Intense Inflammatory Response Research Articles

VDAC1-NF-κB/p65-mediated S100A16 contributes to myocardial ischemia/reperfusion injury by regulating oxidative stress and inflammatory response via Calmodulin/CaMKK2/AMPK pathway

Myocardial injury triggers intense inflammatory reactions and oxidative stress responses. S100 calcium-binding protein A16 (S100A16), a multi-functional calcium (Ca2+)-binding protein, participates in inflammatory responses and contributes to ischemia/reperfusion (I/R) injury. Nevertheless, the precise mechanism by which S100A16 operates in myocardial I/R injury remains uncertain. Cardiac I/R injury was produced by ligation/release of the left anterior descending artery, and mouse cardiac cells were subjected to hypoxia/reoxygenation (H/R) to determine the biological effects in vitro. We demonstrated that S100A16 was upregulated in the ischemic hearts and cardiac cells after I/R and H/R injury. Adenovirus-mediated S100A16 inhibition led to a considerable improvement in cardiac function with a reduced infarct size, accompanied by a reduction in cardiomyocyte apoptosis. Similar effects of S100A16 inhibition on inflammation and reactive oxygen species (ROS) production were observed in cultured cardiomyocytes. Importantly, we showed that I/R and H/R treatment upregulated the expression of voltage-dependent anion channel 1 (VDAC1), which subsequently activated NF-κB/p65 to facilitate the binding of NF-κB/p65 to the S100A16 promoter, thereby activating the transcription and expression of S100A16. Mechanically, S100A16 responded to increasing Ca2+ and interacted with calmodulin (CaM) to regulate the activation of calcium/calmodulin-dependent protein kinase 2 (CAMKK2)/AMPK pathway. In conclusion, VDAC1 sustained the NF-κB p65 pathway activation to elicit increased S100A16 expression, contributing to myocardial damage and heart failure post-I/R via the CaM/CaMKK2/AMPK pathway. This study revealed a crucial role of the VDAC1-S100A16 axis in the process of myocardial I/R injury, providing novel molecular targets for the treatment of cardiac conditions associated with I/R injury.

CCR1 Antagonist as a Potential Modulator of Inflammatory, Autophagic, and Apoptotic Markers in Spinal Cord Injury

Spinal cord injury (SCI) leads to severe and lasting impairments in motor and sensory functions. The intense inflammatory response following SCI is a significant challenge, and autophagy has emerged as a key factor in the recovery process. The C-C chemokine receptor type 1 (CCR1), a G-protein coupled receptor, plays a crucial role in managing the chemokine response under stress. BX471, a selective and potent CCR1 antagonist, has been explored in various disease contexts for its therapeutic potential. In this study, we assessed the effects of BX471 in a mouse model of SCI. The treatment was administered at doses of 3 and 10 mg/kg, 1 hour and 6 hours after the injury occurred. Results showed that BX471 significantly improved tissue structure by positively influencing autophagy and reducing inflammation. Inflammatory markers, including CCR1 ligands RANTES, MIP-1α, TNF-α, and IL-1β, were measured using Western blot analysis. Additionally, histological evaluations revealed that BX471 effectively decreased infiltration and reduced astrocyte and microglial activation, supporting the idea that enhancing autophagy through CCR1 inhibition could promote neuronal survival. The highest efficacy was observed at the 10 mg/kg dose, leading to optimal out-comes across the assessments. These findings suggest that CCR1 blockade with BX471 may offer a promising therapeutic strategy for SCI, addressing a critical gap in the current pharmacological treatment options.

The Potential of Glucosinolates and Their Hydrolysis Products as Inhibitors of Cytokine Storms

