Design, synthesis and biological evaluation of novel procaine derivatives for intravenous anesthesia.

A series of novel procaine derivatives for intravenous anesthesia were prepared and evaluated by physicochemical properties and pharmacodynamic experiments in vivo and in vitro. Systematic optimization of procaine led to the identification of 6f, 6g, 6h, 6o, 6p and 6q with higher TI value and moderate log D. Compared with procaine (TI = 1.65), most procaine derivatives demonstrated better security, among whichcompound 6h (TI = 2.68)was the most notable one and showed fewer adverse events in animals. The result of hNR2B-HEK293 assay indicated that compound 6h suppressed the NMDA receptor 2B subtype channel activity and it showed more than 80% inhibitory effect at the concentration of 500 µM.

HTK-N: Modified Histidine-Tryptophan-Ketoglutarate Solution-A Promising New Tool in Solid Organ Preservation.

To ameliorate ischemia-induced graft injury, optimal organ preservation remains a critical hallmark event in solid organ transplantation. Although numerous preservation solutions are in use, they still have functional limitations. Here, we present a concise review of a modified Histidine-Tryptophan-Ketoglutarate (HTK) solution, named HTK-N. Its composition differs from standard HTK solution, carrying larger antioxidative capacity and providing inherent toxicity as well as improved tolerance to cold aiming to attenuate cold storage injury in organ transplantation. The amino acids glycine, alanine and arginine were supplemented, N-acetyl-histidine partially replaced histidine, and aspartate and lactobionate substituted chloride. Several in vitro studies confirmed the superiority of HTK-N in comparison to HTK, being tested in vivo in animal models for liver, kidney, pancreas, small bowel, heart and lung transplantation to adjust ingredients for required conditions, as well as to determine its innocuousness, applicability and potential advantages. HTK-N solution has proven to be advantageous especially in the preservation of liver and heart grafts in vivo and in vitro. Thus, ongoing clinical trials and further studies in large animal models and consequently in humans are inevitable to show its ability minimizing ischemia-induced graft injury in the sequel of organ transplantation.

Unraveling the Mechanisms Behind the Complete Suppression of Cocaine Electrochemical Signals by Chlorpromazine, Promethazine, Procaine, and Dextromethorphan.

The present work investigates the challenges accompanied by the electrochemical cocaine detection in physiological conditions (pH 7) in the presence of chlorpromazine, promethazine, procaine, and dextromethorphan, frequently used cutting agents in cocaine street samples. The problem translates into the absence of the cocaine oxidation signal (signal suppression) when in a mixture with one of these compounds, leading to false negative results. Although a solution to this problem was provided through earlier experiments of our group, the mechanisms behind the suppression are now fundamentally investigated via electrochemical and liquid chromatography quadrupole-time-of-flight mass spectrometry (LC-QTOF-MS) strategies. The latter was used to confirm the passivation of the electrodes due to their interaction with promethazine and chlorpromazine. Electron transfer mechanisms were further identified via linear sweep voltammetry. Next, adsorption experiments were performed on the graphite screen printed electrodes both with and without potential assistance in order to confirm if the suppression of the cocaine signals is due to passivation induced by the cutting agents or their oxidized products. The proposed strategies allowed us to identify the mechanisms of cocaine suppression for each cutting agent mentioned. Suppression due to procaine and dextromethorphan is caused by fouling of the electrode surface by their oxidized forms, while for chlorpromazine and promethazine the suppression of the cocaine signal is related to the strong adsorption of these (nonoxidized) cutting agents onto the graphite electrode surface. These findings provide fundamental insights in possible suppression and other interfering mechanisms using electrochemistry in general not only in the drug detection sector.

Study of procaine and tetracaine in the lipid bilayer using molecular dynamics simulation.

