Inhibition Of Glutathione S-transferase Research Articles

Synthesis of two novel mercaptobenzimidazole derivative Schiff bases and their in vitro antioxidant and enzyme inhibitory effects

In this study, 5-(2-hydroxy-4-methoxybenzylidenamino)-2-mercaptobenzimidazole and 5-(4-hydroxy-3-methoxybenzylidenamino)-2-mercaptobenzimidazole Schiff base compounds were synthesized and their structure were characterized with spectroscopic techniques, namely, 1H NMR, IR, and 13C NMR. In vitro ABTS, DPPH, CUPRAC, and FRAP tests were applied to calculate the antioxidant activities of the newly designed compounds. Beside, the enzyme inhibitory abilities of the mercaptobenzimidazole derivative Schiff base were assessed against the glutathione S-transferase (GST) enzyme. The Ki values were calculated as 20.06 ± 3.11 and 36.86 ± 6.17 μM, as well as the IC50 values were calculated as 6.30 μM and 5.33 μM respectively. Besides, molecular docking interactions of the compounds with the GST target enzyme (PDB ID:5JCU) were estimated via Chimera and AutoDock Vina software. −8.7 kcal/mol, and −8.5 kcal/mol were calculated as best binding scores of compounds against the GST enzyme. Since the novel Schiff base, 5-(4-hydroxy-3-methoxybenzylidenamino)-2-mercaptobenzimidazole has a good potential in the GST inhibition, it should be subjected to the further pharmacological studies.

Early loss of glutathione -s- transferase (GST) activity during diverse forms of acute renal tubular injury.

Glutathione‐S‐transferases (GSTs) are a diverse group of phase II detoxification enzymes which primarily evoke tissue protection via glutathione conjugation to xenobiotics and reactive oxygen species. Given their cytoprotective properties, potential changes in GST expression during AKI has pathophysiologic relevance. Hence, we evaluated total GST activity, and the mRNA responses of nine cytosolic GST isotypes (GST alpha1, kappa1, mu1/5, omega1, pi1 sigma1, theta1, zeta1 mRNAs), in five diverse mouse models of AKI (glycerol, ischemia/reperfusion; maleate, cisplatin, endotoxemia). Excepting endotoxemia, each AKI model significantly reduced GST activity (~35%) during both the AKI “initiation” (0‐4 h) and “maintenance” phases (18 or 72 h). During the AKI maintenance phase, increases in multiple GST mRNAs were observed. However, no improvement in GST activity resulted. Increased urinary GST excretion followed AKI induction. However, this could not explain the reduced renal GST activity given that it also fell in response to ex vivo renal ischemia (i.e., absent urinary excretion). GST alpha, a dominant proximal tubule GST isotype, manifested 5–10‐fold protein increases following AKI, arguing against GST proteolysis as the reason for the GST activity declines. Free fatty acids (FFAs) and lysophospholipids, which markedly accumulate during AKI, are known to bind to, and suppress, GST activity. Supporting this concept, arachidonic acid addition to renal cortical protein extracts caused rapid GST activity reductions. Based on these results, we conclude that diverse forms of AKI significantly reduce GST activity. This occurs despite increased GST transcription/translation and independent of urinary GST excretion. Injury‐induced generation of endogenous GST inhibitors, such as FFAs, appears to be a dominant cause.

Anticholinesterase activity and Antioxidant Effect of Vitamin E in Aluminum Chloride Induced Toxicity in Drosophila Melanogaster

