ABSTRACT
As an emerging tumor therapy, ideal oncolytic viruses preferentially replicate in malignant cells, reverse the immunosuppressive tumor microenvironment, and eventually can be eliminated by the patient. It is of great significance for cancer treatment to discover new excellent oncolytic viruses. Here, we found that WNV live attenuated vaccine WNV-poly(A) could be developed as a novel ideal oncolytic agent against several types of cancers. Mechanistically, due to its high sensitivity to type Ι interferon (IFN-Ι), WNV-poly(A) could specifically kill tumor cells rather than normal cells. At the same time, WNV-poly(A) could activate Dendritic cells (DCs) and trigger tumor antigen specific response mediated by CD8 + T cell, which contributed to inhibit the propagation of original and distal tumor cells. Like intratumoral injection, intravenous injection with WNV-poly(A) also markedly delays Huh7 hepatic carcinoma (HCC) transplanted tumor progression. Most importantly, in addition to an array of mouse xenograft tumor models, WNV-poly(A) also has a significant inhibitory effect on many different types of patient-derived tumor tissues and HCC patient-derived xenograft (PDX) tumor models. Our studies reveal that WNV-poly(A) is a potent and excellent oncolytic agent against many types of tumors and may have a role in metastatic and recurrent tumors.
Subject(s)
Carcinoma, Hepatocellular , Liver Neoplasms , Oncolytic Viruses , Animals , Mice , CD8-Positive T-Lymphocytes , Cell Line, Tumor , Immunity , Liver Neoplasms/therapy , Neoplasm Recurrence, Local , Oncolytic Viruses/metabolism , Tumor Microenvironment , Virus ReplicationABSTRACT
The genus Flavivirus comprises numerous emerging and re-emerging arboviruses causing human illness. Vaccines are the best approach to prevent flavivirus diseases. But pathogen diversities are always one of the major hindrances for timely development of new vaccines when confronting unpredicted flavivirus outbreaks. We used West Nile virus (WNV) as a model to develop a new live-attenuated vaccine (LAV), WNV-poly(A), by replacing 5' portion (corresponding to SL and DB domains in WNV) of 3'-UTR with internal poly(A) tract. WNV-poly(A) not only propagated efficiently in Vero cells, but also was highly attenuated in mouse model. A single-dose vaccination elicited robust and long-lasting immune responses, conferring full protection against WNV challenge. Such "poly(A)" vaccine strategy may be promising for wide application in the development of flavivirus LAVs because of its general target regions in flaviviruses.
Subject(s)
West Nile Fever , West Nile Virus Vaccines , 3' Untranslated Regions , Animals , Antibodies, Viral , Chlorocebus aethiops , Mice , Poly A , Vero Cells , West Nile Fever/prevention & controlABSTRACT
Three new 3-hydroxy-3-methylglutaryl (HMG) flavone 7-O-diglycosides, argutosides A-C (1-3); two new flavone 7-O-triglycosides, argutosides D-E (4-5); and one known apigenin 7-O-triglycoside (6), were isolated from the leaves of Turpinia arguta. The structures of these compounds were elucidated by spectroscopic and chemical techniques. The NO inhibitory activities of compounds 1-6 were evaluated using lipopolysaccharide-induced RAW264.7 cells. Only compound 2 showed a moderate inhibitory effect on NO production with an IC50 value of 25.74µM. Compounds 1-6 were not cytotoxic to RAW264.7 cells at 10µM.
Subject(s)
Flavones/chemistry , Glycosides/chemistry , Magnoliopsida/chemistry , Plant Leaves/chemistry , Animals , Anti-Inflammatory Agents/chemistry , Mice , Molecular Structure , Nitric Oxide/metabolism , RAW 264.7 CellsABSTRACT
Nine 14,15-secopregnane-type C21-steriosides, stauntosides U, V, V1-V3, W and C1-C3, as well as two known C21-steriosides, were isolated from the roots of Cynanchum stauntonii. Stauntosides U, V and V1-V3 share the same basic structural features of 8α:14α,14:16,15:20,18:20-tetraepoxy-14,15-secopregn-6-ene-3ß,5α,9α-triol, with the numbering system following that of C21-pregnanes. The aglycones of stauntosides U, V and V1-V3 are classified into two subcategories, the 5,9-dihydroxy groups and 5α:9α-peroxy bridge, according to the oxidative states of the two hydroxy groups at the C-5 and C-9 positions. The anti-inflammatory activity of the major compounds was assessed in an in vitro inflammatory model of mouse peritoneal macrophages using IC50 values of the inhibition of nitric oxide (NO) production as an indicator. Stauntosides V1 and V3 exhibited target activity with IC50 values of 9.3 µM and 12.4 µM, respectively, compared with dexamethasone, which was used as a positive control.
