Search

In the present study, we identified that two representative compounds (7 c and 9 f) of our newly synthesized coumarin-tagged bis-triazoles induced apoptosis in human pancreatic cells (PANC-1) by caspase 3/7mediated pathway. Both 7 c and 9 f (IC 50 =7.15±1.19 and 6.09±0.79 μM, respectively) were found to be ~100 times superior against PANC-1 as compared to the standard drug Gemcitabine (IC 50 =>500 μM), without showing any toxicity to the normal pancreatic epithelial cells (H6C7). Molecular docking studies further endorsed them as potential pancreatic cancer therapeutics due to their strong hydrogen bonding interactions with the epidermal growth factor receptor (EGFR) enzyme, which is overexpressed in cancerous cells including pancreatic cancer. Additionally, these compounds also showed moderate inhibitory activity against a panel of microbial strains. Overall, our findings reveal that the coumarin hybrids 7 c and 9 f are viable chemotypes to be adopted as templates for the development of new anticancer drugs, particularly against pancreatic cancer., (© 2024 The Author(s). ChemMedChem published by Wiley-VCH GmbH.)

Envenomations by snakes represent a neglected health problem in tropical and subtropical countries. In South America, Lachesis muta occasionally causes severe human envenomation, with treatment being conditioned to an unspecific antivenom. In this work, we examined the neutralizing ability of Coutarea hexandra stem bark hydroalcoholic extract ( Ch -E), including the commercial phytochemicals coumarin and quinine, on the neuromuscular blockade induced by L. m. muta venom in mouse phrenic nerve-diaphragm preparation. Biological assays were performed following conventional myographic technique ex vivo. Ch -E was phytochemically characterized to detect the presence of coumarin and quinine using analytical methods. Ch -E and commercial phytochemicals were tested separately or combined under pre- and post-venom incubation protocols. Ch -E attenuated the venom-induced neuromuscular blockade only under the pre-venom incubation protocol. Quinine was not detected in Ch -E. Commercial coumarin and quinine exhibited a concentration-dependent counteracting effect on the venom-induced neuromuscular blockade. The pre-venom incubation protocol showed to be efficient in attenuating the L. m. muta venom-induced neuromuscular blockade, most likely due to the presence of coumarin derivatives and unknown alkaloids in this extract., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Grazielle D. Pilon et al.)

The continued research of novel reversible inhibitors targeting monoamine oxidase (MAO) B remains crucial for effectively symptomatic treatment of Parkinson's disease. In this study we synthesized and evaluated a new series of 3-aryl benzo[g] and benzo[h] coumarin derivatives as MAO-B inhibitors. Compound A6 has been found to display the most potent inhibitory activity and selectivity against the MAO-B isoform (IC 50  = 13 nM and SI = >7693.31 respectively). Inhibition mode of A6 on MAO-B was predicted as mixed reversible inhibition with a Ki value of 3.274 nM. Furthermore, in order to elaborate structure-activity relationships, the binding mode of A6 was investigated by molecular docking simulations., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Androgen receptor (AR) is a crucial driver of prostate cancer (PCa), but acquired resistance to AR antagonists significantly undermines their clinical efficacy. We previously discovered coumarin derivative 1 , which is capable of disrupting AR ligand-binding domain dimers, offering the potential for overcoming resistance. However, its poor oral bioavailability limited further development. In this study, comprehensive structure optimizations led to compound 4a (IC 50 = 0.051 μM), which exhibited comparable AR antagonistic activity to enzalutamide (IC 50 = 0.060 μM) and demonstrated excellent selectivity over other nuclear receptors in vitro. Especially, 4a showed superior efficacy against AR F876L/T877A and AR W741C mutants compared to darolutamide and enzalutamide. Moreover, 4a exhibited favorable pharmacokinetic profiles ( F = 66.24%) in vivo and significant tumor growth inhibition in an LNCaP xenograft mouse model upon oral administration. These results highlight the potential of 4a as a promising oral AR antagonist for overcoming drug resistance in PCa.

Inflammatory bowel disease (IBD) treatment often involves systemic administration of anti-inflammatory drugs or biologics such as anti-TNF-α antibodies. However, current drug therapies suffer from limited efficacy due to unresponsiveness and adverse side effects. To address these challenges, we developed inflammation-targeting nanoparticles (ITNPs) using biopolymers derived from the gum kondagogu (Cochlospermum gossypium) plant. These ITNPs enable selective drug delivery to inflamed regions, offering improved therapeutic outcomes. We designed ITNPs that specifically bind to inflamed regions in both human and mouse intestines, facilitating more effective, uniform, and prolonged drug delivery within the inflamed tissues. Furthermore, we demonstrated that oral administration of ITNPs loaded with urolithin A (UroA), a microbial metabolite or its synthetic analogue UAS03 significantly attenuated chemical- and immune checkpoint inhibitor- induced colitis in pre-clinical models. In conclusion, ITNPs show great promise for delivering UroA or its analogues while enhancing therapeutic efficacy at lower doses and reduced frequency compared to free drug administration. This targeted approach offers a potential solution to enhance IBD treatment while minimizing systemic side effects., Competing Interests: Declarations Competing interests VRJ and PKV are co-founders of Artus Therapeutics. Others declare no competing interest. Classification Biological Sciences, Immunology and Inflammation, Applied Biological Sciences., (© 2024. The Author(s).)

Objective: Isoscopoletin is one of the primary metabolites of natural product scoparone, which was reported to against tumor proliferation. The aim of this study was to explore the mechanism of isoscopoletin against hepatocellular carcinoma (HCC)., Methods: Transcriptomics was used to reveal the possible pathways of isoscopoletin against HCC in vitro. The potential targets of isoscopoletin against HCC through affecting glycolysis were analyzed by network pharmacology, then the potential binding abilities of isoscopoletin to glycolysis-related proteins were initially verified by high throughput virtual molecular docking. The affinities of isoscopoletin for glycolysis-related proteins were assayed using microscale thermophoresis (MST), which was reverse-validated by inhibiting the binding ability of isoscopoletin to GPD2. Glucose consumption and lactate production were examined to evaluate the effects of isoscopoletin on intracellular glycolysis, and the regulation of glycolysis-related targets by isoscopoletin was detected using RT-qPCR and ELISA kits., Results: The results of transcriptomics showed that the differentially expressed genes (DEGs) were mainly enriched in glycolysis and other metabolic-related pathways. Network pharmacology and molecular docking revealed that GPD2, GPI, HSP90AA1 and PGK2 were the core targets in the glycolysis process of isoscopoletin against HCC. MST results showed that there was a strong affinity between isoscopoletin and GPD2, GPI, Hsp90α and PGK2. In vitro results showed that isoscopoletin inhibited glucose consumption and lactate production, while regulating the levels of glycolysis-related proteins., Conclusion: This study suggests that isoscopoletin may exist an anti-tumor effect by regulating the glycolysis-related proteins GPD2, GPI, Hsp90α and PGK2, inhibiting the glycolysis process in HCC cells, then blocking the energy supply of tumor cells., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Ruan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Coumarins are a specific type of secondary metabolite that can be found in many plants. These compounds are predominantly produced through the phenylpropanoid pathway. Coumarins have been proven to possess a range of biological activities, including antimicrobial properties and antioxidant functions that aid in plant disease resistance response. The antimicrobial effect of coumarins is achieved through various mechanisms. They disrupt the cell membranes of pathogens, inhibit enzymatic activity, and hinder nucleic acid synthesis. Additionally, coumarins stimulate plant defense responses by triggering the production of reactive oxygen species (ROS) and activating the expression of immunity-related genes and signaling pathways such as the salicylic acid-dependent pathway. Due to their crucial role in defense mechanisms, coumarins can be effectively used in sustainable agriculture practices that emphasize environmentally friendly integrated pest management strategies. By providing a comprehensive overview of the biosynthetic pathways, mode of action, and application of coumarins in plant defense, this review aims to highlight the potential importance of coumarins in developing safe and sustainable crop protection strategies., Competing Interests: Declaration of Competing interest All authors have direct intellectual contribution to the manuscript. The authors are in complete agreement to make submission with microbial pathogenesis. The authors declare no conflict of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Structural modification based on natural privileged scaffolds has proven to be an attractive approach to generate potential antitumor candidates with high potency and specific targeting. As a continuation of our efforts to identify potent PARP-1 inhibitors, natural 3-arylcoumarin scaffold was served as the starting point for the construction of novel structural unit for PARP-1 inhibition. Herein, a series of novel 8-carbamyl-3-arylcoumarin derivatives were designed and synthesized. The antiproliferative activities of target compounds against four BRCA-mutated cancer cells (SUM149PT, HCC1937, MDA-MB-436 and Capan-1) were evaluated. Among them, compound 9b exhibited excellent antiproliferative effects against SUM149PT, HCC1937 and Capan-1 cells with IC 50 values of 0.62, 1.91 and 4.26 μM, respectively. Moreover, 9b could significantly inhibit the intracellular PARP-1/2 activity in SUM149PT cells with IC 50 values of 2.53 nM and 6.45 nM, respectively. Further mechanism studies revealed that 9b could aggravate DNA double-strand breaks, increase ROS production, decrease mitochondrial membrane potential, arrest cell cycle at G2/M phase and ultimately induce apoptosis in SUM149PT cells. In addition, molecular docking study demonstrated that the binding mode of 9b with PARP-1 was similar to that of niraparib, forming multiple hydrogen bond interactions with the active site of PARP-1. Taken together, these findings suggest that 8-carbamyl-3-arylcoumarin scaffold could serve as an effective structural unit for PARP-1 inhibition and offer a valuable paradigm for the structural modification of natural products., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

