Interleukin IL-6 Research Articles

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.

Comparative proteome analysis identifies species-specific signature proteins in Aspergillus pathogens.

Aspergillus flavus and Aspergillus fumigatus are important human pathogens that can infect the lung and cornea. During infection, Aspergillus dormant conidia are the primary morphotype that comes in contact with the host. As the conidial surface-associated proteins (CSPs) and the extracellular proteins during the early stages of growth play a crucial role in establishing infection, we profiled and compared these proteins between a clinical strain of A. flavus and a clinical strain of A. fumigatus. We identified nearly 100 CSPs in both Aspergillus, and these non-covalently associated surface proteins were able to stimulate the neutrophils to secrete interleukin IL-8. Mass spectrometry analysis identified more than 200 proteins in the extracellular space during the early stages of conidial growth and germination (early exoproteome). The conidial surface proteins and the early exoproteome of A. fumigatus were enriched with immunoreactive proteins and those with pathogenicity-related functions while that of the A. flavus were primarily enzymes involved in cell wall reorganization and binding. Comparative proteome analysis of the CSPs and the early exoproteome between A. flavus and A. fumigatus enabled the identification of a common core proteome and potential species-specific signature proteins. Transcript analysis of selected proteins indicate that the transcript-protein level correlation does not exist for all proteins and might depend on factors such as membrane-anchor signals and protein half-life. The probable signature proteins of A. flavus and A. fumigatus identified in this study can serve as potential candidates for developing species-specific diagnostic tests. KEY POINTS: • CSPs and exoproteins could differentiate A. flavus and A. fumigatus. • A. fumigatus conidial surface harbored more antigenic proteins than A. flavus. • Identified species-specific signature proteins of A. flavus and A. fumigatus.

34 Successive Bouts of Exercise Influences the Inflammatory Cytokine Response in Thoroughbred Horses Regardless of Recovery Aid Supplementation

Abstract In equine sports, the rate of recovery after an exhaustive exercise session greatly affects the ability of the animal to perform subsequently, especially if the next exercise session occurs quickly. Carnitine participates in fatty acid delivery to the mitochondria and may facilitate muscle recovery post-exercise. The objective of the study was to determine the effects of a commercially available carnitine supplement (Renew, Platinum Performance, Buellton, CA) on adult The ability of Thoroughbred horses (16 geldings, 2 mares, 6.69 ± 0.49 years, 524.81 ± 10.07 kg, 5.66 ± 0.12 BCS) to perform successive bouts of exhaustive exercise. All horses participated in a moderate workload conditioning program for 6-weeks before testing. Horses received a ration of applesauce (30 mL, CON, n = 8) or ration of applesauce containing 19.6 g of the product (30 mL, AID, n = 8) 1 h before performing an incremental standardized exercise test (iSET) to exhaustion (day 1). Heart rate (HR) and gait biomechanics were recorded throughout the duration of the iSET. Blood was collected at 0, 10 min, 1, 4 and 6 h relative to exercise for the measurement of lactate and interleukin (IL) 1b, 8 and 10 mRNA content. for the measurement of lactate and interleukin (IL) 1b, IL8 and IL10 mRNA content. The AID was administered again at 1 h post-iSET after collection of the blood sample. All horses were rested for 24 h before repeating the iSET (day 3) with performance data and sample collection. The AID did not affect time to maximum HR, time to reach V200 or total gallop time during the iSET on day 1 or day 3. The rate of HR decline post iSET was slower (P < 0.05) for all horses on day 3 compared with day 1. Blood lactate concentration was not affected by AID or day. The right front limb posterior fetlock angle at full stance phase increased (P < 0.05) with speed for both CON and AID supplemented horses on day 1. Horses receiving AID demonstrated an increase (P < 0.05) in this measure at day 3 while no significant differences (P > 0.05) in posterior angle were detected in CON. Administration of AID did not affect whole blood IL1b, IL8 or IL10 mRNA content on day 1 or day 3. Consolidation of the data demonstrates increased (P < 0.05) expression of IL1b and IL8 mRNA during post-exercise recovery time on day 1 that was absent on day 3. Expression of IL10 was altered (P < 0.05) over time post-exercise on both days. Results of the experiment demonstrate that successive bouts of exercise affect the inflammatory response to exhaustion. Although AID did not affect IL gene expression, it did promote retention of flexion at the fetlock joint suggesting that carnitine products may facilitate recovery from strenuous exercise.

Beyond the Mat: Exploring the Potential Clinical Benefits of Yoga on Epigenetics and Gene Expression: A Narrative Review of the Current Scientific Evidence.

