Elecampane (Inula helenium) Root Extract and Its Major Sesquiterpene Lactone, Alantolactone, Inhibit Adipogenesis of 3T3-L1 Preadipocytes.

Recent studies have shown that Nur77 and AMPKα play an important role in regulating adipogenesis and isoalantolactone (ISO) dual-targeting AMPKα and Nur77 inhibits adipogenesis. In this study, we hypothesized that Inula helenium (elecampane) root extract (IHE), which contains two sesquiterpene lactones, alantolactone (ALA) and ISO, as major compounds, might inhibit adipogenesis. Here, we found that ALA and IHE simultaneously target AMPKα and Nur77 and inhibited adipogenic differentiation of 3T3-L1 cells, accompanied by the decreased expression of adipocyte markers. Further mechanistic studies demonstrated that IHE shares similar mechanisms of action with ISO that reduce mitotic clonal expansion during the early phase of adipogenic differentiation and decrease expression of cell cycle regulators. These results suggest that IHE inhibits adipogenesis, in part, through co-regulation of AMPKα and Nur77, and has potential as a therapeutic option for obesity and related metabolic dysfunction.

Bee Venom Suppresses EGF-Induced Epithelial-Mesenchymal Transition and Tumor Invasion in Lung Cancer Cells.

Bee venom of Apis mellifera is a traditional medicine in Asia. It has been used with promoting results for the treatment of pain, rheumatoid, and cancer disease. The purpose of this study was to investigate the effects of bee venom on epidermal growth factor (EGF)-induced epithelial-mesenchymal transition (EMT) in non-small cell lung cancer (NSCLC) and determine possible signaling pathway affected in EGF-induced EMT in A549 cells. Bee venom inhibited EGF-induced F-actin reorganization and cell invasion, and suppressed EGF-induced EMT, processes associated with tumor metastasis in NSCLC. Bee venom enhanced the upregulation of E-cadherin and the downregulation of vimentin and inhibited EGF-induced ERK, JNK, FAK, and mTOR phosphorylation in A549 cells. However, the inhibition of JNK phosphorylation by bee venom was not related to the inhibitory effects of EMT. Furthermore, we found that bee venom suppressed the EMT-related transcription factors ZEB2 and Slug by blocking EGF-induced ERK, FAK and mTOR phosphorylation. Bee venom inhibits EGF-induced EMT by blocking the phosphorylation of ERK, FAK, and mTOR, resulting in the suppression of ZEB2 and Slug. These data suggest bee venom as a potential antimetastatic agent for NSCLC.

Melittin has a chondroprotective effect by inhibiting MMP-1 and MMP-8 expressions via blocking NF-κB and AP-1 signaling pathway in chondrocytes.

Bee venom is a natural ingredient produced by the honey bee (Apis mellifera), and has been widely used in China, Korea and Japan as a traditional medicine for various diseases such as arthritis, rheumatism, and skin diseases However, the regulation of the underlying molecular mechanisms of the anti-arthritis by bee venom and its major peptides is largely unknown. In this study, we investigated the potential molecular mechanisms underlying the anti-arthritis effect of bee venom and its major peptides, melittin and apamin, in tumor necrosis factor-α (TNF-α) responsive C57BL/6 mice chondrocyte cells. The bee venom and melittin significantly and selectively suppressed the TNF-α-mediated decrease of type II collagen expression, whereas the apamin had no effects on the type II collagen expression. We, furthermore, found that the bee venom and melittin inhibited the protein expression of matrix metalloproteinase (MMP)-1 and MMP-8, which suggests that the chondroprotective effect of bee venom may be caused by melittin. The inhibitory effects of melittin on the TNF-α-induced MMP-1 and MMP-8 protein expression were regulated by the inhibition of NF-kB and AP-1. In addition, melittin suppressed the TNF-α-induced phosphorylation of Akt, JNK and ERK1/2, but did not affect the phosphorylation of p38 kinase. These results suggest that melittin suppresses TNF-α-stimulated decrease of type II collagen expression by the inhibiting MMP-1 and MMP-8 through regulation of the NF-kB and AP-1 pathway and provision of a novel role for melittin in anti-arthritis action.

