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Cremastranone is a member of the homoisoflavanone family with anti-angiogenic activity in the eyes. SH-11037, a potent and selective synthetic homoisoflavonoid derived from cremastranone, was studied here for pharmacokinetics and metabolism characterization with a special focus on esterase-mediated hydrolysis. SH-11037 was shown to be converted rapidly and nearly completely to SH-11008 following an intravenous dose in mice. SH-11008 showed a high systemic clearance well exceeding the hepatic blood flow in mice. Neither SH-11037 nor SH-11008 were detected in plasma following oral administration of SH-11037 and SH-11008 in mice. Carboxylesterase was shown to be responsible for the rapid and quantitative hydrolysis of SH-11037 to SH-11008 in mouse plasma; the hydrolytic bioconversion was much slower in dog and human plasma, with butyrylcholinesterase and paraoxonase 1 likely being responsible. In vitro metabolism studies with liver S9 fractions suggested that SH-11008 was likely to have a high hepatic metabolic clearance with a predicted hepatic extraction ratio close to 1 in both mouse and human. In conclusion, SH-11037 and SH-11008 both appear to possess pharmacokinetic profiles suboptimal as a systemic agent. SH-11008 is suggested to possess a low potential for systemic toxicity suitable as a topical ocular therapeutic agent.

Angiogenesis should be precisely regulated because disordered neovascularization is involved in the aggravation of multiple diseases. The vascular endothelial growth factor (VEGF)-A/VEGF receptor 2 (VEGFR-2) axis is crucial for controlling angiogenic responses in vascular endothelial cells (ECs). Therefore, inactivating VEGFR-2 signaling may effectively suppress aberrant angiogenesis and alleviate related symptoms. In this study, we performed virtual screening, identified the synthetic disaccharide 6′-sialylgalactose (6SG) as a potent VEGFR-2-binding compound and verified its high binding affinity by Biacore assay. 6SG effectively suppressed VEGF-A-induced VEGFR-2 phosphorylation and subsequent in vitro angiogenesis in HUVECs without inducing cytotoxicity. 6SG also inhibited VEGF-A-induced extracellular-regulated kinase (ERK)/Akt activation and actin stress fiber formation in HUVECs. We demonstrated that 6SG inhibited retinal angiogenesis in a mouse model of retinopathy of prematurity and tumor angiogenesis in a xenograft mouse model. Our results suggest a potential therapeutic benefit of 6SG in inhibiting angiogenesis in proangiogenic diseases, such as retinopathy and cancer., Abnormal blood vessel formation: Synthetic disaccharide shows therapeutic promise Therapy based on a synthetic molecule can block abnormal blood vessel formation, limiting the progression of diabetic eye conditions and tumor growth in mice. The growth of new blood vessels from existing vessels, called angiogenesis, is critical to wound healing and embryonic development. The main angiogenesis signalling pathway involves growth factors, including one called VEGFR-2. Disruption to this pathway plays a significant part in the development of multiple diseases. A South Korean team led by Ki-Tae Ha at Pusan National University, Yangsan, and Young Jun Koh at Dongguk University, Seoul, identified and trialed a synthetic disaccharide capable of binding to and limiting the activity of VEGFR-2 during faulty signaling. Trials on mice with the diabetic eye condition retinopathy, and mice with implanted tumors, showed that the compound inhibited excessive angiogenesis and limited disease progression.

Benign prostatic hyperplasia (BPH), a common disease in elderly males, is accompanied by non-malignant growth of prostate tissues, subsequently causing hypoxia and angiogenesis. Although VEGF-related angiogenesis is one of the therapeutic targets of prostate cancer, there is no previous study targeting angiogenesis for treatment of BPH. Dihydrotestosterone (DHT)- induced expressions of vascular endothelial growth factor (VEGF) in prostate epithelial RWPE-1 cells and human umbilical vascular endothelial cells (HUVECs). Conditioned media (CM) from DHT-treated RWPE-1 cells were transferred to HUVECs. Then, 6SL inhibited proliferation, VEGFR-2 activation, and tube formation of HUVECs transferred with CM from DHT-treated RWPE-1 cells. In the rat BPH model, 6SL reduced prostate weight, size, and thickness of the prostate tissue. Formation of vessels in prostatic tissues were also reduced with 6SL treatment. We found that 6SL has an ameliorative effect on in vitro and in vivo the BPH model via inhibition of VEGFR-2 activation and subsequent angiogenesis. These results suggest that 6SL might be a candidate for development of novel BPH drugs. [BMB Reports 2019; 52(9): 560-565].

Molecular glue degraders, such as lenalidomide and pomalidomide, bind to cereblon (CRBN) E3 ligase and subsequently recruit neosubstrate proteins, Ikaros (IKZF1) and Aiolos (IKZF3), for the ubiquitination-proteasomal degradation process. In this study, we explored structure-activity relationship analysis for novel GSPT1 degraders utilizing a benzotriazinone scaffold previously discovered as a novel CRBN binder. In particular, we focused on the position of the ureido group on the benzotriazinone scaffold, substituent effect on the phenylureido group, and methyl substitution on the benzylic position of benzotriazinone. As a result, we identified 34f (TD-522), which exhibits strong anti-proliferative effects in both KG-1 (EC

Background and objectives We evaluated the changes in natural killer cell activity (NKA) during the entire treatment period of patients with resectable biliopancreatic cancers and investigated the predictors of the failure of recovery of NKA after surgery. Methods A total of 202 patients who underwent curative resection for biliopancreatic cancer were enrolled in the study. NKA levels were measured six times during the treatment period. We investigated whether there was any difference in postoperative NKA recovery according to the period-by-time NKA value. Results NKA decreased after surgery (mean, 40 pg/ml) compared to the NKA value at admission (200.2 pg/ml), then began to increase from 3 weeks after surgery (139.7 pg/ml) and rose to normal NKA levels at 5 weeks (217.1 pg/ml). The pattern of NKA changes was distinct according to the NKA values at admission. In multivariate analysis, NKA values of less than 250 pg/ml at admission (odds ratio = 5.898, p = 0.044) were a predictor of NKA recovery failure 5 weeks after surgery. Conclusions NKA rapidly decreased after curative surgery for biliopancreatic cancer and recovered to normal levels about 5 weeks later. Clinicians should be aware and cautious that patients with low NKA at admission may fail to recover NKA postoperatively.

