Cytokines IL-6 Research Articles

Design, Synthesis, and Biological Evaluation of 2-Arylaminopyrimidine Derivatives as Dual Cathepsin L and JAK Inhibitors for the Treatment of Acute Lung Injury.

Acute lung injury (ALI) is a disease characterized by pulmonary inflammation, blood barrier functional disorder, and hypoxemia. Herein, a series of 2-aminopyrimidine derivatives were synthesized. Most of them exhibited inhibitory effects on inflammatory cytokines IL-6 and IL-8 in human bronchial epithelial (HBE) cells at a concentration of 5 μM without significant cytotoxicity. Compound A8 displayed an excellent anti-inflammatory activity, achieving inhibition rates of 83% for IL-6 and 85% for IL-8. Besides, A8 has a strong binding affinity to CTSL and a good inhibitory activity on JAKs. Western blot analysis indicated that compound A8 strongly blocked the maturation of CTSL and the phosphorylation of p-38, p-65, and STATs, thereby repressing the activation of the MAPK, NF-κB, and JAK/STAT signaling pathway. Moreover, animal experiments showed that A8 played a protective and therapeutic role in ALI in mice, validating its potential as a treatment for ALI.

Pasteurella multocida Serotype D Infection Induces Activation of the IL-17 Signaling Pathway in Goat Lymphocytes

(1) Background: Pasteurellosis is a global zoonotic bacterial disease, which has caused significant economic impacts in animal husbandry. Nevertheless, there is limited understanding of the immune response between goat peripheral blood lymphocytes (PBLs) and goat-derived Pasteurella multocida (P. multocida). (2) Methods: To investigate the immune response of host PBLs during infection with P. multocida type D, we established an in vitro cell model utilizing isolated primary goat PBLs. Utilizing this in vitro infection model, we employed an enzyme-linked immunosorbent assay (ELISA) to assess the cytokine profile variation in goat PBLs following infection. Meanwhile, RNA sequencing and quantitative PCR (qPCR) methods were employed to analyze the gene expression profile. (3) Results: The ELISA test results indicated that the expression levels of pro-inflammatory cytokines, such as IL-6, IFN-γ, CXCL10, and IL-17A, were significantly elevated within 12 h after infection with P. multocida. In contrast, the levels of the anti-inflammatory cytokine IL-10 were found to be reduced. RNA sequencing and functional enrichment analysis identified 2114 differentially expressed genes (DEGs) that were primarily associated with cytokine-cytokine receptor interactions, viral protein-cytokine interactions, and the IL-17 signaling pathway. Furthermore, protein-protein interaction (PPI) network analysis and qPCR highlighted CD86, CCL5, CD8A, CXCL8, CTLA4, TNF, CD274, IL-10, IL-6, CXCL10, IFNG, and IL-17A that were crucial for the response of PBLs to P. multocida infection. (4) Conclusions: This study systematically revealed the characteristics of PBLs in goats following infection with goat-derived P. multocida type D through the analysis of cytokines and gene expression, providing important theoretical insights for a deeper understanding of the defense mechanisms in goats against P. multocida.

Evaluation of the Changes in Some Hematological and Immunological Parameters in Patients with Rheumatoid Arthritis

Rheumatoid arthritis [RA] is a persistent inflammatory polyarthritis condition characterized by distinct immunological, clinical, genetic, and pathological characteristics, as well as remissions and exacerbations. This study was designed to estimate some Haematological and immunological parameters of Iraqi patients with RA. The data were collected between August 2023 and May 2024 from a total of 60 patients and 30 healthy controls. A serological test was assessed, including erythrocyte precipitation rate, and CRP. Complete blood count was measured using a fully automated quantitative Samsung device. The levels of IL-1β, IL-2, IL-4, IL-10 cytokines were assessed by sandwich ELISA. The result of this study showed that most RA patients were female compared to males. The levels of RF, CRP, and ESR test were significantly higher in patients with RA compared to the control group. RA patients showed statistically significant higher in WBC and Ptt tests while they had lower RBCs, Hb, and RDW compared to controls. When compared to healthy individuals, we observed that patients with RF had greater levels of cytokines IL-1β, IL-2, IL-4, and IL-10. RF patients had higher levels of IL-1β, IL-2, IL-4, and IL-10 than did healthy people.

