Guanxining injection alleviates fibrosis in heart failure mice and regulates SLC7A11/GPX4 axis.

ETHNOPHARMACOLOGICAL RELEVANCE: Radix et Rhizoma Salviae Miltiorrhizae (Salvia miltiorrhiza Bge., Lamiaceae, Danshen in Chinese) and Chuanxiong Rhizoma (rhizomes of Ligusticum chuanxiong Hort., Apiaceae, Chuanxiong in Chinese) both are important traditional Chinese medicine (TCM) for activating blood and eliminating stasis. Danshen-chuanxiong herb pair has been used for more than 600 years in China. Guanxinning injection (GXN) is a Chinese clinical prescription refined from aqueous extract of Danshen and Chuanxiong at the ratio of 1:1 (w/w). GXN has been mainly used in the clinical therapy of angina, heart failure (HF) and chronic kidney disease in China for almost twenty years. AIM OF THE STUDY: This study aimed to explore the role of GXN on renal fibrosis in heart failure mice and the regulation of GXN on SLC7A11/GPX4 axis. MATARIALS AND METHODS: The transverse aortic constriction model was used to mimic HF accompanied by kidney fibrosis model. GXN was administrated by tail vein injection in dose of 12.0, 6.0, 3.0 mL/kg, respectively. Telmisartan (6.1 mg/kg, gavage) was used as a positive control drug. Cardiac ultrasound indexes of ejection fraction (EF), cardiac output (CO), left ventricle volume (LV Vol), HF biomarker of pro-B type natriuretic peptide (Pro-BNP), kidney function index of serum creatinine (Scr), kidney fibrosis index of collagen volume fraction (CVF) and connective tissue growth factor (CTGF) were evaluated and contrasted. Metabolomic method was employed to analyze the endogenous metabolites changes in kidneys. Besides, contents of catalase (CAT), xanthine oxidase (XOD), nitricoxidesynthase (NOS), glutathione peroxidase 4 (GPX4), the x(c)(-) cysteine/glutamate antiporter (SLC7A11) and ferritin heavy chain (FTH1) in kidney were quantitatively analyzed. In addition, ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was used to analyze the chemical composition of GXN and network pharmacology was used to predict possible mechanisms and the active ingredients of GXN. RESULTS: The cardiac function indexes of EF, CO and LV Vol, kidney functional indicators of Scr, the degree of kidney fibrosis indicators CVF and CTGF were all relieved to different extent for the model mice treated with GXN. 21 differential metabolites involved in redox regulation, energy metabolism, organic acid metabolism, nucleotide metabolism, etc were identified. Aspartic acid, homocysteine, glycine, and serine, methionine, purine, phenylalanine and tyrosine metabolism were found to be the core redox metabolic pathways regulated by GXN. Furthermore, GXN were found to increase CAT content, upregulate GPX4, SLC7A11 and FTH1 expression in kidney significantly. Not only that, GXN also showed good effect in down-regulating XOD and NOS contents in kidney. Besides, 35 chemical constituents were initially identified in GXN. Active ingredients of GXN-targets-related enzymes/transporters-metabolites network was established to find out that GPX4 was a core protein for GXN and the top 10 active ingredients with the most relevant to renal protective effects of GXN were rosmarinic acid, caffeic acid, ferulic acid, senkyunolide E, protocatechualdehyde, protocatechuic acid, danshensu, L-Ile, vanillic acid, salvianolic acid A. CONCLUSION: GXN could significantly maintain cardiac function and alleviate the progression of fibrosis in the kidney for HF mice, and the mechanisms of action were related to regulating redox metabolism of aspartate, glycine, serine, and cystine metabolism and SLC7A11/GPX4 axis in kidney. The cardio-renal protective effect of GXN may be attributed to multi-components like rosmarinic acid, caffeic acid, ferulic acid, senkyunolide E, protocatechualdehyde, protocatechuic acid, danshensu, L-Ile, vanillic acid, salvianolic acid A et al.

Recent advances of traditional Chinese medicine for the prevention and treatment of atherosclerosis.