A cytokine storm is an intense inflammatory response characterized by the overproduction of proinflammatory cytokines, resulting in tissue damage, and organ dysfunction. Cytokines play a crucial role in various conditions, such as coronavirus disease, in which the immune system becomes overactive and releases excessive levels of cytokines, including interleukins, tumor necrosis factor-alpha (TNF-α), and interferon-gamma (IFN-γ). This anomalous response often leads to acute respiratory distress syndrome (ARDS), disseminated intravascular coagulation (DIC), and multiple organ injury (MOI). Glucosinolates are plant secondary metabolites predominantly found in Brassica vegetables, but are also present in other species, such as Moringa Adens and Carica papaya L. When catalyzed by the enzyme myrosinase, glucosinolates produce valuable products, including sulforaphane, phenethyl isothiocyanate, 6-(methylsulfinyl) hexyl isothiocyanate, erucin, goitrin, and moringin. These hydrolyzed products regulate proinflammatory cytokine production by inhibiting the nuclear factor kappa-light-chain-enhancer of activated B-cell (NF-κB) signaling pathway and stimulating the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway. This action can alleviate hyperinflammation in infected cells and modulate cytokine storms. In this review, we aimed to examine the potential role of glucosinolates in modulating cytokine storms and reducing inflammation in various conditions, such as coronavirus disease. Overall, we found that glucosinolates and their hydrolysis products can potentially attenuate cytokine production and the onset of cytokine storms in diseased cells. In summary, glucosinolates could be beneficial in regulating cytokine production and preventing complications related to cytokine storms.

Role of Nitric oxide synthase II in cognitive impairment due to experimental cerebral malaria

The role of nitric oxide (NO) in the pathogenesis of cerebral malaria and its cognitive sequelae remains controversial. Cerebral malaria is still the worst complication of Plasmodium falciparum infection, which is characterized by high rates of morbidity and mortality. Even after recovery from infection due to antimalarial therapy, the development of cognitive impairment in survivors reinforces the need to seek new therapies that demonstrate efficacy in preventing long-lasting sequelae. During disease pathogenesis, reactive oxygen and nitrogen species (RONS) are produced after the established intense inflammatory response. Increased expression of the enzyme inducible nitric oxide synthase (iNOS) seems to contribute to tissue injury and the onset of neurological damage. Elevated levels of NO developed by iNOS can induce the production of highly harmful nitrogen-reactive intermediates such as peroxynitrite. To address this, we performed biochemical and behavioral studies in C57BL6 mice, aminoguanidine (specific pharmacological inhibitor of the enzyme iNOS) treated and iNOS−/−, infected with Plasmodium berghei ANKA (PbA), with the aim of clarifying the impact of iNOS on the pathogenesis of cerebral malaria. Our findings underscore the effectiveness of both strategies in reducing cerebral malaria and providing protection against the cognitive impairment associated with the disease. Here, the absence or blockade of the iNOS enzyme was effective in reducing the signs of cerebral malaria detected after six days of infection. This was accompanied by a decrease in the production of pro-inflammatory cytokines and reactive oxygen and nitrogen species. In addition, nitrotyrosine (NT-3), a marker of nitrosative stress, was also reduced. Futher, cognitive dysfunction was analyzed fifteen days after infection in animals rescued from infection by chloroquine treatment (25 mg/kg bw). We observed that both interventions on the iNOS enzyme were able to improve memory and learning loss in mice. In summary, our data suggest that the iNOS enzyme has the potential to serve as a therapeutic target to prevent cognitive sequelae of cerebral malaria.

Diacerein reduces inflammasome activation and SARS-CoV-2 virus replication: a proof-of-concept translational study.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is linked to high mortality, primarily through an intense inflammatory response. Diacerein has emerged as a potential therapy for COVID-19 due to its potential impact in decreasing the inflammasome activation and coronavirus replication. This study aims to explore diacerein's influence in inhibiting both viral replication and the inflammatory response after SARS-CoV-2 infection. Human peripheral blood mononuclear cells (PBMCs) were obtained from healthy volunteers and infected in vitro with SARS-CoV-2. Additionally, we carried out a pilot randomized, double-blind, placebo-controlled study with 14 participants allocated to diacerein (n = 7) or placebo (n = 7) therapies every 12h for 10 days. The primary endpoint was change in plasma markers of inflammasome activation (NLRP3, caspase-1, and gasdermin-D). In vitro protocols have shown that rhein, diacerein's primary metabolite, decreased IL-1β secretion caused by SARS-CoV-2 infection in human PBMCs (p < 0.05), and suppressed viral replication when administered either before or after the virus incubation (p < 0.05). This later effect was, at least partially, attributed to its inhibitory effect on 3-chymotrypsin-like protease (SARS-CoV-2 3CLpro) and papain-like protease in the SARS-CoV-2 (SARS-CoV-2 PLpro) virus and in the phosphorylation of proteins related cytoskeleton network (p < 0.05). Diacerein-treated COVID-19 patients presented a smaller area under the curve for NLRP3, caspase-1 and GSDM-D measured on days 2, 5, and 10 after hospitalization compared to those receiving a placebo (p < 0.05). The indicated mechanisms of action of diacerein/rhein can reduce viral replication and mitigate the inflammatory response related to SARS-CoV-2. These findings are preliminary and require confirmation in clinical trials.

