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Nano Letters Sep 2023Peritoneal metastasis is very common in gastrointestinal, reproductive, and genitourinary tract cancers in late stages or postsurgery, causing poor prognosis, so...
Peritoneal metastasis is very common in gastrointestinal, reproductive, and genitourinary tract cancers in late stages or postsurgery, causing poor prognosis, so effective and nontoxic prophylactic strategies against peritoneal metastasis are highly imperative. Herein, we demonstrate the first gene transfection as a nontoxic prophylaxis preventing peritoneal metastasis or operative metastatic dissemination. Lipopolyplexes of TNF-related-apoptosis-inducing-ligand (TRAIL) transfected peritonea and macrophages to express TRAIL for over 15 days. The expressed TRAIL selectively induced tumor cell apoptosis while exempting normal tissue, providing long-term tumor surveillance. Therefore, tumor cells inoculated in the pretransfected peritoneal cavity quickly underwent apoptosis and, thus, barely formed tumor nodules, significantly prolonging the mouse survival time compared with chemotherapy prophylaxis. Furthermore, lipopolyplex transfection showed no sign of toxicity. Therefore, this peritoneal TRAIL-transfection is an effective and safe prophylaxis, preventing peritoneal metastasis.
Topics: Animals; Mice; Apoptosis Regulatory Proteins; Ligands; Peritoneal Neoplasms; Membrane Glycoproteins; Apoptosis; Tumor Necrosis Factor-alpha; Transfection; TNF-Related Apoptosis-Inducing Ligand; Receptors, TNF-Related Apoptosis-Inducing Ligand
PubMed: 37433066
DOI: 10.1021/acs.nanolett.3c01568 -
Modern Pathology : An Official Journal... Dec 2023The anaplastic lymphoma kinase (ALK) gene encodes a receptor tyrosine kinase, and fusions involving this gene have been reported in a variety of mesenchymal neoplasms....
The anaplastic lymphoma kinase (ALK) gene encodes a receptor tyrosine kinase, and fusions involving this gene have been reported in a variety of mesenchymal neoplasms. ALK-altered tumors with epithelioid morphology have been described in epithelioid inflammatory myofibroblastic sarcoma and epithelioid fibrous histiocytoma. Herein, we describe the clinicopathologic features of 7 ALK-rearranged mesenchymal tumors with epithelioid morphology occurring predominately in the pediatric population. Tumors occurred in 4 females and 3 males with an age ranging from 1 month to 28 years. Five tumors were superficial and solitary, while 1 presented with multiple peritoneal/omental nodules, and 1 presented as a large mediastinal mass. Morphologically, all tumors comprised epithelioid cells arranged in sheets, anastomosing cords, or small clusters embedded in a myxohyaline stroma. The cells had slightly variably sized ovoid nuclei with moderately prominent nucleoli and abundant eosinophilic cytoplasm. Four cases had sparse mitotic figures without necrosis. The remaining 3 tumors (2 deep and 1 superficial) had more than 10 mitoses per 10 high-power fields as well as foci of necrosis. ALK fusions were identified in all cases. The fusion partners included HMBOX1 (n = 1), VCL (n = 1), PRRC2B (n = 1), MYH10 (n = 1), STRN (n = 1), and EML4 (n = 2). One tumor recurred locally 2 years after initial resection; 1 patient had widely metastatic disease (mediastinal tumor). At the time of last follow-up (n = 6), 4 patients were alive without evidence of disease, 1 died due to complications of therapy (peritoneal tumor), and 1 was alive with disease. Our findings expand the spectrum of ALK-rearranged mesenchymal tumors. Our cases predominately occurred in older children and mainly exhibited epithelioid to round cell morphology, as opposed to spindle cell morphology. We also show that tumors in a deep location with higher-grade features follow a more aggressive clinical course.
