scholarly journals Xiaoxuming Decoction: A Traditional Herbal Recipe for Stroke With Emerging Therapeutic Mechanisms

2021 ◽  
Vol 12 ◽  
Author(s):  
Qian Zhang ◽  
Yue Wang ◽  
Aiwen Chen ◽  
Xinwei Huang ◽  
Qianyu Dong ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Molecular Mechanisms ◽  
Neurovascular Unit ◽  
Alternative Therapy ◽  
Acute Stage ◽  
Therapeutic Effects ◽  
Active Compounds ◽  
Endovascular Thrombectomy ◽  
Therapeutic Mechanisms ◽  
New Perspective

Xiaoxuming decoction (XXMD) has been traditionally used to manage stroke though debates on its clinical efficacy were present in the history. Till nowadays, it is still one of the most commonly used herbal recipes for stroke. One of the reasons is that a decent proportion of ischemic stroke patients still have residue symptoms even after thrombolysis with rt-PA or endovascular thrombectomy. Numerous clinical studies have shown that XXMD is an effective alternative therapy not only at the acute stage, but also at the chronic sequelae stage of ischemic stroke. Modern techniques have isolated groups of compounds from XXMD which have shown therapeutic effects, such as dilating blood vessels, inhibiting thrombosis, suppressing oxidative stress, attenuating nitric oxide induced damage, protecting the blood brain barrier and the neurovascular unit. However, which of the active compounds is responsible for its therapeutic effects is still unknown. Emerging studies have screened and tested these active compounds aiming to find individual compounds that can be used as drugs to treat stroke. The present study summarized both clinical evidence of XXMD in managing stroke and experimental evidence on its molecular mechanisms that have been reported recently using advanced techniques. A new perspective has also been discussed with an aim to provide new targets that can be used for screening active compounds from XXMD.

scholarly journals Repair Mechanisms of the Neurovascular Unit after Ischemic Stroke with a Focus on VEGF

2021 ◽  
Vol 22 (16) ◽  
pp. 8543
Author(s):  
Sunhong Moon ◽  
Mi-Sook Chang ◽  
Seong-Ho Koh ◽  
Yoon Kyung Choi
Keyword(s):  
Stem Cells ◽  
Endothelial Cells ◽  
Ischemic Stroke ◽  
Neural Stem Cells ◽  
Molecular Mechanisms ◽  
Late Phase ◽  
Neurovascular Unit ◽  
Regeneration Ability ◽  
Therapeutic Effects ◽  
Related Factors

The functional neural circuits are partially repaired after an ischemic stroke in the central nervous system (CNS). In the CNS, neurovascular units, including neurons, endothelial cells, astrocytes, pericytes, microglia, and oligodendrocytes maintain homeostasis; however, these cellular networks are damaged after an ischemic stroke. The present review discusses the repair potential of stem cells (i.e., mesenchymal stem cells, endothelial precursor cells, and neural stem cells) and gaseous molecules (i.e., nitric oxide and carbon monoxide) with respect to neuroprotection in the acute phase and regeneration in the late phase after an ischemic stroke. Commonly shared molecular mechanisms in the neurovascular unit are associated with the vascular endothelial growth factor (VEGF) and its related factors. Stem cells and gaseous molecules may exert therapeutic effects by diminishing VEGF-mediated vascular leakage and facilitating VEGF-mediated regenerative capacity. This review presents an in-depth discussion of the regeneration ability by which endogenous neural stem cells and endothelial cells produce neurons and vessels capable of replacing injured neurons and vessels in the CNS.

scholarly journals Mesenchymal Stem Cell Derived Extracellular Vesicles for Repairing the Neurovascular Unit after Ischemic Stroke

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 767
Author(s):  
Courtney Davis ◽  
Sean I. Savitz ◽  
Nikunj Satani
Keyword(s):  
Ischemic Stroke ◽  
Extracellular Vesicles ◽  
Neurovascular Unit ◽  
Culture Conditions ◽  
Therapeutic Effects ◽  
Stroke Treatment ◽  
Inflammatory Molecules ◽  
The Brain

