Ginsenosides from Korean Red Ginseng ameliorate lung inflammatory responses: inhibition of the MAPKs/NF-κB/c-Fos pathways.

BACKGROUND: Korean Red Ginseng (steamed and dried white ginseng, Panax ginseng Meyer) is well known for enhancing vital energy and immune capacity and for inhibiting cancer cell growth. Some clinical studies also demonstrated a therapeutic potential of ginseng extract for treating lung inflammatory disorders. This study was conducted to establish the therapeutic potential of ginseng saponins on the lung inflammatory response. METHODS: From Korean Red Ginseng, 11 ginsenosides (Rb1, Rb2, Rb3, Rc, Rd, Re, Rf, Rg1, Rg2, Rg3, and Rh2) were isolated. Their inhibitory potential and action mechanism were evaluated using a mouse model of lung inflammation, acute lung injury induced by intranasal lipopolysaccharide administration. Their anti-inflammatory activities were also examined in lung epithelial cell line (A549) and alveolar macrophage (MH-S). RESULTS: All ginsenosides orally administered at 20 mg/kg showed 11.5-51.6% reduction of total cell numbers in bronchoalveolar lavage fluid (BALF). Among the ginsenosides, Rc, Re, Rg1, and Rh2 exhibited significant inhibitory action by reducing total cell numbers in the BALF by 34.1-51.6% (n = 5). Particularly, Re showed strong and comparable inhibitory potency with that of dexamethasone, as judged by the number of infiltrated cells and histological observations. Re treatment clearly inhibited the activation of mitogen-activated protein kinases, nuclear factor-κB, and the c-Fos component in the lung tissue (n = 3). CONCLUSION: Certain ginsenosides inhibit lung inflammatory responses by interrupting these signaling molecules and they are potential therapeutics for inflammatory lung diseases.

Flavonoids interfere with NLRP3 inflammasome activation.

NOD-like receptor (NLR) family, pyrin domain-containing 3 (NLRP3) inflammasome is a component of innate immunity, and is responsible for producing mature IL-1ß and -18. Several flavonoids were found to affect inflammasome pathway, but the mechanism of action is still obscure. To elucidate the effects on NLRP3 inflammasome pathway and to determine the structure-activity relationships, NLRP3 inflammasome in differentiated THP-1 cells was activated via treatment with monosodium urate (MSU) crystals. Levels of mature IL-1ß, NLRP3 inflammasome components and apoptosis-associated speck-like protein containing a CARD (caspase recruitment domain) (ASC) oligomerization were investigated and the mechanisms of action were also elucidated. Among the 56 flavonoids initially tested, only flavone, 2',4'-dihhydroxyflavone, 3',4'-dichloroflavone, 4',5,7-trihydroxyflavone (apigenin), 3,4',5,7-tetrahydroxyflavone (kaempferol) and 3,3',4',5,7-pentahydroxyflavone (quercetin) significantly inhibited IL-1ß production at 10 µM. Apigenin, kaempferol and 3',4'-dichloroflavone inhibited ASC oligomerization without affecting the ASC level in cell lysates. Apigenin also inhibited absent in melanoma 2 (AIM2) inflammasome-related pathway, but not NLR family CARD domain-containing protein 4 (NLRC4) inflammasome activation. The action of apigenin on NLRP3 inflammasome activation is mediated partly via inhibition of phosphorylation of spleen tyrosine kinase/protein tyrosine kinase 2 (Syk/Pyk2) pathway. Furthermore, orally administered apigenin (100 mg/kg) strongly reduced the number of neutrophils and monocytes in MSU-induced peritonitis in mice. The present study, for the first time, demonstrated the structure-activity profiles of flavonoids in NLRP3 inflammasome activation and mechanisms of cellular action. Certain flavonoids including apigenin are expected to ameliorate the inflammatory symptoms in autoinflammatory diseases associated with NLRP3 inflammasome activation.

Impressic acid from Acanthopanax koreanum, possesses matrix metalloproteinase-13 down-regulating capacity and protects cartilage destruction.

ETHNOPHARMACOLOGICAL RELEVANCE: Acanthopanax koreanum (Araliaceae) has been used in traditional medicine for enhancing vitality, rheumatism, and bone-related pains. But its activity on cartilage protection has not been known yet. AIM OF THE STUDY: Matrix metalloproteinase (MMP)-13 has an important role in degrading cartilage materials under pathologic conditions such as arthritis. The present study was designed to find the inhibitory activity of impressic acid on MMP-13 expression and cartilage protective action. MATERIALS AND METHODS: 70% ethanol extract of Acanthopanax koreanum leaves and impressic acid, a major constituent isolated from the same plant materials, were examined on MMP-13 down-regulating capacity in IL-1ß-treated human chondrocyte cell line (SW1353) and rabbit cartilage explants. RESULTS: In IL-1ß-treated SW1353 cells, impressic acid significantly and concentration-dependently inhibited MMP-13 expression at 0.5-10µM. Impressic acid was found to be able to inhibit MMP-13 expression by blocking the phosphorylation of signal transducer and activator of transcription-1/-2 (STAT-1/-2) and activation of c-Jun and c-Fos among the cellular signaling pathways involved. Further, impressic acid was found to inhibit the expression of MMP-13 mRNA (47.7% inhibition at 10µM), glycosaminoglycan release (42.2% reduction at 10µM) and proteoglycan loss in IL-1-treated rabbit cartilage explants culture. In addition, a total of 21 lupane-type triterpenoids structurally-related to impressic acid were isolated from the same plant materials and their suppressive activities against MMP-13 expression were also examined. Among these derivatives, compounds 2, 3, 16, and 18 clearly down-regulated MMP-13 expression. However, impressic acid was more potent than these derivatives in down-regulating MMP-13 expression. CONCLUSIONS: Impressic acid, its related triterpenoids, and A. koreanum extract have potential as therapeutic agents to prevent cartilage degradation by inhibiting matrix protein degradation.

