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Frontiers in Immunology 2023Endoplasmic reticulum stress (ERS) is a critical factor in the development of ulcerative colitis (UC); however, the underlying molecular mechanisms remain unclear. This...
BACKGROUND
Endoplasmic reticulum stress (ERS) is a critical factor in the development of ulcerative colitis (UC); however, the underlying molecular mechanisms remain unclear. This study aims to identify pivotal molecular mechanisms related to ERS in UC pathogenesis and provide novel therapeutic targets for UC.
METHODS
Colon tissue gene expression profiles and clinical information of UC patients and healthy controls were obtained from the Gene Expression Omnibus (GEO) database, and the ERS-related gene set was downloaded from GeneCards for analysis. Weighted gene co-expression network analysis (WGCNA) and differential expression analysis were utilized to identify pivotal modules and genes associated with UC. A consensus clustering algorithm was used to classify UC patients. The CIBERSORT algorithm was employed to evaluate the immune cell infiltration. Gene Set Variation Analysis (GSVA), Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) were used to explore potential biological mechanisms. The external sets were used to validate and identify the relationship of ERS-related genes with biologics. Small molecule compounds were predicted using the Connectivity Map (CMap) database. Molecular docking was performed to simulate the binding conformation of small molecule compounds and key targets.
RESULTS
The study identified 915 differentially expressed genes (DEGs) and 11 ERS-related genes (ERSRGs) from the colonic mucosa of UC patients and healthy controls, and these genes had good diagnostic value and were highly correlated. Five potential small-molecule drugs sharing tubulin inhibitors were identified, including albendazole, fenbendazole, flubendazole, griseofulvin, and noscapine, among which noscapine exhibited the highest correlation with a high binding affinity to the targets. Active UC and 10 ERSRGs were associated with a large number of immune cells, and ERS was also associated with colon mucosal invasion of active UC. Significant differences in gene expression patterns and immune cell infiltration abundance were observed among ERS-related subtypes.
CONCLUSION
The results suggest that ERS plays a vital role in UC pathogenesis, and noscapine may be a promising therapeutic agent for UC by affecting ERS.
Topics: Humans; Colitis, Ulcerative; Molecular Docking Simulation; Noscapine; Endoplasmic Reticulum Stress
PubMed: 37287987
DOI: 10.3389/fimmu.2023.1158648 -
International Journal of Molecular... Mar 2024Breast cancer is the second leading contributor to the age-standardized mortality rate, for both sexes and all ages worldwide. In Europe and the United States, it is the... (Review)
Review
Breast cancer is the second leading contributor to the age-standardized mortality rate, for both sexes and all ages worldwide. In Europe and the United States, it is the second leading cause of mortality, with an incidence rate of about 2.6 million cases per year. Noscapine, a well-known alkaloid used as a cough suppressant, demonstrated anti-tumor effects by triggering apoptosis in various cancer cell lines and has the potential to become another ally against breast, ovarian, colon, and gastric cancer, among other types of malignancy. Apoptosis plays a crucial role in the treatment of cancer. Noscapine affected , , , , and gene and protein expression in the MCF-7 and MDA-MB-231 cell lines. Gene expression was higher in tumor than in normal tissue, including the BAX expression levels in lung, ovary, endometrium, colon, stomach, and glioblastoma patients; BCL2L1 expression in endometrium, colon, and stomach patients; CASP8 gene expression levels in lung, endometrium, colon, stomach, and glioblastoma patients; RELA in colon, stomach, and glioblastoma patients; and NFKBIA in glioblastoma patients. It can be concluded that noscapine affected genes and proteins related to apoptosis in cancer cell lines and several types of cancer patients.
