Decreased Serum Interleukin-6 Research Articles

Parathyroidectomy Reduces Inflammatory Cytokines and Increases Vitamin D Metabolites in Patients With Primary Hyperparathyroidism

ContextPrimary hyperparathyroidism (PHPT) is accompanied by a decreased 25-hydroxyvitamin D (25OHD) and vitamin D binding protein (DBP). High parathyroid hormone (PTH) is associated with elevated interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1), yet the effect of parathyroidectomy (PTX) on DBP and cytokines is not clear. ObjectiveTo prospectively evaluate the effect of PTX on inflammatory profiles, total and free 25OHD, and DBP in patients with PHPT. MethodsNewly diagnosed patients with PHPT were recruited for the study (n = 70). Twenty-eight patients returned after PTX, 3 months later. Biochemical markers were measured before and after PTX. A group of age and body mass index-matched healthy subjects were included as controls (n = 70). ResultsBefore PTX, patients had lower serum DBP (37.5 ± 6.0 vs 41.5 ± 6.1 mg/dL, P < .001) and total 25OHD (30.1 ± 9.5 vs 33.3 ± 7.9 ng/mL, P < .05) but similar free 25OHD when compared to controls. Serum IL-6, C-reactive protein, and MCP-1 were higher in patients with PHPT (P < .05), whereas interleukin-10 was similar to that in controls. PTX increased total and free 25OHD and DBP (P < .001) and decreased serum IL-6 and MCP-1 (P < .05), but not C-reactive protein and interleukin-10. Multiple regression analysis indicated that the preoperative PTH explained a significant portion of the variance of IL-6 and MCP-1 (P < .05). ConclusionThese findings suggest that PTH may upregulate the production of MCP-1 and IL-6 and downregulate circulating DBP in patients with PHPT that are normalized by PTX. The exact mechanism of IL-6 and MCP-1 on DBP, vitamin D metabolites, and clinical outcomes in patients with PHPT is an area requiring further study.

Lipocalin-2 as a fundamental protein in type 2 diabetes and periodontitis in mice.

Lipocalin-2 (LCN-2) is an osteokine that suppresses appetite, stimulates insulin secretion, regulates bone remodeling, and is induced by proinflammatory cytokines. The aim of this work was to investigate the participation of LCN-2 in periodontitis associated with type 2 diabetes (T2D) by evaluating alveolar bone loss, glycemic control, inflammation, and femur fragility. A murine model of periodontitis with T2D and elevated LCN-2 concentration was used. Functional LCN-2 inhibition was achieved using an anti-LCN-2 polyclonal antibody, and isotype immunoglobulin G was used as a control. The alveolar bone and femur were evaluated by micro-CT. Glucose metabolism was determined. Tumor necrosis factor (TNF-α) and receptor activator of nuclear factor kappa-B ligand (RANKL) levels in alveolar bone lysates were quantified using ELISA, and serum cytokines were quantified using flow cytometry. A three-point bending test was performed in the femur, and RANKL levels were measured in femur lysates using ELISA. Functional inhibition of LCN-2 in T2D-periodontitis mice decreased alveolar bone loss in buccal and palatal surfaces and preserved the microarchitecture of the remaining bone, decreased TNF-α and RANKL in alveolar bone, reduced hyperglycemia, glucose intolerance, and insulin resistance, and increased insulin production through improving the functionality of pancreatic β cells. Furthermore, this inhibition increased serum free-glycerol levels, decreased serum interleukin (IL)-6, increased serum IL-4, and reduced femur fragility and RANKL expression in the femur. LCN-2 participates in periodontitis associated with T2D. Inhibiting its function in mice with T2D and periodontitis improves pancreatic β-cell function, and glucose metabolism and decreases inflammatory cytokines and bone-RANKL levels, which results in the preservation of femoral and alveolar bone microarchitecture. In this study, we explored the role of a bone protein known as lipocalin-2 (LCN-2) in the connection between periodontitis and type 2 diabetes (T2D). Periodontitis is a destructive gum and alveolar bone disease. LCN-2 levels are increased in both T2D and periodontitis. Using a mouse model of T2D with periodontitis, we examined how blocking LCN-2 function affected various aspects of these two diseases. We found that this inhibition led to significant improvements. First, it reduced alveolar bone loss and preserved bone structure by decreasing local inflammation and bone resorption. Second, it improved glucose and lipid metabolism, leading to better blood-sugar control and decreased insulin resistance. Blocking the functions of LCN-2 also decreased systemic inflammation throughout the body and strengthened bone integrity. Overall, our results suggest that LCN-2 plays a crucial role in the periodontitis associated with T2D. By inhibiting LCN-2 function, we were able to improve pancreatic function, improve glucose metabolism, reduce inflammation, and enhance bone health. Targeting LCN-2 could be a promising strategy for the harmful effects of T2D and periodontitis.

The analysis of low-dose glucocorticoid maintenance therapy in patients with primary nephrotic syndrome suffering from COVID-19.

