Connective tissue disease-associated interstitial lung disease (CTD-ILD) is a systemic autoimmune disease with high morbidity and hazard, characterized by progressive pulmonary inflammation and fibrosis. The monomer formulation of polydatin and curcumin (PD + Cur) for lung injury in CTD-ILD was optimized from Curcumae Longae Rhizoma (Curcuma Longa L.) and Polygoni Cuspidati Rhizoma Et Radix (Polygonum cuspidatum Sieb. et Zucc.). Mice with CTD-ILD-like lung injury were established by a single intratracheal drip of bleomycin. After intervening in model mice for 4 weeks, PD + Cur attenuated alveolar atrophy, fibrillar collagen formation, and thickened alveolar septa in the lung, improved serum biomarkers TOLLIP, MUC5B, KL-6, SP-D, and RCN3, and suppressed serum immunoinflammatory factors IL-6, CCL-18, and SF. The transcriptome sequencing showed that PD + Cur ameliorated CTD-ILD mainly by regulating aberrant immunoinflammation, which was further confirmed by proteomics that the PI3K/AKT/TGF-β pathway was a key pathway. Further, PD + Cur was found to affect amino acid metabolism in the serum significantly. The B-type receptor for GABA (GABBR) agonist baclofen was further found to attenuate CTD-ILD-like lung injury and modulate PI3K/AKT/TGF-β signaling. However, the inhibition of AKT, transforming growth factor beta receptor type 3 (TGFβR3), a key indicator downstream of PI3-kinase subunit p85-alpha (PI3KR1), by PD + Cur was reversed after intervention with the GABBR receptor inhibitor CGP52432. PD + Cur has an ameliorative effect on CTD-ILD-like lung injury by targeting GABBR to modulate the PI3K/AKT/TGF-β pathway.

Ethnopharmacological relevance: Recently, interstitial lung disease (ILD) morbidity and mortality have been increasing with insidious epidemiological characteristics. Jianghu decoction (JH) is an effective Chinese medicine for ILD.Aim of the study: We aimed to reveal the material basis and mechanism of action of JH in the treatment of ILD. Materials and methods: In this study, an ILD mouse model was constructed with bleomycin. HE staining, transcriptome analysis, parallel reaction monitoring-mass spectrometry (PRM-MS), UPLC-MS, and western blotting assays were conducted.Results: HE staining results showed that JH effectively reduced inflammation and fibrosis foci in the lungs of the ILD model. Furthermore, transcriptome analysis revealed that JH regulates a set of biological signaling pathways related to immune inflammation and fibrosis. PRM-MS combined with western blotting was applied to detect inflammation and fibrosis involving proteins in lung tissue. JH effectively reversed the aberrant expression of HMGB1, RAGE, SEPTIN4, ACTA2, and ITGAV proteins in the model group. AMPK was identified as the core upstream regulatory protein for JH-mediated ILD regulation. In addition, UHPLC-MS technology was applied to determine the active ingredients of JH. A total of 80 components were identified from JH, and polydatin (PD) was identified as the active ingredient that effectively alleviated lung fibrosis and inflammatory injury in ILD mice. To illustrate the molecular regulatory network of JH and PD in alleviating lung fibrosis and inflammatory injury, we also examined inflammation and fibrosis-related molecules downstream of the AMPK pathway with RT-qPCR and western blotting.Conclusions: The results showed that both JH and its active component PD exert synergistic inhibition on pulmonary fibrosis and inflammation. Specifically, the AMPK/PGC1 & alpha;/PPAR & gamma; signaling pathway was activated, and the AMPK/HMGB1/RAGE signaling pathway was inhibited in ILD lungs responding to JH or PD administration.

作为《金匮要略》五种水气病之一,黄汗病症状表现复杂多样,病机虚实兼见,并涉及多个脏腑.种种原因,导致其理论内涵尚未得到充分的阐发.系统性红斑狼疮是现代医学累及多系统的难治性疾病.其临床表现,发展转归与黄汗病具有极高的契合度,将系统性红斑狼疮归入黄汗病范畴具有合理性.素有肝肾亏虚、阳明热盛,又因调摄不慎,外感寒湿之邪,是系统性红斑狼疮的关键病机.基于《伤寒杂病论》黄汗病以及其余相关理论,针对系统性红斑狼疮肾脏、皮肤黏膜、骨骼肌肉、消化、呼吸、心脏、神经等系统受累所表现出的各种临床表现,以补益肝肾、清解阳明、散寒除湿为原则,分别提出了相应的经方治疗,为系统性红斑狼疮的现代中医诊治提供了思路.

