Polyacetylene glycoside attenuates ischemic kidney injury by co-inhibiting inflammation, mitochondria dysfunction and lipotoxicity.

AIMS: Ischemic acute kidney injury (AKI) is a serious clinical problem and no efficient therapeutics is available in clinic now. Natural polyacetylene glycosides (PGAs) had shown antioxidant and anti-inflammatory properties, but their effects on kidney injury have not been evaluated. This study aimed to investigate the protective effect of PGA on ischemic kidney injury in renal tubular epithelial cells (TECs) and mice. MAIN METHODS: Hypoxic HK-2 cells and renal ischemia/reperfusion injury (IRI) mice were treated with PGA from Coreopsis tinctoria, and the cell viability, renal function, apoptosis, inflammation, mitochondrial injury, lipids metabolism were analyzed. KEY FINDINGS: In vitro results showed that PGA improved cell viability and reduced oxidative stress, pro-apoptotic/pro-inflammatory factors expression and NFκB activation in TECs under hypoxia/reperfusion (H/R). Moreover, PGA reduced mitochondria oxidative stress and improved ATP production, ΔΨm and mitochondria biogenesis, and inhibited lipids uptake, biosynthesis and accumulation in hypoxic TECs. In vivo, PGA significantly attenuated kidney injury and reduced blood urea nitrogen (BUN), serum creatinine (CREA) and urinary albumin (Alb), and increased creatinine clearance (CC) in IRI mice. PGA also decreased cell apoptosis, mitochondria oxidative stress, inflammatory response and lipid droplets accumulation, and promoted ATP generation in kidney of IRI mice. SIGNIFICANCE: Our results proved that PGA ameliorated ischemic kidney injury via synergic anti-inflammation, mitochondria protection and anti-lipotoxicity actions, and it might be a promising multi-target therapy for ischemic AKI.

Cytopiloyne, a polyacetylenic glucoside from Bidens pilosa, acts as a novel anticandidal agent via regulation of macrophages.

ETHNOPHARMACOLOGICAL RELEVANCE: Bidens pilosa, a tropical and sub-tropical herbal plant, is used as an ethnomedicine for bacterial infection or immune modulation in Asia, America and Africa. It has been demonstrated that cytopiloyne (CP), a bioactive polyacetylenic glucoside purified from B. pilosa, increases the percentage of macrophages in the spleen but the specific effects on macrophages remain unclear. AIM OF THE STUDY: The aim of this study was to evaluate the effects of CP on macrophage activity and host defense in BALB/c mice with Candida parapsilosis infection and investigate the likely mechanisms. MATERIALS AND METHODS: RAW264.7 cells, a mouse macrophage cell line, were used to assess the effects of CP on macrophage activity by phagocytosis assay, colony forming assay and acridine orange/crystal violet stain. To evaluate the activity of CP against C. parapsilosis, BALB/c mouse infection models were treated with/without CP and histopathological examination was performed. The role of macrophages in the infection model was clarified by treatment with carrageenan, a selective macrophage-toxic agent. RAW264.7 macrophage activities influenced by CP were further investigated by lysosome staining, phagosomal acidification assay, lysosome enzyme activity and PKC inhibitor GF109203X. RESULTS: The results showed that CP in vitro enhances the ability of RAW264.7 macrophages to engulf and clear C. parapsilosis. In the mouse model, CP treatment improved the survival rate of Candida-infected mice and lowered the severity of microscopic lesions in livers and spleens via a macrophage-dependent mechanism. Furthermore, with CP treatment, the fusion and acidification of phagolysosomes were accelerated and the lysosome enzyme activity of RAW264.7 macrophages was elevated. PKC inhibitor GF109203X reversed the increase in phagocytic activity by CP demonstrating that the PKC pathway is involved in the macrophage-mediated phagocytosis of C. parapsilosis. CONCLUSIONS: Our data suggested that CP, as an immunomodulator, enhances macrophage activity against C. parapsilosis infections.

Dual-Targeting Lactoferrin-Conjugated Polymerized Magnetic Polydiacetylene-Assembled Nanocarriers with Self-Responsive Fluorescence/Magnetic Resonance Imaging for In Vivo Brain Tumor Therapy.

