Natural Herb Mixture Extract Accelerates Osteogenic Differentiation of Human Bone Marrow-Derived Mesenchymal Stem Cells by Activating the SMAD Pathway.

We aimed to analyze the effects and explore the molecular mechanisms of a natural herb mixture extract (NME) on osteoblasts during differentiation in human bone marrow-derived mesenchymal stem cells (hBMSCs). We tried to confirm the regulation of osteogenic differentiation during NME treatment. Alkaline phosphatase assay and Alizarin red S staining were performed to evaluate the regulation of osteogenic differentiation. Real-time polymerase chain reaction was performed to analyze the expression of osteoblast maker genes, and Western blot was used to verify the signaling pathway. Signaling pathway conformation, selective bone morphogenetic protein receptor inhibitor, and dorsomorphin homolog 1 were used as pretreatments before inducing osteogenic differentiation. We determined that MME (natural herb mixture extract) was a safe material and significantly increased osteoblast differentiation and that SMAD phosphorylation is a key signaling pathway that regulates osteogenic differentiation in hBMSCs.

National practice patterns and direct medical costs for prostate cancer in Korea across a 10 year period: a nationwide population-based study using a national health insurance database.

BACKGROUND: A complete enumeration study was conducted to evaluate trends in national practice patterns and direct medical costs for prostate cancer (PCa) in Korea over a 10-year retrospective period using data from the Korean National Health Insurance Service. METHODS: Reimbursement records for 874,924 patients diagnosed between 2002 and 2014 with primary PCa according to the International Classification of Disease (ICD) 10th revision code C61 were accessed. To assess direct medical costs for patients newly diagnosed after 2005, data from 68,596 patients managed between January 2005 and 31 December 2014 were evaluated. RESULTS: From 2005 to 2014, the total number of PCa patients showed a 2.6-fold increase. Surgery and androgen deprivation therapy were the most common first-line treatment, alone or within the context of combined therapy. Surgery as a monotherapy was performed in 23.5% of patients in 2005, and in 39.4% of patients in 2014. From 2008, the rate of robot-assisted RP rose sharply, showing a similar rate to open RP in 2014. Average total treatment costs in the 12 months post-diagnosis were around 10 million Korean won. Average annual treatment costs thereafter were around 5 million Korean won. Out-of-pocket expenditure was highest in the first year post-diagnosis, and ranged from 12 to 17% thereafter. CONCLUSIONS: Between 2005 and 2014, a substantial change was observed in the national practice pattern for PCa in Korea. The present data provide a reliable overview of treatment patterns and medical costs for PCa in Korea.

Medical Travel among Non-Seoul Residents to Seek Prostate Cancer Treatment in Medical Facilities of Seoul.

PURPOSE: This study aims to investigate the trend in medical travel by non-Seoul residents to Seoul for treatment of prostate cancer and also to investigate the possible factors affecting the trend. MATERIALS AND METHODS: This study represents a retrospective cohort study using data from theKoreanNationalHealth Insurance System from 2002 to 2015. Annual trends were produced for proportions of patients who traveled according to the age group, economic status and types of treatment. Multiple logistic analysiswas used to determine factors affecting surgeries at medical facilities in Seoul among the non-Seoul residents. RESULTS: A total of 68,543 patients were defined as newly diagnosed prostate cancer cohorts from 2005 to 2014. The proportion of patients who traveled to Seoul for treatment, estimated from cases with prostate cancer-related claims, decreased slightly over 9 years (28.0 at 2005 and 27.0 at 2014, p=0.02). The average proportion of medical travelers seeking radical prostatectomy increased slightly but the increase was not statistically significant (43.1 at 2005 and 45.4 at 2014, p=0.26). Income level and performance ofrobot-assisted radical prostatectomy were significant positive factors for medical travel to medical facilities in Seoul. Combined comorbidity diseases and year undergoing surgery were significant negative factors for medical travel to medical facilities in Seoul. CONCLUSION: The general trend of patients travelling from outside Seoul for prostate cancer treatment decreased from 2005 to 2014. However, a large proportion of traveling remained irrespective of direct distance from Seoul.