Reactive oxygen species (ROS)-mediated alveolar epithelial cell (AEC) injury and apoptosis are considered to be the initiating link of idiopathic pulmonary fibrosis (IPF), and protecting AECs can alleviate IPF. This study aimed to explore the protective effect of number 2 Feibi recipe (FBR-2) medicated serum on H2O2-mediated oxidative stress injury in AECs and further explore its mechanism. We found that FBR-2 can regulate downstream antioxidant enzymes expression by activating nuclear factor erythroid 2-related factor 2 (Nrf2), reducing the level of intracellular ROS, protecting mitochondrial function and improving cell survival. FBR-2 can also activate mitophagy through the PINK1/Parkin pathway. Moreover, FBR-2 can inhibit apoptosis by blocking the mitochondrial apoptosis mechanism. In summary, these data indicate that FBR-2 medicated serum can inhibit H2O2-mediated oxidative stress damage in AECs by regulating the balance of mitophagy/apoptosis. This study provides new evidence for the antifibrotic effect of FBR-2 and provides new drug candidates for the clinical treatment of IPF.

周平安教授治疗慢性咳嗽时,讲究中西医医理汇通,辨病与辨证相结合,对于咳嗽变异性哮喘、嗜酸粒细胞性支气管炎及变应性咳嗽,抓住其过敏本质,缓解气道挛急及敏感状态;对于上气道咳嗽综合征及胃食管反流性咳嗽,详查其病位本源,消除刺激因素;同时,治咳时注重咽喉局部症状的辨证及整体气机的调理;治痰时,重视痰的真假及性质的辨证以及痰瘀同治理论的运用;参照患者宿疾、体质特点,详参药性,明辨药用,是中西医结合运用的典范,在临床中获效颇丰,其治疗思路和方法值得临床借鉴和学习.

Calycosin (CA) is a flavonoid extracted from the root of Astragalus membranaceus and has antioxidant, anti-inflammation, and antiapoptosis properties. The objective of this study was to investigate the efficacy of CA in protecting against pulmonary fibrosis. CA (14 mg/kg) and SB216763 (20 mg/kg) were administrated to bleomycin-induced pulmonary fibrosis mice for 3 weeks. The results concluded that CA alleviated the inflammation and collagen deposition in pulmonary fibrosis. In addition, CA reduced MDA level, enhanced SOD and TAC activities, and increased the activity of the Nrf2/HO-1 pathway. CA also regulated the expressions of apoptosis-related proteins. Moreover, CA enhanced autophagy via upregulating LC3, beclin1, PINK1, and reducing p62. CA also increased expression of LAMP1 and TFEB, and inhibited the release of lysosome enzymes from ruptured lysosomes. These results provide new evidence that CA protects against pulmonary fibrosis through inhibiting oxidative stress and apoptosis. In addition, autophagy abnormality and lysosome dysfunction are restored by CA.

