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Cyclocarya paliurus, a Chinese herbal medicine and new food resource, contains a triterpenic-acid-rich extract that demonstrated ameliorative effect on diabetic nephropathy (DN). A more in-depth discovery of functional components led to the isolation of seven new triterpenoids including two pentacyclic triterpenes, 1α,2α,3β,23-tetrahydroxyolean-12-en-28-oic acid and 2α,3β,22α-tirhydroxyurs-12-en-28-oic acid 28-O-β-D-glucopyranoside, and five tetracyclic triterpenoid glycosides (cypaliurusides N-R), together with twelve known compounds from the leaves of C. paliurus. Their structures were determined using a comprehensive analysis of chemical and spectroscopic data. Partial compounds were assessed for anti-fibrotic activities in high-glucose and TGF-β1 induced HK-2 cells. Compound 16 remarkably decreased the level of fibronectin with an inhibition rate of 37.1%. Furthermore, 16 effectively alleviated the epithelial-mesenchymal transformation (EMT) process by upregulating E-cadherin expression and downregulating α-SMA expression, and it significantly decreased the level of the transcriptional inhibitors (Snail and Twist) of E-cadherin. The discovery of anti-fibrotic compounds from C. paliurus provides the potential utilization and functional candidates for the DN prevention.

Background Cryptococcal meningitis (CM) is a significant source of mortality, the pathogenesis of which has not been fully understood, especially in non-HIV infected populations. We aimed to compare single nucleotide polymorphisms (SNPs) of Toll-like receptor (TLR) in non-HIV CM patients with those of healthy controls, and to assess the links among TLR SNPs, cytokine concentrations in cerebrospinal fluid (CSF), and clinical severity. Methods This observational cohort study was done in 2 stages: a discovery stage and a validation stage. We conducted a case-control genetic association study between 159 non-HIV CM patients and 468 healthy controls. TLR SNPs significantly related to susceptibility were further validated in a second cohort of 583 subjects from a certain district. Cytokine concentrations in CSF were used to evaluate the in situ immune response of CNS after infection. Correlations among TLR SNPs, CSF cytokine concentrations, and clinical severity were validated in a third prospective cohort of 99 previously untreated non-HIV CM patients. Logistic regression model was used to determine the independent predictors for disease severity. Findings In the discovery stage, the genotype distributions of 8 TLR SNPs in non-HIV CM patients exhibited a significant difference in comparison with controls, of which 3 SNPs remained statistically significant in patients without predisposing factors. In the validation stage, 5 of the 8 nominated TLR SNPs were found to influence CSF cytokine expression. Eighteen cytokines were significantly up-regulated in severely ill patients, among which 12 were affected by TLR2 rs3804099. The rs3804099 was also found in relation to disease severity. High IL-10 levels in CSF (OR 2*97, 95% CI 1*49-5*90; p=0*002) was suggested as an independent predictor for severity after adjusted for possible confounders. Interpretation TLR participate in both the occurrence and the pathogenesis of non-HIV CM. The in situ immune responses of CM were under genetic influence of TLR and contributed to disease severity. Our findings inform of an opportunity for early evaluation and treatment of non-HIV CM. TLR might also become a potential target on which to base host-directed immunotherapy. Funding: National Natural Science Foundation of China and National Key Basic Research Program of China (973 Program). Declaration of Interest: We declare no competing interests. Ethical Approval: Ethical approval was obtained from the medical ethics committee of Huashan Hospital, Mengchao Hepatobiliary Hospital, Fujian HIV/AIDS Diagnosis and Treatment Center, and No. 476 Hospital of Fuzhou General Hospital.

Four new cytochalasans, arbuschalasins A-D (1-4), along with thirteen known analogues (5-17), were isolated from the solid rice medium of endophytic fungus Xylaria arbuscula. Arbuschalasins A-B feature a rare 5/6/6/6 fused ring system while arbuschalasin D was characterized as the first example of natural cytochalasans that possesses a 5/5/11 fused scaffold. The structures of 1-4 were assigned by spectroscopic data, with their absolute structures being determined by electronic circular dichroism (ECD) calculations. All of the isolates were evaluated against the human colorectal adenocarcinoma cell lines (HCT15). Compounds 6 and 7 showed significant inhibitory effects (IC

