Thioredoxin reductase (TrxR) is one class of the most important antioxidant selenoproteins and is involved in regulating tumor genesis and progression. It has been reported that naphthoquinones can target and inhibit TrxR1 activity therefore produce reactive oxygen species (ROS) mediated by TrxR1, resulting into cellular redox imbalance and making the naphthoquinone compounds to become potential antitumor chemotherapy drugs. The purpose of this work is to explore the interaction between TrxR1 and menadione using biochemical and mass-spectrometric (MS) analyses, to further reveal the detailed mechanisms of TrxR1-mediated naphthoquinone reduction and inhibition of TrxR1 by naphthoquinone compounds. Using the site-directed mutagenesis and recombinantly expressed TrxR1 variants, we measured the steady-state kinetic parameters of menadione reduction mediated by TrxR1 and its variants, performed the inhibition analysis of menadione on TrxR1 activity, and eventually identified the interaction between menadione and TrxR1 through MS analysis. We found that Sec-to-Cys mutation at residue of 498 significantly enhanced the efficiency of TrxR1-mediated menadione reduction, though the Sec⁴⁹⁸ is capable to catalyze the menadione reduction, indicating that TrxR1-mediated menadione reduction is dominantly in a Se-independent manner. Mutation experiments showed that Cys⁴⁹⁸ is mainly responsible for menadione catalysis in comparison to Cys⁴⁹⁷, while the N-terminal Cys⁶⁴ is slightly stronger than Cys⁵⁹ regarding the menadione reduction. LC-MS results detected that TrxR1 was arylated with one molecule of menadione, suggesting that menadione irreversibly modified the hyper-reactive Sec residue at the C-terminus of selenoprotein TrxR1. This study revealed that TrxR1 catalyzes the reduction of menadione in a Se-independent manner meanwhile its activity is irreversibly inhibited by menadione. Hereby it will be useful for the research and development of naphthoquinone anticancer drugs targeting TrxR1.
Catalysis ; Drug Development ; Oxidation-Reduction ; Thioredoxin Reductase 1/metabolism* ; Vitamin K 3/metabolism*

From the roots of Vietnamese Plumbago zeylanica L. was isolated plumbagin. Its struture was elucidated by spectral methods in comparison with literatural data. Plumbagin showed high antibacterial activity, high inhibition of vasopermeability and can be applied for therapeutic uses.
Naphthoquinones ; Biological Sciences ; Pharmaceutical Preparations

BACKGROUND: Cases of dermatitis induced by the injection of certain drugs have been reported. OBJECTIVE: The aim of this study was to assess the cause and clinicopathologic findings of injection-induced dermatitis, and to reveal whether the reaction has any relation to the patient's age, injection site, drug concentration, and time interval from the injection to the occurrence of the skin lesion. METHODS: In this study, we enrolled 10 patients who developed erythematous skin lesions after the injection of causative drugs. The lesions were compared to each other according to the injection site, time interval from the injection to the occurrence of the skin lesion, and clinical characteristics. We performed intradermal and patch tests in each patient with different concentrations of causative drugs. RESULTS: The most common causative drugs were diclofenac and vitamin K1. The eczematous type was the most frequent clinical type. The intradermal test showed more positive results than the patch test. The patch tests with diclofenac (as is, 2.5%, 5%, and 10%) and vitamin K1 (10%) were all negative in 10 patients. Furthermore, intradermal tests with diclofenac (as is) and vitamin K1 (0.1%, 1%, and 10%) were performed in 8 patients. Six patients had a positive reaction, consisting of erythema, induration, and vesiculation, after 1 and 2 days. CONCLUSION: Our results showed that the most common causative agents were diclofenac and vitamin K1. Moreover, it seems that that intradermal test is more useful than the patch test in the diagnosis of injection-induced dermatitis.
Dermatitis* ; Diagnosis ; Diclofenac ; Erythema ; Humans ; Intradermal Tests ; Patch Tests ; Skin ; Vitamin K ; Vitamin K 1