Rheumatoid arthritis (RA) is an autoimmune disease that is associated with burdened personal, social, and economic costs. Enhanced understanding of RA pathogenesis and the development of effective therapies is pressingly needed. Seeking effective solution for diseases from natural medicine has become an attractive point of providing a new perspective for drug development. Polydatin (PD) has been found to be beneficial to arthritis. However, the pharmacological action of PD is weak in clinical practice due to poor aqueous solubility, chemical instability in aqueous alkaline medium, and extensive first-pass metabolism. Biodegradable nanoparticle, which is of better solubility and lower degradation, could be a good choice for PD targeted delivery to overcome these obstacles. With advantages in straightforward synthesis,1-3 mesoporous silica nanoparticles (MSNs) were chosen for developing an efficient and safe nanocarrier for PD in this study. We developed PD@MSN-FA/RGD (Figure 1A, Figures S1–S8, Table S1) as a dual-target nano-drug delivery system that aimed at folate receptor and ανβ3 integrin receptor. Drug release profiles of PD@MSN-FA/RGD were illustrated to be sustained and mass ratio dependent (Figure 1B). To further evaluate the possibility of in vivo application of PD@MSN-FA/RGD, the hemolysis test was performed in vitro and in vivo. No significant difference was observed between MSN and control (-) samples. It was demonstrated that no false negative or false-positive results, which could be caused by adsorption of hemoglobin on particle surfaces4 or toxicity of the residual surfactant,5 occurred in hemolysis assay of PD@MSN-FA/RGD. No significant hemolysis occurred with the concentration below 13.80 mg/ml, and excellent biocompatibility was displayed with the concentration below 4.60 mg/ml in vitro (Figure 1E and F). Likewise, no hemolysis effect of PD@MSN-FA/RGD was observed with dosage below 438.28 mg/kg in mice (Table S2). Moreover, no significant acute toxicity was observed in mice subjected to PD@MSN-FA/RGD administration (Table S3, Figure S9) except for slight or local liver lesions, including diffuse swelling (Figure S9B5) and local necrosis (Figure S9B3 and B4) in some samples. How these lesions being induced deserved further investigation. In addition, the performance of PD@MSN-FA/RGD in vivo was illustrated by employing a selective ion monitoring model in UHPLC-Q-Exactive Orbitrap MS. It displayed an extremely low content of PD@MSN-FA/RGD in tissues except plasma, synovial fluid, and synovial membrane, suggesting a significantly targeted delivery of PD@MSN-FA/RGD injection comparing with that of polydatin injection (Figure 1C and D, Figure S10). No significant degradation product was detected in the liver upon PD@MSN-FA/RGD injection, suggesting a lower degradation of PD with nanoparticles embedding (Figure S11). In the collagen-induced arthritis (CIA) model, joint damages were observed significantly improved upon PD@MSN-FA/RGD treatment based on vertical and horizontal diameters of hind legs and ankle joints, the thickness of footpads, as well as histopathology changes in synovial membrane and cartilage tissue (Figure 2, Tables S4–S10). The metabolic profile of PD@MSN-FA/RGD in synovial fluid was further studied. PCA and OPLS-DA results showed the availability of CIA modeling as well as the significant influence of PD@MSN-FA/RGD (R2X = 0.62, R2Y > 0.6, Q2 > 0.6) (Figure S12). Note that 115 molecules were identified from 187 ions that contributed to good separations among groups (VIP > 1 in ESI+, p < 0.05). Among the metabolites identified, 26 were found upregulated and 2 were downregulated responding to CIA modeling and significantly reversed by positive drug methotrexate and PD@MSN-FA/RGD treatment (Table S11, Figure S13). Moreover, metabolomics analysis was performed by employing IPA software. High-dose and low-dose PD@MSN-FA/RGD treatment showed compatible metabolism on the CIA model (Figure 3A and B). Numerous metabolic pathways shifted toward rheumatoid arthritis-related intermediates and metabolic endpoints were suggested by pathway analysis (Figure 3C and D). Moreover, dramatical downregulation of PD@MSN-FA/RGD on D-serine, guanine, and hypoxanthine (Figure 3E–G) indicated a strong inhibition of fibroblasts proliferation. With changes in guanine, d-serine, l-arginine, choline, kynurenic acid, and 5-methylcytosine, it was suggested that mitogen-activated protein kinase (MAPK) family proteins playing key roles in PD@MSN-FA/RGD regulation (Figure 3I). Increased expression of p38 MAPK, a crucial molecule in the progression of RA,6 was found significantly inversed upon administration of PD@MSN-FA/RGD in synovial tissues (Figure 3L, P, and S). Moreover, we found δ-guanidinovaleric acid (Figure 3H), aγ-aminobutyric acid (GABA)-receptor antagonist, increased significantly responding to CIA modeling, suggesting inhibition of GABA receptor. These changes were reversed by PD@MSN-FA/RGD administration, suggesting the promotion on GABA signaling. Based on the effect of inhibited p38 MAPK on joint inflammation, and the inhibitory role of GABA in p38 MAPK signaling, a hypothesis7 was proposed that GABA may downregulate p38 MAPK activity to suppress inflammation in RA. How does PD@MSN-FA/RGD suppress fibroblasts proliferation via the GABA-p38 MAPK pathway? To address