Mealworm and mealworm oil (MWO) have been reported to affect antioxidant, anti-coagulation, anti-adipogenic and anti-inflammatory activities. However, the function of MWO in wound healing is still unclear. In this study, we found that MWO induced the migration of fibroblast cells and mRNA expressions of wound healing factors such as alpha-smooth muscle actin (α-SMA), collagen-1 (COL-1) and vascular endothelial growth factor (VEGF) in fibroblast cells. The tube formation and migration of endothelial cells were promoted through the activation of VEGF/VEGF receptor-2 (VEGFR-2)-mediated downstream signals including AKT, extracellular signal-regulated kinase (ERK) and p38 by MWO-stimulated fibroblasts for angiogenesis. Moreover, we confirmed that MWO promoted skin wound repair by collagen synthesis, re-epithelialization and angiogenesis in an in vivo excisional wound model. These results demonstrate that MWO might have potential as a therapeutic agent for the treatment of skin wounds.

The Warburg effect, wherein cancer cells prefer glycolysis rather than oxidative phosphorylation even under normoxic conditions, is a major characteristic of malignant tumors. Lactate dehydrogenase A (LDHA) is the main enzyme regulating the Warburg effect, and is thus, a major target for novel anti-cancer drug development. Through our ongoing screening of novel inhibitors, we found that several selenobenzene compounds have inhibitory effects on LDHA activity. Among them, 1-(phenylseleno)-4-(trifluoromethyl) benzene (PSTMB) had the most potent inhibitory effect on the enzymatic activity of LDHA. The results from biochemical assays and computational modeling showed that PSTMB inhibited LDHA activity. In addition, PSTMB inhibited the growth of several tumor cell lines, including NCI-H460, MCF-7, Hep3B, A375, HT29, and LLC. In HT29 human colon cancer cells, PSTMB dose-dependently inhibited the viability of the cells and activity of LDHA, without affecting the expression of LDHA. Under both normoxic and hypoxic conditions, PSTMB effectively reduced LDHA activity and lactate production. Furthermore, PSTMB induced mitochondria-mediated apoptosis of HT29 cells via production of reactive oxygen species. These results suggest that PSTMB may be a novel candidate for development of anti-cancer drugs by targeting cancer metabolism.

본 연구는 여자청소년의 쉼터 퇴소 후 자립경험에 대해 질적연구를 하였으며 자료분석은 Van Manen의 현상학적 연구 방법을 통해 자립경험을 시간성, 공간성, 신체성, 관계성을 중심으로 분석하여 그 본질을 드러내도록 하였다. 연구 참여자 8명의 자료를 통해 분석한 결과 쉼터 퇴소 후 자립경험은 ‘세상과 동거하기’,‘생을 포기하고 싶은 순간’,‘실패와 고통의 허물벗기’,‘마음으로 홀로서기’,‘나로 살아가기’의 5가지 본질과 12개의 주제를 도출할 수 있었다. 또한 체험한 공간의 경험은 ‘퇴소후의 공간’,‘다시 쉼터로’, 체험한 시간은 ‘외로움의 시간’,‘후회의 시간’,‘발견의 시간’,‘다시 시작하는 시간’으로 경험되었다. 체험한 신체는 ‘고통스러운 몸’,‘수용하는 몸’으로 표현되었고 체험한 관계성은‘만들어가는 관계’,‘유지하는 관계’로 정리하였다. 쉼터 퇴소 여자청소년의 자립경험의 본질은‘모나고 거친 돌이 풍파에 깍이어 둥글어 지는 것’이었다. 쉼터 퇴소 청소년의 자립경험은 순환적이며 다양한 실패와 경험의 반복을 통해 만들어지는 자립의 과정이었다. 이를 바탕으로 쉼터기능이 충분한 자립을 준비하여 성인기 과업을 수행할 수 있도록 개인별 특성과 사례에 따라 탄력적으로 운영할 수 있는 이용자 중심의 기능전환이 필요하며 체계적이고 지속적인 사후관리가 필요하다. 또한 퇴소청소년의 자립경험에서 가족은 중요한 기반이 되고 있어 가족기능을 강화하는 정부차원의 정책마련과 쉼터 현장의 다양한 교육과 접근방법 등의 실질적인 대안들이 개발되어야 할 것이다.

Cinnamomum cassia Blume has been widely reported as the anti-tumor agent. However, the precise mechanism underlying its pro-apoptotic action is still not clear. Restraining aerobic glycolysis through suppression of pyruvate dehydrogenase kinase (PDHK) is a promising strategy for cancer inhibition. In this study, we performed to investigate the anti-tumor action of C. cassia is mediated by PDHK inhibition. The inhibition of water-extracted branch of C. cassia (WBCC) on the activity of PDHK using both in vitro and cell-based kinase assay were examined in several lung cancer cells. WBCC reduced viabilities of several lung cancer cells with minimal cytotoxicity on normal bronchial epithelial cells. WBCC decreased lactate production through inhibiting activity of PDHK. In consequence of PDHK inhibition, WBCC increased ROS production, which damage mitochondria membrane stability. In addition, WBCC induced ROS- and mitochondria-dependent apoptotic cell death. Among the components of WBCC, cinnamic acid was founded as a major inhibitor on PDHK activity. This is first report that WBCC induces apoptosis of lung cancer cells through inhibiting PDHK activity. Our findings suggest that WBCC and cinnamic acid can be potential candidates for developing novel anti-cancer drugs through glycolysis metabolism. Keywords: Cinnamomum cassia, Pyruvate dehydrogenase kinase, Aerobic glycolysis, Apoptosis, Cinnamic acid