Ischemic stroke is a debilitating disease and one of the leading causes of long-term disability. During the early phase after ischemic stroke, the blood-brain barrier (BBB) exhibits increased permeability and disruption, leading to an influx of immune cells and inflammatory molecules that exacerbate the damage to the brain tissue. Mesenchymal stem cells have been investigated as a promising therapy to improve the recovery after ischemic stroke. The therapeutic effects imparted by MSCs are mostly paracrine. Recently, the role of extracellular vesicles released by these MSCs have been studied as possible carriers of information to the brain. This review focuses on the potential of MSC derived EVs to repair the components of the neurovascular unit (NVU) controlling the BBB, in order to promote overall recovery from stroke. Here, we review the techniques for increasing the effectiveness of MSC-based therapeutics, such as improved homing capabilities, bioengineering protein expression, modified culture conditions, and customizing the contents of EVs. Combining multiple techniques targeting NVU repair may provide the basis for improved future stroke treatment paradigms.

scholarly journals Early alterations of neurovascular unit in the retina in mouse models of tauopathy

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Fan Xia ◽  
Yonju Ha ◽  
Shuizhen Shi ◽  
Yi Li ◽  
Shengguo Li ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Mouse Models ◽  
Molecular Mechanisms ◽  
Early Stage ◽  
Leukocyte Adhesion ◽  
Neurovascular Unit ◽  
Integrated Analysis ◽  
Therapeutic Effects ◽  
Retinal Ganglion ◽  
Potential Biomarker

AbstractThe retina, as the only visually accessible tissue in the central nervous system, has attracted significant attention for evaluating it as a biomarker for neurodegenerative diseases. Yet, most of studies focus on characterizing the loss of retinal ganglion cells (RGCs) and degeneration of their axons. There is no integrated analysis addressing temporal alterations of different retinal cells in the neurovascular unit (NVU) in particular retinal vessels. Here we assessed NVU changes in two mouse models of tauopathy, P301S and P301L transgenic mice overexpressing the human tau mutated gene, and evaluated the therapeutic effects of a tau oligomer monoclonal antibody (TOMA). We found that retinal edema and breakdown of blood–retina barrier were observed at the very early stage of tauopathy. Leukocyte adhesion/infiltration, and microglial recruitment/activation were constantly increased in the retinal ganglion cell layer of tau transgenic mice at different ages, while Müller cell gliosis was only detected in relatively older tau mice. Concomitantly, the number and function of RGCs progressively decreased during aging although they were not considerably altered in the very early stage of tauopathy. Moreover, intrinsically photosensitive RGCs appeared more sensitive to tauopathy. Remarkably, TOMA treatment in young tau transgenic mice significantly attenuated vascular leakage, inflammation and RGC loss. Our data provide compelling evidence that abnormal tau accumulation can lead to pathology in the retinal NVU, and vascular alterations occur more manifest and earlier than neurodegeneration in the retina. Oligomeric tau-targeted immunotherapy has the potential to treat tau-induced retinopathies. These data suggest that retinal NVU may serve as a potential biomarker for diagnosis and staging of tauopathy as well as a platform to study the molecular mechanisms of neurodegeneration.

scholarly journals Identification of Active Compounds of Mahuang Fuzi Xixin Decoction and Their Mechanisms of Action by LC-MS/MS and Network Pharmacology

2020 ◽  
Vol 2020 ◽  
pp. 1-11
Author(s):  
Xiao Liang ◽  
Chang-Shun Liu ◽  
Ting Xia ◽  
Qing-Fa Tang ◽  
Xiao-Mei Tan
Keyword(s):  
Signaling Pathways ◽  
Bioactive Compounds ◽  
Cell Receptor ◽  
Mechanisms Of Action ◽  
Network Pharmacology ◽  
Therapeutic Effects ◽  
Active Compounds ◽  
Beneficial Effects ◽  
T Cell Receptor Signaling ◽  
Therapeutic Mechanisms

