MCP-1 Research Articles

Exploring Causal Associations Between Serum Inflammatory Markers and Female Reproductive Disorders: A Mendelian Randomisation Study

Although inflammation may disrupt immunoendocrine crosstalk essential for female reproductive function, causal links to disorders like polycystic ovary syndrome (PCOS) and endometriosis remain unestablished. This study aimed to utilise Mendelian randomisation (MR) methods to explore causal associations between serum inflammatory markers and common reproductive disorders, aiming to identify novel mechanisms and potential avenues for treatment. Total causal effects of serum inflammatory markers (interleukins, monocyte chemoattractant protein-1, etc.) on female reproductive disorders in large sample cohorts of Finnish ancestry were assessed using univariable two-sample MR methods, including the inverse variance weighted (IVW) method as the primary analysis, with relevant quality assessments (e.g., leave-one out, heterogeneity, and horizontal pleiotropy testing). The main outcome measures were PCOS (642 cases and 118,228 controls) and endometriosis (8288 cases and 68,969 controls) from the FINNGEN cohort. Monocyte chemoattractant protein-1/C-C motif chemokine ligand demonstrated a positive causal association with polycystic ovary syndrome (odds ratio [95% CI]: 1.48 [1.10, 2.00], p = 0.0097), while higher interleukin-9 levels were positively associated with endometriosis (1.15 [1.02, 1.30], p = 0.0277), both via the IVW method. These markers should be investigated as key candidates for future research into the mechanistic pathways underpinning these conditions.

<em>Influenzinum</em> and <em>Echinacea</em>: boosters of immune response in vitro

Background: Some homeopathic medicines are traditionally used in medical practice to strengthen immunity and reduce inflammation. In particular, Influenzinum is used in clinical practice for the prevention of influenza-like illness, the management of possible symptoms following an anti-influenza vaccination and post-infectious convalescence. Echinacea angustifolia is the best known for its beneficial effects on the immune system and infectious syndrome. During an infection (viral or bacterial), the innate immunity is the first body response. It is an immediate inflammatory reaction which involves, among other factors, phagocytosis and oxidative stress at the cellular level (1). Objectives: To evaluate in vitro the effect of homeopathic dilutions of Influenzinum 9CH and 15CH and Echinacea angustifolia 5CH on biological markers of cellular inflammation and phagocytosis in several cellular models. Results: In inflamed macrophages, Influenzinum 9CH significantly increases the production of IL-6 (Interleukin-6) and MCP-1 (Monocyte Chemoattractant Protein-1) by 26% and 34%, respectively, compared with placebo which help to eliminate pathogens. In inflamed endothelial cells, Influenzinum 9CH and 15CH significatly decrease ICAM-1(InterCellular Adhesion Molecule-1) production by 20% compared with placebo, limiting the vascular inflammation. Furthermore, Influenzinum 9CH and 15CH demonstrated an antioxidant effects by significantly decreasing total ROS (reactive oxygen species) in inflamed primary microglia cells. Moreover, Echinacea angustifolia 5CH significantly increases the phagocytosis by 15% in monocytes and 25% in microglial cells compared with water (placebo) in non-inflammatory conditions. Conclusions: We demonstrated that Influenzinum and Echinacea angustifolia have a biological action in cell models in vitro. In inflammatory conditions, Influenzinum 9CH and 15CH have (i) immunostimulant effect, (ii) anti-inflammlatory effect on vascular cells, (iii) antioxidant effect. Echinacea angustifolia 5CH stimulates phagocytosis. Overall, Influenzinum and Echinacea angustifolia have a boosting effect on various biological parameters of innate immunity.

Circulating biomarkers of macrophage activation in different stages of chronic pancreatitis: A pilot study.

Activation of type M2 macrophages has been implicated in the pathogenesis of chronic pancreatitis (CP). In a clinical pilot study, we investigated blood-based markers of macrophage activation at different stages of CP. We performed a cross-sectional analysis of prospectively collected plasma samples from healthy controls and patients with suspected or definitive CP according to the M-ANNHEIM criteria. Plasma concentrations of soluble CD163 (sCD163), soluble CD206 (sCD206), and monocyte chemoattractant protein-1 (MCP-1) were analyzed using enzyme-linked immunosorbent assays. Group and pairwise comparisons of analytes were performed using regression models and area under the receiver operating curves (AUC-ROC). In total, 73 subjects with CP (28 suspected CP and 45 definitive CP) and 40 controls were included. Compared to controls, the median plasma concentrations of sCD163 (p = 0.019) and sCD206 (p = 0.033) were elevated in patients with definitive CP. sCD206 was also elevated in patients with definitive CP (p = 0.042). ROC analysis revealed that the optimal sCD163 cutpoint to distinguish definitive CP from controls was 1.84 mg/ml (AUC-ROC 0.65; 95 % confidence interval [CI], 0.54-0.77). The optimal sCD206 cutpoint to distinguish definitive CP from controls was 0.24 mg/ml (AUC-ROC 0.66; 95 % CI 0.54-0.78). The analytes did not significantly discriminate patients with suspected CP from controls. MCP-1 concentrations showed no differences across subgroups. Our study demonstrates that subjects with definitive CP, sampled during a clinically quiescent phase, exhibited increased levels of sCD163 and sCD206. This indicates the presence of activated M2 macrophages in patients with CP at advanced, but not early, clinical stages.

