Water extract of Cayratia albifolia C.L.Li root relieves zymosan A-induced inflammation by restraining M1 macrophage polarization.

BACKGROUND: Cayratia albifolia C.L.Li (CAC) is a traditional Chinese herbal medicine used to treat inflammatory diseases. Our laboratory has firstly reported that the water extract from CAC relieved lipopolysaccharide (LPS)-induced inflammation, however stronger evidence is still needed to prove its anti-inflammatory effects and the mechanisms involved are also ambiguous. PURPOSE: This study sought to provide more evidence for the application of CAC in alleviating infectious inflammation and disclose novel pharmacological mechanisms. METHODS: Mice were injected with zymA into their paws or peritoneal cavities, and then treated with CAC. ELISA, immunofluorescence and flow cytometry were performed to detect the cytokines (IL-1ß, IL-6, TNF-α and IL-10) generation, the cell infiltration, and the CD86 or CD206 expression of macrophages. Then in vitro assays were performed on bone marrow-derived macrophages (BMDMs) and peritoneal macrophages (PMs) to detect their expression of iNOS, arg-1 and the cytokines above. On mechanisms, western blotting (WB), electrophoretic mobility shift assay (EMSA) and flow cytometry were carried out to measure NF-κB transcriptional activity, mitochondrial bioactivity and the mTORC1 activation when BMDMs were stimulated by zymA and treated with CAC. Finally, the chemical components consisted in the extract were analyzed by LC-MS. RESULTS: 200 mg/kg CAC clearly inhibited zymA induced mouse paw edema and reduced the contents of IL-1ß, IL-6 and TNF-α rather than IL-10 in local tissues. CAC also reduced CD86 but not CD206 in macrophages in situ. Through in vitro experiments, it was discovered that CAC reduced the protein and mRNA levels of IL-1ß, IL-6 and TNF-α, and also inhibited iNOS expression, but showed no influence on IL-10 and arg-1 in macrophages. We found CAC reduced NF-κB transcriptional activity, down-regulated mitochondrial membrane potential and ROS levels, and inhibited mTORC1 activity. Finally, we identified 15 major compounds in the extract, among which 4-guanidinobutyric acid and kynurenic acid were the most abundant. CONCLUSION: This study provides further evidence that CAC significantly reduces zymA induced infectious inflammation. In addition, this novel data revealed that CAC restrained M1 rather than promoting M2 macrophages polarization via multi-target inhibitory effects, based on its potentially active components.

Preventing cardiovascular heart disease: Promising nutraceutical and non-nutraceutical treatments for cholesterol management.

Hypercholesterolemia is one of the major risk factors for the development of cardiovascular disease. Atherosclerosis resulting from hypercholesterolemia causes many serious cardiovascular diseases. Statins are generally accepted as a treatment of choice for lowering low-density lipoprotein (LDL) cholesterol, which reduces coronary heart disease morbidity and mortality. Since statin use can be associated with muscle problems and other adverse symptoms, non-adherence and discontinuation of statin therapy often leads to inadequate control of plasma cholesterol levels and increased cardiovascular risk. Moreover, there is compelling evidence on the presence of still considerable residual cardiovascular risk in statin-treated patients. Ezetimibe improves cholesterol-lowering efficacy and provides mild additional cardiovascular protection when combined with statin treatment. Despite a favorable safety profile compared to statins, ezetimibe-induced cholesterol-lowering is modest when used alone. Hence, there is a critical need to identity additional effective hypolipidemic agents that can be used either in combination with statins, or alone, if statins are not tolerated. Thus, hypolipidemic agents such as proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, apolipoprotein B-100 antisense oligonucleotides, cholesteryl ester transfer protein (CETP) inhibitors, and microsomal triglyceride transfer protein (MTTP) inhibitors, as well as yeast polysaccharides (beta-glucans and mannans) and compounds derived from natural sources (nutraceuticals) such as glucomannans, plant sterols, berberine, and red yeast rice are being used. In this review, we will discuss hypercholesterolemia, its impact on the development of cardiovascular disease (CVD), and the use of yeast polysaccharides, various nutraceuticals, and several therapeutic agents not derived from 'natural' sources, to treat hypercholesterolemia.

