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• PGE 2 promotes cytokines and DAMPs expression in heat killed S. aureus treated bovine endometrial tissue regulated by EP4-p38 MAPK pathway. • S. aureus adhere and invade into bovine endometrial epithelial cells associated with PGE 2 generation. • The strategy of decreasing PGE 2 accumulation is helpful in reducing the inflammation stage caused by S. aureus. S. aureus isolated from bacterial bovine endometritis is common in epidemiological reports, but is often ignored as a subclinical pathogenic microorganism. In a previous study, we showed that live S. aureus (LSA) and heat killed S. aureus (HK–SA) induce different inflammatory responses in bovine endometrial tissue, and possibly being associated with the accumulation of prostaglandin E2 (PGE 2). Thus, in this study, we varied PGE 2 concentrations using inhibitors or agonists in HK–SA-treated bovine endometrial tissues. The results demonstrated that PGE 2 has a positive relationship with IL-6, TNF-α, and damage-associated molecular patterns (DAMPs; e.g., HMGB-1 and HABP-1) expression and tissues damage, and is regulated by the EP4-p38 MAPK pathway. We concluded that lipoproteins of S. aureus are associated with PGE 2 generation. To further explore the relationship between LSA and PGE 2 accumulation, we used the S. aureus strain SA113 lipoprotein knockout (SA113Δlpl) to infect bovine endometrial epithelial cells (BECs). LSA decreased PGE 2 , cAMP, EP4, IL-6, IL-8, cAMP secretion, and the MAPK and PKA signaling pathways when infected with SA113Δlpl, as compared with SA113-infected groups. Moreover, the adhesion and invasion of BECs were similarly downregulated when lipoproteins in S. aureus were knocked out. The results of this study show that PGE 2 is involved in both HK–SA- and LSA-induced inflammatory responses in the bovine endometrium. We suggest that S. aureus infection is associated with bovine endometritis, and although HK–SA and LSA induce different inflammatory responses, the strategy of decreasing PGE 2 accumulation is helpful in reducing the inflammation stage caused by S. aureus. [ABSTRACT FROM AUTHOR]

Introduction: Angiotensin II (AngII) induces hypertension and pathophysiological vascular thickening and atherosclerosis. This study aims to validate the effects of Angiopoietin-like 7 (ANGPTL7) in AngII-induced hypertension. Methods: ANGPTL7 in blood samples were determined by quantitative real-time polymerase chain reaction. AngII-induced cell growth were detected by CCK-8. Cell cycle arrest and cell apoptosis by downregulation of ANGPTL7 were detected by flow cytometric assay. AngII-induced inflammation was evaluated by Western blotting and ELISA. Results: ANGPTL7 was highly expressed in patients with hypertension. AngII promoted cell viability and the expression level of ANGPTL7 in vascular smooth muscle cells (VSMC). Downregulation of ANGPTL7 inhibited AngII-induced cell proliferation and cell inflammation. Moreover, ANGPTL7 expression decreases also promoted cell apoptosis. Conclusions: Downregulation of ANGPTL7 reversed AngII-induced cell proliferation and cell inflammation and promoted apoptosis in AngII-induced VSMC cells. Therefore, ANGPTL7 can be a potential target in AngII-induced hypertension. [ABSTRACT FROM AUTHOR]

