Ultra-high-performance liquid chromatography-Q exactive orbitrap tandem mass spectrometry(UHPLC-QEOrbitrap-MS/MS) was used to explore the inhibitory effect and mechanism of ginkgo flavone aglycone(GA) combined with doxorubicin(DOX) on H22 cells. The effects of different concentrations of GA and DOX on the viability of H22 cells were investigated, and combination index(CI) was used to evaluate the effects. In the experiments, control(CON) group, DOX group, GA group, and combined GA and DOX(GDOX) group were constructed. Then the metabolomics strategy was employed to explore the metabolic markers that were significantly changed after combination therapy on the basis of single medication treatment, and by analyzing their biological significance, the effect and mechanism of the anti-tumor effect of GA combined with DOX were explained. The results revealed that when 30 μg·mL~(-1) GA and 0.5 μmol·L~(-1) DOX was determined as the co-administration concentration, the CI value was 0.808, indicating that the combination of GA and DOX had a synergistic anti-tumor effect. Metabolomics analysis identified 23 metabolic markers, including L-arginine, L-tyrosine and L-valine, mostly amino acids. Compared with the CON group, 22 and 17 metabolic markers were significantly down-regulated after DOX treatment and GA treatment, respectively. Compared with the DOX and GA groups, the treatment of GA combined with DOX further down-regulated the levels of these metabolic markers in liver cancer, which might contribute to the synergistic effect of the two. Five key metabolic pathways were found in pathway enrichment analysis, including glutathione metabolism, phenylalanine metabolism, arginine and proline metabolism, β-alanine metabolism, and valine, leucine and isoleucine degradation. These findings demonstrated that the combination of GA and DOX remarkably inhibited the viability of H22 cells and exerted a synergistic anti-tumor effect. The mechanism might be related to the influence of the energy supply of tumor cells by interfering with the metabolism of various amino acids.
Arginine/therapeutic use* ; Doxorubicin/therapeutic use* ; Flavones/therapeutic use* ; Ginkgo biloba/chemistry* ; Glutathione ; Humans ; Isoleucine/therapeutic use* ; Leucine/therapeutic use* ; Liver Neoplasms/drug therapy* ; Metabolomics/methods* ; Phenylalanine/therapeutic use* ; Proline ; Tandem Mass Spectrometry/methods* ; Tyrosine/therapeutic use* ; Valine/therapeutic use* ; beta-Alanine/therapeutic use*

This study aims to investigate the efficacy of forsythiaside A(FTA) against CCl_4-induced liver fibrosis and the mechanism. Specifically, activities of serum alanine/aspartate aminotransferase(ALT/AST) and hydroxyproline(HYP) level in liver were detected, and pathological morphology of liver was observed based on hematoxylin-eosin(HE) staining, Masson's trichrome staining, and Sirius red staining of liver. On this basis, the effect of FTA on liver fibrosis was evaluated. The mRNA expression of actin alpha 2/α-smooth muscle actin(Acta2/α-SMA), transforming growth factor β(Tgfβ), collagen Ⅰ alpha 1(Col1 a1), and collagen Ⅲ alpha 1(Col3 a1) in liver tissue and hepatic stellate cells(HSC) was determined by qPCR, and the protein expression of α-SMA in liver tissue and HSC was measured by Western blot to assess the inhibition of FTA on HSC activation. The protein expression of α-SMA, vi-mentin(Vim), vascular endothelial cadherin(Ve-cadherin), and platelet endothelial cell adhesion molecule-1(PECAM-1/CD31) was measured by Western blot to evaluate the reverse of endothelial-mesenchymal transition(EMT) by FTA. The efficacy of FTA in relieving CCl_4-induced liver fibrosis was evidenced by the alleviation of hepatocyte necrosis, liver inflammation, and hepatic collagen deposition. FTA decreased the mRNA expression of Acta2, Tgfβ, Col1 a1, and Col3 a1 and protein expression of α-SMA both in vivo and in vitro. FTA reversed the increase of α-SMA and Vim and the decrease of CD31 and Ve-cadherin in livers from mice treated with CCl_4. Therefore, FTA alleviated CCl_4-induced liver fibrosis in mice via suppressing HSC activation and reversing EMT.
Animals ; Mice ; Actins/metabolism* ; Alanine Transaminase/blood* ; Carbon Tetrachloride/metabolism* ; Collagen/metabolism* ; Hepatic Stellate Cells ; Liver/drug effects* ; Liver Cirrhosis/genetics* ; RNA, Messenger/metabolism* ; Transforming Growth Factor beta/metabolism* ; Glycosides/therapeutic use*

