Recent findings established (–)-isostemonamine as an anti-proliferator for estrogen receptor α-negative human breast cancer cells, MDA-MB-231, known to grow/divide at an aggressive rate. However, ST-4, a thioamide derivative of (–)-isostemonamine, is believed to not affect the viability of these cells. Epigenetic changes, such as DNA methylation and histone modification, are involved in the progression of many cancers, including breast cancer. In the present study, we investigated whether ST-4 and its related compounds (ST-3 and ST-5) can potentiate the anti-proliferative activity of the established epigenetic modifiers, 5-aza-2'-deoxycytidine (5-aza-dC; a DNA methyltransferase 1 inhibitor), trichostatin A (TSA; a class I/II histone deacetylase inhibitor), and etoposide (a DNA topoisomerase IIα inhibitor). Data obtained from this study demonstrate that, among the studied compounds, ST-4 displays the strongest enhancement of the anti-proliferative activity of TSA, against MDA-MB-231 cells (IC20 of TSA = 14 ± 3.4 nM versus that of TSA/ST-4 combination = 7.8 ± 1.1 nM). However, this effect was not observed at higher concentrations of above 25 nM of TSA, at which the IC50 values of TSA with or without ST-4 were not significantly different (30 ± 4.4 nM versus 28 ± 1.4 nM, respectively). Results from the study suggest that combining ST-4 with established anti-cancer agents could potentiate the latter’s anti-proliferative activity, thereby potentially minimizing the concentration of these agents needed for optimal clinical efficacy and safety.
Dysregulation of the biological clock disrupts the homeostasis of physiological functions, which may lead to the development of various disorders. To investigate the relationship between biological rhythms and disorders, an efficient monitoring method of the biological clock is necessary. In this study, we analyzed the circadian rhythmicity profile of bile acids in urine and investigated whether urinary bile acid (UBA) could reflect the circadian rhythm in liver physiology. Male Wistar-Hannover rats were maintained in metabolic cages under ad lib feeding and later subjected to restricted feeding (in which rats were fed only during light periods). Excreted urine was collected in each session, and bile acid contents were analyzed via an enzyme-based total bile acid assay. UBA content showed diurnal fluctuations under both ad lib and restricted feeding conditions and reached a peak during the dark period of ad lib feeding. In contrast, with restricted feeding, the peak was observed during light periods. Restricted feeding induced an 8-12 h phase shift. Diurnal fluctuation and phase shift by restricted feeding are distinctive features controlled by biological clocks in peripheral tissues. Since bile acids are synthesized in the liver, we propose that UBA might reflect the circadian fluctuation in liver physiology.
Antibiotics influence the anticoagulation effect of warfarin and increase the bleeding risk in patients who are receiving warfarin. Piperacillin/tazobactam (PIPC/TAZ) is commonly used to treat infections such as healthcare-associated infection. However, there have been few reports about the interaction between warfarin and PIPC/TAZ. In this study, we investigated the influence of PIPC/TAZ on the anticoagulation effect of warfarin in hospitalized patients. The primary outcome was elevation of prothrombin time international normalized ratio (PT-INR) after PIPC/TAZ administration. Secondary outcomes were the proportion of patients with supratherapeutic levels of PT-INR, discontinuation of administration or reduction in the dose of warfarin, bleeding, transfusion, and vitamin-K rescue. Fifteen patients were enrolled in this study. PT-INR elevation occurred in 11 (73.3%) of the 15 patients. The median value of PT-INR after administration of PIPC/TAZ was significantly higher than the value before administration: 2.22 (interquartile range (IQR), 2.05-2.76) and 1.90 (IQR, 1.36-2.45), respectively (p = 0.024). Three (20%) of the 15 patients had PT-INR over 4, and discontinuation of administration or reduction in the dose of warfarin was needed in 6 (40%) of the 15 patients. Bleeding occurred in one patient, transfusion was performed in one patient and vitamin-K rescue was performed in one patient. This study showed that PIPC/TAZ induced elevation of PT-INR in patients receiving warfarin and that discontinuation or reduction in the dose of warfarin was needed in 40% of the patients. Therefore, we recommend to close monitoring of PT-INR in patients treated with warfarin during PIPC/TAZ administration.
