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Journal of Immunology (Baltimore, Md. :... May 2024Endometriosis is a chronic inflammatory disease in which endometrial-like tissue grows ectopically, resulting in pelvic pain and infertility. IL-23 is a key contributor...
Endometriosis is a chronic inflammatory disease in which endometrial-like tissue grows ectopically, resulting in pelvic pain and infertility. IL-23 is a key contributor in the development and differentiation of TH17 cells, driving TH17 cells toward a pathogenic profile. In a variety of inflammatory and autoimmune disorders, TH17 cells secrete proinflammatory cytokines, including IL-17, contributing to disease pathophysiology. Our studies and others have implicated IL-17 and TH17 cell dysregulation in endometriosis, which is associated with disease severity. In this article, we address whether IL-23-driven TH17 cells contribute to cardinal features of lesion proliferation, vascularization, and inflammation in endometriosis using patient samples, representative cell lines, and our established mouse model of endometriosis. The results indicated dysregulated expression of key genes in the IL-23/TH17 axis in patient ectopic and eutopic endometrial samples and increased IL-23 protein in patient plasma compared with controls. In vitro studies using primary human TH cells determined that rIL-23 mixture treatment increased pathogenic TH17 cell frequency. Similarly, rIL-23 treatment of cell lines (12Z cells, EECCs, HUVECs, and hESCs) representative of the endometriotic lesion microenvironment increased cytokines and growth factors, which play a role in lesion establishment and maintenance. In a syngeneic mouse model of endometriosis, rIL-23 treatment altered numbers of myeloid and T cell subsets in peritoneal fluid and increased giant cells within the lesion. Lesions from rIL-23-treated mice did not reveal significant alterations in proliferation/vascularization, although trends of increased proliferation and vascularization were observed. Collectively, these findings provide insights into the impact of the IL-23/TH17 axis on local immune dysfunction and broadly on endometriosis pathophysiology.
Topics: Animals; Female; Humans; Mice; Cytokines; Endometriosis; Endometrium; Interleukin-17; Interleukin-23; Th17 Cells
PubMed: 38466035
DOI: 10.4049/jimmunol.2400018 -
Peritoneal Dialysis International :... Jan 2024Long-term peritoneal dialysis is associated with the development of peritoneal membrane alterations, both in morphology and function. Impaired ultrafiltration (UF) is... (Review)
Review
Long-term peritoneal dialysis is associated with the development of peritoneal membrane alterations, both in morphology and function. Impaired ultrafiltration (UF) is the most important functional change, and peritoneal fibrosis is the major morphological alteration. Both are caused by the continuous exposure to dialysis solutions that are different from plasma water with regard to the buffer substance and the extremely high-glucose concentrations. Glucose has been incriminated as the major cause of long-term peritoneal membrane changes, but the precise mechanism has not been identified. We argue that glucose causes the membrane alterations by peritoneal pseudohypoxia and by the formation of advanced glycosylation end products (AGEs). After a summary of UF kinetics including the role of glucose transporters (GLUT), and a discussion on morphologic alterations, relationships between function and morphology and a survey of the pathogenesis of UF failure (UFF), it will be argued that impaired UF is partly caused by a reduction in small pore fluid transport as a consequence of AGE-related vasculopathy and - more importantly - in diminished free water transport due to pseudohypoxia, caused by increased peritoneal cellular expression of GLUT-1. The metabolism of intracellular glucose will be reviewed. This occurs in the glycolysis and in the polyol/sorbitol pathway, the latter is activated in case of a large supply. In both pathways the ratio between the reduced and oxidised form of nicotinamide dinucleotide (NADH/NAD ratio) will increase, especially because normal compensatory mechanisms may be impaired, and activate expression of hypoxia-inducible factor-1 (HIF-1). The latter gene activates various profibrotic factors and GLUT-1. Besides replacement of glucose as an osmotic agent, medical treatment/prevention is currently limited to tamoxifen and possibly Renin/angiotensis/aldosteron (RAA) inhibitors.
Topics: Humans; Peritoneal Dialysis; Glucose; Glycosylation; Peritoneum; Dialysis Solutions; Water; Ultrafiltration
PubMed: 37723976
DOI: 10.1177/08968608231196033 -
Biochimica Et Biophysica Acta.... Oct 2023Endometriosis is an estrogen-dependent, progesterone-resistant gynecological disease with an unknown pathogenesis. Compared to women without endometriosis, women with...
