RESUMEN
Lyme disease is on the rise. Caused by a spirochete Borreliella burgdorferi, it affects an estimated 500,000 people in the United States alone. The antibiotics currently used to treat Lyme disease are broad spectrum, damage the microbiome, and select for resistance in non-target bacteria. We therefore sought to identify a compound acting selectively against B. burgdorferi. A screen of soil micro-organisms revealed a compound highly selective against spirochetes, including B. burgdorferi. Unexpectedly, this compound was determined to be hygromycin A, a known antimicrobial produced by Streptomyces hygroscopicus. Hygromycin A targets the ribosomes and is taken up by B. burgdorferi, explaining its selectivity. Hygromycin A cleared the B. burgdorferi infection in mice, including animals that ingested the compound in a bait, and was less disruptive to the fecal microbiome than clinically relevant antibiotics. This selective antibiotic holds the promise of providing a better therapeutic for Lyme disease and eradicating it in the environment.
Asunto(s)
Antibacterianos/uso terapéutico , Enfermedad de Lyme/tratamiento farmacológico , Animales , Borrelia burgdorferi/efectos de los fármacos , Calibración , Cinamatos/química , Cinamatos/farmacología , Cinamatos/uso terapéutico , Evaluación Preclínica de Medicamentos , Heces/microbiología , Femenino , Células HEK293 , Células Hep G2 , Humanos , Higromicina B/análogos & derivados , Higromicina B/química , Higromicina B/farmacología , Higromicina B/uso terapéutico , Enfermedad de Lyme/microbiología , Ratones , Pruebas de Sensibilidad Microbiana , Microbiota/efectos de los fármacosRESUMEN
Estrogen receptor-positive (ER+) breast cancers frequently remain dependent on ER signaling even after acquiring resistance to endocrine agents, prompting the development of optimized ER antagonists. Fulvestrant is unique among approved ER therapeutics due to its capacity for full ER antagonism, thought to be achieved through ER degradation. The clinical potential of fulvestrant is limited by poor physicochemical features, spurring attempts to generate ER degraders with improved drug-like properties. We show that optimization of ER degradation does not guarantee full ER antagonism in breast cancer cells; ER "degraders" exhibit a spectrum of transcriptional activities and anti-proliferative potential. Mechanistically, we find that fulvestrant-like antagonists suppress ER transcriptional activity not by ER elimination, but by markedly slowing the intra-nuclear mobility of ER. Increased ER turnover occurs as a consequence of ER immobilization. These findings provide proof-of-concept that small molecule perturbation of transcription factor mobility may enable therapeutic targeting of this challenging target class.
Asunto(s)
Neoplasias de la Mama/metabolismo , Antagonistas del Receptor de Estrógeno/farmacología , Fulvestrant/farmacología , Receptores de Estrógenos/antagonistas & inhibidores , Receptores de Estrógenos/metabolismo , Animales , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Proliferación Celular/efectos de los fármacos , Cinamatos/farmacología , Resistencia a Antineoplásicos , Antagonistas del Receptor de Estrógeno/uso terapéutico , Femenino , Fulvestrant/uso terapéutico , Células HEK293 , Xenoinjertos , Humanos , Indazoles/farmacología , Ligandos , Células MCF-7 , Ratones , Ratones Endogámicos NOD , Ratones Desnudos , Ratones SCID , Polimorfismo de Nucleótido Simple , Proteolisis/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Transcripción Genética/efectos de los fármacosRESUMEN
TRPV1 is a Ca(2+)-permeable channel studied mostly as a pain receptor in sensory neurons. However, its role in other cell types is poorly understood. Here we found that TRPV1 was functionally expressed in CD4(+) T cells, where it acted as a non-store-operated Ca(2+) channel and contributed to T cell antigen receptor (TCR)-induced Ca(2+) influx, TCR signaling and T cell activation. In models of T cell-mediated colitis, TRPV1 promoted colitogenic T cell responses and intestinal inflammation. Furthermore, genetic and pharmacological inhibition of TRPV1 in human CD4(+) T cells recapitulated the phenotype of mouse Trpv1(-/-) CD4(+) T cells. Our findings suggest that inhibition of TRPV1 could represent a new therapeutic strategy for restraining proinflammatory T cell responses.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Inflamación/inmunología , Activación de Linfocitos/inmunología , Receptores de Antígenos de Linfocitos T/metabolismo , Canales Catiónicos TRPV/genética , Anilidas/farmacología , Animales , Linfocitos T CD4-Positivos/citología , Calcio/metabolismo , Canales de Calcio/inmunología , Señalización del Calcio/efectos de los fármacos , Señalización del Calcio/inmunología , Capsaicina/farmacología , Células Cultivadas , Cinamatos/farmacología , Colitis/inmunología , Humanos , Interleucina-10/genética , Intestinos/inmunología , Intestinos/patología , Activación de Linfocitos/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Fármacos del Sistema Sensorial/farmacología , Canales Catiónicos TRPV/antagonistas & inhibidores , Canales Catiónicos TRPV/biosíntesisRESUMEN
Chemical inhibitors are often implemented for the functional characterization of genes to overcome the limitations associated with genetic approaches. Although it is well established that the specificity of the compound is key to success of a pharmacological approach, off-target effects are often overlooked or simply neglected in a complex biological setting. Here we illustrate the cause and implications of such secondary effects by focusing on piperonylic acid (PA), an inhibitor of CINNAMATE-4-HYDROXYLASE (C4H) that is frequently used to investigate the involvement of lignin during plant growth and development. When supplied to plants, we found that PA is recognized as a substrate by GRETCHEN HAGEN 3.6 (GH3.6), an amido synthetase involved in the formation of the indole-3-acetic acid (IAA) conjugate IAA-Asp. By competing for the same enzyme, PA interferes with IAA conjugation, resulting in an increase in IAA concentrations in the plant. In line with the broad substrate specificity of the GH3 family of enzymes, treatment with PA increased not only IAA levels but also those of other GH3-conjugated phytohormones, namely jasmonic acid and salicylic acid. Finally, we found that interference with the endogenous function of GH3s potentially contributes to phenotypes previously observed upon PA treatment. We conclude that deregulation of phytohormone homeostasis by surrogate occupation of the conjugation machinery in the plant is likely a general phenomenon when using chemical inhibitors. Our results hereby provide a novel and important basis for future reference in studies using chemical inhibitors.
