Design, synthesis and evaluation of phenoxyacetic acid-based PTP1B inhibitors / 药学学报

Protein tyrosine phosphatase (PTP) 1B is a potential therapeutic target for type 2 diabetes. Phosphotyrosine (pTyr) mimetics still dominate the currently available PTP1B inhibitors. The phenoxyacetic acid moiety was taken as a pTyr mimetic herein and phenoxyacetic acid-based compounds 2a-2g and 3a-3c were designed. Among them, compounds 2a-2g exhibited potent inhibition against PTP1B, and compound 2g showed an IC50 of 0.42 μmol·L-1 against PTP1B. Compound 2f exhibited pharmacological profiles similar to that of rosiglitazone, and could improve the insulin sensitivity and the serum total cholesterol level. The results suggest that PTP1B inhibitors might be effective in treating type 2 diabetes as well as associated metabolic syndromes.

Effects of unsafe sexual behavior and sexual orientation on previous HIV testing and HIV testing willingness among college students in Harbin / 中华流行病学杂志

Objective: To analyze the effects of unsafe sexual behavior and sexual orientation on previous HIV testing and HIV testing willingness among college students in Harbin, to provide a theoretical basis for promoting and promoting HIV testing among them. Methods: A cross-sectional survey design was used to place the automatic vending machine of HIV urine test kit in 9 universities in Harbin from December 2017 to January 2018. The questionnaire star was used to design and recruit college students to carry out an anonymous online survey. The estimated sample size was 6 659. A multivariate logistic regression model was used to analyze the effects of unsafe sexual behavior and sexual orientation on previous HIV testing and HIV testing willingness among college students. WPS 2016 was used to sort out the database, and SPSS 21.0 software was used for statistical analysis. Results: A total of 60 849 valid questionnaires were collected. 19.1% (11 189/58 605) of college students reported having sex. College students who used condoms correctly every time, occasionally or never during sex in the past six months 58.5% (6 206/10 603), 25.2%(2 669/10 603)and 16.3% (1 728/10 603), respectively. Heterosexuality, homosexuality and bisexuality accounted for 94.1% (54 393/57 823), 2.4% (1 369/57 823) and 3.5% (2 061/57 823), respectively. The HIV testing willingness of college students was 73.3% (44 572/60 849). The proportion of previous HIV testing was 10.3% (951/9 241). Results of the multivariate logistic analysis showed that compared with the college students who used condoms correctly whenever they had sex in the past six months, there was no significant difference in the proportion of previous HIV testing among college students who sometimes/occasionally used or never used condoms (OR=0.94,95%CI:0.69-1.29; OR=1.11,95%CI:0.73-1.67), but their willingness to HIV testing was lower (OR=0.79, 95%CI:0.71-0.89; OR=0.48, 95%CI:0.42-0.55); Compared with heterosexual college students, homosexual or bisexual college students have a higher proportion of previous HIV testing (OR=2.62, 95%CI:1.62-4.24; OR=2.04, 95%CI:1.25-3.32), but have lower HIV testing willingness (OR=0.76, 95%CI: 0.62-0.93; OR=0.64, 95%CI: 0.53-0.77). Conclusions: Unsafe sexual behavior existed among college students in Harbin, and college students with weak awareness of HIV prevention also have weak awareness of testing. Behavioral intervention should be strengthened and HIV testing promoted. Compared with heterosexuals, homosexual or bisexual college students had a higher proportion of previous HIV testing, but their willingness to test was lower. The HIV detection mode with better concealment, accuracy, and convenience should be promoted on the college's campus.

Recent studies on the natural products with xanthine oxidase inhibitory effect / 药学学报

Xanthine oxidase (XOD), catalyzing purine metabolism, is the key enzyme in uric acid (UA) biosynthesis, and becomes an important target for hyperuricemia treatment. The inhibition on XOD plays an important role in the treatment of hyperuricemia-related diseases, such as gout, as well as oxidative stress-induced tissue injury. Here, studies on the natural products with XOD inhibition are reviewed.

