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Guo B.,Hong Kong Baptist University | Guo B.,Institute of Integrated Bioinfomedicine and Translational Science | Guo B.,China Institute of Technology | Zhang B.,Chinese University of Hong Kong | And 36 more authors.
Bone | Year: 2013

Objectives: Casein kinase 2 interacting protein 1 (CKIP-1) is a newly discovered intracellular negative regulator of bone formation without affecting bone resorption. In this study, we aimed to identify a cross-species siRNA sequence targeting CKIP-1 to facilitate developing a novel RNAi-based bone anabolic drug for reversing established osteoporosis. Methods: Eight specifically designed cross-species CKIP-1 siRNA sequences were screened in human, rhesus, rat and mouse osteoblast-like cells in vitro to identify the optimal sequence with the highest knockdown efficiency. The effect of this optimal siRNA sequence on osteogenic differentiation and matrix mineralization was further examined in osteoblast-like cells across different species, followed by an immunogenicity assessment in human peripheral blood mononuclear cells in vitro. The intra-osseous localization and silencing efficiency of the optimal siRNA were examined in vivo using a biophotonic system and real-time polymerase chain reaction, respectively. The RNAi-mediated cleavage of the CKIP-1 transcript was confirmed by rapid amplification of the 5' cDNA ends in vivo. Furthermore, the effect of the optimal siRNA sequence on osteogenic differentiation, bone turnover biomarkers, bone mass and micro-architecture parameters was investigated in healthy and osteoporotic rodents. Results: The CKIP-1 siRNA sequence (si-3) was identified as the optimal sequence, which consistently maintained CKIP-1 mRNA/protein expression at the lowest level across species in vitro. The si-3 significantly increased mRNA expression levels of osteoblast phenotypic genes and matrix mineralization across species without inducing an immunostimulatory activity in vitro. The intra-osseous localization and RNAi-mediated CKIP-1 silencing with high efficiency were confirmed in vivo. Periodic intravenous injections of si-3 promoted mRNA expression of osteoblast phenotypic genes, enhanced bone formation, increased bone mass and elevated serum level of bone formation marker without raising urine level of bone resorption marker in the healthy rodents. Moreover, the si-3 treatment promoted bone formation, improved trabecular micro-architecture and reversed bone loss in the osteoporotic mice. Conclusions: The identified optimal CKIP-1 siRNA sequence (si-3) could promote osteogenic differentiation across species in vitro, stimulate bone formation in the healthy rodents and reverse bone loss in the osteoporotic mice. © 2013.


Wu J.,State Key Laboratory of Chinese Medicine and Molecular Pharmacology | Liu X.,State Key Laboratory of Chinese Medicine and Molecular Pharmacology | Chan C.-O.,State Key Laboratory of Chinese Medicine and Molecular Pharmacology | Chan C.-O.,Hong Kong Polytechnic University | And 9 more authors.
Journal of Ethnopharmacology | Year: 2014

Ethnopharmacological relevance The hip of Rosa multiflora Thunb. (HRM) has been traditionally used as a dietary supplement and a herbal remedy for the treatment of various diseases, including inflammation, osteoarthritis, rheumatoid arthritis and chronic pain, in China. The current study was to evaluate the therapeutic efficacy of the petroleum ether extractive of HRM (PEE) on type II collagen-induced rheumatoid arthritis (CIA) in male Wistar rats. In addition, the anti-inflammatory mechanism(s) of PEE on type II CIA was explored. Materials and methods Rheumatoid arthritis (RA) was induced by intradermal injection of bovine type II collagen on Day 1 and Day 8. Starting from Day 13, normal rats were treated with vehicle (serving as the control group); the CIA rats were treated with vehicle (CIA group), dexamethasone (0.25 mg/kg bw per day, p.o.) (a positive control), lei-gong-teng (LGT: 10 mg/kg bw per day, p.o.) (a clinically used Chinese patent medicine in RA therapy) or PEE (12, 36 or 120 mg/kg bw per day, p.o.) for 28 days. Results and conclusions PEE (120 mg/kg bw per day) efficiently attenuated the severity of arthritis in the CIA rats by reducing the mean arthritis severity scores and the fore/hind paw swelling as well as reduced histological changes by decreasing the cartilage surface erosion and cartilage proteoglan depletion. PEE's therapeutic effect in RA may involve the inhibition of pro-inflammatory cytokines, such as TNF-α, IL-1β and IL-6, in serum and/or the elevation of the activities of hepatic anti-oxidative enzymes including SOD, CAT and GSH-Px. However, the detailed anti-inflammatory mechanism, the main effective components and the interaction between different ingredients in PEE are still not clear and require more studies. © 2014 Elsevier Ireland Ltd.