ETHNOPHARMACOLOGICAL RELEVANCE: Atherosclerosis (AS) is a common systemic disease with increasing morbidity and mortality worldwide. Traditional Chinese medicine (TCM) with characteristics of multiple pathways and targets, presents advantages in the diagnosis and treatment of atherosclerosis. AIM OF THE STUDY: With the modernization of TCM, the active ingredients and molecular mechanisms of TCM for AS treatment have been gradually revealed. Therefore, it is necessary to examine the existing studies on TCM therapies aimed at regulating AS over the past two decades. MATERIALS AND METHODS: Using "atherosclerosis" and "Traditional Chinese medicine" as keywords, all relevant TCM literature published in the last 10 years was collected from electronic databases (such as Elsevier, Springer, PubMed, CNKI, and Web of Science), books and papers until March 2022, and the critical information was statistically analyzed. RESULTS: In this review, we highlighted extracts of 8 single herbs, a total of 41 single active ingredients, 20 TCM formulae, and 25 patented drugs, which were described with chemical structure, source, model, efficacy and potential mechanism. CONCLUSION: We summarized the cytopathological basis for the development of atherosclerosis involving vascular endothelial cells, macrophages and vascular smooth muscle cells, and categorically elaborated the medicinal TCM used for AS, all of which provide the current evidence on the better management of atherosclerosis by TCM.

Oxysophocarpine inhibits airway inflammation and mucus hypersecretion through JNK/AP-1 pathway in vivo and in vitro.

Asthma is a high-incidence disease in the world. Oxysophocarpine (OSC), a quinolizidine alkaloid displays various pharmacological functions including anti-inflammation, neuroprotective, anti-virus and antioxidant. Here, we established mice and cell asthmatic model to explore the effects of OSC for asthma treatment. Mice were sensitized and challenged with ovalbumin (OVA) and treated with OSC before challenge. Enzyme-linked immuno sorbent assay (ELISA), hematoxylin and eosin (H&E), periodic acid-schiff (PAS), tolonium chloride staining and immunohistochemical assay were performed. OSC treatment inhibited inflammatory cell infiltration and mucus secretion in the airway, reduced IgE level in mouse serum and decreased IL-4, IL-5 production in bronchoalveolar lavage fluid (BALF). OSC also reduced the spleen index to regulate immune function. Meanwhile, NCI-H292 cells were induced by lipopolysaccharide (LPS) to simulate airway epithelial injury. OSC pretreatment decreased the IL-6 and IL-8 cytokine levels, mucin 5 AC expression, and mucin 5 AC mRNA level in the cell model. Further, OSC suppressed the phosphorylation of c-Jun N-terminal kinase (JNK), and activator protein 1 (AP-1, Fos and Jun). These findings revealed that OSC alleviated bronchial asthma associated with JNK/AP-1 signaling pathway.

Ta-Xi-San Suppresses Atopic Dermatitis Involved in Multitarget Mechanism Using Experimental and Network Pharmacology Analysis.

