Natural Coumarin Research Articles

Inhibition of melanoma cell migration and invasion by natural coumarin auraptene through regulating EMT markers and reducing MMP-2 and MMP-9 activity

Melanoma, the most invasive form of skin cancer, shows a rising incidence trend in industrial countries. Since the main reason for the failure of current therapeutic approaches against melanoma is metastasis, there is a great interest in introducing effective natural agents to combat melanoma cell migration and invasion. Auraptene (AUR) is the most abundant coumarin derivative in nature with valuable pharmaceutical effects. In this study, we aimed to investigate whether AUR could induce inhibitory effects on the migration and invasion of melanoma cells. B16F10 melanoma cells were treated with different concentrations of AUR and the viability of cells was evaluated by alamarBlue assay. Then, cells were treated with 20 μM AUR, and wound healing, invasion, and adhesion assays were carried out. In addition, the activity of matrix metalloproteinase-2 (MMP-2) and MMP-9 was assessed by gelatin zymography and the expression of genes related to epithelial-mesenchymal transition (EMT) was investigated by qPCR. Finally, the interactions between AUR and MMPs were stimulated by molecular docking. Findings revealed that AUR significantly reduced the migration and invasion of B16F10 cells while improved their adhesion. Furthermore, results of gelatin zymography indicated that AUR suppressed the activity of MMP-2 and MMP-9, and qPCR revealed negative regulatory effect of AUR on the expression of mesenchymal markers including fibronectin and N-cadherin. In addition, molecular docking verified the interactions between AUR and the active sites of wild-type and mutant MMP-2 and MMP-9. Accordingly, AUR could be considered as a potential natural agent with inhibitory effects on the migration and invasion of melanoma cells for future preclinical studies.

Protective Effects and Mechanisms of Esculetin against H2O2-Induced Oxidative Stress, Apoptosis, and Pyroptosis in Human Hepatoma HepG2 Cells.

Oxidative stress plays a crucial role in the pathogenesis of many diseases. Esculetin is a natural coumarin compound with good antioxidant and anti-inflammatory properties. However, whether esculetin can protect HepG2 cells through inhibiting H2O2-induced apoptosis and pyroptosis is still ambiguous. Therefore, this study aimed to investigate the protective effects and mechanisms of esculetin against oxidative stress-induced cell damage in HepG2 cells. The results of this study demonstrate that pretreatment with esculetin could significantly improve the decrease in cell viability induced by H2O2 and reduce intracellular ROS levels. Esculetin not only apparently reduced the apoptotic rates and prevented MMP loss, but also markedly decreased cleaved-Caspase-3, cleaved-PARP, pro-apoptotic protein (Bax), and MMP-related protein (Cyt-c) expression, and increased anti-apoptotic protein (Bcl-2) expression in H2O2-induced HepG2 cells. Meanwhile, esculetin also remarkably reduced the level of LDH and decreased the expression of the pyroptosis-related proteins NLRP3, cleaved-Caspase-1, Il-1β, and GSDMD-N. Furthermore, esculetin pretreatment evidently downregulated the protein expression of p-JNK, p-c-Fos, and p-c-Jun. Additionally, anisomycin, a specific activator of JNK, blocked the protection of esculetin against H2O2-induced HepG2 cells apoptosis and pyroptosis. In conclusion, esculetin can protect HepG2 cells against H2O2-induced oxidative stress, apoptosis, and pyroptosis via inhibiting the JNK signaling pathway. These findings indicate that esculetin has the potential to be used as an antioxidant that improves oxidative stress-related diseases.

Isolating Antipathogenic Fungal Coumarins from Coriaria nepalensis and Determining Their Primary Mechanism In Vitro.

Through bioassay-guided isolation, eight undescribed coumarins (1-8), along with six reported coumarins (9-14), were obtained from Coriaria nepalensis. The new structures were determined by using IR, UV, NMR, HRESIMS, and ECD calculations. The results of the biological activity assays showed that compound 9 exhibited broad spectrum antifungal activities against all tested fungi in vitro and a significant inhibitory effect on Phytophthora nicotianae with an EC50 value of 3.00 μg/mL. Notably, compound 9 demonstrated greater curative and protective effects against tobacco balack shank than those of osthol in vivo. Thus, 9 was structurally modified to obtain new promising antifungal agents, and the novel derivatives (17b, 17j, and 17k) exhibited better effects on Sclerotinia sclerotiorum than did lead compound 9. Preliminary mechanistic exploration illustrated that 9 could enhance cell membrane permeability, destroy the morphology and ultrastructure of cells, and reduce the exopolysaccharide content of P. nicotianae mycelia. Furthermore, the cytotoxicity results revealed that compound 9 exhibited relatively low cytotoxicity against HEK293 cell lines with an inhibition rate of 33.54% at 30 μg/mL. This research is promising for the discovery of new fungicides from natural coumarins with satisfactory ecological compatibility.

