The Daily calorie intake of non-alcoholic fatty liver disease Flavonoidw has been increasing an the last few decades. Most recent estimates, as per the Flavonoids and liver protection journalsuggest that an in 3 adults globally are currently Flavonoids and liver protection with NAFLD.
Flavonoids have been associated not only with a Flavonoids and liver protection risk of lover liver disease protwction also a reduced risk pdotection its progression in Increase energy and focus who already Flavonods it.
My interest in flavonoids stems from Flavinoids fact that wherever I look in liverr literature, I simply Flavonoids and liver protection help but observe FFlavonoids Flavonoids and liver protection Flavlnoids associated with positive health outcomes.
Whether you are looking at mental health, longevity, insulin resistance, inflammation or otherwise — flavonoids keep popping up. Fortunately, a paper out of The Journal Of Nutritional Biochemistryhad some answers for me. Please note that these are observational findings based on a sample size of nearly 18, adults from the United States.
Take a look at my flavonoid-finder below, while keeping in mind even more recent research suggests that the anthocyanin and isoflavone groups may be the most beneficial flavonoids for liver health. I can help, reach out today to learn more about my new fatty liver nutrition coaching program.
Eat More Flavonoids To Reduce Fatty Liver Risk Posted on May 3, December 11, by Andy the RD. PREVIOUS POST. NEXT POST. Sign up for My Newsletter. By completing this form for Andy The RD, I expressly provide my consent to receive electronic messages from Andy The RD retroactively, today and in the future.
I understand that I may withdraw my consent by unsubscribing at anytime. Sign Up for My Newsletter.
: Flavonoids and liver protection| Study investigates liver disease protective effect of flavonoids | I can help, reach out today to learn more about my new fatty liver nutrition coaching program. Eat More Flavonoids To Reduce Fatty Liver Risk Posted on May 3, December 11, by Andy the RD. PREVIOUS POST. NEXT POST. Sign up for My Newsletter. These compounds exhibit antioxidant and anti-inflammatory properties, which contribute to the prevention of oxidative stress, inflammation, and lipid accumulation in the liver, all of which are key factors in the development and progression of liver diseases Tang et al. Specifically, they can stimulate liver enzymes such as superoxide dismutase SOD and glutathione peroxidase GSH-Px , which play crucial roles in the antioxidant defense system and hepatic detoxification Yu et al. The hepatoprotective effects of flavonoids also extend to mitigating liver damage caused by factors such as alcohol consumption, drug-induced toxicity, and viral infections Brunetti et al. These compounds exert protective effects by reducing inflammation, oxidative stress, and apoptosis in liver cells, thereby preserving liver structure and function Wan et al. It is important to note that further studies are necessary to establish optimal dosage, bioavailability, and specific mechanisms of action for flavonoids in liver health Tang et al. Additionally, the effects of different types of flavonoids and their interactions with other compounds need to be explored to fully understand their hepatoprotective potential. In conclusion, current research suggests that flavonoids possess hepatoprotective properties and offer potential applications in preventing liver diseases, supporting liver function, and mitigating liver damage Li et al. The antioxidant, anti-inflammatory, and detoxifying properties of flavonoids contribute to their beneficial effects on liver health. However, more comprehensive studies are required to determine the specific mechanisms and clinical implications of flavonoids in liver disease prevention and treatment. References Brunetti, C. The study findings suggest that increased consumption of the flavonoid subclasses of anthocyanins and isoflavones may provide protection against MAFLD. The study exhibits promising data in support of a modifiable lifestyle factor for the prevention of a highly prevalent disease, highlighting a need to focus on flavonoid subclass and their differing mechanisms of action. In addition, the variation of effects by established risk factor such as gender, age and obesity have further emphasised the need for personalisation in future prevention and treatment interventions. Whilst the study provides reliable data due to the large, representative sample size used, cause and effect cannot be established due to the study design. Therefore, further RCTs would be required to prove the protective effect. CONTINUE TO SITE Or wait Facebook Twitter Linkedin. |
| Top bar navigation | The use of carbon tetrachloride [ 22 ] and other composite factors such as a high-fat, high-cholesterol, and low-protein diet as well as alcohol drinking can induce liver injury models in animals, with pathological results very similar to human chronic liver diseases. We extended our search range to assess whether the top-predicted flavonoids and their metabolic byproducts have reported beneficial effects on NAFLD. Elsevier, ; pp. Taken together, these results indicate that the proximity scores are reliable traits for predicting novel candidates for preventing NAFLD progression. The researchers utilised data from 4, participants gained from the National Health and Nutrition Examination Survey NHANES , with flavonoid and subclasses intake calculated using the Food and Nutrient Database for Dietary Studies FNDDS of |
| ORIGINAL RESEARCH article | Supplementing with flavonoids has also shown promise in preventing and treating liver diseases. However, it's important to note that the effectiveness of supplements may vary based on the specific dose and formulation. Further research is needed to determine the optimal dosage and duration of supplementation for liver disease prevention and treatment. How to Incorporate Flavonoids into Your Diet: Practical Tips Incorporating flavonoids into your diet can be a simple and enjoyable process since you have so many food options. The first step is understanding the benefits of flavonoids for liver health and overall well-being. You can start by identifying foods high in these bioactive compounds, such as berries, green tea, and citrus fruits. These natural sources are delicious and packed with antioxidant activity, thanks to compounds like anthocyanins and quercetin. To make incorporating these foods into your daily diet easier, you can get creative with recipes and meal plans. For example, you can add berries to your morning oatmeal or incorporate them into a refreshing smoothie. Green tea can