Mushroom Phellinus linteus (" Sanghuang " in Chinese) is a popular medicinal polypore used to treat several disorders through its various biological functions. Inonotus sanghuang is claimed to produce general immune-potentiating and strengthening, anti-inflammatory, anti-tumor and anti-microbial properties, but its effect on acute lung inflammation and oxidative stress are not clearly understood. To determine the effect and mechanism of the polyphenols-rich ethyl acetate fraction from wild I. sanghuang extract (ISE) on acute lung injury (ALI) induced by bleomycin (BLM), female C57BL/6 mice were fed ISE (0%, 0.15% or 0.6% in diet) for 4 weeks prior to challenge with BLM. Bronchoalveolar lavage fluid (BALF) from lung, spleen and lung tissues were collected on day 3 after BLM challenge for histological, oxidative stress, molecular and biochemical analysis. ISE supplementation improved pathological features in lung injury scores and reduced lung wet-to-dry ratios. Moreover, ISE reduced inflammatory cell infiltration and the pro-inflammatory cytokines including IL-1β, IL-6 and TNF-α in BALF, decreased the MPO activity and the MDA level and increased the SOD, CAT and GSH-Px activities in lung tissue homogenates. Further mechanism analysis demonstrated that dietary ISE inhibited NF-κB signal. Finally, peripheral immune function analysis showed that ISE had less effect on immune response including splenocyte producing inflammatory cytokines and T cell proliferation except for IL-1β and IL-2. Our findings indicate the possibility that dietary ISE attenuates ALI induced by BLM through correcting the inflammation and oxidation balance at least in part via inhibiting NF-κB signal in vivo , suggesting that ISE might be a valuable medicinal food effective in improving lung injury. Mushroom Phellinus linteus (" Sanghuang " in Chinese) is a popular medicinal polypore and has been reported to have benefits for health. Current study showed that supplementation with a polyphenols-rich extract from wild Inonotus Sanghuang could inhibit lung inflammation and edema via anti-oxidation and anti-inflammatory effects in mice, which might be mediated at least in part via inhibiting NF-κB signal. Unlabelled Image • ISE may attenuate acute lung injury in bleomycin-treated mice. • ISE may reduce the pro-inflammatory cytokines and oxidative stress in lung tissues. • This inhibitory effect of ISE might be mediated by downregulation of NK-κB signal. • ISE has less immune-modulating effects in BLM-treated mice. [ABSTRACT FROM AUTHOR]

Background IL-37 emerges as a natural suppressor of inflammatory responses. The potential role of IL-37 in the pathology of atherosclerosis is unclear. The purpose of this study was to assess IL-37 profile in acute coronary syndrome (ACS) and the prognostic role of this cytokine in patients with ST-segment elevation acute myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI). Methods In a case-control study, we prospectively enrolled 216 patients undergoing the first coronary angiography, which consisted of 5 groups: normal (n = 57), stable angina (SAP, n = 36), unstable angina (UAP, n = 42), non-STEMI (n = 36), STEMI (n = 45). Plasma IL-37, IL-6 and serum amyloid A (SAA) were measured using a commercially ELISA kit. Besides, in a prospective cohort study, 125 patients with STEMI of onset < 12 h undergoing PPCI were enrolled and divided into 2 groups according to the concentrations of IL-37 (< 341.1 pg/ml or ≥ 341.1 pg/ml). In-hospital major adverse cardiac event (MACE) including nonfatal myocardial infarction (MI), target lesion revascularization, acute heart failure, and cardiac death were estimated for prognosis. Results IL-37 was gradually increased in accordance with the severity of coronary artery disease. The circulating concentration of IL-37 was remarkably higher in the ACS patients than in either of the normal or SAP patients ( p < 0.05), and especially higher in the AMI patients including STEMI and non-STEMI than in the angina pectoris subjects no matter SAP or UAP ( p < 0.05). There was no statistical difference of IL-37 between normal and SAP patients, STEMI and non-STEMI patients ( p > 0.05). The trend of the change of IL-37 was consistent with that of SAA or IL-6. A higher circulating concentration of IL-37 before PPCI was accompanied with the decreased LVEF and the increased NT-proBNP concentrations, and independently predictive of in-hospital MACE rate in patients with STEMI undergoing PPCI (OR = 3.652, 95% CI = 1.113–11.983, p < 0.05). Conclusions We demonstrated the IL-37 profile in patients with acute coronary syndrome and the increased IL-37 concentration was associated with a worse clinical in-hospital outcome in STEMI patients undergoing PPCI. [ABSTRACT FROM AUTHOR]

