Lipeng Xu

Design, synthesis and antibacterial activity of novel andrographolide derivatives.

A series of andrographolide derivatives were synthesized through a facile condensation reaction with different carboxylic acids. The new compounds were characterized and screened for their antibacterial activities. A number of the new compounds significantly reduced bacterial quorum sensing virulence factors production in Pseudomonas aeruginosa, essential for pathogenesis. Compound 11b showed the best activity among all the new compounds.

Neuroprotective effects of the andrographolide analogue AL-1 in the MPP⁺/MPTP-induced Parkinson's disease model in vitro and in mice.

The andrographolide-lipoic acid conjugate AL-1 is a newly synthesized molecule by covalently linking andrographolide (Andro) with α-lipoic acid (LA). In the present work, the neuroprotective effect of AL-1 was investigated in vitro and in a mouse model of the Parkinsons disease (PD). We found that AL-1 significantly prevented 1-methyl-4-phenylpyridinium (MPP(+))-induced neurotoxicity in SH-SY5Y cells and primary cerebellar granule neurons. In a mouse model of Parkinsons disease, AL-1 rescued 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-induced loss of tyrosine hydroxylase (TH)-positive neurons, improved the behavioral impairment, and elevated the striatal levels of dopamine and its metabolites 3,4-dihydroxyphenylacetic acid. Furthermore, AL-1 remarkably lowered the nitric oxide and malondialdehyde levels while increased the superoxide dismutase level in the substantial nigra of MPTP-treated mice. The immunoblotting data showed that AL-1 significantly ameliorated the decreased expression of TH protein in the substantial nigra and inhibited the up-regulation of phosphorylated NF-κB p65 in vitro and in vivo. Taken together, AL-1 exerted neuroprotective effect in vitro and in animal model of PD through anti-oxidation and inhibition of NF-κB activation.

Synthesis and preliminary evaluation of neuroprotection of celastrol analogues in PC12 cells

A series of celastrol analogues were synthesized, and their neuroprotective effect against t-BHP-induced cytotoxicity was investigated in neuronal PC12 cells. Their effects on Hsp70 protein expression were quantified by Western blot analysis. The study found that compound CL12 is more effective than the parent celastrol against t-BHP-induced cytotoxicity. CL12 up-regulates Hsp70 protein expression dose-dependently. These results suggest that CL12 is a potential candidate for the intervention of neurodegenerative diseases.

Andrographolide derivative AL-1 improves insulin resistance through down-regulation of NF-κB signalling pathway

Andrographolide is the most active constituent of the medicinal plant Andrographis paniculata. Previously, we synthesized a novel andrographolide derivative AL‐1, conjugating andrographolide with lipoic acid. Although the antioxidative and/or anti‐inflammatory activity of AL‐1 contributes to its cytoprotective effects, whether AL‐1 can improve insulin resistance and the mechanisms responsible for its action have not been elucidated.

Cytotoxic quassinoids from Ailanthus altissima

Two new quassinoids, altissinol A (1) and B (7), together with 12 known quassinoids, were isolated from the 95% ethanol extract of the barks of Ailanthus altissima. The structures of the new compounds (1 and 7) were determined on the basis of the spectroscopic methods including UV, IR, HR-ESI-MS, 1D and 2D NMR. The cytotoxic potential of all isolates were evaluated in vitro against three human hepatoma cell lines. Quassinoids 1-7 displayed potent cytotoxic activities against human hepatoma Hep3B and HepG2 cell lines. Interestingly, compounds 2, 3, and 5 exhibited cytotoxic activity against multidrug resistance HepG2/ADM cell line with IC(50) value 4.3-fold more sensitive to Doxorubicin (DOX).

A Rhodium(III) Complex as an Inhibitor of Neural Precursor Cell Expressed, Developmentally Down-Regulated 8-Activating Enzyme with in Vivo Activity against Inflammatory Bowel Disease

We report herein the identification of the rhodium(III) complex [Rh(phq)2(MOPIP)]+ (1) as a potent and selective ATP-competitive neural precursor cell expressed, developmentally down-regulated 8 (NEDD8)-activating enzyme (NAE) inhibitor. Structure-activity relationship analysis indicated that the overall organometallic design of complex 1 was important for anti-inflammatory activity. Complex 1 showed promising anti-inflammatory activity in vivo for the potential treatment of inflammatory bowel disease.

