IL-1beta Levels Research Articles

Effects of carvacrol on ketamine-induced cardiac injury in rats: an experimental study

Aim We aimed to investigate the preventive effects of carvacrol against ketamine-induced cardiotoxicity biochemically and histopathologically in an experimental model. Material and method The rats were divided into three groups; healthy control (HC), ketamine alone (KG), and ketamine + carvacrol (KCG) groups. Serum Creatine Kinase Myocardial Band (CK-MB) and Troponin I (TP I) levels were determined. Malondialdehyde (MDA), Glutathione (GSH), Superoxide Dismutase (SOD), Tumor Necrosis Factor α (TNF-α), Interleukin 1 beta (IL-1beta), and Interleukin 6 (IL-6) levels were measured in the heart tissues of the rats. Heart tissues were also evaluated histopathologically. Results In the ketamine-treated group, tissue MDA, TNF-α, IL-1beta, and IL-6 levels increased while tissue GSH and SOD levels decreased significantly compared with the control group. However, in the ketamine plus carvacrol applied group, all those alterations were significantly less pronounced, close to the healthy controls. Severe mononuclear cell infiltrations, degenerated myocytes and hemorrhage were determined in the ketamine alone administered group, and these alterations were at a mild level in the carvacrol + ketamine administered group. Conclusion Prolonged exposure to ketamine resulted in induced oxidative stress in rat heart tissue; concomitant carvacrol application could counteract the negative effects of ketamine by protecting tissues from lipid peroxidation and decreasing the inflammatory response.

In vitro antioxidant analysis of flavonoids extracted from Artemisia argyi stem and their anti-inflammatory activity in lipopolysaccharide-stimulated RAW 264.7 macrophages

In this study, flavonoids were successfully extracted from Artemisia argyi stem, and their yield reached 15.3 mg/g dry A. argyi stem. The flavonoid extract from A. argyi stem had a purity of 88.58 % (w/w), meanwhile, which also contained 1.57 % (w/w) carbohydrates, 2.04 % (w/w) proteins and 7.81 % (w/w) polyphenols, respectively. In vitro antioxidant activity analysis showed the increased scavenging effects of flavonoid extract from A. argyi stem on 1,1-diphenyl-2-picrylhydrazyl, 2,2′-azinobis-di-(3-ethyl-benzothiazolin-6-sulfonic acid) diammonium salt, hydroxyl, and superoxide radicals in a concentration-dependent manner. Furthermore, the flavonoid extract from A. argyi stem exerted protective effects on lipopolysaccharide-stimulated RAW 264.7 macrophages via inhibiting the levels of tumor necrosis factor-alpha, interleukin-6, interleukin-1 beta, and nitric oxide free radicals. Overall, this work will provide guidance and help in the utilization of edible A. argyi as plant-based diet and its bioactive flavonoid extract as antioxidant and anti-inflammatory ingredients to improve the function, nutrition, and healthiness of foods.

Trans-anethole exerts protective effects on lipopolysaccharide-induced acute jejunal inflammation of broilers via repressing NF-κB signaling pathway

This study aimed to explore the effects of trans-anethole (TA) on lipopolysaccharide (LPS)-induced acute jejunal inflammation model of broilers. A total of 160 one-day-old broilers (male; Arbor Acres) were randomly allocated into four treatment groups with 8 replicates of 5 birds each. On d 20, the dose of 5 mg/kg body weight LPS solution and the equal amount of sterile saline were intraperitoneally injected into LPS-challenged and unchallenged broilers, respectively. Compared with the control group, LPS decreased (P < 0.05) the villus height (VH) and the ratio of villus height to crypt depth (VCR) but increased (P < 0.05) the crypt depth (CD), meanwhile, enhanced (P < 0.01) the levels of interleukin-6 (IL-6), interleukin-1beta (IL-1β) and tumor necrosis factor-alpha (TNF-α) but decreased (P < 0.01) the level of interleukin-10 (IL-10). The group supplemented with 600 mg/kg of TA had lower (P < 0.01) CD and higher (P < 0.01) VCR than the LPS group. TA increased (P < 0.01) the level of IL-10 and decreased (P < 0.01) the level of IL-1β. The mRNA expression levels of IL-6, nuclear factor kappa B (NF-κB), TNF-α were up-regulated (P < 0.05) and the levels of IL-10 and inhibitor of NF-κB alpha (IκBα) were down-regulated (P < 0.05) by LPS as compared with the control group. TA down-regulated (P < 0.05) the increased mRNA expression levels of genes caused by LPS, as well as up-regulated (P < 0.05) the levels of IL-10 and IκBα. Furthermore, LPS down-regulated (P < 0.05) and up-regulated (P < 0.05) the protein expression levels of IκBα and NF-κB p65, respectively. TA up-regulated (P < 0.05) the level of IκBα and down-regulated (P < 0.05) the level of NF-κB p65. The conclusion of this study is that TA could exert protective effect on the LPS-induced acute jejunal inflammation of broilers via repressing the activation of NF-κB and the 600 mg/kg is the optimal dose against LPS-induced acute jejunal inflammation of broilers.

