Chronic Cerebral Circulation Insufficiency Research Articles

Immunological Profile and Markers of Endothelial Dysfunction in Elderly Patients with Cognitive Impairments.

The process of aging is accompanied by a dynamic restructuring of the immune response, a phenomenon known as immunosenescence. Further, damage to the endothelium can be both a cause and a consequence of many diseases, especially in elderly people. The purpose of this study was to carry out immunological and biochemical profiling of elderly people with acute ischemic stroke (AIS), chronic cerebral circulation insufficiency (CCCI), prediabetes or newly diagnosed type II diabetes mellitus (DM), and subcortical ischemic vascular dementia (SIVD). Socio-demographic, lifestyle, and cognitive data were obtained. Biochemical, hematological, and immunological analyses were carried out, and extracellular vesicles (EVs) with endothelial CD markers were assessed. The greatest number of significant deviations from conditionally healthy donors (HDs) of the same age were registered in the SIVD group, a total of 20, of which 12 were specific and six were non-specific but with maximal differences (as compared to the other three groups) from the HDs group. The non-specific deviations were for the MOCA (Montreal Cognitive Impairment Scale), the MMSE (Mini Mental State Examination) and life satisfaction self-assessment scores, a decrease of albumin levels, and ADAMTS13 (a Disintegrin and Metalloproteinase with a Thrombospondin Type 1 motif, member 13) activity, and an increase of the VWF (von Willebrand factor) level. Considering the significant changes in immunological parameters (mostly Th17-like cells) and endothelial CD markers (CD144 and CD34), vascular repair was impaired to the greatest extent in the DM group. The AIS patients showed 12 significant deviations from the HD controls, including three specific to this group. These were high NEFAs (non-esterified fatty acids) and CD31 and CD147 markers of EVs. The lowest number of deviations were registered in the CCCI group, nine in total. There were significant changes from the HD controls with no specifics to this group, and just one non-specific with a maximal difference from the control parameters, which was α1-AGP (alpha 1 acid glycoprotein, orosomucoid). Besides the DM patients, impairments of vascular repair were also registered in the CCCI and AIS patients, with a complete absence of such in patients with dementia (SIVD group). On the other hand, microvascular damage seemed to be maximal in the latter group, considering the biochemical indicators VWF and ADAMTS13. In the DM patients, a maximum immune response was registered, mainly with Th17-like cells. In the CCCI group, the reaction was not as pronounced compared to other groups of patients, which may indicate the initial stages and/or compensatory nature of organic changes (remodeling). At the same time, immunological and biochemical deviations in SIVD patients indicated a persistent remodeling in microvessels, chronic inflammation, and a significant decrease in the anabolic function of the liver and other tissues. The data obtained support two interrelated assumptions. Taking into account the primary biochemical factors that trigger the pathological processes associated with vascular pathology and related diseases, the first assumption is that purine degradation in skeletal muscle may be a major factor in the production of uric acid, followed by its production by non-muscle cells, the main of which are endothelial cells. Another assumption is that therapeutic factors that increase the levels of endothelial progenitor cells may have a therapeutic effect in reducing the risk of cerebrovascular disease and related neurodegenerative diseases.

Neuroprotective action of hydroxybenzoic acid derivative with glycine (C40) in the middle cerebral artery occlusion in rats with chronic cerebral circulation insufficiency

The neuroprotective effect of a novel conjugate of hydroxybenzoic acid with glycine (C40) was investigated in a model of ischemic stroke in rats with chronic cerebral circulation insufficiency (CCCI). The study was conducted in two stages: first, CCCI was modeled by stenosing the common carotid arteries by 50 %, followed by a 60-minute middle cerebral artery occlusion (stroke) after 40 days. Compound C40 and the reference drug citicoline were administered for 10 days before stroke and for 3 days after. Further, neurological deficit (the Garcia and Combs D’Alecy scales), sensorimotor functions (Open Field test, Adhesive Removal test, and Rotarod test), cognitive impairments (Novel Object Recognition and Morris Water Maze tests), cerebral blood flow level, and endothelial function were evaluated. Animals receiving the test substances demonstrated a statistically significant reduction in neurological deficit, less pronounced motor coordination and sensorimotor function impairments, as well as fewer short-term and long-term memory deficits compared to the negative control group. The observed decrease in neurological deficit in the experimental groups was accompanied by improved endothelial function and increased cerebral blood flow. The neuroprotective effect of the novel hydroxybenzoic acid derivative with glycine (C40) was comparable to that of reference drug citicoline.

