Phloretin and phlorizin mitigates inflammatory stress and alleviate adipose and hepatic insulin resistance by abrogating PPARγ S273-Cdk5 interaction in type 2 diabetic mice.

AIMS: The rising prevalence of type 2 diabetes mellitus (T2DM) and accompanying insulin resistance is alarming globally. Natural and synthetic agonists of PPARγ are potentially attractive candidates for diabetics and are known to efficiently reverse adipose and hepatic insulin resistance, but related side effects and escalating costs are the causes of concern. Therefore, targeting PPARγ with natural ligands is advantageous and promising approach for the better management of T2DM. The present research aimed to assess the antidiabetic potential of phenolics Phloretin (PTN) and Phlorizin (PZN) in type 2 diabetic mice. MAIN METHODS: In silico docking was performed to check the effect of PTN and PZN on PPARγ S273-Cdk5 interactions. The docking results were further validated in preclinical settings by utilizing a mice model of high fat diet-induced T2DM. KEY FINDINGS: Computational docking and further MD-simulation data revealed that PTN and PZN inhibited the activation of Cdk5, thereby blocking the phosphorylation of PPARγ. Our in vivo results further demonstrated that PTN and PZN administration significantly improved the secretory functions of adipocytes by increasing adiponectin and reducing inflammatory cytokine levels, which ultimately reduced the hyperglycaemic index. Additionally, combined treatment of PTN and PZN decreased in vivo adipocyte expansion and increased Glut4 expression in adipose tissues. Furthermore, PTN and PZN treatment reduced hepatic insulin resistance by modulating lipid metabolism and inflammatory markers. SIGNIFICANCE: In summary, our findings strongly imply that PTN and PZN are candidates as nutraceuticals in the management of comorbidities related to diabetes and its complications.

[From the discovery of phlorizin (a Belgian story) to SGLT2 inhibitors]. / De la découverte de la phlorizine (une histoire belge) aux inhibiteurs des SGLT2.

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.

Ameliorative potential of phloridzin in type 2 diabetes-induced memory deficits in rats.

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

Phlorizin from sweet tea inhibits the progress of esophageal cancer by antagonizing the JAK2/STAT3 signaling pathway.

Phlorizin, an important member of the dihydrochalcone family, has been widely used as a Chinese Traditional Medicine for treatment of numerous diseases. The present study aimed to investigate the potential therapeutic effects of phlorizin on esophageal cancer. Phlorizin, extracted from sweet tea, was used to treat esophageal cancer cells. Cell proliferation, migration and invasion were determined using Cell Counting Kit­8 and colony formation assays, and wound healing and Transwell assays, respectively. RNA sequencing and bioinformatics analysis was used to investigate the potential mechanism of phlorizin in the development of esophageal cancer. Fluorescent staining and flow cytometry was used to measure the level of apoptosis. The expression level of the proteins, P62/SQSTM1 and LC3 Ð†/II, and the effect of phlorizin on the JAK2/STAT3 signaling pathway was detected using western blot analysis. The results demonstrated that phlorizin could inhibit cell proliferation, migration and invasion. Bioinformatics analysis showed that phlorizin might be involved in pleiotropic effects, such as the 'JAK/STAT signaling pathway' (hsa04630), 'MAPK signaling pathway'(hsa04010) and 'apoptosis' (hsa04210). It was also confirmed that phlorizin promoted apoptosis and inhibited autophagy in the esophageal cancer cells. Notably, phlorizin might inhibit the proteins in the JAK/STAT signaling pathway, which would affect cancer cells. Taken together, the present data showed that phlorizin inhibited the progression of esophageal cancer by antagonizing the JAK2/STAT3 signaling pathway.

Phlorizin attenuates visceral hypersensitivity and colonic hyperpermeability in a rat model of irritable bowel syndrome.

