Journal articles: 'Phlorizin'

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GIUDICELLI, Jean, Marie-France BERTRAND, Stephane BILSKI, T. Than TRAN, and Jean-Claude POIREE. "Effect of cross-linkers on the structure and function of pig-renal sodium–glucose cotransporters after papain treatment." Biochemical Journal 330, no. 2 (March 1, 1998): 733–36. http://dx.doi.org/10.1042/bj3300733.

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Kidney brush-border membranes contain two sodium-dependent glucose transporters, one with low and one with high affinity for phlorizin, the specific inhibitor of these transporters. Using Scatchard analysis of phlorizin binding and Western blotting with specific antibodies against these transporters, we demonstrate in this study that although both transporters were proteolysed by papain treatment, only the high-affinity phlorizin-binding sites were decreased. Papain treatment followed by cross-linking with homobifunctional disuccinimidyl tartarate restored only the structure of the low-affinity phlorizin-binding protein (approx. molecular mass 70 kDa) without modifying the phlorizin-binding sites. When disuccinimidyl tartarate was replaced with dithiobis(succinimidyl acetate), another homobifunctional cross-linker with a higher spacer arm, the low- and high-affinity sites were both restored, with reappearance of two phlorizin-binding proteins with approx. molecular masses of 70 and 120 kDa. We conclude that high-affinity phlorizin-binding sites depend on the presence of the heterodimeric 120 kDa protein.

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Ehrenkranz, Joel R. L., Norman G. Lewis, C. Ronald Kahn, and Jesse Roth. "Phlorizin: a review." Diabetes/Metabolism Research and Reviews 21, no. 1 (January 2005): 31–38. http://dx.doi.org/10.1002/dmrr.532.

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Holtenius, Kjell, and Paul Holtenius. "Effects of peroral alanine administration in lactating ewes with decreased availability of glucose." British Journal of Nutrition 78, no. 5 (November 1997): 805–13. http://dx.doi.org/10.1079/bjn19970196.

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The metabolic effects of a phlorizin-induced drainage of glucose were studied in six lactating ewes with or without peroral alanine drenches in a study of crossover design. Phlorizin gave rise to a small, but significant, elevation of plasma β-hydroxybutyrate. The plasma level of alanine decreased by about 30 % due to the phlorizin injections and alanine was negatively correlated to β-hydroxybutyrate. The plasma level of free fatty acids increased due to phlorizin. Plasma insulin and glucose concentrations were not significantly affected by phlorizin while glucagon level showed a small but significant increase. Peroral alanine drenches to phlorizin-treated ewes gave rise to a transitory elevation of alanine in plasma. The plasma level of free fatty acids was about 40 % lower in phlorizin-treated ewes receiving alanine and β-hydroxybutyrate tended to be lower (P < 0.08). We suggest that β-hydroxybutyrate, apart from its function as an oxidative fuel, might play an important role by limiting glucose oxidation and protein degradation in skeletal muscles during periods of negative energy balance in ruminants. Furthermore, it is suggested that alanine supplementation decreases lipolysis and ketogenesis in lactating ewes.

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Nguyen, Ngoc Anh, Ngoc Tan Cao, Thi Huong Ha Nguyen, Jung-Hwan Ji, Gun Su Cha, Hyung-Sik Kang, and Chul-Ho Yun. "Enzymatic Production of 3-OH Phlorizin, a Possible Bioactive Polyphenol from Apples, by Bacillus megaterium CYP102A1 via Regioselective Hydroxylation." Antioxidants 10, no. 8 (August 23, 2021): 1327. http://dx.doi.org/10.3390/antiox10081327.

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Phlorizin is the most abundant glucoside of phloretin from the apple tree and its products. Phlorizin and its aglycone phloretin are currently considered health-beneficial polyphenols from apples useful in treating hyperglycemia and obesity. Recently, we showed that phloretin could be regioselectively hydroxylated to make 3-OH phloretin by Bacillus megaterium CYP102A1 and human P450 enzymes. The 3-OH phloretin has a potent inhibitory effect on differentiating 3T3-L1 preadipocytes into adipocytes and lipid accumulation. The glucoside of 3-OH phloretin would be a promising agent with increased bioavailability and water solubility compared with its aglycone. However, procedures to make 3-OH phlorizin, a glucoside of 3-OH phloretin, using chemical methods, are not currently available. Here, a biocatalytic strategy for the efficient synthesis of a possibly valuable hydroxylated product, 3-OH phlorizin, was developed via CYP102A1-catalyzed regioselective hydroxylation. The production of 3-OH phlorizin by CYP102A1 was confirmed by HPLC and LC–MS spectroscopy in addition to enzymatic removal of its glucose moiety for comparison to 3-OH phloretin. Taken together, in this study, we found a panel of mutants from B. megaterium CYP102A1 could catalyze regioselective hydroxylation of phlorizin to produce 3-OH phlorizin, a catechol product.

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Dinda, P. K., and I. T. Beck. "Phlorizin increases the permeability of intestinal mucosal membrane to sodium." Canadian Journal of Physiology and Pharmacology 65, no. 4 (April 1, 1987): 579–86. http://dx.doi.org/10.1139/y87-098.

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We reported previously that when jejunal transmural glucose transport was inhibited by phlorizin the ratio of Na:giucose transport increased from 2.0:1 (in controls) to 3.3:1. To elucidate the mechanism of this increased ratio of Na:glucose transport, in the present study we have investigated the effect of phlorizin on Na uptake by brush border membrane vesicles and by everted sacs of hamster jejunum. In experiments on membrane vesicles the following observations were made. The time course of Na uptake showed that the control vesicles were in complete equilibrium with a Na-containing (100 mM) medium between 30 and 90 min incubation. In these periods of incubation, the vesicles incubated with phlorizin presumably also equilibrated with the medium, but lost their intravesicular Na during Millipore filtration and washing, and consequently the residual Na content was lower than that of controls. This effect of phlorizin was concentration dependent, and appeared to be unrelated to Na-coupled glucose transport, because it was also observed in the absence of glucose. This loss of Na during Millipore filtration and washing was also observed (i) when vesicles were equilibrated in a Na-containing solution in the absence of phlorizin and then exposed to a similar solution containing phlorizin, or (ii) when vesicles were equilibrated in a Na-containing solution in the presence of phlorizin and then washed repeatedly following Millipore filtration. Preincubation of vesicles for 10 min in a Na- and glucose-free solution containing phlorizin followed by incubation for 30–90 s in solutions containing 1 mM glucose and various concentrations of Na (from 10 to 100 mM) caused an increase in Na uptake from all concentrations of Na. After similar preincubation, when jejunal everted sacs were incubated for 15 s in a Na- and glucose-containing medium, Na uptake by the sacs increased. These findings suggest that phlorizin causes an increase in permeability of mucosal membrane of the enterocyte to Na. This may cause a rapid dissipation of Na gradient and an increase in the ratio of Na:glucose transport. The dissipation of Na gradient may be an additional mechanism for phlorizin-induced inhibition of intestinal sugar transport.

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Zhang, Yantong, Limei Lin, Yuehong Long, Hongyu Guo, Zhuo Wang, Minghui Cui, Jian Huang, and Zhaobin Xing. "Comprehensive Transcriptome Analysis Revealed the Effects of the Light Quality, Light Intensity, and Photoperiod on Phlorizin Accumulation in Lithocarpus polystachyus Rehd." Forests 10, no. 11 (November 7, 2019): 995. http://dx.doi.org/10.3390/f10110995.

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Lithocarpus polystachyus Rehd. is an important medicinal plant species grown in southern China, with phlorizin as its main active substance. The effects of light conditions on phlorizin biosynthesis in L. polystachyus remain unclear. Thus, we analyzed the transcriptomes of L. polystachyus plants cultivated under diverse light qualities, light intensities, and photoperiods. The light treatments resulted in 5977–8027 differentially expressed genes (DEGs), which were functionally annotated based on the gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases. Genes encoding transcription factors from 89 families were differentially expressed after the light treatments, implying these transcription factors are photoresponsive. Phenylalanine ammonia lyase (PAL) and 4-coumarate-CoA ligase (4CL) are the key enzymes for the accumulation of phlorizin. The transcription levels of PAL2, PAL, 4CL1 (DN121614), 4CLL7, and 4CL1 (DN102161) were positively correlated with phlorizin accumulation, suggesting that these genes are important for phlorizin biosynthesis. An ultra-high-performance liquid chromatography method was used to quantify the phlorizin content. Phlorizin accumulated in response to the green light treatment and following appropriate decreases in the light intensity or appropriate increases in the duration of the light exposure. The green light, 2000 lx, and 3000 lx treatments increased the PAL activity of L. polystachyus, but the regulatory effects of the light intensity treatments on PAL activity were relatively weak. This study represents the first comprehensive analysis of the light-induced transcriptome of L. polystachyus. The study results may form the basis of future studies aimed at elucidating the molecular mechanism underlying phlorizin biosynthesis in L. polystachyus. Moreover, this study may be relevant for clarifying the regulatory effects of light on the abundance of bioactive components in medicinal plants.

