Umbelliferone Treatment Research Articles

Umbelliferone reduces inflammation and ligature-induced osteoclastic alveolar bone resorption in mice.

This study aimed to investigate the effects of Umbelliferone (UMB) on the inflammation underlying alveolar bone resorption in mouse periodontitis. Male Swiss mice subjected to a ligature of molars were grouped as non-treated (NT), received UMB (15, 45, or 135 mg/kg) or saline daily for 7 days, respectively, and were compared with naïve mice as control. Gingival tissues were evaluated by myeloperoxidase (MPO) activity and interleukin-1β level by ELISA. The bone resorption was directly assessed on the region between the cement-enamel junction and the alveolar bone crest. Microscopically, histomorphometry of the furcation region, immunofluorescence for nuclear factor-kappa B (NF-ĸB), and immunohistochemistry for tartrate-resistant acid phosphatase (TRAP), and cathepsin K (CTSK) were performed. Systemically, body mass variation and leukogram were analyzed. Periodontitis significantly increased MPO activity, interleukin-1β level, and NF-ĸB+ immunofluorescence, and induced severe alveolar bone and furcation resorptions, besides increased TRAP+ and CTSK+ cells compared with naïve. UMB significantly prevented the inflammation by reducing MPO activity, interleukin-1β level, and NF-ĸB+ intensity, besides reduction of resorption of alveolar bone and furcation area, and TRAP+ and CTSK+ cells compared with the NT group. Periodontitis or UMB treatment did not affect the animals systemically. UMB improved periodontitis by reducing inflammation and bone markers.

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. Invitro, 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.

Umbelliferone Ameliorates Memory Impairment and Enhances Hippocampal Synaptic Plasticity in Scopolamine-Induced Rat Model.

Alzheimer's disease (AD) is a neurodegenerative disorder, characterized by memory loss and cognitive decline. Among the suggested pathogenic mechanisms of AD, the cholinergic hypothesis proposes that AD symptoms are a result of reduced synthesis of acetylcholine (ACh). A non-selective antagonist of the muscarinic ACh receptor, scopolamine (SCOP) induced cognitive impairment in rodents. Umbelliferone (UMB) is a Apiaceae-family-derived 7-hydeoxycoumarin known for its antioxidant, anti-tumor, anticancer, anti-inflammatory, antibacterial, antimicrobial, and antidiabetic properties. However, the effects of UMB on the electrophysiological and ultrastructure morphological aspects of learning and memory are still not well-established. Thus, we investigated the effect of UMB treatment on cognitive behaviors and used organotypic hippocampal slice cultures for long-term potentiation (LTP) and the hippocampal synaptic ultrastructure. A hippocampal tissue analysis revealed that UMB attenuated a SCOP-induced blockade of field excitatory post-synaptic potential (fEPSP) activity and ameliorated the impairment of LTP by the NMDA and AMPA receptor antagonists. UMB also enhanced the hippocampal synaptic vesicle density on the synaptic ultrastructure. Furthermore, behavioral tests on male SD rats (7-8 weeks old) using the Y-maze test, passive avoidance test (PA), and Morris water maze test (MWM) showed that UMB recovered learning and memory deficits by SCOP. These cognitive improvements were in association with the enhanced expression of BDNF, TrkB, and the pCREB/CREB ratio and the suppression of acetylcholinesterase activity. The current findings indicate that UMB may be an effective neuroprotective reagent applicable for improving learning and memory against AD.

Umbelliferone attenuates diabetic cardiomyopathy by suppression of JAK/STAT signaling pathway through amelioration of oxidative stress and inflammation in rats.

Umbelliferone (UMB), 7-hydroxycoumarin, is a naturally occurring coumarin derivative that has a plethora of biological and therapeutic activities. The focus of this research was to elucidate the curative effects of two different doses of UMBon diabetic cardiomyopathy (DCM) in a type 2 diabetic rat model induced by 50 mg/kg body weight of streptozotocin (STZ). Diabetic rats orally received 10 or 30 mg/kg of UMBdaily for 8 weeks. Compared to the nontreated diabetic group, both UMB treatment doses significantly decreased glucose levels, glycated hemoglobin (HbA1c), tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), creatine kinase MB (CK-MB), cardiovascular risk indices, and oxidative stress by reducing malondialdehyde (MDA) and increasing the activity of the antioxidant enzymes. The hypercholesterolemia and hypertriglyceridemia also dramatically decreased in diabetic groups with UMB treatments accompanied by an improvement in insulin, and insulin sensitivity indices (HOMA-IR and QUICKI). Furthermore, the cardiac gene expressions and protein levels of Janus kinase2 (JAK2), signal transducer and activator of transcription3 (STAT3), and transforming growth factor beta1 (TGF-β1) were also markedly downregulated in a dose-dependent manner by UMB treatments. Finally, the biochemical results were assured by the reduction of histological alterations in cardiac tissues. In conclusion, UMB is a propitious substance for the treatment of DCM by virtuousness of its antihyperglycemic, antihyperlipidemic, antioxidant, and anti-inflammatory properties through modulating the JAK/STAT signaling pathway that may be the underlying mechanism in UMB action.

