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Journal of Extracellular Vesicles Jun 2024Migrasomes represent a recently uncovered category of extracellular microvesicles, spanning a diameter range of 500 to 3000 nm. They are emitted by migrating cells and...
Migrasomes represent a recently uncovered category of extracellular microvesicles, spanning a diameter range of 500 to 3000 nm. They are emitted by migrating cells and harbour a diverse array of RNAs and proteins. Migrasomes can be readily identified in bodily fluids like serum and urine, rendering them a valuable non-invasive source for disease diagnosis through liquid biopsy. In this investigation, we introduce a streamlined and effective approach for the capture and quantitative assessment of migrasomes, employing wheat germ agglutinin (WGA)-coated magnetic beads and flow cytometry (referred to as WBFC). Subsequently, we examined the levels of migrasomes in the urine of kidney disease (KD) patients with podocyte injury and healthy volunteers using WBFC. The outcomes unveiled a substantial increase in urinary podocyte-derived migrasome concentrations among individuals with KD with podocyte injury compared to the healthy counterparts. Notably, the urinary podocyte-derived migrasomes were found to express an abundant quantity of phospholipase A2 receptor (PLA2R) proteins. The presence of PLA2R proteins in these migrasomes holds promise for serving as a natural antigen for the quantification of autoantibodies against PLA2R in the serum of patients afflicted by membranous nephropathy. Consequently, our study not only pioneers a novel technique for the isolation and quantification of migrasomes but also underscores the potential of urinary migrasomes as a promising biomarker for the early diagnosis of KD with podocyte injury.
Topics: Podocytes; Humans; Cell-Derived Microparticles; Male; Female; Kidney Diseases; Flow Cytometry; Middle Aged; Adult; Biomarkers; Receptors, Phospholipase A2
PubMed: 38853287
DOI: 10.1002/jev2.12460 -
The Journal of Reproduction and... Jun 2024For the intracytoplasmic sperm injection (ICSI) procedure in pigs, an electrical pulse (EP) has been used as an effective method for oocyte stimulation, but unlike...
For the intracytoplasmic sperm injection (ICSI) procedure in pigs, an electrical pulse (EP) has been used as an effective method for oocyte stimulation, but unlike sperm, EP is unable to induce Ca oscillations. In this study, we investigated the effects of generating artificial Ca oscillations with phospholipase Cζ (PLCζ) mRNA, a candidate sperm factor, on fertilization, embryonic development, and gene expression after ICSI. Firstly, the concentration of PLCζ mRNA of a fixed volume (1.0 pl) that would induce a pattern of Ca rise similar to that of in vitro fertilized (IVF) sperm was examined and determined to be 300 ng/μl. Secondly, the effects of oocyte stimulation methods on fertilization and embryonic development were investigated. ICSI-oocytes were activated by EP (EP group) or by PLCζ mRNA (PLCζ group). Furthermore, IVF-oocytes (IVF group) and ICSI-oocytes with and without an injection of buffer (buffer and untreated groups, respectively) were used as controls. It was found that the rates of normal fertilization in the PLCζ and EP groups were significantly higher than those in the buffer and untreated groups. The blastocyst formation rates did not differ among the groups. The embryo quality in the EP group was inferior to those in the PLCζ and IVF groups. Additionally, the expression level of a proapoptosis-related gene (Caspase-3) in the EP group was significantly higher than those in the PLCζ and IVF groups. Our data suggest that oocyte activation by PLCζ mRNA has the effect of improving embryo quality.
PubMed: 38853022
DOI: 10.1262/jrd.2023-105 -
Nature Communications Jun 2024The I148M variant of PNPLA3 is closely associated with hepatic steatosis. Recent evidence indicates that the I148M mutant functions as an inhibitor of...