The Flavonoid Jaceosidin from Artemisia princeps Induces Apoptotic Cell Death and Inhibits the Akt Pathway in Oral Cancer Cells.

Jaceosidin is a single compound from the Japanese mugwort Artemisia princeps, which is used as a food and a traditional medicinal herb. A. princeps extracts and flavonoid components have been shown to have antihyperglycaemic, antioxidant, and anti-inflammatory properties. Although the anticancer properties of these extracts were recently demonstrated, the related mechanisms have not been characterised. In this study, we investigated the effects of jaceosidin in oral squamous cell carcinoma (OSCC) cells and initially showed selective suppression of proliferation (IC50 = 82.1 µM in HSC-3 cells and 97.5 µM in Ca9.22 cells) and accumulation of cells at the sub-G1 stage of the cell cycle. In addition, jaceosidin increased cleavage of caspase-9 and caspase-3 in OSCC cells, although caspase-8 was not detected. In further experiments, jaceosidin downregulated Akt phosphorylation and ectopic activation of Akt blocked the antiproliferative effects of jaceosidin. Finally, we showed that jaceosidin has no effects on HaCaT normal epithelial cell viability, indicating selective chemotherapeutic potential of jaceosidin and that tumour-specific downregulation of Akt increases apoptosis and inhibits growth in OSCC cells.

Kochia scoparia induces apoptosis of oral cancer cells in vitro and in heterotopic tumors.

ETHNOPHARMACOLOGICAL RELEVANCE: Kochia scoparia grows commonly in China, Japan, and Korea and its mature fruit has been used throughout the area in traditional medicine to treat diseases including skin problems and inflammatory and allergic disease. More importantly, Kochia scoparia has been prescribed to treat the malignant tumor of head and neck region and breast mass. Although it has been proposed as an anti-cancer agent for several cancers, its exact in vivo anti-cancer properties and the molecular mechanisms underlying its effects are poorly understood. AIM OF THE STUDY: To evaluate the anti-cancer activity of the methanol extract of K. scoparia, mature fruit (MEKS) on oral squamous cell carcinoma (OSCC) and to explore its mode of action. MATERIALS AND METHODS: To assess proliferation inhibition and apoptosis induction by MEKS, MTT assays, cell analysis, ANNEXIN V and PI double staining, and Hoechst 33342 staining were performed. The activation of caspases and the MAP kinase p38 was evaluated using Western blot analysis. The anti-cancer properties of MEKS in vivo were elucidated in a heterotopic OSCC animal model. RESULTS: After OSCC cells were treated with MEKS, the numbers of sub-G1 accumulated cells and apoptotic bodies increased, indicating that MEKS inhibited OSCC cell proliferation selectively through induction of apoptosis. Apoptosis of MEKS-treated OSCC cells was induced in a dose-dependent manner by caspase-3 and -9 activation. In addition, pretreatment with p38 inhibitor SB203580 in combination with MEKS significantly prevented MEKS-induced apoptosis in OSCC cells and also decreased cleaved capase 3, 9, and cleaved PARP activity in western blotting. MEKS treatment significantly increased the apoptosis of OSCC and inhibited tumour growth in our animal model. CONCLUSION: Taken together, these results indicated that MEKS induced apoptosis of OSCC cells through caspase activation involving the p38 MAPK pathway. MEKS could be a promising anti-cancer candidate for OSCC treatment.

Clinical outcomes and prognostic factors of patients with advanced hepatocellular carcinoma treated with sorafenib as first-line therapy: a Korean multicenter study.

