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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.bNEWamp; NOTEWORTHY/bGlucose 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.

SGLTs are sodium glucose transporters found on the luminal membrane of the proximal tubule, where they reabsorb some 180 grams (one mole) of glucose from the glomerular filtrate each day. The natural glucoside phlorizin completely blocks glucose reabsorption. Oral SGLT2 inhibitors are rapidly absorbed into the blood stream where they remain in in the circulation for hours. On glomerular filtration, they bind specifically to SGLT2 in the luminal membrane of the early proximal tubule to reduce glucose reabsorption by 50-60%. Because of glucose excretion, these drugs lower plasma glucose and glycosylated hemoglobin levels in patients with type 2 diabetes mellitus. The drugs also protect against heart and renal failure. The aim of this review is to summarize what is currently known about the physiology of renal SGLTs and the pharmacology of SGLT drugs.

Bovine viral diarrhea virus (BVDV) is one of the most serious pathogens affecting the cattle industry worldwide. Phlorizin, a kind of flavonoids extracted from apple tree roots, leaves, and fruits, has a variety of biological functions and has been widely used as a herbal supplement and food additive. Here, BALB/c mouse and Madin-Darby bovine kidney (MDBK) cells were used to explore the effect and mechanism of phlorizin against BVDV infection. The results showed that phlorizin significantly inhibited CP BVDV replication and improved the histopathological changes of duodenum and spleen in mice. In vitro studies also confirmed the activity of phlorizin against CP BVDV. Exploration on its potential mechanism suggested that phlorizin inhibited CP BVDV-induced beclin-1 level and the conversion rate of LC3B-I to LC3B-II. Interestingly, although phlorizin also showed a protective effect on MDBK cells, which were treated with 3-methyladenine A (3-MA), the effect was significantly weakened. Furthermore, phlorizin suppressed the stage of BVDV replication but showed no effect on stages of attachment and internalization. Our data further indicated that phlorizin promoted IFN-α and IFN-β levels, decreased IL-1β and IL-6 expression, and regulated RIG-I, MDA5, TLR3, and NLRP3 levels. Similar to CP BVDV results, in vivo and in vitro, phlorizin inhibited NCP BVDV (NY-1 and YNJG2020 strains) infection. These results were the first to be discovered that phlorizin might be used as a new dietary strategy for controlling BVDV infection.

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.

In this current study, Vitex agnus-castus seed ethanol extracts were analyzed for their phytochemical component content, anticholinergic and antioxidant activities, and antibacterial properties. The phenolic compound composition of these seeds was determined by using LC/MS/MS. Antioxidant activity of the seeds was examined by the DPPH, ABTS, Fe3+–Fe2+ reducing, and CUPRAC. Also, the anticholinergic activity was measured by the inhibition of acetylcholinesterase (AChE). The antibacterial activity was performed by disc diffusion and minimum inhibitory concentration methods. The main phenolic compound was vanillic acid (22812.05 μg/L) and followed by luteolin, fumaric acid, quercetin, caffeic acid, 4-hydroxybenzoic acid, salicylic acid, kaempferol, butein, ellagic acid, resveratrol, catechin hydrate, phloridzin dehydrate, naringenin, respectively. The DPPH free radical scavenging value of ethanol extract of plant seeds was 9.41 %, while the ABTS radical scavenging activity was determined as 12.66 %. The ethanol extract of the seeds exhibited antibacterial activity on Escherichia coli, Staphylococcus aureus, and Salmonella Typhimurium, differently. S. aureus was found to be more susceptible to the extract than other bacteria. Also, the inhibition effect of seed ethanolic extract on the AChE with IC50 values were 36.34±5.6 μg/mL. From the results, V. agnus-castus seed can be suggested as a promising natural antioxidant and antibacterial candidate for the preservation of foods.

