Search

Delirium is defined as a state that patient is in acute disturbance of consciousness with decreased ability to focus, maintain, or attention, accompanied by cognition change and perceptual disturbances. Postoperative delirium (POD) is a form of delirium, characterized in patients who have undergone surgical procedure and newly diagnosed with a delirium after surgical procedure and anesthesia. There is no definite mechanism how POD happens, but some possible causes are known : inflammation, neurotransmitter, chronic stress, metabolic disorders, electrolyte disorders and sleep-wake disturbance. Though incidence of POD is about 5%-15%, POD is still under-recognised among health care provider. And POD often fatal for patients. It can leads to increasing health care cost, making poor prognosis after surgery and lengthening hospital stay. Acupuncture is defined as an intervention stimulated specific points using needles with various manipulations. Acupuncture is widely used in managing pain recently but also used for mental problems like an anxiety, insomnia, anxiety, depression, dementia, cognitive impairment, and delirium. For producing sedation without complications, acupuncture could be a potential intervention for POD. There are several clinical trials that acupuncture is effective for POD. However, there is no systematic reviews of acupuncture on this condition. Therefore, the aim of this review is to draw a definitive conclusion on acupuncture for POD.

Obesity is associated with chronic low back pain (CLBP), but the association between fat distribution and CLBP is unclear. This cross-sectional study evaluated the relationship using the Korean National Health and Nutrition Examination Survey data. A total of 10,606 adults (average age: 45.4, female: 57.1%) were included. We estimated the regional fat distribution, waist circumference, and body fat proportion, compared the values in people with and without CLBP, and stratified the estimates by sex and obesity status using a multivariable linear model. There were no statistically significant differences in the average waist circumference between the people with and without CLBP (p = 0.731) and the average fat proportion between those with and without CLBP (p = 0.731). The average regional fat distribution was significantly higher in the people with CLBP than in those without CLBP, in the upper limbs (11.4%, 95% confidence interval [CI]: [11.3, 11.5] vs. 11.2%, 95% CI: [11.1, 11.3], p < 0.05) and in the lower limbs (31.9%, 95% CI: [31.6, 32.2] vs. 31.4%, 95% CI: [31.2, 31.6], p < 0.01). More obvious among men, fat distribution in the lower limbs is higher than in people without obesity (p < 0.001). People with CLBP tend to have a higher fat distribution in the limbs than those without it and obese people with CLBP would need to reduce the fat in the lower limbs.

Context:Allium senescens Linn. (Liliaceae) (ASL) has been traditionally used in Korea and other Asian countries for improving digestive and liver functions. Objective: The anti-hepatofibrosis effect of ASL ethanol extract in cellular and experimental fibrosis rat model was investigated. Materials and methods:In vitro cell viability, cell cycle and apoptosis in hepatic stellate cells (HSCs) were studied using MTT assay, flow cytometry and Annexin V-FITC/PI staining. Thioacetamide (TAA; 200 mg/kg, i.p.)-induced liver fibrosis model using Sprague Dawley rats (n = 10) was developed in vivo by injecting TAA twice per week for 13 weeks. ASL (25 and 100 mg/kg) and silymarin (50 mg/kg) were administered through oral gavage 2 times per week from 7th to 13th week. Specific fibrotic-related biomarkers such as aspartate transaminase (AST), alanine transaminase (ALT), glutathione and hydroxyproline levels in serum were analyzed by spectrophotometer using commercial kits. Morphological, histopathological and fibrotic-related gene expression such as TGF-β, Col1α1 and α-SMA in liver tissues was estimated by hematoxylin and eosin staining, Picrosirius red stain and quantitative real-time polymerase chain reaction, respectively. Results: ASL (0.1 mg/mL) and silymarin (0.05 mg/mL) treatment induced apoptosis (4.06% and 8.67%) in activated HSC-T6 cells, compared with control group (3.7%). The altered morphology in activated primary HSCs was also restored by ASL (0.1 mg/mL) treatment. Further, ASL (100 and 25 mg/kg) ameliorated the TAA-induced altered fibrotic-related biomarkers, histopathological changes and fibrotic-related gene expression significantly (p

Background/Aims: Sofosbuvir plus ribavirin is a standard treatment for patients infected with chronic hepatitis C virus (HCV) genotype 2 in Korea. The purpose of this study was to examine the efficacy and safety of this treatment in Korean patients with chronic HCV genotype 2 infection. Methods: We retrospectively analyzed clinical data of patients treated with sofosbuvir plus ribavirin for chronic HCV genotype 2 from May 2016 to December 2017 at eight hospitals located in the Daejeon-Chungcheong area. Results: A total of 172 patients were treated with sofosbuvir plus ribavirin. Of them, 163 patients completed the treatment, and 162 patients were tested for sustained virologic response 12 weeks after treatment discontinuation (SVR12). Mean age was 59.6±12.3 years (27-96), and 105 (64.4%) patients were female. Of the total patients, 49 (30.1%) were diagnosed with cirrhosis, and 31 of them were treated for 16 weeks. Sofosbuvir plus ribavirin was the first-line treatment for 144 (88.3%) patients. Eleven (6.7%) patients were intolerant to previous interferon-based treatment. Eight (5.0%) patients relapsed after interferon-based treatment. HCV RNA non-detection rate at 4, 8, and 12 weeks was 97.5%, 99.1%, and 99.3%, respectively, and SVR12 was 98.8% (161/163). During treatment, 18 (11.0%) patients had to reduce their administrated dose of ribavirin because of anemia. One patient stopped the treatment because of severe anemia. Other adverse events, including dizziness, indigestion, and headache, were found in 26 (16.0%) patients. Conclusions: A 12-16 week treatment with sofosbuvir plus ribavirin is remarkably effective and well tolerated in Korean patients with chronic HCV genotype 2 infection. (Clin Mol Hepatol 2018;24:311-318)

Background This study aims to assess the efficacy and safety of geonchildan, a Korean traditional herbal medicine, for patients with active rheumatoid arthritis (RA) and evaluate the feasibility of a large-scale confirmatory clinical trial. Methods/design This is a randomized, double-blind, placebo-controlled, parallel two-arm pilot trial in Seoul, Korea. Altogether, 30 patients diagnosed with RA for at least 3 months and with a Disease Activity Score for 28 joints (DAS28) ≥ 3.2 will be enrolled. Participants are randomly assigned to one of two groups, the experimental group or the placebo group, in a 1:1 ratio and will make four scheduled visits. The participants will be administered geonchildan or a placebo three times per day for 12 weeks. The change in DAS28 will be examined as the primary efficacy outcome. The secondary efficacy outcomes include the proportion of patients achieving ACR20, ACR50, ACR70, and EULAR responses; the DAS28 sub-items; the consumption of medication; Korean Health Assessment Questionnaire scores; inflammatory parameters; and the Korean medical diagnostic pattern indicator. Adverse events and laboratory test results will be recorded to evaluate safety. The process, resources used, and management of the study will also be assessed to determine the feasibility of a large-scale trial. Discussion This is the first clinical trial to explore the efficacy and safety of geonchildan in patients with active RA. If the superiority of geonchildan versus the placebo is demonstrated and the study design is feasible, this study could form the foundation for a large-scale clinical trial. The results will be published in a peer-reviewed journal. Trial registration Clinical Research Information Service, KCT0001943. Registered on 14 June 2016. Electronic supplementary material The online version of this article (10.1186/s13063-018-2849-3) contains supplementary material, which is available to authorized users.

Rhus javanica Linn, a traditional medicinal herb from the family Anacardiaceae, has been used in the treatment of liver diseases, cancer, parasitic infections, malaria and respiratory diseases in China, Korea and other Asian countries for centuries. In the present study, the protective effects of R. javanica ethanolic extract (RJE) on hydrogen peroxide (H2O2)-induced oxidative stress in human Chang liver cells was investigated. The cell cytotoxicity and viability were assessed using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The activities of superoxide dismutase (SOD) and catalase (CAT) were measured using respective enzymatic kits. Cell cycle analysis was performed using flow cytometric analysis. The protein expression levels of p53, B-cell lymphoma (Bcl)-2, Bcl-2-associated X protein (Bax) and caspase-3 were assessed by western blotting. Human Chang liver cells were treated with different concentrations (0.1, 0.3 or 0.5 mg/ml) of RJE, and were subsequently exposed to H2O2 (30 µM). Treatment with H2O2 (30 µM) significantly induced cytotoxicity (P

Background: This study aims to evaluate the efficacy, safety, and appropriate dose of Hanslim, a Korean traditional herbal medicine, for obese patients, when compared to a placebo. Methods/design: This study is a randomized, double-blinded, multicenter, multidose, placebo-controlled, phase IIb clinical trial. A total of 165 obese patients with a body mass index (BMI) of more than 30 kg/m2 or obese patients with a BMI of 27 to 29.9 kg/m2 and one or more risk factors such as hypertension, diabetes, or hyperlipidemia will be enrolled. Participants will be randomly assigned to 1 of 3 groups (high-dose, low-dose, or placebo) with a 1:1:1 allocation ratio and will have 4 scheduled visits during the 12-week treatment period. The participants will be administered 2 tablets of Hanslim or placebo, 2 times per day. The difference in the proportion of participants who lost weight by more than 5% from their baseline at 12 weeks compared to the placebo group will be examined as the primary efficacy outcome. Secondary efficacy outcomes include differences in body weight, BMI, body-fat percentage, fat mass, skeletal-muscle mass, edema index, waist circumference, hip circumference, waist-hip ratio, serum lipid, blood glucose, C-reactive protein, and total score of Korean version of obesity-related quality of life after 12 weeks of treatment. Adverse events, laboratory test results, vital sings, and electrocardiography will be recorded to evaluate safety. Discussion: This is the first prospective clinical trial to explore the efficacy and safety of Hanslim for obese patients. If the results provide the appropriate dosage of Hanslim, this study would contribute to the confirmatory evidence for the use of Hanslim as a treatment for obesity needed to conduct a large-scale, phase III clinical trial. The results will be published in a peer-reviewed journal. Trial registration: Clinical Research Information Service, ID: KCT0002193. Registered on January 6, 2017. https://cris.nih.go.kr/cris/search/search_result_st01_en.jsp?seq=7468

