Protective effects of esculetin against doxorubicin-induced toxicity correlated with oxidative stress in rat liver: In vivo and in silico studies.

Doxorubicin (DOX) is widely used in cancer treatment but the dose-related toxicity of DOX on organs including the liver limit its use. Therefore, there is great interest in combining DOX with natural compounds with antioxidant properties to reduce toxicity and increase drug efficacy. Esculetin is a natural coumarin derivative with biological properties encompassing anti-inflammatory and antioxidant activities. In light of these properties, this study was meticulously crafted to investigate the potential of esculetin in preventing doxorubicin (DOX)-induced hepatotoxicity in Sprague-Dawley rats. The rats were divided into a total of six groups: control group, DOX group (administered DOX at a cumulative dose of 5 mg/kg intraperitoneally every other day for 2 weeks), E50 group (administered 50 mg/kg of esculetin intraperitoneally every day), E100 group (administered 100 mg/kg of esculetin intraperitoneally every day) and combined groups (DOX + E50 and DOX + E100) in which esculetin was administered together with DOX. The treatments, both with DOX alone and in combination with E50, manifested a reduction in catalase (CAT mRNA) levels in comparison to the control group. Notably, the enzymatic activities of superoxide dismutase (SOD), CAT, and glutathione peroxidase (GPx) witnessed significant decreases in the liver of rats treated with DOX. Moreover, DOX treatment induced a statistically significant elevation in malondialdehyde (MDA) levels, coupled with a concurrent decrease in glutathione (GSH) levels. Additionally, molecular docking studies were conducted. However, further studies are needed to confirm the hepatoprotective properties of esculetin and to precisely elucidate its mechanisms of action.

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-1ß, 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.

Heparin-stabilized gold nanoparticles embedded in graphene for the electrochemical determination of esculetin.

A conductive nanocomposite consisting of heparin-stabilized gold nanoparticles embedded in graphene was prepared and characterized to develop an electrochemical sensor for the determination of esculetin in tea and jam samples. The gold nanoparticles were characterized by spectroscopic and microscopic techniques. The different proportions of graphene in the nanocomposite were evaluated and characterized by electrochemical practices. The heterostructure material on the glassy carbon electrode with esculetin showed π-π stacking interactions with an adsorption-controlled process. The voltammetric profile of esculetin using the proposed nanomaterial presented oxidation and reduction peaks at +0.61 and +0.58 V vs. Ag/AgCl, respectively, facilitating the electron transfer with esculetin through the transfer of two moles of protons and two moles of electrons per mole of esculetin. Using optimized conditions and square wave voltammetry, the calibration curve was obtained with two linear ranges, from 0.1 to 20.5 µmol L-1, with a detection limit of 43.0 nmol L-1. The electrochemical sensor showed satisfactory results for repeatability and stability, although interferences were observed in the presence of high concentrations of ascorbic acid or quercetin. The sensor was successfully applied in the determination of esculetin in samples of mulberry jam, white mulberry leaf tea, and white mulberry powder tea, presenting adequate recovery ranges. This directive provides valuable insights for the development of novel electrochemical sensors using heparin-based conductive nanomaterials with improved sensitivity and sensibility.

Renoprotective effect of esculetin against ischemic acute kidney injury-diabetic comorbidity.

