RESUMEN
Valerian root (Valeriana officinalis) is a popular and widely available herbal supplement used to treat sleeping disorders and insomnia. The herb's ability to ameliorate sleep dysfunction may signify an unexplored anti-tumorigenic effect due to the connection between circadian factors and tumorigenesis. Of particular interest are the structural similarities shared between valeric acid, valerian's active chemical ingredient, and certain histone deacteylase (HDAC) inhibitors, which imply that valerian may play a role in epigenetic gene regulation. In this study, we tested the hypothesis that the circadian-related herb valerian can inhibit breast cancer cell growth and explored epigenetic changes associated with valeric acid treatment. Our results showed that aqueous valerian extract reduced growth of breast cancer cells. In addition, treatment of valeric acid was associated with decreased breast cancer cell proliferation, migration, colony formation and 3D formation in vitro in a dose- and time-dependent manner, as well as reduced HDAC activity and a global DNA hypomethylation. Overall, these findings demonstrate that valeric acid can decrease the breast cancer cell proliferation possibly by mediating epigenetic modifications such as the inhibition of histone deacetylases and alterations of DNA methylation. This study highlights a potential utility of valeric acid as a novel HDAC inhibitor and a therapeutic agent in the treatment of breast cancer.
Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Epigénesis Genética/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Ácidos Pentanoicos/farmacología , Valeriana/química , Antineoplásicos Fitogénicos/química , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Movimiento Celular/genética , Metilación de ADN/efectos de los fármacos , Femenino , Redes Reguladoras de Genes , Humanos , Ácidos Pentanoicos/química , Extractos Vegetales/química , Extractos Vegetales/farmacologíaRESUMEN
BACKGROUND: Gastroesophageal reflux and Barrett's esophagus are significant risk factors for the development of esophageal adenocarcinoma. Group IIa secretory phospholipase A2 (sPLA2) catalyzes the production of various proinflammatory metabolites and plays a critical role in promoting reflux-induced inflammatory changes within the distal esophagus. We hypothesized that inhibition of sPLA2 in human Barrett's cells would attenuate adhesion molecule expression via decreased activation of nuclear factor kappa B (NF-κB) and decrease cell proliferation, possibly mitigating the invasive potential of Barrett's esophagus. MATERIALS AND METHODS: Normal human esophageal epithelial cells (HET1A) and Barrett's cells (CPB) were assayed for baseline sPLA2 expression. CPB cells were treated with a specific inhibitor of sPLA2 followed by tumor necrosis factor-α. Protein expression was evaluated using immunoblotting. Cell proliferation was assessed using an MTS cell proliferation assay kit. Statistical analysis was performed using the Student's t-test or analysis of variance, where appropriate. RESULTS: CPB cells demonstrated higher baseline sPLA2 expression than HET1A cells (P = 0.0005). Treatment with 30 µM sPLA2 inhibitor significantly attenuated intercellular adhesion molecule-1 (P = 0.004) and vascular cell adhesion molecule-1 (P < 0.0001) expression as well as decreased NF-κB activation (P = 0.002). sPLA2 inhibition decreased cell proliferation in a dose-dependent manner (P < 0.001 for 15, 20, and 30 µM doses). CONCLUSIONS: sPLA2 inhibition in human Barrett's cells decreases cellular adhesive properties and NF-κB activation as well as decreases cell proliferation, signifying downregulation of the inflammatory response and possible attenuation of cellular malignant potential. These findings identify sPLA2 inhibition as a potential chemopreventive target for premalignant lesions of the esophagus.
Asunto(s)
Esófago de Barrett/patología , Esófago/patología , Fosfolipasas A2 Grupo II/antagonistas & inhibidores , Ácidos Pentanoicos/farmacología , Adenocarcinoma/patología , Adenocarcinoma/prevención & control , Esófago de Barrett/tratamiento farmacológico , Adhesión Celular/efectos de los fármacos , Línea Celular , Proliferación Celular/efectos de los fármacos , Evaluación Preclínica de Medicamentos , Neoplasias Esofágicas/patología , Neoplasias Esofágicas/prevención & control , Esófago/citología , Fosfolipasas A2 Grupo II/metabolismo , Humanos , Ácidos Pentanoicos/uso terapéuticoRESUMEN
The aim of this work was to profile, by using an HPLC-MS/MS method, cranberry compounds and metabolites found in human urine after ingestion of a highly standardized cranberry extract (Anthocran®). Two different strategies were adopted for the data analysis: a targeted and an untargeted approach. These strategies allowed the identification of 42 analytes including cranberry components, known metabolites and metabolites hitherto unreported in the literature, including six valerolactones/valeric acid derivatives whose presence in urine after cranberry consumption has never been described before. Absolute concentrations of 26 over 42 metabolites were obtained by using pure available standards. Urine collected at different time points after the last dosage of Anthocran® were tested on the reference strain C. albicans SC5314, a biofilm-forming strain. Fractions collected after 12 h were found to significantly reduce the adhesion and biofilm formation compared to the control (p < 0.05). A similar effect was then obtained by using Anthocran™ Phytosome™, the lecithin formulation containing 1/3 of standardized cranberry extract and formulated to enhance the absorption of the cranberry components. The urinary profile of cranberry components and metabolites in the urine fractions collected at 1 h, 6 h and 12 h after the last capsule intake were then reproduced by using the pure standards at the concentration ranges found in the urine fraction, and tested on C. albicans. Only the mixture mimicking the urinary fraction collected at 12 h and containing as main components, quercetin and 5-(3',4'-dihydroxyphenyl)-γ-valerolactone was found effective thus confirming the ex-vivo results.