Background Osteoporosis is becoming more prevalent in aging societies worldwide, and the economic burden attributable to osteoporotic fractures is substantial. The medications presently available to treat osteoporosis have side effects, and the development of safer and more effective treatments is urgently needed. The aim of this study is to evaluate the efficacy and safety of BHH10, a traditional Korean herbal medicine, in the treatment of postmenopausal osteoporosis. Methods/Design This is a phase II, multicenter, randomized, double-blinded, placebo-controlled clinical trial and will include 168 postmenopausal women aged 55 years and older with osteoporosis. The participants will be recruited competitively from two sites of the Acupuncture and Moxibustion Department of Kyung Hee University Hospital of Korean Medicine, either Hoegidong or Gangdong in Seoul, Korea. Participants will be assigned randomly to one of two groups, the BHH10 group or the placebo group, in a 1:1 ratio, and will have five scheduled visits. Participants will take two tablets of BHH10 or placebo three times daily for 12 weeks. The primary efficacy outcome is the change in bone mineral density at the lumbar spine (L1–4) between baseline (visit 1) and 12 weeks after randomization (visit 5). Other outcome variables include changes in bone turnover markers, the Deficiency Syndrome of the Kidney Index, EuroQol five-dimension questionnaire score, and laboratory parameters, as well as adverse events. Discussion To our knowledge, this will be the first clinical trial to assess the efficacy and safety of BHH10 in postmenopausal women with osteoporosis. It is anticipated that the results will contribute to the development of traditional herbal medicines that can be used to treat osteoporosis in postmenopausal women in Korea. If the superiority of BHH10 over placebo is demonstrated, this study could provide the foundation for a phase III clinical trial. The results of the study will be published in a peer-reviewed journal. Trial registration Clinical Research Information Service, KCT0001842. Registered on 14 March 2016. Electronic supplementary material The online version of this article (10.1186/s13063-018-2854-6) contains supplementary material, which is available to authorized users.

Context: Cuscuta chinensis Lam. (Convolvulaceae) has been used as a traditional herbal remedy for treating liver and kidney disorders. Objective: Anti-fibrotic effects of C. chinensis extract (CCE) in cellular and experimental animal models were investigated. Materials and methods: HSC-T6 cell viability, cell cycle and apoptosis were analysed using MTT assay, flow cytometry and Annexin V-FITC/PI staining techniques. Thioacetamide (TAA)-induced fibrosis model was established using Sprague Dawley rats (n = 10). Control, TAA, CCE 10 (TAA with CCE 10 mg/kg), CCE 100 (TAA with CCE 100 mg/kg) and silymarin (TAA with silymarin 50 mg/kg). Fibrosis was induced by TAA (200 mg/kg, i.p.) twice per week for 13 weeks. CCE and silymarin were administered orally two times per week from the 7th to 13th week. Fibrotic related gene expression (α-SMA, Col1α1 and TGF-β1) was measured by RT-PCR. Serum biomarkers, glutathione (GSH) and hydroxyproline were estimated by spectrophotometer using commercial kits. Results: CCE (0.05 and 0.1 mg/mL) and silymarin (0.05 mg/mL) treatment significantly (p

The study objectives were to establish ojeok-san (Five Accumulation Powder: wu ji san) administration criteria and a questionnaire to evaluate the holistic effects of ojeok-san on patients with low back pain (LBP).Texts and literatures, recommended by specialists, were searched to gather ojeok-san-related symptoms. Then, the opinions of Oriental medicine doctors (OMDs) practicing in Seoul were surveyed to ask which symptoms they consider the most in clinical practice. Based on the survey, selection of potential items for the questionnaire was made. The final version was established based on the results of the survey and Delphi process of musculoskeletal diseases specialists. In order to evaluate the reliability and validity of the newly developed assessment tool (Ojeok-san Low Back Questionnaire: OLQ), patients with chronic LBP were recruited. OLQ and other tools such as visual analogue scale, numeric rating scale, Roland-Morris Disability Questionnaire, Modified-Modified Schober test, and 36-Item Short Form Health Survey were applied to the subjects in a 2-week interval. Test-retest reliability, internal consistency, and convergent and discrimination validity were assessed.A total of 90 potential items were generated by the research team. One hundred and two (102) OMDs fully replied to the survey. Based on the survey results, 34 items were initially selected as potential items. Through Delphi method of experts, 10 top items, rated more than 5 points on a scale of 10, were finally established. The 10 items were each established as a response scale of 0-10 (0 as no symptom and 10 as the most excessive form of symptom). Based on the above stages, an initial OLQ was established and used in the evaluation phase. The validity and reliability of OLQ assessment results showed high test-retest reliability, intraclass correlation coefficient, and internal consistency.The newly developed Ojeok-san administration criteria and questionnaire may be a promising tool for future Oriental medicine clinical study protocols.

We investigated the effect of galangin, a natural flavonoid, on osteoclastic bone destruction in collagen-induced arthritis and examined the molecular mechanisms by which galangin affects osteoclastogenesis in bone marrow derived macrophages. In mice with collagen-induced arthritis, administration of galangin significantly reduced the arthritis clinical score, edema and severity of disease without toxicity. Interestingly, galangin treatment during a later stage of collagen-induced arthritis, using mice with a higher clinical arthritis score, still significantly slowed the progression of the disease. Extensive cartilage and bone erosive changes as well as synovial inflammation, synovial hyperplasia and pannus formation were dramatically inhibited in arthritic mice treated with galangin. Furthermore, galangin-treated arthritic mice showed a significant reduction in the concentrations of IL-1β, TNF-α and IL-17. We found that galangin inhibited osteoclastogenic factors and osteoclast formation in bone marrow-derived macrophages and osteoblast co-cultured cells, and increased osteoprotegerin (OPG) levels in osteoblasts. Galangin and NF-κB siRNA suppressed RANKL-induced phosphorylation of the c-jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK), but not AKT and extracellular signal-regulated kinase 1/2 (ERK1/2). Also, the JNK inhibitor SP600125 and p38 inhibitor SB203580 reduced RANKL-induced expressions of phospho-c-Jun, c-fos and NFATc1 genes during osteoclast development. In addition, galangin suppressed RANKL-induced phosphorylation of NF-κB, phospho-IκBα, inflammatory cytokines and osteoclast formation in bone marrow-derived macrophages. Our data suggest that galangin prevented osteoclastic bone destruction and osteoclastogenesis in osteoclast precursors as well as in collagen-induced arthritis mice without toxicity via attenuation of RANKL-induced activation of JNK, p38 and NF-κB pathways.

Melittin (1) is a major polypeptide in honey bee venom that has been used traditionally against chronic inflammation and cancer. However, its molecular mechanism has not been determined. In this study, the antitumor effect of 1 was compared with that of NS398, a cyclooxygenase-2 (COX-2) inhibitor, in vivo and in vitro. Subcutaneous injection of 1 at 0.5 and 5 mg/kg suppressed significantly vascular endothelial growth factor (VEGF)-A-transfected highly metastatic Lewis lung cancer (VEGF-A-hm LLC) tumor growth by 25% and 57%, respectively. Also, 1 inhibited significantly the number of vessels around VEGF-A-hm LLC cells. The results were superior to those obtained in the mice treated with NS398. Compound 1 dose-dependently inhibited proliferation and tube formation in human umbilical vein endothelial cells (VEGF-A-HUVECs), without affecting cell viability in native HUVECs. In addition, 1 decreased the expression of VEGF receptor-2 (VEGFR-2), COX-2, and prostaglandin E2 (PGE2) in VEGF-A-transfected HUVECs. These effects were accompanied by a reduction of the phosphorylation of extracellular signal-regulated kinase 1/2 and c-jun N-terminal kinase, whereas it increased the phosphorylation of p38 mitogen-activated protein kinase (MAPK). SB203580 abolished the downregulation of COX-2 and VEGFR-2 and the inhibition of cell proliferation by 1. The antitumor activity of 1 may be associated with antiangiogenic actions via inhibiting VEGFR-2 and inflammatory mediators involved in the MAPK signaling pathway.

Ethnopharmacological relevance The dried flowers of Lonicera japonica Thunb and dried roots of Anemarrhena asphodeloides BUNGE have been used for the treatment of a variety of inflammatory diseases in traditional Korean medicine. Objective The aim of the study is to evaluate the anti-inflammatory effects of WIN-34B, a new herbal medicine, in fibroblast-like synoviocytes (FLS) obtained from patients with osteoarthritis (OA). Materials and methods WIN-34B is isolated from the n-butanol fraction of dried flowers of L. japonica and dried roots of A. asphodeloides. The anti-inflammatory effects of WIN-34B on cell viability, the production and release of inflammatory mediators, matrix metalloproteinases (MMPs), aggrecanases, tissue inhibitor of matrix proteinases (TIMP) is compared with celecoxib in IL-1β-stimulated human OA FLS. Furthermore, the effect of WIN-34B on inhibitory kappa B-α (IκB-α) phosphorylation and mitogen-activated protein kinases (MAPK) in the IL-1β-stimulated OA FLS was also evaluated. Results WIN-34B significantly inhibited the IL-1β-induced cell viability in human OA FLS without cytotoxicity. Compared to celecoxib, WIN-34B exhibited similar or better anti-inflammatory effects through significant suppression of inflammatory mediators (IL-1β, TNF-α, PGE2 and NO), MMPs (MMP-1, MMP-3 and MMP-13) and aggrecanases (ADAMTS-4 and ADAMTS-5), and enhancement of TIMPs (TIMP-1 and TIMP-3). Moreover, WIN-34B reduced the phosphorylation of IκB-α, ERK1/2, p38 and JNK1/2 in IL-1β-stimulated OA FLS. Conclusions WIN-34B exhibited similar or better anti-inflammatory properties in IL-1β-stimulated OA FLS compared to celecoxib. The anti-inflammatory effects of WIN-34B are due to inhibition of inflammatory mediators (IL-1β, TNF-α, PGE2 and NO) and regulation of MMPs, ADAMTSs and TIMPs via the inhibition of IκB-α and MAPK phosphorylation in IL-1β-stimulated OA FLS.

