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The Journal of Pharmacology and... Aug 2023The NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome is a multiprotein complex and component of the innate immune system that is activated by...
Pharmacology of a Potent and Novel Inhibitor of the NOD-Like Receptor Pyrin Domain-Containing Protein 3 (NLRP3) Inflammasome that Attenuates Development of Nonalcoholic Steatohepatitis and Liver Fibrosis.
The NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome is a multiprotein complex and component of the innate immune system that is activated by exogenous and endogenous danger signals to promote activation of caspase-1 and the maturation and release of the proinflammatory cytokines interleukin (IL)-1 and IL-18. Inappropriate activation of NLRP3 has been implicated in the pathophysiology of multiple inflammatory and autoimmune diseases, including cardiovascular disease, neurodegenerative diseases, and nonalcoholic steatohepatitis (NASH), thus increasing the clinical interest of this target. We describe in this study the preclinical pharmacologic, pharmacokinetic, and pharmacodynamic properties of a novel and highly specific NLRP3 inhibitor, JT001 (6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonylurea). In cell-based assays, JT001 potently and selectively inhibited NLRP3 inflammasome assembly, resulting in the inhibition of cytokine release and the prevention of pyroptosis, a form of inflammatory cell death triggered by active caspase-1. Oral administration of JT001 to mice inhibited IL-1 production in peritoneal lavage fluid at plasma concentrations that correlated with mouse in vitro whole blood potency. Orally administered JT001 was effective in reducing hepatic inflammation in three different murine models, including the CreT model of Muckle-Wells syndrome (MWS), a diet-induced obesity NASH model, and a choline-deficient diet-induced NASH model. Significant reductions in hepatic fibrosis and cell damage were also observed in the MWS and choline-deficient models. Our findings demonstrate that blockade of NLRP3 attenuates hepatic inflammation and fibrosis and support the use of JT001 to investigate the role of NLRP3 in other inflammatory disease models. SIGNIFICANCE STATEMENT: Persistent inflammasome activation is the consequence of inherited mutations of NLRP3 and results in the development of cryopyrin-associated periodic syndromes associated with severe systemic inflammation. NLRP3 is also upregulated in nonalcoholic steatohepatitis, a metabolic chronic liver disease currently missing a cure. Selective and potent inhibitors of NLRP3 hold great promise and have the potential to overcome an urgent unmet need.
Topics: Mice; Animals; Non-alcoholic Fatty Liver Disease; Inflammasomes; NLR Family, Pyrin Domain-Containing 3 Protein; NLR Proteins; Pyrin Domain; Liver Cirrhosis; Caspase 1; Inflammation; Choline; Interleukin-1beta
PubMed: 37308266
DOI: 10.1124/jpet.123.001639 -
Immunological Investigations Jul 2020The objectives of the study were to analyze the dosage of a cytokine panel (IL2, IL5, IL6, IL8, IL10, and TNF-α) in the peritoneal fluid and relate the dosage of these...
The objectives of the study were to analyze the dosage of a cytokine panel (IL2, IL5, IL6, IL8, IL10, and TNF-α) in the peritoneal fluid and relate the dosage of these cytokines to prognostic para- meters and survival in ovarian cancer. Peritoneal fluid was collected intraopera- tively from 29 patients with primary malignant ovarian neoplasia. Cytokine panel dosing was performed with ELISA. Comparisons of cytokines with prognostic factors were performed using the Wilcoxon-Mann-Whitney test. ROC curves were used to determine the cutoff value of NLR, PLR, and IL6. Univariate and multivariate analysis of disease-free survival (DFS) or overall survival (OS) were performed (Kaplan-Meier and Cox regression). The differences were considered significant when the value of p < .05. Higher levels of IL-6 were related to a neutrophil-lymphocyte ratio (NLR) >3.18 (p = .04), a platelet-lymphocyte ratio (PLR) >219.23 (p = .0051), CA-125 levels >35 U/mL (p = .0019), stage IIIC (p = .0203), and DFS ≤ 24 months (p = .0267). For IL-8, higher levels were related to PLR > 219.23 (p = .0426), and CA-125 >35 U/mL (p = .0292). In the univariate analysis, IL-6 levels ≥87.23 in peritoneal fluid had a relationship with shorter DFS at significance threshold (p = .05), and with a shorter OS (p = .039). Multivariate survival analysis proved that IL-6 level in the peritoneal fluid was an independent predictor of OS. Therefore, IL-6 and IL-8 in peritoneal lavage were related to poor prognostic factors. These cytokines may represent new biomarkers for ovarian cancer therapies.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Ascitic Fluid; Biomarkers, Tumor; Cytokines; Female; Humans; Interleukin-6; Interleukin-8; Lymphocytes; Middle Aged; Neoplasm Staging; Ovarian Neoplasms; Prognosis; Survival Analysis; Young Adult
PubMed: 31755326
DOI: 10.1080/08820139.2019.1691222 -
Cancer Diagnosis & Prognosis 2023Patients with pancreatic ductal adenocarcinoma (PDAC) with positive peritoneal lavage cytology (CY) reportedly have poor prognoses. However, the value of diagnosis of...