The I148M variant of PNPLA3 is closely associated with hepatic steatosis. Recent evidence indicates that the I148M mutant functions as an inhibitor of PNPLA2/ATGL-mediated lipolysis, leaving the role of wild-type PNPLA3 undefined. Despite showing a triglyceride hydrolase activity in vitro, PNPLA3 has yet to be established as a lipase in vivo. Here, we show that PNPLA3 preferentially hydrolyzes polyunsaturated triglycerides, mobilizing polyunsaturated fatty acids for phospholipid desaturation and enhancing hepatic secretion of triglyceride-rich lipoproteins. Under lipogenic conditions, mice with liver-specific knockout or acute knockdown of PNPLA3 exhibit aggravated liver steatosis and reduced plasma VLDL-triglyceride levels. Similarly, I148M-knockin mice show decreased hepatic triglyceride secretion during lipogenic stimulation. Our results highlight a specific context whereby the wild-type PNPLA3 facilitates the balance between hepatic triglyceride storage and secretion, and suggest the potential contribution of a loss-of-function by the I148M variant to the development of fatty liver disease in humans.
Topics: Animals; Lipase; Liver; Triglycerides; Mice; Lipoproteins, VLDL; Humans; Mice, Knockout; Fatty Acids, Unsaturated; Male; Fatty Liver; Mice, Inbred C57BL; Lipolysis; Membrane Proteins; Acyltransferases; Phospholipases A2, Calcium-Independent
PubMed: 38844467
DOI: 10.1038/s41467-024-49224-x -
Frontiers in Pharmacology 2024Treatment of glomerulonephritis presents several challenges, including limited therapeutic options, high costs, and potential adverse reactions. As a recognized Chinese... (Review)
Review
Treatment of glomerulonephritis presents several challenges, including limited therapeutic options, high costs, and potential adverse reactions. As a recognized Chinese patent medicine, poly-glycosides (TWP) have shown promising benefits in managing autoimmune diseases. To evaluate clinical effectiveness and safety of TWP in treating glomerulonephritis, we systematically searched PubMed, Cochrane Library, Web of Science, and Embase databases for controlled studies published up to 12 July 2023. We employed weighted mean difference and relative risk to analyze continuous and dichotomous outcomes. This meta-analysis included 16 studies that included primary membranous nephropathy (PMN), type 2 diabetic kidney disease (DKD), and Henoch-Schönlein purpura nephritis (HSPN). Analysis revealed that additional TWP administration improved patients' outcomes and total remission rates, reduced 24-h urine protein (24hUP) and decreased relapse events. The pooled results demonstrated the non-inferiority of TWP to glucocorticoids in achieving total remission, reducing 24hUP, and converting the phospholipase A2 receptor (PLA2R) status to negative. For DKD patients, TWP effectively reduced 24hUP levels, although it did not significantly improve the estimated glomerular filtration rate (eGFR). Compared to valsartan, TWP showed comparable improvements in 24hUP and eGFR levels. In severe cases of HSPN in children, significant clinical remission and a reduction in 24hUP levels were observed with the addition of TWP treatment. TWP did not significantly increase the incidence of adverse reactions. Therefore, TWP could offer therapeutic benefits to patients with PMN, DKD, and severe HSPN, with a minimal increase in the risk of side effects.
PubMed: 38841368
DOI: 10.3389/fphar.2024.1339153 -
Toxicon : Official Journal of the... Jul 2024African cobras (Naja species) represent one of the most encountered medically important snakes in Africa. They are classified as African spitting (Afronaja subgenus) and... (Review)
Review Comparative Study
African cobras (Naja species) represent one of the most encountered medically important snakes in Africa. They are classified as African spitting (Afronaja subgenus) and non-spitting cobras (Uraeus and Boulengerina subgenera) with similar and different characteristics. Snake venom toxins including three-finger toxin (3FTx), phospholipase A2 (PLA), and snake venom metalloproteinase (SVMP) cause snakebite envenomation leading to morbidity and mortality. The profile of the proteome of African cobra venoms will help to develop safer and more effective antivenoms. The approval of Captopril by the US Food and Drug Administration (FDA) for the treatment of cardiovascular diseases, has led to intensified research towards possible use of venom toxins as therapeutics. In this review, we compare the venom proteome profile of 3 African Naja subgenera. In both Afronaja and Boulengerina subgenera, 3FTx (Afronaja-69.79%; Boulengerina-60.56%) followed by PLA (Afronaja-21.15%; Boulengerina-20.21%) dominated the venoms compared to the Uraeus subgenus dominated by 3FTx (84.55%) with little to no PLA abundance (0.8%). The venom of subgenus Uraeus was distinct from the other two subgenera by the almost total absence of PLA, thus indicating little or no contribution of PLA in the envenomation caused by Uraeus compared to Afronaja and Boulengerina. Furthermore, we report studies on the experimental testing of African cobra venoms and toxins against diseases including anti-cancer properties.
