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ETHNOPHARMACOLOGICAL RELEVANCE: Dried roots of Peucedanum decursivum, a traditional Chinese medicine (TCM), has historically respiratory diseases such as cough, thick phlegm, headache, fever, and gynecological diseases, rheumatoid arthritis, and nasopharyngeal carcinoma. AIM OF THE STUDY: Made an endeavor to evaluate the research trajectory of P. decursivum, comprehensively discern its developmental status, and offer a guideline for future investigations. MATERIALS AND METHODS: A meticulous search of literatures and books from 1955 to 2024 via databases like PubMed, Web of Science and CNKI was conducted, including topics and keywords of " P. decursivum" "Angelica decursivum" and "Zihua Qianhu". RESULTS: P. decursivum and its prescriptions have traditionally been used for treating phlegm-heat cough, wind-heat cough, gastrointestinal diseases, pain relief and so on. It contains 234 identified compounds, encompassing coumarins, terpenes, volatile oils, phenolic acids, fatty acids and derivatives. It exhibits diverse pharmacological activities, including anti-asthmatic, anti-inflammatory, antioxidant effects, anti-hypertensive, anti-diabetic, anti-Alzheimer, and anti-cancer properties, primarily attributed to coumarins. Microscopic identification, HPLC fingerprinting, and bioinformatics identification are the primary methods currently used for the quality control. CONCLUSION: P. decursivum demonstrates anti-asthmatic, anti-inflammatory, and antioxidant effects, aligning with its traditional use. However, experimental validation of its efficacy against phlegm and viruses is needed. Additionally, analgesic effects mentioned in historical texts lack modern pharmacological studies. Numerous isolated compounds exhibit highly valuable medicinal properties. Future research can delve into exploring these substances further. Rigorous of heavy metal contamination, particularly Cd and Pb, is necessary. Simultaneously, investigating its pharmacokinetics and toxicity in humans is crucial for the safety.
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Apiaceae , Etnobotánica , Etnofarmacología , Fitoquímicos , Control de Calidad , Humanos , Fitoquímicos/farmacología , Fitoquímicos/química , Fitoquímicos/uso terapéutico , Apiaceae/química , Animales , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/química , Medicamentos Herbarios Chinos/uso terapéutico , Medicina Tradicional China/métodosRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Ramulus Cinnamomi, the dried twig of Cinnamomum cassia (L.) J.Presl., is a traditional Chinese medicine (TCM) with anti-inflammatory effects. The medicinal functions of Ramulus Cinnamomi essential oil (RCEO) have been confirmed, although the potential mechanisms by which RCEO exerts its anti-inflammatory effects have not been fully elucidated. AIM OF THE STUDY: To investigate whether N-acylethanolamine acid amidase (NAAA) mediates the anti-inflammatory effects of RCEO. MATERIALS AND METHODS: RCEO was extracted by steam distillation of Ramulus Cinnamomi, and NAAA activity was detected using HEK293 cells overexpressing NAAA. N-Palmitoylethanolamide (PEA) and N-oleoylethanolamide (OEA), both of which are NAAA endogenous substrates, were detected by liquid chromatography with tandem mass spectrometry (HPLC-MS/MS). The anti-inflammatory effects of RCEO were analyzed in lipopolysaccharide (LPS)-stimulated RAW264.7 cells, and the cell viability was measured with a Cell Counting Kit-8 (CCK-8) kit. The nitric oxide (NO) in the cell supernatant was measured using the Griess method. The level of tumor necrosis factor-α (TNF-α) in the RAW264.7 cell supernatant was determined using an enzyme-linked immunosorbent assay (ELISA) kit. The chemical composition of RCEO was assessed by gas chromatography-mass spectroscopy (GC-MS). The molecular docking study for (E)-cinnamaldehyde and NAAA was performed by using Discovery Studio 2019 software (DS2019). RESULTS: We established a cell model for evaluating NAAA activity, and we found that RCEO inhibited the NAAA activity with an IC50 of 5.64 ± 0.62 µg/mL. RCEO significantly elevated PEA and OEA levels in NAAA-overexpressing HEK293 cells, suggesting that RCEO might prevent the degradation of cellular PEA and OEA by inhibiting the NAAA activity in NAAA-overexpressing HEK293 cells. In addition, RCEO also decreased NO and TNF-α cytokines in lipopolysaccharide (LPS)-stimulated macrophages. Interestingly, the GC-MS assay revealed that more than 93 components were identified in RCEO, of which (E)-cinnamaldehyde accounted for 64.88%. Further experiments showed that (E)-cinnamaldehyde and O-methoxycinnamaldehyde inhibited NAAA activity with an IC50 of 3.21 ± 0.03 and 9.62 ± 0.30 µg/mL, respectively, which may represent key components of RCEO that inhibit NAAA activity. Meanwhile, docking assays revealed that (E)-cinnamaldehyde occupies the catalytic cavity of NAAA and engages in a hydrogen bond interaction with the TRP181 and hydrophobic-related interactions with LEU152 of human NAAA. CONCLUSIONS: RCEO showed anti-inflammatory effects by inhibiting NAAA activity and elevating cellular PEA and OEA levels in NAAA-overexpressing HEK293 cells. (E)-cinnamaldehyde and O-methoxycinnamaldehyde, two components in RCEO, were identified as the main contributors of the anti-inflammatory effects of RCEO by modulating cellular PEA levels through NAAA inhibition.