BackgroundAluminum chloride (AlCl3) has been used to model neurotoxicity and Alzheimer’s disease (AD) like neurodegeneration in various animal models (Bondy, 2010). AlCl3 toxicity has been reported to be associated with impaired locomotor performance, learning, memory, oxidative stress and cholinergic impairment which are features seen in AD patients (Ribes et al., 2008). AlCl3acts as a cholinotoxin (Gulya et al., 1990) and cause alterations on the cholinergic activity, a key event in the neurochemistry of AD (Rakonczay et al., 2005). Reduced cholinergic function in the brain has been shown to result in memory impairment in AD (Mukherjee et al., 2007). The use of compounds to inhibit acetylcholinesterase (AChE) activity (to reduce the hydrolysis of acetylcholine) has been a therapeutic approach in managing AD (Taylor and Radić 1994). Vitamin E has been proposed as a potential clinical intervention for AD given its antioxidant and anti‐inflammatory characteristics. However, there are very few studies on its anticholinesterase activity and there also controversies as to whether vitamin E is beneficial in AD. We therefore evaluated the anticholinesterase and antioxidant activity of vitamin E in aluminium chloride induced toxicity in Drosophila melanogaster.MethodsD. melanogaster (Harwich strain, 3‐5 days) were utilized for this study. In order to determine the appropriate dose of vitamin E to be utilized for this study, a 15 days survival study (where mortality rate was recorded daily) was carried out with varying dose of Vitamin E (2.5mg and 5mg). Subsequently, 2.5mg of vitamin E produced the least mortality of flies and was utilized for this study. The choice of concentration for AlCl3was based on previous studies on aluminum toxicity in D. melanogaster [Wu et al., 2012; Ogunsuyi, 2020]. Flies (both genders) were divided into 4 groups with 50 flies per vial. Group I served as control and were reared on their cornmeal diet while group II were treated with 40mM aluminum chloride (AlCl3) via their diet. Group III flies were fed with normal diet containing 2.5mg of vitamin E while Group IV were co‐administered with 40 mM AlCl3and 2.5mg of vitamin E via their diet. The flies were maintained on these treatments at room temperature for seven (7) days. All experiments were carried out in five replicates (n=5). Negative geotaxis was carried out to assess for locomotion deficit. At the end of the experimental period, the flies were homogenized and the supernatant were used to assay for AchE activity, malonaldehyde (MDA) concentration, superoxide dismutase (SOD), catalase (CAT) and glutathione S‐transferase (GST) activities.ResultsAlCl3induced toxicity reduced the survival rate, decreased the climbing activity, elevated MDA concentration and AChE activities of flies. SOD, CAT and GST activities were also reduced in AlCl3treated flies. Vitamin E was able to improve the survival rate, restored AlCl3induced reduction in climbing activity, ameliorated AlCl3 increase in AChE activity and MDA concentration in flies. In addition, Vitamin E attenuated AlCl3induced inhibition of SOD, CAT and GST activities.ConclusionThis study has shown that Vitamin E has both antioxidant and anticholinesterase activities and can be regarded as a therapeutic agent against AlCl3 induced toxicity and associated diseases.

Pinoxaden resistance in Lolium perenne L. is due to both target-site and non-target-site mechanisms

Application of herbicides inhibiting acetyl CoA carboxylase (ACCase) has been one of the main strategies for selectively controlling grass weed species such as perennial ryegrass (Lolium perenne L.) in wheat and barley crops in New Zealand. In this study, we have confirmed and characterized resistance to pinoxaden, an ACCase-inhibiting herbicide, in a population of L. perenne. Dose-response experiments were conducted to assess the level of pinoxaden resistance, and based on the LD50 values, the studied population was 41.4-times more resistant to pinoxaden than a susceptible population. Application of malathion, an inhibitor of the cytochrome P450s, preceding pinoxaden treatment reduced the level of resistance to 9.7-fold. However, pre-treatment with the glutathione S-transferase (GST) inhibitor 4-chloro7- nitrobenzoxadiazole prior to pinoxaden treatment did not affect pinoxaden resistance. Partial sequencing of the ACCase gene revealed that the resistant population had an isoleucine to valine replacement at position 2041. These results suggest that both cytochrome P450-based and target-site mechanisms are jointly associated with this instance of pinoxaden resistance in L. perenne. The pinoxaden-resistant L. perenne individuals were also resistant to quizalofop-p-ethyl (108.6-fold), but they were susceptible to clethodim, which can, therefore, be used to manage this pinoxaden-resistant L. perenne. This is the first report of a L. perenne population in which a rare target-site mutation works in concert with enhanced cytochrome P-450 activity to confer pinoxaden resistance. Evolution of resistance to ACCase-inhibiting herbicides in this L. perenne population indicates that integrated weed management practices are required to prevent widespread resistance developing in New Zealand cereal crop systems.

MiR-513a-3p promotes radiation-induced apoptosis of human lung cells by inhibiting glutathione S-transferase P1.