Topics: Animals; Elapid Venoms; Proteome; Antivenins; Naja; Phospholipases A2
PubMed: 38838860
DOI: 10.1016/j.toxicon.2024.107792 -
Hepatology Communications Jun 2024Abnormal phospholipid metabolism is linked to metabolic dysfunction-associated steatotic liver disease (MASLD) development and progression. We aimed to clarify whether...
BACKGROUND
Abnormal phospholipid metabolism is linked to metabolic dysfunction-associated steatotic liver disease (MASLD) development and progression. We aimed to clarify whether genetic variants of phospholipid metabolism modify these relationships.
METHODS
This case-control study consecutively recruited 600 patients who underwent MRI-based proton density fat fraction examination (240 participants with serum metabonomics analysis, 128 biopsy-proven cases) as 3 groups: healthy control, nonobese MASLD, and obese MASLD, (n = 200 cases each). Ten variants of phospholipid metabolism-related genes [phospholipase A2 Group VII rs1805018, rs76863441, rs1421378, and rs1051931; phospholipase A2 receptor 1 (PLA2R1) rs35771982, rs3828323, and rs3749117; paraoxonase-1 rs662 and rs854560; and ceramide synthase 4 (CERS4) rs17160348)] were genotyped using SNaPshot.
RESULTS
The T-allele of CERS4 rs17160348 was associated with a higher risk of both obese and nonobese MASLD (OR: 1.95, 95% CI: 1.20-3.15; OR: 1.76, 95% CI: 1.08-2.86, respectively). PLA2R1 rs35771982-allele is a risk factor for nonobese MASLD (OR: 1.66, 95% CI: 1.11-1.24), moderate-to-severe steatosis (OR: 3.24, 95% CI: 1.96-6.22), and steatohepatitis (OR: 2.61, 95% CI: 1.15-3.87), while the paraoxonase-1 rs854560 T-allele (OR: 0.50, 95% CI: 0.26-0.97) and PLA2R1 rs3749117 C-allele (OR: 1.70, 95% CI: 1.14-2.52) are closely related to obese MASLD. After adjusting for sphingomyelin level, the effect of the PLA2R1 rs35771982CC allele on MASLD was attenuated. Furthermore, similar effects on the association between the CERS4 rs17160348 C allele and MASLD were observed for phosphatidylcholine, phosphatidic acid, sphingomyelin, and phosphatidylinositol.
CONCLUSIONS
The mutations in PLA2R1 rs35771982 and CERS4 rs17160348 presented detrimental impact on the risk of occurrence and disease severity in nonobese MASLD through altered phospholipid metabolism.
Topics: Humans; Male; Female; Middle Aged; Case-Control Studies; Genotype; Receptors, Phospholipase A2; Phospholipids; Adult; Obesity; Polymorphism, Single Nucleotide; Fatty Liver; Genetic Predisposition to Disease
PubMed: 38836837
DOI: 10.1097/HC9.0000000000000388 -
Renal Failure Dec 2024The M-type phospholipase A2 receptor (PLA2R)-associated primary membranous nephropathy (PMN) is an immune-related disease in adults with increasing morbidity and...
BACKGROUND
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.
METHODS
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.
RESULTS
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, = 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, = 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, = 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.