Clinical characteristics of liver, kidney and coagulation injury in elderly patients with novel coronavirus pneumonia (COVID-19) / 上海预防医学

Objective To evaluate the clinical features and clinical outcome of liver, kidney and coagulation injury in patients with novel coronavirus pneumonia (COVID-19), especially in those elderly COVID-19 patients. Methods Clinical data of 72 COVID-19 patients admitted to the Shanghai Public Health Clinical Center from January 20, 2020 to April 20, 2020 was collected, including demographic data, clinical symptoms, laboratory testing results, underlying comorbidities, discharge and death, and then conducted the analysis stratified by clinical severity and age. Results Of the 72 COVID-19 patients, 27 were critically ill and 45 were mild.There were 31 elderly patients (≥60 years old) and 41 young patients (< 60 years old).Fever (83.3%), cough (36.1%) and fatigue (23.6%) were the most common clinical symptoms.The median age of the patients was 56.1 years (15-80 years); the mean age of mild and critically ill patients were 47.4 years and 64.6 years, respectively.The proportion of critically ill cases in the elderly group and the young group was 67.7% (21/31) and 14.6% (6/41), respectively.Organ injury in elderly patients included significantly increased aspartate aminotransferase, creatinine D-dimer, and FDP) (P < 0.05).Of the patients, the length of hospital stay of the elderly patients was significantly longer (P < 0.001), and the mortality increased significantly (P < 0.05). Conclusion Elderly COVID-19 patients have severe liver, kidney and coagulation injury, which may induce longer duration of hospital stay and increased mortality.Therefore, elderly COVID-19 patients may have worse clinical outcome.

Experimental study of bicyclol for type 2 diabetic treatment using KKAy mice / 药学学报

To investigate the effects of small molecule compound bicyclol on type 2 diabetes mellitus (T2DM) and its mechanism of action, KKAy mice were treated with various doses of bicyclol (100, 200, and 400 mg·kg-1·d-1) with metformin (200 mg·kg-1·d-1) as a positive control, respectively. Age-matched C57BL/6J mice were used as the non-diabetic control (Con). The effect on hyperglycemia was evaluated by the levels of no-fasting blood glucose, fasting blood glucose (FPG), and glucose tolerance. Whole body insulin sensitivity was evaluated by fasting plasma insulin (FPI) and homeostasis model assessment-insulin resistance (HOMA-IR). The hepatic response to insulin was evaluated by insulin-induced activation of insulin signaling pathway. Western blot was performed to detect hepatic protein expressions. All animal experimental procedures were approved by the Animal Ethics Committee of Chinese Academy of Medical Sciences. KKAy mice showed T2DM characteristics such as hyperglycemia and insulin resistance, including attenuated response to insulin in the liver. A 28-day treatment of bicyclol suppressed both FPG and no-fasting blood glucose, in a dose- and time-dependent manner. Moreover, FPI and HOMA-IR values were both significantly decreased, and hepatic insulin-induced-phosphorylation of IRβ and Akt were up-regulated in KKAy mice after bicyclol treatment. Phosphorylation of FoxO1, the key transcription factor for regulating gluconeogenesis, was also significantly elevated by bicyclol treatment. These results suggested that bicyclol has some therapeutic effects on hyperglycemia in a time- and dose-dependent manner in KKAy mice. Its mechanism might be attributed to improving insulin resistance, enhancing hepatic insulin signaling pathway, and inhibiting gluconeogenesis. No significant interference on the hypoglycemic effect of metformin by bicyclol was observed in this study.

Analysis of serum specific IgE in children with allergic conjunctivitis and associated allergic diseases / 国际眼科杂志(Guoji Yanke Zazhi)

