Production Of Pro-inflammatory Mediators Research Articles

Skin-permeable gold nanoparticles with modifications azelamide monoethanolamine ameliorate inflammatory skin diseases

BackgroundTraditional topical drug delivery for treating inflammatory skin diseases suffers from poor skin penetration and long-term side effects. Metal nanoparticles show promising application in topical drug delivery for inflammatory skin diseases.MethodsHere, we synthesized a new type of nanoparticles, azelamide monoethanolamine-functionalized gold nanoparticles (Au-MEA NPs), based on citrate-capped gold nanoparticles (Au-CA NPs) via the ligand exchange method. The physical and chemical properties of Au-CA NPs and Au-MEA NPs were characterized. In vivo studies were performed using imiquimod-induced psoriasis and LL37-induced rosacea animal models, respectively. For in vitro studies, a model of cellular inflammation was established using HaCaT cells stimulated with TNF-α. In addition, proteomics, gelatin zymography, and other techniques were used to investigate the possible therapeutic mechanisms of the Au-MEA NPs.ResultsWe found that Au-MEA NPs exhibited better stability and permeation properties compared to conventional Au-CA NPs. Transcutaneously administered Au-MEA NPs exerted potent therapeutic efficacy against both rosacea-like and psoriasiform skin dermatitis in vivo without overt signs of toxicity. Mechanistically, Au-MEA NPs reduced the production of pro-inflammatory mediators in keratinocytes by promoting SOD activity and inhibiting the activity of MMP9.ConclusionAu-MEA NPs have the potential to be a topical nanomedicine for the effective and safe treatment of inflammatory skin diseases.

The Role of Next-Generation Sequencing (NGS) in the Relationship between the Intestinal Microbiome and Periprosthetic Joint Infections: A Perspective

Periprosthetic joint infections are still a challenge in orthopedics and traumatology. Nowadays, genomics comes to the aid of diagnosis and treatment, in addition to traditional methods. Recently, a key role of the intestinal microbiota has been postulated, and great efforts are aimed at discovering its interconnection, which shows to be at different levels. Firstly, the gut microbiome influences the immune system through the gut-associated lymphoid tissue (GALT). A balanced microbiome promotes a strong immune response, which is essential to prevent all local and systemic infections, including PJI. Thus, a dysbiosis, i.e., the disruption of this system, leads to an imbalance between the various strains of microorganisms co-existing in the gut microbiome, which can result in a weakened immune system, increasing susceptibility to infections, including PJI. Additionally, the dysbiosis can result in the production of pro-inflammatory mediators that enter the systemic circulation, creating a state of chronic inflammation that can compromise the immune system’s ability to fend off infections. Furthermore, the microbiome maintains the integrity of the gut barrier, preventing the translocation of harmful bacteria and endotoxins into the bloodstream; dysbiosis can compromise this protective “wall”. In addition, the gut microbiome may harbor antibiotic-resistance genes; during antibiotic treatment for other infections or prophylaxis, these genes may be transferred to pathogenic bacteria, making the treatment of PJI more difficult. In this complex landscape, next-generation sequencing (NGS) technology can play a key role; indeed, it has revolutionized the study of the microbiome, allowing for detailed and comprehensive analysis of microbial communities. It offers insights into the functional potential and metabolic capabilities of the microbiome, studies the collective genome of the microbiome directly from environmental samples sequencing DNA without isolating individual organisms, analyzes the RNA transcripts to understand gene expression and functional activity of the microbiome, analyzes the RNA transcripts to understand gene expression and functional activity of the microbiome, investigates the metabolites produced by the microbiome and studies the entire set of proteins produced by the microbiome. NGS technology, the study of the micromyoma and its implications in the field of orthopedic trauma are innovative topics on which few publications are yet to be found in the international scientific literature. The costs are still high, the focus of research is maximum, and it will certainly change our approach to infections. Our study is an up-to-date review of the hot topic application of NGS in the study and investigation of periprosthetic infections and the microbiome.

