CP-25, a compound derived from paeoniflorin: research advance on its pharmacological actions and mechanisms in the treatment of inflammation and immune diseases.

Total glycoside of paeony (TGP) has been widely used to treat inflammation and immune diseases in China. Paeoniflorin (Pae) is the major active component of TGP. Although TGP has few adverse drug reactions, the slow onset and low bioavailability of Pae limit its clinical use. Enhanced efficacy without increased toxicity is pursued in developing new agents for inflammation and immune diseases. As a result, paeoniflorin-6'-O-benzene sulfonate (CP-25) derived from Pae, is developed in our group, and exhibits superior bioavailability and efficacy than Pae. Here we describe the development process and research advance on CP-25. The pharmacokinetic parameters of CP-25 and Pae were compared in vivo and in vitro. CP-25 was also compared with the first-line drugs methotrexate, leflunomide, and hydroxychloroquine in their efficacy and adverse effects in arthritis animal models and experimental Sjögren's syndrome. We summarize the regulatory effects of CP-25 on inflammation and immune-related cells, elucidate the possible mechanisms, and analyze the therapeutic prospects of CP-25 in inflammation and immune diseases, as well as the diseases related to its potential target G-protein-coupled receptor kinases 2 (GRK2). This review suggests that CP-25 is a promising agent in the treatment of inflammation and immune diseases, which requires extensive investigation in the future. Meanwhile, this review provides new ideas about the development of anti-inflammatory immune drugs.

CP-25 reverses prostaglandin E4 receptor desensitization-induced fibroblast-like synoviocyte dysfunction via the G protein-coupled receptor kinase 2 in autoimmune arthritis.

Paeoniflorin-6'-O-benzene sulfonate (CP-25) is a novel compound derived from paeoniflorin that has been demonstrated to have therapeutic effects in a rat model of rheumatoid arthritis (RA). However, the underlying mechanism has not been elucidated to date. We explored this mechanism in the present study by treating rats with adjuvant arthritis (AA) with CP-25. We found that the membrane EP4 protein level was downregulated; whereas, GRK2 was upregulated, in fibroblast-like synoviocyte (FLS)s of AA rats. Prostaglandin (PGE)2 stimulated FLS proliferation and enhanced the membrane EP4 receptor protein level; the latter was reversed by the administration of an EP4 receptor agonist, whereas the membrane GRK2 protein level gradually increased. The changes in the EP4 receptor and GRK2 expression were enhanced by TNF-α, and the former was accompanied by an alteration in the cyclic (c)AMP level. The EP4 receptor agonist stimulation increased the association between GRK2 and the EP4 receptor. GRK2 knockdown abrogated the abnormalities in FLS proliferation. The CP-25 treatment (100 mg/kg) suppressed joint inflammation with an efficacy that was similar to that of methotrexate. This finding was associated with EP4 upregulation and GRK2 downregulation in FLSs. Thus, GRK2 plays an important role in the abnormal FLS proliferation observed in AA possibly by promoting EP4 receptor desensitization and decreasing the cAMP level. Our results demonstrate that CP-25 has therapeutic potential for the treatment of human RA via GRK2 regulation.

Regulatory effects of paeoniflorin-6'-O-benzene sulfonate (CP-25) on dendritic cells maturation and activation via PGE2-EP4 signaling in adjuvant-induced arthritic rats.

Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disease. Dendritic cells (DCs) are one of the most powerful antigen-presenting cells, and they play an important role in RA pathogenesis. Prostaglandin E2 (PGE2) is a potent lipid mediator that can regulate the maturation and activation of DCs, but the molecular mechanisms have not been elucidated. In this study, both in vitro and in an RA rat model, we investigated the mechanisms involved by focusing on PGE2-mediated signaling and using a novel anti-inflammatory compound, paeoniflorin-6'-O-benzene sulfonate (CP-25). PGE2 combined with tumor necrosis factor-α promoted DC maturation and activation through EP4-cAMP signaling. Treatment with CP-25 increased the endocytic capacity of DCs induced by PGE2. CP-25 inhibited the potency of DCs induced by the EP4 receptor agonist, CAY10598, to stimulate allogeneic T cells. Consistent with these findings, the CAY10598-induced upregulation of DC surface activation markers and production of IL-23 was significantly inhibited by CP-25 in a concentration-dependent manner. In vivo administration of CP-25 alleviated adjuvant arthritis (AA) in rats through inhibition of DC maturation and activation. Our results indicate that PGE2-EP4-cAMP signal hyperfunction can lead to abnormal activation of DC functions, which correlates with the course of disease in AA rats and provides a possible treatment target. The inhibition of DC maturation and activation by CP-25 interference of the PGE2-EP4 pathway may significantly contribute to the immunoregulatory profile of CP-25 when used to treat RA and other immune cell-mediated disorders.

