Herbal formula Jiawei Xiaochengqi decoction prevents postoperative abdominal adhesion in a rat model through inhibition of CXCL2-CXCR2 pathway.

BACKGROUND: Postoperative abdominal adhesion (PAA) is the most common complication after abdominal surgeries, which can lead to intestinal obstruction, chronic abdominal pain or female infertility. Jiawei Xiaochengqi decoction (JWXCQ) is a hospital preparation widely used for PAA treatment in Nanfang Hospital of Southern Medical University for more than twenty years. PURPOSE: This study aimed to investigate the therapeutic effects and potential mechanism of JWXCQ against PAA and provide beneficial information for its clinical application. METHODS: The main active components of JWXCQ were identified using ultra high performance liquid chromatography (UHPLC) combined with standard substance comparison. The efficacy and underlying mechanism of JWXCQ were evaluated through in vivo experiments with a postsurgical-induced peritoneal adhesion rat model, and in vitro studies with LPS-stimulated Raw 264.7 macrophages and primary fibroblasts. H&E and Masson staining were performed to assess histopathological changes. The levels of cytokines/proteins-associated with inflammation and degradation of extracellular matrix as well as CXCL2-CXCR2 pathway-related proteins were determined by ELISA, qRT-PCR, western blot assays or immunohistochemistry, respectively. Furthermore, siCXCR2 transfection was used to validate the mechanism of action of JWXCQ. RESULTS: JWXCQ treatment significantly reduced the formation of PAA, inhibited the inflammation and collagen deposition, and facilitated the secretion of MMP9, decreased the levels of IL-1ß, IL-6, TIMP1, COL-1, and suppressed the CXCL2-CXCR2 pathway in PAA rats. Furthermore, JWXCQ inhibited its downstream pathways, the JAK2-STAT3 and PI3K-AKT signaling, as indicated by the suppression of the phosphorylation levels of STAT3 and AKT. In vitro cell experiments revealed that JWXCQ reduced IL-1ß and IL-6 secretion in Raw 264.7 macrophages and COL-1 in primary fibroblasts. The CXCL2-CXCR2, JAK2-STAT3 and PI3K-AKT pathways were also inhibited after JWXCQ treatment, which were consistent with the in vivo results. More importantly, silence of CXCR2 eliminated the regulatory effects of JWXCQ. CONCLUSION: JWXCQ could effectively prevent the PAA formation by alleviating inflammation and collagen deposition, which was associated with the inhibition of CXCL2-CXCR2 pathway. This study investigated the relevant pharmacological mechanisms of JWXCQ, providing further evidence for the application of JWXCQ in clinical PAA treatment.

Bone marrow derived mast cells injected into the osteoarthritic knee joints of mice induced by sodium monoiodoacetate enhanced spontaneous pain through activation of PAR2 and action of extracellular ATP.

Conditions that resemble osteoarthritis (OA) were produced by injection of sodium monoiodoacetate (MIA) into the knee joints of mice. Bone marrow derived mast cells (BMMCs) injected into the OA knee joints enhanced spontaneous pain. Since no spontaneous pain was observed when BMMCs were injected into the knee joints of control mice that had not been treated with MIA, BMMCs should be activated within the OA knee joints and release some pain-inducible factors. Protease activated receptor-2 (PAR2) antagonist (FSLLRY-NH2) almost abolished the pain-enhancing effects of BMMCs injected into the OA knee joints, suggesting that tryptase, a mast cell protease that is capable of activating PAR2, should be released from the injected BMMCs and enhance pain through activation of PAR2. When PAR2 agonist (SLIGKV-NH2) instead of BMMCs was injected into the OA knee joints, it was also enhanced pain. Apyrase, an ATP degrading enzyme, injected into the OA knee joints before BMMCs suppressed the pain enhanced by BMMCs. We showed that purinoceptors (P2X4 and P2X7) were expressed in BMMCs and that extracellular ATP stimulated the release of tryptase from BMMCs. These observations suggest that ATP may stimulate degranulation of BMMCs and thereby enhanced pain. BMMCs injected into the OA knee joints stimulated expression of IL-1ß, IL-6, TNF-α, CCL2, and MMP9 genes in the infrapatellar fat pads, and PAR2 antagonist suppressed the stimulatory effects of BMMCs. Our study suggests that intermittent pain frequently observed in OA knee joints may be due, at least partly, to mast cells through activation of PAR2 and action of ATP, and that intraarticular injection of BMMCs into the OA knee joints may provide a useful experimental system for investigating molecular mechanisms by which pain is induced in OA knee joints.