Fenofibrate attenuates renal lipotoxicity in uninephrectomized mice with high-fat diet-induced obesity.

The objective of this study was to investigate the role of fenofibrate, a peroxisome proliferator-activated receptor-α agonist, in obesity-induced kidney damage (lipotoxicity) in mice with uninephrectomy. C57BL/6 mice underwent uninephrectomy and sham surgeries and were fed normocaloric or high-fat diets. After 10 weeks, obese mice were administered 0.02% fenofibrate for 10 weeks. Kidney function and morphology were evaluated, as well as levels of inflammatory and fibrotic mediators and lipid metabolism markers. High-fat diet-fed mice developed characteristic obesity and hyperlipidemia, with subsequent renal lipid accumulation and damage, including mesangial expansion, interstitial fibrosis, inflammation, and proteinuria. These changes were greater in obese uninephrectomy mice than in obese sham mice. Fenofibrate treatment prevented hyperlipidemia and glomerular lesions, lowered lipid accumulation, ameliorated renal dysfunction, and attenuated inflammation and renal fibrosis. Furthermore, fenofibrate treatment downregulated renal tissue expression of plasminogen activator inhibitor-1, monocyte chemoattractant protein-1, and local expression of fibroblast growth factor-21. Peroxisome proliferator-activated receptor-α activation by fenofibrate, with subsequent lipolysis, attenuated glomerular and tubulointerstitial lesions induced by renal lipotoxicity, thus protecting the kidneys of uninephrectomy mice from obesity-induced lesions. The study findings suggest a pathway in the pharmacological action of fenofibrate, providing insight into the mechanisms involved in kidney damage caused by obesity in kidney donors.

Exploring the Causal Relationship Between Inflammatory Cytokines and MRI-Derived Brain Iron: A Mendelian Randomization Study.

The association between inflammation and brain iron deposition is widely acknowledged. However, the precise causal impact of peripheral inflammatory cytokines on changes in brain iron content remains uncertain. The study utilized an available genome-wide association study (GWAS) summary associated with inflammatory cytokines from The Cardiovascular Risk in Young Finns Study and the FINRISK surveys. The GWAS data for brain iron markers were obtained from the UK Biobank. We assessed the iron content of each brain region using susceptibility-weighted magnetic resonance imaging, utilizing both quantitative susceptibility mapping and T2* measurements. The primary outcomes were susceptibility (χ) and T2*, which serve as indices of iron deposition. To investigate the causal relationship between exposure and outcome, we primarily employed inverse variance weighting, MR Egger, weighted median, simple mode, and weighted mode methods, collectively enhancing the robustness of our results. The results of MR analyses demonstrate that our study unveiled that nerve growth factor-β, hepatocyte growth factor, interleukin-1 (IL-1), IL-8, macrophage inflammatory protein 1α, and tumor necrosis factor-α were associated with elevated brain iron content in the regions of left hippocampus, putamen, left thalamus, right pallidum, right hippocampus, left amygdala, respectively. Furthermore, our investigation provides evidence for a negative relationship between IL-1, IL-17, monocyte chemotactic protein-3, tumor necrosis factor-β, and brain iron content in distinct regions. Our findings suggest a causal association between circulating inflammatory cytokines and brain iron deposition across various brain regions. This provides new insights into the immunopathogenesis of neurodegenerative diseases and potential preventive strategies targeting iron metabolism.

Taurine potentiates artemisinin efficacy against malaria by modulating the immune response in Plasmodium berghei-infected mice

