High-throughput identification and determination of antifungal triazoles in human plasma using UPLC-QDa.

Triazoles are common agents for invasive fungal infections, while therapeutic drug monitoring is needed to improve antifungal efficacy and reduce toxicity. This study aimed to exploit a simple and reliable liquid chromatography-mass spectrometry method for high-throughput monitoring of antifungal triazoles in human plasma using UPLC-QDa. Triazoles in plasma were separated by chromatography on a Waters BEH C18 column and detected using positive ions electrospray ionization fitted with single ion recording. M+ for fluconazole (m/z 307.11) and voriconazole (m/z 350.12), M2+ for posaconazole (m/z 351.17), itraconazole (m/z 353.13) and ketoconazole (m/z 266.08, IS) were selected as representative ions in single ion recording mode. The standard curves in plasma showed acceptable linearities over 1.25-40 μg/mL for fluconazole, 0.47-15 μg/mL for posaconazole and 0.39-12.5 μg/mL for voriconazole and itraconazole. The selectivity, specificity, accuracy, precision, recovery, matrix effect, and stability met acceptable practice standards under Food and Drug Administration method validation guidelines. This method was successfully applied to the therapeutic monitoring of triazoles in patients with invasive fungal infections, thereby guiding clinical medication.

Impact of SLCO4C1 Genotypes, Creatinine, and Spironolactone on Digoxin Population Pharmacokinetic Variables in Patients With Cardiac Insufficiency.

Corrigendum to "Impact of SLCO4C1 Genotypes, Creatinine, and Spironolactone on Digoxin Population Pharmacokinetic Variables in Patients With Cardiac Insufficiency" [Clin Therapeut 42(9) 1799-1810].

In Vitro and In Vivo Studies of Metabolic Activation of Marrubiin, a Bioactive Constituent from Marrubium Vulgare.

Marrubiin, a furanoid compound, is a well-known diterpenoid lactone isolated from Marrubium vulgare, which displays a wide spectrum of pharmacological effects and potential hepatotoxicity. Considering that marrubiin contains a structural alert, furan ring, metabolic activation may be one of the major metabolic pathways, and the reactive metabolite may be involved in the hepatotoxicity. The present study was carried out to investigate the bioactivation mechanism of marrubiin in rats and humans. Marrubiin was initially metabolized into cis-butene-1,4-dial intermediate, which was readily trapped by glutathione (GSH) and N-acetyl-lysine (NAL) in the microsomal incubations supplemented with NADPH. A total of nine conjugates were detected and identified by high-resolution mass spectrometry and nuclear magnetic resonance (NMR) spectroscopy. M1-M3 and M6 and M7 were characterized as mono-GSH conjugates, and M4 and M5 were identified as bis-GSH conjugates. M8 and M9 were identified as NAL conjugates. In rat bile, five GSH conjugates (M1-M3; M6 and M7) were detected. M1, M8, and M9 were chemically synthesized, and their structures were characterized by 13C NMR. Sulfaphenazole, ticlopidine, and ketoconazole displayed significant inhibitory effect on the bioactivation of marrubiin. Further phenotyping revealed that CYP2C9, CYP2C19, and CYP3A4 were the primary enzymes catalyzing the bioactivation of marrubiin. The current study provides evidence for the CYP-dominated bioactivation of marrubiin to the corresponding cis-butene-1,4-dial intermediate, which enables us to better understand the potential side effects caused by marrubiin.

T-2 toxin cytotoxicity mediated by directly perturbing mitochondria in human gastric epithelium GES-1 cells.