CONCLUSIONS
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.
Topics: Humans; Glomerulonephritis, Membranous; Male; Female; Middle Aged; Receptors, Phospholipase A2; Nephrotic Syndrome; Adult; Biomarkers; Fibrinogen; ROC Curve; Retrospective Studies; Remission Induction; Treatment Outcome; Immunosuppressive Agents; Kaplan-Meier Estimate; Serum Albumin; Risk Factors
PubMed: 38832491
DOI: 10.1080/0886022X.2024.2359024 -
Heliyon May 2024Polyphyllin is a class of saponins extracted from Paris polyphylla rhizomes and has been used in clinical application in China for more than 2000 years. However, the...
BACKGROUND
Polyphyllin is a class of saponins extracted from Paris polyphylla rhizomes and has been used in clinical application in China for more than 2000 years. However, the mechanism for treating gastric cancer (GC) is still unclear. This study was designed to predict the targets and mechanisms of total Polyphyllin from Paris polyphylla rhizomes for the treatment of GC.
METHOD
Firstly, PubChem and Swiss Target Prediction databases were utilized to collect the 12 ingredients of total Polyphyllin from Paris polyphylla rhizomes and their targets. GC-related genes were obtained from the GEO database. Then the intersecting targets to all these molecules that identified using Venny. Secondly, the intersecting targets were imported into STRING platform for protein-protein interaction (PPI) network. Moreover, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted in DAVID website. In addition, the GEPIA was applied to perform the expression levels, transcript levels, staging, and overall survival of hub genes. In addition, we used AutoDock Vina to evaluate binding affinity of molecular docking between key ingredients and anti-GC targets. cell experiments, we detected the cell viability of gastric cancer cells at 24, 36, and 48 h using CCK-8 assay. The G0/G1 of cell cycle and apoptosis were detected by flow cytometry. Finally, quantitative real time polymerase chain reaction (qRT-PCR) was used to detect the level of hub genes, and Western blot was used to detect the changes of PI3K/Akt signal pathway.
RESULTS
Firstly, we identified 12 ingredients and 286 targets of total Polyphyllin. A total of 2653 GC-related differentially expressed genes (DEGs) were collected, including 1366 up-regulated genes and 1287 down-regulated genes. Moreover, 45 targets were obtained after intersection. Secondly, results of the GO enrichment suggested that these genes were closely related to cell proliferation, migration and aging. KEGG analysis suggested that Polyphyllin in GC therapy were mostly regulated by multiple pathways, including the pathways in cancer, calcium signaling pathway, Rap1 signaling pathway, phospholipase D signaling pathway, etc. In addition, GEPIA results exhibited that and were associated with GC progression, stage, and survival. Besides, the molecular docking results further confirmed that the binding energy of Polyphyllin Ⅲ with was minimal. cell experiments, Polyphyllin Ⅲ inhibited the cell viability of gastric cancer cells, blocked the cell cycle G0/G1 phase, and induced cell apoptosis. In addition, Polyphyllin Ⅲ down-regulated the mRNA levels of , and , and regulated the PI3K/Akt signal pathway.
CONCLUSIONS
The results revealed that total Polyphyllin treated GC through multiple targets, multiple channels, and multiple pathways. In addition, Polyphyllin Ⅲ played an anti-gastric cancer role by inhibiting the proliferation of gastric cancer.
PubMed: 38831826
DOI: 10.1016/j.heliyon.2024.e31452 -
Biological & Pharmaceutical Bulletin 2024Nonalcoholic steatohepatitis (NASH) is characterized by hepatic inflammation and fibrosis due to excessive fat accumulation. Monocyte chemoattractant protein-1 (MCP-1)...
Group IVA Phospholipase A in Collagen-Producing Cells Promotes High-Fat Diet-Induced Infiltration of Inflammatory Cells into the Liver by Upregulating the Expression of MCP-1.