Asunto(s)
Biopelículas/efectos de los fármacos , Candida albicans/efectos de los fármacos , Lactonas/farmacología , Ácidos Pentanoicos/farmacología , Extractos Vegetales/orina , Vaccinium macrocarpon/química , Adulto , Antocianinas/orina , Biopelículas/crecimiento & desarrollo , Candida albicans/fisiología , Cromatografía Líquida de Alta Presión/métodos , Femenino , Flavonoides/orina , Humanos , Hidroxibenzoatos/orina , Lactonas/química , Lactonas/orina , Espectrometría de Masas/métodos , Ácidos Pentanoicos/química , Ácidos Pentanoicos/orina , Extractos Vegetales/administración & dosificación , Extractos Vegetales/metabolismo , Polifenoles/clasificación , Polifenoles/orina , Adulto JovenRESUMEN
Psoriasis is a common inflammatory skin disorder that is characterized by keratinocyte hyperproliferation and abnormal differentiation, resulting in the thickening of the epidermis and stratum corneum. In this study, we investigated in vitro and in vivo pharmacological effects of tussilagonone (TGN), a sesquiterpenoid isolated from Tussilago farfara, on transcription factors relevant for the pathogenesis of psoriasis. TGN inhibited activation of NF-κB and STAT3, leading to the attenuated expression of psoriasis-related inflammatory genes and suppression of keratinocyte hyperproliferation. Mechanistically, we show that the inhibition of NF-κB and STAT3 by TGN is mediated through activation of the cytoprotective transcription factor NRF2. Evaluation of in vivo antipsoriatic effects of topical TGN in the imiquimod-induced psoriasis-like dermatitis mouse model demonstrated amelioration of imiquimod-induced phenotypical changes, lesion severity score, epidermal thickening, and reduction in dermal cellularity. The spleen index also diminished in TGN-treated mice, suggesting anti-inflammatory properties of TGN. Moreover, TGN significantly attenuated the imiquimod-induced mRNA levels of psoriasis-associated inflammatory cytokines and antimicrobial peptides and reduced epidermal hyperproliferation. Taken together, TGN, as a potent NRF2 activator, is a promising therapeutic candidate for the development of antipsoriatic agents derived from medicinal plants.
Asunto(s)
Antiinflamatorios/farmacología , Factor 2 Relacionado con NF-E2/agonistas , Ácidos Pentanoicos/farmacología , Psoriasis/tratamiento farmacológico , Sesquiterpenos/farmacología , Administración Cutánea , Adulto , Animales , Antiinflamatorios/uso terapéutico , Línea Celular , Proliferación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Femenino , Humanos , Imiquimod/toxicidad , Queratinocitos/efectos de los fármacos , Queratinocitos/patología , Ratones , Factor 2 Relacionado con NF-E2/metabolismo , Ácidos Pentanoicos/uso terapéutico , Psoriasis/inducido químicamente , Psoriasis/inmunología , Psoriasis/patología , Sesquiterpenos/uso terapéutico , Tussilago/químicaRESUMEN
BACKGROUND & OBJECTIVES: Oral administration of tender leaf extract of Glycosmis pentaphylla is traditionally known to prevent the chikungunya virus infection. Even with wide usage, the antiviral components in this plant are neither identified nor characterized. This study was carried out with the objectives of profiling the phytocompounds in this plant through LC-MS/MS and to identify the active antiviral constituents and their drug-likeliness through molecular docking. METHODS: Phytocompounds were extracted hydro-alcoholically from powdered plant parts and analyzed using LC-MS/MS. Based on mass-to-charge ratio from LC-MS/MS, compounds were identified and used as ligands for molecular docking against chikungunya target proteins. The active principles were subjected to ADME/T analysis to verify their drug-likeliness. RESULTS: The docking results and ADME/T evaluation showed that the compounds, isovaleric acid and avicequinone- C have good interaction with the protein targets and hence could be the antiviral principles of the selected plant. These compounds presented acceptable drug properties and hence could be carried forward to in vivo studies for drug development. INTERPRETATION & CONCLUSION: The antiviral properties of G. pentaphylla are known since time-immemorial. This study revealed the probable interactions after the oral administration of tender leaves of Glycosmis in preventing the chikungunya virus infection and paves the path for designing future plant-based drugs.