Endometriosis is an estrogen-dependent, progesterone-resistant gynecological disease with an unknown pathogenesis. Compared to women without endometriosis, women with endometriosis have a remarkably high heme level in the peritoneal fluid. To further investigate the pathomechanisms of heme in endometriosis, we aimed to identify the dysregulated expression of heme-trafficking proteins, such as PGRMC1/2 that are also receptors that mediate the non-genomic responses to progesterone, and heme-degrading enzymes between ectopic endometrial stromal cells and their normal counterparts. We found that heme could regulate progesterone receptor-related gene expression. Functional human endometrial stromal cell experiments showed that heme promotes cell proliferation and migration in a heme oxygenase-1-independent manner; moreover, blocking oxidative phosphorylation/ATP generation could abolish these effects of heme in vitro, whereas intraperitoneal hemopexin administration could alleviate heme-triggered ectopic lesions in vivo. Therefore, heme likely mediates the induction of progesterone resistance and simultaneously induces endometriosis via the mitochondrial oxidative phosphorylation pathway.
Topics: Female; Humans; Progesterone; Endometriosis; Uterine Diseases; Endometrium; Estrogens; Membrane Proteins; Receptors, Progesterone
PubMed: 37247698
DOI: 10.1016/j.bbadis.2023.166761 -
Frontiers in Immunology 2023The NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome has been described in both immune cells and platelets, but its role in the megakaryocyte (MK)...
BACKGROUND
The NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome has been described in both immune cells and platelets, but its role in the megakaryocyte (MK) lineage remains elusive.
OBJECTIVE
The aim of this study was to explore the role of NLRP3 inflammasome in megakaryocytes and platelets.
METHODS
We generated /Cre mice carrying a mutation genetically similar to the one observed in human Muckle-Wells syndrome, which leads to hyperactivity of NLRP3 specifically in MK and platelets.
RESULTS
Platelets from the mutant mice expressed elevated levels of both precursor and active form of caspase-1, suggesting hyperactivity of NLRP3 inflammasome. /Cre mice developed normally and had normal platelet counts. Expression of major platelet receptors, platelet aggregation, platelet deposition on collagen under shear, and deep vein thrombosis were unchanged. /Cre mice had mild anemia, reduced Ter119 cells in the bone marrow, and splenomegaly. A mild increase in MK TGF-β1 might be involved in the anemic phenotype. Intraperitoneal injection of zymosan in /Cre mice induced increased neutrophil egression and elevated levels of a set of proinflammatory cytokines, alongside IL-10 and G-CSF, in the peritoneal fluid as compared with control animals.
CONCLUSION
MK/platelet NLRP3 inflammasome promotes the acute inflammatory response and its hyperactivation in mice leads to mild anemia and increased extramedullary erythropoiesis.
Topics: Animals; Mice; Anemia; Inflammasomes; Megakaryocytes; Mice, Inbred NOD; NLR Family, Pyrin Domain-Containing 3 Protein
PubMed: 37622117
DOI: 10.3389/fimmu.2023.1226196 -
Archives of Gynecology and Obstetrics Nov 2023To assess whether endometriosis (EMs) was related to systematic and/or local deviations of cluster of differentiation (CD)4 + T cells. (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
To assess whether endometriosis (EMs) was related to systematic and/or local deviations of cluster of differentiation (CD)4 + T cells.
METHODS
Until November 2022, we enrolled a total of 1363 EMs and 1564 healthy women from 32 studies who met the inclusion criteria.
RESULTS
After systematically retrieving the literature, we identified 1086 citations and 32 case-control studies were enrolled. Cumulative results suggested that there were insignificant deviations of CD4 + T cells during peripheral blood (PB) between EMs and healthy women (RR: - 0.83, I = 99%, p = 0.65), also no statistically significant difference was found between mild and severe EMs (RR: 3.19, I = 94%, p = 0.19). We also found insignificant deviations of CD4 + /CD8 + during PB between EMs and healthy women (RR: 0.09, I = 99%, p = 0.39), and between mild and severe EMs (RR: - 0.16, I = 99%, p = 0.29). The results might suggest that there was no significant correlation between EMs and systematic deviations of CD4 + T cells. When it came to local deviation during peritoneal fluid (PF), the polled results suggested that the frequency of CD4 + T cells during EMs was significantly lower than healthy women (RR: - 5.38, I = 93%, p = 0.01), and the ratio of CD4 + /CD8 + during EMs was significantly lower than healthy women (RR: - 0.13, I = 0%, p < 0.0001). However, there were insignificant deviations of CD4 + during PF between mild and severe EMs (RR: 1.65, I = 53%, p = 0.15), also there was an insignificant difference of CD4 + /CD8 + between mild and severe EMs (RR: - 0.09, I = 14%, p = 0.19). EMs might be closely related to local deviations of CD4 + T cells.