Background People living with chronic kidney disease (CKD) experience a range of symptoms and often have complex comorbidities. Many pharmacological interventions for people with CKD have known risks of adverse events. Acupuncture is widely used for symptom management in patients with chronic diseases and in other palliative care settings. However, the safety and efficacy of acupuncture for people with CKD remains largely unknown. Objectives We aimed to evaluate the benefits and harms of acupuncture, electro-acupuncture, acupressure, moxibustion and other acupuncture-related interventions (alone or combined with other acupuncture-related interventions) for symptoms of CKD. In particular, we planned to compare acupuncture and related interventions with conventional medicine, active non-pharmacological interventions, and routine care for symptoms of CKD. Search methods We searched the Cochrane Kidney and Transplant Specialised Register up to 28 January 2016 through contact with the Information Specialist using search terms relevant to this review. We also searched Korean medical databases (including Korean Studies Information, DBPIA, Korea Institute of Science and Technology Information, Research Information Centre for Health Database, KoreaMed, the National Assembly Library) and Chinese databases (including the China Academic Journal). Selection criteria We included randomised controlled trials (RCTs) and quasi-RCTs that investigated the effects of acupuncture and related point-stimulation interventions with or without needle penetration that involved six sessions or more in adults with CKD stage 3 to 5, regardless of the language and type of publication. We excluded studies that used herbal medicine or co-interventions administered unequally among the study groups. Data collection and analysis Two authors independently extracted data and assessed risk of bias. We calculated the mean difference (MD) or standardised mean difference (SMD) with 95% confidence intervals (CI) for continuous outcomes and risk ratio (RR) for dichotomous outcomes. Primary outcomes were changes in pain and depression, and occurrence of serious of adverse events. Main results We included 24 studies that involved a total of 1787 participants. Studies reported on various types of acupuncture and related interventions including manual acupuncture and acupressure, ear acupressure, transcutaneous electrical acupuncture point stimulation, far-infrared radiation on acupuncture points and indirect moxibustion. CKD stages included pre-dialysis stage 3 or 4 and end-stage kidney disease on either haemodialysis or peritoneal dialysis. None of the included studies assessed pain outcomes, nor formally addressed occurrence of serious adverse events, although three studies reported three participant deaths and three hospitalisations as reasons for attrition. Three studies reported minor acupuncture-related harms; the remainder did not report if those events occurred. All studies were assessed at high or unclear risk of bias in terms of allocation concealment. Seventeen studies reported outcomes measured for only two months. There was very low quality of evidence that compared with routine care, manual acupressure reduced scores of the Beck Depression Inventory score (scale from 0 to 63) (3 studies, 128 participants: MD -4.29, 95% CI -7.48 to -1.11, I2 = 0%), the revised Piper Fatigue Scale (scale from 0 to 10) (3 studies, 128 participants: MD -1.19, 95% CI -1.77 to -0.60, I2 = 0%), and the Pittsburgh Sleep Quality Index (scale from 0 to 21) (4 studies, 180 participants: MD -2.46, 95% CI -4.23 to -0.69, I2 = 50%). We were unable to perform further meta-analyses because of the paucity of data and problems with clinical heterogeneity, such as different interventions, comparisons and timing of outcome measurements. Authors' conclusions There was very low quality of evidence of the short-term effects of manual acupressure as an adjuvant intervention for fatigue, depression, sleep disturbance and uraemic pruritus in patients undergoing regular haemodialysis. The paucity of evidence indicates that there is little evidence of the effects of other types of acupuncture for other outcomes, including pain, in patients with other stages of CKD. Overall high or unclear risk of bias distorts the validity of the reported benefit of acupuncture and makes the estimated effects uncertain. The incomplete reporting of acupuncture-related harm does not permit us to assess the safety of acupuncture and related interventions. Future studies should investigate the effects and safety of acupuncture for pain and other common symptoms in patients with CKD and those undergoing dialysis.

Cordycepin (3'-deoxyadenosin), a specific polyadenylation inhibitor, is the main functional component in Cordyceps militaris, one of the top three renowned traditional Chinese medicines. Cordycepin has been shown to possess many pharmacological activities including immunological stimulation, and anti-bacterial, anti-viral, and anti-tumor effects. However, the mechanisms underlying its anti-cancer mechanisms are not yet understood. In this study, the apoptotic effects of cordycepin were investigated in human leukemia cells. Treatment with cordycepin significantly inhibited cell growth in a concentration-dependent manner by inducing apoptosis but not necrosis. This induction was associated with generation of reactive oxygen species (ROS), mitochondrial dysfunction, activation of caspases, and cleavage of poly(ADP-ribose) polymerase protein. However, apoptosis induced by cordycepin was attenuated by caspase inhibitors, indicating an important role for caspases in cordycepin responses. Administration of N-acetyl-l-cysteine, a scavenger of ROS, also significantly inhibited cordycepin-induced apoptosis and activation of caspases. These results support a mechanism whereby cordycepin induces apoptosis of human leukemia cells through a signaling cascade involving a ROS-mediated caspase pathway.

Bee venom has been reported to have antinociceptive and anti-inflammatory effects in experimental studies. However, questions still remain regarding the clinical use of bee venom. This report describes the successful outcome of bee venom treatment for refractory postherpetic neuralgia.A 72-year-old Korean man had severe pain and hypersensitivity in the region where he had developed a herpes zoster rash 2 years earlier. He was treated with antivirals, painkillers, steroids, and analgesic patches, all to no effect.The patient visited the East-West Pain Clinic, Kyung Hee University Medical Center, to receive collaborative treatment. After being evaluated for bee venom compatibility, he was treated with bee venom injections. A 1:30,000 diluted solution of bee venom was injected subcutaneously along the margins of the rash once per week for 4 weeks.Pain levels were evaluated before every treatment, and by his fifth visit, his pain had decreased from 8 to 2 on a 10-point numerical rating scale. He experienced no adverse effects, and this improvement was maintained at the 3-month, 6-month, and 1-year phone follow-up evaluations.Bee venom treatment demonstrates the potential to become an effective treatment for postherpetic neuralgia. Further large-sample clinical trials should be conducted to evaluate the overall safety and efficacy of this treatment.

Because tumor necrosis factor-alpha (TNF-alpha) is well-known to induce inflammatory responses, thus its clinical use is limited in cancer treatment. Rosmarinic acid (RA), a naturally occurring polyphenol flavonoid, has been reported to inhibit TNF-alpha-induced NF-kappaB activation in human dermal fibroblasts. However, the precise mechanisms of RA have not been well elucidated in TNF-alpha-mediated anti-cancer therapy. In this study, we found that RA treatment significantly sensitizes TNF-alpha-induced apoptosis in human leukemia U937 cells through the suppression of nuclear transcription factor-kappaB (NF-kappaB) and reactive oxygen species (ROS). Activation of caspases in response to TNF-alpha was markedly increased by RA treatment. However, pretreatment with the caspase-3 inhibitor, z-DEVD-fmk, was capable of significantly restoring cell viability in response to combined treatment. RA also suppressed NF-kappaB activation through inhibition of phosphorylation and degradation of IkappaBalpha, and nuclear translocation of p50 and p65. This inhibition was correlated with suppression of NF-kappaB-dependent anti-apoptotic proteins (IAP-1, IAP-2, and XIAP). RA treatment also normalized TNF-alpha-induced ROS generation. Additionally, ectopic Bcl-2 expressing U937 reversed combined treatment-induced cell death, cytochrome c release into cytosol, and collapse of mitochondrial potential. These results demonstrated that RA inhibits TNF-alpha-induced ROS generation and NF-kappaB activation, and enhances TNF-alpha-induced apoptosis.

Introduction Thread embedding acupuncture (TEA) is a special type of acupuncture that inserts certain medical threads (eg, catgut or polydioxanone) into subcutaneous tissue or muscles at specific points. Although TEA has been widely used for the treatment of musculoskeletal pain in Korea, China and Taiwan, evidence regarding its efficacy is lacking. The aim of this protocol is to evaluate the effectiveness and safety of TEA in the treatment of musculoskeletal pain, by conducting a systematic review and meta-analysis. Methods and analysis The following 16 databases will be searched from their inception to 14 May 2017: MEDLINE, the Cochrane Central Register of Controlled Trials, EMBASE, the Cumulative Index to Nursing and Allied Health Literature, the Allied and Complementary Medicine Database, three Chinese database (China National Knowledge Infrastructure, the Chongqing VIP Chinese Science and Technology Periodical Database and the Wanfang database) and eight Korean databases (Korean Medical Database, Korean Association of Medical Journal Editors, Korean Studies Information Service System, Korean National Assembly Digital Library, National Digital Science Library, Oriental Medicine Advanced Searching Integrated System, ’Database Periodical Information Academic and Korean Traditional Knowledge Portal9). The WHO International Clinical Trials Registry Platform will also be searched to retrieve the recently completed studies. All randomised controlled studies in which TEA was used on specific points for the treatment of musculoskeletal pain will be included and no restrictions on language will be applied. The risk of bias of each study will be evaluated by the Cochrane risk of bias tool. Mean difference or standardised mean difference for continuous data and risk ratio for dichotomous data will be calculated with 95% CIs using a random effects model or a fixed effects model. Additional subgroup and sensitivity analyses will be conducted according to a predefined protocol. Ethics and dissemination No ethical issues are predicted. The systematic review will be published in a peer-reviewed journal or conference presentation. These findings will summarise the current evidence of TEA for the treatment of musculoskeletal pain and may provide guidance for clinicians and patients to select TEA for musculoskeletal pain. PROSPERO registration number CRD42015019046.

