RESUMO
The objective of our research was to determine the effects of xanthohumol (XN), a flavonoid isolated from hops (Humulus lupulus), and the anti-inflammatory drug niflumic acid (NA), separately and in combination with each other, on the proliferation of human cancer cells. Additionally, so as to understand the mechanism underlying the anticancer properties of the tested compounds, their effects on the biophysical parameters of a model membrane were assessed. The cells were incubated with XN and NA at various concentrations, either individually or in combination with each other. Cell proliferation was quantified using the sulforodamine B (SRB) assay. In addition, the IC50 values for niflumic acid and xanthohumol applied separately were determined by cell proliferation tests for the following human cancer cell lines: 5637 (urinary bladder carcinoma), A-431 (epidermoid carcinoma), UM-SCC-17A (head and neck squamous carcinoma), SK-MEL-3 (melanoma), MCC13 (Merkel cell cancer), and A172 (glioblastoma), in comparison with the mouse normal fibroblasts (BALB/3T3 clone A31). The results show that the two-compound combinations of XN and NA significantly decreased the proliferation of cancer cells in a dose-dependent manner, and the effects were stronger than the additive responses to XN and NA individually. The membrane studies revealed a synergistic effect on the membrane rigidity when using the mixture of XN and NA, which may explain the observed increase in anticancer activity for the combined XN and NA. Our results suggest that NSAIDs, such as niflumic acid, may be a promising strategy for co-application with xanthohumol as anticancer drugs.
Assuntos
Membrana Celular , Proliferação de Células , Sinergismo Farmacológico , Flavonoides , Glioblastoma , Ácido Niflúmico , Propiofenonas , Propiofenonas/farmacologia , Flavonoides/farmacologia , Humanos , Proliferação de Células/efeitos dos fármacos , Glioblastoma/tratamento farmacológico , Glioblastoma/metabolismo , Glioblastoma/patologia , Ácido Niflúmico/farmacologia , Linhagem Celular Tumoral , Animais , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Camundongos , Antineoplásicos/farmacologiaRESUMO
Xanthohumol (1) is a major prenylated flavonoid in hops (Humulus lupulus L.) which exhibits a broad spectrum of health-promoting and therapeutic activities, including anti-inflammatory, antioxidant, antimicrobial, and anticancer effects. However, due to its lipophilic nature, it is poorly soluble in water and barely absorbed from the gastrointestinal tract, which greatly limits its therapeutic potential. One method of increasing the solubility of active compounds is their conjugation to polar molecules, such as sugars. Sugar moiety introduced into the flavonoid molecule significantly increases polarity, which results in better water solubility and often leads to greater bioavailability. Entomopathogenic fungi are well known for their ability to catalyze O-glycosylation reactions. Therefore, we investigated the ability of selected entomopathogenic filamentous fungi to biotransform xanthohumol (1). As a result of the experiments, one aglycone (2) and five glycosides (3-7) were obtained. The obtained (2â³E)-4â³-hydroxyxanthohumol 4'-O-ß-D-(4â´-O-methyl)-glucopyranoside (5) has never been described in the literature so far. Interestingly, in addition to the expected glycosylation reactions, the tested fungi also catalyzed chalcone-flavanone cyclization reactions, which demonstrates chalcone isomerase-like activity, an enzyme typically found in plants. All these findings undoubtedly indicate that entomopathogenic filamentous fungi are still an underexploited pool of novel enzymes.
