Publications by authors named "Da-Peng Chen"

37 Publications

Clinical features of Chinese children with COVID-19 and other viral respiratory infections.

Pediatr Pulmonol 2021 Sep 24. Epub 2021 Sep 24.

Department of Infectious Diseases, National Clinical Research Center for Child Health and Disorders, The Children's Hospital of Chongqing Medical University, Chongqing, China.

Objective: Few studies have explored the clinical features in children infected with SARS-CoV-2 and other common respiratory viruses, including respiratory syncytial virus (RSV), Influenza virus (IV), and adenovirus (ADV). Herein, we reported the clinical characteristics and cytokine profiling in children with COVID-19 or other acute respiratory tract infections (ARTI).

Methods: We enrolled 20 hospitalized children confirmed as COVID-19 positive, 58 patients with ARTI, and 20 age and sex-matched healthy children. The clinical information and blood test results were collected. A total of 27 cytokines and chemokines were measured and analyzed.

Results: The median age in the COVID-19 positive group was 14.5 years, which was higher than that of the ARTI groups. Around one-third of patients in the COVID-19 group experienced moderate fever, with a peak temperature of 38.27°C. None of the patients displayed wheezing or dyspnea. In addition, patients in the COVID-19 group had lower white blood cells, platelet counts as well as a neutrophil-lymphocyte ratio. Lower serum concentrations of 14 out of 27 cytokines were observed in the COVID-19 group than in healthy individuals. Seven cytokines (IL-1Ra, IL-1β, IL-9, IL-10, TNF-α, MIP-1α, and VEGF) changed serum concentration in COVID-19 compared with other ARTI groups.

Conclusion: Patients with COVID-19 were older and showed milder symptoms and a favorable prognosis than ARTI caused by RSV, IV, and ADV. There was a low grade or constrained innate immune reaction in children with mild COVID-19.
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http://dx.doi.org/10.1002/ppul.25700DOI Listing
September 2021

[Differences of Energy Spectrum CT Findings between Small Cell Lung Cancer with Mediastinal Lymph Node Metastasis and Mediastinal Sarcoidosis].

Zhongguo Yi Xue Ke Xue Yuan Xue Bao 2021 Feb;43(1):53-56

Medical Department,Tangshan People's Hospital,Tangshan,Hebei 063000,China.

Objective To compare the differences of energy spectrum CT between small cell lung cancer(SCLC)with mediastinal lymph node metastasis and mediastinal sarcoidosis.Methods Twenty-five SCLC patients with mediastinal lymph node metastasis(SCLC group)and 26 patients with mediastinal sarcoidosis(sarcoidosis group)confirmed by bronchoscopy and biopsy in Tangshan People's Hospital from January 2018 to June 2019 were selected as the research objects.The CT value,iodine concentration,water concentration and energy spectrum curve slope under different single energy levels were compared between SCLC group and sarcoidosis group.Results The single-energy CT values of 40-80 keV segments in the arterial phase of the SCLC group were significantly higher than those in the sarcoidosis group(all P <0.05).The single-energy CT values of 90-140 keV segments were not significantly different from those in the sarcoidosis group(all P >0.05).The single-energy CT values of 40-90 keV segments in venous phase of the SCLC group were significantly higher than those of the sarcoidosis group(all P <0.05),and the single-energy CT values of 100-140 keV segments were not significantly different from those of the sarcoidosis group(all P >0.05).The concentrations of iodine in the arterial phase and venous phase of the SCLC group were(11.56±4.06)μg/cm and(13.39±0.87)μg/cm ,respectively,which were significantly higher than those [(4.43±3.85)μg/cm ,t=11.564,P=0.026;(7.23±2.71)μg/cm ,t=13.653,P=0.021] in the sarcoidosis group.The concentrations of water in the arterial and venous phases of the SCLC group were(1040.67±5.62)mg/cm and(1035.23±8.57)mg/cm ,respectively,which showed no statistically significant difference compared with those [(1028.87±6.94)mg/cm ,t=3.155,P=1.861;(1021.53±4.68)mg/cm ,t=3.265,P=1.687] in the sarcoidosis group.The slopes of energy spectrum curve at 40-70 keV,70-100 keV and 100-140 keV in venous phase of the SCLC group were significantly higher than those of the sarcoidosis group(all P <0.05),whereas they showed no significant difference between the two groups in arterial phase(all P >0.05).Conclusion The differences between SCLC with mediastinal lymph node metastasis and mediastinal sarcoidosis can be shown on the single-energy CT values of 40-80 keV in arterial phase and 40-90 keV in venous phase,iodine concentrations in arterial phase and venous phase,and the slope of energy spectrum curve in venous phase.
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http://dx.doi.org/10.3881/j.issn.1000-503X.12514DOI Listing
February 2021

Ginsenoside Rb1 alleviates colitis in mice via activation of endoplasmic reticulum-resident E3 ubiquitin ligase Hrd1 signaling pathway.

Acta Pharmacol Sin 2021 Sep 2;42(9):1461-1471. Epub 2020 Dec 2.

Compartive Medicine, Dalian Medical University, Dalian, 116044, China.

Endoplasmic reticulum (ER) homeostasis is regulated by ER-resident E3 ubiquitin ligase Hrd1, which has been implicated in inflammatory bowel disease (IBD). Ginsenoside Rb1 (GRb1) is the major ginsenoside in ginseng with multiple pharmacological activities. In this study we investigated the role of Hrd1 in IBD and its regulation by GRb1. Two mouse colitis models were established to mimic human IBD: drinking water containing dextran sodium sulfate (DSS) as well as intra-colonic infusion of 2, 4, 6-trinitrobenzene sulfonic acid (TNBS). Colitis mice were treated with GRb1 (20, 40 mg·kg·d, ig) or a positive control drug sulfasalazine (500 mg·kg·d, ig) for 7 days. The model mice showed typical colitis symptoms and pathological changes in colon tissue. In addition to significant inflammatory responses and cell apoptosis in colon tissue, colon epithelial expression of Hrd1 was significantly decreased, the expression of ER stress markers GRP78, PERK, CHOP, and caspase 12 was increased, and the expression of Fas was increased (Fas was removed by Hrd1-induced ubiquitination). These changes were partially, or completely, reversed by GRb1 administration, whereas injection of Hrd1 inhibitor LS102 (50 mg·kg· d, ip, for 6 days) exacerbated colitis symptoms in colitis mice. GRb1 administration not only normalized Hrd1 expression at both the mRNA and protein levels, but also alleviated the ER stress response, Fas-related apoptosis, and other colitis symptoms. In intestinal cell line IEC-6, the expression of Hrd1 was significantly decreased by LPS treatment, but was normalized by GRb1 (200 μM). GRb1 alleviated LPS-induced ER stress and cell apoptosis in IEC-6 cells, and GRb1 action was inhibited by knockdown of Hrd1 using small interfering RNA. In summary, these results reveal a pathological role of Hrd1 in colitis, and provide a novel insight into alternative treatment of colitis using GRb1 activating Hrd1 signaling pathway.
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http://dx.doi.org/10.1038/s41401-020-00561-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8379258PMC
September 2021

[Different Energy Spectrum CT Findings between Anterior Mediastinal Lymphoma and Thymic Carcinoma].

Zhongguo Yi Xue Ke Xue Yuan Xue Bao 2020 Aug;42(4):431-435

College of Traditional Chinese Medicine,North China University of Science and Technology,Tangshan,Hebei 063000,China.