Cerebroprotective effect of sitagliptin and aminoguanidine combination in disorders of cerebral circulation

The aim of the study was to evaluate a cerebroprotective activity of the sitagliptin and aminoguanidine combination in rats with an acute and chronic cerebral circulation insufficiency, as well as with a traumatic brain injury.Materials and methods. The study was carried out on male Wistar rats in 3 stages using, respectively, a model of a chronic pathology: a chronic cerebral circulation insufficiency (CCCI), as well as 2 models of the acute brain injury (BI): an acute cerebral circulation insufficiency (ACCI), and a traumatic brain injury (TBI). А CCCI was modeled by a bilateral stenosis of the common carotid arteries (by 50%), a model of a hemorrhagic stroke caused by an intracerebral injection of the autologous blood was used as a stroke, a TBI was modeled by a mechanical damage to the brain tissue. To assess the pathology course severity, the following tests were used: Adhesion test, Open field, Morris water maze test, as well as Garcia and Combs&D’Alecy scales. In the animals with an acute damage to the brain at the end of the experiment, the severity of edema of the affected hemisphere was also determined. The treatment was with sitagliptin (10 mg/kg), aminoguanidine (25 mg/kg), or a combination thereof. The obtained data were subjected to the statistical processing.Results. In the course of the study, it was found out that the administration of a sitagliptin and aminoguanidine combination, unlike each of the components, had a cerebroprotective effect in the animals with a chronic or acute damage to the brain, reducing the severity of psychoneurological (cognitive and sensory-motor) disorders, as well as the brain edema.Conclusion. Aminoguanidine, as an iNOS blocker, enhances the action of sitagliptin, preventing the brain edema development and reducing the neurological deficit severity (the severity of cognitive and sensory-motor impairments) in the animals with an acute and chronic cerebral circulation insufficiency.

Exploring the active components and mechanism of modified bazhen decoction in treatment of chronic cerebral circulation insufficiency based on network pharmacology and molecular docking.

Modified bazhen decoction (MBZD) is a classical Chinese medicine formula with potential efficacy in the treatment of chronic cerebral circulation insufficiency (CCCI), and its main components and potential mechanisms are still unclear. The study aimed to investigate the active ingredients and mechanism of action of MBZD in treating CCCI through network pharmacology combined with molecular docking. The chemical composition and targets of 11 Chinese herbs in MBZD were retrieved utilizing the traditional Chinese medicine systems pharmacology database and analysis platform platform, and the targets for CCCI were screened by Genecards, online mendelian inheritance in man, therapeutic target database, and comparative toxicogenomics database databases. The targets were genetically annotated with the Uniprot database. We created a compound-target network employing Cytoscape software and screened the core targets for the treatment of CCCI by CytoNCA clustering analysis; the AutoDock Vina program performed molecular docking study of crucial targets. One thousand one hundred ninety-one active compounds were obtained, 2210 corresponding targets were predicted, 4971 CCCI-related targets were obtained, and 136 intersecting genes were identified between them. The central core targets were IL6, MAPK14, signal transducer and activator of transcription 3, RELA, VEGFA, CCND1, CASP3, AR, FOS, JUN, EGFR, MAPK1, AKT1, MYC, and ESR1; gene ontology functional enrichment analysis yielded 911 gene ontology items (P < .01), while Kyoto Encyclopedia of Genes and Genomes pathway enrichment yielded 138 signal pathways (P < .01), primarily including oxidative reactions, vascular regulation, apoptosis, and PI3K-Akt signaling pathway. The molecular docking results showed that the core active component of MBZD had good binding with the main target. This research initially uncovered the mechanism of action of MBZD via multi-component-multi-target-multi-pathway for the treatment of CCCI, providing the theoretical basis for the clinical application of MBZD.

Peculiarities of Rehabilitation of Patients with Chronic Cerebral Circulation Insufficiency During the War

Aim: To improve the clinical diagnosis of CCCI and to develop methods of personalized treatment and rehabilitation of patients with CCCI during the war. Materials and Methods: 38 patients were examined in age range from 49 to 73 years with diagnosis of CCCI and comorbidity, stressed during the war – 16 males і 22 females. Informed participation consent was obtained from all patients. The diagnosis was confirmed by the data of general clinical, neurological examination, neuroimaging techniques, instrumental, laboratory and neuropsychological testing – Mini-Mental State Examination (MMSE), Depression, Anxiety And Stress Scale-21 (DASS-21), Fatigue Assessment Scale (FAS) and Modified Assessment Of Neurological And Neuropsychological Deficit Scale (MANND) Results: As a result of the examination of 38 patients with a diagnosis of CCCI and comorbidity using such scales as MANND, MMSE, DASS-21, FAS and provided treatment through combination of acetylcholinesterase inhibitors and choline precursors, data were obtained on decreasing severity of neurological symptoms, regression of anxiety and depression indicators, and the most significant regression of stress and fatigue indicators. Conclusions: Therapeutic regimen should be personalized, taking into account a wide range of complaints, assessment of neurological and neuropsychological deficit, and management of chronic diseases. The appointment of acetylcholinesterase inhibitors in combination with choline precursors as targeted cholinergic insufficiency correction leads to reduction of asthenic syndrome, indicators of stress, depression and anxiety.

