Including Interleukin Research Articles

Modeling the response to interleukin-21 to inform natural killer cell immunotherapy.

Natural killer (NK) cells are emerging agents for cancer therapy. Several different cytokines are used to generate NK cells for adoptive immunotherapy including interleukin (IL)-2, IL-12, IL-15 and IL-18 in solution, and membrane-bound IL-21. These cytokines drive NK cell activation through the integration of signal transducers and activators of transcription (STAT) and nuclear factor-kappa B (NF-κB) pathways, which overlap and synergize, making it challenging to predict optimal cytokine combinations for both proliferation and cytotoxicity. We integrated functional assays for NK cells cultured in a variety of cytokine combinations with mathematical modeling using feature selection and mechanistic regression models. Our regression model successfully predicts NK cell proliferation for different cytokine combinations and indicates synergy of activated STATs and NF-κB transcription factors between priming and post-priming phases. The use of IL-21 in solution in the priming of NK cell culture resulted in an improved NK cell proliferation, without compromising cytotoxicity potential or interferon gamma secretion against hepatocellular carcinoma cell lines. Our work provides an integrative framework for interrogating NK cell proliferation and activation for cancer immunotherapy.

Interleukin-6 is significantly increased in severe pneumonia after allo-HSCT and might induce lung injury via IL-6/sIL-6R/JAK1/STAT3 pathway.

Severe pneumonia after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is associated with high mortality. Given that cytokine, including Interleukin-6 (IL-6), play a critical role in immune-mediated organ injury in patients with severe COVID-19, we hypothesized that cytokines may also contribute to the pathogenesis of severe pneumonia after allo-HSCT. This study aimed to investigate the role of IL-6 in severe pneumonia post-allo-HSCT and explore its underlying mechanism. Serum cytokine levels were prospectively measured in patients with severe and non-severe pneumonia following allo-HSCT. A mouse model of acute lung injury (ALI) and in vitro experiment using primary murine pulmonary microvascular endothelial cells (PMVECs) were conducted to assess the effects of IL-6 blockade, the mechanism of IL-6 in ALI, and immune-induced ALI. Serum IL-6 and sIL-6R levels were higher in the severe pneumonia group than in the non-severe group and were associated with disease progression. In a mouse model, preventive IL-6 blockade reduced ALI and improved survival. In vitro, the IL-6 trans-signaling complex caused more severe damage to mouse PMVECs than the classical signaling pathway. Soluble glycoprotein 130 and ruxolitinib effectively blocked the JAK1/STAT3 pathway activated by IL-6 trans-signaling in mouse PMVECs and reduced downstream inflammatory responses. IL-6 levels were elevated in patients with severe pneumonia after allo-HSCT and were linked to disease progression. This injury may be driven by the IL-6/sIL-6R/JAK1/STAT3 pathway. This preliminary study suggests that targeting the IL-6 trans-signaling pathway may be a promising therapeutic approach for severe pneumonia/ALI following allo-HSCT.

Metabolically activated and highly polyfunctional intratumoral VISTA+ regulatory B cells are associated with tumor recurrence in early-stage NSCLC

B cells have emerged as central players in the tumor microenvironment (TME) of non-small cell lung cancer (NSCLC). However, although there is clear evidence for their involvement in cancer immunity, scanty data exist on the characterization of B cell phenotypes, bioenergetic profiles and possible interactions with T cells in the context of NSCLC. In this study, using polychromatic flow cytometry, mass cytometry, and spatial transcriptomics we explored the intricate landscape of B cell phenotypes, bioenergetics, and their interaction with T cells in NSCLC. Our analysis revealed that TME contains diverse B cell clusters, including VISTA+ Bregs, with distinct metabolic and functional profiles. Target liquid chromatography-tandem mass spectrometry confirmed the expression of VISTA on B cells. VISTA+ Bregs displayed high metabolic demand and were able to produce different cytokines, including interleukin (IL)-10, transforming growth factor (TGF)-β, IL-6, tumor necrosis factor (TNF), and granulocyte–macrophage colony-stimulating factor (GM-CSF). Spatial analysis showed colocalization of B cells with CD4+/CD8+ T lymphocytes in TME. The computational analysis of intercellular communications that links ligands to target genes, performed by NicheNet, predicted B-T interactions via VISTA-PSGL-1 axis. Colocalization analyses revealed that PSGL-1 T cells and VISTA+ B cells are adjacent in the TME. Notably, tumor infiltrating CD8+ T cells expressing PSGL-1 exhibited enhanced metabolism and cytotoxicity. In NSCLC patients, prediction analysis performed by PENCIL revealed the presence of an association between PSGL-1+CD8+ T cells and VISTA+ Bregs with lung recurrence. Our findings suggest a potential interaction between Bregs and T cells through the VISTA-PSGL-1 axis, that could influence NSCLC recurrence.

