Plasma Levels Of Inflammatory Cytokines Research Articles

Elevations in interleukin-8 levels in individuals with alcohol use disorder and clinical insomnia symptoms.

Insomnia commonly co-occurs with alcohol use disorder (AUD) and predicts poorer outcomes for those with AUD. Insomnia and AUD are individually associated with increases in systemic inflammation. Insomnia and inflammation both serve as risk factors for relapse in AUD. However, little is known about the relationship between insomnia and systemic inflammation in individuals with AUD. Therefore, the present study examined the relationship between the severity of insomnia symptoms and plasma levels of inflammatory cytokines in a sample of treatment-seeking individuals with an AUD. This secondary analysis included 101 (61M/40F) individuals with an AUD. Participants were categorized into groups based on their scores on the Insomnia Severity Index: no insomnia (n = 47), subthreshold insomnia (n = 37), and clinical insomnia (n = 17). Participants provided blood samples to measure plasma levels of four peripheral markers of inflammation (IL-6, IL-8, TNF-α, and CRP). Inflammatory marker levels were compared between groups. Interactive effects of sex and AUD severity were examined. There was a significant main effect of insomnia group on log IL-8 levels (F = 6.52, p = 0.002), such that individuals with AUD and clinical insomnia had higher log IL-8 levels compared to both the no insomnia and subthreshold insomnia groups (ps ≤ 0.05). Sex and AUD severity interacted with this relationship, such that men with clinical insomnia and AUD and individuals with severe AUD had higher log IL-8 levels. There were no significant effects of insomnia on IL-6, TNF-α, or CRP levels. The present study identified a specific elevation in IL-8 levels in individuals with an AUD and clinical insomnia that was not identified in other markers of peripheral inflammation (IL-6, TNF-α, CRP). Sex and AUD severity interacted with insomnia symptoms, indicating that those with clinical insomnia and severe AUD or male sex may be the most vulnerable to the inflammatory consequences associated with AUD and clinical insomnia symptoms.

1, 6-dilauroyl-D-fructofuranose ameliorates lipopolysaccharide induced sepsis acute kidney injury via inhibiting caspase 1-mediated pyroptosis formation in rat

Background: Sepsis is a systemic inflammatory state associated with acute kidney injury (AKI) and high mortality. However, sepsis induced AKI cannot be efficiently prevented or cured using current antimicrobial therapies and supportive measures. We explored the therapeutic effect of newly developed fructose esters on sepsis-induced AKI (S-AKI). Methods: We used the surface plasmon resonance technique and ultrasensitive chemiluminescence analyzer to characterize the lipopolysaccharide (LPS)/endotoxin binding activity and antioxidant capability of fructose esters. We evaluated the degree of fructose ester gastrointestinal digestion using rat intestinal acetone powder. We examined the therapeutic effect of fructose esters on LPS-induced S-AKI by evaluating the blood and renal reactive oxygen species (ROS) amounts, Caspase 1 mediated pyroptosis, inflammation, microcirculation, and renal dysfunction. Results: Our data showed that the fructose esters are not easily hydrolyzed by the rat intestinal acetone powder implicating its high stability in the gastrointestinal tract. 1,6-dilauroyl-D-fructofuranose (FDL) dose-dependently scavenged H2O2 activity displayed a higher binding affinity to LPS than sialic acid and fructose did. LPS significantly enhanced Caspase 1 mediated pyroptosis and increased leukocyte infiltration, blood and renal ROS amount and BUN and creatinine level, whereas FDL significantly depressed these LPS-enhanced parameters. In addition, the increased plasma inflammatory cytokines levels using LPS could be reduced by intravenous fructose ester FDL treatment. Conclusion: Our data suggest that FDL with antioxidant H2O2 activity can neutralize LPS toxicity using a high binding affinity, and attenuate S-AKI by inhibiting Caspase 1 mediated pyroptosis resulting in ameliorating renal oxidative stress and dysfunction.

Extracellular matrix remodelling pathway in peripheral blood mononuclear cells from severe COVID-19 patients: an explorative study.

There is a reciprocal relationship between extracellular matrix (ECM) remodelling and inflammation that could be operating in the progression of severe COVID-19. To explore the immune-driven ECM remodelling in COVID-19, we in this explorative study analysed these interactions in hospitalised COVID-19 patients. RNA sequencing and flow analysis were performed on peripheral blood mononuclear cells. Inflammatory mediators in plasma were measured by ELISA and MSD, and clinical information from hospitalised COVID-19 patients (N=15) at admission was included in the analysis. Further, we reanalysed two publicly available datasets: (1) lung tissue RNA-sequencing dataset (N=5) and (2) proteomics dataset from PBCM. ECM remodelling pathways were enriched in PBMC from COVID-19 patients compared to healthy controls. Patients treated at the intensive care unit (ICU) expressed distinct ECM remodelling gene profiles compared to patients in the hospital ward. Several markers were strongly correlated to immune cell subsets, and the dysregulation in the ICU patients was positively associated with plasma levels of inflammatory cytokines and negatively associated with B-cell activating factors. Finally, our analysis of publicly accessible datasets revealed (i) an augmented ECM remodelling signature in inflamed lung tissue compared to non-inflamed tissue and (ii) proteomics analysis of PBMC from severe COVID-19 patients demonstrated an up-regulation in an ECM remodelling pathway. Our results may suggest the presence of an interaction between ECM remodelling, inflammation, and immune cells, potentially initiating or perpetuating pulmonary pathology in severe COVID-19.