The BE COOL Treatments (Batroxobin, oxygEn, Conditioning, and cOOLing): Emerging Adjunct Therapies for Ischemic Cerebrovascular Disease.

Ischemic cerebrovascular disease (ICD), the most common neurological disease worldwide, can be classified based on the onset time (acute/chronic) and the type of cerebral blood vessel involved (artery or venous sinus). Classifications include acute ischemic stroke (AIS)/transient ischemic attack (TIA), chronic cerebral circulation insufficiency (CCCI), acute cerebral venous sinus thrombosis (CVST), and chronic cerebrospinal venous insufficiency (CCSVI). The pathogenesis of cerebral arterial ischemia may be correlated with cerebral venous ischemia through decreased cerebral perfusion. The core treatment goals for both arterial and venous ICDs include perfusion recovery, reduction of cerebral ischemic injury, and preservation of the neuronal integrity of the involved region as soon as possible; however, therapy based on the current guidelines for either acute ischemic events or chronic cerebral ischemia is not ideal because the recurrence rate of AIS or CVST is still very high. Therefore, this review discusses the neuroprotective effects of four novel potential ICD treatments with high translation rates, known as the BE COOL treatments (Batroxobin, oxygEn, Conditioning, and cOOLing), and subsequently analyzes how BE COOL treatments are used in clinical settings. The combination of batroxobin, oxygen, conditioning, and cooling may be a promising intervention for preserving ischemic tissues.

Effects of tumor necrosis factor α on the structure of brain networks and cognitive functions in patients with chronic cerebral ischemia

Introduction. The processes of cognitive decline, which are typical for elderly and senile people, as well as for patients with chronic cerebral circulation insufficiency, involve pro-inflammatory cytokines, such as tumor necrosis factor (TNF-), interleukin-6, etc.&#x0D; The aim of this work was to study the association of TNF- with brain network structure and cognitive functions in patients with chronic cerebral ischemia (CCI).&#x0D; Materials and methods. We examined 101 patients with CCI (5085 years old, men and women) who were assessed for the saliva levels of TNF- during cognitive testing. The status of resting-state networks was analyzed in 55 patients using functional magnetic resonance therapy.&#x0D; Results. After cognitive tasks, the saliva level of TNF- increased by 17.6 6.2 pg/mL. Half of the CCI patients older than 60 years showed a significant increase in the level of TNF-. This cytokine correlated with delayed word recall and the ratio of delayed recall to their performance on the Luria Memory Words Test. The change in TNF- saliva levels correlated with the status of the resting-state network, mainly with the salience network. An increase in TNF- levels was associated with a higher frequency of negative correlations than at lower values of TNF- (less than 80 pg/mL). TNF--sensitive connectivities correlated with cognitive tasks, not only memory tests, but also with the Montreal Cognitive Assessment Scale, verbal fluency test scores, etc.&#x0D; Discussion. The study revealed two significant facts: an increase in the TNF- saliva level during cognitive performance and a lower success rate of cognitive performance associated with an increase in the levels of this cytokine. The central mechanism for the implementation of this relationship includes the restructuring of the salience network, namely the additional increase of negative correlations within the connective structure of the salience neural network of the right hemisphere.&#x0D; Conclusions. A change in the saliva level of TNF- affects the connectivity of resting-state networks, mainly the salience network

Alteration of circulating unconventional T cells in cerebral ischemia: an observational study

Immune reactions provoked by cerebral ischemia play crucial roles in the pathogenesis of brain damage and contribute to tissue regeneration processes. While functions of many immune cell types in post-ischemic inflammation have been well studied in experimental stroke, the exact roles played by unconventional T cells in pathogenesis of the clinical stroke remain to be precisely determined. In the present study, we investigated the frequencies and absolute cell numbers of peripheral blood T lymphocyte subpopulations including those of invariant natural killer T (iNKT) cells, CD3+CD56+ NKT-like (NKTL) cells, and γδ T cells from patients with acute cerebral infarction (ACI), chronic cerebrovascular disease (CCD) or chronic cerebral circulation insufficiency (CCI) by flow cytometry, and analyzed their association with the disease severity and the clinical outcome. We observed significantly reduced cell numbers of circulating iNKT cells, NKTL cells and γδ T cells in cerebral ischemia patients as compared with the healthy controls. Of note, we also demonstrated that numbers of peripheral blood iNKT and γδ T cells are significantly reduced in patients with ACI when compared among different cerebral ischemia patient groups. Moreover, the reduced number of iNKT cells is significantly associated with the disease severity and recovery in cerebral ischemia patients. Our results demonstrate for the first time the reduction of peripheral blood NKTL, iNKT and γδ T cells in patients with the cerebral ischemia, and particularly reduced iNKT and γδ T cells in the acute phase. The reduction of iNKT cells seems to be significantly associated with the disease severity and recovery. We hope that our findings might lead to the identification of predictive and prognostic values of human peripheral unconventional T cell subsets in the cerebral ischemia.