Tulipalin A suppressed the pro-inflammatory polarization of M1 macrophage and mitigated the acute lung injury in mice via interference DNA binding activity of NF-κB

Acute lung injury (ALI) is an inflammatory disorder accompanied by higher morbidity and mortality. The pathological mechanism of ALI has been reported to be associated with the release of inflammatory cytokines by macrophages. Sesquiterpene lactones (SLs) represent the principal anti-inflammatory components of many natural products. Tulipalin A is a natural small molecule and a conserved moiety in anti-inflammatory SLs. However, the anti-inflammatory potential of Tulipalin A has yet to be fully disclosed. The present study aims to investigate TulipalinA's anti-inflammatory activity and underlying mechanisms in vitro and in vivo. Tulipalin A suppressed inflammatory responses in lipopolysaccharide (LPS)-stimulated bone marrow-derived primary macrophages and ameliorated LPS-induced ALI in mice. Mechanistically, Tulipalin A directly targets the NF-κB p65 and disrupts its DNA binding activity, thereby impeding the activation of NF-κB. Inhibition of NF-κB attenuated M1 polarization of macrophages, consequently suppressing the production of pro-inflammatory mediators and ameliorating the onset and progression of ALI. These findings suggest Tulipalin A's potential to mitigate inflammatory disorders like ALI via targeting NF-κB p65 and disrupting its DNA binding activity.

Plant extracts and omega-3 supplementation modulate hippocampal oxylipin profile in response to LPS-induced neuroinflammation.

Neuroinflammation is a protective mechanism but can become harmful if chronic and/or unregulated, leading to neuronal damage and cognitive alterations. Limiting inflammation and promoting resolution could be achieved with nutrients such as grapes and blueberries polyphenols, saffron carotenoids, and omega-3, which have anti-inflammatory and proresolutive properties. This study explored the impact of 18-day supplementation with plant extracts (grape, blueberry and saffron), omega-3 or both (mix) on neuroinflammation induced by lipopolysaccharide (LPS, 250µg/kg) in 149 mice at different time points post-LPS treatment (30min, 2h, 6h). Inflammatory, oxidative and neuroprotective gene expression; oxylipin quantification; and fatty acid composition were analyzed at each time point. PCA analysis was performed with all these biomarkers. Mix supplementation induced changes in the resolution of inflammation. In fact, the production of proinflammatory mediators in the hippocampus started earlier in the supplemented group than in the LPS group. Pro-resolving mediators were also found in higher quantities in supplemented mice. These changes were associated with increased hippocampal antioxidant status at 6h post-LPS. These findings suggest that such dietary interventions with plant extracts, and omega-3 could be beneficial in preventing neuroinflammation and, consequently, age-related cognitive decline. Further research is needed to explore the effects of these supplements on chronic inflammation in the context of aging.

RBM25 is required to restrain inflammation via ACLY RNA splicing-dependent metabolism rewiring.

Spliceosome dysfunction and aberrant RNA splicing underline unresolved inflammation and immunopathogenesis. Here, we revealed the misregulation of mRNA splicing via the spliceosome in the pathogenesis of rheumatoid arthritis (RA). Among them, decreased expression of RNA binding motif protein 25 (RBM25) was identified as a major pathogenic factor in RA patients and experimental arthritis mice through increased proinflammatory mediator production and increased hyperinflammation in macrophages. Multiomics analyses of macrophages from RBM25-deficient mice revealed that the transcriptional enhancement of proinflammatory genes (including Il1b, Il6, and Cxcl10) was coupled with histone 3 lysine 9 acetylation (H3K9ac) and H3K27ac modifications as well as hypoxia inducible factor-1α (HIF-1α) activity. Furthermore, RBM25 directly bound to and mediated the 14th exon skipping of ATP citrate lyase (Acly) pre-mRNA, resulting in two distinct Acly isoforms, Acly Long (Acly L) and Acly Short (Acly S). In proinflammatory macrophages, Acly L was subjected to protein lactylation on lysine 918/995, whereas Acly S did not, which influenced its affinity for metabolic substrates and subsequent metabolic activity. RBM25 deficiency overwhelmingly increased the expression of the Acly S isoform, enhancing glycolysis and acetyl-CoA production for epigenetic remodeling, macrophage overactivation and tissue inflammatory injury. Finally, macrophage-specific deletion of RBM25 led to inflammaging, including spontaneous arthritis in various joints of mice and inflammation in multiple organs, which could be relieved by pharmacological inhibition of Acly. Overall, targeting the RBM25-Acly splicing axis represents a potential strategy for modulating macrophage responses in autoimmune arthritis and aging-associated inflammation.