be enjoyed as a beverage or used as a base for flavorful iced teas, and citrus fruits can be used in salads, desserts or enjoyed as a snack. In addition to food, you may also consider taking supplements or extracts to increase your flavonoid intake. However, it is important to remember that these supplements should not replace a balanced diet. They should only be used as a complement to a healthy lifestyle. What is the Future of Flavonoid Research? The future of flavonoid research holds great promise. Ongoing studies are exploring the potential health benefits of these compounds, particularly in preventing chronic diseases like cancer and cardiovascular disease. Researchers are also investigating specific types of flavonoids for their therapeutic effects and role in brain function and cognitive decline. As with any kind of healthcare belief, it is important to give the research time to fully develop and mature before you rely on it too heavily. If you are at risk of liver disease or are treating it, don't jump headfirst into this treatment option. Discuss it with your healthcare professional to see what they think regarding your specific situation. Conclusion Flavonoids have shown great promise in promoting human health and fighting against various diseases. Their anti-inflammatory and antioxidant properties make them powerful allies in maintaining heart health and preventing cancer. This is also something that may prove to be a possible option in fighting liver disease. Bioinformatics 36, — Cheng, F. Quantitative Network Mapping of the Human Kinome Interactome Reveals New Clues for Rational Kinase Inhibitor Discovery and Individualized Cancer Therapy. Oncotarget 5, — Cowley, M. PINA v2. Davis, A. The Comparative Toxicogenomics Database: Update Demain, A. Importance of Microbial Natural Products and the Need to Revitalize Their Discovery. do Valle, I. Network Medicine Framework Shows that Proximity of Polyphenol Targets and Disease Proteins Predicts Therapeutic Effects of Polyphenols. Food 2, — CrossRef Full Text Google Scholar. Duez, H. Nuclear Receptors in the Control of the NLRP3 Inflammasome Pathway. Fazekas, D. SignaLink 2 - a Signaling Pathway Resource with Multi-Layered Regulatory Networks. BMC Syst. Guney, E. Network-based In Silico Drug Efficacy Screening. Gysi, D. Network Medicine Framework for Identifying Drug-Repurposing Opportunities for COVID Hornbeck, P. PhosphoSitePlus: A Comprehensive Resource for Investigating the Structure and Function of Experimentally Determined Post-translational Modifications in Man and Mouse. Huang, K. DeepPurpose: A Deep Learning Library for Drug-Target Interaction Prediction. Bioinformatics 36, 1—3. Huttlin, E. Architecture of the Human Interactome Defines Protein Communities and Disease Networks. Nature , — Jadeja, R. Jaeger, S. Mol2vec: Unsupervised Machine Learning Approach with Chemical Intuition. Keshava Prasad, T. Human Protein Reference Database Update. Kim, S. PubChem in New Data Content and Improved Web Interfaces. Koeberle, A. Multi-Target Approach for Natural Products in Inflammation. Drug Discov. Today 19, — Lee, W. Predicting Activatory and Inhibitory Drug-Target Interactions Based on Mol2vec and Genetically Perturbed Transcriptomes. bioRxiv , 1— Li, T. A Scored Human Protein-Protein Interaction Network to Catalyze Genomic Interpretation. Liu, Y. CB-dock: a Web Server for Cavity Detection-Guided Protein-Ligand Blind Docking. Acta Pharmacol. Luo, Y. A Network Integration Approach for Drug-Target Interaction Prediction and Computational Drug Repositioning from Heterogeneous Information. Mazidi, M. A Higher Flavonoid Intake Is Associated with Less Likelihood of Nonalcoholic Fatty Liver Disease: Results from a Multiethnic Study. Meyer, M. INstruct: A Database of High-Quality 3D Structurally Resolved Protein Interactome Networks. Bioinformatics 29, — Interactome INSIDER: a Structural Interactome Browser for Genomic Studies. Mi, H. Protocol Update for Large-Scale Genome and Gene Function Analysis with the PANTHER Classification System v. Millar, J. Short-term Overexpression of DGAT1 or DGAT2 Increases Hepatic Triglyceride but Not VLDL Triglyceride or apoB Production. Lipid Res. Mitra, S. Epidemiology of Non-alcoholic and Alcoholic Fatty Liver Diseases. Moon, D. Cancer Lett. Mosca, R. Interactome3D: Adding Structural Details to Protein Networks. Methods 10, 47— Müller, F. Human In Vitro Models of Nonalcoholic Fatty Liver Disease. Orchard, S. The MIntAct Project-IntAct as a Common Curation Platform for 11 Molecular Interaction Databases. Acids Res. Peri, S. Human Protein Reference Database as a Discovery Resource for Proteomics. Qiu, T. Exploring the Mechanism of Flavonoids through Systematic Bioinformatics Analysis. Rajendran, P. Suppression of Signal Transducer and Activator of Transcription 3 Activation by Butein Inhibits Growth of Human Hepatocellular Carcinoma In Vivo. Cancer Res. Rodrigues, T. Counting on Natural Products for Drug Design. Rolland, T. A Proteome-Scale Map of the Human Interactome Network. Cell , — Rothwell, J. Phenol-Explorer 3. Database , bat Shannon, P. Cytoscape: a Software Environment for Integrated Models of Biomolecular Interaction Networks. Genome Res. Subramanian, A. Resource A Next Generation Connectivity Map : L Platform Resource A Next Generation Connectivity Map. Tariq, Z. Are Oxidative Stress Mechanisms the Common Denominator in the Progression from Hepatic Steatosis towards Non-alcoholic Steatohepatitis NASH? Liver Int. Wang, W. Glycitin Suppresses Cartilage Destruction of Osteoarthritis in Mice. Inflammation 43, — Wen, M. Deep-Learning-Based Drug-Target Interaction Prediction. Proteome Res. Wu, Q. COACH-D: Improved Protein-Ligand Binding Sites Prediction with Refined Ligand-Binding Poses through Molecular Docking. Wu, W. Muscle-specific Deletion of Prkaa1 Enhances Skeletal Muscle Lipid Accumulation in Mice Fed a High-Fat Diet. Xue, R. TCMID: Traditional Chinese Medicine Integrative Database for Herb Molecular Mechanism Analysis. You, J. Predicting Drug-Target Interaction Network Using Deep Learning Model. Yu, J. Update on GlycerolPhosphate Acyltransferases: The Roles in the Development of Insulin Resistance. Nutr Diabetes 8, Zang, Y. Zhan, Z. Taxifolin Ameliorate High-Fat-Diet Feeding Plus Acute Ethanol Binge-Induced Steatohepatitis through Inhibiting Inflammatory Caspasedependent Pyroptosis. Food Funct. Keywords: flavonoids, non-alcoholic fatty liver disease, network pharmacology, network medicine, machine learning. Citation: Lee W-Y, Lee C-Y, Lee J-S and Kim C-E Identifying Candidate Flavonoids for Non-Alcoholic Fatty Liver Disease by Network-Based Strategy. doi: Received: 09 March ; Accepted: 22 April ; Published: 26 May Copyright © Lee, Lee, Lee and Kim. This is an open-access article distributed under the terms of the Creative Commons Attribution License CC BY. The use, distribution or reproduction in other forums is permitted, provided the original author s and the copyright owner s are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. kr ; Chang-Eop Kim, eopchang gachon. Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. Top bar navigation. About us About us. Who we are Mission Values History Leadership Awards Impact and progress Frontiers' impact Progress Report All progress reports Publishing model How we publish Open access Fee policy Peer review Research Topics Services Societies National consortia Institutional partnerships Collaborators More from Frontiers Frontiers Forum Press office Career opportunities Contact us. Sections Sections. About journal About journal. Article types Author guidelines Editor guidelines Publishing fees Submission checklist Contact editorial office. The study findings suggest that increased consumption of the flavonoid subclasses of anthocyanins and isoflavones may provide protection against MAFLD. The study exhibits promising data in support of a modifiable lifestyle factor for the prevention of a highly prevalent disease, highlighting a need to focus on flavonoid subclass and their differing mechanisms of action. In addition, the variation of effects by established risk factor such as gender, age and obesity have further emphasised the need for personalisation in future prevention and treatment interventions. Whilst the study provides reliable data due to the large, representative sample size used, cause and effect cannot be established due to the study design. Therefore, further RCTs would be required to prove the protective effect. CONTINUE TO SITE Or wait Facebook Twitter Linkedin. |
Flavonoids and liver protection -
To determine whether quercetin restricts hepatic injury, inflammation, and fibrosis through switching macrophages phenotype and influencing its function, we assessed the status of M1 macrophages and expression of proinflammatory cytokines associated with M1 markers in the fibrotic liver [such as TNF-α, IL-1β, IL-6, and monocyte chemotactic protein-1 MCP-1 ].
Of note, IL, an important cytokine produced by classically activated macrophages, could be served as an IHC marker to detect the M1-dominant subset in livers Beljaars et al.
Notably, these macrophages were found solely in the fibrotic collagen bands. We also confirmed these results via quantitative RT-PCR and found that repeated CCl 4 injection has been associated with enhanced proinflammatory cytokine markers in the liver, including TNF-α, MCP-1, IL-6, and IL-1β mRNA, as compared with the normal control.
However, compared with fibrotic mice receiving DMSO treatment, fibrotic mice receiving quercetin decreased the levels of TNF-α, IL-1β, IL-6, and MCP-1 mRNA expression by 4.
FIGURE 5. Effect of quercetin on M1 macrophage polarization and expression of inflammatory properties in fibrotic livers. A Representative immunostaining of IL, CD11c, and IRF5 in liver sections original magnification: × B Quantification of IL, CD11c, and IRF5 immunostaining in the liver from each group.
Taken together, these results show that quercetin inhibited M1 polarization of macrophage and reduced the expression of inflammatory properties in fibrotic livers following repeated injection CCl 4. In addition, we also evaluated the effect of quercetin on M2-polarized macrophages and activation in the development of liver fibrosis in vivo.
We used chitinaselike 3 Chi3l3; also known as Ym-1; mouse only and CD Beljaars et al. Moreover, the M2 skewing was further confirmed with quantitative RT-PCR for selective M2 typical markers such as Arginase I Arg I and Ym-1; and we observed the levels of M2 marker genes Arg I and Ym-1 in fibrotic livers decreased by quercetin-treated fibrotic mice when compared with DMSO-treated animals Figure 6C.
Together, these results show that quercetin inhibited M2-dominant macrophage polarization in fibrotic livers and limited immunosuppressive genes following CCl 4 administration in mice. FIGURE 6. Effect of quercetin on M2 macrophages polarization and expression of immunosuppressive genes in fibrotic livers.
A Representative immunostaining of Ym-1 and CD in liver sections original magnification: × B Quantification of Ym-1 and CD immunostaining in the liver from each group. To further interrogate whether quercetin treatment may prevent M1-polarized macrophages in fibrotic liver, we used the RAW Indeed, our experiment demonstrated that incubation with quercetin to the cells markedly suppressed M1-macrophages polarization as shown in immunostaining with anti-IL12 and anti-IRF5 Figure 7A.
Notably, we observed that quercetin, at this dosage, did not affect the cell viability of macrophages in vitro Figure 7B. We then examined the expression of M1 macrophages markers such as IL12 and IRF5 by western blotting; our results demonstrated that quercetin treatment significantly decreased the levels of those markers expression on macrophages when compared with vehicle-treated cells Figure 7C.
Furthermore, we also revealed that quercetin led to the substantially reduced M1-polarized macrophages as depicted in M1-related markers such as TNF -α, IL -1β, IL-6 , and nitric oxide synthase 2 NOS2 Figure 7D. Taken together, these data suggested that quercetin treatment may regulate the M1-polarized macrophages upon injury in vitro.
FIGURE 7. Quercetin treatment suppressed M1 polarization of macrophages in vitro. A Representative fluorescence microscopic images of RAW macrophages with anti-IL12 and anti-IRF5 whole-mount staining.
Quercetin- 50 μM or DMSO-treated M1-differentiated macrophages conditioned medium. Bars represent mean ± SD of at least three independent experiments. B Effect of quercetin 50 μM on the cell viability of macrophages.
C Western blotting analysis of M1-markers IL12 and IRF5 protein expression in macrophages RAW D Quantification gene expression analysis of M1-specific markers TNF-α, IL-1β, IL-6, and NOS2.
The mRNA levels were normalized to GAPDH mRNA levels and presented as fold stimulation mean ± SD versus vehicle-treated control. Recent data have suggested that Notch1 signaling was widely known as a key transcription factor related to M1 macrophage activation Lawrence and Natoli, ; Bansal et al.
To verify the involvement of quercetin in regulating M1 macrophages in liver fibrogenesis through Notch1 signaling pathway, we first examined the Notch1 expression and subcellular location in the liver. Then, we assessed the expression of Notch1 in livers from each group by quantitative RT-PCR and western blots.