The Use of GC‐MS and Network Pharmacology to Analyze the Material Basis and Mechanism of Ligusticum chuanxiong Hort. in Treating Chronic Cerebral Circulation Insufficiency

AbstractUse Gas chromatography‐mass spectrometry technology (GC‐MS) to identify volatile chemical components in Ligusticum chuanxiong Hort. (LCH). The TCMSP and Swiss Target Prediction online platform were used to screen and predict the potential targets of the chemical components of LCH, and GeneCards, CTD, OMIM, DisGeNET, GEO databases were used to collect the potential targets of chronic cerebral circulation insufficiency (CCCI). A total of 50 volatile chemical components in LCH were analyzed and identified, and 126 potential targets for LCH treatment of CCCI were screened on this basis. Through further network topology analysis, 33 core components and 36 potential core targets were screened out. GO and KEGG enrichment analysis revealed that LCH played a therapeutic role through signaling pathways such as Neuroactive ligand‐receptor interaction, Alzheimer disease, Pathways of neurodegeneration‐multiple diseases, Proteoglycans in cancer, and Chemical carcinogenesis‐receptor activation. The molecular docking results showed the top 4 active ingredients, Ligustilide, Terpineol, 3‐Butylidenephthalide, and Linalool, and the top 5 core targets CREBBP, HSP90AA1, ESR1, VEGFA, and NR3 C1 all have good binding activity. The free energy is less than ≤‐5 kcal/mol, and the molecular docking conformation is stable. LCH may improve the symptoms of CCCI by acting on inhibiting inflammatory factors, protecting nerve cells, and promoting angiogenesis pathways.

Multiple component-pharmacokinetic studies on 10 bioactive constituents of Peiyuan Tongnao capsule using parallel reaction monitoring mode.

Peiyuan Tongnao capsule (PTC) plays an important role in clinical application due to its excellent curative efficacy in the treatment of ischemic stroke and chronic cerebral circulation insufficiency. To standardize and rationalize the clinical application of PTC, a rapid and sensitive method based on ultra-high performance liquid chromatography/quadrupole-Orbitrap mass spectrometry with parallel reaction monitoring (PRM) mode was developed and validated for the pharmacokinetic (PK) study. Ten bioactive compounds (aucubin, salidroside, echinacoside, paeoniflorin, verbascoside, liquiritin, 2,3,5,4'-tetrahydroxy stilbene-2-O-β-d-glucoside, coumarin, glycyrrhizic acid, and emodin) were simultaneously determined in rat plasma. All calibration curves exhibited good linearity (r2 > 0.99). The lower limits of quantification were 0.082-13.291 ng mL-1 . The intra- and inter-day precision was 0.54-12.36%, whereas the intra- and inter-day accuracy ranged from 100.45 to 114.00%. The mean extraction recoveries were 81.77-117.66%, and the average matrix effects (MEs) were 86.23-109.96%. The high extraction recoveries and acceptable MEs indicated that the pretreatment method was feasible. And the stability was acceptable under various storage conditions and processing procedures. The validated method was successfully applied to the multiple components-PK studies, which lay the foundation for further pharmacological and clinical research of PTC and may provide a reference for other traditional Chinese medicines.

Analysis of Herbal Mechanisms and Prescriptions for Chronic Cerebral Circulatory Insufficiency Based on Data Mining and Network Pharmacology.