Telomerase, a ribonucleoprotein that plays an important role in neoplastic immortality, is up-regulated in approximately 85% of cancers, especially in leukemia. The polyphenol, butein, has potent effects against various types of cancer cells, but its effects on telomerase activity have not been well characterized. In this study, we show that butein causes a down-regulation of hTERT gene expression and a concomitant decrease of telomerase activity. Butein also suppresses expression of c-Myc at the transcriptional level and down-regulates DNA-binding activity, regardless of cell type specificity, in leukemia cells. DNA-binding activities of c-Myc to the hTERT core promoter were decreased in butein-treated cells, as seen by chromatin immunoprecipitation assay. Treatment with butein also suppressed the activation of Akt, thereby inhibiting hTERT phosphorylation and translocation into the nucleus. In this process, butein also up-regulated the surface expression of CD11b in leukemia cells. Inhibition of telomerase activity by butein was followed by loss of proliferative capacity, induction of apoptosis, and differentiation. These findings demonstrate the effectiveness of butein at inhibiting telomerase activity by down-regulating hTERT gene expression in human leukemia cells.

KHBJ-9B has been formulated by n-butanol fraction from 2 herbs known to have cartilage protection and anti-inflammatory effects. We elected to determine the osteoarthritic efficacy and mechanism of KHBJ-9B on human osteoarthritis cartilage explants culture and in a rabbit model of collagenase-induced osteoarthritis (CIA). The major chemical composition and quantification of KHBJ-9B was determined by high performance liquid chromatography. The efficacy of KHBJ-9B and its major compounds on cartilage protective effects such as inhibition of GAG release and type II collagen degradation, and their cytotoxicity in IL-1beta-treated human cartilage culture were examined. The mechanism of action of KHBJ-9B and its major compounds were evaluated by measuring inflammatory cytokines (IL-1beta and TNF-alpha) and matrix proteinases (ADAMTS-4, ADAMTS-5, MMP-1, MMP-13 and TIMP-3) in IL-1beta-treated human cartilage cultures. Also, the therapeutic effect of KHBJ-9B was confirmed using a collagenase-induced osteoarthritis (CIA) rabbit model. KHBJ-9B and 3 combined triterpenoids potently inhibited the release of proteoglycan and type II collagen in a dose dependent manner without cytotoxicity in IL-1beta-treated human cartilage explants culture, whereas its single major compounds (betulin, pimaradienoic acid and betulinic acid) and COX-2 inhibitor (NS398) showed little inhibition even at high concentrations. KHBJ-9B and the combination of 3 triterpenoids markedly inhibited the level of IL-1beta and TNF-alpha, and down-regulated the level of aggrecanases, ADAMTS-4, ADAMTS-5, MMP-1 and MMP-13, and up-regulated TIMP-3 in human cartilage explants culture. However, standard compounds and NS398 do not much affect the level of TNF-alpha, aggrecanases, and TIMP-3 in cartilage explants culture. In in vivo studies, KHBJ-9B significantly suppressed the stiffness level and global histologic score. Cartilage loss was significantly inhibited in the knee joint in a dose dependent manner, and this was associated with the finding that loss of proteoglycan, degradation of aggrecan and type II collagen was markedly reduced. These results suggest that the effect of KHBJ-9B is bigger than the effects of its single major compounds of triterpenoids or celecoxib inhibitors on cartilage protection and anti-inflammation in human cartilage and in in vivo model of osteoarthritis, and thus has potential for use in osteoarthritis treatment.

In this study, we found that pectenotoxin-2 (PTX-2) decreased cell viability and inhibited telomerase activity with downregulation of hTERT expression in human leukemia cells. PTX-2 treatment also reduced c-Myc and Sp1 gene expression and DNA binding activity. Further chromatin immunoprecipitation assay demonstrated that PTX-2 attenuated the binding of c-Myc and Sp1 to the regulatory regions of hTERT. We also observed that PTX-2 treatment attenuated the phosphorylation of Akt, thereby reducing the phosphorylation and nuclear translocation of hTERT. We concluded that PTX-2 suppressed telomerase activity through the transcriptional and post-translational suppression of hTERT and this process precedes cellular differentiation of human leukemia cells.Structured summaryMINT-6742762:hTERT (uniprotkb:O14746) physically interacts (MI:0218) with AKT (uniprotkb:P31749) by anti bait coimmunoprecipitation (MI:0006)

The cytotoxic effect of the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is limited in some cancer cells, including A549 lung adenocarcinoma cells. However, treatment with TRAIL in combination with subtoxic concentrations of sulforaphane (SFN) sensitizes TRAIL-resistant A549 cells to TRAIL-mediated apoptosis. Combined treatment with SFN and TRAIL induced chromatin condensation, DNA fragmentation, annexin V staining and sub-G(1) phase DNA content. These indicators of apoptosis correlate with the induction of caspase-3 activity that results in the cleavage of poly(ADP-ribose) polymerase and the release of lactate dehydrogenase. Both the cytotoxic effect and apoptotic characteristics induced by combined treatment were significantly inhibited by z-DEVD-fmk, a caspase-3 inhibitor, demonstrating the important role of caspase-3 in the observed cytotoxic effect. Combined treatment also triggered the activation of p38 MAPK and JNK, and downregulation of ERK and Akt. Inhibitors of ERK (PD98059) or Akt (LY294002), but not p38 MAPK, resulted in significantly decreased cell viability. Although the activation of JNK was increased in response to combined treatment, inhibition of the JNK pathway significantly attenuated cell viability. These results indicate that caspase-3 is a key regulator of apoptosis in response to combined SFN and TRAIL in human lung adenocarcinoma A549 cells through downregulation of ERK and Akt.

Immunostimulating factor (ISTF) isolated from Actinobacillus actinomycetemcomitans which has been described previously, is distinct from lipopolysaccharide and induces proliferation of B cells. This study was undertaken to investigate whether ISTF might enhance the stimulation of other immune cells. Immunohistochemically, ISTF exhibited a profound stimulating effect on macrophages and dendritic cells as well as B cells in the spleen of BALB/c mice. ISTF was also recognized for its capacity to induce direct activation of mouse macrophages to produce IL-6, TNF-alpha, and NO and MHC class II expression. Therefore, it is postulated that ISTF stimulates macrophages and possibly other cells to produce a wide variety of proinflammatory mediators, which may be involved in the chronicity and tissue destruction of periodontal disease.

Puerariae radix (PR) is a traditional medicine herb used for enhancing body resistance against various diseases. The aim of this study was to identify whether Puerariae radix extract induces osteogenic activity in human osteoblast-like SaOS-2 cells. Puerariae radix had no effect on the viability of osteoblastic cells, and dose-dependently increased alkaline phosphatase (ALP) activity. Puerariae radix markedly increased mRNA expression for vascular endothelial growth factor (VEGF), osteocalcin (OCN), osteopontin (OPN), and type I collagen (Col I) in SaOS-2 cells. Extracellular accumulation of proteins such as VEGF and Col I was increased in a dose-dependent manner. Also, Puerariae radix significantly induced mineralization in the culture of SaOS-2 cells. In conclusion, this study showed that Puerariae radix had no effect on viability, but enhanced ALP activity, VEGF, bone matrix proteins such as OCN, OPN, and Col I, and mineralization in SaOS-2 cells. These results propose that Puerariae radix can play an important role in osteoblastic bone formation, and may possibly lead to the development of bone-forming drugs.

We previously reported that herbimycin A (HMA) alters the mode of cell death of K562 cells induced by radiation and enhanced their radiosensitivity. In the present study, we explored the apoptosis-inducing activity of HMA and the fundamental mechanism via which it regulates radiation-induced cell death.Chronic myelogenous leukemia (CML) cell line K562 was used. For X-irradiation and drug treatment, cells were plated at approximately 2x10(5) cells/ml. Exponentially growing cells were treated with 10 Gy of X-ray using a 6-MeV X-ray machine at a dose rate of 200-300 cGy/min. The cells were treated with 0.25 microM HMA immediately after irradiation and HMA remained for the entire culture period. The modes of cell death were discriminated by morphological changes, analysis of cell cycle, analysis of the mitochondrial events, and the expression of apoptosis-related proteins.Our data demonstrates that radiation induced a significant time-dependent increase of cell death and failed to sustain a prolonged G2 arrest in K562 cells. Radiation-induced cell death caused the accumulation of cyclinB1 and weak nuclear fragmentation, suggesting a mitotic catastrophe. This mitotic catastrophe was dependent upon the mitochondrial permeability transition pore (PTP) opening and was independent of caspase-3. In contrast, K562 cells treated with radiation and HMA had an accelerated cell death and induced a p53-independent apoptosis. This apoptotic pathway was dependent upon an initial hyperpolarization of the mitochondrial inner membrane, following the release of cytochrome c and subsequent caspase-3 activation.Two mechanisms of radiation-induced cell death in K562 cells, mitotic catastrophe and apoptosis, are regulated through distinct pathways, mitochondria and caspase-independent and -dependent, respectively. The findings of this study may provide new insights into improving the efficiency of radiotherapy in CML patients.