Despite available experimental results, the molecular mechanism of action of local anesthetics upon the nervous system and contribution of the cell membrane to the process are still controversial. In this work, molecular dynamics simulations were performed to investigate the effect of two clinically used local anesthetics, procaine and tetracaine, on the structure and dynamics of a fully hydrated dimyristoylphosphatidylcholine lipid bilayer. We focused on comparing the main effects of uncharged and charged drugs on various properties of the lipid membrane: mass density distribution, diffusion coefficient, order parameter, radial distribution function, hydrogen bonding, electrostatic potential, headgroup angle, and water dipole orientation. To compare the diffusive nature of anesthetic through the lipid membrane quantitatively, we investigated the hexadecane/water partition coefficient using expanded ensemble simulation. We predicted the permeability coefficient of anesthetics in the following order: uncharged tetracaine > uncharged procaine > charged tetracaine > charged procaine. We also shown that the charged forms of drugs are more potent in hydrogen bonding, disturbing the lipid headgroups, changing the orientation of water dipoles, and increasing the headgroup electrostatic potential more than uncharged drugs, while the uncharged drugs make the lipid diffusion faster and increase the tail order parameter. The results of these simulation studies suggest that the different forms of anesthetics induce different structural modifications in the lipid bilayer, which provides new insights into their molecular mechanism.

Efficacy of liver graft washout as a function of the perfusate, pressure, and temperature.

Donor graft washout can be impaired by colloids in organ preservation solutions that increase the viscosity and agglutinative propensity of red blood cells (RBCs) and potentially decrease organ function. The colloid-induced agglutinative effects on RBCs and RBC retention after liver washout with Ringer's lactate (RL), histidine tryptophan ketoglutarate solution, University of Wisconsin solution, and Polysol were determined as a function of the washout pressure (15 or 100 mm Hg) and temperature (4 or 37°C) in a rat liver washout model with (99m) Tc-pertechnetate-labeled RBCs. Colloids (polyethylene glycol in Polysol and hydroxyethyl starch in University of Wisconsin) induced RBC agglutination, regardless of the solution's composition. RL was associated with the lowest degree of (99m) Tc-pertechnetate-labeled RBC retention after simultaneous arterial and portal washout at 37°C and 100 mm Hg. RL washout was also associated with the shortest washout time. A single portal washout with any of the solutions did not result in differences in the degree of RBC retention, regardless of the temperature or pressure. In conclusion, no differences were found in portal washout efficacy between colloidal solutions, histidine tryptophan ketoglutarate, and RL. Simultaneous arterial and portal washout with RL at 37°C and 100 mm Hg resulted in the least RBC retention and the shortest washout time.

The comparison of the effects of Bretschneider's histidine-tryptophan-ketoglutarate and conventional crystalloid cardioplegia on pediatric myocardium at tissue level.

Cardioplegic arrest is one of the most common myocardial protection strategies. A wide variety of cardioplegic solutions are routinely being used. There is an ongoing discussion about the relative effectiveness of these solutions considering myocardial protection. This study aims to investigate the hypothesis that the use of histidine-tryptophan-ketoglutarate (HTK) cardioplegia leads to decreased ischemic damage on myocardium compared with the use of conventional crystalloid cardioplegia. The study population was 32 patients operated on at Baskent University, Department of Cardiovascular Surgery for congenital heart diseases. The first group of 16 patients received conventional crystalloid cardioplegia (KK group) which is a modification of St. Thomas' solution, while the second group of 16 patients received HTK solution (HTK group). The echocardiographic measurements and the laboratory values of the patients were taken as the clinical variables. Right ventricular biopsies were taken from every patient before and after cardioplegic arrest. These biopsies were histopathologically examined for apoptosis using caspase-3 antigen and cell proliferation using Ki-67 antigen. The statistical analysis revealed no significant difference between the two groups regarding the clinical variables, apoptotic indices and proliferation indices. The apoptotic indices in the postcardioplegic arrest biopsies positively correlated with aortic clamp time in the KK group but not in the HTK group. Liver function tests on postoperative day 1 positively correlated with aortic clamp time in both groups. On postoperative day 2, this correlation was sustained in the KK group and ceased in HTK group. The difference in the correlation of apoptotic indices and liver function tests between the groups is accepted as a supportive finding for HTK solution. However, it can be postulated that when the aortic clamp times are similar to those in the present study, the clinical manifestation of the difference between the two solutions would not be significant.