Biomarkers in a phase 1b study of investigational microbiome therapeutic SER-155 in adults undergoing allogeneic hematopoietic cell transplantation (allo-HCT).

6554 Background: Acute graft- versus-host disease (aGvHD) is a life-threatening complication following allo-HCT. Microbiome dysfunction and associated GI barrier disruption may contribute to aGvHD via activation of inflammatory immune responses. Circulating biomarkers in the peri-transplant period are correlated with risk of severe aGvHD, including suppression of tumorigenicity 2 (ST2), regenerating islet-derived 3-alpha (Reg3a) and inflammatory cytokines (IL6, IFNϒγ & TNFα). SER-155 is an investigational cultivated oral microbiome therapeutic designed to restructure the GI microbiome, improve GI barrier integrity and reduce GI inflammation and is being assessed in a 2-part Phase 1b study in adults undergoing allo-HCT. We present preliminary safety, GvHD, PK, and exploratory biomarker data from the completed open-label Cohort 1 through Day 100 post-HCT. Methods: Adult recipients of allo-HCT were eligible. HCT conditioning and aGvHD prophylaxis were per investigator discretion. Patients received 2 courses of SER-155 (pre-HCT and post-neutrophil engraftment, each comprised of 4 days of microbiome conditioning with oral vancomycin followed by 10 days oral SER-155. The primary endpoint was safety. Strain engraftment (PK) and biomarkers were assessed in stool and plasma samples. Results: Fifteen adults enrolled; 13 received at least 1 course of study drug (median age 67; 54% male), and 11 underwent allo-HCT. Following each course, the majority of the 16 SER-155 strains were detected in stool. Treatment-emergent adverse events (AEs) were reported in all patients with GI AEs the most common. No serious AEs (SAEs) were deemed related to SER-155. Most SAEs and AEs of special interest (ie, BSIs, invasive or GI infections) occurred between HCT and the 2nd SER-155 course. There were no deaths before Day 100. No BSIs were attributable to SER-155 strains. The rate of grade 2-4 aGvHD based on MAGIC criteria through Day 100 was 45.5%; no severe grade 3-4 aGvHD was observed. Median levels of plasma biomarkers REG3α, ST2 and inflammatory cytokines were not elevated relative to a reference range (Table). Conclusions: In this small open-label cohort, SER-155 was generally well-tolerated through Day 100 without drug-related SAEs and no severe aGvHD. Plasma biomarkers were not elevated at HCT Day 0 or neutrophil recovery. These preliminary observations align with the design and preclinical evaluation of SER-155. Clinical trial information: NCT04995653 . [Table: see text]

Plasma microRNA-320c as a Potential Biomarker for the Severity of Knee Osteoarthritis and Regulates cAMP Responsive Element Binding Protein 5 (CREB5) in Chondrocytes.

Osteoarthritis (OA) is a commonly known prevalent joint disease, with limited therapeutic methods. This study aimed to investigate the expression of plasma microRNA-320c (miR-320c) in patients with knee OA and to explore the clinical value and potential mechanism of miR-320c in knee OA. Forty knee OA patients and 20 healthy controls were enrolled. The levels of plasma miR-320c and plasma inflammatory cytokines were measured by real-time PCR or ELISA. Correlations of Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores and cytokine levels with the miR-320c expression level were evaluated by Pearson correlation analysis. Then, a receiver operating characteristic (ROC) curve was drawn to analyse the diagnostic value of miR-320c in OA. Finally, the interaction of miR-320c and cAMP responsive element binding protein 5 (CREB5) was determined using a luciferase reporter assay, and the effect of CREB5 on the cAMP pathway was assessed. The expression level of plasma miR-320c was significantly higher in OA patients than in healthy controls (p < 0.05). The increased plasma miR-320c level was positively correlated with the WOMAC score (r = 0.796, p < 0.001) and the plasma interleukin (IL)-1β (r = 0.814, p < 0.001) and IL-6 (r = 0.695, p < 0.001) levels in patients with OA. ROC curve analysis demonstrated the relatively high diagnostic accuracy of plasma miR-320c for OA. Furthermore, the luciferase reporter assay results showed that miR-320c regulates CREB5 expression by binding to the CREB5 3'-untranslated region. Moreover, suppression of CREB5 significantly reduced the expression levels of c-fos and c-jun. Our results indicate that plasma miR-320c may serve as a potential novel predictor of the severity of knee OA and that miR-320c may play an important role in the pathogenesis of OA through inhibiting the cAMP pathway by targeting CREB5.