Bioguided Optimization of the Nutrition-Health, Antioxidant, and Immunomodulatory Properties of Manihot esculenta (Cassava) Flour Enriched with Cassava Leaves.

Manihot esculenta (cassava) roots is a major food crop for its energy content. Leaves contain nutrients and demonstrate biological properties but remain undervalorized. In order to develop a bioguided optimization of cassava nutrition-health properties, we compared the phytochemistry and bioactive potential of cassava root flour extract (CF) with cassava flour extract enriched with 30% leaves powder (CFL). Cassava flour supplementation impact was explored on flour composition (starch, fiber, carotenoids, phenolic compounds), in vivo glycemic index, and bioactivity potential using macrophage cells. We assessed the impact of cassava flour supplementation on free radicals scavenging and cellular production of pro-inflammatory mediators. CFL showed higher levels of fiber, carotenoids, phenolic compounds, and lower glycemic index. Significantly higher bioactive properties (anti-inflammatory and antioxidant) were recorded, and inhibition of cytokines production has been demonstrated as a function of extract concentration. Overall, our results indicate that enrichment of cassava flour with leaves significantly enhances its nutrition-health and bioactive potential. This bioguided matrix recombination approach may be of interest to provide prophylactic and therapeutic dietary strategy to manage malnutrition and associated chronic non-communicable diseases characterized by low-grade inflammation and unbalanced redox status. It would also promote a more efficient use of available food resources.

Measures of spatial memory, peripheral inflammation and negative emotional state predict social-cognitive skills in healthy aging cats

Aging is a complex, multidimensional process. Normative aging is typically accompanied by declines in several cognitive domains, including memory and social cognition. As aging progresses, the often-overlooked early manifestations of cognitive decline can advance, leading to an inability to adapt to new situations and environments. Potential mechanisms influencing cognitive decline remain elusive, but, among other mechanisms, inflammaging, an age-related increase in the chronic production of pro-inflammatory mediators, and emotional stress are implicated. Cognitive function in cats is under-researched, with no studies on the link between potential risk factors and cognitive signs in aging subjects. Understanding this link is essential as it may facilitate the early identification of cognitive decline and encourage preventative, individualized interventions. We carried out a citizen science study to investigate, for the first time, the relationship between cognitive functions, stress, and the inflammatory markers interleukin (IL)-1β and IL-10 in 44 healthy, privately owned pet cats (7–14 years of age), who underwent standardized testing in their home environment. A task was employed to test spatial memory, requiring the cat to recall the location of a food-baited container. An unsolvable task was used to assess cats' social cognition and cognitive flexibility by measuring how they used referential communication (i.e., gaze alternation between the apparatus and the caregivers) compared to their persistence in trying to obtain food which was out of reach. Generalized linear regression analysis, conducted while adjusting for demographic factors and stress behaviors, revealed: 1) a predictive positive relationship connecting spatial memory and the use of social referencing with the caregiver (more gaze alternation) in the unsolvable task, highlighting the importance of the interplay between cognitive domains in sustaining complex behaviors, and 2) a reduced engagement in social referencing toward caregivers (less gaze alternation) in the presence of higher serum levels of IL-1β in the unsolvable task, especially as cats get older. A cat’s social cognitive performance was also negatively predicted by stress-related behaviors, which is not surprising given that cats are sentient creatures whose everyday behavior is also influenced by emotional states. These findings provide new insights into the crosstalk between different cognitive domains during aging and the potential contributions of emotions and inflammation to cognitive changes in healthy aging cats. Further research using this multidimensional approach will help explore these mechanisms of cognitive aging and potential markers for early detection of cognitive changes in older cats, which is critical for timely interventions.

