Multi-level advances in databases related to systems pharmacology in traditional Chinese medicine: a 60-year review.

The therapeutic effects of traditional Chinese medicine (TCM) involve intricate interactions among multiple components and targets. Currently, computational approaches play a pivotal role in simulating various pharmacological processes of TCM. The application of network analysis in TCM research has provided an effective means to explain the pharmacological mechanisms underlying the actions of herbs or formulas through the lens of biological network analysis. Along with the advances of network analysis, computational science has coalesced around the core chain of TCM research: formula-herb-component-target-phenotype-ZHENG, facilitating the accumulation and organization of the extensive TCM-related data and the establishment of relevant databases. Nonetheless, recent years have witnessed a tendency toward homogeneity in the development and application of these databases. Advancements in computational technologies, including deep learning and foundation model, have propelled the exploration and modeling of intricate systems into a new phase, potentially heralding a new era. This review aims to delves into the progress made in databases related to six key entities: formula, herb, component, target, phenotype, and ZHENG. Systematically discussions on the commonalities and disparities among various database types were presented. In addition, the review raised the issue of research bottleneck in TCM computational pharmacology and envisions the forthcoming directions of computational research within the realm of TCM.

Xin Su Ning-A Review of Basic and Clinical Pharmacology Integrated With Traditional Chinese Medicine Antiarrhythmic Theory.

Xin Su Ning (XSN) is a patented multicomponent medicine, which was certified in 2005 by the China State Food and Drug Administration to be produced pharmaceutically and to be used clinically. The XSN capsule was developed from an effective formula composed by Prof. Shuwen Ding of Shandong University of Traditional Chinese Medicine. Through more than 30 years of clinical observation, Prof. Ding concluded that XSN has a significant effect on arrhythmia with phlegm-heat heart-disturbed syndrome according to the traditional Chinese medicine (TCM) diagnosis. XSN, derived from a classical TCM formula Huanglian Wen Dan Decoction, is formulated with 11 Chinese herbal medicines to treat cardiac ventricular arrhythmia. Clinical evidence suggests that it is particularly efficacious for the arrhythmias induced by cardiac ischemia and viral myocarditis without obvious adverse reactions being reported. Cellular electrophysiological studies in ventricular myocytes revealed that XSN prolongs the duration and suppresses the amplitude of the action potential (AP), which is supported by the blockage of sodium and potassium channels indicating the characteristics of class I and III antiarrhythmic drugs. A recently reported double-blind, placebo-controlled, multicenter clinical trial of XSN enrolled 861 patients (ChiCTR-TRC-14004180) and showed that XSN significantly inhibited premature ventricular contraction (PVC). The cellular electrophysiological discoveries provided the mechanistic evidence for the clinical efficacy on inhibition of PVC by XSN as demonstrated in the clinical trial. These studies, for the first time, provided exclusive evidence that multicomponent TCM antiarrhythmic medicine can be evaluated using conventional research methods that have been used for antiarrhythmic drug discoveries for decades. We aimed to give a comprehensive review on XSN including its origin with the support of TCM theory, its pre-licensing clinical use and development, and its pharmacological and clinical study discoveries. The review will be summarized with the discoveries reported in a novel network pharmacological study that introduced a weight coefficient, which made it possible to evaluate the pharmacological properties of the TCM formula with regard to its formation based on TCM theory. Limitations regarding XSN's basic and clinical research and possible future studies are listed. We hope that the advances in how XSN was studied may offer useful guidance on how other TCM could be studied with respect to the integrity of the TCM formulas.

Investigation of the Cellular Pharmacological Mechanism and Clinical Evidence of the Multi-Herbal Antiarrhythmic Chinese Medicine Xin Su Ning.

