Advanced Molecular Knowledge of Therapeutic Drugs and Natural Products Focusing on Inflammatory Cytokines in Asthma.

Asthma is a common respiratory disease worldwide. Cytokines play a crucial role in the immune system and the inflammatory response to asthma. Abnormal cytokine expression may lead to the development of asthma, which may contribute to pathologies of this disease. As cytokines exhibit pleiotropy and redundancy characteristics, we summarized them according to their biologic activity in asthma development. We classified cytokines in three stages as follows: Group 1 cytokines for the epithelial environment stage, Group 2 cytokines for the Th2 polarization stage, and Group 3 cytokines for the tissue damage stage. The recent cytokine-targeting therapy for clinical use (anti-cytokine antibody/anti-cytokine receptor antibody) and traditional medicinal herbs (pure compounds, single herb, or natural formula) have been discussed in this review. Studies of the Group 2 anti-cytokine/anti-cytokine receptor therapies are more prominent than the studies of the other two groups. Anti-cytokine antibodies/anti-cytokine receptor antibodies for clinical use can be applied for patients who did not respond to standard treatments. For traditional medicinal herbs, anti-asthmatic bioactive compounds derived from medicinal herbs can be divided into five classes: alkaloids, flavonoids, glycosides, polyphenols, and terpenoids. However, the exact pathways targeted by these natural compounds need to be clarified. Using relevant knowledge to develop more comprehensive strategies may provide appropriate treatment for patients with asthma in the future.

Effect of osthole on advanced glycation end products-induced renal tubular hypertrophy and role of klotho in its mechanism of action.

BACKGROUND: Osthole has been widely reported to have pharmacological activities such as anti-cancer, anti-inflammation and anti-hyperlipidemic effects. Klotho was identified as an anti-senescence protein in a variety of tissues. Loss of klotho has been associated with chronic kidney disease. However, potential roles and molecular events for osthole and klotho in diabetic nephropathy remain unclear. PURPOSE: In the current study, we undertook to study the effect of osthole on klotho expression in advanced glycation end products (AGE)-cultured human renal proximal tubular cells, and to investigate the molecular mechanisms of osthole and exogenous klotho against AGE-induced renal tubular hypertrophy. METHODS: Cell viability was elucidated by MTT assay. Protein expression was measured by Western blotting. mRNA level was analyzed by real-time PCR. Cellular hypertrophy growth was evaluated by hypertrophy index. Relative cell size was detected by flow cytometry. RESULTS: We found that raising the ambient AGE concentration causes a dose-dependent decrease in klotho synthesis. Osthole significantly increased AGE-inhibited klotho mRNA and protein expression. Osthole and exogenous klotho treatments significantly attenuated AGE-induced Janus kinase 2 (JAK2)-signal transducers and activators of transcription 1 (STAT1) and STAT3 activation. Moreover, protein levels of suppressor of cytokine signaling 1 (SOCS1) and SOCS3 were augmented by osthole and exogenous klotho. The abilities of osthole and exogenous klotho to reverse AGE-induced cellular hypertrophy were verified by the observation that osthole and exogenous klotho inhibited p21Waf1/Cip1/collagen IV/RAGE expression, total protein content, and cell size. CONCLUSION: Consequently, we found that osthole attenuated AGE-induced renal tubular hypertrophy via induction of klotho expression and suppression of the JAK2-STAT1/STAT3 signaling. These results also showed that klotho might be used as a unique molecular target for the treatment of diabetic nephropathy.

Sweet Olive Extract Attenuates Dextran Sulfate Sodium-Induced Colitis in Mice.

Sweet olive (Osmanthus fragrans flowers) is used to treat dysentery and reduce phlegm and stasis in traditional Chinese medicine. Recently, we found that verbascoside, the major component in the sweet olive ethanolic extract (OFE), inhibited IL-8 secretion in human colorectal adenocarcinoma WiDr cells. However, evidence-based treatment of inflammatory bowel disease (IBD) with the extract is yet to be performed. To evaluate the therapeutic effect of OFE, we measured IL-8 suppression by OFE and verbascoside in a WiDr cell culture assay. In the IL-8 secretion assay, both OFE (100 µg/mL) and verbascoside (10 µM) significantly inhibited IL-8 production in WiDr cells. Furthermore, we designed cotreated (dextran sulfate sodium [DSS]+OFE-treated) and post-treated (DSS-OFE-treated) protocols to access the therapeutic effects of OFE in vivo. Mice treated with 500 mg/kg per day OFE exhibited significant improvement in IBD symptoms, including disease activity index score, body weight, and colon length maintenance. The suppressive effects on myeloperoxidase expression and lower histopathology scores (including neutrophil infiltration) for the colon were also found. These findings suggest that OFE exerts anti-inflammatory effect on DSS-induced colitis.

Suppression of IL-8 Release by Sweet Olive Ethanolic Extract and Compounds in WiDr Colon Adenocarcinoma Cells.

