Model Of Inflammatory Disease Research Articles

The role of neutrophil extracellular traps in inflammatory rheumatic diseases.

Dysregulation in neutrophil extracellular trap (NET) formation and degradation has been reported in several inflammatory rheumatic diseases. This review summarizes the recent advances in the understanding the role of NETs in the context of inflammatory rheumatic diseases. NET formation is enhanced in peripheral blood of patients with large vessel vasculitis and polymyalgia rheumatica. NETs are detected in affected organs in autoimmune conditions, and they might play pathological roles in tissues. Several understudied medications and supplements suppress NET formation and ameliorate animal models of inflammatory rheumatic diseases. NETs and anti-NET antibodies have potential utility as disease biomarkers. Growing evidence has suggested the contribution of NET dysregulation to the pathogenesis of several inflammatory rheumatic diseases. Further research is warranted in regard to clinical impact of modulating aberrant NET formation and clearance in inflammatory rheumatic diseases.

Establishment of an in-vitro inflammatory bowel disease model using immunological differentiation of Caco-2 cells

Studies on intestinal cell differentiation, particularly in dextran sodium sulfate (DSS)-induced inflammatory bowel disease (IBD), have predominantly focused on the disruption of intestinal crypts and suppressive effects on the intestinal microbiota; however, repeated administration of DSS is required to induce inflammatory pathology, and there is a lack of observation of early responses and consideration of differentiation stages. Although colonic adenocarcinoma (Caco-2) cells can be used as intestinal cell models, research on these cells in an immature state is limited. We, therefore, investigated the relationship between Caco-2 cell culture duration and immunological differentiation using α-defensin5 (DEFA5) as an indicator of intestinal immunity and differentiation. Changes in protein and gene expression levels in response to DSS were examined at each differentiation stage. Expression of immune- and differentiation-related proteins, including DEFA5 and lysozyme, was evident from Day 8 of culture. Immune responses to DSS varied with the differentiation stage, affecting cell viability and cytokine expression.•Caco-2 cell culture duration correlates with the differentiation stage of Paneth cells.•DSS exposure elicits different effects depending on the differentiation stage.•Our in-vitro model of IBD facilitates the characterization of the cell differentiation process and provides a methodology to help elucidate the causal mechanisms of IBD.

Lemairamin (Wgx-50) Attenuates DSS-Induced Intestinal Inflammation in Zebrafish.

Inflammatory bowel disease (IBD) is a chronic non-specific intestinal inflammatory disease that affects millions of people worldwide, and current treatment methods have certain limitations. This study aimed to explore the therapeutic potential and mechanism of action of lemairamin (Wgx-50) in inflammatory bowel disease (IBD). We used dextran sulfate sodium (DSS)-treated zebrafish as an inflammatory bowel disease model, and observed the effect of Wgx-50 on DSS-induced colitis inflammation. The results of the study showed that Wgx-50 could reduce the expression of pro-inflammatory cytokines induced by DSS and inhibit the recruitment of neutrophils to the site of intestinal injury. Further experiments revealed that Wgx-50 exerted its anti-inflammatory effect by regulating the activation of the Akt pathway. These research findings indicate that Wgx-50 possesses anti-inflammatory activity.

Suppressive effect of the anesthetic propofol on the T cell function and T cell-dependent immune responses

General anesthesia is thought to suppress the immune system and negatively affect postoperative infection and the long-term prognosis of cancer. However, the mechanism underlying immunosuppression induced by general anesthetics remains unclear. In this study, we focused on propofol, which is widely used for sedation under general anesthesia and intensive care and examined its effects on the T cell function and T cell-dependent immune responses. We found that propofol suppressed T cell glycolytic metabolism, differentiation into effector T cells, and cytokine production by effector T cells. CD8 T cells activated and differentiated into effector cells in the presence of propofol in vitro showed reduced antitumor activity. Furthermore, propofol treatment suppressed the increase in the number of antigen-specific CD8 T cells during Listeria infection. In contrast, the administration of propofol improved inflammatory conditions in mouse models of inflammatory diseases, such as OVA-induced allergic airway inflammation, hapten-induced contact dermatitis, and experimental allergic encephalomyelitis. These results suggest that propofol may reduce tumor and infectious immunity by suppressing the T cell function and T cell-dependent immune responses while improving the pathogenesis and prognosis of chronic inflammatory diseases by suppressing inflammation.