Background: Acute lung injury is a frequent complication after cardiopulmonary bypass (CPB). Recent studies have reported that NF-κB plays an important role in the pathogenesis of post-CPB pulmonary dysfunction. Several signaling pathways, including the TLR4 pathway, induce NF-κB leading to an inflammatory response. We designed this study to determine whether or not curcumin inhibits TLR4 and MyD88 protein levels and ameliorates lung inflammatory injury in a rat CPB model. Materials and methods: Sprague-Dawley rats were randomly divided into the following five groups (n = 12): sham; control (CPB); vehicle; low-dose curcumin (L-Cur); and high-dose curcumin (H-Cur). The percutaneous beating heart CPB model of rat was established. Animals were pretreated with a single intraperitoneal injection of vehicle, L-Cur (50 mg/kg), or H-Cur (200 mg/kg) 2 h prior to CPB. Blood were sampled at various time points, then lung tissues and bronchoalveolar lavage fluid were harvested 24 h after CPB. Results: CPB induced a marked increase in the concentrations of interleukin-8, tumor necrosis factor-α, and matrix metalloproteinase-9 in plasma, bronchoalveolar lavage fluid, and lung tissues (P < 0.05 versus sham group), whereas curcumin pretreatment reduced these inflammatory markers. Curcumin had effective inhibitory effects on the expression of TLR4, MyD88, and NF-κB in lung tissues 24 h post-CPB (P < 0.05 versus vehicle group). Administration of curcumin remarkably decreased the lung injury score (L-Cur versus vehicle group, P = 0.024; H-Cur versus vehicle group, P = 0.013). Conclusions: Curcumin may be an alternative therapy for protecting CPB-induced lung injury by suppressing the expression of inflammatory cytokines. This anti-inflammatory effect of curcumin is partly related to the inhibition of TLR4, MyD88, and NF-κB. [ABSTRACT FROM AUTHOR]

Abstract: TRPA1 channels have been found to play an important role in mammalian pain sensation, especially when the pain is caused by chemicals on site of inflammation. A large number of structurally diverse chemicals are found to activate TRPA1 channels, implicating a potential chemosensor in neuronal nociception. Identification of the channel activation by cysteine modification through covalent chemical reaction provides arguments for the diversity of the agonist structures. However, it is largely unknown how nonreactive compounds activate TRPA1 channels. Here, we report that NPPB, a classic Cl− channel blocker, potently activated human TRPA1 channels overexpressed in mammalian HEK-293 cells. This effect was confirmed in Ca2+ imaging assay, patch clamp whole cell and single channel recordings. The NPPB response was quick, fully reversible and replicable, contrary to the effect of covalent modification by AITC. The mutagenesis studies revealed a refreshed look at several mutations known to be critical for the actions of AITC and menthol. The blocking profile of NPPB on these mutants showed that the NPPB activation was similar to that of FTS and different from AITC and menthol. The results indicated a possible close interaction between S5 and N-terminal domains of the channel. We also tested a group of NPPB analogs on TRPA1 channel activities. The results demonstrated that NPPB activation was tightly associated with chemical structure. None of the single chemical group was sufficient to activate the channel, indicating that NPPB activated TRPA1 through a structure-specific mechanism. [Copyright &y& Elsevier]

Background: Lipid peroxidation is a characteristic metabolic manifestation of diabetic retinopathy (DR) that causes inflammation, eventually leading to severe retinal vascular abnormalities. Selenium (Se) can directly or indirectly scavenge intracellular free radicals. Due to the narrow distinction between Se's effective and toxic doses, porous Se@SiO2 nanospheres have been developed to control the release of Se. They exert strong antioxidant and anti-inflammatory effects. Methods: The effect of anti-lipid peroxidation and anti-inflammatory effects of porous Se@SiO2 nanospheres on diabetic mice were assessed by detecting the level of Malondialdehyde (MDA), glutathione peroxidase 4 (GPX4), decreased reduced/oxidized glutathione (GSH/GSSG) ratio, tumor necrosis factor (TNF)-α, interferon (IFN)-γ, and interleukin (IL) -1β of the retina. To further examine the protective effect of porous Se@SiO2 nanospheres on the retinal vasculopathy of diabetic mice, retinal acellular capillary, the expression of tight junction proteins, and blood–retinal barrier destruction was observed. Finally, we validated the GPX4 as the target of porous Se@SiO2 nanospheres via decreased expression of GPX4 and detected the level of MDA, GSH/GSSG, TNF-α, IFN-γ, IL -1β, wound healing assay, and tube formation in high glucose (HG) cultured Human retinal microvascular endothelial cells (HRMECs). Results: The porous Se@SiO2 nanospheres reduced the level of MDA, TNF-α, IFN-γ, and IL -1β, while increasing the level of GPX4 and GSH/GSSG in diabetic mice. Therefore, porous Se@SiO2 nanospheres reduced the number of retinal acellular capillaries, depletion of tight junction proteins, and vascular leakage in diabetic mice. Further, we identified GPX4 as the target of porous Se@SiO2 nanospheres as GPX4 inhibition reduced the repression effect of anti-lipid peroxidation, anti-inflammatory, and protective effects of endothelial cell dysfunction of porous Se@SiO2 nanospheres in HG-cultured HRMECs. Conclusion: Porous Se@SiO2 nanospheres effectively attenuated retinal vasculopathy in diabetic mice via inhibiting excess lipid peroxidation and inflammation by target GPX4, suggesting their potential as therapeutic agents for DR. [ABSTRACT FROM AUTHOR]

