Human transcription factor YY1 could upregulate the HIV-1 gene expression.

Gene expression in HIV-1 is regulated by the promoters in 5' long-terminal repeat (LTR) element, which contain multiple DNA regulatory elements that serve as binding sites for cellular transcription factors. YY1 could repress HIV-1 gene expression and latent infection. Here, however, we observed that virus production can be increased by YY1 over-expression and decreased under YY1 depleted condition by siRNA treatment. To identify functional domain(s) of YY1 activation, we constructed a number of YY1 truncated mutants. Our data show that full-length YY1 enhances the viral transcription both through U3 and U3RU5 promoters. Moreover, the C-terminal region (296-414 residues) of YY1 is responsible for the transcriptional upregulation, which could be enhanced further in the presence of the viral Tat protein. The central domain of YY1 (155-295 residues) does not affect LTR activity but has a negative effect on HIV-1 gene expression. Taken together, our study shows that YY1 could act as a transcriptional activator in HIV-1 replication, at least in the early stages of infection. [BMB Reports 2020; 53(5): 248-253].

Benefit of Adjuvant Traditional Herbal Medicine With Chemotherapy for Resectable Gastric Cancer.

INTRODUCTION: Stomach cancer, historically, has a low survival rate advances in curative resection procedures. OBJECTIVES: To assess the potential benefits of traditional herbal medicines in conjunction with chemotherapy in postoperative gastric cancer patients in terms of overall survival and disease-free survival. DATA SOURCES: We searched the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, a Chinese database (CNKI), a Korean database, a Japanese database, AMED, and CINAHL up to September 2016. We summarized survival data from all RCTs. STUDY SELECTION: All RCTs of oral traditional medicines for resectable gastric cancer compared with chemotherapy alone were eligible. DATA EXTRACTION: Thirteen eligible trials with survival data (1075 patients) were deemed eligible for inclusion. RESULTS: There were 217 documented deaths of the 574 patients assigned to adjuvant traditional medicines groups and 319 documented deaths of the 501 patients assigned to the chemotherapy-only groups. Adjuvant traditional medicines were associated with a statistically significant benefit in terms of overall survival rate (hazard ratio = 0.56; 95% confidence interval = 0.47-0.66; P < .00001) and disease-free survival (hazard ratio = 0.54; 95% confidence interval = 0.43-0.66; P < .00001). CONCLUSION: Among the RCTs included, the inclusion of postoperative adjuvant traditional medicines was associated with reduced risk of death in gastric cancer patients, when survival rates were compared with the group of patients who received chemotherapy alone. However, most of the included studies utilized are thought to be of low quality, so it would certainly appear that more trials are both advisable and necessary to arrive at correct and convincing conclusions.

Evaluation of cadmium-induced nephrotoxicity using urinary metabolomic profiles in sprague-dawley male rats.

The aim of this study was to investigate urinary metabolomic profiles associated with cadmium (Cd)-induced nephrotoxicity and their potential mechanisms. Metabolomic profiles were measured by high-resolution (1)H-nuclear magnetic resonance (NMR) spectroscopy in the urine of rats after oral exposure to CdCl2 (1, 5, or 25 mg/kg) for 6 wk. The spectral data were further analyzed by a multivariate analysis to identify specific urinary metabolites. Urinary excretion levels of protein biomarkers were also measured and CdCl2 accumulated dose-dependently in the kidney. High-dose (25 mg/kg) CdCl2 exposure significantly increased serum blood urea nitrogen (BUN), but serum creatinine (sCr) levels were unchanged. High-dose CdCl2 (25 mg/kg) exposure also significantly elevated protein-based urinary biomarkers including osteopontin, monocyte chemoattractant protein-1 (MCP-1), kidney injury molecules-1 (Kim-1), and selenium-binding protein 1 (SBP1) in rat urine. Under these conditions, six urinary metabolites (citrate, serine, 3-hydroxyisovalerate, 4-hydroxyphenyllactate, dimethylamine, and betaine) were involved in mitochondrial energy metabolism. In addition, a few number of amino acids such as glycine, glutamate, tyrosine, proline, or phenylalanine and carbohydrate (glucose) were altered in urine after CdCl2 exposure. In particular, the metabolites involved in the glutathione biosynthesis pathway, including cysteine, serine, methionine, and glutamate, were markedly decreased compared to the control. Thus, these metabolites are potential biomarkers for detection of Cd-induced nephrotoxicity. Our results further indicate that redox metabolomics pathways may be associated with Cd-mediated chronic kidney injury. These findings provide a biochemical pathway for better understanding of cellular mechanism underlying Cd-induced renal injury in humans.