A Family of Cyclic Lipopeptides Found in Human Isolates of Bacillus Ameliorates Acute Colitis via Direct Agonism of Toll-Like Receptor 2 in a Murine Model of Inflammatory Bowel Disease.

The Bacillus-derived cyclic lipopeptides (surfactin, iturin, and fengycin) form potent Heterogeneous Lipopeptide Micelle (HeLM) complexes. HeLM is a small molecule that has been shown to have immunomodulatory effects. However, how HeLM regulates inflammation is not clear, moreover its application to Inflammatory Bowel Disease (IBD), specifically Ulcerative Colitis (UC), has not been tested before. To use a murine model of IBD and determine the effects of HeLM and related molecular mechanisms of action. Colitis was induced in mice by administration of 4% Dextran Sodium Sulfate. Three preparations were tested against negative and positive controls: Purified HeLM, the wild-type strain that produces it, and an isogenic mutant that does not produce HeLM. Clinical, biochemical, and histological scoring systems were used to assess the severity of colitis. RT-qPCR and cell cultures were used to determine the levels of molecular signaling. Fecal samples were processed for metagenomic analysis. Purified HeLM, and the wild-type strain, significantly decreased the severity of colitis as determined by the disease activity index (DAI), mouse colitis histology index (MCHI), fecal calprotectin, and colonic length. This effect was not seen in the mutant. HeLM was found to be an agonist to TLR-2, seemingly activating the Toll-Like Receptor 2/IL-10 pathway, with subsequent downregulation of inflammatory cytokines (TNF-α, IL-1β, and IL-6). At higher concentrations HeLM inhibited lipopolysaccharide ligands from activating TLR-4. The reduction in colitis was not due to microbiome modulation, as had previously been hypothesized. Our results indicate that HeLM ameliorates colitis by TLR-2-induced IL-10 production and possibly via the inhibition of lipopolysaccharide.

Characterization of novel CD8+ regulatory T cells and their modulatory effects in murine model of inflammatory bowel disease

Dysregulation of mucosal immune system has been proposed to be critical in the pathogenesis of inflammatory bowel diseases (IBDs). Regulatory T cells (Tregs) play an important role in regulating immune responses. Tregs are involved in maintaining intestinal homeostasis and exerting suppressive function in colitis. Our previous studies showed that a novel forkhead box protein P3 (Foxp3) negative Tregs (Treg-of-B cells), induced by culturing naïve CD4+ T cells with B cells, could protect against colitis and downregulate T helper (Th) 1 and Th17 cell cytokines in T cell-mediated colitis. In the present study, we aimed to induce Treg-of-B cells in the CD8+ T-cell population and investigate their characteristics and immunomodulatory functions. Our results showed that CD8+ Treg-of-B cells expressed Treg-associated markers, including lymphocyte-activation gene-3 (LAG3), inducible co-stimulator (ICOS), programmed death-1 (PD-1), cytotoxic T-lymphocyte-associated protein-4 (CTLA-4), tumor necrosis factor receptor superfamily member-4 (TNFRSF4, OX40), and tumor necrosis factor receptor superfamily member-18 (TNFRSF18, GITR), but did not express Foxp3. CD8+ Treg-of-B cells produced higher concentration of inhibitory cytokine interleukin (IL)-10, and expressed higher levels of cytotoxic factor granzyme B and perforin after stimulation, compared to those of CD8+CD25- T cells. Moreover, CD8+ Treg-of-B cells suppressed T cell proliferation in vitro and alleviated colonic inflammation in chronic dextran sulfate sodium (DSS)-induced colitis. In conclusion, our study identified a novel subpopulation of CD8+ Tregs with suppressive effects through cell contact. These CD8+ Treg-of-B cells might have therapeutic potential for IBDs.