ATL I, Acts as a SIRT6 Activator to Alleviate Hepatic Steatosis in Mice via Suppression of NLRP3 Inflammasome Formation.

Accumulating evidence has highlighted that sirtuin-6 (SIRT6) plays an important role in hepatic gluconeogenesis and lipogenesis. We aim to investigate the underlying mechanisms and pharmacological interventions of SIRT6 on hepatic steatosis treatment. Herein, our results showed that atractylenolide I (ATL I) activated the deacetylase activity of SIRT6 to promote peroxisome proliferator-activated receptor alpha (PPARα) transcription and translation, while suppressing nuclear factor NF-kappa-B (NFκB)-induced NACHT, LRR, and PYD domains containing protein 3 (NLRP3) inflammasome formation. Together, these decreased the infiltration of F4/80 and CD11B positive macrophages, accompanied by decreased mRNA expression and serum levels of tumor necrosis factor alpha (TNF-α), interleukin-6 (IL6), and interleukin-1 beta (IL1β). Additionally, these changes decreased sterol regulatory element-binding protein-1c (SREBP-1c) expression, while restoring carnitine O-palmitoyltransferase 1a (Cpt1a) expression, to decrease the size of adipocytes and adipose deposition, which, in turn, reversed high-fat diet (HFD)-induced liver weight and body weight accumulation in C57 mice. SIRT6 knockout or hepatic SIRT6 knockout in C57 mice largely abolished the effect of ATL I on ameliorating hepatic steatosis. Taken together, our results suggest that ATL I acts as a promising compound that activates SIRT6/PPARα signaling and attenuates the NLRP3 inflammasome to ameliorate hepatic inflammation and steatosis.

Increased expression of NLRP3 inflammasome components in granulosa cells and follicular fluid interleukin(IL)-1beta and IL-18 levels in fresh IVF/ICSI cycles in women with endometriosis.

The inflammasomes are a family of recently described multi-protein cytoplasmic sensors that orchestrate the inflammatory response and participate in a variety of inflammatory conditions. We hypothesized that the activation of pyrin domain‑containing protein 3 (NLRP3) inflammasome by granulosa cells (hGCs) may be activated in women with endometriosis and influence oocyte maturation and IVF outcomes. We performed a cross-sectional study to investigate the NLRP3 inflammasome status in follicular fluid (FF) and in hGCs from 44 women undergoing controlled ovarian stimulation for IVF/ICSI. Study subjects were divided into two groups according to the infertility etiology: group with tubal or male factor (control, n = 22) vs. group with endometriosis (n = 22). The FF IL-1beta and IL-18 levels in the endometriosis group were significantly higher than those in the non-endometriosis group, i.e., 5010pg/mL and 2738pg/mL, respectively (p < 0.05). No correlation was found between clinical pregnancy and live birth rate and analyzed inflammasome component levels (p > 0.05). In addition, the hGCs from endometriosis women demonstrated high expression of NLRP3 inflammasome at both protein and mRNA levels. Higher expression of inflammasome components within the ovary compartment may result from the exaggerated inflammatory state associated with endometriosis and thus impact the fertility of these women.

XANTHOHUMOL REDUCES THE EXPRESSION OF PRO-INFLAMMATORY AND OXIDATIVE STRESS MARKERS IN THE LUNG OF SENESCENCE-ACCELERATED PRONE MICE (SAMP8)

<h3>Objective</h3> Aging consists of a series of deleterious changes in cells and tissues along time, which lead to altered homeostasis. Nowadays we consider oxidative stress and inflammation the most relevant mechanisms of cell damage and dysfunction during aging. Both clinical and subclinical antigen exposure along life trigger a chronic inflammatory and oxidative response in the host. The lung, due to its position between the internal and the external milieu, is particularly exposed to pathogens and pollutants. An upregulation of oxidative stress and inflammation in lung tissue is expected. Xanthohumol, the major prenylated chalcone found in hops, has been shown to present anti-inflammatory and antioxidant properties in several organs, including liver, brain, and the reproductive system. Its effect on the aging lung has yet to be elucidated. For this reason, the aim of the present study was to evaluate the possible anti-inflammatory role of xanthohumol on a model of male senescence-accelerated prone mice (SAMP8). Design and method: Animals: young and old animals, aged 2 and 10 months respectively, were maintained under a 12:12 h light-dark cycle in an environmentally-controlled room and fed ad libitum. They were divided into 4 experimental groups: young non-treated, old non-treated, old treated with 1 mg/kg/day xanthohumol, and old treated with 5 mg/kg/day xanthohumol. Young and old non-treated male senescence-accelerated resistant mice (SAMR1) were used as controls. Treatment: xanthohumol was dissolved in ethanol and added to the drinking water. Only ethanol was administered to the water of non-treated animals. After 30 days of treatment, animals were sacrificed and lungs were collected and immediately frozen in liquid nitrogen. Inflammation and oxidative stress markers: both mRNA and protein levels of tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and heme oxygenase 1 (HO-1) were analyzed. mRNA nuclear factor NF-kappa-B (NFκB) levels were also quantified. mRNA and protein expressions were measured by RT-PCR and Western blotting, respectively. The results were analyzed by using ANOVA followed by Fisher's post-hoc test. <h3>Results</h3> Compared to the young animals, old non-treated SAMP8 mice presented significantly elevated (p<0.05) mRNA and protein levels of TNF-α, IL-1β, and HO-1. mRNA NFκB2 levels were also significantly increased (p<0.05). SAMR1 mice showed significantly decreased values (p<0.05). <h3>Conclusions</h3> Treatment with xanthohumol was able to decrease significantly (p<0.05) the age-induced elevation at any of the doses administered. Supplementing the diet with foodstuffs containing xanthohumol may be used as a potential tool for counteracting inflammation and oxidative stress in the aging lung.

