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In the present study, we demonstrated the marked activity of SW033291, an inhibitor of 15-hydoxyprostaglandin dehydrogenase (15-PGDH), in preventing acute kidney injury (AKI) in a murine model of ischemia-reperfusion injury. AKI due to ischemic injury represents a significant clinical problem. PGE2is vasodilatory in the kidney, but it is rapidly degraded in vivo due to catabolism by 15-PGDH. We investigated the potential of SW033291, a potent and specific 15-PGDH inhibitor, as prophylactic treatment for ischemic AKI. Prophylactic administration of SW033291 significantly increased renal tissue PGE2levels and increased post-AKI renal blood flow and renal arteriole area. In parallel, prophylactic SW033291 decreased post-AKI renal morphology injury scores and tubular apoptosis and markedly reduced biomarkers of renal injury that included blood urea nitrogen, creatinine, neutrophil gelatinase-associated lipocalin, and kidney injury molecule-1. Prophylactic SW033291 also reduced post-AKI induction of proinflammatory cytokines, high-mobility group box 1, and malondialdehyde. Protective effects of SW033291 were mediated by PGE2signaling, as they could be blocked by pharmacological inhibition of PGE2synthesis. Consistent with activation of PGE2signaling, SW033291 induced renal levels of both EP4receptors and cAMP, along with other vasodilatory effectors, including AMP, adenosine, and the adenosine A2Areceptor. The protective effects of SW0333291 could largely be achieved with a single prophylactic dose of the drug. Inhibition of 15-PGDH may thus represent a novel strategy for prophylaxis of ischemic AKI in multiple clinical settings, including renal transplantation and cardiovascular surgery.

Photodynamic therapy (PDT) is a rapidly evolving area of cancer management against solid tumors. PDT is either administrated by injecting photosensitizer (porphyrins) or by accumulation of intracellular protoporphyrin IX via the inhibition of human Protoporphyrinogen Oxidase IX (hPPO). In this study, novel inhibitors of hPPO have been investigated by integrating virtual screening, molecular docking, and molecular dynamics (MD) simulation. A ligand-based pharmacophore was generated from a training set of 22 inhibitors of hPPO. The selected pharmacophore had four chemical features including three hydrogen bond acceptors and one hydrophobic. The pharmacophore was characterized by highest correlation coefficient of 0.96, cost difference of 53.20, and lowest root mean square deviation of 0.73. The resultant pharmacophore was validated by Fischer’s Randomization and Test Set Validation methods. The validated pharmacophore was used as a 3D query to screen chemical databases including NCI, Asinex, Chembridge, and Maybridge. The screening of chemical databases and the subsequent application of Lipinski’s Rule of Five, and ADMET Assessment Test, retrieved 1176 drug-like compounds. The drug-like compounds were subjected to molecular docking studies in the active site of hPPO to eliminate false positive hits and to elucidate their true binding orientation. Top three candidate molecules with high docking scores and hydrogen bond interactions with catalytic active residues were selected as best candidate inhibitors against hPPO. The binding stability of selected candidate inhibitors was evaluated by MD simulation. The MD simulation of hits portrayed strong hydrogen bonds and key hydrophobic interactions with catalytic active residues of hPPO including R59, R97, G159, G332 and flavin moiety of FAD (coenzyme of hPPO). Our study predicts three hit compounds against hPPO, which could possibly accumulate high concentration of protoporphyrinogen-IX, and thereby acting as an intracellular photosensitizer against tumor cells through photodynamic therapy. Keywords: Photodynamic therapy (PDT), hPPO Inhibition, Virtual screening, Pharmacophore modeling, Molecular docking simulation, Molecular dynamics (MD) simulation

In this study, gold nanoparticles were supported at graphene derivatives (AuNPs@GDs) from chloroauric acid and graphene oxide (GO) by using sodium citrate, L-ascorbic acid, and 4-(2-hydroxyethyl)-1-piperazineethane-sulfonic acid (HEPES) as green reductants to evaluate the catalytic activity in the 4-nitrophenol (4-NP) reduction system. Among the three reductants, HEPES which derived AuNP@GD (3) exhibited up to 8.44-fold higher catalytic activity compared with sodium citrate and L-ascorbic acid. To evaluate the influence of mass ratio between Au and GO on the catalytic activity, we controlled adding amounts of chloroauric acid while the other conditions using HEPES were fixed. Notably, decreasing the mass ratio of Au/GO from 0.59 to 0.10 increased the rate constant in the range of 7.6 × 10−3 to 16.1 × 10−3/s. However, when the turnover frequency (TOF) was considered, the maximum value was obtained when Au/GO was 0.39. It can be concluded that AuNPs@GD (4) synthesized using HEPES significantly improved the catalytic activity in both rate constant (10.4 × 10−3/s) and TOF (8.08 × 10−5 mol/g·s) in 4-NP reduction. These results suggest that the type of reductants used to synthesize AuNPs@GDs is a significant factor on the catalytic activity and that GO can help increase the catalytic activity, but has an effective ratio with Au.

