Inosine 5'-monophosphate dehydrogenase (IMPDH) is a key enzyme of de novo GMP biosynthesis. The expression and activity of IMPDH can be affected by diseases and physiological process. It is the drug target for anticancer, antiviral, antimicrobial and immunosuppressive therapeutics. Not only catalytic action but the other biological functions of IMPDH also play an important role in diseases. The basic functions, mechanism of catalysis, classification of inhibitors, biological functions and the latest advances to IMPDH will be illustrated in this review. It is expected to be helpful to the discovery of new inhibitors and biological functions of IMPDH.
Animals ; Binding Sites ; Catalysis ; Drug Design ; Drug Discovery ; Enzyme Inhibitors ; classification ; pharmacology ; Humans ; IMP Dehydrogenase ; antagonists & inhibitors ; genetics ; metabolism ; Inosine Monophosphate ; metabolism ; Molecular Structure ; NAD ; metabolism ; Polymorphism, Genetic

Objective To investigate the effects of goal‐directed volume therapy (GDVT )on the intracranial pressure(ICP) and the balance of cerebral oxygen consumption and supply in selective neurosurgery. Methods Twenty‐four patients sched‐uled for intracranial tumor resection were randomly divided into 2 groups:conventional fluid management group (group C ,n=12) and GDVT group(group G ,n=12). Patients in group C received introperative fluid transfusion according to classical fluid management strategies while those in group G received GDT according to stroke volume variation (SVV) ,guided by Flotrac‐Vigileo system.Mean arterial pressure(MAP) ,heart rate(HR) ,cardiac index(CI) ,ICP ,SVV and jugular bulb oxygen saturation (SjvO2 )were recorded before the anesthesia induction(T1 ) ,at the moment of intubation(T2 ) ,at the moment of opening the hard meninges(T3),1hafteropeningthehardmeninges(T4),andattheendofthesurgery(T5).Thecerebraloxygenextractionra‐tio(CERO2 )was calculated. The duration of surgery ,crystalloid volume ,colloid volume ,blood transfusion volume ,urinary output and bleeding volume were recorded as well.Results The colloid transfusion volume ,the total fluid transfusion volume and uri‐nary output were significantly increased in group G when compared with those in group C (P<0.05).MAP ,CI ,and SjvO2 were much higher and CERO2 were much lower at T4 and T5 in group G than in group C(P<0.05). There was no significant differ‐ence in the ICP at each time point between groups G and C (P>0.05).Conclusion Goal‐directed fluid therapy optimizes the cardiac preload without increasing the ICP in selective neurosurgery ,and it also improves the balance of cerebral oxygen con‐sumption and supply.

Objective To study the role of src-suppressed C kinase substrate (SSeCKS) in the secretion of tumor necrosis factor (TNF-α) in rat pulmonary micro-vascular endothelial cells (PMVEC) induced by lipopolysaccharide (LPS).Methods Wistar rat PMVEC cultured in vitro were randomly (random number) divided into several groups (n =4) as per exposure to given dosage of LPS for different lengths of time and to different dosages of LPS for given length of time.After PMVEC exposed to 10 mg/L LPS for 1 hour (h),3 h,6 h,12 h and 24 h or 0.1 mg/L,1 mg/L and 10 mg/L LPS for 24 h,the levels of TNF-αin the supernatant of culture medium were examined by the method of enzyme linked immunosorbent assay (ELISA).Another PMVEC was pre-treated by protein kinase C (PKC) inhibitor bis-indolylmaleimide (BIM) for 0.5 h or had the transfection of SSeCKS-specific small interfering RNA (siRNA) for 48 h before 10 mg/L LPS challenge for 24 h,and subsequently the supernatant was also examined by ELISA.One-way analysis of variance (ANOVA) was employed for statistical analysis by SPSS version 10.0 to compare values among all groups.A significant difference was presumed as a probability value ＜ 0.05.Results After PMVEC incubated with 0.1 mg/L,1 mg/L and 10 mg/L LPS for 24 hours,the levels of TNF-αsecreted were (253.70 ± 23.55),(327.88 ± 37.25),(403.20 ± 36.22),respectively,which were higher than that in un-stimulated PMVEC (82.28 ± 22.56,all P =0.000).After 10 mg/L LPS challenge for one hour,the level of TNF-αin the supernatant of PMVEC raised substantially (170.11 ±49.22),peaked at the time of 6 h (404.82 ± 13.78),then persisted at a higher level until 24 h (395.67 ± 36.23) than that in un-stimulated PMVEC (84.60 ± 23.61,P =0.001,0.000,0.000,respectively).After PMVEC pre-incubated with BIM,the level of LPS-induced TNF-αdecreased obviously (200.44 ± 27.39 vs.402.28 ± 31.07,P =0.000).Compared with LPS challenged PMVEC (407.28 ± 32.64),depletion of endogenous SSeCKS in PMVEC after inhibited by SSeCKS-siRNA significantly attenuated increase in the level of LPS-induced TNF-α (195.20 ± 13.28,P =0.000).Conclusions Down-activation of SSeCKS and PKC can inhibit the secretion of TNF-αin PMVEC induced by LPS,relieving the inflammatory response of PMVEC.