Our data revealed that the levels of Notch1 expression in fibrotic livers were marked increase when compared with those in the normal control livers; however, quercetin-treated fibrotic mice decreased the levels of Notch1 gene and protein expression when compared with vehicle-treated fibrotic animals Figures 8B,C.
FIGURE 8. Quercetin inhibited hepatic Notch1 expression in CCl 4 -treated mice. A Immunofluorescent double staining of Notch1 in liver sections from each group. C Hepatic Notch1 mRNA expression was measured by quantitative RT-PCR. Finally, we determined whether quercetin inhibits M1 polarization macrophages through regulating Notch1 expression on macrophages in vitro.
RAW The results showed that the expression of Notch1 was increased in RAW Moreover, these alterations in expression of Notch1 are paralleled by the reduced genetic expression of the M1-specific markers in macrophages, such as IL-1β, IL-6, and NOS2 Figure 7D.
Collectively, these results indicated that quercetin inhibited M1-porlizated macrophages via targeting Notch1. FIGURE 9. Quercetin inhibited M1-macrophages polarization through regulating the expression Notch1 on macrophages in vitro.
A Undifferentiated RAW B Western blotting analysis for Notch1 in RAW C The levels of Notch1 mRNA expression in RAW The mRNA levels were normalized to GAPDH mRNA levels and presented as fold stimulation mean ± SD versus DMSO.
In this study, we have provided both in vivo validation and mechanistic insights regarding the protective effects of the flavonoid quercetin in CCl 4 -induced liver injury and fibrosis in mice.
Importantly, our current finding provides a novel insight for understanding the antifibrotic activity of quercetin, which owing to its inhibition of hepatic macrophages activation and infiltration, and modulation of M1-polarized macrophages via the Notch1 pathway.
In addition, we also have strongly reinforced the notion that hepatic macrophages play a critical role in the development of liver fibrosis, and strategies restraining M1 macrophage polarization phenotype may protect against exacerbated inflammation and thus restrict liver fibrosis Sica et al.
Quercetin, a polyphenol diferuloylmethane , has manifested a diverse range of pharmacological activities including anti-inflammatory, antioxidant, antibacterial, and antitumor properties Russo et al. In the present experiment, using the well-established liver fibrosis model by injection CCl 4 in mice, we provided more evidence that quercetin ameliorated liver inflammation and fibrosis Figure 1.
In liver fibrogenesis, excess ECMs, including collagen, are mainly produced by activated HSCs Friedman, ; Tsuchida and Friedman, Our results also demonstrated that quercetin inhibited the activation of HSCs by CCl 4 intoxication Figure 3.
Moreover, when we examined collagen synthesis by measuring the levels of expression of mRNA encoding Collagen α3 I and Collagen α4 I , and the activated HSC markers, we found that the expression levels of these fibrogenic markers were markedly lower in quercetin- than in vehicle-treated mice after 8 weeks of CCl 4 injection Figure 2C.
These data are consistent with the observation that quercetin treatment inhibited HSC activation in vitro as shown for the expression of genetic markers such as Collagen α1 I , TGF-β1, and α-SMA Li et al. Here, we provided evidence that quercetin inhibited liver fibrosis through regulating macrophage polarization and function via Notch1 pathway.
Emerging data have recently demonstrated that macrophages play a complex role in liver fibrogenesis, involved in progression and resolution of hepatic fibrosis Sica et al.
Inflammatory cytokines released from those cells perpetuate inflammation as well as activating HSCs Pradere et al. In this study, we demonstrated that quercetin reduced hepatic macrophage number and ameliorated liver fibrosis following CCl 4 treatment Figure 4.
Notably, our data further suggested that quercetin suppressed M1-polarized macrophages that have inflammatory properties and mediate excessive liver inflammation and fibrosis Figure 5.
Consistent with the inhibition in M1 macrophages activation and shift, the inflammatory cytokines were decreased in quercetin-treated fibrotic livers and in quercetin-treated macrophages when compared with the respective controls Figure 5C.
In order to investigate the effect of quercetin on M1-polarized macrophages, we used Raw We found that quercetin indeed blocked LPS-mediated M1 macrophages activation as measured by immunofluorescence, western blots, and quantitative RT-PCR Figure 7.
Therefore, our data indicated that quercetin could serve as a regulator of macrophage recruitment and polarization in injury liver. We also assessed the effect of quercetin on M2-polarized macrophages in fibrotic livers in mice induced by CCl 4 for 8 weeks.
However, treatment of fibrotic mice with quercetin inhibited M2 macrophages polarization and decreased expression of classic M2 genes in fibrotic livers Figure 6. On the contrary, previous in vitro study has demonstrated that quercetin could induce M2 polarized macrophages Dong et al. It is worth to note that inactivation of the M2 macrophages contributed to diet-induced NASH in vivo studies and data have recently demonstrated that M2-polarized macrophages promote resolution of inflammation and tissue repair Beljaars et al.
Those different results indicated there is remarkable heterogeneity of liver macrophages with diverse functions, and that function varies according to the phage of injury and depending on the hepatic microenvironment, and is also influenced by the nature of the underlying liver injury Tacke and Zimmermann, ; Tacke, Thus, understanding of macrophage polarization and function is a keystone of deciphering liver fibrogenesis.
Future studies are needed to further confirm whether quercetin mediated the M2 macrophages polarization both in vivo and in vitro.
Recent investigations have focused on elucidating the molecular mechanisms that suppress inflammation and prevent the development of fibrosis Wynn and Vannella, It has revealed that macrophage differentiation and activation is subjected to tight control by several mechanisms, including signaling molecules, transcription factors, epigenetic mechanisms, and posttranscriptional regulators Lawrence and Natoli, ; Wynn et al.
Of note, emerging evidence has suggested that Notch pathway plays an important role in macrophage-mediated inflammation Palaga et al. A recent study demonstrated that Notch1-mediated signaling regulation of M1 macrophage activation contributed to the inflammatory pathologies in alcoholic liver disease and obesity-induced liver disease Xu et al.
It has also been reported that suppressor of cytokine signaling 3 SOCS3 may play an important role in Notch signaling-mediated M1 macrophage polarization Eun and Jeong, In this study, we demonstrated that Notch1 expression on macrophages was increased during liver injury in mice; however, quercetin treatment abrogated the increased level of Notch1 expression Figure 8.
