Serum Concentrations Of IL-1β Research Articles

Single-Nucleotide Variants in the AIM2 - Absent in Melanoma 2 Gene (rs1103577) Associated With Protection for Tuberculosis.

Tuberculosis (TB) remains a serious public health burden worldwide. TB is an infectious disease caused by the Mycobacterium tuberculosis Complex. Innate immune response is critical for controlling mycobacterial infection. NOD-like receptor pyrin domain containing 3/ absent in melanoma 2 (NLRP3/AIM2) inflammasomes are suggested to play an important role in TB. NLRP3/AIM2 mediate the release of pro-inflammatory cytokines IL-1β and IL-18 to control M. tuberculosis infection. Variants of genes involved in inflammasomes may contribute to elucidation of host immune responses to TB infection. The present study evaluated single-nucleotide variants (SNVs) in inflammasome genes AIM2 (rs1103577), CARD8 (rs2009373), and CTSB (rs1692816) in 401 patients with pulmonary TB (PTB), 133 patients with extrapulmonary TB (EPTB), and 366 healthy control (HC) subjects with no history of TB residing in the Amazonas state. Quantitative Real Time PCR was performed for allelic discrimination. The SNV of AIM2 (rs1103577) is associated with protection for PTB (padj: 0.033, ORadj: 0.69, 95% CI: 0.49-0.97). CTSB (rs1692816) is associated with reduced risk for EPTB when compared with PTB (padj: 0.034, ORadj: 0.50, 95% CI: 0.27-0.94). Serum IL-1β concentrations were higher in patients with PTB than those in HCs (p = 0,0003). The SNV rs1103577 of AIM2 appeared to influence IL-1β release. In a dominant model, individuals with the CC genotype (mean 3.78 ± SD 0.81) appeared to have a higher level of IL-1β compared to carriers of the T allele (mean 3.45 ± SD 0.84) among the patients with PTB (p = 0,0040). We found that SNVs of AIM2 and CTSB were associated with TB, and the mechanisms involved in this process require further study.

Diagnostic Significance of Selected Serum Inflammatory Markers in Women with Advanced Endometriosis.

Endometriosis is a gynecological disease, the pathogenesis of which seems to be directly associated with inflammatory processes. Serum concentrations of IL-1β, IL-6, hs-CRP, IgG, YKL 40 and PRL, in comparison to the well-known CA 125 levels, were studied with the aim of identifying an additional noninvasive inflammatory marker or set of markers characteristic for endometriosis. The study group included 43 women with endometriosis (E), 35 women with benign gynecological disorders but without endometriosis (NE, non-endometriosis) as a comparative group, and a control group consisting of 18 healthy subjects (C). The serum concentrations of IL-1β, IL-6, hs-CRP, YKL-40, PRL and CA 125 were significantly higher in the E group (median values: 0.41 pg/mL, 2.42 pg/mL, 2.33 mg/L, 79.30 ng/mL, 21.88 ng/mL and 68.00 U/mL, respectively) than in the control group (median values: 0.21 pg/mL, 0.98 pg/mL, 0.52 mg/L, 49.77 ng/mL, 12.08 ng/mL and 12.20 U/mL respectively), with the significance of p = 0.011, p < 0.001, p = 0.028, p = 0.005, p < 0.001 and p < 0.001, respectively. The IgG concentrations were significantly lower in the endometriosis group (median value: 1061.21 mg/dL) as compared to healthy women (median value: 1210.50 mg/dL; p = 0.025). Significant differences in concentrations of IL-6 (p = 0.040), hs-CRP (p = 0.007) and CA 125 (p < 0.001) were observed in stage III vs. stage IV of endometriosis. Significantly higher concentrations of IL-6 (p = 0.010), hs-CRP (p = 0.037) and PRL (p < 0.001) were observed in the NE group vs. the control group. Only CA 125 concentrations were significantly higher in endometriosis patients as compared to the non-endometriosis group (p < 0.001). The proposed panel of inflammatory markers, especially IL-6, PRL and CA 125, may become a useful tool to identify women with advanced endometriosis who could qualify for treatment.

Carthamin yellow improves cerebral ischemia‑reperfusion injury by attenuating inflammation and ferroptosis in rats.

