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Background:
The Coronavirus Disease 2019 (COVID-19) outbreak in Wuhan, China, was caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Anisodamine hydrobromide injection (AHI), the main ingredient of which is anisodamine, is a listed drug for improving microcirculation in China. Anisodamine can improve the condition of patients...
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Background: In osteosarcoma, the lung is the most common metastatic organ. Intensive work has been made to illuminate the pathogeny, but the specific metastatic mechanism remains unclear. Thus, we conducted the study to seek to find the key genes and critical functional pathways associated with progression and treatment in osteosarcoma with lung me...
Background:
Although RNA-binding proteins play an essential role in a variety of different tumours, there are still limited efforts made to systematically analyse the role of RNA-binding proteins (RBPs) in the survival of colorectal cancer (CRC) patients.
Methods:
Analysis of CRC transcriptome data collected from the TCGA database was conducted,...
Citations
... So the integration of network pharmacology and molecular docking benefits to the acceleration of target validation. [21] Here, we conducted a network pharmacological model to analyze the potential mechanism of QRLSF against ircAEs. In order to verify the predicted outcome, the molecular docking models with some potential targets were established. ...
Immune-related cutaneous adverse events (ircAEs) will undermine the patients’ quality of lives, and interrupt the antitumor therapy. A clinical proved recipe for external use of clearing heat and removing dampness (Qing-Re-Li-Shi Formula, hereinafter referred to as “QRLSF”) is beneficial to the treatment of ircAEs in clinical practice. Our study will elucidate the mechanism of QRLSF against ircAEs based on network pharmacology and molecular docking. The active components and corresponding targets of QRLSF were collected through traditional Chinese medicine systems pharmacology database. GeneCards, online Mendelian inheritance in man, and pharmacogenomics knowledgebase were used to screen the targets of ircAEs. The intersecting targets between drug and disease were acquired by venn analysis. Cytoscape software was employed to construct “components-targets” network. Search tool for the retrieval of interacting genes/proteins database was applied to establish the protein–protein interaction network and then its core targets were identified. Gene ontology and Kyoto encyclopedia of genes and genomes analysis was performed to predict the mechanism. The molecular docking verification of key targets and related phytomolecules was accomplished by AutoDock Vina software. Thirty-nine intersecting targets related to QRLSF against ircAEs were recognized. The analysis of network clarified 5 core targets (STAT3, RELA, TNF, TP53, and NFKBIA) and 4 key components (quercetin, apigenin, luteolin, and ursolic acid). The activity of QRLSF against ircAEs could be attributed to the regulation of multiple biological effects via multi-pathways (PI3K-Akt pathway, cytokine-cytokine receptor interaction, JAK-STAT pathway, chemokine pathway, Th17 cell differentiation, IL-17 pathway, TNF pathway, and Toll-like receptor pathway). The binding activities were estimated as good level by molecular docking. These discoveries disclosed the multi-component, multi-target, and multi-pathway characteristics of QRLSF against ircAEs, providing a new strategy for such medical problem.
... In 2003, anisodamine was used to treat patients with hypoxemia caused by the severe acute respiratory syndrome coronavirus (SARS-CoV) in China [12]. By using network pharmacology integrated molecular docking technology, Su et al. predicted that anisodamine hydrobromide injections (AHI) might indirectly limit the expression of angiotensin-converting enzyme 2 (ACE2), the main target of SARS-CoV-2 [13]. According to its pharmacological properties, Zhen et al. hypothesized that anisodamine might be a feasible treatment for cytokine storm, sticky phlegm in the lung, abnormal coagulation, acute respiratory distress syndrome, and multi-organs damage in COVID-19 infection [14]. ...
... In our study, anisodamine inhibited spike pseudovirus entry into HEK293/hACE2 cells. The primary mechanism is the inhibition of the ACE2 expression in HEK293 cells, given that previous research has revealed that anisodamine could indirectly inhibit ACE2 expression [13]. Rayner et al. reported that AR12 suppressed the production of infectious virions via autophagosome formation, which was also associated with the degradation of GRP78 [28]. ...
