Interleukin-1β Levels Research Articles

Pentoxifylline as a Novel Add-on Therapy for Major Depressive Disorder in Adult Patients: A Randomized, Double-Blind, Placebo-Controlled Trial.

Evidence indicates an association between immune dysregulation and major depressive disorder (MDD). Pentoxifylline (PTX), a phosphodiesterase inhibitor, has been shown to reduce pro-inflammatory activities. The aim of this study was to evaluate changes in depressive symptoms and pro-inflammatory markers after administration of PTX as an adjunctive agent to citalopram in patients with MDD. One hundred patients were randomly assigned to either citalopram (20 mg/day) plus placebo (twice daily) (n=50) or citalopram (20 mg/day) plus PTX (400 mg) (twice daily) (n=50). The Hamilton Depression Rating Scale-17 (HAM-D-17) scores at baseline, weeks 2, 4, 6, 8, 10, and 12 and serum levels of interleukin1-β (IL-1-β), tumor necrosis factor-α, C-reactive protein, IL-6, serotonin, IL-10, and brain-derived neurotrophic factor (BDNF) at baseline and week 12 were evaluated. HAM-D-17 score in the PTX group significantly reduced in comparison to the control group after weeks 4, 6, 8,10, and 12 ((LSMD): - 2.193, p=0.021; - 2.597, p=0.036; - 2.916, p=0.019; - 4.336, p=0.005; and - 4.087, p=0.008, respectively). Patients who received PTX had a better response (83%) and remission rate (79%) compared to the placebo group (49% and 40%, p=0.006 and p=0.01, respectively). Moreover, the reduction in serum concentrations of pro-inflammatory factors and increase in serotonin and BDNF in the PTX group was significantly greater than in the placebo group (p<0.001). These findings support the safety and efficacy of PTX as an adjunctive antidepressant agent with anti-inflammatory effects in patients with MDD.

A formulation of combined Poria cocos and Cordyceps militaris rice ameliorates depressive-like effects by downregulating p38 MAPK signaling pathways

Background and aimPoria cocos (PC) is traditional Chinese medicine with sedative, diuretic, and tonic properties. Cordyceps militaris rice (CMR) is a matrix used for the solid-state culture of C. militaris, which has been used for anti-angiogenetic and anti-inflammation effects. To investigate a formulation of combined Poria cocos and Cordyceps militaris rice (PC-CMR) alleviates anxiety behaviours and depressive-like effects for the first time. Experimental procedureAfter five-week of stress, rats were induced by unpredictable chronic mild stress (UCMS) treated with PC-CMR formulation. Then, rats underwent various behavior tests, testing serum inflammatory mediators by enzyme-linked immunosorbent assays (ELISA), evaluated monoamines by high-performance liquid chromatography (HPLC) analysis, and protein expression by western blotting. ResultsTreatment with doses of formulated PC-CMR reversed sucrose preference and increased amount of time spent on the open arms in rat behavioral tests. The formulated PC-CMR significantly reduced glutamate content and turnover rates of serotonin and dopamine in the prefrontal cortex of rats. In the inflammation-related pathway, PC-CMR decreased interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) levels in serum and downregulated the expression of p38 mitogen-activated protein kinase (p38 MAPK), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) in the prefrontal cortex and signal transducer and activator of transcription 3 (STAT3), and indoleamine 2,3-dioxygenase (IDO) in the amygdala. ConclusionOur findings suggest that the formulated PC-CMR could have antidepressive and anxiolytic effects by modulating neurotransmitter levels and reducing inflammation.

Effect of Diosmin on Pharmacokinetics and Pharmacodynamics of Rivaroxaban in Rats

Background and Objective: Rivaroxaban, a direct oral anticoagulant, has become the first-line therapy medicine to prevent and treat Venous Thromboembolism (VTE). Patients with femoropopliteal venous thrombosis may use rivaroxaban along with diosmin. Rivaroxaban is the substrate of CYP3A4 and P-glycoprotein (P-gp), but diosmin is the inhibitor. The combination might lead to Drug-drug Interaction (DDI). The aim of this study was to assess the effect of diosmin on the pharmacokinetics and pharmacodynamics of rivaroxaban in rats. Methods: Plasma concentration of rivaroxaban in the absence or presence of diosmin groups was determined by High-performance Liquid Chromatography (HPLC). Pharmacokinetics parameters were calculated and used to evaluate pharmacokinetics interactions. Anticoagulation was investigated by Prothrombin Time (PT), International Normalized Ratio (INR), and Activated Partial Thromboplastin Time (APTT). Antithrombotic efficacy was investigated by the length of tail thrombosis, the content levels of Interleukin-1β (IL-1β) and D-dimer (D-D) in rats, and histopathological sections in the tail thrombosis model. Results: Maximum concentration (Cmax), 0-t Area Under the Curve (AUC0–t), 0-∞ Area Under the Curve (AUC0–∞) of rivaroxaban increased significantly in the combination group. PT, INR, and APPT in the combination group exhibited an increase compared to the Rivaroxaban group. Simultaneously, the length of tail thrombosis and levels of IL-1β and D-D were significantly reduced. Significant improvement of tissue histology in tail thrombosis could be observed. Conclusion: Taken together, diosmin could significantly affect the pharmacokinetics and pharmacodynamics of rivaroxaban, and enhance anticoagulant and antithrombotic efficacy in rats. More attention should be paid to avoid harmful DDI in the clinic.