Mitophagy maintains cellular homeostasis by eliminating damaged mitochondria. Accumulated damaged mitochondria can lead to oxidative stress and cell death. Induction of the PINK1/Parkin-mediated mitophagy is reported to be renoprotective in acute kidney injury (AKI). Esculetin, a naturally available coumarin, has shown protective action against diabetic complications. However, its effect on AKI-diabetes comorbidity has not been explored yet. Therefore, we aimed to investigate the renoprotective effect of esculetin against AKI under diabetic conditions via regulating PINK1/Parkin-mediated mitophagy. For this, type 1 diabetic male Wistar rats were treated with two doses of esculetin (50 and 100 mg/kg/day orally) for five days followed by AKI induction by bilateral ischemic-reperfusion injury (IRI). NRK-52E cells grown in high glucose were exposed to sodium azide (10 mM) for induction of hypoxia/reperfusion injury (HRI) in-vitro. Esculetin (50 µM) treatment for 24 h was given to the cells before HRI. The in-vitro samples were utilized for cell viability and ΔΨm assay, immunoblotting, and immunofluorescence. Rats' plasma, urine, and kidney samples were collected for biochemical analysis, histopathology, and western blotting. Our results showed a significant decrease in kidney injury-specific markers and increased expression of mitophagy markers (PINK1 and Parkin) with esculetin treatment. Moreover, esculetin prevented the HRI and hyperglycemia-induced decrease in ΔΨm and autophagosome marker. Also, esculetin therapy reduced oxidative stress via increased Nrf2 and Keap1 expression. Esculetin attenuated AKI under diabetic condition by preventing mitochondrial dysfunction via inducing PINK1/Parkin-mediated mitophagy, suggesting its potential as an effective therapy for preventing AKI-diabetes comorbidity.

Impaired mitophagy and increased oxidative stress are major contributors to AKI development.Esculetin treatment reduces oxidative stress in AKI-diabetes comorbidity.Esculetin activated Nrf2/PINK1/Parkin axis and improved mitophagy.Esculetin can be a potential therapy for AKI-diabetes comorbidity prevention and management.

Effect of Herniarin on Cell Viability, Cell Cycle, and Erk Protein Levels in Different Stages of Bladder Cancer Cells.

This study examines the potential of herniarin from tarragon, as an agent with multifaceted effects on bladder cancer cells and investigates herniarin's impact on cell viability, migration, cell cycle regulation, apoptosis induction, and Erk signaling pathways in bladder cancer cell lines, including RT-112 (grade 1, non-invasive), HTB9 (grade 2, invasive), and HT1376 (grade 3, invasive), through comprehensive in vitro experiments. The compound causes cell cycle arrest at distinct phases in different cell lines: G1/S arrest in RT112 cells, G2/M arrest in HTB9 cells, and S phase arrest in HT1376 cells. Furthermore, herniarin induces caspase-mediated apoptosis in various cell lines and simultaneously modulates protein levels of apoptotic and anti-apoptotic proteins, indicating its potential as a therapeutic agent. Herniarin's influence also extends to Erk signaling, a crucial pathway that regulates cell growth and differentiation. In conclusion, this study reveals herniarin's potential as a versatile agent in the treatment of bladder cancer.

Esculetin unveiled: Decoding its anti-tumor potential through molecular mechanisms-A comprehensive review.

BACKGROUND: The growing complexity of cancer has made it a significant concern in the medical community. Although cancer research has advanced, it is still challenging to create new effective medications due to the limitations and side effects of existing treatment strategies. These are enforcing the development of some alternative drugs from natural compounds with fewer drawbacks and side effects. AIM: Therefore, this review aims to provide up-to-date, crucial, and all-encompassing data on esculetin's anticancer activity, including all relevant molecular and cellular processes based on in vivo and in vitro investigations. RESULTS: According to the literature review, esculetin is available in nature and is effective against 16 different types of cancer. The general mechanism shown by esculetin is modulating signaling cascades and its related pathways, like cell proliferation, cell growth, autophagy, apoptosis, necrosis, inflammation, angiogenesis, metastasis, invasion, and DNA damage. Nanoformulation of esculetin improves this natural product's efficacy by improving water solubility. Esculetin's synergistic effects with both natural substances and conventional treatments have been shown, and this method aids in reversing resistance mechanisms by modulating resistance-related proteins. In addition, it has fewer side effects on humans than other phytochemicals and standard drugs with some good pharmacokinetic features. CONCLUSION: Therefore, until standard chemotherapeutics are available in pharmaceutical markets, esculetin should be used as a therapeutic drug against various cancer types.

