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1.  Laparoscopic repair of diaphragm perforation with heart patch after microwave ablation 
Saudi Medical Journal  2016;37(3):320-323.
Microwave ablation (MWA) is a new technology developed in recent years, which is widely used in various disciplines. Microwave ablation is an alternative to surgery in the management of various tumors, and it has been demonstrated to be effective in the management of primary tumors and metastatic tumors. Microwave ablation is widely used in the treatment of hepatocellular carcinoma with an obvious effect and less side effects, and only 2.7% had serious complications. Many studies have confirmed the complications are thermal damage, hemorrhage, pleural effusion, bile leak, tumor seeding, hepatic abscess, cholangitis, and so forth. But diaphragm perforation is rare, and it is probably the first case reported. This article describes diaphragmatic perforation secondary to MWA of the liver with subsequent pleural effusion and diaphragmatic hernia. We also describe its management via the laparoscopic approach.
PMCID: PMC4800899  PMID: 26905357
2.  Resveratrol attenuates neuronal autophagy and inflammatory injury by inhibiting the TLR4/NF-κB signaling pathway in experimental traumatic brain injury 
Previous research has demonstrated that traumatic brain injury (TBI) activates autophagy and a neuroinflammatory cascade that contributes to substantial neuronal damage and behavioral impairment, and Toll-like receptor 4 (TLR4) is an important mediator of this cascade. In the present study, we investigated the hypothesis that resveratrol (RV), a natural polyphenolic compound with potent multifaceted properties, alleviates brain damage mediated by TLR4 following TBI. Adult male Sprague Dawley rats, subjected to controlled cortical impact (CCI) injury, were intraperitoneally injected with RV (100 mg/kg, daily for 3 days) after the onset of TBI. The results demonstrated that RV significantly reduced brain edema, motor deficit, neuronal loss and improved spatial cognitive function. Double immunolabeling demonstrated that RV decreased microtubule-associated protein 1 light chain 3 (LC3), TLR4-positive cells co-labeled with the hippocampal neurons, and RV also significantly reduced the number of TLR4-positive neuron-specific nuclear protein (NeuN) cells following TBI. Western blot analysis revealed that RV significantly reduced the protein expression of the autophagy marker proteins, LC3II and Beclin1, in the hippocampus compared with that in the TBI group. Furthermore, the levels of TLR4 and its known downstream signaling molecules, nuclear factor-κB (NF-κB), and the inflammatory cytokines, interleukin (IL)-1β and tumor necrosis factor (TNF)-α were also decreased after RV treatment. Our results suggest that RV reduces neuronal autophagy and inflammatory reactions in a rat model of TBI. Thus, we suggest that the neuroprotective effect of RV is associated with the TLR4/NF-κB signaling pathway.
PMCID: PMC4790669  PMID: 26936125
resveratrol; autophagy; traumatic brain injury; Toll-like receptor 4; inflammation
3.  Liver-targeting Resibufogenin-loaded poly(lactic-co-glycolic acid)-d-α-tocopheryl polyethylene glycol 1000 succinate nanoparticles for liver cancer therapy 
Liver cancer remains a major problem around the world. Resibufogenin (RBG) is a major bioactive compound that was isolated from Chansu (also called toad venom or toad poison), which is a popular traditional Chinese medicine that is obtained from the skin secretions of giant toads. RBG has strong antitumor effects, but its poor aqueous solubility and its cardiotoxicity have limited its clinical use. The aim of this study was to formulate RBG-loaded poly(lactic-co-glycolic acid) (PLGA)-d-α-tocopheryl polyethylene glycol 1000 succinate nanoparticle (RPTN) to enhance the treatment of liver cancer. RPTN, RBG-loaded PLGA nanoparticle (RPN), and RBG/coumarin-6-loaded PLGA-d-α-tocopheryl polyethylene glycol 1000 succinate nanoparticle (RCPTN) were prepared. The cellular uptake of RCPTN by HepG2 and HCa-F cells was analyzed using confocal laser scanning microscopy. Apoptosis was induced in HepG2 cells by RPTN, RBG solution (RS), and 5-fluorouracil solution (used as the negative controls), as assayed using flow cytometry. LD50 (median lethal dose) values were determined for RS and RPTN, and the liver-targeting properties were determined for RCPTN in intravenously injected mice. A pharmacokinetic study was conducted in rats, and the in vivo therapeutic effects of RPTN, RPN, and RS were examined in a mouse tumor model. The results showed that RCPTN simultaneously delivered both coumarin-6 and RBG into HepG2 and HCa-F cells. The ratio of apoptotic cells was increased in the RPTN group. The LD50 for RPTN was 2.02-fold higher than the value for RS. Compared to RS, RPTN and RPN both showed a significant difference in vivo not only in the pharmacodynamic study but also in anticancer efficacy, and RPTN performed much better than RPN. The detection indexes for drug concentration and fluorescence inversion microscopy images both demonstrated that RCPTN was much better at targeting the liver than RS. The liver-targeting RPTN, which displayed enhanced pharmacological effects and decreased toxicity for the loaded drug RBG, is therefore a promising intravenous dosage form that may be useful in the treatment of liver cancer.
PMCID: PMC4734807  PMID: 26869788
Resibufogenin; PLGA-TPGS; nanoparticles; liver cancer; HepG2 cells; HCa-F cells
4.  Innate immune system gene polymorphisms in maternal and child genotype and risk of preterm delivery 
There is little information about the combination of genetic variability in pregnant women and their children in relation to the risk of preterm delivery (PTD). In a sub-cohort of 487 non-Hispanic white and 288 African-American mother/child pairs, the Pregnancy Outcomes and Community Health Study assessed ten functional polymorphisms in nine genes involved in innate immune function.