Atopic dermatitis (AD) is a relapsing and chronic skin inflammation with a common incidence worldwide. Ta-Xi-San (TXS) is a Chinese herbal formula usually used for atopic dermatitis in clinic; however, its active compounds and mechanisms of action are still unclear. Our study was designed to reveal the pharmacological activities, the active compounds, and the pharmacological mechanisms of TXS for atopic dermatitis. Mice were induced by 2,4-dinitrocluorobenzene (DNCB) to build atopic dermatitis model. The pathological evaluation, enzyme-linked immunosorbent assay (ELISA), and hematoxylin and eosin (H&E) assay were performed. The UPLC-Q-Exactive-MSE and network pharmacology analysis were performed to explore active ingredients and therapeutic mechanisms of TXS. TXS treatment decreased levels of immunoglobulin E (IgE), interleukin-4 (IL-4), and tumor necrosis factor-α (TNF-α) in serum induced by DNCB. TXS reduced scratching behavior and alleviated inflammatory pathology of skin and ear. Meanwhile, TXS decreased the spleen index and increased spleen index. The UPLC-Q-Exactive-MSE results showed that 65 compounds of TXS were detected and 337 targets were fished. We collected 1371 AD disease targets, and the compound-target gene network reveled that the top 3 active ingredients were (-)-epigallocatechin gallate, apigenin, and esculetin, and the core target genes were PTGS2, PTGS1, and HSP90AA1. The KEGG pathway and GO analysis showed that TXS remedied atopic dermatitis via PI3K-Akt signaling pathway, mitogen-activated protein kinase (MAPK) signaling pathway, and Toll-like receptor (TLR) signaling pathway with the regulation of inflammatory response and transcription. Further, we found that the targets of PTGS2 and HSP90AA1 were both elevated in ears and skin of AD model mouse; however, TXS decreased the elevated expressions of PTGS2 and HSP90AA1. Our study revealed that TXS ameliorated AD based on (-)-epigallocatechin gallate, apigenin, and esculetin via targeting PTGS2 and HSP90AA1.

Identification of Constituents and Exploring the Mechanism for Toutongning Capsule in the Treatment of Migraine.

Toutongning capsule (TTNC) is an effective and safe traditional Chinese medicine used in the treatment of migraine. In this present study, a multiscale strategy was used to systematically investigate the mechanism of TTNC in treating migraine, which contained UPLC-UESI-Q Exactive Focus network pharmacology and experimental verification. First, 88 compounds were identified by the UPLC-UESI-Q Exactive Focus method for TTNC. Then, the target fishing for these compounds was performed by means of an efficient drug similarity search tool. Third, a series of network pharmacology experiments were performed to predict the key compounds, targets, and pathways. They were protein-protein interaction (PPI), KEGG pathway enrichment analysis, and herbs-compounds-targets-pathways (H-C-T-P) network construction. As a result, 18 potential key compounds, 20 potential key targets, and 6 potential signaling pathways were obtained for TTNC in treatment with migraine. Finally, molecular docking and experimental were carried out to verify the key targets. In short, the results showed that TTNC is able to treat migraine through multiple components, multiple targets, and multiple pathways. This work may provide a theoretical basis for further research on the molecular mechanism of TTNC in the treatment of migraine.

[Prediction of Pathogenesis and Potential Therapeutic Targets for Asthma Based on Proteomics of Mouse Lung Tissue].

Objective To predict the mechanism and potential therapeutic targets of asthma based on proteomic analysis and network pharmacology.Methods The mouse model of asthma was established via intraperitoneal injection of 200 µl suspension containing 100 µg ovalbumin(OVA)and 2 mg aluminum hydroxide and intranasal administration with 5% OVA.Maxquant system was used to retrieve the protein and gene data.The analysis of variance and t test were performed to obtain differential proteins,and then clustering map and target set of differential proteins were established.The protein-protein interaction network of differential proteins was constructed.The pathogenesis of asthma was investigated via gene ontology annotation and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis.Results A total of 5063 genes were identified,from which 904 differentially expressed genes were selected with the thresholds of fold change(model/control)≥2 and P≤0.05 as well as thresholds of fold change(model/control)≤1/2 and P≤0.05.The 904 genes were classified into 3 clusters.The 904 differentially expressed genes included 595 up-regulated genes and 309 down-regulated genes in the model group compared with the control group.The pathogenesis of asthma was associated with regulatory metabolism,Fc gamma-R mediated phagocytosis,leukocyte transendothelial migration,tumor necrosis factor signaling pathway,Toll-like receptor signaling pathway,B cell receptor signaling pathway,phosphoinositol 3-kinase/protein kinase B signaling pathway,vascular smooth muscle contraction and cell adhesion signaling pathway.ITGB3,CYBB,SYK,VWF,ITGB2,MYD88,COMP,VEGFA,and FCGR2B were identified as the therapeutic targets for asthma.Meanwhile,the biological processes such as signal transduction,redox process,immune response,inflammatory response,cell adhesion,positive regulation of GTPase activity,apoptosis,and extracellular matrix formation were the main participants in asthma.Conclusion This study systematically revealed the pathogenesis,biological processes,and 9 potential therapeutic targets of asthma.