Neutrophil membrane-coated multifunctional biomimetic nanoparticles for spinal cord injuries

Spinal cord injury (SCI) is one of the most complex diseases. After SCI, severe secondary injuries can cause intense inflammatory storms and oxidative stress responses, leading to extensive neuronal apoptosis. Effective regulation of inflammation and oxidative stress after SCI remains an unresolved challenge. In this study, resveratrol-loaded nanoparticles coated with neutrophil membranes (NMR) were prepared using the emulsion-solvent evaporation method and membrane encapsulation technology. Multifunctional biomimetic nanoparticles retain neutrophil membrane-related receptors and possess a strong adsorption capacity for inflammatory factors. As a drug carrier, NMR can sustainably release resveratrol for >72 h. Moreover, co-culture studies in vitro show that the NMR help regulate macrophage polarization to relieve inflammatory response, reduce intracellular reactive oxygen species by approximately 50%, and improve mitochondrial membrane potential to alleviate oxidative stress. After injecting NMR into the injury site, it reduces early apoptosis, inhibit scar formation, and promote neural network recovery to improve motor function. This study demonstrates the anti-inflammatory, antioxidant, and neuroprotective effects of NMR, thus providing a novel therapeutic strategy for SCI.

Factores de riesgo asociados a lesión renal aguda en pacientes en cuidados intensivos con covid-19.

Introduction: Patients with COVID-19 admitted to intensive care units are at high risk of developing acute kidney injury (AKI). SARS-CoV-2 can directly infect kidney cells, causing an intense inflammatory response with lymphocytic infiltration and severe tubular necrosis. These factors, together with others not yet fully understood, contribute to the development of acute kidney failure. This study aimed to identify risk factors in this specific group of patients. Methods: The present observational study was conducted at the Pablo Arturo Suárez Hospital Intensive Care Unit in Quito, Ecuador, from January 2020 to December 2021. With a probabilistic sample, adult patients in intensive care with COVID-19 were included. The variables were age, sex, education, body mass index, comorbidities, increase in serum creatinine, severity scales, vital signs, and the PAO2/FIO2 ratio. Presence of respiratory distress. Laboratory parameters: Interleukin 6, lactate dehydrogenase, ferritin, and serum lactate levels; blood count; days in the ICU; and mortality. The odds ratio is obtained to present the risk. Results: A total of 294 patients were included in the study. The prevalence of AKI was 16.0% (95% CI 12.1% -20.6%). The risk factor for developing AKI was the presence of comorbidities, which presented an influential association with the development of renal failure, 8.7% vs. 20.4% (P = 0.02), indicating an OR of 2.68 (95% CI: 1.24, 5.78; P = 0.02). Female sex constituted a protective factor with an OR of 0.30 (95% CI: 0.09, 0.85; P = 0.03). Conclusion: The leading risk factor for the development of acute kidney injury was comorbidities related to male sex, and female sex was a protective factor.

Dachengqi decoction dispensing granule ameliorates LPS-induced acute lung injury by inhibiting PANoptosis in vivo and in vitro

