IL-10 producing regulatory B cells are decreased in blood from smokers and COPD patients.

BACKGROUND: Two opposing B cell subsets have been defined based on their cytokine profile: IL-6 producing effector B cells (B-effs) versus IL-10 producing regulatory B cells (B-regs) that respectively positively or negatively regulate immune responses. B-regs are decreased and/or impaired in many autoimmune diseases and inflammatory conditions. Since there is increasing evidence that links B cells and B cell-rich lymphoid follicles to the pathogenesis of COPD, the aim of this study was to investigate the presence and function of B-regs in COPD. METHODS: First, presence of IL-10 producing regulatory B cells in human lung tissue was determined by immunohistochemistry. Secondly, quantification of IL-10 + B-regs and IL-6 + B-effs in peripheral blood mononuclear cells (PBMCs) from healthy controls, smokers without airflow limitation, and COPD patients (GOLD stage I-IV) was performed by flow cytometry. Thirdly, we exposed blood-derived B cells from COPD patients in vitro to cigarette smoke extract (CSE) and quantified IL-10 + B-regs and IL-6 + B-effs. Furthermore, we aimed at restoring the perturbed IL10 production by blocking BAFF. Fourthly, we determined mRNA expression of transcription factors involved in IL-10 production in FACS sorted memory- and naive B cells upon exposure to medium or CSE. RESULTS: The presence of IL-10 producing regulatory B cells in parenchyma and lymphoid follicles in lungs was confirmed by immunohistochemistry. The percentage of IL-10 + B-regs was significantly decreased in blood-derived memory B cell subsets from smokers without airflow limitation and patients with COPD, compared to never smokers. Furthermore, the capacity of B cells to produce IL-10 was reduced upon in vitro exposure to CSE and this could not be restored by BAFF-blockade. Finally, upon CSE exposure, mRNA levels of the transcription factors IRF4 and HIF-1α, were decreased in memory B cells. CONCLUSION: Decreased numbers and impaired function of B-regs in smokers and patients with COPD might contribute to the initiation and progression of the disease.

Aliskiren, tadalafil, and cinnamaldehyde alleviate joint destruction biomarkers; MMP-3 and RANKL; in complete Freund's adjuvant arthritis model: Downregulation of IL-6/JAK2/STAT3 signaling pathway.

Rheumatoid arthritis (RA) is an autoimmune inflammatory disease, which is accompanied by progressive joint damage and disability. The intolerability of conventional antirheumatic drugs by some patients necessitates the search for effective antirheumatic agents having better tolerability. In the current work, we aimed to investigate the efficacy of cinnamaldehyde, tadalafil, and aliskiren as potential antirheumatic candidates and to explore their modulatory effects on joint destruction, inflammatory response, and intracellular signaling. Arthritis was induced in female Wistar rats by complete Freund's adjuvant (CFA) 0.4 ml s.c. on days 1, 4, and 7. Treated groups received their respective drugs, starting from day 13, daily for 3 weeks. Methotrexate and prednisolone were the standard antirheumatic drugs, while cinnamaldehyde, tadalafil, and aliskiren were the test agents. Treatment with cinnamaldehyde, tadalafil, or aliskiren reduced serum levels of rheumatoid factor, and pro-inflammatory cytokines; tumor necrosis factor-alpha and interleukin-6 (IL-6), along with elevated level of IL-10 which is an anti-inflammatory cytokine. Besides, cartilage and bone destruction biomarkers; matrix metalloproteinase-3 (MMP-3) and receptor activator of nuclear factor-kappa B ligand (RANKL); were significantly reduced after treatment with the test agents, which was further confirmed by histopathological investigation. The elevated protein expressions of phosphorylated-Janus kinase 2 (p-JAK2), phosphorylated-signal transducer and activator of transcription 3 (p-STAT3), and inducible nitric oxide synthase (iNOS) in articular tissue were markedly attenuated after treatment with cinnamaldehyde, tadalafil, or aliskiren, while that of endothelial nitric oxide synthase (eNOS) was greatly enhanced. In addition, oxidative stress and inflammatory markers such as malondialdehyde, nitric oxide, and myeloperoxidase were reduced in joint tissue after treatment with the test agents, while glutathione content was elevated. Furthermore, the renin inhibitor aliskiren produced effects close to those of the normal and methotrexate, the gold standard antirheumatic drug, in most of the measured parameters. Collectively, these findings led to the assumption that the downregulation of IL-6/JAK2/STAT3 signaling by cinnamaldehyde, tadalafil, and aliskiren could alleviate joint destruction by MMP-3 and RANKL, reduce iNOS, and enhance eNOS expressions. Moreover, aliskiren could be a promising therapeutic agent for RA, because of its ability to normalize most of the measured parameters after CFA-induced arthritis.

