WO2022172072A1 - Composition comprising bioactive molecules having beneficial effects on senescence of adult renal stem cells - Google Patents
Composition comprising bioactive molecules having beneficial effects on senescence of adult renal stem cells Download PDFInfo
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
- A61K31/201—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having one or two double bonds, e.g. oleic, linoleic acids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
- A61K31/727—Heparin; Heparan
Definitions
- the present invention is related to a compound comprising bioactive molecules having beneficial effects on senescence of adult renal stem cells.
- ARPC have an important role in the prevention of the endothelium dysfunction and they could be used in novel strategies to protect the endothelium compartment and to promote the renal healing, such as reported in the article "Renal progenitor cells revert LPS-induced endothelial-to-mesenchymal transition by secreting CXCL6, SAA4, and BPIFA2 antiseptic peptides" (Sallustio).
- ARPC could regulate the immune response inducing T-reg cells of the immune system and modulating T Double Negative cells (T DN), which are involved in the equilibrium between the immune tolerance and autoimmunity (Curci et al., "Adult Renal Stem/Progenitor Cells Can Modulate T Regulatory Cells and Double Negative T Cells", Int. J. Mol. Sci. 2020). All these healing properties of ARPC could be invalidated by renal senescence, that could influence renal progenitors causing renal aging and the incapacity of damage repair. In fact, renal senescence is physiologically associated to aging and it reduces the healing capacity of tissues.
- pl6INK4a senescence marker
- Senescence of renal tubular cells is related to tubular atrophy, interstitial fibrosis and glomerulosclerosis (Melk et al., 2004; Sis et al., 2007). Moreover, removing senescent tubular cells cause the reduction of glomerulosclerosis (Baker et al., 2016).
- CKD chronic kidney disease
- Acute kidney disease (AKI) leads kidney to CKD with aging or after a second damage.
- patients with CKD are more predisposed to AKI after injuries (Jin et al., 2019).
- a possible explanation could be the accumulation of senescent cells during aging and during post-trauma, because, after AKI, senescent cells increase slowly with time (Jin et al., 2019).
- the senescence level before renal transplant could predict the result of the transplant (McGlynn et al., 2009), suggesting that targeting senescent cells could be an effective therapy against renal diseases.
- Klotho gene Another related aspect to premature senescence induced by AKI is the deficiency of Klotho gene, which codifies an anti-aging protein.
- Klotho gene is expressed mainly in kidney, in particular in renal tubules (Hu et al., 2010;
- CD133 expression is essential in the regulation of cellular senescence, that is characterized also by cellular depletion after repeated proliferation cycles (Ferenbach & Bonventre, 2015).
- CD133 is involved in signaling of Wnt / b-catenin and its expression limits the cellular senescence.
- CD133 could act as permissive factor for signaling of Wnt / beta catenin (has a role in the prevention of b-catenin degradation) and it plays an important role in tissue healing.
- CD133 absence affects the cellular proliferation after the damage, leading to the senescence (Brossa et al., 2018).
- CD133 the number of senescent cells, measured by the senescence marker b-galactosidase, is significantly higher than CD133 control cells where CD133 is not silenced. Moreover, there is a significant reduction of telomers length in CD133 silenced cells than their controls CD133 + (Brossa et al., 2018).
- Scope of the present invention is providing a compound comprising bioactive molecules able to increase CD133 expression in ARPC, namely an inverse marker of senescence of renal stem cells, and therefore slow down their senescence, and therefore having characteristics to overcome drawbacks of known compounds.
- figure 1 shows diagrams of flow cytometry that highlight an increase of marker CD133 expression in renal stem cells engaged toward cellular senescence (BASAL) and stimulated for 48 hours with the compound comprising bioactive molecules having beneficial effects on senescence of adult renal stem cells, according to the present invention; the CD133 expression increased from 3.7% in BASAL up to 43.5 % in stimulated cells;
- FIG. 2 shows mean levels (from five experiments) of marker CD133 expression in renal stem cells engaged toward cellular senescence (BASAL) and stimulated individually with bioactive molecules, bioactive molecules being comprised by the compound having beneficial effects on senescence of adult renal stem cells, according to the present invention
- Figures 3a and 3b show diagrams of flow cytometry that highlight marker CD133 expression in renal stem cells engaged toward cellular senescence, with a reduced marker CD133 expression (BASAL) and stimulated for 48 hours with the compound comprising bioactive molecules alone ( Figure 3a) or in combination ( Figure 3b) having beneficial effects on senescence of adult renal stem cells, according to the present invention;
- the bioactive molecules compound having beneficial effects on senescence of adult renal stem cells comprises decenoic acid, nonanoic acid, valproic acid and heparin.
