Biomedical subjects

Vimon Tantishaiyakul

Publications and source records attributed to Vimon Tantishaiyakul.

8 recordsLinked to original sources

PubMed2006

S-nitrosylation of Bcl-2 inhibits its ubiquitin-proteasomal degradation. A novel antiapoptotic mechanism that suppresses apoptosis.

Bcl-2 is a key apoptosis regulatory protein of the mitochondrial death pathway whose function is dependent on its expression levels. Although Bcl-2 expression is controlled by various mechanisms, post-translational modifications, such as ubiquitination and proteasomal degradation, have emerged as important regulators of Bcl-2 function. However, the underlying mechanisms of this regulation are unclear. We report here that Bcl-2 undergoes S-nitrosylation by endogenous nitric oxide (NO) in response to multiple apoptotic mediators and that this modification inhibits ubiquitin-proteasomal degradation of Bcl-2. Inhibition of NO production by the NO scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide and by NO synthase inhibitor aminoguanidine effectively inhibited S-nitrosylation of Bcl-2, increased its ubiquitination, and promoted apoptotic cell death induced by chromium (VI). In contrast, the NO donors dipropylenetriamine NONOate and sodium nitroprusside showed opposite effects. The effect of NO on Bcl-2 stability was shown to be independent of its dephosphorylation. Mutational analysis of Bcl-2 further showed that the two cysteine residues of Bcl-2 (Cys158 and Cys229) are important in the S-nitrosylation process and that mutations of these cysteines completely inhibited Bcl-2 S-nitrosylation. Treatment of the cells with other stress inducers, including Fas ligand and buthionine sulfoxide, also induced Bcl-2 S-nitrosylation, suggesting that this is a general phenomenon that regulates Bcl-2 stability and function under various stress conditions. These findings indicate a novel function of NO and its regulation of Bcl-2, which provides a key mechanism for the control of apoptotic cell death and cancer development.

Apoptosis↗

PubMed2006

Prediction of solubility parameters using partial least square regression.

The total solubility parameter (delta) values were effectively predicted by using computed molecular descriptors and multivariate partial least squares (PLS) statistics. The molecular descriptors in the derived models included heat of formation, dipole moment, molar refractivity, solvent-accessible surface area (SA), surface-bounded molecular volume (SV), unsaturated index (Ui), and hydrophilic index (Hy). The values of these descriptors were computed by the use of HyperChem 7.5, QSPR Properties module in HyperChem 7.5, and Dragon Web version. The other two descriptors, hydrogen bonding donor (HD), and hydrogen bond-forming ability (HB) were also included in the models. The final reduced model of the whole data set had R(2) of 0.853, Q(2) of 0.813, root mean squared error from the cross-validation of the training set (RMSEcv(tr)) of 2.096 and RMSE of calibration (RMSE(tr)) of 1.857. No outlier was observed from this data set of 51 diverse compounds. Additionally, the predictive power of the developed model was comparable to the well recognized systems of Hansen, van Krevelen and Hoftyzer, and Hoy.

Algorithms↗

PubMed2005

Experimental and computational studies of epithelial transport of mefenamic acid ester prodrugs.

PURPOSE: A series of ester derivatives of mefenamic acid were synthesized with the aim of suppressing local gastrointestinal toxicity of mefenamic acid. A computational method was used to assist the design of the prodrug and to gain insights into the structure relationship of these compounds as P-glycoprotein (P-gp) substrates. The prodrugs were studied for their enzymatic stability, bidirectional permeability across Caco-2 monolayer, and their potential as transporter modulators METHODS: Bidirectional transport studies were performed using Caco-2 cells. Compounds exhibiting an efflux ratio of > or =2 were further examined for their potential interaction with P-gp and multidrug resistance-associated protein (MRP) using verapamil and indomethacin. Calcein efflux inhibition studies were conducted to investigate the efflux mechanism of these compounds. Geometry optimization of the esters was performed, and the spatial separation of two electron donor groups of each prodrug was measured. RESULTS: Morpholinoethyl ester (3) and pyrrolidinoethyl ester (4) of mefenamic acid showed evidence of efflux mechanism. Inhibition by verapamil had a pronounced effect on the transport of 3 and 4. Indomethacin, however, completely inhibited the apical efflux of 3 but enhanced the efflux ratio of 4. Both compounds increased the ratio of cellular calcein accumulation by 3- to 5-fold over control. Consistent with the experimental data, the computational results suggest the involvement of P-gp or its interaction in 3 and 4 transport. CONCLUSIONS: Apical efflux of 3 is associated with P-gp and MRP, but the efflux of 4 involves P-gp and/or MRP. The computational approach used in this study provided the basis for P-gp substrates of compounds 3 and 4 from their electron donor subunits spatial separation.