Xin Su Ning (XSN), a China patented and certified multi-herbal medicine, has been available in China since 2005 for treating cardiac ventricular arrhythmia including arrhythmia induced by ischemic heart diseases and viral myocarditis, without adverse reactions being reported. It is vitally important to discover pharmacologically how XSN as a multicomponent medicine exerts its clinical efficacy, and whether the therapeutic effect of XSN can be verified by standard clinical trial studies. In this paper we report our discoveries in a cellular electrophysiological study and in a three-armed, randomized, double-blind, placebo-controlled, parallel-group, multicenter trial. Conventional electrophysiological techniques were used to study the cellular antiarrhythmic mechanism of XSN. Data was then modeled with computational simulation of human action potential (AP) of the cardiac ventricular myocytes. The clinical trial was conducted with a total of 861 eligible participants randomly assigned in a ratio of 2:2:1 to receive XSN, mexiletine, or the placebo for 4 weeks. The primary and secondary endpoint was the change of premature ventricular contraction (PVC) counts and PVC-related symptoms, respectively. This trial was registered in the Chinese Clinical Trial Register Center (ChiCTR-TRC-14004180). We found that XSN prolonged AP duration of the ventricular myocytes in a dose-dependent, reversible manner and blocked potassium channels. Patients in XSN group exhibited significant total effective responses in the reduction of PVCs compared to those in the placebo group (65.85% vs. 27.27%, P < 0.0001). No severe adverse effects attributable to XSN were observed. In conclusion, XSN is an effective multicomponent antiarrhythmic medicine to treat PVC without adverse effect in patients, which is convincingly supported by its class I & III pharmacological antiarrhythmic mechanism of blocking hERG potassium channels and hNaV1.5 sodium channel reported in our earlier publication and prolongs AP duration both in ventricular myocytes and with computational simulation of human AP presented in this report.

Deciphering the Active Compounds and Mechanisms of Qixuehe Capsule on Qi Stagnation and Blood Stasis Syndrome: A Network Pharmacology Study.

BACKGROUND: Qixuehe capsule (QXH), a Chinese patent medicine, has been demonstrated to be effective in the treatment of menstrual disorders. In traditional Chinese medicine (TCM) theory, qi stagnation and blood stasis syndrome (QS-BSS) is the main syndrome type of menstrual disorders. However, the pharmacodynamic effect of QXH in treating QS-BSS is not clear, and the main active compounds and underlying mechanisms remain unknown. METHODS: A rat model of QS-BSS was established to evaluate the pharmacodynamic effect of QXH. Thereafter, a network pharmacology approach was performed to decipher the active compounds and underlying mechanisms of QXH. RESULTS: QXH could significantly reduce the rising whole blood viscosity (WBV) and plasma viscosity (PV) but also normalize prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), and fibrinogen (FIB) content in QS-BSS rats. Based on partial least-squares-discriminant analysis (PLS-DA), the low-dose QXH-intervened (QXH-L) and the high-dose QXH-intervened (QXH-H) groups seemed the most effective by calculating the relative distance to normality. Through network pharmacology, QXH may improve hemorheological abnormality mainly via 185 compounds-51 targets-28 pathways, whereas 184 compounds-68 targets-28 pathways were associated with QXH in improving coagulopathy. Subsequently, 25 active compounds of QXH were verified by UPLC-Q/TOF-MS. Furthermore, 174 active compounds of QXH were shared in improving hemorheological abnormality and coagulopathy in QS-BSS, each of which can act on multiple targets to be mainly involved in complement and coagulation cascades, leukocyte transendothelial migration, PPAR signaling pathway, VEGF signaling pathway, and arachidonic acid metabolism. The attribution of active compounds indicated that Angelicae Sinensis Radix (DG), Paeoniae Radix Rubra (CS), Carthami Flos (HH), Persicae Semen (TR), and Corydalis Rhizoma (YHS) were the vital herbs of QXH in treating QS-BSS. CONCLUSION: QXH can improve the hemorheology abnormality and coagulopathy of QS-BSS, which may result from the synergy of multiple compounds, targets, and pathways.

A Network Pharmacology Study of the Multi-Targeting Profile of an Antiarrhythmic Chinese Medicine Xin Su Ning.

