Efficacy and safety of traditional Chinese medicine for acute ischemic stroke by resolving phlegm and unblocking fu-organs: A systematic review and meta-analysis.

ETHNOPHARMACOLOGICAL RELEVANCE: Many researchers have adopted resolving phlegm and unblocking fu-organs (RPUF) therapy for acute ischemic stroke (AIS) patients and yielded beneficial results in terms of clinical symptoms. However, there has been no systematically pooled analysis of RPUF therapy for AIS to date. Therefore, a well-designed systematic review and meta-analysis is necessary. AIM: This systematic review aims to determine the efficacy and safety of traditional Chinese medicine (TCM) therapy for resolving phlegm and unblocking fu-organs (RPUF) for the treatment of acute ischemic stroke (AIS). METHODS: Eight databases were searched to identify eligible randomized controlled trials (RCTs) involving RPUF therapy for AIS. The primary outcome included the modified Rankin Scale (mRS), and the secondary outcomes were the National Institute of Health Stroke Scale (NIHSS), the Neurological Deficit Score (NDS), Barthel Index (BI), Fugel-Meyer assessment (FMA), and the Glasgow Coma Scale (GCS). The Cochrane Handbook for Systematic Reviews of Interventions was used to assess risk of bias. The quantitative synthesis was analyzed using RevMan 5.3 and Stata 14.0 software. RESULTS: The systematic review and meta-analysis comprised 61 RCTs with a total of 6056 participants. RPUF prescriptions combined with usual care were superior to usual care alone in individuals with AIS, as evidenced by decreased mRS (MD＝-0.34; 95%CI [-0.65, -0.03]; P＝0.03), NIHSS (MD＝-3.38; 95%CI [-4.07, -2.68]; P＜0.00001), and NDS (MD＝-3.65; 95%CI [-4.07, -3.24]; P＜0.00001), as well as improved BI (MD＝10.4; 95%CI [8.21, 12.59]; P＜0.00001), FMA (MD＝20.41; 95%CI [17.40, 23.41]; P＜0.00001), and GCS (MD＝3.08; 95%CI [1.95, 4.20]; P＜0.00001). No significant difference was observed in the incidence of adverse effects between the RPUF therapy group and the usual care group. CONCLUSION: RPUF therapy appears to be an effective and safe approach for treating AIS; it could decrease mRS, NIHSS, and NDS while improving BI, FMA, and GCS. However, the methodological quality of the included RCTs was far from sufficient, and further high-quality, well-designed RCTs with long-term follow-up are still required.

A propensity score matched comparison of blood pressure lowering in essential hypertension patients treated with antihypertensive Chinese herbal Medicine: comparing the real-world registry data vs. randomized controlled trial.

BACKGROUND: Randomized controlled trials have demonstrated that Songling Xuemaikang capsule (SXC) is effective in blood pressure (BP) lowering for essential hypertension. However, the effectiveness of SXC in real-world clinical practice remains unknown. We aimed to investigate whether the BP-lowering effectiveness of SXC in the real-world practice setting is comparable to the efficacy of the intervention in a randomized controlled trial. METHODS: We included 1325 patients treated with SXC monotherapy from a real-world registry and 300 from the SXC-BP trial. A propensity score matching (PSM) approach was used to select participants from the two cohorts. The primary outcome was a change in the office of BP from baseline to 8 weeks. RESULTS: After PSM, there were 552 patients for the comparative analysis. Clinically meaningful BP reductions were observed both in the real world and in the RCT cohorts after 8-week SXC treatment. The 8-week systolic/diastolic BP was 129.50/81.33 mm Hg vs. 134.97/84.14 mm Hg in the real-world population and the RCT population, respectively. The changes in systolic BP (15.82 ± 10.71 vs. 10.48 ± 10.24; P < .001), and diastolic BP (10.01 ± 7.73 vs. 7.75 ± 8.14; P = .001) from baseline to 8 weeks were significantly greater in the real-world population. CONCLUSION: The current comparison demonstrated that SXC monotherapy is at least as effective in real-world settings as within the randomized controlled trial for BP lowering in patients with grade 1 hypertension.

Benefits and risks of antiplatelet therapy for moyamoya disease: a systematic review and meta-analysis.