Assuntos
Biotransformação , Flavonoides , Propiofenonas , Propiofenonas/metabolismo , Propiofenonas/química , Flavonoides/metabolismo , Flavonoides/química , Glicosilação , Fungos/metabolismo , Humulus/metabolismo , Humulus/química , Glicosídeos/metabolismo , Glicosídeos/químicaRESUMO
Bitter taste receptors, also known as taste 2 receptors (T2R), are expressed throughout the body and are involved in regulating different physiological processes. T2R expression in the intestinal tract regulates orexigenic and anorexigenic peptide secretion, thus becoming potential a potential target for controlling food intake and the prevalence of obesity and overweight. The present study aims to investigate the implication of hop bitter compounds such as α-acids, ß-acids, and xanthohumol in the secretion of anorexigenic hormones and T2R expression in intestinal STC-1 cells. The tested bitter compounds induced the secretion of the anorexigenic hormones glucagon-like peptide 1 and cholecystokinin concurrently with a selective increase of murine Tas2r expression. Xanthohumol and α-acids selectively increase Tas2r138 and Tas2r130-Tas2r138 expression, respectively, in STC-1 cells, while ß-acids increased the expression of all bitter receptors studied, including Tas2r119, Tas2r105, Tas2r138, Tas2r120, and Tas2r130. Increased intracellular calcium levels confirmed this activity. As all investigated bitter molecules increased Tas2r138 expression, computational studies were performed on Tas2r138 and its human orthologue T2R38 for the first time. Molecular docking experiments showed that all molecules might be able to bind both bitter receptors, providing an excellent basis for applying hop bitter molecules as lead compounds to further design gastrointestinal-permeable T2R agonists.
Assuntos
Humulus , Simulação de Acoplamento Molecular , Receptores Acoplados a Proteínas G , Humulus/química , Receptores Acoplados a Proteínas G/metabolismo , Animais , Camundongos , Humanos , Propiofenonas/farmacologia , Propiofenonas/química , Flavonoides/farmacologia , Flavonoides/química , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Colecistocinina/metabolismo , Colecistocinina/química , Linhagem Celular , Trato Gastrointestinal/metabolismo , Estrutura MolecularRESUMO
Avobenzone (AVO) is a sunscreen with high global production and is constantly released into the environment. Incorporating sewage biosolids for fertilization purposes, the leaching from cultivated soils, and the use of wastewater for irrigation explain its presence in the soil. There is a lack of information about the impact of this sunscreen on plants. In the present study, the ecotoxicity of AVO was tested at concentrations 1, 10, 100, and 1,000 ng/L. All concentrations caused a reduction in root growth of Allium cepa, Cucumis sativus, and Lycopersicum esculentum seeds, as well as a mitodepressive effect, changes in the mitotic spindle and a reduction in root growth of A. cepa bulbs. The cell cycle was disturbed because AVO disarmed the enzymatic defense system of root meristems, leading to an accumulation of hydroxyl radicals and superoxides, besides lipid peroxidation in cells. Therefore, AVO shows a high potential to cause damage to plants and can negatively affect agricultural production and the growth of non-cultivated plants.
Assuntos
Protetores Solares , Protetores Solares/toxicidade , Propiofenonas/toxicidade , Cebolas/efeitos dos fármacos , Cucumis sativus/efeitos dos fármacosRESUMO
In this study we report on efforts to develop an enantioselective method for the detection of the drug of abuse clephedrone (1-(4-chlorophenyl)-2-(methylamino)-1-propanone (4-chloromethcathinone, also known as 4-CMC or para-chloro-methcathinone)) and its phase-1 metabolites in human biological fluids. The major goal is not to only report results, but primarily to emphasize the various challenges encountered when developing a reliable analytical method for the detection and quantification of novel psychoactive substances (NPS) and their metabolites in the matrix of interest. Such challenges start with the lack of chemical stability of some NPS in biological matrices. Additionally, most often metabolites are unavailable in pure form to serve as analytical standards, just as deuterated standards for native drugs and metabolites are frequently not commercially available. Furthermore, if the NPS is chiral, enantiomerically pure standards with known absolute stereochemistry are required, as well as a stereochemical stability of a drug and its metabolites becomes an issue. In addition, the chirality of a NPS significantly increases the number of species to be detected in the sample and thus challenges the development of an adequate separation method. These issues are shortly addressed, and some solutions offered in this manuscript.
Assuntos
Psicotrópicos , Estereoisomerismo , Psicotrópicos/análise , Psicotrópicos/química , Humanos , Propiofenonas/química , Propiofenonas/análise , Drogas Ilícitas/análise , Drogas Ilícitas/química , Detecção do Abuso de Substâncias/métodosRESUMO
The stereochemical stability of the popular drugs of abuse 2-, 3- and 4-chloromethcathinone was studied in the mobile phase used for the isolation of their enantiomers by high-performance liquid chromatography, as well as in various biological matrixes such as whole blood, saliva and urine. For 2-, 3-, and 4-chloromethcathinones the rate constants and half-lives of their first order racemization reaction was assessed. It was found that at 25 °C the racemization rate constant decreases in the order 2-CMC > 3-CMC > 4-CMC while their stereochemical stability in biological matrixes decreases in the order urine > saliva > whole blood. This information must be considered for the adequate storage of purified enantiomers in the collected fractions, as well as in the studies focused on their enantioselective transformation in the human body.
