Alterations In Inflammatory Cytokines Research Articles

Correlation of White Matter Microstructure MRI and Inflammatory Cytokine Alterations With Symptom Severity in Premenstrual Syndrome.

Women with premenstrual syndrome (PMS) are at increased risk for depression throughout their lives. White matter (WM) microstructure and inflammatory cytokine alterations have been proposed in its etiology. To investigate whether WM, assessed using diffusion tensor imaging (DTI), and inflammatory cytokine levels are altered in PMS, and to examine the relationships between WM microstructure, inflammatory cytokines, and symptom severity. Prospective. Forty-two PMS patients and 58 healthy controls (HCs), categorized according to the daily record of severity of problems (DRSP). 3-T, echo planar imaging DTI. Fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) were measured by using tract-based spatial statistics (TBSS). Venous blood was collected to measure cytokines, including interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α). Symptoms were assessed by using the DRSP. Two-sample t test or Mann-Whitney U test were used to compare the DRSP and cytokines. Abnormal DTI metrics in WM were extracted and the differences between groups were analyzed by using two sample t-tests. Spearman's correlation (r) was used to assess the relationship between DTI metrics, cytokines, and DRSP. A P-value <0.05 with FDR correction was considered statistically significant. Compared with HCs, PMS patients showed significantly lower FA in the corpus callosum and corona radiata, and significantly higher MD, AD, and RD in the corticospinal tract (CST), and significantly higher MD and RD in the anterior thalamic radiation (ATR). These differential metrics were significantly correlated with DRSP. Patients showed significantly higher IL-1β and TNF-α than HCs. Moreover, TNF-α correlated positively with MD, AD, and RD in both groups (r range, 0.256-0.315). Alterations of WM microstructure and IL-1β and TNF-α may be associated with PMS symptom severity, and TNF-α may correlate with DTI metrics of CST and ATR pathways. 1 TECHNICAL EFFICACY: Stage 2.

High-fat diet elicits sex-based differences in liver inflammatory cytokines and redox homeostasis.

Sex differences in metabolic dysfunction-associated steatotic liver disease (MASLD) have been reported. Oxidative stress and inflammation are involved in the progression of MASLD. Thus, we aimed to evaluate liver redox homeostasis and inflammation in male and female rats fed a high-fat diet (HFD). Male and female Wistar rats were divided into the following groups: standard chow diet (SCD) or HFD during 12 weeks. HFD groups of both sexes had higher hepatocyte injury, with no differences between the sexes. Portal space liver inflammation was higher in females-HFD compared to females-SCD, whereas no differences were observed in males. Lobular inflammation and overall liver inflammation were higher in HFD groups, regardless of sex. TNF-α, IL-6, and IL-1β levels were higher in males-HFD compared to males-SCD, but no differences were observed in females. Catalase activity was higher in males compared to females, with no differences between the SCD and HFD groups of both sexes. Glutathione peroxidase activity was higher in females compared to males, with no differences between the SCD and HFD groups in both sexes. Lipid peroxidation was higher in female-SCD when compared to male-SCD, and in both male- and female-HFD compared to SCD groups. Furthermore, both cytoplasmic and nuclear NRF2 staining were lower in the HFD group compared to the SCD group in males. However, female-HFD exhibited reduced nuclear NRF2 staining compared to the female-SCD group. In conclusion, our study demonstrated that while both male and female rats developed metabolic dysfunction-associated steatohepatitis after 12 weeks of HFD, the alterations in inflammatory cytokines and redox balance were sexually dimorphic.

Investigating the synergistic effects of amitriptyline and H. pylori eradication on depressive-like behaviors and inflammatory cytokines in mice

