DHPS-Mediated Hypusination Regulates METTL3 Self-m6A-Methylation Modification to Promote Melanoma Proliferation and the Development of Novel Inhibitors.

Discovering new treatments for melanoma will benefit human health. The mechanism by which deoxyhypusine synthase (DHPS) promotes melanoma development remains elucidated. Multi-omics studies have revealed that DHPS regulates m6A modification and maintains mRNA stability in melanoma cells. Mechanistically, DHPS activates the hypusination of eukaryotic translation initiation factor 5A (eIF5A) to assist METTL3 localizing on its mRNA for m6A modification, then promoting METTL3 expression. Structure-based design, synthesis, and activity screening yielded the hit compound GL-1 as a DHPS inhibitor. Notably, GL-1 directly inhibits DHPS binding to eIF5A, whereas GC-7 cannot. Based on the clarification of the mode of action of GL-1 on DHPS, it is found that GL-1 can promote the accumulation of intracellular Cu2+ to induce apoptosis, and antibody microarray analysis shows that GL-1 inhibits the expression of several cytokines. GL-1 shows promising antitumor activity with good bioavailability in a xenograft tumor model. These findings clarify the molecular mechanisms by which DHPS regulates melanoma proliferation and demonstrate the potential of GL-1 for clinical melanoma therapy.

Hypolipidemic effect of gypenosides in experimentally induced hypercholesterolemic rats.

BACKGROUND: To investigate the anti-hyperlipidemic effect of gynosaponins (GPs) in hyperlipidemic rats induced by high lipid diet. METHODS: Animal model of hyperlipidemia was established by high-fat and high-cholesterol diet. Rats were randomly divided into 6 groups, except the normal and model groups, rats in GPs groups were daily administered intragastrically with GPs (50, 100, and 200 mg/kg), and rats in simvastatin group were daily administered intragastrically with simvastatin (10 mg/kg). It was measured that the contents of glutathione peroxidase (GSH-Px), superoxide dismutase (SOD), catalase (CAT), malondialdehyde (MDA), total cholesterol (TC), triglyceride (TG), high-density lipoprotein-cholesterol (HDL-C) and low-density lipoprotein-cholesterol (LDL-C) in the serum, TG and TC in the liver during this experiment, respectively. The left lobe of liver was observed by histopathological staining, and the immunohistochemical staining was used to observe the effects on the effect of GPs on liver functions. RESULTS: Compared with the model group, GPs groups could remarkably decrease the content of lipids, GSH-Px, SOD, CAT and MDA in the serum and TC and TG in the liver of the hyperlipidemic rats. The pathomorphological results of hepatic tissue showed that fatty degeneration and inflammatory reaction of GPs groups were lightened compared with the model group. CONCLUSIONS: The results show that GPs has good effects on the treatment of hyperlipidemia induced by high lipid diet in rats. The possible anti-hyperlipidemia mechanism maybe those GPs can regulate the disorder of lipid metabolism as well as ameliorate hepatic function.

Hypusination-induced DHPS/eIF5A pathway as a new therapeutic strategy for human diseases: A mechanistic review and structural classification of DHPS inhibitors.

The discovery of new therapeutic strategies for diseases is essential for drug research. Deoxyhypusine synthase (DHPS) is a critical enzyme that modifies the conversion of the eukaryotic translation initiation factor 5A (eIF5A) precursor into physiologically active eIF5A (eIF5A-Hyp). Recent studies have revealed that the hypusine modifying of DHPS on eIF5A has an essential regulatory role in human diseases. The hypusination-induced DHPS/eIF5A pathway has been shown to play an essential role in various cancers, and it could regulate immune-related diseases, glucose metabolism-related diseases, neurological-related diseases, and aging. In addition, DHPS has a more defined substrate and a well-defined structure within the active pocket than eIF5A. More and more researchers are focusing on the prospect of advanced development of DHPS inhibitors. This review summarizes the regulatory mechanisms of the hypusination-induced DHPS/eIF5A pathway in a variety of diseases in addition to the inhibitors related to this pathway; it highlights and analyzes the structural features and mechanisms of action of DHPS inhibitors and expands the prospects of future drug development using DHPS as an anticancer target.

[The solubilization effect of 2-hydroxypropyl-beta-cyclodextrin on paeonolum].

OBJECTIVE: To study the solubilization effect of 2-hydroxypropyl-beta-cyclodextrin(HPCD) on paeonolum at various pH value. METHOD: Phase-solubility method was adopted to study the solubilization effect at 25 degrees C and UV spectrohotometer was used to determine paeonolum content. RESULTS: The apparent solubility of paeonolum was significantly enhanced by increased HPCD concentration. The apparent stability constant of paeonolum compounds was calculated up to 1 425 in which pH was 3 and HPCD concentration was 133.33 mmol x L(-1). The solubility of paeonolum came up to 10 mg x mL(-1). CONCLUSION: HPCD is an ideal solubilizer for paeonolum.

[Phenolic acid derivatives from the rhizome of Fagopyrum cymosum].

OBJECTIVE: To study the chemical constituents of Fagopyrum cymosum. METHOD: The chemical constituents were isolated by various chromatographic methods and their structures were elucidated by the analysis of spectral data and physiochemical properties. RESULT: Four phenolic acid derivatives were isolated from F. cymosum. The chemical structures were elucidated as trans-p-hydroxy cinnamic methyl ester (I), 3, 4-dihydroxy benzamide (II), protocatechuic acid (III), protocatechuic acid methyl ester (IV). CONCLUSION: Compounds I, II, IV were obtained from the genus Fagopyrum for the first time.

Study on the preparation of nifedipine-loaded oral copolymer micelles and its pharmacokinetics in rats.

The objective of this paper was to prepare nifedipine-loaded oral copolymer micelles and to improve bioavailability of hydrophobic drugs. The methoxy poly(ethylene glycol)-b-polycaprolactone diblock copolymer (mPEG-b-PCL) we developed was the research object; solvent evaporation method was utilized to prepare nifedipine-loaded copolymer micelles, and the drug concentration, drug-loaded amount, and entrapment efficiency were also determined. Transmission electron microscopy and dynamic light scattering were used to characterize the morphology and size distributions of micelles, and the in vivo pharmacokinetics were studied in rats with the research objects of nifedipine-loaded oral copolymer micelles. The drug concentration, drug-loaded amount, and entrapment efficiency of mPEG-b-PCL-nifedipine micelles were (69.39 ± 4.33) µg mL(-1), (3.35 ± 0.21)%, and (8.67 ± 0.54)%, respectively. The micelles were globular shaped with a narrow size distribution and a mean diameter of (34.8 ± 3.2) nm, and the relative bioavailability of the micelles we developed was 246.20% when compared with the tablets available in the market. The mPEG-b-PCL-nifedipine oral copolymer micelles can improve the bioavailability of hydrophobic drugs. Oral polymer micelles drug delivery system has a good prospect.