Tight junction proteins related to blood-brain barrier and their regulatory signaling pathways in ischemic stroke.

Tight junctions (TJs) are crucial for intercellular connections. The abnormal expression of proteins related to TJs can result in TJ destruction, structural damage, and endothelial and epithelial cell dysfunction. These factors are associated with the occurrence and progression of several diseases. Studies have shown that blood-brain barrier (BBB) damage and dysfunction are the prominent pathological features of stroke. TJs are directly associated with the BBB integrity. In this article, we first discuss the structure and function of BBB TJ-related proteins before focusing on the crucial events that cause TJ dysfunction and BBB damage, as well as the regulatory mechanisms that affect the qualitative and quantitative expression of TJ proteins during ischemic stroke. Multiple regulatory mechanisms, including phosphorylation, matrix metalloproteinases (MMPs), and microRNAs, regulate TJ-related proteins and affect BBB permeability. Some signaling pathways and mechanisms have been demonstrated to have dual functions. Hopefully, our understanding of the regulation of BBB TJs in ischemic stroke will be applied to the development of targeted medications and therapeutic therapies.

Network pharmacology analysis reveals neuroprotective effects of the Qin-Zhi-Zhu-Dan Formula in Alzheimer's disease.

There is yet no effective drug for Alzheimer's disease (AD) which is one of the world's most common neurodegenerative diseases. The Qin-Zhi-Zhu-Dan Formula (QZZD) is derived from a widely used Chinese patent drug-Qing-Kai-Ling Injection. It consists of Radix Scutellariae, Fructus Gardeniae, and Pulvis Fellis Suis. Recent study showed that QZZD and its effective components played important roles in anti-inflammation, antioxidative stress and preventing brain injury. It was noted that QZZD had protective effects on the brain, but the mechanism remained unclear. This study aims to investigate the mechanism of QZZD in the treatment of AD combining network pharmacology approach with experimental validation. In the network pharmacology analysis, a total of 15 active compounds of QZZD and 135 putative targets against AD were first obtained. Gene Ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were then applied to clarify the biological mechanism. The anti-inflammatory mechanism of QZZD was proved, and a synthetic pathway-TNFR1-ERK1/2-NF-κBp65 signaling pathway was obtained. On the basis of the above discoveries, we further validated the protective effects QZZD on neurons with an APP/PS1 double transgenic mouse model. Weight change of the mice was monitored to assess QZZD's influence on the digestive system; water maze experiment was used for evaluating the effects on spatial learning and memory; Western blotting and immunohistochemistry analysis were used to detect the predicted key proteins in network pharmacology analysis, including Aß, IL-6, NF-κBp65, TNFR1, p-ERK1/2, and ERK1/2. We proved that QZZD could improve neuroinflammation and attenuate neuronal death without influencing the digestive system in APP/PS1 double transgenic mice with dementia. Combining animal pharmacodynamic experiments with network pharmacology analysis, we confirmed the importance of inflammation in pathogenesis of AD, clarified the pharmacodynamic characteristics of QZZD in treating AD, and proved its neuroprotective effects through the regulation of TNFR1-ERK1/2-NF-κBp65 signaling pathway, which might provide reference for studies on treatment of AD in the future.

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.

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).

"Possible mechanisms underlying treatment of Alzheimer's disease with Traditional Chinese Medicine: active components, potential targets and synthetic pathways of Bulao Elixir".