Ethnopharmacological relevanceAcute lung injury (ALI) is a serious health-threatening syndrome of intense inflammatory response in the lungs, with progression leading to acute respiratory distress syndrome (ARDS). Dachengqi decoction dispensing granule (DDG) has a pulmonary protective role, but its potential modulatory mechanism to alleviate ALI needs further excavation. Aim of the studyThis study aims to investigate the effect and potential mechanism of DDG on lipopolysaccharide (LPS)-induced ALI models in vivo and in vitro. Materials and methodsLPS-treated Balb/c mice and BEAS-2B cells were used to construct in vivo and in vitro ALI models, respectively. Hematoxylin-eosin (HE), Wet weight/Dry weight (W/D) calculation of lung tissue, and total protein and Lactic dehydrogenase (LDH) assays in BALF were performed to assess the extent of lung tissue injury and pulmonary edema. Enzyme-linked immunosorbent assay (ELISA) was used to detect the levels of tumor necrosis factor-alpha (TNF-α), interleukin-1β (IL-1β), and interleukin-18 (IL-18) in BALF, serum, and cell supernatant. The qRT-PCR was used to detect inflammatory factors, Z-DNA binding protein 1 (ZBP1), and receptor-interacting protein kinase 1 (RIPK1) expression in lung tissues and BEAS-2B cells. Double immunofluorescence staining and co-immunoprecipitation were used to detect the relative expression and co-localization of ZBP1 and RIPK1. The effects of LPS and DDG on BEAS-2B cell activity were detected by Cell Counting Kit-8 (CCK-8). Western blot (WB) was performed to analyze the expression of PANoptosis-related proteins in lung tissues and BEAS-2B cells. ResultsIn vivo, DDG pretreatment could dose-dependently improve the pathological changes of lung tissue in ALI mice, and reduce the W/D ratio of lung, total protein concentration, and LDH content in BALF. In vitro, DDG reversed the inhibitory effect of LPS on BEAS-2B cell viability. Meanwhile, DDG significantly reduced the levels of inflammatory factors in vitro and in vivo. In addition, DDG could inhibit the expression levels of PANoptosis-related proteins, especially the upstream key regulatory molecules ZBP1 and RIPK1. ConclusionDDG could inhibit excessive inflammation and PANoptosis to alleviate LPS-induced ALI, thus possessing good anti-inflammatory and lung-protective effects. This study establishes a theoretical basis for the further development of DDG and provides a new prospect for ALI treatment by targeting PANoptosis.

Polyphenol-Reinforced Glycocalyx-Like Hydrogel Coating Induced Myocardial Regeneration and Immunomodulation.

Although minimally invasive interventional occluders can effectively seal heart defect tissue, they still have some limitations, including poor endothelial healing, intense inflammatory response, and thrombosis formation. Herein, a polyphenol-reinforced medicine/peptide glycocalyx-like coating was prepared on cardiac occluders. A coating consisting of carboxylated chitosan, epigallocatechin-3-gallate (EGCG), tanshinone IIA sulfonic sodium (TSS), and hyaluronic acid grafted with 3-aminophenylboronic acid was prepared. Subsequently, the mercaptopropionic acid-GGGGG-Arg-Glu-Asp-Val peptide was grafted by the thiol-ene "click" reaction. The coating showed good hydrophilicity and free radical-scavenging ability and could release EGCG-TSS. The results of biological experiments suggested that the coating could reduce thrombosis by promoting endothelialization, and promote myocardial repair by regulating the inflammatory response. The functions of regulating cardiomyocyte apoptosis and metabolism were confirmed, and the inflammatory regulatory functions of the coating were mainly dependent on the NF-kappa B and TNF signaling pathway.

Abstract We055: Role of Classical Dendritic Cells in the Sterile Inflammatory Response Following Myocardial Infarction

Myocardial infarction and the subsequent development of chronic ischemic cardiomyopathy is the most common cause of congestive heart failure. Infarction is associated with an intense sterile inflammatory response which can lead to adverse remodeling over the long term. Dendritic cells (DCs) are antigen presenting cells that function as a bridge between innate and adaptive immunity. Precursor DCs give rise to several distinct classical DC (cDC) subsets that mediate a variety of functions. The cDC1 subset is essential for cross-presentation of antigens to CD8 + T cells, while the cDC2 lineage is a potent inducer of CD4 + T cell proliferation. The aim of the study was to characterize the profile of the cDC populations present during the various stages of the development of chronic ischemic cardiomyopathy. We hypothesized that cDCs are essential mediators of chronic LV remodeling in the period following ischemic myocardial injury. We sought to determine which specific cDC subtype (cDC1 vs cDC2) forms the predominant population in the heart and secondary lymphoid tissues following ischemic injury. Adult male C57BL/6 (WT) mice underwent non-perfused myocardial infarction by ligating the left anterior descending artery (LAD) to induce sterile injury, with sham operated mice used as controls. Left ventricular (LV) remodeling was assessed by echocardiography at 1 w and 8 w following surgery. Alterations in cDC1 (CD45+CD11c+CD103-XCR1-) and cDC2 (CD45+CD11c+CD103+XCR1+) profile were examined by flow cytometry. When compared with the sham operated mice, mice with ischemic cardiomyopathy following LAD ligation exhibited the following features. There is an initial influx of cDC2 into the myocardium 1 w after MI (mean of 3.0% vs 0.26% of CD45 + leukocytes, p=0.02). This is followed by a subsequent influx of cDC1 into the myocardium 4 weeks after MI (mean of 1.98% vs 0.16% of CD45 + leukocytes, p=0.001). This influx of cDC into the heart is accompanied by an egress of cDC from the spleen (mean of 0.37% vs 0.76% of CD45 + leukocytes, P=0.001) at 4 weeks following MI. In conclusion, the findings of our study suggest that there is an initial influx of cDC2 followed by a more sustained influx of cDC1 into the myocardium in the weeks following an infarct. Antigen presentation by cDC likely plays a critical role in driving the inflammatory response and inducing chronic LV remodeling in the period following MI.