Rat PKU Model Display Gender-Based Neuroinflammatory Changes: Proinflamatuary Cytokines and Lipid Peroxidation

Phenylketonuria (PKU) results from congenital defects of amino acid metabolism. Accumulated phenylalanine crosses the blood-brain barrier and causes permanent brain damage, but the neuro-pathophysiology underlying phenylketonuria is not fully understood. Chemically-induced rat phenylketonuria model of both genders was generated to examine the role of inflammatory response, lipid peroxidation and oxidative stress in the prefrontal cortex. Our results showed that in phenylketonuria there was an increase in lipid peroxidation compared to controls, which was significantly different only in males (p&amp;lt;0.001). In male rat PKU groups, statistically significant differences were also observed in serum tryptophan (p&amp;lt;0.001) and interleukin-1β levels (p=0.014) as compared to male controls. In this study, gender-based changes in neuroinflammation and lipid peroxidation were reported for the first time in a PKU model.

Chemical composition, antioxidant, cytotoxic, antiviral, and lung-protective activities of Salvia officinalis L. ethanol extract herb growing in Sinai, Egypt

BackgroundPulmonary fibrosis (PF) is a respiratory ailment that causes the substitution of healthy lung tissue with scar tissue due to collagen deposition and fibroblast proliferation. The incidence of PF increased with the successive waves of Coronaviruses and other viruses affecting the lungs. Therefore, the priority is moving toward treatment with medicinal plants for their active constituents. Salvia officinalis L. herbal drug (sage, family; Lamiaceae) is characterized by its strong antioxidative activity. This study aims to declare the effect of using sage ethanol extract (SOEE) as a protective agent from PF through an in vivo study on mercuric chloride (HgCl2)-induced lung fibrosis and in vitro evaluation of its anticancer, antiviral, and antioxidant activities concerning its phytoconstituents.ResultsTwelve compounds were isolated and identified as apigenin, luteolin, genkwanin, quercetin, hispidulin, luteolin-7-O-β- glucopyranoside, rutin, rosmarinic acid, caffeic acid, ferulic acid chlorogenic acid, and ellagic acid. The results of antioxidants indicated that SOEE exhibited the greatest efficacy as an antioxidant agent in the 1,1-Diphenyl-2-picrylhydrazyl assay with inhibitory concentration (IC50) 23.21 ± 1.17 µg/ mL followed by 1864.71 and 1793.80 µM Trolox equivalent/mg extract for ferric ion reducing antioxidant power and 3-ethylbenzothiazoline-6-sulfonic acid (ABTS), respectively. SOEE showed notable cytotoxic activity against A549. Oral administration of SOEE at 69.4 and 173.5 mg/kg.bw afforded a noteworthy protective effect against HgCl2-induced pulmonary fibrosis. Also, lung superoxide dismutase (SOD), catalase (CAT), and reduced glutathione (GSH) were increased by SOEE. That was in parallel with working to reduce the malondialdehyde (MDA), necrosis factor kappa (NF-κB), interleukin-1β (IL-1β), and cyclooxygenase-2 (COX-2) levels. The lung P53, Bcl-2, Bcl-XL, AKT, and vanin-1 gene expression was upregulated in SOEE-treated rats compared to HgCl2-treated rats.ConclusionSOEE reduces acute lung injury and can be used to inhibit the proliferation and migration of lung fibrotic cells. These activities may be related to its high antioxidant activity, which could result from the phenolic constituents. The authors recommended using sage in the treatment of lung diseases to protect from lung fibrosis. Additional animal and human experiments are needed for future research.Graphical abstract

Unlocking renal Restoration: Mesaconine from Aconitum plants restore mitochondrial function to halt cell apoptosis in acute kidney injury