T-2 toxin is one of the most toxic trichothecenes and harmful to human health and animal husbandry. The mechanism underlying its growth suppression remains unclear, especially for mitochondrial damage in human gastric epithelial cells. In the present study, we investigated cell death caused by T-2 toxin in a human gastric epithelial cell line (GES-1) and the possible mechanism of T-2-induced cytotoxicity. T-2 strongly reduced the viability of GES-1 cells in a time- and dose-dependent manner within a small range of concentrations. However, when the concentrations of T-2 were >40 nM, there was no concentration dependence, only time dependence. Moreover, T-2 induced apoptosis, with the activation of caspase-3 in GES-1 and mitochondrial membrane potential (MMP) decrease and cytochrome c release. T-2 also resulted in the accumulation of reactive oxygen species (ROS) and DNA damage with a positive signal of p-H2A.X in GES-1 cells. While T-2 caused a MMP decrease, DNA damage and cell death were not blocked by pretreatment with 3 mM glutathione (GSH), a typical scavenger of ROS. The induction of mitochondrial permeability transition pore (mPTP) regulators voltage-dependent anion channel (VDAC1) and cyclophilin D (CypD) were also observed in T-2-treated cells. Interestingly, cyclosporine A (CsA), a CypD inhibitor, significantly reversed the drop in MMP and the DNA damage, as well as ROS accumulation caused by T-2. Additionally, GES-1 cell death could also be protected to some extent by 4, 4'-diisothiocyanatostilbene-2, 2'-disulfonic acid (DIDS), an inhibitor of VDAC1, especially the combination of CsA and DIDS, and 3 mM GSH could further enhance the effect of CsA + DIDS on cell viability. In conclusion, our present findings indicate that the T-2 induced MMP decrease, DNA damage and cell death, as well as ROS accumulation in GES-1 cells, starts with T-2 directly perturbing the mitochondria triggering ROS generation by acting on CypD and VDAC1. This study presents a new viewpoint for evaluating the toxicity of T-2 toxin.

Impact of SLCO4C1 Genotypes, Creatinine, and Spironolactone on Digoxin Population Pharmacokinetic Variables in Patients With Cardiac Insufficiency.

PURPOSE:This study aimed to utilize a population pharmacokinetic method to obtain information about the influence of covariates on the in vivo behavior of digoxin in patients with cardiac insufficiency.METHODS:A total of 228 therapeutic drug monitoring concentrations were retrospectively collected from 176 inpatients. The patients were randomly divided into a modeling group (n = 126) and a validation group (n = 50). The first-order absorption one-compartment model was used to develop a population pharmacokinetic model from a nonlinear mixed effects modeling approach. Sixteen single nucleotide polymorphisms involved in the pharmacokinetic variables of digoxin were identified by using the MassARRAY system. Various demographic parameters, biochemical test values, concomitant medications, and genetic variants were investigated.FINDINGS:The typical population value of digoxin CL/F was 5.06 L/h, and the volume of distribution was 211.82 L. The drug CL/F was significantly related to serum creatinine, in a combination of spironolactone and SLCO4C1 genotypes of 2 variants (rs3114660 and rs3114661). Results of model evaluation and internal/external validation indicated a stable and precise performance of the final model.IMPLICATIONS:For the first time, 2 single nucleotide polymorphisms (rs3114660 and rs3114661) in SLCO4C1 were found to significantly affect the elimination of digoxin in vivo. The final population model may be useful for the individualized dosing of digoxin for patients with cardiac insufficiency.

Silibinin suppresses epithelial-mesenchymal transition in human non-small cell lung cancer cells by restraining RHBDD1.