- decenoic acid was tested in four different isoforms (10— Hydroxy-2-decenoic acid, Ethyl trans-2-decenoate, 3- Decenoic acid, 1O-Hydroxydecanoic acid).
- Decenoic acid and nonanoic acid are two naturally occurring compounds.
- nonanoic acid also known as pelargonic acid
- pelargonic acid is a fatty acid obtained by ozonolysis of oleic acid and it is used for esters synthesis used in fragrances and aroma industries.
- Decenoic acid is comprised in several compounds and it is one the main components of royal jelly.
- Heparin is a naturally occurring molecule.
- Bioactive molecules of decenoic acid, nonanoic acid, valproic acid and heparin comprised in the compound, according to the present invention are able to increase CD133 expression in ARPC, namely an inverse marker of senescence of renal stem cells, therefore slow down their senescence .
- the compound comprising bioactive molecules of decenoic acid, nonanoic acid, valproic acid and heparin could be used to produce natural supplements, to improve the quality of renal stem cells, and to counteract the senescence of this specific stem/progenitor cells .
- the formulation of the compound according to the present invention increases considerably the capacity of renal stem cells to delay aging.
- the compound consists of:
- Ethyl trans-2-decenoate from 0.1 mM to 1 mM 1O-Hydroxy-trans-2-decenoic acid: from 0.1 mM to 1 mM 10-Hydroxydecanoic acid: from 0.1 mM to 1 mM 3-Decenoic acid: from 0.1 mM to 1 mM
- Nonanoic acid from 0.1 mM to 2 mM
- Heparin from 0.025 U/ml to lU/ml
- Valproic acid from 0.1 mM to 10 mM.
- the compound consists of the following formulation of bioactive molecules:
- Figure 2 shows the levels of the marker CD133 expression in renal stem cells engaged toward cellular senescence (BASAL) and stimulated individually with the bioactive molecules. Data show a statistically substantial increase of CD133 in ARPCs stimulated for 48 hours with the bioactive molecules comprised by the compound having beneficial effects on senescence of adult renal stem cells. Experimental tests were done on five different lines of tubular renal stem cells isolated from kidneys of five different patients.
- Figures 3a and 3b show diagrams of flow cytometry that highlight marker CD133 expression in renal stem cells engaged toward cellular senescence, with a reduced marker CD133 expression (BASAL) and stimulated for 48 hours with the compound comprising bioactive molecules having beneficial effects on senescence of adult renal stem cells, according to the present invention.
- the stimulation of individual molecules increases considerably the CD133 expression, while the stimulation with the combinations of bioactive molecules causes a higher increase of marker CD133 expression than the stimulation with individual molecules.
- the compound comprising bioactive molecules according to the present invention can substantially increase the marker of sternness CD133 expression in renal stem cells engaged toward cellular senescence.
- Another convenience of the compound comprising bioactive molecules according to the present invention is that it comprises naturally occurring molecules with general beneficial effects and without generating side effects.
- the compound comprising bioactive molecules according to the present invention could be administered in part as protein products and in part as messenger RNA, like it occurs in nature by ARPC mediation, possibly conveyed by artificial microvesicle or lipidic microparticles which, based on the composition, structure, charge and dimension, will be able to drive the interaction with the biological substrate of the conveyed molecules.
Abstract
The present invention is related to a composition comprising bioactive molecules having beneficial effects on senescence of adult renal stem cells, in particular comprising: decenoic acid, nonanoic acid, valproic acid and heparin.
