Gentiopicroside targets PAQR3 to activate the PI3K/AKT signaling pathway and ameliorate disordered glucose and lipid metabolism

The obstruction of post-insulin receptor signaling is the main mechanism of insulin-resistant diabetes. Progestin and adipoQ receptor 3 (PAQR3), a key regulator of inflammation and metabolism, can negatively regulate the PI3K/AKT signaling pathway. Here, we report that gentiopicroside (GPS), the main bioactive secoiridoid glycoside of Gentiana manshurica Kitagawa, decreased lipid synthesis and increased glucose utilization in palmitic acid (PA) treated HepG2 cells. Additionally, GPS improved glycolipid metabolism in streptozotocin (STZ) treated high-fat diet (HFD)-induced diabetic mice. Our findings revealed that GPS promoted the activation of the PI3K/AKT axis by facilitating DNA-binding protein 2 (DDB2)-mediated PAQR3 ubiquitinated degradation. Moreover, results of surface plasmon resonance (SPR), microscale thermophoresis (MST) and thermal shift assay (TSA) indicated that GPS directly binds to PAQR3. Results of molecular docking and cellular thermal shift assay (CETSA) revealed that GPS directly bound to the amino acids of the PAQR3 NH2-terminus including Leu40, Asp42, Glu69, Tyr125 and Ser129, and spatially inhibited the interaction between PAQR3 and the PI3K catalytic subunit (P110α) to restore the PI3K/AKT signaling pathway. In summary, our study identified GPS, which inhibits PAQR3 expression and directly targets PAQR3 to restore insulin signaling pathway, as a potential drug candidate for the treatment of diabetes.

Expression level of Dickkopf-1 protein in bone mesenchymal stem cells in Type 2 diabetic rats and its relationship with osteogenic activity / 中南大学学报(医学版)

To examine the growth activity and osteogenic differentiation of bone mesenchymal stem cells (BMSCs) in rats with Type 2 diabetes mellitus (T2DM) as well as the expression level of Dickkopf-1 (DKK-1) in bone marrow, and to explore the relationship between the osteogenic activity of BMSCs and the expression of DKK-1.
 Methods: The BMSCs were isolated from T2DM rats and were cultured in vitro. The BMSCs were divided into a T2DM group and a control group. The proliferation of BMSCs was detected by cell counting kit-8 (CCK8). Apoptosis rate was detected by annexin V- fluorescein isothiocyanate (FITC)/propidium iodide (PI) double staining. In the osteogenic induction phase, the expression level of alkaline phosphatase (ALP) in BMSCs was detected by ALP staining and ALP activity assay kit. The osteogenic differentiation of BMSCs was analyzed by alizarin red staining and mineralized nodule quantification. In addition, the expression of Runx2 and DKK-1 in BMSCs was detected by qRT-PCR.
 Results: Compared with the control group, the proliferation of BMSCs was decreased and the apoptosis was increased in the T2DM group (both P<0.01). In the osteogenic induction process of BMSCs, the expression of ALP significantly decreased, the formation of calcium nodules reduced, and the expression of osteoblast transcription factor Runx2 was down-regulated in the T2DM group compared with those in the control group (all P<0.01). The levels of DKK-1 protein and mRNA were up-regulated in the T2DM group, which were higher than those in the control group (both P<0.01). The levels of DKK-1 protein and mRNA were related to the increase of Runx2 (both P<0.01).
 Conclusion: The growth activity of BMSCs and the potential of osteogenic differentiation are attenuated in the T2DM rats, which may be related to the increase of DKK-1 expression in BMSCs.

MRTF-A mediates FN and ICAM-1expressions by NF-κB pathway in AGEs-induced GMCs / 中国药理学通报

Aim To observe the expression of MRTF-A in rat glomerular mesangial cells(GMCs) induced by advanced glycation end products(AGEs) and its effect on ICAM-1 and FN;to explore whether MRTF-A is involved in the process of diabetic nephropathy by affecting NF-κB pathway.Methods Under the condition of AGEs, CCG-1423 and anti-MRTF-A small interfering RNA were used to knock down MRTF-A and MRTF-A plasmid was used to activatt MRTF-A, The expression level of MRTF-A, ICAM-1, FN and p65 in nucleus were detected by Western blot.Results The protein expressions of MRTF-A was increased in AGEs-induced GMCs.The expressions of FN and ICAM-1 and p65 in nucleus were downregulated by knocking down MRTF-A.However, the expressions of FN, ICAM-1 and p65 in nucleus were upregulated by overexpressing MRTF-A.Conclusions AGEs can upregulate the expression of MRTF-A in GMCs, and MRTF-A mediates the protein expressions of FN and ICAM-1 by affecting NF-κB signaling pathway in AGEs-induced GMCs.

