We studied the role of NF-κB-, cAMP/PKA-, JAKs/STAT3-, ERK1/2-, p38-, JNK- and p53- mediated signaling pathways in the realization of the growth potential of neural stem cells and committed neuronal ...progenitors under
in vitro
conditions. The method of pharmacological blockade with selective inhibitors of individual signaling molecules revealed some principal differences in their role in the determination of the proliferation and differentiation status of progenitor cells of different classes. Analysis of the peculiarities of intracellular signaling in cells and comparison of the role of its individual elements attest to the prospects of developing new drugs with neuroregenerative activity based on STAT3 inhibitors or JNK activators. These modulations of activity of signaling molecules can stimulate the realization of the growth potential of committed neuronal progenitors and neutral stem cells, respectively. The blockade of STAT3 and an increase in the content of phosphorylated forms of JNK had no “negative” effects on the functioning of multipotent neural stem cells and committed neuronal progenitors, respectively.
We studied the participation of ERK1/2 and p38 in secretion of neurotrophic growth factors by various types of neuroglia under conditions of
in vitro
and
in vivo
modeled ethanol-induced ...neurodegeneration. The inhibitory role of these protein kinases in the production of neurotrophins by intact astrocytes and the absence of their participation in the regulation of functions of oligodendrocytes and microglial cells were shown. Under conditions of ethanol neurotoxicity, the role of ERK1/2 and p38 in the production of growth factors by glial elements was significantly changed. Neurodegeneration modeled
in vitro
led to inversion of the role of both protein kinases in the secretion of neurotrophins by astroglia and inhibition of the cytokine-synthesizing function of oligodendrocytes and microglial cells by ERK1/2 and p38. In mice receiving ethanol
per os
for a long time (as well as in cells in vitro exposed to ethanol), mitogen-activated kinases stimulated the function of astrocytes and inhibited the production of growth factors by microglial cells. At the same time, chronic alcoholization was accompanied by the appearance of the stimulating role of ERK1/2 and p38 in the implementation of the secretory function by oligodendrocytes.
The role of NF-κB, cAMP/PKA, JAKs/STAT3, ERK1/2, p38, JNK, and p53 signaling pathways in the realization of growth potential of mesenchymal, neural, erythroid, and granulomonocytic progenitor cells ...were examined
in vitro
. Using selective blockers of signaling molecules, we revealed some principal distinctions of their involvement in determination of proliferation-differentiation status of the progenitor cells of different functional classes. The most salient peculiarities were observed in the roles of cAMP/PKA, JNK, and JAKs/STAT3 signaling pathways in the control of functions of various types of the regeneration-competent elements. The specific features of intracellular signaling revealed in histogenetically and functionally different progenitor cells attest to visibility of differentiated pharmacological stimulation of regeneration in individual tissues and prospectiveness in the development of targeted remedies for regenerative medicine based on modifiers of activity of the intracellular signaling molecules.
We studied the involvement of cAMP and PKA in the regulation of the secretion of neurotrophic growth factors by macro-and microglial cells in the model of ethanol-induced neurodegeneration
in vitro
...and
in vivo
. The stimulating role of cAMP in the secretion of neurotrophins by intact astrocytes and oligodendrocytes was shown, while PKA does not participate in this process. On the contrary, the inhibitory role of cAMP (implemented via PKA activation) in the production of neurogenesis stimulators by microglial cells under conditions of optimal vital activity was found. Under the influence of ethanol, the role of cAMP and PKA in the production of growth factors by macroglial cells was considerably changed. The involvement of PKA in the cAMP-dependent signaling pathways and inversion of the role of this signaling pathway in the implementation of the neurotrophic secretory function of astrocytes and oligodendrocytes, respectively, directly exposed to ethanol
in vitro
were noted. Long-term exposure of the nervous tissue to ethanol
in vivo
led to the loss of the stimulating role of cAMP/PKA signaling on neurotrophin secretion by macroglial cells without affecting its inhibitory role in the regulation of this function in microglial cells.
The psychopharmacological effects of a stimulator of functions of progenitor cells of the nervous tissue STAT3 inhibitor (STAT3 Inhibitor XIV, LLL12) were studied under conditions of modeled ...alcoholic encephalopathy in C57BL/6 mice. The pharmacological agent corrected the parameters of exploratory behavior (characterizing predominantly cognitive activity) in the experimental animals at the late terms of observation. At the same time, the reproducibility of the conditioned passive avoidance response developed at the beginning of the course STAT3 inhibitor administration decreased. These effects developed against the background of a significant increase in the content of neural stem cells and their proliferative activity in the paraventricular zone of the brain.