Low iodine diet for one week is sufficient for adequate preparation of high dose radioactive iodine ablation therapy of differentiated thyroid cancer patients in iodine-rich areas.

BACKGROUND: Most current guidelines suggest one or two weeks of low iodine diet (LID) before radioactive iodine ablation therapy (RAIT) to increase its efficacy in differentiated thyroid cancer (DTC) patients after total thyroidectomy. LID duration is particularly important for patients living in iodine excess areas. However, there is no standardized LID protocol and there are limited reports regarding the relationship between LID and ablation outcome. Therefore, we aimed to evaluate the optimal LID duration and define clinical features that affect ablation outcome. METHODS: A total of 202 papillary thyroid cancer patients with total thyroidectomy preparing for RAIT were enrolled. All patients had undergone two weeks of LID before (131)I administration. Morning spot urine specimens were obtained twice (one week or two weeks after LID, respectively) from each patient. Urine iodine excretion (UIE) values were used to evaluate LID efficacy. Successful ablation was defined using two definitions: (i) no visible uptake on a follow-up diagnostic (131)I scans, and (ii) no visible uptake on a follow-up diagnostic (131)I scans and stimulated serum thyroglobulin (Tg) levels <1 ng/mL. RESULTS: The UIE median values after LID for one and two weeks were lower than 50 µg/L, and the median UIE values were not significantly different according to the LID duration. Based on the first criterion for successful ablation, 175 of the 195 patients were successfully ablated. There were no significant differences in mean and median UIE levels between the ablated and non-ablated groups after LID for two weeks. The rate of ablation did not differ between the mild and moderate iodine deficient groups. Based on the second criterion for successful ablation, 149 of 188 patients were successfully ablated. The ablation success rate did not differ between UIE levels. When we analyzed clinical factors that affect ablation outcome, serum Tg level at the time of ablation was the only significant variable in multivariate logistic analysis. CONCLUSION: Strict LID for one week was sufficient to achieve target UIE values for RAIT preparation, even in iodine-rich areas.

Pharmacokinetics of isoliquiritigenin and its metabolites in rats: low bioavailability is primarily due to the hepatic and intestinal metabolism.

Isoliquiritigenin, a chalcone found in licorice has shown a variety of biological activities including antioxidative, anti-inflammatory, estrogenic, chemopreventive and antitumor effects. Thus, pharmacokinetics of isoliquiritigenin and its metabolites [liquiritigenin, glucuronidated isoliquiritigenin (M1), and glucuronidated liquiritigenin (M2)] after intravenous and oral administration of isoliquiritigenin was evaluated in rats. The pharmacokinetics of isoliquiritigenin, liquiritigenin, M1, and M2 showed no dose dependence after both intravenous and oral administration of isoliquiritigenin. Although approximately 92.0 % of the oral isoliquiritigenin was absorbed, the extent of the absolute bioavailability value was only 11.8 % of the oral dose. The low absolute bioavailability value of isoliquiritigenin might be due to the considerable metabolism of isoliquiritigenin in the small intestine and liver. This was supported by the facts that the ratios of AUC(M1)/AUC(isoLQ) and AUC(M2)/AUC(isoLQ) were high (over 0.25), isoliquiritigenin disappeared, and M1 and M2 were formed mainly in S9 fractions of the liver and small intestine. The affinities of liquiritigenin, isoliquiritigenin, M1, and M2 were high in the liver, small intestine, large intestine, and/or kidney.

Effects of Korean red ginseng extract on acute renal failure induced by gentamicin and pharmacokinetic changes by metformin in rats.

AIM OF THE STUDY: Korean red ginseng is one of the best selling dietary supplements and its individual constituents enhance renal function. Acute renal failure (ARF) is a predisposing complication of diabetes mellitus as a result of combination drug therapy. The combination of antibiotic-antidiabetic drugs can entail toxicities and drug interactions because of the antibiotic resistance in patients with severe bacterial infection. Currently, gentamicin-metformin combination therapy is commonly prescribed for treating bacterial infections and diabetes, even though both drugs are mainly excreted via the kidney. Thus, this study was designed to investigate whether a Korean red ginseng extract (KRG) prevents renal impairment and pharmacokinetic changes by metformin in rats with renal failure induced by gentamicin. MATERIALS AND METHODS: The in vivo pharmacokinetics and in vitro hepatic/intestinal metabolism of metformin were assessed using control (CON), control with Korean red ginseng extract (KRG-CON), acute renal failure induced by gentamicin (ARF), and ARF with Korean red ginseng (KRG-ARF) rats. RESULTS AND CONCLUSIONS: Pharmacokinetic changes of metformin did not occur in KRG-ARF rats because KRG reduce the renal accumulation of gentamicin compared to ARF rats. Thus, KRG seemed to prevent acute renal failure induced by gentamicin treatment.