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) provoked a pandemic of acute respiratory disease, namely coronavirus disease 2019 (COVID-19). Currently, effective drugs for this disease are urgently warranted. Anisodamine is a traditional Chinese medicine that is predicted as a potential therapeutic drug for the treatment of COVID-19. Therefore, this study aimed to investigate its antiviral activity and crucial targets in SARS-CoV-2 infection. SARS-CoV-2 and anisodamine were co-cultured in Vero E6 cells, and the antiviral activity of anisodamine was assessed by immunofluorescence assay. The antiviral activity of anisodamine was further measured by pseudovirus entry assay in HEK293/hACE2 cells. Finally, the predictions of crucial targets of anisodamine on SARS-CoV-2 were analyzed by molecular docking studies. We discovered that anisodamine suppressed SARS-CoV-2 infection in Vero E6 cells, and reduced the SARS-CoV-2 pseudovirus entry to HEK293/hACE2 cells. Furthermore, molecular docking studies indicated that anisodamine may target SARS-CoV-2 main protease (Mpro) with the docking score of −6.63 kcal/mol and formed three H-bonds with Gly143, Cys145, and Cys44 amino acid residues at the predicted active site of Mpro. This study suggests that anisodamine is a potent antiviral agent for treating COVID-19.
... Since its first report in Wuhan, Hubei, China, COVID-19 has spread to the whole world with almost 100 million diagnosed patients and caused more than 2,141,468 deaths by 11:55 am Central European Time (CET) 27 January 2021, as reported by the World Health Organization (WHO). Patients with COVID-19 exhibited hyperinflammatory response, also called a cytokine storm, which has been observed and is suspected of causing the detrimental progression of COVID-19 (4). The common symptoms of COVID-19 patients have been dry cough, fever, upper airway congestion, shortness of breath, sputum production, fatigue, arthralgia, and myalgia (5). ...
... The potential of TCM in the prevention and treatment of COVID-19 has attracted mounting interest. Based on the classification system of TCM, the core pathogenesis of COVID-19 is a wet epidemic caused by cold and humidity outside the lung and spleen, which transforms into heat and leads to heat stagnation (4). Throughout the thousands of years of Chinese civilization, TCM has acquired rich clinical experience in diagnosing and treating epidemics and has been shown to reduce the mortality rate and improve the prognosis of a range of diseases. ...
... The targets found by network pharmacology are considered as receptors. Therefore, the integration of network pharmacology and molecular docking helps accelerate experimental verification and target discovery (4). With the help of network pharmacology and molecular docking, we explored the molecular mechanism of how AS improves COVID-19 and laid the foundation for investigating the molecular basis of COVID-19 treatment with AS. ...
Background:
Asiaticoside (AS) is a saponin extracted from the traditional Chinese herbal medicine Centella Asiatica, which has the effects of reducing inflammatory infiltration and anti-oxidation in pneumonia and combating pulmonary fibrosis. We hypothesize that AS might have therapeutic potential for the treatment of the coronavirus disease 2019 (COVID-19). With the help of network pharmacology and molecular docking techniques, this study discussed the underlying molecular mechanism of AS in the treatment of COVID-19.
Methods:
The molecular structure of AS was obtained from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) system. The targets of AS were achieved using PharmMapper, SwissTargetPrediction, and the Comparative Toxicogenomics Database (CTD). The targets corresponding to COVID-19 were obtained using GeneCards, Online Mendelian Inheritance in Man (OMIM), and CTD database. Then, a target protein-protein interaction (PPI) network was formed using the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database. A network of AS, COVID-19, and their co-targets was built using Cytoscape. Afterwards, the co-targets were analyzed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment. Moreover, the predictions of crucial targets were further investigated by performing molecular docking with AS.
Results:
A total of 45 core targets of AS were found to be engaged in the pathogenesis of COVID-19. The KEGG enrichment analysis indicated that AS might be protective against COVID-19 through inflammation- and immune-related signaling pathways, including interleukin-17 (IL-17) signaling, T helper 17 (Th17) cell differentiation pathway, Coronavirus disease-COVID-19, MAPK, the PI3K-Akt signaling pathway, and so on. The results of molecular docking showed that AS had a high affinity with those core targets.