Three-Case Report of Embolic Stroke of Undetermined Source.

BACKGROUND: Embolic stroke of undetermined source (ESUS) is a new clinical construct. It signifies that the embolus in the thromboembolic ischemic stroke is of unknown origin. The anticoagulants are usually prescribed for antithrombotic prophylaxis, but whether it is appropriate for all patients with ESUS is still unknown. METHODS AND RESULTS: In this article, we describe 3 cases of ESUS, all of whose antithrombotic therapy was antiplatelet medication, and the 3 patients had no recurrence on 3- to 7-month follow-up. CONCLUSIONS: Because there was no obvious risk factor found in these ESUS cases, the recurrence risk is difficult to evaluate, and the optimum means of secondary prevention are still unknown. Hence, many aspects warrant resolution.

A new machine learning model to predict the prognosis of cardiogenic brain infarction.

Cardiogenic cerebral infarction (CCI) is a disease in which the blood supply to the blood vessels in the brain is insufficient due to atherosclerosis or stenosis of the coronary arteries in the patient's heart, which leads to neurological deficits. To predict the pathogenic factors of cardiogenic cerebral infarction, this paper proposes a machine learning based analytical prediction model. 494 patients with CCI who were hospitalized for the first time were consecutively included in the study between January 2017 and December 2021, and followed up every three months for one year after hospital discharge. Clinical, laboratory and imaging data were collected, and predictors associated with relapse and death in CCI patients at six months and one year after discharge were analyzed using univariate and multivariate logistic regression methods, meanwhile established a new machine learning model based on the enhanced moth-flame optimization (FTSAMFO) and the fuzzy K-nearest neighbor (FKNN), called BITSAMFO-FKNN, which is practiced on the dataset related to patients with CCI. Specifically, this paper proposes the spatial transformation strategy to increase the exploitation capability of moth-flame optimization (MFO) and combines it with the tree seed algorithm (TSA) to increase the search capability of MFO. In the benchmark function experiments FTSAMFO beat 5 classical algorithms and 5 recent variants. In the feature selection experiment, ten times ten-fold cross-validation trials showed that the BITSAMFO-FKNN model proved actual medical importance and efficacy, with an accuracy value of 96.61%, sensitivity value of 0.8947, MCC value of 0.9231, and F-Measure of 0.9444. The results of the trial showed that hemorrhagic conversion and lower LVDD/LVSD were independent risk factors for recurrence and death in patients with CCI. The established BITSAMFO-FKNN method is helpful for CCI prognosis and deserves further clinical validation.

Predicting the One-Year Prognosis and Mortality of Patients with Acute Ischemic Stroke Using Red Blood Cell Distribution Width Before Intravenous Thrombolysis.

PURPOSE: Red blood cell (RBC) distribution width (RDW) is known to reflect the heterogeneity of RBC volume, which may be associated with cardiovascular events or mortality after myocardial infarction. However, the association between RDW and stroke, especially regarding endpoints such as death, remains ambiguous. This study aimed to explore the prognostic value of RDW and its effect on mortality among patients with acute ischemic stroke (AIS) undergoing intravenous thrombolysis (IVT) after one year. PATIENTS AND METHODS: We retrospectively reviewed patients with AIS treated with IVT between January 2016 and March 2018. We grouped the patients according to modified ranking scale (MRS) scores as follows:0-2, favorable functional outcome group; and 3-6, unfavorable functional outcome. Predictors were determined using multivariate logistic regression (MVLR). The area under receiver-operating characteristic curve (AUC) was used to evaluate the predictive capability of variables. Furthermore, the Cox proportional hazard model was used to assess the contribution of risk factors to the outcome of death at one year later. RESULTS: MVLR analysis showed that RDW (odds ratio [OR], 1.179; 95% confidence interval [CI], 0.900-1.545; p = 0.232) was not an independent predictor of unfavorable functional outcome, but it (OR 1.371; 95% CI 1.109-1.696; p = 0.004) was an independent biomarker for all-cause mortality. The optimal RDW cut-off value to predict mortality was 14.65% (sensitivity: 42%, specificity: 88.3%, AUC: 0.649, p < 0.001). Furthermore, higher RDW (hazard ratio, 2.860; 95% CI, 1.724-4.745; p < 0.001) indicated a greater risk of death. CONCLUSION: The baseline RDW is a potential predictor of mortality in patients with AIS undergoing IVT, but RDW might not be associated with worse survival function among stroke survivors, which will help us to improve treatments and the management of patients with AIS.

PM2.5 induces vascular permeability increase through activating MAPK/ERK signaling pathway and ROS generation.