Topics: Male; Female; Humans; Noscapine; bcl-2-Associated X Protein; Glioblastoma; Apoptosis; Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation
PubMed: 38542508
DOI: 10.3390/ijms25063536 -
Sheng Wu Gong Cheng Xue Bao = Chinese... Oct 2020Pictet-Spenglerases (P-Sases) catalyze the Pictet-Spengler (P-S) reactions and exhibit high stereoselectivity and regioselectivity under mild conditions. The typical P-S... (Review)
Review
Pictet-Spenglerases (P-Sases) catalyze the Pictet-Spengler (P-S) reactions and exhibit high stereoselectivity and regioselectivity under mild conditions. The typical P-S reaction refers to the condensation and recyclization of β-arylethylamine with aldehyde or ketone under acidic conditions to form tetrahydroisoquinoline and β-carboline alkaloid derivatives. The related enzymatic products of P-Sases are the backbones of various bioactive compounds, including clinical drugs: morphine, noscapine, quinine, berberine, ajmaline, morphine. Furthermore, the activity of P-Sases in stereoselective and regioselective catalysis is also valuable for chemoenzymatic synthesis. Therefore, this review summarizes the research progress in the discovery, functional identification, biological characteristics and catalytic applications of P-Sases, which provide the useful theoretical reference in future P-Sases research and development.
Topics: Alkaloids; Catalysis; Enzymes; Research; Tetrahydroisoquinolines
PubMed: 33169566
DOI: 10.13345/j.cjb.200064 -
Archives of Toxicology Aug 2014Liquid chromatography-mass spectrometry (LC-MS)-based metabolomics can have a major impact in multiple research fields, especially when combined with other technologies,... (Review)
Review
Liquid chromatography-mass spectrometry (LC-MS)-based metabolomics can have a major impact in multiple research fields, especially when combined with other technologies, such as stable isotope tracers and genetically modified mice. This review highlights recent applications of metabolomic technology in the study of xenobiotic metabolism and toxicity, and the understanding of disease pathogenesis and therapeutics. Metabolomics has been employed to study metabolism of noscapine, an aryl hydrocarbon receptor antagonist, and to determine the mechanisms of liver toxicities of rifampicin and isoniazid, trichloroethylene, and gemfibrozil. Metabolomics-based insights into the pathogenesis of inflammatory bowel disease, alcohol-induced liver diseases, non-alcoholic steatohepatitis, and farnesoid X receptor signaling pathway-based therapeutic target discovery will also be discussed. Limitations in metabolomics technology such as sample preparation and lack of LC-MS databases and metabolite standards, need to be resolved in order to improve and broaden the application of metabolomic studies.
Topics: Animals; Biotransformation; Chromatography, Liquid; Disease; Humans; Mass Spectrometry; Metabolomics; Pharmaceutical Preparations; Xenobiotics
PubMed: 24710571
DOI: 10.1007/s00204-014-1234-6 -
Evidence-based Complementary and... 2021Noscapine is a benzylisoquinoline alkaloid isolated from poppy extract, used as an antitussive since the 1950s, and has no addictive or euphoric effects. Various studies... (Review)
Review
Noscapine is a benzylisoquinoline alkaloid isolated from poppy extract, used as an antitussive since the 1950s, and has no addictive or euphoric effects. Various studies have shown that noscapine has excellent anti-inflammatory effects and potentiates the antioxidant defences by inhibiting nitric oxide (NO) metabolites and reactive oxygen species (ROS) levels and increasing total glutathione (GSH). Furthermore, noscapine has indicated antiangiogenic and antimetastatic effects. Noscapine induces apoptosis in many cancerous cell types and provides favourable antitumour activities and inhibitory cell proliferation in solid tumours, even drug-resistant strains, via mitochondrial pathways. Moreover, this compound attenuates the dynamic properties of microtubules and arrests the cell cycle in the G2/M phase. Noscapine can reduce endothelial cell migration in the brain by inhibiting endothelial cell activator interleukin 8 (IL-8). In fact, this study aimed to elaborate on the possible mechanisms of noscapine against different disorders.