Traditional Chinese medicine has accumulated rich resources and experience through clinical research to explore the prevention and treatment of chronic cerebral circulatory insufficiency, but current medicine lacks in-depth research and confirmation on the established protocols and mechanism of prescribed TCMs at the macro and micro levels. To explore the prescription of Chinese medicines for the treatment of Chronic Cerebral Circulation Insufficiency (CCCI) and to explore the mechanism of core drugs. 229 Chinese prescriptions for CCCI were collected from CNKI, CBM, VIP and WANFANG databases for this study. The frequency and association rules of drugs were analyzed and the core drugs by TCMISSV2.5 software was extracted. The active ingredients and targets were obtained by TCMSP, and genes of CCCI were collected from the DisGeNET, OMIM, DrugBank disease databases. The intersection targets of herbal medicine and disease were imported into the STRING database for PPI network. The key targets were screened by the network topology algorithm. The Systems Dock website was used to verify the molecular docking. The GOEAST and DAVID tools were used to perform GO and KEGG pathway analysis with the key target genes. 117 drugs involved in 229 prescriptions were identified, 2 core drugs were identified. We identified 8 active ingredients, which were mandenol, myricanone, perlolyrine, senkyunone, wallichilide, sitosterol, beta-sitosterol and stigmasterol. 371 herbal targets predicted and 335 disease targets. The enrichment analysis showed that the core herbal medicines could prevent CCCI by 15 key signaling pathways. There are direct or indirect connections in key signaling pathways, which not only participate in energy metabolism, hormone regulation, signal transduction, but also play a role in the comprehensive intervention of nervous system, immune system, circulatory system and other systems, which is consistent with the comprehensive pathogenesis of CCCI induced by multiple factors.

MicroRNA-195 prevents hippocampal microglial/macrophage polarization towards the M1 phenotype induced by chronic brain hypoperfusion through regulating CX3CL1/CX3CR1 signaling

BackgroundMicroglial polarization is a dynamic response to acute brain hypoxia induced by stroke and traumatic brain injury (TBI). However, studies on the polarization of microglia in chronic cerebral circulation insufficiency (CCCI) are limited. Our objective was to investigate the effect of CCCI on microglial polarization after chronic brain hypoperfusion (CBH) and explore the underlying molecular mechanisms.MethodsCBH model was established by bilateral common carotid artery occlusion (2-vessel occlusion, 2VO) in rats. Using the stereotaxic injection technique, lenti-pre-miR-195 and anti-miR-195 oligonucleotide fragments (lenti-pre-AMO-miR-195) were injeted into the CA1 region of the hippocampus to construct animal models with high or low expression of miR-195. Immunofluorescence staining and flow cytometry were conducted to examine the status of microglial polarization. In vitro, Transwell co-culture system was taken to investigate the role of miR-195 on neuronal-microglial communication through CX3CL1-CX3CR1 signaling. Quantitative real-time PCR was used to detect the level of miR-195 and inflammatory factors. The protein levels of CX3CL1 and CX3CR1 were evaluated by both western blot and immunofluorescence staining.ResultsCBH induced by 2VO initiated microglial/macrophage activation in the rat hippocampus from 1 week to 8 weeks, as evaluated by increased ratio of (CD68+ and CD206+)/Iba-1 immunofluorescence. And the microglial/macrophage polarization was shifted towards the M1 phenotype at 8 weeks following CBH. The expression of CX3CL1 and CX3CR1 was increased in the hippocampus of 2VO rats at 8 weeks. An in vitro study in a Transwell co-culture system demonstrated that transfection of either primary-cultured neonatal rat neurons (NRNs) or microglial BV2 cells with AMO-195-induced M1 polarization of BV2 cells and increased CX3CL1 and CX3CR1 expression and that these effects were reversed by miR-195 mimics. Furthermore, the upregulation of miR-195 induced by lenti-pre-miR-195 injection prevented microglial/macrophage polarization to M1 phenotype triggered by hippocampal injection of lenti-pre-AMO-miR-195 and 2VO surgery.ConclusionsOur findings conclude that downregulation of miR-195 in the hippocampus is involved in CBH-induced microglial/macrophage polarization towards M1 phenotype by governing communication between neurons and microglia through the regulation of CX3CL1 and CX3CR1 signaling. This indicates that miR-195 may provide a new strategy for clinical prevention and treatment of CBH.

A meta-analysis of the effectiveness of Yangxue Qingnao granules for the treatment of chronic cerebral circulation insufficiency.