A series of 7-substituted coumarin derivatives have been characterized as pan-aldo-keto reductase family 1C (AKR1C) inhibitors. The AKR1C family of enzymes are overexpressed in numerous cancers where they are involved in drug resistance development. 7-hydroxy coumarin ethyl esters and their corresponding amides have high potency for AKR1C3 and AKR1C2 inhibition. Coumarin amide 3 a possessed IC 50 values of 50 nM and 90 nM for AKR1C3 and AKR1C2, respectively, and exhibits 'drug-like' metabolic stability and half-life in human and mouse liver microsomes and plasma. Compound 3 a was employed as a chemical tool to determine pan-AKR1C2/3 inhibition effects both as a radiation sensitizer and as a potentiator of chemotherapy cytotoxicity. In contrast to previously reported pan-AKR1C inhibitors, 3 a demonstrated no radiation sensitization effect in a radiation-resistant prostate cancer cell line model. Pan-AKR1C inhibition also did not potentiate the in vitro cytotoxicity of ABT-737, daunorubicin or dexamethasone, in two patient-derived T-cell ALL and pre-B-cell ALL cell lines. In contrast, a highly selective AKR1C3 inhibitor, compound K90, enhanced the cytotoxicity of both ABT-737 and daunorubicin in the T-cell ALL cell line model. Thus, the inhibitory profile required to enhance chemotherapeutic cytotoxicity in leukemia may be AKR1C isoform and drug specific., (© 2024 The Authors. ChemMedChem published by Wiley-VCH GmbH.)

Alzheimer's disease, characterized by cognitive decline and memory loss, is associated with decreased acetylcholine levels due to acetylcholinesterase (AChE) activity. Compounds containing a coumarin heterocyclic core coupled with thiazole exhibit excellent acetylcholinesterase inhibitory activity. In this work, we designed and synthesized a series of 4-(benzo[d]thiazole-2-yl) phenols based on 4-hydroxycoumarin. The compounds were synthesized and their inhibitory activities were evaluated through in vitro biological assays. Of the compounds investigated, 3i exhibited the strongest inhibitory activity, with an IC50 value of 2.7 µM. Molecular docking and molecular dynamics simulations were employed to elucidate the binding interactions and stability of the synthesized compounds with AChE. The results demonstrated promising inhibitory activity, suggesting potential therapeutic applications for Alzheimer's disease. This research contributes to the development of coumarin-based heterocyclic compounds as effective AChE inhibitors., (© 2024. The Author(s).)

Objective: This study aimed to investigate the effect of psoralidin, a natural phenolic coumarin compound, on MK-801-induced neurotoxicity that may cause Alzheimer's disease and to determine the phosphodiesterase (PDE)-related molecular mechanism of action., Materials and Methods: In this study, neurotoxicity was performed using the MK-801 in the HT-22 cell line. The effects of compounds on the proliferation of HT-22 cells were determined by Real-Time Cell Analysis (RTCA). After measuring the total protein concentration, the PDE4A protein level was determined using the Western blot method., Results: Psoralidin (100, 200, 400 µM) has been shown to have a neuroprotective effect against MK-801-induced neurotoxicity, as indicated by Real-Time Cell Analysis. In HT-22 cells, the half maximal effective concentration (EC50) value of psoralidin was calculated to be 230.4 µM, IC50 value of MK-801 was calculated to be 62.4 µM at 24 hours. It has been determined that psoralidin (200, 400 µM) inhibits PDE4A by using the Western blot method., Conclusions: This research uncovers that psoralidin has neuroprotective effects in MK801-associated accumulation of the excitatory amino acid glutamate neurodegeneration and Alzheimer's disease.

Quinazolinone-coumarin conjugates synthesized through Late-Stage Functionalization approach are evaluated for their in vitro biological activity for 60 human cancer cell lines representing nine different cancer types. Among the synthesized compounds, eight displayed significant growth inhibitory activity across a spectrum of cancer types, with compound 23 demonstrating particularly notable cytotoxicity. Further investigation involved a five-dose assay of compound 23 against NCI-60 cancer cell lines, revealing its efficacy at different concentrations. Additionally, binding studies elucidated its interaction with Human Serum Albumin (HSA) and DNA. The results indicated a strong binding affinity of 23 with HSA, evidenced by a high binding constant (2.26 × 10 5  M -1 ). Moreover, its interaction with DNA occurred via intercalation, specifically between the base pairs of DNA strands, with a binding constant of 5.51 × 10 4  M -1 . This suggests that compound 23 has the ability to bind to both DNA and transport proteins, making it a promising pharmacophore with potential therapeutic applications., (© 2024 John Wiley & Sons Ltd.)

The white spot syndrome virus (WSSV) causes white spot disease (WSD), a severe condition in crustacean aquaculture, leading to significant economic losses. Our previous study demonstrated that C7 is an effective therapeutic agent against WSSV infection in aquaculture. It specifically blocked viral horizontal transmission and reduced shrimp mortality in a dose- and time-dependent manner. Here, we report the potential antiviral mechanism of C7 in shrimp. C7 regulated abnormal glycerophospholipid metabolism caused by WSSV and inhibited phosphatidylcholine (PC) synthesis by more than twofold, potentially enhancing shrimp resistance to viral infection. As the primary phospholipid in the cell membrane, PC is one of the main reactants in lipid peroxidation. Our results indicated that C7 significantly reduced the levels of lipid peroxidation products 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA) induced by WSSV, whereas PC had the opposite effect. Accumulation of lipid peroxidation products inhibits stimulator of interferon genes (STING) signaling. Further evidence showed that C7 promoted STING transport from the endoplasmic reticulum to the Golgi apparatus, significantly activating the expression of the shrimp interferon analogue Vago4 gene. In contrast, PC suppressed Vago4 expression. Our results demonstrated that C7 inhibited PC synthesis, reduced the degree of lipid peroxidation, promoted STING translocation, activated Vago4 expression, and ultimately exerted antiviral effects. Therefore, C7 exhibits immunoregulatory activity as a preventative agent for enhancing the innate immunity of shrimp, making it potentially useful for future immunomodulatory approaches., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The liquid chromatography-high resolution mass spectrometry (LC-HRMS) technique enables the detection of phytochemicals present in the extracts. LC-HRMS-generated mass list showed abundant compounds of interest, artifacts, and primary metabolites. The identification of a secondary metabolite of interest within the extract is very challenging. We hypothesized that identifying the "new metabolite" in the whole metabolome is more challenging than identifying it within the class of metabolites. The proposed prioritization strategy focused on the elimination of unknown and prioritizing the known class of secondary metabolites to identify new metabolites. The prioritization strategy demonstrated on Murraya paniculata for the identification of new metabolites. LC-HRMS-generated information is used as a filter to target the secondary metabolite and the new metabolites. This strategy successfully annotated the new coumarin and coumarin alkaloids from the mass list of 1448 metabolites. Varanasine ( 3 ), schroffanone ( 4 ), schroffanene ( 5 ), and O -methylmurraol ( 9 ) are new compounds, and coumarin ( 1 , 2 , and 6-8 ) are known. Varanasine ( 3 ) is the first naturally occurring 7-aminocoumarin with additional N -formyl functionality. The isolates were screened for cytotoxicity against the panel of cancer cell lines. Varanasine ( 3 ) and minumicrollin ( 6 ) showed significant cytotoxicity and apoptosis-inducing potential. The immunoblot analysis confirmed inhibition of apoptotic protein PARP-1 and caspase-3 expression by 3 and 6 .

