Natural Coumarins: Exploring the Pharmacological Complexity and Underlying Molecular Mechanisms.
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ABSTRACT:
SUBMITTER: Sharifi-Rad J
PROVIDER: S-EPMC8440074 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Breathing is maintained and controlled by a network of automatic neurons in the brainstem that generate respiratory rhythm and receive regulatory inputs. Breathing complexity therefore arises from respiratory central pattern generators modulated by peripheral and supra-spinal inputs. Very little is known on the brainstem neural substrates underlying breathing complexity in humans. We used both experimental and theoretical approaches to decipher these mechanisms in healthy humans and patients with chronic obstructive pulmonary disease (COPD). COPD is the most frequent chronic lung disease in the general population mainly due to tobacco smoke. In patients, airflow obstruction associated with hyperinflation and respiratory muscles weakness are key factors contributing to load-capacity imbalance and hence increased respiratory drive. Unexpectedly, we found that the patients breathed with a higher level of complexity during inspiration and expiration than controls. Using functional magnetic resonance imaging (fMRI), we scanned the brain of the participants to analyze the activity of two small regions involved in respiratory rhythmogenesis, the rostral ventro-lateral (VL) medulla (pre-Bötzinger complex) and the caudal VL pons (parafacial group). fMRI revealed in controls higher activity of the VL medulla suggesting active inspiration, while in patients higher activity of the VL pons suggesting active expiration. COPD patients reactivate the parafacial to sustain ventilation. These findings may be involved in the onset of respiratory failure when the neural network becomes overwhelmed by respiratory overload We show that central neural activity correlates with airflow complexity in healthy subjects and COPD patients, at rest and during inspiratory loading. We finally used a theoretical approach of respiratory rhythmogenesis that reproduces the kernel activity of neurons involved in the automatic breathing. The model reveals how a chaotic activity in neurons can contribute to chaos in airflow and reproduces key experimental fMRI findings.
| S-EPMC3789752 | biostudies-literature
Project description:ObjectivesAccumulating evidence indicates a strong link between knee osteoarthritis (KOA) and sarcopenia. However, the mechanisms involved have not yet been elucidated. This study primarily aims to explore the molecular mechanisms that explain the connection between these 2 disorders.MethodsThe gene expression profiles for KOA and sarcopenia were obtained from the Gene Expression Omnibus database, specifically from GSE55235, GSE169077, and GSE1408. Various bioinformatics techniques were employed to identify and analyze common differentially expressed genes (DEGs) across the 3 datasets. The techniques involved the analysis of Gene Ontology and pathways to enhance understanding, examining protein-protein interaction (PPI) networks, and identifying hub genes. In addition, we constructed the network of interactions between transcription factors (TFs) and genes, the co-regulatory network of TFs and miRNAs for hub genes, and predicted potential drugs.ResultsIn total, 14 common DEGs were found between KOA and sarcopenia. Detailed information on biological processes and signaling pathways of common DEGs was obtained through enrichment analysis. After performing PPI network analysis, we discovered 4 hub genes (FOXO3, BCL6, CDKN1A, and CEBPB). Subsequently, we developed coregulatory networks for these hub genes involving TF-gene and TF-miRNA interactions. Finally, we identified 10 potential chemical compounds.ConclusionsBy conducting bioinformatics analysis, our study has successfully identified common gene interaction networks between KOA and sarcopenia. The potential of these findings to offer revolutionary understanding into the common development of these 2 conditions could lead to the identification of valuable targets for therapy.
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Project description:Visual sensations evoked by stimuli other than luminance changes are called phosphenes. Phosphenes may be an early symptom in a variety of diseases of the retina or of the visual pathways, but healthy individuals may perceive them as well. Phosphene-like phenomena are perhaps the most common side effect reported in clinical pharmacology. Ivabradine, a novel anti-anginal drug that reduces heart-rate by inhibiting the hyperpolarization activated current expressed in cardiac sinoatrial node cells (I(f)) induces phosphenes in some patients. One hypothesis is that ivabradine interacts with the visual system by inhibiting hyperpolarization-activated current in retinal cells (Ih). An Ih current with properties similar to cardiac I(f) has been reported in retinal neurones. Under normal circumstances most of the random fluctuations generated within the retinal circuits do not reach the level of conscious perception because they are filtered out. Presumably, filtering occurs mostly within the retina and one serious candidate for this action is the ability of Ih to act as a negative-feedback mechanism. Ih activation in the membrane of visual cells causes dampening of responses to slow noisy inputs thus tuning the visual system to perceptually more relevant signals of higher frequency. Ih inhibition, by altering at the retinal synapses the filtering of signals generated by thermal breakdown of rhodopsin or other fluctuations, is expected to increase the probability of phosphene occurrence. It is the purpose of the present paper to outline and discuss the features of the visual system and the pharmacological conditions relevant to phosphene perception.