Race-stratified weighted logistic regression models were used to calculate odds ratios for genotype and PTD/PTD subtypes. Polymorphisms significantly associated with PTD/PTD subtypes were tested for mother/child genotype interactions.
Three maternal polymorphisms (IL-1 receptor antagonist intron two repeat (IL-1RN), matrix metalloproteinase-9 -C1562T, and TNF receptor two T198G (TNFR2)) and three child polymorphisms (IL1-RN, tumor necrosis factor-alpha -G308A, and TNFR2) were associated with PTD, but associations varied by PTD subtype and race. Two interactions were detected for maternal and child genotype. Among non-Hispanic white women, the odds of PTD was higher when both mother and child carried the IL-1RN allele two (additive interaction p<.05). Among African-American women, the odds of PTD was higher when both mother and child carried the TNFR2 G allele (multiplicative interaction p<.05).
These results highlight the importance of assessing both maternal and child genotype in relation to PTD risk.
PMCID: PMC4643033  PMID: 21627550
premature birth; inflammation; maternal & child genotype; gene-gene interactions; genetic polymorphisms; premature birth genetics
5.  eIF3a improve cisplatin sensitivity in ovarian cancer by regulating XPC and p27Kip1 translation 
Oncotarget  2015;6(28):25441-25451.
The eukaryotic translation initiation factor 3a (eIF3a) is one of the core subunits of the translation initiation complex eIF3, responsible for ribosomal subunit joining and mRNA recruitment to the ribosome. Our previous study identified that it was correlated with platinum response in lung cancer. The current study aims to test the hypothesis that eIF3a may affect the drug response and prognosis of ovarian cancer patients receiving platinum-based chemotherapy by regulating xeroderma pigmentosum complementation group C (XPC) and p27Kip1. Immunohistochemistry and western blot was used to determine the expression of eIF3a in 126 human ovarian cancer tissues followed by association analysis of eIF3a expression with patient's response and survival. Ectopic over-expression and RNA interference knockdown of eIF3a were carried out in A2780/cisplatin (DDP) and its parental A2780 cells, respectively, to determine the effect of altered eIF3a expression on cellular response to cisplatin by employing MTT assay. Western Blot analyses were also carried out to determine the regulation of eIF3a on XPC and p27Kip1. eIF3a expression was associated with response of ovarian cancer patients to DDP-based chemotherapy and their survival. Overexpression and knockdown of eIF3a increased and decreased the cellular response to cisplatin in A2780/DDP and A2780 cells, respectively. In addition, XPC and p27Kip1 were down regulated by eIF3a. eIF3a improves ovarian cancer patients' response to DDP-based chemotherapy via down regulating XPC and p27Kip1.
PMCID: PMC4694843  PMID: 26213845
eIF3a; platinum; ovarian cancer; drug resistance; XPC
6.  Red Light Combined with Blue Light Irradiation Regulates Proliferation and Apoptosis in Skin Keratinocytes in Combination with Low Concentrations of Curcumin 
PLoS ONE  2015;10(9):e0138754.
Curcumin is a widely known natural phytochemical from plant Curcuma longa. In recent years, curcumin has received increasing attention because of its capability to induce apoptosis and inhibit cell proliferation as well as its anti-inflammatory properties in different cancer cells. However, the therapeutic benefits of curcumin are severely hampered due to its particularly low absorption via trans-dermal or oral bioavailability. Phototherapy with visible light is gaining more and more support in dermatological therapy. Red light is part of the visible light spectrum, which is able to deeply penetrate the skin to about 6 mm, and directly affect the fibroblast of the skin dermis. Blue light is UV-free irradiation which is fit for treating chronic inflammation diseases. In this study, we show that curcumin at low concentrations (1.25–3.12 μM) has a strong anti-proliferative effect on TNF-α-induced psoriasis-like inflammation when applied in combination with light-emitting-diode devices. The treatment was especially effective when LED blue light at 405 nm was combined with red light at 630 or 660 nm, which markedly amplified the anti-proliferative and apoptosis-inducing effects of curcumin. The experimental results demonstrated that this treatment reduced the viability of human skin keratinocytes, decreased cell proliferation, induced apoptosis, inhibited NF-κB activity and activated caspase-8 and caspase-9 while preserving the cell membrane integrity. Moreover, the combined treatment also down-regulated the phosphorylation level of Akt and ERK. Taken together, our results indicated that the combination of curcumin with LED blue light united red light irradiation can attain a higher efficiency of regulating proliferation and apoptosis in skin keratinocytes.
PMCID: PMC4575166  PMID: 26382065
7.  Exploring the Intrinsic Piezofluorochromic Mechanism of TPE-An by STS Technique 
9,10-bis(4-(1,2,2-triphenylvinyl)styryl)anthracene (TPE-An) materials have attracted considerable attention in recent years because they have high luminescence efficiency and excellent piezofluorochromic properties, which have potential applications in organic light-emitting display (OLED) area. Scanning tunneling spectroscopy (STS) technique was used to study the piezofluorochromic mechanism of aggregation-induced emission (AIE) materials for the first time. Photoluminescence (PL) experiments revealed that the emission peak of TPE-An is observed to exhibit a red-shift with the increase of the grinding time. A theoretical calculation was carried out to find the relationship between the bandgap of TPE-An and the external force by combination of the classical tunneling theory and STS results. It is found that when the pressure variation on the surface of TPE-An film was increased to be over 4.38 × 104 Pa, the shrink of the highest occupied molecular orbital (HOMO)-lowest unoccupied molecular orbital (LUMO) gap can arrive at 1.1 eV. It is concluded that the piezofluorochromic behaviors of TPE-An should originate from the shrinking effect of the bandgap under external force. Moreover, this research method may shed light on comprehending and adjusting the piezofluorochromic characters of other AIE materials.