MiR-338-3p Is a Biomarker in Neonatal Acute Respiratory Distress Syndrome (ARDS) and Has Roles in the Inflammatory Response of ARDS Cell Models.

To investigate the association between serum miR-338-3p levels and neonatal acute respiratory distress syndrome (ARDS) and its mechanism. The relative miR-338-3p expression in serum was detected by quantitative real-time RT-PCR. Interleukin-1beta (IL-1β), IL-6, and tumor necrosis factor-alpha (TNF-α) levels were detected by ELISAs. A receiver operating characteristic (ROC) curve analysis of serum miR-338-3p evaluated the diagnosis of miR-338-3p in neonatal ARDS. Pearson's correlation analysis evaluated the correlation between serum miR-338-3p and neonatal ARDS clinical factors. Flow cytometry evaluated apoptosis, and a CCK-8 assay assessed cell viability. A luciferase assay evaluated the miR-338-3p/AKT3 relationship. The miR- 338-3p expression was decreased in neonatal ARDS patients and in lipopolysaccharide (LPS)-treated cells. The ROC curve showed the accuracy of miR-338-3p for evaluating neonatal ARDS patients. The correlation analysis demonstrated that miR-338-3p was related to PRISM-III, PaO2/FiO2, oxygenation index, IL-1β, IL-6, and TNF-α in neonatal ARDS patients. MiR-338-3p overexpression inhibited the secretion of inflammatory components, stifled cell apoptosis, and LPS-induced advanced cell viability. The double-luciferase reporter gene experiment confirmed that miR-338-3p negatively regulates AKT3 mRNA expression. Serum miR-338-3p levels were related to the diagnosis and severity of neonatal ARDS, which may be attributed to its regulatory effect on inflammatory response in ARDS.

Icaritin inhibits neuroinflammation in a rat cerebral ischemia model by regulating microglial polarization through the GPER–ERK–NF-κB signaling pathway

BackgroundActivated microglia play a key role in initiating the inflammatory cascade following ischemic stroke and exert proinflammatory or anti-inflammatory effects, depending on whether they are polarized toward the M1 or M2 phenotype. The present study investigated the regulatory effect of icaritin (ICT) on microglial polarization in rats after cerebral ischemia/reperfusion injury (CI/RI) and explored the possible anti-inflammatory mechanisms of ICT.MethodsA rat model of transient middle cerebral artery occlusion (tMCAO) was established. Following treatment with ICT, a G protein-coupled estrogen receptor (GPER) inhibitor or an extracellular signal-regulated kinase (ERK) inhibitor, the Garcia scale and rotarod test were used to assess neurological and locomotor function. 2,3,5-Triphenyltetrazolium chloride (TTC) and Fluoro-Jade C (FJC) staining were used to evaluate the infarct volume and neuronal death. The levels of inflammatory factors in the ischemic penumbra were evaluated using enzyme-linked immunosorbent assays (ELISAs). In addition, western blotting, immunofluorescence staining and quantitative PCR (qPCR) were performed to measure the expression levels of markers of different microglial phenotypes and proteins related to the GPER–ERK–nuclear factor kappa B (NF-κB) signaling pathway.ResultsICT treatment significantly decreased the cerebral infarct volume, brain water content and fluorescence intensity of FJC; improved the Garcia score; increased the latency to fall and rotation speed in the rotarod test; decreased the levels of interleukin-1 beta (IL-1β), tumor necrosis factor-alpha (TNF-α), Iba1, CD40, CD68 and p-P65-NF-κB; and increased the levels of CD206 and p-ERK. U0126 (an inhibitor of ERK) and G15 (a selective antagonist of GPER) antagonized these effects.ConclusionsThese findings indicate that ICT plays roles in inhibiting the inflammatory response and achieving neuroprotection by regulating GPER–ERK–NF-κB signaling and then inhibiting microglial activation and M1 polarization while promoting M2 polarization, which provides a new therapeutic for against cerebral ischemic stroke.Graphical

Intranasally administered human MSC-derived extracellular vesicles inhibit NLRP3-p38/MAPK signaling after TBI and prevent chronic brain dysfunction