To investigate the differences in energy spectrum CT findings between anterior mediastinal lymphoma and thymic carcinoma. Twenty-two cases of anterior mediastinal lymphoma and 28 cases of thymic carcinoma confirmed by biopsy in Tangshan People's Hospital were selected.The CT values and changes of iodine content and water content in lesion sites were measured by energy spectrum analysis software.The differences between anterior mediastinal lymphoma and thymic carcinoma were compared. The single-energy CT value of 40-80 keV in thymus carcinoma was higher than that in anterior mediastinal lymphoma(=0.001,=0.037,=0.042,=0.034,=0.002;=0.016,=0.013,=0.018,=0.024,=0.012).The difference in the single-energy CT value of 90-110 keV between anterior mediastinal lymphoma and thymic carcinoma showed no statistical significance(all >0.05).The concentrations of water in the arterial and venous stages of thymic carcinoma were significantly lower than those in the anterior mediastinal lymphoma(=0.030,=0.037),whereas the iodine concentrations were significantly higher(=0.026,=0.000). Anterior mediastinal lymphoma and thymic carcinoma have remarkably different 40-80 keV single energy CT value and iodine concentration in arterial and venous phases,which may be helpful for the differential diagnosis of these two malignancies.
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http://dx.doi.org/10.3881/j.issn.1000-503X.11708DOI Listing
August 2020

Salvianolic acid B decreases interleukin-1β-induced colitis recurrence in mice.

Chin Med J (Engl) 2020 Jun;133(12):1436-1444

Teaching and Research Section of Comparative Medicine, Dalian Medical University, Dalian, Liaoning 116044, China.

Background: Degree of mucosal recovery is an important indicator for evaluating the therapeutic effects of drugs in treatment of inflammatory bowel disease (IBD). Increasing evidences has proved that tight junction (TJ) barrier dysfunction is one of the pathological mechanisms of IBD. The aim of this study was to observe whether enhancement of TJ can decrease colitis recurrence.

Methods: Eighty C57BL/6 mice were randomly divided into four groups including normal group, colitis group, sulfasalazine (SASP) treated group, and traditional Chinese drug salvianolic acid B (Sal B) treated group. Colitis was established in mice by free drinking water containing dextran sulfate sodium, after treatments by SASP and Sal B, recombinant human interleukin-1β (IL-1β) was injected intraperitoneally to induce colitis recurrence.

Results: Compared with sham control, cell apoptosis in colitis group was increased from 100.85 ± 3.46% to 162.89 ± 11.45% (P = 0.0038), and TJ dysfunction marker myosin light chain kinase (MLCK) was also significantly increased from 99.70 ± 9.29% to 296.23 ± 30.78% (P = 0.0025). The increased cell apoptosis was reversed by both SASP (125.99 ± 8.45% vs. 162.89 ± 11.45%, P = 0.0059) and Sal B (104.27 ± 6.09% vs. 162.89 ± 11.45%, P = 0.0044). High MLCK expression in colitis group was reversed by Sal B (182.44 ± 89.42% vs. 296.23 ± 30.78%, P = 0.0028) but not influenced by SASP (285.23 ± 41.04% vs. 296.23 ± 30.78%, P > 0.05). The recurrence rate induced by recombinant human IL-1β in Sal B-treated group was significantly lower than that in SASP-treated group.

Conclusions: These results suggested a link between intestinal mucosal barrier dysfunction, especially TJ barrier dysfunction, and colitis recurrence. The TJ barrier dysfunction in remission stage of colitis increased the colitis recurrence. This study might provide potential treatment strategies for IBD recurrence.
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http://dx.doi.org/10.1097/CM9.0000000000000773DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7339324PMC
June 2020

Cinnamaldehyde protects against rat intestinal ischemia/reperfusion injuries by synergistic inhibition of NF-κB and p53.

Acta Pharmacol Sin 2020 Sep 1;41(9):1208-1222. Epub 2020 Apr 1.

Pharmaceutical College, Dalian Medical University, Dalian, 116044, China.

Our preliminary study shows that cinnamaldehyde (CA) could protect against intestinal ischemia/reperfusion (I/R) injuries, in which p53 and NF-κB p65 play a synergistic role. In this study, we conducted in vivo and in vitro experiments to verify this proposal. SD rats were pretreated with CA (10 or 40 mg · kg · d, ig) for 3 days, then subjected to 1 h mesenteric ischemia followed by 2 h reperfusion. CA pretreatment dose-dependently ameliorated morphological damage and reduced inflammation evidenced by decreased TNF-α, IL-1β, and IL-6 levels and MPO activity in I/R-treated intestinal tissues. CA pretreatment also attenuated oxidative stress through restoring SOD, GSH, LDH, and MDA levels in I/R-treated intestinal tissues. Furthermore, CA pretreatment significantly reduced the expression of inflammation/apoptosis-related NF-κB p65, IKKβ, IK-α, and NF-κB p50, and downregulated apoptotic protein expression including p53, Bax, caspase-9 and caspase-3, and restoring Bcl-2, in I/R-treated intestinal tissues. We pretreated IEC-6 cells in vitro with CA for 24 h, followed by 4 h hypoxia and 3 h reoxygenation (H/R) incubation. Pretreatment with CA (3.125, 6.25, and 12.5 μmol · L) significantly reversed H/R-induced reduction of IEC-6 cell viability. CA pretreatment significantly suppressed oxidative stress, NF-κB activation and apoptosis in H/R-treated IEC-6 cells. Moreover, CA pretreatment significantly reversed mitochondrial dysfunction in H/R-treated IEC-6 cells. CA pretreatment inhibited the nuclear translocation of p53 and NF-κB p65 in H/R-treated IEC-6 cells. Double knockdown or overexpression of p53 and NF-κB p65 caused a synergistic reduction or elevation of p53 compared with knockdown or overexpression of p53 or NF-κB p65 alone. In H/R-treated IEC-6 cells with double knockdown or overexpression of NF-κB p65 and p53, CA pretreatment caused neither further decrease nor increase of NF-κB p65 or p53 expression, suggesting that CA-induced synergistic inhibition on both NF-κB and p53 played a key role in ameliorating intestinal I/R injuries. Finally, we used immunoprecipitation assay to demonstrate an interaction between p53 and NF-κB p65, showing the basis for CA-induced synergistic inhibition. Our results provide valuable information for further studies.
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http://dx.doi.org/10.1038/s41401-020-0359-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7609352PMC
September 2020

Enhancement of epithelial cell autophagy induced by sinensetin alleviates epithelial barrier dysfunction in colitis.

Pharmacol Res 2019 10 19;148:104461. Epub 2019 Sep 19.

First Affiliated Hospital of Dalian Medical University, Dalian, China. Electronic address:

Intestinal epithelial barrier dysfunction is a key pathology of colitis. Autophagy of epithelial cells maintains homeostasis of the intestinal barrier by inhibiting apoptosis and stimulating degradation of the tight junction protein claudin-2. This study investigated the effects and mechanism of activity of sinensetin, a polymethylated flavonoid isolated from tangerine peel and citrus, on intestinal barrier dysfunction in colitis. Animal model of colitis were established by intracolonic administration of 2, 4, 6-trinitrobenzene sulfonic acid and oral treatment with dextran sulfate sodium. Epithelial barrier function was evaluated by measuring the serum recovery of fluorescein isothiocyanate-4 kD dextran in vivo and transepithelial electrical resistance in Caco-2 cells, respectively. Epithelial cell autophagy assayed by autophagosome formation and expression of autophagy-related protein. Sinensetin reversed colitis-associated increase in intestinal permeability, significantly promoted epithelial cell autophagy, and further decreased epithelial cell apoptosis, and reduced mucosal claudin-2. Sinenstetin alleviated colitis symptoms rats and mice with colitis. Knockdown of 5' adenosine monophosphate-activated protein kinase (AMPK) reversed the promotion of epithelial autophagy by sinensetin. In conclusion, sinensetin significantly alleviated intestinal barrier dysfunction in colitis by promoting epithelial cell autophagy, and further inhibiting apoptosis and promoting claudin-2 degradation. The results highlighted novel potential benefits of sinensetin in colitis.
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http://dx.doi.org/10.1016/j.phrs.2019.104461DOI Listing
October 2019

[Current status of antibiotic therapy for Staphylococcus aureus sepsis in children].