BACKGROUND:Rhomboid domain containing 1 (RHBDD1) plays a crucial role in tumorigenesis. Silibinin, which is a natural extract from milk thistle, has shown anti-tumor effects against various tumors. Here, we investigate whether silibinin affects the function of RHBDD1 in non-small cell lung cancer (NSCLC) cell proliferation, migration and invasion.METHODS:The Oncomine database and an immunohistochemistry (IHC) assay were used to determine the RHBDD1 expression levels in lung cancer tissues. The associations between RHBDD1 and overall survival rate or clinicopathological parameters were respectively assessed using the Kaplan-Meier overall survival analysis or Chi-squared test. CCK-8 and Transwell assays were applied to analyze cell proliferation, migration and invasion. A549 cells were incubated with increasing concentrations of silibinin. RHBDD1 knockdown and overexpression were achieved via transfection with si-RHBDD1 or RHBDD1 overexpression plasmid, respectively. Western blotting was performed to measure the expressions of epithelial-mesenchymal transition (EMT) markers.RESULTS:We found that overexpression of RHBDD1 in lung cancer tissues correlates with a poor prognosis of survival. Clinical specimen analysis showed that upregulation of RHBDD1 correlates remarkably well with TNM stage and lymph node metastasis. Silibinin suppresses A549 cell proliferation, migration, invasion and EMT in a dose-dependent manner. Importantly, RHBDD1 was downregulated in silibinin-treated A549 cells. RHBDD1 overexpression reversed the suppressive effects of silibinin on A549 cell proliferation, migration, invasion and EMT expression, while its knockdown enhanced them.CONCLUSIONS:These findings shown an anti-tumor impact of silibinin on NSCLC cells via repression of RHBDD1.

The Synergistic Antitumor Activity of Chidamide in Combination with Bortezomib on Gastric Cancer.

PURPOSE:The aim of this study was to investigate the antitumor effect of chidamide in combination with bortezomib on gastric cancer cell lines.MATERIALS AND METHODS:First, the sensitivity and IC50 values of chidamide and bortezomib in several gastric cancer cell lines (MGC-803, BGC-823, SGC-7901, and MKN45) were measured using the CCK-8 assay. Then, the relatively insensitive gastric cancer cell lines (MGC-803 and BGC-823) were treated with low concentrations of chidamide alone, bortezomib alone, or chidamide and bortezomib combination to detect the effects on cell proliferation, apoptosis, migration, and invasion. Finally, the inhibitory effect of the combined chidamide and bortezomib treatment on MGC-803 cells was verified in vivo through tumor formation experiments in nude mice.RESULTS:Compared with low-dose chidamide or bortezomib alone, the low-dose drug combination significantly inhibited the proliferation, migration, and invasion of MGC-803 and BGC-823 cells and induced apoptosis of the cells. The effects of the low-dose chidamide and bortezomib combination reduced the growth on gastric cancer in vivo were investigated by using a subcutaneous tumor mouse model.CONCLUSION:Our results suggest that the combination of chidamide and bortezomib can significantly reduce the proliferation, invasion, and migration of MGC-803 and BGC-823 cells, providing a framework for the clinical evaluation of combined therapies for gastric cancers.

A novel ent-kaurane diterpenoid analog, DN3, selectively kills human gastric cancer cells via acting directly on mitochondria.

Targeting mitochondria using proper pharmacological agents is considered an attractive strategy for cancer control and management. Herein, we report a newly synthetic triazole analog of Jaridonin, DN3, which exhibits more potent antitumor activity via acting directly on mitochondria. DN3 potently reduced viabilities of gastric cancer cell lines HGC-27 and MGC-803 through inducing apoptosis and cell cycle arrest. But, normal human gastric epithelial cell line GES-1 is more resistant to the growth inhibition by DN3 compared with gastric cancer cells. DN3 induced mitochondrial membrane potential (MMP) decrease and cytochrome c release in intact gastric cancer cell lines. Meanwhile, the DN3 treatment also caused the release of cytochrome c from mitochondria isolated from cancer cell lines in a mitochondrial permeability transition pore complex (PTPC) mediated manner, but not from mitochondria isolated from normal gastric epithelial cell. The induction of mitochondrial PTPC proteins voltage-dependent anion channel (VDAC) and cyclophilin D (CypD) were also observed in DN3-treated cells. More interestingly, DN3 mediated MMP decrease, release of cytochrome c, the expression of VDAC and CypD and apoptosis were blocked by the pretreatment of VDAC1 inhibitor (4, 4'-diisothiocyanatostilbene-2,2'-disulfonic acid, DIDS) and CypD inhibitor (cyclosporine A, CsA). In a mouse xenograft model of human gastric cancer, the treatment of 5 mg/kg DN3 led to significant tumor regression without affecting body weight. In conclusion, our findings indicate that DN3 is a potential agent for the treatment of gastric cancer through acting directly on mitochondria, and would be useful for us to design more and better anti-cancer compounds.

