Design, Synthesis, and Anticancer Activity of Cinnamoylated Barbituric Acid Derivatives.

This work deals with the design and synthesis of 18 barbituric acid derivatives bearing 1,3-dimethylbarbituric acid and cinnamic acid scaffolds to find potent anticancer agents. The target molecules were obtained through Knoevenagel condensation and acylation reaction. The cytotoxicity was assessed by the MTT assay. Flowcytometry was performed to determine the cell cycle arrest, apoptosis, ROS levels and the loss of MMP. The ratios of GSH/GSSG and the MDA levels were determined by using UV spectrophotometry. The results revealed that introducing substitutions (CF3 , OCF3 , F) on the meta- of the benzyl ring of barbituric acid derivatives led to a considerable increase in the antiproliferative activities compared with that of corresponding ortho- and para-substituted barbituric acid derivatives. Mechanism investigation implied that the 1c could increase the ROS and MDA level, decrease the ratio of GSH/GSSG and MMP, and lead to cell cycle arrest. Further research is needed for structural optimization to enhance hydrophilicity, thereby improve the biological activity of these compounds.

Piperlongumine Analogs Promote A549 Cell Apoptosis through Enhancing ROS Generation.

Chemotherapeutic agents, which contain the Michael acceptor, are potent anticancer molecules by promoting intracellular reactive oxygen species (ROS) generation. In this study, we synthesized a panel of PL (piperlongumine) analogs with chlorine attaching at C2 and an electron-withdrawing/electron-donating group attaching to the aromatic ring. The results displayed that the strong electrophilicity group at the C2-C3 double bond of PL analogs plays an important role in the cytotoxicity whereas the electric effect of substituents, which attached to the aromatic ring, partly contributed to the anticancer activity. Moreover, the protein containing sulfydryl or seleno, such as TrxR, could be irreversibly inhibited by the C2-C3 double bond of PL analogs, and boost intracellular ROS generation. Then, the ROS accumulation could disrupt the redox balance, induce lipid peroxidation, lead to the loss of MMP (Mitochondrial Membrane Potential), and ultimately result in cell cycle arrest and A549 cell line death. In conclusion, PL analogs could induce in vitro cancer apoptosis through the inhibition of TrxR and ROS accumulation.

Cocrystallization with syringic acid presents a new opportunity for effectively reducing the hepatotoxicity of isoniazid.

Objective: With the aim of surmounting the severe hepatotoxicity induced by antituberculosis drug isoniazid (INH), a novel cocrystal of INH with hepatoprotective nutraceutical syringic acid (SYA), namely INH-SYA, was designed and prepared through cocrystallization strategy, which is an intriguing attempt to reduce the toxic side effects of INH.Significance: The study not only provides new thinking for inhibiting toxic side effects of drugs through cocrystallization strategy, but also opens a new pathway for the application of nutraceuticals in the pharmacy.Methods: INH and SYA were successfully crystallized into the same crystal lattice through combining volatilization with solvent assisted methods. The resulting cocrystal was structurally characterized by single crystal X-ray diffraction (SCXRD), powder X-ray diffraction (PXRD), and differential scanning calorimetry (DSC).Results: The SCXRD analysis for the present cocrystal revealed that it has a 1:1 ratio of INH to SYA with two molecules INH homodimers and two SYA molecules, in which they are arranged alternately linked by hydrogen bonds to form a six molecules ring structure (R66(40)) in crystal. The systematic evaluation of the in vitro/in vivo suggested that, owing to the formation of cocrystal, the dissolution efficiency of SYA was increased 5.85-fold compared with that of coarse SYA, and the oral bioavailability of the cocrystal in rats was enhanced by 3.66 times. As a result, the present INH-SYA cocrystal almost removed INH induced serious hepatotoxicity, which was further demonstrated by the hepatotoxicity studies in rats.Conclusion: INH-SYA cocrystal could effectively reduce the hepatotoxicity of INH.

Coumarin and 3,4-dihydroquinolinone derivatives: Synthesis, antidepressant activity, and molecular docking studies.