Boswellia serrate Gum Resin Mitigates Renal Toxicity: Role of TNF-α, Interleukins, TGF-β, and Lipid Peroxidation

Background and aim: Being a central organ in homeostasis and maintaining the health of the biological system, kidneys are exposed to variable toxicants. Long-term exposure to nephrotoxic molecules causes chronic renal damage that causes fibrosis and loss of function. Such damage can be initiated by oxidative stress which provokes inflammation. We aim at investigating the potential therapeutic effects of Boswellia serrata (BS) gum resin extract in managing CCl4-induced renal toxicity. Methods: Male Wistar albino rats were assigned to groups: healthy control; CCl4-treated (CCl4, twice/week, for 6 weeks); CCl4 + BS-treated: CCl4 for 6 weeks followed by BS (150 mg/kg/day) for 2 weeks; and CCl4 + Silymarin-treated: CCl4 for 6 weeks followed by Silymarin (100 mg/kg/day) for 2 weeks. Blood and kidney tissue were utilized to assess oxidative stress status, inflammatory cytokines, and histopathological changes. Results: BS treatment ameliorated signs of renal damage and fibrosis as it improved renal antioxidant status and renal function markers and significantly reduced the levels of inflammatory cytokines TNF-α, IL-1β, IL-6, and IL-8 along with the fibrogenic marker TGF-β. Kidney tissues showed improved histological features after BS treatment. Conclusions: BS gum resin extract has significant therapeutic potential against CCl4-induced renal damage and fibrosis. These effects could be mediated via its previously reported antioxidant, free radical scavenging, and anti-inflammatory effects.

Fishmeal intervention after short-term novel proteins stimulates compensatory growth and affects intestinal health in largemouth bass (Micropterus salmoides).

This research utilized a compensatory growth phenomenon aimed at reducing the use of fishmeal in aquatic animal feed. However, the compensatory growth triggered by fishmeal restriction with novel protein replacement has yet to be understood. Five isonitrogenous and isolipidic diets containing different proteins were manufactured, with fishmeal serving as the control and diets containing novel proteins, i.e., Chlorella (Chlorella vulgaris), cottonseed protein concentrate, Clostridium autoethanogenum, and yellow mealworm (Tenebrio molitor), serving as the experimental diets. Largemouth bass (Micropterus salmoides) with a starting body weight of 4.73 ± 0.04g were respectively fed these five diets for the first 29days (first stage), followed by a fishmeal diet for the remaining 29days (second stage). The diet of fishmeal, Chlorella vulgaris, cottonseed protein concentrate, Clostridium autoethanogenum, and Tenebrio molitor was referred to as FM, ChM, CSM, CAP, and TM, respectively. All novel protein groups showed a 60-73% higher weight gain compared to the fishmeal group during the second phase; however, they did not reach the weight level seen in the control group. In addition, the second stage of fishmeal intervention resulted in a reduction of approximately 35% in the area of positive Alcian blue (AB) staining of intestinal tissues in the CSM group, and about 40% in the CAP group, compared to the first stage. Furthermore, the area of intestinal apoptosis in TM was enlarged after fishmeal intervention while it was decreased in other experimental groups. At day 58, gene expression analysis of the CAP group fish at the end of the trial revealed increased levels of the anti-apoptotic gene bcl-2, as well as higher expression of intestinal inflammatory cytokines il-1β, tnf-α, nf-κb p65, and il-10, compared to the FM group. In terms of the biochemical indices, the levels of catalase (CAT) and glutathione peroxidase (GSH-Px) were reduced in CSM on day 58. An assessment of potential microbial function at end of trial demonstrated that CAP could reduce the lipid metabolism and amino acid metabolism, and increased carbohydrate metabolism pathways in the largemouth bass intestine. In conclusion, both CAP and ChM groups showed promise to reduce fishmeal with respect to intestinal health rather than growth. This study should be of value to practitioners wishing to use novel proteins to reduce fishmeal via the utilization of the compensatory growth phenomenon.