BackgroundRecent research has highlighted the potential role of Helicobacter pylori in the pathogenesis of psychiatric disorders. This study aimed to evaluate the potential synergistic effects of an antidepressant drug and H. pylori eradication therapy in a mouse model. MethodsMale C57BL/6 mice were divided into four groups: control, H. pylori infection, antidepressant treatment, and combined treatment. H. pylori infection was induced by oral gavage with a clinically relevant strain, and the antidepressant drug was administered via intraperitoneal injections. Behavioral tests including the forced swim test, sucrose preference test, and open field test were conducted to assess depressive-like behaviors and locomotor activity. ResultsThe study demonstrated that H. pylori infection induced depressive-like behaviors in mice, as evidenced by increased immobility time in the forced swim test and reduced sucrose preference. Antidepressant treatment alone partially ameliorated these behavioral changes. Strikingly, the combined treatment of the antidepressant drug and H. pylori eradication therapy led to a significantly greater reduction in depressive-like behaviors compared to either treatment alone. Furthermore, the combined treatment group exhibited increased locomotor activity in the open field test, suggesting a potential improvement in overall psychomotor functioning. ELISA assays revealed alterations in inflammatory cytokines in the H. pylori-infected mice, which were partially attenuated by the combined treatment. ConclusionThe study provides novel evidence for the potential synergistic effects of an antidepressant drug and H. pylori eradication therapy in alleviating depressive-like behaviors in a mouse model.

Comparative immunohistochemical analysis of inflammatory cytokines in distinct subtypes of Sweet syndrome.

A dysregulated immune response has been implicated in Sweet syndrome (SS) pathogenesis; however, cytokine profiles across different conditions associated with SS - including adult-onset immunodeficiency (AOID) due to anti-interferon (IFN)-γ autoantibodies - remain unknown. To investigate alterations in inflammatory cytokines in skin lesions of distinct subtypes of SS. Skin biopsies were collected from 42 AOID- and 52 non-AOID-associated SS patients and 18 healthy controls. The comparative immunohistochemical study was conducted using monoclonal antibodies against interleukin (IL)-1β, IL-6, IL-17, IFN-γ, and tumor necrosis factor-α on paraffin-embedded sections. The quantitative percentage positivity and intensity were calculated using computer-based image analysis. The results showed stronger and more diffuse dermal immunoreactivity for IFN-γ and IL-17 in the AOID-associated (p < 0.001 and p < 0.001, respectively) and non-AOID-associated SS (p < 0.001 and p < 0.001, respectively) groups. However, no significant differences in the levels of these two cytokines were observed between the AOID- and non-AOID-associated SS groups. Increased expression of IFN-γ together with IL-17 was also noted in almost all subtypes among non-AOID-associated SS. These results demonstrate that IFN-γ and IL-17 are implicated in immunopathology of all SS subtypes, including AOID-associated SS, despite the presence of anti-IFN-γ autoantibodies.

Peripheral Blood Mononuclear Cells from Patients with Type 1 Diabetes and Diabetic Retinopathy Produce Higher Levels of IL-17A, IL-10 and IL-6 and Lower Levels of IFN-γ-A Pilot Study.

Inflammation is key to the pathogenesis of diabetic retinopathy (DR). This prospective study investigated alterations in inflammatory cytokines in peripheral blood mononuclear cells (PBMCs) in 41 people with type 1 diabetes (T1D), sub-grouped into mild non-proliferative DR (mNPDR; n = 13) and active and inactive (each n = 14) PDR. Age/gender-matched healthy controls (n = 13) were included. PBMCs were isolated from blood samples. Intracellular cytokine expression by PBMCs after 16-h stimulation (either E. coli lipopolysaccharide (LPS), phorbol 12-myristate 13-acetate plus ionomycin, D-glucose or D-mannitol) were assessed by flow cytometry. Cytokine production in plasma, non-stimulated and LPS-stimulated PBMC supernatant was also assessed. Increased BMC IL-10 secretion and reduced expression of IL-6 and IFN-γ in CD3+ cells were observed in mNPDR. Reduced IL-6 and IL-10 secretion, and higher levels of intracellular IL-6 expression, especially in CD11b+ PBMCs, was detected in aPDR; levels were positively correlated with DR duration. Patients with T1D demonstrated increased intracellular expression of IL-17A in myeloid cells and reduced IFN-γ expression in CD3+ cells. Plasma levels of IL-1R1 were increased in mNPDR compared with controls. Results suggest that elevated PBMC-released IL-10, IL-6, in particular myeloid-produced IL-17A, may be involved in early stages of DR. IL-6-producing myeloid cells may play a role in PDR development.