·AIM: To investigate the distribution of serum specific IgE in children with allergic conjunctivitis and associated allergic diseases. ·METHODS: Retrospective analysis of 708 cases of allergic conjunctivitis in children, according to age divided into the infant group (2 months to 1 years old) 232 cases, the children group (>1 years to 3 years old) 255 cases and the preschool group (>3 years to 6 years old) 221 cases. A automatic in vitro detection system was used to detect serum inhaled allergens and food allergen specific IgE by immune capture method. A questionnaire survey was conducted to investigate the associated allergic diseases and consultation with relevant departments. ·RESULTS: The sIgE positive rate was the lowest in the infant group (87.1%). There were significant differences in the number of sIgE positive species in the infant group compared with those in the other two groups (χ2=10. 96, 21. 78; P<0. 01). The most common allergens in all three groups were milk, egg white and household dust mites, and the positive rate of SIgE in milk was higher in the infant group than in the other two groups. The positive rate of sIgE in dust mites, house dust, tree pollen, mulberry, dog fur, egg white, pineapple and mango were higher in the preschool group than in the other two groups. The positive rate of 3-6 grade sIgE in household dust mites and house dust were higher in preschool group than that in the other two groups (P<0. 01). The infant group had the highest proportion of gastrointestinal allergy (28. 9%). The preschool group had the highest proportion of allergic rhinitis. The proportion with more than three kinds of allergic diseases in children group was higher than that of the other two groups(P<0. 01). ·CONCLUSION: With the increase of age, the positive rate and types of allergen in children with allergic conjunctivitis increased gradually. House dust mites become the primary inhalation allergen from infancy. Allergic diseases associated with allergic conjunctivitis in children are consistent with allergic march.

Detection of Subclinical Anthracyclines' Cardiotoxicity in Children with Solid Tumor / 中华医学杂志(英文版)

<p><b>Background</b>Cardiotoxicity is one of the most serious chronic complications of anthracyclines therapy. Assessment of the left ventricular ejection fraction (LVEF) fails to detect subtle cardiac dysfunction of left ventricular (LV). This study aimed to detect and evaluate new parameters of subclinical anthracyclines' cardiotoxicity in children with solid tumor.</p><p><b>Methods</b>A detailed echocardiographic examination was performed in 36 children with hepatoblastoma or rhabdomyosarcoma after receiving anthracyclines' chemotherapy and 36 healthy controls from January 2015 to December 2016. The LVEF, ratio of early diastolic peak velocity of transmitral flow (E) and septal diastolic e' mitral annular peak velocity (e'), tricuspid annular plane systolic excursion (TAPSE), and LV global longitudinal strain (GLS) were evaluated using M-mode, tissue Doppler imaging (TDI), and two-dimensional speckle tracking echocardiography (2D-STE), respectively. Echocardiographic parameters were compared between patient group and healthy controls. All patients were divided into two subgroups based on their anthracyclines' cumulative dosage (<300 mg/m subgroup and ≥300 mg/m subgroup).</p><p><b>Results</b>All patients had no presentation of heart failure and LVEF within normal range (65.7 ± 5.1%). Compared with healthy controls, the mean E/e' increased significantly (7.9 ± 0.7 vs. 10.2 ± 3.5, t = 3.72, P < 0.01), mean TAPSE decreased significantly (17.2 ± 1.3 mm vs. 14.2 ± 3.0 mm, t = -4.03, P < 0.01), and mean LV GLS decreased significantly (-22.2% ± 1.9% vs. -17.9% ± 2.9%, t = -5.58, P < 0.01) in patient group. Compared with subgroup with anthracyclines' cumulative dosage < 300 mg/m, mean LV GLS decreased significantly (-18.7 ± 2.7% vs. -16.5 ± 2.1%, t = 2.15, P = 0.04), the mean E/e' increased significantly (9.1 ± 1.5 vs. 11.5 ± 4.9, t = -2.17, P = 0.04), and mean TAPSE decreased significantly (14.2 ± 2.1 mm vs. 12.5 ± 2.2 mm, t = -2.82, P = 0.02) in subgroup with anthracyclines' cumulative dosage ≥300 mg/m.</p><p><b>Conclusions</b>LV GLS is helpful in the early detection of subclinical LV dysfunction using 2D-STE. E/e' and TAPSE are other sensitive parameters in detecting subclinical cardiac dysfunction of both ventricles by TDI. These parameters show significant change with different anthracyclines' cumulative dosage, so cumulative dosage should be controlled in clinical treatment.</p>

In Silico System Pharmacology for the Potential Bioactive Ingredients Contained in Xingnaojing Injection () and Its Material Basis for Sepsis Treatment / 中国结合医学杂志