Angiogenesis consists of the proliferation, migration, and differentiation of endothelial cells, and angiogenic factors and matrix protein interactions modulate this process. The aim of this study was to determine the angiogenic properties of Uncaria rhynchophylla. Uncaria rhynchophylla significantly enhanced human umbilical vein endothelial cells (HUVECs) proliferation in a dose-dependent manner. Neutralization of vascular endothelial growth factor (VEGF) or basic fibroblast growth factor (bFGF) by monoclonal antibody suppressed the Uncaria rhynchophylla stimulatory effect on proliferation. In addition, Uncaria rhynchophylla significantly increased chemotactic-migration on gelatin and tubular structures on Matrigel of HUVECs in a dose-dependent manner. Interestingly, Uncaria rhynchophylla dose-dependently increased VEGF, and bFGF gene expression and protein secretion of HUVEC. The angiogenic activity of Uncaria rhynchophylla was confirmed using an in vivo Matrigel angiogenesis model, showing promotion of blood vessel formation. These results suggest that Uncaria rhynchophylla could potentially used to accelerate vascular wound healing or to promote the growth of collateral blood vessel in ischemic tissues.

It has been known that acupuncture has various effects such as analgesia, promotion of homeostasis, improvements in brain circulation, and rectification of internal disorders. Neuropeptide Y (NPY), a 36-amino-acid peptide, is known to increase appetite. In the present study, the effect of acupuncture stimulation at Zusanli (St.36) on NPY expression in the Streptozotocin (STZ)-induced diabetic rats was investigated via immunohistochemistry. Increased NPY expression was detected in both the Arcuate nucleus (ARN) and the Paraventricular nucleus (PVN) of the Hypothalamus in rats with in STZ-induced diabetes. Needling on Zusanli resulted in decreased NPY levels in both the ARN and PVN of diabetic rats. The present study shows that acupuncture suppressed NPY expression in the ARN and PVN of the Hypothalamus in STZ-induced diabetic rats, suggesting the possibility that acupuncture treatment is effective in curbing the hyperphagia of diabetes.

AIM To evaluate the safety and efficacy of tenofovir disoproxil fumarate (TDF) as a first-line therapy in decompensated liver disease. METHODS We enrolled 174 chronic hepatitis B-related liver cirrhosis patients treated with 300 mg/d TDF at six Korean centers. Of the 174 cirrhosis patients, 57 were assigned to the decompensated cirrhosis group and 117 were assigned to the compensated cirrhosis group. We followed the patients for 12 mo and evaluated clinical outcomes, including biochemical, virological, and serological responses. We also evaluated changes in hepatic and renal function and compared the decompensated and compensated cirrhosis groups. RESULTS The 1-year complete virological response (CVR) and Hepatitis B e antigen (HBeAg) seroconversion were seen in 70.2% and 14.2% in the decompensated cirrhosis group, respectively. The rates of HBeAg seroconversion/loss and ALT normalization at month 12 were similar in both groups. TDF treatment was also effective for decreasing the level of hepatitis B virus (HBV) DNA in both groups, but CVR was higher in the compensated group (88.9% vs 70.2%, P = 0.005). Tenofovir treatment for 12 mo resulted in improved Child-Turcotte-Pugh (CTP) and model for end-stage liver disease (MELD) scores in decompensated group (P < 0.001). Of the 57 decompensated patients, 39 (68.4%) achieved CTP class A and 27 (49.1%) showed improvement in the CTP score of 2 points after 12 mo of TDF. The observed rate of confirmed 0.5 mg/dL increases in serum levels of creatinine in the decompensated and compensated cirrhosis group were 7.0% and 2.5%, respectively (P < 1.000). CONCLUSION TDF therapy in decompensated cirrhosis patients was effective for decreasing HBV DNA levels and improving hepatic function with relatively lower CVR than in compensated cirrhosis. Thus, physicians should carefully monitor not only renal function but also treatment responses when using TDF in decompensated cirrhosis patients.

Background/Aims: The atrophic gastritis with intestinal metaplasia of gastric mucosa has been considered to be the major factor of carcinogenesis in the stomach. However, the key molecules are still poorly understood. To elucidate the molecular genetic basis, we report the results of our initial microarray data to analyze the genome pattern in patients with atrophic gastritis and intestinal metaplasia of the stomach. Methods: We used oligonucleotide microarray technique to evaluate the gene expression profiles in atrophic gastritis with intestinal metaplasia, in comparison with those of normal mucosa. For the identification of differentially expressed genes, Significance Analysis of Microarrays (SAM) package method was used. The results were analyzed using global normalization, intensity dependent normalization, and box plot normalization. Results: Eight genes including FABP, REG, OR6C1, MEP1, SLC6A1, SI, Mucin 1, and RAB23 in mucosa of atrophic gastritis and intestinal metaplasia were up-regulated by more than 10 times as compared with normal gastric mucosa. Only one gene, LOC44119 was down-regulated by more than 10 times of the expression as compared with normal gastric mucosa. In respect to the expression of known genes related to gastric carcinogenesis, 8 genes including FN1, SRMS, TP53, TP53IMP2, TP53I3, FGFR4, TGFB1, and TGFA showed up- and down-regulations more than 2 folds in expression pattern. Conclusions: We could identify a total genome pattern in patient with atrophic gastritis and intestinal metaplasia using oligonucleotide microarray. We believe that the current results will serve as a fundamental bioinformative basis for clinical applications in diagnosis and treatment of gastric cancer and precancerous lesion in the future. (Korean J Gastroenterol 2007;49:209-224)

Objectives This study aims to assess the completeness of reporting of randomised controlled trials (RCTs) of acupuncture in the Korean literature. Design Systematic review. Methods We searched 12 Korean databases and 7 Korean journals to identify eligible RCTs of acupuncture published from 1996 to July 2011. We used the Consolidated Standards of Reporting Trials (CONSORT) checklist for parallel RCTs and the revised STandards for Reporting Interventions in Clinical Trials of Acupuncture (STRICTA) to assess the quality of reporting in Korean RCTs. We compared the completeness of reporting of CONSORT and STRICTA items in RCTs published in two time periods (1996–2004 referred to as the early period and 2005–2011 referred to as the late period). Results We analysed 146 eligible RCTs using the CONSORT statement concerning RCTs of both needling and non-needling acupuncture and the STRICTA guidelines for 90 trials of needling acupuncture. Among the 103 RCTs in the late period, the proportion of RCTs that completely reported the CONSORT items of outcome definition (15.5%), sample size calculation (2.9%), randomisation (56%), allocation concealment (5.8%), implementation of allocation (11.7%), outcome assessor blinding (20.3%), flow of participants (25.2%), number of participants analysed (19.4%), ancillary analyses (0.0%), adverse events (24.3%), generalisability of findings (1.9%) and overall evidence (32.0%) remained small. Among the 61 RCTs of needling acupuncture in the late period, the STRICTA items of setting/context (24.6%) and practitioner background (27.9%) showed incomplete reporting. The completeness of reporting improved over time in several CONSORT and STRICTA items. Conclusions The completeness of reporting of Korean RCTs of acupuncture was suboptimal according to the CONSORT and revised STRICTA statements. Trial authors and journal editors should use the CONSORT statement and STRICTA guidelines for transparent reporting in Korean RCTs of acupuncture. The endorsement of the CONSORT and revised STRICTA statements in author instructions is also required.

Arginine, an alpha-amino acid, has been reported to exert beneficial effects that ameliorate health problems and prevent excessive fat deposition. In this study, we investigated whether the activation of cell signaling by arginine can induce osteogenic differentiation and modulate excessive adipogenic differentiation in human mesenchymal stem cells (MSCs). Arginine potently induced the expression of type I alpha 1 collagen, osteocalcin, and ALP in a dose-dependent manner without causing cytotoxicity. Arginine significantly increased the mRNA expression of the osteogenic transcription factors runt-related transcription factor 2 (Runx2), DIx5, and osterix. Furthermore, arginine demonstrated its antiadipogenicity by decreasing adipocyte formation and triglyceride (TG) content in MSCs and inhibiting the mRNA expression of the adipogenic transcription factors peroxisome proliferator-activated receptor gamma (PPAR gamma), CCAAT/enhancer-binding protein alpha (C/EBP alpha), and fatty acid binding protein 4 (Fabp4). This effect was associated with increased expression of Wnt5a, and nuclear factor of activated T-cells (NFATc), and was abrogated by antagonists of Wnt and NFATc, which indicated a role of Wnt and NFATc signaling in the switch from adipogenesis to osteoblastogenesis induced by arginine. In conclusion, this is the first report of the dual action of arginine in promoting osteogenesis and inhibiting adipocyte formation through involving Wnt5a and NFATc signaling pathway.

