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1.
Am J Physiol Gastrointest Liver Physiol ; 325(6): G582-G592, 2023 12 01.
Article in English | MEDLINE | ID: mdl-37847682

ABSTRACT

Zinc fingers and homeoboxes 2 (Zhx2) are transcriptional regulators of liver gene expression with key functions in embryonic development as well as tissue regeneration in response to damage and disease, presumably through its control of target genes. Previous microarray data suggested that elongation of very long chain fatty acids-3 (Elovl3), a member of the ELOVL family of enzymes that synthesize very long chain fatty acids (VLCFAs), is a putative Zhx2 target gene. VLCFAs are core component of ceramides and other bioactive sphingolipids that are often dysregulated in diseases and regulate key cellular processes including proliferation. Since several previously identified Zhx2 targets become dysregulated in liver damage, we investigated the relationship between Zhx2 and Elovl3 in liver development, damage, and regeneration. Here, using mouse and cell models, we demonstrate that Zhx2 positively regulates Elovl3 expression in the liver and that male-biased hepatic Elovl3 expression is established between 4 and 8 wk of age in mice. Elovl3 is dramatically repressed in mouse models of liver regeneration, and the reduced Elovl3 levels in the regenerating liver are associated with changes in hepatic VLCFAs. Human hepatoma cell lines with forced Elovl3 expression have lower rates of cell growth; analysis of synchronized cells indicates that this reduced proliferation correlates with cells stalling in S-phase and lower mRNA levels of cell cyclins. Taken together, these data indicate that Elovl3 expression helps regulate cellular proliferation during liver development and regeneration, possibly through control of VLCFAs.NEW & NOTEWORTHY Numerous targets of the transcription factor Zhx2 are dysregulated in liver disease. We show that the elongase Elovl3 is a novel Zhx2 target. Elovl3 and Zhx2 expression change during liver regeneration, which is associated with changes in very long chain fatty acids. Forced Elovl3 expression reduces cell growth and blocks cell cycle progression. This suggests that Elovl3 may account, at least in part, for the relationship between Zhx2 and proliferation during liver development and disease.


Subject(s)
Carcinoma, Hepatocellular , Liver Neoplasms , Male , Mice , Humans , Animals , Carcinoma, Hepatocellular/metabolism , Liver Neoplasms/metabolism , Fatty Acids , Cell Cycle , Homeodomain Proteins/genetics , Homeodomain Proteins/metabolism , Transcription Factors/genetics
2.
J Orthop Surg Res ; 18(1): 154, 2023 Mar 02.
Article in English | MEDLINE | ID: mdl-36864518

ABSTRACT

CONTEXT: Osteoarthritis is a common degenerative disease, the cause of it is still unknown, and the treatment mainly focuses on improving symptoms. Studies have found that Isorhynchophylline (Isorhy) has antioxidant, anti-inflammatory, antiproliferative and neuroprotective effects. OBJECTIVE: This study investigates the role and mechanism of Isorhy in OA. METHODS: The destabilized medial meniscus model was used to mimic OA. Fifteen male Sprague Dawley rats were partitioned into three portions: Normal group, OA group (surgery; normal saline treatment) and OA + Isorhy group (surgery; 50 µM Isorhy treatment) were performed on the first day of every week from the 5th to the 8th week after surgery. After 4 weeks of drug treatment, the rats have been processed without debridement of the knee specimens and fixed using 4% paraformaldehyde for two days. The morphological analysis was performed by H&E, Safranin O-Fast green staining and micro-CT analysis. The specimens were researched employing Micro-CT. In the part of the aggregate methods that were evaluated by qRT-PCR and western blot of the following proteins LC3II/LC3I, Beclin-1, ATG5, ATG7, MMP3 andMMP13. Akt/PI3K signaling related proteins (p-AKT, AKT, p-PI3K, PI3K, p-mTOR, mTOR) were detected by Western blot. BECLIN1 and MMP3 were detected by Immunofluorescence assay. RESULTS: In this present research, it was proved that autophagy-related and cartilage matrix-related proteins in osteoarthritis could be regulated by Isorhynchophylline treatment. The transcriptome sequencing results suggested the regulation was closely associated with PI3K/AKT/mTOR pathway, thereby alleviating osteoarticular inflammation. In-depth study showed that Isorhy could also affect OA in rat OA models, that was indicated by H&E, Safranin O-Fast green staining, and also micro-CT analysis. CONCLUSION: Our findings indicated that Isorhy could be regarded as a prospective candidate for OA treatment.