Radiotherapy is a common treatment for lung cancer. However, radiation pneumonitis caused by radiotherapy can affect the quality of life and prognosis of lung cancer patients. miR-513a-3p has been found to sensitize human lung adenocarcinoma cells to chemotherapy by targeting glutathione S-transferase P1 (GSTP1). Here, we found that x-ray induced the apoptosis of BEAS-2B and miR-513a-3p expression in a dose- and time-dependent manner, and miR-513a-3p-mimic significantly increased x-ray induced apoptosis, while miR-513a-3p-inhibitor significantly decreased x-ray induced apoptosis. Dual luciferase gene reporter system showed that miR-513a-3p targeted to inhibit the expression of GSTP1 in BEAS-2B cells. Moreover, knockdown of GSTP1 significantly increased, while overexpression of GSTP1 decreased the apoptosis of BEAS-2B induced by x-ray. Importantly, overexpression of GSTP1 significantly reduced miR-513a-3p-mimic elevated x-ray -induced apoptosis in BEAS-2B cells. In conclusion, x-ray caused increased expression of miR-513a-3p, and miR-513a-3p promoted x-ray-induced apoptosis of human lung cells by inhibiting GSTP1.

Mefenacet resistance in multiple herbicide-resistant Echinochloa crus-galli L. populations

Echinochloa crus-galli L., a notorious weed in rice paddy fields, is usually kept under control by mefenacet application at the pre-emergence or early post-emergence stage. Due to continuous and repeated usage, E. crus-galli is developing resistance to mefenacet in China. Two putative resistant and one susceptible E. crus-galli populations were collected from paddy fields in Jiangsu Province to characterize their herbicide resistance. Compared with the susceptible population, the two mefenacet-resistant populations had 2.8- and 4.1-times greater pre-emergence resistance, and 10- and 6.8-times greater early post-emergence resistance to mefenacet. These mefenacet-resistant E. crus-galli populations also exhibited cross- or multiple-resistance to acetochlor, pyraclonil, imazamox, and quinclorac. However, when the glutathione S-transferase (GST) inhibitor 4-chloro-7-nitrobenzoxadiazole (NBD-Cl) was applied prior to post-emergence treatment, mefenacet resistance levels were reduced in both populations. Additionally, GST activity in vivo in one resistant population was much higher than the susceptible population after mefenacet application. The very long chain fatty acid elongases (VLCFAEs) from both mefenacet-resistant populations required much higher mefenacet concentration to inhibit their activity. The reduced sensitivity of VLCFAEs to mefenacet indicates the presence of a target-site resistance mechanism and induction of high GST activity may provide additional contribution to E. crus-galli mefenacet resistance through a non-target-site mechanism.

Carrier-free nanomedicine for enhanced photodynamic tumor therapy through glutathione S-transferase inhibition

A chlorine e6 and coniferyl ferulate-based self-delivery nanomedicine is developed to inhibit intracellular glutathione S-transferase (GST) and enhance the photodynamic therapy (PDT)-mediated oxidative damage on tumor cells.

Lethal and sublethal effects of fenazaquin and acequinocyl on demographic and some biochemical parameters of Panonychus citri (McGregor) (Acari: Tetranychidae)

ABSTRACT A major pest of citrus orchards in northern regions of Iran is Panonychus citri which is mainly controlled by using chemical acaricides. Knowledge of the lethal and sublethal effects of pesticides on pests is necessary for successful performance of each control programme. In this study, the toxicities of fenazaquin and acequinocyl as well as the effects of the sublethal concentration LC20 and LC30 on demographic and some biochemical traits of P. citri offspring were studied. The results showed that the toxicity of acequinocyl was 2.18 times higher than that of fenazaquin. The developmental time of females was influenced and prolonged by sublethal concentrations of both acaricides. Sublethal concentration effects of both acaricides considerably decreased the total fecundity. A significant reduction was observed in the net reproduction rate (R0 ), and intrinsic rate of natural increase (r) of the mites exposed to LC20 and LC30 concentrations of both acaricides compared to control. Both acaricides showed a negative impact on the content of lipid, carbohydrate, and glycogen. The LC20 concentration of fenazaquin resulted in an increase in general esterase activity, and both acaricides inhibited glutathione S-transferase (GST) activities. Our findings show that the sublethal doses of both acaricides had adverse effects on the biological and physiological characters of P. citri.