Xin Su Ning (XSN) is a China patented and certified traditional Chinese herbal medicine used to treat premature ventricular contractions (PVCs) since 2005. XSN is formulated with 11 herbs, designed to treat arrhythmia with phlegm-heat heart-disturbed syndrome (PHHD) according to Chinese medicine theory. The rational compatibility of the 11 herbs decides the therapeutic outcome of XSN. Due to the multicomponent nature of traditional Chinese medicine, it is difficult to use conventional pharmacology to interpret the therapeutic mechanism of XSN in terms of clear-cut drug molecule and target interactions. Network pharmacology/systematic pharmacology usually consider all the components in a formula with the same weight; therefore, the proportion of the weight of the components has been ignored. In the present study, we introduced a novel coefficient to mimic the relative amount of all the components in relation with the weight of the corresponding herb in the formula. The coefficient is also used to weigh the pharmacological effect of XSN on all relative biological pathways. We also used the cellular electrophysiological data generated in our lab, such as the effect of liensinine and isoliquiritigenin on NaV1.5 channels; we therefore set sodium channel as one of the targets of these two components, which would support the clinical efficacy of XSN in treating tachyarrhythmia. Combining the collected data and our discovery, a panoramagram of the pharmacological mechanism of XSN was established. Pathway enrichment and analysis showed that XSN treated PHHD arrhythmia through multiple ion channels regulation, protecting the heart from I/R injury, inhibiting the apoptosis of cardiomyocyte, and improving glucose and lipid metabolism.

Corrigendum: Ion Channel Targeted Mechanisms of Anti-arrhythmic Chinese Herbal Medicine Xin Su Ning.

[This corrects the article DOI: 10.3389/fphar.2019.00070.].

Ion Channel Targeted Mechanisms of Anti-arrhythmic Chinese Herbal Medicine Xin Su Ning.

Xin Su Ning (XSN) is a China patented and certified herbal medicine used to treat premature ventricular contractions (PVCs) since 2005. A recent completed clinical trial of 861 patients showed that XSN had similar PVC inhibition rate to the class I antiarrhythmic drug mexiletine, at 65.85% for XSN and 63.10% for mexiletine. We have previously reported that XSN prolongs action potential duration (APD) and suppresses action potential amplitude (APA) of the cardiac ventricular myocytes. In this report we aim to reveal the effect of XSN on the ionic channels that govern APD and APA, which would help to explain the cellular electrophysiological mechanism of XSN. Our main findings are: (1) On ECG recorded in isolated rat, in the presence of XSN the amplitude of R wave was significantly decreased and the amplitude of T wave was increased significantly; (2) XSN blocked hNaV1.5 channel stably transfected cell line in a dose-dependent manner with an IC50 of 0.18 ± 0.02 g/L; and (3) XSN suppresses hERG channels in a dose-dependent manner with an IC50 of 0.34 ± 0.01 g/L. In conclusion, the clinical antiarrhythmic efficacy of XSN is based on its class I and Class III antiarrhythmic properties by suppression hNaV1.5 channel and hERG channels, which are directly responsible for XSN's effect on APA suppression and APD prolongation.

[Arsenic Adsorption and Its Species on Ferrihydrite and Ferrihydrite Colloid].

Batch experiments were conducted to investigate the adsorption kinetics and adsorption isotherms of As(Ⅲ) and As(Ⅴ) on ferrihydrite and its colloid. A sequential extraction technique and As speciation extraction were used to assess the chemically bound fractions of As and As species in solids, respectively. The kinetic and isotherm data showed that the adsorption was multilevel and readily occurred. The adsorption of As(Ⅲ) and As(Ⅴ) on the ferrihydrite colloid was 194.8 g·kg-1 and 107.3 g·kg-1, respectively, which was higher than that on ferrihydrite (155.2 g·kg-1 and 104.4 g·kg-1). The specifically adsorbed As, amorphous oxide bound As, and crystalline oxide bound As were the major fractions of adsorbed As on ferrihydrite and its colloid. The residual As was absorbed on the ferrihydrite surface instead of on the ferrihydrite colloid. Therefore, As adsorption on ferrihydrite was much stronger than that on ferrihydrite colloid. The ferrihydrite and ferrihydrite colloid could not reduce As(Ⅴ) to As(Ⅲ).

[Progress in research of traditional Chinese medicine Citrus aurantium].