Traumatic brain injury (TBI) leads to lasting brain dysfunction with chronic neuroinflammation typified by nucleotide-binding domain leucine-rich repeat and pyrin domain-containing receptor 3 (NLRP3) inflammasome activation in microglia. This study probed whether a single intranasal (IN) administration of human mesenchymal stem cell-derived extracellular vesicles (hMSC-EVs) naturally enriched with activated microglia-modulating miRNAs can avert chronic adverse outcomes of TBI. Small RNA sequencing confirmed the enrichment of miRNAs capable of modulating activated microglia in hMSC-EV cargo. IN administration of hMSC-EVs into adult mice ninety minutes after the induction of a unilateral controlled cortical impact injury resulted in their incorporation into neurons and microglia in both injured and contralateral hemispheres. A single higher dose hMSC-EV treatment also inhibited NLRP3 inflammasome activation after TBI, evidenced by reduced NLRP3, apoptosis-associated speck-like protein containing a CARD, activated caspase-1, interleukin-1 beta, and IL-18 levels in the injured brain. Such inhibition in the acute phase of TBI endured in the chronic phase, which could also be gleaned from diminished NLRP3 inflammasome activation in microglia of TBI mice receiving hMSC-EVs. Proteomic analysis and validation revealed that higher dose hMSC-EV treatment thwarted the chronic activation of the p38 mitogen-activated protein kinase (MAPK) signaling pathway by IL-18, which decreased the release of proinflammatory cytokines. Inhibition of the chronic activation of NLRP3-p38/MAPK signaling after TBI also prevented long-term cognitive and mood impairments. Notably, the animals receiving higher doses of hMSC-EVs after TBI displayed better cognitive and mood function in all behavioral tests than animals receiving the vehicle after TBI. A lower dose of hMSC-EV treatment also partially improved cognitive and mood function. Thus, an optimal IN dose of hMSC-EVs naturally enriched with activated microglia-modulating miRNAs can inhibit the chronic activation of NLRP3-p38/MAPK signaling after TBI and prevent lasting brain dysfunction.

Pergularia tomentosa coupled with selenium nanoparticles salvaged lead acetate-induced redox imbalance, inflammation, apoptosis, and disruption of neurotransmission in rats’ brain

Abstract In this study, the neuroprotective potential of either Pergularia tomentosa leaf methanolic extract (PtE) alone or in combination with selenium nanoparticles (SeNPs-PtE) was investigated against lead acetate (PbAc)-induced neurotoxicity. Experimental rats were pretreated with PtE (100 mg/kg) or SeNPs-PtE (0.5 mg/kg) and injected intraperitoneally with PbAc (20 mg/kg) for 2 weeks. Notably, SeNPs-PtE decreased brain Pb accumulation and enhanced the level of dopamine and the activity of AChE compared to the control rats. In addition, elevated neural levels of superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, and glutathione along with decreased lipid peroxidation levels were noticed in pretreated groups with SeNPs-PtE. Moreover, SeNPs-PtE significantly suppressed neural inflammation, as indicated by lower levels of interleukin-1 beta, interleukin-6, tumor necrosis factor-alpha, nuclear factor-kappa B p65, and nitric oxide in the examined brain tissue. The molecular results also unveiled significant down-regulation in iNOS gene expression in the brains of SeNPs-PtE-treated rats. In addition, SeNPs-PtE administration counteracted the neural loss by increasing B-cell lymphoma 2 (Bcl-2) and brain-derived neurotrophic factor levels as well as decreasing BCL2-associated X protein and caspase-3 levels. To sum up, our data suggest that P. tomentosa extract alone or in combination with SeNPs has great potential in reversing the neural tissue impairment induced by PbAc via its antioxidant, anti-inflammatory, and anti-apoptotic activities. This study might have therapeutic implications in preventing and treating several lead-induced neurological disorders.

Abamectin causes cardiac dysfunction in carp via inhibiting redox equilibrium and resulting in immune inflammatory response and programmed cell death.

This study aims to investigate the effects of environmentally relevant concentrations of abamectin on the cardiac function of carp and the potential mechanisms. Here, male carp were exposed to abamectin, and cardiac function-related enzymatic markers were examined. Cardiac histopathology, redox equilibrium, inflammation, and cell death were evaluated. Abamectin exposure caused cardiac dysfunction by upregulating lactate dehydrogenase (LDH), aspartate aminotransferase (AST), creatine kinase (CK), creatine Kinase MB isoenzyme (CK-MB) and white blood cells (WBCs), and decreasing red blood cells (RBCs) and hemoglobin (Hb). DHE staining and biochemical assays revealed that abamectin caused ROS release and oxidative stress by inhibiting Nrf2-ARE pathway. Histopathological and real-time fluorescence quantitative PCR (RT-qPCR) assays revealed that abamectin caused myocardial fiber swelling and inflammatory cell infiltration, enhanced pro-inflammatory cytokines tumor necrosis factor-α (Tnf-α), interleukin-1 beta (Il-1β), and Il-6 levels and attenuated anti-inflammatory cytokines Il-10 and transforming growth factor beta 1 (Tgf-β1) through activating NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome and nuclear factor kappa-B (NF-κB) pathway. Tunel staining showed that abamectin triggered cardiac apoptosis via activating p53-mediated mitochondrial apoptosis with elevated bcl2-associated X (Bax), reduced B-cell lymphoma-2 (Bcl-2), and activated Caspase-9 and Caspase-3. Immunoblot analysis revealed that abamectin activated autophagic flow by inhibiting mammalian target of rapamycin (mTOR), resulting in the conversion of LC3B from LC3-I to LC3-II, elevation of autophagy protein 5 (Atg5), and reduction of p62. Overall, abamectin caused cardiac dysfunction in carp via inhibiting redox equilibrium and resulting in immune inflammatory response and programmed cell death.

