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1.
Zhongguo Zhong Yao Za Zhi ; 47(15): 4074-4083, 2022 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-36046897

RESUMO

The lignan glycosyltransferase UGT236(belonging to the UGT71 B family) from Isatis indigotica can catalyze the production of phloridzin from phloretin in vitro. UGT236 shares high identity with P2'GT from apple. In this study, the recombinant plasmid pET28 a-MBP-UGT236 was transferred into Escherichia coli Rosetta(DE3) cells and induced by isopropyl-ß-D-thiogalactoside(IPTG). The purified UGT236 protein was used for enzymatic characterization with phloretin as substrate. The results showed that UGT236 had the optimal reaction temperature of 40 ℃ and the optimal pH 8(Na_2HPO_4-NaH_2PO_4 system). The UGT236 activity was inhibited by Ni~(2+) and Al~(3+), enhanced by Fe~(2+), Co~(2+), and Mn~(2+), and did not affected by Mg~(2+), Ca~(2+), Li~+, Na~+, or K~+. The K_m, K_(cat), and K_(cat)/K_m of phloretin were 61.03 µmol·L~(-1), 0.01 s~(-1), and 157.11 mol~(-1)·s~(-1)·L, and those of UDPG were 183.6 µmol·L~(-1), 0.01 s~(-1), and 51.91 mol~(-1)·s~(-1)·L, respectively. The possible active sites were predicted by homologous modeling and molecular docking. By mutagenisis and catalytic activity detection, three key active sites, Glu391, His15, and Thr141, were identified, while Phe146 was related to product diversity. In summary, we found that the lignan glycosyltransferase UGT236 from I.indigotica could catalyze the reaction of phloretin into phloridzin. Several key amino acid residues were identified by structure prediction, molecular docking, and site-mutagenesis, which provided a basis for studying the specificity and diversity of phloretin glycoside products. This study can provide a reference for artificially producing glycosyltransferase elements with high efficiency and specific catalysis.


Assuntos
Isatis , Lignanas , Glucosiltransferases/genética , Glicosiltransferases/genética , Glicosiltransferases/metabolismo , Lignanas/metabolismo , Simulação de Acoplamento Molecular , Floretina/metabolismo , Florizina/metabolismo
2.
Am J Physiol Gastrointest Liver Physiol ; 323(4): G331-G340, 2022 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-35916412

RESUMO

A portion of absorbed dietary triglycerides (TG) is retained in the intestine after the postprandial period, within intracellular and extracellular compartments. This pool of TG can be mobilized in response to several stimuli, including oral glucose. The objective of this study was to determine whether oral glucose must be absorbed and metabolized to mobilize TG in rats and whether high-fat feeding, a model of insulin resistance, alters the lipid mobilization response to glucose. Lymph flow, TG concentration, TG output, and apolipoprotein B48 (apoB48) concentration and output were assessed after an intraduodenal lipid bolus in rats exposed to the following intraduodenal administrations 5 h later: saline (placebo), glucose, 2-deoxyglucose (2-DG, absorbed but not metabolized), or glucose + phlorizin (intestinal glucose absorption inhibitor). Glucose alone, but not 2-DG or glucose + phlorizin treatments, stimulated lymph flow, TG output, and apoB48 output compared with placebo. The effects of glucose in high-fat-fed rats were similar to those in chow-fed rats. In conclusion, glucose must be both absorbed and metabolized to enhance lymph flow and intestinal lipid mobilization. This effect is qualitatively and quantitatively similar in high-fat- and chow-fed rats. The precise signaling mechanism whereby enteral glucose enhances lymph flow and mobilizes enteral lipid remains to be determined.NEW & NOTEWORTHY Glucose potently enhances mesenteric lymph flow in chow- and high-fat-fed rats. The magnitude of glucose effect on lymph flow is no different in chow- and high-fat-fed rats. Glucose must be absorbed and metabolized to enhance lymph flow and mobilize intestinal lipid.


Assuntos
Quilomícrons , Glucose , Animais , Apolipoproteína B-48 , Quilomícrons/metabolismo , Desoxiglucose/metabolismo , Desoxiglucose/farmacologia , Glucose/metabolismo , Linfa/metabolismo , Florizina/metabolismo , Florizina/farmacologia , Ratos , Triglicerídeos/metabolismo
3.
Colloids Surf B Biointerfaces ; 217: 112692, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35834996

RESUMO

Electrospinning-based wound dressings have multiple functions such as antibacterial, anti-inflammatory, and therapeutic, and are important in skin wound care. Herein, we designed a phlorizin (PHL)-loaded silk protein/polyvinylpyrrolidone (SF/PVP) composite nanofibrous membrane, which can be used as multiple wound dressings. In particular, SF/PVP/PHL scaffolds have high porosity and mechanical properties, exhibiting suitable permeability and hydrophilicity. The SF/PVP/PHL scaffolds containing PHL also have excellent antibacterial and antioxidant activities. Furthermore, the nanofiber significantly accelerated the wound healing process in a full-thickness skin injury model by enhancing wound re-epithelialization and collagen deposition density, increasing the content of macrophage antigen (CD68), platelet-endothelial cell adhesion molecule (CD31), proliferating cell nuclear antigen (PCNA) and inhibiting the expression of α-smooth muscle actin (α-SMA) at the wound site. The mechanism may be related to the inhibition of activation of phosphatidylinositol 3-kinase/serine-threonine kinase/ target of rapamycin (PI3K/AKT/mTOR) signaling pathway to enhance autophagy. Therefore, SF/PVP/PHL nanofibers can ideally meet the various requirements of the wound healing process and are promising wound dressing candidates for future clinical applications.