Carthamin yellow (CY), a flavonoid compound extracted from safflower, has been reported to attenuate cardiac ischemia and reperfusion injury. However, whether CY could ameliorate ischemic stroke is not completely understood. In the present study, the preventive effects of CY on experimental ischemic stroke were investigated using middle cerebral artery occlusion (MCAO) model rats. Neurological scores, brain edema, infarct area and microtubule-associated protein 2 (MAP-2) immunoreactivity were assessed to evaluate the effects of CY on ischemic brain injury. The involvement of inflammation and ferroptosis were examined to investigate the mechanism underlying the effects of CY. The results demonstrated that 2-week CY treatment attenuated the neurological deficit score, brain water content and infarct area, and increased MAP-2 immunoreactivity in the cortex in MCAO model rats. CY administration also deactivated the cortex NF-κB/NLR family pyrin domain containing 3 inflammasome signaling pathway, and decreased serum TNF-α, IL-1β and IL-6 concentrations. Moreover, CY treatment inhibited Fe2+ and reactive oxygen species accumulation, and reversed acyl-CoA synthetase long-chain family member 4, transferrin receptor 1, glutathione peroxidase 4 and ferritin heavy chain 1 protein expression levels in the brain. The levels of glutathione, superoxide dismutase and malondialdehyde in the serum were also reversed by CY treatment. Collectively, the results of the present study demonstrated that CY protected rats against ischemic stroke, which was associated with mitigation of inflammation and ferroptosis.

Tiaochang Xiaoyan extract tablets ameliorate chronic inflammation by activating macrophage lysosomes in chronic colitis rats.

Tiaochang Xiaoyan tablet (TCXYT) is a traditional Chinese medicine prescription derived from the Xianglian pill, which is a traditional Chinese medicine for treating chronic dysentery recorded in the Taiping Huimin Heji Bureau [1078-1085]. For many years, TCXYT has been used to treat ulcerative colitis, however, its therapeutic mechanism is still unclear. In the present study, we used colonic lamina propria macrophages (LPM) and mouse-derived macrophage cell line RAW264.7 cells as the research objects, with the aim of exploring the therapeutic effects and mechanisms of TCXYT on colitis. We used 2,4,6-trinitrobenzenesulfonic acid (TNBS) to induce a rat model of chronic colitis, and normal rats as the control. The disease activity index (DAI) and colonic histopathological changes of rats were used to evaluate the severity of colitis. Rats were divided into the control group; model group; high, middle-, and low-dose TCXYT group; and the hydroxychloroquine sulfate group. TCXYT was administered by gavage on the 3rd day after model replication and lasted for 7 days. The doses used for the high-, middle-, and low-dose TCXYT groups were 0.8, 0.4 and 0.2 g/kg, respectively. Enzyme-linked immunosorbent assay was used to detect the serum concentration of cytokines. Western blot was used to detect the expressions of Toll-like receptor 9 (TLR9), myeloid differentiation primary response 88 (MyD88), interleukin (IL) receptor-associated kinase (IRAK) 1, and IRAK4 in colonic LPM and RAW264.7 cells. Immunofluorescence was used to detect lysosomal activity. The chemical constituents of TCXYT were separated and identified based on Q-Orbitrap high resolution LC/MS data. TCXYT promoted the repair of colonic mucosal injury, attenuated inflammation, increased lysosome activity in macrophages, and decreased the DAI in rats with colitis compared with those in the model group. TCXYT decreased the serum concentrations of IL-1β and tumor necrosis factor-α (TNF-α), increased those of IL-4 and IL-10, and decreased the TLR9, MyD88, IRAK1, and IRAK4 protein levels in LPM and RAW264.7 cells compared to the model group. TCXYT could ameliorate colon inflammation and CD11c+ macrophage infiltration in rats with chronic colitis. This effect may be mediated by activating lysosomes in macrophages by inhibiting the TLR9/MyD88/IRAK signaling pathway.

Melatonin ameliorates hepatic steatosis by inhibiting NLRP3 inflammasome in db/db mice.

Introduction: Type 2 diabetes mellitus (T2DM) is commonly accompanied by obesity and non-alcoholic fatty liver disease (NAFLD), yet the mechanism underlying diabetes-related NAFLD is not fully understood. It has been reported that melatonin can regulate glucose and lipid metabolism. This study aims to investigate the actions and mechanisms of melatonin toward the development of diabetes-related NAFLD. Methods: Melatonin (bid, 30 mg/kg/day, i.p.) was administrated to db/db mice for 8 weeks, while saline was administrated to db/m mice. The metabolic parameters of mice were measured using an automatic biochemistry analyzer. The oxidative stress indexes and mitochondrial membrane potential (MMP) were determined with kits. Pathological assessment in liver tissues was used to analyze the effects of melatonin on hepatic steatosis. The levels of IL-1β and IL-18 were detected with ELISA kits. The mRNA levels of NLRP3 inflammasome were detected using quantitative real-time PCR assay, and protein expressions were estimated using Western blotting assay. Immunofluorescence staining was used to evaluate the caspase-1 expression in the liver. Results: Melatonin treatment significantly reduced blood glucose, serum insulin, body weight, related liver weight, serum lipids, and hepatic enzymes in db/db mice. Melatonin markedly corrected the NAFLD phenotypes, including lipid accumulation, steatohepatitis, fibrosis, and oxidative stress levels. Melatonin significantly improved the MMP level and decreased the serum IL-1β and IL-18 concentrations. The mRNA levels of the NLRP3 inflammasome could also be remarkably reversed by melatonin in the liver tissues. The activation of the NLRP3 inflammasome was also suppressed, evidenced by the downregulated proteins of NLRP3, caspase-1, IL-1β, and IL-18. The enhanced fluorescence intensity of caspase-1 in the liver tissues was also obviously weakened by the melatonin treatment. Conclusion: Our study concluded that melatonin could safeguard against NAFLD by improving hepatic steatosis in db/db mice, and this action could be associated with the regulation of the NLRP3 inflammasome activation.