| S-EPMC2189731 | biostudies-other
Project description:IntroductionThe European Medicines Agency has suspended the use of ulipristal acetate (UPA) in the treatment of uterine fibroids and is reassessing its association with a risk of liver injury.ObjectivesOur objectives were to characterize the post-marketing reporting of drug-induced liver injury (DILI) with UPA and investigate the underlying pharmacological basis.MethodsWe queried the worldwide FDA Adverse Event Reporting System and performed a disproportionality analysis, selecting only hepatic designated medical events (DMEs) where UPA was reported as suspect. The reporting odds ratios (RORs) were calculated, and we considered a lower limit of the 95% confidence interval (LL95% CI) > 1 as significant. Physiochemical/pharmacokinetic features were extracted to assess the risk of hepatotoxicity by applying predictive DILI risk models. Mifepristone and leuprolide were selected as comparators.ResultsA significantly higher proportion of liver disorders was reported for UPA than for mifepristone (2.9 vs. 0.8%; p < 0.00001) and leuprolide (2.9 vs. 1.6%; p = 0.015). As regards hepatic DMEs, statistically significant RORs were found for autoimmune hepatitis (N = 5; LL95% CI 16.8), DILI (n = 5; LL95% CI 5.9), and acute hepatic failure (N = 5; LL95% CI 9.3). No signals of DILI emerged for mifepristone and leuprolide acetate. UPA and mifepristone showed high lipophilicity and hepatic metabolism (predicted intermediate DILI risk). Leuprolide exhibited contrasting features, resulting in no DILI concern. Inhibition of different liver transporters and the presence of a reactive metabolite were also recognised for UPA.ConclusionDifferent drug properties previously linked to the occurrence of DILI may partially explain the reporting pattern observed with UPA. Our "bedside-to-bench" approach may support regulators in the risk-benefit assessment of UPA.
| S-EPMC7686198 | biostudies-literature
Project description:Major recent advances and previous data have led to a plausible model of how key proteins mediate neurotransmitter release. In this model, the soluble N-ethylmaleimide-sensitive factor (NSF) attachment protein (SNAP) receptor (SNARE) proteins syntaxin-1, SNAP-25, and synaptobrevin form tight complexes that bring the membranes together and are crucial for membrane fusion. NSF and SNAPs disassemble SNARE complexes and ensure that fusion occurs through an exquisitely regulated pathway that starts with Munc18-1 bound to a closed conformation of syntaxin-1. Munc18-1 also binds to synaptobrevin, forming a template to assemble the SNARE complex when Munc13-1 opens syntaxin-1 while bridging the vesicle and plasma membranes. Synaptotagmin-1 and complexin bind to partially assembled SNARE complexes, likely stabilizing them and preventing fusion until Ca2+ binding to synaptotagmin-1 causes dissociation from the SNARE complex and induces interactions with phospholipids that help trigger release. Although fundamental questions remain about the mechanism of membrane fusion, these advances provide a framework to investigate the mechanisms underlying presynaptic plasticity.
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Project description:BackgroundOvarian cancer was one of the gynecological malignant tumors. Salvia miltiorrhiza Bunge (SMB) was a kind of herbal medicine with an antitumor effect. However, the inhibitory effect of SMB on ovarian cancer and its potential mechanism were still unclear.ObjectiveThe antitumor effect of SMB on ovarian cancer was studied by network pharmacology and molecular docking techniques, and its possible molecular mechanisms were analyzed.MethodThe active ingredients of SMB and the target data of ovarian cancer were obtained from the Traditional Chinese Medicines for Systems Pharmacology Database (TCMSP) and the GeneCards database. The relationship between active ingredients of SMB and ovarian cancer targets was analyzed by String database, David 6.8 online database, and Cytoscape 3.7.2 software, and then potential pathways were screened out. In addition, molecular docking technology was used to verify further the binding effect of antiovarian cancer pathway targets with active ingredients of SMB. Finally, survival analysis was performed for all potential targets.ResultsWe analyzed 71 SMB-ovarian cancer common targets, and the Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis showed that the PI3K-Akt signaling pathway might be an essential pathway for SMB to inhibit ovarian cancer. Luteolin, Tanshinone IIA, and Cryptotanshinone in SMB might play an important role. HSP90AA1, CDK2, and PIK3CG might be potential targets of SMB in inhibiting ovarian cancer.ConclusionThrough network pharmacology and molecular docking analysis, we found that SMB might partially inhibit ovarian cancer by the PI3K-Akt signaling pathway. We believe that SMB might be a potential therapeutic agent for ovarian cancer patients.
