Urolithins: Diet-Derived Bioavailable Metabolites to Tackle Diabetes

Diabetes remains one of the leading causes of deaths and co-morbidities in the world, with tremendous human, social and economic costs. Therefore, despite therapeutics and technological advancements, improved strategies to tackle diabetes management are still needed. One of the suggested strategies is the consumption of (poly)phenols. Positive outcomes of dietary (poly)phenols have been pointed out towards different features in diabetes. This is the case of ellagitannins, which are present in numerous foodstuffs such as pomegranate, berries, and nuts. Ellagitannins have been reported to have a multitude of effects on metabolic diseases. However, these compounds have high molecular weight and do not reach circulation at effective concentrations, being metabolized in smaller compounds. After being metabolized into ellagic acid in the small intestine, the colonic microbiota hydrolyzes and metabolizes ellagic acid into dibenzopyran-6-one derivatives, known as urolithins. These low molecular weight compounds reach circulation in considerable concentrations ranging until micromolar levels, capable of reaching target tissues. Different urolithins are formed throughout the metabolization process, but urolithin A, isourolithin A, and urolithin B, and their phase-II metabolites are the most frequent ones. In recent years, urolithins have been the focus of attention in regard to their effects on a multiplicity of chronic diseases, including cancer and diabetes. In this review, we will discuss the latest advances about the protective effects of urolithins on diabetes.

The Gut Microbiota Metabolite Urolithin B Improves Cognitive Deficits by Inhibiting Cyt C-Mediated Apoptosis and Promoting the Survival of Neurons Through the PI3K Pathway in Aging Mice

Background: Despite considerable advances in pharmacotherapy, more effective therapeutic interventions for aging-related neurodegenerative disorders (NDs), such as Alzheimer’s disease (AD), remain limited. Urolithin B (UB), one of the major subcategories of urolithins (microbiota metabolites) found in various tissues after ellagitannin consumption, has been shown to possess antioxidant, anti-inflammatory, and antiapoptotic effects. However, the neuroprotective effect of UB on brain aging in mice and its potential mechanisms were still unknown.Methods: In the current research, we first assessed the ameliorative effects of UB on oxidative injury and apoptosis induced by H2O2 in neuro-2a cells. Then a subcutaneous injection of D-galactose in mice for 8 weeks was used to establish the aging model to evaluate the protective effects of UB. The capacity of memory and learning, alterations of hippocampus histology and corresponding molecular mechanisms were all evaluated.Results: The D-gal-induced accelerated aging model in vivo demonstrated that UB could significantly ameliorate deficits in learning and memory by inhibiting the accumulation of advanced glycation end products (AGEs) and elevating the expression and activity of Cu, Zn-SOD and CAT. Furthermore, UB downregulated the c-Jun N-terminal kinase (JNK) signaling pathway and prevented cytochrome c release from isolated mitochondria, thereby inhibiting neuronal apoptosis during the aging process. More importantly, UB stimulation of aging mice activated ERK and phosphoinositide 3-kinase (PI3K), leading to neuronal survival along with Akt and p44/42 mitogen-activated protein kinase (MAPK) phosphorylation and activation.Conclusion: In summary, UB effectively alleviated cognitive deficits and ameliorated brain aging-related conditions and could be considered a healthcare product to prevent aging-associated NDs such as AD.

The Gut Microbiota Metabolite Urolithin B Improves Cognitive Deficits by Inhibiting Cyt C-mediated Apoptosis and Promoting the Survival of Neurons Through the PI3K Pathway in Aging Mice

BackgroundDespite considerable advances in pharmacotherapy, more effective therapeutic interventions for aging-related neurodegenerative disorders (NDs), such as Alzheimer's disease (AD), remain limited. Urolithin B (UB), one of the major subcategories of urolithins (microbiota metabolites) found in various tissues after ellagitannin consumption, has been shown to possess antioxidant, anti-inflammatory, and antiapoptotic effects. However, the neuroprotective effect of UB on brain aging in mice and its potential mechanisms were still unknown. MethodsIn the current research, we first assessed the ameliorative effects of UB on oxidative injury and apoptosis induced by H2O2 in neuro-2a cells. Then a subcutaneous injection of D-galactose in mice for 8 weeks was used to establish the aging model to evaluate the protective effects of UB. The capacity of memory and learning, alterations of hippocampus histology and corresponding molecular mechanisms were all evaluated. ResultsThe D-gal-induced accelerated aging model in vivo demonstrated that UB could significantly ameliorate deficits in learning and memory by inhibiting the accumulation of advanced glycation end products (AGEs) and elevating the expression and activity of Cu, Zn-SOD and CAT. Furthermore, UB downregulated the c-Jun N-terminal kinase (JNK) signaling pathway and prevented cytochrome c release from isolated mitochondria, thereby inhibiting neuronal apoptosis during the aging process. More importantly, UB stimulation of aging mice activated ERK and phosphoinositide 3-kinase (PI3K), leading to neuronal survival along with Akt and p44/42 mitogen-activated protein kinase (MAPK) phosphorylation and activation. ConclusionIn summary, UB effectively alleviated cognitive deficits and ameliorated brain aging-related conditions and could be considered a healthcare product to prevent aging-associated NDs such as AD.