Cashew apple byproduct: Gastroprotective effects of standardized extract.

ETHNOPHARMACOLOGICAL RELEVANCE: The incidence of gastric mucosa lesions in the adult population has increased mainly due to the continued use of nonsteroidal anti-inflammatory drugs (NSAIDs). The cashew (Anacardium occidentale L.) is a tropical tree, cultivated in several countries, whose barks, leaves and pseudofruit (cashew apple) are popularly used in traditional medicine for the treatment of many diseases, including gastric ulcer. AIM: Our study evaluated the potential gastroprotective effect of the carotenoid and anacardic acids-enriched aqueous extract (CAE), prepared from cashew apple pomace, in the dose-repeated acetylsalicylic acid (ASA)-induced gastric lesions model in rats. MATERIAL AND METHODS: After randomly distribution into five group (G1 - G5, n = 8 animals/group), male Wistar rats were daily treated with ASA solution (200 mg/kg, 5 ml/kg, G2 - G5) or potable water (Satellite group, G1) during 14 days. From 8th to 14th experimental day, rats in G3 - G5 groups were orally treated with CAE (50, 100 and 500 mg/kg, 5 ml/kg, respectively). Body weight was measured on 0, 7th and 14th day. On the 14th experimental day, all surviving animals were euthanized for macroscopic evaluation of the inner organs and stomach removal. After weighting, each stomach was properly prepared for biochemical analysis [myeloperoxidase activity (MPO), reduced glutathione analysis (GSH), IL-1ß, CXCL2/MIP-2, TNF-α and IL-10 levels]. RESULTS: At the most efficient dose (100 mg/kg, p.o.), CAE-treated animals showed a slight improvement in the macroscopic aspect of gastric mucosa associated with significant (p < 0.05) reduced levels of IL-1ß, CXCL2/MIP-2, and MPO activity besides increased levels of GSH (partially), and IL-10 in stomach tissues. CONCLUSIONS: The present study demonstrated that the carotenoid and anacardic acids-enriched extract obtained from cashew apple pomace is a promising raw material for the development of herbal medicine and/or functional food supplements for the adjuvant treatment of NSAIDs-induced gastric ulcers.

Herbal Combinational Medication of Glycyrrhiza glabra, Agastache rugosa Containing Glycyrrhizic Acid, Tilianin Inhibits Neutrophilic Lung Inflammation by Affecting CXCL2, Interleukin-17/STAT3 Signal Pathways in a Murine Model of COPD.

Chronic obstructive pulmonary disease (COPD) is caused by exposure to toxic particles, such as coal fly ash (CFA), diesel-exhaust particle (DEP), and cigarette smoke (CS), leading to chronic bronchitis, mucus production, and a subsequent lung dysfunction. This study, using a mouse model of COPD, aimed to evaluate the effect of herbal combinational medication of Glycyrrhiza glabra (GG), Agastache rugosa (AR) containing glycyrrhizic acid (GA), and tilianin (TN) as active ingredients. GA, a major active component of GG, possesses a range of pharmacological and biological activities including anti-inflammatory, anti-allergic, anti-oxidative. TN is a major flavonoid that is present in AR. It has been reported to have anti-inflammatory effects of potential utility as an anti-COPD agent. The COPD in the mice model was induced by a challenge with CFA and DEP. BALB/c mice received CFA and DEP alternately three times for 2 weeks to induce COPD. The herbal mixture of GG, AR, and TN significantly decreased the number of neutrophils in the lungs and bronchoalveolar lavage (BAL) fluid. It also significantly reduced the production of C-X-C motif chemokine ligand 2 (CXCL-2), IL-17A, CXCL-1, TNF-α, symmetric dimethylarginine (SDMA) in BALF and CXCL-2, IL-17A, CXCL-1, MUC5AC, transient receptor potential vanilloid-1 (TRPV1), IL-6, COX-2, NOS-II, and TNF-α mRNA expression in the lung tissue. Notably, a combination of GG and AR was more effective at regulating such therapeutic targets than GG or AR alone. The histolopathological lung injury was alleviated by treatment with the herbal mixture and their active ingredients (especially TN). In this study, the herbal combinational mixture more effectively inhibited neutrophilic airway inflammation by regulating the expression of inflammatory cytokines and CXCL-2 by blocking the IL-17/STAT3 pathway. Therefore, a herbal mixture of GG and AR may be a potential therapeutic agent to treat COPD.

