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1.  Cracking the Cytotoxicity Code: Apoptotic Induction of 10-Acetylirciformonin B is Mediated through ROS Generation and Mitochondrial Dysfunction 
Marine Drugs  2014;12(5):3072-3090.
A marine furanoterpenoid derivative, 10-acetylirciformonin B (10AB), was found to inhibit the proliferation of leukemia, hepatoma, and colon cancer cell lines, with selective and significant potency against leukemia cells. It induced DNA damage and apoptosis in leukemia HL 60 cells. To fully understand the mechanism behind the 10AB apoptotic induction against HL 60 cells, we extended our previous findings and further explored the precise molecular targets of 10AB. We found that the use of 10AB increased apoptosis by 8.9%–87.6% and caused disruption of mitochondrial membrane potential (MMP) by 15.2%–95.2% in a dose-dependent manner, as demonstrated by annexin-V/PI and JC-1 staining assays, respectively. Moreover, our findings indicated that the pretreatment of HL 60 cells with N-acetyl-l-cysteine (NAC), a reactive oxygen species (ROS) scavenger, diminished MMP disruption and apoptosis induced by 10AB, suggesting that ROS overproduction plays a crucial rule in the cytotoxic activity of 10AB. The results of a cell-free system assay indicated that 10AB could act as a topoisomerase catalytic inhibitor through the inhibition of topoisomerase IIα. On the protein level, the expression of the anti-apoptotic proteins Bcl-xL and Bcl-2, caspase inhibitors XIAP and survivin, as well as hexokinase II were inhibited by the use of 10AB. On the other hand, the expression of the pro-apoptotic protein Bax was increased after 10AB treatment. Taken together, our results suggest that 10AB-induced apoptosis is mediated through the overproduction of ROS and the disruption of mitochondrial metabolism.
doi:10.3390/md12053072
PMCID: PMC4052332  PMID: 24857964
10-acetylirciformonin B; apoptosis; hexokinase; mitochondria; reactive oxygen species (ROS); topoisomerase
2.  Efficacy of novel antibacterial compounds targeting histidine kinase YycG protein 
Treating staphylococcal biofilm-associated infections is challenging. Based on the findings that compound 2 targeting the HK domain of Staphylococcus epidermidis YycG has bactericidal and antibiofilm activities against staphylococci, six newly synthesized derivatives were evaluated for their antibacterial activities. The six derivatives of compound 2 inhibited autophosphorylation of recombinant YycG′ and the IC50 values ranged from 24.2 to 71.2 μM. The derivatives displayed bactericidal activity against planktonic S. epidermidis or Staphylococcus aureus strains in the MIC range of 1.5–3.1 μM. All the derivatives had antibiofilm activities against the 6- and 24-h biofilms of S. epidermidis. Compared to the prototype compound 2, they had less cytotoxicity for Vero cells and less hemolytic activity for human erythrocytes. The derivatives showed antibacterial activities against clinical methicillin-resistant staphylococcal isolates. The structural modification of YycG inhibitors will assist the discovery of novel agents to eliminate biofilm infections and multidrug-resistant staphylococcal infections.
Electronic supplementary material
The online version of this article (doi:10.1007/s00253-014-5685-8) contains supplementary material, which is available to authorized users.
doi:10.1007/s00253-014-5685-8
PMCID: PMC4057637  PMID: 24737057
Staphylococcus epidermidis; Methicillin-resistant Staphylococcus aureus (MRSA); Antibacterial; Minimal inhibitory concentration (MIC); Minimal bactericidal concentration (MBC); Antibiofilm activity
3.  The Pilot Study of Fibrin with Temporomandibular Joint Derived Synovial Stem Cells in Repairing TMJ Disc Perforation 
BioMed Research International  2014;2014:454021.
TMJ disc related diseases are difficult to be cured due to the poor repair ability of the disc. TMJ-SDSCs were ideal cell sources for cartilage tissue engineering which have been widely used in hyaline cartilage regeneration. Fibrin gel has been demonstrated as a potential scaffold for neocartilage formation. The aim of this study was to repair the TMJ disc perforation using fibrin/chitosan hybrid scaffold combined with TMJ-SDSCs. Rat TMJ-SDSCs were cultured on hybrid scaffold or pure chitosan scaffolds. The cell seeding efficiency, distribution, proliferation, and chondrogenic differentiation capacity were investigated. To evaluate the in vivo repair ability of cell/scaffold construct, rat TMJ disc explants were punched with a defect to mimic TMJ disc perforation. Cell seeded scaffolds were inserted into the defect of TMJ disc explants and then were implanted subcutaneously in nude mice for 4 weeks. Results demonstrated that fibrin may improve cell seeding, proliferation, and chondrogenic induction in vitro. The in vivo experiments showed more cartilage ECM deposition in fibrin/chitosan scaffold, which suggested an enhanced reparative ability. This pilot study demonstrated that the regenerative ability of TMJ-SDSCs seeded in fibrin/chitosan scaffold could be applied for repairing TMJ disc perforation.
doi:10.1155/2014/454021
PMCID: PMC4009306  PMID: 24822210
4.  Briarane Diterpenoids Isolated from Gorgonian Corals between 2011 and 2013 
Marine Drugs  2014;12(4):2164-2181.