Citrus aurantium is one of the most common traditional Chinese medicines. In this paper, the chemical components, content determination and pharmacological actions of C. aurantium were summarized for the comprehensive utilization of its resources. Because of the complicated resources of C. aurantium, only one single component as index couldn't reflect the quality and effects and comprehensive evaluation which concluding multiple components should be established in the future quality control. In recent years, the pharmacological effects research of C. aurantium has made tremendous progress, and it is important to explore new drugs from the development and utilization of the active ingredient of C. aurantium. In recent years, the pharmacological effects research of C. aurantium has made tremendous progress, and it is important to explore new drugs from the development and utilization of the active ingredient of C. aurantium.

Rosai-Dorfman disease (RDD) in the paraglottic space: report of a case and review of literature.

Sinus histiocytosis with massive lymphadenopathy is also known as Rosai-Dorfman disease (RDD) and is characterized by painless bilateral cervical lymphadenopathy. In the present case report, a 67-year-old Chinese woman presented with a 3-month history of progressive voice hoarseness, progressive dyspnea on exertion and a foreign body sensation. MRI revealed a lesion involving the right side of the paraglottic space. The lesion was totally resected. Based on the histologic features and immunoreactivity for the S-100 protein and CD68, a diagnosis of RDD was made. We described an extremely unique case of RDD that was observed in the paraglottic space and discussed its clinical and histopathologic features, differential diagnoses and treatment options.

Sarcolemmal localisation of Na+/H+ exchange and Na+-HCO3- co-transport influences the spatial regulation of intracellular pH in rat ventricular myocytes.

Membrane acid extrusion by Na(+)/H(+) exchange (NHE1) and Na(+)-HCO3(-) co-transport (NBC) is essential for maintaining a low cytoplasmic [H(+)] (∼60 nm, equivalent to an intracellular pH (pHi) of 7.2). This protects myocardial function from the high chemical reactivity of H(+) ions, universal end-products of metabolism. We show here that, in rat ventricular myocytes, fluorescent antibodies map the NBC isoforms NBCe1 and NBCn1 to lateral sarcolemma, intercalated discs and transverse tubules (t-tubules), while NHE1 is absent from t-tubules. This unexpected difference matches functional measurements of pHi regulation (using AM-loaded SNARF-1, a pH fluorophore). Thus, myocyte detubulation (by transient exposure to 1.5 m formamide) reduces global acid extrusion on NBC by 40%, without affecting NHE1. Similarly, confocal pHi imaging reveals that NBC stimulation induces spatially uniform pHi recovery from acidosis, whereas NHE1 stimulation induces pHi non-uniformity during recovery (of ∼0.1 units, for 2-3 min), particularly at the ends of the cell where intercalated discs are commonly located, and where NHE1 immunostaining is prominent. Mathematical modelling shows that this induction of local pHi microdomains is favoured by low cytoplasmic H(+) mobility and long H(+) diffusion distances, particularly to surface NHE1 transporters mediating high membrane flux. Our results provide the first evidence for a spatial localisation of [H(+)]i regulation in ventricular myocytes, suggesting that, by guarding pHi, NHE1 preferentially protects gap junctional communication at intercalated discs, while NBC locally protects t-tubular excitation-contraction coupling.

The effects of paeonol on the electrophysiological properties of cardiac ventricular myocytes.

Previous studies have shown that "Mudanpi", a Chinese herbal medicine, has a significant cardioprotective effect against myocardial ischaemia. Based on these findings we hypothesised that paeonol, the main component of Mudanpi, might have an effect on the cellular electrophysiology of cardiac ventricular myocytes. The effects of paeonol on the action potential and ion channels of cardiac ventricular myocytes were studied using the standard whole-cell configuration of the patch-clamp technique. Ventricular myocytes were isolated from the hearts of adult guinea-pig by enzymic dispersion. The myocytes were continuously perfused with various experimental solutions at room temperature and paeonol applied in the perfusate. Action potentials and membrane currents were recorded using both current and voltage clamp modes of the patch-clamp technique. Paeonol, at concentrations 160 microM and 640 microM, decreased the action potential upstroke phase, an action associated with the blockade of the voltage-gated, fast sodium channel. The effects of paeonol on both action potential and Na(+) current were concentration dependent. Paeonol had a high affinity for inactivated sodium channels. Paeonol also shortened the action potential duration, in a manner not associated with the blockade of the calcium current, or the enhancement of potassium currents. These findings suggest that paeonol, and therefore Mudanpi, may possess antiarrhythmic activity, which may confer its cardioprotective effects.

