Model Of Inflammation Research Articles

Effect of gamma-terpinene on the articular inflammatory response.

This study investigates the anti-inflammatory and antinociceptive effects of gamma-terpinene (GT), a monoterpene present in essential oils, in models of acute joint inflammation and pain. GT was administered orally at doses of 25, 50, 75, and 100 mg/kg. Joint inflammation was induced by an intra-articular injection of zymosan to assess joint edema, leukocyte migration, and myeloperoxidase (MPO) enzyme activity. A carrageenan-induced paw edema model was used to evaluate edema and mechanical hyperalgesia, with measurements taken via plethysmometry and Von Frey testing. Results showed that GT significantly decreased leukocyte migration, joint edema, and MPO activity in the zymosan model, indicating an anti-inflammatory effect. In the carrageenan model, GT also demonstrated a dose-dependent reduction in paw edema and mechanical hyperalgesia, highlighting its analgesic potential. These findings support that GT possesses notable anti-inflammatory and antinociceptive properties, making it a promising candidate for natural therapeutic applications in managing inflammatory joint conditions. This suggests a potential role of GT as a natural alternative to NSAIDs and glucocorticoids (GCs), reducing inflammation while minimizing side effects. Future studies should explore its clinical applicability and long-term safety.

Diosmetin Attenuates Painful Symptoms Caused by Antineoplastics Paclitaxel and Anastrozole in Mice.

Cancer patients often experience painful symptoms as an adverse effect resulting from various factors, including antineoplastic therapy. Paclitaxel is a chemotherapeutic agent used to treat solid tumours and, unfortunately, causes acute and chronic peripheral neuropathic pain in patients. Anastrozole is an antineoplastic used to treat hormone receptor-positive breast cancer and causes musculoskeletal pain symptoms. The therapies used to control these pain symptoms have limited efficacy and cause adverse effects, highlighting the importance of finding new treatments. Diosmetin is a flavonoid that has shown efficacy in neuropathic, nociplastic, and inflammatory pain models. Therefore, we verified the antinociceptive effects of diosmetin on nociceptive parameters induced by paclitaxel and anastrozole. We investigated the effects of diosmetin (0.015, 0.15 and 1.5 mg/kg; oral route (p.o.)) on nociceptive parameters (mechanical and cold allodynia and pain affective‑motivational behaviour) induced by a single and repeated paclitaxel (1 mg/kg, intraperitoneal (i.p.)) administrations, as well as on the pain-like symptoms (mechanical allodynia, muscle strength, and pain affective‑motivational behaviour) of a single administration of anastrozole (0.2 mg/kg, p.o.) and the combination of both antineoplastics in mice. Diosmetin reduced the nociceptive parameters induced by paclitaxel and anastrozole. In addition, we observed that anastrozole exacerbated the mechanical allodynia induced by paclitaxel, an effect that was also reversed by diosmetin. These results suggest that diosmetin may be an effective therapeutic alternative for the treatment of painful symptoms caused by antineoplastic drugs, such as paclitaxel and anastrozole.

A Pharmacokinetic–Pharmacodynamic Study of Protosappanoside D, a Component Derived from Biancaea decapetala Extracts, for Its Anti-Inflammatory Effects

Biancaea decapetala (Roth) O. Deg. (Fabaceae), traditionally used by the Hmong people to treat rheumatoid arthritis (RA), has not been extensively studied for the correlation between its anti-inflammatory activity and its active components. Protosappanoside D (PTD), a new component, has been isolated for the first time from the extract of Biancaea decapetala. This study focused on the anti-arthritic and anti-inflammatory effects of Biancaea decapetala extracts (BDE) and PTD, along with their pharmacokinetic–pharmacodynamic (PK-PD) analysis. In the adjuvant-induced arthritis (AA) rat model, HE staining and cytokine assays showed that BDE alleviated joint damage and reduced inflammatory cytokines, similar to the positive control. In the LPS-induced inflammatory cell model, both BDE and PTD demonstrated anti-inflammatory effects by inhibiting the secretion of inflammatory factors. A PK-PD analysis of BDE in AA rats and inflammatory cells, as well as an analysis of PTD as a monomer, was conducted. The results indicated that PTD had different regulatory effects on cytokines like TNF-α, with a certain lag and sustained effects. These findings suggest the potential of BDE and PTD as treatments for rheumatoid arthritis, though further in vivo studies and clinical trials are needed.

