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Objectives: The hepatoprotective properties of scopoletin have been explored in carbon tetrachloride (CCl4) induced liver injury but not in drug-induced liver injury (DILI) scenarios. Only N-acetyl-cysteine (NAC) has proven efficacy in DILI treatment. Accordingly, we conducted a study to assess the hepatoprotective action of scopoletin in the anti-tubercular treatment (ATT)-DILI model in Wistar rats, if any., Methods: A total of 36 rats were evaluated, with six in each group. A 36-day ATT at 100 mg/kg dose for isoniazid, 300 mg/kg for rifampicin and 700 mg/kg for pyrazinamide were fed to induce hepatotoxicity in rats. Group I and II-VI received normal saline and ATT, respectively. Oral scopoletin (1,5 and 10 mg/kg) and NAC 150 mg/kg were administered in groups III, IV, V and VI, respectively, once daily for the last 15 days of the experiment. LFT monitoring was performed at baseline, days 21, 28, and 36. Rats were sacrificed for the histopathology examination., Results: Aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP) and bilirubin levels were significantly increased in group II (receiving ATT) compared to normal control on day 28 and day 36 (p<0.05). All three doses of scopoletin and NAC groups led to the resolution of AST, ALT, ALP, and bilirubin changes induced by ATT medications effect beginning by day 28 and persisting on day 36 (p<0.01). An insignificant effect was observed on albumin and total protein levels. The effect was confirmed with antioxidants and histopathology analysis., Conclusions: The study confirms the hepatoprotective efficacy of scopoletin in a more robust commonly encountered liver injury etiology., (© 2023 Walter de Gruyter GmbH, Berlin/Boston.)

Chronic diseases are considered a major public health concern worldwide, and most of these diseases like cancer, cardiovascular, metabolic, and neurological disorders occur due to atypical regulation of multiple signaling pathways. It has also been observed that most of the currently approved therapies for these diseases fail to show prolonged efficacy due to their mono-targeted nature and are associated with the development of chemoresistance, thus restricting their utility. The plant-derived compounds, on the other hand, show multi-targeted nature, and thus these phytochemicals have gained wide attention as they offer negligible side effects. The present review aims to recapitulate the potential effects of one such phytochemical, Scopoletin, which was found to have a diverse range of pharmacological activities such as anti-cancer, anti-diabetic, anti-inflammatory, cardioprotective, hepatoprotective, etc. Scopoletin modulated multiple molecular signatures in cancer, including AMPK, EGFR, MAPK/ ERK, NF-κB, PI3K/Akt/ mTOR, and STAT3; regulated the levels of critical markers of metabolic diseases such as ALT, AST, TG, and TC; inflammatory diseases such as ILs and TNFs; neurological diseases such as AChE, etc. thus relieving the symptoms and severity associated with these diseases. Further, this compound has a non-toxic nature and possesses an excellent pharmacokinetic property, which warrants further investigation in clinical settings for developing it as a potential drug., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Alzheimer's disease (AD) is one of the most prevalent diseases with rapidly increasing numbers, but there is still no medication to treat or stop the disease. Previous data on coumarins suggests that scopoletin may have potential benefits in AD., Objective: Evaluate the therapeutic potential of the coumarins with natural origin - scopoletin and pteryxin- in a 5xFAD mouse model of AD., Methods: Both compounds were administered at two doses to 12-month-old mice, which represent severe AD pathology. The effects of coumarins were assessed on cognition in mouse experiments. Changes in the overall brain proteome were evaluated using LCMS/ MS analyses., Results: The Morris water maze test implicated that a higher dose of pteryxin (16 mg/kg) significantly improved learning, and the proteome analysis showed pronounced changes of specific proteins upon pteryxin administration. The amyloid-β precursor protein, glial fibrillary acid protein, and apolipoprotein E protein which are highly associated with AD, were among the differentially expressed proteins at the higher dose of the pteryxin., Conclusion: Overall, pteryxin may be evaluated further as a disease-modifying agent in AD pathology in the late stages of AD., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Nephrotoxicity is an indication for the damage of kidney-specific detoxification and excretion mechanisms by exogenous or endogenous toxicants. Exposure to vancomycin predominantly results in renal damage and losing the control of body homeostasis. Vancomycin-treated rats (200 mg/kg/once daily, for seven consecutive days, i.p.) revealed significant increase in serum pivotal kidney function, oxidative stress, and inflammatory biomarkers. Histologically, vancomycin showed diffuse acute tubular necrosis, denudation of epithelium and infiltration of inflammatory cells in the lining tubular epithelium in cortical portion. In the existing study, the conservative consequences of scopoletin against vancomycin nephrotoxicity was investigated centering on its capacity to alleviate oxidative strain and inflammation through streamlining nuclear factor (erythroid-derived-2) like 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling and prohibiting the nuclear factor kappa B (NF-κB)/mitogen-activated protein kinase (p38 MAPK) pathway. With respect to vancomycin group, scopoletin pretreatment (50 mg/kg/once daily, i.p.) efficiently reduced kidney function, oxidative stress biomarkers and inflammatory mediators. Moreover, histological and immunohistochemical examination of scopoletin-treated group showed remarkable improvement in histological structure and reduced vancomycin-induced renal expression of iNOS, NF-κB and p38 MAPK. In addition, scopoletin downregulated (Kelch Like ECH Associated Protein1) Keap1, P38MAPK and NF-κB expression levels while upregulated renal expression levels of regulatory protein (IκBα), Nrf2 and HO-1. Furthermore, molecular docking and network approach were constructed to study the prospect interaction between scopoletin and the targeted proteins that streamline oxidative stress and inflammatory pathways. The present investigations elucidated that scopoletin co-treatment with vancomycin may be a rational curative protocol for mitigation of vancomycin-induced renal intoxication., (Copyright © 2021. Published by Elsevier B.V.)