BackgroundArtemisinin (ART) is a frontline drug for the treatment of malaria; however, the emergence of ART-resistant Plasmodium strains necessitates increasing ART sensitivity. Given that taurine (TAU) has been shown to have immunomodulatory activity, we investigated the effects of TAU as an adjunct therapy to ART in mice infected with Plasmodium berghei.MethodsMice infected with P. berghei ANKA strain (P. berghei ANKA) were treated with TAU alone, ART alone or a combination of TAU and ART (TAU + ART), and their survival time and parasitaemia were recorded. The cytotoxic effects of TAU and ART were subsequently assessed. The expression levels of inflammasome-related genes and inflammatory factors in mice infected with P. berghei ANKA were analysed in relation to those in mice treated with TAU alone, ART alone or the TAU + ART combination. The therapeutic effects were further evaluated by histological analysis and measurement of the spleen index.ResultsCompared with the control mice, P. berghei ANKA-infected mice treated with ART in combination with TAU presented significantly lower parasitaemia and prolonged survival. The combined treatment resulted in significant reductions in the expression levels of inflammasome-related genes in the spleen, including absent in melanoma 2 (AIM2), caspase-1, NOD-, LRR- and pyrin domain-containing protein 3 (Nlrp3), Nlrp1b, Nlrp1b, NLR family CARD domain containing 4 (Nlrc4), Nlrp6, nucleotide binding oligomerization domain containing 1 (NOD1) and NOD2, and decreases in the levels of inflammatory cytokines in the serum, including interleukin (IL)-12p70, tumour necrosis factor-alpha, monocyte chemoattractant protein-1, IL-10 and IL-6. Histopathological analysis confirmed that TAU + ART combination treatment reduced spleen pathology caused by P. berghei ANKA infection.ConclusionsThe findings indicate that TAU potentiates ART efficacy by modulating the immune response in P. berghei-infected mice.Graphical

Effects of 3-month liraglutide treatment on oxidative stress and inflammation in type 2 diabetes patients with different urinary albumin-to-creatinine ratio categories

This study evaluates the effects of liraglutide on albuminuria, oxidative stress, and inflammation in type 2 diabetes (T2D) patients with different urinary albumin-to-creatinine ratio (UACR) categories. We enrolled 107 patients with T2D who were initiating liraglutide for glycemic control. Patients were categorized into 3 groups: group I (UACR < 30 mg/g); group II (30 mg/g ≤ UACR ≤ 300 mg/g); group III (UACR > 300 mg/g). We observed the changes in body mass index, fasting plasma glucose, glycated hemoglobin, lipid profile, serum liver enzymes, creatinine, uric acid, cystatin C, UACR, as well as oxidative stress and inflammation biomarkers such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), monocyte chemotactic protein-1 (MCP-1), malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione peroxidase before and after 3 months of liraglutide treatment. After 3-month liraglutide treatment, fasting plasma glucose, glycated hemoglobin, and body mass index significantly decreased in all 3 groups regardless of the baseline UACR (all P < .05). UACR significantly decreased in groups II (P = .005) and III (P = .001). Patients with higher UACR at baseline showed significantly greater albuminuria reduction (P < .001). Compared with baseline, TNF-α, IL-6, MCP-1, and MDA were remarkably decreased, while SOD and glutathione peroxidase were significantly increased in all 3 groups (P < .05). UACR at baseline showed a positive correlation with TNF-α, IL-6, and MDA, and a negative correlation with SOD at baseline. The change in UACR was negatively correlated with UACR, TNF-α, and MDA at baseline, while it was positively correlated with SOD at baseline, and also positively correlated with the change in MCP-1. Liraglutide ameliorated albuminuria in T2D patients with microalbuminuria and macroalbuminuria. The renoprotective effect of liraglutide was associated with the alleviation of oxidative stress and inflammation. These findings may provide new therapeutic strategies for patients with diabetic kidney disease.

Immune traits in combination with inflammatory proteins revealing the pathogenesis of autoimmune liver diseases: A Mendelian randomization study

BackgroundPrior observational research has shown relationships between immune cells, inflammatory proteins, and autoimmune liver diseases (AILD), but their causal associations remain controversial. Therefore, we aimed to clarify the causal association between them. MethodsWe carried out a comprehensive Mendelian randomization (MR) analysis to clarify causal associations between 731 immune traits, 91 circulating inflammatory proteins, and AILD, including primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), and autoimmune hepatitis (AIH). A two-step MR analysis was used to explore the mediating role of circulating inflammatory proteins. Additionally, we performed sensitivity analyses to evaluate the robustness of the results. ResultsCD27 on IgD+CD24+B cell, CD27 on IgD−CD38dimB cell, CD27 on unswitched memory B cell, CD27 on switched memory B cell, and CD27 on CD24+CD27+B cell were risk factors for PBC. However, we detected protective effects of CD25 on IgD−CD27−B cell against PBC and CD28 on resting CD4+Treg cell against PSC. Circulating CD40, Interleukin-33, and Delta and Notch-like epidermal growth factor-related receptor were protective factors for PBC. Furthermore, CD40 mediated the association between immune traits and PBC, with the mediated proportions ranging from 18.3 % to 35.4 %. Tumor necrosis factor superfamily member 12 was identified as a risk factor for PSC, and monocyte chemotactic protein 3 was identified as a protective factor for PSC. Additionally, PBC and PSC had effects on eleven immune traits, which are suggested to be the consequences of them. We found no causal association between immune traits, circulating inflammatory proteins, and AIH. Sensitivity analyses demonstrated our results were robust. ConclusionsOur results demonstrate the causal roles of immune traits and inflammatory proteins in PBC and PSC, which reveals their pathogenesis. It is necessary to investigate the specific mechanism by which immune cells and inflammatory proteins affecting the occurrence of AILD.