Objectives: This study aimed to describe the effects of low-dose (prednisolone acetate 2.5-7.5mg/day) glucocorticoids (GCs) maintenance therapy in patients with primary nephrotic syndrome (NS) suffering from coronavirus disease 2019 (COVID-19). Methods: A single-center retrospective study of NS patients with COVID-19 infection in Zhongda Hospital Affiliated to Southeast University from 1 February 2022 to 31 March 2023 was conducted. All enrolled patients underwent renal biopsy for the pathological diagnosis and reached complete remission (CR) or near-CR before COVID-19 infection. According to the maintained therapy regimen, patients were divided into low-dose GCs group and non-GCs group. Results: A total of 125 patients were enrolled in the study. Their median age was 46.0 ± 15.6years, and the median value of 24-h urine protein was 0.77g. The majority of these patients received treatment for more than 6months, with a significant portion achieving CR (29.6%) or near-CR (43.2%). The leading cause of NS was membranous nephropathy (52%). There were no significant differences in the baseline characteristics between low-dose GCs and non-GCs group. As compared to those in the non-GCs group, patients receiving low-dose GCs treatment showed less fatigue or muscle weakness, smell disorder, palpitations, decreased appetite, taste disorder, dizziness, sore throat or difficult to swallow and fever (p < 0.05). Moreover, patients in the low-dose GCs group were with higher median quality of life scores (85.0) than in the non-GCs group (p = 0.001). Further serum inflammatory factor analysis indicated that interleukin-6 (IL-6) levels in the non-GCs group were significantly higher than that in the low-dose GCs group (p < 0.05). Conclusion: Patients with NS in low-dose GCs maintenance therapy stage showed milder symptom, higher quality of life and decreased serum IL-6 levels compared to those, who were not on GCs maintenance therapy. These results suggest the beneficial effect of low-dose GCs therapy in NS patients with CR/near-CR suffering from COVID-19 infection.

Sturgeon-derived peptide LLLE alleviates colitis via regulating gut microbiota and its metabolites

Inflammatory bowel disease (IBD), encompassing ulcerative colitis (UC) and Crohn's disease, entails chronic inflammation of the gastrointestinal tract. The pathogenesis of IBD implicates genetic factors, gut microbiome alterations, and immune dysregulation, contributing to its increasing global prevalence. The sturgeon-derived peptide, which exhibits promising anti-inflammatory effects, provides potential therapeutic insights for managing IBD symptoms. This study aims to elucidate the therapeutic mechanisms of novel sturgeon-derived peptide (LLLE, Leu-Leu-Leu-Glu) by investigating their effects on intestinal inflammation, gut microbiota composition, and fecal metabolites in a mouse model of IBD. LLLE administration alleviated weight loss and disease activity index (DAI) scores in dextran sulfate sodium salt (DSS)-induced colitis in mice. Histopathological examination showed LLLE pretreatment improved colon morphology and histopathological condition and decreased serum interleukin-6 (IL-6) levels. 16S rRNA sequencing indicated LLLE-modulation of gut microbiota, especially alleviated DSS-elevated Bacteroidetes. Fecal metabolomic analysis unveiled that LLLE restores critical metabolites such as indole-3-propionic acid, which is pivotal in anti-inflammatory responses. Altogether, sturgeon peptide exhibits considerable promise as a therapeutic agent for colitis, owing to its anti-inflammatory effects, modulation of gut microbiota, and restoration of essential fecal metabolites.

Endothelial Effects of Simultaneous Expression of Human HO-1, E5NT, and ENTPD1 in a Mouse.

The vascular endothelium is key target for immune and thrombotic responses that has to be controlled in successful xenotransplantation. Several genes were identified that, if induced or overexpressed, help to regulate the inflammatory response and preserve the transplanted organ function and metabolism. However, few studies addressed combined expression of such genes. The aim of this work was to evaluate in vivo the effects of the simultaneous expression of three human genes in a mouse generated using the multi-cistronic F2A technology. Male 3-month-old mice that express human heme oxygenase 1 (hHO-1), ecto-5'-nucleotidase (hE5NT), and ecto-nucleoside triphosphate diphosphohydrolase 1 (hENTPD1) (Transgenic) were compared to wild-type FVB mice (Control). Background analysis include extracellular nucleotide catabolism enzymes profile on the aortic surface, blood nucleotide concentration, and serum L-arginine metabolites. Furthermore, inflammatory stress induced by LPS in transgenic and control mice was used to characterize interleukin 6 (IL-6) and adhesion molecules endothelium permeability responses. Transgenic mice had significantly higher rates of extracellular adenosine triphosphate and adenosine monophosphate hydrolysis on the aortic surface in comparison to control. Increased levels of blood AMP and adenosine were also noticed in transgenics. Moreover, transgenic animals demonstrated the decrease in serum monomethyl-L-arginine level and a higher L-arginine/monomethyl-L-arginine ratio. Importantly, significantly decreased serum IL-6, and adhesion molecule levels were observed in transgenic mice in comparison to control after LPS treatment. Furthermore, reduced endothelial permeability in the LPS-treated transgenic mice was noted as compared to LPS-treated control. The human enzymes (hHO-1, hE5NT, hENTPD1) simultaneously encoded in transgenic mice demonstrated benefits in several biochemical and functional aspects of endothelium. This is consistent in use of this approach in the context of xenotransplantation.

