The Tumor Suppressor Par-4 Regulates Adipogenesis by Transcriptional Repression of PPARγ.

Prostate apoptosis response-4 (Par-4, also known as PAWR) is a ubiquitously expressed tumor suppressor protein that induces apoptosis selectively in cancer cells, while leaving normal cells unaffected. Our previous studies indicated that genetic loss of Par-4 promoted hepatic steatosis, adiposity, and insulin-resistance in chow-fed mice. Moreover, low plasma levels of Par-4 are associated with obesity in human subjects.

Elongation of very long chain fatty acids-3 () is activated by ZHX2 and is a regulator of cell cycle progression.

Zinc fingers and homeoboxes 2 () 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 (), a member of the ELOVL family of enzymes that synthesize very long chain fatty acids (VLCFAs), is a putative 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.

Isorhynchophylline alleviates cartilage degeneration in osteoarthritis by activating autophagy of chondrocytes.

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.

Zinc fingers and homeoboxes 2 is required for diethylnitrosamine-induced liver tumor formation in C57BL/6 mice.

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.

Liver size and lipid content differences between BALB/c and BALB/cJ mice on a high-fat diet are due, in part, to Zhx2.

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).

Autophagic flux modulation by Wnt/β-catenin pathway inhibition in hepatocellular carcinoma.

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/β-catenin pathway that exhibits anti-proliferative and anti-angiogenic effects on different types of cancer cells.

Zhx2 (zinc fingers and homeoboxes 2) regulates major urinary protein gene expression in the mouse liver.

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.

Zinc Fingers and Homeoboxes 2 (Zhx2) Regulates Sexually Dimorphic Cyp Gene Expression in the Adult Mouse Liver.

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.

Discovery of novel hybrids of diaryl-1,2,4-triazoles and caffeic acid as dual inhibitors of cyclooxygenase-2 and 5-lipoxygenase for cancer therapy.

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.

Design, synthesis, biological evaluation and docking study of 4-isochromanone hybrids bearing N-benzyl pyridinium moiety as dual binding site acetylcholinesterase inhibitors.

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.

N-Aryl benzenesulfonamide inhibitors of [3H]-thymidine incorporation and β-catenin signaling in human hepatocyte-derived Huh-7 carcinoma cells.

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/β-catenin signaling pathway that is frequently upregulated in hepatocellular carcinoma (HCC). FH535 was reported as an inhibitor of both β-catenin in the Wnt signaling pathway and the peroxisome proliferator-activated receptor (PPAR). A β-catenin/T-cell factor (TCF)/Lymphoid-enhancer factor (LEF)-dependent assay (i.

Design, synthesis and antitumor activity of triterpenoid pyrazine derivatives from 23-hydroxybetulinic acid.

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.

Synthesis and Biological Evaluation of Oxygen-containing Heterocyclic Ring-fused 23-Hydroxybetulinic Acid Derivatives as Antitumor Agents.

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.

Synthesis, in vitro and in vivo antitumor activity of pyrazole-fused 23-hydroxybetulinic acid derivatives.

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.

Synthesis and biological evaluation of ambradiolic acid as an inhibitor of glycogen phosphorylase.

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.

Synthesis and antitumor activity of novel 3-oxo-23-hydroxybetulinic acid derivatives.

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.

First total synthesis of antihypertensive natural products S-(+)-XJP and R-(-)-XJP.

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.

Targeting the Wnt/β-catenin signaling pathway in liver cancer stem cells and hepatocellular carcinoma cell lines with FH535.

Activation of the Wnt/β-catenin pathway has been observed in at least 1/3 of hepatocellular carcinomas (HCC), and a significant number of these have mutations in the β-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 β-catenin pathway, could inhibit β-catenin activation of target genes and inhibit proliferation of Liver Cancer Stem Cells (LCSC) and HCC cell lines.

Discovery of potential anti-inflammatory drugs: diaryl-1,2,4-triazoles bearing N-hydroxyurea moiety as dual inhibitors of cyclooxygenase-2 and 5-lipoxygenase.

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.

Design, synthesis, and biological evaluation of 1,2,4-triazole bearing 5-substituted biphenyl-2-sulfonamide derivatives as potential antihypertensive candidates.

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.

Apolipoprotein E mediates attachment of clinical hepatitis C virus to hepatocytes by binding to cell surface heparan sulfate proteoglycan receptors.

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).

Enmein-type diterpenoid analogs from natural kaurene-type oridonin: Synthesis and their antitumor biological evaluation.

A series of enmein-type diterpenoid analogs (11-20) derived from natural kaurene-type diterpenoid oridonin were synthesized and biologically evaluated. All target compounds showed improved anti-proliferative activities against four human cancer cell lines compared with natural oridonin and parent compound 10. Some compounds were more potent than positive control Taxol.

Syndecan-1 serves as the major receptor for attachment of hepatitis C virus to the surfaces of hepatocytes.

Our recent studies demonstrated that apolipoprotein E mediates cell attachment of hepatitis C virus (HCV) through interactions with the cell surface heparan sulfate (HS). HS is known to covalently attach to core proteins to form heparan sulfate proteoglycans (HSPGs) on the cell surface. The HSPG core proteins include the membrane-spanning syndecans (SDCs), the lycosylphosphatidylinositol-linked glypicans (GPCs), the basement membrane proteoglycan perlecan (HSPG2), and agrin.

Novel hybrids of natural isochroman-4-one bearing N-substituted isopropanolamine as potential antihypertensive candidates.

A series of novel hybrids of natural isochroman-4-one bearing isopropanolamine moiety were designed, synthesized and evaluated for their antihypertensive activity. It was found that compound IIId, prepared by hybridizing N-isopropyl substituted isopropanolamine functionality to a phenolic oxygen of isochroman-4-one, exhibited potent β(1)-adrenoceptor blocking effect comparable to the well-known antihypertensive drug propranolol. Additionally, IIId significantly reduced the systolic and diastolic blood pressure in SHRs by over 40%, which was obviously stronger than the lead compounds 7,8-dihydroxy-3-methyl-isochroman-4-one (XJP) and its analogue XJP-B.

Library construction and biological evaluation of enmein-type diterpenoid analogues as potential anticancer agents.

A library of promising enmein-type 14-O-diterpenoid derivatives was constructed from a commercially available kaurene-type oridonin by practical and efficient synthetic methods. These synthetic derivatives were evaluated for their antiproliferative activities against a set of four human cancer cell lines. The IC50 values are similar to or improved over those of the parent molecule and paclitaxel, the latter of which was used as a positive control.