Background: Moyamoya disease (MMD) is a leading cause of stroke in children and young adults, whereas no specific drugs are available. Antiplatelet therapy (APT) has been considered a promising treatment option, but its effectiveness remains controversial. Therefore, we aimed to comprehensively evaluate the benefits and risks of APT for MMD. Methods: We systematically searched PubMed, Embase, and Cochrane Library electronic databases from their inception to 30 June 2022 and conducted a systematic review. All-cause mortality was taken as the primary outcome. Results: Nine studies that enrolled 16,186 patients with MMD were included. The results from a single study showed that APT was associated with lower mortality [hazard ratio (HR) = 0.60; 95% confidence interval (CI) (0.50-0.71); p < 0.01] and improved bypass patency after surgical revascularization [HR = 1.57; 95% CI (1.106-2.235); p < 0.05]. The results of the meta-analysis showed that APT reduced the risk of hemorrhagic stroke [HR = 0.47; 95% CI (0.24-0.94); p < 0.05] but neither reduced the risk of ischemic stroke [HR = 0.80; 95% CI (0.33-1.94); p = 0.63] nor increased the proportion of independent patients [RR = 1.02; 95% CI (0.97-1.06); p = 0.47]. Conclusion: Current evidence showed that APT was associated with a reduced risk of hemorrhagic stroke in MMD patients but did not reduce the risk of ischemic stroke or increase the proportion of independent patients. There was insufficient evidence about the benefit of APT on survival and postoperative bypass patency after surgical revascularization. However, the results should be interpreted cautiously because of the limited number of studies. Systematic review registration: https://www.crd.york.ac.uk/prospero/.

Plasma exosome proteomics reveals the pathogenesis mechanism of post-stroke cognitive impairment.

Exploration and utilization of exosome biomarkers and their related functions provide the possibility for the diagnosis and treatment of post-stroke cognitive impairment (PSCI). To identify the new diagnostic and prognostic biomarkers of plasma exosome were uzed label-free quantitative proteomics and biological information analysis in PSCI patients. Behavioral assessments were performed, including the Mini-Mental Status Examination (MMSE), the Montreal Cognitive Assessment (MoCA), the Barthel index, the Morse Fall Seale (MFS) between control group (n = 10) and PSCI group (n = 10). The blood samples were collected to analyse the biomarker and differentially expressed proteins of plasma exosome using label-free quantitative proteomics and biological information. The exosomes marker proteins were determined by Western blot. The exosome morphology was observed by transmission electron microscopy. The scores of MMSE and MoCA were significantly decreased in the PSCI group. The PT% and high-density lipoprotein decreased and the INR ratio increased in PSCI group. The mean size of exosome was approximately 71.6 nm and the concentration was approximately 6.8E+7 particles/mL. Exosome proteomics identified 259 differentially expressed proteins. The mechanisms of cognitive impairment are related to regulate the degradation of ubiquitinated proteins, calcium dependent protein binding, cell adhesive protein binding, formation of fibrin clot, lipid metabolism and ATP-dependent degradation of ubiquitinated proteins in plasma exosome of PSCI patients. Plasma levels of YWHAZ and BAIAP2 were significantly increased while that of IGHD, ABCB6 and HSPD1 were significantly decreased in PSCI patients. These proteins might be target-related proteins and provide global insights into pathogenesis mechanisms of PSCI at plasma exosome proteins level.

DrugAI: a multi-view deep learning model for predicting drug-target activating/inhibiting mechanisms.

Understanding the mechanisms of candidate drugs play an important role in drug discovery. The activating/inhibiting mechanisms between drugs and targets are major types of mechanisms of drugs. Owing to the complexity of drug-target (DT) mechanisms and data scarcity, modelling this problem based on deep learning methods to accurately predict DT activating/inhibiting mechanisms remains a considerable challenge. Here, by considering network pharmacology, we propose a multi-view deep learning model, DrugAI, which combines four modules, i.e. a graph neural network for drugs, a convolutional neural network for targets, a network embedding module for drugs and targets and a deep neural network for predicting activating/inhibiting mechanisms between drugs and targets. Computational experiments show that DrugAI performs better than state-of-the-art methods and has good robustness and generalization. To demonstrate the reliability of the predictive results of DrugAI, bioassay experiments are conducted to validate two drugs (notopterol and alpha-asarone) predicted to activate TRPV1. Moreover, external validation bears out 61 pairs of mechanism relationships between natural products and their targets predicted by DrugAI based on independent literatures and PubChem bioassays. DrugAI, for the first time, provides a powerful multi-view deep learning framework for robust prediction of DT activating/inhibiting mechanisms.