Peripheral Gamma Delta T cells secrete inflammatory cytokines in women with idiopathic recurrent pregnancy loss.

BACKGROUND: Gamma delta (γδ) T cells are known to link innate and adaptive immunity. Decidual γδ T cells are known to provide immunotolerance by producing IL-10 and TGF-ß. In recurrent pregnancy loss (RPL) females, the role of peripheral γδ T cells remain unstudied. OBJECTIVE: To investigate the different phenotypes of γδ T cells in the peripheral blood of women with idiopathic RPL and their possible involvement in RPL condition. METHODS: A total of 120 women were recruited for the study. Peripheral blood lymphocytes were isolated and they were stained with appropriate antibodies to determine the phenotype of γδ T cells and major cytokines produced by them in the blood using flow cytometry. RESULTS: We observed a significant decrease in the proportion of CD3+CD4-CD8-γδ T cells (p<0.001) and increase in the percentage of IFN-γ (p<0.05) and IL-17 (p<0.001) producing γδ T cells in RPL pregnant as compared to normal pregnant females. CONCLUSION: Increase in IFN-γ and IL-17-producing CD3+ CD4-CD8- γδ T cells is associated with creating inflammatory cytokine milieu, thereby, may contribute towards pregnancy loss in RPL females.

Autoimmunity and Primary Immunodeficiency Disorders.

Advances in DNA sequencing technologies have led to a quickening in the pace at which new genetic immunodeficiency disorders have been identified. Among the newly identified defects are a number of disorders that present primarily with autoimmunity as opposed to recurrent infections. These "immune dysregulation" disorders have begun to cluster together to form an increased understanding of some of the basic molecular mechanisms that underlie the establishment and maintenance of immune tolerance and the development of autoimmunity. This review will present three major themes that have emerged in our understanding of the mechanisms that underlie autoimmunity and immune dysregulation in humans.

SEMA4A promotes prostate cancer invasion: involvement of tumor microenvironment.

Semaphorin 4A (SEMA4A) belonged to a family of membrane-bound proteins that were initially recognized as a kind of axon guidance factors in nervous system. It was preferentially expressed on immune cells and has been proven to play a prominent role in immune function and angiogenesis. In this study, we found that SEMA4A was highly expressed in prostate cancer (PCa) tissues and correlated with Gleason scores and distant metastasis. SEMA4A could induce Epithelial-mesenchymal transition (EMT) of PCa cells and consequently promote invasion by establishing a positive loop with IL-10 in stromal cells. In vivo experiments showed more dissemination in mice injected with SEMA4A-overexpressing cells in mouse models and both the number and size of lung metastases were significantly increased in SEMA4A-overexpressing tumors. SEMA4A depletion by genetic means prevents lung metastasis in PCa xenograft models. Our data suggest a crucial role of SEMA4A in PCa and blocking SEMA4A-IL-10 axis represents an attractive approach to improving therapeutic outcomes.

T cell intrinsic STAT1 signaling prevents aberrant Th1 responses during acute toxoplasmosis.