Mitochondrial dysfunction with aging is associated with the development of age-related hearing loss. Mitophagy is a cardinal mechanism to maintain a healthy mitochondrial population through the turnover of damaged mitochondria. Declining mitophagy with age causes a buildup of damaged mitochondria, leading to sensory organ dysfunction. The effect of Urolithin A (UA), a mitophagy inducer, was investigated on age-related hearing loss in a mouse model. C57BL/6J mice were treated with UA from 6 to 10 months of age. UA attenuated an auditory brainstem responses (ABR) threshold shift at 8, 16, and 32 kHz frequencies, and improved mitochondrial DNA integrity and ATP production in the cochlea and auditory cortex. The mRNA levels of mitophagy-related genes and protein levels of PINK1, Parkin, BNIP3, and LC3B increased in the cochlea and auditory cortex. The expression of mitophagosomes and mitophagolysosomes in the cochlea, spiral ganglion, auditory cortex, and inferior colliculus increased, together with the expression of Parkin and BNIP3 in the cochlea, spiral ganglion, auditory cortex, and inferior colliculus. These results indicate that UA counteracted mitophagy decline in the auditory system and prevented age-related hearing loss. UA can be used as a potential agent to prevent age-related hearing loss., Competing Interests: Declaration of competing interest None of the authors has a conflict of interest to declare., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Coumarins, abundantly distributed in a plethora of biologically active compounds, serve as a fundamental motif in numerous natural products, drugs, and therapeutic leads. Despite their small size, they exhibit a diverse range of biological activities, intriguing researchers with their immense pharmacological potential., Purpose: This study consolidates the evidence regarding the essential role of coumarins in modern drug discovery, exploring their broad-spectrum pharmaceutical effects, structural versatility, and mechanisms of action across various domains., Methods: For literature search, we utilized PubMed, Google scholar, and SciFinder databases. Keyword and keyword combinations such as "coumarins", "natural coumarins", "specific natural coumarins for particular diseases", and "therapeutic effects" were employed to retrieve relevant studies. The search encompassed articles published between 2005 and 2023. Selection criteria included studies reporting on the pharmacological activities of natural coumarins against various diseases., Results: The results highlight the therapeutic potential of natural coumarins against various diseases, demonstrating anti-cancer, anti-oxidant, and anti-inflammatory activities. They also act as monoamine oxidase inhibitors and phosphodiesterase inhibitors, and as anti-thrombotic, anti-diabetic, and hepatoprotective agents. They also show efficacy against diabetic nephropathy, neurodegenerative diseases, microbial infections and many other diseases., Conclusion: This review underscores the significant role of natural coumarins in medicinal chemistry and drug discovery. Their diverse biological activities and structural versatility make them promising therapeutic agents. This study serves as a catalyst for further research in the field, aiming to address emerging challenges and opportunities in drug development., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

In the present study, the design and synthesis of novel coumarin derivatives 8a-h, 11a-d and 16a-c as potential selective inhibitors for the tumor associated human carbonic anhydrase isoforms (hCA IX and XII) was reported. All the newly synthesized derivatives showed potent to mild activity against the targeted CA IX (K I  = 0.08-9.57 µM), with selectivity indices over CA I (SI = 2.0-21.9) and over CA II (SI = 1.1-15.7). They showed similar activities against CA XII (K I  = 0.06-9.48 µM) with selectivity indices over CA I (SI = 1.4-21.2) and CA II (SI = 0.9-15.5). Compound 16b featuring sulfonamide function possessed promising inhibitory activities against the targeted isoforms CA IX and XII with K I values of 0.08 and 0.06 µM, respectively. Interestingly, it was found that using compound 16b at a nontoxic concentration as an adjuvant with Doxorubicin against MCF-7 cells enhanced the cytotoxicity under hypoxia by almost 3.5 folds; IC 50 decreased from 25.74 to 7.43 µM. Therefore, compound 16b restored the cytotoxicity of Doxorubicin against MCF-7 cells under hypoxia, almost as normoxia. Furthermore, flow cytometry analysis of a combination treatment of compound 16b and Doxorubicin to the MCF7 cell line revealed an increase in cell cycle arrest at the G2/M phase and a more efficient apoptotic effect than Doxorubicin alone. Furthermore, compound 16b showed no cytotoxicity against normal breast MCF-10A cell line (IC 50  = 296.25 µM)., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Urolithin A (UroA), a dietary phytochemical, is produced by gut bacteria from fruits rich in natural polyphenols ellagitannins (ETs). The efficiency of ETs metabolism to UroA in humans depends on gut microbiota. UroA has shown a variety of pharmacological activities. In this study we investigated the effects of UroA on atherosclerotic lesion development and stability. Apolipoprotein E-deficient (ApoE -/- ) mice were fed a high-fat and high-cholesterol diet for 3 months to establish atherosclerosis model. Meanwhile the mice were administered UroA (50 mg·kg -1 ·d -1 , i.g.). We showed that UroA administration significantly decreased diet-induced atherosclerotic lesions in brachiocephalic arteries, macrophage content in plaques, expression of endothelial adhesion molecules, intraplaque hemorrhage and size of necrotic core, while increased the expression of smooth muscle actin and the thickness of fibrous cap, implying features of plaque stabilization. The underlying mechanisms were elucidated using TNF-α-stimulated human endothelial cells. Pretreatment with UroA (10, 25, 50 μM) dose-dependently inhibited TNF-α-induced endothelial cell activation and monocyte adhesion. However, the anti-inflammatory effects of UroA in TNF-α-stimulated human umbilical vein endothelial cells (HUVECs) were independent of NF-κB p65 pathway. We conducted RNA-sequencing profiling analysis to identify the differential expression of genes (DEGs) associated with vascular function, inflammatory responses, cell adhesion and thrombosis in UroA-pretreated HUVECs. Human disease enrichment analysis revealed that the DEGs were significantly correlated with cardiovascular diseases. We demonstrated that UroA pretreatment mitigated endothelial inflammation by promoting NO production and decreasing YAP/TAZ protein expression and TEAD transcriptional activity in TNF-α-stimulated HUVECs. On the other hand, we found that UroA administration modulated the transcription and cleavage of lipogenic transcription factors SREBP1/2 in the liver to ameliorate cholesterol metabolism in ApoE -/- mice. This study provides an experimental basis for new dietary therapeutic option to prevent atherosclerosis., (© 2024. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

Hyperoxia-induced acute lung injury (HALI) is a complication of oxygen therapy. Ferroptosis is a vital factor in HALI. This paper was anticipated to investigate the underlying mechanism of wedelolactone (WED) on ferroptosis in HALI. The current study used hyperoxia to injure two models, one HALI mouse model and one MLE-12 cell injury model. We found that WED treatment attenuated HALI by decreasing the lung injury score and lung wet/dry (W/D) weight ratio and alleviating pathomorphological changes. Then, the inflammatory reaction and apoptosis in HALI mice and hyperoxia-mediated MLE-12 cells were inhibited by WED treatment. Moreover, WED alleviated ferroptosis with less iron accumulation and reversed expression alterations of ferroptosis markers, including MDA, GSH, GPX4, SLC7A11, FTH1, and TFR1 in hyperoxia-induced MLE-12 cells in vitro and in vivo. Nrf2-KO mice and Nrf2 inhibitor (ML385) decreased WED's ability to protect against apoptosis, inflammatory response, and ferroptosis in hyperoxia-induced MLE-12 cells. Collectively, our data highlighted the alleviatory role of WED in HALI by activating the Nrf2/HO-1 pathway., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

One new bithiophene derivative, 5-(but-3-en-1-yn-1-yl)-5'-(methoxymethyl)-2,2'-bithiophene (1), along with twelve known compounds, senecioester (2), tiglinsaureester (3), 5-acetoxymethyl-2'-(but-3-en-1-yn-1-yl)-2,5'-bithiophene ( 4), 5-(4-isovaleroyloxybut-1-ynyl)-2,2'-bithiophene (5), 5-hydroxymethyl-(2,5':2',5'')-terthienyl tiglate (6), 5-hydroxymethyl-(2,5':2',5'')-terthienyl agelate (7), 5- hydroxymethyl-2,5':2',5''-terthiophene dimethylacrylate (8), 5-methoxymethyl-2,2':5',2''-terthiophene (9), α-terthiophene (10), 1,3,8,9-tetrahydroxycoumestan 3-sulfate (11), demethylwedelolactone (12), and wedelolactone (13) were isolated from the methanol extract of aerial parts of Eclipta prostrata (L.) L. All isolated compounds were evaluated for the protective ability on the HepG2 cells. At the concentration of 100 μM, compounds 11 - 13 showed the highest hepatoprotective effects, with HepG2 cell viability ranging from 38.68% to 48.54%. Bithiophenes showed higher hepatoprotective cell viability than terthiophenes.