Association between the UGT1A1*28 allele and hyperbilirubinemia in HIV-positive patients receiving atazanavir: a meta-analysis.

Objectives The uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1)*28 allele in HIV-positive patients receiving atazanavir (ATV) might be associated with the risk of hyperbilirubinemia. Owing to mixed and inconclusive results, a meta-analysis was conducted to systematically summarize and clarify this association.Methods Based on a comprehensive search of PubMed, Embase and Web of Science databases, studies investigating the association between UGT1A1 alleles and hyperbilirubinemia was retrieved. We evaluated the strength of this relationship using odds ratios (ORs) with 95% confidence intervals (CIs). Sensitivity analysis was performed by removing each study one at a time and calculating the pooled ORs of the remaining studies to test the robustness of the meta-analysis results. The Q statistic and the I2 index statistic were used to assess heterogeneity. Publication bias was evaluated using Orwin's fail-safe N test.Results A total of six individual studies were included in this meta-analysis. A significantly increased risk of hyperbilirubinemia was observed in HIV-positive patients receiving ATV with the UGT1A1*1/*28 or UGT1A1*28/*28 genotype, and the risk was higher with the UGT1A1*28/*28 genotype than with the UGT1A1*1/*28 genotype. (UGT1A1*28/*28 versus UGT1A1*1/*28: OR = 3.69, 95%CI = 1.82-7.49; UGT1A1*1/*28 versus UGT1A1*1/*1: OR = 3.50, 95%CI = 1.35-9.08; UGT1A1*28/*28 versus UGT1A1*1/*1: OR = 10.07, 95%CI = 4.39-23.10). All of the pooled ORs were not significantly affected by the remaining studies and different modeling methods, indicating robust results.Conclusions This meta-analysis suggests that the UGT1A1*28 allele represents a biomarker for an increased risk of hyperbilirubinemia in HIV-positive patients receiving ATV.

High-throughput identification and determination of antifungal triazoles in human plasma using UPLC-QDa.

Triazoles are common agents for invasive fungal infections, while therapeutic drug monitoring is needed to improve antifungal efficacy and reduce toxicity. This study aimed to exploit a simple and reliable liquid chromatography-mass spectrometry method for high-throughput monitoring of antifungal triazoles in human plasma using UPLC-QDa. Triazoles in plasma were separated by chromatography on a Waters BEH C18 column and detected using positive ions electrospray ionization fitted with single ion recording. M+ for fluconazole (m/z 307.11) and voriconazole (m/z 350.12), M2+ for posaconazole (m/z 351.17), itraconazole (m/z 353.13) and ketoconazole (m/z 266.08, IS) were selected as representative ions in single ion recording mode. The standard curves in plasma showed acceptable linearities over 1.25-40 μg/mL for fluconazole, 0.47-15 μg/mL for posaconazole and 0.39-12.5 μg/mL for voriconazole and itraconazole. The selectivity, specificity, accuracy, precision, recovery, matrix effect, and stability met acceptable practice standards under Food and Drug Administration method validation guidelines. This method was successfully applied to the therapeutic monitoring of triazoles in patients with invasive fungal infections, thereby guiding clinical medication.

Impact of SLCO4C1 Genotypes, Creatinine, and Spironolactone on Digoxin Population Pharmacokinetic Variables in Patients With Cardiac Insufficiency.

Corrigendum to "Impact of SLCO4C1 Genotypes, Creatinine, and Spironolactone on Digoxin Population Pharmacokinetic Variables in Patients With Cardiac Insufficiency" [Clin Therapeut 42(9) 1799-1810].

In Vitro and In Vivo Studies of Metabolic Activation of Marrubiin, a Bioactive Constituent from Marrubium Vulgare.