Parkinson's disease (PD) is a neuromotor disorder, primarily manifested by motor anomalies due to progressive loss of dopaminergic neurons. Although alterations in genetic factors have been linked with its etiology, exponential accumulation of environmental entities such as reactive oxygen species (ROS) initiate a cyclic chain reaction resulting in accumulation of cellular inclusions, dysfunctional mitochondria, and overwhelming of antioxidant machinery, thus accelerating disease pathogenesis. Involvement of oxidative stress in PD is further substantiated through ROS induced Parkinsonian models and elevated oxidative markers in clinical PD samples; thereby, making modulation of neuronal oxidative load as one of the major approaches in management of PD. Here we have found a potent antioxidant moiety Scopoletin (Sp), a common derivative in most of the nootropic herbs, with robust neuroprotective ability. Sp increased cellular resistance to ROS through efficient recycling of GSH to prevent oxidative damage. The Sp treated cells showed higher loads of reduced glutathione making them resistant to perturbation of antioxidant machinery or neurotoxin MPP + . Sp could restore the redox balance, mitochondrial function, and prevented oxidative damage, leading to recovery of dopaminergic neural networks and motion abilities in Drosophila genetic model of PD. Our data also suggest that Sp, in combination increases the therapeutic potency of L-DOPA by mitigating its chronic toxicity. Together, we highlight the possible ability of Sp in preventing oxidative stress mediated loss of dopaminergic neurons and at the same time enhance the efficacy of dopamine recharging regimens.

Immature dendritic cells (iDCs) play very important roles in the pathological process of rheumatoid arthritis (RA). Therefore, it is urgent to search for natural products with antiproliferative activity on iDCs for anti-RA drug discovery. Erycibe schmidtii , a traditional Chinese medicine, has been used to treat RA in China. Its bioactive ingredients on RA are still unclear. In this study, twenty compounds including a new caffeoylquinic acid derivative, 3- O -caffeoyl-4- O -syringoylquinic acid methyl ester ( 16 ), were isolated from E. schmidtii . Their structures were elucidated by NMR and mass spectroscopic analysis, and comparison with literature data. Seventeen compounds were obtained from this plant for the first time, and ten were first found from the genus Erycibe . Scopoletin ( 1 , 5.0  μ M) functionally reduced proliferation level of bone marrow immature dendritic cells (BM-iDCs) more than 50%, relative to vehicle. However, scopoletin ( 1 ) exhibited no effect on the phagocytosis or survival of BM-iDCs in vitro .

Scopoletin (Sco) has great potential for hyperuricemia therapy. However, the relatively low oral bioavailability of Sco limits its further applications. Soluplus-based Sco micelles (Sco-Ms) were successfully prepared in our previous work. The oral bioavailability of Sco-Ms was increased by 438% compared with free Sco. In this study, we aimed to compare the biodistribution and antihyperuricemic efficacy of Sco and Sco-Ms, and explore their therapeutic mechanisms as well. We studied the tissue biodistribution of Sco and Sco-Ms after they were orally administered to mice. The antihyperuricemic effect and the therapeutic mechanisms of Sco and Sco-Ms were evaluated using yeast extract/potassium oxonate-induced hyperuricemia model in mice. The Sco concentration in each tissue was significantly higher than that of Sco suspension after orally administrating Sco-Ms to mice. Oral delivery of Sco-Ms exhibited significantly stronger hypouricemic efficacy in hyperuricemic mice than Sco. Meanwhile, Sco-Ms showed a better protective effect on mice kidney injury. The hypouricemic efficacy of Sco was due to promoting the excretion of uric acid via modulating the alteration of gene expression levels of renal uric acid transporter (URAT1), glucose transporter (GLUT9), and organic anion transporter 1 (OAT1). Sco-Ms could not only restore the dysregulation of URAT1, GLUT9, and OAT1 more effectively, but also down-regulate the activity of hepatic xanthine oxidase (XOD) to inhibit the production of uric acid. In conclusion, taken together, Sco-Ms represents a potential oral strategy for the treatment of hyperuricemia.

