Inflammation-related Disorders Research Articles

Salvimulticanol from Salvia multicaulis suppresses LPS-induced inflammation in RAW264.7 macrophages: in vitro and in silico studies.

Sustained inflammatory responses can badly affect several vital organs and lead to chronic inflammation-related disorders, such as atherosclerosis, pneumonia, rheumatoid arthritis, obesity, diabetes, Alzheimer's disease, and cancers. Salvia multicaulis is one of the widely distributed plants that contains several biologically active phytochemicals and diterpenoids with anti-inflammatory effects. Therefore, finding alternative and safer natural plant-extracted compounds with good curative anti-inflammatory efficiencies is an urgent need for the clinical treatment of inflammation-related diseases. In the current study, S. multicaulis Vahl was used to extract and isolate two compounds identified as salvimulticanol and candesalvone B methyl ester to examine their effects against inflammation in murine macrophage RAW264.7 cells that were induced by lipopolysaccharide (LPS). Accordingly, after culturing RAW264.7 cells and induction of inflammation by LPS (100ng/ml), cells were exposed to different concentrations (9, 18, 37.5, 75, and 150µM) of each compound. Then, Griess assay for detection of nitric oxide (NO) levels and western blotting for the determination of inducible nitric oxide synthase (iNOS) expression were performed. Molecular docking and molecular dynamics (MD) simulation studies were employed to investigate the anti-inflammatory mechanism. Our obtained results validated that the level of NO was significantly decreased in the macrophage cell suspensions as a response to salvimulticanol treatment in a dose-dependent manner (IC50: 25.1 ± 1.2µM) as compared to the methyl ester of candesalvone B which exerted a weaker inhibition (IC50: 69.2 ± 3.0µM). This decline in NO percentage was comparable with a down-regulation of iNOS expression by western blotting. Salvimulticanol strongly interacted with both the Toll-like receptor 4 (TLR4)/myeloid differentiation factor 2 (MD-2) complex and the inhibitor of nuclear factor kappa-B (NF-κB) kinase subunit beta (IKKβ) to disrupt their inflammatory activation due to the significant hydrogen bonds and effective interactions with amino acid residues present in the target proteins' active sites. S.multicaulis is a rich natural source of the aromatic abietane diterpenoid, salvimulticanol, which exerted a strong anti-inflammatory effect through targeting iNOS and diminishing NO production in LPS-induced RAW264.7 cells in a mechanism that is dependent on the inhibition of TLR4-MD-2 and IKKβ as activators of the classical NF-κB-mediated inflammatory pathway.

Isolation, Identification and in-Silico Characterization of Bioactive Peptide from the Venom Sac of Conus inscriptus

Nature has been the source of new medications since ancient times, and at least half of all commercialised pharmaceuticals have been made from renewable resources to treat various illnesses, including pain, inflammation, and infection. In recent years, interest has risen in bioprospecting of new bioactive peptides, especially for medical and health-related applications. Therefore, the production of functional meals is starting to get recognition for its potential to enhance quality of life when combined with a healthy lifestyle. In view of this, the current work aimed to isolate, purify, and identify bioactive peptides from Conus inscriptus venom sac protein extracts, with an emphasis on antioxidant and anti-inflammatory properties. The findings reveal that the DPPH radical scavenging activity, albumin denaturation, and HRBC membrane stabilisation inhibition activities of Conus inscriptus venom sac crude protein extracts are 23.76±2.4, 66.23±3.1, and 57.32±2.6% respectively. Secondary screening of purified protein fractions obtained through sephadex G100 gel filtration exhibited increased anti-inflammatory efficacy from fractions 19 to 23. Electrophoresis and PMF analysis revealed that the purified anti-inflammatory peptide was homogenous with a molecular weight of 12 KDa, and it was identified as a conotoxin MI15b precursor. The 3D model of conotoxin exhibits the highest similarity with template c6nk9A with a confidence of 54.1%, and its function was predicted as a potassium ion channel inhibitor. The findings of the Insilco characterisation of the conotoxin MI15b precursor concluded that this protein might serve as an anti-inflammatory agent and may be responsible for therapeutic actions in the medical management of many inflammatory-related disorders.

Cholesterol transport and beyond: Illuminating the versatile functions of HDL apolipoproteins through structural insights and functional implications.

