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1.
Diabetes Metab J ; 47(4): 500-513, 2023 07.
Article in English | MEDLINE | ID: mdl-37096379

ABSTRACT

BACKGRUOUND: Curcumin 2005-8 (Cur5-8), a derivative of curcumin, improves fatty liver disease via AMP-activated protein kinase activation and autophagy regulation. EW-7197 (vactosertib) is a small molecule inhibitor of transforming growth factor ß (TGF-ß) receptor I and may scavenge reactive oxygen species and ameliorate fibrosis through the SMAD2/3 canonical pathway. This study aimed to determine whether co-administering these two drugs having different mechanisms is beneficial. METHODS: Hepatocellular fibrosis was induced in mouse hepatocytes (alpha mouse liver 12 [AML12]) and human hepatic stellate cells (LX-2) using TGF-ß (2 ng/mL). The cells were then treated with Cur5-8 (1 µM), EW-7197 (0.5 µM), or both. In animal experiments were also conducted during which, methionine-choline deficient diet, Cur5-8 (100 mg/kg), and EW-7197 (20 mg/kg) were administered orally to 8-week-old C57BL/6J mice for 6 weeks. RESULTS: TGF-ß-induced cell morphological changes were improved by EW-7197, and lipid accumulation was restored on the administration of EW-7197 in combination with Cur5-8. In a nonalcoholic steatohepatitis (NASH)-induced mouse model, 6 weeks of EW-7197 and Cur5-8 co-administration alleviated liver fibrosis and improved the nonalcoholic fatty liver disease (NAFLD) activity score. CONCLUSION: Co-administering Cur5-8 and EW-7197 to NASH-induced mice and fibrotic hepatocytes reduced liver fibrosis and steatohepatitis while maintaining the advantages of both drugs. This is the first study to show the effect of the drug combination against NASH and NAFLD. Similar effects in other animal models will confirm its potential as a new therapeutic agent.


Subject(s)
Curcumin , Non-alcoholic Fatty Liver Disease , Mice , Humans , Animals , Non-alcoholic Fatty Liver Disease/drug therapy , Curcumin/pharmacology , Curcumin/therapeutic use , Mice, Inbred C57BL , Liver Cirrhosis/drug therapy , Liver Cirrhosis/metabolism , Fibrosis , Transforming Growth Factor beta/metabolism , Transforming Growth Factors/therapeutic use
2.
Metabolism ; 103: 154015, 2020 02.
Article in English | MEDLINE | ID: mdl-31758951

ABSTRACT

OBJECTIVE: Nonalcoholic fatty liver disease (NAFLD) occurs when excess fat storage in the liver and it is strongly linked with metabolic syndrome including obesity, insulin resistance, dyslipidemia and hypertension. Curcumin5-8 (CUR5-8) is a synthetic derivative of naturally active curcumin (CUR) that has anti-oxidative and anti-inflammatory properties. In the present study, we investigated the effects of CUR5-8, a novel CUR analog, on hepatic steatosis in mice with high-fat diet (HFD)-induced obesity. METHODS: Based on their diets for 13 weeks, the mice were categorized into the following six groups: regular diet (RD, n = 10), RD with CUR (RD + CUR, 100 mg/kg/day, n = 10), RD with CUR5-8 (RD + CUR5-8, 100 mg/kg/day, n = 10), high-fat diet-induced obese mice (HFD, n = 10), HFD with CUR (HFD + CUR, 100 mg/kg/day, n = 10), and HFD with CUR5-8 (HFD + CUR5-8, 100 mg/kg/day, n = 10) for 13 weeks. Hematoxylin and eosin (H&E) staining of the sections revealed hepatic steatosis. RESULTS: CUR5-8 administration prevented increase in body and liver weights in mice with HFD-induced obesity. Compared to the HFD group, insulin resistance was significantly improved in the HFD + CUR5-8 group. Serum alanine aminotransferase level, which is an indicator of liver damage, was also decreased after CUR5-8 administration. H&E staining revealed that CUR5-8 treatment decreased hepatic steatosis in mice with HFD-induced obesity. Interestingly, CUR5-8, and not CUR, decreased the elevated liver triglyceride level induced by the HFD. CONCLUSIONS: These findings suggest that CUR5-8 ameliorates insulin resistance and hepatic steatosis in mice with HFD-induced obesity.