The CXCR2/CXCL2 signalling pathway - An alternative therapeutic approach in high-grade glioma.

OBJECTIVE: Besides VEGF, alternative signalling via CXCR2 and its ligands CXCL2/CXCL8 is a crucial part of angiogenesis in glioblastoma. Our aim was to understand the role of CXCR2 for glioma biology and elucidate the therapeutic potential of its specific inhibition. METHODS: GL261 glioma cells were implanted intracranially in syngeneic mice. The 14 or 7 days of local or systemic treatment with CXCR2-antagonist (SB225002) was initiated early on the day of tumour cell implantation or delayed after 14 days of tumour growth. Glioma volume was verified using MRI before and after treatment. Immunofluorescence staining was used to investigate tumour progression, angiogenesis and microglial behaviour. Furthermore, in vitro assays and gene expression analyses of glioma and endothelial cells were performed to validate inhibitor activity. RESULTS: CXCR2-blocking led to significantly reduced glioma volumes of around 50% after early and delayed local treatments. The treated tumours were comparable with controls regarding invasiveness, proliferation and apoptotic cell activity. Furthermore, no differences in CXCR2/CXCL2 expression were observed. However, immunostaining revealed reduction in vessel density and accumulation of microglia/macrophages, whereas interaction of these myeloid cells with tumour vessels was enhanced. In vitro analyses of the CXCR2-antagonist showed its direct impact on proliferation of glioma and endothelial cells if used at higher concentrations. In addition, expression of CXCR2/CXCL2 signalling genes was increased in both cell types by SB225002, but VEGF-relevant genes were unaffected. CONCLUSION: The CXCR2-antagonist inhibited glioma growth during tumour initiation and progression, whereas treatment was well-tolerated by the recipients. Thus, the CXCR2/CXCL2 signalling represents a promising therapeutic target in glioma.

Protective Effect of Traditional Chinese Medicine Formula RP on Lung Microenvironment in Pre-Metastasis Stage of Breast Cancer.

Background: Inflammatory response and inflammation-induced vascular hyper-permeability were established leading to the abnormalities of the pulmonary microenvironment in pre-metastasis stage of breast cancer. Ruyiping is a commonly used compound drug for clinical treatment of breast cancer metastasis, and Platycodon grandiflorum is mainly used to treat pulmonary inflammatory diseases. Therefore, this study used ruyiping combined with Platycodon grandiflorum (abbreviated as RP) to investigate their inhibitory effect on pre-metastatic microenvironment of lung in 4T1 tumor-bearing mice. Study Design and Methods: The permeability of lung tissue was detected by Evans blue method. The localization of S100A8/A9 in lung tissue was obtained by double-labeling immunofluorescence staining. The level of fibrinogen in pre-metastatic microenvironment of lung as well as the levels of pro-inflammatory factors (interleukin [IL]-1ß and IL-6) and chemokines (CXCL2 and CXCL5) in bronchoalveolar lavage fluid was detected by ELISA (enzyme-linked immunosorbent assay). Results: From the experimental results, RP could protect the integrity of microvascular, inhibit the release of S100A8/A9, reduce the extravasation of fibrinogen, and decrease the expressions of IL-1ß, IL-6, CXCL2, and CXCL5. Conclusions: RP could inhibit the extravasation of fibrinogen by protecting pulmonary vascular integrity and then interrupted its interaction with carcinoma in situ, thereby inhibiting the formation of inflammatory pre-metastatic microenvironment.

Potential anti-inflammatory effect of Madi-Ryuk and its active ingredient tannic acid on allergic rhinitis.

Madi-Ryuk (MDR) is a traditional Korean medicine and it has been widely used in Korea to treat arthritis and we previously reported the anti-allergic inflammatory effect of MDR in vitro model. However, therapeutic evidence of MDR on in vivo model of allergic inflammatory reaction has not yet been demonstrated. The research purpose was to investigate the efficacy of MDR and its active ingredient tannic acid (TA) in ovalbumin (OVA)-induced AR mice model. OVA-challenged AR mice orally medicated MDR or its active ingredient TA daily for ten days. In mice having a AR, MDR and TA prominently diminished number of rubs and levels of histamine, IgE, thymic stromal lymphopoietin, interleukin (IL)-1ß, IL-4, IL-5, IL-13, IL-33, and tumor necrosis factor-α. In addition, protein expression levels and activities of caspase-1 were declined by oral medication of MDR and TA. Decline in levels of macrophage inflammatory protein-2 and intercellular adhesion molecules-1 and reduction in penetrations of inflammatory cells into inflamed tissue were also noted in MDR and TA groups. Taken together, identification of MDR effect in preclinical models suggests that MDR may be a therapeutic drug for the treatment and prevention of AR.

