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1.  In vitro analysis of phosphorothioate modification of DNA reveals substrate recognition by a multiprotein complex 
Scientific Reports  2015;5:12513.
A wide variety of prokaryotes possess DNA modifications consisting of sequence-specific phosphorothioates (PT) inserted by members of a five-gene cluster. Recent genome mapping studies revealed two unusual features of PT modifications: short consensus sequences and partial modification of a specific genomic site in a population of bacteria. To better understand the mechanism of target selection of PT modifications that underlies these features, we characterized the substrate recognition of the PT-modifying enzymes termed DptC, D and E in a cell extract system from Salmonella. The results revealed that double-stranded oligodeoxynucleotides underwent de novo PT modification in vitro, with the same modification pattern as in vivo, i. e., GpsAAC/GpsTTC motif. Unexpectedly, in these in vitro analyses we observed no significant effect on PT modification by sequences flanking GAAC/GTTC motif, while PT also occurred in the GAAC/GTTC motif that could not be modified in vivo. Hemi-PT DNA also served as substrate of the PT-modifying enzymes, but not single-stranded DNA. The PT-modifying enzymes were then found to function as a large protein complex, with all of three subunits in tetrameric conformations. This study provided the first demonstration of in vitro DNA PT modification by PT-modifying enzymes that function as a large protein complex.
PMCID: PMC4515589  PMID: 26213215
2.  Efficacy of Acupuncture in Children with Nocturnal Enuresis: A Systematic Review and Meta-Analysis of Randomized Controlled Trials 
Background. Nocturnal enuresis (NE) is recognized as a widespread health problem in young children and adolescents. Clinical researches about acupuncture therapy for nocturnal enuresis are increasing, while systematic reviews assessing the efficacy of acupuncture therapy are still lacking. Objective. This study aims to assess the effectiveness of acupuncture therapy for nocturnal enuresis. Materials and Methods. A comprehensive literature search of 8 databases was performed up to June 2014; randomized controlled trials which compared acupuncture therapy and placebo treatment or pharmacological therapy were identified. A meta-analysis was conducted. Results. This review included 21 RCTs and a total of 1590 subjects. The overall methodological qualities were low. The results of meta-analysis showed that acupuncture therapy was more effective for clinical efficacy when compared with placebo or pharmacological treatment. Adverse events associated with acupuncture therapy were not documented. Conclusion. Based on the findings of this study, we cautiously suggest that acupuncture therapy could improve the clinical efficacy. However, the beneficial effect of acupuncture might be overstated due to low methodological qualities. Rigorous high quality RCTs are urgently needed.
PMCID: PMC4488007  PMID: 26167190
3.  Comparison between Solitaire™ AB and Enterprise stent-assisted coiling for intracranial aneurysms 
The aim of the present study was to analyze the feasibility, rate of procedure-related complications and midterm angiographic follow-up outcomes using the Enterprise (EP) and Solitaire™ AB (ST) stents in the stent-assisted coiling of intracranial aneurysms. In total, 81 patients with 90 aneurysms were included in the study, with the aim to treat 43 aneurysms with the EP stent (47.8%) and 47 aneurysms with the ST stent (52.2%). The 90 aneurysms were successfully stented and subsequently coiled; however, in four patients undergoing treatment with the EP stent, the stent was not navigable; thus, treatment with the ST stent was employed (EP, n=39, 43.3%; ST, n=51, 56.7%). Of the 90 aneurysms, 44 cases were ruptured aneurysms, with 74 located in the anterior circulation and 16 located in the posterior circulation. The stenting success rate of the ST stent was significantly higher compared with the EP stent. However, no statistically significant differences were observed with regard to the packing density, complete occlusion, progressive occlusion, recurrence rate, procedure-related complications, in-stent stenosis and stent migration rates between the two groups. In conclusion, the two common medical devices used for intracranial aneurysms are relatively safe and effective for the treatment of intracranial aneurysms. However, due to the higher stenting success rate of the ST stent, this medical devise was demonstrated to be more flexible and feasible compared with the EP stent.
PMCID: PMC4486898  PMID: 26170926
Solitaire™ AB stent; Enterprise stent; stent-assisted coiling; intracranial aneurysms; endovascular treatment
4.  Effects of neuromuscular joint facilitation on bridging exercises with respect to deep muscle changes 
Journal of Physical Therapy Science  2015;27(5):1417-1419.
[Purpose] This study examined the effects of neuromuscular joint facilitation on bridging exercises by assessing the cross-sectional area of the multifidus muscle and thickness of the musculus transversus abdominis. [Subjects] Twelve healthy men. [Methods] Four exercises were evaluated: (a) supine resting, (b) bridging resistance exercise involving posterior pelvic tilting, (c) bridging resistance exercise involving anterior pelvic tilting, and (d) bridging resistance exercise involving neuromuscular joint facilitation. The cross-sectional area of the multifidus muscle and thickness of the musculus transversus abdominis were measured during each exercise. [Results] The cross-sectional area of the multifidus muscle and thickness of the musculus transversus abdominis were significantly greater in the neuromuscular joint facilitation group than the others. [Conclusion] Neuromuscular joint facilitation intervention improves the function of deep muscles such as the multifidus muscle and musculus transversus abdominis. Therefore, it can be recommended for application in clinical treatments such as that for back pain.