Synergistic combinations of Angelica sinensis for myocardial infarction treatment: network pharmacology and quadratic optimization approach

Background and aimAngelica sinensis (Oliv.) Diels (Danggui, DG), exhibits potential in myocardial infarction (MI) treatment. However, research on its synergistic combinations for cardioprotective effects has been limited owing to inadequate approaches.Experimental procedureWe identified certain phenolic acids and phthalein compounds in DG. Network pharmacology analysis and experimental validation revealed the components that protected H9c2 cells and reduced lactate dehydrogenase levels. Subsequently, a combination of computational experimental strategies and a secondary phenotypic optimization platform was employed to identify effective component combinations with synergistic interactions. The Chou-Talalay and Zero Interaction Potency (ZIP) models were utilized to quantify the synergistic relationships. The optimal combination identified, Z-Ligustide and Chlorogenic acid (Z-LIG/CGA), was evaluated for its protective effects on cardiac function and cardiomyocytes apoptosis induced by inflammatory in a mouse model of induced by left anterior descending coronary artery ligation. Flow cytometry was further utilized to detect the polarization ratio of M1/M2 macrophages and the expression of inflammatory cytokines in serum was measured, assessing the inhibition of inflammatory responses and pro-inflammatory signaling factors by Z-LIG/CGA.Key resultsQuadratic surface analysis revealed that the Z-LIG/CGA combination displayed synergistic cardioprotective effects (combination index value <1; ZIP value >10). In vivo, Z-LIG/CGA significantly improved cardiac function and reduced the fibrotic area in mice post-MI, surpassing the results in groups treated with Z-LIG or CGA alone. Compared to the MI group, the Z-LIG/CGA group exhibited decreased ratios of the myocardial cell apoptosis-related proteins BAX/Bcl-2 and Cleaved Caspase-3/Caspase-3 in mice. Further research revealed that Z-LIG/CGA treatment significantly increased IL-1R2 levels, significantly decreased IL-17RA levels, and inhibited the activation of p-STAT1, thereby alleviating cell apoptosis after MI. Additionally, the Z-LIG/CGA combination significantly inhibited the ratio of M1/M2 macrophages and suppressed the expression levels of pro-inflammatory cytokines IL-1β, IL-6, IL-17, and TNF-α in the serum.Conclusion and implicationsWe successfully identified a synergistic drug combination, Z-LIG/CGA, which improves MI outcomes by inhibiting cardiomyocyte apoptosis and inflammatory damage through modulating macrophage polarization and regulating the IL-1R2/IL-17RA/STAT1 signaling pathway. This study provides a charming paradigm to explore effective drug combinations in traditional Chinese medicine and a promising treatment for MI.

Evaluation of the safety, tolerability, pharmacokinetics and pharmacodynamics of SM17 in healthy volunteers: results from pre-clinical models and a first-in-human, randomized, double blinded clinical trial

BackgroundAlarmins mediate type 2 T helper cell (Th2) inflammation and serve as upstream signaling elements in allergic inflammation and autoimmune responses. The alarmin interleukin (IL)-25 binds to a multi-domain receptor consisting of IL-17RA and IL-17RB subunits, resulting in the release of Th2 cytokines IL-4, IL-5, IL-9 and IL-13 to drive an inflammatory response. Therefore, the blockage of IL-17RB via SM17, a novel humanized monoclonal antibody, offers an attractive therapeutic target for Th2-mediated diseases, such as asthma.MethodsWild-type mice were stimulated with house dust mite (HDM) extracts for evaluation of SM17’s pre-clinical efficacy in allergic asthma. The safety, pharmacokinectics (PK), pharmacodynamics (PD), and immunogenicity of intravenous (IV) doses of SM17 were assessed in a 2-part clinical study in healthy adult subjects. In Part A, 53 healthy participants were enrolled to receive a single IV dose of SM17 (2, 20, 70, 200, 400, 600, 1200 mg) or placebo. In Part B, 24 healthy subjects were enrolled to receive a single IV dose of SM17 every two weeks (Q2W; 200, 400, 600 mg) or placebo for a total of 3 doses.ResultsAnimal studies demonstrated that SM17 significantly suppressed Th2 inflammation in the bronchoalveolar lavage fluid and infiltration of immune cells into the lungs. In the Phase I clinical study, no drug-related serious adverse events were observed. Total SM17 exposure increased by approximately 60- to 188-fold with a 60-fold increase in dose from 20 to 1200 mg SM17. Upon administration of the third dose, mean accumulation ratios over 200-600 mg was 1.5 to 2.1, which confirms moderate accumulation of SM17. After Q2W dosing of SM17 over 4 weeks, total exposure increased in a dose-proportional manner from 200 mg to 600 mg SM17.ConclusionIn the pre-clinical studies, we demonstrated that SM17 is a potential therapeutic agent to treat allergic asthma. In the Phase 1 clinical trial, a single IV dose of SM17 up to 1200 mg and three Q2W doses up to 600 mg were well tolerated in healthy participants and demonstrated a favorable safety profile. The pre-clinical efficacy and clinical PK and immunogenicity results of SM17 support further clinical development.Clinical trial registrationhttps://clinicaltrials.gov/, identifier NCT05332834.