The decoction is an important dosage form of traditional Chinese medicine (TCM) administration. The Mahuang Fuzi Xixin decoction (MFXD) is widely used to treat allergic rhinitis (AR) in China. However, its active compounds and therapeutic mechanisms are unclear. The aim of this study was to establish an integrative method to identify the bioactive compounds and reveal the mechanisms of action of MFXD. LC-MS/MS was used to identify the compounds in MFXD, followed by screening for oral bioavailability. TCMSP, BindingDB, STRING, DAVID, and KEGG databases and algorithms were used to gather information. Cytoscape was used to visualize the networks. Twenty-four bioactive compounds were identified, and thirty-seven predicted targets of these compounds were associated with AR. DAVID analysis suggested that these compounds exert their therapeutic effects by modulating the Fc epsilon RI, B-cell receptor, Toll-like receptor, TNF, NF-κB, and T-cell receptor signaling pathways. The PI3K/AKT and cAMP signaling pathways were also implicated. Ten of the identified compounds, quercetin, pseudoephedrine, ephedrine, β-asarone, methylephedrine, α-linolenic acid, cathine, ferulic acid, nardosinone, and higenamine, seemed to account for most of the beneficial effects of MFXD in AR. This study showed that LC-MS/MS followed by network pharmacology analysis is useful to elucidate the complex mechanisms of action of TCM formulas.

scholarly journals Systems Pharmacology Dissection of Traditional Chinese Medicine Wen-Dan Decoction for Treatment of Cardiovascular Diseases

2018 ◽  
Vol 2018 ◽  
pp. 1-14 ◽  
Author(s):  
Tao-Hua Lan ◽  
Lu-Lu Zhang ◽  
Yong-Hua Wang ◽  
Huan-Lin Wu ◽  
Dan-Ping Xu
Keyword(s):  
Chinese Medicine ◽  
Cardiovascular Diseases ◽  
Traditional Chinese Medicine ◽  
Molecular Mechanisms ◽  
Modern Medicine ◽  
System Level ◽  
Therapeutic Effects ◽  
Active Compounds ◽  
System Pharmacology ◽  
Underlying Mechanisms

Cardiovascular diseases (CVDs) have been recognized as first killer of human health. The underlying mechanisms of CVDs are extremely complicated and not fully revealed, leading to a challenge for CVDs treatment in modern medicine. Traditional Chinese medicine (TCM) characterized by multiple compounds and targets has shown its marked effects on CVDs therapy. However, system-level understanding of the molecular mechanisms is still ambiguous. In this study, a system pharmacology approach was developed to reveal the underlying molecular mechanisms of a clinically effective herb formula (Wen-Dan Decoction) in treating CVDs. 127 potential active compounds and their corresponding 283 direct targets were identified in Wen-Dan Decoction. The networks among active compounds, targets, and diseases were built to reveal the pharmacological mechanisms of Wen-Dan Decoction. A “CVDs pathway” consisted of several regulatory modules participating in therapeutic effects of Wen-Dan Decoction in CVDs. All the data demonstrates that Wen-Dan Decoction has multiscale beneficial activity in CVDs treatment, which provides a new way for uncovering the molecular mechanisms and new evidence for clinical application of Wen-Dan Decoction in cardiovascular disease.

scholarly journals Elucidation of the active compounds and molecular mechanisms of Smilacis Chinae Rhizoma for treatment of pelvic inflammatory disease based on network pharmacology and MMGBSA-docking

2020 ◽  
Author(s):  
Yunsen Zhang ◽  
Zikuang Zhao ◽  
Wenxiang Wang ◽  
Qi Li ◽  
Huimin Chen ◽  
...  
Keyword(s):  
Pelvic Inflammatory Disease ◽  
Signaling Pathway ◽  
Inflammatory Disease ◽  
Molecular Mechanisms ◽  
Binding Free Energy ◽  
Network Pharmacology ◽  
Therapeutic Effects ◽  
Active Ingredients ◽  
Active Compounds ◽  
Bidirectional Regulation