2-methylindole analogs as cholinesterases and glutathione S-transferase inhibitors: Synthesis, biological evaluation, molecular docking, and pharmacokinetic studies

• 2-methylindole analogs were designed, synthesized and characterized. • The target 2-methylindole analogs ( 4a–4j ) were evaluated for their inhibitory potential against glutathione S-transferase (GST), acetylcholinesterase (AChE), butyrylcholinesterase (BChE) inhibitory activities. • Molecular docking studies were conducted to correlate the in vitro results and to identify possible mode of interactions at the active pocket site of the receptors. • The pharmacokinetic studies of 2-methylindole analogs were carried out using SwissADMET analyses. In this study, we aimed to (i) synthesize new 2-methylindole analogs containing various amino structures, pyrrolidine, piperidine, morpholine, and substituted phenyl groups through structural and molecular modifications, (ii) evaluate the pharmaceutical potential of 2-methylindole analogs via assessing enzyme inhibitory activity against glutathione S-transferase (GST), acetylcholinesterase (AChE), and butyrylcholinesterase (BChE), (iii) predict ADMET and pharmacokinetic properties of the synthesized 2-methylindole analogs, (iv) reveal the possible interactions between the synthesized 2-methylindole analogs with GST, AChE, and BChE enzymes using several molecular docking software. In vitro enzyme inhibition assays showed that the synthesized indole analogs exhibited moderate to good inhibitory activities against GST, AChE, and BChE enzymes. Briefly, the inhibitory activities of the analogs 4b and 4i against AChE, 4a and 4b against BChE, and analogs 1 and 4i against GST were detected to be higher or close to the standard inhibitor compounds. The analog 4b was detected to have the best inhibitory activity against both AChE and BChE enzymes with the lowest IC 50 values as 0.648 µM for AChE and 0.745 µM for BChE. The analyses of enzyme inhibition relationship with the synthesized analogs could help to design new analogs for the inhibitors of cholinergic and glutathione pathways based on the indole derivatives.

Thiacalix[4]arene phosphoric acids. Synthesis, structure, and inhibition of glutathione S-transferases

Regioselective phosphorylation of tetrahydroxythiacalix[4] arenes by diethyl chlorophosphate in the presence of triethylamine or by the system diethylphosphite/carbon tetrachloride/triethylamine gave ethyl esters of thiacalix[4] arene monophosphoric or thiacalix[4] arene diphosphoric acids, respectively. The obtained esters were converted with quantitative yields into corresponding free acids by sequential treatment with trimethylbromosilane and methanol. The thiacalix[4] arene diphosphoric acids were evaluated in vitro as inhibitors of glutathione S-transferases.

Insecticidal and growth inhibitory effects of some thymol derivatives on the beet armyworm, Spodoptera exigua (Lepidoptera: Noctuidae) and their impact on detoxification enzymes.

Thymol is a known natural product with insecticidal activity against several insect species. A recent study on structural modifications of thymol to thymyl esters and their efficacy against Spodoptera litura suggested that such an approach could develop generalized novel insecticides/insect growth inhibitors and requires further studies to establish the efficacy against lepidopterans. Thymol and structurally modified eight esters were evaluated against beet armyworm, Spodoptera exigua using the topical application. Thymyl butanoate was the most toxic compound with a median lethal dose (LD50 ) of 2.33 and 1.62 μg/larva after 24 and 48 h posttreatment, respectively. All thymyl esters were potentially better than the parent compound thymol, except thymyl dibromoacetate, in their efficacy against Spodoptera exigua. Essentially, there were three levels of activity vis-à-vis the compounds used, that is, with the LD50 range of 1.5 to 5.0, 7.0 to 15.0, and > 20 μg/larva, respectively. Ovicidal activity and reduction in larval growth were also determined by treating third instars at sub-lethal doses, that is, LD50 doses of second instars. Thymyl butanoate treated larvae inhibited glutathione S-transferase, carboxylesterase, and acetylcholinesterase activities, whereas the other thymyl esters induced these enzymes. Thymyl butanoate exhibited higher toxicity against Spodoptera exigua and is the first to report about > 15.5× more toxicity than thymol and > 6.5× than thymyl cinnamate, which suggests that the efficacy was species-specific versus the chemical structural variation of the esters. © 2021 Society of Chemical Industry.

