Two new sesquiterpenoids, pinnatifone A (1) and pinnatifone B (2), and two new lignans, pinnatifolin (3) and isopinnatifolin (4), along with six known lignans (5-10), were isolated from the roots of Syringa pinnatifolia. The structures of the new compounds were elucidated by extensive spectroscopic methods, including NMR, MS, UV, and IR spectra. The lignans were screened for their anti-oxidant activity (2,2-diphenyl-1-picrylhydrazyl (DPPH) assay). Most of them showed potent anti-oxidant activity, especially compound 5, whose potent anti-oxidant activity had an SC50 value higher than that of the positive control vitamin C.
Linezolid may be effective in treating multidrug-resistant tuberculosis and extensively drug-resistant tuberculosis. We conducted a prospective, multicentre, randomised study to further evaluate the efficacy, safety and tolerability of linezolid in patients with extensively drug-resistant tuberculosis in China. 65 patients who had culture-positive sputum for extensively drug-resistant tuberculosis were randomly assigned to a linezolid therapy group or a control group. Patients in the two groups adopted a 2-year individually based chemotherapy regimen. The linezolid therapy group was given linezolid at a start dose of 1200 mg per day for a period of 4-6 weeks and this was then followed by a dose of 300-600 mg per day. The proportion of sputum culture conversions in the linezolid therapy group was 78.8% by 24 months, significantly higher than that in the control group (37.6%, p<0.001). The treatment success rate in linezolid therapy group was 69.7%, significantly higher than that in the control group (34.4%, p = 0.004). 27 (81.8%) patients had clinically significant adverse events in the linezolid group, of whom 25 (93%) patients had events that were possibly or probably related to linezolid. Most adverse events resolved after reducing the dosage of linezolid or temporarily discontinuing linezolid. Linezolid containing chemotherapy for treatment of extensively drug-resistant tuberculosis may significantly promote cavity closure, increase sputum culture-conversion rate and improve treatment success rate.
A new ursane-type triterpenoid saponin, flaccidoside IV (1), and three new oleanane-type triterpenoid saponins, flaccidosides V-VII (2-4), along with 17 known saponins (5-21), were isolated from the rhizomes of Anemone flaccida. The structures of the new triterpenoid saponins were determined based on spectroscopic analyses and chemical methods. All the isolated saponins were tested for their inhibitory activities on lipopolysaccharide-induced nitric oxide production in RAW264.7 macrophages, and several bisdesmosidic oleanane-type triterpenoid saponins (2, 7, and 10) showed significant inhibitory activities, which indicated they had potential anti-inflammatory activities under their noncytotoxic concentrations in vitro.
To correlate the characteristic images of hepatic alveolar echinococcosis (HAE) in rats using contrast-enhanced ultrasonography (CEUS) and microvascular density (MVD) in the surrounding invasion range of HAE lesions.
Abstract 1.?Anhuienoside C (A-C) is the main active component of the saponin exact of "Di Wu", an oral drug for rheumatism treatment in China. In this study, we aimed to elucidate the metabolic pathways of A-C by intestinal bacteria using the metabolomic approach. 2.?Four deglycosylated metabolites (M1, M2, M3 and M4) were identified after A-C (50?µM) was incubated with rat fecal lysate. Chemical structures of these metabolites were determined by high-resolution masses and nuclear magnetic resonance (NMR). 3.?A one-compartment pharmacokinetic model was used to describe the formation of bacterial metabolites at a dose of 10?µM A-C. The results revealed that formation of M1 and M2 was rapid, whereas formation of M3 was rather slow. Further, it was found that the metabolites were generated by successive cleavage of the glycosyl residues. 4.?This is the first report that A-C is subjected to efficient bacterial metabolism in the gut with M1 and M2 as main metabolites. Our study should be helpful for a better understanding of in vivo disposition of oral A-C.
Fourteen compounds were obtained from Glechoma longituba by the chromatographic methods of silica gel, ODS, Sephadex LH-20 and preparative of HPLC. According to physicochemical properties and spectral data, these compounds were identified as stilbostemin B (1), trilepisiumic acid (2), 3, 4-dihydroxyphenyl ethanol ketone (3), bergeninmonohydrate (4), oresbiusin A (5), norbergenin (6), stilbostemin D (7), ehretioside B (8), ethyl ferulate (9), E-p-hydroxy-cinnamic acid (10), methyl gallate (11), protocatechuic acid (12), 4'-Hydroxyacetophenone (13), and E-3-2,4-dihydroxyphenyl-2-acrylic acid (14). Among them, compounds 1-10, 13 and 14 were isolated from this plant for the first time.
We have developed an improved tool for imaging acidic tumors by reporting the insertion of a transmembrane helix: the pHLIP-Fluorescence Insertion REporter (pHLIP-FIRE). In acidic tissues, such as tumors, peptides in the pHLIP family insert as ?-helices across cell membranes. The cell-inserting end of the pHLIP-FIRE peptide has a fluorophore-fluorophore or fluorophore-quencher pair. A pair member is released by disulfide cleavage after insertion into the reducing environment inside a cell, resulting in dequenching of the probe. Thus, the fluorescence of the pHLIP-FIRE probe is enhanced upon cell-insertion in the targeted tissues but is suppressed elsewhere due to quenching. Targeting studies in mice bearing breast tumors show strong signaling by pHLIP-FIRE, with a contrast index of ?17, demonstrating (i) direct imaging of pHLIP insertion and (ii) cargo translocation in vivo. Imaging and targeted cargo delivery should each have clinical applications.
microRNA-29b (miR-29b) is known to be associated with TGF-?-mediated fibrosis, but the mechanistic action of miR-29b in liver fibrosis remains unclear and is warranted for investigation. We found that miR-29b was significantly downregulated in human and mice fibrotic liver tissues and in primary activated HSCs. miR-29b downregulation was directly mediated by Smad3 through binding to the promoter of miR-29b in hepatic stellate cell (HSC) line LX1, whilst miR-29b could in turn suppress Smad3 expression. miR-29b transduction in the liver of mice prevented CCl4 induced-fibrogenesis, concomitant with decreased expression of ?-SMA, collagen I and TIMP-1. Ectopic expression of miR-29b in activated HSCs (LX-1, HSC-T6) inhibited cell viability and colony formation, and caused cell cycle arrest in G1 phase by downregulating cyclin D1 and p21cip1. Further, miR-29b induced apoptosis in HSCs mediated by caspase-9 and PARP. miR-29b inhibited its downstream effectors of PIK3R1 and AKT3 through direct targeting their 3'UTR regions. Moreover, knockdown of PIK3R1 or AKT3 suppressed ?-SMA and collagen I and induced apoptosis in both HSCs and in mice. In conclusion, miR-29b prevents liver fibrogenesis by inhibiting HSC activation and inducing HSC apoptosis through inhibiting PI3K/AKT pathway. These results provide novel mechanistic insights for the anti-fibrotic effect of miR-29b.