PMCID: PMC4558996  PMID: 26334542
TPE-An; STS technique; Piezofluorochromic; The HOMO-LUMO gap
8.  MicroRNA-26a regulates insulin sensitivity and metabolism of glucose and lipids 
The Journal of Clinical Investigation  2015;125(6):2497-2509.
Type 2 diabetes (T2D) is characterized by insulin resistance and increased hepatic glucose production, yet the molecular mechanisms underlying these abnormalities are poorly understood. MicroRNAs (miRs) are a class of small, noncoding RNAs that have been implicated in the regulation of human diseases, including T2D. miR-26a is known to play a critical role in tumorigenesis; however, its function in cellular metabolism remains unknown. Here, we determined that miR-26a regulates insulin signaling and metabolism of glucose and lipids. Compared with lean individuals, overweight humans had decreased expression of miR-26a in the liver. Moreover, miR-26 was downregulated in 2 obese mouse models compared with control animals. Global or liver-specific overexpression of miR-26a in mice fed a high-fat diet improved insulin sensitivity, decreased hepatic glucose production, and decreased fatty acid synthesis, thereby preventing obesity-induced metabolic complications. Conversely, silencing of endogenous miR-26a in conventional diet–fed mice impaired insulin sensitivity, enhanced glucose production, and increased fatty acid synthesis. miR-26a targeted several key regulators of hepatic metabolism and insulin signaling. These findings reveal miR-26a as a regulator of liver metabolism and suggest miR-26a should be further explored as a potential target for the treatment of T2D.
PMCID: PMC4497741  PMID: 25961460
Endocrinology; Genetics; Metabolism
9.  Metatranscriptomic Analyses of Plant Cell Wall Polysaccharide Degradation by Microorganisms in the Cow Rumen 
The bovine rumen represents a highly specialized bioreactor where plant cell wall polysaccharides (PCWPs) are efficiently deconstructed via numerous enzymes produced by resident microorganisms. Although a large number of fibrolytic genes from rumen microorganisms have been identified, it remains unclear how they are expressed in a coordinated manner to efficiently degrade PCWPs. In this study, we performed a metatranscriptomic analysis of the rumen microbiomes of adult Holstein cows fed a fiber diet and obtained a total of 1,107,083 high-quality non-rRNA reads with an average length of 483 nucleotides. Transcripts encoding glycoside hydrolases (GHs) and carbohydrate binding modules (CBMs) accounted for ∼1% and ∼0.1% of the total non-rRNAs, respectively. The majority (∼98%) of the putative cellulases belonged to four GH families (i.e., GH5, GH9, GH45, and GH48) and were primarily synthesized by Ruminococcus and Fibrobacter. Notably, transcripts for GH48 cellobiohydrolases were relatively abundant compared to the abundance of transcripts for other cellulases. Two-thirds of the putative hemicellulases were of the GH10, GH11, and GH26 types and were produced by members of the genera Ruminococcus, Prevotella, and Fibrobacter. Most (∼82%) predicted oligosaccharide-degrading enzymes were GH1, GH2, GH3, and GH43 proteins and were from a diverse group of microorganisms. Transcripts for CBM10 and dockerin, key components of the cellulosome, were also relatively abundant. Our results provide metatranscriptomic evidence in support of the notion that members of the genera Ruminococcus, Fibrobacter, and Prevotella are predominant PCWP degraders and point to the significant contribution of GH48 cellobiohydrolases and cellulosome-like structures to efficient PCWP degradation in the cow rumen.
PMCID: PMC4309707  PMID: 25501482
10.  Impact of body mass index on complications following pancreatectomy: Ten-year experience at National Cancer Center in China 
AIM: To examine the impact of body mass index (BMI) on outcomes following pancreatic resection in the Chinese population.
METHODS: A retrospective cohort study using prospectively collected data was conducted at the Cancer Hospital of the Chinese Academy of Medical Sciences, China National Cancer Center. Individuals who underwent pancreatic resection between January 2004 and December 2013 were identified and included in the study. Persons were classified as having a normal weight if their BMI was < 24 kg/m2 and overweight/obese if their BMI was ≥ 24 kg/m2 as defined by the International Life Sciences Institute Focal Point in China. A χ2 test (for categorical variables) or a t test (for continuous variables) was used to examine the differences in patients’ characteristics between normal weight and overweight/obese groups. Multiple logistic regression models were used to assess the associations of postoperative complications, operative difficulty, length of hospital stay, and cost with BMI, adjusting for age, sex, and type of surgery procedures.
RESULTS: A total of 362 consecutive patients with data available for BMI calculation underwent pancreatic resection for benign or malignant disease from January 1, 2004 to December 31, 2013. Of the 362 patients, 156 were overweight or obese and 206 were of normal weight. One or more postoperative complications occurred in 35.4% of the patients following pancreatic resection. Among patients who were overweight or obese, 42.9% experienced one or more complications, significantly higher than normal weight (29.6%) individuals (P = 0.0086). Compared with individuals who had normal weight, those with a BMI ≥ 24.0 kg/m2 had higher delayed gastric emptying (19.9% vs 5.8%, P < 0.0001) and bile leak (7.7% vs 1.9%, P = 0.0068). There were no significant differences seen in pancreatic fistula, gastrointestinal hemorrhage, reoperation, readmission, or other complications. BMI did not show a significant association with intraoperative blood loss, operative time, length of hospital stay, or cost.
CONCLUSION: Higher BMI increases the risk for postoperative complications after pancreatectomy in the Chinese population. The findings require replication in future studies with larger sample sizes.