this question, a transcriptomic study was carried out. Pathway analysis showed that GABA-p38 MAPK signaling is significantly regulated by PD@MSN-FA/RGD, consistent with that of metabolome study (Figure 3J). Intriguingly, myocardin-related transcription factor A (MRTFA), myocardin-related transcription factor B (MRTFB), and serum response factor (SRF) that played key roles in fibroblast activation were predicted as potential upstream regulators in PD@MSN-FA/RGD's regulation (Figure 3K). Upregulated mRNA expressions of MRTFA, MRTFB, and SRF in the CIA model were found reversed with PD@MSN-FA/RGD in synovial tissues to different extents (Figure 3L–O). Similar regulations were also observed at the protein level (Figure 3P–S). p38 MAPK cascades could promote the formation of ternary nucleoprotein complex and activate the early response gene transcription initiated by SRF.8 SRF functions in partnership with MRTFA/B and acts as a key mediator in fibroblasts activation.9, 10 Taken together, it was suggested that PD@MSN-FA/RGD alleviated inflammation and fibroblasts proliferation in RA by regulating GABA-p38 MAPK-MRTFs/SRF signaling pathway (Figure 4). In this work, a folate/RGD-dual-functionalized mesoporous silica nanoparticles (MSNs-FA/RGD) with reproducible and stable production, as well as good biocompatibility, was developed to carry PD to the synovial area to achieve promising clinical translation and application in RA therapy. Protective effects of PD@MSNs-FA/RGD on rheumatoid arthritis were illustrated with CIA modeling rats. PD@MSNs-FA/RGD was found targeting on GABA-p38 MAPK-MRTFs/SRF signaling pathway in vivo to exert its beneficial influence. We reported a novel drug of RA with both characterization and regulatory mechanism carefully discussed and clarified. This research was funded by the National Natural Science Foundation of China (51772032). The authors have declared no conflict of interest. Figure S1. (A and B) TEM images of MSNs, and it was observed that MSNs are spherical nanoparticles with a diameter of about 80 nm. Figure S2. Hydrodynamic diameter (A) and Zeta potential (B) of MSNs. The average hydrodynamic size of MSNs is 277.5 nm and their surface charge is 28.9 mV. Figure S3. SEM (A) and TEM (B) images of MSNs. SEM (C) and TEM (D) images of MSN-NH2. No significant influence of -NH2 modification on the spherical morphology, size, as well as mesoporous property of MSNs was observed. Figure S4. Zeta potential of MSN-NH2. The surface charge is about 16.9 mV. Figure S5. The FTIR spectra of MSNs and MSN-NH2. A new FTIR spectra band appeared at 3421 cm-1 after modification due to the stretching vibration of -NH2 groups. Figure S6. The linear relationship between the concentration of PD and their optical absorption intensity. The fitted linear equation is y = 0.04009 + 0.02998x, R2 = 0.99897. Figure S7. (A) N2 adsorption-desorption isotherms and (B) pore-size distributions of MSNs. (C) N2 adsorption-desorption isotherms and (D) pore-size distributions of PD@MSNs. Figure S8. (A) UV-Vis spectra of PD@MSN-NH2, NHS-PEG-FA, PD@MSN-FA/SH. (B) Zeta potential of PD@MSN-NH2, PD@NHS-FA/SH, PD@MSN-FA/RGD. Figure S9. H&E staining of pathological changes in response to different dosages of PD@MSN-FA/RGD after 14 days’ administration. Figure S10. UPLC-Q exactive quantitative analysis of polydatin in plasma, heart, liver, spleen, kidney, synovial fluid, and synovial membrane tissue of rats which subject to PLN injection based on selective ion monitoring (SIM)-based method. Figure S11. Metabolic trait of polydatin in vivo. 7 major metabolites generated from polydatin degradation were detected in the liver of rats which subject to polydatin injection, while none significant degradation product was detected upon PD@MSN-FA/RGD injection. Figure S12. Multi-dimensional statistics of metabolomics data. A–B. PCA analysis based on LC-MS data obtained from synovial fluid of Control, Model, Positive, high-dose PLN, and low-dose PLN group. (A) Result based on HILIC mode data; (B) Result based on RP-C18 mode data; C-H. OPLS-DA on LC-MS data of common metabolites of the control group, model group, positive group, high-dose PLN group, and low-dose PLN group. (C, F) Control vs. Model groups under HILIC and RP-C18 mode. (D, G) Model vs. high-dose PLN groups under HILIC and RP-C18 mode (E, H) Model vs. low-dose PLN groups under HILIC and RP-C18 mode; I-N. Robustness assessments of OPLS-DA model. Figure S13. Hierarchical clustering analysis on common differential metabolites detected and identified in each group. Table S1. The loading content and entrapment efficiency of PD@MSN and PD@MSN-NH2. Table S2. OD values of serum in mice subjecting to different dosages of PD@MSN-FA/RGD. Table S3. Organ coefficients of heart, liver, spleen, lung, and kidney in mice subjecting to different dosages of PD@MSN-FA/RGD. Table S4. Horizontal diameters of right hind legs (mm) Table S5. Vertical diameters of right hind legs (mm) Table S6. Horizontal diameters of left hind legs (mm) Table S7. Vertical diameters of left hind legs (mm) Table S8. Thickness of right hind footpads (mm) Table S9. Thickness of left hind footpads (mm) Table S10. Vertical and horizontal diameters of left/right ankle joints Table S11. Differential metabolites being detected and identified. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