Visceral hypersensitivity and impaired gut barrier are crucial contributors to the pathophysiology of irritable bowel syndrome (IBS), and those are mediated via corticotropin-releasing factor (CRF)-Toll like receptor 4-pro-inflammatory cytokine signaling. Phlorizin is an inhibitor of sodium-linked glucose transporters (SGLTs), and known to have anti-cytokine properties. Thus, we hypothesized that phlorizin may improve these gastrointestinal changes in IBS, and tested this hypothesis in rat IBS models, i.e., lipopolysaccharide (LPS) or CRF-induced visceral hypersensitivity and colonic hyperpermeability. The visceral pain threshold in response to colonic balloon distention was estimated by abdominal muscle contractions by electromyogram, and colonic permeability was measured by quantifying the absorbed Evans blue in colonic tissue. Subcutaneous (s.c.) injection of phlorizin inhibited visceral hypersensitivity and colonic hyperpermeability induced by LPS in a dose-dependent manner. Phlorizin also blocked CRF-induced these gastrointestinal changes. Phlorizin is known to inhibit both SGLT1 and SGLT2, but intragastric administration of phlorizin may only inhibit SGLT1 because gut mainly expresses SGLT1. We found that intragastric phlorizin did not display any effects, but ipragliflozin, an orally active and selective SGLT2 inhibitor improved the gastrointestinal changes in the LPS model. Compound C, an adenosine monophosphate-activated protein kinase (AMPK) inhibitor, NG-nitro-L-arginine methyl ester, a nitric oxide (NO) synthesis inhibitor and naloxone, an opioid receptor antagonist reversed the effects of phlorizin. In conclusions, phlorizin improved visceral hypersensitivity and colonic hyperpermeability in IBS models. These effects may result from inhibition of SGLT2, and were mediated via AMPK, NO and opioid pathways. Phlorizin may be effective for the treatment of IBS.

Targeting Colorectal Cancer with Conjugates of a Glucose Transporter Inhibitor and 5-Fluorouracil.

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.

The Bioavailability, Extraction, Biosynthesis and Distribution of Natural Dihydrochalcone: Phloridzin.

Phloridzin is an important phytochemical which was first isolated from the bark of apple trees. It is a member of the dihydrochalcones and mainly distributed in the plants of the Malus genus, therefore, the extraction method of phloridzin was similar to those of other phenolic substances. High-speed countercurrent chromatography (HSCCC), resin adsorption technology and preparative high-performance liquid chromatography (HPLC) were used to separate and purify phloridzin. Many studies showed that phloridzin had multiple pharmacological effects, such as antidiabetic, anti-inflammatory, antihyperglycaemic, anticancer and antibacterial activities. Besides, the physiological activities of phloridzin are cardioprotective, neuroprotective, hepatoprotective, immunomodulatory, antiobesity, antioxidant and so on. The present review summarizes the biosynthesis, distribution, extraction and bioavailability of the natural compound phloridzin and discusses its applications in food and medicine.

Restoration of the Attenuated Neuroprotective Effect of Ischemic Postconditioning in Diabetic Mice by SGLT Inhibitor Phlorizin.

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.

Prunin suppresses viral IRES activity and is a potential candidate for treating enterovirus A71 infection.

Human enterovirus A71 (HEVA71) causes hand, foot, and mouth disease (HFMD) in young children and is considered a major neurotropic pathogen but lacks effective antivirals. To identify potential therapeutic agents against HFMD, we screened a 502-compound flavonoid library for compounds targeting the HEVA71 internal ribosome entry site (IRES) that facilitates translation of the HEVA71 genome and is vital for the production of HEVA71 viral particles. We validated hits using cell viability and viral plaque assays and found that prunin was the most potent inhibitor of HEVA71. Downstream assays affirmed that prunin disrupted viral protein and RNA synthesis and acted as a narrow-spectrum antiviral against enteroviruses A and B, but not enterovirus C, rhinovirus A, herpes simplex 1, or chikungunya virus. Continuous HEVA71 passaging with prunin yielded HEVA71-resistant mutants with five mutations that mapped to the viral IRES. Knockdown studies showed that the mutations allowed HEVA71 to overcome treatment-induced suppression by differentially regulating recruitment of the IRES trans-acting factors Sam68 and hnRNPK without affecting the hnRNPA1-IRES interaction required for IRES translation. Furthermore, prunin effectively reduced HEVA71-associated clinical symptoms and mortality in HEVA71-infected BALB/c mice and suppressed hepatitis C virus at higher concentrations, suggesting a similar mechanism of prunin-mediated IRES inhibition for both viruses. These studies establish prunin as a candidate for further development as a HEVA71 therapeutic agent.

Role of Apple Phytochemicals, Phloretin and Phloridzin, in Modulating Processes Related to Intestinal Inflammation.