PMCID: PMC4476883  PMID: 26109808
Body mass index; China; Pancreatectomy; Pancreatic cancer; Postoperative complications
11.  Circulating microRNAs are promising novel biomarkers for drug-resistant epilepsy 
Scientific Reports  2015;5:10201.
MicroRNAs (miRNAs) open up a new field for molecular diagnosis for cancer and other diseases based on their stability in serum. However, the role of circulating miRNAs in plasma/serum in epilepsy diagnosis is still unclear. The aim of this study was to evaluate whether miRNAs can be used as biomarkers for drug-resistant epilepsy. We measured the differences in serum miRNA levels between 30 drug-resistant patients and 30 drug-responsive epilepsy patients in discovery and training phases using Illumina HiSeq2000 sequencing followed by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) assays. The selected miRNAs were then validated in 77 drug-resistant epilepsy patients, 81 drug-responsive epilepsy patients and 85 healthy controls by qRT-PCR. We found that circulating miRNAs are differentially expressed between drug-resistant group and drug-responsive group. MiR-194-5p, -301a-3p, -30b-5p, -342-5p and -4446-3p were significantly deregulated in drug-resistant group compared to drug-responsive group and control group. Among these 5 miRNAs, miR-301a-3p had the best diagnostic value for drug-resistant epilepsy with 80.5% sensitivity and 81.2% specificity, and was negatively associated with seizure severity. These provide the rationale for further confirmation studies in larger prospective cohorts and in other ethnics.
PMCID: PMC4435024  PMID: 25984652
12.  Synergistic anti-tumor effect of combined inhibition of EGFR and JAK/STAT3 pathways in human ovarian cancer 
Molecular Cancer  2015;14:100.
The EGFR signaling pathway is frequently activated in human ovarian cancer and associated with poor prognosis. However, inhibition of EGFR signaling in patients with recurrent ovarian cancer has been disappointing. It remains to be addressed whether ovarian cancer patients could benefit from targeting EGFR signaling. Here we investigated the mechanisms underlying the resistance to EGFR inhibition in ovarian cancer and developed a strategy to overcome it.
We found that treatment of human ovarian cancer cells with an EGFR inhibitor, gefitinib, resulted in increased STAT3 phosphorylation in a dose- and time-dependent manner. Inhibiting STAT3 activation with a small molecule inhibitor of JAK, an upstream kinase that phosphorylates and activates STAT3, synergistically increased the anti-tumor activity of gefitinib in vitro. Similar results were obtained when STAT3 or JAK1 expression was knocked down. In contrast, inhibiting other signaling pathways, such as AKT/mTOR, MEK or SRC, was relatively less effective. The combined treatment resulted in simultaneous attenuation of multiple survival pathways and increased inhibition of ERK pathway. In addition, the dual inhibition showed a stronger suppression of xenograft tumor growth than either single inhibition.
Our findings demonstrate that feedback activation of STAT3 pathway might contribute to the resistance to EGFR inhibition. Combined blockade of both pathways appears to be more effective against human ovarian cancer than inhibition of each pathway alone both in vitro and in vivo. This study may provide a strategy to improve clinical benefit of targeting EGFR pathway in ovarian cancer patients.
PMCID: PMC4437681  PMID: 25928246
Ovarian cancer; EGFR resistance; JAK/STAT3; feedback; combination; synergy
13.  Genome-wide circulating microRNA expression profiling indicates biomarkers for epilepsy 
Scientific Reports  2015;5:9522.
MicroRNAs (miRNAs) have been proposed as biomarkers for cancer and other diseases due to their stability in serum. In epilepsy, miRNAs have almost been studied in brain tissues and in animals' circulation, but not in circulation of human. To date, a major challenge is to develop biomarkers to improve the current diagnosis of epilepsy. The aim of this study was to evaluate whether circulating miRNAs can be used as biomarkers for epilepsy. We measured the differences in serum miRNA levels between 30 epilepsy patients and 30 healthy controls in discovery and training phases using Illumina HiSeq2000 sequencing followed by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) assays. The selected miRNAs were then validated in 117 epilepsy patients and 112 healthy controls by qRT-PCR. Let-7d-5p, miR-106b-5p, -130a-3p and -146a-5p were found up-regulated, whereas miR-15a-5p and -194-5p were down-regulated in epilepsy patients compared to controls (P < 0.0001). Among these miRNAs, miR-106b-5p had the best diagnostic value for epilepsy with 80.3% sensitivity and 81.2% specificity. Circulating miRNAs were differentially regulated in epilepsy patients as compared with controls. MiR-106b-5p may serve as a novel, noninvasive biomarker to improve the current diagnosis of epilepsy.
PMCID: PMC4379481  PMID: 25825351
14.  A population pharmacokinetic study of tacrolimus in healthy Chinese volunteers and liver transplant patients 
Acta Pharmacologica Sinica  2014;36(2):281-288.
To develop a population pharmacokinetic (PopPK) model of tacrolimus in healthy Chinese volunteers and liver transplant recipients for investigating the difference between the populations, and for potential individualized medication.
A set of 1100 sparse trough concentration data points from 112 orthotopic liver transplant recipients, as well as 851 dense data points from 40 healthy volunteers receiving a single dose of tacrolimus (2 mg, po) were collected. PopPK model of tacrolimus was constructed using the program NONMEM. Related covariates such as age, hepatic and renal functions that were potentially associated with tacrolimus disposition were evaluated. The final model was validated using bootstrapping and a visual predictive check.