[目的]探讨虎杖有效成分对糖尿病肾病小鼠肾组织病理改变的影响.[方法]采用自发性2型糖尿病模型KK-Ay小鼠予高脂饲料诱导3周制备DN模型,造模成功后随机分为模型组,阳性药组,大黄素、虎杖苷高、中、低剂量组,每组各6只.另设6只C57BL/6J小鼠为正常组.每天灌胃给药1次,连续干预12周后处死小鼠,取肾脏行HE,PAS染色.光镜下观察肾组织病变并进行评分,PAS染色下测定肾小球基质相对面积.电镜下观察肾组织超微结构形态学改变.[结果]与模型组比较,虎杖苷高剂量组小鼠肾小管病变显著减轻(P<0.05);大黄素高剂量组,虎杖苷各剂量组小鼠肾小球基质相对面积显著降低(P<0.01,P<0.05);大黄素各剂量可改善DN模型小鼠肾小球病变,虎杖苷中剂量可明显改善DN模型小鼠肾组织超微结构病变,足细胞足突结构基本正常.[结论]大黄素、虎杖苷能不同程度的减轻DN模型小鼠肾组织病理损伤,对肾脏组织具有保护作用.

目的 观察秦苓液对尿酸性肾病大鼠NLRP3、Caspase-1、IL-18、NF-κB mRNA转录及蛋白表达的影响,探讨该方抑制尿酸性肾病大鼠免疫炎性损伤的分子机制.方法 采用腺嘌呤灌胃伴酵母饲料喂养方法造模,成模大鼠随机分为模型组、阳性药组,秦苓液高、中、低剂量组,每组12只.选6只正常大鼠作为正常组.各组分别用药连续干预6周和8周后采用RT-PCR、Western-blot和免疫组化方法检测大鼠肾组织NLRP3、Caspase-1、NF-κB、IL-18基因和蛋白表达水平及ELISA方法检测大鼠血清IL-18蛋白表达水平.结果 与正常组比较,6周时和8周时模型组NLRP3、IL-18基因转录和蛋白表达水平及NF-κB蛋白表达水平显著上调,8周时模型组Caspase-1基因转录水平显著上调(P<0.05,P<0.01).与模型组比较,6周时和8周时秦苓液各剂量组NLRP3、NF-κB蛋白表达水平及6周时高、中剂量组和8周时低剂量组NLRP3基因转录水平显著下调,8周时低剂量组Caspase-1基因转录水平显著下调,6周时和8周时各剂量组IL-18基因转录水平及6周时高、中剂量组IL-18蛋白表达水平和8周时各剂量组IL-18蛋白表达水平显著下调(P<0.05,P<0.01).结论 秦苓液抑制尿酸性肾病模型大鼠炎性代谢性损伤,其分子机制可能与下调NLRP3、Caspase-1的水平,抑制IL-18激活NF-κB,进而减轻炎症反应有关.

目的 通过观察藤莓汤(Tengmei Decoction,TMD)对胶原诱导性(collagen-induced arthritis,CIA)大鼠滑膜中突变型P53 (Mutant P53,mt-p53)、增殖诱导配体(a proliferation-inducing ligand,APRIL),白细胞介素2 (Lnterleukin 2,IL-2)表达的影响,探讨藤莓汤抑制类风湿关节炎(rheumatoid arthritis,RA)滑膜免疫炎性损伤的分子机制.方法 建立CIA大鼠模型,中药给药组分为TMD高剂量组、TMD低剂量组,分别以TMD生药量31.8、15.9g/(kg·d-1)灌胃;模型组、阳性对照组分别予去离子水10 mL/(kg·d-1)、来氟米特1.87mg/(kg-1·d-1)灌胃;另设正常对照组,予去离子水10 mL/(kg·d-1),各组连续干预12周.干预结束后检测mt-P53、APRIL、IL-2蛋白及mRNA表达.结果 与正常组比较,模型组APRIL、mt-P53、IL-2 mRNA转录水平上调(P＜0.01);mt-P53、IL-2蛋白表达上调(P＜ 0.01,P＜0.05).与模型组比较,各治疗组APRIL mRNA转录水平,mt-P53、IL-2mRNA转录水平及蛋白表达水平下调,(P＜ 0.01,P＜0.05);结论TMD能够降低大鼠关节滑膜、血清中mt-P53、IL-2、APRIL表达水平,改善关节炎模型大鼠关节滑膜免疫炎性损伤,可能与TMD抑制关节滑膜过度增殖,降低炎症因子的表达有关.

目的 观察秦苓液对尿酸性肾病大鼠过氧化物酶体增殖物激活受体 γ 辅助激活因子-1α(peroxi-some proliferator activated receptor coactivator-1 alpha,PGC-1α)、白介素-1β(interleukin beta,IL-1β)、受激活调节正常T细胞表达和分泌因子(regulated upon activation normal T cell expressed and secreted factor,RANTES)的影响.方法采用腺嘌呤灌胃伴酵母饲料喂养大鼠的方法进行造模,成模后随机分为模型组,阳性药物组,秦苓液大、中、小剂量组,每组12只大鼠.选6只正常大鼠作为正常对照组.各组分别用药连续干预6周和8周后采用实时荧光定量逆转录聚合酶链反应(real time reverse transcription-polymerase chain reaction,RT-PCR)、蛋白免疫印迹法(Western blot)、免疫组化和酶联免疫吸附试验(enzyme linked immunosorbent assay,ELISA)检测大鼠PGC-1α、IL-1β、RANTES基因和蛋白表达水平.结果与正常对照组比较,6周时和8周时模型组PGC-1α 蛋白表达水平及8周时PGC-1α基因转录水平显著下调,6周时IL-1β基因转录、蛋白表达水平和RANTES蛋白表达水平及8周时两者水平显著上调(P<0.05,P<0.01).与模型组比较,6周时秦苓液各剂量组PGC-1α蛋白表达水平及8周时中、小剂量组PGC-1α基因水平及蛋白表达水平显著上调,6周时秦苓液各剂量组IL-1β基因转录及大、中剂量组IL-1β蛋白表达水平以及各剂量组RANTES蛋白表达水平显著下调,8周时秦苓液小剂量组IL-1β及中、小剂量组RANTES基因转录及中、小剂量组IL-1β、RANTES蛋白表达水平显著下调(P<0.05,P<0.01).结论秦苓液抑制UN模型大鼠免疫炎性损伤,其分子机制可能与上调PGC-1α的水平,抑制IL-1β、RANTES的生物学活性有关.