Zhongguo Dang Dai Er Ke Za Zhi 2019 Apr;21(4):387-392

Department of Respiratory Medicine, Children's Hospital of Chongqing Medical University, Chongqing 400014, China.

Objective: To investigate the current status of empirical antibiotic therapy for children with Staphylococcus aureus sepsis and the effect of therapeutic paradigm on prognosis based on a retrospective analysis.

Methods: A total of 78 children with Staphylococcus aureus sepsis who were admitted from January 2014 to August 2017 were enrolled. According to the preferred empirical antibiotics before the detection of Staphylococcus aureus by blood culture, these children were divided into a carbapenem group with 16 children, a β-lactam group with 37 children, a vancomycin group with 15 children and a vancomycin+β-lactam group with 10 children. A retrospective analysis was performed for related clinical data including general status, underlying diseases, Acute Physiology and Chronic Health Evaluation II (APACHE II) score, history of use of immunosuppressant, drug resistance to methicillin and prognosis. A logistic regression analysis was used to investigate the effect of empirical antibiotic therapy on the clinical outcome and prognosis of children with Staphylococcus aureus sepsis.

Results: There were no significant differences among these groups in general status, underlying diseases, history of use of immunosuppressant, APACHE II score, nosocomial infection and detection rate of methicillin-resistant Staphylococcus aureus (P>0.05). There were significant differences in the incidence rate of septic shock and in-hospital mortality among these four groups (P<0.05). The carbapenem group had the highest incidence rate of septic shock and in-hospital mortality (69% and 50% respectively). The multivariate logistic regression analysis showed that empirical antibiotic therapy with different antibiotics had different risks for septic shock and in-hospital death in children with Staphylococcus aureus sepsis (P<0.05), and that an APACHE II score of ≥15 was an independent risk factor for septic shock in these children (P<0.05). The carbapenem group had significantly higher risks of septic shock and in-hospital death than the vancomycin group (P<0.05).

Conclusions: Inappropriate empirical use of antibiotics may lead to a poor prognosis in children with Staphylococcus aureus sepsis. Empirical use of carbapenems is not recommended for children suspected of Staphylococcus aureus sepsis.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7389225PMC
April 2019

Microwave ablation of hyperplastic parathyroid glands is a treatment option for end-stage renal disease patients ineligible for surgical resection.

Int J Hyperthermia 2019 ;36(1):29-35

b Department of Interventional Ultrasound , China-Japan Friendship Hospital , Beijing , People's Republic of China.

Background: Secondary hyperparathyroidism (SHPT) is a frequently encountered problem in patients with end-stage renal disease (ESRD). Some patients with severe SHPT could not be managed by medical treatment and are ineligible for surgical resection.

Purpose: Our objective was to evaluate the efficacy, safety of microwave ablation (MWA) on these patients.

Materials And Methods: Between 1 April 2015 and 28 February 2017, 35 patients (M/F 19/16, age 49.8 ± 12.9 years) were enrolled. All patients were treated with MWA. Levels of intact parathyroid hormone (iPTH) and of serum calcium and phosphorus were compared pre- and post-ablation. Repeated-measures ANOVA was used to compare treatment outcomes pre- and post-ablation.

Results: Complete ablation was achieved in all 63 glands in the 35 patients with SHPT. The mean follow-up time was 15.9 ± 2.2 months. The maximum gland diameter was 6-31 mm (mean, 14.9 ± 5.5 mm). The trends of the changes in iPTH and calcium levels showed a curve: the level of iPTH and calcium at 6 months post-ablation were lower than those pre-ablation (both p < .0001); after then iPTH remained relatively stable and the end of follow up, with no rebound (p < .0001), while instead of calcium at the end of follow up was not significantly lower than pre-ablation (p = .462). The trend in the change in phosphate levels showed a straight line; the level of phosphate at 6 months post-ablation and at the end of follow up both were significantly lower than pre-MWA (p < .001). There was no major complication.

Conclusions: In this series, MWA was used successfully to treat SHPT patients who are ineligible for surgical resection.
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http://dx.doi.org/10.1080/02656736.2018.1528392DOI Listing
January 2020

A Functional Variant in Ubiquitin Conjugating Enzyme E2 L3 Contributes to Hepatitis B Virus Infection and Maintains Covalently Closed Circular DNA Stability by Inducing Degradation of Apolipoprotein B mRNA Editing Enzyme Catalytic Subunit 3A.

Hepatology 2019 05 15;69(5):1885-1902. Epub 2019 Mar 15.

The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China.

Hepatitis B virus (HBV) infection is a common infectious disease, in which nuclear covalently closed circular DNA (cccDNA) plays a key role in viral persistence, viral reactivation after treatment withdrawal, and drug resistance. A recent genome-wide association study has identified that the ubiquitin conjugating enzyme E2 L3 (UBE2L3) gene is associated with increased susceptibility to chronic HBV (CHB) infection in adults. However, the association between UBE2L3 and children with CHB and the underlying mechanism remain unclear. In this study, we performed two-stage case-control studies including adults and independent children in the Chinese Han population. The rs59391722 allele in the promoter of the UBE2L3 gene was significantly associated with HBV infection in both adults and children, and it increased the promoter activity of UBE2L3. Serum UBE2L3 protein levels were positively correlated with HBV viral load and hepatitis B e antigen (HBeAg) levels in children with CHB. In an HBV infection cell model, UBE2L3 knockdown significantly reduced total HBV RNAs, 3.5-kb RNA, as well as cccDNA in HBV-infected HepG2-Na /taurocholate cotransporting polypeptide cells and human primary hepatocytes. A mechanistic study found that UBE2L3 maintained cccDNA stability by inducing proteasome-dependent degradation of apolipoprotein B mRNA editing enzyme catalytic subunit 3A, which is responsible for the degradation of HBV cccDNA. Moreover, interferon-α (IFN-α) treatment markedly decreased UBE2L3 expression, while UBE2L3 silencing reinforced the antiviral activity of IFN-α on HBV RNAs, cccDNA, and DNA. rs59391722 in UBE2L3 was correlated with HBV DNA suppression and HBeAg loss in response to IFN-α treatment of children with CHB. Conclusion: These findings highlight a host gene, UBE2L3, contributing to the susceptibility to persistent HBV infection; UBE2L3 may be involved in IFN-mediated viral suppression and serve as a potential target in the prevention and treatment of HBV infection.
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http://dx.doi.org/10.1002/hep.30497DOI Listing
May 2019

The Spectrum of Biopsy-Proven Glomerular Disease in China: A Systematic Review.

Chin Med J (Engl) 2018 Mar;131(6):731-735

Department of Nephrology, China-Japan Friendship Hospital, Beijing 100029, China.

Background: Chronic kidney disease has become a leading public health concern in China, as it is associated with increased morbidity, mortality, and costs. However, the overall situation regarding common glomerular diseases in China remains unclear. Hence, the aim of this study was to assess the national profile of the common types of glomerulonephritis in China.