BACKGROUND: Coumarin and 3,4-dihydroquinolinone nuclei are two heterocyclic rings that are important and widely exploited for the development of bioactive molecules. Here, we designed and synthesized a series of 3,4-dihydroquinolinone and coumarin derivatives (Compounds 8, 9, 11, 14, 15, 18-20, 23, 24 and 28 are new compounds) and studied their antidepressant activities. METHODS: Forced swimming test (FST) and tail suspension test (TST) were used to evaluate the antidepressant activity of the target compounds. The most active compound was used to evaluate the exploratory activity of the animals by the open-field test. 5-HT concentration was estimated to evaluate if the compound has an effect on the mouse brain, by using ELISA. A 5-HT1A binding assay was also performed. The biological activities of the compounds were verified by molecular docking studies. The physicochemical and pharmacokinetic properties of the target compounds were predicted by Discovery Studio and ChemBioDraw Ultra. RESULTS: Of all the compounds tested, compound 7 showed the best antidepressant activity, which decreased the immobility time by 65.52 s in FST. However, in the open-field test, compound 7 did not affect spontaneous activity. The results of 5-HT concentration estimation in vivo showed that compound 7 may have an effect on the mouse brain. Molecular docking results indicated that compound 7 showed significant interactions with residues at the 5-HT1A receptor using homology modeling. The results show that compound 7 exhibits good affinity for the 5-HT1A receptor. CONCLUSION: Coumarin and 3,4-dihydroquinolinone derivatives synthesized in this study have a significant antidepressant activity. These findings can be useful in the design and synthesis of novel antidepressants.

Blockade of Extracellular High-Mobility Group Box 1 Attenuates Systemic Inflammation and Coagulation Abnormalities in Rats with Acute Traumatic Coagulopathy.

BACKGROUND As an extracellularly released mediator, high-mobility group box 1 (HMGB1) initiates sterile inflammation following severe trauma. Serum HMGB1 levels correlate well with acute traumatic coagulopathy (ATC) in trauma patients, which is independently associated with higher mortality. We investigated the involvement of HMGB1 in ATC through blocking extracellular HMGB1. MATERIAL AND METHODS The ATC model was induced by polytrauma and hemorrhage in male Sprague-Dawley rats, which were randomly assigned to sham, ATC, and ATCH (ATC with HMGB1 blockade) groups. Thrombelastography (TEG) was performed to monitor changes in coagulation function. Serum levels of HMGB1, TNF-α, and IL-6 were measured, as well as lung levels of HMGB1 and nuclear factor (NF)-κB and expression of receptor for advanced glycation end-products (RAGE). RESULTS Compared with the sham group, HMGB1 increased the serum levels of TNF-α and IL-6, whereas HMGB1 blockade inhibited the induction of TNF-α and IL-6. HMGB1 also induced elevated serum soluble P-selectin and fibrinolysis markers plasmin-antiplasmin complex, which both were reduced by HMGB1 blockade. Thrombelastography revealed the hypocoagulability status in the ATC group, which was attenuated by anti-HMGB1 antibody. Furthermore, the lung level of NF-κB and expression of RAGE were decreased by anti-HMGB1 antibody, suggesting the role of RAGE/NF-κB pathway in ATC. CONCLUSIONS HMGB1 blockade can attenuate inflammation and coagulopathy in ATC rats. Anti-HMGB1 antibody might exert protective effects partly through the RAGE/NF-κB pathway. Thus, HMGB1 has potential as a therapeutic target in ATC.

Evaluation of the Value of d-Dimer, P-Selectin, and Platelet Count for Prediction of Portal Vein Thrombosis After Devascularization.

