Targeted inhibition of GRK2 kinase domain by CP-25 to reverse fibroblast-like synoviocytes dysfunction and improve collagen-induced arthritis in rats

Rheumatoid arthritis (RA) is an autoimmune disease and is mainly characterized by abnormal proliferation of fibroblast-like synoviocytes (FLS). The up-regulated cellular membrane expression of G protein coupled receptor kinase 2 (GRK2) of FLS plays a critical role in RA progression, the increase of GRK2 translocation activity promotes dysfunctional prostaglandin E4 receptor (EP4) signaling and FLS abnormal proliferation. Recently, although our group found that paeoniflorin-6'-

Expression and significance of FBXW10 and cyclin E in renal clear cell carcinoma / 实用肿瘤学杂志

Objective The aim of this study was to investigate the expressions of and clinical significance of F-box/WD-40 domain protein 10(FBXW10) as well as the expression of cell cycle protein cyclin E( cyclin E) in renal clear cell carcinoma. Methods Immunohistochemistry SP method was used to detect the expressions of FBXW10 and cyclin E protein in 60 cases of renal clear cell carcinoma and 20 cases of adjacent normal tissues. The relationship between the expressions of FBXW10 and cyclin E,and the clinical pathological characteristics was analyzed. Results The expression rates of FBXW10 and cyclin E protein in renal clear cell carcinoma were 40. 0% ,70. 0% ,respectively and adjacent normal tissues were 55. 0% and 25. 0% ( P<0. 05). The expression of FBXW10 was correlated with the histologic grade of renal clear cell carcinoma(P=0. 041),histologic grade( P=0. 030);the ex-pression of cyclin E was correlated with the pathological tumor stage of clear cell renal cell carcinoma(P=0. 005),degree of differen-tiation(P=0. 035),and distant metastasis(P=0. 011). There was a significant correlation between the expressions of FBXW10 and cyclin E in renal clear cell carcinoma(r=0. 533,P<0. 001). Conclusion FBXW10 and cyclin E may play important roles in the development of renal clear cell carcinoma.

Relationship between dietary inflammatory index during the second trimester of pregnancy and preterm ;birth / 中华临床营养杂志

Objective To assess the diet quality of pregnant women during the second trimester using the dietary inflammatory index ( DII) and to explore the correlation between the DII in second trimester of preg-nancy and preterm delivery.Methods A total of 253 women with singleton pregnancy in 16-20 gestational weeks who had received routine prenatal care between August 2014 and April 2015 at the First Affiliated Hospi-tal of Anhui Medical University were enrolled with cluster random sampling.The included women were asked to recall daily dietary intake in the 3 days prior to the survey.All dietary data were analyzed for energy and nutri-ents intake with a nutritional analysis software, followed by calculation of DII according to previous reports. Based on quartiles of the DII scores, the participants were divided into three groups, namely the anti-inflam-matory group (DII-2.55).The participants were followed up until delivery and the pregnancy outcomes were recorded. The relationship between the DII in second trimester of pregnancy and preterm delivery were analyzed. Results DII scores of the 253 pregnant women during the second trimester of pregnancy ranged from -7.913 to 3.872.The risks of preterm birth in the anti-inflammatory diet group, the intermediate group, and the pro-inflammatory diet group were 0, 1.6%, and 6.3%, respectively, with statistically significant differences among the groups (P=0.034).The higher DII scores (pro-inflammatory) were associated with higher inci-dence of preterm birth ( P<0.05 ) .Conclusion DII may be used to assess diet quality of pregnant women during the second trimester and to predict the risk of preterm birth.