Lipophilicity as a determinant of binding of procaine analogs to rat α3ß4 nicotinic acetylcholine receptor.

Nicotinic acetylcholine receptors (nAChRs) have been studied in detail with regard to their interaction with therapeutic and drug addiction-related compounds. Using a structure-activity approach, we have examined the relationship among the molecular features of a set of eight para-R-substituted N,N-[(dimethylamino)ethyl] benzoate hydrochlorides, structurally related to procaine and their affinity for the α(3)ß(4) nAChR heterologously expressed in KXα3ß4R2 cells. Affinity values (log[1/IC50]) of these compounds for the α(3)ß(4) nAChR were determined by their competition with [(3)H]TCP binding. Log(1/IC50) values were analyzed considering different hydrophobic and electronic parameters and those related to molar refractivity. These have been experimentally determined or were taken from published literature. In accordance with literature observations, the generated cross-validated quantitative structure-activity relationship (QSAR) equations indicated a significant contribution of hydrophobic term to binding affinity of procaine analogs to the receptor and predicted affinity values for several local anesthetics (LAs) sets taken from the literature. The predicted values by using the QSAR model correlated well with the published values both for neuronal and for electroplaque nAChRs. Our work also reveals the general structure features of LAs that are important for interaction with nAChRs as well as the structural modifications that could be made to enhance binding affinity.

Role of viscosity in influencing the glass-forming ability of organic molecules from the undercooled melt state.

PURPOSE: Understanding the critical factors governing the crystallization tendency of organic compounds is vital when assessing the feasibility of an amorphous formulation to improve oral bioavailability. The objective of this study was to investigate potential links between viscosity and crystallization tendency for organic compounds from the undercooled melt state. METHODS: Steady shear rate viscosities of numerous compounds were measured using standard rheometry as a function of temperature through the undercooled melt regime. Data for each compound were fit to the Vogel-Tamman-Fulcher (VTF) equation; kinetic fragility via strength parameter (D) was determined. RESULTS: Compounds with high crystallization tendencies exhibited lower melt viscosities than compounds with low crystallization tendencies. A correlation was observed between rate of change in viscosity with temperature and crystallization tendency, with slowly crystallizing compounds exhibiting larger increases in viscosity as temperature decreased below T(m). Calculated strength parameters indicated all compounds were kinetically fragile liquids; thus, kinetic fragility may not accurately assess glass-forming ability from undercooled melt state. CONCLUSIONS: A link was observed between the viscosity of a compound through the undercooled melt regime and its resultant crystallization tendency, indicating viscosity is a critical parameter to fully understand crystallization tendency of organic compounds.

Use of procaine and procainamide as derivatizing co-matrices for the analysis of oligosaccharides by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry.

RATIONALE: Analysis of oligosaccharides by matrix-assisted laser desorption/ionization (MALDI) mass spectrometry often yields only alkali metal cation adducts, which results in lower fragmentation yields and difficulty to retrieve sequence information. Derivatization by reductive amination may be used to promote Y-type glycosidic cleavages. However, this involves time-consuming preparations and purifications with sample loss. Here, procaine and procainamide were used directly as co-matrices with 2,5-dihydroxybenzoic acid (DHB). METHODS: Acidified 10 g/L procaine hydrochloride or procainamide hydrochloride solutions in water/acetonitrile were added to the oligosaccharide solution one minute before preparing our MALDI targets using DHB with the dried-droplet method. This simple protocol resulted in deposits of very fine homogeneous crystals. RESULTS: Positive ion mass spectra, easily acquired in an automated mode, presented a high percentage of oligosaccharides derivatized as Schiff base or glycosylamine notably detected as protonated molecules [M + H](+). The high abundance of procaine or procainamide on the target did not impede the ionization process, improved the signal-to-noise ratio and eliminated the need to search for 'sweet spots'. Fragmentation of the protonated precursor ions of the derivatives largely favored Y-type glycosidic cleavages. CONCLUSIONS: This easy and fast sample preparation, involving low toxicity and easily accessible chemicals, allowed the selection of protonated molecules as precursor ions for post-source decay analyses. This opened the possibility of simplifying sequence retrieval in routine oligosaccharide analyses.