Yoga, an ancient practice rooted in Indian philosophy, has gained widespread popularity for its numerous physical and mental health benefits. In the recent years, there has been growing interest in understanding how yoga influences gene expression and epigenetic modifications. This narrative review investigates the molecular mechanisms, by which yoga influences gene expression, focusing on deoxyribonucleic acid (DNA) methylation, and histone modifications. Research literature was sourced from various databases to select randomized clinical trials and comparative cohort studies examining yoga's impact on gene expression and epigenetic changes. Our findings suggest that yoga could exert anti-inflammatory effects, as it downregulates pro-inflammatory cytokines, soluble interleukin IL-2 receptor gene expression, and transcription factors. Yoga also boosts the innate antiviral response and brain health by enhancing natural defense genes and microRNA-29c expression. Notably, it activates telomerase, linked with cellular longevity, and promotes nitric oxide synthetase and neuroprotective gene expression, implying benefits for ocular health. In addition, yoga fosters DNA repair and cellular integrity maintenance by increasing oxoguanine glycosylase one protein and p53 gene expression. However, the diversity of yoga interventions in these studies complicates direct comparisons and broader application. The current research primarily focuses on short-term outcomes, offering a limited understanding of yoga's long-term epigenetic impacts. Future research should address these gaps by studying the enduring effects of Yoga, personalizing interventions, and contrasting techniques.

Dextran Sulfate Sodium Salt (DSS) induced enteritis in Orange-spotted grouper, Epinephelus coioides

The enteritis is a common disease in fish farming, but the pathogenesis is still not fully understood. The aim of the present study was to investigate the inducement of Dextran Sulfate Sodium Salt (DSS) intestinal inflammation on Orange-spotted grouper (Epinephelus coioides). The fish were challenged with 200 μl 3% DSS via oral irrigation and feeding, an appropriate dose based on the disease activity index of inflammation. The results indicated that the inflammatory responses induced by DSS were closely associated with the expression of pro-inflammatory cytokines including interleukin 1β (IL-1β), IL-8, IL16, IL-10 and tumor necrosis factor α (TNF-α), as well as NF-κB and myeloperoxidase (MPO) activity. At day5 after DSS treatment, the highest levels of all parameters were observed. Also, the severe intestinal lesions (intestinal villus fusion and shedding), strong inflammatory cell infiltration and microvillus effacement were seen through histological examination and SEM (scanning electronic microscopy) analysis. During the subsequent 18 days of the experimental period, the injured intestinal villi were gradually recovery. These data is beneficial to further investigate the pathogenesis of enteritis in farmed fish, which is helpful for the control of enteritis in aquaculture.

Inflammatory, Oxidative Stress and Small Cellular Particle Response in HUVEC Induced by Debris from Endoprosthesis Processing.

We studied inflammatory and oxidative stress-related parameters and cytotoxic response of human umbilical vein endothelial cells (HUVEC) to a 24 h treatment with milled particles simulating debris involved in sandblasting of orthopedic implants (OI). We used different abrasives (corundum-(Al2O3), used corundum retrieved from removed OI (u. Al2O3), and zirconia/silica composite (ZrO2/SiO2)). Morphological changes were observed by scanning electron microscopy (SEM). Concentration of Interleukins IL-6 and IL-1β and Tumor Necrosis Factor α (TNF)-α was assessed by enzyme-linked immunosorbent assay (ELISA). Activity of Cholinesterase (ChE) and Glutathione S-transferase (GST) was measured by spectrophotometry. Reactive oxygen species (ROS), lipid droplets (LD) and apoptosis were measured by flow cytometry (FCM). Detachment of the cells from glass and budding of the cell membrane did not differ in the treated and untreated control cells. Increased concentration of IL-1β and of IL-6 was found after treatment with all tested particle types, indicating inflammatory response of the treated cells. Increased ChE activity was found after treatment with u. Al2O3 and ZrO2/SiO2. Increased GST activity was found after treatment with ZrO2/SiO2. Increased LD quantity but not ROS quantity was found after treatment with u. Al2O3. No cytotoxicity was detected after treatment with u. Al2O3. The tested materials in concentrations added to in vitro cell lines were found non-toxic but bioactive and therefore prone to induce a response of the human body to OI.