Wu J.,Hong Kong Baptist University | Wu J.,Fudan University | Du J.,Hong Kong Baptist University | Fu X.,Hong Kong Baptist University | And 9 more authors.
Oncotarget | Year: 2016

Icaritin (IT) is a flavonoid isolated from Herba Epimedii. In this study, we evaluated the anti-melanoma activities of IT, and determined its cytotoxic mechanism. We found that IT exerted cytotoxicity to melanoma cells. Furthermore, IT induced melanoma cell apoptosis, which was accompanied with PARP cleavage. Mechanistically, IT suppressed p-STAT3 (tyr705) level in parallel with increases of p-STAT3 (ser727), p-ERK and p-AKT. IT significantly inhibited STAT3 nuclear translocation and reduced the levels of STAT3 -targeted genes. IT also inhibited IGF-1-induced STAT3 activation through down-regulation of total IGF-1R level. No dramatic changes in IGF-1R mRNA levels were observed in IT-treated cells, suggesting that IT acted primarily at a posttranscriptional level. Using molecular docking analysis, IT was identified as a novel fatty acid synthase (FASN) inhibitor. We found that IT reduced the level of total IGF-1R via FASN inhibition. In summary, we reported that IT exerted anti-melanoma activities, and these effects were partially due to inhibition of FASN/IGF-1R/STAT3 signaling.


Cheng B.C.Y.,Hong Kong Baptist University | Cheng B.C.Y.,Institute of Integrated Bioinfomedicine and Translational Science | Yu H.,Hong Kong Baptist University | Yu H.,Institute of Integrated Bioinfomedicine and Translational Science | And 17 more authors.
Scientific Reports | Year: 2016

RL, a traditional remedy for Rheumatoid arthritis (RA), comprises two edible herbs, Rosae Multiflorae Fructus and Lonicerae Japonicae Flos. We have reported that RL could inhibit the production of inflammatory mediators in immune cells. Here we investigated the effects and the mechanism of action of RL in collagen-induced arthritis (CIA) rats. RL significantly increased food intake and weight gain of CIA rats without any observable adverse effect; ameliorated joint erythema and swelling; inhibited immune cell infiltration, bone erosion and osteophyte formation in joints; reduced joint protein expression levels of TLR4, phospho-TAK1, phospho-NF-κB p65, phospho-c-Jun and phospho-IRF3; lowered levels of inflammatory factors (TNF-α, IL-6, IL-1β, IL-17A and MCP-1 in sera and TNF-α, IL-6, IL-1β and IL-17A in joints); elevated serum IL-10 level; reinvigorated activities of antioxidant SOD, CAT and GSH-Px in the liver and serum; reduced Th17 cell proportions in splenocytes; inhibited splenocyte proliferation and activation; and lowered serum IgG level. In conclusion, RL at nontoxic doses inhibited TLR4 signaling and potently improved clinical conditions of CIA rats. These findings provide further pharmacological justifications for the traditional use of RL in RA management. © 2016, Nature Publishing Group. All rights reserved.