Fundamentals of ionic conductivity relaxation gained from study of procaine hydrochloride and procainamide hydrochloride at ambient and elevated pressure.

The pharmaceuticals, procaine hydrochloride and procainamide hydrochloride, are glass-forming as well as ionically conducting materials. We have made dielectric measurements at ambient and elevated pressures to characterize the dynamics of the ion conductivity relaxation in these pharmaceuticals, and calorimetric measurements for the structural relaxation. Perhaps due to their special chemical and physical structures, novel features are found in the ionic conductivity relaxation of these pharmaceuticals. Data of conductivity relaxation in most ionic conductors when represented by the electric loss modulus usually show a single resolved peak in the electric modulus loss M(")(f) spectra. However, in procaine hydrochloride and procainamide hydrochloride we find in addition another resolved loss peak at higher frequencies over a temperature range spanning across T(g). The situation is analogous to many non-ionic glass-formers showing the presence of the structural α-relaxation together with the Johari-Goldstein (JG) ß-relaxation. Naturally the analogy leads us to name the slower and faster processes resolved in procaine hydrochloride and procainamide hydrochloride as the primary α-conductivity relaxation and the secondary ß-conductivity relaxation, respectively. The analogy of the ß-conductivity relaxation in procaine HCl and procainamide HCl with JG ß-relaxation in non-ionic glass-formers goes further by the finding that the ß-conductivity is strongly related to the α-conductivity relaxation at temperatures above and below T(g). At elevated pressure but compensated by raising temperature to maintain α-conductivity relaxation time constant, the data show invariance of the ratio between the ß- and the α-conductivity relaxation times to changes of thermodynamic condition. This property indicates that the ß-conductivity relaxation has fundamental importance and is indispensable as the precursor of the α-conductivity relaxation, analogous to the relation found between the Johari-Goldstein ß-relaxation and the structural α-relaxation in non-ionic glass-forming systems. The novel features of the ionic conductivity relaxation are brought out by presenting the measurements in terms of the electric modulus or permittivity. If presented in terms of conductivity, the novel features are lost. This warns against insisting that a log-log plot of conductivity vs. frequency is optimal to reveal and interpret the dynamics of ionic conductors.

Selective effect of procaine, tetracaine and dibucaine on gold nanoparticles.

An aqueous colloid dispersion of gold nanoparticles (AuNPs) was prepared by reduction of gold(III) chloride and its interaction with three local anesthetics (procaine, dibucaine or tetracaine) was investigated. Optical spectra reveal the modifications in the absorption band of nanoparticles related to their self assembly mediated by anesthetic molecules and depending on the progress in time of the aggregation process. TEM images show the features of the self assemblies formed by the association of gold nanoparticles in presence of anesthetics, and reveal marked differences in the behavior of the AuNPs against the three anesthetics. The main effect of various anesthetics can be described in terms of electrostatic forces between the negatively charged metal nanoparticles and anesthetic molecules, existing in their cationic form at the working pH. Then, the anesthetics functionalized nanoparticles trigger specific interactions to form different self assemblies through a selective combination of hydrophobic and hydrogen bonding interactions between the coated nanoparticles and anesthetics molecular species.

HTK-N, a modified HTK solution, decreases preservation injury in a model of microsteatotic rat liver transplantation.