Alterations in Inflammatory Cytokines and Redox Homeostasis in LPS-Induced Pancreatic Beta-Cell Toxicity and Mitochondrial Stress: Protection by Azadirachtin

Inflammation and redox imbalance are hallmarks of cancer, diabetes, and other degenerative disorders. Pathophysiological response to these disorders leads to oxidative stress and mitochondrial dysfunction by alterations and reprogramming in cellular signaling and metabolism. Pancreatic beta cells are very sensitive to the inflammatory and altered nutrient signals and hence play a crucial role in diabetes and cancer. In this study, we treated insulin-secreting pancreatic beta cells, Rin-5F, with the bacterial endotoxin, LPS (1 μg/ml) to induce an inflammatory response in vitro and then treated the cells with a known anti-inflammatory, anticancer and antioxidant phytochemical, azadirachtin (AZD, 25 µM for 24 h). Our results demonstrated lipid peroxidation and nitric oxide production causing increased nitro/oxidative stress and alterations in the activities of anti-oxidant enzymes, superoxide dismutase and catalase after LPS treatment. Pro-inflammatory responses caused by translocation of nuclear factor kappa B and release of inflammatory cytokines were also observed. These changes were accompanied by GSH-dependent redox imbalance and alterations in mitochondrial membrane potential and respiratory complexes enzyme activities leading to mitochondrial respiratory dysfunction, reduced ATP synthesis, and intrinsic caspase-9 mediated apoptosis. Caspase-9 was activated due to alterations in Bcl-2 and Bax proteins and release of cytochrome c into the cytosol. The activities of oxidative stress-sensitive mitochondrial matrix enzymes, aconitase, and glutamate dehydrogenase were also inhibited. Treatment with AZD showed beneficial effects on the recovery of antioxidant enzymes, inflammatory responses, and mitochondrial functions. GSH-dependent redox homeostasis also recovered after the treatment with AZD. This study may help in better understanding the etiology and pathogenesis of inflammation-induced disorders in pancreatic beta cells to better manage therapeutic strategies.

IL-17 gene polymorphism (rs763780) in kidney recipients with post-transplant diabetes

Introduction: New-onset diabetes mellitus after transplantation (NODAT) is a common complication of organ transplantation, leading to allograft dysfunction. Genetic alterations of inflammatory cytokines have been reported to be associated with glucose homeostasis and diabetes. Objectives: This study evaluated the rs763780 polymorphism of IL-17F gene in transplant recipients with and without NODAT. Patients and Methods: The present retrospective study was conducted on ninety-one patients who have had a kidney transplant for at least three months. Patients were divided into two subgroups; recipients with NODAT (n=32) and kidney recipients without NODAT (n=59). After DNA extraction from patients’ blood samples, amplification and evaluation of specific polymorphism of the gene were performed using amplification refractory mutation system-polymerase chain reaction (ARMS-PCR). Clinical and demographic data of patients were collected. Results: The NODAT was detected in 81.3% (n=26) of TT genotype carriers, 12.5% of TC genotype carriers and 6.3% of CC genotype carriers. No statistically significant differences between the studied groups in the frequency of C and T alleles and the distribution of the abovementioned genotypes were detected (P≥0.721). In the NODAT group, graft rejection and age of patients were higher significantly (P≤0.017). Conclusion: No significant correlation between the incidence of diabetes and rs763780 polymorphism of IL-17F gene was observed.

P38α deficiency in macrophages ameliorates murine experimental colitis by regulating inflammation and immune process