Therapeutic Effects of (+)-Afzelechin on Particulate Matter-Induced Pulmonary Injury.

Particulate matter (PM) constitutes a hazardous blend of organic and inorganic particles that poses health risks. Inhalation of fine airborne PM with a diameter of ≤ 2.5 μm (PM2.5) can lead to significant lung impairments. (+)-afzelechin (AZC), a natural compound sourced from Bergenia ligulata, boasts a range of attributes, including antioxidant, antimicrobial, anticancer, and cardiovascular effects. However, knowledge about the therapeutic potential of AZC for patients with PM2.5-induced lung injuries remains limited. Thus, in this study, we investigated the protective attributes of AZC against lung damage caused by PM2.5 exposure. AZC was administered to the mice 30 min after intratracheal instillation of PM2.5. Various parameters, such as changes in lung tissue wet/dry (W/D) weight ratio, total protein/total cell ratio, lymphocyte counts, levels of inflammatory cytokines in bronchoalveolar lavage fluid (BALF), vascular permeability, and histology, were evaluated in mice exposed to PM2.5. Data demonstrated that AZC mitigated lung damage, reduced W/D weight ratio, and curbed hyperpermeability induced by PM2.5 exposure. Furthermore, AZC effectively lowered plasma levels of inflammatory cytokines produced by PM2.5 exposure. It reduced the total protein concentration in BALF and successfully alleviated PM2.5-induced lymphocytosis. Additionally, AZC substantially diminished the expression levels of Toll-like receptors 4 (TLR4), MyD88, and autophagy-related proteins LC3 II and Beclin 1. In contrast, it elevated the protein phosphorylation of the mammalian target of rapamycin (mTOR). Consequently, the anti-inflammatory attribute of AZC positions it as a promising therapeutic agent for mitigating PM2.5-induced lung injuries by modulating the TLR4-MyD88 and mTOR-autophagy pathways.

Whole blood transcriptomics identifies subclasses of pediatric septic shock

BackgroundSepsis is a highly heterogeneous syndrome, which has hindered the development of effective therapies. This has prompted investigators to develop a precision medicine approach aimed at identifying biologically homogenous subgroups of patients with septic shock and critical illnesses. Transcriptomic analysis can identify subclasses derived from differences in underlying pathophysiological processes that may provide the basis for new targeted therapies. The goal of this study was to elucidate pathophysiological pathways and identify pediatric septic shock subclasses based on whole blood RNA expression profiles.MethodsThe subjects were critically ill children with cardiopulmonary failure who were a part of a prospective randomized insulin titration trial to treat hyperglycemia. Genome-wide expression profiling was conducted using RNA sequencing from whole blood samples obtained from 46 children with septic shock and 52 mechanically ventilated noninfected controls without shock. Patients with septic shock were allocated to subclasses based on hierarchical clustering of gene expression profiles, and we then compared clinical characteristics, plasma inflammatory markers, cell compositions using GEDIT, and immune repertoires using Imrep between the two subclasses.ResultsPatients with septic shock depicted alterations in innate and adaptive immune pathways. Among patients with septic shock, we identified two subtypes based on gene expression patterns. Compared with Subclass 2, Subclass 1 was characterized by upregulation of innate immunity pathways and downregulation of adaptive immunity pathways. Subclass 1 had significantly worse clinical outcomes despite the two classes having similar illness severity on initial clinical presentation. Subclass 1 had elevated levels of plasma inflammatory cytokines and endothelial injury biomarkers and demonstrated decreased percentages of CD4 T cells and B cells and less diverse T cell receptor repertoires.ConclusionsTwo subclasses of pediatric septic shock patients were discovered through genome-wide expression profiling based on whole blood RNA sequencing with major biological and clinical differences.Trial Registration This is a secondary analysis of data generated as part of the observational CAF-PINT ancillary of the HALF-PINT study (NCT01565941). Registered March 29, 2012.

Neurotensin agonist PD149163 modulates lipopolysaccharide induced inflammation and oxidative stress in the female reproductive system of mice

Inflammation-mediated reproductive health problems in females have become an emerging concern. The present investigation was aimed to elucidate the efficacy of the PD149163, agonist of the type I neurotensin receptor, in preventing/ameliorating the lipopolysaccharide (LPS) induced inflammation of the female reproductive system of the mice. Female Swiss Albino Mice (8 weeks old) were maintained in three groups (6/group): Group I as Control, Group II and Group III were exposed to intraperitoneal (i.p) LPS (1 mg/kg bw) for 5 days followed by treatment with PD149163 (100 μg/kg BW i.p.) to Group III (LPS + PD) for 28 days. After termination of the experiment on 29th day, plasma levels of inflammatory cytokines, LH, FSH, estradiol, corticosterone, oxidative stress effects in the ovary and histopathological study of the ovary and uterine horn were done. LPS-induced inflammation of the ovary and uterine horn was ameliorated/prevented by PD149163 as reflected in the reduced histopathological scores, significant elevation of the plasma anti-inflammatory cytokine IL-10 and decrease of the pro inflammatory cytokines TNF-α and IL-6. Significant decrease of lipid peroxide, increase of antioxidant defense enzymes, Superoxide dismutase and Catalase in the ovary indicated reduction of oxidative stress. The plasma levels of the reproduction related hormones and corticosterone were restored. PD149163 acts as an anti-inflammatory and anti-oxidative agent in modulation of inflammation in the female reproductive system (ovary & uterine horn). These findings suggest that the therapeutic potential of the analogs of neurotensin including PD149163 should be explored for the treatment of the female reproductive health issues.