Description
COMPOSITION COMPRISING BIOACTIVE MOLECULES HAVING BENEFICIAL EFFECTS ON SENESCENCE OF ADULT RENAL STEM CELLS
The present invention is related to a compound comprising bioactive molecules having beneficial effects on senescence of adult renal stem cells.
Several studies have showed the active role of adult renal stem / progenitor cells of (ARPC) in renal healing processes during acute or chronic wounds. Recently, the article "Human renal stem/progenitor cells repair tubular epithelial cell injury through TLR2-driven inhibin-A and microvesicle-shuttled decorin" (Sallustio et al., Kidney international 2013), has proved that tubular ARPCs, but not glomerulus, have a healing effect on damaged renal proximal tubule cells (RPTEC), preventing the apoptosis and the proliferation increase of survived cells. This effect is given essentially by their secretome, through the TLR2, showing a relevant functional role of this receptor in the healing promoted by renal progenitors.
Moreover, it has been observed that ARPC have an important role in the prevention of the endothelium dysfunction and they could be used in novel strategies to protect the endothelium compartment and to promote the renal healing, such as reported in the article "Renal progenitor cells revert LPS-induced endothelial-to-mesenchymal transition by secreting CXCL6, SAA4, and BPIFA2 antiseptic peptides" (Sallustio). Recent studies instead have proved that ARPC could regulate the immune response inducing T-reg cells of the immune system and modulating T Double Negative cells (T DN), which are involved in the equilibrium between the immune tolerance and autoimmunity (Curci et al., "Adult Renal Stem/Progenitor Cells Can Modulate T Regulatory Cells and Double Negative T Cells", Int. J. Mol. Sci. 2020). All these healing properties of ARPC could be invalidated by renal senescence, that could influence renal progenitors causing renal aging and the incapacity of damage repair. In fact, renal senescence is physiologically associated to aging and it reduces the healing capacity of tissues. Moreover, it could be related to disadaptive repair and the development of fibrosis after an injury (Brossa et al., 2018). Many normal cells grow, die and replicate continuously. Cellular senescence is a process in which cells lose their functionality, including the
capacity of divide and replicate, but they are resistant to cellular death. It has been demonstrated that senescent cells influence neighboring cells secreting several pro- inflammatory molecules and remodelling tissue molecules. Senescent cells increase in many tissues with aging or in organs associated to many chronic diseases and after radiotherapy or chemotherapy. Aging is related to the decline of renal functionality. During aging, there is an increased expression of the senescence marker pl6INK4a at renal level, especially in the tubular epithelium and, to a lesser extent, in glomerulus cells (podocyte and parietal epithelium) and interstitial cells. Changes of pl6INK4a are more evident in the cortex than the marrow (Melk et al., 2004; Sis et al ., 2007). In rodents, the amount of senescent proximal tubular cells increases with aging, while in glomerulus an increase of senescent cells is not observed. Senescence of renal tubular cells is related to tubular atrophy, interstitial fibrosis and glomerulosclerosis (Melk et al., 2004; Sis et al., 2007). Moreover, removing senescent tubular cells cause the reduction of glomerulosclerosis (Baker et al., 2016).
Nevertheless, a prolonged renal damage or a repeated damage cause a maladaptative repair (inflammation, accumulation of myofibroblasts, fibrosis and vascular rarefaction) that
lead to a chronic kidney disease (CKD). Acute kidney disease (AKI) leads kidney to CKD with aging or after a second damage. Alternatively, patients with CKD are more predisposed to AKI after injuries (Jin et al., 2019). A possible explanation could be the accumulation of senescent cells during aging and during post-trauma, because, after AKI, senescent cells increase slowly with time (Jin et al., 2019). Moreover, the senescence level before renal transplant could predict the result of the transplant (McGlynn et al., 2009), suggesting that targeting senescent cells could be an effective therapy against renal diseases.
For this reason, the prevention of senescence is really important also for treatment of a renal injury. Nevertheless, ARPC show a very important role of renal senescence processes because they supervise tissue homeostasis and healing processes.