IntroductionP38α is a mitogen-activated protein kinase (MAPK) that mediates inflammatory responses. P38α alterations have been associated with the inflammation-related diseases. However, the role of macrophages-derived p38α in dextran sulfate sodium (DSS)-induced murine experimental colitis remains unclear. ObjectivesWe characterized the role of macrophages-derived p38α in DSS-induced colitis. MethodsThe expression of macrophage-derived p38α in human colitis and normal tissues was measured by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) analysis. Macrophage-specific p38α knockout (p38αΔMφ) and wild type (WT) mice administrated by 3% DSS were used to establish experimental colitis. The alterations in inflammatory cytokines, intestinal epithelial barrier, cell proliferation and cell apoptosis between p38αΔMφ and WT groups were determined by IHC, immunofluorescence (IF), TdT-mediated dUTP Nick-End Labeling (TUNEL) and Western blot analyses. The enriched pathways between p38αΔMφ and WT groups were identified by RNA-seq and KEGG analysis. SB203580 and BIRB796 as the p38 MAPK inhibitors were used to treat DSS-induced colitis. Resultsp38α was co-localized with CD68 in the cytoplasm and their co-expression indicated an increased level in colitis tissues as compared with the normal tissues. P38α deficiency in macrophages was sufficient to suppress the exacerbated clinical symptoms and inflammation responses in experimental colitis, followed by reducing cytokine release, increasing MUC-2 and Claudin-2 secretion and promoting colonic mucosa repair. Further investigations validated that the immune process-related factors such as Lgals9, Rtp4, Ddx60, Nlrp1b, Hsh2d, Oas2 and Oas3 were upregulated in colon tissues from p38αΔMφ group as compared with the WT group. Inhibition of p38 MAPK attenuated DSS-induced colitis. ConclusionOur findings demonstrated that p38α deficiency in macrophages ameliorated murine experimental colitis by regulating inflammation and immune process.

Alterations of inflammatory cytokines in super-acute stroke patients and the potential pathogenesis

BackgroundSufficient understanding of the systemic inflammatory response after stroke will make the therapeutic strategy targeting inflammation more feasible. Here, we aimed to identify the globally alterations of circulating cytokines in super-acute ischemic stroke (AIS). MethodsA broad panel of 65 cytokines was measured in the plasma of twenty-eight AIS patients within 6 h after stroke onset (n = 28), cerebral hemorrhagic patients (n = 28) and healthy controls (n = 18). The diagnostic power of the candidate cytokines and their relationship with the number of lymphocytes and neutrophils were analyzed by receiver operating characteristic (ROC) and spearman rank correlation respectively. ResultsThe expression level of plasma IL-1beta, IL-2, IL-2R, IL-5, IL-10, CD40L, HGF, MIP-3alpha and MMP-1 were obviously up-regulated, while IL-16 was down-regulated in AIS patients compared to healthy controls. Among them, IL-2R, IL-10, IL-16, MIP-3alpha, and MMP-1 were specially altered in AIS patients, while IL-1beta, IL-2, IL-5, CD40L and HGF were elevated simultaneously in AIS and hemorrhagic stroke patients. Interestingly, IL-6 and TNF-beta were found to be key facytors among the 65 cytokines to distinguish hemorrhage from ischemia. Furthermore, IL-1beta, IL-16, CD40L and HGF were obviously correlated with the number of lymphocytes, and IL-1beta and IL-16 were significantly associated with the number of neutrophils in AIS patients. These results suggest that lymphocytes and neutrophils associated inflammation may play a pivotal role in AIS. ConclusionsImportantly, except for some mutual pathological processes, AIS and hemorrhage had their own distinctive pathogenesis, and transformation of this knowledge to further research may provide novel treatment strategy for AIS.

Predictive Role of IL-2R and IL-10 in the Anti-inflammatory Response and Antiplatelet Therapy of Kawasaki Disease: A Retrospective Study.

To date, Kawasaki disease (KD) has only been able to be diagnosed and evaluated using clinical characteristics. Additionally, the therapeutic effect and cardiovascular complications could not be verified until its occurrence. The present retrospective study analyzed the dynamic alterations of inflammatory cytokines, platelet (PLT) count, and subgroups of lymphocytes, such as cluster of differentiation (CD) 8+ T cells and CD19+ B cells, under different conditions in 64 children with KD. The percentage distribution of lymphocyte subgroups and the altered neutrophil lymphocyte ratio demonstrated that the inflammatory response was dominated by the B cell-mediated humoral immune response before intravenous immunoglobulin (IVIG) treatment, but mainly by T cells via cellular cytotoxic effects after IVIG treatment. Among the different types of inflammatory cytokines, the results of the present study revealed that the altered levels of interleukin-2 receptor (IL-2R) and interleukin-10 (IL-10) were closely associated with the percentage of CD8+ T cells and CD19+ B cells. Additionally, the two cytokines exhibited more sensitive fluctuations based on the status of the children with KD in various circumstances compared with other indexes, such as the percentages of CD8+ T cells and CD19+ B cells or the PLT count. These results suggested that children with KD who are ≥4 years old may benefit from IVIG but will not benefit from decreased platelet activation or suffer less cardiovascular complications. Additionally, starting clopidogrel usage earlier as an antiplatelet strategy should be considered based on the observed continuous rise in the PLT count in children with KD receiving IVIG. In conclusion, dynamically monitoring the levels of IL-2R and IL-10 has the potential to provide indications of the intensity and development of the inflammatory response in children with KD and may contribute to the early prediction and adjustment of pathological and pharmacological effects of therapy.