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Einhorn, Todd C., Cecil Stushnoff, Ann E. McSay, Phil L. Forsline, Sam Cox, Joel R. L. Ehrenkranz, and Loretta Sandoval. "(18) Biodiversity of the Flavonoid Phlorizin in a Subset of the USDA Apple Germplasm Core Collection." HortScience 40, no. 4 (July 2005): 1067D—1067. http://dx.doi.org/10.21273/hortsci.40.4.1067d.

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Phlorizin is known for its role in reducing glucotoxicity and has a long history of use in diabetes research. In addition, its contribution to the pool of total phenolics adds to the overall health benefits attributed to fruit. Phlorizin is limited to Rosaceae family plants, of which apple comprises its current commercial source; however, limited information exists regarding its biodiversity among apple taxa. A subset of 22 taxa from a core collection of apple accessions representative of the global genetic diversity of apple was used to investigate the biodiversity of phlorizin present in apple shoots and in fruit relative to total phenolic content and free radical scavenging capacity. Fruit and shoots were harvested from the USDA Plant Genetic Resources Unit in Geneva, N.Y. Validation and quantification of phlorizin was conducted using a rigorous high-pressure liquid chromatography (HPLC) procedure. Total phenolics in fruit, assayed using a Folin-Ciocalteu method and expressed as gallic acid equivalents, ranged from 227 to 7181 mg·L-1 and were strongly related to 2,2' azinobis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) antioxidant capacity for the core collection (r= 0.778). On a molar basis, phlorizin had lower antioxidant capacity than other major phenolic compounds present in apple fruit, but was more effective than ascorbic acid. Phlorizin yield in dormant apple shoots, expressed as percent weight, ranged from 0.9% to 5.5%. A rapid, 96 well micro-plate spectrophotometric assay was also developed to aid in the screening of multiple samples for selection of high phlorizin yielding apple taxa. Spectrophotometry overestimated phlorizin content as expected, but the calibration curve between HPLC and spectrophotometry was acceptable, r2 = 0.88.

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Cai, Qian, Baoying Li, Fei Yu, Weida Lu, Zhen Zhang, Mei Yin, and Haiqing Gao. "Investigation of the Protective Effects of Phlorizin on Diabetic Cardiomyopathy indb/dbMice by Quantitative Proteomics." Journal of Diabetes Research 2013 (2013): 1–9. http://dx.doi.org/10.1155/2013/263845.

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Patients with diabetes often develop hypertension and atherosclerosis leading to cardiovascular disease. However, some diabetic patients develop heart failure without hypertension and coronary artery disease, a process termed diabetic cardiomyopathy. Phlorizin has been reported to be effective as an antioxidant in treating diabetes mellitus, but little is known about its cardioprotective effects on diabetic cardiomyopathy. In this study, we investigated the role of phlorizin in preventing diabetic cardiomyopathy indb/dbmice. We found that phlorizin significantly decreased body weight gain and the levels of serum fasting blood glucose (FBG), triglycerides (TG), total cholesterol (TC), and advanced glycation end products (AGEs). Morphologic observations showed that normal myocardial structure was better preserved after phlorizin treatment. Using isobaric tag for relative and absolute quantitation (iTRAQ) proteomics, we identified differentially expressed proteins involved in cardiac lipid metabolism, mitochondrial function, and cardiomyopathy, suggesting that phlorizin may prevent the development of diabetic cardiomyopathy by regulating the expression of key proteins in these processes. We used ingenuity pathway analysis (IPA) to generate an interaction network to map the pathways containing these proteins. Our findings provide important information about the mechanism of diabetic cardiomyopathy and also suggest that phlorizin may be a novel therapeutic approach for the treatment of diabetic cardiomyopathy.

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Kemp, P. J., and C. A. Boyd. "Pathways for glucose transport in type II pneumocytes freshly isolated from adult guinea pig lung." American Journal of Physiology-Lung Cellular and Molecular Physiology 263, no. 5 (November 1, 1992): L612—L616. http://dx.doi.org/10.1152/ajplung.1992.263.5.l612.

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Previous in vivo studies of sugar transport across the mature pulmonary epithelium have provided evidence for the existence of a specific phlorizin-inhibitable, sodium-dependent transport process for D-glucose, although no direct evidence for the cellular location of this transport system in fresh cells has been shown to date. With the use of elastase digestion and lectin agglutination, a pure preparation of type II alveolar epithelial cells was isolated from adult guinea pig lung. This preparation always contained >90% type II cells and typically showed approximately 85% cell viability 2-3 h after the isolation procedure had begun. At 37 degrees C, cells showed specific [3H]phlorizin binding that was attenuated by D-glucose and completely abolished by sodium replacement. Substantial accumulation of the hexose [14C]methyl alpha-D-glucopyranoside (14C-labeled AMG), a substrate specific for the sodium-dependent glucose cotransporter was found in the presence of extracellular sodium; this accumulation above equilibrium was abolished on removal of sodium, addition of phlorizin, or in the presence of a saturating concentration (69 mM) of D-glucose. The apparent inhibition constant (Ki) for glucose inhibition of AMG uptake was 0.4 mM and for phlorizin, 0.5 microM. The Hill plot of sodium activation of AMG uptake gave a coefficient of 2.8, suggesting cooperativeness between sodium and AMG transport. 3-O-[14C]methyl-D-glucose (3-OMG) transport was also blocked by phlorizin. Phloretin, in the presence of phlorizin, slowed the initial rate of entry but did not affect the equilibrium that was attained in the presence of phlorizin alone.(ABSTRACT TRUNCATED AT 250 WORDS)

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Nagata, Takumi, Masayuki Suzuki, Masanori Fukazawa, Kiyofumi Honda, Mizuki Yamane, Ayae Yoshida, Hiroko Azabu, et al. "Competitive inhibition of SGLT2 by tofogliflozin or phlorizin induces urinary glucose excretion through extending splay in cynomolgus monkeys." American Journal of Physiology-Renal Physiology 306, no. 12 (June 15, 2014): F1520—F1533. http://dx.doi.org/10.1152/ajprenal.00076.2014.

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Sodium-glucose cotransporter 2 (SGLT2) inhibitors showed a glucose lowering effect in type 2 diabetes patients through inducing renal glucose excretion. Detailed analysis of the mechanism of the glucosuric effect of SGLT2 inhibition, however, has been hampered by limitations of clinical study. Here, we investigated the mechanism of urinary glucose excretion using nonhuman primates with SGLT inhibitors tofogliflozin and phlorizin, both in vitro and in vivo. In cells overexpressing cynomolgus monkey SGLT2 (cSGLT2), both tofogliflozin and phlorizin competitively inhibited uptake of the substrate (α-methyl-d-glucopyranoside; AMG). Tofogliflozin was found to be a selective cSGLT2 inhibitor, inhibiting cSGLT2 more strongly than did phlorizin, with selectivity toward cSGLT2 1,000 times that toward cSGLT1; phlorizin was found to be a nonselective cSGLT1/2 inhibitor. In a glucose titration study in cynomolgus monkeys under conditions of controlled plasma drug concentration, both tofogliflozin and phlorizin increased fractional excretion of glucose (FEG) by up to 50% under hyperglycemic conditions. By fitting the titration curve using a newly introduced method that avoids variability in estimating the threshold of renal glucose excretion, we found that tofogliflozin and phlorizin lowered the threshold and extended the splay in a dose-dependent manner without significantly affecting the tubular transport maximum for glucose (TmG). Our results demonstrate the contribution of SGLT2 to renal glucose reabsorption (RGR) in cynomolgus monkeys and demonstrate that competitive inhibition of cSGLT2 exerts a glucosuric effect by mainly extending splay and lowering threshold without affecting TmG.

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Fedorak, R. N., C. I. Cheeseman, A. B. Thomson, and V. M. Porter. "Altered glucose carrier expression: mechanism of intestinal adaptation during streptozocin-induced diabetes in rats." American Journal of Physiology-Gastrointestinal and Liver Physiology 261, no. 4 (October 1, 1991): G585—G591. http://dx.doi.org/10.1152/ajpgi.1991.261.4.g585.