Proteome profiling reveals the efficacy and targets of sophocarpine against asthma.

Sophocarpine (SPC) as a quinolizidine alkaloid displays powerful effects on inflammatory diseases through regulating multiple targets. Asthma is a complex heterogeneous and inflammatory disease with an increasing incidence worldwide. Here we established a mice asthma model and investigated the effect of SPC. Mice induced by ovalbumin (OVA) exhibits exacerbated Th1/Th2 immune imbalance and allergic lung inflammation. SPC treatment regulated Th1/Th2 cytokines production (IL-4, IL-5 and INF-γ) in BALF, reduced IgE level in serum, inhibited inflammatory cell infiltration, and improved the lung tissue pathology. Proteomic results showed that 5064 proteins in lung tissue were detected and among them 223 preliminary therapeutic targets of SPC were selected. Subsequently, excluding non-human genes, 109 targets with established crystal structures were harvested. Meanwhile, the molecular docking results showed that the binding energy of 87 targets with SPC was varied from -9.72 kcal/mol to 227.16 kcal/mol. Further, SPC suppressed arrb2, anxa1, myd88 and sphk1 expression and activated p-stat1. All of the five targets based on the screened results of proteomics and molecular docking are critical in allergic asthma. Thus, our data revealed that SPC alleviated bronchial asthma via targeting multi-targets.

Cinnamaldehyde attenuates atherosclerosis via targeting the IκB/NF-κB signaling pathway in high fat diet-induced ApoE-/- mice.

Cinnamaldehyde is a flavor isolated from the bark of Cinnamomum cassia Presl and exerts anti-inflammation effects in various diseases. In our study, we investigated the protective effects and the potential mechanism of cinnamaldehyde on atherosclerosis (AS) by using a high fat diet (HFD)-fed ApoE-/- atherosclerotic mouse model. Here, we found that the serum LDL-C, TG and TC levels were elevated and the HDL-C level was decreased in HFD-fed ApoE-/- mice. Cinnamaldehyde treatment significantly decreased inflammatory cytokine (TNF-α, IL-6, NO and MCP-1) overproduction and the serum lipid level. Meanwhile, cinnamaldehyde increased the HDL-C level and down-regulated the activity of lipid peroxidation product MDA in serum. Moreover, cinnamaldehyde reduced the atherosclerotic plaque area in ApoE-/- mice. Furthermore, cinnamaldehyde reduced matrix metalloproteinase-2 (MMP-2) expression and attenuated the high phosphorylation level of IκBα and p65 NF-κB. Overall, our study indicates that cinnamaldehyde may achieve the anti-atherosclerotic effect via the IκB/NF-κB signaling pathway.

Harmine mitigates LPS-induced acute kidney injury through inhibition of the TLR4-NF-κB/NLRP3 inflammasome signalling pathway in mice.

Acute kidney injury is a common clinical condition associated with increased morbidity and mortality. It is essential to find effective drugs with low side effects in the treatment of acute kidney injury. Harmine is one of the major active components of Peganum harmala L. Harmine possesses various pharmacological activities, including anti-inflammatory activity. Nevertheless, the protective effect of harmine in acute kidney injury induced by lipopolysaccharide (LPS) in mice is unknown. Therefore, we investigated the protective effect of harmine in LPS-induced renal inflammation and the involved molecular mechanisms. The results showed that pretreatment with harmine (25 or 50 mg/kg) markedly alleviated kidney injury by reducing the release of kidney biomarkers and inflammatory mediators and the formation of malondialdehyde (MDA) and myeloperoxidase (MPO) while increasing superoxide dismutase (SOD) and glutathione (GSH) activities and improving renal histopathological changes. In addition, immunohistochemistry staining and western blot analysis indicated that harmine treatment suppressed the expression of toll-like receptor 4 (TLR4) and the phosphorylation of nuclear factor-kappa B (NF-κB) p65 and inhibitor of κBα (IκBα) while inhibiting the expression of NLRP3, caspase-1 and interleukin-1ß (IL-1ß). In brief, harmine protects against acute kidney injury induced by LPS in mice through reducing oxidative stress and inflammation responses. The involved underlying mechanisms of harmine in LPS-induced acute kidney injury might be related to inhibition of the TLR4-NF-κB pathway and NLRP3 inflammasome pathway. Based on the above conclusion, it is possible for harmine to be used to clinically treat acute kidney injury.