Acute kidney injury (AKI) is characterized by a sudden decline in renal function. Traditional Chinese medicine has employed Fuzi for kidney diseases; however, concerns about neurotoxicity and cardiotoxicity have constrained its clinical use. This study explored mesaconine, derived from processed Fuzi, as a promising low-toxicity alternative for AKI treatment. In this study, we assessed the protective effects of mesaconine in gentamicin (GM)-induced NRK-52E cells and AKI rat models in vitro and in vivo, respectively. Mesaconine promotes the proliferation of damaged NRK-52E cells and down-regulates intracellular transforming growth factor β1 (TGF-β1) and kidney injury molecule 1 (KIM-1) to promote renal cell repair. Concurrently, mesaconine restored mitochondrial morphology and permeability transition pores, reversed the decrease in mitochondrial membrane potential, mitigated mitochondrial dysfunction, decreased ATP production, inhibited inflammatory factor release, and reduced early apoptosis rates. In vivo, GM-induced AKI rat models exhibited elevated AKI biomarkers, in which mesaconine was effectively reduced, indicating improved renal function. Mesaconine enhanced superoxide dismutase activity, reduced malondialdehyde content, alleviated inflammatory infiltrate, mitigated tubular and glomerular lesions, and downregulated NF-κB (nuclear factor-κb) p65 expression, leading to decreased tumor necrosis factor-α (TNF-α) and IL-1β (interleukin-1β) levels in GM-induced AKI animals. Furthermore, mesaconine inhibited the expression of renal pro-apoptotic proteins (Bax, cytochrome c, cleaved-caspase 9, and cleaved-caspase 3) and induced the release of the anti-apoptotic protein bcl-2, further suppressing apoptosis. This study highlighted the therapeutic potential of mesaconine in GM-induced AKI. Its multifaceted mechanisms, including the restoration of mitochondrial dysfunction, anti-inflammatory and antioxidant effects, and apoptosis mitigation, make mesaconine a promising candidate for further exploration in AKI management.

Protective Effects of Resveratrol Against Airway Hyperreactivity, Oxidative Stress, and Lung Inflammation in a Rat Pup Model of Bronchopulmonary Dysplasia

Oxygen therapy provides an important treatment for preterm and low-birth-weight neonates, however, it has been shown that prolonged exposure to high levels of oxygen (hyperoxia) is one of the factors contributing to the development of bronchopulmonary dysplasia (BPD) by inducing lung injury and airway hyperreactivity. There is no effective therapy against the adverse effects of hyperoxia. Therefore, this study was undertaken to test the hypothesis that natural phytoalexin resveratrol will overcome hyperoxia-induced airway hyperreactivity, oxidative stress, and lung inflammation. Newborn rats were exposed to hyperoxia (fraction of inspired oxygen - FiO2&gt;95 % O2) or ambient air (AA) for seven days. Resveratrol was supplemented either in vivo (30 mg·kg-1·day-1) by intraperitoneal administration or in vitro to the tracheal preparations in an organ bath (100 μM). Contractile and relaxant responses were studied in tracheal smooth muscle (TSM) using the in vitro organ bath system. To explain the involvement of nitric oxide in the mechanisms of the protective effect of resveratrol against hyperoxia, a nitric oxide synthase inhibitor – Nω-nitro-L-arginine methyl ester (L-NAME), was administered in some sets of experiments. The superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities and the tumor necrosis factor-alpha (TNF-α) and interleukin-1β (IL-1β) levels in the lungs were determined. Resveratrol significantly reduced contraction and restored the impaired relaxation of hyperoxia-exposed TSM (p&lt;0.001). L-NAME reduced the inhibitory effect of resveratrol on TSM contractility, as well as its promotion relaxant effect (p&lt;0.01). Resveratrol preserved the SOD and GPx activities and decreased the expression of TNF-α and IL-1β in hyperoxic animals. The findings of this study demonstrate the protective effect of resveratrol against hyperoxia-induced airway hyperreactivity and lung damage and suggest that resveratrol might serve as a therapy to prevent the adverse effects of neonatal hyperoxia. Keywords: Bronchopulmonary dysplasia • Hyperoxia • Airway hyperreactivity • Resveratrol • Pro-inflammatory cytokines

A Pilot Study of the Clinical Effectiveness of a Single Intra-Articular Injection of Stanozolol in Canines with Knee Degenerative Joint Disease and Its Correlation with Serum Interleukin-1β Levels.

Stanozolol shows promise as an anabolic and anti-catabolic agent for treating degenerative joint disease (DJD). This study assessed the clinical efficacy of a single intra-articular stanozolol injection in canine knees with DJD and its correlation with serum IL-1β levels. Thirty dogs (n = 30) were divided into a control group (CG, n = 10) and a study group (SG, n = 20) with DJD. Pain levels were assessed using the Brown query, and radiographs were taken at T0 and T3. IL-1β levels were quantified via ELISA. Apart from 2 patients, all showed reduced pain intensity, with 15 patients showing improvement at T1 and 3 patients at T2. A positive correlation (r = 0.84; p < 0.01) was found between pain level and IL-1β in 15 patients. No systemic effects were observed. Most patients (18/20) experienced reduced pain. This pilot study suggests stanozolol's potential in managing DJD in dogs. Further research is warranted to validate these findings and understand stanozolol's mechanism in DJD treatment.