OBJECTIVE: To elucidate the mechanisms underlying the treatment of Alzheimer's disease (AD) with Traditional Chinese Medicine (TCM), by examining the active components, potential targets and synthetic pathways of Bulao Elixir (BLE). METHODS: The Absorption, Distribution, Metabolism, Excretion (ADME) / Toxicology (T) calculation was used to screen the active components of Bulao Elixir. Based on the TCM Systems Pharmacology Analysis Platform (TCMSP database) and a text mining tool (GoPubMed database), we predicted and screened the active components of Bulao Elixir and its therapeutic targets for AD. Using the Database for Annotation, Visualization and Integrated Discovery (DAVID), we obtained the targets for AD. Cytoscape software was used to establish a network map of the active component-target and target-pathway of Bulao Elixir. Gene function, related biological processes and signaling pathways were analyzed using the DAVID database. RESULTS: Twelve active components were selected from 196 components of Bulao Elixir. Among 2209 targets, 102 effective targets were selected, and 30 important targets were identified via matching with the disease targets. After further analysis, 14 core targets were identified. Enrichment analysis revealed that most of these important targets were involved in multiple biological processes, including apoptosis, inflammatory reactions, and cell regulation cycles. The synthetic pathways for AD treatment were identified after analyzing and confirming the relevant pathways, providing potentially useful information for diagnosis and treatment methods for AD. CONCLUSION: The current study elucidated the potential treatment mechanisms of Bulao Elixir in AD using network pharmacology, providing a foundation for further clarification of its treatment targets.

Majie cataplasm provides a shield against asthmatic punch from the neuroimmune system.

Asthma poses a threat to human health, and its pathogenesis is closely related to the neuroimmune system. Majie cataplasm can not only regulate the immune system but also the nervous system in asthma patients for its components. We speculate that Majie cataplasm may relieve asthmatic patients with sensitivity to hormone or not by regulating the body's neuroimmune system. METHODS: In this experiment, a mouse model of asthma was well established by ovalbumin. The lung function of animals was examined and pathological changes in the lung tissue were assessed by hematoxylin-eosin staining. Serum immunoglobulin E (IgE), calcitonin gene-related peptide (CGRP) and neurokinin A (NKA) were measured by ELISA. The location of CGRP, CD3 and neutrophil in lung tissue and their expressions were detected by immunofluorescence staining. In addition, contents of CGRP mRNA, Substance P (SP) mRNA, interleukin (IL)-17 mRNA and interleukin(IL)-13 mRNA were detected by quantitative polymerase chain reaction. RESULTS: Compared with the asthma model group, Majie cataplasm and dexamethasone can not only equivalently relieve airway hyperresponsiveness, but also make the content of serum IgE reduced. In addition, they can lower the content of serum CGRP and NKA after OVA stimulation, and this effect was more obvious for Majie cataplasm. Our results also showed that Majie Cataplasm and dexamethasone could inhibit the secretion of CGRP and the infiltration of T lymphocytes together with neutrophils in lung tissue and reduce expressions of CGRP mRNA, SP mRNA, IL-17 mRNA and IL-13 mRNA in lung tissue. CONCLUSION: Majie cataplasm effectively relieves expressions of neuropeptides such as CGRP, reduces the infiltration of immune cells in lung tissue, regulates the body's neuroimmune system, and has a therapeutic potential for both Th2 asthma and neutrophilic asthma.

The mediatory role of Majie cataplasm on inflammation of allergic asthma through transcription factors related to Th1 and Th2.

BACKGROUND: Asthma, a common respiratory disease, is harmful biological effect to our health. As a traditional Chinese medicine for asthma, Majie cataplasm could alleviate the symptoms of asthma and its compositions have immunomodulatory effects. Previous experiments showed that Majie cataplasm was an effective approach to mitigate asthma airway remodeling and had the potential to regulate Th2 cytokines of IL-5 and IL-13. Therefore, our further research focuses on the explanation about the regulatory effect of Majie cataplasm on reshaping Th1/Th2 through their related transcription factors. METHODS: In this experiment, the launch of asthma model was made by inducing with Ovalbumin (OVA) in C57 mice (n = 40), including 4 groups: the untreated control group (n = 10), the asthma model group (n = 10), the dexamethasone group (n = 10) and the Majie cataplasm group (n = 10). After the intervention, all groups of animals got detected for serum IgE levels, and HE staining of lung tissues was to observe and examine pathological changes. Meanwhile, we analyzed the secretion of IL-4+ T cells and IFN-γ+ T cells in spleen by flow cytometry. The expressions of transcription factor STAT6 mRNA, GATA-3 mRNA and T-bet mRNA in lung tissues was tested by PCR, and western blot had been used to detect levels of JAK2 and STAT3. RESULTS: We found that Majie cataplasm eased the content of serum IgE and lung inflammation. It could lower the increased number of IL-4+ T cells and IFN-γ+ T cells (P < 0.0001, P < 0.01) in asthmatic mice and curb the expression of STAT6 mRNA and GATA-3 (P < 0.0001, P < 0.01) mRNA as well as the protein levels of JAK2 (P < 0.001) and the ratio of pSTAT3/STAT3 (P < 0.05). Besides, Majie cataplasm made its mark on T-bet mRNA by improving it (P < 0.0001). CONCLUSION: These data suggest that Majie cataplasm exert an anti-inflammatory effect of Th2 by rebalancing Th1/Th2 through corresponding transcription factor STAT6, GATA-3, STAT3, and T-bet, which providing a strong cornerstone for asthma control.