Methods: We searched Medline, Embase, Cochrane Library, CNKI, SinoMed, VIP, and Wanfang databases for English and Chinese language articles from inception to September 2017. We also collected potentially relevant studies and reviews using a manual search. The following words in combinations are as keywords: "renal biopsy", "kidney pathological diagnosis", and "spectrum of pathological types".

Results: We identified 23 studies involving 176,355 patients from 15 provinces/cities in China. The detection rates of primary glomerulonephritis (PGN) and secondary glomerulonephritis (SGN) were 0.740 and 0.221, respectively. Over the past 30 years, the top five types of PGN were immunoglobulin A nephropathy (IgAN; 24.3%), mesangial proliferative glomerulonephritis (MsPGN; 10.5%), membranous nephropathy (MN; 12.6%), minimal change disease (MCD; 9.8%), and focal segmental glomerulosclerosis (FSGS; 4.6%), and the top four types of SGN were lupus nephritis (LN; 8.6%), Henoch-Schönlein purpura glomerulonephritis (4.1%), hepatitis B virus-associated glomerulonephritis (HBV-GN; 2.6%), and diabetic nephropathy (DN; 1.6%). The proportion of MN, MCD, HBV-GN, and DN tended to increase, while those of IgAN, MsPGN, FSGS, and LN tended to drop.

Conclusions: Although the incidence of SGN is increasing gradually, PGN is still the leading form of kidney disease in patients undergoing renal biopsies in China. IgAN and LN are the most common types of PGN and SGN, respectively. Differences between regions are related to various factors such as nationality, environment, and diet. Furthermore, unified standards and norms for evaluating renal biopsies are urgently needed.
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http://dx.doi.org/10.4103/0366-6999.226906DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5865320PMC
March 2018

1,25-Dihydroxyvitamin D inhibits the proliferation of rat mesangial cells induced by high glucose via DDIT4.

Oncotarget 2018 Jan 9;9(1):418-427. Epub 2017 Dec 9.

Graduate School of Peking Union Medical College, Beijing 100730, China.

1,25-Dihydroxyvitamin D(1,25(OH) D) is a secosteroid with antiproliferative property. It also plays a pivotal renoprotective role in diabetic nephropathy. We investigated whether 1,25(OH)D could inhibit the proliferation of rat mesangial cells exposed to high glucose via the DNA-damage-inducible transcript 4/mammalian target of rapamycin(DDIT4/mTOR) pathway. The cell proliferation rate and cell cycle duration were measured using cell counting kit-8 assay and flow cytometry. Protein expression was assayed by Western blot. Glucose acted as a growth factor in rat mesangial cells, promoted cell proliferation. In parallel, the protein expression of DDIT4, TSC1/TSC2, and 4E-BP1 were decreased, and Rheb, mTOR, and p70S6K were increased. Acting via the DDIT4/mTOR signaling, 1,25(OH) D treatment reversed these pathological changes, upregulated DDIT4, TSC1/TSC2, and 4E-BP1, downregulated Rheb, mTOR, and p70S6K. The short-term overexpression of DDIT4 inhibited the proliferation of rat mesangial cells, similar to 1,25(OH) D treatment. siRNA knockdown of DDIT4 suppressed antiproliferative responses to 1,25(OH) D. These results suggest that 1,25(OH) D inhibits the proliferation of rat mesangial cells induced by high glucose via the DDIT4/mTOR signaling pathway.
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http://dx.doi.org/10.18632/oncotarget.23063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5787477PMC
January 2018

A Meta-Analysis of Antiviral Therapy for Hepatitis B Virus-Associated Membranous Nephropathy.

PLoS One 2016 6;11(9):e0160437. Epub 2016 Sep 6.

Department of nephrology, China-Japan friendship hospital, Beijing, PR China.

Hepatitis B virus-associated membranous nephropathy (HBV-MN) is the most common renal extra-hepatic manifestation in patients with chronic HBV infection. In September 2015, we searched the MEDLINE, EMBASE, and CENTRAL databases, and the reference lists of retrieved articles, to identify relevant studies. Descriptions of antiviral drugs used to treat HBV-MN were included in our review. Two authors independently screened all relevant articles, extracted data, and assessed the risk of bias. Nine hundred and fifty-four papers have been considered after electronic and manual searching, only five relevant studies were identified. Complete remission (OR = 26.87, 95% CI: 8.06 to 89.52), total remission (OR = 10.31, 95% CI: 3.59 to 29.63) of proteinuria and HBeAg clearance (OR = 20.91, 95% CI: 6.90 to 63.39) increased significantly after antiviral therapy. No significant differences were seen between interferon and nucleoside analog treatments. Our study found that antiviral therapy was an effective treatment in HBV-MN patients; interferon and nucleoside analogs were equally effective at causing proteinuria remission and HBeAg clearance.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0160437PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5012684PMC
August 2017

Hesperidin alleviates rat postoperative ileus through anti-inflammation and stimulation of Ca(2+)-dependent myosin phosphorylation.

Acta Pharmacol Sin 2016 Aug 27;37(8):1091-100. Epub 2016 Jun 27.

Laboratory Animal Center, Dalian Medical University, Dalian 116044, China.

Aim: Postoperative ileus (POI) is a postoperative dysmotility disorder of gastrointestinal tract, which remains one of the most perplexing problems in medicine. In the present study we investigated the effects of hesperidin, a major flavonoid in sweet oranges and lemons, on POI in rats.

Methods: SD rats were administered hesperidin (5, 20, and 80 mg·kg(-1)·d(-1), ig) for 3 consecutive days. POI operation (gently manipulating the cecum for 1 min) was performed on d 2. The gastrointestinal motility and isolated intestinal contraction were examined 1 d after the operation. Then the myosin phosphorylation and inflammatory responses in cecum tissue were assessed. Smooth muscle cells were isolated from rat small intestine for in vitro experiments.

Results: The gastric emptying and intestinal transit were significantly decreased in POI rats, which were reversed by administration of hesperidin. In ileum and cecum preparations of POI rats in vitro, hesperidin (2.5-160 μmol/L) dose-dependently increased the spontaneous contraction amplitudes without affecting the contractile frequency, which was blocked by the myosin light chain kinase (MLCK) inhibitor ML-7 or verapamil, but not by TTX. Furthermore, administration of hesperidin increased the phosphorylation of MLC20 in the cecum tissue of POI rats. Moreover, administration of hesperidin reversed the increased levels of inflammatory cytokines, iNOS and COX-2 in cecum tissue of POI rats. In freshly isolated intestinal smooth muscle cells, hesperidin (5-80 μmol/L) dose-dependently increased the intracellular Ca(2+) concentration as well as the phosphorylation of MLC20, which was abrogated by ML-7 or siRNA that knocked down MLCK.

Conclusion: Oral administration of hesperidin effectively alleviates rat POI through inhibition of inflammatory responses and stimulation of Ca(2+)-dependent MLC phosphorylation.
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http://dx.doi.org/10.1038/aps.2016.56DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4973386PMC
August 2016

[Investigation of pharmacokinetics and pharmacodynamics of different doses of aminophylline in very low birth weight infants].

Zhongguo Dang Dai Er Ke Za Zhi 2015 Nov;17(11):1171-5

Department of Pediatrics, West China Second Hospital of Sichuan University, Chengdu 610041, China.

Objective: To study the pharmacokinetic and pharmacodynamic features of different doses of aminophylline in very low birth weight (VLBW) infants with different postmenstrual ages, weights, and ages (in days).