Assuntos
Estabilidade de Medicamentos , Estereoisomerismo , Humanos , Cromatografia Líquida de Alta Pressão/métodos , Saliva/química , Propiofenonas/química , Propiofenonas/sangue , Meia-VidaRESUMO
CONTEXT: Although quantum mechanical calculations have proven effective in accurately predicting UV absorption and assessing the antioxidant potential of compounds, the utilization of computer-aided drug design (CADD) to support sustainable synthesis research of new sunscreen active ingredients remains an area with limited exploration. Furthermore, there are ongoing concerns about the safety and effectiveness of existing sunscreens. Therefore, it remains crucial to investigate photoprotection mechanisms and develop enhanced strategies for mitigating the harmful effects of UVR exposure, improving both the safety and efficacy of sunscreen products. A previous study conducted synthesis research on eight novel hybrid compounds (I-VIII) for use in sunscreen products by molecular hybridization of trans-resveratrol (RESV), avobenzone (AVO), and octinoxate (OMC). Herein, time-dependent density functional theory (TD-DFT) calculations performed in the gas phase on the isolated hybrid compounds (I-VIII) proved to reproduce the experimental UV absorption. Resveratrol-avobenzone structure-based hybrids (I-IV) present absorption maxima in the UVB range with slight differences between them, while resveratrol-OMC structure-based hybrids (V-VIII) showed main absorption in the UVA range. Among RESV-OMC hybrids, compounds V and VI exhibited higher UV absorption intensity, and compound VIII stood out for its broad-spectrum coverage in our simulations. Furthermore, both in silico and in vitro analyses revealed that compounds VII and VIII exhibited the highest antioxidant activity, with compound I emerging as the most reactive antioxidant within RESV-AVO hybrids. The study suggests a preference for the hydrogen atom transfer (HAT) mechanism over single-electron transfer followed by proton transfer (SET-PT) in the gas phase. With a strong focus on sustainability, this approach reduces costs and minimizes effluent production in synthesis research, promoting the eco-friendly development of new sunscreen active ingredients. METHODS: The SPARTAN'20 program was utilized for the geometry optimization and energy calculations of all compounds. Conformer distribution analysis was performed using the Merck molecular force field 94 (MMFF94), and geometry optimization was carried out using the parametric method 6 (PM6) followed by density functional theory (DFT/B3LYP/6-31G(d)). The antioxidant behavior of the hybrid compounds (I-VIII) was determined using the highest occupied molecular orbital (εHOMO) and the lowest unoccupied molecular orbital (εLUMO) energies, as well as the bond dissociation enthalpy (BDE), ionization potential (IP), and proton dissociation enthalpy (PDE) values, all calculated at the same level of structural optimization. TD-DFT study is carried out to calculate the excitation energy using the B3LYP functional with the 6-31G(d) basis set. The calculated transitions were convoluted with a Gaussian profile using the Gabedit program.
Assuntos
Antioxidantes , Desenho Assistido por Computador , Desenho de Fármacos , Resveratrol , Protetores Solares , Raios Ultravioleta , Protetores Solares/química , Antioxidantes/química , Antioxidantes/farmacologia , Resveratrol/química , Propiofenonas/química , Teoria da Densidade Funcional , Estilbenos/química , Estilbenos/farmacologia , Modelos Moleculares , Teoria Quântica , Estrutura MolecularRESUMO
Ammonia is a colorless gas, yet it can be fatal if inhaled or ingested in high enough concentrations. Herein, a solid-state colorimetric smart wool (WL) sensor for ammonia was developed. Common hop (Humulus lupulus L.) is a natural resource of spectroscopical dyestuff known as xanthohumol (XN). Wool fabrics were dyed with different concentrations of xanthohumol extract using the high-temperature high-pressure method in the presence of a mordant. The coloration parameters and absorption spectra were employed to explore the yellow-to-white colorimetric shift of the wool fabric after it was exposed to aqueous ammonia. The wool fabric showed an excellent detection limit of 5 to 125 ppm. When the ammonia concentration was increased, the absorbance spectra demonstrated a hypsochromic shift from 498 nm to 367 nm. This could be attributed to changes in the molecular structure of xanthohumol that happen owing to intramolecular charge delocalization. Using transmission electron microscopy (TEM), the mordant/xanthohumol nanoparticles were measured to have diameters of 15-40 nm. The xanthohumol-finished wool fabrics showed good colorfastness properties. The incorporation of mordant/xanthohumol nanoparticles into wool fabrics showed no negative effects on their stiffness or air-permeability.