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Intestinal adaptation of glucose transport during streptozocin-induced diabetes in rats was examined using microdensitometric analysis of [3H]phlorizin binding. Results of specific phlorizin binding were correlated with measurements of maximal transport capacity, carrier affinity, villus height, and enterocyte birth rate determined by the metaphase arrest technique. Animals diabetic for 14 days (acute) and 60 days (chronic) were compared with age-matched controls. In the jejunum, adaptation occurred only in chronically diabetic rats and consisted of a 10-fold increase in the density of phlorizin binding sites in the upper villus region (i.e., that portion normally transporting glucose), while in the ileum, adaptation occurred both in acute and chronically diabetic rats and consisted of 1) a 3-fold increase in density of phlorizin binding sites in the upper villus region of acutely diabetic rats and 2) an increased density in the upper villus region as well as the recruitment of phlorizin binding sites in the mid to lower villus region (i.e., that portion not normally transporting glucose) of chronically diabetic rats. Enhancement of glucose Vmax and villus length accompanied changes in binding, whereas enterocyte birth rates were similar in each group.

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McCrimmon, R. J., M. L. Evans, R. J. Jacob, X. Fan, Y. Zhu, G. I. Shulman, and R. S. Sherwin. "AICAR and phlorizin reverse the hypoglycemia-specific defect in glucagon secretion in the diabetic BB rat." American Journal of Physiology-Endocrinology and Metabolism 283, no. 5 (November 1, 2002): E1076—E1083. http://dx.doi.org/10.1152/ajpendo.00195.2002.

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Individuals with type 1 diabetes demonstrate a hypoglycemia-specific defect in glucagon secretion. To determine whether intraislet hyperinsulinemia plays a role in the genesis of this defect, glucagon-secretory responses to moderate hypoglycemia induced by either insulin or a novel combination of the noninsulin glucose-lowering agents 5-aminoimidazole-4-carboxamide (AICAR) and phlorizin were compared in diabetic BB rats (an animal model of type 1 diabetes) and nondiabetic BB rats. The phlorizin-AICAR combination was able to induce moderate and equivalent hypoglycemia in both diabetic and nondiabetic BB rats in the absence of marked hyperinsulinemia. Diabetic BB rats demonstrated impaired glucagon and epinephrine responses during insulin-induced hypoglycemia compared with nondiabetic rats. In contrast, both glucagon (9- to 10-fold increase) and epinephrine (5- to 6-fold increase) responses were markedly improved during phlorizin-AICAR hypoglycemia. Combining phlorizin, AICAR, and insulin attenuated the glucagon response to hypoglycemia by 70% in the diabetic BB rat. Phlorizin plus AICAR had no effect on counterregulatory hormones under euglycemic conditions. We conclude that α-cell glucagon secretion in response to hypoglycemia is not defective if intraislet hyperinsulinemia is prevented. This suggests that exogenous insulin plays a pivotal role in the etiology of this defect.

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Herrera-González, Azucena, Gema Núñez-López, Nelson Núñez-Dallos, Lorena Amaya-Delgado, Georgina Sandoval, Magali Remaud-Simeon, Sandrine Morel, Javier Arrizon, and Lázaro Hernández. "Enzymatic synthesis of phlorizin fructosides." Enzyme and Microbial Technology 147 (June 2021): 109783. http://dx.doi.org/10.1016/j.enzmictec.2021.109783.

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Atisook, K., S. Carlson, and J. L. Madara. "Effects of phlorizin and sodium on glucose-elicited alterations of cell junctions in intestinal epithelia." American Journal of Physiology-Cell Physiology 258, no. 1 (January 1, 1990): C77—C85. http://dx.doi.org/10.1152/ajpcell.1990.258.1.c77.

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Glucose alters absorptive cell tight junction structure and, as deduced from an impedance analysis model, diminishes tight junction resistance in the small intestine (J.R. Pappenheimer, J. Membr. Biol. 100: 137-148, 1987; and J.L. Madara and J.R. Pappenheimer, J. Membr. Biol. 100: 149-164, 1987). Here we provide further evidence in support of this hypothesis using the conventional approach of analysis of mucosal sheets mounted in Ussing chambers. This approach offers advantages for investigating underlying mechanisms, including the effects of ions and inhibitors on the regulation of intercellular junctions by glucose. We show that phlorizin blocks a resistance decrease elicited by glucose and demonstrate that substitution of choline for sodium also prevents the response. The dilatations in absorptive cell tight junctions that accompany this glucose-elicited response are similarly prevented by phlorizin exposure or sodium substitution. The effects of phlorizin on junctional permeability can also be demonstrated in vivo. Phlorizin reduces the transjunctional flux of creatinine in glucose-perfused intestines of anesthetized animals, even when account is taken of the reduction of fluid absorption caused by phlorizin. Last, in vivo perfusion studies suggest that although, at 25 mM luminal glucose, virtually all glucose absorption is transcellular, at a luminal glucose concentration of 125 mM approximately 30% of glucose absorption occurs paracellularly because of solvent drag across tight junctions of altered permeability.(ABSTRACT TRUNCATED AT 250 WORDS)

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Beaulieu, A. D., T. R. Overton, and J. K. Drackley. "Substrate oxidation by isolated ovine enterocytes is increased by phlorizin-induced glucosuria." Canadian Journal of Animal Science 81, no. 4 (December 1, 2001): 585–88. http://dx.doi.org/10.4141/a01-032.

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Intestinal cells harvested from wethers injected with phlorizin were utilized to determine the effects of decreased glucose availability on glucose, glutamine, and butyrate oxidation by ovine intestinal cells. Phlorizin injection increased (P = 0.002) conversion of substrates to CO2 by isolated enterocytes but not by colonocytes (P = 0.098). Key words: Enterocytes, colonocytes, ruminant, glucose

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16

Blaschek, Wolfgang. "Natural Products as Lead Compounds for Sodium Glucose Cotransporter (SGLT) Inhibitors." Planta Medica 83, no. 12/13 (April 10, 2017): 985–93. http://dx.doi.org/10.1055/s-0043-106050.

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AbstractGlucose homeostasis is maintained by antagonistic hormones such as insulin and glucagon as well as by regulation of glucose absorption, gluconeogenesis, biosynthesis and mobilization of glycogen, glucose consumption in all tissues and glomerular filtration, and reabsorption of glucose in the kidneys. Glucose enters or leaves cells mainly with the help of two membrane integrated transporters belonging either to the family of facilitative glucose transporters (GLUTs) or to the family of sodium glucose cotransporters (SGLTs). The intestinal glucose absorption by endothelial cells is managed by SGLT1, the transfer from them to the blood by GLUT2. In the kidney SGLT2 and SGLT1 are responsible for reabsorption of filtered glucose from the primary urine, and GLUT2 and GLUT1 enable the transport of glucose from epithelial cells back into the blood stream.The flavonoid phlorizin was isolated from the bark of apple trees and shown to cause glucosuria. Phlorizin is an inhibitor of SGLT1 and SGLT2. With phlorizin as lead compound, specific inhibitors of SGLT2 were developed in the last decade and some of them have been approved for treatment mainly of type 2 diabetes. Inhibition of SGLT2 eliminates excess glucose via the urine. In recent times, the dual SGLT1/SGLT2 inhibitory activity of phlorizin has served as a model for the development and testing of new drugs exhibiting both activities.Besides phlorizin, also some other flavonoids and especially flavonoid enriched plant extracts have been investigated for their potency to reduce postprandial blood glucose levels which can be helpful in the prevention and supplementary treatment especially of type 2 diabetes.

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Loike, J. D., S. Hickman, K. Kuang, M. Xu, L. Cao, J. C. Vera, S. C. Silverstein, and J. Fischbarg. "Sodium-glucose cotransporters display sodium- and phlorizin-dependent water permeability." American Journal of Physiology-Cell Physiology 271, no. 5 (November 1, 1996): C1774—C1779. http://dx.doi.org/10.1152/ajpcell.1996.271.5.c1774.

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Expression of Na(+)-glucose cotransporters of the SGLT-1 type by Xenopus laevis oocytes increased the osmotic water permeability (Pf) of oocytes by a factor of 1.9-2.8, in the presence and in the absence of 5 mM extracellular glucose. The Pf increase was correlated with the amount of SGLT-1 cRNA injected. In oocytes expressing SGLT-1, either addition of phlorizin to the medium or the replacement of Na+ by choline inhibited the uptake of methyl-alpha-D-glucopyranoside, a specific substrate for SGLT-1, and returned oocyte Pf to its level in uninjected oocytes. Phlorizin inhibited the SGLT-1-attributable increase in Pf with an inhibition constant (Ki) of 6.1 microM, a value analogous to the Ki for phlorizin inhibition of sugar uptake. However, neither the presence of phlorizin nor the absence of extracellular Na+ significantly affected the increase in Pf elicited in oocytes expressing GLUT-1, a facilitative glucose transporter. These findings suggest that SGLT-1 forms a pore that allows the transmembrane passage of water and that water and glucose traverse the protein through this pore. The finding that removal of extracellular Na+ abolishes the increase in Pf attributable to SGLT-1 suggests that extracellular Na+ is required to maintain patency of this transporter's water-permeable transmembrane pore.