A series of phenylsulfonyfuroxan-based NO-releasing scopoletin derivatives were designed and synthesized in the study. All target compounds showed significantly improved antiproliferative activity against four cancer cell lines (MDA-MB-231, MCF-7, HepG2 and A459) and lower cytotoxicity toward normal liver LO2 cells. Derivative 47 concentration-dependently inhibited the colony formation of MDA-MB-231 cells. NO-releasing assessment indicated that the intracellular NO level was almost positively correlated with the antiproliferative ability. Compound 47, which released the highest amounts of NO, showed the best potency (IC 50  = 1.23 μM) against MDA-MB-231 cells. Mechanism research revealed for the first time that 47 blocked the proliferation of MDA-MB-231 cells by activating mitochondrial apoptosis pathway and arresting cell cycle at G2/M phase. Taken together, as a novel scopoletin derivative, 47 exhibited excellent inhibitory effects against malignant cancer cells and lower toxicity on normal cells. Thus, an in-depth evaluation of 47 to explore its complete therapeutic potential for cancer treatment is warranted., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Anxiety disorder is highly prevalent worldwide and represents a chronic and functionally disabling condition, with high levels of psychological stress characterized by cognitive and physiological symptoms. Scopoletin (SP), a main active compound in Angelica dahurica, is traditionally used for the treatment of headache, rhinitis, pain, and other conditions. Here, we evaluated the effects of SP in a mouse model of complete Freund's adjuvant (CFA)-induced chronic inflammation anxiety. SP (2.0, 10.0, 50.0 mg/kg) administration for 2 weeks dose-dependently ameliorated CFA-induced anxiety-like behaviors in the open field test and elevated plus maze test. Moreover, we found that SP treatment inhibited microglia activation and decreased both peripheral and central IL-1β, IL-6, and TNF-α levels in a dose-dependent manner. Additionally, the imbalance in excitatory/inhibitory receptors and neurotransmitters in the basolateral nucleus after CFA injection was also modulated by SP administration. Our findings indicate that the inhibition of the nuclear factor-kappa B and mitogen-activated protein kinase signaling pathways involving anti-inflammatory activities and regulation of the excitatory/inhibitory balance can be attributed to the anxiolytic effects of SP. Moreover, our molecular docking analyses show that SP also has good affinity for gamma-aminobutyric acid (GABA) transaminase and GABA A receptors. Therefore, these results suggest that SP could be a candidate compound for anxiolytic therapy and for use as a structural base for developing new drugs.

Background: Scopoletin (SPT) is known to exert neuroprotective autophagy effect. However, the efficacy of SPT in the treatment of spinal cord injury (SCI) has yet not been explored. The investigation was intended to elucidate whether SPT can exert neuroprotective effect by triggering neuronal autophagy after SCI. The study was also directed to investigate the role of adenosine monophosphate-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) signaling pathway in the autophagy facilitated by SPT., Materials and Methods: The SCI was developed in female Sprague-Dawley rats by damaging the T10 spinal level using an impounder impact. Three animals groups were investigated - Sham group, SCI group, and SCI + SPT group. The SCI + SPT group was administered with SPT (100 mg/kg) intraperitoneally. Basso, Beattie, and Bresnahan scores and angle of incline test revealed that SPT administration improved the movement of hind limbs after SCI induction., Results: Results indicated that SPT imparted neuronal protection, alleviated neuronal apoptosis, and improved neuronal autophagy. SPT-induced autophagy was identified by increased Beclin-1 expression and LC3B-positive neuronal cells. Further investigations revealed that SPT triggers the pathway involving AMPK/mTOR signaling, thereby stimulating autophagy in SCI-induced rat model., Conclusion: The findings of the present investigation strongly advocate the beneficial effects of SPT in the treatment of the SCI. SPT ameliorates the AMPK/mTOR signaling-induced autophagy and thereby improves functional recovery in SCI-induced rats., (© 2020 S. Karger AG, Basel.)

Purpose: Cervical cancer causes considerable mortality in women world over and the current treatment options create severe adverse effects. Hence, there is an urgent need to develop novel and efficient treatment regimens for cervical cancer. Herein, we examined the anticancer effects of a natural coumarin, Scopoletin, against a panel of cervical cancer cell lines., Methods: The antiproliferative effect of Scopoletin was examined by cell counting and colony formation assays. Apoptosis was detected by acridine orange (AO) ethidium promide (EB) staining. Cell cycle distribution was determined by flow cytometry. Cell invasion was examined by Boyden chamber assay. Protein expression was checked by western blotting., Results: Scopoletin inhibited the growth of all the cell lines and the IC50 ranged between 7.5 to 25 µM. Nonetheless, the cytotoxic effects of Scopoletin were comparatively negligible against the normal cells with an IC50 of 90 µM. Investigation of the mechanism of action, revealed that the anticancer effects of Scopoletin against the HeLa cervical cancer cells were due to induction of apoptotic cell death as indicated AO/EB staining. Scopoletin treatment also resulted in enhancement of the Bax, Caspase 3, 8 and 9 expression and decline of the Bcl-2 expression. Scopoletin also blocked the HeLa cells at G2/M checkpoint of the cell cycle. Furthermore, cell invasion assay revealed that Scopoletin inhibited the migration of the HeLa cells concentration-dependently. PI3K/AKT is an imperative pathway involved in theproliferation and tumorigenesis of cancer cells and herein it was found that Scopoletin could inhibit this pathway., Conclusion: Taken together, Scopoletin may prove essential in the development of novel treatment regimes for cervical cancer.