Assuntos
Amônia , Flavonoides , Humulus , Propiofenonas , Propiofenonas/química , Humulus/química , Flavonoides/química , Flavonoides/análise , Amônia/química , Amônia/análise , Animais , Extratos Vegetais/química , Fibra de Lã/análise , Colorimetria/métodos , Nanopartículas/químicaRESUMO
Synthetic cathinones, which are novel psychoactive substances, have caused major social problems worldwide. A substance called 2-methyl-4'-(methylthio)-2-morpholinopropiophenone (MMMP), which is employed as a commercial industrial photoinitiator for triggering polymerization, has a basic cathinone backbone; however, few reports regarding MMMP have been published. In the current study, three potential metabolites of MMMP-namely hydroxy-MMMP (HO-MMMP), HO-MMMP-sulfoxide (HO-MMMP-SO), and HO-MMMP-sulfone (HO-MMMP-SO2)-were successfully synthesized, and MMMP and these three potential metabolites were used as standards to establish an analytic method based on liquid chromatography-tandem mass spectrometry for the quantitative analysis of urine. This analytic method and related parameters-including dynamic range, limit of quantification, selectivity, precision, accuracy, carryover effect, matrix effect, interference, and dilution integrity-were optimized and validated. Forty urine samples from 1,691 individuals who abused drugs were determined to contain MMMP, HO-MMMP, HO-MMMP-SO, or HO-MMMP-SO2; the results of this study indicate that approximately 2.37â¯% of drug abusers in Taiwan consumed MMMP in 2023. These 40 urine samples were analyzed to investigate the metabolism of MMMP in humans. The results indicate that HO-MMMP-SO is the main metabolite in human urine. This study recommends HO-MMMP-SO with a concentration of 2â¯ng/mL as a target and cutoff value, respectively, for identifying individuals who have consumed MMMP.
Assuntos
Psicotrópicos , Espectrometria de Massas em Tandem , Humanos , Psicotrópicos/urina , Psicotrópicos/análise , Cromatografia Líquida , Propiofenonas/urina , Detecção do Abuso de Substâncias/métodos , Drogas Ilícitas/análise , Morfolinas/urina , Morfolinas/análise , Limite de DetecçãoRESUMO
Xanthohumol (Xn) is an antioxidant flavonoid mainly extracted from hops (Humulus lupulus), one of the main ingredients of beer. As with other bioactive compounds, their therapeutic potential against different diseases has been tested, one of which is Alzheimer's disease (AD). Adenosine is a neuromodulatory nucleoside that acts through four different G protein-coupled receptors: A1 and A3, which inhibit the adenylyl cyclases (AC) pathway, and A2A and A2B, which stimulate this activity, causing either a decrease or an increase, respectively, in the release of excitatory neurotransmitters such as glutamate. This adenosinergic pathway, which is altered in AD, could be involved in the excitotoxicity process. Therefore, the aim of this work is to describe the effect of Xn on the adenosinergic pathway using cell lines. For this purpose, two different cellular models, rat glioma C6 and human neuroblastoma SH-SY5Y, were exposed to a non-cytotoxic 10 µM Xn concentration. Adenosine A1 and A2A, receptor levels, and activities related to the adenosine pathway, such as adenylate cyclase, protein kinase A, and 5'-nucleotidase, were analyzed. The adenosine A1 receptor was significantly increased after Xn exposure, while no changes in A2A receptor membrane levels or AC activity were reported. Regarding 5'-nucleotidases, modulation of their activity by Xn was noted since CD73, the extracellular membrane attached to 5'-nucleotidase, was significantly decreased in the C6 cell line. In conclusion, here we describe a novel pathway in which the bioactive flavonoid Xn could have potentially beneficial effects on AD as it increases membrane A1 receptors while modulating enzymes related to the adenosine pathway in cell cultures.