BACKGROUND/AIM
Patients with pancreatic ductal adenocarcinoma (PDAC) with positive peritoneal lavage cytology (CY) reportedly have poor prognoses. However, the value of diagnosis of suspicious for malignancy on CY is unknown. This study aimed to elucidate the prognostic impact of CY by focusing on CY subgroups.
PATIENTS AND METHODS
Data were collected from 231 resectable PDAC patients who underwent curative-intent resection. Patients were divided into three CY-based groups: negative (CY0), suspicious for malignancy (CY-S), and positive (CY1). Clinicopathological characteristics and prognostic factors were analyzed.
RESULTS
CY1 and CY-S were diagnosed in 7.8% and 3.9% of the patients, respectively. The CY1 group had significantly larger tumors and higher frequencies of distal tumors, anterior pancreatic tissue invasion, retropancreatic tissue invasion, and R1 resection than the CY0 group. Patient characteristics did not differ between the CY0 and CY-S groups. The CY1 group exhibited worse survival than the CY0 and CY-S groups (median survival time: 18.8 vs. 39.6 months, p=0.0021 and vs. 62.2 months, p=0.018). Multivariate analysis for survival indicated that a tumor size >2 cm, preoperative CA19-9 value >100 U/ml, CY1, lymph node metastasis, R1 resection, and lack of adjuvant chemotherapy were associated with poor prognosis. Both the CY1 and CY-S groups had higher frequencies of peritoneal recurrence than the CY0 group (50% vs. 11.8%, p<0.001 and 44.4% vs. 11.8%, p=0.019).
CONCLUSION
The prognosis of the CY1 group was poor. Although CY-S was associated with a higher frequency of peritoneal recurrence than CY0, the long-term outcomes of patients with surgical treatment were acceptable.
PubMed: 37168974
DOI: 10.21873/cdp.10221 -
PancreasThe aims of this review were to determine whether positive peritoneal lavage cytology (CY+) precludes radical resection in pancreatic cancer and to propose prospections... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVES
The aims of this review were to determine whether positive peritoneal lavage cytology (CY+) precludes radical resection in pancreatic cancer and to propose prospections for future studies.
METHODS
MEDLINE, Embase, and Cochrane Central were searched for related articles. Dichotomous variables and survival outcomes were analyzed with the estimation of odds ratio and hazards ratio (HR), respectively.
RESULTS
A total of 4905 patients were included, of which 7.8% were CY+. Positive peritoneal lavage cytology was correlated with poor overall survival (univariate survival analysis [HR, 2.35; P < 0.00001]; multivariate analysis [HR, 1.62; P < 0.00001]), poor recurrence-free survival (univariate survival analysis [HR, 2.50; P < 0.00001]; multivariate analysis [HR, 1.84; P < 0.00001]), and higher initial peritoneal recurrence rate (odds ratio, 5.49; P < 0.00001).
CONCLUSIONS
Although CY+ predicts poor prognosis and a higher risk of peritoneal metastasis after curative resection, it is not sufficient to preclude curative resection based on the current evidence, and high-quality trials should be conducted to assess the prognostic impact of operation among resectable CY+ patients. In addition, more sensitive and accurate methods to detect peritoneal exfoliated tumor cells and more effective comprehensive treatment for resectable CY+ pancreatic cancer patients are clearly warranted.
Topics: Humans; Cytology; Peritoneum; Pancreatic Neoplasms; Peritoneal Lavage; Peritoneal Neoplasms; Prognosis; Retrospective Studies
PubMed: 37099766
DOI: 10.1097/MPA.0000000000002163 -
Translational Oncology Feb 2022Intraperitoneal (i.p.) tumor dissemination and the consequent malignant ascites remain unpredictable and incurable in patients with gastrointestinal (GI) cancer, and...