Asunto(s)
Ácidos Indolacéticos , Reguladores del Crecimiento de las Plantas , Ácidos Indolacéticos/farmacología , Benzoatos , Oxigenasas de Función Mixta/genética , Cinamatos/farmacología , Regulación de la Expresión Génica de las PlantasRESUMEN
Loss of proteostasis and cellular senescence have been previously established as characteristics of aging; however, their interaction in the context of lung aging and potential contributions to aging-associated lung remodeling remains understudied. In this study, we aimed to characterize endoplasmic reticulum (ER) stress response, cellular senescence, and their interaction in relation to extracellular matrix (ECM) production in lung fibroblasts from young (25-45 yr) and old (>60 yr) humans. Fibroblasts from young and old patients without significant preexisting lung disease were exposed to vehicle, MG132, etoposide, or salubrinal. Afterward, cells and cell lysates or supernatants were analyzed for ER stress, cellular senescence, and ECM changes using protein analysis, proliferation assay, and senescence-associated beta-galactosidase (SA-ß-Gal) staining. At baseline, fibroblasts from aging individuals showed increased levels of ER stress (ATF6 and PERK), senescence (p21 and McL-1), and ECM marker (COL1A1) compared to those from young individuals. Upon ER stress induction and etoposide exposure, fibroblasts showed an increase in senescence (SA-ß-Gal, p21, and Cav-1), ER stress (PERK), and ECM markers (COL1A1 and LUM) compared to vehicle. Additionally, IL-6 and IL-8 levels were increased in the supernatants of MG132- and etoposide-treated fibroblasts, respectively. Finally, the ER stress inhibitor salubrinal decreased the expression of p21 compared to vehicle and MG132 treatments; however, salubrinal inhibited COL1A1 but not p21 expression in MG132-treated fibroblasts. Our study suggests that ER stress response plays an important role in establishment and maintenance of a senescence phenotype in lung fibroblasts and therefore contributes to altered remodeling in the aging lung.NEW & NOTEWORTHY The current study establishes functional links between endoplasmic reticulum (ER) stress and cellular senescence per se in the specific context of aging human lung fibroblasts. Recognizing that the process of aging per se is complex, modulated by the myriad of lifelong and environmental exposures, it is striking to note that chronic ER stress may play a crucial role in the establishment and maintenance of cellular senescence in lung fibroblasts.
Asunto(s)
Senescencia Celular , Estrés del Retículo Endoplásmico , Fibroblastos , Pulmón , Humanos , Senescencia Celular/efectos de los fármacos , Estrés del Retículo Endoplásmico/efectos de los fármacos , Fibroblastos/metabolismo , Fibroblastos/efectos de los fármacos , Fibroblastos/patología , Persona de Mediana Edad , Pulmón/metabolismo , Pulmón/patología , Pulmón/efectos de los fármacos , Adulto , Anciano , Masculino , Femenino , Matriz Extracelular/metabolismo , Tiourea/farmacología , Tiourea/análogos & derivados , Células Cultivadas , Cinamatos/farmacología , Factor de Transcripción Activador 6/metabolismo , Proliferación Celular/efectos de los fármacos , Etopósido/farmacología , Colágeno Tipo I/metabolismo , Envejecimiento/metabolismo , Envejecimiento/patología , Cadena alfa 1 del Colágeno Tipo I/metabolismo , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , eIF-2 Quinasa/metabolismoRESUMEN
The SARS-CoV-2 coronavirus is characterized by high mutation rates and significant infectivity, posing ongoing challenges for therapeutic intervention. To address potential challenges in the future, the continued development of effective drugs targeting SARS-CoV-2 remains an important task for the scientific as well as the pharmaceutical community. The main protease (Mpro) of SARS-CoV-2 is an ideal therapeutic target for COVID-19 drug development, leading to the introduction of various inhibitors, both covalent and non-covalent, each characterized by unique mechanisms of action and possessing inherent strengths and limitations. Natural products, being compounds naturally present in the environment, offer advantages such as low toxicity and diverse activities, presenting a viable source for antiviral drug development. Here, we identified a natural compound, rosmarinic acid, which exhibits significant inhibitory effects on the Mpro of the SARS-CoV-2. Through detailed structural biology analysis, we elucidated the precise crystal structure of the complex formed between rosmarinic acid and SARS-CoV-2 Mpro, revealing the molecular basis of its inhibitory mechanism. These findings not only enhance our understanding of the antiviral action of rosmarinic acid, but also provide valuable structural information and mechanistic insights for the further development of therapeutic strategies against SARS-CoV-2.