Plant-derived food consumption has gained attention as potential intervention for the improvement of intestinal inflammatory diseases. Apple consumption has been shown to be effective at ameliorating intestinal inflammation symptoms. These beneficial effects have been related to (poly)phenols, including phloretin (Phlor) and its glycoside named phloridzin (Phldz). To deepen the modulatory effects of these molecules we studied: i) their influence on the synthesis of proinflammatory molecules (PGE2, IL-8, IL-6, MCP-1, and ICAM-1) in IL-1ß-treated myofibroblasts of the colon CCD-18Co cell line, and ii) the inhibitory potential of the formation of advanced glycation end products (AGEs). The results showed that Phlor (10-50 µM) decreased the synthesis of PGE2 and IL-8 and the formation of AGEs by different mechanisms. It is concluded that Phlor and Phldz, compounds found exclusively in apples, are positively associated with potential beneficial effects of apple consumption.

[Sodium-Glucose Transporters as a Therapeutic Target for Diabetes from the Viewpoint of Drug Discovery and Pharmacotherapy].

　Sodium-glucose transporter (SGLT)-2 inhibitors, which are currently in clinical use in most of the world, are unique as their hypoglycemic effects are completely independent of insulin action. Potential benefits and indications for the treatment of other diseases like circulatory and renal disorders are attracting attention. SGLT2 inhibitors not only reduce blood glucose levels but also alter the whole-body energy balance to lower body weight, which should result in the amelioration of multiple metabolic disorders like metabolic syndrome. In the symposium, we briefly introduced the physiological as well as biological functions of SGLTs and discussed strategies for drug design by looking back at the history of drug discovery for SGLT2 inhibitors. We also shared our recent data on their combined usage with other hypoglycemic agents and effects on glucagon secretion, which are current clinical topics relevant to SGLT2 inhibitors. Among those topics, strategies for drug discovery of SGLT2 inhibitors are discussed in this review.

Diabetic macular edema-like ocular lesions in male spontaneously diabetic torii fatty rats.

Diabetic macular edema (DME) is a major factor contributing to visual disabilities in diabetic patients, and the number of patients is increasing. Animal models play a key role in the development of novel therapies. In this study, pathophysiological analyses of ocular lesions in Spontaneously Diabetic Torii (SDT) fatty rats were performed. First, vascular endothelial growth factor (VEGF) concentrations in vitreous humor, retinal vascular permeability and retinal thickness were measured in SDT fatty rats (Experiment 1). Furthermore, the pharmacological effects of two anti-diabetic drugs, phlorizin and pioglitazone, on retinal lesions were evaluated (Experiment 2). As results, the SDT fatty rats exhibited VEGF increase in vitreous humor at 8 and 16 weeks of age, and both retinal vascular hyperpermeability and retinal thickening at 16 weeks of age. In particular, the layers between the retinal internal limiting membrane and the outer nuclear layer were thickened. Phlorizin treatment from 4 to 16 weeks of age improved hyperglycemia and normalized retinal thickness; however, the effect of pioglitazone on retinal thickness was not strong despite the normalization of hyperglycemia. These data demonstrate that the male SDT fatty rat is a useful model for developing new therapeutic approaches in DME.

Dietary phlorizin enhances osteoblastogenic bone formation through enhancing ß-catenin activity via GSK-3ß inhibition in a model of senile osteoporosis.

Osteoporosis is one of the most prevalent forms of age-related bone diseases. Increased bone loss with advancing age has become a grave public health concern. This study examined whether phlorizin and phloretin, dihydrochalcones in apple peels, inhibited senile osteoporosis through enhancing osteoblastogenic bone formation in cell-based and aged mouse models. Submicromolar phloretin and phlorizin markedly stimulated osteoblast differentiation of MC3T3-E1 cells with increased transcription of Runx2 and osteocalcin. Senescence-accelerated resistant mouse strain prone-6 (SAMP6) mice were orally supplemented with 10 mg/kg phlorizin and phloretin daily for 12 weeks. Male senescence-accelerated resistant mouse strain R1 mice were employed as a nonosteoporotic age-matched control. Oral administration of ploretin and phorizin boosted bone mineralization in all the bones of femur, tibia and vertebra of SAMP6. In particular, phlorizin reduced serum RANKL/OPG ratio and diminished TRAP-positive osteoclasts in trabecular bones of SAMP6. Additionally, treating phlorizin to SAMP6 inhibited the osteoporotic resorption in distal femoral bones through up-regulating expression of BMP-2 and collagen-1 and decreasing production of matrix-degrading cathepsin K and MMP-9. Finally, phlorizin and phloretin antagonized GSK-3ß induction and ß-catenin phosphorylation in osteoblasts and aged mouse bones. Therefore, phlorizin and phloretin were potential therapeutic agents encumbering senile osteoporosis through promoting bone-forming osteoblastogenesis via modulation of GSK-3ß/ß-catenin-dependent signaling.