Efficacy and Toxicity Analysis of Selective BET Bromodomain Inhibitors in Models of Inflammatory Liver Disease.

BET bromodomain inhibitors demonstrate significant promise as anti-inflammatory agents. However, clinical data demonstrated that nonselective BET bromodomain inhibitors led to significant dose-limiting toxicity in clinical settings. Here, we use three orally bioavailable inhibitors, 1-3, that are either BRD4-D1 selective or pan-D1-biased + BRD4-D2, for assessing their cellular and in vivo efficacy and safety profile compared to known BET inhibitors in two inflammatory disease models. Our results show that pan-D1-biased + BRD4-D2 inhibitor, 3, is as efficacious as pan-BET inhibitor, I-BET151, in reducing inflammation in both models, whereas pan-D2 inhibitors are less effective. BRD4-D1 selective inhibitors are also efficacious; however, inhibitors with improved cellular engagement will be necessary to better assess their effects. Finally, BRD4-D1 selective inhibitors are better tolerated in a preclinical thrombocytopenia model than 3, while gastrointestinal toxicity may be a BRD4-driven effect. These results highlight the importance of assessing specific BET bromodomain functions due to their diverse roles in disease models.

Photoacoustic detecting of brain lymphatic dysfunction in inflammatory models

Photoacoustic detecting of brain lymphatic dysfunction in inflammatory models

Activation and maturation of antigen-specific B cells in nonectopic lung infiltrates are independent of germinal center reactions in the draining lymph node.

Pulmonary T and B cells are important for protection of this mucosal barrier site. While viral infections lead to the development of ectopic lymphoid structures highly similar to those in germinal centers in secondary lymphoid organs, little is known about how T/B cooperation occurs in the unstructured, diffuse tissue infiltrates characteristic of autoimmune diseases and nonviral infections. Using a mouse model of interstitial lung inflammation, we found that naive B cells are directly activated in lung tissue. Despite the absence of any germinal center-like structures, the interaction of B cells with peripheral T helper cells results in efficient somatic hypermutation and class switching. As antigen-presenting cells, macrophages are critical for this process. Unique B-cell repertoires indicated that the lung response was autonomous from the lung-draining lymph node. Only lung GC-like B cells were switched to IgA and had a broader repertoire, making them ideal candidates for producing broadly neutralizing immunoglobulins against respiratory pathogens.

Targeting vascular adhesion protein-1 and myeloperoxidase with a dual inhibitor SNT-8370 in preclinical models of inflammatory disease

Inflammatory diseases are a major source of morbidity and mortality world-wide, the pathogenesis of which are characterised by the interplay of key pro-inflammatory and oxidative enzymes. Here, we report the development of a small molecule dual inhibitor targeting vascular adhesion protein-1 (VAP-1) and myeloperoxidase (MPO), two clinically relevant pro-inflammatory/oxidative enzymes that play complementary pathogenic roles in various inflammatory diseases. This agent, SNT-8370 [(E)-3-(3-((2-(aminomethyl)-3-fluoroallyl)oxy)benzyl)-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one)], irreversibly inhibits VAP-1 and MPO activity with equivalent and enhanced nanomolar potency, respectively, when compared to benchmark clinical VAP-1 and MPO inhibitors. SNT-8370 is selective, exhibiting >100-1000-fold more potency for VAP-1 and MPO versus other mammalian (per)oxidases and shows no significant off-target activity in established preclinical screening panels. In vivo, SNT-8370 is metabolically stable, exhibits a favourable pharmacokinetic/pharmacodynamic profile without CNS penetration, and effectively inhibits VAP-1 and MPO activities. Moreover, compared to monotherapy, SNT-8370 more effectively inhibits leukocyte infiltration in mouse peritonitis, carrageenan air pouch, and lipopolysaccharide-induced lung injury models of acute inflammation. SNT-8370 is also protective in preclinical models of myocardial ischemia-reperfusion injury and unilateral-ureteral-obstruction-induced nephropathy. Collectively, our results support SNT-8370 as a first-in-class, mechanism-based dual inhibitor of VAP-1 and MPO, and as a promising therapeutic for the clinical treatment of inflammatory disorders.

