RESUMO
Liver injury caused by type-II diabetes mellitus (DM) is a significant public-health concern worldwide. We used chitosan (CS) to modify dihydromyricetin (DHM)-loaded liposomes (DL) through charge interaction. The effect of CS-modified DL (CDL) on liver injury in mice suffering from DM was investigated in vivo and in vitro. CDL exhibited superior antioxidant capacity and stability. Pharmacokinetic analyses revealed a 3.23- and 1.92-fold increase in the drug concentration-time curve (953.60 ± 122.55 ng/mL/h) in the CDL-treated group as opposed to the DHM-treated group (295.15 ± 25.53 ng/mL/h) and DL-treated group (495.31 ± 65.21 ng/mL/h). The maximum drug concentration in blood (Tmax) of the CDL group saw a 2.26- and 1.21-fold increase compared with that in DHM and DL groups. We observed a 1.49- and 1.31-fold increase in the maximum drug concentration in blood (Cmax) in the CDL group compared with that in DHM and DL groups. Western blotting suggested that CDL could alleviate liver injury in mice suffering from DM by modulating inflammatory factors and the transforming growth factor-ß1/Smad2/Smad3 signaling pathway. In conclusion, modification of liposomes using CS is a viable approach to address the limitations of conventional liposomes and insoluble drugs.
Assuntos
Quitosana , Flavonóis , Lipossomos , Animais , Quitosana/química , Quitosana/farmacologia , Lipossomos/química , Flavonóis/farmacologia , Flavonóis/administração & dosagem , Camundongos , Masculino , Diabetes Mellitus Experimental/tratamento farmacológico , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/lesões , Fígado/patologia , Antioxidantes/farmacologia , Antioxidantes/química , Diabetes Mellitus Tipo 2/tratamento farmacológico , HumanosRESUMO
We purposed to explore the consequences of the use quercetin and fisetin alone and in combination with pregabalin and gabapentin, which are used in the management of neuropathic pain, and on neuropathic pain in general. The anti-allodynic effect of various doses (5, 10, and 20 mg/kg) of quercetin and fisetin, both singly and in combination with pregabalin and gabapentin, was evaluated by developing a neuropathic pain model induced by chronic constrictive nerve damage in rats. The effectiveness of these flavonoids was investigated by combining them with gabapentin (50 mg/kg) and pregabalin (15 mg/kg), choosing the effectual dose of 10 mg/kg and the dose of 5 mg/kg, which did not show significant antiallodynic effects. In groups combined with gabapentin and pregabalin, it was determined that they showed a significant antiallodynic effect compared with 50 mg/kg gabapentin and 15 mg/kg pregabalin. In conclusion, in our combination studies, it was observed that the effectiveness of gabapentin and pregabalin, was increased and the duration of effect was prolonged when used with lower doses of flavonoids. Based on these findings; it is possible to say that quercetin and fisetin are potential agents that can be used alone or in combination with other effective treatments to alleviate neuropathic pain.
Assuntos
Analgésicos , Quimioterapia Combinada , Flavonoides , Flavonóis , Gabapentina , Neuralgia , Pregabalina , Quercetina , Ácido gama-Aminobutírico , Pregabalina/administração & dosagem , Pregabalina/uso terapêutico , Gabapentina/administração & dosagem , Gabapentina/uso terapêutico , Gabapentina/farmacologia , Animais , Neuralgia/tratamento farmacológico , Flavonoides/administração & dosagem , Flavonoides/farmacologia , Flavonoides/uso terapêutico , Flavonóis/farmacologia , Flavonóis/administração & dosagem , Flavonóis/uso terapêutico , Masculino , Analgésicos/administração & dosagem , Analgésicos/uso terapêutico , Analgésicos/farmacologia , Quercetina/administração & dosagem , Quercetina/farmacologia , Quercetina/uso terapêutico , Ratos , Ácido gama-Aminobutírico/administração & dosagem , Ácido gama-Aminobutírico/uso terapêutico , Ácido gama-Aminobutírico/análogos & derivados , Aminas/administração & dosagem , Aminas/uso terapêutico , Aminas/farmacologia , Ratos Wistar , Relação Dose-Resposta a Droga , Modelos Animais de Doenças , Ácidos Cicloexanocarboxílicos/administração & dosagem , Ácidos Cicloexanocarboxílicos/uso terapêutico , Hiperalgesia/tratamento farmacológicoRESUMO
PURPOSE: Cold-induced vasodilation (CIVD) is an oscillatory rise in blood flow to glabrous skin that occurs in cold-exposed extremities. Dietary flavanols increase bioavailable nitric oxide, a proposed mediator of CIVD through active vasodilation and/or withdrawal of sympathetic vascular smooth muscle tone. However, no studies have examined the effects of flavanol intake on extremity skin perfusion during cold exposure. We tested the hypothesis that acute and 8-day flavanol supplementation would augment CIVD during single-digit cold water immersion (CWI). METHODS: Eleven healthy adults (24 ± 6 years; 10 M/1F) ingested cocoa flavanols (900 mg/day) or caffeine- and theobromine-matched placebo for 8 days in a double-blind, randomized, crossover design. On Days 1 and 8, CIVD was assessed 2 h post-treatment. Subjects immersed their 3rd finger in warm water (42 °C) for 15 min before CWI (4 °C) for 30 min, during which nail bed and finger pad skin temperature were measured. RESULTS: Flavanol ingestion had no effect on CIVD frequency (Day 1, Flavanol: 3 ± 2 vs. Placebo: 3 ± 2; Day 8, Flavanol: 3 ± 2 vs. Placebo: 3 ± 1) or amplitude (Day 1, Flavanol: 4.3 ± 1.7 vs. Placebo: 4.9 ± 2.6 °C; Day 8, Flavanol: 3.9 ± 1.9 vs. Placebo: 3.9 ± 2.0 °C) in the finger pad following acute or 8-day supplementation (P > 0.05). Furthermore, average, nadir, and apex finger pad temperatures during CWI were not different between treatments on Days 1 or 8 of supplementation (P > 0.05). Similarly, no differences in CIVD parameters were observed in the nail bed following supplementation (P > 0.05). CONCLUSION: These data suggest that cocoa flavanol ingestion does not alter finger CIVD. Clinical Trial Registration Clinicaltrials.gov Identifier: NCT04359082. April 24, 2020.