Fourteen compounds, including rubiprasin D (1), rubiprasin B (2), rubiprasin C (3), oleanolic acid (4), methyl-5-hydroxy-dinaphtho[1, 2-2'3']furan-7, 12-dione-6-carboxylate (5), rubioncolin C (6), mollugin (7), furomollugin (8), 3-amino-2-methoxycarbonyl-1, 4-naphthoquinone (9), 1-hydroxy-2-methyl-9, 10-anthraquinone (10), 2-hydroxy-6-methyl-9, 10-anthraquinone (11), 1, 4-dihydroxy-2-hydroxymethyl-9, 10-anthraquinone (12), 2-hydroxy-1-methoxy-9, 10-anthraquinone (13), and 1-hydroxy-2-methoxy-6-methyl-9, 10-anthraquinone(14), were isolated from the methanol extract of the roots and rhizomes of Rubia oncotricha using various column chromatographies. Their structures were mainly determined on basis of NMR and MS spectroscopic data analyses. Among them, 1 is a new oleanane triterpene, and compounds 2-5, 9 and 11-13 were obtained from this plant for the first time. Cytotoxic and nematicidal activities of all these compounds were evaluated, and the results showed that only 4, 6, 11 and 12 exhibited cytotoxicities against A549, SGC-7901 and HeLa cancer cell lines. The IC₅₀ of 6 were 19.42, 2.74, 8.07 μmol·L⁻¹, respectively.
Molecular Structure ; Naphthoquinones ; Plant Extracts ; Plant Roots ; Rhizome ; Rubia

BACKGROUNDS/AIMS: Vitamin K may plays a role in controlling hepatocellular carcinoma (HCC) cell growth. In this study, we intended to present 5-year experience of 72 patients receiving oral vitamin K with or without sorafenib. Its end-point was to evaluate the safety of combination therapy using sorafenib and vitamin K. METHODS: An interim analysis was performed as a single-arm cross-sectional study, including 72 HCC patients who underwent liver resection or transplantation and administered oral vitamin K2 alone (n=47) or with sorafenib (n=25). RESULTS: In all patients, administration of vitamin K2 analog 45 mg/day did not show any noticeable adverse side-effect during vitamin K therapy of 23.3+/-10.6 months, except for one patient who experienced skin rash at the third day of vitamin K therapy. In 25 patients receiving sorafenib and vitamin K for 6 months or longer, any noticeable adverse side-effect suspected of vitamin K origin was not identified yet. A small proportion of patients showed unexpectedly favorable anti-tumor effects after use of vitamin K with or without sorafenib. CONCLUSIONS: Because add-on of oral vitamin K did not increase the adverse side-effects of sorafenib, a combination therapy with these two agents appears to be worthy of further clinical trial with an expectation of synergistic therapeutic effects.
Carcinoma, Hepatocellular* ; Cross-Sectional Studies ; Exanthema ; Humans ; Liver ; Neoplasm Metastasis ; Vitamin K 2 ; Vitamin K*

Vitamin K is a lipid-soluble vitamin used in the treatment of hypoprothrombinemia found in diseases of the liver, biliary tract and small intestine. Vitamin K1 (Phytonadione) is the natural form of vitamin K. Recently, a cream containing vitamin K1 has been marketed for topical use in the treatment of periorbital hyperpigmentation, telangiectasia and rosacea. Vitamin K1 dermatitis is a cutaneous adverse reaction to vitamin K1 and can cause acute pruritic, erythematous, eczematoid, indulated plaques or slowly-appearing sclerodermatous plaques. We present a case of dermatitis caused by a vitamin K1 intralesional injection for treatment of facial telangiectasia and flushing.
Biliary Tract ; Dermatitis* ; Flushing ; Hyperpigmentation ; Hypoprothrombinemias ; Injections, Intralesional* ; Intestine, Small ; Liver ; Rosacea ; Telangiectasis ; Vitamin K ; Vitamin K 1* ; Vitamins*

BACKGROUND/OBJECTIVES: Rheumatoid arthritis (RA) is associated with an excess mortality from cardiovascular disease which is likely attributed to an atherogenic lipid profile. Among nutritional factors vitamin K has been recently focused as a pivotal nutrient in improvement of lipid related markers. Thus, this study was designed to determine the effects of vitamin K on lipid profile in this disease. SUBJECTS/METHODS: Fifty eight patients with definitive RA were participated in the present double blind placebo controlled study. They were randomly allocated into two groups to receive vitamin K1 as phylloquinone [10 mg/day] (n = 30) or placebo pills (n = 28), for eight weeks. In order to control the effects of probable confounders dietary intakes, anthropometric measurements including weight and height, clinical status using disease activity score-28 (DAS-28), physical activity and anxiety status were evaluated at baseline. Moreover, serum levels of lipid related markers including total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and triglyceride (TG) were measured at baseline and at the end of intervention. RESULTS: There were no significant differences between the two groups regarding any of the baseline characteristics. After adjusting for some relevant confounders, in comparison between two groups, we observed no significant changes in lipid related markers at the end of intervention. Also, there was no significant difference between before and after intervention values within groups (P > 0.05). CONCLUSIONS: Function of vitamin K1 in lipid profile modification remains still controversial. This study showed that vitamin K1 has no effect on lipid profile in women with rheumatoid arthritis. Further studies with a longer follow-up are required to determine the effects of vitamin K on atherogenic lipid profile.
Anxiety ; Arthritis, Rheumatoid* ; Cardiovascular Diseases ; Cholesterol ; Female ; Humans ; Lipoproteins ; Mortality ; Motor Activity ; Triglycerides ; Vitamin K ; Vitamin K 1*