Among the herbal ingredients of HangAmDan-B, a medicinal formula that redirects macrophages to become tumoricidal effectors, we found that Panax notoginseng (Burk.) F. H. Chen is the active component responsible for its macrophage-mediated antitumor activity. The water extracted roots of P. notoginseng (PN) did not affect the viability of RAW264.7 murine macrophage-like cells and murine Lewis lung carcinoma (LLC) cells up to a concentration of 100[Formula: see text][Formula: see text]g/mL. However, the transfer of culture media from PN-treated RAW264.7 cells suppressed the growth of LLC cells. The expression of classically activated (M1) markers, such as interleukin (IL)-1[Formula: see text], monocyte chemotactic protein (MCP)-1, tumor necrosis factor (TNF)-[Formula: see text], and inducible nitric oxide synthase (iNOS), was increased by PN treatment. The expression of alternatively activated (M2) markers including CD206, IL-10, and [Formula: see text]-[Formula: see text]-acetylhexosaminidases (YM-1) was reduced by PN treatment in the presence of IL-4. Flow cytometry also revealed that PN drives M1 activation of RAW264.7 cells. The transfer of culture media from PN-treated RAW264.7 cells induced the apoptosis of LLC cells as measured by flow cytometry using Annexin-V staining and western blot analysis for caspase cascade-related proteins. In addition, the results from in vivo tumor allograft model demonstrated that PN reduced both tumor volume and weight. The activation of macrophages toward an M1 phenotype was confirmed in the tumor allograft tumor model. These results collectively show that PN can serve as a potent anticancer agent through reeducation of macrophages toward an M1 phenotype.

(1S,5R)-4-((E)-3,4-dihydroxy-5-methoxystryryl)-6,6-dimethylbicylco[3.1.1]hept-3-en-2-one (SP-8356) is a novel (1S)-(−)-verbenone derivative that is currently in preclinical development for the treatment of ischemic stroke and atherosclerosis. This report aimed at characterization of the metabolism and pharmacokinetic properties of SP-8356. Following intravenous dose in rats and dogs, plasma concentrations of SP-8356 declined rapidly with high clearance (CL) and short half-life; after oral administration in both species, its plasma levels were below the quantitation limit. Fourteen circulating metabolites, formed by mono-oxygenation, demethylation, glucuronidation, catechol O-methylation, sulfation and oxidation (bioactivation) followed by glutathione (GSH) conjugation, were tentatively identified in both species. Urinary excretion of SP-8356 appeared to be minimal in rats, compared to its metabolites. GSH conjugate of SP-8356 was also formed during incubation with rat liver S9 fraction consistent with oxidative bioactivation; this bioactivation was almost completely inhibited by the cofactors for glucuronidation, sulfation and methylation, indicating that it may be abolished by competing metabolic reactions in the body. The human pharmacokinetics of SP-8356 was predicted to be similar to that of the animals based on the current in vitro metabolic stability results. In summary, rapid phase II metabolism appears to be mainly responsible for its suboptimal pharmacokinetics, such as high CL and low oral absorption. Because of competing metabolic reactions, potential safety risks related to SP-8356 bioactivation may be low.

Background: 6&prime, Sialyllactose (6SL) displays a wide range of the bioactive benefits, such as anti-proliferative and anti-angiogenic activities. However, the therapeutic effects of 6SL on benign prostatic hyperplasia (BPH) remain unknown. Methods: Six-week-old male Wistar rats (n = 40) were used for in vivo experiments. All rats were castrated and experimental BPH was induced in castrated rats by intramuscular injection of testosterone, with the exception of those in the control group. Rats with BPH were administrated finasteride and 0.5 or 1.0 mg/kg 6SL. Furthermore, the inhibitory effects of 6SL on human epithelial BPH cell line (BPH-1) cells were determined in vitro. Results: Rats with BPH exhibited outstanding BPH manifestations, including prostate enlargement, histological alterations, and increased prostate-specific antigen (PSA) levels. Compared to those in the BPH group, rats in the 6SL group showed fewer pathological changes and normal androgen events, followed by restoration of retinoblastoma protein (pRb) and cell cycle-related proteins. In BPH-1 cells, treatment with 6SL significantly suppressed the effects on the androgen receptor (AR), PSA, and E2F transcription factor 1 (E2F1)-dependent cell cycle protein expression. Conclusions: 6SL demonstrated anti-proliferative effects in a testosterone-induced BPH rat model and on BPH-1 cells by regulating the pRB/E2F1&ndash, AR pathway. According to our results, we suggest that 6SL may be considered a potential agent for the treatment of BPH.

BACKGROUND AND OBJECTIVES To assess the prognostic significance of postoperative changes in immune status represented by total lymphocyte count (TLC) and neutrophil-to-lymphocyte ratio (NLR) in resectable pancreatic cancer. METHODS Patients who underwent curative pancreatectomy for pancreatic adenocarcinoma were divided into high and low groups according to cut-off values of TLC, and NLR measured preoperatively, immediately after surgery, and 1 or 6 months after surgery. Oncologic outcomes were compared between the two groups at different times, and prognostic roles of TLC and NLR were evaluated. RESULTS Of 193 patients, the median follow-up time was 22 months, and median survival was 18 months. Their immunologic status deteriorated within 3 to 4 days after the operation and recovered after that. At 1 and 6 months postoperatively, overall survival rates were significantly lower in the group with high NLR (>2.535 and >3.21, respectively) and low TLC (

Lactate dehydrogenase A (LDHA) is an important enzyme responsible for cancer growth and energy metabolism in various cancers via the aerobic glycolytic pathway. Here, we report that machilin A (MA), which acts as a competitive inhibitor by blocking the nicotinamide adenine dinucleotide (NAD) binding site of LDHA, suppresses growth of cancer cells and lactate production in various cancer cell types, including colon, breast, lung, and liver cancers. Furthermore, MA markedly decreased LDHA activity, lactate production, and intracellular adenosine triphosphate (ATP) levels induced by hypoxia-induced LDHA expression in cancer cells, and significantly inhibited colony formation, leading to reduced cancer cell survival. In mouse models inoculated with murine Lewis lung carcinoma, MA significantly suppressed tumor growth as observed by a reduction of tumor volume and weight, resulting from the inhibition of LDHA activity. Subsequently, the suppression of tumor-derived lactic acid in MA-treated cancer cells resulted in decrease of neovascularization through the regulation of alternatively activated macrophages (M2) polarization in macrophages. Taken together, we suggest that the reduction of lactate by MA in cancer cells directly results in a suppression of cancer cell growth. Furthermore, macrophage polarization and activation of endothelial cells for angiogenesis were indirectly regulated preventing lactate production in MA-treated cancer cells.

