Interleukin (IL)-33, a member of the IL-1 family of cytokines, is produced when epithelial and endothelial cells are exposed to stimuli. Hematopoietic cells such as macrophages also produce IL-33. IL-33 is considered to function as an ‘alarmin’, activating various immune cells through its receptor ST2, which leads to the production of various molecules. The IL-33-induced production of pro-inflammatory cytokines is a critical event that aggravates atopic diseases such as asthma, atopic dermatitis, and pollenosis and suggests that IL-33-blocking agents could represent new therapeutic drugs. The anti-IL-33 antibody was effective in allergic models, whereas the anti-ST2 antibody has yielded controversial results because soluble ST2 functions as a decoy receptor for IL-33. IL-33-mediated pulmonary inflammation may be glucocorticoid-resistant especially when other cytokines act synergistically. Anti-tumor necrosis factor (TNF)-α therapy may also be effective against IL-33-mediated diseases. ERK1/2 inhibitors have also been shown to suppress the production of IL-33. On the other hand, activation of β₂-receptors enhanced the expression of IL-33 mRNA in dendritic cells by activating protein kinase A (PKA), suggesting that PKA inhibitors may be candidates for IL-33–blocking agents. The effects of IL-33–blocking agents on atopic diseases need to be pharmacologically assessed in experimental and clinical studies.

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The present article reviewed the biological activities and possible dental application of three major polyphenols, i.e., lignin-carbohydrate complexes, tannins, and flavonoids, citing mostly our in vitro studies together with those from other groups. All these polyphenols showed much lower tumor-selective cytotoxicity against oral squamous cell carcinoma cells vs. normal oral cells (gingival fibroblast, pulp cell, periodontal ligament fibroblast), in comparison to popular chemotherapeutic antitumor drugs. Several compounds showing higher tumor-selectivity did not induce internucleosomal DNA fragmentation, a biochemical hallmark of apoptosis, in oral carcinoma cell lines. Lignin-carbohydrate complex protected the cells from the cytopathic effects of HIV infection and UV irradiation more efficiently than other polyphenols. Limited digestion of lignin-carbohydrate complex suggests that the lignin moiety is involved in the prominent anti-HIV activity, whereas the carbohydrate moiety may function in immunopotentiating activity through a cell surface receptor. Alkaline extract of plant leaf, which contains higher amounts of lignin-carbohydrate complex, showed potent anti-inflammatory action against IL-1β-stimulated human gingival fibroblasts. Local application of lignin-carbohydrate complex through oral mucosa is recommended, considering its poor intestinal absorption.

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Safflower yellow (SY) has been widely used in Chinese medicine for the treatment of ischemic cardiocerebrovascular disease. Recent studies have indicated that SY has a reverse effect on vascular remodeling (VR). However, its detailed mechanisms require further study to provide more scientific evidence for the clinical treatment of VR. This study aims to investigate the effects of SY on angiotensin II (Ang II)-induced cell proliferation, migration, apoptosis, and extracellular matrix in rat aortic adventitial fibroblasts (AFs). The proliferation and migration rates of AFs treated with Ang II for 24 h were higher than those of untreated AFs; and increases in the expression of p-ERK1/2, AP-1, collagen I, and collagen III were observed. Treatment with SY significantly downregulated cell proliferation, migration, and the expression of p-ERK1/2, AP-1, collagen I, and collagen III. We also found that the cell percentage of apoptosis of AFs treated with Ang II for 24 h was lower than those of untreated AFs. After treatment with SY, the percentage of apoptosis was increased. SY exhibits anti-proliferative, anti-migratory, and pro-apoptotic activities in rat aortic AFs, perhaps through the Ang II/ERK/AP-1 signaling pathway. The present findings may provide new clues regarding the potential function of SY to treat or prevent VR.

