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Aging Jun 2024Microbial infection-induced sepsis causes excessive inflammatory response and multiple organ failure. An effective strategy for the treatment of sepsis-related syndromes...
Microbial infection-induced sepsis causes excessive inflammatory response and multiple organ failure. An effective strategy for the treatment of sepsis-related syndromes is still needed. Rosuvastatin, a typical β-hydroxy β-methylglutaryl-CoA reductase inhibitor licensed for reducing the levels of low-density lipoprotein cholesterol in patients with hyperlipidemia, has displayed anti-inflammatory capacity in different types of organs and tissues. However, its effects on the development of sepsis are less reported. Here, we found that the administration of Rosuvastatin reduced the mortality of sepsis mice and prevented body temperature loss. Additionally, it inhibited the production of inflammatory cytokines such as tumor necrosis factor (TNF-α), Interleukin-6 (IL-6), interleukin-1β (IL-1β), and migration inhibitory factor (MIF) in peritoneal lavage supernatants of animals. The increased number of mononuclear cells in the peritoneum of sepsis mice was reduced by Rosuvastatin. Interestingly, it ameliorated lung inflammation and improved the hepatic and renal function in the sepsis animals. Further experiments show that Rosuvastatin inhibited lipopolysaccharide (LPS)-induced production of proinflammatory cytokines in RAW 264.7 macrophages by preventing the activation of nuclear factor kappa-B (NF-κB). Our findings demonstrate that the administration of Rosuvastatin hampered organ dysfunction and mitigated inflammation in a relevant model of sepsis.
PubMed: 38885061
DOI: 10.18632/aging.205937 -
Ulusal Travma Ve Acil Cerrahi Dergisi =... Jun 2024This study evaluated the use of metformin or pioglitazone in preventing or reducing the development of post-operative intra-abdominal adhesion (PIAA) by employing...
BACKGROUND
This study evaluated the use of metformin or pioglitazone in preventing or reducing the development of post-operative intra-abdominal adhesion (PIAA) by employing histopathological, immunohistochemical, and biochemical analyses in an experimental adhesion model.
METHODS
Fifty Wistar-Albino rats were divided into five groups: Group I (Control), Group II (Sham Treatment), Group III (Hy-aluronic Acid), Group IV (Metformin), and Group V (Pioglitazone). Adhesions were induced in the experimental groups, except for the sham group, using the scraping method. After 10 days, rats were euthanized for evaluation. Macroscopic adhesion degrees were assessed using Nair's scoring system. Immunohistochemical and enzyme-linked immunosorbent assay (ELISA) methods were utilized to assess serum, peritoneal lavage, and intestinal tissue samples. Fructosamine, interleukin-6 (IL-6), transforming growth factor-beta (TGF-β), and fibronectin levels were measured in serum and peritoneal lavage samples.
RESULTS
The groups exhibited similar Nair scores and Type I or Type III Collagen staining scores (all, p>0.05). Pioglitazone significantly reduced serum IL-6 and TGF-β levels compared to controls (p=0.002 and p=0.008, respectively). Both metformin and pioglitazone groups showed elevated IL-6 in peritoneal lavage relative to controls, while fibronectin levels in the lavage were lower in pioglitazone-treated rats compared to the sham group (all, p<0.005).
CONCLUSION
Pioglitazone, but not metformin, demonstrated a positive biochemical impact on preventing PIAA formation in an experimental rat model, although histological impacts were not observed. Further experimental studies employing different dose/duration regimens of pioglitazone are needed to enhance our understanding of its effect on PIAA formation.
Topics: Animals; Pioglitazone; Metformin; Tissue Adhesions; Rats, Wistar; Rats; Disease Models, Animal; Hypoglycemic Agents; Male; Thiazolidinediones; Postoperative Complications
PubMed: 38863295
DOI: 10.14744/tjtes.2024.61732 -
Intensive Care Medicine Experimental Jun 2024Dipeptidyl peptidase 3 (DPP3) is a ubiquitous cytosolic enzyme released into the bloodstream after tissue injury, that can degrade angiotensin II. High concentrations of...
BACKGROUND
Dipeptidyl peptidase 3 (DPP3) is a ubiquitous cytosolic enzyme released into the bloodstream after tissue injury, that can degrade angiotensin II. High concentrations of circulating DPP3 (cDPP3) have been associated with worse outcomes during sepsis. The aim of this study was to assess the effect of Procizumab (PCZ), a monoclonal antibody that neutralizes cDPP3, in an experimental model of septic shock.