High-density lipoproteins (HDLs) play a vital role in lipid metabolism and cardiovascular health, as they are intricately involved in cholesterol transport and inflammation modulation. The proteome of HDL particles is indeed complex and distinct from other components in the bloodstream. Proteomics studies have identified nearly 285 different proteins associated with HDL; however, this review focuses more on the 15 or so traditionally named "apo" lipoproteins. Important lipid metabolizing enzymes closely working with the apolipoproteins are also discussed. Apolipoproteins stand out for their integral role in HDL stability, structure, function, and metabolism. The unique structure and functions of each apolipoprotein influence important processes such as inflammation regulation and lipid metabolism. These interactions also shape the stability and performance of HDL particles. HDLs apolipoproteins have multifaceted roles beyond cardiovascular diseases (CVDs) and are involved in various physiological processes and disease states. Therefore, a detailed exploration of these apolipoproteins can offer valuable insights into potential diagnostic markers and therapeutic targets. This comprehensive review article aims to provide an in-depth understanding of HDL apolipoproteins, highlighting their distinct structures, functions, and contributions to various physiological processes. Exploiting this knowledge holds great potential for improving HDL function, enhancing cholesterol efflux, and modulating inflammatory processes, ultimately benefiting individuals by limiting the risks associated with CVDs and other inflammation-based pathologies. Understanding the nature of all 15 apolipoproteins expands our knowledge of HDL metabolism, sheds light on their pathological implications, and paves the way for advancements in the diagnosis, prevention, and treatment of lipid and inflammatory-related disorders.

Exploring the Anti-Inflammatory Potential of Cyperus pangorei Rhizome Extracts An In Vitro and In Vivo Study

Background and aim: Inflammation is a pivotal process implicated in various physiological and pathological conditions, necessitating the exploration of alternative anti-inflammatory agents with minimal side effects. This study aimed to investigate the anti-inflammatory potential of the standardized ethyl acetate (EtAc) fraction derived from Cyperus pangorei rhizomes. Methods: The rhizomes of C. pangorei were collected, processed, and subjected to extraction and fractionation to obtain the EtAc fraction. RP-HPLC analysis was employed to standardized the EtAc fraction against standard quercetin, luteolin, and apigenin. In vitro studies utilized peritoneal macrophages isolated from male Swiss albino rats to assess NO production and cytokine levels (IL-1β, IL-6, TNF-α) upon treatment with the EtAc fraction. In vivo evaluation was conducted using a carrageenan-induced rat paw edema model. Results: RP-HPLC analysis revealed the presence of quercetin, luteolin, and apigenin in the EtAc fraction. In vitro studies demonstrated dose-dependent inhibition of LPS-induced NO production and suppression of inflammatory cytokines (IL-1β, IL-6, TNF-α) by the EtAc fraction. Furthermore, in the carrageenan-induced rat paw edema model, the EtAc fraction exhibited dose-dependent inhibition of paw edema. Conclusion: The findings of this study highlight the significant anti-inflammatory potential of C. pangorei rhizome extracts, particularly the EtAc fraction. The identified compounds, quercetin, luteolin, and apigenin, contribute to its anti-inflammatory activity by modulating key inflammatory mediators. These results support the potential therapeutic use of C. pangorei in managing inflammation-related disorders. Further research is warranted to elucidate the underlying mechanisms and evaluate the long-term efficacy and safety of C. pangorei extracts as anti-inflammatory agents.

Peptidylarginine Deiminases Inhibitors Decrease Endothelial Cells Angiogenic Potential by Affecting Akt Signaling and the Expression and Secretion of Angiogenic Factors.