Subject(s)
Cynanchum/chemistry , Plant Roots/chemistry , Pregnanes/chemistry , Animals , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/isolation & purification , Macrophages, Peritoneal/drug effects , Mice , Mice, Inbred C57BL , Molecular Structure , Nitric Oxide/metabolism , Pregnanes/isolation & purificationABSTRACT
Seven new sesquiterpenes (1, 3-8), a new sesquiterpene natural product (2), and two new lignans (9 and 10), together with 15 known compounds, were isolated from the fruits of Xanthium sibiricum. The structures of the new compounds were established by NMR spectroscopic analysis, ECD calculations, and Mo2(OAc)4-induced circular dichroism, with the structures of 1 and 4 confirmed by single-crystal X-ray diffraction. Compound 1 is the first example of a 3/5/6/5 tetracyclic eudesmane sesquiterpene lactone formed at C-6 and C-7. In turn, compound 4 is the first example of a natural xanthane tetranorsesquiterpene, while compounds 5-8 are the first xanthane trinorsesquiterpenes found to date. Compounds 8, 11-15, 17, and 24 exhibited indirect anti-inflammatory activity by suppressing the lipopolysaccharide-induced proinflammatory factors in BV2 microglial cells, with IC50 values between 1.6 and 8.5 µM. Furthermore, compounds 13 and 17 exhibited anti-inflammatory activity against ear edema in mice produced by croton oil, with inhibition rates of 46.9% and 37.7%, respectively. Compounds 8, 11, 12, 23, and 24 exhibited potent activity against influenza A virus (A/FM/1/47, H1N1) with IC50 values between 3.7 and 8.4 µM.
Subject(s)
Anti-Inflammatory Agents/isolation & purification , Anti-Inflammatory Agents/pharmacology , Drugs, Chinese Herbal/isolation & purification , Drugs, Chinese Herbal/pharmacology , Lignans/isolation & purification , Lignans/pharmacology , Sesquiterpenes/isolation & purification , Sesquiterpenes/pharmacology , Xanthium/chemistry , Animals , Anti-Inflammatory Agents/chemistry , Crystallography, X-Ray , Dogs , Drugs, Chinese Herbal/chemistry , Fruit/chemistry , Influenza A Virus, H1N1 Subtype/drug effects , Inhibitory Concentration 50 , Lignans/chemistry , Macrophages/drug effects , Madin Darby Canine Kidney Cells/drug effects , Mice , Molecular Conformation , Molecular Structure , Nuclear Magnetic Resonance, Biomolecular , Sesquiterpenes/chemistry , Vero Cells/drug effectsABSTRACT
Three new saikosaponin analogs, comastomasaponins I-K (1-3), were isolated from the aerial portions of Comastomapedunculatum. The structures of these compounds were elucidated on the basis of spectroscopic data analysis, and their nitric oxide production inhibitory activity was evaluated invitro.
Subject(s)
Araliaceae/chemistry , Drugs, Chinese Herbal/isolation & purification , Oleanolic Acid/analogs & derivatives , Saponins/isolation & purification , Drugs, Chinese Herbal/chemistry , Drugs, Chinese Herbal/pharmacology , Molecular Structure , Nitric Oxide/biosynthesis , Nuclear Magnetic Resonance, Biomolecular , Oleanolic Acid/chemistry , Oleanolic Acid/isolation & purification , Plant Components, Aerial/chemistry , Saponins/chemistryABSTRACT
P2X7 is the most important subtype of the ATP receptors known so far. Recent investigations showed that the downstream signaling pathway of P2X7 is coupled with several key inflammatory molecules including IL-1beta and IL-18, this suggests P2X7 might have roles in the inflammatory diseases. Moreover, attenuation of P2X7 by selective antagonists in vitro and knockout mice in vivo reducing the inflammatory response indicated that P2X7 is a potential therapeutic target for inflammatory diseases. However, most previous studies on P2X7 were focused on nerve system diseases most, while its effects in inflammatory respiratory diseases, especially in asthma, chronic obstructive pulmonary disease (COPD) and lung cancer have been poorly investigated. In this paper, we reviewed the research progress on the structure, distribution, biological activities of P2X7 and its relationship with inflammatory respiratory diseases including asthma, COPD and lung cancer, along with the development of P2X7 antagonist as therapeutics.