Anti-rheumatoid arthritis effects of traditional Chinese medicine Fufang Xiaohuoluo pill on collagen-induced arthritis rats and MH7A cells.

Fufang Xiaohuoluo pill (FFXHL) is a commonly used prescription in clinical practice for treating rheumatoid arthritis in China, yet its specific mechanism remains unclear. This study aims to elucidate the pharmacological mechanisms of FFXHL using both in vivo and in vitro experiments. The collagen-induced arthritis (CIA) rat model was established to evaluate FFXHL's therapeutic impact. Parameters that include paw swelling, arthritis scores, and inflammatory markers were examined to assess the anti-inflammatory and analgesic effects of FFXHL. Human fibroblast-like synoviocytes (MH7A cells) is activated by tumour necrosis factor-alpha (TNF-α) were used to explore the anti-inflammatory mechanism on FFXHL. Our findings indicate that FFXHL effectively reduced paw swelling, joint pain, arthritis scores, and synovial pannus hyperplasia. It also lowered serum levels of TNF-α, interleukin-1β (IL1β), and interleukin-6 (IL-6). Immunohistochemical analysis revealed decreased expression of nuclear factor-kappa B (NF-κB) p65 in FFXHL-treated CIA rat joints. In vitro experiments demonstrated FFXHL's ability to decrease protein secretion of IL-1β and IL-6, suppress mRNA expression of matrix metalloproteinases (MMP) -3, -9, and -13, reduce reactive oxygen species (ROS) levels, and inhibit NF-κB p65 translocation in TNF-α stimulated MH7Acells. FFXHL also suppressed protein levels of extracellular signal-regulated kinase (ERK), c-Jun Nterminal kinase (JNK), p38 MAP kinase (p38), protein kinase B (Akt), p65, inhibitor of kappa B kinase α/β (IKKα/β), Toll-like receptor 4 (TLR4), and myeloid differentiation primary response 88 (MyD88) induced by TNF-α in MH7A cells. The findings imply that FFXHL exhibits significant anti-inflammatory and antiarthritic effects in both CIA rat models and TNF-α-induced MH7A cells. The potential mechanism involves the inactivation of TLR4/MyD88, mitogen-activated protein kinases (MAPKs), NF-κB, and Akt pathways by FFXHL.

Erjingwan and Alzheimer's disease: research based on network pharmacology and experimental confirmation.

Alzheimer's disease (AD), a challenging neurodegenerative condition, has emerged as a significant global public health concern. The Chinese medicine decoction Erjingwan (EJW) has shown promising efficacy in AD treatment, though its mechanism remains unclear. This study aims to elucidate the mechanism by which EJW treats AD through network pharmacology analysis and in vivo experiments. We identified EJW's components using the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database and determined AD-related targets from various databases. A network comprising herbs-compounds-targets was established, and EJW's core targets were ascertained through protein-protein interaction (PPI) analysis. This study assessed the cognitive abilities of APP/PS1 mice using Morris water mazes and Y mazes, in addition to analyzing blood samples for triglyceride (TG), total cholesterol (TC), low-density lipoprotein (LDL), and high-density lipoprotein (HDL) levels. Brain tissues were examined histologically with HE staining, Nissl staining, and immunohistochemistry (IHC) for amyloid β-protein (Aβ) detection. Superoxide dismutase (SOD), reactive oxygen species (ROS), Interleukin-1β (IL-1β), and Interleukin-6 (IL-6) levels in the hippocampal region were measured by ELISA. mRNA expression of apolipoprotein A-I (APOA-I), apolipoprotein B (APOB), apolipoprotein E4 (APOE4), advanced glycation end products (AGE), the receptor for AGE (RAGE), and nuclear factor kappa-B (NF-κB) was evaluated by quantitative PCR (q-PCR). Western blotting was used to detect the expression of AGE, RAGE, NF-κB, and Tau protein. Screening identified 57 chemical components and 222 potential targets of EJW. Ten core targets for AD treatment were identified, with enrichment analysis suggesting EJW's effects are related to lipid metabolism and AGEs/RAGE pathways. EJW enhanced learning and memory in APP/PS1 mice, protected neuronal structure in the hippocampal region, reduced Aβ deposition, and altered levels of TG, TC, LDL, IL-1β, and IL-6, and the expression of APOE4, AGEs, RAGE, NF-κB, and Tau protein, while increasing SOD, APOA-I, and APOB mRNA expression. The study identified four core components of EJW-iosgenin, baicalein, beta-sitosterol, quercetin-and ten core targets including AKT1, IL6, VEGFA, TP53, CASP3, for treating AD. Experimental results demonstrate EJW's capacity to modulate lipid profiles, reduce pathological markers such as Aβ1-42, Tau, IL-6, IL-1β, reactive oxygen species, SOD, and enhance cognitive functions in APP/PS1 mice, potentially through inhibiting the AGEs/RAGE/NF-κB pathway.

