Neolignans from Piper betle Have Synergistic Activity against Antibiotic-Resistant Staphylococcus aureus.

A phytochemical investigation of an extract of the leaves of Piper betle, guided by a synergistic antibacterial screen, led to the isolation and structural elucidation of 10 new neolignans, Pibeneolignan A-J (1-10), together with 11 known compounds. The structures and absolute configurations of the new compounds were elucidated on the basis of spectroscopic data, single-crystal X-ray diffraction analysis, and experimental and calculated ECD investigations. Compounds 1 and 2 are new naturally occurring neolignan skeletons, based on the cyclohept-2-ene-1,4-dione framework. We propose that these natural products are biosynthetically formed from bicyclic [3.2.1] neolignans by oxidative cleavage and ring opening at C-1' and C-2'. Among these compounds, 9, 13, 15, and 16, in combination with norfloxacin against an effluxing S. aureus strain (SA1199B), exhibited significant synergistic activity with fractional inhibitory concentration indices (FICIs) of 0.078, 0.156, 0.125, and 0.25, respectively. Bacterial growth curves, ethidium bromide (EtBr) efflux, and qRt-PCR were further employed to verify their synergistic antibacterial mechanism. Furthermore, computational molecular modeling suggested the binding of compounds 14-17 and 19 to the active site of the modeled structure of the NorA efflux pump, which is the main efflux pump in SA1199B.

Baicalin inhibits autophagy induced by influenza A virus H3N2.

Baicalin, a natural product isolated from Scutellariaradix, has been reported to have significant in vivo and in vitro anti-influenza virus activity, but the underlying mechanism remains poorly understood. In this study, we found that baicalin inhibited autophagy induced by influenza virus A3/Beijing/30/95 (H3N2) in both A549 and Ana-1 cells. The results showed that H3N2 induced autophagy by suppressing mTOR signaling pathway, which however could be significantly inhibited by baicalin. Baicalin could suppress the expression of Atg5-Atg12 complex and LC3-II, and attenuate autophagy induced by starvation. Thus, the inhibition of autophagy induced by virus may account for the antiviral activities of baicalin against H3N2. Autophagy may be a potential marker in developing novel anti-influenza drugs.

Qiangzhi decoction protects mice from influenza A pneumonia through inhibition of inflammatory cytokine storm.

OBJECTIVE: To investigate the preventive effects of Qiangzhi Decoction (, QZD) on influenza A pneumonia through inhibition of inflammatory cytokine storm in vivo and in vitro. METHODS: One hundred ICR mice were randomly divided into the virus control, the Tamiflu control and the QZD high-, medium-, and low-dose groups. Mice were infected intranasally with influenza virus (H1N1) at 10 median lethal dose (LD50). QZD and Tamiflu were administered intragastrically twice daily from day 0 to day 7 after infection. The virus control group was treated with distilled water alone under the same condition. The number of surviving mice was recorded daily for 14 days after viral infection. The histological damage and viral replication and the expression of inflammatory cytokines were monitored. Additionally, the suppression capacity on the secretion of regulated on activation normal T cells expressed and secreted (RANTES) and tumor necrosis factor-α (TNF-α) in epithelial and macrophage cell-lines were evaluated. RESULTS: Compared with the virus control group, the survival rate of the QZD groups significantly improved in a dose-dependent manner (P<0.05), the viral titers in lung tissue was inhibited (P<0.05), and the production of inflammatory cytokines interferon-γ (IFN-γ), interleukin-6 (IL-6), TNF-α, and intercellular adhesion molecule-1 (ICAM-1) were suppressed (P<0.05). Meanwhile, the secretion of RANTETS and TNF-α by epithelial and macrophage cell-lines was inhibited with the treatment of QZD respectively in vitro (p<0.05) CONCLUSIONS: The preventive effects of QZD on influenza virus infection might be due to its unique cytokine inhibition mechanism. QZD may have significant therapeutic potential in combination with antiviral drugs.

131I-chTNT radioimmunotherapy of 43 patients with advanced lung cancer.