Umbelliferone Ameliorates Hepatic Steatosis and Lipid-Induced ER Stress in High-Fat Diet-Induced Obese Mice.

Among the characteristics of non-alcoholic fatty liver disease (NAFLD), hepatic steatosis is due to excessive fat accumulation and causes liver damage and lipotoxicity, which are associated with insulin resistance, endoplasmic reticulum (ER) stress, and apoptosis. Umbelliferone (UMB) has various powerful pharmacological properties, such as antioxidant, anti-hyperglycemic, anti-viral, and anti-inflammatory effects. However, the mechanism of action in hepatic steatosis and lipid-induced ER stress is still unclear. Thus, the efficacy of UMB in hepatic steatosis and palmitate (PA)-induced hepatocellular lipotoxicity was evaluated in the present study. Male C57BL/6J mice (n=40) were divided into four groups: regular diet (RD), UMB-supplemented RD, high-fat diet (HFD), and UMB-supplemented HFD. All mice were fed orally for 12 weeks. In addition, the effects of UMB on lipotoxicity were investigated in AML12 cells treated with PA (250 µM) for 24 h; Western blot analysis was used to evaluate the changes in ER stress and apoptotic-associated proteins. Administration with UMB in HFD-fed mice reduced lipid accumulation and hepatic triglyceride (TG) as well as serum insulin and glucose levels. In AML12 cells, UMB treatment reduced lipid accumulation as indicated by decreases in the levels of lipogenesis markers, such as SREBP1, FAS, PPAR-γ, and ADRP. Furthermore, UMB reduced both oxidative stress and ER stress-related cellular apoptosis. UMB supplementation ameliorated hepatic steatosis and improved insulin resistance by inhibiting lipid accumulation and regulating ER stress. These findings strongly suggest that UMB may be a potential therapeutic compound against NAFLD.

Anti-allergic activities of Umbelliferone against histamine- and Picryl chloride-induced ear edema by targeting Nrf2/iNOS signaling in mice

BackgroundThe current study was aimed to investigate the anti-allergic activities of the Umbelliferone (UMB) against the acute Histamine and chronic Picryl chloride (PiCl)-induced allergy in mice. UMB is a coumarin derivative (isolated from Angelica decursiva) found in various parts of the plants such as flowers, roots and, stems isolated from the plants of Umbelliferae family.MethodsThe UMB (1, 10, 50 mg/kg) was administered intraperitoneally (i.p) half an h before or 2 h after the induction of allergic ear edema. The acute ear edema was induced by histamine (intradermally, i.d), while the chronic ear edema was induced by painting the PiCl (sensitized with the toluene) on the ear. The antioxidants and oxidative stress markers were assessed. The histological changes were assessed using Hematoxylin and eosin (H and E) and giemsa staining. The immunohistochemistry studies were performed to assess the expression of the nuclear factor erythroid 2-related factor 2 (Nrf2) and inducible nitric oxide synthase (iNOS). The data was analyzed using one-way ANOVA tests followed by Tukey’s test with p < 0.05 was chosen as criteria for statistical significance.ResultsUMB treatment markedly reduced the allergic ear edema and ear weight compared to the negative control. Furthermore, the UMB attenuated the oxidative stress markers, while induced the antioxidants enzymes. Similarly, the UMB treatment significantly attenuated the serum immunoglobulin E (IgE) level. The UMB treatment markedly improved the histological parameters using H and E staining and Giemsa staining. The UMB administration induced the Nrf2 expression, while attenuated the iNOS expression. Furthermore, the computational analysis was performed to assess the interaction of the UMB with the various protein targets and to determine the mechanism of interaction with the target proteins.ConclusionIn conclusion, the UMB treatment significantly alleviated the allergic symptoms, attenuating the oxidative stress, improved the histological features using in vivo and computational approaches.