Methods: A total of 40 VLBW infants with apnea were enrolled. After an intravenous loading dose of 5 mg/kg aminophylline, they were randomized into two groups with different maintenance doses of aminophylline (1 mg/kg and 2 mg/kg, once every 8 hours). Blood concentrations of aminophylline and liver and renal functions were monitored at 8 hours, 3 days, and 7 days after the loading dose. Attacks of apnea were documented. Pharmacokinetic data of aminophylline were compared between the two groups.

Results: The steady-state plasma concentration of aminophylline and plasma clearance in the 2 mg/kg group were significantly higher than those in the 1 mg/kg group (P<0.05). However, the elimination half life was shorter in the 2 mg/kg group (P<0.05). Days of apnea attacks within 7 days after birth in the 2 mg/kg group were significantly fewer than in the 1 mg/kg group (P<0.05). Aminophylline plasma clearance was positively correlated with age (in days) after birth and postmenstrual age in both groups.

Conclusions: In VLBW infants, pharmacokinetics and pharmacodynamics are different when different maintenance doses of aminophylline are given. The maintenance dose of 2 mg/kg is associated with a better effect in the treatment of apnea. Postmenstrual age and age (in days) should be considered during the adjustment of dose, and routine blood concentration monitoring should be performed.
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November 2015

[Preliminary study of contrast-enhanced ultrasonography in the evaluation of angiogenesis in ovarian tumors].

Sichuan Da Xue Xue Bao Yi Xue Ban 2014 Nov;45(6):964-9

Department of Diagnostic Ultrasound, West China Second University Hospital, Sichuan University, Chengdu, China.

Objective: To investigate the role of contrast-enhanced ultrasonography (CEUS) with pulsed inversion harmonic imaging in the evaluation of angiogenesis in ovarian tumors.

Methods: Forty-two patients of ovarian tumor received CEUS examination, in which the rise time (RT), peak intensity (PI), area under the curve (AUC), time from peak to one half (TTH) and time to peak (TTP) of ovarian tumors were measured. The post- surgical specimens of ovarian tumors were analysed by the stain with polyclonal antibodies against vascular endothelial growth factor (VEGF) and CD34. Correlations between the index of VEGF, microvessel density (MVD) and ultrasonic perfusion parameters were studied.

Results: MVD and VEGF index of ovarian tumors were significantly correlated with CEUS perfusion parameters including PI, AUC and TTH. The correlation coefficients of MVD with PI, AUC and TTH were 0. 569, 0. 623 and 0. 585 respectively; and the correlation coefficients of VEGF with PI, AUG and TTH were 0. 516,0. 640 and 0. 591 respectively. There were significant differences of the perfusion parameters between high and low MVD group.

Conclusion: The perfusion parameters PI, AUC and TTH in CEUS were correlated with MVD and VEGF in ovarian tumors, which may be useful in the evaluation of tumors angiogenesis.
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November 2014

[Intracerebral transplantation of human umbilical cord-derived mesenchymal stem cells in neonatal rat model of hypoxic-ischemic brain damage: protective effect to injured brain].

Zhongguo Dang Dai Er Ke Za Zhi 2014 Sep;16(9):927-32

Department of Neonatology, West China Second University Hospital, Chengdu 610041, China.

Objective: To study the brain protection and the possible mechanism of human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) in neonatal rat model of hypoxic-ischemic brain damage (HIBD).

Methods: Successfully establishing a neonatal rat model of HIBD, hUC-MSCs labeled with BrdU were transplanted into the lateral ventricle 24 hours after HIBD. The number of apoptotic cells and the expression of Caspase-3 were detected by TUNEL and Western blot respectively at 24 and 48 hours after transplantation. The neurological functions of HIBD rats were evaluated by Longa score, and the survival, differentiation and pro-differentiation effects of hUC-MSCs were identified by immunofluorescence at 1 to 3 weeks after transplantation.

Results: At 24 and 48 hours after transplantation, apoptotic cells and Caspase-3 expression in the MSCs group were less than in the HIBD group (P<0.05). At 2 and 3 weeks after transplantation, the Longa score in the MSCs group was lower than in the HIBD group (P<0.05). After transplantation, positive cells labeled with BrdU were seen in the brain tissue. The expression levels of glial fibrillary acidic protein (GFAP) and neuron specific esterase (NSE) in the MSCs group were higher than in the HIBD and sham-operated control groups (P<0.05), and increased gradually with the transplantation time (P<0.05).

Conclusions: hUC-MSCs transplantation in HIBD rats can inhibit Caspase-3 expression and reduce apoptotic cells in the early stage, and in the later period, the survival hUC-MSCs can differentiate into neural-like cells and promote the differentiation of endogenous neural-like cells, providing protective effects to brain.
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September 2014

Characteristics of evodiamine-exerted stimulatory effects on rat jejunal contractility.

Nat Prod Res 2015 12;29(4):388-91. Epub 2014 Aug 12.

a Pharmaceutical College, Dalian Medical University , 9 West Section, Lvshun South Road, Dalian 116044 , P.R. China.

This study was designed to characterise the effects of evodiamine on intestinal contractility and reveal the correlated mechanisms. Evodiamine (2.5-80.0 μM) increased normal jejunal contractility and jejunal hypocontractility established under a variety of experimental conditions. Evodiamine-exerted stimulatory effects were blocked by the L-type Ca(2+) channel blocker nifedipine or abolished in the Ca(2+)-free assay condition. The stimulatory effects of evodiamine on jejunal contractility were partially blocked in the presence of neurotoxin tetrodotoxin or endogenous acetylcholine synthesis blocker hemicholinium-3 or muscarinic receptor antagonist atropine, respectively. Evodiamine-exerted stimulatory effects were blocked by c-kit receptor tyrosine kinase inhibitor imatinib. Evodiamine increased myosin phosphorylation in jejunal smooth muscle of constipation-prominent rats. These results showed that evodiamine-exerted stimulatory effects on jejunal segments are Ca(2+)-dependent, need the presence of interstitial cell of Cajal, requirement of cholinergic neuron and correlate with increased myosin phosphorylation, implicating the potential value of evodiamine in relieving hypo-motility disorders.
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http://dx.doi.org/10.1080/14786419.2014.947485DOI Listing
April 2015

Characteristics of diprophylline-induced bidirectional modulation on rat jejunal contractility.

Korean J Physiol Pharmacol 2014 Feb 13;18(1):47-53. Epub 2014 Feb 13.

Department of Pharmacology, Dalian Medical University, Dalian 116044, China.

In this study, we propose that diprophylline exerts bidirectional modulation (BM) on the isolated rat jejunal segment depending on its contractile state. The results supported the hypothesis. Diprophylline (20 µM) exerted stimulatory effects on the contractility of jejunal segment in six low contractile states while inhibitory effects in six high contractile states, showing the characteristics of BM. Diprophylline-induced stimulatory effect was significantly blocked by atropine, indicating the correlation with cholinergic activation. Diprophylline-induced inhibitory effect was partially blocked by phentolamine, propranolol, and L-N-Nitro-Arginine respectively, indicating their correlation with sympathetic activation and nitric oxide-mediated relaxing mechanisms. Diprophylline-induced BM was abolished by tetrodotoxin or in a Ca(2+) free condition or pretreated with tyrosine kinase inhibitor imatinib, suggesting that diprophylline-induced BM is Ca(2+) dependent, and that it requires the presence of enteric nervous system as well as pacemaker activity of interstitial cells of Cajal. Diprophylline significantly increased the reduced MLCK expression and myosin extent in constipation-prominent rats and significantly decreased the increased MLCK expression and myosin extent in diarrhea-prominent rats, suggesting that the change of MLCK expression may also be involved in diprophylline-induced BM on rat jejunal contractility. In summary, diprophylline-exerted BM depends on the contractile states of the jejunal segments, requires the presence of Ca(2+), enteric nervous system, pacemaker activity of interstitial cells of Cajal, and MLCK-correlated myosin phosphorylation. The results suggest the potential implication of diprophylline in relieving alternative hypo/hyper intestinal motility.
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http://dx.doi.org/10.4196/kjpp.2014.18.1.47DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3951823PMC
February 2014

Characteristics of nobiletin-induced effects on jejunal contractility.