Su T.,Hong Kong Baptist University | Cheng B.C.-Y.,Hong Kong Baptist University | Fu X.-Q.,Hong Kong Baptist University | Li T.,Hong Kong Baptist University | And 8 more authors.
BMC Complementary and Alternative Medicine | Year: 2016

Background: Although toxic, the Chinese medicinal herb Xanthii Fructus (XF) is commonly used to treat traditional Chinese medicine (TCM) symptoms that resemble cold, sinusitis and arthritis. According to TCM theory, stir-baking (a processing method) can reduce the toxicity and enhance the efficacy of XF. Methods: Cytotoxicities of raw XF and processed XF (stir-baked XF, SBXF) were determined by the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay in normal liver derived MIHA cells. Nitric oxide (NO) production and inducible nitric oxide synthase (iNOS) mRNA expression were measured by the Griess reagent and quantitative real-time PCR, respectively. The chemical profiles of XF and SBXF were compared using an established ultra-performance liquid chromatography/quadrupole-time-of-flight mass spectrometry (UPLC/Q-TOF-MS) method. Results: SBXF was less toxic than XF in MIHA cells. Both XF and SBXF had anti-inflammatory effects as demonstrated by their abilities to reduce nitric oxide production as well as inducible nitric oxide synthase mRNA expression in lipopolysaccharide-stimulated RAW 264.7 macrophages. Interestingly, the anti-inflammatory effects of SBXF were more potent than that of XF. By comparing the chemical profiles, we found that seven peaks were lower, while nine other peaks were higher in SBXF than in XF. Eleven compounds including carboxyatractyloside, atractyloside and chlorogenic acid corresponding to eleven individual changed peaks were tentatively identified by matching with empirical molecular formulae and mass fragments, as well as literature data. Conclusion: Our study showed that stir-baking significantly reduced the cytotoxicity and enhanced the anti-inflammatory effects of XF; moreover, with a developed ultra-performance liquid chromatography/quadrupole-time-of-flight mass spectrometry method we differentiated XF and SBXF by their chemical profiles. Further studies are warranted to establish the relationship between the alteration of chemical profiles and the changes of medicinal properties caused by stir-baking. © 2016 Su et al.


Fu X.-Q.,Hong Kong Baptist University | Chou G.-X.,Shanghai University of Traditional Chinese Medicine | Kwan H.Y.,Hong Kong Baptist University | Tse A.K.-W.,Hong Kong Baptist University | And 10 more authors.
Experimental Dermatology | Year: 2014

Our previous studies showed that atractylenolide II (AT-II) has antimelanoma effects in B16 melanoma cells. In this study, we investigated the involvement of STAT3 signalling in the antimelanoma action of AT-II. Daily administration of AT-II (12.5, 25 mg/kg, i.g.) for 14 days significantly inhibited tumor growth in a B16 xenograft mouse model and inhibited the activation/phosphorylation of STAT3 and Src in the xenografts. In B16 and A375 cells, AT-II (20, 40 μm) treatment for 48 h dose-dependently reduced protein expression levels of phospho-STAT3, phospho-Src, as well as STAT3-regulated Mcl-1 and Bcl-xL. Overexpression of a constitutively active variant of STAT3, STAT3C in A375 cells diminished the antiproliferative and apoptotic effects of AT-II. These data suggest that inhibition of STAT3 signalling contributes to the antimelanoma action of AT-II. Our findings shed new light on the mechanism of action underlying the antimelanoma effects of AT-II and provide further pharmacological basis for developing AT-II as a novel melanoma chemopreventive/chemotherapeutic agent. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.


Kwan H.Y.,Hong Kong Baptist University | Kwan H.Y.,Institute of Integrated Bioinfomedicine and Translational Science | Chao X.,Hong Kong Baptist University | Chao X.,Institute of Integrated Bioinfomedicine and Translational Science | And 11 more authors.
Journal of Nutritional Biochemistry | Year: 2015

Lipids play an important role to support the rapid growth of cancer cells, which can be derived from both the endogenous synthesis and exogenous supplies. Enhanced de novo fatty acid synthesis and mobilization of stored lipids in cancer cells promote tumorigenesis. Besides, lipids and fatty acids derived from diet or transferred from neighboring adipocytes also influence the proliferation and metastasis of cancer cells. Indeed, the pathogenic roles of adipocytes in the tumor microenvironment have been recognized recently. The adipocyte-derived mediators or the cross talk between adipocytes and cancer cells in the microenvironment is gaining attention. This review will focus on the impacts of lipids on cancers and the pathogenic roles of adipocytes in tumorigenesis and discuss the possible anticancer therapeutic strategies targeting lipids in the cancer cells. © 2015 Elsevier Inc.