Assuntos
Temperatura Baixa , Suplementos Nutricionais , Vasodilatação , Humanos , Masculino , Feminino , Vasodilatação/efeitos dos fármacos , Vasodilatação/fisiologia , Adulto , Método Duplo-Cego , Adulto Jovem , Estudos Cross-Over , Temperatura Cutânea/efeitos dos fármacos , Temperatura Cutânea/fisiologia , Cacau , Flavonóis/farmacologia , Flavonóis/administração & dosagem , Pele/irrigação sanguínea , Pele/efeitos dos fármacos , ChocolateRESUMO
Osteoporosis is a bone related disease that is characterised by bone loss that further increases the susceptibility to bone fractures and bone frailty due to disturbances in the micro-architecture of bone tissue. Fisetin (flavonoids) exhibited anti-inflammatory and antioxidative stress effects against various diseases. In this protocol, we make an effort to comfort the anti-osteoporosis effect of fisetin against ovariectomy (OVX) induced osteoporosis. A docking study of fisetin and alendronate on the estrogen (α and ß) and vitamin D receptors was carried out. SaOS-2 (osteoblast like human) cells were used for the estimation of cell proliferation. The OVX induced OVX model was used and three doses of fisetin and alendronate was given to rats till 16 weeks. The hormone levels, bone turnover markers and biochemical parameters were estimated. Fisetin was docked into estrogen (α and ß) and vitamin D receptors, resulting in stable complexes with lower binding scores. Fisetin significantly (p < 0.001) exhibited the induction of cell proliferation against the SaOS-2 cells. OVX induced osteoporosis rats exhibited a suppression of body weight and uterus index, after the Fisetin treatment. Fisetin treatment significantly (p < 0.001) improved the level of bone mineral content (BMC), bone mineral density (BMD) and biochemical parameters such as energy, maximum load, stiffness, young modules, maximum stress and reduced the level of 1,25(OH) 2 D3 and E 2 . Fisetin treatment significantly (p < 0.001) declined the level of phosphorus (P), calcium (Ca) and boosted the level of VitD. Fisetin treatment significantly (p < 0.001) reduced the malonaldehyde (MDA) level and enhanced the glutathione (GSH), catalase (CAT), superoxide dismutase (SOD) level in the bone, intestine and hepatic tissue. Fisetin treatment suppressed the cytokines, RANKL/OPG ratio, receptor activator of nuclear factor-κB ligand (RANKL) and improved the level of osteoprotegerin (OPG). The findings suggest that fisetin could be a beneficial phytoconstituent for the treatment and prevention of postmenopausal osteoporotic complications.
Assuntos
Anti-Inflamatórios , Antioxidantes , Flavonóis/administração & dosagem , Flavonóis/farmacologia , Osteoporose Pós-Menopausa/tratamento farmacológico , Osteoporose Pós-Menopausa/prevenção & controle , Ovariectomia/efeitos adversos , Fitoterapia , Alendronato/metabolismo , Animais , Densidade Óssea/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Flavonóis/metabolismo , Humanos , Osteoporose Pós-Menopausa/etiologia , Osteoporose Pós-Menopausa/metabolismo , Osteoprotegerina/metabolismo , Ligante RANK/metabolismo , Ratos Sprague-Dawley , Receptores de Calcitriol/metabolismo , Receptores de Estrogênio/metabolismoRESUMO
BACKGROUND: Fisetin, the effective ingredient of the traditional Chinese medicine named Cotinus coggygria, is recommended to be active therapeutic in many disorders. However, its role in sepsis-associated encephalopathy (SAE) remains unclarified. METHODS: Cecal ligation and puncture (CLP) operation was performed to establish a rat model of SAE. Rats were grouped according to the surgery operation and fisetin administration. Cognitive impairment was assessed by Morris water maze test. Disruption of blood-brain barrier (BBB) integrity was detected by Evan's blue staining. The mitophagy, reactive oxygen species (ROS) generation, NLRP3 inflammasome activation, and pro-inflammatory cytokines levels were measured through western blot and double immunofluorescence labeling. A transmission electron microscope was applied for the observation of mitochondrial autophagosomes. RESULTS: Rats in the CLP group presented increased expression of IL-1R1, pNF-κB, TNF-α, and iNOS in microglial cells, indicating severe inflammation in the central nervous system (CNS). Nevertheless, there was no increase in BBB permeability. Meanwhile, NLRP3 inflammasome was activated in cerebral microvascular endothelial cells (CMECs), presented with an elevation of caspase-1 expression and IL-1ß secretion into CNS. In addition, we found fisetin significantly improved cognitive dysfunction in rats with SAE. Neuroprotective effects of fisetin might be associated with inhibition of neuroinflammation, represented with decreased expression of IL-1R1, pNF-κB, TNF-α, and iNOS in microglia. Furthermore, fisetin induced mitophagy, scavenged ROS, blocked NLRP3 inflammasome activation of CMECs, as evidenced by decreased expression of caspase-1 and reduced release of IL-1ß into CNS. CONCLUSION: Collectively, fisetin-blocked NLRP3 inflammasome activation via promoting mitophagy in CMECs may suppress the secretion of IL-1ß into CNS, reduce neuroinflammation, and contribute to the amelioration of cognitive impairment.