The structures, names, bioactivities and references of 138 briarane-type diterpenoids, including 87 new compounds, are summarized in this review. All the briarane-type compounds mentioned in this review article were obtained from gorgonian corals including the genus Briareum, Dichotella, Junceella and Verrucella. Some of these compounds showed potential bioactivities.
doi:10.3390/md12042164
PMCID: PMC4012436  PMID: 24727390
Gorgonacea; briarane; Briareum; Dichotella; Junceella; Verrucella
5.  Cladieunicellins M–Q, New Eunicellins from Cladiella sp. 
Marine Drugs  2014;12(4):2144-2155.
Five new 7α-hydroxyeunicellin-based diterpenoids, designated as cladieunicellins M–Q (1–5), were isolated from a Formosan octocoral Cladiella sp. The structures of 1–5 were elucidated on the basis of spectroscopic methods and by comparison of the data with those of the related metabolites. Cytotoxicity of metabolites 1–5 against the human leukemia Molt 4 and HL 60 is also described. Among them, compounds 1, 3 and 5 exhibited moderate cytotoxicity toward Molt 4 cells with IC50 values 16.43, 14.17 and 15.55 μM, respectively. Preliminary SAR (structure activity relationship) information was obtained from these compounds and their analogues.
doi:10.3390/md12042144
PMCID: PMC4012457  PMID: 24717524
eunicellin; Cladiella; cladieunicellin; cytotoxicity
6.  Renal tuberculosis and iliopsoas abscess: Two case reports 
The urinary system is the second most commonly affected site of extrapulmonary tuberculosis (TB). Due to the diverse and atypical clinical manifestations of urinary TB, the disease is easy to misdiagnose. In the present study, two cases of renal TB are reported, which had completely different clinical manifestations. The first case is a female who presented with loin pain and fever. Purified protein derivative (PPD) and TB antibody tests were negative and computed tomography (CT) scans showed a low density focus in the right kidney with an iliopsoas abscess. The typical CT findings indicated renal tuberculosis. Anti-TB drugs were effective proved the diagnosis. The second case is a male who presented with intermittent gross hematuria. Acid-fast bacilli in urine and TB antibody tests were positive. CT scans revealed a low density focus in the unilateral kidney with a slight expansion of the pelvis, calices and ureter. The patients were treated with the anti-TB drugs and the clinical manifestations disappeared. The diagnosis of urinary TB is challenging in certain cases; when there is no response to the usual antibiotics in patients with fever or gross hematuria, TB should be suspected. CT is the mainstay for investigating possible urinary TB.
doi:10.3892/etm.2014.1623
PMCID: PMC4043625  PMID: 24926373
renal tuberculosis; iliopsoas abscess
7.  Application of vitamin E to antagonize SWCNTs-induced exacerbation of allergic asthma 
Scientific Reports  2014;4:4275.
The aggravating effects of zero-dimensional, particle-shaped nanomaterials on allergic asthma have been previously investigated, but similar possible effects of one-dimensional shaped nanomaterials have not been reported. More importantly, there are no available means to counteract the adverse nanomaterial effects to allow for their safe use. In this study, an ovalbumin (OVA)-sensitized rat asthma model was established to investigate whether single walled carbon nanotubes (SWCNTs) aggravate allergic asthma. The results showed that SWCNTs in rats exacerbated OVA-induced allergic asthma and that this exacerbation was counteracted by concurrent administration vitamin E. A mechanism involving the elimination of reactive oxygen species, downregulation of Th2 responses, reduced Ig production, and the relief of allergic asthma symptoms was proposed to explain the antagonistic effects of vitamin E. This work could provide a universal strategy to effectively protect people with allergic asthma from SWCNTs or similar nanomaterial-induced aggravating effects.