Maintaining a high concentration of therapeutic agents in the brain is difficult due to the restrictions of the blood-brain barrier (BBB) and rapid removal from blood circulation. To enable controlled drug release and enhance the blood-brain barrier (BBB)-crossing efficiency for brain tumor therapy, a new dual-targeting magnetic polydiacetylene nanocarriers (PDNCs) delivery system modified with lactoferrin (Lf) is developed. The PDNCs are synthesized using the ultraviolet (UV) cross-linkable 10,12-pentacosadiynoic acid (PCDA) monomers through spontaneous assembling onto the surface of superparamagnetic iron oxide (SPIO) nanoparticles to form micelles-polymerized structures. The results demonstrate that PDNCs will reduce the drug leakage and further control the drug release, and display self-responsive fluorescence upon intracellular uptake for cell trafficking and imaging-guided tumor treatment. The magnetic Lf-modified PDNCs with magnetic resonance imaging (MRI) and dual-targeting ability can enhance the transportation of the PDNCs across the BBB for tracking and targeting gliomas. An enhanced therapeutic efficiency can be obtained using Lf-Cur (Curcumin)-PDNCs by improving the retention time of the encapsulated Cur and producing fourfold higher Cur amounts in the brain compared to free Cur. Animal studies also confirm that Lf targeting and controlled release act synergistically to significantly suppress tumors in orthotopic brain-bearing rats.

Stable and compact zwitterionic polydiacetylene micelles with tumor-targeting properties.

Compact polymerized polydiacetylene-micelles with "stealth" zwitterionic surface coating were assembled and tested in a murine xenograft model of breast cancer. In vivo fluorescence imaging indicated accumulation in the tumor area and histological studies revealed predominant uptake of the micelles at the margins of the tumor, thereby allowing the delineation of its volume.

Chemical and pharmacological studies of Oplopanax horridus, a North American botanical.

Oplopanax horridus (OH), or Devil's club, is an ethnobotanical used by the indigenous people native to the Pacific Northwest of North America. There are three species in the genus Oplopanax, and OH is the only species that is distributed in North America. Compared with the extensive research on OH's "cousin," American ginseng, there is comparatively little reported about the chemical makeup and pharmacological effects of OH. Nevertheless, there has been some research over the past few years that shows promise for the future usage perspectives of OH. To date, 17 compounds were isolated and elucidated, including polyynes, glycosides, lignans, and polyenes, with most of the attention being paid to the polyynes. Gas chromatography (GC) and high-performance liquid chromatography (HPLC) were used to determine the contents of volatile compounds and polyynes in the essential oil and extracts of OH. For the pharmacological studies, antibacterial and antidiabetes effects of polyynes were reported. Our recent study has focused more on the anticancer effects of OH and the involved mechanisms of action. In this review, we will summarize the research status in the botany, phytochemistry, and pharmacology of OH.

Stereoselective total synthesis of (+)-oploxyne A, (-)-oploxyne B, and their C-10 epimers and structure revision of natural oploxyne B.

The first total synthesis of recently isolated diacetylene alcohols oploxyne A, oploxyne B, and their C-10 epimers was accomplished. The structure of natural oploxyne B has been revised. The key steps involved are base-induced double elimination of a carbohydrate-derived ß-alkoxy chloride to generate the chiral acetylenic alcohol and Cadiot-Chodkiewicz cross-coupling reaction. The target compounds displayed potent cytotoxicity against neuroblastoma and prostate cancer cell lines.

Isolation and identification of a potent antimalarial and antibacterial polyacetylene from Bidens pilosa.

Diseases caused by malaria parasites and pathogenic bacteria were thought to be on the brink of eradication in the 1950-1960s, but they have once again become a serious threat to mankind as a result of the appearance of multidrug resistant strains. The spread of these multidrug resistant organisms has prompted a worldwide search for new classes of effective antimalarial and antibacterial drugs. Natural products have been recognized as highly important candidates for this purpose. Our attention has focused on the herbal plant Bidens pilosa, a weed common throughout the world, as one of the target plants in the search for new active compounds, owing to its empirical use in the treatment of infectious diseases and to pharmaco-chemical studies of its crude extract. We report the isolation of two new compounds of B. pilosa, the linear polyacetylenic diol 1 and its glucoside 2 which have previously been isolated from different plants. Compound 1 exhibited highly potent antimalarial and antibacterial properties in vitro as well as potent antimalarial activity by way of intravenous injection in vivo, thereby representing a promising new class of drugs potentially effective in the treatment of malarial and bacterial diseases. We suspect that discovery of these compounds in B. pilosa in appreciable quantity is because the Fijian tradition of using the fresh plant for extraction rather than the Asian tradition of using dried plants (1 is unstable in the dried state) was followed.

