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1.
J Agric Food Chem ; 70(47): 14831-14840, 2022 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-36383360

RESUMO

Hesperetin-7-O-glucoside (Hes-7-G) is a typical flavonoid monoglucoside, which can be generated from hesperidin with the removal of rhamnose by hydrolysis. Untargeted and targeted metabolomics together with 16S rRNA gene sequencing were employed to explore the exact absorption site of Hes-7-G and its beneficial effect in mice. Intestinal 1H nuclear magnetic resonance (NMR)-based metabolomics screening showed that Hes-7-G is mainly metabolized in the small intestine of mice, especially the ileum segment. Quantification analysis of bile acids (BAs) in the liver, intestinal tract, feces, and serum of mice suggests that Hes-7-G intake accelerates the processes of biosynthesis and excretion of BAs, thus promoting digestion and lowing hepatic cholesterol and triglyceride. 16S rRNA gene sequencing reveals that Hes-7-G significantly elevates the diversity of the gut microbiota in mice, especially those bacteria associated with BA secondary metabolism. These results demonstrated that long-term dietary Hes-7-G plays beneficial roles in health by modulating the gut bacteria and BA metabolism in mice.


Assuntos
Microbioma Gastrointestinal , Hesperidina , Camundongos , Animais , Microbioma Gastrointestinal/genética , Hesperidina/metabolismo , RNA Ribossômico 16S/genética , Ácidos e Sais Biliares/metabolismo , Fígado/metabolismo , Bactérias/genética , Bactérias/metabolismo , Glucosídeos/metabolismo , Camundongos Endogâmicos C57BL
2.
Zhongguo Yi Xue Ke Xue Yuan Xue Bao ; 44(5): 777-784, 2022 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-36325774

RESUMO

Objective To explore the effect and mechanism of hesperidin in treating the lung injury in the mouse model of respiratory syncytial virus (RSV)-induced bronchiolitis. Methods A mouse model of RSV-induced bronchiolitis was established,and 60 BALB/c mice were assigned into a control group,a model group,a low-dose hesperidin (18 mg/kg) group,a high-dose hesperidin (36 mg/kg) group,and a high-dose hesperidin (36 mg/kg)+Jagged1(1 mg/kg) group by random number table method,with 12 mice in each group. Corresponding doses of drugs were administrated for intervention,and the control group and model group were administrated with the same amount of saline.The bronchoalveolar lavage fluid (BALF) samples were collected and alveolar macrophages were isolated.ELISA was employed to detect the levels of interleukin (IL)-4,IL-6,tumor necrosis factor-α (TNF-α),and IL-10 in BALF,and flow cytometry to detect the M1/M2 polarization of macrophages.qRT-PCR and Western blotting were respectively conducted to detect the mRNA and protein levels of inducible nitric oxide synthase (iNOS),arginase 1 (Arg-1),Jagged1,and Notch1 in the lung tissue. Results Compared with the control group,the modeling of RSV-induced bronchiolitis elevated the IL-4,IL-6,and TNF-α levels,increased the proportion of M1-type macrophages and the lung inflammation and mucus secretion scores,and up-regulated the mRNA and protein levels of iNOS,Jagged1,and Notch1 in BALF (all P<0.001).Meanwhile,the modeling lowered the IL-10 level,decreased the proportion of M2-type macrophages,and down-regulated the mRNA and protein levels of Arg-1 (all P<0.001).Compared with the model group,low- and high-dose hesperidin lowered the IL-4,IL-6,TNF-α levels,decreased the proportion of M1-type macrophages and the lung inflammation and mucus secretion scores,and down-regulated the mRNA and protein levels of iNOS,Jagged1,and Notch1 in BALF (all P<0.05).Moreover,hesperidin elevated the IL-10 level,increased the proportion of M2-type macrophages,and up-regulated the mRNA and protein levels of Arg-1 (all P<0.001).Using recombinant Jagged1 protein to activate Notch1 signaling pathway can significantly attenuate the promotion of high-dose hesperidin on M2 macrophage polarization and amelioration of lung inflammation damage (all P<0.01). Conclusion Hesperidin may alleviate the lung inflammation damage in mice with RSV-induced bronchiolitis by inhibiting the Jagged1/Notch1 signaling pathway and promoting the M2-type polarization of macrophages.