Therapeutic efficacies of mitochondria-targeted esculetin and metformin in the improvement of age-associated atherosclerosis via regulating AMPK activation.

Atherosclerosis, in general, is an age-associated cardiovascular disease wherein a progressive decline in mitochondrial function due to aging majorly contributes to the disease development. Mitochondria-derived ROS due to dysregulated endothelial cell function accentuates the progression of atherosclerotic plaque formation. To circumvent this, mitochondrially targeted antioxidants are emerging as potential candidates to combat metabolic abnormalities. Recently, we synthesized an alkyl TPP+ tagged esculetin (Mito-Esc), and in the current study, we investigated the therapeutic efficacies of Mito-Esc and metformin, a well-known anti-diabetic drug, in the amelioration of age-associated plaque formation in the aortas of 12 months aged Apoe-/- and 20 months aged C57BL/6 mice, in comparison to young C57BL/6 control mice. Administration of Mito-Esc or metformin significantly reduced age-induced atherosclerotic lesion area, macrophage polarization, vascular inflammation, and senescence. Further, chronic passaging of human aortic endothelial cells (HAEC) with either Mito-Esc or metformin significantly delayed cellular senescence via the activation of the AMPK-SIRT1/SIRT6 axis. Conversely, depletion of either AMPK/SIRT1/SIRT6 caused premature senescence. Consistent with this, Mito-Esc or metformin treatment attenuated NFkB-mediated inflammatory signaling and enhanced ARE-mediated anti-oxidant responses in comparison to late passage control HAECs. Importantly, culturing of HAECs for several passages with either Mito-Esc or metformin significantly improved mitochondrial function. Overall, Mito-Esc and metformin treatments delay age-associated atherosclerosis by regulating vascular senescence via the activation of AMPK-SIRT1/SIRT6 axis.

In vivo comprehensive metabolite profiling of esculetin and esculin derived from chicory in hyperuricemia rats using ultra-high-performance liquid chromatography coupled with quadrupole-orbitrap high-resolution mass spectrometry.

Chicory, renowned for its multifaceted benefits, houses two vital coumarins, esculetin and esculin, both instrumental in reducing uric acid. This study emphasizes the metabolic pathways of esculetin and esculin under both standard and hyperuricemia conditions. Hyperuricemia was induced in Sprague-Dawley rats using oxonic acid potassium salt (300 mg·kg-1 ) and a 10% fructose water regimen over 21 days. Leveraging the ultra-high-performance liquid chromatography-Q Exactive hybrid quadrupole-orbitrap high resolution mass spectrometry, we analyzed the fragmentation behaviors of esculetin and esculin in rat bio-samples. Post oral-intake of esculetin or esculin, a notable dip in serum uric acid levels was observed in hyperuricemia rats. The investigation unveiled 24 esculetin metabolites and 14 for esculin. The metabolic pathways of both compounds were hydrolysis, hydroxylation, hydrogenation, dehydroxylation, glucuronidation, sulfation, and methylation. Interestingly, certain metabolites presented variations between standard and hyperuricemia rats, indicating that elevated levels of uric acid may affect enzyme activity linked to these metabolic reactions. This is the first systematic study on comparison of metabolic profiles of esculetin and esculin in both normal and hyperuricemia states, which was helpful to enrich our understanding of the complicated structure-activity relationships between esculin and esculetin and shed light to their action mechanism.

Comparative study of the antioxidant and anti-inflammatory effects of the natural coumarins 1,2-benzopyrone, umbelliferone and esculetin: in silico, in vitro and in vivo analyses.