Subject(s)
Chondrocytes , Osteoarthritis , Male , Animals , Rats , Rats, Sprague-Dawley , Matrix Metalloproteinase 3 , Phosphatidylinositol 3-Kinases , Proto-Oncogene Proteins c-akt , Osteoarthritis/drug therapy , Autophagy , Beclin-1 , Matrilin Proteins , Menisci, Tibial
3.
Hepatol Commun ; 6(12): 3550-3562, 2022 12.
Article in English | MEDLINE | ID: mdl-36194180

ABSTRACT

Liver cancer, comprised primarily of hepatocellular carcinoma (HCC), is the third leading cause of cancer deaths worldwide and increasing in Western countries. We previously identified the transcription factor zinc fingers and homeoboxes 2 (Zhx2) as a regulator of hepatic gene expression, and many Zhx2 target genes are dysregulated in HCC. Here, we investigate HCC in Zhx2-deficient mice using the diethylnitrosamine (DEN)-induced liver tumor model. Our study using whole-body Zhx2 knockout (Zhx2KO ) mice revealed the complete absence of liver tumors 9 and 10 months after DEN exposure. Analysis soon after DEN treatment showed no differences in expression of the DEN bioactivating enzyme cytochrome P450 2E1 (CYP2E1) and DNA polymerase delta 2, or in the numbers of phosphorylated histone variant H2AX foci between Zhx2KO and wild-type (Zhx2wt ) mice. The absence of Zhx2, therefore, did not alter DEN bioactivation or DNA damage. Zhx2KO livers showed fewer positive foci for Ki67 staining and reduced interleukin-6 and AKT serine/threonine kinase 2 expression compared with Zhx2wt livers, suggesting that Zhx2 loss reduces liver cell proliferation and may account for reduced tumor formation. Tumors were reduced but not absent in DEN-treated liver-specific Zhx2 knockout mice, suggesting that Zhx2 acts in both hepatocytes and nonparenchymal cells to inhibit tumor formation. Analysis of data from the Cancer Genome Atlas and Clinical Proteomic Tumor Consortium indicated that ZHX2 messenger RNA and protein levels were significantly higher in patients with HCC and associated with clinical pathological parameters. Conclusion: In contrast to previous studies in human hepatoma cell lines and other HCC mouse models showing that Zhx2 acts as a tumor suppressor, our data indicate that Zhx2 acts as an oncogene in the DEN-induced HCC model and is consistent with the higher ZHX2 expression in patients with HCC.


Subject(s)
Carcinoma, Hepatocellular , Liver Neoplasms , Animals , Humans , Mice , Carcinoma, Hepatocellular/chemically induced , Diethylnitrosamine/adverse effects , Genes, Homeobox , Homeodomain Proteins/genetics , Liver Neoplasms/chemically induced , Mice, Inbred C57BL , Mice, Knockout , Proteomics , Transcription Factors/genetics , Zinc Fingers
4.
Mamm Genome ; 30(7-8): 226-236, 2019 08.
Article in English | MEDLINE | ID: mdl-31321500

ABSTRACT

BALB/cJ mice exhibit considerable phenotypic differences with other BALB/c substrains. Some of these traits involve the liver, including persistent postnatal expression of genes that are normally expressed only in the fetal liver and reduced expression of major urinary proteins. These traits are due to a mutation that dramatically reduces expression of the gene encoding the transcription factor Zinc fingers and homeoboxes 2 (Zhx2). BALB/cJ mice also exhibit reduced serum lipid levels and resistance to atherosclerosis compared to other mouse strains when placed on a high-fat diet. This trait is also due, at least in part, to the Zhx2 mutation. Microarray analysis identified many genes affecting lipid homeostasis, including Lipoprotein lipase, that are dysregulated in BALB/cJ liver. This led us to investigate whether hepatic lipid levels would be different between BALB/cJ and BALB/c mice when placed on a normal chow or a high-fat chow diet. On the high-fat chow, BALB/cJ mice had increased weight gain, increased liver:body weight ratio, elevated hepatic lipid accumulation and markers of liver damage when compared to BALB/c mice. These traits in BALB/cJ mice were only partially reversed by a hepatocyte-specific Zhx2 transgene. These data indicate that Zhx2 reduces liver lipid levels and is hepatoprotective in mice on a high-fat diet, but the partial rescue by the Zhx2 transgene suggests a contribution by both parenchymal and non-parenchymal cells. A model to account for the cardiovascular and liver phenotype in mice with reduced Zhx2 levels is provided.


