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.

OBJECTIVES:This study was designed to investigate the pharmacological activity and therapeutic mechanism of Mahuang Xixin Fuzi decoction (MXFD) on migraine.METHODS:Migraine model rats induced by nitroglycerin were established, and then orally administered with MXFD for 7 days. Blood and urine samples were collected to identify differential metabolites with metabolomics. To integrate the findings from network pharmacology and metabolomics analysis, the metabolites and targets related to MXFD therapy for migraine were filtered.KEY FINDINGS:MXFD was found to alleviate the symptoms of migraines in rats. After treatment with MXFD, nine metabolites were found to be regulated and returned to normal levels. MXFD acted directly on nine key targets including MAOB, MAOA, ADRB1, ADRB2, ADRB3, ADORA2A, ADORA2B, DRD5, and HTR4 and regulated two out of nine metabolites, namely deoxycholic acid and 5-methoxyindoleacetate.CONCLUSIONS:The study found that MXFD can alleviate migraines through multitarget and multicomponent interaction networks.

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.

ETHNOPHARMACOLOGICAL RELEVANCE:Paeonol (PAE) and glycyrrhizic acid (GLY) are predominate components of 14 blood-entering ones of Piantongtang No. 1, which is a traditional Chinese medicine prescription for chronic migraine with minimal side effects. Both paeonol and glycyrrhizic acid exhibit analgesic, neuroprotective and anti-inflammatory properties individually. Our previous research has highlighted their combined effect (PAE + GLY) in ameliorating migraine symptoms. However, there are not yet any studies exploring the mechanism of action of PAE + GLY in the treatment of migraine. AIM OF THE STUDY:This research aimed to determine the mechanism of PAE + GLY in ameliorating the recurrent nitroglycerin-induced migraine-like phenotype in rats. MATERIALS AND METHODS:Using a nitroglycerin-induced migraine model via subcutaneous injection in the neck, we evaluated the effect of PAE + GLY on migraine-like symptoms. Behavioural tests and biomarkers analysis were employed, alongside transcriptome sequencing (RNA-seq). Mechanistic insights were further verified utilising reverse transcription quantitative PCR (RT-qPCR), Western blot (WB), ELISA and immunofluorescence (IF) techniques. RESULTS:Following treatment with PAE + GLY, hyperalgesia threshold and 5-hydroxytryptamine (5-HT) levels increased, and migraine-like head scratching, histamine and calcitonin gene-related peptide (CGRP) levels were reduced. RNA-Seq experiments revealed that PAE + GLY upregulated the expression of Glutamate decarboxylase 2 (GAD2) and γ-aminobutyric acid type B receptor subunit 2 (GABBR2) genes. This upregulation activated the GABAergic synapse pathway, effectively inhibiting migraine attacks. Further validation demonstrated an increase in γ-aminobutyric acid (GABA) content in cerebrospinal fluid post PAE + GLY treatment, coupled with increased expression of dural GAD2, GABBR2 and transient receptor potential channel M8 (TRPM8). Consequently, this inhibited the expression of dural cAMP-dependent protein kinase catalytic subunit alpha (PRKACA) and transient receptor potential channel type 1 (TRPV1), subsequently downregulating p-ERK1/2, p-AKT1, IL-1β and TNF-α. CONCLUSIONS:Our findings underscore that PAE + GLY ameliorates inflammatory hyperalgesia migraine by upregulating inhibitory neurotransmitters and modulating the GABBR2/TRPM8/PRKACA/TRPV1 pathway.