Golimumab Ameliorates Pancreatic Inflammatory Response in the Cerulein-Induced Acute Pancreatitis in Rats.

The aim of the study was to evaluate whether a new and successful treatment opportunity can be provided in acute pancreatitis and may prevent symptomatic treatments and show its effect through etiopathogenesis. Therefore, we want to investigate the efficacy of golimumab in an experimental rat model of cerulein-induced acute pancreatitis. A total of 35 rats, including 7 rats in each group, were distributed into 5 groups (sham, acute pancreatitis, placebo, acute pancreatitis+golimumab 5 mg/kg, and acute pancreatitis+golimumab 10 mg/kg). An experimental cerulein-induced acute pancreatitis model was accomplished by intraperitoneal cerulein injections. After sacrification, rat blood samples were collected for amylase, IL-6, and IL-1beta measurements. Histopathological analysis of the pancreas was performed with Tunel and hematoxylin and eosin staining. Amylase, IL-6, and IL-1beta levels were found to be increased in the acute pancreatitis group. IL-1beta, amylase, IL-6 levels, and pancreatic inflammation were all significantly decreased in golimumab groups (P < .01). Moreover, in both golimumab groups, golimumab treatment significantly reduced apoptosis in pancreatic tissues (P < .05). Golimumab treatment was found to significantly reduce edema formation, inflammation, vacuolization, and fat necrosis of pancreatic tissues (P < .05). Firstly in the literature, we investigated the efficacy of golimumab in the experimental acute pancreatitis model. In the light of our findings, it could be suggested that golimumab may be an effective and safe therapeutic option in the treatment of patients with acute pancreatitis.

High-Risk Cytokine Profiles Predict Lower Survivals in AML after Allotransplantation

Introduction: In a context of allogeneic hematopoietic stem cell transplantation (Allo-HSCT) for acute myeloid leukemia (AML), the impact of peripheral cytokine levels has been poorly studied so far. Methods: The aim of this prospective study (NCT02693899) was to analyze peripheral levels of 8 cytokines in 35 AML patients (pts) before conditioning (BC) then at Day (D) 0, 30, 60 and 100 post-Allo-HSCT by comparison to median levels from 20 healthy controls (16 males, median age 48.5 yo). ELISA (Bio-Techne, Minneapolis, MN) was used to assay the levels of FLt3-ligand (FL), TNF-alpha, stem-cell factor (SCF), c-kit, IL-1 beta, IL-6, IL-10 and granulocyte-monocyte colony-stimulating factor (GM-CSF). A total of 1313 and 157 samples were analyzed in pts and controls, respectively. The impact of BC, D0 and D30 levels and secretion (secretors = pts with detectable cytokine levels) on overall (OS), disease free (DFS) and GVHD and relapse free survival (GRFS) was also assessed. Results: Pts characteristics and cytokine levels are given in Tables 1 and 2. At D0, IL-6 (p=0.0006), FL (p<0.001) and SCF (p=0.003) levels were significantly higher in pts than controls. This remained true for SCF levels on D30 (p=0.0009), D60 (p=0.001) and D100 (p=0.01). Median GM-CSF and c-kit levels were significantly lower in pts at any time (p<0.001). Two-by-two paired cytokine comparisons showed no correlation, especially considering c-kit and its ligand SCF. ELN2017 classification and disease-risk index (DRI) were significantly associated with OS and LFS by univariate analysis (UA), only the former remaining associated with both OS (HR 8.51; 95%CI 1.18-61.54, p=0.034) and LFS (HR 8.10; 95%CI 1.20-54.82, p=0.032) in multivariate analysis (MA). Only SCF, IL-6 and c-kit levels impacted survivals. Higher pre-transplant SCF levels were associated with lower OS (p=0.02), DFS (p=0.01) and GRFS (P<0.001) by UA and remained associated with lower GRFS (HR 3.19; 95%CI 1.48-6.88, p=0.003) in MA, with a trend for lower LFS (HR 1.96; 95%CI 0.94-4.08, p=0.07). There was also an association between the absence of SCF secretion and better OS, LFS and GRFS (p=0.02, p=0.02, p=0.03) while c-kit secretion was associated with better OS (p=0.03) in UA. This remained true in MA for OS (HR 0.30; 95%CI 0.10-0.92, p=0.03) and there was a trend between no SCF secretion and GRFS (HR 0.45; 95%CI 0.18-1.14, p=0.09) by MA. Higher IL-6 levels at D0 were associated with lower OS (p=0.01) by UA and lower LFS both by UA (p=0.01) and MA (HR: 2.83; 95%CI: 1.04-7.70, p=0.04), with a trend for lower OS (HR: 2.55; 95%CI: 0.90-7.29, p=0.07) in MA. ROC curve analysis identified 7pg/mL as the best cut-off for D0 IL-6 levels which resulted, for pts under this level, in significantly better 4-year OS (80% (62-1) vs 35.7% (18-69), p=0.02) and LFS (73.3% (54-99) vs 28.6% (13-63) p=0.01; Figure). For alive patients at D30, higher c-kit and lower SCF levels were associated with better OS (p=0.003 and p=0.01) and LFS (p=0.009 and p=0.04) by UA while c-kit levels remained associated with LFS (HR: 0.37; 95%CI: 0.17-0.80, p=0.01) by MA. The absence of SCF secretion was associated with better OS (p=0.03) and a trend for better LFS (p=0.07). c-kit secretion was associated with better OS (p=0.008), LFS (p=0.01) and a trend for better GRFS (p=0.07). Only c-kit secretion remained associated with better OS (HR: 0.15; 95%CI: 0.04-0.57, p=0.005), LFS (HR: 0.19; 95%CI: 0.06-0.62, p=0.006) and GRFS (HR: 0.40.95%CI: 0.16-1.00, p=0.05) by MA. Conclusion: In this cohort, early higher IL-6 and SCF and lower c-kit levels appeared to be significantly associated with lower survivals in AML pts after Allo-HSCT. These high-risk cytokine profiles might allow to propose therapeutic intervention to decrease relapses in selected pts, either by modulating cytokine levels or by starting early maintenance treatment post-Allo-HSCT. These results have to be confirmed on larger studies. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