Anti-inflammatory effect of combining fish oil and evening primrose oil supplementation on breast cancer patients undergoing chemotherapy: a randomized placebo-controlled trial

Breast cancer is the most common malignant tumor and one of the leading causes of cancer-related death in women throughout the world. This study is a parallel, randomized, double-blind, controlled, 12-week supplementation trial, investigating the anti-inflammatory effects of dietary intake of fish oil and evening primrose oil (EPO), in patients with breast cancer undergoing chemotherapy. The primary outcomes were changes in the nutritional status and inflammatory cytokines of patients during the study. The secondary outcomes were changes in hematological and biochemical parameters and fatty acid profile. Of the 32 eligible patients, half of them is randomly assigned to a treatment arm with fish oil and EPO (n = 16), or a control arm (n = 16) with mineral oil as a placebo. The intervention group was taking 2 gel capsules of fish oil and 3 gel capsules of EPO (400 mg eicosapentaenoic acid, 600 mg docosahexaenoic acid, and 351 mg gamma-linolenic acid) fish oil and evening primrose oil for 12 weeks, during their chemotherapy. The control/placebo group was taking 5 gel capsules of 1g of mineral oil. One of the patients dropped out due to discontinuation of the treatment (in the placebo group) and two did not show up at the post-treatment measurements (in the intervention group), thus, 29 women completed the study. The results showed an increase in plasma levels of docosapentaenoic acid (22:5n-3), docosahexaenoic acid (22:6n-3), total n-3PUFA, vaccenic acid (18:1n-7), and a decrease in n-6/n-3 PUFA ratio in the intervention group. An increase in the plasma level of dihomo-gamma-linolenic acid (20:3n-6) was observed in the placebo group. There was no difference in plasma levels of interleukin (IL) IL-8, IL-10, and tumor necrosis factor-alpha, while the level of IL-6 decreased in both groups and was significantly lower in the intervention group at the end of the study. In conclusion, this supplementation improved the PUFA status and decreased the level of IL-6 in breast cancer patients undergoing chemotherapy. Consequently, this treatment may help reduce cancer complications resulting from impaired lipid metabolism and inflammation. ClinicalTrials.gov Identifier: NCT03516253. Date of registration 04/05/2018.

Expression of Th1/2/17 Cytokines in CML with or without Pulmonary Bacterial and Fungal Coinfection.

Tyrosine kinase inhibitors (TKIs) are the standard therapy for patients with chronic myeloid leukemia (CML). While their use greatly increases patient survival rates and can lead to normal life expectancy, bacterial infections in the lungs continue to play a significant role in determining patient outcomes. In this study, the medical records of 272 CML and 53 healthy adults were analyzed. Information on age, sex, body temperature, procalcitonin (PCT), C-reactive protein (CRP), and cytokine levels were collected from patients. Since the data belonged to a nonstate distribution, we used the Mann-Whitney U test to examine differences between groups. Cut-off values were analyzed by receiver operating characteristic (ROC) curves. No significant differences in the Th1/2/17 levels were observed in relation to TKI treatment. Further analysis showed that the levels of the interleukins IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-22, IL-12p70, IL-17A, IL-17F, and IL-1β, interferon (IFN-γ), and tumor necrosis factors (TNF α and β) were higher in patients with pulmonary bacterial infections compared with uninfected patients. IL-6, IL-8, and IL-10 levels in CML patients with bacterial and fungal coinfection were higher than those in patients without infection. The areas under the ROC curves (AUCs) were found to be 0.73 for IL-5, 0.84 for IL-6, 0.82 for IL-8, 0,71 for IL-10, and 0.84 for TNF-α. AUC values were higher for patients with pulmonary bacterial infection, especially IL-6 (AUC = 0.84, cut-off = 13.78 pg/ml) and IL-8 (AUC = 0.82, cut-off = 14.35 pg/ml), which were significantly better than those for CRP (AUC = 0.80, cut-off = 6.18 mg/l), PCT (AUC = 0.71, cut-off = 0.25 ng/ml), and body temperature (AUC = 0.68, cut-off = 36.8°C). In addition, according to the cut-off values, we found that 83.33% of patients with pulmonary bacterial infections had IL-6 ≥ 13.78 pg/ml, while when IL-6, IL-8, and IL-10 levels simultaneously exceeded the cut-off values, the probability of pulmonary bacterial infection was 93.55%. TKI treatment did not appear to affect cytokine expression in CML patients. However, CML patients with pulmonary bacterial infection had significantly higher levels of Th1/2/17 cytokines. In particular, abnormally elevated IL-6, IL-8, and IL-10 levels were associated with a pulmonary bacterial infection in patients with CML.

RAGE-TLR4 Crosstalk Is the Key Mechanism by Which High Glucose Enhances the Lipopolysaccharide-Induced Inflammatory Response in Primary Bovine Alveolar Macrophages.