Umbelliferone Ameliorates Benign Prostatic Hyperplasia by Inhibiting Cell Proliferation and G1/S Phase Cell Cycle Progression through Regulation of STAT3/E2F1 Axis.

Umbelliferone (UMB), also known as 7-hydroxycoumarin, is a derivative of coumarin, which is widely found in many plants such as carrots, coriander, and garden angelica. Although many studies have already revealed the various pharmacological properties of UMB, its effect on benign prostatic hyperplasia (BPH) remains unclear. Therefore, the present study aimed to elucidate the underlying mechanism of the anti-proliferative effect of UMB in a human benign prostatic hyperplasia cell line (BPH-1), as well as its ameliorative effect on BPH in testosterone propionate (TP)-induced rats. The results showed that UMB exerts an anti-proliferative effect in BPH-1 cells by modulating the signal transducer and activator of transcription 3 (STAT3)/E2F transcription factor 1 (E2F1) axis. UMB treatment not only inhibited androgen/androgen receptor (AR) signaling-related markers, but also downregulated the overexpression of G1/S phase cell cycle-related markers. In TP-induced rats, UMB administration demonstrated an anti-BPH effect by significantly reducing prostate size, weight, and epithelial thickness. In addition, UMB suppressed cell proliferation by reducing the expression of proliferating cell nuclear antigen (PCNA) and p-STAT3 (Tyr 705) in prostate tissue following TP injection. These findings suggest that UMB has pharmacological effects against BPH.

Nephroprotective effect of umbelliferone against cisplatin-induced kidney damage is mediated by regulation of NRF2, cytoglobin, SIRT1/FOXO-3, and NF- kB-p65 signaling pathways.

Cisplatin (Cis) is one of the most potent and effective broad-spectrum antitumor drugs, but its use is limited due to nephrotoxicity. The current study investigated the renoprotective effect of umbelliferone (UMB) on Cis-induced nephrotoxicity in rats. Renal injury was induced by a single injection of Cis (7 mg/kg, ip). Our results exhibited that the injection of Cis significantly disrupted renal function biomarkers as well as KIM-1 expression. The expressions of TNF-α, IL-1β, NF-kB-p65, and IKKβ were elevated along with downregulation of IkBα expression. Also, Cis disrupted cellular oxidant/antioxidant balance through the reduction of glutathione (GSH), glutathione-S-transferase (GST), and superoxide dismutase (SOD) levels and elevation of malondialdehyde (MDA) content. On the contrary, the levels of renal function biomarkers, cytokines, NF-kB-p65, IkBα, IKKβ, and oxidant/antioxidant status have been improved after UMB treatment. Mechanistically, rats administered Cis only exhibited a significant decrease in NRF2 and cytoglobin expressions as well as the CREB, SIRT1, FOXO-3, and PPAR-γ genes. Treatment with UMB significantly upregulated NRF2 and cytoglobin proteins, as well as effectively increased the expression of CREB, SIRT1, FOXO-3, PPAR-γ, and NRF2 genes. Histopathological findings strongly supported our biochemical results, as evidenced by attenuation of renal hemorrhage, cast diffusion, and inflammatory cell infiltration. Interestingly, UMB significantly enhanced Cis cytotoxicity in both HL-60 and HeLa cells in a dose-dependent manner. Together, our results demonstrated that UMB can protect against Cis-induced nephrotoxicity in normal rats along with the enhancement of its in vitro antitumor activity. These findings suggested that UMB could be used as a potential adjuvant therapy in Cis chemotherapeutic protocols.

Umbelliferone Ameliorates Complete Freund Adjuvant-Induced Arthritis via Reduction of NF-κB Signaling Pathway in Osteoclast Differentiation.

