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The VHL-containing cullin-RING E3 ubiquitin ligase (CRL2 VHL ) complex is an E3 ligase commonly used in targeted protein degradation (TPD). Hydroxyproline-based ligands that mimic VHL substrates have been developed as anchor molecules for proteolysis-targeting chimeras (PROTACs) in TPD. To expand the chemical space for VHL ligands, we conducted fragment screening using VHL–ELOB–ELOC (VBC) proteins. We found that certain 7-hydroxycoumarin derivatives (7HCs), rather than VHL, would bind to the ELOC component of the VBC complex. The 7HC binding site overlapped with the CUL2 binding interface on ELOC but did not overlap with the CUL5 binding interface, suggesting that 7HCs may influence the formation of CRL2 but not CRL5. Although the binding affinities of these 7HCs to the VBC complex were relatively low, they represent novel and promising foundational agents for the development of chemical probes or inhibitors that target ELOC-containing CRLs.

More efficient and preferably more convenient and greener synthetic solutions in coumarin scaffold functionalization are in steady demand. The Duff ortho-formylation of unsubstituted umbelliferone was revised in this study. The reaction conditions were optimized based upon data from the literature analysis and resulted in unexpectedly rapid ortho-formylation of umbelliferone, yielding a mixture of ortho-formyl position isomers. Thorough studies on the separation of ortho-formylated umbelliferones using chromatographic and recrystallization methods as well as the evaluation of their solubility in common organic solvents led to complete resolution of 8-formyl- and 6-formylumbelliferones. The precise protocol for simultaneous preparation, extraction, and purification of 8-formyl- and 6-formylumbelliferones is provided, and the prospective studies of biological and pharmacological activities of these compounds are synopsized.

Umbelliferone (UMB; 7-hydroxycoumarin) is a natural compound that exhibited a diversity of pharmacological activities. Its protective effects against various ischemia/reperfusion (IR) injuries, including heart, kidney, and testis, have been observed. However, their effect on hepatic IR is still not investigated yet. Here, this study was conducted to examine the potential protective role of UMB during the early phase of hepatic IR injury via targeting Keap-1/Nrf-2/ARE and its closely related signaling pathway, TLR4/NF-κB-p65. Experimentally, forty Wistar albino rats were randomly divided into 4 groups: Sham control group (received 1% carboxymethyl cellulose as a vehicle), UMB group (30 mg/kg/day, P.O.), IR group (subjected to complete hepatic IR injury), and IR + UMB group. Our results revealed that oral UMB effectively reduced the serum levels of ALT, AST, ALP, and LDH along with the restoration of oxidant/antioxidant status. At the molecular level, UMB markedly activated Nrf-2 expression and its down-streaming targets: HO-1, NQO1, GCLC, SOD3, and TNXRD1, along with Keap-1 down-regulation. Besides, UMB significantly down-regulated NF-κB-p65 and TLR4 expressions with subsequent decreased TNF-α and IL-1β levels coupled with the up-regulation of the IL-10 level. Finally, biochemical findings were confirmed by attenuation of histopathological changes in liver tissues. Together, UMB is a promising agent for the amelioration of liver tissues against IR-induced oxidative injury through activation of the Keap-1/Nrf-2/ARE signaling pathway along with suppression of its closely related signaling pathways: TLR4/NF-κB-p65. Graphical abstract Illustrated diagram explored the prospective underlying protective mechanism of UMB against IR-induced hepatic damage.

In Apiaceae, furanocoumarins (FCs) are plant defence compounds that are present as linear or angular isomers. Angular isomers appeared during plant evolution as a protective response to herbivores that are resistant to linear molecules. Isomeric biosynthesis occurs through prenylation at the C6 or C8 position of umbelliferone. Here, we report cloning and functional characterization of two different prenyltransferases, Pastinaca sativa prenyltransferase 1 and 2 (PsPT1 and PsPT2), that are involved in these crucial reactions. Both enzymes are targeted to plastids and synthesize osthenol and demethylsuberosin (DMS) using exclusively umbelliferone and dimethylallylpyrophosphate (DMAPP) as substrates. Enzymatic characterization using heterologously expressed proteins demonstrated that PsPT1 is specialized for the synthesis of the linear form, demethylsuberosin, whereas PsPT2 more efficiently catalyses the synthesis of its angular counterpart, osthenol. These results are the first example of a complementary prenyltransferase pair from a single plant species that is involved in synthesizing defensive compounds. This study also provides a better understanding of the molecular mechanisms governing the angular FC biosynthetic pathway in apiaceous plants, which involves two paralogous enzymes that share the same phylogenetic origin.

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.