Assuntos
Adenosina , Flavonoides , Glioma , Humulus , Neuroblastoma , Propiofenonas , Receptor A1 de Adenosina , Humanos , Flavonoides/farmacologia , Ratos , Propiofenonas/farmacologia , Animais , Adenosina/metabolismo , Adenosina/farmacologia , Linhagem Celular Tumoral , Humulus/química , Neuroblastoma/metabolismo , Neuroblastoma/tratamento farmacológico , Glioma/metabolismo , Glioma/tratamento farmacológico , Receptor A1 de Adenosina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Adenilil Ciclases/metabolismo , Receptor A2A de Adenosina/metabolismoRESUMO
A method of analysis was developed for the simultaneous chemo- and enantioseparation of 2-, 3-, and 4-chloromethcathinones by high-performance liquid chromatography tandem mass-spectrometry. The fast method enables the reliable identification of positional isomers of chloromethcathinones in biological samples. In addition, the same method can be used for the enantioselective quantitative determination of one of these compounds and its major phase-1 metabolites in biological fluids. The developed method was applied to oral fluid samples collected by police during routine random traffic control in Belgium from January to November, 2023. It was found that 3-CMC was more frequently abused compared to 4-CMC. Although some differences were observed between the concentrations of enantiomers in OF, most likely the drugs were abused in the racemic form. No abuse of 2-CMC was detected at the timepoint of sample collection.
Assuntos
Saliva , Espectrometria de Massas em Tandem , Espectrometria de Massas em Tandem/métodos , Cromatografia Líquida de Alta Pressão/métodos , Humanos , Saliva/química , Estereoisomerismo , Propiofenonas/química , Propiofenonas/análise , Detecção do Abuso de Substâncias/métodos , BélgicaRESUMO
Synthetic cathinones represent one of the largest and most abused new psychoactive substance classes, and have been involved in numerous intoxications and fatalities worldwide. Methcathinone analogues like 3-methylmethcathinone (3-MMC), 3-chloromethcathinone (3-CMC), and 4-CMC currently constitute most of synthetic cathinone seizures in Europe. Documenting their consumption in clinical/forensic casework is therefore essential to tackle this trend. Targeting metabolite markers is a go-to to document consumption in analytical toxicology, and metabolite profiling is crucial to support investigations. We sought to identify 3-CMC, 4-CMC, and 4-bromomethcathinone (4-BMC) human metabolites. The substances were incubated with human hepatocytes; incubates were screened by liquid chromatography-high-resolution tandem mass spectrometry and data were mined with Compound Discoverer (Themo Scientific). 3-CMC-positive blood, urine, and oral fluid and 4-CMC-positive urine and saliva from clinical/forensic casework were analyzed. Analyses were supported by metabolite predictions with GLORYx freeware. Twelve, ten, and ten metabolites were identified for 3-CMC, 4-CMC, and 4-BMC, respectively, with similar transformations occurring for the three cathinones. Major reactions included ketoreduction and N-demethylation. Surprisingly, predominant metabolites were produced by combination of N-demethylation and ω-carboxylation (main metabolite in 3-CMC-positive urine), and combination of ß-ketoreduction, oxidative deamination, and O-glucuronidation (main metabolite in 4-CMC-positive urine). These latter metabolites were detected in negative-ionization mode only and their non-conjugated form was not detected after glucuronide hydrolysis; this metabolic pathway was never reported for any methcathinone analogue susceptible to undergo the same transformations. These results support the need for comprehensive screening strategies in metabolite identification studies, to avoid overlooking significant metabolites and major markers of consumption.