Urolithin A and B Alter Cellular Metabolism and Induce Metabolites Associated with Apoptosis in Leukemic Cells

Leukemia is persistently a significant cause of illness and mortality worldwide. Urolithins, metabolites of ellagic acid and ellagitannins produced by gut microbiota, showed better bioactive compounds liable for the health benefits exerted by ellagic acid and ellagitannins containing pomegranate and walnuts. Here, we assessed the potential antileukemic activities of both urolithin A and urolithin B. Results showed that both urolithin A and B significantly inhibited the proliferation of leukemic cell lines Jurkat and K562, among which urolithin A showed the more prominent antiproliferative capability. Further, urolithin treatment alters leukemic cell metabolism, as evidenced by increased metabolic rate and notable changes in glutamine metabolism, one-carbon metabolism, and lipid metabolism. Next, we evidenced that both urolithins equally promoted apoptosis in leukemic cell lines. Based on these observations, we concluded that both urolithin A and B alter leukemic cell metabolome, resulting in a halt of proliferation, followed by apoptosis. The data can be used for designing new combinational therapies to eradicate leukemic cells.

Gut microbiota metabolite urolithin B attenuates intestinal immunity function through regulation of oxidative stress and inflammatory signaling in aging mice

Urolithin B (Uro B), one of the major subcategories of urolithins (microbiota metabolites) found in various tissues after ellagitannin consumption, has been shown to possess antioxidant and anti-inflammatory effects. The...

A Molecular Docking Study against COVID-19 Protease with a Pomegranate Phyto-Constituents 'Urolithin' and Other Repurposing Drugs: From a Supplement to Ailment

Aim: We conducted an in silico study on Urolithin and different antimicrobial agents targeting virus protease and peptidase. Methodology: The docking study was completed by using docking tools. Drug compounds and COVID-19 receptor molecules were prepared, docking was performed and interaction was visualized through Discovery Studio visualizer. Results: Urolithin A has interacted against peptidase (PDB ID:2GTB) with binding energy -6.93 kcal/mol and against protease (PDB ID:6LU7) with the binding energy -5.46 kcal/mol, while Urolithin B has interacted to peptidase (PDB ID:2GTB) with binding energy -6.74 kcal/mol and with protease it interacted with a binding energy -4.67 kcal/mol. The antimicrobial agent Ofloxacin was found to interact against protease (PDB ID:6LU7) with a binding energy -6.84 kcal/mol and against protease (PDB:6LU7) with a binding energy -8.00 kcal/mol. Conclusion: The most common interacting amino acids of target enzymes of the virus with studied drugs were His41, His164, Met165, Glu166, Gln189. From the docking studies, it is observed that Ofloxacin and Urolithin have the potential to inhibit the virus protease as well as peptidase significantly and these could prevent the entry of the virus to the inside of the host cell. Thus, further antiviral research on these antimicrobial agents and Urolithin could be helpful to control the COVID-19 disease.

Microbial Metabolite Urolithin B Inhibits Recombinant Human Monoamine Oxidase A Enzyme

Urolithins are gut microbial metabolites derived from ellagitannins (ET) and ellagic acid (EA), and shown to exhibit anticancer, anti-inflammatory, anti-microbial, anti-glycative and anti-oxidant activities. Similarly, the parent molecules, ET and EA are reported for their neuroprotection and antidepressant activities. Due to the poor bioavailability of ET and EA, the in vivo functional activities cannot be attributed exclusively to these compounds. Elevated monoamine oxidase (MAO) activities are responsible for the inactivation of monoamine neurotransmitters in neurological disorders, such as depression and Parkinson’s disease. In this study, we examined the inhibitory effects of urolithins (A, B and C) and EA on MAO activity using recombinant human MAO-A and MAO-B enzymes. Urolithin B was found to be a better MAO-A enzyme inhibitor among the tested urolithins and EA with an IC50 value of 0.88 µM, and displaying a mixed mode of inhibition. However, all tested compounds exhibited higher IC50 (>100 µM) for MAO-B enzyme.