Topics: Male; Female; Humans; Child; Anaplastic Lymphoma Kinase; Protein-Tyrosine Kinases; Neoplasm Recurrence, Local; Receptor Protein-Tyrosine Kinases; Sarcoma; Necrosis; Biomarkers, Tumor; Homeodomain Proteins
PubMed: 37726067
DOI: 10.1016/j.modpat.2023.100334 -
Antioxidants (Basel, Switzerland) Sep 2023Acute kidney injury and chronic kidney disease are among the most common non-communicable diseases in the developed world, with increasing prevalence. Patients with... (Review)
Review
Acute kidney injury and chronic kidney disease are among the most common non-communicable diseases in the developed world, with increasing prevalence. Patients with acute kidney injury are at an increased risk of developing chronic kidney disease. One of kidney injury's most common clinical sequelae is increased cardiovascular morbidity and mortality. In recent years, new insights into the pathophysiology of renal damage have been made. Oxidative stress is the imbalance favoring the increased generation of ROS and/or reduced body's innate antioxidant defense mechanisms and is of pivotal importance, not only in the development and progression of kidney disease but also in understanding the enhanced cardiovascular risk in these patients. This article summarizes and emphasizes the role of oxidative stress in acute kidney injury, various forms of chronic kidney disease, and also in patients on renal replacement therapy (hemodialysis, peritoneal dialysis, and after kidney transplant). Additionally, the role of oxidative stress in the development of drug-related nephrotoxicity and also in the development after exposure to various environmental and occupational pollutants is presented.
PubMed: 37760075
DOI: 10.3390/antiox12091772 -
Frontiers in Pharmacology 2023Apolipoprotein A-I (apoA-I), 90% of which is present in high-density lipoprotein (HDL), is the main constituent of HDL, has anti-inflammatory and anti-oxidant...
Apolipoprotein A-I (apoA-I), 90% of which is present in high-density lipoprotein (HDL), is the main constituent of HDL, has anti-inflammatory and anti-oxidant properties, and has received extensive attention in anti-atherosclerosis. Yet little is known about apoA-I 's role in peritoneal dialysis. In this study, by analyzing PD patients ( = 81), we found that decreased apoA/HDL-C ratio is significantly associated with rapid decline in peritoneal function. Further studies were performed in animal experiments to determine the ascendancy of apolipoprotein A-I mimetic peptide (D-4F) on peritoneum, we found that D-4F administration reduced peritoneal fibrosis and peritoneal endothelial mesenchymal transformation (EMT) induced by high glucose peritoneal dialysate, such as N-cadherin, Fibronectin, Vimentin, and α-smooth muscle actin (α-SMA) expression decreased. In mechanism, D-4F can significantly inhibit Smad2/3 phosphorylation, which is the major pathway leading to fibrosis. Furthermore, D-4F treatment inhibited NADPH oxidase and thiobarbituric acid reactive substances (TBARS) expression, increased the activity of certain enzymes, such as superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px). Finally, treatment with D-4F inhibits the expression of interleukins-6(IL-6), Interleukin-1β(IL-1β), and tumor necrosis factor-α(TNF-α). Taken together, based on the above research evidence, apoA-I and its peptide mimic may regulate the oxidative stress, TGF- β1/Smads signaling pathway and inflammatory response to reduce peritoneal fibrosis due to peritoneal dialysis.
PubMed: 37576813
DOI: 10.3389/fphar.2023.1106339 -
International Immunopharmacology Nov 2023Guggulsterone (GS) is a phytosterol used to treat inflammatory diseases. Although many studies have examined the anti-inflammatory activities of GS, the detailed...