The protective effect of phloridzin (PHL) and its potential mechanism were examined in mice with liver injury induced by isoniazid (INH) and rifampicin (RFP). The mice were randomly divided into normal control group, model group, low (80 mg/kg), medium (160 mg/kg) and high (320 mg/kg) phloridzin-treated groups. After 28 d treatment, blood and liver tissue were collected and analysed. The results revealed that PHL regulated liver function related indicators and reduced the pathological tissue damage, indicating that PHL significantly alleviated the liver injury. Furthermore, the level of CYP450 enzyme, the expression of CYP3A4, CYP2E1, heme oxygenase-1 (HO-1) and nuclear factor erythroid 2-related factor 2 (Nrf2) mRNA and protein were inhibited by PHL. These results indicated that PHL exerts a protecting effect against liver injury induced by combination of RFP and INH. The potential mechanisms may be concerned with the activation of Nrf2/HO-1 signaling pathway containing its key antioxidant enzymes and regulation of CYP3A4 and CYP2E1.

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-β-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.

The purpose of this study was to identify and characterize the chemical composition present in aerial parts of Prosopis farcta in petroleum ether and hydro-methanol extracts through LC-PDA-ESI-MS/MS and GC-MS techniques respectively for the first time. The plant samples were collected from northeast of Iran during maturity stage. LC-MS/MS profile revealed 47 phenolic compounds in hydro-methanol extracts, including phenolic acids, flavonoids, and their glycoside derivatives. Flavonoid-O-glycosides (19), flavonoid aglycones (11), phenolic acid derivatives (9), flavonoid-C-glycosides (4), and flavonoid-O, C-glycosides (1) were dominant class phenolics in all studied parts. The extracts contained a significant amount of major compounds, including gallic and vanillic acids, luteolin, apigenin, phloridzin, and vicenin-2. Also, GC-MS analysis of petroleum ether extracts showed that fatty acids, organic acids, steroids, terpenoids, and hydrocarbons were the group of major compounds in all parts. Twenty-four, 27, and 25 components were identified, which represent 99.2%, 96.1%, and 99.4% of the total composition in fruits, leaves, and stems, respectively. These results suggested that other genetic resources of P. farcta can be further explored to screen genotypes with high bioactive compounds and purification of phytochemical compounds, which are valuable to produce, expand, and develop natural antioxidants in production of bio-medicine and food.

Overexpression of glucose transporters (GLUTs) in colorectal cancer cells is associated with 5-fluorouracil (1, 5-FU) resistance and poor clinical outcomes. We designed and synthesized a novel GLUT-targeting drug conjugate, triggered by glutathione in the tumor microenvironment, that releases 5-FU and GLUTs inhibitor (phlorizin (2) and phloretin (3)). Using an orthotopic colorectal cancer mice model, we showed that the conjugate exhibited better antitumor efficacy than 5-FU, with much lower exposure of 5-FU during treatment and without significant side effects. Our study establishes a GLUT-targeting theranostic incorporating a disulfide linker between the targeting module and cytotoxic payload as a potential antitumor therapy.

Aim: The study has been commenced to discover the potential of sodium dependent glucose co-transporters (SGLT) in neuroprotective mechanism of ischemic postconditioning (iPoCo) in diabetic and non-diabetic mice. Methods: Cerebral ischemic injury in mice was induced by bilateral carotid artery occlusion (BCAO) for 12 min followed by reperfusion for 24 hr. For iPoCo, three episodes of carotid artery reperfusion and occlusion of 10 sec each were instituted immediately after BCAO, followed by 24 hr reperfusion. Learning and memory were evaluated using the Morris water maze test. Motor coordination was assessed using rotarod test, inclined beam walking test, neurological severity score (NSS), and lateral push response. Glutathione and Thiobarbituric acid reactive species level was quantified to evaluate the oxidative stress; the cholinergic activity of the brain was estimated in terms of acetylcholinestrase activity, and the levels of myeloperoxidase were measured as inflammation marker. Cerebral infarct size was evaluated using triphenyltetrazolium chloride staining. Fasting blood glucose levels of animals were taken before and 6 hr after the surgical procedure. Results: BCAO resulted in impairment of memory and motor coordination and biochemical alterations along with a marked rise in cerebral infarct size and NSS. iPoCo diminished the deadly effect of BCAO in non-diabetic mice; however, it failed to abolish the deleterious effects of ischemia- reperfusion injury in diabetic mice. Pretreatment of Phlorizin (SGLT-inhibitor) potentiated the neuroprotective effects of iPoCo in non-diabetics and restored the protective effect of iPoCo in diabetic mice. Conclusion: It may be concluded that the neuroprotective effect of iPoCo is abolished in diabetic mice, and SGLT plays an important role in neuroprotection.