BACKGROUND: Ischemia/reperfusion injury is an obstacle especially in steatotic livers, including those with steatosis induced by acute toxic stress. Recently, a modified histidine-tryptophan-ketoglutarate (HTK) solution, HTK-N, has been developed. This solution contains N-acetylhistidine, amino acids, and iron chelators. This study was designed to test the effects of HTK-N on preservation injury to rat livers after acute toxic injury. METHODS: Microvesicular steatosis was induced by a single dose of ethanol (8 g/kg BW). Livers were harvested and stored at 4 °C for 8 h with HTK or HTK-N before transplantation. Tissue and blood samples were taken at 1, 8, and 24 h after reperfusion to compare serum liver enzymes (aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase), standard histology, and immunohistochemistry for myeloperoxidase (MPO), caspase-3, and inducible nitric oxide synthase. Survival was compared after 1 week. For statistics, Analysis of Variance and t test were used. RESULTS: HTK-N improved survival from 12.5% in HTK to 87.5% (p < 0.05). Furthermore, liver enzymes were decreased to 2-75% of HTK values (p < 0.05). Necrosis and leukocyte infiltration and MPO, caspase-3, and iNOS expression after transplantation were decreased (p < 0.05). CONCLUSIONS: This study demonstrates that HTK-N protects liver grafts with microvesicular steatosis caused by acute toxic injury from cold ischemic injury better than standard HTK most likely via inhibition of hypoxic injury and oxidative stress and amelioration of the inflammatory reaction occurring upon reperfusion.

Kidney transplantation from a donor following cardiac death supported with extracorporeal membrane oxygenation.

To expand the donor pool, organ donation after cardiac death (DCD) has emerged. However, kidneys from DCD donors have a period of long warm ischemia between cardiac arrest and the harvesting of the organs. Recently, we used extracorporeal membrane oxygenation (ECMO) to minimize ischemic injury during 'no touch' periods in a Maastricht category II DCD donor and performed two successful kidney transplantations. The kidneys were procured from a 49-yr-old male donor. The warm ischemia time was 31 min, and the time of maintained circulation using ECMO was 7 hr 55 min. The cold ischemia time was 9 hr 15 min. The kidneys were transplanted into two recipients and functioned immediately after reperfusion. The grafts showed excellent function at one and three months post-transplantation; serum creatinine (SCr) levels were 1.0 mg/dL and 0.8 mg/dL and the estimated glomerular filtration rates (eGFR) were 63 mL/min/1.73 m(2) and 78 mL/min/1.73 m(2) in the first recipient, and SCr levels were 1.1 mg/dL and 1.0 mg/dL and eGFR were 56 mL/min/1.73 m(2) and 64 mL/min/1.73 m(2) in the second recipient. In conclusion, it is suggested that kidney transplantation from a category II DCD donor assisted by ECMO is a reasonable modality for expanding donor pool.

Prolonged cold storage using a new histidine-tryptophan-ketoglutarate-based preservation solution in isogeneic cardiac mouse grafts.

AIMS: The aim of this study was to evaluate a new histidine-tryptophan-ketoglutarate (HTK)-based cold preservation solution in comparison with traditional HTK solution in a mouse cardiac transplant model and to assess the impact of chloride ions and of iron chelators. METHODS AND RESULTS: After 24 h cold ischaemia, traditional HTK-preserved hearts survived up to 13 days (4.4 ± 1.7 days; n = 8)). Hearts stored in the new solution without iron chelators (N46) showed significantly prolonged survival up to 2 months (N46: 11.9 ± 8.7 days; P < 0.01; n = 7) and with iron chelators (DesfLK) up to 3 months (N46 DesfLK: 12.7 ± 13.7 days; n = 6). Re-beating time was significantly shorter with the new solution (HTK: 14.5 ± 5.9 min, N46: 9.2 ± 2.7 min, N46 DesfLK: 7.1 ± 3.7 min; P < 0.01). The new solution showed significantly decreased release of creatine kinase (HTK: 25998 ± 8471 U/L, N46: 13829 ± 7679 U/L, N46 DesfLK: 3093 ± 597 U/L; P < 0.01 and n = 7 each) and lactate dehydrogenase (HTK: 5391 ± 1062 U/L, N46: 3428 ± 1890 U/L, P < 0.05; N46 DesfLK: 682 ± 344 U/L, P < 0.01) and decreased histological evidence of injury. A chloride-poor variant of the new solution showed inferior graft survival. CONCLUSION: The new solution markedly attenuates myocardial injury and yields better graft survival than traditional HTK solution. The presence of chloride ions is crucial for heart preservation. Some protective effects are obviously caused by iron chelators.