Assuntos
Bronquiolite , Hesperidina , Lesão Pulmonar , Animais , Camundongos , Bronquiolite/metabolismo , Hesperidina/farmacologia , Hesperidina/uso terapêutico , Hesperidina/metabolismo , Interleucina-10/metabolismo , Interleucina-10/farmacologia , Interleucina-4/metabolismo , Interleucina-4/farmacologia , Interleucina-6/metabolismo , Proteína Jagged-1/metabolismo , Proteína Jagged-1/farmacologia , Lesão Pulmonar/metabolismo , Macrófagos , Camundongos Endogâmicos BALB C , RNA Mensageiro/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
3.
J Agric Food Chem ; 70(36): 11224-11235, 2022 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-36048007

RESUMO

The present study investigated the mechanism underlying the impact of hesperidin (HES) on nonalcoholic fatty liver (NAFLD). C57BL/6J male mice were administered a low-fat diet, high-fat diet (HFD), or HFD plus 0.2% (wt/wt) HES (HFD + HES) diet. After 16 weeks of intervention, the mice in the HFD+HES group showed a lower final body weight and liver weight and improved serum lipid profiles when compared with the HFD group. Alleviation of liver dysfunction induced by HFD was observed in HES-fed mice, and the expression of genes involved in lipid metabolism was also altered. Moreover, HES changed the composition of the intestinal microbiota and enriched specific genera such as Bacteroidota. Liver metabolomics analysis indicated that HES enhanced the abundance of metabolites in arginine-related as well as mitochondrial oxidation-related pathways, and these metabolites were predicted to be positively correlated with the gut genera enriched by HES. Together, these results indicate that HFD-fed mice supplemented with HES showed a markedly regulated hepatic metabolism concurrent with shifts in specific gut bacteria.


Assuntos
Microbioma Gastrointestinal , Hesperidina , Hepatopatia Gordurosa não Alcoólica , Animais , Dieta Hiperlipídica/efeitos adversos , Suplementos Nutricionais , Modelos Animais de Doenças , Hesperidina/metabolismo , Hesperidina/farmacologia , Metabolismo dos Lipídeos , Fígado/metabolismo , Masculino , Metabolômica , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo
4.
Andrologia ; 54(10): e14562, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-35985655

RESUMO

Bisphenol A (BPA) is one of the chemicals that cause dysfunction and infertility in testicles. Therefore, it is crucial to develop effective treatments against this damage. In this study, the effects of Hesperidin (HESP), a flavonoid in testicular toxicity induced by BPA in rats, on oxidative stress, inflammation, apoptosis, histological damage, spermatogenesis, steroidogenic enzymes and reproductive hormones were investigated. Our study used 52 Sprague Dawley male rats weighing 250-300 g, and four experimental groups were formed. From the experimental groups, 1 ml of olive oil was administered to the control group, HESP at a dose of 50 mg/kg to the HESP group, BPA at a dose of 100 mg/kg to the BPA group, HESP at a dose of 50 mg/kg to the BPA + HESP group and 100 mg/kg BPA was administered intragastrically (ig) for 14 days. We determined that BPA administration causes apoptosis, histological damage, inflammation, oxidative stress and toxic effects on spermatogenesis and steroidogenic enzymes in testicles. We observed that the administration of HESP with BPA attenuated oxidative stress, inflammation and apoptosis resulting in therapeutic effects on both steroidogenic enzymes and spermatogenesis and reproductive hormones (FSH, LH and testosterone). Our findings from this study clearly showed that while HESP treatment alleviates oxidative damage, inflammation and apoptosis in testicles of rats treated with BPA, it has regulatory effects on steroidogenic enzymes, spermatogenesis and serum reproductive hormones.


Assuntos
Hesperidina , Testículo , Animais , Compostos Benzidrílicos/toxicidade , Hormônio Foliculoestimulante , Hesperidina/metabolismo , Hesperidina/farmacologia , Inflamação/metabolismo , Masculino , Azeite de Oliva , Estresse Oxidativo , Fenóis , Ratos , Ratos Sprague-Dawley , Testosterona
5.
Nutrients ; 14(15)2022 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-35956303

RESUMO

Alzheimer's disease (AD) is an irreversible neurodegenerative disease characterized by memory and cognitive impairments. Neurogenesis, which is related to memory and cognitive function, is reduced in the brains of patients with AD. Therefore, enhancing neurogenesis is a potential therapeutic strategy for neurodegenerative diseases, including AD. Hesperidin (HSP), a bioflavonoid found primarily in citrus plants, has anti-inflammatory, antioxidant, and neuroprotective effects. The objective of this study was to determine the effects of HSP on neurogenesis in neural stem cells (NSCs) isolated from the brain of mouse embryos and five familial AD (5xFAD) mice. In NSCs, HSP significantly increased the proliferation of NSCs by activating adenosine monophosphate (AMP)-activated protein kinase (AMPK)/cAMP-response element-binding protein (CREB) signaling, but did not affect NSC differentiation into neurons and astrocytes. HSP administration restored neurogenesis in the hippocampus of 5xFAD mice via AMPK/brain-derived neurotrophic factor/tropomyosin receptor kinase B/CREB signaling, thereby decreasing amyloid-beta accumulation and ameliorating memory dysfunction. Collectively, these preclinical findings suggest that HSP is a promising candidate for the prevention and treatment of AD.