PubMed: 34880922
DOI: 10.1155/2021/8402517 -
ACS Omega Dec 2023Noscapine, a phthalide isoquinoline alkaloid isolated from the opium poppy, alongside cotarnine, a tetrahydroisoquinoline (THIQ) scaffold produced by the oxidative...
Noscapine, a phthalide isoquinoline alkaloid isolated from the opium poppy, alongside cotarnine, a tetrahydroisoquinoline (THIQ) scaffold produced by the oxidative degradation of noscapine, has exhibited antitumor activities against several types of cancer. Although derivatization with amino acids is regarded as a promising strategy to improve chemotherapeutics' anticancer properties, amino acid conjugates of noscapine and cotarnine have been the least investigated. In the present study, 20 amino acid conjugated derivatives of noscapine and cotarnine at the 6-position were synthesized and evaluated for anticancer activity in both in vitro and in vivo conditions. Analysis of the antiproliferative activity against 4T1 mammary carcinoma tumor cells showed that compounds (noscapine-phenylalanine), (noscapine-tryptophan), and (cotarnine-tryptophan) with IC values of 11.2, 16.3, and 54.5 μM, respectively, were found to be far more potent than noscapine (IC = 215.5 μM) and cotarnine (IC = 575.3 μM) and were consequently opted for further characterization. Annexin V and propidium iodide staining followed by flow cytometry demonstrated improved apoptotic activity of compounds , , and compared to those of noscapine and cotarnine. In a murine model of 4T1 mammary carcinoma, noscapine-tryptophan inhibited tumor growth more effectively than noscapine and the other amino acid conjugates without adverse effects. Moreover, molecular docking studies conducted on tubulin as the intracellular target of noscapine suggested a good correlation with experimental observations. Based on these results, noscapine-tryptophan could be a promising candidate for further preclinical investigations.
PubMed: 38075843
DOI: 10.1021/acsomega.3c05488 -
Naunyn-Schmiedeberg's Archives of... Mar 2022Coronavirus disease 2019 (COVID-19) is a potentially fatal disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that preferentially infects... (Review)
Review
Coronavirus disease 2019 (COVID-19) is a potentially fatal disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that preferentially infects the respiratory tract. Bradykinin (BK) is a hypotensive substance that recently emerged as one of the mechanisms to explain COVID-19-related complications. Concerning this, in this review, we try to address the complex link between BK and pathophysiology of COVID-19, investigating the role of this peptide as a potential target for pharmacological modulation in the management of SARS-CoV-2. The pathology of COVID-19 may be more a result of the BK storm than the cytokine storm, and which BK imbalance is a relevant factor in the respiratory disorders caused by SARS-CoV-2 infection. Regarding this, an interesting point of intervention for this disease is to modulate BK signaling. Some drugs, such as icatibant, ecallantide, and noscapine, and even a human monoclonal antibody, lanadelumab, have been studied for their potential utility in COVID-19 by modulating BK signaling. The interaction of the BK pathway and the involvement of cytokines such as IL-6 and IL1 may be key to the use of blockers, even if only as adjuvants. In fact, reduction of BK, mainly DABK, is considered a relevant strategy to improve clinical conditions of COVID-19 patients. In this context, despite the current unproven clinical efficacy, drugs repurposing that block B1 or B2 receptor activation have gained prominence for the treatment of COVID-19 in the world.
Topics: Bradykinin; COVID-19; Drug Repositioning; Humans; Interleukin-6; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 35089406
DOI: 10.1007/s00210-022-02206-6 -
Journal of Natural Products Mar 2009This review provides an overview of the discovery, structures, and biological activities of anticancer natural products that act by inhibiting or promoting the assembly... (Review)
Review
This review provides an overview of the discovery, structures, and biological activities of anticancer natural products that act by inhibiting or promoting the assembly of tubulin to microtubules. The emphasis is on providing recent information on those compounds in clinical use or in advanced clinical trials. The vinca alkaloids, the combretastatins, NPI-2358, the halichondrin B analogue eribulin, dolastatin 10, noscapine, hemiasterlin, and rhizoxin are discussed as tubulin polymerization inhibitors, while the taxanes and the epothilones are the major classes of tubulin polymerization promoters presented, with brief treatments of discodermolide, eleutherobin, and laulimalide. The challenges and future directions of tubulin-interactive natural products-based drug discovery programs are also discussed briefly.