Marrubiin, a furanoid compound, is a well-known diterpenoid lactone isolated from Marrubium vulgare, which displays a wide spectrum of pharmacological effects and potential hepatotoxicity. Considering that marrubiin contains a structural alert, furan ring, metabolic activation may be one of the major metabolic pathways, and the reactive metabolite may be involved in the hepatotoxicity. The present study was carried out to investigate the bioactivation mechanism of marrubiin in rats and humans. Marrubiin was initially metabolized into cis-butene-1,4-dial intermediate, which was readily trapped by glutathione (GSH) and N-acetyl-lysine (NAL) in the microsomal incubations supplemented with NADPH. A total of nine conjugates were detected and identified by high-resolution mass spectrometry and nuclear magnetic resonance (NMR) spectroscopy. M1-M3 and M6 and M7 were characterized as mono-GSH conjugates, and M4 and M5 were identified as bis-GSH conjugates. M8 and M9 were identified as NAL conjugates. In rat bile, five GSH conjugates (M1-M3; M6 and M7) were detected. M1, M8, and M9 were chemically synthesized, and their structures were characterized by 13C NMR. Sulfaphenazole, ticlopidine, and ketoconazole displayed significant inhibitory effect on the bioactivation of marrubiin. Further phenotyping revealed that CYP2C9, CYP2C19, and CYP3A4 were the primary enzymes catalyzing the bioactivation of marrubiin. The current study provides evidence for the CYP-dominated bioactivation of marrubiin to the corresponding cis-butene-1,4-dial intermediate, which enables us to better understand the potential side effects caused by marrubiin.

T-2 toxin cytotoxicity mediated by directly perturbing mitochondria in human gastric epithelium GES-1 cells.

T-2 toxin is one of the most toxic trichothecenes and harmful to human health and animal husbandry. The mechanism underlying its growth suppression remains unclear, especially for mitochondrial damage in human gastric epithelial cells. In the present study, we investigated cell death caused by T-2 toxin in a human gastric epithelial cell line (GES-1) and the possible mechanism of T-2-induced cytotoxicity. T-2 strongly reduced the viability of GES-1 cells in a time- and dose-dependent manner within a small range of concentrations. However, when the concentrations of T-2 were >40 nM, there was no concentration dependence, only time dependence. Moreover, T-2 induced apoptosis, with the activation of caspase-3 in GES-1 and mitochondrial membrane potential (MMP) decrease and cytochrome c release. T-2 also resulted in the accumulation of reactive oxygen species (ROS) and DNA damage with a positive signal of p-H2A.X in GES-1 cells. While T-2 caused a MMP decrease, DNA damage and cell death were not blocked by pretreatment with 3 mM glutathione (GSH), a typical scavenger of ROS. The induction of mitochondrial permeability transition pore (mPTP) regulators voltage-dependent anion channel (VDAC1) and cyclophilin D (CypD) were also observed in T-2-treated cells. Interestingly, cyclosporine A (CsA), a CypD inhibitor, significantly reversed the drop in MMP and the DNA damage, as well as ROS accumulation caused by T-2. Additionally, GES-1 cell death could also be protected to some extent by 4, 4'-diisothiocyanatostilbene-2, 2'-disulfonic acid (DIDS), an inhibitor of VDAC1, especially the combination of CsA and DIDS, and 3 mM GSH could further enhance the effect of CsA + DIDS on cell viability. In conclusion, our present findings indicate that the T-2 induced MMP decrease, DNA damage and cell death, as well as ROS accumulation in GES-1 cells, starts with T-2 directly perturbing the mitochondria triggering ROS generation by acting on CypD and VDAC1. This study presents a new viewpoint for evaluating the toxicity of T-2 toxin.

Impact of SLCO4C1 Genotypes, Creatinine, and Spironolactone on Digoxin Population Pharmacokinetic Variables in Patients With Cardiac Insufficiency.