Assuntos
Hepatócitos , Humanos , Hepatócitos/metabolismo , Hepatócitos/efeitos dos fármacos , Espectrometria de Massas em Tandem/métodos , Propiofenonas/farmacocinética , Propiofenonas/metabolismo , Cromatografia Líquida/métodos , Detecção do Abuso de Substâncias/métodos , Metanfetamina/análogos & derivados , Metanfetamina/metabolismo , Metanfetamina/administração & dosagem , Metanfetamina/farmacocinética , Psicotrópicos/farmacocinética , Psicotrópicos/metabolismo , Psicotrópicos/administração & dosagem , Metabolômica/métodos , Alcaloides/metabolismo , Drogas IlícitasRESUMO
This study reports the first application of in silico methods to assess the toxicity of 4-chloromethcathinone (4-CMC), a novel psychoactive substance (NPS). Employing advanced toxicology in silico tools, it was possible to predict crucial aspects of the toxicological profile of 4-CMC, including acute toxicity (LD50), genotoxicity, cardiotoxicity, and its potential for endocrine disruption. The obtained results indicate significant acute toxicity with species-specific variability, moderate genotoxic potential suggesting the risk of DNA damage, and a notable cardiotoxicity risk associated with hERG channel inhibition. Endocrine disruption assessment revealed a low probability of 4-CMC interacting with estrogen receptor alpha (ER-α), suggesting minimal estrogenic activity. These insights, derived from in silico studies, are critical in advancing the understanding of 4-CMC properties in forensic and clinical toxicology. These initial toxicological findings provide a foundation for future research and aid in the formulation of risk assessment and management strategies in the context of the use and abuse of NPSs.
Assuntos
Simulação por Computador , Psicotrópicos , Psicotrópicos/toxicidade , Psicotrópicos/química , Humanos , Animais , Cardiotoxicidade/etiologia , Propiofenonas/toxicidade , Propiofenonas/química , Receptor alfa de Estrogênio/metabolismo , Disruptores Endócrinos/toxicidade , Disruptores Endócrinos/química , Dano ao DNA/efeitos dos fármacosRESUMO
Ovarian cancer is a common, highly lethal tumor. Herein, we reported that S-phase kinase-associated protein 2 (Skp2) is essential for the growth and aerobic glycolysis of ovarian cancer cells. Skp2 was upregulated in ovarian cancer tissues and associated with poor clinical outcomes. Using a customized natural product library screening, we found that xanthohumol inhibited aerobic glycolysis and cell viability of ovarian cancer cells. Xanthohumol facilitated the interaction between E3 ligase Cdh1 and Skp2 and promoted the Ub-K48-linked polyubiquitination of Skp2 and degradation. Cdh1 depletion reversed xanthohumol-induced Skp2 downregulation, enhancing HK2 expression and glycolysis in ovarian cancer cells. Finally, a xenograft tumor model was employed to examine the antitumor efficacy of xanthohumol in vivo. Collectively, we discovered that xanthohumol promotes the binding between Skp2 and Cdh1 to suppress the Skp2/AKT/HK2 signal pathway and exhibits potential antitumor activity for ovarian cancer cells.
Assuntos
Flavonoides , Glicólise , Neoplasias Ovarianas , Propiofenonas , Proteínas Quinases Associadas a Fase S , Ubiquitinação , Propiofenonas/farmacologia , Proteínas Quinases Associadas a Fase S/metabolismo , Proteínas Quinases Associadas a Fase S/genética , Flavonoides/farmacologia , Feminino , Humanos , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/metabolismo , Glicólise/efeitos dos fármacos , Animais , Transdução de Sinais/efeitos dos fármacos , Caderinas/metabolismo , Carcinogênese/efeitos dos fármacos , Antígenos CD/metabolismo , Hexoquinase/metabolismo , Linhagem Celular Tumoral , Proteínas Proto-Oncogênicas c-akt/metabolismo , Camundongos , Fitoterapia , Camundongos Nus , Antineoplásicos Fitogênicos/farmacologiaRESUMO