Integrated Analysis of the Mechanisms of Da-Chai-Hu Decoction in Type 2 Diabetes Mellitus by a Network Pharmacology Approach.

BACKGROUND: The incidence of type 2 diabetes mellitus (T2DM) has increased year by year, which not only seriously affects people's quality of life, but also imposes a heavy economic burden on the family, society, and country. Currently, the pathogenesis, diagnosis, and treatment of T2DM are still unclear. Therefore, exploration of a precise multitarget treatment strategy is urgent. Here, we attempt to screen out the active components, effective targets, and functional pathways of therapeutic drugs through network pharmacology with taking advantages of traditional Chinese medicine (TCM) formulas for multitarget holistic treatment of diseases to clarify the potential therapeutic mechanism of TCM formulas and provide a systematic and clear thought for T2DM treatment. METHODS: First, we screened the active components of Da-Chai-Hu Decoction (DCHD) by absorption, distribution, metabolism, excretion, and toxicity (ADME/T) calculation. Second, we predicted and screened the active components of DCHD and its therapeutic targets for T2DM relying on the Traditional Chinese Medicine Systems Pharmacology Analysis Platform (TCMSP database) and Text Mining Tool (GoPubMed database), while using the Database for Annotation, Visualization, and Integrated Discovery (DAVID) to obtain T2DM targets. Third, we constructed a network of the active component-target, target-pathway of DCHD using Cytoscape software (http://cytoscape.org/,ver.3.5.1) and then analyzed gene function, related biological processes, and signal pathways through the DAVID database. RESULTS: We screened 77 active components from 1278 DCHD components and 116 effective targets from 253 ones. After matching the targets of T2DM, we obtained 38 important targets and 7 core targets were selected through further analysis. Through enrichment analysis, we found that these important targets were mainly involved in many biological processes such as oxidative stress, inflammatory reaction, and apoptosis. After analyzing the relevant pathways, the synthetic pathway for the treatment of T2DM was obtained, which provided a diagnosis-treatment idea for DCHD in the treatment of T2DM. CONCLUSIONS: This article reveals the mechanism of DCHD in the treatment of T2DM related to inflammatory response and apoptosis through network pharmacology, which lays a foundation for further elucidation of drugs effective targets.

Sini powder ameliorates the inflammatory response in rats with stress-induced non-alcoholic fatty liver disease by inhibiting the nuclear factor kappa-B / pyrin domain-containing protein 3 pathway.

OBJECTIVE: To evaluate the effectiveness of Sini powder for the treatment of non-alcoholic fatty liver disease (NAFLD) in rats and the molecular mechanisms involved. METHODS: A rat model of stress-induced NAFLD was established by a combination of long-term tethering and feeding of a high-fat, high-calorie diet. These rats were then intragastrically administered with either simvastatin, Sini powder, or vehicle for 1 week. The body mass and field test scores for each group were recorded weekly. Serum aspartate aminotransferase and alanine aminotransferase activities, and triglyceride, total cholesterol, and free fatty acid concentrations were measured. Liver tissue histopathology was examined on hematoxylin and eosin-stained paraffin sections and oil red O-stained frozen sections. The hepatic mRNA expression of nuclear factor kappa-B (NF-κB), NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3), apoptosis-associated speck-like protein containing CARD (ASC), and caspase-1 were measured by reverse transcription-polymerase chain reaction (RT-PCR). The hepatic protein concentrations of NF-κB and NLRP3, ASC, caspase-1, interleukin-1ß (IL-1ß), interleukin-6 (IL-6), and the serum concentrations of IL-1ß and IL-6 were measured by enzyme-linked immunosorbent assay. RESULTS: Compared with the Blank group, rats in the Compound model group showed significant pathologic manifestations of NAFLD, and the expression of NF-κB, NLRP3, ASC, caspase-1, IL-1ß and IL-6 were significantly higher (all P < 0.01). Both simvastatin and Sini powder significantly ameliorated the NAFLD pathology and the abnormal expression of NF-κB, NLRP3, ASC, caspase-1, IL-1ß, and IL-6 (all P < 0.01). CONCLUSION: Sini powder inhibits the inflammatory response in rats with NAFLD, which is mediated by NF-κB/NLRP3, IL-1ß, and IL-6, reduces the effects of psychological stress, and improves lipid metabolism. Therefore, Sini powder may be effective for the treatment of stress-related NAFLD through multiple mechanisms.

