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Urolithin A Backgroud

Pomegranate’s heart benefits have led researchers to investigate in what ways this red fruit can keep us healthy. In a recent finding, Swiss researchers have identified a new molecule that results from digesting two compounds found in pomegranates: punicalagins and ellagitannins. This unique molecule, known as urolithin A, helps rejuvenate mitochondria, our cellular powerhouses. Urolithin A opens the door to potential new therapeutic treatments against age-related disorders, including frailty, which is a risk factor for disability, hospitalizations, and mortality.

Urolithin A Overview

Urolithin A is a metabolite compound, which belongs to the class of organic compounds known as benzo-coumarins. It is the end product produced from the consumption of food that contains ellagitannins (polyphenols) and is metabolized by the body’s gut bacteria. In other words, Urolithin A is produced when an individual ingests food sources containing ellagitannins.

Urolithin A does not occur naturally in its end form. Ellagitannin food sources, like certain types of berries and pomegranate, must be metabolized with gut bacteria to be created. In order for the compound to have viable applications, it has to be manufactured in a lab, or in other words, artificial Urolithin A must be produced so that it can be utilized.

Scientific studies have shown that Urolithin A possesses anti-ageing properties. It is said to aid in muscle mass formation, features anti-inflammatory properties, and has even shown potential in improving cognitive health in ageing individuals.

Urolithin A Mechanism of Action

How does Urolithin A work? Ellagic acids and Ellagitannins are Urolithin A precursors.

Ellagitannins are hydrolyzed from the intestine into release Ellagic acid, and this is processed from the gut microflora to urolithins through the increasing loss in 1 of its two lactones successive removal of hydroxyl groups. Once It’s consumed in the intestines, then Urolithin A powder enters the flow System of this intestine.

Mitophagy, according to Wikipedia definition, is the selective degradation of your mitochondria by autophagy. It often occurs to defective mitochondria following damage or stress. However, as we age, Mitophagy function becomes less efficient. Luckily, Urolithin A is approved to stimulate mitophagy in a conserved manner across different species.

Benefits/Effects of Urolithin A

❶ Urolithin A Helps Fight Cancer

Despite aggressive surgical care and chemotherapy, nearly 50% of people with colorectal cancers develop recurrent tumors. This may be due in part to the survival of dangerous colon-cancer stem cells that resist conventional chemotherapy and act as ‘’seeds’’ for subsequent cancers.6
In an interesting finding, researchers exposed colon-cancer stem cells from a patient with colorectal cancer to either a mixture containing 85% urolithin A or 30% urolithin A. The results were impressive. The higher urolithin A concentration mixture was most effective at inhibiting the number and size of colon-cancer stem cells and inhibiting the activity of aldehyde dehydrogenase, a marker of chemoresistance.
This therapeutic approach is exciting because traditional therapies against cancer lack the ability to kill or stop the proliferation of cancerous stem cells. These new findings support the notion that a nutrient approach may prove valuable as an alternative treatment or preventive intervention for targeting these harmful cells.

❷ Urolithin A -- Neuroprotective Effects

The connection between pomegranate and its neuroprotective effects against Alzheimer’s disease has been well established in animal studies.8 However, the bioactive constituents for this action were unknown until now.
Alzheimer’s disease is expected to affect over 115 million people worldwide by the year 2050.A group of researchers looked at a previous animal study that reported on the anti-Alzheimer’s effects of pomegranate extract constituents.
The team evaluated the ability of these components to cross the blood-brain barrier and found that a methylated form of urolithin A (mUA), derived from pomegranate, along with other urolithins were capable of doing so.
And, although more research is needed, the authors concluded that urolithins are the possible compounds responsible for the anti-Alzheimer’s effects that include protection against neurotoxicity and b-amyloid fibrillation. These results are promising, and suggest the need for exploring other naturally-based dietary intervention strategies for preventing or slowing down the progression of Alzheimer’s.
The results and data from these various studies further support the importance of polyphenol metabolite compounds like urolithin A from pomegranate and their role in the fight against colon cancer and neurodegenerative diseases.
Studies also have shown that Urolithin A can improve muscle strength and endurance in ageing individuals. Recent research shows that preliminary evidence presents promising other benefits of Urolithin A, which include the following:

-Anti-inflammatory
-Anticarcinogenic
-Antioxidant
-Antiglycative
-Antimicrobial


Urolithin A is also strongly seen as a supplement to protein products to enhance the effects of exercise, as well as to reduce obesity.

Urolithin A Side Effects

In the aforementioned human clinical trial, no adverse side effects were reported. In investigations over a series of preclinical and clinical studies, there seems to be evidence of support to the safety of Urolithin A use.