A series of oxazole[5,4-d] pyrimidine derivatives were designed and synthesized to discover novel compounds with antitumor activity.Compounds 8a-8m were synthesized using acetamidine hydrochloride as the start material.The structures of synthesized compounds were confirmed by IR,1H NMR,EI-MS and elemental analysis.The antiangiogenesis activities of the synthesized compounds were determined by MTT in human umbilical vein endothelial cell (HUVEC).The in vitro antitumor activities of the synthesized compounds were determined by MTT assay in A549,HepG2 and U251.Compounds 8c,8d,8g,8i and 8l were found to inhibit the proliferation of all the tested cell lines.Compound 8l exhibited noteworthy activities in A549,HepG2 and U251 cell lines with IC50value lower than the positive reference sunitinib,suggesting that compound 8l might be the promising antitumor agent for further investigation.

Aim To investigate the role of cAMP re-sponse element binding protein (CREB)in the injury of rat pulmonary microvascular endothelial cell (RPM-VEC)induced by LPS.Methods RPMVECs were i-solated and cultured in vitro,Western-blot was used to assay phosphorylation levels of CREB.Endothelial per-meability was determined by measuring the influx of Evans blue-labeled albumin across endothelial mono-layer.Results LPS increased CREB phosphorylation at Ser 1 3 3 in RPMVEC in a time-dependent manner , peaked at 30 min,but still higher at 120 min compared with basal control group.Pretreatment of cells with PKA inhibitor V5681 nearly suppressed the CREB phosphorylation stimulated in the presence of LPS,and the monolayer permeability of PMVEC was significantly increased. Conclusions LPS rapidly induces the phosphorylation of CREB in RPMVEC,and PKA me-diates the process.During the process of LPS-stimula-ted injury of RPMVEC,phosphorylation of CREB may play a protective role.

Penaeidin-2 (Pen-2) is an important antimicrobial peptide derived from the Pacific white shrimp, Penaeus vannamei, and possesses both antibacterial and antifungal activities. Recent studies suggest that recombinant penaeidins show similar activities to the native Pen-2 protein. Previous researches have shown that some antimicrobial peptides (AMPs) exhibit cytotoxic activity against cancer cells. To date, there have been no studies on the antitumor effects of Pen-2. This study evaluated the potential of recombinant pen-2 (rPen-2) in the selective killing of kidney cancer cell lines ACHN and A498, and its action mechanism. MTT assays found the maximal growth inhibition of HK-2, ACHN and A498 cells treated with 100 μg/mL rPen-2 at 48 h was 13.2%, 62.4%, and 70.4%, respectively. DNA-specific fluorescent dye staining showed a high percentage of apoptosis on cancer cells. Flow cytometry revealed that the apoptosis rate of HK-2, ACHN and A498 cells was 15.2%, 55.2%, and 61.5% at 48 h respectively, suggesting that rPen-2 induced higher apoptosis rate in cancer cells than in HK-2 cells. Laser confocal scanning microscopy demonstrated that the plasma membrane was the key site where rPen-2 interacted with and destroyed tumor cells. Scanning electron microscopy showed the morphologic changes of the cell membranes of kidney cancer cells treated with rPen-2. These results suggest that rPen-2 is a novel potential therapeutic agent that may be useful in treating kidney cancers.