PMCID: PMC4483410  PMID: 26157232
Back pain; Cross-sectional area of multifidus muscle; Bridging exercises
5.  C-reactive protein promotes atherosclerosis by increasing LDL transcytosis across endothelial cells 
British Journal of Pharmacology  2014;171(10):2671-2684.
Background and Purpose
The retention of plasma low-density lipoprotein (LDL) particles in subendothelial space following transcytosis across the endothelium is the initial step of atherosclerosis. Whether or not C-reactive protein (CRP) can directly affect the transcytosis of LDL is not clear. Here we have examined the effect of CRP on transcytosis of LDL across endothelial cells and have explored the underlying mechanisms.
Experimental Approach
Effects of CRP on transcytosis of FITC-labelled LDL were examined with human umbilical vein endothelial cells and venous rings in vitro and, in vivo, ApoE-/- mice. Laser scanning confocal microscopy, immunohistochemistry and Oil Red O staining were used to assay LDL.
Key Results
CRP increased transcytosis of LDL. An NADPH oxidase inhibitor, diphenylene iodonium, and the reducing agent, dithiothreitol partly or completely blocked CRP-stimulated increase of LDL transcytosis. The PKC inhibitor, bisindolylmaleimide I and the Src kinase inhibitor, PP2, blocked the trafficking of the molecules responsible for transcytosis. Confocal imaging analysis revealed that CRP stimulated LDL uptake by endothelial cells and vessel walls. In ApoE-/- mice, CRP significantly promoted early changes of atherosclerosis, which were blocked by inhibitors of transcytosis.
Conclusions and Implications
CRP promoted atherosclerosis by directly increasing the transcytosis of LDL across endothelial cells and increasing LDL retention in vascular walls. These actions of CRP were associated with generation of reactive oxygen species, activation of PKC and Src, and translocation of caveolar or soluble forms of the N-ethylmaleimide-sensitive factor attachment protein.
PMCID: PMC4009008  PMID: 24517733
LDL; transcytosis; C-reactive protein; endothelial cells; atherosclerosis; caveolae; PKC; Src; ROS
6.  The Role of Vitamin D in Pediatric Asthma 
The detrimental effects of vitamin D deficiency in pediatrics have become increasingly apparent and extend beyond skeletal health. Unfortunately, vitamin D deficiency is highly prevalent in atopic pediatric patients, in whom it may disrupt the immune system and induce significant worsening of reactive airways. This review presents evidence that lung development and immune regulatory functions are vitamin D-dependent. We also review clinical studies that explore how vitamin D supplementation may prevent respiratory infections and help improve asthma control, and we elaborate how these effects may vary among populations. We reveal the strong need of screening measures for vitamin D deficiency in high risk pediatric populations, particularly African-Americans, Hispanic-Americans, and children with obesity. Finally, we emphasize that all children, especially those who are asthmatic, should be assessed to ensure adequate intake or supplementation with at least the minimum recommended doses of vitamin D. The simple intervention of vitamin D supplementation may provide significant clinical improvement in atopic disease, especially asthma.
PMCID: PMC4415725  PMID: 25938135
Vitamin D; asthma; atopy; allergen immunotherapy; pediatrics
7.  Efficacy of Acupuncture in Itch: A Systematic Review and Meta-Analysis of Clinical Randomized Controlled Trials 
Background. Itch (pruritus) is a sensitive state that provokes the desire to scratch. It is not only a common symptom of skin diseases but it also occurs in some systemic diseases. Clinical studies on the efficacy of the acupuncture therapy in alleviating itch are increasing, while systematic reviews assessing the efficacy of acupuncture therapy are still lacking. Objective. This systematic review aims to assess the effectiveness of acupuncture therapy for itch. Materials and Methods. A comprehensive literature search of eight databases was performed up to June 2014, and randomized controlled trials which compared acupuncture therapy and placebo acupuncture or no treatment group were identified. Accordingly, a meta-analysis was conducted. Results. This review included three articles of randomized controlled trials (RCTs) from a total of 2530 articles. The results of Meta-analysis showed that acupuncture therapy was effective to alleviate itch compared with placebo acupuncture and no treatment group. Conclusion. Based on the findings of this systematic review, we cautiously suggest that acupuncture therapy could improve the clinical efficacy of itch. However, this conclusion needs more studies on various ethnic samples to confirm our final conclusion.
PMCID: PMC4430643  PMID: 26064156
8.  Effects on ROM and joint position sense of the neck of two different interventions 
Journal of Physical Therapy Science  2015;27(4):1041-1043.