Osteoclasts, bone-resorbing somatic cells, are directly responsible for bone destruction during rheumatoid arthritis. Complete Freund adjuvant (CFA) is a widely used animal model using rodents for studying rheumatoid arthritis (RA), which effectively manifests serious cartilage destruction and progressive bone erosion, affecting synovial joints and serious joint dysfunction. It was considered that joint injury in RA is induced through systemic inflammation pathway. Umbelliferone (UF), a coumarin derivative of Agele marmilosa, possesses anti-inflammatory activity. In the current study, we scrutinize the effect of umbelliferone on CFA-induced arthritis model and explore the possible mechanism on bone destruction. Intradermal administration of CFA (0.05mL) was to induce RA manifestations in the experimental rats and the same oral administration of UF was received. The anti-arthritic activity of UF was determined by its inhibitory activity on various biochemical markers, viz., pro-inflammatory, inflammatory, antioxidant enzymes, and hematological parameters elevated during RA condition. We also estimated the mRNA expression of osteoclast parameters. Obtained result disclosed significant reduction in the paw edema and increment of the body weight after UF administration. UF reduce the inflammatory mediatory such as COX-2, PGE2, NF-kB, and VEGF; pro-inflammatory cytokines include TNF-α, IL-1β, IL-6, IL-10, and IL-17 significantly. Moreover, UF treatment significantly reduced the osteoclast number via modulating the RANKL/RANK/OPG ratio. Furthermore, administration of umbelliferone significantly (P< 0.001) suppressed the NF-κB and VEGF. Collectively, our results indicated the novel role of umbelliferone in osteoclastogenesis and proved that umbelliferone is a modern therapeutic tool as a natural agent for treating arthritis and other autoimmune disorders with bone degradation.

Short-term effects of the allelochemical umbelliferone on Triticum durum L. metabolism through GC–MS based untargeted metabolomics

The present study used untargeted metabolomics to investigate the short-term metabolic changes induced in wheat seedlings by the specialized metabolite umbelliferone, an allelochemical. We used 10 day-old wheat seedlings treated with 104 μM umbelliferone over a time course experiment covering 6 time points (0 h, 6 h, 12 h, 24 h, 48 h, and 96 h), and compared the metabolomic changes to control (mock-treated) plants. Using gas chromatography mass spectrometry (GCMS)-based metabolomics, we obtained quantitative data on 177 metabolites that were derivatized (either derivatized singly or multiple times) or not, representing 139 non-redundant (unique) metabolites. Of these 139 metabolites, 118 were associated with a unique Human Metabolome Database (HMDB) identifier, while 113 were associated with a Kyoto Encyclopedia of Genes and Genomes (KEGG) identifier. Relative quantification of these metabolites across the time-course of umbelliferone treatment revealed 22 compounds (sugars, fatty acids, secondary metabolites, organic acids, and amino acids) that changed significantly (repeated measures ANOVA, P-value < 0.05) over time. Using multivariate partial least squares discriminant analysis (PLS-DA), we showed the grouping of samples based on time-course across the control and umbelliferone-treated plants, whereas the metabolite-metabolite Pearson correlations revealed tightly formed clusters of umbelliferone-derived metabolites, fatty acids, amino acids, and carbohydrates. Also, the time-course umbelliferone treatment revealed that phospho-l-serine, maltose, and dehydroquinic acid were the top three metabolites showing highest importance in discrimination among the time-points. Overall, the biochemical changes converge towards a mechanistic explanation of the plant metabolic responses induced by umbelliferone. In particular, the perturbation of metabolites involved in tryptophan metabolism, as well as the imbalance of the shikimate pathways, which are strictly interconnected, were significantly altered by the treatment, suggesting a possible mechanism of action of this natural compound.

Umbelliferone modulates depression-like symptoms by altering monoamines in a rat post-traumatic stress disorder model.

Post-traumatic stress disorder (PTSD) is a debilitating psychological disease that is triggered by traumatic events. It is known to cause various complications, including anxiety and depression. Umbelliferone (UMB) is a natural product of the coumarin family. This substance has been reported to exert antioxidant, anti-inflammatory, neuroprotective, and other biological effects. We used the open field test (OFT) and the forced swimming test (FST) to examine the effects of UMB on depression-like symptoms in rats after exposure to a single prolonged stress (SPS), which led to dysregulated activation of the serotonergic system. Male rats were given UMB (20, 40, or 60mg/kg, intraperitoneal injection) once daily for 14days after exposure to an SPS. Daily UMB administration significantly improved depression-like behaviors on the FST, increased the number of lines crossed in the central zone of the OFT, and reduced freezing behavior in both contextual and cued fear conditioning. UMB treatment attenuated the SPS-induced decrease in serotonin (5-HT) concentrations in the hippocampus and amygdala. The increased 5-HT concentration during UMB treatment was partially due to a decrease in the ratio of 5-hydroxyindoleacetic acid/5-HT in the hippocampus of rats with PTSD. According to our results, UMB has an antidepressant effect in rats exposed to an SPS, suggesting that this natural product of the coumarin family can be used to effectively treat PTSD.