Hovenia dulcis Thunb. monofloral honey attenuates LPS-induced inflammation and endotoxemia through the activation of the Nrf2/HO-1 axis

Monofloral honey derived from Hovenia dulcis Thunb. (HMH) is known for its antimicrobial and antioxidant properties. However, its potential to alleviate the inflammatory response has not yet been explored. The aim of this study was to investigate the anti-inflammatory and anti-endotoxemic effects of HMH. The findings showed that HMM did not exhibit toxicity to RAW 264.7 macrophages at low concentrations and suppressed the production of proinflammatory mediators, such as nitric oxide and prostaglandin E2, as well as cytokines, including tumor necrosis factor-α and interleukin-12 in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages, by inhibiting NF-κB activation. Additionally, HMH prevented mortality and abnormalities in LPS-microinjected zebrafish larvae along with the inhibition of proinflammatory genes. In addition, HMH was found to reduce mitochondrial membrane potential depolarization and mitochondrial reactive oxygen species production in both LPS-stimulated RAW 264.7 macrophages and zebrafish larvae. Furthermore, HMH induces the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) and promotes the nuclear translocation of Nrf2. The anti-inflammatory effects of HMH are mediated via the Nrf2-HO-1 axis, and an HO-1 inhibitor reverses HMH-induced responses. This study is the first to demonstrate the anti-inflammatory and anti-endotoxemic effects of HMH, highlighting its potential as a therapeutic.

Schisandrin B alleviates testicular inflammation and Sertoli cell apoptosis via AR-JNK pathway

Bacterial testicular inflammation is one of the important causes of male infertility. Using plant-derived compounds to overcome the side effects of antibiotics is an alternative treatment strategy for many diseases. Schizandrin B (SchB) is a bioactive compound of herbal medicine Schisandra chinensis which has multiple pharmacological effects. However its effect and the mechanism against testicular inflammation are unknown. Here we tackled these questions using models of lipopolysaccharide (LPS)-induced mice and -Sertoli cells (SCs). Histologically, SchB ameliorated the LPS-induced damages of the seminiferous epithelium and blood-testicular barrier, and reduced the production of pro-inflammatory mediators in mouse testes. Furthermore, SchB decreased the levels of pro-inflammatory mediators and inhibited the nuclear factor kB (NF-κB) and MAPK (especially JNK) signaling pathway phosphorylation in LPS-induced mSCs. The bioinformatics analysis based on receptor prediction and the molecular docking was further conducted. We targeted androgen receptor (AR) and illustrated that AR might bind with SchB in its function. Further experiments indicate that the AR expression was upregulated by LPS stimulation, while SchB treatment reversed this phenomenon; similarly, the expression of the JNK-related proteins and apoptotic-related protein were also reversed after AR activator treatment. Together, SchB mitigates LPS-induced inflammation and apoptosis by inhibiting the AR-JNK pathway.

Unveiling the Unexplored Multifactorial Potential of 5-Aminosalicylic Acid in Diabetic Wound Therapy.

Diabetic wounds (DWs) are considered chronic complications observed in patients suffering from type 2 diabetes mellitus (DM). Usually, DWs originate from the interplay of inflammation, oxidation, impaired tissue re-epithelialization, vasculopathy, nephropathy, and neuropathy, all of which are related to insulin resistance and sensitivity. The conventional approaches available for the treatment of DWs are mainly confined to the relief of wound pressure, debridement of the wound, and management of infection. In this paper, we speculate that treatment of DWs with 5-aminosalicylic acid (5-ASA) and subsequent activation of peroxisome proliferator-activated receptor gamma (PPAR-γ) and transforming growth factor beta (TGF-β) via the AhR pathway might be highly beneficial for DW patients. This estimation is based on several lines of evidence showing that 5-ASA and PPAR-γ activation are involved in the restoration of insulin sensitivity, re-epithelialization, and microcirculation. Additionally, 5-ASA and TGF-β activate inflammation and the production of pro-inflammatory mediators. Suitable stabilized formulations of 5-ASA with high absorption rates are indispensable for scrutinizing its probable pharmacological benefits since 5-ASA is known to possess lower solubility profiles because of its reduced permeability through skin tissue. In vitro and in vivo studies with stabilized formulations and a control (placebo) are mandatory to determine whether 5-ASA indeed holds promise for the curative treatment of DWs.