Atractylodes lancea (Thunb.) DC. [Asteraceae] rhizome-derived exosome-like nanoparticles suppress lipopolysaccharide-induced inflammation in murine microglial cells.

Exosome-like nanoparticles (ELNs) mediate interspecies intercellular communications and modulate gene expression. In this study, we isolated and purified ELNs from the dried rhizome of Atractylodes lancea (Thunb.) DC. [Asteraceae] (ALR-ELNs), a traditional natural medicine, and investigated their potential as neuroinflammatory therapeutic agents. ALR-ELN samples were isolated and purified using differential centrifugation, and their physical features and microRNA contents were analyzed through transmission electron microscopy and RNA sequencing, respectively. BV-2 microglial murine cells and primary mouse microglial cells were cultured in vitro, and their ability to uptake ALR-ELNs was explored using fluorescence microscopy. The capacity of ALR-ELNs to modulate the anti-inflammatory responses of these cells to lipopolysaccharide (LPS) exposure was assessed through mRNA and protein expression analyses. Overall, BV-2 cells were found to internalize ALR-ELNs, which comprised three microRNAs (ath-miR166f, ath-miR162a-5p, and ath-miR162b-5p) that could have anti-inflammatory activity. Pretreatment of BV-2 cells with ALR-ELN prevented the pro-inflammatory effects of LPS stimulation by significantly reducing the levels of nitric oxide, interleukin-1β, interleukin-6, and tumor necrosis factor-α. Notably, the mRNA levels of Il1b, Il6, iNos, ccl2, and cxcl10 in BV-2 cells, which increased upon LPS exposure, were significantly reduced following ALR-ELN treatment. Moreover, the mRNA levels of heme oxygenase 1, Irf7, ccl12, and Irg1 also increased significantly following ALR-ELN treatment. In addition, pretreatment of primary mouse microglial cells with ALR-ELN prevented the pro-inflammatory effects of LPS stimulation by significantly reducing the levels of nitric oxide. Our findings indicate that ALR-ELNs exhibit anti-inflammatory effects on murine microglial cells. Further validation may prove ALR-ELNs as a promising neuroinflammatory therapeutic agent.

An observation study of the effect of "Internet + Nursing" on psychological status and quality of life of patients with thyroid eye disease.

"Internet + Nursing" refers to medical institutions using Internet technologies and big data to provide nursing services to discharged patients or those with severe illnesses unable to visit hospitals, through online applications and offline care provision. This study aimed to explore the influence of "Internet + Nursing" on the psychological status and quality of life of patients with thyroid eye disease. Sixty-eight patients with thyroid eye disease from January 2021 to December 2022 were divided into a research group (n = 34, joined the platform) and control group (n = 34, not joined the platform) based on their voluntary participation in our hospital's "Internet + Nursing Platform." The self-rating anxiety scale (SAS) and self-rating depression scale (SDS) scores of the research group were lower than those of the control group (P < .05). The short form-36 health survey (SF-36) scores in various dimensions were higher in the research group compared to the control group (P < .05). The incidence rates of retinal detachment, vitreous hemorrhage, diabetic retinopathy, and iris neovascularization were lower in the research group compared to the control group (P < .05). After nursing, exophthalmos, blink frequency, and eyelid height of the research group were lower than those of the control group, while tear film breakup time was higher than that of the control group (P < .05). The visual acuity of the research group was higher than that of the control group (P < .05). After nursing, the National Eye Institute Visual Function Questionnaire 25 (NEI-VFQ-25) scores in various dimensions were significantly higher in the research group than those in the control group (P < .05). Additionally, after nursing, the levels of interleukin-6 (IL-6), interleukin-1β (IL-1β), and tumor necrosis factor-α (TNF-α) in the research group were lower than those in the control group (P < .05). The patients in the research group exhibited higher recognition scores of nursing compared to those in the control group (P < .05). Through the implementation of "Internet + Nursing" for patients with thyroid eye disease discharged from our hospital, we can provide better out-of-hospital nursing for patients, reduce the occurrence of complications, improve ocular surface symptoms, promote visual acuity recovery, and improve patients' psychological status and quality of life.