Nonalcoholic steatohepatitis (NASH) is characterized by hepatic inflammation and fibrosis due to excessive fat accumulation. Monocyte chemoattractant protein-1 (MCP-1) is a key chemokine that infiltrates inflammatory cells into the liver during the development of NASH. Our previous studies demonstrated that a systemic deficiency of group IVA phospholipase A (IVA-PLA), an enzyme that contributes to the production of lipid inflammatory mediators, protects mice against high-fat diet-induced hepatic fibrosis and markedly suppresses the CCl-induced expression of MCP-1 in the liver. However, it remains unclear which cell types harboring IVA-PLA are involved in the elevated production of MCP-1. Hence, the present study assessed the types of cells responsible for IVA-PLA-mediated production of MCP-1 using cultured hepatic stellate cells, endothelial cells, macrophages, and hepatocytes, as well as cell-type specific IVA-PLA deficient mice fed a high-fat diet. A relatively specific inhibitor of IVA-PLA markedly suppressed the expression of MCP-1 mRNA in cultured hepatic stellate cells, but the suppression of MCP-1 expression was partial in endothelial cells and not observed in monocytes/macrophages or hepatocytes. In contrast, a deficiency of IVA-PLA in collagen-producing cells (hepatic stellate cells), but not in other types of cells, reduced the high-fat diet-induced expression of MCP-1 and inflammatory cell infiltration in the liver. Our results suggest that IVA-PLA in hepatic stellate cells is critical for hepatic inflammation in the high-fat diet-induced development of NASH. This supports a potential therapeutic approach for NASH using a IVA-PLA inhibitor targeting hepatic stellate cells.
Topics: Animals; Diet, High-Fat; Chemokine CCL2; Hepatic Stellate Cells; Mice, Inbred C57BL; Liver; Up-Regulation; Male; Mice; Non-alcoholic Fatty Liver Disease; Group IV Phospholipases A2; Hepatocytes; Humans; Mice, Knockout; Collagen; Macrophages; Endothelial Cells; Cells, Cultured
PubMed: 38825533
DOI: 10.1248/bpb.b24-00035 -
Journal of Animal Science and... Jun 2024The hypothalamus plays a crucial role in the health and productivity of dairy cows, yet studies on its functionality and its impact on peripheral circulation in these...
BACKGROUND
The hypothalamus plays a crucial role in the health and productivity of dairy cows, yet studies on its functionality and its impact on peripheral circulation in these animals are relatively scarce, particularly regarding dietary interventions. Therefore, our study undertook a comprehensive analysis, incorporating both metabolomics and transcriptomics, to explore the effects of a grain-based diet on the functionality of the hypothalamus, as well as on blood and milk in dairy cows.
RESULTS
The hypothalamic metabolome analysis revealed a significant reduction in prostaglandin E (PGE) level as a prominent response to the grain-based diet introduction. Furthermore, the hypothalamic transcriptome profiling showed a notable upregulation in amino acid metabolism due to the grain-based diet. Conversely, the grain-based diet led to the downregulation of genes involved in the metabolic pathway from lecithin to PGE, including phospholipase A2 (PLA2G4E, PLA2G2A, and PLA2G12B), cyclooxygenase-2 (COX2), and prostaglandin E synthase (PTGES). Additionally, the plasma metabolome analysis indicated a substantial decrease in the level of PGE, along with a decline in adrenal steroid hormones (tetrahydrocortisol and pregnenolone) following the grain-based diet introduction. Analysis of the milk metabolome showed that the grain-based diet significantly increased uric acid level while notably decreasing PGE level. Importantly, PGE was identified as a critical metabolic marker in the hypothalamus, blood, and milk in response to grain intervention. Correlation analysis demonstrated a significant correlation among metabolic alterations in the hypothalamus, blood, and milk following the grain-based diet.
CONCLUSIONS
Our findings suggest a potential link between hypothalamic changes and alterations in peripheral circulation resulting from the introduction of a grain-based diet.
PubMed: 38822422
DOI: 10.1186/s40104-024-01034-3