TGF-?1 signals through downstream Smad-dependent and independent pathways to exert its biological activities. It is reported that overexpression of TGF-?1 results in the development of psoriasis-like lesions in a mouse model of K5.TGF-? (WT) transgenic mice. However, signaling mechanisms by which TGF-?1 mediates psoriasis-like lesions remain undefined. In the present study, we hypothesized that TGF-?1 may mediate psoriasis-like lesions via a Smad3-dependent mechanism. This was tested in a mouse model of K5.TGF-? (WT) transgenic mice by blocking TGF-? signaling with a specific Smad3 inhibitor. Results showed that topical treatment with a Smad3 inhibitor markedly blocked TGF-?/Smad3 signaling and progressive psoriasis-like lesions in K5.TGF-? (WT) transgenic mice by reducing the skin severity score, DSFT score, infiltration of CD3(+) T cells and F4/80(+) macrophages, and degree of fibrosis in the dermis. This was associated with a marked reduction in TGF-?1, IL-6, IL-23, and IL-17A both locally in the skin plaque lesions and systemically in plasma, resulting in inhibition of a Th17 transcriptional factor ROR?t and CD4(+) IL-17A(+) cells accumulation within the skin plaque lesions. In conclusion, TGF-?1 mediates psoriasis-like lesions via a Smad3-dependent, Th17-mediated mechanism. Targeting TGF ?/Smad3 signaling with a Smad3 inhibitor may represent a novel and effective therapy for psoriasis. This article is protected by copyright. All rights reserved.
Several kinds of column chromatography methods were used to investigate the chemical constituents of roots of Polygonum multiflorum. The structures of the isolated compounds were identified based on their physicochemical properties, spectral data and chemical methods. A new chromone glycoside was isolated and its structure was identified as (S)-2-(2'-hydroxypropyl)-5-methyl7-hydroxychromone-7-0-alpha-L-fucopyranosyl (1-->2)-beta-D-glucopyranoside (1).
Many types of kidney injury induce inflammation as a protective response. However, unresolved inflammation promotes progressive renal fibrosis, which can culminate in end-stage renal disease. Kidney inflammation involves cells of the immune system as well as activation of intrinsic renal cells, with the consequent production and release of profibrotic cytokines and growth factors that drive the fibrotic process. In glomerular diseases, the development of glomerular inflammation precedes interstitial fibrosis; although the mechanisms linking these events are poorly understood, an important role for tubular epithelial cells in mediating this link is gaining support. Data have implicated macrophages in promoting both glomerular and interstitial fibrosis, whereas limited evidence suggests that CD4(+) T cells and mast cells are involved in interstitial fibrosis. However, macrophages can also promote renal repair when the cause of renal injury can be resolved, highlighting their plasticity. Understanding the mechanisms by which inflammation drives renal fibrosis is necessary to facilitate the development of therapeutics to halt the progression of chronic kidney disease.
Smad7 is well demonstrated as a negative regulator of TGF-? signaling. Its alteration in expression often results in diseases such as cancer and fibrosis. However, the exact role of Smad7 in regulating bone remodeling during mammalian development has not been properly delineated. In this study we performed experiments to clarify the involvement of Smad7 in regulating osteogenesis and osteoclastogenesis both invivo and invitro. Genetically engineered Smad7(?E1) (KO) mice were used, whereby partial functional of Smad7 is lost by deleting exon I of the Smad7 gene and the truncated proteins cause a hypomorphic allele. Analysis with ?CT imagery and bone histomorphometry showed that the KO mice had lower TbN, TbTh, higher TbSp in the metaphysic region of the femurs at 6, 12, 24weeks from birth, as well as decreased MAR and increased osteoclast surface compared with the WT mice. In vitro BM-MSC multi-lineage differentiation evaluation showed that the KO group had reduced osteogenic potential, fewer mineralized nodules, lower ALP activity, and reduced gene expression of Col1A1, Runx2 and OCN. The adipogenic potential was elevated in the KO group with more formation of lipid droplets, and increased gene expression of Adipsin and C/EBP?. The osteoclastogenic potential of KO mice BMMs was elevate, with emergence of more osteoclasts, larger resorptive areas, and increased gene expression of TRAP and CTR. Our results indicate that partial loss of Smad7 function in mice leads to compromised bone formation and enhanced bone resorption. Thus, Smad7 is acknowledged as a novel key regulator between osteogenesis and osteoclastogenesis.
N-doped carbon catalysts have attracted great attention as potential alternatives to expensive Pt-based catalysts used in fuel cells. Herein, an ordered hierarchically porous carbon codoped with N and Fe (Fe-NOHPC) is prepared by an evaporation-induced self-assembly process followed by carbonization under ammonia. The soft template and Fe species promote the formation of the porous structure and facilitate the oxygen reduction reaction (ORR).The catalyst possesses an ordered hierarchically porous structure with a large surface area (1172.5?m(2) ?g(-1) ) and pore volume of 1.03?cm(3) ?g(-1) . Compared to commercial 20?% Pt/C, it exhibits better ORR catalytic activity and higher stability as well as higher methanol tolerance in an alkaline electrolyte, which demonstrates its potential use in fuel cells as a nonprecious cathode catalyst. The N configuration, Fe species, and pore structure of the catalysts are believed to correlate with its high catalytic activity.
Rationale: TGF-?1 is a potent mediator known to induce lung fibrosis. However, the role of latent TGF-?1 in lung inflammation and fibrosis is unclear. Objective: To investigate the role of circulating latent TGF-?1 in bleomycin-induced lung injury. Methods: Lung disease was induced in Keratin-5 promoter-driven TGF-?1wt transgenic mice by bleomycin. Role of latent TGF-?1 in pulmonary inflammation and fibrosis was examined at days 7 and 28 after administration of bleomycin. Results: Compared to littermate wild-type (WT) mice, TGF-?1wt transgenic mice had >2-fold higher levels of latent TGF-?1 in both plasma and lung tissue and were protected from bleomycin-induced pulmonary inflammation such as upregulation of IL-1?, TNF-?, and MCP-1, and infiltration of CD3+ T cells and F4/80+ macrophages. In addition, the severity of lung fibrosis with massive collagen matrix accumulation was markedly reduced in TGF-?1wt transgenic mice. These protective effects were associated with higher levels of Smad7, inactivation of both NF-?B and TGF-?/Smad3 signaling pathways, in addition to an increase in Foxp3-dependent regulatory T cells (Treg) but inhibition of Th17-mediated lung injury. Conclusions: Mice overexpressing latent TGF-?1 are protected from bleomycin-induced lung injury. Triggering the Smad7 negative feedback mechanism to inhibit both NF-?B and TGF-?/Smad signaling pathways and enhancing the Treg response to counter-regulate the Th17-mediated lung injury are potential mechanisms by which latent TGF-?1 protects against bleomycin-induced lung injury.
An unusual nor-monoterpene with only nine carbons, nor-paeonilactone (1), two new monoterpenes, paeonisuffrone C (2), paeonilactone D (9), and a new monoterpene glucoside, paeonin D (3), along with ten known compounds were isolated from the dried roots of Paeonia lactiflora. Their structures were elucidated on the basis of spectroscopic analysis, including 1D and 2D NMR, and computational data. Compounds 4-14 were evaluated for their anti-proliferative activities against BT 483 human breast cancer cells and OVCA 429 human ovarian cancer cells by MTT assay.