Subject(s)
Curcumin , Diet, High-Fat , Non-alcoholic Fatty Liver Disease/drug therapy , Obesity/drug therapy , Animals , Autophagy/drug effects , Cells, Cultured , Curcumin/analogs & derivatives , Curcumin/pharmacology , Cytoprotection/drug effects , Lipid Metabolism/drug effects , Liver/drug effects , Liver/metabolism , Liver/pathology , Male , Mice , Mice, Inbred C57BL , Mice, Obese , Non-alcoholic Fatty Liver Disease/etiology , Non-alcoholic Fatty Liver Disease/pathology , Obesity/etiology , Weight Gain/drug effects
3.
Drug Discov Ther ; 13(4): 198-206, 2019.
Article in English | MEDLINE | ID: mdl-31534071

ABSTRACT

Curcumin, a compound found in Indian yellow curry, is known to possess various biological activities, including anti-oxidant, anti-inflammatory, and anti-cancer activities. Cur2004-8 is a synthetic curcumin derivative having symmetrical bis-alkynyl pyridines that shows a strong anti-angiogenic activity. In the present study, we examined the effect of dietary supplementation with Cur2004-8 on response to environmental stresses and aging using Caenorhabditis elegans as a model system. Dietary intervention with Cur2004-8 significantly increased resistance of C. elegans to oxidative stress. Its anti-oxidative-stress effect was greater than curcumin. However, response of C. elegans to heat stress or ultraviolet irradiation was not significantly affected by Cur2004-8. Next, we examined the effect of Cur2004-8 on aging. Cur2004-8 significantly extended both mean and maximum lifespan, accompanying a shift in time-course distribution of progeny production. Age-related decline in motility was also delayed by supplementation with Cur2004-8. In addition, Cur2004-8 prevented amyloid-beta-induced toxicity in Alzheimer's disease model animals which required a forkhead box (FOXO) transcription factor DAF-16. Dietary supplementation with Cur2004-8 also reversed the increase of mortality observed in worms treated with high-glucose-diet. These results suggest that Cur2004-8 has higher anti-oxidant and anti-aging activities than curcumin. It can be used for the development of novel anti-aging product.


Subject(s)
Aging/drug effects , Catechols/administration & dosage , Curcumin/analogs & derivatives , Longevity/drug effects , Alzheimer Disease/chemically induced , Alzheimer Disease/prevention & control , Amyloid beta-Peptides/toxicity , Animals , Caenorhabditis elegans , Catechols/chemistry , Catechols/pharmacology , Curcumin/administration & dosage , Curcumin/pharmacology , Dietary Supplements , Disease Models, Animal , Molecular Structure , Oxidative Stress/drug effects
4.
Bioorg Med Chem ; 23(20): 6673-82, 2015 Oct 15.
Article in English | MEDLINE | ID: mdl-26386817

ABSTRACT

We synthesized a library of curcumin mimics with diverse alkylsulfonyl and substituted benzenesulfonyl modifications through a simple addition reaction of important intermediate, 1-(3-Amino-phenyl)-3-(4-hydroxy-3-methoxy-phenyl)-propenone (10), with various sulfonyl chloride reactants and then tested their vasodilatation effect on depolarization (50 mM K(+))- and endothelin-1 (ET-1)-induced basilar artery contraction. Generally, curcumin mimics with aromatic sulfonyl groups showed stronger vasodilation effect than alkyl sulfonylated curcumin mimics. Among the tested compounds, six curcumin mimics (11g, 11h, 11i, 11j, 11l, and 11s) in a depolarization-induced vasoconstriction and seven compounds (11g, 11h, 11i, 11j, 11l, 11p, and 11s) in an ET-1-induced vasoconstriction showed strong vasodilation effect. Based on their biological properties, synthetic curcumin mimics can act as dual antagonist scaffold of L-type Ca(2+) channel and endothelin A/B2 receptor in vascular smooth muscle cells. In particular, compounds 11g and 11s are promising novel drug candidates to treat hypertension related to the overexpression of L-type Ca(2+) channels and ET peptides/receptors-mediated cardiovascular diseases.