Correlations between inflammatory cytokine levels and degree of pigmentation in acral melanomas.

Cutaneous melanoma, a highly aggressive skin tumor, is characterized by complex signaling pathways in terms of its pathogenesis and progression. Although the degree of pigmentation in melanoma determines its progression, metastasis, and prognosis, its association with inflammatory cytokines remains unclear. Thus, we evaluated the associations between melanoma pigmentation and plasma levels of inflammatory cytokines; furthermore, we investigated the potential variations in this relationship across the primary anatomic sites of melanoma. We enrolled patients with cutaneous melanoma who visited Chonnam National University Hwasun Hospital between January 2021 and December 2021. The anatomical sites of melanoma were categorized as acral and non-acral sites. The degree of pigmentation was quantified using computer software. In total, nine inflammatory cytokines were analyzed, including interleukin (IL)-2, IL-4, IL-5, IL-10, IL-12, IL-13, granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon-γ (IFN-γ), and tumor necrosis factor-α (TNF-α). This study included 80 melanoma patients. Of these, 53 had acral melanoma and 27 had non-acral melanoma. Overall, plasma concentrations of IL-2, IL-4, IL-5, GM-CSF, and IFN-γ demonstrated significant correlations with diminished pigmentation. Furthermore, in the acral melanoma patients group, plasma concentrations of IL-2, IL-4, IL-5, GM-CSF, IFN-γ, and TNF-α revealed significant correlations with diminished pigmentation. Our results reveal significant associations between melanoma pigmentation and various cytokine levels, particularly in acral melanoma patients; these associations can be influenced by factors related to acral melanoma, such as physical stress or trauma. These correlations may also provide directions for the treatment of acral melanoma.

Galantamine improves glycemic control and diabetic nephropathy in Leprdb/db mice

Galantamine, a centrally acting acetylcholinesterase inhibitor, has been shown to attenuate inflammation and insulin resistance in patients with metabolic syndrome. We investigated the effects of galantamine on glycemic control and development of diabetic nephropathy (DN) in Leprdb/db mice. Galantamine significantly reduced food intake, body weight, blood glucose and HbA1c levels. Insulin resistance (HOMA-IR, QUICKI), HOMA-β and elevations in plasma inflammatory cytokine levels (TNF-α, IL-6 and HMGB-1) were all attenuated by galantamine. Galantamine also ameliorated diabetes-induced kidney injury as evidenced by improvements in renal function (BUN, creatinine, albuminuria), histologic injury and apoptosis. Improved glycemic control and nephropathy were associated with increased circulating GLP-1, decreased renal P-38 MAPK and caspase-1 activation and reduced SGLT-2 expression. These findings provide insights into the mechanisms by which galantamine improves glycemic control and attenuates DN in the Leprdb/db mouse model.

Systemic and local vascular inflammation and arterial reactive oxygen species generation in patients with advanced cardiovascular diseases.

Systemic inflammation may cause endothelial activation, mediate local inflammation, and accelerate progression of atherosclerosis. We examined whether the levels of circulating inflammatory cytokines reflect local vascular inflammation and oxidative stress in two types of human arteries. Human internal mammary artery (IMA) was obtained in 69 patients undergoing coronary artery bypass graft (CABG) surgery and left anterior descending (LAD) artery was obtained in 17 patients undergoing heart transplantation (HTx). Plasma levels of tumor necrosis factor α (TNF-α), interleukin-6 (IL-6) and interleukin-1β (IL-1β) were measured using ELISA, high-sensitivity C-reactive protein (hs-CRP) was measured using Luminex, and mRNA expression of proinflammatory cytokines in the vascular tissues was assessed. Furthermore, formation of superoxide anion was measured in segments of IMA using 5 uM lucigenin-dependent chemiluminescence. Vascular reactivity was measured using tissue organ bath system. TNF-α, IL-6 and IL-1β mRNAs were expressed in all studied IMA and LAD segments. Plasma levels of inflammatory cytokines did not correlate with vascular cytokine mRNA expression neither in IMA nor in LAD. Plasma TNF-α and IL-6 correlated with hs-CRP level in CABG group. Hs-CRP also correlated with TNF-α in HTx group. Neither vascular TNF-α, IL-6 and IL-1β mRNA expression, nor systemic levels of either TNF-α, IL-6 and IL-1β were correlated with superoxide generation in IMAs. Interestingly, circulating IL-1β negatively correlated with maximal relaxation of the internal mammary artery (r = -0.37, p = 0.004). At the same time the mRNA expression of studied inflammatory cytokines were positively associated with each other in both IMA and LAD. The positive correlations were observed between circulating levels of IL-6 and TNF-α in CABG cohort and IL-6 and IL-1β in HTx cohort. This study shows that peripheral inflammatory cytokine measurements may not reflect local vascular inflammation or oxidative stress in patients with advanced cardiovascular disease (CVD). Circulating pro-inflammatory cytokines generally correlated positively with each other, similarly their mRNA correlated in the arterial wall, however, these levels were not correlated between the studied compartments.