FRI0429 UROLITHIN B ATTENUATES THE INFLAMMATORY AND NITROSATIVE STRESS ON INTERLEUKIN-1 INDUCED CHONDROCYTES

Background:Osteoarthritis (OA) is one of the most common degenerative disorders with cartilage degradation especially to the elderly resulting in disability. Many inflammatory cytokines involve the pathogenesis of the OA and causes destruction and decomposition of articular cartilage, including interleukin 1 beta (IL-1β). Urolithin B is a small polyphenolic compound, produced by gut flora from ellagitannins-rich foods, such as pomegranate, strawberries, raspberries, etc. Urolithin B has been documented in anti-inflammatory and antioxidant properties. However, the mechanism underlying the effects of Urolithin B on IL-1 stimulated human osteoarthritis (OA) chondrocytes remains unrevealedObjectives:The aim of this study was to investigate the biologic effects of Urolithin B on OA models and associated mechanism.Methods:Primary culture of human chondrocyte, knee joint obtained from total knee replacement of patients with osteoarthritis, were used IL-1β induced and treated with/without 100μM Urolithin B for 24 hours respectively. Total cell lysates were collected for western blotting to analyze the catabolic molecules. Culture medium were collected for gelatin zymography to analyze the secretion of MMP 2 and 9.Results:Urolithin B inhibits the overexpression of not only inflammatory marker COX2 and nitrosative marker NOS2, but also matrix metalloproteinases (MMPs)-1, -3, 13 in IL-1β induced chondrocytes by western blotting. It also restored the IL-1β induced glycosaminoglycan degeneration in ex vivo articular cartilage evaluated by Safranin O stain. Meanwhile, Urolithin B can activate autophagy, increasing LC3 II/I ratio, in IL-1β induced chondrocytes.Conclusion:Collectively, the study demonstrates that Urolithin B may be of value in the treatment of osteoarthritis through its anti-inflammatory, anti-oxidant and anti-proteinase activities.References:[1]Decker, R.S., E. Koyama, and M. Pacifici,Articular Cartilage: Structural and Developmental Intricacies and Questions.Curr Osteoporos Rep, 2015.13(6): p. 407-14.[2]Luo, Y., et al.,The minor collagens in articular cartilage.Protein Cell, 2017.8(8): p. 560-572.[3]Sophia Fox, A.J., A. Bedi, and S.A. Rodeo,The basic science of articular cartilage: structure, composition, and function.Sports Health, 2009.1(6): p. 461-8.[4]Carballo, C.B., et al.,Basic Science of Articular Cartilage.Clin Sports Med, 2017.36(3): p. 413-425.[5]Taruc-Uy, R.L. and S.A. Lynch,Diagnosis and treatment of osteoarthritis.Prim Care, 2013.40(4): p. 821-36, vii.[6]Rhon, D., Re: Zhang W, Moskowitz RW, Nuki G, et al. OARSI recommendations for the management of hip and knee osteoarthritis, Part II: OARSI evidence-based, expert consensus guidelines. Osteoarthritis Cartilage 2008;16:137-62. Osteoarthritis Cartilage, 2008.16(12): p. 1585; author reply 1589.[7]Wang, S.T., et al., Antimelanogenic Effect of Urolithin A and Urolithin B, the Colonic Metabolites of Ellagic Acid, in B16 Melanoma Cells. J Agric Food Chem, 2017.65(32): p. 6870-6876.Feng-Cheng Wu1, Feng-Cheng Liu2, Chih-Chien Wang3, Yi-Jen Peng1,4*1Graduate Institute of Pathology and Parasitology, National Defense Medical Center, Taipei, Taiwan, R.O.C.2Rheumatology, Immunology and Allergy, Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, R.O.C.3Department of Orthopedic, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, R.O.C.4Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, R.O.C.Title:Urolithin B attenuates the inflammatory and nitrosative stress on interleukin-1 induced chondrocytesKey words:Urolithin B, Osteoarthritis, chondrocytes, Cyclooxygenase 2, Nitric Oxide Synthase 2, matrix metalloproteinaseDisclosure of Interests:None declared