The aim of this work was to compare the anti-inflammatory and antioxidant effects of three natural coumarins: 1,2-benzopyrone, umbelliferone and esculetin. The antioxidant capacity of coumarins was evaluated using both chemical and biological in vitro assays. Chemical assays included DPPH and ABTS∙+ radical scavenging as well as ferric ion reducing ability power (FRAP) assay. Inhibition of mitochondrial ROS generation and lipid peroxidation in brain homogenates were used as biological in vitro assays. The experimental method of carrageenan-induced pleurisy in rats was used for the in vivo investigation of the anti-inflammatory activity. In silico molecular docking analysis was undertaken to predict the affinity of COX-2 to the coumarins. Considering the antioxidant capacity, esculetin was the most efficient one as revealed by all employed assays. Particularly, the mitochondrial ROS generation was totally abolished by the compound at low concentrations (IC50 = 0.57 µM). As for the anti-inflammatory effects, the COX-2 enzyme presented good affinities to the three coumarins, as revealed by the molecular docking analyses. However, considering the in vivo anti-inflammatory effects, 1,2-benzopyrone was the most efficient one in counteracting pleural inflammation and it potentiated the anti-inflammatory actions of dexamethasone. Umbelliferone and esculetin treatments failed to reduce the volume of pleural exudate. Overall, therefore, our results support the notion that this class of plant secondary metabolites displays promising effects in the prevention and/or treatment of inflammation and other diseases associated with oxidative stress, although the singularities regarding the type of the inflammatory process and pharmacokinetics must be taken into account.

Protective effects of esculetin against ovary ischemia-reperfusion injury model in rats.

AIMS: Ovarian ischemia-reperfusion (I/R) injury is a phenomenon that necessitates urgent intervention, which occurs as a result of ovarian torsion, and it is frequently seen in young women. A large amount of free radical and oxidative damage as a result of I/R plays a role in the cause of the incident. Antioxidant agents are thought to be beneficial in preventing this damage, and the potential protective effects of esculetin, which had not been tested previously, were investigated in this study. STUDY DESIGN: The rats in the study were divided into five groups at random: control, sham, esculetin, I/R, and treatment. Oxidative stress parameters, proinflammatory cytokines, nuclear factor erythroid 2-related factor 2 (Nrf-2)/nuclear factor-kß (NF-κß) pathway, and histopathological analyses were evaluated at the end of the study. KEY FINDINGS: After I/R, malondialdehyde levels, proinflammatory cytokines, tumor necrosis factor-α and interleukin-1ß levels and NF-κß expressions were increased, Nrf-2 expression and glutathione level decreased and the histopathologic picture deteriorated. However, as a result of the esculetin treatment, ameliorative effects in the aforementioned parameters were determined, and it was ensured that they returned to normal levels. CONCLUSION: According to these findings, esculetin has protective effects on I/R damage by lowering lipid peroxidation and having antioxidant and anti-inflammatory properties. SIGNIFICANCE: Our results proved the protective effect of esculetin against ovarian IR injury in rats and this may be attributed to Nrf-2/NF-κß axis which showed antioxidant and anti-inflammatory effects. Therefore, esculetin can be used in the future for preventive effects to ovarian IR injury.

Non-covalent binding interaction of bioactive coumarin esculetin with calf thymus DNA and yeast transfer RNA: A detailed investigation to decipher the binding affinities, binding location, interacting forces and structural alterations at a molecular level.

Esculetin is a well-known coumarin derivative found abundantly in nature possessing an extensive array of pharmacological and therapeutic properties. Consequently, to comprehend its molecular recognition mechanism, our objective is to conduct a complete investigation of its interactions with the nucleic acid, specifically ct-DNA, and t-RNA, using spectroscopic and computational techniques. The intrinsic fluorescence of esculetin is quenched when it interacts with ct-DNA and t-RNA, and this occurs through a static quenching mechanism. The thermodynamic parameters demonstrated that the interaction is influenced by hydrogen bonding and weak van der Waals forces. CD and FT-IR results revealed no conformational changes in ct-DNA and t-RNA structure on binding with esculetin. Furthermore, competitive displacement assay with ethidium bromide, melting temperature, viscosity measurement, and potassium iodide quenching experiments, reflected that esculetin probably binds to the minor groove of ct-DNA. The molecular docking results provided further confirmation for the spectroscopic findings, including the binding location of esculetin and binding energies of esculetin complexes with ct-DNA and t-RNA. Molecular dynamics simulation studies demonstrated the conformational stability and flexibility of nucleic acids.