Subject(s)
Diet, High-Fat/adverse effects , Homeodomain Proteins/genetics , Lipid Metabolism/genetics , Liver/pathology , Alanine Transaminase/blood , Animals , Female , Hepatocytes/metabolism , Hepatocytes/pathology , Lipids/blood , Liver/metabolism , Mice , Mice, Inbred BALB C , Mice, Transgenic , Mutation , Weight Gain/genetics
5.
PLoS One ; 14(2): e0212538, 2019.
Article in English | MEDLINE | ID: mdl-30794613

ABSTRACT

Autophagy targets cellular components for lysosomal-dependent degradation in which the products of degradation may be recycled for protein synthesis and utilized for energy production. Autophagy also plays a critical role in cell homeostasis and the regulation of many physiological and pathological processes and prompts this investigation of new agents to effect abnormal autophagy in hepatocellular carcinoma (HCC). 2,5-Dichloro-N-(2-methyl-4-nitrophenyl) benzenesulfonamide (FH535) is a synthetic inhibitor of the Wnt/ß-catenin pathway that exhibits anti-proliferative and anti-angiogenic effects on different types of cancer cells. The combination of FH535 with sorafenib promotes a synergistic inhibition of HCC and liver cancer stem cell proliferation, mediated in part by the simultaneous disruption of mitochondrial respiration and glycolysis. We demonstrated that FH535 decreased HCC tumor progression in a mouse xenograft model. For the first time, we showed the inhibitory effect of an FH535 derivative, FH535-N, alone and in combination with sorafenib on HCC cell proliferation. Our study revealed the contributing effect of Wnt/ß-catenin pathway inhibition by FH535 and its derivative (FH535-N) through disruption of the autophagic flux in HCC cells.


Subject(s)
Autophagy/drug effects , Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/pathology , Liver Neoplasms/drug therapy , Liver Neoplasms/pathology , Sulfonamides/administration & dosage , Animals , Antineoplastic Agents/administration & dosage , Carcinoma, Hepatocellular/metabolism , Cell Line, Tumor , Cell Proliferation/drug effects , Female , Gene Knockdown Techniques , Humans , Liver Neoplasms/metabolism , Liver Neoplasms, Experimental/drug therapy , Liver Neoplasms, Experimental/metabolism , Liver Neoplasms, Experimental/pathology , Mice , Mice, Nude , Sorafenib/administration & dosage , Wnt Signaling Pathway/drug effects , Xenograft Model Antitumor Assays , beta Catenin/antagonists & inhibitors , beta Catenin/genetics , beta Catenin/metabolism
6.
J Biol Chem ; 292(16): 6765-6774, 2017 04 21.
Article in English | MEDLINE | ID: mdl-28258223

ABSTRACT

The mouse major urinary proteins (Mups) are encoded by a large family of highly related genes clustered on chromosome 4. Mups, synthesized primarily and abundantly in the liver and secreted through the kidneys, exhibit male-biased expression. Mups bind a variety of volatile ligands; these ligands, and Mup proteins themselves, influence numerous behavioral traits. Although urinary Mup protein levels vary between inbred mouse strains, this difference is most pronounced in BALB/cJ mice, which have dramatically low urinary Mup levels; this BALB/cJ trait had been mapped to a locus on chromosome 15. We previously identified Zhx2 (zinc fingers and homeoboxes 2) as a regulator of numerous liver-enriched genes. Zhx2 is located on chromosome 15, and a natural hypomorphic mutation in the BALB/cJ Zhx2 allele dramatically reduces Zhx2 expression. Based on these data, we hypothesized that reduced Zhx2 levels are responsible for lower Mup expression in BALB/cJ mice. Using both transgenic and knock-out mice along with in vitro assays, our data show that Zhx2 binds Mup promoters and is required for high levels of Mup expression in the adult liver. In contrast to previously identified Zhx2 targets that appear to be repressed by Zhx2, Mup genes are positively regulated by Zhx2. These data identify Zhx2 as a novel regulator of Mup expression and indicate that Zhx2 activates as well as represses expression of target genes.


Subject(s)
Homeodomain Proteins/physiology , Liver/metabolism , Proteins/physiology , Transcription Factors/physiology , Alleles , Animals , Cell Line , Chromatin/metabolism , HEK293 Cells , Hep G2 Cells , Humans , Kidney/metabolism , Ligands , Male , Mice , Mice, Inbred BALB C , Mice, Knockout , Promoter Regions, Genetic , Protein Binding
7.
Gene Expr ; 17(1): 7-17, 2016.
Article in English | MEDLINE | ID: mdl-27197076