Assuntos
Doença de Alzheimer , Hesperidina , Doenças Neurodegenerativas , Proteínas Quinases Ativadas por AMP/metabolismo , Doença de Alzheimer/metabolismo , Animais , Modelos Animais de Doenças , Hesperidina/metabolismo , Hesperidina/farmacologia , Hesperidina/uso terapêutico , Hipocampo/metabolismo , Camundongos , Camundongos Transgênicos , Doenças Neurodegenerativas/metabolismo , Neurogênese
6.
Molecules ; 27(15)2022 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-35956749

RESUMO

Particulate matter 2.5 (PM2.5) exposure can trigger adverse health outcomes in the human skin, such as skin aging, wrinkles, pigment spots, and atopic dermatitis. PM2.5 is associated with mitochondrial damage and the generation of reactive oxygen species (ROS). Hesperidin is a bioflavonoid that exhibits antioxidant and anti-inflammatory properties. This study aimed to determine the mechanism underlying the protective effect of hesperidin on human HaCaT keratinocytes against PM2.5-induced mitochondrial damage, cell cycle arrest, and cellular senescence. Human HaCaT keratinocytes were pre-treated with hesperidin and then treated with PM2.5. Hesperidin attenuated PM2.5-induced mitochondrial and DNA damage, G0/G1 cell cycle arrest, and SA-ßGal activity, the protein levels of cell cycle regulators, and matrix metalloproteinases (MMPs). Moreover, treatment with a specific c-Jun N-terminal kinase (JNK) inhibitor, SP600125, along with hesperidin markedly restored PM2.5-induced cell cycle arrest and cellular senescence. In addition, hesperidin significantly reduced the activation of MMPs, including MMP-1, MMP-2, and MMP-9, by inhibiting the activation of activator protein 1. In conclusion, hesperidin ameliorates PM2.5-induced mitochondrial damage, cell cycle arrest, and cellular senescence in human HaCaT keratinocytes via the ROS/JNK pathway.


Assuntos
Hesperidina , Apoptose , Pontos de Checagem do Ciclo Celular , Senescência Celular , Hesperidina/metabolismo , Hesperidina/farmacologia , Humanos , Queratinócitos , Material Particulado/metabolismo , Material Particulado/toxicidade , Espécies Reativas de Oxigênio/metabolismo
7.
J Agric Food Chem ; 70(36): 11290-11300, 2022 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-36039965

RESUMO

Here, the mechanism of vasorelaxant Mas receptor (MasR) expression elevated by hesperidin in spontaneously hypertensive rats was investigated in human umbilical vein endothelial cells (HUVECs). HUVECs were cultured with 1 µM hesperidin for 2 h, following the measurements of nitric oxide (NO) production and vasomotor-related receptors' expression. Hesperidin significantly promoted NO production (224.1 ± 18.3%, P < 0.01 vs control) in the HUVECs. Only the MasR expression was upregulated (141.2 ± 12.5%, P < 0.05 vs control), whereas a MasR antagonist did not alter the hesperidin-induced NO production. When a transient receptor potential vanilloid 1 (TRPV1) was knocked down by silencing RNA or Ca2+/calmodulin-dependent kinase II (CaMKII) and p38 mitogen-activated protein kinase (p38 MAPK) were inhibited, the increased MasR expression by hesperidin was abrogated. The inhibitions of CaMKII and endothelial NO synthase (eNOS) abolished the hesperidin-induced NO production. The structure-activity relationship analysis of flavonoids demonstrated that the B ring of the twisted flavonoid skeleton with a hydroxy group at the 3' position was a crucial factor for TRPV1 stimulation. Taken together, it was demonstrated that hesperidin may stimulate TRPV1-mediated cascades, leading to the activation of two signaling axes, CaMKII/p38 MAPK/MasR expression and CaMKII/eNOS/NO production in HUVECs.


Assuntos
Hesperidina , Óxido Nítrico , Canais de Cátion TRPV/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Células Cultivadas , Hesperidina/metabolismo , Hesperidina/farmacologia , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo III/genética , Óxido Nítrico Sintase Tipo III/metabolismo , Fosforilação , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
8.
Nutrients ; 14(14)2022 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-35889917

RESUMO

The regulation of blood flow to peripheral muscles is crucial for proper skeletal muscle functioning and exercise performance. During exercise, increased mitochondrial oxidative phosphorylation leads to increased electron leakage and consequently induces an increase in ROS formation, contributing to DNA, lipid, and protein damage. Moreover, exercise may increase blood- and intramuscular inflammatory factors leading to a deterioration in endurance performance. The aim of this review is to investigate the potential mechanisms through which the polyphenol hesperidin could lead to enhanced exercise performance, namely improved endothelial function, reduced exercise-induced oxidative stress, and inflammation. We selected in vivo RCTs, animal studies, and in vitro studies in which hesperidin, its aglycone form hesperetin, hesperetin-metabolites, or orange juice are supplemented at any dosage and where the parameters related to endothelial function, oxidative stress, and/or inflammation have been measured. The results collected in this review show that hesperidin improves endothelial function (via increased NO availability), inhibits ROS production, decreases production and plasma levels of pro-inflammatory markers, and improves anaerobic exercise outcomes (e.g., power, speed, energy). For elite and recreational athletes, hesperidin could be used as an ergogenic aid to enhance muscle recovery between training sessions, optimize oxygen and nutrient supplies to the muscles, and improve anaerobic performance.