Animals↗

PubMed2005

Prediction of the aqueous solubility of benzylamine salts using QSPR model.

Models predicting aqueous solubility of benzylamine salts were developed using multivariate partial least squares (PLS) and artificial neural network (ANN). Molecular descriptors, including binding energy (BE) and surface area of salts (SA), were calculated by the use of Hyperchem and ChemPlus QSAR programs for Windows. Other physicochemical properties, such as hydrogen acceptor for oxygen atoms, hydrogen acceptor for nitrogen atoms, hydrogen bond donors, hydrogen bond forming ability, molecular weight (MW), and calculated log partition coefficient (clog P) of p-substituted benzoic acids, were also used as descriptors. In this study, the predictive ability of ANN, especially multilayer perceptron (MLP) architecture networks, was founded to be superior to PLS models. The best ANN model derived, a 6-1-1 architecture, had an overall R(2) of 0.850 and root mean square error (RMSE) for cross-verification and test set of 0.189 and 0.185 log units, respectively. Since all the utilized descriptors are readily obtained from calculation, these derived models offer the advantage of not requiring the experimental determination of some descriptors.

Benzylamines↗

PubMed2004

ATR-FTIR characterization of transport properties of benzoic acid ion-pairs in silicone membranes.

A novel technique based on Attenuated Total Reflectance Fourier Transform Infrared (ATR-FTIR) spectroscopy was used to study the transport of benzoic acid ion-pairs/salts in silicone membranes. The benzoic acid ion-pairs were prepared using various counter-ions with different degrees of lipophilicity, e.g. triethylamine (TA), diethylamine (DE), tert-butylamine (t-BA), 2-amino-2-methyl-propanol (AMP), and 2-amino-2-methyl-propanediol (AMPD). Silicone membrane, treated or untreated with propylene glycol (PG), was placed on the surface of a ZnSe crystal and the transport solution was applied to the upper surface of the membrane. A mathematical model, based on Fick's second law describing the build up of permeant concentration at the membrane/crystal interface with time was applied to determine diffusion coefficients. Absorption due to the acid (1700 cm(-1)) or benzoate anion (1555 cm(-1)) was observed at different regions without the interference from PG or silicone membrane. Benzoate anion, a charged species, was observed to permeate the membrane. The permeation of benzoate anion from sodium benzoate and polar ion-pairs of AMP and AMPD was very low in contrast to their high-saturated concentrations in PG as compared to the t-BA ion-pair. This indicated that benzoate anion preferentially permeates the membrane as an ion-pair rather than a single anion; otherwise its permeation should correspond to its concentration in PG instead of the lipophilicity of the ion-pairs. Additionally, the diffusion coefficient values of benzoic acid and benzoate anions through the treated and untreated membranes were not statistically different.

Antifungal Agents↗

PubMed2004

Prediction of aqueous solubility of organic salts of diclofenac using PLS and molecular modeling.