Umbelliferone Impedes Biofilm Formation and Virulence of Methicillin-Resistant Staphylococcus epidermidis via Impairment of Initial Attachment and Intercellular Adhesion.

Staphylococcus epidermidis is an opportunistic human pathogen, which is involved in numerous nosocomial and implant associated infections. Biofilm formation is one of the prime virulence factors of S. epidermidis that supports its colonization on biotic and abiotic surfaces. The global dissemination of three lineages of S. epidermidis superbugs highlights its clinical significance and the imperative need to combat its pathogenicity. Thus, in the current study, the antibiofilm activity of umbelliferone (UMB), a natural product of the coumarin family, was assessed against methicillin-resistant S. epidermidis (MRSE). UMB exhibited significant antibiofilm activity (83%) at 500 μg/ml concentration without growth alteration. Microscopic analysis corroborated the antibiofilm potential of UMB and unveiled its potential to impair intercellular adhesion, which was reflected in auto-aggregation and solid phase adherence assays. Furthermore, real time PCR analysis revealed the reduced expression of adhesion encoding genes (icaD, atlE, aap, bhp, ebh, sdrG, and sdrF). Down regulation of agrA and reduced production of secreted hydrolases upon UMB treatment were speculated to hinder invasive lifestyle of MRSE. Additionally, UMB hindered slime synthesis and biofilm matrix components, which were believed to augment antibiotic susceptibility. In vivo assays using Caenorhabditis elegans divulged the non-toxic nature of UMB and validated the antibiofilm, antivirulence, and antiadherence properties of UMB observed in in vitro assays. Thus, UMB impairs MRSE biofilm by turning down the initial attachment and intercellular adhesion. Altogether, the obtained results suggest the potent antibiofilm activity of UMB and the feasibility of using it in clinical settings for combating S. epidermidis infections.

The antitumor activity of umbelliferone in human renal cell carcinoma via regulation of the p110γ catalytic subunit of PI3Kγ.

Umbelliferone exhibits extensive pharmacological activity, including anti-immunomodulatory, anti-inflammatory and antigenotoxicity activities. However, its antitumor properties still remain unclear in human renal cell carcinoma (RCC) cells. Our results have revealed that treatment of human RCC cells (786-O, OS-RC-2, and ACHN) with umbelliferone reduced cell proliferation in a concentration-dependent manner and induced dose-dependent apoptotic events. In addition, cell cycle analysis determined that umbelliferone treatment induced cell cycle arrest in the G1 phase in a dose-dependent manner. Furthermore, western blotting analysis showed a dose-dependent decrease in Ki67, MCM2, Bcl-2, CDK2, CyclinE1, CDK4, and CyclinD1 and a dose-dependent increase in Bax in RCC cells cultured with umbelliferone. Similarly, umbelliferone exhibited a dose-dependent reduction of p110γ when using western blotting analyses. Taken together, these results provide an insight into the pharmacology regarding the potential application of umbelliferone, which contributes to cell death by decreasing p110γ protein expression.

The protective effect of umbelliferone ameliorates myocardial injury following ischemia‑reperfusion in the rat through suppression NLRP3 inflammasome and upregulating the PPAR-γ.

The present study investigated whether the protective effect of umbelliferone could regulate myocardial injury following ischemia‑reperfusion and improve mitochondrial respiratory function, thereby relieving myocardial injury following ischemia‑reperfusion in rats. In the present study, the extent of inflammation and oxidative stress were analyzed using ELISA. Western blot analysis was employed to investigate the protein expression levels of the PYD domains‑containing protein3 (NLRP3) inflammasome and peroxisome proliferator‑activated receptor-γ (PPAR‑γ). Compared with the myocardial injury following ischemia‑reperfusion group, umbelliferone significantly prevented myocardial injury, inhibited oxidative stress markers (superoxide dismutase and malondialdehyde), reduced inflammation (tumor necrosis factor‑α and interleukin‑6) and myocardial apoptosis levels (caspase‑3/9 and apoptosis regular B‑cell lymphoma‑2‑associated X protein) in the myocardial injury following ischemia‑reperfusion group of rats. Umbelliferone treatment also suppressed NACHT, LRR and NLRP3 inflammasome activation and induced PPAR‑γ expression. The results of the present study suggested that the protective effect of umbelliferone may ameliorate myocardial injury following ischemia‑reperfusion in the rat through the suppression of the NLRP3 inflammasome and upregulating PPAR‑γ expression.