Infection-induced T cell responses must be properly tempered and terminated to prevent immuno-pathology. Using transgenic mice, we demonstrate that T cell intrinsic STAT1 signaling is required to curb inflammation during acute infection with Toxoplasma gondii. Specifically, we report that mice lacking STAT1 selectively in T cells expel parasites but ultimately succumb to lethal immuno-pathology characterized by aberrant Th1-type responses with reduced IL-10 and increased IL-13 production. We also find that, unlike STAT1, STAT3 is not required for induction of IL-10 or suppression of IL-13 during acute toxoplasmosis. Each of these findings was confirmed in vitro and ChIP-seq data mining showed that STAT1 and STAT3 co-localize at the Il10 locus, as well as loci encoding other transcription factors that regulate IL-10 production, most notably Maf and Irf4. These data advance basic understanding of how infection-induced T cell responses are managed to prevent immuno-pathology and provide specific insights on the anti-inflammatory properties of STAT1, highlighting its role in shaping the character of Th1-type responses.

PD-1 and CTLA-4 exert additive control of effector regulatory T cells at homeostasis.

At homeostasis, a substantial proportion of Foxp3+ T regulatory cells (Tregs) have an activated phenotype associated with enhanced TCR signals and these effector Treg cells (eTregs) co-express elevated levels of PD-1 and CTLA-4. Short term in vivo blockade of the PD-1 or CTLA-4 pathways results in increased eTreg populations, while combination blockade of both pathways had an additive effect. Mechanistically, combination blockade resulted in a reduction of suppressive phospho-SHP2 Y580 in eTreg cells which was associated with increased proliferation, enhanced production of IL-10, and reduced dendritic cell and macrophage expression of CD80 and MHC-II. Thus, at homeostasis, PD-1 and CTLA-4 function additively to regulate eTreg function and the ability to target these pathways in Treg cells may be useful to modulate inflammation.

Neuroprotective effects of daidzein against ifosfamide-induced neurotoxicity in male rats: role of selected inflammatory and apoptotic markers.

Ifosfamide (IFO), an alkylating chemotherapy agent, is known for its association with neurotoxicity and encephalopathy. This trial was designed to evaluate the protective action of daidzein (DZN) against IFO-induced neurotoxicity in male rats by determining the difference in certain inflammatory and apoptotic markers in the brain tissue of rats. Twenty-eight Wistar rats, weighing 120-150 g, were divided into four groups of seven rats: Group 1 (Control) received no treatment; Group 2 was orally administered DZN (100 mg/kg/day) for seven days; Group 3 received a single intraperitoneal (IP) dose of IFO (500 mg/kg); Group 4 received oral DZN (100 mg/kg/day) for one week prior to a single IP dose of IFO on the seventh day. Twenty-four hours post-treatment, serum and brain tissue samples were collected for analysis. The results indicated a significant increase in serum inflammatory markers (TNF-alpha, IL-6, and iNOS) and the anti-inflammatory marker (IL-10), along with elevated caspase-3 enzyme activity in the brain tissue of the IFO-treated group compared to the control group. Conversely, pre-treatment with DZN significantly reduced serum inflammatory markers and caspase-3 levels in tissue. The findings suggest that daidzein has anti-inflammatory and anti-apoptotic properties, potentially offering protection against IFO-induced neurotoxicity in rats.

Barrier-penetrating liposome targeted delivery of basic fibroblast growth factor for spinal cord injury repair.