The receptor of advanced glycation end products (RAGE) and Toll-like receptor 4 (TLR4) are important receptors for inflammatory responses induced by high glucose (HG) and lipopolysaccharide (LPS) and show crosstalk phenomena in inflammatory responses. However, it is unknown whether RAGE and TLR4 can influence each other's expression through a crosstalk mechanism and whether the RAGE-TLR4 crosstalk related to the molecular mechanism of HG enhances the LPS-induced inflammatory response. In this study, the implications of LPS with multiple concentrations (0, 1, 5, and 10 μg/mL) at various treatment times (0, 3, 6, 12, and 24 h) in primary bovine alveolar macrophages (BAMs) were explored. The results showed that a 5 μg/mL LPS treatment at 12 h had the most significant increment on the pro-inflammatory cytokine interleukin 1β (IL-1β), IL-6, and tumor necrosis factor (TNF)-α levels in BAMs (p < 0.05) and that the levels of TLR4, RAGE, MyD88, and NF-κB p65 mRNA and protein expression were upregulated (p < 0.05). Then, the effect of LPS (5 μg/mL) and HG (25.5 mM) co-treatment in BAMs was explored. The results further showed that HG significantly enhanced the release of IL-1β, IL-6, and TNF-α caused by LPS in the supernatant (p < 0.01) and significantly increased the levels of RAGE, TLR4, MyD88, and NF-κB p65 mRNA and protein expression (p < 0.01). Pretreatment with FPS-ZM1 and TAK-242, the inhibitors of RAGE and TLR4, significantly alleviated the HG + LPS-induced increment of RAGE, TLR4, MyD88, and NF-κB p65 mRNA and protein expression in the presence of HG and LPS (p < 0.01). This study showed that RAGE and TLR4 affect each other's expression through crosstalk during the combined usage of HG and LPS and synergistically activate the MyD88/NF-κB signaling pathway to promote the release of pro-inflammatory cytokines in BAMs.

Melanoma Clinical Decision Support System: An Artificial Intelligence-Based Tool to Diagnose and Predict Disease Outcome in Early-Stage Melanoma Patients.

This study set out to assess the performance of an artificial intelligence (AI) algorithm based on clinical data and dermatoscopic imaging for the early diagnosis of melanoma, and its capacity to define the metastatic progression of melanoma through serological and histopathological biomarkers, enabling dermatologists to make more informed decisions about patient management. Integrated analysis of demographic data, images of the skin lesions, and serum and histopathological markers were analyzed in a group of 196 patients with melanoma. The interleukins (ILs) IL-4, IL-6, IL-10, and IL-17A as well as IFNγ (interferon), GM-CSF (granulocyte and macrophage colony-stimulating factor), TGFβ (transforming growth factor), and the protein DCD (dermcidin) were quantified in the serum of melanoma patients at the time of diagnosis, and the expression of the RKIP, PIRIN, BCL2, BCL3, MITF, and ANXA5 proteins was detected by immunohistochemistry (IHC) in melanoma biopsies. An AI algorithm was used to improve the early diagnosis of melanoma and to predict the risk of metastasis and of disease-free survival. Two models were obtained to predict metastasis (including "all patients" or only patients "at early stages of melanoma"), and a series of attributes were seen to predict the progression of metastasis: Breslow thickness, infiltrating BCL-2 expressing lymphocytes, and IL-4 and IL-6 serum levels. Importantly, a decrease in serum GM-CSF seems to be a marker of poor prognosis in patients with early-stage melanomas.

The role of macrophages, myeloperoxidase, interleukins IL-12, IL-13 in the formation of bronchial response to hyperosmolar stimulus in patients with bronchial asthma

Introduction. The involvement of macrophages in the realization of oxidative / halogenating stress andthe role of macrophage populations in maintaining the balance of Th1/Th2 cytokines in patients with asthma with osmotic types of bronchial hyperresponsiveness has not been sufficiently studied.Aim. To study the role of macrophages, myeloperoxidase (MPO), IL-12, IL-13 in the formation of the bronchial response to the hyperosmolar trigger in patients with asthma.Materials and methods. The object of the study was asthma patients (n=35). The level of asthma control (Asthma Control Test, points), cellular composition (%) and MPO (pixel) of induced sputum (IS), bronchial response (ΔFEV1IHS, %) after 3-minute ultrasonic inhalation of hypertonic (4.5% NaCl) solution (IHS) were assessed. Before and after the IHS test, exhaled air condensate was collected, in which the concentration of IL-12, IL-12 (pg/mL) was determined.Results. Patients with asthma did not control the disease, ACT was 14 (11; 16.5) points. Group 1 (n=15) included individuals with bronchial hyperresponsiveness to the IHS, group 2 (n=20) included patients with lack of it (ΔFEV1IHS -19.8±1.9 and 1.43±0.72%, respectively, p&lt;0.001). Baseline FEV1 in groups 1 and 2 was 89.5±2.8 and 93.7±2.3%, respectively (p&gt;0.05). The percentage of sputum macrophages in group 1 was lower (40 [15.95; 50.75]%), and the average cytochemical coefficient in phagocytes was higher (141.4±9.7) than in group 2 (50 [42.5; 63.6]; p=0.039 and 98.8±12.3; p=0.013, respectively). IL-12 expression was to be more significant than IL-13 expression in the initiation of airway inflammation and hyperresponsiveness to hyperosmolar stimulus.Conclusion. The lower concentration of macrophages in the bronchi of asthma patients with airway hyperresponsiveness to hyperosmolar stimulus is most likely due to an increase in the secretory function of cells. A high level of MPO activity in these patients depended on the peroxidase function of secreting macrophages, was associated with M1 polarization of macrophages, and indicated a Th1 immune response associated with the participation of IL-12 in the regulation of airway hyperresponsiveness to a hypertonic trigger.