Introduction: Neutrophils are important participants in the innate immune response. They rapidly and efficiently identify and clear infectious agents by expressing large numbers of membrane receptors. Upon tissue injury or pathogen invasion, neutrophils are the first immune cells to reach the site of injury and participate in the inflammatory response. Materials and methods: A thorough search on PubMed related to neutrophil death or clearance pathways was performed. Conclusion: Inflammatory response and tissue damage can be aggravated when neutrophils are not removed rapidly from the site of injury. Recent studies have shown that neutrophils can be cleared through a variety of pathways, including non-inflammatory and inflammatory death, as well as reverse migration. Non-inflammatory death pathways include apoptosis and autophagy. Inflammatory death pathways include necroptosis, pyroptosis and NETosis. This review highlights the basic properties of neutrophils and the impact of their clearance pathways on the inflammatory response. [ABSTRACT FROM AUTHOR]

In keratitis, keratocytes play a vital role by releasing inflammatory cytokines and expressing intercellular cell adhesion molecule-1(ICAM-1). GC31 is a peptide derived from thrombomodulin, an endogenous protein with potential anti-inflammation properties. We evaluated the protective effect of GC31 in LPS- or poly(I:C)-induced corneal fibroblasts. Cultured keratocytes were treated with either LPS or poly(I:C); The mRNA and protein expressions of IL-6, IL-8, MCP-1, and IFN-γ were determined by real-time RT-PCR and ELISA. The expression level of ICAM-1 was estimated by real-time RT-PCR, immunofluorescence, and western blot. The underlying pathways were investigated by detecting NF-κB p65 translocation and phosphorylation of IκBα, p65, p38, JNK, and ERK. The MTS assay was used to measure cell viability of keratocytes after GC31 incubation. The elevation of IL-6, IL-8, MCP-1, and IFN-γ expression induced by LPS or poly(I:C) was significantly inhibited by GC31 in a dose-dependent manner at both mRNA and protein levels. GC31 also reduced the expression of ICAM-1 in keratocytes after LPS or poly(I:C) stimulation. LPS or poly(I:C) induced p65 translocation and phosphorylation of IκBα, p65, p38, and JNK were suppressed by GC31.GC31 is not only an effective inhibitor of LPS-induced inflammatory response, but it also inhibits poly(I:C)-induced release of inflammatory cytokines and ICAM-1 expression by blocking the NF-κB and MAPK (p38 and JNK) pathways. This suggested that GC31 may exert a protective effect in attenuating corneal inflammation by suppressing the immune response of the fibroblasts. [ABSTRACT FROM AUTHOR]

Keratitis is a worldwide sight-threatening disease. Current drugs generate various adverse effects. Large molecules hardly penetrate ocular tissues. Small peptides derived from endogenous protein display certain advantages. Previously we indentified a novel peptide (PAPep) from human pancreatitis-associated protein (PAP), a protein with protective effect against inflammatory diseases. To further examine the effect of PAPep on inflammatory disease and expand its scope of potential clinical application, especially in keratitis, we tested the effect of PAPep on various aspects of lipopolysaccharide (LPS)—induced corneal inflammation in vivo and in vitro. Dexamethasone (DXM) was used as a drug control. Our results suggested that PAPep suppressed the clinical manifestation, histological disorder and inflammatory cells infiltration and reduced the release of interleukin (IL)-6, IL-8 and monocyte chemotactic protein (MCP)-1 in the cornea. Moreover, PAPep inhibited LPS-induced mRNA and protein expression of the three cytokines in the corneal fibroblasts, prevented translocation of NF–κB and interrupted the phosphorylation of IKKα/β/IκBα/NF–κB. Our study demonstrates that PAPep could effectively attenuate LPS-induced keratitis, more likely by virtue of inhibiting the activation of the IKKα/β/IκBα/NF–κB pathway. PAPep may be considered to be a promising and safe drug for therapeutic application for ocular inflammation. [ABSTRACT FROM AUTHOR]