Higher cytotoxic activities of CD8+ T cells and natural killer cells from peripheral blood of early diagnosed lung cancer patients

IntroductionCytotoxic (CD8+) and natural killer (NK) cells play critical roles in anti-tumor immunity. Dysfunction in these cells is considered as one of the extrinsic mechanisms for tumor relapse.AimWe aimed in this study to assess cytotoxic activities of CD8 + T and NK cells in the peripheral blood from lung cancer patients before and after induction of chemotherapy.Subjects and methodsHealthy (n = 5) volunteers and lung cancer patients (n = 15:5 before, 5 during, and 5 after induction of chemotherapy) were recruited. Flow cytometry was used to analyze the numbers of CD8 + T cells, NK and CD56+T cells and their intracellular expression of granzyme B (GzB) in fresh peripheral blood mononuclear cells (PBMCs) and after 72 h of their culture in vitro and stimulation with 5 µg/ml Concanavalin A (Con A) and 50ng/ml IL-2). In addition, the plasma levels of inflammatory cytokines were measured using luminex.ResultsAfter culture, significant increases in the number of GzB expressing cells gated on CD3+, CD4+, CD8 + and NKCD8 + T cells in the PBMCs from lung cancer patients before induction of chemotherapy as compared to control individuals as well as patients during and after induction of chemotherapy. Serum levels of IL-1 and CXCL8 in patients before induction of chemotherapy showed 37- and 40-fold increases, respectively, as compared to control individuals. Both GzB expression and cytokines levels in patients during and after chemotherapy were similar.ConclusionPolyclonal stimulation of PBMCs can restore the cytolytic activities of cytotoxic CD8 and NK cells from lung cancer patients even after chemotherapy.

Effects of Buyang Huanwu Decoction and Astragali Radix-Angelicae Sinensis Radix combination on inflammatory responses in atherosclerotic mice

The study aims to observe the effects and explore the mechanisms of Buyang Huanwu Decoction and Astragali Radix-Angelicae Sinensis Radix combination in the treatment of the inflammatory response of mice with atherosclerosis(AS) via the Toll-like receptor 4(TLR4)/myeloid differentiation primary response protein 88(MyD88)/nuclear factor-κB(NF-κB) signaling pathway. Male ApoE~(-/-) mice were randomly assigned into a model group, a Buyang Huanwu Decoction group, an Astragali Radix-Angelicae Sinensis Radix combination group, and an atorvastatin group, and male C57BL/6J mice of the same weeks old were used as the control group. Other groups except the control group were given high-fat diets for 12 weeks to establish the AS model, and drugs were administrated by gavage. Aortic intimal hyperplasia thickness, blood lipid level, plasma inflammatory cytokine levels, M1/M2 macrophage markers, and expression levels of proteins in TLR4/MyD88/NF-κB pathway in the vessel wall were measured to evaluate the effects of drugs on AS lesions and inflammatory responses. The results showed that the AS model was successfully established with the ApoE~(-/-) mice fed with high-fat diets. Compared with the control group, the model group showed elevated plasma total cholesterol(TC), triglyceride(TG), and low-density lipoprotein cholesterol(LDL-c) levels(P&lt;0.05), thickened intima(P&lt;0.01), and increased plasma tumor necrosis factor-α(TNF-α) and interleukin-6(IL-6) levels(P&lt;0.01). Moreover, the model group showed increased expression of vascular cell adhesion molecule-1(VCAM-1) and inducible nitric oxide synthase(iNOS)(P&lt;0.01), inhibited expression of endothelial nitric oxide synthase(eNOS) and cluster of differentiation 206(CD206)(P&lt;0.01), and up-regulated mRNA and protein levels of TLR4, MyD88, NF-κB inhibitor alpha(IκBα), and NF-κB in the vessel wall(P&lt;0.05). Compared with the model group, Buyang Huanwu Decoction and Astragali Radix-Angelicae Sinensis Radix combination lowered the plasma TC and LDL-c levels(P&lt;0.01), alleviated the intimal hyperplasia(P&lt;0.01), and reduced the plasma TNF-α and IL-6 levels(P&lt;0.05). Moreover, the two interventions promoted the expression of eNOS and CD206(P&lt;0.05), inhibited the expression of VCAM-1 and iNOS(P&lt;0.01), and down-regulated the mRNA and protein levels of TLR4, MyD88, IκBα, and NF-κB(P&lt;0.05) in the vessel wall. This study indicated that Buyang Huanwu Decoction and Astragali Radix-Angelicae Sinensis Radix combination could delay the progression of AS, inhibit the polarization of vascular wall macrophages toward M1 type, and attenuate vascular inflammatory response by inhibiting the activation of TLR4/MyD88/NF-κB signaling pathway in the vascular wall. Astragali Radix and Angelicae Sinensis Radix were the main pharmacological substances in Buyang Huanwu Decoction for alleviating the AS vascular inflammatory response.