Cortical thickness correlated with peripheral inflammatory cytokines in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a rare, devastating neurodegenerative disease that affects upper and lower motor neurons, resulting in muscle atrophy, spasticity, hyperreflexia, and paralysis. Inflammation plays an important role in the development of ALS, and associated with rapid disease progression. Current observational studies indicate the thinning of cortical thickness in patients with ALS is associated with rapid disease progression and cognitive changes. However, the effects of inflammatory cytokines on cortical thickness in patients with ALS are unclear. Here, we investigated the relationship between inflammatory cytokines and cortical thickness in patients with ALS. We evaluated 51 patients with ALS for inflammatory cytokines including interleukin (IL)-4, interferon (IFN)-α, IL-1β, IL-2, IL-5, IL-12, tumor necrosis factor (TNF)-α, IL-6, IL-10, IL-8, IL-17, and IFN-γ and analyzed the correlation between these indicators and the ALS functional rating scale-revised (ALSFRS-R) score or disease progression rate (ΔFS score). Twenty-six patients with ALS and 26 controls were studied using whole-cortex analysis, and post-hoc analyses were performed to examine the correlation between brain cortical thickness and ALSFRS-R or ΔFS scores. IL-4, IFN-α, IL-1β, and IL-2 levels were significantly correlated with ALSFRS-R scores, and the IL-2 level was significantly correlated with ΔFS scores. After controlling for age and sex, the ALS group had thinner cortexes in multiple clusters across the brain than the control group. Further analyses revealed that cortical thickness in the right superior temporal and lingual gyrus regions was inversely correlated with ΔFS scores. There was a significant positive correlation between the clusters in the right lingual cortex and IL-2 level. These results suggest cortical thickness was reduced in patients with ALS in motor and non-motor cortical areas. Inflammatory factors (especially IL-2) were correlated with cortical thickness, and both were related to the disease progression rate, suggesting IL-2 plays an important role in ALS.

The Role of IL-6 and TNF-Alpha Biomarkers in Predicting Disability Outcomes in Acute Ischemic Stroke Patients.

Inflammatory biomarkers, including Interleukin-6 (IL-6) and Tumor Necrosis Factor-alpha (TNF-alpha), play a significant role in influencing stroke outcomes, particularly in the progression of post-stroke disability. While numerous studies have suggested a correlation between elevated levels of these cytokines and poor functional recovery, further investigation is needed to understand their prognostic value in acute ischemic stroke. We conducted a prospective study on 56 patients diagnosed with acute ischemic stroke, evaluating IL-6 and TNF-alpha levels on days 1 and 7 post symptom onset. Stroke severity was assessed using the National Institutes of Health Stroke Scale (NIHSS) and functional outcomes were measured with the modified Rankin Scale (mRS). Statistical analyses were performed to evaluate the association between biomarker levels and stroke severity and recovery. Our study demonstrated that elevated levels of IL-6 and TNF-alpha on both days 1 and 7 were significantly correlated with greater stroke severity and poorer functional outcomes, as indicated by higher NIHSS and mRS scores. These findings are consistent with broader research indicating strong associations between inflammatory cytokines and post-stroke disability, further reinforcing their relevance as prognostic indicators. IL-6 and TNF-alpha are promising biomarkers for predicting stroke severity and functional recovery in acute ischemic stroke. Monitoring these cytokines in the early stages of stroke could aid in identifying patients at higher risk for long-term disability, potentially guiding personalized therapeutic strategies. Further research into anti-inflammatory therapies targeting these cytokines may improve stroke rehabilitation and outcomes.

Lysoglycerophospholipid metabolism alterations associated with ambient fine particulate matter exposure: Insights into the pro-atherosclerotic effects.