Syringin from Tinospora crispa downregulates pro-inflammatory mediator production through MyD88-dependent pathways in lipopolysaccharide (LPS)-induced U937 macrophages.

Syringin, a phenylpropanoid glycoside, has exhibited numerous biological properties including inhibitory activities against various immune and inflammatory disorders. In this study, syringin isolated from Tinospora crispa was evaluated for its ability to down-regulate activated nuclear factor-kappa B (NF-κB), phosphoinositide-3-kinase-Akt (PI3K-Akt) and mitogen-activated protein kinases (MAPKs) signal transducing networks in U937 macrophages activated by lipopolysaccharide. The attenuating effects of syringin on the productions of prostaglandin E2 (PGE2), cyclooxygenase-2 (COX-2), interleukin-1β (IL-1β), and tumor necrosis factor-α (TNF-α), and the expressions of signaling molecules of the signaling pathways were investigated by using ELISA, Western blot, and qRT-PCR. Syringin downregulated the NF-κB, MAPKs, and PI3K-Akt signal networks by significantly reducing PGE2 production in the macrophages via suppression of COX-2 gene and protein expression levels. It also reduced TNF-α and IL-1β secretion and their mRNA expression, suppressed phosphorylation of NF-κB (p65), IKKα/β, and IκBα, and restored ability of IκBα to degrade. Syringin dose-dependently attenuated Akt, p38 MAPKs, JNK, and ERK phosphorylation. Also, the expression of corresponding upstream signaling molecules toll-like receptor 4 (TLR4) and myeloid differentiation primary response gene 88 (MyD88) were down-regulated in response to syringin treatment. The suppressive effect of syringin on the inflammatory signaling molecules in MyD88-dependent pathways suggested it's potential as a drug candidate for development into an agent for treatment of various immune-mediated inflammatory disorders.

Network Pharmacology-Based Strategy Integrated with Molecular Docking and In Vitro Experimental Validation to Explore the Underlying Mechanism of Fangji Huangqi Decoction in Treating Rheumatoid Arthritis.

Fangji Huangqi decoction (FHD), as a classic traditional Chinese medicine formula, has been clinically proven effective against rheumatoid arthritis (RA), yet its therapeutic mechanism remains unclear. This study employed network pharmacology and molecular docking methods to explore the major active components, biological targets, and signaling pathways of FHD. Subsequently, lipopolysaccharide (LPS)-stimulated RAW264.7 cells were used as the in vitro model to validate the modulating effects of FHD on molecules/inflammatory mediators using various biomedical techniques/kits such as MTT assay, Griess reagents, flow cytometry, RT-qPCR, and immunoblotting. Network pharmacology analyses indicated a total of 20 major active components and 30 core biological targets of FHD against RA. Pathway enrichment analyses demonstrated the involvement of mitogen-activated protein kinase (MAPK) signaling pathways in the efficacy of the formula. Furthermore, experimental evidence demonstrated that FHD dose-dependently and significantly inhibited the productions of nitric oxide (NO) and reactive oxygen species; lowered the mRNA expression levels of proinflammatory mediators including iNOS, COX-2, TNF-α, ΙL-1β, and IL-6; decreased protein levels of the phosphorylated forms of p38, ERK, JNK, and NF-κB p65. Additionally, the results of molecular docking showed that tetrandrine, licochalcone A, oxonantenine, isorhamnetin, and kaempferol in FHD exerted the potent capability of binding to target molecules in the focused signaling pathway, probably being the potential effective substances for FHD. Our network pharmacology study integrated with cellular validation has elucidated that FHD exerts downregulating effects of the MAPK and NF-κB signaling pathway, ultimately leading to inhibitory effects on the productions of proinflammatory mediators in LPS-stimulated RAW264.7 cells. This work comprehensively demonstrated the effective substances, key targets, and signaling pathways involved in the anti-RA effects of the formula, and these findings provide a further understanding of the underlying mechanism of FHD in managing RA.