Asunto(s)
Virus Chikungunya/efectos de los fármacos , Hemiterpenos/farmacología , Ácidos Pentanoicos/farmacología , Extractos Vegetales/farmacología , Quinonas/farmacología , Rutaceae/química , Administración Oral , Descubrimiento de Drogas , Simulación del Acoplamiento Molecular , Hojas de la Planta/químicaRESUMEN
PURPOSE: Short-chain fatty acids (SCFA) are known for their anti-inflammatory properties and may also prevent against the development of metabolic diseases. This study investigated possible effects of two valeric acid esters, monovalerin (MV) and trivalerin (TV) in rats fed high-fat diets. METHODS: Four groups of rats were given a low-fat diet (LF) or a high-fat control diet (HFC) with or without supplementation of MV or TV (5 g/kg) for 3 weeks (n = 7/group). SCFA (caecum, blood, liver and brain), succinic acid (liver), microbiota (caecum), lipid profile (liver and blood) and the inflammatory biomarker, lipopolysaccharide-binding protein (blood) were analysed at the end of the experiment. RESULTS: Supplementation of MV and TV to a high-fat diet increased 1.5-fold the amounts of acetic acid in the brain and 1.7-fold serum concentration of valeric acid, whereas liver succinic acid was reduced by 1.5-fold. Although liver triglyceride levels were higher in both MV and TV groups compared with the LF group, liver LDL/HDL ratio was lower in the MV group (P < 0.05). The caecal microbiota composition was altered, with threefold higher abundance of Bacteroidetes and higher ratio of Bacteroidetes/Firmicutes in the MV group compared with the HFC and LF groups. Acetic acid in the brain was negatively correlated with TM7, family S24-7 and rc4-4, and positively associated to Tenericutes and Anaeroplasma. CONCLUSIONS: The present study shows that MV and TV in the specified dose can affect caecal microbiota composition and, therefore, bacterial metabolites in the liver, serum and brain as well as the lipid profile in the liver.
Asunto(s)
Ácido Acético/metabolismo , Encéfalo/efectos de los fármacos , Dieta Alta en Grasa , Microbioma Gastrointestinal/efectos de los fármacos , Hígado/efectos de los fármacos , Ácidos Pentanoicos/farmacología , Ácido Succínico/metabolismo , Animales , Encéfalo/metabolismo , Hígado/metabolismo , Masculino , Modelos Animales , Ratas , Ratas WistarRESUMEN
Antimicrobial resistance is the greatest threat to the treatment of bacterial infectious diseases. The development of resistance-modifying agents (RMAs) represents a promising strategy to mitigate the spread of bacterial antimicrobial resistance. In this study, a natural product, isovalerylshikonin (IVS), was isolated from Arnebia euchroma, a traditional Chinese medicine herb, that exhibited marginal antibacterial activity against drug-resistant Staphylococcus aureus RN4220, with a minimum inhibitory concentration (MIC) of 16 mg/L. In addition, a synergistic effect between IVS and streptomycin (STM) was detected by the microdilution antimicrobial chequerboard assay, with a reduction in the MIC of STM by up to 16-fold against strain RN4220. A bacterial ethidium bromide efflux assay and reverse transcription PCR were performed to investigate the synergistic mechanism. IVS significantly inhibited bacterial efflux and expression of msrA mRNA in vitro. A murine peritonitis/sepsis model was employed to test the in vivo synergistic activity of IVS and STM. IVS synergistically decreased bacterial counts with STM in peritoneal, spleen and liver tissue and increased mouse survival with STM in 7 days. The acute toxicity of IVS was tested and the 50% lethal dose (LD50) of IVS with a single exposure was 2.584 g/kg in mice. Overall, IVS, a low-toxicity RMA, exhibited synergistic antibacterial activities in vitro and in vivo against drug-resistant S. aureus. The effects were mediated by suppression of msrA mRNA expression and reduced bacterial efflux. In addition, these data support that IVS is a potential RMA against microbial resistance caused by the MsrA efflux pump.
Asunto(s)
Antibacterianos/farmacología , Boraginaceae/química , Naftoquinonas/farmacología , Ácidos Pentanoicos/farmacología , Infecciones Estafilocócicas/tratamiento farmacológico , Staphylococcus aureus/efectos de los fármacos , Animales , Antibacterianos/administración & dosificación , Antibacterianos/farmacocinética , Sinergismo Farmacológico , Ratones , Pruebas de Sensibilidad Microbiana , Naftoquinonas/administración & dosificación , Naftoquinonas/química , Naftoquinonas/farmacocinética , Ácidos Pentanoicos/administración & dosificación , Ácidos Pentanoicos/química , Ácidos Pentanoicos/farmacocinética , Peritonitis/tratamiento farmacológico , Peritonitis/microbiología , Sepsis/tratamiento farmacológico , Sepsis/microbiología , Infecciones Estafilocócicas/microbiologíaRESUMEN
Epilepsy has been treated for centuries with herbal remedies, including leaves of the African shrub Mallotus oppositifolius, yet the underlying molecular mechanisms have remained unclear. Voltage-gated potassium channel isoforms KCNQ2-5, predominantly KCNQ2/3 heteromers, underlie the neuronal M-current, which suppresses neuronal excitability, protecting against seizures. Here, in silico docking, mutagenesis and cellular electrophysiology reveal that two components of M. oppositifolius leaf extract, mallotoxin (MTX) and isovaleric acid (IVA), act synergistically to open neuronal KCNQs, including KCNQ2/3 channels. Correspondingly, MTX and IVA combine to suppress pentylene tetrazole-induced tonic seizures in mice, whereas individually they are ineffective. Co-administering MTX and IVA with the modern, synthetic anticonvulsant retigabine creates a further synergy that voltage independently locks KCNQ2/3 open. Leveraging this synergy, which harnesses ancient and modern medicines to exploit differential KCNQ isoform preferences, presents an approach to developing safe yet effective anticonvulsants.
