Effects Of Phloretin Research Articles

Cytoprotective Effects of Phloretin on Long-Term Post-Prandial Hyperglycemia-induced Esophageal Damage in Rats .

Esophageal damage arises from gastroesophageal reflux disease, where the contents of the stomach and duodenum flow back into the esophagus, causing an inflammatory lesion. Phloretin, a phytoconstituent classified as a flavonoid possessing both nutritional and medicinal properties, was the focus of this study. The experiment aimed to investigate the impact of phloretin on experimental esophagitis in albino rats. Rats in various groups underwent the induction of esophagitis through the administration of a Fructose solution (10%) and indomethacin (5mg/Kg). The resulting hyperglycemia from regular Fructose solution intake over 28 days was assessed. After sacrifice, the rats were evaluated for the esophagitis index. Additionally, esophageal tissues underwent further analysis for oxidative stress parameters, including TBARS, SOD, Catalase and GSH. Treatment with phloretin demonstrated a significant inhibition of the esophagitis index. Furthermore, phloretin contributed to the restoration of altered levels of oxidative stress parameters back to normal.

Phloretin inhibits the growth of Arabidopsis shoots by inducing chloroplast damage and programmed cell death

Phloretin is a key secondary metabolite produced by apple trees. Known for its strong antioxidant properties, this dihydrochalcone has been extensively studied in animals but less so in plants. Recently, we identified phloretin as a phytotoxic allelochemical that inhibits growth in the model plant Arabidopsis by disrupting auxin metabolism and distribution in the roots. In this study, we found that phloretin significantly hinders the growth of Arabidopsis seedlings' aerial parts after a short-term treatment (10 days) and causes their decay after long-term exposure (28 days). These effects result from ultrastructural damage in the mesophyll cells of the leaves, including chloroplast displacement and swelling, lesions, and alterations in thylakoid and cell wall organization. Interestingly, phloretin-treated plants showed a decrease in malondialdehyde levels and antioxidant enzyme activities, while hydrogen peroxide and proline levels remained unchanged. This suggests that phloretin-induced chlorosis and seedling decay are not due to oxidative stress but rather to severe chloroplast structural damage, leading to inefficient photosynthesis, starch degradation, starvation, and activation of micro- and macroautophagic processes for self-preservation. Ultimately, these processes result in programmed cell death. These new insights into the phytotoxic effects of phloretin on Arabidopsis shoots could pave the way for future research into phloretin as a potential multitarget bioherbicide and enhance our understanding of autoallelopathy in apple trees.

Effects of Phloretin on Seedling Growth and Histochemical Distribution of Phenols, Polysaccharides and Lipids in Capsella bursa-pastoris (L.) Medik.

The present study evaluates the phytotoxic effects of phloretin, a prevalent secondary metabolite of apple trees, on the broadleaf weed Capsella bursa-pastoris (L.) Medik. known for its resistant myxospermous seeds that form a long-lasting soil bank. The results indicate a significant, dose-dependent inhibitory effect of phloretin on the growth and morphological parameters of weed seedlings grown in vitro. Although the applied phloretin concentrations (250-1000 µM) were not lethal to the C. bursa-pastoris seedlings after two weeks, the metabolism of the seedlings was impaired, resulting in an accumulation of lipid droplets in the root tips and root hairs. Histochemical analysis shows deposits of phenols in the root epidermal cells, which are probably aggregates of phloretin or its metabolic derivatives. The accumulation of pectin in the cell walls of root border cells in phloretin-treated seedlings indicates an attempt to reduce the uptake of phloretin and reduce its concentration in the cells. Inhibition of shoot growth associated with chlorosis and reduced photosynthetic pigment content is a consequence of seedling exposure to phloretin. This study provides a basis for further evaluation of phloretin as a new bioherbicidal compound and for elucidating the mechanism underlying its phytotoxic activity.

Antiproliferative and Anti-Inflammatory Effects of the Polyphenols Phloretin and Balsacone C in a Coculture of T Cells and Psoriatic Keratinocytes.