Abstract PO-104: Activation of WNT signaling in CD4+ T cells promotes immune suppression in pancreatic cancer

Abstract WNT ligand expression and activation of the WNT signaling have been associated with pancreatic ductal adenocarcinoma (PDA). Using a mouse model that recapitulates the stepwise progression of PDA, we previously showed that epithelial WNT signaling is required for PDA initiation and progression. Through single cell RNA sequencing, we discovered that, in addition to epithelial cells, infiltrating immune cells and in particular T cells express the WNT signaling machinery, including receptors, downstream effectors and target genes. In particular, T cells express high levels of Tcf7, encoding the transcription factor TCF1. TCF1 is important for T cell development, but its role in adult T cells and specifically in the setting of pancreatic cancer remained unknown. To address this, we generated mice that allow deletion of Tcf7 specifically in CD4+ T cells in an inducible manner. We then implanted orthotopic syngeneic tumors in control mice or in mice lacking Tcf7 in CD4+ T cells, and observed reduced tumor growth in the latter. Analysis of the tumors revealed an increase in apoptotic cells; while the prevalence of infiltrating T cells did not change, we observed an increase in cytotoxic marker expression, such as Granzyme B, consistent with increased T cell activation. We observed decreased regulatory T cells, possibly indicating less immune suppression. However, we also observed a compensatory infiltration of increased granulocytic myeloid derived suppressor cells. Deletion of Tcf7 in CD4+ T cells also re-polarized the immunosuppressive macrophages into pro-inflammatory macrophages, and alterations of inflammatory cytokines secreted by cancer associated fibroblasts. Taken together, this study reveals an important role of WNT signaling in CD4+ T cells in the PDA microenvironment. We are currently evaluating ways to exploit changes in the immune microenvironment upon inactivation of Tcf7 in CD4+ T cells in combination therapy approaches. Citation Format: Wenting Du, Rosa E. Menjivar, Katelyn Donahue, Ashley Velez-Delgado, Marina Pasca di Magliano. Activation of WNT signaling in CD4+ T cells promotes immune suppression in pancreatic cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-104.

Inflammatory cytokine alterations in women veterans from pregnancy to postpartum: Exploratory analyses with depression

Inflammatory cytokine alterations in women veterans from pregnancy to postpartum: Exploratory analyses with depression

Irisin attenuates inflammation in a mouse model of ulcerative colitis by altering the intestinal microbiota.

Evidence has demonstrated that the gut microbiota, which consists of probiotics and pathogenic microorganisms, is involved in the initiation of ulcerative colitis (UC) via the dysregulation of intestinal microflora and normal immune interactions, which ultimately leads to intestinal mucosal dysfunction. Irisin is released from muscle cells and displays anti-inflammatory effects; however, the mechanisms underlying irisin-mediated anti-inflammatory effects in UC have not been previously reported. In the present study, mice were divided into the following four groups: i) Control; ii) irisin; iii) dextran sulfate sodium (DSS) salt; and iv) DSS + irisin. Subsequently, the effects of irisin were investigated by observing alterations in intestinal microbes. Irisin significantly reduced the degree of inflammation in UC by reversing alterations to the macroscopic score, histological score, number of CD64+ cells and inflammatory cytokine alterations (P<0.05). Analysis of the microbial diversity in the stools of mice with active UC indicated that the five bacteria that displayed the greatest alterations in relative abundance were Alloprevotella, Bacteroides, Lachnospiraceae-UCG-001, Prebotellaceae-UCG-001 and Rikenellaceae-RCB-gut-group. Furthermore, Bactoroides were positively correlated with the histopathological score (P=0.001; R=0.977) and interleukin (IL)-23 levels (P=0.008; R=0.924). Alloprevotella (P=0.001; R=-0.943), Lachnospiraceae-UCG-001 (P=0.000; R=-0.973) and Rikenollaceae-RC8-gut-group (P=0.001; R=-0.971) were negatively correlated with the histopathological score. Furthermore, Lachnospiraceae-UCG-001 (P=0.01; R=-0.873) and Rikenollaceae-RC8-gut-group (P=0.049; R=-0.814) were negatively correlated with IL-23 levels. In summary, the results of the present study suggested that irisin improved inflammation in a UC mouse model potentially via altering the gut microbiota.