A large-scale study on uric acid-related biomarkers in patients with bipolar disorder

Objective: Recent research has provided strong evidence supporting the use of uric acid-related ratios as potential biomarkers for disease diagnosis. Notable ratios among these include uric acid-to-albumin ratio (UAR), uric acid-to-creatinine ratio (UCR), uric acid-to-high-density lipoprotein ratio (UHR), and uric acid-to-lymphocyte ratio (ULR). The aim of the study is to analyze these biomarkers in bipolar disorder (BD) patients. Methods: 5465 BD patients were enrolled in this study and 6629 healthy subjects served as controls. We compared differences of the above ratio indicators among different BD diagnostic groups and analyzed factors leading to the onset of BD. Results: BD-M (manic episodes of BD) group had higher ULR, UHR, UCR, UAR than HC (Heathy Controls) and BD-D (depressive episodes of BD) groups, while BD-D group showed lower ULR and UCR than HC group. P-BD-M (BD-M with psychotic symptoms) group displayed higher ULR, UHR, UCR, UAR than HC group, while even higher ULR, UHR, UAR than NP-BD-M (BD-M without psychotic symptoms) group. High UAR was risk factor in BD-M. Conclusions: Our study suggests BD-M has more intense inflammatory response than BD-D. Furthermore, there is heterogeneity in the pathogenesis of psychotic symptoms between BD-M and BD-D. Additionally, High UAR was risk factor in BD-M.

HbpA from Glaesserella parasuis induces an inflammatory response in 3D4/21 cells by activating the MAPK and NF-κB signalling pathways and protects mice against G. parasuis when used as an immunogen

Glaesserella parasuis is usually a benign swine commensal in the upper respiratory tract, but virulent strains can cause systemic infection characterized by pneumonia, meningitis, and fibrinous polyserositis. The intensive pulmonary inflammatory response following G. parasuis infection is the main cause of lung injury and death in pigs. Vaccination has failed to control the disease due to the lack of extended cross-protection. Accumulating evidence indicates that the heme-binding protein A (HbpA) is a potential virulence determinant and a promising antigen candidate for the development of a broader range of vaccines. However, it is not yet known whether HbpA contributes to G. parasuis virulence or has any potential immune protective effects against G. parasuis. Here, we show that HbpA can induce the transcription and secretion of proinflammatory cytokines (IL-6, TNF-α, and MCP-1) in porcine alveolar macrophages (PAM, 3D4/31). The HbpA protein is recognized by Toll-like receptors 2 and 4 on 3D4/21 macrophages, resulting in the activation of MAP kinase and NF-κB signalling cascades and the transcription and secretion of proinflammatory cytokines. HbpA contributes to virulence and bacterial pulmonary colonization in C57BL/6 mice and plays a role in adhesion to host cells and evasion of the bactericidal effect of pulmonary macrophages. In addition, mice immunized with HbpA were partially protected against challenge by G. parasuis SC1401. The results suggest that HbpA plays an important role in the pathogenesis of disease caused by G. parasuis and lay a foundation for the development of a subunit or chimeric anti-G. parasuis vaccine.

Controlled Release of Ceria and Ferric Oxide Nanoparticles via Collagen Hydrogel for Enhanced Osteoarthritis Therapy.