PURPOSE:This study aimed to utilize a population pharmacokinetic method to obtain information about the influence of covariates on the in vivo behavior of digoxin in patients with cardiac insufficiency.METHODS:A total of 228 therapeutic drug monitoring concentrations were retrospectively collected from 176 inpatients. The patients were randomly divided into a modeling group (n = 126) and a validation group (n = 50). The first-order absorption one-compartment model was used to develop a population pharmacokinetic model from a nonlinear mixed effects modeling approach. Sixteen single nucleotide polymorphisms involved in the pharmacokinetic variables of digoxin were identified by using the MassARRAY system. Various demographic parameters, biochemical test values, concomitant medications, and genetic variants were investigated.FINDINGS:The typical population value of digoxin CL/F was 5.06 L/h, and the volume of distribution was 211.82 L. The drug CL/F was significantly related to serum creatinine, in a combination of spironolactone and SLCO4C1 genotypes of 2 variants (rs3114660 and rs3114661). Results of model evaluation and internal/external validation indicated a stable and precise performance of the final model.IMPLICATIONS:For the first time, 2 single nucleotide polymorphisms (rs3114660 and rs3114661) in SLCO4C1 were found to significantly affect the elimination of digoxin in vivo. The final population model may be useful for the individualized dosing of digoxin for patients with cardiac insufficiency.

Silibinin suppresses epithelial-mesenchymal transition in human non-small cell lung cancer cells by restraining RHBDD1.

BACKGROUND:Rhomboid domain containing 1 (RHBDD1) plays a crucial role in tumorigenesis. Silibinin, which is a natural extract from milk thistle, has shown anti-tumor effects against various tumors. Here, we investigate whether silibinin affects the function of RHBDD1 in non-small cell lung cancer (NSCLC) cell proliferation, migration and invasion.METHODS:The Oncomine database and an immunohistochemistry (IHC) assay were used to determine the RHBDD1 expression levels in lung cancer tissues. The associations between RHBDD1 and overall survival rate or clinicopathological parameters were respectively assessed using the Kaplan-Meier overall survival analysis or Chi-squared test. CCK-8 and Transwell assays were applied to analyze cell proliferation, migration and invasion. A549 cells were incubated with increasing concentrations of silibinin. RHBDD1 knockdown and overexpression were achieved via transfection with si-RHBDD1 or RHBDD1 overexpression plasmid, respectively. Western blotting was performed to measure the expressions of epithelial-mesenchymal transition (EMT) markers.RESULTS:We found that overexpression of RHBDD1 in lung cancer tissues correlates with a poor prognosis of survival. Clinical specimen analysis showed that upregulation of RHBDD1 correlates remarkably well with TNM stage and lymph node metastasis. Silibinin suppresses A549 cell proliferation, migration, invasion and EMT in a dose-dependent manner. Importantly, RHBDD1 was downregulated in silibinin-treated A549 cells. RHBDD1 overexpression reversed the suppressive effects of silibinin on A549 cell proliferation, migration, invasion and EMT expression, while its knockdown enhanced them.CONCLUSIONS:These findings shown an anti-tumor impact of silibinin on NSCLC cells via repression of RHBDD1.

The Synergistic Antitumor Activity of Chidamide in Combination with Bortezomib on Gastric Cancer.

PURPOSE:The aim of this study was to investigate the antitumor effect of chidamide in combination with bortezomib on gastric cancer cell lines.MATERIALS AND METHODS:First, the sensitivity and IC50 values of chidamide and bortezomib in several gastric cancer cell lines (MGC-803, BGC-823, SGC-7901, and MKN45) were measured using the CCK-8 assay. Then, the relatively insensitive gastric cancer cell lines (MGC-803 and BGC-823) were treated with low concentrations of chidamide alone, bortezomib alone, or chidamide and bortezomib combination to detect the effects on cell proliferation, apoptosis, migration, and invasion. Finally, the inhibitory effect of the combined chidamide and bortezomib treatment on MGC-803 cells was verified in vivo through tumor formation experiments in nude mice.RESULTS:Compared with low-dose chidamide or bortezomib alone, the low-dose drug combination significantly inhibited the proliferation, migration, and invasion of MGC-803 and BGC-823 cells and induced apoptosis of the cells. The effects of the low-dose chidamide and bortezomib combination reduced the growth on gastric cancer in vivo were investigated by using a subcutaneous tumor mouse model.CONCLUSION:Our results suggest that the combination of chidamide and bortezomib can significantly reduce the proliferation, invasion, and migration of MGC-803 and BGC-823 cells, providing a framework for the clinical evaluation of combined therapies for gastric cancers.