Background Chronic obstructive pulmonary disease (COPD) concomitant with obstructive sleep apnea (OSA) is known as overlap syndrome. It has an increased rate of hospitalization due to COPD exacerbation which is believed to indicate a worsening of the underlying chronic airway inflammation. Therefore, the aim of this prospective study was to explore whether OSA exacerbates airway inflammation in subjects with COPD by examining the bronchoalveolar lavage (BAL) fluid. Methods This prospective study included 47 patients with overlap syndrome and 28 patients with moderate-to-severe stage stable COPD. Twenty-five patients with overlap syndrome adhered to the continuous positive airway pressure (CPAP) treatment; the remaining patients either refused CPAP treatment or discontinued it within two weeks owing to adverse effects or other reasons. BAL fluid was collected from all subjects for the evaluation of cell numbers and tumor necrosis factor alpha (TNFα) and interleukin-8 (IL-8) levels. Results The BAL fluid of patients with overlap syndrome showed a significantly increased proportion of neutrophils and higher TNFα concentration and IL-8 levels than that of COPD patients; however, the serum CRP levels were not significantly different. An association was found between the percentage of neutrophils and the TNFα concentration and IL-8 levels. Moreover, the TNFα concentration was significantly correlated with the percentage of nighttime spent with oxygen saturation less than 90%. After CPAP treatment, airway inflammation was found to decrease significantly. Conclusions OSA exacerbates airway inflammation in COPD patients. CPAP treatment can improve nocturnal hypoxemia and decrease airway inflammation. [ABSTRACT FROM AUTHOR]

• tFNA-Que can alleviate radiation-induced oxidative stress and inflammation. • tFNA-Que presents a straightforward and efficient synergistic delivery nano-system. Radiation cystitis (RC) has impacted millions globally with high morbidity and a dearth of effective strategies. Earlier research indicated that quercetin (Que) could alleviate radiation-induced bladder damage. However, Que's limited application arises from issues such as poor water solubility, rapid degradation, and low oral bioavailability. To address these challenges, a nano-system, named tFNA-Que, has been developed for Que delivery, utilizing the tetrahedral framework nucleic acid (tFNA). Due to the anti-inflammatory, antioxidant, and delivery capabilities of tFNA, it is purposefully designed as an efficient carrier for delivering Que. The tFNA-Que formulation exhibits an easily synthesized structure, stable performance, sustained release, good water solubility, robust cellular internalization ability, desirable biocompatibility, and biosafety. As a result, tFNA-Que can alleviate radiation-induced oxidative stress and inflammation while promoting angiogenesis in RC. In summary, the synthesis of tFNA-Que presents a straightforward and efficient synergistic delivery nano-system, making it as a promising candidate for RC treatment. [ABSTRACT FROM AUTHOR]

Abstract: Thrombomodulin (TM) is a single-transmembrane glycoprotein receptor for thrombin, which is best known as a cofactor for thrombin-mediated activation of anticoagulant protein C. C-type lectin-like domain (CTLD) of TM has distinct coagulation/fibrinolysis-independent anti-inflammatory properties. Here we found anti-inflammatory effects of a novel peptide (GC31) from CTLD of TM in endotoxin-induced uveitis, which was characterized by a reduction of leukocyte counts, protein concentration, tumor necrosis factor (TNF)-α and monocyte chemoattractant protein (MCP)-1 levels in aqueous humor. Through in vitro experiments, we further found that GC31 suppressed TNF-α and interleukin (IL)-6 expressions in lipopolysaccharide (LPS)-stimulated macrophage-like RAW264.7 cells and interrupted LPS-induced nuclear factor-κB (NF-κB) activation. These data indicate a beneficial role of peptide GC31 in preventing intraocular inflammatory response, especially uveitis. [Copyright &y& Elsevier]