A new coumarin ( 1 ) and a new flavonoid ( 2 ) were isolated from the air-dried flower buds of Ochrocarpus longifolius , together with ten known compounds ( 3 - 12 ). The structures of two new compounds were established by 1D and 2D NMR and MS data. In addition, the new compound 2 showed significant proliferation inhibitory activity on Eca-109 and MGC-803 cells. The results of this study may enrich the diversity of compounds from O. longifolius and provide a basis for further research on its natural products and pharmacological activities.

Urolithin A (UroA) is well-recognized for its anti-oxidative, anti-inflammatory, and immunomodulatory potentials and has been proven to have neuroprotective effects. Nevertheless, the potential of UroA on bupivacaine (BUP)-induced neurotoxicity has never been reported. Using SH-SY5Y cells to establish a cell model, it was revealed that BUP stimulated cell viability reduction, LDH release increase, and suppression of SIRT1-activated PI3K/AKT signaling in SH-SY5Y cells, whereas UroA treatment caused an effective abrogation of the effects of BUP. Besides, SIRT1 overexpression caused an enhancement in the activity of PI3K/AKT signaling in BUP and UroA co-treated cells, indicating that SIRT1 mediated the activity of PI3K/AKT signaling. Moreover, UroA inhibited BUP-induced apoptosis, oxidative stress, and inflammatory responses in SH-SY5Y cells. However, the effects of UroA on BUP-induced neurotoxicity were all abated by inhibiting SIRT1 or PI3K/AKT signaling through EX527 or LY294002. In conclusion, UroA protected SH-SY5Y cells against BUP-induced injuries through PI3K/AKT signaling in a SIRT1-dependent manner., (©The Author(s) 2024. Open Access. This article is licensed under a Creative Commons CC-BY International License.)

Autoimmune diseases encompass a wide range of disorders characterized by disturbed immunoregulation leading to the development of specific autoantibodies, which cause inflammation and multiple organ involvement. However, its pathogenesis remains unelucidated. Furthermore, the cumulative medical and economic burden of autoimmune diseases is on the rise, making these diseases a ubiquitous global phenomenon that is predicted to further increase in the coming decades. Coumarins, a class of aromatic natural products with benzene and alpha-pyrone as their basic structures, has good therapeutic effects on autoimmune diseases. In this review, we systematically highlighted the latest evidence on coumarins and autoimmune diseases data from clinical and animal studies. Coumarin acts on immune cells and cytokines and plays a role in the treatment of autoimmune diseases by regulating NF-κB, Keap1/Nrf2, MAPKs, JAK/STAT, Wnt/β-catenin, PI3K/AKT, Notch and TGF-β/Smad signaling pathways. This systematic review will provide insight into the interaction of coumarin and autoimmune diseases, and will lay a groundwork for the development of new drugs for autoimmune diseases., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Li, Wang and Li.)

Ethnopharmacological Relevance: Ficus erecta, a traditional Chinese She Ethnomedicine, has been historically utilized to treat various inflammatory conditions such as arthritis, nephritis, and osteoporosis. However, the underlying mechanisms accounting for its anti-inflammatory activity, as well as its active components, largely remain elusive., Aim of the Study: The purpose of this research was to investigate the chemical constituents of F. erecta that contribute to its anti-inflammatory effects., Materials and Methods: Coumarins and flavones were obtained from the 95% EtOH extract of F. erecta using virous column chromatography and reversed-phase semipreparative HPLC. The structures of the new compounds were elucidated by extensive analysis of spectroscopic methods, including HRESIMS, 1D and 2D NMR spectra, and CD experiments. Cultured macrophage RAW264.7 cells were utilized for the anti-inflammatory experiments. MTT cell viability assay, Griess reagent method, ELISA, and Western blot experiments were employed to evaluate the anti-inflammatory activity and investigate the related mechanism., Results: Four new (1-4) and eleven previously identified (5-16) coumarins, together with one new (17) and six known flavones (18-23) were isolated from the whole plant of F. erecta. Compounds 7 and 17 significantly reduced nitric oxide (NO) and prostaglandin E2 (PGE 2 ) production without cytotoxic effects. Furthermore, compounds 7 and 17 reduced the production of proinflammatory cytokines including tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 in a concentration-dependent manner. Western blot analysis indicated that compounds 7 and 17 suppressed the expression of iNOS, COX-2, and p-IκBα in LPS-stimulated RAW264.7 macrophage cells., Conclusion: The current phytochemical investigations revealed that coumarins and flavones represent the primary chemical constituents of F. erecta. Compounds 7 and 17 exhibit potent anti-inflammatory properties, linked with the inhibition of NF-κB activation by preventing the degradation of IκBα phosphorylation. These compounds may serve as promising candidates for treating or preventing certain inflammatory diseases., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

The inflammation causes the destroyed osseointegration at the implant-bone interface, significantly increasing the probability of implant loosening in osteoporotic patients. Currently, inhibiting the differentiation of M1 macrophages and the inflammatory response could be a solution to stabilize the microenvironment of implants. Interestingly, some natural products have anti-inflammatory and anti-polarization effects, which could be a promising candidate for stabilizing the implants' microenvironment in osteoporotic patients. This research aims to explore the inhibitory effect of Urolithin B(UB) on macrophage M1 polarization, which ameliorates inflammation, thus alleviating implant instability. We established an osteoporosis mouse model of implant loosening. The mouse tissues were taken out for morphological analysis, staining analysis, and bone metabolic index analysis. In in vitro experiments, RAW264.7 cells were polarized to M1 macrophages using lipopolysaccharide (LPS) and analyzed by immunofluorescence (IF) staining, Western blot (WB), and flow cytometry. The CSP100 plus chip experiments were used to explore the potential mechanisms behind the inhibiting effects of UB. Through observation of these experiments, UB can improve the osseointegration between the implants and femurs in osteoporotic mice and enhance the stability of implants. The UB can inhibit the differentiation of M1 macrophages and local inflammation via inhibiting the phosphorylation of VEGFR2, which can be further proved by the weakened inhibited effects of UB in macrophages with lentivirus-induced overexpression of VEGFR2. Overall, UB can specifically inhibit the activation of VEGFR2, alleviate local inflammation, and improve the stability of implants in osteoporotic mice., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objectives: Treatment of hemorrhagic shock (HS) induced multi-organ injury remains a challenge. Bergapten (BeG) is a bioactive coumarin-derived compound, and previous articles have suggested that BeG may serve as a prospective therapeutic modality for HS. This study was designed to investigate the efficacy of BeG in the treatment of HS and its underlying mechanisms., Methods: In this research, we established a rat model of HS, following which we assessed the protective effects of BeG on HS induced multi-organ injury. Subsequently, we scrutinized the activation of NLRP3 inflammasomes and pyroptosis in damaged organs. Additionally, we conducted examinations of AMPK and the downstream mitophagy pathway in damaged organs. Finally, we established a hypoxia/reoxygenation (H/R) model in HK-2 cells to simulate the in vitro HS process. Following AMPK inhibition with compound C, we evaluated the levels of mitophagy and cellular pyroptosis in BeG-treated HK-2 cells subjected to H/R., Results: BeG treatment alleviated HS induced multi-organ injury. Subsequent analyses indicated that the therapeutic effects of BeG were related to the attenuation of NLRP3 inflammasome activation and pyroptosis. Additionally, we found BeG treatment stimulated the phosphorylation of AMPK, thereby enhancing mitophagy. Lastly, we found that the inhibition of AMPK in vitro attenuates BeG's enhancement of mitophagy and its suppression of pyroptosis., Conclusion: Our research indicates that BeG has the potential to alleviate multi-organ injury induced by HS. The protective effect of BeG is likely associated with its promotion of mitophagy through AMPK activation, thereby inhibiting NLRP3 inflammasome-mediated pyroptosis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Two new Ag(I) complexes with coumaric carboxylic acid derivatives have been synthesized. Structural studies of these noncrystalline complexes have been performed using a methodology that combines laboratory and synchrotron techniques, supported by density functional theory calculations. The arrangement of ligands around the Ag(I) cation has been refined using infrared, extended X-ray absorption fine structure, and X-ray absorption near edge structure spectroscopies. Different coordination modes of carboxylate ligands are observed for the studied compounds. Carboxylate bridges are characteristic for the Ag(I) complex with 4-oxo-4 H -1-benzopyran-2-carboxylic acid ( 1 ), while a bidentate chelating motif was found for the complex with 2-oxo-2 H -1-benzopyran-3-carboxylic acid ( 2 ). Additionally, the carbonyl oxygen atom of the coumarin ring coordinates to the silver cation in complex 2 , while it is inactive in complex 1 . Antimicrobial evaluation has been performed for both compounds. The complexes show activity against selected bacteria as well as Candida yeast. This activity is slightly lower for bacteria and the same or higher for Candida in relation to the reference substances: ciprofloxacin or fluconazole.