Fitoterapia 2014 Apr 25;94:1-9. Epub 2014 Jan 25.

College of Pharmacy, Dalian Medical University, Dalian, Liaoning 116044, PR China. Electronic address:

Nobiletin, a citrus polymethoxylated flavone, exhibits multiple biological properties including anti-inflammatory, anti-carcinogenic, and anti-insulin resistance effects. The present study found that nobiletin exerted significant stimulatory effects on the contractility of isolated rat jejunal segments in all 6 different low contractile states, and meanwhile significant inhibitory effects in all 6 different high contractile states, showing characteristics of bidirectional regulation (BR). Nobiletin-exerted BR on jejunal contractility was abolished in the presence of c-kit receptor tyrosine kinase inhibitor imatinib or Ca(2+) channel blocker verapamil. In the presence of neuroxin tetrodotoxin, nobiletin only exerted stimulatory effects on jejunal contractility in both low and high contractile states. Hemicholinium-3 and atropine partially blocked nobiletin-exerted stimulatory effects on jejunal contractility in low-Ca(2+)-induced low contractile state. Phentolamine or propranolol or l-NG-nitro-arginine significantly blocked nobiletin-exerted inhibitory effects on jejunal contractility in high-Ca(2+)-induced high contractile state respectively. The effects of nobiletin on myosin light chain kinase (MLCK) mRNA expression, MLCK protein content, and myosin light chain phosphorylation extent were also bidirectional. In summary, nobiletin-exerted BR depends on the contractile states of rat jejunal segments. Nobiletin-exerted BR requires the enteric nervous system, interstitial cell of Cajal, Ca(2+), and myosin phosphorylation-related mechanisms.
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http://dx.doi.org/10.1016/j.fitote.2014.01.018DOI Listing
April 2014

[Effect of integrin β8 on TGF-β1 activation in astrocytes with oxygen glucose deprivation].

Zhongguo Dang Dai Er Ke Za Zhi 2014 Jan;16(1):73-6

Department of Pediatrics, West China Second Hospital, Sichuan University; West China Children's Medical Center; Key Laboratory of Obstetric & Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, Chengdu 610041, China.

Objective: To study the effect of β8 expression on transforming growth factor β1(TGF-β1) activation in astrocytes with oxygen glucose deprivation (OGD).

Methods: Astrocytes were cultured and then subjected to OGD to generate hypoxia-ischemia (HI) model in vitro. Immunocytochemistry was used to detect the expression and distribution of β8 in nomoxia cultured cells. β8 protein expression was quantified by Western blot at 12 hours, 1 day and 2 days after OGD. Astrocytes and luciferase reporter cells (TMLC) were co-cultured. β8 RNA interference system was established to specifically inhibit β8 expression in cultured astrocytes. TGF-β1 activation was then detected in the co-culture system.

Results: β8 was mainly located in the cytoplasm and neurites of astrocytes. OGD resulted in increase of β8 protein expression at 12 hours after reoxygenation in astrocytes, which was peaked at 1 day after reoxygenation. TGF-β1 activation was in accordance with β8 expression in astrocyte-TMLC co-culture system after reoxygenation. After the inhibition of β8, TGF-β1 activation was significantly reduced in all time points.

Conclusions: The highly expressed β8 plays important roles in the regulation of TGF-β1 activation in neonatal rats with hypoxic-ischemic brain damage.
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January 2014

[Visualization study of current research on nutrition of premature infants in China].

Zhongguo Dang Dai Er Ke Za Zhi 2013 Oct;15(10):835-40

Department of Pediatrics, West China Second Hospital of Sichuan University, Chengdu 610041, China.

Objective: Inadequate postnatal nutritional support is an important factor contributing to growth failure, which leads to poor neurological outcome. In this study, co-word analysis was used to investigate the research on nutrition of premature infants over the last six years in China, describe the research trend in this field in China, and provide possible directions for future research.

Methods: A literature search was performed in January 2013 using the CNKI database and the key words "preterm infant" and "nutrition". A total of 772 articles were retrieved. Then high-frequency key words were extracted using Excel 2010 to create a co-occurrence matrix. Finally, a visualized network was built using Ucinet 6.0.

Results: The knowledge domain map of research on nutritional support for premature infants in China showed that the major topic of relevant research is still the combination of parenteral nutrition and enteral nutrition, with the goal of maintaining appropriate growth rates in premature infants. Researchers have paid much attention to the adverse effects of parenteral nutrition. Feeding intolerance is still the main problem in nutritional support, especially enteral nutrition, for premature infants.

Conclusions: A visualized network of current research on nutrition of premature infants in China has been created, and a knowledge domain map has been drawn to reflect the hot topics in this field of study over the last six years.
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October 2013

[Investigation on pharmacokinetics of aminophylline in very low birth weight infants].

Sichuan Da Xue Xue Bao Yi Xue Ban 2013 Mar;44(2):291-4

Department of Pediatrics, West China Second Hospital, Sichuan University, Chengdu 610041, China.

Objective: To investigate the pharmacokinetics of aminophylline in very low birth weight infant.

Methods: This study investigated 104 very low birth weight infants using aminophylline 5 mg/kg treating apnea who were hospitalized in our department during 2011-2012. The blood concentration of aminophylline was measured in 30 min before, 8 h and 5 d after first time loading dose, and was counterchecked every week before aminophylline withdrawal. The pharmacokinetic parameters of aminophylline were calculated and population pharmacokinetic model was established by MW/Pharm3.6 statistical analysis.

Results: The average birth weight of these 104 very low birth weight infants was (1.15 +/- 0.23) kg, average gestational age was (31.19 +/- 2.50) weeks. The results of aminophylline pharmacokinetics showed: the plasma clearance was (17.88 +/- 5.61) mL/(kg x h), the apparent volume of distribution was (0.93 +/- 0.18) L/kg, the half life time was (28.6 +/- 7.59) h. The aminophylline plasma clearance was related to creatinine clearance, gestational age and days of age after birth (related coefficient was 0.68, 0.62, 0.56 respectively, P < 0.05),the apparent volume of distribution was related to birth weight (related coefficient was 0.82, P < 0.05). The population pharmacokinetics model established can predict the concentration-time curve of the patients.

Conclusion: The pharmacokinetics of aminophylline in very low birth weight infant was quite different from adult, which suggest blood concentration monitoring and dose adjustment for the clinical use of aminophylline in low birth weight infants.
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March 2013

Effects of berberine on rat jejunal motility.

J Pharm Pharmacol 2013 May 25;65(5):734-44. Epub 2013 Jan 25.

Department of Pharmacology, Dalian Medical University, Dalian, China.

Objectives: The aim of the study was to evaluate berberine-induced bidirectional regulation on the contractility of jejunum.

Methods: Different low and high contractile states of isolated jejunal segment from rat were established to investigate the effects of berberine.