METHODS
In this randomized, open-label, controlled study, 16 anesthetized and mechanically ventilated pigs with peritonitis were randomized to receive PCZ or standard treatment when the mean arterial pressure (MAP) dropped below 50 mmHg. Resuscitation with fluids, antimicrobial therapy, peritoneal lavage, and norepinephrine was initiated one hour later to maintain MAP between 65-75 mmHg for 12 h. Hemodynamic variables, tissue oxygenation indices, and measures of organ failure and myocardial injury were collected. Organ blood flow was assessed using isotopic assessment (technetium albumin). cDPP3 activity, equilibrium analysis of the renin-angiotensin system and circulating catecholamines were measured. Tissue mRNA expression of interleukin-6 and downregulation of adrenergic and angiotensin receptors were assessed on vascular and myocardial samples.
RESULTS
PCZ-treated animals had reduced cDPP3 levels and required less norepinephrine and fluid than septic control animals for similar organ perfusion and regional blood flow. PCZ-treated animals had less myocardial injury, and higher PaO/FiO ratios. PCZ was associated with lower circulating catecholamine levels; higher circulating angiotensin II and higher angiotensin II receptor type 1 myocardial protein expression, and with lower myocardial and radial artery mRNA interleukin-6 expression.
CONCLUSIONS
In an experimental model of septic shock, PCZ administration was associated with reduced fluid and catecholamine requirements, less myocardial injury and cardiovascular inflammation, along with preserved angiotensin II signaling.
PubMed: 38849640
DOI: 10.1186/s40635-024-00638-3 -
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 -
Saudi Pharmaceutical Journal : SPJ :... Jun 2024Post-operative peritoneal adhesions (PA) are a common and important clinical problem. In this study, we focused on the ameliorative efficacy of ginger and gingerol...
Intra-peritoneal lavage of rhizome and its active constituent gingerol impede inflammation, angiogenesis, and fibrosis following post-operative peritoneal adhesion in male rats.
Post-operative peritoneal adhesions (PA) are a common and important clinical problem. In this study, we focused on the ameliorative efficacy of ginger and gingerol compounds on surgical-induced peritoneal adhesion, and their strategies that disrupted the PA formation pathways to suppress their incidence. First, liquid chromatography-mass spectrometry (LC-MS) was established to separate and identify several chemical groups of ginger rhizome extract. In the next steps, male Wistar albino rats were randomly selected and divided into various groups, namely sham, control, ginger extract (0.6, 1.8, 5 %w/v), and gingerol (0.05, 0.1, 0.3, and 1 %w/v). Finally, we investigated the macroscopic parameters such as wound healing, body weight as well as spleen height and weight. In addition, visual peritoneal adhesion assessment was performed via Nair et al and Adhesion Scoring Scheme. Moreover, the microscopic parameters and biological assessment was performed via and immunoassays. The present findings revealed significant improvement in wound healing and reduction of the adhesion range, as Nair et al. and Adhesion Scoring Scheme scoring, in both the ginger and gingerol groups compared to the PA group (). Whereas, gingerol (0.3 % w/v) was able to increase the body weight in rats () at end stage of experiment. Also, inflammation, angiogenesis, and fibrosis were significantly decreased due to the downregulation of interleukin (IL)-6, tumor necrosis factor (TNF)-α, transforming growth factor (TGF)-β1, vascular endothelial growth factor (VEGF), respectively, in the ginger and gingerol groups compared to the PA group (). In contrast, the levels of IL-10 were increased in the ginger and gingerol groups compared to the control group (). Our results proved that ginger rhizome and gingerol, as novel therapeutic compounds, could be used to prevent PA for their beneficial anti-inflammatory as well as anti-fibrosis properties in clinical trials. However, further clinical studies are required to approve the effectiveness of ginger and gingerol.
PubMed: 38737808
DOI: 10.1016/j.jsps.2024.102092 -
Scientific Reports May 2024Endothelial glycocalyx (eGC) covers the inner surface of the vessels and plays a role in vascular homeostasis. Syndecan is considered the "backbone" of this structure....
Endothelial glycocalyx (eGC) covers the inner surface of the vessels and plays a role in vascular homeostasis. Syndecan is considered the "backbone" of this structure. Several studies have shown eGC shedding in sepsis and its involvement in organ dysfunction. Matrix metalloproteinases (MMP) contribute to eGC shedding through their ability for syndecan-1 cleavage. This study aimed to investigate if doxycycline, a potent MMP inhibitor, could protect against eGC shedding in lipopolysaccharide (LPS)-induced sepsis and if it could interrupt the vascular hyperpermeability, neutrophil transmigration, and microvascular impairment. Rats that received pretreatment with doxycycline before LPS displayed ultrastructural preservation of the eGC observed using transmission electronic microscopy of the lung and heart. In addition, these animals exhibited lower serum syndecan-1 levels, a biomarker of eGC injury, and lower perfused boundary region (PBR) in the mesenteric video capillaroscopy, which is inversely related to the eGC thickness compared with rats that only received LPS. Furthermore, this study revealed that doxycycline decreased sepsis-related vascular hyperpermeability in the lung and heart, reduced neutrophil transmigration in the peritoneal lavage and inside the lungs, and improved some microvascular parameters. These findings suggest that doxycycline protects against LPS-induced eGC shedding, and it could reduce vascular hyperpermeability, neutrophils transmigration, and microvascular impairment.