Angiopoietin-like 3 (ANGPTL3) acts as an inhibitor of lipoprotein lipase (LPL), impeding the breakdown of triglyceride-rich lipoproteins (TGRLs) in circulation. Targeting ANGPTL3 is considered a novel strategy for improving dyslipidemia and atherosclerotic cardiovascular diseases (ASCVD). Hops (Humulus lupulus L.) contain several bioactive prenylflavonoids, including xanthohumol (Xan), isoxanthohumol (Isoxan), 6-prenylnaringenin (6-PN), and 8-prenylnaringenin (8-PN), with the potential to manage lipid metabolism. The aim of this study was to investigate the lipid-lowering effects of Xan, the effective prenylated chalcone in attenuating ANGPTL3 transcriptional activity, both in vitro using hepatic cells and in vivo using zebrafish models, along with exploring the underlying mechanisms. Xan (10 and 20⯵M) significantly reduced ANGPTL3 mRNA and protein expression in HepG2 and Huh7 cells, leading to a marked decrease in secreted ANGPTL3 proteins via hepatic cells. In animal studies, orally administered Xan significantly alleviated plasma triglyceride (TG) and cholesterol levels in zebrafish fed a high-fat diet. Furthermore, it reduced hepatic ANGPTL3 protein levels and increased LPL activity in zebrafish models, indicating its potential to modulate lipid profiles in circulation. Furthermore, molecular docking results predicted that Xan exhibits a higher binding affinity to interact with liver X receptor α (LXRα) and retinoic acid X receptor (RXR) than their respective agonists, T0901317 and 9-Cis-retinoic acid (9-Cis-RA). We observed that Xan suppressed hepatic ANGPTL3 expression by antagonizing the LXRα/RXR-mediated transcription. These findings suggest that Xan ameliorates dyslipidemia by modulating the LXRα/RXR-ANGPTL3-LPL axis. Xan represents a novel potential inhibitor of ANGPTL3 for the prevention or treatment of ASCVD.
Assuntos
Proteína 3 Semelhante a Angiopoietina , Dieta Hiperlipídica , Flavonoides , Metabolismo dos Lipídeos , Lipase Lipoproteica , Receptores X do Fígado , Propiofenonas , Peixe-Zebra , Animais , Receptores X do Fígado/metabolismo , Propiofenonas/farmacologia , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , Dieta Hiperlipídica/efeitos adversos , Flavonoides/farmacologia , Lipase Lipoproteica/metabolismo , Receptores X de Retinoides/metabolismo , Células Hep G2 , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Chalconas/farmacologia , Fígado/efeitos dos fármacos , Fígado/metabolismoRESUMO
Colorectal cancer stands as the third most prevalent form of cancer worldwide, with a notable increase in incidence in Western countries, mainly attributable to unhealthy dietary habits and other factors, such as smoking or reduced physical activity. Greater consumption of vegetables and fruits has been associated with a lower incidence of colorectal cancer, which is attributed to their high content of fiber and bioactive compounds, such as flavonoids. In this study, we have tested the flavonoids quercetin, luteolin, and xanthohumol as potential antitumor agents in an animal model of colorectal cancer induced by azoxymethane and dodecyl sodium sulphate. Forty rats were divided into four cohorts: Cohort 1 (control cohort), Cohort 2 (quercetin cohort), Cohort 3 (luteolin cohort), and Cohort 4 (xanthohumol cohort). These flavonoids were administered intraperitoneally to evaluate their antitumor potential as pharmaceutical agents. At the end of the experiment, after euthanasia, different physical parameters and the intestinal microbiota populations were analyzed. Luteolin was effective in significantly reducing the number of tumors compared to the control cohort. Furthermore, the main significant differences at the microbiota level were observed between the control cohort and the cohort treated with luteolin, which experienced a significant reduction in the abundance of genera associated with disease or inflammatory conditions, such as Clostridia UCG-014 or Turicibacter. On the other hand, genera associated with a healthy state, such as Muribaculum, showed a significant increase in the luteolin cohort. These results underline the anti-colorectal cancer potential of luteolin, manifested through a modulation of the intestinal microbiota and a reduction in the number of tumors.