Acute kidney injury (AKI) is a global health concern with high incidence and mortality, where diabetes further worsens the condition. The available treatment options are not uniformly effective against the complex pathogenesis of AKI–diabetes comorbidity. Hence, combination therapies based on the multicomponent, multitarget approach can tackle more than one pathomechanism and can aid in AKI–diabetes comorbidity management. This study aimed to investigate the therapeutic potential of esculetin and phloretin combination against AKI–diabetes comorbidity by network pharmacology followed by validation by molecular docking and dynamics. The curative targets for diabetes, AKI, esculetin, and phloretin were obtained from DisGeNET, GeneCards, SwissTargetPrediction database. Further, the protein–protein interaction of the potential targets of esculetin and phloretin against AKI–diabetes comorbidity was investigated using the STRING database. Gene ontology and pathway enrichment analysis were performed with the help of the DAVID and KEGG databases, followed by network construction and analysis via Cytoscape. Molecular docking and dynamic simulations were performed to validate the targets of esculetin and phloretin against AKI–diabetes comorbidity. We obtained 6341 targets for AKI–diabetes comorbidity. Further, a total of 54 and 44 targets of esculetin and phloretin against AKI–diabetes comorbidity were retrieved. The top 10 targets for esculetin selected based on the degree value were AKR1B1, DAO, ESR1, PLK1, CA3, CA2, CCNE1, PRKN, HDAC2, and MAOA. Similarly, phloretin’s 10 key targets were ACHE, CDK1, MAPK14, APP, CDK5R1, CCNE1, MAOA, MAOB, HDAC6, and PRKN. These targets were enriched in 58 pathways involved in the pathophysiology of AKI–diabetes comorbidity. Further, esculetin and phloretin showed an excellent binding affinity for these critical targets. The findings of this study suggest that esculetin and phloretin combination as a multicomponent multitarget therapy has the potential to prevent AKI–diabetes comorbidity. Graphical abstract

Today, with the prevalence of metabolic diseases such as diabetes, which can be caused by insulin resistance, the need for targeted drug delivery seems essential. Using Nano crystals that contain antioxidant materials such as Umbelliprenin and are surface modified may be a solution to this problem. This study aims to investigate the IR/PDK1 pathway in the presence of cellulose nano-crystal surface-modified with cetyltrimethylammonium bromide containing Umbelliprenin (UCC-NCs delivery system). The UCC-NCs delivery system was synthesized and characterized by FTIR and zeta-potential methods. Forty-two Wistar male rats (aged 12 weeks, 250–300 g) were divided into seven groups of six. After induction of diabetes with a single dose of intraperitoneal injection of STZ (60 mg.kg − 1 ), the treatment groups were treated orally with doses of 5 and 10 mg.kg − 1 UM and Nano crystals. After the treatment period, the rats were anesthetized, and blood was taken from the rats’ retro-orbital plexus area, and their serum glucose, total cholesterol (TC), triglyceride, and HDL levels were measured. RNA was extracted from the tissue samples, and cDNA was synthesized, and the expression of IR and PDK1 genes was examined by real-time. Pathological changes were evaluated in the prepared sections. The results showed that Nano crystals were much better and more effective than UM in improving glucose and blood factors. Gene expression analysis showed a significant increase in the expression of IR and PDK1 genes in the groups receiving Nano crystals compared to UM. Therefore, nano crystals were probably able to prevent hyperglycemia by activating the IR/PDK1 pathway through anti-inflammatory and antioxidant properties. It is suggested that this drug delivery system be further tested for metabolic diseases such as diabetes.

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 (IC 50  = 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.

Obesity-induced chronic inflammation is a key factor in type 2 diabetes. A vicious cycle involving pro-inflammatory mediators between adipocytes and macrophages is a common cause of chronic inflammation in the adipose tissue. Tomato is one of the most popular vegetables and is associated with a reduced risk of diabetes. However, the molecular mechanism underlying the effect of tomato on diabetes is unclear. In this study, we focused on anti-inflammatory compounds in tomato. We found that the extract of tomato reduced plasma glucose and inflammatory markers in mice. We screened anti-inflammatory fractions in tomato using lipopolysaccharide-stimulated RAW264.7 macrophages, and active compounds were estimated by liquid chromatography-mass spectrometry over a wide range. Surprisingly, a large number of compounds including oxylipin and coumarin derivatives were estimated as anti-inflammatory compounds. Especially, 9-oxo-octadecadienoic acid and daphnetin suppressed pro-inflammatory cytokines in RAW264.7 macrophages inhibiting mitogen-activated protein kinase phosphorylation and inhibitor of kappa B α protein degradation. These findings suggest that tomato containing diverse anti-inflammatory compounds ameliorates chronic inflammation in obese adipose tissue.

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.