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At least 19 recordsLinked to original sources

PubMed1978

Effects of phloretin and dextran-linked phloretin on pancreatic islet metabolism and insulin release.

The effects of phloretin on islet metabolism and insulin release have been studied in isolated pancreatic islets of the rat. At a concentration of 0.18 mM phloretin inhibited insulin release stimulated by glucose or leucine but did not affect the oxidation rates of glucose or leucine, the rate of glucose utilization and the islet content of ATP. Higher concentrations of phloretin caused inhibition of the rate of glucose metabolism, but stimulation of insulin release. Insulin release stimulated by phloretin was inhibited by mannoheptulose but was independent on extracellular Ca2+ and was not potentiated by caffeine. Both inhibitory and stimulatory effects of dextran-linked phloretin on insulin release were also seen; a concentration of dextran-linked phloretin that did not inhibit islet metabolism inhibited glucose-stimulated insulin release, but not release stimulated by leucine or glyceraldehyde. Higher concentrations of dextran-linked phloretin inhibited glucose oxidation but stimulated insulin release. These data are discussed in terms of current models of the beta-cell glucose-sensor mechanism.

Animals↗

PubMed1976

Interaction between phloretin and the red blood cell membrane.

Phloretin binding to red blood cell components has been characterized at pH6, where binding and inhibitory potency are maximal. Binding to intact red cells and to purified hemoglobin are nonsaturated processes approximately equal in magnitude, which strongly suggests that most of the red cell binding may be ascribed to hemoglobin. This conclusion is supported by the fact that homoglobin-free red cell ghosts can bind only 10% as much phloretin as an equivalent number of red cells. The permeability of the red cell membrane to phloretin has been determined by a direct measurement at the time-course of the phloretin uptake. At a 2% hematocrit, the half time for phloretin uptake is 8.7s, corresponding to a permeability coefficient of 2 x 10(-4) cm/s. The concentration dependence of the binding to ghosts reveals two saturable components. Phloretin binds with high affinity (K diss = 1.5 muM) to about 2.5 x 10(6) sites per cell; it also binds with lower affinity (Kdiss = 54 muM) to a second (5.5 x 10(7) per cell) set of sites. In sonicated total lipid extracts of red cell ghosts, phloretin binding consists of a single, saturable component. Its affinity and total number of sites are not significantly different from those of the low affinity binding process in ghosts. No high affinity binding of phloretin is exhibited by the red cell lipid extracts. Therefore, the high affinity phloretin binding sites are related to membrane proteins, and the low affinity sites result from phloretin binding to lipid. The identification of these two types of binding sites allows phloretin effects on protein-mediated transport processes to be distinguished from effects on the lipid region of the membrane.

Binding Sites↗

PubMed1978

Phosphorylated derivatives of phloretin inhibit cyclic AMP accumulation in neuronal and glial tumor cells in culture.

The potencies of polyphloretin phosphate, di-4-phloretin phosphate, 4-phloretin phosphate and phloretin to inhibit the stimulation of cAMP accumulation by prostaglandins, isoproterenol and adenosine were studied in 2 clonal cell lines of CNS origin. The sequence of potency to inhibit PGE1 effects was the same in neuroblastoma (N4TG3) and human astrocytoma cells (1321N1): di-4-phloretin phosphate greater than polyphloretin phosphate greater than phloretin greater than 4-phloretin phosphate. The inhibition of PGE1 stimulated cAMP accumulation by the most prostaglandin-specific inhibitor di-4-phloretin phosphate was rapidly established after its addition, fully reversible after a 30 min preincubation period and independent of the presence of calcium. Kinetic studies of the inhibition of PGE1 effects by di-4-phloretin-phosphate suggest a different type of inhibition in 1321N1 and N4TG3 cells.

Calcium↗

PubMed1978

Effects of phloretin and theophylline on 3-O-methylglucose transport by intestinal epithelial cells.

Phloretin and theophylline each exert an immediate inhibitory effect on the Na+-independent, facilitated-diffusion transport system for sugar associated with intestinal epithelial cells. Phloretin inhibits approximately 50% more of the total Na+-independent sugar flux than theophylline. Neither agent has an immediate effect on the Na+-dependent, concentrative sugar transport system, although preincubation of the cells with phloretin causes a significant inhibition. The slowly developing effect is correlated with a decrease in cellular adenosine triphosphate (ATP) and an elevation of intracellular Na+. Other agents which elevate cell Na+ also inhibit Na+-dependent sugar influx, even if ATP levels are not depleted. On the other hand, if ATP is depleted by phloretin under conditions in which the cells do not gain Na+, the inhibitory effect on Na+-dependent sugar flux tends to disappear. The slow-onset phloretin effects are due to transinhibition of the Na+-dependent sugar carrier by cellular Na+. When the passive sugar carrier is inhibited by phloretin or theophylline, the concentrative system can establish an enhanced sugar gradient. Because of the secondary metabolic effects of phloretin, theophylline induces a greater gradient enhancement despite its more limited effect on the passive sugar-transport system. Sugar gradients as large as 20-fold are induced by theophylline, in contrast to 12-fold gradients observed in the presence of phloretin and approximately 7- to 8-fold for untreated cells. These results are discussed in terms of conceptual questions regarding the energetics of Na+-dependent transport systems.

