, we observed remarkable differences at the molecular level. E. nostras produces particularly complex venom secreted from three different glands, indicating functional compartmentalization. Furthermore, E. nostras venom and digestive tissues were devoid of bacteria, strongly suggesting that all venom proteins are of insect origin rather than the products of bacterial symbionts. We identified several toxins exclusive to E. nostras venom, including phospholipase A2 and several undescribed proteins with no homologs in the C. carnea genome. The compositional differences have significant ecological implications because only antlion venom conferred insecticidal activity, indicating its use for the immobilization of large prey. Our results indicate that molecular venom evolution plays a role in the adaptation of antlions to their unique ecological niche. A combination of methods excludes the contribution of bacteria to venom production in predacious antlions and reveals differences in neuropteran venom compositions and activities reflecting the insects' distinct ecological niches. [ABSTRACT FROM AUTHOR]

OBJECTIVE:To observe the effects of Simiao Yong’ an Decoction combined with self-adhesive soft silicone edged-type foam dressing on the end-hemodynamics, epidermal growth factor (EGF), serum fibroblast growth factor-21 (FGF21) and C1q tumor necrosis factor-associated protein 9 (CTRP9) of Wagner Grade 1-2 diabetic feet. METHODS: A total of 102 patients with Wanger grade 1 to 2 diabetic feet admitted into the hospital from Feb. 2020 to Jun. 2023 were grouping via random number table method. Fifty-one cases in the control group was given self-adhesive soft silicone rimmed foam dressing, 51 cases in the observation group received Simiao Yong’ an decoction combined with self-adhesive soft silicone rimmed foam dressing. Clinical efficacy were compared between two groups, the patients’ wound area and skin temperature at the lesion were measured, transcutaneous oxygen partial pressure at the dorsum of foot was detected, the visual analog scores (VAS) were recorded, the patients’ arterial flow velocity and intravascular diameter at the dorsum of foot were detected, the microvascular basal perfusion volume at the dorsum of foot was measured, EGF, amyloid A (SAA), FGF-21, CTRP9 and lipoprotein-associated phospholipase A2 (Lp-PLA2) levels were detected. RESULTS: The total effective rate of the observation group was 96. 08% (49 / 51), higher than 80. 39% (41 / 51) of the control group, with statistically significant difference (P < 0. 05). After treatment, the VAS was lower, the wound area was smaller, the skin temperature and transcutaneous oxygen partial pressure were higher in the observation group than those in the control group, with statistically significant differences (P<0. 05). After treatment, the arterial flow velocity and intravascular diameter at the dorsum of foot was faster, the intravascular diameter and microvascular basal perfusion volume at the dorsum of foot were larger, the FGF21 level was lower, the CTRP9 level and EGF content were higher, the SAA and Lp-PLA2 contents were lower in the observation group than those in the control group, with statistically significant differences (P < 0. 05). CONCLUSIONS: Simiayongan Decoction combined with self-adhesive soft silicone edging foam dressing in the treatment of Wagner Grade 1-2 diabetic foot patients can inhibit body inflammation, increase EGF level, regulate FGF-21 and CTRP9 levels, improve acroarterial blood flow dynamics and microvascular circulation, promote wound healing, relieve wound pain, increase skin temperature and transcutaneous oxygen partial pressure, and improve the treatment of patients with Wagner Grade 1-2 diabetic foot. Improve clinical efficacy. [ABSTRACT FROM AUTHOR]

Spectroscopic studies on domains and peptides of large proteins are complicated because of the tendency of short peptides to form oligomers in aquatic buffers, but conjugation of a peptide with a carrier protein may be helpful. In this study we approved that a fragment of SK30 peptide from phospholipase A2 domain of VP1 Parvovirus B19 capsid protein (residues: 144–159; 164; 171–183; sequence: SAVDSAARIHDFRYSQLAKLGINPYTHWTVADEELLKNIK) turns from random coil to alpha helix in the acidic medium only in case if it had been conjugated with BSA (through additional N-terminal Cys residue, turning it into CSK31 peptide, and SMCC linker) according to CD-spectroscopy results. In contrast, unconjugated SK30 peptide does not undergo such shift because it forms stable oligomers connected by intermolecular antiparallel beta sheet, according to IR-spectroscopy, CD-spectroscopy, blue native gel electrophoresis and centrifugal ultrafiltration, as, probably, the whole isolated phospholipase domain of VP1 protein does. However, being a part of the long VP1 capsid protein, phospholipase domain may change its fold during the acidification of the medium in the endolysosome by the way of the formation of contacts between protonated His153 and Asp175, promoting the shift from random coil to alpha helix in its N-terminal part. This study opens up a perspective of vaccine development, since rabbit polyclonal antibodies against the conjugate of CSK31 peptide with BSA, in which the structure of the second alpha helix from the phospholipase A2 domain should be reproduced, can bind epitopes of the complete recombinant unique part of VP1 Parvovirus B19 capsid (residues: 1-227). [ABSTRACT FROM AUTHOR]