Deep hypothermic circulatory arrest (DHCA) has been widely used in the operations involving the aortic arch and brain aneurysm since 1950s; but prolonged DHCA contributes significantly to neurological deficit which remains a major cause of postoperative morbidity and mortality. It has been reported that hydrogen exerts a therapeutic antioxidant activity by selectively reducing hydroxyl radical. In this study, DHCA treated rats developed a significant oxidative stress, inflammatory reaction and apoptosis. The administration of HRS resulted in a significant decrease in the brain injury, together with lower production of IL-1β, TNF-α, 8-OHdG and MDA as well as decreased activity of NOS while increased activity of SOD. The apoptotic index as well as the expressions of caspase-3 in brain tissue was significantly decreased after treatment. HRS administration significantly attenuated the severity of DHCA induced brain injury by mechanisms involving amelioration of oxidative stress, down-regulation of inflammatory factors and reduction of apoptosis. [ABSTRACT FROM AUTHOR]

The pathophysiology of diabetic retinopathy (DR) was complex. Under hyperglycemic conditions, the release of proinflammatory cytokines and the adhesion of leukocytes to retinal capillaries contribute to endothelial damage and the subsequent increase in vascular permeability resulting in macular edema. Melatonin, produced in the retina to regulate redox reactions and dopamine metabolism, plays protective roles against inflammation and oxidative stress. Considering its anti‐inflammatory and antioxidative properties, melatonin was speculated to exert beneficial effects in DR. In this study, we characterized the protective effects of melatonin on the inner blood–retinal barrier (iBRB), as well as the possible mechanisms in experimental DR. Results showed that in diabetic rat retinas, the leakage of iBRB and the expression of inflammatory factors (VEGF, TNF‐α, IL‐1β, ICAM‐1, and MMP9) increased dramatically, while the expression of tight junction proteins (ZO‐1, occludin, JAM‐A, and claudin‐5) decreased significantly. The above changes were largely ameliorated by melatonin. The in vivo data were confirmed in vitro. In addition, the protein expressions of p38 MAPK, NF‐κB, and TXNIP were upregulated significantly in diabetes and were downregulated following melatonin treatment. Melatonin could maintain the iBRB integrity by upregulating the expression of tight junction proteins via inhibiting p38/TXNIP/NF‐κB pathway, thus decreasing the production of inflammatory factors. This study may shed light on the development of melatonin‐based DR therapy. [ABSTRACT FROM AUTHOR]

Prostaglandin E 2 (PGE 2) is an inflammatory mediator involved in the pathogenesis of several chronic inflammatory conditions, including endometritis. Previous studies have shown that PGE 2 accumulates in Escherichia coli -challenged ex vivo endometrial explants, increasing the expression of pro-inflammatory factors and aggravating tissue damage; these alterations are linked to key enzymes involved in the synthesis of PGE 2 , including cyclooxygenases-2 (COX-2) and microsomal PGES-1 (mPGES-1). In this study, we aimed to investigate whether administration of PGE 2 modulated the activities of nitric oxide synthase 2 (NOS2), platelet-activating factor receptor (PAFR), and matrix metalloproteinase (MMP)-2 in E. coli- challenged ex vivo bovine endometrial explants. Our findings showed that COX-2 and mPGES-1 inhibitors significantly reduced NOS2, PAFR, and MMP-2 expression in the E. coli -challenged ex vivo endometrial explants. In addition, NOS2, PAFR, and MMP-2 expression levels were strongly increased in response to treatment with 15-prostaglandin dehydrogenase inhibitors in the E. coli- challenged ex vivo endometrial explants. However, these stimulatory effects could be blocked by PGE 2 receptor 4 (EP4) and protein kinase A (PKA) inhibitors. Overall, these findings show that pathogenic PGE 2 upregulated NOS2, PAFR, and MMP-2 expression, which may enhance inflammatory damage via the EP4/PKA signaling pathway in E. coli- challenged ex vivo endometrial explants. • Pathogenic bacteria (E. coli) infected bovine endometrial tissue in vitro. • PGE 2 promotes NOS2, PAFR, and MMP-2 expression in E. coli -infected bovine endometrial tissues in vitro. • PGE 2 promotes NOS2, PAFR, and MMP-2 expression via the prostaglandin E 2 receptor 4/protein kinase A signaling pathway. [ABSTRACT FROM AUTHOR]