Plant-derived verbascoside and isoverbascoside regulate Toll-like receptor 2 and 4-driven neutrophils priming and activation.

BACKGROUND: Neutrophils have a short live in circulation and accelerate greatly local immune responses via increased granulopoiesis and migration at high numbers to infected or inflamed tissue. HYPOTHESIS: Since neutrophils produce a variety of factors with destructive and pro-inflammatory potential the regulation of their homeostasis and functions might be eventually beneficial in inflammation-related pathological conditions. Herein we investigated the effect of natural-derived verbascoside (Verb) and its positional isomer isoverbascoside (IsoVerb) on neutrophil functions. METHODS: We used purified murine bone marrow (BM) neutrophils to study cell responsiveness to priming or activation via Toll-like receptors (TLRs) 2 and 4. The expression of CD11b, chemokine (CXC motif) receptor 2 (CXCR2), the intracellular level of phosphorylated p38 mitogen-activated protein kinase (MAPK) and tumor necrosis factor (TNF)-α in neutrophils were determined by flow cytometry while the release of macrophage inflammatory protein (MIP)-2 in culture supernatant was determined by enzyme-linked immunosorbent assay (ELISA). RESULTS: We found that Verb appeared less powerful inhibitor of TLR2 and TLR4-mediated apoptosis than IsoVerb. However at concentrations below 16 µM and in LPS priming conditions Verb was more selective inhibitor of CD11b and CXCR2 expression than IsoVerb. Both compounds showed similar activity on integrin/chemokine receptor expression when neutrophils were stimulated with ZY or were activated with LPS. Verb sustained CXCR2 expression and turnover via regulation of the cell responsiveness to its ligand KC (CXCL1) and via the release of MIP-2 (CXCL2). Both Verb and IsoVerb increased TNF-α production and inhibited p38 phosphorylation in TNF-α+ cells. We fail to discriminate sharply between Verb's and IsoVerb's efficacy when studying p38 phosphorylation in LPS stimulated neutrophils. The multi-parametric analysis provides critical insight on the range of on-target effects of Verb and IsoVerb. CONCLUSION: The strength and selectivity of Verb and IsoVerb depended on the degree of activation and functional state of neutrophils, and both compounds are with potential to affect neutrophil-related pathologies/conditions in heterogenic populations.

Effects of Scutellaria baicalensis Extract on Cigarette Smoke-Induced Airway Inflammation in a Murine Model of Chronic Obstructive Pulmonary Disease.

Chronic obstructive pulmonary disease (COPD), including pulmonary emphysema and chronic bronchitis as well as structural and inflammatory changes in small airways, is insensitive to corticosteroid therapies. This study aimed to evaluate the effects of Scutellaria baicalensis root extract (SB_E) in a mouse model of COPD. The COPD mouse model was produced by challenging C57BL/6 mice with a cigarette smoke extract and lipopolysaccharide (LPS). SB_E significantly decreased the neutrophil counts in blood and bronchoalveolar lavage fluid (BALF), and the production of tumor necrosis factor (TNF)-α, interleukin (IL)-17A, macrophage inflammatory protein 2 (MIP2), and chemokine (C-X-C motif) ligand 1 (CXCL-1) in BALF, and TNF-α mRNA expression in lung tissue. The histological lung injury was also alleviated by treatment with SB_E. Thus, SB_E effectively inhibited airway inflammation by regulating the expression of inflammatory cytokines by blocking MIP2 and CXCL-1 secretion. Therefore, S. baicalensis may be a potential therapeutic agent for COPD.

Mechanical strain determines the site-specific localization of inflammation and tissue damage in arthritis.