Nanoparticle technologies offer a non-invasive means to deliver basic fibroblast growth factor (bFGF) for the treatment of spinal cord injury (SCI). However, the inability of bFGF to accumulate at the injury site and inefficient penetration across the blood-spinal cord barrier (BSCB) remain challenges. The present study describes a dual-targeting liposome (bFGF@Lip-Cp&Rp) with injury lesion targeting and BSCB-penetrating capability to deliver bFGF for SCI treatment. The CAQK peptide (Cp) with injury lesion targeting ability and R2KC peptide (Rp) with BSCB-penetrating capability were grafted onto the liposomes for a flexible and non-invasive drug delivery systems preparation. Results exhibit that the dual-targeted liposomes could significantly cross the BSCB and accumulate at the injury site. During the early stage of SCI, bFGF@Lip-Cp&Rp promotes repair of BSCB and facilitates M2-polarization of macrophages. Regular delivery of bFGF@Lip-Cp&Rp increase HUVECs tube formation and angiogenesis, ameliorate the microenvironment of lesion site, suppress the neuronal apoptosis and axonal atrophy in SCI rats. Importantly, continuous treatment of bFGF@Lip-Cp&Rp supports the restoration of limb motor function in SCI rats. In summary, this research implies that the injury site-targeting and BSCB-penetrating liposomes could be a promising therapeutic approach for the treatment of SCI.

Xanthohumol ameliorates cardiac injury induced by sepsis in a mice model: role of toll-like receptor 4.

Sepsis, a life-threatening condition arising from infection, often results in multi-organ failure, including cardiac dysfunction. This study investigated Xanthohumol, a natural compound, and its potential mechanism of action to enhance heart function following sepsis. A total of twenty-four adult male Swiss albino mice were allocated randomly to one of four equal groups (n=6): sham, CLP, vehicle Xanthohumol the same amount of DMSO injected IP 10 minutes before the CLP, and Xanthohumol group (0.4 mg/kg of Xanthohumol administered IP before the CLP process). Toll-like receptor 4, pro-inflammatory mediators, anti-inflammatory markers, oxidative stress indicators, apoptosis markers, and serum cardiac damage biomarkers were measured in the cardiac tissue using ELISA. Data with normal distribution were analyzed using t-test and ANOVA tests (p<0.05). In comparison to the sham group, the sepsis group had significantly higher levels of TLR-4, IL-6, TNF-α, MIF, F2-isoprostane, caspase-3, cTn-I, and CK-MB, while the pre-treated group with Xanthohumol had significantly lower levels (p<0.05) of these markers than the sepsis group. Bcl-2 showed no significant difference in Xanthohumol pre-treated group relative to the sepsis group, while IL-10 was significantly elevated. Xanthohumol dramatically reduced cardiac tissue injury (p<0.05) relative to the CLP group. By blocking the downstream signal transduction pathways of TLR-4 and NF-kB, Xanthohumol was shown to lessen cardiac damage in male mice during CLP-induced polymicrobial sepsis.

Effect of Sulforaphane on cardiac injury induced by sepsis in a mouse model: Role of toll-like receptor 4.

As sepsis is associated with a 50% increase in mortality, sepsis-induced cardiomyopathy has become a critical topic. A multidisciplinary approach is required for the diagnosis and treatment of septic cardiomyopathy. This study looked at Sulforaphane, a natural product that aims to evaluate cardiac function after sepsis, and its likely mechanism of action. Twenty-four adult male Swiss albino mice were randomly divided into 4 equal groups (n=6): sham, CLP, vehicle Sulforaphane (the same amount of DMSO injected IP one hour before the CLP), and Sulforaphane group (one hour before the CLP, a 5mg/kg dose of Sulforaphane was injected). Cardiac tissue levels of toll-like receptor 4 (TLR-4), pro-inflammatory mediators, anti-inflammatory markers, oxidative stress markers, apoptosis markers, and serum cardiac damage biomarkers were assessed using ELISA. Statistical analyses, including t-tests and ANOVA tests, were performed with a significance level of 0.05 for normally distributed data. Compared to the sham group, the sepsis group had significantly elevated levels of TLR-4, IL-6, TNF-α, MIF, F2-isoprostane, caspase-3, cTn-I, and CK-MB (p<0.05). In contrast, the Sulforaphane pre-treated group demonstrated significantly lower levels of these markers (p<0.05). Additionally, Bcl-2 levels were significantly reduced (p<0.05) in the Sulforaphane group. Sulforaphane administration also significantly attenuated cardiac tissue injury (p<0.05). The findings suggest that Sulforaphane can decrease heart damage in male mice during CLP-induced polymicrobial sepsis by suppressing TLR-4/NF-kB downstream signal transduction pathways.