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Spinelli, Fernanda Rodrigues, Sandra Valduga Dutra, Susiane Leonardelli, Gilberto João Carnieli, and Regina Vanderlinde. "Phlorizin and sorbitol inVitis labruscagrape juices." BIO Web of Conferences 7 (2016): 02006. http://dx.doi.org/10.1051/bioconf/20160702006.

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Hummel, Charles S., Chuan Lu, Jie Liu, Chiari Ghezzi, Bruce A. Hirayama, Donald D. F. Loo, Vladimir Kepe, Jorge R. Barrio, and Ernest M. Wright. "Structural selectivity of human SGLT inhibitors." American Journal of Physiology-Cell Physiology 302, no. 2 (January 15, 2012): C373—C382. http://dx.doi.org/10.1152/ajpcell.00328.2011.

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Human Na+-d-glucose cotransporter (hSGLT) inhibitors constitute the newest class of diabetes drugs, blocking up to 50% of renal glucose reabsorption in vivo. These drugs have potential for widespread use in the diabetes epidemic, but how they work at a molecular level is poorly understood. Here, we use electrophysiological methods to assess how they block Na+-d-glucose cotransporter SGLT1 and SGLT2 expressed in human embryonic kidney 293T (HEK-293T) cells and compared them to the classic SGLT inhibitor phlorizin. Dapagliflozin [(1 S)-1,5,5-anhydro-1-C-{4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl}-d-glucitol], two structural analogs, and the aglycones of phlorizin and dapagliflozin were investigated in detail. Dapagliflozin and fluoro-dapagliflozin [(1 S)-1,5-anhydro-1-C-{4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl}-4-F-4-deoxy-d-glucitol] blocked glucose transport and glucose-coupled currents with ≈100-fold specificity for hSGLT2 ( Ki = 6 nM) over hSGLT1 ( Ki = 400 nM). As galactose is a poor substrate for SGLT2, it was surprising that galacto-dapagliflozin [(1 S)-1,5-anhydro-1-C-{4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl}-d-galactitol] was a selective inhibitor of hSGLT2, but was less potent than dapagliflozin for both transporters (hSGLT2 Ki = 25 nM, hSGLT1 Ki = 25,000 nM). Phlorizin and galacto-dapagliflozin rapidly dissociated from SGLT2 [half-time off rate ( t1/2,Off) ≈ 20–30 s], while dapagliflozin and fluoro-dapagliflozin dissociated from hSGLT2 at a rate 10-fold slower ( t1/2,Off ≥ 180 s). Phlorizin was unable to exchange with dapagliflozin bound to hSGLT2. In contrast, dapagliflozin, fluoro-dapagliflozin, and galacto-dapagliflozin dissociated quickly from hSGLT1 ( t1/2,Off = 1–2 s), and phlorizin readily exchanged with dapagliflozin bound to hSGLT1. The aglycones of phlorizin and dapagliflozin were poor inhibitors of both hSGLT2 and hSGLT1 with Ki values > 100 μM. These results show that inhibitor binding to SGLTs is composed of two synergistic forces: sugar binding to the glucose site, which is not rigid, and so different sugars will change the orientation of the aglycone in the access vestibule; and the binding of the aglycone affects the binding affinity of the entire inhibitor. Therefore, the pharmacophore must include variations in both the structure of the sugar and the aglycone.

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Sala-Rabanal, Monica, Bruce A. Hirayama, Donald D. F. Loo, Vincent Chaptal, Jeff Abramson, and Ernest M. Wright. "Bridging the gap between structure and kinetics of human SGLT1." American Journal of Physiology-Cell Physiology 302, no. 9 (May 1, 2012): C1293—C1305. http://dx.doi.org/10.1152/ajpcell.00397.2011.

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The Na+-glucose cotransporter hSGLT1 is a member of a class of membrane proteins that harness Na+ electrochemical gradients to drive uphill solute transport. Although hSGLT1 belongs to one gene family (SLC5), recent structural studies of bacterial Na+ cotransporters have shown that Na+ transporters in different gene families have the same structural fold. We have constructed homology models of hSGLT1 in two conformations, the inward-facing occluded (based on vSGLT) and the outward open conformations (based on Mhp1), mutated in turn each of the conserved gates and ligand binding residues, expressed the SGLT1 mutants in Xenopus oocytes, and determined the functional consequences using biophysical and biochemical assays. The results establish that mutating the ligand binding residues produces profound changes in the ligand affinity (the half-saturation concentration, K0.5); e.g., mutating sugar binding residues increases the glucose K0.5 by up to three orders of magnitude. Mutation of the external gate residues increases the Na+ to sugar transport stoichiometry, demonstrating that these residues are critical for efficient cotransport. The changes in phlorizin inhibition constant ( Ki) are proportional to the changes in sugar K0.5, except in the case of F101C, where phlorizin Ki increases by orders of magnitude without a change in glucose K0.5. We conclude that glucose and phlorizin occupy the same binding site and that F101 is involved in binding to the phloretin group of the inhibitor. Substituted-cysteine accessibility methods show that the cysteine residues at the position of the gates and sugar binding site are largely accessible only to external hydrophilic methanethiosulfonate reagents in the presence of external Na+, demonstrating that the external sugar (and phlorizin) binding vestibule is opened by the presence of external Na+ and closes after the binding of sugar and phlorizin. Overall, the present results provide a bridge between kinetics and structural studies of cotransporters.

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Ye, Qiang, Li Guo, Hongmei Liu, Yushi Liu, Cunyan Zhang, Cheng Peng, Zhiming Liu, Shan Huang, and Bin Li. "Optimization of Ultrasound-Assisted Extraction on Antioxidative Activity of Malus toringoides Using Response Surface Methodology." Processes 7, no. 5 (May 8, 2019): 270. http://dx.doi.org/10.3390/pr7050270.

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Ultrasonic-assisted extraction (UAE) was optimized using response surface methodology (RSM) to maintain the cyto-protective activity of M.toringoides against oxidative stress. The optimal conditions for UAE were a 58 mL/g liquid-solid ratio, a 38 °C extraction temperature, an 85% solvent concentration, and a 19-min extraction time, which resulted in a protection rate of 54.57% against hydrogen peroxide-induced oxidative stress in human umbilical vein endothelial cells (HUVECs). These results were comparable to the predicted value of 53.75%. The extracts showed excellent antioxidant activity, and phlorizin was detected in the dried leaves of Malus.toringoides. The highest yield of phlorizin (101.239 mg/g) was also obtained using these conditions. Taken together, these results showed that the method successfully integrated RSM and partial least squares regression methods to optimize M.toringoides extraction to yield the highest cyto-protective activity and effectively increase the yield of phlorizin from M.toringoides.

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Jasra, Nisha, Sankar N. Sanyal, and S. Khera. "Characterization of glucose uptake by Trichuris globulosa (Nematoda) in vitro." Journal of Helminthology 64, no. 3 (September 1990): 248–54. http://dx.doi.org/10.1017/s0022149x00012232.

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ABSTRACT14C-glucose uptake by adult Trichuris globulosa is found to be a non-linear function of time and limiting substrate concentration. The uptake is a two component process, an initial rapid burst is followed by a lower steady state, implying a mediated process. The uptake is dependent on Na+ ions which cannot be replaced by K+, Li+ or choline. The uptake is also dependent on pH, being maximal at pH 7·4. 14C-glucose absorption is markedly inhibited by glucose, phlorizin, ouabain and to a smaller extent by a number of monosaccharides and other sugar-phosphates, nucleosides and metabolic inhibitors like p-nitrophenyl phosphate and iodoacetate. The inhibition constant for glucose, phlorizin and ouabain has been found to be 8 mM, 5 mM and 7 mM, respectively. A modified Dixon-plot shows that glucose is a completely competitive inhibitor for 14C-glucose uptake while the nature of competitive inhibition of phlorizin and ouabain are found to be partial.

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Ferraris, R. P., S. A. Villenas, B. A. Hirayama, and J. Diamond. "Effect of diet on glucose transporter site density along the intestinal crypt-villus axis." American Journal of Physiology-Gastrointestinal and Liver Physiology 262, no. 6 (June 1, 1992): G1060—G1068. http://dx.doi.org/10.1152/ajpgi.1992.262.6.g1060.

