RESUMEN

BACKGROUND: Myocardial infarction (MI) is the main contributor to most cardiovascular diseases (CVDs), and the available post-treatment clinical therapeutic options are limited. The development of nanoscale drug delivery systems carrying natural small molecules provides biotherapies that could potentially offer new treatments for reactive oxygen species (ROS)-induced damage in MI. Considering the stability and reduced toxicity of gold-phenolic core-shell nanoparticles, this study aims to develop ellagic acid-functionalized gold nanoparticles (EA-AuNPs) to overcome these limitations. RESULTS: We have successfully synthesized EA-AuNPs with enhanced biocompatibility and bioactivity. These core-shell gold nanoparticles exhibit excellent ROS-scavenging activity and high dispersion. The results from a label-free imaging method on optically transparent zebrafish larvae models and micro-CT imaging in mice indicated that EA-AuNPs enable a favorable excretion-based metabolism without overburdening other organs. EA-AuNPs were subsequently applied in cellular oxidative stress models and MI mouse models. We found that they effectively inhibit the expression of apoptosis-related proteins and the elevation of cardiac enzyme activities, thereby ameliorating oxidative stress injuries in MI mice. Further investigations of oxylipin profiles indicated that EA-AuNPs might alleviate myocardial injury by inhibiting ROS-induced oxylipin level alterations, restoring the perturbed anti-inflammatory oxylipins. CONCLUSIONS: These findings collectively emphasized the protective role of EA-AuNPs in myocardial injury, which contributes to the development of innovative gold-phenolic nanoparticles and further advances their potential medical applications.

Asunto(s)

Ácido Elágico , Oro , Nanopartículas del Metal , Infarto del Miocardio , Estrés Oxidativo , Especies Reactivas de Oxígeno , Pez Cebra , Animales , Oro/química , Nanopartículas del Metal/química , Infarto del Miocardio/tratamiento farmacológico , Ratones , Especies Reactivas de Oxígeno/metabolismo , Ácido Elágico/farmacología , Ácido Elágico/química , Estrés Oxidativo/efectos de los fármacos , Materiales Biocompatibles/química , Materiales Biocompatibles/farmacología , Masculino , Apoptosis/efectos de los fármacos , Modelos Animales de Enfermedad , Humanos , Ratones Endogámicos C57BL

RESUMEN

The objective of the study was to develop a novel topical gel by mixing Potentilla tormentilla ethanolic extract, thermosensitive poloxamer 407, and carbomer 940 and evaluating its stability and rheological behavior. The irritation potential of the gel was evaluated in accordance with the Organization for Economic Cooperation and Development Guidelines 404. The potential anti-inflammatory effects of the developed gel were evaluated in vivo in rats using the carrageenan-induced paw edema test. Moreover, the in silico binding affinity for chlorogenic and ellagic acid, as dominant components in the extract, against cyclooxygenase (COX) 1 and 2 was also determined. Our findings suggest that the gel containing Potentilla tormentilla extract remained stable throughout the observation period, exhibited pseudoplastic behavior, and caused no irritation in rats, thus being considered safe for topical treatment. Additionally, the developed gel showed the capability to reduce rat paw edema, which highlights significant anti-inflammatory potential. In silico analysis revealed that chlorogenic and ellagic acid exhibited a reduced binding affinity against COX-1 but had a similar inhibitory effect on COX-2 as flurbiprofen, which was confirmed by molecular dynamics results. The study proposes the possible application of Potentilla tormentilla ethanolic extract gel for the alleviation of localized inflammatory diseases; however, future clinical evaluation is required.

Asunto(s)

Antiinflamatorios , Ciclooxigenasa 1 , Edema , Extractos Vegetales , Potentilla , Animales , Potentilla/química , Extractos Vegetales/química , Extractos Vegetales/farmacología , Ratas , Antiinflamatorios/farmacología , Antiinflamatorios/química , Edema/tratamiento farmacológico , Edema/inducido químicamente , Masculino , Ciclooxigenasa 1/metabolismo , Ciclooxigenasa 1/química , Geles/química , Ácido Elágico/farmacología , Ácido Elágico/química , Ciclooxigenasa 2/metabolismo , Carragenina , Ratas Wistar , Poloxámero/química , Resinas Acrílicas/química , Ácido Clorogénico/química , Ácido Clorogénico/farmacología

RESUMEN

Arsenic, a neurotoxic metalloid, poses significant health risks. However, ellagic acid, renowned for its antioxidant properties, has shown potential in neuroprotection. This study aimed to investigate the neuroprotective effects of ellagic acid against arsenic-induced neuronal ferroptosis and cognitive impairment and elucidate the underlying mechanisms. Using an arsenic-exposed Wistar rat model and an arsenic-induced HT22 cells model, we assessed cognitive ability, measured serum and brain arsenic levels, and evaluated pathological damage through histological analysis and transmission electron microscopy. Additionally, we examined oxidative stress and iron ion levels using GSH, MDA, ROS and tissue iron biochemical kits, and analyzed the expression of ferroptosis-related markers using western blot and qRT-PCR. Our results revealed that arsenic exposure increased both serum and brain arsenic levels, resulting in hippocampal pathological damage and subsequent decline in learning and memory abilities. Arsenic-induced neuronal ferroptosis was mediated by the inhibition of the xCT/GSH/GPX4/Nrf2 signaling axis and disruption of iron metabolism. Notably, ellagic acid intervention effectively reduced serum and brain arsenic levels, ameliorated neuronal damage, and improved oxidative stress, ferroptosis, and cognitive impairment. These beneficial effects were associated with the activation of the Nrf2/Keap1 signaling pathway, upregulation of GPX4 expression, and enhanced iron ion excretion. In conclusion, ellagic acid demonstrates promising neuroprotective effects against arsenic-induced neurotoxicity by mitigating neuronal ferroptosis and cognitive impairment.