ABSTRACT

The mammalian cytochrome P450 (Cyp) gene family encodes a large number of structurally related enzymes that catalyze a variety of metabolic and detoxification reactions. The liver is the primary site of Cyp expression in terms of expression levels and number of expressed genes, consistent with this organ's essential role in metabolism of endogenous and xenobiotic compounds. Many Cyp genes exhibit sexually dimorphic expression. For example, Cyp2a4 is expressed significantly higher in the adult liver of female mice compared to male mice. An exception to this pattern is seen in BALB/cJ mice, where male hepatic Cyp2a4 mRNA levels are substantially elevated compared to male mice of other strains. The Zinc fingers and homeoboxes 2 (Zhx2) protein governs the silencing of several genes in the postnatal liver, including α-fetoprotein, H19, and glypican 3. Zhx2 also regulates numerous hepatic genes that govern lipid homeostasis. We previously showed that the Zhx2 gene is mutated in BALB/cJ mice, which led us to consider whether elevated male hepatic Cyp2a4 levels in this strain are due to this Zhx2 mutation. Using mice with a conditional Zhx2 deletion, we show here that the absence of Zhx2 in hepatocytes results in increased Cyp2a4 expression in adult male liver. We extend this finding to show that additional Cyp genes are disregulated in the absence of Zhx2. We also show that mRNA levels of Cyp2a4 and several other female-biased Cyp genes are increased, and male-biased Cyp4a12 is decreased in mouse liver tumors. These data indicate that Zhx2 is a novel regulator of sex-biased Cyp gene expression in the normal and diseased liver.


Subject(s)
Cytochrome P-450 Enzyme System/genetics , Gene Expression/genetics , Homeodomain Proteins/metabolism , Liver/metabolism , Animals , Female , Glypicans/metabolism , Hepatocytes/metabolism , Homeostasis/physiology , Lipids/physiology , Liver Neoplasms/genetics , Liver Neoplasms/metabolism , Male , Mice , Mice, Inbred C3H , Mice, Inbred C57BL , RNA, Messenger/genetics , Sex Characteristics , alpha-Fetoproteins/metabolism
8.
Eur J Med Chem ; 108: 89-103, 2016 Jan 27.
Article in English | MEDLINE | ID: mdl-26638042

ABSTRACT

Inflammation plays a key role in cancer initiation and propagation. Cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX), two important enzymes in inflammatory responses are up-regulated in various tumor types. Dual inhibition of COX-2 and 5-LOX constitutes a rational concept for the design of more efficacious anti-tumor agents with an improved safety profile. We have previously reported a series of diaryl-1,2,4-triazole derivatives as selective COX-2 inhibitors. Herein, we hybridized the diaryl-1,2,4-triazoles with caffeic acid (CA) which was reported to display 5-LOX inhibitory and anti-tumor activities, affording a novel class of COX-2/5-LOX dual inhibitors as anti-tumor drug candidates. Most of these compounds exhibited potent COX-2/5-LOX inhibitory and antiproliferative activities in vitro. And the most potent compound 22b could significantly inhibit tumor growth in vivo. Furthermore, mechanistic investigation showed that the representative compound 15c blocked cell cycle in G2 phase and induced apoptosis in human non-small cell lung cancer A549 cells in a dose-dependent manner. Our preliminary investigation results would provide new clues for the cancer theatment with COX-2/5-LOX dual inhibitors.


Subject(s)
Antineoplastic Agents/pharmacology , Caffeic Acids/pharmacology , Cyclooxygenase 2 Inhibitors/pharmacology , Drug Discovery , Lipoxygenase Inhibitors/pharmacology , Lung Neoplasms/drug therapy , Triazoles/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Apoptosis/drug effects , Arachidonate 5-Lipoxygenase/metabolism , Caffeic Acids/chemical synthesis , Caffeic Acids/chemistry , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/metabolism , Carcinoma, Non-Small-Cell Lung/pathology , Cell Line, Tumor , Cell Proliferation/drug effects , Cyclooxygenase 2/metabolism , Cyclooxygenase 2 Inhibitors/chemical synthesis , Cyclooxygenase 2 Inhibitors/chemistry , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Lipoxygenase Inhibitors/chemical synthesis , Lipoxygenase Inhibitors/chemistry , Lung Neoplasms/metabolism , Lung Neoplasms/pathology , Molecular Structure , Structure-Activity Relationship , Triazoles/chemical synthesis , Triazoles/chemistry
9.
Bioorg Med Chem Lett ; 25(22): 5212-6, 2015 Nov 15.
Article in English | MEDLINE | ID: mdl-26454504

ABSTRACT

A series of novel 4-isochromanone hybrids bearing N-benzyl pyridinium moiety as dual binding site acetylcholinesterase inhibitors have been designed and synthesized. The screening results showed that most of the compounds exhibited potent anti-AChE activity in the range of nM concentrations. The 1-(4-fluorobenzyl) substituted derivative 9d exhibited the most potent anti-AChE activity with IC50 value of 8.9 nM and high AChE/BuChE selectivity (SI>230). Kinetic and molecular modeling studies suggested that compound 9d was mixed-type inhibitor, binding simultaneously to CAS and PAS of AChE. Besides, the preliminary structure-activity relationships were discussed.