Mouse strain differences in immobility and in sensitivity to antidepressants have been observed in the forced swimming test (FST) and the tail suspension test (TST). However, the neurotransmitter systems and neural substrates that contribute to these differences remain unknown. To investigate the role of the hippocampal serotonin transporter (5-HTT), we measured baseline immobility and the immobility responses to fluoxetine (FLX) in the FST and the TST in male CD-1, C57BL/6, DBA and BALB/c mice. We observed strain differences in baseline immobility time, with CD-1 mice showing the longest and DBA mice showing the shortest. In contrast, DBA and BALB/c mice showed the highest sensitivity to FLX, whereas CD-1 and C57BL/6 mice showed the lowest sensitivity. Also we found strain differences in both the total 5-HTT protein level and the membrane-bound 5-HTT level (estimated by V max) as follows: DBA>BALB/c>CD-1=C57BL/6. The uptake efficiency of the membrane-bound 5-HTT (estimated by 1/K m) was highest in DBA and BALB/c mice and lowest in CD-1 and C57BL/6 mice. A correlation analysis of subregions within the hippocampus revealed that immobility time was negatively correlated with V max and positively correlated with K m in the hippocampus. Therefore a higher uptake capacity of the membrane-bound 5-HTT in the hippocampus was associated with lower baseline immobility and greater sensitivity to FLX. These results suggest that alterations in hippocampal 5-HTT activity may contribute to mouse strain differences in the FST and the TST.
MicroRNAs (miRNAs) are small molecules negatively regulating gene expression by diminishing their target mRNAs. Emerging studies have shown that miRNAs play diverse roles in diabetes mellitus. Type 1 diabetes (T1D) and T2D are two major types of diabetes. T1D is characterized by a reduction in insulin release from the pancreatic ?-cells, while T2D is caused by islet ?-cell dysfunction in response to insulin resistance. This review describes the miRNAs that control insulin release and production by regulating cellular membrane electrical excitability (ATP:ADP ratio), insulin granule exocytosis, insulin synthesis in ?-cells, and ?-cell fate and islet mass formation. This review also examines miRNAs involved the insulin resistance of liver, fat, and skeletal muscle, which change insulin sensitivity pathways (insulin receptors, glucose transporter type 4, and protein kinase B pathways). This review discusses the potential application of miRNAs in diabetes, including the use of gene therapy and therapeutic compounds to recover miRNA function in diabetes, as well as the role of miRNAs as potential biomarkers for T1D and T2D.
Several kinds of column chromatography method were used to investigate the chemical constituents of the leaves of Lophatherum gracile. The structures of the isolated compounds were identified based on their physicochemical properties and spectral data. A new flavone C-glycoside was isolated and its structure was identified as 3'-methoxyl-luteolin 6-C-beta-D-galactopyranosiduronic acid (1 --> 2) -alpha-L-arabinopyranoside (1).
The purpose of this study was to conduct a pilot evaluation of a Proto Tai Chi exercise program for older adults and gain insight into the design of future trials involving those who are physically and cognitively frail. Proto Tai Chi (aka Wu Qin Xi) is a simple and intuitive Chinese exercise from which Tai Chi evolved. Twenty-four older adults (74.2 ± 7.5 years, range 65-92) participated in a 5-day, 90-minute/day structured evaluation of a Proto Tai Chi exercise program. Mean completed exercise time by participants per protocol was 98.6%. Participants reported the program to be enjoyable and beneficial. Preliminary efficacy of the program was supported by improvement in measures of walking speed and range of motion at post-test. Results indicate that Proto Tai Chi is a well-accepted exercise option for older adults that may improve physical function and mobility. These preliminary findings merit further investigation in the frail elderly.
Recent data have shown that piperlongumine (PL), an important component of Piper longum fruits, is known to possess anti-inflammatory and vascular-protective activities. This study aimed to examine the therapeutic effects and underlying mechanisms of PL on lupus-prone MRL-Fas(lpr) mice. Female MRL-Fas(lpr) mice were intraperitoneally treated with PL (2.4 mg kg(-1) d(-1)) for 10 weeks, and the proteinuria level was biweekly monitored. After the mice were euthanized, serum biochemical parameters and renal damage were determined. Splenocytes of MRL-Fas(lpr) mice were isolated for in vitro study. Treatment of the mice with PL significantly attenuated the progression of proteinuria and glomerulonephritis. The improvement was accompanied by decreased serum levels of nephritogenic anti-dsDNA antibodies, IL-6, IL-17, IL-23 and TNF-?. Treatment of the mice with PL suppressed the frequency of Th17 cells and increased the regulatory T cells (Tregs). In vitro, the levels of IL-6, IL-17, IL-23 and TNF-? were significantly decreased in the cultures of splenocytes from PL-treated mice compared with those from vehicle-treated mice. In addition, PL treatment impeded activation of the JAK/STAT3 signaling in splenocytes. Of great important, the survival of MRL-Fas(lpr) mice were improved by PL treatment. In summary, PL effectively ameliorates lupus syndrome in MRL-Fas(lpr) mice by suppressing the pathogenic Th17 cells and increasing the Tregs as well as inhibiting activation of the JAK/STAT3 signaling pathway. This study sheds new light on the immune-modulatory role of PL.
Transient receptor potential (TRP) channels are abundant in the brain where they regulate transmission of sensory signals. The expression patterns of different TRPC subunits (TRPC1, 4, and 5) are consistent with their potential role in fear-related behaviors. Accordingly, we found recently that mutant mice lacking a specific TRP channel subunit, TRPC5, exhibited decreased innate fear responses. Both TRPC5 and another member of the same subfamily, TRPC4, form heteromeric complexes with the TRPC1 subunit (TRPC1/5 and TRPC1/4, respectively). As TRP channels with specific subunit compositions may have different functional properties, we hypothesized that fear-related behaviors could be differentially controlled by TRPCs with distinct subunit arrangements. In this study, we focused on the analysis of mutant mice lacking the TRPC4 subunit, which, as we confirmed in experiments on control mice, is expressed in brain areas implicated in the control of fear and anxiety. In behavioral experiments, we found that constitutive ablation of TRPC4 was associated with diminished anxiety levels (innate fear). Furthermore, knockdown of TRPC4 protein in the lateral amygdala via lentiviral-mediated gene delivery of RNAi mimicked the behavioral phenotype of constitutive TRPC4-null (TRPC4(-/-)) mouse. Recordings in brain slices demonstrated that these behavioral modifications could stem from the lack of TRPC4 potentiation in neurons in the lateral nucleus of the amygdala through two G?q/11 protein-coupled signaling pathways, activated via Group I metabotropic glutamate receptors and cholecystokinin 2 receptors, respectively. Thus, TRPC4 and the structurally and functionally related subunit, TRPC5, may both contribute to the mechanisms underlying regulation of innate fear responses.
TGF-?/Smad3 signaling plays a pivotal role in the pathogenesis of peritoneal fibrosis associated with peritoneal dialysis (PD). MicroRNA-29 (miR-29) is known as a potent downstream inhibitor of TGF-?/Smad3 in renal fibrosis. In this study, we examined the therapeutic potential for miR-29b on PD-related peritoneal fibrosis in a mouse model of PD induced by daily infusion of 4.25% dextrose-containing PD fluid (PDF). MiR-29b-expressing plasmid was delivered into the peritoneum via an ultrasound-microbubble-mediated system before and at day 14 after PDF. We found that mice on PD developed peritoneal fibrosis with impaired peritoneal function, which was associated with a loss of miR-29b. In contrast, overexpression of miR-29b before the PDF infusion showed a protective effect on peritoneal fibrosis including EMT and prevented peritoneal dysfunction. Moreover, delayed miR-29b treatment until peritoneal fibrosis was established at day 14 also halted the progression of peritoneal fibrosis at day 28. Further studies identified that blockade of the Sp1-TGF-?/Smad3 pathway may be a mechanism by which miR-29b inhibited peritoneal fibrosis. In conclusion, treatment with miR-29b may represent a novel and effective therapy for PD-associated peritoneal fibrosis.