ObjectiveYangxue Qingnao granules (YXQNG), which translates to granules that tonify the blood and clear liver heat, are widely available in China for the treatment of Chronic Cerebral Circulation Insufficiency (CCCI). This systematic review aimed to evaluate the effectiveness and safety of YXQNG in treating CCCI.MethodsPubMed, the Cochrane Central Register of Controlled Trials, Embase, the Chinese National Knowledge Infrastructure, and the Wanfang Database were searched from their inception to February 2019. Randomized controlled trials of YXQNG used alone or in combination with other drugs against a placebo, with no intervention or used with other drugs in CCCI patients were identified. The reviewers identified studies, extracted data, and assessed the quality of the evidence, independently and in duplicate. The Cochrane risk of bias assessment tool was used for quality assessment.ResultsA total of 31 RCTs and 2,877 patients were selected. The meta‐analysis indicated that the ratio between the combined RR of the total effective rate and the 95% confidential interval (95% CI) was 1.21 (1.17, 1.26). The combined MD of transcranial Doppler (TCD) detecting carotid artery, vertebral artery, and basilar artery blood flows (95% CI), respectively, were 8.84 (5.83, 11.85), 4.72 (3.71, 5.73), and 3.89 (3.03, 4.76). The combined MD of plasma viscosity and fibrinogen, respectively, were −0.35 (−0.40, −0.30) and −0.81 (−1.12, −0.50). Serious adverse effects were not reported in all the included trials.ConclusionThis systematic review revealed that YXQNG could increase cerebral blood flow in patients with CCCI and improve their symptoms, with no serious adverse effects. Since the literature reviewed was affected by factors such as lower quality of the included studies, the systematic evaluation's conclusion is not very reliable. Thus, more rigorously designed trials are needed.

Systematic quality evaluation of Peiyuan Tongnao capsule by offline two-dimensional liquid chromatography/quadrupole-Orbitrap mass spectrometry and adjusted parallel reaction monitoring of quality markers.

Peiyuan Tongnao capsule (PTC) is a prescription medicine of traditional Chinese medicine with the effects of "nourishing the kidney," "replenishing essence," "extinguishing wind," and "opening the meridian". PTC is also widely used in clinic for the treatment of stroke and chronic cerebral circulation insufficiency. However, the quality control studies of PTC are hitherto quite limited. Here, we aim to fully utilize an advanced chromatography-mass spectrometry hyphenation technique to qualitatively and quantitatively evaluate the quality of PTC. Firstly, a two-dimensional liquid chromatography/quadrupole-Orbitrap mass spectrometry (2D-LC/Q-Orbitrap-MS) approach was established for multicomponent characterization. An offline 2D-LC system fitted with an Xbridge Amide column and an HSS T3 column showed an orthogonality of 0.63 and a theoretical peak capacity of 6930. Eleven fractions of PTC, after hydrophilic interaction chromatography (first dimension), were further analyzed by reversed-phase ultrahigh-performance liquid chromatography/Q-Orbitrap-MS (UHPLC/Q-Orbitrap-MS, second dimension) using a rapid negative/positive switching mode. Consequently, 178 compounds were separated, 96 of which were identified or tentatively characterized. Secondly, co-condition fingerprint analysis of seven constituted herbal medicines of PTC was performed to unveil ten active ingredients (citric acid, rehmannioside D, echinacoside, paeoniflorin, verbascoside, liquiritin, 2,3,5,4'-tetrahydroxystilbene-2-O-β-D-glucoside, cinnamic aldehyde, glycyrrhizic acid, and emodin) as the quality markers of PTC. Thirdly, a UHPLC/PRMad (adjusted parallel reaction monitoring) method was established and validated to quantify the ten marker compounds in 14 batches of PTC. To the best of our knowledge, this is the first study to report comprehensive multicomponent characterization, authentication, and quality evaluation of PTC, which could be used to lay the foundation for quality control, biological efficacy research, and further development. Graphical abstract.

Safety and Clinical Efficacy of Yangxue Qingnao Granules in the Treatment of Chronic Cerebral Circulation Insufficiency: A Systematic Review and Meta-Analysis.

To evaluate the safety and clinical efficacy of Yangxue Qingnao (YXQN) granules in the treatment of chronic cerebral circulation insufficiency (CCCI), electronic databases—PubMed, Embase, CNKI, VIP, and Wangfang—were searched for randomized controlled trials (RCTs) published up to January 2019. GRADE and RevMan 5.3.0 were used for grading and analysis, respectively. Fifteen trials involving 1211 CCCI patients were included. Subgroup analysis was performed owing to study heterogeneity. Compared to nimodipine plus routine treatment, YXQN granules plus routine treatment were more effective in increasing basilar artery (BA) blood flow velocity (mean difference (MD) = 3.34, 95% confidence interval (CI) = [2.31, 4.37], P < 0.00001), vertebral artery (VA) blood flow velocity (MD = 0.52, 95% CI = [0.27, 0.76], P < 0.0001), and internal carotid artery (ICA) blood flow velocity (MD = 7.46, 95% CI = [2.01, 12.90], P=0.007). In improving the clinical efficacy of traditional Chinese medicine (TCM) for symptoms such as headache, dizziness, and insomnia, YXQN granules plus routine treatment were shown to be superior to the following control treatments: nimodipine plus routine treatment (mean difference (M-H) = 4.21, 95% CI = [2.49, 7.12], P < 0.00001), flunarizine plus routine treatment (mean difference (M-H) = 3.92, 95% CI = [1.36, 11.29], P=0.01), troxerutin plus routine treatment (mean difference (M-H) = 4.79, 95% CI = [2.20, 10.42], P < 0.00001), and routine treatment (mean difference (M-H) = 6.13, 95% CI = [1.48, 25.34], P=0.01). Risk of bias was assessed in 15 trials. One analysis was graded using GRADE and showed poor results. Adverse events were not reported explicitly in all but one trial. Thus, this meta-analysis suggests that YXQN granules may be beneficial for patients with CCCI. However, owing to the poor quality of the clinical trials and small sample sizes, a definite conclusion on the efficacy and safety of YXQN granules cannot be drawn from existing information.