Evaluation of the expression of red blood cell CD36, interleukin-6 and interleukin-8 in sickle cell anemia pediatric patients

Sickle cell anemia (SCA) is a complex multisystem disease characterized by acute and chronic inflammation, with alterations in inflammatory cytokines and adhesion molecules.This case-control study was carried out to assess the levels of CD36, immature reticulocytes, interleukin (IL)-6 and IL8 in SCA patients (in crisis and the steady state) and healthy controls. It included 90 children who were 2–18 years old; 60 with SCA and 30 healthy controls. Complete blood count, total reticulocyte count, reticulocyte subpopulations, immature reticulocyte fraction (IRF), percentage of CD36-positive red blood cells (RBCs), IL-6 and IL-8 levels were evaluated.The total white blood cell (WBC) and neutrophil counts, CD36-positive RBCs percentage, IRF, IL-6 and IL-8 levels were significantly higher in crises than in the steady state (P < 0.05). We also found that patients with SCA had significantly higher reticulocyte, WBC and neutrophil counts, fetal hemoglobin, CD36-positive RBCs percentage, IRF, and IL-6 and IL-8 levels than healthy children (P < 0.05). A significant positive linear correlation was reported between IL-6 and neutrophils during crises (Spearman correlation coefficient = 0.397, P = 0.03). These findings suggest that the levels of adhesion molecules and inflammatory markers and IRF, as evidenced by CD36-positive RBCs, IL-6 and IL-8, are elevated in SCA patients, both during steady state and crises, although these elevations are more marked during crises. Further knowledge about these cytokines and adhesion molecules will help in understanding the pathogenesis and improve therapy of SCA.

Sleep disturbance induces depressive behaviors and neuroinflammation by altering the circadian oscillations of clock genes in rats

Sleep loss leads to a spectrum of mood disorders such as anxiety disorders, bipolar disorder and depression in many individuals. However, the underlying mechanisms are largely unknown. In this study, sleep-disturbed animals were tested for anxiety and depressive behaviors. We then studied the effects of SD on hypothalamic-pituitary-adrenal (HPA) axis function by measuring serum and CSF levels of corticosterone (CORT), and at the end of the experiment, brains were collected to measure the circadian oscillations of clock genes expression in the hypothalamus, glial cell activation and inflammatory cytokine alterations. Our results indicated that SD for 3 days resulted in anxiety- and depressive-like behaviors. SD exaggerated cortisol response to HPA axis, significantly altered the circadian oscillations of clock genes, decreased the expression of tight junction protein ZO-1 and Claudin 5 and increased the number of GFAP-positive cells and Iba-1-positive cells and caused subsequent elevation of pro-inflammatory cytokines IL-6, IL-1β and TNFα. These findings demonstrated that SD for 3 days induced anxiety- and depression-like behaviors in rats in company with altering the circadian oscillations of clock genes and inducing neuroinflammation, indicating the underlying mechanism of sleep loss induced neuronal dysfunction.

Social isolation induces hyperactivity and exploration in aged female mice.