Breast cancer (BC) is the leading cause of death among women worldwide devoid of effective treatment. It is therefore important to develop agents that can reverse, reduce, or slow the growth of BC. The use of natural products as chemopreventive agents provides enormous advantages. The aim of the current investigation is to determine the efficacy of the phytochemicals against BC along with the approved drugs to screen the most desirable and effective phytocompound. In the current study, 36 phytochemicals have been evaluated against aromatase to identify the potential candidate drug along with the approved drugs employing the Cdocker module accessible on the Discovery Studio (DS) v4.5 and thereafter analysing the stability of the protein ligand complex using GROningen MAchine for Chemical Simulations v5.0.6 (GROMACS). Additionally, these compounds were assessed for the inhibitory features employing the structure-based pharmacophore (SBP). The Cdocker protocol available with the DS has computed higher dock scores for the phytochemicals complemented by lower binding energies. The top-ranked compounds that have anchored with key residues located at the binding pocket of the protein were subjected to molecular dynamics (MD) simulations employing GROMACS. The resultant findings reveal the stability of the protein backbone and further guide to comprehend on the involvement of key residues Phe134, Val370, and Met374 that mechanistically inhibit BC. Among 36 compounds, curcumin, capsaicin, rosmarinic acid, and 6-shogaol have emerged as promising phytochemicals conferred with the highest Cdocker interaction energy, key residue interactions, stable MD results than reference drugs, and imbibing the key inhibitory features. Taken together, the current study illuminates the use of natural compounds as potential drugs against BC. Additionally, these compounds could also serve as scaffolds in designing and development of new drugs.

In the present study, we demonstrated the marked activity of SW033291, an inhibitor of 15-hydoxyprostaglandin dehydrogenase (15-PGDH), in preventing acute kidney injury (AKI) in a murine model of ischemia-reperfusion injury. AKI due to ischemic injury represents a significant clinical problem. PGE(2) is vasodilatory in the kidney, but it is rapidly degraded in vivo due to catabolism by 15-PGDH. We investigated the potential of SW033291, a potent and specific 15-PGDH inhibitor, as prophylactic treatment for ischemic AKI. Prophylactic administration of SW033291 significantly increased renal tissue PGE(2) levels and increased post-AKI renal blood flow and renal arteriole area. In parallel, prophylactic SW033291 decreased post-AKI renal morphology injury scores and tubular apoptosis and markedly reduced biomarkers of renal injury that included blood urea nitrogen, creatinine, neutrophil gelatinase-associated lipocalin, and kidney injury molecule-1. Prophylactic SW033291 also reduced post-AKI induction of proinflammatory cytokines, high-mobility group box 1, and malondialdehyde. Protective effects of SW033291 were mediated by PGE(2) signaling, as they could be blocked by pharmacological inhibition of PGE(2) synthesis. Consistent with activation of PGE(2) signaling, SW033291 induced renal levels of both EP(4) receptors and cAMP, along with other vasodilatory effectors, including AMP, adenosine, and the adenosine A(2A) receptor. The protective effects of SW0333291 could largely be achieved with a single prophylactic dose of the drug. Inhibition of 15-PGDH may thus represent a novel strategy for prophylaxis of ischemic AKI in multiple clinical settings, including renal transplantation and cardiovascular surgery.

Dihydrofolate reductase (DHFR) is an essential cellular enzyme and thereby catalyzes the reduction of dihydrofolate to tetrahydrofolate (THF). In cancer medication, inhibition of human DHFR (hDHFR) remains a promising strategy, as it depletes THF and slows DNA synthesis and cell proliferation. In the current study, ligand-based pharmacophore modeling identified and evaluated the critical chemical features of hDHFR inhibitors. A pharmacophore model (Hypo1) was generated from known inhibitors of DHFR with a correlation coefficient (0.94), root mean square (RMS) deviation (0.99), and total cost value (125.28). Hypo1 was comprised of four chemical features, including two hydrogen bond donors (HDB), one hydrogen bond acceptor (HBA), and one hydrophobic (HYP). Hypo1 was validated using Fischer’s randomization, test set, and decoy set validations, employed as a 3D query in a virtual screening at Maybridge, Chembridge, Asinex, National Cancer Institute (NCI), and Zinc databases. Hypo1-retrieved compounds were filtered by an absorption, distribution, metabolism, excretion, and toxicity (ADMET) assessment test and Lipinski’s rule of five, where the drug-like hit compounds were identified. The hit compounds were docked in the active site of hDHFR and compounds with Goldfitness score was greater than 44.67 (docking score for the reference compound), clustering analysis, and hydrogen bond interactions were identified. Furthermore, molecular dynamics (MD) simulation identified three compounds as the best inhibitors of hDHFR with the lowest root mean square deviation (1.2 Å to 1.8 Å), hydrogen bond interactions with hDHFR, and low binding free energy (−127 kJ/mol to −178 kJ/mol). Finally, the toxicity prediction by computer (TOPKAT) affirmed the safety of the novel inhibitors of hDHFR in human body. Overall, we recommend novel hit compounds of hDHFR for cancer and rheumatoid arthritis chemotherapeutics.