Endocannabinoid receptor 2 is a potential biomarker and therapeutic target for the lysosomal storage disorders.

Herein, we studied the expression of endocannabinoid receptor 2 (CB2R), a known inflammation mediator, in several lysosomal storage disorder (LSD) animal models and evaluated it as a potential biomarker and therapeutic target for these diseases. CB2R was highly elevated in the plasma of Farber disease and mucopolysaccharidosis (MPS) type IIIA mice, followed by Fabry disease and MPS type I mice. Mice with acid sphingomyelinase-deficient Niemann-Pick disease (ASMD) and rats with MPS type VI exhibited little or no plasma CB2R elevation. High-level expression of CB2R was also observed in tissues of Farber and MPS IIIA mice. Treatment of MPS IIIIA patient cells with CB2R agonists led to a reduction of CB2R and monocyte chemoattractant protein-1 (MCP-1), a chemotactic factor that is elevated in this LSD. Treatment of MPS IIIA mice with one of these agonists (JWH133) led to a reduction of plasma and tissue CB2R and MCP-1, a reduction of glial fibrillary acidic protein (GFAP) in the brain, and an improvement in hanging test performance. JWH133 treatment of Farber disease mice also led to a reduction of MCP-1 in tissues and plasma, and treatment of these mice by enzyme replacement therapy (ERT) led to a reduction of plasma CB2R, indicating its potential to monitor treatment response. Overall, these findings suggest that CB2R should be further examined as a potential therapeutic target for the LSDs and may also be a useful biomarker to monitor the impact of therapies.

Correlation of Cytokine Profiles with Prostate-Specific Antigen and Disease Grade in Prostate Cancer.

BACKGROUND The development and progression of prostate cancer are multistep processes involving several growth factors, hormones, and cytokines. This study aimed to measure the serum concentrations of different cytokines and determine their correlation with prostate-specific antigen (PSA) levels and disease grade in patients with prostate adenocarcinoma. MATERIAL AND METHODS This cross-sectional study was conducted from March 2023 to March 2024 at the Clinic of Oncology of the University Hospital Center in Mostar, Bosnia and Herzegovina. Altogether, 50 male patients with prostate adenocarcinoma were included, of whom 28 had no proven metastases (PC group) and 22 had metastatic disease (MPC group). Serum concentrations of total (tPSA), free (fPSA), and complexed (cPSA) PSA were determined using a chemiluminescent microparticle immunoassay, whereas serum concentrations of cytokines were measured using a flow cytometry bead-based assay. RESULTS The MPC group had higher serum tPSA, fPSA, and cPSA levels than the PC group. The PC group had significantly higher serum levels of monocyte chemotactic protein (MCP)-1 than the MPC group (P=0.008). In the PC group, serum levels of interleukin (IL)-10 significantly correlated with cPSA. In the MPC group, serum concentrations of IL-1ß, tumor necrosis factor (TNF)-alpha, and IL-23 significantly correlated with disease grade. CONCLUSIONS Our study emphasizes the importance of MCP-1 in the development of prostate cancer, while IL-10 was the only cytokine whose serum level significantly correlated with cPSA. Serum concentrations of IL-1ß, TNF-alpha, and IL-23 may serve as potential biomarkers for disease grade.

A systematic review and meta-analysis of blood level of MCP-1/CCL-2 in severe and uncomplicated malaria

Monocyte chemoattractant protein-1 (MCP-1) or C-C Motif Chemokine Ligand 2 (CCL-2) is a key chemokine implicated in the inflammatory response to malaria. The objective of the study was to synthesize the evidence on variations in MCP-1/CCL-2 levels in relation to Plasmodium spp. infections and the severity of malaria. The protocol for this systematic review and meta-analysis was registered at PROSPERO (CRD42024565867). To identify relevant studies, a comprehensive search strategy was conducted using major databases, including PubMed, Scopus, Embase, Medline, Journals@Ovid, and Nursing & Allied Health Premium. The Joanna Briggs Institute (JBI) critical appraisal checklists were used to determine the risk of bias in selected studies. The pooled standardized mean difference (SMD, Hedge’s g) and their 95% confidence interval (CI) were estimated using the random-effects model. Thirty-three studies, with a total of 6,804 participants enrolled, were included in the systematic review. Most studies (60.6%) were published between 2010 and 2019; the majority (57.6%) were conducted in Africa. The predominant Plasmodium species studied was P. falciparum (66.7%). The meta-analysis revealed no significant difference in MCP-1/CCL-2 levels between Plasmodium-infected and uninfected individuals (P: 0.16, SMD: 0.99, 95% CI: -0.39–2.37, I2: 97.2%, number of participants: 2140). Subgroup analysis found an increase in MCP-1/CCL-2 levels in children with Plasmodium infections, with no heterogeneity observed (I2: 0%). Subgroup analysis found no difference in MCP-1/CCL-2 levels between P. falciparum-infected participants and uninfected participants, as well as between P. falciparum or non-P. falciparum-infected participants and uninfected participants. The meta-analysis revealed significantly higher MCP-1/CCL-2 levels in participants with severe Plasmodium infections compared to those with non-severe malaria (P: 0.04, SMD: 1.51, 95% CI: 0.06–2.95, I2: 98.5%, number of participants: 1371). The systematic review and meta-analysis suggest no statistically significant difference in MCP-1/CCL-2 levels in participants with Plasmodium infections overall. However, there was a significant increase in MCP-1/CCL-2 levels in patients with severe malaria. These findings suggest that MCP-1/CCL-2 may have potential as a prognostic biomarker for severe malaria. Future research should focus on large-scale, well-designed studies to validate the role of MCP-1/CCL-2 in malaria and further explore its prognostic potential.