Plaque psoriasis is a chronic inflammatory skin disease causing red inflamed lesions covered by scales. Leukocytes, including dendritic cells and T cells, participate in the inflammation of the skin by producing multiple cytokines, thus contributing to the hyperproliferation of keratinocytes. Lack of effectiveness and toxic side effects are the main concerns with conventional treatments, and research involving new antipsoriatic molecules is essential. In this study, the anti-inflammatory and antiproliferative effects of two natural polyphenols, phloretin and balsacone C, were investigated using the coculture of T cells and psoriatic keratinocytes. Phloretin exerted antiproliferative activity by regulating the expression of antigen Ki67 and proliferating cell nuclear antigen (PCNA). These effects were comparable to those of methotrexate, a reference treatment for moderate to severe psoriasis. With balsacone C, the expression of Ki67 was also reduced. Additionally, phloretin decreased the levels of multiple pro-inflammatory cytokines: monocyte chemoattractant protein-1 (MCP-1/CCL2), macrophage inflammatory protein-1α (MIP-1α), granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-1 alpha (IL-1α), interleukin-1 beta (IL-1β), interleukin-6 (IL-6), interleukin-17A (IL-17A), and tumor necrosis factor alpha (TNF-α). The increased interleukin-2 (IL-2) levels with phloretin and methotrexate also represented anti-inflammatory activity. Balsacone C and methotrexate decreased the levels of IL-1α and IL-1β, but methotrexate exerted a higher reduction. In summary, the anti-inflammatory effects of phloretin were more pronounced than those of methotrexate and balsacone C. In addition, the expression of lymphocyte common antigen (CD45) was more similar to that of the healthy condition after using phloretin or methotrexate. Finally, phloretin stood out from the other compounds and appears promising for psoriasis treatment.

Phloretin prolongs lifespan of Caenorhabditis elegans via inhibition of NDUFS1 and NDUFS6 at mitochondrial complex Ⅰ

Phloretin has been widely perceived as an antioxidant. However, the bioavailability of phloretin in vivo is generally far too low to elicit a direct antioxidant effect by scavenging reactive oxygen species (ROS). Here we showed that administration of phloretin of apple polyphenols extended lifespan of Caenorhabditis elegans and promoted fitness. Specially phloretin enhanced the survival rates of nematodes under oxidants in an inverted U-shaped dose-response manner. The lifespan-extending effects of phloretin were mediated by ROS via mitochondrial complex I inhibition. The increase of ROS stimulated p38 MAPK/PMK-1 as well as transcription factors of NRF2/SKN-1 and FOXO/DAF-16. Consistent with the involvement of NRF2/SKN-1 and FOXO/DAF-16 in lifespan-extending effects, activities of superoxide dismutase (SOD) and catalase (CAT) were enhanced by phloretin. The exogenous application of antioxidants butylated hydroxyanisole and N-acetylcysteine abolished the increase of ROS, the enhancement of SOD and CAT activities, and the lifespan extending effects of phloretin. Meanwhile, with the inhibition of mitochondrial complex I, ATP was instantly decreased. Both energy sensors of AMPK/AAK-2 and SIRT1/SIR-2.1 were involved in the lifespan extension by phloretin. Transcriptomic, real-time qPCR and molecular docking analyses demonstrated that the binding of phloretin at complex I located at NDUFS1/NUO-5, NDUFS2/GAS-1, and NDUFS6/NDUF-6. The molecular dynamic simulation and binding free energy calculations showed that phloretin had high binding affinities towards NDUFS1 (−7.21 kcal/mol) and NDUFS6 (−7.02 kcal/mol). Collectively, our findings suggested phloretin had effects of life expectancy enhancement and fitness promotion via redox regulations in vivo. NDUFS1/NUO-5 and NDUFS6/NDUF-6 might be new targets in the lifespan and wellness regulations.

Phloretin inhibits transmissible gastroenteritis virus proliferation via multiple mechanisms.