Additionally, in the presence of LPS-induced macrophage activation in vitro , in line with M1 polarization, the expression of Notch1 on macrophages was increased. However, quercetin treatment inhibited M1 polarization and the Notch1 expression on macrophages Figure 9.
Collectively, our data highlight a key role for the Notch1 pathway in regulating M1 macrophage polarization in liver injury and fibrosis, indicating that blockade of Notch1 signaling may represent a promising therapeutic target for chronic liver inflammation and fibrosis. Our data lead the evidence for supporting the concept that the hepatic macrophages play a key role in the development of liver fibrosis; and quercetin treatment could be a potential agent for chronic liver inflammation and fibrosis, at least in part, by manipulating macrophage phenotype and activation.
The present study was approved by the Animal Care Committee of Fudan University Shanghai, China. XL and CT conceived the study and wrote the manuscript. XL, SZ, and CT contributed to the work designing, performing, analyzing, and interpreting data from all the experiments.
QY, QJ, SZ, and LL participated in the design, acquisition, analysis, and interpretation of the data. CT and XL carried out the animal model and all the in vivo animal experiments. CT, SZ, and XL interpreted the data and finalized the article. All authors have critically revised and approved the final manuscript and agreed to be accountable for all aspects of the work.
This work was supported by the National Natural Science Foundation of China grant no. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Alzaid, F. IRF5 governs liver macrophage activation that promotes hepatic fibrosis in mice and humans. JCI Insight 1:e doi: PubMed Abstract CrossRef Full Text Google Scholar. Bansal, R. The interplay of the notch signaling in hepatic stellate cells and macrophages determines the fate of liver fibrogenesis.
Beljaars, L. Hepatic localization of macrophage phenotypes during fibrogenesis and resolution of fibrosis in mice and humans. Dong, J. Lipid Res. Duffield, J. Selective depletion of macrophages reveals distinct, opposing roles during liver injury and repair. Eun, H.
Dual notch signaling in proinflammatory macrophage activation. Hepatology 63, — Friedman, S. Mechanisms of hepatic fibrogenesis. Gastroenterology , — Hernandez-Ortega, L. Horrillo, R. Comparative protection against liver inflammation and fibrosis by a selective cyclooxygenase-2 inhibitor and a nonredox-type 5-lipoxygenase inhibitor.
Kim, Y. Anti-Inflammatory effect of quercetin on RAW Molecules Kimball, A. Notch regulates macrophage-mediated inflammation in diabetic wound healing. Kobuchi, H. Quercetin inhibits inducible ICAM-1 expression in human endothelial cells through the JNK pathway. Labonte, A. Expression of scavenger receptor-AI promotes alternative activation of murine macrophages to limit hepatic inflammation and fibrosis.
Hepatology 65, 32— Lawrence, T. Transcriptional regulation of macrophage polarization: enabling diversity with identity. Li, X. Quercetin protects mice from ConA-Induced hepatitis by inhibiting HMGB1-TLR expression and down-regulating the nuclear factor Kappa B pathway.
Inflammation 39, 96— Placental growth factor contributes to liver inflammation, angiogenesis, fibrosis in mice by promoting hepatic macrophage recruitment and activation.
Placental growth factor silencing ameliorates liver fibrosis and angiogenesis and inhibits activation of hepatic stellate cells in a murine model of chronic liver disease. Marcolin, E. Quercetin treatment ameliorates inflammation and fibrosis in mice with nonalcoholic steatohepatitis.
Miura, K. Hepatic recruitment of macrophages promotes nonalcoholic steatohepatitis through CCR2. Liver Physiol. Ohtsuki, T. M2 macrophages play critical roles in progression of inflammatory liver disease in hepatitis C virus transgenic mice.
Overman, A. Quercetin attenuates inflammation in human macrophages and adipocytes exposed to macrophage-conditioned media.
Palaga, T. Notch signaling is activated by TLR stimulation and regulates macrophage functions. Pellicoro, A. Liver fibrosis and repair: immune regulation of wound healing in a solid organ. Pradere, J. Hepatic macrophages but not dendritic cells contribute to liver fibrosis by promoting the survival of activated hepatic stellate cells in mice.
Hepatology 58, — Russo, M. The flavonoid quercetin in disease prevention and therapy: facts and fancies. Scheuer, P. Classification of chronic viral hepatitis: a need for reassessment.
CrossRef Full Text Google Scholar. Seki, E. Hepatic inflammation and fibrosis: functional links and key pathways. Hepatology 61, — Sica, A. Macrophage plasticity and polarization in liver homeostasis and pathology. Hepatology 59, — Macrophage plasticity and polarization: in vivo veritas. Svendsen, P.
Antibody-directed glucocorticoid targeting to CD in M2-type macrophages attenuates fructose-induced liver inflammatory changes. Methods Clin. Tacke, F. Targeting hepatic macrophages to treat liver diseases. Macrophage heterogeneity in liver injury and fibrosis. Tosello-Trampont, A. Tsuchida, T.
Content: Citation Only. Citation and Abstract. About this article ×. Cite this article as: Pisonero-Vaquero Sandra, Gonzalez-Gallego Javier, Sanchez-Campos Sonia and Garcia-Mediavilla Victoria Maria, Flavonoids and Related Compounds in Non-Alcoholic Fatty Liver Disease Therapy, Current Medicinal Chemistry ; 22 Close About this journal.
Related Journals Anti-Cancer Agents in Medicinal Chemistry. Current Analytical Chemistry. Current Computer-Aided Drug Design. Current Bioactive Compounds.
Current Cancer Drug Targets. Current Cancer Therapy Reviews. Current Diabetes Reviews. Current Drug Safety.
View More. Related Books Frontiers in Computational Chemistry. Advances in Dye Degradation. COVID 19 — Monitoring with IoT Devices. Frontiers in Clinical Drug Research: Anti-Infectives.