Targeting SIRT1 by Scopoletin to Inhibit XBB.1.5 COVID-19 Life Cycle.

Natural products have historically driven pharmaceutical discovery, but their reliance has diminished with synthetic drugs. Approximately 35% of medicines originate from natural products. Scopoletin, a natural coumarin compound found in herbs, exhibits antioxidant, hepatoprotective, antiviral, and antimicrobial properties through diverse intracellular signaling mechanisms. Furthermore, it also enhances the activity of antioxidants. Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) causes viral pneumonia through cytokine storms and systemic inflammation. Cellular autophagy pathways play a role in coronavirus replication and inflammation. The Silent Information Regulator 1 (SIRT1) pathway, linked to autophagy, protects cells via FOXO3, inhibits apoptosis, and modulates SIRT1 in type-II epithelial cells. SIRT1 activation by adenosine monophosphate-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) enhances the autophagy cascade. This pathway holds therapeutic potential for alveolar and pulmonary diseases and is crucial in lung inflammation. Angiotensin-converting enzyme 2 (ACE-2) activation, inhibited by reduced expression, prevents COVID-19 virus entry into type-II epithelial cells. The coronavirus disease 2019 (COVID-19) virus binds ACE-2 to enter into the host cells, and XBB.1.5 COVID-19 displays high ACE-2-binding affinity. ACE-2 expression in pneumocytes is regulated by signal transducers and activators of transcription-3 (STAT3), which can increase COVID-19 virus replication. SIRT1 regulates STAT3, and the SIRT1/STAT3 pathway is involved in lung diseases. Therapeutic regulation of SIRT1 protects the lungs from inflammation caused by viral-mediated oxidative stress. Scopoletin, as a modulator of the SIRT1 cascade, can regulate autophagy and inhibit the entry and life cycle of XBB.1.5 COVID-19 in host cells.

Galbanic acid suppresses melanoma cell migration and invasion by reducing MMP activity and downregulating N-cadherin and fibronectin.

High mortality rate of melanoma is due to the metastasis of malignant cells. Galbanic acid (GBA) is a natural sesquiterpene coumarin with valuable pharmaceutical activities. Our study aimed to investigate whether GBA can affect the migration, invasion, and adhesion of melanoma cells. The survival rate of B16F10 cells was measured using the alamarBlue assay. Scratch, adhesion, and invasion assays were performed to determine the effect of GBA on metastatic behavior of cells. Moreover, gelatin zymography was done to assess the activity of MMP-2 and MMP-9, and qRT-PCR was used to investigate the effect of GBA on the expression of candidate genes. Based on the results of alamarBlue assay, 40µM GBA was chosen as the optimum concentration for all tests. Our findings indicated that GBA significantly decreased the invasion and migration of B16F10 cells while enhancing their adhesion ability. In addition, gelatin zymography demonstrated that GBA reduced the enzymatic activity of MMP-2 and MMP-9. Moreover, qRT-PCR revealed that GBA reduced the expression of N-cadherin and fibronectin. Current findings demonstrated, for the first time, that GBA inhibited the migration and invasion of melanoma cells via reducing the activity of MMP-2 and MMP-9 and downregulating N-cadherin and fibronectin expression. Accordingly, GBA could be suggested as a potential therapeutic agent for the treatment of melanoma.

Natural Coumarin Derivatives Targeting Melanoma.