Assuntos
Hesperidina , Substâncias para Melhoria do Desempenho , Animais , Antioxidantes/farmacologia , Hesperidina/metabolismo , Hesperidina/farmacologia , Humanos , Inflamação , Estresse Oxidativo , Substâncias para Melhoria do Desempenho/farmacologia , Espécies Reativas de Oxigênio/metabolismo
9.
Appl Biochem Biotechnol ; 194(10): 4915-4929, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35670906

RESUMO

Enzymatic deramnosylation of flavonoids is a convenient tool for improving the quality of citrus juices. α-L-rhamnosidase with a specific activity of 33.1 units/mg was isolated and characterized from the culture liquid of Penicillium tardum. The molecular weight of the enzyme was 95 kDa according to the data of gel filtration on Sepharose 6B and gel electrophoresis in SDS-PAGE. The pH optimum of the enzyme activity was 5.0, and the thermo optimum was 60 °C. Enzyme showed high stability in the temperature range of 45-50 and at 60-70 °C. It retained 80 to 50% of the initial activity for 90 min. The half-life of α-L-rhamnosidase at 70 °C increased twofold in the presence of 20-40% glycerol and 2.3-fold in the presence of 4 M sorbitol. The enzyme was completely inhibited in the presence of 10-3 M Ag+ and Cd2+ and approximately by 90% in the presence of Fe2+, Fe3+, and Al3+ ions. More than 60%, the enzyme activity was inhibited by Hg2+, Co2+, and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide methiodide. Activating effect of Ca2+ ions was also noted. Km and Vmax for the hydrolysis of p-nitrophenyl-α-L-rhamnopyranoside and naringin were 0.7 mM and 38.3 µM/min/mg and 1.34 mM and 43.7 µM/min/mg, respectively. Penicillium tardum α-L-rhamnosidase hydrolyzed naringin, neohesperidin, hesperidin, rutin, and narirutin at high rate, which allowed us to consider it as an effective tool for transformation of bioflavonoids in food industry.


Assuntos
Citrus , Hesperidina , Mercúrio , Biotransformação , Cádmio , Flavonoides/metabolismo , Glicerol , Glicosídeo Hidrolases/química , Hesperidina/metabolismo , Concentração de Íons de Hidrogênio , Penicillium , Rutina/metabolismo , Sefarose , Sorbitol , Especificidade por Substrato , Temperatura
10.
FEBS Open Bio ; 12(6): 1166-1177, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35384415

RESUMO

Kaposi's sarcoma-associated herpesvirus (KSHV), also known as human herpes virus 8 (HHV-8), causes primary effusion lymphoma, multicentric Castleman's disease, and Kaposi's sarcoma. Few antiviral drugs are available to efficiently control KSHV infection, and therefore, the development of novel, effective anti-KSHV treatments is needed. The aim of this study was to determine the antiviral activity of ethanolic and aqueous extracts, essential oils, and certain flavonoids (hesperidin, eupafolin, and vicenin) derived from Thymus capitatus (commonly known as thyme). We assessed the toxicity of these different extracts and components in RPE-1 cell cultures using the MTS test and evaluated their antiviral effect using the TCID50 method. The mechanism of action was determined through time-of-addition tests as well as viral entry, attachment, and virucidal assays. Additionally, western blot analysis was also used to assess their modes of action. Total treatment assay showed that the aqueous extract of T. capitatus has the highest inhibitory effect against KSHVLYT with an EC50 value of 0.2388 µg·mL-1 . Both hesperidin and eupafolin showed the ability to inactivate viral infection in a dose-response manner (EC50 values of 0.2399 and 1.396 µm, respectively). Moreover, they were able to inactivate KSHVLyt postinfection by reducing viral protein expression. In summary, the effective antiviral property of the aqueous extract is likely a result of the inhibition of viral growth within the host cells by both hesperidin and eupafolin.


Assuntos
Herpesvirus Humano 8 , Hesperidina , Sarcoma de Kaposi , Antivirais/farmacologia , Flavonoides/metabolismo , Flavonoides/farmacologia , Herpesvirus Humano 8/metabolismo , Hesperidina/metabolismo , Hesperidina/farmacologia , Humanos , Sarcoma de Kaposi/patologia
11.
Biomarkers ; 27(4): 349-360, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35254184