doi:10.1038/srep04275
PMCID: PMC3940970  PMID: 24589727
8.  Cognitive deficits and decreased locomotor activity induced by single-walled carbon nanotubes and neuroprotective effects of ascorbic acid 
Single-walled carbon nanotubes (SWCNTs) have shown increasing promise in the field of biomedicine, especially in applications related to the nervous system. However, there are limited studies available on the neurotoxicity of SWCNTs used in vivo. In this study, neurobehavioral changes caused by SWCNTs in mice and oxidative stress were investigated. The results of ethological analysis (Morris water maze and open-field test), brain histopathological examination, and assessments of oxidative stress (reactive oxygen species [ROS], malondialdehyde [MDA], and glutathione [GSH]), inflammation (nuclear factor κB, tumor necrosis factor α, interleukin-1β), and apoptosis (cysteine-aspartic acid protease 3) in brains showed that 6.25 and 12.50 mg/kg/day SWCNTs in mice could induce cognitive deficits and decreased locomotor activity, brain histopathological alterations, and increased levels of oxidative stress, inflammation, and apoptosis in mouse brains; however, 3.125 mg/kg/day SWCNTs had zero or minor adverse effects in mice, and these effects were blocked by concurrent administration of ascorbic acid. Down-regulation of oxidative stress, inflammation, and apoptosis were proposed to explain the neuroprotective effects of ascorbic acid. This work suggests SWCNTs could induce cognitive deficits and decreased locomotor activity, and provides a strategy to avoid the adverse effects.
doi:10.2147/IJN.S56339
PMCID: PMC3930484  PMID: 24596461
behavioral changes; oxidative stress; inflammation; apoptosis
9.  High-Throughput Flow Cytometry Compatible Biosensor Based on Fluorogen Activating Protein Technology 
Monitoring the trafficking of multiple proteins simultaneously in live cells is of great interest because many receptor proteins are found to function together with others in the same cell. However, existing fluorescent labeling techniques have restricted the mechanistic study of functional receptor pairs. We have expanded a hybrid system combining fluorogen activating protein (FAP) technology and high-throughput flow cytometry to a new type of biosensor that is robust, sensitive, and versatile. This provides the opportunity to study multiple trafficking proteins in the same cell. Human beta2 adrenergic receptor (β2AR) fused with FAP AM2.2 and murine C-C chemokines receptor type 5 fused with FAP MG13 was chosen for our model system. The function of the receptor and the binding between MG13 and fluorogen MG-2p have been characterized by flow cytometry and confocal microscopy assays. The binding of fluorogen and the FAP pair is highly specific, while both FAP-tagged fusion proteins function similarly to their wild type counterparts. The system has successfully served as a counter screen assay to eliminate false positive compounds identified in a screen against NIH Molecular Libraries Small Molecule Repository targeting regulators of the human β2AR.
doi:10.1002/cyto.a.22242
PMCID: PMC3621705  PMID: 23303704
High-throughput; Flow Cytometry; Fluorogen Activating Protein; Live Cell; Protein Trafficking
10.  The Potential Role of As-sumo-1 in the Embryonic Diapause Process and Early Embryo Development of Artemia sinica 
PLoS ONE  2014;9(1):e85343.
During embryonic development of Artemia sinica, environmental stresses induce the embryo diapause phenomenon, required to resist apoptosis and regulate cell cycle activity. The small ubiquitin-related modifier-1 (SUMO), a reversible post-translational protein modifier, plays an important role in embryo development. SUMO regulates multiple cellular processes, including development and other biological processes. The molecular mechanism of diapause, diapause termination and the role of As-sumo-1 in this processes and in early embryo development of Artemia sinica still remains unknown. In this study, the complete cDNA sequences of the sumo-1 homolog, sumo ligase homolog, caspase-1 homolog and cyclin B homolog from Artemia sinica were cloned. The mRNA expression patterns of As-sumo-1, sumo ligase, caspase-1, cyclin B and the location of As-sumo-1 were investigated. SUMO-1, p53, Mdm2, Caspase-1, Cyclin B and Cyclin E proteins were analyzed during different developmental stages of the embryo of A. sinica. Small interfering RNA (siRNA) was used to verify the function of sumo-1 in A. sinica. The full-length cDNA of As-sumo-1 was 476 bp, encoding a 92 amino acid protein. The As-caspases-1 cDNA was 966 bp, encoding a 245 amino-acid protein. The As-sumo ligase cDNA was 1556 bp encoding, a 343 amino acid protein, and the cyclin B cDNA was 739 bp, encoding a 133 amino acid protein. The expressions of As-sumo-1, As-caspase-1 and As-cyclin B were highest at the 10 h stage of embryonic development, and As-sumo ligase showed its highest expression at 0 h. The expression of As-SUMO-1 showed no tissue or organ specificity. Western blotting showed high expression of As-SUMO-1, p53, Mdm2, Caspase-1, Cyclin B and Cyclin E at the 10 h stage. The siRNA caused abnormal development of the embryo, with increased malformation and mortality. As-SUMO-1 is a crucial regulation and modification protein resumption of embryonic diapause and early embryo development of A. sinica.
doi:10.1371/journal.pone.0085343
PMCID: PMC3880333  PMID: 24404204
11.  Discovery of Novel Diterpenoids from Sinularia arborea 
Marine Drugs  2014;12(1):385-393.