In general, a cancerous process starts from uncontrolled cell growth, apoptosis, and rapid proliferation of cellular clones, as well as, reactive oxygen species (ROS) and imbalance of ROS-antioxidant production also could be involved in the genesis of the disease. Cancer has accounted for millions of deaths worldwide every year, representing a relevant threat to human lives. In this context, malignant melanoma represents the most aggressive and deadliest type of cancer, leading to increased rates of patient deaths. Natural active compounds have demonstrated their pharmacological benefits in several different studies. Among these compounds, coumarin analogs have demonstrated promising biological profiles, considering their efficacy and low toxicity. In this context, this phytochemical oxygenated core has been broadly investigated since it presents several biological properties of interest in the medicinal field. Herein, we reported a complete compilation of studies focused on natural coumarins against melanoma, as well as, tyrosinase since it is a cooper-catalyzed oxidase that performs an essential role during melanogenesis (Eu-melanins and Pheo-melanins), which is associated with melanoma. Thus, three different subclasses of natural coumarin were described in detail, such as simple coumarin core, furanocoumarins, pyranocoumarins, and pyrone-substituents. Additionally, insights on tyrosinase have been provided, allowing an overview of some structural/functional aspects of its enzyme, such as the presence of a binuclear type 3 cooper coordination at the binding site of this target, acting as cofactors. Posteriorly, several coumarin-based analogs with anti-tyrosinase activity also were reported and discussed. Finally, we believe that unprecedented review can be a valuable source of information, which can be used to design and develop novel coumarin-based analogs targeting melanoma and also tyrosinase enzyme, contributing to the advances in the field of natural products.

The Effect of Osthole on Transient Receptor Potential Channels: A Possible Alternative Therapy for Atopic Dermatitis.

Chronic recurrent skin inflammation and severe itching in patients with atopic dermatitis (AD) significantly impair their quality of life. The H4 histamine receptor plays a key role in histamine-induced itching. During the skin inflammation associated with AD, pro-inflammatory mediators (interleukins, cytokines) are released from neurons. Ultimately, a cascade of reactions leads to the activation and sensitization of transient receptor potential channels (TRP), which exacerbate the inflammation and itching associated with AD. Osthole (OST) is a natural coumarin with a proven versatile pharmacological effect: anti-cancer, anti-inflammatory and immunomodulatory. However, the molecular mechanism of OST in relieving inflammation in histamine-mediated itching is not yet clear. In the studies presented, the possible effect of the OST action on the inhibition of the gene expression of the histamine H4 receptor and the key genes of the TRP channels as well as on the concentration of proinflammatory interleukins was analyzed. Inflammation was induced in a 3D skin model and a keratinocyte cell line Normal Human Epidermal Keratinocytes (NHEK) identical to that of AD, and then OST was administered at various doses. The concentrations of IL-4/-13 were determined by ELISA. RNA was isolated from the 3D skin cells and the NHEK cell line, and the qPCR method was used to determine the expression of: IL-4α, H4R, TRPV1, TRPV4, TRPM8 analyzed. The study showed that OST significantly reduced the secretion of IL-4/-13 in a keratinocyte cell line and in a 3D skin model. In addition, OST was found to significantly decrease the gene expression of IL-4α, H4R, TRPV1, TRPV4 and increase TRPM8 in both the NHEK cell line and the organotypic 3D skin model. The data obtained provide the first in vitro evidence of itch relief following the application of OST to atopic skin. Research on the use of OST as an active component of emollients in the treatment of AD should be continued in the future.

Natural and Synthetic Coumarins as Potential Drug Candidates Against SARS-CoV-2/CoViD-19.

COVID-19, an airborne disease caused by a betacoronavirus named SARS-- CoV-2, was officially declared a pandemic in early 2020, resulting in more than 770 million confirmed cases and over 6.9 million deaths by September 2023. Although the introduction of vaccines in late 2020 helped reduce the number of deaths, the global effort to fight COVID-19 is far from over. While significant progress has been made in a short period, the fight against SARS-CoV-2/COVID-19 and other potential pandemic threats continues. Like AIDS and hepatitis C epidemics, controlling the spread of COVID-19 will require the development of multiple drugs to weaken the virus's resistance to different drug treatments. Therefore, it is essential to continue developing new drug candidates derived from natural or synthetic small molecules. Coumarins are a promising drug design and development scaffold due to their synthetic versatility and unique physicochemical properties. Numerous examples reported in scientific literature, mainly by in silico prospection, demonstrate their potential contribution to the rapid development of drugs against SARS-CoV-2/COVID-19 and other emergent and reemergent viruses.