Asunto(s)
Anticonvulsivantes/farmacología , Canales de Potasio KCNQ/efectos de los fármacos , Mallotus (Planta)/química , Ácidos Pentanoicos/farmacología , Animales , Anticonvulsivantes/uso terapéutico , Carbamatos/farmacología , Carbamatos/uso terapéutico , Sinergismo Farmacológico , Hemiterpenos , Ratones , Fenilendiaminas/farmacología , Fenilendiaminas/uso terapéutico , Fitoterapia , Convulsiones/prevención & control , Xenopus laevisRESUMEN
Isovalerate supplements could stimulate rumen development by improving morphology and function of rumen mucosa, and then promote the growth of calves. This study was done to evaluate the effects of isovalerate supplements on morphology and functional gene expression of rumen mucosa in dairy calves. In total, 48 Chinese Holstein male calves with 15 days of age and 45.1±0.36 kg of BW were randomly assigned to four groups. The treatments were: control, low-isovalerate, moderate-isovalerate and high-isovalerate with 0, 3, 6 and 9 g isovalerate per calf per day, respectively. Supplementary isovalerate was hand-mixed into milk in pre-weaning calves and into concentrate portion in post-weaning calves. The study consisted of a 15-day-adaptation period and a 60-day-sampling period. Calves were weaned at 60 days of age. Three calves were slaughtered from each of the four treatments at 30, 60 and 90 days of age. The weight of body and stomach were measured, samples of ruminal tissues and blood were analyzed. Total stomach weight, total stomach to BW ratio, rumen wall and keratinized layer thickness, serum growth hormone and IGF-1 for both pre- and post-weaning calves increased linearly with increasing isovalerate supplements. Rumen to total stomach weight ratio, the length and width of rumen papillae, and serum ß-hydroxybutyrate increased linearly for post-weaning calves. However, abomasum weight to total stomach weight ratio decreased linearly for both pre- and post-weaning calves. The relative messenger RNA expression for growth hormone receptor, IGF-1 receptor and 3-hydroxy-3-methylglutaryl-CoA synthase 1 in rumen mucosa increased linearly for post-weaning calves. Our results suggested that isovalerate supplements promoted rumen development in a dose-dependent manner. The optimum dose was 6.0 g isovalerate per calf per day.
Asunto(s)
Alimentación Animal/análisis , Bovinos/genética , Suplementos Dietéticos , Regulación de la Expresión Génica/efectos de los fármacos , Leche/química , Ácidos Pentanoicos/farmacología , Ácido 3-Hidroxibutírico/sangre , Animales , Bovinos/fisiología , Dieta/veterinaria , Hemiterpenos , Factor I del Crecimiento Similar a la Insulina/análisis , Masculino , Membrana Mucosa , Distribución Aleatoria , Rumen/metabolismo , DesteteRESUMEN
Cranberry procyanidins and quercetin derivatives are considered possible active compounds against urinary tract infections (UTIs). In this paper a small group (n=6) of healthy subjects consumed a product containing 360mg of cranberry extract (42.6% w/w of PAC-A and 14.6% w/w of PAC-B) and 200mg of quercetin. Urine samples were collected after 2,4,6,8, and 24h. The changes in antiadhesive properties against urophatogenic E. coli of the urinary output were determined in vitro and modification to urinary metabolome were studied by LC-MS. Significant antiadhesive properties of urine samples were observed, with the greatest effect 6-8h after oral administration, confirming the possible usefulness of cranberry containing products in urinary tract infections (UTI). Metabolomic analysis revealed that valeric acid and valerolactone derivatives that were detected in 6 and 8h sample, while 4-hydroxy-5-(phenyl)-valeric acid-O-glucuronide and 5-(3',4'-dihydroxyphenyl)-γ-valerolactone at 6h and 4-hydroxy-5-(phenyl)-valeric acid-O-sulphate, 3-hydroxyphenyl-valeric acid, 5-(4'-hydroxyphenyl)-gamma-valerolactone-4'-O-glucuronide and 4-hydroxy-5-(3'-hydroxyphenyl)-valeric acid-3'-O-sulphate were the most abundant at 8h. The present study shows that the antiadhesive properties of urine sample after cranberry consumption are not ascribable to the direct effect of PAC-A, because their levels in urinary output are in the range of ng/mL. On the other hand, significant metabolites that were detected are mainly metabolites of intestinal action on polyphenols and PACs, as well as glucuronidated and sulphated quercetin, suggesting an important role of intestinal modification of phytoconstituents in the cranberry extract mechanism of action.