Two novel diterpenoids, sinularbols A (1) and B (2), which were found to possess a new carbon skeleton were isolated from the soft coral Sinularia arborea. The structures of compounds 1 and 2 were elucidated by spectroscopic methods and 2 displayed a moderately inhibitory effect on the generation of superoxide anion by human neutrophils.
doi:10.3390/md12010385
PMCID: PMC3917279  PMID: 24445307
sinularbol; sinularborane; diterpenoid; Sinularia arborea; superoxide anion
12.  Quantitative Assessment of the Association of COX-2 (Cyclooxygenase-2) Immunoexpression with Prognosis in Human Osteosarcoma: A Meta-Analysis 
PLoS ONE  2013;8(12):e82907.
Background
Numerous studies examining the relationship between Cyclooxygenase-2 (COX-2) immunoexpression and clinical outcome in osteosarcoma patients have yielded inconclusive results.
Methods
We accordingly conducted a meta-analysis of 9 studies (442 patients) that evaluated the correlation between COX-2 immunoexpression and clinical prognosis (death). Pooled odds ratios (OR) and risk ratios (RR) with 95% confidence intervals (95% CI) were calculated using the random-effects or fixed-effects model.
Results
Meta–analysis showed no significant association between COX-2 positivity and age, gender, tumor location, histology, stage, metastasis or 90% necrosis. Conversely, COX-2 immunoexpression was associated with overall survival rate (RR=2.12; 95% CI: 1.10–3.74; P=0.009) and disease-free survival rate (RR=1.63; 95% CI: 1.17–2.28; P=0.004) at 2 years. Sensitivity analysis performed by omitting low quality studies showed that the pooled results were stable.
Conclusions
COX-2 positivity was associated with a lower 2-year overall survival rate and disease-free survival rate. COX-2 expression change is an independent prognostic factor in patients with osteosarcoma.
doi:10.1371/journal.pone.0082907
PMCID: PMC3865095  PMID: 24358237
13.  The Effect of an Adding Histidine on Biological Activity and Stability of Pc-pis from Pseudosciaena crocea 
PLoS ONE  2013;8(12):e83268.
Pc-pis is a novel piscidin-like antimicrobial polypeptide that was identified in Pseudosciaena crocea. Although active against most bacteria tested, Pc-pis was inactive against Aeromonas hydrophila and Pseudomonas aeruginosa. The Pc-pis analogue Pc-pis-His was designed by adding a histidine residue at the carboxyl terminal. Pc-pis-His demonstrated a more broad-spectrum and stronger antimicrobial activity against a representative set of microorganisms and more potent antiparasitic activity against Cryptocaryon irritans trophonts than Pc-pis. The stability assay revealed that Pc-pis-His was active against Staphylococcus aureus not only in acidic (pH 5.5–7.3) and relatively low concentration monovalent cation (0–160 mM NaCl) environments but also in alkaline (pH 7.5–9.5), divalent cation (1.25–160 mM MgCl2 and 1.25–40 mM CaCl2) and high concentration monovalent cation (320–2560 mM NaCl) environments, which indicates that the added histidine residue conferred better salt-, acid- and alkali-tolerance to Pc-pis-His. Pc-pis-His also possessed the desired heat-tolerance, which was reflected by the antimicrobial activity of the peptide after being boiled for 10–60 minutes. Hemolytic activity analysis revealed that Pc-pis-His at concentrations up to 6 µM exhibited no hemolysis against human erythrocytes, with 6 µM being a concentration that is highly active against most of the microorganisms tested, although the hemolytic activity of Pc-pis-His was enhanced compared to Pc-pis. These results provide a unique, reasonable basis for designing novel piscidins with potent, broad-spectrum and stable antimicrobial activity and new insight into the future development of piscidins as potential therapeutic agents against microbial and external protozoan parasite infections.
doi:10.1371/journal.pone.0083268
PMCID: PMC3862765  PMID: 24349477
14.  Protective Effect of Ginsenoside Rb1 against Intestinal Ischemia-Reperfusion Induced Acute Renal Injury in Mice 
PLoS ONE  2013;8(12):e80859.
