基于网络药理学的气滞胃痛颗粒抗炎镇痛活性作用分析

目的通过网络药理学的方法预测气滞胃痛颗粒抗炎镇痛主要活性成分的作用靶点,结合中医方解配伍理论对其多成分-多靶点-多通路的作用进行分析。方法基于TCMSP中药系统生物学分析数据库收集气滞胃痛颗粒中6味中药的主要化学成分,并借助LC-MS技术对所筛成分进行分析,通过TCMSP检索和Pharmmapper软件预测获取各成分主要的作用靶标,并通过DIP数据库,利用蛋白质相互作用信息建立药物靶标与炎症疼痛靶标的关联,构建药物-靶标-疾病网络,通过网络特征分析气滞胃痛颗粒抗炎镇痛的作用靶标,阐释其抗炎镇痛的主要作用机制。结果根据网络分析,共有44个炎症疼痛靶点与气滞胃痛颗粒密切相关,其中直接作用靶点有20个,主要是对环加氧酶-2(COX-2)和诱导型一氧化氮合酶(i NOS)等蛋白酶的作用,作用机制可能与调节肿瘤坏死因子(TNF)信号通路、NOD样受体(NLR)信号通路、血管内皮生长因子(VEGF)信号通路等与炎症疼痛密切相关的信号通路有关。结论气滞胃痛颗粒抗炎镇痛作用体现了中药多成分、多靶点、多途径的作用特点,该研究为深入阐释气滞胃痛颗粒抗炎镇痛作用机制提供科学依据,并且进一步说明了中医药古方配伍理论的科学性。     

Perception of a Natural Joint After Total Knee Arthroplasty

BackgroundAssessing patients’ functional outcomes following total knee arthroplasty (TKA) with traditional scoring systems is limited by their ceiling effects. Patient’s Joint Perception (PJP) question of the reconstructed joint is also of significant interest. Forgotten Joint Score (FJS) was created as a more discriminating option. The actual score constituting a “forgotten joint” has not yet been defined. The primary objective of this study is to compare the PJP and the FJS in TKA patients to determine the FJS score that corresponds to the patient’s perception of a natural joint.MethodsOne hundred TKAs were assessed at a mean of 40.6 months of follow-up using the PJP question, FJS, and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Correlation between the 3 scores and their ceiling effects were analyzed.ResultsWith PJP question, 39% of the patients perceived a natural joint (FJS: 92.9; 95% confidence interval [CI], 89.4-96.4), 12% an artificial joint with no restriction (FJS: 79.5; 95% CI, 65.7-93.3), 36% an artificial joint with minor restrictions (FJS: 70.0; 95% CI, 63.2-76.9), and 13% had major restrictions (FJS: 47.3; 95% CI. 32.8-61.7). PJP has a high correlation with FJS and WOMAC (Spearman’s rho, −0.705 and −0.680, respectively). FJS and WOMAC had a significant ceiling effect with both reaching the best possible score in >15%.ConclusionPatients perceiving their TKA as a natural knee based on PJP have a FJS ≥89. PJP has a good correlation with FJS and may be a shorter, simple, and acceptable alternative.     

Chalcone hybrids and their antimalarial activity

Malaria, one of the most striking, re-emerging infectious diseases caused by the genus Plasmodium, places a huge burden on global healthcare systems. A major challenge in the control and eradication of malaria is the continuous emergence of increasingly widespread drug-resistant malaria, creating an urgent need to develop novel antimalarial agents. Chalcone derivatives are ubiquitous in nature and have become indispensable units in medicinal chemistry applications due to their diverse biological profiles. Many chalcone derivatives demonstrate potential in vitro and in vivo antimalarial activity, so chalcone could be a useful template for the development of novel antimalarial agents. This review covers the recent development of chalcone hybrids as antimalarial agents. The critical aspects of the design and structure–activity relationship of these compounds are also discussed.     

Baroreflex activation in conscious rats modulates the joint inflammatory response via sympathetic function

The baroreflex is a critical physiological mechanism controlling cardiovascular function by modulating both the sympathetic and parasympathetic activities. Here, we report that electrical activation of the baroreflex attenuates joint inflammation in experimental arthritis induced by the administration of zymosan into the femorotibial cavity. Baroreflex activation combined with lumbar sympathectomy, adrenalectomy, celiac subdiaphragmatic vagotomy or splenectomy dissected the mechanisms involved in the inflammatory modulation, highlighting the role played by sympathetic inhibition in the attenuation of joint inflammation. From the immunological standpoint, baroreflex activation attenuates neutrophil migration and the synovial levels of inflammatory cytokines including TNF, IL-1β and IL-6, but does not affect the levels of the anti-inflammatory cytokine IL-10. The anti-inflammatory effects of the baroreflex system are not mediated by IL-10, the vagus nerve, adrenal glands or the spleen, but by the inhibition of the sympathetic drive to the knee. These results reveal a novel physiological neuronal network controlling peripheral local inflammation.     