Asunto(s)
Antivirales , Cinamatos , Proteasas 3C de Coronavirus , Depsidos , Ácido Rosmarínico , SARS-CoV-2 , Depsidos/química , Depsidos/farmacología , Cinamatos/química , Cinamatos/farmacología , SARS-CoV-2/efectos de los fármacos , SARS-CoV-2/enzimología , Proteasas 3C de Coronavirus/antagonistas & inhibidores , Proteasas 3C de Coronavirus/química , Proteasas 3C de Coronavirus/metabolismo , Humanos , Antivirales/farmacología , Antivirales/química , Inhibidores de Proteasas/química , Inhibidores de Proteasas/farmacología , Modelos Moleculares , Cristalografía por Rayos X , Tratamiento Farmacológico de COVID-19 , COVID-19/virología , Sitios de Unión , Unión ProteicaRESUMEN
Modern intensive cropping systems often contribute to the accumulation of phenolic acids in the soil, which promotes the development of soilborne diseases. This can be suppressed by intercropping. This study analyzed the effects of intercropping on Fusarium wilt based on its effect on photosynthesis under stress by the combination of Fusarium commune and cinnamic acid. The control was not inoculated with F. commune, while the faba bean plants (Vicia faba L.) were inoculated with this pathogen in the other treatments. The infected plants were also treated with cinnamic acid. This study examined the development of Fusarium wilt together with its effects on the leaves, absorption of nutrients, chlorophyll fluorescence parameters, contents of photosynthetic pigments, activities of photosynthetic enzymes, gas exchange parameters, and the photosynthetic assimilates of faba bean from monocropping and intercropping systems. Under monocropping conditions, the leaves of the plants inoculated with F. commune grew significantly less, and there was enhanced occurrence of the Fusarium wilt compared with the control. Compared with the plants solely inoculated with F. commune, the exogenous addition of cinnamic acid to the infected plants significantly further reduced the growth of faba bean leaves and increased the occurrence of Fusarium wilt. A comparison of the combination of F. commune and cinnamic acid in intercropped wheat and faba bean compared with monocropping showed that intercropping improved the absorption of nutrients, increased photosynthetic pigments and its contents, electron transport, photosynthetic enzymes, and photosynthetic assimilates. The combination of these factors reduced the occurrence of Fusarium wilt in faba bean and increased the growth of its leaves. These results showed that intercropping improved the photosynthesis, which promoted the growth of faba bean, thus, reducing the development of Fusarium wilt following the stress of infection by F. commune and cinnamic acid. This research should provide more information to enhance sustainable agriculture.
Asunto(s)
Cinamatos , Fusarium , Fotosíntesis , Enfermedades de las Plantas , Vicia faba , Fusarium/fisiología , Vicia faba/microbiología , Vicia faba/fisiología , Cinamatos/metabolismo , Cinamatos/farmacología , Enfermedades de las Plantas/microbiología , Estrés Fisiológico , Hojas de la Planta/microbiología , Producción de Cultivos/métodos , Clorofila/metabolismo , Productos Agrícolas/microbiologíaRESUMEN
Fungal keratitis (FK) is an infectious keratopathy can cause serious damage to vision. Its severity is related to the virulence of fungus and response of inflammatory. Rosmarinic acid (RA) extracted from Rosmarinus officinalis exhibits antioxidant, anti-inflammatory and anti-viral properties. The aim of this study was to investigate the effect of RA on macrophage autophagy and its therapeutic effect on FK. In this study, we demonstrated that RA reduced expression of proinflammatory cytokine, lessened the recruitment of inflammatory cells in FK. The relative contents of autophagy markers, such as LC3 and Beclin-1, were significantly up-regulated in RAW 264.7 cells and FK. In addition, RA restored mitochondrial membrane potential (MMP) of macrophage to normal level. RA not only reduced the production of intracellular reactive oxygen species (ROS) but also mitochondria ROS (mtROS) in macrophage. At the same time, RA induced macrophage to M2 phenotype and down-regulated the mRNA expression of IL-6, IL-1ß, TNF-α. All the above effects could be offset by the autophagy inhibitor 3-Methyladenine (3-MA). Besides, RA promote phagocytosis of RAW 264.7 cells and inhibits spore germination, biofilm formation and conidial adherence, suggesting a potential therapeutic role for RA in FK.