The Effect of Parenteral Selenium Therapy on Serum Concentration of Inflammatory Mediators: a Systematic Review and Dose-Response Meta-Analysis of Randomized Clinical Trials.

Selenium can protect against inflammation through its incorporation in selenoenzymes; therefore, in this study, we assessed the effect of parenteral selenium on C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α) through a systematic review and meta-analysis on randomized controlled trials (RCTs). A systematic search was performed in the databases, including PubMed, Scopus, Cochrane, clinicaltrials.gov, and ISI Web of Science, up to October 2022, with no limitation in study location or publication time. We calculated the effect size by the mean change from baseline in serum concentration of selected inflammatory mediators and their standard deviations. DerSimonian and Laird random effects model was used to estimate the heterogeneity and summary of the overall effects. Included studies in this systematic review and meta-analysis were 10 and 8 RCTs, respectively. Our results revealed parenteral selenium significantly decreased serum IL-6 (Weighted Mean Difference (WMD) = -3.85 pg/ml; 95% confidence interval (CI) = -7.37, -0.34 pg/ml; p = 0.032) but did not significantly change serum levels of CRP (WMD = 4.58mg/L; 95% CI = -6.11, 15.27mg/L; P = 0.401) compared to the comparison groups. According to our results, parenteral selenium supplementation might reduce serum levels of inflammatory mediators.

Suppression of NASH-Related HCC by Farnesyltransferase Inhibitor through Inhibition of Inflammation and Hypoxia-Inducible Factor-1α Expression.

Inflammatory processes play major roles in carcinogenesis and the progression of hepatocellular carcinoma (HCC) derived from non-alcoholic steatohepatitis (NASH). But, there are no therapies for NASH-related HCC, especially focusing on these critical steps. Previous studies have reported that farnesyltransferase inhibitors (FTIs) have anti-inflammatory and anti-tumor effects. However, the influence of FTIs on NASH-related HCC has not been elucidated. In hepatoblastoma and HCC cell lines, HepG2, Hep3B, and Huh-7, we confirmed the expression of hypoxia-inducible factor (HIF)-1α, an accelerator of tumor aggressiveness and the inflammatory response. We established NASH-related HCC models under inflammation and free fatty acid burden and confirmed that HIF-1α expression was increased under both conditions. Tipifarnib, which is an FTI, strongly suppressed increased HIF-1α, inhibited cell proliferation, and induced apoptosis. Simultaneously, intracellular interleukin-6 as an inflammation marker was increased under both conditions and significantly suppressed by tipifarnib. Additionally, tipifarnib suppressed the expression of phosphorylated nuclear factor-κB and transforming growth factor-β. Finally, in a NASH-related HCC mouse model burdened with diethylnitrosamine and a high-fat diet, tipifarnib significantly reduced tumor nodule formation in association with decreased serum interleukin-6. In conclusion, tipifarnib has anti-tumor and anti-inflammatory effects in a NASH-related HCC model and may be a promising new agent to treat this disease.

Heat-Killed Bifidobacterium longum BBMN68 in Pasteurized Yogurt Alleviates Mugwort Pollen-Induced Allergic Airway Responses through Gut Microbiota Modulation in a Murine Model.

Many probiotic bacteria have been proven to prevent allergic airway responses through immunomodulation. This study was conducted to evaluate the effects of heat-killed Bifidobacterium longum BBMN68 (BBMN68) in pasteurized yogurt on the alleviation of mugwort pollen (MP)-induced allergic inflammation. BALB/c mice aged 5-6 weeks were randomly assigned and fed pasteurized yogurt containing heat-killed BBMN68 for 27 days, followed by allergic sensitization and challenge with MP extract. The allergic mice that received pasteurized yogurt containing heat-killed BBMN68 had improved immune status, including a lower serum IgE level, decreased serum interleukin (IL)-4, IL-5, and IL-13 concentrations, and alleviated airway inflammation manifested by increased macrophage and decreased eosinophil and neutrophil counts in BALF, as well as airway remodeling and suppressed peribronchial cellular infiltration. Moreover, oral administration of pasteurized yogurt containing heat-killed BBMN68 significantly modulated gut microbiota composition by influencing the proportion of beneficial genera associated with inflammation and immunity, such as Lactobacillus, Candidatus_Saccharimonas, Odoribacter, and Parabacteroides, which also negatively correlated with serum IgE and Th2 cytokine levels. These results demonstrated that pasteurized yogurt containing heat-killed BBMN68 had mitigative effects on allergic airway inflammation, likely through maintaining the systemic Th1/Th2 immune balance by altering the structure and function of the gut microbiota.

Efficacy of a paper-based interleukin-6 test strip combined with a spectrum-based optical reader for sequential monitoring and early recognition of respiratory failure in elderly pneumonia-a pilot study.