1-O-alkyl-glycerols from Squid Berryteuthis magister Reduce Inflammation and Modify Fatty Acid and Plasmalogen Metabolism in Asthma Associated with Obesity.

Asthma associated with obesity is considered the most severe phenotype and can be challenging to manage with standard medications. Marine-derived 1-O-alkyl-glycerols (AGs), as precursors for plasmalogen synthesis, have high biological activity, making them a promising substance for pharmacology. This study aimed to investigate the effect of AGs from squid Berryteuthis magister on lung function, fatty acid and plasmalogen levels, and cytokine and adipokine production in obese patients with asthma. The investigational trial included 19 patients with mild asthma associated with obesity who received 0.4 g of AGs daily for three months in addition to their standard treatment. The effects of AGs were evaluated at one and three months of treatment. The results of the study demonstrated that intake of AGs increased the FEV1 and FEV1/VC ratios, and significantly decreased the ACQ score in 17 of the 19 patients after three months of treatment. The intake of AGs increased concentration of plasmalogen and n-3 PUFA in plasma, and modified leptin/adiponectin production by adipose tissue. The supplementation of AGs decreased the plasma levels of inflammatory cytokines (TNF-α, IL-4, and IL-17a), and oxylipins (TXB2 and LTB4), suggesting an anti-inflammatory property of AGs. In conclusion, 1-O-alkyl-glycerols could be a promising dietary supplement for improving pulmonary function and reducing inflammation in obese asthma patients, and a natural source for plasmalogen synthesis. The study highlighted that the beneficial effects of AG consumption can be observed after one month of treatment, with gradual improvement after three months of supplementation.

Chronic stress, neuroinflammation, and depression: an overview of pathophysiological mechanisms and emerging anti-inflammatories.

In a subset of patients, chronic exposure to stress is an etiological risk factor for neuroinflammation and depression. Neuroinflammation affects up to 27% of patients with MDD and is associated with a more severe, chronic, and treatment-resistant trajectory. Inflammation is not unique to depression and has transdiagnostic effects suggesting a shared etiological risk factor underlying psychopathologies and metabolic disorders. Research supports an association but not necessarily a causation with depression. Putative mechanisms link chronic stress to dysregulation of the HPA axis and immune cell glucocorticoid resistance resulting in hyperactivation of the peripheral immune system. The chronic extracellular release of DAMPs and immune cell DAMP-PRR signaling creates a feed forward loop that accelerates peripheral and central inflammation. Higher plasma levels of inflammatory cytokines, most consistently interleukin IL-1β, IL-6, and TNF-α, are correlated with greater depressive symptomatology. Cytokines sensitize the HPA axis, disrupt the negative feedback loop, and further propagate inflammatory reactions. Peripheral inflammation exacerbates central inflammation (neuroinflammation) through several mechanisms including disruption of the blood-brain barrier, immune cellular trafficking, and activation of glial cells. Activated glial cells release cytokines, chemokines, and reactive oxygen and nitrogen species into the extra-synaptic space dysregulating neurotransmitter systems, imbalancing the excitatory to inhibitory ratio, and disrupting neural circuitry plasticity and adaptation. In particular, microglial activation and toxicity plays a central role in the pathophysiology of neuroinflammation. Magnetic resonance imaging (MRI) studies most consistently show reduced hippocampal volumes. Neural circuitry dysfunction such as hypoactivation between the ventral striatum and the ventromedial prefrontal cortex underlies the melancholic phenotype of depression. Chronic administration of monoamine-based antidepressants counters the inflammatory response, but with a delayed therapeutic onset. Therapeutics targeting cell mediated immunity, generalized and specific inflammatory signaling pathways, and nitro-oxidative stress have enormous potential to advance the treatment landscape. Future clinical trials will need to include immune system perturbations as biomarker outcome measures to facilitate novel antidepressant development. In this overview, we explore the inflammatory correlates of depression and elucidate pathomechanisms to facilitate the development of novel biomarkers and therapeutics.