Breast cancer exhibits high lethality in women because it is frequently detected at an advanced stage and aggressive forms such as triple-negative breast cancer (TNBC), which are often characterized by metastasis through colonization of secondary tumors. Thus, developing therapeutic agents that target the metastatic process is crucial to successfully treat aggressive breast cancer. We evaluated SP-8356, an anti-inflammatory synthetic verbenone derivative, with respect to its regulation of breast cancer cell behavior and cancer progression. Treatment of SP-8356 arrested cell cycle and reduced growth in various types of breast cancer cells with mild cytotoxicity. Particularly, SP-8356 significantly reduced the motility and invasiveness of TNBC cells. Assays using an in vivo xenograft mouse model confirmed the cell-specific anti-proliferative and anti-metastatic activity of SP-8356. Functional studies revealed that SP-8356 suppressed serum response element-dependent reporter gene expression and NF-κB-related signaling, resulting in downregulation of many genes related to cancer invasion. We conclude that SP-8356 suppresses breast cancer progression through multimodal functions, including inhibition of NF-κB signaling and growth-related signaling pathways.

Introduction To assess the prognostic significance of postoperative changes in immune status represented by total lymphocyte count (TLC) and neutrophil-to-lymphocyte ratio (NLR) in resectable pancreatic cancer. Methods Patients who underwent curative pancreatectomy for pancreatic adenocarcinoma were divided into high and low groups according to cut-off values of TLC, and NLR measured preoperatively, immediately after surgery, and 1- or 6-month after surgery. Oncologic outcomes were compared between the two groups at different times, and prognostic roles of TLC and NLR were evaluated. Results Of 193 patients, the median follow-up time was 22 months, and median survival was 18 months. Their immunologic status deteriorated within 3-4 days after the operation and recovered after that. At 1- and 6-month postoperatively, overall survival rates were significantly lower in the group with high NLR (> 2.535 and > 3.21, respectively) and low TLC (< 1.66 × 109/L and < 1.62 × 109/L, respectively). In multiple regression analysis, elevated NLR at postoperative 1- and 6-month and decreased TLC at postoperative 1-month were significant prognosis predictors. Conclusions Changes in immune status such as decreased TLC and elevated NLR at postoperative 1- and 6-month are effective prognostic predictors after curative pancreatectomy in patients with pancreatic adenocarcinoma.

The leaves and stems of Perilla frutescens var. acuta Kudo (PF) have been used to prevent threatened abortion in traditional medicine in the East Asian countries. Because reduced receptivity of endometrium is a cause of abortion, we analyzed the action of PF on the endometrial receptivity. PF increased the level of leukemia inhibitory factor (LIF), a major cytokine regulating endometrial receptivity, and LIF receptor in human endometrial Ishikawa cells. The PF-induced LIF expression was mediated by c-jun N-terminal kinase (JNK) and p38 pathways. Adhesion between Ishikawa cells and trophoblastic JAr cells stimulated by PF treatment was abolished by knock down of LIF expression or antagonism of LIFR. In addition, the expressions of integrin beta 3 and beta 5 were increased by PF treatment in Ishikawa cells. The PF-induced expression of integrin beta 3 and beta 5 was reduced with an LIFR antagonist. Neutralization of both integrins successfully blocked PF-stimulated adhesion of JAr cells and Ishikawa cells. These results suggest that PF enhanced the adhesion between Ishikawa cells and JAr cells by increasing the expression of integrin b3 and b5 via an LIF-dependent pathway. Given the importance of endometrial receptivity in successful pregnancy, PF can be a novel and effective candidate for improving pregnancy rate. (C) 2016 The Authors. Production and hosting by Elsevier B.V. on behalf of Japanese Pharmacological Society.

In our previous study, Hwang-Ryun-Hae-Dok-Tang, which contains berberine (BBR) as a main active ingredient, inhibited cytochrome P450 (CYP) 2D6 in a quasi-irreversible manner. However, no information is available on the detailed mechanism of BBR-induced CYP2D6 inhibition. Thus, the present study aimed to characterize the inhibition mode and kinetics of BBR and its analogues against CYP2D6 using pooled human liver microsomes (HLM). BBR exhibited selective quasi-irreversible inhibition of CYP2D6 with inactivation rate constant (kinact) of 0.025 min&minus, 1, inhibition constant (KI) of 4.29 &micro, M, and kinact/KI of 5.83 mL/min/&micro, mol. In pooled HLM, BBR was metabolized to thalifendine (TFD), demethyleneberberine (DMB), M1 (proposed as demethylene-TFD), and to a lesser extent berberrubine (BRB), showing moderate metabolic stability with a half-life of 35.4 min and a microsomal intrinsic clearance of 7.82 &micro, L/min/mg protein. However, unlike BBR, those metabolites (i.e., TFD, DMB, and BRB) were neither selective nor potent inhibitors of CYP2D6, based on comparison of half-maximal inhibitory concentration (IC50). Notably, TFD, but not DMB, exhibited metabolism-dependent CYP2D6 inhibition as in the case of BBR, which suggests that methylenedioxybenzene moiety of BBR may play a critical role in the quasi-irreversible inhibition. Moreover, the metabolic clearance of nebivolol (&beta, blocker, CYP2D6 substrate) was reduced in the presence of BBR. The present results warrant further evaluation of BBR&ndash, drug interactions in clinical situations.