Ethnopharmacological relevance Cyclocarya paliurus (CP) is a traditional Chinese herb and possesses a variety of biological activities including anti-hyperglycemia, anti-hyperlipidemia, antioxidant and anti-inflammation. Arjunolic acid (AA) is an abundant and bioactive ingredient in CP that shows significant protection against many metabolic diseases such as diabetic complication. Diabetic retinopathy (DR) is a serious complication of diabetes and may lead to vision loss. However, the protective effects and underlying mechanisms of AA against DR is not still understood. Aim of the study We aimed to investigate whether AA activates AMPK/mTOR/HO-1 regulated autophagy pathway to alleviate DR. Materials and methods In the study, the STZ-induced diabetic model of rats was established, and AA with 10 and 30 mg/kg dosages was given orally for ten weeks to investigate their effect on retinal injury of DR. H2O2-induced ARPE-19 cells were applied to evaluate anti-apoptosis and anti-oxidant effect of AA. Results The results revealed that AA could prevent STZ-induced weight loss and increase the retinal thickness and nuclei counts. The level of HO-1 protein was upregulated both in vivo and in vitro. In addition, AA prevented retinal damage and cell apoptosis through the AMPK-mTOR-regulated autophagy pathway. Furthermore, anti-apoptosis capacity, as well as the expression of HO-1 and LC3 protein, were effectively locked by AMPK inhibitor dorsomorphin dihydrochloride (compound C). Conclusions This finding implies that AA may be a promising candidate drug by protecting retinal cells from STZ-induced oxidative stress and inflammation through the AMPK/mTOR/HO-1 regulated autophagy pathway.

Four new C-11 monosaccharide attached dammarane triterpenoid glycosides cypaliurusides S V (1–4), along with nine known dammarane triterpenoid glycosides (5–13) were isolated from a CHCl3-soluble extract of the leaves of Cyclocarya paliurus. All characterized compounds were assayed for their cytotoxicities against HepG2 cells and 10 compounds were evaluated for the agonistic effects on sirtuin1 (SIRT1). The results showed that compounds 1, 5 and 6 were strongly cytotoxic in HepG2 cell line. Two dammarane triterpenoid glycosides 3 and 10 exhibited agonistic activities on SIRT1 with IC50 of 10 μM and 20 μM, respectively.

ResumoObjetivosO aumento da prevalência da obesidade é um problema sério de saúde e econômico. A obesidade tem sido relatada como um dos principais contribuintes para uma variedade de doenças crônicas. A obesidade infantil tem aumentado nas últimas décadas e levado a complicações de saúde. Milhões de bebês e crianças são submetidos a cirurgia todos os anos por diversos motivos de saúde. O presente estudo foi feito para avaliar o efeito da raquianestesia com doses equipotentes de ropivacaína e bupivacaína em ratos recém‐nascidos com sobrepeso.MétodosAs crias de ratos Sprague‐Dawley foram alimentadas em excesso com dieta rica em gordura para induzir obesidade. Avaliações comportamentais para bloqueio sensorial e motor foram feitas por meio da avaliação das latências de retirada térmicas e mecânicas em vários intervalos de tempo após injeções por via intratecal de bupivacaína (5,0mg·kg−1) e ropivacaína (7,5mg·kg−1) em ratos P14. Tecido medular foi analisado para apoptose por determinação da caspase‐3 ativada, com o uso de anticorpo monoclonal anti‐caspase 3 ativada e ecoloração com Fluoro‐Jade C. A função da coluna vertebral em longo prazo em filhotes de ratos P30 foi avaliada.ResultadosA exposição à anestesia intratecal em P14 aumentou as latências térmicas e mecânicas e observamos aumento da apoptose, como apresentado pelo aumento da caspase‐3 ativada e células positivas para Fluro‐Jade C. Alterações significativas da função da coluna vertebral foram observadas em filhotes alimentados com dieta rica em gordura versus filhotes controles não obesos em dieta padrão. Bupivacaína produziu efeitos apoptóticos mais pronunciados sobre os filhotes P14; ropivacaína, entretanto, produziu efeitos duradouros, como evidenciado nos testes de função motora em P30.ConclusãoRopivacaína e bupivacaína induziram toxicidade medular mais pronunciada nos filhotes de ratos sobrealimentados do que nos controles normais.AbstractObjectivesThe increase in the prevalence of obesity presents a significant health and economic problem. Obesity has been reported to be a major contributor to variety of chronic diseases. Childhood obesity has been rising over the past decades leading to various complications in health. Millions of infants and children undergo surgery every year on various health grounds. The present investigation was undertaken to evaluate the effect of spinal anesthesia of equipotent doses of ropivacaine and bupivacaine on over‐weight neonatal rats.MethodsThe Sprague‐Dawley rat pups were overfed on high fat diet to induce obesity. Behavioral assessments for sensory and motor blockade was made by evaluating thermal and mechanical withdrawal latencies at various time intervals following intrathecal injections of bupivacaine (5.0mg·kg−1) and ropivacaine (7.5mg·kg−1) in P14 rats. Spinal tissue was analyzed for apoptosis by determination of activated caspase‐3 using monoclonal anti‐activated caspase‐3 and Fluoro‐Jade C staining. Long‐term spinal function in P30 rat pups was evaluated.ResultsExposure to intrathecal anesthesia in P14 increased thermal and mechanical latencies and was observed to increase apoptosis as presented by increase in activated caspase‐3 and Fluro‐Jade C positive cells. Significant alterations in spinal function were observed in high fat diet‐fed pups as against non‐obese control pups that were on standard diet. Bupivacaine produced more pronounced apoptotic effects on P14 pups; ropivacaine however produced long lasting effects as evidenced in motor function tests at P30.ConclusionRopivacaine and bupivacaine induced spinal toxicity that was more pronounced in over‐fed rat pups as against normal controls.