Exploring the anti-inflammatory effects of postbiotic proteins from Lactobacillus delbrueckii CIDCA 133 on inflammatory bowel disease model

Lactobacillus delbrueckii CIDCA 133 is a promising health-promoting bacterium shown to alleviate intestinal inflammation. However, the specific bacterial components responsible for these effects remain largely unknown. Here, we demonstrated that consuming extractable proteins from the CIDCA 133 strain effectively relieved acute ulcerative colitis in mice. This postbiotic protein fraction reduced the disease activity index and prevented colon shortening in mice. Furthermore, histological analysis revealed colitis prevention with reduced inflammatory cell infiltration into the colon mucosa. Postbiotic consumption also induced an immunomodulatory profile in colitic mice, as evidenced by both mRNA transcript levels (Tlr2, Nfkb1, Nlpr3, Tnf, and Il6) and cytokines concentration (IL1β, TGFβ, and IL10). Additionally, it enhanced the levels of secretory IgA, upregulated the transcript levels of tight junction proteins (Hp and F11r), and improved paracellular intestinal permeability. More interestingly, the consumption of postbiotic proteins modulated the gut microbiota (Bacteroides, Arkkemansia, Dorea, and Oscillospira). Pearson correlation analysis indicated that IL10 and IL1β levels were positively associated with Bacteroides and Arkkemansia_Lactobacillus abundance. Our study reveals that CIDCA 133-derived proteins possess anti-inflammatory properties in colonic inflammation.

Functional properties and molecular docking of different nanoparticles with ROS-sensitive phenylboronylated chitosan as the carrier

ObjectiveTo prepare chitosan-loaded nanoparticles (NPs) that enhance the oral bioavailability of puerarin (Pur) and render it responsive to reactive oxygen species (ROS). SignificanceThis research makes substantial progress towards the theory of intelligent drug delivery, offering a new reference for combining Pur with other natural medicinal active ingredients. MethodsThe acylation reaction between chitosan and ROS-sensitive 3-carboxyphenylboronic acid (PBA) was used to synthesise ROS-sensitive phenylboronylated chitosan (PBACS). Subsequently, PBACS-PBA-Pur-NPs and PBACS-TPP-Pur-NPs were prepared via ion gelation after the addition of PBA and sodium tripolyphosphate(TPP), respectively. The physicochemical and functional properties of both NPs were compared, and their differences were preliminarily studied through molecular docking. ResultsReactive oxygen species-sensitive PBACS was successfully synthesised. Of the two NPs prepared, PBACS-TPP-Pur-NPs had a size of 127.2 ± 0.80 nm, polydispersity index (PDI) of 0.129 ± 0.0008, and an encapsulation rate of 95.75 ± 0.387%, whereas PBACS-PBA-Pur-NPs had a size of 149.8 ± 0.1414 nm, PDI of 0.389 ± 0.0012, and an encapsulation rate of 91.77 ± 0.279%. The micromorphology of the PBACS-TPP-Pur-NPs exhibited better physical properties. However, PBACS-PBA-Pur-NPs demonstrated a faster in vitro release and more significant in vitro anti-inflammatory effects. Pharmacokinetically, the AUC0-24, Tmax, and Cmax of PBACS-PBA-Pur-NPs were 3.485, 2.117, and 3.339 times higher, respectively, than those of Pur. The AUC0-24, Tmax, and Cmax of PBACS-TPP-Pur-NPs were 2.41, 1.33, and 2.03 times higher, respectively, than those of Pur. Molecular simulation revealed that the binding energy of PBACS-PBA-Pur -NPs was approximately -4.34 kcal/mol and that of PBACS-TPP-Pur-NPs was even lower, approximately -5.93 kcal/mol, suggesting that the NPs prepared with TPP are more densely packed than those designed with PBA, resulting in slower and reduced drug release. ConclusionThe NPs constructed in this study effectively reduced inflammatory factors at the disease site, providing a theoretical and experimental basis for the application of nano drugs in inflammatory disease models. In addition, the molecular docking study of the two NPs offered insights into the relationship between the release and structure of subsequent nano drugs.

Enteric neuroprotection-A matter of balancing redox potentials, limiting inflammation, and boosting resilience.

The enteric nervous system (ENS) orchestrates intricate and autonomous functions throughout the gastrointestinal (GI) tract. Disruptions in ENS function are associated GI disorders. This mini review focuses on the past decade's research, utilizing rodent models, with an emphasis on protecting enteric neurons from loss. The review specifically looks at efforts to reduce oxidative stress, limit inflammation, and enhance neuronal resilience. Protective interventions including administration of antioxidants and compounds targeting cellular redox buffer systems, are evaluated for their effectiveness in preventing loss of enteric neurons in the ischemia-reperfusion model and streptozotocin-induced diabetes model. Interventions such as engrafting mesenchymal stem cells and targeting inflammatory signaling pathways in enteric neurons and glial cells are evaluated in inflammatory bowel disease models including the Winnie mouse, DSS-, and DNBS/TNBS-induced colitis models. The review also touches upon neuronal resilience, particularly in the context of Parkinson's disease models. Including estrogen's neuroprotective role, and the influence of metal ions on enteric neuronal protection. Understanding the dynamic interplay within the ENS and its role in disease pathogenesis holds promise for developing targeted therapies to effectively manage and treat various GI ailments.