Efficacy and safety of oral traditional Chinese patent medicine for chronic cerebral circulation insufficiency patients: A protocol for a systematic review and network meta-analysis.

Background:Chronic cerebral circulation insufficiency (CCCI) is a common clinical cerebrovascular disease, especially among middle-aged and elderly patients, which seriously endangers their quality of life and physical and mental health. At present, Oral traditional Chinese patent medicine (OTCPM) is widely used in the treatment of CCCI in China, but its actual efficacy and safety lack of evidence-based evidence. Therefore, we will screen out the most effective OTCPM through a systematic review and network meta-analysis to provide a reliable theoretical basis for clinical decisions.Methods:We will search electronic databases to collect relevant RCT studies from inception to October 2019. Those electronic databases include PubMed, Cochrane Library, Web of Science, EMBASE, China Biomedical Literature Database (CBM), China National Knowledge Infrastructure (CNKI), Chinese Scientific Journal Database (VIP), and Wan-fang database. Only randomized clinical trials (RCTs) concerned any OTCPM treatments for CCCI will be collected. The included studies will no restrictions on language or publication year. There were no publication year or language for the included literature. Risk bias tools will assess the quality of the included literature. A Bayesian NMA will be performed to combine the direct and indirect comparisons of TCPMs interventions. The surface under the cumulative ranking curve (SUCRA) will be drawn to display the hierarchy of each TCPMs treatment. All statistical analyses will be implemented using R v3.5.2. and GeMTC v1.4.3.We will publish this systematic review in academic journals. Since this literature review will not involve directly contacting patients, ethical approval and informed consent are not required.Trial registration number:CRD42019123878.

Potential Applications of Remote Limb Ischemic Conditioning for Chronic Cerebral Circulation Insufficiency.

Chronic cerebral circulation insufficiency (CCCI) refers to a chronic decrease in cerebral blood perfusion, which may lead to cognitive impairment, psychiatric disorders such as depression, and acute ischemic stroke. Remote limb ischemic conditioning (RLIC), in which the limbs are subjected to a series of transient ischemic attacks, can activate multiple endogenous protective mechanisms to attenuate fatal ischemic injury to distant organs due to acute ischemia, such as ischemic stroke. Recent studies have also reported that RLIC can alleviate dysfunction in distant organs caused by chronic, non-fatal reductions in blood supply (e.g., CCCI). Indeed, research has indicated that RLIC may exert neuroprotective effects against CCCI through a variety of potential mechanisms, including attenuated glutamate excitotoxicity, improved endothelial function, increased cerebral blood flow, regulation of autophagy and immune responses, suppression of apoptosis, the production of protective humoral factors, and attenuated accumulation of amyloid-β. Verification of these findings is necessary to improve prognosis and reduce the incidence of acute ischemic stroke/cognitive impairment in patients with CCCI.

Link between Chronic Isolated Lightheadedness and Abnormal Blood Phospholipids

Background: To evaluate whether Chronic Isolated Light-headedness (CIL) commonly manifested in elderly patients with Suspected Chronic Cerebral Circulation Insufficiency (SCCCI) is related with a certain abnormality in circulation. Methods: In this case-control study, 462 patients (aged 40-83 years) with CIL and 238 clinical data matched controls were enrolled consecutively from January 2011 to September 2014. The plasma level of phospholipids with solubility similar to that of lysophosphatidic acid (PSS-LPA), a surrogate marker for cerebral oxidative stress, was determined in all subjects to compare the occurrence and severity of CIL with the values of PSS-LPA. Findings: Patients with CIL had significantly higher plasma levels of PSS-LPA than controls, χ2 = 448, odds ratio (95% CI) = 140 (72-260), P<0*001; the mean plasma levels were 0*573 vs. 0*290 mmol/L respectively (P<0*001). Regardless of having or having not psychogenic abnormalities, patients with CIL had significantly higher level of PSS-LPA than those patients without light-headedness. Receiver operator characteristic (ROC) analyses showed plasma PSS-LPA was both sensitive and specific for CIL. The area under ROC curve (AUC) was as high as 0*953 (0*938-0*968). The changes in severity of CIL between two separate assays of one month apart were correlated closely with the changes in plasma levels of PSS-LPA for the same patients, correlation coefficient (Spearman) = 0*90, p<0*001. Interpretation: CIL is a manifestation of abnormal blood phospholipids. This new finding initially revealed a possible mechanism of CIL. PSS-LPA can at least be used in excluding the psychogenic lightheadedness. Funding: Grant of the 304 Hospital, China. Declaration of Interests: The authors declare no conflict of interest. Ethics Approval: This study was conducted according to the Helsinki II Declaration and approved by the ethics committee of the 304 Hospital, Chinese Army.