The objective of this study was to characterize pharmacokinetics and metabolism of (±)-cremastranone (CMT) in mouse. Plasma concentrations of CMT following a single oral dose (10 mg/kg) were all below quantitation limit throughout 24-h time course, indicating poor oral bioavailability. Its plasma levels declined rapidly, with a half-life (t

IMPORTANCE: Primary care is increasingly delivered at or near workplaces, yet utilization and cost of employer-sponsored primary care services remain unknown. OBJECTIVE: To compare the health care utilization and cost of an employer-sponsored on-site, near-site, and virtual comprehensive primary care service delivery model with those of traditional community-based primary care. DESIGN, SETTING, AND PARTICIPANTS: This population-based cohort study of 23 518 commercially insured employees and dependents of an engineering and manufacturing firm headquartered in southern California was performed from January 1, 2016, to July 1, 2019. A subset of the population with most (≥50%) primary care visits through employer-sponsored on-site, near-site, or virtual care clinics was matched to a subset not having most such visits through the employer-sponsored clinics using propensity score matching (n = 1983 each). In sensitivity analyses, employees were matched to dependents at neighboring firms that lacked access to the employer-sponsored primary care delivery model (additional n = 1680). EXPOSURES: Integrated primary care, mental health, and physical therapy delivered through on-site, near-site, and virtual clinics. MAIN OUTCOMES AND MEASURES: Utilization (inpatient, outpatient, emergency department, pharmaceutical, radiology, and laboratory visits per 1000 member-months) and spending (2019 costs per member per month in US dollars) by service type. RESULTS: A total of 23 518 individuals (mean [SD] age, 27 [15] years; 14 604 [62.1%] male) were included in the full population sample and had been enrolled in the employer-sponsored health plan for a mean of 29 months (interquartile range, 14-48 months). Of eligible members, 5292 (22.5%) used the employer-sponsored services, with 2305 (9.8%) using them for most of their primary care. The mean (SD) cost of employer-sponsored service delivery was $87 ($32) per member month. Among the matched populations (mean [SD] age, 31 [11] years; 3349 [84.5%] male) of primary users vs control individuals, total spending was 45% lower per member per month (95% CI, 35%-55%; cost difference, −$167 per member per month; 95% CI, −$204 to −$130; P

(1S,5R)-4-((E)-3,4-dihydroxy-5-methoxystryryl)-6,6-dimethylbicylco[3.1.1]hept-3-en-2-one (SP-8356) is a novel (1S)-(&minus, )-verbenone derivative that is currently in preclinical development for the treatment of ischemic stroke and atherosclerosis. This report aimed at characterization of the metabolism and pharmacokinetic properties of SP-8356. Following intravenous dose in rats and dogs, plasma concentrations of SP-8356 declined rapidly with high clearance (CL) and short half-life, after oral administration in both species, its plasma levels were below the quantitation limit. Fourteen circulating metabolites, formed by mono-oxygenation, demethylation, glucuronidation, catechol O-methylation, sulfation and oxidation (bioactivation) followed by glutathione (GSH) conjugation, were tentatively identified in both species. Urinary excretion of SP-8356 appeared to be minimal in rats, compared to its metabolites. GSH conjugate of SP-8356 was also formed during incubation with rat liver S9 fraction consistent with oxidative bioactivation, this bioactivation was almost completely inhibited by the cofactors for glucuronidation, sulfation and methylation, indicating that it may be abolished by competing metabolic reactions in the body. The human pharmacokinetics of SP-8356 was predicted to be similar to that of the animals based on the current in vitro metabolic stability results. In summary, rapid phase II metabolism appears to be mainly responsible for its suboptimal pharmacokinetics, such as high CL and low oral absorption. Because of competing metabolic reactions, potential safety risks related to SP-8356 bioactivation may be low.

Background Previous studies have reported that higher serum uric acid (SUA) levels are associated with higher bone mineral density (BMD) in men and postmenopausal women, and lower risk of fragility fracture in men. However, whether this association is also present in patients with rheumatoid arthritis (RA) has not yet been investigated. Objectives To examine the association of SUA levels with BMD and osteoporosis in postmenopausal women with RA. Methods We retrospectively evaluated 447 postmenopausal female RA patients (mean age 61.1 years) who underwent measurement of L1–4, femoral neck, and total hip BMD using dual energy X-ray absorptiometry, in addition to SUA levels at a university rheumatology centre in South Korea between 2004 and 2017. Osteoporosis was defined as a T-score of ≤−2.5 according to the World Health Organisation classification. Results The median (interquartile range) SUV level was 4 (3.3–4.8) mg/dL. The mean (±SD) L1–4, femoral neck, and total hip BMD were 0.93±0.16 g/cm2, 0.75±0.12 g/cm2, and 0.81±0.12 g/cm2, respectively, and the frequencies of osteoporosis in the spine, hip, and either site were 25.6%, 15.9%, and 32.5%, respectively. SUA levels were positively correlated with L1–4 (ρ=0.102, p=0.032), femoral neck (ρ=0.123, p=0.01), and total hip BMD values (ρ=0.146, p=0.002) and body mass index (ρ=0.231, p Conclusions Higher SUA levels were associated with a reduced risk of low BMD and osteoporosis at hip in postmenopausal women with RA, but no significant association between SUA levels and lumbar spine BMD was found. Our data suggests that uric acid may act as a protective factor against hip bone loss in RA patients. Disclosure of Interest None declared

Eye diseases characterized by excessive angiogenesis such as wet age-related macular degeneration, proliferative diabetic retinopathy, and retinopathy of prematurity are major causes of blindness. Cremastranone is an antiangiogenic, naturally occurring homoisoflavanone with efficacy in retinal and choroidal neovascularization models and antiproliferative selectivity for endothelial cells over other cell types. We undertook a cell-based structure-activity relationship study to develop more potent cremastranone analogues, with improved antiproliferative selectivity for retinal endothelial cells. Phenylalanyl-incorporated homoisoflavonoids showed improved activity and remarkable selectivity for retinal microvascular endothelial cells. A lead compound inhibited angiogenesis in vitro without inducing apoptosis and had efficacy in the oxygen-induced retinopathy model in vivo.