The biological pathways connecting ambient fine particulate matter (PM2.5)-induced initial adverse effects to the development of atherosclerotic cardiovascular diseases are not fully understood. We hypothesize that lysoglycerophospholipids (LysoGPLs) are pivotal mediators of atherosclerosis induced by exposure to PM2.5. This study investigated the changes of LysoGPLs in response to PM2.5 exposure and the mediation role of LysoGPLs in the pro-atherosclerotic effects of PM2.5 exposure. In this longitudinal panel study, 110 adults aged 50-65 years from Beijing, China, were followed between 2013 and 2015. Targeted metabolomics analyses were utilized to quantify 18 LysoGPLs from five subclasses in 579 plasma samples. Daily PM2.5 mass concentration was monitored at a station. We used linear mixed-effect models to estimate the responses of LysoGPLs to PM2.5 exposure. Subsequently, mediation analyses were conducted to investigate the mediating role of LysoGPLs in PM2.5-associated changes in non-high density lipoprotein-cholesterol (Non-HDL-C), a biomarker for pro-atherosclerotic apolipoprotein B-containing lipoproteins, and various inflammatory biomarkers, including interleukin (IL)-8, monocyte chemoattractant protein-1 (MCP-1), soluble CD40 ligand, and interferon (IFN)-γ. Short-to medium-term (1-30 days) PM2.5 exposure was associated with significant increases in six lysophosphatidic acids (LPAs), three lysoalkylphosphatidylcholines [LPC(O)s], and three lysophosphatidylglycerols (LPGs), as well as decreases in two LPAs and one lysophosphatidylserine (LysoPS), with maximus changes of 0.5-2.1%, 0.8-2.1%, 1.9-3.0%, -1.4-3.7%, and -8.0%, respectively. Furthermore, the elevated levels of LPA 18:1/18:2, LPC(O) 18:0/18:1, and LPG 16:0/16:1/18:0 significantly mediated the PM2.5-associated increase in Non-HDL-C (18-49%), IL-8 (9-24%), MCP-1 (12-26%), and IFN-γ (4-12%) over 30 days. In conclusion, short-to medium-term PM2.5 exposure was associated with altered metabolism of LysoGPLs, which mediated the PM2.5-associated pro-atherosclerotic response.

Total alkaloids in Fritillaria cirrhosa D. Don alleviate OVA-induced allergic asthma by inhibiting M2 macrophage polarization

Fritillaria cirrhosa D. Don (FCD) is a traditional Chinese medicine used to treat respiratory disorders, known for its effects in clearing heat, moistening the lungs, resolving phlegm, and relieving cough. Additionally, the total alkaloids extracted from FCD can alleviate asthma symptoms and reduce airway inflammation. However, no studies have investigated the effects of total alkaloids on lung macrophages. This study explored whether the total alkaloids of FCD (TAs-FCD) reduce M2 macrophage polarization and, consequently, attenuate airway remodeling in asthmatic mice. This study further elucidated its mechanism of action in treating allergic asthma. The extracted TAs-FCD was analyzed for its composition using UPLC-Q-TOF/MS. Network pharmacology was employed to identify the active ingredients and potential mechanisms of TAs-FCD in the treatment of allergic asthma. A mouse model of ovalbumin-induced allergic asthma was established, adopted, and validated through in vivo experiments. Hematoxylin-eosin staining (H&E), immunohistochemistry (IHC), immunofluorescence staining (IF), enzyme-linked immunosorbent assay (ELISA), Western blotting (WB), and real-time fluorescence quantitative polymerase chain reaction (q-PCR) were used to investigate the role of TAs-FCD in inhibiting M2 macrophage polarization in the context of allergic asthma. A total of 66 active ingredients were screened from 116 compounds using SWISSADME. The targets of these 66 compounds were predicted by SwissTargetPrediction, resulting in 808 unique drug targets after excluding duplicates. Additionally, 1756 targets related to allergic asthma were identified from the DisGeNET, Genecard, and OMIM databases. This led to 267 cross-targets between the active ingredient targets and allergic asthma targets, including interleukin (IL)-1β, tumor necrosis factor (TNF), and STAT3. Animal experiments demonstrated that TAs-FCD improved histopathological injury in mouse lungs, reduced peri-airway collagen fiber accumulation, airway mucus secretion, and airway smooth muscle proliferation. TAs-FCD also lowered IL-1β, TNF-α and IL-4 levels in lung tissues and alleviated airway inflammation. Furthermore, TAs-FCD significantly reduced levels of Arg1 and CD206, which are closely associated with M2 macrophages, and downregulated the expression of p-STAT3 and p-JAK2. TAs-FCD may inhibit M2 macrophage polarization by regulating the JAK2/STAT3 pathway, thereby alleviating airway remodeling and inflammation in allergic asthmatic mice.