The Effect of Fixed Orthodontic Appliance Therapy on Periodontal Health Status And Salivary Cytokine Levels

BACKGROUND AND OBJECTIVE: Fixed orthodontic appliance therapy (FOAT) is universally recognized and most common method for treating malocclusion. Periodontal complications are frequent consequences of orthodontic therapy that need to be evaluated. The study aimed to evaluate clinical periodontal parameters and salivary cytokines levels among patients undergoing FOAT. METHODS: 30 systemically healthy subjects (males and females), age ranged from 17-28 years with health periodontium and malalignment teeth attended Khanzad teaching center for FOAT. Clinical periodontal parameters (plaque index, gingival index, sulcus bleeding index, probing depth, debris index simplified, calculus index simplified &amp; oral hygiene index simplified) and unstimulated saliva were assessed at baseline (0 day) before Fixed orthodontic appliance application and after one and three months of therapy. IL-1beta, IL-6, IL-8 and IL-10 levels were assessed in saliva by enzyme-linked immunosorbent assay (ELISA). RESULTS: The results showed significant increase in the mean values of clinical periodontal parameters and salivary cytokines levels of IL-1beta, IL-6, IL-8 after one and three months of FOAT as compared to base line (P &lt; 0.05), as well as significant decrease in the mean value of IL-10 level after one and three months as compared to baseline (P &lt; 0.05). No significant correlations were detected between periodontal and immunological parameters. CONCLUSION: Fixed orthodontic appliance therapy had a negative influence on periodontal health, since it promotes dental plaque accumulation &amp; gingival inflammation. As well as FOAT led to significant increase of pro inflammatory and significant decrease of anti-inflammatory cytokines

Multiple Cytokine Analysis of Th1/Th2/Th9/Th17/Th22/Treg Cytokine Pathway for Individual Immune Profile Assessment in Patients with Psoriasis.

BACKGROUND Psoriasis is an autoimmune and autoinflammatory disorder that has a significant impact on patient quality of life. The aim of the study was to assess the immune profiles of patients with psoriasis with multiple cytokine analysis. MATERIAL AND METHODS Fifty-two male psoriatic patients and 24 healthy male volunteers were recruited. Granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon gamma (IFN-gamma), interleukin (IL)-1 beta, IL-2, Il-4, IL-5, IL-6, IL-9, IL-10, IL-12p70, IL-13, IL-17A, IL-18, IL-21, IL-22, IL-23, IL-27, and tumor necrosis factor (TNF)-alpha were measured in patients' serum with a Th1/Th2/Th9/Th17/Th22/Treg Cytokine 18-Plex Human ProcartaPlex Panel, based on Luminex xMAP technology. RESULTS The median fluorescence intensities of serum GM-CSF, IL-2, IL-5, IL-10, IL-13, IL-17A, IL-21, and IL-22 were not intensive enough to calculate the cytokine concentration. We observed elevated levels of IL-6 (P=0.001) and IL-9 (P=0.003) in patients, compared with the control group. The levels of IL-1beta (P=0.008) and IL-27 (P=0.006) were decreased. In patients with psoriatic arthritis, we noticed a decreased level of IL-9 compared with that in patients without arthritis (P=0.034). The levels of IL-12 (P<0.05) and IL-18 (P<0.05) correlated positively with the Psoriasis Area and Severity Index. We found negative correlations of IL-9 (P<0.05), IL-12 (P<0.05), and IL-23 (P<0.05) with the age of psoriatic patients; IL-12 (P<0.05) and IL-23 (P<0.05) with psoriasis duration; and IL-6 (P<0.05) and IL-9 (P<0.05) with the Nail Psoriasis Severity Index. CONCLUSIONS Multiple cytokine analysis seems to be an important form of individual immune profile assessment before treatment selection.