OBJECTIVE@#To elucidate the action mechanism of Xingnaojing Injection (, XNJI) for sepsis, and to target screen the potential bioactive ingredients.@*METHODS@#An integrated protocol that combines in silico target screen (molecular docking) and database mapping was employed to find the potential inhibitors from XNJI for the sepsis-related targets and to establish the compound-target (C-T) interaction network. The XNJI's bioactive components database was investigated and the sepsis-associated targets were comprehensively constructed; the 3D structure of adenosine receptor A2a and 5-lipoxygenase proteins were established and evaluated with homology modeling method; system network pharmacology for sepsis treatment was studied between the bioactive ingredients and the sepsis targets using computational biology methods to distinguish inhibitors from non inhibitors for the selected sepsis-related targets and C-T network construction.@*RESULTS@#Multiple bioactive compounds in the XNJI were found to interact with multiple sepsis targets. The 32 bioactive ingredients were generated from XNJI in pharmacological system, and 21 potential targets were predicted to the sepsis disease; the biological activities for some potential inhibitors had been experimentally confirmed, highlighting the reliability of in silico target screen. Further integrated C-T network showed that these bioactive components together probably display synergistic action for sepsis treatment.@*CONCLUSIONS@#The uncovered mechanism may offer a superior insight for understanding the theory of the Chinese herbal medicine for combating sepsis. Moreover, the potential inhibitors for the sepsis-related targets may provide a good source to find new lead compounds against sepsis disease.

Development of a method to study the activity and selectivity of SGLT2 inhibitors / 药学学报

The purpose of this study was to develop a screening method to determine the activity and selectivity of SGLT2 inhibitor. Human SGLT1/SGLT2 cDNA was inserted into the pMSCVpuro mammalian expression vector and the plasmid was transfected into HEK293 cells. Stably transfected clones were selected in puromycin containing medium. To evaluate the expression of human SGLT1 and SGLT2 in stable transfected cells, RT-PCR, Western blot and immunofluorescence analysis were performed. 1-[N-(7-Nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-1-deoxy-D-glucose (1-NBDG) was used as a substrate in the uptake assay to evaluate the Na+ dependent glucose transport activities of SGLT1/2. The inhibitory activity and selectivity of dapagliflozin/phloridzin were also determined, respectively. The hypoglycemic efficacy of dapagliflozin was evaluated in mice with normal blood glucose and mice with alloxan-induced T1DM. The result showed that SGLT1 was overexpressed in pMSCVpuro-SGLT1 transfected HEK293 cells. SGLT2 protein was overexpressed in pMSCVpuro-SGLT2 transfected HEK293 cells and located in both cytoplasm and membrane. The Na+ dependent 1-NBDG uptake was significantly increased in pMSCVpuro-SGLT1/SGLT2 transfected cells compared to that in pMSCVpuro-null transfected cells. The selectivity of dapagliflozin, whose half maximal inhibitory concentration (IC50) for SGLT2 (2.24×10-10 mol·L-1) was far lower than that for SGLT1 (6.20×10-7 mol·L-1), was better than that of phloridzin. The oral glucose tolerance was elevated after a single dose of dapagliflozin in normal mice. In T1DM mice, compared with model group, no-fasting glucose level was decreased at 1 h after administration and maintained at a lower level for 24 h in a dose-dependent manner. A 20-day administration with dapagliflozin dose-dependently improved the hyperglycemia status. Taken together, a system to evaluate the activity and selectivity of SGLT2 inhibitors was established using 1-NBDG in vitro and the hypoglycemic efficacy in vivo in this study. The advantages of this system include non-radioactivity, high efficiency, and good stability which may provide a technique platform for development of novel SGLT2 inhibitors.

Investigating the effects of compound WS090152 on non-alcoholic fatty liver in mice / 药学学报

To investigate the effects and the mechanism of compound WS090152 on non-alcoholic fatty liver (NAFL), the compound was administrated in C57BL/6J mice fed a high fat diet at 50 mg·kg-1 by lavage. The lipid accumulation in liver was determined by the content of hepatic triglyceride (TG) and the histological pathological analysis. The levels of body weight gain, serum total cholesterol (TC) and TG were measured to evaluate lipid metabolism. Insulin sensitivity was determined by glucose infusion rate (GIR) value in hyperinsulinemic-euglycemic clamp test. The expression of related proteins in liver was measured by Western blot. The effect on the target protein tyrosine phosphatase 1B (PTP1B) was assessed by the activity of recombinate human PTP1B in vitro, and by the expressions of PTP1B in vivo, respectively. The content of hepatic TG (PPPPP50 value of 0.34 μmol·L-1; the expression of PTP1B was significantly downregulated, and the phosphorylation of its downstream insulin receptor (IR) and AKT was upregulated by WS090152 administration in the livers of NAFL mice. The expression of hepatic lipogenesis-related proteins-1c (SREBP-1c), fatty acid synthase (FAS), and acetyl-CoA carboxylase (ACC) was attenuated. These results suggest that compound WS090152 can ameliorate NAFL by increasing insulin sensitivity and decreasing hepatic lipogenesis probably through inhibition of PTP1B.