Synthesis and Structural Elucidation of P-stereogenic Coumarins

This paper presents the general synthesis of a comprehensive group of P-chiral phosphinyl derivatives with a natural coumarin-type motif. A chiral substituent was attached at the third position of the coumarin molecule via the Knoevenagel procedure using readily available P-chiral phoshinylacetic acid esters without loss of enantiomeric purity. The application of salicylaldehyde-based derivatives allowed the incorporation of substituents of different electron character into the backbone of these coumarins making them suitable for subsequent chemical modifications. As a result, we gained access to six achiral (2a–g) and a large number ((Sp)-4a–f, (Sp)-6a–e and (Rp)-8a) of new potential chiral ligand precursors, pharmaceuticals, etc. with an imbedded phosphinyl group with evidenced biological activity based on the natural coumarin backbone. The molecular structure, including absolute configuration, was determined for seven compounds.

Oral administration of a new copper (I) complex with coumarin as ligand: modulation of the immune response and the composition of the intestinal microbiota in Onchorhynchus mykiss.

[Cu(NN1)2]ClO4 is a copper (I) complex, where NN1 is an imine ligand 6-((quinolin-2-ylmethylene) amino)-2H-chromen-2-one obtained by derivatization of natural compound coumarin, developed for the treatment of infectious diseases that affect salmonids. In previous research, we showed that the Cu(I) coordination complex possesses antibacterial activity against Flavobacterium psychrophilum, providing protection against this pathogen in rainbow trout during challenge assays (with an RPS of 50%). In the present study, the effects of administering [Cu(NN1)2]ClO4 to Oncorhynchus mykiss over a 60-days period were evaluated with regard to systemic immune response and its potential to alter intestinal microbiota composition. In O. mykiss, an immunostimulatory effect was evident at days 30 and 45 after administration, resulting in an increment of transcript levels of IFN-γ, IL-12, TNF-α, lysozyme and perforin. To determine whether these immunomodulatory effects correlated with changes in the intestinal microbiota, we analyzed the metagenome diversity by V4 16S rRNA sequencing. In O. mykiss, both [Cu(NN1)2]ClO4 and commercial antibiotic florfenicol had comparable effects at the phylum level, resulting in a predominance of proteobacteria and firmicutes. Nonetheless, at the genus level, florfenicol and [Cu(NN1)2]ClO4 complex exhibited distinct effects on the intestinal microbiota of O. mykiss. In conclusion, our findings demonstrate that [Cu(NN1)2]ClO4 is capable of stimulating the immune system at a systemic level, while inducing alterations in the composition of the intestinal microbiota in O. mykiss.

Semi-synthesis, α-amylase inhibition, and kinetic and molecular docking studies of arylidene-based sesquiterpene coumarins isolated from Ferula tunetana Pomel ex Batt.

Despite all the significant progresses made to enhance the efficacy of the existing bank of drugs used to manage and cure type II diabetes mellitus, there is still a need to search and develop novel bioactive compounds with superior efficacy and minimal adverse effects. This study describes the valorization of the natural bioactive sesquiterpene coumarin via the semi-synthesis of new analogs and the study of their α-amylase inhibition activity. The sesquiterpene coumarin named coladonin (1) was quantitatively isolated from the chloroform extract of endemic Ferula tunetana roots. Subsequently, the oxidation of 1via the Jones oxidation reaction, used as a key reaction, afforded precursor 2. The condensation of oxidized coladonin (2) with various aryl aldehydes provided a series of new arylidene-based sesquiterpene coumarin derivatives (3a-m), which were characterized by NMR and ESI-HRMS experiments. All derivatives evaluated in vitro for their α-amylase inhibitory potential showed interesting α-amylase inhibition with IC50 values ranging from 7.24 to 28.98 μM. Notably, compounds 3k and 3m exhibited lower IC50 values (7.24 μM and 8.38 μM, respectively) compared to the standard (acarbose: IC50 = 9.83 μM). In addition, the structure-activity relationship (SAR) for all the compounds was studied. The most active compounds were found to be mixed-type inhibitors, which was revealed by kinetic studies. Furthermore, molecular in silico docking studies were established for all synthesized analogs with the binding site for the α-amylase enzyme.

Esculetin attenuates cerebral ischemia-reperfusion injury and protects neurons through Nrf2 activation in rats.

