Therapeutic effect and mechanisms of traditional Chinese medicine compound (Qilong capsule) in the treatment of ischemic stroke.

Background Qilong capsule (QLC) is a well-known traditional Chinese medicine compound extensively used in clinical practice. It has been approved by the China's FDA for the treatment of ischemic stroke (IS). In our clinical trial involving QLC (ClinicalTrials.gov identifier: NCT03174535), we observed the potential of QLC to improve neurological function in IS patients at the 24th week, while ensuring their safety. However, the effectiveness of QLC beyond the initial 12-week period remains uncertain, and the precise mechanisms underlying its action in IS have not been fully elucidated. Purpose In order to further explore the clinical efficacy of QLC in treating IS beyond the initial 12-week period and systematically elucidate its underlying mechanisms. Study Design This study employed an interdisciplinary integration strategy that combines post hoc analysis of clinical trials, transcriptome sequencing, integrated bioinformatics analysis, and animal experiments. Methods In this study, we conducted a post-hoc analysis with 2302 participants to evaluate the effectiveness of QLC at the 12th week. The primary outcome was the proportion of patients achieving functional independence at the 12th week, defined as a score of 0-2 on the modified Rankin Scale (mRS), which ranges from 0 (no symptoms) to 6 (death). Subsequently, we employed RNA sequencing (RNA-Seq) and quantitative reverse transcription polymerase chain reaction (RT-qPCR) techniques in the QLC trial to investigate the potential molecular mechanisms underlying the therapeutic effect of QLC in IS. Simultaneously, we utilized integrated bioinformatics analyses driven by external multi-source data and algorithms to further supplement the exploration and validation of QLC's therapeutic mechanism in treating IS. This encompassed network pharmacology analysis and analyses at the mRNA, cellular, and pathway levels focusing on core targets. Additionally, we developed a disease risk prediction model using machine learning. By identifying differentially expressed core genes (DECGs) between the normal and IS groups, we quantitatively predicted IS occurrence. Furthermore, to assess its protective effects and determine the key regulated pathway, we conducted experiments using a middle cerebral artery occlusion and reperfusion (MACO/R) rat model. Results Our findings demonstrated that the combination of QLC and conventional treatment (CT) significantly improved the proportion of patients achieving functional independence (mRS score 0-2) at the 12th week compared to CT alone (n = 2,302, 88.65 % vs 87.33 %, p = 0.3337; n = 600, 91.33 % vs 84.67 %, p = 0.0165). Transcriptome data revealed that the potential underlying mechanism of QLC for IS is related to the regulation of the NF-κB inflammatory pathway. The RT-qPCR results demonstrated that the regulatory trends of key genes, such as MD-2, were consistent with those observed in the RNA-Seq analysis. Integrated bioinformatics analysis elucidated that QLC regulates the NF-κB signaling pathway by identifying core targets, and machine learning was utilized to forecast the risk of IS onset. The MACO/R rat model experiment confirmed that QLC exerts its anti-CIRI effects by inhibiting the MD-2/TLR-4/NF-κB signaling axis. Conclusion: Our interdisciplinary integration study has demonstrated that the combination of QLC with CT exhibits significant superiority over CT alone in improving functional independence in patients at the 12th week. The potential mechanism underlying QLC's therapeutic effect in IS involves the inhibition of the MD-2/TLR4/NF-κB inflammatory signaling pathway, thereby attenuating cerebral ischemia/reperfusion inflammatory injury and facilitating neurofunctional recovery. The novelty and innovative potential of this study primarily lie in the novel finding that QLC significantly enhances the proportion of patients achieving functional independence (mRS score 0-2) at the 12th week. Furthermore, employing a "multilevel-multimethod" integrated research approach, we elucidated the potential mechanism underlying QLC's therapeutic effect in IS.

Clinical effectiveness of Qilong capsule in patients with ischemic stroke: A prospective, multicenter, non-randomized controlled trial.