Melatonin alleviates endoplasmic reticulum stress at an early stage during bleomycin-induced lung fibrosis in mice / 中国药理学通报

Aim To investigate whether melatonin ( MT) can alleviate endoplasmic reticulum( ER) stress at an early stage of bleomycin( BLM)-induced lung fi-brosis in mice. Methods Adult healthy male ICR mice were divided randomly into control group, MT group, BLM group and MT + BLM group. In MT group, mice had saline treatment 30 minutes after hav-ing the intraperitoneal injection of MT (10 mg·kg-1 ) and had been intraperitoneally injected with MT once in the following every 24 hours. In BLM group, mice were intratracheally injected with a single dose of BLM (5 mg·kg-1). In MT+BLM group, mice had been intraperitoneally injected with BLM 30 minutes after having MT and had been injected with MT once in the following every 24 hours. In control group, mice re-ceived the same level of saline treatment in the same manner. All mice were dissected for collecting the tis-sue of lungs at different time points (24h, 72h) after BLM treatment. Inflammatory cell infiltration of lungs was determined by HE staining. The level of ER stress related proteins ( GRP78 , p-eIF2α, p-IRE1α) in lungs was determined using Western blot. The distribu-tion of ER stress related proteins ( GRP78 , p-IRE1α, ATF6α, p-PERK) in lungs was detected by immuno-histochemistry. Results The model of BLM-induced acute inflammation of lung fibrosis in mice had been successfully constructed. After BLM treatment, lung weight, lung weight ratio and inflammatory cell infiltra-tion were significantly increased with a significant cor-relation between time and effectiveness. After MT treatment, lung weight, lung weight ratio and inflam-matory cell infiltration were significantly reduced. The results of Western blot showed that MT pretreatment not only prevented the increase of BLM-induced GRP78 protein significantly, but also restrained the phosphorylation of eIF2α and IRE1α in mouse lungs. Immunohistochemistry also showed that MT pretreat-ment reduced the expression of GRP78 , p-IRE1α, ATF6α and p-PERK. Conclusion MT alleviates ER stress effectively at an early stage of BLM-induced lung fibrosis in mice.

Effects of 4-phenylbutyric acid on carbon tetrachloride-induced acute liver injury in mice / 中华肝脏病杂志

<p><b>OBJECTIVE</b>To explore the effects and the molecular mechanisms of 4-phenylbutyric acid (PBA) on carbon tetraehloride (CCl4)-induced acute liver injury in mice.</p><p><b>METHODS</b>Sixty adult, healthy, male ICR mice were divided equally into the control group, PBA group, CCl4 12 h group, CCl4 24 h group, CCl4 48 h group, CCl4 72 h group, PBA+CCl4 12 h group, PBA+CCl4 24 h group, PBA+CCl4 48 h group, and PBA+CCl4 72 h group. The CCl4 groups and the PBA+CCl4 groups were intraperitoneally (i.p.) injected with CCl4 (300 mL/kg). In the PBA+CCl4 groups, the mice were i.p. injected with PBA (400 mg/kg). All mice were sacrificed to collect blood and liver specimens at different time points after the CCl4 treatment. Serum alanine aminotransferase (ALT) was detected. Histological examination was performed using hematoxylin-eosin staining and light microscopy, and apoptosis was detected using terminal transferase dUTP nick end labeling. The hepatic distribution of proliferating cell nuclear antigen (PCNA) was detected by immunohistochemistry. The hepatic protein expression of glucose-regulated protein (GRP78), C/EBP homologousprotein (CHOP), phosphorylated c-Jun N-terminal kinases (p-JNK), phosphorylated eukaryotic initiation factor 2a subunit (p-eIF2a), phosphorylated serine threonine kinase (p-akt), and nuclear factor-kappa B p65 (NF-kappa Bp65) were determined by western blot.</p><p><b>RESULTS</b>The serum ALT level in the PBA+CCl4 groups was reduced as compared with that in the CCl4 groups at the various time points examined.The liver-to-body weight ratio of two groups showed a significant difference only at the 48 h time point (P<0.01). PBA reduced the degree of hepatic necrosis and apoptosis caused by CCl4, and reduced the expression of hepatic GRP78 and other endoplasmic reticulum stress-related proteins (P<0.01). The protein levels of p-akt, NF-kappa Bp65 and PCNA was significantly decreased in the PBA+CCl4 groups (P<0.01).</p><p><b>CONCLUSION</b>The endoplasmic reticulum stress inhibitor PBA alleviated acute hepatic necrosis and apoptosis but restrained hepatic proliferation.</p>