Transmissible gastroenteritis virus (TGEV), an enteropathogenic coronavirus, has caused huge economic losses to the pig industry, with 100% mortality in piglets aged 2 weeks and intestinal injury in pigs of other ages. However, there is still a shortage of safe and effective anti-TGEV drugs in clinics. In this study, phloretin, a naturally occurring dihydrochalcone glycoside, was identified as a potent antagonist of TGEV. Specifically, we found phloretin effectively inhibited TGEV proliferation in PK-15 cells, dose-dependently reducing the expression of TGEV N protein, mRNA, and virus titer. The anti-TGEV activity of phloretin was furthermore refined to target the internalization and replication stages. Moreover, we also found that phloretin could decrease the expression levels of proinflammatory cytokines induced by TGEV infection. In addition, we expanded the potential key targets associated with the anti-TGEV effect of phloretin to AR, CDK2, INS, ESR1, ESR2, EGFR, PGR, PPARG, PRKACA, and MAPK14 with the help of network pharmacology and molecular docking techniques. Furthermore, resistant viruses have been selected by culturing TGEV with increasing concentrations of phloretin. Resistance mutations were reproducibly mapped to the residue (S242) of main protease (Mpro). Molecular docking analysis showed that the mutation (S242F) significantly disrupted phloretin binding to Mpro, suggesting Mpro might be a potent target of phloretin. In summary, our findings indicate that phloretin is a promising drug candidate for combating TGEV, which may be helpful for developing pharmacotherapies for TGEV and other coronavirus infections.

Effects of Phloretin on Bisphenol-A Induced Liver and Kidney Toxicity in Prepubertal Female Rats

Effects of Phloretin on Bisphenol-A Induced Liver and Kidney Toxicity in Prepubertal Female Rats

Phloretin as an add-on therapy to losartan attenuates diabetes-induced AKI in rats: A potential therapeutic approach targeting TLR4-induced inflammation

AimTargeting Toll-like receptor 4 (TLR4) and Angiotensin II type 1 receptor (AT1R) could provide renoprotection during acute kidney injury (AKI) mainly by regulating inflammation, oxidative stress, mitochondrial dysfunction, and apoptosis. Phloretin (TLR4 inhibitor) as an add-on therapy to losartan (AT1R inhibitor) could provide more therapeutic benefits against AKI under diabetic condition. We aimed to study the effect of phloretin as an add-on therapy to losartan against AKI under diabetic condition. Main methodsTo mimic diabetic AKI condition, bilateral ischemia-reperfusion injury (BIRI) was done in diabetic male Wistar rats, and sodium azide treatment was given to high glucose NRK52E cells to mimic hypoxia-reperfusion injury. In diabetic rats, phloretin (50 mg/kg/per os (p.o.)) and losartan (10 mg/kg/p.o.) treatment was given for 4 days and 1 h prior to surgery while in NRK52E cells, both drugs (phloretin 50 μM and losartan 10 μM) were given 24 h prior to the hypoxia condition. The in vivo and in vitro samples were further used for different experiments. Key findingsTreatment with phloretin and losartan decreased diabetic and AKI biomarkers such as plasma creatinine, blood urea nitrogen (BUN), and kidney injury molecular 1 (KIM1). Moreover, a combination of phloretin and losartan significantly preserved ΔΨm and kidney morphology potentially by inhibiting TLR4-associated inflammation and AT1R-associated mitochondrial dysfunction, thereby oxidative stress. SignificanceCombination therapy of phloretin and losartan was more effective than monotherapies. Both drugs target TLR4/MyD88/NF-κB pathway and reduce inflammation and mitochondrial dysfunction in AKI under diabetic condition.

Phloretin Ameliorates Succinate-Induced Liver Fibrosis by Regulating Hepatic Stellate Cells.