Topics: Antineoplastic Agents; Biological Products; Diketopiperazines; Imidazoles; Microtubules; Molecular Structure; Piperazines; Tubulin; Vinca Alkaloids
PubMed: 19125622
DOI: 10.1021/np800568j -
Foods (Basel, Switzerland) Jul 2022In this work, the thermal degradation of tropane and opium alkaloids was studied in samples of breadsticks prepared with corn flour, contaminated with seeds of , and...
Evaluation of Thermal Degradation of Tropane and Opium Alkaloids in Gluten-Free Corn Breadsticks Samples Contaminated with Stramonium Seeds and Baked with Poppy Seeds under Different Conditions.
In this work, the thermal degradation of tropane and opium alkaloids was studied in samples of breadsticks prepared with corn flour, contaminated with seeds of , and containing seeds of L. A total of seven different samples were prepared and eight alkaloids were studied, three tropane (atropine, scopolamine, and anisodamine) and five opium (morphine, codeine, thebaine, papaverine, and noscapine) alkaloids. For this purpose, a fast, easy and efficient method based on solid-liquid extraction (SLE) prior to the analysis by high-performance liquid chromatography with a diode array detector (HPLC-DAD) was developed and validated. Thermal degradation studies showed a decrease in the TAs and OAs content under baking (180 °C for 20 min) that was between 7-65% for atropine, depending on the preparation conditions used, between 35-49% for scopolamine and anisodamine, up to 100% for morphine and codeine and between 14-58% for thebaine, papaverine, and noscapine. Results also evidenced that degradation of morphine and codeine was higher when the seeds were added as topping to the breadsticks.
PubMed: 35892780
DOI: 10.3390/foods11152196 -
Medicinal Research Reviews Sep 2015Given its manifold potential therapeutic applications and amenability to modification, noscapine is a veritable "Renaissance drug" worthy of commemoration. Perhaps the... (Review)
Review
Given its manifold potential therapeutic applications and amenability to modification, noscapine is a veritable "Renaissance drug" worthy of commemoration. Perhaps the only facet of noscapine's profile more astounding than its versatility is its virtual lack of side effects and addictive properties, which distinguishes it from other denizens of Papaver somniferum. This review intimately chronicles the rich intellectual and pharmacological history behind the noscapine family of compounds, the length of whose arms was revealed over decades of patient scholarship and experimentation. We discuss the intriguing story of this family of nontoxic alkaloids, from noscapine's purification from opium at the turn of the 19th century in Paris to the recent torrent of rationally designed analogs with tremendous anticancer potential. In between, noscapine's unique pharmacology; impact on cellular signaling pathways, the mitotic spindle, and centrosome clustering; use as an antimalarial drug and cough suppressant; and exceptional potential as a treatment for polycystic ovarian syndrome, strokes, and diverse malignancies are catalogued. Seminal experiments involving some of its more promising analogs, such as amino-noscapine, 9-nitronoscapine, 9-bromonoscapine, and reduced bromonoscapine, are also detailed. Finally, the bright future of these oftentimes even more exceptional derivatives is described, rounding out a portrait of a truly remarkable family of compounds.
Topics: Alkaloids; Animals; Antineoplastic Agents; Centrosome; Chemistry, Pharmaceutical; Drug Evaluation, Preclinical; Female; Humans; Male; Microtubules; Neoplasms; Noscapine; Papaver; Plant Extracts; Stroke; Warfarin
PubMed: 26179481
DOI: 10.1002/med.21357