We investigated the long-term performance degradation in a solid oxide carbon fuel cell (SO-CFC) integrated with a steam gasifier that used activated carbon as a fuel. The steam gasifier-integrated SO-CFC was continuously operated for 2000 h at 750 °C under galvanostatic conditions. Fuel analysis, in-situ electrochemical tests, and post-mortem characterization were performed to determine the dominant degradation factors during the extended operation of the SO-CFC. During the 2000 h continuous operation, the overall degradation rate of the SO-CFC was 0.108 V per 1000 h. Electrochemical impedance spectroscopy analysis showed that the polarization and ohmic resistance of the SO-CFC increased gradually with the operation time. The post-mortem diagnosis via SEM, XRD, EDS, and XPS analyses revealed that the increased Ni particle coarsening and carbon deposition at the anode functional layer induced increased performance degradation in the SO-CFC. The long-term durability study of the SO-CFC with a steam gasifier confirmed that conventional anode materials result in rapid performance degradation during 2000 h continuous operation, and further development of anode materials will be necessary for the long and durable operation of SO-CFCs.

Aromatase inhibitors with an $\mathrm{IC}_{50}$ IC 50 value ranging from 1.4 to 49.7 µM are known to act as antiepileptic drugs besides being potential breast cancer inhibitors. The aim of the present study is to identify novel antiepileptic aromatase inhibitors with higher activity exploiting the ligand-based pharmacophore approach utilizing the experimentally known inhibitors. The resultant Hypo1 consists of four features and was further validated by using three different strategies. Hypo1 was allowed to screen different databases to identify lead molecules and were further subjected to Lipinski's Rule of Five and ADMET to establish their drug-like properties. Consequently, the obtained 68-screened molecules were subjected to molecular docking by GOLD v5.2.2. Furthermore, the compounds with the highest dock scores were assessed for molecular interactions. Later, the MD simulation was applied to evaluate the protein backbone stabilities and binding energies adapting GROMACS v5.0.6 and MM/PBSA which was followed by the density functional theory (DFT), to analyze their orbital energies, and further the energy gap between them. Eventually, the number of Hit molecules was culled to three projecting Hit1, Hit2, and Hit3 as the potential lead compounds based on their highest dock scores, hydrogen bond interaction, lowest energy gap, and the least binding energies and stable MD results.

This study aims at developing and evaluating reconstitutable dry suspension (RDS) improved for dissolution rate, oral absorption, and convenience of use of poorly water-soluble celecoxib (CXB). Micro-sized CXB particle was used to manufacture nanosuspension by using bead milling and then RDS was made by spray-drying the nanosuspension with effective resuspension agent, dextrin. The redispersibility, morphology, particle size, crystallinity, stability, dissolution, and pharmacokinetic profile of the RDS were evaluated. RDS was effectively reconstituted into nanoparticles in 775.8 &plusmn, 11.6 nm. It was confirmed that CXB particles are reduced into needle-shape ones in size after the bead-milling process, and the description of CXB was the same in the reconstituted suspension. Through the CXB crystallinity study using differential scanning calorimetry (DSC) and XRD analysis, it was identified that CXB has the CXB active pharmaceutical ingredient (API)&rsquo, s original crystallinity after the bead milling and spray-drying process. In vitro dissolution of RDS was higher than that of CXB powder (93% versus 28% dissolution at 30 min). Furthermore, RDS formulation resulted in 5.7 and 6.3-fold higher area under the curve (AUC&infin, ) and peak concentration (Cmax) of CXB compared to after oral administration of CXB powder in rats. Collectively, our results suggest that the RDS may be a potential oral dosage formulation for CXB to improve its bioavailability and patient compliance.

Proteins deacetylation by Histone deacetylase 6 (HDAC6) has been shown in various human chronic diseases like neurodegenerative diseases and cancer, and hence is an important therapeutic target. Since, the existing inhibitors have hydroxamate group, and are not HDAC6-selective, therefore, this study has designed to investigate non-hydroxamate HDAC6 inhibitors. Ligand-based pharmacophore was generated from 26 training set compounds of HDAC6 inhibitors. The statistical parameters of pharmacophore (Hypo1) included lowest total cost of 115.63, highest cost difference of 135.00, lowest RMSD of 0.70 and the highest correlation of 0.98. The pharmacophore was validated by Fischer’s Randomization and Test Set validation, and used as screening tool for chemical databases. The screened compounds were filtered by fit value ([Formula: see text]), estimated Inhibitory Concentration (IC[Formula: see text]) ([Formula: see text]), Lipinski’s Rule of Five and Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) Descriptors to identify drug-like compounds. Furthermore, the drug-like compounds were docked into the active site of HDAC6. The best docked compounds were selected having goldfitness score [Formula: see text] and [Formula: see text], and hydrogen bond interaction with catalytic active residues. Finally, three inhibitors having sulfamoyl group were selected by Molecular Dynamic (MD) simulation, which showed stable root mean square deviation (RMSD) (1.6–1.9[Formula: see text]Å), lowest potential energy ([Formula: see text][Formula: see text]kJ/mol), and hydrogen bonding with catalytic active residues of HDAC6.