Predictive Value of Serum Interleukins in Children with Idiopathic Nephrotic Syndrome.

Pro-inflammatory cytokines have been suggested in the pathogenesis of idiopathic nephrotic syndrome (INS), with conflicting results. This study was performed to identify alteration of different serum interleukins (ILs) in children with INS, and their predictive value in response to steroid treatment. Three groups of children (27; steroid-sensitive INS, 21; steroid-resistant INS, and 19 healthy controls) with normal serum C3, negative serologic tests of hepatitis B virus (HBV), hepatitis C virus (HCV), human immune deficiency virus (HIV), and parasitic infections were included in this study. Serum concentrations of IL-1β, IL-2, IL-6, IL-8, IL-13, and IL-18 were measured, using quantitative colorimetric sandwich ELISA kits. Children with secondary nephrotic syndrome, inflammations, systemic disorders, and chronic kidney disease were excluded. The serum concentration of all ILs; except IL-13 and IL-18; was significantly higher in children with INS, compared with the healthy controls. Serum IL-2 had the highest sensitivity of (95.24%) in patients with INS. All of the serum ILs had acceptable accuracy in children with INS, compared with the control group. The serum concentration of IL-1β, IL-6, and IL-8 was significantly higher in children with steroid-sensitive nephrotic syndrome (SSNS), compared with steroid-resistant nephrotic syndrome (SRNS). All of these ILs had acceptable accuracy for the prediction of steroid response in patients with INS. Our findings suggested the pathogenic role of pro-inflammatory cytokines in children with INS, of which IL-1β, IL-6, and IL-8 were accurate biomarkers for the prediction of steroid response in these patients.

Effects of curcumin gel on osteoclastogenic bone markers in experimental periodontitis and alveolar bone loss in wistar rats

Background/purposeCurcumin has anti-inflammatory impacts and was suggested as an inflammatory disease therapy. This study aimed to investigate the implications of curcumin gel on experimental periodontitis (EPD) and alveolar bone loss in rats. Materials and methodsIn this study, twenty-four male Wistar rats were divided equally into four groups: negative control (with no EPD); positive control (EPD induced around lower centrals without treatment); control-treated group: EPD treated with chlorhexidine; and test EPD group treated with curcumin. After 30 days, the serum concentrations of RANKL and IL-1β were measured via ELISA. All animals were sacrificed, and mandibular central incisors with the periodontium were removed. The lingual probing depth and radiographical alveolar bone loss were measured, then samples processed for routine preparation of H&E stained sections and histologically assessed for counting inflammatory cells, osteoclasts, and PDL width. ResultsA significant decrease in the inflammatory cells infiltration, probing depth, and osteoclast numbers with the improvement of PDL associated with a reduction in RANKL and IL-1β serum concentration were seen in both EPD treated groups. ConclusionCurcumin is as effective as chlorhexidine in treating experimental periodontitis in rats. It was demonstrated to stop bone destruction related to periodontitis by regulating the RANKL and IL-1β markers level in the blood.

QT interval parameters, anti-Ro antibody status, and disease activity in systemic lupus erythematosus.

The QT interval a marker of ventricular depolarization and repolarization is reported to be prolonged in some proportion of patients with systemic lupus erythematosus (SLE). We studied electrocardiographic (ECG) abnormalities, in particular QT interval and its relationship with anti-Ro antibodies, disease activity, and serum interleukin 1β (IL-1β), interleukin 6 (IL-6) in SLE. A 12-lead resting ECG was performed on 140 adult SLE patients fulflling SLICC/ACR classification criteria. All patients received hydroxychloroquine and prednisolone. Corrected QT (QTc) °440 milliseconds (ms) was defined as prolonged QTc. QT dispersion (QTd) °60 ms was defined as increased QTd. Eighty-four patients had some form of ECG abnormality. Prolongation of QTc and QTd was present in 24 (17.1%) and 50 (35.7%) respectively. Anti-Ro/SSA antibodies were present in 63 (45%). Prolongation of QTc in anti-Ro positive versus anti-Ro negative was 17.5% and 17% respectively, p=0.98. Prolongation of QTd in anti-Ro-positive versus anti-Ro-negative was 32% and 39% respectively, p=0.37. Prolonged QTc was observed in 15% patients with SLEDAI ˛4 compared to 17.5% patients with SLEDAI °5, p=0.78. The median serum concentrations of IL-1β and IL-6 were similar in the groups with and without prolonged QTc, with and without prolonged QTd. On binary logistic regression analyses neither clinical nor laboratory factors were predictors of prolonged QTc. However, having valvular regurgitation and hypercholesterolemia was associated with significantly reduced odds of having prolonged QTd, adjusted OR 0.33 (CI 0.14-0.83), p=0.018 and 0.19 (CI 0.05-0.80), p=0.023 respectively. Those with high LDL cholesterol and hypertriglyceridemia had a significantly higher odds of having a normal QTd with adjusted OR of 4.34 (1.31-14.46) p=0.017and 5.59 (1.62-19.38) p=0.007respectively. Though 17% and 35% SLE patients have QTc and QTd prolongation, association with anti-Ro antibodies or disease activity was absent. A large proportion has other asymptomatic ECG abnormalities that may reflect subclinical cardiac involvement.