Recent advances in neuroprotective effect of histone deacetylase inhibitors / 中国生化药物杂志

Objective Central nervous system trauma, ischemia, hemorrhagic stroke were all experienced the same pathological damage, in related animal experiments,histone deacetylase inhibitors have a wide range of neuroprotective effect, it is expected to become a new class of potential therapeutic agents.However,the specific mechanism is not clear.In this paper, the research progress of neuroprotective effect of histone deacetylase inhibitors is reviewed,in order to improve recognition of histone deacetylase inhibitors and provide foundation for futher study.

Regulatory effects of the bile acid membrane receptor TGR5 on FN and TGF-β1 in rat glomerular mesangial cells cultured under high glucose condition / 中国药理学通报

Aim To investigate the expression of G protein-coupled receptor TGR5 and its effects on FN and TGF-β1 expression cultured under high glucose condition in rat glomerular mesangial cells , and then to explore the role of TGR5 in diabetic nephropathy. Methods INT-777 and TGR5 plasmid were used to activate TGR5 under high glucose(HG,30 mmol·L - 1 glucose ) condition, and anti-TGR5 small interfering RNA(TGR5 siRNA) was used to knock down TGR5. The protein expression of FN and TGF-β1 in rat me-sangial cells was detected by Western blot. Results TGR5 could be detected in rat glomerular mesangial cells. Both FN and TGF-β1 protein levels could be in-creased by high glucose compared with control group(P < 0. 05),and be inhibited by activiation of TGR5(P <0. 05). On the other hand,knockdown of TGR5 could increase FN and TGF-β1 protein to abnormal levels(P< 0. 01,P < 0. 05). Conclusion TGR5 suppresses HG-induced FN and TGF-β1 expression in rat glomer-ular mesangial cells,suggesting a protective role in the process of diabetic nephropathy.

Establishment of a national teaching center for virtual simulation experiment on disaster medicine / 中华医院管理杂志

Presented in the paper are the necessity,general ideas and principles of building a teaching center for virtual simulation experiment on disaster medicine,covering the teaching modules, capability objectives and education resources deployment among other basics of such a center.The authors propose to build a comprehensive platform for teaching by experimentation,integrating basic clinical skills training to trainings targeted to disaster rescue in view of actual needs in experiments and teaching.This way resources can be shared between the experiment center website and virtual simulation teaching software,promoting a regular,standardized and scientific development of disaster medicine in China.

Application of PDCA circle model in medical college students' clinical practice training and evaluation / 中华医学教育探索杂志

In order to strengthen the management of clinical teaching, improve the teaching quality of clinical practice, the advantages of the traditional medical education, teaching reform and medical simulation were further integrated, using PDCA (Plan-Do-Check-Action) cycle model in medi-cal college students' clinical practice training and evaluation. The skills of training and evaluation were optimized and practiced by thechain model of teaching-assistance-guidance to improve the train-ing quality of interns, and make continuous improvement from the angle of teaching, learning and management and with PDCA circulation mode. Practice shows that the application of PDCA circulation management has greatly improved teachers' teaching quality and their own quality, and the students' satisfaction of practice teaching management and clinical teachers has also significantly increased. The effect is obvious.

Methods and practice of systematic clinical first-aid skills training for community doctor / 局解手术学杂志

Objective To observe the effect of clinical first-aid skills training for community doctor. Methods Effect of systematic clinical first-aid skills training and traditional teaching methods were scored by the questionnaire survey in order to compare their difference. Results Through systematic clinical first-aid skills training, the score on contacting the actual work, improving the diagnosis and treatment, analyzing and problem-solving skills, enhancing learning initiative, participation, scientific learning method and self-learning ability, impro-ving clinical thinking, strengthening team spirit and humane education were significantly improved compared to that of the traditional teaching methods (P<0. 01). Conclusion The systematic clinical first-aid skills training is an effective way for community physicians.