The protective of folic acid supplementation in different ways on lipopolysaccharide-induced teratogenesis in mice / 中国实用护理杂志

Objective To explore the protective effect of folic acid supplementation in different ways on lipopolysaccharide-induced external malformations and skeletal malformations in mice.Methods The pregnant mice were divided into six groups randomly,including saline control group,FA control group,LPS group,LPS+FAig group,LPS+FAip group,and LPS+FAdw group.All dams were medicated on gestational day 8～12,and then sacrificed on gestational day 18,for each litter,the number of live fetuses,dead fetuses,resorption fetuses and external malformations of live fetuses were all counted.All fetuses were subsequently evaluated the skeletal malformations.Results A low dose of LPS injection during the second trimester resulted in external and skeletal malformations.Exencephaly and encephalomeningocele were two of the most common external malformations,skeletal malformations consisted mainly of the incompletion of supraoccipital ossification,sternal malformation and rib malformation.FA supplementation by three ways all attenuated the external and skeletal malformations.And the best protective effect was by oral administration.The incidence of external,sternal and rib malformation was all decreased.Conclusions Three ways can prevent the mice during the second trimester from the external and skeletal malformations caused by LPS injection,and the best protective effect was by intragastric administration.

Associations between vitamin D deficiency and nonalcoholic fatty liver disease / 中华消化杂志

Objective To explore the association between vitamin D deficiency and nonalcoholic fatty liver disease (NAFLD).Methods From April to June 2013,104 outpatients met NAFLD diagnostic criteria were enrolled.At the same period,98 age and gender matched healthy individuals were enrolled as control.The clinical data were collected through questionnaire,physical examination and lab tests.The severity of hepatic steatosis was dertermined with upper abdominal ultrasound examination.The serum concentration of 25 (OH )D was detected by radio-immunology.The association between vitamin D deficiency and NAFLD was analyzed with two independent sampling t analysis,chi-square test,analysis of variance (ANOVA)and Logistic regression analysis.Results The clinical indexes including body mass index (BMI ), abdominal circumference, blood pressure, aspartate aminotransferase, alanine aminotransferase,glutamyl ranspeptidase,lactate dehydrogenase,uric acid,triglyceride,overall cholesterol, lower density lipoprotein cholesterol and fasting blood glucose of NAFLD group were higher than those of the healthy control group,and the differences were statistically significant (all P 0.05).The results of stratification analysis in age and BMI indicated that the rate of 25 (OH )D deficiency (<37.5 nmol/L)in NAFLD patients aged less than 30 was higher than that of healthy control group (χ2 =6.679, OR = 13.71,P = 0.025 );the rate of 25 (OH)D deficiency in NAFLD patients with BMI≤25 kg/m2 was higher than that of healthy control group (χ2 = 3.734,OR = 4.97,P < 0.01).Among BMI≤25 kg/m2 group,after the adjustment of age,gender and metabolic syndrome,the results of multiple group Logistic regression analysis indicated that serum 25(OH)D concentration was negatively correlated to NAFLD (OR= 1 .16,95 % CI :1 .03 to 1 .30,P = 0.032).Conclusion Vitamin D deficiency might be a risk factor in pathogenesis of NAFLD patients with age less than 30 year old and BMI ≤25 kg/m2 .