Hepatic stellate cells (HSCs) are the major cells which play a pivotal role in liver fibrosis. During injury, extracellular stimulators can induce HSCs transdifferentiated into active form. Phloretin showed its ability to protect the liver from injury, so in this research we would like to investigate the effect of phloretin on succinate-induced HSCs activation in vitro and liver fibrosis in vivo study. In in vitro, succinate was used to induce HSCs activation, and then the effect of phloretin on activated HSCs was examined. In in vivo, succinate was used to generated liver fibrosis in mouse and phloretin co-treated to check its protection on the liver. Phloretin can reduce the increase of fibrogenic markers and inhibits the proliferation, migration, and contraction caused by succinate in in vitro experiments. Moreover, an upregulation of proteins associated with aerobic glycolysis occurred during the activation of HSCs, which was attenuated by phloretin treatment. In in vivo experiments, intraperitoneal injection of phloretin decreased expression of fibrotic and glycolytic markers in the livers of mice with sodium succinate diet-induced liver fibrosis. These results suggest that aerobic glycolysis plays critical role in activation of HSCs and succinate can induce liver fibrosis in mice, whereas phloretin has therapeutic potential for treating hepatic fibrosis. Conclusion: Intraperitoneal injection of phloretin attenuated succinate-induced hepatic fibrosis and alleviates the succinate-induced HSCs activation.

Antimicrobial Susceptibility of Staphylococcus aureus Strains and Effect of Phloretin on Biofilm Formation.

Staphylococcus aureus and methicillin-resistant S. aureus (MRSA) are known to be responsible of various infections, including biofilm-associated diseases. The aim of this study was to analyze 19 strains of S. aureus from orthopedic sites in terms of phenotypic antimicrobial susceptibility against 13 selected antibiotics, slime/biofilm formation, molecular analysis of specific antibiotic resistance genes (mecA, cfr, rpoB), and biofilm-associated genes (icaADBC operon). Furthermore, the effect of phloretin on the production of biofilm was evaluated on 8 chosen isolates. The susceptibility test confirmed almost allstrains were resistant to cefoxitin and oxacillin. Most strains possessthe mecA, whereas none of the strains had the cfr gene. Four strains (1, 7, 10, and 24) presented single-nucleotide polymorphisms (SNPs) in rpoB, which confer rifampicin resistance. IcaD was detected in all tested strains, whereas icaR was only found in two strains (24 and 30). Phloretin had a dose-dependent effect on biofilm production. Specifically, 0.5 × MIC determined biofilm inhibition in 5 out of 8 strains (8, 24, 25, 27, 30), whereas an increase in biofilm production was detected with phloretin at the 0.125 × MIC across all tested strains. These data are useful to potentially develop novel compounds against antibiotic-resistant S. aureus.

Neuroprotective Effect of Phloretin in Rotenone-Induced Mice Model of Parkinson's Disease: Modulating mTOR-NRF2-p62 Mediated Autophagy-Oxidative Stress Crosstalk.

Parkinson's disease (PD) is an age-related progressive multifactorial, neurodegenerative disease. The autophagy and Keap1-Nrf2 axis system are both implicated in the oxidative-stress response, metabolic stress, and innate immunity, and their dysregulation is associated with pathogenic processes in PD. Phloretin (PLT) is a phenolic compound reported possessing anti-inflammatory and antioxidant activities. To evaluate the neuroprotective potential of PLT in PD via modulating the autophagy-antioxidant axisMethods:The neuroprotective effect of PLT was evaluated in vitro using rotenone (ROT) exposed SH-SY5Y cell line and in vivo using ROT administered C57BL/6 mice. Mice were administered with PLT (50 and 100 mg/kg, p.o.) concomitantly with ROT (1 mg/kg, i.p) for 3 weeks. Locomotive activity and anxiety behaviors were assessed using rotarod and open field tests respectively. Further apoptosis (Cytochrome-C, Bax), α-Synuclein (α-SYN), tyrosine hydroxylase (TH), antioxidant proteins (nuclear factor erythroid 2-related factor 2 (NRF2), heme oxygenase-1 (HO-1) and autophagic (mTOR, Atg5,7, p62, Beclin,LC3B-I/II) protein activity were evaluated both in in vitro and in vivo. PLT improved locomotive activity and anxiety-like behavior in mice. Further PLT diminished apoptotic cell death, α-SYN expression and improved the expression of TH, antioxidant, and autophagic regulating protein. Taken together, present data deciphers that the PLT effectively improves motor and non-motor symptoms via modulating the mTOR/NRF2/p62 pathway-mediated feedback loop. Hence, PLT could emerge as a prospective disease-modifying drug for PD management.