SolitaireAB stent-assisted endovascular embolization of intracranial wide-necked aneurysms:a clinical ;follow-up study / 介入放射学杂志

Objective To investigate the mid-term effect of SolitaireAB stent-assisted interventional embolization with spring coils for the treatment of intracranial wide-necked aneurysms. Methods During the period from May 2009 to April 2013, a total of 49 patients with intracranial wide-necked aneurysm (49 aneurysms in total) received SolitaireAB stent-assisted interventional embolization treatment at authors’ hospital. In 41 patients, a total of 41 aneurysms were detected, of which ruptured aneurysm with bleeding was confirmed in 26 and un-ruptured aneurysm in 15. These 41 patients were followed up for 12-48 months. Based on modified Rankin scoring and DSA, CTA or MRA manifestations, the clinical results were evaluated. Results After the embolization treatment, re-bleeding of the aneurysm occurred in 2 cases, cerebral infarction in 3 cases, occlusion of the parent artery in one case and death in one case; the occurrence rate of complications was 14.2%. DSA, MRA or CTA performed at 12 months after the embolization treatment, showed that 32 aneurysms (78.0%) were completely obstructed, which was obviously higher than that observed on DSA performed immediately after the embolization procedure (21 aneurysms, 42.9%), the difference was statistically significant (P=0.02);residue of aneurismal neck was seen in 7 cases (17.1%) and partial occlusion in 2 cases (4.9%), which were much better than those observed on DSA that was performed immediately after the embolization procedure. Twenty-four aneurysms (58.5%) remained stable, showing no any change, and recurrence of aneurysm was observed in 4 cases (9.7%). At the last follow-up exam, the modified Rankin scoring showed that 0 point was seen in 18 cases (43.9%), one point in 10 cases (24.4%), 2 points in 5 cases (12.2%), 3 points in 4 cases (9.8%), 4 points in 2 cases (4.85%) and 5 points in 2 cases (4.85%). The self-care rate for daily activities was 80.5%, the prognosis was good. Conclusion For the treatment of intracranial wide-necked aneurysms, SolitaireAB stent-assisted interventional embolization with spring coils is safe and effective. This technique can improve the embolization rate and reduce the procedure-related complications.

The study on the influencing factors of rheumatism's treatment / 中华风湿病学杂志

Objective To study influencing factors in patients with rheumatic diseases.Methods One hundred and twenty patients with rheumatic diseases were selected from November 2013 to February 2014 in our hospital for the study.The influencing factors in patients with rheumatic diseases were obtained by proposed questionnaires,and then the univariate and multivariate Logistic regression analysis were performed to study factors affecting the treatment.Results Patients older than 50 of the observation group accounted for 38％ (18/48),the proportion of farmer,patients with primary school education level or below,and monthly income ＜3 000 RMB was 35％(17/48),60％(29/48),and 46％ (22/48) respectively.Compared with the control group,they were significantly higher than the control group,which were 64％(46/72),58％ (42/72),79％(57/72),65％(47/72) (x2=8.058,P=0.005; x2=6.025,P=0.014; x2=4.986,P=0.226; x2=4.456,P=0.035) respectively.Using the treatment as the dependent variable,age ≥50 years of age,farmer,primary school and lower education level,and monthly income ＜3 000 RMB as the independent variable,we carried out the regression analysis.Age (OR=1.124,95％CI:1.084-7.236),occupation (OR=1.871,95％CI:1.054-7.243),education level (OR=1.982,95％CI:1.157-6.256),monthly income (OR=1.363,95％CI:1.012-8.227) are the influencing factors of rheumatism's treatment.Conclusion The treatment of rheumatic diseases are influenced by many factors,and more societal support should be provided to help patients with rheumatic disease receive professional treatment and better control of the disease.