Therapeutic potential of naturally derived carbon dots in sepsis-associated acute kidney injury

BackgroundSepsis is a life-threatening infectious disease characterized by an uncontrolled inflammatory response and consequent multi-organ dysfunction. The kidneys, as primary excretory organs with high blood flow, are particularly susceptible to damage during sepsis. Nonetheless, the existing treatment options for sepsis-associated acute kidney injury (SA-AKI) are still restricted. Nanomedicine, especially carbon dots (CDs), has attracted considerable interest lately for outstanding biomedical characteristics.MethodsTo avoid the generation of toxic effects, the natural CDs derived from Ziziphi Spinosae Semen (Z-CDs) were synthesized employing a hydrothermal method. The free radical scavenging capabilities of Z-CDs were evaluated by utilizing ABTS assay, NBT method, and Fenton reaction. A lipopolysaccharide (LPS)-stimulated RAW 264.7 cell model was used to explore the therapeutic potential of Z-CDs on cellular oxidative stress and inflammation. The CuSO4-induced zebrafish inflammation model and LPS-exposed SA-AKI mouse model were employed to assess the therapeutic efficacy of Z-CDs in vivo.ResultsThe synthesized Z-CDs exhibited distinctive unsaturated surface functional groups, which confer exceptional biocompatibility and the ability to scavenge free radicals. Moreover, Z-CDs were particularly effective in eliminating excess reactive oxygen species (ROS) in cells, thus protecting mitochondrial function from oxidative damage. Notably, Z-CDs have demonstrated significant therapeutic benefits in protecting kidney tissue in SA-AKI mouse model with minimizing side effects. In mechanism, Z-CDs effectively reduced ROS production, thereby alleviating inflammatory responses in macrophages through the suppression of the NF-κB pathway.ConclusionsThis study developed a multifunctional nanomedicine derived from traditional medicinal herb, providing a promising pathway for the advancement of innovative drug therapies to treat SA-AKI.

Protect Effects of Perilla Seed Extract and Its Active Ingredient Luteolin Against Inflammatory Bowel Disease Model via the PI3K/AKT Signal Pathway In Vivo and In Vitro