BACKGROUND/OBJECTIVES: Rheumatoid arthritis (RA) is associated with an excess mortality from cardiovascular disease which is likely attributed to an atherogenic lipid profile. Among nutritional factors vitamin K has been recently focused as a pivotal nutrient in improvement of lipid related markers. Thus, this study was designed to determine the effects of vitamin K on lipid profile in this disease. SUBJECTS/METHODS: Fifty eight patients with definitive RA were participated in the present double blind placebo controlled study. They were randomly allocated into two groups to receive vitamin K1 as phylloquinone [10 mg/day] (n = 30) or placebo pills (n = 28), for eight weeks. In order to control the effects of probable confounders dietary intakes, anthropometric measurements including weight and height, clinical status using disease activity score-28 (DAS-28), physical activity and anxiety status were evaluated at baseline. Moreover, serum levels of lipid related markers including total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and triglyceride (TG) were measured at baseline and at the end of intervention. RESULTS: There were no significant differences between the two groups regarding any of the baseline characteristics. After adjusting for some relevant confounders, in comparison between two groups, we observed no significant changes in lipid related markers at the end of intervention. Also, there was no significant difference between before and after intervention values within groups (P > 0.05). CONCLUSIONS: Function of vitamin K1 in lipid profile modification remains still controversial. This study showed that vitamin K1 has no effect on lipid profile in women with rheumatoid arthritis. Further studies with a longer follow-up are required to determine the effects of vitamin K on atherogenic lipid profile.
Anxiety ; Arthritis, Rheumatoid* ; Cardiovascular Diseases ; Cholesterol ; Female ; Humans ; Lipoproteins ; Mortality ; Motor Activity ; Triglycerides ; Vitamin K ; Vitamin K 1*

The study was aimed to investigate the possible mechanism of vitamin K(2) (VK(2)) on myelodysplastic syndrome (MDS) cell line MUTZ-1 in vitro. The flow cytometry was used to analyze apoptosis rate and the change of cell cycle. The expression of apoptosis-related genes bcl-2, survivin and bax were detected by reverse transcription-polymerase chain reaction (RT-PCR). The activity of caspase-3 was detected by chemiluminescence assay. The results indicated that the apoptosis peak on FCM and positive Annexin-V FITC on cell membrane showed that VK(2) induced apoptosis of MUTZ-1 cells in a dose-and-time-dependent manner, S and G(2) cell decrement, G(0)/G(1) cell arrest, VK(2) significantly down-regulated the expression of bcl-2 and survivin, but had no effect on the expression of bax, the activity of caspase-3 was significantly increased. It is concluded that VK(2) induces apoptosis of MUTZ-1 cells through activating caspase-3 pathways and the apoptosis-related genes bcl-2 and survivin may play important roles in the process of apoptosis induction.
Antineoplastic Agents ; pharmacology ; Apoptosis ; drug effects ; Caspase 3 ; metabolism ; Cell Line, Tumor ; Humans ; Inhibitor of Apoptosis Proteins ; Microtubule-Associated Proteins ; biosynthesis ; genetics ; Myelodysplastic Syndromes ; drug therapy ; pathology ; Neoplasm Proteins ; biosynthesis ; genetics ; Proto-Oncogene Proteins c-bcl-2 ; biosynthesis ; genetics ; RNA, Messenger ; biosynthesis ; genetics ; Vitamin K 2 ; pharmacology ; bcl-2-Associated X Protein ; biosynthesis ; genetics

Action Potentials ; Animals ; Female ; Male ; Nifedipine ; pharmacology ; Rabbits ; Ureter ; drug effects ; physiology ; Urination ; drug effects ; Vitamin K 3 ; pharmacology