Asunto(s)
Aspergilosis , Aspergillus fumigatus , Autofagia , Cinamatos , Depsidos , Infecciones Fúngicas del Ojo , Macrófagos , Especies Reactivas de Oxígeno , Ácido Rosmarínico , Depsidos/farmacología , Animales , Autofagia/efectos de los fármacos , Ratones , Aspergilosis/tratamiento farmacológico , Aspergilosis/microbiología , Aspergilosis/metabolismo , Infecciones Fúngicas del Ojo/microbiología , Infecciones Fúngicas del Ojo/tratamiento farmacológico , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Macrófagos/microbiología , Cinamatos/farmacología , Especies Reactivas de Oxígeno/metabolismo , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Queratitis/microbiología , Queratitis/tratamiento farmacológico , Queratitis/metabolismo , Modelos Animales de Enfermedad , Células RAW 264.7 , Citocinas/metabolismo , Fagocitosis/efectos de los fármacosRESUMEN
Drug repurposing and rescuing have been widely explored as cost-effective approaches to expand the portfolio of chemotherapeutic agents. Based on the reported antitumor properties of both trans-cinnamic acids and quinacrine, an antimalarial aminoacridine, we explored the antiproliferative properties of two series of N-cinnamoyl-aminoacridines recently identified as multi-stage antiplasmodial leads. The compounds were evaluated in vitro against three cancer cell lines (MKN-28, Huh-7, and HepG2), and human primary dermal fibroblasts. One of the series displayed highly selective antiproliferative activity in the micromolar range against the three cancer cell lines tested, without any toxicity to non-carcinogenic cells.
Asunto(s)
Antimaláricos , Antineoplásicos , Proliferación Celular , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Proliferación Celular/efectos de los fármacos , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Relación Estructura-Actividad , Antimaláricos/farmacología , Antimaláricos/química , Antimaláricos/síntesis química , Línea Celular Tumoral , Reposicionamiento de Medicamentos , Estructura Molecular , Aminoacridinas/farmacología , Aminoacridinas/química , Aminoacridinas/síntesis química , Relación Dosis-Respuesta a Droga , Cinamatos/farmacología , Cinamatos/química , Cinamatos/síntesis químicaRESUMEN
Although used in in vitro culture to boost secondary metabolite production, UV-B radiation can seriously affect plant growth if not properly dosed. Rosemary callus can be used as an important source of effective ingredients in the food and medicine industry. To balance the positive and negative effects of UV-B on rosmary callus, this study investigated the effects of melatonin on rosemary callus under UV-B radiation. The results showed that melatonin improved rosemary callus growth, with fresh weight and dry weight increased by 15.81% and 8.30%, respectively. The addition of 100 µM melatonin increased antioxidant enzyme activity and NO content in rosemary callus. At the same time, melatonin also significantly reduced membrane lipid damage and H2O2 accumulation in rosemary callus under UV-B stress, with malondialdehyde (MDA) and H2O2 contents reduced by 13.03% and 14.55%, respectively. In addition, melatonin increased the total phenol and rosmarinic acid contents in rosemary callus by 19% and 54%, respectively. Melatonin significantly improved the antioxidant activity of the extracts from rosemary callus. These results suggest that exogenous melatonin can alleviate the adverse effects of UV-B stress on rosemary callus by promoting NO accumulation while further enhancing phenolic accumulation and biological activity.
Asunto(s)
Antioxidantes , Peróxido de Hidrógeno , Melatonina , Fenoles , Rosmarinus , Rayos Ultravioleta , Melatonina/farmacología , Melatonina/metabolismo , Rosmarinus/metabolismo , Rosmarinus/efectos de los fármacos , Rosmarinus/efectos de la radiación , Antioxidantes/metabolismo , Fenoles/metabolismo , Peróxido de Hidrógeno/metabolismo , Malondialdehído/metabolismo , Estrés Fisiológico/efectos de la radiación , Estrés Fisiológico/efectos de los fármacos , Ácido Rosmarínico , Cinamatos/metabolismo , Cinamatos/farmacología , Depsidos/metabolismoRESUMEN
Uranium accumulation in the kidneys and bones following internal contamination results in severe damage, emphasizing the pressing need for the discovery of actinide decorporation agents with efficient removal of uranium and low toxicity. In this work, cinnamic acid (3-phenyl-2-propenoic acid, CD), a natural aromatic carboxylic acid, is investigated as a potential uranium decorporation ligand. CD demonstrates markedly lower cytotoxicity than that of diethylenetriaminepentaacetic acid (DTPA), an actinide decorporation agent approved by the FDA, and effectively removes approximately 44.5% of uranyl from NRK-52E cells. More importantly, the results of the prompt administration of the CD solution remove 48.2 and 27.3% of uranyl from the kidneys and femurs of mice, respectively. Assessments of serum renal function reveal the potential of CD to ameliorate uranyl-induced renal injury. Furthermore, the single crystal of CD and uranyl compound (C9H7O2)2·UO2 (denoted as UO2-CD) reveals the formation of uranyl dimers as secondary building units. Thermodynamic analysis of the solution shows that CD coordinates with uranyl to form a 2:1 molar ratio complex at a physiological pH of 7.4. Density functional theory (DFT) calculations further show that CD exhibits a significant 7-fold heightened affinity for uranyl binding in comparison to DTPA.