BACKGROUND/AIM: To evaluate the value of d-dimer, P-selectin, and platelet count in patients with cirrhotic portal hypertension (PHT) for prediction of portal vein thrombosis (PVT) after devascularization. METHODS: A total of 137 patients with cirrhotic PHT who undergone devascularization from January 2012 to April 2014 were retrospectively reviewed, all of them were divided into 2 groups (PVT group and non-PVT group) by Doppler ultrasonography (DU) examination. The level of d-dimer, P-selectin, and platelet count was tested during the perioperative period. RESULTS: In all, 38 (27.7%) patients were found to have PVT by DU examination postoperatively. In contrast to the non-PVT group, the level of d-dimer, P-selectin, and platelet count in the PVT group was much higher significantly at 1, 3, and 7 days after devascularization. (P < .05). However, in the 15 days after surgery, the difference in P-selectin between the 2 groups was not significant (P = .260). It was shown that the highest sensitivity of the 3 markers for PVT was d-dimer, the highest specificity belonged to P-selectin. The area under receiver-operating characteristic (ROC) curve of P-selectin was the biggest of the 3 markers. When the 3 markers were combined to be used to diagnose PVT, the sensitivity was increased to 0.907, with a slight drop of specificity to 0.693, the area under the ROC curve was 0.927. CONCLUSION: The level of d-dimer, P-selectin, and platelet count might be good candidate predictive markers for PVT in patients with cirrhotic PHT after devascularization. The combined test of the 3 markers can increase the value of prediction.

Evaluation the value of markers for prediction of portal vein thrombosis after devascularization.

AIM: To evaluate the value of D-dimer and P-selectin in cirrhotic portal hypertension (PHT) patients for prediction of portal vein thrombosis (PVT) after devascularization. MATERIAL AND METHODS: 137 patients with cirrhotic PHT who undergone devascularization from January 2012 to April 2014 were retrospectively reviewed, all of them were divided into two groups (PVT group and non-PVT group) by Doppler ultrasonography (DU) examination. The level of D-dimer and P-selectin was tested during the peri-operative period. RESULTS: 38 patients (27.7%) were found PVT by DU examination post-operatively. In contrast to the non- PVT group, the level of D-dimer and P-selectin in the PVT group was much higher significantly at 1, 3 and 7 days after devascularization (P < 0.05). However, in the 15 days after surgery, the difference of P-selectin between the two groups was not significant (P = 0.260). It was shown that the higher sensitivity of the two markers for PVT was D-dimer, the higher specificity belonged to P-selectin. The area under receiver operating characteristic (ROC) curve of P-selectin was the bigger of the two markers. When the two markers were combined to be used to diagnose PVT, the sensitivity was increased to 0.911, with a slight drop of specificity to 0.715, the area under ROC curve was 0.919. CONCLUSION: The level of D-dimer and P-selectin might be good candidate predictive markers for PVT in patients with cirrhotic PHT after devascularization. The combined test of the two markers can increase the value of prediction.

Fast-track protocols in devascularization for cirrhotic portal hypertension.

INTRODUCTION/OBJECTIVE: fast-tract surgery (FTS) has been rapidly embraced by surgeons as a mechanism for improving patient care and driving down complications and costs. The aim of this study was to determine if any improvement in outcomes occurred after FTS protocol for selective double portazygous disconnection with preserving vagus (SDPDPV) compared with non-FTS postoperative care. METHODS: patients eligible for SDPDPV in the period January 2012-April 2014 were randomly selected for the FTS group or non-FTS group. A designed protocol was used in the FTS group with emphasis on an interdisciplinary approach. The non-FTS group was treated using previously established standard procedures. The number of postoperative complications, time of functional recovery and duration of hospital stay were recorded. RESULTS: patients in the FTS group (n=59) and non-FTS group (n=57) did not differ in terms of preoperative data and operative details (p>0.05). The FTS procedure led to significantly better control and faster restoration of gastrointestinal functions, food tolerance, rehabilitation and hospital discharge (p<0.05). Postoperative complications, including nausea/vomiting, severe ascites, wound infection, urinary tract infection and pulmonary infection were all significantly lower in the FTS group (p<0.05). According to the postoperative morbidity classification used by Clavien, overall complications and grade I complications were both significantly lower in the FTS group compared with the non-FTS group (p<0.05). CONCLUSION: adopting the FTS protocol helped to recover gastrointestinal functions, to reduce frequency of postoperative complications and to reduce hospital stay. The FTS strategy is safe and effective in improving postoperative outcomes.

Fast-track protocols in devascularization for cirrhotic portal hypertension / Protocolos rápidos em desvascularização para hipertensão portal por cirrose.

