7,4'-dimethoxy-3-hydroxyflavone, a protease-activated receptor 4 (PAR4) inhibitor with antioxidant activity, ameliorates diabetic endothelial dysfunction.

Background And Purpose: Hyperglycaemia-induced protease-activated receptor 4 (PAR4) has been suggested to be linked with vascular complications in patients with diabetes mellitus. In the present study, we investigated if 7,4'-dimethoxy-3-hydroxyflavone (DMF-OH), a flavonoid-derived PAR4 antagonist, can ameliorate hyperglycaemia-associated endothelial dysfunction, which is a key early event in the pathogenesis of diabetic vasculopathy.

Experimental Approach: The effects of hyperglycaemia on PAR4 expression and endothelial dysfunction were examined in a streptozotocin-induced diabetic mouse model and in a high glucose-treated human endothelial cell model.

Discovery and biological evaluation of potent 2-trifluoromethyl acrylamide warhead-containing inhibitors of protein disulfide isomerase.

Protein disulfide isomerase (PDI) regulates multiple protein functions by catalyzing the oxidation, reduction, and isomerization of disulfide bonds. The enzyme is considered a potential target for treating thrombosis. We previously developed a potent PDI inhibitor, CPD, which contains the propiolamide as a warhead targeting cysteine residue in PDI.

Discovery of 5-Hydroxy-1,4-naphthoquinone (Juglone) Derivatives as Dual Effective Agents Targeting Platelet-Cancer Interplay through Protein Disulfide Isomerase Inhibition.

In this study, a series of 2- and/or 3-substituted juglone derivatives were designed and synthesized. Among them, , , , , and showed stronger inhibition activity against cell surface PDI or recombinant PDI and higher inhibitory effects on U46619- and/or collagen-induced platelet aggregation than juglone. The glycosylated derivatives and showed improved selectivity for inhibiting the proliferation of multiple myeloma RPMI 8226 cells, and the IC values reached 61 and 48 nM, respectively, in a 72 h cell viability test.

Discovery of 7, 4'-dimethoxy-3-hydroxyflavone as a protease-activated receptor 4 antagonist with antithrombotic activity and less bleeding tendency in mice.

There is growing evidence of the importance of protease-activated receptor 4 (PAR4), one of thrombin receptors, as a therapeutic target in thrombotic cardiovascular diseases. In the present study, we utilized ligand-based virtual screening, bioassay, and structure-activity relationship study to discover PAR4 antagonists with new chemical scaffolds from natural origin, and examined their application as antiplatelet agents. By using these approaches, we have identified a flavonoid, 7, 4'-dimethoxy-3-hydroxyflavone, that exhibits anti-PAR4 activity.

Golden berry 4β-hydroxywithanolide E prevents tumor necrosis factor α-induced procoagulant activity with enhanced cytotoxicity against human lung cancer cells.

Inflammation in the tumor microenvironment is positively correlated with cancer progression and metastasis as well as the risk of thromboembolism in lung cancer patients. Here we show, in human non-small cell lung cancer (NSCLC) cell lines, the master inflammatory cytokine tumor necrosis factor (TNF-α) induced tissue factor expression and procoagulant activity, and these effects were potently inhibited by 4β-hydroxywithanolide E (4HW), a natural compound isolated from Physalis peruviana. Furthermore, combination of 4HW and TNF-α caused synergistic cytotoxicity against NSCLC cells by inducing caspase-dependent apoptosis.

12-Deoxyphorbol Esters Induce Growth Arrest and Apoptosis in Human Lung Cancer A549 Cells Via Activation of PKC-δ/PKD/ERK Signaling Pathway.

Prostratin, a non-tumor promoting 12-deoxyphorbol ester, has been reported as a protein kinase C (PKC) activator and is shown to have anti-proliferative activity in certain cancer cell types. Here we show that GRC-2, a prostratin analogue isolated from , is ten-fold more potent than prostratin for inhibiting the growth of human non-small cell lung cancer (NSCLC) A549 cells. Flow cytometry assay revealed that GRC-2 and prostratin inhibited cell cycle progression at the G2/M phase and induced apoptosis.