PSV-8 Enriched environment improves the resistance to transport stress in laying hens via modulating the heat shock protective response and inflammation

Abstract Enriched environment can promote the adaptability of animals to cope with the complex environments. To evaluate how enriched environment experience can help laying hens resist to transport stress, a total of 432 18-week-old laying hens were randomly divided into two treated groups of which one group was housed in conventional battery cages (CC, 24 replicate cages, 3 birds/cage) and the other was in furnished cages (FC, 24 repeated cages, 15 birds/cage). At their 64 weeks of age, one hen per replicate was selected for 4h transportation. The spleen of hens was collected before transportation, after the transportation and 48h for recovery. The expression of heat shock proteins (HSPs), heat shock factors (HSFs) and inflammatory factors were measured. The serum from those birds was collected to detect inflammatory cytokines levels. Variance analysis showed that the expression of most of the detected HSPs and HSFs indicators were decreased after transportation and then elevated later. The mRNA expression of HSP10, 40, 60, 70, 90 and 110, HSF2 and HSF3 and the protein expression of HSP 60, 70 and 90 were higher in FC group than CC after the transportation and recovery (P &amp;lt; 0.05). Moreover, the hens housed in FC group had the lower mRNA expression of pro-inflammatory factors of nuclear transcription factor (NF-κB), cyclooxygenase-2 (COX-2) and prostaglandin E synthase (PTGEs) before and after the transportation compared to CC group (P &amp;lt; 0.05). The mRNA expression of inflammatory cytokines of interleukin-2 (IL-2), -6 (IL-6) and tumor necrosis factor (TNF-α) and serum concentration of IL-1β and TNF-α in FC hens were lower than CC after the transportation (P &amp;lt; 0.05), respectively. Therefore, by regulating the heat shock protective response and inflammatory cytokines expression, the enriched environment can reduce the stress damage of laying hens and improve the resistance to transport stress.

PSI-4 Changes in serum cortisol concentrations and cytokine profiles of growing pigs subjected to low-intensity heat stress

Abstract This study was to determine the impact of low-intensity heat stress on inflammatory biomarkers in serum, ileum, jejunum and lung lavage samples. Pigs (n = 64; 24.6 ± 3.7 kg BW) were housed four per pen in thermoneutral conditions (CON; 23.9°C ± 2.5°C) or constant high ambient temperatures (HS; 28.7°C ± 1.3°C) for 16 d, followed by thermoneutral conditions (24.4°C ± 1.8°C) for both groups through d 21, and subsequent heat stress (28.0°C ± 3.0°C) for both groups through d 30. Respiration rate (P &amp;lt; 0.01) was greater in HS than CON pigs from d 2 through d 15 (mean: 82.54 breaths/min vs. 59.26 breaths/min). HS pigs had greater cortisol concentration (40.1 ng/mL vs. 27.3 ng/mL) than CON on d 2, but lower concentrations on d 22 (32.9 ng/mL vs. 48.9 ng/mL) and d 25 (25.4 ng/mL vs. 42.0 ng/mL; treatment x day: P &amp;lt; 0.001). HS pigs tended to have greater serum IL1β (190.1 vs. 143.4 pg/mL; P = 0.06) and greater serum IL12 concentrations (914.9 vs. 785.4 pg/mL; P &amp;lt; 0.01) than CON pigs. HS pigs tended to have greater ileal mucosa IL6 concentrations than CON pigs (50.4 vs. 30.9 pg/mL; P = 0.08). Jejunal mucosa IL1α concentrations tended (P = 0.10) to be greater for CON than HS pigs (13.5 vs. 9.0 pg/mL) and CON pigs had greater jejunal IL12 concentrations (18.1 vs. 11.8 pg/mL) than HS pigs (P = 0.02). Bronchioalveolar lavage from HS pigs tended (P = 0.10) to have a greater granulocyte-macrophage colony-stimulating factor concentration (6.9 vs. 5.3 pg/mL) than CON pigs and had greater IL4 (7.7 vs. 4.2 pg/mL) and IL12 concentrations (34.8 vs. 24.5 pg/mL) than CON pigs (P = 0.01). Increased inflammatory activity and endocrine stress response occurred during low-intensity heat stress, indicating it may be more detrimental than previously accepted.