A Real-Life Study on the Use of Tildrakizumab in Psoriatic Patients.

Tildrakizumab is a humanized IgG1κ monoclonal antibody that selectively targets the p19 subunit of interleukin IL-23, thereby inhibiting the IL-23/IL-17 axis, which is primarily implicated in the immunopathogenesis of psoriasis. Tildrakizumab is approved for the treatment of moderate-to-severe plaque-type psoriasis in adults based on the evidence of two randomized and controlled phase-III clinical trials (reSURFACE 1 and reSURFACE 2). Here, we report our real-life experience treating 53 psoriatic patients (19 female and 34 male) who were administered tildrakizumab every 12 weeks and received follow-ups over 52 weeks. Descriptive and inferential statistical analyses were performed, in particular the Psoriasis Area and Severity Index (PASI), Dermatology Life Quality Index (DLQI) and, if applicable, the Nail Psoriasis Severity Index (NAPSI) and Palmoplantar Psoriasis Physician Global Assessment (PPPGA). These were assessed at baseline and after different timepoints (weeks) during the follow-up period. We described and evaluated demographical and epidemiological characteristics in our cohort group, focusing on comorbidities. In this group, 35.9% of patients were female and 64.1% were male, with 47.1% being smokers and with a mean age of 51.2 years. A total of 37.7% of these patients was affected by scalp psoriasis; regarding comorbidities, hypertension was the most frequent (32.5%), followed by psoriatic arthritis (PsA) (18.60%) and diabetes (13.9%). At week 52, 93%, 90.2% and 77% of patients achieved a PASI reduction ≥75% (PASI 75), PASI 90 and PASI 100, respectively. In addition, NAPSI, PPPGA and DLQI scores were significantly reduced by week 52. In our cohort of complex psoriasis patients, disease remission began at the end of the fourth week of treatment and remained constant from week 16 to week 52.

The Role of Corticosteroids in the Management of Drug Allergy: A Narrative Literature Review

Drug allergy is an adverse drug reaction that occurs through an immune reaction that occurs through IgE or a rapid hypersensitivity reaction with various mechanisms and clinical presentations. One of the therapeutic modalities for drug allergies is corticosteroids. In allergic processes, corticosteroids can suppress the production and effects of humoral factors involved in the inflammatory response, inhibit the migration of leukocytes to sites of inflammation, and interfere with the function of endothelial cells, granulocytes, mast cells, and fibroblasts. This literature review aimed to describe the role of corticosteroids in the management of drug allergies. Corticosteroids are used very widely in the treatment of various allergic diseases because of their strong anti-inflammatory properties. Corticosteroids inhibit the synthesis of a number of cytokines, such as the interleukins IL-1 to IL-6, tumor necrosis factor-α (TNF-α), and granulocyte-macrophage colony-stimulating factor (GM-CSF). In conclusion, corticosteroids are one of the therapeutic modalities in various manifestations of drug allergies. Every drug allergy gets the anti-inflammatory effects of corticosteroids with different choices, routes, and doses for each manifestation.

Effect of the bone marrow mesenchymal stromal cells cytokine-producing activity on mobilization of hematopoietic stem cells

