RESUMEN
Accurate assessment of the carcinogenic potential of oral mucosal diseases can significantly reduce the prevalence of oral cancer. We speculate that precancerous stem cells (pCSCs) arise during the evolution of carcinomas based on long-term experimental findings, published literature, and the cancer stem cell (CSC) theory, wherein pCSCs exist in precancerous lesions and have characteristics of both CSCs and normal stem cells. This apparently contradictory feature may be the foundation of the reversible transformation of precancerous lesions. Predicting malignant transformation in potentially malignant oral illnesses would allow for focused treatment, prognosis, and secondary prevention. Currently available clinical assays for chromosomal instability and DNA aneuploidy have several deficiencies. We hope that our study will increase attention to pCSC research and lead to the development of novel strategies for the prevention and treatment of oral cancer by identifying pCSC markers.
Asunto(s)
Carcinoma de Células Escamosas , Neoplasias de la Boca , Lesiones Precancerosas , Humanos , Mucosa Bucal , Lesiones Precancerosas/genética , Lesiones Precancerosas/patología , Neoplasias de la Boca/genética , Carcinoma de Células Escamosas/patología , Células Madre Neoplásicas/patología , Transformación Celular Neoplásica/patologíaRESUMEN
Increased intracellular reactive oxygen species (ROS) are involved in doxorubicin (DOX)-induced myocardial cell apoptosis, and paeoniflorin (PEF) has been shown to exert an antioxidant effect. The aim of the present study was to explore the protective effect of PEF on DOX-induced myocardial cell apoptosis and the underlying mechanisms. In cultured H9c2 cells, different concentrations (1, 10, or 100 µmol/L) of PEF was added for 2 h prior to exposure to DOX (5 µmol/L) for 24 h. Cell apoptosis was evaluated by hoechst 33342 staining, and caspase-3 expression and activity. The mRNA and protein expression of NADPH oxidase (NOX) 2 and NOX4 was determined by real-time polymerase chain reaction and Western blot, respectively. Intracellular ROS and NOX activity were measured by assay kit. The results showed that DOX significantly increased myocardial cell apoptosis, increased caspase-3 expression and activity concomitantly with enhanced ROS production, and increased NOX2, NOX4 mRNA and protein expression, and NOX activity. These effects were remarkably inhibited by pretreatment of PEF. Our results suggested that PEF has a protective effect against DOX-induced myocardial cell apoptosis through a mechanism involving a decrease in ROS production by inhibition of NOX2, NOX4 expression, and NOX activity.
Asunto(s)
Antibióticos Antineoplásicos/toxicidad , Apoptosis/efectos de los fármacos , Benzoatos/farmacología , Hidrocarburos Aromáticos con Puentes/farmacología , Doxorrubicina/toxicidad , Glucósidos/farmacología , Miocitos Cardíacos/efectos de los fármacos , NADPH Oxidasas/antagonistas & inhibidores , Animales , Apoptosis/genética , Caspasa 3/genética , Caspasa 3/metabolismo , Células Cultivadas , Interacciones Farmacológicas , Glicoproteínas de Membrana/antagonistas & inhibidores , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Monoterpenos , Miocitos Cardíacos/metabolismo , NADPH Oxidasa 2 , NADPH Oxidasa 4 , NADPH Oxidasas/genética , NADPH Oxidasas/metabolismo , ARN Mensajero/genética , Ratas , Especies Reactivas de Oxígeno/metabolismoRESUMEN
A key objective for herbicide research is to develop new compounds with improved bioactivity. Protoporphyrinogen IX oxidase (PPO) is an essential target for herbicide discovery. Here, we report using an in silico structure-guided optimization approach of our previous lead compound 1 and designed and synthesized a new series of compounds 2-6. Systematic bioassays led to the discovery of a highly potent compound 6g, 1-methyl-3-(2,2,7-trifluoro-3-oxo-4-(prop-2-yn-1-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione, which exhibited an excellent and wide spectrum of weed control at the rates of 30-75 g ai/ha by the postemergence application and is relatively safe on maize at 75 g ai/ha. Additionally, the Ki value of 6g to Nicotiana tabacum PPO (NtPPO) was found to be 2.5 nM, showing 3-, 12-, and 18-fold higher potency relative to compound 1 (Ki = 7.4 nM), trifludimoxazin (Ki = 31 nM), and flumioxazin (Ki = 46 nM), respectively. Furthermore, molecular simulations further suggested that the thieno[2,3-d]pyrimidine-2,4-dione moiety of 6g could form a more favorable π-π stacking interaction with the Phe392 of NtPPO than the heterocyclic moiety of compound 1. This study provides an effective strategy to obtain enzyme inhibitors with improved performance through molecular simulation and structure-guided optimization.