“Pincer movement”: Reversing cisplatin resistance based on simultaneous glutathione depletion and glutathione S-transferases inhibition by redox-responsive degradable organosilica hybrid nanoparticles

The therapeutic efficacy of cisplatin has been restricted by drug resistance of cancers. Intracellular glutathione (GSH) detoxification of cisplatin under the catalysis of glutathione S-transferases (GST) plays important roles in the development of cisplatin resistance. Herein, a strategy of “pincer movement” based on simultaneous GSH depletion and GST inhibition is proposed to enhance cisplatin-based chemotherapy. Specifically, a redox-responsive nanomedicine based on disulfide-bridged degradable organosilica hybrid nanoparticles is developed and loaded with cisplatin and ethacrynic acid (EA), a GST inhibitor. Responding to high level of intracellular GSH, the hybrid nanoparticles can be gradually degraded due to the break of disulfide bonds, which further promotes drug release. Meanwhile, the disulfide-mediated GSH depletion and EA-induced GST inhibition cooperatively prevent cellular detoxification of cisplatin and reverse drug resistance. Moreover, the nanomedicine is integrated into microneedles for intralesional drug delivery against cisplatin-resistant melanoma. The in vivo results show that the nanomedicine-loaded microneedles can achieve significant GSH depletion, GST inhibition, and consequent tumor growth suppression. Overall, this research provides a promising strategy for the construction of new-type nanomedicines to overcome cisplatin resistance, which extends the biomedical application of organosilica hybrid nanomaterials and enables more efficient chemotherapy against drug-resistant cancers.

In-silico Investigation of the Interaction between Beta-class Glutathione S-Transferase and Five Antibiotics, namely; Ampicillin, Tetracycline, Chloramphenicol, Ciprofloxacin and Cephalexin

Glutathione s-transferases(GSTs) are enzymes involved in the conjugation and deactivation of various xenobiotics including drugs. Thisin-silico study was undertaken in order to investigate the interaction between beta-class glutathione s-transferase and five selected antibiotics, namely; ampicillin, tetracycline, chloramphenicol, ciprofloxacin and cephalexin using molecular docking study. RaptorX server was used to predict the amino acids involved at the binding sitewhile molecular docking study was employed in order to investigate the binding interactions.RaptorX predicted several amino acids which were different from the ones observed in molecular docking because of the variability in the substrate binding site of GSTs however, all the amino acids predicted by RaptorX were also found to be involved in the GSH binding.Lys107, Phe109, Ser110, Leu113, Trp114, His115 and Arg123, Leu168 were the amino acids involved in the binding of various antibiotics to the substrate binding site of the protein while Ala9, Cys10, Leu32, Tyr51, Val52, Pro53, Glu65 and Ala66were involved in the binding of the co-substrate GSH to the binding site of the protein. The results indicated that all the antibiotics showed a good binding affinity with the beta class GST and are therefore capable of deactivating the drugs. With these, finding a beta class GST inhibitors alongside antibiotics during a treatment of diseases will be of beneficial in the current fight against antibiotic resistance.

Chemical composition of essential oils from Thymus mongolicus, Cinnamomum verum, and Origanum vulgare and their acaricidal effects on Haemaphysalis longicornis (Acari: Ixodidae)

Chemical acaricides are mainly used in traditional tick control, which leads to the emergence of tick resistance and concurrently results in environmental pollution. In the present study, the chemical constituents of essential oils (EOs) from Thymus mongolicus, Cinnamomum verum, and Origanum vulgare was analyzed, and their potential application was evaluated to control the vector tick Haemaphysalis longicornis, which is widely distributed over vast areas of Eurasia, Australia, and New Zealand. Gas chromatography-mass spectrometry analysis revealed that the phenols thymol and carvacrol accounted for 34.66% and 75.72% of the EOs of T. mongolicus and O. vulgare, respectively, whereas trans-cinnamaldehyde (49.42%) was the main constituent of C. verum EO. Immersion tests showed that the EOs of C. verum and O. vulgare had significant acaricidal activity against larval H. longicornis, with the 50% lethal concentration (LC50) being 16.07 and 18.02 mg/mL, respectively, and the 95% lethal concentration (LC95) being 120.37 and 130.09 mg/mL, respectively. The EOs of O. vulgare and T. mongolicus showed significant acaricidal activity against unfed adult H. longicornis, with LC50 being 43.50 and 44.21 mg/mL, respectively, and LC95 being 113.66 and 137.99 mg/mL, respectively. The fumigant toxicity test showed significant acaricidal activity of the three EOs against both unfed and engorged nymphal and adult H. longicornis. Enzyme assays revealed that the EOs of both C. verum and O. vulgare significantly inhibited glutathione S-transferase activity (P < 0.05). In contrast, the activities of carboxylesterase and multifunction oxidases were significantly inhibited by EOs extracted from all three plants (P < 0.05). Taken together, these findings suggest that plant EOs may serve as an environment-friendly alternative for synthetic acaricides in future tick control.