Many pro-inflammatory pathways leading to arthritis have global effects on the immune system rather than only acting locally in joints. The reason behind the regional and patchy distribution of arthritis represents a longstanding paradox. Here we show that biomechanical loading acts as a decisive factor in the transition from systemic autoimmunity to joint inflammation. Distribution of inflammation and erosive disease is confined to mechano-sensitive regions with a unique microanatomy. Curiously, this pathway relies on stromal cells but not adaptive immunity. Mechano-stimulation of mesenchymal cells induces CXCL1 and CCL2 for the recruitment of classical monocytes, which can differentiate into bone-resorbing osteoclasts. Genetic ablation of CCL2 or pharmacologic targeting of its receptor CCR2 abates mechanically-induced exacerbation of arthritis, indicating that stress-induced chemokine release by mesenchymal cells and chemo-attraction of monocytes determines preferential homing of arthritis to certain hot spots. Thus, mechanical strain controls the site-specific localisation of inflammation and tissue damage in arthritis.

Fisetin inhibits pristine-induced systemic lupus erythematosus in a murine model through CXCLs regulation.

Systemic lupus erythematosus (SLE) is associated with an increased risk of vascular complications. Lupus nephritis is a major manifestation of SLE in the clinic. Lupus nephritis is elevated by T helper type 17 (Th17) cells, the major pro­inflammatory T­cell subset, leading to autoimmunity modulation. Therapeutic treatments targeting leukocyte recruitment may be useful in attenuating vascular complications linked to SLE progression. 3,7,3',4'­Tetrahydroxyflavone (fisetin) is a flavonol and a member of the flavonoid polyphenols. It is present in various fruits and vegetables, including persimmons, apples, kiwis, grapes, onions, strawberries and cucumbers. In the present study, the effects of fisetin against SLE induced by pristane (PRI) were evaluated in mice. Fisetin was indicated to reduce PRI­induced anti­double stranded DNA, anti­ small nuclear ribonucleoprotein and the ratio of albumin to creatinine in urine. In addition, the chemokine (C­X­C motif) ligand (CXCL) signaling pathway was activated for PRI treatment, which was reversed by fisetin administration by reducing CXCL­1 and 2, chemokine (C­C motif) ligand 3, as well as CXC receptor 2 expression. In addition, the induction of inflammatory cytokines, including interleukin (IL)­6, tumor necrosis factor­α, IL­1ß, as well as the chemokine interferon­Î³, by PRI were downregulated by fisetin treatment in mice. Furthermore, Th17 cells and their associated cytokines were highly induced by PRI treatment, which was inhibited by fisetin administration. The present results indicated that fisetin may be an effective management for SLE by targeting the CXCL signaling pathway and regulating Th17 differentiation during lupus nephritis development.

Cold-inducible RNA-binding protein-derived peptide C23 attenuates inflammation and tissue injury in a murine model of intestinal ischemia-reperfusion.

BACKGROUND: Cold-inducible RNA-binding protein is a novel damage-associated molecular pattern that causes inflammation. C23, a short peptide derived from cold-inducible RNA-binding protein, has been found to have efficacy in blocking cold-inducible RNA-binding protein's activity. We hypothesized that C23 reduces inflammation and tissue injury induced by intestinal ischemia-reperfusion. METHODS: Male C57BL/6 mice were subjected to 60 minutes of intestinal ischemia by clamping the superior mesenteric artery. Immediately after reperfusion, either normal saline (vehicle) or C23 peptide (8 mg/kg body weight) was injected intraperitoneally. Four hours after reperfusion, blood, intestinal, and lung tissues were collected for analysis of inflammatory and tissue injury parameters. RESULTS: Cold-inducible RNA-binding protein levels in the intestinal tissues were significantly increased following intestinal ischemia-reperfusion. Histologic examination of the intestine revealed a significant reduction in injury score in the C23 group by 48% as compared with the vehicles after intestinal ischemia-reperfusion. The serum levels of lactate dehydrogenase and aspartate aminotransferase were increased in animals that underwent vehicle-treated intestinal ischemia-reperfusion, whereas C23-treated animals exhibited significant reductions by 48% and 53%, respectively. The serum and intestinal tissue levels of tumor necrosis factor α were elevated in vehicle-treated intestinal ischemia-reperfusion mice but decreased by 72% and 69%, respectively, in C23-treated mice. Interleukin-6 mRNA levels in the lungs were reduced by 86% in the C23-treated group in comparison to the vehicle-treated group after intestinal ischemia-reperfusion. Expression of macrophage inflammatory protein 2 and level of myeloperoxidase activity in the lungs were dramatically increased after intestinal ischemia-reperfusion and significantly reduced by 91% and 25%, respectively, in the C23-treated group. CONCLUSION: C23 has potential to be developed into a possible therapy for reperfusion injury after mesenteric ischemia and reperfusion.