Serum Concentrations of Pro- and Anti-Inflammatory Cytokines in Wistar Rats Subjected to Immobilization Stress and Treated with Tuftsin-Pro-Gly-Pro Peptide.

It was found that 28-day immobilization stress in male Wistar rats leads to significant increase in the serum concentrations of proinflammatory cytokines IL-1β, IL-6, IFNγ, and monocyte chemoattractant protein-1 (MCP-1) and a decrease in the content of anti-inflammatory IL-10, as well as the ratio IL-1β/IL-10, IL-6/IL-10, and IFNγ/IL-10 compared to non-stressed animals. Administration of the heptapeptide tuftsin-Pro-Gly-Pro produced a corrective effect on cytokine concentrations under stress conditions: at a dose of 750 μg/kg, the peptide decreased the concentrations of IL-1β, IFNγ, and MCP-1 and cytokine ratios (IL-1β/IL-10 and IFNγ/IL-10), while at a dose of 250 μg/kg, it increased IL-10 levels and decreased IL-6/IL-10 and IFNγ/IL-10 ratios.

Pharmacotherapeutic potential of bilobetin to combat chromium induced hepatotoxicity via regulating TLR-4, Nrf-2/Keap-1, JAK1/STAT3 and NF-κB pathway: A pharmacokinetic and molecular dynamic approach

BackgroundChromium (Cr) is one of the top-notch noxious heavy metals that is documented to exert deleterious effects on various body organs including the liver. Bilobetin (BLB) is a natural flavonoid which exhibits a wide range of medicinal properties. AimThis trial was executed to investigate the pharmacotherapeutic potential of BLB to avert Cr instigated hepatotoxicity via modulating TLR4, JAK1/STAT3, Nrf-2/Keap-1 and NF-κB pathway. Research layoutOur trial was executed on thirty-six male albino rats that were segregated into four equal groups including the control, Cr (10 mg/kg), Cr (10 mg/kg) + BLB (12 mg/kg) and BLB (12 mg/kg) alone treated group. Various biochemical parameters were assessed by using qRT-PCR, molecular docking, molecular dynamic simulation and histological approaches. FindingsOur results revealed that Cr administration significantly impaired the health of hepatic tissues by reducing the gene expression of Nrf-2 and its downregulating genes while promoting the levels of oxidative stress markers (ROS and MDA). Moreover, Cr administration upregulated the hepatic enzymes including ALT, GGT, AST, and ALP while concurrently decreasing the levels of total protein and albumin. Cr exposure also elevated the gene expression of pro-inflammatory cytokines including toll-like receptor 4 (TLR4), high mobility group box 1 (HMGB1) nuclear factor kappa B (NF-κB), Janus kinase 1 (JAK1), signal transducer and activator of transcription 3 (STAT3), tumor necrosis factor alpha (TNF-α), C-reactive proteins, interferon-gamma inducible protein-10 (IP-10), Interleukin beta-1(IL-1β), monocyte chemoattractant protein-1 (MCP-1), interleukin-6 (IL-6) and cyclooxygenase-2 (COX-2). Hepatic apoptosis was observed to be elevated following the Cr intoxication. Nonetheless, BLB treatment remarkably alleviated the hepatic damages via regulating the biochemical as well as histological profile of liver. Our findings are further endorsed by molecular docking analysis that demonstrated that BLB exhibit strong binding affinity to Keap-1 and STAT3 thus supporting its efficient hepatoprotective potential. ConclusionBLB protected the hepatic tissues via regulating Cr induced impairments. These findings were confirmed by molecular docking and molecular dynamic simulation analysis.