Loss of miR-29 is associated with cardiac fibrosis. This study examined the role and therapeutic potential of miR-29 in mouse model of hypertension induced by angiotensin II (AngII). By using microRNA microarray, in situ hybridization, and real-time polymerase chain reaction, we found that AngII-induced cardiac fibrosis in the hypertensive heart and in cultured cardiac fibroblasts were associated with downregulation of miR-29a-c via a Smad3-dependent mechanism. In vitro knockdown of miR-29b enhanced but overexpression of miR-29b inhibited AngII-induced fibrosis, revealing a protective role of miR-29b in cardiac fibrosis in response to AngII. This was further demonstrated in vivo by the ability of overexpressing miR-29b in the mouse heart to prevent AngII-mediated cardiac fibrosis and cardiac dysfunction. Importantly, we also found that restored miR-29b in the established hypertensive heart was capable of blocking progressive cardiac fibrosis and improving cardiac dysfunction, demonstrating a therapeutic potential of miR-29b for chronic heart disease. Further studies revealed that targeting the transforming growth factor (TGF)-?1 coding sequence region, thereby inhibiting TGF-?/Smad3 signaling, could be a new mechanism by which miR-29b inhibited AngII-induced cardiac fibrosis. In conclusion, miR-29b plays a protective role in AngII-mediated cardiac remodeling and may be a therapeutic agent for cardiac fibrosis by targeting the TGF-?/Smad3 pathway.
Phytochemical investigation of the ethanol extract from the leaves of Momordica charantia L. led to the isolation of two new (1, 2) and four known (3-6) cucurbitane-type triterpenoids. Their structures were elucidated on the basis of extensive analyses of spectroscopic data including IR, UV, MS, 1D, and 2D NMR. Also the absolute configurations of momordicines I (3) and II (4) were determined for the first time by application of the modified Mosher's method, acid hydrolysis, and GC analysis.
To perform an updated meta-analysis of observational studies with unstratified cohort addressing whether compression-only cardiopulmonary resuscitation (CPR), compared with standard CPR, improves outcomes in adult patients with out-of-hospital cardiac arrest and a subgroup meta-analysis for the patients with cardiac etiology arrest.
Eight new oleanane-type triterpenoid saponins, named schefflesides A-H (1-8), were isolated from the aerial parts of Schefflera kwangsiensis. The structures of these new compounds were established on the basis of hydrolysis and spectroscopic evidence, including 1D- and 2D-NMR (HSQC, HMBC, ROESY and TOCSY) and HR-MS analyses.
In the present study, six new phenolic compounds (1-6) along with five known ones were isolated from the ethanol extract of the whole plants of Origanum vulgare. The structures of the new compounds were identified on the basis of extensive spectroscopic analyses (UV, IR, NMR, and HRESIMS) and acid hydrolysis. Twenty-one phenolic compounds isolated from O. vulgare in our previous and present studies were evaluated for their in vitro antioxidant activity using 2,2-diphenyl-1-picryhydrazyl (DPPH) radical-scavenging and ferric-reducing antioxidant power (FRAP) assays; twelve of them including two new compounds exhibited significant antioxidant activity comparable to that of ascorbic acid. In addition, the antiviral effects against respiratory syncytial virus (RSV), Coxsackie virus B3 (CVB3) and herpes simplex virus type 1 (HSV-1) were tested by cytopathic effect (CPE) reduction assay.
The perennial herbaceous plant Euphorbia jolkinii (Euphorbiaceae) is a noxious weed widely distributed in the grasslands of northwestern Yunnan and has greatly threatened the local biodiversity. Phytochemical investigation on the fresh roots of E. jolkinii afforded six new diterpenoids 1, 2, 4-6, and 8, together with fifteen known diterpenoids. Their structures were elucidated on the basis of 1D and 2D NMR and other spectroscopic methods. Casbane, lathyrane, abietane, and ent-kaurane diterpenoids were reported from this plant for the first time. Selected compounds were evaluated for their antifeedant and anti-RSV (respiratory syncytial virus) activities. Compound 2 and ingenol (3) exhibited moderate antifeedant activity against a generalist insect herbivore, Spodoptera exigua, with EC50 values of 17.88 and 17.71 ?g/cm(2) respectively. Compound 19 showed significant anti-RSV activity, with 50 % inhibition (IC50) value of 10.0 ?M and selective index of 8.0. Compounds 1 and 2 were less active against RSV virus, both with IC50 value of 25 ?M, and with selective indices of 1.0 and 3.2 respectively. These findings provided new evidence for the biological functions and utilization of the diversified diterpenoid metabolites in the roots of this rich but harmful plant.
Haze episodes often hit urban cities in China recently. Here, we present several continuous haze episodes with extremely high PM2.5 levels that occurred over several weeks in early 2013 and extended across most parts of the northern and eastern China-far exceeding the Beijing-Tianjin-Hebei region. Particularly, the haze episode covered ~1 million km(2) on January 14, 2013 and the daily averaged PM2.5 concentration exceeded 360 ?g m(-3) in Ji'nan. The observed maximum hourly PM2.5 concentration in urban Ji'nan reached 701 ?g m(-3) at 7:00 am (local time) in January 30. During these haze episodes, several fog events happened and the concurrent fog water was found to be seriously polluted. For the fog water collected in Ji'nan from 10:00 pm in January 14 to 11:00 am in January 15, sulfate, nitrate, and ammonium were the major ions with concentrations of 1.54 × 10(6), 8.98 × 10(5), and 1.75 × 10(6) ?eq L(-1), respectively, leading to a low in-situ pH of 3.30. The sulfate content in the fog sample was more than 544 times as high as those observed in other areas. With examination of the simultaneously observed data on PM2.5 and its chemical composition, the fog played a role in scavenging and removing fine particles from the atmosphere during haze episodes and thus was seriously contaminated. However, the effect was not sufficient to obviously cleanse air pollution and block haze episodes.
Peritoneal fibrosis is a major cause of ultrafiltration failure in patients receiving continuous ambulatory peritoneal dialysis. Transforming growth factor (TGF)-?1 is an important mediator in this process; however, its signaling mechanisms had not been explored. Thus, we examined TGF-?1/Smad signaling in human peritoneal biopsy specimens associated with continuous ambulatory peritoneal dialysis. We found that TGF-?/Smad2/3 signaling was highly activated in patients with increased collagen deposition and thickening of the peritoneal membrane who were receiving continuous ambulatory peritoneal dialysis. Long-term exposure of wild-type mice to 4.25% peritoneal dialysis solution for 30 days induced significant peritoneal fibrosis with impaired peritoneal equilibrium, which was prevented in Smad3 knockout mice. In contrast, conditional Smad2 gene deletion in the peritoneum exacerbated peritoneal fibrosis and dysfunction. The contrasting roles of Smad2 and Smad3 in peritoneal fibrosis were also examined in vitro. Cultured mesothelial cells from Smad3 knockout mice were resistant to TGF-?1-induced collagen I production and the transition toward a myofibroblast phenotype as seen in wild-type cells, whereas Smad2 deficiency in mesothelial cells failed to modulate the profibrotic response to TGF-?1. In conclusion, this study found activation of TGF-?/Smad signaling in peritoneal fibrosis in patients receiving continuous ambulatory peritoneal dialysis and identifies opposing roles for Smad2 and Smad3 in peritoneal dialysis-associated peritoneal fibrosis. These findings provide a mechanistic basis for future therapies targeting TGF-?/Smad signaling in peritoneal fibrosis.