Introduction: Community-acquired pneumonia (CAP) is lethal in elderly individuals who are more vulnerable to respiratory failure and require more emergency ventilation support than younger individuals. Interleukin-6 (IL-6) plays a crucial role and has predictive value in CAP; high serum IL-6 concentrations in adults are associated with high respiratory failure and mortality rates. Early detection of IL-6 concentrations can facilitate the timely stratification of patients at risk of acute respiratory failure. However, conventional enzyme-linked immunosorbent assay (ELISA) IL-6 measurement is laborious and time-consuming. Methods: The IL-6 rapid diagnostic system combined with a lateral flow immunoassay-based (LFA-based) IL-6 test strip and a spectrum-based optical reader is a novel tool developed for rapid and sequential bedside measurements of serum IL-6 concentrations. Here, we evaluated the correlation between the IL-6 rapid diagnostic system and the ELISA and the efficacy of the system in stratifying high-risk elderly patients with CAP. Thirty-six elderly patients (median age: 86.5years; range: 65-97years) with CAP were enrolled. CAP diagnosis was established based on the Infectious Diseases Society of America (IDSA) criteria. The severity of pneumonia was assessed using the CURB-65 score and Pneumonia Severity Index (PSI). IL-6 concentration was measured twice within 24h of admission. Results: The primary endpoint variable was respiratory failure requiring invasive mechanical or non-invasive ventilation support after admission. IL-6 rapid diagnostic readouts correlated with ELISA results (p < 0.0001) for 30 samples. Patients were predominantly male and bedridden (69.4%). Ten patients (27.7%) experienced respiratory failure during admission, and five (13.9%) died of pneumonia. Respiratory failure was associated with a higher mortality rate (p = 0.015). Decreased serum IL-6 concentration within 24h after admission indicated a lower risk of developing respiratory failure in the later admission course (Receiver Operating Characteristic [ROC] curve = 0.696). Conclusion: Sequential IL-6 measurements with the IL-6 rapid diagnostic system might be useful in early clinical risk assessment and severity stratification of elderly patients with pneumonia. This system is a potential point-of-care diagnostic device for sequential serum IL-6 measurements that can be applied in variable healthcare systems.

Clinical characteristics of bipolar 1 disorder in relation to interleukin-6: a cross-sectional study among Egyptian patients

BackgroundStrong evidence in the literature points to the role of pro-inflammatory cytokines in bipolar disorder (BD) pathophysiology. Interleukin-6 (IL-6) is a pro and anti-inflammatory cytokine that was repeatedly found higher in bipolar patients than in healthy controls. However, studies on the phasic differences of IL-6 in bipolar type I (BP-I) were limited. This study aims to explore the phasic differences of serum IL-6 levels in BP-I during euthymia, depression, and mania and their association with the disease’s clinical characteristics in a sample of Egyptian BP-I patients. Thirty currently euthymic, 24 currently depressed, 29 currently manic BP-I patients, and 20 healthy subjects were recruited. Serum IL-6 levels were compared among BP-I groups and then between each group and a group of 20 healthy controls. Serum IL-6 levels (pg/ml) were measured with a sandwich enzyme-linked immunosorbent assay (ELISA). Depression and mania symptoms were assessed using the Hamilton Depression Rating Scale (HDRS) and the Young Mania Rating Scale (YMRS), respectively. Clinical characteristics were evaluated through a semi-structured clinical psychiatric interview, and cognitive status was tested using the Montreal Cognitive Assessment (MoCA).ResultsSerum IL-6 levels were significantly higher in each bipolar phase than in healthy subjects. In the BP-I patients, IL-6 levels were lower in patients with a current manic episode than in patients with a current depressive episode (P < 0.05) or who were currently euthymic (P < 0.001). Moreover, IL-6 levels correlated inversely with the YMRS score (rs = − 0.29; P < 0.05). Compared to patients without psychotic features, patients with psychotic features had decreased serum IL-6. Moreover, IL-6 levels were lower in inpatients compared to outpatients.ConclusionsBP-I disorder is associated with an inflammatory state. The decreased levels of IL-6 during manic episodes, affective episodes with psychotic features, and their inverse correlation with the severity of mania symptoms indicate a possible anti-inflammatory role of IL-6 in mania and psychotic symptoms pathogenesis.

Neoadjuvant Pseudomonas aeruginosa mannose-sensitive hemagglutinin (PA-MSHA) and chemotherapy versus placebo plus chemotherapy in patients with HER2-negative breast cancer: a randomized, controlled, double-blind trial.