Melittin inhibits TGF-ß-induced pro-fibrotic gene expression through the suppression of the TGFßRII-Smad, ERK1/2 and JNK-mediated signaling pathway.

Renal fibrosis is characterized by the excessive accumulation of extracellular matrix (ECM) proteins such as type I collagen, fibronectin, and by the increased expression of PAI-1. This study evaluated the anti-fibrotic effect of bee venom and its major compounds (melittin and apamin) on TGF-ß-induced pro-fibrotic gene expression. Bee venom and melittin significantly suppressed type I collagen, fibronectin, and PAI-1 protein expression in the TGF-ß-treated kidney fibroblast. However, apamin only inhibited the expression of fibronectin and type I collagen. These results indicated that the inhibitory effects of bee venom on TGF-ß-induced pro-fibrotic gene expression are caused by melittin. Moreover, we attempted to elucidate mechanisms underlying the anti-fibrotic effect of melittin. Melittin dramatically inhibited the phosphorylation of TGFßRII and Smad2/3. Also, melittin inhibited the phosphorylation of ERK1/2 and JNK, but not the phosphorylation of PI3K, Akt, and p38. These results suggested that melittin inhibits TGF-ß-induced pro-fibrotic genes expression through the suppression of TGFßR-Smad2/3, ERK1/2, and JNK phosphorylation, and melittin can be used as a clinical drug for the treatment of fibrosis associated with renal diseases.

The impact of lifestyle behaviors on the acquisition of pandemic (H1N1) influenza infection: a case-control study.

PURPOSE: The purpose of this study was to evaluate the effects of lifestyle behaviors and health habits on the risk for acquiring pandemic influenza (H1N1) virus infection. MATERIALS AND METHODS: We conducted a case-control study in a secondary care hospital in South Korea between November 2009 and August 2010. We enrolled patients with H1N1 infection, as confirmed by a positive result of the real-time reverse transcriptase polymerase chain reaction assay; for each patient, we enrolled 4 age- and gender-matched controls with no history of H1N1 infection or severe acute respiratory illness during the H1N1 pandemic in South Korea (1:4 match). RESULTS: During the study period, 33 cases and 132 age- and gender-matched controls were enrolled. The case group had a higher percentage of current smokers (p<0.01), fewer subjects reporting regular physical activity (p=0.03), or regular vitamin supplementation (p<0.01), and more subjects reporting a higher annual incidence of the common cold (p=0.048) as compared to the control group. In the multivariable analysis, 2 factors were independently associated with the acquisition of H1N1 infection: current smoking [adjusted odds ratio (OR)=5.53; 95% confidence interval (CI), 1.60-19.16; p<0.01] and a higher annual incidence of the common cold (adjusted OR=1.24; 95% CI, 1.002-1.53; p=0.048). CONCLUSION: A current smoking status and a history of frequent colds were associated with an increased risk of acquiring H1N1 infection.

Moringa fruit inhibits LPS-induced NO/iNOS expression through suppressing the NF-κ B activation in RAW264.7 cells.

In this study, we evaluated the anti-inflammatory effects of moringa (Moringa oleifera Lam.), a natural biologically active substance, by determining its inhibitory effects on pro-inflammatory mediators in lipopolysaccharide (LPS)-stimulated macrophage RAW264.7 cells. Extracts from different parts of moringa (root, leaf, and fruit) reduced LPS-induced nitric oxide (NO) release in a dose-dependent manner. The moringa fruit extract most effectively inhibited LPS-induced NO production and levels of inducible nitric oxide synthase (iNOS). The moringa fruit extract also was shown to suppress the production of inflammatory cytokines including IL-1ß, TNF-α, and IL-6. Furthermore, moringa fruit extract inhibited the cytoplasmic degradation of I κ B -α and the nuclear translocation of p65 proteins, resulting in lower levels of NF -κ B transactivation. Collectively, the results of this study demonstrate that moringa fruit extract reduces the levels of pro-inflammatory mediators including NO , IL-1ß, TNF-α, and IL-6 via the inhibition of NF -κ B activation in RAW264.7 cells. These findings reveal, in part, the molecular basis underlying the anti-inflammatory properties of moringa fruit extract.