Discovery of GPR84 Fluorogenic Probes Based on a Novel Antagonist for GPR84 Bioimaging.

GPR84 is a promising therapeutic target and biomarker for a range of diseases. In this study, we reported the discovery of BINOL phosphate (BINOP) derivatives as GPR84 antagonists. By investigating the structure-activity relationship, we identified 15S as a novel GPR84 antagonist. 15S exhibits low nanomolar potency and high selectivity for GPR84, while its enantiomer 15R is less active. Next, we rationally designed and synthesized a series of GPR84 fluorogenic probes by conjugating Nile red and compound 15S. The leading hybrid, probe F8, not only retained GPR84 activity but also exhibited low nonspecific binding and a turn-on fluorescent signal in an apolar environment. F8 enabled visualization and detection of GPR84 in GPR84-overexpressing HEK293 cells and lipopolysaccharide-stimulated neutrophils. Furthermore, we demonstrated that F8 can detect upregulated GPR84 protein levels in mice models of inflammatory bowel disease and acute lung injury. Thus, compound F8 represents a promising tool for studying GPR84 functions.

Hydroethanolic Extract of Lepidium apetalum Willdenow Alleviates Dextran Sulfate Sodium-Induced Colitis by Enhancing Intestinal Barrier Integrity and Inhibiting Oxidative Stress and Inflammasome Activation.

The prevalence of ulcerative colitis (UC) has surged in Asian nations recently. The limitations of traditional drug treatments, including biologics, have spurred interest in herbal medicines for managing UC. This study aimed to elucidate the protective mechanisms of hydroethanolic extract from Lepidium apetalum Willdenow (LWE) on intestinal integrity and inflammation in a dextran sodium sulfate (DSS)-induced colitis model of inflammatory bowel disease (IBD). Using UPLC-MS/MS analysis, eleven phytochemicals were identified in LWE, including catechin, vicenin-2, and quercetin. LWE restored transepithelial electrical resistance (TEER) and reduced paracellular permeability in IL-6-stimulated Caco-2 cells, increasing the expression of the tight junction proteins ZO-1 and occludin. LWE treatment alleviated DSS-induced colitis symptoms in mice, reducing body weight loss, disease activity index values, and spleen size, while improving colon length and reducing serum FITC-dextran levels, indicating enhanced intestinal barrier function. LWE suppressed NLRP3 inflammasome activation, reducing protein levels of pro-caspase-1, cleaved-caspase-1, ASC, and NLRP3, as well as mRNA levels of IL-1β, IL-6, and TNF-α. LWE treatment upregulated activity and mRNA levels of the antioxidant enzymes SOD1 and NQO1. Additionally, LWE modulated the Nrf2/Keap1 pathway, increasing p-Nrf2 levels and decreasing Keap1 levels. LWE also restored goblet cell numbers and reduced fibrosis in DSS-induced chronic colitis mice, increasing gene and protein expressions of ZO-1 and occludin. In summary, LWE shows promise as a therapeutic intervention for reducing tissue damage and inflammation by enhancing intestinal barrier function and inhibiting colonic oxidative stress-induced inflammasome activation.

Fucoidan modulates gut microbiota and immunity in Peyer's patches against inflammatory bowel disease

Although fucoidan has potential use as an anti-inflammatory agent, the specific mechanisms by which it influences signaling and immunomodulatory pathways between gut microbiota and Peyer's patches remain unclear. Therefore, the aim of this study was to investigate the therapeutic potential of fucoidan in a dextran sulfate sodium (DSS)-induced mouse model of inflammatory bowel disease (IBD) by examining the effects on gut microbiota and the underlying anti-inflammatory mechanisms. Purified fucoidan, which upon characterization revealed structural fragments comprising →3)-β-D-Galp-(1→, →4)-α-L-Fucp-(1→, and →3)-α-L-Fucp-(1→ residues with a sulfation at position C2 was used. Treatment of the mice with fucoidan significantly alleviated the symptoms of IBD and restored the diversity of gut microbiota by enhancing the abundance of Bacteroidetes and reducing the proportion of Firmicutes. The administration of fucoidan also elevated levels of short-chain fatty acids while reducing the levels of pro-inflammatory cytokines, including interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ. Most importantly, fucoidan attenuated the expression of integrin α4β7/MAdCAM-1 and CCL25/CCR9, which are involved in homing intestinal lymphocytes within Peyer's patches. These findings indicate that fucoidan is a promising gut microbiota modulator and an anti-inflammatory agent for IBD.