Context The association between 3-hydroxy-3methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) and bone mineral density (BMD) is controversial because of conflicting findings from previous studies. Objective and design The purpose of the present study was to evaluate the effect of statins on BMD reported in randomized and non-randomized controlled trials. We searched PubMed and Embase, using text, medical subject headings (MeSH) and keywords “bone mineral density” and “statins” or “HMG-CoA reductase inhibitors”. Our last PubMed and Embase queries were updated to August 2012. Data on participants, interventions, and outcomes from each study were abstracted independently by two authors. Results Five case–control studies, six cohort studies and four randomized controlled trials (RCTs) met the inclusion criteria. Included studies involved 34,877 subjects (3824 in the intervention group and 31,053 in the control group) in 12 different countries with ages ranging from 44 to 66 years. Statins significantly increased BMD at lumbar spine [standardized mean difference (SMD) 0.15, 95% CI 0.09–0.22], total hip (SMD 0.22, 95% CI 0.17–0.27) and femoral neck (SMD 0.19, 95% CI 0.09–0.29). We carried out subgroup analyses on selected populations of the cohorts. Statistically significant increases were also observed in the lumbar spine (SMD 0.12, 95% CI 0.04–0.21), total hip (SMD 0.23, 95% CI 0.17–0.28) and femoral neck BMD (SMD 0.22, 95% CI 0.08–0.36). Conclusion The results of this study suggest that statins may help improve and maintain BMD at the lumbar spine, hip and femoral neck, especially in Caucasians and Asians. It also provides justification for prospective RCTs to evaluate the possible role of statins in BMD in different ethnic populations, such as Latin American and Africans.

One of the most common life-threatening infections in immunosuppressive patients, like AIDs patients, is cryptococcal meningitis or meningoencephalitis. Current therapeutic options are mostly ineffective and mortality rates remain high. Hydrophobic antifungal drug Amphotericin B (AmB), has become a golden standard in severe systemic fungal infection therapy. However, most AmB commercial formulations, including deoxycholate AmB and lipid formulations of AmB, show poor penetration into the CNS and difficulty to reach the therapeutic levels. To improve the CNS permeability of AmB, we have successfully developed an effective brain-targeting polymeric micellar system with angiopep-2 modified, named Angiopep-PEG-PE/AmB polymeric micelles. An immunosuppressive murine model with Cryptococcus neoformans meningoencephalitis (CNME) was established to evaluate the CNS penetration efficiency and antifungal treatment efficacy of the AmB-incorporated brain-vectored polymeric micellar formulation, compared with the AmB commercial formulations. After three consecutive days of i.v. administration, the results showed that the group treated with Angiopep-PEG-PE/AmB achieved the greatest treatment efficacy, which reached the highest AmB level in brain, reduced the brain fungal burden significantly, decreased histopathological severity and prolonged the median survival time. The increased treatment efficacy could be attributed to the brain-targeting delivery system promoted AmB crossing the BBB and penetrating into the brain to reach the therapeutic concentration. The underlying mechanism was also explored in this work. Therefore, the brain-targeting delivery system could have potential and promising implications for treatment of intracerebral fungal infection.