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High-carbohydrate diets stimulate intestinal brush-border glucose uptake and increase the number of glucose-protectable phlorizin binding sites, but it has been unknown where along the crypt-villus axis these effects are expressed. We attacked this problem by three methods. First, by measuring phlorizin binding to isolated mouse enterocytes fractionated along the crypt-villus axis by the Weiser method, we identified a high-affinity binding site predominating from villus tip to midvillus and a site of possibly lower affinity predominating in the crypts. A high-carbohydrate diet increased by severalfold the density of the villus sites and probably also of the crypt sites, without changing their binding constants. Second, autoradiography revealed increased glucose-protectable phlorizin binding along the whole crypt-villus axis on a high-carbohydrate diet. Finally, a polyclonal antibody against the Na(+)-glucose cotransporter recognized a protein in the brush-border membrane of villus cells. Hence, substrate-dependent upregulation of intestinal glucose transport involves increased numbers of transporters along the crypt-villus axis.

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Malatiali, Slava, Issam Francis, and Mario Barac-Nieto. "Phlorizin Prevents Glomerular Hyperfiltration but not Hypertrophy in Diabetic Rats." Experimental Diabetes Research 2008 (2008): 1–7. http://dx.doi.org/10.1155/2008/305403.

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The relationships of renal and glomerular hypertrophies to development of hyperfiltration and proteinuria early in streptozotocin-induced diabetes were explored. Control, diabetic, phlorizin-treated controls, and diabetic male Fischer rats were used. Phlorizin (anNa+-glucose cotransport inhibitor) was given at a dose sufficient to normalize blood glucose. Inulin clearance (Cinulin) and protein excretion rate (PER) were measured. For morphometry, kidney sections were stained with periodic acid Schiff. At one week, diabetes PER increased 2.8-folds (P<.001),Cinulinincreased 80% (P<.01). Kidney wet and dry weights increased 10%–12% (P<.05), and glomerular tuft area increased 9.3% (P<.001). Phlorizin prevented proteinuria, hyperfiltration, and kidney hypertrophy, but not glomerular hypertrophy. Thus, hyperfiltration, proteinuria, and whole kidney hypertrophy were related to hyperglycemia but not to glomerular growth. Diabetic glomerular hypertrophy constitutes an early event in the progression of glomerular pathology which occurs in the absence of mesangial expansion and persists even after changes in protein excretion and GFR are reversed through glycemic control.

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25

Han, Ying, Young-Eun Cho, Ramon Ayon, Rui Guo, Katia D. Youssef, Minglin Pan, Anzhi Dai, Jason X. J. Yuan, and Ayako Makino. "SGLT inhibitors attenuate NO-dependent vascular relaxation in the pulmonary artery but not in the coronary artery." American Journal of Physiology-Lung Cellular and Molecular Physiology 309, no. 9 (November 1, 2015): L1027—L1036. http://dx.doi.org/10.1152/ajplung.00167.2015.

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Inhibitors of sodium-glucose cotransporter (SGLT)2 are a new class of oral drugs for type 2 diabetic patients that reduce plasma glucose levels by inhibiting renal glucose reabsorption. There is increasing evidence showing the beneficial effect of SGLT2 inhibitors on glucose control; however, less information is available regarding the impact of SGLT2 inhibitors on cardiovascular outcomes. The present study was designed to determine whether SGLT inhibitors regulate vascular relaxation in mouse pulmonary and coronary arteries. Phlorizin (a nonspecific SGLT inhibitor) and canagliflozin (a SGLT2-specific inhibitor) relaxed pulmonary arteries in a dose-dependent manner, but they had little or no effect on coronary arteries. Pretreatment with phlorizin or canagliflozin significantly inhibited sodium nitroprusside (SNP; a nitric oxide donor)-induced vascular relaxation in pulmonary arteries but not in coronary arteries. Phlorizin had no effect on cGMP-dependent relaxation in pulmonary arteries. SNP induced membrane hyperpolarization in human pulmonary artery smooth muscle cells, and pretreatment of cells with phlorizin and canagliflozin attenuated SNP-induced membrane hyperpolarization by decreasing K+ activities induced by SNP. Contrary to the result observed in ex vivo experiments with SGLT inhibitors, SNP-dependent relaxation in pulmonary arteries was not altered by chronic administration of canagliflozin. On the other hand, canagliflozin administration significantly enhanced SNP-dependent relaxation in coronary arteries in diabetic mice. These data suggest that SGLT inhibitors differentially regulate vascular relaxation depending on the type of arteries, duration of the treatment, and health condition, such as diabetes.

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Liu, Yaojie, Ying Liu, Yatu Guo, Lin Xu, and Hao Wang. "Phlorizin exerts potent effects against aging induced by d-galactose in mice and PC12 cells." Food & Function 12, no. 5 (2021): 2148–60. http://dx.doi.org/10.1039/d0fo02707c.

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27

Singh, Ranjodh Jeet, Ashwani Kumar Gupta, and Kanika Kohli. "DIABETES MELLITUS: A REVIEW WITH EDGE OF SGLT2 INHIBITORS." International Journal of Current Pharmaceutical Research 10, no. 5 (September 15, 2018): 1. http://dx.doi.org/10.22159/ijcpr.2018v10i5.29693.

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The relative (Type 2 DM) or absolute (Type 1 DM) deficiency of insulin hormone could result into hyperglycemia, which is a characteristic feature of diabetes mellitus. Diabetes mellitus is a leading cause of morbidity and mortality because of its associated complications viz. Neuropathy, Nephropathy, Retinopathy, Cardiovascular disorders.The feature which has to be noted down is the death of individuals before the age of 70 y, which is attributable to high blood glucose levels. According to WHO diabetes mellitus will be the seventh leading cause of deaths till 2030.The induction of glycosuria as meant for glycaemiac control in patients with DM is an extension of the physiological role of renal TmG to curb the menace of hyperglycemia. The first biologically derived SGLT2 inhibitor phlorizin, isolated in 1835 from the root bark of apple tree, was not developed as an antihyperglycaemic drug because of rapid degradation by lactase-phlorizin hydrolase and poor absorption from the gastrointestinal tract. Other glycoside moieties derived from phlorizin structure have subsequently been developed recently.

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Buller, H. A., A. G. Van Wassenaer, S. Raghavan, R. K. Montgomery, M. A. Sybicki, and R. J. Grand. "New insights into lactase and glycosylceramidase activities of rat lactase-phlorizin hydrolase." American Journal of Physiology-Gastrointestinal and Liver Physiology 257, no. 4 (October 1, 1989): G616—G623. http://dx.doi.org/10.1152/ajpgi.1989.257.4.g616.

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Lactase-phlorizin hydrolase, a small intestinal disaccharidase, has been considered mainly an enzyme important only for the hydrolysis of lactose. After weaning in most mammals lactase-specific activity falls markedly, and, functionally, adult mammals are considered to be lactase deficient. However, the persistence of low levels of lactase activity in adulthood has never been explained. In addition, it has been suggested that lactase-phlorizin hydrolase is associated with glycosylceramidase activity when the enzyme is prepared by column chromatography, but it is unclear whether this represents copurified activities or two catalytic sites on one peptide. The developmental patterns of lactase-phlorizin hydrolase and other disaccharidases were investigated in homogenates of total rat small intestine; lactase and several glycosylceramidases were measured in immunoprecipitates from these homogenates using a monoclonal antibody. The developmental pattern of total lactase activity showed a steady 2.3-fold increase to adult levels (specific activity decreased eightfold), whereas total phlorizin-hydrolase activity increased 10.7-fold (specific activity decreased threefold). As expected, levels of both total and specific sucrase and maltase activities increased during development. In lactating rats total lactase activity showed a significant increase compared with adult males. The developmental pattern of the enzyme activities for the glycolipid substrates was similar to that found for lactase, and the immunoprecipitated enzyme showed a 40- to 55-fold higher affinity for the glycolipids than for lactose. Galactosyl- and lactosylceramide inhibited lactose hydrolysis by 38%, without a competitive pattern, suggesting two different active sites for lactose and glycolipid hydrolysis, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

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29

Torp, N., M. Rossi, J. T. Troelsen, J. Olsen, and E. M. Danielsen. "Lactase-phlorizin hydrolase and aminopeptidase N are differentially regulated in the small intestine of the pig." Biochemical Journal 295, no. 1 (October 1, 1993): 177–82. http://dx.doi.org/10.1042/bj2950177.