According to preclinical experiments, Pseudomonas aeruginosa mannose-sensitive hemagglutinin (PA-MSHA) exerts antiproliferative effects against breast cancer cells. It has been approved by the State Food and Drug Administration in China for complementary cancer treatment, and its safety has been confirmed in previous clinical trials. The present randomized, controlled, double-blind clinical trial was conducted to investigate the efficacy and safety of neoadjuvant PA-MSHA and placebo with chemotherapy in patients with human epidermal growth factor receptor 2 (HER2)-negative breast cancer. Eligible patients aged 18 years or older with previously untreated HER2-negative stage II-III breast cancer were enrolled and randomly assigned at a 1:1 ratio to receive neoadjuvant chemotherapy with PA-MSHA or a placebo. The Response Evaluation Criteria in Solid Tumors (RECIST) was used to assess clinical response every 2 cycles. The primary endpoint was the objective response rate (ORR) based on the clinical response following neoadjuvant chemotherapy. A total of 75 patients were randomly assigned to either the PA-MSHA group (37 patients) or the control group (38 patients). The ORR was found to be significantly higher in the PA-MSHA group compared with the control group [86.5% versus 60.5%; rate difference 26.0; 95% confidence interval (CI): 5.9-43.5%; P=0.011]. The pathological complete response (pCR) and survival outcomes did not differ significantly between the 2 groups. Patients with immune-related adverse events (irAEs) appeared to benefit from the PA-MSHA treatment, with greater disease-free, relapse-free, and overall survival. The application of PA-MSHA to neoadjuvant chemotherapy did not increase the incidence of severe adverse events. Moreover, the addition of PA-MSHA increased serum interferon-γ levels and the percentage of peripheral blood T cells, CD8+/CD4+ T cells, CD8+CD28+ T cells, and natural killer (NK) cells, and decreased serum interleukin 4 levels. The addition of PA-MSHA to neoadjuvant chemotherapy is an effective alternative regimen for HER2-negative breast cancer. Patients with irAEs caused by PA-MSHA may obtain more benefits from this treatment. Chinese Clinical Trial Registry ChiCTR-TRC-10000794.

Anxiolytic-like effects of hochuekkito in lipopolysaccharide-treated mice involve interleukin-6 inhibition.

Hochuekkito (HET) is a Kampo medicine used to treat postoperative and post-illness general malaise and decreased motivation. HET is known to regulate immunity and modulate inflammation. However, the precise mechanism and effects of HET on inflammation-induced central nervous system disorders remain unclear. This study aimed to assess the effect of HET on inflammation-induced anxiety-like behavior and the mechanism underlying anxiety-like behavior induced by lipopolysaccharide (LPS). Institute of Cancer Research mice were treated with LPS (300 μg/kg, intraperitoneally), a bacterial endotoxin, to induce systemic inflammation. The mice were administered HET (1.0 g/kg, orally) once a day for 2 weeks before LPS treatment. The light-dark box test and the hole-board test were performed 24 h after the LPS injection to evaluate the effects of HET on anxiety-like behaviors. Serum samples were obtained at 2, 5, and 24 h after LPS injection, and interleukin-6 (IL-6) levels in serum were measured. Human and mouse macrophage cells (THP-1 and RAW264.7 cells, respectively) were used to investigate the effect of HET on LPS-induced IL-6 secretion. The repeated administration of HET prevented anxiety-like behavior and decreased serum IL-6 levels in LPS-treated mice. HET significantly suppressed LPS-induced IL-6 secretion in RAW264.7 and THP-1 cells. Similarly, glycyrrhizin, one of the chemical constituents of HET, suppressed LPS-induced anxiety-like behaviors. Our study revealed that HET ameliorated LPS-induced anxiety-like behavior and inhibited IL-6 release in vivo and in vitro. Therefore, we postulate that HET may be useful against inflammation-induced anxiety-like behavior.

Comparative Efficacy of Fish Meal Replacement With Enzymatically Treated Soybean Meal on Growth Performance, Immunity, Oxidative Capacity and Fecal Microbiota in Weaned Pigs.

This study investigated the growth performance, immunity, antioxidant capacity and fecal microbiota of weaned pigs by partially or completely replacing dietary fish meal with enzymatically treated soybean meal. A total of 144 piglets (initial body weight of 7.19 ± 0.11 kg) weaned at 28 d were allotted to 3 dietary treatments (6 replicates per treatment): 4% fish meal diet (FM); 2% fishmeal plus 6% enzymatically treated soybean meal (ESBM1); and 6% enzymatically treated soybean meal without fish meal (ESBM2). The experimental period was 28 d, serum was collected at day 14 and day 28 for biochemical parameters analysis, feces was obtained for microbiota analysis at 28d. The body weight, average daily gain and average daily feed intake of piglets in the ESBM2 group were significantly increased compared with those in the FM and ESBM1 groups from 0 to 28 d, respectively (P < 0.05). The diets with enzymatically treated soybean meal in ESBM1 and ESBM2 groups decreased the diarrhea rate (P < 0.05). Compared with FM, ESBM1 and ESBM2 decreased 5-hydroxytryptamine (5-HT) (P < 0.05). ESBM1 decreased diamine oxidase (DAO) and Interleukin 6 (IL-6) compared with FM and ESBM2 (P < 0.05). ESBM1 decreased serum Interleukin 1β (IL-1β) compared with FM at d 14 (P < 0.05). The serum Immunoglobulin E (IgE), secretory curl associated protein 5 (sFRP-5) were higher in ESBM1 compared with FM and ESBM2 (P < 0.05). ESBM2 increased super oxidase dismutase (SOD) level and decreased malondialdehyde (MDA) content compared with FM and ESBM1, the concentration of SOD in ESBM1was higher than that in FM (P < 0.05). ESBM1 decreased cortisol and caspase 3 (Casp-3) (P < 0.05). FM showed a higher content of tri-iodothyronine (T3) (P < 0.05) and a lower thyroxine/ tri-iodothyronine ratio compared with those in the other two groups (P < 0.05). The concentration of leptin was lower in ESBM2 (P < 0.05). ESBM1 had a higher α-diversity than ESBM2 (P < 0.05). The microbiota composition was different among three treatments (difference between FM and ESBM1, p = 0.005; FM and ESBM2, p = 0.009; ESBM1 and ESBM2, p = 0.004). ESBM2 tend to increase the abundance of Firmicutes (P = 0.070) and decrease Bacteroidetes (P = 0.069). ESBM2 decreased the abundance of Parabacteroides and increased SMB53 compared with FM (P < 0.05). The spearman correlation analysis revealed that the abundance of Parabacteroides enriched in FM group was negatively correlated with SOD, Megasphaera enriched in ESBM2 group were positively correlated with SOD. The abundance of Lachnospira enriched in ESBM2 group were negatively correlated with serum concentration of D-lactate, DAO, IL-6, and NO. In conclusion, under the conditions of this study, diet with only ESBM demonstrate the beneficial impact on intestinal microbiota developments, antioxidant capacity as well as growth performance for weaned pigs.