Subject(s)
Calcium Channel Blockers/pharmacology , Curcumin/pharmacology , Endothelin A Receptor Antagonists/pharmacology , Endothelin B Receptor Antagonists/pharmacology , Animals , Calcium Channel Blockers/chemical synthesis , Calcium Channel Blockers/chemistry , Calcium Channels, L-Type/metabolism , Curcumin/chemical synthesis , Curcumin/chemistry , Dose-Response Relationship, Drug , Endothelin A Receptor Antagonists/chemical synthesis , Endothelin A Receptor Antagonists/chemistry , Endothelin B Receptor Antagonists/chemical synthesis , Endothelin B Receptor Antagonists/chemistry , Male , Molecular Structure , Rabbits , Receptor, Endothelin A/metabolism , Receptor, Endothelin B/metabolism , Structure-Activity Relationship
5.
Biochem Biophys Res Commun ; 445(1): 16-22, 2014 Feb 28.
Article in English | MEDLINE | ID: mdl-24491556

ABSTRACT

Mesenchymal stem cells (MSCs) are an active topic of research in regenerative medicine due to their ability to secrete a variety of growth factors and cytokines that promote healing of damaged tissues and organs. In addition, these secreted growth factors and cytokines have been shown to exert an autocrine effect by regulating MSC proliferation and differentiation. We found that expression of EGF, FGF-4 and HGF were down-regulated during serial passage of bone marrow-derived mesenchymal stem cells (BMSCs). Proliferation and differentiation potentials of BMSCs treated with these growth factors for 2 months were evaluated and compared to BMSCs treated with FGF-2, which increased proliferation of BMSCs. FGF-2 and -4 increased proliferation potentials at high levels, about 76- and 26-fold, respectively, for 2 months, while EGF and HGF increased proliferation of BMSCs by less than 2.8-fold. Interestingly, differentiation potential, especially adipogenesis, was maintained only by HGF treatment. Treatment with FGF-2 rapidly induced activation of AKT and later induced ERK activation. The basal level of phosphorylated ERK increased during serial passage of BMSCs treated with FGF-2. The expression of LC3-II, an autophagy marker, was gradually increased and the population of senescent cells was increased dramatically at passage 7 in non-treated controls. But FGF-2 and FGF-4 suppressed LC3-II expression and down-regulated senescent cells during long-term (i.e. 2month) cultures. Taken together, depletion of growth factors during serial passage could induce autophagy, senescence and down-regulation of stemness (proliferation via FGF-2/-4 and differentiation via HGF) through suppression of AKT and ERK signaling.


Subject(s)
Bone Marrow Cells/drug effects , Cell Differentiation/drug effects , Cell Proliferation/drug effects , Intercellular Signaling Peptides and Proteins/pharmacology , Mesenchymal Stem Cells/drug effects , Adult , Blotting, Western , Bone Marrow Cells/cytology , Bone Marrow Cells/metabolism , Cells, Cultured , Dose-Response Relationship, Drug , Epidermal Growth Factor/pharmacology , Extracellular Signal-Regulated MAP Kinases/metabolism , Fibroblast Growth Factor 2/pharmacology , Fibroblast Growth Factor 4/pharmacology , Hepatocyte Growth Factor/pharmacology , Humans , Mesenchymal Stem Cells/cytology , Mesenchymal Stem Cells/metabolism , Microtubule-Associated Proteins/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Young Adult
6.
BMC Gastroenterol ; 12: 4, 2012 Jan 10.
Article in English | MEDLINE | ID: mdl-22230186