Another related aspect to premature senescence induced by AKI is the deficiency of Klotho gene, which codifies an anti-aging protein. Klotho gene is expressed mainly in kidney, in particular in renal tubules (Hu et al., 2010;
Kuro-o et al., 1997). Cellular lines derived from internal medullar duct express Klotho gene too. Moreover, kidney represents an important target of Klotho protein, which has several renal effects, such as the regulation of 1,25- (OH)
2-vitamin D3 renal production, as well as homeostasis of phosphate, calcium and potassium.
Experimental data of the Applicant show that the Klotho expression in ARPC is greater than other stem cells (human amniotic stem cells) and normal renal cells (Human Renal Proximal Tubule Epithelial Cells, RPTEC, isolated from healthy individuals), which normally develop high amount of Klotho protein.
In this context, CD133 expression is essential in the regulation of cellular senescence, that is characterized also by cellular depletion after repeated proliferation cycles (Ferenbach & Bonventre, 2015). In fact, CD133 is involved in signaling of Wnt / b-catenin and its expression limits the cellular senescence. CD133 could act as permissive factor for signaling of Wnt / beta catenin (has a role in the prevention of b-catenin degradation) and it plays an important role in tissue healing. Moreover, CD133 absence affects the cellular proliferation after the damage, leading to the senescence (Brossa et al., 2018). Additionally, silencing CD133, the number of senescent cells, measured by the senescence marker b-galactosidase, is significantly higher than CD133 control cells where CD133 is not silenced. Moreover, there is a significant
reduction of telomers length in CD133 silenced cells than their controls CD133+ (Brossa et al., 2018).
All data of the applicant, in vitro and in vivo, suggest that ARPC become senescent as individuals age and as in vitro cell culture passage number increase, losing the CD133 expression and their healing capacity (Brossa et al., 2008; Sallustio et al., 2010, 2017).
Known compounds however have the drawback of not increasing CD133 expression in ARPC. Scope of the present invention is providing a compound comprising bioactive molecules able to increase CD133 expression in ARPC, namely an inverse marker of senescence of renal stem cells, and therefore slow down their senescence, and therefore having characteristics to overcome drawbacks of known compounds.
According to the present invention, it is provided a compound comprising bioactive molecules having beneficial effects on senescence of adult renal stem cells, as defined in claim 1. For a better understanding of the present invention, it is described a preferred embodiment, as a not limiting example, referring to the enclosed drawings, in which: figure 1 shows diagrams of flow cytometry that highlight an increase of marker CD133 expression in renal
stem cells engaged toward cellular senescence (BASAL) and stimulated for 48 hours with the compound comprising bioactive molecules having beneficial effects on senescence of adult renal stem cells, according to the present invention; the CD133 expression increased from 3.7% in BASAL up to 43.5 % in stimulated cells;
- figure 2 shows mean levels (from five experiments) of marker CD133 expression in renal stem cells engaged toward cellular senescence (BASAL) and stimulated individually with bioactive molecules, bioactive molecules being comprised by the compound having beneficial effects on senescence of adult renal stem cells, according to the present invention;
- Figures 3a and 3b show diagrams of flow cytometry that highlight marker CD133 expression in renal stem cells engaged toward cellular senescence, with a reduced marker CD133 expression (BASAL) and stimulated for 48 hours with the compound comprising bioactive molecules alone (Figure 3a) or in combination (Figure 3b) having beneficial effects on senescence of adult renal stem cells, according to the present invention;
- figure 4 shows results of another experiment carried out by the Applicant.
According to the present invention, the bioactive molecules compound having beneficial effects on senescence of adult renal stem cells comprises decenoic acid, nonanoic acid, valproic acid and heparin. According to an aspect of the present invention, decenoic acid was tested in four different isoforms (10— Hydroxy-2-decenoic acid, Ethyl trans-2-decenoate, 3- Decenoic acid, 1O-Hydroxydecanoic acid).
Decenoic acid and nonanoic acid are two naturally occurring compounds.
In particular, nonanoic acid, also known as pelargonic acid, is a fatty acid obtained by ozonolysis of oleic acid and it is used for esters synthesis used in fragrances and aroma industries. Decenoic acid is comprised in several compounds and it is one the main components of royal jelly.
Heparin is a naturally occurring molecule.
Bioactive molecules of decenoic acid, nonanoic acid, valproic acid and heparin comprised in the compound, according to the present invention, are able to increase CD133 expression in ARPC, namely an inverse marker of senescence of renal stem cells, therefore slow down their senescence .