Conclusions:
The beneficial effect of AS on COVID-19 might be through regulating multiple immune or inflammation-related targets and signaling pathways.
Background:
Radiation-induced lung injury (RILI) is a common side effect of thoracic tumor radiotherapy, including early-stage radiation-induced lung injury (RP) and late-stage radiation-induced pulmonary fibrosis (RIPF). Currently, it is urgently needed to clarify the pathogenesis of RILI and find safe and effective RILI treatment methods. Irradiation causes DNA damage and oxidative stress in tissues and cells, induces cellular senescence, and promotes the occurrence and development of RILI. In recent years, Anisodamine (654-2) has shown potential therapeutic value in acute lung injury, acute kidney injury, chlamydial pneumonia, and COVID-19. However, there is currently no research on the mechanism of 654-2-mediated cellular senescence and its preventive and therapeutic effects on RILI.
Purpose:
This study aimed to investigate the protective effect and mechanism of 654-2 on X-ray-induced RILI.
Methods:
In vivo experiments involved a mouse RILI model with 18 Gy X-ray irradiation. Mice were divided into control, model, medication (control + 654-2), and treatment (model + 654-2) groups. And mice in medication and treatment groups were intraperitoneal injection of 5 mg/kg 654-2 every other day until being sacrificed at week 6. In vitro experiments used MLE-12 cells irradiated with 16 Gy and divided into control, model, and model + 654-2（2 μM and 10 μM） groups. Various assays were performed to evaluate lung tissue morphology, fibrosis, apoptosis, cytokine expression, cellular senescence, protein expression, and antioxidant capacity.
Results:
654-2 mitigated pulmonary pathological damage, inflammation, DNA damage, cellular senescence, and apoptosis in RILI mice and MLE-12 cells. It restored epithelial cell proliferation ability and enhanced antioxidant capacity. Additionally, 654-2 activated the Nrf2/ARE pathway, increased Nrf2 phosphorylation, and upregulated antioxidant gene expression. Inhibition of Nrf2 reversed the effects of 654-2 on ROS production, antioxidant capacity, and cell senescence.
Conclusion:
654-2 can activate the Nrf2/ARE pathway, enhance cellular antioxidant capacity, and inhibit cellular senescence, thereby exerting a protective effect against RILI.
Background
Coronavirus disease 2019 (COVID-19) has spread rapidly worldwide, leading to a pandemic. In China, Xiyanping injection (XYP) has been recommended as a drug for COVID-19 treatment in the Guideline on Diagnosis and Treatment of COVID-19 by the National Health Commission of the People Republic of China and National Administration of Traditional Chinese Medicine (Trial eighth Edition). However, the relevant mechanisms at the molecular-level need to be further elucidated.
Methods
In this study, XYP related active ingredients, potential targets and COVID-19 related genes were searched in public databases. Protein-protein interaction network and module analyzes were used to screen for key targets. gene ontology and Kyoto encyclopedia of genes and genomes were performed to investigate the potentially relevant signaling pathways. Molecular docking was performed using Autodock Tools and Vina. For the validation of potential mechanism, PolyI:C was used to induce human lung epithelial cells for an inflammation model. Subsequently, CCK-8 assays, enzyme-linked immunosorbent assay, reverse transcription quantitative polymerase chain reaction and western blot were employed to determine the effect of XYP on the expression of key genes.
Results
Seven effective active ingredients in XYP were searched for 123 targets in the relevant databases. Furthermore, 6446 COVID-19 disease targets were identified. Sodium 9-dehydro-17-hydro-andrographolide-19-yl sulfate was identified as the vital active compounds, and IL-6, TNF, IL-1β, CXCL8, STAT3, MAPK1, MAPK14, and MAPK8 were considered as the key targets. In addition, molecular docking revealed that the active compound and the targets showed good binding affinities. The enrichment analysis predicted that the XYP could regulate the IL-17, Toll-like receptor, PI3K-Akt and JAK-STAT signaling pathways. Consistently, further in vitro experiments demonstrated that XYP could slow down the cytokine storm in the lung tissue of COVID-19 patients by down-regulating IL-6, TNF-α, IL-1β, CXCL8, and p-STAT3.
