Wenwei Qiu

Maslinic acid potentiates the anti-tumor activity of tumor necrosis factor α by inhibiting NF-κB signaling pathway

BackgroundTumor necrosis factor alpha (TNFα) has been used to treat certain tumors in clinic trials. However, the curative effect of TNFα has been undermined by the induced-NF-κB activation in many types of tumor. Maslinic acid (MA), a pharmacological safe natural product, has been known for its important effects as anti-oxidant, anti-inflammatory, and anti-viral activities. The aim of this study was to determine whether MA potentiates the anti-tumor activity of TNFα though the regulation of NF-κB activation.ResultsIn this study, we demonstrate that MA significantly enhanced TNFα-induced inhibition of pancreatic cancer cell proliferation, invasion, and potentiated TNFα-induced cell apoptosis by suppressing TNFα-induced NF-κB activation in a dose- and time-dependent manner. Addition of MA inhibited TNFα-induced IκBα degradation, p65 phosphorylation, and nuclear translocation. Furthermore, MA decreased the expression levels of NF-κB-regulated genes, including genes involved in tumor cell proliferation (Cyclin D1, COX-2 and c-Myc), apoptosis (Survivin, Bcl-2, Bcl-xl, XIAP, IAP-1), invasion (MMP-9 and ICAM-1), and angiogenesis (VEGF). In athymic nu/nu mouse model, we further demonstrated that MA significantly suppressed pancreatic tumor growth, induced tumor apoptosis, and inhibited NF-κB-regulated anti-apoptotic gene expression, such as Survivin and Bcl-xl.ConclusionsOur data demonstrate that MA can potentiate the anti-tumor activities of TNFα and inhibit pancreatic tumor growth and invasion by activating caspase-dependent apoptotic pathway and by suppressing NF-κB activation and its downstream gene expression. Therefore, MA together with TNFα could be new promising agents in the treatment of pancreatic cancer.

Maslinic Acid Suppresses Osteoclastogenesis and Prevents Ovariectomy-Induced Bone Loss by Regulating RANKL-Mediated NF-κB and MAPK Signaling Pathways

Activation of NF‐κB and MAPK/activator protein 1 (AP‐1) signaling pathways by receptor activator NF‐κB ligand (RANKL) is essential for osteoclast activity. Targeting NF‐κB and MAPK/AP‐1 signaling to modulate osteoclast activity has been a promising strategy for osteoclast‐related diseases. In this study we examined the effects of maslinic acid (MA), a pentacyclic triterpene acid that is widely present in dietary plants, on RANKL‐induced osteoclastogenesis, osteoclast function, and signaling pathways by in vitro and in vivo assay systems. In mouse bone marrow monocytes (BMMs) and RAW264.7 cells, MA inhibited RANKL‐induced osteoclastogenesis in a dose‐dependent manner within nongrowth inhibitory concentration, and MA decreased osteoclastogenesis‐related marker gene expression, including TRACP, MMP9, c‐Src, CTR, and cathepsin K. Specifically, MA suppressed osteoclastogenesis and actin ring formation at early stage. In ovariectomized mice, administration of MA prevented ovariectomy‐induced bone loss by inhibiting osteoclast activity. At molecular levels, MA abrogated the phosphorylation of MAPKs and AP‐1 activity, inhibited the IκBα phosphorylation and degradation, blocked NF‐κB/p65 phosphorylation, nuclear translocation, and DNA‐binding activity by downregulating RANK expression and blocking RANK interaction with TRAF6. Together our data demonstrate that MA suppresses RANKL‐induced osteoclastogenesis through NF‐κB and MAPK/AP‐1 signaling pathways and that MA is a promising agent in the treatment of osteoclast‐related diseases such as osteoporosis.

Synthesis and biological evaluation of heterocyclic ring-fused betulinic acid derivatives as novel inhibitors of osteoclast differentiation and bone resorption.