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The longitudinal expression of two brush-border enzymes, lactase-phlorizin hydrolase (EC 3.2.1.23/62) and aminopeptidase N (EC 3.4.11.2), was studied in the small intestine of the post-weaned pig. Whereas the level of mRNA, encoding aminopeptidase N (relative to that of beta-actin), only varied moderately from the duodenum to the terminal ileum, the amount of lactase-phlorizin hydrolase mRNA exhibited a sharp maximum in the proximal jejunum. For both enzymes, the level of protein synthesis, studied in cultured mucosal explants, correlated well with the level of mRNA, and no major variation in post-translational processing or intracellular transport was observed along the intestine. The mRNA/specific-activity ratio for both enzymes was markedly (3-5-fold) higher in the duodenum and proximal jejunum, compared with the ileum. This indicates an increased proximal turnover rate, most likely caused by the presence in the gut lumen of pancreatic proteases. In neonatal animals, the level of mRNA for lactase-phlorizin hydrolase in both proximal and distal regions of the intestine was of the same magnitude as in the proximal jejunum of the post-weaned pigs. Our results point to two mechanisms that affect the expression of lactase-phlorizin hydrolase in the pig during development: (1) a primary regulation at the level of mRNA (predominantly in the ileum); (2) an increased rate of turnover of the enzyme, mainly in the duodenum and proximal jejunum, and most likely due to an increased secretion into the gut lumen of pancreatic proteases (a mechanism also affecting aminopeptidase N and probably other brush-border enzymes as well).

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Jacob, Ralf, Neil J. Bulleid, and Hassan Y. Naim. "Folding of Human Intestinal Lactase-phlorizin Hydrolase." Journal of Biological Chemistry 270, no. 31 (August 4, 1995): 18678–84. http://dx.doi.org/10.1074/jbc.270.31.18678.

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Wright, Stephen H., Ana M. Pajor, Debra A. Moon, and Theresa M. Wunz. "High-affinity phlorizin binding in Mytilus gill." Biochimica et Biophysica Acta (BBA) - Biomembranes 1103, no. 2 (January 1992): 212–18. http://dx.doi.org/10.1016/0005-2736(92)90089-5.

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32

Nagata, Takumi, Masanori Fukazawa, Kiyofumi Honda, Tatsuo Yata, Mio Kawai, Mizuki Yamane, Naoaki Murao, et al. "Selective SGLT2 inhibition by tofogliflozin reduces renal glucose reabsorption under hyperglycemic but not under hypo- or euglycemic conditions in rats." American Journal of Physiology-Endocrinology and Metabolism 304, no. 4 (February 15, 2013): E414—E423. http://dx.doi.org/10.1152/ajpendo.00545.2012.

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To understand the risk of hypoglycemia associated with urinary glucose excretion (UGE) induced by sodium-glucose cotransporter (SGLT) inhibitors, it is necessary to know the relationship between the ratio of contribution of SGLT2 vs. SGLT1 to renal glucose reabsorption (RGR) and the glycemic levels in vivo. To examine the contributions of SGLT2 and SGLT1 in normal rats, we compared the RGR inhibition by tofogliflozin, a highly specific SGLT2 inhibitor, and phlorizin, an SGLT1 and SGLT2 (SGLT1/2) inhibitor, at plasma concentrations sufficient to completely inhibit rat SGLT2 (rSGLT2) while inhibiting rSGLT1 to different degrees. Under hyperglycemic conditions by glucose titration, tofogliflozin and phlorizin achieved ≥50% inhibition of RGR. Under hypoglycemic conditions by hyperinsulinemic clamp, RGR was reduced by 20–50% with phlorizin and by 1–5% with tofogliflozin, suggesting the smaller contribution of rSGLT2 to RGR under hypoglycemic conditions than under hyperglycemic conditions. Next, to evaluate the hypoglycemic potentials of SGLT1/2 inhibition, we measured the plasma glucose (PG) and endogenous glucose production (EGP) simultaneously after UGE induction by SGLT inhibitors. Tofogliflozin (400 ng/ml) induced UGE of about 2 mg·kg−1·min−1 and increased EGP by 1–2 mg·kg−1·min−1, resulting in PG in the normal range. Phlorizin (1,333 ng/ml) induced UGE of about 6 mg·kg−1·min−1 and increased EGP by about 4 mg·kg−1·min−1; this was more than with tofogliflozin, but the minimum PG was lower. These results suggest that the contribution of SGLT1 to RGR is greater under lower glycemic conditions than under hyperglycemic conditions and that SGLT2-selective inhibitors pose a lower risk of hypoglycemia than SGLT1/2 inhibitors.

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33

Tsujii, S., and G. A. Bray. "Effects of glucose, 2-deoxyglucose, phlorizin, and insulin on food intake of lean and fatty rats." American Journal of Physiology-Endocrinology and Metabolism 258, no. 3 (March 1, 1990): E476—E481. http://dx.doi.org/10.1152/ajpendo.1990.258.3.e476.

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Glucose, 2-deoxyglucose, phlorizin, and insulin were injected into the third ventricle of lean and fatty rats, and food intake recorded hourly for the next 6 h. In the lean rats, there was a significant but unimpressive decrease in food intake after the intraventricular injection of glucose, but there was no effect of glucose in the fatty rat. Phlorizin in the lowest dose (10 micrograms) increased the food intake in lean animals at 1 and 2 h, and all three doses increased it significantly at 6 h after intraventricular injection. The fatty rat, in contrast, showed no response to phlorizin. 2-Deoxyglucose showed a dose-related stimulation of food intake in the lean rats at 1, 2, 3, and 6 h after injection. In the fatty rat, there was no significant effect on food intake at any dose. The intraventricular injection of insulin had no effect on food intake in either the lean or fatty rats. These studies indicate that glucose-responding systems in the region of the third ventricle are defective in the fatty rat to signals that normally increase or decrease food intake in lean animals.

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34

Osorio, Horacio, Israel Coronel, Abraham Arellano, Ursino Pacheco, Rocío Bautista, Martha Franco, and Bruno Escalante. "Sodium-Glucose Cotransporter Inhibition Prevents Oxidative Stress in the Kidney of Diabetic Rats." Oxidative Medicine and Cellular Longevity 2012 (2012): 1–7. http://dx.doi.org/10.1155/2012/542042.

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The hyperglycemia triggers several chronic diabetic complications mediated by increased oxidative stress that eventually causes diabetic nephropathy. The aim of this study was to examine if the sodium-glucose cotransporter (SGLT2) inhibition prevents the oxidative stress in the kidney of diabetic rats.Methods. The diabetic rat model was established by intraperitoneal injection of streptozotocin (50 mg/kg). The inhibition of SGLT2 was induced by daily subcutaneous administration of phlorizin (0.4 g/kg). Oxidative stress was assessed by catalase (CAT), glutathione peroxidase (GPx), and superoxide dismutase (SOD) activities and by immunohistochemical analysis of 3-nitrotyrosine (3-NT).Results. Streptozotocin-induced diabetes caused hyperglycemia and lower body weight. The CAT activity decreased in cortex and medulla from diabetic rats; in contrast, the GPx activity increased. Furthermore the 3-NT staining of kidney from diabetic rats increased compared to control rats. The inhibition of SGLT2 decreased hyperglycemia. However, significant diuresis and glucosuria remain in diabetic rats. The phlorizin treatment restores the CAT and GPX activities and decreases 3-NT staining.Conclusion. The inhibition of SGLT2 by phlorizin prevents the hyperglycemia and oxidative stress in kidney of diabetic rats, suggesting a prooxidative mechanism related to SGLT2 activity.

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35

Burcelin, R., M. Eddouks, J. Kande, R. Assan, and J. Girard. "Evidence that GLUT-2 mRNA and protein concentrations are decreased by hyperinsulinaemia and increased by hyperglycaemia in liver of diabetic rats." Biochemical Journal 288, no. 2 (December 1, 1992): 675–79. http://dx.doi.org/10.1042/bj2880675.

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GLUT-2, glucokinase (GK) and phosphoenolpyruvate carboxykinase (PEPCK) mRNA expression was studied in the liver of chronically catheterized diabetic rats during the 3 days after an intravenous injection of 65 mg of streptozotocin (STZ)/kg. At 6 h after the STZ injection, portal plasma insulin levels were 270 +/- 32 mu-units/ml and blood glucose was 1.4 +/- 0.4 mmol/l, owing to pancreatic beta-cell destruction. GLUT-2 and PEPCK mRNA concentrations were rapidly and dramatically decreased (> 90%), whereas GK mRNA was increased. After 30 h, plasma insulin concentrations were lower than 5 mu-units/ml and blood glucose was > 20 mmol/l. GLUT-2 and PEPCK mRNA concentrations increased 2-fold and GK mRNA disappeared progressively. In order to assess the relative roles of hyperglycaemia and insulinopenia, blood glucose was clamped at 6.4 +/- 0.5 mmol/l from 18 to 72 h after STZ injection by phlorizin infusion (0.5-2 g/day per kg) or at 6.6 +/- 0.3 mmol/l from 18 to 48 h after STZ injection by insulin infusion (0.25 unit/min per kg). GLUT-2 mRNA concentrations were 50% lower in phlorizin-infused than in untreated diabetic rats. The low levels of GK mRNA and the high levels of PEPCK mRNA were unaffected by normalization of hyperglycaemia in phlorizin-infused diabetic rats. In insulin-infused rats (portal plasma insulin levels of 40 mu-units/ml) GLUT-2 mRNA levels were 25% of those in untreated diabetic rats, and they increased rapidly 6 h after insulin infusion was stopped. Liver GLUT-2 protein concentration showed similar changes in response to STZ injection and to phlorizin or insulin treatment, but after a delay of several hours. From this work we conclude that GLUT-2 gene expression is dramatically and rapidly (< 6 h) decreased by portal hyperinsulinaemia and increased by hyperglycaemia.