Asunto(s)

Arsénico , Disfunción Cognitiva , Ácido Elágico , Ferroptosis , Factor 2 Relacionado con NF-E2 , Neuronas , Fosfolípido Hidroperóxido Glutatión Peroxidasa , Ratas Wistar , Transducción de Señal , Animales , Ácido Elágico/farmacología , Ferroptosis/efectos de los fármacos , Factor 2 Relacionado con NF-E2/metabolismo , Disfunción Cognitiva/inducido químicamente , Disfunción Cognitiva/tratamiento farmacológico , Arsénico/toxicidad , Transducción de Señal/efectos de los fármacos , Fosfolípido Hidroperóxido Glutatión Peroxidasa/metabolismo , Ratas , Masculino , Neuronas/efectos de los fármacos , Neuronas/patología , Estrés Oxidativo/efectos de los fármacos , Fármacos Neuroprotectores/farmacología

RESUMEN

Osteoarthritis (OA) is a degenerative joint disease characterised by inflammation and cartilage degeneration. Ellagic acid (EA) might have therapeutic potential in OA, but its molecular mechanisms of action remain unclear. In this study, we aimed to identify the docking protein of EA in M1 macrophage-related pro-inflammation in OA. Bioinformatics analysis was performed to identify ellagic acid's potential targets among OA-related dysregulated genes. THP-1 cells were induced into M0 and polarised into M1 macrophages for in vitro studies. Mice knee models of OA were generated for in vivo studies. Results showed that PTGS2 (also known as COX-2) is a potential target of ellagic acid among OA-related dysregulated genes. EA has multiple low-energy binding sites on PTGS2, including sites containing amino acid residues critical for the enzyme's catalytic activity. Surface plasmon resonance (SPR) assays confirmed the physical interaction between ellagic acid and recombinant PTGS2 protein, with a dissociation constant (KD) of 5.03 ± 0.84 µM. EA treatment suppressed PTGS2 expression and prostaglandin E2 (PGE2) production in M1 macrophages. Besides, ellagic acid can directly inhibit PTGS2 enzyme activity, with an IC50 around 50 µM. Importantly, in a mouse model of OA, ellagic acid administration alleviated disease severity, reduced collagen II degradation and MMP13 generation, and decreased serum PGE2 levels. Collectively, these results suggest that PTGS2 is a key target of ellagic acid's anti-inflammatory and chondroprotective effects in OA.

Asunto(s)

Ciclooxigenasa 2 , Dinoprostona , Ácido Elágico , Macrófagos , Osteoartritis , Ácido Elágico/farmacología , Ciclooxigenasa 2/metabolismo , Animales , Ratones , Humanos , Dinoprostona/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Osteoartritis/tratamiento farmacológico , Osteoartritis/metabolismo , Osteoartritis/patología , Células THP-1 , Masculino , Ratones Endogámicos C57BL

RESUMEN

Ellagic acid (EA) is a phenolic phytochemical found in many plants and their fruits. Vaginal epithelial cells are the first line of defense against pathogen invasion in the female reproductive tract and express antimicrobial peptides, including hBD2 and SLPI. This study investigated the in vitro effects of EA (1) on vaginal innate immunity using human vaginal epithelial cells, and (2) on HPV16 pseudovirus infection. Vaginal cells were cultured in the presence or absence of EA, and the expression of hBD2 and SLPI was determined at both transcriptional and translational levels. In addition, secretion of various cytokines and chemokines was measured. Cytotoxicity of EA was determined by CellTiter-blue and MTT assays. To investigate the ability of EA to inhibit HPV16 infection, EA was used to treat HEK-293FT cells in pre-attachment and adsorption steps. We found significant increases in both hBD2 mRNA (mean 2.9-fold at 12.5 µM EA, p < 0.001) and protein (mean 7.1-fold at 12.5 µM EA, p = 0.002) in response to EA. SLPI mRNA also increased significantly (mean 1.4-fold at 25 µM EA, p = 0.01), but SLPI protein did not. Secretion of IL-2 but not of other cytokines/chemokines was induced by EA in a dose-dependent manner. EA was not cytotoxic. At the pre-attachment step, EA at CC20 and CC50 showed a slight trend towards inhibiting HPV16 pseudovirus, but this was not significant. In summary, vaginal epithelial cells can respond to EA by producing innate immune factors, and at tested concentrations, EA is not cytotoxic. Thus, plant-derived EA could be useful as an immunomodulatory agent to improve vaginal health.

Asunto(s)

Ácido Elágico , Papillomavirus Humano 16 , Inmunidad Innata , Infecciones por Papillomavirus , Vagina , Humanos , Femenino , Ácido Elágico/farmacología , Inmunidad Innata/efectos de los fármacos , Vagina/virología , Vagina/inmunología , Vagina/efectos de los fármacos , Infecciones por Papillomavirus/inmunología , Infecciones por Papillomavirus/virología , Infecciones por Papillomavirus/tratamiento farmacológico , Citocinas/metabolismo , Células Epiteliales/efectos de los fármacos , Células Epiteliales/virología , Células Epiteliales/metabolismo , Células Epiteliales/inmunología , beta-Defensinas/metabolismo , Células HEK293