Efficacy and safety of Songling Xuemaikang capsule for essential hypertension: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Hypertension is one of the most significant public health challenges worldwide. An increasing number of patients prefer to incorporate traditional Chinese medicine into their hypertensive care. The Songling Xuemaikang capsule (SXC), a Chinese herbal formula, is widely used in China for essential hypertension. PURPOSE: To assess the efficacy and safety of SXC for essential hypertension. STUDY DESIGN: Systematic review and meta-analysis of randomized controlled trials (RCTs). METHODS: We conducted a systematic literature search of seven databases to identify randomized controlled trials of SXC for hypertension. The outcome measures included blood pressure parameters and patient-reported outcomes. Potential heterogeneity between the studies was resolved by subgroup and sensitivity analyses. The quality of the results was evaluated using the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) approach. RESULTS: A total of 34 trials with 4306 patients were included. The results showed that SXC plus antihypertensive drugs produced a greater effect on reducing systolic blood pressure (SBP) (MD: -7.54 mmHg; 95% CI: -8.92, -6.17; p < 0.00001), diastolic blood pressure (DBP) (MD: -6.42 mmHg; 95% CI: -7.54, -5.29; p < 0.00001), 24-hour SBP (MD: -6.88 mmHg; 95% CI: -8.36, -5.39; p < 0.00001), and 24-hour DBP (MD: -4.31 mmHg; 95% CI: -6.55, -2.07; p = 0.0002) and improving hypertensive symptoms (SMD: -1.09; 95% CI: -1.34, -0.84; p < 0.00001) than antihypertensive drugs alone. SXC monotherapy was less effective than antihypertensive drugs for 24-hour SBP reduction (MD: 2.07 mmHg; 95% CI: 0.19, 3.96; p = 0.03). No significant difference was observed in the incidence of adverse events between the SXC and control groups. CONCLUSION: SXC is beneficial for essential hypertension; it can lower BP, improve hypertensive symptoms and is well tolerated.

Trial of a prehospital intervention with traditional Chinese medicine for acute stroke (TRACE): Protocol for a mixed-methods research study.

Background: As the only traditional Chinese medicine injection approved by the China Food and Drug Administration for use as stroke first aid in ambulances, Xingnaojing Injection (XNJI) has been widely used in cases of both acute ischemic stroke (IS) and intracerebral hemorrhage (ICH). However, there is no robust clinical evidence regarding the efficacy and safety of the early use of XNJI during stroke first aid. The main purpose of this trial is to observe whether XNJI, intravenously administered within 24 h of onset in the prehospital ambulance setting, protects against early neurological deterioration (END) on the third day of onset in patients with acute stroke. Methods: The Trial of a prehospital intervention with traditional Chinese medicine for acute stroke (TRACE) is a Mixed-Methods research (MMR) study that involves a combination of quantitative and qualitative research. The quantitative research part of this project is a prospective, multicenter, observational, clinical registry study, for which we aimed to recruit 1,000 patients with acute stroke (IS and ICH). Based on our observation of whether XNJI was intravenously administered within 24 h of onset in the prehospital ambulance setting, patients with acute stroke will be divided into two groups: the exposure group comprising patients who were intravenously administered XNJI and the nonexposure group comprising patients who were not. The primary outcome is early neurological deterioration (END) on the third day of onset defined as an increase of 2 or more points in the National Institute of Health Stroke Scale score between baseline and day 3. In addition, based on the aforementioned quantitative research, qualitative research will be conducted by interviewing emergency doctors about their knowledge and attitude regarding XNJI used for stroke first aid. Discussion: The results of the TRACE study will provide preliminary evidence for the relationship between XNJI used within 24 h of onset and the presence of END on the third day after stroke onset; it will aid in improving the current knowledge regarding the early use of XNJI for stroke first aid. Clinical Trial Registration: clinicaltrials.gov, identifier NCT04275349.

Efficacy and safety of LongShengZhi capsule on functional recovery after acute ischemic stroke (LONGAN): Protocol and statistical analysis plan for a randomized, double-blind, placebo-controlled trial.