[Purpose] The purpose of this study was to evaluate whether neuromuscular joint facilitation (NJF) training is superior to NJF distal resistance training at improving the ROM and proprioceptive acuity of the neck. [Subjects] 10 healthy subjects (8 males, 2 females) participated in this study. [Methods] The participants were allocated to three groups: 10 in the control group, 10 in the NJF distal resistance training group, and 10 in the NJF training group. A miniature wireless motion recorder was used to record the maximum cervical range of motion and joint position error (JPE) before and after the interventions. The three interventions were tested on different days. [Results] No difference of ROM was observed among the three groups. A significant pre- to post-intervention decrease in JPE in extension was identified in the NJF group. No other significant differences were observed among the three groups. [Conclusion] The NJF training conferred remarkable benefits on the cervical JPE of healthy people. This result suggests that the best way to improve proprioceptive acuity is intervention together with proximal resistance training, such as NJF training.
PMCID: PMC4433972  PMID: 25995551
Neck; Joint position sense; Neuromuscular joint facilitation (NJF)
9.  1H-NMR and MS Based Metabolomics Study of the Intervention Effect of Curcumin on Hyperlipidemia Mice Induced by High-Fat Diet 
PLoS ONE  2015;10(3):e0120950.
Curcumin, a principle bioactive component of Curcuma longa L, is well known for its anti-hyperlipidemia effect. However, no holistic metabolic information of curcumin on hyperlipidemia models has been revealed, which may provide us an insight into the underlying mechanism. In the present work, NMR and MS based metabolomics was conducted to investigate the intervention effect of curcumin on hyperlipidemia mice induced by high-fat diet (HFD) feeding for 12 weeks. The HFD induced animals were orally administered with curcumin (40, 80 mg/kg) or lovastatin (30 mg/kg, positive control) once a day during the inducing period. Serum biochemistry assay of TC, TG, LDL-c, and HDL-c was conducted and proved that treatment of curcumin or lovastatin can significantly improve the lipid profiles. Subsequently, metabolomics analysis was carried out for urine samples. Orthogonal Partial Least Squares-Discriminant analysis (OPLS-DA) was employed to investigate the anti-hyperlipidemia effect of curcumin and to detect related potential biomarkers. Totally, 35 biomarkers were identified, including 31 by NMR and nine by MS (five by both). It turned out that curcumin treatment can partially recover the metabolism disorders induced by HFD, with the following metabolic pathways involved: TCA cycle, glycolysis and gluconeogenesis, synthesis of ketone bodies and cholesterol, ketogenesis of branched chain amino acid, choline metabolism, and fatty acid metabolism. Besides, NMR and MS based metabolomics proved to be powerful tools in investigating pharmacodynamics effect of natural products and underlying mechanisms.
PMCID: PMC4364983  PMID: 25786031
10.  Transgenic Expression of Interleukin-13 in the Skin Induces a Pruritic Dermatitis and Skin Remodeling 
IL-13 has been implicated in the pathogenesis of allergic diseases, including atopic dermatitis (AD). However, a direct role of IL-13 in AD has not been established. We aimed to develop an inducible transgenic model in which IL-13 can be expressed in the skin and to define the resulting dermal phenotype and mechanisms involved. The keratin 5 promoter was used with a tetracycline-inducible system to target IL-13 to the skin. The clinical manifestations, dermal histology, cytokine gene regulation, and systemic immune responses in the transgenic mice were assessed. IL-13 was produced exclusively in the skin and caused a chronic inflammatory phenotype characterized by xerosis and pruritic eczematous lesions; dermal infiltration of CD4 + T cells, mast cells, eosinophils, macrophages, and Langerhans cells; upregulation of chemokine and cytokine genes, including thymic stromal lymphopoietin; and skin remodeling with fibrosis and increased vasculature. The dermal phenotype was accompanied by elevated serum total IgE and IgG1 and increased production of IL-4 and IL-13 by CD4 + cells from lymphoid tissues and peripheral blood mononuclear cells. IL-13 is a potent stimulator of dermal inflammation and remodeling and this transgenic model of AD is a good tool for investigating the underlying mechanisms in the pathogenesis of AD.
PMCID: PMC4356214  PMID: 18830273
11.  The comparison of surgical patients with primary hepatic squamous cell carcinoma or adenosquamous carcinoma and surgical patients with hepatocellular carcinoma 
There are still several controversies and ambiguities in the aspects of primary hepatic squamous cell carcinoma and primary hepatic adenosquamous carcinoma. To further clarify the specific features of these two infrequent diseases and provide beneficial propose for clinical decision, we did this retrospective study.
We reviewed the clinical features and outcomes of three primary hepatic squamous cell carcinoma (SCC) patients and six primary hepatic adenosquamous carcinoma (ASC) patients from January 1998 to December 2011 in Eastern Hepatobiliary Surgery Hospital in China. Meanwhile, 40 hepatocellular carcinoma (HCC) patients and 26 metastatic hepatic SCC or ASC patients who were hospitalized in the same period were also reviewed to make a comparison. In order to find out the definite survival information of SCC and ASC patients, 30 previous studies containing 37 primary hepatic SCC (16) and ASC (21) patients were reviewed, and their information of survival was analyzed together with the included patients in our hospital.
