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Research Atlas Analysis on the Application of Huoxue Lishui Method (Promoting Blood Circulation and Diuresis) in Ophthalmology Based on VOSviewer’s and CiteSpace’s Methods

Abstract Objective: The objective of this study was to summarize the research context, hotspots, and the development trend of Huoxue lishui method in ophthalmology in the past decade by reviewing the relevant publications. Materials and Methods: Relevant publications on the application of Huoxue lishui method in ophthalmology from January 1, 2011, to December 31, 2021, in databases such as CNKI, VIP, and Wanfang were retrieved. The analysis of coauthorship, keyword co-occurrence, keyword clustering, keyword emergence, and keyword timeline map of the publications was done with bibliometrics tools CiteSpace and VOSviewer. Results: A total of 100 publications were included in the analysis. The year 2020 saw the publication of most papers concerning the application of Huoxue lishui method in ophthalmology. High-frequency words are macular edema, Huoxue lishui, diabetic macular edema, Huoxue lishui method, Huoxue lishui formula, and promoting Qi and nourishing Yin. Three research hotspots were identified through keyword clustering analysis. Keyword emergence analysis and keyword timeline map indicated that a combined treatment of Huoxue lishui method and promoting Qi and nourishing Yin and diabetic ophthalmology is predicted to be research frontiers. Conclusions: Through the use of knowledge maps, this article reveals the research status in this field in the past decade and highlights the major directions, research hotspots, and development trends, providing references for further research in this field.

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Compatibility with Fructus Ligustri Lucidi Effectively Mitigates Idiosyncratic Liver Injury of Epimedii Folium by Modulating NOD-like Receptor Family Pyrin Domain Containing 3 Inflammasome Activation

Abstract Background: Idiosyncratic drug-induced liver injury (IDILI) is a serious side effect of drugs, Epimedii Folium (EF) is unequivocally implicated in idiosyncratic liver injury onset, potentially due to its ability to perturb the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome. Fructus Ligustri Lucidi (FLL), a frequently used medicinal combination with EF, has not yet been investigated for its ability to ameliorate EF-associated hepatotoxicity. Aims and Objectives: Study on the mechanism of compatibility of FLL to alleviate liver injury caused by EF. Materials and Methods: Western blot was used to determine the expression of related proteins, ELISA was used to detect the secretion of related inflammatory factors IL-1β, IL-18, IL-6 and TNF-α, liver injury indexes were detected and liver pathological tissue staining was used to evaluate the liver injury. Results: Our results demonstrated that EF exerted a particular augmenting effect on the stimulation of the NLRP3 inflammasome mediated by nigericin or ATP, whereas FLL suppressed the NLRP3 inflammasome stimulation. Furthermore, an equal EF to FLL ratio significantly reduced the stimulatory effects of EF. Moreover, EF has the potential to induce hepatic injury and augment pro-inflammatory cytokine synthesis in rats subjected to LPS. However, when combined with FLL, the detrimental effects of EF were mitigated. Conclusion: FLL possesses the capacity to attenuate EF-associated hepatotoxicity by suppressing EF-triggered NLRP3 inflammasome activation. Thus, FLL holds promise for improving the clinical safety profile of EF, shedding light on the potential of compatibility and detoxification theories in traditional Chinese medicine.

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Uncovering Chemical Interactions between Danshen and Danggui Using Liquid Chromatography–Mass Spectrometry and Network Pharmacology-Based Research on Stroke

Abstract Objective: The objective of this study was to decipher chemical interactions between Danshen and Danggui using liquid chromatography–mass spectrometry (LC-MS) and explore the mechanisms of Danshen–Danggui against stroke using network pharmacology and molecular docking. Materials and Methods: First, the chemical compounds of Danshen–Danggui were profiled using ultra-high-performance liquid chromatography (HPLC)-quadrupole time-of-flight MS. Accurately characterized compounds in various proportions of Danshen–Danggui were quantified using HPLC combined with triple quadrupole electrospray tandem MS. Network pharmacology was used to uncover the essential mechanisms of action of Danshen–Danggui against stroke. Discovery Studio Software was used for the molecular docking verification of key active chemicals and stroke-related targets. Results: A total of 53 compounds were characterized, and 22 accurately identified constituents (10 phenolic acids, 8 phthalides, and 4 tanshinones) were quantified in 15 proportions of Danshen–Danggui. The quantification results showed that Danggui significantly increased the dissolution of most phenolic acids (compounds from Danshen), whereas Danshen promoted the dissolution of most phthalides (compounds from Danggui). Overall, the combination of Danshen and Danggui at a 1:1 ratio resulted in the maximum total dissolution rate. Further network pharmacology and molecular docking results indicated that Danshen–Danggui exerted anti-stroke effects mainly by regulating inflammation-related (tumor necrosis factor, hypoxia-inducible factor, and toll-like receptor) signaling pathways, which ranked among the top three pathways based on Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. Conclusion: The chemical compounds in Danshen–Danggui could interact with each other to increase the dissolution of the most active compounds, which could provide a solid basis for uncovering the compatibility mechanisms of Danshen–Danggui and Danshen–Danggui-based formulae.