RESUMEN

Heat stress has been shown to have a detrimental impact on testicular activity and spermatogenesis. Ellagic acid is a plant-derived organic compound that has a variety of biological functions. Thus, it is believed that ellagic acid may improve heat-stressed testicular dysfunction. There has been no research on the impact of ellagic acid on heat-stressed testicular dysfunction. The mice were divided into 4 groups. The first group was the normal control group (CN), and the second received heat stress (HS) by submerging the lower body for 15 min in a water bath with a thermostatically controlled temperature kept at 43°C (HS), and the third and fourth groups were subjected to heat-stress similar to group two and given two different dosages of ellagic acid (5 mg/kg (EH5) and 50 mg/kg (EH50) for 14 days. Ellagic acid at a dose of 50 mg/kg improved the level of circulating testosterone (increased 3ßHSD) and decreases the oxidative stress. The testicular and epididymal architecture along with sperm parameters also showed improvement. Ellagic acid treatment significantly increases the germ cell proliferation (GCNA, BrdU staining) and Bcl2 expression and decreases active caspase 3 expression. Heat stress downregulated the expression of AR, ER-α and ER-ß, and treatment with ellagic acid increased the expression of ER-α and ER-ß markers in the 50 mg/kg treatment group. Thus, our finding suggests that ellagic acid ameliorates heat-induced testicular impairment through modulating testosterone synthesis, germ cell proliferation, and oxidative stress. These effects could be manifested by regulating androgen and estrogen receptors. However, the two doses showed differential effects of some parameters, which require further investigation.

Asunto(s)

Ácido Elágico , Estrés Oxidativo , Testículo , Testosterona , Ácido Elágico/farmacología , Animales , Masculino , Testículo/efectos de los fármacos , Testículo/metabolismo , Ratones , Testosterona/sangre , Estrés Oxidativo/efectos de los fármacos , Calor/efectos adversos , Espermatogénesis/efectos de los fármacos , Respuesta al Choque Térmico/efectos de los fármacos , Apoptosis/efectos de los fármacos , Espermatozoides/efectos de los fármacos , Espermatozoides/metabolismo , Modelos Animales de Enfermedad , Trastornos de Estrés por Calor/tratamiento farmacológico , Trastornos de Estrés por Calor/metabolismo , Trastornos de Estrés por Calor/prevención & control

RESUMEN

Photothermal therapy (PTT) of tumor would ineluctably cause oxidative stress and related inflammation in adjacent normal tissues, leading to a discounted therapeutic outcome. To address this issue, herein an innovative therapeutic strategy that integrates photothermal anticancer and normal cell protection is developed. A new type of nitrogen-doped carbon dot (ET-CD) has been synthesized in one step by hydrothermal method using ellagic acid and L-tyrosine as reaction precursors. The as-prepared ET-CD exhibits high photothermal conversion efficiency and good photothermal stability. After intravenous injection, ET-CD can accumulate at the tumor site and the hyperthermia generated under near infrared laser irradiation effectively ablates tumor tissues, thereby significantly inhibiting tumor growth. Importantly, owing to the inherited antioxidant activity from ellagic acid, ET-CD can remove reactive oxygen and nitrogen species produced in the body and reduce the levels of inflammatory factors induced by oxidative stress, so as to alleviate the damage caused by heat-induced inflammation to normal cells and tissues while photothermal anticancer. These attractive features of ET-CD may open the exploration of innovative therapeutic strategies to promote the clinical application of PTT.

Asunto(s)

Carbono , Ácido Elágico , Nitrógeno , Terapia Fototérmica , Tirosina , Carbono/química , Carbono/farmacología , Nitrógeno/química , Ácido Elágico/farmacología , Ácido Elágico/química , Ácido Elágico/uso terapéutico , Animales , Tirosina/química , Humanos , Ratones , Terapia Fototérmica/métodos , Antiinflamatorios/farmacología , Antiinflamatorios/química , Puntos Cuánticos/química , Línea Celular Tumoral , Inflamación/tratamiento farmacológico , Antineoplásicos/farmacología , Antineoplásicos/química , Estrés Oxidativo/efectos de los fármacos , Neoplasias/tratamiento farmacológico , Neoplasias/terapia , Neoplasias/patología