Baicalein Alleviates Testicular Ischemia-Reperfusion Injury in a Rat Model of Testicular Torsion-Detorsion.

Testicular torsion/detorsion-induced ischemia/reperfusion injury is partly due to the overgeneration of reactive oxygen species. Baicalein, a main bioactive constituent derived from the dried root of Scutellaria baicalensis Georgi, possesses powerful antioxidative and anti-inflammatory properties. Therefore, we designed the research to explore the possible protective effect of baicalein against testicular ischemia-reperfusion injury. Sprague-Dawley rats were randomized into 4 groups, including control, testicular ischemia-reperfusion, testicular ischemia-reperfusion+vehicle injection, and testicular ischemia-reperfusion+baicalein therapy groups. The control group received surgical exposure of the left testis without torsion-detorsion. In the testicular ischemia-reperfusion group, the left testis underwent 720° counterclockwise torsion for two hours and then was allowed detorsion. Rats in the testicular ischemia-reperfusion+vehicle injection group received intraperitoneal injection of the vehicle at detorsion. In the baicalein-treated group, the intraperitoneal administration of baicalein dissolved in the vehicle was performed at detorsion. At four hours or three months following testicular detorsion, testicular tissues were removed to detect the levels of tumor necrosis factor-alpha (TNF-α) and interleukin-1beta (IL-1β) which can recruit neutrophils into the testis, myeloperoxidase activity (an index of neutrophil infiltration in the testis), protein expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in neutrophils which can catalyze reactive oxygen species production, malondialdehyde concentration (a common marker of reactive oxygen species), and spermatogenesis. Both testicular ischemia-reperfusion and testicular ischemia-reperfusion+vehicle injection significantly increased the TNF-α and IL-1β levels, myeloperoxidase activity, NADPH oxidase protein expression, and malondialdehyde concentration, while decreased spermatogenesis in ipsilateral testes. In contrast, baicalein administration remarkably reduced TNF-α and IL-1β levels, myeloperoxidase activity, NADPH oxidase protein expression, and malondialdehyde concentration and also elevated spermatogenesis in ipsilateral testes. The results of our experiment demonstrate that baicalein alleviates testicular ischemia-reperfusion injury by inhibiting TNF-α and IL-1β secretion, neutrophil infiltration in the testis, and NADPH oxidase protein expression in neutrophils to reduce reactive oxygen species production.

Increased plasma levels of IL-6 are associated with striatal structural atrophy in major depressive disorder patients with anhedonia.

Anhedonia, as the core endophenotype of major depressive disorder (MDD), is closely related to poor prognosis, but the mechanism of this feature remains to be understood. The aim of this study was to investigate the inflammatory factors and brain structural alterations in MDD patients with anhedonia and evaluate the relationship between these factors. We assessed the plasma levels of interleukin-1 beta (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) in MDD patients with anhedonia (n = 22), MDD patients without anhedonia (n = 20), and age- and sex-matched healthy controls (HCs, n = 20) by enzyme-linked immunosorbent assay kits. All participants underwent high-resolution brain magnetic resonance imaging (MRI) scans, and voxel-based morphometry (VBM) was used to evaluate their gray matter volume (GMV). We compared inflammatory factors and GMV among the three groups and explored their relationships in MDD patients with anhedonia. Compared with those of HCs, plasma levels of IL-1β were increased in patients with MDD independent of anhedonia features, while plasma levels of IL-6 were elevated in MDD patients with anhedonia only. Meanwhile, MDD patients with anhedonia exhibited reduced GMV in the left striatal structures compared to MDD patients without anhedonia and HCs. Moreover, a significant association was observed between increased plasma levels of IL-6 and decreased GMV of the left putamen in MDD patients with anhedonia. The present research outcomes suggest that anhedonia is associated with increased plasma levels of IL-6 and decreased GMV in the left striatal structures. In addition, this study demonstrates that GMV loss in the left putamen is related to increased plasma levels of IL-6 in MDD with anhedonia, which provides further insights into the possible mechanisms of anhedonia.