Effects of vitamin D deficiency on pregnancy and fetal development in mice / 安徽医科大学学报

Objective To investigate the effects of vitamin D deficiency on pregnancy and fetal development in mice. Methods All female ICR mice were randomly divided into two groups. In control group, mice were fed with standard feeds (vitamin D3 >800 IU/kg). In vitamin D deficiency group (VDD), female mice were fed with feeds with vitamin D depletion (vitamin D3 <25 IU/kg). For mating purposes, four females were housed overnight with two males starting at 9 : 00 PM. Females were checked 7 : 00 AM the next morning, and the presence of a vaginal plug was designated as gestational day (GD) 0. All pregnancy mice were sacrificed on GD18. For each litter, the number of live fetuses, dead fetuses and resorption sites were counted. Live fetuses in each litter were weighed. Crown-rump lengths were examined. And skeletal development of all live fetuses in each litter was evaluated. Re-sults The pregnancy rate was lower in VDD group than that in control group(P<0.05). The number of live fetu-ses was significantly decreased(P<0.05). By contrast, the numbers of dead fetuses and resorption sites were sig-nificantly increased(P<0.05). In addition, the average weights of fetuses and placenta were reduced in vitamin D deficiency group. Moreover, vitamin D deficiency resulted in skeletal development retardation in fetuses. Conclu-sion Vitamin D deficiency impairs pregnancy and developmental outcomes in mice.

Effects of pyrrolidine dithiocarbamate on acute apoptotic liver injury in mice / 中国药理学通报

Aim To investigate the effects of pyrrolidine dithiocarbamate (PDTC) on D-galactosamine/lipopolysaccharides (GalN/LPS)-induced acute apoptotic liver injury and its mechanism.Methods All mice were randomly divided into four groups.Mice in GalN/LPS group were co-injected with GalN (600 mg·kg~(-1),ip) and LPS (20 μg·kg~(-1), ip). Mice in PDTC+GalN/LPS group were injected with two doses of PDTC,one (100 mg·kg~(-1), ip) at 24 h before LPS and the other at 2 h before LPS (20 μg·kg~(-1), ip).Mice in control groups were treated with PDTC (100 mg·kg~(-1), ip) or saline. Ten mice in each group were observed for animal survival within 72 h after LPS treatment. Six mice in each group were sacrificed 1.5 h after LPS for collecting blood and isolating livers. The expression of hepatic TNF-α mRNA was determined by reverse transcription and polymerase chain reaction (RT-PCR). Hepatic nuclear factor-κB (NF-κB) binding activity was measured with electrophoretic mobility shift assay (EMSA).Twelve mice in each group were sacrificed 8 h after LPS treatment. Serum was collected for measurement of alanine aminotransferase (ALT) and hepatocellular apoptosis and histological examination.Results Co-injection of GalN and LPS markedly increased serum ALT activity. Histopathological examination of liver sections revealed that GalN/LPS induced hepatic congestion, necrosis and massive macrophages infiltration, and increased the number of TUNEL-positive cells in mouse liver.GalN/LPS treatments, led to 90% mortality within 72 h with severe congestion and necrosis in the liver of all the dead mice. PDTC pretreatment significantly inhibited GalN/LPS-induced hepatic NF-κB activation and TNF-α expression. In contrast, PDTC aggravated GalN/LPS-triggered hepatocellular apoptosis, increased serum ALT activity, exacerbated hepatic hemorrhage and necrosis, and accelerated death.Conclusion PDTC aggravates GalN/LPS-induced acute apoptotic liver injury via inhibiting NF-κB-mediated anti-apoptotic effects.

Thought about construction reinforcement of hospital medical engineering section / 医疗卫生装备

With the development of modem clinical medical engineering,especially some large medical equipment,medical engineering section needs more talents in management and maintenance profession.Aiming at problems in the section construction,some viewpoints and suggestions are put forward.It is expected that the leadership could attach importance to medical engineering section,make good use of the talents and lay solid foundation for the development of hospitals.