RESUMEN

Rosa laxa Retz. is an unexplored Rosaceae plant in Xinjiang, China, and its flower is traditionally used in Kazak to treat the common cold, fever, and epileptic seizures and lessen the effects of aging. In the present study, the pharmacognostic profiles, physicochemical properties, phytochemical characteristics, and in vitro antioxidant potency of Rosa laxa Retz. flos (RLF) were presented. In the pharmacognostic evaluation of RLF, organoleptic characteristics, internal structures, and powder information were observed, and physicochemical parameters, including moisture content, ash, pH value, swelling degree, and extractives were examined. The quantitative analysis of the chemical composition of four different polar extracts of RLF showed that the aqueous part had the highest total triterpene acid, flavonoid, and polyphenol content (4.50 ± 0.04 mg/g, 50.56 ± 0.03 mg/g, and 60.20 ± 0.09 mg/g, respectively). A high-performance liquid chromatography (HPLC)-diode array detector (DAD) method was established and the contents of gallic acid, ellagic acid, astragalin, and tiliroside in RLF were determined simultaneously. In the set concentration range, the linear relationship among the four components was good (r > 0.999), the average recoveries were 97.36%-100.54%. The contents of gallic acid, ellagic acid, astragalin, and tiliroside in RLF samples were (9.46 ± 2.31) mg/g, (10.60 ±0.75) mg/g, (1.13 ± 2.50) mg/g, and (1.11 ± 2.65) mg/g, respectively. The types of its secondary metabolites were determined by fluorescence, color reaction by chemical solvent method, and ultraviolet-visible (UV-Vis) spectroscopy. The functional groups of its secondary metabolites were determined by Fourier transform infrared (FTIR) spectroscopy. Results showed that RLF contains a variety of secondary metabolic products, including flavonoids, phenolic acid, glycoside, and organic acid. TLC identification showed it contains ursolic acid, ß-sitosterol, tiliroside, astragalin, isoquercitrin, kaempferol-3-O-rutinoside, gallic acid, and ellagic acid. The in vitro antioxidant activity of different polar parts of RLF was investigated by DPPH, ABTS, and reduction performance experiments. The aqueous extract had the strongest antioxidant capacity, consistent with the high content of triterpene acids, flavonoids, and polyphenolic compounds. These findings will provide critical information for the study of quality standards and medicinal value of RLF and its extracts, justify its usage in traditional medicinal systems, and encourage the use of this plant in disease prevention and treatment. Its phytochemical composition and pharmacological studies need to be explored in future. RESEARCH HIGHLIGHTS: Optical microscope and scanning electron microscope (SEM) were used to observe the morphology, and microstructure of Rosa laxa Retz. flos (RLF). The physicochemical properties, fluorescence and phytochemical composition of four different polar extracts of RLF were analyzed by UV-Vis and FTIR. Determination of total triterpenic acid, total flavonoids, and total polyphenols in four different polar extracts of RLF by UV spectrophotometry. A high-performance liquid chromatography (HPLC)-diode array detector (DAD) method was established and the contents of gallic acid, ellagic acid, astragalin, and tiliroside in RLF were determined simultaneously. TLC confirmed that RLF contains ursolic acid, ß-sitosterol, tiliroside, astragalin, isoquercitrin, kaempferol 3-rutinoside, gallic acid, and ellagic acid. The in vitro antioxidant activity of RLF was studied by DPPH, ABTS, and reducing ability experiments.

Asunto(s)

Antioxidantes , Flavonoides , Flores , Ácido Gálico , Extractos Vegetales , Rosa , Rosa/química , Antioxidantes/farmacología , Antioxidantes/análisis , Antioxidantes/química , Extractos Vegetales/farmacología , Extractos Vegetales/química , Flores/química , Flavonoides/análisis , Flavonoides/química , Ácido Gálico/farmacología , Ácido Gálico/química , Cromatografía Líquida de Alta Presión , Ácido Elágico/farmacología , Ácido Elágico/análisis , Quempferoles/análisis , Quempferoles/farmacología , Fitoquímicos/farmacología , Fitoquímicos/química , Fitoquímicos/análisis , Polifenoles/análisis , Polifenoles/química , Polifenoles/farmacología , Triterpenos/análisis , Triterpenos/farmacología , Triterpenos/química , China , Farmacognosia

RESUMEN

The aim of this work was to develop and characterize a thin films composed of hyaluronic acid/ellagic acid for potential medical application. Its principal novelty, distinct from the prior literature in terms of hyaluronic acid films supplemented with phenolic acids, resides in the predominant incorporation of ellagic acid-a distinguished compound-as the primary constituent of the films. Herein, ellagic acid was dissolved in two different solvents, i.e., acetic acid (AcOH) or sodium hydroxide (NaOH), and the surface properties of the resultant films were assessed using atomic force microscopy and contact angle measurements. Additionally, various physicochemical parameters were evaluated including moisture content, antioxidant activity, and release of ellagic acid in phosphate buffered saline. Furthermore, the evaluation of films' biocompatibility was conducted using human epidermal keratinocytes, dermal fibroblasts, and human amelanotic melanoma cells (A375 and G361), and the antimicrobial activity was elucidated accordingly against Staphylococcus aureus ATCC 6538 and Pseudomonas aeruginosa ATCC 15442. Our results showed that the films exhibited prominent antibacterial properties particularly against Staphylococcus aureus, with the 80HA/20EA/AcOH film indicating the strong biocidal activity against this strain leading to a significant reduction in viable cells. Comparatively, the 50HA/50EA/AcOH film also displayed biocidal activity against Staphylococcus aureus. This experimental approach could be a promising technique for future applications in regenerative dermatology or novel strategies in terms of bioengineering.

Asunto(s)

Materiales Biocompatibles , Ácido Elágico , Ácido Hialurónico , Staphylococcus aureus , Ácido Hialurónico/química , Ácido Hialurónico/farmacología , Humanos , Staphylococcus aureus/efectos de los fármacos , Materiales Biocompatibles/química , Materiales Biocompatibles/farmacología , Ácido Elágico/farmacología , Ácido Elágico/química , Pseudomonas aeruginosa/efectos de los fármacos , Antibacterianos/farmacología , Antibacterianos/química , Antioxidantes/farmacología , Antioxidantes/química , Fibroblastos/efectos de los fármacos , Queratinocitos/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Línea Celular Tumoral , Propiedades de Superficie

RESUMEN

Oxidative stress (OS) plays an important role in the emergence and prevention of neurodegenerative diseases, such as Alzheimer's disease (AD). Excess reactive oxygen species (ROS) accumulated in a neuronal cell can lead to OS, producing cell injury and death. Seeking nanoantioxidants against AD-related oxidative stress has attracted a lot of attention, especially those potential antioxidant agents derived from natural polyphenols. However, the transformation of abundant plant polyphenols to antioxidative biomaterials against OS is still challenging. In this work, we report a new method to transform amorphous tannic acid (TA) into tailorable shaped ellagic acid (EA) crystalline particles without using an organic solvent. EA crystalline particles were generated from TA, which underwent a chemical transformation, in situ metal phenolic coordination and acid-induced assembly process, and the size and shape could be controlled by varying the amount of acid. As-prepared EA crystalline particles showed excellent stability in water and lysosomal mimicking fluid and possess unique fluorescence properties and a strong response in mass spectrometry, which is beneficial for their imaging analysis in cells and tissues. More importantly, EA particles have shown significant H2O2-related ROS scavenging ability, a high cellular uptake capacity, an excellent neuroprotective effect in PC12 cells, a high drug loading capacity and BBB permeability to enter the brain. Our study suggested that the EA crystalline particles show great potential for OS-mediated AD treatment.