Prescription of Jingdan Yimin for treatment of metabolic syndrome / 中国中药杂志

Based on the theory of traditional Chinese medicine, modern methods for drug investigation such as molecular targets in vitro and effects in vivo were used to study the prescription of Jingdan Yimin(JD), including selection of raw materials, composition, proportion, and effective dose of the compounds for treatment of metabolic syndrome. The IRF mice models, characterized by insulin resistance and hypercholesterolemia, were induced by high fat diet. The insulin sensitivity was estimated with insulin tolerance test(ITT) and glucose tolerance test(GTT); the levels of blood glucose and total cholesterol(TC), and the activities of α-glucosidase, protein tyrosine phosphatase 1B(PTP1B), and fructose phosphate amide transferase(GFAT)were measured with biochemical methods, respectively. The sample H13(h) extracted from Rhodiola crenulata, Y12(y) from Cordyceps militaris, and D(d) from Rheum palmatum were selected according to the inhibition activity on both PTP1B and α-glucosidase in vitro, regulation on hypercholesterolemia in IRF mice, and effects on GFAT activity, respectively; their synergistic effects on the treatment of metabolic syndrome were determined in IRF mice; composition proportion of h∶y∶d was measured in accordance with the results of L8(27) orthogonal experiments targeting on the inhibition of both PTP1B and α-glucosidase; finally, the effective dose was assessed based on the effects on IGT and hypercholesterolemia, respectively, in IRF mice. In conclusion, the prescription JD is composed by R. crenulata, C. militaris, and R. palmatum with the rate of 20∶1∶1, and its effective oral dose is 200 mg•kg⁻¹ for treatment of metabolic syndrome; its main mechanism is to inhibit the targets PTP1B and α-glucosidase. Monarch drug, R. crenulata, can clear away the lung-heat, tonify Qi, resolve stasis and nourish the heart. Adjuvant drug, C. militaris, can tonify the lung Qi and the kidney essence, strengthen waist and knee, accompanied with R. crenulata to enhance the function of invigorating lung and kidney. Assistant drug, rhubarb, can clear heat, detoxify, and remove blood stasis. These three herbs are compatible to show the effects of tonifying Qi, nourishing essence, clearing heat, reducing phlegm and resolving masses for the treatment of metabolic syndrome.

In silico target fishing for the potential bioactive components contained in Huanglian Jiedu Tang (HLJDD) and elucidating molecular mechanisms for the treatment of sepsis / 中国天然药物

The present study was designed to target fish for potential bioactive components contained in a Huang Lian Jie Du decoction (HLJDD) and identify the underlying mechanisms of action for the treatment of sepsis at the molecular level. he bioactive components database of HLJDD was constructed and the sepsis-associated targets were comprehensively investigated. The 3D structures of the PAFR and TXA2R proteins were established using the homology modelling (HM) method, and the molecular effects for sepsis treatment were analysed by comparing the bioactive components database and the sepsis targets using computational biology methods. The results of the screening were validated with biological testing against the human oral epidermal carcinoma cell line KB in vitro. We found that multiple bioactive compounds contained in the HLJDD interacted with multiple targets. We also predicted the promising compound leads for sepsis treatment, and the first 28 compounds were characterized. Several compounds, such as berberine, berberrubine and epiberberine, dose-dependently inhibited PGE2 production in human KB cells, and the effects were similar in the presence or absence of TPA. This study demonstrates a novel approach to identifying natural chemical compounds as new leads for the treatment of sepsis.