Hematopoietic stem cell transplantation is used to treat hemoblastoses and some other diseases. Depending on the diagnosis, autologous cells of the patient or allogeneic cells obtained from a healthy related or unrelated donor are used. A sufficient count of harvested hematopoietic progenitor cells is necessary for successful transplantation. Currently, stimulation of their egress from the bone marrow into the peripheral blood by a granulocyte colony-stimulating factor, followed by collection by leukapheresis, is widely used for their preparation. Hematopoietic stem cells leave the bone marrow niche formed by the stromal microenvironment when their holding bonds are interrupted. Mesenchymal stromal cells regulate the release of hematopoietic precursors by producing various cytokines and other biologically active substances. Therefore, the study of the functional properties of bone marrow mesenchymal cells can help in solving the problem of “poor” mobilizations that occur in patients with multiple myeloma.The aim of the study was to estimate the effectiveness of mobilization of hematopoietic stem cells depending on the cytokine-producing ability of mesenchymal stromal cells in the bone marrow of donors and patients with multiple myeloma.The yields of hematopoietic progenitors were studied in 10 donors (median age 27 years) and 18 patients with multiple myeloma (median age 57 years). In donors, the release of hematopoietic stem cells into the peripheral blood was stimulated by subcutaneous administration of G-CSF at a dose of 10 μg/kg/day. Patients with multiple myeloma received vinorelbine at a dose of 35 mg/m2 of body surface, followed by administration of G-CSF (10 μg/kg/day subcutaneously). A culture of mesenchymal stromal cells was obtained from bone marrow taken prior to mobilization and the content of interleukins IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, TNF-α and IFN-γ in supernatants was studied by enzyme-linked immunosorbent assay using kits of reagents produced by Vector-Best (Novosibirsk).Patients with multiple myeloma were characterized by high secretion of the pro-inflammatory cytokine IL-2 (4.70 pg/ml vs 3.55 pg/ml in healthy individuals, p=0.003) and low IFN-γ (0.41 pg/ml vs 2.14 pg/ml in healthy, p&lt;0.001), but no relationship was found between these cytokines and the hematopoietic stem cells yield. The present study showed that in patients with ineffective harvesting of hematopoietic precursors, secretion of IL-8 by stromal cells was low (308.08 pg/ml vs 561.29 pg/ml in healthy individuals, p=0.04).The obtained results are consistent with the literature data on the important role of IL-8 in the mobilization of hematopoietic stem cells, which allows to consider IL-8 as an informative marker for predicting the insufficient yields of hematopoietic precursors.

Interleukins in serum and bronchoalveolar lavage in patients with chronic obstructive pulmonary disease or bronchial asthma after pulmonary tuberculosis or pneumonia

The spread of respiratory diseases has become a topical issue of modern medicine. The prevalence of the diseases caused the rising rates of disability and mortality among people affected by respiratory diseases. The clinical course of respiratory diseases includes the disorders of general and local adaptive and protective mechanisms and cell-mediated connections. Objective — to determine the interleukin profile of serum and bronchoalveolar lavage for the verification of chronic obstructive pulmonary disease (COPD) or bronchial asthma in patients with pulmonary tuberculosis or pneumonia with bronchial obstruction syndrome. Materials and methods. 67 patients affected by chronic obstructive pulmonary disease and 33 patients diagnosed with bronchial asthma who were hospitalized in the Pulmonology Lviv Regional Diagnostic Center during 2015—2020, were examined. The patients were verified with a non-complicated tuberculosis without any destructive changes evident in the lungs (the first or third clinical category of patients), the community-acquired pneumonia with the bronchial obstruction syndrome. Pro-inflammatory interleukins IL-1β, IL-2, IL-6, TNF-α and anti-inflammatory IL-4 in serum and bronchoalveolar lavage were revealed during the lobar and tertiary bronchi fiber-optic bronchoscopy. Results and discussion. The interleukins misbalance was evident: the decrease in IL-1β and IL-2 and the increase in IL-6 and TNF-α by 4.5 times as compared to the unaffected donors was revealed in the patients with chronic obstructive pulmonary disease. The significant decrease in IL-4 was revealed pointing at the high probability of the severe and prolonged COPD and leading to frequent exacerbation and compilations of the disease. By contrast, the patients diagnosed with bronchial asthma showed higher IL-1β and IL-2 as compared to the unaffected patients; the level of IL-6 was higher as compared to the COPD patients, while TNF-α was lower. The patients with bronchial asthma showed higher IL-4 than the unaffected donors and the patients with COPD. Conclusions. The intensity of interleukins expression (especially pro-inflammatory) revealed the level of inflammation based on the acute-phase proteins in the proteolytic-antiproteolytic balance, which may be also used as the additional criteria for the differential diagnostics and justification for the treatment optimization.

Effects of 4'-Demethylnobiletin and 4'-Demethyltangeretin on Osteoclast Differentiation In Vitro and in a Mouse Model of Estrogen-Deficient Bone Resorption.