Overexpression of connexin 43 using a retroviral vector improves electrical coupling of skeletal myoblasts with cardiac myocytes in vitro.

BACKGROUND: Organ transplantation is presently often the only available option to repair a damaged heart. As heart donors are scarce, engineering of cardiac grafts from autologous skeletal myoblasts is a promising novel therapeutic strategy. The functionality of skeletal muscle cells in the heart milieu is, however, limited because of their inability to integrate electrically and mechanically into the myocardium. Therefore, in pursuit of improved cardiac integration of skeletal muscle grafts we sought to modify primary skeletal myoblasts by overexpression of the main gap-junctional protein connexin 43 and to study electrical coupling of connexin 43 overexpressing myoblasts to cardiac myocytes in vitro. METHODS: To create an efficient means for overexpression of connexin 43 in skeletal myoblasts we constructed a bicistronic retroviral vector MLV-CX43-EGFP expressing the human connexin 43 cDNA and the marker EGFP gene. This vector was employed to transduce primary rat skeletal myoblasts in optimised conditions involving a concomitant use of the retrovirus immobilising protein RetroNectin and the polycation transduction enhancer Transfectam. The EGFP-positive transduced cells were then enriched by flow cytometry. RESULTS: More than four-fold overexpression of connexin 43 in the transduced skeletal myoblasts, compared with non-transduced cells, was shown by Western blotting. Functionality of the overexpressed connexin 43 was demonstrated by microinjection of a fluorescent dye showing enhanced gap-junctional intercellular transfer in connexin 43 transduced myoblasts compared with transfer in non-transduced myoblasts. Rat cardiac myocytes were cultured in multielectrode array culture dishes together with connexin 43/EGFP transduced skeletal myoblasts, control non-transduced skeletal myoblasts or alone. Extracellular field action potential activation rates in the co-cultures of connexin 43 transduced skeletal myoblasts with cardiac myocytes were significantly higher than in the co-cultures of non-transduced skeletal myoblasts with cardiac myocytes and similar to the rates in pure cultures of cardiac myocytes. CONCLUSION: The observed elevated field action potential activation rate in the co-cultures of cardiac myocytes with connexin 43 transduced skeletal myoblasts indicates enhanced cell-to-cell electrical coupling due to overexpression of connexin 43 in skeletal myoblasts. This study suggests that retroviral connexin 43 transduction can be employed to augment engineering of the electrocompetent cardiac grafts from patients' own skeletal myoblasts.

Alpha 1-acid glycoprotein reverses cocaine-induced sodium channel blockade in cardiac myocytes.

UNLABELLED: Alpha 1-acid glycoprotein (AAG) is an acute phase protein capable of binding basic drugs. This action explains its reversal of sodium channel blockade by drugs such as amitriptyline and quinidine. We report here the reversal of cocaine-induced sodium channel blockade by AAG. The sodium channel blocking property of cocaine is a major mechanism behind cocaine-induced sudden cardiac death, since sodium channels play a key role in the initiation and regulation of the heart beat. Voltage-gated sodium current (I(Na)) was recorded using whole-cell patch-clamp techniques. Guinea-pig cardiac ventricular myocytes were isolated and continuously perfused at room temperature with physiological solutions. At concentrations ranging from 5 to 320 microM cocaine showed a dose-dependent and reversible blockade of I(Na) with an IC50 of 45.9 microM. The addition of equimolar amounts of AAG to cocaine produced almost complete reversal of cocaine's effects, suggesting a single binding site for cocaine on the AAG molecule. With changes of peak I(Na) normalized against control as 1, cocaine at 20 and 40 microM reduced I(Na) to 0.62+/-0.042 (n = 6) and 0.57+/-0.052 (n = 9), respectively, and the addition of an equimolar concentration of AAG reversed I(Na) to 0.86+/-0.022 and 0.91+/-0.060, respectively. IN CONCLUSION: AAG reverses cocaine-induced sodium channel blockade in a dose-dependent manner, indicating a therapeutic potential to reverse acute cocaine cardiac toxicity.