Zerumbone from Zingiber zerumbet Ameliorates Lipopolysaccharide-Induced ICAM-1 and Cytokines Expression via p38 MAPK/JNK-IκB/NF-κB Pathway in Mouse Model of Acute Lung Injury.

Acute lung injury (ALI) is a clinical syndrome with high morbidity and mortality rates mainly caused by Gram-negative bacteria. Nevertheless, an effective treatment strategy for ALI is yet to be developed. Zerumbone, a sesquiterpene isolated from Zingiber zerumbet Smith, possesses several advantageous bioeffects such as antioxidation, anti-inflammation, and antiulcer. Pretreatment of zerumbone inhibited lipopolysaccharide (LPS)-induced arterial blood gas exchange, neutrophils infiltration, and increased pulmonary vascular permeability. LPS-induced expression of intercellular adhesion molecule-1 (ICAM-1) was inhibited by zerumbone at a lower concentration than that of vascular cell adhesion molecule-1 (VCAM-1). In addition, proinflammatory cytokines, such as interleukin (IL)-1ß and macrophage inflammatory protein (MIP)-2 were suppressed by zerumbone. The phosphorylation of nuclear factor (NF)-κB, a proinflammatory transcription factor, and degradation of inhibitor of κB (IκB), an inhibitor of NF-κB, were also reduced by zerumbone. Furthermore, we found the inhibitory concentration of zerumbone on phosphorylation of p38 mitogen-activated protein kinase (MAPK) and c-Jun NH2-terminal kinase (JNK) was lower than that of extracellular signal-regulated kinase (ERK). In conclusion, zerumbone could be a potential protective agent for ALI, possibly via expression of ICAM-1, IL-1ß, and MIP-2. The protective mechanism of zerumbone was by reversing the activation of p38 MAPK/JNK-IκB/NF-κB pathway.

Melittin Constrains the Expression of Identified Key Genes Associated with Bladder Cancer.

This work is aimed at investigating the effect of melittin on identified key genes in bladder cancer (BC) and further providing a theoretical basis for BC treatment. GSE35014 downloaded from the Gene Expression Omnibus (GEO) database was used to screen differentially expressed genes (DEGs) in BC cells and control. Results showed that a total of 389 upregulated and 169 downregulated genes were identified. Subsequently, GO analysis, KEGG pathway enrichment analysis, and PPI network analysis were employed to disclose the crucial genes and signaling pathways involved in BC. Fifteen module-related DEGs and their associated signaling pathways were obtained according to the PPI network and modular analyses. Based on the analysis of articles retrieved in the PubMed database, we found that melittin could induce apoptosis and constrain the progression of tumor cells as a result of regulating critical cancer-related signaling pathways, such as PI3K-Akt and TNF signaling pathways. Furthermore, PI3K-Akt and TNF signaling pathways were also found to be associated with module-related DEGs according to biological analyses. At last, qRT-PCR analysis demonstrated that melittin could constrain the expression of module-related DEGs (LPAR1, COL5A1, COL6A2, CXCL1, CXCL2, and CXCL3) associated with PI3K-Akt and TNF signaling pathways in BC cells. Functional assays revealed that melittin could constrain the proliferative and migrated abilities of BC cells. Conjointly, these findings provide a theoretical basis for these six genes as drug-sensitive markers of melittin in BC treatment.

Frondanol, a Nutraceutical Extract from Cucumaria frondosa, Attenuates Colonic Inflammation in a DSS-Induced Colitis Model in Mice.

Frondanol is a nutraceutical lipid extract of the intestine of the edible Atlantic sea cucumber, Cucumaria frondosa, with potent anti-inflammatory effects. In the current study, we investigated Frondanol as a putative anti-inflammatory compound in an experimental model of colonic inflammation. C57BL/6J male black mice (C57BL/6J) were given 3% dextran sodium sulfate (DSS) in drinking water for 7 days to induce colitis. The colitis group received oral Frondanol (100 mg/kg body weight/per day by gavage) and were compared with a control group and the DSS group. Disease activity index (DAI) and colon histology were scored for macroscopic and microscopic changes. Colonic tissue length, myeloperoxidase (MPO) concentration, neutrophil and macrophage marker mRNA, pro-inflammatory cytokine proteins, and their respective mRNAs were measured using ELISA and real-time RT-PCR. The tissue content of leukotriene B4 (LTB4) was also measured using ELISA. Frondanol significantly decreased the DAI and reduced the inflammation-associated changes in colon length as well as macroscopic and microscopic architecture of the colon. Changes in tissue MPO concentrations, neutrophil and macrophage mRNA expression (F4/80 and MIP-2), and pro-inflammatory cytokine content (IL-1β, IL-6 and TNF-α) both at the protein and mRNA level were significantly reduced by Frondanol. The increase in content of the pro-inflammatory mediator leukotriene B4 (LTB4) induced by DSS was also significantly inhibited by Frondanol. It was thus found that Frondanol supplementation attenuates colon inflammation through its potent anti-inflammatory activity.