RESUMO

CONTEXT: Nanotechnology is widely used nowadays in several fields of industry, engineering, and medicine, the biological action mechanisms of AgNPs, which mainly involve the release of silver ions (Ag+), generation of reactive oxygen species (ROS). OBJECTIVE: The potential toxicity AgNPs of damages to hepatic cells, hesperidin, and naringin role for their protective effect against the increase of ROS due to AgNPs toxicity. They can be restored, most cellular biochemical parameters, genotoxicity, mutagenicity, and histopathological analysis. MATERIALS AND METHODS: Toxicity was induced by an oral dose of Ag NPs of (20-100 nm) for one month, after that treated with hesperidin, naringin (100 mg/kg) for three weeks, malondialdehyde (MDA) levels, nitric oxide (NO), glutathione (GSH) and catalase were estimated. Also, aminotransferases (AST and ALT), alkaline phosphatase (ALP), γ-glutamyltransferase (GGT), albumin, and total bilirubin were determined, following Chromosomal aberrations, DNA breaks, and histological analyses. RESULTS: hesperidin, and naringin treatment, recorded amelioration in most biochemical, genetic, and spermatogenesis disturbances Also, histological Investigations were improved. CONCLUSION: Their biological safety problems, such as potential toxicity on cells, tissue, and organs should be paid enough attention, hesperidin and naringin amelioration fundamental alterations, as hepatic architectural and DNA damage, related to its role as an antioxidant and anti-inflammatory agent.


Assuntos
Hesperidina , Nanopartículas Metálicas , Animais , Aberrações Cromossômicas , Dano ao DNA , Glutationa/metabolismo , Hesperidina/metabolismo , Hesperidina/farmacologia , Humanos , Fígado/metabolismo , Masculino , Nanopartículas Metálicas/toxicidade , Camundongos , Estresse Oxidativo , Tamanho da Partícula , Espécies Reativas de Oxigênio/metabolismo , Prata/metabolismo , Prata/toxicidade
12.
Insect Sci ; 29(5): 1240-1250, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35146929

RESUMO

Insects employ various types of gustatory receptors (GRs) to identify nutrient-rich food and avoid toxic substances. The larval gustatory system is the critical checkpoint for food acceptance or rejection. As a specialist herbivore, the larvae of Bactrocera minax feed only on unripe citrus fruits. However, how larvae use GRs to check and adapt to the secondary metabolites in unripe citrus fruits remains unknown. In this study, we first performed developmental expression profiles showing that most BminGRs genes were highly expressed in 1st and 2nd instar larvae and that tissue-specific expression indicated high expression of most BminGRs genes in the mouthparts of 2nd instar larvae. Furthermore, we found that silencing BminGR59f by RNA interference (RNAi) affected the growth of 2nd instar B. minax larvae. Hesperidin and naringin were screened as ligands of BminGR59f via RNAi and cell calcium imaging, and the combination of these two flavones increased the body weight of larvae. In summary, we identified a novel gustatory perception pattern in B. minax for detecting hesperidin and naringin, which boosted the growth of B. minax larvae. These results shed light on how specialist herbivores detect and adapt to host metabolites in adverse environments depending on larval GRs.


Assuntos
Citrus , Flavonas , Hesperidina , Tephritidae , Animais , Cálcio/metabolismo , Flavonas/metabolismo , Hesperidina/metabolismo , Larva/genética , Ligantes
13.
Aging (Albany NY) ; 14(3): 1265-1279, 2022 02 10.
Artigo em Inglês | MEDLINE | ID: mdl-35143415

RESUMO

OBJECTIVE: The current study aimed to establish a non-alcoholic fatty liver disease (NAFLD) model using HFD-fed SD rats and FFA-stimulated human THP-1 cells to examine whether hesperidin (HSP) plays a role in endoplasmic reticulum stress (ERS)-induced inflammation in the pathogenesis of NAFLD. METHODS: Oil red O staining was used to determine the effect of HSP on hepatic steatosis in rat liver tissues. Differentially expressed genes (DEGs) were subjected to functional enrichment analysis by bioinformatics. Western blotting was used to detect the protein expression of GRP94, ATF6, ATF4, p-PERK, p-IRE1α, IL-1ß, IL-6, and TNF-α in liver tissues and THP-1 cell lines, and the expression of GRP94 and p-PERK in vitro was detected through immunofluorescence staining. RESULTS: HSP significantly decreased the weight gain, hepatic steatosis but not serum lipid profile and suppressed the serum levels of inflammatory factors in HFD-fed rats. It was revealed by bioinformatics analysis that the inflammatory response and IRE1α activation were enriched signaling pathways in NAFLD. The expression of ERS-related biomarkers, GRP94, ATF6, ATF4, p-PERK and p- IRE1α, was significantly suppressed by HSP in vivo and in vitro. Moreover, the inflammatory markers, including IL-1ß, IL-6, and TNF-α, were also decreased by HSP in vivo and in vitro. Immunofluorescence staining exposed that the expression of GRP94 and p-PERK was decreased by HSP in vitro. CONCLUSION: HSP may suppress ERS-induced inflammation in the pathogenesis of NAFLD.