Intraperitoneal (i.p.) tumor dissemination and the consequent malignant ascites remain unpredictable and incurable in patients with gastrointestinal (GI) cancer, and practical advances in diagnosis and treatment are urgently needed in the clinical settings. Here, we explored tumor biological and immunological mechanisms underlying the i.p. tumor progression for establishing more effective treatments. We established mouse tumor ascites models that murine and human colorectal cancer cells were both i.p. and subcutaneously (s.c.) implanted in mice, and analyzed peritoneal exudate cells (PECs) obtained from the mice. We then evaluated anti-tumor efficacy of agents targeting the identified molecular mechanisms using the ascites models. Furthermore, we validated the clinical relevancy of the findings using peritoneal lavage fluids obtained from gastric cancer patients. I.p. tumor cells were giant with large nuclei, and highly express AURKA, but less phosphorylated TP53, as compared to s.c. tumor cells, suggesting polyploidy-like cells. The i.p. tumors impaired phagocytic activity and the consequent T-cell stimulatory activity of CD11bGr1PD1 myeloid cells by GDF15 that is regulated by AURKA, leading to treatment resistance. Blocking AURKA with MLN8237 or siRNAs, however, abrogated the adverse events, and induced potent anti-tumor immunity in the ascites models. This treatment synergized with anti-PD1 therapy. The CD11bPD1 TAMs are also markedly expanded in the PECs of gastric cancer patients. These suggest AURKA is a determinant of treatment resistance of the i.p. tumors. Targeting the AURKA-GDF15 axis could be a promising strategy for improving clinical outcome in the treatment of GI cancer.
PubMed: 34902741
DOI: 10.1016/j.tranon.2021.101307 -
Frontiers in Immunology 2024Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest forms of cancer and peritoneal dissemination is one major cause for this poor prognosis. Exosomes have...
BACKGROUND
Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest forms of cancer and peritoneal dissemination is one major cause for this poor prognosis. Exosomes have emerged as promising biomarkers for gastrointestinal cancers and can be found in all kinds of bodily fluids, also in peritoneal fluid (PF). This is a unique sample due to its closeness to gastrointestinal malignancies. The receptor tyrosine kinase-like orphan receptor 1 (ROR1) has been identified as a potential biomarker in human cancers and represents a promising target for an immunotherapy approach, which could be considered for future treatment strategies. Here we prospectively analyzed the exosomal surface protein ROR1 (exo-ROR1) in PF in localized PDAC patients (PER-) on the one hand and peritoneal disseminated tumor stages (PER+) on the other hand followed by the correlation of exo-ROR1 with clinical-pathological parameters.
METHODS
Exosomes were isolated from PF and plasma samples of non-cancerous (NC) (n = 15), chronic pancreatitis (CP) (n = 4), localized PDAC (PER-) (n = 18) and peritoneal disseminated PDAC (PER+) (n = 9) patients and the surface protein ROR1 was detected via FACS analysis. Additionally, soluble ROR1 in PF was analyzed. ROR1 expression in tissue was investigated using western blots (WB), qPCR, and immunohistochemistry (IHC). Exosome isolation was proven by Nano Tracking Analysis (NTA), WB, Transmission electron microscopy (TEM), and BCA protein assay. The results were correlated with clinical data and survival analysis was performed.
RESULTS
PDAC (PER+) patients have the highest exo-ROR1 values in PF and can be discriminated from NC (p <0.0001), PDAC (PER-) (p <0.0001), and CP (p = 0.0112). PDAC (PER-) can be discriminated from NC (p = 0.0003). In plasma, exo-ROR1 is not able to distinguish between the groups. While there is no expression of ROR1 in the exocrine pancreatic tissue, PDAC and peritoneal metastasis show expression of ROR1. High exo-ROR1 expression in PF is associated with lower overall survival (p = 0.0482).
CONCLUSION
With exo-ROR1 in PF we found a promising diagnostic and prognostic biomarker possibly discriminating between NC, PDAC (PER-) and PDAC (PER+) and might shed light on future diagnostic and therapeutic concepts in PDAC.
Topics: Humans; Receptor Tyrosine Kinase-like Orphan Receptors; Exosomes; Male; Ascitic Fluid; Pancreatic Neoplasms; Female; Carcinoma, Pancreatic Ductal; Middle Aged; Biomarkers, Tumor; Prognosis; Aged; Peritoneal Neoplasms; Adult; Prospective Studies
PubMed: 38846943
DOI: 10.3389/fimmu.2024.1253072 -
Surgery Apr 2021Open abdominal surgery is frequently related to excessive inflammation and a compromised intestinal barrier, leading to poor clinical outcomes. The administration of...