The microbiota plays important roles for polyphenols exerting bioactivity, which needs support to calculate the accumulated polyphenols in the gastrointestinal tract. Taking phlorizin as an example, fecal excretion kinetics was suggested to be ingenious for achieving it. No phlorizin was excreted with feces, implying almost 100 % total availability. Combined with its 0-5 % bioavailability, more than 95 % of phlorizin quantitatively accumulated in the gastrointestinal tract. Instead, trace phloretin was excreted, and the acquired kinetic parameters were influenced by physical conditions and dietary patterns. Dosage-total-availability curves indicated different relationships among normal-diet and obese mice, resulting in critical dosages of ∼ 159 and ∼ 196 mg/kg when taking 95 % total availability by phloretin. The dietary matrix affects the intake, digestion, metabolism and absorption of polyphenols, and may alter its total availability, and fecal excretion kinetics can provide further support for polyphenol dietary supplements targeting microbiota.

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.

Mediating glucose absorption in the small intestine and renal clearance, sodium glucose cotransporters (SGLTs) have emerged as an attractive therapeutic target in diabetic patients. A substantial fraction of patients, however, only achieve inadequate glycemic control. Thus, we aimed to assess the potential of the SGLT-targeting PET radiotracer alpha-methyl-4-deoxy-4-[We investigated healthy rats using a dedicated small animal PET system. Dynamic imaging was conducted after administration of the reference radiotracer 2-deoxy-2-[Serving as reference, intestinal administration of [As a noninvasive read-out of the concurrent SGLT expression in both the digestive tract and the renal cortex, [

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.

Flavonoids are known to undergo phase II metabolism and produce metabolites with similar or stronger biological effects compared to the parent flavonoids. However, the limited cellular uptake and bioavailability restrict their clinical use. We synthesized phloridzin docosahexaenoate (PZ-DHA), a novel fatty acid ester of polyphenol, through an acylation reaction with the aim of increasing the cellular availability and stability of the parent biomolecules, phloridzin (PZ) and docosahexaenoic acid (DHA). Here, we report metabolites and pharmacokinetic parameters of PZ-DHA, determined using ultra-high-performance liquid chromatography-electrospray ionization tandem mass spectrometry. PZ-DHA was taken-up by human (MDA-MB-231, MDA-MB-468, and MCF-7) and mouse (4T1) mammary carcinoma and human non-malignant mammary epithelial cells (MCF-10A) in cellular uptake assays. Our results suggested that the acylation improves the cellular uptake of PZ and stability of DHA within cells. In mouse hepatic microsomal assays, two major glucuronides of PZ-DHA, PZ-DHA-4-O-glucuronide and PZ-DHA-4′-O-glucuronide (MW = 923.02 g/mol), were detected. One tri-methylated- (4,4′,6′-O-trimethyl-PZ-DHA) (MW = 788.88 g/mol) and one di-sulphated- (PZ-DHA-4,4′-O-disulphide) PZ-DHA metabolite (MW = 906.20 g/mol) were also identified. Intraperitoneal injections of PZ-DHA (100 mg/kg) into Balb/c female mice was rapidly absorbed with a serum Cmax and Tmax of 23.7 µM and 60 min, respectively, and rapidly eliminated (t1/2 = 28.7 min). PZ-DHA and its metabolites are readily distributed throughout the body (Vd = 57 mL) into many organs. We identified in vitro and in vivo metabolites of PZ-DHA, which could be tested for potential use to treat diseases such as cancer in multiple organ systems.

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.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 (ICThe 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.

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.

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.

Tyrosinase-catalyzed synthesis of soy 7S/11S-phlorizin conjugates was performed, and the reaction sites, conformation alterations and functional properties of complexes were evaluated using proteomic, in combination with multispectral technologies. Phlorizin was conjugated to 7S/11S primarily via residues of Lys, Cys, His and Arg residues. The phlorizin binding equivalents and decreased contents of free and total sulfhydryl groups and free amino groups confirmed the covalent interaction in the 7S/11S-phlorizin complexes. Conjugation with phlorizin promoted the conversion of α-helix to β-sheet and β-turn, with simultaneous transformation of the microenvironments around Trp and Tyr residues to hydrophilic and hydrophobic microenvironments, respectively, and lowering of the surface hydrophobicity of 7S/11S. The DPPH and ABTS radical scavenging abilities and α-glucosidase inhibitory activities of 7S/11S were increased by three-, two- and three-fold after the covalent binding of phlorizin. The study provided an ideal tyrosinase-catalyzed approach to fabricate custom-tailored nutritional soy protein-polyphenol products.