Subject(s)
Inflammation/metabolism , Purinergic P2X Receptor Antagonists/therapeutic use , Receptors, Purinergic P2X7/metabolism , Respiratory Tract Diseases/metabolism , Animals , Asthma/drug therapy , Asthma/metabolism , Humans , Inflammation/drug therapy , Interleukin-18/metabolism , Interleukin-1beta/metabolism , Lung Neoplasms/drug therapy , Lung Neoplasms/metabolism , Mice , Polymorphism, Single Nucleotide , Pulmonary Disease, Chronic Obstructive/drug therapy , Pulmonary Disease, Chronic Obstructive/metabolism , Receptors, Purinergic P2X7/chemistry , Receptors, Purinergic P2X7/genetics , Respiratory Tract Diseases/drug therapyABSTRACT
Eight compounds were isolated from the leaves of Turpinia arguta by various chromatograhic techniques such as D101 macroporous resin, polyamide, Sephadex LH-20,and HPLC chromatography, and their structures were elucidated as rhoifolin (1), apigenin-7-O- [2"-O-alpha-L-rhamnopyranosyl-6"-O-alpha-L-rhamnopyranosyl] -beta-D-glucopyranoside (2), acacetin-7-O- [2"-O-alpha-L-rhamnopyranosyl-6"-O-beta-D-glucopyranosyl] -beta-D-glucopyranoside (3), acacetin-7-O- [2"-O-alpha-L-rhamnopyranosyl-6"-O-alpha-L-rhamnopyranosyl] -beta-D-glucopyranoside(neobudofficide, 4), luteolin-7-O-[2"-O-beta-D-glucopyranosyl] -beta-D-glucopyranoside (5), chrysoeiml-7-O-[2"-O-beta-D-glucopyranosyl] -beta-D-glucopyranoside (6), acacetin-7-O-alpha-L-rhamnopyranosyl-(1 --> 6) -O-beta-D-glucopyranoside (buddleoside, linarin, 7), and apigenin 6, 8-di-C-beta-D-glucopyranoside (8) on the basis of spectral data analysis. Compounds 3-8 were isolated from T. arguta for the first time. Compounds 2, 3 showed weak anti-inflammatory effect on LPS-stimulated RAW264.7 cell.
Subject(s)
Anti-Inflammatory Agents/chemistry , Drugs, Chinese Herbal/chemistry , Flavonoids/chemistry , Glycosides/chemistry , Magnoliopsida/chemistry , Animals , Anti-Inflammatory Agents/pharmacology , Cell Line , Drugs, Chinese Herbal/pharmacology , Flavonoids/pharmacology , Glycosides/pharmacology , Mass Spectrometry , Mice , Molecular Structure , Plant Leaves/chemistryABSTRACT
Fifteen epi-aleuritolic acid derivatives were synthesized and evaluated for anti-HIV activity in 293 T cells and NO production inhibition activity. Of the derivatives, 1, 2, 3, 4, 11, and 13 showed relatively potent anti-HIV activity with EC50 values ranging from 5.80 to 13.30 µM. The most potent compound, 3α-2',2'-dimethylsuccinic acyl epi-aleuritolic acid (11), displayed significant anti-HIV activity with an EC50 value of 5.80 µM. Compounds 1, 3, 4, and 11 showed NO inhibition activity, with IC50 values ranging from 3.40 to 7.10 µM and compound 1 inhibited NO production with an IC50 value of 3.40 µM.