Synthesis and biological evaluations of novel apocynin analogues.

We have designed and synthesized a series of novel apocynin analogues, and evaluated their biological activity. Compound 10, an apocynin dimer analogue, compound 12, the lipoic acid (LA) and apocynin conjugate, were the most potent in protecting cells from lipopolysaccharide (LPS)-induced cytotoxicity, had significant activity scavenging ROS induced by LPS, and greatly decreased LPS-induced P67(phox) protein expression. SAR analysis suggests that modification of apocynin can increase its activity. Our results demonstrate that arming apocynin with a powerful antioxidant such as lipoic acid is a valid strategy to design new apocynin analogues with enhanced biological activity.

Andrographolide derivative AL-1 ameliorates TNBS-induced colitis in mice: involvement of NF-кB and PPAR-γ signaling pathways

Andrographolide is a traditional herb medicine, widely used in Asia for conditions involving inflammation. The andrographlide-lipoic acid conjugate, AL-1, has been found being able to alleviate inflammation in our previous reports. Although the anti-inflammatory activity of AL-1 contributes to its cytoprotective effects, whether AL-1 can improve inflammatory bowel disease (IBD) and the underlying mechanisms of its action remain largely unknown. In this study, we investigated the anti-inflammatory effects of AL-1 in C57BL/6 mice with trinitrobenzenesulfonic acid (TNBS)-induced colitis. The body weight loss and length change of colon after TNBS instillation were more severe than those in normal mice. AL-1 treatment led to significant reductions in disease activity index (DAI), macroscopic score and colon mucosa damage index (CMDI) associated with TNBS administration. AL-1 inhibited the inflammatory response via lowering the level of inflammatory cytokines and myeloperoxidase (MPO) activity. AL-1 attenuated the expression of p-p65, p-IκBα and COX-2 in the colitis mice. The alleviation of colon injury by AL-1 treatment was also evidenced by the increased expression of PPAR-γ. These results indicated that AL-1 could protect intestinal tract from the injury induced by TNBS in mice, suggesting that AL-1 may have potential in treatment for IBD.

Protective effects of apocynin nitrone on acute lung injury induced by lipopolysaccharide in rats

Acute lung injury (ALI) is a major cause of mortality and morbidity worldwide. In a previous study we reported the synthesis of a series of apocynin derivatives. Although the anti-inflammatory activity of them contributes to these cytoprotective effects. However, the mechanisms and effects of improving LPS-induced ALI in vivo remain unknown, so the purpose of our investigation was designed to reveal the effect of apocynin derivatives on LPS-induced acute lung injury in rats. The present study showed that apocynin derivatives reduces overall protein levels and tumor necrosis factor α (TNF-α) level, inhibits the activation of NADPH oxidase, and increases the levels of superoxide dismutase (SOD). Especially, compound 11 significantly reduces pulmonary vascular permeability, white blood cell content and protein expressions of p67(phox) and p47(phox). These results suggest that compound 11 can ameliorate ALI induced by LPS through inhibition of NADPH oxidase.

Protective effects of andrographolide derivative AL-1 on high glucose-induced oxidative stress in RIN-m cells.

AL-1 is a novel andrographolide derivative synthesized by conjugating andrographolide and alpha lipoic acid. AL-1 has been found to increase insulin secretion, decrease blood glucose level and protect β-cell mass and function in alloxan-induced diabetic mouse model. However, the protective mechanism of AL-1 on high glucose-induced pancreatic β-cell injury is still not clear. In the present study, we found that AL-1 reduced reactive oxygen species (ROS) and nitric oxide (NO) generation induced by high glucose in RIN-m cells, and which elevated the activities of superoxide dismutase (SOD) and catalase (CAT). In addition, AL-1 increased the expression of NF-E2-related factor 2 (Nrf2), thioredoxin-1 (Trx-1) and heme oxygenase-1 (HO- 1) proteins in RIN-m cells. These results suggest that AL-1 prevented RIN-m cells from high glucose-induced oxidative damage via upregulation of Nrf2 signaling pathway.