Serum tumor markers showed significant differences between primary hepatic SCC/ASC and HCC patients, especially for serum alpha fetal protein (AFP) level and carbohydrate antigen 19-9 (CA 19-9). On the pathologic performance, primary SCC/ASC tumor was rarely accompanied with tumor capsule. They presented peripheral hepatic lymph node metastasis more likely and showed low proportion of microvascular invasion. The median survival time of primary hepatic SCC/ASC patients after liver resection (LR) was 15 months. And the 1-, 3-, 5-year survival rates after LR were 60%, 24%, and 12%, respectively. Significant difference was not discovered when SCC and ASC patients were compared with HCC patients (P = 0.294). The median survival time after LR for primary SCC and ASC patients was respectively 23 months and 13 months.
The comprehensive application of some clinical characteristics, histopathologic features, and imaging findings may be useful for us in making definite diagnoses for primary hepatic SCC and ASC patients preoperatively. And the treatment of liver resection was effective for those patients who met the selection criteria for liver resection.
PMCID: PMC4358902  PMID: 25890009
Hepatic squamous cell carcinoma (SCC); Adenosquamous carcinoma (ASC); Hepatocellar carcinoma (HCC)
12.  Norisoboldine, an Anti-Arthritis Alkaloid Isolated from Radix Linderae, Attenuates Osteoclast Differentiation and Inflammatory Bone Erosion in an Aryl Hydrocarbon Receptor-Dependent Manner 
Norisoboldine (NOR), the primary isoquinoline alkaloid constituent of the root of Lindera aggregata, has previously been demonstrated to attenuate osteoclast (OC) differentiation. Accumulative evidence has shown that aryl hydrocarbon receptor (AhR) plays an important role in regulating the differentiation of various cells, and multiple isoquinoline alkaloids can modulate AhR. In the present study, we explored the role of NOR in the AhR signaling pathway. These data showed that the combination of AhR antagonist resveratrol (Res) or α-naphthoflavone (α-NF) nearly reversed the inhibition of OC differentiation through NOR. NOR could stably bind to AhR, up-regulate the nuclear translocation of AhR, and enhance the accumulation of the AhR-ARNT complex, AhR-mediated reporter gene activity and CYP1A1 expression in RAW 264.7 cells, suggesting that NOR might be an agonist of AhR. Moreover, NOR inhibited the nuclear translocation of NF-κB-p65, resulting in the evident accumulation of the AhR-NF-κB-p65 complex, which could be markedly inhibited through either Res or α-NF. Although NOR only slightly affected the expression of HIF-1α, NOR markedly reduced VEGF mRNA expression and ARNT-HIF-1α complex accumulation. In vivo studies indicated that NOR decreased the number of OCs and ameliorated the bone erosion in the joints of rats with collagen-induced arthritis, accompanied by the up-regulation of CYP1A1 and the down-regulation of VEGF mRNA expression in the synovium of rats. A combination of α-NF nearly completely reversed the effects of NOR. In conclusion, NOR attenuated OC differentiation and bone erosion through the activation of AhR and the subsequent inhibition of both NF-κB and HIF pathways.
PMCID: PMC4515821  PMID: 26221077
Norisoboldine; Aryl hydrocarbon receptor; Osteoclast differentiation; Rheumatoid arthritis; Inflammatory bone erosion
13.  TRPA1-Dependent Pruritus in IL-13-Induced Chronic Atopic Dermatitis 
Chronic debilitating pruritus is a cardinal feature of a topic dermatitis (AD). Little is known about the underlying mechanisms. Antihistamines lack efficacy in treating itch in AD, suggesting the existence of histamine-independent itch pathways in AD. Transient receptor potential ankyrin 1 (TRPA1) is essential in the signaling pathways that promote histamine-independent itch. In the present study, we tested the hypothesis that TRPA1-dependent neural pathways play a key role in chronic itch in AD using an IL-13 transgenic mouse model of AD. In these mice, IL-13 causes chronic AD characterized by intensive chronic itch associated with markedly enhanced growth of dermal neuropeptide-secreting afferent nerve fibers and enhanced expression of TRPA1 in dermal sensory nerve fibers, their dorsal root ganglia, and mast cells. Inhibition of TRPA1 with a specific antagonist in these mice selectively attenuated itch-evoked scratching. Genetic deletion of mast cells in these mice led to significantly diminished itch-scratching behaviors and reduced TRPA1 expression in dermal neuropeptide containing afferents in the AD skin. Interestingly, IL-13 strongly stimulates TRPA1 expression, which is functional in calcium mobilization in mast cells. In accordance with these observations in the AD mice, TRPA1 expression was highly enhanced in the dermal afferent nerves, mast cells, and the epidermis in the lesional skin biopsies from patients with AD, but not in the skin from normal subjects. These studies demonstrate a novel neural mechanism underlying chronic itch in AD and highlight the complex interactions among TRPA1+ dermal afferent nerves and TRPA1+ mast cells in a Th2-dominated inflammatory environment.