Asunto(s)
Herbicidas , Malezas , Protoporfirinógeno-Oxidasa/antagonistas & inhibidores , Pirimidinas/farmacología , Herbicidas/farmacología , Relación Estructura-Actividad , Control de MalezasRESUMEN
Protoporphyrinogen oxidase (PPO, EC 1.3.3.4) is an effective target for green herbicide discovery. In this work, we reported the unexpected discovery of a novel series of N-phenylaminomethylthioacetylpyrimidine-2,4-diones (2-6) as promising PPO inhibitors based on investigating the reaction intermediates of our initially designed N-phenyluracil thiazolidinone (1). An efficient one-pot procedure that gave 41 target compounds in good to high yields was developed. Systematic Nicotiana tabacum PPO (NtPPO) inhibitory and herbicidal activity evaluations led to identifying some compounds with improved NtPPO inhibition potency than saflufenacil and good post-emergence herbicidal activity at 37.5-150 g of ai/ha. Among these analogues, ethyl 2-((((2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-(trifluoromethyl)-3,6-dihydropyrimidin-1(2H)-yl)phenyl)amino)methyl)thio)acetate (2c) (Ki = 11 nM), exhibited excellent weed control at 37.5-150 g of ai/ha and was safe for rice at 150 g of ai/ha, indicating that compound 2c has the potential to be developed as a new herbicide for weed management in paddy fields. Additionally, our molecular simulation and metabolism studies showed that the side chains of compound 2c could form a hydrogen-bond-mediated seven-membered ring system; substituting a methyl group at R1 could reinforce the hydrogen bond of the ring system and reduce the metabolic rate of target compounds in planta.
Asunto(s)
Inhibidores Enzimáticos , Herbicidas , Inhibidores Enzimáticos/farmacología , Herbicidas/farmacología , Protoporfirinógeno-Oxidasa , Nicotiana , Control de MalezasRESUMEN
Strigolactones (SLs) are plant hormones that play various roles in plant physiology, including provoking the germination of parasitic weeds Orobanche and Striga. A family of α/ß-hydrolases have been proposed to be the SL receptor proteins. Effective assays for measuring the activity of SL receptors could promote the development of SL-related biology and chemistry. In this study, we developed a new approach called pharmacophore-linked probe virtual screening (PPVS). Its application yielded an effective "off-on" probe named Xilatone Red (XLR). This probe showed a broad spectrum and excellent sensitivity toward SL receptors, including ShD14 (Striga D14), for which the detection limit was determined to be in the micromolar range, outperforming that of the commercial fluorogenic agonist Yoshimulactone Green (YLG). Upon hydrolysis by SL receptors, XLR provided fluorogenic and colorimetric signaling responses. Furthermore, XLR could induce germination of Phelipanche aegyptiaca seeds and prevent Arabidopsis max4-1 branching defects at micromolar concentrations. Our molecular simulations revealed the essential factors in the molecular perception of XLR. We anticipate that this study can prompt the discovery of high-performance SL agonists/antagonists to combat parasitic weeds.
Asunto(s)
Orobanche , Striga , Germinación , Compuestos Heterocíclicos con 3 Anillos , LactonasRESUMEN
Protoporphyrinogen oxidase (PPO, EC 1.3.3.4) is an important target for green agrochemical discovery. Herein, a novel N-phenylisoxazoline-thiadiazolo[3,4-a]pyridazine herbicidal active scaffold was designed by the scaffold hybridization strategy. Systematic structural optimization enabled the discovery of a series of derivatives with excellent weed control at 9.375-150 g ai/ha by the post-emergent application. Some derivatives exhibited improved Nicotiana tabacum PPO (NtPPO)-inhibitory activity than fluthiacet-methyl. Of these, 2b, with Ki = 21.8 nM, displayed higher weed control than fluthiacet-methyl at the rate of 12-75 g ai/ha, and selective to maize at 75 g ai/ha. In planta, 2b was converted into a bioactive metabolite 5 (Ki = 4.6 nM), which exhibited 4.6-fold more potency than 2b in inhibiting the activity of NtPPO. Molecular dynamics simulation explained that 5 formed stronger π-π interaction with Phe392 than that of 2b. This work not only provides a promising lead compound for weed control in maize fields but is also helpful to understand the molecular mechanism and basis of the designed hybrids.