Assuntos
Disfunção Cognitiva/tratamento farmacológico , Flavonóis/farmacologia , Mitofagia/efeitos dos fármacos , Doenças Neuroinflamatórias/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Encefalopatia Associada a Sepse/complicações , Animais , Comportamento Animal/efeitos dos fármacos , Disfunção Cognitiva/etiologia , Modelos Animais de Doenças , Flavonóis/administração & dosagem , Inflamassomos/efeitos dos fármacos , Masculino , Proteína 3 que Contém Domínio de Pirina da Família NLR/efeitos dos fármacos , Fármacos Neuroprotetores/administração & dosagem , RatosRESUMO
BACKGROUND & AIMS: Microalbuminuria is an early sign of vascular complications of type 2 diabetes and predicts cardiovascular disease and mortality. Monomeric and oligomeric flavanols (MOFs) are linked to improved vascular health. The aim of this study was to assess the effect of 3 months MOFs on albuminuria and endothelial function markers in patients with type 2 diabetes and microalbuminuria. METHODS: We conducted a double-blind, placebo-controlled trial among patients with type 2 diabetes and microalbuminuria. Patients with type 2 diabetes received either 200 mg MOFs or placebo daily on top of their habitual diet and medication. The primary endpoint was the between-group difference of the change in 24-h Albumin Excretion Rate (AER) over three months. Secondary endpoints were the between-group differences of the change in plasma levels of different markers of endothelial dysfunction. Mixed-modelling was applied for the longitudinal analyses. RESULTS: Participants (n = 97) were 63.0 ± 9.5 years old; diabetes-duration was 15.7 ± 8.5 years. Median baseline AER was 60 (IQR 20-120) mg/24 h. There was no within-group difference in median change of AER from baseline to 3 months in the intervention (0 (-35-21) mg/24 h, p = 0.41) or the control group (0 (-20-10) mg/24 h, p = 0.91). There was no between-group difference in the course of AER over three months (log-transformed data: ß = -0.02 (95%CI -0.23-0.20), p = 0.88), nor in the plasma levels of the endothelial dysfunction markers. CONCLUSION: Daily 200 mg MOFs for three months on top of habitual diet and usual care did not reduce AER and plasma markers of endothelial dysfunction compared to placebo, in patients with long-term type 2 diabetes and microalbuminuria. CLINICAL TRIALS REGISTRATION: NTR4669, www.trialregister.nl.
Assuntos
Albuminúria/terapia , Diabetes Mellitus Tipo 2/terapia , Suplementos Nutricionais , Endotélio Vascular/efeitos dos fármacos , Flavonóis/administração & dosagem , Idoso , Albuminúria/complicações , Albuminúria/fisiopatologia , Biomarcadores/sangue , Biomarcadores/urina , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/fisiopatologia , Método Duplo-Cego , Feminino , Flavonóis/química , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
It is becoming progressively more understandable that pharmaceutical targeting of drug-resistant cancers is challenging because of intra- and inter-tumor heterogeneity. Interestingly, naturally derived bioactive compounds have unique ability to modulate wide-ranging deregulated oncogenic cell signaling pathways. In this review, we have focused on the available evidence related to regulation of PI3K/AKT/mTOR, Wnt/ß-catenin, NF-κB and TRAIL/TRAIL-R by fisetin in different cancers. Fisetin has also been shown to inhibit the metastatic spread of cancer cells in tumor-bearing mice. We have also summarized how fisetin regulated autophagy in different cancers. In addition, this review also covers fisetin-mediated regulation of VEGF/VEGFR, EGFR, necroptosis and Hippo pathway. Fisetin has entered into clinical trials particularly in context of COVID19-associated inflammations. Furthermore, fisetin mediated effects are also being tested in clinical trials with reference to osteoarthritis and senescence. These developments will surely pave the way for full-fledge and well-designed clinical trials of fisetin in different cancers. However, we still have to comprehensively analyze and fully unlock pharmacological potential of fisetin against different oncogenic signaling cascades and non-coding RNAs. Fisetin has remarkable potential as chemopreventive agent and future studies must converge on the identification of additional regulatory roles of fisetin for inhibition and prevention of cancers.
Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Flavonóis/administração & dosagem , Nanoestruturas/administração & dosagem , Neoplasias/tratamento farmacológico , Animais , Quimioprevenção , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , NF-kappa B/metabolismo , Neoplasias/metabolismo , Neoplasias/prevenção & controle , Receptores de Fatores de Crescimento do Endotélio Vascular/metabolismo , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , beta Catenina/metabolismoRESUMO
Nowadays, chronic diseases have become a potential danger to human health and are highly concerning. Given that pigs are a suitable animal model for human nutrition and metabolism for its similar anatomical and physiological properties to those of humans, this study has used 24 castrated male Duroc × Landrace × Yorkshire (DLY) pigs as experimental subjects to explore the effects of dietary dihydromyricetin (DHM) supplementation on the antioxidant capacity and lipid metabolism. Results showed that dietary 300 and 500 mg DHM kg-1 diet supplementation increased the serum total superoxide dismutase (T-SOD) level, serum and liver reduced glutathione (GSH), muscle catalase (CAT) level and serum high-density lipoprotein cholesterol (HDL-C) level, and reduced the liver malondialdehyde (MDA) level and muscle triglyceride (TG) level in finishing pigs. Western blot analysis showed that dietary DHM supplementation activated the nuclear-related factor 2 (Nrf2) and AMP-activated protein kinase (AMPK)/acetyl-CoA carboxylase (ACC) signals. Real-time quantitative PCR analysis showed that dietary DHM supplementation upregulated the mRNA levels of lipolysis and fatty acid oxidation-related genes, and down-regulated the mRNA expression of lipogenesis-related genes in finishing pigs. Together, we provide evidence that dietary DHM supplementation improved the antioxidant capacity and lipid metabolism in finishing pigs.
Assuntos
Antioxidantes , Suplementos Nutricionais , Flavonóis , Metabolismo dos Lipídeos/efeitos dos fármacos , Ração Animal , Animais , Antioxidantes/administração & dosagem , Antioxidantes/análise , Antioxidantes/farmacologia , Catalase/sangue , Flavonóis/administração & dosagem , Flavonóis/farmacologia , Masculino , Malondialdeído/sangue , Músculo Esquelético/química , Músculo Esquelético/efeitos dos fármacos , Sus scrofa , SuínosRESUMO
BACKGROUND: The naturally occurring flavonol fisetin (3,3',4',7-tetrahydroxyflavone), widely dispersed in fruits, vegetables and nuts, has been reported to exert anti-inflammatory, antioxidant and anti-angiogenic effects. Our previous study indicated fisetin ameliorated inflammation and apoptosis in septic kidneys. However, the potential nephroprotective effect of fisetin in hyperuricemic mice remains unknown. PURPOSE: The current study was designed to investigate the effect of fisetin on hyperuricemic nephropathy (HN) and explore the underlying mechanisms. METHODS: The HN was induced in mice by mixing of potassium oxonate (2400 mg/kg) and adenine (160 mg/kg) in male C57BL/6J mice. Fisetin (50 or 100 mg/kg) was orally administrated either simultaneously with the establishment of HN or after HN was induced. As a positive control, allopurinol of 10 mg/kg was included. Uric acid levels in the serum and urine as well as renal function parameters were measured. Renal histological changes were measured by periodic acid-Schiff (PAS) and Masson's trichrome stainings. The expression of gene/protein in relation to inflammation, fibrosis, and uric acid excretion in the kidneys of HN mice or uric acid-treated mouse tubular epithelial (TCMK-1) cells were measured by RNA-seq, RT-PCR, western blot and immunohistochemical analysis. RESULTS: Treatment with fisetin, regardless of administration regimen, dose-dependently attenuated hyperuricemia-induced kidney injury as indicated by the improved renal function, preserved tissue architecture, and decreased urinary albumin-to-creatinine ratio. Additionally, fisetin lowered uricemia by modulating the expression of kidney urate transporters including urate transporter 1(URAT1), organic anion transporter 1 (OAT1), organic anion transporter 3 (OAT3) and ATP binding cassette subfamily G member 2 (ABCG2). Moreover, hyperuricemia-induced secretions of proinflammatory factors including tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6) and monocyte chemoattractant protein-1(MCP-1) in HN mice and uric acid-stimulated TCMK-1 cells were mitigated by fisetin treatment. Meanwhile, fisetin attenuated kidney fibrosis in HN mice with restored expressions of alpha-smooth muscle actin (α-SMA), collagen I and fibronectin. Mechanistically, fisetin regulated the aberrant activation of signal transducer and activator of transcription-3 (STAT3) signaling and transforming growth factor-ß (TGF-ß) signaling in the HN kidneys and uric acid-stimulated TCMK-1 cells. CONCLUSION: Fisetin lowered uricemia, suppressed renal inflammatory response, and improved kidney fibrosis to protect against hyperuricemic nephropathy via modulation of STAT3 and TGF-ß signaling pathways. The results highlighted that fisetin might represent a potential therapeutic strategy against hyperuricemic nephropathy.