NRF2 Plays a Crucial Role in the Tolerogenic Effect of Ethyl Pyruvate on Dendritic Cells.

Ethyl pyruvate (EP) is a redox-active compound that has been previously shown to be effective in restraining immune hyperactivity in animal models of various autoimmune and chronic inflammatory diseases. Importantly, EP has also been proven to have a potent tolerogenic effect on dendritic cells (DCs). Here, the influence of EP on the signaling pathways in DCs relevant for their tolerogenicity, including anti-inflammatory NRF2 and pro-inflammatory NF-κB, was explored. Specifically, the effects of EP on DCs obtained by GM-CSF-directed differentiation of murine bone marrow precursor cells and matured under the influence of lipopolysaccharide (LPS) were examined via immunocytochemistry and RT-PCR. EP counteracted LPS-imposed morphological changes and down-regulated the LPS-induced expression of pro-inflammatory mediators in DCs. While it reduced the activation of NF-κB, EP potentiated NRF2 and downstream antioxidative molecules, thus implying the regulation of NRF2 signaling pathways as the major reason for the tolerizing effects of EP on DCs.

Tryptanthrin suppresses multiple inflammasome activation to regulate NASH progression by targeting ASC protein

BackgroundThe adaptor protein apoptosis-associated speck-like protein (ASC) containing a caspase recruitment domain (CARD) can be activated through pyrin domain (PYD) interactions between sensors and ASC, and through CARD interactions between caspase-1 and ASC. Although the majority of ternary inflammasome complexes depend on ASC, drugs targeting ASC protein remain scarce. After screening natural compounds from Isatidis Radixin, we found that tryptanthrin (TPR) could inhibit NLRP3-induced IL-1β and caspase-1 production, but the underlying anti-inflammatory mechanisms remain to be elucidated. PurposeThe purpose of this study was to determine the impact of TPR on the NLRP3, NLRC4, and AIM2 inflammasomes and the underlying mechanisms. Additionally, the efficacy of TPR was analysed in the further course of methionine- and choline-deficient (MCD)–induced NASH and lipopolysaccharide (LPS)–induced sepsis models of mice. MethodsIn vitro studies used bone marrow-derived macrophages to assess the anti-inflammatory activity of TPR, and the techniques included western blot, testing of intracellular K+ and Ca2+, immunofluorescence, enzyme-linked immunosorbent assay (ELISA), co-immunoprecipitation, ASC oligomerization assay, surface plasmon resonance (SPR), and molecular docking. We used LPS-induced sepsis models and MCD-induced NASH models in vivo to evaluate the effectiveness of TPR in inhibiting inflammatory diseases. ResultsOur observations suggested that TPR could inhibit NLRP3, NLRC4, and AIM2 inflammasome activation. As shown in a mouse model of inflammatory diseases caused by MCD-induced NASH and LPS-induced sepsis, TPR significantly alleviated the progression of diseases. TPR interrupted the interactions between ASC and NLRP3/NLRC4/AIM2 in the co-immunoprecipitation experiment, and stable binding of TPR to ASC was also evident in SPR experiments. The underlying mechanisms of anti-inflammatory activities of TPR might be associated with targeting ASC, in particular, PYD domain of ASC. ConclusionIn general, the requirement for ASC in multiple inflammasome complexes makes TPR, as a novel broad-spectrum inflammasome inhibitor, potentially useful for treating a wide range of multifactorial inflammasome-related diseases.

Elevated WTAP promotes hyperinflammation by increasing m6A modification in inflammatory disease models.