Extracellular vesicles from primary human macrophages stimulated with VIP or PACAP mediate anti-SARS-CoV-2 activities in monocytes through NF-κB signaling pathway

Infection by SARS-CoV-2 is associated with uncontrolled inflammatory response during COVID-19 severe disease, in which monocytes are one of the main sources of pro-inflammatory mediators leading to acute respiratory distress syndrome. Extracellular vesicles (EVs) from different cells play important roles during SARS-CoV-2 infection, but investigations describing the involvement of EVs from primary human monocyte-derived macrophages (MDM) on the regulation of this infection are not available. Here, we describe the effects of EVs released by MDM stimulated with the neuropeptides VIP and PACAP on SARS-CoV-2-infected monocytes. MDM-derived EVs were isolated by differential centrifugation of medium collected from cells cultured for 24 h in serum-reduced conditions. Based on morphological properties, we distinguished two subpopulations of MDM-EVs, namely large (LEV) and small EVs (SEV). We found that MDM-derived EVs stimulated with the neuropeptides inhibited SARS-CoV-2 RNA synthesis/replication in monocytes, protected these cells from virus-induced cytopathic effects and reduced the production of pro-inflammatory mediators. In addition, EVs derived from VIP- and PACAP-treated MDM prevented the SARS-CoV-2-induced NF-κB activation. Overall, our findings suggest that MDM-EVs are endowed with immunoregulatory properties that might contribute to the antiviral and anti-inflammatory responses in SARS-CoV-2-infected monocytes and expand our knowledge of EV effects during COVID-19 pathogenesis.

The Hydroxypyridinone Iron Chelator DIBI Reduces Bacterial Load and Inflammation in Experimental Lung Infection.

Iron plays a critical role in lung infections due to its function in the inflammatory immune response but also as an important factor for bacterial growth. Iron chelation represents a potential therapeutic approach to inhibit bacterial growth and pathologically increased pro-inflammatory mediator production. The present study was designed to investigate the impact of the iron chelator DIBI in murine lung infection induced by intratracheal Pseudomonas aeruginosa (strain PA14) administration. DIBI is a polymer with a polyvinylpyrrolidone backbone containing nine 3-hydroxy-1-(methacrylamidoethyl)-2-methyl-4(1H) pyridinone (MAHMP) residues per molecule and was given by intraperitoneal injection either as a single dose (80 mg/kg) immediately after PA14 administration or a double dose (second dose 4 h after PA14 administration). The results showed that lung NF-κBp65 levels, as well as levels of various inflammatory cytokines (TNFα, IL-1β, IL-6) both in lung tissue and bronchoalveolar lavage fluid (BALF), were significantly increased 24 h after PA14 administration. Single-dose DIBI did not affect the bacterial load or inflammatory response in the lungs or BALF. However, two doses of DIBI significantly decreased bacterial load, attenuated NF-κBp65 upregulation, reduced inflammatory cytokines production, and relieved lung tissue damage. Our findings support the conclusion that the iron chelator, DIBI, can reduce lung injury induced by P. aeruginosa, via its anti-bacterial and anti-inflammatory effects.

Native Mexican black bean purified anthocyanins fractionated by high-performance counter-current chromatography modulate inflammatory pathways

In addition to their pigment properties, the potential health benefits of anthocyanins have made them a subject of interest in recent years. This study aimed to obtain purified anthocyanin fractions from native Mexican black bean cultivars using Amberlite XAD-7 resin column and HPCCC and evaluate their anti-inflammatory properties using RAW 264.7 cells. The major anthocyanins in the purified anthocyanin fractions were delphinidin 3-glucoside (61.8%), petunidin 3-glucoside (25.2%), and malvidin 3-glucoside (12.2%). Purified anthocyanin fractions at 12.5 μg/mL effectively prevented LPS-induced ERK1/ERK2 phosphorylation and reduced the protein expression of COX-2 and mRNA expression of iNOS. Results showed that purified anthocyanin fractions have the potential to modulate the inflammatory response by inhibiting the production of pro-inflammatory mediators through the ERK1/ERK2 and NF-κB pathways. This study suggests that anthocyanins from black beans could be used as a natural strategy to help modulate inflammation-associated diseases.