Endothelial cells (ECs) play a crucial role in various physiological processes, particularly those related to the cardiovascular system, but also those affecting the entire organism. The biology of ECs is regulated by multiple biochemical stimuli and epigenetic drivers that govern gene expression. We investigated the angiogenic potential of ECs from a protein citrullination perspective, regulated by peptidyl-arginine deiminases (PADs) that modify histone and non-histone proteins. Although the involvement of PADs has been demonstrated in several physiological processes, inflammation-related disorders and cancer, their role in angiogenesis remains unclear. To elucidate the role of PADs in endothelial angiogenesis, we used two human EC models: primary vein (HUVECs) and microvascular endothelial cells (HMEC-1). PADs activity was inhibited using irreversible inhibitors: BB-Cl-amidine, Cl-amidine and F-amidine. We analyzed all three steps of angiogenesis in vitro : proliferation, migration, and capillary-like tube formation, as well as secretory activities, gene expression and signaling in ECs. All used PAD inhibitors reduced the histone H3 citrullination (H3cit) mark, inhibited endothelial cell migration and capillary-like tube formation, and favored an angiostatic activity in HMEC-1 cells, by increasing PEDF (pigment epithelium-derived factor) and reducing VEGF (vascular endothelial growth factor) mRNA expression and protein secretion. Additionally, BB-Cl-amidine reduced the total activity of MMPs (Matrix metalloproteinases). The observed effects were underlined by the inhibition of Akt phosphorylation.>. Our findings suggest that pharmacological inhibitors of citrullination are promising therapeutic agents to target angiogenesis.

Purple Sweet Potato Polysaccharide Exerting an Anti-inflammatory Effect via a TLR-Mediated Pathway by Regulating Polarization and Inhibiting the Inflammasome Activation.

Purple sweet potato polysaccharide (PSPP-1) is a novel glucan; this study aimed to examine the anti-inflammatory effect of PSPP-1 and elucidate its potential mechanisms. Lipopolysaccharide (LPS)-induced RAW264.7 was used as the model of inflammation, cell viability, and levels of nitric oxide (NO), reactive oxygen species (ROS), and calcium ion (Ca2+) were analyzed. ELISA and qPCR were used to assess the productions and mRNA expression of cytokines, and Western blotting was used to assess protein expressions in the TLR-mediated pathway, macrophage polarization, and inflammasome activation. The results demonstrated PSPP-1 inhibited cell proliferation and markedly decreased NO, ROS, and Ca2+ levels. Moreover, PSPP-1 suppressed the secretions and mRNA expressions of pro-inflammatory cytokines and increased those of anti-inflammatory cytokines. Furthermore, PSPP-1 could exert anti-inflammatory effects through different pathways mediated by both TLR2 and TLR4, which modulated the expressions of essential proteins in the myeloid differentiation factor 88 (MyD88)-dependent and toll/IL-1 receptor domain-containing adaptor-inducing interferon-β (TRIF)-dependent signaling pathways. PSPP-1 even regulated the polarization of M1/M2 macrophages and inhibited the nucleotide oligomerization domain-like receptor protein 3 (NLRP3) inflammasome activation. These findings indicate that PSPP-1 can suppress LPS-induced inflammation via multiple pathways and may be a potential agent for therapeutic inflammation-related pathophysiological processes and disorders.

Retracted: Watery Rose Apple: A Comprehensive Review of Its Traditional Uses, Nutritional Value, Phytochemistry, and Therapeutic Merits against Inflammation-Related Disorders.

[This retracts the article DOI: 10.1155/2022/7502185.].

Understanding the Mode of Action of a Micro-Immunotherapy Formulation: Pre-Clinical Evidence from the Study of 2LEBV® Active Ingredients.

Epstein-Barr virus (EBV) is often kept silent and asymptomatic; however, its reactivation induces a chronic and/or recurrent infection that is associated with numerous diseases, including cancer and inflammation-related disorders. As no specific treatment is currently available, the immune factors-based micro-immunotherapy (MI) medicine 2LEBV® could be considered a valuable therapeutic option to sustain the immune system in EBV reactivation. The present work aimed to investigate, for the first time, the effect of 2LEBV® in several in vitro models of uninfected immune-related cells. 2LEBV® displayed phagocytosis-enhancing capabilities in granulocytes. In human peripheral blood mononuclear cells (PBMCs), it increased the intra- and extra-cellular expression of interleukin (IL)-2. Moreover, it modulated the secretion of other cytokines, increasing IL-4, IL-6, and tumor necrosis factor-α levels or lowering other cytokines levels such as IL-9. Finally, 2LEBV® reduced the expression of human leukocyte antigen (HLA)-II in endothelial cells and macrophages. Although these data are still preliminary and the chosen models do not consider the underlying EBV-reactivation mechanisms, they still provide a better understanding of the mechanisms of action of 2LEBV®, both at functional and molecular levels. Furthermore, they open perspectives regarding the potential targets of 2LEBV® in its employment as a therapeutic intervention for EBV-associated diseases.