Assuntos
Nanofibras , Antibacterianos/farmacologia , Bandagens , Florizina , Fosfatidilinositol 3-Quinases
4.
Biochem Biophys Res Commun ; 621: 176-182, 2022 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-35841764

RESUMO

We previously found that glucagon-like peptide 1 (GLP-1) secretion by co-administration of maltose plus an α-glucosidase inhibitor miglitol (maltose/miglitol) was suppressed by a GLUT2 inhibitor phloretin in mice. In addition, maltose/miglitol inhibited glucose-dependent insulinotropic polypeptide (GIP) secretion through a mechanism involving short chain fatty acids (SCFAs) produced by microbiome. However, it remains unknown whether phloretin suppresses GLP-1 secretion by modulating SCFAs. In this study, we examined the effect of phloretin on SCFA release from microbiome in vitro and in vivo. In Escherichia coli, acetate release into the medium was suppressed by phloretin, when cultured with maltose/miglitol. In mice, phloretin inhibited maltose/miglitol-induced SCFA increase in the portal vein. In addition, alpha methyl-d-glucose (αMDG), a poor substrate for GLUT2, significantly increased GLP-1 secretion when co-administered with phloridzin in mice, suggesting that GLUT2 is not essential for glucose/phloridzin-induced GLP-1 secretion. αMDG increased portal SCFA levels, thereby increasing GLP-1 secretion and suppressing GIP secretion in mice, suggesting that αMDG is metabolizable not for mammals, but for microbiota. In conclusion, phloretin is suggested to suppress maltose/miglitol-induced GLP-1 secretion via inhibiting SCFAs produced by microbiome.


Assuntos
Microbioma Gastrointestinal , Peptídeo 1 Semelhante ao Glucagon , Animais , Ácidos Graxos Voláteis , Polipeptídeo Inibidor Gástrico , Glucose , Maltose , Mamíferos , Camundongos , Floretina/farmacologia , Florizina , Receptores Acoplados a Proteínas G
5.
Exp Gerontol ; 165: 111863, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35660419

RESUMO

We explored the effect of phlorizin against cholinergic memory impairment and dysbacteriosis in D-galactose induced ICR mice. The control (CON) group, D-galactose model (DGM) group, and three groups (DG-PL, DG-PM, DG-PH) treated with phlorizin at 0.01%, 0.02%, and 0.04% (w/w) in diets were raised for 12 weeks. Supplementing with phlorizin reversed the loss of organ coefficient and body weight caused by D-galactose. The functional abilities of phlorizin on hippocampal-dependent spatial learning and memory, anti-oxidation, anti-inflammation were also observed. Meanwhile, phlorizin intervention upregulated the gene expression of Nrf2, GSH-PX, SOD1, decreased the gene expression of NF-κB, TLR-4, TNF-α, and IL-1ß in the hippocampus, while enhanced the gene expression of JAM-A, Mucin2, Occludin in the caecum. Furthermore, a neurotransmitter of acetylcholine (ACh) was enhanced, while acetylcholinesterase (AChE) activity was inhibited by phlorizin administration. Moreover, phlorizin administration increased short-chain fatty acids (SCFAs) content, and reduced lipopolysaccharides (LPS) levels, which may relate to the rebuilding of gut microbiota homeostasis. Treatment with phlorizin may be an effective intervention for alleviating cognitive decline and gut microbiota dysbiosis.


Assuntos
Galactose , Microbioma Gastrointestinal , Acetilcolinesterase/metabolismo , Animais , Colinérgicos , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/tratamento farmacológico , Camundongos , Camundongos Endogâmicos ICR , Florizina
6.
Curr Pharm Des ; 28(22): 1854-1862, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35585811