Anlotinib Enhances the Antitumor Activity of High-Dose Irradiation Combined with Anti-PD-L1 by Potentiating the Tumor Immune Microenvironment in Murine Lung Cancer

<h3>Purpose/Objective(s)</h3> Radioimmunotherapy has become one of the most promising strategies for cancer treatment. Preclinical and clinical studies have demonstrated that antiangiogenic therapy can improve the efficacy of immunotherapy and sensitize radiotherapy through a variety of mechanisms. However, it is undefined whether angiogenesis inhibitors can enhance the effect of radioimmunotherapy. In this study, we aim to explore the role of anlotinib (AL3818) on the combination of radiotherapy and immune checkpoint inhibitors in Lewis lung carcinoma mouse. <h3>Materials/Methods</h3> C57BL/6 mouse subcutaneous tumor model was used to evaluate the ability of different treatment regimens in tumor growth control. Immune response and immunophenotyping including the quantification and activation were determined by flow cytometry, multiplex immunofluorescence and multiplex immunoassay. <h3>Results</h3> Triple therapy (radiotherapy combined with anti-PD-L1 and anlotinib) increased tumor-infiltrating lymphocytes and reversed the immunosuppressive effect of radiation on the tumor microenvironment in mouse model. Compared with radioimmunotherapy, the addition of anlotinib also boosted the infiltration of CD8⁺ T cells and M1 cells, and caused a decrease in the number of MDSCs and M2 cells in mice. The levels of IFN-gamma, IL-18 were the highest in the triple therapy group, while the levels of IL-23, IL-13, IL-1 beta, IL-2, IL-6, IL-10 and Arg-1 were significantly reduced. NF-κB, MAPK and AKT pathways were down regulated in triple therapy compared with radioimmunotherapy. Thus, the tumor immune microenvironment was significantly improved. As a consequence, triple therapy displayed greater benefit in antitumor efficacy. <h3>Conclusion</h3> Our findings indicate that anlotinib might be a potential synergistic treatment for radioimmunotherapy to achieve better antitumor efficacy in NSCLC patients by potentiating the tumor immune microenvironment.

Human poliovirus receptor contributes to biliary atresia pathogenesis by exacerbating natural-killer-cell-mediated bile duct injury.

Natural killer (NK) cells play an important role in biliary atresia (BA) pathogenesis; human poliovirus receptor (PVR) is an important NK-cell modulator. Here, we explored the role of PVR in BA pathogenesis. Poliovirus receptor expression and NK cell-associated genes were detected in human BA samples and a rotavirus-induced BA mouse model using quantitative PCR and immunofluorescence staining. Chemically modified small interfering RNA silenced PVR expression in the BA model, and its effects on the population and function of intrahepatic NK cells were investigated using flow cytometry (FCM). The effects of PVR overexpression and knockdown on proliferation, apoptosis and NK-cell-mediated lysis of cultured human cholangiocytes were analysed using FCM and cell viability assays. Serum PVR, high-mobility group box 1 (HMGB1), and interleukin-1beta (IL-1beta) levels were measured in a cohort of 50 patients using ELISA. Poliovirus receptor expression was upregulated in the biliary epithelium of BA patients and BA model and was positively correlated with the population and activation of intrahepatic NK cells. Silencing of PVR expression impaired the cytotoxicity of NK cells, reduced inflammation and protected mice from rotavirus-induced BA. Activation of the TLR3-IRF3 signalling pathway induced PVR expression in cultured cholangiocytes. PVR overexpression promoted proliferation and inhibited the apoptosis of cholangiocytes but exacerbated NK cell-mediated cholangiocyte lysis. Serum PVR levels were elevated in BA patients and were positively correlated with HMGB1 and IL-1beta levels. Poliovirus receptor contributes to BA pathogenesis by regulating NK cell-mediated bile duct injury; PVR has the value as a biomarker of BA.

To Analyze the Mechanism of SalB Regulating SIRT1 to Inhibit NLRP3 and Its Ameliorative Effect on Tubulogastric Junction Tumor Lesions Complicated with Myocardial Injury.

The objective of this research is to investigate the mediating impact of salvianolic acid B (SalB) on SIRT1 signaling pathway and the mechanism by which it inhibits Nod-like receptor protein 3 (NLRP3), as well as to examine how SalB affects myocardial injury brought on by tumor lesions at the junction of the tube and the stomach. Through the establishment of the integration of a stomach tube tumor lesion rats combined with the experimental rat model, this study establishes the normal group, model group, and different SalB dose groups. For each group of cells, cell activity and cell apoptosis were determined and compared using colorimetry and enzyme-linked immunosorbent method about lactate dehydrogenase (LDH). Interleukin-1 beta levels are measured. DCFH-DA fluorescent probe was applied to identify intracellular “reactive oxygen species” (ROS). “Western blot” was used to determine NLRP3, caspase-1, and apoptosis-related spotted protein (ASC) in each group of cells. And SIRT1 signaling pathway related to SIRT1, phosphorylated AMP protein-activated kinase α (P-AMPK α), AMP protein-activated kinase α (AMPKα), and “peroxisome-proliferator-activated receptor γ coactivator 1α (PGC-1α) protein expression” are used. According to the final findings, SalB mediated the SIRT1 signaling pathway and had a beneficial impact on the upregulation of SIRT1, P-AMPK/AMPK, and PGC-1 protein expressions. SalB positively affects the downregulation of NLRP3 inflammasome-related proteins. Caspase-1 and ASC protein expression suggesting that SalB may inhibit the activation of NLRP3 inflammasome induced by oxidative stress by activating SIRT1/AMPK/PGC-1α signaling pathway. This plays an antimyocardial injury effect.