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.

Phloridzin is a lead compound of the prestigious antidiabetic gliflozins. The present study found that phloridzin highly accumulated in Malus rockii Rehder. The content of phloridzin in M. rockii was the highest among wild plants, with the percentage of 15.54% in the dry leaves. The structure of phloridzin was revised by proton exchange experiments and extensive 2D NMR spectra. Phloridzin exhibited significant hypolipidemic activity in golden Syrian hamsters maybe by increasing the expression of CYP7A1, at the doses of 50 mg/kg and 200 mg/kg. The total performance of anti-hyperlipidemic effect of phloridzin may be superior to that of lovastatin, though lovastatin was more active than phloridzin. In addition, phloridzin exhibited moderate antimalarial activity with inhibition ratio of 31.3 ± 10.9% at a dose of 25 mg/kg/day, and showed moderate analgesic activity with 28.0% inhibition at a dose of 50 mg/kg.

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-1β 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.

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-1β/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.

Nephrolithiasis is a common renal disease with no effective medication. Sodium-glucose cotransporter-2 (SGLT2) inhibitors, an anti-diabetic agent, have diuretic and anti-inflammatory properties and could prevent nephrolithiasis. Here, we investigated the potential of SGLT2 inhibition against nephrolithiasis using large-scale epidemiological data, animal models, and cell culture experiments.This study included the data of diabetic patients (n = 1,538,198) available in the Japanese administrative database and divided them according to SGLT2 inhibitor prescription status. For animal experiments, renal calcium oxalate stones were induced by ethylene glycol in Sprague-Dawley rats, and phlorizin, an SGLT1/2 inhibitor, was used for the treatment. The effects of SGLT2-specific inhibition for renal stone formation were assessed in SGLT2-deficient mice and a human proximal tubular cell line, HK-2.Nephrolithiasis prevalence in diabetic men was significantly lower in the SGLT2 inhibitor prescription group than in the non-SGLT2 inhibitor prescription group. Phlorizin attenuated renal stone formation and downregulated the kidney injury molecule 1 (Kim1) and osteopontin (Opn) expression in rats, with unchanged water intake and urine volume. It suppressed inflammation and macrophage marker expression, suggesting the role of the SGLT2 inhibitor in reducing inflammation. SGLT2-deficient mice were resistant to glyoxylic acid-induced calcium oxalate stone formation with reduced Opn expression and renal damages. High glucose-induced upregulation of OPN and CD44 and cell surface adhesion of calcium oxalate reduced upon SGLT2-silencing in HK-2 cells.Overall, our findings identified that SGLT2 inhibition prevents renal stone formation and may be a promising therapeutic approach against nephrolithiasis.

The mechanisms underlying the interaction between different dietary flavonoids and soybean β-conglycinin (7S) and glycinin (11S) were comparatively investigated, and the alterations in conformation and function of the complexes were further evaluated. Among the 23 flavonoids studied, 3 flavonoids with glycosides with the top three ranked T Scores in molecular docking analysis-phlorizin, luteoloside, and vitexin-4'-O-glucoside-with the highest binding affinity to 7S and 11S and quenched their intrinsic fluorescence in a static manner. The binding interactions of these flavonoids to 7S and 11S were structure dependent. Hydrophobic forces played important roles in interactions between 7S and both luteoloside and vitexin-4'-O-glucoside, whereas the binding of phlorizin to 7S, and of the three flavonoids to 11S, was driven by hydrogen bonding and van der Waals forces. The binding of these flavonoids interfered with the microenvironment around tyrosine and tryptophan, thereby altering the secondary structures of 7S and 11S. The binding of the three flavonoids enhanced solubility, emulsifying properties, thermal stability, and antioxidant capacity of 7S and 11S. The use of flavonoids could facilitate the design of soybean protein-based products with desirable functional properties.