Summary Introduction/objective: fast-tract surgery (FTS) has been rapidly embraced by surgeons as a mechanism for improving patient care and driving down complications and costs. The aim of this study was to determine if any improvement in outcomes occurred after FTS protocol for selective double portazygous disconnection with preserving vagus (SDPDPV) compared with non-FTS postoperative care. Methods: patients eligible for SDPDPV in the period January 2012-April 2014 were randomly selected for the FTS group or non-FTS group. A designed protocol was used in the FTS group with emphasis on an interdisciplinary approach. The non-FTS group was treated using previously established standard procedures. The number of postoperative complications, time of functional recovery and duration of hospital stay were recorded. Results: patients in the FTS group (n=59) and non-FTS group (n=57) did not differ in terms of preoperative data and operative details (p>0.05). The FTS procedure led to significantly better control and faster restoration of gastrointestinal functions, food tolerance, rehabilitation and hospital discharge (p<0.05). Postoperative complications, including nausea/vomiting, severe ascites, wound infection, urinary tract infection and pulmonary infection were all significantly lower in the FTS group (p<0.05). According to the postoperative morbidity classification used by Clavien, overall complications and grade I complications were both significantly lower in the FTS group compared with the non-FTS group (p<0.05). Conclusion: adopting the FTS protocol helped to recover gastrointestinal functions, to reduce frequency of postoperative complications and to reduce hospital stay. The FTS strategy is safe and effective in improving postoperative outcomes. .

Resumo Objetivo: a cirurgia fast-track (FTS) foi rapidamente abraçada por cirurgiões como um mecanismo para melhorar o atendimento ao paciente e reduzir complicações e custos. O objetivo deste estudo foi determinar se qualquer melhoria nos resultados de um protocolo FTS para desconexão seletiva dupla porta (SDPDPV), quando comparado ao cuidado pós-operatório não FTS. Métodos: pacientes candidatos a SDPDPV, no período de janeiro de 2012 a abril de 2014, foram selecionados aleatoriamente para o grupo FTS ou grupo não FTS. Um protocolo projetado foi utilizado no grupo FTS, com ênfase em uma abordagem interdisciplinar. O grupo não FTS foi tratado por meio de procedimentos padrão, estabelecidos previamente. O número de complicações pós- -operatórias, o tempo de recuperação funcional e o tempo de internação hospitalar foram registrados. Resultados: os pacientes do grupo de FTS (n=59) e grupo não FTS (n=57) não diferiram em termos de dados pré-operatórios e detalhes cirúrgicos (p>0,05). O procedimento FTS levou à melhora significativa do controle e à restauração mais rápida das funções gastrointestinais, tolerância alimentar, reabilitação e alta hospitalar (p<0,05). Complicações pós-operatórias, incluindo náuseas/vômitos, ascite grave, infecção da ferida, infecção urinária e infecção pulmonar foram significativamente menores no grupo FTS (p<0,05). De acordo com a classificação de morbidade pós-operatória utilizado por Clavien, complicações gerais e complicações de classe I foram ambas significativamente mais baixas no grupo de FTS em comparação com o grupo não FTS (p<0,05). Conclusão: a adoção do protocolo FTS ajudou a recuperar as funções gastrointestinais, reduzir a frequência de complicações pós-operatórias e reduzir tempo de internação hospitalar. A estratégia FTS é segura e eficaz para melhorar os resultados pós-operatórios. .

Comparison of effects of devascularization versus shunt on patients with portal hypertension: a meta-analysis.

BACKGROUND/AIMS: To systematically evaluate the effectiveness of devascularization and shunt on patients with portal hypertension. METHODOLOGY: Relevant studies compared devascularization and shunt for the treatment of portal hypertension were identified searching the PubMed, Embase, Elsevier, CNKI (China National Knowledge Infrastructure) database and Cochrane Trial Register searches until December 2013. Data of interest for devascularization and shunt including postoperative recurrent bleeding, postoperative hepatic encephalopathy, ascites, operative mortality rate, and long term survival rate were subjected to meta-analysis. RESULTS: Eleven studies were included in the study, the results of the meta-analysis showed that all eleven clinical studies demonstrated a significantly higher postoperative recurrent bleeding rate with devascularization group than with shunt group, the rate of hepatic encephalopathy in the devascularization group was significantly lower compared with the shunt group. CONCLUSION: Devascularization and shunt have different advantages and disadvantages respectively which reflected in postoperative complications and long term survival rate.