BACKGROUND
Open abdominal surgery is frequently related to excessive inflammation and a compromised intestinal barrier, leading to poor clinical outcomes. The administration of beta-1 blocker has been shown to effectively reduce inflammation and preserve intestinal barrier function in patients with sepsis, shock, or other critical illnesses. The underlying mechanism of these effects may be associated with the autonomic nervous system's activation via cholecystokinin receptors. This study aimed to investigate the effect of beta-1 blocker on systemic and local inflammatory responses and the intestinal barrier function in the context of open abdominal surgery.
METHODS
A rat model of open abdominal surgery was induced through peritoneal air exposure for 3 hours and treated via gavage with the beta-1 blocker, metoprolol, or saline. Cholecystokinin-receptor antagonists were administered before the metoprolol treatment. Peritoneal lavage fluid, serum, and tissues were collected 24 hours after surgery to determine systemic and local inflammation and intestinal integrity.
RESULTS
The intervention with metoprolol significantly reduced serum tumor necrosis factor-alpha and interleukin-6 (P < .05) and peritoneal interleukin-6 (P < .01) compared with those of animals treated with saline. The intestinal myeloperoxidase indicating the influx of neutrophils was also significantly prevented by the administration of metoprolol (P < .05). Above all, this intervention resulted in a significant decrease in serum D-lactate and intestinal fatty acid-binding protein, intestinal permeability, bacterial translocation, and Chiu's score for intestinal mucosa injury (P < .05). However, the anti-inflammatory and intestinal integrity protective effects of metoprolol were prevented by the blockage of cholecystokinin receptors (P < .05).
CONCLUSION
Our data indicate that beta-1 blocker reduces systemic and local inflammatory responses and preserves intestinal barrier function after open abdominal surgery through a mechanism that depends on cholecystokinin receptors. Clinically, these findings imply that perioperative intervention with a beta-1 blocker may be an effective new therapy to enhance recovery after open abdominal surgery.
Topics: Abdomen; Adrenergic beta-1 Receptor Antagonists; Animals; Anti-Inflammatory Agents; Cytokines; Digestive System Surgical Procedures; Disease Models, Animal; Inflammation Mediators; Intestinal Mucosa; Male; Metoprolol; Permeability; Postoperative Care; Postoperative Complications; Rats
PubMed: 33303271
DOI: 10.1016/j.surg.2020.11.004 -
Surgical Laparoscopy, Endoscopy &... Mar 2021Some reports asserted that the stimulation of ultrasonic scalpel and the persistent state of carbon dioxide (CO2) pneumoperitoneum in laparoscopic surgery may affect the...
BACKGROUND
Some reports asserted that the stimulation of ultrasonic scalpel and the persistent state of carbon dioxide (CO2) pneumoperitoneum in laparoscopic surgery may affect the adhesion and invasion of gastric cancer (GC) cells. This study aimed to reveal the effects of laparoscopic radical gastrectomy on peritoneal micrometastases (PM) of GC.
MATERIALS AND METHODS
Fifty-three patients who underwent laparoscopic radical gastrectomy for GC were enrolled in the study. The expressions of carcinoembryonic antigen (CEA) mRNA and dopa decarboxylase (DDC) mRNA in peritoneal lavage fluid were detected by reverse transcription-polymerase chain reaction. The positive rates of CEA mRNA and DDC mRNA in preoperative peritoneal lavage fluid (pre-CEA, pre-DDC) were compared with those in postoperative lavage fluid (post-CEA, post-DDC). The correlation between the expressions of pre-CEA and pre-DDC and clinicopathologic factors and disease-free survival was analyzed.
RESULTS
There was no significant difference in the positive rates of pre-CEA and pre-DDC compared with those of post-CEA and post-DDC (all P>0.05). The positive rates of pre-CEA and pre-DDC increased with the increase of TNM stage, deepening of invasion, lymph node metastasis, and serosal invasion (all P<0.05), but had no correlation with tumor location, size, degree of differentiation, nerve invasion, and vascular invasion (all P>0.05). The disease-free survival in the combined positive patients was lower than that in the negative patients.
CONCLUSIONS
Laparoscopic radical gastrectomy for GC is safe and feasible, without increasing the risk of PM. The PM of GC may be associated with late tumor stage, deep infiltration, lymph node metastasis, and serosal invasion.