OBJECTIVE Hypoxia inducible factor 1α (HIF1α) has been reported to activate inflammatory cascade. Recently, exosomes have been known to have pivotal roles in intercellular communication. The aim of this study was to compare the concentration of amniotic fluid (AF) HIF1α, exosomal HIF1α, and inflammatory cytokines such as interleukin 1α (IL1α), interleukin 1β (IL1β), interleukin 6 (IL6), and tumor necrosis factor α (TNFα) between physical examination-indicated cerclage (PEIC) and control group. We also investigated the associations between biomarkers and amniocentesis-to-delivery interval and the correlations of inflammatory cytokines, HIF1α, and exosomal HIF1α. METHODS Case-control study was performed. Cases are defined as 16 patients who underwent PEIC and controls are 19 women who underwent amniocentesis for confirming chromosomal abnormalities. The concentration of IL1α, IL1β, IL6, TNFα, HIF1α, and exosomal HIF1α were measured using enzyme-linked immunosorbent assay (ELISA). Exosomes were confirmed by tumor susceptibility Gene 101 (TSG 101) and transmission electron microscopy (TEM). RESULTS The mean HIF1α in PEIC group was higher than control group (PEIC, 15.03 ± 9.60-pg/mL versus control, 2.96 ± 1.99 pg/mL; p

Breast cancer is one of the major impediments affecting women globally. The ATP-dependant heat shock protein 90 (Hsp90) forms the central component of molecular chaperone machinery that predominantly governs the folding of newly synthesized peptides and their conformational maturation. It regulates the stability and function of numerous client proteins that are frequently upregulated and/or mutated in cancer cells, therefore, making Hsp90 inhibition a promising therapeutic strategy for the development of new efficacious drugs to treat breast cancer. In the present in silico investigation, a structure-based pharmacophore model was generated with hydrogen bond donor, hydrogen bond acceptor and hydrophobic features complementary to crucial residues Ala55, Lys58, Asp93, Ile96, Met98 and Thr184 directed at inhibiting the ATP-binding activity of Hsp90. Subsequently, the phytochemical dataset of 3210 natural compounds was screened to retrieve the prospective inhibitors after rigorous validation of the model pharmacophore. The retrieved 135 phytocompounds were further filtered by drug-likeness parameters including Lipinski's rule of five and ADMET properties, then investigated via molecular docking-based scoring. Molecular interactions were assessed using Genetic Optimisation for Ligand Docking program for 95 drug-like natural compounds against Hsp90 along with two clinical drugs as reference compounds - Geldanamycin and Radicicol. Docking studies revealed three phytochemicals are better than the investigated clinical drugs. The reference and hit compounds with dock scores of 48.27 (Geldanamycin), 40.90 (Radicicol), 73.04 (Hit1), 72.92 (Hit2) and 68.12 (Hit3) were further validated for their binding stability through molecular dynamics simulations. We propose that the non-macrocyclic scaffolds of three identified phytochemicals might aid in the development of novel therapeutic candidates against Hsp90-driven cancers.

Kidney transplantation is the best treatment option for end stage renal disease. As a result of disparity between the demand for kidney transplantation and the supply of suitable organs, kidneys from suboptimal donors have been used in kidney transplantation. Since demonstration of better patient survival, using marginal donor kidney rather than remaining on hemodialysis, more expanded criteria for donor kidneys were adopted in kidney transplantation. Several donor scoring systems, including Nyberg's donor scoring system, donor risk score by Schold, delayed graft function nomogram, kidney donor risk index (KDRI), and histological graft variable have been developed for evaluation of the quality of deceased donor kidneys showing an increased risk for graft dysfunction and loss and for improvement of the stratification; 15% highest risk donors by KDRI and grade C (20∼29 points) and grade D (30∼39 points) by Nyberg's deceased donor scoring system are compatible with the definition of expanded criteria for kidney donors of United Network for Organ Sharing. Utilization of these scoring systems would be very useful in allocation of expanded criteria for donors for improvement of graft and patient survival.

A novel pectate lyase 3 (Bx-PEL3) gene from the stage-specifically expressed sequence tag library of Bursaphelenchus xylophilus was cloned. Bx-PEL1 and Bx-PEL2 were relatively predominant to Bx-PEL3 in quantitative real-time PCR analysis. The variation of expression level among Bx-PELs according to different life stages suggests that each Bx-PEL may play different biochemical roles in pathogenesis. Recombinant Bx-PEL3 showed activity against polygalacturonic acid and its optimized physical conditions for pH and Ca2 + concentrations were 9.0 and 0.5 mM, respectively. Homology modeling revealed that Bx-PELs were structurally similar to PEL from the Bacillus strain KSM P-15 and shared essential residues for calcium binding and catalytic activity. Bx-PEL3 was expressed near the esophageal gland as shown in other Bx-PELs, indicating that Bx-PEL3 may be involved in the degradation of the cell wall after secretion from the stylet. Our data suggest that the novel PEL3 gene is a putative pathogenic factor which is biochemically functional.