Asunto(s)
Cinamatos , Uranio , Cinamatos/química , Cinamatos/farmacología , Animales , Ligandos , Ratones , Uranio/química , Uranio/metabolismo , Uranio/toxicidad , Riñón/efectos de los fármacos , Riñón/metabolismo , Línea Celular , Teoría Funcional de la Densidad , Ratas , Estructura Molecular , Supervivencia Celular/efectos de los fármacos , Quelantes/química , Quelantes/farmacología , Quelantes/síntesis químicaRESUMEN
High proportions of soybean meal in aquafeed have been confirmed to induce various intestinal pathologies. This study aims to investigate the regulatory effects of rosmarinic acid (RA), an antioxidant with anti-inflammatory and antimicrobial properties, when added to high soybean meal feeds in different doses, (0, 0.5, 1, and 4 g/kg). During the 56-day feeding trial, results indicated that, compared to the control group without RA (0 g/kg), the 1 g/kg and 4 g/kg RA groups increased bullfrog survival rates and total weight gain while reducing feed coefficient. Additionally, these doses markedly suppressed the expression of key intestinal inflammatory markers (tlr5, myd88, tnfα, il1ß, cxcl8, cxcl12) and the activity and content of intestinal antioxidants (CAT, MDA, GSH, GPX). Concurrently, RA significantly downregulated the transcription levels of antioxidant-related genes (cat, gpx5, cyba, cybb, mgst, gclc, gsta, gstp), suggesting RA's potential to alleviate intestinal inflammation and oxidative stress induced by high soybean meal and to help downregulate and restore normal expression of antioxidant enzyme genes. However, the 0.5 g/kg RA group did not show a significant improvement in survival rates; instead, it upregulated the transcription of some antioxidant genes (cat, gpx5, cyba, cybb), revealing the complexity and dose-dependency of RA's antioxidant action. Furthermore, RA supplementation significantly reshaped the intestinal microbial community structure and relative abundance in bullfrogs, particularly affecting the genera Hafnia, Phascolarctobacterium, and Lactococcus. Notably, high doses of RA (1 g/kg, 4 g/kg) were able to downregulate pathways associated with the enrichment of gut microbiota in diseases such as Parkinson's, Staphylococcus aureus infection, and Systemic lupus erythematosus, suggesting its potential in anti-inflammatory action and health maintenance to prevent potential diseases.
Asunto(s)
Alimentación Animal , Cinamatos , Depsidos , Dieta , Suplementos Dietéticos , Glycine max , Estrés Oxidativo , Rana catesbeiana , Ácido Rosmarínico , Animales , Depsidos/farmacología , Depsidos/administración & dosificación , Glycine max/química , Cinamatos/farmacología , Cinamatos/administración & dosificación , Alimentación Animal/análisis , Dieta/veterinaria , Estrés Oxidativo/efectos de los fármacos , Rana catesbeiana/inmunología , Suplementos Dietéticos/análisis , Inflamación/veterinaria , Relación Dosis-Respuesta a Droga , Intestinos/efectos de los fármacos , Intestinos/inmunología , Distribución Aleatoria , Enfermedades de los Peces/inmunología , Microbioma Gastrointestinal/efectos de los fármacos , Antioxidantes/administración & dosificación , Antioxidantes/farmacología , Antioxidantes/metabolismo , Antiinflamatorios/farmacología , Antiinflamatorios/administración & dosificaciónRESUMEN
Hyperpigmentation disorders may result from inappropriate melanin deposition and/or excessive melanin synthesis. They are classified mainly as aesthetic problems, but they can significantly affect human health by decreasing self-esteem. There are available only limited treatment options for hyperpigmentation disorder, among others, cosmetic products applied topically. Depigmenting ingredients were found to be ineffective and characterized by various side effects. As a result, many efforts are made to discover novel, potent, and safe melanogenesis inhibitors for possible use in topical cosmetic depigmenting formulations. Cinnamic acid derivatives constitute a widely tested group for that purpose. This article reports research in the group of N-alkyl cinnamamide derivatives (un)substituted in phenyl ring. Among tested series, (E)-3-(4-chlorophenyl)-N-(5-hydroxypentyl)acrylamide (compound 21) showed the most promising inhibitory properties in mushroom tyrosinase assay (IC50 = 36.98 ± 1.07 µM for monophenolase activity, IC50 = 146.71 ± 16.82 µM for diphenolase activity) and melanin production inhibition in B16F10 mouse melanoma cell line at concentration 6.25 µM resulting probably from decreasing of Tyr, Mitf, Tyrp-1, and Tyrp-2 genes expression. This compound also showed melanin production inhibitory properties in pigmented reconstructed human epidermis when used in 1 % and 2 % solutions in 50 % PEG400. In vitro evaluation of its safety profile showed no cytotoxicity to human keratinocytes HaCaT, human skin fibroblasts BJ, and human primary epidermal melanocytes HEMa, no mutagenicity in the Ames test, no genotoxicity in micronucleus test, no phototoxicity, as well as no skin irritation potential tested in PEG400 solution. This compound was also shown to penetrate across the epidermis to reach the possible site of action. The performed research led to classify (E)-3-(4-chlorophenyl)-N-(5-hydroxypentyl)acrylamide as a novel potential depigmenting cosmetic ingredient.