Flavonoid diversity and roles in the lipopolysaccharide-mediated inflammatory response of monocytes and macrophages.

Targeting lipopolysaccharide (LPS)/toll-like receptor4 signaling in mononuclear phagocytes has been explored for the treatment of inflammation and inflammation-related disorders. However, only a few key targets have been translated into clinical applications. Flavonoids, a class of ubiquitous plant secondary metabolites, possess a privileged scaffold which serves as a valuable template for designing pharmacologically active compounds directed against diseases with inflammatory components. This perspective provides a general overview of the diversity of flavonoids and their multifaceted mechanisms that interfere with LPS-induced signaling in monocytes and macrophages. Focus is placed on flavonoids targeting MD-2, IκB kinases, c-Jun N-terminal kinases, extracellular signal-regulated kinase, p38 MAPKand PI3K/Akt or modulating LPS-related gene expression.

Comprehensive HLA Typing from a Current Allele Database Using Next-Generation Sequencing Data.

HLA allele information is essential for a variety of medical applications, such as genomic studies of multifactorial diseases, including immune system and inflammation-related disorders, and donor selection in organ transplantation and regenerative medicine. To obtain this information, an accurate HLA typing method that is applicable for any allele registered in HLA allele databases is needed. Here we describe a method-called HLA-HD-for determining alleles from a current HLA database using next-generation sequencing (NGS) results.

Anti-inflammatory, antithrombotic and anti-oxidant bioactives of beer and brewery by-products, as ingredients of bio-functional foods, nutraceuticals, cosmetics, cosmeceuticals and pharmaceuticals with health promoting properties

<abstract> <p>Fermented alcoholic beverages and their by-products, including beer and breweries' bio-wastes like spent yeasts, grain, and hops, contain a plethora of natural bioactive compounds that have recently gained attention for their valorization as functional ingredients in several novel foods and nutraceuticals, as well as in drugs and cosmetics applications. Within this article, the natural bio-functional compounds of fermented beer product and breweries' by-products with anti-inflammatory, antithrombotic, and anti-oxidant bioactivities are thoroughly reviewed. The important roles of yeasts involved for such bioactives to be present in the fermented product and in the brewery bio-wastes are also outlined. The health promoting benefits of beer moderate consumption resulting from these bioactives, as part of a balanced diet, against inflammation-related chronic disorders is also discussed, along with the detrimental effects of beer consumption abuse and the potential benefits of alternative non-alcoholic beers. The mechanisms of action and synergism of the natural bioactives present in the fermented beer product and in breweries' by-products, with anti-inflammatory, anti-thrombotic, and antioxidant properties are also presented. Current research and future perspectives on valorizing bioactives of fermented beer and brewery by-products, such as spent yeasts, grain and hops in health-promoting functional foods, supplements, nutraceuticals cosmetics, cosmeceuticals, and pharmaceuticals are also thoroughly evaluated, while the limitations of their use are also discussed.</p> </abstract>

Fatsia japonica extract exerts antioxidant and anti-neuroinflammatory effects on neuronal cells and a zebrafish model

Ethnopharmacological relevanceFatsia japonica is a traditional medicine used to treat various diseases, including inflammation-related disorders. However, its antineuroinflammatory and neuroprotective effects remain unclear. Aim of the studyWe aimed to evaluate the anti-neuroinflammatory and neuroprotective effects of F. japonica extract to identify the underlying mechanisms. Materials and methodsThe components of F. japonica extract were profiled using ultra-high-performance liquid chromatography-mass spectrometry. The effects of F. japonica extract were investigated in BV2 microglia and HT22 hippocampal cells. Furthermore, in vivo effects of F. japonica extract were assessed using zebrafish models treated with H2O2 and LPS to evaluate the effects of in vivo. ResultsWe identified 27 compounds in the F. japonica extract. F. japonica extract demonstrated anti-inflammatory properties by suppressing LPS-induced inflammatory responses in both BV2 cells and zebrafish, along with inhibiting the activation of the nuclear factor (NF)-κB (p65) pathway. The protective effects of this extract were also observed on glutamate-treated HT22 cells and in H2O2-induced zebrafish. Furthermore, F. japonica extract upregulated nuclear factor E2-related (Nrf) 2/heme oxygenase (HO)-1 expression in BV2 and HT22 cells. ConclusionsF. japonica extract exerted anti-neuroinflammatory and neuroprotective effects through Nrf2/HO-1 and the NF-κB pathway.