Recognizing the vaccination strategy of pertussis according to the family aggregation feature of transmission / 中华流行病学杂志

<p><b>OBJECTIVE</b>To understand the age distribution of pertussis patients admitted in the children hospital and to analyze the source of infection as well as its transmission patterns.</p><p><b>METHODS</b>Patients visiting to the Children Hospital and epidemiologically related cases during Feb. 2012 to Aug. 2013 were tested to confirm the diagnosis. Excel 2007 software was used to analyze the age distribution and clinical symptoms of clinic cases, the source of infection or subsequent cases.</p><p><b>RESULTS</b>165 out of 254 clinically suspicious pertussis cases and 38 out of the 54 epidemiologically related cases were confirmed of having pertussis infection. There were 138 (83.6%) cases under 1 year of age in the confirmed clinical cases and 36 (94.7%) cases older than 20 years of age among the confirmed epidemiologically related pertussis cases. All the confirmed epidemiologically related cases were misdiagnosed or missed for diagnosis. As the source of pertussis infection in confirmed clinical cases, parents played an imported role among 25 of the 32 cases. Transmission from infants and/or little children to adults were also observed in this study.</p><p><b>CONCLUSION</b>Infants accounted for the most among the pertussis patients that visiting the clinics. Adults, being misdiagnosed or missed diagnosed, were the main sources of infection to infants. Epidemics of pertussis occurred under family aggregation. Further study was in need to develop the proper strategy for pertussis booster vaccination.</p>

Sphingosine Kinase-1/sphingosine 1-phosphate pathway in diabetic nephropathy / 中华医学杂志(英文版)

<p><b>OBJECTIVE</b>Diabetic nephropathy (DN) is the major cause of end-stage renal disease worldwide and its prevalence continues to increase. Currently, therapies for DN provide only partial renoprotection; hence new targets for therapeutic intervention need to be identified. In this review, we summarized the new target, sphingosine kinase-1/sphingosine 1-phosphate (SphK1/S1P) pathway, explored its potential therapeutic role in the prevention and treatment of DN.</p><p><b>DATA SOURCES</b>Most relevant articles were mainly identified by searching PubMed in English.</p><p><b>STUDY SELECTION</b>Mainly original articles and critical review articles by major pioneer investigators in this field were selected to be reviewed.</p><p><b>RESULTS</b>SphK1/S1P pathway can be activated by hyperglycemia, advanced glycation end products, and many pro-inflammatory cytokines, which leads to fibronectin, transforming growth factor-β1 up-regulation and AP-1 activation. And then it could promote glomerular mesangial cells proliferation and extracellular matrix accumulation, mediating the initiation and progression of diabetic renal fibrosis.</p><p><b>CONCLUSIONS</b>SphK1/S1P pathway is closely correlated with the pathogenesis of DN. The results suggest that SphK1/S1P pathway as a new target for clinically improving DN in future is of great prospect.</p>

Discussion on training of non-technical skills (NTS) in critical care medicine based on high fidelity human patient simulator / 中华医学教育探索杂志

High fidelity human patient simulator has become more and more important in clinical medical practice education.Medical circle has more and more realized that non-technical skill (NTS) is closely associated with the improvement of medical quality.This paper attempted to carry out a preliminary discussion on theory and practice of applying NTS in simulation training of critical care medicine based on their own teaching experiences.

Exploration and practice of opening selective course of basic clinical skill / 中华医学教育探索杂志

Objective To explore an effective method for enhancing basic clinical skill of students.Methods Selective course of basic clinical skill was launched for the fourth grade clinical medicine students by using simulation-based medical education (SBME).Elective courses have 21 class hours,involving 15 items of basic clinical skills in internal medicine,surgery and nursing.Training methods include preparation,explanation,demonstration,operation,group competition,examination and questionnaire.Selective course examination includes class activation and final examination,accounting for 20％ and 80％ of the final scores,respectively.Scores were classified into A (excellent),B (good) and C (moderate) levels.Scores and questionnaire data were processed by Microsoft Office Excel 2007 software and percentages of score and questionnaire feedback were calculated.Results Results suggested that the scores of 70％ students were more than 90.Results of questionnaire indicated that the basic clinical skills of 76.6％ of the students were improved a lot.79.2％ considered that it was useful for their clinical practices.Conclusion Clinical-skill course based on SBME is conducive to enhancing basic clinical skills of students.