BACKGROUND: The Qilong capsule (QLC) is a Chinese patented medicine characterized by an equal emphasis on replenishing Qi and activating blood circulation. In 2000, China's FDA approved the use of QLC for ischemic stroke (IS). However, there is not yet much high-quality evidence of the clinical effectiveness of QLC combined with conventional treatment (CT) for IS with Qi deficiency and blood stasis syndrome. PURPOSE: In this study, we conducted a prospective, multicenter, non-randomized controlled trial at 7 hospitals in China to investigate the clinical effectiveness of QLC combined with CT for IS with Qi deficiency and blood stasis syndrome. METHODS: Participants aged 35 to 80 years old diagnosed as IS with Qi deficiency and blood stasis syndrome in TCM were recruited. Participants were treated with QLC (intervention group) or non-QLC (control group). The intervention course of QLC was 12 weeks. All participants in two groups received standard treatment. All participants returned for in-person follow-up visits at the 12th week and 24th week. Primary outcome measures included a modified Rankin Scale (mRS), the National Institute of Health Stroke Scale (NIHSS), and the Barthel Index (BI). Secondary outcome measures included TCM syndromes (Qi deficiency syndrome score, blood stasis syndrome score), psychological index (self-rating depression scale, SDS; self-rating anxiety scale, SAS), blood lipid index, blood coagulation index, homocysteine, and favorable functional outcome (mRS 0 - 3). Multiple imputations were used for any missing data. Propensity score matching (PSM) was used to deal with any confounding factors (age, gender, scale score, etc.). Rank alignment transformation variance analysis (ART ANOVA) and generalized linear mixed model (GLMM) were introduced to improve the scientific and accuracy of repeated measurement data. All statistical calculations were carried out with R 3.6.1 statistical analysis software. RESULTS: A total of 2468 participants were screened from November 2016 to January 2019. Finally, 2302 eligible participants were included in the analysis. There were 1260 participants in the intervention group (QLC group) and 1042 participants in the control group (non-QLC group). After PSM matching, sub-samples of 300 participants in the QLC group and 300 participants in the non-QLC group were finally formed. The final results of clinical effectiveness are the same results shared by the total samples and sub-samples after PSM. In the 24th week after treatment, QLC combined with CT proved to be significantly better than CT alone in reducing the scores of mRS (p < 0.05), NIHSS (p < 0.001), Qi deficiency syndrome (p < 0.01), and blood stasis syndrome (p < 0.001), SAS (p < 0.05), as well as in improving BI score (p < 0.05). The favourable functional outcome (mRS score of 0 to 3 at week 12) was statistically different between QLC and non-QLC group in the sub-samples (p < 0.01, 97% vs 91.7%). The results of the ART ANOVA showed that the improvement of mRS (p < 0.01), BI (p < 0.05) and NIHSS (p < 0.001) in QLC group was better than non-QLC group when the interaction effect was considered. The results of GLMM showed that the reduction of mRS and NIHSS scores of patients in the QLC group were better than those of the non-QLC group (p < 0.001). The BI score of the QLC group in the sub-samples after PSM increased more than the non-QLC group (p < 0.001). There was no evidence showing that QLC can cause serious adverse reactions (ADRs) in treating patients with IS. CONCLUSION: QLC combined with CT was better than CT alone in reducing mRS score, NIHSS score, Qi deficiency syndrome score, blood stasis syndrome score, and SAS score, as well as improving BI score after treatment. Further high-quality RCTs are needed to confirm the positive results. The study protocol was embedded in a registry study that registered in the Clinical Trials USA Registry (registration No. NCT03174535).

Onset and Recurrence Characteristics of Chinese Patients with Noncardiogenic Ischemic Stroke in Chinese Medicine Hospital.