Ethanol-induced neurodegeneration was modeled
in vitro
to study the roles of ERK1/2 and p38 in realization of the growth potential of neural progenitor cells and secretion of neurotrophic growth ...factors by glial elements. Addition of the neurotoxic dose of C
2
H
5
OH (65 mM) to the culture medium abolished the effects of specific ERK1/2 and p38 inhibitors on the formation of colonies (neurospheres) and proliferative activity of neural CFU in cultured cells derived from paraventricular region of the mouse brain. The study established that these protein kinases are not implicated in ethanol-induced stimulation of the formation of neural CFU, differentiation of neural progenitors, and synthesis of humoral functional regulators of neural CFU by glial cells.
Peculiar roles of JAKs and STAT3 in realization of growth potential of various types of progenitor cells in neural tissue were examined during ethanol-induced neurodegeneration modeled both
in vitro
...and
in vivo
. During
in vitro
action of C
2
H
5
OH, these signal molecules exerted the opposite effects on mitotic activity of multipotent neural stem cells and committed neural progenitors (the clonogenic PSA-NCAM
+
cells). The JAKs and STAT3 inhibitors down-regulated the rate of neural stem cell division (proliferative activity) but up-regulated such activity of the committed neural progenitors. A long-term
in vivo
exposure of mice to ethanol inversed the roles of JAKs and STAT3 in determination of proliferative status of neural stem cells and eliminated involvement of JAKs in functional control over the committed progenitors of neurons. The data attest to much promise of STAT3 inhibitors in treatment of ethanol-induced CNS diseases as the remedies that stimulate realization of growth potential in multipotent neural stem cells and committed neural progenitors.
One of the leading causes of hospitalization, disability, and mortality in 50% of women and 20% of men in age group over 50 years of age is bone fractures and their complications caused by diseases ...musculoskeletal system. There is an active search for a solution to the problem associated with the limitations of using auto-, allo-, and xenografts in the clinic to replace bone defects initiated the development a regenerative approach based on the gradual replacement of artificial material with growing bone tissue. Promise is presented in this regard by materials based on calcium phosphates, which act as an active source of chemical elements (calcium, phosphorus, etc.) capable of optimizing the process of healing of a bone defect and ensuring the replacement of an implant with new bone tissue. This review summarizes data from the literature on the local biological activity, target cells, and molecular effects of calcium phosphates. Calcium phosphate materials have been shown to be biocompatible and are able to adsorb regulatory proteins and cells, influencing their genetic and secretory apparatus and triggering the process of differentiation of mesenchymal stem cells in the osteogenic direction. At the same time, the successful implementation of local mechanisms of osseointegration at the bone–implant interface reduces the risk of periprosthetic infection and rejection of artificial products. Further study and use of calcium phosphate materials will make it possible to make a significant breakthrough in solving modern problems of bone tissue regeneration associated with a precise (digital) bioengineering approach based on additive technologies and artificial intelligence.
The features of the participation of Smad3 in the functioning of neural stem cells (NSC), neuronal committed precursors (NCP), and neuroglial elements were studied
in vitro
. It was found that this ...intracellular signaling molecule enhances the clonogenic and proliferative activities of NCP and inhibits specialization of neuronal precursors. At the same time, Smad3 does not participate in the realization of the growth potential of NSC. With regard to the secretory function (production of neurotrophic growth factors) of neuroglial cells, the stimulating role of Smad3-mediated signaling was shown. These results indicate the promise of studying the possibility of using Smad3 as a fundamentally new target for neuroregenerative agents.
The effects of JAK and STAT3 inhibitors on the production of neurotrophic growth factors by different types of neuroglial cells were studied under conditions of
in vitro
and
in vivo
models of ...ethanol-induced neurodegeneration. It was shown that these signaling molecules do not participate in the secretion of neurotrophins by intact astrocytes and oligodendrocytes. The inhibitory role of JAK in the regulation of this function of microglial cells was revealed. We also revealed significant changes in the role of JAK and the presence of STAT3 specifics within the framework of JAK/STAT signaling in the production of growth factors by various glial elements under the influence of ethanol. Neurodegeneration modeled
in vitro
led to the appearance of a “negative” effect of STAT3 on the production of neurogenesis stimulants by all types of glial cells. Moreover, the role of STAT3 in oligodendrocytes and microglial cells generally corresponded to that of JAK/STAT signaling. In astrocytes, only selective blockade of STAT3 (but not JAK) led to stimulation of their function. In mice subjected to prolonged peroral alcoholization, the neuroglial responses to the pharmacological regulation of JAK/STAT signaling were different. An inversion of the role of JAK and STAT3 in the production of neurotrophins by oligodendrocytes was noted. In addition, JAK inhibitor did not stimulate secretory function of microglial cells under conditions of prolonged exposure to ethanol
in vivo
.