Abstract Background Smilacis Chinae Rhizoma (SCR) is widely used in the treatment of pelvic inflammatory disease (PID). However, its active ingredients and the mechanisms against PID remain elusive. This study aimed to clarify the active ingredients and explore their molecular mechanisms on PID. Method Network pharmacology and MMGBSA-docking exploited the active compounds and mechanisms against PID, as well as validating the binding mode of candidate targets.Results Network pharmacology revealed 32 active compounds and 718 compound-related targets mapped to 91 pathways which were clustered 7 genres (e.g., immunoregulation). C-T-P network and PPI analysis illustrated 17 PID-related targets, indicating that SCR may decrease inflammation, ameliorate fibrosis, and inhibit microorganisms via bidirectionally regulating IL-17 signaling pathway. Furthermore, active compounds were uncovered that bound to prostaglandin-endoperoxide synthase 2, matrix metalloprotein-9, lipocalin, signal transducer and activator of transcription 3, myeloperoxidase, and tumor necrosis factor. 19 active compounds (e.g., rutin (-66.43 kcal/mol), moracin M (-37.01 kcal/mol) and oxyresveratrol (-38.84 kcal/mol)) were found to show excellent binding free energy, demonstrating that H-bond, Pi electron cloud and electrostatic potential as the main binding ability to these targets. Conclusion Approach of network pharmacology and MMGBSA-docking revealed the active ingredients, such as rutin, moracin M, and oxyresveratrol, in SCR and dissected it exhibits the therapeutic effects (e.g., decrease inflammation, ameliorate fibrosis, and inhibit microorganisms) of PID by the bidirectional regulation of IL-17 signaling pathway.

Abstract WP307: Molecular Mechanisms, Temporal and Spatial Dynamics of Inflammasome Activation in Ischemic Stroke

Stroke ◽  
2020 ◽  
Vol 51 (Suppl_1) ◽  
Author(s):  
Wei Cai ◽  
Mengyan Hu ◽  
Zhengqi Lu
Keyword(s):  
Ischemic Stroke ◽  
Molecular Mechanisms ◽  
Spatial Dynamics ◽  
Inflammasome Activation ◽  
Therapeutic Effects ◽  
Stroke Patients ◽  
Stroke Outcomes ◽  
Post Stroke ◽  
Caspase 1 ◽  
Temporal And Spatial

Background: Multiple sensors, executors and products are involved in inflammasome activation. Inflammasome activation has been found in several immune cells after stroke. However, the molecular mechanisms, the temporal and spatial dynamics of inflammasome activation in stroke remain elusive. Therapeutic value of modifying inflammasome activation in stroke is still debatable. Methods: Inflammasome markers of NLRP3 and IL-1β in stroke patients and healthy control were evaluated with flow cytometry. Correlation of NLRP3/IL-1β expression with stroke outcomes of patients was assessed. Ischemic stroke was induced in mice with transient middle cerebral artery occlusion (tMCAO, 1h). Expression dynamics of inflammasome components, location and cellular target of inflammasome activation in tMCAO models were analyzed. Therapeutic effects of inhibiting inflammasome activation on stroke outcomes were evaluated. Results: Rapid increase of inflammasome markers NLRP3 and IL-1β was detected at 1d after disease onset in stroke patients, which was positively correlated with patients’ infarct volume and NIHSS score. The sensors of NLRP3 and NLRC4 were involved in post stroke inflammasome activation, which increased at 1-3d after stroke and peaked at 3-5d in tMCAO models. Similar dynamics of the executors cleaved Caspase-1/11, as well as the products IL-1β, IL-18 and GSDMD were detected. AIM2 and Caspase-8 seemed not to take any part in post-stroke inflammasome activation. Macrophage was demonstrated as the main cell in which inflammasome was formed in both patients and mice, while microglia, dendritic cells and neutrophil also had inflammasome formation. Inflammasome activation of macrophage was mostly detected in stroke lesion. The executors of Caspase-1 and -11 were the key factors in inflammasome activation in stroke. Preventing inflammasome activation by inhibiting Caspase-1/11 signalings showed promising therapeutic efficacy. Conclusion: The impact of inflammasome activation is detrimental to ischemic stroke. Inhibiting Caspase-1/11 signalings is a promising therapeutic strategy for stroke.