Phloretin suppresses intestinal inflammation and maintained epithelial tight junction integrity by modulating cytokines secretion in in vitro model of gut inflammation

Ulcerative colitis is a type of inflammatory bowel disease which in long run can lead to colorectal cancer (CRC). Chronic inflammation can be a key factor for the occurrence of CRC thus mitigating an inflammation can be a preventive strategy for the occurrence of CRC. In this study we have explored the anti-inflammatory potential of phloretin, in in vitro gut inflammation model, developed by co-culture of Caco2 (intestinal epithelial) cells and RAW264.7 macrophages (immune cells). Phloretin is a dihydrochalcone present in apple, pear and strawberries. An anti-inflammatory effect of phloretin in reducing LPS induced inflammation and maintenance of transepithelial electric resistance (TEER) in Caco2 cells was examined. Paracellular permeability assay was performed using Lucifer yellow dye to evaluate the effect of phloretin in inhibiting gut leakiness caused by inflammatory mediators secreted by activated macrophages. Phloretin attenuated LPS induced nitric oxide levels, oxidative stress, depolarization of mitochondrial membrane potential in Caco2 cells as evidenced by reduction in reactive oxygen species (ROS), and enhancement of MMP, and decrease in inflammatory cytokines IL8, TNFα, IL1β and IL6. It exhibited anti-inflammatory activity by inhibiting the expression of NFκB, iNOS and Cox2. Phloretin maintained the epithelial integrity by regulating the expression of tight junction proteins ZO1, occludin, Claudin1 and JAM. Phloretin reduced LPS induced levels of Cox2 along with the reduction in Src expression which further regulated an expression of tight junction protein occludin. Phloretin in combination to sodium pyruvate exhibited potential anti-inflammatory activity via targeting NFkB signaling. Our findings paved a way to position phloretin as nutraceutical in preventing the occurrence of colitis and culmination of disease into colitis associated colorectal cancer.

Phloretin-induced STAT3 inhibition suppresses pancreatic cancer growth and progression via enhancing Nrf2 activity

BackgroundPancreatic ductal adenocarcinoma (PDAC) is a malignant pancreatic tumor charactered by a rapid progression and high lethal rate. Hyperactivation of STAT3 signaling exerts a vital effect on the growth and progression of PDAC. While dietary flavonoid phloretin has anti-inflammatory and antioxidant activities, it remains unclear whether phloretin has anti-tumor effects on PDAC. PurposeThe focus of the present study is to elucidate the effects of phloretin on PDAC and investigate its underlying molecular mechanisms. Study design and methodsEffect of phloretin were assessed in the pancreatic cancer cells (PCCs) by colony formation assay, real-time cell analysis, flow cytometry, Immunofluorescence staining, and cell migration assay. The expressions of mRNA and protein were respectively analyzed by quantitative PCR and Western blotting. A xenograft model was used to appraise the antitumor efficacy of phloretin. ResultsPhloretin treatment significantly restrained cell viability and metastasis, induced DNA injury and ROS accumulation, and triggered mitochondrial-dependent apoptosis in PCCs. Mechanistically, phloretin exhibits anti-tumor potential via inactivating STAT3 signaling and enhancing Nrf2 activity. STAT3 overexpression and Nrf2 silencing partially relieved phloretin-induced inhibition on cell growth and metastasis in PCCs. Phloretin remarkably blocked pancreatic tumor growth and metastasis in vivo. ConclusionsPhloretin suppresses pancreatic cancer growth and progression through inhibition of STAT3 mediated by enhancing Nrf2 activity. Phloretin may serve as a promising therapeutic agent for PDAC.