Although in-vivo exposure of PM2.5 has been suggested to initiate a disorder on vascular permeability, the effects and related mechanism has not been well defined. In this work, an obvious increase on vascular permeability has been confirmed in vivo by vein injection of PM2.5 into Balb/c mouse. Human umbilical vein vascular endothelial cells and the consisted ex-vivo vascular endothelium were used as model to investigate the effects of PM2.5 on the vascular permeability and the underlying molecular mechanism. Upon PM2.5 exposure, the vascular endothelial growth factor receptor 2 on cell membrane phosphorylates and activates the downstream mitogen-activated protein kinase (MAPK)/ERK signaling. The adherens junction protein VE-cadherin sheds and the intercellular junction opens, damaging the integrity of vascular endothelium via paracellular pathway. Besides, PM2.5 induces the intracellular reactive oxygen species (ROS) production and triggers the oxidative stress including activity decrease of superoxide dismutase, lactate dehydrogenase release and permeability increase of cell membrane. Taken together, the paracellular and transcellular permeability enhancement jointly contributes to the significant increase of endothelium permeability and thus vascular permeability upon PM2.5 exposure. This work provides an insight into molecular mechanism of PM2.5 associated cardiovascular disease and offered a real-time screening method for the health risk of PM2.5.

[A new opinion on detection methods for pulse shape and pulse force].

Pulse shape and pulse force are difficult to detect in pulse taking study. But the application of visualized technology extends the space acquisition of pulse taking information, and it is possible to realize the objective detection of pulse shape and pulse force. Rational research thoughts and strategies could be informed by combining image information and other data, and it is a necessary method in implementing the objective detection of pulse.

Effects of Pulsatile Cupping on Body Pain and Quality of Life in People with Suboptimal Health:A Randomized Controlled Exploratory Trial.

Objective: The curative effect of pneumatic pulsatile cupping on pain has been shown. This study was conducted to investigate effects of the pulsating frequency of pneumatic pulsatile cupping, compared with traditional cupping (TC), on body pain and quality of life (QoL) in people with suboptimal health status (SHS). Materials and Methods: Ninety-six participants with SHS were randomized to low-frequency (LF; n = 24) or high-frequency (HF; n = 24) pulsating cupping, traditional cupping (TC; n = 24), or wait-list (WL; n = 24) groups. The LF, HF, and TC groups received 4 sessions of cupping over 2 weeks. Visual analogue scale (VAS; 0-100 mm) pain level and Short-Form-36 (SF-36) QoL measurements were taken before and after the intervention. Results: Both LF and HF reduced pain significantly (VAS: -28.26; 95% confidence interval [CI] -36.18 to -20.34; and -31.88, 95% CI -39.81 to -23.96; both P = 0.000) and improved QoL more than WL (SF-36, Bodily Pain dimension: 1.46, 95% CI: 0.85 to 2.07; and 1.75, 95% CI: 1.14 to 2.36, both P = 0.000). Compared to TC, LF and HF significantly reduced pain (VAS: -7.92, 95% CI: -15.75 to -0.08, P LT = 0.048; and -11.54, 95% CI: -19.38 to -3.70, P HT = 0.004) and improved QoL (SF-36, Bodily Pain dimension: 0.61, 95% CI: 0.01 to 1.21, P LT = 0.046; and 0.90, 95% CI: 0.30 to 1.50, P HT = 0.004). There was no significant difference between LF and HF. Conclusions: This study showed that, in patients with SHS, pulsatile cupping therapy could have a more-favorable effect to relieve body pain, compared to TC. LF and HF pulsation produced equivalent pain relief. Further studies investigating the underlying mechanism are needed. Trial registration: This trial was registered in the Chinese Clinical Trial Registry (ChiCTR-INR-16009345).

[Discussion on methods for searching traditional Chinese medical literature in English in PubMed-MEDLINE database].

The methods for searching traditional Chinese medical literature in English with subject headings in PubMed-MEDLINE database were discussed from the practical view, and seven useful searching methods with free words according to practical experiences were put forward in order to assist the domestic TCM researchers to utilize PubMed-MEDLINE database in searching overseas TCM literature in English.

[Percutaneous absorption of aconitine and mesaconitine in extracts of Radix Aconitum kusnezoffii].

OBJECTIVE: This study was conducted to evaluate the percutaneous absorption of aconitine and mesaconitine in extracts of Radix Aconitum kusnezoffii. METHODS: The extracts of Radix Aconitum kusnezoffii were collected by using Franz diffusion cells after permeation through the skin of rats. Then rate constants of skin permeation of aconitine and mesaconitine were determined by high-performance liquid chromatography (HPLC). RESULTS: Under the condition that the concentrations of azone and propylene glycol were both 4%, the cumulative doses of skin permeation (Q) of mesaconitine and aconitine in the extracts of Radix Aconitum kusnezoffii (600 mg/ml) for 24 hours were 165.819 and 487.747 microg/cm(2) respectively, and their rate constants of skin permeation were 18.391 and 78.805 microg.cm(-2).h(-1) respectively. CONCLUSION: The aconitine and mesaconitine in the extracts of Radix Aconitum kusnezoffii can penetrate well through the skin of rats. Propylene glycol and azone can promote this penetration effects. The formula of skin permeation of mesaconitine and aconitine is in accordance with Higuchi equation and there is a linear relationship between Q and t(1/2).