Prolonged social isolation is associated with poor physical and mental health outcomes, findings observed in both humans, and rodent models of isolation. Humans, like mice, may engage in enhanced exploratory and social behaviour following isolation, which may protect against subsequent cognitive decline and psychological distress. Understanding how these effects may impact behaviour in older adults is particularly relevant, as this population is likely to experience periods of late-life social isolation. We report that late-life social isolation in female mice did not lead to robust depressive-like symptomology, altered social interaction behaviour, sensitivity to context fear acquisition and memory, or alterations in inflammatory cytokines (IL-6, IL-1β, Tnf-α) or microglial activation (Itgam) within the hippocampus. Rather, isolation increased hyperactivity and exploration behaviours. These findings have translational value as the first female mouse model of late-life social isolation, and provide evidence to inform the development of interventions aimed at promoting functional recovery following isolation in late-life.

Neuropeptide Substance P Enhances Inflammation-Mediated Tumor Signaling Pathways and Migration and Proliferation of Head and Neck Cancers.

Head and neck cancers (HNC) are extremely aggressive, highly recurrent, and the sixth most common cancer worldwide. Neuropeptide substance P, along with its primary receptor, neurokinin-1 (NK-1R), is overexpressed in HNC and is a central player in inflammation and growth and metastasis of several cancers. However, the precise SP-mediated signaling that promotes HNC progression remains ill defined. Using a panel of HNC lines, in this study, we investigated the effects of SP on proliferation and migration of HNC. Tumor cells were also treated with SP and alterations in inflammatory cytokines and chemokines, and their cognate receptors were analyzed by real-time PCR. Furthermore, we investigated the role of SP in inducing epithelial-mesenchymal transition (EMT), and matrix metalloproteases that promote tumor invasion. Our results showed that SP significantly increased tumor cell proliferation and migration and induced the expression of several genes that promote tumor growth, invasion, and metastasis which was suppressed by a specific NK1R antagonist L-703606. SP also activated NFκB that was suppressed on inhibiting NK1R. Collectively, our data shows that SP-NK1R-mediated inflammatory signaling comprises an important signaling axis in promoting HNC and may prove to be effective clinical target against HNC cells that are resistant to traditional therapy.

Smoke exposure from chronic biomass burning induces distinct accumulative systemic inflammatory cytokine alterations compared to tobacco smoking in healthy women

Long-term exposure to biomass-burning smoke (BS) is associated with chronic obstructive pulmonary disease (COPD), asthma, and other chronic inflammatory lung diseases. BS results from such processes as the burning of wood for indoor cooking and heating, with women and children having the highest exposure rate. This study aimed to analyze the accumulative alterations in cytokine levels associated with BS (from wood) compared to tobacco smoke (TS) in healthy adult women. The levels of 27 cytokines were analyzed in the serum of 100 women, including 40 tobacco smokers/non-exposed to BS (TS+/BS-), 30 never-smokers/exposed to BS (TS-/BS+) and 30 never-smokers/non-exposed to BS (TS-/BS-) as controls, using 27-Plex immunoassay. The chronic BS exposure index was rated at ≥100 h-years, and the tobacco-smoking index was ≥10 pack-years. Compared to TS-/BS-, TS+/BS- had higher levels of IL-2, IL-9, MCP-1, MIP-1β, and VEGF, while TS-/BS+ showed higher levels of IL-1ra, IL-6, IL-8, Eotaxin, IP-10, RANTES, and VEGF, presenting a distinct inflammatory profile that may favor an eosinophil-derived inflammatory response to BS exposure. Compared to TS+/BS-, TS-/BS+ expressed higher levels of IP-10 and IL-8, but lower levels of IL-2 and MIP-1β. Gene–disease database analysis showed that altered cytokines in both TS+/BS- and TS-/BS+ are associated with asthma, COPD, lung fibrosis, and lung cancer. In conclusion, chronic BS exposure induces distinct systemic inflammatory cytokine alterations compared to tobacco smokers in healthy women. These findings provide new insights into how long-term exposure to BS affects the inflammatory response—and potentially the health—of adult women.