Targeting CB2R in astrocytes for Parkinson's disease therapy: unraveling the Foxg1-mediated neuroprotective mechanism through autophagy-mediated NLRP3 degradation

BackgroundInflammasomes in astrocytes have been shown to play a crucial role in the pathogenesis of neurodegenerative diseases such as Parkinson's disease (PD) and Alzheimer's disease (AD). Cannabinoid Receptor 2(CB2R), a G protein-coupled receptor (GPCR), is considered a promising therapeutic target in inflammation-related disorders. This study aims to explore the role of CB2R in regulating NOD-like receptor family pyrin domain containing 3 (NLRP3)-mediated neuroinflammation in astrocytes.MethodsIn an in vivo animal model, specific targeting of astrocytic CB2R was achieved by injecting CB2R-specific adenovirus (or fork head box g1(foxg1) adenovirus) to knock down CB2R or administering CB2R agonists, inhibitors, etc., in the substantia nigra pars compacta (SNc) of mice. A PD mouse model was established using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induction. Animal behavioral tests, western blot, immunofluorescence, and other experiments were performed to assess the loss of midbrain tyrosine hydroxylase (TH) neurons, activation of astrocytes, and activation of the NLRP3 pathway. Primary astrocytes were cultured in vitro, and NLRP3 inflammasomes were activated using 1-methyl-4-phenylpyridinium (MPP+) or lipopolysaccharide (LPS) and adenosine triphosphate (ATP). Western blot and ELISA experiments were conducted to assess the release of inflammatory factors. Transcriptomic sequencing and CUT&RUN techniques were employed to study the CB2R regulation of the foxg1 binding site on the autophagy molecule microtubule-associated protein 1 light chain 3 beta (MAP1LC3B).ResultsAstrocytic CB2R knockdown impaired the motor abilities of MPTP-induced mice, exacerbated the loss of TH neurons, and induced activation of the NLRP3/Caspase-1/interleukin 1 (IL-1β) pathway. Activation of CB2R significantly alleviated motor impairments in mice while reducing NLRP3 deposition on astrocytes. In vitro cell experiments showed that CB2R activation attenuated the activation of the NLRP3/Caspase-1/IL-1β pathway induced by LPS + ATP or MPP+. Additionally, it inhibited the binding of foxg1 to MAP1LC3B, increased astrocytic autophagy levels, and facilitated NLRP3 degradation through the autophagy–lysosome pathway.ConclusionActivation of CB2R on astrocytes effectively mitigates NLRP3-mediated neuroinflammation and ameliorates the disease characteristics of PD in mice. CB2R represents a potential therapeutic target for treating PD.

Serum sulfatide level is associated with severe systemic vasculitis with kidney involvement.

Sulfatides are a type of sulfated glycosphingolipid that are secreted with lipoproteins into the serum. These molecules are involved in the inflammatory pathway of vessels in addition to coagulation and platelet aggregation. Previous studies have proposed that sulfatides play a pivotal role in regulating inflammation-related disorders. Systemic vasculitis (SV) diseases are generally caused by autoimmune diseases and often involve kidney vasculitis, which may lead to rapidly progressive kidney dysfunction and end-stage kidney disease. Our earlier pilot study revealed that the level of serum sulfatides (SSs) was significantly decreased in patients with anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV), a representative disease-causing SV with kidney involvement (SVKI), especially in patients exhibiting active crescentic findings on kidney biopsy. To further explore the clinical significance of an association between SS and SVKI, we analyzed and compared the SS level of patients with various SVKI diseases in this retrospective cohort study. Among patients admitted to our hospital between 2008 and 2021, we ultimately enrolled 26 patients with IgA vasculitis (IgAV), 62 patients with AAV, and 10 patients with anti-glomerular basement membrane disease (GBM) as examples of SVKI diseases, as well as 50 patients with IgA nephropathy (IgAN) and 23 donors for living kidney transplantation as controls. The mean ± standard deviation SS level in the donor, IgAN, IgAV, AAV, and GBM groups was 8.26 ± 1.72, 8.01 ± 2.21, 6.01 ± 1.73, 5.37 ± 1.97, and 2.73 ± 0.99 nmol/mL, respectively. Analysis of patients in the SVKI disease group showed that those with the crescentic class kidney biopsy finding exhibited a significantly lower SS level than did those with other class biopsy features. Additionally, the SS level had a higher detection ability for SVKI patients with crescentic class kidney biopsy findings (area under the receiver operating characteristic curve 0.90, 95% confidence interval 0.82-0.99) than did several other predictor candidates. Our results indicate that the SS level is decreased in more severe SVKI diseases and may be associated with active glomerular lesions in SVKI kidney biopsy samples.