High level of hematopoietic cell kinase (Hck) is associated with drug resistance in chronic myeloid leukemia. Additionally, Hck activity has also been connected with the pathogenesis of HIV-1 and chronic obstructive pulmonary disease. In this study, three-dimensional (3D) QSAR pharmacophore models were generated for Hck based on experimentally known inhibitors. A best pharmacophore model, Hypo1, was developed with high correlation coefficient (0.975), Low RMS deviation (0.60) and large cost difference (49.31), containing three ring aromatic and one hydrophobic aliphatic feature. It was further validated by the test set (r = 0.96) and Fisher’s randomization method (95%). Hypo 1 was used as a 3D query for screening the chemical databases, and the hits were further screened by applying Lipinski’s rule of five and ADMET properties. Selected hit compounds were subjected to molecular docking to identify binding conformations in the active site. Finally, the appropriate binding modes of final hit compounds were revealed by molecular dynamics (MD) simulations and free energy calculation studies. Hence, we propose the final three hit compounds as virtual candidates for Hck inhibitors.

Progeria is a rare genetic disorder characterized by premature aging that eventually leads to death and is noticed globally. Despite alarming conditions, this disease lacks effective medications; however, the farnesyltransferase inhibitors (FTIs) are a hope in the dark. Therefore, the objective of the present article is to identify new compounds from the databases employing pharmacophore based virtual screening. Utilizing nine training set compounds along with lonafarnib, a common feature pharmacophore was constructed consisting of four features. The validated Hypo1 was subsequently allowed to screen Maybridge, Chembridge, and Asinex databases to retrieve the novel lead candidates, which were then subjected to Lipinski’s rule of 5 and ADMET for drug-like assessment. The obtained 3,372 compounds were forwarded to docking simulations and were manually examined for the key interactions with the crucial residues. Two compounds that have demonstrated a higher dock score than the reference compounds and showed interactions with the crucial residues were subjected to MD simulations and binding free energy calculations to assess the stability of docked conformation and to investigate the binding interactions in detail. Furthermore, this study suggests that the Hits may be more effective against progeria and further the DFT studies were executed to understand their orbital energies.

Azole antifungal agents are essential drugs in the treatment of fungal infections in renal transplant patients. As azoles, these antifungal agents are inhibitors of CYP3A4 and P-glycoprotein (P-gp); and thus therapeutic drug monitoring is important. We evaluated a patient with cutaneous and pulmonary aspergillosis who was successfully treated with voriconazole and a low cyclosporine trough level (3.2 - 27.9 ng/ml) for 3 months. During that period, the patient showed good allograft function with the co-administration of voriconazole and cyclosporine. We measured the patient's genotype of MDR1, CYP3A4, CYP3A5 and CYP2C19 enzymes in addition to the intracellular concentration of cyclosporine in peripheral blood mononuclear cells (PBMCs). The intracellular concentration of cyclosporine in PBMC is 3.2 times higher with no functionally defected alleles in MDR1, CYP3A4, CYP3A5 or CYP2C19 enzymes when cyclosporine is co-administered with voriconazole ex vivo. Although other confounding factors causing immunological modulation may exist, it is plausible that low serum and high intracellular cyclosporine concentrations, due to the inhibition of P-gp activity by voriconazole, also contribute to an immunosuppressive state.

Aspergillosis is a serious infectious complication with high mortality in transplant recipients. Voriconazole is a broad spectrum triazole antifungal agent, but it has a drug-drug interaction with immunosuppressants. Herein we report a case of the use of a small dose of cyclosporine (CsA) with coadministration of voriconazole. A 23 year old woman received a kidney transplant from a deceased donor. The initial immunosuppressant was tacrolimus, mycophenolate mofetil, steroids, and basiliximab. Thirty-two days after kidney transplantation, because of hemolytic uremic syndrome, she received Rabbit anti-human thymocyte immunoglobulin and plasmapheresis. Cyclosporine was used instead of tacrolimus. Three months after transplantation, she was admitted to the hospital because of an erythematous nodule on her trunk and a dry cough. Skin biopsy revealed an Aspergillus species and tissue culture showed that it was A. fumigatus. We treated her with itraconazole and subsequently with amphotericin B. Afterwards, her condition got worse. So we changed amphotericin B to voriconazole and a minimum dose of CsA (25 mg bid) at the peril of graft failure. Eventually, she recovered and maintained good graft function. The trough level of CsA ranged from 3.2 to 27.9 ng/mL.