95 N-Acetyl cysteine as a potential treatment for equine persistent breeding-induced endometritis

Persistent breeding-induced endometritis (PBIE) is a major cause of infertility in mares. Transient uterine inflammation is a normal response to breeding; however, PBIE-susceptible mares do not clear this inflammation in a timely fashion. Uterine inflammation at the time of embryonic descent from the oviducts ultimately results in early embryonic death and is seen clinically as infertility. Several risk factors for PBIE have been identified and include age, parity, anatomical conformation, such as poor perineal conformation and cervical fibrosis, as well as other reproductive tract abnormalities. N-Acetyl cysteine (NAC), a mucolytic used to treat endometritis in mares, has anti-inflammatory properties, affects inflammatory cytokines, and is a mild inhibitor of nitric oxide synthase. Increased nitric oxide, causing smooth muscle relaxation and alterations in inflammatory cytokines, has been documented in PBIE mares. The objective of our study was to determine if NAC treatment would lower nitric oxide and inflammatory cytokine levels, thereby resolving PBIE. A randomised, blinded, crossover design clinical trial was performed utilising PBIE-susceptible mares (n=10). Mares were screened for bacterial endometritis before enrolment in the study and only mares that had negative bacterial cultures were used. No other treatments were given to mares while they were enrolled in the study. Intrauterine infusion of 180mL of 3.3% NAC was performed 12h before insemination, when a follicle &amp;gt;35mm was present. Mares were sampled for endometrial cytology and endometrial fluid to determine inflammatory cytokine (ELISA) and nitric oxide (colourimetric assay) levels at 12 and 72h post-insemination. Endometrial biopsies were taken at the same time points post-insemination to determine gene expression of inflammatory cytokines by qPCR. Clinical signs of endometrial oedema and intrauterine fluid volumes were assessed at 12 and then every 24h post-breeding. Statistical assessment of the data was performed using a repeated-measures ANOVA. Uterine inflammation, as determined by percent number of neutrophils on endometrial cytology (P=0.0006), and interleukin 6 gene expression (P=0.003) were highest at 12h. Uterine oedema was greatest at 12 and 24h (P=0.02) and uterine fluid volumes were highest at 24h (P=0.02). Interestingly, interleukin-6 protein levels were not in accordance with gene expression, and were highest at 72h. In this clinical trial, pre-breeding intrauterine treatment with NAC did not affect nitric oxide levels, cytokine gene expression, or clinical signs of PBIE. However, the pattern of inflammation noted in this study is consistent with that described in PBIE mares. Nevertheless, the assessment of inflammatory cytokines, both at the gene and protein level at different time points post-AI, in combination with clinical signs will add to the understanding of the alterations in inflammatory cytokine levels in mares susceptible to PBIE.

Associations of plasma interleukin-6 with plasma and cerebrospinal fluid monoamine biosynthetic pathway metabolites in treatment-resistant depression

BackgroundCurrent research suggests that depression is associated with several changes in the immune system, including alterations in inflammatory cytokines, the hypothalamic-pituitary-adrenal axis, and downstream effects on neurotransmitters. Specifically, plasma interleukin-6 (IL-6) is elevated in depressed individuals compared to non-depressed controls, and these same inflammatory processes may be implicated in treatment resistant depression (TR-MDD). IL-6 has also been theorized to affect central monoamine pathway metabolites. Few studies have assessed the relationship of IL-6 and plasma/CSF monoamine biosynthetic pathway metabolites and symptomatic correlates of depression. MethodsWe analyzed plasma IL-6 levels in an outpatient treatment-resistant depressed cohort (n = 67) and healthy control cohort (n = 40). We also assessed relationship of plasma IL-6 with plasma/CSF monoamine pathway metabolites and symptomatic correlates of depression. ResultsHigher levels of plasma IL-6 were found in the TR-MDD cohort compared to the control cohort. Plasma IL-6 correlated with plasma serotonin levels among all participants, although there was no association of plasma IL-6 and plasma serotonin in the TR-MDD cohort on subgroup analysis. No correlations were found between plasma IL-6 and plasma/CSF monoamine breakdown products, depressive symptomatology, or suicidality. LimitationsOur analysis was a post-hoc analysis and we were not able to exhaustively control for confounds of IL-6 levels, such as sleep or stress. ConclusionThe findings of the current study extend current evidence that plasma IL-6 levels are elevated in TR-MDD, after adjusting for body mass index. Additionally, plasma IL-6 and serotonin regulation may vary between healthy and TR-MDD populations. Lastly, our study finds no association between plasma IL-6 and CSF monoamine pathway metabolites, suggesting that further research is needed to elucidate the association of IL-6 and depression.