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IMPORTANCE OF LIVER IN HUMAN LIFE AND DISEASES
Baqoev Shukur Muzafarovich
Buxoro davlat tibbiyot instituti
Telefon: +998934529493
baqoyevshukur93@gmail.com
https://doi.org/10.5281/zenodo.13907058
Abstract.
As a result of the work carried out, data were obtained on the role of population
risk factors, as well as some interleukins (receptor for interleukin-1 type II and interleukin-6)
in the process of bone tissue remodeling and the development of osteoporosis in early
rheumatoid arthritis. For the first time, the influence of the parameters of the course of early
rheumatoid arthritis, including the activity and serotype of rheumatoid factor (RF) and the
presence of antibodies to cyclic citrullinated peptide (ACCP), on the change in the state of bone
mineral density and the change in bone metabolism markers in patients with early rheumatoid
arthritis depending on gender and the presence of menopause has been shown. Based on the
data of regression analysis, the most significant factors influencing the change in bone mineral
density in patients with early rheumatoid arthritis have been identified. For the first time, it has
been shown that along with population risk factors, factors associated with the underlying
disease (parameters of the course of early rheumatoid arthritis) have a significant effect.
Key words
: cell, senescence, SASP, DDR, inflammaging, liver, elderly.
Introduction.
It implies the harmful influence of senescent cells on younger cells through
reactive forms of oxygen (ROS). They cause DNA damage and introduce non-senescent cells
into permanent cell cycle arrest. In this way, the proliferative capacity of cells is reduced. The
existence of “the bystander effect” was proven by determining senescence markers in younger
cells, and it is interesting that in epithelial cells and cancer cells, this effect more often
stimulates proliferation, which is the opposite of what was previously describe. It has been
proven that SASP products of human diploid fibroblasts can lead to the proliferation and
transformation of premalignant epithelial cells into malignant ones. The uniqueness,
complexity and importance of SASP are also in the fact that it abounds in a multitude of effects,
some of which are contradictory. For example, another paracrine effect of SASP is the
stimulation of anti-tumor immunity. SASP paracrine products trigger the so-called “senescence
surveillance” composed of components of the innate and adaptive immune response, which has
a role in the removal of senescent cells, the suppression of tumor formation and their
regression. SASP components actually enable tissue infiltration by natural killer (NK) cells that
then eliminate senescent and tumor cells. In addition, individual SASP components play a role
in changes in tissue morphology. For example, IL-1β, in addition to having a pro-inflammatory
role, participates in the modulation of the tissue microenvironment. In a study conducted by
Krizhanovsky et al. on mice liver models, chronic toxic liver damage is accompanied by the
activity of hepatic stellate cells in terms of proliferation and formation of profibrotic secretome.
This leads to the accumulation of hepatic stellate cells in which senescence is induced, and their
secretome changes into a secretome similar to SASP. It is characterized by the presence of
matrix-degrading enzymes, which limits the degree of liver fibrosis. Senescent hepatic stellate
cells on the end are removed by the “senescence surveillance” mechanism.
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After all, we can conclude that cellular senescence is very complex as it involves many
different pathways, many molecules of different origins, enzymes and transcription factors.
Therefore, it is necessary to take into account several different markers, as well as their
combinations, in an attempt to detect senescence.
As we have seen, SASP involves the production of numerous pro-inflammatory cytokines
that play different roles in multiple processes that are vital for the cell. Their main role is in
promoting the occurrence of chronic inflammation in tissues. According to numerous studies,
chronic inflammation is an irreplaceable factor in aging process and the onset of age-related
diseases such as dementia, atherosclerosis, osteoporosis, cancers, metabolic syndrome and
vascular diseases. It leads to the activation of numerous proinflammatory signaling pathways.
In light of the connection between cellular aging and inflammation, the term “inflammaging”
was introduced. This term was created after Fagiolo et al. showed in that peripheral blood
mononuclear cells of elderly people produce a higher amount of pro-inflammatory cytokines
compared to cells of younger people. After that, this phenomenon was the subject of numerous
studies that came to the conclusion that “inflammaging” is associated with the aforementioned
increased production of pro-inflammatory cytokines in the elderly, genetic components and
frequent subclinical viral infections seen in the elderly (Epstein Barr virus and cytomegalovirus
infection). Inflammation as part of “inflammaging” is the so-called “sterile inflammation”, i.e.,
inflammation in which the existence of a pathogen that would cause it has not been proven. It
affects the tissues in multiple ways, for example, by enabling infiltration of tissue by cells of the
immune system and, on the other hand, by the effect of proinflammatory cytokines that can
cause phenotypic changes in previously normal cells (disruption of cellular communication,
damage to the innate immune response, stimulation of angiogenesis, etc.). Baker et al. have
shown in repeated research that by reducing the number of senescent cells, there is a reduction
in SASP and the release of pro-inflammatory cytokines, thus, proving that SASP plays a role in
“inflammaging”. The importance of inflammation in the senescence process can also be
concluded based on the fact that the complex known as “inflammasome” participates in the
regulation of SASP. It is a complex composed of several molecules belonging to the innate
immune response. It activates caspase-1, which is responsible for the activation of the IL-1
inflammatory cascade that promotes the induction of senescence through oxidative stress and
DNA damaga. Other pro-inflammatory cytokines similarly lead to age-related inflammation, for
example, IL-6 and TNF-α . Some authors mention the blockade of the inflammatory response in
SASP as one of the potential therapeutic possibilities for diseases associated with senescence.
Drugs with this effect are called senomorphics. They lead to inhibition of SASP, but not to
apoptosis of senescent cells. They achieve their effect by inhibiting the pathways responsible
for the formation of SASP as well as transcription factors signal transducer and activator of
transcription (STAT) protein, NF-κB and C/EBP β. Senomorphics include rapamycin,
everolimus, resveratrol, apigenin and ruxolitinib. Some well-known drugs that are used for
other indications have also shown a senomorphic effect, for example, metformin. Bearing in
mind that in senescence-related diseases there is an increase in the number of senescent cells,
the possibility of removing these cells could eventually prevent the onset of the disease. Studies
on mouse models have shown that the removal of senescent macrophages reduces the risk of
atherosclerosis and that reducing the number of senescent glial cells can prevent cognitive
disorders. Drugs that have this function are called senolytics and they selectively induce
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apoptosis of senescent cells. Senescent cells initiate pro-survival pathways that hinder the
occurrence of apoptosis; however, this mechanism enables the targeting senescent cells by
senolytic drugs. The first discovered senolytics are natural substances whose role was
discovered in 2015, namely quercetin and dasatinib. After that, research progressed and seven
more classes of the mentioned drugs were discovered, some of them are: fisetin,
piperlongumine, curcumin, navitoclax, ABT-737, A1331852, UBX3125, P5091, geldanamycin,
tanespimycin, FOXO4-DRI, etc. They act according to different principles, some of them are
kinase inhibitors, BCL-2 family inhibitors, inhibitors of MDM2/p53 interaction, Hsp90
inhibitors, p53 binding inhibitors, etc.
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