Asunto(s)
Cinamatos , Cosméticos , Hiperpigmentación , Melaninas , Monofenol Monooxigenasa , Humanos , Animales , Hiperpigmentación/tratamiento farmacológico , Ratones , Monofenol Monooxigenasa/antagonistas & inhibidores , Monofenol Monooxigenasa/metabolismo , Cinamatos/química , Cinamatos/farmacología , Cinamatos/síntesis química , Relación Estructura-Actividad , Estructura Molecular , Cosméticos/química , Cosméticos/farmacología , Melaninas/metabolismo , Relación Dosis-Respuesta a Droga , Acrilamida/química , Acrilamida/farmacología , Descubrimiento de Drogas , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/síntesis química , AgaricalesRESUMEN
Molecular hybridization between structural fragments from the structures of curcumin (1) and resveratrol (2) was used as a designing tool to generate a new N-acyl-cinnamoyl-hydrazone hybrid molecular architecture. Twenty-eight new compounds were synthesized and evaluated for multifunctional activities related to Parkinson's disease (PD), including neuroprotection, antioxidant, metal chelating ability, and Keap1/Nrf2 pathway activation. Compounds 3b (PQM-161) and 3e (PQM-164) were highlighted for their significant antioxidant profile, acting directly as induced free radical stabilizers by DPPH and indirectly by modulating intracellular inhibition of t-BOOH-induced ROS formation in neuronal cells. The mechanism of action was determined as a result of Keap1/Nrf2 pathway activation by both compounds and confirmed by different experiments. Furthermore, compound 3e (PQM-164) exhibited a significant effect on the accumulation of α-synuclein and anti-inflammatory activity, leading to an expressive decrease in gene expression of iNOS, IL-1ß, and TNF-α. Overall, these results highlighted compound 3e as a promising and innovative multifunctional drug prototype candidate for PD treatment.
Asunto(s)
Hidrazonas , Fármacos Neuroprotectores , Enfermedad de Parkinson , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/química , Fármacos Neuroprotectores/síntesis química , Hidrazonas/farmacología , Hidrazonas/química , Hidrazonas/síntesis química , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/metabolismo , Humanos , Estructura Molecular , Relación Estructura-Actividad , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Antioxidantes/farmacología , Antioxidantes/síntesis química , Antioxidantes/química , Animales , Cinamatos/farmacología , Cinamatos/química , Cinamatos/síntesis químicaRESUMEN
Developing multitargeted ligands as promising therapeutics for Alzheimer's disease (AD) has been considered important. Herein, a novel class of cinnamamide/ester-triazole hybrids with multifaceted effects on AD was developed based on the multitarget-directed ligands strategy. Thirty-seven cinnamamide/ester-triazole hybrids were synthesized, with most exhibiting significant inhibitory activity against Aß-induced toxicity at a single concentration in vitro. The most optimal hybrid compound 4j inhibited copper-induced Aß toxicity in AD cells. its action was superior to that of donepezil and memantine. It also moderately inhibited intracellular AChE activity and presented favorable bioavailability and blood-brain barrier penetration with low toxicity in vivo. Of note, it ameliorated cognitive impairment, neuronal degeneration, and Aß deposition in Aß1-42-injured mice. Mechanistically, the compound regulated APP processing by promoting the ADAM10-associated nonamyloidogenic signaling and inhibiting the BACE1-mediated amyloidogenic pathway. Moreover, it suppressed intracellular AChE activity and tau phosphorylation. Therefore, compound 4j may be a promising multitargeted active molecule against AD.