RESUMO

BACKGROUND: Docosahexaenoic acid-acylated phloridzin (PZ-DHA), a novel polyphenol fatty acid ester derivative, is synthesized through an acylation reaction of phloridzin (PZ) and docosahexaenoic acid (DHA). PZ-DHA is more stable than DHA and exhibits higher cellular uptake and bioavailability than PZ. OBJECTIVE: The study aims to investigate the effects of PZ-DHA on insulin resistance in the skeletal muscle and the related mechanisms; we used palmitic acid (PA)-treated C2C12 myotubes as an insulin resistance model. RESULTS: We found that PZ-DHA increased the activity of AMP-activated protein kinase (AMPK) and improved glucose uptake and mitochondrial function in an AMPK-dependent manner in untreated C2C12 myotubes. PZ-DHA treatment of the myotubes reversed PA-induced insulin resistance; this was indicated by increases in glucose uptake and the expression of membrane glucose transporter 4 (Glut4) and phosphorylated Akt. Moreover, PZ-DHA treatment reversed PA-induced inflammation and oxidative stress. These effects of PZ-DHA were mediated by AMPK. Furthermore, the increase in AMPK activity, improvement in insulin resistance, and decrease in inflammatory and oxidative responses after PZ-DHA treatment diminished upon co-treatment with a liver kinase B1 (LKB1) inhibitor, suggesting that PZ-DHA improved AMPK activity by regulating its upstream kinase, LKB1. CONCLUSION: The effects of PZ-DHA on insulin resistance in C2C12 myotubes may be mediated by the LKB1- AMPK signaling pathway. Hence, PZ-DHA is a promising therapeutic agent for insulin resistance in type 2 diabetes.


Assuntos
Diabetes Mellitus Tipo 2 , Resistência à Insulina , Proteínas Quinases Ativadas por AMP , Linhagem Celular , Ácidos Docosa-Hexaenoicos , Ésteres , Glucose , Humanos , Inflamação , Insulina , Fibras Musculares Esqueléticas , Ácido Palmítico , Florizina
7.
J Sci Food Agric ; 102(13): 5891-5902, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35437748

RESUMO

BACKGROUND: The different parts of pomegranate fruit are considered a powerful mixture of bioactive compounds yet the peels and pulps of the fruits are usually discarded and considered as industrial waste. In this work, ultra-performance liquid chromatography coupled with triple quadrupole mass spectrometry (UPLC-QqQ-MS) was utilized for metabolomics analysis of different parts (peel, pulp, seed and juice) of pomegranate fruit cultivars to verify possible variations among the fruits and their waste products as potential sources of functional constituents. RESULTS: Orthogonal projection to latent structure-discriminant analysis (OPLS-DA) coefficient-plot showed enrichment of phenolic compounds such as punicalagin and ellagic acid derivatives in pulp samples while seeds class was enriched in phlorizin, catechin and quercetin, juice class showed abundance of naringenin and pelargonidin-3-pentoside while peels were enriched in anthocyanins and flavonoids including cyanidin diglycoside, quercetin and luteolin glycosides. Although the juice samples of almost all tested cultivars showed remarkable cytotoxic activity, the pulp samples, particularly the Manfalouti cultivar, exhibited the most potent [half maximal inhibitory concentration (IC50 ) = 2.367 ± 0.14 µg/mL in MCF-7, IC50  = 3.854 ± 0.23 µg/mL in Hep-G2 cell lines]. OPLS models were constructed for determination of cytotoxicity-associated metabolites among where the coefficients plots revealed tannins; granatin A, ellagic acid derivatives, punicalagin α and ß, in addition to anthocyanins and phenolic compounds; cyanidin diglycoside, quercetin, phlorizin, 3-O-caffeoylquinic acid, naringenin and liquiritin were more pertinent with cytotoxicity of the different parts of pomegranate fruit. CONCLUSION: The results obtained allow for the full utilization of the resources of pomegranate fruit and its industrial waste as sources of bioactive compounds. © 2022 Society of Chemical Industry.


Assuntos
Lythraceae , Romã (Fruta) , Antocianinas/análise , Ácido Elágico/análise , Ácido Elágico/farmacologia , Frutas/química , Resíduos Industriais/análise , Lythraceae/química , Metabolômica , Fenóis/análise , Florizina/análise , Quercetina/análise , Resíduos/análise
8.
Biol Reprod ; 106(6): 1206-1217, 2022 06 13.
Artigo em Inglês | MEDLINE | ID: mdl-35420639

RESUMO

Glucose is a key substrate for supporting sperm energy production and function. Previous studies have demonstrated that sperm glucose uptake is facilitated by several isoforms of the glucose transporters (GLUT). Here, we report that sperm also expresses the Na+-dependent sodium glucose cotransporter (SGLT). This was first suggested by our observation that genetic deletion of the testis-specific Na,K-ATPase α4, which impairs the sperm plasma membrane Na+ gradient, reduces glucose uptake and ATP production. Immunoblot analysis revealed the presence of an SGLT in sperm, with specific expression of isoform 1 (SGLT-1), but not of isoform 2 (SGLT-2). Immunocytochemistry identified SGLT-1 in the mid- and principal piece of the sperm flagellum. Inhibition of SGLT-1 with the isotype-selective inhibitor phlorizin significantly reduced glucose uptake, glycolytic activity, and ATP production in noncapacitated and capacitated sperm from wild-type mice. Phlorizin also decreased total sperm motility, as well as other parameters of sperm movement. In contrast, inhibition of SGLT-1 had no significant effect on sperm hyperactivation, protein tyrosine phosphorylation, or acrosomal reaction. Importantly, phlorizin treatment impaired the fertilizing capacity of sperm. Altogether, these results demonstrate that mouse sperm express a functional SGLT transport system that is important for supporting sperm energy production, motility, and fertility.