SIRT1 alleviates hepatic ischemia-reperfusion injury via the miR-182-mediated XBP1/NLRP3 pathway

The hepatoprotection of histone deacetylase sirtuin 1 (SIRT1) has been identified to attenuate ischemia-reperfusion (IR)-triggered inflammation and liver damage. This study was performed to characterize the function of SIRT1 in hepatic IR injury. In in vivo assays on liver-specific knockout mice of SIRT1, we first validated the effect of SIRT1 knockout on liver damage and XBP1/NLRP3 inflammasome activation. Next, we examined whether knockdown of XBP1/NLRP3 or miR-182 agomir could reverse the effect of SIRT1 knockout. In in vitro assays, NCTC1469 cells subjected to hypoxia/reoxygenation (H/R) were transduced with small interfering RNA (siRNA)/activator of SIRT1 or miR-182 agomir to confirm the effect of SIRT1 on NCTC1469 cell behaviors as well as the regulation of miR-182 and the XBP1/NLRP3 signaling pathway. Hepatic IR injury was appreciably aggravated in SIRT1 knockout mice, and SIRT1 knockdown abolished the inhibition of XBP1/NLRP3 inflammasome activation, which was reversed by NLRP3 knockdown, XBP1 knockdown, or miR-182 agomir. Mechanistically, miR-182 expression was positively regulated by SIRT1 in hepatic IR injury in mice, and miR-182 inhibited the expression of XBP1 by binding to the 3′ untranslated region (UTR) of XBP1. The histone deacetylase SIRT1 inhibits the downstream XBP1/NLRP3 inflammatory pathway by activating miR-182, thus alleviating hepatic IR injury in mice.

Inhibitory effects of nodakenin on inflammation and cell death in lipopolysaccharide-induced liver injury mice

BackgroundNodakenin, a coumarin glucoside isolated from the roots of Angelica biserrata, has been reported to have anti-inflammatory, antibacterial, anticancer effects. However, despite these studies, the potential liver protective effects of nodakenin in inflammatory liver injury models have not been reported. MethodsA mouse model of inflammatory liver injury was induced by injection of lipopolysaccharide (LPS) (15 mg/kg, intraperitoneally (i.p)). Liver tissue AST, ALT, ROS, T-GSH and T-SOD were analyzed by ELISA. The concentrations of TNF-α, IL-6, and IL-1β in serum of LPS-induced inflammatory liver injury mice were analyzed. The mRNA expression levels of GPx1, catalase, SOD1, SOD2, TNF-α, IL-6, IL-1β, iNOS and COX-2 were analyzed using real-time PCR. The expressions of MAPK, IRF3, NF-κB, Nrf2, HO-1, caspase-3 and caspase-7 were analyzed using western blotting. Liver tissue was stained with IHC to confirm NF-κB, Nrf-2, HO-1, caspase-3, Bax, and Bcl2. Tunnel analysis was performed to confirm the fragmented nuclear DNA characteristics of apoptosis. ResultsThe administration of nodakenin (10 and 30 mg/kg) reduced serum aminotransferase levels compared to LPS-induced liver damage and significantly improved the oxidative state of liver tissue and pathological damage. Moreover, inhibited the phosphorylation of transforming growth factor beta (TGF-β)-activated kinase (TAK)-1 in LPS-induced inflammatory liver injury model, and significantly inhibited the transcriptional of nuclear factor-kappa B (NF-kB) and the secretion of pro-inflammatory mediators. In addition nodakenin pre-treatment also attenuated hepatocyte death by regulating apoptosis-related mitochondrial proteins, such as cysteinyl aspartate specific proteinase 3 (caspase 3), poly (ADP-ribose) polymerase (PARP), B-cell lymphoma 2 (Bcl-2) and Bcl-2-associated X (Bax). ConclusionOur findings suggest that nodakenin has anti-inflammatory, anti-oxidant and anti-apoptotic activity and may be an adjunctive prevention agent for liver injury.

Eff ects of hyperbaric oxygen on NLRP3 infl ammasome activation in the brain aft er carbon monoxide poisoning