Aerobic glycolysis is one of the important metabolic characteristics of many malignant tumors. Pyruvate dehydrogenase kinase (PDHK) plays a key role in aerobic glycolysis by phosphorylating the E1&alpha, subunit of pyruvate dehydrogenase (PDH). Hence, PDHK has been recognized as a molecular target for cancer treatment. Here, we report that huzhangoside A (Hu.A), a triterpenoid glycoside compound isolated from several plants of the Anemone genus, acts as a novel PDHK inhibitor. Hu.A was found to decrease the cell viability of human breast cancer MDA-MB-231, hepatocellular carcinoma Hep3B, colon cancer HT-29, DLD-1, and murine lewis lung carcinoma LLC cell lines. The activity of PDHK1 was decreased by Hu.A in both in vitro assays and in vivo assays in DLD-1 cells. Hu.A significantly increased the oxygen consumption and decreased the secretory lactate levels in DLD-1 cells. In addition, Hu.A interacted with the ATP-binding pocket of PDHK1 without affecting the interaction of PDHK1 and pyruvate dehydrogenase complex (PDC) subunits. Furthermore, Hu.A significantly induced mitochondrial reactive oxygen species (ROS) and depolarized the mitochondrial membrane potential in DLD-1 cells. Consistently, when Hu.A was intraperitoneally injected into LLC allograft mice, the tumor growth was significantly decreased. In conclusion, Hu.A suppressed the growth of tumors in both in vitro and in vivo models via inhibition of PDHK activity.

Small amounts of allyl isocyanate modified graphene (iG, 0–2.5 phr) were incorporated into acrylate terminated polyurethane (PU) by UV curing. The effects of this incorporation on the morphological, mechanical, thermal and shape memory properties of the nanocomposites were examined. The iG nanoparticles incorporated into the PU chains acted as both multifunctional crosslinkers and reinforcing fillers, and the effects were most pronounced at 1.5 phr iG. Consequently, the glassy and rubbery state moduli, yield strength, glass transition temperature ( T g ), shape fixity and shape recovery ratios were increased by adding up to 1.5 phr iG. Above the loadings, most of the above properties decreased due to aggregation and the auto-inhibition reaction of allyl compounds.

Ethnopharmacological relevance Anemone rivularis Buch.-Ham. ex DC. (Ranunculaceae) have been used as a traditional remedy for treatment of inflammation and cancer. However, there is no report demonstrating experimental evidence on anti-tumor action of A. rivularis. Aim of study The Warburg's effect, preference of aerobic glycolysis rather than oxidative phosphorylation (OXPHOS) even in oxygen rich condition, is focused as one of major characteristics of malignant tumor. Thus, we investigated the effect of A. rivularis on the Pyruvate dehydrogenase (PDH) kinases (PDHKs), a major molecular targets for reducing aerobic glycolysis. Materials and methods The ethanol extract of whole plant of A. rivularis (ARE), fingerprinted by high performance liquid chromatography (HPLC), was applied to in vitro and cell-based PDHK activity assays. The effect of ARE on cell viabilities of several tumor cells was estimated by MTT assay. The expression of phosphor-PDH, PDH and PDHK1 were measured by Western blot analysis. The production of reactive oxygen species (ROS) and apoptosis was measured by fluorescence-activated cell sorting analysis, using 5-(and-6)-carboxy-2′,7′-dichlorodihydrofluorescein diacetate (carboxy-H2DCFDA) and Annexin V/propidium iodide (PI) staining, respectively. Mitochondrial membrane potential was examined by tetramethylrhodamine methyl ester (TMRM) staining. In vivo anti-tumor efficacy of ARE was estimated by means of tumor volume and weight using allograft injection of murine Lewis lung carcinoma (LLC) cells to dorsa of C57BL/6 mice. Results ARE inhibited the viabilities of several cancer cells, including MDA-MB321, K562, HT29, Hep3B, DLD-1, and LLC. ARE suppressed PDHK activity in in vitro kinase assay, and also inhibited aerobic glycolysis by reducing phosphorylation of PDHA in human DLD-1 colon cancer and murine LLC cells. The expression of PDHK1, a major isoform of PDHKs in cancer, was not affected by ARE treatment. Moreover, ARE increased the both ROS production and mitochondrial damage. In addition, ARE suppressed the in vitro tumor growth through mitochondria-mediated apoptosis. The growth rates of allograft LLC cells were also reduced by ARE treatment. Conclusions Here, we firstly report that ARE inhibits PDHK activity and growth of tumor in both in vitro and in vivo experiments. Therefore, we suggest ARE as a potential candidate for developing anti-cancer drugs.

Most cancer cells predominantly produce ATP by maintaining a high rate of lactate fermentation, rather than by maintaining a comparatively low rate of tricarboxylic acid cycle, i.e., Warburg’s effect. In the pathway, the pyruvate produced by glycolysis is converted to lactic acid by lactate dehydrogenase (LDH). Here, we demonstrated that water extracts from the seeds of Myristica fragrans Houtt. (MF) inhibit the in vitro enzymatic activity of LDH. MF effectively suppressed cell growth and the overall Warburg effect in HT29 human colon cancer cells. Although the expression of LDH-A was not changed by MF, both lactate production and LDH activity were decreased in MF-treated cells under both normoxic and hypoxic conditions. In addition, intracellular ATP levels were also decreased by MF treatment, and the uptake of glucose was also reduced by MF treatment. Furthermore, the experiment on tumor growth in the in vivo mice model revealed that MF effectively reduced the growth of allotransplanted Lewis lung carcinoma cells. Taken together, these results suggest that MF effectively inhibits cancer growth and metabolism by inhibiting the activity of LDH, a major enzyme responsible for regulating cancer metabolism. These results implicate MF as a potential candidate for development into a novel drug against cancer through inhibition of LDH activity.