Assuntos
ATPase Trocadora de Sódio-Potássio , Motilidade Espermática , Trifosfato de Adenosina/metabolismo , Animais , Fertilidade , Glucose/metabolismo , Masculino , Camundongos , Florizina/metabolismo , Florizina/farmacologia , Isoformas de Proteínas/metabolismo , Sódio/metabolismo , Sódio/farmacologia , Transportador 1 de Glucose-Sódio , ATPase Trocadora de Sódio-Potássio/metabolismo , Motilidade Espermática/fisiologia , Espermatozoides/metabolismo
9.
Exp Gerontol ; 163: 111769, 2022 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-35337894

RESUMO

Aging is an inevitable and complicated process involving many physiological changes. Screening of natural biologically active anti-aging substances is a current research hotspot. Phlorizin (PZ), an important dihydrochalcone phytoconstituent, has been demonstrated to have antioxidant and anti-tumor effects. In this paper, different doses of PZ (20 and 40 mg/kg) were used to research the protective effect on D-galactose (D-gal)-induced aging mice. Following hematoxylin and eosin staining and by observing the hippocampus, we found that PZ alleviated the damage caused by D-gal in neuronal cells, while PZ enhanced the learning and memory abilities of aging mice in a radical eight-arm maze. In order to explain the reasons for these anti-aging effects, we tested the antioxidant enzyme activity and malonic dialdehyde concentration in mouse serum, liver, and brain tissue. The contents of proteins related to anti-inflammation and apoptosis in brain tissue were analyzed, and the gut microbiota was also analyzed. The results indicated that PZ improved antioxidant enzyme activity while significantly reducing the malonic dialdehyde content. Western blotting analysis suggested that PZ effectively alleviated neuro-apoptosis via regulating the expressions of Bax, Bcl-2, and caspase-3. PZ also exerted anti-inflammation effects by regulating the interleukin-1ß/inhibitor of nuclear factor kappa B alpha/nuclear factor kappa-light-chain-enhancer of activated B-cells signaling pathways in brain tissues. Importantly, PZ improved the structure and diversity of the gut microbiota, and the microbiota-gut-brain axis may hold a key role in PZ-induced anti-aging effects. In conclusion, PZ can be used as a potential drug candidate to combat aging.


Assuntos
Galactose , Microbioma Gastrointestinal , Envelhecimento/metabolismo , Animais , Anti-Inflamatórios/farmacologia , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Apoptose , Galactose/farmacologia , Camundongos , Estresse Oxidativo , Florizina/farmacologia
10.
Rev Med Liege ; 77(3): 175-180, 2022 Mar.
Artigo em Francês | MEDLINE | ID: mdl-35258866

RESUMO

Most physicians do not know, or do not remember, the name of phlorizin. Hence this molecule has a major historical importance because it was the precursor of gliflozins, a new class of oral antidiabetic drugs with recent therapeutic perspectives beyond diabetes. This article recalls the history of phlorizin: its discovery in the 19th century by De Koninck and Stas, the demonstration of its ability to induce glucosuria and reduce hyperglycaemia by von Mering, its use to demonstrate the concept of glucose toxicity by the team of DeFronzo and finally the development of selective (phlorizin being not selective) sodium-glucose cotransporter type 2 inhibitors (gliflozins) which block glucose reabsorption in renal tubules. Gliflozins have increasing therapeutic indications, not only in type 2 diabetes, but also in cardiology and nephrology among non-diabetic people with heart failure or renal insufficiency.


La plupart des médecins ne connaissent pas, ou ne se souviennent plus, de la phlorizine. Pourtant, cette molécule a une grande importance historique car elle a été le précurseur des gliflozines, une nouvelle classe d'antidiabétiques oraux ouvrant maintenant de nouvelles perspectives thérapeutiques au-delà du diabète. Cet article retrace l'histoire de la phlorizine : sa découverte au 19ème siècle par De Koninck et Stas, la démonstration de l'induction d'une glucosurie abaissant la glycémie par von Mering, son utilisation pour conceptualiser la notion de glucotoxicité par l'équipe de DeFronzo et, enfin, le développement d'inhibiteurs sélectifs (la phlorizine étant non sélective) des cotransporteurs sodium-glucose de type 2 (SGLT2, gliflozines),dans les tubules rénaux, bloquant la réabsorption du glucose. Les gliflozines ont, maintenant, des indications thérapeutiques de plus en plus larges, non seulement dans le diabète de type 2, mais aussi en cardiologie et en néphrologie chez des personnes non diabétiques avec insuffisance cardiaque ou insuffisance rénale.