Citrus nobiletin (NOB) and tangeretin (TAN) show protective effects against disease-related bone destruction. We achieved demethylation of NOB and TAN into 4'-demethylnobiletin (4'-DN) and 4'-demethyltangeretin (4'-DT) using enzyme-manufacturing methods. In this study, we examined the effects of 4'-DN and 4'-DT on in vitro osteoclast differentiation, and on in vivo osteoporotic bone loss in ovariectomized (OVX) mice. 4'-DN and 4'-DT clearly suppressed the osteoclast differentiation induced by interleukin IL-1 or RANKL treatment. 4'-DN and 4'-DT treatments resulted in higher inhibitory activity in osteoclasts in comparison to NOB or TAN treatments. RANKL induced the increased expression of its marker genes and the degradation of IκBα in osteoclasts, while these were perfectly attenuated by the treatment with 4'-MIX: a mixture of 4'-DN and 4'-DT. In an in silico docking analysis, 4'-DN and 4'-DT directly bound to the ATP-binding pocket of IKKβ for functional inhibition. Finally, the intraperitoneal administration of 4'-MIX significantly protected against bone loss in OVX mice. In conclusion, 4'-DN, 4'-DT and 4'-MIX inhibited the differentiation and function of bone-resorbing osteoclasts via suppression of the NF-κB pathway. Novel 4'-DN, 4'-DT and 4'-MIX are candidates for maintaining bone health, which may be applied in the prevention of metabolic bone diseases, such as osteoporosis.

Effect of dietary phenylalanine on growth performance and intestinal health of triploid rainbow trout (Oncorhynchus mykiss) in low fishmeal diets.

This study aimed to investigate the effects of phenylalanine on the growth, digestive capacity, antioxidant capability, and intestinal health of triploid rainbow trout (Oncorhynchus mykiss) fed a low fish meal diet (15%). Five isonitrogenous and isoenergetic diets with different dietary phenylalanine levels (1.82, 2.03, 2.29, 2.64, and 3.01%) were fed to triplicate groups of 20 fish (initial mean body weight of 36.76 ± 3.13 g). The weight gain rate and specific growth rate were significantly lower (p < 0.05) in the 3.01% group. The trypsin activity in the 2.03% group was significantly higher than that in the control group (p < 0.05). Amylase activity peaked in the 2.64% treatment group. Serum superoxide dismutase, catalase, and lysozyme had the highest values in the 2.03% treatment group. Liver superoxide dismutase and catalase reached their maximum values in the 2.03% treatment group, and lysozyme had the highest value in the 2.29% treatment group. Malondialdehyde levels in both the liver and serum were at their lowest in the 2.29% treatment group. Interleukin factors IL-1β and IL-6 both reached a minimum in the 2.03% group and were significantly lower than in the control group, while IL-10 reached a maximum in the 2.03% group (p < 0.05). The tight junction protein-related genes occludin, claudin-1, and ZO-1 all attained their highest levels in the 2.03% treatment group and were significantly higher compared to the control group (p < 0.05). The intestinal villi length and muscle layer thickness were also improved in the 2.03% group (p < 0.05). In conclusion, dietary phenylalanine effectively improved the growth, digestion, absorption capacity, antioxidant capacity, and intestinal health of O. mykiss. Using a quadratic curve model analysis based on WGR, the dietary phenylalanine requirement of triploid O. mykiss fed a low fish meal diet (15%) was 2.13%.

Pseudorabies Virus Infection Activates the TLR-NF-κB Axis and AIM2 Inflammasome To Enhance Inflammatory Responses in Mice.

Pseudorabies virus (PRV) infection activates inflammatory responses to release robust proinflammatory cytokines, which are critical for controlling viral infection and clearance of PRV. However, the innate sensors and inflammasomes involved in the production and secretion of proinflammatory cytokines during PRV infection remain poorly studied. In this study, we report that the transcription and expression levels of some proinflammatory cytokines, including interleukin 1β (IL-1β), IL-6, and tumor necrosis factor alpha (TNF-α), are upregulated in primary peritoneal macrophages and in mice during PRV infection. Mechanistically, Toll-like receptor 2 (TLR2), TLR3, TLR4, and TLR5 were induced by the PRV infection to enhance the transcription levels of pro-IL-1β, pro-IL-18, and gasdermin D (GSDMD). Additionally, we found that PRV infection and transfection of its genomic DNA triggered AIM2 inflammasome activation, apoptosis-related speckle-like protein (ASC) oligomerization, and caspase-1 activation to enhance the secretion of IL-1β and IL-18, which was mainly dependent on GSDMD, but not GSDME, in vitro and in vivo. Taken together, our findings reveal that the activation of the TLR2-TLR3-TRL4-TLR5-NF-κB axis and AIM2 inflammasome, as well as GSDMD, is required for proinflammatory cytokine release, which resists the PRV replication and plays a critical role in host defense against PRV infection. Our findings provide novel clues to prevent and control PRV infection. IMPORTANCE PRV can infect several mammals, including pigs, other livestock, rodents, and wild animals, causing huge economic losses. As an emerging and reemerging infectious disease, the emergence of PRV virulent isolates and increasing human PRV infection cases indicate that PRV is still a high risk to public health. It has been reported that PRV infection leads to robust release of proinflammatory cytokines through activating inflammatory responses. However, the innate sensor that activates IL-1β expression and the inflammasome involved in the maturation and secretion of proinflammatory cytokines during PRV infection remain poorly studied. In this study, our findings reveal that, in mice, activation of the TLR2-TLR3-TRL4-TLR5-NF-κB axis and AIM2 inflammasome, as well as GSDMD, is required for proinflammatory cytokine release during PRV infection, and it resists PRV replication and plays a critical role in host defense against PRV infection. Our findings provide novel clues to prevent and control PRV infection.