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Enfermedad de Alzheimer , Péptidos beta-Amiloides , Cinamatos , Triazoles , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Animales , Triazoles/química , Triazoles/farmacología , Triazoles/síntesis química , Cinamatos/química , Cinamatos/farmacología , Cinamatos/síntesis química , Humanos , Ratones , Péptidos beta-Amiloides/metabolismo , Péptidos beta-Amiloides/antagonistas & inhibidores , Relación Estructura-Actividad , Estructura Molecular , Ésteres/química , Ésteres/farmacología , Ésteres/síntesis química , Relación Dosis-Respuesta a Droga , Acetilcolinesterasa/metabolismo , Inhibidores de la Colinesterasa/química , Inhibidores de la Colinesterasa/farmacología , Inhibidores de la Colinesterasa/síntesis química , Descubrimiento de Drogas , Fármacos Neuroprotectores/química , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/síntesis química , Fragmentos de Péptidos/metabolismo , Fragmentos de Péptidos/antagonistas & inhibidores , MasculinoRESUMEN
AIM: We evaluated the efficacy and safety of Nuvastatic™ (C5OSEW5050ESA) in improving cancer-related fatigue (CRF) among cancer patients. METHODS: This multicenter randomized double-blind placebo-controlled phase 2 trial included 110 solid malignant tumor patients (stage II-IV) undergoing chemotherapy. They were randomly selected and provided oral Nuvastatic™ 1000 mg (N = 56) or placebo (N = 54) thrice daily for 9 weeks. The primary outcomes were fatigue (Brief Fatigue Inventory (BFI)) and Visual Analog Scale for Fatigue (VAS-F)) scores measured before and after intervention at baseline and weeks 3, 6, and 9. The secondary outcomes were mean group difference in the vitality subscale of the Medical Outcome Scale Short Form-36 (SF-36) and urinary F2-isoprostane concentration (an oxidative stress biomarker), Eastern Cooperative Oncology Group scores, adverse events, and biochemical and hematologic parameters. Analysis was performed by intention-to-treat (ITT). Primary and secondary outcomes were assessed by two-way repeated-measures analysis of variance (mixed ANOVA). RESULTS: The Nuvastatic™ group exhibited an overall decreased fatigue score compared with the placebo group. Compared with the placebo group, the Nuvastatic™ group significantly reduced BFI-fatigue (BFI fatigue score, F (1.4, 147) = 16.554, p < 0.001, partial η2 = 0.333). The Nuvastatic™ group significantly reduced VAS-F fatigue (F (2, 210) = 9.534, p < 0.001, partial η2 = 0.083), improved quality of life (QoL) (F (1.2, 127.48) = 34.07, p < 0.001, partial η2 = 0.243), and lowered urinary F2-IsoP concentrations (mean difference (95% CI) = 55.57 (24.84, 86.30)), t (55) = 3.624, p < 0.001, Cohen's d (95% CI) = 0.48 (0.20, 0.75)). Reported adverse events were vomiting (0.9%), fever (5.4%), and headache (2.7%). CONCLUSION: Nuvastatic™ is potentially an effective adjuvant for CRF management in solid tumor patients and worthy of further investigation in larger trials. TRIAL REGISTRATION: ClinicalTrial.gov ID: NCT04546607. Study registration date (first submitted): 11-05-2020.
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Cinamatos , Depsidos , Fatiga , Neoplasias , Ácido Rosmarínico , Humanos , Método Doble Ciego , Fatiga/etiología , Fatiga/tratamiento farmacológico , Femenino , Persona de Mediana Edad , Masculino , Neoplasias/complicaciones , Anciano , Depsidos/farmacología , Depsidos/administración & dosificación , Depsidos/uso terapéutico , Adulto , Cinamatos/administración & dosificación , Cinamatos/uso terapéutico , Cinamatos/farmacología , Extractos Vegetales/administración & dosificaciónRESUMEN
Polycystic ovary syndrome (PCOS) is a multidisciplinary endocrinopathy that affects women of reproductive age. It is characterized by menstrual complications, hyperandrogenism, insulin resistance, and cardiovascular issues. The current research investigated the efficacy of rosmarinic acid in letrozole-induced PCOS in adult female rats as well as the potential underlying molecular mechanisms. Forty female rats were divided into the control group, the rosmarinic acid group (50 mg/kg per orally, po) for 21 days, PCOS group; PCOS was induced by administration of letrozole (1 mg/kg po) for 21 days, and rosmarinic acid-PCOS group, received rosmarinic acid after PCOS induction. PCOS resulted in a marked elevation in both serum luteinizing hormone (LH) and testosterone levels and LH/follicle-stimulating hormone ratio with a marked reduction in serum estradiol and progesterone levels. A marked rise in tumor necrosis factor-α (TNF-α), interleukin-1ß, monocyte chemotactic protein-1, and vascular endothelial growth factor (messenger RNA) in the ovarian tissue was reported. The histological analysis displayed multiple cystic follicles in the ovarian cortex with markedly thin granulosa cell layer, vacuolated granulosa and theca cell layers, and desquamated granulosa cells. Upregulation in the immune expression of TNF-α and caspase-3 was demonstrated in the ovarian cortex. Interestingly, rosmarinic acid ameliorated the biochemical and histopathological changes. In conclusion, rosmarinic acid ameliorates letrozole-induced PCOS through its anti-inflammatory and antiangiogenesis effects.