Background: Due to limited time windows and technical requirements, only a small percentage of patients can receive reperfusion therapy for acute ischemic stroke (AIS). Previous studies have shown that LongShengZhi (LSZ) capsule can improve neurological outcomes in patients after AIS, yet those results have not been finally verified through rigorous randomized controlled trials. Thus, this trial was designed to further clarify the efficacy and safety of LSZ capsule for patients with AIS. Methods: LSZ capsule on Functional Recovery after Acute Ischemic Stroke (LONGAN) trial is a prospective, multicenter, randomized, placebo-controlled, double-blind, parallel-group, superiority trial that enrolls patients from stroke and rehabilitation units in China. We will enroll 1,376 patients aged 18 years or older with AIS within 7 days of symptom onset and a National Institute of Health Stroke Scale (NIHSS) score of 4-15. Eligible patients will be randomized to receive either 2 g LSZ capsules three times a day or placebo LSZ capsules for 90 days. The primary outcome is the proportion of patients with favorable outcomes, as measured by the modified Rankin Scale (mRS) 90 days after randomization. The main safety outcome is the proportion of severe adverse events. Conclusion: This study will be the first randomized, double-blind trial to evaluate the efficacy and safety of LSZ capsule in patients with AIS. In order to improve the transparency and reproducibility of the trial, the data will be analyzed in accordance with this pre-specified plan for statistical analysis to reduce bias due to selective analysis and reporting. This trial aims to provide high-quality evidence for the efficacy and safety of LSZ capsule for AIS.

Platelet-activating factor receptor antagonists of natural origin for acute ischemic stroke: a systematic review of current evidence.

Background: Acute ischemic stroke (AIS) is a common cause of death and long-term disability worldwide. Recent trials of platelet-activating factor receptor antagonists (PAFRA) appeared to indicate that they could play a neuroprotective role in the treatment of AIS; therefore, we conducted a systematic literature review to evaluate the clinical efficacy and safety of PAFRA in patients with AIS. Methods: A systematic literature search was performed in seven electronic databases from inception to 11 March 2022. All randomized controlled trials (RCTs) in which patients were treated with PAFRA strategies within 7 days of stroke onset were included. Modified Rankin Scale (mRS) was selected as the primary outcome of this systematic review. The methodological quality of included studies was assessed based on the Cochrane Collaborations tool. The review protocol was previously registered (PROSPERO CRD42020182075). Results: Fifteen RCTs comprising a total of 3,907 participants were included in this study. The PAFRA-related compounds included natural preparations of terpenoids, flavonoids, and saponins, namely, ginkgo endoterpene diester meglumine (GEDM, seven RCTs), ginkgo biloba dropping pill (GBDP, one RCT), ginkgolide injection (GDI, four RCTs), hesperidin (HES, one RCT), ginsenoside Rd injection (GSRI, one RCT), and hydroxysafflor yellow A (HSYA, one RCT). All studies were conducted in China between 2017 and 2021, employing a two-arm parallel design with sample sizes ranging from 40 to 1,113. Eight studies (53.3%) provided no information on their method of randomization, and only two studies (13.3%) utilized the double-blind design. Treatment was associated with improved clinical outcomes for (1) GEDM, GDI, and GBDP in patients treated with conventional treatment (CM) [GEDM + CM for AIS on mRS: MDmRS = -0.42, 95% CI (-0.47, -0.37), five trials, p < 0.00001; GEDM + CM for AIS on NIHSS: MDNIHSS = -1.02, 95% CI (-1.51, -0.52), four trials, p < 0.0001]; (2) GEDM and GDI in patients treated with neuroprotective agent (NPA) [GEDM + NPA + CM for AIS on mRS: MDmRS = -0.40, 95% CI (-0.54, -0.26), p < 0.00001; GEDM + NPA + CM for AIS on NIHSS: MDNIHSS = -3.93, 95%CI (-7.72, -0.14), p = 0.04]; (3) GBDP in patients treated with CM; (4) GDI and GSRI in patients treated with IV rt-PA therapy (IVT); and (5) HSYA in patients compared with Dengzhan Xixin injection (DZXXI). No access to improved clinical outcome was associated with HES in patients treated with IVT. Seven RCTs reported adverse events (AEs) but found that taking PAFRA-related preparations was not associated with an increased incidence of AEs. Conclusions: This systematic review not only makes an important contribution to the existing body of current evidence but also lays a well-conducted basis for providing opinions and recommendation on the evaluation of PAFRA-based medicine, which could also highlight the need for well-designed clinical trials of PAFRA for AIS to increase the quality of available evidence. Further research is required, using standardized functional outcome measures for AIS, adequate blinding and suitable comparator groups reflecting current best practice.