Assuntos
Hesperidina , Hepatopatia Gordurosa não Alcoólica , Animais , Biomarcadores/metabolismo , Dieta Hiperlipídica/efeitos adversos , Estresse do Retículo Endoplasmático , Endorribonucleases/metabolismo , Hesperidina/metabolismo , Hesperidina/farmacologia , Hesperidina/uso terapêutico , Inflamação/metabolismo , Interleucina-6/metabolismo , Fígado/metabolismo , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Proteínas Serina-Treonina Quinases , Ratos , Ratos Sprague-Dawley , Fator de Necrose Tumoral alfa/metabolismo
14.
J Biotechnol ; 347: 67-76, 2022 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-35192875

RESUMO

Hesperetin, a methoxylated flavanone, has numerous biological activities. Access to this compound is currently restricted by its low abundance in plants, which limits its practical applicability. To provide an alternative, eco-friendly production source, we developed a biosynthetic pathway of hesperetin in an engineered Escherichia coli consortium, which was fed with naringenin as a precursor and demonstrated good hesperetin production. The biosynthetic pathway was divided into two modules. The first recombinant host harbored the pathway genes from two different species: a flavonoid 3'-hydroxylase (F3'H) gene from Gentiana triflora and a cytochrome P450 reductase (CPR) gene from Arabidopsis thaliana. The second strain heterologously expressed a gene encoding a flavonoid 4'-O-methyltransferase (MpOMT) from Mentha × piperita, which was N-terminally fused to a Sumo tag. A construct expressing a 29 aa N-terminally truncated F3'H and CPR was the most effective combination for the conversion of naringenin. The strain expressing the Sumo-tagged MpOMT protein exhibited an increase in the final hesperetin titer, reaching 5.9 mg/L. Simultaneous overexpression of metK (coding for the endogenous S-adenosyl-l-methionine [SAM] synthase) further improved the hesperetin titer by 25.1%. Finally, the designed E. coli consortium harboring the two modules efficiently converted naringenin to hesperetin (37.1 mg/L). This work reports the construction of a multi-step in vivo cascade biocatalyst for the biotransformation of naringenin to hesperetin. It also illustrates the potential of the E. coli consortium system for producing other O-methylated flavonoids.


Assuntos
Flavanonas , Hesperidina , Escherichia coli/genética , Escherichia coli/metabolismo , Flavanonas/metabolismo , Hesperidina/metabolismo
15.
J Healthc Eng ; 2021: 9938874, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34956584

RESUMO

This study aimed to explore the influence of hesperidin on the polarization of microglia to clarify the key mechanism of regulating the polarization of M2 microglia. C57BL/6 mice were randomly divided into middle cerebral artery occlusion model group (MCAO group), MCAO + hesperidin treatment group (MCAO + hesperidin group), and sham group (sham operation group). The mice were assessed with neurological scores for their functional status. 2,3,5-Triphenyltetrazole chloride (TTC) was used to determine the volume of cerebral infarction. Hematoxylin and eosin (H&E) staining was performed to detect brain loss. The system with 1% O2, 5% CO2, and 92% N2 was applied to establish BV2 in vitro model induced by MCAO. TNF-α, IL-1ß, TGF-ß, and IL-10 levels of cytokines in the supernatant were detected by ELISA. RT-qPCR was used to detect mRNA levels of M1 iNOS, CD11b, CD32, and CD86, and mRNA levels of M2 CD206, Arg-1, and TGF-ß. The Iba-1, iNOS, and Arg-1 of microglia and protein levels of TLR4 and p-NF-κB related to the pathway were detected by Western blot. After treatment with hesperidin, BV2 cells induced by MCAO in vitro can reduce the proinflammatory cytokines of TNF-α and IL-1ß significantly, further upregulating anti-inflammatory cytokines of TGF-ß, IL-10 while inhibiting TLR4 and p-NF-κB expression. The MCAO-induced BV2 cells treated by TLR-4 inhibitor TAK-242 and NF-κB inhibitor BAY 11-7082 had similar polarization effects to those treated with hesperidin. This study found that hesperetin gavage treatment can improve the neurological deficit and regulate the polarization of microglia in MCAO mice. In vitro experiments further verified that hesperidin plays a neuroprotective role by inhibiting the TLR4-NF-κB pathway, thus providing new targets and strategies for neuroprotection and nerve repair after ischemic stroke.


Assuntos
Hesperidina , AVC Isquêmico , Fármacos Neuroprotetores , Animais , Citocinas/metabolismo , Citocinas/farmacologia , Hesperidina/metabolismo , Hesperidina/farmacologia , Hesperidina/uso terapêutico , Humanos , Interleucina-10/metabolismo , Interleucina-10/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Microglia/metabolismo , NF-kappa B/genética , NF-kappa B/metabolismo , NF-kappa B/farmacologia , Fármacos Neuroprotetores/metabolismo , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , RNA Mensageiro , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Fator de Crescimento Transformador beta/farmacologia , Fator de Necrose Tumoral alfa/metabolismo , Fator de Necrose Tumoral alfa/farmacologia
16.
Mol Nutr Food Res ; 65(17): e2001175, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34272817