Ginsenoside Rb1 (RB1), the most clinically effective constituent of ginseng, possesses a variety of biological activities. The objectives of this study were to investigate the protective effects of RB1 and its underlying mechanism on renal injury induced by intestinal ischemia-reperfusion (IIR) in mice. RB1 was administered prior to inducing IIR achieved by occluding the superior mesenteric artery for 45 min followed by 120 min of reperfusion. All-trans-retinoic acid (ATRA) was used as an inhibitor of NF-E2-related factor-2 (Nrf2) signaling. Adult male C57BL/6J mice were randomly divided into six groups: (1) sham group, (2) IIR group, (3) RB1 group, (4) sham + ATRA group, (5) IIR + ATRA group, and (6) RB1 + ATRA group. Intestinal histology and pathological injury score were observed. Intestinal mucosal injury was also evaluated by measuring serum diamine oxidase (DAO). Renal injury induced by IIR was characterized by increased levels of histological severity score, blood urea nitrogen (BUN), serum creatinine (Scr) and neutrophil gelatinase-associated lipocalin (NGAL), which was accompanied with elevated renal TUNEL-positive cells and the Bcl-2/Bax expression ratio. RB1 significantly reduced renal injury and apoptosis as compared with IIR group, which was reversed by ATRA treatment. Immunohistochemistry and Western blot analysis demonstrated that RB1 significantly upregulated the protein expression of heme oxygenase-1 (HO-1) and Nrf2, which were attenuated by ATRA treatment. Taken together, these results suggest that the protective effects of RB1 pretreatment against renal injury induced by IIR are associated with activation of the Nrf2/ anti-oxidant response element (ARE) pathway.
doi:10.1371/journal.pone.0080859
PMCID: PMC3851764  PMID: 24324637
15.  R2NA: Received Signal Strength (RSS) Ratio-Based Node Authentication for Body Area Network 
Sensors (Basel, Switzerland)  2013;13(12):16512-16532.
The body area network (BAN) is an emerging branch of wireless sensor networks for personalized applications. The services in BAN usually have a high requirement on security, especially for the medical diagnosis. One of the fundamental directions to ensure security in BAN is how to provide node authentication. Traditional research using cryptography relies on prior secrets shared among nodes, which leads to high resource cost. In addition, most existing non-cryptographic solutions exploit out-of-band (OOB) channels, but they need the help of additional hardware support or significant modifications to the system software. To avoid the above problems, this paper presents a proximity-based node authentication scheme, which only uses wireless modules equipped on sensors. With only one sensor and one control unit (CU) in BAN, we could detect a unique physical layer characteristic, namely, the difference between the received signal strength (RSS) measured on different devices in BAN. Through the above-mentioned particular difference, we can tell whether the sender is close enough to be legitimate. We validate our scheme through both theoretical analysis and experiments, which are conducted on the real Shimmer nodes. The results demonstrate that our proposed scheme has a good security performance.
doi:10.3390/s131216512
PMCID: PMC3892831
authentication; body area network; sensor; RSS ratio
16.  Discovery of New Eunicellin-Based Diterpenoids from a Formosan Soft Coral Cladiella sp. 
Marine Drugs  2013;11(11):4585-4593.
A new eunicellin diterpenoid, cladieunicellin I (1), and a new natural eunicellin, litophynin I diacetate (2), were isolated from a Formosan soft coral identified as Cladiella sp. The structures of eunicellins 1 and 2 were elucidated by spectroscopic methods and by comparison of the spectral data with those of related analogues. Eunicellin 1 exhibited significant cytotoxicity toward the DLD-1 human colorectal adenocarcinoma cells.
doi:10.3390/md11114585
PMCID: PMC3853747  PMID: 24240980
eunicellin; Cladiella; cladieunicellin; litophynin; cytotoxicity
17.  Oxygenated Ylangene-Derived Sesquiterpenoids from the Soft Coral Lemnalia philippinensis 
Marine Drugs  2013;11(10):3735-3741.
Chemical examination of a Taiwanese soft coral Lemnalia philippinensis led to the isolation of three oxygenated ylangene-derived sesquiterpenoids 1–3, including two new metabolites, philippinlins A and B (1 and 2). The structures of these compounds were elucidated on the basis of detailed spectroscopic data. Compound 1 was shown to exhibit cytotoxicity against HepG2, MDA-MB231 and A549 cancer cell lines.