Potency Material Bases of Xuebijing Formula and Its Multi-target Effects on Sepsis / 中国中西医结合杂志

<p><b>OBJECTIVE</b>To explore potency material bases of Xuebijing (XBJ) formula, and to analyze its effects at the molecular network level.</p><p><b>METHODS</b>Totally 16 sepsis-related targets were selected and classified into three categories such as inflammation, immune, and coagulation referring to biological roles. Then molecular database of chemical compositions in XBJ formula were constructed to explore mutual actions with inflammation, immune, and coagulation targets.</p><p><b>RESULTS</b>Danshen root and safflower, with more effector molecules with immune and coagulation targets, have extensive anticoagulation and anti-inflammation effects. The former 10 molecules with better mutual actions with sepsis targets were sequenced as tryptophane, danshensu, gallic acid, salvianolic acid D, protocatechuic acid, salvianolic acid A, danshensu C, vanillic acid, rosmarinic acid, phenylalanine. There existed two phenomena in XBJ formula as follows. One component had stronger actions with multi-targets, for example, danshensu had actions with 13 targets. Meanwhile, different components acted on the same target protein, for example, 8 molecules acted with MD-2.</p><p><b>CONCLUSION</b>XBJ formula had certain potential synergistic effects with sepsis targets, which could provide certain referential roles for findina new type anti-septic drugs.</p>

Role of Gonadotropin-releasing Hormone Stimulation Test in Diagnosing Gonadotropin Deficiency in Both Males and Females with Delayed Puberty / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Delayed puberty can result either from constitutional delay of growth and puberty (CDP) or idiopathic hypogonadotropic hypogonadism (IHH). Gonadotropin-releasing hormone (GnRH) stimulation test has been generally accepted as a current method for diagnosing delayed puberty. The objective of this research was to assess the cut-off values and the efficacy of GnRH stimulation test in the diagnosis of delayed puberty in both males and females.</p><p><b>METHODS</b>A study of 91 IHH, 27 CDP patients, 6 prepubertal children, and 20 pubertal adults was undertaken. Blood samples were obtained at 0, 30, 60, and 120 min after GnRH administration and the levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) were measured. For each parameter, the sensitivities and specificities were estimated, and the receiver operating characteristic (ROC) curves were constructed.</p><p><b>RESULTS</b>The ROC curves indicated that a serum basal LH <0.6 IU/L or peak LH <9.74 IU/L resulted in moderate sensitivity (73.8% or 80.0%) and specificity (90.9% or 86.4%) in the diagnosis of HH in males. Serum basal LH <0.85 IU/L or basal FSH <2.43 IU/L resulted in moderate sensitivity (80.0% or 100.0%) and specificity (75.0% or 50.0%) in the diagnosis of HH in females.</p><p><b>CONCLUSIONS</b>Our data suggest that isolated use of the gonadorelin stimulation test is almost sufficient to discriminate between HH and CDP in males, but unnecessary in females. The most useful predictor is serum basal or peak LH to differentiate these two disorders in males, but serum basal LH or FSH in females.</p>

α-GalCer reduces Acute Graft-versus-Host Disease by Altering Donor T Cells Migration / 中国实验血液学杂志

<p><b>OBJECTIVE</b>This study was aimed to explore the new mechanism of α-Galactosyleramide (α-GalCer), a synthetic glycolipid, and a well-known activator of natural killer T cells (NKT) for improving acute graft-versus-host disease(aGVHD).</p><p><b>METHODS</b>Murine allogeneic bone marrow transplantation (allo-BMT) model was established. Recipient mice were injected intraperitoneally with α-GalCer immediately after allo-BMT, whereas mice from the vehicle groups received the diluent (DMSO) only. The severity degree of aGVHD was estimated by survival, aGVHD clinical score and pathology. The mechanism of aGVHD reduced by α-GalCer was explored by detecting T cells migration in vivo and in vitro.</p><p><b>RESULTS</b>Mice in α-GalCer group survived longer than in control group, and their clinical and pathological status of aGVHD were lighter. α-GalCer reduced aGVHD by altering donors T cell migration.</p><p><b>CONCLUSION</b>After allo-BMT α-GalCer reduces aGVHD by altering donor T cells migration.</p>

The effects of compound CX09040 on the inhibition of PTP1B and protection of pancreatic β cells / 药学学报