Organic salts of diclofenac were predicted by using computed molecular descriptors and multivariate partial least squares (PLS). The molecular descriptors including binding energy and surface area of salts were calculated by the use of Hyperchem and ChemPlus QSAR programs for Windows. Other physicochemical properties such as hydrogen acceptor for oxygen atoms, hydrogen acceptor for nitrogen atoms, hydrogen bond donors, hydrogen bond-forming ability, molecular weight, and log partition coefficient (logP) of bases were also used as descriptors. Good statistical models were derived that permit simple computational prediction of salt solubility of a same parent structure. The final models derived had R2 value = 0.96 and root mean square error for prediction (RMSEP) values ranging from 0.021 to 0.054 (log scale). Preferably all utilized descriptors in the final models can readily obtain from the chemical structure of salt and base. Molecular weight of base is one of the important factors associated with salt solubility. While increased molecular weight of base, surface area of salt and hydrogen bonding ability of base increase solubility, and increased binding energy and logP of base have negative effect on salt solubility.

Diclofenac↗

PubMed2002

Inhibition of TNF-alpha gene expression and bioactivity by site-specific transcription factor-binding oligonucleotides.

The present study investigated transcriptional inactivation of TNF-alpha gene by nuclear factor-binding oligonucleotides (ON) and their effects on pulmonary inflammatory responses in mice. PCR-based gene mutation and gel shift assays were used to identify specific cis-acting elements necessary for nuclear factor binding and transactivation of TNF-alpha gene by lipopolysaccharide (LPS). LPS inducibility of TNF-alpha was shown to require transcriptional activation by NF-kappaB at multiple binding sites, including the -850 (kappa1), -655 (kappa2), and -510 (kappa3) sites, whereas the -210 (kappa4) site had no effect. Maximum inducibility was associated with the activation of kappa3 site. The sequence-specific, double-stranded ON targeting this site was most effective in inhibiting TNF-alpha activity induced by LPS. The inhibitory effect of ON on TNF-alpha bioactivity was also investigated using a murine lung inflammation model. Pretreatment of mice with ON, but not its mutated sequence, inhibited LPS-induced inflammatory neutrophil influx and TNF-alpha production by lung cells. Effective inhibition by ON in this model was shown to require a liposomal agent for efficient cellular delivery of the ON. Together, our results indicate that transcriptional inactivation of TNF-alpha gene can be achieved by using ON that compete for nuclear factor binding to TNF-alpha gene promoter. This gene inhibition approach may be used as a research tool or as potential therapeutic modality for diseases with etiology dependent on aberrant gene expression.

Animals↗

PubMed2002

Characterization of mefenamic acid-guaiacol ester: stability and transport across Caco-2 cell monolayers.

PURPOSE: Prodrug of non-steroidal anti-inflammatory drugs (NSAIDs) or NSAIDs linked with guaiacol have been reported to suppress gastrointestinal (GI) toxicity or induce GI protective effect. In this study. mefenamic-guaiacol ester was synthesized and its physicochemical properties. stability, and transport across Caco-2 monolayers were investigated. METHODS: Synthesis of the ester was carried out using mefenamic acid, guaiacol. N. N'-dimethylaminopyridine, and N,N'dicyclohexylcarbodiimide. The hydrolysis of the ester was investigated in aqueous buffer solutions pH 1-12 as well as in Caco-2 homogenate, human plasma, and porcine liver esterase. Caco-2 cell monolayers were utilized for transport studies. Due to the high lipophilicity of the ester with a calculated logP of 6.15, bovine serum albumin (BSA, 4%) was included in the receiver compartment to obtain a good in vitro-in vivo correlation. Permeation of the ester was assessed with or without the exposure of cells to PMSF, an inhibitor of esterase. RESULTS: The ester was stable at a wide pH range from 1-10. However, it was hydrolyzed by enzymes from porcine liver esterase and Caco-2 homogenate. With the PMSF exposure on the apical (AP) side and in the presence of 4% BSA on the basolateral (BL) side, the transported amount of the ester from AP-to-BL direction was 14.63% after 3 hr with a lag time of 23 min. The Papp for the ester was 4.72 x 10(-6) cm s(-1). CONCLUSION: The results from hydrolysis studies indicate that this ester is a prodrug. The Papp value suggests the moderate absorption characteristic of the compound. The accumulation of this highly lipophilic ester in Caco-2 cells is reduced in the presence of BSA.

Animals↗