Tephrosin attenuates sepsis induced acute lung injury in rats by impeding expression of ICAM-1 and MIP-2.

Acute lung injury (ALI), a devastating form of respiratory infections, is characterized by increased edema, release of cytokines, weakened arterial oxygenation and infiltration of neutrophils and lymphocytes. The objective of the research envisaged was to reveal protective effects of tephrosin (TP) in ALI. In the present investigation, sepsis was triggered in rats by cecal ligation and puncture (CLP) method, and TP was administered intraperitonially. Five groups - Group A (control), Group B (Sham group) Group C (infected and untreated), and Group D and E (infected and treated with 25 and 50 mg/kg TP respectively) - of ten rats each, were used for the investigation. Evaluation parameters included measurement of arterial oxygenation, lung water content, protein determination, cytokine determination, neutrophil and lymphocyte count in the bronchoalveolar lavage fluid (BALF). As indicated by histopathological examination, the lung injury score was maximum in group C, but indicated reduction in group D and E. Intracellular adhesion molecule (ICAM)-1 and macrophage inflammatory protein-2 (MIP-2) are known to be important mediators responsible for ALI. Reduction in the ICAM-1 and MIP-2 expression was found to reduce after treatment with TP. In comparison to group D, group E reflected higher magnitude of ICAM-1 and MIP-2 suppression due to administration of higher TP dose. Compared to Group A and B, Group E indicated slightly higher expression of ICAM-1 and MIP-2. The research envisaged thus supports that TP attenuates ICAM-1 and MIP-2 expression in sepsis induced ALI rat model.

Anti-inflammatory activity of resveratrol prevents inflammation by inhibiting NF­κB in animal models of acute pharyngitis.

Recent studies have demonstrated that resveratrol can reduce blood sugar, improve insulin resistance, regulate abnormalities in lipid metabolism, and lower the secretion and expression of inflammatory factors. The present study investigated the anti­inflammatory effects of resveratrol in animal models of acute pharyngitis, and its possible mechanisms. Commercial ELISA kits were used to measure tumor necrosis factor­α, interleukin (IL)­6, macrophage inflammatory protein­2, cyclooxygenase­2 levels and caspase­3/9 activity. Toll­like receptor (TLR)­4, myeloid differentiation primary response protein MyD88, phosphorylated (p)­nuclear factor (NF)­κB and p­IκB were analyzed using western blotting. In a rabbit model of acute pharyngitis, it was demonstrated that resveratrol inhibited tumor necrosis factor­α and interleukin­6 serum levels, macrophage inflammatory protein­2 and cyclooxygenase­2 activity levels, reactive oxygen species production and caspase­3/9 activity. Resveratrol suppressed NACHT, LRR and PYD domains­containing protein 3 and caspase­1 protein expression, and reduced IL­1ß and IL­18 protein expression in animal models of acute pharyngitis. Additionally, resveratrol suppressed TLR4 and myeloid differentiation primary response protein 88 protein expression, and reduced p­NF­κB and increased p­IκB protein expression in animal models of acute pharyngitis. In conclusion, these findings indicated that the anti­inflammatory activity of resveratrol prevents acute pharyngitis­induced inflammation by inhibiting NF­κB in animal models. Therefore, these data suggested an important clinical application of resveratrol in preventing acute pharyngitis.

Dusuqing granules (DSQ) suppress inflammation in Klebsiella pneumonia rat via NF-κB/MAPK signaling.