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The present study examined whether hemin could prevent the development of high-fat diet–induced insulin resistance in the liver and skeletal muscle using a hyperinsulinemic-euglycemic clamp. A four-week high-fat feeding to mice increased the body weight, fat mass, and plasma levels of insulin and lipid, which were reduced by hemin. High-fat diet reduced whole body glucose uptake, which were increased by hemin. Insulin-stimulated hepatic glucose production (HGP) was increased by high-fat diet, but hemin had no significant effect on HGP. Skeletal muscle glucose uptake was reduced by high-fat diet, and hemin normalized the glucose uptake. High-fat diet increased triglyceride levels and mRNA levels of lipogenic enzymes, and decreased mRNA levels of enzymes involved in lipid β-oxidation, which was reversed by hemin. Phosphorylated AMP-activated protein kinase levels were increased in the skeletal muscle of high fat–fed hemin-injected mice. High-fat diet reduced mRNA levels of antioxidant enzymes and increased mRNA levels of inflammatory cytokines and nitrotyrosine levels, which was normalized by hemin in the skeletal muscle. However, hemin had no significant effect on these factors in the liver. These results suggest that hemin prevents the development of high-fat diet–induced insulin resistance by increased insulin sensitivity in the skeletal muscle.

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Salidroside is a biologically active ingredient of Rhodiola rosea, which has several interesting biological properties, including anti-oxidant and anti-inflammatory; however, its anti-allergic effects are poorly understood. The objective of this study is to determine whether salidroside attenuates the inflammatory response in an ovalbumin (OVA)-induced asthma model. OVA-sensitized/challenged mice show airway hyperresponsiveness (AHR) to inhaled methacholine and have an increased amount of T-helper2 type cytokines [interleukin (IL)-4, IL-5, and IL-13] and eosinophils in their bronchoalveolar lavage fluids and lung tissues. However, three successive intraperitoneal administrations of salidroside before the last OVA challenge result in significant inhibition of these asthmatic reactions. Moreover, OVA significantly increases the activation of nuclear factor-kappa B (NFκB) and p38 mitogen–activated protein kinase (MAPK) in lung tissues, whereas salidroside markedly suppresses NF-κB translocation and reduces phosphorylation of p38 MAPK. Furthermore, salidroside attenuates the expression of intercellular adhesion molecule 1 and IL-6 through modulating the activities of p38 MAPK and NF-κB in the BEAS-2B cells stimulated by proinflammatory cytokines. These findings indicate that salidroside protects against OVA-induced airway inflammation and AHR, at least in part via downregulation of NF-κB and p38 MAPK activities. Our data support the utility of salidroside as a potential medicine for the treatment of asthma.

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Fluvoxamine, a selective serotonin (5-HT) reuptake inhibitor, has been shown to exert analgesic effects in humans and laboratory animals. However, its effects on spinal nociceptive synaptic transmission have not been fully characterized. Here, whole-cell recordings were made from dorsal horn neurons in spinal slices with attached dorsal roots from adult mice, and the effects of fluvoxamine on monosynaptic A-fiber- and C-fiber-mediated excitatory postsynaptic currents (EPSCs) evoked in response to electrical stimulation of a dorsal root were studied. Fluvoxamine (10 – 100 μM) concentration-dependently suppressed both monosynaptic A-fiber- and C-fiber-mediated EPSCs, which were attenuated by the selective 5-HT_1A receptor antagonist WAY100635. In the presence of the selective 5-HT₃ receptor antagonist tropisetron, fluvoxamine hardly suppressed A-fiber-mediated EPSCs, whereas its inhibitory effect on C-fiber-mediated EPSCs was not affected. Although fluvoxamine increased the paired-pulse ratio of A-fiber-mediated EPSCs, it increased the frequency of spontaneous and miniature EPSCs (sEPSCs and mEPSCs). Since sEPSCs and mEPSCs appeared to arise largely from spinal interneurons, we then recorded strontium-evoked asynchronous events occurring after A-fiber stimulation, whose frequency was reduced by fluvoxamine. These results suggest that fluvoxamine reduces excitatory synaptic transmission from primary afferent fibers via presynaptic mechanisms involving 5-HT_1A and/or 5-HT₃ receptors, which may contribute to its analgesic effects.

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The pregnane X receptor (PXR, NR1I2), a member of the nuclear receptor superfamily, is activated by a number of clinically prescribed drugs and herbal extracts. The inducible expression of several important cytochrome P450 (CYP450) enzymes has been shown to be regulated by the activation of PXR in the liver. In the current study, reporter gene–transfected cells were used to identify potential antagonists of PXR. Here, we showed that resveratrol (RES), a natural polyphenolic compound could significantly suppress the rifampicin-induced PXR transactivation of the CYP3A4 promoter. Treatment of hPXR-over-expressed cells with RES reduced the rifampicin-inducible expression of CYP3A4 in a concentration-dependent manner. Moreover, the induction of mRNA and protein expression of CYP3A11 by pregnenolone 16α-carbonitrile was also significantly reduced when RES was applied in primary cultures of mouse hepatocytes. Taking together, these findings suggest that RES can attenuate the PXR-mediated induction of CYP3A enzyme. Therefore, it would be possible for RES to antagonize the elevation in CYP3A-mediated drug metabolism by identified PXR activators.