Effects of cysteine on the pharmacokinetics of tamoxifen in rats with protein-calorie malnutrition.

Protein-calorie malnutrition (PCM) could occur frequently in cancer patients and alter the pharmacokinetics of drugs. Also cysteine shows anti-oxidative effect and changes the activities of drug metabolizing enzyme and/or transporters. Herein, we investigated the effects of cysteine on the pharmacokinetics of tamoxifen in rats with protein-calorie malnutrition (PCM). The in vivo pharmacokinetics and in vitro hepatic/intestinal metabolism of tamoxifen were assessed using control, CC (control with cysteine), PCM, PCMC (PCM with cysteine) rats. The effects of cysteine on the intestinal absorption of tamoxifen were further investigated through in vitro transport studies using rat intestine. The AUCs of intravenous tamoxifen in PCM rats were significantly greater than control rats due to the decrease in the hepatic metabolism via CYP3A. In PCMC rats, the elevated AUCs in PCM rats returned to control levels by oral cysteine supplement. The AUC of oral tamoxifen in PCM rats was significantly smaller than in control rats mainly due to the decrease in gastrointestinal absorption. In CC and PCMC rats, oral cysteine supplement enhanced the gastrointestinal absorption of tamoxifen probably via intestinal P-gp inhibition. The present study demonstrated that PCM state and/or oral cysteine supplement had a profound impact on the pharmacokinetics of tamoxifen in rats. If the present rat data are extrapolated to humans, the alterations in tamoxifen absorption and metabolism should be considered in designing a dosage regimen for cancer patients with PCM and/or oral cysteine supplement.

Effects of cysteine on the pharmacokinetics of paclitaxel in rats.

Paclitaxel is a P-gp substrate and metabolized via CYP2C and 3A subfamily in rats. It has been reported that cysteine causes the changes in expression of CYP isozymes and intestinal P-gp mediated efflux activity in rats. Thus, the effects of cysteine on the pharmacokinetics of intravenous and oral paclitaxel were investigated in rats. After intravenous administration of paclitaxel (30 mg/kg) to control (CON), single cysteine treatment (ST) and cysteine treatment for a week (CT) rats, the pharmacokinetic parameters were comparable among three groups of rats. Also the pharmacokinetic parameters between CON and ST rats were comparable after oral administration of paclitaxel (30 mg/kg) to rats. These results are consistent with that oral cysteine supplement on a single day did not considerably inhibit the metabolism of paclitaxel via hepatic and/or intestinal CYP3A subfamily and P-gp mediated efflux of paclitaxel in the liver and/or intestine both after intravenous and oral administration to rats. After oral administration of paclitaxel (30 mg/kg) to rats, the greater AUC(06 h) in CT rats was mainly due to that oral cysteine supplement for seven consecutive days enhanced the gastrointestinal absorption of paclitaxel compared with those in CON and ST rats.

Sequential therapy with JX-594, a targeted oncolytic poxvirus, followed by sorafenib in hepatocellular carcinoma: preclinical and clinical demonstration of combination efficacy.

JX-594 is a targeted and granulocyte-macrophage colony stimulating factor (GM-CSF) expressing oncolytic poxvirus designed to selectively replicate in and destroy cancer cells through viral oncolysis and tumor-specific immunity. In a phase 1 trial, JX-594 injection into hepatocellular carcinoma (HCC) was well-tolerated and associated with viral replication, decreased tumor perfusion, and tumor necrosis. We hypothesized that JX-594 and sorafenib, a small molecule inhibitor of B-raf and vascular endothelial growth factor receptor (VEGFR) approved for HCC, would have clinical benefit in combination given their demonstrated efficacy in HCC patients and their complementary mechanisms-of-action. HCC cell lines were uniformly sensitive to JX-594. Anti-raf kinase effects of concurrent sorafenib inhibited JX-594 replication in vitro, whereas sequential therapy was superior to either agent alone in murine tumor models. We therefore explored pilot safety and efficacy of JX-594 followed by sorafenib in three HCC patients. In all three patients, sequential treatment was (i) well-tolerated, (ii) associated with significantly decreased tumor perfusion, and (iii) associated with objective tumor responses (Choi criteria; up to 100% necrosis). HCC historical control patients on sorafenib alone at the same institutions had no objective tumor responses (0 of 15). Treatment of HCC with JX-594 followed by sorafenib has antitumoral activity, and JX-594 may sensitize tumors to subsequent therapy with VEGF/VEGFR inhibitors.