No toxicological effects have been reported, even in studies that involved the highest dose given to rats in such studies.

Urolithin A is set to transform the anti-aging industry. Clinical studies are still in their early stages but most trials reveal positive results with no adverse side effects. From food to supplements, Urolithin A is bound to be the next new superfood discovery that everyone should be taking.

Urolithin A Food Sources

As mentioned, Urolithin A in its end form does not appear naturally. It is not known to be found in any food sources. However, the precursor to the compound can be found in certain fruits and nuts. Food sources that contain ellagitannins such as pomegranate, raspberries, strawberries, cloudberries, and walnuts are some examples.

The ellagitannins in these fruits and nuts are hydrolyzed in the gut to produce ellagic acid, which is then further processed in the gut and metabolized with gut microflora into Urolithin A.

It is important to note that Urolithin A does not always occur when ingested. Some people’s guts do not have a healthy mix of microflora needed to convert ellagic acid into Urolithin A. This means that not everyone will produce Urolithin A in their gut if they eat pomegranate, walnuts, or berries. It all depends on the gut bacteria present in your body.

Urolithin A Manufacturing Process

Urolithin A is manufactured via chemical syntheses using one of the two processes described below. Both processes involve an Ullmann coupling reaction, followed by a Lewis acid treatment to yield a highly purified urolithin A product.

The final product is purified by standard means of treatment in solvents, filtered, washed, and dried to obtain pure urolithin A. The product is later subjected to a particle size reduction.

According to well-established processes, Urolithin A powder is synthetically manufactured and purified in several main steps to a highly pure specification of 99%. Raw Materials and processing steps involved in the synthesis of urolithin A include 2-Bromo-5-methoxy benzoic acid, 2-Bromo-5-hydroxy benzoic acid, Resorcinol, 50% sodium hydroxide, Copper sulfate pentahydrate, Methanol, Aluminum chloride, Toluene, DMSO, Methanol, Acetic Acid, and TBME (tert-butyl-methyl ether).

Synthetic Urolithin A VS Natural Urolithin A

As mentioned above, Urolithin A is a gut‐derived bacterial metabolite of ellagitannins(ET) or ellagic acid (EA). If you want to obtain a large quantity of Urolithin A, you have to first eat bulky fruits, and then wait for them to transfer from ellagitannins and ellagic acid to Urolithin A. This process is long, and its purity is low, and most importantly, it will be extremely expensive to do so.

Not everyone has the right microflora that can make the metabolite. In addition, this process can never be applied to mass production in a GMP-compliant manufacturing facility.

The good news is that, as a novel ingredient, Urolithin A is finally commercially available in 2019 from Cima Science. It now can be synthesized in the lab and factory. The synthetic urolithin A is identical in structure to natural urolithin A. The manufacturing capability is up to 3000 kgs or 2.5 tons/month.

Urolithin A Safety

Urolithin A is approved by the European Union as a novel food ingredient.

The US Food and Drug Administration (FDA) in 2018 has granted urolithin A its GRAS status used in dietary supplement formula. GRAS means that Urolithin A is generally regarded as safe with a dosage of 500mg to 1 gram per serving.

Urolithin A safety was researched at a series of preclinical and clinical trials, which encourage its health safety for its intended uses. Repeated dosage 28-day and 90-day studies of urolithin A in rats didn’t demonstrate any toxicological impact in some of the parameters measured in any way doses tested.

Supplementation for up to 90 days with urolithin A didn’t lead to any signs of neurological or reproductive toxicities in improved screening periods of repeated-dose studies such as evaluation of spermatogenesis or oestrus cycles, ophthalmoscopic examinations, operational observatory battery display, and motor activity assessments.

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The discovery of urolithin A, that results from the punicalagins and ellagitannins compounds found in pomegranates, provides new opportunities to fight age-related decline of mitochondrial function and the resulting frailty and loss of muscle.

By helping cells renew themselves and optimizing muscle performance, pomegranate extract and its newly identified metabolite, urolithin A—could prove successful.

Along with these findings, there is supportive evidence of the powerful effects that urolithin A has against Alzheimer’s disease and cancer, offering yet another tool to fight against these devastating conditions that affect many aging individuals.

This nutritional approach opens up possibilities that traditional pharmaceutical approaches have never explored. If you want buy Urolithin A powder/Urolithin A 8-Methyl Ether powder, AASraw maybe good choice.

Urolithin B Description

Urolithin B is an urolithin, a type of phenolic compounds produced in the human gut after absorption of ellagitannins-containing food such as pomegranate, strawberries, red raspberries, walnuts or oak-aged red wine. Urolithin B is found in the urine in the form of urolithin B glucuronide.