Back Ground: 7-Methoxycoumarin (7-MC) is well recognized for its anti-inflammatory and anti-nociceptive actions. Its capacity to lessen neuropathic pain hasn't been documented yet. Hence the impact of 7-MC on vincristine-induced peripheral neuropathic pain in rodents was investigated. The investigation also looked at the impact of 7-MC in reducing neuropathic pain via voltage-gated calcium channels and phospholipase enzyme inhibition using pertinent in vitro and in silico methods., Methods and Results: Vincristine (0.1 mg/kg, i.p., daily) was administered continuously for 7 days to induce peripheral neuropathic pain in mice, with cold allodynia and thermal hyperalgesia and evaluated on the 8th day using the acetone bubble test and hot water tail immersion test. In order to derive the mechanistic approach for ameliorating neuropathic pain, the role of 7-MC in the inhibition of the phospholipase enzyme, gene expression studies on voltage-gated calcium channels using mouse BV2 microglial cells and in silico studies for its calcium channel binding affinity were also performed. The test compounds reduced vincristine-induced cold allodynia and thermal hyperalgesia in mice in a dose-dependent experiments. In vitro studies on phospholipase inhibition by 7-MC showed an IC 50 of 27.08 µg/ml and down-regulated the gene expression of calcium channels in the BV2 microglial cell line. In silico docking scores for 7-MCwere higher than the standard drug gabapentin., Conclusion: The compound 7-MC has shown promise in alleviating vincristine-induced peripheral neuropathicin mice. Studies conducted in parallel, both in silico and in vitro have demonstrated that 7-MC effectively reduces neuropathic pain. This pain reduction is achieved through two mechanisms: inhibiting the phospholipase enzyme and blocking voltage-gated calcium channels., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Triple negative breast cancer (TNBC) is a notoriously difficult disease to treat, and many of the existing TNBC chemotherapeutics lack tumor selectivity and the capability for simultaneously visualizing and monitoring their own activity in the biological context. However, TNBC cells have been known to generate high levels of reactive oxygen species (ROS), such as hydrogen peroxide (H 2 O 2 ). To this end, three novel small molecule theranostics 1a, 1c, and 2 consisting of both H 2 O 2 -responsive nitrogen mustard prodrug and profluorophore character have been designed, synthesized, and evaluated as targeted cancer therapeutics and bioimaging agents. The three theranostics comprise of boronate esters that deactivate nitrogen mustard functional groups and fluorophores but allow their selective activation through H 2 O 2 -specific oxidative deboronation for the release of the active drug and fluorophore. The three theranostics demonstrated H 2 O 2 -inducible DNA-alkylating capability and fluorescence turn-on properties in addition to selective anticancer activity. They are particularly effective in killing TNBC MDA-MB-468 cells with high H 2 O 2 level while safe to normal epithelial MCF-10A cell. The conjugated boron-masked fluorophores in 1c and 2 are highly responsive towards H 2 O 2 , which enabled tracking of the theranostics in living cellular mitochondria and nucleus organelles. The three theranostics 1a, 1c, and 2 are capable of both selective release of the active drug to take effect in H 2 O 2 -rich cancer sites and simultaneously monitoring its activity. This single molecule system is of utmost importance to understand the function, efficacy, and mechanism of the H 2 O 2 -activated prodrugs and theranostics within the living recipient., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Xiaohua Peng reports financial support was provided by National Institutes of Health. Xiaohua Peng has patent pending to University of Wisconsin Milwaukee Research Foundation. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Background: Urolithin A (Uro-A), a type of polyphenol derived from pomegranate, is known to improve memory function when ingested, in addition to its direct effect on the skin epidermal cells through the activation of longevity gene SIRT1. However, the molI ecular mechanism by which orally ingested Uro-A inhibits cognitive decline via the intestine remains unexplored. Objectives: This study aimed to evaluate the role of Uro-A in improving cognitive function via improved intestinal function and the effect of Uro-A on the inflammation levels and gene expression in hippocampus. Methods: Research to clarify the molecular basis of the functionality of Uro-A was also conducted. Results: The results demonstrated that Uro-A suppressed age-related memory impairment in Aged mice (C57BL/6J Jcl, male, 83 weeks old) by reducing inflammation and altering hippocampal gene expression. Furthermore, exosomes derived from intestinal cells treated with Uro-A and from the serum of Aged mice fed with Uro-A both activated neuronal cells, suggesting that exosomes are promising candidates as mediators of the Uro-A-induced activation of gut-brain interactions. Additionally, neurotrophic factors secreted from intestinal cells may contribute to the Uro-A-induced activation of gut-brain interactions. Conclusions: This study suggests that Uro-A suppresses age-related cognitive decline and that exosomes and other secreted factors may contribute to the activation of the gut-brain interaction. These findings provide new insights into the therapeutic potential of Uro-A for cognitive health.

Understanding the spatiotemporal dynamics of formaldehyde (FA) is crucial for elucidating its pathophysiology. In this study, we designed a series of organelle-resolved probes to investigate FA dynamics. By incorporating various organelle anchors into a coumarin hydrazonate, we developed a series of probes with excellent organelle selectivity and FA specificity, enabling rapid and precise sensing of FA in an organelle-resolved way. Leveraging these probes, we captured the spatiotemporal dynamics of native FA in response to exogenous FA or oxidative stress challenges. In particular, we unveiled the distinct responses of various organelles to identical cellular stressors. Moreover, we observed the dynamic response within individual organelles when cells were exposed to stressors for varying durations. We envision these probes will serve as versatile tools for probing FA pathophysiology.

The aim of this study was to explore the role of NADH:ubiquinone oxidoreductase subunit B3 (NDUFB3) in human gynecological malignancies and to screen potential natural compounds targeting it. GEPIA and HPA databases were used to study the expression characteristics of NDUFB3. GO and KEGG enrichment analyses were performed using the R software clusterProfiler package. GSEA for NDUFB3 was performed using the LinkedOmics database. Natural compounds targeting NDUFB3 were screened by virtual screening and molecular docking. After NDUFB3 was depleted or wedelolactone treatment, cell proliferation was detected by CCK-8 assay. The production of reactive oxide species (ROS) in tumor cells was detected by dihydroethidium fluorescent probe. The cell cycle and apoptosis were evaluated by flow cytometry. It was revealed that NDUFB3 was highly expressed in ovarian cancer (OV), uterine corpus endometrial carcinoma (UCEC), and cervical squamous cell carcinoma (CESC). NDUFB3 expression was associated with multiple immunomodulators in CESC, OV, and UCEC. NDUFB3 was predicted to modulate MAPK signaling pathways in CESC, OV, and UCEC. Knocking down NDUFB3 inhibited the proliferation of CESC, OV, and UCEC cells, increased intracellular ROS production, and induced cell cycle arrest and apoptosis. Wedelolactone was a potential small molecule with a strong ability to bind with the active pocket of NDUFB3, and wedelolactone could kill CESC, OV, and UCEC cells partly via NDUFB3. In conclusion, NDUFB3 may be a potential biomarker and a new target for gynecological tumors, and wedelolactone may exert antitumor activity via targeting NDUFB3., (© 2024 John Wiley & Sons Ltd.)