Effect of zymosan on antioxidant and immune function of S180 tumor-bearing mice.

The objective is to study the effect of zymosan on antioxidant and immune function of S(180) tumor-bearing mice. Seventy Kunming mice were randomly divided into seven groups: a normal control group (NC), a tumor control group (TC), three dose groups of zymosan (low, medium, high), a cyclophosphamide (Cy) group, and a combination of zymosan and Cy group. The S(180) tumor-bearing mice model was established by the inoculation of cancer cell suspension subcutaneously in the mouse's right anterior limb. At the 19th day, malondialdehyde (MDA), glutathione peroxidase (GSH-Px), and superoxide dismutase (SOD) activity in liver homogenate were analyzed. The reverse transcriptase-polymerase chain reaction was used to determine the mRNA expression levels of IL-2, TNF-α, and TGF-ß(1). The activity of GSH-Px and SOD in the liver increased with the dose of zymosan, whereas the activity of MDA significantly decreased in the higher-dose groups of zymosan, compared to the TC group (P < 0.01). In the zymosan groups, mRNA expression levels in tissues of S(180) tumor-bearing mice were significantly higher for TNF-α and IL-2, but lower for TGFß(1) than in the Cy or TC group (P < 0.01). The high-dose of zymosan markedly showed a depressant effect on S(180) tumor, enhanced by the action of Cy that increased mRNA expression levels of TNF-α and IL-2. The mechanism of zymosan on the inhibition of tumor growth may be due to its ability to enhance the antioxidant and immune function in a dose-dependent manner.

The mechanisms of serum-treated zymosan (STZ)-induced oxidative metabolism by human eosinophils and the effects of IL-5 priming.

BACKGROUND: The aim of this work was to study the mechanisms of action of IL-5 on the subsequent stimulation of the oxidative metabolism of blood eosinophils by serum-treated zymosan (STZ), in terms of signal transduction characteristics, and by comparing the response of cells from healthy and allergic subjects during environmental exposure to birch pollen. METHODS: Eosinophils from healthy controls and allergic patients were purified to over 95% by Percoll gradients and the MACS system. Oxidative metabolism was measured by a lucigenin-enhanced chemiluminescence (CL) assay. Eosinophils were primed with IL-5 and subsequently stimulated with STZ. The signal transduction mechanisms of IL-5 priming were studied with the MEK inhibitor PD 98059,the PkC inhibitors staurosporine and Ro 318220, and the PI3 kinase inhibitor wortmannin. RESULTS: IL-5 increased the maximum radical production (P=0.0079) and reduced the t(1/2) rise (0.000018) of the CL reactions. The t(1/2) rise was PkC dependent and MEK independent, while the maximum radical production was PkC, MEK, and PI3 kinase dependent. During the pollen season, IL-5 reduced the total STZ-induced CL response in the patients' cells (P=0.016), but not in the control cells, whereas it primed the response to STZ of both cell populations in terms of the t(1/2) rise (P=0.012 and 0.00066, respectively). CONCLUSION: STZ-induced oxidative metabolism consists of different stages. The initial stage (t(1/2) rises of the curves) is PkC dependent and MEK independent, while the end stage (maximum radical production) is PkC, MEK, and PI3 kinase dependent. IL-5 shortened the initial stage, and increased the end stage. During allergen exposure, however, the end stage was reduced by IL-5. This could be due to increased amounts of hypodense eosinophils and/or some abnormality in cell responses.

Mouse paw oedema induced by Habu snake (Trimeresurus flavoviridis) venom: inhibition by morphine, naloxone and methylnaloxone alone or in combinations.

The oedema produced in the mouse by intraplantar injection of the venom of Trimeresurus flavoviridis was inhibited by morphine (Mo) and by naloxone (Nx); the action of Mo increased with the dose, whereas that of Nx first progressed and thereafter regressed with the dose; very small doses of Nx antagonized Mo. Methylnaloxone (MeNx), a quaternary ammonium derivative of Nx was much less effective than Nx by the subcutaneous route but almost as effective by the intraplantar route. Peripheral opioidergic receptors are thus likely to be involved. Very high doses of Mo acted an synergistically with an optimal dose of EDTA or zymosan; complex interactions occurred between lower doses of Mo or Nx and EDTA or zymosan.