Objective: To understand the characteristics and trends of colorectal cancer incidence and mortality in Lishui residents from 2014 to 2018,so as to provide basis for the development of prevention and treatment measures of colorectal cancer. Methods : The incidence and mortality data of colorectal cancer in Lishui from 2014 to 2018 were collected through the information management system of chronic disease surveillance in Zhejiang Province. The incidence,mortality and annual percentage change(APC)of colorectal cancer were calculated and analyzed in different genders,ages and regions were analyzed. Results: From 2014 to 2018,there were 4 403 new cases of colorectal cancer in Lishui,with the crude and standardized incidence rate of 34.89/100 000 and 20.99/100 000,respectively. There were 2 369 deaths,with a crude mortality rate of 18.77/100 000 and a standardized mortality rate of 10.17 /100 000. The crude incidence rate and crude mortality rate in males were higher than those in females(39.71/100 000 vs. 29.77/100 000,21.31/100 000 vs. 16.08/100 000,both p<0.05). There were no statistically significant differences between urban and rural residents in the crude incidence rate and crude mortality rate(37.24/100 000 vs. 34.44/100 000,19.75/100 000 vs. 18.45/100 000,both p<0.05). The crude incidence rate and crude mortality rate increased with age. The APC of the mortality rate of colorectal cancer among urban residents was 11.31%,showing an increasing trend from 2014 to 2018(p<0.05). Conclusion The incidence and mortality of colorectal cancer are high in Lishui,and the focus groups are men,people aged over 40 years and urban residents.

Objective: To learn the characteristics of gastric cancer incidence and mortality in Lishui from 2014 to 2018，and to provide basis for prevention and control strategies for gastric cancer. Methods: The data of gastric cancer in Lishui from 2014 to 2018 was collected from Zhejiang Chronic Disease Surveillance Information Management System. The incidence and mortality rates of gastric cancer were calculated，and the trend of them was evaluated by annual percentage change（APC）. Results: The crude incidence rate of gastric cancer in Lishui was 44.77/100 000（5 650 cases）and the standardized one was 26.93/100 000. From 2014 to 2018，the incidence rates of gastric cancer showed a decreasing trend（APC=-0.79%，P<0.05）. The crude mortality rate of gastric cancer in Lishui was 25.39/100 000（3 205 cases）and the standardized one was 14.21/100 000. From 2014 to 2018，the mortality rates of gastric cancer were stable（APC=-4.61%，P>0.05）. The standardized incidence and mortality rates of gastric cancer in males were 34.77/100 000 and 18.35/100 000，which were higher than 16.77/100 000 and 8.52/100 000 in females（P<0.05）. The standardized incidence and mortality rates of gastric cancer in rural residents were 46.07/100 000 and 26.11/100 000，which were higher than 38.49/100 000 and 22.02/100 000 in urban residents. The incidence and mortality rates increased with age after 15 years old，and reached the peak at the age group of 80-84 years old. Conclusion The incidence and mortality of gastric cancer in Lishui from 2014 to 2018 were at a high level，which were higher in males than in females and were higher in rural than in urban areas；while the incidence had a downward trend.