Hypertension is a disease of high prevalence and morbidity where vascular inflammation and associated oxidative stress (endothelial dysfunction) is the underlying cause of this pathology. We are reporting the antihypertensive activity of extracts and fractions of Malva parviflora in mice with chronic and acute hypertension. Also, the treatments of this plant were able to counteract the kidney inflammation and associated oxidative stress. The chronic hypertension model consisted of administration of angiotensin II (AGII) during 12 weeks, causing a sustained increase in systolic (SBP) or diastolic (DBP) pressure, with values of pharmacological constants of: ED 50  = 0.038 mg/kg y E max  = 135 mmHg for SBP and ED 50  = 0.046 mg/kg y E max  = 98 mmHg for DBP. The chronic hypertension caused the inflammation and lipid peroxidation in kidneys, measured by of tissue level of cytokines such as interleukin-1β (IL-1β), IL-6, Tumor Necrosis Factor-α (TNF-α), IL-10 and malondialdehyde, and treatments for M. parviflora were able to modulate these parameters. The chemical fractionation allowed to identify three compounds: oleanolic acid, tiliroside and scopoletin, which were tested in a model of acute hypertension. The pharmacodynamic parameters for SBP were ED 50  = 0.01 and 0.12 mg/kg while E max  = 33.22 and 37.74 mmHg for scopoletin and tiliroside, respectively; whereas that for DBP data were ED 50  = 0.01 and 0.02 mg/kg; with an E max  = 7.00 and 6.24 mmHg, in the same order. M. parviflora, is able to counteract the effect of chronic and acute administration of AGII, on hypertension, but also the inflammatory and oxidative damage in the kidney. The oleanolic acid, scopoletin and tiliroside are the compounds responsible for such activities.

The aim of this study was to investigate whether scopoletin could inhibit the activities of the carbohydrate digestive enzymes, α-glucosidase and α-amylase, and reduce postprandial hyperglycemia in streptozotocin (STZ)-induced diabetes in mice. Scopoletin showed a distinct inhibitory effect on α-glucosidase and α-amylase. The half maximal inhibitory concentration (IC 50 ) of scopoletin was 85.12 and 37.36 μM for α-glucosidase and α-amylase, respectively, which were lower values than those for acarbose. The increase in postprandial blood glucose levels was significantly suppressed in the scopoletin group compared to the control group of STZ-induced diabetes in mice. Moreover, the area under the curve significantly decreased with the administration of scopoletin in STZ-induced diabetes in mice. These results showed that scopoletin might help to lower postprandial hyperglycemia through inhibition of carbohydrate digestive enzymes., (Copyright © 2018 Elsevier B.V. All rights reserved.)

In an earlier report, we demonstrated an antipsychotic-like activity of a methanolic extract of Morinda citrifolia Linn fruit in mouse models and postulated the contribution of its bioactive principles, scopoletin and rutin. Moreover, the antidopaminergic activities of scopoletin and rutin were reported in isolated vas deferens preparations. In the present study, scopoletin and rutin were assessed for antipsychotic-like activity using apomorphine-induced climbing behavior and methamphetamine-induced stereotypy in mice. The results of this study revealed that scopoletin and rutin (0.05, 0.1, 0.5, and 1 mg/kg, p.o.) had a "U-shaped" dose-dependent effect on climbing and stereotyped behaviors induced by apomorphine and methamphetamine, respectively, in mice. A significant reduction in climbing and stereotyped behaviors caused by scopoletin and rutin was observed only at a dose 0.1 mg/kg. This study suggests that scopoletin and rutin can alleviate positive symptoms of schizophrenia only at a specific dose. Further studies evaluating the effects of scopoletin and rutin on animal models for negative symptoms of schizophrenia are required for a novel drug discovery in the treatment of neuropsychiatric diseases.