Involvement of P2X7R-mediated microglia polarization and neuroinflammation in the response to electroacupuncture on post-stroke memory impairment

PurposePost-stroke cognitive impairment (PSCI) is a common complication of ischemic stroke episodes. Memory impairment is an important component of the poststroke cognitive syndrome. Microglial activation plays a critical role in stroke-induced neuroinflammation. Previous studies have reported that electroacupuncture (EA) provides neuroprotective effects by reducing the expression levels of the Purinergic receptor P2X ligand-gated ion channel 7 (P2X7) and inhibiting neuroinflammation in rat model of ischemic stroke. Further understanding of the role and connections between P2X7R and microglial activation in EA-induced anti-inflammatory can reveal novel targets for post-stroke memory impairment treatment. MethodsA Middle cerebral artery occlusion and reperfusion (MCAO/R) model was established. We used 2’(3’)-O-(4-benzoyl) benzoyl ATP (BzATP) as a P2X7R agonist. Following MCAO/R injury, the rats underwent EA therapy at the Baihui (DU20) and Shenting (DU24) acupoints for seven consecutive days. The Barnes maze test was used to evaluate memory function. Following intervention, a T2 weighted images (T2WI) scan was performed to identify changes in cerebral infarction volume in MCAO/R rats. The levels of Interleukin-1β (IL-1β), Interleukin-6 (IL-6) and Interleukin-4 (IL-4), Interleukin-10 (IL-10) in the peri-infarct hippocampal were examined by ELISA. Immunofluorescence was employed to evaluate Iba-1+ / P2X7R+, Iba-1+/ iNOS+ and Iba-1+/ Arg-1+ cell populations in the peri-infarct hippocampal DG area. The protein expression of P2X7R, Nuclear factor E2-related factor 2 (Nrf2), Recombinant nlr family, pyrin domain containing protein 3 (NLRP3), Inducible nitric oxide synthase (iNOS) and Arginase-1 (Arg-1) in the peri-infarct hippocampal were investigated using western blot assays. Besides, we also measured the levels of reactive oxygen species (ROS), superoxide dismutase (SOD) and malondialdehyde (MDA). ResultsWe found EA treatment reduced inflammation and oxidative stress, which is consistent with a decrease in P2X7R expression and improved learning and memory functions. In contrast, we found BzATP enhanced inflammation and oxidative stress. Moreover, our results showed EA treatment up-regulated Nrf2, down-regulated NLRP3, and promoted microglia M2 polarization. Finally, EA-mediated positive effects were reversed by intracerebroventricular injection of BzATP, which is consistent with an increase in P2X7R expression. ConclusionEA ameliorates memory impairment in a rat model of ischemic stroke by reducing inflammation and ROS through the inhibition of P2X7R expression. In turn, this mechanism regulates Nrf2 and NLRP3 expression, suggesting EA is beneficial for ischemic stroke treatment using P2X7R as target.

INFLUENCES OF HEAT STRESS ON GLUTAMATE TRANSMISSION-DEPENDENT EXPRESSION LEVELS OF IL-1β and IL-18 IN BV-2 MICROGLIAL CELLS.

Objective: This study aimed to explore the impact of heat stress (HS) on glutamate transmission-dependent expression levels of interleukin-1β (IL-1β) and IL-18 in BV-2 microglial cells. Methods: BV-2 microglial cells were cultured in vitro , with cells maintained at 37°C serving as the control. The HS group experienced incubation at 40°C for 1 h, followed by further culturing at 37°C for 6 or 12 h. The experimental group was preincubated with glutamate, the glutamate antagonist riluzole, or the mGluR5 agonist, 2-chloro-5-hydroxyphenylglycine (CHPG), before HS. Glutamate content in BV-2 culture supernatant was assessed using colorimetric assay. Moreover, mRNA expression levels of EAAT3 and/or mGluR5 in BV-2 cells were determined via quantitative polymerase chain reaction. Interleukins (IL-1β and IL-18) in cell culture supernatant were measured using enzyme-linked immunosorbent assay. Western blot analysis was employed to assess protein levels of IL-1β and IL-18 in BV-2 cells. Results: HS induced a significant release of glutamate and increased the expression levels of mGluR5 and EAAT3 in BV-2 cells. It also triggered the expression levels and release of proinflammatory factors, such as IL-1β and IL-18, synergizing with the effects of glutamate treatment. Preincubation with both riluzole and CHPG significantly reduced HS-induced glutamate release and mitigated the increased expression levels and release of IL-1β and IL-18 induced by HS. Conclusion: The findings confirmed that microglia could be involved in HS primarily through glutamate metabolisms, influencing the expression levels and release of IL-1β and IL-18.

Effects of Prevotella copri on insulin, gut microbiota and bile acids

ABSTRACT Obesity is becoming a major global health problem in children that can cause diseases such as type 2 diabetes and metabolic disorders, which are closely related to the gut microbiota. However, the underlying mechanism remains unclear. In this study, a significant positive correlation was observed between Prevotella copri (P. copri) and obesity in children (p = 0.003). Next, the effect of P. copri on obesity was explored by using fecal microbiota transplantation (FMT) experiment. Transplantation of P. copri. increased serum levels of fasting blood glucose (p < 0.01), insulin (p < 0.01) and interleukin-1β (IL-1β) (p < 0.05) in high-fat diet (HFD)-induced obese mice, but not in normal mice. Characterization of the gut microbiota indicated that P. copri reduced the relative abundance of the Akkermansia genus in mice (p < 0.01). Further analysis on bile acids (BAs) revealed that P. copri increased the primary BAs and ursodeoxycholic acid (UDCA) in HFD-induced mice (p < 0.05). This study demonstrated for the first time that P. copri has a significant positive correlation with obesity in children, and can increase fasting blood glucose and insulin levels in HFD-fed obese mice, which are related to the abundance of Akkermansia genus and bile acids.