In this study, we demonstrate the preparation of nanocapsules using the self-assembly of preformed polymers at the interface of a three-way controlled laminated stream flow in a microchannel. The production process occurs without the use of surfactants and allows the regulation of nanocapsule size with solvent recycling. Problems associated with nanocapsule attachment to the channel surface disturbing the lamination flow and producing nanocapsules of poor quality were overcome by altering the microchannel aspect ratio. The aspect ratio was altered by considering the mixing ratio and velocity distribution on the cross section along the microchannel. Modeling and practical experiment identified the aspect ratio of the microchannel of 1.6 as producing clear lamination flow. Ovalbumin-encapsulated nanocapsules were produced with a narrow size distribution of

Leukemia inhibitory factor (LIF) is a member of the IL-6 cytokine family, having pleiotropic actions such as maintaining stem cell pluripotency and enabling blastocyst implantation. Because the action of LIF is mediated by a ligand-receptor interaction with the LIF receptor (LIF-R), an antagonist for LIF-R has been developed to inhibit LIF-induced signaling. In this study, we present a novel method for the production and purification of an antagonist to human LIF-R (hLA). His-tagged hLA was expressed in E. coli, and simple purification methods without any endopeptidase cleavage were designed. In addition, we determined the optimal temperature conditions for enhancing the production of soluble hLA. Finally, the bioactivity of His-tagged hLA was examined using STAT3 phosphorylation and receptivity of human endometrial ECC-1 cells. Our strategy provides a rapid and efficient method to produce biologically active recombinant hLA.

Physicochemical characteristics of Kwangyang Bay, have been investigated on the effects of inputting rivers just after rainy season in summer 2003. The results ranged from 4.96～8.01 mg/L for DO, 1.16～3.09 mg/L for COD, 7.21～67.71 uM for DIN and 0.12～121.84 uM for phosphate. The COD of Yeosu Area was 1.19～3.09 mg/L, Kwangyang Area was 1.23～2.76 mg/L. The COD of Wallae cheon in Yeosu Area was 3.09 mg/L and Donghoan in Kwangyang Area was 2.76 mg/L. The reason of high COD might be industrial sewage of organic chemical plants and iron foundry. DIN of Yeosu Area and Kwangyang Area were 7.21～63.43 and 8.43～67.71 respectively. The average phosphate of Yeosu Area was 23.65 u. The source of phosphate might be industrial sewages of fertilizer plant and phosphate gypsum stocked with high amounts. The metal concentrations were measured in the range of 1.01～175.10 for Cu, 0.13～1.78 for Cd, 1.13～5.21 for Pb, 1.58～13.57 for Cr and 1.07～20.68 for As. The average Cu concentration was 78.99 in Kwangyang Area. The source of Cu might be industrial sewage of iron foundry. The average Cr concentration of Yeosu Area was 9.07 . That is 2 times higher than Kwangyang Bay 5.74 , because of sewage of chemical plants.

Polycyclic aromatic hydrocarbons(PAHs) in sediments of Kwangyang bay on Korea, have been investigated by gas chromatography-mass spectrometery (GC/MS). The average content of total PAHs in all samples was 2,211ppb, and the range was from 36 to 22,699ppb. The higher concentrations were found in sediment sampled near Kwangyang iron processing plant, Taeindo. The resulting distributions of PAHs according to the number of aromatic ring and molecular ratios of specific aromatic compounds (phenanthrene, anthracene, fluoranthene and pyrene) have been discussed in terms of sample location, origin of the organic matter. Four, five and six rings of PAHs were mainly found near to Kwangyang iron processing plant, and three and four rings near to Yeosu chemical kombinat This result typically indicated the local characteristics, depending on the origin of PAHs.

This study tried to investigate the effect of elderly women`s participation in community dance on suicidal ideation, and the effect of their social capital on suicidal ideation. The data was collected from 167 elderly women, participating in community dance, were sampled from senior welfare centers and community centers. This study used a questionnaire as survey tool. We asked old women to respond the questions in the self-administration method, or the assistants read questions to old women and filled out the questionnaire. The data were under the t-test, one way ANOVA, correlation analysis, and multiple regression analysis. The results were as follows. First, there were significant differences in social capital and serious suicidal ideation according to community dance participating frequency and satisfaction level with participation. Second, self-trust and social relation network had negative effects on serious suicidal ideation, and, trust in others, self-trust, and trust in policy had negative effects on slight suicidal ideation. To change elderly women`s thinking and attitude toward suicidal ideation positively, it was need to attract elderly women to make social capital by active participation in community dance.

BackgroundWe evaluated the effects of pre-transplant locoregional treatment on survival in living donor liver transplantation (LDLT), and the most accurate method for predicting survival after LDLT in patients who received pre-transplant locoregional treatment.MethodsFrom December 2003 to December 2012, 234 patients underwent LDLT for hepatocellular carcinoma (HCC) at our transplant center. We retrospectively reviewed 86 patients newly diagnosed with HCC and who received pre-transplant locoregional treatments at our hospital.ResultsOf the 33 patients with HCC initially beyond the Milan criteria, 12 experienced successful down-staging after locoregional treatments, and the 5-year recurrence-free survival was 81.8%, which was comparable to those in patients with HCC initially within the Milan criteria. A bad responder according to the modified Response Evaluation Criteria in Solid Tumors (mRECIST) [HR, 4.874 (1.059–22.442), p = 0.042], and increased AFP levels [HR 4.002 (1.540–10.397), p = 0.004] during pre-transplant locoregional treatments were independent risk factors for HCC recurrence after LDLT in multivariate analysis.ConclusionsLiver transplantation may be considered after successful down-staging in patients with HCC initially beyond the Milan criteria. The mRECIST and serum AFP level changes are better selection criteria for LDLT in patients who have received locoregional treatments.

Signal transducer and activator of transcription 3 (STAT3) is associated with various human diseases, such as cancer, auto-immune disease, and intestinal inflammation. The limited and inadequate effect of standard approaches for treating inflammatory bowel disease (IBD) has prompted to develop alternative anti-colitis agents through inhibition of STAT3. Here, we show that gallic acid (GA), a 3,4,5-trihydroxybenzoic acid, markedly reduced phosphorylation of STAT3. Among the derivatives of benzoic acids, GA showed significant inhibition on STAT3 phosphorylation. In addition, GA ameliorated the dextran sodium sulfate (DSS)-induced acute colitis as determined by the measurement of symptomatic and histological indices. The suppression of DSS-induced acute colitis by GA treatment may be related to the regulation of cytokines and growth factors. Furthermore, GA inhibited phosphorylation of STAT3 in the colon tissue of DSS-treated mice. These findings may be useful in comprehending the molecular action of GA on STAT3 phosphorylation and provide novel insights into the potential application of GA in the treatment of STAT3-related inflammatory disease, such as IBD.