Multi-omics approaches for deciphering the complexity of traditional Chinese medicine syndromes in stroke: A systematic review.

Background: Deciphering the biological basis of traditional Chinese medicine (TCM) syndromes in complex diseases is challenging. Rapid advances in multi-omics approaches provide new opportunities to unveil the biological basis of TCM syndromes. We intend to summarize the latest significant progress and highlight the crucial value of applying multi-omics approaches to reveal TCM syndromes of stroke in a new horizon. Methods: We systematically searched PubMed, EMBASE, Web of Science Core Collection (WOSCC), Cochrane Library, China National Knowledge Infrastructure (CNKI), Chinese Science and Technology Periodical Database (VIP), Wanfang database and China Biology Medicine Database (SinoMed) for relevant studies from their inception to 31 March 2022, and conducted a comprehensive systematic review (PROSPERO registration number: CRD42021285922). Results: A total of 43 relevant studies were included in the final systematic review, genomics, transcriptomics, proteomics, and metabolomics were all involved. Some gene polymorphisms, differential lncRNAs, mRNAs, miRNAs, proteins, and metabolites may be associated with TCM syndromes of stroke. In addition, some studies conducted a preliminary exploration on the different diseases with the same TCM syndrome. The results showed that thioredoxin-dependent peroxidase reductase may be the specific marker protein of Liver-yang transforming into wind syndrome, and the network formed by mir-146b-5p, -199a-5p, and 23 targeted mRNAs may be the biomarker of Blood-stasis syndrome. Conclusion: Multi-omics technologies have served as powerful tools to investigate the complexity of TCM syndromes and may hold the promise of promoting the modernization of TCM as well as personalized medicine of TCM in stroke.

Edaravone use in acute intracerebral hemorrhage: A systematic review and meta-analysis of randomized controlled trials.

Background: Edaravone alleviates neurological deficits among patients with intracerebral hemorrhage; however, its effects on mortality and long-term functional outcomes remain unknown. Objective: To assess clinical outcomes associated with edaravone initiated within 7 days of symptoms onset in intracerebral hemorrhage. Methods: We systematically searched PubMed, Embase, Cochrane Library, CiNii, China National Knowledge Infrastructure, Chinese VIP information, Wanfang Data, and SinoMed for relevant randomized controlled trials from their inception to 1 May 2021 and conducted a comprehensive systematic review and meta-analysis (PROSPERO registration number: CRD42019147801). All-cause mortality and long-term functional outcomes were taken as the primary outcomes. Results: A total of 38 randomized controlled trials including 3,454 participants with acute intracerebral hemorrhage were included. The selected articles were of poor quality. Meta-analysis revealed that edaravone could not reduce all-cause mortality [relative risk (RR) = 0.51; 95% confidence interval (CI) (0.11-2.32); p = 0.38]. No studies reported on long-term functional outcomes in those trials. In addition, edaravone alleviated neurological deficits [mean difference (MD) = -5.44; 95% CI (-6.44 to -4.44); p<0.00001], improved the activities of daily living [MD = 8.44; 95% CI (7.65-9.23); p<0.00001], reduced the hematoma volume [MD = -4.71; 95% CI (-5.86 to -3.56); p<0.00001], and increased treatment response [RR = 1.26; 95% CI (1.22-1.31); p<0.00001]. In terms of safety outcome, there was no significant difference between the edaravone group and the control groups [RR = 1.67; 95% CI (0.92 to 3.06); p = 0.09]. Conclusion: Till date, edaravone does not associate with mortality reduction when initiated within 7 days of intracerebral hemorrhage onset. The effect of edaravone on long-term functional outcomes remains unknown due to lack of data. Although edaravone alleviated neurological deficits, improved activities of daily living, and reduced hematoma volume, we cautiously interpreted the results owing to the overall poor quality and high heterogeneity of the included trials. Presently, the results are insufficient to support edaravone as a routine treatment option for acute intracerebral hemorrhage.

Cerebral Small Vessel Disease: Neuroimaging Features, Biochemical Markers, Influencing Factors, Pathological Mechanism and Treatment.

Cerebral small vessel disease (CSVD) is the most common chronic vascular disease involving the whole brain. Great progress has been made in clinical imaging, pathological mechanism, and treatment of CSVD, but many problems remain. Clarifying the current research dilemmas and future development direction of CSVD can provide new ideas for both basic and clinical research. In this review, the risk factors, biological markers, pathological mechanisms, and the treatment of CSVD will be systematically illustrated to provide the current research status of CSVD. The future development direction of CSVD will be elucidated by summarizing the research difficulties.