目的:通过观察虎杖对胶原诱导性关节炎(CIA)模型大鼠滑膜组织、血清中抑癌基因p53突变型(mt-p53)、增殖诱导配体(APRIL)、肿瘤坏死因子-α(TNF-α)表达的影响,探讨虎杖抑制类风湿关节炎滑膜免疫炎性损伤的作用机制.方法:采用大鼠尾根部注射牛Ⅱ型胶原方法制备CIA模型,将成模大鼠按随机数字表法分为模型组、阳性对照组、虎杖2倍剂量组、虎杖常量组,另设正常对照组,每组6只.正常对照组与模型组予去离子水10mL·kg-1·d-1灌胃,阳性对照组予来氟米特1.87mg·kg-1·d-1灌胃,虎杖2倍剂量组、虎杖常量组分别以虎杖颗粒8、4g·kg-1·d-1灌胃,连续干预12周.观察各组大鼠偶数周体质量、AI评分及各组大鼠滑膜组织中APRIL、mt-p53、TNF-αmRNA,mt-p53、TNF-α蛋白及血清中TNF-α蛋白表达情况.结果:与正常对照组比较,模型组大鼠体质量及AI评分有明显变化(P＜0.05,P＜0.01);与模型组比较,各治疗组大鼠体质量及AI评分有明显改善.与正常对照组比较,模型组APRIL、mt-P53、TNF-α mRNA转录水平显著上调(P＜0.01),mt-P53、TNF-α蛋白表达水平显著上调(P＜0.01);与模型组比较,各治疗组APRIL、mt-p53、TNF-αmRNA转录水平显著下调(P＜0.01);mt-p53、TNF-α蛋白表达水平显著下调(P＜0.01).结论:虎杖改善CIA大鼠关节滑膜免疫炎性损伤的机制可能与抑制滑膜细胞增殖相关.

Objective: To observe the effects of Tangshenqing Formula Ⅱ (TSQF Ⅱ) extract on the gene transcription and protein expressions of mouse glomerular mesangial cell line including AMP-activated protein kinase-α1 (AMPK-α1) 、inhibitor of nuclear factor kappa B-α (IκBα) 、toll like receptor-4 (TLR-4) mRNA, and to explore its the molecular mechanism of inhibiting the immune-inflammatory pathological injury of mesangial cell lines in high glucose environment. Methods: To culture mouse glomerular mesangial cell line SV40 MES 13 in 5％ CO2, 37 ℃ constant temperature incubator. Experimental groups:control group (D-Glucose 5.6/L), high glucose group (D-Glucose 30 mmol/L), high glucose+TSQF Ⅱextract 5 μmol/L group, high glucose+TSQF Ⅱextract 10 μmol/L group, high glucose+TSQF Ⅱextract 20 μmol/L group.Cells in all groups were coculture12 h, 24 h, 36 h.Rt-PCR was used to detect mRNA transcriptional levels of AMPKα1, IκBα, TLR4 mRNA.Western-blot was used to detect protein expression levels of AMPKα1, IκBα, TLR4.Results: compared with the control group, the mRNA transcriptional and protein expression level of AMPKα1 and IκBα in the high glucose group were down-regulated (P<0.05), the mRNA transcription and protein expression level of TLR4 were up-regulated (P<0.01).Compared with the high glucose group, the expression level of AMPKα1 and IκBα proteins were up-regulated (P<0.05), and the mRNA transcriptional level of AMPKα1 and IκBα were up-regulated in the high and low dose Chinese medicine groups (P<0.05).TLR4 mRNA transcription level was down-regulated in all groups of TSQF Ⅱ extract (P<0.01), and the TLR4 protein expression level was down-regulated in the middle and high dose groups (P<0.01).Conclusion: TSQF Ⅱextract can inhibit immune-inflammatory pathological injury of mesangial cell lines in high glucose environment, and this molecular mechanism may be related to the regulation of AMPK signaling pathway.