Modified Jiaoqi Powder enhances epithelial autophagy against TNF-triggered apoptosis in chronic ulcerative colitis

BackgroundA vicious cycle of dysregulated intestinal epithelial cell death, intestinal barrier defect, and subsequent inflammation response is core to chronic ulcerative colitis (UC). Modified Jiaoqi Powder (MJQP), a traditional Chinese medicine formula, has been clinically applied to treat chronic relapsing type and chronic persistent type of UC . Nevertheless, the underlying mechanism of MJPQ in chronic UC remains unknown. PurposeThe present study aimed to demonstrate the favorable effect and potential molecular mechanism of MJQP in chronic UC. MethodsThe chemical components of MJQP and MJQP drug serum were identified by LC-MS/MS. The curative effect of MJQP was evaluated in a well-established DSS-induced chronic UC mice model by measuring body weight, colon length, disease activity index (DAI) and histological scores . Serum cytokines, including interleukin (IL)-1β, IL-12, IL-13, IL-4, tumor necrosis factor-alpha (TNF-α) and INF-γ were measured using enzyme-linked immunosorbent assay. Western blotting, immunofluorescence, and MTT assay were used to analyze the effects of MJQP on colonic barrier function in chronic UC mice and human epithelial cell lines. TUNEL assay, western blotting, and flow cytometry were used to examine the related apoptosis indicators. An electron microscope was used to observe autophagosomes and autolysosomes, while western blotting and immunofluorescence were used to detect autophagy-associated proteins. Network pharmacology was used to predict potential targets and pathways of MJQP in UC. Finally, the TNF pathway-related proteins were detected by immunohistochemistry and western blotting. ResultsMJQP administration prevented the UC progression with faster weight gain, longer colon length, lower histological scores and DAI, and up/down- regulation of inflammatory factors. The expressions of tight junction proteins ki67 and E-cadherin increased dose-dependently after MJQP intervention. Moreover, MJQP treatment promoted the viability of NCM460 and Caco2 cells in a concentration-dependent manner. MJQP dose-dependently decreased the proportion of TUNEL-positive cells and attenuated the pro-apoptotic proteins cleaved-caspase 8 and cleaved-caspase 3 in colonic tissues. Flow cytometry also showed that MJQP dose-dependently decreased the apoptotic cell population of LPS-induced NCM460 and Caco2 cells. Electron microscopy revealed that autophagosomes and autolysosomes were significantly improved in the MJQP-treated groups. Additionally, autophagy-related proteins were significantly expressed after MJQP treatment. Network pharmacological analysis predicted that MJQP may alleviate chronic UC by affecting TNF-related signaling pathways and promoting intestinal epithelial cell proliferation. As anticipated, the TNF pathway-associated proteins were attenuated dose-dependently in colonic tissues after MJQP treatment. ConclusionThese results provide novel therapeutic strategies, indicating that MJQP may be a promising candidate treatment for chronic UC by promoting epithelial barrier restitution by enhancing epithelial autophagy against TNF–mediated apoptosis.

Effect of immunoadsorption on clinical presentation and immune alterations in COVID-19-induced and/or aggravated ME/CFS.

Autoantibodies (AABs) are currently being investigated as causative or aggravating factors during post-COVID. In this study, we analyze the effect of immunoadsorption therapy on symptom improvement and the relationship with immunological parameters in post-COVID patients exhibiting symptoms of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) induced or aggravated by an SARS-CoV-2 infection. This observational study includes 12 post-COVID patients exhibiting a predominance of ME/CFS symptoms alongside increased concentrations of autonomic nervous system receptor (ANSR) autoantibodies and neurological impairments. We found that following immunoadsorption therapy, the ANSR AABs were nearly eliminated from the patients' blood. The removal of immunoglobulin G antibodies was accompanied by a decrease of pro-inflammatory cytokines including interleukin (IL)-4, IL-2, IL-1β, tumor necrosis factor, and IL-17A serum levels, and a significant reduction of soluble spike protein. Notably, a strong positive correlation between pro-inflammatorycytokines and ASNR-AABs β1, β2, M3, and M4 was observed in spike protein-positive patients, whereas no such correlation was evident in spike protein-negative patients. Thirty days post-immunoadsorption therapy, patients exhibited notable improvement in neuropsychological function and a modest but statistically significant amelioration ofhand grip strength was observed. However, neither self-reportedsymptoms nor scores on ME/CFS questionnaires showed a significant improvement and a rebound of the removed proteins occurring within a month.