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Lipopolisacáridos , Aceites Volátiles , Humanos , Lipopolisacáridos/farmacología , Factor de Necrosis Tumoral alfa , Aceites Volátiles/farmacología , Espectrometría de Masas en Tándem , Células HEK293 , Simulación del Acoplamiento Molecular , Antiinflamatorios/farmacología , Amidohidrolasas/metabolismoRESUMEN
Subcritical water extraction (SWE) of four flavoring compounds from cinnamon was performed at various temperatures and for various extraction times. The extraction temperature (°C) and time (min) corresponding to the maximum content of flavoring compounds were 190 °C and 5 min for cinnamyl alcohol, 200 °C and 20 min for cinnamic acid, 130 °C and 10 min for cinnamaldehyde, and 170 °C and 20 min for coumarin, respectively. Cinnamaldehyde underwent structural conversion to benzaldehyde via hydrolysis at high temperatures, and the rate of conversion rapidly increased above 150 °C. The extraction efficiency using subcritical water was slightly higher or comparable to that using conventional extractants. SWE is a potential and highly selectivity technology for extracting flavoring compounds from cinnamon.
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Cinnamomum zeylanicum , Aceites Volátiles , Cinnamomum zeylanicum/química , Aromatizantes , Hidrólisis , AguaRESUMEN
This study aims at determining the potentials of cinnamon (Cinnamomun burmannii) extracts to improve the health-promoting properties of white chocolate. LC-HRMS analysis was employed to obtain information regarding the phytochemical content while the phosphomolybdenum, FRAP and DPPH assays were used to determine antioxidant activity of cinnamon extract. Furthermore, the cinnamon extract was loaded into nanoparticles before adding it to white chocolate. The results show that cinnamon extracts contained phenols up to 310 mg EE and possessed antioxidant activity up to 260 mg TAE per gram of dry extract depending on the extraction mode (i.e., traditional and ultrasonic-assisted method) and the solvent type. The cinnamon extract contained catechin, epicatechin, procyanidin B2, quercitrin, 3,4-dihydroxybenzaldehyde, protocatechuic acid and cinnamic acid at levels of 51, 53, 1396, 13, 1138, 228 and 934 µg/g of dry extract, respectively. The encapsulated cinnamon extract increased the phenolic content of white chocolate from 47.6 to 1060.6 µg EE/g.
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Antioxidantes/química , Chocolate , Cinnamomum zeylanicum/química , Fitoquímicos/análisis , Extractos Vegetales/química , Biflavonoides/análisis , Catequina/análisis , Chocolate/análisis , Microscopía por Crioelectrón , Industria de Procesamiento de Alimentos , Hidroxibenzoatos/análisis , Fenoles/análisis , Extractos Vegetales/análisis , Proantocianidinas/análisis , Quercetina/análogos & derivados , Quercetina/análisis , UltrasonidoRESUMEN
Natural products have represented attractive alternatives for disease prevention and treatment over the course of human history and have contributed to the development of modern drugs. These natural products possess beneficial efficacies as well as adverse efffects, which vary largely among individuals because of genetic variations in their pharmacokinetics and pharmacodynamics. As with other synthetic chemical drugs, the dosing of natural products can be optimized to improve efficacy and reduce toxicity according to the pharmacogenetic properties. With the emergence and development of pharmacogenomics, it is possible to discover and identify the targets/mechanisms of pharmacological effects and therapeutic responses of natural products effectively and efficiently on the whole genome level. This review covers the effects of genetic variations in drug metabolizing enzymes, drug transporters, and direct and indirect interactions with the pharmacological targets/pathways on the individual response to natural products, and provides suggestions on dosing regimen adjustments of natural products based on their pharmacokinetic and pharmacogenetic paratmeters. Finally, we provide our viewpoints on the importance and necessity of pharmacogenetic and pharmacogenomic research of natural products in natural medicine's rational development and clinical application of precision medicine.