Objective: Nordalbergin is a coumarin extracted from Dalbergia sissoo DC. To date, the biological effects of nordalbergin have not been well investigated. To investigate the anti-inflammatory responses and the anti-oxidant abilities of nordalbergin using lipopolysaccharide (LPS)-activated macrophages and LPS-induced sepsis mouse model., Materials and Methods: Production of nitrite oxide (NO), prostaglandin E2 (PGE 2 ), pro-inflammatory cytokines (tumor necrosis factor (TNF)-α, interleukin (IL)-6 and IL-1β), reactive oxygen species (ROS), tissue damage and serum inflammatory markers, and the activation of the NLRP3 inflammasome were examined., Results: Our results indicated that nordalbergin reduced the production of NO and pro-inflammatory cytokines in vitro and ex vivo. Nordalbergin also suppressed iNOS and cyclooxygenase-2 expressions, decreased NF-κB activity, and attenuated MAPKs signaling pathway activation by decreasing JNK and p38 phosphorylation by LPS-activated J774A.1 macrophages. Notably, nordalbergin diminished NLRP3 inflammasome activation via repressing the maturation of IL-1β and caspase-1 and suppressing ROS production by LPS/ATP- and LPS/nigericin-activated J774A.1 macrophages. Furthermore, nordalbergin exhibited protective effects against the infiltration of inflammatory cells and also inhibited the levels of organ damage markers (AST, ALT, BUN) by LPS-challenged mice., Conclusion: Nordalbergin possesses anti-inflammatory effects in macrophage-mediated innate immune responses, alleviates ROS production, decreases NLRP3 activation, and exhibits protective effects against LPS-induced tissue damage in mice., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Globally, breast cancer (BC) has the highest prevalence among malignant diseases. BC is also the primary cause of death among women. Notably, BC morbidity has been increasing continuously at an approximate growth rate of 2.2% per year. Persistent BC is a major public health issue worldwide. Consequently, novel chemotherapeutic agents to combat this lethal disease should be developed urgently. Coumarins with interesting structural and mechanistic variations exhibit promising activity in several forms of BC, including BCs with multidrug resistance. In particular, coumarin hybrids composed of coumarin and one or more anti-BC pharmacophores can target different biological components in BC cells simultaneously. Thus, coumarin hybrids are useful scaffolds that can help improve the anti-BC efficacy of coumarins, reduce side effects, improve pharmacokinetics, minimize drug-drug interactions, and circumvent drug resistance. This review, in which articles published from 2020 to the present day have been evaluated, highlights the landscape of coumarin hybrids that exhibit therapeutic effects against breast cancer. These findings can aid further investigations on novel antibreast-cancer therapeutics., (© 2024 Deutsche Pharmazeutische Gesellschaft.)

One new canthinone glycoside ( 1 ), together with six known compounds ( 2 - 7 ) including three lignans ( 2 - 4 ), two coumarins ( 5 - 6) and one phenol ( 7) was isolated from the root barks of Ailanthus altissima . The structure of new compound 1 was established by the interpretation of UV, IR, MS and NMR data, while its absolute configuration was determined by acid hydrolysis and GIAO NMR calculations with DP4+ probability analysis. The inhibitory effects of all compounds on Nitric oxide (NO) production were investigated in lipopolysaccharide (LPS)-induced RAW 264.7 cells. Results showed that compounds 2 and 5 displayed NO production inhibitory activity with IC 50 values of 30.1 and 15.3  μ M, respectively.

In this study, pharmacological profiling and investigation of the anticoagulant activity of the newly synthesized coumarin derivative: ( E )-3-(1-((4-hydroxy-3-methoxyphenyl)amino)ethylidene)-2,4-dioxochroman-7-yl acetate ( L ) were performed. The obtained results were compared with the parameters obtained for Warfarin ( WF ), which is a standard good oral anticoagulant. The estimated high binding affinity of L toward plasma proteins (PPS% value is > 90%) justifies the investigation of binding affinity and comparative analysis of L and WF to Human Serum Albumin ( HSA ) using the spectrofluorimetric method (296, 303 and 310 K) as well as molecular docking and molecular dynamics simulations. Compound L shows a very good binding affinity especially to the active site of WF (the active site I -subdomain IIA), quenching HSA fluorescence by a static process. Also, the finite element smeared model (Kojic Transport Model, KTM), which includes blood vessels and tissue, was implemented to compute the convective-diffusion transport of L and WF within the liver. Finally, compound L shows a high degree of inhibitory activity toward the VKOR receptor comparable to the inhibitory activity of WF . Stabilization and limited flexibility of amino acid residues in the active site of the VKOR after binding of L and WF indicates a very good inhibitory potential of compound L . The high affinity of the L for the VKOR enzyme (Vitamin K antagonist), as well as the structural similarity to commercial anticoagulants ( WF ), provide a basis for further studies and potential application in the treatment of venous thrombosis, pulmonary embolism and ischemic heart disease.Communicated by Ramaswamy H. Sarma.

Background: Plants have numerous defensive secondary metabolites to withstand insect attacks. Scoparone, which is extracted from the medicinal plant Artemisia capillaris, has potent acaricidal effects on Tetranychus cinnabarinus. Spirodiclofen, derived from a tetronic acid derivative, is a potent commercial acaricide that is extensively used globally. However, whether scoparone has synergistic effects when used in conjunction with spirodiclofen and the underlying synergistic mechanism remains unclear., Results: Scoparone exhibited a potent synergistic effect when it was combined with spirodiclofen at a 1:9 ratio. Subsequently, cytochrome P450 monooxygenase (P450) activity, RNA-Seq and qPCR assays indicated that the enzyme activity of P450 and the expression of one P450 gene from T. cinnabarinus, TcCYP388A1, were significantly inhibited by scoparone and spirodiclofen + scoparone; conversely, P450 was activated in spirodiclofen-exposed mites. Importantly, RNAi-mediated silencing of the TcCYP388A1 gene markedly increased the susceptibility of spider mites to spirodiclofen, scoparone and spirodiclofen + scoparone, and in vitro, the recombinant TcCYP388A1 protein could metabolize spirodiclofen. Molecular docking and functional analyses further indicated that R117, which is highly conserved in Arachnoidea species, may be a vital specific binding site for scoparone in the mite TcCYP388A1 protein. This binding site was subsequently confirmed using mutagenesis data, which revealed that this binding site was the sole site selected by scoparone in spider mites over mammalian or fly CYP388A1., Conclusions: These results indicate that the synergistic effects of scoparone and spirodiclofen on mites occurs through the inhibition of P450 activity, thus reducing spirodiclofen metabolism. The synergistic effect of this potent natural product on the detoxification enzyme-targeted activity of commercial acaricides may offer a sustainable strategy for pest mite resistance management. © 2024 Society of Chemical Industry., (© 2024 Society of Chemical Industry.)

Introduction: Cyclophosphamide (CP), which is a commonly used chemotherapy drug, can lead to a range of side effects such as immunosuppression, bone marrow suppression, leukopenia, and oxidative stress. This study aims to explore the effects of Auraptene (AUR), which has immunomodulatory and antioxidant properties, on immune function in mice that are experiencing suppression induced by CP., Materials and Methods: The experiment involved 60 male BALB/c mice that underwent a 10-day treatment. On days 1, 3, and 9, CP was given at 80 mg/kg IP doses to induce immunosuppression. The mice were divided into five groups: Control group, CP group, CP + liposomal AUR 0.2 mg/kg (AUR 0.2), CP + liposomal AUR 0.25 mg/kg (AUR 0.25), and liposomal vehicle group. Various parameters were measured, including mouse weight, immune organ weight index (spleen and thymus), spleen and thymus histopathology, levels of inflammatory cytokines (IL2, IL10, IL4, IFN-γ), TH1/TH2 balance ratio, IgG and IgM immunoglobulin levels, white blood cell count, platelets, neutrophils, lymphocytes, and oxidative activity measured by MDA, SOD, and Total Antioxidant., Results: In the group treated with CP, the mice showed a significant decrease in weight compared to the control group. In contrast, the group treated with AUR maintained their weight and did not show a significant difference from the control group. AUR 0.25 reduced the damage to the spleen and thymus caused by CP. Additionally, AUR 0.25 demonstrated a significant decrease in IL4 and IL10 levels compared to the CP group (p = 0.04), approaching the levels of the control group. Furthermore, IL2 and IFN-γ levels in the AUR 0.25 group significantly increased (p = 0.04) compared to the CP group, reaching levels similar to the control group. AUR also increased serum IgM and IgG levels two to three times compared to the CP group, approaching the levels of the control group. MDA levels in the AUR 0.25 group decreased to normal and control levels. AUR 0.25 also showed increased SOD and Total Antioxidant levels. Additionally, white blood cells, platelets, neutrophils, and lymphocytes in the AUR group significantly increased compared to the CP group, reaching normal levels similar to the control group. The TH1/TH2 ratio in the AUR group exhibited a significant increase of two and a half times (p = 0.002) compared to the CP group., Conclusion: These results show that AUR protects against the side effects of CP by increasing the function of the humoral and cellular immune system through the balance of TH1/TH2 and increasing the level of immunoglobulins, as well as increasing the antioxidant activity and the protective role of cytotoxicity., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