Neuroinflammation plays an important role in brain damage after acute carbon monoxide poisoning (ACOP). The nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing (NLRP) 3 inflammasome triggers the activation of inflammatory caspases and maturation of interleukin (IL)-1β and -18, and has been linked to various human autoinflammatory and autoimmune diseases. In this study we investigated the effects of hyperbaric oxygen (HBO2) on NLRP3 inflammasome activation after ACOP. Mice were randomly divided into four groups: sham group (exposure to normobaric air – i.e., 21% O2 at 1 atmosphere absolute); HBO2-only group; CO + normobaric air group; and CO + HBO2 group. Cognitive function was evaluated with the Morris water maze; myelin injury was assessed by Fluoro-Myelin GreenTM fluorescent myelin staining and myelin basic protein (MBP) immunostaining; and mRNA and protein levels of NLRP3 inflammasome complex proteins were measured by quantitative real-time PCR and Western blot, respectively. Additionally, serum and brain levels of IL-1β and -18 and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase were determined by enzyme-linked immunosorbent assay. It was found that HBO2 improved learning and memory, and alleviated myelin injury in mice subjected to acute CO exposure. Furthermore, HBO2 decreased NLRP3, absent in melanoma 2 (AIM2), caspase-1, and apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain mRNA and protein levels, and reduced brain and serum concentrations of IL-1β and -18 and NADPH oxidase. These results indicate that HBO2 suppresses the inflammatory response after ACOP by blocking NLRP3 inflammasome activation, thereby alleviating cognitive deficits.

Cathelicidin-related antimicrobial peptide alleviates alcoholic liver disease through inhibiting inflammasome activation.

Alcoholic liver disease (ALD) is associated with gut dysbiosis and hepatic inflammasome activation. While it is known that antimicrobial peptides (AMPs) play a critical role in the regulation of bacterial homeostasis in ALD, the functional role of AMPs in the alcohol-induced inflammasome activation is unclear. The aim of this study was to determine the effects of cathelicidin-related antimicrobial peptide (CRAMP) on inflammasome activation in ALD. CRAMP knockout (Camp-/-) and wild-type (WT) mice were subjected to binge-on-chronic alcohol feeding and synthetic CRAMP peptide was administered. Serum/plasma and hepatic tissue samples from human subjects with alcohol use disorder and/or alcoholic hepatitis were analyzed. CRAMP deficiency exacerbated ALD with enhanced inflammasome activation as shown by elevated serum interleukin (IL)-1β levels. Although Camp-/- mice had comparable serum endotoxin levels compared to WT mice after alcohol feeding, hepatic lipopolysaccharide (LPS) binding protein (LBP) and cluster of differentiation (CD) 14 were increased. Serum levels of uric acid (UA), a Signal 2 molecule in inflammasome activation, were positively correlated with serum levels of IL-1β in alcohol use disorder patients with ALD and were increased in Camp-/- mice fed alcohol. In vitro studies showed that CRAMP peptide inhibited LPS binding to macrophages and inflammasome activation stimulated by a combination of LPS and UA. Synthetic CRAMP peptide administration decreased serum UA and IL-1β concentrations and rescued the liver from alcohol-induced damage in both WT and Camp-/- mice. In summary, CRAMP exhibited a protective role against binge-on-chronic alcohol-induced liver damage via regulation of inflammasome activation by decreasing LPS binding and UA production. CRAMP administration may represent a novel strategy for treating ALD. © 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Baicalin-Copper Complex Modulates Gut Microbiota, Inflammatory Responses, and Hormone Secretion in DON-Challenged Piglets.

Simple SummaryDeoxynivalenol (DON) is the most common mycotoxin contaminant in the agriculture industry worldwide. Copper is very efficacious in promoting growth performance and improving feed remuneration, and baicalin may alleviate oxidative stress and inflammatory responses in humans and animals. We speculated that the combined effect of baicalin and copper would have some effect in DON-challenged piglets. The present study examined the effects of a baicalin-copper complex on inflammatory responses, hormone secretion, and gut microbiota in DON challenged piglets. These findings provide new application prospects in piglets involving the combination of baicalin and copper.The present experiment assessed the inflammatory responses, hormone secretion, and gut microbiota of weanling piglets administered baicalin-copper complex (BCU) or deoxynivalenol (DON) supplementation diets. Twenty-eight piglets were randomly assigned to four groups: control diet (Con group), a 4 mg DON/kg diet (DON group), a 5 g BCU/kg diet (BCU group), a 5 g BCU + 4 mg DON/kg diet (DBCU group). After 14 days, the results showed that dietary BCU supplementation remarkably increased the relative abundance of Clostrium bornimense and decreased the relative abundance of Lactobacillus in the DBCU group (p < 0.05). BCU decreased the serum concentration of IgG, IL-2, IFN-γ, and IgA in DON treated piglets (p < 0.05), and promoted the serum concentration of IL-1β, IgG, IL-2, IFN-γ, IgA, IL-6, IgM, and TNFα in normal piglets (p < 0.05). BCU increased the concentrations of serum IGF1, insulin, NPY, GLP-1, and GH, and decreased the concentrations of serum somatostatin in no DON treated piglets (p < 0.05). Dietary BCU supplementation significantly promoted the secretion of somatostatin, and inhibited the secretion of leptin in piglets challenged with DON (p < 0.05). BCU regulated the expression of food intake-related genes in the hypothalamus and pituitary of piglets. Collectively, dietary BCU supplementation alleviated inflammatory responses and regulated the secretion of appetite-regulating hormones and growth-axis hormones in DON challenged piglets, which was closely linked to changes of intestinal microbes.