Attenuation of renal damage in type I diabetic rats by umbelliferone - a coumarin derivative.

It is well known that diabetes is one of the non-communicable disease affecting a large population worldwide. When diabetes remains untreated or uncontrolled, it leads to further serious complications, affecting vital organs like eyes, kidney, heart, etc. The present study was designed to evaluate effects of umbelliferone, a phytochemical, in treatment of diabetic nephropathy. Experimental model used was streptozotocin (55mg/kg, ip) induced diabetic nephropathy in male Sprague Dawley rats. After 28days of streptozotocin administration, diabetic animals were treated with umbelliferone at two dose levels, 20 and 40mg/kg for next 28days. The results of the study showed that umbelliferone treatment significantly decreased the elevated plasma creatinine and blood urea nitrogen level while significantly increased the total protein and albumin level in diabetic animals. Creatinine clearance was improved in umbelliferone treated animals. Renal oxidative stress was decreased in umbelliferone treated animals significantly. Histopathological study of the kidney was carried out by specific stains like Hematoxylin-Eosin, Periodic Acid Schiff and Masson Trichrome stain. The sections of the kidney showed that umbelliferone treatment decreased the glomerular damage, mesangial matrix expansion as well as the renal fibrosis. Determination of renal transforming growth factor beta one (TGF-β1) expression by immunohistochemical analysis, western blotting and circulating TGF-β1 by ELISA assay showed that umbelliferone decreased the renal tissue and circulating TGF-β1 level. Umbelliferone treatment can significantly reduce the diabetes induced renal damage and can improve the pathological conditions related to the diabetic nephropathy by down regulation of TGF-β.

Umbelliferone stimulated melanogenesis and increased glutathione level in B16F10 cells

Umbelliferone (7-hydroxycoumarin) treatment caused an increase in melanin content in B16F10 melanoma cells in a dose-dependent manner, without causing toxicity. The increase in melanin content was correlated with increases in the activity of tyrosinase, the rate-limiting enzyme in melanin synthesis, and the expressions of melanogenic proteins, including tyrosinase, tyrosinase-related protein 1, and microphthalmia-associated transcription factor, the master transcriptional regulator for melanogenesis. Unlike α-melanocyte-stimulating hormone, umbelliferone did not cause melanogenesis-associated oxidation and depletion of glutathione. Conversely, umbelliferone treatment resulted in a significant and dose-dependent increase in glutathione. Umbelliferone caused activation of JNK, p38 MAPK, and GSK3β in a dose- dependent manner, suggesting possible involvement of those protein kinases in umbelliferone-induced stimulations of melanogenesis and antioxidant system. Our results suggest that umbelliferone stimulates both melanogenesis and antioxidant defense, providing more effective protection against UV-induced photodamage. They also imply possible applications of umbelliferone in self-tanning and treatment of skin disorders related with melanin deficiency.

Umbelliferone ameliorates cerebral ischemia–reperfusion injury via upregulating the PPAR gamma expression and suppressing TXNIP/NLRP3 inflammasome

Umbelliferone (UMB), a natural antioxidant belonging to coumarin derivatives, is able to cross the blood-brain barrier and protect neuronal cells from death. Here we aimed to investigate the effects of UMB in a rat model of focal cerebral ischemia induced by middle cerebral artery occlusion/reperfusion (MCAO/R). Pretreatment with UMB (15 and 30mg/kg) for 7 consecutive days ameliorated the neurological outcomes, infarct volume and brain edema in brains of MCAO rats. Our results provided evidence that UMB significantly protected neuronal cells against cerebral ischemia reperfusion-induced injury. Furthermore, UMB treatment could inhibited the level of oxidative stress and the production of inflammatory cytokines in brain tissues of MCAO rats. In addition, UMB significantly upregulated the expression of peroxisome proliferator-activated receptor-γ (PPAR-γ), which exhibited neuroprotective effects in neurodegenerative disease. UMB treatment also suppressed NLRP3 inflammasome activation via reducing expression of Thiredoxin-interactive protein (TXNIP). These results suggest that UMB may have beneficial effects for neuroprotection against focal cerebral ischemic partly through the inhibition of TXNIP/NLRP3 inflammasome and activation of PPAR-γ.