The purpose of this study was to investigate the anti-inflammatory effects of Perilla Seed Extract (PSE) and its active ingredient on Inflammatory Bowel Disease (IBD) in vitro and in vivo. Thirty-two C57/BL mice were randomly divided into four groups (n = 8): control group (CON), PBS group, LPS group (LPS 3.5 mg/kg given intraperitoneally [ip] on day 7 of the study only), and PSE group (100 mg/kg orally daily + LPS ip at 3.5 mg/kg on day 7). Mice were euthanized 24 h after LPS administration. MODE-K cells were divided into five groups: control group (CON), LPS group (50 μg/mL LPS for 2 h), and PSE group (low dose, 25 μg/mL PSE + LPS; middle dose, 50 μg/mL PSE + LPS; high dose, 100 μg/mL PSE + LPS). In vivo, compared with the CON group, LPS revealed a significant decrease in the villus length-to-crypt depth ratio (p < 0.01) and goblet cell density per unit area (p < 0.01). Conversely, PSE administration resulted in a significant increase in the villus length-to-crypt depth ratio (p < 0.01) and goblet cell density (p < 0.01). LPS significantly increased the ROS content (p < 0.01), the secretion of inflammatory cytokines of IL-6 (p < 0.01), TNF-α (p < 0.01), and the mRNA expressions of HO-1 (p < 0.01). LPS significantly decreased the mRNA expressions of Occludin (p < 0.01) and Claudin1 (p < 0.01). In contrast, PSE treatment led to a marked decrease in ROS levels (p < 0.01), along with a reduction in the secretion of inflammatory factors IL-6 (p < 0.01) and TNF-α(p < 0.05), as well as the mRNA expressions of HO-1 (p < 0.01). Concurrently, PSE significantly increased the mRNA expressions of Occludin (p < 0.05) and Claudin1 (p < 0.01). In vitro, PSE treatment also significantly reversed LPS-induced inflammation, oxidation and tight junction–related factors. Network pharmacology identified 97 potential targets for PSE in treating IBD, while transcriptomics analysis revealed 342 differentially expressed genes (DEGs). Network pharmacology and transcriptomics analysis indicated that significant pathways included the PI3K-Akt signaling pathway, MAPK signaling pathway, and TNF signaling pathway, of which the PI3K-AKT pathway may represent the primary mechanism. In an in vivo setting, compared with the CON group, LPS led to a significant increase in the protein expression of p-PI3K/PI3K (p < 0.01) and p-AKT1/AKT1 (p < 0.01). Conversely, PSE resulted in a significant decrease in the protein expression of p-PI3K/PI3K (p < 0.01) and p-AKT1/AKT1 (p < 0.01). In vitro, compared with the LPS group, PSE also significantly blocked the protein expression of p-PI3K/PI3K (p < 0.01) and p-AKT1/AKT1 (p < 0.01). The chemical composition of PSE was analyzed using UPLC-MS/MS, which identified six components including luteolin (content 0.41%), rosmarinic acid (content 0.27%), α-linolenic acid (content 1.2%), and oleic acid (content 0.2%). Molecular docking found that luteolin could establish stable binding with eight targets, and luteolin significantly decreased the p-AKT1/AKT1 ratio (p < 0.01) compared to the LPS group in MODE-K cells. In summary, PSE demonstrates efficacy against IBD progression by enhancing intestinal barrier function and inhibiting inflammatory responses and oxidative stress via the PI3K/AKT signaling pathway, and luteolin’s inhibition of AKT1 protein phosphorylation appears to play a particularly crucial role in this therapeutic mechanism.

Artificial Intelligence-Enabled Quantitative Assessment and Intervention for Heart Inflammation Model Organoids.

Inflammation plays a crucial role in progression of cardiovascular diseases (CVDs), thus the discovery of rapid and precise analytical tools to assess inflammation related to CVDs is highly desirable for its diagnosis and therapeutics discovery. However, a straightforward and systematic method for quantitative assessment of inflammation levels in heart organoids has yet to be developed. Herein, we describe the construction of human heart inflammatory organoids with intricate structures and diverse cell lineages and the development of an artificial intelligent (AI)-enabled method for quantitative assessment of inflammation levels in this model. Furthermore, we devised a novel therapeutic strategy to boost endogenous energy molecule production in heart inflammatory organoids to address energy metabolic disorders. This research provides a convenient method for quantitative inflammation evaluation and offers a promising tool for drug discovery.

Artificial Intelligence‐Enabled Quantitative Assessment and Intervention for Heart Inflammation Model Organoids

Artificial Intelligence‐Enabled Quantitative Assessment and Intervention for Heart Inflammation Model Organoids

Polypeptide-based multilayer capsules with anti-inflammatory properties: exploring different strategies to incorporate hydrophobic drugs.