CONCLUSION
There was no obvious correlation between EMs and systematic deviations of CD4 + T cells, EMs might be closely related to local deviations of CD4 + T cells. Further study on the functional deviations and subpopulation distribution of CD4 + T cells is urgently needed.
Topics: Female; Humans; Ascitic Fluid; Endometriosis; Lymphocyte Count; T-Lymphocytes; Case-Control Studies
PubMed: 36840769
DOI: 10.1007/s00404-023-06964-3 -
Journal of Obstetrics and Gynaecology :... Dec 2023Peritoneal effusion is a common event in ovarian cancer (OC) patients. LncRNA H19 and vascular endothelial growth factor (VEGF) are implicated in cancer progression. The...
Efficacy and safety of intraperitoneal bevacizumab combined with hyperthermic intraperitoneal chemotherapy in the treatment of patients with ovarian cancer and peritoneal effusion and the effect on serum lncRNA H19 and VEGF levels.
Peritoneal effusion is a common event in ovarian cancer (OC) patients. LncRNA H19 and vascular endothelial growth factor (VEGF) are implicated in cancer progression. The study evaluated the curative effect and safety of bevacizumab combined with hyperthermic intraperitoneal chemotherapy (HIPEC) in OC patients with peritoneal effusion and the effect on serum lncRNA H19/VEGF levels. Totally 248 OC patients with peritoneal effusion were treated with intraperitoneal bevacizumab + HIPEC (observation group) or abdominal paracentesis without HIPEC (control group). The clinical efficacy, quality of life, and adverse reactions were evaluated after two treatment cycles. The serum lncRNA H19 and VEGF levels pre-/post-treatment were determined by RT-qPCR and ELISA. The observation group exhibited better clinical efficacy than the control group, evidenced by a higher partial response rate, response rate, and disease control rate. The observation group exhibited reduced physical/cognitive/role/social/emotional function scores and total adverse reactions. LncRNA H19/VEGF levels showed no significant difference between the two groups before treatment but were significantly downregulated in the observation group after treatment. Summarily, intraperitoneal bevacizumab + HIPEC has significant efficacy in treating peritoneal effusion, improves the quality of life, and reduces serum lncRNA H19 and VEGF levels in OC patients, with fewer adverse reactions and higher safety.Impact statement The utilization of hyperthermic intraperitoneal chemotherapy (HIPEC) as an emerging treatment option for abdominal malignancies has garnered the attention of numerous researchers over the years, which has significant clinical effects on peritoneal effusion in ovarian cancer and can control patients' conditions and improve their signs and symptoms to a certain extent. In this paper, we investigated the efficacy and safety of intraperitoneal bevacizumab combined with hyperthermic intraperitoneal chemotherapy in the treatment of peritoneal effusion in ovarian cancer. Meanwhile, we compared serum lncRNA H19 and VEGF levels before and after treatment. Our findings may provide a clinically worthy method for the treatment of peritoneal effusion in ovarian cancer. The treatment method reduces serum lncRNA H19 and VEGF levels in patients, which provides a theoretical basis for further research.
Topics: Humans; Female; Bevacizumab; Vascular Endothelial Growth Factor A; Hyperthermic Intraperitoneal Chemotherapy; RNA, Long Noncoding; Ascitic Fluid; Quality of Life; Peritoneal Neoplasms; Hyperthermia, Induced; Antineoplastic Combined Chemotherapy Protocols; Ovarian Neoplasms; Combined Modality Therapy; Cytoreduction Surgical Procedures
PubMed: 37186893
DOI: 10.1080/01443615.2023.2204940 -
IScience Dec 2023A crucial requirement for metastasis formation in ovarian high-grade serous carcinoma (HGSC) is the disruption of the protective peritoneal mesothelium. Using co-culture...