Mitochondrial proteins associated with a wide spectrum of human diseases and currently large amounts of tissue or organ specific human mitochondrial proteome datasets are generated. However, high-throughput comparative proteomic methods have yet to be applied to extract subtle differences among mitochondria from different tissues or muscle types. The aim of this work was to provide an integrated way to identify and compare huge mitochondrial protein or peptide mass spectral data sets acquired from expert mitochondrial proteome or biomarker discovery community. Proteome comparison of human mitochondria (PCHM) is a web-based analysis environment for manual or automatic analysis of individual peptide mass fingerprints alongside a database of proteins and peptides identified in various organs for human mitochondrial proteins. PCHM provides a suite of graphical tools that allow the virtual plot of peptide mass fingerprinting (PMF) spectra and a fully automatic protein function classification based on gene ontology (GO) annotation system. The new virtual PMF plot is very useful to validate fragmented ion loses of any identical proteins and to remove unwanted foreign ion peaks. Fully automatic protein function classifier provides an easier way to compare the subtle differences of compositionally biased mitochondrial protein functions. PCHM also provides a variety of query algorithms aid in browsing, searching, and accessing complete annotations of data relevant to each mitochondrial protein of interest, which link external databases and users. PCHM will be a useful tool for the systematic and functional characterization of the mitochondrial proteins in relation to human diseases or biological research applications. PCHM can be accessed freely via a web interface http://pchm.inje.ac.kr.

"To be, or not to be?" This question is not only Hamlet`s agony but also the dilemma of mitochondria in a cancer cell. Cancer cells have a high glycolysis rate even in the presence of oxygen. This feature of cancer cells is known as the Warburg effect, named for the first scientist to observe it, Otto Warburg, who assumed that because of mitochondrial malfunction, cancer cells had to depend on anaerobic glycolysis to generate ATP. It was demonstrated, however, that cancer cells with intact mitochondria also showed evidence of the Warburg effect. Thus, an alternative explanation was proposed: the Warburg effect helps cancer cells harness additional ATP to meet the high energy demand required for their extraordinary growth while providing a basic building block of metabolites for their proliferation. A third view suggests that the Warburg effect is a defense mechanism, protecting cancer cells from the higher than usual oxidative environment in which they survive. Interestingly, the latter view does not conflict with the high-energy production view, as increased glucose metabolism enables cancer cells to produce larger amounts of both antioxidants to fight oxidative stress and ATP and metabolites for growth. The combination of these two different hypotheses may explain the Warburg effect, but critical questions at the mechanistic level remain to be explored. Cancer shows complex and multi-faceted behaviors. Previously, there has been no overall plan or systematic approach to integrate and interpret the complex signaling in cancer cells. A new paradigm of collaboration and a well-designed systemic approach will supply answers to fill the gaps in current cancer knowledge and will accelerate the discovery of the connections behind the Warburg mystery. An integrated understanding of cancer complexity and tumorigenesis is necessary to expand the frontiers of cancer cell biology.

The purpose of the present study was designed to evaluate the bioequivalence of two oxiracetam tablets, Neuromed tablet (Korea Drug Co., reference drug) and Neuracetam tablet (Sam Jin Pharmaceutical Co., test drug), according to the guidelines of Korea Food and Drug Administration (KFDA). Release of oxiracetam from the tablet in vitro was tested using KP VIII Apparatus II method with various dissolution media (pH 1.2, 4.0, 6.8 buffer solution and water). Twenty-four healthy volunteers, year in age and kg in body weight, were divided into two groups and a randomized cross-over study was performed. After oral administration of a tablet containing 800 mg of oxiracetam, blood samples were taken at predetermined time intervals and concentrations of oxiracetam in plasma were determined using HPLC-MS-MS. The dissolution profiles of two formulations were very similar at all dissolution media. In addition, pharmacokinetic parameters such as , and were calculated and ANOVA test was utilized for the statistical analysis of the parameters using logarithmically transformed and untransformed . The results showed that the differences between two formulations based on the reference drug were 0.42%, 0.45% and -12.58% for , and , respectively. There were no sequence effects between two formulations in these parameters. The 90% confidence intervals for the log transformed data were within the acceptance range of log 0.8 to log 1.25 (e.g., and for , and , respectively), indicating that Neuracetam tablet is bioequivalent to Neuromed tablet. The major pharmacokinetic parameters, , and met the criteria set by KFDA for bioequivalence indicating that Neuracetam tablet is bioequivalent to Neuromed tablet.