Atherosclerosis was previously thought to be a disease that primarily involves lipid accumulation in the arterial wall. In this report, we investigated the effect of Viola mandshurica W. Becker (V. mandshurica) water extract on atherosclerosis in apolipoprotein E deficient (ApoE[Formula: see text]) mice. The administration of V. mandshurica to high-fat diet-fed mice reduced body weight, liver weight, and serum levels of lipids (total cholesterol, low-density lipoprotein-cholesterol, triglycerides), glucose, alanine transaminase, and aspartate transaminase. Histopathologic analyses of the aorta and liver revealed that V. mandshurica attenuated atherosclerotic lesions and reduced lipid accumulation, inflammatory responses and fatty acid synthesis. V. mandshurica also increased phosphorylation of adenosine monophosphate-activated protein kinase (AMPK), thereby reducing acetyl-CoA carboxylase (ACC) in liver tissue and inhibiting sterol regulatory element-binding protein 1c (SREBP-1c). V. mandshurica reduced protein expression levels of adhesion molecules (intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and E-selectin) as well as ACC, fatty acid synthase, and SREBP-1c. In addition, quantitative analysis of V. mandshurica by high-performance liquid chromatography revealed the presence of esculetin and scopoletin. Esculetin and scopoletin reduced adhesion molecules in human aortic smooth muscle cells. Our results indicate that the anti-atherosclerotic effects of V. mandshurica may be associated with activation of the AMPK pathway. Therefore, AMPK-dependent phosphorylation of SREBP-1c by V. mandshurica may be an effective therapeutic strategy for combatting atherosclerosis and hepatic steatosis.

Alzheimer's disease, one of the most common forms of dementia, is a progressive neurodegenerative disorder symptomatically characterized by declines in memory and cognitive abilities. To date, the successful therapeutic strategy to treat AD is maintaining levels of acetylcholine by inhibiting acetylcholinesterase (AChE). In the present study, coumarin derivatives were designed and synthesized as AChE inhibitors based on the lead structure of scopoletin. Of those synthesized, pyrrolidine-substituted coumarins 3b and 3f showed ca. 160-fold higher AChE inhibitory activities than scopoletin. These compounds also ameliorated scopolamine-induced memory deficit in mice when administered orally at the dose of 1 and 2 mg/kg., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: Traditional preparations of the root of Biebersteinia multifida DC (Geraniaceae), a native medicinal plant of Irano-Turanian floristic region, have been used for the treatment of phobias as anxiolytic herbal preparation., Methods: We utilized the phobic behavior of mice in an elevated plus-maze as a model to evaluate the anxiolytic effect of the plant extract and bio-guided fractionation was applied to isolate the active compounds. Total root extract, alkaline and ether fraction were administered to mice at different doses 30 and 90 min prior to the maze test. Saline and diazepam were administered as negative and positive controls, respectively. The time spent in open and closed arms, an index of anxiety behavior and entry time, was measured as an index of animal activity., Results: The total root extract exhibited anxiolytic effect which was comparable to diazepam but with longer duration. This sustained effect of the crude extract was sustained for 90 min and was even more after injection of 45 mg/kg while the effect of diazepam had been reduced by 90 min. The anxiolytic effect factor was only present in the alkaline fraction and displayed its effect at lower doses than diazepam while pure vasicinone as the previously known alkaloid did not shown anxiolytic effect. The effect of the alkaline fraction was in a dose dependent manner starting at 0.2 mg/kg with a maximum at 1.0 mg/kg. Bio-guided fractionation using a variety of chromatographic methods led to isolation and purification of three coumarin derivatives from the bioactive fraction, including umbelliferone, scopoletin, and ferulic acid., Conclusion: For the first time, bio-guided fractionation of the root extract of B. multifida indicates significant sustained anxiolytic effects which led to isolation of three coumarin derivatives with well-known potent MAO inhibitory and anti-anxiety effects. These data contribute to evidence-based traditional use of B. multifida root for anxiety disorders.