BACKGROUND:Excessive deposition of uric acid (UA) is one of the risk factors for kidney damage. Qinling liquid (QL) has a certain therapeutic effect on uric acid nephropathy (UAN), but its regulation mechanism is still unclear.METHODS:UAN rat models and UA induced rat renal tubular epithelial cells (NRK-52E) were constructed to evaluate the functional roles of QL. We firstly evaluated the kidney function and the degree of kidney damage in rats after QL treatment. Then, effects of QL on autophagy and NLRP3 inflammasome activation were assessed. Moreover, the regulation of QL in AMPK and Stat3 phosphorylation levels and the relationship among autophagy, AMPK/Stat3 pathway and NLRP3 inflammasomes were determined.RESULTS:QL could alleviate the inflammatory damage in UAN rats and promote the activation of autophagy. In addition, QL suppressed UA-induced activation of NLRP3 inflammasomes in rat renal tubular epithelial cells, which was partially reversed by autophagy inhibitor. Further, AMPK/Stat3 axis-mediated autophagy participated in the regulation of UA-induced NLRP3 inflammasome activation in NRK-52E cells. Finally, we confirmed that inhibiting AMPK/Stat3 pathway partly deteriorated the ameliorating effect of QL on renal immune inflammatory injury in UAN rats.CONCLUSION:Through in vivo and in vitro experiments, we found that QL promotes autophagy by activating the AMPK/Stat3 pathway, thereby improving renal immune inflammatory injury in UAN.

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 观察秦苓液联合别嘌醇治疗尿酸性肾病的临床疗效.方法 将88例尿酸性肾病患者随机分为对照组和治疗组,每组44例.对照组采用别嘌醇治疗,治疗组在对照组基础上加用秦苓液煎剂治疗,疗程3个月.治疗后比较两组患者临床疗效、血尿酸(serum uric acid,sUA)、血肌酐(serum creatinine,SCr)、血尿素氮(blood urea nitrogen,BUN)、β2微球蛋白(beta 2-microglobulin,β2-MG)、同型半胱氨酸(homocysteine,HCY)、尿蛋白(urine protein,uPRO)、估算肾小球滤过率(estimated glomerular filtration rate,eGFR)等情况.结果 脱落剔除病例14例,实际纳入74例,其中对照组35例,治疗组39例,两组脱落剔除率比较,差异无统计学意义(P＞0.05).对照组有效率为65.71％ (23/35),治疗组为89.74％(35/39),两组比较差异具有统计学意义(P＜0.05).与治疗前比较,两组患者sUA显著降低、eGFR显著升高,治疗组SCr、HCY、uPRO显著降低,差异具有统计学意义(P＜0.05,P＜0.01).与对照组比较,治疗后治疗组eGFR显著升高,sUA、SCr、HCY、uPRO显著降低,差异具有统计学意义(P＜0.05,P＜0.01).两组患者安全性指标均未见明显异常,且无不良反应发生.结论 秦苓液联合别嘌醇是治疗尿酸性肾病的有效方法,能明显降低sUA水平,改善肾功能,且不增加患者不良反应,具有良好的安全性.

重镇潜阳药物是临床常用的药物,但金石之性猛烈,使用不慎容易伤人,所以使用时须结合患者全身气血阴阳之虚实强弱,同时配合益阴、温阳等法,整体辨证、综合配伍才能充分发挥其功效.文章通过对常用重镇类药物的整理研究,结合古今医家经典论述,总结出平肝潜阳、益阴潜阳、镇心安神、降逆止呕、下气平喘、坠痰降浊、制衡升药7种用法,并参考经典配伍,分别阐明主要药物及治法的应用要点、配伍规律与禁忌,以期为临床合理使用重镇类药物提供参考.

[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.