Fibrillary glomerulonephritis (FGN) is a rare cause of progressive renal dysfunction resulting in fibrillary deposits in the mesangium and/or glomerular basement membrane (GBM). Some case reports have shown FGN in patients with rheumatoid arthritis and other autoimmune diseases. This is the first case report of FGN in a patient with Behçet's syndrome. The most common renal histological finding in Behçet's syndrome is secondary amyloidosis. A 46-year-old woman with a 4-year history of Behçet's syndrome was referred to the nephrology clinic with foamy urine with non-selective proteinuria (urine protein-to-creatinine ratio was 1400 mg protein/g creatinine) and microscopic hematuria. Serum and urine protein electrophoresis showed no evidence of monoclonal gammopathy. A renal biopsy was performed. Light microscopy showed mesangial widening and nodular expansion with hyaline deposits. Immunofluorescence microscopy revealed immunoglobulin M deposits in the mesangium. Congo red staining was negative. Electron microscopy showed fibrillary deposits on the GBM. Pathological findings were consistent with FGN. She had been taking 50 mg azathioprine and 3000 mg mesalazine per day for 4 years due to Behçet's syndrome, so we did not add any other immunosuppressive agents or corticosteroids. Treatment of this glomerulopathy is not promising. It has been noted that none of the various approaches, including corticosteroid, plasmapheresis, and cytotoxic therapy, improves prognosis.

Transforming growth factor-β (TGF-β) has a significant role in the response to injury and tissue repair, and it has been detected in various cell types. However, the mechanism by which it regulates the response to ischemia‑reperfusion injury (IRI) and manipulates natural killer (NK) cells is not well understood. In the present study, TGF‑β modulated NK cell function, thereby promoting recovery from renal IRI. Human renal proximal tubular epithelial cells (HK‑2) treated with TGF‑β exhibited increased surface and intracellular expression of the NK group 2 member D (NKG2D) ligand MICA. This increased surface expression of MICA inhibited NK cell cytotoxicity to the HK‑2 cells. In addition, an enzyme‑linked immunosorbent assay revealed that TGF‑β treatment evidently increased the amount of soluble MICA released into the culture supernatant from HK‑2 cells. Taken together, these findings suggest that TGF‑β‑induced release of soluble MICA leads to downregulation of NKG2D, thereby preventing NK cell‑mediated cytotoxicity toward renal proximal tubular epithelial cells in renal IRI, which in turn improves the survival of these cells.

Aims: This study examined changes in the perceptions and attitudes as well as the sense of individual and collective responsibility in medical students after they received patient safety education. Method: A three-day patient safety curriculum was implemented for third-year medical students shortly before entering their clerkship. Before and after training, we administered a questionnaire, which was analysed quantitatively. Additionally, we asked students to answer questions about their expected behaviours in response to two case vignettes. Their answers were analysed qualitatively. Results: There was improvement in students’ concepts of patient safety after training. Before training, they showed good comprehension of the inevitability of error, but most students blamed individuals for errors and expressed a strong sense of individual responsibility. After training, students increasingly attributed errors to system dysfunction and reported more selfconfidence in speaking up about colleagues’ errors. However, due to the hierarchical culture, students still described difficulties communicating with senior doctors. Conclusions: Patient safety education effectively shifted students’ attitudes towards systems-based thinking and increased their sense of collective responsibility. Strategies for improving superior-subordinate communication within a hierarchical culture should be added to the patient safety curriculum.

Herein, we report galvanic displacement of metal nanoparticles and films onto single-crystalline GaAs (100) substrates, a simple and cost-effective method to fabricate highly controlled metal/semiconductor interface. A time-resolved surface analysis of Au/GaAs system was conducted and microscopic mechanism of galvanic displacement was elucidated in detail. Quantitative temporal XPS measurements of the Au/GaAs interface showed that, initially, fast Au growth was slowed down as the deposition process proceeded. This was attributed to growing oxide layer blocking hole conduction and causing quenching of the deposition process. Addition of various inorganic acids, which function as oxide etchants, was found to enhance deposition rates by effectively removing surface oxide, with HF the most effective. Various precious metals, such as Pt and Ag, could be deposited onto GaAs through galvanic displacement, which demonstrates the versatility of the method.

Transforming growth factor-β (TGF-β) signaling transduction initiates TGF-β activation, resulting in activation of TGF-β receptor II (TGFBR2). Any quantitative and qualitative changes in TGFBR2 are expected to affect the TGF-β signaling pathway, which occupies a central position with respect to the regulation of cell growth, differentiation, apoptosis, immune reaction, angiogenesis and extracellular matrix formation. Recent studies have shown that TGF-β1 gene polymorphisms may confer susceptibility to early acute and chronic allograft rejection in kidney transplantation recipients. In this study, we assessed whether polymorphisms of the TGFBR2 gene were associated with susceptibility to kidney transplantation rejection. A total of 347 renal allograft recipients transplanted at three centers in Korea were analyzed. Three SNPs (rs764522, rs3087465, rs2228048) of the TGFBR2 gene were genotyped from genomic DNA with direct sequencing. Multiple logistic regression models (codominant, dominant, recessive, and log-additive) were performed to evaluate odds ratios (ORs), 95% confidence intervals (CIs), and p-values. A total of 63 patients (18%) developed acute rejection (AR). There were no significant differences in age, sex, number of HLA mismatches, cause of renal failure, or immunosuppressant regimen between the AR and non-AR group. The synonymous SNP rs2228048 was significantly associated with AR (p = 0.020 in recessive model, and p = 0.036 in log-additive model. The allele frequencies of rs2228048 were different between the AR and non-AR group (p = 0.026). These results suggest that the synonymous TGFBR2 gene SNP rs2228048 may be associated with the development of AR in Korean kidney transplantation recipients. Authors Yeong-Hoon Kim and Tae Hee Kim contributed equally to this work and are considered co-first authors.