Luteolin Exhibits Anxiolytic and Antidepressant Potential in Parkinson's Disease Rat: Antioxidant and Anti-Inflammatory Effects.

Parkinson's disease (PD) is accompanied by a complex array of nonmotor and motor manifestations. The exploration of anti-inflammatory and antioxidant active ingredient as potential therapeutic interventions in PD-associated mood alterations has gained significant attention. This study aimed to assess the antidepressant and anxiolytic properties of luteolin (LTN), a potent antioxidant and anti-inflammatory component, using a 6-hydroxydopamine (6-OHDA)-induced animal model of PD. Rats were administered LTN (10, 25, and 50 mg/kg, per oral) and fluoxetine (10 mg/kg/per oral) over a 28-day period. Behavioral tests were employed to estimate the depression- and anxiety-like behaviors. Rats treated with LTN exhibited significant improvement in 6-OHDA-induced mood alterations, as per behavioral tests. Additionally, LTN treatment led to increased hippocampal levels of catalase and superoxide dismutase, and a reduction in malondialdehyde. LTN downregulated the gene expression of nuclear factor kappa B (NF-κB)/nod-like receptor (NLR) pyrin domain-containing 3 (NLRP3) axis components, including NF-κB, NLRP3, ASC, and Caspase1 and reduced the protein level of pro-inflammatory cytokines, including interleukin (IL)-6, interleukin (IL)-1β, and tumor necrosis factor alpha (TNF-α), in addition to augmenting the protein levels of TNF-α, IL-1β, and IL-6. Furthermore, LTN exhibited an upregulatory effect on the anti-inflammatory cytokine IL-10 within the hippocampus of 6-OHDA-induced PD rats. Also, molecular docking showed higher affinity between LTN and NF-κB/NLRP3 axis components. These findings highlight the potential anxiolytic and antidepressant impacts of LTN through its antioxidant and anti-inflammatory mechanisms against 6-OHDA-induced alterations in a rat PD model.

Berberine Attenuates Cerulein-Induced Acute Pancreatitis by Modulating Nrf2/NOX2 Signaling Pathway via AMPK Activation.

AMP-activated protein kinase (AMPK) is the master regulator of cellular energy which gets activated during energy stress and restores tissue homeostasis. AMPK is widely expressed in the pancreas and is involved in protein synthesis. In cerulein-induced acute pancreatitis (AP), diminished AMPK activity in the pancreatic tissue may be associated with pancreatic inflammation and oxidative stress. Our results demonstrated that berberine (BR) treatment produced significant decrease in plasma amylase and lipase levels and improved histopathological features in AP mice model. Myeloperoxidase (MPO) activity indicated that BR suppressed the infiltration of neutrophils in pancreas. BR treatment markedly decreased the levels of proinflammatory cytokines including interleukins (IL)-6, IL-1β, and tumor necrosis factor-α (TNF-α) via inhibition of nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2) expression. In addition, BR activates the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling and inhibits cerulein-induced oxidative-nitrosative stress. Mechanistically, we found inhibition of AMPK activity in cerulein-induced AP, while BR-treated animals showed marked increase in the AMPK expression. Together, our study indicated that BR-mediated AMPK activation in pancreatic tissues demonstrated attenuation of cerulein-induced oxidative stress and inflammation. Based on our observations, further exploration of this promising natural product against AP and associated complications may lead to promising therapeutic options.

Relationship Between the Biomarkers of Collagen Regulation and Echocardiography Parameters in Patients With Heart Failure With Preserved Ejection Fraction.