PMCID: PMC4175413  PMID: 24140646
14.  Therapeutic detoxification of quercetin against carbon tetrachloride-induced acute liver injury in mice and its mechanism*  
This study observes the therapeutic detoxification of quercetin, a well-known flavonoid, against carbon tetrachloride (CCl4) induced acute liver injury in vivo and explores its mechanism. Quercetin decreased CCl4-increased serum activities of alanine and aspartate aminotransferases (ALT/AST) when orally taken 30 min after CCl4 intoxication. The results of a histological evaluation further evidenced the ability of quercetin to protect against CCl4-induced liver injury. Quercetin decreased the CCl4-increased malondialdehyde (MDA) and reduced the glutathione (GSH) amounts in the liver. It also reduced the enhanced immunohistochemical staining of the 4-hydroxynonenal (4-HNE) in the liver induced by CCl4. Peroxiredoxin (Prx) 1, 2, 3, 5, 6, thioredoxin reductase 1 and 2 (TrxR1/2), thioredoxin 1 and 2 (Trx1/2), nuclear factor erythroid 2-related factor 2 (Nrf2), and heme oxygenase-1 (HO-1) all play critical roles in maintaining cellular redox homeostasis. Real-time polymerase chain reaction (PCR) results demonstrated that quercetin reversed the decreased mRNA expression of all those genes induced by CCl4. In conclusion, our results demonstrate that quercetin ameliorates CCl4-induced acute liver injury in vivo via alleviating oxidative stress injuries when orally taken after CCl4 intoxication. This protection may be caused by the elevation of the antioxidant capacity induced by quercetin.
PMCID: PMC4265558  PMID: 25471833
Hepatotoxicity; Oxidative stress; Peroxiredoxin (Prx); Nuclear factor erythroid 2-related factor 2 (Nrf2); TrxR; Trx; HO-1
15.  Controlled release of stromal cell-derived factor-1α from silk fibroin-coated coils accelerates intra-aneurysmal organization and occlusion of neck remnant by recruiting endothelial progenitor cells 
This study is to test the efficacy of stromal cell-derived factor-1α (SDF-1α)-coated coils together with endothelial progenitor cells (EPCs) transplantation in occluding aneurysms. Bone marrow-derived EPC surface markers were analyzed using flow cytometry. The migratory function of EPCs in response to SDF-1α was evaluated using a modified Boyden chamber assay. Capillary-like tube formation was assessed using Matrigel gel. Coil morphologies before and after coating with SDF-1α were observed under a scanning electron microscope. The level of SDF-1α in supernatants was measured by ELISA. Sprague-Dawley rats were randomly allocated into five groups. Histological analysis was performed on days 14 and 28 after coil implantation. The bone marrow-EPCs could express CD133, CD34, and VEGFR-2 and form tubule-like structures in vitro. Migratory ability of EPCs in the presence of SDF-1α-coated coils was similar to that in the presence of 5 ng/ml SDF-1α gradient. Sustained release of SDF-1α was achieved using silk fibroin as a carrier. In SDF-1α-coated coils + EPCs transplantation group, a well-organized fibrous tissue bridging the orifice of aneurysms was shown on days 14 and 28. On day 28, tissue organization was greater in the SDF-1α-coated coils group than in the unmodified coils group. Immunofluorescence showed α-smooth muscle actin-positive cells in organized tissue in sacs. Combined treatment with SDF-1α-coated coils and EPCs transplantation is a safe and effective treatment for rat aneurysms. This may provide a new strategy for endovascular therapy following aneurysmal subarachnoid hemorrhage.
PMCID: PMC4314014  PMID: 25674201
Stromal cell-derived factor-1α; endothelial progenitor cells; silk fibroin; cerebral aneurysm; recanalization; endothelialization
16.  The Atopic March: Progression from Atopic Dermatitis to Allergic Rhinitis and Asthma 
The development of atopic dermatitis (AD) in infancy and subsequent allergic rhinitis and asthma in later childhood is known as the atopic march. This progressive atopy is dependent on various underlying factors such as the presence of filaggrin mutations as well as the time of onset and severity of AD. Clinical manifestations vary among individuals. Previously it was thought that atopic disorders may be unrelated with sequential development. Recent studies support the idea of a causal link between AD and later onset atopic disorders. These studies suggest that a dysfunctional skin barrier serves as a site for allergic sensitization to antigens and colonization of bacterial super antigens. This induces systemic Th2 immunity that predisposes patients to allergic nasal responses and promotes airway hyper reactivity. While AD often starts early in life and is a chronic condition, new research signifies that there may be an optimal window of time in which targeting the skin barrier with therapeutic interventions may prevent subsequent atopic disorders. In this review we highlight recent studies describing factors important in the development of atopic disorders and new insights in our understanding of the pathogenesis of the atopic march.
PMCID: PMC4240310  PMID: 25419479
Eczema; Atopic dermatitis; Allergic rhinitis; Asthma; The atopic march
17.  Immune Modulatory Effects of IL-22 on Allergen-Induced Pulmonary Inflammation 
PLoS ONE  2014;9(9):e107454.