doi:10.3390/md11103735
PMCID: PMC3826132  PMID: 24084789
Lemnalia philippinensis; ylangene; philippinlins A and B; cytotoxicity
18.  Clinical and pathological analysis of the kidney in patients with hypertensive nephropathy 
The aim of the present study was to identify the association between pathological types of kidney and clinical manifestations in patients with hypertensive nephropathy. The blood pressure, fundus, urinalysis test results and renal function changes were analysed in patients who were treated for hypertensive nephropathy. Downward kidney puncture biopsy was performed using a 16G ejection needle with the aid of B ultrasound in 47 cases. The specimens were observed using light microscopy and immunofluorescence. The pathological changes observed in the patients exhibiting symptoms of hypertensive nephropathy varied. The majority of clinical manifestations were benign arteriolar nephrosclerosis, hyaline degeneration of the renal artery and the appearance of a thickened wall of a thickened renal artery wall. Severe cases showed malignant arteriolar nephrosclerosis characterised by fibrinoid necrosis of renal arterioles and intimal hyperplasia. In addition, in the severe cases, fibrinoid necrosis of the afferent arteriole and arcuate artery wall was observed, with severe interlobular artery and arcuate artery myointimal thickening. Renal biopsy in patients with hypertensive nephropathy is safe and feasible. The prognosis and treatment of pathological and clinical disease related to renal pathology is necessary.
doi:10.3892/etm.2013.1306
PMCID: PMC3820837  PMID: 24223652
hypertensive; nephropathy; kidney; pathology
19.  Bone Marrow Injury Induced via Oxidative Stress in Mice by Inhalation Exposure to Formaldehyde 
PLoS ONE  2013;8(9):e74974.
Objective
Formaldehyde, a ubiquitous environmental pollutant has been classified as a human leukemogen. However, toxicity of formaldehyde in bone marrow, the target site of leukemia induction, is still poorly understood.
Methodology/Principal Findings
To investigate bone marrow toxicity (bone marrow pathology, hematotoxicity) and underlying mechanisms (oxidative stress, inflammation, apoptosis) in formaldehyde-exposed mice. Male Balb/c mice were exposed to formaldehyde (0, 0.5, and 3.0 mg/m3) by nose-only inhalation for 8 hours/day, over a two week period designed to simulate a factory work schedule, with an exposure-free “weekend” on days 6 and 7, and were sacrificed on the morning of day 13. Counts of white blood cells, red blood cells and lymphocytes were significantly (p<0.05) decreased at 0.5 mg/m3 (43%, 7%, and 39%, respectively) and 3.0 mg/m3 (52%, 27%, and 43%, respectively) formaldehyde exposure, while platelet counts were significantly increased by 109% (0.5 mg/m3) and 67% (3.0 mg/m3). Biomarkers of oxidative stress (reactive oxygen species, glutathione depletion, cytochrome P450 1A1 and glutathione s-transferase theta 1 expression), inflammation (nuclear factor kappa-B, tomour necrosis factor alpha, interleukin-1 beta), and apoptosis (activity of cysteine-aspartic acid protease 3) in bone marrow tissues were induced at one or both formaldehyde doses mentioned above.
Conclusions/Significance
Exposure of mice to formaldehyde by inhalation induced bone marrow toxicity, and that oxidative stress, inflammation and the consequential apoptosis jointly constitute potential mechanisms of such induced toxicity.
doi:10.1371/journal.pone.0074974
PMCID: PMC3770590  PMID: 24040369
20.  Combination lamivudine and adefovir versus entecavir for the treatment of naïve chronic hepatitis B patients: A pilot study 
Background
The aim of this study was to compare the effect of combination lamivudine (LAM) and adefovir dipivoxil (ADV) versus entecavir (ETV) monotherapy for naïve HBeAg-positive chronic hepatitis B (CHB) patients.
Material/Methods
Fifty enrolled patients with CHB were evenly divided into 2 groups: a group treated with of lamivudine (LAM) (100 mg/day) plus adefovir (ADV) (10 mg/day) combination, and a group treated with entecavir (ETV) (0.5 mg/day). Serum levels of ALT, AST, creatinine, bilirubin, HBsAg, HBeAg and HBV viral load, and genotypic resistance were analyzed at 0, 12, 24, 52, and 104 weeks. HBV DNA levels were determined by real-time PCR and HBsAg and HBeAg by chemiluminescence. Serum levels of ALT, AST, creatinine, and bilirubin were measured by an automatic biochemical analyzer. Data analysis was performed with SPSS 12.0 software.
Results
There were no significant differences in the virological response (VR) rates between LAM+ADV and ETV cohorts at 24, 52, and 104 weeks (P>0.05). The HBeAg seroconversion rates were 28% and 20%, and the biochemical response (BR) rates were 88% and 84% at week 104 in the LAM+ADV and ETV groups, respectively. The rates of undetectable HBV DNA, HBeAg seroconversion, and ALT normalization rates were similar in both cohorts. No virological breakthrough or serious adverse effects were noted for any patient during the study period.
Conclusions
Both LAM + ADV combination therapy and ETV monotherapy were effective and safe in the treatment of naïve HBeAg-positive CHB patients. However, further studies are needed to obtain long-term results.
doi:10.12659/MSM.889443
PMCID: PMC3775615  PMID: 24019010
chronic hepatitis B; HBeAg-positive; lamivudine; adefovir dipivoxil; entecavir
21.  Translating research into practice: the role of provider based research networks in the diffusion of an evidence-based colon cancer treatment innovation 
Medical Care  2012;50(8):737-748.