Guggulsterone (GS) is a phytosterol used to treat inflammatory diseases. Although many studies have examined the anti-inflammatory activities of GS, the detailed mechanisms of GS in lipopolysaccharide (LPS)-induced inflammation and endotoxemia have not yet been examined. Therefore, we investigated the anti-inflammatory effects of GS on LPS-induced inflammation. In murine peritoneal macrophages, the anti-inflammatory activity of GS was primarily mediated by heme oxygenase-1 (HO-1) induction. HO-1 induction by GS was mediated by GSH depletion and reactive oxygen species (ROS) production. The ROS generated by GS caused the phosphorylation of GSK3β (ser9/21) and p38, leading to the translocation of nuclear factor erythroid-related factor 2 (Nrf2), which ultimately induced HO-1. In addition, GS pretreatment significantly inhibited inducible nitric oxide synthase (iNOS), iNOS-derived NO, and COX-2 protein and mRNA expression, and production of COX-derived prostaglandin PGE2, interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNF-α). In a mouse model of endotoxemia, GS treatment prolonged survival and inhibited the expression of inflammatory mediators, including IL-1β, IL-6, and TNF-α. GS treatment also inhibited LPS-induced liver injury. These results suggest that GS-induced HO-1 could exert anti-inflammatory effects via ROS-dependent GSK (ser21/9)-p38 phosphorylation and nuclear translocation of Nrf2.
Topics: Animals; Mice; Lipopolysaccharides; NF-kappa B; Interleukin-6; Tumor Necrosis Factor-alpha; Heme Oxygenase-1; NF-E2-Related Factor 2; Reactive Oxygen Species; Endotoxemia; Inflammation; Anti-Inflammatory Agents; Nitric Oxide Synthase Type II
PubMed: 37844468
DOI: 10.1016/j.intimp.2023.111073 -
Frontiers in Immunology 2023The recent discovery of TAK981(Subasumstat), the first-in-class selective inhibitor of SUMOylation, enables new immune treatments. TAK981 is already in clinical trials...
INTRODUCTION
The recent discovery of TAK981(Subasumstat), the first-in-class selective inhibitor of SUMOylation, enables new immune treatments. TAK981 is already in clinical trials to potentiate immunotherapy in metastatic tumors and hematologic malignancies. Cancer patients have more than ten times higher risk of infections, but the effects of TAK981 in sepsis are unknown and previous studies on SUMO in infections are conflicting.
METHODS
We used TAK981 in two sepsis models; polymicrobial peritonitis (CLP) and LPS endotoxemia. Splenectomy was done in both models to study the role of spleen. Western blotting of SUMO-conjugated proteins in spleen lysates was done. Global SUMO1 and SUMO3 knockout mice were used to study the specific SUMO regulation of inflammation in LPS endotoxemia. Splenocytes adoptive transfer was done from SUMO knockouts to wild type mice to study the role of spleen SUMOylation in experimental sepsis.
RESULTS AND DISCUSSION
Here, we report that inhibition of SUMOylation with TAK981 improved survival in mild polymicrobial peritonitis by enhancing innate immune responses and peritoneal bacterial clearance. Thus, we focused on the effects of TAK981 on the immune responses to bacterial endotoxin, showing that TAK981 enhanced early TNFα production but did not affect the resolution of inflammation. Splenectomy decreased serum TNFα levels by nearly 60% and TAK981-induced TNFα responses. In the spleen, endotoxemia induced a distinct temporal and substrate specificity for SUMO1 and SUMO2/3, and both were inhibited by TAK981. Global genetic depletion of SUMO1, but not SUMO3, enhanced TNFα production and metabolic acidosis. The transfer of SUMO1-null, but not wild-type, splenocytes into splenectomized wild-type mice exacerbated TNFα production and metabolic acidosis in endotoxemia.
CONCLUSION
These results suggest that specific regulation of splenic SUMO1 can modulate immune and metabolic responses to bacterial infection.
Topics: Animals; Mice; Endotoxemia; Lipopolysaccharides; Mice, Knockout; Peritonitis; Small Ubiquitin-Related Modifier Proteins; Spleen; Tumor Necrosis Factor-alpha; SUMO-1 Protein
PubMed: 37520526
DOI: 10.3389/fimmu.2023.1200939 -
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