Asunto(s)

Ácido Elágico , Fármacos Neuroprotectores , Estrés Oxidativo , Especies Reactivas de Oxígeno , Taninos , Ácido Elágico/farmacología , Ácido Elágico/química , Taninos/farmacología , Taninos/química , Estrés Oxidativo/efectos de los fármacos , Células PC12 , Animales , Ratas , Especies Reactivas de Oxígeno/metabolismo , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/química , Fármacos Neuroprotectores/síntesis química , Antioxidantes/farmacología , Antioxidantes/química , Antioxidantes/síntesis química , Barrera Hematoencefálica/metabolismo , Barrera Hematoencefálica/efectos de los fármacos , Peróxido de Hidrógeno/farmacología , Peróxido de Hidrógeno/química , Neuroprotección/efectos de los fármacos , Tecnología Química Verde , Polifenoles

RESUMEN

BACKGROUND: Mediterranean diet rich in polyphenolic compounds holds great promise to prevent and alleviate multiple sclerosis (MS), a central nervous system autoimmune disease associated with gut microbiome dysbiosis. Health-promoting effects of natural polyphenols with low bioavailability could be attributed to gut microbiota reconstruction. However, its underlying mechanism of action remains elusive, resulting in rare therapies have proposed for polyphenol-targeted modulation of gut microbiota for the treatment of MS. RESULTS: We found that oral ellagic acid (EA), a natural polyphenol rich in the Mediterranean diet, effectively halted the progression of experimental autoimmune encephalomyelitis (EAE), the animal model of MS, via regulating a microbiota-metabolites-immunity axis. EA remodeled the gut microbiome composition and particularly increased the relative abundances of short-chain fatty acids -producing bacteria like Alloprevotella. Propionate (C3) was most significantly up-regulated by EA, and integrative modeling revealed a strong negative correlation between Alloprevotella or C3 and the pathological symptoms of EAE. Gut microbiota depletion negated the alleviating effects of EA on EAE, whereas oral administration of Alloprevotella rava mimicked the beneficial effects of EA on EAE. Moreover, EA directly promoted Alloprevotella rava (DSM 22548) growth and C3 production in vitro. The cell-free supernatants of Alloprevotella rava co-culture with EA suppressed Th17 differentiation by modulating acetylation in cell models. C3 can alleviate EAE development, and the mechanism may be through inhibiting HDAC activity and up-regulating acetylation thereby reducing inflammatory cytokines secreted by pathogenic Th17 cells. CONCLUSIONS: Our study identifies EA as a novel and potentially effective prebiotic for improving MS and other autoimmune diseases via the microbiota-metabolites-immunity axis. Video Abstract.

Asunto(s)

Ácido Elágico , Encefalomielitis Autoinmune Experimental , Microbioma Gastrointestinal , Esclerosis Múltiple , Propionatos , Ácido Elágico/farmacología , Animales , Microbioma Gastrointestinal/efectos de los fármacos , Encefalomielitis Autoinmune Experimental/inmunología , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Encefalomielitis Autoinmune Experimental/microbiología , Propionatos/metabolismo , Ratones , Esclerosis Múltiple/tratamiento farmacológico , Esclerosis Múltiple/microbiología , Ratones Endogámicos C57BL , Modelos Animales de Enfermedad , Femenino , Autoinmunidad/efectos de los fármacos , Disbiosis/microbiología , Sistema Nervioso Central/efectos de los fármacos , Sistema Nervioso Central/inmunología , Humanos , Administración Oral

Asunto(s)

Demencia , Ácido Elágico , Óxido Nítrico Sintasa de Tipo III , Fosfatidilinositol 3-Quinasas , Transducción de Señal , Estreptozocina , Animales , Transducción de Señal/efectos de los fármacos , Óxido Nítrico Sintasa de Tipo III/metabolismo , Ratas , Ácido Elágico/farmacología , Demencia/tratamiento farmacológico , Demencia/prevención & control , Fosfatidilinositol 3-Quinasas/metabolismo , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/metabolismo