Bee venom suppresses PMA-mediated MMP-9 gene activation via JNK/p38 and NF-kappaB-dependent mechanisms.

ETHNOPHARMACOLOGICAL RELEVANCE: Bee venom has been used for the treatment of inflammatory diseases such as rheumatoid arthritis and for the relief of pain in traditional oriental medicine. AIM OF THE STUDY: The purpose of this study is to elucidate the effects of bee venom on MMP-9 expression and determine possible mechanisms by which bee venom relieves or prevents the expression of MMP-9 during invasion and metastasis of breast cancer cells. We examined the expression and activity of MMP-9 and possible signaling pathway affected in PMA-induced MCF-7 cells. MATERIAL AND METHODS: Bee venom was obtained from the National Institute of Agricultural Science and Technology of Korea. Matrigel invasion assay, wound-healing assay, zymography assay, western blot assay, electrophoretic mobility shift assay and luciferase gene assay were used for assessment. RESULTS: Bee venom inhibited cell invasion and migration, and also suppressed MMP-9 activity and expression, processes related to tumor invasion and metastasis, in PMA-induced MCF-7 cells. Bee venom specifically suppressed the phosphorylation of p38/JNK and at the same time, suppressed the protein expression, DNA binding and promoter activity of NF-kappaB. The levels of phosphorylated ERK1/2 and c-Jun did not change. We also investigated MMP-9 inhibition by melittin, apamin and PLA(2), representative single component of bee venom. We confirmed that PMA-induced MMP-9 activity was significantly decreased by melittin, but not by apamin and phospholipase A(2). These data demonstrated that the expression of MMP-9 was abolished by melittin, the main component of bee venom. CONCLUSION: Bee venom inhibits PMA-induced MMP-9 expression and activity by inhibition of NF-kappaB via p38 MAPK and JNK signaling pathways in MCF-7 cells. These results indicate that bee venom can be a potential anti-metastatic and anti-invasive agent. This useful effect may lead to future clinical research on the anti-cancer properties of bee venom.

Artemisia capillaris inhibits lipid accumulation in 3T3-L1 adipocytes and obesity in C57BL/6J mice fed a high fat diet.

The purpose of the current study was to determine the effect of the Artemisia capillaris ethyl acetate (ACE) fraction on diet-induced obesity and to elucidate the underlying mechanism. The ACE fraction treatment decreased the leptin level and fat accumulation in cultured 3T3-L1 adipocytes through the free fatty acids released in the medium. The ACE fraction significantly suppressed the expression of peroxisome proliferator-activated receptor-gamma in cultured 3T3-L1 adipocytes. To determine the effect of the ACE fraction on C57BL/6J male mice, the mice were separated into six groups: normal control (N), N plus 0.1 g/kg body weight ACE (NB), high fat control group (HF), HF plus 0.05 g/kg of body weight ACE (HFA), HF plus 0.1 g/kg of body weight ACE (HFB), and HF plus 0.03 g/kg of body weight rosiglitazone (RG) groups. We speculate that the HFB group exhibits a lipid-lowering effect via increased mitochondrial beta-oxidation, of which the rate-limiting enzyme is carnitine palmitoyl transferase I, the activity of which was significantly increased. Also, the activity of fatty acid synthase, a key enzyme of fatty acid synthesis, was markedly suppressed (19%) in the HFB group, as compared to the HF group, and glycerol-3-phosphate dehydrogenase activity, which is very useful in studying adipogenic differentiation in vitro, was markedly suppressed (30%) in the HFB group compared with the HF group. Furthermore, the HFB group showed lowered hepatic lipid droplet accumulation and adipose tissue weight and size. We suggest that 0.1 g of the ACE fraction/kg of body weight may exert an anti-obesity effect in C57BL/6J mice by enhancing lipid metabolism.