Assessment of ultra-structure, viability and function of lipopolysaccharides-stimulated human dermal fibroblasts treated with chrysin and exosomes (in vitro study).

Background: Lipopolysaccharides (LPS) stimulate production of inflammatory cytokines. Chrysin is flavonoid beneficial for treatment of inflammatory conditions. Bone marrow mesenchymal stem cell (BM-MSC) exosomes have regenerative ability in different tissues. Objective: To assess potential role of chrysin and BM-MSC exosomes on ultra-structure, viability and function of human dermal fibroblasts-adult (HDFa) stimulated by LPS. Methods: HDFa cells were divided into: Group I: Cells received no treatment. Group II: Cells were stimulated with LPS. Group III: LPS stimulated cells were treated with chrysin. Group IV: LPS stimulated cells were treated with exosomes. Results: After 48 h, ultrastructural examination of HDFa cells in Group I revealed intact plasma membrane and numerous cytoplasmic organelles. Group II displayed destructed plasma membrane and apoptotic bodies. Group III showed intact plasma membrane with loss of its integrity at some areas. Group IV demonstrated intact plasma membrane that showed fusion with exosomes at some areas. Statistical analysis of MTT represented highest mean value of cell viability% in Group IV followed by Groups III, I and II respectively. Statistical analysis of enzyme-linked immunosorbent assay (ELISA) showed the highest mean value of interleukin-1ß (IL-1ß) was in Group II followed by Groups III, IV and I, while highest mean values of interleukin-10 (IL-10), nuclear factor-erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) proteins were in Group I, followed by Groups IV, III and II respectively. Conclusions: LPS have harmful consequences on ultra-structure, viability and function of HDFa cells. BM-MSC exosomes have better regenerative action on inflamed fibroblasts in comparison to chrysin.

Glucose and MMP-9 dual-responsive hydrogel with temperature sensitive self-adaptive shape and controlled drug release accelerates diabetic wound healing.

Chronic diabetic wounds are an important healthcare challenge. High concentration glucose, high level of matrix metalloproteinase-9 (MMP-9), and long-term inflammation constitute the special wound environment of diabetic wounds. Tissue necrosis aggravates the formation of irregular wounds. All the above factors hinder the healing of chronic diabetic wounds. To solve these issues, a glucose and MMP-9 dual-response temperature-sensitive shape self-adaptive hydrogel (CBP/GMs@Cel&INS) was designed and constructed with polyvinyl alcohol (PVA) and chitosan grafted with phenylboric acid (CS-BA) by encapsulating insulin (INS) and gelatin microspheres containing celecoxib (GMs@Cel). Temperature-sensitive self-adaptive CBP/GMs@Cel&INS provides a new way to balance the fluid-like mobility (self-adapt to deep wounds quickly, approximately 37 °C) and solid-like elasticity (protect wounds against external forces, approximately 25 °C) of self-adaptive hydrogels, while simultaneously releasing insulin and celecoxib on-demand in the environment of high-level glucose and MMP-9. Moreover, CBP/GMs@Cel&INS exhibits remodeling and self-healing properties, enhanced adhesion strength (39.65 ± 6.58 kPa), down-regulates MMP-9, and promotes cell proliferation, migration, and glucose consumption. In diabetic full-thickness skin defect models, CBP/GMs@Cel&INS significantly alleviates inflammation and regulates the local high-level glucose and MMP-9 in the wounds, and promotes wound healing effectively through the synergistic effect of temperature-sensitive shape-adaptive character and the dual-responsive system.

Online, low-volume meditation does not alter immune-related biomarkers.