Antibiotic cocktail-induced gut microbiota depletion in different stages could cause host cognitive impairment and emotional disorders in adulthood in different manners

Gut microbiota depletion may result in cognitive impairment and emotional disorder. This study aimed to determine the possible association between host gut microbiota, cognitive function, and emotion in various life stages and its related underlying mechanisms. Seventy-five neonatal mice were randomly divided into five groups (n = 15 per group). Mice in the vehicle group were administered distilled water from birth to death, and those in the last four groups were administered antibiotic cocktail from birth to death, from birth to postnatal day (PND) 21 (infancy), from PND 21 to 56 (adolescence), and from PND 57 to 84 (adulthood), respectively. Antibiotic exposure consistently altered the gut microbiota composition and decreased the diversity of gut microbiota. Proteobacteria were the predominant bacteria instead of Firmicutes and Bacteroidetes after antibiotic exposure in different life stages. Long-term and infant gut microbiota depletion resulted in anxiety- and depression-like behaviors, memory impairments, and increased expression of γ-aminobutyric acid type A receptor α1 of adult mice. Long-term antibiotic exposure also significantly decreased serum interleukin (IL)-1β, IL-10, and corticosterone of adult mice. Gut microbiota depletion in adolescence resulted in anxiety-like behaviors, short-term memory decline, decreased serum interferon-γ (IFN-γ), mRNA expression of 5-hydroxytryptamine receptor 1A, and neuropeptide Y receptor Y2 in the prefrontal cortex of adult mice. Antibiotic exposure in adulthood damaged short-term memory and decreased serum IL-10, IFN-γ, and increased γ-aminobutyric acid type B receptor 1 mRNA expression of adult mice. These results suggest that antibiotic-induced gut microbiota depletion in the long term and infancy resulted in the most severe cognitive and emotional disorders followed by depletion in adolescence and adulthood. These results also suggest that gut microbes could influence host cognitive function and emotion in a life stage-dependent manner by affecting the function of the immune system, hypothalamic-pituitary-adrenal axis, and the expression of neurochemicals in the brain.

Keel bone damage affects behavioral and physiological responses related to stress and fear in two strains of laying hens.

Keel bone damage (KBD) is more prevalent in alternative laying hen housing systems than in conventional cages, and its incidence differs from strain to strain. However, the information of KBD in Lindian chickens, a native Chinese strain, is limited. To investigate the effect of KBD on fearfulness and physiological indicators of stress in Lindian chickens and commercial laying hens, a total of two hundred 25-wk-old chickens (100 Hy-line Brown and 100 Lindian chickens) were studied for 7wk. The birds were housed in furnished cages with 10 birds per cage for each strain. At 32-wk of age, the birds in each strain were divided into normal (NK), deviated (DK), and fractured (FK) hens according to the keel bone status. Ten birds in each keel bone status per strain were subsequently selected to collect blood for the determination of stress and fear-related indicators, including corticosterone, serotonin, interleukin-1β, and interleukin-6, and measure fear responses, including novel object test (NOT), human approach test (HAT), and tonic immobility (TI) test. The results showed that egg production was lower and the incidence of keel bone fractures was higher in Lindian chickens than in Hy-line Brown hens (P < 0.05). Lindian chickens showed a significantly increased whole blood serotonin content, NOT-latency, HAT-score, and TI induction times (P < 0.05) and decreased serum interleukin-6 content and TI-duration (P < 0.05) compared with Hy-line Brown hens. Additionally, FK hens had significantly elevated whole blood corticosterone, serum interleukin-1β and interleukin-6 levels, TI-duration, and NOT-latency (P < 0.05), and a reduced whole blood serotonin content (P < 0.05) compared with NK and DK hens. Our results indicated that KBD affected stress and fear responses, and this impact was mainly reflected by FK hens compared with NK and DK hens. We suggest that keel bone fractures are the main factor impairing hen welfare. Besides, the incidence of keel bone fractures and stress and fear responses of Lindian chickens are more severe than Hy-line Brown laying hens, indicating that the strain type can affect the health and welfare of laying hens.