Ethnopharmacological Relevance: Sphaeralcea angustifolia Cavanilles & Don (Malvaceae), known in Mexico as "Vara de San José", is used in Mexican Traditional Medicine as an anti-inflammatory and, more specifically, for treating rheumatism. Anti-inflammatory properties have been demonstrated in different pharmacological models., Aim of the Study: The therapeutic effectiveness and tolerability of the topical administration of a gel elaborated with a standardized Sphaeralcea angustifolia extract applied to patients with Hand osteoarthritis (HOA) was evaluated., Materials and Methods: A pharmaceutical formulation in a gel presentation that contained a standardized extract (hydroxycoumarin content) of Sphaeralcea angustifolia was elaborated and later evaluated in a double-blind, randomized study controlled with a similar formulation containing 2% diclofenac. Treatments were administered topically for 4 weeks on the affected hand(s). Clinical evolution was followed weekly by means of the Algofunctional Index (AFI) and the Visual Analog Scale (VAS)., Results and Discussion: A total of 130 participants were included in the study. Among these, 113 were considered in the analysis (55 in the experimental group and 58 in the control group). In both groups, important improvement in the patients' symptomatology was noted. Therapeutic effectiveness was 89% and 91.3% in the two groups, respectively, without a statistically significant difference between the groups. None of the treatments presented any adverse effects., Conclusion: The 4-week topical administration of a gel formulation elaborated with a 1% standardized extract of Sphaeralcea angustifolia showed therapeutic effectiveness and tolerability when administered to patients with HOA, without exhibiting significant differences when compared with the effect observed in patients treated with 2% diclofenac., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Aims of the Study: The present study was carried out to evaluate the effect of dried mature unripe Morinda citrifolia L. (Rubiaceae) fruit, commonly known as "Noni", in an aqueous extract preparation (AFE) as used in Thai traditional medicine and its biomarker scopoletin on gastro-esophageal inflammatory models that are related to the claimed pharmacological properties of AFE and/or resembled the human esophagitis or gastric ulcer., Materials and Methods: The powder of dried mature unripe Noni fruit was boiled in water until it became a sticky paste and was then dried into a powder by lyophilization. The pharmacological activity of AFE and pure scopoletin at the same equivalent dose present in AFE was investigated in rat on gastro-esophageal inflammatory models (acid reflux esophagitis, acute gastritis induced by ethanol and serotonin, and chronic gastric ulcer induced by acetic acid); gastric biochemical parameters and gastrointestinal motility., Results: AFE (0.63-2.50 g/kg) significantly prevented the formation of acid reflux esophagitis, reduced the formation of ethanol-induced acute gastric lesions, suppressed the development of gastric lesions in response to serotonin, and accelerated the healing of acetic acid-induced chronic gastric ulcer in rats with equal potency to those obtained by standard antisecretory agents (ranitidine and lansoprazole). AFE also significantly inhibited gastric acid secretion and pepsin activity in pylorus ligated rats. Additionally, AFE strongly increased the gastrointestinal transit of charcoal meal with a higher potency than cisapride. Pure scopoletin, when compared at the same equivalent dose containing in AFE, possessed similar antiulcer and antisecretory properties to that of AFE although it exerted a less prokinetic activity than AFE., Conclusion: The findings indicated that AFE as well as its biomarker: scopoletin may be beneficial as a potential preventive and therapeutic agent for gastro-esophageal inflammatory diseases, mainly through its antisecretory and prokinetic activities including an inhibitory activity on serotonin, free radicals, and cytokine-mediated inflammation. Additionally, scopoletin might be one of the biomarker constituents to use for the quality assessment of Noni fruit products used for treating gastro-esophageal inflammatory diseases., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

The hepatoprotective potential of Crossostephium chinensis (L.) Makino water extract (CCW) on carbon tetrachloride (CCl(4)) induced liver damage was evaluated in preventive and curative rat models. Not only were indicators of hepatic damage including GPT, GOT, lipid peroxides and TBARS were examined, the activities of antioxidant enzymes (SOD, CAT, GPx) and GSH were examined as well. The results showed that CCW (0.1, 0.5 and 1.0 g/kg) significantly reduced the elevated levels of GPT and GOT by CCl(4) administration (p < 0.05). TBARS level was dramatically reduced, and SOD, CAT, GPx and GSH activities were significantly increased. In addition, CCW decreased NO production and TNF-α activation in CCl(4)-treated rats. Therefore, we speculate that CCW protects against acute liver damage through its radical scavenging ability. CCW inhibited the expression of MMP-9 protein, indicating that MMP-9 played an important role in the development of CCl(4)-induced chronic liver damage in rats. In LC-MS-MS analysis, the chromatograms of CCW with good hepatoprotective activities were established. Scopoletin may be an important bioactive compound in CCW.

The relationship between depression and monoaminergic systems has been hypothesized for many years. In this study, we have investigated the possible antidepressant-like effect of scopoletin, a coumarin from Polygala sabulosa in the tail suspension test and forced swimming test. Moreover, the ability of scopoletin to reverse the depression-like behavior in the forced swimming test induced by immobility stress in mice was evaluated. Scopoletin reduced the immobility time in the tail suspension test (10-100mg/kg, p.o.), but not in the forced swimming test. Fluoxetine (positive control) decreased the immobility time in the forced swimming and tail suspension tests (20mg/kg, p.o. and 10mg/kg. p.o., respectively). Immobility stress caused an increase in the immobility time in the forced swimming test (depression-like behavior), which was reversed by scopoletin (1-100mg/kg, p.o.) and fluoxetine (10mg/kg, p.o.). Scopoletin produced no psychostimulant effect in the open-field test. The pretreatment of mice with ketanserin (5mg/kg, i.p., a preferential 5-HT(2A) receptor antagonist), prazosin (1mg/kg, i.p., an alpha(1)-adrenoceptor antagonist), yohimbine (1mg/kg, i.p., an alpha(2)-adrenoceptor antagonist), haloperidol (0.2mg/kg, i.p., a dopaminergic receptor antagonist), SCH23390 (0.05 mg/kg, s.c., a dopamine D(1) receptor antagonist) or sulpiride (50mg/kg, i.p., a dopamine D(2) receptor antagonist), but not WAY100635 (0.1mg/kg, s.c., a selective 5-HT(1A) receptor antagonist) prevented the antidepressant-like effect of scopoletin (10mg/kg, p.o.) in the tail suspension test. The results indicate that its antidepressant-like effect is dependent on the serotonergic (5-HT(2A) receptors), noradrenergic (alpha(1)- and alpha(2)-adrenoceptors) and dopaminergic (dopamine D(1) and D(2) receptors) systems., (2010 Elsevier B.V. All rights reserved.)