A series of betulinic acid (BA) derivatives were designed and synthesized by introducing various fused heterocyclic rings at C-2 and C-3 positions. Their inhibitory effects of RANKL-induced osteoclastogenesis were evaluated by using a cell-based tartrate-resistant acid phosphatase (TRAP) activity assay. To our delight, most of these compounds exhibited a dramatic increase in inhibitory potency, compared with BA. The most potent compound, 20, showed 66.9% inhibition even at the low concentration of 0.1 μM, which was about 200-fold more potent than the lead compound BA. Whats more, the cytotoxicity assay on RAW264.7 suggested that the inhibition of 20 on osteoclast differentiation did not result from its cytotoxicity. The primary mechanistic study indicated that 20 could inhibit osteoclastogenesis-related marker gene expression levels of cathepsin K and TRAP. More importantly, 20 could attenuate bone loss of ovariectomy mouse in vivo. Therefore, these BA derivatives could be used as potential leads for the development of a new type of antiosteoporosis agent.

A powerful new construction of complex chiral polycycles by an indium(III)-catalyzed cationic cascade.

InI(3) and InBr(3) have been found to be effective catalysts for the π activation of C≡C bonds to initiate the conversion of chiral propargylic alcohols or silyl ethers to polycyclic products in excellent yields and with high stereoselectivity. The method has been applied to the synthesis of chiral fused hexacyclic ring systems with the creation of multiple new stereocenters. The power and scope of the method are illustrated by a variety of examples.

Synthesis and biological evaluation of heterocyclic ring-substituted maslinic acid derivatives as novel inhibitors of protein tyrosine phosphatase 1B.

A series of maslinic acid derivatives have been synthesized by introducing various fused heterocyclic rings at C-2 and C-3 positions. Their inhibitory effects on PTP1B, TCPTP and related PTPs are evaluated. Most of the compounds exhibited a dramatic increase in inhibitory potency and selectivity, the two most potent PTP1B inhibitors 20 (IC(50)=0.61 microM) and 29 (IC(50)=0.64 microM) showed about 10-fold more potent than lead compound maslinic acid. More importantly, 29 possesses the best selectivity of 6.9-fold for PTP1B over TCPTP.

Selective formation of six-membered oxa- and carbocycles by the In(III)-activated ring closure of acetylenic substrates.

Fifteen examples are disclosed of efficient In(III)-catalyzed six-membered ring closure leading to bi-, tri-, and tetracyclic products.

Caffeic acid 3,4-dihydroxy-phenethyl ester suppresses receptor activator of NF-κB ligand–induced osteoclastogenesis and prevents ovariectomy-induced bone loss through inhibition of mitogen-activated protein kinase/activator protein 1 and Ca2+–nuclear factor of activated T-cells cytoplasmic 1 signaling pathways.