A new biocompatible microemulsion increases extraction yield and bioavailability of Andrographis paniculata.

The purpose of this study was to design and prepare a biocompatible microemulsion of Andrographis paniculata (BMAP) containing both fat-soluble and water-soluble constituents. We determined the contents of active constituents of BMAP and evaluated its bioavailability. The biocompatible microemulsion (BM), containing lecithin and bile salts, was optimized in the present study, showing a good physical stability. The mean droplet size was 19.12 nm, and the average polydispersity index (PDI) was 0.153. The contents of andrographolide and dehydroandrographolide in BMAP, as determined by high performance liquid chromatography (HPLC), were higher than that in ethanol extraction. The pharmacokinetic results of BMAP showed that the AUC0-7 and AUC0→∞ values of BMAP were 2.267 and 27.156 µg·mL(-1)·h(-1), respectively, and were about 1.41-fold and 6.30-fold greater than that of ethanol extraction, respectively. These results demonstrated that the bioavailability of and rographolide extracted by BMAP was significantly higher than that extracted by ethanol. In conclusion, the BMAP preparation displayed ann improved dose form for future clinical applications.

[Dynamic effect of low frequency complex impulse current on transdermal absorption of secretio bufonis].

OBJECTIVE: To explore the regulation of transdermal absorption of Secretio Bufonis (SB) and the effect of low frequency complex impulse current (LFCIC) on it. METHODS: By modifying three-chamber flow diffusion pool to develop a prototype LFCIC device for transdermal delivery, using high performance liquid chromatograph (HPLC) to determine the quantitative transdermal absorption of the amount of ingredients of SB, including bufalin, cinobufagin and resibufogenin, etc. and the transdermal absorption velocity was calculated. RESULTS: The chief ingredients of SB could be absorbed through skin, but the volume was low. Additional application of LFCIC could enhance the cumulative infiltration volume and velocity of transdermal diffusion. Difference appeared 2 hrs after and significant difference appeared 4 hrs after the application, and 13.8 Hz showed the optimal effect of transdermal delivery. CONCLUSION: Chief ingredients of SB could be absorbed through transdermal medication, and LFCIC can evidently enhance the amount and velocity of transdermal absorption of SB.

Design and application of pulse information acquisition and analysis system with dynamic recognition in traditional Chinese medicine.

BACKGROUND: To design the pulse information which includes the parameter of pulse-position, pulse-number, pulse-shape and pulse-force acquisition and analysis system with function of dynamic recognition, and research the digitalization and visualization of some common cardiovascular mechanism of single pulse. METHODS: To use some flexible sensors to catch the radial artery pressure pulse wave and utilize the high frequency B mode ultrasound scanning technology to synchronously obtain the information of radial extension and axial movement, by the way of dynamic images, then the gathered information was analyzed and processed together with ECG. Finally, the pulse information acquisition and analysis system was established which has the features of visualization and dynamic recognition, and it was applied to serve for ten healthy adults. RESULTS: The new system overcome the disadvantage of one-dimensional pulse information acquisition and process method which was common used in current research area of pulse diagnosis in traditional Chinese Medicine, initiated a new way of pulse diagnosis which has the new features of dynamic recognition, two-dimensional information acquisition, multiplex signals combination and deep data mining. CONCLUSIONS: The newly developed system could translate the pulse signals into digital, visual and measurable motion information of vessel.

Specific role of synovial macrophages in rheumatoid arthritis / 中国药理学与毒理学杂志

Rheumatoid arthritis (RA) is an autoimmune disease, which is characterized by synovial inflammation. Hyperplasia sublining macrophages found in synovium is an early hallmark of RA and effective treatment results in their diminution. However, the origin of these sublining macrophages in synovium (including infiltrated macrophages and tissue-resident macrophages) are still unknown both in animal models of arthritis and RA patients, let alone the differences and feature of these macro?phages. In rheumatic synovium, macrophages are submitted to a large variety of micro-environmental signals which influence the phenotypic polarization and activation of macrophages. Understanding the mechanisms and functional consequences of the heterogeneous macrophages will contribute to confirm their potential role in synovial inflammation development. Furthermore, research on macrophage plasticity to soft-control their phenotypic polarization could lead to novel therapeutic approaches.