Intraperitoneal Treatment of Cambinol, a Synthetic SIRT1 and SIRT2 Inhibitory Compound, Exacerbates Brucella abortus 544 Burden in the Spleens of Institute of Cancer Research Mice

Our preliminary data using bone marrow-derived macrophages (BMDMs) collected from ICR mice treated with anti-sirtuin (anti-SIRT) 1 antibody showed that Brucella uptake was significantly attenuated. We then further investigated the effect of an inhibitor of SIRT1/2, cambinol, in the progression of Brucella. The in vitro results using RAW264.7 cells revealed that cambinol treatment had no effect on adhesion, uptake, intracellular survival and nitric oxide (NO) production during B. abortus infection, nor did it directly affect bacterial growth for up to 72 h. Finally, intraperitoneal treatment of 8-week-old female ICR mice infected with Brucella showed no differences in the total average weights of spleens and livers; however, the treated mice displayed higher Brucella colony-forming units (CFUs) from the spleens. Furthermore, the interleukin (IL)-10 serum level was observed to be lower in treated mice at 7 d post-infection, and none of the cytokines tested showed a change at 14 d post-infection. The overall findings showed that cambinol treatment had no effect on the proliferation of Brucella in RAW264.7 macrophages but exacerbated the splenic proliferation of the bacteria in mice and displayed reduced anti-inflammatory cytokine IL-10 at the first week of infection, suggesting that cambinol as an inhibitory of SIRT1/2 could be beneficial in the context of Brucella dissemination in animal hosts and that exploration of activating SIRTs could be an alternative treatment against Brucella infection.

Pharmacodynamic Evaluation of Phage Therapy in Ameliorating ETEC-Induced Diarrhea in Mice Models

Enterotoxigenic Escherichia coli (ETEC) is a major pathogen causing diarrhea in humans and animals, with increasing antimicrobial resistance posing a growing challenge in recent years. Lytic bacteriophages (phages) offer a targeted and environmentally sustainable approach to combating bacterial infections, particularly in eliminating drug-resistant strains. In this study, ETEC strains were utilized as indicators, and a stable, high-efficiency phage, designated vB_EcoM_JE01 (JE01), was isolated from pig farm manure. The genome of JE01 was a dsDNA molecule, measuring 168.9 kb, and a transmission electron microscope revealed its characteristic T4-like Myoviridae morphology. JE01 effectively lysed multi-drug-resistant ETEC isolates. Stability assays demonstrated that JE01 retained its activity across a temperature range of 20 °C to 50 °C and a pH range of 3–11, showing resilience to ultraviolet radiation and chloroform exposure. Furthermore, JE01 effectively suppressed ETEC adhesion to porcine intestinal epithelial cells (IPEC-J2), mitigating the inflammatory response triggered by ETEC. To investigate the in vivo antibacterial efficacy of phage JE01 preparations, a diarrhea model was established using germ-free mice infected with a drug-resistant ETEC strain. The findings indicated that 12 h post-ETEC inoculation, intragastric administration of phage JE01 significantly reduced mortality, alleviated gastrointestinal lesions, decreased ETEC colonization in the jejunum, and suppressed the expression of the cytokines IL-6 and IL-8. These results demonstrate a therapeutic benefit of JE01 in treating ETEC-induced diarrhea in mice. Additionally, a fluorescent phage incorporating red fluorescent protein (RFP) was engineered, and the pharmacokinetics of phage therapy were preliminarily assessed through intestinal fluorescence imaging in mice. The results showed that the phage localized to ETEC in the jejunum rapidly, within 45 min. Moreover, the pharmacokinetics of the phage were markedly slowed in the presence of its bacterial target in the gut, suggesting sustained bacteriolytic activity in the ETEC-infected intestine. In conclusion, this study establishes a foundation for the development of phage-based therapies against ETEC.