Objectives: Prior studies of mindfulness meditation have demonstrated anti-inflammatory and immunoregulatory effects but whether meditation courses delivered online can exert similar effects is poorly understood. Barriers to large scale implementation of traditional mindfulness meditation programs has created an increased interest in the effect of less time- and resource-intensive online meditation courses. The purpose of this study was to determine whether a 6-week online mindfulness program with low time demands on nurses would lead to changes in gene expression, cytokine profiles, telomerase activity, and cortisol profiles. Methods: This was a randomized, parallel pilot study comparing an online mindfulness-based stress management program to an active control group from December 2018 to May 2019. Healthy nurses with above average levels of perceived stress were randomized to receive a 6-week online mindfulness-based stress management program including ≥5 min daily meditation practice or listen to relaxing music for ≥5 min daily as the control arm. Blood samples were collected at baseline and after 6 weeks, and various self-reported measures of stress, physical and emotional health were collected at baseline, after 6 weeks, and after 12 weeks. Whole transcriptome mRNA sequencing of whole blood at baseline and after 6 weeks was performed along with measurement of plasma IL-6, IL-8, IL-10, TNF-α, and IFN-γ. Peripheral blood mononuclear cells were isolated, and telomerase activity was measured. Diurnal salivary cortisol profiles were assessed at baseline and after 6 weeks. The primary outcome was change over time in a pre-determined set of 53 genes representative of the immune-related changes seen with stress, which was analyzed using a mixed linear model. Secondary outcomes included all other self-reported measures and biomarkers mentioned above. Results: A total of 61 nurses were randomized, with 52 having sufficient data to include in the final analysis. After 6 weeks, nurses in the control group reported significant reductions in stress as measured by the Perceived Stress Scale while those in the mindfulness group did not. However, after 12 weeks, the mindfulness group also showed a significant reduction in stress. When compared to the control group, no significant changes in RNA gene expression or any other biomarkers were observed in the nurses who participated in the mindfulness program. Conclusions: Our study found that this brief online mindfulness-based intervention was effective in reducing stress in nurses, albeit with a delayed effect compared to listening to relaxing music. Regarding immunoregulatory effects, there were no significant differences between treatment and control groups in transcriptomic or other tested biomarkers of immune function. This study provides evidence for a floor effect of mindfulness on transcriptional and circulating biomarkers of immune function.

Time course of changes in inflammatory and oxidative biomarkers in lung tissue of mice induced by exposure to electronic cigarette aerosol.

Significance: Electronic cigarettes (e-cigarettes) have become a popular way to smoke all over the world. Chronic exposure to e-cigarette aerosol may influence lung health. This study uses an animal model to explore the time course of the effect of exposure to e-cigarette aerosols on the lung. Methods: Lung samples were collected after exposure of Balb/c mice to e-cigarette aerosols for 1 h/day (6 times/week) for 1, 2 and 4 weeks and compared to sham-exposed controls. Examined biomarkers including inflammatory cells, tumor necrosis factor α (TNFα), interleukin-6 (IL-6), interleukin-10 (IL-10), reduced glutathione (GSH), oxidized glutathione (GSSG), glutathione peroxidase (GPx), catalase, superoxide dismutase (SOD), and Thiobarbituric acid reactive substances (TBARS). Results: Exposure of animals to e-cigarette aerosols induced significant increases (P < 0.05) in total inflammatory cells, eosinophils, macrophages and TNFα in the lung tissue after 1, 2 and 4 weeks of exposure. Furthermore, level of IL-10 significantly decreased, whereas levels of neutrophils and basophils significantly increased (P < 0.05) after 1 week of exposure. Exposure of animals to e-cigarette aerosol also induced significant decreases (P < 0.05) in the GSH/GSSG ratio, and GPx levels after 2 and 4 weeks of exposures. The activity of catalase was also reduced (P < 0.05) after 4 weeks of exposure. Level of TBARS showed a trend of elevation with time and it reached a significant elevation after 4 weeks (P < 0.01). Conclusion: Current results indicate that inhalation of unflavored e-cigarette aerosol might be associated with inflammation in lung tissue that worsen as the duration of exposure increases. Further experiments including more time points, histopathology and pulmonary physiology experiments are needed to confirm the current results.