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Research on the Orientated Effective Components of Huangqi in Huangqi Jianzhong Tang Against Chronic Atrophic Gastritis Based on Multi-Spectrum–Effect Correlation

Abstract Objective: This study aimed to investigate the orientated effective components of Astragali Radix Huangqi (HQ) in HQ Jianzhong Tang (HQJZ), a classical formula of traditional Chinese medicine (TCM) used for treating chronic atrophic gastritis (CAG), using HQ as a monarch medicine. Materials and Methods: The spectra of HQJZ containing different polar parts of HQ were obtained using ultra-high-performance liquid chromatography-Q-Exactive mass spectrometry. Furthermore, the efficacy of HQJZ, which contains different polar parts of HQ, in treating rats with CAG was evaluated using traditional pharmacodynamic and nuclear magnetic resonance-based metabonomics. Grey relation analysis and partial least squares analysis were applied to analyze the spectrum–effect relationship and to screen out the orientated effective components related to HQ in the treatment of CAG. Results: Spectrum–effect relationship analysis showed that 24 compounds identified from the fingerprint spectrum were strongly correlated with efficacy. Compounds 8 (calycosin-7-O-glc-6”- O-acetate), 9 (3-hydroxy-9, 10-dimethoxyptercarpan), and 22 (astragaloside II) were ranked among the top three. Conclusions: This study showed that integrating metabolomics and spectrum–effect relationship analysis is a powerful tool for obtaining orientated effective components of Chinese medicine in a given TCM formula.

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Pudilan Anti-inflammatory Oral Liquid and Organic Acid Component from Taraxaci Herba Attenuate Allergic Asthma in Young Mice through Toll-like Receptor 2/Toll-like Receptor 4 Signaling Pathway

Abstract Objective: Allergic asthma (AA) is a chronic airway inflammatory disease characterized by airway hyper-responsiveness (AHR). Pudilan anti-inflammatory oral liquid (PDL) along with its main medicinal material, Taraxaci Herba (Taraxacum mongolicum Hand.-Mazz, TH) has been widely used to treat upper respiratory tract infections. Research has shown that the major ingredient of TH, the organic acid component (OAC), possesses favorable AA activity. However, the attenuated effects of PDL and OAC from TH (TH-OAC) on AA and their possible mechanisms remain poorly understood. This study analyzed the attenuating effects of PDL and TH-OAC on AA and the underlying mechanisms. Methods: Young BALB/c mice were sensitized and stimulated to develop asthma using ovalbumin. Histological examinations were performed by hematoxylin and eosin staining. Western blotting, immunohistochemistry, and protein expression detection of toll-like receptor 2 (TLR2), TLR4, and orosomucoid 1-like protein 3 (ORMDL3) were performed to detect the presence of inflammatory components in the lung tissue. The messenger RNA (mRNA) expression levels were determined using quantitative real-time polymerase chain reaction. Results: Results showed that PDL and TH-OAC alleviated augmented AHR and typical asthmatic pathological changes, including inflammatory infiltration and thickening of the alveolar wall. They also significantly reduced the levels of the immunoglobulin E, IL-4, IL-5, IL-6, tumor necrosis factor-α, and Nitric oxide (NO) in lung tissues of mice. Protein and mRNA expression levels of TLR2, TLR4, and ORMDL3 were downregulated following treatment with PDL and TH-OAC. Conclusions: PDL and TH-OAC can reduce asthma-induced inflammatory damage to the bronchi. These results provide a theoretical basis for the treatment of asthma in clinical settings.

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Effects of Rutaecarpine on Chronic Atrophic Gastritis Through Nucleotide-binding Oligomerization Domain-like Receptors and Inflammasomes