In ovo sodium butyrate administration differentially impacts growth performance, intestinal barrier function, immune response, and gut microbiota characteristics in low and high hatch-weight broilers

BackgroundHatch weight (HW) affects broiler growth and low HW (LHW) often leads to suboptimal performance. Sodium butyrate (SB) has been shown to promote growth through enhanced intestinal health. This study investigated how broilers with different HW responded to in ovo SB injection and whether SB could enhance gut health and performance in LHW chicks. Ross 308 broiler eggs were injected on incubation d 12 with physiological saline (control) or SB at 0.1% (SB1), 0.3% (SB3), or 0.5% (SB5). Post-hatch, male chicks from each treatment were categorized as high HW (HHW) or LHW and assigned to 8 groups in a 4 × 2 factorial design. Production parameters were recorded periodically. Intestinal weight, length, and gene expression related to gut barrier function and immune response were examined on d 14 and 42. Cecal microbiota dynamics and predicted functionality were analyzed using 16S rRNA gene sequencing.ResultsSB treatments did not affect hatchability. HHW-control group exhibited consistently better weight gain and FCR than LHW-control group. SB dose-dependently influenced performance and gut health in both HW categories, with greater effects in LHW broilers at 0.3%. LHW-SB3 group attained highest body weight on d 42, exceeding controls but not significantly differing from HHW-SB3 group. LHW-SB3 group showed upregulation of gut-barrier genes CLDN1 in ileum, TJP1 in jejunum and anti-inflammatory cytokine IL-10 in both jejunum and ileum on d 14. Additionally, LHW-SB3 group upregulated mucin-producing MUC6 gene in ileum, while HHW-SB5 group increased pro-inflammatory IL-12p40 cytokine in caecum on d 42. LHW-SB3 group demonstrated shorter relative intestinal lengths, while HHW-SB5 had longer lengths. HHW-control group had higher bacterial diversity and growth-promoting bacteria while LHW-control group harbored the potential pathogen Helicobacter. SB reshaped gut microbiota biodiversity, composition, and predicted metabolic pathways in both HW categories. The LHW-SB3 group exhibited highest alpha diversity on d 14 and most beneficial bacteria at all timepoints. HHW-SB5 group presented increased pathogenic Escherichia-Shigella and Campylobacter on d 42.ConclusionsHW significantly affects subsequent performance and SB has differential effects based on HW. LHW chicks benefited more from 0.3% SB, showing improvements in growth, intestinal development, health, and gut microbiota characteristics.

Cytokine profiling reveals HLA-linked Th2 and Th17 driven immune activation in pemphigus vulgaris patients and genetically susceptible healthy controls.

Cytokines and chemokines direct the inflammatory response and may serve as markers of immune dysregulation in Pemphigus vulgaris (PV), an autoimmune blistering skin disorder. Previous studies on limited numbers of patients and cytokine profiles in PV have produced equivocal results regarding the role these mediators play in disease. In this study, we interrogated serum samples from 116 PV patients and 29 healthy controls by multiplexed bead array assays across a comprehensive set of cytokines and chemokines covering several functional categories, including IL-1α, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-9, IL-10, IL-12, IL-13, IL-15, IL-17, IL-21, IL-22, IL-23, TNFα, IFNγ, MCP-1, and Eotaxin. We found that patients with PV generally display an activated cytokine and chemokine immune response compared to controls, but also show remarkable interindividual heterogeneity in terms of cytokine levels, with a limited activation of different T helper cell pathways in different patients. Surprisingly, we also found that healthy individuals that carry the PV susceptibility alleles HLA DR4 (DRB1*0402) and/or DR6 (DQB1*0503) (HLA-matched controls) show an upregulation of cytokine and chemokine levels that are on par with those seen in PV patients for certain pro-inflammatory, Th2, and Th17 mediators and IL-8, while healthy controls that did not carry the PV susceptibility alleles (HLA-unmatched controls) express significantly lower levels of these cytokines and chemokines. Our data suggest the existence of a limited immune activation linked to the presence of key PV associated HLA alleles regardless of disease status. Interestingly, the cytokines IL-10 and IL-15 were found to be significantly downregulated in the HLA-matched control group, suggesting the presence of a possible counter-regulatory function in genetically susceptible but disease-free individuals.

The identification of a SARs-CoV2 S2 protein-derived peptide with super-antigen-like stimulatory properties on T-cells.