Emerging evidence has linked the dysregulation of N6-methyladenosine (m6A) modification to inflammation and inflammatory diseases, but the underlying mechanism still needs investigation. Here, we found that high levels of m6A modification in a variety of hyperinflammatory states are p65-dependent because Wilms tumor 1-associated protein (WTAP), a key component of the "writer" complex, is transcriptionally regulated by p65, and its overexpression can lead to increased levels of m6A modification. Mechanistically, upregulated WTAP is more prone to phase separation to facilitate the aggregation of the writer complex to nuclear speckles and the deposition of m6A marks on transcriptionally active inflammatory transcripts, thereby accelerating the proinflammatory response. Further, a myeloid deficiency in WTAP attenuates the severity of LPS-induced sepsis and DSS-induced IBD. Thus, the proinflammatory effect of WTAP is a general risk-increasing mechanism, and interrupting the assembly of the m6A writer complex to reduce the global m6A levels by targeting the phase separation of WTAP may be a potential and promising therapeutic strategy for alleviating hyperinflammation.

Tectorigenin inhibits inflammatory responses in murineinflammatory bowel disease and LPS-stimulated macrophages via inactivating MAPK signaling pathway.

Considering the antihepatitis effects of Tectorigenin (TEC), and the same adenosine mitogen-activated protein kinase (MAPK) pathway in both hepatitis and inflammatory bowel disease (IBD) models, exploring the role of TEC in IBD is contributive to develop a new treatment strategy against IBD. The IBD mouse model was constructed by feeding with dextran sodium sulfate (DSS) and injection of TEC. Afterward, the mouse body weight, colon length, and disease activity index (DAI) were tested to assess the enteritis level. Mouse intestine lesions were detected by hematoxylin and eosin staining. Murine macrophages underwent lipopolysaccharide (LPS) induction to establish an inflammation model. Cell viability was determined by cell counting kit-8 assay. Enzyme-linked immunosorbent assay was performed to measure interleukin 6(IL-6) and tumor necrosis factor-α (TNF-α) levels. Cyclooxygenase-2(COX-2) and inducible nitric oxide synthase(iNOS) expressions were quantified via quantitative reverse transcription polymerase chain reaction. Levels of MAPK pathway-related proteins (p-P38, P38, p-Jun N-terminal kinase(JNK), JNK, signal-regulated kinase(ERK), p-ERK), COX-2 and iNOS were quantitated by Western blot. TEC improved the inflammatory response through ameliorating weight loss, shortening colon, and increasing DAI score in IBD mouse. Expressions of intestinal inflammatory factors (IL-6, TNF-α, iNOS and COX-2) and MAPK pathway-related proteins (p-P38, p-JNK, and p-ERK) were increased both in DSS-induced mouse intestinal tissue, but TEC inhibited expressions of inflammatory factors. The same increased trend was identified in LPS-induced macrophages, but TEC improved macrophage inflammation, as evidenced by downregulation of inflammatory factors. TEC mitigates IBD and LPS-induced macrophage inflammation in mice via inhibiting MAPK signaling pathway.

Research Progress on Anti-Inflammatory Effects and Related Mechanisms of Astragalin.

Chronic inflammation is a significant contributor to the development of cancer, cardiovascular disease, diabetes, obesity, autoimmune disease, inflammatory bowel disease, and other illnesses. In the academic field, there is a constant demand for effective methods to alleviate inflammation. Astragalin (AST), a type of flavonoid glycoside that is the primary component in several widely used traditional Chinese anti-inflammatory medications in clinical practice, has garnered attention from numerous experts and scholars. This article focuses on the anti-inflammatory effects of AST and conducts research on relevant literature from 2003 to 2023. The findings indicate that AST demonstrates promising anti-inflammatory potential in various models of inflammatory diseases. Specifically, AST is believed to possess inhibitory effects on inflammation-related factors and protein levels in various in vitro cell models, such as macrophages, microglia, and epithelial cells. In vivo studies have shown that AST effectively alleviates neuroinflammation and brain damage while also exhibiting potential for treating moderate diseases such as depression and stroke; it also demonstrates significant anti-inflammatory effects on both large and small intestinal epithelial cells. Animal experiments have further demonstrated that AST exerts therapeutic effects on colitis mice. Molecular biology studies have revealed that AST regulates complex signaling networks, including NF-κB, MAPK, JAK/STAT pathways, etc. In conclusion, this review will provide insights and references for the development of AST as an anti-inflammatory agent as well as for related drug development.

The Effects of Endosomal Toll-like Receptor Inhibitors in an EBV DNA-Exacerbated Inflammatory Bowel Disease Mouse Model.