Scopoletin is the main constituent of coumarin found in the stems of Erycibe obtusifolia Benth, a traditional Chinese medicine used in the treatment of rheumatoid arthritis. We have previously demonstrated that scopoletin is able to decrease the serum level of uric acid in hyperuricemic mice induced by potassium oxonate, and attenuate croton oil-induced inflammation. In the present study, we evaluated the anti-arthritic effects of scopoletin in rat adjuvant-induced arthritis by assessing paw swelling, pathology, and synovial angiogenesis. It was found that scopoletin, injected intraperitoneally at doses of 50, 100 mg/kg, reduced both inoculated and non-inoculated paw swelling as well as articular index scores, and elevated the mean body weight of adjuvant-induced arthritic rats. Rats treated with higher dose of scopoletin showed a near-normal histological architecture of the joints and a reduced new blood vessel formation in the synovial tissues. Furthermore, scopoletin downregulated the overexpression of vascular endothelial growth factor, basic fibroblast growth factor and interleukin 6 in the synovial tissues of adjuvant-induced arthritic rats. In conclusion, scopoletin is capable of ameliorating clinical symptoms of rat adjuvant-induced arthritis, by reducing numbers of new blood vessels in the synovium and the production of important endogenous angiogenic inducers. Therefore, this compound may be a potential agent for angiogenesis-related diseases and could serve as a structural base for screening more potent synthetic analogs.

Objective: Anti-cancer potentials of scopoletin (7-hydroxy-6-methoxy coumarin) separated from plant extract (Gelsemium sempervirens) were demonstrated earlier from our in vitro studies. In the present study, its in vivo effects have been evaluated in mice., Methods: Mice were chronically administered 7,12-dimethylbenz [a] anthracene (DMBA) once a week and croton oil twice a week on their back, which resulted in the development of fully grown finger-like projections (papilloma) after 24 weeks. Two subgroups of mice (drug-treated) were treated with two doses of scopoletin (50 mg and 100 mg/kg body weight) respectively while control received 2% ethyl alcohol (the "vehicle" of scopoletin). After the 24-week drug administration, expressions of several key receptors such as aryl hydrocarbon receptor (AhR) and signal proteins like p53, cytochrome P450 1A1 (CYP1A1), proliferating cell nuclear antigen (PCNA), signal transducer and activator of transcription-3 (Stat-3), survivin, matrix metalloproteinase-2 (MMP-2), cyclin D1, c-myc, tissue inhibitor of matrix metalloproteinase-2 (TIMP-2) and caspase-3, and some anti-oxidant markers were studied. Lipid peroxidation, superoxide dismutase, catalase, glutathione peroxidase and glutathione-s-transferase in supernatant were also detected., Results: Carcinogens induced toxicity, and over-expression of AhR, CYP1A1, PCNA, Stat-3, survivin, MMP-2, cyclin D1 and c-myc and down-regulation of p53, caspase-3 and TIMP-2. In mice treated with scopoletin, the expressions of these proteins and toxicity biomarkers were reverted., Conclusion: Since AhR is known to be ligand-activated by DMBA to release signals for several downstream proteins initiating reactive oxygen species generation, the down-regulation of AhR by scopoletin appeared to play a significant role in subsequent down-regulation of some key signal proteins. One possible mechanism of down-regulation of AhR may be through competitive inhibition by scopoletin. Mitogen-activated protein kinases may also have some critical role. This compound can be considered as a possible candidate for chemoprevention.

Aim of the Study: To systematically investigate the anticonvulsant activity of methanol extract of Benkara malabarica roots and to provide a biochemical basis elucidating its mode of action., Methods: The median lethal dose (LD(50)) of Benkara malabarica extract was determined. The anticonvulsant activity of the extract was assessed in strychnine-induced and isoniazide-induced convulsion models; phenytoin (20mg/kg) and diazepam (1mg/kg) were used as standards, respectively. Percentage protection provided by the drug was accounted as decrease in the number of convulsions within 8h of observation. Mechanism of action was studied by performing GABA transaminase (GABA-T) assay, isolated from rat brain. Active constituent was isolated and characterized from the plant extract., Results: The median lethal dose (LD50) of Benkara malabarica was found to be more than 500 mg/kg. It demonstrated 30% and 35% protection against strychnine-induced convulsions and 60% and 80% protection against isoniazide-induced convulsions, at doses of 25mg/kg and 50mg/kg, respectively. Enzyme assay results revealed that Benkara malabarica extract possesses GABA-T inhibitory activity (IC50=0.721 mg/ml). Scopoletin which was identified as the major constituent of the extract was found to be an inhibitor of GABA-T (IC50=10.57 microM)., Conclusions: The anticonvulsant activity of the plant extract is predominantly GABA mediated and may be due to the action of scopoletin alone or is a result of synergy of different compounds in the extract in which scopoletin is the major constituent., (Copyright (c) 2010 Elsevier Ireland Ltd. All rights reserved.)