• NLRP3 engaged in the secretion of inflammatory mediators after E. coli treatment. • NLRP3 engaged in the activation of MAPK and NF-κB signaling-pathway. • NLRP3 engaged in caspase1 signaling-pathway activation after E. coli treatment. • NLRP3 contributes to liver damage in mice after E. coli infection. The host Toll-like Receptor-2 (TLR2) and Toll-like Receptor-4 (TLR4) play critical roles in defense against Escherichia coli (E. coli) infection is well-known. The NLR pyrin domain-containing 3 (NLRP3) inflammasome is also an important candidate during the host-recognized pathogen, while the roles of NLRP3 in the host inflammatory response to E. coli infection remains unclear. This study aimed to explore the roles of NLRP3 in regulating the inflammatory response in E. coli infection-induced mice. Our result indicated that compared to wild-type mice, the TLR2-deficient (TLR2-/-), TLR4-deficient (TLR4-/-), and NLRP3-deficient (NLRP3-/-) mice had significant decrease in liver damage after stimulation with Lipopolysaccharide (LPS, 1 μg/mL), Braun lipoprotein (BLP, 1 μg/mL), or infected by WT E. coli (1 × 107 CFU, MOI 5:1). Meanwhile, compared with wild-type mice, the TNF-α and IL-1β production in serum decreased in TLR2-/-, TLR4-/-, and NLRP3-/- mice after LPS, BLP treatment, or WT E. coli infection. In macrophages from NLRP3-/- mice showed significantly reduced secretion of TNF-α and IL-1β in response to stimulation with LPS, BLP, or WT E. coli infection compared with macrophages from wild-type mice. These results indicate that besides TLR2 and TLR4, NLRP3 also plays a critical role in host inflammatory responses to defense against E. coli infection, and might provide a therapeutic target in combating disease with bacterium infection. [ABSTRACT FROM AUTHOR]

Highlights: [•] miR-93 is downregulated in the eyes of LPS-induced EIU rats. [•] miR-93 is downregulated in LPS-treated RAW 264.7 cells. [•] miR-93 inhibits LPS-induced inflammatory cytokine production. [•] miR-93 inhibits LPS-induced activation of NF-κB signaling through IRAK4. [Copyright &y& Elsevier]

Cucurbitacin IIb (CuIIb) is one of the major active compounds in Hemsleyadine tablets which have been used for clinical treatment of bacillary dysentery, enteritis and acute tonsilitis. However, its action mechanism has not been completely understood. This study aimed to explore the anti-inflammatory activity of CuIIb and its underlying mechanism in mitogen-activated lymphocytes isolated from mouse mesenteric lymph nodes. The results showed that CuIIb inhibited the proliferation of concanavalin A (Con A)-activated lymphocytes in a time- and dose-dependent manner. CuIIb treatment arrested their cell cycle in S and G2/M phases probably due to the disruption of the actin cytoskeleton and the modulation of p27Kip1 and cyclin levels. Moreover, the surface expression of activation markers CD69 and CD25 on Con A-activated CD3+ T lymphocytes was suppressed by CuIIb treatment. Both Con A- and phorbol ester plus ionomycin-induced expression of TNF-α, IFN-γ and IL-6 proteins was attenuated upon exposure to CuIIb. Mechanistically, CuIIb treatment suppressed the phosphorylation of JNK and Erk1/2 but not p38 in Con A-activated lymphocytes. Although CuIIb unexpectedly enhanced the phosphorylation of IκB and NF-κB (p65), it blocked the nuclear translocation of NF-κB (p65). In support of this, CuIIb significantly decreased the mRNA levels of IκBα and TNF-α, two target genes of NF-κB, in Con A-activated lymphocytes. In addition, CuIIb downregulated Con A-induced STAT3 phosphorylation and increased cell apoptosis. Collectively, these results suggest that CuIIb exhibits its anti-inflammatory activity through modulating multiple cellular behaviors and signaling pathways, leading to the suppression of the adaptive immune response. [ABSTRACT FROM AUTHOR]