Guan Y.,Hong Kong Baptist University | Guan Y.,Institute of Integrated Bioinfomedicine and Translational Science | Wang D.,Hong Kong Baptist University | Wang D.,Institute of Integrated Bioinfomedicine and Translational Science | And 8 more authors.
American Journal of Chinese Medicine | Year: 2016

Litsea verticillata Hance (Lauraceae), a Chinese medicine used to treat swelling caused by injury or by snake bites, was the first plant identified by our National Institutes of Health (NIH)-funded International Cooperative Biodiversity Group (ICBG) project to exhibit anti-HIV activities. From this plant, we discovered a class of 8 novel litseane compounds, prototypic sesquite rpenes, all of which demonstrated anti-HIV activities. In subsequent studies, 26 additional compounds of different structural types were identified. During our continuing investigation of this plant species, we identified two new litseanes, litseaverticillols L and M, and a new sesquiterpene butenolide, litseasesquibutenolide. Litseaverticillols L and M were found to inhibit HIV-1 replication, with an IC50 value of 49.6μM. To further determine the antiviral properties of this plant, several relatively abundant isolates, including a litseane compound, two eudesmane sesquiterpenes and three lignans, were evaluated against an additional 21 viral targets. Lignans 8 and 9 were shown to be active against the Epstein-Barr Virus (EBV), with EC50 values of 22.0μM (SI=3.8) and 16.2μM (SI>6.2), respectively. Since many antiviral compounds have been discovered in L. verticillata, we further prepared 38 plant extracts made from the different plant parts of 9 additional Litsea species. These extracts were evaluated for their anti-HIV and cytotoxic activities, and four of the extracts, which ranged across three different species, displayed 97-100% inhibitory effects against HIV replication without showing cytotoxicity to a panel of human cell lines at a concentration of 20μg/mL. © 2016 World Scientific Publishing Company.


Su T.,Hong Kong Baptist University | Yu H.,Hong Kong Baptist University | Kwan H.-Y.,Hong Kong Baptist University | Ma X.-Q.,Hong Kong Baptist University | And 9 more authors.
Journal of Ethnopharmacology | Year: 2014

Ethnopharmacological relevance: Although slightly toxic, the Chinese medicinal herb Herba Siegesbeckiae (HS) has long been used as a remedy for traditional Chinese medicine symptoms that resemble inflammatory joint disorders, because it can eliminate the wind-dampness and soothe painful joints. Proper processing can reduce the toxicity and/or enhance the efficacy of raw herbs. In this study, we aim to examine if processing with rice wine reduces the cytotoxicities and/or enhances the anti-inflammatory effects of HS, and to explore the chemical basis behind the potential changes of medicinal properties caused by the processing. Materials and methods: We used cell models to examine the cytotoxicities and anti-inflammatory effects of HS and rice wine-processed HS (WHS). The chemical profiles of HS and WHS were compared using the ultra-performance liquid chromatography/quadrupole-time-of-flight mass spectrometry (UPLC/Q-TOF-MS) analysis. Results: We found that WHS was less toxic than HS in cultured cells as shown in the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. Both HS and WHS had anti-inflammatory effects as demonstrated by their abilities to reduce nitric oxide (NO) production as well as protein and mRNA expressions of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. Interestingly, the anti-inflammatory effects of WHS were more potent than that of HS at the concentration of 100 μg/mL. By comparing the chemical profiles, we found that 19 peaks were lower, while 2 other peaks were higher in WHS than in HS. Four compounds including neodarutoside, darutoside, stigmasterol and 16-O-acetyldarutoside corresponding to 4 individual changed peaks were tentatively identified by matching with empirical molecular formulae and mass fragments. Conclusion: Our study showed that processing with rice wine significantly reduced the cytotoxicities and enhanced the anti-inflammatory effects of HS as demonstrated in cell models. We also developed a UPLC/Q-TOF-MS method to clearly differentiate HS from WHS by their different chemical profiles. Further study is warranted to establish the relationship between the alteration of chemical profiles and the changes of medicinal properties caused by processing with rice wine. © 2014 Elsevier Ireland Ltd. All rights reserved.

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