Fraxin ameliorates lipopolysaccharide-induced acute lung injury in mice by inhibiting the NF-κB and NLRP3 signalling pathways.

Fraxin, the effective component of the Chinese traditional medicine Cortex Fraxini, is reported to have anti-inflammatory effects. This study assessed the anti-inflammatory effect of fraxin on the lipopolysaccharide (LPS)-induced inflammatory response in A549 cells and the protective efficacy on LPS-induced acute lung injury (ALI) in mice. Fraxin reduced LPS-induced TNF-α, IL-6 and IL-1ß production in A549 cells and alleviated the LPS-induced wet/dry (W/D) weight ratio and the effects observed via histopathological examination of the lung in vivo. Furthermore, fraxin reduced the protein concentrations in the broncho-alveolar lavage (BAL) fluid and cytokine production in the sera. Fraxin also clearly attenuated the oxidation index, including the activity of myeloperoxidase (MPO), malondialdehyde (MDA), superoxide dismutase (SOD) and glutathione (GSH). Immunohistochemistry analysis showed that fraxin suppressed LPS-induced inflammatory damage. The expression of proteins involved in the NF-κB and NLRP3 inflammatory corpuscle signalling pathways was consistent between the lung tissues and cell samples. Overall, fraxin played a protective role in LPS-induced lung injury by inhibiting the NF-κB and NLRP3 signalling pathways.

Cinnamaldehyde protects VSMCs against ox-LDL-induced proliferation and migration through S arrest and inhibition of p38, JNK/MAPKs and NF-κB.

Cinnamaldehyde (Cin), as a traditional flavor constituent isolated from the bark of Cinnamonum cassia Presl, has been commonly used for - digestive, cardiovascular and immune system diseases. The pathology of vascular smooth muscle cells (VSMCs) accelerated the progression of atherosclerosis. In our study, we found that cinnamaldehyde significantly suppressed ox-LDL-induced VSMCs proliferation, migration and inflammatory cytokine overproduction, as well as foam cell formation in VSMCs and macrophages. Moreover, cinnamaldehyde inhibited the phosphorylation of p38, JNK and p65 NF-κB and increased heme oxygenase-1 (HO-1) activity. In addition, cinnamaldehyde reduced monocyte chemotactic protein-1 (MCP-1), matrix metalloproteinase-2 (MMP-2) and lectin-like oxidized low density lipoprotein receptor-1 (LOX-1) expression. Furthermore, cinnamaldehyde arrested cell cycle in S phase. Thus, results indicated that cinnamaldehyde antagonized the ox-LDL-induced VSMCs proliferation, migration, inflammation and foam cell formation through regulation of HO-1, MMP-2, LOX-1 and blockage of cell cycle, and - suppression of p38, JNK/MAPK and NF-κB signaling pathways.

Nobiletin-Ameliorated Lipopolysaccharide-Induced Inflammation in Acute Lung Injury by Suppression of NF-κB Pathway In Vivo and Vitro.