Assuntos
Flavonóis/farmacologia , Hiperuricemia/tratamento farmacológico , Interleucina-6/metabolismo , Nefropatias/tratamento farmacológico , Fator de Crescimento Transformador beta/metabolismo , Administração Oral , Animais , Fibrose , Flavonóis/administração & dosagem , Flavonóis/uso terapêutico , Regulação da Expressão Gênica/efeitos dos fármacos , Hiperuricemia/patologia , Interleucina-6/antagonistas & inibidores , Interleucina-6/genética , Janus Quinase 2/antagonistas & inibidores , Janus Quinase 2/genética , Janus Quinase 2/metabolismo , Rim/efeitos dos fármacos , Rim/patologia , Nefropatias/sangue , Nefropatias/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fator de Transcrição STAT3/antagonistas & inibidores , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Proteína Smad3/genética , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta/genética , Ácido Úrico/sangue , Ácido Úrico/urinaRESUMO
Dietary polyphenol exposure is known to change protein saliva composition in rodents, but less is known in humans. The present study aimed to assess the relationship between saliva protein composition and adherence to Mediterranean Diet (MD) and polyphenol intake levels. Participants were assessed for their dietary habits, which were converted in Mediterranean adherence level, according to Mediterranean Diet Adherence Score (MEDAS) score. Total polyphenol and total flavanol intakes were extrapolated from dietary data, using Phenol explorer database. Whole saliva was collected, and proteins were separated by SDS-PAGE. Salivary S-type cystatins were highly expressed in the group with medium adherence to MD, being positively correlated with wine intake in overweight individuals. The association between salivary amylase and MD adherence also depended on Body Mass Index (BMI), with a positive association only in normal weight individuals. Polyphenol intake was positively associated with S-type cystatins levels, particularly when flavanols were considered separately. These results show that saliva relationship with MD adherence depend on BMI, suggesting that normal weight and overweight individuals may have different salivary responses to diet. Moreover, these results reinforce the link between saliva and dietary polyphenols (flavanols) levels, leading to the hypothesis that salivary proteome can have a role in polyphenol-rich foods acceptance.
Assuntos
Dieta Mediterrânea , Preferências Alimentares/fisiologia , Saliva/química , Adolescente , Adulto , Idoso , Amilases/análise , Amilases/metabolismo , Índice de Massa Corporal , Feminino , Flavonóis/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , Polifenóis/administração & dosagem , Proteômica , Saliva/metabolismo , Cistatinas Salivares/análise , Cistatinas Salivares/metabolismo , Adulto JovemRESUMO
Dihydromyricetin (DMY) is highly effective in counteracting acute alcohol intoxication. However, its poor aqueous solubility and permeability lead to the low oral bioavailability and limit its clinic application. The aim of this work is to use Solutol®HS15 (HS 15) as surfactant to develop novel micelle to enhance the oral bioavailability of DMY by improving its solubility and permeability. The DMY-loaded Solutol®HS15 micelles (DMY-Ms) were prepared by the thin-film hydration method. The particle size of DMY-Ms was 13.97 ± 0.82 nm with an acceptable polydispersity index of 0.197 ± 0.015. Upon entrapped in micelles, the solubility of DMY in water was increased more than 25-fold. The DMY-Ms had better sustained release property than that of pure DMY. In single-pass intestinal perfusion models, the absorption rate constant (Ka) and permeability coefficient (Papp) of DMY-Ms were 5.5-fold and 3.0-fold than that of pure DMY, respectively. The relative bioavailability of the DMY-Ms (AUC0-∞) was 205% compared with that of pure DMY (AUC0-∞), indicating potential for clinical application. After administering DMY-Ms, there was much lower blood alcohol level and shorter duration of the loss of righting relax (LORR) in drunk animals compared with that treated by pure DMY. In addition, the oral administration of DMY-Ms greatly reduced oxidative stress, and significantly defended liver and gastric mucosa from alcoholic damages in mice with alcohol-induced tissue injury. Taken together, HS 15-based micelle system greatly improves the bioavailability of DMY and represents a promising strategy for the management of acute alcoholism. Graphical abstract.
Assuntos
Intoxicação Alcoólica/tratamento farmacológico , Flavonóis/administração & dosagem , Flavonóis/uso terapêutico , Intoxicação Alcoólica/patologia , Animais , Área Sob a Curva , Disponibilidade Biológica , Depressores do Sistema Nervoso Central/sangue , Etanol/sangue , Excipientes , Flavonóis/farmacocinética , Mucosa Gástrica/patologia , Hepatite Alcoólica/prevenção & controle , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Micelas , Nanopartículas , Equilíbrio Postural/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , TensoativosRESUMO
With the world's population aging, age-related memory decline is an impending cognitive epidemic. Assessing the impact of diet on cognitive aging, we conducted a controlled, randomized, parallel-arm dietary intervention with 211 healthy adults (50-75 years) investigating effects of either a placebo or 260, 510 and 770 mg/day of cocoa flavanols for 12-weeks followed by 8-weeks washout. The primary outcome was a newly-developed object-recognition task localized to the hippocampus' dentate gyrus. Secondary outcomes included a hippocampal-dependent list-learning task and a prefrontal cortex-dependent list-sorting task. The alternative Healthy Eating Index and a biomarker of flavanol intake (gVLM) were measured. In an MRI substudy, hippocampal cerebral blood volume was mapped. Object-recognition and list-sorting performance did not correlate with baseline diet quality and did not improve after flavanol intake. However, the hippocampal-dependent list-learning performance was directly associated with baseline diet quality and improved after flavanol intake, particularly in participants in the bottom tertile of baseline diet quality. In the imaging substudy, a region-of-interest analysis was negative but a voxel-based-analysis suggested that dietary flavanols target the dentate gyrus. While replication is needed, these findings suggest that diet in general, and dietary flavanols in particular, may be associated with memory function of the aging hippocampus and normal cognitive decline.