Dendrazawaynes A and B, antifungal polyacetylenes from Dendranthema zawadskii (Asteraceae).

Two new C(14) polyacetylenes dendrazawayne A(7) and dendrazawayne B (9) together with known C(13) polyacetylenes (2, 3), C(14) polyacetylenes (1, 4, and 8) and polyacetylene amides (5 and 6) were isolated from the roots of Dendranthema zawadskii. The structures of 7 and 9 were elucidated based on spectroscopic methods including 2D-NMR, HR-TOF-MS, IR, and UV. Compounds 1, 2, 3, 5, and 6 showed moderate activity against tumor cell lines (human small lung cancer cell line A549, melanoma SK-Mel-2, and mouse melanoma B16F1) with IC(50) values in the range of 7.4 - 30 microg/mL. Compounds 7 and 9, including other polyacetylenes, showed strong activity against the fungus Trichophyton (MIC: 5 - 10 microg/mL).

A novel polyacetylene significantly inhibits angiogenesis and promotes apoptosis in human endothelial cells through activation of the CDK inhibitors and caspase-7.

A novel bioactive polyacetylene compound, 1,2-dihydroxy-5(E)-tridecene-7,9,11-triyne (compound 1), was identified from the Bidens pilosa extract using an ex vivo primary human umbilical vein endothelium cell (HUVEC) bioassay-guided fractionation protocol. Our results demonstrate that compound 1 (at 2.5 microg/mL) possessed significant anti-angiogenic effects, as manifested by an inhibition of HUVEC proliferation, migration, and the formation of tube-like structures in collagen gel. Moreover, compound 1 induced HUVECs to undergo cell death in a concentration- and time-dependent manner. The mechanisms underlying these pharmacological effects include reduced expression of cell cycle mediators such as CDK4, cyclins D1 and A, retinoblastoma (Rb) and vascular endothelial growth factor receptor 1 (VEGFR-1), and promotion of caspase-mediated activation of CDK inhibitors p21(Cip1) and p27(Kip). Moreover, apoptotic induction in HUVECs mediated by compound 1 was found to be in part through overexpression of FasL protein, down-regulation of anti-apoptotic Bcl-2, and activation of caspase-7 and poly(ADP-ribose) polymerase. This study demonstrates the potent anti-angiogenic and apoptotic activities of compound 1, suggesting that phytocompounds such as polyacetylenes deserve more attention regarding their potential as candidates for anti-angiogenic therapeutics.

Cytopiloyne, a polyacetylenic glucoside, prevents type 1 diabetes in nonobese diabetic mice.

Some polyacetylenes from the plant Bidens pilosa have been reported to treat diabetes. In this study, we report that the cytopiloyne from B. pilosa, which is structurally different from the above-mentioned polyacetylenes and inhibits CD4(+) T cell proliferation, effectively prevents the development of diabetes in nonobese diabetic mice as evidenced by a normal level of blood glucose and insulin and normal pancreatic islet architecture. Cytopiloyne also suppresses the differentiation of type 1 Th cells but promotes that of type 2 Th cells, which is consistent with it enhancing GATA-3 transcription. Also, long-term application of cytopiloyne significantly decreases the level of CD4(+) T cells inside pancreatic lymph nodes and spleens but does not compromise total Ab responses mediated by T cells. Coculture assays imply that this decrease in CD4(+) T cells involves the Fas ligand/Fas pathway. Overall, our results suggest that cytopiloyne prevents type 1 diabetes mainly via T cell regulation.

A bioactive polyacetylene compound isolated from Centella asiatica.

A polyacetylene compound was isolated from the aerial parts of Centella asiatica. The chemical structure of this new compound was identified as methyl 5-[(E)-9-hydroxy-1-(1-hydroxyhexyl)-2-methoxyundeca-3,10-diene-5,7-diynyloxy]pentanoate (cadiyenol). This compound induces apoptosis (63%) independent of cell cycle regimen in mouse lymphoma cells (P388D1) at 28 microM (IC (50) = 24 +/- 2 microM) in 24 hours. The compound also reduces nitric oxide production by 70 +/- 2% in lipopolysacharride-activated mouse macrophages at 24 microM with no measurable cytotoxicity.