To study the relationship between laboratory markers and echocardiography (EchoCG) parameters in heart failure with preserved ejection fraction (HFpEF) depending on the results of the diastolic stress test (DST). The diagnostic algorithm provided by the current guidelines for the assessment of left ventricular (LV) diastolic function was used to select patients. If there were not enough criteria to make a conclusion about increased LV filling pressure (FP) based on standard resting echocardiography data in patients with arterial hypertension and ischemic heart disease, DST was performed to detect HFpEF. 80 patients (50.0% men, mean age 66.3±5.4 years) were included. Group 1 consisted of 41 patients with a positive DST, and group 2 included 39 patients with a negative DST. Concentrations of the markers of immune inflammation, endothelial dysfunction, collagen homeostasis, and myocardial stress were measured. The DST showed significant differences in the E/e' ratio (15.1 [13.4; 15.9] in group 1 and 9.5 [7.9; 10.3] in group 2, respectively, p<0.001) and the diastolic functional reserve index (DFRI) (9.8 [6.8; 14.0] and 21.0 [13.0; 29.0], p < 0.001). Resting EchoCG revealed significant differences in the left atrial reservoir strain (LASr) (22.8 [19.6; 25.6]% and 28.0 [24.8; 30.2]%, p<0.001) and the left atrial stiffness index (LASI) (0.50 [0.40; 0.57] and 0.34 [0.27; 0.41], p<0.001). In patients with HFpEF, the laboratory parameters of collagen regulation had the greatest number of relationships. Correlations were found between the concentrations of matrix metalloproteinase-9 and other biomarkers, including interleukin-10 (IL-10) (r=0.311; p=0.048), myeloperoxidase (r=0.382; p=0.014), N-terminal propeptide of procollagen type I (procollagen I N-terminal propeptide, PINP) (r=0.722; p<0.001) and type III (r=0.591; p<0.001), C-terminal propeptide of procollagen type I (r=0.330; p=0.035), tissue inhibitor of metalloproteinases type 1 (r=0.410; p=0.008), EchoCG parameters, including left atrial volume index (LAVI) (r=0.414; p=0.007) and DFRI (r=0.354; p=0.025). In addition, correlations were found for the concentrations of PINP with IL-10 (r=0.401; p=0.009) and endothelin-1 (r= -0.337; p=0.031); PINP with LAVI (r=0.498; p=0.001) and DFRI (r=0.420; p=0.007). Patients with HFpEF have a greater number of relationships between markers of collagen homeostasis disorders and EchoCG parameters characterizing an increase in LV FP.

Gentiopicroside Alleviates Atherosclerosis by Suppressing Reactive Oxygen Species-Dependent NLRP3 Inflammasome Activation in Vascular Endothelial Cells via SIRT1/Nrf2 Pathway.

To evaluate the protective effects of gentiopicroside (GPS) against reactive oxygen species (ROS)-induced NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome activation in endothelial cells, aiming to reduce atherosclerosis. Eight-week-old male ApoE-deficient mice were randomly divided into 2 groups (n=10 per group): the vehicle group and the GPS treatment group. Both groups were fed a high-fat diet for 16 weeks. GPS (40 mg/kg per day) was administered by oral gavage to the GPS group, while the vehicle group received an equivalent volume of the vehicle solution. At the end of the treatment, blood and aortic tissues were collected for assessments of atherosclerosis, lipid profiles, oxidative stress, and molecular expressions related to NLRP3 inflammasome activation, ROS production, and apoptosis. Additionally, in vitro experiments on human aortic endothelial cells treated with oxidized low-density lipoprotein (ox-LDL) were conducted to evaluate the effects of GPS on NLRP3 inflammasome activation, pyroptosis, apoptosis, and ROS production, specifically examining the role of the sirtuin 1 (SIRT1)/nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. SIRT1 and Nrf2 inhibitors were used to confirm the pathway's role. GPS treatment significantly reduced atherosclerotic lesions in the en face aorta (P<0.01), as well as in the thoracic and abdominal aortic regions, and markedly decreased sinus lesions within the aortic root (P<0.05 or P<0.01). Additionally, GPS reduced oxidative stress markers and proinflammatory cytokines, including interleukin (IL)-1 β and IL-18, in lesion areas (P<0.05, P<0.01). In vitro, GPS inhibited ox-LDL-induced NLRP3 activation, as evidenced by reduced NLRP3 (P<0.01), apoptosis-associated speck-like protein containing a CARD, cleaved-caspase-1, and cleaved-gasdermin D expressions (all P<0.01). GPS also decreased ROS production, apoptosis, and pyroptosis, with the beneficial effects being significantly reversed by SIRT1 or Nrf2 inhibitors. GPS exerts an antiatherogenic effect by inhibiting ROS-dependent NLRP3 inflammasome activation via the SIRT1/Nrf2 pathway.