Atorvastatin is not only an antilipemic but also used as an anti-inflammatory medicine in heart disease. Our working hypothesis was that atorvastatin preconditioning could improve the forward blood flow in the no-reflow rats associated with inflammation. We investigated that two doses of atorvastatin preconditioning (20 and 5 mg/kg/day) could alleviate deterioration of early cardiac diastolic function in rats with inflammation detected by echocardiography and haemodynamics. This benefit was obtained from the effect of atorvastatin preconditioning on improving forward blood flow and preserving the infarct cardiomyocytes, which was estimated by Thioflavin S and TTC staining in rats with myocardial ischemia/reperfusion. Subsequently, the improving of forward blood flow was ascribed to reduction of microthrombus in microvascular and myocardial fibrosis observed by MSB and Masson's trichrome staining with atorvastatin preconditioning. Ultimately, we found that atorvastatin preconditioning could reduce inflammation factor, such as tumor necrosis factor-α and fibrinogen-like protein 2, both in myocardial and in mononuclear cells, which probably attribute to microcirculation dysfunction in no-reflow rats detected by immunohistochemistry staining, western blot, and ELISA detection, respectively. In conclusion, atorvastatin preconditioning could alleviate deterioration of early cardiac diastolic function and improve the forward blood flow in the no-reflow rats attributing to reduction of TNF-α and fgl-2 expression. [ABSTRACT FROM AUTHOR]

Objective Proinflammatory cytokine TNF-α during MI/R injury has been studied extensively. However, how TNF-α induces microvascular dysfunction in MI/R is still unclear. This study investigates whether TNF-α regulates fibrinogen-like protein 2 (fgl2) expression, a procoagulant resulting in the formation of fibrin-rich microthrombus in MI/R injury. Methods and Results Microthrombosis, TNF-α and fgl2 expression were assessed in rats with MI/R injury. The effect of TNF-α on fgl2 expression and fgl2 prothrombinase activity was investigated in CMECs, then CMECs were pretreated with selective inhibitors of NF-κB and p38 MAPK pathways. TNF-α and fgl2 expression were both upregulated in MI/R group. When neutralization of TNF-α, fgl2 expression was decreased in vivo. Fgl2 expression was upregulated in CMECs exposed to TNF-α. Accordingly, the ability of thrombin generation was increased in CMECs. Besides, TNF-α-induced fgl2 expression in the cells was suppressed by NF-κB inhibitor PDTC and/or p38 MAPK inhibitor SB203580. Conclusion TNF-α upregulates fgl2 expression via activation of NF- kB and p38 MAPK in CMECs. TNF-α-induced flg2 in CMECs mediates the formation of fibrin-rich microthrombus, which may be one of the mechanisms of microvascular dysfunction or obstruction due to MI/R injury. [ABSTRACT FROM AUTHOR]

Chronic pain is commonly accompanied with anxiety disorder, which complicates treatment. In this study, we investigated the analgesic and anxiolytic effects of Formononetin (FMNT), an active component of traditional Chinese medicine red clover (Trifolium pratense L.) that is capable of protecting neurons from N-methyl-D-aspartate (NMDA)-evoked excitotoxic injury, on mice suffering from complete Freund's adjuvant (CFA)-induced chronic inflammatory pain. The results show that FMNT administration significantly reduces anxiety-like behavior but does not affect the nociceptive threshold in CFA-injected mice. The treatment reverses the upregulation of NMDA, GluA1, and GABAA receptors, as well as PSD95 and CREB in the basolateral amygdala (BLA). The effects of FMNT on NMDA receptors and CREB binding protein (CBP) were further confirmed by the potential structure combination between these compounds, which was analyzed by in silico docking technology. FMNT also inhibits the activation of the NF-κB signaling pathway and microglia in the BLA of mice suffering from chronic inflammatory pain. Therefore, the anxiolytic effects of FMNT are partially due to the attenuation of inflammation and neuronal hyperexcitability through the inhibition of NMDA receptor and CBP in the BLA. [ABSTRACT FROM AUTHOR]