Rheum palmatum L. and Coptis chinensis Franch., are two representative cold-natured traditional Chinese medicine with heat-clearing effect, and were widely used to treat fever associated diseases in China for a long history. To elucidate the mechanism of the antipyretic effect of Rheum palmatum L. and Coptis chinensis Franch. from the perspective of transient receptor potential vanilloid 1 and transient receptor potential melastatin 8 expression on yeast-induced pyrexia rat model.
P,C-stereogenic ?-hydroxyl phosphinates or phosphine oxides were prepared from the additions of (RP)-phosphinate to ketones or (RP)-phosphine oxide to aldehydes, respectively, catalyzed by bases at room temperature in up to >99:1 diasteromeric ratio (d.r.P/d.r.C) and 99?% yields. The diastereoselectivity was induced by reversible equilibrium and different stabilities between two diastereomers of adduct, which was caused by the spatial interaction between menthoxyl or menthyl to alkyl groups of aldehydes or ketones.
In the last few decades, health systems research (HSR) has garnered much attention with a rapid increase in the related literature. This study aims to review and evaluate the global progress in HSR and assess the current quantitative trends.
Increasing evidence shows that TGF-?1 is a key mediator in diabetic nephropathy (DN) and induces renal fibrosis positively by Smad3 but negatively by Smad7. However, treatment of DN by blocking the TGF-?/Smad pathway remains limited. The present study investigated the anti-fibrotic effect of a traditional Chinese medicine, Chaihuang-Yishen granule (CHYS), on DN.
Tissue kallikrein (KLK1) expression is up-regulated in human diabetic kidney tissue and induced by high glucose (HG) in human proximal tubular epithelial cells (PTEC). Since the kallikrein-kinin system (KKS) has been linked to cellular inflammatory process in many diseases, it is likely that KLK1 expression may mediate the inflammatory process during the development of diabetic nephropathy. In this study, we explored the role of KLK1 in tubular pro-inflammatory responses under the diabetic milieu. Recombinant KLK1 stimulated the production of inflammatory cytokines in PTEC via the activation of p42/44 and p38 MAPK signaling pathways. Molecular knockdown of endogenous KLK1 expression by siRNA transfection in PTEC attenuated advanced glycation end-products (AGE)-induced IL-8 and ICAM-1 productions in vitro. Interestingly, exposure of PTEC to KLK1 induced the expression of protease-activated receptors (PARs). There was a 2.9-fold increase in PAR-4, 1.4-fold increase in PAR-1 and 1.2-fold increase in PAR-2 mRNA levels. Activation of PAR-4 by a selective agonist was found to elicit the pro-inflammatory and pro-fibrotic phenotypes in PTEC while blockade of the receptor by specific antagonist attenuated high glucose-induced IL-6, CCL-2, CTGF and collagen IV expression. Calcium mobilization by the PAR-4 agonist in PTEC was desensitized by pretreatment with KLK1. Consistent with these in vitro findings, there was a markedly up-regulation of tubular PAR-4 expression in human diabetic renal cortical tissues. Together, these results suggest that up-regulation of KLK1 in tubular epithelial cells may mediate pro-inflammatory pathway and PAR activation during diabetic nephropathy and provide a new therapeutic target for further investigation.
In order to further understand the association between cellulose and lignin in gymnosperm plant, carbohydrate part of the lignin-carbohydrate complexes was analyzed. Cellulose precursor, i.e., (6(-13) C) uridine diphoshphate glucose, was synthesized, and injected into a living ginkgo tree with lignin inhibitor AOPP and exogenous lignin precursor. The results from the determination of 13C abundance indicate that the deposition of cellulose in the cell wall is very fast and effective in the primary wall. The analysis of high resolution solid nuclear magnetic 13C NMR spectra confirms that the bonds between C5 position of glucose units in cellulose and alpha-carbons of lignin side chain are benzyl ether linkage.
A pair of new enantiomeric stilbene dimers, (+)- and (-)-cajanusine [(+)-1 and (-)-1], with a unique coupling pattern were isolated from the leaves of Cajanus cajan . Their structures including absolute configurations were elucidated on the basis of comprehensive spectroscopic and single-crystal X-ray diffraction analyses, as well as CD calculations. The plausible biogenetic pathway of 1 was also proposed. Additionally, (±)-1, (+)-1, and (-)-1 exhibited inhibitory activities on the growth of human hepatocellular carcinoma cells.
Eight new bisdesmosidic triterpenoid saponins, clematiunicinosides A--H (1--8), along with eleven known ones (9--19), were isolated from the roots of Clematis uncinata. Their structures were elucidated on the basis of spectroscopic analysis and chemical evidence. All the isolated saponins were tested for their cytotoxic activities on human caski cervical cancer (Caski) cells, and compounds 13, 17 and 19 exhibited inhibitory effect on Caski cells.
The aim of this study was evaluated the prevalence of Treg cells in peripheral blood in patients with gastric cancer, and investigate the effect of gastric cancer cells on their differentiation. ELISA was employed to assess the concentrations of TGF-? and IL-10 in gastric cancer patients serum. Then, mouse gastric cancer cells were co-cultured with T lymphocytes or T lymphocytes + anti-TGF-?. Flow cytometric analysis and RT-PCR were then performed to detect Treg cells and TGF-? and IL-10 expression in gastric cancer cells. Our data showed that the expression of TGF-? and IL-10 in the patients with gastric cancer was increased compared to the case with healthy donors. The population of Treg cells and the expression levels of TGF-? and IL-10 in the co-culture group were much higher than in the control group (18.6% vs 9.5%) (P<0.05). Moreover, the population of Treg cells and the expression levels of TGF-? and IL-10 in the co-culture systerm were clearly decreased after addition of anti-TGF-? (7.7% vs 19.6%) (P<0.01). In conclusion, gastric cancer cells may induce Treg cell differentiation through TGF-?, and further promote immunosuppression.
Three new quinic acid derivatives, 4-O-caffeoyl-3-O-sinapoylquinic acid methyl ester (1), 5-O-caffeoyl-4-O-syringoylquinic acid methyl ester (2), and 4-O-caffeoyl-3-O-syringoylquinic acid methyl ester (3), as well as four new coumarin glycosides, 7-O-(3-O-sinapoyl-?-D-glucopyranosyl)-6-methoxycoumarin (12), 7-O-(6-O-sinapoyl-?-D-glucopyranosyl)-6-methoxycoumarin (13), 7-O-(2-O-sinapoyl-?-D-glucopyranosyl)-6-methoxycoumarin (14), and 7-O-(6-O-syringoyl-?-D-glucopyranosyl)-6-methoxycoumarin (15), together with eight known compounds (4-11) were isolated from the roots and stems of Erycibe obtusifolia. Their structures were elucidated on the basis of spectroscopic analysis and chemical evidence. All the compounds were screened for their in vitro antiviral activity against respiratory syncytial virus with a cytopathic effect reduction assay. Among them, the di-O-caffeoyl quinates 8-11 displayed a potent in vitro anti-respiratory syncytial virus effect.