Production and Release of Proinflammatory Mediators by the Cockroach Allergen Bla g 1 via a Shared Membrane-Destabilization Mechanism.

The cockroach allergen Bla g 1 encloses an exceptionally large hydrophobic cavity, which allows it to bind and deliver unsaturated fatty acid ligands. Bla g 1-mediated delivery of naturally occurring (nMix) ligands has been shown to destabilize lipid membranes, contributing to its digestive/antiviral functions within the source organism. However, the consequences of this activity on Bla g 1 allergenicity following human exposure remain unknown. In this work, we show that Bla g 1-mediated membrane disruption can induce a proinflammatory immune response in mammalian cells via two complementary pathways. At high concentrations, the cytotoxic activity of Bla g 1 induces the release of proinflammatory cytosolic contents including damage-associated molecular patterns (DAMPs) such as heat-shock Protein-70 (HSP70) and the cytokine interleukin-1 (IL-1β). Sublytic concentrations of Bla g 1 enhanced the ability of phospholipase A2 (PLA2) to extract and hydrolyze phospholipid substrates from cellular membranes, stimulating the production of free polyunsaturated fatty acids (PUFAs) and various downstream inflammatory lipid mediators. Both of these effects are dependent on the presence of Bla g 1's natural fatty-acid (nMix) ligands with CC50 values corresponding to the concentrations required for membrane destabilization reported in previous studies. Taken together, these results suggest that mechanisms through which Bla g 1-mediated lipid delivery and membrane destabilization could directly contribute to cockroach allergic sensitization.

The impact of astrocytic NF-κB on healthy and Alzheimer’s disease brains

Astrocytes play a role in healthy cognitive function and Alzheimer’s disease (AD). The transcriptional factor nuclear factor-κB (NF-κB) drives astrocyte diversity, but the mechanisms are not fully understood. By combining studies in human brains and animal models and selectively manipulating NF-κB function in astrocytes, we deepened the understanding of the role of astrocytic NF-κB in brain health and AD. In silico analysis of bulk and cell-specific transcriptomic data revealed the association of NF-κB and astrocytes in AD. Confocal studies validated the higher level of p50 NF-κB and phosphorylated-p65 NF-κB in glial fibrillary acidic protein (GFAP)+-astrocytes in AD versus non-AD subjects. In the healthy mouse brain, chronic activation of astrocytic NF-κB disturbed the proteomic milieu, causing a loss of mitochondrial-associated proteins and the rise of inflammatory-related proteins. Sustained NF-κB signaling also led to microglial reactivity, production of pro-inflammatory mediators, and buildup of senescence-related protein p16INK4A in neurons. However, in an AD mouse model, NF-κB inhibition accelerated β-amyloid and tau accumulation. Molecular biology studies revealed that astrocytic NF-κB activation drives the increase in GFAP and inflammatory proteins and aquaporin-4, a glymphatic system protein that assists in mitigating AD. Our investigation uncovered fundamental mechanisms by which NF-κB enables astrocytes' neuroprotective and neurotoxic responses in the brain.

The Impact of Weight Cycling on Health and Obesity.

Obesity is a systemic and chronic inflammation, which seriously endangers people's health. People tend to diet to control weight, and the short-term effect of dieting in losing weight is significant, but the prognosis is limited. With weight loss and recovery occurring frequently, people focus on weight cycling. The effect of weight cycling on a certain tissue of the body also has different conclusions. Therefore, this article systematically reviews the effects of body weight cycling on the body and finds that multiple weight cycling (1) increased fat deposition in central areas, lean mass decreased in weight loss period, and fat mass increased in weight recovery period, which harms body composition and skeletal muscle mass; (2) enhanced the inflammatory response of adipose tissue, macrophages infiltrated into adipose tissue, and increased the production of pro-inflammatory mediators in adipocytes; (3) blood glucose concentration mutation and hyperinsulinemia caused the increase or decrease in pancreatic β-cell population, which makes β-cell fatigue and leads to β-cell failure; (4) resulted in additional burden on the cardiovascular system because of cardiovascular rick escalation. Physical activity combined with calorie restriction can effectively reduce metabolic disease and chronic inflammation, alleviating the adverse effects of weight cycling on the body.