Protective Effect of Lycium barbarum Polysaccharides and Capsaicin in Rats With Dextran Sulfate Sodium-Induced Ulcerative Colitis via Anti-inflammation and Antioxidation

Abstract Objectives Ulcerative colitis (UC) is a chronic inflammatory disease in the colon, and the prevalence of UC is increasing worldwide. Lycium barbarum polysaccharides (LBP) from wolfberry extract has immunomodulatory effects, and act as a prebiotics candidate. Capsaicin (CAP) as an active ingredient of chili peppers has the potential for anti-inflammation and antioxidation. This study investigated the effects of LBP and CAP on anti-inflammation and antioxidation in rats with dextran sulfate sodium (DSS)-induced UC. Methods Male Sprague-Dawley rats were divided into five groups: control, UC (DSS), UC treated with 100 mg/kg bw LBP (LBP), UC treated with 12 mg/kg bw CAP (CAP), and UC treated with a combination of 50 mg/kg bw LBP and 6 mg/kg bw CAP (MIX) groups. The treatment of LBP and/or CAP was daily given by oral gavage from week 1 to week 4, and UC was induced by 5% DSS in drinking water for 6 days during week 3. Results The DSS group significantly increased disease activity index (DAI) scores, the levels of pro-inflammatory cytokines interleukin-6 (IL-6) in the serum and tumor necrosis factor-α (TNF-α) in the colon, and serum lipid peroxidation malondialdehyde (MDA) levels compared with the control group. While the activities of antioxidant enzymes such as superoxide dismutase (SOD) and catalase (CAT) in the serum were significantly decreased in the DSS group. The LBP, CAP, and MIX groups significantly decreased DAI scores on day 6 during the DSS-induced period. Compared with the DSS group, the LBP group significantly decreased serum IL-6 and serum MDA levels, but increased serum CAT activity. The CAP group significantly decreased serum IL-6 levels. The MIX group significantly reduced serum IL-6 and colon TNF-α levels, but elevated serum SOD activity. Conclusions The results suggest that administration of LBP and/or CAP attenuate DSS-induced UC symptoms in rats through the anti-inflammatory and antioxidant activities. Funding Sources This study was supported by the Ministry of Science and Technology, Taiwan (grant no. MOST 108–2320-B-038–052-MY3).

Effect of artificial liver blood purification treatment on the survival of critical ill COVID-19 patients.

Our aim was to investigate the effect of artificial liver blood purification treatment on the survival of severe/critical patients with coronavirus disease 2019 (COVID‐19). A total of 101 severe and critical patients with coronavirus SARS‐CoV‐2 infection were enrolled in this open, case‐control, multicenter, prospective study. According to the patients’ and their families’ willingness, they were divided into two groups. One was named the treatment group, in which the patients received artificial liver therapy plus comprehensive treatment (n = 50), while the other was named the control group, in which the patients received only comprehensive treatment (n = 51). Clinical data and laboratory examinations, as well as the 28‐day mortality rate, were collected and analyzed. Baseline data comparisons on average age, sex, pre‐treatment morbidity, initial symptoms, vital signs, pneumonia severity index score, blood routine examination and biochemistry indices etc. showed no difference between the two groups. Cytokine storm was detected, with a significant increase of serum interleukin‐6 (IL‐6) level. The serum IL‐6 level decreased from 119.94 to 20.49 pg/mL in the treatment group and increased from 40.42 to 50.81 pg/mL in the control group (P < .05), indicating that artificial liver therapy significantly decreased serum IL‐6. The median duration of viral nucleic acid persistence was 19 days in the treatment group (ranging from 6 to 67 days) and 17 days in the control group (ranging from 3 to 68 days), no significant difference was observed (P = .36). As of 28‐day follow‐up,17 patients in the treatment group experienced a median weaning time of 24 days, while 11 patients in the control group experienced a median weaning time of 35 days, with no significant difference between the two groups (P = .33). The 28‐day mortality rates were 16% (8/50) in the treatment group and 50.98% (26/51) in the control group, with a significant difference (z = 3.70, P < .001). Cytokine storm is a key factor in the intensification of COVID‐19 pneumonia. The artificial liver therapy blocks the cytokine storm by clearing inflammatory mediators, thus preventing severe cases from progressing to critically ill stages and markedly reducing short‐term mortality.

Gut Microbiota Is Not Involved in the Induction of Acute Phase Protein Expression Caused by Vitamin C Deficiency.