Nobiletin (NOB), a citrus polymethoxy flavonoid, has been reported to exhibit anti-inflammatory, anti-cancer, and anti-insulin resistance activities. Although the anti-inflammatory activity of NOB already reported, its involvement in lung protection has not been reported. Thus, this study aimed to investigate the anti-inflammatory response of NOB in lipopolysaccharide (LPS)-stimulated A549 cells and LPS-induced acute lung injury (ALI) in mice. The animals were pre-treated with NOB (5, 10, and 20 mg/kg) or DEX (5 mg/kg) at 12 and 1 h before intranasal instillation of LPS. The severity of pulmonary injury was evaluated 6 h after LPS administration. Results suggested that treatment with NOB dramatically attenuated lung histopathological changes, wet-to-dry (W/D) ratio, myeloperoxidase (MPO) activity, the numbers of inflammatory cells, and TNF-α, IL-6, and NO in BALF induced by LPS. Furthermore, NOB also significantly inhibited the expression of iNOS and the phosphorylation of NF-κBp65 and IκBα. In vitro, NOB inhibited NF-κB activation and TNF-α, IL-6 production in LPS-stimulated A549 cells. Taken together, these results indicated that NOB exhibited a protective effect on ALI, and the possible mechanism is involved in inhibiting NF-κB activation, subsequently inhibiting LPS-induced inflammatory response.

Paeoniflorin inhibits VSMCs proliferation and migration by arresting cell cycle and activating HO-1 through MAPKs and NF-κB pathway.

The proliferation, migration and inflammation of vascular smooth muscle cells (VSMCs) contributes to the pathogenesis and progression of atherosclerosis. Paeoniflorin (PF) as active compound in the Rhizoma Atractylodes macrocephala has been used for various diseases like cancer, splenic asthenia, anaphylaxis and anorexia. This study aimed to explore whether and how PF regulated the inflammation, proliferation and migration of VSMCs under ox-LDL stimulation. Here, we found that PF dose-dependently inhibited ox-LDL-induced VSMCs proliferation and migration, and decreased inflammatory cytokines and chemokine overexpression. Mechanistically, PF prevented p38, ERK1/2 and NF-κB phosphorylation, and arrested cell cycle in S phase. Meanwhile, PF regulated the HO-1 and PCNA expression. Furthermore, PF blocked the foam cell formation in macrophages induced by ox-LDL. These results indicate that PF antagonizes the ox-LDL-induced VSMCs proliferation, migration and inflammation through activation of HO-1, cell cycle arrest and then suppression of p38, ERK1/2/MAPK and NF-κB signaling pathways.

Hepatoprotective effect of fraxin against carbon tetrachloride-induced hepatotoxicity in vitro and in vivo through regulating hepatic antioxidant, inflammation response and the MAPK-NF-κB signaling pathway.

Fraxin, a main active component isolated from Cortex Fraxini, possesses a variety of bioactivities. However, there is a research gap in studies related to the hepatoprotective activity of fraxin against carbon tetrachloride (CCl4)-induced liver damage has been rarely studied. Thus, the purpose of this study is to evaluate the protective effect of fraxin against CCl4-induced liver damage in mice as well as in HepG2 cells, in addition to further improve the underlying mechanisms of hepatoprotective effect for fraxin. In mice model, pretreatment with fraxin (10, 20 or 40mg/kg) along with CCl4 significantly alleviated liver damage as indicated by the decreased levels of liver index, liver marker enzymes, lipid peroxidation, inflammatory mediators, increased levels of the antioxidant enzymatic and non-enzymatic defense parameters, and improved hepatic histopathology changes. Further, the results of the in vitro study conducted in HepG2 cells indicated that the CCl4-induced changes were significantly ameliorated by pretreatment of fraxin. Moreover, immunohistochemistry staining and western blot assay demonstrated that pretreatment with fraxin can down-regulate CCl4-induced protein expression of MAPKs, NF-κB and COX-2. Overall, these studies indicate that fraxin exhibits hepatoprotective effect against CCl4-induced liver damage by reducing inflammation response, suppressing oxidative stress and lipid peroxidation and enhancing antioxidant activity. The underlying mechanisms of fraxin in CCl4-induced acute liver injury may be due to inhibition of MAPK and NF-κB activation. It is possible for fraxin to be used as a hepatoprotective agent.

The gastroprotective effect of nobiletin against ethanol-induced acute gastric lesions in mice: impact on oxidative stress and inflammation.