Ethnopharmacological relevance Salvia miltiorrhiza Bunge named Danshen in China has been used for hundreds of years in both China and other countries. Danshen injection made from the aqueous extract of Danshen which is widely adopted in China is one of the traditional Chinese medicine injections for preventing and treating cardiovascular diseases in most of the time. The present study was carried out on re-evaluating the safety of Danshen injection by determining toxicity after acute and sub-chronic administration in Sprague-Dawley (SD) rats. Materials and methods In acute toxicity study, rats (10 males and 10 females) were intravenously administered Danshen injection dose of 32 g/kg body weight, two times in one day. General behavior, adverse effects and mortality were recorded for up to 14 days post treatment. In the sub-chronic study, Danshen injection was given intravenously at the doses of 0, 1.92, 5.76, and 19.20 g/kg per day ( n = 15/group each sex) for 13 weeks to rats. Animal body weight and food intakes were observed weekly. Hematological, biochemical parameters and organ weight were determined in all animals at the end of the 13-week administration and 2-week recovery. However, histological examinations were carried out in the control and high-dose groups only. Results In acute study, the sign of struggling was observed in some animals at the moment of intravenous administration. No deaths and other signs of toxicity occurred in any of the animals tested during the 14 days of the study. In sub-chronic study, Danshen injection did not result to death, adverse effects or dose-dependent changes in food consumption, but had an effect on body weight gain. Some statistically significant differences were observed in hematological and biochemical parameters, as well as in some organ weights of both male and female rats treated with Danshen injection. In these changes, the significant decrease in triglycerides and increase in total bilirubin were considered related to treatment, indicating the lipid-modulating activity of Danshen. Histopathological examinations of the injection site showed that Danshen injection could cause dose-dependent focal inflammation. There was no abnormality of other organs noted in both gross and histopathological examinations. Conclusions The results showed that acute or sub-chronic administration of Danshen injection was low or non-toxic in male and female rats, and the no-observed-adverse-effect-level for sub-chronic administration of Danshen injection dose was 5.76 g/kg bw/day, which was suggested that it was safe in clinical use.

Based on the background that large amount of copper tailings are stockpiled in China, the utilization of skarn-type copper tailings to prepare autoclaved aerated concrete (AAC) was studied. The AAC samples were prepared on a laboratory scale with a dry density of 610.2 kg m −3 and compressive strength of 4.0 MPa. Compared with the traditional AAC, lime was totally substituted by skarn-type copper tailings and blast furnace slag in order to develop a potential technique of reducing CO 2 emission during the AAC production process. The samples of different curing stage were examined by XRD, FESEM as well as 29 Si and 27 Al NMR analyses. Results show that the main minerals in the AAC product are tobermorite-11 A, anhydrite, augite, quartz, calcite and dolomite, with small amount of other minerals brought in by the copper tailings. It was also suggested that most minerals in the copper tailings participated in the hydration reaction during the procuring process, and the chemical elements in them got into the structure of platy tobermorite in the subsequent autoclaving process.

We simulate the processes of electron extraction from 1D conjugated polymers to metal electrodes in the presence of electric fields based on the Su–Schrieffer–Heeger (SSH) model extended to a polymer/electrode contact structure. From the simulation, we can obtain the lifetime of the process that a charged carrier known as polaron at the polymer chain end starts to dissociate and the released electron tunnels to the electrode immediately. An effective carrier mobility named interface mobility can be defined for this process and calculated from the lifetime. It is found that the interface mobility is independent on the external electric fields. However, this mobility increases with decreasing the work function of the electrode. By enhancing the coupling between the polymer and the electrode, the interface mobility is shown to increase. Kinetic energy of the electrons is also shown to favor the improvement of the mobility.

This paper studies the generalized state density (GDOS) of near-historical extreme events of a set of independent and identically distributed (i.i.d.) random variables. The generalized density of states is proposed which is defined as a probability density function (p.d.f.). For the underlying distribution in the domain of attraction of the three well-known extreme value distribution families, we show the approximate form of the mean GDOS. Estimates of the mean GDOS are presented when the underlying distribution is unknown and the sample size is sufficiently large. Some simulations have been performed, which are found to agree with the theoretical results. The closing price data of the Dow-Jones industrial index are used to illustrate the obtained results.

The purpose of this paper was to investigate the crystallization process of glass ceramics prepared from a mixture which was composed of nickel slag, blast furnace slag and a small amount of quartz sand. First, the parent glass of the mixture was prepared. Then, the glass ceramics were obtained by heat-treating for the parent glass. The crystallization behavior was studied by differential scanning calorimetry (DSC), X-ray diffraction (XRD) and field emission scanning electron microscope (FESEM). A large number of tiny spherical crystals were observed when the glass was heated up to 700 °C. Subsequently, the radial crystals were observed when the glass was heated up to 820 °C. By XRD analyzing, the spherical crystals and radial crystals were likely to be the crystals of diopside (CaMg(Si,Al,Fe)2O6) and hedenbergite (CaFe(Si,Al,Fe)2O6). The crystallization temperature was 860 °C and the final crystalline phases were identified to be diopside and hedenbergite. In addition, the activation energy of crystallization was evaluated by Kissinger method.