Gut microbiotas, inflammatory factors, and mental-behavioral disorders: A mendelian randomization study

BackgroundThe Mendelian randomization approach has emerged as a powerful tool, leveraging genetic variations as natural random experiments to minimize confounding and infer causality with unique advantages. Previous research has highlighted the crucial roles of gut microbiotas and inflammatory factors in mental-behavioral disorders, albeit to varying degrees. However, the precise causal relationship between gut microbiotas and mental-behavioral disorders remains elusive, and the potential role of inflammatory factors as mediators in this process is unclear. MethodsTo investigate the associations between gut microbiotas, inflammatory factors, and mental-behavioral disorders, we pooled data from large-scale genome-wide association studies (GWAS). Our study screened 27 diseases, encompassing nine subtypes of mental-behavioral disorders: neurodevelopmental disorders, eating disorders, sleep disorders, schizophrenia spectrum disorders, stress- and trauma-related disorders, mood and affective disorders, cognitive and executive function disorders, personality and somatization disorders, and addiction disorders. Mendelian randomization(MR) was employed to assess causal relationships between gut microbiotas, inflammatory factors, and these mental-behavioral disorders, with inverse variance weighting (IVW) as the primary statistical method. Furthermore, we explored whether inflammatory factors mediate the relationship between gut microbiotas and mental-behavioral disorders. ResultsHaving investigated the intricate interplay among gut microbiota, inflammatory factors, and mental-behavioral disorders, we have identified nine pivotal inflammatory factors that intricately regulate the progression of eight distinct disease subtypes. Noteworthy among these findings, levels of CC motif chemokine ligand 28 (CCL28) and CC motif chemokine ligand 25 (CCL25) are associated with the progression of attention-deficit/hyperactivity disorder (ADHD), interleukin-18 (IL-18) levels are linked to anorexia, IL-12β levels are related to schizophrenia (SZ) progression, IL-8 levels are associated with manic episodes, and IL-10 and monocyte chemoattractant protein-2 (MCP-2) levels are closely related to enduring personality changes(EPC). Additionally, fibroblast growth factor 19 (FGF19) levels are associated with cognitive disorders, while C-X-C motif chemokine ligand 1 (CXCL1) levels are related to executive functioning. ConclusionGut microbiotas and mental-behavioral disorders have causal relationships, with inflammatory factors mediating the pathway from gut microbiotas to these disorders.

Aromadendrin Ameliorates Airway Inflammation in Experimental Mice with Chronic Obstructive Pulmonary Disease.

Aromadendrin (ARO) is an active plant compound that exerts anti-inflammatory effects. However, its ameliorative effects on chronic obstructive pulmonary disease (COPD) remain unclear. Therefore, we investigated the inhibitory effects of ARO on bronchial inflammation using an experimental model of COPD. In vivo analysis confirmed a notable increase in the number of neutrophils/macrophages and the formation of reactive oxygen species (ROS), myeloperoxidase (MPO), interleukin (IL)-6/IL1β, and monocyte chemoattractant protein (MCP)-1 in the bronchoalveolar lavage (BAL) fluid of COPD mice, which was attenuated by oral gavage of ARO. In addition, hematoxylin and eosin staining showed a notable cell influx in the lungs of the COPD group, which was ameliorated by ARO. Western blotting revealed that ARO decreased the upregulation of neutrophil elastase expression in the lungs of the COPD group. Furthermore, periodic acid-Schiff staining showed that increased mucus formation in the lungs of the COPD group was downregulated by ARO. ARO also blocked CREB activation in the lungs of COPD mice. This in vivo, anti-inflammatory effect of ARO was accompanied by its modulatory effect on the activation of the MAPK/NF-κB/NLRP3 inflammasome. In summary, our study demonstrated that ARO has protective effects on bronchial inflammation by attenuating immune cell accumulation, toxic molecule/cytokine/chemokine formation, and MAPK/NF-κB/NLRP3 inflammasome activation, suggesting the potential development of ARO as an adjuvant for the prevention and treatment of COPD.

Carnosine Supplementation Has No Effect on Inflammatory Markers in Adults with Prediabetes and Type 2 Diabetes: A Randomised Controlled Trial.