RESUMEN

The aim of this research was to explore the effects of ellagic acid (EA) on growth performance, meat quality, and metabolomics profile of broiler chickens. 240 healthy yellow-feathered broilers were randomly divided into 4 groups (6 replicates/group and 10 broilers /replicate): 1) a standard diet (CON); 2) CON+0.01% EA; 3) CON+0.02% EA; 4) CON+0.04% EA. Compared with the CON group, dietary 0.02% EA increased linearly and quadratically the ADG and lowered F/G ratio from 29 to 56 d and from 1 to 56 d of age (P < 0.05). The EA groups had higher spleen index and showed linear and quadratic improve thymus index (P < 0.05). A total of 0.02% EA linearly and quadratically increased the leg muscle percentage and quadratically increased the breast muscle percentage (P < 0.05). Compared to the control diet, 0.02% EA decreased quadratically the L* and increased a* of breast muscle at 45 min postslaughter (P < 0.05), and quadratically decreased (P < 0.05) the b* and increased linearly and quadratically (P < 0.05) drip loss. Additionally, EA improved linearly and quadratically (P < 0.05) serum total protein concentration and reduced linearly and quadratically (P < 0.05) serum blood urea nitrogen concentration. A total of 0.02% EA quadratically increased catalase activity and decreased malondialdehyde concentration in breast muscle compared with the control diet (P < 0.05). 0.02% and 0.04% EA could linearly and quadratically increase (P < 0.05) the concentrations of histidine, leucine and essential amino acids (EAA), 0.02% EA could linearly and quadratically increase (P < 0.05) the concentrations of threonine, glutamate, and flavored amino acids in breast muscle. 0.02% EA linearly and quadratically improved the C20:3n6, C22:6n3, polyunsaturated fatty acid (PUFA) concentrations, and the ratio of PUFA to saturated fatty acids (SFA), but reduced the C16:0 and the SFA concentrations in breast muscle than the CON group (P < 0.05). The EA diet linearly increased (P = 0.035) and quadratically tended (P = 0.068) to regulate the C18:2n6c concentration of breast muscle. Metabolomics showed that alanine metabolism, aspartate and glutamate metabolism, arginine and proline metabolism, taurine and hypotaurine metabolism, and glycerophospholipid metabolism were the most differentially abundant. These results showed that EA supported moderate positive effects on growth performance, meat quality, and metabolomics profile of broilers.

Asunto(s)

Alimentación Animal , Pollos , Dieta , Suplementos Dietéticos , Ácido Elágico , Carne , Animales , Pollos/crecimiento & desarrollo , Pollos/fisiología , Pollos/metabolismo , Alimentación Animal/análisis , Dieta/veterinaria , Suplementos Dietéticos/análisis , Carne/análisis , Ácido Elágico/administración & dosificación , Ácido Elágico/farmacología , Metabolómica , Distribución Aleatoria , Masculino , Metaboloma/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Fenómenos Fisiológicos Nutricionales de los Animales/efectos de los fármacos

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Androgenic alopecia (AGA) is the most prevalent form of hair loss in clinical practice and affects the physical and psychological well-being of adolescents. Paeonia lactiflora Pallas (PL), which is widely used in traditional Chinese medicine, enhances blood function and promotes hair growth, and ellagic acid (EA), a polyphenol in PL extract, shows strong antioxidant, anti-aging, and anti-inflammatory properties and also plays a role in the treatment of various skin conditions. However, its role and mechanism of action in AGA remain unclear. AIM OF THE STUDY: To determine whether EA can rescue slow hair regeneration by regulating dihydrotestosterone (DHT)-induced ferroptosis in AGA mice and clarify the effect of EA on DHT-induced ferroptosis in dermal papilla cells (DPCs). MATERIALS AND METHODS: Male C57BL/6 mice were used to establish a DHT-induced AGA mouse model, whereas DPCs were used to establish a DHT-induced cellular model. Thereafter, we investigated the therapeutic mechanism of action of EA via immunofluorescence, western blot analysis, immunohistochemistry, electron microscopy, and molecular docking. RESULTS: EA stimulated hair regeneration in mice and reversed DHT-induced increases in iron content, lipid peroxidation, and DHT-induced mitochondrial dysfunction by activating the Wnt/ß-catenin signaling pathway. Further, ß-catenin knockdown suppressed the inhibitory effect of EA on DHT-induced ferroptosis in DPCs. CONCLUSION: EA inhibits DHT-induced ferroptosis and promotes hair regrowth in mice by activating the Wnt/ß-catenin signaling pathway. Thus, it has potential for use as a treatment option for AGA.

Asunto(s)

Alopecia , Dihidrotestosterona , Ácido Elágico , Cabello , Regeneración , Vía de Señalización Wnt , Animales , Masculino , Ratones , Alopecia/tratamiento farmacológico , Alopecia/inducido químicamente , beta Catenina/metabolismo , Dihidrotestosterona/farmacología , Ácido Elágico/farmacología , Ferroptosis/efectos de los fármacos , Cabello/efectos de los fármacos , Cabello/crecimiento & desarrollo , Ratones Endogámicos C57BL , Regeneración/efectos de los fármacos , Vía de Señalización Wnt/efectos de los fármacos

RESUMEN

The target and mechanism of ellagic acid (EA) against rotavirus (RV) were investigated by network pharmacology, computational biology, and surface plasmon resonance verification. The target of EA was obtained from 11 databases such as HIT and TCMSP, and RV-related targets were obtained from the Gene Cards database. The relevant targets were imported into the Venny platform to draw a Venn diagram, and their intersections were visualized. The protein-protein interaction networks (PPI) were constructed using STRING, DAVID database, and Cytoscape software, and key targets were screened. The target was enriched by Gene Ontology (GO) and KEGG pathway, and the 'EA anti-RV target-pathway network' was constructed. Schrodinger Maestro 13.5 software was used for molecular docking to determine the binding free energy and binding mode of ellagic acid and target protein. The Desmond program was used for molecular dynamics simulation. Saturation mutagenesis analysis was performed using Schrodinger's Maestro 13.5 software. Finally, the affinity between ellagic acid and TLR4 protein was investigated by surface plasmon resonance (SPR) experiments. The results of network pharmacological analysis showed that there were 35 intersection proteins, among which Interleukin-1ß (IL-1ß), Albumin (ALB), Nuclear factor kappa-B1 (NF-κB1), Toll-Like Receptor 4 (TLR4), Tumor necrosis factor alpha (TNF-α), Tumor protein p53 (TP53), Recombinant SMAD family member 3 (SAMD3), Epidermal growth factor (EGF) and Interleukin-4 (IL-4) were potential core targets of EA anti-RV. The GO analysis consists of biological processes (BP), cellular components (CC), and molecular functions (MF). The KEGG pathways with the highest gene count were mainly related to enteritis, cancer, IL-17 signaling pathway, and MAPK signaling pathway. Based on the crystal structure of key targets, the complex structure models of TP53-EA, TLR4-EA, TNF-EA, IL-1ß-EA, ALB-EA, NF-κB1-EA, SAMD3-EA, EGF-EA, and IL-4-EA were constructed by molecular docking (XP mode of flexible docking). The MMGBS analysis and molecular dynamics simulation were also studied. The Δaffinity of TP53 was highest in 220 (CYS → TRP), 220 (CYS → TYR), and 220 (CYS → PHE), respectively. The Δaffinity of TLR4 was highest in 136 (THR → TYR), 136 (THR → PHE), and 136 (THR → TRP). The Δaffinity of TNF-α was highest in 150 (VAL → TRP), 18 (ALA → GLU), and 144 (PHE → GLY). SPR results showed that ellagic acid could bind TLR4 protein specifically. TP53, TLR4, and TNF-α are potential targets for EA to exert anti-RV effects, which may ultimately provide theoretical basis and clues for EA to be used as anti-RV drugs by regulating TLR4/NF-κB related pathways.