Adenosine Triphosphate↗

PubMed2026

Inhibitory mechanism of phloretin on the AgrA LytTR domain-agr operon complex formation and its application in beef.

Staphylococcus aureus (S. aureus) represents a major foodborne pathogen whose enterotoxin production poses significant challenges to food safety due to its high environmental resistance and limited efficacy of conventional sterilization. Since the expression of enterotoxins is predominantly governed by the agr quorum sensing system, targeting this regulatory pathway has become a strategic choice for virulence control. This study elucidated the mechanism by which phloretin, a potential quorum sensing inhibitor, interferes with the agr system to attenuate virulence. To achieve this, the recombinant AgrA LytTR domain was expressed and purified, and its interaction with phloretin was characterized using thermal shift assays (TSA), electrophoretic mobility shift assays (EMSA), and molecular dynamics (MD) simulations. The results showed that phloretin specifically binds to the AgrA LytTR domain, enhancing its thermal stability and disrupting AgrA LytTR-agr operon binding by reducing the free energy of interaction between them, without causing significant structural rearrangement. Mechanistic analysis indicated that phloretin sterically hinders key β-sheet turn residues (HIS169, ASN201, ARG233), thereby impairing DNA recognition, downregulating RNAIII transcription, and inhibiting agr signaling. In cooked beef, phloretin significantly inhibited the secretion of enterotoxins and α-hemolysin, while delaying lipid oxidation and protein degradation, and maintaining the meat texture. These findings suggested that phloretin is a multifunctional substance with anti-virulence, antioxidant, and preservative properties, demonstrating its potential as a natural food preservative.

Phloretin↗

PubMed1976

Effect of phloretin on the permeability of thin lipid membranes.

Phloretin dramatically increases cation conductances and decreases anion conductances of membranes treated with ion carriers (nonactin, valinomycin, carbonyl-cyanide-m-chlorophenylhydrazone [CCCP], and Hg(C6F5)2) or lipophilic ions (tetraphenylarsonium [tphAs+] and tetraphenylborate [TPhB-]). For example, on phosphatidylethanolamine membranes, 10(-4) M phloretin increases K+ -nonactin and TPhAs+ conductances and decreases CCCP- and TPhB- conductances 10(3)-fold; on lecithin: cholesterol membranes, it increases K+-nonactin conductance 10(5)-fold and decreases CCCP- conductance 10(3)-fold. Similar effects are obtained with p- and m-nitrophenol at 10(-2) M. These effects are produced by the un-ionized form of phloretin and the nitrophenols. We believe that phloretin, which possesses a large dipole moment, adsorbs and orients at the membrane surface to introduce a dipole potential of opposite polarity to the preexisting positive one, thus increasing the partition coefficient of cations into the membrane interior and decreasing the partition coefficient of anions. (Phloretin may also increase the fluidity of cholesterol-containing membranes; this is manifested by its two- to three-fold increase in nonelectrolyte permeability and its asymmetrical effect on cation and anion conductances in cholesterol-containing membranes.) It is possible that pholoretin's inhibition of chloride, urea, and glucose transport in biological membranes results from the effects of these intense intrafacial dipole fields on the translocator(s) of these molecules.

Anti-Bacterial Agents↗

PubMed1977

Phloretin-induced changes in ion transport across lipid bilayer membranes.

Phloretin, the aglucone derivative of phlorizin, increases cation conductance and decreases anion conductance in lipid bilayer membranes. In this paper we present evidence that phloretin acts almost exclusively by altering the permeability of the membrane interior and not by modifying the partition of the permanent species between the membrane and the bulk aqueous phases. We base our conclusion on an analysis of the current responses to a senylborate, and the cation complex, peptide PV-K+. These results are consistent with the hypothesis that phloretin decreases the intrinsic positive internal membrane potential but does not modify to a great extent the potential energy minima at the membrane interfaces. Phloretin increases the conductance for the nonactin-K+ complex, but above 10(-5) M the steady-state nonactin-K+ voltage-current curve changes from superlinear to sublinear. These results imply that, above 10(-5) M phloretin, the nonactin-5+ transport across the membrane becomes interfacially limited.