Topics: Gastrectomy; Humans; Laparoscopy; Neoplasm Micrometastasis; Peritoneal Lavage; Prognosis; Stomach Neoplasms
PubMed: 33788822
DOI: 10.1097/SLE.0000000000000930 -
Journal of Gastrointestinal Cancer Mar 2024Extensive intraperitoneal lavage (EIPL) is a novel therapeutic intervention that aims to limit the chance of peritoneal metastasis during gastrectomy. Clinical... (Meta-Analysis)
Meta-Analysis Review
PURPOSE
Extensive intraperitoneal lavage (EIPL) is a novel therapeutic intervention that aims to limit the chance of peritoneal metastasis during gastrectomy. Clinical trials on using EIPL after gastrectomy show controversial results. We aimed to summarize the evidence of efficacy and safety for using EIPL after gastrectomy to limit the possibility of peritoneal metastasis and improve survival.
METHODS
A literature search on PubMed, Scopus, Embase, and Web of Sciences was conducted till June 2023 to identify eligible RCTs that assess the efficacy and safety of EIPL after gastrectomy. The hazard ratio with 95% CI was used to determine the survival probability, the risk ratio with 95% CI was used to assess the surgical outcomes, and ROB-2 and GRADE guidelines were used to assess the risk of bias and the certainty of evidence respectively.
RESULTS
Six eligible studies with a total of 1993 patients were included in the meta-analysis. Regarding survival benefits, the survival of the EIPL group did not differ significantly from the non-EIPL group, and the pooled HR of overall survival was 0.86 (95% CI 0.58-1.26) P = 0.44, the disease-free survival was 0.81 (0.58-1.13) P = 0.21, and peritoneal recurrence-free survival was 0.97 (0.79-1.2) P = 0.25. There is no significant association between EIPL and short-term postoperative outcomes. The use of EIPL does not appear to affect postoperative mortality, infection, anastomotic leakage, bleeding, ileus, or hospital stay.
CONCLUSION
Our study yielded insufficient evidence about the survival benefits and surgical outcomes of EIPL in patients with gastric cancer after gastrectomy. Therefore, it is not recommended for treating gastric cancer patients.
Topics: Stomach Neoplasms; Humans; Peritoneal Lavage; Gastrectomy; Peritoneal Neoplasms; Treatment Outcome
PubMed: 37750984
DOI: 10.1007/s12029-023-00971-y -
Oxidative Medicine and Cellular... 2021Postoperative peritoneal adhesions are considered the major complication following abdominal surgeries. The primary clinical complications of peritoneal adhesion are...
Postoperative peritoneal adhesions are considered the major complication following abdominal surgeries. The primary clinical complications of peritoneal adhesion are intestinal obstruction, infertility, pelvic pain, and postoperative mortality. In this study, regarding the anti-inflammatory and antioxidant activities of we aimed to evaluate the effects of on the prevention of postsurgical-induced peritoneal adhesion. Male Wistar-Albino rats were used to investigate the preventive effects of extract (0.5%, 0.25% and 0.125% /) against postsurgical-induced peritoneal adhesion compared to pirfenidone (PFD, 7.5% /). We also investigated the protective effects of PFD (100 g/ml) and extract (100, 200, and 400 g/ml) in TGF-1-induced fibrotic macrophage polarization. The levels of cell proliferation and oxidative, antioxidative, inflammatory and anti-inflammatory, fibrosis, and angiogenesis biomarkers were evaluated both and models. extract ameliorates postoperational-induced peritoneal adhesion development by attenuating oxidative stress [malondialdehyde (MDA)]; inflammatory mediators [interleukin- (IL-) 6, tumour necrosis factor- (TNF-) , and prostaglandin E (PGE)]; fibrosis [transforming growth factor- (TGF-) 1, IL-4, and plasminogen activator inhibitor (PAI)]; and angiogenesis [vascular endothelial growth factor (VEGF)] markers, while propagating antioxidant [glutathione (GSH)], anti-inflammatory (IL-10), and fibrinolytic [tissue plasminogen activator (tPA)] markers and tPA/PAI ratio. In a cellular model, we revealed that the extract, without any toxicity, regulated the levels of cell proliferation and inflammatory (TNF-), angiogenesis (VEGF), anti-inflammatory (IL-10), M1 [inducible nitric oxide synthase (iNOS)] and M2 [arginase-1 (Arg 1)] biomarkers, and iNOS/Arg-1 ratio towards antifibrotic M1 phenotype of macrophage, in a concentration-dependent manner. Taken together, the current study indicated that reduces peritoneal adhesion formation by modulating the macrophage polarization from M2 towards M1 cells.
Topics: Animals; Crocus; Disease Models, Animal; Humans; Male; Peritoneum; Postoperative Period; Rats; Therapeutic Irrigation
PubMed: 34956439
DOI: 10.1155/2021/5945101