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Wang, Zhanguo, Ziyang Gao, Anqi Wang, Lan Jia, Xiaoyu Zhang, Ming Fang, Kang Yi, Qijuan Li, and Huiling Hu. "Comparative oral and intravenous pharmacokinetics of phlorizin in rats having type 2 diabetes and in normal rats based on phase II metabolism." Food & Function 10, no. 3 (2019): 1582–94. http://dx.doi.org/10.1039/c8fo02242a.

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37

Norén, Ove, and Hans Sjöström. "Structure, biosynthesis and regulation of lactase-phlorizin hydrolase." Näringsforskning 45, no. 1 (December 2001): 156–60. http://dx.doi.org/10.3402/fnr.v45i0.1798.

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38

Hall, J. L., R. T. Reilly, K. L. Cottrill, W. S. Stone, and P. E. Gold. "Phlorizin enhancement of memory in rats and mice." Pharmacology Biochemistry and Behavior 41, no. 2 (February 1992): 295–99. http://dx.doi.org/10.1016/0091-3057(92)90101-k.

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39

Peerce, B. E., M. Cedilote, and R. D. Clarke. "Role of carboxyl and sulfhydryl residues on rabbit small intestinal brush-border membrane Na(+)-glucose cotransporter." American Journal of Physiology-Gastrointestinal and Liver Physiology 264, no. 2 (February 1, 1993): G294—G299. http://dx.doi.org/10.1152/ajpgi.1993.264.2.g294.

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The role of sulfhydryl (SH) and carboxylic acid residues in Na(+)-dependent glucose uptake, Na(+)-dependent phlorizin binding, and substrate exchange by the rabbit small intestinal brush-border membrane (BBM) Na(+)-glucose cotransporter was examined in sodium dodecyl sulfate-BBM vesicles. The sulfhydryl reagent p-chloromercuribenzoate (PCMB) inhibited all three measures of cotransporter function in a dithiothreitol-sensitive manner with similar K0.5 values (concn of PCMB resulting in 50% inhibition). PCMB sulfonate had no effect on Na(+)-glucose cotransporter function < 250 microM. The carboxylic acid reagent 1-ethyl-3-(4-azonia-4,4-dimethylpentyl)carbodiimide no effect on Na(+)-glucose cotransporter function. N,N'-dicyclohexylcarbodiimide (DCCD) inhibited all three measures of cotransporter function with similar K0.5 values for inhibition. Inhibition by DCCD did not require addition of a nucleophile. In contrast, PCMB-pretreated cotransporter was insensitive to DCCD in the absence of added nucleophile with respect to substrate transport (Na(+)-dependent glucose uptake) but not Na(+)-dependent phlorizin binding. These results indicate an intravesicular or lipophilic environment for both the PCMB-reactive SH residue and the DCCD-reactive carboxylic acid residues, suggesting that a SH residue may act as an endogenous nucleophile for interaction of DCCD with the Na(+)-glucose cotransporter and suggesting that different carboxylic acid residues may be involved in Na(+)-dependent glucose uptake and Na(+)-dependent phlorizin binding.

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Masyuk, Anatoly I., Tatyana V. Masyuk, Pamela S. Tietz, Patrick L. Splinter, and Nicholas F. LaRusso. "Intrahepatic bile ducts transport water in response to absorbed glucose." American Journal of Physiology-Cell Physiology 283, no. 3 (September 1, 2002): C785—C791. http://dx.doi.org/10.1152/ajpcell.00118.2002.

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The physiological relevance of the absorption of glucose from bile by cholangiocytes remains unclear. The aim of this study was to test the hypothesis that absorbed glucose drives aquaporin (AQP)-mediated water transport by biliary epithelia and is thus involved in ductal bile formation. Glucose absorption and water transport by biliary epithelia were studied in vitro by microperfusing intrahepatic bile duct units (IBDUs) isolated from rat liver. In a separate set of in vivo experiments, bile flow and absorption of biliary glucose were measured after intraportal infusion of d-glucose or phlorizin. IBDUs absorbedd-glucose in a dose- and phlorizin-dependent manner with an absorption maximum of 92.8 ± 6.2 pmol · min−1 · mm−1. Absorption of d-glucose by microperfused IBDUs resulted in an increase of water absorption ( J v = 3−10 nl · min−1 · mm−1, P f = 40 × 10−3 cm/sec). Glucose-driven water absorption by IBDUs was inhibited by HgCl2, suggesting that water passively follows absorbed d-glucose mainly transcellularly via mercury-sensitive AQPs. In vivo studies showed that as the amount of absorbed biliary glucose increased after intraportal infusion ofd-glucose, bile flow decreased. In contrast, as the absorption of biliary glucose decreased after phlorizin, bile flow increased. Results support the hypothesis that the physiological significance of the absorption of biliary glucose by cholangiocytes is likely related to regulation of ductal bile formation.

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Raja, M., T. Puntheeranurak, H. J. Gruber, P. Hinterdorfer, and R. K. H. Kinne. "The role of transporter ectodomains in drug recognition and binding: phlorizin and the sodium–glucose cotransporter." MedChemComm 7, no. 6 (2016): 1056–68. http://dx.doi.org/10.1039/c5md00572h.

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This article reviews the role of segments of SLCs located outside the plasma membrane bilayer (ectodomains) using the inhibition of SGLTs (SLC5 family) by the aromatic glucoside phlorizin as a model system.

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TROELSEN, Jesper T., Cathy MITCHELMORE, Nikolaj SPODSBERG, Anette M. JENSEN, Ove NORÉN, and Hans SJÖSTRÖM. "Regulation of lactase–phlorizin hydrolase gene expression by the caudal-related homoeodomain protein Cdx-2." Biochemical Journal 322, no. 3 (March 15, 1997): 833–38. http://dx.doi.org/10.1042/bj3220833.

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Lactase–phlorizin hydrolase is exclusively expressed in the small intestine and is often used as a marker for the differentiation of enterocytes. The cis-element CE-LPH1 found in the lactase–phlorizin hydrolase promoter has previously been shown to bind an intestinal-specific nuclear factor. By electrophoretic mobility-shift assay it was shown that the factor Cdx-2 (a homoeodomain-protein related to caudal) binds to a TTTAC sequence in the CE-LPH1. Furthermore it was demonstrated that Cdx-2 is able to activate reporter gene transcription by binding to CE-LPH1. A mutation in CE-LPH1, which does not affect Cdx-2 binding, results in a higher transcriptional activity, indicating that the CE-LPH1 site contains other binding site(s) in addition to the Cdx-2-binding site.

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Zhang, Xiao-yu, Kang Yi, Jiang Chen, Rui-ping Li, Jie Xie, Yan Jin, Xue-ran Mei, Yao-jun Li, Gang Liu, and Zhan-guo Wang. "Purified Phlorizin from DocynIa Indica (Wall.) Decne by HSCCC, Compared with Whole Extract, Phlorizin and Non-Phlorizin Fragment Ameliorate Obesity, Insulin Resistance, and Improves Intestinal Barrier Function in High-Fat-Diet-Fed Mice." Molecules 23, no. 10 (October 19, 2018): 2701. http://dx.doi.org/10.3390/molecules23102701.

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Natural products generally contain complex and multiple bioactive compounds that are responsible for the effects on health through complicated synergistic and/or suppressive actions. As an important raw material of local ethnic minority tea, ethnomedicines and food supplements in southwestern areas of China, Docynia indica (Wall.) Decne (DID) mainly consists of phlorizin (PHZ), which is the main active component. In this study, the holistic activities and the interactions of components of PHZ, non-phlorizin (NP) in the DID extract (DIDE) were evaluated. A rapid and effective high-speed counter-current chromatography (HSCCC) was performed to knock out PHZ from DIDE and the purity of PHZ was 96.01% determined by HPLC, with a recovery rate of 96.76%. After 13 weeks of treatment course in a high-fat diet (HFD)-induced obese mice model, the results revealed that the DIDE and PHZ significantly decreased weight gain, blood lipid levels, hyperplasia of adipocytes and alleviated inflammation (p < 0.05). Both DIDE and PHZ improves insulin resistance (p < 0.001). Meanwhile, the intestinal barrier function was improved compared to HFD group, through the determination of serum lipopolysaccharides (LPS), glucagon-likepeptide-2 (GLP-2) and hematoxylin-eosin staining of jejunum. Interestingly, after NP treatment, the metabolic syndrome of the HFD-induced obesity appeared to have a similar improvement. All the experiments showed that there is a synergistic weakening phenomenon when PHZ and NP interact with each other in the mixed state. In conclusion, for the PHZ and NP showing a good effect on anti-obesity, anti-inflammation, and intestinal barrier function, DIDE could be a good source of functional food to prevent obesity.