Analysis of relationships between solid-state properties, counterion, and developability of pharmaceutical salts.

The solid-state properties of pharmaceutical salts, which are dependent on the counterion used to form the salt, are critical for successful development of a stable dosage form. In order to better understand the relationship between counterion and salt properties, 11 salts of procaine, which is a base, were synthesized and characterized using a variety of experimental and computational methods. Correlations between the various experimental and calculated physicochemical properties of the salts and counterions were probed. In addition to investigating the key factors affecting solubility, the hygroscopicity of the crystalline salts was studied to determine which solid-state and counterion properties might be responsible for enhancements in moisture uptake, thus providing the potential for adverse chemical stability. Multivariate principal components and partial least squares projection to latent structures analyses were performed in an attempt to establish predictive models capable of describing the relationships between these characteristics and both measured and calculated properties of the counterion and salt. Some success was achieved with respect to modeling crystalline salt solubility and the glass transition temperature of the amorphous salts. Through the modeling, insight into the relative importance of various descriptors on salt properties was achieved. The solid-state properties of crystalline and amorphous salts of procaine are highly dependent on the nature of the counterion. Important properties including aqueous solubility, melting point, hygroscopicity, and glass transition temperature were found to vary considerably between the different salts.

The Effectiveness of Rinsing Organs With Selected Preservation Solutions Based on the Analysis of Their Physicochemical Parameters.

BACKGROUND: One of the key elements of successful transplantation is effectively rinsing off the blood and preserving organs under controlled hypothermia. The aim of the study was to analyze the physicochemical parameters of Biolasol (Biochefa, Sosnowiec, Poland) and histidine-tryptophan-ketoglutarate (HTK) (Custodiol) solutions, which are recommended for perfusion and preservation of abdominal parenchymal organs. METHODS: Biolasol and HTK solution were used for the study. The solutions were subjected to physicochemical analysis involving pH, density, osmolarity, viscosity, refractive index, zeta potential, hydrodynamic diameter, and rheological properties. Rheological parameters were associated with morphologic features of fluids. RESULTS: HTK and Biolasol are non-Newtonian systems with pseudoplastic properties and yield stress. The solutions begin to flow under shear stress greater than the ultimate stress. In addition, a nonlinear relationship of their viscosity as a function of velocity gradient (shear rate) was observed. CONCLUSIONS: The solutions reproduce blood properties, which leads to the conclusion about their effective filling of the vascular bed and high efficiency in organ rinsing.

Synthesis of dual functional procaine-derived carbon dots for bioimaging and anticancer therapy.

Aim: Procaine-derived carbon dots, termed P-dots, expectedly offer both fluorescent biomarker function and anticancer activity. Materials & methods: P-dots were synthesized by condensing procaine, citric acid and ethylenediamine via hydrothermal synthesis and characterized by transmission electron microscopy, Fourier transform infrared spectroscopy and x-ray photoelectron spectroscopy. The cellular uptake behavior and the bioimaging performance of P-dots were assessed by confocal laser scanning microscopy. Their antitumor activity was evaluated using the CCK-8 assays and in vivo antitumor experiments, and the underlying mechanism was evaluated by flow cytometry and western blotting. Results: P-dots exhibited excellent luminescence properties suitable for bioimaging and considerable anticancer activity associated with caspase-3-related cell apoptosis. Conclusion: The synthesized procaine-derived carbon dots presented a dual function consisting of bioimaging and anticancer activity, which may enable their implementation as safe and effective clinical nanotherapeutics.