A two-compartment model of tacrolimus could best describe the data from the two populations. The final model including two covariates, population (liver transplant recipients or volunteers) and serum ALT (alanine aminotransferase) level, was verified and adequately described the pharmacokinetic characteristics of tacrolimus. The estimates of V2/F, Q/F and V3/F were 22.7 L, 76.3 L/h and 916 L, respectively. The estimated CL/F in the volunteers and liver transplant recipients was 32.8 and 18.4 L/h, respectively. Serum ALT level was inversely related to CL/F, whereas age did not influence CL/F. Thus, the elderly (≥65 years) and adult (<65 years) groups in the liver transplant recipients showed no significant difference in the clearance of tacrolimus.
Compared with using the sparse data only, the integrating modeling technique combining sparse data from the patients and dense data from the healthy volunteers improved the PopPK analysis of tacrolimus.
PMCID: PMC4326784  PMID: 25500866
liver transplantation; healthy volunteer; immunosuppressant; tacrolimus; population pharmacokinetics; serum alanine aminotransferase
15.  RhoC, vascular endothelial growth factor and microvascular density in esophageal squamous cell carcinoma 
AIM: To investigate the expression of Ras homolog (Rho)C, vascular endothelial growth factor (VEGF) and CD105 in esophageal squamous cell carcinoma.
METHODS: Semi-quantitative reverse transcriptase polymerase chain reaction, in situ hybridization and immunohistochemical streptavidin-biotin- peroxidase methods were used to detect expression of RhoC mRNA and protein, and VEGF protein in 62 cases with esophageal squamous cell carcinoma, 31 cases with adjacent atypical hyperplastic tissues, and 62 cases with normal esophageal mucosa. CD105 antibody labeling was used to measure microvascular density. Expression levels were compared according to clinicopathologic and patient parameters.
RESULTS: Expression of RhoC mRNA showed a positive correlation with the protein level in esophageal squamous cell carcinoma, as well as with VEGF protein levels. RhoC mRNA expression was mainly located within the cytoplasm of the tumor cells, appearing as blue to purple particles by in situ hybridization. The differences in RhoC mRNA expression in esophageal squamous cell carcinoma, adjacent atypical hyperplasia and normal esophageal mucosa were significant (P < 0.05). The relative expression of RhoC mRNA in cancer tissues with lymph node metastasis was significantly higher than in the tissues without lymph node metastasis (P < 0.05). VEGF protein expression was consistent with microvascular density (t = 25.52, P < 0.05). Positive expression of VEGF protein in esophageal squamous cell carcinoma of different histologic gradings did not differ significantly. Positive expression of VEGF protein in carcinoma tissues with deep infiltration was significantly higher than in tissues with only superficial infiltration (P < 0.05). The positive expression of VEGF protein in cancer tissues with lymph node metastasis was significantly higher than in the tissues without lymph node metastasis (P < 0.05).
CONCLUSION: RhoC protein may upregulate VEGF expression, thereby promoting tumor angiogenesis. RhoC mRNA and protein expression was correlated with metastasis.
PMCID: PMC4299343  PMID: 25624724
Esophageal squamous cell carcinoma; Gene silencing; Ras homolog C; Vascular endothelial growth factor
16.  Analysis of Potato virus Y Coat Protein Epitopes Recognized by Three Commercial Monoclonal Antibodies 
PLoS ONE  2014;9(12):e115766.
Potato virus Y (PVY, genus Potyvirus) causes substantial economic losses in solanaceous plants. Routine screening for PVY is an essential part of seed potato certification, and serological assays are often used. The commercial, commonly used monoclonal antibodies, MAb1128, MAb1129, and MAb1130, recognize the viral coat protein (CP) of PVY and distinguish PVYN strains from PVYO and PVYC strains, or detect all PVY strains, respectively. However, the minimal epitopes recognized by these antibodies have not been identified.
Methodology/Principal Findings
SPOT peptide array was used to map the epitopes in CP recognized by MAb1128, MAb1129, and MAb1130. Then alanine replacement as well as N- and C-terminal deletion analysis of the identified peptide epitopes was done to determine critical amino acids for antibody recognition and the respective minimal epitopes. The epitopes of all antibodies were located within the 30 N-terminal-most residues. The minimal epitope of MAb1128 was 25NLNKEK30. Replacement of 25N or 27N with alanine weakened the recognition by MAb1128, and replacement of 26L, 29E, or 30K nearly precluded recognition. The minimal epitope for MAb1129 was 16RPEQGSIQSNP26 and the most critical residues for recognition were 22I and 23Q. The epitope of MAb1130 was defined by residues 5IDAGGS10. Mutation of residue 6D abrogated and mutation of 9G strongly reduced recognition of the peptide by MAb1130. Amino acid sequence alignment demonstrated that these epitopes are relatively conserved among PVY strains. Finally, recombinant CPs were produced to demonstrate that mutations in the variable positions of the epitope regions can affect detection with the MAbs.
The epitope data acquired can be compared with data on PVY CP-encoding sequences produced by laboratories worldwide and utilized to monitor how widely the new variants of PVY can be detected with current seed potato certification schemes or during the inspection of imported seed potatoes as conducted with these MAbs.
PMCID: PMC4277358  PMID: 25542005
17.  A novel synthetic derivative of the natural product berbamine inhibits cell viability and induces apoptosis of human osteosarcoma cells, associated with activation of JNK/AP-1 signaling 
Cancer Biology & Therapy  2013;14(11):1024-1031.