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Productos Biológicos/farmacología , Productos Biológicos/farmacocinética , Transporte Biológico , Humanos , FarmacogenéticaRESUMEN
UDP-glucuronosyltransferases (UGTs) and cytochrome P450s (CYPs) are the major enzymes involved in hepatic metabolism of drugs. Hepatic drug metabolism is commonly investigated using human liver microsomes (HLM) or primary human hepatocytes (PHH). We describe the development of a sensitive assay to phenotype activities of six major hepatic UGT isoforms (UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9 and UGT2B7) in intact PHH by analysis of glucuronidation of selective probe substrates. The non-selective, general substrate 7-hydroxycoumarin was included for comparison. For each liver donor preparation (five donors) UGT activities in cryopreserved suspended and plated PHH were compared to HLM prepared from the same donors. Standard CYP reaction phenotyping of seven major isoforms was performed in parallel. For all donors, CYP- and UGT-isoforms activity profiles were comparable in PHH and HLM, indicating that reaction phenotyping with selective probe substrates in intact cells primarily reflects respective CYP or UGT activity. System-dependent effects on UGT and CYP isoform activity were still found. While UGT activity of UGT1A1 was equivalent in plated and suspended PHH, UGT1A3, UGT1A6 and UGT2B7 activity was higher in suspended PHH and UGT1A9 and UGT1A4 activity was higher in plated PHH. The well-known decrease in activity of most CYP isoforms in plated compared to suspended PHH was confirmed. Importantly, we found a significant loss in CYP2C19 and CYP2B6 in HLM, activity being lower than in intact cells. Taken together, these findings implicate that, dependent on the UGT or CYP isoforms involved in the metabolism of a given compound, the outcome of metabolic assays is strongly dependent on the choice of the in vitro system. The currently described UGT- and CYP- activity profiling method can be used as a standard assay in intact cells and can especially aid in reaction phenotyping of in vitro systems for which a limited number of cells are available.
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Sistema Enzimático del Citocromo P-450/metabolismo , Glucuronosiltransferasa/metabolismo , Hepatocitos/enzimología , Microsomas Hepáticos/enzimología , Humanos , Hígado/enzimologíaRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: The twigs and bark of Cinnamomum cassia Presl (Lauraceae) are widely used in traditional Chinese medicine in the treatment of tumor, abdominal pain, dysmenorrhea, digestive system disease and inflammatory diseases. The aim of this study was to determine the inhibitory effect of the essential oil from the twigs of Cinnamomum cassia Presl (EOCC) on uterine contraction in vitro and in vivo. MATERIALS AND METHODS: The Institute of Cancer Research (ICR) mouse uterine contraction was induced by oxytocin (OT) exposure following estradiol benzoate pretreatment. Mice were given the EOCC (60, 30, and 15mg/kg) by gavage. The level of prostaglandin F2α (PGF2α) in uterine tissue were determined according to specification of enzyme linked immunosorbent assay (ELISA) kit. Uterine tissue was collected for histopathological analysis (H&E). Myosin light chain 20 (MLC20), phosphorylation of myosin light chain 20 (p-MLC20) and cyclooxygenase-2 (COX-2) proteins in uterine tissue were assessed by Western Blot. Mouse isolated uterus strips were mounted in tissue organ baths containing Locke's solution. The contractile responses were recorded with Power Lab recording system. The effect of the EOCC on uterine contraction induced by OT, PGF2α, and acetylcholine (Ach) was observed. Myometrial cells were exposed to OT (7µM) to induce Ca2+ release, and the effect of the EOCC (100, 50, and 25µg/ml) on intracellular Ca2+ was analysed with fluorometry imaging. RESULTS: In vivo study demonstrated that the EOCC significantly reduced OT-induced writhing responses with a maximal inhibition of 66.5%. It also decreased the level of PGF2α in OT-induced mice uterine tissue. Moreover, Western blot analysis showed that COX-2 and p-MLC20 expressions in uterine tissue of dysmenorrhea mice were significantly reduced. EOCC inhibited spontaneous uterus contractions in a dose-dependent manner, and the concentration of the EOCC giving 50% of maximal contraction (IC50) value was 61.3µg/ml. The IC50 values of the EOCC on OT, PGF2α, and Ach-induced contractions were 113.0µg/ml, 94.7µg/ml, and 61.5µg/ml, respectively. Further in vitro studies indicated that the EOCC could restrain intracellular Ca2+ levels in favour of uterine relaxation. CONCLUSION: Both in vivo and in vitro results suggest that the EOCC possesses significant spasmolytic effect on uterine contraction. Thus, the EOCC yields a possible therapeutic choice for the prevention and treatment of primary dysmenorrhea.