Asunto(s)
Adhesión Bacteriana/efectos de los fármacos , Metaboloma , Extractos Vegetales/farmacología , Escherichia coli Uropatógena/efectos de los fármacos , Vaccinium macrocarpon/química , Adulto , Femenino , Humanos , Mucosa Intestinal/metabolismo , Lactonas/farmacología , Masculino , Metabolómica , Ácidos Pentanoicos/farmacología , Polifenoles/farmacología , Proantocianidinas/farmacología , Quercetina/farmacología , Infecciones Urinarias/tratamiento farmacológico , Orina/química , Adulto JovenRESUMEN
Tussilagonone is a compound derived from the medicinal plant Tussilago farfara L., which is used as a traditional medicine for respiratory diseases, including asthma and pneumonia. Recent reports suggest that tussilagonone exhibits anti-inflammatory effects; however, the scope of protective functions has not been elucidated yet. In this study, we demonstrate that tussilagonone enhances cellular detoxification by increasing quinone reductase activity in Hepa1c1c7 cells. In addition, tussilagonone decreased tert-butyl hydroperoxide(t-BHP)-induced ROS production and cell death, suggesting that it also acts as a potent antioxidant. To verify the molecular mechanism underlying tussilagonone activity, we examined the expression of nuclear factor erythroid 2-related factor 2(Nrf2)-a transcription factor that regulates antioxidant protein expression-in HepG2 cells. Significantly, these results showed that tussilagonone induces Nrf2 activation and nuclear accumulation, resulting in the upregulation of the detoxifying enzymes NAD(P)H quinone dehydrogenase 1(NQO1) and heme oxygenase-1(HO-1) that protect cells from oxidative stress. Further molecular analyses revealed that tussilagonone-induced Nrf2 activation was mediated by ERK1/2 in HepG2 cells. Collectively, these data indicate that tussilagonone attenuates t-BHP-induced ROS and activates quinone reductase activity via Nrf2 pathway activation and target gene expression, and thereby acts as an antioxidant that protects HepG2 cells from oxidative stress and associated damage.
Asunto(s)
Regulación de la Expresión Génica/efectos de los fármacos , Factor 2 Relacionado con NF-E2/metabolismo , Estrés Oxidativo/efectos de los fármacos , Ácidos Pentanoicos/farmacología , Sesquiterpenos/farmacología , Tussilago/química , Elementos de Respuesta Antioxidante , Antioxidantes/metabolismo , Supervivencia Celular , Células Hep G2 , Humanos , Factor 2 Relacionado con NF-E2/genética , Ácidos Pentanoicos/química , Interferencia de ARN , ARN Interferente Pequeño , Especies Reactivas de Oxígeno , Sesquiterpenos/química , Regulación hacia ArribaRESUMEN
BACKGROUND & AIMS: Hepatocyte apoptosis, the hallmark of non-alcoholic steatohepatitis (NASH) contributes to liver injury and fibrosis. Although, both the intrinsic and extrinsic apoptotic pathways are involved in the pathogenesis of NASH, the final common step of apoptosis is executed by a family of cysteine-proteases termed caspases. Thus, our aim was to ascertain if administration of Emricasan, a pan-caspase inhibitor, ameliorates liver injury and fibrosis in a murine model of NASH. METHODS: C57/BL6J-mice were fed regular chow or high fat diet (HFD) for 20 weeks. All mice were treated with vehicle or Emricasan. RESULTS: Mice fed a HFD diet demonstrate a five-fold increase in hepatocyte apoptosis by the TUNEL assay and a 1.5-fold and 1.3-fold increase in caspase-3 and-8 activities respectively; this increase in apoptosis was substantially attenuated in mice fed a HFD treated with Emricasan (HFD-Em). Likewise, liver injury and inflammation were reduced in mice fed HFD-Em as compare to HFD by measuring serum aspartate aminotransferase and alanine aminotransferase levels, NAS histological score and IL 1-ß, TNF-α, monocyte chemoattractant protein (MCP-1) and C-X-C chemokine ligand-2 (CXCL2) quantitative reverse-transcription polymerase chain reaction (qPCR). These differences could not be attributed to differences in hepatic steatosis as liver triglycerides content were similar in both HFD groups. Hepatic fibrosis was reduced by Emricasan in HFD animals by decreasing αSMA (a marker for hepatic stellate cell activation), fibrosis score, Sirius red staining, hydroxyproline liver content and profibrogenic cytokines by qPCR. CONCLUSION: In conclusion, these data demonstrate that in a murine model of NASH, liver injury and fibrosis are suppressed by inhibiting hepatocytes apoptosis and suggests that Emricasan may be an attractive antifibrotic therapy in NASH.