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The main purpose of this study is to evaluate the effect of echinacoside (ECH) on hypoxia-induced proliferation of rat pulmonary artery smooth muscle cells (PASMCs) and the underlying mechanism. PASMCs were incubated under normoxia (nor), hypoxia (hyp), hypoxia + 0.35 mM ECH (hyp + ECH_0.35), or hypoxia + 0.4 mM ECH (hyp + ECH_0.4) for 24 h. Cell viability was assessed by MTS assays. The morphology of apoptosis was observed by DAPI staining, and apoptosis was quantified by flow cytometric analysis. Caspase-3 activity was determined by immunohistochemistry and real-time PCR, and the expressions of HIF-1α, Bax, Bcl-2, and Fas were determined by real-time PCR. Hypoxia induced significant proliferation of PASMCs, which could be inhibited by ECH in a concentration-dependent manner. This was associated with apoptosis of PASMCs. Z-DEVD-FMK could partly reduce the suppression effect of ECH; protein and gene expression of caspase-3 were significantly higher in the hyp + ECH_0.4 and hyp + ECH_0.35 groups. ECH significantly increased the expressions of Bax and Fas, but decreased the expressions of Bcl-2 and HIF-1α. ECH could inhibit hypoxia-induced proliferation of rat PASMCs, which is associated with apoptosis of PASMCs and improvement of hypoxia. ECH might be a potential agent for prevention and treatment of hypoxia-induced PAH.

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Patients with psychiatric disorders, including schizophrenia, are reported to suffer from sleep disorders. In this study, we investigated the effects of lurasidone, an atypical antipsychotic, on sleep architecture in rats using sleep electroencephalography. The course of sleep in rats was classified into 3 stages: WAKE, non-rapid eye movement (NREM) sleep, and rapid eye movement (REM) sleep. Lurasidone shortened REM duration and prolonged the mean duration of one bout in WAKE and NREM. Quantitative frequency band analysis during NREM sleep revealed that lurasidone increases slow waves and decreases fast waves. These results suggest that lurasidone ameliorates sleep disorders associated with psychosis.

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Metabolic syndrome (MetS) induces serious complications; therefore, we developed a noninvasive MetS model using an extremely small minipig, the Microminipig. For 8 weeks, Microminipigs were administrated a high-fat and high-cholesterol diet (HFCD) for atherosclerosis and N^G-nitro-l-arginine methyl ester (l-NAME) for inhibiting nitric oxide synthase. HFCD significantly increased serum low-density lipoprotein levels, l-NAME increased blood pressure and cardiac hypertrophy, and HFCD-induced aortal arteriosclerosis was accelerated by l-NAME administration. Endothelium-dependent relaxation of the coronary artery was remarkably decreased by l-NAME administration. This model may be useful for elucidating the mechanisms of MetS and developing new therapeutic medicines for its treatment.

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We investigated the role of interferon regulatory factor 8 (IRF8) in a model of chronic pain in which repeated cold stress (RCS) exposure produces tactile allodynia. RCS exposure produced a decrease in paw withdrawal threshold (PWT) to mechanical stimulation. Spinal microglia of RCS-exposed mice were morphologically activated. Expression of IRF8 was significantly increased in the spinal cord of RCS-exposed mice and was localized in microglia. IRF8-knockout mice failed to show the RCS-induced decrease in PWT. Thus, RCS exposure activates spinal microglia and upregulation of IRF8 in these cells is involved in the development of tactile allodynia after RCS exposure.

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The pregnane X receptor (PXR) plays a central role in the regulation of metabolism. Only few PXR antagonists have been described and the mechanism of PXR inhibition is mostly hypothetical or believed to be allosteric. Resveratrol is now being discussed as a novel agent that is capable of attenuating the PXR-inducible expression of the CYP3A4 gene, although the mechanistic explanation has not been determined. We discuss herein the effect of resveratrol on PXR in the context of our data from a ligand binding assay and with respect to the effect of resveratrol on various cellular signaling pathways that are known to affect PXR.

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