Dragon is one of the three members of the repulsive guidance molecule (RGM) family, i.e. RGMa, RGMb (Dragon), and RGMc (hemojuvelin). We previously identified the RGM members as bone morphogenetic protein (BMP) co-receptors that enhance BMP signaling. Our previous studies found that Dragon is highly expressed in the tubular epithelial cells of mouse kidneys. However, the roles of Dragon in renal epithelial cells are yet to be defined. We now show that overexpression of Dragon increased cell death induced by hypoxia in association with increased cleaved poly(ADP-ribose) polymerase and cleaved caspase-3 levels in mouse inner medullary collecting duct (IMCD3) cells. Dragon also inhibited E-cadherin expression but did not affect epithelial-to-mesenchymal transition induced by TGF-? in IMCD3 cells. Previous studies suggest that the three RGM members can function as ligands for the receptor neogenin. Interestingly, our present study demonstrates that the Dragon actions on apoptosis and E-cadherin expression in IMCD3 cells were mediated by the neogenin receptor but not through the BMP pathway. Dragon expression in the kidney was up-regulated by unilateral ureteral obstruction in mice. Compared with wild-type mice, heterozygous Dragon knock-out mice exhibited 45-66% reduction in Dragon mRNA expression, decreased epithelial apoptosis, and increased tubular E-cadherin expression and had attenuated tubular injury after unilateral ureteral obstruction. Our results suggest that Dragon may impair tubular epithelial integrity and induce epithelial apoptosis both in vitro and in vivo.
MSCs have been shown to improve functional and pathological outcome in lung fibrosis. However, low in vivo cell engraftment of the transplanted cells limits their overall effectiveness. KGF (also known as FGF-7) is a critical mediator of pulmonary epithelial repair through stimulation of epithelial cell proliferation. However, the role of KGF in MSCs and its therapeutic effects have not been identified. In this study, we investigated the effect of KGF on MSCs and its preventive role in hyperoxia-induced fibrosis in neonatal rats. Neonatal rats exposed to normoxia or hyperoxia were randomly assigned to receive intraperitoneal injections of normal saline (PL), MSCs, or KGF pretreated MSCs on the fourth day of exposure. Our results showed that as compared to PL, while MSCs attenuated lung fibrosis, KGF pretreated MSCs exhibited enhanced preventive effect against lung fibrosis. This effect was partly attributed to enhanced mobilization of MSCs to the fibrotic lungs. In addition, the SHH signaling pathway, which is associated with the differentiation of stem cells was activated by KGF. Our data suggest that MSCs, especially KGF preconditioned MSCs, can attenuate lung fibrosis and KGF may regulate the MSCs behavior by activating SHH pathway.
Several randomized controlled trials (RCTs) have compared endoscopic and symptomatic relapses in patients with erosive gastroesophageal reflux disease (GERD). We have summarized current evidence for rabeprazole 10 or 20 mg once daily for GERD maintenance treatment over 1 or 5 years.
Phytochemical investigation on the stem bark of Schefflera heptaphylla led to the isolation of five new ursane-type triterpenoid saponins (1-5). Their structures were determined on the basis of spectroscopic and chemical methods. It is noteworthy in this study that the genins of all compounds are reported for the first time. All compounds isolated from this plant were evaluated for their inhibitory activities on lipopolysaccharide-induced nitric oxide production in RAW264.7 cells, and compounds 2 and 5 showed weak anti-inflammatory activities under their non-cytotoxic concentrations.
Nine new triterpenoid saponins, including four ursane-type triterpenoid saponins named heptursosides A-D (1-4), four oleanane-type triterpenoid saponins named heptoleosides A-D (5-8), and one dammarane-type triterpenoid saponin, heptdamoside A (9), along with two known saponins, asiaticoside D (10) and scheffoleoside B (11), were isolated from the stem barks of Schefflera heptaphylla. Their structures were determined on the basis of spectroscopic analysis and chemical methods. It is noteworthy in this study that the aglycone of 1-6 is reported for the first time, and to the best of our knowledge, this is the first report for the presence of the tetracyclic triterpenoid saponin from Schefflera. All the saponins were evaluated for their inhibitory effects on lipopolysaccharide-induced nitric oxide production in RAW264.7 cells, and 2, 6, 7, and 10 showed anti-inflammatory activities under their noncytotoxic concentrations.
Translational medical research literature has increased rapidly in the last few decades and played a more and more important role during the development of medicine science. The main aim of this study is to evaluate the global performance of translational medical research during the past few decades.
Smad7 plays a negative regulatory role in many inflammatory diseases, but its effect on hypertensive disease remains unknown. The present study tested the hypothesis that overexpression of Smad7 may have therapeutic potential for angiotensin II (Ang II)-mediated hypertensive cardiac remodelling.
Two new acetylated flavonoid glycosides, quercetin 3-O-?-l-(2,4-di-O-acetyl) rhamnopyranoside-7-O-?-l-rhamnopyranoside (1) and quercetin 3-O-?-l-(3,4-di-O-acetyl) rhamnopyranoside-7-O-?-l-rhamnopyranoside (2), together with two known compounds, quercetin (3) and quercetin 3-O-?-l-rhamnopyranoside (4), were isolated from the ethanol extract of Phyllanthus urinaria. The structures of the new compounds were determined on the basis of extensive spectroscopic data including IR, HR-ESI-MS, 1D NMR, and 2D NMR.
Inhibition of pulmonary arterial smooth muscle cell (PASMC) apoptosis induced by hypoxia plays an important role in pulmonary arterial remodeling leading to aggravate hypoxic pulmonary arterial hypertension. However, the mechanisms of hypoxia acting on PASMC apoptosis remain exclusive. Biliverdin reductase (BVR) has many essential biologic roles in physiological and pathological processes. Nevertheless, it is unclear whether the hypoxia-induced inhibition on PASMC apoptosis is mediated by BVR. In the present work, we found BVR majorly localized in PASMCs and was up-regulated in levels of protein and mRNA by hypoxia. Then we studied the contribution of BVR to anti-apoptotic response of hypoxia in PASMCs. Our results showed that siBVR, blocking generation of bilirubin, reversed the effect of hypoxia on enhancing cell survival and apoptotic protein (Bcl-2, procasepase-9, procasepase-3) expression, preventing nuclear shrinkage, DNA fragmentation and mitochondrial depolarization in starved PASMCs, which were recovered by exogenous bilirubin. Moreover, the inhibitory effect of bilirubin on PASMC apoptosis under hypoxic condition was blocked by the inhibitor of ERK1/2 pathway. Taken together, our data indicate that BVR contributes to the inhibitory process of hypoxia on PASMC apoptosis, which is mediated by bilirubin through ERK1/2 pathway.
A series of methods has been used to evaluate metal ceramic bond strength. However, little attention has been paid to the wettability and interfacial reactions of dental porcelain/alloy systems, which may affect the bond strength of metal ceramic restorations.
Physician payment system (PPS) is a principal incentive system to motivate doctors to provide excellent care for patients. During the past decade, physician remuneration in China has not been in proportional to physicians average work load and massive responsibilities. This paper reviewed the constitution of the PPS in China, and further discussed the problems and issues to be addressed with respect to pay for performance. Our study indicated that the lower basic salary and bonus distribution tied to "profits" was the major contributor to the physicians profit-driven incentive and the potential cause for the speedy growth of health expenditures. We recommend that government funding to hospitals should be increased to fully cover physicians basic salary, a flexible human resource and talent management mechanism needs to be established that severs personal interest between physicians and hospitals, and modern performance assessment and multiplexed payment systems should be piloted to encourage physicians to get the more legitimate compensation.