BACKGROUND AND AIM: Sorafenib is recommended as a standard treatment for advanced hepatocellular carcinoma (HCC). The efficacy and safety of sorafenib as a first-line therapy in Korean patients with advanced HCC were investigated. METHODS: From 2007 to 2012, 86 patients with advanced HCC (Barcelona Clinic Liver Cancer stage C) treated with sorafenib as a first-line therapy were enrolled from five tertiary hospitals. Predictors of overall survival (OS) and progression-free survival (PFS) were analyzed. RESULTS: The median age was 59.5 years, and 71 (82.6%) were males; 57 (66.3%) patients were in Child-Pugh class A. The median OS and PFS were 5.0 (range 4.0-5.9) and 3.2 (range 2.6-3.7) months, respectively. Regarding OS, Child-Pugh class A (6.0 vs 2.8 months), tumor diameter < 5 cm (6.0 vs 4.3 months), baseline α-fetoprotein < 200 ng/mL (5.8 vs 4.1 months), and the advent of hand-foot-skin reaction of ≥ grade 2 (5.9 vs 4.0 months) were independent favorable predictors (all P < 0.05). Similarly, regarding PFS, Child-Pugh class A (4.3 vs 2.1 months), tumor diameter < 5 cm (3.9 vs 2.8 months), baseline α-fetoprotein < 200 ng/mL (5.6 vs 2.8 months), and the advent of hand-foot-skin reaction of ≥ grade 2 (4.5 vs 2.6 months) were independent favorable predictors (all P < 0.05). All toxicities during sorafenib treatment were manageable. CONCLUSIONS: Because the efficacy of sorafenib seems marginal in Korean patients with treatment-naïve HCC, how to select candidates with favorable outcomes should be further investigated.

Does supplementation of in-vitro culture medium with melatonin improve IVF outcome in PCOS?

Human pre-ovulatory follicular fluid (FF) contains a higher concentration of melatonin than serum. The aim of this study was to evaluate the effect of melatonin supplementation of culture medium on the clinical outcomes of an in-vitro maturation (IVM) IVF-embryo transfer programme for patients with polycystic ovarian syndrome (PCOS). Melatonin concentrations in the culture media of granulosa cells (GC) or cumulus-oocyte-complexes (COC) were measured and the clinical outcomes after using IVM media with or without melatonin were analysed. In the culture media of GC or COC, melatonin concentrations gradually increased. When human chorionic gonadotrophin priming protocols were used, implantation rates in the melatonin-supplemented group were higher than those of the non-supplemented control group (P<0.05). Pregnancy rates were also higher, although not significantly. The findings suggest that the addition of melatonin to IVM media may improve the cytoplasmic maturation of human immature oocytes and subsequent clinical outcomes. It is speculated that follicular melatonin may be released from luteinizing GC during late folliculogenesis and that melatonin supplementation may be used to improve the clinical outcomes of IVM IVF-embryo transfer. Melatonin is primarily produced by the pineal gland and regulates a variety of important central and peripheral actions related to circadian rhythms and reproduction. Interestingly, human pre-ovulatory follicular fluid contains a higher concentration of melatonin than serum. However, in contrast to animal studies, the direct role of melatonin on oocyte maturation in the human system has not yet been investigated. So, the aim of the study was to evaluate the effect of melatonin supplementation of culture medium on the clinical outcome of an in-vitro maturation (IVM) IVF-embryo transfer programme for PCOS patients. The melatonin concentrations in culture medium of granulosa cells (GC) or cumulus-oocyte-complexes (COC) were measured and the clinical outcomes of IVM IVF-embryo transfer using IVM medium alone or supplemented with melatonin were analysed. In the culture media of GC or COC, the melatonin concentration gradually increased. With human chorionic gonadotrophin priming, the pregnancy and implantation rates in the melatonin-supplemented group were higher than those of the non-supplemented control (P<0.05). Our findings suggest that follicular melatonin is released from luteinizing GC during late folliculogenesis and plays a positive role in oocyte maturation. Therefore, addition of melatonin into IVM medium may improve cytoplasmic maturation of human immature oocytes and subsequent clinical outcomes.

Targeted chemo-photothermal treatments of rheumatoid arthritis using gold half-shell multifunctional nanoparticles.

We have developed RGD-attached gold (Au) half-shell nanoparticles containing methotrexate (MTX) for the treatment of rheumatoid arthritis (RA), where MTX is the most widely used disease-modifying anti-rheumatic drug (DMARD) for the treatment of RA, and RGD peptide is a targeting moiety for inflammation. Upon near-infrared (NIR) irradiation, heat is locally generated due to Au half-shells, and the drug release rate is enhanced, delivering heat and drug to the inflamed joints simultaneously. RA is a chronic inflammatory disease characterized by synovial inflammation in multiple joints within the penetration depth of NIR light. When combined with NIR irradiation, these nanoparticles containing a much smaller dosage of MTX (1/930 of MTX solution) showed greater therapeutic effects than that of a conventional treatment with MTX solution in collagen-induced arthritic mice. This novel drug delivery system is a good way to maximize therapeutic efficacy and minimize dosage-related MTX side effects in the treatment of RA. Furthermore, these multifunctional nanoparticles could be applied to other DMARDs for RA or other inflammatory diseases.