Severe COVID-19 can trigger a cytokine storm, leading to acute respiratory distress syndrome (ARDS) with similarities to superantigen-induced toxic shock syndrome. An outstanding question is whether SARS-CoV-2 protein sequences can directly induce inflammatory responses. In this study, we identify a region in the SARS-CoV-2 S2 spike protein with sequence homology to bacterial super-antigens (termed P3). Computational modeling predicts P3 binding to sites on MHC class I/II and the TCR that partially overlap with sites for the binding of staphylococcal enterotoxins B and H. Like SEB and SEH peptides, P3 stimulated 25-40% of human CD4+ and CD8+ T cells, increasing IFN-γ and granzyme B production. viSNE and SPADE profiling identified overlapping and distinct IFN-γ and GZMB subsets. The super-antigenic properties of P3 were further evident by its selective expansion of T cells expressing specific TCR Vα and Vβ chain repertoires. In vivo experiments in mice revealed that the administration of P3 led to a significant upregulation of proinflammatory cytokines IL-1β, IL-6, and TNF-α. While the clinical significance of P3 in COVID-19 remains unclear, its homology to other mammalian proteins suggests a potential role for this peptide family in human inflammation and autoimmunity.

The impact of gut microbiota in full-term pregnant women on immune regulation during pregnancy: A prospective, exploratory study.

This study aims to investigate the correlation between gut microbiota and both placental local immune function and the maternal systemic immune system in pregnant women. Twenty-six pregnant women were included in this study, utilizing high-throughput sequencing for gut microbiota analysis. Immune cells and cytokine levels were measured in placental tissue and peripheral venous blood. Integration of gut microbiota data with immune parameters was performed using R, and network correlation analysis was conducted with Cytoscape software. In placental tissues, gut microbiota predominantly influences B lymphocytes (CD3-CD19+/CD3-), indicating a potential bidirectional regulatory role. The impact on CD56+CD16+/CD56+CD16- and CD4+/CD8+ ratios appear minor. Notably, a significant positive correlation was observed between gut microbiota and the placental cytokine interleukin (IL)-5. In peripheral blood, gut microbiota was primarily associated with negative regulation of peripheral B lymphocytes and positive regulation of peripheral Treg cells. Minimal effects are observed on peripheral macrophages and NK cell subtypes. The most substantial impact on peripheral immune balance was reflected in the CD4+/CD8+ ratio, showing a predominant negative correlation, while the influence on the CD56+CD16+/CD56+CD16- ratio is minimal. A significant negative correlation was found between gut microbiota and peripheral cytokines IL-1 and IL-18, while the interaction with the peripheral interferon-γ/IL-4 ratio appears relatively less pronounced. The close correlation between gut microbiota and placental local immune function, as well as maternal systemic immune responses, is evident. This study contributes to a preliminary understanding of the immunomodulatory relationship of gut microbiota during pregnancy.

Consequences of Early Maternal Deprivation on Neuroinflammation and Mitochondrial Dynamics in the Central Nervous System of Male and Female Rats

Early life stress (ELS) is associated with an increased risk for neuropsychiatric disorders, and both neuroinflammation and mitochondrial dysfunction seem to be central to mental health. Herein, using an animal model of ELS, a single episode of maternal deprivation (MD, 24 h on pnd 9) extensively documented to elicit behavioural anomalies in male and female Wistar rats, we investigated its consequences in terms of neuroinflammation and mitochondrial dynamics in the prefrontal cortex (PFC) and the hippocampal formation (HCF). MD differentially affected the brain content of cytokines: MD induced a transient increase in pro-inflammatory cytokines (IL-1β and IL-6) in the PFC, as well as in the levels of the anti-inflammatory cytokine IL-10 in the HCF. MD also induced a significant decrease mitochondria citrate synthase activity, but MD did not exert significant changes in mitochondria Complex IV activity, revealing a generalized decrease in mitochondrial density without any change in mitochondrial respiration. In the present study, we demonstrate that MD induces neuroinflammatory processes in specific brain regions. Additional research is needed to better understand the temporal pattern of such changes, their impact on the developing brain, and their participation in the already well-known behavioural consequences of MD.

Analysis of the Blood Levels of NK and NKT Cells in Patients with Severe SARS-CoV-2 Infection.