Conclusion
Through effective network pharmacology analysis and molecular docking, this study suggests that XYP contains many effective compounds that may target COVID-19 related signaling pathways. Moreover, the in vitro experiment confirmed that XYP could inhibit the cytokine storm by regulating genes or proteins related to immune and inflammatory responses.
Anisodamine is an anticholinergic drug extracted and isolated from the Anisodus tanguticus (Maxim.) Pascher of the Solanaceae family which is also a muscarinic receptor antagonist. Owing to the lack of natural sources of anisodamine, synthetic products are now used. Using ornithine and arginine as precursor compounds, putrescine is catalyzed by different enzymes and then undergoes a series of reactions to produce anisodamine. It has been used clinically to protect cardiac function and treat septic shock, acute pancreatitis, calculous renal colic, bronchial asthma, blood circulation disturbances, jaundice, analgesia, vertigo, acute poisoning, and other conditions.This review describes the relevant pharmacokinetic parameters. Anisodamine is poorly absorbed in the gastrointestinal tract, and it is not as effective as intravenous administration. For clinical medication, intravenous infusion should be used rather than rapid intravenous injection. With the advancement of research in recent years, the application scope of anisodamine has expanded, with significant developments and application values surging.This review systematically describes the sources, pharmacokinetics, pharmacological effects and clinical application of anisodamine, in order to provide a basis for clinical use.
Ethnopharmacological relevance:
Tibetan medicine Qi-Sai-Er-Sang-Dang-Song Decoction(QSD, ཆུ་སེར་སེང་ལྡེང་སུམ་ཐང་།)is a traditional Tibetan medical formulation with demonstrated clinical benefits in atopic dermatitis (AD). However, its potential mechanism and molecular targets remain to be elucidated.
Aim of the study:
This study aims to explore the activity and mechanism of QSD on AD in multiple dimensions by combining in vitro and in vivo experiments with network pharmacology.
Materials and methods:
The AD effect of QSD was investigated by evaluating the levels of nitric oxide (NO) and interleukin-6 (IL-6) in the lipopolysaccharide (LPS) stimulated RAW264.7 cells. AD-like skin lesions in female BALB/c mice were induced by 2,4-dinitrochlorobenzene (DNCB). QSD or dexamethasone (positive control) were gavagely administered daily for 15 consecutive days. The body weight and skin lesion severity were recorded throughout the study. Enzyme-linked immunosorbent assay (ELISA) and Western blot (WB) analysis were used to illuminate the molecular targets associated with the anti-AD effects of QSD. Meanwhile, the ingredients of QSD in the blood were revealed and analyzed by Ultra performance liquid chromatography tandem quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS) method. Network pharmacology was used to predict the targets and mechanism of active ingredient therapy for AD. In addition, the network pharmacology outcomes were further verified by molecular docking.
Result:
After treatment with QSD, the levels of NO and IL-6 were decreased in the cell supernatant. Herein, QSD markedly decreased the eosinophil and mast cells infiltration in the dorsal skin of the 2,4-dinitrochlorobenzene. Moreover, QSD reconstructed the epidermal barrier by increasing the content of collagen fibers and changing the arrangement of DNCB-treated mice. QSD not only inhibited the levels of tumor necrosis factor-α (TNF-α) and interleukin-12 (IL-12) but also inhibited phosphorylation of p38, c-Jun N-terminal kinase (JNK), and extracellular signal-regulated kinase (ERK) proteins in the dorsal skin. Four active ingredients were identified through UPLC-Q-TOF/MS, including (-)-epicatechin, kaempferol-7-O-glucoside, cassiaside, and questin. After the network pharmacological analysis, six core targets of QSD closely related to AD were obtained, including TNF-α, IL-6, Caspase-3 (CASP3), Epidermal growth factor (EGFR), Peroxisome proliferator-activated receptor gamma (PPARG), and Neurotrophic Receptor Tyrosine Kinase 1 (NTRK1). Meanwhile, through Gene ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment, the Mitogen-activated protein kinase (MAPK) signaling pathway occupies an important position in the QSD treatment of AD. The molecular docking results showed that the six core targets are stable in binding to the four active ingredients as indicated by the molecular docking results.