Asunto(s)
Herbicidas , Malezas , Protoporfirinógeno-Oxidasa , Piridazinas , Inhibidores Enzimáticos/farmacología , Herbicidas/farmacología , Protoporfirinógeno-Oxidasa/genética , Piridazinas/farmacología , Control de MalezasRESUMEN
BACKGROUND: Benign immunoglobulin G4 (IgG4)-related orbital disease (IgG4-ROD)-characterized as tumors mimicking malignant orbital lymphoma (OL)-responds well to steroids, instead of chemotherapy, radiotherapy and/or surgery of OL. The objective of this study was to report the differences in computed tomography (CT) features and- serum IgG4 levels of IgG4-ROD and OL. METHODS: This study retrieved records for patients with OL and IgG4-ROD from a pathology database during an eight-year-and-five-month period. We assessed the differences between 16 OL patients with 27 lesions and nine IgG4-ROD patients with 20 lesions according to prebiopsy CT features of lesions and prebiopsy serum IgG4 levels and immunoglobulin G (IgG) levels This study also established the receiver-operating curves (ROC) of precontrast and postcontrast CT Hounsfield unit scales (CTHU), serum IgG4 levels, serum IgG levels and their ratios. RESULTS: Significantly related to IgG4-ROD (all p < 0.05) were the presence of lesions with regular borders, presence of multiple lesions-involving both lacrimal glands on CT scans-higher median values of postcontrast CTHU, postcontrast CTHU/precontrast CTHU ratios, serum IgG4 levels and serum IgG4/IgG level ratios. Compared to postcontrast CTHU, serum IgG4 levels had a larger area under the ROC curve (0.847 [95% confidence interval (CI): 0.674-1.000, p = 0.005] vs. 0.766 [95% CI: 0.615-0.917, p = 0.002]), higher sensitivity (0.889 [95% CI: 0.518-0.997] vs. 0.75 [95% CI: 0.509-0.913]), higher specificity (0.813 [95% CI: 0.544-0.960] vs. 0.778 [95% CI: 0.578-0.914]) and a higher cutoff value (≥132.5 mg/dL [milligrams per deciliter] vs. ≥89.5). CONCLUSIONS: IgG4-ROD showed distinct CT features and elevated serum IgG4 (≥132.5 mg/dL), which could help distinguish IgG4-ROD from OL.
RESUMEN
In continuation of our search for potent protoporphyrinogen IX oxidase (PPO, EC 1.3.3.4) inhibitors, we designed and synthesized a series of novel herbicidal cycloalka[d]quinazoline-2,4-dione-benzoxazinones. The bioassay results of these synthesized compounds indicated that most of the compounds exhibited very strong Nicotiana tabacum PPO (NtPPO) inhibition activity. More than half of the 37 synthesized compounds displayed over 80% control of all three tested broadleaf weeds at 37.5-150 g ai/ha by postemergent application, and a majority of them showed no phytotoxicity toward at least one kind of crop at 150 g ai/ha. Promisingly, 17i (Ki = 6.7 nM) was 6 and 4 times more potent than flumioxazin (Ki = 46 nM) and trifludimoxazin (Ki = 31 nM), respectively. Moreover, 17i displayed excellent, broad-spectrum herbicidal activity, even at levels as low as 37.5 g ai/ha, and it was determined to be safe for wheat at 150 g ai/ha in postemergent application, indicating the great potential for 17i development as a herbicide for weed control in wheat fields.