Asunto(s)
Apoptosis/efectos de los fármacos , Inhibidores de Caspasas/uso terapéutico , Hepatocitos/efectos de los fármacos , Enfermedad del Hígado Graso no Alcohólico/prevención & control , Ácidos Pentanoicos/uso terapéutico , Animales , Inhibidores de Caspasas/farmacología , Dieta Alta en Grasa/efectos adversos , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Fibrosis , Hepatitis/prevención & control , Hígado/efectos de los fármacos , Hígado/patología , Masculino , Ratones Endogámicos C57BL , Enfermedad del Hígado Graso no Alcohólico/etiología , Enfermedad del Hígado Graso no Alcohólico/patología , Ácidos Pentanoicos/farmacologíaRESUMEN
LL-37 is the single cathelicidin host defense peptide in humans with direct antimicrobial and immunomodulatory activities. Specific regulation of LL-37 synthesis has emerged as a novel non-antibiotic approach to disease control and prevention. Short-chain fatty acids, and butyrate in particular, were found recently to be strong inducers of LL-37 gene expression without causing inflammation. Here, we further evaluated the LL-37-inducing efficiency of a broad range of saturated free fatty acids and their derivatives in human HT-29 colonic epithelial cells and U-937 monocytic cells by real-time RT-PCR. Surprisingly, we revealed that valerate, hexanoate, and heptanoate with 5-7 carbons are more potent than 4-carbon butyrate in promoting LL-37 gene expression in both cell types. Free fatty acids with longer than 7 or shorter than 4 carbons showed only a marginal effect on LL-37 expression. Studies with a series of fatty acid derivatives with modifications in the aliphatic chain or carboxylic acid group yielded several analogs such as benzyl butyrate, trans-cinnamyl butyrate, glyceryl tributyrate, and phenethyl butyrate with a comparable LL-37-inducing activity to sodium butyrate. On the other hand, although reactive, the anhydride derivatives of short- and medium-chain fatty acids are as potent as their corresponding free acid forms in LL-37 induction. Thus, these newly identified free fatty acids and their analogs with a strong capacity to augment LL-37 synthesis may hold promise as immune boosting dietary supplements for antimicrobial therapy.
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Antiinfecciosos/farmacología , Péptidos Catiónicos Antimicrobianos/agonistas , Butiratos/farmacología , Células Epiteliales/efectos de los fármacos , Factores Inmunológicos/farmacología , Monocitos/efectos de los fármacos , Antiinfecciosos/química , Péptidos Catiónicos Antimicrobianos/biosíntesis , Péptidos Catiónicos Antimicrobianos/genética , Butiratos/química , Caproatos/química , Caproatos/farmacología , Línea Celular Tumoral , Células Epiteliales/citología , Células Epiteliales/metabolismo , Expresión Génica/efectos de los fármacos , Ácidos Heptanoicos/química , Ácidos Heptanoicos/farmacología , Humanos , Factores Inmunológicos/química , Monocitos/citología , Monocitos/metabolismo , Ácidos Pentanoicos/química , Ácidos Pentanoicos/farmacología , Relación Estructura-Actividad , CatelicidinasRESUMEN
Transient receptor potential vanilloid 1 (TRPV1) is a Ca(2+)-permeable non-selective cation channel that transmits pain signals. TRPV1 is activated by multiple stimuli such as capsaicin, acid, and heat. During inflammation, TRPV1 is reported to be sensitized by protein kinase C (PKC) in dorsal root ganglia (DRG) neurons, which leads to reduction in the threshold of the temperature for TRPV1 activation to body temperature. This sensitization is considered to contribute to chronic inflammatory pain. In a previous study, we discovered orally active 5,5-diarylpentadienamide TRPV1 antagonists. To examine the effects of our TRPV1 antagonists on PKC-sensitized TRPV1, we developed an in vitro assay system to monitor the TRPV1 sensitization by PKC. In this assay system, our TRPV1 antagonists, such as (2E,4Z)-N-[(3R)-3-hydroxy-2-oxo-1,2,3,4-tetrahydro-5-quinolyl]-5-(4-isopropoxyphenyl)-5-(4-trifluoromethylphenyl)-2,4-pentadienamide (K-685), inhibited the activation of TRPV1 sensitized by PKC. The potentiation of heat-induced inward currents by PKC was seen in rat DRG neurons, and K-685 attenuated these currents. Furthermore, K-685 reversed the thermal hyperalgesia and mechanical allodynia in a rat complete Freund's adjuvant-induced inflammatory pain model. These results therefore suggest that K-685 has a strong potential as a new analgesic drug for the treatment of inflammatory pain.
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Analgésicos , Dolor Crónico/tratamiento farmacológico , Dolor Crónico/genética , Adyuvante de Freund/efectos adversos , Inflamación/complicaciones , Ácidos Pentanoicos/farmacología , Ácidos Pentanoicos/uso terapéutico , Proteína Quinasa C/fisiología , Quinolonas/farmacología , Quinolonas/uso terapéutico , Canales Catiónicos TRPV/antagonistas & inhibidores , Canales Catiónicos TRPV/metabolismo , Animales , Dolor Crónico/etiología , Modelos Animales de Enfermedad , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
The crude methanol extract of the dried aerial parts of Siegesbeckia glabrescens (Compositae) showed antibacterial activity against the foodborne pathogen Staphylococcus aureus. Bioactivity-guided separation led to the isolation of 3-(dodecanoyloxy)-2-(isobutyryloxy)-4-methylpentanoic acid from nature for the first time. The structure was determined by spectroscopic data analysis (UV, MS, and NMR). The minimal inhibitory concentration (MIC) of 3-(dodecanoyloxy)-2-(isobutyryloxy)-4-methylpentanoic acid against S. aureus was found to be 3.12 μg/mL. In addition, in a further antimicrobial activity assay against Gram-positive (B. subtilis, E. faecalis, P. acnes, S. epidermidis, S. schleiferi subsp. coagulans, S. agalactiae and S. pyrogens), and Gram-negative bacteria (E. coli and P. aeruginosa), and yeast strains (C. alibicans and F. neoformans), the antimicrobial activity of the compound was found to be specific for Gram-positive bacteria. The MIC values of the compound for Gram-positive bacteria ranged from 3.12 to 25 mg/mL. Furthermore, it was found that the 2-(isobutyryloxy)-4-methylpentanoic acid substituent may operate as a key factor in the antibacterial activity of the compound, together with the laurate group.