In vitro studies suggest that carnosine reduces inflammation by upregulating anti-inflammatory mediators and downregulating pro-inflammatory cytokines. However, human clinical trials examining the effects of carnosine on inflammatory biomarkers are scant. We conducted a secondary analysis of a double-blind randomised controlled trial (RCT) to examine the effects of carnosine supplementation on inflammatory markers and adipokines in participants with prediabetes or well-controlled type 2 diabetes (T2D). Out of 88 participants who were recruited, 49 adults with prediabetes or well-controlled T2D (HbA1c: 6.6 ± 0.7% [mean ± SD]) who were treated with diet and/or metformin were eligible for inclusion. Participants were randomised to receive 2 g/day of carnosine or a matching placebo for 14 weeks. We measured serum concentrations of monocyte chemoattractant protein-1 (MCP-1), interleukin (IL)-6, IL-10, C-reactive protein (CRP), tumour necrosis factor-α (TNF-α), adiponectin, leptin, adipsin, serpin, and resistin levels at baseline and after 14 weeks. The trial was registered at clinicaltrials.gov (NCT02917928). Forty-one participants (M = 29/F = 12) aged 53 (42.6, 59.3) years [median (IQR)] completed the trial. After 14 weeks of supplementation, changes in pro- and anti-inflammatory cytokine and adipokine levels did not differ between the carnosine and placebo groups (p > 0.05 for all). The results remained unchanged after adjustment for confounders including age, sex, and anthropometric measures (e.g., body fat percentage and visceral adipose tissue). In individuals with prediabetes and well-controlled T2D, carnosine supplementation did not result in any significant changes in inflammatory markers. Larger RCTs with longer follow-up durations are needed to evaluate whether carnosine may be beneficial in individuals with poorly controlled T2D.

Transfection of 12/15-lipoxygenase effectively alleviates inflammatory responses during experimental acute pancreatitis

BACKGROUND Acute pancreatitis (AP), the initially triggered inflammatory process in the pancreas, can be life-threatening. It has been reported that 15-lipoxygenase may promote the removal of damaged intracellular components, maintain intracellular homeostasis, and promote apoptosis by upregulating the activity of caspases. Despite an increased understanding of the lipoxygenase pathway in inflammation and immune diseases, the role of the Alox15 gene product in modulating the inflammatory changes during AP is not well defined. AIM To investigate the effect of Alox15 expression in cerulein-induced AP in rats. METHODS Model rats were transfected with Alox15 by injecting a recombinant lentivirus vector encoding Alox15 into the left gastric artery before inducing AP. The expression of Alox15 was then assessed at the mRNA and protein levels. RESULTS Our in vivo results showed that serum amylase activity and pancreatic tissue water content were significantly reduced in Alox15 -transfected rats. Further, the mRNA expression levels of tumor necrosis factor alpha, interleukin (IL)-1β, IL-6, and monocyte chemoattractant protein-1, as well as the protein expression of nuclear factor kappa B in pancreatic tissue were reduced. Additionally, we observed an upregulation of cleaved caspase-3 that implies an induction of apoptosis in pancreatic cells. The transfection of Alox15 resulted in a lower number of autophagic vacuoles in AP. CONCLUSION Our findings demonstrate a regulatory role of Alox15 in apoptosis and autophagy, making it a potential therapeutic target for AP.

Effects of a Saccharomyces cerevisiae-Derived Postbiotic in Adult Labrador Retrievers Undergoing Exercise and Transport Stress

Postbiotics are emerging as potential functional ingredients for companion animal diets. This study aimed to determine if a Saccharomyces cerevisiae-based postbiotic can alter cytokine and stress responses to exercise and transport stress in adult Labrador Retrievers. Dogs received 15 g ground corn germ (Control, n = 12), 7.5 g postbiotic (Low, n = 12), or 15 g postbiotic (High, n = 12), daily for 63 days. Exercise was twice weekly for 7 weeks, and a single transport per dog occurred in week 8. Fecal inflammatory biomarkers, serum chemistries, and complete blood counts were assessed at the beginning and end of the study. Serum cytokines were quantified before and 18–20 h after the first and last exercise runs. Gait analysis was assessed before and 24 h after the first and final runs. Saliva cortisol was measured before and after transportation. Treatment did not affect blood chemistries, gait, fecal biomarkers, or saliva cortisol (p ≥ 0.19). Eosinophils increased slightly in Controls (p = 0.01), though remained below 0.80 × 109 cells/L. Most cytokines were unaffected by treatment (p ≥ 0.15), but there were minor changes in circulating monocyte chemoattractant protein-1 (p = 0.01) and IL-8 over time at the initial run (p = 0.03) and IL-10 in males (p = 0.02) in the Low dose dogs. The High dose decreased Blautia (p = 0.04) slightly and tended to decrease Fusobacterium abundances (p = 0.07). The Low dose tended to increase Clostridium hiranonis (p = 0.07) slightly. The tested S. cerevisiae postbiotic produced small changes in immune function and gut microbial species in dogs.