Understanding Resistance Mechanisms to Trifluralin in an Arkansas Palmer Amaranth Population.

Amaranthus palmeri S. Watson (Palmer amaranth) is considered a problematic and troublesome weed species in many crops in the USA, partly because of its ability to evolve resistance to herbicides. In this study, we explored the mechanism of resistance in a trifluralin-resistant A. palmeri accession collected from Arkansas, USA. Dose-response assays using agar plates demonstrated an EC50 (effective concentration that reduces root length by 50%) of 1.02 µM trifluralin compared to 0.39 µM obtained in the susceptible accession. Thus, under these conditions, the resistant accession required 2.6 times more trifluralin to inhibit root length by 50%. Seeds in the presence or absence of the cytochrome P450-inhibitior malathion displayed a differential response with no significant influence on root length, suggesting that resistance is not P450-mediated. In addition, application of 4-chloro-7-nitrobenzofurazan (NBD-Cl), a glutathione S-transferase (GST) inhibitor, showed significant differences in root length, indicating that GSTs are most likely involved in the resistance mechanism. Sequencing of α- and β-tubulin genes revealed no single nucleotide polymorphisms (SNPs) previously described between accessions. In addition, relative gene copy number of α- and β-tubulin genes were estimated; however, both resistant and susceptible accessions displayed similar gene copy numbers. Overall, our results revealed that GST-mediated metabolism contributes to trifluralin resistance in this A. palmeri accession from Arkansas.

Antitumor Effect of Organometallic Half-Sandwich Ru(II)-Arene Complexes Bearing a Glutathione S-Transferase Inhibitor.

The facile modification of the ligands in organometallic Ru(II)-arene complexes offers more opportunities to optimize their pharmacological profiles. Herein, three Ru(II)-arene complexes containing a glutathione S-transferase (GST) inhibitor (NBDHEX) in chelate ligand have been designed and synthesized in this study. In vitro results indicated that the ligation with NBDHEX significantly increased the activities and selectivities of the organometallic Ru(II)-arene complexes against tumor cells, especially complex 3, which was the most active compound among the tested compounds. DFT calculations and hydrolysis results demonstrated that complex 3 with more alkyl groups in the arene ligand has increased electron density at the Ru(II) center as compared with complexes 1 and 2, thus resulting in the improved hydrolysis rate, which may be responsible for its higher anticancer activity. Further studies showed that complexes 1-3 can cause the loss of the mitochondrial membrane potential and upregulate the expression of Bcl-2 and Bax in A549 cells, suggesting that complexes 1-3-induced cell death may be mediated via the mitochondrial apoptotic pathway. Thus, these findings suggested that simultaneous modification of the chelate ligands and arene rings in the organometallic Ru(II)-arene complexes is an effective way to improve their pharmacological properties.

Synthesis, Properties and Application of Titanium Dioxide Doped with Nitrogen. Its Effectiveness on Photo Degradation Glutathione-S-Transferase (GST) enzymes Pupae Instar of Aedes aegypti