Topics: Glycocalyx; Animals; Sepsis; Doxycycline; Rats; Male; Lipopolysaccharides; Capillary Permeability; Lung; Syndecan-1; Rats, Wistar; Endothelium, Vascular; Endothelial Cells; Neutrophils; Matrix Metalloproteinase Inhibitors
PubMed: 38714743
DOI: 10.1038/s41598-024-60919-5 -
The British Journal of Surgery May 2024Laparoscopic lavage (LPL) has been suggested for treatment of non-feculent perforated diverticulitis. In this observational study, the surgical treatment of diverticular... (Observational Study)
Observational Study
BACKGROUND
Laparoscopic lavage (LPL) has been suggested for treatment of non-feculent perforated diverticulitis. In this observational study, the surgical treatment of diverticular disease in Sweden outside prospective trials was investigated.
METHODS
This population-based study used the National Patient Register to identify all patients in Sweden with emergency admissions for diverticular disease, as defined by ICD codes from July 2014 to December 2020. Demographics, surgical procedures and outcomes were assessed. In addition, register data since 1997 were retrieved to assess co-morbidities, previous abdominal surgeries, and previous admissions for diverticular disease.
RESULTS
Among 47 294 patients with emergency hospital admission, 2035 underwent LPL (427 patients) or sigmoid resection (SR, 1608 patients) for diverticular disease. The mean follow-up was 30.8 months. Patients selected for LPL were younger, healthier and with less previous abdominal surgery for diverticular disease than those in the SR group (P < 0.01). LPL was associated with shorter postoperative hospital stay (mean 9.4 versus 14.9 days, P < 0.001) and lower 30-day mortality (3.5% versus 8.7%, P < 0.001). Diverticular disease-associated subsequent surgery was more common in the SR group than the LPL group except during the first year (P < 0.001). LPL had a lower mortality rate during the study period (stratified HR 0.70, 95% c.i. 0.53-0.92, P = 0.023).
CONCLUSION
Laparoscopic lavage constitutes a safe alternative to sigmoid resection for selected patients judged clinically to require surgery.
Topics: Humans; Male; Female; Laparoscopy; Aged; Sweden; Peritoneal Lavage; Middle Aged; Registries; Intestinal Perforation; Diverticulitis, Colonic; Length of Stay; Treatment Outcome; Aged, 80 and over
PubMed: 38713610
DOI: 10.1093/bjs/znae109 -
Scientific Reports May 2024In pancreatic ductal adenocarcinoma (PDAC) patients, the importance of peritoneal lavage cytology, which indicates unresectability, remains controversial. This study...
In pancreatic ductal adenocarcinoma (PDAC) patients, the importance of peritoneal lavage cytology, which indicates unresectability, remains controversial. This study sought to determine whether positive peritoneal lavage cytology (CY+) precludes pancreatectomy. Furthermore, we propose a novel liquid biopsy using peritoneal lavage fluid to detect viable peritoneal tumor cells (v-PTCs) with TelomeScan F35, a telomerase-specific replication-selective adenovirus engineered to express green fluorescent protein. Resectable cytologically or histologically proven PDAC patients (n = 53) were enrolled. CY was conducted immediately following laparotomy. The resulting fluid was examined by conventional cytology (conv-CY; Papanicolaou staining and MOC-31 immunostaining) and by the novel technique (Telo-CY; using TelomeScan F35). Of them, 5 and 12 were conv-CY+ and Telo-CY+, respectively. All underwent pancreatectomy. The two double-CY+ (conv-CY+ and Telo-CY+) patients showed early peritoneal recurrence (P-rec) postoperatively, despite adjuvant chemotherapy. None of the three conv-CY+ Telo-CY- patients exhibited P-rec. Six of the 10 Telo-CY+ conv-CY- patients (60%) relapsed with P-rec. Of the remaining 38 double-CY- [conv-CY-, Telo-CY-, conv-CY± (Class III)] patients, 3 (8.3%) exhibited P-rec. Although conv-CY+ status predicted poor prognosis and a higher risk of P-rec, Telo-CY was more sensitive for detecting v-PTC. Staging laparoscopy and performing conv-CY and Telo-CY are needed to confirm the indication for pancreatectomy.