Asunto(s)
Benzoxazinas/química , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Herbicidas/química , Herbicidas/farmacología , Proteínas de Plantas/antagonistas & inhibidores , Protoporfirinógeno-Oxidasa/antagonistas & inhibidores , Quinazolinas/química , Benzoxazinas/farmacología , Diseño de Fármacos , Cinética , Proteínas de Plantas/química , Malezas/efectos de los fármacos , Malezas/enzimología , Protoporfirinógeno-Oxidasa/química , Relación Estructura-Actividad Cuantitativa , Quinazolinas/farmacología , Nicotiana/efectos de los fármacos , Nicotiana/enzimología , Control de MalezasRESUMEN
Protoporphyrinogen oxidase (PPO, EC 1.3.3.4) is a promising target for herbicide discovery. Search for new compounds with novel chemotypes is a key objective for agrochemists. Here, we describe the discovery and systematic SAR-based structure optimization of novel N-isoxazolinylphenyltriazinones 5-9 as PPO inhibitors. The in vivo herbicidal activity and in vitro Nicotiana tabacum PPO (NtPPO) inhibitory activity were explored in detail. A number of the new synthetic compounds displayed strong PPO inhibitory activity with Ki values in the nanomolar range. Some compounds exhibited excellent and broad-spectrum weed control at the rate of 9.375-37.5 g ai/ha by postemergence application and showed improved monocotyledonous weed control compared to saflufenacil. Most promisingly, ethyl 3-(2-chloro-5-(3,5-dimethyl-2,6-dioxo-4-thioxo-1,3,5-triazinan-1-yl)-4-fluorophenyl)-5-methyl-4,5-dihydroisoxazole-5-carboxylate, 5a, with a Ki value of 4.9 nM, displayed over 2- and 6-fold higher potency than saflufenacil (Ki = 10 nM) and trifludimoxazin (Ki = 31 nM), respectively. Moreover, 5a showed excellent and broad-spectrum weed control against 32 kinds of weeds at 37.5-75 g ai/ha. Rice exhibited relative tolerance to 5a at 150 g ai/ha by postemergence application, indicating that 5a could be a potential herbicide candidate for weed control in paddy fields.
Asunto(s)
Inhibidores Enzimáticos/farmacología , Herbicidas/química , Herbicidas/farmacología , Proteínas de Plantas/antagonistas & inhibidores , Protoporfirinógeno-Oxidasa/antagonistas & inhibidores , Descubrimiento de Drogas , Inhibidores Enzimáticos/química , Cinética , Proteínas de Plantas/química , Proteínas de Plantas/metabolismo , Malezas/química , Malezas/efectos de los fármacos , Malezas/enzimología , Protoporfirinógeno-Oxidasa/química , Protoporfirinógeno-Oxidasa/metabolismo , Relación Estructura-Actividad Cuantitativa , Nicotiana/química , Nicotiana/efectos de los fármacos , Nicotiana/enzimología , Control de MalezasRESUMEN
A HPLC-MS fingerprint method has been developed based on the consistent chromatographic features of the major chemical constituents among 10 batches of Hedyotis diffusa Willd. Chromatographic separation was conducted on a Hypersil-Keystone Hypurity C(18) column using methanol:water:acetic acid as the mobile phase. Major compounds, including oleanolic acid, ursolic acid and ferulic acid, were analysed by HPLC-MS. Their analysis was ascertained by comparison with data derived from the standard compounds. The HPLC-MS fingerprint was successfully applied to analyse and differentiate samples from different geographical origins, or processing methods. H. diffusa was well distinguished from Hedyotis chrysotricha by HPLC-MS. Therefore the establishment of fingerprint of H. diffusa is critical in assessing and controlling its overall quality.
Asunto(s)
Medicamentos Herbarios Chinos/análisis , Hedyotis/química , Cromatografía Líquida de Alta Presión/métodos , Espectrometría de Masas , Reproducibilidad de los ResultadosRESUMEN
Radix Astragali extract (RAE) is obtained from Astragalus membranaceus. It consists of Astragalus polysaccharide and Astragalus membranaceus saponins. In the study, we observed the subchronic toxicity of RAE in Sprague-Dawley rats and beagle dogs to evaluate the safety dosage range in clinical application. These subjects were daily administered of RAE by intra-peritoneum or vein for three consecutive months. General index were observed such as food-intake, behavior, body weight, hematological parameters, etc. Body weight, the weight of principal organ and hematology index are normal in experimental groups and control groups. The hematological biochemistry examination and histopathology examination of experimental groups are similar to control groups. In conclusion, our studies clearly demonstrated that RAE was safe without any distinct toxicity and side effects, the safety dosage range is 5.7-39.9g/kg for rats and 2.85-19.95g/kg for beagle dogs, which is equal to 70 or 35 times of that of human (0.57g/kg, say, average BW 70kg), respectively.