Humans ; Male ; Minerals ; Miners ; Niacinamide ; Pantothenic Acid ; Recommended Dietary Allowances ; Testosterone ; United States Food and Drug Administration ; Vitamin B 12 ; Vitamin B 6 ; Vitamins ; Zinc

pantothenic acid, sodium, animal iron, zinc, selenium, and cholesterol (negative trends), and carbohydrate rate, fiber, water-soluble fiber, vitamin K, vitamin C, and plant calcium (positive trends). Multivariate analysis revealed that animal fat, animal iron, and niacin (negative trends) and animal protein, fiber, and vitamin C (positive trends) were statistically significant. Pantothenic acid and sodium showed non-significant negative trends (P < 0.1), and vitamin B₁₂ showed a non-significant positive trend.CONCLUSION: This study provided a nutritional basis and extended the utility of ACFS, which is a bridgehead for future cancer-preventive clinical trials using ACFS.]]>
Animals ; Ascorbic Acid ; Asian Continental Ancestry Group ; Calcium ; Cholesterol ; Diet ; Humans ; Iron ; Multivariate Analysis ; Niacin ; Pantothenic Acid ; Plants ; Riboflavin ; Selenium ; Sodium ; Vegetarians ; Vitamin D ; Vitamin K ; Vitamins ; Zinc

BACKGROUND: Iron overload is a risk factor affecting all patients with thalassemia intermedia (TI). We aimed to determine whether there is a relationship of serum ferritin (SF) and alanine aminotransferase (ALT) with liver iron concentration (LIC) determined by R2 magnetic resonance imaging (R2-MRI), to estimate the most relevant degree of iron overload and best time to chelate in patients with TI. METHODS: In this cross-sectional study, 119 patients with TI (mean age years) were randomly selected and compared with 120 patients who had a diagnosis of thalassemia major (TM). Correlations of LIC, as determined by R2-MRI, with SF and ALT levels, were assessed in all participants. A P-value < 0.05 was considered statistically significant. RESULTS: SF and LIC levels were lower in patients with TI than in those with TM; only ferritin values were significant. We found a statistically significant relationship between SF and LIC, with cut-off estimates of SF in patients with TI who had splenectomy and those who entered puberty spontaneously (916 and 940 ng/mL, respectively) with LIC >5 mg Fe/g dry weight (P < 0.0001). A significant relationship was also found for patients with TI who had elevated ALT level (63.5 U/L), of 3.15 times the upper normal laboratory limit, using a cut-off for LIC ≥5 mg Fe/g dry weight. CONCLUSION: We determined the cut-off values for ALT and SF indicating the best time to start iron chelation therapy in patients with TI, and found significant correlations among iron overload, SF, and ALT.
Adolescent ; Alanine Transaminase ; beta-Thalassemia* ; Chelation Therapy ; Cross-Sectional Studies ; Diagnosis ; Ferritins* ; Humans ; Iron Overload ; Iron* ; Liver* ; Magnetic Resonance Imaging ; Puberty ; Risk Factors ; Splenectomy ; Thalassemia*