To investigate the effects of 2-(4-methoxycarbonyl-2-tetradecyloxyphenyl)carbamoylbenzoic acid (CX09040) on protecting pancreatic β cells, the β cell dysfunction model mice were induced by injection of alloxan into the caudal vein of ICR mice, and were treated with compound CX09040. Liraglutide was used as the positive control drug. The amount and the size of islets observed in pathological sections were calculated to evaluate the β cell mass; the glucose stimulated insulin secretion (GSIS) test was applied to estimate the β cell secretary function; the oral glucose tolerance test (OGTT) was taken to observe the glucose metabolism in mice; the expressions of protein in pancreas were detected by Western blotting. The effects on the target protein tyrosine phosphatase 1B (PTP1B) were assessed by the PTP1B activities of both recombinant protein and the intracellular enzyme, and by the PTP1B expression in the pancreas of mice, separately. As the results, with the treatment of CX09040 in alloxan-induced β cell dysfunction mice, the islet amount (P<0.05) and size (P<0.05) increased significantly, the changes of serum insulin in GSIS (P<0.01) and the values of acute insulin response (AIR, P<0.01) were enhanced, compared to those in model group; the impaired glucose tolerance was also ameliorated by CX09040 with the decrease of the values of area under curve (AUC, P<0.01). The activation of the signaling pathways related to β cell proliferation was enhanced by increasing the levels of p-Akt/Akt (P<0.01), p-FoxO1/FoxOl (P<0.001) and PDX-1 (P<0.01). The effects of CX09040 on PTP1B were observed by inhibiting the recombinant hPTP1B activity with IC50 value of 2.78x 10(-7) mol.L-1, reducing the intracellular PTP1B activity of 72.8% (P<0.001), suppressing the PTP1B expression (P<0.001) and up-regulating p-IRβ/IRβ (P<0.01) in pancreas of the β cell dysfunction mice, separately. In conclusion, compound CX09040 showed significant protection effects against the dysfunction of β cell of mice by enlarging the pancreatic β cell mass and increasing the glucose-induced insulin secretion; its major mechanism may be the inhibition on target PTP1B and the succedent up-regulation of β cell proliferation.

The hepatic ChREBP expression and hyperinsulinemia in mice / 药学学报

To explore the effects of serum insulin on the expression of ChREBP, ACC and FAS in vivo, KKAy mice which were characterized with high levels of both serum insulin and glucose and DIO mice which were characterized with high serum insulin level alone were utilized, separately. The age-matched C57BL/6J mice fed with standard chow were used as normal control (Con). Expressions of hepatic ChREBP, ACC and FAS were detected by Western blotting. As the results, in KKAy mice, a positive correlation between the levels of serum insulin and glucose (r = 0.902, P < 0.000), as well as between the levels of serum insulin and TG (r = 0.732, P < 0.000), was observed. Meanwhile, the expressions of hepatic ChREBP, ACC and FAS increased significantly and accompanied with its hyperinsulinemia and hyperglycemia, separately. In DIO mice, correlation between the levels of serum insulin and TG (r = 0.722, P < 0.001) also showed positive, and the expressions of hepatic ChREBP, ACC and FAS increased significantly and also accompanied with its hyperinsulinemia. However, their blood glucose values were almost normal. These demonstrated that hyperinsulinemia may cause glycolipid metabolic disorders by up-regulating the expression of ChREBP in vivo.

Establishment of an ultrasonographic method for evaluating the hepatic lipid accumulation in mice / 药学学报

To investigate the semi-quantitative method for evaluating lipid accumulation in livers, male C57BL/6J mice (CON), HFD mice characterized with the mild fatty liver induced by high-fat diet, and KKAy mice charactered with the moderately severe fatty liver induced by high-caloric diet were used. The lipid accumulation was estimated by the histological examination (HE staining) and the content of hepatic triglyceride, separately. Echo-intensity of two selected regions along the ultrasound transmission direction was recorded using a small animal ultrasonographic system, and the echo-intensity attenuation coefficient was calculated. Correlation between the echo-intensity attenuation coefficient and the content of hepatic triglyceride was analyzed by the Spearman's rank correlation analysis. The results showed that the lipid accumulation in livers increased significantly in both HFD and KKAy mice compared with CON mice and it was more serious in KKAy mice than that in HFD mice. The values of echo-intensity attenuation coefficient were also increased in sequence according to group. These values were positively associated with the content of hepatic triglyceride (r = 0.744, P < 0.01). In conclusion, the echo-intensity attenuation coefficient is a simple, impersonal, and non-invasive method for evaluating the hepatic lipid accumulation. It can be used to research the process and the treatment of fatty liver diseases in mice.