Asunto(s)
Astragalus propinquus/toxicidad , Conducta Animal/efectos de los fármacos , Medicamentos Herbarios Chinos/toxicidad , Animales , Astragalus propinquus/química , Peso Corporal/efectos de los fármacos , Perros , Relación Dosis-Respuesta a Droga , Medicamentos Herbarios Chinos/administración & dosificación , Ingestión de Alimentos/efectos de los fármacos , Tamaño de los Órganos/efectos de los fármacos , Raíces de Plantas/toxicidad , Plantas Medicinales/toxicidad , Polisacáridos/aislamiento & purificación , Polisacáridos/toxicidad , Ratas , Ratas Sprague-Dawley , Saponinas/aislamiento & purificación , Saponinas/toxicidad , Especificidad de la EspecieRESUMEN
The inflammatory response is important in the pathogenesis of myocardial ischemia/reperfusion (I/R) injury. Picroside II, the primary active constituent of Picrorhizae, has been reported to protect the myocardium from I/R-induced injury, however, the exact mechanism underlying these protective effects remains unclear. The aim of the present study was to investigate the mechanism underlying the protective effects of picroside II on I/R-induced myocardial injury. Adult male Sprague-Dawley rats underwent 1 h left coronary artery occlusion followed by 3 h reperfusion. Picroside II was administered (10 mg/kg) via the tail vein 30 min prior to left coronary artery occlusion. The results revealed that pretreatment of picroside II could significantly alleviate I/R-induced myocardial injury concomitantly with a decrease in inflammatory factor production. In addition, picroside II was also able to decrease high mobility group box 1 (HMGB1) expression, and release and downregulate the expression of the receptor for advanced glycation end products (RAGE), toll-like receptor (TLR)-2 and TLR-4. Furthermore, picroside II was able to inhibit nuclear factor-κB (NF-κB) activation. The results indicated that the protective effect of picroside II on I/R-induced myocardial injury was associated, at least partly, with inhibition of the inflammatory response by suppressing the HMGB1-RAGE/TLR-2/TLR-4-NF-κB signaling pathway.
RESUMEN
Doxorubicin (DOX) is an effective anthracycline anti-tumor antibiotic. Because of its cardiotoxicity, the clinical application of DOX is limited. Paeoniflorin (PEF), a monoterpene glucoside extracted from the dry root of Paeonia, is reported to exert multiple beneficial effects on the cardiovascular system. The present study was designed to explore the protective effect of PEF against DOX-induced cardiomyocyte apoptosis and the underlying mechanism. In cultured H9c2 cells, PEF (100 µmol/l) was added for 2 h prior to exposure to DOX (5 µmol/l) for 24 h. Cell viability, creatine kinase activity, cardiomyocyte apoptosis, intracellular reactive oxygen species (ROS) levels, and the expression of microRNA-1 (miR-1) and B-cell lymphoma 2 (Bcl-2) were measured following treatment with PEF and/or DOX. The results showed that treatment with DOX notably induced cardiomyocyte apoptosis, concomitantly with enhanced ROS generation, upregulated miR-1 expression and downregulated Bcl-2 expression. These effects of DOX were significantly inhibited by pretreatment of the cells with PEF. These results suggest that the inhibitory effect of PEF on DOX-induced cardiomyocyte apoptosis may be associated with downregulation of miR-1 expression via a reduction in ROS generation.