Integrated microfluidics platforms for investigating injury and regeneration of CNS axons.

We describe the development of experimental platforms to quantify the regeneration of injured central nervous system (CNS) neurons by combining engineering technologies and primary neuronal cultures. Although the regeneration of CNS neurons is an important area of research, there are no currently available methods to screen for drugs. Conventional tissue culture based on Petri dish does not provide controlled microenvironment for the neurons and only provide qualitative information. In this review, we introduced the recent advances to generate in vitro model system that is capable of mimicking the niche of CNS injury and regeneration and also of testing candidate drugs. We reconstructed the microenvironment of the regeneration of CNS neurons after injury to provide as in vivo like model system where the soluble and surface bounded inhibitors for regeneration are presented in physiologically relevant manner using microfluidics and surface patterning methods. The ability to control factors and also to monitor them using live cell imaging allowed us to develop quantitative assays that can be used to compare various drug candidates and also to understand the basic mechanism behind nerve regeneration after injury.

Overactive bladder is not only overactive but also hypersensitive.

OBJECTIVES: To evaluate differences in bladder filling sensations and current perception threshold (CPT) values between patients with and without overactive bladder (OAB), and to further investigate the correlation between CPT values and voiding patterns in OAB patients. METHODS: Detrusor overactivity and bladder volumes at first sensation of bladder filling, first desire to void, and strong desire to void during filling cystometry were compared between 55 female patients with OAB and 42 with non-OAB. CPT measurements from the bladder mucosa taken after neuroselective electrostimulation at frequencies of 2000, 250, and 5 Hz were compared between the 2 groups. In OAB patients, the correlations between CPT values and voiding variables based on 3-day bladder diaries were investigated. RESULTS: OAB patients showed significantly more detrusor overactivity than non-OAB patients (P <.05). Bladder volumes at first sensation of bladder filling, first desire to void, and strong desire to void were significantly lower in OAB patients than in non-OAB patients (P <.05). CPT values at all 3 frequencies were also significantly lower in OAB patients (P <.05). The total number of urgency episodes correlated with CPT values at 250 (r = -0.274, P = .045) and 5 Hz (r = -0.293, P = .032). The total number of urge incontinence episodes also correlated with CPT values at 250 (r = -0.279, P = .041) and 5 Hz (r = -0.272, P = .046). CONCLUSIONS: Bladder sensory profiles displayed a more sensitive bladder in OAB patients compared with non-OAB subjects. OAB patients may have bladders that are not only overactive, but also hypersensitive.

Inhibitory effects of Stewartia koreana on osteoclast differentiation and bone resorption.

Osteoclasts are responsible for bone lysis in several bone diseases such as osteoporosis and rheumatoid arthritis. Natural products from plants have been invaluable source in discovery of compounds for new therapies. In this study, we screened plant products for potential application to therapy for bone loss using a primary osteoclastogenesis culture system and found that extract of Stewartia koreana (SKE) had a strong inhibitory effect on osteoclast formation. To gain molecular insights, we examined the effect of SKE on signaling pathways and transcription factors stimulated by the osteoclast differentiation factor RANKL. SKE suppressed the induction of c-Fos and NFATc1 by RANKL. However, SKE did not inhibit NF-kappaB activation by RANKL. Among the MAPKs stimulated by RANKL, SKE significantly reduced the activation of ERK and p38. Therefore, the anti-osteoclastogenic effect of SKE is likely to be elicited by interference with RANKL signaling to ERK and p38, which mediate the induction of c-Fos and subsequently that of NFATc1. Consistent with the in vitro effect on osteoclast differentiation, SKE showed a great inhibitory effect on in vivo bone loss in LPS-challenged mice. Taken together, we demonstrated that SKE has inhibitory effects on osteoclast differentiation in vitro and confirmed its in vivo efficacy in prevention of inflammatory bone loss.