The predictive value of drug resistance gene detection for the prognosis of patients with pulmonary tuberculosis / 中华传染病杂志

Objective To identify drug resistance status of Mycobacterium tuberculosis (MTB) strains by the GenoType MTBDRplus line-probe assay (LPA),compare its performance with traditional drug susceptibility testing (DST),and to assess its predictive value for the prognosis of patients with drug resistance tuberculosis.Methods Pulmonary tuberculosis patients who visited Zhuji People's Hospital,Zhejiang Province during February 2011 and January 2012 with a positive result of sputum smear at baseline were all recruited.A total of 275 culture positive specimens were collected,then isolated and cultured for Mycobacterium tuberculosis in the laboratory.DST were performed,meanwhile,GenoType MTBDRplus were also applied to detect resistance to isoniazid (INH) and rifampin (RMP).All the tuberculosis patients who were recruited were followed,including sputum culture and chest radiography.Results There were 192 strains showing drug resistance both by DST and MTBDRplus LPA.Fourteen multidrug resistant (MDR),21 INH mono-resistant and 2 RMP mono-resistant strains were detected by DST.As for GenoType MTBDRplus LPA,MDR,INH mono-resistant and RMP mono-resistant strains were 14,18 and 2,respectively.Taken DST as the gold standard,LPA was more accurate in the detection of resistance to RMP,while it failed to detect 23.8％ (5/21) of the INH-resistant strains.We analyzed the prognosis of patients with drug resistance by GenoType MTBDRplus LPA,the rates of treatment success were 84 ％ (110/131),9/15,3/11 in patients infected with susceptible,INH mono-resistant and MDR strains,respectively.For the 2 cases of RMP mono-resistanee,one was cured and the other failed.The predictive value of molecular drug resistance test for treatment failure in INH mono-resistant patients was 40.0 ％,while that was 83.5 ％ for treatment success in INH susceptible patients.The predictive value for treatment failure in RMP mono-resistant patients was 50.0％,while that was 81.5％ for treatment success in RMP susceptible patients.The predictive value for treatment failure in MDR patients was 72.7％,while that was 81.1％ for treatment success in patients without MDR.Conclusion The GenoType MTBDRplus LPA assay is a rapid and reliable diagnostic test for resistance of MTB,which can be used to predict the prognosis of drug resistant tuberculosis in the clinical practice.

Add-on adefovir dipivoxil versus switch-to entecavir therapy in chronic hepatitis B patients with suboptimal response to lamivudine / 中华临床感染病杂志

Objective To compare the efficacy of add-on adefovir dipivoxil (ADV) therapy and switch-to entecavir (ETV) monotherapy in chronic hepatitis B (CHB) patients with suboptimal response to lamivudine (LAM).Methods A prospective study was performed in 120 CHB patients from Zhuji People' s Hospital and the First Affiliated Hospital of Zhejiang University School of Medicine during June 2010 and June 2011.All patients previously received more than 24 weeks LAM treatment,but HBV DNA was still positive.Patients were randomized assigned to two groups:60 patients received add-on ADV therapy and another 60 switched to ETV monotherapy.Both groups were treated for 48 weeks.Liver and kidney function,alpha-fetal protein (AFP),HBV serum markers,HBV DNA and prothrombin time (PT) were examined,and ultrasonography or CT scan of liver was performed every 1-3 months.x2 test was used to compare the HBV DNA negative rates,HBeAg seroconversion rates,resistance rates and adverse reaction at week 48 between two groups.Results Thirty-three out of 38 patients (86.8％) with baseline HBV DNA 103-105 copies/mL became HBV DNA negative after add-on ADV treatment for 48 weeks,twenty-seven out of 39 patients (69.2％) with baseline HBV DNA 103-105 copies/ml became HBV DNA negative after switch-to ETV treatment.There was a statistical difference between two groups (x2 =4.578,P ＜ 0.05).Sixteen out of 22 patients (72.7％) with baseline HBV DNA ＞ 105 copies/mL became HBV DNA negative after add-on ADV treatment for 48 weeks,while only 52.4％ (11/21) patients achieved HBV DNA negative in the switch-to ETV group.There was also a statistical difference between two groups (x2 =4.865,P ＜0.05).None of patients in add-on group developed virological breakthrough and resistance,while 5 patients in switch-to ETV group developed virogical breakthrough and 3 patients developed genetic mutation.Among them,rtM204V + rtL180M + rtS202G mutation was detected in 2 patients,and rtM204V + rtL180M +rtT184A mutation was detected in 1 patient; all mutations happened in the baseline HBV DNA ＞ 105 copies/mL group.Conclusion The add-on ADV therapy is better in viral inhibition than switch-to ETV therapy for CHB patients with suboptimal response to LAM,and it can reduce the occurrence of drug resistance.