Efficacy and Safety of Chinese Herbal Medicine Compared With Losartan for Mild Essential Hypertension: A Randomized, Multicenter, Double-Blind, Noninferiority Trial.

BACKGROUND: Hypertension is one of the most challenging public health problems worldwide. Previous studies suggested that the Songling Xuemaikang capsule (SXC)-a Chinese herbal formula-was effective for essential hypertension. However, the efficacy of SXC monotherapy for hypertension remains unclear. We aimed to compare the blood pressure (BP)-lowering efficacy and safety of SXC versus losartan in patients with essential hypertension. METHODS: In this multicenter, randomized, double-blind, noninferiority trial in China, patients 18 to 65 years of age with mild essential hypertension were randomly allocated to receive either SXC or losartan for 8 weeks. The primary outcome was the change in sitting diastolic BP from baseline to 8 weeks, with a predefined noninferiority margin of -2.5 mm Hg. RESULTS: Of the 755 patients who entered a 2-week run-in period, 628 patients (327 women and 301 men; mean [SD] age, 52.6 [9.2] years) were randomly assigned to the SXC (n=314) or losartan (n=314) group. The primary analysis based on the intention-to-treat principle showed that the change in diastolic BP from baseline to 8 weeks was similar between the SXC and losartan groups (-7.9 [8.0] versus -8.1 [7.9]). The lower boundary of 95% CI (mean difference, -0.24 [95% CI, -1.51 to 1.03]) was above the margin of -2.5 mm Hg, showing noninferiority. Results were consistent with per-protocol analysis. SXC produced greater improvements in total hypertension symptom score (-5.7 [4.2] versus -5.0 [4.0]; P=0.020) and total cholesterol (-0.1 [1.0] versus 0.1 [1.2]; P=0.025). There were no differences between groups in the other BP and patient-reported outcomes. Incidence and severity of adverse events were similar between groups. CONCLUSIONS: SXC was well tolerated and demonstrated noninferior to losartan in BP lowering in patients with mild hypertension. SXC might be an alternative for mild hypertension, particularly for patients with a preference for natural medicine. REGISTRATION: URL: www.chictr.org.cn; Unique identifier: ChiCTR-IPR-16008108.

FordNet: Recommending traditional Chinese medicine formula via deep neural network integrating phenotype and molecule.

Traditional Chinese medicine (TCM) formula is widely used for thousands of years in clinical practice. With the development of artificial intelligence, deep learning models may help doctors prescribe reasonable formulas. Meanwhile, current studies of formula recommendation only focus on the observable clinical symptoms and lack of molecular information. Here, inspired by the theory of TCM network pharmacology, we propose an intelligent formula recommendation system based on deep learning (FordNet), fusing the information of phenotype and molecule. We collected more than 20,000 electronic health records from TCM Master Li Jiren's experience from 2013 to March 2020. In the FordNet system, the feature of diagnosis description is extracted by convolution neural network and the feature of TCM formula is extracted by network embedding, which fusing the molecular information. A hierarchical sampling strategy for data augmentation is designed to effectively learn training samples. Based on the expanded samples, a deep neural network based quantitative optimization model is developed for TCM formula recommendation. FordNet performs significantly better than baseline methods (hit ratio of top 10 improved by 46.9% compared with the best baseline random forest method). Moreover, the molecular information helps FordNet improve 17.3% hit ratio compared with the model using only macro information. Clinical evaluation shows that FordNet can well learn the effective experience of TCM Master and obtain excellent recommendation results. Our study, for the first time, proposes an intelligent recommendation system for TCM formula integrating phenotype and molecule information, which has potential to improve clinical diagnosis and treatment, and promote the shift of TCM research pattern from "experience based, macro" to "data based, macro-micro combined" as well as the development of TCM network pharmacology.

China Stroke Registry for Patients With Traditional Chinese Medicine (CASES-TCM): Rationale and Design of a Prospective, Multicenter, Observational Study.