Nanoporous hybrid core-shell nanoparticles for sequential release.

In this article, a new type of core-shell nanoparticle is introduced. In contrast to most reported core-shell systems, the particles presented here consist of a porous core as well as a porous shell using only non-metal materials. The core-shell nanoparticles were successfully synthesized using nanoporous silica nanoparticles (NPSNPs) as the starting material, which were coated with nanoporous phenylene-bridged organosilica, resulting in a total particle diameter of about 80 nm. The combination of a hydrophilic nanoporous silica core and a more hydrophobic nanoporous organosilica shell provides regions of different chemical character and slightly different pore sizes within one particle. These different properties combined in one particle enable the selective adsorption of guest molecules at different parts of the particle depending on the molecular charge and polarity. On the other hand, the core-shell make-up of the particles provides a sequential release of guest molecules adsorbed at different parts of the nanoparticles. As a proof of concept, loading and release experiments with dyes were performed using non polar fluorescein and polar and charged methylene blue as model guest molecules. Non polar fluorescein is mostly adsorbed on the hydrophobic organosilica shell and therefore quickly released whereas the polar methylene blue, accumulated in the hydrophilic silica core, is only released subsequently. This occurs in small doses for an extended time corresponding to a sustained release over at least one year, controlled by the organosilica shell which acts as a diffusion barrier. An initial experiment with two drugs - non polar ibuprofen and polar and charged procaine hydrochloride - has been carried out as well and shows that the core-shell nanoparticles presented here can also be used for the sequential release of more relevant combinations of molecules.

Identification of hub genes and discovery of promising compounds in gastric cancer based on bioinformatics analysis.

Aim: To explore the mechanism of gastric carcinogenesis by mining potential hub genes and to search for promising small-molecular compounds for gastric cancer (GC). Materials & methods: The microarray datasets were downloaded from Gene Expression Omnibus database and the genes and compounds were analyzed by bioinformatics-related tools and software. Results: Six hub genes (MKI67, PLK1, COL1A1, TPX2, COL1A2 and SPP1) related to the prognosis of GC were confirmed to be upregulated in GC and their high expression was correlated with poor overall survival rate in GC patients. In addition, eight candidate compounds with potential anti-GC activity were identified, among which resveratrol was closely correlated with six hub genes. Conclusion: Six hub genes identified in the present study may contribute to a more comprehensive understanding of the mechanism of gastric carcinogenesis and the predicted potential of resveratrol may provide valuable clues for the future development of targeted anti-GC inhibitors.

A novel histidine-tryptophan-ketoglutarate formulation ameliorates intestinal injury in a cold storage and ex vivo warm oxygenated reperfusion model in rats.

AIM: The present study aims to evaluate protective effects of a novel histidine-tryptophan-ketoglutarate solution (HTK-N) and to investigate positive impacts of an additional luminal preservation route in cold storage-induced injury on rat small bowels. METHODS: Male Lewis rats were utilized as donors of small bowel grafts. Vascular or vascular plus luminal preservation were conducted with HTK or HTK-N and grafts were stored at 4°C for 8 h followed by ex vivo warm oxygenated reperfusion with Krebs-Henseleit buffer for 30 min. Afterwards, intestinal tissue and portal vein effluent samples were collected for evaluation of morphological alterations, mucosal permeability and graft vitality. RESULTS: The novel HTK-N decreased ultrastructural alterations but otherwise presented limited effect on protecting small bowel from ischemia-reperfusion injury in vascular route. However, the additional luminal preservation led to positive impacts on the integrity of intestinal mucosa and vitality of goblet cells. In addition, vascular plus luminal preservation route with HTK significantly protected the intestinal tissue from edema. CONCLUSION: HTK-N protected the intestinal mucosal structure and graft vitality as a luminal preservation solution. Additional luminal preservation route in cold storage was shown to be promising.