A dual effect of N-acetylcysteine on lipopolysaccharide-induced fetal damage in mice / 中国药理学通报

Aim To investigate the effect of N-acetylcysteine (NAC) pretreatment/posttreatment on lipopolysaccharide (LPS)-induced intra-uterine fetal death (IUFD) and intra-uterine growth retardation (IUGR) in mice.Methods In the first experiment,all pregnant mice except controls received an intraperitoneal (75 ?g?kg-1) injection of LPS on gd 15~17.In LPS+NAC groups,the pregnant mice were treated with NAC before and/or after LPS. The saline-and NAC-treated pregnant mice served as controls. The dams were sacrificed on gd 18. In the second experiment,all pregnant mice except controls received an intraperitoneal (75 ?g?kg-1) injection of LPS on gd 15. In LPS+NAC groups,the pregnant mice were treated with NAC before and/or after LPS. The saline-and NAC-treated pregnant mice served as controls. The dams were sacrificed at 1.5 h or 6 h after LPS.Results pretreatment with NAC significantly alleviated LPS-induced fetal mortality and reversed LPS-induced growth development retardation.Correspondingly,pretreatment with NAC significantly attenuated LPS-induced elevation in TNF-? concentration in maternal serum and amniotic fluid and lipid peroxidation in maternal and fetal livers. By contrast to pretreatment,posttreatment with NAC had no effect on LPS-induced TNF-? production and lipid peroxidation,and did not protect against LPS-induced IUFD and IUGR and in fact aggravated LPS-induced preterm labor.Conclusion Pretreatment with NAC attenuates LPS-induced IUFD and IUGR,whereas posttreatment with NAC aggravates LPS-induced preterm labor.

Effects of N-acetylcysteine on immunological liver injury in mice / 中国药理学通报

Aim To study effects of N-Acetylcysteine on Lipopolysaccharide-induced immunological liver injury in mice. Methods A model of immunological liver injury was induced by injection of LPS in mice primed with BCG. NAC was administered in two different modes. In mode A, mice were pretreated with two doses of NAC before LPS, one (150 mg?kg-1, ip) at 4 h before LPS and the other (150 mg?kg-1, ip) at 15 min before LPS. In mode B, mice were administered with two doses of NAC after LPS, one (150 mg?kg-1, ip) injected immediately after LPS and the other (150 mg?kg-1, ip.) injected 4 h after LPS. Some mice were sacrificed at 1.5 h after LPS and livers were dissected for total RNA extraction. Hepatic TNF-? mRNA level was determined by using RT-PCR. The remaining mice were sacrificed at 8 h after LPS. Blood serum was collected for measurement of alanine aminotransferase (ALT) and nitrate plus nitrite. Livers were dissected for measurements of GSH and lipid peroxidation. Results Pretreatment with NAC significantly alleviated LPS-induced increase in ALT activity, attenuated LPS-induced hepatic GSH depletion and TNF-? mRNA expression in mice primed with BCG. However, NAC had no effects on LPS-induced NO production and hepatic lipid peroxidation. By contrastwith pretreatment, posttreatment with NAC had littleeffects on LPS-induced immunological liver injury and in fact aggravated LPS-induced NO production and hepatic GSH depletion and increased LPS-induced mortality in mice primed with BCG. Conclusion NAC has a dual effect on LPS-induced immunological liver injury. Pretreatment with NAC protects against LPS-induced immunological liver injury via counteracting LPS-induced oxidative stress and TNF-? mRNA expression in mouse liver. However, when administered after LPS, NAC behaves as a prooxidant and aggravates LPS-induced mortality in mice primed with BCG.

Pregnane X receptor is involved in drug metabolism as a key regulator of CYP3A expression / 中国药理学通报

Cytochrome P4503As(CYP3As),the liver microsomal enzymes responsible for oxidative metabolism of numerous clinically used drugs,is known to be induced by a variety of compounds,including naturally occurring and synthetic glucocorticoids,pregnane compounds,and macrolide antibiotics.The pregnane X receptor(PXR;NR1I2) is an important component of the body′s adaptive defense against xenobiotics including drugs.PXR is activated by a large number of endogenous and exogenous chemicals including steroids,antibiotics,antimycotics,bile acids,and the herbal antidepressant St.John′s wort.PXR binds as a heterodimer with the 9-cis retinoic acid receptor(NR2B) to DNA response elements in the regulatory regions of CYP3A genes.Although PXR evolved to protect the body,its activation by a variety of prescription drugs represents the molecular basis for an important class of harmful drug interactions.