Anti-Bacterial Agents↗

PubMed1975

Inhibition by derivatives of phloretin of anaphylactic histamine release from human lung tissue and of prostaglandin F2alpha-induced bronchoconstriction.

Derivatives of phloretin (25-1,000 mug/ml) among them polyphloretin phosphate (PPP), inhibited in a dose-dependent manner anaphylactic (birch pollen or horse dander) histamine release from human lung tissue passively sensitized with reaginic serum. Pretreatment with PPP of lung tissue sensitized both to birch pollen and horse dander counteracted to a similar extent the release of histamine induced by either allergen administered in sequence. The phloretin derivatives also antagonized the constrictor action of prostaglandin F2alpha on isolated human bronchi at concentrations which did not impair the responses to histamine. The low and high molecular weight derivatives of phloretin were comparably active on a weight basis in both experimental systems.

Bronchial Spasm↗

PubMed1978

Phloretin-like action of bioflavonoids on sugar accumulation capability of isolated intestinal cells.

Flavanones and flavones are structural analogues of phloretin. Like phloretin they inhibit the non-Na+-dependent, facilitated diffusion transport system for sugars associated with the lateral serosal boundary of intestinal epithelial cells. The degree of inhibition varies with the extent and position of hydroxylation of the flavonoid nucleus. Flavones are more potent than corresponding flavanones. Tri- and tetrahydroxylated forms are more inhibitory than similar penta- and hexahydroxylated molecules. With one exception, none of the 18 flavonoids tested has secondary effects as metabolic inhibitors, as does phloretin. Inhibition of the passive sugar transport system with flavonoids allows the concentrative Na+-dependent sugar transport system to establish a better concentration gradient than is observed in untreated cells. The degree of gradient enhancement is proportional to the degree of inhibition of the sugar "leak." The flavonoid glycosides, which can be considered as phlorizin analogues, also inhibit the non-Na+-dependent sugar carrier, but less well than corresponding nonglycosylated agents. Only one of the glycosides inhibits the Na+-dependent transport system, and much less potently than phlorizin.

Animals↗

PubMed1979

On the adsorption of phloretin onto a black lipid membrane.

The effect of uncharged, dipolar phloretin on anion and cation conductance through a black lipid membrane can be used to study its adsorption behavior. The adsorption of phloretin can be described by a Langmuir isotherm with weak dipole-dipole interaction.

Electric Conductivity↗

PubMed1978

Asymmetry of the hexose transfer system in human erythrocytes. Comparison of the effects of cytochalasin B, phloretin and maltose as competitive inhibitors.

1. Cytochalasin B inhibits glucose transfer in human red cells. With glucose exit the inhibition is typically non-competitive, but hexose exchange is competitively inhibited. 2. At 16 degrees C the inhibitory constant for inhibition of 3-O-methyl glucose exchange is estimated at 1.1 X 10(-7) M while that for inhibition of glucose exit is 5.0 X 10(-7) M. 3. Uptake of labelled Cytochalasin B includes a saturable component which when correlated with the inhibition of exchange corresponds to a maximal binding of ca. 2.4 X 10(5) molecules per cell. 4. The kinetic parameters are compared with those for maltose (a competitive inhibitor acting on the outside only) and phloretin (an inhibitor acting both inside and out). 5. Kinetic evidence suggests that Cytochalasin B reacts with the inside of the hexose transfer system and that the anomalous inhibitory characteristics are due to the chemical asymmetry of the system. Independent evidence in support of this view is discussed.

Binding, Competitive↗

PubMed1978

Resolution by graphical methods of the equations for allosteric competitive inhibition and activation in Michaelian enzyme and transport systems. Application to the competitive inhibition of glucose transport in brain by phlorizin and phloretin.

A brief exposition of the theory of competition in systems conforming to simple Michaelis-Menten kinetics is given. Emphasis is placed on an operational distinction between: 10 True competition between substrate and inhibitor for a single, common binding site: fully competitive inhibition, type IA. 20 False competition between S and I for two separate sites that are associated allosterically: pseudocompetitive inhibition, type Ib. 30 A simple graphical test is presented that differentiates between the two types of inhibitor and permits calculation of the four dissociation constants governing the partial reactions of a two-site allosteric model. This test is equally applicable to certain cases of activation: affinity-type activation, type Ib. 40 The usefulness of the proposed test is illustrated using data from the literature, dealing with the effect of phlorizin and phloretin on the D-glucose transport system in brain.

Allosteric Site↗

PubMed1979