RESUMEN
Reactive oxygen species (ROS)induced mitochondrial dysfunction plays an important role in cardiomyocyte apoptosis during myocardial ischemia/reperfusion (I/R) injury. Picroside â ¡, isolated from Picrorhiza scrophulariiflora Pennell (Scrophulariaceae), has been reported to protect cardiomyocytes from hypoxia/reoxygenation (H/R)induced apoptosis, but the exact mechanism is not fully clear. The aim of the present study was to explore the protective effects of picroside â ¡ on H/Rinduced cardiomyocyte apoptosis and the underlying mechanism. In the H9c2 rat cardiomyocyte cell line, picroside â ¡ (100 µg/ml) was added for 48 h prior to H/R. The results showed that picroside â ¡ markedly inhibited H/Rinduced cardiomyocyte apoptosis. In addition, picroside â ¡ was also able to decrease the opening degree of mitochondrial permeability transition pore (mPTP), increase the mitochondrial membrane potential, inhibit cytochrome c release from mitochondria to cytosol and downregulate caspase3 expression and activity concomitantly with the decreased ROS production. These results suggested that picroside â ¡ inhibited H/Rinduced cardiomyocyte apoptosis by ameliorating mitochondrial function through a mechanism involving a decrease in ROS production.
Asunto(s)
Cinamatos/farmacología , Glucósidos Iridoides/farmacología , Mitocondrias Cardíacas/metabolismo , Miocitos Cardíacos/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Animales , Caspasa 3/metabolismo , Hipoxia de la Célula/efectos de los fármacos , Línea Celular , Mitocondrias Cardíacas/patología , Proteínas de Transporte de Membrana Mitocondrial/metabolismo , Poro de Transición de la Permeabilidad Mitocondrial , Daño por Reperfusión Miocárdica/tratamiento farmacológico , Daño por Reperfusión Miocárdica/metabolismo , Daño por Reperfusión Miocárdica/patología , Miocitos Cardíacos/patología , RatasRESUMEN
The aim of the present study was to investigate the role of immune regulatory molecules B7-H3 [also known as cluster of differentiation 276] and triggering receptor expressed on myeloid cell-like transcript-2 (TLT-2) in patients with oral squamous cell carcinoma (OSCC). Human OSCC samples were obtained from 76 patients (female, 32; male, 44; age range, 23-81 years; median age, 50.9 years) that underwent resection for OSCC at Peking University Shenzhen Hospital (Shenzhen, China) between 2007 and 2010. In addition, control oral mucosal samples were obtained from 76 healthy individuals (female, 36; male, 40; age range, 21-62 years; median age, 45.3 years) during wisdom tooth extraction. Protein and gene expression levels of B7-H3 and TLT-2 were determined by immunohistochemical analysis and reverse transcription-polymerase chain reaction (RT-PCR). In the healthy oral mucosa samples, B7-H3 expression was identified to be weak, while the expression of TLT-2 was only detected sporadically in the cell membrane and cytoplasm. By contrast, the two regulatory molecules were widely expressed in the aforementioned localizations in human OSCC specimens upon immunohistochemical examination. Furthermore, quantitative RT-PCR confirmed the presence of significantly higher B7-H3 and TLT-2 expression levels in OSCC specimens compared with the oral mucosa of healthy individuals. The significantly higher expression levels of B7-H3 and TLT-2 in human OSCC specimens may indicate an inhibitory role of these molecules in the antitumoral immune response. To investigate interactions between these two molecules and individual antitumoral immune response in OSCC patients, prospective clinical studies with an adequate sample size are required.
RESUMEN
Lysophosphatidylcholine (LPC) plays an important role in atherosclerosis through initiation of endothelial inflammation response. Paeoniflorin (PEF), isolated from the dry root of Paeonia, has been reported to exert an anti-inflammatory effect, but the exact mechanism is not fully understood. The aim of this study was to investigate the inhibitory effects of PEF on LPC-induced inflammatory factor production and the underlying mechanisms. In human umbilical vein endothelial cells (HUVECs), different concentrations (1, 10 or 100 µmol/l) of PEF were added 2 h prior to exposure to LPC (10 mg/l) for 24 h. The results showed that PEF significantly inhibited LPC-induced inflammatory factor production. In addition, PEF was also able to suppress the enhanced high mobility group box-1 (HMGB1) expression and release, upregulated expression of receptor for advanced glycation end product (RAGE), Toll-like receptor (TLR)-2 and TLR-4, and increased nuclear factor-κB (NF-κB) activity induced by LPC. Our results suggest that PEF suppresses LPC-induced inflammatory factor production through inhibition of the HMGB1-RAGE/TLR-2/TLR-4-NF-κB pathway.