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[This corrects the article DOI: 10.1371/journal.pone.0151135.].

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.

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.

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 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.

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.

Acrylamide (ACR) is a toxic, probably carcinogenic compound commonly found in fried foods and used in the production of many industrial consumer products. ACR-induced acute kidney injury is mediated through several signals. In this research, we investigated, for the first time, the therapeutic effects of phytochemicals apocynin (APO) and/or umbelliferone (UMB) against ACR-induced nephrotoxicity in rats and emphasized the underlying molecular mechanism. To achieve this goal, five groups of rats were randomly assigned: the control group received vehicle (0.5% CMC; 1 ml/rat), ACR (40 mg/kg, i.p.), ACR + APO (100 mg/kg, P.O.), ACR + UMB (50 mg/kg, P.O.), and combination group for 10 days. In ACR-intoxicated rats, there was a significant reduction in weight gain while the levels of blood urea, uric acid, creatinine, and Kim-1 were elevated, indicating renal injury. Histopathological injury was also observed in the kidneys of ACR-intoxicated rats, confirming the biochemical data. Moreover, MDA, TNF-α, and IL-1β levels were raised; and GSH and SOD levels were decreased. In contrast, treatment with APO, UMB, and their combination significantly reduced the kidney function biomarkers, prevented tissue damage, and decreased inflammatory cytokines and MDA. Mechanistically, it suppressed the expression of NLRP-3, ASC, GSDMD, caspase-1, and IL-1β, while it upregulated Nrf-2 and HO-1 in the kidneys of ACR-intoxicated rats. In conclusion, APO, UMB, and their combination prevented ACR-induced nephrotoxicity in rats by attenuating oxidative injury and inflammation, suppressing NLRP-3 inflammasome signaling, enhancing antioxidants, and upregulating Nrf-2 and HO-1 in the kidneys of ACR-induced rats.

Nephrotoxicity is the most common adverse effect of gentamicin (GNT). This study aimed to investigate the possible nephroprotective effect of umbelliferone (UMB), against GNT-induced nephrotoxicity. Rats were allocated into the control group; UMB group (50 mg/kg/day, P.O. for 15 days); GNT group (100 mg/kg/day, i.p., for 8 days); and GNT + UMB group. By the end of the experimental period, serum creatinine, urea, and uric acid as well as urine KIM-1 and urine albumin/creatinine ratio were evaluated to estimate kidney function. Moreover, tissue samples were collected for assessment of ERK1/2, p-ERK1/2, TLR-4, p38 MAPK, NF-κB-p65, NLRP-3, IkBα, TNF-α, IL-1β, JAK1, STAT-3, p-STAT, and cleaved caspase-3. In support, the histopathological examination of renal tissues was performed. UMB improves kidney function through regulation of renal serum biomarkers, with alleviations of histological abrasions induced by GNT. Besides, UMB downregulates renal protein expressions of ERK1/ERK2, TLR-4, and p38MAPK, with subsequent suppression of NF-κB-p65/NLRP-3 inflammasome and JAK1/STAT-3 pathways as well as cleaved caspase-3. In parallel, UMB induced IkBα upregulation. Collectively, UMB markedly amended all GNT-induced renal changes. These nephroprotective outcomes could be attributed to its ability to impede TLR-4/NF-κB-p65/NLRP-3 inflammasome and JAK1/STAT-3 pathways activation, as well as to its anti-inflammatory property.

Abstract Pain is a normal response of the central nervous system to trauma, infections, neoplasms, neuropathies, and inflammation. It can arise from physical, emotional, or cognitive conditions, and is classified as orofacial pain when it affects the mouth and face. Umbelliferone, a coumarin from the umbelliferous plant family, is an important component of essential oils, and possesses antioxidant, curative, anti-inflammatory, and anti-tumor activity. The aim of this study was to investigate the orofacial antinociceptive and anti-inflammatory effects of umbelliferone in Swiss male mice Mus musculus, at 3 months of age. Test groups received different doses of umbelliferone (25, 50, or 75 mg/kg, i.p.). The negative control received 0.9% sodium chloride and Tween 80, with the positive control receiving morphine (5 mg/kg, i.p.) or dexamethasone (2 mg/kg, s.c.). We observed a significant reduction in acetic acid-induced abdominal writhing (p<0.001), and a decrease in paw licking in the orofacial nociception test with formalin (p < 0.01). The 50 and 75 mg/kg doses of umbelliferone presented significant reductions in the glutamate (p<0.01) and capsaicin (p<0.01) tests, suggesting activity on glutamatergic receptors and TRPV1. In the carrageenan-induced paw edema test (1%), there was a decrease in limb volume over 240 minutes (p<0.01), suggesting inhibition of the inflammatory process. There was also a reduction in leukocyte count (p<0.001) and TNF-α levels (p<0.001) when compared to the control group, being similar to the animals treated with dexamethasone (p<0.001). It was concluded that umbelliferone exhibits orofacial antinociceptive activity and anti-inflammatory activity via TNF-α. However, further preclinical studies are needed for a better characterization. Resumo A dor é uma resposta do sistema nervoso central contra traumas, infecções, neoplasias, neuropatias e inflamação. Ela decorre de condições físicas, emocionais e cognitivas, sendo classificada como orofacial quando afeta boca e face. A umbeliferona, cumarina encontrada em plantas da família das umbelíferas, é componente importante de óleos essenciais, possuindo atividade antioxidante, cicatrizante, anti-inflamatória e anti-tumoral. O objetivo deste estudo foi investigar o efeito antinociceptivo e anti-inflamatório orofacial da umbeliferona em camundongos Mus musculus machos, linhagem Swiss, com 3 meses de idade. Os grupos-teste receberam diferentes doses de umbeliferona (25, 50 ou 75 mg/kg, i.p.), o controle negativo recebeu cloreto de sódio 0,9% e Tween 80, e o controle positivo recebeu morfina (5 mg/kg, i.p.) ou dexametasona (2 mg/kg, s.c.). Observou-se redução significativa nas contorções abdominais induzidas pelo ácido acético (p<0,001) e diminuição na fricção das patas no teste de nocicepção orofacial com formalina (p < 0,01). Ademais, doses de 50 e 75 mg/kg de umbeliferona mostraram redução significativa nos testes com glutamato (p<0,01) e capsaicina (p<0,01), sugerindo ação nos receptores glutamatérgicos e TRPV1. No teste de edema de pata induzido por carragenina 1%, houve diminuição no volume do membro ao longo de 240 minutos (p<0,01), sugerindo inibição do processo inflamatório. Também observou-se redução na contagem de leucócitos (p<0,001) e na dosagem de TNF-α (p<0,001) em relação ao grupo controle, semelhante aos animais tratados com dexametasona (p<0,001). Conclui-se que a umbeliferona apresenta atividade antinociceptiva orofacial e atividade anti-inflamatória via TNF-α, mas são necessários mais estudos pré-clínicos para melhor caracterização da substância.

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.