Urolithin B also is a natural product with antiproliferative and antioxidant activity. Urolithin B is formed by metabolism from polyphenols found in some nuts and fruits, particularly pomegranates. Urolithin B has been shown to cross the blood brain barrier, and may have neuroprotective effects against Alzheimer’s Disease.

Urolithin B Mechanism of Action

It decreases protein degradation and induces muscle hypertrophy. Urolithin B inhibits the activity of aromatase, an enzyme that interconverts estrogen and testosterone.

Urolithin B is a natural product with antiproliferative and antioxidant activity. Urolithin B is formed by metabolism from polyphenols found in some nuts and fruits, particularly pomegranates. Urolithin B has been shown to cross the blood brain barrier, and may have neuroprotective effects against Alzheimer’s Disease.

Urolithin B inhibits NF-κB activity by reducing the phosphorylation and degradation of IκBα, and suppresses the phosphorylation of JNK, ERK, and Akt, and enhances the phosphorylation of AMPK. Urolithin B is also a regulator of skeletal muscle mass.Urolithin B is one of the gut microbial metabolites of ellagitannins, and has anti-inflammatory and antioxidant effects.

Urolithin B Application

While studying the anti-inflammatory and antioxidant properties of urolithins A and B, UCL researchers happened to discover that the latter had a protective effect on muscles. ‘Muscle cells in culture that were in contact with urolithin B became larger than those that were not. We wanted to know why.

First, they studied the substance in vitro and found urolithin B has a dual effect: it activates muscle protein synthesis and slows degradation.

Second, the researchers studied the effect of urolithin B in vivo, on mice. ‘It increased their muscle development’, Prof. Francaux says. ‘We also administered it to mice with a severed sciatic nerve resulting in leg paralysis, and the subsequent muscle loss occurred 20 to 30% less quickly and to a lesser extent.’

Effects of Urolithin B

Urolithin B is one of the gut microbial metabolites of ellagitannins, and has anti-inflammatory and antioxidant effects. Urolithin B inhibits NF-κB activity by reducing the phosphorylation and degradation of IκBα, and suppresses the phosphorylation of JNK, ERK, and Akt, and enhances the phosphorylation of AMPK. Urolithin B is also a regulator of skeletal muscle mass.

(1). Urolithin B reduces the loss of muscle weight induced by denervation
(2). Urolithin B-induced skeletal muscle hypertrophy in mice
(3). The anabolic effect of urolithin B is mediated by the androgen receptor
(4). Urolithin B stimulates protein synthesis in C2C12 myotubes by activating mTORC1 signalling
(5). Urolithin B inhibits protein degradation by downregulating the ubiquitin–proteasome pathway
(6). Urolithin B enhances differentiation of C2C12 myotubes

Reference:

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[2] Milburn, M. V. & Lawton, K. A. Application of metabolomics to diagnosis of insulin resistance. Annu. Rev. Med. 64, 291–305 (2013).
[3] Laker, R. C. et al. Ampk phosphorylation of Ulk1 is required for targeting of mitochondria to lysosomes in exercise-induced mitophagy. Nat. Commun. 8, 548 (2017).
[4] Singh, R. et al. Enhancement of the gut barrier integrity by a microbial metabolite through the Nrf2 pathway. Nat. Commun. 10, 89 (2019).
[5] Andreux, P. A. et al. Mitochondrial function is impaired in the skeletal muscle of pre-frail elderly. Sci. Rep. 8, 8548 (2018).
[6] Gong, Z. et al. Urolithin A attenuates memory impairment and neuroinflammation in APP/PS1 mice. J. Neuroinflammation 16, 62 (2019).
[7] Felder, T. K. et al. Specific circulating phospholipids, acylcarnitines, amino acids and biogenic amines are aerobic exercise markers. J. Sci. Med. Sport 20, 700–705 (2017).
[8] Schooneman, M. G., Vaz, F. M., Houten, S. M. & Soeters, M. R. Acylcarnitines: reflecting or inflicting insulin resistance? Diabetes 62, 1–8 (2013).
[9] Guideline on Strategies to Identify and Mitigate Risks for First-in-Human Clinical Trials with Investigational Medicinal Products EMEA/CHMP/SWP/28367/07 (European Medicines Agency, 2007).
[10] Keefe, D. M. GRAS Notice No. GRN 000791 (Food and Drug Administration, 2018).
[11] Drake, J. C. & Yan, Z. Mitophagy in maintaining skeletal muscle mitochondrial proteostasis and metabolic health with ageing. J. Physiol. 595, 6391–6399 (2017).
[12] Choi, A. M., Ryter, S. W. & Levine, B. Autophagy in human health and disease. N. Engl. J. Med. 368, 651–662 (2013).