This study examined the characteristics of the foodservice menu items offered at senior welfare centers to provide information on Korean senior menu development. A total of 514 lunch menu items were collected from 27 senior welfare centers in April, July, October and January. The most frequently served staple foods, soups, and side dishes were multi-grain rice, seaweed soup, Bulgogi, Kimchi, and liquid yogurt. The proportions of carbohydrate, protein, and lipids of total energy serving of senior welfare centers were 59.8%: 16.7%: and 22.8%, respectively. The nutrients served at less than 40% of the Recommended Nutrient Intake (RNI) and Adequate Intake (AI) of Dietary Reference Intakes for Koreans (KDRIs) were chloride (1.0%), vitamin D (1.3%), biotin (1.7%), magnessium (4.5%), Iodine (7.5%), pantothenic acid (8.0%), vitamin E (12.5%), vitamin B6 (20.0~21.4%), vitamin K (21.1~24.3%), and water (35.7~39.7%). The nutrients served in excess of the daily intake goal and RNI were iron (98.9~127.1%), sodium (104.9%), and copper (1,100.0%).
Aged* ; Biotin ; Copper ; Humans ; Iodine ; Iron ; Lunch ; Pantothenic Acid ; Recommended Dietary Allowances ; Seaweed ; Sodium ; Vitamin B 6 ; Vitamin D ; Vitamin E ; Vitamin K ; Vitamins ; Water ; Yogurt

BACKGROUND: Twenty-nail dystrophy (TND) is an acquired idiopathic disease characterized by dull, thin, lusterless, and fragile nails with fissuring, small regular pits, and excessive longitudinal ridging. Although various treatment modalities have been performed in order to treat TND, the effects of these treatments are controversial. OBJECTIVE: To evaluate the effectiveness of oral cyclosporine in TND. METHODS: A total of 38 patients with TND were treated with combination therapy using oral cyclosporine with a pantothenic acid complex-based dietary supplement (Pantogar®; Merz Pharmaceuticals GmbH, Germany), whereas 44 patients were treated with the pantothenic acid complex-based dietary supplement alone. The therapeutic efficacy in each group was retrospectively evaluated using medical records and clinical photographs. RESULTS: The cyclosporine therapy group had significantly more patients whose improvement was rated as almost clear, marked, or moderate compared to the control group (p<0.001). While the mean CHATS (Color, Hyperkeratosis, Area, Thickness, Separation) score of the cyclosporine therapy group was decreased by 13.45 (from 30.95 to 17.5) after treatment, the mean CHATS score of the control group was only decreased by 8 (from 29.43 to 21.43, p<0.001). Moreover, greater Dermatology Life Quality Index changes after treatment were observed in the cyclosporine therapy group (p=0.085). CONCLUSION: Oral cyclosporine can be a valuable therapeutic option in patients with TND.
Cyclosporine* ; Dermatology ; Dietary Supplements* ; Humans ; Medical Records ; Pantothenic Acid ; Quality of Life ; Retrospective Studies

BACKGROUND/AIMS: The development of therapeutic strategies for the treatment of cirrhosis has become an important focus for basic and clinical researchers. Adrenergic receptor antagonists have been evaluated as antifibrotic drugs in rodent models of carbon tetrachloride (CCl4)-induced cirrhosis. The aim of the present study was to evaluate the effects of carvedilol and doxazosin on fibrosis/cirrhosis in a hamster animal model. METHODS: Cirrhotic-induced hamsters were treated by daily administration of carvedilol and doxazosin for 6 weeks. Hepatic function and histological evaluation were conducted by measuring biochemical markers, including total bilirubin, aspartate aminotransferase, alanine aminotransferase and albumin, and liver tissue slices. Additionally, transforming growth factor beta (TGF-beta) immunohistochemistry was analyzed. RESULTS: Biochemical markers revealed that hepatic function was restored after treatment with doxazosin and carvedilol. Histological evaluation showed a decrease in collagen type I deposits and TGF-beta-secreting cells. CONCLUSIONS: Taken together, these results suggest that the decrease in collagen type I following treatment with doxazosin or carvedilol is achieved by decreasing the profibrotic activities of TGF-beta via the blockage of alpha1- and beta-adrenergic receptor. Consequently, a diminution of fibrotic tissue in the CCl4-induced model of cirrhosis is achieved.
Adrenergic alpha-1 Receptor Antagonists/*pharmacology ; Alanine Transaminase/blood ; Animals ; Aspartate Aminotransferases/blood ; Bilirubin/blood ; Carbazoles/*pharmacology ; Carbon Tetrachloride ; Collagen Type I/drug effects/metabolism ; Cricetinae ; Doxazosin/*pharmacology ; Liver/metabolism/pathology ; Liver Cirrhosis/blood/chemically induced/*drug therapy ; Liver Function Tests ; Propanolamines/*pharmacology ; Serum Albumin/analysis ; Transforming Growth Factor beta/blood/*drug effects