Nuclear factor erythroid 2 (NF-E2)-related factor 2 (Nrf2) is a key transcription factor in the antioxidant response and is associated with various chronic diseases. The aim of this study was to explore the action of esculetin, a natural dihydroxy coumarin, on attenuating middle cerebral artery occlusion (MCAO) and reperfusion, and whether its effect is dependent on Nrf2 activation, as well as nuclear factor-kappa B (NF-κB) inhibition. Two doses of esculetin (20 and 40 mg/kg) were tested on rats with MCAO reperfusion. Neurological deficiency, oxidative stress, and pathological analyses were performed to evaluate its effect. An in vitro analysis was also used to confirm whether its action was dependent on the Nrf2/HO-1/NQO-1 pathway. Compared with MCAO reperfusion rats, esculetin improved infarct volume and increased normal-shaped neuron cells by decreasing tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6, and IL-1β levels. The oxidative stress parameter malondialdehyde (MDA) decreased and the activity of superoxide dismutase (SOD) and glutathione/glutathione disulfide (GSH/GSSG) ratio increased after esculetin treatment. Moreover, esculetin inhibited NF-κB activation induced by MCAO. In vitro, hypoxia/reoxygenation (H/R) impaired the viability of rat neuron cells and esculetin showed a neuron protection effect on cells. Nrf2 inhibitor Brusatol inhibited the activation of Nrf2, heme oxygenase-1 (HO-1), and NAD(P)H quinone oxidoreductase 1 (NQO-1) caused by esculetin and abolished its protection effect. Esculetin protected cerebral neurons from ischemia-reperfusion injury by inhibiting NF-κB and Nrf2/HO-1/NQO-1 activation.

Network Proximity Analysis Deciphers the Pharmacological Mechanism of Osthole against D-Galactose Induced Cognitive Disorder in Rats.

Osthole, a natural coumarin found in various medicinal plants, has been previously reported to have neuroprotective effects. However, the specific mechanism by which Osthole alleviates dysmnesia associated with Alzheimer's disease (AD) remains unclear. This study aimed to investigate the neuroprotective properties of Osthole against cognitive impairment in rats induced by D-galactose and elucidate its pharmacological mechanism. The rat model was established by subcutaneously injecting D-galactose at a dose of 150 mg/kg/day for 56 days. The effect of Osthole on cognitive impairment was evaluated by behavior and biochemical analysis. Subsequently, a combination of in silico prediction and experimental validation was performed to verify the network-based predictions, using western blot, Nissl staining, and immunofluorescence. The results demonstrate that Osthole could improve memory dysfunction induced by D-galactose in Sprague Dawley male rats. A network proximity-based approach and integrated pathways analysis highlight two key AD-related pathological processes that may be regulated by Osthole, including neuronal apoptosis, i.e., neuroinflammation. Among them, the pro-apoptotic markers (Bax), anti-apoptotic protein (Bcl-2), the microgliosis (Iba-1), Astro-cytosis (GFAP), and inflammatory cytokines (TNF-R1) were evaluated in both hippocampus and cortex. The results indicated that Osthole significantly ameliorated neuronal apoptosis and neuroinflammation in D-galactose-induced cognitive impairment rats. In conclusion, this study sheds light on the pharmacological mechanism of Osthole in mitigating D-galactose-induced memory impairment and identifies Osthole as a potential drug candidate for AD treatment, targeting multiple signaling pathways through network proximity and integrated pathways analysis.

Comparative physiological and transcriptome analysis provide insights into the inhibitory effect of osthole on Penicillium choerospondiatis

Blue mold induced by Penicillium choerospondiatis is a primary cause of growth and postharvest losses in the fruit of Phyllanthus emblica. There is an urgent need to explore novel and safe fungicides to control this disease. Here, we demonstrated osthole, a natural coumarin compound isolated from Cnidium monnieri, exhibited a strong inhibitory effect on mycelia growth, conidial germination rate and germ tube length of P. choerospondiatis, and effectively suppressed the blue mold development in postharvest fruit of P. emblica. The median effective concentration of osthole was 9.86 mg/L. Osthole treatment resulted in cellular structural disruption, reactive oxygen species (ROS) accumulation, and induced autophagic vacuoles containing cytoplasmic components in fungal cells. Transcriptome analysis revealed that osthole treatment led to the differentially expressed genes mainly enriched in the cell wall synthesis, TCA cycle, glycolysis/ gluconeogenesis, oxidative phosphorylation. Moreover, osthole treatment led to increase genes expression involved in peroxisome, autophagy and endocytosis. Particularly, the autophagy pathway related genes (PcATG1, PcATG3, PcATG15, PcATG27, PcYPT7 and PcSEC18) were prominently up-regulated by osthole. Summarily, these results revealed the potential antifungal mechanism of osthole against P. choerospondiatis. Osthole has potentials to develop as a natural antifungal agent for controlling blue mold disease in postharvest fruits.