RESUMO

SCOPE: The aim of the present work is to determine new biomarkers of the biological effects of hesperidin in orange juice (OJ) applying a non-targeted metabolomics approach validated by targeted metabolomics analyses of compliance biomarkers. METHODS AND RESULTS: Plasma/serum and urine targeted (HPLC-MS/MS) and untargeted (1 H-NMR) metabolomics signatures are explored in a subsample with pre- and stage-1 hypertension subjects of the CITRUS study (N = 159). Volunteers received 500 mL day-1 of control drink, OJ, or hesperidin-enriched OJ (EOJ) for 12-weeks. A 6-h postprandrial study is performed at baseline. Targeted analyses reveals plasma and urine hesperetin 7-O-ß-d-glucuronide as the only metabolite differing between OJ and EOJ groups after 12-weeks consumption, and in urine is correlated with a decreased systolic blood pressure level. The non-targeted approach shows that after single dose and 12-weeks consumption of OJ and EOJ change several metabolites related with an anti-inflammatory and antioxidant actions, lower blood pressure levels and uremic toxins. CONCLUSIONS: Hesperetin 7-O-ß-d-glucuronide can be a candidate marker for distinguishing between the consumption of different hesperidin doses at 12-weeks consumption as well as a potential agent mediating blood pressure reduction. Moreover, changes in different endogenous metabolites can explain the mechanisms of action and the biological effects of hesperidin consumption.


Assuntos
Citrus sinensis/química , Hesperidina/farmacologia , Hipertensão/dietoterapia , Adulto , Biomarcadores/sangue , Biomarcadores/urina , Feminino , Sucos de Frutas e Vegetais , Glucuronídeos/sangue , Glucuronídeos/urina , Hesperidina/análogos & derivados , Hesperidina/sangue , Hesperidina/metabolismo , Hesperidina/urina , Humanos , Hipertensão/metabolismo , Masculino , Metabolômica/métodos , Pessoa de Meia-Idade , Período Pós-Prandial
17.
Food Funct ; 12(9): 3872-3882, 2021 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-33977947

RESUMO

2S-Hesperidin is the main flavonoid of orange (Citrus sinensis). Previous researches have pointed its effects in muscle development and fat accumulation reduction, although most of these results have not been assessed in humans. The objective of this study is to evaluate the effect of chronic (8-weeks) intake of 2S-hesperidin on amateur cyclists' body composition. A double-blind, parallel and randomized trial, was carried out with 40 amateur cyclists that were divided in two groups, one taking 2S-hesperidin (500 mg d-1, n = 20) and another taking placebo (500 mg d-1 microcellulose, n = 20) for 8 weeks. Dual-energy X-ray absorptiometry (DXA) and anthropometric measurements were used to assess the effect of both treatments on body composition. In addition, the resting metabolic rate was measured. In comparison to placebo, DXA analysis showed a decrease in percentage body fat (%BF) (-10.4%; p = 0.035) and lower limb fat mass (-10.5%; p = 0.029) in favour of 2S-hesperidin. After evaluation of anthropometric data, a decrease in %BF (-3.7%; p = 0.006), total body fat (-3.0%; p = 0.047), ∑ of 8 skinfolds (-6.1%; p = 0.008) was observed in 2S-hesperidin group, but not in placebo. Additionally, there was an increase in muscle mass percentage (1.0%; p = <0.001) and total muscle mass (1.7%; p = 0.011) after ingestion of 2S-hesperidin, with no changes in placebo. Chronic intake of 2S-hesperidin decreased fat mass in amateur cyclists, evaluated through different body composition measurement methodologies (DXA and anthropometry). In addition, 2S-hesperidin supplementation showed a promoting effect on muscle development.


Assuntos
Atletas , Ciclismo , Composição Corporal , Suplementos Nutricionais , Hesperidina/administração & dosagem , Músculo Esquelético/anatomia & histologia , Absorciometria de Fóton , Tecido Adiposo , Adolescente , Adulto , Metabolismo Basal , Índice de Massa Corporal , Método Duplo-Cego , Hesperidina/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Dobras Cutâneas , Adulto Jovem
18.
Chem Biol Interact ; 342: 109489, 2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-33905740

RESUMO

The development of multi-target-directed ligands (MTDLs) may improve complex central nervous system diseases such as Alzheimer's disease (AD). Here, a series of 7-O-1, 2, 3-triazole hesperetin derivatives was evaluated for their inhibition of cholinesterase, anti-neuroinflammatory, and neuroprotective activity. Among the hesperetin derivatives, compound a8 (7-O-((1-(3-chlorobenzyl)-1H-1,2,3-triazol-4-yl)methyl)hesperetin) possessed excellent anti-butyrylcholinesterase activity (IC50 = 3.08 ± 0.29 µM) and exhibited good anti-neuroinflammatory activity (IC50 = 2.91 ± 0.47 µM) against NO production through remarkably blocking the NF-κB signaling pathway and inhibiting the phosphorylation of P65. In addition, a8 showed a remarkable neuroprotective effect and lacked neurotoxicity up to 50 µM concentration. Furthermore, possessing significant self-mediated Aß1-42 aggregation inhibitory activity, chelated biometals and reduced ROS production were found in compound a8. In the bi-directional transport assay, a8 exhibited a blood-brain barrier penetrating ability. In this study, the Morris water maze task showed that compound a8 significantly improved the learning and memory impairment of the scopolamine-induced AD mice model. Results highlighted the potential of compound a8 to be a potential MTDL for the development of anti-AD agents.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Anti-Inflamatórios/uso terapêutico , Inibidores da Colinesterase/uso terapêutico , Hesperidina/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Triazóis/uso terapêutico , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/metabolismo , Butirilcolinesterase/metabolismo , Linhagem Celular Tumoral , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/metabolismo , Descoberta de Drogas , Hesperidina/síntese química , Hesperidina/metabolismo , Ligantes , Masculino , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/metabolismo , Óxido Nítrico/antagonistas & inibidores , Ligação Proteica , Ratos , Fator de Transcrição RelA/metabolismo , Triazóis/síntese química , Triazóis/metabolismo
19.
J Sep Sci ; 44(11): 2189-2205, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33784419