目的 观察秦苓液对尿酸性肾病大鼠肾组织AMPK/iNOS信号途径的影响,探讨其对尿酸性肾病肾脏损伤的保护机制.方法 采用腺嘌呤灌胃配合酵母饲料喂养的方法制备高尿酸肾病大鼠模型,将成模大鼠随机分为模型组,别嘌呤醇组[23.33 mg/(kg·d)],秦苓液大、中、小剂量组[剂量分别为:36.4、18.2、9.1 g,(kg·d)],每组12只,予对应药物干预.6周和8周时处死各组1,2大鼠,取肾脏组织.RT-PCR检测AMPKα1、iNOS mRNA表达水平,Western Blot检测AMPKα1、p-AMPKα1、iNOS蛋白表达水平.结果 与正常组比较,6周及8周模型组AMPKα1 mRNA和蛋白表达、p-AMPKα1蛋白表达降低,iN-OS mRNA及蛋白表达升高(P＜0.01,P＜0.05).与模型组比较,6周时秦苓液各组AMPKα1 mRNA表达升高,p-AMPK蛋白表达升高,iNOS蛋白表达降低,秦苓液大、小剂量组AMPKα1蛋白表达升高(P＜0.01,P＜0.05);8周时秦苓液小剂量组AMPKα1 mRNA表达升高,中、小剂量组AMPKoα1、P-AMPKα1蛋白表达升高,jNOS mRNA及蛋白表达降低(P＜0.01,P＜0.05).结论 秦苓液可能通过调节AMPK/iNOS信号途径改善代谢,抑制炎性损伤,减轻尿酸性肾病大鼠的肾脏损伤.

This paper presents new results for the Discrete Ordered Median Problem (DOMP). It exploits properties of k-sum optimization to derive specific formulations for the monotone DOMP (MDOMP), that arises when the λ weights are non-decreasing monotone, and new formulations for the general non-monotone DOMP. The main idea in our approach is to express ordered weighted averages as telescopic sums whose terms are k-sums, with positive and negative coefficients. Formulations of k-sums with positive coefficients derive from the linear programming representations obtained by Ogryczack and Tamir (2003) and Blanco, Ali, and Puerto (2014). Valid formulations for k-sums with negative coefficients are more elaborated and we present 4 different approaches, all of them based on mixed integer programming formulations. An extensive computational experience based on a collection of well-known instances shows the usefulness of the new formulations to solve difficult problems such as trimmed and anti-trimmed mean.

目的 观察土藤草汤治疗急性痛风性关节炎的临床效果.方法 回顾性分析2013年4月～2017年5月就诊于北京中医药大学东方医院风湿科证属热毒壅盛、瘀浊内阻型急性痛风性关节炎患者的临床资料,根据用药方案分为土藤草汤组(120例)、秋水仙碱组(63例)、洛索洛芬钠组(118例).土藤草汤组给予土藤草汤饮片煎剂或药物颗粒冲剂,每日1剂,早晚分服.秋水仙碱组给予秋水仙碱1mg/次,3次/d.洛索洛芬钠组给予洛索洛芬钠片60 mg/次,3次/d.干预1周.观察三组关节症状缓解时间、中医症状好转情况和治疗前后血尿酸(sUA)、C反应蛋白(CRP)、血沉(ESR)的改善情况,比较三组临床疗效和安全性.结果 治疗1周后,土藤草汤组关节疼痛、肿胀的缓解时间短于其余两组(P＜0.01),活动受限的缓解时间短于洛索洛芬钠组(P＜0.01).中医症状方面,土藤草汤组口干口渴、头重昏蒙、纳呆的症状好转率明显高于其余两组(P＜ 0.05或P＜0.01),便秘好转率明显高于洛索洛芬钠组(P＜0.01).与治疗前比较,三组治疗后sUA、CRP、ESR均下降(P＜0.05).治疗后,土藤草汤组CRP、ESR水平低于其余两组(P＜0.05),sUA水平低于洛索洛芬钠组(P＜0.05).土藤草汤组有效率明显高于其余两组(P＜0.05).三组均未出现明显不良反应.结论 土藤草汤治疗急性痛风性关节炎在提高临床疗效及降低sUA水平等方面优于单纯使用秋水仙碱或洛索洛芬钠.