Daphnetin Alleviates Bleomycin-Induced Pulmonary Fibrosis through Inhibition of Epithelial-to-Mesenchymal Transition and IL-17A.

Idiopathic pulmonary fibrosis (IPF) is a chronic and refractory interstitial lung disease. Although there is no cure for IPF, the development of drugs with improved efficacy in the treatment of IPF is required. Daphnetin, a natural coumarin derivative, has immunosuppressive, anti-inflammatory, and antioxidant activities. However, its antifibrotic effects have not yet been elucidated. In this study, we investigated the antifibrotic effects of daphnetin on pulmonary fibrosis and the associated molecular mechanism. We examined the effects of daphnetin on splenocytes cultured in Th17 conditions, lung epithelial cells, and a mouse model of bleomycin (BLM)-induced pulmonary fibrosis. We identified that daphnetin inhibited IL-17A production in developing Th17 cells. We also found that daphnetin suppressed epithelial-to-mesenchymal transition (EMT) in TGF-β-treated BEAS2B cells through the regulation of AKT phosphorylation. In BLM-treated mice, the oral administration of daphnetin attenuated lung histopathology and improved lung mechanical functions. Our findings clearly demonstrated that daphnetin inhibited IL-17A and EMT both in vitro and in vivo, thereby protecting against BLM-induced pulmonary fibrosis. Taken together, these results suggest that daphnetin has potent therapeutic effects on lung fibrosis by modulating both Th17 differentiation and the TGF-β signaling pathway, and we thus expect daphnetin to be a drug candidate for the treatment of IPF.

Global research landscape on two coumarin derivatives: A scientometric study of trends and innovations from 1990 to 2022

Daphnetin(7,8-dihydroxycoumarin) and esculin (6,7-dihydroxycoumarin-β-D-glucopyranoside) are natural coumarins that have gained increasing research attention over the years due to their therapeutic applications in a wide range of human ailments. This study assessed the current research status and future research trends of daphnetin and esculin through bibliometric analysis. Relevant articles on these compounds published between 1990 and 2022 were identified in the Web of Science and Scopus databases. “Daphnetin”* or “Esculin”* were used as the search terms to retrieve articles in the “Topic” field of both databases, and RStudio and VOSviewer were used for bibliometric analysis and visualization of meta-data from the retrieved documents. A total of 2172 publications on both compounds were identified. Research outputs on daphnetin and esculin have increased steadily over the years with an annual growth rate of 4.46%. China (576 articles, 28.2%) and USA (198 articles, 9.7%) are the top countries researching on daphnetin and esculin with China being the main country in the international cooperation network. International Journal of Systematic and Evolutionary Microbiology (215 articles), Journal of Clinical Microbiology (71 articles), International Journal of Systematic Bacteriology (29 articles), Archives of Microbiology (24 articles), and Antonie Van Leeuwenhoek (21 articles) are the top five journals publishing articles on these compounds. The most common research topics for both compounds were their biological activities, including anti-microbial, antibiotic resistance, anticancer, anti-inflammatory and antioxidant effects. With an average citation of 21.83 per document, citation analysis revealed that both compounds have been cited a considerable number of times, indicating their significance in the scientific community. Taken together, findings from this review provide insights into the status and trends of daphnetin and esculin research, thus highlighting their increasing interest and potential applications in the medical field.

Development of Sustainable Insecticide Candidates for Protecting Pollinators: Insight into the Bioactivities, Selective Mechanism of Action and QSAR of Natural Coumarin Derivatives against Aphids.

Plants employ abundant toxic secondary metabolites to withstand insect attack, while pollinators can tolerate some natural defensive compounds. Coumarins, as promising green alternatives to chemical insecticides, possess wide application prospects in the crop protection field. Herein, the bioactivities of 30 natural coumarin derivatives against Aphis gossypii were assessed and revealed that 6-methylcoumarin exhibited potent aphicidal activity against aphids but displayed no toxicity to honeybees. Additionally, using biochemical, bioinformatic, and molecular assays, we confirmed that the action mode of 6-methylcoumarin against aphids was by inhibiting acetylcholinesterase (AChE). Meanwhile, functional assays revealed that the difference in action site, which located in Lys585 in aphid AChE (equivalent to Val548 in honeybee AChE), was the principal reason for 6-methylcoumarin being toxic to aphids but safe to pollinators. This action site was further validated by mutagenesis data, which uncovered how 6-methylcoumarin was unique selective to the aphid over honeybee or mammalian AChE. Furthermore, a 2D-QSAR model was established, revealing that the central structural feature was H3m, which offers guidance for the future design of more potent coumarin compounds. This work provides a sustainable strategy to take advantage of coumarin analogues for pest management while protecting nontarget pollinators.