Derivative of 7-hydroxycoumarin has antifungal potential against Candida species and low cytotoxicity against human cells: In silico studies and biological evaluation.

This study investigates the antifungal and cytotoxic properties of 7-(pentyloxy)-2H-chromen-2-one. Through molecular docking and dynamics simulations, we explored the compound's interactions with fungal cell protein targets. Notably, it exhibited strong affinities for 1,3ß-glucan synthase, squalene epoxidase, δ-14-sterol reductase, 14-α-demethylase, and thymidylate synthase, with binding energies ranging from -100.39 to -73.15 kcal/mol. Molecular dynamics simulations confirmed its stable binding at active targets. The MIC and MFC values ranged from 67.16 µM (15.6 µg/mL) to 537.28 µM (125.0 µg/mL). The compound displayed promising antifungal effects, inhibiting fungal growth for at least 24 hours. Fungal plasma membrane function alteration likely contributed to these antifungal mechanisms. Additionally, the combination of the compound with nystatin, fluconazole, and caspofungin showed indifferent effects on antifungal activity. Cytotoxicity assessment in human keratinocyte cells (HaCaT) revealed an IC50 of 100 µM, which was approximately 1.5 times higher than the MIC for C. krusei. Thus, the compound exhibited strongly in silico and in vitro antifungal activity with low cytotoxicity in HaCaT cells. These findings support its potential as a candidate for further development as an antifungal compound.

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.

Umbelliferone attenuates cisplatin-induced acute kidney injury by inhibiting oxidative stress and inflammation via NRF2.

In this study, we investigated the nephroprotective effects of Umbelliferone (UMB) against cisplatin-induced acute kidney injury (AKI). C57BL/6J mice were treated with cisplatin via a single intraperitoneal injection (25 mg/kg) with or without UMB (40 mg/kg/day) by gavage. Renal function, apoptosis, oxidative stress, inflammation, and mitochondrial function were analyzed to evaluate kidney injury. In vitro, human proximal tubule epithelial cells were treated with cisplatin, with or without UMB, for 24 h. Western blotting and immunohistochemistry were performed to explore the mechanisms underlying the nephroprotective effects of UMB. Cisplatin-induced renal dysfunction, including increases in blood urea nitrogen, serum creatinine, and renal tubular injury indices (NGAL and KIM-1), were significantly attenuated by UMB treatment, along with renal phenotypic changes and renal tubular injury, as evidenced by improved renal histology. Moreover, NRF2 was activated by UMB pretreatment, along with the inhibition of oxidative stress and inflammatory response, as evidenced by decreased levels of antioxidant genes and inflammatory cytokines in cisplatin-induced AKI. Our results demonstrate that UMB can protect against cisplatin-induced nephrotoxicity, which is mediated by the NRF2 signaling pathway via antioxidant and anti-inflammatory activities, suggesting the clinical potential of UMB for the treatment of AKI.

Pharmacological activities of esculin and esculetin: A review.

Esculin and esculetin are 2 widely studied coumarin components of Cortex Fraxini, which is a well-known herbal medicine with a 2000-year history. In vivo and in vitro studies have demonstrated that both have a variety of pharmacological activities, including antioxidant, anti-tumor, anti-inflammatory, antibacterial, antidiabetic, immunomodulatory, anti-atherosclerotic, and so on. Their underlying mechanisms of action and biological activities include scavenging free radicals, modulating the nuclear factor erythroid 2-related factor 2 pathway, regulating the cell cycle, inhibiting tumor cell proliferation and migration, promoting mitochondrial pathway apoptosis, inhibiting the NF-κB and MAPK signaling pathways, regulating CD4+ T cells differentiation and associated cytokine release, inhibiting vascular smooth muscle cells, etc. This review aims to provide comprehensive information on pharmacological studies of esculin and esculetin, which is of noteworthy importance in exploring the therapeutic potential of both coumarin compounds.