IL-22 is a Th17/Th22 cytokine that is increased in asthma. However, recent animal studies showed controversial findings in the effects of IL-22 in allergic asthma. To determine the role of IL-22 in ovalbumin-induced allergic inflammation we generated inducible lung-specific IL-22 transgenic mice. Transgenic IL-22 expression and signaling activity in the lung were determined. Ovalbumin (OVA)-induced pulmonary inflammation, immune responses, and airway hyperresponsiveness (AHR) were examined and compared between IL-22 transgenic mice and wild type controls. Following doxycycline (Dox) induction, IL-22 protein was readily detected in the large (CC10 promoter) and small (SPC promoter) airway epithelial cells. IL-22 signaling was evidenced by phosphorylated STAT3. After OVA sensitization and challenge, compared to wild type littermates, IL-22 transgenic mice showed decreased eosinophils in the bronchoalveolar lavage (BAL), and in lung tissue, decreased mucus metaplasia in the airways, and reduced AHR. Among the cytokines and chemokines examined, IL-13 levels were reduced in the BAL fluid as well as in lymphocytes from local draining lymph nodes of IL-22 transgenic mice. No effect was seen on the levels of serum total or OVA-specific IgE or IgG. These findings indicate that IL-22 has immune modulatory effects on pulmonary inflammatory responses in allergen-induced asthma.
PMCID: PMC4177833  PMID: 25254361
18.  Astragalosides from Radix Astragali benefits experimental autoimmune encephalomyelitis in C57BL /6 mice at multiple levels 
Radix Astragali is famous for its beneficial effect on inflammation associated diseases. This study was to assess the efficacy of astragalosides (AST) extracted from Radix Astragali, on the progression of experimental autoimmune encephalomyelitis (EAE), and explore its possible underlying molecular mechanisms.
EAE was induced by subcutaneous immunization of MOG35–55. Infiltration of inflammatory cells was examined by HE staining. ROS level was detected by measuring infiltrated hydroethidine. Leakage of blood brain barrier (BBB) was assessed using Evan’s blue dye extravasation method. Levels of inflammatory cytokines were measured using ELISA kits. Activities of total-SOD, GSH-Px, and iNOS and MDA concentration were measured using biochemical analytic kits. Gene expression was detected using real-time PCR method. Protein expression was assayed using western blotting approach.
AST administration attenuated the progression of EAE in mice remarkably. Further studies manifested that AST treatment inhibited infiltration of inflammatory cells, lessened ROS production and decreased BBB leakage. In peripheral immune-systems, AST up-regulated mRNA expression of transcriptional factors T-bet and Foxp3 but decreased that of RORγt to modulate T cell differentiation. In CNS, AST stopped BBB leakage, reduced ROS production by up-regulation of T-SOD, and reduced neuroinflammation by inhibition of iNOS and other inflammatory cytokines. Moreover, AST inhibited production of p53 and phosphorylation of tau by modulation of the Bcl-2/Bax ratio.
AST orchestrated multiple pathways, including immuno-regulation, anti-oxidative stress, anti-neuroinflammation and anti-neuroapoptosis involved in the MS pathogenesis, to prevent the deterioration of EAE, which paves the way for the application of it in clinical prevention/therapy of MS.
PMCID: PMC4155103  PMID: 25150364
Astragalosides; Experimental autoimmune encephalomyelitis; Multiple sclerosis; Neuroinflammation; Oxidative stress; Apoptosis
19.  Regulation of Nasal Airway Homeostasis and Inflammation in Mice by SHP-1 and Th2/Th1 Signaling Pathways 
PLoS ONE  2014;9(8):e103685.
Allergic rhinitis is a chronic inflammatory disease orchestrated by Th2 lymphocytes. Src homology 2 domain-containing protein tyrosine phosphatase (SHP)-1 is known to be a negative regulator in the IL-4α/STAT-6 signaling pathway of the lung. However, the role of SHP-1 enzyme and its functional relationship with Th2 and Th1 cytokines are not known in the nasal airway. In this study, we aimed to study the nasal inflammation as a result of SHP-1 deficiency in viable motheaten (mev) mice and to investigate the molecular mechanisms involved. Cytology, histology, and expression of cytokines and chemokines were analyzed to define the nature of the nasal inflammation. Targeted gene depletion of Th1 (IFN-γ) and Th2 (IL-4 and IL-13) cytokines was used to identify the critical pathways involved. Matrix metalloproteinases (MMPs) were studied to demonstrate the clearance mechanism of recruited inflammatory cells into the nasal airway. We showed here that mev mice had a spontaneous allergic rhinitis-like inflammation with eosinophilia, mucus metaplasia, up-regulation of Th2 cytokines (IL-4 and IL-13), chemokines (eotaxin), and MMPs. All of these inflammatory mediators were clearly counter-regulated by Th2 and Th1 cytokines. Deletion of IFN-γ gene induced a strong Th2-skewed inflammation with transepithelial migration of the inflammatory cells. These findings suggest that SHP-1 enzyme and Th2/Th1 paradigm may play a critical role in the maintenance of nasal immune homeostasis and in the regulation of allergic rhinitis.