Osteoarthritis (OA), characterized by chronic inflammation and cartilage degeneration, significantly affects over 500 million people globally. Nanoparticles have emerged as promising treatments for OA; however, current strategies often employ a single type of nanoparticle targeting specific disease stages, limiting sustained therapeutic efficacy. In this study, a novel collagen hydrogel is introduced, thiol crosslinked collagen-cerium oxide-poly(D,L-lactic-co-glycolic acid) microspheres encapsulating nanoparticles (CSH-CeO2-pFe2O3), designed for the controlled release of cerium oxide (CeO2) and ferric oxide (Fe2O3) nanoparticles for comprehensive OA management. The sulfhydryl cross-linked collagen matrix embeds CeO2 nanoparticles and poly(D,L-lactic-co-glycolic acid) (PLGA) microspheres encapsulating Fe2O3 nanoparticles. The CSH-CeO2-pFe2O3 hydrogel exhibits enhanced mechanical strength and remarkable injectability, along with a significant promotion of cell adhesion, proliferation, and chondrogenic differentiation. Notably, the hydrogel demonstrates intelligent responsiveness to high levels of reactive oxygen species, initiating the rapid release of CeO2 nanoparticles to address the intense inflammatory responses of early-stage OA, followed by the sustained release of Fe2O3 nanoparticles to facilitate cartilage regeneration during the proliferative phase. In a rat model with cartilage defects, the hydrogel significantly alleviates inflammation and enhances cartilage regeneration, holding substantial potential for effectively managing the pathologically complex OA.

Strategies to attenuate maladaptive inflammatory response associated with cardiopulmonary bypass.

Cardiopulmonary bypass (CPB) initiates an intense inflammatory response due to various factors: conversion from pulsatile to laminar flow, cold cardioplegia, surgical trauma, endotoxemia, ischemia-reperfusion injury, oxidative stress, hypothermia, and contact activation of cells by the extracorporeal circuit. Redundant and overlapping inflammatory cascades amplify the initial response to produce a systemic inflammatory response, heightened by coincident activation of coagulation and fibrinolytic pathways. When unchecked, this inflammatory response can become maladaptive and lead to serious postoperative complications. Concerted research efforts have been made to identify technical refinements and pharmacologic interventions that appropriately attenuate the inflammatory response and ultimately translate to improved clinical outcomes. Surface modification of the extracorporeal circuit to increase biocompatibility, miniaturized circuits with sheer resistance, filtration techniques, and minimally invasive approaches have improved clinical outcomes in specific populations. Pharmacologic adjuncts, including aprotinin, steroids, monoclonal antibodies, and free radical scavengers, show real promise. A multimodal approach incorporating technical, circuit-specific, and pharmacologic strategies will likely yield maximal clinical benefit.

Inflammatory response to bioceramic and epoxy resin-based endodontic sealers implanted in mice subcutaneous tissue: An in vivo study.

To evaluate the inflammatory tissue response to BioRoot™ RCS (BR) and AH Plus Jet (AHPJ) sealers implanted in mice subcutaneous tissue. It was hypothesized that the inflammatory tissue response to BR would be milder than to AHPJ. An in vivo study was carried out using isogenic mice. The sealers were implanted during standardized surgical procedures. The inflammatory response was evaluated by microscopic analysis and von Kossa reaction in the reactionary tissue around the specimens after 7, 21, and 63 days. For comparisons, a zinc oxide and eugenol sealer (ZOE) was used as a positive control, in addition to a negative control without a sealer (n = 10 per group/period). All statistical analyses considered a significance level of 5%. All endodontic sealers triggered an inflammatory tissue response after 7 days. BR had a higher inflammatory cell count and a thicker fibrous capsule when compared with AHPJ, but both were less inflammatory than ZOE (p < .001). After 21 days, BR continued to trigger an intense inflammatory tissue response, higher in both microscopic parameters compared to AHPJ, and a thicker fibrous capsule than ZOE (p < .001). After 63 days, the inflammatory tissue response decreased in BR, matching the fibrous capsule thickness with AHPJ and ZOE. BR promoted intense calcium precipitation in all study periods. After 63 days, AHPJ and BR sealers were more biocompatible to subcutaneous mice tissue, but AHPJ present better early inflammatory response, as well as BR showed potential bioactivity. RESEARCH HIGHLIGHTS: The inflammatory tissue response triggered by a bioceramic endodontic sealer (BR) was not milder than that triggered by an epoxy-resin based endodontic sealer (AHPJ) during the first 3 weeks, considering the microscopic analysis of the reactionary tissue.