Using rats, we previously found that vitamin C deficiency increases serum levels of interleukin-6 (IL-6) and glucocorticoid, and changes the gene expression of acute phase proteins (APP) in the liver. However, it remains unclear how vitamin C deficiency causes these inflammation-like responses. In this study, we investigated the possibility that changes in gut microbiota are involved in the induction of APP gene expression by vitamin C deficiency. ODS rats that cannot genetically synthesize vitamin C were divided into 4 groups based on the presence or absence of vitamin C or antibiotics and were raised for 15 d. Neomycin, vancomycin, and ampicillin were used as antibiotics, and 300 mg L-ascorbic acid/kg was added to the AIN93G diet. Vitamin C deficiency affected neither the wet tissue weights nor relative abundance of bacteria in the cecal contents. Antibiotic administration increased wet weights of the cecum, cecal contents, and colon, changed the relative abundance of some bacteria in the cecal contents, and decreased serum IL-6 level. However, antibiotic administration had no effect on serum concentrations of corticosterone and α1-acid glycoprotein (AGP), vitamin C concentration in the liver, and mRNA levels of haptoglobin and AGP in the liver. Therefore, disturbance of gut microbiota did not attenuate the increase in glucocorticoid level and induction of APP gene expression due to vitamin C deficiency. This suggests that gut microbiota is not involved in the inflammation-like responses caused by vitamin C deficiency.

Melatonin inhibits macrophage infiltration and promotes plaque stabilization by upregulating anti-inflammatory HGF/c-Met system in the atherosclerotic rabbit: USPIO-enhanced MRI assessment

Macrophage plays critical roles in the pathogenesis of atherosclerosis (AS), and is an attractive target for detecting and treating vulnerable plaque. Our previous study showed that melatonin (MLT) ameliorated AS by suppressing the pro-inflammatory Toll-like receptor 4/nuclear factor kappa B system in high-fat-fed rabbit. However, it is unknown whether the anti-atherosclerotic properties of MLT are associated with the upregulation of anti-inflammatory hepatocyte growth factor (HGF)/mesenchymal-epithelial transition factor (c-Met) system. In present study, we examined whether MLT could inhibit macrophage infiltration and promote plaque stabilization by upregulating HGF/c-Met system with ultrasmall superparamagnetic iron oxide (USPIO)-enhanced magnetic resonance imaging (MRI) assessment in AS rabbit. Rabbits in this study were randomly divided into three groups and treated with a standard diet, high-fat diet, and high-fat diet plus 10 mg/kg/day MLT for 12 weeks, respectively. MLT treatment significantly reversed spotty signal void in 3D-TOF MRI, standard signal intensity reduction in T2WI MRI and aortic luminal area reduction in 2D-TOF MRI of the atherosclerotic abdominal aorta 72 h after USPIO injection. It also decreased serum interleukin-6 (IL-6), intima/media thickness ratio of the abdominal aorta, CD68 and iron-positive areas in the aortic intima, and increased serum IL-10, HGF and c-Met protein expression and the accumulation of vascular smooth muscle cell and collagen fiber in the aortic intima of AS rabbit. Our data demonstrated that MLT significantly decreased plaque macrophage infiltration and promoted plaque stability in AS rabbit assessed by USPIO-enhanced MRI. Remarkably, it was very first revealed that upregulation of anti-inflammatory HGF/c-Met system might contribute to the atheroprotective mechanisms of MLT.

Effects of betulinic acid on synovial inflammation in rats with collagen-induced arthritis.

Betulinic acid (BA) inhibits the migration, invasion, and cytoskeletal reorganization of fibroblast-like synoviocytes (RA-FLS) in patients with rheumatoid arthritis. Here, to further explore the mechanism of action of BA in collagen-induced arthritis (CIA) rats, we investigated the pharmacodynamic effects of BA on synovial inflammation in a rat model of type II CIA. After inducing hind paw swelling, the rats were divided into four groups: healthy controls (normal), and rats that underwent CIA and received methotrexate treatment (MTX), BA treatment (BA), or no treatment (CIA). Body weight and hind paw swelling were determined regularly, and arthritis scores were calculated weekly. On day 35, rats were sacrificed and their hind ankle joints sectioned and stained with hematoxylin and eosin for histopathological evaluation. BA significantly reduced CIA-induced hind paw swelling, synovial tissue proliferation, cartilage destruction, and vasospasm. BA treatment also decreased serum interleukin (IL)-1β, IL-6, and tumor necrosis factor-alpha (TNF-α) levels in rats with CIA. The CCK-8 assay was used to detect the proliferation of isolated vimentin+CD68− RA-FLS; RA-FLS were stimulated with TNF-α in vitro. BA significantly inhibited TNF-α-stimulated RA-FLS proliferation, as well as IL-1β and IL-6 secretion. BA also downregulated the transcription of vascular endothelial growth factor (VEGF) and transforming growth factor β (TGF-β) and decreased the expression of the NF-кB pathway proteins (NF-kB-P65, IkBα, and IKKα/β) in the TNF-α-stimulated RA-FLS. These results indicate that BA alleviated the symptoms of CIA by inhibiting synoviocyte proliferation, modifying TNF-α- and NF-кB-related inflammatory pathways, and downregulating inflammatory mediators and growth factors including IL-1β, IL-6, VEGF, and TGF-β.