Selective Inhibition of PAR4 (Protease-Activated Receptor 4)-Mediated Platelet Activation by a Synthetic Nonanticoagulant Heparin Analog.

Objective- PAR4 (protease-activated receptor 4), one of the thrombin receptors in human platelets, has emerged as a promising target for the treatment of arterial thrombotic disease. Previous studies implied that thrombin exosite II, known as a binding site for heparin, may be involved in thrombin-induced PAR4 activation. In the present study, a heparin octasaccharide analog containing the thrombin exosite II-binding domain of heparin was chemically synthesized and investigated for anti-PAR4 effect.

Different effects of 4β-hydroxywithanolide E and withaferin A, two withanolides from Solanaceae plants, on the Akt signaling pathway in human breast cancer cells.

Background: Triple-negative breast cancer (TNBC) represents a clinical challenge because it lacks sensitivity to hormone therapy or other available molecule-targeted agents. In addition, TNBC frequently exhibits over-activation of the PI3K/Akt survival pathway that can contribute to chemotherapy resistance. 4β-Hydroxywithanolide E (4-HW) and withaferin A (WA) are two withanolides from Solanaceae plants that exhibit promising anticancer activity in vitro and in vivo.

The chemopreventive isothiocyanate sulforaphane reduces anoikis resistance and anchorage-independent growth in non-small cell human lung cancer cells.

The capacity of cancer cells to resist detachment-induced apoptosis, i.e. anoikis, as well as anchorage-independent growth are crucial prerequisites for tumor metastasis.

Isolation of Phorbol Esters from Euphorbia grandicornis and Evaluation of Protein Kinase C- and Human Platelet-Activating Effects of Euphorbiaceae Diterpenes.

Human platelets contain conventional (α and β) and novel isoforms of PKC (δ and θ), and PKC activation can result in platelet aggregation and secretion reaction that are important for thrombus formation. Several tumor-promoting Euphorbiaceae diterpenes are known to act as direct activators of PKC, but many types of such diterpenes have not been studied as platelet stimulators. In the present study, two new and five known phorbol esters were isolated from Euphorbia grandicornis.

Effects of indirect actions and oxygen on relative biological effectiveness: estimate of DSB induction and conversion induced by gamma rays and helium ions.

Clustered DNA damage other than double-strand breaks (DSBs) can be detrimental to cells and can lead to mutagenesis or cell death. In addition to DSBs induced by ionizing radiation, misrepair of non-DSB clustered damage contributes extra DSBs converted from DNA misrepair via pathways for base excision repair and nucleotide excision repair. This study aimed to quantify the relative biological effectiveness (RBE) when DSB induction and conversion from non-DSB clustered damage misrepair were used as biological endpoints.

The effect of catalase on migration and invasion of lung cancer cells by regulating the activities of cathepsin S, L, and K.

Abundant clinical evidences indicate that up-regulation of several cathepsins in many human cancers is correlated with malignant progression and poor patient prognosis. In addition, a decrease in catalase activity or accumulation of hydrogen peroxide correlates with cancer metastasis. Recent studies indicate that cathepsin activation and expression can be modulated via H2O2 treatment.

Effects of novel human cathepsin S inhibitors on cell migration in human cancer cells.

Elevated cathepsin S (Cat S) level is correlated with higher migration ability in tumor cells. This study investigates the inhibitory effect of novel synthetic α-ketoamide compounds on cathepsin activity and cancer cell migration. The effect of several α-ketoamide compounds on the activity of recombinant cathepsins (Cat S, Cat L and Cat K) was examined.

Identification and biochemical characterization of a unique Mn2+-dependent UMP kinase from Helicobacter pylori.

Uridine monophosphate (UMP) kinase converts UMP to the corresponding UDP in the presence of metal ions and ATP and is allosterically regulated by nucleotides such as UTP and GTP. Although the UMP kinase reported to date is Mg(2+)-dependent, we found in this study that the UMP kinase of Helicobacter pylori had a preference for Mn(2+) over Mg(2+), which may be related to a conformational difference between the Mn(2+)-bound and Mg(2+)-bound UMP kinase. Similar to previous findings, the UMP kinase activity of H.