Gouty arthritis is an inflammatory joint disease closely related to hyperuricemia. It is characterized by deposition of monosodium urate crystals in the joints, resulting in an intense inflammatory process and pain. Control of hyperuricemia and anti-inflammation treatments are the main therapeutic approaches. However, the commonly used drugs for inhibiting uric acid and acute gouty arthritis have obvious gastrointestinal and renal toxicity; thus, there is an urgency to develop new alternative therapeutic drugs. An extract of Tu-Teng-Cao (TTC), a compound drug used in traditional Chinese medicine, has been widely applied to the clinical treatment of arthritis. In this study, we investigated the therapeutic effects of TTC on gouty arthritis. In this study, an animal model of acute gouty arthritis with hyperuricemia was established using potassium oxonate and monosodium urate crystals. After treatment with TTC, the results showed obvious therapeutic effects on the rat model of acute gouty arthritis. The treatment significantly attenuated the degree of ankle swelling, inflammation, and dysfunction index, and the levels of proinflammatory cytokines. In addition, TTC has significant antihyperuricemia activity in rats with hyperuricemia induced by potassium oxonate. Histological evaluation showed that TTC relieved pathological damage in rats with acute gouty arthritis induced by monosodium urate crystals. All the groups treated with TTC showed improvement in cartilage degeneration, cell degeneration, synovial hyperplasia, and inflammatory cell invasion in the ankle joint of rats. TTC significantly alleviated swelling, inflammation, and bleeding of the renal corpuscle and convoluted tubules of rats. The results of this study suggest that TTC is capable of treating gouty arthritis and decreasing ankle injury through the control of uric acid and inflammation.

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.

Bladder complications may be seen in up to 12% of patients treated with pelvic irradiation. Hyperbaric oxygen therapy (HBOT) is an option for the management of radiation-induced hemorrhagic cystitis (RIHC). The aim of this study was to evaluate the efficacy of HBOT in radiation cystitis and to identify the predictive factors for a successful outcome.We retrospectively reviewed 105 patients diagnosed with RIHC which were treated with HBOT between 2007 and 2016 in our institution. Patients received 100% oxygen in a multiplace hyperbaric chamber at 2.4 atm for 80 min. All patients fulfilled a questionnaire documenting symptom severity pre-HBOT and at the end of the follow-up period.After a median of 40 HBOT sessions, there was success rate of 92,4% in the control of hematuria. During our follow-up period (median of 63 months) 24,7% patients presented with recurrence of hematuria. The mean score of the questionnaire-assessed variables: dysuria, urinary frequency and hematuria, was significantly lower after the follow-up period (p < 0,05).Our data shows that the sooner HBOT is delivered after the first episode of hematuria, better response rates are achieved and lower recurrences concerning hematuria were registered (p < 0,05). No serious complications were observed.Our results support the safety and long-term benefits of HBOT on RIHC and other distressful bladder symptoms, which represents an expected improvement of quality of life in our patientsAlrededor del 12% de los pacientes tratados con radioterapia pélvica desarrollan complicaciones en la vejiga. La terapia de oxígeno hiperbárico (TOHB) es una opción para el manejo de la cistitis hemorrágica inducida por radioterapia (CHIR). El objetivo de este estudio fue evaluar la eficacia de la TOHB para tratar la cistitis por radioterapia e identificar factores predictivos para un resultado exitoso.Revisamos retrospectivamente 105 pacientes diagnosticados con CHIR que recibieron un tratamiento de TOHB entre 2007 y 2016 en nuestro centro. Los pacientes recibieron oxígeno al 100% en una cámara hiperbárica multiplaza a 2,4 ATA durante 80 minutos. Todos los pacientes cumplimentaron un cuestionario en el que se documentaba la gravedad de los síntomas previos a TOHB y tras el período de seguimiento.Después de una media de 40 sesiones de TOHB, hubo una tasa de éxito del 92,4% en el control de la hematuria. Durante nuestro período de seguimiento (mediana de 63 meses), el 24,7% de los pacientes presentaron recurrencia de la hematuria. La puntuación media de las variables evaluadas en el cuestionario –disuria, frecuencia urinaria y hematuria– fue significativamente menor después del período de seguimiento (p < 0,05).Nuestros datos muestran que cuanto antes se administre la TOHB después del primer episodio de hematuria, se logran mejores tasas de respuesta y se registran menores recurrencias en relación con la hematuria (p < 0,05). No se observaron complicaciones graves.Nuestros resultados apoyan la seguridad y los beneficios a largo plazo de la TOHB para la CHIR y otros síntomas molestos de la vejiga, lo que supondría una mejora en la calidad de vida de nuestros pacientes.

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.