Changes in Serum Interferon Gamma and Interleukin-10 in Relation to Direct-Acting Antiviral Therapy of Chronic Hepatitis C Genotype 4: A Pilot Study.

Introduction: This study analyzes the changing levels of circulating inflammatory cytokines Interferon gamma (IFN-γ) and interleukin (IL)-10 (as the main cytokines of T-helper-1 and T-helper-2 immune responses) in patients with chronic hepatitis C virus (HCV) infection undergoing therapy with direct-acting antivirals (DAAs) and to correlate them with laboratory markers. Methods: This Pilot study included 50 HCV monoinfected patients who received DAAs for 12 or 24 weeks. They were followed up monthly during therapy and 3 months after the end of the treatment. Liver disease was determined by transient elastography, in addition to FIB-4 indices. Analysis of IFN-gamma and IL-10 was carried out using an enzyme-linked immunosorbent assay. Results: All patients carried HCV genotype 4. The Sustained virological response was 100% and 92% in cirrhotics and noncirrhotics, respectively. There was no significant difference between groups in baseline IL-10 or IFN-gamma. In noncirrhotics, IL-10 showed a significant reduction at Week 4 after treatment start. In cirrhotics, IL-10 showed a significant reduction at Week 4 after treatment starts and a significant reduction at Week 12 after the end of the treatment. At Week 12 after the end of the treatment, serum IL-10 levels were significantly lower in cirrhotics. IFN-γ showed nonsignificant changes in noncirrhotics. A significant increase of IFN-γ occurred in cirrhotics from Week 4 after treatment starts to 12 weeks after the end of the treatment. IFN-γ was significantly higher in cirrhotics at Week 12 after the end of the treatment. IFN-γ and IL-10 showed different correlations with laboratory markers. Conclusion: Viral eradication induced by DAAs caused a significant change in IL-10 and IFN-gamma.

Within subject rise in serum TNFα to IL-10 ratio is associated with poorer attention, decision-making and working memory in jockeys.

Jockeys work in high-risk environments that rely heavily on attention- and decision-making to perform well and safely. Workplace stress literature has often overlooked the impact of stress on cognition, and designs that include physiological measures are rare. This study assessed the prospective concurrent relationships between workplace stress, depression symptoms and low-grade inflammation with cognitive performance among professional jockeys. Professional jockeys (N = 35, Mage = 32.29) provided information on workplace stress and depression symptoms, with serum levels of inflammatory cytokines (IL-6, IL-10, TNFα) and cytokine balance (IL-6: IL-10, TNFα: IL-10) quantified with SIMOA, and cognitive performance with CogSport computer-based testing battery. These measures were repeated after a twelve-month interval. Increased workplace stress between testing intervals was associated to an increased cytokine imbalance (ß = 0.447, p = .015) after controlling for age and gender. Increases in cytokine imbalance occurred in unison with decreases in attention (ß = 0.516, p = .002), decision-making (ß = 0.452, p = .009) and working memory (ß = 0.492, p = .004). These preliminary findings suggest the underlying mechanisms linking workplace stress and reduced cognitive performance may be influenced by measures of low-grade inflammation and specifically a cytokine imbalance. Our findings suggest a measure of cytokine balance may explain the heterogenous findings in previous studies that have focussed solely on the association of workplace stress with pro-inflammatory cytokines. Future work is needed however, to provide a broader evidence-base for our claims to better inform designs to intervene in the higher workplace stress-poorer cognition relationship.

Long-term orally exposure of dioxins affects antigen-specific antibody production in mice.