The aim of this study was to examine the in vitro/in vivo relationship of the drug release behavior of a sustained-release formulation of gabapentin. The immediate-release formulation was used as the reference formulation. The dissolution test was employed using pH 1.2, 4.0, or 6.8 buffer solution, or water, to determine the in vitro release behaviors of gabapentin tablets. Gabapentin was released completely within 1 h from the immediate-release tablet and released for 12 h from the sustained-release tablet. A single dose (600 mg) of each formulation was orally administered to four beagle dogs under fasted conditions, and the pharmacokinetic parameters were calculated. Although the sustained-release tablet did not disintegrate and had slow drug release characteristics, it showed similar pharmacokinetic parameters to the immediate-release tablet, which rapidly disintegrated and showed fast drug release. Thus, the in vivo release of gabapentin did not correlate with in vitro release of drug.

Acamprosate calcium is a highly soluble drug with low permeability that is used to maintain abstinence in alcohol-dependent patients. The aim of this study was to investigate the relationship between in vitro and in vivo behaviors of acamprosate from enteric-coated tablets. The in vitro release behavior of acamprosate tablets in pH 6.8 buffer solution was determined in three dissolution conditions, 50 and 150 rpm (paddle method) and 180 rpm (basket method). The results of this in vitro experiment indicated that acamprosate tablets hardly disintegrated, and drug dissolution was retarded despite the extremely hydrophilic nature of the drug. A single dose (333 mgx2 tablets) of each formulation was orally administered to four beagle dogs under fasting conditions, and the pharmacokinetic parameters were calculated. The mean AUC0-48, Cmax, Tlag and Tmax for the two types of tablets ranged from 41.5-53.6 microg.h/mL, 4.3-4.5 microg/mL, 2.0-2.5 h and 3.8-4.0 h, respectively. In conclusion, it is suggested that retarded drug release from the tablets and the low drug permeability may result in poor absorption and erratic bioavailability of this drug in humans.

Hydatid cysts (echinococcosis) are caused by an infestation with larval tapeworms of the genus Echinococcus. The disease is extensively distributed worldwide, and it has been rarely reported in Korea. We describe the cytologic features of a case of hepatic hydatid cyst in a 28-year-old male. Computed tomography revealed a cystic mass in the right lobe of the liver. A right hemihepatectomy was performed. The aspirated fluid from the hepatic cystic mass was clear. The smears showed protoscolices, hooklets, and a laminated membrane.

Soft tissue myoepithelioma is a rare neoplasm composed of myoepithelial cells. Here, we describe the cytologic features of soft tissue myoepithelioma arising on the right forearm in an 18-year-old man. The excised tumor (3.0×1.8×1.5 cm) was well-demarcated, yellow-gray, soft, and myxoid. The cytologic smears showed round to spindle, epithelioid, and plasmacytoid cells in the myxoid background. The nuclei were uniform, round to ovoid, with finely distributed chromatin and eosinophilic or pale cytoplasm. The tumor cells demonstrated immunoreactivity for cytokeratin (AE1/AE3), epithelial membrane antigen, S100 protein, and glial fibrillary acidic protein. Electron microscopy showed intermediate filaments, desmosomes, and basal lamina.

Sparganosis of the breast is an uncommon disease. Cytological granulomatous inflammation is a common feature of sparganosis. The presence of larval fragments is necessary for a definitive di ­ agnosis of sparganosis in a cytological specimen. However, calcareous corpuscles entrapped in necrotic debris can be very diagnostic for sparganosis in endemic areas. We experienced three cases of mammary sparganosis diagnosed by fine needle aspiration cytology before surgical ex ­ cision. Two cases showed numerous calcareous corpuscles associated with necrotic debris thou­ ght to be degenerated parasitic bodies. The remaining case revealed a few degenerative calcare­ ous corpuscles and parasitic bodies. The presence of calcareous corpuscles and/or degenerative parasitic bodies can be an aid in the differential diagnosis between sparganosis and other forms of granulomatous mastitis, particularly in endemic areas of sparganosis.

Recently we experienced three cases of human epidermal growth factor receptor 2 (HER2)-amplified invasive breast carcinomas associated with co-amplification or gain of chromosome 17 centromere (CEP17) in silver-enhanced in situ hybridization (SISH) analysis. These cases revealed 2+ or 3+ staining for HER2 immunohistochemistry and > 6 HER2 copies per cell on SISH analyses. However, the calculated HER2/CEP17 ratios were low ( 6 per cell vs HER2/CEP17 ratio> 2.2). We recommend reporting raw SISH or fluorescence in situ hybridization data, including number of cells counted, average numbers of HER2 and CEP17 signals, and the calculated HER2/CEP17 ratio to prevent underreporting of HER2 amplification.