Subject(s)
Benzopyrans/pharmacology , Cholinesterase Inhibitors/pharmacology , Pyridinium Compounds/pharmacology , Acetylcholinesterase/chemistry , Benzopyrans/chemical synthesis , Benzopyrans/chemistry , Binding Sites , Butyrylcholinesterase/chemistry , Cholinesterase Inhibitors/chemical synthesis , Cholinesterase Inhibitors/chemistry , Molecular Docking Simulation , Pyridinium Compounds/chemical synthesis , Pyridinium Compounds/chemistry , Structure-Activity Relationship
10.
Bioorg Med Chem Lett ; 25(18): 3897-9, 2015 Sep 15.
Article in English | MEDLINE | ID: mdl-26243371

ABSTRACT

Structure-activity relationships (SAR) in 2,5-dichloro-N-(2-methyl-4-nitrophenyl)benzenesulfonamide (FH535) were examined as part of a program to identify agents that inhibit the Wnt/ß-catenin signaling pathway that is frequently upregulated in hepatocellular carcinoma (HCC). FH535 was reported as an inhibitor of both ß-catenin in the Wnt signaling pathway and the peroxisome proliferator-activated receptor (PPAR). A ß-catenin/T-cell factor (TCF)/Lymphoid-enhancer factor (LEF)-dependent assay (i.e., luciferase-based TOPFlash assay) as well as a [(3)H]-thymidine incorporation assay were used to explore SAR modifications of FH535. Although replacing the 2,5-dichlorophenylsulfonyl substituent in FH535 with a 2,6-dihalogenation pattern generally produced more biologically active analogs than FH535, other SAR modifications led only to FH535 analogs with comparable or slightly improved activity in these two assays. The absence of a clear SAR pattern in activity suggested a multiplicity of target effectors for N-aryl benzenesulfonamides.


Subject(s)
Hepatocytes/drug effects , Hepatocytes/pathology , Sulfonamides/pharmacology , Thymidine/metabolism , Wnt Signaling Pathway/drug effects , beta Catenin/metabolism , Cell Line, Tumor , Dose-Response Relationship, Drug , Hepatocytes/metabolism , Humans , Molecular Structure , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/chemistry , Benzenesulfonamides
11.
Eur J Med Chem ; 97: 235-44, 2015 Jun 05.
Article in English | MEDLINE | ID: mdl-25984840

ABSTRACT

Pyrazine-fused 23-hydroxybetulinic acid was synthesized by introducing a pyrazine ring between C-2 and C-3 position and further modifications were carried out by substitution of C-28 carboxyl group by ester and amide linkage to enhance the antitumor activity. The biological screening results showed that all of the derivatives exhibited more significant antiproliferative activity than the parent compound. In particular compound 12a exhibited the most potent activity with IC50 values of 3.53 µM, 4.42 µM and 5.13 µM against cell lines SF-763, B16 and Hela, respectively. In the preliminary mechanism study, 12a caused cell arrest in G1 phase and significantly induced apoptosis of B16 cells in a dose-dependent manner. Furthermore, the in vivo antitumor activity of 12a was validated (tumor inhibitory ratio of 55.6% and 62.7%, respectively) in mice with H22 liver cancer and B16 melanoma.


Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Drug Design , Liver Neoplasms/drug therapy , Melanoma, Experimental/drug therapy , Morpholines/chemical synthesis , Morpholines/pharmacology , Pyrazines/chemistry , Triterpenes/chemistry , Animals , Apoptosis/drug effects , Cell Proliferation/drug effects , Drug Screening Assays, Antitumor , G1 Phase/drug effects , HeLa Cells , Humans , Liver Neoplasms/pathology , Melanoma, Experimental/pathology , Mice , Molecular Structure , Pyrazines/chemical synthesis , Pyrazines/pharmacology , Structure-Activity Relationship
12.
Chem Biol Drug Des ; 86(4): 424-31, 2015 Oct.
Article in English | MEDLINE | ID: mdl-25688519

ABSTRACT

A collection of isoxazole and oxadiazole substituted 23-hydroxybetulinic acid (HBA) derivatives were designed, synthesized and evaluated for their antitumor activity. Most of the newly synthesized compounds exhibited more potent antiproliferative activity than patent compound 23-hydroxybetulinic acid, especially 13e and 14a were about four- to sevenfold more potent against all tested cancer cell lines than 23-hydroxybetulinic acid. Furthermore, the in vivo antitumor activity of 13e and 14a was validated in H22 liver cancer and B16 melanoma xenograft mouse models. The structure-activity relationships of these 23-hydroxybetulinic acid derivatives were also discussed based on the present investigation.