Key Findings: Stimulatory effects on jejunal segment were exerted by berberine in six low contractile states and inhibitory effects were produced on jejunal segment in six high contractile states. The effects of berberine on myosin light chain kinase (MLCK) mRNA expression, MLCK protein content, and myosin phosphorylation in jejunum were also bidirectional. Bidirectional regulation was not observed in the presence of tetrodotoxin. No regulatory effects of berberine on jejunal contractility were observed in the presence of verapamil. The stimulatory effects of berberine on jejunal contractility were blocked by atropine. The inhibitory effects of berberine on jejunal contractility were abolished by phentolamine, propranolol and L-NG-nitro-arginine, respectively.

Conclusions: Berberine-induced bidirectional regulation needed the presence of the enteric nervous system, and depended on the influx of extracellular Ca(2+) , related to the cholinergic system while jejunum was in low contractile states, and related to the adrenergic system and nitric oxide relaxing mechanism while jejunum was in high contractile states. The results suggested the potential clinical implication of berberine for alternating-type irritable bowel syndrome.
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http://dx.doi.org/10.1111/jphp.12026DOI Listing
May 2013

The characteristics of genistin-induced inhibitory effects on intestinal motility.

Arch Pharm Res 2013 Mar 23;36(3):345-52. Epub 2013 Feb 23.

Department of Pharmacology, Dalian Medical University, Dalian, 116044, Liaoning, China.

Genistin belongs to isoflavones. Based on the facts that genistin exerts inhibitory effects on the contractility of vascular smooth muscle,the present study was designed to characterize the effects of genistin on intestinal contractility and evaluate its potential clinical implication. Ex vivo [isolated jejunal segment (IJS) of rat], in vitro, and in vivo assays were used in the study. The results indicated that genistin (5-80 μmol/L) inhibited the contraction of IJS in a dose-dependent manner and inhibited the increased-contractility of IJS induced by acetylcholine (ACh), histamine, high Ca(2+), and erythromycin, respectively. The inhibitory effects of genistin were correlated with the stimulation of alpha adrenergic and beta adrenergic receptors since these inhibitory effects were significantly blocked in the presence of phentolamine and propranolol respectively. No further inhibitory effects of genistin were observed in the presence of verapamil or in Ca(2+)-free condition, indicating genistin-induced inhibitory effects are Ca(2+)-dependent. Genistin decreased myosin light chain kinase (MLCK) protein contents and MLCK mRNA expression in IJS, and inhibited both phosphorylation and Mg(2+)-ATPase activity of purified myosin, implicating that the decrease of MLCK contents and inhibition of MLCK activity are involved in the genistin-induced inhibitory effects. The study suggests the potential clinical implications of genistin in relieving intestinal hypercontractility.
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http://dx.doi.org/10.1007/s12272-013-0053-2DOI Listing
March 2013

Characteristics of deslanoside-induced modulation on jejunal contractility.

World J Gastroenterol 2012 Nov;18(41):5889-96

Department of Pharmacology, Dalian Medical University, Dalian 116044, Liaoning Province, China.

Aim: To characterize the dual effects of deslanoside on the contractility of jejunal smooth muscle.

Methods: Eight pairs of different low and high contractile states of isolated jejunal smooth muscle fragment (JSMF) were established. Contractile amplitude of JSMF in different low and high contractile states was selected to determine the effects of deslanoside, and Western blotting analysis was performed to measure the effects of deslanoside on myosin phosphorylation of jejunal smooth muscle.

Results: Stimulatory effects on the contractility of JSMF were induced (45.3% ± 4.0% vs 87.0% ± 7.8%, P < 0.01) by deslanoside in 8 low contractile states, and inhibitory effects were induced (180.6% ± 17.8% vs 109.9% ± 10.8%, P < 0.01) on the contractility of JSMF in 8 high contractile states. The effect of deslanoside on the phosphorylation of myosin light chain of JSMF in low (78.1% ± 4.1% vs 96.0% ± 8.1%, P < 0.01) and high contractile state (139.2% ± 8.5% vs 105.5 ± 7.34, P < 0.01) was also bidirectional. Bidirectional regulation (BR) was abolished in the presence of tetrodotoxin. Deslanoside did not affect jejunal contractility pretreated with the Ca(2+) channel blocker verapamil or in a Ca(2+)-free assay condition. The stimulatory effect of deslanoside on JSMF in a low contractile state (low Ca(2+) induced) was abolished by atropine. The inhibitory effect of deslanoside on jejunal contractility in a high contractile state (high Ca(2+) induced) was blocked by phentolamine, propranolol and L-NG-nitro-arginine, respectively.

Conclusion: Deslanoside-induced BR is Ca(2+) dependent and is related to cholinergic and adrenergic systems when JSMF is in low or high contractile states.
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http://dx.doi.org/10.3748/wjg.v18.i41.5889DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3491595PMC
November 2012

Down-regulated NOD2 by immunosuppressants in peripheral blood cells in patients with SLE reduces the muramyl dipeptide-induced IL-10 production.

PLoS One 2011 19;6(8):e23855. Epub 2011 Aug 19.

Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China.

Background: Pattern recognition receptors (PRRs) such as Toll-like receptors are aberrantly expressed of peripheral blood mononuclear cells (PBMCs) in systemic lupus erythematosus (SLE) patients, for playing immunopathological roles.

Methodology/principal Findings: We investigated the expression and function of the PRR nucleotide-binding oligomerization domain (NOD2) in SLE. NOD2 expression in T, B lymphocytes, monocytes, myeloid dendritic cells (mDCs) and plasmacytoid dendritic cells (pDCs) was assessed in SLE patients and healthy controls (HCs) using flow cytometric analysis. Ex vivo production of cytokines from PBMCs upon NOD2 agonist muramyl dipeptide (MDP) stimulation was assessed using Cytometric Bead Array. Over-expression of NOD2 in monocytes was observed in immunosuppressant naïve SLE patients, and was positively associated with longer disease duration. Immunosuppressive therapy was an independent explanatory variable for downregulating NOD2 expression in CD8+ T, monocytes, mDCs and pDCs. Ex vivo basal productions of cytokines (IL-6, IL-8 and IL-10) were significantly increased in immunosuppressant naïve patients and patients with active disease despite immunosuppressants compared with HCs. Upon MDP stimulaiton, relative induction (%) of cytokines (IL-1β) from PBMC was significantly increased in immunosuppressant naïve patients with inactive disease, and patients with active disease despite immunosuppressant treatment compared with HCs. Immunosuppressant usage was associated with a decreased basal production and MDP induced relative induction (%) of IL-10 in patients with inactive disease compared with immunosuppressant naïve patients and HCs.

Conclusions/significance: Bacterial exposure may increase the NOD2 expression in monocytes in immunosuppressant naïve SLE patients which can subsequently lead to aberrant activation of PBMCs to produce proinflammatory cytokines, implicating the innate immune response for extracellular pathogens in the immunopathological mechanisms in SLE. Immunosuppressant therapy may downregulate NOD2 expression in CD8+ T lymphocytes, monocytes, and DCs in SLE patients which subsequently IL-10 reduction, contributing towards the regulation of immunopathological mechanisms of SLE, at the expense of increasing risk of bacterial infection.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0023855PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3158772PMC
February 2012

Anti-inflammatory activities of Chinese herbal medicine sinomenine and Liang Miao San on tumor necrosis factor-α-activated human fibroblast-like synoviocytes in rheumatoid arthritis.

J Ethnopharmacol 2011 Sep 6;137(1):457-68. Epub 2011 Jun 6.

Department of Chemical Pathology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, N.T., Hong Kong.