Inhibition of matrix metalloproteinase-13 expression in IL-1ß-treated articular chondrocytes by a steroidal saponin, spicatoside A, and its cellular mechanisms of action.

Matrix metalloproteinase-13 (MMP-13) plays a critical role in degrading major collagens in human cartilage under some pathological conditions such as osteoarthritis. To establish the therapeutic potential against cartilage degradation, the effects of 12 naturally-occurring triterpenoids and steroids on MMP-13 induction were examined in the human chondrocyte cell line, SW1353. They included coreanoside F1, suavissimoside R1, spicatoside A, 25(S)-ruscogenin, methyl protogracillin, hederagenin, loniceroside A, loniceroside B, loniceroside C, smilaxin A, smilaxin C, and ursolic acid. Among these, only spicatoside A and 25(S)-ruscogenin were found to inhibit MMP-13 expression in IL-1ß-treated SW1353 cells at a pharmacologically-relevant concentration of 10 µM. These effects were also supported by the finding that spicatoside A (20 µM) reduced glycosaminoglycan release from IL-1α-treated rabbit joint cartilage culture to some degree. When the cellular mechanisms of action of spicatoside A in MMP-13 inhibition were investigated, the blocking point was not found among the MMP-13 signaling molecules examined such as mitogen-activated protein kinases, activator protein-1, and nuclear transcription factor-κB. Instead, spicatoside A was found to reduce MMP-13 mRNA stability. All of these findings suggest that spicatoside A and 25(S)-ruscogenin have a therapeutic potential for protecting against cartilage breakdown in arthritic disorders.

Effect of transurethral resection of the prostate based on the degree of obstruction seen in urodynamic study.

PURPOSE: We retrospectively investigated the effect of transurethral resection of the prostate (TURP) on the basis of the degree of obstruction seen in preoperative urodynamic study in patients with benign prostatic hyperplasia (BPH) who complained of lower urinary tract symptoms (LUTS). MATERIALS AND METHODS: The subjects of this study were 285 patients who were diagnosed with BPH with LUTS and who subsequently underwent TURP. The Abrams-Griffiths number was calculated from the urodynamic results to divide the patients into the following groups: unobstructed, equivocal, and obstructed. There were 26 patients (9.1%) in the unobstructed group, 98 patients (34.4%) in the equivocal group, and 161 patients (56.5%) in the obstructed group. The preoperative and postoperative uroflowmetry, residual urine, International Prostate Symptom Score (IPSS), and quality of life (QoL) score were compared between the three groups to evaluate the outcome of the treatment. RESULTS: The reduction in the IPSS was 14.4 in the obstructed group, which was higher than the reductions of 12.7 in the equivocal group and 9.5 in the unobstructed group, but this difference was not statistically significant (p=0.227). The QoL score was also not significantly different across the three groups (p=0.533). The postoperative maximum flow rate was significantly improved in all three groups. The obstructed group had an improvement of 7.8±7.2 mL/s, which was higher than the improvement of 3.7±6.2 mL/s in the unobstructed group (p=0.049) but was not significantly different from the improvement of 5.6±6.9 mL/s in the equivocal group (p=0.141). CONCLUSIONS: TURP led to an improvement in the maximum flow rate and LUTS even in BPH patients without BOO. Therefore, TURP can be expected to improve LUTS in BPH patients without definite urodynamic obstruction.

Efficacy of alfuzosin after shock wave lithotripsy for the treatment of ureteral calculi.

PURPOSE: We evaluated the efficacy of alfuzosin for the treatment of ureteral calculi less than 10 mm in diameter after extracorporeal shock wave lithotripsy (ESWL). MATERIALS AND METHODS: A randomized, single-blind clinical trial was performed prospectively by one physician between June 2010 and August 2011. A total of 84 patients with ureteral calculi 5 to 10 mm in diameter were divided into two groups. Alfuzosin 10 mg (once daily) and loxoprofen sodium 68.1 mg (as needed) were prescribed to group 1 (n=41), and loxoprofen sodium 68.1 mg (as needed) only was prescribed to group 2 (n=44). The drug administration began immediately after ESWL and continued until stone expulsion was confirmed up to a maximum of 42 days after the procedure. RESULTS: Thirty-nine of 41 (95.1%) patients in group 1 and 40 of 43 (93.0%) patients in group 2 ultimately passed stones (p=0.96). The number of ESWL sessions was 1.34±0.65 and 1.41±0.85 in groups 1 and 2, respectively (p=0.33). The patients who required analgesics after ESWL were 8 (19.5%) in group 1 and 13 (30.2%) in group 2 (p=0.31). Visual analogue scale pain severity scores were 5.33±1.22 and 6.43±1.36 in groups 1 and 2, respectively (p=0.056). The time to stone expulsion in groups 1 and 2 was 9.5±4.8 days and 14.7±9.8 days, respectively (p=0.005). No significant adverse effects occurred. CONCLUSIONS: The use of alfuzosin in combination with ESWL seems to facilitate stone passage and to reduce the time of stone expulsion but does not affect the stone-free rate.