Gastroprotective potential of the aqueous extract of nine-steaming and nine-sun-drying processed Polygonatum cyrtonema Hua against alcoholic gastric injury in mice

Ethnopharmacological relevancePolygonatum (Huangjing) genus has been used as both food and medicine in China for 2000 years, which was regarded as a “Top-grade” herb in the Shennong Bencao Jing. The most commonly used species is the rhizome of Polygonatum cyrtonema Hua (PC) that is traditionally utilized to invigorate Qi, nourish Yin, moisten lung, and tonify spleen and kidney. Aim of the studyExcessive alcohol consumption causes severe upper-gastrointestinal diseases, notably gastric mucosal damage characterized by hemorrhagic gastritis, which lacks safe and effective intervention. This study aims to investigate the gastroprotective effects of nine-steaming and nine-drying processed Polygonatum cyrtonema Hua (PPC) on alcohol-induced gastric mucosal damage in mice. Materials and methodsPPC extract was chemically characterized by UPLC-QE-MS analysis. ICR mice were subjected to an ethanol-induced gastric lesion model and were orally administered PPC aqueous extract for 5 consecutive days. After treatment, gastric tissues were stained with hematoxylin and eosin (H&E), and the pro-inflammatory and oxidative stress factors were determined using ELISA and Multiplex assay, while the gene expressions of gastric tissues were detected by RNA-seq and Western blotting. ResultsPPC reduced the alcohol concentration of liquor in vitro and protected against alcohol-induced gastric mucosal lesion in mice. Notably, PPC aqueous extract relieved alcohol-induced pro-inflammatory and oxidative stress factors, including interleukin 6 (IL-6), IL-8, keratinocyte-derived chemokine (KC), monocyte chemotactic protein-1 (MCP-1), superoxide dismutase (SOD), glutathione (GSH), and malondialdehyde (MDA). RNA-sequencing analysis revealed that ethanol exposure activated mitogen-activated protein kinases (MAPKs), tumor necrosis factor (TNF), and IL-17 signaling pathways in gastric tissue, and these activated signaling pathways were inhibited by the PPC treatment. Consistently, Western blot data showed that PPC treatment suppressed the activation of extracellular signal-regulated kinases (ERK), p38, c-Jun N-terminal kinases (JNK), TNF-α and IL-17A pathways in gastric tissue. ConclusionIn conclusion, the aqueous extract of PPC exerted a gastroprotective effect against alcohol-induced gastric injury by alleviating inflammation and oxidative stress, potentially through the inhibition of the MAPKs, IL-17 and TNF-α pathways. These findings supported the future development of PPC as an effective intervention for alcohol-induced gastric damage.

Abstract 4137693: CC-Chemokine Receptor 2 Inhibition Prevents Monocyte/Macrophages Recruitment in Abdominal Aortic Aneurysms

Intro: Abdominal aortic aneurysm (AAA) is a prevalent condition in the elderly, with a significant risk of mortality if it ruptures. Despite this, there is currently no effective medical therapy to prevent AAA growth and rupture. The monocyte chemoattractant protein (MCP-1) / C-C chemokine receptor type 2 (CCR2) axis appears to play a role in AAA development. We demonstrated the potential of CCR2 as a theranostic marker for predicting AAA rupture, along with the effectiveness of a CCR2 inhibitor (RS-504393) in mitigating rupture. We further hypothesized that CCR2 inhibition can impact monocytes/macrophages trafficking in aortic tissue. Mehtods: Sprague-Dawley rats (N=54) underwent intraluminal aortic exposure to porcine pancreatic elastase (PPE) to induce aneurysmal degeneration. To stimulate AAA rupture, rats also recieved β-aminopropionitrile (BAPN). After 3 days of PPE exposure, a group of rats with AAA were administered a CCR2 inhibitor (CCR2i) either daily until the end of the study (CCR2i Full), or discontinued at day 5 (CCR2i Short), while the remaining rats proceeded without intervention (Fig1A). Ultrasound (12MHz) was performed at 7&14 days to assess diameter, while another cohort of animals were euthanized at 6 days, prior to rupture, for single-cell RNA sequencing analysis. The relative content of inflammatory cells within the aortic tissue was analyzed. Results: Both CCR2i Short and CCR2i Full treated, exhibited a significant reduction in AAA diameter at day 7 and 14 compared to controls (p<0.05; Fig1B&C). Notably, rats treated with CCR2i Full did not experience any AAA ruptures, while controls had a 56% risk of rupture. In contrast, CCR2i Short delayed the occurrence of ruptures without reducing the rupture rate (p<0.01; Fig1D). Single-cell RNA seq analysis of aortic tissue revealed that CCR2 inhibition led to a decrease in the number of recruited monocytes/macrophages. Cell recruitment was also relative to the duration of CCR2i treatment (Fig1E-G). Conclusions: Our study findings highlight the impact of CCR2-targeting in reducing AAA growth and the risk of rupture. Interestingly, length of CCR2i was a crucial variable for AAA rupture prevention. Furthermore, treatment length impacted the relative recruitment of monocytes/macrophages to AAA tissue, highlighting the role these cells in AAA disease pathology. Future analysis of CCR2+ inflammatory cell subgroups may help elucidate how CCR2 mechanistically modulates AAA progression and rupture risk.