Advanced Pharmacy. Advances in Organic Synthesis. Plant-derived Hepatoprotective Drugs. Frontiers in Natural Product Chemistry. The Role of Chromenes in Drug Discovery and Development. Article Metrics. Journal Information. For Authors. Author Guidelines Graphical Abstracts Fabricating and Stating False Information Research Misconduct Post Publication Discussions and Corrections Publishing Ethics and Rectitude Increase Visibility of Your Article Archiving Policies Peer Review Workflow Order Your Article Before Print Promote Your Article Manuscript Transfer Facility Editorial Policies Allegations from Whistleblowers Announcements Forthcoming Thematic Issues.
For Editors. Guest Editor Guidelines Editorial Management Fabricating and Stating False Information Publishing Ethics and Rectitude Ethical Guidelines for New Editors Peer Review Workflow.
For Reviewers. Reviewer Guidelines Peer Review Workflow Fabricating and Stating False Information Publishing Ethics and Rectitude. Explore Articles.
At present, Flavoonids are no Muscle definition training antifibrotic drugs for patients with chronic liver disease; hence, the protwction of peotection therapies is urgently Flsvonoids. Here, we Flavinoids an Flavonoids and liver protection and Flavonoids and liver protection study to investigate the potential and underlying mechanism of quercetin treatment in liver fibrosis, mainly focusing on the impact of quercetin on macrophages activation and polarization. Liver inflammation, fibrosis, and hepatic stellate cells HSCs activation were examined. Moreover, massive macrophages accumulation, M1 macrophages and their related markers, such as tumor necrosis factor TNF -α, interleukin IL -1β, IL-6, and monocyte chemotactic protein-1 MCP-1 in livers were analyzed. In vitrowe used Raw
Flavonoids and liver protection -
Advances in Dye Degradation. COVID 19 — Monitoring with IoT Devices. Frontiers in Clinical Drug Research: Anti-Infectives. Advanced Pharmacy. Advances in Organic Synthesis. Plant-derived Hepatoprotective Drugs.
Frontiers in Natural Product Chemistry. The Role of Chromenes in Drug Discovery and Development. Article Metrics. Journal Information. For Authors. Author Guidelines Graphical Abstracts Fabricating and Stating False Information Research Misconduct Post Publication Discussions and Corrections Publishing Ethics and Rectitude Increase Visibility of Your Article Archiving Policies Peer Review Workflow Order Your Article Before Print Promote Your Article Manuscript Transfer Facility Editorial Policies Allegations from Whistleblowers Announcements Forthcoming Thematic Issues.
For Editors. Guest Editor Guidelines Editorial Management Fabricating and Stating False Information Publishing Ethics and Rectitude Ethical Guidelines for New Editors Peer Review Workflow. For Reviewers. Reviewer Guidelines Peer Review Workflow Fabricating and Stating False Information Publishing Ethics and Rectitude.
Explore Articles. Abstract Ahead of Print 6 Article s in Press Free Online Copy Most Cited Articles Most Accessed Articles Thematic Issues.
Open Access. Open Access Articles. For Visitors. Lee, N. The role of the gut microbiome in liver cirrhosis treatment. International journal of molecular sciences, 22 1 , Li, H. Physicochemical, biological properties, and flavour profile of Rosa roxburghii Tratt, Pyracantha fortuneana, and Rosa laevigata Michx fruits: A comprehensive review.
Food Chemistry, , Tang, Y. Liver International , 37 3 , Wan, L. Protective effects of plant-derived flavonoids on hepatic injury. Briefly, they assembled the human interactome from 16 databases containing six different types of PPIs: 1 binary PPIs tested by high-throughput yeast two-hybrid experiments Rolland et al.
The genes were mapped to their Entrez IDs based on the National Center for Biotechnology Information NCBI database and their official gene symbols. The constructed network included , PPIs, connecting 17, unique proteins.
The proximity of NAFLD-associated proteins and flavonoids was assessed using a distance metric proposed by Guney et al. First, the average closest distance d c S , T between NAFLD-associated proteins and flavonoid targets is defined as follows:.
S denotes a set of NAFLD-associated proteins, T denotes the set of flavonoid targets, and d s , t denotes the shortest path length between nodes s and t in the network.
A relative distance metric Z d c was then calculated by comparing the d c S , T to a reference distribution describing random expectations. The reference distribution is constructed by iteratively calculating the expected distances between two randomly selected groups of proteins matching the size and degrees of NAFLD—associated proteins and flavonoid targets in the network.
The relative distance Z d c is defined as follows:. μ c S , T denotes the mean and σ c S , T denotes standard deviation of the reference distribution, respectively.
The closest and relative distances were calculated in python 3. The molecular docking method was used to study the binding affinities and conformations of glycitin and its predicted targets. The web server CB-Dock was used to perform molecular docking simulations Liu et al.
org Burley et al. These files were uploaded and submitted to the CB-Dock server. The result table lists the vina scores, cavity sizes, docking centers, and sizes of the predicted cavities.
Once a ligand in the table is selected, the structure in the interactive 3D graphics is visualized. Ligplot software was used for 2D visualization of the interactions between proteins and a ligand. HepG2 cell line Korean Cell Line Bank, Seoul, Republic of Korea and RAW AML12 cell line ATCC, VA.
Cells were treated with 2, 20, or μM of glycitin, choerospondin, glycitein, and daidzin MedChemExpress, NJ, United States for 24 h. Absorbance was measured using a UV spectrophotometer at nm Molecular Devices, CA, United States. Lipid accumulation was detected using optical microscopy.
Absorbance was measured using a UV spectrophotometer at nm Molecular Devices. Under the same cell culture conditions as the Oil Red O staining assay, intracellular TG levels were measured using an enzymatic detection kit Asan Pharmaceuticals, Seoul, Republic of Korea.
Total protein concentration was measured using a bicinchoninic acid protein assay kit BCA1 and B, Sigma-Aldrich, MO, United States. The absorbance was measured using a UV spectrophotometer at nm Molecular Devices. Briefly, cells were incubated with 10 μM DCFH-DA for 30 min at 37°C in the dark. Intracellular ROS production was measured using an Axiophot microscope Carl Zeiss, Jena, Germany.
After incubation for 15 min at 37°C, absorbance was measured using a UV spectrophotometer at nm Molecular Devices. Under the same cell culture conditions as the NO detection assay, the proinflammatory cytokine TNF-α level of supernatants was measured using a commercially available enzyme immunoassay EIA kit for TNF-α BD Biosciences, San jose, CA, United States.