Corrigendum to "Systematic Understanding of the Mechanism of Baicalin against Ischemic Stroke through a Network Pharmacology Approach".

[This corrects the article DOI: 10.1155/2018/2582843.].

Synergistic neuroprotective effects of Geniposide and ursodeoxycholic acid in hypoxia-reoxygenation injury in SH-SY5Y cells.

Endoplasmic reticulum stress (ERS) and autophagy activation play important roles in the process of cerebral ischemia/reperfusion (I/R) injury. The synergistic protective effects of Geniposide and ursodeoxycholic acid against cellular apoptosis caused by oxygen-glucose deprivation-reoxygenation (OGD/R) were investigated using a Cell Counting Kit-8 assay, lactate dehydrogenase (LDH) assay, flow cytometry, quantitative polymerase chain reaction (qPCR), and western blotting to examine cellular viability, apoptosis, reactive oxygen species (ROS) levels, mRNA and protein levels, respectively, in relation to ERS and autophagy. We found that pretreatment with Geniposide improved cellular viability. Moreover, treatment with a combination of Geniposide and Tauroursodeoxycholic acid (TUDCA) (GT) protected injured cells better than Geniposide alone. Further studies showed that the increase in cellular ROS levels, and the overexpression of mRNA and proteins related to OGD/R-induced ERS and autophagy, were both counteracted by GT. Our study indicates that the protective effects of GT on OGD/R-induced apoptosis in SH-SY5Y cells are associated with the inhibition of ERS and autophagy.

Systematic Understanding of the Mechanism of Baicalin against Ischemic Stroke through a Network Pharmacology Approach.

Ischemic stroke is accompanied by high mortality and morbidity rates. At present, there is no effective clinical treatment. Alternatively, traditional Chinese medicine has been widely used in China and Japan for the treatment of ischemic stroke. Baicalin is a flavonoid extracted from Scutellaria baicalensis that has been shown to be effective against ischemic stroke; however, its mechanism has not been fully elucidated. Based on network pharmacology, we explored the potential mechanism of baicalin on a system level. After obtaining baicalin structural information from the PubChem database, an approach combined with literature mining and PharmMapper prediction was used to uncover baicalin targets. Ischemic stroke-related targets were gathered with the help of DrugBank, Online Mendelian Inheritance in Man (OMIM), Genetic Association Database (GAD), and Therapeutic Target Database (TTD). Protein-protein interaction (PPI) networks were constructed through the Cytoscape plugin BisoGenet and analyzed by topological methods. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment were carried out via the Database for Annotation, Visualization, and Integrated Discovery (DAVID) server. We obtained a total of 386 potential targets and 5 signaling pathways, including mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT), hypoxia-inducible factor-1 (HIF-1), nuclear factor kappa B (NF-κB), and forkhead box (FOXO) signaling pathways. GO analysis showed that these targets were associated with antiapoptosis, antioxidative stress, anti-inflammation, and other physiopathological processes that are involved in anti-ischemic stroke effects. In summary, the mechanism of baicalin against ischemic stroke involved multiple targets and signaling pathways. Our study provides a network pharmacology framework for future research on traditional Chinese medicine.