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Antibacterianos/farmacología , Asteraceae/química , Ácidos Pentanoicos/farmacología , Componentes Aéreos de las Plantas/química , Extractos Vegetales/farmacología , Antibacterianos/química , Antibacterianos/aislamiento & purificación , Antifúngicos/aislamiento & purificación , Antifúngicos/farmacología , Bacterias Gramnegativas/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Ácidos Pentanoicos/química , Ácidos Pentanoicos/aislamiento & purificación , Extractos Vegetales/química , Extractos Vegetales/aislamiento & purificación , Staphylococcus aureus/efectos de los fármacos , Staphylococcus aureus/crecimiento & desarrollo , Levaduras/efectos de los fármacosRESUMEN
The effect of short chained organic acids and bases on the surface energy and wetting properties of submicrometer alumina powder was assessed. The surface chemistry of treated powders was determined by means of Diffuse Reflectance Infrared Fourier Transform spectroscopy and compared to untreated powder. The wetting of powders was measured using a modified Washburn method, based on the use of precompacted powder samples. The geometric factor needed to calculate the contact angle was derived from measurements of the porous properties of the powder compacts. Contact angle measurements with several probe liquids before and after modification allowed a theoretical estimation of the surface energy based on the surface tension component theory. Trends in the surface energy components were linked to observations in infrared spectra. The results showed that the hydrophobic character of the precompacted powder depends on both the chain length and polar group of the modifying agent.
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Óxido de Aluminio/química , Butilaminas/química , Emulsiones/química , Ácidos Pentanoicos/química , Propionatos/química , Butilaminas/farmacología , Interacciones Hidrofóbicas e Hidrofílicas , Ácidos Pentanoicos/farmacología , Polvos/química , Propionatos/farmacología , Espectroscopía Infrarroja por Transformada de Fourier , Propiedades de Superficie , Tensión SuperficialRESUMEN
It has been known that tissues of porpoise contain unique structured-lipids as combination of iso-valeric acid (iso-C5:0) and omega 3 polyunsaturated fatty acids (omega3 PUFAs). It is well known that omega3 PUFAs have lipid-lowering effects in animal and human studies. Although branched chain fatty acids have been interested in their unique functions, there is no data concerning the effect of iso-C5:0 on lipid metabolism. In this study we investigated the effect of structured-lipids from porpoise adipose tissue (porpoise oil) on lipid metabolism in Otsuka Long-Evans Tokushima Fatty (OLETF) rats. For 4 weeks, rats were fed semisynthetic diets containing either 10% corn oil or 5% corn oil plus 5% porpoise oil. After feeding period, the porpoise oil diet significantly alleviated hepatic triglyceride accumulation compared with the control diet in OLETF rats. Although serum triglyceride level increased, serum level of adiponectin that can protect liver function and alleviate abnormalities of lipid and glucose metabolism increased in rats fed porpoise oil diet. In conclusion, results from the present study suggest that porpoise oil feeding prevents the development of fatty liver disease through the enhancement of lipoprotein secretion and increase of adiponectin production in obese rats.
Asunto(s)
Ácidos Grasos Omega-3/química , Hígado Graso/prevención & control , Obesidad/complicaciones , Obesidad/tratamiento farmacológico , Aceites/química , Aceites/farmacología , Adiponectina/sangre , Adiponectina/metabolismo , Animales , Colesterol/sangre , Colesterol/metabolismo , Aceite de Maíz , Ácidos Grasos Omega-3/administración & dosificación , Ácidos Grasos Omega-3/farmacología , Hígado Graso/sangre , Hígado Graso/tratamiento farmacológico , Hígado Graso/metabolismo , Hemiterpenos , Masculino , Obesidad/sangre , Obesidad/metabolismo , Ácidos Pentanoicos/administración & dosificación , Ácidos Pentanoicos/química , Ácidos Pentanoicos/farmacología , Fosfolípidos/sangre , Fosfolípidos/metabolismo , Marsopas , Ratas , Ratas Endogámicas OLETF , Factores de Tiempo , Triglicéridos/sangre , Triglicéridos/metabolismoRESUMEN
We investigated whether the 2 Hz electroacupuncture (EA) analgesia is associated with phosphorylation of N-methyl-D-aspartate receptor (NMDAR) NR-1 subunits and NMDAR antagonism in the lumbar spinal cord of rats. EA stimulation produced an increase of serine phosphorylation of NMDAR NR-1 subunits in the spinal cord as compared with normal conditions. However, the intrathecal injection of NMDAR antagonist D-2-amino-5-phosphonopentanoic acid significantly prevented serine phosphorylation of NMDAR NR-1 subunits induced by EA stimulation in the dorsal horn of spinal cord. These results indicate that EA analgesia by stimulation of peripheral nerves may be involved in an increase of NR-1 serine phosphorylation in the dorsal horn of the spinal cord.