Anticancer effect of umbelliferone on MKN-45 and MIA PaCa-2 cell lines.

In this study, the anticancer activity of umbelliferone (7-hydroxycoumarin-UMB) was investigated in MKN-45 human gastric cancer and MIA PaCa-2 human pancreatic cancer cells. The cytotoxic effect of UMB on MKN-45 and MIA PaCa-2 cells was determined by WST-8 cell viability assay; the effect on colony formation and migration potential by colony forming assay and wound healing/cell migration assay. Apoptotic effect of UMB was determined by measuring the change in mitochondrial membrane potentials, reactive oxygen species levels, and Caspase-3 activities in cells. Anticancer drugs cisplatin and gemcitabine were used as positive controls in experiments, and NIH/Swiss 3 T3 mouse embryonic fibroblast cells were used as a healthy cell group. The results of this study showed that umbelliferone had a significant cytotoxic effect in MKN-45 and MIA PaCa-2 cells, especially after 72 h treatment, while its cytotoxic effect in NIH/3 T3 cells was low. Furthermore, UMB reduces significantly the potential of cells to colonize and migrate; it has been determined that it causes apoptosis by decreasing the mitochondrial membrane potential, increasing intracellular ROS levels and Caspase-3 activity. UMB was found to have more anticancer effect on MIA PaCa-2 cells compared to MKN-45 cells. This showed that UMB has a cell-selective effect.

7-hydroxycoumarin-ß-D-glucuronide protects against cisplatin-induced acute kidney injury via inhibiting p38 MAPK-mediated apoptosis in mice.

AIMS: Cisplatin is a widely-used drug in the clinical treatment of tumors, but kidney nephrotoxicity is one of the reasons that limits its widespread use. We previously found that 7-hydroxycoumarin-ß-D-glucuronide (7-HCG) was one of metabolites of skimmin and highly enriched in the kidneys and maintained a high blood concentration in skimmin-treated rats. Therefore, we investigated whether 7-HCG has a protective effect on cisplatin-induced acute kidney injury. MATERIALS AND METHODS: Male C57BL/6 mice were continuously administered 7-HCG for five days, and on the third day, an intraperitoneal injection of cisplatin was given to induce acute kidney injury. After 72 h, the mice were sacrificed for analysis. Serum and renal tissue were collected for renal function evaluation. RNA sequencing was used to explore mechanism, and further validated by western blot and immunohistochemistry. In addition, pharmacokinetic study of oral 7-HCG administration was performed to examine how much 7-hydroxycoumarin (7-HC) was metabolized and 7-HC possible effect on renal protection. KEY FINDINGS: 7-HCG significantly reduced serum BUN and SCR levels, and alleviated pathological damage in renal tissue, and reduced the renal index. RNA sequencing revealed that 7-HCG could reverse p38 MAPK regulation and apoptosis. By western blotting, it was found that 7-HCG could reduce renal injury by reducing p-p38, p-ERK, p-JNK, cleaved-caspase3 and Bax. The immunohistochemical results of cleaved-caspase3 were consistent with western blotting. 7-HCG also significantly reduced the production of ROS in kidney tissue. Pharmacokinetic experiments have shown that 7-HCG in the blood increased rapidly and was eliminated slowly, with an average t1/2ß of 18.3 h. And the concentration of 7-HCG in the target organ kidney was about 4 times higher than that in blood. SIGNIFICANCE: Our findings indicate that 7-HCG could exert its protective effect against cisplatin-induced acute kidney injury by inhibiting apoptosis via p38 MAPK regulation and elucidates its pharmacokinetics.

Umbelliferon: a review of its pharmacology, toxicity and pharmacokinetics.