Salt sensitivity (SS) is associated with increased cardiovascular risk in patients with Type 2 diabetes mellitus (T2-DM) due to an increase in renal oxidation. ω-3 polyunsaturated fatty acids have shown antioxidant effects, but a typical Western diet contains limited content. In particular, ω-3 polyunsaturated fatty acids are able to activate nuclear factor erythroid 2-related factor 2 (Nrf-2) to prevent diabetes mellitus–related complications by mitigating oxidative stress. Therefore, we hypothesized that eicosapentaenoic acid (EPA; ω-3) modulates SS in rats with T2-DM by decreasing renal oxidative stress via Nrf-2 activation and enhancing the antiinflammatory response via interleukin (IL) 6 modulation.Three-month-old male rats (n = 40) were fed with a Normal Na-diet (NNaD) and randomly selected into four groups: Healthy Wistar nondiabetic rats (Wi), diabetic controls (eSS), arachidonic acid-treated eSS (AA; ω-6), and EPA-treated eSS (ω-3). After 1 year, rats were placed in metabolic cages for 7 d and fed a NNaD, followed by a 7-d period with a High Na-diet (HNaD). Systolic blood pressure, body weight, serum IL-6 and reactive oxygen species (ROS) levels were determined at the end of each 7-d period. Glycated hemoglobin (HbA1c), triacylglycerol, creatinine, and cholesterol levels were determined. ROS levels and Nrf-2 expression in kidney lysates were also assayed. Histologic changes were evaluated. A t test or analysis of variance was used for the statistical analysis.After a HNaD, systolic blood pressure increased in both the control eSS and AA groups, but not in the EPA and Wi groups. However, HbA1c levels remained unchanged by the treatments, which suggests that the observed beneficial effect was independent of HbA1c levels. The IL-6 levels were higher in the eSS and AA groups, but remained unaltered in EPA and Wi rats after a HNaD diet. Interestingly, EPA protected against serum ROS in rats fed the HNaD, whereas AA did not. In kidney lysates, ROS decreased significantly in the EPA group compared with the eSS group, and Nrf-2 expression was consistently higher compared with the AA and eSS groups. Diabetic rats presented focal segmental sclerosis, adherence to Bowman capsule, and mild-to-moderate interstitial fibrosis. EPA and AA treatment prevented kidney damage.An adequate ω3-to-ω6 ratio prevents SS in diabetic rats by a mechanism that is independent of glucose metabolism but associated with the prevention of renal oxidative stress generation. These data suggest that EPA antioxidant properties may prevent the development of hypertension or kidney damage.

Posttraumatic stress disorder (PTSD) is a trouble that arises in the aftermath of a traumatic event. The overwhelming resulting stressful memory can be desensitized by a brief therapy, Eye Movement Desensitization and Reprocessing (EMDR). The aim of the present study is to explore the functional brain correlate of such an effective treatment (EMDR) in PTSD.Sixteen PTSD patients underwent fMRI during negative emotional face recognition task, before and after EMDR treatment. Brain activity changes at test and retest (P < 0.005) were compared to those of 16 healthy controls matched for age, gender, and education.In PTSD patients, EMDR therapy elicited significant functional decreases in deep gray matter (including the amygdala, thalamus, and caudate nucleus) and cortical activities (including notably the precuneus, and the ventromedial and dorsolateral prefrontal cortex), as compared to healthy controls (P < 0.005). The right thalamic activity decrease was positively correlated with PTSD symptom reduction as assessed by PCL-S (r = 0.62, n = 16, P < 0.01).The healing process of traumatic memory desensitization by EMDR would act through a functional decrease in brain regions shown to be disrupted in PTSD. Given the role of these structures in memory, self-perception, fear extinction, REM sleep, reward, and attention, we discuss possible explanations of EMDR mechanisms of action in PTSD that may help further improve this therapy.

Biomarkers associated with inflammation and immune function are increasingly being used to examine mechanisms of the effects of mind-body therapies. Less researched are biomarkers associated with cognitive and executive functioning in the study of mind-body therapy mechanisms and effects. This study explored the feasibility of recruiting breast cancer patients (BCPs) and implementation fidelity of participation in a research project utilizing the 4-stage Creative Psychosocial Genomic Healing Experience (CPGHE), a mind-body protocol that is theorized to create epigenetic effects via targeted psychological change in emotional triggers in coping with cancer.Eight BCPs were identified as eligible (stages I, II, III, early phases of treatment) and five consented to one of two intervention groups (allocated to a single session or two sessions of CPGHE). Blood draws were examined pre- and post-intervention for a stress/inflammation gene expression marker, Nuclear Factor kappa-B (NF-kB), and three markers associated with synaptic plasticity undergirding cognitive and executive functioning: Early Growth Response 1 (EGR1), activity-regulated cytoskeleton-associated protein (Arc), and brain-derived neurotrophic factor (BDNF).One consented BCP dropped out due to illness. The remaining four adhered to the 4-stage CPGHE protocol and found the CPGHE experience beneficial. Blood samples for the gene expression results were collected and processed according to planned protocol without incident.Implementing the CPGHE and achieving good adherence among a sample of BCPs is feasible. Processing of blood samples collected from BCPs for gene expression data is also feasible.