The sol-gel method was used to create N-doped TiO2. From the characterization results, it was found that N-doped TiO2 using Titanium(IV) ammonia solution and calcination tetraisopropoxide 600 K provided the most appropriate properties for acting as the photo catalyst can be use as inhibitor of GST. SEM, AFM and XRD results indicated that this N-doped TiO2 catalyst had high crystallinity because its titania precursor was simply hydrolyzed completely so no organic contents blocked initial phase construction. SEM and AFM results demonstrated that its surface morphology was spherical like fluffy powders. Moreover, with increasing calcination temperature, its anatase-to-rutile phase transformation was retarded by the incorporated nitrogen. Elemental Analysis and UV-Vis/DR results also suggested that nitrogen could be dormant in the TiO2 lattice with strong bonds, causing the effect on the band gap structure by adding energy states nearly valence band of TiO2. All of these properties enhanced the photocatalytic activity of N-doped TiO2 under visible light. Regarding the photocatalytic activity, N-doped TiO2 with ammonia solution of titanium(IV), calcinated 600 K Tetraisopropoxide succeeded in degrading glutathione-S-transferase (GST) enzymes, with the highest efficiency. However, its photocatalytic activity was drastically decreased when it was calcined at higher temperature. Additionally, the plausible mechanism was also proposed in case of photo degradation of antioxidant content based on two detected intermediates by The association between ln Co/C and photo degradation period (h).

Glutathione S-Transferases in Cancer.

In humans, the glutathione S-transferases (GST) protein family is composed of seven members that present remarkable structural similarity and some degree of overlapping functionalities. GST proteins are crucial antioxidant enzymes that regulate stress-induced signaling pathways. Interestingly, overactive GST proteins are a frequent feature of many human cancers. Recent evidence has revealed that the biology of most GST proteins is complex and multifaceted and that these proteins actively participate in tumorigenic processes such as cell survival, cell proliferation, and drug resistance. Structural and pharmacological studies have identified various GST inhibitors, and these molecules have progressed to clinical trials for the treatment of cancer and other diseases. In this review, we discuss recent findings in GST protein biology and their roles in cancer development, their contribution in chemoresistance, and the development of GST inhibitors for cancer treatment.

The role of detoxification enzymes in the susceptibility of Brevipalpus californicus exposed to acaricide and insecticide mixtures

The intense spraying of pesticides to control different arthropod pests has resulted in negative side effects for the management of pests. It was previously discovered that exposure to non-acaricidal insecticides alone or in a mixture, results in lower efficiency of the acaricide spirodiclofen used for Brevipalpus spp. control. We investigate here whether the induced expression of detoxification enzymes by non-lethal insecticides may antagonize spirodiclofen toxicity. Brevipalpus californicus mites exposed to the insecticide phosmet alone or in combination with spirodiclofen showed increased activity of P450 monooxygenases (P450s). No antagonistic effects in mite mortality were observed by the combination of phosmet and spirodiclofen. On the other hand, mites exposed to the insecticide imidacloprid alone or in combination with spirodiclofen showed an increase in the activity of P450s, carboxylcholinesterases (CCE), and glutathione-S-transferases (GST). An antagonistic effect on mite mortality was observed when mites were exposed to the LC25 of spirodiclofen combined with the field rate treatment of imidacloprid. The addition of PBO (a P450 monooxygenase inhibitor) to the mixture of spirodiclofen and imidacloprid resulted in a synergistic effect over mite mortality but the addition of DEM (a GST inhibitor) resulted in an antagonist effect. Taken together, this study showed that the combination of imidacloprid with spirodiclofen is antagonistic for the control of B. californicus, and this results from the induction of detoxification enzymes, such as P450s, CCE, and GST. The use of inhibitors highlights the role of these enzymes in the antagonism of the mixture.

Alkyl and aryl α-ketophosphonate derivatives as photoactive compounds targeting glutathione S-transferases

In this article, photoactive alkyl and aryl α-ketophosphonate derivatives were studied as inhibitors of glutathione S-transferases (GSTs). The α-ketophosphonate monoesters were synthesized by sodium iodide-induced dealkylation of corresponding phosphonate diesters. The compounds being inactive toward the enzyme without UV light were activated by irradiation at 365 nm which caused inhibition of GSTs from equine liver and human placenta with micromolar IC50 values. Hetaryl α-ketophosphonate monoesters can also be potential candidates for the UV-dependent enzyme targeting. Inhibitory potency of the phosphonate monoesters was comparable to that of free phosphonic acid. No effects were observed in case of dialkyl α-ketophosphonates. The light-induced effects of the inhibitors were found to be related to decrease in maximum velocity but not to Michaelis constants of the enzyme-catalyzed reaction. The kinetics of a decrease in enzyme activity was described by pseudo-first order rate constants dependent on inhibitor concentration. The calculated second order rate constants indicated that the alkyl α-ketophosphonate monoesters can exhibit higher potency in comparison with that of aryl or hetaryl phosphonate derivatives.