OBJECTIVE: To delineate the onset and recurrence characteristics of noncardiogenic ischemic stroke patients in China. METHODS: A prospective, multicenter and registry study was carried out in 2,558 patients at 7 representative clinical sub-centers during November 3, 2016 to February 17, 2019. A questionnaire was used to collect information of patients regarding CM syndromes and constitutions and associated risk factors. Additionally, stroke recurrence was defined as a primary outcome indicator. RESULTS: A total of 327 (12.78 %) patients endured recurrence events, 1,681 (65.72%) were men, and the average age was 63.33 ± 9.45 years. Totally 1,741 (68.06%) patients suffered first-ever ischemic stroke, 1,772 (69.27%) patients reported to have hypertension, and 1,640 (64.11%) of them reported dyslipidemia, 1,595 (62.35%) patients exhibited small-artery occlusion by The Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification. Specifically, 1,271 (49.69%) patients were considered as qi-deficient constitution, and 1,227 (47.97%) patients were determined as stagnant blood constitution. There were 1,303 (50.94%) patients diagnosed as blood stasis syndrome, 1,280 (50.04%) patients exhibited phlegm and dampness syndrome and 1,012 (39.56%) patients demonstrated qi deficiency syndrome. And 1,033 (40.38%) patients declared intracranial artery stenosis, and 478 (18.69%) patients reported carotid artery stenosis. The plaque in 1,508 (41.36%) patients were of mixed. Particularly, 41.09% of them demonstrated abnormal levels of glycated hemoglobin levels. CONCLUSIONS: Recurrence in minor and small-artery stroke cannot be ignored. Hypertension, dyslipidemia, abnormal HbA1c, intracranial artery stenosis and carotid plaque were more common in stroke patients. Particularly, phlegm-dampness and blood stasis syndromes, as well as qi deficiency and blood stasis constitutions, were still the main manifestations of stroke. (Trial registration at ClinicalTrials.gov No. NCT03174535).

Xinglou Chengqi Decoction improves neurological function in experimental stroke mice as evidenced by gut microbiota analysis and network pharmacology.

The current study was designed to explore the brain protection mechanism of Xinglou Chengqi Decoction (XCD) based on gut microbiota analysis and network pharmacology. A transient middle cerebral artery occlusion (MCAO) model of mice was established, followed by behavioral evaluation, TTC and TUNEL staining. Additionally, to investigate the effects of gut microbiota on neurological function after stroke, C57BL/6 mice were treated with anti-biotic cocktails 14 days prior to ischemic stroke (IS) to deplete the gut microbiota. High-throughput 16S rDNA gene sequencing, metabonomics technique, and flow multifactor technology were used to analyze bacterial communities, SCFAs and inflammatory cytokines respectively. Finally, as a supplement, network pharmacology and molecular docking were applied to fully explore the multicomponent-multitarget-multichannel mechanism of XCD in treating IS, implicated in ADME screening, target identification, network analysis, functional annotation, and pathway enrichment analysis. We found that XCD effectively improved neurological function, relieved cerebral infarction and decreased the neuronal apoptosis. Moreover, XCD promoted the release of anti-inflammatory factor like IL-10, while down-regulating pro-inflammatory factors such as TNF-α, IL-17A, and IL-22. Furthermore, XCD significantly increased the levels of short chain fatty acids (SCFAs), especially butyric acid. The mechanism might be related to the regulation of SCFAs-producing bacteria like Verrucomicrobia and Akkermansia, and bacteria that regulate inflammation like Paraprevotella, Roseburia, Streptophyta and Enterococcu. Finally, in the network pharmacological analysis, 51 active compounds in XCD and 44 intersection targets of IS and XCD were selected. As a validation, components in XCD docked well with key targets. It was obviously that biological processes were mainly involved in the regulation of apoptotic process, inflammatory response, response to fatty acid, and regulation of establishment of endothelial barrier in GO enrichment. XCD can improve neurological function in experimental stroke mice, partly due to the regulation of gut microbiota. Besises, XCD has the characteristic of "multi-component, multi-target and multi-channel" in the treatment of IS revealed by network pharmacology and molecular docking.

Effect of Qizhitongluo capsule on lower limb rehabilitation after stroke: A randomized clinical trial.