A crucial requirement for metastasis formation in ovarian high-grade serous carcinoma (HGSC) is the disruption of the protective peritoneal mesothelium. Using co-culture systems of primary human cells, we discovered that tumor-associated NK cells induce TRAIL-dependent apoptosis in mesothelial cells via death receptors DR4 and DR5 upon encounter with activated T cells. Upregulation of TRAIL expression in NK cells concomitant with enhanced cytotoxicity toward mesothelial cells was driven predominantly by T-cell-derived TNFα, as shown by affinity proteomics-based analysis of the T cell secretome in conjunction with functional studies. Consistent with these findings, we detected apoptotic mesothelial cells in the peritoneal fluid of HGSC patients. In contrast to mesothelial cells, HGSC cells express negligible levels of both DR4 and DR5 and are TRAIL resistant, indicating cell-type-selective killing by NK cells. Our data point to a cooperative action of T and NK in breaching the mesothelial barrier in HGSC patients.
PubMed: 38047087
DOI: 10.1016/j.isci.2023.108401 -
Journal of Veterinary Diagnostic... Nov 2023Septic synovitis and peritonitis are routinely diagnosed in horses based on clinical examination findings and laboratory assessment of synoviocentesis and...
Septic synovitis and peritonitis are routinely diagnosed in horses based on clinical examination findings and laboratory assessment of synoviocentesis and abdominocentesis samples, respectively. Diagnosis is difficult in some cases because of an overlap in laboratory results for septic and non-septic inflammation. Neutrophil extracellular trap (NET) formation is part of the innate immune response against pathogens. Identifying and quantifying NETs, which have not been explored in clinical samples from horses with septic synovitis and peritonitis, to our knowledge, may be helpful in detecting infectious processes. Our main objective was to determine whether NETs could be visualized in septic equine synovial and peritoneal fluid cytology samples using immunofluorescence with antibodies against citrullinated histone H3 (Cit-H3) and myeloperoxidase (MPO). We analyzed 9 synovial and 4 peritoneal fluid samples. NET percentages were quantified using a simple counting technique, which is suitable for high-quality, well-preserved, and stained cytospin smears. NETs were evident in all septic samples and were absent in a non-septic sample; NETs were better visualized with Cit-H3 than with MPO immunolabeling. Overall, we believe that there is the potential for NETs and associated markers to be used to investigate and understand septic inflammation in horses.
Topics: Animals; Horses; Extracellular Traps; Ascitic Fluid; Synovitis; Inflammation; Peritonitis; Microscopy, Fluorescence; Neutrophils; Synovial Fluid; Horse Diseases
PubMed: 37661696
DOI: 10.1177/10406387231196552 -
International Journal of Molecular... Aug 2023Gynaecological serous carcinomas (GSCs) constitute a distinctive entity among female tumours characterised by a very poor prognosis. In addition to late-stage diagnosis...
Gynaecological serous carcinomas (GSCs) constitute a distinctive entity among female tumours characterised by a very poor prognosis. In addition to late-stage diagnosis and a high rate of recurrent disease associated with massive peritoneal carcinomatosis, the systematic acquisition of resistance to first-line chemotherapy based on platinum determines the unfavourable outcome of GSC patients. To explore the molecular mechanisms associated with platinum resistance, we generated patient-derived organoids (PDOs) from liquid biopsies of GSC patients. PDOs are emerging as a relevant preclinical model system to assist in clinical decision making, mainly from tumoural tissue and particularly for personalised therapeutic options. To approach platinum resistance in a GSC context, proficient PDOs were generated from the ascitic fluid of ovarian, primary peritoneal and uterine serous carcinoma patients in platinum-sensitive and platinum-resistant clinical settings from the uterine aspirate of a uterine serous carcinoma patient, and we also induced platinum resistance in vitro in a representative platinum-sensitive PDO. Histological and immunofluorescent characterisation of these ascites-derived organoids showed resemblance to the corresponding original tumours, and assessment of platinum sensitivity in these preclinical models replicated the clinical setting of the corresponding GSC patients. Differential gene expression profiling of a panel of 770 genes representing major canonical cancer pathways, comparing platinum-sensitive and platinum-resistant PDOs, revealed cellular response to DNA damage stimulus as the principal biological process associated with the acquisition of resistance to the first-line therapy for GSC. Additionally, candidate genes involved in regulation of cell adhesion, cell cycles, and transcription emerged from this proof-of-concept study. In conclusion, we describe the generation of PDOs from liquid biopsies in the context of gynaecological serous carcinomas to explore the molecular determinants of platinum resistance.
Topics: Humans; Female; Ascites; Organoids; Peritoneum; Ascitic Fluid; Cystadenocarcinoma, Serous
PubMed: 37686015
DOI: 10.3390/ijms241713208