Platelet to albumin ratio: A risk factor related to prognosis in patients with non-ST-segment elevation acute coronary syndrome undergoing percutaneous coronary intervention

BackgroundAtherosclerotic cardiovascular disease (ASCAD) is recognized as a chronic subclinical systemic inflammatory condition. The platelet-albumin ratio (PAR) has shown promise in prognosticating various inflammation-related disorders. Our study aimed to assess the connection between PAR and major adverse cardiovascular events (MACE) in percutaneous coronary intervention (PCI)-treated patients with non-ST-segment elevation acute coronary syndrome (NSTE-ACS). MethodsPAR, derived from platelet and albumin counts, categorized participants into four quartiles. The primary outcome was composite MACE, encompassing all-cause mortality, non-fatal myocardial infarction (MI), and ischemia-driven revascularization. Secondary outcomes comprised individual MACE components. Multivariate Cox regression evaluated PAR's independent impact on adverse events. The non-linear relationship between the PAR value and MACE was explored using a restricted cubic spline (RCS). Receiver operating characteristic (ROC) analysis was conducted and the area under the curve (AUC) was calculated. Subgroup analysis was used to determine the effect of PAR on MACE in different subgroups. ResultsEnrolling 1391 NSTE-ACS patients, high PAR quartiles were correlated with elevated MACE rates (quartile 4 vs. quartile 1: 33.5% vs. 10.2%, p < 0.001). PAR was revealed to be independently related to an increased risk of MACE (quartile 4 vs. quartile 1: HR, 2.04 [95% CI, 1.34–3.08], p = 0.001). RCS indicated a positive PAR-MACE relationship. The AUC of PAR for the 3-year MACE was 0.659 (95% CI: 0.626–0.677, P<0.001). Subgroup analysis showed no significant interactions across subsets. ConclusionPAR independently predicted MACE risk in PCI-treated NSTE-ACS patients.

Role of the Autism Risk Gene Shank3 in the Development of Atherosclerosis: Insights from Big Data and Mechanistic Analyses.

Increased medical attention is needed as the prevalence of autism spectrum disorder (ASD) rises. Both cardiovascular disorder (CVD) and hyperlipidemia are closely associated with adult ASD. Shank3 plays a key genetic role in ASD. We hypothesized that Shank3 contributes to CVD development in young adults with ASD. In this study, we investigated whether Shank3 facilitates the development of atherosclerosis. Using Gene Set Enrichment Analysis software (Version No.: GSEA-4.0.3), we analyzed the data obtained from Shank3 knockout mice (Gene Expression Omnibus database), a human population-based study cohort (from Taiwan's National Health Insurance Research Database), and a Shank3 knockdown cellular model. Shank3 knockout upregulated the expression of genes of cholesterol homeostasis and fatty acid metabolism but downregulated the expression of genes associated with inflammatory responses. Individuals with autism had higher risks of hyperlipidemia (adjusted hazard ratio (aHR): 1.39; p < 0.001), major adverse cardiac events (aHR: 2.67; p < 0.001), and stroke (aHR: 3.55; p < 0.001) than age- and sex-matched individuals without autism did. Shank3 downregulation suppressed tumor necrosis factor-α-induced fatty acid synthase expression; vascular cell adhesion molecule 1 expression; and downstream signaling pathways involving p38, Jun N-terminal kinase, and nuclear factor-κB. Thus, Shank3 may influence the development of early-onset atherosclerosis and CVD in ASD. Furthermore, regulating Shank3 expression may reduce inflammation-related disorders, such as atherosclerosis, by inhibiting tumor necrosis factor-alpha-mediated inflammatory cascades.