Ability of Post-treatment Glycyrrhizic Acid to Mitigate Cerebral Ischemia/Reperfusion Injury in Diabetic Mice.

BackgroundDiabetes aggravates cerebral ischemia/reperfusion (I/R) injury by increasing inflammatory reactions, but its specific mechanism is currently unclear.Material/MethodsDiabetes was induced in mice with a high-fat diet combined with streptozotocin. These mice were subjected to transient middle cerebral artery occlusion (tMCAO) for 60 min, followed by reperfusion for 24–72 h and post-treatment glycyrrhizic acid (GA). Control and diabetic mice were randomly allocated to 8 groups of 18 mice each. Blood glucose, brain infarction, brain edema, and neurological function were monitored. Necrosis was determined by Nissl staining, loss of neurons by immunofluorescent (IF) staining for NeuN, and activation of inflammatory microglia by IF staining for Iba-1. Levels of HMGB1, TLR4, Myd88, and NF-κB mRNA and protein in ischemic brain were determined by qRT-PCR and western blotting, respectively, and serum concentrations of IL-1β, IL-6, and TNF-α by ELISA.ResultsInfarction volume, brain edema, and neurological function after tMCAO were significantly aggravated in diabetes, but ameliorated by post-treatment GA. GA also reduced neuronal loss and microglial activation. Cerebral Myd88 level showed a positive correlation with neurological scores. GA suppressed the expression of Myd88 and a proinflammatory pathway that included Myd88, HMGB1, TLR4, and NF-κB, as well as reducing serum concentrations of IL-1β, IL-6, and TNF-α.ConclusionsPost-treatment inhibited inflammatory responses and provided therapeutic benefits in diabetic mice with cerebral I/R injury, suggesting that GA may be a candidate drug to suppress cerebral I/R in diabetic patients.

Association of pro-inflammatory cytokines with clinical features in euthymic patients with Bipolar-I-Disorder

BackgroundA chronic low-grade inflammatory state appears to be a relevant mechanism in the pathophysiology of bipolar disorder. Pro-inflammatory cytokines may influence disease course and individual symptomatology; and biological markers correlating with illness features may be of utility in clinical decision making during euthymia. Methods51 euthymic outpatients with Bipolar-I-Disorder (BD-I) and 93 healthy controls (HC) were investigated. Comparisons between groups, and correlations with clinical features were performed. Serum concentrations of interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and soluble interleukin-6 receptor (sIL-6R) were evaluated by ELISA under highly standardized conditions. Clinical features included duration of illness, number of previous suicide attempts and mood episodes (manic, hypomanic, depressive), scores of the Young Mania Rating Scale (YMRS), the Inventory of Depressive Symptoms (IDS-30), the Pittsburg Sleep Quality Index (PSQI), and the Global Assessment of Functioning (GAF). ResultsNo significant difference in serum concentrations of IL-1β, TNF-α, and sIL-6R between BD-I euthymic patients and HC could be identified. Among euthymic BD-I patients, a positive correlation of rs = 0.47 (p = 0.004) between levels of IL-1β and IDS-30 score was identified. LimitationsThe design was cross-sectional, most patients were receiving medication, only 3 cytokines were assessed, only euthymic BD-I patients were evaluated. ConclusionsThe findings suggest that elevated pro-inflammatory cytokine concentrations are likely state rather than trait markers of BD-I. It also seems unlikely that cytokine concentrations are clinically informative interepisode. An inflammatory component might possibly be involved in the pathophysiology of subsyndromic depression in BD-I, and conceivably of bipolar depression per se.

Irbesartan may relieve renal injury by suppressing Th22 cells chemotaxis and infiltration in Ang II-induced hypertension

Angiotensin II (Ang II) as an important pathogenic factor, has been implicated in the pathogenesis of hypertension and associated renal injury, and inhibition of Ang II can reduce renal inflammation and exert renal protective effects. In the present study, we determine the infiltration of Th22 cells in kidney and serum IL-22 level in hypertensive renal injury, and explore the effects and mechanisms of a widely used angiotensin II type 1 receptor blocker irbesartan on Th22 cells infiltration and related renal injury. Hypertension was induced by administering 1.5 mg/kg Ang II subcutaneously daily in C57BL/6 mice for 28 days. The mice were additionally treated by irbesartan or amlodipine. Renal Th22 lymphocytes frequency was evaluated through flow cytometry, serum IL-22 was detected by ELISA, and renal histopathological changes were also detected. The levels of renal chemokines (CCL20, CCL22, CCL27) and serum proinflammatory factors (IL-1β, IL-6, TNF-α) were measured by ELISA. Renal expression of alpha-smooth muscle actin (α-SMA), Fibronectin (FN) and collagen I (Col I) were evaluated by western blot. Chemotaxis assay and co-culture assay were conducted to clarify the effect of irbesartan on Th22 cells chemotaxis and differentiation in vitro. Our results showed in Ang II-infused hypertension mice, irbesartan suppressed renal Th22 cells accumulation as well as CCL20, CCL22, CCL27 expression. Serum IL-22, IL-1β, IL-6 and TNF-α concentrations wasere also reduced, in addition to inhibited renal expression of α-SMA, FN and Col I. Irbesartan treatment lowered blood pressure, urinary protein and renal pathological damage. In vitro, irbesartan could abrogate the Th22 cells chemotaxis and differentiation, compared to control and amlodipine groups. Our study reveals a new pharmacological mechanism that irbesartan ameliorates inflammation and fibrosis in hypertensive renal injury induced by Ang II, maybe through inhibiting Th22 cells chemotaxis and infiltration, which provides a new theoretical basis and therapeutic target for hypertensive renal injury.