PMCID: PMC4121172  PMID: 25090641
20.  Microbial Biotransformation of Gentiopicroside by the Endophytic Fungus Penicillium crustosum 2T01Y01 
Endophytic fungi are symbiotic with plants and possess multienzyme systems showing promising metabolite potency with region selectivity and stereoselectivity. The aim of this study was to use these special microorganisms as an in vitro model to mimic the potential mammalian metabolites of a natural iridoid gentiopicroside (GPS, compound 1). The fungi isolated from a medicinal plant, Dendrobium candidum Wall. ex Lindl., were screened for their biotransformation abilities with GPS as the substrate, and one strain with high converting potency was identified as Penicillium crustosum 2T01Y01 on the basis of the sequence of the internal transcribed spacer of the ribosomal DNA region. Upon the optimized incubation of P. crustosum 2T01Y01 with the substrate, seven deglycosylated metabolites were detected by ultraperformance liquid chromatography/quadrupole time of flight mass spectrometry (UPLC/Q-TOF MS). Preparative-scale biotransformation with whole cells of the endophytic fungus resulted in the production of five metabolites, including three novel ones, 5α-(hydroxymethyl)-6β-methyl-3,4,5,6-tetrahydropyrano[3,4-c]pyran-1(8H)-one (compound 2), (Z)-4-(1-hydroxybut-3-en-2-yl)-5,6-dihydropyran-2-one (compound 3), and (E)-4-(1-hydroxybut-3-en-2-yl)-5,6-dihydropyran-2-one (compound 4), along with two known ones, 5α-(hydroxymethyl)-6β-methyl-1H,3H-5,6-dihydropyrano[3,4-c]pyran-1(3H)-one (compound 5) and 5α-(hydroxymethyl)-6α-methyl-5,6-dihydropyrano[3,4-c]pyran-1(3H)-one (compound 6), aided by nuclear magnetic resonance and high-resolution mass spectral analyses. The other two metabolites were tentatively identified by online UPLC/Q-TOF MS as 5-hydroxymethyl-5,6-dihydroisochromen-1-one (compound 7) and 5-hydroxymethyl-3,4,5,6-tetrahydroisochromen-1-one (compound 8), and compound 8 is a new metabolite. To test the metabolic mechanism, the β-glucosidase activity of the fungus P. crustosum 2T01Y01 was assayed with ρ-nitrophenyl-β-d-glucopyranoside as a probe substrate, and the pathway of GPS biotransformation by strain 2T01Y01 is proposed. In addition, the hepatoprotective activities of GPS and metabolite compounds 2, 5, and 6 against human hepatocyte line HL-7702 injury induced by hydrogen peroxide were evaluated.
PMCID: PMC3911023  PMID: 24141132
21.  Comparison and Analysis of Biological Agent Category Lists Based On Biosafety and Biodefense 
PLoS ONE  2014;9(6):e101163.
Biological agents pose a serious threat to human health, economic development, social stability and even national security. The classification of biological agents is a basic requirement for both biosafety and biodefense. We compared and analyzed the Biological Agent Laboratory Biosafety Category list and the defining criteria according to the World Health Organization (WHO), the National Institutes of Health (NIH), the European Union (EU) and China. We also compared and analyzed the Biological Agent Biodefense Category list and the defining criteria according to the Centers for Disease Control and Prevention (CDC) of the United States, the EU and Russia. The results show some inconsistencies among or between the two types of category lists and criteria. We suggest that the classification of biological agents based on laboratory biosafety should reduce the number of inconsistencies and contradictions. Developing countries should also produce lists of biological agents to direct their development of biodefense capabilities.To develop a suitable biological agent list should also strengthen international collaboration and cooperation.
PMCID: PMC4076228  PMID: 24979754
22.  Ferulic acid prevents liver injury and increases the anti-tumor effect of diosbulbin B in vivo *  
The present study is designed to investigate the protection by ferulic acid against the hepatotoxicity induced by diosbulbin B and its possible mechanism, and further observe whether ferulic acid augments diosbulbin B-induced anti-tumor activity. The results show that ferulic acid decreases diosbulbin B-increased serum alanine transaminase/aspartate transaminase (ALT/AST) levels. Ferulic acid also decreases lipid peroxide (LPO) levels which are elevated in diosbulbin B-treated mice. Histological evaluation of the liver demonstrates hydropic degeneration in diosbulbin B-treated mice, while ferulic acid reverses this injury. Moreover, the activities of copper- and zinc-containing superoxide dismutase (CuZn-SOD) and catalase (CAT) are decreased in the livers of diosbulbin B-treated mice, while ferulic acid reverses these decreases. Further results demonstrate that the mRNA expressions of CuZn-SOD and CAT in diosbulbin B-treated mouse liver are significantly decreased, while ferulic acid prevents this decrease. In addition, ferulic acid also augments diosbulbin B-induced tumor growth inhibition compared with diosbulbin B alone. Taken together, the present study shows that ferulic acid prevents diosbulbin B-induced liver injury via ameliorating diosbulbin B-induced liver oxidative stress injury and augments diosbulbin B-induced anti-tumor activity.