Longitudinal links between early adolescent temperament and inflammation among young black adults

A large body of research demonstrates that inflammation is involved in physical health problems that cause substantial morbidity and early mortality. Given inflammation’s role in the etiology of chronic diseases, pediatric scientists have begun to study childhood factors that presage elevation of inflammatory biomarkers later in life. The purpose of this study was to test hypotheses designed to determine whether early adolescent emotionally intense and low attention temperaments forecast (a) inflammation at ages 25 and 29 years and (b) worsening levels of inflammation between these two data points. Toward this end, 307 Black children from the rural southeastern United States participated in an 18-year longitudinal study (mean age at baseline, 11.2 years) to determine whether and how early adolescent’s behavioral styles or emotionally intense and low attention temperaments may be associated with absolute and worsening levels of inflammation in young adulthood. When children were 11–13 years of age, different teachers at each age provided assessments of emotionally intense and low attention temperaments. Thus, multiple measures of the same temperament constructs were obtained across 3 years for each participant. At age 25, participants provided data on their self-regulation abilities. Peripheral blood was collected at ages 25 and 29 years from which inflammation was quantified, using soluble urokinase plasminogen activator (suPAR), the proinflammatory cytokines interleukin (IL) IL-6, IL-10, and tumor necrosis factor-alpha (TNF-α). Covariates associated with inflammation in prior studies were also assessed; these included socioeconomic risk, gender, cigarette smoking, body mass index (BMI), adverse childhood experiences (ACEs), depressive symptoms, and medication use. An early adolescent emotionally intense temperament was associated directly with higher suPAR and cytokine levels at age 29, and with worsening cytokine levels between ages 25 and 29. A low attention temperament was associated with suPAR levels at age 29. Collectively, these observations highlight pathways that could underlie health risks associated with early adolescent temperaments. The findings suggest that emotionally intense and low-attention early adolescent temperaments forecast higher and worsening inflammation levels across young adulthood.

Neuroprotective Effects of Nano-Curcumin against Cypermethrin Associated Oxidative Stress and Up-Regulation of Apoptotic and Inflammatory Gene Expression in Rat Brains.

Cypermethrin (CPM) is the most toxic synthetic pyrethroid that has established neurotoxicity through oxidative stress and neurochemical agitation in experimental rats. The toxic effects are supposed to be mediated by modifying the sodium channels, reducing Na-K ATPase, acetylcholine esterase (AchE), and monoamine oxidase (MAO). The use of curcumin nanoparticles (NC) that have potent antioxidant, anti-inflammatory and antiapoptotic properties with improved bioavailability attenuates neurotoxicity in rat brains. To test this hypothesis, animals were divided into five groups, each having six animals. Group-I control received vehicle only, while Group-II was treated with 50 mg/kg CPM. Group-III and Group-IV received both CPM and NC 2.5 mg/kg and 5 mg/kg, respectively. Group-V received 5 mg of NC alone. The CPM and NC were given by oral route. Afterwards, brain antioxidant status was measured by assessing lipid peroxidation (LPO), 4-HNE, glutathione reduced (GSH), antioxidant enzyme catalase, and superoxide dismutase (SOD) along with neurotoxicity markers Na-K ATPase, AchE, and MAO. Inflammation and apoptosis indices were estimated by ELISA, qRT-PCR, and immunohistochemistry, while morphologic changes were examined by histopathology. Observations from the study confirmed CPM-induced neurotoxicity by altering Na-K ATPase, AchE, and MAO, and by decreasing the activity of antioxidant enzymes and GSH. Oxidative stress marker LPO and the level of inflammatory interleukins IL-6, IL-1β, and TNF-α were notably high, and elevated expressions of Bax, NF-kB, and caspase-3 and -9 were reported in CPM group. However, NC treatment against CPM offers protection by improving antioxidant status and lowering LPO, inflammation, and apoptosis. The neurotoxicity marker's enzyme successfully attenuated after NC treatment. Therefore, this study supports the administration of NC effectively ameliorated CPM-induced neurotoxicity in experimental rats.