Asunto(s)

Medicamentos Herbarios Chinos , Rotavirus , Factor de Necrosis Tumoral alfa , Ácido Elágico/farmacología , Interleucina-4 , Resonancia por Plasmón de Superficie , Receptor Toll-Like 4 , Factor de Crecimiento Epidérmico , Farmacología en Red , Simulación del Acoplamiento Molecular , Biología Computacional , Albúminas

RESUMEN

The early myocardial response of hypertension is an elevation of angiotensin-II (Ang-II) concentration, leading to heart failure and cardiac hypertrophy. This hypertrophic event of the heart is mediated by the interaction of Ang type 1 receptors (AT-R1), thereby modulating NADPH oxidase activity in cardiomyocytes, which alters redox status in cardiomyocytes. Ellagic acid (EA) has anti-inflammatory and anti-oxidative capacities. Thus, EA has potential preventive effects on cardiovascular diseases and diabetes. In the last decades, because the protective effect of EA on Ang-II-induced hypertrophic responses is unclear, this study aims to investigate the protective effect of EA in cardiomyocytes. H9c2 cells were treated to Ang-II 1 µM for 24 h to induce cellular damage. We found that EA protected against Ang-II-increased cell surface area and pro-hypertrophic gene expression in H9c2. EA reduced Ang-II-caused AT-R1 upregulation, thereby inhibiting oxidative stress NADPH oxidase activation. EA mitigated Ang-II-enhanced p38 and extracellular-signal-regulated kinase (ERK) phosphorylation. Moreover, EA treatment under Ang-II stimulation also reversed NF-κB activity and iNOS expression. This study shows that EA protects against Ang-II-induced myocardial hypertrophy and attenuates oxidative stress through reactive oxygen species-mediated mitogen-activated protein kinase signaling pathways in H9c2 cells. Thus, EA may be an effective compound for preventing Ang-II-induced myocardial hypertrophy.

Asunto(s)

Angiotensina II , Ácido Elágico , Humanos , Especies Reactivas de Oxígeno/metabolismo , Angiotensina II/farmacología , Angiotensina II/metabolismo , Ácido Elágico/farmacología , Miocitos Cardíacos , Cardiomegalia , NADPH Oxidasas/metabolismo , NADPH Oxidasas/farmacología

RESUMEN

This study investigates the potential of ellagic acid (EA), a phytochemical with antioxidant and anti-inflammatory properties, in managing perioperative neurocognitive disorders (PND). PND, which represents a spectrum of cognitive impairments often faced by elderly patients, is principally linked to surgical and anesthesia procedures, and heavily impacted by oxidative stress in the hippocampus and microglia-induced neuroinflammation. Employing an aged mice model subjected to abdominal surgery, we delve into EA's ability to counteract postoperative oxidative stress and cerebral inflammation by engaging the Insulin-like growth factor-1 (IGF-1) pathway. Our findings revealed that administering EA orally notably alleviated post-surgical cognitive decline in older mice, a fact that was manifested in improved performance during maze tests. This enhancement in the behavioral performance of the EA-treated mice corresponded with the rejuvenation of IGF-1 signaling, a decrease in oxidative stress markers in the hippocampus (like MDA and carbonylated protein), and an increase in the activity of antioxidant enzymes such as SOD and CAT. Alongside these, we observed a decrease in microglia-driven neuroinflammation in the hippocampus, thus underscoring the antioxidant and anti-inflammatory roles of EA. Interestingly, when EA was given in conjunction with an IGF1R inhibitor, these benefits were annulled, accentuating the pivotal role that the IGF-1 pathway plays in the neuroprotective potential of EA. Hence, EA could serve as a potent candidate for safeguarding against PND in older patients by curbing oxidative stress and neuroinflammation through the activation of the IGF-1 pathway.