BACKGROUND: Dusuqing granules (DSQ) have been used in the treatment of bacterial pneumonia clinically, with remarkable benefits. This study was initiated to explore the effects of DSQ on pulmonary inflammation by regulating nuclear factor (NF)-κB/mitogen-activated protein kinase (MAPK) signaling in bacterial pneumonia rats. METHODS: Rat model was duplicated with Klebsiella pneumonia by a one-time intratracheal injection. Rats were randomized into control, model, DSQ and levofloxacin (LVX) groups. After administrated with appropriate medicines for 7 days, lung tissues were harvested and prepared for pathological analysis, and interleukin (IL)-1, IL-6, monocyte chemotactic protein (MCP)-1and macrophage inflammatory protein (MIP)-2 detections. NF-κB mRNA was measured by real-time qPCR, and the phosphorylation and total proteins of P38MAPK, JNK46/54, ERK42/44 were determined by Western blotting. RESULTS: Marked pathological impairments were observed in model rats, whereas were improved in DSQ group. The cytokines levels, NF-κB mRNA expression and the phosphorylation of P38MAPK, JNK46/54 and ERK42/44 proteins were significantly higher in model group, and were significantly depressed in DSQ group. CONCLUSION: The protective effects of DSQ on Klebsiella pneumonia might be attributed to its inactivative effects of NF-κB/ MAPK pathway.

Hepatoprotective Effects of Corilagin Following Hemorrhagic Shock are Through Akt-Dependent Pathway.

Corilagin, a component of Phyllanthus urinaria extract, possesses antioxidant, thrombolytic, antiatherogenic, and hepatoprotective properties, but the mechanism underlying these effects remains unclear. Previous studies showed that the Akt (protein kinase B) signaling pathway exerts anti-inflammatory and organ protective effects. The aim of this study was to investigate the mechanism of action of corilagin and determine whether these effects are mediated through the Akt-dependent pathway in a trauma-hemorrhagic shock-induced liver injury rodent model. Hemorrhagic shock was induced in male Sprague-Dawley rats; mean blood pressure was maintained at 35 mm Hg to 40 mm Hg for 90 min, followed by fluid resuscitation. During resuscitation, three doses of corilagin alone (1 mg/kg, 5 mg/kg, or 10 mg/kg, intravenously) were administered. Furthermore, a single dose of corilagin (5 mg/kg) with and without Wortmannin (1 mg/kg, PI3K inhibitor), Wortmannin alone, or vehicle was administered. Twenty-four hours after resuscitation, plasma alanine aminotransferase and aspartate aminotransferase concentration and hepatic parameters were measured. One-way ANOVA was used for statistical analysis. Hepatic myeloperoxidase activity and the concentrations of plasma alanine aminotransferase and aspartate aminotransferase, interleukin-6, tumor necrosis factor-α, intercellular adhesion molecule-1, and cytokine-induced neutrophil chemoattractant-1 (CINC-1) and CINC-3 increased following hemorrhagic shock. These parameters were significantly attenuated in corilagin-treated rats following hemorrhagic shock. Hepatic phospho-Akt expression was also higher in corilagin-treated rats than in vehicle-treated rats. The elevation of phospho-Akt was abolished by combined treatment with Wortmannin and corilagin. Our results suggest that corilagin exerts its protective effects on hemorrhagic shock-induced liver injury, at least, via the Akt-dependent pathway.

Inhibitory effects of dietary soyasaponin on 2,4-dinitrofluorobenzene-induced contact hypersensitivity in mice.

Soyasaponins (SSs) abundant in soybean have anti-inflammatory activities; however, their therapeutic effects on allergic contact dermatitis (ACD) remain unknown. To assess the effects of SS-enriched diets on ACD, we used a mouse model of contact hypersensitivity (CHS). Mice were fed low-dose or high-dose SS-containing diets for 3 weeks prior to CHS induction with 2,4-dinitrofluorobenzene (DNFB). The low-dose SS diet attenuated DNFB-induced ear swelling and tissue oedema, and reduced the number of infiltrating Gr-1-positive myeloid cells. Low-dose, but not high-dose, SSs decreased chemokine (C-X-C motif) ligand 2 (CXCL2) and triggering receptor expressed on myeloid cells (TREM)-1 production in ear tissues, compared to a control. Taxonomic 16S rRNA analysis revealed significant alterations in faecal microbiota caused by CHS, which were reversed by low-dose SSs. The low-dose SS and non-CHS groups clustered together, while the high-dose SS group split between CHS and non-CHS clusters. Our results demonstrated that low-dose SSs alleviated CHS symptoms by attenuating inflammation and improving the intestinal microbiota composition, suggesting that dietary SSs may have beneficial effects on ACD.