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Cinnamomum aromaticum/química , Aceites Volátiles/farmacología , Oxitocina/farmacología , Contracción Uterina/efectos de los fármacos , Animales , Calcio/metabolismo , Dinoprost/metabolismo , Femenino , Cromatografía de Gases y Espectrometría de Masas , Técnicas In Vitro , Ratones , Ratones Endogámicos ICR , Aceites Volátiles/química , Útero/efectos de los fármacos , Útero/metabolismo , Útero/patología , Útero/fisiologíaRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Medicinal diets have a history of more than 2000 years. Locally referred to as yaoshan (Chinese: ), a medicinal diet is understood in China as a dietary product that combines herbs and food with the purpose of preventing and treating diseases or improving health under the guidance of traditional Chinese medicine theory. Medicinal diets are used in Chinese people's daily life and in specialized restaurants. Hundreds of Chinese materia medica (CMM) are used in medicinal diets; however, a comprehensive evaluation of medicinal diets is lacking. AIMS OF THE STUDY: This is an exploratory study that aims to identify the CMM that are most frequently used in medicinal diets and to provide an updated view of the current situation of medicinal diets in China. MATERIALS AND METHODS: A field study of 1221 people in 32 Chinese provinces was conducted over a period of approximately 6 months and included various types of interviews as well as a written questionnaire. Two approaches were used to analyse the data collected in the survey: (1) estimating the frequency of CMM consumed in daily diets; and (2) collecting CMM used in medicinal diet restaurants. Complementary information on the selected CMM was obtained from relevant databases, including PubMed, Google Scholar, Baidu Scholar, CNKI, and Web of Science. RESULTS: Ten CMM were reported as commonly used by more than 50% of the participants. Among these 10 species, most medicinally used parts were seeds and fruits. Pharmacological data from the literature revealed that these species are associated with a wide spectrum of biological properties, including antitumour (80%), antioxidant (50%), anti-diabetic (40%), antilipemic (40%), anti-aging (40%), antimicrobial (40%) and cardioprotective (40%) activities. Our survey shows that most medicinal diet restaurants are located in the eastern part of China, with the greatest numbers being found in Beijing and Guangzhou. Only Dioscoreae Rhizoma, Lycii Fructus, Chrysanthemi Flos and Longan Arillus were frequently consumed both in daily diets and at medicinal diet restaurants. Some of the similarities shared by these 4 species include an extensive history of use (>2000 years); a sweet flavour; and antioxidant, antidiabetic, antilipemic and cardioprotective effects. CONCLUSIONS: The 10 most commonly consumed CMM possess various biological effects that are currently target the most frequent health problems for the majority of the population. The development of medicinal diet restaurants has certain regional restrictions and is associated with the local climate environment and dietary culture. The data revealed by this study provided useful information for commercial exploitation of medicinal diets and their components and serve as a basis for further studies on various aspects of medicinal diets.
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Materia Medica/uso terapéutico , Medicina Tradicional China , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Ayurveda, an ancient holistic system of health care practiced on the Indian subcontinent, utilizes a number of multi-plant formulations and is considered by many as a potential source for novel treatments, as well as the identification of new drugs. Our aim is to identify novel phytochemicals for the inhibition of bacterial exotoxin, botulinum neurotoxin A (BoNT/A) based on Ayurvedic literature. BoNT/A is released by Clostridium species, which when ingested, inhibits the release of acetylcholine by concentrating at the neuromuscular junction and causes flaccid paralysis, resulting in a condition termed as botulism, and may also lead to death due to respiratory arrest. METHODS: Fifteen plants were selected from the book 'Diagnosis and treatment of diseases in Ayurveda' by Vaidya Bhagwan Dash and Lalitesh Kashyap, based on their frequency of use in the formulations used for the treatment of six diseases with neuromuscular symptoms similar to botulism. Phytochemicals from these plants were screened using in silico, and in vitro methods. Structures of 570 reported phytochemicals from 14 plants were docked inside six reported BoNT/A light chain crystal structures using ensemble docking module in Maestro (Schrödinger, LLE). RESULTS: From the docking scores and structural diversity, nine compounds including acoric acid 1, three flavonoids, three coumarins derivatives, one kava lactone were selected and screened using an in vitro HPLC-based protease assay. The bioassay results showed that several compounds possess BoNT/A LC inhibition of 50-60% when compared to positive controls NSC 84094 and CB7967495 (80-95%). CONCLUSION: Further testing of the active compounds identified from Ayurvedic literature and structure-activity studies of acoric acid 1 using more sensitive bioassays is under way. The identification of acoric acid 1, a novel scaffold against BoNT/A, exemplifies the utility of Ayurvedic literature for the discovery of novel drug leads.