Advantageously according to the present invention, the compound comprising bioactive molecules of decenoic acid, nonanoic acid, valproic acid and heparin could be used to produce natural supplements, to improve the quality of renal stem cells, and to counteract the senescence of this specific stem/progenitor cells .
The formulation of the compound according to the present invention increases considerably the capacity of renal stem cells to delay aging. According to an aspect of the present invention, the compound consists of:
Ethyl trans-2-decenoate: from 0.1 mM to 1 mM 1O-Hydroxy-trans-2-decenoic acid: from 0.1 mM to 1 mM 10-Hydroxydecanoic acid: from 0.1 mM to 1 mM 3-Decenoic acid: from 0.1 mM to 1 mM
Nonanoic acid: from 0.1 mM to 2 mM Heparin: from 0.025 U/ml to lU/ml Valproic acid: from 0.1 mM to 10 mM.
According to an aspect of the present invention, below are reported the combinations of bioactive molecules:
Experimental data collected by the applicant and showed in figure 1, figure 2, and figure 3 highlight that all molecules could increase CD133 expression in ARPC. In particular, for this study, ARPC were purified by renal sternness marker CD133 and CD24. Each of the identified
molecules were used to stimulate ARPC for 48 hours with the natural molecules of the present patent application.
According to an aspect of the invention the compound consists of the following formulation of bioactive molecules:
1 mM of decenoic acid,
0.4 mM of nonanoic acid,
1 mM of valproic acid,
1 U/ml of heparin. It was also evaluated by flow cytometry the CD133 expression, marker for ARPC, to quantitatively evaluate the increase of CD133 expression.
In fact, the applicant had done experimental tests directed to verify the effects of the compound comprising bioactive molecules on the senescence of adult renal stem cells.
Figure 2 shows the levels of the marker CD133 expression in renal stem cells engaged toward cellular senescence (BASAL) and stimulated individually with the bioactive molecules. Data show a statistically substantial increase of CD133 in ARPCs stimulated for 48 hours with the bioactive molecules comprised by the compound having beneficial effects on senescence of adult renal stem cells.
Experimental tests were done on five different lines of tubular renal stem cells isolated from kidneys of five different patients.
Figures 3a and 3b show diagrams of flow cytometry that highlight marker CD133 expression in renal stem cells engaged toward cellular senescence, with a reduced marker CD133 expression (BASAL) and stimulated for 48 hours with the compound comprising bioactive molecules having beneficial effects on senescence of adult renal stem cells, according to the present invention. The stimulation of individual molecules increases considerably the CD133 expression, while the stimulation with the combinations of bioactive molecules causes a higher increase of marker CD133 expression than the stimulation with individual molecules.
Therefore, the compound comprising bioactive molecules according to the present invention can substantially increase the marker of sternness CD133 expression in renal stem cells engaged toward cellular senescence. Another convenience of the compound comprising bioactive molecules according to the present invention is that it comprises naturally occurring molecules with general beneficial effects and without generating side effects.
Finally, the compound comprising bioactive molecules according to the present invention could be administered in part as protein products and in part as messenger RNA, like it occurs in nature by ARPC mediation, possibly conveyed by artificial microvesicle or lipidic microparticles which, based on the composition, structure, charge and dimension, will be able to drive the interaction with the biological substrate of the conveyed molecules.
It is clear, lastly, that the compound comprising bioactive molecules according to the described and illustrated invention could be modified without, for this reason, exit from the scope of protection of the present invention, as defined by the enclosed claims.
Claims
1. Bioactive molecules compound having beneficial effects on senescence of adult renal stem cells characterized in that it comprises: decenoic acid, nonanoic acid, valproic acid and heparin.
2. Bioactive molecules compound according to claim 1 characterized in that said bioactive molecules of decenoic acid, nonanoic acid, valproic acid and heparin increase the expression of CD133 in adult renal stem cells, slowing down their senescence.