Phloretin ameliorates heart function after myocardial infarction via NLRP3/Caspase-1/IL-1β signaling

Objectives/AimsInflammation is crucial in structural and electrical remodeling after myocardial infarction (MI), affecting cardiac pump function and conduction pathways. Phloretin possesses an anti-inflammation role by inhibiting the NLRP3/Caspase-1/IL-1β pathway. However, the effects of Phloretin on cardiac contractile and electrical conduction function after MI remained unclear. Therefore, we aimed to investigate the potential role of Phloretin in a rat model of MI. MethodsRats were assigned into four groups: Sham, Sham+Phloretin, MI and MI+Phloretin, with ad libitum food and water. In the MI and MI+Phloretin groups, the left anterior descending coronary artery was occluded for 4 weeks, while the Sham and Sham+Phloretin groups received sham operation. The Sham+Phloretin group and the MI+Phloretin group received oral administration of Phloretin. In vitro, H9c2 cells were subjected to hypoxic conditions to simulate an MI model, with Phloretin for 24 h. Cardiac electrophysiological properties were assessed following MI, including the effective refractory period (ERP), action potential duration (APD)90 and ventricular fibrillation (VF) incidence. Echocardiography evaluated left ventricular ejection fraction (LVEF), left ventricular fraction shortening (LVFS), left ventricular internal diameter at end-diastole (LVIDd), left ventricular internal diameter at end-systole (LVIDs), left ventricular end-systolic volume (LVESV) and left ventricular end-diastolic volume (LVEDV) to assess cardiac function. Serum type B natriuretic peptide (BNP) level was applied to evaluate the degree of Heart failure (HF). The fibrosis area and severity were assessed by Masson staining and protein expression levels of collagen 3, collagen 1, TGF-β and α-SMA. Western blot analysis estimated the protein expression levels of NLRP3, Pro Caspase-1, Caspase-1, ASC, IL-18, IL-1β, pp38, p38, and Connexin43(Cx43) to elucidate the influence of inflammation on electrical remodeling after MI. ResultsOur findings demonstrate that Phloretin inhibits the NLRP3/Caspase-1/IL-1β pathway, leading to the upregulation of Cx43 by limiting p38 phosphorylation, which further decreases susceptibility to ventricular arrhythmias (VAs). Additionally, Phloretin attenuated fibrosis by inhibiting inflammation to prevent HF. In vitro experiments also provided strong evidence supporting the inhibitory effects of Phloretin on the NLRP3/Caspase-1/IL-1β pathway. ConclusionOur results suggest that Phloretin could suppress the NLRP3/Caspase-1/IL-1β pathway to reverse structural and electrical remodeling after MI to prevent the occurrence of VAs and HF.

Inhibition of biofilm formation and virulence factors of cariogenic oral pathogen Streptococcus mutans by natural flavonoid phloretin

ABSTRACT Objectives To evaluate the effect and mechanism of action of the flavonoid phloretin on the growth and sucrose-dependent biofilm formation of Streptococcus mutans. Methods Minimum inhibitory concentration, viability, and biofilm susceptibility assays were conducted to assess antimicrobial and antibiofilm effect of phloretin. Biofilm composition and structure were analysed with scanning electron microscopy (SEM) and confocal laser scanning microscopy (CLSM). Water-soluble (WSG) and water-insoluble glucan (WIG) were determined using anthrone method. Lactic acid measurements and acid tolerance assay were performed to assess acidogenicity and aciduricity. Reverse transcription quantitative PCR (RT-qPCR) was used to measure the expression of virulence genes essential for surface attachment, biofilm formation, and quorum sensing. Results Phloretin inhibited S. mutans growth and viability in a dose-dependent manner. Furthermore, it reduced gtfB and gtfC gene expression, correlating with the reduction of extracellular polysaccharides (EPS)/bacteria and WIG/WSG ratio. Inhibition of comED and luxS gene expression, involved in stress tolerance, was associated with compromised acidogenicity and aciduricity of S. mutans. Conclusions Phloretin exhibits antibacterial properties against S. mutans, modulates acid production and tolerance, and reduces biofilm formation. Clinical significance Phloretin is a promising natural compound with pronounced inhibitory effect on key virulence factors of the cariogenic pathogen, S. mutans.