The Efficacy of Transurethral Resection of Prostate on the Patients with Benign Prostatic Hyperplasia and Detrusor Hyperactivity with Impaired Contractility

PURPOSE: Detrusor hyperactivity with impaired contractility(DHIC) can be found in many elderly patients with benign prostatic hyperplasia(BPH). It is hard to expect the efficacy of transurethral resection of prostate(TURP) on such patients. Therefore, we retrospectively estimated the effect of TURP on BPH patients with DHIC. MATERIALS AND METHODS: Eighteen male patients with BPH and DHIC were underwent TURP. Through urodynamic studies, DHIC was identified. Findings of bladder outlet obstruction were evaluated with TRUS and/or diagnostic cystoscopy in all patients. They were requested to go through uroflowmetry and international prostate symptom score(IPSS), before and after TURP. The subjective satisfaction scale was measured after TURP. RESULTS: Total IPSS(from 20.6 to 12.5), obstructive symptom score(from 11.5 to 6.0), and maximal flow rate (from 6.0 ml/sec to 14.6 ml/sec) of the patients were improved significantly(p0.05). Only 2(12%) of the patients were unsatisfied with the outcomes of TURP. CONCLUSION: We suggest that TURP can be used as a good therapeutic option for selected patients with BPH accompanied with DHIC.

Pharmacological Effects of Berberine and Palmatine on the Prostatic and Urethral Smooth Muscle of the Rabbit

PURPOSE: One of the major medical treatments for benign prostatic hyperplasia is targeted toward reducing bladder outlet obstruction by alpha-adrenoceptor blockade to relax the smooth muscle tone of the prostate. Berberine and palmatine, an isoquinoline alkaloids, have varied pharmacological actions and have been extensively used in folk medicine. A previous large scale screening test revealed that berberine derivatives have antagonistic effects at the alpha1-adrenoceptors, although they are less potent than prazosin. The aim of this study is to investigate the effect of the berberine and palmatine on the contractility of the isolated prostate, urethral and vascular smooth muscle tissues of the rabbit. MATERIALS AND METHODS: Muscle strips of the prostate, urethra and renal artery were obtained from 10-week-old male New Zealand White rabbits. In vitro isometric contraction was measured using organ bath study. Cumulative concentrations of phenylephrine as an agonist were added to produce concentration-response relationships. Breberin (1-500 microM) and palmatine (1-500 microM) were added to the bath before the repeated phenylephrine-induced concentration-response curve was made. Responses of developed tension to phenylephrine were plotted as percentage of the maximal increase for each concentration-response curve in the prostate, urethra and renal artery strips. RESULTS: Phenylephrine produced concentration-dependent contractions on the rabbit prostatic and urethral preparations. Berberine and palmatine induced a dose-dependent rightward shift of the dose-response curve of phenylephrine-induced contraction of both prostate and urethra with a reduction of maximal response, indicating the interactions of the two agents with phenylephrine in noncompetitive antagonism. The rank order of potency of the inhibitory effect was palmatine > berberine in the urethral tissue, while there was no significant difference between the two agents in the prostatic tissue. In the renal artery strips, both berberine and palmatine did not significantly inhibited the maximal contractile response to phenylephrine (1-50 microM). Higher concentration of berberine (500 microM) and palmatine (100-500 microM) decreased maximal contractile response induced by phenylephrine (0-10 microM), while they paradoxically increased maximal contraction induced by higher concentrations of phenylephrine (50-100 microM). CONCLUSIONS: Our results indicated that berberine or palmatine inhibited phenylephrine-induced contractions in urethral and prostatic smooth muscles, with no significant inhibition in the renal artery smooth muscle at lower concentration ranges of berberine and palmatine. A deeper understanding of the action mechanisms of berberine and palmatine would widen our therapeutic options for voiding disorders.