Coumarin, a plant secondary metabolite, has various pharmacological activities, including antioxidant stress and anti-inflammatory effects. Umbelliferone, a common coumarin compound found in almost all higher plants, has been extensively studied for its pharmacological effects in different disease models and doses with complex action mechanisms. This review aims to summarize these studies and provide useful information to relevant scholars. The pharmacological studies demonstrate that umbelliferone has diverse effects such as anti-diabetes, anti-cancer, anti-infection, anti-rheumatoid arthritis, neuroprotection, and improvement of liver, kidney, and myocardial tissue damage. The action mechanisms of umbelliferone include inhibition of oxidative stress, inflammation, and apoptosis, improvement of insulin resistance, myocardial hypertrophy, and tissue fibrosis, in addition to regulation of blood glucose and lipid metabolism. Among the action mechanisms, the inhibition of oxidative stress and inflammation is the most critical. In short, these pharmacological studies disclose that umbelliferone is expected to treat many diseases, and more research should be conducted.

The protective effect of 7-hydroxycoumarin against cisplatin-induced liver injury is mediated via attenuation of oxidative stress and inflammation and upregulation of Nrf2/HO-1 pathway.

Cisplatin (CIS) is an effective chemotherapy against different solid cancers. However, the adverse effects, including hepatotoxicity, limit its clinical use. 7-hydroxycoumarin (7-HC) possesses antioxidant and hepatoprotective activities, but its protective effect against CIS hepatotoxicity has not been investigated. This study evaluated the effect of 7-HC on liver injury, oxidative stress (OS), and inflammation provoked by CIS. Rats received 7-HC (25, 50, and 100 mg/kg) orally for 2 weeks followed by intraperitoneal injection of CIS (7 mg/kg) at day 15. CIS increased serum transaminases, alkaline phosphatase (ALP), and bilirubin and provoked tissue injury accompanied by elevated reactive oxygen species (ROS), malondialdehyde (MDA), and nitric oxide (NO). Liver nuclear factor (NF)-κB p65, inducible NO synthase (iNOS), pro-inflammatory cytokines, Bax, and caspase-3 were upregulated, and antioxidant defenses and Bcl-2 were decreased in CIS-treated rats, while 7-HC prevented liver injury and ameliorated OS, inflammatory and apoptosis markers. In addition, 7-HC enhanced nuclear factor erythroid 2-related factor 2 (Nrf2), and heme oxygenase (HO)-1 in CIS-administered rats and in silico studies revealed its binding affinity toward HO-1. In conclusion, 7-HC protected against CIS hepatotoxicity by mitigating OS and inflammatory response and modulating Nrf2/HO-1 pathway.

Umbelliferone potentiates intestinal protective effect of Lactobacillus Acidophilus against methotrexate-induced intestinal injury: Biochemical and histological study.

Intestinal injury is a common adverse effect of methotrexate (MTX) therapy, limiting its clinical use. Despite oxidative stress and inflammation being the most embedded mechanism of injury, pharmacological agents that exhibit antioxidant and anti-inflammatory impacts could prevent such toxicities. This study aimed to assess the enteroprotective effect of lactobacillus acidophilus (LB) and/or umbelliferone (UMB) against MTX-induced intestinal injury. Histologically, pretreatment with LB, UMB, or their combinations preserve the intestinal histological structure and mucin content with superior effect in combination therapy. In addition, oral pretreatment with UMB, LB, or their combinations significantly restored oxidant/antioxidant status, as evidenced by the upregulation of Nrf2, SOD3, HO-1, GSH, and GST levels concurrent with a decline in MDA contents. Besides, they suppressed the inflammatory burden by inhibiting STAT3, MPO, TLR4, NF-κB, TNF-α, and IL-6 levels. Moreover, LB, UMB, or their combinations significantly upregulated Wnt and ß-catenin expression. Notably, pretreatment with the combination therapy is superior to monotherapy in protecting rats' small intestines from MTX-induced enteritis. In conclusion, combined pretreatment with LB and UMB could be a novel therapeutic regimen for conditions of intestinal injury induced by MTX via restoring oxidant/antioxidant balance and suppressing inflammatory burden.