CUT&tag-seq analysis of heat stress response in broiler liver provides novel insights into the improved thermotolerance by dietary phloretin

This work aimed to study the effect of phloretin on antioxidant profiles through nuclear factor erythroid 2–related 2 (Nrf2)-DNA interactions in the liver of heat-stressed broilers by Cleavage Under Targets and Tagmentation combined with high-throughput sequencing (CUT&Tag-seq). One hundred and sixty 22-day-old Arbor Acres broilers were divided into four groups: a normal temperature group (NT: 22.8–23.4 °C and 46–55.8 % humidity) was fed a basal diet and three high temperature groups (China Summer condition: 29.7–31.7 °C and 77.9–94.8 % humidity) were fed the basal diet supplemented with 0 (HT group), 100 mg/kg (LT group) and 200 mg/kg (PT group) phloretin. Liver samples were taken from 42-day-old broilers. High temperature condition increased (P ≤ 0.05) the malondialdehyde (MDA) level, but decreased (P ≤ 0.05) the activities and mRNA expression levels of glutathione peroxidase (GSH-Px), superoxide dismutase (SOD), catalase (CAT), and Nrf2. Dietary 200 mg/kg phloretin decreased (P ≤ 0.05) the MDA level, but increased (P ≤ 0.05) the activities and mRNA expression levels of GSH-Px, SOD, CAT and Nrf2 in the liver of heat-stressed broilers. CUT&Tag-seq showed that 4042 DEPs were up-regulated, while 2322 DEPs were down-regulated in the PT group compared with the HT group. The Nrf2-binding gene of DEPs contained SOD3, CAT, SOD2, and p38 mitogen-activated protein kinase. Most TOP20 significant KEGG pathways were associated with “Environmental Information Processing”. Summary, phloretin could improve oxidative damage by Nrf2 and its downstream DNA-sites including genes and Nrf2-bingding non-coding RNAs in the liver of heat-stressed broilers.

3-OH Phloretin Inhibits High-Fat Diet-Induced Obesity and Obesity-Induced Inflammation by Reducing Macrophage Infiltration into White Adipose Tissue.

Phloretin and its glycoside phlorizin have been reported to prevent obesity induced by high-fat diet (HFD), but the effect of 3-OH phloretin, a catechol metabolite of phloretin, has not been investigated. In this study, we investigated the anti-obesity effects of phloretin and 3-OH phloretin in HFD-fed mice. The body weight gain induced by HFD was more inhibited by administration of 3-OH phloretin than by phloretin. The increases in fat mass, white adipose tissue (WAT) weight, adipocyte size, and lipid accumulation by HFD were also remarkably inhibited by 3-OH phloretin and, to a lesser extent, by phloretin. The HFD-induced upregulation of chemokines and pro-inflammatory cytokines was suppressed by 3-OH phloretin, preventing M1 macrophages from infiltrating into WAT and thereby reducing WAT inflammation. 3-OH phloretin also showed a more potent effect than phloretin on suppressing the expression of adipogenesis regulator genes, such as PPARγ2, C/EBPα, FAS, and CD36. Fasting blood glucose and insulin levels increased by HFD were diminished by the administration of 3-OH phloretin, suggesting that 3-OH phloretin may alleviate obesity-induced insulin resistance. These findings suggested that 3-OH phloretin has the potential to be a natural bioactive compound that can be used in the prevention or treatment of obesity and insulin resistance.