scholarly journals A Network Pharmacology Approach to Uncover the Molecular Mechanisms of Herbal Formula Ban-Xia-Xie-Xin-Tang

2018 ◽  
Vol 2018 ◽  
pp. 1-22 ◽  
Author(s):  
Ming Yang ◽  
Jialei Chen ◽  
Liwen Xu ◽  
Xiufeng Shi ◽  
Xin Zhou ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Synergistic Effects ◽  
Network Pharmacology ◽  
Disease Genes ◽  
Traditional Theory ◽  
Therapeutic Effects ◽  
Proximity Analysis ◽  
Path Distance ◽  
Therapeutic Mechanisms ◽  
Shortest Path Distance

Ban-Xia-Xie-Xin-Tang (BXXXT) is a classical formula from Shang-Han-Lun which is one of the earliest books of TCM clinical practice. In this work, we investigated the therapeutic mechanisms of BXXXT for the treatment of multiple diseases using a network pharmacology approach. Here three BXXXT representative diseases (colitis, diabetes mellitus, and gastric cancer) were discussed, and we focus on in silico methods that integrate drug-likeness screening, target prioritizing, and multilayer network extending. A total of 140 core targets and 72 representative compounds were finally identified to elucidate the pharmacology of BXXXT formula. After constructing multilayer networks, a good overlap between BXXXT nodes and disease nodes was observed at each level, and the network-based proximity analysis shows that the relevance between the formula targets and disease genes was significant according to the shortest path distance (SPD) and a random walk with restart (RWR) based scores for each disease. We found that there were 22 key pathways significantly associated with BXXXT, and the therapeutic effects of BXXXT were likely addressed by regulating a combination of targets in a modular pattern. Furthermore, the synergistic effects among BXXXT herbs were highlighted by elucidating the molecular mechanisms of individual herbs, and the traditional theory of “Jun-Chen-Zuo-Shi” of TCM formula was effectively interpreted from a network perspective. The proposed approach provides an effective strategy to uncover the mechanisms of action and combinatorial rules of BXXXT formula in a holistic manner.

scholarly journals Bacopa monnieri and Their Bioactive Compounds Inferred Multi-Target Treatment Strategy for Neurological Diseases: A Cheminformatics and System Pharmacology Approach

Biomolecules ◽  
2020 ◽  
Vol 10 (4) ◽  
pp. 536 ◽  
Author(s):  
Rajendran Jeyasri ◽  
Pandiyan Muthuramalingam ◽  
Vellaichami Suba ◽  
Manikandan Ramesh ◽  
Jen-Tsung Chen
Keyword(s):  
Treatment Strategy ◽  
Molecular Mechanisms ◽  
Neurological Diseases ◽  
Bacopa Monnieri ◽  
System Level ◽  
Therapeutic Effects ◽  
Asiatic Acid ◽  
Biological Processes ◽  
Human Beings ◽  
Active Compounds