| S-EPMC9726254 | biostudies-literature
Project description:Triatoma dimidiata, a Chagas disease vector widely distributed along Central America, has great capability for domestic adaptation as the majority of specimens caught inside human dwellings or in peridomestic areas fed human blood. Exploring the salivary compounds that overcome host haemostatic and immune responses is of great scientific interest. Here, we provide a deeper insight into its salivary gland molecules. We used high-throughput RNA sequencing to examine in depth the T. dimidiata salivary gland transcriptome. From >51 million reads assembled, 92.21% are related to putative secreted proteins. Lipocalin is the most abundant gene family, confirming it is an expanded family in Triatoma genus salivary repertoire. Other putatively secreted members include phosphatases, odorant binding protein, hemolysin, proteases, protease inhibitors, antigen-5 and antimicrobial peptides. This work expands the previous set of functionally annotated sequences from T. dimidiata salivary glands available in NCBI from 388 to 3815. Additionally, we complemented the salivary analysis through proteomics (available data via ProteomeXchange with identifier PXD008510), disclosing the set complexity of 119 secreted proteins and validating the transcriptomic results. Our large-scale approach enriches the pharmacologically active molecules database and improves our knowledge about the complexity of salivary compounds from haematophagous vectors and their biological interactions. SIGNIFICANCE:Several haematophagous triatomine species can transmit Trypanosoma cruzi, the etiological agent of Chagas disease. Due to the reemergence of this disease, new drugs for its prevention and treatment are considered priorities. For this reason, the knowledge of vector saliva emerges as relevant biological finding, contributing to the design of different strategies for vector control and disease transmission. Here we report the transcriptomic and proteomic compositions of the salivary glands (sialome) of the reduviid bug Triatoma dimidiata, a relevant Chagas disease vector in Central America. Our results are robust and disclosed unprecedented insights into the notable diversity of its salivary glands content, revealing relevant anti-haemostatic salivary gene families. Our work expands almost ten times the previous set of functionally annotated sequences from T. dimidiata salivary glands available in NCBI. Moreover, using an integrated transcriptomic and proteomic approach, we showed a correlation pattern of transcription and translation processes for the main gene families found, an important contribution to the research of triatomine sialomes. Furthermore, data generated here reinforces the secreted proteins encountered can greatly contribute for haematophagic habit, Trypanosoma cruzi transmission and development of therapeutic agent studies.
| S-EPMC5803406 | biostudies-literature
Project description:BackgroundAsthma is a chronic inflammatory disease characterized by Th2-predominant inflammation and airway remodeling. Modified Guo Min decoction (MGMD) has been an extensive practical strategy for allergic disorders in China. Although its potential anti-asthmatic activity has been reported, the exact mechanism of action of MGMD in asthma remains unexplored.MethodsNetwork pharmacology approach was employed to predict the active components, potential targets, and molecular mechanism of MGMD for asthma treatment, including drug-likeness evaluation, oral bioavailability prediction, protein-protein interaction (PPI) network construction and analysis, Gene Ontology (GO) terms, and Reactome pathway annotation. Molecular docking was carried out to investigate interactions between active compounds and potential targets.ResultsA total of 92 active compounds and 72 anti-asthma targets of MGMD were selected for analysis. The GO enrichment analysis results indicated that the anti-asthmatic targets of MGMD mainly participate in inflammatory and in airway remolding processes. The Reactome pathway analysis showed that MGMD prevents asthma mainly through regulation of the IL-4 and IL-13 signaling and the specialized pro-resolving mediators (SPMs) biosynthesis. Molecular docking results suggest that each bioactive compounds (quercetin, wogonin, luteolin, naringenin, and kaempferol) is capable to bind with STAT3, PTGS2, JUN, VEGFA, EGFR, and ALOX5.ConclusionThis study revealed the active ingredients and potential molecular mechanism by which MGMD treatment is effective against airway inflammation and remodeling in asthma through regulating IL-4 and IL-13 signaling and SPMs biosynthesis.
| S-EPMC8100455 | biostudies-literature
Project description:Inactivation of the RB protein is one of the most fundamental events in cancer. Coming to a molecular understanding of its function in normal cells and how it impedes cancer development has been challenging. Historically, the ability of RB to regulate the cell cycle placed it in a central role in proliferative control, and research focused on RB regulation of the E2F family of transcription factors. Remarkably, several recent studies have found additional tumour-suppressor functions of RB, including alternative roles in the cell cycle, maintenance of genome stability and apoptosis. These advances and new structural studies are combining to define the multifunctionality of RB.
| S-EPMC4754300 | biostudies-literature
Project description:The main characteristic of alcohol use disorder is the consumption of large quantities of alcohol despite the negative consequences. The transition from the moderate use of alcohol to excessive, uncontrolled alcohol consumption results from neuroadaptations that cause aberrant motivational learning and memory processes. Here, we examine studies that have combined molecular and behavioural approaches in rodents to elucidate the molecular mechanisms that keep the social intake of alcohol in check, which we term 'stop pathways', and the neuroadaptations that underlie the transition from moderate to uncontrolled, excessive alcohol intake, which we term 'go pathways'. We also discuss post-transcriptional, genetic and epigenetic alterations that underlie both types of pathways.
| S-EPMC5131788 | biostudies-literature