As an important material in pharmaceutical and chemical industry, &beta;-alanine was mainly produced by chemical methods. L-aspartate-α-decarboxylase could catalyze the α-decarboxylation from L-aspartate to &beta;-alanine. Determinations for specific activities of PanDs from Escherichia coli, Corynebacterium glutamicum and Bacillus subtilis were performed in this study (0.98 U/mg, 7.52 U/mg and 8.4 U/mg respectively). The optimal temperature and pH of PanDs from C. glutamicum and B. subtilis were 65 degrees C, pH 6.5 and 60 degrees C, pH 6.5 respectively. According to our research, PanD from B. subtilis could be more appropriate for industrial application because of the higher activity and thermostability when compared to PanDs from E. coli and C. glutamicum which had been the most studied. We also analyzed and discussed the special post-translation self-cleavage phenomenon and the mechanism based inactivation.
Bacillus subtilis ; enzymology ; Bacterial Proteins ; genetics ; metabolism ; Corynebacterium glutamicum ; enzymology ; Escherichia coli ; enzymology ; Glutamate Decarboxylase ; genetics ; metabolism ; Industrial Microbiology ; Temperature ; beta-Alanine

BACKGROUND AND OBJECTIVES: The prevalence of atrial fibrillation (AF) doubles in the extreme elderly and is higher than in the rest of the population. Warfarin therapy to prevent thromboembolic events secondary to AF is often underutilized and under-prescribed in this subgroup, due to the fear of bleeding and other complications. Newer oral anticoagulants such as rivaroxaban and dabigatran offer alternative therapeutic options for the extreme elderly. We review the clinical trial data of these newer agents in the extreme elderly population. SUBJECTS AND METHODS: The primary literature was identified through PubMed, using the following search terms: anticoagulation, rivaroxaban, dabigatran, warfarin, elderly, AF, bleeding, stroke, and aging. Additional references were identified through the review of references from the articles obtained. We included clinical studies evaluating anticoagulation therapies in AF. Selection emphasis was placed on those evaluating anticoagulation in the elderly population. RESULTS: Dabigatran and rivaroxaban have predictable, dose-proportional pharmacokinetic and pharmacodynamic properties, which make them favorable options for the elderly. Fewer monitoring parameters and drug interactions allow for the greater ease of use. A landmark trial shows that the rate of intracranial hemorrhage with dabigatran is lower in this population compared to warfarin. However, the data is based on a small number of subjects enrolled in the clinical trials. As such, the real-world use of these agents may not replicate the published rates of bleeding and thrombosis in the study populations. CONCLUSION: More research is needed in this area, specifically in this population, before newer agents such as rivaroxaban and dabigatran are widely recommended for use in the extreme elderly patients.
Aged ; Aging ; Anticoagulants ; Atrial Fibrillation ; Benzimidazoles ; beta-Alanine ; Drug Interactions ; Hemorrhage ; Humans ; Intracranial Hemorrhages ; Morpholines ; Prevalence ; Stroke ; Thiophenes ; Thrombosis ; Warfarin ; Dabigatran ; Rivaroxaban