Oxidative stress can stimulate the secretion of pro-inflammatory cytokines. Interleukin-8 (IL-8) has been implicated in the pathogenesis of inflammatory bowel disease and the metastatic spread of colorectal cancer. The flowers of Osmanthus fragrans (sweet olive) are used to alleviate dysentery with blood in the bowel, as well as stomach ache and diarrhea. However, the evidence of their therapeutic effects on these symptoms remains unclear. In the present study, the protective effects of sweet olive flower ethanolic extract (OFE) against oxidative stress in WiDr cells was assessed by evaluating its 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical scavenging activity. In addition, cellular IL-8 secretion was evaluated. Notably, high-performance liquid chromatography showed verbascoside to be the primary constituent in OFE; it exhibited a DPPH scavenging activity with an IC50 of 8.23 µg/mL. Moreover, OFE (1 to 100 µg/mL) showed a potent, dose-dependent inhibitory effect on H2 O2 -induced IL-8 secretion in WiDr cells. Nine compounds were isolated from OFE based on a protective effect-guided purification process. Of these compounds, 5 phenolic compounds-verbascoside, phillygenin, tyrosol, methyl 4-hydroxycinnamate, and eutigoside A-reduced IL-8 secretion at 10 µg/mL treatment concentrations. Further analysis showed that the anti-inflammatory effects of OFE likely occurred via nuclear factor-κB pathway inhibition, which attenuates IL-8 secretion in cells. Collectively, these data suggest that OFE could be developed as an agent that suppresses IL-8 secretion to treat chronic inflammatory diseases.

Effect of floral sources on the antioxidant, antimicrobial, and anti-inflammatory activities of honeys in Taiwan.

We evaluated the antioxidant, antibacterial, and anti-inflammatory activities of honey made from different floral sources, including the medicinal herb Bidens pilosa, fruit trees, Dimocarpus longan, Litchi chinensis, and Citrus maxima, the Taiwanese endemic plant Aglaia formosana, and a multifloral forest. The total phenolic and flavonoid contents of the honey made from B. pilosa were significantly higher than those of the other honeys. The honey from B. pilosa also had significantly greater scavenging activities for 1,1-diphenyl-2-picrylhydrazyl (DPPH·) and hydroxyl radical, and substantially more reducing power. In addition, the honey from B. pilosa showed greater antibacterial activity against gram-positive and gram-negative bacteria. However, B. pilosa honey showed little inhibitory activity against IL-8 secretion, whereas the other honeys did. These findings suggest that the levels of antioxidant and antibacterial activities are attributable to the total phenolic and flavonoid contents of honeys, while the IL-8 inhibition is attributable to components other than phenols.

The Ethanol Extract of Osmanthus fragrans Flowers Reduces Oxidative Stress and Allergic Airway Inflammation in an Animal Model.

The Osmanthus fragrans flower, a popular herb in Eastern countries, contains several antioxidant compounds. Ben Cao Gang Mu, traditional Chinese medical literature, describes the usefulness of these flowers for phlegm and stasis reduction, arrest of dysentery with blood in the bowel, and stomachache and diarrhea treatment. However, modern evidence regarding the therapeutic efficacy of these flowers is limited. This study was aimed at assessing the antioxidative effects of the ethanol extract of O. fragrans flowers (OFE) in vivo and evaluating its antioxidant maintenance and therapeutic effect on an allergic airway inflammation in mice. After OFE's oral administration to mice, the values obtained in the oxygen radical absorbance capacity assay as well as the glutathione concentration in the lungs and spleens of mice increased while thiobarbituric acid reactive substances decreased significantly, indicating OFE's significant in vivo antioxidant activity. OFE was also therapeutically efficacious in a mouse model of ovalbumin-induced allergic airway inflammation. Orally administered OFE suppressed ovalbumin-specific IgE production and inflammatory cell infiltration in the lung. Moreover, the antioxidative state of the mice improved. Thus, our findings confirm the ability of the O. fragrans flowers to reduce phlegm and suggest that OFE may be useful as an antiallergic agent.

Depleted folate pool and dysfunctional mitochondria associated with defective mitochondrial folate proteins sensitize Chinese ovary cell mutants to tert-butylhydroperoxide-induced oxidative stress and apoptosis.

The functional role of mitochondrial (mt) folate-associated proteins in mammalian cells is not clearly understood. We investigated the respiratory function and apoptosis phenotype of Chinese hamster ovary (CHO) mutant cells with defective mt serine hydroxymethyltransferase (SHMT) activities (glyA) or with defective mt folate transporter (glyB) in the absence/presence of oxidant challenge. The mechanisms underlying their aberrant phenotypes were explored. Compared with CHOK1 wild-type cells, both mutants carried dysfunctional mitochondria with reduced respiratory complex IV activity and depolarized mt membrane potential (P<.05). Elevated superoxide levels and accumulated mtDNA large deletions were observed in glyB in association with a depleted compartmental folate pool (P<.05). tert-Butylhydroperoxide (tBH) treatment at 50 microM for 72 h significantly depleted mt and cytosolic folate levels, impaired antioxidant defenses, and aggravated mt oxidative dysfunction in both mutants (P<.05), more severely in glyB. Only tBH-treated glyB cells displayed an elevated ratio of mt Bax/Bcl-2, activation of procaspases 9 and 3, and apoptosis promotion. The apoptotic phenotype of tBH-treated glyB could be partially corrected by folate supplementation (10-1000 microM), which enriched compartmental folate levels, restored antioxidant defenses, eliminated mt oxidative injuries, and normalized mt membrane function. Our data identify previously unrecognized roles of mt folate-associated proteins in the protection of mitochondria against oxidative insults. Defective mt folate transporter sensitized glyB cells to elevated oxidative stress and tBH-induced apoptosis, partly mediated by depleted compartmental folate and mt dysfunction. Defective mt SHMT sensitized glyA to respiratory dysfunction and tBH-induced oxidative injury without apoptosis promotion.