c-MET and STAT-3 are significant targets for cancer treatments. Here, we describe a class of very effective dual STAT-3 and c-MET inhibitors with coumarin-based thiazoles (3a-o) as its scaffold. Spectroscopic evidence (NMR, HRMS, and HPLC) validated the structural discoveries of the new compounds. The cytotoxic activity of these compounds was also tested against a panel of cancer cells in accordance with US-NCI guidelines. Compound 3g proved to be active at 10 µM, thus it was automatically scheduled to be tested at five doses. Towards SNB-75 (CNS cancer cell line), compound 3g showed notable in vitro anti-cancer activity with GI 50  = 1.43 μM. For the molecular targets, compound 3g displayed potent activity towards STAT-3 and c-MET having IC 50 of 4.7 µM and 12.67, respectively, compared to Cabozantinib (IC 50  = 15 nM of c-MET) and STAT-3-IN-3 (IC 50  = 2.1 µM of STAT-3). Moreover, compound 3g significantly induced apoptosis in SNB-75 cells, causing a 3.04-fold increase in apoptotic cell death (treated cells exhibited 11.53 % overall apoptosis, against 3.04 % in reference cells) and a 3.58-fold increase in necrosis. Moreover, it arrests cells at the G2 phase. Dual inhibition of c-MET and STAT-3 protein kinase was further validated using RT-PCR. The target compound's binding mechanism was determined by the application of molecular docking., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Acetaminophen, a centrally-acting old analgesic drug, is a weak inhibitor of cyclooxygenase (COX) isoforms with some selectivity toward COX-2. This compound was used in this work as a precursor to create nine acetaminophen based coumarins (ACFs). To satisfy the aim of this work, which states the synthesis of acetaminophen-based coumarins as selective COX-2 inhibitors, the ACFs were subjected to two types of investigation: in vitro and in silico. Given the former type, the ACFs capacity to block COX-1 and COX-2 was investigated in lab settings. On the other hand, the in silico investigation included docking the chemical structures of ACFs into the active sites of these enzymes, predicting their anticipated toxicities, and determining the ADME characteristics. The results of the in vitro study revealed that the synthesized ACFs demonstrated good-to-excellent inhibitory properties against the enzymes under study. Also, these ACFs exhibited a high level of COX-2 selectivity, which improved as the capacity of the aromatic substitute for withdrawing electrons was enhanced. Results of docking were comparable to the in vitro investigation in case of COX-2. On the other hand, the in silico investigations indicated that the synthesized ACFs are safer than their precursor, acetaminophen, with a high potential to consider oral-administrated candidates., (© 2024 Wiley-VHCA AG, Zurich, Switzerland.)

Ruthenium(II/III) coordination compounds have gained widespread attention as chemotherapy drugs, photosensitizers, and photodynamic therapy reagents. Herein, a family of 11 novel coumarin-coordinated 8-hydroxyquinoline ruthenium(II/III) compounds, i.e., [Ru II 2 (μ 2 -Cl) 2 (QL1a) 2 (DMSO) 4 ] (YNU-4a = Yulin Normal University-4a), [Ru II 2 (μ 2 -Cl) 2 (QL1b) 2 (DMSO) 4 ] (YNU-4b), [Ru II 2 (μ 2 -Cl) 2 (QL1c) 2 (DMSO) 4 ] (YNU-4c), [Ru II 2 (μ 2 -Cl) 2 (QL1d) 2 (DMSO) 4 ]⋅2CH 3 OH (YNU-4d), [Ru II (QL1e) 2 (DMSO) 2 ] (YNU-4e), [Ru III (QL1e) 2 (QL3a)] (YNU-4f), [Ru III (QL1e) 2 (QL3b)] (YNU-4g), [Ru III (QL1e) 2 (QL3c)] (YNU-4h), [Ru II Cl 2 (H-QL3a) 2 (DMSO) 2 ] (YNU-4i), [Ru II Cl 2 (H-QL3b) 2 (DMSO) 2 ] (YNU-4j), and [Ru II Cl 2 (H-QL3c) 2 (DMSO) 2 ] (YNU-4k), featuring the coligands 5,7-diiodo-8-hydroxyquinoline (H-QL1a), 5,7-dichloro-8-quinolinol (H-QL1b), 5-chloro-7-iodo-8-hydroxyquinolin (H-QL1c), 5,7-dibromo-8-hydroxyquinoline (H-QL1d), and 5,7-dichloro-8-hydroxy-2-methylquinoline (H-QL1e) and the main ligands 6,7-dichloro-3-pyridin-2-yl-chromen-2-one (H-QL3a), 6-bromo-3-pyridin-2-yl-chromen-2-one (H-QL3b), and 6-chloro-3-pyridin-2-yl-chromen-2-one (H-QL3c), respectively. The structure of compounds YNU-4a-YNU-4k was fully confirmed by conducting various spectroscopic analyses. The anticancer activity of YNU-4a-YNU-4k was evaluated in cisplatin-resistant A549/DDP lung cancer cells (LC549) versus normal embryonic kidney (HEK293) cells. Notably, compound YNU-4f bearing QL1e and QL3a ligands showed a more pronounced antiproliferative effect against LC549 cells (IC 50  = 1.75 ± 0.09 μM) with high intrinsic selectivity toward LC549 cancer cells than YNU-4a-YNU-4e, H-QL1a-H-QL1e, cisplatin (PDD), YNU-4g-YNU-4k, and H-QL3a-H-QL3c. Additionally, a colocalization assay analysis of YNU-4e and YNU-4f showed that these two ruthenium(II/III) compounds were subcellularly accumulated in the mitochondria and other regions of the cytoplasm, where they induce mitophagy, adenosine triphosphate (ATP) reduction, mitochondrial respiratory chain complex I/IV(RC1/RC4) inhibition, and mitochondrial dysfunction. Accordingly, compounds YNU-4a-YNU-4k can be regarded as mitophagy inductors for the eradication of cisplatin-resistant LC549 cancer cells., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Inc.)

Unraveling the intricacies of β-glucuronidase inhibition is pivotal for developing effective strategies in applications specific to gastrointestinal health and drug metabolism. Our study investigated the efficacy of some Hibiscus trionum phytochemicals as β-glucuronidase inhibitors. The results showed that cleomiscosin A and mansonone H emerged as the most potent inhibitors, with IC 50 values of 3.97 ± 0.35 μM and 10.32 ± 1.85 μM, respectively. Mechanistic analysis of β-glucuronidase inhibition indicated that cleomiscosin A and the reference drug EGCG displayed a mixed inhibition mode against β-glucuronidase, while mansonone H exhibited noncompetitive inhibition against β-glucuronidase. Docking studies revealed that cleomiscosin A and mansonone H exhibited the lowest binding affinities, occupying the same site as EGCG, and engaged significant key residues in their binding mechanisms. Using a 30 ns molecular dynamics (MD) simulation, we explored the interaction dynamics of isolated compounds with β-glucuronidase. Analysis of various MD parameters showed that cleomiscosin A and mansonone H exhibited consistent trajectories and significant energy stabilization with β-glucuronidase. These computational insights complemented experimental findings, underscoring the potential of cleomiscosin A and mansonone H as β-glucuronidase inhibitors., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Ammi majus L. is a rich source of coumarins in addition to various flavonoids, alkaloids, and terpenoids. Medicinal products of Ammi majus seed, with sunlight exposure, are worldwide used for the treatment of vitiligo (pale-white patches on the skin). To increase the content of seed-coumarins and to investigate the physiological reasons in this respect, two net-house experiments were conducted using foliar-spray treatments (0, 25, 50, 100 and 200 mg L -1 ) of salicylic acid (SA) (Experiment 1) and putrescine (PUT) (Experiment 2). All studied parameters were improved due to the foliar application of both growth elicitors (SA and PUT). The best outcomes for SA and PUT were obtained at 50 mg L -1 which maximally increased the growth characteristics, physiological and biochemical attributes, and seed quality parameters. In comparison to the control, 50 mg L -1 of SA and PUT increased the chlorophyll content by 26.3% and 25.5%, carotenoid content by 31.4% and 18.5%. In addition 50 mg L -1 of both SA and PUT gives the best results of FTIR (Fourier Transform Infrared Spectrophotometer) & XRD (X-ray Diffraction) analysis. In GC-MS analysis, 50 mg L -1 of SA and PUT increases the Methoxsalen content (17.44 and 16.81%) and 7H-Furo[3,2-g]. Bown (1995) [1] Benzopyran-7-one, 4,9-dimethoxy content(14.92 and 13.93%) and p-camphorene content (13.11 and 12.27%) in contrast to the control. Other important constituents were Pimpinellin (6.31 and 4.08%), Bergapten (8.72 and 6.220, Isospathulenol (7.80 and 2.47), Octadecenoic acid (5.78 and 3.59) and Vitamin E (1.48 and 0.16)., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Phytochemical characteristics and antimicrobial properties of extracts were studied in Nonea rossica Steven (Boraginaceae), which is widespread in Russia. The aerial part (herb) of N. rossica was harvested from a steppe meadow in the Novosibirsk region during flowering. The qualitative composition of biologically active compounds (BACs) was determined by thin-layer chromatography. Quantitative assays were carried out by spectrophotometry; flavonoids, hydroxycinnamic acids, and coumarin-like compounds were measured with reference to rutin, caffeic acid, and coumarin, respectively. Antimicrobial activity was determined by the serial dilution method. Gram-positive bacterial (Staphylococcus aureus ATCC 6538 FDA 209P and Bacillus cereus ATCC 10702) and fungal (Candida albicans NCTC 885-653) strains were used as test cultures. Phenolic BACs (hydroxycinnamic acids, flavonoids, and coumarins) were detected, and their quantitative contents determined. The highest yield of phenolic BACs was achieved using 40-70% ethanol as an extractant. Antimicrobial activity against S. aureus and B. cereus and antifungal activity against C. albicans were detected in N. rossica herb extracts prepared using 40-70% ethanol. The extracts were tested for the contents of caffeic acid and coumarin. Synergistic interactions of these compounds determined the bactericidal and fungistatic properties of the extracts., (© 2024. Pleiades Publishing, Ltd.)