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Toxinas Botulínicas Tipo A/antagonistas & inhibidores , Fitoquímicos/química , Fitoquímicos/farmacología , Cumarinas/química , Cumarinas/farmacología , Ciclohexanonas/química , Ciclohexanonas/farmacología , Etnofarmacología/métodos , Flavonoides/química , Flavonoides/farmacología , Kava/química , Lactonas/química , Lactonas/farmacología , Medicina AyurvédicaRESUMEN
The dietary phenol tyrosol has been reported to be endogenously transformed into hydroxytyrosol, a potent antioxidant with multiple health benefits. In this work, we evaluated whether tyrosine hydroxylase (TH) and cytochrome P450s (CYPs) catalyzed this process. To assess TH involvement, Wistar rats were treated with α-methyl-L-tyrosine and tyrosol. Tyrosol was converted into hydroxytyrosol whilst α-methyl-L-tyrosine did not inhibit the biotransformation. The role of CYP was assessed in human liver microsomes (HLM) and tyrosol-to-hydroxytyrosol conversion was observed. Screening with selective enzymatic CYP inhibitors identified CYP2A6 as the major isoform involved in this process. Studies with baculosomes further demonstrated that CYP2D6 and CYP3A4 could transform tyrosol into hydroxytyrosol. Experiments using human genotyped livers showed an interindividual variability in hydroxytyrosol formation and supported findings that CYP2D6 and CYP2A6 mediated this reaction. The dietary health benefits of tyrosol-containing foods remain to be evaluated in light of CYP pharmacogenetics.
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Citocromo P-450 CYP2A6/metabolismo , Citocromo P-450 CYP2D6/metabolismo , Alcohol Feniletílico/análogos & derivados , Animales , Antioxidantes/metabolismo , Biotransformación , Humanos , Masculino , Microsomas Hepáticos/metabolismo , Alcohol Feniletílico/metabolismo , Ratas , Ratas Wistar , Tirosina/metabolismoRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Cinnamomum cassia Presl (Lauraceae) can be found southern China and its bark is commonly used for centuries as ingredient in food and cosmetic industry. The twigs of Cinnamomum cassia Presl is popularly used in China to treat inflammatory processes, pain, menstrual disorders, hypertension, fever etc. The aim of this study is to evaluate the antinociceptive and anti-inflammatory properties of the essential oil (EO) from the twigs of Cinnamomum cassia Presl. MATERIAL AND METHODS: The chemical characterization of the EO was performed by gas chromatography coupled with mass spectrometry (GC-MS). The EO doses of 15, 30, and 60mg/kg were employed in the biological assays. The antinociceptive effects of the EO were evaluated using the models of acetic acid-induced writhing, oxytocin-induced writhing, and formalin and complete Freund's adjuvant (CFA) -induced overt pain tests. we also investigated the effect of the EO in pain intensity to a mechanical stimulus (mechanical hyperalgesia) after carrageenan by using an electronic version of von Frey filaments. Evaluation of anti-inflammatory activity was based on paw edema induced by carrageenan (300µg/25µL/paw) in mice. The levels of cytokines, NO, and PGE2 in paw skin tissue were determined according to instructions. COX-2 and iNOS proteins in paw skin tissue were assessed by Western Blot. RESULTS: The EO (15, 30, and 60mg/kg) reduced the number of abdominal writhings induced by acetic acid with inhibition of 38.0%, 55.4% and 58.7%, respectively. The EO (15, 30, and 60mg/kg) also reduced the number of abdominal writhings induced by oxytocin with inhibition of 27.3%, 51.7% and 69.0%, respectively. The EO significant inhibited the inflammatory (second phase: 10-30min) phase of the formalin-induced paw flinching and licking at the doses of 15, 30, and 60mg/kg. The EO at the tested doses of 15, 30, and 60mg/kg showed inhibited CFA-induced paw flinching and licking. The EO (15, 30, and 60mg/kg) also inhibited carrageenan-induced mechanical hyperalgesia and paw edema. It also decreased the levels of cytokines (TNF-α, and IL-1ß), NO, and PGE2 in carrageenan-induced mice paw skin tissue. Moreover, Western blot analysis showed that COX-2 and iNOS expressions in paw skin tissue of mice were significantly reduced. CONCLUSIONS: These results demonstrate that the antinociceptive and anti-inflammatory properties of the EO from the twigs of Cinnamomum cassia Presl, corroborating its use in folk medicine.