Objective To compare the different time of administration of hCG affecting pregnancy rate of IUI. Methods A total of 189 infertile couples underwent 331 cycles of IUI with husband's sperm. They were separated into 3 groups according to the time of hCG administration in IUI: hCG 1–23 h (group A); hCG 24–36 h (group B); hCG 37–48 h (group C). Results There were no statistical differences among 3 groups. None of the other relative factors, such as the female age, the different methods of ovulation and the cause of infertility, showed differences in pregnancy rate among 3 groups. Conclusion IUI can be performed any time after administration of hCG (1–48 h).

Objective To compare the medical outcomes of infants delivered by cesarean section with those of infants delivered vaginally. Methods A total of 301 healthy women with cesarean section and a matched control group of 301 women delivered vaginally were identified at three district-level hospitals in Shanghai from May 2001 to February 2003. Two groups were matched according to their medical indications for cesarean section. Their infants were assessed at delivery, 1 month, 6 month and 1 year after birth. Results The incidence of neonatal complications and infant morbidities at all measurement occasions did not differ significantly between groups. Rehospitalization was found to be more likely among infants delivered by cesarean section in the first month after birth. However, there was no difference between two groups in the incidence of rehospitalization in the first year after birth. Cesarean section was also associated with a higher risk of infant diarrhea (adjusted relative risk=1.25, 95% CI: 1.01, 1.56). Conclusion Infants did not have health benefits from cesarean section if the pregnancy was at low risk.

Recombinant human endostatin (rhEndostatin) has been shown to inhibit tumor growth, but the variable antitumor activity of different rhEndostatin preparations has necessitated the development of an accurate, reproducible in vivo bioassay for evaluating the rhEndostatin activity. To assess the in vivo antitumor efficacy of rhEndostatin, H22 tumor-bearing mice received three doses of rhEndostatin and the potency of rhEndostatin preparations in inhibiting tumor growth was determined by ED(50)-potency assay and validated by dose-response parallel-line assay. There was a consistent and highly reproducible linear regression relationship between rhEndostatin dosage and tumor growth inhibition rate. The ED(50) values were determined from dose-response regression lines for seven rhEndostatin preparations with high reproducibility. On the basis of the current study, the potency of rhEndostatin preparations was assigned a value of 6.09 x 10(5) U/ampoule and a 95% confidence limit of 5.96 x 10(5)-6.22 x 10(5). We consider that this procedure can be served as a potential candidate pharmacopoeial method for potency measurement of different rhEndostatin preparations.

In this paper, we use the kernel method to estimate sliced average variance estimation (SAVE) and prove that this estimator is both asymptotically normal and root n consistent. We use this kernel estimator to provide more insight about the differences between slicing estimation and other sophisticated local smoothing methods. Finally, we suggest a Bayes information criterion (BIC) to estimate the dimensionality of SAVE. Examples and real data are presented for illustrating our method.

The relationship between the appearance of cells producing antibody to tetanus toxoid (TT) in the circulation and the serum titers of anti-TT IgG following booster immunization has been studied. It was found that cells producing anti-TT antibody can be detected in the circulation in a hemolytic plaque assay using sheep red blood cells (SRBC) coated with TT by the chromic chloride method. In symmetric inhibition studies using cells from TT or keyhole limpet hemocyanin (KLH)-immune donors, the homologous antigen inhibited 100% of the PFC with no cross-inhibition. Thus, the plaque-forming cells (PFC) detected in this assay are specific for the immunizing antigen. No evidence of polyclonal B-cell activation in response to TT was found, as shown by a failure to detect any PFC against unmodified or KLH or human serum albumin-treated SRBC. In addition, the increase in total Ig-secreting cells observed in a staphylococcal protein A reverse hemolytic plaque assay was always accounted for by the number of anti-TT antibody-producing cells observed. The peak number of anti-TT antibody-producing cells varied between donors, but the kinetics of their appearance was highly reproducible—none before Day 5, peak numbers between Days 6 and 8, and a sharp decline with only rare anti-TT Ig-secreting cells in the circulation by Day 15 postimmunization. Anti-TT antibody-producing cells appeared in the circulation prior to any detectable increase in serum anti-TT antibody titers, and following the disappearance of PFC from the circulation, there was no further increase in serum IgG anti-TT levels. These observations demonstrate a marked specificity of B-cell activation on boosting with a recall antigen, and a parallelism between the appearance of activated B cells in the circulation and of IgG anti-TT synthesis by the subject as a whole.