Assuntos
Envelhecimento Cognitivo , Dieta , Suplementos Nutricionais , Flavonóis/administração & dosagem , Idoso , Envelhecimento/psicologia , Encéfalo/diagnóstico por imagem , Encéfalo/fisiopatologia , Cognição , Feminino , Voluntários Saudáveis , Humanos , Aprendizagem , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Estado Nutricional , Desempenho Físico Funcional , Vigilância em Saúde Pública , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
Oxidative stress plays an important role in the pathogenesis of Parkinson's disease (PD), particularly the inhibition of mitochondrial complex-I. This study aimed to evaluate the effect of fisetin in the rotenone-induced rat model of PD. Rotenone was administered (2 mg/kg s.c.) for 35 days to induce PD in animals. Fisetin was administered at two doses (10 mg/kg and 20 mg/kg p.o.) for 25 days to the animals that were given rotenone. Behavioral experiment, i.e. cylinder test, was performed to assess the motor asymmetry. Animals were euthanized, and mid brains were isolated for the estimation of tricarboxylic acid cycle enzymes, oxidative measures (lipid peroxidation (LPO), glutathione (GSH) and catalase) and complex-I activity. In addition, histopathological studies were conducted. Fisetin treatment improved motor function in the cylinder test and reversed the rotenone-induced changes in mitochondrial enzymes, striatal dopamine levels, antioxidant enzyme levels and histological changes. An important finding of this study was both the doses of fisetin significantly (p < 0.05) enhanced rotenone-induced behavioral and biochemical changes and the effects were found to be dose dependent. Based on the present results, we hypothesize that fisetin may improve the mitochondrial enzyme activity, thereby preventing the pathogenesis of PD.
Assuntos
Flavonóis , Transtornos Mentais/tratamento farmacológico , Doenças Mitocondriais/tratamento farmacológico , Fármacos Neuroprotetores , Estresse Oxidativo/efeitos dos fármacos , Doença de Parkinson , Animais , Modelos Animais de Doenças , Flavonóis/administração & dosagem , Flavonóis/farmacologia , Flavonóis/uso terapêutico , Inseticidas/efeitos adversos , Inseticidas/farmacologia , Masculino , Transtornos Mentais/etiologia , Mitocôndrias/efeitos dos fármacos , Doenças Mitocondriais/induzido quimicamente , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/etiologia , Ratos , Ratos Wistar , Rotenona/efeitos adversos , Rotenona/farmacologiaRESUMO
BACKGROUND: Caffeine has an anti-obesity effect, although chronic excessive caffeine consumption also causes caffeinism, which is marked by increased anxiety or depression, amongst other symptoms. The present study aimed to investigate whether the addition of flavonoids such as astilbin can reduce the caffeine dose needed to inhibit obesity. RESULTS: ICR mice (n = 80) were fed with normal diet, high-fat diet (HFD), HFD supplemented with astilbin, caffeine, or astilbin + caffeine for 12 weeks. When diets supplemented with astilbin, 0.3 g kg-1 diet caffeine had the same effect as 0.6 g kg-1 diet caffeine alone, and 0.6 g kg-1 diet caffeine combined with astilbin most effectively inhibited HFD-induced obesity. Astilbin improved the anti-obesity effects of caffeine on lipid accumulation via the activation of AMP-activated protein kinase α (AMPKα). (i) Activated AMPKα decreased lipid biosynthesis by suppressing the activity or mRNA expression of 3-hydroxy-3-methylglutaryl-CoA reductase, sterol regulatory element binding protein 1c and its target gene fatty acid synthase. (ii) Activated AMPKα also up-regulated lipolysis by enhancing the expression of adipose triglyceride lipase and increasing the phosphorylation of hormone-sensitive lipase. (iii) Finally, activated AMPKα increased carnitine acyltransferase and acyl-CoA oxidase activities, which further promoted fatty acid ß-oxidation. CONCLUSION: The results obtained in the present study indicate that astilbin may decrease the effective dose of caffeine needed for an anti-obesity effect and also suggest that it suppresses fat accumulation via the activation of AMPK. © 2020 Society of Chemical Industry.
Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Fármacos Antiobesidade/administração & dosagem , Cafeína/administração & dosagem , Flavonóis/administração & dosagem , Metabolismo dos Lipídeos/efeitos dos fármacos , Obesidade/tratamento farmacológico , Proteínas Quinases Ativadas por AMP/genética , Animais , Fármacos Antiobesidade/antagonistas & inibidores , Cafeína/antagonistas & inibidores , Dieta Hiperlipídica/efeitos adversos , Suplementos Nutricionais/análise , Humanos , Lipogênese/efeitos dos fármacos , Lipólise/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos ICR , Camundongos Obesos , Obesidade/genética , Obesidade/metabolismo , Obesidade/fisiopatologia , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismoRESUMO
BACKGROUND: Dihydromyricetin (DMY) is a natural dihydroflavonol with many bioactive effects. However, the physicochemical properties of DMY related to its bioavailability, especially its stability, are unclear. RESULTS: The effects of pH, temperature, metal ions and ascorbic acid (AA) on the stability of DMY were studied using high-performance liquid chromatography (HPLC). The bioavailability of DMY in the presence and absence of AA was compared. Dihydromyricetin was unstable in weak alkaline solutions, and the degradation was significantly accelerated in the presence of Cu2+ and Fe3+ . The degradation process followed the first-order kinetic model. The degradation rate constant (k) increased with increasing pH and temperature. The remaining DMY was only 49% of its initial concnentration after 4 h in simulated intestinal fluid (SIF) at 37 °C. However, by supplementing with AA, the degradation of DMY was rarely occured within 6 h. The solubility of DMY at pH 3-5 was about 750 µg mL-1 , slightly increasing to 853 µg mL-1 at pH 6. Pharmacokinetic studies showed that the bioavailability of DMY increased from 0.122% to 0.341% by supplementing with AA (10% of DMY). CONCLUSION: The degradation of DMY is one reason for its poor bioavailability. The presence of AA could significantly improve the stability of DMY, and further improve its bioavailability in rats. © 2020 Society of Chemical Industry.
Assuntos
Ácido Ascórbico/química , Flavonóis/química , Flavonóis/farmacocinética , Animais , Disponibilidade Biológica , Cromatografia Líquida de Alta Pressão , Estabilidade de Medicamentos , Feminino , Flavonóis/administração & dosagem , Cinética , Ratos , Ratos Sprague-Dawley , SolubilidadeRESUMO
Aging and the emergence of age-associated illnesses are one of the major challenges of our present society. Alzheimer's disease (AD) is closely associated with aging and is defined by increasing memory loss and severe dementia. Currently, there are no therapy options available that halt AD progression. This work investigates three hallmarks of the disease (autophagy, neuroinflammation, and senescence) and systematically analyzes if there is a beneficial effect from three substances derived from food sources, the so called "nutraceuticals" epigallocatechin gallate, fisetin, and spermidine, on these hallmarks. The results imply a positive outlook for the reviewed substances to qualify as a novel treatment option for AD. A combination of nutraceutical substances and other preventive measures could have significant clinical impact in a multi-layered therapy approach to counter AD.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Autofagia/efeitos dos fármacos , Catequina/análogos & derivados , Flavonóis/farmacologia , Inflamação/tratamento farmacológico , Espermidina/farmacologia , Animais , Catequina/administração & dosagem , Catequina/farmacologia , Senescência Celular/efeitos dos fármacos , Suplementos Nutricionais , Flavonóis/administração & dosagem , Humanos , Espermidina/administração & dosagemRESUMO
Cocoa flavanols protect humans against vascular disease, as evidenced by improvements in peripheral endothelial function, likely through nitric oxide signalling. Emerging evidence also suggests that flavanol-rich diets protect against cognitive aging, but mechanisms remain elusive. In a randomized double-blind within-subject acute study in healthy young adults, we link these two lines of research by showing, for the first time, that flavanol intake leads to faster and greater brain oxygenation responses to hypercapnia, as well as higher performance only when cognitive demand is high. Individual difference analyses further show that participants who benefit from flavanols intake during hypercapnia are also those who do so in the cognitive challenge. These data support the hypothesis that similar vascular mechanisms underlie both the peripheral and cerebral effects of flavanols. They further show the importance of studies combining physiological and graded cognitive challenges in young adults to investigate the actions of dietary flavanols on brain function.
Assuntos
Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Cognição/efeitos dos fármacos , Flavonóis/administração & dosagem , Oxigênio/metabolismo , Adulto , Cacau , Córtex Cerebral/irrigação sanguínea , Circulação Cerebrovascular/efeitos dos fármacos , Suplementos Nutricionais , Método Duplo-Cego , Voluntários Saudáveis , Humanos , Hipercapnia/dietoterapia , Hipercapnia/fisiopatologia , Hipercapnia/psicologia , Masculino , Pessoa de Meia-Idade , Consumo de Oxigênio/efeitos dos fármacos , Oxiemoglobinas/metabolismo , Adulto JovemRESUMO
Pelvic inflammatory disease (PID) is a common inflammation in the upper reproductive tract in women and may cause serious and costly consequences without effective treatment. Engeletin is a flavanonol glycoside and a naturally derived aldose reductase (AR) inhibitor that is widely distributed in vegetables, fruits, and plant-based foods. The present study investigated the anti-PID activity of engeletin in a mucilage-induced rat model of PID and LPS-stimulated RAW 264.7 macrophages. Engeletin significantly reduced inflammation and ameliorated the typical uterine pathological changes in PID rats. Engeletin also inhibited AR-dependent PLC/PKC/NF-κB and MAPK inflammatory pathways, as indicated by the suppression of the phosphorylation levels of PLC, PKC, p38, ERK, and JNK and the nuclear translocation of NF-κB p65. In vitro studies demonstrated that engeletin significantly inhibited inflammatory mediator expression and enhanced the phagocytic ability of LPS-induced RAW 264.7 macrophages. RNA interference of AR prevented the engeletin-induced inhibition of inflammatory mediators. Engeletin also inhibited AR-dependent PLC/PKC/NF-κB and MAPK inflammatory pathways, which was consistent with the in vivo results. These findings support engeletin as a potential agent for prevention or treatment of PID.