In-Vivo And Histological Toxicity Profiling Of A Natural Phenol: Phloretin

Phloretin is a flavonoid, which is having strong antioxidant potentials and used in the treatment of numerous disorders. The aim of this study to evaluate the possible toxicological effect of Phloretin in Swiss albino mice. Methods: Single dose of Phloretin was administered stepwise in two groups by oral route and general behaviour, adverse effects and mortality were determined up to 14 days and compared to normal group. In sub-acute study, Phloretin was administered orally for 28 days to the four experimental groups and their body weight was measured each alternate day from the first day of dosing. The final body weight was recorded on 29th day and animals were euthanized by using thiopentone sodium, blood was collected and later haematological, lipid profile, biochemical parameter was evaluated and compared to normal group. Result: In acute toxicity study, no abnormal general behaviour, adverse effects were reported. The body weight, haematological, lipid profile and biochemical parameter also not recorded with any significant changes in sub-acute toxicity study. No significant mortality was reported in both the study. Histopathological examination revealed no alterations in clinical signs or organ weight at any dose. Conclusion: The result concludes that the oral administration of Phloretin did not produce any significant toxic effect in swiss albino mice. Hence, the test drug Phloretin is safe for therapeutic uses.

Protective Effect of Phloretin against Hydrogen Peroxide-Induced Oxidative Damage by Enhancing Autophagic Flux in DF-1 Cells.

Phloretin (PHL) is a dihydrochalcone flavonoid isolated from the peel and root bark of apples, strawberries, and other plants with antioxidative characteristic. In this study, we aimed to investigate the protective effect and the potential mechanism of PHL on hydrogen peroxide (H2O2)-induced oxidative damage in DF-1 cells. The results showed that PHL exhibited no cytotoxic effect on DF-1 cells at concentration below 20 μM. PHL markedly increased H2O2-reduced cell viability, decreased H2O2-induced apoptosis, as evidenced by reduced apoptosis rate, the upregulation of gene and protein level of Bcl-2, and the downregulation of gene and protein level of Bax and Cleaved caspase3. In addition, PHL reduced H2O2-induced reactive oxygen species (ROS) production and restored antioxidant enzymes activities as well as mitochondrial membrane potential in a dose-dependent manner. Moreover, PHL prior to H2O2 further increased LC3-II level, promoted p62 turnover and improved lysosomal function. Importantly, autophagy inhibitor chloroquine (CQ) reversed the protective effect of PHL, and increased H2O2-induced apoptosis. Furthermore, PHL inhibited the phosphorylation levels of ERK, p38, and JNK. Collectively, these results indicate that PHL could attenuate H2O2-induced oxidative injury and apoptosis by maintaining lysosomal function and promoting autophagic flux, and MAPKs pathway may be involved in this process. Our study provides evidence that PHL could as a new strategy to against oxidative damage in poultry industry.

Therapeutic Potential and Pharmaceutical Development of a Multitargeted Flavonoid Phloretin.

Phloretin is a flavonoid of the dihydrogen chalcone class, present abundantly in apples and strawberries. The beneficial effects of phloretin are mainly associated with its potent antioxidant properties. Phloretin modulates several signaling pathways and molecular mechanisms to exhibit therapeutic benefits against various diseases including cancers, diabetes, liver injury, kidney injury, encephalomyelitis, ulcerative colitis, asthma, arthritis, and cognitive impairment. It ameliorates the complications associated with diabetes such as cardiomyopathy, hypertension, depression, memory impairment, delayed wound healing, and peripheral neuropathy. It is effective against various microbial infections including Salmonella typhimurium, Listeria monocytogenes, Mycobacterium tuberculosis, Escherichia coli, Candida albicans and methicillin-resistant Staphylococcus aureus. Considering the therapeutic benefits, it generated interest for the pharmaceutical development. However, poor oral bioavailability is the major drawback. Therefore, efforts have been undertaken to enhance its bioavailability by modifying physicochemical properties and molecular structure, and developing nanoformulations. In the present review, we discussed the pharmacological actions, underlying mechanisms and molecular targets of phloretin. Moreover, the review provides insights into physicochemical and pharmacokinetic characteristics, and approaches to promote the pharmaceutical development of phloretin for its therapeutic applications in the future. Although convincing experimental data are reported, human studies are not available. In order to ascertain its safety, further preclinical studies are needed to encourage its pharmaceutical and clinical development.