1,2-Dihydroxy-9H-Xanthen-9-One, a Multifunctional Nature-Inspired Active Ingredient

Incorporating antioxidants into cosmetics is the mainstay for developing new products to mitigate skin aging. However, identifying novel multifunctional antioxidant ingredients with additional relevant properties that block the skin hallmarks of aging is a very striking strategy. Many natural compounds, including xanthones, have demonstrated biologically notable properties. In particular, 1,2-dihydroxy-9H-xanthen-9-one (1,2-DHX) has inhibitory activity against skin enzymes, and metal-chelating and radical-scavenging activities. Therefore, 1,2-DHX is an attractive molecule for cosmetic purposes. With this goal in mind, the anti-inflammatory, antioxidant, and anti-allergic potentials of 1,2-DHX were investigated. 1,2-DHX demonstrated anti-inflammatory properties by inhibiting the synthesis of specific pro-inflammatory mediators, including interleukin-6 (IL-6) and prostaglandin E2 (PGE2), in human macrophages. This xanthone did not elicit sensitization reactions and did inhibit allergic reactions triggered by a strong skin allergen, suggesting its potential as an anti-allergic compound. 1,2-DHX also revealed mitochondrial antioxidant activity by mitigating rotenone-induced oxidative stress in macrophages by up to 40%. Overall, 1,2-DHX displayed a safety profile and noteworthy biological activities, highlighting its multifunctional profile as an active cosmetic ingredient with anti-inflammatory, antioxidant, and anti-allergic properties.

Acute effect of exercise on appetite-related factors in males with obesity: A pilot study.

To investigate the role of appetite-related factors, including interleukin 6 (IL-6), irisin, interleukin 7 (IL-7), neuropeptide Y (NPY), and leptin, on appetite perception in males with obesity. Eleven males (BMI 35.3 ± 4.2 kg/m2, V̇O2peak 29 ± 3.1 mL/kg/min) participated in two experimental trials (MICE: 60 min of cycling at 60% of V̇O2peak; CTRL: 60 min of quiet resting) using a crossover design. Appetite parameters, including IL-6, IL-7, irisin, and leptin, were measured. Additionally, appetite perception was assessed. IL-6 concentration increased significantly immediately post-exercise (95% CI: [2.207-12.192] pg/mL, p = 0.007) and remained elevated 1 hour post-exercise (95% CI: [2.326-11.855] pg/mL, p = 0.006) compared to CTRL. Irisin also rose significantly immediately post-exercise (95% CI: [0.084-3.061] ng/mL, p = 0.039). NPY decreased significantly 1 h post-exercise (95% CI: [(-20.601) - (-1.380)] ng/L, p = 0.027). No significant differences were observed for IL-7 (p = 0.748, = 0.077) and leptin (p = 0.285, ). Appetite perceptions were suppressed immediately post-exercise (95% CI: [3.407-19.547] mm, p = 0.008) compared to CTRL. Sixty minutes of MICE increased IL-6 and irisin concentrations while suppressed NPY and appetite perceptions in males with obesity.

Vitamin D and Molecules Related to Vitamin D Metabolism in Children with Sepsis.

This study aimed to evaluate the association between vitamin D and molecules related to vitamin D metabolism in children with sepsis. A total of 98hospitalized children with sepsis were included in this study. Blood samples were collected within the first 4h of admission. Blood vitamin D; molecules related to vitamin D metabolism including vitamin-D-binding protein (VDBP), 7-dehydrocholesterol reductase (DHCR7), 25-hydroxylase (CYP2R1), 24-hydroxylase (CYP24A1), and cathelicidin (CATH); and other inflammatory markers including interleukin-6 (IL-6), procalcitonin (PCT), C-reactive protein (CRP), and white blood cell count (WBC) were measured. Of the enrolled children, 23.47% (23/98) were confirmed to have severe sepsis, and 10.20% (10/98) died. The prevalence of hypovitaminosis D was 46.94% (46/98) in the children with sepsis. Children with hypovitaminosis D had lower levels of CYP2R1 and CATH and higher levels of CYP24A1, PCT, and IL-6 compared to children with vitamin D sufficiency. Blood vitamin D level was positively correlated with blood VDBP, CYP2R1, and CATH and negatively correlated with CYP24A1, PCT, and IL-6. Blood vitamin D was not independently associated with severe sepsis and mortality, but it was independently associated with the requirement of intensive care unit (ICU) stay. Molecules related to vitamin D metabolism such as VDBP, CYP2R1, and CYP24A1 are involved in regulating the levels of circulating vitamin D. Children with sepsis had a high prevalence of hypovitaminosis D. Hypovitaminosis D was independently associated with the requirement of ICU stay in children with sepsis.