Subject(s)
Antineoplastic Agents , Neoplasms/diet therapy , Triterpenes , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Drug Screening Assays, Antitumor , HL-60 Cells , HeLa Cells , Humans , Mice , Triterpenes/chemistry , Triterpenes/pharmacology
13.
Fitoterapia ; 100: 50-5, 2015 Jan.
Article in English | MEDLINE | ID: mdl-25447165

ABSTRACT

Ambradiolic acid (3) with oleanane skeleton is a natural pentacyclictriterpene. The first synthesis of 3 starting from 23-hydroxybetulinic acid (2) has been accomplished in 12-steps with a total yield of 18.1% in our study. Compound 3 was further biologically evaluated and found to exhibit significant inhibitory activity against rabbit muscle glycogen phosphorylase (GP) with an IC50 value of 12.4 µM, suggesting it could be a potential lead compound for the development of hypoglycemic drugs.


Subject(s)
Enzyme Inhibitors/pharmacology , Glycogen Phosphorylase/antagonists & inhibitors , Oleanolic Acid/analogs & derivatives , Pentacyclic Triterpenes/pharmacology , Animals , Enzyme Inhibitors/chemical synthesis , Molecular Structure , Muscle, Skeletal/enzymology , Oleanolic Acid/chemical synthesis , Oleanolic Acid/chemistry , Oleanolic Acid/pharmacology , Pentacyclic Triterpenes/chemical synthesis , Rabbits , Structure-Activity Relationship , Triterpenes/chemistry
14.
Bioorg Med Chem Lett ; 25(3): 728-32, 2015 Feb 01.
Article in English | MEDLINE | ID: mdl-25529742

ABSTRACT

A collection of pyrazole-fused 23-hydroxybetulinic acid derivatives were designed, synthesized and evaluated for their antitumor activity. Most of the newly synthesized compounds exhibited significant antiproliferative activity. Especially compound 15e displayed the most potent activity with the IC50 values of 5.58 and 6.13µM against B16 and SF763 cancer cell lines, respectively. Furthermore, the significant in vivo antitumor activity of 15e was validated in H22 liver cancer and B16 melanoma xenograft mouse models. The structure-activity relationships of these 23-hydroxybetulinic acid derivatives were also discussed based on the present investigation.


Subject(s)
Antineoplastic Agents/chemical synthesis , Pyrazoles/chemistry , Triterpenes/chemistry , Animals , Antineoplastic Agents/therapeutic use , Antineoplastic Agents/toxicity , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Disease Models, Animal , Drug Screening Assays, Antitumor , Humans , Liver Neoplasms/drug therapy , Melanoma, Experimental/drug therapy , Mice , Structure-Activity Relationship , Transplantation, Heterologous , Triterpenes/therapeutic use , Triterpenes/toxicity
15.
Eur J Med Chem ; 87: 159-67, 2014 Nov 24.
Article in English | MEDLINE | ID: mdl-25247772

ABSTRACT

A series of novel derivatives of 3-oxo-23-hydroxybetulinic acid was designed, synthesized, and evaluated for their antiproliferative activity against a panel of cancer cell lines (HL-60, BEL-7402, SF-763, HeLa, B16 and A375). The results indicated that majority of the derivatives exhibited more significant antitumor activity than the parent compound. In particular compound 10e showed the most potent activity with IC50 values of 5.85, 6.23 and 7.22 µM against B16, SF-763 and BEL-7402 cells, respectively. Furthermore, 10e inhibited tumor growth by 51.8% and 62.7% (w/w) in H22 and B16 xenograft mouse models, comparable to cyclophosphamide and 5-fluorouracil, respectively.


Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Carcinoma, Hepatocellular/drug therapy , Liver Neoplasms/drug therapy , Melanoma, Experimental/drug therapy , Neoplasms/drug therapy , Triterpenes/chemistry , Animals , Carcinoma, Hepatocellular/pathology , Cell Proliferation/drug effects , Humans , Liver Neoplasms/pathology , Melanoma, Experimental/pathology , Mice , Molecular Structure , Neoplasms/pathology , Structure-Activity Relationship , Tumor Cells, Cultured , Xenograft Model Antitumor Assays
16.
Org Biomol Chem ; 12(37): 7338-44, 2014 Oct 07.
Article in English | MEDLINE | ID: mdl-25116266

ABSTRACT

The first asymmetric total synthesis of antihypertensive natural products S-(+)-XJP and R-(-)-XJP has been achieved in 8 steps starting from commercially available 6-bromo-2-hydroxy-3-methoxybenzaldehyde. Key steps included intramolecular Heck reaction and oxidative ozonolysis reaction with the retention of stereochemistry. A latent functionality strategy was implemented to circumvent the racemization in this endeavor. The protocol described here provided a fast and easily accessible synthetic method to obtain optically pure isochroman-4-one derivatives. Furthermore, the in vivo antihypertensive effects of (±)-XJP, S-(+)-XJP and R-(-)-XJP were investigated on spontaneously hypertensive rats. The obtained results could provide valuable information to identify a promising lead for further chemical modification research.


Subject(s)
Benzopyrans/chemical synthesis , Biological Products/chemical synthesis , Benzopyrans/chemistry , Biological Products/chemistry , Molecular Structure , Stereoisomerism
17.
PLoS One ; 9(6): e99272, 2014.
Article in English | MEDLINE | ID: mdl-24940873

ABSTRACT

Activation of the Wnt/ß-catenin pathway has been observed in at least 1/3 of hepatocellular carcinomas (HCC), and a significant number of these have mutations in the ß-catenin gene. Therefore, effective inhibition of this pathway could provide a novel method to treat HCC. The purposed of this study was to determine whether FH535, which was previously shown to block the ß-catenin pathway, could inhibit ß-catenin activation of target genes and inhibit proliferation of Liver Cancer Stem Cells (LCSC) and HCC cell lines. Using ß-catenin responsive reporter genes, our data indicates that FH535 can inhibit target gene activation by endogenous and exogenously expressed ß-catenin, including the constitutively active form of ß-catenin that contains a Serine37Alanine mutation. Our data also indicate that proliferation of LCSC and HCC lines is inhibited by FH535 in a dose-dependent manner, and that this correlates with a decrease in the percentage of cells in S phase. Finally, we also show that expression of two well-characterized targets of ß-catenin, Cyclin D1 and Survivin, is reduced by FH535. Taken together, this data indicates that FH535 has potential therapeutic value in treatment of liver cancer. Importantly, these results suggest that this therapy may be effective at several levels by targeting both HCC and LCSC.


Subject(s)
Antineoplastic Agents/pharmacology , Carcinoma, Hepatocellular/pathology , Liver Neoplasms/pathology , Neoplastic Stem Cells/drug effects , Sulfonamides/pharmacology , Wnt Signaling Pathway/drug effects , Carcinoma, Hepatocellular/drug therapy , Cell Cycle Checkpoints/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Cyclin D1/genetics , Cyclin D1/metabolism , Drug Screening Assays, Antitumor , Humans , Inhibitor of Apoptosis Proteins/genetics , Inhibitor of Apoptosis Proteins/metabolism , Liver Neoplasms/drug therapy , Molecular Targeted Therapy , Survivin , Transcriptional Activation/drug effects
18.
Org Biomol Chem ; 12(13): 2114-27, 2014 Apr 07.
Article in English | MEDLINE | ID: mdl-24562695

ABSTRACT

A series of hybrids from diaryl-1,2,4-triazole and hydroxamic acid or N-hydroxyurea were synthesized and evaluated as novel anti-inflammatory agents. The biological data showed that (i) all the compounds showed dual COX-2/5-LOX inhibitory activities in vitro, and 15e showed optimal inhibitory activities (COX-2: IC50 = 0.15 µM, 5-LOX: IC50 = 0.85 µM), (ii) 15e selectively inhibited COX-2 relative to COX-1 with selectivity index (SI = 0.012) comparable to celecoxib (SI = 0.015), (iii) 15e exhibited potent anti-inflammatory activity (inhibition: 54.1%) which was comparable to the reference drug celecoxib (inhibition: 46.7%) in a xylene-induced ear edema assay, and (iv) 15e displayed promising analgesic activity in acetic acid-induced writhing response and hot-plate assay. Finally, a molecular modeling study revealed the binding interactions of 15e with COX-2 and 5-LOX. Our findings suggest that 15e may be a promising anti-inflammatory agent for further evaluation.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Cyclooxygenase 2 Inhibitors/pharmacology , Drug Discovery , Hydroxyurea/pharmacology , Lipoxygenase Inhibitors/pharmacology , Triazoles/pharmacology , Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Arachidonate 5-Lipoxygenase/metabolism , Cyclooxygenase 2/metabolism , Cyclooxygenase 2 Inhibitors/chemical synthesis , Cyclooxygenase 2 Inhibitors/chemistry , Dose-Response Relationship, Drug , Hydroxyurea/chemistry , Lipoxygenase Inhibitors/chemical synthesis , Lipoxygenase Inhibitors/chemistry , Structure-Activity Relationship , Triazoles/chemical synthesis , Triazoles/chemistry
19.
Bioorg Med Chem ; 21(24): 7742-51, 2013 Dec 15.
Article in English | MEDLINE | ID: mdl-24200932