Myeloid-derived suppressor cells (MDSCs), which are derived from immature bone marrow cell (BMC) populations that proliferate in the tumor microenvironment, suppress T cell immune responses. Transient receptor potential vanilloid (TRPV) 4, which is a Ca2+ channel, is involved in tumor growth, but the role of TRP channels in MDSC differentiation and function remains unclear. Here, we first investigated the involvement of TRP channels in the differentiation of MDSCs. The selective TRPV4 channel antagonist RN-1734 increased the population of MDSCs (CD11b+Gr-1+) at Day 3, while the TRPV4 agonist GSK1016790A decreased it, suggesting that stimulation of TRPV4 suppresses the differentiation of BMCs to MDSCs. GSK1016790A also increased the production of nitric oxide and reactive oxygen species, but suppressed the expression of Arg-1 mRNA, which encodes arginase-1, in MDSCs. Furthermore, GSK1016790A decreased the phosphorylation of signal transducer and activator of transcription 3 (STAT3) in MDSCs, thereby attenuating STAT3 signaling. Our results suggest that TRPV4 plays a role in regulating both the differentiation and function of MDSCs, and therefore could be a promising target for cancer immunotherapy.
Curcumin is a polyphenol compound derived from the roots of Curcuma longa. Although the biological activities of curcumin, such as its anti-inflammatory, anti-oxidant, anti-microbial and anti-cancer effects, have been well applied, its poor chemical stability is a major problem. Pentagamavunon-0 (PGV-0) and Pentagamavunon-1 (PGV-1) were developed as curcumin analogues with higher bioavailability; however, their anti-cancer activity has not yet been assessed. In this study, we evaluated the anti-metastatic activity of PGV-0 and PGV-1 in 4T1 breast cancer cells. Although both curcumin analogues demonstrated similar anti-proliferative effects to curcumin in 4T1 breast cancer cells, they did not inhibit nuclear factor kappa B (NF-ĸB) activity which is a well-defined molecular target of curcumin for its anti-cancer effects. As PGV-0 and PGV-1 exhibited stronger inhibition of the metastatic capacity in a 4T1 breast cancer model than curcumin, PGV-0 and PGV-1 may be promising curcumin analogues to target cancer metastasis having a distinct molecular mechanism from that of curcumin.
Calcined Ni–Al complex hydroxide (NA12) was produced through calcination at 400°C, and its capability on phosphate ion adsorption was examined. Initially, the physicochemical characteristics including specific surface area, the number of hydroxyl groups, pore volume, scanning electron microscope images, and X-ray diffraction patterns of calcined Ni–Al complex hydroxides were evaluated. The level of phosphate ion adsorbed onto NA12 in the value of 128.5 mg/g was higher than that of other compared adsorbents. This study indicated that the level of phosphate ion adsorbed using calcined Ni–Al complex hydroxide was correlated to the properties of an adsorbent surface. Moreover, the binding energy of the NA12 surface before and after the phosphate ion adsorption was also determined, and phosphorus energy (2p and 2s) could be detected after adsorption. The results demonstrated that the NA12 surface properties were important for phosphate ion removal from the aqueous solution. Additionally, the effects of pH, temperature, and contact time on the phosphate ion adsorption were also investigated. The results confirmed a potent recovery of the phosphate ion (over 90%) when using a NaOH solution at 1000 mmol/L in this experiment. Thus, NA12 is a promising adsorbent for the phosphate ion.
Human serum albumin (HSA) dimer, where two molecules of HSA are genetically fused with a linker of 10 amino acid, has superior blood retention property, compared with HSA monomer. Moreover, HSA dimer derivative, s-nitrosated HSA dimer, functions as an enhanced permeability and retention effects enhancer. HSA dimer has gained considerable attention as drug delivery system carrier based on its prominent function. However, for the HSA dimer to be used clinically, the safety profile of the HSA dimer is required in order to exclude any potential toxicity or unwanted effects. Thus, the present study was undertaken to investigate the occurance of tissue damage and serologic changes due to repeated administration of HSA dimer (66.5 mg/kg) to mice every 3 d for 56 d, as part of a basic consideration on safety evaluation. The evaluation on survival, behavior and body weight indicate that HSA dimer has no effect on physical growth and physiological functions. Hematological tests suggest that HSA dimer has no direct influence on hemocytes, such as hemolysis and platelet aggregation. Moreover, plasma clinical chemistry and histological examinations indicate that the HSA dimer has no deleterious effect on liver and renal functions. The results obtained here indicate HSA dimer is safe and should be useful for medical and pharmaceutical applications.