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Antiinflamatorios/farmacología , Cinnamomum aromaticum/química , Inflamación/tratamiento farmacológico , Aceites Volátiles/farmacología , Dolor/tratamiento farmacológico , Extractos Vegetales/farmacología , Analgésicos/química , Analgésicos/farmacología , Animales , Carragenina/farmacología , Edema/inducido químicamente , Edema/tratamiento farmacológico , Femenino , Inflamación/inducido químicamente , Masculino , Ratones , Ratones Endogámicos ICR , Dolor/inducido químicamente , Fitoterapia/métodosRESUMEN
Currently, there is no effective therapy for high grade gliomas. 8-Methoxypsoralen (8-MOP) is a compound used in the treatment of skin diseases combined with UV light irradiation. In this work, rat glioma C6 cells, normal astrocytes and human glioblastoma GL-15 cells comprised an in vitro model to evaluate the antitumor activity of 8-MOP. We found that 8-MOP promoted a time- and concentration-dependent reduction of cell viability in tumor, but not in normal cells. This effect was more evident in log-phase growing culture, indicating antiproliferative activity, which was confirmed by colony formation assay. Long-term effect of 8-MOP at low concentration was also attested. The concentrations used in the tests (0.02-0.4 mM) were lower than plasmatic concentration found in patients. Despite the treatment leads to considerable morphological changes and apoptosis when used at high concentrations, 8-MOP did not promote cell cycle arrest, change in migration pattern neither necrosis. In addition, we evaluated the effect of 8-MOP in MDA-MB-231, CT-26 and SCC-3 cell lines, derived from other kind of primary tumors, and found that CT-26 cells did not respond to 8-MOP treatment, indicating that this compound does not act through a generic mechanism. Coumarin derivatives structurally related to 8-MOP were screened for its antitumor potential and presented different patterns of biological activity, and then it was possible to suggest the relevance of 8-MOP molecular structure for antiproliferative action. Therefore, 8-MOP, a drug with an outstanding record of safety, and related coumarins are good prototypes for development of a new class of anti-glioma drugs.
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Proliferación Celular/efectos de los fármacos , Proliferación Celular/efectos de la radiación , Glioma , Metoxaleno/farmacología , Fármacos Fotosensibilizantes/farmacología , Rayos Ultravioleta , Animales , Línea Celular Tumoral , Proliferación Celular/fisiología , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Supervivencia Celular/efectos de la radiación , Células Cultivadas , Relación Dosis-Respuesta a Droga , Glioma/tratamiento farmacológico , Glioma/patología , Humanos , Metoxaleno/química , Metoxaleno/uso terapéutico , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/uso terapéutico , Ratas , Ratas WistarRESUMEN
We investigated a potential molecular target for anti-colitic effects of esculetin, 6,7-dihydroxycoumarin. Esculetin administered rectally effectively ameliorated TNBS-induced rat colitis and attenuated the expression of pro-inflammatory mediators in the inflamed colon. In human colon carcinoma HCT116 cells, esculetin induced hypoxia-inducible factor-1α (HIF-1α), leading to secretion of vascular endothelial growth factor, a HIF-1 target gene product involved in ulcer healing of the gastrointestinal mucosa. Esculetin directly inhibited HIF prolyl hydroxylase-2 (HPH-2), an enzyme playing a major role in negatively regulating HIF-1α protein stability. Esculetin inhibition of HPH and consequent induction of HIF-1α were attenuated by escalating dose of either ascorbate or 2-ketoglutarate, the required factors of the enzyme. Structurally, the catechol moiety in esculetin was required for HPH inhibition. Collectively, HPH may be a molecular target for esculetin-mediated anti-colitic effects and the catechol moiety in esculetin is the pharmacophore for HPH inhibition.