Humanistic spirit cultivation of the medical students during the clinical internship / 中华医学教育探索杂志

The clinical internship is an important transitional period for humanistic spirit cultivation of the medical students.But in this period there are some problems exposed.For example,there is the lack of transitional link in management; the clinical instruction doctors lack educational consciousness or guidance ability,the medical students pay little attention to enhancing the individual humanistic spirit level and there is a gap between theory and practice of humanistic spirit for them.Strengthening training for students,attaching importance to training,selection and incentive of clinical instruction doctors and revising handbook of clinical internship will help to solve the problems.

Practice and thinking of assessment scale design for simulated clinical skills examination / 中华医学教育探索杂志

This article described systematically the design basis,passing standard and influential factor of test score of the assessment scale of simulated clinical skills examination.Through developing and modifying OSCE examination scale design for many years,we have found that the use of 360-degree assessment for designing OSCE assessment rating scale can effectively reduce the impact on the score of examinee owing to the environment,the candidates,raters and question design,which has an important role for scientific development of OSCE assessment scales,as well as improving the reliability and validity for development of a scientific OSCE assessment.

Dissociation and Recombination Mechanism of Ferritin Subunits in the Liver of Sphyrna Zygaena / 分析化学

Liver ferritin of Sphyrna zygaena(SZLF) with purity of mass spectrum was prepared in batch. Under) the condition of acidifying medium at pH 1.0, PAGE showed that SZLF subunits treated for 20 min began) to dissociate. A whole process of subunit dissociation and recombination was monitored by transmission electron microscopy(TEM). In addition, the changes of size of both protein shell and iron core were also determined) by TEM directly. It was found that in the acid dissociation process of SZLF subunits, the size of iron) core and protein shell showed the same trend of change, which might be related to not only the iron release) of inner iron core but the dissociation and unfolding of the protein shell. The passway of SZLF recombination is a fast step, which is a conversion process from incompact moltenglobule to compact ferritin. Under the assistant of matrix acidity pH 3.0 and laser, SZLF mixed with horse spleen ferritin(HSF) still has capacity to release) its subunits to form subunit ions for mass analysis by a MALDI-TOF mass spectrometer, which indicates that the interaction intensity between the subunits was weaken but they were not unfolded under this pH condition. TEM technology can be applied in studying both dissociation and recombination in ferritin subunits.

The detection of interleukin-33 and the correlated research of interleukin-33 and early rheumatoid arthritis / 中华风湿病学杂志

Objective To analyze the correlation between serum interleukin (IL)-33 and early rheumatoid arthritis (RA) by testing the serum IL-33 of patients with RA.Methods One hundred patients with early RA whose disease duration was less than 1 year were selected,40 patients with osteoarthritis (OA) and 70 healthy controis were selected.The serum IL-33 levels of the three groups were detected by enzyme-linked immunosorbent assay (ELISA).The correlation between serum IL-33 levels and clinical features of patients with RA were analyzed.Kruskal-Wallis test,Mann-Whitney U test,X2 test and Spearman correlation analysis were used for statistical analysis. Results The level of serum IL-33 in RA patients [(282±871)pg/ml ] was significantlv higher than that of the healthy controls [(7±38) pg/ml,P<O.01 ] and OA patients [(8±35)pg/ml,P<0.01].The levels of serum IL-33 in RA patients were related with rheumatoid factor (RF),occult rheumatoid factor immunoglobulin G (HRF-IgG),anti-cyclic citrullinated peptide antibodies (anti-CCP),anti-mutated citrullinated vimentin antibodies (anti-MCV).The positive rate of RF,HRF-IgG,anti-CCP and anti-MCV in IL-33 positive group (86%,31%,86%,94%) was significantly higher than that of the IL-33 negative group (54%,11%,42%,72%)(P<0.05).Conclusion The level of serum IL-33 is significantly elevated in RA and it is significanfly associated with some of the auto-antibodies (including RF,anti-CCP antibodies,anti-MCV antibodies and HRF-IgG).Thus,IL-33 may be a factor for unfavorable prognosis to RA patients.