Assuntos
Diabetes Mellitus Tipo 2 , Inibidores do Transportador 2 de Sódio-Glicose , Bélgica , Diabetes Mellitus Tipo 2/tratamento farmacológico , Humanos , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Florizina/farmacologia , Florizina/uso terapêutico , Transportador 2 de Glucose-Sódio/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico
11.
J Exp Bot ; 73(3): 886-902, 2022 01 27.
Artigo em Inglês | MEDLINE | ID: mdl-34486649

RESUMO

The high accumulation of phloridzin makes apple (Malus domestica) unique in the plant kingdom, which suggests a vital role of its biosynthesis in physiological processes. In our previous study, silencing MdUGT88F1 (a key UDP-GLUCOSE: PHLORETIN 2'-O-GLUCOSYLTRANSFERASE gene) revealed the importance of phloridzin biosynthesis in apple development and Valsa canker resistance. Here, results from MdUGT88F1-silenced lines showed that phloridzin biosynthesis was indispensable for normal chloroplast development and photosynthetic carbon fixation by maintaining MdGLK1/2 (GOLDEN2-like1/2) expression. Interestingly, increased phloridzin biosynthesis did not affect plant (or chloroplast) development, but reduced nitrogen accumulation, leading to chlorophyll deficiency, light sensitivity, and sugar accumulation in MdUGT88F1-overexpressing apple lines. Further analysis revealed that MdUGT88F1-mediated phloridzin biosynthesis negatively regulated the cytosolic glutamine synthetase1-asparagine synthetase-asparaginase (GS1-AS-ASPG) pathway of ammonium assimilation and limited chlorophyll synthesis in apple shoots. The interference of phloridzin biosynthesis in the GS1-AS-ASPG pathway was also assumed to be associated with its limitation of the carbon skeleton of ammonium assimilation through metabolic competition with the tricarboxylic acid cycle. Taken together, our findings shed light on the role of MdUGT88F1-mediated phloridzin biosynthesis in the coordination between carbon and nitrogen accumulation in apple trees.


Assuntos
Ascomicetos , Malus , Carbono/metabolismo , Malus/metabolismo , Nitrogênio/metabolismo , Florizina/metabolismo
12.
Eur J Pharmacol ; 918: 174563, 2022 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-34942162

RESUMO

Oxidative stress plays a crucial role in fatigue, thus it is of significance to develop safe and efficient antioxidant to prevent fatigue. Phlorizin (PHZ) is a major active ingredient of dihydrochalcone from Lithocarpus polystachyus Rehd., which has already been approved as a new food material in China since 2017. The current study was designed to investigate the effect of PHZ on fatigue, and further to elucidate its possible underlying mechanism. Our results revealed that PHZ exerted beneficial effect on exhaustive exercise-induced fatigue in mice, as reflected by rotarod test and exhaustive swimming test. Moreover, PHZ also effectively decreased the levels of blood urea nitrogen, creatine kinase and plasma lactic acid, increased the liver glycogen and skeletal muscle glycogen of fatigued mice, as evidenced by enzyme linked immunosorbent assay. PHZ balanced the redox status through reducing generation of reactive oxygen species, enhancing the activities of antioxidative enzymes. Furthermore, PHZ not only increased the ratio of Bcl2/Bax, but also decreased the level of cleaved-caspase 3. Notably, PHZ facilitated nuclear factor erythroid 2-related factor 2 (Nrf2) translocated from cytoplasm to nucleus, and up-regulated its downstream antioxidant response element including heme oxygenase-1 and NADPH quinone oxidoreductase-1. Intriguingly, PHZ directly bound to Nrf2, as evidenced by molecular docking, and the anti-fatigue effects of PHZ were almost abolished in Nrf2 deficient mice. In summary, our findings suggest that PHZ might be a natural occurring antioxidant with safety profile to relieve fatigue via targeting Nrf2 to inhibit apoptosis.


Assuntos
Fadiga Muscular/efeitos dos fármacos , Fator 2 Relacionado a NF-E2 , Estresse Oxidativo/efeitos dos fármacos , Florizina/farmacologia , Animais , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Chalconas/farmacologia , Camundongos , Simulação de Acoplamento Molecular , Fator 2 Relacionado a NF-E2/antagonistas & inibidores , Fator 2 Relacionado a NF-E2/metabolismo , Oxirredução/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
13.
J Agric Food Chem ; 70(1): 149-156, 2022 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-34939801