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Electroacupuntura/métodos , N-Metilaspartato/antagonistas & inhibidores , Subunidades de Proteína/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Médula Espinal/metabolismo , Animales , Masculino , Ácidos Pentanoicos/farmacología , Fosforilación/efectos de los fármacos , Proteínas Proto-Oncogénicas c-fos/metabolismo , Ratas , Ratas Sprague-DawleyRESUMEN
Cholecystokinin (CCK), peptide YY (PYY), and ghrelin have been proposed to act as satiety hormones. CCK and PYY are stimulated during meal intake by the presence of nutrients in the small intestine, especially fat, whereas ghrelin is inhibited by eating. The sequence of events (fat intake followed by fat hydrolysis and CCK release) suggests that this process is crucial for triggering the effects. The aim of this study was therefore to investigate whether CCK mediated the effect of intraduodenal (ID) fat on ghrelin secretion and PYY release via CCK-1 receptors. Thirty-six male volunteers were studied in three consecutive, randomized, double-blind, cross-over studies: 1) 12 subjects received an ID fat infusion with or without 120 mg orlistat, an irreversible inhibitor of gastrointestinal lipases, compared with vehicle; 2) 12 subjects received ID long-chain fatty acids (LCF), ID medium-chain fatty acids (MCF), or ID vehicle; and 3) 12 subjects received ID LCF with and without the CCK-1 receptor antagonist dexloxiglumide (Dexlox) or ID vehicle plus intravenous saline (placebo). ID infusions were given for 180 min. The effects of these treatments on ghrelin concentrations and PYY release were quantified. Plasma hormone concentrations were measured in regular intervals by specific RIA systems. We found the following results. 1) ID fat induced a significant inhibition in ghrelin levels (P < 0.01) and a significant increase in PYY concentrations (P < 0.004). Inhibition of fat hydrolysis by orlistat abolished both effects. 2) LCF significantly inhibited ghrelin levels (P < 0.02) and stimulated PYY release (P < 0.008), whereas MCF were ineffective compared with controls. 3) Dexlox administration abolished the effect of LCF on ghrelin and on PYY. ID fat or LCF significantly stimulated plasma CCK (P < 0.006 and P < 0.004) compared with saline. MCF did not stimulate plasma CCK release. In summary, fat hydrolysis is essential to induce effects on ghrelin and PYY through the generation of LCF, whereas MCF are ineffective. Furthermore, LCF stimulated plasma CCK release, suggesting that peripheral CCK is the mediator of these actions. The CCK-1 receptor antagonist Dexlox abolished the effect of ID LCF, on both ghrelin and PYY. Generation of LCF through hydrolysis of fat is a critical step for fat-induced inhibition of ghrelin and stimulation of PYY in humans; the signal is mediated via CCK release and CCK-1 receptors.
Asunto(s)
Inhibidores Enzimáticos/farmacología , Lactonas/farmacología , Hormonas Peptídicas/metabolismo , Péptido YY/metabolismo , Receptores de Colecistoquinina/antagonistas & inhibidores , Adulto , Caprilatos/administración & dosificación , Caprilatos/química , Colecistoquinina/sangre , Estudios Cruzados , Método Doble Ciego , Ácidos Grasos/administración & dosificación , Ácidos Grasos/química , Ácidos Grasos/fisiología , Ghrelina , Humanos , Infusiones Intravenosas , Lactonas/administración & dosificación , Lipasa/antagonistas & inhibidores , Masculino , Ácido Oléico/administración & dosificación , Ácido Oléico/química , Ácido Oléico/fisiología , Aceite de Oliva , Orlistat , Ácidos Pentanoicos/administración & dosificación , Ácidos Pentanoicos/farmacología , Hormonas Peptídicas/sangre , Péptido YY/sangre , Aceites de Plantas/administración & dosificación , Factores de TiempoRESUMEN
Brickellia paniculata has been used as spasmolytic in Mexican traditional medicine. Xanthomicrol and 3alpha-angeloyloxy-2alpha-hydroxy-13,14Z-dehydrocativic acid (AAHDD) are two of the main leaf components with antispasmodic activity. However, their mechanism of action remains unknown. An in vitro comparative study between xanthomicrol and AAHDD on rat uterus precontracted by either KCl (60 mM) or oxytocin (10 mIU/ml) was carried out to investigate the mechanism of action of these compounds on smooth muscle. Relaxant effect was measured as median inhibitory concentration (IC(50)) and maximal effect as maximal relaxant response (R(max)). Xanthomicrol was significantly more potent than AAHDD in inhibiting contractions induced by KCl 60 mM, whereas AAHDD was more potent than xanthomicrol in inhibiting contractions induced by oxytocin 10 mIU/ml. These results suggest that xanthomicrol induces a greater blocking effect on voltage-operated calcium channels than on receptor-operated gates.