Evodiamine-inspired dual inhibitors of histone deacetylase 1 (HDAC1) and topoisomerase 2 (TOP2) with potent antitumor activity

A great challenge in multi-targeting drug discovery is to identify drug-like lead compounds with therapeutic advantages over single target inhibitors and drug combinations. Inspired by our previous efforts in designing antitumor evodiamine derivatives, herein selective histone deacetylase 1 (HDAC1) and topoisomerase 2 (TOP2) dual inhibitors were successfully identified, which showed potent in vitro and in vivo antitumor potency. Particularly, compound 30a was orally active and possessed excellent in vivo antitumor activity in the HCT116 xenograft model (TGI = 75.2%, 150 mg/kg, p.o.) without significant toxicity, which was more potent than HDAC inhibitor vorinostat, TOP inhibitor evodiamine and their combination. Taken together, this study highlights the therapeutic advantages of evodiamine-based HDAC1/TOP2 dual inhibitors and provides valuable leads for the development of novel multi-targeting antitumor agents.     

The 2018 International Consensus Meeting Minor Criteria for Chronic Hip and Knee Periprosthetic Joint Infection: Validation From a Single Center

BackgroundRecently, a revised definition of the minor criteria scoring system for diagnosing periprosthetic joint infection (PJI) was developed by the second International Consensus Meeting on musculoskeletal infection. The new system combines preoperative and intraoperative findings, reportedly achieving high sensitivity and specificity. We aimed to validate the modified scoring system at a high-volume center.MethodsWe retrospectively reviewed patients who underwent a revision total hip or knee arthroplasty at our institution from May 2015 to August 2018. Serum C-reactive protein, synovial white blood cell count and polymorphonuclear percentage, leukocyte esterase test, alpha-defensin, microbiological and histologic results, and documented existence of sinus tract and intraoperative purulence were available for all patients. Cases with at least 1 major criterion were considered as infected. Using the new minor criteria, a score of ≥6 reflects PJI, while a score <3 can be considered as noninfected. Sensitivity, specificity, mean accuracy (ACC), positive predictive value (PPV), and negative predictive value (NPV) were analyzed.ResultsA total of 345 cases were included. A cutoff score of ≥6 points had the following diagnostic performance: area under the curve (AUC) = 0.90; ACC = 0.88; sensitivity = 0.96; specificity = 0.84; PPV = 0.70; NPV = 0.98. Diagnostic performance was better for the hip (AUC = 0.92; ACC = 0.90; sensitivity = 0.96; specificity = 0.86; PPV = 0.81; NPV = 0.98) than the knee (AUC = 0.89; ACC = 0.85; sensitivity = 0.95; specificity = 0.83; PPV = 0.59; NPV = 0.98).ConclusionThe modified scoring system proposed by the 2018 International Consensus Meeting in diagnosing PJI showed high sensitivity and a good performance, especially as rule-out diagnostic criteria. The cutoff level seems to be different between the hip and knee. Further validation studies considering the acknowledged limitations are recommended.     

Osteointegrative Sleeves for Metaphyseal Defect Augmentation in Revision Total Knee Arthroplasty: Clinical and Radiological 5-Year Follow-Up

BackgroundCementless metaphyseal implant fixation of revision total knee arthroplasty has encouraging early results. We analyzed midterm results and implant survival of osteointegrative augments in Anderson Orthopedic Research Institute (AORI) type 2a, 2b, and 3 defects. Reasons for implant failure were explored and the potential for anatomic joint line reconstruction evaluated.MethodsSixty-seven consecutive patients (68 revision total knee arthroplasties) received cementless metaphyseal sleeves between 2011 and 2014. The mean follow-up was 5.0 years, mean age was 68.5 years, and mean body mass index was 31.4 kg/m². The clinical and radiographic results were determined using established scoring systems. Additionally, the survival rate was calculated and reasons for failure were analyzed.ResultsIn 2 patients (4.3%), sleeves had to be removed early postoperatively for deep infection after second-stage reimplantation. With continuously functioning remaining implants, the aseptic survival rate was 93.6%. Cleared up for initial technical issues due to poor bone quality, it is as high as 98%. The scores remained to be significantly improved by 64.8 points (Western Ontario and McMaster Universities Osteoarthritis Index) and 25.8 points (Knee Society score) (P < .001). In 10 patients (29.4%), diaphyseal radiolucencies were observed without suspicion of loosening. The mean joint line was noted to be 0.36 mm lower to the anatomic level.ConclusionAt a mean follow-up of 5.0 years, cementless osteointegrative sleeves for metaphyseal fixation in AORI 2a, AORI 2b, and AORI 3 defects yielded continuous implant fixation even in cases with preceding revisions. The cleared up aseptic survival rate was 98% at 5 years. The modular sleeve design allowed joint line reconstruction near the anatomic level.