Effects of selective double portazygous disconnection and devascularization on hemodynamics of the portal venous system.

AIM: Selective double portazygous disconnection with preserving vagus (SDPDPV) is currently used for the therapy of portal hypertension. Doppler ultrasonography (DU) has been proposed for non-invasive evaluation of splanchnic hemodynamics, but the effect of SDPDPV on portal vein (PV) hemodynamics has not been analyzed with DU. This was the aim of the study. MATERIAL AND METHODS: Two hundred and thirty six patients with cirrhotic portal hypertension who underwent either SDPDPV or pericardial devascularization with splenectomy (PDS) for variceal bleeding were enrolled. The hemodynamics parameter, operation-relevant information, change of lavatory examination data, postoperative complications, and clinical outcomes were analyzed. RESULTS: The free portal pressure (FPP) in the SDPDPV group was significantly lower than the PDS group after operation (p<0.05). Velocities and blood flow of PV after SDPDPV decreased; however, when the hepatic artery (HA) and superior mesenteric vein (SMV) increased, the differences were significant (p<0.05). The correlation between the decreased FPP and changed blood flow of portal vein(PVF), hepatic artery (HAF) or superior mesenteric vein (SMVF) was significant (p<0.05) after SDPDPV. The difference between pre and postoperative values of portal congestion index (CI) in SDPDPV was significant (p<0.05). Occurrences or development of postoperative rebleeding showed a great difference between the two groups (p< 0.05). PVF and SMVF were significant independent indicators of postoperative rebleeding (p< 0.05). CONCLUSIONS: Compared with the PDS, the SDPDPV apparently decreased the blood velocity and blood flow of PV, and increased that of HA and SMV which has a beneficial effect on hepatic function and encourages the controlof the recurrent bleeding from varices. PVF and SMVF may be value indicators in predicting postoperative rebleeding.

[Chemical constituents of Trichosanthes kirilowii peels].

OBJECTIVE: To study the chemical constituents of the peels of Trichosanthes kirilowii. METHODS: Many chromatographic techniques were used including repeated silica column chromatography, polyamide resin and semi-preparative high performance liquid chromatography. According to the physical and chemical properties and spectral analysis, the chemical structures of the compounds were determined. RESULTS: Thirteen compounds were isolated and identified as quercetin-3-O-[alpha-L-rhamnose(1 --> 2)-beta-D-glucopyranosyl]-5-O-beta-D-glucopyranoside (1), quercetin-3-O-rutinoside (2), apigenin-7-O-beta-D-glucopyranoside (3), diosmetin-7-O-beta-D-glucopyranoside (4), luteolin (5), apigenin (6), diosmetin (7), methyl palmitate (8), methyl stearate (9), palmitic acid (10), beta-sitosterol (11), alpha-spin-asterol (12) and stigmasterol (13). CONCLUSION: Compounds 1 - 3, 5 - 7 are isolated from this plant for the first time.

Rapid pretreatment and determination of bisphenol A in water samples based on vortex-assisted liquid-liquid microextraction followed by high-performance liquid chromatography with fluorescence detection.

A method for the rapid pretreatment and determination of bisphenol A in water samples based on vortex-assisted liquid-liquid microextraction followed by high-performance liquid chromatography with fluorescence detection was proposed in this paper. A simple apparatus consisting of a test tube and a cut-glass dropper was designed and applied to collect the floating extraction drop in liquid-liquid microextraction when low-density organic solvent was used as the extraction solvent. Solidification and melting steps that were tedious but necessary once the low-density organic solvent used as extraction solvent could be avoided by using this apparatus. Bisphenol A was selected as model pollutant and vortex-assisted liquid-liquid microextraction was employed to investigate the usefulness of the apparatus. High-performance liquid chromatography with fluorescence detection was selected as the analytical tool for the detection of bisphenol A. The linear dynamic range was from 0.10 to 100 µg/L for bisphenol A, with good squared regression coefficient (r(2) = 0.9990). The relative standard deviation (n = 7) was 4.7% and the limit of detection was 0.02 µg/L. The proposed method had been applied to the determination of bisphenol A in natural water samples and was shown to be economical, fast, and convenient.