Normobaric oxygen: a novel approach for treating chronic cerebral circulation insufficiency.

Chronic cerebral circulation insufficiency (CCCI) is viewed as an alarming state induced by long-term reduction in cerebral perfusion, which is associated with neurological deficits and high risk of stroke occurrence or recurrence. CCCI accounts for a large proportion of both outpatients and inpatients with cerebrovascular diseases, while management of CCCI remains a formidable challenge to clinicians. Normobaric oxygen (NBO) is an adjuvant hyperoxygenation intervention supplied with one atmosphere pressure (1 ATA =101.325 kPa). A plethora of studies have demonstrated the efficacy of NBO on the penumbra in acute stroke. NBO has been shown to increase the oxygen pressure, raise the intracranial blood flow, protect blood–brain barrier and enhance neuroprotective effects. As similar underlying mechanisms are shared by the penumbra in stroke and the ischemic–hypoxic brain tissues in CCCI, we speculate that NBO may serve as a promising therapeutic strategy for attenuating short-term symptoms or improving long-term clinical outcomes among patients with CCCI. Due to the scant research exploring the efficacy and safety of NBO for treating CCCI so far, both experimental and clinical studies are warranted to verify our hypothesis in the future.

Clinical study on treatment of Bushen-Huoxue decoction for the patients with senile chronic cerebral circulation insufficiency

Objective To observe the effect of Bushen-Huoxue decoction combined with conventional therapy on the clinical symptoms, vertigo degree and cognitive function of elderly patients with chronic cerebral cerebral circulation insufficiency (CCCI) and to explore its mechanism. Methods A total of 70 patients were randomly divided into observation group and control group according to random number table method. The two groups were given antihypertensive, hypoglycemic, lipid and other western medicine treatment. On this basic treatment, the control group added orally flunarizine hydrochloride capsules, 5 mg /day before sleeping, while the observation group with Bushen-Huoxue decoction per day. All the treatment last 30 days. dizziness handicap inventory (DHI) and montreal cognitive assessment (MoCA) were used for the symptoms evaluation, and the mean flow velocity of the following arteries basilar artery (BA), bilateral vertebral artery (VA) and middle cerebral artery (MCA) were assessed by the Ultrasound transcranial doppler blood flow analyzer. The acidity phosphatidic acid, AP were detected by chemical colorimetric method. And the clinical effect rates were compared after treatment. Results The total effective rate of observation group was 94.3% (33/35), higher than 82.9% (29/35) in the control group, and the difference in group 2 was statistically significant (χ2=9.728, P<0.05). After treatment, the TCM symptom scores (6.2 ± 3.3 vs. 9.8 ± 3.7, t=8.920), DHI score (4.4 ± 2.5 vs. 9.3 ± 3.6, t=12.081) and MoCA score (25.7 ± 2.6 vs. 23.2 ± 2.8, t=6.638) improvement of the observation group were significantly better than those of control group (P<0.05). The Vms of LVA (37.2 ± 8.5 cm/s vs. 34.9 ± 7.6 cm/s, t=9.103), LMCA (63.3 ± 9.8 cm/s vs. 60.1 ± 8.4 cm/s, t=7.839), RMCA (62.8 ± 10.5 cm/s vs. 60.9 ± 9.5 cm/s, t=6.583) and plasma AP (3.74 ± 1.08 μmol/L vs. 5.81 ± 1.35 μmol/L, t=9.627) improvement of the observation group were significantly better than those of control group (P<0.05). Conclusions The Bushen-Huoxue decoction can improve the clinical symptoms and vertigo of the elderly and improve the cognitive level of the patients. The mechanism may be related to the improvement of the cerebral blood flow velocity, the decrease of plasma AP, and the state of ischemia and hypoxia. Key words: Brain ischemia; Aged; Bushen-Huoxue decoction; Blood flow velocity; Phosphatidic acids; Dizziness handicap inventory; Montreal cognitive assessment