UNLABELLED: The treatment of advanced lung cancer remains a major challenge in clinical medicine, justifying an urgent need for new therapeutic approaches. In a rather unique international collaboration, 43 patients with advanced lung cancer were treated using iodine-131-labeled tumor necrosis therapy chimeric antibody (131I-chTNT). METHODS: Patients were treated either with intravenous (i.v.) infusion (n = 22), intratumoral injection using a computer tomography (CT)-guided catheter (n = 16), or combination i.v. and intratumoral infusion (n = 5). All patients, regardless of route of administration, received 2 doses of 131I-chTNT on days 1 and 14. RESULTS: The results showed that of those patients receiving i.v. injection alone, 2 achieved partial response (PR) (9%), 16 had stable disease (73%), and 4 progressed (18%). Of those patients receiving intratumoral injection only, 1 had a complete response (CR) (6%), 8 achieved PR (50%), 7 had stable disease (44%), and none (0%) progressed. Finally, of those patients receiving both i.v. and intratumoral administration, 1 had a CR (20%), 1 achieved PR (20%), 2 had stable disease (40%), and 1 (20%) showed progression. CONCLUSIONS: These promising results demonstrate that sufficient doses of radiolabeled antibody can be safely delivered to tumors to cause significant therapeutic effects in advanced lung cancer.

Pivotal study of iodine-131-labeled chimeric tumor necrosis treatment radioimmunotherapy in patients with advanced lung cancer.

PURPOSE: Tumor necrosis treatment (TNT) uses degenerating tumor cells and necrotic regions of tumors as targets for radioimmunotherapy. Previous studies in animal tumor models and clinical trials have demonstrated that when linked to the therapeutic radionuclide iodine-131, recombinant chimeric TNT antibody ((131)I-chTNT) can deliver therapeutic doses to tumors regardless of the location or type of malignancy. Therapeutic efficacy and toxicity of (131)I-chTNT in advanced lung cancer patients were studied in this pivotal registration trial. PATIENTS AND METHODS: Patients with advanced lung cancer were treated with systemic or intratumoral injection of (131)I-chTNT in eight oncology centers in China. The objective response rate (ORR) was assessed as the primary end point. RESULTS: All 107 patients who were entered onto the study and completed therapy had experienced treatment failure after prior radiotherapy or chemotherapy a mean of three times. The results showed an ORR of 34.6% (complete response, 3.7%; partial response, 30.8%; no change, 55.1%; and progressive disease, 10.3%) in all patients and 33% in 97 non-small-cell lung cancer patients. A biodistribution study demonstrated excellent localization of the radioactivity in tumors in both systemically and intratumorally injected patients. The most obvious adverse side effect was mild and reversible bone marrow suppression. CONCLUSION: Radioimmunotherapy with (131)I-chTNT was well tolerated and can be used systemically or locally to treat refractory tumors of the lung.

Systemic genetic transfer of p21WAF-1 and GM-CSF utilizing of a novel oligopeptide-based EGF receptor targeting polyplex.

Based on the fact that aberrant overexpression of some growth factor receptors was observed in a variety of human cancer cells, a novel nonviral gene delivery system GE7, which contains a 16-amino-acid ligand for identifying EGF receptor was constructed for tumor-targeted gene therapy. Intravenous administration of GE7 system revealed that it has the ability to target beta-galactosidase (beta-gal) reporter gene into murine hepatoma (Hepa) cells. Owing to the limited antitumor effects elicited by a single-gene transfer, recent efforts to treat malignancy using combined gene therapy have been accomplished with varying degrees of success. In this study, the human cyclin-dependent kinase inhibitor gene p21(WAF-1) and the murine cytokine gene granulocyte-macrophage colony-stimulating factor (GM-CSF) were used simultaneously for in vivo gene therapy through systemic injection of the EGF R targeted GE7/DNA complex into murine hepatoma-bearing mice. The results demonstrated that combined administration of p21(WAF-1) and GM-CSF could remarkably inhibit the growth of subcutaneously transplanted hepatoma Hepa cells, and significantly increase the survival rate of tumor-bearing mice. The activities of natural killer (NK) cells and specific cytotoxic T lymphocytes (CTL) were clearly enhanced after combined gene therapy. In vitro experiments showed that p21(WAF-1) gene transfer exhibited a suppressive function on the growth of Hepa cells and the expression of H-2K(b) and B7-1 molecules on Hepa cells increased significantly after combined genes delivery. All these results suggested that the GE7 system was able to target therapeutic genes efficiently to cancer cells, which showed high EGF R expression. The cotransfer of p21(WAF-1) and GM-CSF genes apparently inhibited the growth of tumors through (a) the arrest of tumor cell growth and (b) the enhancement of systemic antitumor immunity.