RESUMO

Plant pathogenic fungi are able to utilize the principal metabolites of their hosts, which is one reason pathogens can so seriously harm the plants, although the mechanisms behind this utilization are not always clear. Valsa mali var. mali is a pathogenic fungus specific to the plant genus Malus. The fungus can seriously endanger apple crops and has caused serious economic losses. Phlorizin (1), the principal component in the stems, roots, and leaves of Malus pumila and M. sieversii, was able to promote spore germination of Valsa mali var. mali (Vmm-30) significantly over 120-168 h in a non-nutritional suspension. Compared with the control, the concentrations of nine phenolic compounds (3-11) in the stems of M. pumila increased after inoculation with Vmm-30. Moreover, compounds 3, 4, and 9-11 were able to promote the germination of Vmm-30 spores over 24-36 h, which was a significantly shorter time than that of phlorizin. High-performance liquid chromatography with diode-array detection (HPLC-DAD) and ultraperformance liquid chromatography with tandem mass spectrometry (UPLC-MS/MS) analyses further suggested that compounds 2-11 were the degradation products of phlorizin (1) and are produced through carbon oxidation cracking, decarboxylation, and oxidation reactions. This suggests that the degradation of phlorizin is able to effectively promote the growth of Vmm-30. The Vmm-30 strain is therefore able to utilize the principal metabolite phlorizin to generate a series of degradation products, which further promote its germination and the infection of its host plants in the genus Malus.


Assuntos
Malus , Ascomicetos , Cromatografia Líquida , Mali , Florizina , Doenças das Plantas , Espectrometria de Massas em Tandem
14.
Eur J Pharmacol ; 913: 174645, 2021 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-34800467

RESUMO

Diabetes associated oxidative stress and impaired cholinergic neurotransmission causes cognitive deficits. Although phloridzin shows antioxidant- and insulin sensitizing-activities, its ameliorative potential in diabetes-induced memory dysfunction remains unexplored. In the present study, type 2 diabetes (T2D) was induced by streptozotocin (35 mg/kg, intraperitoneal) in rats on ad libitum high-fat diet. Diabetic animals were treated orally with phloridzin (10 and 20 mg/kg) for four weeks. Memory functions were evaluated by passive avoidance test (PAT) and novel object recognition (NOR) test. Brains of rats were subjected to biochemical analysis of glutathione (GSH), brain-derived neurotrophic factor (BDNF), malonaldehyde (MDA) and acetylcholinesterase (AChE). Role of cholinergic system in the effects of phloridzin was evaluated by scopolamine pre-treatment in behavioral studies. While diabetic rats showed a significant decrease in step through latency in PAT, and exploration time and discrimination index in NOR test; a substantial increase in all parameters was observed following phloridzin treatment. Phloridzin reversed abnormal levels of GSH, BDNF, MDA and AChE in the brain of diabetic animals. Moreover, in silico molecular docking study revealed that phloridzin acts as a potent agonist at M1 receptor as compared to acetylcholine. Viewed collectively, reversal of T2D-induced memory impairment by phloridzin might be attributed to upregulation of neurotrophic factors, reduced oxidative stress and increased cholinergic signaling in the brain. Therefore, phloridzin may be a promising molecule in the management of cognitive impairment comorbid with T2D.


Assuntos
Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Tipo 2/complicações , Transtornos da Memória/tratamento farmacológico , Florizina/farmacologia , Acetilcolina/agonistas , Acetilcolina/metabolismo , Animais , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Humanos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Memória/efeitos dos fármacos , Transtornos da Memória/diagnóstico , Transtornos da Memória/etiologia , Simulação de Acoplamento Molecular , Fatores de Crescimento Neural/agonistas , Fatores de Crescimento Neural/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Florizina/uso terapêutico , Ratos , Receptor Muscarínico M1/agonistas , Receptor Muscarínico M1/metabolismo , Receptor Muscarínico M1/ultraestrutura , Escopolamina/farmacologia , Estreptozocina/administração & dosagem , Estreptozocina/toxicidade , Transmissão Sináptica/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos
15.
J Pharmacol Sci ; 147(3): 245-250, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34507633

RESUMO

Sodium/glucose cotransporter 2 (SGLT2) is a renal low-affinity high-capacity sodium/glucose cotransporter expressed in the apical membrane of the early segment of proximal tubules. SGLT2 reabsorbs filtered glucose in the kidney, and its inhibitors represent a new class of oral medications used for type 2 diabetes mellitus, which act by increasing glucose and sodium excretion in urine, thereby reducing blood glucose levels. However, clinical trials showed marked improvement of renal outcomes, even in nondiabetic kidney diseases, although the underlying mechanism of this renoprotective effect is unclear. We showed that long-term excretion of salt by the kidneys, which predisposes to osmotic diuresis and water loss, induces a systemic body response for water conservation. The energy-intensive nature of water conservation leads to a reprioritization of systemic body energy metabolism. According to current data, use of SGLT2 inhibitors may result in similar reprioritization of energy metabolism to prevent dehydration. In this review article, we discuss the beneficial effects of SGLT2 inhibition from the perspective of energy metabolism and water conservation.