Meckel's diverticulum is the most common anomaly of the intestine. It is usually asymptomatic but approximately 4% are symptomatic with complications such as bleeding, intestinal obstruction, and inflammation. Gastrointestinal bleeding is the most common presenting symptoms of Meckel's diverticulum in children, however, intestinal obstruction is the most common complications in adult patients. Reported mechanism of intestinal obstruction in Meckel's diverticulum include intussusception, adhesion, and volvulus. Recently, we experienced a case with Meckel's diverticulum associated with ileal stricture causing recurrent partial intestinal obstruction in a 48-year-old man. In contrast to other published cases of small bowel obstruction in Meckel's diverticulum, this case was caused by ileal stricture associated with Meckel's diverticulum.

Keun Sang Oh,1,* Kyungim Kim,1,* Byeong Deok Yoon,1 Hye Jin Lee,1 Dal Yong Park,1 Eun-yeong Kim,1 Kiho Lee,1 Jae Hong Seo,2 Soon Hong Yuk1,2 1College of Pharmacy, Korea University, Sejong, 2Biomedical Research Center, Korea University Guro Hospital, Guro-gu, Seoul, Republic of Korea *These authors contributed equally to this work Abstract: A mixture of docetaxel (DTX) and Solutol® HS 15 (Solutol) transiently formed nanodroplets when it was suspended in an aqueous medium. However, nanodroplets that comprised DTX and Solutol showed a rapid precipitation of DTX because of their unstable characteristics in the aqueous medium. The incorporation of nanodroplets that comprised DTX and Solutol through vesicle fusion and subsequent stabilization was designed to prepare multilayer nanoparticles (NPs) with a DTX-loaded Solutol nanodroplet (as template NPs) core for an efficient delivery of DTX as a chemotherapeutic drug. As a result, the DTX-loaded Solutol nanodroplets (~11.7nm) were observed to have an increased average diameter (from 11.7nm to 156.1nm) and a good stability of the hydrated NPs without precipitation of DTX by vesicle fusion and multilayered structure, respectively. Also, a long circulation of the multilayer NPs was observed, and this was due to the presence of Pluronic F-68 on the surface of the multilayer NPs. This led to an improved antitumor efficacy based on the enhanced permeation and retention effect. Therefore, this study indicated that the multilayer NPs have a considerable potential as a drug delivery system with an enhanced therapeutic efficacy by blood circulation and with low side effects. Keywords: multilayer nanoparticles, Solutol, Pluronic F-68, docetaxel, cancer therapy

Purpose To compare postoperative exodrift of the first unilateral lateral rectus (ULR) muscle recession with the exodrift of the second contralateral ULR muscle recession in patients with recurrent small-angle exotropia (XT). Methods We evaluated the results of a second ULR muscle recession in 19 patients with recurrent XT with deviation angles under 25 prism diopter (PD), following a first procedure of ULR muscle recession for small-angle XT. Recession of the lateral rectus muscle ranged from 8 to 9 mm. The postoperative motor alignment and degree of exodrift were investigated after the first ULR muscle recession and the second ULR muscle recession in the same patients. Results Observed differences in postoperative ocular alignment between the first ULR muscle recession and the second ULR muscle recession were statistically significant at follow-up periods of six months (7.84 ± 4.43 vs. 3.89 ± 3.47 PD), one year (9.58 ± 4.97 vs. 5.21 ± 4.94 PD), and at a final follow-up (21.11 ± 2.98 vs. 7.52 ± 4.06 PD) after surgery (p = 0.006, 0.013, and 0.000). Postoperative exodrift was statistically different between the first and second ULR muscle recessions at three to six months (2.89 ±3.75 vs. 0.63 ± 3.45 PD) and one year to final follow-up (11.52 ± 5.50 vs. 2.32 ± 3.53 PD) (p = 0.034 and 0.000). All of the first ULR muscle recession patients showed XT with deviation angles of more than 15 PD at the final follow-up. Regardless, the surgical success rate (

Purpose: To evaluate the risk factors and incidence of neodymium-doped yttrium aluminium garnet (Nd:YAG) posterior capsulotomy due to posterior capsular opacification in adult cataract patients under 50 years of age according to different age groups. Methods: We retrospectively studied 280 eyes that received phacoemulsification and intraocular lens implantation. The total observation period was 26.2 months on average. The subjects were divided into 3 different age groups, 20's, 30's and 40's to evaluate the incidence of posterior capsulotomy. Risk factors based on gender, age, type of cataract, type of intraocular lens (IOLs), axial length, existence of diabetes mellitus, history of ocular trauma, atopic dermatitis and refractive surgery were also investigated using statistical analysis. Results: The incidence of posterior capsulotomy was 13.9% (39 of 280 eyes) and statistically significant differences were not observed based on age (7.7% in the 20’s group, 13.8% in the 30’s group and 14.4% in the 40’s group, p=0.595). We divided subjects into 3 different groups based on axial length, below 22 mm, 22 to 26 mm and over 26 mm; posterior capsulotomy was performed in 0% (0/2), 7.2% (12/166) and 24.1% (27/112) of the patients, respectively, showing the longer axial length resulted in statistically significant increase in the incidence of posterior capsulotomy (p=0.036). The incidence of posterior capsulotomy was higher in females than in males (p=0.006). Correlations among posterior capsulotomy and type of cataract, type of IOLs and existence of diabetes mellitus, history of ocular trauma, atopic dermatitis and refractive surgery were not statistically significant. Conclusions: The difference in the incidence of Nd:YAG laser posterior capsulotomy according to age was not statistically significant in adult cataract patients under 50 years of age. We showed that longer axial length resulted in higher risk of posterior capsulotomy. J Korean Ophthalmol Soc 2015;56(6):868-874