Clinical features of SARS-CoV-2 infection vary, ranging from asymptomatic cases to pneumonia, and other serious complications. Some populations have been observed to be at higher risk for severe disease and death compared to other ethnical groups. To evaluate two parameters of the innate immune system, that play a significant role in viral immunity. In samples of peripheral blood from sixteen patients with severe COVID-19, ten with asymptomatic to mild illness, and fifteen healthy subjects, the percentage of NK and NKT cells, the expression of different NK cell receptors and the blood levels of pro-inflammatory cytokines were tested. We observed that patients with severe COVID-19 showed significantly lower frequencies of both CD56dim and CD56bright NK cells compared to patients with mild illness or healthy controls. Furthermore, patients with severe manifestation of COVID-19 exhibited an aberrant expression of the natural cytotoxicity receptors NKp30, NKp44 and NKp46. Similarly, NK cells from these patients showed statistically significant differences in the expression of various killer immunoglobulin-like receptors (KIRs) in the two main cell subsets (CD56bright, CD56dim) compared to controls or patients with mild disease. Moreover, patients with severe illness displayed decreased frequency of NKT cells (defined as CD3+CD56+) and elevated blood levels of the cytokines IL-6 and IL-8. This study suggests that the abnormal features of NK and NKT cells observed in patients with severe SARS-CoV-2 infection may play an important role in the outcome of this infectious disease in various population groups.

Intestinal epithelial-specific occludin deletion worsens gut permeability and survival following sepsis.

Sepsis induces intestinal hyperpermeability, which is associated with higher mortality. Occludin is a tight junction protein that plays a critical role in regulating disease-associated intestinal barrier loss. This study examined the role of intestinal occludin on gut barrier function and survival in a pre-clinical model of sepsis. Intestinal epithelial-specific occludin knockout (occludin KOIEC) mice and wild type controls were subjected to intra-abdominal sepsis and sacrificed at pre-determined endpoints for mechanistic studies or followed for survival. Occludin KOIEC mice had a significant increase in intestinal permeability, that was induced only in the setting of sepsis as knockout mice and control mice had similar baseline permeability. The worsened barrier was specific to the leak pathway of permeability, without changes in either the pore or unrestricted pathways. Increased sepsis-induced permeability was associated with increased levels of the tight junction ZO-1 in occludin KOIEC mice. Occludin KOIEC mice also had significant increases in systemic cytokines IL-6 and MCP-1and increased bacteremia. Further, occludin KOIEC mice had higher levels of jejunal IL-1β and MCP-1 as well as increased MCP-1 and IL-17A in the peritoneal fluid although peritoneal bacteria levels were unchanged. Notably, 7-day mortality was significantly higher in occludin KOIEC mice following sepsis. Occludin thus plays a critical role in preserving gut barrier function and mediating survival during sepsis, associated with alterations in inflammation and bacteremia. Agents that preserve occludin function may represent a new therapeutic strategy in the treatment of sepsis.

The dichotomic role of cytokines in aging.

The chronic inflammation present in aged individuals is generally depicted as a detrimental player for longevity. Here, it is discussed several beneficial effects associated with the cytokines that are chronically elevated in inflammaging. These cytokines, such as IL-1β, type I interferons, IL-6 and TNF positively regulate macroautophagy, mitochondrial function, anti-tumor immune responses and skeletal muscle biogenesis, possibly contributing to longevity. On the other side, the detrimental and antagonistic role of these cytokines including the induction of sarcopenia, tissue damage and promotion of tumorigenesis are also discussed, underscoring the dichotomy associated with inflammaging and its players. In addition, it is discussed the role of the anti-inflammatory cytokine IL-10 and other cytokines that affect aging in a more linear way, such as IL-11, which promotes senescence, and IL-4 and IL-15, which promotes longevity. It is also discussed more specific regulators of aging that are downstream cytokines-mediated signaling.

The influence of light on Interleukin-10: A preliminary study

Light influences circadian rhythms, including that of the stress hormone cortisol. Cortisol, in turn, has been observed to promote expression of the anti-inflammatory cytokine IL-10. It is thus of interest whether the cytokine IL-10 is also influenced by light, perhaps in accord with the diurnal variations in cortisol. Hence, this highly standardized preliminary sleep laboratory study in healthy adult men investigated a potential influence of different light exposure on IL-10 and cortisol concentrations in blood. In a between-subject design, N = 42 participants were exposed to either bright, dim, blue or red light after wake-up. Two mixed-model analyses with the factors of light condition and time (across eight IL-10 and cortisol sampling points) were conducted. Additionally, area under the curve measurements (AUCg and AUCi) were calculated for both cortisol and IL-10. Across all conditions, IL-10 and cortisol concentrations significantly changed over time. However, none of the light conditions exerted a greater influence on IL-10 or cortisol levels than others. For cortisol, there was greater total output (AUCg) in the blue-light condition in particular. Further research is needed to gain insight into whether or not types of light or cortisol levels have a hand in influencing natural IL-10 concentrations.