Objectives High-quality reporting of treatment details can aid replication of study results in real-world clinical practice. The Standards for Reporting Interventions in Clinical Trials of Acupuncture (STRICTA) is a reporting guideline for key elements of acupuncture interventions in clinical trials. This study used STRICTA to investigate whether Cochrane reviews of acupuncture adequately report important treatment details. Design Systematic review Methods Cochrane reviews of acupuncture were identified from The Cochrane Library (issue 7, 2012). Randomised controlled trials (RCTs) included in the reviews and published after 2005 were obtained. Using STRICTA, we extracted acupuncture-related information from the Cochrane reviews and the RCTs. The characteristics of the included studies’ table were the major source of intervention information from Cochrane reviews. Reporting quality of acupuncture interventions in Cochrane reviews was assessed and compared with the respective RCTs. Results 25 Cochrane reviews of acupuncture and 92 RCTs met the selection criteria. Cochrane reviews were 16% less likely to report the acupuncture-related items of STRICTA than RCTs (risk ratio 0.84, 95% CI 0.79 to 0.88, I2=8%). Information was significantly better reported for 10 of the 15 treatment-group items of STRICTA in RCTs than in Cochrane reviews (p

In recent years, ubiquitous computing has been rapidly emerged in our lives and extensive studies have been conducted in a variety of areas related to smart devices, such as tablets, smartphones, smart TVs, smart refrigerators, and smart media devices, as a measure for realizing the ubiquitous computing. In particular, smartphones have significantly evolved from the traditional feature phones. Increasingly higher-end smartphone models that can perform a range of functions are now available. Smart devices have become widely popular since they provide high efficiency and great convenience for not only private daily activities but also business endeavors. Rapid advancements have been achieved in smart device technologies to improve the end users’ convenience. Consequently, many people increasingly rely on smart devices to store their valuable and important data. With this increasing dependence, an important aspect that must be addressed is security issues. Leaking of private information or sensitive business data due to loss or theft of smart devices could result in exorbitant damage. To mitigate these security threats, basic embedded locking features are provided in smart devices. However, these locking features are vulnerable. In this paper, an original security-locking scheme using a rhythm-based locking system (RLS) is proposed to overcome the existing security problems of smart devices. RLS is a user-authenticated system that addresses vulnerability issues in the existing locking features and provides secure confidentiality in addition to convenience.

We studied the modulating effect of protein tyrosine kinase inhibitors on the response of cells of the human chronic myelogenous leukemia cell line K562 to radiation. The radiosensitivity of the cells was increased by treatment with herbimycin A and decreased by treatment with genistein. This modulating effect of protein tyrosine kinase inhibitors on radiation sensitivity was associated with the alteration of the mode of radiation-induced cell death. After X irradiation, the cells arrested in the G(2) phase of the cell cycle, but these TP53(-/-) cells were unable to sustain cell cycle arrest. This G(2)-phase checkpoint deficit caused cell death. The morphological pattern of cell death was characterized by swelling of the cytoplasmic compartments, cytosolic vacuolation, disruption of the plasma membrane, less evident nuclear condensation, and faint DNA fragmentation, all of which were consistent with oncosis or cytoplasmic apoptosis. The nonreceptor protein tyrosine kinase inhibitor herbimycin A accelerated the induction of typical apoptosis by X irradiation, which was demonstrated by morphological assessments using nuclear staining and electron microscopy as well as oligonucleosomal fragmentation and caspase 3 activity. Herbimycin A is known to be a selective antagonist of the BCR/ABL kinase of Philadelphia chromosome-positive K562 cells; this kinase blocks the induction of apoptosis after X irradiation. Our results showed that the inhibition of protein tyrosine kinase by herbimycin A enhanced radiation-induced apoptosis in K562 cells. This effect was associated with the activation of caspase 3 and rapid abrogation of the G(2)-phase checkpoint with progression out of G(2) into G(1) phase. In contrast, the receptor-type protein tyrosine kinase inhibitor genistein protected K562 cells from all types of radiation-induced cell death through the inhibition of caspase 3 activity and prolonged maintenance of G(2)-phase arrest. Further investigations using this model may give valuable information about the mechanisms of radiation-induced apoptosis and about the radiosensitivity and radioresistance of chronic myelogenous leukemia cells having the Philadelphia chromosome.

The telecare medical information systems (TMISs) support convenient and rapid health-care services. A secure and efficient authentication scheme for TMIS provides safeguarding patients' electronic patient records (EPRs) and helps health care workers and medical personnel to rapidly making correct clinical decisions. Recently, Kumari et al. proposed a password based user authentication scheme using smart cards for TMIS, and claimed that the proposed scheme could resist various malicious attacks. However, we point out that their scheme is still vulnerable to lost smart card and cannot provide forward secrecy. Subsequently, Das and Goswami proposed a secure and efficient uniqueness-and-anonymity-preserving remote user authentication scheme for connected health care. They simulated their scheme for the formal security verification using the widely-accepted automated validation of Internet security protocols and applications (AVISPA) tool to ensure that their scheme is secure against passive and active attacks. However, we show that their scheme is still vulnerable to smart card loss attacks and cannot provide forward secrecy property. The proposed cryptanalysis discourages any use of the two schemes under investigation in practice and reveals some subtleties and challenges in designing this type of schemes.

A novel immunostimulating factor (ISTF) ofActinobacillus actinomycetemcomitansATCC 29522 was isolated and characterized as inducing proliferation of mouse B cells and human peripheral blood mononuclear cells. This factor was isolated from the bacterial culture medium and purified by size exclusion chromatography, dye-ligand affinity chromatography, immunoaffinity chromatography using monoclonal antibodies, and preparative electrophoresis. Analysis by sodium dodecyl sulfate-polyacrylamide gel electrophoresis revealed that the purified ISTF migrated as a single band corresponding to a molecular mass of 13 kDa. ISTF was a proteinaceous material distinct from lipopolysaccharide; it directly induced the proliferation of B lymphocytes but had no effect on the proliferation of T lymphocytes, even in the presence of antigen-presenting cells. A B-lymphocyte-mitogenic activity of ISTF was also shown by flow cytometric analysis of responding cell subpopulations. Immunoblot analysis revealed that ISTF was a component of the outer membranes of bacteria, could exist as a soluble form, and was released by growing and/or lysed bacteria. These results suggest that ISTF produced byA. actinomycetemcomitansmay play an important role in immunopathologic changes associated withA. actinomycetemcomitansinfections.

AIM: To investigate anxiety and depression propensities in patients with toxic liver injury. METHODS: The subjects were divided into three groups: a healthy control group (Group 1, n = 125), an acute non-toxic liver injury group (Group 2, n = 124), and a group with acute toxic liver injury group caused by non-commercial herbal preparations (Group 3, n = 126). These three groups were compared and evaluated through questionnaire surveys and using the Hospital Anxiety-Depression Scale (HADS), Beck Anxiety Inventory (BAI), Beck Depression Inventory (BDI), and the hypochondriasis scale. RESULTS: The HADS anxiety subscale was 4.9 ± 2.7, 5.0 ± 3.0 and 5.6 ± 3.4, in Groups 1, 2, and 3, respectively. The HADS depression subscale in Group 3 showed the most significant score (5.2 ± 3.2, 6.4 ± 3.4 and 7.2 ± 3.4 in Groups 1, 2, and 3, respectively) (P < 0.01 vs Group 1, P < 0.05 vs Group 2). The BAI and BDI in Group 3 showed the most significant score (7.0 ± 6.3 and 6.9 ± 6.9, 9.5 ± 8.6 and 8.8 ± 7.3, 10.7 ± 7.2 and 11.6 ± 8.5 in Groups 1, 2, and 3, respectively) (BAI: P < 0.01 vs Group 1, P < 0.05 vs Group 2) (BDI: P < 0.01 vs Group 1 and 2). Group 3 showed a significantly higher hypochondriasis score (8.2 ± 6.0, 11.6 ± 7.5 and 13.1 ± 6.5 in Groups 1, 2, and 3, respectively) (P < 0.01 vs Group 1, P < 0.05 vs Group 2). CONCLUSION: Psychological factors that present vulnerability to the temptation to use alternative medicines, such as herbs and plant preparations, are important for understanding toxic liver injury.

Among cancer patients, cancer-related fatigue (CRF) is one of the most common symptoms and adversely affects physical ability and quality of life even several years after treatment. This study aims to evaluate the current evidence for moxibustion in patients with CRF. Eighteen databases were searched from their inception to April 2013. All randomized controlled trials (RCTs) of moxibustion for treating CRF without language restriction were considered for inclusion. The risk of bias and reporting quality of each study were assessed using the Cochrane risk of bias tool, Consolidated Standards of Reporting Trials (CONSORT), and Revised Standards for Reporting Interventions in Clinical Trials of Acupuncture (STRICTA). Risk ratio (RR) or mean difference (MD) was used to measure the treatment effect with 95 % confidence intervals (CIs) in a random effects model. Four RCTs with a total of 374 subjects were included for the review. These four studies compared moxibustion plus routine care with routine care alone. Most studies were determined to have a moderate to high risk of bias with low reporting quality. An indirect moxa stick was used in two studies, an indirect ginger cake-separated moxa was used in one study, and in one remaining study, both moxibustion methods were used. Meta-analysis showed the favorable effects of moxibustion on the response rate (RR, 1.73; 95 % CI, 1.29 to 2.32; p = .0003; heterogeneity, I 2 = 15 %, p = .32). Burning with a mild blister after moxibustion was reported in one study. Because of a high risk of bias and low reporting quality of the studies included in this review, it is difficult to draw the conclusion that moxibustion is an effective and safe treatment for patients with CRF. Further rigorous research will be necessary to evaluate whether moxibustion has beneficial effects on CRF. PROSPERO. Unique identifier: CRD42013004501.