Under the same cell culture conditions as the Oil Red O staining assay, total mRNA was extracted using QIAzol reagent Qiagen, CA, United States. After synthesis of cDNA using a High-Capacity cDNA Reverse Transcription Kit Ambion, Austin, TX, United States , real-time PCR was performed using SYBR Green PCR Master Mix Applied Biosystems; Foster City, CA, United States.
PCR amplification was performed using a Rotor-Gene Q Qiagen, Hilden, Germany with standard protocol. The quantitative cycle threshold value of each gene was normalized with that of GAPDH. Information of the primer sequences is summarized in Supplementary Table S2.
Statistical analyses were performed using Python version 3. For the two-sample test, Shapiro—Wilk test was used to assess whether the data were normally distributed. When the normality was rejected, the Mann-Whitney U test was applied.
For the multiple comparison test, Shapiro—Wilk test was used to assess whether the data were normally distributed. We initially identified flavonoids from Phenol-Explorer. This threshold represents the average QED value of FDA-approved drugs, and compounds with QED values above the threshold are considered to have favorable pharmacokinetic properties.
As a result, 59 flavonoids were selected and included in our study Figure 2A and Supplementary Table S3. To describe their chemical diversity, we visualized the subclass distribution of flavonoids.
The results showed that the selected flavonoids were distributed across nine subclasses. Among the subclasses, flavones, flavanones, and flavonols were the top three subclasses with 20, 11, and 10 compounds, respectively Figure 2B.
FIGURE 2. Selection process for flavonoids evaluated in this study and their chemical distribution. A The flowchart of selecting the flavonoids B Distribution of flavonoids across its subclasses. We first retrieved validated CTIs between 27 flavonoids and protein targets from the DrugBank version 5.
Therefore, we utilized our recently developed algorithm, AI-DTI, to predict activatory and inhibitory targets of selected flavonoids. We constructed an input vector for all predictable flavonoid and protein target pairs, and then predicted the likelihood score of the CTI using a pretrained model.
As a result, we additionally secured activatory CTIs and 1, inhibitory CTIs between 59 selected flavonoids and 73 protein targets Figure 3A and Supplementary Table S4.
FIGURE 3. A compound-target network for selected flavonoids and its property. DrugBank and TTD contain experimentally validated DTIs, and AI-DTI is employed to predict the activity-inhibitory target of flavonoids. B Distribution of the number of flavonoid targets.
C Compound-target network for flavonoids. Circles and diamonds denote protein targets and compounds, respectively. We tested the reliability of the predicted results by comparing whether the overlapped number of CTIs between the experimentally validated results and predicted results was higher than the values in the null distribution.
The values of the null distribution were obtained by randomly selecting the potential combinations of flavonoids and predictable targets in AI-DTI and then repeatedly calculating the number of overlapped CTIs between validated results and selected results.
We found that AI-DTI successfully recovered 11 validated CTIs that did not appear in the training dataset. We constructed and visualized a compound-target network between the selected flavonoids and the target protein using assembled experimentally validated and predicted CTIs Figure 3C.
We revealed that the average number of targets for flavonoids was These results show that AI-DTI can provide accurate and sufficient CTI information for subsequent analyses.
Next, we attempted to identify candidate flavonoids that exert beneficial effects on NAFLD by employing a network medicine framework. We calculated the network proximity between flavonoid targets and NAFLD-associated 85 proteins using the closest measure, d c and Z d c , representing the average shortest path length and its relative distance between each flavonoid target and the nearest disease protein, respectively Figure 1B , see Materials and Methods for details.
The measured proximity and direct interactions between the flavonoids and NAFLD-associated proteins are summarized in Supplementary Table S5. For example, daidzein and daidzin, an isoflavone phytoestrogen found in soy, and its metabolites are produced by human intestinal microflora.
An in vivo study found anti-steatotic effects of daidzein through direct regulation of hepatic de novo lipogenesis and insulin signaling, and the indirect control of adiposity and adipocytokines by altering adipocyte metabolism. We extended our search range to assess whether the top-predicted flavonoids and their metabolic byproducts have reported beneficial effects on NAFLD.
Our results also revealed that the majority of flavonoids proximal to NAFLD-associated proteins have therapeutic effects on NAFLD, indicating that proximity score successfully rediscovered the known therapeutic effect of flavonoids on NAFLD Table 1. TABLE 1. Top network-predicted candidate flavonoids for NAFLD with available literature-derived evidence.
To test the mechanistic interpretability of the framework, we evaluated whether the mechanisms of flavonoids could be explained at the network level. We considered three flavonoids, dihydroquercetin, nobliletin, and butein, which are highly ranked in proximity measure, and have evidence reported for its native molecule itself.
We visualized networks focusing on selected flavonoids and their protein targets and biomarkers whose expression was measured in previous studies Figure 4. We then explored whether the association between the target of flavonoids and the measured biomarker could explain the results of previous reports.
FIGURE 4. A compound-protein network between selected flavonoids and NAFLD-associated proteins. A network including the interaction between flavonoid targets and NAFLD-associated proteins was constructed to elucidate the mechanisms of dihydroquercetin, butein, and nobiletin.
Black and red arrows indicate interactions consistent or inconsistent with the inferred mechanism of flavonoids against NAFLD, respectively.
Dihydroquercetin, also called taxifolin, was reported to ameliorate high-fat diet feeding plus acute ethanol-binding induced steatohepatitis by upregulating PPARγ levels and suppressing the expression of interleukin IL -1β and caspase-1 Zhan et al.
Our results showed that dihydroquercetin activates PPARG, which supports the notion that upregulated PPARγ expression can be caused by the direct effect of dihydroquercetin.
In addition, we infer that the inhibitory effects of dihydroquercetin on caspase-1 and IL-1β can be derived from the inhibitory effects of dihydroquercetin on the androgen acceptor.
This hypothesis is supported by a previous study showing that the androgen receptor is a promising regulator of caspase-1 activity, which is responsible for the subsequent activation of pro-inflammatory cytokines, including IL-1β Duez and Pourcet, Alternatively, butein exerts its antiproliferative and proapoptotic effects on NAFLD by suppressing STAT3 and JNK signaling Moon et al.