Epstein-Barr virus (EBV), a Herpesviridae family member, is associated with an increased risk of autoimmune disease development in the host. We previously demonstrated that EBV DNA elevates levels of the pro-inflammatory cytokine IL-17A and that inhibiting Toll-like receptor (TLR) 3, 7, or 9 reduces its levels. Moreover, this DNA exacerbated colitis in a mouse model of inflammatory bowel disease (IBD). In the study at hand, we examined whether inhibition of TLR3, 7, or 9 alleviates this exacerbation. Mice were fed 1.5% dextran sulfate sodium (DSS) water and administered EBV DNA. Then, they were treated with a TLR3, 7, or 9 inhibitor or left untreated. We also assessed the additive impact of combined inhibition of all three receptors. Mice that received DSS, EBV DNA, and each inhibitor alone, or a combination of inhibitors, showed significant improvement. They also had a decrease in the numbers of the pathogenic colonic IL-17A+IFN-γ+ foci. Inhibition of all three endosomal TLR receptors offered no additive benefit over administering a single inhibitor. Therefore, inhibition of endosomal TLRs reduces EBV DNA exacerbation of mouse colitis, offering a potential approach for managing IBD patients infected with EBV.

Alpha 7 Nicotinic Acetylcholine Receptor Agonist PHA 568487 Reduces Acute Inflammation but Does Not Affect Cardiac Function or Myocardial Infarct Size in the Permanent Occlusion Model.

Stimulation of the alpha 7 nicotinic acetylcholine receptor (α7nAChR) has shown beneficial effects in several acute inflammatory disease models. This study aims to examine whether treatment with the selective α7nAChR agonist PHA 568487 can dampen inflammation and thereby improve cardiac function after myocardial infarction in mice. The possible anti-inflammatory properties of α7nAChR agonist PHA 568487 were tested in vivo using the air pouch model and in a permanent occlusion model of acute myocardial infarction in mice. Hematologic parameters and cytokine levels were determined. Infarct size and cardiac function were assessed via echocardiography 24 h and one week after the infarction. Treatment with α7nAChR agonist PHA 568487 decreased 12 (CCL27, CXCL5, IL6, CXCL10, CXCL11, CXCL1, CCL2, MIP1a, MIP2, CXCL16, CXCL12 and CCL25) out of 33 cytokines in the air pouch model of acute inflammation. However, α7nAChR agonist PHA 568487 did not alter infarct size, ejection fraction, cardiac output or stroke volume at 24 h or at 7 days after the myocardial infarction compared with control mice. In conclusion, despite promising immunomodulatory effects in the acute inflammatory air pouch model, α7nAChR agonist PHA 568487 did not affect infarct size or cardiac function after a permanent occlusion model of acute myocardial infarction in mice. Consequently, this study does not strengthen the hypothesis that stimulation of the α7nAChR is a future treatment strategy for acute myocardial infarction when reperfusion is lacking. However, whether other agonists of the α7nAChR can have different effects remains to be investigated.

Metabolic rewiring promotes anti-inflammatory effects of glucocorticoids.

Glucocorticoids represent the mainstay of therapy for a broad spectrum of immune-mediated inflammatory diseases. However, the molecular mechanisms underlying their anti-inflammatory mode of action have remained incompletely understood1. Here we show that the anti-inflammatory properties of glucocorticoids involve reprogramming of the mitochondrial metabolism of macrophages, resulting in increased and sustained production of the anti-inflammatory metabolite itaconate and consequent inhibition of the inflammatory response. The glucocorticoid receptor interacts with parts of the pyruvate dehydrogenase complex whereby glucocorticoids provoke an increase in activity and enable an accelerated and paradoxical flux of the tricarboxylic acid (TCA) cycle in otherwise pro-inflammatory macrophages. This glucocorticoid-mediated rewiring of mitochondrial metabolism potentiates TCA-cycle-dependent production of itaconate throughout the inflammatory response, thereby interfering with the production of pro-inflammatory cytokines. By contrast, artificial blocking of the TCA cycle or genetic deficiency in aconitate decarboxylase 1, the rate-limiting enzyme of itaconate synthesis, interferes with the anti-inflammatory effects of glucocorticoids and, accordingly, abrogates their beneficial effects during a diverse range of preclinical models of immune-mediated inflammatory diseases. Our findings provide important insights into the anti-inflammatory properties of glucocorticoids and have substantial implications for the design of new classes of anti-inflammatory drugs.