BACKGROUND: An individual's level of lower limb motor function is associated with his or her disability level after stroke, and motor improvement may lead to a better prognosis and quality of life. Data from animal models show that Qizhitongluo (QZTL) capsule facilitates recovery after focal brain injury. We aimed to validate the efficacy and safety of the QZTL capsule for promoting lower limb motor recovery in poststroke patients. METHODS: In this randomized, multicenter, double-blind, placebo- and active-controlled trial from 13 sites in China, participants with ischemic stroke and Fugl-Meyer motor scale (FMMS) scores of <95 were eligible for inclusion. Patients were randomly assigned in a 2:1:1 ratio to the QZTL group, Naoxintong (NXT) group or placebo group for 12 weeks at 15-28 days after the onset of stroke. The primary outcome was the change in the Lower Limb FMMS (FMMS-LL) score from baseline over the 12-week intervention period. RESULTS: 622 participants were randomly assigned to the QZTL group (309), NXT group (159), or placebo group (154). The FMMS-LL score increased by 4.81 points (95 % CI, 4.27-5.35) in the QZTL group, by 3.77 points (95 % CI, 3.03-4.51) in the NXT group and by 3.00 points (95 % CI, 3.03-4.51) in the placebo group at week 12. The QZTL group showed significantly larger improvements compared with the placebo group at each interview from weeks 4-12 (difference, 0.89 [0.30,1.49] at week 4, P = 0.0032; difference, 1.83[1.01,2.66] at 90 days poststroke, P < 0.0001; difference, 1.81[0.88,2.74] at week 12, P = 0.0001). CONCLUSION: The QZTL capsule is an effective treatment for lower limb motor impairment. The finding indicates that the QZTL capsule may be used as a potential new strategy for stroke rehabilitation.

Brain Imaging Changes and Related Risk Factors of Cognitive Impairment in Patients With Heart Failure.

BACKGROUND/AIMS: To explore the imaging changes and related risk factors of heart failure (HF) patients with cognitive impairment (CI). METHODS: A literature search was systematically carried out in PubMed, Web of Science, Embase, and Cochrane Library. In this systematic review, important relevant information was extracted according to the inclusion and exclusion criteria. The methodological quality was assessed by three scales according to the different study types. RESULTS: Finally, 66 studies were included, involving 33,579 patients. In the imaging changes, the severity of medial temporal lobe atrophy (MTA) and the decrease of gray Matter (GM) volume were closely related to the cognitive decline. The reduction of cerebral blood flow (CBF) may be correlated with CI. However, the change of white matter (WM) volume was possibly independent of CI in HF patients. Specific risk factors were analyzed, and the data indicated that the increased levels of B-type natriuretic peptide (BNP)/N-terminal pro-B-type natriuretic peptide (NT-proBNP), and the comorbidities of HF, including atrial fibrillation (AF), diabetes mellitus (DM) and anemia were definitely correlated with CI in patients with HF, respectively. Certain studies had also obtained independent correlation results. Body mass index (BMI), depression and sleep disorder exhibited a tendency to be associated with CI. Low ejection fraction (EF) value (<30%) was inclined to be associated with the decline in cognitive function. However, no significant differences were noted between heart failure with preserved ejection fraction (HFpEF) and heart failure with reduced ejection fraction (HFrEF) in cognitive scores. CONCLUSION: BNP/NT-proBNP and the comorbidities of HF including AF, DM and anemia were inextricably correlated with CI in patients with HF, respectively. These parameters were independent factors. The severity of MTA, GM volume, BMI index, depression, sleep disorder, and low EF value (<30%) have a disposition to associated with CI. The reduction in the CBF volume may be related to CI, whereas the WM volume may not be associated with CI in HF patients. The present systematic review provides an important basis for the prevention and treatment of CI following HF.

[Experts consensus statement on Qilong Capsules in clinical practice].