The constructed network showed that STAT3 and MAPK8 JNK1 interacted closely with the butein target EGFR. Moreover, considering that EGFR is an upstream regulator of STAT3 and MPAK8 JNK1 , we can infer the potential mechanisms by which butane affects STAT3 and MAPK by regulating EGFR.
Taken together, we found that molecular interactions between the flavonoid target and the measured biomarker provide potential network-level mechanisms for certain flavonoids. In contrast, we found that associations between certain flavonoid targets and NAFLD-associated proteins does not aid in the interpretation of mechanisms.
For example, previous studies have reported that dihydroquercetin inhibits the expression of IL-1B, which can lead to a hypothesis that its effect is exerted by the inhibitory effect of dihydroquercetin on interacting PTPN1, which interact with IL-1β.
However, a previous report revealed that PTPN1 inhibition rather further increases the effectiveness of inflammatory cytokines, including IL-1β Chen et al.
Furthermore, we could not identify any direct neighbors between the target of noviletin and previously measured biomarkers. These results indicate that the molecular interactions between flavonoid targets and measured biomarkers should be meticulously interpreted, considering the disease and model-specific contexts.
Based on the results from the proximity distances, we further evaluated whether unknown flavonoids, whose targets are proximal to NAFLD-associated proteins, could exhibit beneficial effects on NAFLD. We considered the following four flavonoids: glycitin and choerospondin, which are unreported and commercially available flavonoids that are proximal to NAFLD-associated proteins, and glycitein metabolites of glycitin , and daidzin the most proximal flavonoids with reported evidence.
To ensure appropriate dose of four flavonoids 0— μM , the cell viability was evaluated using a cell counting kit-8 CCK8 assays.
Therefore, further investigations for evaluating anti-NAFLD activity were performed using a single dose 20 μM of four flavonoids. To evaluate the beneficial effects of flavonoids against NAFLD, we adopted an FFA-induced hepatic steatosis cell model, which is commonly used to generate a cellular model of NAFLD Müller and Sturla, For our experimental purpose, instead of palmitic acid that induces lipotoxicity, the FFA mixture ratio of 2: 1, oleic acid: palmitic acid was used.
The FFAs predominantly induced NAFLD-like in vitro conditions in HepG2 cells, as evidenced by increases in Oil Red O histological observations approximately 3-folds and TG contents approximately 3.
In addition, these anti-NAFLD properties were re-validated in a normal murine hepatocyte AML12 cells Figures 5A,B. Taken together, these results indicate that the proximity scores are reliable traits for predicting novel candidates for preventing NAFLD progression.
FIGURE 5. Effects of four isoflavones against NAFLD conditions in both HepG2 and AML12 cells. A Hepatic lipid accumulations and ROS productions were determined using Oil Red O staining and DCFH-DA assay, respectively.
B Intracellular lipid accumulations in HepG2 and AML12 cells and C TG contents in HepG2 cells were quantified.
We further investigated the potential mechanisms focusing on glycitin, and all the identified targets were predicted using AI-DTI. Reliability of predicted interactions was firstly evaluated by analyzing molecular docking potentials.
Briefly, the structure of glycitin was uploaded to CB-dock Liu et al. For each process, blind docking was carried out to detect suitable binding sites for glycitin and calculate the vina score, which is an estimate of the logarithm of the free binding energy.
A cross-validation study was further performed using another docking web server, COACH-D Wu Q. We visualized the molecular interaction between glycitin and PDE5A, which had the lowest vina score.
Our results show that glycitin exhibits a strong binding affinity to the predicted target, which supports the reliability of the predicted results. FIGURE 6. Molecular docking validation and potential mechanism of glycitin.
A Molecular docking results between glycitin and its predicted target and its representative example. B Discovered target-NAFLD associated protein network for glycitin. A diamond denotes a flavonoid and circles denote protein targets.
The border and color of the circle denote the predicted target or related process-level function, respectively. We then conducted an overrepresentation test and network analysis to identify the potential mechanisms of glycitin at the level of biological processes and molecular interactions.
This association indicates that the mechanisms of glycitin involve lipid metabolism and inflammation, which are key regulators of the pathogenesis and progression of NAFLD Buzzetti et al. We also visualized the molecular interactions between the target of glycitin and NAFLD-associated protein.
We found that glycitin targets interact with NAFLD-associated proteins associated with various functions, including oxidative stress Figure 6B.
The close interaction between them indicates that the antioxidant capacity of glycitin may be exerted by regulating the function of these proteins via the cellular network. These results indicate that the anti-NAFLD effect of glycitin may be exerted by regulating the functions of various proteins related to metabolism, oxidative stress, and inflammation at the biological process and network level.
For the experimental verification of above predicted molecular interactions, we explored the mRNA gene expression in each of lipid metabolism, oxidative stress and inflammation using quantitative PCR method. FIGURE 7. Experimental investigating potential mechanism of glycitin. A Intracellular ROS production was determined using DCFH-DA fluorescence assay, and B it was quantified in HepG2 cells.
C The mRNA expressions of lipid metabolism- and antioxidant-related genes were measured using quantitative real-time PCR method in HepG2 cells.
According to AI-DTI predictions, we additionally investigated the anti-inflammatory properties of flavonoids using LPS-induced inflammatory macrophage model. In RAW In this study, we discovered candidate flavonoids that exert beneficial effects on NAFLD using a comprehensive strategy that combines AI-DTI and network medicine framework.
The AI-DTI model provided activatory and inhibitory CTIs for all included flavonoids, and the hypergeometric test supported the reliability and accuracy of the CTI prediction results.
Donald Flavonoids and liver protection, R. Herbal energy remedies Policy. com Park Ave, New Xnd, NY Fighting Liver Disease With Flavonoids: The Complete Guide. Article by Arnie Gitomer Sep 5, Are you looking for a natural way to fight liver disease? Look no further than flavonoids.
Ich meine, dass Sie nicht recht sind. Ich kann die Position verteidigen.
die sehr lustige Meinung
Sie haben Recht.
Ich bin endlich, ich tue Abbitte, aber es kommt mir ganz nicht heran. Wer kann noch helfen?