Conclusions:
The anti-AD effect of QSD might be related to the reconstruction of the epidermal barrier and inhibition of inflammation, which regulated the MAPK pathway. Hence, it provided a promising idea for the study of Tibetan medicine prescriptions for the treatment of AD.
Blaps rynchopetera Fairmaire is a medicinal insect of Yi-nationality medicine used for a long time in Yunnan, China. In the present study, a new blapsimidazolium A (1), together with twelve known N-containing compounds (2−13), were isolated from this insect. The structures were elucidated by extensive spectroscopic analyses (1D and 2D NMR, HR-MS) and comparisons with the reported literature. Blapsimidazolium A was identified as racemic mixture by optical rotation and chiral analysis. Blapsimidazolium A (1) has a unique architecture containing an imidazolium carboxylate moiety. The results of molecular docking showed that blapsimidazolium A bound well to IL-1β, IL-6 and iNOS. The racemates of (±)-blapsimidazolium A (1) exerted anti-inflammatory activity in LPS-stimulated THP-1 cells by significantly decreasing the production of the proinflammatory cytokines IL-1β, IL-6 and iNOS. This is the first report describing the anti-inflammatory activity of this type imidazolium carboxylate derivative.
Anisodamine is one of the major components of the tropine alkaloid family and is widely used in the treatment of pain, motion sickness, pupil dilatation, and detoxification of organophosphorus poisoning. As a muscarinic receptor antagonist, the low toxicity and moderate drug effect of anisodamine often result in high doses for clinical use, making it important to fully investigate its toxicity. In this study, zebrafish embryos were exposed to 1.3-, 2.6-, and 5.2-mM anisodamine for 7 days to study the toxic effects of drug exposure on pigmentation, mineral density, craniofacial area, and eye development. The results showed that exposure to anisodamine at 1.3 mM resulted in cranial malformations and abnormal pigmentation in zebrafish embryos; 2.6- and 5.2-mM anisodamine resulted in significant eye development defects and reduced bone density in zebrafish embryos. The associated toxicities were correlated with functional development of neural crest cells through gene expression (col1a2, ddb1, dicer1, mab21l1, mab21l2, sox10, tyrp1b, and mitfa) in the dose of 5.2-mM exposed group. In conclusion, this study provides new evidence of the developmental toxicity of high doses of anisodamine in aqueous solutions to organisms and provides a warning for the safe use of this drug.
The Coronavirus disease, 2019 (COVID-19) is caused by severe acute respiratory syndrome Coronavirus 2 (SARS‐CoV‐2), which poses a major threat to human life and health. Given its continued development, limiting the spread of COVID-19 in the population remains a challenging task. Currently, multiple therapies are being tried around the world to deal with SARS-CoV-2 infection, and a variety of studies have shown that natural products have a significant effect on COVID-19 patients. The combination of SARS-CoV-2 S protein with Angiotensin converting enzyme II(ACE2) of host cell to promote membrane fusion is an initial critical step for SARS-CoV-2 infection. Therefore, screening natural products that inhibit the binding of SARS-CoV-2 S protein and ACE2 also provides a feasible strategy for the treatment of COVID-19. Establishment of high throughput screening model is an important basis and key technology for screening S protein-ACE2 blockers. Based on this, the molecular structures of SARS-CoV-2 and ACE2 and their processes in the life cycle of SARS-CoV-2 and host cell infection were firstly reviewed in this paper, with emphasis on the methods and techniques of screening S protein-ACE2 blockers, including Virtual Screening (VS), Surface Plasmon Resonance (SPR), Biochromatography, Biotin-avidin with Enzyme-linked Immunosorbent assay and Gene Chip Technology. Furthermore, the technical principle, advantages and disadvantages and application scope were further elaborated. Combined with the application of the above screening technologies in S protein-ACE2 blockers, a variety of natural products, such as flavonoids, terpenoids, phenols, alkaloids, were summarized, which could be used as S protein-ACE2 blockers, in order to provide ideas for the efficient discovery of S protein-ACE2 blockers from natural sources and contribute to the development of broad-spectrum anti coronavirus drugs.