Human MRP1 protein plays a vital role in cancer multidrug resistance. Coumarins show promising pharmacological properties. Virtual screening, ADMET, molecular docking and molecular dynamics (MD) simulations were utilized as pharmacoinformatic tools to identify potential MRP1 inhibitors among coumarin derivatives. Using in silico ADMET, 50 hits were further investigated for their selectivity toward the nucleotide-binding domains (NBDs) of MRP1 using molecular docking. Accordingly, coumarin, its symmetrical ketone derivative Lig. No. 4, and Reversan were candidates for focused docking study with the NBDs domains compared with ATP. The result indicates that Lig. No. 4, with the best binding score, interacts with NBDs via hydrogen bonds with residues: GLN713, LYS684, GLY683, CYS682 in NBD1, and GLY1432, GLY771, SER769 and GLN1374 in NBD2, which mostly overlap with ATP binding residues. Moreover, doxorubicin (Doxo) was docked to the transmembrane domains (TMDs) active site of MRP1. Doxo interaction with TMDs was subjected to MD simulation in the NBDs free and occupied with Lig. No. 4 states. The results showed that Doxo interacts more strongly with TMD residues in inward facing feature of TMDs helices. However, when Lig. No. 4 exists in NBDs, Doxo interactions are different, and TMD helices show more outward-facing conformation. This result may suggest a partial competitive inhibition mechanism for the Lig. No. 4 on MRP1 compared with ATP. So, it may inhibit active complex formation by interfering with ATP entrance to NBDs and locking MRP1 conformation in outward-facing mode. This study suggests a valuable coumarin derivative that can be further investigated for potent MRP1 inhibitors.Communicated by Ramaswamy H. Sarma.

Psychological stress induces neuroinflammatory responses, which are associated with the pathogenesis of various psychiatric disorders, such as posttraumatic stress disorder and anxiety. Osthole-a natural coumarin isolated from the seeds of the Chinese herb Cnidium monnieri-exerts anti-inflammatory and antioxidative effects on the central nervous system. However, the therapeutic benefits of osthole against psychiatric disorders remain largely unknown. We previously demonstrated that mice subjected to repeated social defeat stress (RSDS) in the presence of aggressor mice exhibited symptoms of posttraumatic stress disorder, such as social avoidance and anxiety-like behaviors. In this study, we investigated the therapeutic effects of osthole and the underlying molecular mechanisms. Osthole exerted therapeutic effects on cognitive behaviors, mitigating anxiety-like behaviors and social avoidance in a mouse model of RSDS. The anti-inflammatory response induced by the oral administration of osthole was strengthened through the upregulation of heme oxygenase-1 expression. The expression of PPARα was inhibited in mice subjected to RSDS. Nonetheless, osthole treatment reversed the inhibition of PPARα expression. We identified a positive correlation between heme oxygenase-1 expression and PPARα expression in osthole-treated mice. In conclusion, osthole has potential as a Chinese herbal medicine for anxiety disorders. When designing novel drugs for psychiatric disorders, researchers should consider targeting the activation of PPARα., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Targeted delivery systems combined with the stimuli-responsive release of drug molecules hold noteworthy promise for precision medicine, enabling treatments with enhanced effectiveness and reduced adverse effects. An ideal drug delivery platform with versatile targeting moieties, the capability of combinational payloads, and simple preparation is highly desirable. Herein, we developed pH-sensitive fluorescent self-assembled complexes (SACs) of a galactose-functionalized G-quadruplex (G4) and a coumarin carboxamidine derivative as a targeted delivery platform through the nanoprecipitation method. These SACs selectively targeted hepatocellular carcinoma (HepG2) cells in fluorescence imaging after a short incubation and exerted specific anticancer effects in an appropriate dose range. Co-delivery of 1 μM prodrug floxuridine oligomers and 16 μg/mL SACs (minimal hemolytic effect) significantly reduced the cytotoxicity of the nucleoside anticancer drug on normal cells (NIH/3T3), kept up to 70% alive after 72-h incubation, and improved anticancer efficacy compared to SACs alone. This strategy can be extended to ratiometric multidrug delivery through self-assembly for targeted combinational therapy.

Quorum sensing (QS) is a bacterial cell-to-cell communication mechanism that plays an essential role in bacterial pathogenesis. QS governs bacterial behavior and controls biofilm formation, which in turn contributes to antibiotic resistance. Therefore, identifying and synthesizing novel compounds to overcome QS and inhibit biofilm formation are essential. Coumarins are important plant-derived natural products with wide-ranging bioactivities and extensive applications, including antibacterial, antifungal, anticoagulant, antioxidant, anticancer, and anti-inflammatory properties. Additionally, coumarins are capable of QS rewiring and biofilm formation inhibition, leading to higher susceptibility to antimicrobial agents and less antibiotic resistance. Therefore, in this review, we aim to provide an overview of QS and biofilm formation. This review also discusses the role of natural and synthesized coumarins in controlling QS, inhibiting biofilm formation, and inducing synergy in antibiotic-coumarin combinations. Hence, this review emphasizes the potential of coumarin compounds to act as antibacterial agents and demonstrates their ability to alleviate antibiotic resistance.

Leonurus japonicus Houtt is an exceptional medicinal herb used to treat obstetrical and gynecological diseases in traditional Chinese medicine, and it has significant effects on the treatment of dysmenorrhea and postpartum hemorrhage. This study investigated the effects of coumarins with diverse substituent groups from L. japonicus on isolated uterine smooth muscle and the preliminary mechanism of the most effective compound. Eight coumarins isolated from L. japonicus were assessed for their effects on the isolated uterine smooth muscle of nonpregnant rats in vitro. Coumarins 1 and 2 significantly promoted the contraction of rat uterine smooth muscle strips, whereas coumarins 3 - 5 showed remarkable relaxing effects against oxytocin (OT)-induced rat uterine smooth muscle contraction. Further mechanism investigations revealed that bergapten (coumarin 1 ) significantly increased the level of Ca 2+ in uterine tissues by promoting extracellular Ca 2+ influx and intracellular Ca 2+ release, which were related to the activation of L-type Ca 2+ channels and α-receptors. By contrast, osthole (coumarin 5 ), an α receptor antagonist, inhibited OT-induced uterine smooth muscle contraction by decreasing the level of Ca 2+ in uterine tissues via inhibition of extracellular Ca 2+ influx and intracellular Ca 2+ release. This study demonstrates that the coumarins from L. japonicus are effective substances for regulating uterine smooth muscle contraction, but different coumarins with diverse substituent groups have different, even opposite effects. It can be inferred that coumarins are closely related to the efficacy of L. japonicus in the treatment of dysmenorrhea and postpartum hemorrhage.

Staphylococcus aureus infections are the primary causes of morbidity, and mortality, particularly in immuno-compromised individuals. S. aureus associated infections are acquired from community, as well as hospital settings, and difficult to treat because of the emerging resistance against available antibiotics. One of the key factors of its resistance is the biofilm formation, which can be targeted to treat S. aureus-induced infections. Currently, there is no drug available that function by targeting the biofilm. This unmet need demands the discovery of drug candidates against S. aureus biofilm. The present study was designed to evaluate coumarin derivatives 1-21 against S. aureus biofilm. The 96-well plate crystal violet assay was employed for the quantification of biofilm. Results showed that the coumarin derivatives 2-4, 10, and 17 possess potent antibiofilm activity, with MBIC values between 25-100 μg/mL. The results were further confirmed through atomic force microscopy (AFM), scanning electron (SEM), and fluorescence microscopic studies. The quantitative RT-PCR analysis revealed the downregulation of biofilm associated genes, icaA and icaD. These coumarin derivatives were also found to be non-cytotoxic to fibroblasts. This study, therefore, identifies the antibiofilm potential of coumarin derivatives that will pave the way for further research on these derivatives., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Wahab et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)