The hepatocyte epidermal growth factor receptor (EGFR) pathway regulates the cellular interactome within the liver fibrotic niche.

Liver fibrosis is the consequence of chronic liver injury in the presence of an inflammatory component. Although the main executors of this activation are known, the mechanisms that lead to the inflammatory process that mediates the production of pro-fibrotic factors are not well characterized. Epidermal growth factor receptor (EGFR) signaling in hepatocytes is essential for the regenerative processes of the liver; however, its potential role in regulating the fibrotic niche is not yet clear. Our group generated a mouse model that expresses an inactive truncated form of the EGFR specifically in hepatocytes (ΔEGFR mice). Here, we have analyzed the response of WT and ΔEGFR mice to chronic treatment with carbon tetrachloride (CCl4), which induces a pro-inflammatory and fibrotic process in the liver. The results indicated that the hallmarks of liver fibrosis were attenuated in CCl4-treated ΔEGFR mice when compared with CCl4-treated WT mice, coinciding with a faster resolution of the fibrotic process and ameliorated damage. The absence of EGFR activity in hepatocytes induced changes in the pattern of immune cells in the liver, with a notable increase in the population of M2 macrophages, more related to fibrosis resolution, as well as in the population of lymphocytes related to eradication of the damage. Transcriptome analysis of hepatocytes, and secretome studies of extracellular media from in vitro experiments, allowed us to elucidate the specific molecular mechanisms regulated by EGFR that mediate hepatocyte production of both pro-fibrotic and pro-inflammatory mediators; these have consequences for the deposition of extracellular matrix proteins, as well as for the immune microenvironment. Overall, our study uncovered novel mechanistic insights regarding EGFR kinase-dependent actions in hepatocytes that reveal its key role in chronic liver damage. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Anti‑obesity and immunostimulatory activity of Chrysosplenium flagelliferum in mouse preadipocytes 3T3‑L1 cells and mouse macrophage RAW264.7 cells.

Chrysosplenium flagelliferum (CF) is known for its anti-inflammatory, antioxidant and antibacterial activities. However, there is a lack of research on its other pharmacological properties. In the present study, the bifunctional roles of CF in 3T3-L1 and RAW264.7 cells were investigated, focusing on its anti-obesity and immunostimulatory effects. In 3T3-L1 cells, CF effectively mitigated the accumulation of lipid droplets and triacylglycerol. Additionally, CF downregulated the peroxisome proliferator-activated receptor (PPAR)-γ and CCAAT/enhancer-binding protein α protein levels; however, this effect was impeded by the knockdown of β-catenin using β-catenin-specific small interfering RNA. Consequently, CF-mediated inhibition of lipid accumulation was also decreased. CF increased the protein levels of adipose triglyceride lipase and phosphorylated hormone-sensitive lipase, while decreasing those of perilipin-1. Moreover, CF elevated the protein levels of phosphorylated AMP-activated protein kinase and PPARγ coactivator 1-α. In RAW264.7 cells, CF enhanced the production of pro-inflammatory mediators, such as nitric oxide (NO), inducible NO synthase, interleukin (IL)-1β, IL-6 and tumor necrosis factor-α, and increased their phagocytic capacities. Inhibition of Toll-like receptor (TLR)-4 significantly reduced the effects of CF on the production of pro-inflammatory mediators and phagocytosis, indicating its crucial role in facilitating these effects. CF-induced increase in the production of pro-inflammatory mediators was controlled by the activation of c-Jun N-terminal kinase (JNK) and nuclear factor (NF)-κB pathways, and TLR4 inhibition attenuated the phosphorylation of these kinases. The results of the pesent study suggested that CF inhibits lipid accumulation by suppressing adipogenesis and inducing lipolysis and thermogenesis in 3T3-L1 cells, while stimulating macrophage activation via the activation of JNK and NF-κB signaling pathways mediated by TLR4 in RAW264.7 cells. Therefore, CF simultaneously exerts both anti-obesity and immunostimulatory effects.