PMCID: PMC4116857  PMID: 24903991
Ferulic acid; Diosbulbin B; Hepatotoxicity; Oxidative stress injury; Anti-tumor activity
23.  Comparative Analysis of the Effectiveness of Three Immunization Strategies in Controlling Disease Outbreaks in Realistic Social Networks 
PLoS ONE  2014;9(5):e95911.
The high incidence of emerging infectious diseases has highlighted the importance of effective immunization strategies, especially the stochastic algorithms based on local available network information. Present stochastic strategies are mainly evaluated based on classical network models, such as scale-free networks and small-world networks, and thus are insufficient. Three frequently referred stochastic immunization strategies—acquaintance immunization, community-bridge immunization, and ring vaccination—were analyzed in this work. The optimal immunization ratios for acquaintance immunization and community-bridge immunization strategies were investigated, and the effectiveness of these three strategies in controlling the spreading of epidemics were analyzed based on realistic social contact networks. The results show all the strategies have decreased the coverage of the epidemics compared to baseline scenario (no control measures). However the effectiveness of acquaintance immunization and community-bridge immunization are very limited, with acquaintance immunization slightly outperforming community-bridge immunization. Ring vaccination significantly outperforms acquaintance immunization and community-bridge immunization, and the sensitivity analysis shows it could be applied to controlling the epidemics with a wide infectivity spectrum. The effectiveness of several classical stochastic immunization strategies was evaluated based on realistic contact networks for the first time in this study. These results could have important significance for epidemic control research and practice.
PMCID: PMC4008523  PMID: 24787718
24.  Endogenous Ceramide Contributes to the Transcytosis of oxLDL across Endothelial Cells and Promotes Its Subendothelial Retention in Vascular Wall 
Oxidized low density of lipoprotein (oxLDL) is the major lipid found in atherosclerotic lesion and elevated plasma oxLDL is recognized to be a risk factor of atherosclerosis. Whether plasma oxLDL could be transported across endothelial cells and initiate atherosclerotic changes remains unknown. In an established in vitro cellular transcytosis model, the present study found that oxLDL could traffic across vascular endothelial cells and further that the regulation of endogenous ceramide production by ceramide metabolizing enzyme inhibitors significantly altered the transcytosis of oxLDL across endothelial cells. It was found that acid sphingomyelinase inhibitor, desipramine (DES), and de novo ceramide synthesis inhibitor, myriocin (MYR), both decreasing the endogenous ceramide production, significantly inhibited the transcytosis of oxLDL. Ceramidase inhibitor, N-oleoylethanolamine (NOE), and sphingomyelin synthase inhibitor, O-Tricyclo[,6]dec-9-yl dithiocarbonate potassium salt (D609), both increasing the endogenous ceramide production, significantly upregulated the transcytosis of oxLDL. In vivo, injection of fluorescence labeled oxLDL into mice body also predisposed to the subendothelial retention of these oxidized lipids. The observations provided in the present study demonstrate that endogenous ceramide contributes to the transcytosis of oxLDL across endothelial cells and promotes the initiating step of atherosclerosis—the subendothelial retention of lipids in vascular wall.
PMCID: PMC4003761  PMID: 24817993
25.  Peritumoral ductular reaction: a poor postoperative prognostic factor for hepatocellular carcinoma 
BMC Cancer  2014;14:65.
The role of ductular reaction (DR) in hepatocellular carcinoma (HCC) remains to be elucidated.
In this study, we tried to uncover possible effect by correlating peritumoral DR in a necroinflammatory microenvironment with postoperative prognosis in HCC. The expression of peritumoral DR/CK19 by immunohistochemistry, necroinflammation and fibrosis were assessed from 106 patients receiving curative resection for HCC. Prognostic values for these and other clinicopathologic factors were evaluated.
Peritumoral DR significantly correlated with necroinflammation (r = 0.563, p = 3.4E-10), fibrosis (r = 0.435, p = 3.1E-06), AFP level (p = 0.010), HBsAg (p = 4.9E-4), BCLC stage (p = 0.003), TNM stage (p = 0.002), multiple nodules (p = 0.004), absence of tumor capsule (p = 0.027), severe microscopic vascular invasion (p = 0.031) and early recurrence (p = 0.010). Increased DR was significantly associated with decreased RFS/OS (p = 4.8E-04 and p = 2.6E-05, respectively) in univariate analysis and were identified as an independent prognostic factor (HR = 2.380, 95% CI = 1.250-4.534, p = 0.008 for RFS; HR = 4.294, 95% CI = 2.255-8.177, p = 9.3E-6 for OS) in multivariate analysis.
These results suggested that peritumoral DR in a necroinflammatory microenvironment was a poor prognostic factor for HCC after resection.
PMCID: PMC3916808  PMID: 24495509
Ductular reaction (DR); Hepatic progenitor cells (HPCs); Necroinflammation; Fibrosis; Hepatocellular carcinoma (HCC); Prognosis

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