A novel ent-kaurane diterpenoid analog, DN3, selectively kills human gastric cancer cells via acting directly on mitochondria.

Targeting mitochondria using proper pharmacological agents is considered an attractive strategy for cancer control and management. Herein, we report a newly synthetic triazole analog of Jaridonin, DN3, which exhibits more potent antitumor activity via acting directly on mitochondria. DN3 potently reduced viabilities of gastric cancer cell lines HGC-27 and MGC-803 through inducing apoptosis and cell cycle arrest. But, normal human gastric epithelial cell line GES-1 is more resistant to the growth inhibition by DN3 compared with gastric cancer cells. DN3 induced mitochondrial membrane potential (MMP) decrease and cytochrome c release in intact gastric cancer cell lines. Meanwhile, the DN3 treatment also caused the release of cytochrome c from mitochondria isolated from cancer cell lines in a mitochondrial permeability transition pore complex (PTPC) mediated manner, but not from mitochondria isolated from normal gastric epithelial cell. The induction of mitochondrial PTPC proteins voltage-dependent anion channel (VDAC) and cyclophilin D (CypD) were also observed in DN3-treated cells. More interestingly, DN3 mediated MMP decrease, release of cytochrome c, the expression of VDAC and CypD and apoptosis were blocked by the pretreatment of VDAC1 inhibitor (4, 4'-diisothiocyanatostilbene-2,2'-disulfonic acid, DIDS) and CypD inhibitor (cyclosporine A, CsA). In a mouse xenograft model of human gastric cancer, the treatment of 5 mg/kg DN3 led to significant tumor regression without affecting body weight. In conclusion, our findings indicate that DN3 is a potential agent for the treatment of gastric cancer through acting directly on mitochondria, and would be useful for us to design more and better anti-cancer compounds.

Association between the UGT1A1*28 allele and hyperbilirubinemia in HIV-positive patients receiving atazanavir: a meta-analysis.

Objectives The uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1)*28 allele in HIV-positive patients receiving atazanavir (ATV) might be associated with the risk of hyperbilirubinemia. Owing to mixed and inconclusive results, a meta-analysis was conducted to systematically summarize and clarify this association.Methods Based on a comprehensive search of PubMed, Embase and Web of Science databases, studies investigating the association between UGT1A1 alleles and hyperbilirubinemia was retrieved. We evaluated the strength of this relationship using odds ratios (ORs) with 95% confidence intervals (CIs). Sensitivity analysis was performed by removing each study one at a time and calculating the pooled ORs of the remaining studies to test the robustness of the meta-analysis results. The Q statistic and the I2 index statistic were used to assess heterogeneity. Publication bias was evaluated using Orwin's fail-safe N test.Results A total of six individual studies were included in this meta-analysis. A significantly increased risk of hyperbilirubinemia was observed in HIV-positive patients receiving ATV with the UGT1A1*1/*28 or UGT1A1*28/*28 genotype, and the risk was higher with the UGT1A1*28/*28 genotype than with the UGT1A1*1/*28 genotype. (UGT1A1*28/*28 versus UGT1A1*1/*28: OR = 3.69, 95%CI = 1.82-7.49; UGT1A1*1/*28 versus UGT1A1*1/*1: OR = 3.50, 95%CI = 1.35-9.08; UGT1A1*28/*28 versus UGT1A1*1/*1: OR = 10.07, 95%CI = 4.39-23.10). All of the pooled ORs were not significantly affected by the remaining studies and different modeling methods, indicating robust results.Conclusions This meta-analysis suggests that the UGT1A1*28 allele represents a biomarker for an increased risk of hyperbilirubinemia in HIV-positive patients receiving ATV.