Neurological diseases (NDs), especially Alzheimer’s and Spinocerebellar ataxia (SCA), can severely cause biochemical abnormalities in the brain, spinal cord and other nerves of human beings. Their ever-increasing prevalence has led to a demand for new drug development. Indian traditional and Ayurvedic medicine used to combat the complex diseases from a holistic and integrative point of view has shown efficiency and effectiveness in the treatment of NDs. Bacopa monnieri is a potent Indian medicinal herb used for multiple ailments, but is significantly known as a nootropic or brain tonic and memory enhancer. This annual herb has various active compounds and acts as an alternative and complementary medicine in various countries. However, system-level insights of the molecular mechanism of a multiscale treatment strategy for NDs is still a bottleneck. Considering its prominence, we used cheminformatics and system pharmacological approaches, with the aim to unravel the various molecular mechanisms represented by Bacopa-derived compounds in identifying the active human targets when treating NDs. First, using cheminformatics analysis combined with the drug target mining process, 52 active compounds and their corresponding 780 direct receptors were retrieved and computationally validated. Based on the molecular properties, bioactive scores and comparative analysis with commercially available drugs, novel and active compounds such as asiatic acid (ASTA) and loliolide (LLD) to treat the Alzheimer’s and SCA were identified. According to the interactions among the active compounds, the targets and diseases were further analyzed to decipher the deeper pharmacological actions of the drug. NDs consist of complex regulatory modules that are integrated to dissect the therapeutic effects of compounds derived from Bacopa in various pathological features and their encoding biological processes. All these revealed that Bacopa compounds have several curative activities in regulating the various biological processes of NDs and also pave the way for the treatment of various diseases in modern medicine.

scholarly journals Systems Pharmacology-Dissection of the Molecular Mechanisms of Dragon’s Blood in Improving Ischemic Stroke Prognosis

2020 ◽  
Vol 2020 ◽  
pp. 1-14
Author(s):  
Meng Jiang ◽  
Xing Su ◽  
Jianling Liu ◽  
Chunli Zheng ◽  
Xiaogang Li
Keyword(s):  
Ischemic Stroke ◽  
Cell Survival ◽  
Pc12 Cells ◽  
Molecular Mechanisms ◽  
Active Compounds ◽  
Dragon’S Blood ◽  
Anti Inflammatory ◽  
Main Component ◽  
Loureirin B ◽  
Anti Inflammation

Ethnopharmacological Relevance. Dragon’s blood (DB) is a widely used traditional Chinese medicine that has many pharmacological effects, including antiplatelet aggregation, promoting epidermal growth, and anti-inflammatory and antioxidant activities. The main component of Longxuetongluo capsule and Dragon’s blood dropping pills is DB’s standard phenolic extract, which was used for ischemic stroke prognosis in China. Aim of Study. To dissect the molecular mechanisms of Dragon’s blood (DB) in improving ischemic stroke prognosis. Materials and Methods. (1) Based on system-pharmacology platform, the potential active compounds of DB are screened out according to ADME. (2) The ischemic stroke-related targets are predicted by utilizing these active compounds as probes, mapping the targets to the CTD database to establish a molecular-target-disease network. (3) To analyze the mechanism of DB treatment for the prognosis of ischemic stroke, we used the Metascape and DAVID databases to construct “ischemic stroke pathways”. (4) PC12 cells were used to explore the protective effect of loureirin B on oxygen-glucose deprivation/reperfusion (OGD/R) injury, and BV-2 cells were used to determine the anti-inflammation effect of 4′,7-dihydroxyflavone. Results. Finally, we obtained 38 active compounds and 58 stroke-related targets. Network and pathway analysis indicate that DB is effective in the treatment of ischemic stroke by enhancing cell survival and inhibiting inflammatory and antiplatelet activation. In in vitro experiments, the main component loureirin B promoted the expression of HO-1 and Bcl-2 via positive regulation of PI3K/AKT/CREB and Nrf2 signaling pathways in PC12 cells against OGD/R damage. And the anti-inflammatory activity of 4′,7-dihydroxyflavone was related to the inhibition of COX-2, TNF-α, and IL-6 in LPS-induced BV-2 cells. Conclusions. In our study, the results illustrated that DB in improving ischemic stroke prognosis may involve enhancing cell survival and antioxidant, anti-inflammation, and antiplatelet activities.

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