Long-term impact of adherence to muscle-strengthening guidelines on inflammation markers: a 17-year follow-up study with obesity parameters as mediators

ObjectiveTo evaluate the relationship between adherence to muscle-strengthening guidelines in young adulthood and inflammation markers over a 17-year follow-up period. Additionally, it aims to examine whether body mass index (BMI)...

Bicalutamide Reveals Immunomodulatory Effects in Prostate Cancer by Regulating Immunogenic Dendritic Cell Maturation

Prostate cancer poses a significant global health challenge, ranking as the second most prevalent and fifth most lethal malignancy among males. The intricate interplay between androgen signaling and the immune microenvironment underscores the complexity of prostate cancer progression. Notably, androgen receptor (AR) signaling has been shown to affect immune response mediated by tumor antigen-presenting dendritic cells (DCs). Therefore, this study aimed to explore the potential of Bicalutamide, a nonsteroidal anti-androgen, in modulating DCs-mediated immune responses. Peripheral blood mononuclear cells (PBMCs) were isolated, and monocytes were extracted, followed by their differentiation into immature dendritic cells (iDCs) using GM-CSF and IL-4. Harvested tumor cell lysates from human prostate cancer cells were then utilized to induce the transformation of iDCs into mature dendritic cells (mDCs). Then, mDCs were treated with non-toxic concentration of Bicalutamide determined by annexin V/PI assay. The morphological characteristics of mDCs were investigated using an inverted light microscope. Flow cytometry was used to determine the cell surface expression of molecular markers of DC maturation, and qRT-PCR was employed to evaluate expression levels of proinflammatory genes involved in DC maturation. The obtained results indicated that Bicalutamide treatment of monocyte-derived mDCs induces an immunogenic and matured phenotype, marked by increased expression of CD86 and HLA-DR. Besides, qRT-PCR results evidenced that Bicalutamide decreased the expression of anti-inflammatory genes, including Interleukin-10 (IL-10) and TGF-beta, as an indication of immunogenic DCs. These findings suggest that beyond its established anti-androgen role, Bicalutamide may exert anti-tumor effects through the modulation of DCs-mediated immune responses. This novel immunomodulatory feature holds promise for the development of novel therapies, including combination therapies, in prostate cancer treatment.

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

Shedding light on microglial dysregulation in Alzheimer's disease: exploring molecular mechanisms and therapeutic avenues.

Alzheimer's disease (AD) stands out as the foremost prevalent neurodegenerative disorder, characterized by a complex etiology. Various mechanisms have been proposed to elucidate its onset, encompassing amyloid-beta (Aβ) toxicity, tau hyperphosphorylation, oxidative stress and reactive gliosis. The hallmark of AD comprises Aβ and tau aggregation. These misfolded protein aggregates trigger the activation of glial cells, primarily microglia. Microglial cells serve as a major source of inflammatory mediators and their cytotoxic activation has been implicated in various aspects of AD pathology. Activated microglia can adopt M1 or M2 phenotypes, where M1 promotes inflammation by increasing pro-inflammatory cytokines and M2 suppresses inflammation by boosting anti-inflammatory factors. Overexpressed pro-inflammatory cytokines include interleukin (IL)-1β, IL-6 and tumor necrosis factor-α (TNF-α) in adjacent brain regions.Furthermore, microglial signaling pathways dysregulated in AD are myeloid differentiation primary-response protein 88 (Myd 88),colony-stimulating factor-1receptor (CSF1R) anddedicator of cytokinesis 2 (DOCK2), which alter the physiology. Despite numerous findings, the causative role of microglia-mediated neuroinflammation in AD remains elusive. This review concisely explores cellular and molecular mechanisms of activated microglia and their correlation with AD pathogenesis. Additionally, it highlights promising therapeutics targeting microglia modulation, currently undergoing preclinical and clinical studies, for developing effective treatment for AD.