CONTEXT: Gastric ulcer is a common gastrointestinal disorder with increasing incidence and prevalence attributed to loss of balance between aggressive and protective factors. Nobiletin (NOB), a major component of polymethoxyflavones in citrus fruits, has a broad spectrum of health beneficial properties including anti-inflammatory and anti-tumor activities. Although NOB was originally shown to possess anti-inflammatory activity, its effects on gastric ulcer were rarely explored previously. OBJECTIVE: The aim of the present study was to investigate the anti-ulcerogenic activity of NOB on ethanol-induced gastric ulcer in mice and to elucidate the underlying mechanisms. METHODS: Seventy-two male Kunming mice administered with absolute ethanol (0.2 ml/animal) were pretreated with NOB (5, 10 or 20 mg/kg), cimetidine (100 mg/kg), or vehicles by intragastric administration in different experimental groups for three days, and animals were euthanized 3 h after ethanol ingestion. Gross and microscopic lesions, immunological and biochemical parameters were taken into consideration. RESULTS: The results showed that ethanol induced gastric injury, increased malondialdehyde (MDA) levels, decreased glutathione (GSH) content, superoxide dismutase (SOD) activity, and prostaglandin E2 (PGE2) levels, increased pro-inflammatory cytokines tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) levels and myeloperoxidase (MPO) activity, as well as the expression MAPK signaling pathway. Pretreatment with NOB significantly attenuated the gastric lesions as compared to the ethanol group. CONCLUSIONS: These findings suggest that the gastroprotective activity is attribute to the improvement of antioxidant activities, the stimulation of PGE2, and the reduction of pro-inflammatory cytokines through the MAPK pathway.

Immunomodulatory Activity of the Glycoprotein Isolated from the Chinese Yam (Dioscorea opposita Thunb).

The yam (Dioscorea opposita Thunb) is a well-known edible food and widely used as the traditional Chinese medicine. The present investigation was designed to evaluate the immunomodulatory activity of glycoprotein (DOT) from yam and explore its possible molecular mechanisms. Results showed that the DOT could improve the cell immunity, humoral immunity and phagocytic system function of the normal mice. The DOT could also increase the production of TNF-α, interleukin-6 and nitric oxide and enhance the pinocytosis function of macrophages. Furthermore, the DOT increased phosphor-p38, JNK, ERK1/2 and nuclear factor kappa B (NF-κB) p65 protein expression in peritoneal macrophages. Taken together, our data suggest that DOT could be used as a potential immunostimulant and exert its immunomodulatory activity via mitogen-activated protein kinases and NF-κB signal pathways. Copyright © 2017 John Wiley & Sons, Ltd.

Cavidine Ameliorates Lipopolysaccharide-Induced Acute Lung Injury via NF-κB Signaling Pathway in vivo and in vitro.

Acute lung injury (ALI) is characterized by widespread inflammation in the lungs and alveolar-capillary destruction, causing high morbidity and mortality. Cavidine, isolated from Corydalis impatiens, have been exhibited to have potent anti-inflammatory effects in previous studies. The purpose of this study was to evaluate the protective effect of cavidine on lipopolysaccharide (LPS)-induced ALI and to enunciate the underlying in vivo and in vitro mechanisms. Mice were intraperitoneally administrated with cavidine (1, 3, or 10 mg/kg) at 1 and 12 h, prior to the induction of ALI by intranasal administration of LPS (30 mg/kg). Blood samples, lung tissues, and bronchoalveolar lavage fluid (BALF) were harvested after LPS challenge. Furthermore, we used LPS-induced lung epithelial cells A549 to examine the mechanism of cavidine to lung injury. The results showed that pretreatment with cavidine significantly decreased lung wet-to-dry weight (W/D) ratio, reduced pro-inflammatory cytokine levels including TNF-α and IL-6 in BALF and serum from LPS-stimulated mice, and attenuated lung histopathological changes. In addition, western blot results showed that cavidine inhibited the phosphorylation of nuclear factor-kappaB (NF-κB) p65 and IκBα induced by LPS. In conclusion, our results demonstrate that cavidine protects against LPS-induced acute lung injury in mice via inhibiting of pro-inflammatory cytokine TNF-α and IL-6 production and NF-κB signaling pathway activation. Taken together, cavidine may be useful for the prevention and treatment of pulmonary inflammatory diseases, such as ALI.