Combined EORTC FDG-PET/CT and RECIST 1.1 response criteria and prediction of pathological response to neoadjuvant nivolumab and ipilimumab for clinical stage III melanoma.

9590 Background: Accurate identification of pathological response to neoadjuvant therapy for clinical stage III melanoma before surgery may allow us to better tailor the treatment. RECIST 1.1 has shown poor concordance rates with pathological responses and EORTC FDG-PET/CT response criteria using SUV max is susceptible to internal and external variables leading to difficulty in determining accuracy appropriately. Methods: We conducted a multicenter retrospective analysis of patients with clinical stage III melanoma treated with neoadjuvant nivolumab 3mg/kg + ipilimumab 1mg/kg(N3+I1) for two cycles who did baseline and pre-operative 18F-FDG-PET/CT. RECIST 1.1 and EORTC PETCT criteria were used to classify patients in terms of response. The pathological results were correlated to the image findings. Results: Between Jan 2019 and Jan 2024, 37 patients with clinical stage III melanoma treated with neoadjuvant N3+I1 were identified. Gender: 25 males (67%), median age (years): 58 (range: 31-78), BRAFV600 mut: 25(67%), positive nodes on baseline exam:1=30 (81%), 2=4(11%), and 3 or more =3(8%). Stage AJCC 8th edition: IIIB=23 (62%), IIIC=12 (32%), IIID=2(6%). Among them, 34 had baseline and post-neoadjuvant therapy PET-CT. Twenty-one (62%) had major pathological response (MPR) and 13(38%) had non-MPR. Using objective response and non-objective criteria to capture MPR and non-MPR, respectively, we found the following results: RECIST 1.1 (sensitivity= 48%, specificity=100%, accuracy=68%), EORTC-PET (sensitivity=90%, specificity=69%, accuracy=82%). Combining RECIST 1.1 and EORTC-PET/CT analysis, we found that: double objective responders (CR/PR and CMR/PMR, n=10) had 100% specificity to MPR and double progressors (PD/PMD, n=9) had 95% specificity to non-MPR. The only patient classified as double progressor that did not have non-MPR presented an intense inflammatory response with fever, pain and erythema leading to an increase in the size and number of lymph-nodes. No viable cells were found in the pathological report. Conclusions: Using combined RECIST 1.1 and EORTC-PET/CT response criteria may help to predict pathological response in patients with clinical stage III melanoma who undergo to neoadjuvant nivolumab and ipilimumab.

The role of pyroptosis in heart failure and related traditional chinese medicine treatments.

Pyroptosis is a type of programmed cell death that is mediated by both typical and atypical pathways and ultimately leads to the lysis and rupture of cell membranes and the release of proinflammatory factors, triggering an intense inflammatory response. Heart failure (HF) is a serious and terminal stage of various heart diseases. Myocardial hypertrophy, myocardial fibrosis, ventricular remodeling, oxidative stress, the inflammatory response and cardiomyocyte ionic disorders caused by various cardiac diseases are all risk factors for and aggravate HF. Numerous studies have shown that pyroptosis can induce and exacerbate these reactions, causing progression to HF. Therefore, targeting pyroptosis is a promising strategy to treat HF. This paper summarizes the role of pyroptosis in the development of HF and the underlying mechanism involved. Recent research progress on the ability of traditional Chinese medicine (TCM) extracts and formulas to inhibit pyroptosis and treat HF was summarized, and some traditional Chinese medicine extracts and formulas can alleviate different types of HF, including heart failure with preserved ejection fraction (HFpEF), heart failure with reduced ejection fraction (HFrEF), and heart failure with midrange ejection fraction (HFmrEF), by targeting pyroptosis. These findings may provide new ideas and evidence for the treatment or adjuvant treatment of HF by targeting pyroptosis.