The clinical application of two-and three-dimensional ultrasonography in the prenatal diagnosis of fetal hand deformity / 中华医学超声杂志（电子版）

Objective To summarize the characteristics of fetal hand deformity in prenatal two-and three-dimensional u1trasonography. To analyze the causes of missed diagnosis of prenatal u1trasonography in detecting fetal hand deformity. Methods Systematic continuous sequence approach was performed with two-and three-dimensional u1trasonography in 11 854 cases to detect the fetal hand development, deformity and accompanied malformations. Prenatal sonographic features of fetal hand deformities (59 cases) were correlated with the morphology and X-ray characteristics of the delivered fetuses. Results Fifty-nine cases of fetal hand deformity were diagnosed out of 11 854 fetuses by prenatal u1trasonography:44 cases of abnormal wrist posture,1 case of full-ifnger absence, 2 cases of metacarpal and phalanx absence, 3 cases of clinodactyly, 2 cases of forearm and hand absence, 1 case of syndacty, 1 case of polydacty, 5 cases of lethal bone dysplasia. The detection rate was 0.50%(59/11 854). Eight cases were missed:3 cases of partial ifnger absence, 2 cases of clinodactyly, 1 case of syndacty, and 2 cases of polydacty. The rate of missed diagnosis is 11.90%(8/67). Abnormal wrist posture showed a hook-shaped hand in the wrist. Full-finger absence showed that one or multiple ifngers were absent. Metacarpal and phalanx absence showed no fetal hands. Clinodactyly showed that four ifngers were not in the same plane. Forearm and hand missing showed that ulna, metacarpal and phalangeal were absent. Syndacty showed a beak-like hand. Multi-ifnger indicated six ifngers in one hand. Lethal bone dysplasia showed very short limbs. Conclusions Prenatal u1trasonography played an important role in detecting and diagnosing severe type of fetal hand deformity. The detection rate of fetal hand deformities can be greatly improved by appropriate use of the scan-time, fetal position, systematic continuous sequence approach and real three-dimensional u1trasonography.

Gene polymorphisms of interleukin-28, p21-activated protein kinases 4, and response to interferon-α based therapy in Chinese patients with chronic hepatitis B / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Peg-Interferon-α treatment is expensive and associated with considerable adverse effects, selection of patients with the highest probability of response is essential for clinical practice. The objective of this study was to assess the relationship between the gene polymorphisms of interleukin-28 (IL-28), p21-activated protein kinase 4 (PAK4) and the response to interferon treatment in chronic hepatitis B patients.</p><p><b>METHODS</b>Two hundred and forty interferon-naive treatment HBeAg seropositive chronic hepatitis B patients were enrolled in the present prospective nested case-control study. Peripheral blood samples were collected, including 92 with favorable response and 148 without response to the interferon treatment. Rs8099917, rs12980602, and rs9676717 SNP was genotyped using matrix assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF MS).</p><p><b>RESULTS</b>IL-28 genotype was not associated with response to interferon treatment (OR for GT/GG vs. TT, 0.881 (95%CI 0.388 - 2.002); P = 0.762; OR for CT/CC vs. TT, 0.902 (95%CI 0.458 - 1.778); P = 0.766). Rs9676717 in PAK4 genotype was independently associated with the response (OR for CT/CC vs. TT, 0.524 (95%CI 0.310 - 0.888); P = 0.016). When adjusting for age, gender, smoking, drinking, levels of hepatitis B virus DNA, and alanine aminotransferase (ALT), rs9676717 genotype TT appeared to be associated with a higher probability of response for interferon treatment (OR, 0.155 (95%CI 0.034 - 0.700); P = 0.015).</p><p><b>CONCLUSION</b>Genotype TT for rs9676717 in PAK4 gene and no drinking may be predictive of the interferon-a treatment success.</p>