Qilong Capsules is the representative Chinese patent medicine of the theory of " invigorating Qi and activating blood circulation" in traditional Chinese medicine( TCM),with distinct characteristics of TCM in clinical application. Qilong Capsules indication on package insert is ischemic stroke( cerebral infarction),which is a complex disease and has many pathological links. The treatment principles and methods at various stages are different. Inappropriate time of intervention,dosage and course of treatment make it difficult to give full play to the efficacy,but also cause adverse reactions,such as bleeding. In order to promote the rational use of Qilong Capsules,the project team invited frontline clinical experts,pharmaceutical experts and methodologist of evidence-based medicine around China to develop the consensus. The consensus is based on a combination of clinical research evidence and expert experi-ence to give recommendations for clinical problems with evidence support and expert consensus suggestions for clinical problems without evidence support. The consensus recommends the indication,timing of intervention,dosage,course of treatment,combined medication and contraindications of Qilong Capsules in clinical application,and introduced its safety characteristics,in order to guide clinical medical workers( involving Chinese medicine,Western medicine,combining traditional Chinese and Western medicine) to use Qilong Capsules reasonably in the treatment of cerebral infarction.

Efficacy and safety of the Chaihuguizhiganjiang-suanzaoren granule on primary insomnia: study protocol for a randomised controlled trial.

INTRODUCTION: Insomnia is a highly prevalent, often debilitating and economically burdensome sleep disorder with limited effective therapies. Few data are available to understand which of the therapeutic alternatives is the most effective for patients with insomnia, especially for Traditional Chinese Medicine (TCM). Chinese herbal medicine, as a typical TCM, is one of the most popular complementary and alternative therapies for insomnia. We aim to evaluate the efficacy and safety of the Chaihuguizhiganjiang-suanzaoren granule (CSG), a Chinese herbal medicine treatment, in patients with primary insomnia. METHODS AND ANALYSIS: This is a multicentre, placebo-controlled, double-blinded, randomised controlled clinical trial. A total of 258 participants are randomly allocated to two groups: the intervention group or the placebo group. The intervention group receives CSG and the placebo group receives a placebo granule. The patients receive either CSG or placebo two times daily for 8 weeks. The primary outcome is the Pittsburgh sleep quality index (PSQI). Secondary outcomes include the Insomnia Severity Index (ISI), Total Sleep Time (TST) and the Short-Form Health Survey (SF-36). The assessment is performed at baseline (before randomisation), 4, 8 and 12 weeks after randomisation. ETHICS AND DISSEMINATION: The protocol has been approved by the Research Ethical Committee of Beijing Hospital of Traditional Chinese Medicine Affiliated to Capital Medical University (reference: 2014BL-003-01). The trial will be helpful in identifying the efficacy and safety of CSG in patients with primary insomnia. TRIAL REGISTRATION NUMBER: ISRCTN22001145; Pre-results.

The MIL-88A-Derived Fe3O4-Carbon Hierarchical Nanocomposites for Electrochemical Sensing.

Metal or metal oxides/carbon nanocomposites with hierarchical superstructures have become one of the most promising functional materials in sensor, catalysis, energy conversion, etc. In this work, novel hierarchical Fe3O4/carbon superstructures have been fabricated based on metal-organic frameworks (MOFs)-derived method. Three kinds of Fe-MOFs (MIL-88A) with different morphologies were prepared beforehand as templates, and then pyrolyzed to fabricate the corresponding novel hierarchical Fe3O4/carbon superstructures. The systematic studies on the thermal decomposition process of the three kinds of MIL-88A and the effect of template morphology on the products were carried out in detail. Scanning electron microscopy, transmission electron microscopy, X-ray powder diffraction, X-ray photoelectron spectroscopy and thermal analysis were employed to investigate the hierarchical Fe3O4/carbon superstructures. Based on these resulted hierarchical Fe3O4/carbon superstructures, a novel and sensitive nonenzymatic N-acetyl cysteine sensor was developed. The porous and hierarchical superstructures and large surface area of the as-formed Fe3O4/carbon superstructures eventually contributed to the good electrocatalytic activity of the prepared sensor towards the oxidation of N-acetyl cysteine. The proposed preparation method of the hierarchical Fe3O4/carbon superstructures is simple, efficient, cheap and easy to mass production. It might open up a new way for hierarchical superstructures preparation.