Background: Given the complexity of stroke treatment and the current widespread use of traditional Chinese medicine (TCM) in the absence of robust, large, long-term effectiveness and safety studies, and the lack of nationwide epidemiology and clinical characteristics of patients with stroke receiving TCM treatment, the acquisition of data from longitudinal cohorts is essential. We intend to generate the major clinical characteristics of patients with stroke who receive TCM treatment and to investigate the effectiveness and safety of TCM in the Chinese population. Methods: The China Stroke Registry for Patients with Traditional Chinese Medicine (CASES-TCM) study is a prospective, multicenter, observational disease registry aiming to register 20,000 hospitalized patients. Eligible adult patients with clearly diagnosed acute ischemic stroke or intracerebral hemorrhage within 7 days of symptom onset will be consecutively registered from 126 participating sites across China. Baseline data will be recorded, and all patients will be regularly followed up at 3, 6, 12, and 24 months after stroke onset. Collected data will be entered into a web-based system with high-level data security. The primary outcomes include the distribution of scores on the modified Rankin Scale at the 3-months follow-up, and recurrent stroke events within the 12-months follow-up. Conclusion: To our knowledge, the CASES-TCM study is the first and largest nationwide registry to document comprehensive data on TCM treatment in patients with acute stroke. The findings of this study will be valuable to improve our knowledge about TCM treatment for patients with stroke and its subsequent outcomes in the actual clinical setting, consequently facilitating and standardizing the optimization of individualized interventions with TCM for stroke prevention and treatment in China. Study registration: This study was registered with Clinicaltrials.gov (URL: https://clinicaltrials.gov/, Unique identifier: NCT04921397).

Network pharmacology to explore the anti-inflammatory mechanism of Xuebijing in the treatment of sepsis.

BACKGROUND: Xuebijing (XBJ) is a traditional Chinese patent medicine for sepsis. However, the mechanism of action (MoA) of XBJ on sepsis remain unclear. PURPOSE: Elucidate the MoA of XBJ for treating sepsis based on network pharmacology. STUDY DESIGN: Integrate computational prediction, experimental validation and literature reported clinical results analysis based on network pharmacology. METHODS: Computationally, representative compounds of XBJ were characterized by LC-MS/MS and the target profiles of each compound were identified using network-based method. Compounds from XBJ were compared with FDA approved drugs or experimental agents for sepsis by hierarchical clustering of target profile. Key biological functional modules of XBJ for treating sepsis were identified by enrichment analysis. Differential expressed analysis for each biological functional module was conducted from sepsis related public omics datasets. Herb-biological functional module network was constructed to reveal part of the traditional combinatorial rules of herbs for modules. Experimentally, the action of XBJ compounds on genes in biological functional module was validated by detecting quantitative transcriptional profiling and sepsis animal model. Clinically, combined with the clinical results recorded in literature, computational and experimental results were used to interpret the anti-inflammatory effect of XBJ for treating sepsis. RESULTS: The target profiles of compound cover most of the compound's related biomolecules reported in literature, which can characterize the comprehensive function of compound. XBJ has similar pharmacological effect as FDA approved drugs or experimental agents. Four key biological functional modules including inflammation, immune, cell apoptosis and coagulation of XBJ for treating sepsis were identified. Cell line experimental results show that part of ingredients in XBJ regulate the expression of genes in inflammation modules as predicted. Animal experiments show that compounds from XBJ could reduce the expression level of IL-1ß. Combined with literature reported clinical results, XBJ was found to exert anti-inflammatory effect through regulating the NF-kappa B signaling pathway. CONCLUSION: The network pharmacology framework integrating computational prediction, experimental validation and literature reported clinical results analysis provides a novel approach for analyzing MoA of XBJ for treating sepsis.

Deciphering the Pharmacological Mechanisms of Guizhi-Fuling Capsule on Primary Dysmenorrhea Through Network Pharmacology.