Assuntos
Água Corporal/metabolismo , Metabolismo Energético/efeitos dos fármacos , Rim/metabolismo , Florizina/farmacologia , Transportador 2 de Glucose-Sódio/metabolismo , Transportador 2 de Glucose-Sódio/fisiologia , Administração Oral , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Diurese , Glucose/metabolismo , Humanos , Hipoglicemiantes , Túbulos Renais Proximais/metabolismo , Malus/química , Osmose , Florizina/administração & dosagem , Fitoterapia , Sódio/metabolismo , Sódio/urina
16.
Ecotoxicol Environ Saf ; 225: 112723, 2021 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-34481354

RESUMO

Perennial tree soil inhibits the growth of replanting apples, but the mechanism that underlies this inhibition is poorly understood. A total of 57 perennial tree soils were selected for the collection of soil samples in the Bohai Bay in May 2018. The severity of apple replant disease (ARD) for each soil was determined by calculating the rate of inhibition of growth replanted apple trees. A high-throughput sequencing analysis of internal transcribed spacer (ITS) was used to determine the soil fungal community. A correlation analysis was used to determine the relationship between the rate of inhibition of apple growth and soil factors. The degree of inhibition of plant growth varied substantially among the 57 soil samples examined. Different perennial tree soils have varying degrees of ARD. There was no significant difference in the composition of fungal community at the phylum level, but the genus level differed substantially. The abundances of Fusarium and Mortierella species and the contents of phloridin in the soil and soil organic matter (SOM) were significantly correlated with ARD severity. Structural equation modeling also emphasized that the degree of occurrence of ARD was directly or indirectly affected by Fusarium, Mortierella, phloridin and SOM. A correlation analysis can only be used as an indicator, and further research is merited to reveal how soil parameters affect ARD.


Assuntos
Malus , Micobioma , Florizina , Solo , Microbiologia do Solo , Árvores
17.
J Food Biochem ; 45(11): e13956, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34590315

RESUMO

The effects of phloridzin (PHL), main component of Malus hupehensis (MH) tea leaves, on blood glucose (BG) and glucose-6-phosphatase (G-6-Pase) were investigated to provide a basis for finding a scheme of stabilizing BG. Glucose uptake of insulin resistant HepG2 cells was measured by glucose oxidase method. Glucose tolerance, fasting BG (FBG) and postprandial BG (PBG) were determined by BG test strips. The expression of G-6-Pase was detected by Western blot. The results showed that glucose uptake was enhanced and the expression of G-6-Pase was inhibited by PHL in insulin resistant HepG2 cells. Glucose tolerance was enhanced, FBG level was increased and PBG level was decreased by PHL in mice. The expression of G-6-Pase in the liver was enhanced under fasting state, and was inhibited by the low and medium dose under postprandial state. It indicated that PHL has a positive effect on stabilizing BG in mice, which is related to bidirectional regulation of G-6-Pase activity. PRACTICAL APPLICATIONS: Malus hupehensis, edible and medicinal plant, which has been proved by long-term application and experiments that it has a good effect on stabilizing blood glucose, preventing diabetes and adjuvant treatment. Its effect is closely related to its main component PHL. Thus, MH can be used as a dietary regulating drink for daily life to maintain blood glucose. Its main ingredient is PHL, which can be developed as a candidate drug for diabetes treatment.


Assuntos
Glicemia , Gluconeogênese , Animais , Glucose-6-Fosfatase/metabolismo , Insulina/metabolismo , Camundongos , Florizina/farmacologia
18.
Pharmacol Res Perspect ; 9(5): e00869, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34586752

RESUMO

Previously, we showed that sodium/glucose cotransporter 1 (SGLT1) participates in vascular cognitive impairment in small vessel disease. We hypothesized that SGLT1 inhibitors can improve the small vessel disease induced-vascular cognitive impairment. We examined the effects of mizagliflozin, a selective SGLT1 inhibitor, and phlorizin, a non-selective SGLT inhibitor, on vascular cognitive impairment in a mouse model of small vessel disease. Small vessel disease was created using a mouse model of asymmetric common carotid artery surgery (ACAS). Two and/or 4 weeks after ACAS, all experiments were performed. Cerebral blood flow (CBF) was decreased in ACAS compared with sham-operated mice. Phlorizin but not mizagliflozin reversed the decreased CBF of ACAS mice. Both mizagliflozin and phlorizin reversed the ACAS-induced decrease in the latency to fall in a wire hang test of ACAS mice. Moreover, they reversed the ACAS-induced longer escape latencies in the Morris water maze test of ACAS mice. ACAS increased SGLT1 and proinflammatory cytokine gene expressions in mouse brains and phlorizin but not mizagliflozin normalized all gene expressions in ACAS mice. Hematoxylin/eosin staining demonstrated that they inhibited pyknotic cell death in the ACAS mouse hippocampus. In PC12HS cells, IL-1ß increased SGLT1 expression and decreased survival rates of cells. Both mizagliflozin and phlorizin increased the survival rates of IL-1ß-treated PC12HS cells. These results suggest that mizagliflozin and phlorizin can improve vascular cognitive impairment through the inhibition of neural SGLT1 and phlorizin also does so through the improvement of CBF in a mouse model of small vessel disease.