More than 90% of drug candidates used in the drug development pipeline and about 40% of drugs on the market are poorly soluble in water based on the definition of the biopharmaceutical classification system. The advent of drug delivery approaches has represented a striking tool to overcome the challenges associated with the use of hydrophobic drugs, such as their low bioavailability and off-target effects. Drug carrier formulations composed of biodegradable and biocompatible polymers, such as polypeptides, have been explored as platforms to host poorly water-soluble drugs to prolong drug circulation, enhance their safety, reduce their immunogenicity, and promote their controlled release. In this work, we evaluated three strategies-co-precipitation, post-encapsulation, and conjugation-to incorporate a hydrophobic model drug, i.e., curcumin (CUR), into biodegradable multilayer capsules fabricated via a layer-by-layer (LbL) approach. Poly(L-lysine) (PLys) and poly(L-glutamic acid) (PGlu) were adopted as building blocks and alternately assembled onto calcium carbonate (CaCO3) microparticles to build a polypeptide-multilayer membrane, which acted as a barrier to control the release of the drug. The application of our three formulations in in vitro inflammatory models of THP-1 derived human macrophages and murine microglia showed a reduction of the inflammation with the suppression of three pivotal pro-inflammatory cytokines (i.e., interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α). Moreover, the intracellular release of CUR detected upon uptake studies on activated microglia suggested that our systems could represent a potential therapeutic approach to reduce acute neuroinflammation and modulate microglia phenotype.

Self-disassembling nanoparticles as oral nanotherapeutics targeting intestinal microenvironment

Inspired by the survival strategies of pyomelanin-producing microbes, we synthesize pyomelanin nanoparticles (PMNPs) from homogentisic acid- γ-lactone via auto-oxidation and investigate their biomedical potential. PMNPs possess distinct physicochemical properties, including reactive oxygen species scavenging and microenvironment-responsive self-disassembly. Under intestinal conditions, PMNPs self-disassemble and penetrate the nanoscale pores of the mucin layer. In an inflammatory bowel disease model, orally administered PMNPs withstand gastric acidity and, in their solubilized form, interact with macrophages and epithelial cells. They significantly reduce reactive oxygen species levels, exert anti-inflammatory effects, and restore gut microbiota composition. Compared to conventional nanoparticles and 5-aminosalicylic acid, PMNPs exhibit greater therapeutic efficacy. Clinical symptoms and intestinal inflammation are alleviated, and the gut microbiota is restored to near-normal levels. These findings underscore the therapeutic potential of PMNPs for inflammatory bowel disease treatment and suggest broader biomedical applications.

Pro-inflammatory effects of all-trans retinoic acid in experimental acute inflammation - insights into eosinophil and neutrophil dynamics

Context All-trans retinoic acid (ATRA), a metabolite of vitamin A, regulates embryogenesis, regeneration, hematopoiesis, differentiation, and apoptosis. It also exerts immunomodulatory effects and is used in inflammatory disease models. Objective This study aimed to investigate the paradoxical pro-inflammatory effects of ATRA on eosinophil and neutrophil recruitment and activation. Materials and methods We used thioglycolate- and zymosan-induced peritonitis models in mice to evaluate leukocyte recruitment following ATRA treatment. The roles of inducible nitric oxide synthase (iNOS), tumor necrosis factor (TNF), and the 5-lipoxygenase (5-LO) pathway were assessed using genetically deficient mice and pharmacological inhibitors. Results and discussion ATRA increased total leukocyte, eosinophil, and neutrophil counts in peritoneal exudates, enhancing the response to both thioglycolate and zymosan. The effects were microenvironment-dependent and likely mediated by local release of pro-inflammatory cytokines and chemokines. iNOS was required for eosinophil recruitment, while TNF contributed to both eosinophil and neutrophil recruitment. The 5-LO pathway was essential for eosinophil involvement. These findings suggest that ATRA can paradoxically enhance inflammation by modulating innate immune cell responses. Conclusions ATRA promotes inflammation through iNOS, TNF, and 5-LO-dependent pathways, revealing complex mechanisms of immune modulation with potential relevance for inflammatory disease management.

Breaking down barriers with sensory science-improving accessibility to neuroimmunology for the blind and low-vision communities.