Osteosarcoma is the most common primary bone tumor in children and adolescents. There is a critical need to find more potent drugs for patients with metastatic or recurrent disease. Berbamine (BBM) is a natural compound derived from the Berberis amurensis plants. BBM and its derivatives have been shown to have antitumor effects in several cancers. Here, we report that a novel synthetic berbamine derivative, BBMD3, inhibits cell viability and induces apoptosis of G292, KHOS, and MG-63 human osteosarcoma cells. Induction of apoptosis in these tumor cells depends on activation of caspase-3 and cleavage of poly(ADP-ribose) polymerase (PARP). Since pan-caspase inhibitor (Z-VAD-FMK) and caspase-9 inhibitor (Z-LEHD-FMK) could block the cleavage of PARP, the apoptosis induced by BBMD3 is through intrinsic signaling pathway. BBMD3 increased phosphorylation of c-Jun N-terminal kinase (JNK)/stress-activated protein kinase (SAPK), resulting in increase of phosphorylated c-Jun and total c-Fos, the major components of transcriptional factor AP-1. JNK inhibitor could partially suppress antitumor effect of BBMD3 on osteosarcoma cells. BBMD3 increased the production of reactive oxygen species (ROS) and ROS scavenger, N-acetylcysteine (NAC), could block the phosphorylation of JNK and c-Jun induced by BBMD3. BBMD3 increased the expression of the pro-apototic gene Bad, associated with apoptosis induction. Finally, BBMD3 also decreased the expression of cyclin D1 and D2, the positive cell cycle regulators, which is correlated with growth inhibition in osteosarcoma cells. Collectively, these findings indicate that BBMD3 is a potentially promising drug for the treatment of human osteosarcoma.
PMCID: PMC3925657  PMID: 24025361
berbamine derivative; osteosarcoma; apoptosis; JNK; AP-1; natural product
18.  Alzheimer's disease progression model based on integrated biomarkers and clinical measures 
Acta Pharmacologica Sinica  2014;35(9):1111-1120.
Biomarkers and image markers of Alzheimer's disease (AD), such as cerebrospinal fluid Aβ42 and p-tau, are effective predictors of cognitive decline or dementia. The aim of this study was to integrate these markers with a disease progression model and to identify their abnormal ranges.
The data of 395 participants, including 86 normal subjects, 108 early mild cognitive impairment (EMCI) subjects, 120 late mild cognitive impairment (LMCI) subjects, and 81 AD subjects were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. For the participants, baseline and long-term data on cerebrospinal fluid Aβ42 and p-tau, hippocampal volume, and ADAS-cog were available. Various linear and nonlinear models were tested to determine the associations among the ratio of Aβ42 to p-tau (the Ratio), hippocampal volume and ADAS-cog.
The most likely models for the Ratio, hippocampal volume, and ADAS-cog (logistic, Emax, and linear models, respectively) were used to construct the final model. Baseline disease state had an impact on all the 3 endpoints (the Ratio, hippocampal volume, and ADAS-cog), while APOEε4 genotype and age only influence the Ratio and hippocampal volume.
The Ratio can be used to identify the disease stage for an individual, and clinical measures integrated with the Ratio improve the accuracy of mild cognitive impairment (MCI) to AD conversion forecasting.
PMCID: PMC4155529  PMID: 25088003
Alzheimer's disease; mild cognitive impairment; Aβ42; p-tau; hippocampus; ADAS-cog; disease progression model; NONMEM
19.  Dopamine D1 receptor activation induces dehydroepiandrosterone sulfotransferase (SULT2A1) in HepG2 cells 
Acta Pharmacologica Sinica  2014;35(7):889-898.
Dopamine receptors are present in the nervous system and also widely distributed in the periphery. The aim of this study was to investigate the role of D1 subtype dopamine receptors (DRD1) in the regulation of dehydroepiandrosterone sulfotransferase (SULT2A1) in HepG2 cells.
HepG2 cells were treated with DRD1 agonists with or without DRD1 antagonist for 9 d. DRD1 and SULT2A1 mRNA expression, protein expression, and SULT2A1 activity were detected using RT-PCR, Western blotting and HPLC, respectively. The level of cAMP was measured using a commercial kit.
All the 5 DR subtypes (DRD1–DRD5) were found to be expressed in HepG2 cells. Treatment of HepG2 cells with the specific DRD1 agonists SKF82958 (2.5 μmol/L) or SKF38393 (5 and 50 μmol/L) significantly increased the mRNA and protein expression of both DRD1 and SULT2A1, and increased SULT2A1 activity and cAMP levels. These effects were partially blocked by co-treatment with the specific DRD1 antagonist SCH23390 (2.5 μmol/L). In addition, transfection of HepG2 cells with DRD1-specific siRNAs decreased DRD1 mRNA expression by 40%, which resulted in the reduction of SULT2A1 mRNA expression by 60%, protein expression by 40%, and enzyme activity by 20%.
DRD1 activation upregulates DRD1 and SULT2A1 expression and SULT2A1 activity in HepG2 cells, suggesting that the DRD1 subtype may be involved in the metabolism of drugs and xenobiotics through regulating SULT2A1.
PMCID: PMC4088277  PMID: 24909515
dopamine; D1 receptor; dehydroepiandrosterone sulfotransferase (SULT2A1); drug-metabolizing enzyme; SKF82958; SKF38393; SCH23390; siRNA; HepG2 cell
20.  C-Reactive Protein and Preterm Delivery 
Reproductive Sciences  2013;20(6):715-722.
To study the association between maternal C-reactive protein (CRP) and preterm delivery (PTD) pathways, CRP was measured in maternal plasma collected at mid-pregnancy (n = 1310). PTD was subdivided into spontaneous (sPTD) or medically indicated (MI-PTD). Histologic chorioamnionitis (HCA) was determined by placental histopathology (n = 1076). Adjusted CRP levels were elevated for sPTD (5.5 µg/mL) versus term deliveries (4.8 µg/mL) and higher in sPTD with HCA (6.3 µg/mL). After removing HCA, an interaction between body mass index (BMI) and sPTD in relation to CRP was noted. In BMI-stratified models, an association between CRP and sPTD among women with prepregnancy BMI >25 (8.9 µg/mL for sPTD; 7.2 µg/mL for term) was absent among women with lower BMI. We propose that this remaining association in overweight/obese women suggests that CRP may mark an obesity/inflammation PTD pathway that is distinct from the pathway indicated by HCA.