Objective: To screen the representing components in different germplasms of Canarium album and determine the content by HPLC for laying the foundation for the quality specification., Method: Gallic acid and scopoletin and scoparone were chosen as the main chemical components for clearing heat and relieving sore throat by reviewing literature and qualitative experiment. Gallic acid was determined according the method of Galla chinensis in Chinese pharmacopoeia. Scopoletin and scoparone were determined by HPLC on C18 column (4.6 mm x 250 mm, 5 microm) and the mobile phase was acetonitrile-water-acetic acid (16:84:0.5) with the detection wavelength at 345 nm and column temperature at 35 degrees C , the flow rate was 1.0 mL x min(-1)., Result: The resolution is good for gallic acid and scopoletin and scoparone. The standard curve in detection range showed good linear relation, the average recoveries were 100.22%, 101.22% and 100.42%, respectively, RSD were all less than 2.0%. The content of gallic acid in the large fruit C. album from Guangdong was higher than that in the small fruit C. album, while the result was contrary in samples from Sichuan. The content of total coumarins in the small fruit C. album was generally higher than that in the large fruit C. album, which from Sichuan was higher than those from Guangdong., Conclusion: The efficacies of clearing heat and relieving sore throat in C. album were formed by synergistic effect of gallic acid and scopoletin and scoparone. The small fruit C. album was better than the large fruit C. album as medicinal materials, the results provide reliable basis for quality control in medicinal materials and its preparation.

ABSTRACT. The purpose of this study was to determine a maximum tolerated dose of noni in cancer patients and whether an optimal quality of life-sustaining dose could be identified as an alternative way to select a dose for subsequent Phase II efficacy trials. Dose levels started at two capsules twice daily (2 g), the suggested dose for the marketed product, and were escalated by 2 g daily in cohorts of at least five patients until a maximum tolerated dose was found. Patients completed subscales of the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 quality of life (physical functioning, pain, and fatigue) the brief fatigue inventory (BFI), questionnaires at baseline and at approximately 4-week intervals. Blood and urine were collected at baseline and at approximately 4-week intervals for measurement of scopoletin. Fifty-one patients were enrolled at seven dose levels. The maximum tolerated dose was six capsules four times daily (12 g). Although no dose-limiting toxicity was found, seven of eight patients at the next level (14 g), withdrew due to the challenges of ingesting so many capsules. There were dose-related differences in self-reported physical functioning and pain and fatigue control. Overall, patients taking three or four capsules four times daily experienced better outcomes than patients taking lower or higher doses. Blood and urinary scopoletin concentrations related to noni dose. We concluded that it is feasible to use quality of life measures to select a Phase II dose. Three or four capsules four times daily (6-8 g) is recommended when controlling fatigue, pain, and maintaining physical function are the efficacies of interest. Scopoletin, a bioactive component of noni fruit extract, is measurable in blood and urine following noni ingestion and can be used to study the pharmacokinetics of noni in cancer patients.

Scopoletin exhibited an immediate and dose-dependent hypouricemic effect after intraperitoneal administration (50, 100, 200 mg/kg) in hyperuricemic mice induced by potassium oxonate; however, it did not affect the serum uric acid level in normal mice at the tested doses. For exploring the involved mechanisms of action of scopoletin, potential inhibitory effects on xanthine oxidase and possible uricosuric effects were investigated. Scopoletin (50, 100, 200 mg/kg) significantly inhibited the activity of xanthine oxidase in liver homogenates of hyperuricemic mice although it only showed a relatively weak, albeit competitive-type, inhibition of xanthine oxidase in a commercial assay. Furthermore, a potent uricosuric effect of scopoletin (100, 200 mg/kg) was ascertained. These results demonstrated for the first time that scopoletin exhibits, hypouricemic activities through decreasing uric acid production and as well as a uricosuric mechanism.

Scopoletin (1-50 microg/ml) inhibited the release of PGE2, TNF-alpha, IL-1beta and IL-6 and suppressed the expression of COX-2 in a concentration-dependent manner. These results suggest that scopoletin might suppress the production of such pro-inflammatory cytokines and exert inhibitory activity on LPS-induced PGE2 production through the depression of COX-2 expression., (Copyright 2004 Elsevier B.V.)

Scopoletin was isolated from Sinomonium acutum and studied using four experimental models designed to assess antioxidant properties. The results indicated that scopoletin scavenged superoxide anion in the xanthine/xanthine oxidase reaction system in a concentration-dependent manner, but did not inhibit xanthine oxidase. Scopoletin may therefore be responsible for the superoxide anion scavenging activity seen in Sinomonium acutum extracts and may be of use in preventing superoxide anion-induced damage in vivo., (Copyright 2003 John Wiley & Sons, Ltd.)