Topics: Humans; Peritoneal Lavage; Pancreatic Neoplasms; Male; Female; Aged; Middle Aged; Pancreatectomy; Carcinoma, Pancreatic Ductal; Cytodiagnosis; Aged, 80 and over; Neoplasm Recurrence, Local; Liquid Biopsy; Peritoneal Neoplasms; Adult; Cytology
PubMed: 38702437
DOI: 10.1038/s41598-024-60936-4 -
World Journal of Gastrointestinal... Apr 2024With less than 90 reported cases to date, stercoral perforation of the colon is a rare occurrence. Stercoral ulceration is thought to occur due to ischemic pressure...
BACKGROUND
With less than 90 reported cases to date, stercoral perforation of the colon is a rare occurrence. Stercoral ulceration is thought to occur due to ischemic pressure necrosis of the bowel wall, which is caused by the presence of a stercoraceous mass. To underscore this urgent surgical situation concerning clinical presentation, surgical treatment, and results, we present the case of a 66-year-old man with a stercoral perforation.
CASE SUMMARY
A 66-year-old man with a history of hypertension, hyperlipidemia, and gout presented at the emergency department with lower abdominal pain and a low-grade fever lasting for a few hours. Abdominal computed tomography indicated a suspected bezoar (approximately 7.6 cm) in the dilated cecum, accompanied by pericolic fat stranding, mild proximal dilatation of the ileum, pneumoperitoneum, and minimal ascites. Intraoperatively, feculent peritonitis with isolated cecal perforation were observed. Consequently, a right hemicolectomy with peritoneal lavage was performed. A histopathological examination supported the intraoperative findings.
CONCLUSION
In stercoral perforations, a diagnosis should be diligently pursued, especially in older adults, and prompt surgical intervention should be implemented.
PubMed: 38690055
DOI: 10.4240/wjgs.v16.i4.1189 -
Cellular & Molecular Biology Letters Apr 2024Macrophage proinflammatory activation contributes to the pathology of severe acute pancreatitis (SAP) and, simultaneously, macrophage functional changes, and increased...
Mitochondrial (mt)DNA-cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling promotes pyroptosis of macrophages via interferon regulatory factor (IRF)7/IRF3 activation to aggravate lung injury during severe acute pancreatitis.
BACKGROUND
Macrophage proinflammatory activation contributes to the pathology of severe acute pancreatitis (SAP) and, simultaneously, macrophage functional changes, and increased pyroptosis/necrosis can further exacerbate the cellular immune suppression during the process of SAP, where cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) plays an important role. However, the function and mechanism of cGAS-STING in SAP-induced lung injury (LI) remains unknown.
METHODS
Lipopolysaccharide (LPS) was combined with caerulein-induced SAP in wild type, cGAS and sting mice. Primary macrophages were extracted via bronchoalveolar lavage and peritoneal lavage. Ana-1 cells were pretreated with LPS and stimulated with nigericin sodium salt to induce pyroptosis in vitro.
RESULTS
SAP triggered NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome activation-mediated pyroptosis of alveolar and peritoneal macrophages in mouse model. Knockout of cGAS/STING could ameliorate NLRP3 activation and macrophage pyroptosis. In addition, mitochondrial (mt)DNA released from damaged mitochondria further induced macrophage STING activation in a cGAS- and dose-dependent manner. Upregulated STING signal can promote NLRP3 inflammasome-mediated macrophage pyroptosis and increase serum interleukin (IL)-6, IL-1β, and tumor necrosis factor (TNF)-α levels and, thus, exacerbate SAP-associated LI (SAP-ALI). Downstream molecules of STING, IRF7, and IRF3 connect the mtDNA-cGAS-STING axis and the NLRP3-pyroptosis axis.
CONCLUSIONS
Negative regulation of any molecule in the mtDNA-cGAS-STING-IRF7/IRF3 pathway can affect the activation of NLRP3 inflammasomes, thereby reducing macrophage pyroptosis and improving SAP-ALI in mouse model.
Topics: Animals; Pyroptosis; Interferon Regulatory Factor-3; Mice; Signal Transduction; DNA, Mitochondrial; Membrane Proteins; Nucleotidyltransferases; Pancreatitis; Macrophages; Lung Injury; Interferon Regulatory Factor-7; Mice, Inbred C57BL; Mice, Knockout; NLR Family, Pyrin Domain-Containing 3 Protein; Inflammasomes; Lipopolysaccharides; Male; Disease Models, Animal
PubMed: 38671352
DOI: 10.1186/s11658-024-00575-9