SGLT2 Inhibitors as a Therapeutic Option for Diabetic Nephropathy.

Diabetic nephropathy (DN) is a major cause of end-stage renal disease (ESRD) worldwide. Glycemic and blood pressure (BP) control are important but not sufficient to attenuate the incidence and progression of DN. Sodium-glucose cotransporter (SGLT) 2 inhibitors are a new class of glucose-lowering agent suggested to exert renoprotective effects in glucose lowering-dependent and independent fashions. Experimental studies have shown that SGLT2 inhibitors attenuate DN in animal models of both type 1 diabetes (T1D) and type 2 diabetes (T2D), indicating a potential renoprotective effect beyond glucose reduction. Renoprotection by SGLT2 inhibitors has been demonstrated in T2D patients with a high cardiovascular risk in randomized controlled trials (RCTs). These favorable effects of SGLT2 inhibitors are explained by several potential mechanisms, including the attenuation of glomerular hyperfiltration, inflammation and oxidative stress. In this review article, we discuss the renoprotective effects of SGLT2 inhibitors by integrating experimental findings with the available clinical data.

Targeting renal glucose reabsorption to treat hyperglycaemia: the pleiotropic effects of SGLT2 inhibition.

Healthy kidneys filter ∼160 g/day of glucose (∼30% of daily energy intake) under euglycaemic conditions. To prevent valuable energy from being lost in the urine, the proximal tubule avidly reabsorbs filtered glucose up to a limit of ∼450 g/day. When blood glucose levels increase to the point that the filtered load exceeds this limit, the surplus is excreted in the urine. Thus, the kidney provides a safety valve that can prevent extreme hyperglycaemia as long as glomerular filtration is maintained. Most of the capacity for renal glucose reabsorption is provided by sodium glucose cotransporter (SGLT) 2 in the early proximal tubule. In the absence or with inhibition of SGLT2, the renal reabsorptive capacity for glucose declines to ∼80 g/day (the residual capacity of SGLT1), i.e. the safety valve opens at a lower threshold, which makes it relevant to glucose homeostasis from day-to-day. Several SGLT2 inhibitors are now approved glucose lowering agents for individuals with type 2 diabetes and preserved kidney function. By inducing glucosuria, these drugs improve glycaemic control in all stages of type 2 diabetes, while their risk of causing hypoglycaemia is low because they naturally stop working when the filtered glucose load falls below ∼80 g/day and they do not otherwise interfere with metabolic counterregulation. Through glucosuria, SGLT2 inhibitors reduce body weight and body fat, and shift substrate utilisation from carbohydrates to lipids and, possibly, ketone bodies. Because SGLT2 reabsorbs sodium along with glucose, SGLT2 blockers are natriuretic and antihypertensive. Also, because they work in the proximal tubule, SGLT2 inhibitors increase delivery of fluid and electrolytes to the macula densa, thereby activating tubuloglomerular feedback and increasing tubular back pressure. This mitigates glomerular hyperfiltration, reduces the kidney's demand for oxygen and lessens albuminuria. For reasons that are less well understood, SGLT2 inhibitors are also uricosuric. These pleiotropic effects of SGLT2 inhibitors are likely to have contributed to the results of the EMPA-REG OUTCOME trial in which the SGLT2 inhibitor, empagliflozin, slowed the progression of chronic kidney disease and reduced major adverse cardiovascular events in high-risk individuals with type 2 diabetes. This review discusses the role of SGLT2 in the physiology and pathophysiology of renal glucose reabsorption and outlines the unexpected logic of inhibiting SGLT2 in the diabetic kidney.

Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors from Natural Products: Discovery of Next-Generation Antihyperglycemic Agents.

Diabetes mellitus is a chronic condition associated with the metabolic impairment of insulin actions, leading to the development of life-threatening complications. Although many kinds of oral antihyperglycemic agents with different therapeutic mechanisms have been marketed, their undesirable adverse effects, such as hypoglycemia, weight gain, and hepato-renal toxicity, have increased demand for the discovery of novel, safer antidiabetic drugs. Since the important roles of the sodium-glucose cotransporter 2 (SGLT2) for glucose homeostasis in the kidney were recently elucidated, pharmacological inhibition of SGLT2 has been considered a promising therapeutic target for the treatment of type 2 diabetes. Since the discovery of the first natural SGLT2 inhibitor, phlorizin, several synthetic glucoside analogs have been developed and introduced into the market. Furthermore, many efforts to find new active constituents with SGLT2 inhibition from natural products are still ongoing. This review introduces the history of research on the development of early-generation SGLT2 inhibitors, and recent progress on the discovery of novel candidates for SGLT2 inhibitor from several natural products that are widely used in traditional herbal medicine.