PMCID: PMC3713547  PMID: 23221172
preterm birth; C-reactive protein; prepregnancy body mass index; placentas; chorioamnionitis
21.  Xanthoceraside Ameliorates Mitochondrial Dysfunction Contributing to the Improvement of Learning and Memory Impairment in Mice with Intracerebroventricular Injection of Aβ1-42 
The effects of xanthoceraside on learning and memory impairment were investigated and the possible mechanism associated with the protection of mitochondria was also preliminarily explored in Alzheimer's disease (AD) mice model induced by intracerebroventricular (i.c.v.) injection of Aβ1-42. The results indicated that xanthoceraside (0.08–0.32 mg/kg) significantly improved learning and memory impairment in Morris water maze test and Y-maze test. Xanthoceraside significantly reversed the aberrant decrease of ATP levels and attenuated the abnormal increase of ROS levels both in the cerebral cortex and hippocampus in mice injected with Aβ1-42. Moreover, xanthoceraside dose dependently reversed the decrease of COX, PDHC, and KGDHC activity in isolated cerebral cortex mitochondria of the mice compared with Aβ1-42 injected model mice. In conclusion, xanthoceraside could improve learning and memory impairment, promote the function of mitochondria, decrease the production of ROS, and inhibit oxidative stress. The improvement effects on mitochondria may be through withstanding the damage of Aβ to mitochondrial respiratory chain and the key enzymes in Kreb's cycle. Therefore, the results from present study and previous study indicate that xanthoceraside could be a competitive candidate for the treatment of AD.
PMCID: PMC4058193  PMID: 24976855
22.  Long-term effects of three Tiao-Bu Fei-Shen therapies on NF-κB/TGF-β1/smad2 signaling in rats with chronic obstructive pulmonary disease 
The three Tiao-Bu Fei-Shen (Bufei Jianpi, Bufei Yishen, Yiqi Zishen) granules have been confirmed for their beneficial clinical efficacy in chronic obstructive pulmonary disease (COPD) patients on reducing frequency and duration of acute exacerbation, improving syndromes, pulmonary function and exercise capacity. But the short- or long-term mechanism of them is not fully clear. Nuclear factor (NF)-κB/transforming growth factor (TGF)-β1/smad2 signaling pathway is involved in the progress of inflammation and remodeling in chronic obstructive pulmonary disease COPD. This study aimed to explore the long-term effects mechanism of Tiao-Bu Fei-Shen granules by regulating NF-κB/TGF-β/Smads signaling in rats with COPD.
Sprague Dawley rats were randomized into control, model, Bufei Jianpi, Bufei Yishen, Yiqi Zishen and aminophylline groups. COPD rats, induced by cigarette smoke and bacterial infections exposures, were administrated intragastricly by normal saline, Bufei Jianpi, Bufei Yishen, Yiqi Zishen granules or aminophylline from week 9 through 20, respectively. At week 20 and 32, lung tissues were harvested. Immunohistochemistry was used to detect interleukin (IL)-1β and tumor necrosis factor (TNF)-α, quantitative real-time polymerase chain reaction (qRT-PCR) was used for TGF-β1 and Smad2 mRNA analysis, western blotting was used to determine the phosphorylation of NF-κB (p-NF-κB) and IκBα (p-IκBα).
COPD rats had marked airway injury, such as chronic airway inflammation and remodeling, emphysema, which were improved in the three traditional Chinese medicines (TCM)-treated animals. The levels of IL-1β, TNF-α, p-NF-κB, p-IκBα, TGF-β1 and Smad2 were significantly higher in COPD rats than in controls, while they were dramatically reduced in the three TCM- and aminophylline-treated groups. At the meantime, all these endpoints were significantly lower in three TCM-treated groups than in aminophylline group, especially in Bufei Jianpi and Bufei Yishen groups. Compared to week 20, all endpoints decreased significantly in three TCM groups at week 32.
The three Tiao-Bu Fei-Shen therapies can reduce pulmonary inflammation and remodeling in COPD and have significant long-term effects. NF-κB/TGF-β1/smad2 signaling might be involved in the mechanism.
PMCID: PMC4006455  PMID: 24766819
Chronic obstructive pulmonary disease; Bufei jianpi; Bufei yishen; Yiqi zishen; Traditional Chinese medicine
23.  Tumors of the angle of Treitz: A single-center experience 
AIM: To explore the feasibility and oncologic outcomes of segmental jejunal resection on the left side of the mesenteric vessels in patients with tumors of the angle of Treitz using data from a single center.
METHODS: Thirteen patients with tumors of the angle of Treitz who underwent surgery at our institution were prospectively followed. A segmental jejunal resection on the left side of the mesenteric vessels was performed in all patients. Formalin-fixed and paraffin-embedded tumor samples were examined. The primary end point of this analysis was disease-free survival.
RESULTS: In this study, there were 8 males and 5 females (mean age, 50.1 years; range, 36-74 years). The mean tumor size was 8.1 cm (range, 3.2-15 cm). Histologic examination showed 11 gastrointestinal stromal tumors (GISTs) and 2 adenocarcinomas. Five of the GIST patients presented with potential low risk, and 6 presented with intermediate and high risk, according to the National Institutes of Health criteria. One potentially high-risk patient showed tumor progression at 46 mo and died 52 mo after surgery. One patient with locally advanced adenocarcinoma received neoadjuvant chemotherapy and adjuvant radiotherapy, but the disease progressed, and the patient died 9 mo after surgery. One GIST patient without progression died 16 mo after surgery because of a postoperative intestinal obstruction. The median overall survival rate was 84.6 mo, and the median disease-free survival rate was 94.5 mo.