NLRP3 inflammasome-driven IL-1β and IL-18 contribute to lipopolysaccharide-induced septic cardiomyopathy

Sepsis is a life-threatening syndrome, and its associated mortality is increased when cardiac dysfunction and damage (septic cardiomyopathy [SCM]) occur. Although inflammation is involved in the pathophysiology of SCM, the mechanism of how inflammation induces SCM in vivo has remained obscure. NLRP3 inflammasome is a critical component of the innate immune system that activates caspase-1 (Casp1) and causes the maturation of IL-1β and IL-18 as well as the processing of gasdermin D (GSDMD). Here, we investigated the role of the NLRP3 inflammasome in a murine model of lipopolysaccharide (LPS)-induced SCM. LPS injection induced cardiac dysfunction, damage, and lethality, which was significantly prevented in NLRP3−/− mice, compared to wild-type (WT) mice. LPS injection upregulated mRNA levels of inflammatory cytokines (Il6, Tnfa, and Ifng) in the heart, liver, and spleen of WT mice, and this upregulation was prevented in NLRP3−/− mice. LPS injection increased plasma levels of inflammatory cytokines (IL-1β, IL-18, and TNF-α) in WT mice, and this increase was markedly inhibited in NLRP3−/− mice. LPS-induced SCM was also prevented in Casp1/11−/− mice, but not in Casp11mt, IL-1β−/−, IL-1α−/−, or GSDMD−/− mice. Notably, LPS-induced SCM was apparently prevented in IL-1β−/− mice transduced with adeno-associated virus vector expressing IL-18 binding protein (IL-18BP). Furthermore, splenectomy, irradiation, or macrophage depletion alleviated LPS-induced SCM. Our findings demonstrate that the cross-regulation of NLRP3 inflammasome-driven IL-1β and IL-18 contributes to the pathophysiology of SCM and provide new insights into the mechanism underlying the pathogenesis of SCM.

KW2449 ameliorates collagen-induced arthritis by inhibiting RIPK1-dependent necroptosis.

Necroptosis has recently been found to be associated with the pathogenesis of many autoimmune diseases, including rheumatoid arthritis (RA). This study was undertaken to explore the role of RIPK1-dependent necroptosis in the pathogenesis of RA and the potential new treatment options. The plasma levels of receptor-interacting protein kinase 1 (RIPK1) and mixed lineage kinase domain-like pseudokinase (MLKL) in 23 controls and 42 RA patients were detected by ELISA. Collagen-induced arthritis (CIA) rats were treated with KW2449 by gavage for 28 days. Arthritis index score, H&E staining, and Micro-CT analysis were used to evaluate joint inflammation. The levels of RIPK1-dependent necroptosis related proteins and inflammatory cytokines were detected by qRT-PCR, ELISA and Western blot, and the cell death morphology was detected by flow cytometry analysis and high-content imaging analysis. The plasma levels of RIPK1 and MLKL in RA patients were higher than those in healthy people, and were positively correlated with the severity of RA. KW2449 could reduce joint swelling, joint bone destruction, tissue damage, and the plasma levels of inflammatory cytokines in CIA rats. Lipopolysaccharide combined with zVAD (LZ) could induce necroptosis in RAW 264.7 cells, which could be reduced by KW2449. RIPK1-dependent necroptosis related proteins and inflammatory factors increased after LZ induction and decreased after KW2449 treatment or knockdown of RIPK1. These findings suggest that the overexpression of RIPK1 is positively correlated with the severity of RA. KW2449, as a small molecule inhibitor targeting RIPK1, has the potential to be a therapeutic strategy for RA treatment by inhibiting RIPK1-dependent necroptosis.

Therapeutic Effects of Cornuside on Particulate Matter-Induced Lung Injury.

Particulate matter (PM) is a mixture comprising both organic and inorganic particles, both of which are hazardous to health. The inhalation of airborne PM with a diameter of ≤2.5 μm (PM2.5) can cause considerable lung damage. Cornuside (CN), a natural bisiridoid glucoside derived from the fruit of Cornus officinalis Sieb, exerts protective properties against tissue damage via controlling the immunological response and reducing inflammation. However, information regarding the therapeutic potential of CN in patients with PM2.5-induced lung injury is limited. Thus, herein, we examined the protective properties of CN against PM2.5-induced lung damage. Mice were categorized into eight groups (n = 10): a mock control group, a CN control group (0.8 mg/kg mouse body weight), four PM2.5+CN groups (0.2, 0.4, 0.6, and 0.8 mg/kg mouse body weight), and a PM2.5+CN group (0.2, 0.4, 0.6, and 0.8 mg/kg mouse body weight). The mice were administered with CN 30 min following intratracheal tail vein injection of PM2.5. In mice exposed to PM2.5, different parameters including changes in lung tissue wet/dry (W/D) lung weight ratio, total protein/total cell ratio, lymphocyte counts, inflammatory cytokine levels in the bronchoalveolar lavage fluid (BALF), vascular permeability, and histology were examined. Our findings revealed that CN reduced lung damage, the W/D weight ratio, and hyperpermeability caused by PM2.5. Moreover, CN reduced the plasma levels of inflammatory cytokines produced because of PM2.5 exposure, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and nitric oxide, as well as the total protein concentration in the BALF, and successfully attenuated PM2.5-associated lymphocytosis. In addition, CN substantially reduced the expression levels of Toll-like receptors 4 (TLR4), MyD88, and autophagy-related proteins LC3 II and Beclin 1, and increased protein phosphorylation of the mammalian target of rapamycin (mTOR). Thus, the anti-inflammatory property of CN renders it a potential therapeutic agent for treating PM2.5-induced lung injury by controlling the TLR4-MyD88 and mTOR-autophagy pathways.