Using COSMO-RS to design organic biphasic systems containing deep eutectic solvents for the separation of natural compounds

This study is aimed at evaluating the potential of the conductor-like screening model for real solvents (COSMO-RS) in designing biphasic systems for the separation of natural compounds. This model was used to predict binodal curves and phases composition of organic biphasic systems containing deep eutectic solvents. The results obtained demonstrate that COSMO-RS in most cases predict the binodal curves of the biphasic systems with a good precision. Moreover, the partition coefficients of six natural compounds, namely quercetin, apigenin, coumarin, β-ionone, retinol, and α-tocopherol, were evaluated, with COSMO-RS predictions showing excellent agreement with experimental data when the compound partition significantly in both phases. Furthermore, COSMO-RS was able to effectively capture the influence of changes in the system composition on partition coefficients. Thus, these results indicate that COSMO-RS can be a powerful tool in the design of separation and purification systems.

Imperatorin Restores Chemosensitivity of Multidrug-Resistant Cancer Cells by Antagonizing ABCG2-Mediated Drug Transport.

The high expression of the ATP-binding cassette (ABC) drug transporter ABCG2 in cancer cells contributes to the emergence of multidrug resistance (MDR) in individuals afflicted with either solid tumors or blood cancers. MDR poses a major impediment in the realm of clinical cancer chemotherapy. Recently, substantial endeavors have been dedicated to identifying bioactive compounds isolated from nature capable of counteracting ABCG2-mediated MDR in cancer cells. Imperatorin, a natural coumarin derivative renowned for its diverse pharmacological properties, has not previously been explored for its impact on cancer drug resistance. This study investigates the chemosensitizing potential of imperatorin in ABCG2-overexpressing cancer cells. Experimental results reveal that at sub-toxic concentrations, imperatorin significantly antagonizes the activity of ABCG2 and reverses ABCG2-mediated MDR in a concentration-dependent manner. Furthermore, biochemical data and in silico analysis of imperatorin docking to the inward-open conformation of human ABCG2 indicate that imperatorin directly interacts with multiple residues situated within the transmembrane substrate-binding pocket of ABCG2. Taken together, these results furnish substantiation that imperatorin holds promise for further evaluation as a potent inhibitor of ABCG2, warranting exploration in combination drug therapy to enhance the effectiveness of therapeutic agents for patients afflicted with tumors that exhibit high levels of ABCG2.

Network pharmacology and molecular docking reveal potential mechanism of esculetin in the treatment of ulcerative colitis.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease of the colonic mucosa. Esculetin is a type of natural coumarin that has many pharmacological activities such as antioxidant, anticancer, anti-inflammatory, etc. A previous study showed that esculetin improved intestinal inflammation and reduced serum proinflammatory cytokines in UC. The present study aimed to utilize network pharmacology and molecular docking to explore the potential mechanism of esculetin against UC. The potential gene targets of esculetin were predicted through SwissTargetPrediction and Super-PRED web servers. UC-related genes were obtained from DisGeNet, OMIM, and GeneCards databases. The overlap between gene targets of esculetin and UC-related genes were identified as the potential targets of esculetin against UC. The interaction between these overlapping genes was analyzed by the STRING database and the core genes were identified by Cytoscape platform. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis of the core genes were then performed. And the results of these analyses were further confirmed through molecular docking. A total of 50 overlapping genes were identified as the potential action targets of esculetin against UC. Among them, 10 genes (AKT1, STAT1, CCND1, SRC, PTGS2, EGFR, NFKB1, ESR1, MMP9, SERPINE1) were finally identified as the core genes. The Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis results showed that the top signaling pathway associated with the core genes of esculetin against UC was the prolactin (PRL) signaling pathway. Molecular docking results showed that esculetin has a strong binding affinity to the core genes, as well as PRL and prolactin receptor. This study suggests that esculetin may have a crucial impact on UC through the PRL signaling pathway and provides insights into the potential mechanism of esculetin in the treatment of UC, which may shed light on the mechanism and treatment of UC.