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Quimiocina CCL2 , Cinamatos , Depsidos , Modelos Animales de Enfermedad , Letrozol , Síndrome del Ovario Poliquístico , Ácido Rosmarínico , Factor A de Crecimiento Endotelial Vascular , Animales , Síndrome del Ovario Poliquístico/tratamiento farmacológico , Síndrome del Ovario Poliquístico/inducido químicamente , Síndrome del Ovario Poliquístico/metabolismo , Síndrome del Ovario Poliquístico/patología , Femenino , Cinamatos/farmacología , Depsidos/farmacología , Factor A de Crecimiento Endotelial Vascular/metabolismo , Ratas , Quimiocina CCL2/metabolismo , Letrozol/farmacología , Hormona Luteinizante/sangre , Hormona Luteinizante/metabolismo , Inmunohistoquímica , Testosterona/sangre , Ratas Sprague-DawleyRESUMEN
An ethyl acetate extract of a marine actinomycete strain, Nocardiopsis mentallicus SCSIO 53858, isolated from a deep-sea sediment sample in the South China Sea, exhibited anti-quorum-sensing (QS) activity against Chromobacterium violaceum CV026. Guided by the anti-QS activity, a novel active compound was isolated and purified from the extract and was identified as 2,3-dimethoxycinnamic acid (2,3-DCA) through spectral data analysis. At a concentration of 150 µg/mL, 2,3-DCA exhibited robust inhibitory effects on three QS-regulated traits of C. violaceum CV026: violacein production, swarming motility, and biofilm formation, with inhibition rates of 73.9%, 65.9%, and 37.8%, respectively. The quantitative reverse transcription polymerase chain reaction results indicated that 2,3-DCA can disrupt the QS system in C. violaceum CV026 by effectively suppressing the expression of QS-related genes, including cviR, vioA, vioB, and vioE. Molecular docking analysis revealed that 2,3-DCA hinders the QS system by competitively binding to the same binding pocket on the CviR receptor as the natural signal molecule N-hexanoyl-L-homoserine lactone. Collectively, these findings suggest that 2,3-DCA exhibits promising potential as an inhibitor of QS systems, providing a potential solution to the emerging problem of bacterial resistance.
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Antibacterianos , Chromobacterium , Indoles , Simulación del Acoplamiento Molecular , Percepción de Quorum , Percepción de Quorum/efectos de los fármacos , Chromobacterium/efectos de los fármacos , Antibacterianos/farmacología , Antibacterianos/aislamiento & purificación , Antibacterianos/química , Actinobacteria/química , Cinamatos/farmacología , Cinamatos/aislamiento & purificación , Cinamatos/química , Biopelículas/efectos de los fármacos , Sedimentos Geológicos/microbiología , Organismos Acuáticos , ChinaRESUMEN
Noncovalent interactions of 4 selected phenolic acids, including gallic acid (GA), caffeic acid (CA), chlorogenic acid (CGA), and rosmarinic acid (RA) with lactoferrin (LF) were investigated. Compound combined with LF in the binding constant of CA > GA > RA > CGA, driven by van der Waals and hydrogen bonding for GA, and hydrophobic forces for others. Conformation of LF was affected at secondary and ternary structure levels. Molecular docking indicated that GA and CA located in the same site near the iron of the C-lobe, whereas RA and CGA bound to the C2 and N-lobe, respectively. Significantly enhanced antioxidant activity of complexes was found compared with pure LF, as demonstrated by 2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2'-azinobis(2-ethylbenzothiazoline-6-sulfonate) (ABTS), and ferric reducing antioxidant power (FRAP) models. Caffeic acid, CGA, and RA significantly decreased the emulsifying stability index and improved foam ability of LF, and the effect of CA and RA was the most remarkable, respectively.
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Antioxidantes , Hidroxibenzoatos , Lactoferrina , Lactoferrina/metabolismo , Lactoferrina/química , Animales , Antioxidantes/farmacología , Hidroxibenzoatos/química , Bovinos , Simulación del Acoplamiento Molecular , Ácidos Cafeicos/química , Ácidos Cafeicos/farmacología , Cinamatos/química , Cinamatos/farmacología , Ácido Gálico/química , Ácido Clorogénico/química , Depsidos/químicaRESUMEN
Organic UV filters, which are often found in the environment, have been the focus of much public health concern. 2-ethylhexyl-4-methoxycinnamate (EHMC) is one of the most common organic UV filters present in the environment. However, few studies have investigated its developmental neurotoxic (DNT) effects and the underlying molecular mechanisms. In the present study, zebrafish embryos were exposed to low concentration of EHMC (0, 0.01, 0.1, 1 mg/L) in static water starting from 6 h post-fertilization (hpf). Results showed that EHMC exposure caused a reduction in somite count at 13 hpf, a diminishment in head-trunk angle at 30 hpf, a delay in hatching at 48 hpf, and a decrease in head depth and head length at both 30 and 48 hpf. Additionally, EHMC led to abnormal motor behaviors at various developmental stages including altered spontaneous movement at both 23 and 24 hpf, and decreased touch response at 30 hpf. Consistent with these morphological changes and motor behavior deficits, EHMC inhibited axonal growth of primary motor neurons at 30 and 48 hpf, and yielded subtle changes in muscle fiber length at 48 hpf, suggesting the functional relevance of structural changes. Moreover, EHMC exposure induced excessive cell apoptosis in the head and spinal cord regions, increased the production of reactive oxygen species (ROS) and malondialdehyde (MDA), and reduced the level of glutathione (GSH). Defects of lateral line system neuromasts were also observed, but no structural deformity of blood vessels was seen in developing zebrafish. Abnormal expression of axonal growth-related genes (gap43, mbp, shha, and α1-tubulin) and apoptosis-related genes (bax/bcl-2 and caspase-3) revealed potential molecular mechanisms regarding the defective motor behaviors and aberrant phenotype. In summary, our findings indicate that EHMC induced developmental neurotoxicity in zebrafish, making it essential to assess its risks and provide warnings regarding EHMC exposure.