The effect of Brazilian Green Propolis extract on inflammation in patients with chronic kidney disease on peritoneal dialysis: A randomised double-blind controlled clinical trial

BackgroundChronic kidney disease (CKD) patients on dialysis display a low-grade systemic inflammatory burden. Nutritional interventions designed to activate the cytoprotective nuclear factor erythroid-2-related factor 2 (Nrf2) and inhibit nuclear factor-kB (NF-κB) have been proposed to mitigate this burden. Several bioactive compounds have been investigated to achieve this, including propolis, a resin produced by Apis mellifera bees. Considering the safety and efficacy of propolis, it could be a strategy to benefit these patients. Still, there are no studies using propolis in patients with CKD on peritoneal dialysis (DP), and clinical studies to support this application are lacking. Hypothesis/PurposeThe objective and novelty of the present study are to evaluate the effects of propolis supplementation on inflammatory markers in patients with CKD on PD. Study designA longitudinal, double-blind, placebo-controlled trial with CKD patients on PD. MethodsThe patients were randomised into two groups: propolis that received four capsules of 100 mg (400 mg/day), containing concentrated and standardised dry EPP-AF® Brazilian green propolis extract) or placebo, four capsules of 100 mg (400 mg/day), of magnesium stearate, silicon dioxide, and microcrystalline cellulose, for two months. Plasma levels of inflammatory cytokines, including tumour necrosis factor (TNF-α) and interleukin-6 (IL-6), were evaluated by ELISA. Quantitative real-time PCR analyses were performed to evaluate the transcriptional expression levels of Nrf2 and NF-κB in peripheral blood mononuclear cells (PBMCs). Plasma malondialdehyde (MDA) levels, a lipid peroxidation marker, was measured as thiobarbituric acid reactive substances (TBARS). Routine biochemical markers, including C-reactive protein (CRP), were analysed using commercial kits. Carotid Intima-Media Thickness (CIMT) was measured with a doppler ultrasonography device. The study was registered on ClinicalTrials.gov under the number NCT04411758. ResultsA total of 19 patients completed the study, ten patients in the propolis group (54 ± 1.0 years, five men, 7.2 (5.1) months on PD) and 9 in the placebo group (47.5 ± 15.2 years, three men, 10.8 (24.3) months on PD). The plasma levels of TNF-α reduced significantly (p = 0.02), and expression of Nrf2 showed a trend to increase (p = 0.07) after propolis supplementation. ConclusionEPP-AF® Green Propolis extract (400 mg/day) supplementation for two months appears as a potential strategy to mitigate inflammation, reducing TNF-α plasma levels in CKD patients on PD.

Effects of propolis on inflammation markers in patients undergoing hemodialysis: A randomized, double-blind controlled clinical trial

Background and aimsSeveral studies have been performed in vitro and in animals showing that propolis (a resin made by bees) has excellent anti-inflammatory properties, but no study has been performed in patients with chronic kidney disease (CKD) on hemodialysis (HD). The present study aimed to evaluate the effects of propolis supplementation on inflammatory markers in patients with CKD on HD. MethodsThis is a longitudinal, double-blind, placebo-controlled trial with patients randomized into two groups: propolis (4 capsules of 100 mg/day containing concentrated and standardized dry EPP-AF® green propolis extract) or placebo (4 capsules of 100 mg/day containing microcrystalline cellulose, magnesium stearate and colloidal silicon dioxide) for two months. Routine parameters were analyzed using commercial kits. The plasma levels of inflammatory cytokines were evaluated by flow luminometry. ResultsForty-one patients completed the follow-up, 21 patients in the propolis group (45 ± 12 years, 13 women, BMI, 22.8 ± 3.7 kg/m2) and 20 in the placebo group (45.5 ± 14 years, 13 women, BMI, 24.8 ± 6.8 kg/m2). The obtained data revealed that the intervention with propolis significantly reduced the serum levels of tumour necrosis factor α (TNFα) (p = 0.009) as well as had the tendency to reduce the levels of macrophage inflammatory protein-1β (MIP-1β) (p = 0.07). There were no significant differences in the placebo group. ConclusionShort-term EPP-AF® propolis dry extract 400 mg/day supplementation seems to mitigate inflammation, reducing the plasma levels of TNFα and MIP-1β in patients with CKD on HD. This study was registered at clinicaltrials.gov (NCT04411758).