Background
Provider-based research networks (PBRNs) – collaborative research partnerships between academic centers and community-based practitioners – are a promising model for accelerating the translation of research into practice; however, empirical evidence of accelerated translation is limited. Oxaliplatin in adjuvant combination chemotherapy is an innovation with clinical trial-proven survival benefit compared to prior therapies. The goal of this study is to examine the diffusion of oxaliplatin into community practice, and whether affiliation with the National Cancer Institute’s (NCI’s) Community Clinical Oncology Program (CCOP) – a nationwide cancer-focused PBRN – is associated with accelerated innovation adoption.
Design, Setting, and Participants
This retrospective observational study used linked SEER-Medicare and NCI-CCOP data to examine Medicare participants with stage III colon cancer initiating treatment in 2003 through 2006, the years surrounding oxaliplatin’s FDA approval. A fixed-effects analysis examined chemotherapy use among patients treated outside academic centers at CCOP-affiliated practices compared to non-CCOP practices. Two-group modeling controlled for multiple levels of clustering, year of chemotherapy initiation, tumor characteristics, patient age, race, comorbidity, Medicaid dual-eligibility status, and education.
Results
Of 4,055 community patients, 35% received 5-FU, 20% received oxaliplatin, 7% received another chemotherapy, and 38% received no chemotherapy. 25% of CCOP patients received oxaliplatin, compared to 19% of non-CCOP patients. In multivariable analysis, CCOP exposure was associated with higher odds of receiving guideline-concordant treatment in general, and oxaliplatin specifically.
Conclusions
These findings contribute to a growing set of evidence linking PBRNs with a greater probability of receiving treatment innovations and high quality cancer care, with implications for clinical and research policy.
doi:10.1097/MLR.0b013e31824ebe13
PMCID: PMC3389231  PMID: 22437624
colon cancer; translational research; diffusion of innovation; organization and administration; provider-based research networks
22.  Phyto-SERM Constitutes from Flemingia macrophylla 
The methanolic extract of Flemingia macrophylla roots exhibited significant estrogenic activity in the transgenic plant assay system which was comparable to the activity of soybean extract. Utilizing estrogenic activity-guided fractionation, one new compound, fleminigin, together with 23 known compounds were isolated from F. macrophylla roots’ methanolic extract. The structure of the new compound was identified based on intensive spectroscopic analysis and the full spectral data for one of the isolated compounds, flemichin E, was introduced for the first time in the current investigation. The estrogenic and anti-estrogenic activities of the isolated compounds were evaluated revealing that the isolated isoflavonoids may act as partial estrogen agonists, as well as antagonists. Additionally, the anti-inflammatory and the cytotoxic activities of the isolated compounds were studied. These results suggested the potential applications of F. macrophylla extract and its isolated compounds as selective estrogen receptor modulators (SERMs).
doi:10.3390/ijms140815578
PMCID: PMC3759874  PMID: 23896592
Flemingia macrophylla; menopausal; phytoestrogen; fleminigin; flemichin E; pER8:GUS
23.  Intensity-Modulated Radiation Therapy, Proton Therapy, or Conformal Radiation Therapy and Morbidity and Disease Control in Localized Prostate Cancer 
Context
There has been rapid adoption of newer radiation treatments such as intensitymodulated radiation therapy (IMRT) and proton therapy despite greater cost and limited demonstrated benefit compared with previous technologies.
Objective
To determine the comparative morbidity and disease control of IMRT, proton therapy, and conformal radiation therapy for primary prostate cancer treatment.
Design, Setting, and Patients
Population-based study using Surveillance, Epidemiology, and End Results–Medicare-linked data from 2000 through 2009 for patients with nonmetastatic prostate cancer.
Main Outcome Measures
Rates of gastrointestinal and urinary morbidity, erectile dysfunction, hip fractures, and additional cancer therapy.
Results
Use of IMRT vs conformal radiation therapy increased from 0.15% in 2000 to 95.9% in 2008. In propensity score–adjusted analyses (N=12 976), men who received IMRT vs conformal radiation therapy were less likely to receive a diagnosis of gastrointestinal morbidities (absolute risk, 13.4 vs 14.7 per 100 person-years; relative risk [RR], 0.91; 95% CI, 0.86–0.96) and hip fractures (absolute risk, 0.8 vs 1.0 per 100 person-years; RR, 0.78; 95% CI, 0.65–0.93) but more likely to receive a diagnosis of erectile dysfunction (absolute risk, 5.9 vs 5.3 per 100 person-years; RR, 1.12; 95% CI, 1.03–1.20). Intensitymodulated radiation therapy patients were less likely to receive additional cancer therapy (absolute risk, 2.5 vs 3.1 per 100 person-years; RR, 0.81; 95% CI, 0.73–0.89). In a propensity score–matched comparison between IMRT and proton therapy (n=1368), IMRT patients had a lower rate of gastrointestinal morbidity (absolute risk, 12.2 vs 17.8 per 100 person-years; RR, 0.66; 95% CI, 0.55–0.79). There were no significant differences in rates of other morbidities or additional therapies between IMRT and proton therapy.