Asunto(s)

Antioxidantes , Ácido Elágico , Humanos , Ratones , Animales , Anciano , Antioxidantes/farmacología , Antioxidantes/metabolismo , Ácido Elágico/farmacología , Enfermedades Neuroinflamatorias , Factor I del Crecimiento Similar a la Insulina/metabolismo , Estrés Oxidativo , Trastornos Neurocognitivos/metabolismo , Hipocampo/metabolismo , Antiinflamatorios/farmacología , Administración Oral

RESUMEN

Phyllanthus emblica L. (syn. Emblica officinalis), popularly known as amla, Indian gooseberry, or the King of Rasyana, is a member of Phyllanthaceae family and is traditionally used in Ayurveda as an immunity booster. The present study aimed to investigate the synergistic interaction of Phyllanthus emblica (FPE) fruits and its selected phytocompounds with ampicillin against selected bacteria. Further, an in silico technique was used to find if major phytocompounds of FPE could bind to proteins responsible for antibiotic resistance in bacterial pathogens and enhance the bioactivity of ampicillin. FPE and all the selected phytocompounds were found to have synergistic antibacterial activity with ampicillin against tested bacteria in different combinations. However, ellagic acid and quercetin interactions with ampicillin resulted in maximum bioactivity enhancement of 32-128 folds and 16-277 folds, respectively. In silico analysis revealed strong ellagic acid, quercetin, and rutin binding with penicillin-binding protein (PBP-) 3, further supported by MD simulations. Ellagic acid and quercetin also fulfill Lipinski's rule, showing similar toxicity characteristics to ampicillin. FPE showed synergistic interaction with ampicillin, possibly due to the presence of phytocompounds such as gallic acid, ellagic acid, quercetin, and rutin. Molecular docking and MD simulations showed the strong interaction of ellagic acid and quercetin with PBP-3 protein. Therefore, these compounds can be explored as potential non-toxic drug candidates to combat bacterial antimicrobial resistance.

Asunto(s)

Phyllanthus emblica , Phyllanthus emblica/química , Frutas/química , Quercetina , Simulación del Acoplamiento Molecular , Ácido Elágico/farmacología , Extractos Vegetales/química , Antibacterianos/farmacología , Ampicilina/farmacología , Ampicilina/análisis , Rutina

RESUMEN

The present study investigated the effects of ellagic acid, a type of polyphenol that does not have a glycan and is composed of four hydroxyl groups and two lactone functional groups, on porcine in vitro fertilization (IVF) by focusing on its anti-hyaluronidase activity. A comparative analysis of ellagic acid and apigenin, which is commonly used as a hyaluronidase inhibitor, was performed. It compared the effects of ellagic acid and apigenin on hyaluronidase activity at different concentrations. The results showed that 10, 20, and 40 µM ellagic acid strongly reduced hyaluronidase activity (P < 0.05). The addition of 20 µM ellagic acid, but not apigenin, to porcine IVF medium effectively reduced polyspermy without decreasing sperm penetration or the formation rates of male pronuclei in cumulus-free oocytes. However, neither ellagic acid nor apigenin affected the number of sperm that bound to zona pellucida (ZP) or the induction of zona hardening and protease resistance. The percentage of acrosome-reacting sperm that bound to the ZP was markedly lower in the presence of 20 µM ellagic acid than in the untreated and apigenin-treated groups, even though the antioxidant capacity of ellagic acid was weaker than that of apigenin. Furthermore, a markedly higher percentage of embryos developed to the blastocyst stage in the ellagic acid-treated group, and the apoptotic indexes of expanded blastocysts produced by the ellagic acid treatment during IVF were significantly low. Therefore, the anti-hyaluronidase effect of ellagic acid markedly suppressed the induction of the acrosome reaction in sperm that bound to the ZP, resulting in a marked decrease in polyspermy under conditions that maintained high sperm penetrability during IVF and sustainment of the developmental potency in porcine oocytes.

Asunto(s)

Ácido Elágico , Hialuronoglucosaminidasa , Porcinos , Masculino , Animales , Ácido Elágico/farmacología , Ácido Elágico/metabolismo , Hialuronoglucosaminidasa/farmacología , Hialuronoglucosaminidasa/metabolismo , Apigenina/metabolismo , Apigenina/farmacología , Semen , Fertilización In Vitro/veterinaria , Fertilización In Vitro/métodos , Oocitos , Zona Pelúcida , Interacciones Espermatozoide-Óvulo , Espermatozoides , Fertilización

RESUMEN

Targeting SHP2 has become a potential cancer treatment strategy. In this study, ellagic acid was first reported as a competitive inhibitor of SHP2, with an IC50 value of 0.69 ± 0.07 µM, and its inhibitory potency was 34.86 times higher that of the positive control NSC87877. Ellagic acid also had high inhibitory activity on the SHP2-E76K and SHP2-E76A mutants, with the IC50 values of 1.55 ± 0.17 µM and 0.39 ± 0.05 µM, respectively. Besides, the IC50 values of ellagic acid on homologous proteins SHP1, PTP1B, and TCPTP were 0.93 ± 0.08 µM, 2.04 ± 0.28 µM, and 11.79 ± 0.83 µM, with selectivity of 1.35, 2.96, and 17.09 times, respectively. The CCK8 proliferation experiment exhibited that ellagic acid would inhibit the proliferation of various cancer cells. It was worth noting that the combination of ellagic acid and KRASG12C inhibitor AMG510 would produce a strong synergistic effect in inhibiting NCI-H358 cells. Western blot experiment exhibited that ellagic acid would downregulate the phosphorylation levels of Erk and Akt in NCI-H358 and MDA-MB-468 cells. Molecular docking and molecular dynamics studies revealed the binding information between SHP2 and ellagic acid. In summary, this study provides new ideas for the development of SHP2 inhibitors.

Asunto(s)

Ácido Elágico , Neoplasias , Humanos , Ácido Elágico/farmacología , Simulación del Acoplamiento Molecular , Neoplasias/tratamiento farmacológico , Inhibidores Enzimáticos/química , Fosforilación