Background WIN-34B is a novel Oriental medicine, which represents the n-butanol fraction prepared from dried flowers of Lonicera japonica Thunb and dried roots of Anemarrhena asphodeloides BUNGE. The component herb of WIN-34B is used for arthritis treatment in East Asian countries. The aim of this study was to determine the cartilage-protective effects and mechanisms of WIN-34B and its major phenolic compounds, chlorogenic acid and mangiferin, in osteoarthritis (OA) human cartilage explants culture and chondrocytes. Methods The investigation focused on whether WIN-34B and its standard compounds protected cartilage in interleukin (IL)-1β-stimulated cartilage explants culture and chondrocytes derived from OA patients. Also, the mechanisms of WIN-34B on matrix metalloproteinases (MMPs), tissue inhibitor of matrix metalloproteinases (TIMPs), inflammatory mediators, and mitogen-activated protein kinases (MAPKs) pathways were assessed. Results WIN-34B was not cytotoxic to cultured cartilage explants or chondrocytes. WIN-34B dose-dependently inhibited the release of glycosaminoglycan and type II collagen, increased the mRNA expression of aggrecan and type II collagen, and recovered the intensity of proteoglycan and collagen by histological analysis in IL-1β-stimulated human cartilage explants culture. The cartilage protective effect of WIN-34B was similar to or better than that of chlorogenic acid and mangiferin. Compared to chlorogenic acid and mangiferin, WIN-34B displayed equal or greater decreases in the levels of MMP-1, MMP-3, MMP-13, ADAMTS-4, and ADAMTS-5, and markedly up-regulated TIMP-1 and TIMP-3. WIN-34B inhibited inflammatory mediators involved in cartilage destruction, such as prostaglandin E2, nitric oxide, tumor necrosis factor-alpha, and IL-1β. The phosphorylation of extracellular signal-regulated kinase, c-Jun N-terminal kinase (JNK), and p38 was significantly reduced by WIN-34B treatment, while phosphorylation of JNK was only inhibited by chlorogenic acid or mangiferin in IL-1β-stimulated chondrocytes. Conclusions WIN-34B is potentially valuable as a treatment for OA by virtue of its suppression of MMPs, ADAMTSs, and inflammatory mediators, and it’s up-regulation of TIMP-1 and TIMP-3 involved in the MAPK pathway.

Cordycepin (3'-deoxyadenosine), a major bioactive compound of Cordyceps militaris, has many pharmacological actions, such as anti-inflammatory and anticancer activities. In this study, the relationship between inhibition of cell motility and anti-invasive activity by cordycepin in LNCaP human prostate carcinoma cells was investigated. Within the concentration range that was not cytotoxic, cordycepin time-dependently inhibited cell motility and invasiveness of LNCaP cells. The inhibitory effects of cordycepin on cell invasiveness were associated with tightening of tight junctions (TJs), which was demonstrated by an increase in transepithelial electrical resistance (TER). Immunoblotting indicated that cordycepin decreases levels of claudin proteins, which are major components of TJs that play a key role in control and selectivity of paracellular transport. Furthermore, cordycepin inhibited the expression and activity of matrix metalloproteinase (MMP)-2 and MMP-9, and simultaneously increased levels of tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2. These effects were related to inactivation of the phosphoinositide 3-kinase (PI3K)/Akt pathway in LNCaP cells. These findings suggest that cordycepin inhibits the migration and invasion of LNCaP cells by downregulating the activity of TJs and MMPs, possibly in association with suppression of Akt activation.

The purpose of this review is to provide an overview of the effects that natural products have on inflammatory bowel disease (IBD) and to provide insight into the relationship between these natural products and cytokines modulation. More than 100 studies from the past 10 years were reviewed herein on the therapeutic approaches for treating IBD. The natural products having anti-IBD actions included phytochemicals, antioxidants, microorganisms, dietary fibers, and lipids. The literature revealed that many of these natural products exert anti-IBD activity by altering cytokine production. Specifically, phytochemicals such as polyphenols or flavonoids are the most abundant, naturally occurring anti-IBD substances. The anti-IBD effects of lipids were primarily related to the n-3 polyunsaturated fatty acids. The anti-IBD effects of phytochemicals were associated with modulating the levels of tumor necrosis factor α (TNF-α), interleukin (IL)-1, IL-6, inducible nitric oxide synthase, and myeloperoxide. The anti-IBD effects of dietary fiber were mainly mediated via peroxisome proliferator-activated receptor-γ, TNF-α, nitric oxide, and IL-2, whereas the anti-IBD effects of lactic acid bacteria were reported to influence interferon-γ, IL-6, IL-12, TNF-α, and nuclear factor-κ light-chain enhancer of activated B cells. These results suggest that the anti-IBD effects exhibited by natural products are mainly caused by their ability to modulate cytokine production. However, the exact mechanism of action of natural products for IBD therapy is still unclear. Thus, future research is needed to examine the effect of these natural products on IBD and to determine which factors are most strongly correlated with reducing IBD or controlling the symptoms of IBD.

Chitosan, which is derived from chitin, has drawn much attention due to its low toxicity and potential use in medical and pharmaceutical applications. The biological activities of chitosan have been shown to depend on its molecular weight (MW) and degree of deacetylation. In this study, we investigated whether oral chitooligosaccharides, which are easily absorbed into the body, can reduce the plasma level of lipid in smokers and non-smokers because smoking is a high-risk factor for cardiovascular diseases. All healthy men (11 smokers and 8 non-smokers) consumed 500 mg of chitooligosaccharides in water twice daily before a meal (breakfast and dinner) over a 6-week period. Total cholesterol and low-density lipoprotein cholesterol levels were significantly decreased in both the smoker group and non-smoker group when compared with baseline. These results suggest that low MW chitooligosaccharides would be an effective dietary supplement for lowering cholesterol level.

Ethnopharmacological relevance Traditional medicine has widely been used Betula platyphylla var. japonica to treat various inflammatory diseases including arthritis. Aim of the study To determine the anti-inflammatory, anti-nociceptive, and anti-arthritic effects of Betula platyphylla in interleukin-1β (IL-1β)-stimulated fibroblast-like synoviocytes from human rheumatoid arthritis and in nociceptive and inflammatory animal model. Materials and methods The inflammatory mediators such as IL-6, tumor necrosis factor (TNF)-α matrix metalloproteinase (MMP)-1, MMP-13, inducible nitric oxide synthesis (iNOS), nitrites, prostaglandin E2 (PGE2) and cyclo-oxygenase 2 (COX-2) activity of Betula platyphylla were tested in IL-1β-stimulated fibroblast-like synoviocytes. Tail withdrawal in response to thermal stimulation in tail flick test or paw flinching and shaking in response to sc hind paw formalin injection was measured 1 h after oral administration of Betula platyphylla. The former was evaluated with a paw pressure test, and the latter was measured using the squeaking score, and paw volume in inflammatory arthritis tests. Results Betula platyphylla significantly inhibited proliferation of IL-1β-induced synoviocytes. Betula platyphylla reduced the levels of inflammatory mediators, such as IL-6, TNF-α, MMP-1, MMP13, and PGE2. In particular, Betula platyphylla significantly inhibited the releases of nitrites and iNOS, as well as release of NFκB, into the nucleus of IL-1β-treated synoviocytes, even at concentrations as low as 1 μg/ml. Oral administrant of Betula platyphylla at 400 mg/kg significantly decreased about 27.8% of tail flick withdrawal and inhibited about the number of paw flinches in both phases 1 and 2 of the formalin test. In the carrageenan-induced acute pain and arthritis model, Betula platyphylla dose dependently reduced the nociceptive threshold and the arthritic symptoms at day 8, respectively, and Betula platyphylla at 400 mg/kg markedly reduced the inflammatory area about 48% in the ankle joints. This capacity of Betula platyphylla at 400 mg/kg was similar to that of the celecoxib-2 inhibitor in carrageenan-induced nociceptive and inflammatory arthritis model. Conclusions These results suggest that Betula platyphylla has anti-nociceptive and anti-inflammatory effects in IL-1β-stimulated RA FLS and in an animal model of arthritis. Thus, the use of Betula platyphylla as a pharmaceutical candidate for the treatment of arthritis should be further studied.

Ethnopharmacological relevance OAH19T, a new herbal extract from a mixture of Aralia cordata Thunb and Cimicifuga heracleifolia, is traditionally used for the treatment of arthritis in far East Asia. To investigate the chondroprotective effects of OAH19T on osteoarthritis was examined and compared with its major compounds pimaradienoic acid (PA) and ferulic acid (FA) of human osteoarthritis (OA) chondrocytes. Materials and methods Chondrocytes, alone or in the presence of IL-1β, were cultured with or without OAH19T, PA or FA (10, 20, 40 μg/ml). The release of sulfated glycosaminoglycan (GAG) was measured by colorimetric assay using 1,9-dimethylmethylene blue (DMB) reagent from the cultured media. The level of aggrecanases and VEGF was measured by reverse transcription polymerase chain reaction (RT-PCR). The expression of MMP-1 and MMP-3 analyzed by real time RT-PCR and enzyme-linked immunosorbent assay (ELISA). The phosphorylation of mitogen-activated protein kinases was performed by immunoblotting in OA chondrocytes. The proliferation was examined by the BrdU assay. Results OAH19T markedly inhibited the release of proteoglycan and the degradation of aggrecan, in a dose-dependent manner in OA chondrocytes. OAH19T also inhibited the level of aggrecanase-1, aggrecanase-2, MMP-1, MMP-3, and VEGF in OA chondrocytes. PA and FA also inhibited the level of aggrecanase-2, MMP-3 and VEGF, while did not significantly affect the levels of aggrecanase-1, MMP-3 in OA chondrocytes. OAH19T exhibited the down-regulation of p38 MAP kinase unlike PA and FA in OA chondrocytes without cytotoxicity. In addition, p38 inhibitor SB203580 abolished the antiproliferative activity and proteoglycan degradation by OAH19T, while had no effect by PA or FA. Conclusion OAH19T have shown the chondroprotective effect by inhibiting cell proliferation, expression of cartilage-specific matrix proteinases and release of VEGF, but bigger than PA or FA, through down-regulation of p38 MAP kinase in human OA chondocyte. These results provide pharmacological basis for use in treatment of OA.