Selective double disconnection for cirrhotic portal hypertension.

BACKGROUND: To evaluate the effect of selective double portazygous disconnection with preserving vagus (SDPDPV) for patients with portal hypertension (PHT) in the authors' hospital. METHODS: Patients (453) with cirrhotic PHT who underwent either SDPDPV or pericardial devascularization with splenectomy (PDS) for variceal bleeding from February 2007 to January 2013 were retrospectively reviewed. The operation-relevant information, change of lavatory examination data, postoperative complications, and clinical outcomes were analyzed. RESULTS: There were no significant difference between the SDPDPV group and the PDS group of mean operative time and intraoperative blood loss (P >0.05). The free portal pressure in the SDPDPV group was much lower than PDS group significantly after operation (P <0.05). The test of biochemical profile of hepatocyte functions and Child-Pugh score at the end of the first postoperative year were significantly more altered in the SDPDPV group than in the PDS group (P <0.05). Except encephalopathy, occurrences or development of postoperative complications including rebleeding, ascites, and gastric stasis showed great difference between the two groups (P <0.05). The operative mortality rate and the 3-y survival rates were great difference between the two groups too (P <0.05). CONCLUSIONS: The SDPDPV not only controls recurrent bleeding from varices with PHT effectively but also maintains normal dynamics of stomach and physiological function of intestine and hepatobiliary.

Electrochemical performance of 8-hydroxy-2'-deoxyguanosine and its detection at poly(3-methylthiophene) modified glassy carbon electrode.

8-Hydroxy-2'-deoxyguanosine (8-OH-dG) has attracted enormous attention in recent years because it has been acknowledged as a typical biomarker of oxidative DNA damage. In this paper, the electrochemical performance of 8-OH-dG at the poly(3-methylthiophene) (P3MT) modified glassy carbon electrode (GCE) was investigated by cyclic voltammetry (CV) and linear sweep voltammetry (LSV). The conducting polymer P3MT can effectively decrease the oxidation peak potential of 8-OH-dG and greatly enhance its peak current. In 0.1 M pH 7.0 phosphate buffer solution (PBS), the anodic peak currents of cyclic voltammograms are linear with the 8-OH-dG concentration in two intervals, viz. 0.700-35.0 microM and 35.0-70.0 microM, with the correlative coefficients of 0.9992 and 0.9995, respectively. The detection limit of 8-OH-dG can be estimated to be 0.100 microM (S/N=3). This modified electrode can be used to detect the amount of 8-OH-dG in human urine. Furthermore, the effects of scan rate, pH, and interference of uric acid (UA) for the voltammetric behavior and detection of 8-OH-dG are also discussed. This proposed modified electrode also shows excellent reproducibility and stability that makes it an ideal candidate for amperometric detection of 8-OH-dG in flow injection analysis (FIA) and high performance liquid chromatography (HPLC).

[Separation and identification of alkaloids in Stephania tetrandra by capillary electrophoresis electrospray-MS/MS].

AIM: To establish a method for separation and identification of alkaloids in Stephania tetrandra S. Moore methanol extracts by using non-aqueous capillary electrophoresis interfaced with electrospray ionization ion trap mass spectrometry. METHODS: The molecular ions or adducts of alkaloids and fragments of specific parent ions were used for the identification. An uncoated capillary (86 cm x 75 microm ID, on-line UV detection occurred at 21 cm from the inlet of the capillary) was used. Ammonium acetate (50 mmol x L(-1)) containing 4% HAc in methanol was used as the running buffer; separation voltage was 25 kV. A coaxial sheath flow interface was used as the CE-MS interface; the electrospray voltage was 4.5 kV; the temperature of aluminium capillary was 170 degrees C; 60% isopropanol-39% water-1% HAc was used as the sheath liquid with the flow rate of 5 microL x min(-1); the collision energy of MS-MS was set at 30% and the least ion counts was 1 x 10(5). RESULTS AND CONCLUSION: The alkaloids in Stephania tetrandra S. Moore methanol extracts were separated and identified by CE-ESI-MS/MS. The proposed method is of high accuracy and can be used for the investigation of traditional Chinese medicine.