Synergies of co-infecting pathogens, sea lice (Lepeophetheirus salmonis) and Moritella viscosa, are impacted by exposure order, and host response to initial infection

Sea lice infestations and winter ulcer disease caused by Moritella viscosa are two major challenges for the Atlantic salmon (Salmo salar) aquaculture industry. Despite their common tropisms for the skin/muscle, we know very little about the interaction between these two significant pathogens. The objective of this study was to elucidate the transcriptomic response of Atlantic salmon to sea louse (Lepeophtheirus salmonis) and M. viscosa under single infection and different scenarios of co-infection (i.e., first, L. salmonis and then, M. viscosa and vice versa). After exposure, sampling was performed from the infestation site as well as the adjacent area on fish skin, followed by transcriptome analysis. RNA-seq analysis revealed that infection with either L.salmonis or M. viscosa induced a significant immune response from the skin and resulted in extensive transcriptomic changes. More differentially expressed genes (DEGs) were detected at M. viscosa lesion sites compared to L. salmonis attachment sites. In addition, the effect of the infection order was evaluated. Interestingly, we found that primary infection with lice was associated with a significantly higher number of DEGs during the co-infection process on fish skin compared to the fish first infected with M. viscosa (721 and 5336 DEGs from lice attachment and M. viscosa lesion sites, respectively, vs 291 and 3601 DEGs from lice attachment and M. viscosa lesion sites, respectively). We also found that lice infection caused localized effects on the skin of Atlantic salmon, while single infection with M. viscosa caused a moderate systemic impact and inhibited the tissue repair function of the skin, leading to severe ulceration. In addition, the C-type lectin receptor signaling pathway was drastically activated at the lice attachment sites during both lice alone- and co-infections, regardless of the order of infections, and similar results were observed in M. viscosa infection at both lesion and adjacent sites, indicating that this pathway played an essential role for immunity in Atlantic salmon. A more intense inflammatory and immune response was also observed at M. viscosa lesion sites. These results will promote our understanding of the immune interactions between L. salmonis and M. viscosa during the co-infection process and provide insights for the development of preventive and treatment strategies for these pathogens in salmonid aquaculture.

Advances in the study of polydopamine nanotechnology in central nervous system disorders

Disorders of the central nervous system (CNS) constitute a significant global health concern at the moment. Most CNS disorders are characterized by severe neuronal damage with excessive production of reactive oxygen species, which induces high levels of oxidative stress and intense inflammatory responses in the affected tissues, thus aggravating disease pathology. Notably, the blood–brain barrier makes it difficult to deliver many drugs and biologics to the CNS, which creates great difficulties in the diagnosis and treatment of CNS disorders. Recent research on polydopamine nanotechnology has led to the discovery of many promising properties; it shows strong scavenging ability for reactive oxygen species, prevents activation of pro-inflammatory microglia, and its repair function can reduce brain damage and protect neurons. Moreover, polydopamine nanotechnology can improve the blood–brain barrier permeability of biologics and reduce their neurotoxicity. It is therefore a promising candidate in the treatment of CNS disorders associated with oxidative stress. In the present paper, we review the functionality of polydopamine nanotechnology as well as the potential and recent advances of polydopamine-based nanosystems in the diagnosis and treatment of various CNS disorders, including Alzheimer’s disease, Parkinson’s disease, stroke, spinal cord injury, and glioma. Finally, we predict how polydopamine nanoparticles may guide future therapeutic strategies to address CNS disorders such as epilepsy, which currently have no cure.

VCP Inhibition Augments NLRP3 Inflammasome Activation.

Lysosomal membrane permeabilization caused either via phagocytosis of particulates or the uptake of protein aggregates can trigger the activation of NLRP3 inflammasome- an intense inflammatory response that drives the release of the pro-inflammatory cytokine IL-1β by regulating the activity of CASPASE 1. The maintenance of lysosomal homeostasis and lysosomal membrane integrity is facilitated by the AAA+ ATPase, VCP/p97 (VCP). However, the relationship between VCP and NLRP3 inflammasome activity remains unexplored. Here, we demonstrate that the VCP inhibitors, DBeQ and ML240 elicit the activation of NLRP3 inflammasome in bone marrow-derived macrophages (BMDMs) when used as activation stimuli. Moreover, genetic inhibition of VCP or VCP chemical inhibition enhances lysosomal membrane damage and augments LLoME-associated NLRP3 inflammasome activation in BMDMs. Similarly, VCP inactivation also augments NLRP3 inflammasome activation mediated by aggregated alpha-synuclein fibrils and lysosomal damage. These data suggest that VCP is a participant in the complex regulation of NLRP3 inflammasome activation.