Atractylenolide I restores HO-1 expression and inhibits Ox-LDL-induced VSMCs proliferation, migration and inflammatory responses in vitro.

Pathogenesis of atherosclerosis is characterized by the proliferation and migration of vascular smooth muscle cells (VSMCs) and inflammatory lesions. The aim of this study is to elucidate the effect of atractylenolide I (AO-I) on smooth muscle cell inflammation, proliferation and migration induced by oxidized modified low density lipoprotein (Ox-LDL). Here, We found that atractylenolide I inhibited Ox-LDL-induced VSMCs proliferation and migration in a dose-dependent manner, and decreased the production of inflammatory cytokines and the expression of monocyte chemoattractant protein-1 (MCP-1) in VSMCs. The study also identified that AO-I prominently inhibited p38-MAPK and NF-κB activation. More importantly, the specific heme oxygenase-1 (HO-1) inhibitor zinc protoporphyrin (ZnPP) IX partially abolished the beneficial effects of atractylenolide I on Ox-LDL-induced VSMCs. Furthermore, atractylenolide I blocked the foam cell formation in macrophages induced by Ox-LDL. In summary, inhibitory roles of AO-I in VSMCs proliferation and migration, lipid peroxidation and subsequent inflammatory responses might contribute to the anti-atherosclerotic property of AO-I.

Gastroprotective effect of esculin on ethanol-induced gastric lesion in mice.

The gastroprotective effect of esculin was investigated in a mouse model of ethanol-induced gastric lesion. Administration of esculin at doses of 5, 10, and 20 mg/kg body weight prior to ethanol ingestion led to significant gastroprotection compared with untreated mice. Gastric mucosal lesions were evaluated by macroscopic and histopathological alterations, lesion index, and myeloperoxidase (MPO) activity. Pretreatment with esculin significantly reduced macroscopic and histopathological damage, gastric lesion index, and MPO activity in a dose-dependent manner. Moreover, esculin significantly reduced nitric oxide (NO) production, inducible NO synthase (iNOS) levels, and nuclear factor-kappa B (NF-κB) p65 protein expression in gastric tissues after ethanol challenge. Analysis of inflammatory cytokines indicated that esculin pretreatment markedly suppressed the increased expression of tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) in ethanol-treated mice. The results demonstrate a protective effect of esculin against gastric injury and suggest that the underlying mechanism might be associated with inhibition of NF-κB activation, which subsequently reduces expression of iNOS, TNF-α, and IL-6.

Esculin attenuates endotoxin shock induced by lipopolysaccharide in mouse and NO production in vitro through inhibition of NF-κB activation.

Esculin, a coumarin compound derived from the traditional Chinese herbs such as Cortex Fraxini, has long been used for treating inflammatory and vascular diseases. In present study, we analyzed the role of esculin against macrophages and endotoxin shock induced by lipopolysaccharide (LPS) in mice. Here, we demonstrated that esculin suppressed inflammatory reactions in macrophages and protected mice from LPS-induced endotoxin shock. We found that esculin significantly inhibited the production of nitric oxide (NO) production via the inhibition of nuclear factor-κB (NF-κB) activation in macrophages. In animal model, esculin pretreatment significantly improved the survival rate of mice. LPS-induced increase of tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) in serum, lung, liver and kidney were markedly inhibited by esculin. IL-10, an anti-inflammatory cytokine, was up-regulated by esculin. Moreover, the histopathological analyses showed that esculin significantly attenuated the tissues injury of lung, liver, kidney in endotoxic mice. In addition, esculin significantly diminished the protein expression of NF-κB p65 in lung, liver, kidney, which resulted in lower levels of inflammatory mediators. These results suggest that esculin may be a potential drug for treatment of various inflammatory diseases.