ABSTRACT

A series of novel 1,2,4-triazole bearing 5-substituted biphenyl-2-sulfonamide derivatives were designed and synthesized to develop new angiotensin II subtype 2 (AT2) receptor agonists as novel antihypertensive candidates. It was found that 14f (IC50=0.4 nM) and 15e (IC50=5.0 nM) displayed potent AT2 receptor affinity and selectivity in binding assays. Biological evaluation in vivo suggested that 14f is obviously superior to that of reference drug losartan in RHRs, and meanwhile, 14f has no significant impact on heart rate. The interesting activities of these compounds may make them promising candidates as antihypertensive agents.


Subject(s)
Antihypertensive Agents/pharmacology , Drug Design , Receptor, Angiotensin, Type 2/agonists , Sulfonamides/chemistry , Triazoles/pharmacology , Animals , Antihypertensive Agents/chemical synthesis , Antihypertensive Agents/chemistry , Dose-Response Relationship, Drug , Female , Heart Rate/drug effects , Liver/drug effects , Liver/metabolism , Male , Molecular Structure , Myometrium/drug effects , Myometrium/metabolism , Rats , Rats, Inbred SHR , Receptor, Angiotensin, Type 2/metabolism , Structure-Activity Relationship , Swine , Triazoles/chemical synthesis , Triazoles/chemistry
20.
PLoS One ; 8(7): e67982, 2013.
Article in English | MEDLINE | ID: mdl-23844141

ABSTRACT

Our previous studies demonstrated that the cell culture-grown hepatitis C virus of genotype 2a (HCVcc) uses apolipoprotein E (apoE) to mediate its attachment to the surface of human hepatoma Huh-7.5 cells. ApoE mediates HCV attachment by binding to the cell surface heparan sulfate (HS) which is covalently attached to the core proteins of proteoglycans (HSPGs). In the present study, we further determined the physiological importance of apoE and HSPGs in the HCV attachment using a clinical HCV of genotype 1b (HCV1b) obtained from hepatitis C patients and human embryonic stem cell-differentiated hepatocyte-like cells (DHHs). DHHs were found to resemble primary human hepatocytes. Similar to HCVcc, HCV1b was found to attach to the surface of DHHs by the apoE-mediated binding to the cell surface HSPGs. The apoE-specific monoclonal antibody, purified HSPGs, and heparin were all able to efficiently block HCV1b attachment to DHHs. Similarly, the removal of heparan sulfate from cell surface by treatment with heparinase suppressed HCV1b attachment to DHHs. More significantly, HCV1b attachment was potently inhibited by a synthetic peptide derived from the apoE receptor-binding region as well as by an HSPG-binding peptide. Likewise, the HSPG-binding peptide prevented apoE from binding to heparin in a dose-dependent manner, as determined by an in vitro heparin pull-down assay. Collectively, these findings demonstrate that HSPGs serve as major HCV attachment receptors on the surface of human hepatocytes to which the apoE protein ligand on the HCV envelope binds.


Subject(s)
Apolipoproteins E/metabolism , Hepacivirus/metabolism , Heparan Sulfate Proteoglycans/metabolism , Hepatocytes/metabolism , Receptors, Cell Surface/metabolism , Antibodies, Monoclonal/immunology , Antibodies, Monoclonal/pharmacology , Apolipoproteins E/immunology , Blotting, Western , Cell Line , Cell Line, Tumor , Dose-Response Relationship, Drug , Genotype , HEK293 Cells , Hepacivirus/genetics , Hepacivirus/physiology , Heparan Sulfate Proteoglycans/pharmacology , Heparin/pharmacology , Heparin Lyase/metabolism , Heparin Lyase/pharmacology , Hepatitis C/virology , Hepatocytes/virology , Host-Pathogen Interactions , Humans , Low Density Lipoprotein Receptor-Related Protein-1/metabolism , Peptides/metabolism , Peptides/pharmacology , Protein Binding/drug effects , Virus Attachment/drug effects
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