Scientific public engagement activities and participation in bioscience discussions need to be open to everyone, as they play a significant role in connecting the general public to research and breaking down barriers of scientific skepticism. In a society increasingly shaped by scientific progress, it is crucial that everyone, regardless of their background or ability, feels empowered to participate in these conversations. However, this is not usually the case for blind or low-vision communities who are often excluded, in part due to scientific outreach events being historically limited to visual imagery. To break down such barriers, we organized a multisensory exhibition as part of the Cambridge Festival 2024. The initiative was inspired by Monash Sensory Science, a targeted outreach program designed to engage individuals who are blind, have low vision or diverse needs. Our aim was to use novel, tactile and informative models to explore the role of the immune system in the central nervous system health and disease, focusing on two inflammation models: traumatic brain injury and multiple sclerosis. In Sensory Science, we fostered the involvement of the blind and low-vision community through tactile scientific posters, resin and plaster brain models, and interactive experiences involving heat, sound, tactile poetry and photography. The Sensory Science exhibition held during March 2024 not only promoted equality but also reminded us that true innovation lies in the collective efforts of a diverse and inclusive community.

The anthocyanin‐enriched extract of Vaccinium corymbosum exerted in vitro and ex vivo antiproliferative and anti‐inflammatory activities

AbstractBackgroundVaccinium corymbosum berries represent a source of anthocyanins and polyphenols studied and tested for their healthy potential. The present study was aimed at isolating, characterizing, and quantifying the anthocyanin‐enriched fraction obtained from blueberry and at assessing its biological and protective effects against head and neck cell lines and under inflammatory‐related conditions. V. corymbosum berries extract was subjected to colorimetric analysis, antioxidant evaluation, and HPLC‐DAD analysis. This extract was characterized by chlorogenic acid and 12 glycosylated anthocyanins, being the most abundant delphinidin‐3‐O‐galactoside, delphinidin‐3‐O‐arabinoside, malvidin‐3‐O‐galactoside, malvidin‐3‐O‐glucoside, and malvidin‐3‐O‐arabinoside. The blueberry extract (BL) was further used in extensive biological evaluation. Head and neck cell lines, namely CAL27 and A253, were treated at different concentrations in order to evaluate cell migration ability and ErbB receptors and antioxidant enzymes gene expression.ResultsThe gene expression analysis highlighted the capability of BL to reduce ErbB receptors expression in CAL27 cell lines. The same treatments induced an opposite effect in A253 cell line for ErbB2/ErbB3 receptors. Moreover, in A253 cell line, BL increased SOD2 levels and reduced cell migration. The action of BL was also studied in an ex vivo experimental model of colon inflammation and was effective both in reducing the lipopolysaccharide‐induced gene expression of different proinflammatory biomarkers involved in colon inflammation, among which tumor necrosis factor α, interleukin (IL)‐6, and in stimulating the gene expression of the anti‐inflammatory cytokine IL‐10.ConclusionThe content of specific anthocyanins and chlorogenic acid can be considered responsible of such biological activities providing a new food supplement as coadjuvant of standard therapies.

In vivo and in vitro anti-inflammatory activity of the methanolic leaves extract of Gymnopodium floribundum Rolfe.

In vivo and in vitro anti-inflammatory activity of the methanolic leaves extract of Gymnopodium floribundum Rolfe.

Swine Gut Lactic Acid Bacteria and Their Exopolysaccharides Differentially Modulate Toll-like Receptor Signaling Depending on the Agave Fructans Used as a Carbon Source.

Exopolysaccharides (EPSs) produced by probiotic bacteria have garnered attention due to their effects on the gut health of humans and animals. The nutrients that probiotics access during their growth are essential for producing beneficial effects on host health. Direct immunomodulatory effects of graminan-type fructans (GTFs) from Agave tequilana through toll-like receptors (TLRs) have been demonstrated. However, the immunomodulatory effects of these fructans, mediated through the EPSs produced by the probiotics cultivated with them, remain unexplored. We explored the immunomodulatory effects of lactic acid bacteria (LAB) strains isolated from swine and their EPSs, based on the GTFs used as carbon sources during their growth. While the LAB strains activated the NF-κB pathway independently of the GTF source, their EPSs activated it in a GTF source-dependent manner. LAB activation through TLR2 showed a GTF source dependency, whereas their EPSs activated TLR2 independently of the GTF source. The LAB and their EPSs activated TLR4 in a GTF source-dependent manner. Both the LAB and their EPSs inhibited the activation of TLR2 and TLR4 agonists, which exhibited a strong dependence on the GTF source. The strength of GTF C's immunomodulatory effects on LAB illustrates its specificity, its impact on the EPS structure, and its biological effects. Our results support the promising health benefits of this synbiotic model for swine health and lowering inflammation.