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44

Khan, A., and S. Efendic. "Evidence that increased glucose cycling in islets of diabetic ob/ob mice is a primary feature of the disease." American Journal of Physiology-Endocrinology and Metabolism 269, no. 4 (October 1, 1995): E623—E626. http://dx.doi.org/10.1152/ajpendo.1995.269.4.e623.

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Glucose cycling (GC) is increased in pancreatic islets from hyperglycemic 6-mo-old ob/ob mice. We determined whether normalization of glycemia alters islet GC and insulin release in response to glucose as well as oxidation and utilization of the glucose. Mice were treated with phlorizin in dimethyl sulfoxide (DMSO) for 10 days, which resulted in normalization of blood glucose concentrations. Controls received DMSO. The mice were fasted overnight and killed, and their islets were isolated for measurements of insulin release at 5.5 and 16.7 mM glucose and at 16.7 mM glucose plus 10 mM arginine. GC was measured by the incorporation of 3H from 3H2O into carbon 2 of glucose, glucose oxidation by the yield of 14CO2 from [U-14C]glucose, and glucose utilization by the yield of 3H2O from [5-3H]glucose. Phlorizin treatment did not alter the response of insulin to glucose and to glucose plus arginine. GC was 30% in control and phlorizin-treated animals. Glucose oxidation and utilization were also the same in both groups. In fed 10- to 12-mo-old mice exhibiting a broad range of blood glucose levels, there was no correlation between GC and either insulin release or glucose concentrations. Thus the islets of ob/ob mice exhibit an increased rate of GC regardless of glycemia. This indicates that the increased rate of GC is an important characteristic of the diabetic syndrome in these animals and not simply secondary to hyperglycemia.

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45

Li, Dan, Yongli Yang, Xi Yang, Xiaoyu Wang, Chuo Guo, Lijun Sun, and Yurong Guo. "Modulation of gelatinized wheat starch digestion and fermentation profiles by young apple polyphenols in vitro." Food & Function 12, no. 5 (2021): 1983–95. http://dx.doi.org/10.1039/d0fo02752a.

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To evaluate the effect of young apple polyphenols (YAP) on starch digestion and gut microbiota, complexes of native wheat starch (NWS) with YAP, and their main components chlorogenic acid (CA) and phlorizin (P) were fabricated and gelatinized.

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46

Qin, Xiang-Dong, and Ji-Kai Liu. "A New Sweet Dihydrochalcone-Glucoside from Leaves of Lithocarpus pachyphyllus (Kurz) Rehd. (Fagaceae)." Zeitschrift für Naturforschung C 58, no. 9-10 (October 1, 2003): 759–62. http://dx.doi.org/10.1515/znc-2003-9-1029.

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AbstractA new sweet dihydrochalcone-glucoside, trilobatin 2″- acetate (1), was isolated from the leaves of Lithocarpus pachyphyllus, together with phlorizin and trilobatin. The structures were established by spectroscopic methods, including one- and two-dimensional NMR (COSY, HMQC and HMBC).

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47

Hetenyi, G., C. Gauthier, M. Byers, and M. Vranic. "Phlorizin-induced normoglycemia partially restores glucoregulation in diabetic dogs." American Journal of Physiology-Endocrinology and Metabolism 256, no. 2 (February 1, 1989): E277—E283. http://dx.doi.org/10.1152/ajpendo.1989.256.2.e277.

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The plasma concentration of glucagon (IRG), catecholamines, and hepatic glucose production (Ra) were followed in insulin-induced hypoglycemia in dogs before (normal) and at 14-21 and again at 89-119 days after the injection of alloxan (diabetic). Some diabetic dogs were also tested when euglycemia was restored by phlorizin. In the normal state plasma IRG and epinephrine were raised by a factor of 3 and 15, respectively. Ra increased in two phases, an early peak (350% basal) was followed by a plataeu at about twice basal. In diabetes, irrespective of its duration, plasma IRG was decreased in hypoglycemia, and the rise in plasma epinephrine was significantly reduced. Ra remained unchanged. In phlorizin-treated euglycemic diabetic dogs plasma IRG fell, and the response in plasma epinephrine remained blunted. There was no early rise in Ra, but the same elevated plateau was reached at the same time as in normal animals. In conclusion, the following is observed in diabetic dogs. 1) The sensitivity of alpha-cells to insulin is maintained, but that to hypoglycemia is lost. The concentration of plasma catecholamines is raised less than in normals. With no increase in plasma glucagon this rise is not sufficient to increase Ra. 2) Restoration of euglycemia with phlorizin does not restore normal IRG and epinephrine responses to hypoglycemia but restores the delayed increase of Ra. Thus the restoration of euglycemia in severely diabetic dogs partially restores the responses of the liver, but not of the alpha-cell or sympathetic discharge, to hypoglycemia.

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48

Büller, H. A., E. H. M. Rings, R. K. Montgomery, W. V. Sasak, and R. J. Grand. "Further studies of glycosylation and intracellular transport of lactase–phlorizin hydrolase in rat small intestine." Biochemical Journal 263, no. 1 (October 1, 1989): 249–54. http://dx.doi.org/10.1042/bj2630249.

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Previous studies [Büller, Montgomery, Sasak & Grand (1987) J. Biol. Chem. 262, 17206-17211] have demonstrated that lactase-phlorizin hydrolase is inserted into the microvillus membrane (MVM) as a large precursor of approx. 220 kDa, which then undergoes two proteolytic cleavage steps to become the 130 kDa mature MVM protein. In order to assess the role of glycosylation in intracellular transport, the processing of this enzyme has been studied in the presence of castanospermine, an inhibitor of N-linked oligosaccharide modification and subsequent treatment with two endoglycosidases, endo-beta-N-acetyl-glucosaminidase (endo-H) and peptide:N-glycosidase-F (N-glycanase). We now show that the intracellular precursor (205 kDa) undergoes carbohydrate processing (220 kDa) and transport to the MVM where its further proteolytic cleavage is as described. Treatment of the intracellular 205 kDa precursor with either endo-H which cleaves only high-mannose N-linked oligosaccharides, or with N-glycanase, which cleaves both high-mannose and complex N-linked oligosaccharides, results in the conversion of the 205 kDa protein band to one of 195 kDa. These data suggest that the 205 kDa precursor contains only high-mannose N-linked carbohydrates, and that the unglycosylated nascent protein is 195 kDa. In the presence of castanospermine, an intracellular precursor of approx. 210 kDa is observed. When treated with endo-H or N-glycanase, this form also produces a protein of 195 kDa. The transport of the intracellular precursor to the MVM and further proteolytic processing is not blocked by the inhibitor. However, all MVM forms of lactase-phlorizin hydrolase show an increase of approx. 5 kDa. Treatment of these three MVM forms with endo-H indicates the increased presence of high mannose oligosaccharides in comparison with non-castanospermine-treated forms. The susceptibility to endo-H of the 130 kDa MVM band synthesized in the absence of castanospermine implies the presence of high-mannose N-linked oligosaccharides in the mature form of lactase-phlorizin hydrolase. Incubation of these MVM forms with N-glycanase further reduces their electrophoretic mobility, indicating the presence of complex N-linked oligosaccharides in the MVM forms, in contrast with the intracellular precursor. Altered glycosylation reduces but does not abolish intracellular transport of lactase-phlorizin hydrolase to the MVM.

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49

Naim, H. Y., R. Jacob, H. Naim, J. F. Sambrook, and M. J. Gething. "The pro region of human intestinal lactase-phlorizin hydrolase." Journal of Biological Chemistry 269, no. 43 (October 1994): 26933–43. http://dx.doi.org/10.1016/s0021-9258(18)47109-8.

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50

Link, J. T., and Bryan K. Sorensen. "A method for preparing C-glycosides related to phlorizin." Tetrahedron Letters 41, no. 48 (November 2000): 9213–17. http://dx.doi.org/10.1016/s0040-4039(00)01709-3.

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Journal articles on the topic 'Phlorizin'

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