Assuntos
Neoplasias Colorretais , Flavonoides , Microbioma Gastrointestinal , Luteolina , Propiofenonas , Quercetina , Animais , Luteolina/farmacologia , Neoplasias Colorretais/prevenção & controle , Neoplasias Colorretais/microbiologia , Microbioma Gastrointestinal/efeitos dos fármacos , Propiofenonas/farmacologia , Flavonoides/farmacologia , Quercetina/farmacologia , Ratos , Masculino , Modelos Animais de Doenças , Azoximetano , Antineoplásicos/farmacologia , Ratos WistarRESUMO
Ulcerative colitis (UC) is a chronic inflammatory disorder affecting the colon, with symptomatology influenced by factors including environmental, genomic, microbial, and immunological interactions. Gut microbiota dysbiosis, characterized by bacterial population alterations, contributes to intestinal homeostasis disruption and aberrant immune system activation, thereby exacerbating the inflammatory state. This study assesses the therapeutic efficacy of intraperitoneal (IP) injected flavonoids (apigenin, luteolin, and xanthohumol) in the reduction of inflammatory parameters and the modulation of the gut microbiota in a murine model of ulcerative colitis. Flavonoids interact with gut microbiota by modulating their composition and serving as substrates for the fermentation into other anti-inflammatory bioactive compounds. Our results demonstrate the effectiveness of luteolin and xanthohumol treatment in enhancing the relative abundance of anti-inflammatory microorganisms, thereby attenuating pro-inflammatory species. Moreover, all three flavonoids exhibit efficacy in the reduction of pro-inflammatory cytokine levels, with luteolin strongly demonstrating utility in alleviating associated physical UC symptoms. This suggests that this molecule is a potential alternative or co-therapy to conventional pharmacological interventions, potentially mitigating their adverse effects. A limited impact on microbiota is observed with apigenin, and this is attributed to its solubility constraints via the chosen administration route, resulting in its accumulation in the mesentery.
Assuntos
Colite Ulcerativa , Colite , Microbioma Gastrointestinal , Propiofenonas , Ratos , Camundongos , Animais , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/diagnóstico , Apigenina/farmacologia , Apigenina/uso terapêutico , Luteolina/farmacologia , Luteolina/uso terapêutico , Colo , Inflamação/tratamento farmacológico , Flavonoides/farmacologia , Flavonoides/uso terapêutico , Anti-Inflamatórios/farmacologia , Sulfato de Dextrana/farmacologia , Modelos Animais de Doenças , Colite/tratamento farmacológicoRESUMO
Xanthohumol (Xn), a prenylated chalcone found in Hop (Humulus lupulus L.), has been shown to have potent anti-aging, diabetes, inflammation, microbial infection, and cancer properties. Unfortunately, this molecule has undesirable characteristics such as inadequate intake, low aqueous solubility, and a short half-life. To address these drawbacks, researchers have made numerous attempts to improve its absorption, solubility, and bioavailability. Polymeric drug delivery systems (PDDSs) have experienced significant development over the last two decades. Polymeric drug delivery is defined as a formulation or device that allows the introduction of a therapeutic substance into the body. Biodegradable and bioreducible polymers are the ideal choice for a variety of new DDSs. Xn formulations based on biodegradable polymers and naturally derived compounds could solve some of the major drawbacks of Xn-based drug delivery. In this regard, the primary concern of this study is on presenting innovative formulations for Xn delivery, such as nanoparticles (NPs), nanomicelles, nanoliposomes, solid lipid nanoparticles (SLNs), and others, as well as the received in vitro and in vivo data. Furthermore, this work describes the chemistry and broad biological activity of Xn, which is particularly useful in modern drug technology as well as the cosmetics industry. It is also important to point out that the safety of using Xn, and its biotransformation, pharmacokinetics, and clinical applications, have been thoroughly explained in this review.
Assuntos
Humulus , Neoplasias , Propiofenonas , Humanos , Flavonoides/química , Propiofenonas/química , Humulus/química , PolímerosRESUMO
Eperisone Hydrochloride was launched in Japan in 1983 and has been used to improve muscle tone and treat spastic paralysis (Originator: Eisai Co., Ltd.). However, its biochemical mechanism of action is unknown. SB Drug Discovery was used to evaluate purinergic P2X (P2X) receptor antagonism using fluorescence. In this study, we discovered that its target protein is the P2X7 receptor. Also, P2X receptor subtype selectivity was high. This finding demonstrates the (Eperisone-P2X7-pain linkage), the validity of P2X7 as a drug target, and the possibility of drug repositioning of Eperisone Hydrochloride.