Receptor activator of NF‐κB ligand (RANKL) stimulation leads to the activation of mitogen‐activated protein kinase (MAPK)/AP‐1 and Ca2+–nuclear factor of activated T‐cells cytoplasmic 1 (NFATc1) signaling pathways in osteoclastogenesis. Targeting these pathways has been an encouraging strategy for bone‐related diseases, such as postmenopausal osteoporosis. In this study, we examined the effects of caffeic acid 3,4‐dihydroxy‐phenethyl ester (CADPE) on osteoclastogenesis. In mouse bone marrow monocytes (BMMs) and RAW264.7 cells, CADPE suppressed RANKL‐induced osteoclast differentiation and actin‐ring formation in a dose‐dependent manner within non–growth inhibitory concentrations at the early stage, while CADPE had no effect on macrophage colony‐stimulating factor (M‐CSF)‐induced proliferation and differentiation. At the molecular level, CADPE inhibited RANKL‐induced phosphorylation of MAPKs, including extracellular signal‐regulated kinases 1/2 (ERK1/2), p38, and c‐Jun N‐terminal kinase (JNK), without significantly affecting the NF‐κB signaling pathway. CADPE abrogated RANKL‐induced activator protein 1 (AP‐1)/FBJ murine osteosarcoma viral oncogene homolog (c‐Fos) nuclear translocation and activation. Overexpression of c‐Fos prevented the inhibition by CADPE of osteoclast differentiation. Furthermore, CADPE suppressed RANKL‐induced the tumor necrosis factor receptor associated factor 6 (TRAF6) interaction with c‐src tyrosine kinase (c‐Src), blocked RANKL‐induced the phosphorylation of protein kinase B (AKT), and inhibited RANKL‐induced Ca2+ oscillation. As a result, CADPE decreased osteoclastogenesis‐related marker gene expression, including NFATc1, TRAP, cathepsin K, and c‐Src. To test the effects of CADPE on osteoclast activity in vivo, we showed that CADPE prevented ovariectomy‐induced bone loss by inhibiting osteoclast activity. Together, our data demonstrate that CADPE suppresses osteoclastogenesis and bone loss through inhibiting RANKL‐induced MAPKs and Ca2+‐NFATc1 signaling pathways. CADPE is a novel agent in the treatment of osteoclast‐related diseases, such as osteoporosis.

Nonlinear optical absorption properties of two multisubstituted p-dimethylaminophenylethenyl pyridiniums.

Two multisubstituted D-pi-A type pyridinium salts, N-methyl-2,6-di[(E)-p-dimethylaminophenylethenyl]pyridinium iodide (1) and N-methyl-2,4,6-tri[(E)-p-dimethylaminophenylethenyl]pyridinium iodide (2), were synthesized with good yields by a modified method, and the structure of 1 was confirmed by X-ray diffraction. The nonlinear optical absorption (NOA) properties of the two compounds in the solution state were investigated by the Z-scan technique. Compounds 1 and 2 both exhibited very strong saturated absorption at picosecond pulse, and 1 displayed reverse saturated absorption, while 2 revealed saturated absorption properties at the nanosecond pulse. The electron-donating ability, number of side chains, and molecular coplanar characteristics of the compounds have a significant impact on their NOA properties.

Cholesterol Modification of Smoothened Is Required for Hedgehog Signaling

Hedgehog (Hh) has been known as the only cholesterol-modified morphogen playing pivotal roles in development and tumorigenesis. A major unsolved question is how Hh signaling regulates the activity of Smoothened (SMO). Here, we performed an unbiased biochemical screen and identified that SMO was covalently modified by cholesterol on the Asp95 (D95) residue through an ester bond. This modification was inhibited by Patched-1 (Ptch1) but enhanced by Hh. The SMO(D95N) mutation, which could not be cholesterol modified, was refractory to Hh-stimulated ciliary localization and failed to activate downstream signaling. Furthermore, homozygous SmoD99N/D99N (the equivalent residue in mouse) knockin mice were embryonic lethal with severe cardiac defects, phenocopying the Smo-/- mice. Together, the results of our study suggest that Hh signaling transduces to SMO through modulating its cholesterylation and provides a therapeutic opportunity to treat Hh-pathway-related cancers by targeting SMO cholesterylation.

The synthesis and antibacterial activity of pyrazole-fused tricyclic diterpene derivatives.

The diterpenoid compound 5 was identified as an antibacterial lead in our screening of small synthetic natural product-like (NPL) library. A series of novel diterpene derivatives were synthesized and investigated for their activity against Staphylococcus aureus Newman strain and multidrug-resistant strains (NRS-1, NRS-70, NRS-100, NRS-108 and NRS-271). Among the compounds tested, 42 and 43 showed highest activity with a MIC of 1 μg/mL against strain Newman, 45 and 52 showed the most potent activity with MIC values of 0.71-3.12 μg/mL against five multidrug-resistant S. aureus. All high-antimicrobial active compounds showed no obvious toxicity to human fibroblast (HAF) cells at the MIC concentration.