Chinas New Rural Cooperative Medical Scheme (NCMS) is designed to improve health-service access for rural residents and prevent impoverishment due to medical expenses. Ethnic minority regions in China have specific socioeconomic conditions and policy environments worthy of exploration to assist in the development of rural health insurance schemes.
Objective: To evaluate the impact of two medical insurers policies on the hospitalization of people with schizophrenia and the economic burden they faced during a period of rapid health services reform in China. Methodology: A comparative analysis was made of Urban Employee-Basic Medical Insurance (UE-BMI) and Urban Residents-Basic Medical Insurance (UR-BMI) policies on the medical management of schizophrenics, and was compared with hospitalization expenses, insurer reimbursement data and other information collected from the HMO (health maintenance organization) and social insurance agencies on the care of people with schizophrenia in Changsha in 2010. In-depth interviews were also conducted with relevant managers. Results: Compared with inpatients covered by UR-BMI, the inpatients of UE-BMI were admitted to higher level medical institutions and were prescribed expensive second generation antipsychotics (SGA) medicines. Nevertheless, the hospitalization service utilization and cost of inpatients hospitalization under UE-BMI were far less than that of inpatients under UR-BMI. Conclusions: The insurance level difference between two medical insurance schemes influences the treatment regimens and benefits received by patients. Furthermore, the integration of schizophrenia management into the outpatient services pooling fund for special diseases(OS-PFSD) can appropriately reduce hospitalization utilization, which, together with the payment way reform and the prescription of reasonable medications, can significantly reduce the overall hospitalization cost for patients.
The size-fractionated characteristics of particulate polycyclic aromatic hydrocarbons (PAHs) were studied from January 2011 to October 2011 using a Micro-orifice Uniform Deposit Impactor (MOUDI) at the Yellow River Delta National Nature Reserve (YRDNNR), a background site located in the North China Plain. The average annual concentration of total PAHs in the YRDNNR (18.95 ± 16.51 ng/m(3)) was lower than that in the urban areas of China; however, it was much higher than that in other rural or remote sites in developed countries. The dominant PAHs, which were found in each season, were fluorene (5.93%-26.80%), phenanthrene (8.17%-26.52%), fluoranthene (15.23%-27.12%) and pyrene (9.23%-16.31%). A bimodal distribution was found for 3-ring PAHs with peaks at approximately 1.0-1.8 ?m and 3.2-5.6 ?m; however, 4-6 ring PAHs followed a nearly unimodal distribution, with the highest peak in the 1.0-1.8 ?m range. The mass median diameter (MMD) values for the total PAHs averaged 1.404, 1.467, 1.218 and 0.931 ?m in spring, summer, autumn and winter, respectively. The toxicity analysis indicated that the carcinogenic potency of particulate PAHs existed primarily in the <1.8 ?m size range. Diagnostic ratios and PCA analysis indicated that the PAHs in aerosol particles were mainly derived from coal combustion. In addition, back-trajectory calculations demonstrated that atmospheric PAHs were produced primarily by local anthropogenic sources.
RPS19 (ribosomal protein S19), a component of the 40S small ribosomal subunit, has recently been identified to bind the pro-inflammatory cytokine macrophage MIF (migration inhibitory factor). In vitro experiments identify RPS19 as the first endogenous MIF inhibitor by blocking the binding of MIF to its receptor CD74 and MIF functions on monocyte adherence to endothelial cells. In the present study, we sought to establish whether recombinant RPS19 can exert anti-inflammatory effects in a mouse model of anti-GBM (glomerular basement membrane) GN (glomerulonephritis) in which MIF is known to play an important role. Accelerated anti-GBM GN was induced in C57BL/6J mice by immunization with sheep IgG followed 5 days later by administration of sheep anti-mouse GBM serum. Groups of eight mice were treated once daily by intraperitoneal injection with 6 mg of RPS19/kg of body weight or an irrelevant control protein (human secretoglobin 2A1), or received no treatment, from day 0 until being killed on day 10. Mice that received control or no treatment developed severe crescentic anti-GBM disease on day 10 with increased serum creatinine, declined creatinine clearance and increased proteinuria. These changes were associated with up-regulation of MIF and its receptor CD74 activation of ERK (extracellular-signal-regulated kinase) and NF-?B (nuclear factor ?B) signalling, prominent macrophage and T-cell infiltration, as well as up-regulation of Th1 [T-bet and IFN? (interferon ?)] and Th17 [STAT3 (signal transducer and activator of transcription 3) and IL (interleukin)-17A] as well as IL-1? and TNF? (tumour necrosis factor ?). In contrast, RPS19 treatment largely prevented the development of glomerular crescents and glomerular necrosis, and prevented renal dysfunction and proteinuria (all P<0.001). Of note, RPS19 blocked up-regulation of MIF and CD74 and inactivated ERK and NF-?B signalling, thereby inhibiting macrophage and T-cell infiltration, Th1 and Th17 responses and up-regulation of pro-inflammatory cytokines (all P<0.01). These results demonstrate that RPS19 is a potent anti-inflammatory agent, which appears to work primarily by inhibiting MIF signalling.
Smad7 is a principal inhibitor of the TGF?-Smad signalling pathway. We have investigated the functional significance of Smad7 in hepatocellular carcinoma (HCC). Smad7 knockout (KO) and wild-type (WT) mice were injected with diethylnitrosamine (DEN) to induce HCC. The effects of Smad7 on cellular features were examined in HCC cells, using a Smad7 over-expression or deletion approach. Signalling pathway components modulated by Smad7 in HCC were evaluated using luciferase reporter assay and co-immunoprecipitation. Smad7 was down-regulated in human HCCs compared with the adjacent normal tissues (p < 0.001). Smad7 KO mice were more susceptible to DEN-induced HCC than WT mice (78% versus 22%, p < 0.05). HCCs from KO mice displayed a greater proliferation activity (p < 0.05) and a reduced apoptotic index compared with WT littermates (p < 0.05). Deletion of Smad7 promoted cell proliferation in primary cultured HCC cells. In addition, over-expression of Smad7 in HCC cell lines markedly suppressed cell growth (p < 0.0001) and colony formation (p < 0.01). Cell cycle analysis revealed an increase in the G1 phase and a reduction in the S-phase populations, accompanied by up-regulation of p27(Kip1) and down-regulation of cyclin D1. Smad7 increased cell apoptosis (p < 0.01) by mediating an intrinsic [caspase-9, caspase-3 and poly(ADP-ribose) polymerase] apoptotic pathway. Moreover, Smad7 inhibited NF-?B signalling by interacting with TAB2, an upstream activator of NF-?B, and inhibited TGF? signalling by suppressing phosphorylation of Smad3. In conclusion, loss of Smad7 enhances susceptibility to HCC. Smad7 suppresses HCC cell growth by inhibiting proliferation and G1 -S phase transition and inducing apoptosis through attenuation of NF-?B and TGF? signalling. Smad7 acts as a potential tumour suppressor in liver.