Assuntos
Doenças de Pequenos Vasos Cerebrais/fisiopatologia , Circulação Cerebrovascular/efeitos dos fármacos , Cognição/efeitos dos fármacos , Disfunção Cognitiva/fisiopatologia , Glucosídeos/farmacologia , Hipocampo/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Pirazóis/farmacologia , Transportador 1 de Glucose-Sódio/antagonistas & inibidores , Animais , Artéria Carótida Primitiva/cirurgia , Doenças de Pequenos Vasos Cerebrais/patologia , Disfunção Cognitiva/patologia , Citocinas/efeitos dos fármacos , Citocinas/genética , Modelos Animais de Doenças , Hipocampo/patologia , Inflamação/genética , Camundongos , Teste do Labirinto Aquático de Morris , Neurônios/patologia , Florizina/farmacologia
19.
J Agric Food Chem ; 69(31): 8671-8683, 2021 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-34342231

RESUMO

We aimed to investigate whether phloridzin could alleviate nonalcoholic fatty liver disease (NAFLD) in mice, which was induced by feeding a high-fat diet (HFD). We initially analyzed the effect of phloridzin on alleviating HFD-induced NAFLD in C57BL/6J mice and oleic acid (OA)-stimulated human normal liver L-02 cells (L02). Then, we investigated the mechanism of phloridzin on the mTORC1/sterol-regulatory element-binding protein-1c (SREBP-1c) signaling pathway by siRNA analysis, qRT-PCR, flow cytometry, and western blot analysis in vivo and in vitro. The results revealed that phloridzin significantly inhibited the increase in body weight, alleviated abnormal lipid metabolism, and decreased lipid biosynthesis and insulin resistance. Moreover, phloridzin augmented the number of CD8+CD122+PD-1+ Tregs and CD4+FoxP3+ Tregs in HFD-fed C57BL/6J mice and HFD-fed aP2-SREBF1c mice and downregulated the mTORC1/SREBP-1c signaling pathway-related protein expressions in vivo and in vitro. Furthermore, phloridzin reduced the expression of SREBP-1c in SREBP-1c-RNAi-lentivirus-transfected L02 cells and reversed the SREBP-1c expression in HFD-fed aP2-SREBF1c transgenic mice. Phloridzin ameliorates lipid accumulation and insulin resistance via inhibiting the mTORC1/SREBP-1c pathways. These results indicated that phloridzin may actively ameliorate NAFLD.


Assuntos
Hepatopatia Gordurosa não Alcoólica , Animais , Dieta Hiperlipídica/efeitos adversos , Humanos , Metabolismo dos Lipídeos , Lipídeos , Fígado/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/genética , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/metabolismo , Florizina , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo
20.
Molecules ; 26(13)2021 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-34206687

RESUMO

Apple trees (Malus domestica Borgh) are a rich source of dihydrochalcones, phenolic acids and flavonoids. Considering the increasing demand for these phytochemicals with health-benefitting properties, the objective of this study was to evaluate the profile of the main bioactive compounds-phloridzin, phloretin, chlorogenic acid and rutin-in apple tree bark, leaves, flower buds and twigs. The variety in the phenolic profiles of four apple tree cultivars was monitored during the vegetation period from March to September using chromatography analysis. Phloridzin, the major glycoside of interest, reached the highest values in the bark of all the tested cultivars in May (up to 91.7 ± 4.4 mg g-1 of the dried weight (DW), cv. 'Opal'). In the leaves, the highest levels of phloridzin were found in cv. 'Opal' in May (82.5 ± 22.0 mg g-1 of DW); in twigs, the highest levels were found in cv. 'Rozela' in September (52.4 ± 12.1 mg g-1 of DW). In the flower buds, the content of phloridzin was similar to that in the twigs. Aglycone phloretin was found only in the leaves in relatively low concentrations (max. value 2.8 ± 1.4 mg g-1 of DW). The highest values of rutin were found in the leaves of all the tested cultivars (10.5 ± 2.9 mg g-1 of DW, cv. 'Opal' in September); the concentrations in the bark and twigs were much lower. The highest content of chlorogenic acid was found in flower buds (3.3 ± 1.0 mg g-1 of DW, cv. 'Rozela'). Whole apple fruits harvested in September were rich in chlorogenic acid and phloridzin. The statistical evaluation by Scheffe's test confirmed the significant difference of cv. 'Rozela' from the other tested cultivars. In conclusion, apple tree bark, twigs, and leaves were found to be important renewable resources of bioactive phenolics, especially phloridzin and rutin. The simple availability of waste plant material can therefore be used as a rich source of phenolic compounds for cosmetics, nutraceuticals, and food supplement preparation.


Assuntos
Frutas/metabolismo , Malus/metabolismo , Florizina/metabolismo , Casca de Planta/metabolismo , Folhas de Planta/metabolismo , Rutina/metabolismo
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