Aim Of The Study: Sinomenine, an alkaloid isolated from the root of Sinomenium acutum, has been used to alleviate the symptoms of rheumatic diseases. Liang Miao San (LMS), composed of the herbs Rhizoma Atractylodis (Cangzhu) and Cotex Phellodendri (Huangbai), is another traditional Chinese medicine formula for rheumatoid arthritis (RA) treatment. Although numerous studies have demonstrated the potential anti-inflammatory activities of sinomenine and LMS, the underlying intracellular mechanisms regulating the anti-inflammatory activities of sinomenine and LMS on human primary fibroblast-like synoviocytes (FLS) from RA patients and normal control subjects have not been elucidated.

Materials And Methods: We investigated the in vitro anti-inflammatory activity of sinomenine and LMS on inflammatory cytokine tumor necrosis factor (TNF)-α-mediated activation of human normal and RA-FLS. The underlying intracellular signaling molecules were analyzed quantitatively using flow cytometry.

Results: Sinomenine was found to significantly inhibit TNF-α induced cell surface expression of vascular cell adhesion molecule (VCAM)-1 and release of inflammatory cytokine and chemokine IL-6, CCL2 and CXCL8 from both normal and RA-FLS (all p<0.05). Moreover, the suppression of sinomenine on TNF-α induced VCAM-1 expression and IL-6 release of RA-FLS was significantly higher than that of normal FLS (p<0.05). LMS significantly inhibited TNF-α-induced inflammatory chemokines CXCL10 and CCL5 release from both normal and RA-FLS, with significantly higher suppression on CXCL10 secretion in RA-FLS than that of normal FLS (all p<0.05). Further investigations showed that sinomenine and LMS could significantly suppress TNF-α-induced phosphorylation of inhibitor κBα and extracellular signal-regulated protein kinase, the central signaling molecules mediating TNF-α-induced VCAM-1 expression and chemokine production.

Conclusion: Our results therefore provide a new insight into the differential anti-inflammatory activities of sinomenine and LMS through the suppression of TNF-α-activated FLS by modulating distinct intracellular signaling pathways in RA.
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http://dx.doi.org/10.1016/j.jep.2011.05.048DOI Listing
September 2011

Activation of human eosinophils and epidermal keratinocytes by Th2 cytokine IL-31: implication for the immunopathogenesis of atopic dermatitis.

Int Immunol 2010 Jun 21;22(6):453-67. Epub 2010 Apr 21.

Department of Chemical Pathology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, NT, Hong Kong.

IL-31 is a novel T(h) type 2 cytokine that can induce pruritus and dermatitis in mice resembling human atopic dermatitis (AD). Eosinophil infiltration in skin lesions is a predominant pathological feature of AD. In the present study, we investigated the effects of IL-31 on the activation of human eosinophils and epidermal keratinocytes. Eosinophils and keratinocytes were cultured either together or separately in the presence or absence of IL-31 stimulation. IL-31 could significantly induce the release of pro-inflammatory cytokines IL-1beta, IL-6 and AD-related chemokines CXCL1, CXCL8, CCL2 and CCL18 from eosinophils, via functional cell surface IL-31 receptor. Such induction was further enhanced upon the co-culture of eosinophils and keratinocytes, in which eosinophils were the main source for releasing pro-inflammatory cytokines and chemokines. The presence of transwell inserts in co-culture system demonstrated that the direct interaction between eosinophils and keratinocytes was required for IL-31-induced cytokine and chemokine release. Cell surface expression of adhesion molecule CD18 on eosinophils and intercellular adhesion molecule-1 on keratinocytes was up-regulated in the co-culture, and levels were further enhanced upon IL-31 stimulation. The interaction between eosinophils and keratinocytes under IL-31 stimulation was differentially mediated through intracellular mitogen-activated protein kinases, nuclear factor-kappaB and phosphatidylinositol 3-kinase-Akt pathways. The above findings suggest a crucial immunopathological role of IL-31 in AD through activation of eosinophils-keratinocytes system.
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http://dx.doi.org/10.1093/intimm/dxq027DOI Listing
June 2010

[Protective effect of calpain inhibitor-3 on hypoxic-ischemic brain damage of neonatal rats].

Zhonghua Er Ke Za Zhi 2008 Jan;46(1):13-7

Department of Pediatrics, West China Second Hospital, Sichuan University, Chengdu 610041, China.

Objective: The mechanisms of hypoxic-ischemic brain damage (HIBD) are still largely unknown. Elevation of intracellular calcium concentration and subsequent calcium-dependent proteases activation such as calpains seem to play an important role in the process of neuronal death. Calpain inhibitors showed neuroprotective effects in adult rat cerebral ischemia models. This study aimed to investigate the protective effect and associated mechanisms of calpain inhibitor-3 (MDL28170) on HIBD of neonatal rats.

Methods: Seven-day old Sprague-Dawley rats were randomly divided into three groups: the control group (n = 18), HIBD group (n = 48) and calpain inhibitor-3 treated group (MDL group, n = 48). The mice in the latter two groups were subjected to hypoxia-ischemia (HI) insult. The puppies in MDL group were intraperitoneally injected with MDL28170 (25 mg/kg) at 0, 2 and 4 h after HI, while those in the other two groups were intraperitoneally injected with normal saline instead. All the pupies were sacrificed at 6 h, 24 h and 72 h after HI. Quantitative real-time fluorescent polymerase chain reaction was employed to detect micro-calpain gene expression, immunoblotting technique was used to measure mu-calpain and caspase-3 protein activation, apoptosis of ipsilateral cortex was detected by terminal deoxynucleotidyl transferase mediated d-UTP nick end labeling staining (TUNEL). CA1 neuronal loss was counted 24 h after HI by light microscopy.

Results: After HI mu-calpain mRNA began to increase at 6 h and reached peak at 24 h compared to the control (1.805 and 4.83 vs. 1, P < 0.05); mu-calpain was activated through autolysis, the ratio of its activated fragment (76 000) vs. whole fragment (80 000) was significantly higher at 6 h (0.547 +/- 0.095) compared to the control (0.095 +/- 0.016, P < 0.05), it reached peak at 24 h (0.921 +/- 0.058, P < 0.01) and was still at a high level at 72 h (0.708 +/- 0.025, P < 0.05). Expression of activated caspase-3 protein reached peak at 24 h (3.78 +/- 0.30, P < 0.01), decreased to the same level as the control (1.56 +/- 0.07) at 72 h (1.82 +/- 0.11, P > 0.05). Apoptotic cells in the cortex ipsilateral to HI insult increased after HIBD, reached peak at 24 h (135.46 +/- 17.52/visual field) and was still markedly higher at 72 h (79.32 +/- 17.79/visual field) compared with the control (5.33 +/- 1.53/visual field, P < 0.01). At 24 h after HI CA1 neuronal loss (30.0 +/- 6.2/oil immersion lens field) in the HIBD group was significantly higher than that of the control (2.4 +/- 0.3/oil immersion lens field, P < 0.01). However, in the MDL group the expressions of mu-calpain and caspase-3 proteins were diminished, TUNEL positive cells at 6 h and 24 h were decreased and CA1 neuronal loss (18.2 +/- 2.4/oil immersion lens field, P < 0.05) was alleviated. The amount of micro-calpain mRNA was decreased in the MDL group, but there was no significant difference compared with the HIBD group.

Conclusion: mu-calpain gene and protein expressions increased after HI, which may contribute to the pathogenensis of HIBD. Calpain inhibitor-3 may intervene neural necrosis and apoptosis by diminishing expressions of mu-calpain and caspase-3 to play a protective role after HI insult of neonatal brain.
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January 2008
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