China embarked on an ambitious health system reform in 2009, and pledged to achieve universal health insurance coverage by 2020. However, there are gaps in access to healthcare for some children in China. We assessed health insurance status and associated variables among children under five in twelve communities in 2010: two urban community health centers and two rural township health centers in each of three municipalities located in Chinas distinctly different East, Central and Western regions. Information on demographic and socio-economic variables and childrens insurance status was gathered from parents or caregivers of all children enrolled in local health programs, and others recruited from the local communities. Only 62% of 1131 children assessed were insured. This figure did not vary across geographic regions, but urban children were less likely to be insured than rural children. In multivariate analysis, infants were 2.44 times more likely to be uninsured than older children and children having at least one migrant parent were 1.90 times more likely to be uninsured than those living with non-migrant parents. Low maternal education was also associated with being uninsured. Gaps in Chinas child health insurance coverage might be bridged if newborns are automatically covered from birth, and if insurance is extended to all urban migrant children, regardless of the familys residential registration status and size.
Ten eudesmane-type sesquiterpene derivatives (1-10), including six cuauhtemone derivatives (1-6), one di-norsesquiterpene (3-oxo-di-nor-eudesma-4-en-11-oic acid, 7), and three eudesmane glycosides (alatoside F-H, 8-10) were isolated from the whole plants of Laggera alata together with 12 known compounds. Their structures were elucidated on the basis of extensive spectroscopic analysis, acid hydrolysis, and compounds 1 and 7 were studied by single-crystal X-ray diffraction analysis. The absolute configuration of 1 was determined by the application of the modified Moshers method. All of the isolated eudesmane-type sesquiterpenes were evaluated for their cytotoxic activities on six human cancer cell lines, but all of the compounds were inactive on the tested cell lines in the concentration of 100?g/mL.
Controllable doping of semiconductor nanowires is critical to realize their proposed applications, however precise and reliable characterization of dopant distributions remains challenging. In this article, we demonstrate an atomic-resolution three-dimensional elemental mapping of pristine semiconductor nanowires on growth substrates by using atom probe tomography to tackle this major challenge. This highly transferrable method is able to analyze the full diameter of a nanowire, with a depth resolution better than 0.17 nm thanks to an advanced reconstruction method exploiting the specimens crystallography, and an enhanced chemical sensitivity of better than 8-fold increase in the signal-to-noise ratio.
We develop a method for pH-dependent fusion between liposomes and cellular membranes using pHLIP® (pH Low Insertion Peptide), which inserts into lipid bilayer of membrane only at low pH. Previously we establish the molecular mechanism of peptide action and show that pHLIP can target acidic diseased tissue. Here we investigate how coating of PEGylated liposomes with pHLIP might affect liposomal uptake by cells. The presence of pHLIP on the surface of PEGylated-liposomes enhanced membrane fusion and lipid exchange in a pH dependent fashion, leading to increase of cellular uptake and payload release, and inhibition of cell proliferation by liposomes containing ceramide. A novel type of pH-sensitive, "fusogenic" pHLIP-liposomes was developed, which could be used to selectively deliver various diagnostic and therapeutic agents to acidic diseased cells.
Dill, a small annual herb, is widely used as a flavoring agent in dishes including salads. It has been demonstrated that dill extract and its essential oil show hypolipidemic effects in rats. However, the mechanism of these effects has not been elucidated yet. We found that dill seed extract (DSE) activated peroxisome proliferator-activated receptor-? (PPAR-?), an indispensable regulator for hepatic lipid metabolism, by luciferase assay. Thus, we performed DSE feeding experiments using diabetic obese model KK-Ay mice to examine the effects of DSE on PPAR-? activation in vivo. A 4-week feeding of DSE contained in a high-fat diet decreased plasma triacylglyceride and glucose levels and increased the mRNA expression levels of fatty acid oxidation-related genes in the liver. In addition, the DSE feeding as well as bezafibrate (a PPAR-? potent agonist) feeding increased oxygen consumption rate and rectal temperature. These results indicate that DSE suppresses high-fat diet-induced hyperlipidemia through hepatic PPAR-? activation.
QX-314 (N-ethyl-lidocaine) is a cationic lidocaine derivative that blocks voltage-dependent sodium channels when applied internally to axons or neuronal cell bodies. Coapplication of external QX-314 with the transient receptor potential vanilloid 1 protein (TRPV1) agonist capsaicin produces long-lasting sodium channel inhibition in TRPV1-expressing neurons, suggestive of QX-314 entry into the neurons. We asked whether QX-314 entry occurs directly through TRPV1 channels or through a different pathway (e.g., pannexin channels) activated downstream of TRPV1 and whether QX-314 entry requires the phenomenon of "pore dilation" previously reported for TRPV1. With external solutions containing 10 or 20 mM QX-314 as the only cation, inward currents were activated by stimulation of both heterologously expressed and native TRPV1 channels in rat dorsal root ganglion neurons. QX-314-mediated inward current did not require pore dilation, as it activated within several seconds and in parallel with Cs-mediated outward current, with a reversal potential consistent with PQX-314/PCs = 0.12. QX-314-mediated current was no different when TRPV1 channels were expressed in C6 glioma cells, which lack expression of pannexin channels. Rapid addition of QX-314 to physiological external solutions produced instant partial inhibition of inward currents carried by sodium ions, suggesting that QX-314 is a permeant blocker. Maintained coapplication of QX-314 with capsaicin produced slowly developing reduction of outward currents carried by internal Cs, consistent with intracellular accumulation of QX-314 to concentrations of 50-100 ?M. We conclude that QX-314 is directly permeant in the "standard" pore formed by TRPV1 channels and does not require either pore dilation or activation of additional downstream channels for entry.
Five new phenolic glycosides, hedyotosides A-E (1-5), including a new cyanogenic glycoside (1), along with 10 known compounds (6-15) were isolated from the whole plants of Hedyotis scandens. The structures of compounds 1-5 were established by extensive spectroscopic analyses and acid hydrolysis. All the isolated compounds were evaluated for their in vitro antiviral activity against respiratory syncytial virus (RSV) with cytopathic effect (CPE) reduction assay. Compounds 6 and 15 showed anti-RSV effects with IC(50) values of 20 and 25 ?g/mL, respectively.
The treatment of patients with MDR- and XDR-TB is usually more complex, toxic and costly and less effective than treatment of other forms of TB. However, there is little information available on risk factors for poor outcomes in patients with MDR- and XDR-TB in China.
Smad7 has been shown to negatively regulate fibrosis and inflammation, but its role in angiotensin II (Ang II)-induced hypertensive cardiac remodeling remains unknown. Therefore, the present study investigated the role of Smad7 in hypertensive cardiopathy induced by angiotensin II infusion. Hypertensive cardiac disease was induced in Smad7 gene knockout (KO) and wild-type (WT) mice by subcutaneous infusion of Ang II (1.46 mg/kg/day) for 28 days. Although equal levels of high blood pressure were developed in both Smad7 KO and WT mice, Smad7 KO mice developed more severe cardiac injury as demonstrated by impairing cardiac function including a significant increase in left ventricular (LV) mass (P<0.01),reduction of LV ejection fraction(P<0.001) and fractional shortening(P<0.001). Real-time PCR, Western blot and immunohistochemistry detected that deletion of Smad7 significantly enhanced Ang II-induced cardiac fibrosis and inflammation, including upregulation of collagen I, ?-SMA, interleukin-1?, TNF-?, and infiltration of CD3(+) T cells and F4/80(+) macrophages. Further studies revealed that enhanced activation of the Sp1-TGF?/Smad3-NF-?B pathways and downregulation of miR-29 were mechanisms though which deletion of Smad7 promoted Ang II-mediated cardiac remodeling. In conclusions, Smad7 plays a protective role in AngII-mediated cardiac remodeling via mechanisms involving the Sp1-TGF-?/Smad3-NF.?B-miR-29 regulatory network.
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