The Effect of Antiretroviral Therapy on IL-6, IL-1β, TNF-α, IFN-γ Levels and their Relationship with HIV-RNA and CD4+ T Cells in HIV Patients.

Serum cytokine levels over the course of HIV infection usually increase with immunosuppression and decrease after antiretroviral treatment (ART). The aim of the study is to compare cytokine levels between HIV-infected patients (HIP) and controls and investigate the relationship between CD4+T cell count, HIV-RNA levels, and cytokine levels. The study subjects comprised ART-naive HIP (n=30) with no comorbidities and age-and sex-matched healthy controls. We measured levels of IL-6, IL-1β, TNF-α, and IFN-γ in serum samples of HIP at the beginning and at month 6 of ART and in controls. The mean age of the study subjects was 38.7 ±10.3 years, with men making up 86.7% of the study subjects (n=26). IL-6, IL-1β, and TNF-α levels were significantly higher in both ART-naive (p<0.001, p=0.002, p=0.001) and ART-experienced HIP (p<0.001) than controls. The IFN-γ level was lower in both ART-naive and ART-experienced HIP compared to controls (p=0.082 and p=0.002). There was a positive correlation between the CD4+T cell count and serum concentration of IFN- γ(r=0.320, p<0.05). While the serum IFN-γ concentration showed a negative correlation with the HIVRNA level(r=-0.412, p<0.001), the serum IL-1β, IL-6, and TNF-α concentrations showed a positive correlation with the HIV-RNA level (r=0.349, p<0.001; r:0.54, p<0.001; r:0.438, p<0.00). Although serum concentrations of IL-6, IL-1β and TNF-α showed a significant decrease after ART, they were still significantly higher than the controls. IFN-γ responded differently to ART compared to the other cytokines, indicating that it may play a distinct and important role in the pathogenesis of HIV infection.

A preliminary evaluation of the circulating leptin/adiponectin ratio in dogs with pituitary-dependent hyperadrenocorticism and concurrent diabetes mellitus

Leptin and adiponectin are thought to modulate insulin sensitivity and pancreatic β-cell function, but there is limited information regarding the adipokine status of hyperglycemic dogs with hyperadrenocorticism. This study aimed to determine whether alterations in the leptin/adiponectin ratio, insulin sensitivity, and/or pancreatic β-cell function are associated with diabetes mellitus (DM) in dogs with pituitary-dependent hyperadrenocorticism (PDH). A total of 48 client-owned dogs were included in this prospective observational study: 20 dogs with PDH (10 normoglycemic and 10 with DM), 15 dogs with DM, and 13 healthy dogs. The serum concentrations of leptin, adiponectin, resistin, interleukin (IL)-1β, IL-6, IL-10, IL-18, and tumor necrosis factor (TNF)-α were measured, and homeostatic model assessment indices (HOMAs) were calculated and compared among the groups. Serum leptin was significantly higher in PDH dogs with and without DM than in healthy and DM dogs, and it was lower in DM dogs than in PDH dogs without DM. Serum adiponectin was significantly lower in PDH dogs with DM than in healthy and PDH dogs, and it was significantly lower in DM dogs than in healthy dogs. Serum IL-10 was significantly higher in PDH dogs with DM than in healthy and PDH dogs without DM. The leptin/adiponectin ratio was significantly higher in PDH dogs with DM than in normoglycemic PDH dogs. Serum IL-6 concentrations were significantly higher in DM dogs than in healthy dogs. Serum IL-1β concentration was significantly higher in DM dogs than in healthy dogs and PDH dogs with DM and without DM. Serum TNF-α and IL-18 concentrations were not different among groups. The HOMAβ-cell function was significantly lower in PDH dogs with DM than in normoglycemic PDH dogs, while HOMAinsulin sensitivity was significantly lower in PDH dogs with DM than in healthy dogs. These results suggest that adipokine dysregulation, a reduction in insulin sensitivity, and a further impairment in pancreatic β-cell function might predispose PDH dogs to DM. Further longitudinal study will be necessary to confirm this result.