CONCLUSION: The overall survival of patients with tumors of the angle of Treitz was encouraging even when the tumor size was relatively large. A segmental resection on the left side of the mesenteric vessels is considered to be a reliable and curative option for tumors of the angle of Treitz.
PMCID: PMC3974531  PMID: 24707147
Gastrointestinal stromal tumor; Adenocarcinoma; Angle of Treitz; Surgical treatment; Prognosis
24.  Inflammation biomarkers in vaginal fluid and preterm delivery 
Which inflammation biomarkers detected in the vaginal fluid are most informative for identifying preterm delivery (PTD) risk?
Elevated interleukin (IL)-6 at mid-trimester was associated with increased odds of spontaneous PTD at <35 weeks and with PTD plus histologic chorioamnionitis (HCA), and had the greatest sensitivity for detecting these two PTD subtypes.
Maternal and/or fetal inflammation play a role in some preterm deliveries, therefore inflammation biomarkers might help to identify women at greater risk.
We examined 1115 women from the Pregnancy Outcomes and Community Health Study, a cohort study conducted from September 1998 through June 2004, for whom data were available on mid-pregnancy inflammatory biomarkers.
At enrollment at 16–27 weeks gestation, vaginal fluid samples were collected from a swab and 15 eluted biomarkers were measured using the Meso Scale Discovery multiplex electrochemiluminescence platform. Associations of biomarkers with PTD were examined, according to clinical circumstance, week at delivery and presence/absence of HCA. Weighted logistic regression was used to determine odds ratios (OR) and 95% confidence intervals (CI) adjusted for race. Sensitivity and specificity were compared between individual and multiple biomarkers, identified by a bootstrapping method.
Elevated IL-6 (>75th percentile) displayed the strongest association with spontaneous PTD <35 weeks (OR 2.3; CI 1.3–4.0) and PTD with HCA (OR 2.8; CI 1.4–6.0). The sensitivity of IL-6 to detect spontaneous PTD <35 weeks or PTD with HCA was 0.43 and 0.51, respectively, while specificity was 0.74 and 0.75, respectively. IL-6 plus IL1β, IL-6r, tumor necrosis factor-alpha or granulocyte-macrophage colony-stimulating factor increased specificity (range 0.84–0.88), but decreased sensitivity (range 0.28–0.34) to detect both PTD subtypes. Results were similar when a combination of IL-6 and bacterial vaginosis (BV) was explored. Thus, the use of multiple biomarkers did not detect PTD subtypes with a greater sensitivity than IL-6 alone, and IL-6 is a specific but non-sensitive marker for the detection of spontaneous PTD.
Our ability to find small effect size associations between PTD and inflammation biomarkers (OR <2.0) might have been limited by the modest number of less common PTD subtypes in our population (e.g. spontaneous delivery <35 weeks, PTD accompanied by HCA) and by relatively higher variability for some cytokines, for example tumor necrosis factor-α, IL-12p70, IL-10 and granulocyte-macrophage colony-stimulating factor, that are less stable and commonly undetectable or detectable at low levels in human vaginal secretions.
Larger studies are needed to further explore a role of inflammation biomarkers in combination with other risk factors, including specific BV-associated organisms, for the prediction of PTD subtypes.
This work was supported by the National Institute of Child Health and Human Development, National Institute of Nursing, March of Dimes Foundation, Thrasher Research Foundation and Centers for Disease Control and Prevention. The authors have no conflicts of interest.
PMCID: PMC3600841  PMID: 23416276
biomarker; histologic chorioamnionitis; inflammation; preterm birth
25.  Inhibition of EGFR autophosphorylation plays an important role in the anti-breast cancer efficacy of the dithiocarbamate derivative TM208 
Acta Pharmacologica Sinica  2013;35(2):239-247.
To investigate the effects of a novel dithiocarbamate derivative TM208 on human breast cancer cells as well as the pharmacokinetic characteristics of TM208 in human breast cancer xenograft mice.
Human breast cancer MCF-7 and MDA-MB-231 cells were treated with TM208 or a positive control drug tamoxifen. Cell proliferation was examined using SRB and colony formation assays. Cell apoptosis was analyzed with Annexin V-FITC/PI staining assay. Protein expression was examined with Western blot, ELISA and immunohistochemical analyses. MCF-7 breast cancer xenograft nude mice were orally administered TM208 (50 or 150 mg·kg−1·d−1) or tamoxifen (50 mg·kg−1·d−1) for 18 d. On d 19, the tumors were collected for analyses. Blood samples were collected from the mice treated with the high dose of TM208, and plasma concentrations of TM208 were measured using LC-MS/MS.
Treatment of MCF-7 and MDA-MB-231 cells with TM208 dose-dependently inhibited the cell proliferation and colony formation in vitro (the IC50 values were 36.38±3.77 and 18.13±0.76 μmol/L, respectively). TM208 (20–150μmol/L) dose-dependently induced apoptosis of both the breast cancer cells in vitro. In MCF-7 breast cancer xenograft nude mice, TM208 administration dose-dependently reduced the tumor growth, but did not result in the accumulation of TM208 or weight loss. TM208 dose-dependently inhibited the phosphorylation of EGFR and ERK1/2 in both the breast cancer cells in vitro as well as in the MCF-7 xenograft tumor.
Inhibition of EGFR autophosphorylation plays an important role in the anticancer effect of TM208 against human breast cancer.
PMCID: PMC4651224  PMID: 24374811
breast cancer; dithiocarbamate; TM208; tyrosine kinase inhibitor; EGFR; ERK1/2; phosphorylation; tumor xenograft nude mice

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