Deoxynivalenol and T-2 toxin cause liver damage and egg quality degradation through endoplasmic reticulum stress in summer laying hens.

The present study aimed to find whether low doses of mixed mycotoxins would affect egg quality in laying hens, and to explore the oxidative stress induced liver damage through endoplasmic reticulum during summer stress. A total of 96 Jinghong laying hens, 36 wks of age, were divided into four treatments, with eight repetitions per treatment and three hens per repetition. All the hens were raised in summer (average temperature: 31.3 ± 0.5℃; average humidity: 85.5 ± 0.2%) for 28d. One treatment was fed a basal diet as control (CON), and the other three treatments were fed the same diets containing 3.0mg/kg deoxynivalenol (DON), 0.5mg/kg T-2 toxin (T-2), and 1.5mg/kg DON + 0.25mg/kg T-2 toxin (Mix). Albumen height and Haugh unit were decreased (P < 0.05) in the Mix group on day 14 and 28. The activity of total antioxidant capacity, glutathione peroxidase, catalase, and superoxide dismutase were decreased (P < 0.05) in the DON, T-2, and Mix groups. The alkaline phosphatase level in DON, T-2, and Mix groups was significantly increased (P < 0.05). The level of interleukin-1β, interferon-γ, and tumor necrosis factor-α in the Mix group were higher (P < 0.05) than CON, DON, and T-2 groups. Mix group upregulated the mRNA expressions of protein kinase RNA-like ER kinase, activating transcription factor4, IL-1β, nuclear factor-κ-gene binding, and nuclear respiratory factor 2 in the liver (P < 0.05). The results showed that low doses of DON and T-2 toxin could cause oxidative stress in the liver, but DON and T-2 toxin have a cumulative effect on virulence, which can reduce egg quality and cause endoplasmic reticulum stress in the liver.

Effect of Salvia sclarea L. extract on growth performance, antioxidant capacity, and immune function in lambs.

This study aimed to explore the effects of Salvia sclarea extract on the growth performance, apparent nutrient digestibility, antioxidant capacity, and immune function of the lambs. Sixty female lambs (Chinese Merino sheep) aged 2 months and weighing 20 ± 2 kg were selected and randomly divided into five groups of 12 lambs each. The control group (CK) received only basal feed, whereas the experimental group was supplemented with different concentrations of salvia sclarea extract in the basal feed at 0.04, 0.08, 0.12, and 0.16 mL/kg (CL1, CL2, CL3, and CL4, respectively). The feeding period was 85 days, including 15 days of pre-feeding and 70 days of regular feeding. Body weight and feed intake were recorded during the test period, and blood was collected at the end of the test to determine immune and antioxidant indices. The results showed that the average daily weight gain and feed intake of the lambs were significantly higher in the CL3 group than in the CK group (p < 0.05). In addition, the apparent nutrient digestibility of crude protein and neutral detergent fiber increased significantly (p < 0.05). The dry matter, acid detergent fiber, and ether extract were not significantly different (p > 0.05). Serum levels of superoxide dismutase, catalase, and glutathione peroxidase and antioxidant capacity were significantly higher in the CL2, CL3, and CL4 groups than in the CK group, whereas malondialdehyde levels were significantly lower (p < 0.05). The serum levels of immune globulin immune globulin A, immune globulin G, immune globulin M, interferon-γ, and interleukin-10 were significantly higher and the levels of tumor necrosis factor-α and interleukin-1β were significantly lower in the CL2, CL3, and CL4 groups (p < 0.05). In conclusion, the addition of the S. sclarea extract to the diet promoted growth performance and nutrient digestion in lambs. Immune response was improved by increasing Ig and cytokine concentrations. It enhances antioxidant status by increasing antioxidant enzyme activity in lambs.

Synthesis, Anti-Inflammatory Activities, and Molecular Docking Study of Novel Pyxinol Derivatives as Inhibitors of NF-κB Activation.