Synergistic Antinociceptive Effects of Ketorolac and Ascorbic Acid in a Formalin-Induced Pain Model

Pain is a widespread global issue and one of the most common disabling conditions in daily life. A wide range of medications are available to reduce or eliminate pain, with nonsteroidal anti-inflammatory drugs (NSAIDs) being among those most commonly used. Additionally, new analgesic approaches, such as antioxidants (Ascorbic Acid), have been explored for their potential to relieve acute pain after surgery, cancer-related pain, and chronic pain not related to cancer with fewer adverse effects. Furthermore, the use of pharmacological combinations is an alternative treatment strategy to obtain a higher efficacy using lower drug concentrations, at which side effects are minimal. Background/Objectives: The aim of this study was to evaluate the pharmacological synergism of ketorolac and ascorbic acid in an inflammatory pain model. Methods: The individual and combined effects of ketorolac and ascorbic acid were evaluated in a formalin-induced pain model in mice. Four experimental groups were established: control (vehicle), ketorolac (KET), ascorbic acid (AA), and combination (KET/AA). Results: The combination of ketorolac and ascorbic acid produced a greater antinociceptive effect compared to the vehicle and individual treatments in the formalin model. Notably, even the lowest dose of the combination (KET 6.26/AA 3.21 µg/paw) exhibited a stronger effect than the maximum doses of each individual treatment KET (100 µg/paw) and AA (100 µg/paw). The effective concentration that produced 30% of antinociception (EC30) for the tested treatments were determined, and an isobologram analysis confirmed the presence of a synergistic interaction in these combinations. Conclusions: These findings suggest that the combination of ketorolac and ascorbic acid produces a synergistic antinociceptive effect in the formalin-induced pain model. The enhanced efficacy of the combination indicates a potential therapeutic advantage in pain management by reducing the required dosage of each compound while maintaining or improving analgesic effects.

Keratinocyte SR-B1 expression and targeting in cytokine-driven skin inflammation

BackgroundStrategies to treat inflammatory skin conditions require identifying new targets involved in interactions between overlying epithelial and underlying dermal immune cells. Scavenger receptor class B type 1 (SR-B1) is a cell surface receptor that binds high-density lipoproteins (HDL) and mediates inflammatory responses in immune and endothelial cells. The SR-B1 receptor is also expressed in keratinocytes, but its role in inflammatory skin diseases remains unexplored.MethodsTo investigate keratinocyte SR-B1 in the setting of inflammation, we measured its expression in skin biopsy samples obtained from patients with psoriasis; human skin explants exposed to the inflammatory cytokine, interleukin-17A (IL-17A); and mouse skin exposed to the pro-inflammatory agent, imiquimod (IMQ). We also evaluated the effects of SR-B1 knockdown on primary keratinocyte responses to IL-17A. Finally, we employed a synthetic HDL-nanoparticle (HDL NP) to investigate the therapeutic potential of targeting SR-B1 in IL-17A-stimulated keratinocytes and in male C57BL/6 mice with IMQ-induced skin inflammation.ResultsOur data show SR-B1 expression is increased in diseased human skin and in both human and mouse models of skin inflammation. SR-B1 knockdown in keratinocytes exacerbates the inflammatory response to IL-17A, whereas targeting SR-B1 with HDL NP attenuates this response. In the IMQ murine model, topical application of HDL NPs improves the skin phenotype, normalizes SR-B1 expression, and reduces molecular and cellular markers of inflammation.ConclusionsOverall, SR-B1 plays a role in skin inflammation and HDL NP-mediated targeting of SR-B1 in keratinocytes may offer a targeted new therapy for inflammatory skin disease.