Mirtazapine Improves Locomotor Activity and Attenuates Neuropathic Pain Following Spinal Cord Injury in Rats via Neuroinflammation Modulation.

Neuroinflammation-related locomotor deficits and neuropathic pain are expected outcomes of spinal cord injury (SCI). The atypical antidepressant mirtazapine has exhibited potential neuroprotective and anti-inflammatory effects. This research aims to investigate the impacts of mirtazapine on post-SCI neuropathic pain and locomotor recovery, with a particular focus on neuroinflammation. The study utilized 30 male Wistar rats divided into five groups: Sham, SCI with vehicle treatment, and SCI administered with mirtazapine (3, 10, and 30mg/kg/day,ip, for one week). Locomotor activity was assessed using the Basso, Beattie, and Bresnahan (BBB) scale. Mechanical, thermal, and cold allodynia were assessed using von-Frey filaments, tail flick latency, and the acetone test, respectively. ELISA was utilized to measure cytokines, while Western blotting was used to determine TRPV1 channel, 5-HT2A receptor, NLRP3, and iNOS expression. Histopathological analyses were also examined, including hematoxylin and eosin (H&E) and Luxol fast blue (LFB) staining. Mirtazapine (10 and 30mg/kg/day) significantly improved locomotor recovery according to BBB score. It attenuated mechanical, thermal, and cold allodynia post-SCI. Moreover, it decreased pro-inflammatory cytokines TNF-α, IL-1β, IL-6, and IL-18, while increasing anti-inflammatory cytokine IL-4 and IL-10. Furthermore, it downregulated iNOS, NLRP3, and TRPV1 expression and upregulated the 5-HT2A receptor. H&E and LFB staining further revealed attenuated tissue damage and decreased demyelination. Our findings suggest that mirtazapine can alleviate neuropathic pain and reinforce locomotor recovery post-SCI by modulating neuroinflammatory responses, NLRP3, iNOS, TRPV1 channel, and 5-HT2A receptor expression.

Bailing capsule alleviates autoimmune thyroiditis regulating peroxisome proliferator-activated receptor signaling pathway: a multi-omics analysis.

To investigate the efficacy and potential mechanism of Bailing capsule (, BL) anti-autoimmune thyroiditis (AIT). Based on the AIT rat model, the effect of BL in alleviating AIT was evaluated by detecting serum thyroid index free triiodothyronine (FT3), free thyroxine (FT4), thyroid-stimulating hormone (TSH), thyroglobulin antibody (TGAb), thyroid peroxidase antibody (TPOAb), and inflammatory factors Interferon-gamma (IFN-γ), Interleukin-4, -10, and -12 (IL-4, IL-10, and IL-12) as well as thyroid tissue Hematoxylin-eosin (HE) staining and ultrastructure observation. The mechanism of BL was explored by combining transcriptome and proteome analysis, and further verified by Western blot (WB). BL effectively reduced serum FT3, FT4, TGAb, and TPOAb levels in AIT rats, restored TSH balance, inhibited the release of pro-inflammatory cytokines IFN-γ and IL-12, promoted the production of anti-inflammatory cytokines IL-4 and IL-10, and significantly reduced IFN-γ/IL-4 and IL-12/IL-10, improved thyroid follicular structure, and protected thyroid tissue from injury. Kyoto Encyclopedia of Genes and Genomes and protein interaction network analysis showed that BL affected the expression of fatty acid-binding protein 4, acyl-CoA synthetase long-chain family member 1, and acyl-CoA dehydrogenase long chain to regulate the peroxisome proliferator-activated receptor signaling pathway, thereby inhibiting the fatty acid metabolism and the inflammatory state of AIT rats. BL could effectively reduce thyroid inflammation in AIT model rats. The possible BL mechanism was to regulate the peroxisome proliferator-activated receptor signaling pathway and inhibit fatty acid metabolism. This study suggested that BL has the potential to be used in clinical treatment of AIT.