Subject(s)
Anti-HIV Agents/chemical synthesis , Anti-HIV Agents/pharmacology , Nitric Oxide/antagonists & inhibitors , Palmitic Acids/chemical synthesis , Palmitic Acids/pharmacology , Animals , Anti-HIV Agents/chemistry , Inhibitory Concentration 50 , Male , Mice , Mice, Inbred C57BL , Molecular Structure , Nitric Oxide/biosynthesis , Palmitic Acids/chemistryABSTRACT
Three new tirucallane triterpenoids, brumollisols A-C (1-3, resp.), together with five known analogues, (23R,24S)-23,24,25-trihydroxytirucall-7-ene-3,6-dione (4), piscidinol A (5), 24-epipiscidinol A (6), 21α-methylmelianodiol (7), and 21ß-methylmelianodiol (8), were isolated from an EtOH extract of the stems of Brucea mollis. Their structures were elucidated by means of spectroscopic methods including 1D- and 2D-NMR techniques and mass spectrometry. In the in vitro assays, compound 6 exhibited significant cytotoxic activity against A549 and BGC-823 cancer cells with IC50 values of 1.16 and 3.01â µM, respectively. At a concentration of 10â µM, compounds 1-5, 7, and 8 were found to inhibit NO production in mouse peritoneal macrophages with inhibitory ratios ranging from 39.8±7.7 to 68.2±4.5%.
Subject(s)
Antineoplastic Agents, Phytogenic/chemistry , Brucea/chemistry , Triterpenes/chemistry , Animals , Antineoplastic Agents, Phytogenic/isolation & purification , Antineoplastic Agents, Phytogenic/toxicity , Cell Survival/drug effects , Humans , Macrophages/drug effects , Macrophages/metabolism , Magnetic Resonance Spectroscopy , Mice , Molecular Conformation , Nitric Oxide/metabolism , Plant Stems/chemistry , Triterpenes/isolation & purification , Triterpenes/toxicityABSTRACT
Four new neolignans, wilfordiols A-D (1-4), together with five known compounds (5-9), were isolated from an aqueous extract of the dried leaves of Tripterygium wilfordii. Their structures were determined by spectroscopic methods, including 1D and 2D NMR, HRESIMS, and CD experiments. The anti-inflammation activities of compounds 1-9 were evaluated by the inhibitory effect on NO production, in vitro.
Subject(s)
Anti-Inflammatory Agents/chemistry , Drugs, Chinese Herbal/chemistry , Lignans/chemistry , Tripterygium/chemistry , Anti-Inflammatory Agents/isolation & purification , Anti-Inflammatory Agents/pharmacology , Drugs, Chinese Herbal/isolation & purification , Drugs, Chinese Herbal/pharmacology , Lignans/isolation & purification , Lignans/pharmacology , Molecular Structure , Nitric Oxide/antagonists & inhibitors , Plant Leaves/chemistry , Plants, Medicinal/chemistryABSTRACT
Five new 9,10-anthraquinones (1-5) were isolated from an ethanol extract of the roots of Knoxia valerianoides. Their structures including absolute configuration of 1 were determined by spectroscopic analysis. Compounds 4 and 5 showed moderate activity against nitrogen oxide production in macrophages induced by lipopolysaccharide, at 10(- 5) M, with inhibition ratios of 50.4 ± 3.6 and 41.7 ± 2.1%, respectively.
Subject(s)
Anthraquinones/isolation & purification , Drugs, Chinese Herbal/isolation & purification , Plants, Medicinal/chemistry , Rubiaceae/chemistry , Animals , Anthraquinones/chemistry , Anthraquinones/pharmacology , Drugs, Chinese Herbal/chemistry , Drugs, Chinese Herbal/pharmacology , Lipopolysaccharides/pharmacology , Macrophages, Peritoneal/drug effects , Mice , Molecular Structure , Nitric Oxide/biosynthesis , Plant Roots/chemistryABSTRACT
Eight new linear polyacetylene glucosides (1-8), containing two C(10)-, one C(13)- and five C(14)-acetylenes, together with three known polyacetylenes (9-11) were isolated from the florets of Carthamus tinctorius L. Their structures were elucidated by means of spectroscopic methods and chemical evidence. The absolute configurations of compounds 3-9 were confirmed by Snatzke and Gerards's method, observing the induced circular dichroism after addition of dirhodium tetrakis (trifluoroacetate) [Rh(2)(OCOCF(3))(4)] in CHCl(3). All the isolated compounds (1-11) were also tested for inhibitory activities against LPS-induced NO production in murine macrophages and just showed weak activities at concentrations of 1×10(-5)M.