Objective Analyse the change of left ventricular (LV) longitudinal and radial strain in patients with aortic regurgitation (AR) and discuss the relationship between the 2D strain parameter and the filling and ejection of LV. Methods Thirty healthy controls and 45 patients with AR (24 patients with moderate AR and 21 with severe AR) were enrolled in this study, LV systolic global peak radial strain(GRS), systolic global peak longitudinal strain(GLS) and systolic peak longitudinal strain(S), systolic peak longitudinal strain rate(SRs), early diastolic peak longitudinal strain rate(SRe) of every segment were measured or calculated using 2D-STE, early and late diastolic transmitral flow velocity (E, A) were recorded by pulsed Doppler echocardiography and early diastolic mitral annular velocity (Ea) were assessed by tissue Doppler imaging,the E/A and E/Ea ratio were calculated. Discuss the relationship of GLS and LV ejection fraction (LVEF), GLS and E/Ea using the Pearson correlation analysis. Results The GLS were (-20.09±1.47)%, (-18.68±1.52)%, (-12.56±3.25)%and the GRS were (46.71±7.65)%, (43.01±5.95)%, (28.52±6.13)% in control group, patients with moderate and severe AR (MAR group and SAR group) respectively. There were significant differences among the groups (F =82.08,47.69, both P < 0.01) as following:SAR group with control group and MAR group [ q=17.56,13.60 (GLS), q=13.44, 10.20 (GRS), all P<0.01),MAR group and control group [ q=3.42 (GLS), P<0.01]. The SRs of the apical segment were (-1.24±0.22)s-1, (-1.19±0.25)s-1, (-1.04±0.28)s-1 in control group,MAR group and SAR group respectively. There were significant differences among the groups (F=4.47, P < 0.05) as following:SAR group with control group and MAR group ( q=4.02,3.28, both P<0.01). The S, SRe of apical segment and the S,SRs,SRe of basal and midventricular in MAR group were all lower than the control group ( q=4.42, 5.01, 3.48, 3.24, 4.78, 4.12, 3.61, 6.72, all P < 0.01). Pearson correlation analysis revealed the GLS had a relationship with LVEF and E/Ea ( r=-0.73, 0.64, both P<0.01). Conclusion The reduced longitudinal strain and strain rate could detect LV dysfunction in patients with AR in early stage and the GLS had the ability to reflect the diastolic filling and systolic ejecting of the LV.

Objective To study the clinicopathologieal features and expression of cyclin D1 and p53 in epithelial ovarian tumors,and to investigate the correlation between pathogenesis of ovarian cancer and epithelial borderline tumors.Methods Fifty four cases of ovarian borderline tumors and 45 cases of ovarian carcinomas from the People's Hospital,Peking University were reviewed retrospectively.The clinical data and pathological findings were analyzed.Immunohistochemical study of cyclin D1 and p53 was performed in all 99 cases.Results(1)In borderline tumors,the age of patients ranged from 14-82 (mean age=42.5)years.International Federation of Gynecology and Obstetrics(FIGO)stage of borderline tumors was stage Ⅰ in 48 cases,stage Ⅱ in 3 cases,and stage Ⅲ in 3 cases.In ovarian carcinomas,the age of patients ranged from 26-80(mean age=53.5)years.FIGO stage of carcinoma was stage Ⅰ in 6 cases, stage Ⅱ in 8 cases,stage Ⅲ in 26 cases,and stage Ⅳ in 5 cases.In follow-up of 54 cases with borderline tumors the 5-year survival rate was 98% and of 45 cases with carcinomas a 5-year survival rate of 51% was noted.(2)In 54 cases of borderline tumors,mucinous types accounted for 56%(30/54)and serous types accounted for 30%(16/54).There were 5 cases with micropapillary pattern,3 cases with peritoneal implants,3 cases with lymph node involvement,6 cases with microinvasion,one case with intraepithelial carcinoma,and one case with mural nodules.In 45 cases of carcinomas,serous carcinoma was the most (49%,22/45).The remainder included 3 cases of mucinous types,8 cases of endometrioid types,6 cases of transitional cell types,3 cases of mixed phenotype and 3 cases of undifferentiated types.(3) Overexpression of cyclin D1 and p53 was observed in 31%(14/45)and 56%(25/45)of ovarian carcinomas, respectively.There was a significant association between p53 overexpression and tumor grade.In the borderline tumor group,69%(37/54)had overexpression of cyelin D1 and 6%(3/54)had overexpression of p53.There were significant differences in expression of cyclin D1 and p53 between conventional serous borderline tumors and high-grade serous carcinomas(cyclin D1:91% vs 26%;p53:0 vs 58%).However, micropapillary serous borderline tumors and low-grade serous carcinomas showed remarkably similar expression of cyelin D1 and p53.Conclusions Epithelial ovarian borderline tumors are distinct from ovarian cancer in clinical progress and prognosis,and histological types.Overexpression of cyclin D1 is common in ovarian borderline tumors and low grade carcinomas.And overexpression of p53 is more common in high grade ovarian carcinomas.Conventional serous borderline tumors are distinct from high-grade serous carcinomas in pathogenesis.Micropapillary serous borderline ovarian tumors may be closely related to low grade serous carcinomas.