Dioxins are persistent environmental toxins that are still present in the food supply despite strong efforts to minimize exposure. Dioxins ingested by humans accumulate in fat and are excreted very slowly, so their long-term effects at low concentrations are a matter of concern. It is necessary to consider long-term, low-dose continuous administration under conditions that are as close as possible to a person's diet. In this study, we orally administered 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), the most common dioxin, at low doses in mice and observed the immunological effects. We found that antigen-specific (OVA) antibody production in the serum increased dose-dependently by TCDD concentrations below 500 ng/kg after long-term (10 weeks) exposure. Similar increases were seen in fecal and vaginal samples but were not significant. Th1 and Th2 lymphocyte responses, as determined by antibody and cytokine production, also significantly increased dose-dependently up to 500 ng/kg TCDD, and the Th1/Th2 balance was shifted toward Th1. These results indicate that low-dose, long-term TCDD exposure results in immunological abnormalities, perhaps by increasing antigen permeability. Different doses of dioxins may have opposing effects, being immunostimulatory at low doses (100 ng/kg/day) and immunosuppressive at high doses (500 ng/kg/day).

Histological changes of cervical tumours following Zanthoxylum acanthopodium DC treatment, and its impact on cytokine expression.

Cervical cancer is the second most lethal cancer in Indonesia, behind breast cancer. One of the reasons cancer cells are difficult to treat is that the immune system is sometimes unable to recognise them as foreign. Cytokinin therapy is carried out so that the immune system can strengthen its response to cancer cells, with the aim of slowing or stopping the development of malignant cells. Zanthoxylum acanthopodium DC, also known as andaliman, is an Indonesian herb and a member of the Rutaceae family. It is rich in antioxidants and has anti-inflammatory and anti-cancer properties. The current study aimed to investigate the histological changes and changes in the expression of cytokines, such as IL-10, IL1ß, VEGFR1, and TGFß1, associated with andaliman treatment. Sample tissues and serums extracted from cervical cancer rat models were used. Rats were divided into five groups: a control group (C-), cancer model group (C+), cancer with a dose of Z. acanthopodium methanolic extract (ZAM) 100 mg/body weight (BW) ZAM (ZAM100), cancer with a dose of ZAM 200 mg/BW ZAM (ZAM200), and cancer with a dose of ZAM 400 mg/BW ZAM (ZAM400). Treatment lasted for 1 month. Blood samples were prepared for ELISA analysis, and cervical tissue was stained for immunohistochemistry using antibodies against IL-10, IL-1ß, VEGFR1, and TGFß1. Administration of ZAM had no significant effect on rat body weight and cervical organs (p > 0.05). However, it impacted haematological parameters in rats with cervical cancer (p < 0.05). Elevated malondialdehyde levels may be linked to superoxide dismutase deficiency in tumour tissue. ZAM significantly decreased the expression of IL1ß, TGFß1, and VEGFR1 (p < 0.01), while it increased the expression of IL-10. Therefore, ZAM may be a potential target for molecular cytokine therapy for cervical cancer.

Navigating the cellular landscape in tissue: Recent advances in defining the pathogenesis of human disease.

Over the past decade, our understanding of human diseases has rapidly grown from the rise of single-cell spatial biology. While conventional tissue imaging has focused on visualizing morphological features, the development of multiplex tissue imaging from fluorescence-based methods to DNA- and mass cytometry-based methods has allowed visualization of over 60 markers on a single tissue section. The advancement of spatial biology with a single-cell resolution has enabled the visualization of cell-cell interactions and the tissue microenvironment, a crucial part to understanding the mechanisms underlying pathogenesis. Alongside the development of extensive marker panels which can distinguish distinct cell phenotypes, multiplex tissue imaging has facilitated the analysis of high dimensional data to identify novel biomarkers and therapeutic targets, while considering the spatial context of the cellular environment. This mini-review provides an overview of the recent advancements in multiplex imaging technologies and examines how these methods have been used in exploring pathogenesis and biomarker discovery in cancer, autoimmune and infectious diseases.