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.

A blood glucose level lowering effect is postulated for polyphenols (PPs), which is in part attributed to the inhibition of α-amylase. To estimate structure-effect relationships, chlorogenic acid (CA), phlorizin (PHL), epigallocatechin gallate (EGCG), epicatechin (EC), and malvidin-3-glucoside (Mlv-3-glc) were used as inhibitors in an enzyme assay, on the basis of the conversion of GalG

In the present study, a systematic validated method was developed for the determination of two key dietary dihydrochalcones (DHC) viz. phloridzin (PZ) and phloretin (PT) in the leaves of Sikkim crabapple (Malus sikkimensis) using HPLC-Photo Diode Array (PDA). Chromatographic separation was optimized on a C18 column using a gradient elution of water/acetonitrile with the flow rate of 1.0 mL/min at 25°C at 280 nm. Sample preparation approach is rapid and energy efficient, and it requires no pre-concentration before analysis. Validation showed a good analytical performance in terms of specificity, linearity (r2 > 0.999), precision (% RSD

Background Recent large-scale clinical trials have shown that SGLT2-inhibitors reduce cardiovascular events in diabetic patients. However, the regulation and functional role of cardiac sodium–glucose cotransporter (SGLT1 is the dominant isoform) compared with those of other glucose transporters (insulin-dependent GLUT4 is the major isoform) remain incompletely understood. Given that glucose is an important preferential substrate for myocardial energy metabolism under conditions of ischemia–reperfusion injury (IRI), we hypothesized that SGLT1 contributes to cardioprotection during the acute phase of IRI via enhanced glucose transport, particularly in insulin-resistant phenotypes. Methods and results The hearts from mice fed a high-fat diet (HFD) for 12 weeks or a normal-fat diet (NFD) were perfused with either the non-selective SGLT-inhibitor phlorizin or selective SGLT2-inhibitors (tofogliflozin, ipragliflozin, canagliflozin) during IRI using Langendorff model. After ischemia–reperfusion, HFD impaired left ventricular developed pressure (LVDP) recovery compared with the findings in NFD. Although phlorizin-perfusion impaired LVDP recovery in NFD, a further impaired LVDP recovery and a dramatically increased infarct size were observed in HFD with phlorizin-perfusion. Meanwhile, none of the SGLT2-inhibitors significantly affected cardiac function or myocardial injury after ischemia–reperfusion under either diet condition. The plasma membrane expression of GLUT4 was significantly increased after IRI in NFD but was substantially attenuated in HFD, the latter of which was associated with a significant reduction in myocardial glucose uptake. In contrast, SGLT1 expression at the plasma membrane remained constant during IRI, regardless of the diet condition, whereas SGLT2 was not detected in the hearts of any mice. Of note, phlorizin considerably reduced myocardial glucose uptake after IRI, particularly in HFD. Conclusions Cardiac SGLT1 but not SGLT2 plays a compensatory protective role during the acute phase of IRI via enhanced glucose uptake, particularly under insulin-resistant conditions, in which IRI-induced GLUT4 upregulation is compromised. Electronic supplementary material The online version of this article (10.1186/s12933-019-0889-y) contains supplementary material, which is available to authorized users.

A new series of glucose-conjugated Pt(IV) complexes that target tumor-specific glucose transporters (GLUTs) was designed, synthesized, and evaluated for their anticancer activities. All six compounds, namely, A1-A6, exhibited increased cytotoxicity that were almost six fold higher than that of oxaliplatin to MCF-7 cells. These Pt(IV) complexes can be reduced to release Pt(II) complexes and cause the death of tumor cells. Simultaneously, the glycosylated Pt(IV) complexes (30.21–91.33 μM) showed lower cytotoxicity that normal LO2 cells compared with cisplatin (5.25 μM) and oxaliplatin (8.34 μM). The intervention of phlorizin as a GLUTs inhibitor increased the IC50 value of the glycosylated Pt(IV) complexes, thereby indicating the potential GLUT transportability. The introduction of glucose moiety to Pt(IV) complexes can effectively enhance the Pt cellular uptake and DNA platination. Results suggested glucose-conjugated Pt(IV) complexes had potential for further study as new anticancer agents.

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.