Assuntos
Aldeído Redutase/antagonistas & inibidores , Anti-Inflamatórios/administração & dosagem , Inibidores Enzimáticos/administração & dosagem , Flavonóis/administração & dosagem , Glicosídeos/administração & dosagem , Doença Inflamatória Pélvica/dietoterapia , Proteína Quinase C/imunologia , Fator de Transcrição RelA/imunologia , Fosfolipases Tipo C/imunologia , Aldeído Redutase/genética , Aldeído Redutase/imunologia , Animais , Feminino , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Camundongos , Doença Inflamatória Pélvica/genética , Doença Inflamatória Pélvica/imunologia , Proteína Quinase C/genética , Células RAW 264.7 , Ratos , Ratos Sprague-Dawley , Fator de Transcrição RelA/genética , Fosfolipases Tipo C/genéticaRESUMO
Myrianthus arboreus is use traditionally as an antidiabetic agent in Ghana. We reported the in vivo antidiabetic activity of its 70 % ethanol stem bark extract (MAB) which we found to be strongly concentrated in its EtOAc fraction using glucose uptake and enzyme inhibitory assays. The present study sought to investigate the in vivo hypoglycaemic and anti-hyperlipidaemic activity of this ethyl acetate fraction of MAB (MAB-EtOAc, 50 and 100 mg/kg) in streptozotocin (STZ)-induced diabetic rats for 21 days, isolate and evaluate the bioactive constituents responsible for the antidiabetic activity. In silico pharmacokinetic and toxicity properties of the most active compound was also determined. MAB-EtOAc significantly (p < 0.001) reduced the blood glucose levels while normalizing considerably the altered serum lipid parameters of the diabetic rats which was comparable to glibenclamide (5 mg/kg). Chemical investigation of MAB-EtOAc led to the isolation of seven known compounds including three flavanols which are reported for the first time in the plant: epicatechin (1), epigallocatechin (2), dulcisflavan (3), euscaphic acid (4), tormentic acid (5), sitosterol-3-O-ß-d-glucopyranoside (6) and arjunolic acid (7). The compounds markedly inhibited the action of α-amylase and, except for 4 and 6, which stimulated considerably glucose uptake in C2C12 cells. Compounds 2, 3, 5, 6 and 7 which were further evaluated in STZ-induced diabetic rats demonstrated hypoglycaemic and anti-hyperlipidaemic activities which, however, were not comparable with MAB-EtOAc. Compound 3, the most active compound was predicted to be non-toxic, non-mutagenic, has reasonable oral bioavailability and a decent substrate for further drug development. The findings of this study show that the isolated compounds may contribute to the antidiabetic activity of M. arboreus and could serve as marker compounds for the quality control of herbal medicines that would be made from the plant.
Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Hipoglicemiantes/farmacologia , Extratos Vegetais/farmacologia , Urticaceae/química , Animais , Linhagem Celular , Simulação por Computador , Relação Dose-Resposta a Droga , Flavonóis/administração & dosagem , Flavonóis/isolamento & purificação , Flavonóis/farmacologia , Glucose , Hiperglicemia/tratamento farmacológico , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/isolamento & purificação , Masculino , Camundongos , Extratos Vegetais/administração & dosagem , Ratos , Ratos Sprague-Dawley , Estreptozocina , Triterpenos/administração & dosagem , Triterpenos/isolamento & purificação , Triterpenos/farmacologiaRESUMO
OBJECTIVE: To evaluate the validity and reproducibility of a 152-item semi-quantitative FFQ (SFFQ) for estimating flavonoid intakes. DESIGN: Over a 1-year period, participants completed two SFFQ and two weighed 7-d dietary records (7DDR). Flavonoid intakes from the SFFQ were estimated separately using Harvard (SFFQHarvard) and Phenol-Explorer (SFFQPE) food composition databases. 7DDR flavonoid intakes were derived using the Phenol-Explorer database (7DDRPE). Validity was assessed using Spearman's rank correlation coefficients deattenuated for random measurement error (rs), and reproducibility was assessed using rank intraclass correlation coefficients. SETTING: This validation study included primarily participants from two large observational cohort studies. PARTICIPANTS: Six hundred forty-one men and 724 women. RESULTS: When compared with two 7DDRPE, the validity of total flavonoid intake assessed by SFFQPE was high for both men and women (rs = 0·77 and rs = 0·74, respectively). The rs for flavonoid subclasses ranged from 0·47 for flavones to 0·78 for anthocyanins in men and from 0·46 for flavonols to 0·77 for anthocyanins in women. We observed similarly moderate (0·4-0·7) to high (≥0·7) validity when using SFFQHarvard estimates, except for flavonesHarvard (rs = 0·25 for men and rs = 0·19 for women). The SFFQ demonstrated high reproducibility for total flavonoid and flavonoid subclass intake estimates when using either food composition database. The intraclass correlation coefficients ranged from 0·69 (flavonolsPE) to 0·80 (proanthocyanidinsPE) in men and from 0·67 (flavonolsPE) to 0·77 (flavan-3-ol monomersHarvard) in women. CONCLUSIONS: SFFQ-derived intakes of total flavonoids and flavonoid subclasses (except for flavones) are valid and reproducible for both men and women.