Abstract Objective: Chronic atrophic gastritis (CAG) is a complex and burdensome disease. However, side effects and compliance issues cannot be ignored due to the long treatment cycle. Numerous studies have confirmed the effectiveness of rutaecarpine (RUT) for treating digestive dysfunction. However, the potential mechanism of action of RUT in the context of CAG treatment remains unclear. This study aimed to explore the therapeutic effects and mechanisms of RUT in 1-methyl-3-nitro-1-nitrosoguanidine-induced CAG using network pharmacology, metabolomics, and traditional pharmacological approaches. Materials and Methods: Pathological tests and ELISA assays were used to observe the therapeutic effects of RUT treatment on CAG. Differential metabolites were identified using ultra-high-performance liquid chromatography-tandem mass spectrometry, and metabolism-related target genes were enriched. The same target genes were identified between RUT and CAG diseases. The intersectional target genes were uploaded to Cytoscape for enrichment, and the nucleotide-binding oligomerization domain (NOD)-like receptor signaling pathway was selected to validate the mechanisms of the study. Finally, cell pyroptosis status was evaluated using the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay, and the expressions of associated proteins of the NOD-like receptor signaling pathway were assessed by Western blotting and immunohistochemistry. Results: RUT alleviated gastric mucosal damage and significantly downregulated indicators associated with inflammation and gastric atrophy. A total of 29 intersection target genes were identified, and core pathways were obtained. The NOD-like receptor signaling pathway and pyroptosis status were selected to validate the mechanisms of RUT treatment in CAG rats. The expression of NOD-related proteins and downstream factors was downregulated in the RUT group. Conclusions: RUT exerts a pharmacological effect on relieving gastric damage in CAG rats by inhibiting NOD-like receptors and inflammasomes.

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Dissecting Combinational Mechanisms of Herbal Formula from a Transcriptome-based Multi-scale Network Pharmacology Model

Abstract Objective: Illumination of the integrative effects of herbs in a formula is a bottleneck that limits the development of traditional Chinese medicine (TCM). In the present study, we developed a transcriptome-based multi-scale network pharmacology model to explore the combined effects of different herbs. Materials and Methods: First, we curated gene signatures at different biological scales, from the molecular to higher tissue levels, including tissues, cells, pathological processes, biological processes, pathways, and targets. Second, using the Xiexin Tang (XXT) formula as an example, we collected transcriptomic data in response to the treatment of XXT or its three compositive herbs on Michigan cancer foundation7 cells. Third, we linked each herbal drug to different biological scales by calculating the correlation scores between herb-induced gene expression profiles and gene signatures. Finally, the combined mechanisms of the three constituent herbs in XXT were deciphered by comparing their multi-scale effects with those of the formula. Results: The results showed that although XXT or single herbs regulated a large number of signatures on each biological scale, the phenotypic effects of these herbal drugs are concentrated onto the “Blood” tissue, types of hemocytes, and hemorrhagic injury-related pathological processes. At the molecular level, these herbs consistently regulate processes such as the cell cycle and blood coagulation-related pathways, as well as protein targets related to the immunoinflammatory response and blood coagulation, such as proteinase-activated receptor 2, integrin beta-3, inhibitor of nuclear factor kappa-B kinase subunit beta, and coagulation factor XII. The analysis of the combinational modes demonstrated that different herbs can cooperate by acting on the same objects and/or regulating different objects in related functions, and cooperative behaviors change at different biological scales. Conclusions: Our model can dissect the combined effects of herbal formulae from a multi-scale perspective and should be beneficial for the development and exploitation of TCM.

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Shuangshen Granules Suppress Myeloid-derived Suppressor Cell-mediated Lung Premetastatic Niche Development by Targeting Sphingosine-1-Phosphate Receptor-1/Signal Transducer, Activator of Transcription 3 Signaling

Abstract Background: Shuangshen granules (SSGs) are extensively utilized for the treatment of lung cancer in China and have been reported to possess tumor-protective and anti-metastatic effects. Therefore, it is crucial to understand the precise mechanism. Building upon the findings of our previous study, the objective of the present study was to explore the impact of SSGs on the sphingosine-1-phosphate receptor-1 (S1PR1)/signal transducer and activator of transcription 3 (STAT3) axis, as well as the recruitment of myeloid-derived suppressor cells (MDSCs) during the formation of the premetastatic niches (PMNs). Methods: In a mouse xenograft model utilizing Lewis lung carcinoma (LLC) cells that express green fluorescent protein (GFP), the initiation of lung metastasis was monitored every three days until day 35 following transplantation. Lung metastasis, MDSC recruitment, the expression of PMN and S1PR1/STAT3 axis biomarkers, as well as the blood levels of granulocyte-macrophage colony-stimulating factor (GM-CSF) and transforming growth factor-β (TGF-β) were assessed in the SSG treatment and control groups. Results: The LLC cells did not reach the lung until 14–17 days following subcutaneous implantation, which was concurrent with the formation of lung PMNs. SSG significantly postponed the initiation of lung metastasis and reduced the recruitment of MDSCs to the lung PMNs. SSG also suppressed the S1PR1/STAT3 axis in tumor tissues, bone marrow, and lung PMNs. Additionally, SSG suppressed the blood levels of GM-CSF and TGF-β, as well as the PMN markers, matrix metalloproteinase-9 and versican. Conclusion: Our findings suggested that SSG suppressed the development of MDSC-mediated PMNs by inhibiting the S1PR1/STAT3 axis, consequently postponing the initiation of lung metastasis.

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