Conclusions
Among patients with nonmetastatic prostate cancer, the use of IMRT compared with conformal radiation therapy was associated with less gastrointestinal morbidity and fewer hip fractures but more erectile dysfunction; IMRT compared with proton therapy was associated with less gastrointestinal morbidity.
doi:10.1001/jama.2012.460
PMCID: PMC3702170  PMID: 22511689
24.  Design and synthesis of gambogic acid analogs as potent cytotoxic and anti-inflammatory agents 
Prenyl- and pyrano-xanthones derived from 1,3,6-trihydroxy-9H-xanthen-9-one, a basic backbone of gambogic acid (GA), were synthesized and evaluated for in vitro cytotoxic effects against four human cancer cell lines (KB, KBvin, A549, and DU-145) and anti-inflammatory activity toward superoxide anion generation and elastase release by human neutrophils in response to fMLP/CB. Among them, prenylxanthones 7-13 were generally less active than pyranoxanthones 14-21 in both anticancer and anti-inflammatory assays. Furthermore, two angular 3,3-dimethypyranoxanthones (16 and 20) showed the greatest and selective activity against the KBvin multidrug resistant (MDR) cell line with IC50 values of 0.9 and 0.8 μ g/mL, respectively. An angular 3-methyl-3-prenylpyranoxanthone (17) selectively inhibited elastase release with 200 times more potency than phenylmethylsulfonyl fluoride (PMSF), the positive control.
doi:10.1016/j.bmcl.2012.04.084
PMCID: PMC3374489  PMID: 22595179
1,3,6-Trihydroxy-9H-xanthen-9-one; Gambogic acid (GA); Prenylxanthones; Pyranoxanthones; Cytotoxicity; Anti-inflammatory activity
25.  Teng-Long-Bu-Zhong-Tang, a Chinese herbal formula, enhances anticancer effects of 5 - Fluorouracil in CT26 colon carcinoma 
Background
Colorectal cancer remains one of the leading causes of cancer death worldwide. Traditional Chinese Medicine (TCM) has played a positive role in colorectal cancer treatment. There is a great need to establish effective herbal formula for colorectal cancer treatment. Based on TCM principles and clinical practices, we have established an eight herbs composed formula for colorectal cancer treatment, which is Teng-Long-Bu-Zhong-Tang (TLBZT). We have demonstrated the anticancer effects of TLBZT against colorectal carcinoma in vitro. In present study, we evaluated the anticancer potential of TLBZT, used alone or in combination with low dose of 5-Fluorouracil (5-Fu), in CT26 colon carcinoma in vivo.
Methods
CT26 colon carcinoma was established in BALB/c mice and treated with TLBZT, 5-Fu, or TLBZT plus 5-Fu. The tumor volumes were observed. Apoptosis was detected by TUNEL assay. Caspases activities were detected by colorimetric assay. Cell senescence was indentified by senescence β-galactosidase staining. Gene expression and angiogenesis was observed by immunohistochemistry or western blot.
Results
TLBZT significantly inhibited CT26 colon carcinoma growth. TLBZT elicited apoptosis in CT26 colon carcinoma, accompanied by Caspase-3, 8, and 9 activation and PARP cleavage, and downregulation of XIAP and Survivin. TLBZT also induced cell senescence in CT26 colon carcinoma, with concomitant upregulation of p16 and p21 and downregulation of RB phosphorylation. In addition, angiogenesis and VEGF expression in CT26 colon carcinoma was significantly inhibited by TLBZT treatment. Furthermore, TLBZT significantly enhanced anticancer effects of 5-Fu in CT26 colon carcinoma.
Conclusions
TLBZT exhibited significantly anticancer effect, and enhanced the effects of 5-Fu in CT26 colon carcinoma, which may correlate with induction of apoptosis and cell senescence, and angiogenesis inhibition. The present study provides new insight into TCM approaches for colon cancer treatment that are worth of further study.
doi:10.1186/1472-6882-13-128
PMCID: PMC3702481  PMID: 23758730
Colon carcinoma; Chinese herbal formula; Apoptosis; Cell senescence; Angiogenesis

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