Cisplatin (CDDP) is a platinum-based drug with anti-cancer activity and is widely used as a standard therapy for bladder cancer. It is well known that CDDP causes cell death by increasing the generation of reactive oxygen species (ROS) and lipid peroxidation, but the mechanism of its anti-cancer effects has not been fully elucidated. There are still some problems such as chemoresistance in CDDP therapy. In the present study, we found the expression of Ca2+-independent phospholipase A 2 γ (iPLA 2 γ), which has been reported to regulate cellular redox homeostasis by inhibiting lipid peroxide accumulation, in human bladder cancer tissues. Thus, we investigated the effect of iPLA 2 γ knockdown on CDDP-induced bladder cancer cell death. As a result, we found that iPLA 2 γ knockdown significantly enhanced CDDP-induced apoptosis, intracellular and mitochondrial ROS production, cytochrome c release and caspase activation in bladder cancer cells. Moreover, mitochondrial membrane potential was decreased and peroxidation of mitochondrial phospholipids was increased by iPLA 2 γ knockdown. It was also shown that co-treatment of bromoenol lactone, an iPLA 2 inhibitor, increased CDDP-induced apoptosis. These results indicated that iPLA 2 γ plays an important role in protecting bladder cancer cells from CDDP-induced apoptosis, and that iPLA 2 γ inhibitors might represent a novel strategy in CDDP-based multi-drug therapy. [Display omitted] • iPLA 2 γ knockdown enhanced CDDP-induced apoptosis of bladder cancer cells. • iPLA 2 γ knockdown accelerated CDDP-induced mitochondrial oxidative stress. • iPLA 2 γ knockdown increased CDDP-induced peroxidation of cardiolipin. • Inhibition of iPLA 2 γ might represent a novel strategy in CDDP-based drug therapy. [ABSTRACT FROM AUTHOR]

Background:Bougainvillea x buttiana is an ornamental plant with antioxidant, anti-inflammatory, and cytotoxic activities, which has been traditionally used to treat respiratory diseases. This study aimed to investigate whether the acetonic extract of Bougainvillea x buttiana var. Rose (BxbRAE-100%) has analgesic and anti-inflammatory properties and its potential action mechanisms. Methods: Analgesic and anti-inflammatory activities were evaluated using three murine pain models and two acute inflammation models. In vitro, the ability of the extract to inhibit proteolytic activity and the activities of the enzymes phospholipase A2 (PLA2) and cyclooxygenase (COX) were evaluated. In silico analysis was performed to predict the physicochemical and Absorption, distribution, metabolism, and excretion (ADME) profiles of the compounds previously identified in BxbRAE-100%. Results: In vivo BxbRAE-100% decreased the nociceptive behaviors in the writhing model, the tail immersion, and the formalin test, suggesting that the extract has the potential to relieve pain at peripheral and central levels. Additionally, topical or oral BxbRAE-100% treatment reduced dose-dependent 12-O-Tetradecanoylphorbol-13-acetate (TPA)-induced ear inflammation and carrageenan-induced paw edema, respectively. In vitro, BxbRAE-100% significantly inhibited proteolytic activity and PLA2, COX-1 and COX-2 activities. In silico, the compounds previously identified in BxbRAE-100% met Lipinski's rule of five and showed adequate ADME properties. Conclusions: These results support the use of B. x buttiana in Traditional Mexican Medicine and highlight its potential for the development of new treatments for pain and inflammation. [ABSTRACT FROM AUTHOR]

Transient receptor potential vanilloid 1 (TRPV1) is a calcium‐permeable ion channel that is gated by the pungent constituent of red chili pepper, capsaicin, and by related chemicals from the group of vanilloids, in addition to noxious heat. It is expressed mostly in sensory neurons to act as a detector of painful stimuli produced by pungent chemicals and high temperatures. Although TRPV1 is also found outside the sensory nervous system, its expression and function in the bladder detrusor smooth muscle (DSM) remain controversial. Here, by using Ca2+ imaging and patch clamp on isolated rat DSM cells, in addition to tensiometry on multicellular DSM strips, we show that TRPV1 is expressed functionally in only a fraction of DSM cells, in which it acts as an endoplasmic reticulum Ca2+‐release channel responsible for the capsaicin‐activated [Ca2+]i rise. Carbachol‐stimulated contractions of multicellular DSM strips contain a TRPV1‐dependent component, which is negligible in the circular DSM but reaches ≤50% in the longitudinal DSM. Activation of TRPV1 in rat DSM during muscarinic cholinergic stimulation is ensured by phospholipase A2‐catalysed derivation of arachidonic acid and its conversion by lipoxygenases to eicosanoids, which act as endogenous TRPV1 agonists. Immunofluorescence detection of TRPV1 protein in bladder sections and isolated DSM cells confirmed both its preferential expression in the longitudinal DSM sublayer and its targeting to the endoplasmic reticulum. We conclude that TRPV1 is an essential contributor to the cholinergic contraction of bladder longitudinal DSM, which might be important for producing spatial and/or temporal anisotropy of bladder wall deformation in different regions during parasympathetic stimulation. Key points: The transient receptor potential vanilloid 1 (TRPV1) heat/capsaicin receptor/channel is localized in the endoplasmic reticulum membrane of detrusor smooth muscle (DSM) cells of the rat bladder, operating as a calcium‐release channel.Isolated DSM cells are separated into two nearly equal groups, within which the cells either show or do not show TRPV1‐dependent [Ca2+]i rise.Carbachol‐stimulated, muscarinic ACh receptor‐mediated contractions of multicellular DSM strips contain a TRPV1‐dependent component.This component is negligible in the circular DSM but reaches ≤50% in longitudinal DSM.Activation of TRPV1 in rat DSM during cholinergic stimulation involves phospholipase A2‐catalysed derivation of arachidonic acid and its conversion by lipoxygenases to eicosanoids, which act as endogenous TRPV1 agonists. [ABSTRACT FROM AUTHOR]