Control of CD4+ T cells to restrain inflammatory diseases via eukaryotic elongation factor 2 kinase

CD4+ T cells, particularly IL-17-secreting helper CD4+ T cells, play a central role in the inflammatory processes underlying autoimmune disorders. Eukaryotic Elongation Factor 2 Kinase (eEF2K) is pivotal in CD8+ T cells and has important implications in vascular dysfunction and inflammation-related diseases such as hypertension. However, its specific immunological role in CD4+ T cell activities and related inflammatory diseases remains elusive. Our investigation has uncovered that the deficiency of eEF2K disrupts the survival and proliferation of CD4+ T cells, impairs their ability to secrete cytokines. Notably, this dysregulation leads to heightened production of pro-inflammatory cytokine IL-17, fosters a pro-inflammatory microenvironment in the absence of eEF2K in CD4+ T cells. Furthermore, the absence of eEF2K in CD4+ T cells is linked to increased metabolic activity and mitochondrial bioenergetics. We have shown that eEF2K regulates mitochondrial function and CD4+ T cell activity through the upregulation of the transcription factor, signal transducer and activator of transcription 3 (STAT3). Crucially, the deficiency of eEF2K exacerbates the severity of inflammation-related diseases, including rheumatoid arthritis, multiple sclerosis, and ulcerative colitis. Strikingly, the use of C188-9, a small molecule targeting STAT3, mitigates colitis in a murine immunodeficiency model receiving eEF2K knockout (KO) CD4+ T cells. These findings emphasize the pivotal role of eEF2K in controlling the function and metabolism of CD4+ T cells and its indispensable involvement in inflammation-related diseases. Manipulating eEF2K represents a promising avenue for novel therapeutic approaches in the treatment of inflammation-related disorders.

Current knowledge of the immune reconstitution inflammatory syndrome in Whipple disease: a review.

Immune reconstitution inflammatory syndrome (IRIS) is characterized by exaggerated and dysregulated inflammatory responses that occur as a result of reconstitution of adaptive or innate immunity. A wide range of microorganisms have been found to be associated with IRIS, such as human immunodeficiency virus (HIV), Mycobacterium and actinobacteria. Whipple disease (WD) is an infectious disorder caused by the Gram-positive bacterium Tropheryma whipplei (T. whipplei) and IRIS also serves as a complication during its treament. Although many of these pathological mechanisms are shared with related inflammatory disorders, IRIS in WD exhibits distinct features and is poorly described in the medical literature. Novel investigations of the intestinal mucosal immune system have provided new insights into the pathogenesis of IRIS, elucidating the interplay between systemic and local immune responses. These insights may be used to identify monitoring tools for disease prevention and to develop treatment strategies. Therefore, this review synthesizes these new concepts in WD IRIS to approach the feasibility of manipulating host immunity and immune reconstitution of inflammatory syndromes from a newer, more comprehensive perspective and study hypothetical options for the management of WD IRIS.

Anti-inflammatory, antioxidant and photoprotective activity of standardised Gaultheria procumbens L. leaf, stem, and fruit extracts in UVA-irradiated human dermal fibroblasts