RESUMO

Fructus Aurantii is a traditional medicated diet in East Asia. To determine the underlying chemical markers responsible for the quality and efficacy of Fructus Aurantii, a sensitive metabolomic method was applied to distinguish Fructus Aurantii in Jiangxi Province from other two geographical locations (Hunan Province and Chongqing City) in China. In the present study, multivariate analyses were adopted to compare chemical compositions in 21 batches of Fructus Aurantii samples. Among three geographical origins, 23 differential compounds were structurally identified. Serum pharmacochemistry exhibited that 22 components could be detected in rat serum. Six differential and absorbed components were selected as six potential markers. Statistical analysis revealed that the content of six markers varied widely in three origins of Fructus Aurantii. Six differential and absorbed components were evaluated further by biological activity. Neohesperidin, naringin, and meranzin showed inhibitory effect on acetylcholinesterase that regulates gastrointestinal motility in vitro and in silico, suggesting that these three components may be determined as the active biomarkers of Fructus Aurantii. These findings demonstrate the potential of biomarkers for identification and quality control of Fructus Aurantii.


Assuntos
Inibidores da Colinesterase/farmacologia , Citrus/química , Cumarínicos/farmacologia , Flavanonas/farmacologia , Hesperidina/análogos & derivados , Metabolômica , Acetilcolinesterase/metabolismo , Animais , Biomarcadores/sangue , Biomarcadores/metabolismo , China , Inibidores da Colinesterase/sangue , Inibidores da Colinesterase/metabolismo , Cumarínicos/sangue , Cumarínicos/metabolismo , Descoberta de Drogas , Flavanonas/sangue , Flavanonas/metabolismo , Hesperidina/sangue , Hesperidina/metabolismo , Hesperidina/farmacologia , Masculino , Ratos , Ratos Sprague-Dawley
20.
Biomed Pharmacother ; 138: 111467, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33740520

RESUMO

The present study aimed to develop novel hesperetin-loaded on multiple wall carbon nanotubes (Hst-MWCNTs) to resolve the restricted bioavailability of hesperetin (Hst) and to enhance its preventive effect on cerebral ischemia-reperfusion (I/R). The physicochemical characteristics of Hst-MWCNTs were evaluated by Fourier-transform infrared spectra (FT-IR) and field emission scanning electron microscopy (FE-SEM). Forty male Wistar rats were randomly divided into five groups (control, I/R, MWCNTs, Hst, and Hst-MWCNTs). Hst, MWCNTs and Hst-MWCNTs (15 mg/kg orally) were pretreated for 14 days, and then I/R was induced by bilateral common carotid artery occlusion (BCCAO). Learning and memory deficits were evaluated using the novel object recognition test (NORT). The percentage of infarct size, catalase (CAT), superoxide dismutase (SOD), glutathione reductase (GRx), glutathione peroxidase (GPx) activities, malondialdehyde (MDA), and glutathione (GSH) levels was evaluated. Caspase-3 and Bcl-2 expressions were detected by qRT-PCR and Western blot analysis. Compared to the I/R group, Hst-MWCNTs considerably reduced learning and memory deficits, infarct size, and MDA levels. CAT, SOD, GRx, GPx activities and GSH levels were significantly increased in the Hst-MWCNTs group than in the I/R group. Additionally, Hst-MWCNTs significantly reduced the Caspase-3 expression but increased the Bcl-2 expression. All these results indicated that MWCNTs could be used as a promising novel carrier to enhance the oral bioavailability of Hst and to treat cerebral I/R injury.


Assuntos
Isquemia Encefálica/tratamento farmacológico , Hesperidina/administração & dosagem , Hesperidina/síntese química , Nanotubos de Carbono/química , Traumatismo por Reperfusão/tratamento farmacológico , Animais , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Avaliação Pré-Clínica de Medicamentos/métodos , Hesperidina/metabolismo , Masculino , Ratos , Ratos Wistar , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Espectroscopia de Infravermelho com Transformada de Fourier/métodos
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