3. Bioactive molecules compound according to claim 1 characterized in that it consists of:
- Ethyl trans-2-decenoate: in a concentration ranging from 0.1 mM to 1 mM; - 1O-Hydroxy-trans-2-decenoic acid: in a concentration ranging from 0.1 mM to 1 mM;
10-Hydroxydecanoic acid: in a concentration ranging from 0.1 mM to 1 mM;
- 3-Decenoic acid: in a concentration ranging from 0.1 mM to 1 mM;
- Nonanoic acid: in a concentration ranging from 0.1 mM to 2 mM;
- Heparin: in a concentration ranging from 0.025 U/ml to lU/ml;
- Valproic acid: in a concentration ranging from 0.1 mM to 10 mM.
4. Bioactive molecules compound according to claim 1 characterized in that it contains a combination of bioactive molecules selected from the group consisting of:
- Nonanoic acid + 1O-Hydroxy-trans-2-decenoic acid, respectively in concentrations comprised between 0.1 mM and 2 mM and betweenO.1 mM and 1 mM;
Nonanoic acid + 10-Hydroxydecanoic acid, respectively in concentrations between 0.1 mM and 2 mM and between 0.1 mM and 1 mM;
Nonanoic acid + Ethyl trans-2-decenoate, respectively in concentrations between 0.1 mM and 2 mM and between 0.1 mM and 1 mM; - Nonanoic acid + 3-Decenoic acid respectively in concentrations between 0.1 mM and 2 mM and between 0.1 mM and 1 mM;
Heparin + Valproic acid respectively in concentrations between 0.025 U / ml and 1U / ml and between 0.1 mM and 10 mM;
Nonanoic acid + Valproic acid respectively in concentrations between 0.1 mM and 2 mM and between
0.1 mM and 10 mM;
Ethyl trans-2-decenoate + Valproic acid respectively in concentrations between 0.1 mM and 1 mM and between 0.1 mM and 10 mM;
- 1O-Hydroxy-trans-2-decenoic acid + Valproic acid in a concentration between 0.1 mM and 1 mM and between
0.1 mM and 10 mM;
10-Hydroxydecanoic acid + Valproic acid in a concentration between 0.1 mM and 1 mM and between 0.1 mM and 10 mM; - 3-Decenoic acid + Valproic acid in a concentration between 0.1 mM and 1 mM and between 0.1 mM and 10 mM;
- Heparin + Nonanoic acid in a concentration between 0.025 U / ml and 1U / ml and between 0.1 mM and 2 mM;
Heparin + Ethyl trans-2-decenoate in a concentration comprised between 0.025 U / ml and 1U
/ ml and between 0.1 mM and 1 mM;
- Heparin + 1O-Hydroxy-trans-2-decenoic acid in a concentration comprised between 0.025 U / ml and 1U / ml and between 0.1 mM and 1 mM; - Heparin + 10-Hydroxydecanoic acid in a concentration comprised between 0.025 U / ml and 1U
/ ml and between 0.1 mM and 1 mM;
Heparin + 3-Decenoic acid in a concentration between 0.025 U / ml and 1U / ml and between 0.1 mM and 1 mM .
5. Bioactive molecules compound according to claim 1 characterized in that it consists of the following formulation of bioactive molecules:
1 mM of decenoic acid;
0.4 mM of nonanoic acid;
1 mM of valproic acid; - 1 U/ml of heparin.
6. Use of bioactive molecules compound according to claim 1, in natural food supplements, formulated to improve kidney stem cells quality.
7. Use of the compound comprising bioactive molecules according to claim 1, in a drug for improving renal stem cells quality.
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| IT102021000002783 | 2021-02-09 | ||
| IT102021000002783A IT202100002783A1 (en) | 2021-02-09 | 2021-02-09 | COMPOUND COMPRISING BIOACTIVE MOLECULES HAVING BENEFICIAL EFFECTS ON ADULT RENAL STEM CELL SENESCENCE |
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2021
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| WO2009015183A1 (en) * | 2007-07-23 | 2009-01-29 | University Of Utah Research Foundation | Method for blocking ligation of the receptor for advanced glycation end-products (rage) |
| JP2012197239A (en) * | 2011-03-18 | 2012-10-18 | Kyoto Univ | Intrarenal casein kinase 2 inhibitor |
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