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.

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.

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.

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.

Adenocarcinoma ; metabolism ; pathology ; Chromogranin A ; metabolism ; Colonic Neoplasms ; metabolism ; pathology ; Humans ; Immunohistochemistry ; methods ; Proliferating Cell Nuclear Antigen ; metabolism ; Staining and Labeling ; methods ; Vimentin ; metabolism

ObjectiveTo evaluate the anticancer activity of 5'-dexoxy-fluorouridine on colon cancer experimental models in BALB/C mice,compared with 5'-fluorouracil,an anticancer agent widely used in clinic,meanwhile,examined the conversion of 5'-Dexoxy-fluorouridine to 5' -fluorouracil in cancer tissues and serum of mouse models.MethodsThe xenografts of mouse colon cancer cell line CT 26 were transplantated to cecum in 60 male BALB/C mice.Three days lated,these mice were divided into 3 groups and intro- peritoneally injected:( 1 ) 5' - dexoxy- fluorouridine 0.1 mg/g,(2) 5' - Fluorouracil 0.02 mg/g,(3)0.9％ sodium chloride 0.4 mL (as a control),respectively.Two and three weeks later,6 mice were sacririced in every group respectively to measure the weight of tumors and bodies,to examine the Hb,RBC,WBC,PLT,AST,ALT,UREA,and CREA in blood.The rest 8 mice in each group were fed generally,and the survival time from operation to natural death was recorded.In addition,14 mice with xenografts of CT 26 about 2 weeks,were divided into 2 groups averagely,5' -dexoxy-fluorouridine 0.1 mg/g and 5' -fluorouracil 0.02 mg/g were intro-peritoneally injected respectively.Fifteen min later,the converted 5' -fluorouracil was detected from the blood and tumor tissues in sacrificed mice.ResultsThe lest tumor average weight was found in the mice injected 5 '-dexoxy-fluorouridine,being (0.07 ± 0.12) g and (0.24g ±0.29) g for the mice sacrificed at 2 and 3 weeks later,respectively.The average survival time for rest mice was ( 32.6 ± 8.9) d.The average tumor weight in 5' - fluorouracil group was (0.74 ± 0.43 ) g and ( 1.13 ±0.75) g at 2 and 3 weeks later,and the average survival time for the rest was (22.8 ±5.9)d,respectively.The average tumor weight in the control group was (0.70 ±0.47) g and ( 1.93 ±0.83) g at 2 and 3 weeks,and the average survival time for the rest was ( 17.5 ± 2.8 ) d.Either the average tumor weight or average survival time in the mice of 5 ' -dexoxy-fluorouridine group was significantly differen from either 5' -fluorouracil group or control (P ＜ 0.05 ).However,there was no significant difference for the numbers of WBC,PLC,Hb,and some function examination of liver and kidney among 3 group mice,besides the loss of weights in 5'-fluorouracil group mice after operation and medicine therapy which was significantly obvious than that in 5' -deoxy-fluorouridine and control groups ( P ＜ 0.05 ).In addition,( 54.71 ± 12.82) μg/g 5' -fluorouracil was detected in xenografts of mice injected 5' -dexoxy-fluorouridine 15 min later,which was the 6.20 folds of 5' -fluorouracil detected in serum from sthe ame group,P ＜0.05.However,( 133.35 ±20.69) μg/m 5'-fluorouracil were detected in serum of mice after 5' -fluorouracil were injected 15 min later,which was the 1.55 folds of 5' -fluorouracil detected in the xenografts from same group ( P ＜ 0.05 ).ConclusionsIn colon cancer tissues of mouse experimental models,5' - dexoxy- fluorouridine could be converted effectively to 5'-fluorouracil,an obvious high concentration being detected in serum of mice than in cancer tissues.The anticancer effect of 5'-dexoxy-fluorouridine on mouse colon cancer models was more effective than 5'-fluorouracil,resulting in a longer survival duration,less side effect and no significant injury on liver and kidney functions.However,the mechanism of 5' -dexoxy-fluorouridine converted to 5' -fluorouracil in cancer tissue is needed further investigation.

Objective To investigate the effects of erythropoietin (EPO) pretreatment on the acute lung injury induced by lipopolysaccharide (LPS) in rats and the underlying mechanism. Methods Thirty-two male SD rats weighing 180-220 g were randomly divided into 4 groups (n=8 each): group Ⅰ control (C);group Ⅱ EPO;group Ⅲ LPS and group Ⅳ EPO + LPS. EPO 3 000 U/kg was given IP in group Ⅱ , LPS 6 mg/kg was given iv in group Ⅲ . In group Ⅳ EPO 3 000 U/kg was given IP at 30 rain before iv LPS 6 mg/kg, The animals were killed at 4 h after LPS administration. Lung tissue specimens were obtained for microscopic examination. Wet/dry ratio (W/D), myeloperoxidase (MPO) activity, malondialdehyde (MDA) and nitric oxide (NO) content in lung tissue were determined. The expression of inducible nitric oxide synthase (iNOS) and nitrotyrosine (NT) in lung tissue was determined by Western blot. Results W/D ratio, MPO activity, MDA and NO content were significantly increased and iNOS and NT expression was significantly up-regulated in LPS group as compared with control group. EPO pretreatment significantly attenuated the LPS-induced changes in group EPO + LPS. Conclusion EPO pretreatment can ameliorate the acute lung injury induced by LPS by down-regulating iNOS expression and reducing NO production.

ObjectiveTo explore a minimally invasive,reliable,and efficient method for endotracheal intubation to instill lipopolysaccharide (LPS) for preparation of acute lung injury (ALI) in mice.MethodsA total of 80 BALB/C mice was randomly selected into LPS group ( n =40) and control group (Normal saline,NS; n =40).After a successfully endotracheal intubation,each mouse was instilled by LPS (3 mg/kg) in LPS group,and NS ( 1.5 ml/kg) in NS group,respectively.The one-time success rate and final success rate of the endotracheal intubation,and survival rate were recorded.After 24 hours,the total number of cells in bronchoalveolar lavage fluid (BALF) of left lung was counted with light microscope.The cells were classified and counted after Wright's stain.Total protein concentration in BALF was assayed with a BCA kit.Wet/dry value was calculated after the lung became dry.Artery blood PaO2 was tested and the oxygenation index was counted.ResultsCompared to NS group,the LPS group had the one-time success rate 92.5％,and the final success rate 100％,survival rate 100％,the total number of cells [ ( 10.82±3.51) ×105/mlvs (0.72±0.52)×105/ml.t =-6.294 P ＜0 01]the rate of polymorphonulear leukocytes in total cells [ (93.93 ± 1.77) ％ vs (2.2 ± 0.91 ) ％,t =- 105.565,P ＜ 0.01 ],the rate of mononuclear leukocytes in total cells[ (6.07 ± 1.77)％ vs (97.8 ±0.91 )％,t =- 105.565,P ＜0.01 ],total protein concentration[ (0.49 ± 0.13 ) mg/ml vs (0.29 ± 0.11 ) mg/ml,t =- 2.823,P ＜ 0.05 ],W/D ratio(4.60 ±0.18 vs 4.16 ±0.25,t =-4.793,P ＜0.01 ),PaO2[ (68.57 -±7.23)％ vs(87.00 ±6.33 )％,t =4.571,P ＜ 0.01 ],and oxygenation index [ (326.53± 34.43 )mmHg vs (414.29 ± 30.16)mmHg,t =4.571,P ＜0.01 ].ConclusionsImproved method for endotracheal intubation has high success rate and minimal injury,and instillation of LPS (3 mg/kg)can induce mice ALI successfully.