Stimulator of tissue regeneration
Researchers at Case Western Reserve University and the University of Texas Southwestern Medical Center, working under the guidance of Professor Sanford Markowitz, in experiments on animal models demonstrated the ability of the new drug to significantly accelerate the process of repairing damage to the colon, liver and bone marrow.A compound synthesized by the body, known as prostaglandin E2, is involved in the key mechanism, the effect on which underlies the effectiveness of the experimental drug. The ability of prostaglandin E2 to support the proliferation of stem cells in many types of tissues is well known to specialists.
Earlier studies by the authors showed that the enzyme 15-hydroxyprostaglandine dehyrogenase is synthesized in the body of each person, which cleaves prostaglandin E2 molecules and reduces its content in the body. Based on this, they hypothesized that inhibition of 15-hydroxyprostaglandine dehyrogenase can increase the level of prostaglandin E2 in tissues, which, in turn, stimulates and accelerates damage recovery.
To confirm their hypothesis, the researchers created genetically modified mice that do not have 15-hydroxyprostaglandine dehyrogenase. Such animals were characterized by a twofold increase in prostaglandin E2 levels in many tissues, including bone marrow, colon and liver. All these tissues showed increased resistance to damage and faster recovery compared to the tissues of ordinary mice. These data prompted researchers to search for approaches that allow reversible inactivation of 15-hydroxyprostaglandine dehyrogenase for a short time.
Preliminary studies began with experiments on cell cultures. First, the authors created cells that emit a glow when the level of 15-hydroxyprostaglandine dehyrogenase changes. After that, they searched the database of the University of Texas Southwestern Medical Center, containing information on 230,000 different chemical compounds, and identified one molecule capable of inactivating this enzyme. According to the authors, this compound, encoded under the number SW033291, has an unusually powerful potential. It inactivates 15-hydroxyprostaglandine dehyrogenase when added to the reaction mixture in a ratio of 1:10 billion, which indicates its promise when used as a drug.
Inhibition of 15-hydroxyprostaglandine dehyrogenase accelerates tissue repair (scheme from an article in Science).
(A) The enzyme 15-hydroxyprostaglandine dehyrogenase degrades and has a negative regulatory effect on the level of prostaglandin E2.
(B) SW033291 inhibits 15-hydroxyprostaglandin dehyrogenase, increases the concentration of prostaglandin E2 in tissues and induces the expression of CXCL12 (chemokine ligand 12 with the C-X-C motif, also known as stromal cell factor-1, SDF-1) and SCF (stem cell factor) by CD45 bone marrow cells.
This, in turn, accelerates the homing (transfer to the bone marrow) of hematopoietic stem cells, the formation of mature blood cells and post-transplant restoration of normal levels of cellular components of the blood.
Inhibition of 15-hydroxyprostaglandine dehyrogenase similarly stimulates cell proliferation after damage to the colon and liver, accelerating the recovery of tissues of these organs.
Further experiments showed that SW033291 inactivates 15-hydroxyprostaglandine dehyrogenase not only in a mixture of reagents, but also inside a living cell and even when administered to a live animal. The latter was demonstrated in a study on mice exposed to lethal doses of radioactive radiation and subsequently underwent partial bone marrow transplantation. The introduction of SW033291 ensured the recovery of the animals, while all the mice of the control group died.
A more detailed study showed that during bone marrow transplantation, SW033291 shortens the period of restoration of hematopoietic function in the bone marrow by 6 days, which accelerates the normalization of the number of neutrophils, platelets and erythrocytes in the blood of animals. In addition, the administration of the drug led to an increase in the level of prostaglandin E2 in the bone marrow and stimulation of the production of substances necessary for the survival of hematopoietic stem cells. All these changes did not cause any side effects even when using dosages of SW033291, significantly exceeding the doses required for inhibition of 15-hydroxyprostaglandine dehyrogenase.
In the treatment of mice with other diseases, the drug SW033291 also significantly accelerated tissue repair. For example, in a mouse model of ulcerative colitis, the introduction of an experimental drug ensured the healing of almost all ulcers and prevented the appearance of colitis symptoms. With the removal of two-thirds of the liver against the background of the introduction of SW033291, the process of organ restoration proceeded almost twice as fast as without medical intervention.
Since the bone marrow, large intestine and liver have very little in common, researchers believe that SW033291 has a universal mechanism of action and can be useful in restoring many body tissues. However, the next stages of the study will be devoted to the three therapeutic areas described above, in which SW033291 has already demonstrated impressive results.
In the near future, the authors will conduct safety studies of SW033291 on large animal models, which is a prerequisite for obtaining permission to conduct clinical trials, to which they plan to switch over the next three years.
Article by Yongyou Zhang et al. Inhibition of the prostaglandin-degrading enzyme 15-PGDH potentiates tissue regeneration is published in the journal Science.
Evgeniya Ryabtseva
Portal "Eternal youth" http://vechnayamolodost.ru based on the materials of Case Western Reserve University: New drug stimulates tissue regeneration, catalyzing faster regrowth and healing of damaged tissues.
18.06.2015