ABSTRACT

BACKGROUND: Clevudine is a nucleoside analog reverse transcriptase inhibitor that exhibits potent antiviral activity against hepatitis B virus (HBV) without serious side effects. However, mitochondrial myopathy has been observed in patients with chronic HBV infection taking clevudine. Moreover, the development of diabetes was recently reported in patients receiving long-term treatment with clevudine. In this study, we investigated the effects of clevudine on mitochondrial function and insulin release in a rat clonal ß-cell line, INS-1E. METHODS: The mitochondrial DNA (mtDNA) copy number and the mRNA levels were measured by using quantitative PCR. MTT analysis, ATP/lactate measurements, and insulin assay were performed. RESULTS: Both INS-1E cells and HepG2 cells, which originated from human hepatoma, showed dose-dependent decreases in mtDNA copy number and cytochrome c oxidase-1 (Cox-1) mRNA level following culture with clevudine (10 µM-1 mM) for 4 weeks. INS-1E cells treated with clevudine had reduced total mitochondrial activities, lower cytosolic ATP contents, enhanced lactate production, and more lipid accumulation. Insulin release in response to glucose application was markedly decreased in clevudine-treated INS-1E cells, which might be a consequence of mitochondrial dysfunction. CONCLUSIONS: Our data suggest that high-dose treatment with clevudine induces mitochondrial defects associated with mtDNA depletion and impairs glucose-stimulated insulin secretion in insulin-releasing cells. These findings partly explain the development of diabetes in patients receiving clevudine who might have a high susceptibility to mitochondrial toxicity.


Subject(s)
Antiviral Agents/pharmacology , Arabinofuranosyluracil/analogs & derivatives , Glucose/pharmacology , Insulin-Secreting Cells/metabolism , Insulin/metabolism , Mitochondria/drug effects , Mitochondria/physiology , Adenosine Triphosphate/metabolism , Animals , Antiviral Agents/adverse effects , Arabinofuranosyluracil/adverse effects , Arabinofuranosyluracil/pharmacology , Cell Line , DNA Copy Number Variations/drug effects , DNA, Mitochondrial/drug effects , Dose-Response Relationship, Drug , Electron Transport Complex IV/metabolism , Hep G2 Cells , Humans , Insulin-Secreting Cells/cytology , Insulin-Secreting Cells/drug effects , Lactates/metabolism , RNA, Messenger/drug effects , RNA, Messenger/metabolism , Rats
7.
Bioorg Med Chem Lett ; 22(2): 933-6, 2012 Jan 15.
Article in English | MEDLINE | ID: mdl-22222040

ABSTRACT

A novel curcumin mimic library (14a-14h and 15a-15h) possessing variously substituted benzimidazole groups was synthesized through the aldol reaction of (E)-4-(4-hydroxy-3-methoxyphenyl)but-3-en-2-one (7) or (E)-4-(3-hydroxy-4-methoxyphenyl)but-3-en-2-one (13) with diversely substituted benzimidazolyl-2-carbaldehyde (12a-12h). The MTT assay of the cancer cells MCF-7, SH-SY5Y, HEP-G2, and H460 showed that compound 14c with IC(50) of 1.0 and 1.9µM has a strong inhibitory effect on the growth of SH-SY5Y and Hep-G2 cells, respectively, and that compound 15h with IC(50) of 1.9µM has a strong inhibitory effect on the growth of MCF-7 cancer cells.


Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Benzimidazoles/chemistry , Benzimidazoles/pharmacology , Curcumin/chemistry , Curcumin/pharmacology , Small Molecule Libraries/pharmacology , Antineoplastic Agents/chemistry , Benzimidazoles/chemical synthesis , Cell Line, Tumor , Cell Proliferation/drug effects , Curcumin/chemical synthesis , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Molecular Mimicry , Molecular Structure , Small Molecule Libraries/chemical synthesis , Small Molecule Libraries/chemistry , Structure-Activity Relationship
8.
Bioorg Med Chem Lett ; 19(5): 1481-3, 2009 Mar 01.
Article in English | MEDLINE | ID: mdl-19179077

ABSTRACT

In order to discover novel small vasodilatory molecules for potential use in the treatment of vascular disease, we tested the vasodilatation effect of two types of synthetic curcumin mimics, amide type (3) and sulfonyl amide type (4), upon the basilar artery of rabbits. In general, the sulfonyl amide type mimic (4) is more potent than the amide type (3). Curcumin (1) and compounds 12 and 20 effectively dilated the basilar artery of white rabbits.


Subject(s)
Basilar Artery/physiology , Curcumin/chemical synthesis , Molecular Mimicry , Sulfinic Acids/chemical synthesis , Vasodilation/physiology , Animals , Basilar Artery/drug effects , Curcumin/pharmacology , Dose-Response Relationship, Drug , In Vitro Techniques , Male , Molecular Mimicry/physiology , Rabbits , Sulfinic Acids/pharmacology , Vasodilation/drug effects , Vasodilator Agents/chemical synthesis , Vasodilator Agents/pharmacology
9.
Bioorg Med Chem ; 16(7): 3608-15, 2008 Apr 01.
Article in English | MEDLINE | ID: mdl-18295490

ABSTRACT

In order to discover novel multidrug resistance (MDR) reversal agents for efficient cancer chemotherapy, the unsymmetrical curcumin mimics with various amide moieties (6-19) were synthesized and evaluated their MDR reversal activities in MDR cell line KBV20C. Among the tested compounds, 13, 16, and 17 showed potent MDR reversal activities by inhibiting drug efflux function of P-glycoprotein in KB20C cells, and almost recovered the cytotoxicity of vincristine and paclitaxel against KBV20C cell to the degree of potency against drug sensitive KB cells.


Subject(s)
Curcumin/analogs & derivatives , Curcumin/pharmacology , Drug Resistance, Multiple/drug effects , Cell Line, Tumor , Cell Survival/drug effects , Cross-Linking Reagents/chemistry , Curcumin/chemical synthesis , Curcumin/chemistry , Drug Resistance, Neoplasm/drug effects , Humans , Molecular Structure , Stereoisomerism
10.
Biochem Biophys Res Commun ; 355(1): 136-42, 2007 Mar 30.
Article in English | MEDLINE | ID: mdl-17286965

ABSTRACT

Overexpression of P-glycoprotein (P-gp) is one of the major obstacles to successful cancer chemotherapy. In this study, we examined the ability of 4-chloro-N-(3-((E)-3-(4-hydroxy-3-methoxyphenyl)acryloyl)phenyl)benzamide (C-4) to reverse multidrug resistance (MDR) in P-gp expressing KBV20C cells. Treatment of KBV20C cells with C-4 led to a dramatic increase in paclitaxel- or vincristine-induced cytotoxicity without any cytotoxicity by itself. In parallel, C-4 treatment caused an increase in apoptotic cell death by paclitaxel or vincristine. Furthermore, C-4 treatment significantly increases in intracellular accumulation of fluorescent P-gp substrate rhodamine 123, indicating that C-4 treatment leads to reversal of the MDR phenotype resulting from an increased accumulation of anticancer drugs by inhibiting drug efflux function of P-gp. This notion is further supported by the observation that C-4 treatment potentiates paclitaxel-induced G(2)/M arrest of the cell cycle. In addition, the drug efflux function of P-gp was reversibly inhibited by C-4 treatment, while the expression level of P-gp was not affected. Collectively, our results describe the potential of C-4 to reverse the P-gp-mediated MDR phenotype through reversible inhibition of P-gp function, which may make it an attractive new agent for the chemosensitization of cancer cells.


Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/adverse effects , Antineoplastic Agents/toxicity , Benzamides/toxicity , Drug Resistance, Multiple/drug effects , Guaiacol/analogs & derivatives , ATP Binding Cassette Transporter, Subfamily B, Member 1/drug effects , Animals , Cell Line , Cell Line, Tumor , Cell Survival/drug effects , Flow Cytometry , Guaiacol/toxicity
11.
Bioorg Med Chem Lett ; 15(16): 3782-6, 2005 Aug 15.
Article in English | MEDLINE | ID: mdl-15993583

ABSTRACT

Novel curcumin mimics with asymmetrical units phenyl group with alkyl amide, chloro-substituted benzamide, or heteroaromatic amide moieties were synthesized and their anti-angiogenic activity was evaluated with the proliferation and tube formation inhibitory activity on the human umbilical vein endothelial cells. Compounds 5, 14, 17, and 18 showed potent growth inhibitory activity and tube formation inhibitory activity.


Subject(s)
Angiogenesis Inhibitors/chemical synthesis , Angiogenesis Inhibitors/pharmacology , Curcumin/chemical synthesis , Curcumin/pharmacology , Molecular Mimicry , Angiogenesis Inhibitors/chemistry , Cell Proliferation/drug effects , Curcumin/analogs & derivatives , Endothelial Cells/drug effects , Humans , Molecular Structure , Structure-Activity Relationship
12.
Bioorg Med Chem Lett ; 14(15): 3893-6, 2004 Aug 02.
Article in English | MEDLINE | ID: mdl-15225692

ABSTRACT

Fourteen symmetrical bis-alkynyl pyridine and thiophene derivatives were synthesized and their antiangiogenic activity was evaluated with the proliferation and tube formation inhibitory activity on the human umbilical vein endothelial cells (HUVEC). Compounds 6, 8, and 10, rigid mimetic structure of curcumin, showed the potent growth inhibitory activity and the potent tube formation inhibitory activity.


Subject(s)
Angiogenesis Inhibitors/chemical synthesis , Endothelium, Vascular/drug effects , Pyridines/chemical synthesis , Thiophenes/chemical synthesis , Angiogenesis Inhibitors/chemistry , Angiogenesis Inhibitors/pharmacology , Cell Division/drug effects , Curcumin/pharmacology , Endothelium, Vascular/cytology , Humans , Models, Molecular , Molecular Conformation , Molecular Structure , Pyridines/chemistry , Pyridines/pharmacology , Thiophenes/chemistry , Thiophenes/pharmacology , Umbilical Veins
13.
Bioorg Med Chem ; 12(14): 3783-90, 2004 Jul 15.
Article in English | MEDLINE | ID: mdl-15210144

ABSTRACT

Various thioacetal artemisinin derivatives can inhibit the angiogenesis and might be angiogenesis inhibitors. In particular, 10 alpha-phenylthiodihydroartemisinins (5), 10 beta-benzenesulfonyl-9-epi-dihydroartemisinin (11) and 10 alpha-mercaptodihydroartemisinin (13) exhibit strong growth inhibition activity against HUVEC proliferation. Compound 11 have a good inhibitiory activity upon HUVEC tube formation, and 5 and 11 show a strong inhibitory effect on angiogenesis using CAM assay at 5 microg/egg by 90%.


Subject(s)
Acetals/chemistry , Angiogenesis Inhibitors/chemical synthesis , Angiogenesis Inhibitors/pharmacology , Artemisinins/chemical synthesis , Artemisinins/pharmacology , Sesquiterpenes/chemical synthesis , Sesquiterpenes/pharmacology , Angiogenesis Inhibitors/chemistry , Animals , Artemisinins/chemistry , Cell Division/drug effects , Cell Line , Chick Embryo , Endothelium, Vascular/cytology , Endothelium, Vascular/drug effects , Gas Chromatography-Mass Spectrometry , Humans , Magnetic Resonance Spectroscopy , Sesquiterpenes/chemistry , Spectrophotometry, Infrared
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