Objective Incomplete recovery from facial palsy has a long-term impact on the quality of life, and medical options for the sequelae of Bell's palsy are limited. Invasive treatments and physiotherapy have been employed to relieve symptoms, but there is limited clinical evidence for their effectiveness. Acupuncture is widely used on Bell's palsy patients in East Asia, but there is insufficient evidence for its effectiveness on Bell's palsy sequelae. The objective is to evaluate the efficacy and safety of acupuncture in patients with sequelae of Bell's palsy. Method/Design This study consists of a randomized controlled trial with two parallel arms: an acupuncture group and a waitlist group. The acupuncture group will receive acupuncture treatment three times per week for a total of 24 sessions over 8 weeks. Participants in the waitlist group will not receive any acupuncture treatments during this 8 week period, but they will participate in the evaluations of symptoms at the start of the study, at 5 weeks and at 8 weeks after randomization, at which point the same treatment as the acupuncture group will be provided. The primary outcome will be analyzed by the change in the Facial Disability Index (FDI) from baseline to week eight. The secondary outcome measures will include FDI from baseline to week five, House-Brackmann Grade, lip mobility, and stiffness scales. Trial registration Current Controlled-Trials ISRCTN43104115; registration date: 06 July 2010; the date of the first patient's randomization: 04 August 2010

Formononetin, a phytoestrogen from the root of Astragalus membranaceus, is used as a blood enhancer and to improve blood microcirculation in complementary and alternative medicine. The present study investigated the influence of formononetin on the expression of early growth response factor-1 (Egr-1) and growth factors contributing to wound healing. Formononetin significantly increased growth factors such as transforming growth factor-beta 1 (TGF-β1), vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF) and basic fibroblast growth factor (bFGF) in human umbilical vein endothelial cells (HUVECs). Formononetin also increased the expression of Egr-1 transcription factor by 3.2- and 10.5-fold, compared with recombinant VEGF(125) in HUVECs. The formononetin-mediated 12%-43% increase induced endothelial cell proliferation and recovered the migration of wounded HUVECs. In an ex vivo angiogenesis assay, formononetin produced a larger capillary sprouting area than produced using recombinant VEGF(125). Cell proliferation and migration of HUVECs were also greater in the presence of formonectin than VEGF(125). Western blot analysis of scratch-wounded confluent HUVECs showed that formononetin induced the phosphorylation of extracellular signal-regulated kinase (ERK) and slightly inhibited the phosphorylation of p38 mitogen-activated protein kinase (MAPK). The formononetin-mediated sustained activation of Egr-1 was suppressed by the ERK inhibitor PD98059 and the p38 inhibitor SB203580. PD98059 inhibited the formononetin-induced endothelial proliferation and repair in scratch-wounded HUVECs, SB203580 increased the cell proliferation and wound healing. Formononetin accelerate wound closure rate as early as day 3 after surgery and consistently observed until day 10 after in wound animal model. These data suggest that formononetin promotes endothelial repair and wound healing in a process involving the over-expression of Egr-1 transcription factor through the regulation of the ERK1/2 and p38 MAPK pathways.

Ethnopharmacological relevance Traditional medicine has been widely using Phellodendron amurense Rupr. (Rutaceae) to treat various inflammatory diseases including arthritis. Aim of the study This study investigated the effects of Phellodendron amurense in protecting cartilage, including regulating the levels of aggrecanases, matrix metalloproteinases (MMPs)/tissue inhibitor of metalloproteinase (TIMP), proinflammatory cytokines and signaling of the mitogen activated protein kinase (MAPK) pathway in human osteoarticular cartilage and chondrocytes. Materials and methods Explants from human osteoarthritis cartilage were cultured alone or in IL-1α for 7 days with or without Phellodendron amurense ethanol extract or celecoxib (40, 100, 200 μg/ml). The effect of Phellodendron amurense on matrix degradation induced by IL-1α in human articular cartilage was assessed by staining, and the quantities of sulfated glycosaminoglycan (GAG) and type II collagen were calculated from the culture media. The levels of aggrecanases, MMPs, TIMP, and PGE2 in the culture media were investigated using an enzyme-linked immunosorbent assay (ELISA). In addition, reverse transcription polymerase chain reaction (RT-PCR) evaluated the mRNA expression of aggrecanases, MMPs and TIMP. Furthermore, Western blot analysis was performed to identify the roles that Phellodendron amurense played in the ERK, JNK and p38 signaling pathways. Results Phellodendron amurense showed no evident cytotoxicity on human articular cartilage. Phellodendron amurense significantly inhibited the IL-1α-induced degradation of GAG and type II collagen from human osteoarticular cartilage in a concentration-dependent manner. Celecoxib did not significantly inhibit IL-1α-induced release of GAG and only slightly reduced type II collagen. Phellodendron amurense also dose-dependently decreased the levels of aggrecanase-1 and -2, MMP-1, -3, and -13, whereas it increased TIMP-1 expression in human osteoarticular cartilage. Celecoxib only decreased MMP-1 and MMP-13 levels in human osteoarticular cartilage. In addition, Phellodendron amurense reduced the phosphorylation of extracellular signal regulated kinase (ERK)1/2, Jun NH2-terminal kinase (JNK) and activated phospho-p38 MAPK in a dose-dependent manner in human osteoarthritic chondrocytes. Conclusions Phellodendron amurense inhibited osteoarticular cartilage and chondrocyte destruction by inhibiting proteoglycan release and type II collagen degradation, down-regulating aggrecanases, MMP activities and phospho-ERK1/2, JNK and p38 MAP kinase signaling, and up-regulating TIMP-1 activity. Therefore, our results suggest that Phellodendron amurense is a potential therapeutic agent to protect cartilage against OA progression.

Up-regulation of telomerase activity is associated with immortalization and unlimited cell division in most cancer cells. Therefore, telomerase represents a particularly attractive target for anticancer therapy. Recent reports have suggested that beta-lapachone (LAPA), the product of the South American Tabebuia avellanedae tree, inhibits growth of tumor cells. However, the underlying relationship between telomerase activity and apoptosis in response to LAPA exposure in leukemia cells remains poorly understood. In this study, we confirmed that LAPA treatment induces direct cytotoxicity in human leukemia cells (U937, K562, HL60, and THP-1) through activation of caspase-3 and subsequent cleavage of poly(ADP-ribose) polymerase. The observed induction of cell death was associated with decreased telomerase activity, which was ascribed to down-regulation of telomerase reverse transcriptase. Additionally, overexpression of anti-apoptotic Bcl-2 could not overcome the induction of apoptosis or the decreased telomerase activity in response to treatment of U937 cells with LAPA. We conclude that LAPA has a direct cytotoxic effect and the loss of telomerase activity in leukemia cells.

Osteoarthritis is a multifactorial disease characterized by loss of articular cartilage and subchondral plate thickening. Therefore, biochemical analysis of the underlying bone tissue has provided important information for treatment of osteoarthritis. In this study, we determined the potential role of formononetin, a phytoestrogen isolated from Astragalus membranaceus to alter the expression of metabolic markers and cytokine production of human normal osteoblasts (Obs) and osteoarthritis subchondral osteoblasts (OA Obs). Human OA Obs and normal Obs were cultured for 3days, 7days or 14days in the present medium only or were treated with various doses of formononetin. Cells were analyzed for viability by WST-8 assay, alkaline phosphatase (ALP) activity, osteogenic markers (osteocalcin (OCN) and type I collagen (Col I)) and cytokines (interleukin-6 (IL-6), vascular endothelial growth factor (VEGF), bone morphogenic protein-2 (BMP-2)). The level of IL-6, VEGF, BMP-2, OCN and Col I was increased in OA Obs compared with normal Obs. Formononetin dose-dependently decreased ALP, IL-6, VEGF, BMP-2, OCN and Col I in OA Obs, while markedly increased ALP, VEGF, BMP-2, OCN and Col I in normal Obs. Interestingly, formononetin markedly increased the expression of VEGF and BMP-2 for 3days of culture and significantly increased OCN and Col I at 14days in human normal Obs. The remodeling effect of formononetin on osteogenic markers and cytokines of inflammatory mediators was more striking in OA Obs as well. Taken together, these results could suggest that formononetin has biphasic positive effects on normal Obs and OA Obs by modifying their biological synthetic capacities.

Complementary and alternative medicine, Cinnamomum cassia is one of the medicinal plants that have been used to improve various diseases caused by insufficient blood circulation. However, relatively little work has been carried out on the angiogenic responses of C. cassia and its active compound cinnamic acid (CA), despite its excellent pharmacological action. In this study, we study the effect of the ethanol extract of C. cassia (CCE) and its active compound CA, on angiogenic processes in in vitro and in vivo. In the Matrigel plug assay in vivo, CCE and CA dose dependently increased von Willebrand Factor (vWF) antigen expression, and hemoglobin contents, whose elevation paralleled the onset of angiogenesis and was considered an early indicator of endothelial activation. CCE and CA induced endothelial cells proliferation, migration and tubule-like structure in vitro. The 25-50% increase observed with CCE (at low doses of 1 or 10 ng/ml) in HUVEC and BAEC proliferation was similar to that observed with CA. The migration and tubule-like structure effect were observed with HUVEC and BAEC. However, the effect of CCE, CA and VEGF on cell proliferation, migration and tubule-like structure in HUVEC were bigger than the effect of CCE, CA and VEGF in BAEC. In addition, CCE and CA each induced 2.2-fold and 2.5-fold increases the production of VEGF, the mRNA expression of VEGF and Flk-1/KDR, the receptor involved in proliferation, migration, and tubule-like structure of endothelial cells. These data suggest that CCE and its active compound CA induce angiogenesis in vivo and in vitro, and this pathway is related with VEGF and Flk-1/KDR expression of endothelial cells.