Umbelliferone exhibits anticancer activity via the induction of apoptosis and cell cycle arrest in HepG2 hepatocellular carcinoma cells.

Hepatocellular carcinoma (HCC) is a highly malignant tumor, associated with poor patient prognoses, and high rates of morbidity and mortality. To date, the therapeutic strategies available for the treatment of HCC remain limited. The present study aimed to elucidate the anticancer activity of umbelliferone, a naturally occurring coumarin derivative isolated from Ferula communis, against the HepG2 HCC cell line. A 3‑(4,5‑dimthylthaizol‑2‑yl)‑2,5, diphenyltetrazolium bromide assay was used to evaluate cell viability following umbelliferone treatment, and the effects of umbelliferone on cell cycle progression and apoptosis were evaluated using flow cytometry. The presence of morphological features characteristic of apoptosis, including cell shrinkage, membrane blebbing, nuclear condensation and apoptotic body formation, were evaluated in HepG2 cells following umbelliferone treatment. Cell cycle analysis conducted via propidium iodide (PI) staining indicated that umbelliferone treatment induced cell cycle arrest at S phase in HepG2 cells. Analysis with Annexin V and PI staining revealed that umbelliferone induced apoptotic events in HepG2 cells in a concentration‑dependant manner (0‑50 µM). Umbelliferone also induced dose‑dependant DNA fragmentation. In conclusion, umbelliferone was found to exhibit significant anticancer effects via the induction of apoptosis, cell cycle arrest and DNA fragmentation in HepG2 cancer cells.

Umbelliferone increases the expression of adipocyte-specific genes in 3T3-L1 adipocyte.

Umbelliferone (UMB), a natural product of coumarin family, has been shown to reduce blood glucose and to improve lipid profiles in streptozotocin (STZ)-induced diabetic rats. Our objective was to examine the effect of UMB on adipogenesis by investigating its stimulatory effect on lipid accumulation and mRNA expression of adipogenic transcription factors and adipocyte-specific genes in 3 T3-L1 preadipocyte culture. An Oil Red O staining was used to monitor lipid accumulation, and we found that UMB treatment at concentration range of 10-100 μM significantly increased lipid accumulation of differentiating 3 T3-L1 cells. At the molecular level of adipogenesis, we examined the mRNA expression of adipogenic transcription factors, peroxisome proliferator-activated receptor γ, CCAAT/enhancer-binding protein α, and sterol regulatory element-binding protein 1c. Those transcription factors were increased by UMB at 10-100 μM. Interestingly, UMB also stimulated the mRNA expression of adipocyte-specific genes, adipocyte fatty acid-binding protein, lipoprotein lipase, fatty acid synthase, fatty acid translocase, and adiponectin. Our findings indicate that the stimulatory effect of UMB on adipocyte differentiation likely occurs through up-regulation of adipogenic transcription factors and downstream adipocyte-specific gene expression.

Effects of umbelliferone on lipid peroxidation and antioxidant status in diethylnitrosamine-induced hepatocellular carcinoma

Hepatocellular carcinoma (HCC) represents a major source of global mortality, still rising in worldwide. The present study aims at elucidating the antioxidant efficiency of umbelliferone (UMB) in N-Nitrosodiethylamine (DEN) induced rat liver carcinogenesis. Rats were randomly divided into six groups of six rats each as follows. Rats are in group I received standard pellet diet and served as control, group II rats were induced with hepatocellular carcinoma by providing 0.01 % DEN through drinking water 15 weeks. Group III rats received umbelliferone via intragastric intubation at a daily dose of 30 mg/kg body weight for 16 weeks every day. Groups IV–VI rats received 0.01% of DEN as in group II along with umbelliferone via intragastric intubation at a daily dose of 10, 20 and 30 mg/kg body weight for throughout the experimental period of 16 weeks. DEN induction in experimental animals resulted in increased activities of liver marker enzymes and lipid peroxidation levels and decreased levels of antioxidant enzymes. Umbelliferone treatment restored the elevated activities of liver marker enzymes and antioxidant status to near-normal with decreased lipid peroxidation levels. Histological observations of liver tissue too correlated with the above biochemical findings. These results clearly suggest that umbelliferone treatment prevents liver damage, lipid peroxidation and protects the antioxidant defense system in DEN-induced liver carcinogenesis in rats.