Phlorizin Supplementation Attenuates Obesity, Inflammation, and Hyperglycemia in Diet-Induced Obese Mice Fed a High-Fat Diet.

Obesity, along with its related complications, is a serious health problem worldwide. Many studies reported the anti-diabetic effect of phlorizin, while little is known about its anti-obesity effect. We investigated the beneficial effects of phlorizin on obesity and its complications, including diabetes and inflammation in obese animal. Male C57BL/6J mice were divided into three groups and fed their respective experimental diets for 16 weeks: a normal diet (ND, 5% fat, w/w), high-fat diet (HFD, 20% fat, w/w), or HFD supplemented with phlorizin (PH, 0.02%, w/w). The findings revealed that the PH group had significantly decreased visceral and total white adipose tissue (WAT) weights, and adipocyte size compared to the HFD. Plasma and hepatic lipids profiles also improved in the PH group. The decreased levels of hepatic lipids in PH were associated with decreased activities of enzymes involved in hepatic lipogenesis, cholesterol synthesis and esterification. The PH also suppressed plasma pro-inflammatory adipokines levels such as leptin, adipsin, tumor necrosis factor-α, monocyte chemoattractant protein-1, interferon-γ, and interleukin-6, and prevented HFD-induced collagen accumulation in the liver and WAT. Furthermore, the PH supplementation also decreased plasma glucose, insulin, glucagon, and homeostasis model assessment of insulin resistance levels. In conclusion, phlorizin is beneficial for preventing diet-induced obesity, hepatic steatosis, inflammation, and fibrosis, as well as insulin resistance.

Phloretin-induced cytoprotective effects on mammalian cells: A mechanistic view and future directions.

Phloretin (C15 H14 O5 ), a dihydrochalcone flavonoid, is mainly found in fruit, leaves, and roots of apple tree. Phloretin exerts antioxidant, anti-inflammatory, and anti-tumor activities in mammalian cells through mechanisms that have been partially elucidated throughout the years. Phloretin bioavailability is well known in humans, but still remains to be better studied in experimental animals, such as mouse and rat. The focus of the present review is to gather information regarding the mechanisms involved in the phloretin-elicited effects in different in vitro and in vivo experimental models. Several manuscripts were analyzed and data raised by authors were described and discussed here in a mechanistic manner. Comparisons between the effects elicited by phloretin and phloridzin were made whenever possible, as well as with other polyphenols, clarifying questions about the use of phloretin as a potential therapeutic agent. Toxicological aspects associated to phloretin exposure were also discussed here. Furthermore, a special section containing future directions was created as a suggestive guide towards the elucidation of phloretin-related actions in mammalian cells and tissues.

Contribution of hyperglycemia on diabetic complications in obese type 2 diabetic SDT fatty rats: effects of SGLT inhibitor phlorizin.

The spontaneously diabetic torii (SDT) fatty rat is a new model of type 2 diabetes showing overt obesity, hyperglycemia and hyperlipidemia. With early onset of diabetes mellitus, diabetic microvascular complications, including nephropathy, peripheral neuropathy and retinopathy, are observed at young ages. In the present study, blood glucose levels of female SDT fatty rats were controlled with phlorizin, a non-selective SGLT inhibitor, to examine whether and how these complications are caused by hyperglycemia. Phlorizin treatment adequately controlled plasma glucose levels during the experiment. At 29 weeks of age, urinary albumin excretion considerably increased in SDT fatty rats. Glomerulosclerosis and tubular pathological findings also indicate diabetic nephropathy. These renal parameters tended to decrease with phlorizin; however, effects were partial. Sciatic nerve conduction velocities were significantly delayed in SDT fatty rats compared with Sprague-Dawley (SD) rats. Intraepidermal nerve fiber density, an indicator of subclinical small nerve fiber neuropathy, significantly decreased in SDT fatty rats. Retinal dysfunction (prolongation of peak latency for oscillatory potential in electroretinograms) and histopathological eye abnormalities, including retinal folding and mature cataracts were also observed. Both nerve and eye disorders were prevented with phlorizin. These findings indicate that severe hyperglycemia mainly causes diabetic complications in SDT fatty rats. However, other factors, such as hyperlipidemia and hypertension, may affect diabetic nephropathy. These characteristics of diabetic complications will become helpful in evaluating new drugs for diabetic complications using SDT fatty rats.