Ethnopharmacological relevanceGaultheria procumbens L. is a polyphenolic-rich medicinal and food plant. Its leaves, stems, and fruits are traditional anti-inflammatory, antipyretic, antioxidant, and antimicrobial herbal medicines used to treat internal and external inflammation-related ailments, including rheumatic diseases, influenza, the common cold, fever, and skin and periodontal problems. Moreover, G. procumbens leaf extract is used for skin care as an anti-ageing and anti-wrinkle ingredient. Aim of the studyVarious environmental factors, especially solar ultraviolet radiation, accelerate skin ageing by promoting oxidative stress and inflammation. Despite the dermoprotective and anti-ageing applications, the impact of G. procumbens on human dermal fibroblasts is unknown. Therefore, the study aimed to evaluate the anti-inflammatory, antioxidant, and photoprotective activity of G. procumbens standardised leaf, stem, and fruit extracts in cellular models, including human dermal fibroblasts (Hs68 cells) under UVA-irradiation, the primary pro-ageing skin stressor. Materials and methodsHs68 fibroblasts were pre-treated (24h) with G. procumbens extracts (0.5–100 μg/mL) or reference compounds followed by UVA-irradiation (8 J/cm2). Cell viability and metabolic activity were measured by CCK-8 and MTT assays in human Hs68 and mouse L929 fibroblasts, respectively. The ROS level, SOD, and GST activities were estimated by fluorescence and spectrophotometric techniques. The pro-inflammatory potential (NF-κB transcription factor activation) was checked using THP1-Blue™ NF-κB cells, and the anti-inflammatory activity was studied by measuring IL-8, ICAM-1, and NF-κB levels and phosphorylation of Erk kinase in LPS-stimulated Hs68 cells by spectrophotometry and confocal microscopy. The UVA-induced DNA damage and cell migration were evaluated by comet and scratch assays, respectively. ResultsThe extracts did not affect the metabolic activity of mouse L929 fibroblasts and the viability of unirradiated human Hs68 cells. Additionally, the extracts noticeably enhanced the viability of UVA-irradiated Hs68 cells up to 115–120% (p < 0.001) for stem and leaf extract at 25 μg/mL. All extracts in a wide concentration range (0.5–100 μg/mL) did not activate monocytes or induce the NF-κB transcription factor in LPS-stimulated Hs68 fibroblasts. On the other hand, the extracts (5–25 μg/mL) restored the activity of endogenous antioxidant enzymes, i.e., SOD and GST, up to 120–140% (p < 0.001) in the UVA-irradiated Hs68 cells. Moreover, a statistically significant reduction of ROS, IL-8, ICAM-1, and NF-κB levels by up to 48%, 88%, 43%, and 39%, respectively (p < 0.001) and strong suppression of Erk kinase activation was observed for the extracts (25–50 μg/mL) in LPS-stimulated human fibroblasts. The total DNA damage (% tail DNA) in irradiated Hs68 cells was also strongly decreased by up to 66–69% (p < 0.001) at 50 μg/mL. However, the treatment with the extracts did not relevantly enhance the cell migration of Hs68 fibroblasts. ConclusionsThe results suggest that G. procumbens may effectively protect human skin fibroblast from UVA irradiation. The leaf and stem extracts were the most potent antioxidants, while fruit and stem extracts revealed the strongest anti-inflammatory activity. The observed effects support the traditional use of aerial plant parts (leaves, stems, and fruits) in treating inflammation-related skin disorders cross-linked with oxidative stress and the topical application of Gaultheria extracts as anti-ageing agents intended for skin care.

Winemaking: “With One Stone, Two Birds”? A Holistic Review of the Bio-Functional Compounds, Applications and Health Benefits of Wine and Wineries’ By-Products

The plethora of bio-functional compounds present in fermented alcoholic beverages like wine, as well as the valorisation of bioactives from wineries’/breweries’ by-products like grape pomace and grape seed, has gained significant interest in the functional foods sector. This functional beverage, wine, has always accompanied humanity, for religion or for health, especially in the Mediterranean, while the benefits of its moderate consumption were documented even by the Greek physician Hippocrates of Kos (460–370 BC). After a big gap, an outbreak of research on wine benefits has surfaced only since the 1990s, when the term “French paradox” was introduced to the US public during a CBS show, while recent evidence has outlined that the beneficial effects of wine consumption are derived by the synergisms of its bio-functional compounds and their digestion-derived metabolites. Within this article, the proposed health benefits of moderate wine consumption, as a functional component of a balanced diet (i.e., the Mediterranean diet) against inflammation-related chronic disorders, is thoroughly reviewed. The various bio-functional compounds of both wine and wineries’ by-products, such as their bioactive phenolics, unsaturated fatty acids, polar lipids and dietary fibres, and their functional antioxidant, anti-inflammatory and antithrombotic health-promoting properties, are also thoroughly evaluated. The mechanisms of action and synergism, by which the health benefits are elicited, are also explored. Functional properties of non-alcoholic wine products are also introduced. Emphasis is also given to applications of wineries’ by-products bioactives, as ingredients of bio-functional foods, supplements and nutraceuticals. Limitations and future perspectives for this popular functional alcoholic beverage (wine) and its rich in bioactives by-products are also addressed.