Pyxinol, an active metabolite of ginsenosides in human hepatocytes, exhibits various pharmacological activities. Here, a series of C-3 modified pyxinol derivatives was designed and virtually screened by molecular docking with the key inflammation-related proteins of the nuclear factor kappa B (NF-κB) pathway. Some of the novel derivatives were synthesized to assess their effects in inhibiting the production of nitric oxide (NO) and mitochondrial reactive oxygen species (MtROS) in lipopolysaccharide-triggered RAW264.7 cells. Derivative 2c exhibited the highest NO and MtROS inhibitory activities with low cytotoxicity. Furthermore, 2c decreased the protein levels of interleukin 1β, tumor necrosis factor α, inducible nitric oxide synthase, and cyclooxygenase 2 and suppressed the activation of NF-κB signaling. Cellular thermal shift assays indicated that 2c could directly bind with p65 and p50 in situ. Molecular docking revealed that 2c's binding to the p65-p50 heterodimer and p50 homodimer was close to their DNA binding sites. In summary, pyxinol derivatives possess potential for development as NF-κB inhibitors.

SP1 transcriptionally activates HTR2B to aggravate traumatic spinal cord injury by shifting microglial M1/M2 polarization.

Spinal cord injury (SCI) can result in structural and functional damage to the spinal cord, which may lead to loss of limb movement and sensation, loss of bowel and bladder control, and other complications. Previous studies have revealed the critical influence of trans-acting transcription factor 1 (SP1) in neurological pathologies, however, its role and mechanism in SCI have not been fully studied. The study was performed using mouse microglia BV2 stimulated using lipopolysaccharide (LPS) and male adult mice subjected to spinal hitting. Western blotting was performed to detect protein expression of SP1, 5-hydroxytryptamine (serotonin) receptor 2B (HTR2B), BCL2-associated x protein (Bax), B-cell lymphoma-2 (Bcl-2), inducible nitric oxide synthase (iNOS), clusters of differentiation 86 (CD86), Arginase 1 (Arg-1) and clusters of differentiation 206 (CD206). Cell viability and apoptosis were analyzed by MTT assay and TUNEL assay. mRNA levels of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-4 (IL-4) and tumor necrosis factor-β (TNF-β) were quantified by quantitative real-time polymerase chain reaction. The association of SP1 and HTR2B was identified by chromatin immunoprecipitation assay and dual-luciferase reporter assay. HE staining assay was performed to analyze the pathological conditions of spinal cord tissues. LPS treatment induced cell apoptosis and inhibited microglia polarization from M1 to M2 phenotype, accompanied by an increase of Bax protein expression and a decrease of Bcl-2 protein expression, however, these effects were relieved after SP1 silencing. Mechanism assays revealed that SP1 transcriptionally activated HTR2B in BV2 cells, and HTR2B knockdown rescued LPS-induced effects on BV2 cell apoptosis and microglial M1/M2 polarization. Moreover, SP1 absence inhibited BV2 cell apoptosis and promoted microglia polarization from M1 to M2 phenotype by decreasing HTR2B expression. SCI mouse model assay further showed that SP1 downregulation could attenuate spinal hitting-induced promoting effects on cell apoptosis of spinal cord tissues and microglial M1 polarization. SP1 transcriptionally activated HTR2B to aggravate traumatic SCI by shifting microglial M1/M2 polarization.

Neutrophil extracellular trap formation and its implications in nonsteroidal anti-inflammatory drug-induced small intestinal injury.

Nonsteroidal anti-inflammatory drugs (NSAIDs) damage the small intestine via neutrophil infiltration driven by the mucosal invasion of enterobacteria. The antimicrobial function of neutrophils is partially dependent on neutrophil extracellular traps (NETs). Excessive NET formation has been associated with several inflammatory diseases. Here, we aimed to investigate the role of NETs in NSAID-induced small intestinal damage using human samples and an experimental mouse model. Human small intestine specimens were obtained from NSAID users during double-balloon enteroscopy. Wild-type, protein arginine deiminase 4 (PAD4) knockout, and antibiotic-treated mice were administered indomethacin to induce small intestinal injury. The expression of NET-associated proteins, including PAD4, citrullinated histone H3 (CitH3), cell-free DNA, and myeloperoxidase (MPO), was evaluated. The double-positive stained area with CitH3 and MPO, which is specific for neutrophil-derived extracellular traps, was significantly high in the injured small intestinal mucosa of NSAID users. In a mouse model, small intestinal damage developed at 6h after indomethacin administration, accompanied by increased mRNA levels of interleukin-1β and keratinocyte chemoattractant and elevated NET-associated protein levels of PAD4, CitH3, and MPO in small intestine and serum levels of cell-free DNA. Both genetic deletion and pharmacological inhibition of PAD4 attenuated this damage by reducing the mRNA expression of inflammatory cytokines and NET-associated proteins. Furthermore, mice pretreated with antibiotics showed resistance to indomethacin-induced small intestinal damage, with less NET formation. These results suggest that NETs aggravate NSAID-induced small intestinal injury. Therefore, NET inhibition could be a potential treatment for NSAID-induced small intestinal injury.