Guizhi-Fuling capsule (GZFLC), originated from a classical traditional Chinese herbal formula Guizhi-Fuling Wan, has been clinically used for primary dysmenorrhea in China. Nonetheless, the underlying pharmacological mechanisms of GZFLC remain unclear. The integration of computational and experimental methods of network pharmacology might be a promising way to decipher the mechanisms. In this study, the target profiles of 51 representative compounds of GZFLC were first predicted by a high-accuracy algorithm, drugCIPHER-CS, and the network target of GZFLC was identified. Then, potential functional modules of GZFLC on primary dysmenorrhea were investigated using functional enrichment analysis. Potential bioactive compounds were recognized by hierarchical clustering analysis of GZFLC compounds and first-line anti-dysmenorrhea drugs. Furthermore, the potential anti-dysmenorrhea mechanisms of GZFLC were verified through enzyme activity assays and immunofluorescence tests. Moreover, effects of GZFLC on primary dysmenorrhea were evaluated in oxytocin-induced dysmenorrhea murine model. In the network target analysis, GZFLC may act on five functional modules of pain, inflammation, endocrine, blood circulation and energy metabolism. Integrating computational and experimental approaches, we found that GZFLC significantly inhibited the writhing response and reduced the degree of uterine lesions in oxytocin-induced dysmenorrhea murine model. Furthermore, GZFLC may partially alleviate primary dysmenorrhea by inhibiting cyclooxygenase 2 (COX2) and downregulating MAPK signaling pathway. Consequently, GZFLC presented pain relief and sustained benefits for primary dysmenorrhea. This study could provide a scientific approach for deciphering pharmacological mechanisms of herbal formulae through network pharmacology.

Clinical, laboratory and imaging predictors for critical illness and mortality in patients with COVID-19: protocol for a systematic review and meta-analysis.

INTRODUCTION: With the threat of a worldwide pandemic of COVID-19, it is important to identify the prognostic factors for critical conditions among patients with non-critical COVID-19. Prognostic factors and models may assist front-line clinicians in rapid identification of high-risk patients, early management of modifiable factors, appropriate triaging and optimising the use of limited healthcare resources. We aim to systematically assess the clinical, laboratory and imaging predictors as well as prediction models for severe or critical illness and mortality in patients with COVID-19. METHODS AND ANALYSIS: All peer-reviewed and preprint primary articles with a longitudinal design that focused on prognostic factors or models for critical illness and mortality related to COVID-19 will be eligible for inclusion. A systematic search of 11 databases including PubMed, EMBASE, Web of Science, Cochrane Library, CNKI, VIP, Wanfang Data, SinoMed, bioRxiv, Arxiv and MedRxiv will be conducted. Study selection will follow the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Data extraction will be performed using the modified version of the Critical Appraisal and Data Extraction for Systematic Reviews of Prediction Modelling Studies checklist and quality will be evaluated using the Newcastle-Ottawa Scale and the Quality In Prognosis Studies tool. The association between prognostic factors and outcomes of interest will be synthesised and a meta-analysis will be conducted with three or more studies reporting a particular factor in a consistent manner. ETHICS AND DISSEMINATION: Ethical approval was not required for this systematic review. We will disseminate our findings through publication in a peer-reviewed journal. PROSPERO REGISTRATION NUMBER: CRD 42020178798.

Network Pharmacology to Uncover the Biological Basis of Spleen Qi Deficiency Syndrome and Herbal Treatment.

Spleen qi deficiency (SQD) syndrome is one of the basic traditional Chinese medicine (TCM) syndromes related to various diseases including chronic inflammation and hypertension and guides the use of many herbal formulae. However, the biological basis of SQD syndrome has not been clearly elucidated due to the lack of appropriate methodologies. Here, we propose a network pharmacology strategy integrating computational, clinical, and experimental investigation to study the biological basis of SQD syndrome. From computational aspects, we used a powerful disease gene prediction algorithm to predict the SQD syndrome biomolecular network which is significantly enriched in biological functions including immune regulation, oxidative stress, and lipid metabolism. From clinical aspects, SQD syndrome is involved in both the local and holistic disorders, that is, the digestive diseases and the whole body's dysfunctions. We, respectively, investigate SQD syndrome-related digestive diseases including chronic gastritis and irritable bowel syndrome and the whole body's dysfunctions such as chronic fatigue syndrome and hypertension. We found innate immune and oxidative stress modules of SQD syndrome biomolecular network dysfunction in chronic gastritis patients and irritable bowel syndrome patients. Lymphocyte modules were downregulated in chronic fatigue syndrome patients and hypertension patients. From experimental aspects, network pharmacology analysis suggested that targets of Radix Astragali and other four herbs commonly used for SQD syndrome are significantly enriched in the SQD syndrome biomolecular network. Experiments further validated that Radix Astragali ingredients promoted immune modules such as macrophage proliferation and lymphocyte proliferation. These findings indicate that the biological basis of SQD syndrome is closely related to insufficient immune response including decreased macrophage activity and reduced lymphocyte proliferation. This study not only demonstrates the potential biological basis of SQD syndrome but also provides a novel strategy for exploring relevant molecular mechanisms of disease-syndrome-herb from the network pharmacology perspective.