ACS by A. A. Bogomolets (Описание сыворотки А.А.Богомольца на английском языке)
Proposed by Professor A.A. Bogomolets, Anti-reticular Cytotoxic Serum can improve the body’s connective tissue to rejuvenate the organism, prolong life, and treat many diseases.
Today it is no longer necessary to dwell on the importance of the general and local body reactivity for youth, health, and the disease course. This reactivity is determined to a greater extent by the functioning of its physiological system of connective tissue.
The term “physiological system of connective tissue” was proposed by Professor A.A. Bogomolets in his work “The Constitution and Mesenchyme” in 1924.
As is known, the connective tissue was long considered only as a kind of elastic skeleton or the stroma of the body.
- I. Mechnikov believed the connective tissue was of less importance. He introduced the concept of a macrophage system, which revealed to science one of the most vital functions of the physiological system of connective tissue. However, I. I. Mechnikov still underestimated the importance of the physiological system of connective tissue for the health of the body, its resistance to various diseases, and its longevity.
More recent work has significantly contributed to the elucidation of this importance.
ACS has a versatile effect on the structure and metabolism of connective tissue. In other words, it is the conductor of a connective tissue biomolecular orchestra.
Connective tissue is the backbone of all body tissues. It is its structural support, the exoskeleton of any body tissue. The connective tissue begins to develop in the embryonic period from the mesenchyme and then forms a supporting frame (fascia, ligaments, and bone tissue) and the skin. Therefore, its structural disturbances by nutritional and genetic factors will contribute to the development of numerous diseases.
Connective tissue is an integral part of the human body. Its structure and functions are far from fully understood. According to various estimates, its share is from 60 to 80%. Many human body functions depend on the state of the connective tissue; it is the connecting link of all the tissues of our body.
Violation of the structure and function of the connective tissue plays a vital role in chronic diseases of the internal organs. In medicine, it needs more attention.
Connective tissue supports the soft tissues of the body and internal organs. It covers the internal organs (liver, kidney capsule, etc.) and separates a group of cells, forming a lobular structure of the liver, spleen, pancreas, thyroid, mammary, prostate glands, etc. It is a so-called skeleton of soft parenchymal organs, which gives them shape. Connective tissue is part of the structure of blood vessels and ducts. It covers the nerve trunks, thus providing nerve insulation (it’s like the insulation of electrical wires). Such vital structures as the pleura, pericardium, and peritoneum also consist of connective tissue. The meninges also contain connective tissue. The skin, bone, cartilage, and ligament collagen are connective tissue, too.
Cartilage is a type of connective tissue that forms joint mobility. When joints are damaged and cartilage destroyed, you feel pain, inflammation, and stiffness, which can eventually progress to osteoarthritis, the most common type of arthritis.
ACS can be an excellent way to counter osteoarthritis and other diseases resulting from connective tissue degeneration.
ACS inhibits (suppresses) the connective tissue growth factor, which causes aging processes, organ fibrosis, skin fibrosis, cardiosclerosis, nephrosclerosis, defects in chondrogenesis, osteogenesis, angiogenesis, and other states related to poor health.
At the same time, there is increasing evidence that the connective tissue growth factor becomes active during aging. This fact makes it vital for preventing premature aging, rejuvenation, and overall recovery with the help of ACS.
Connective tissue growth factor is a small secreted protein of the CCN family, named for its three original members, including the Cesteine-rich61 (Cyr61/CCN1), CTGF/CCN2, and Nephroblastoma overexpressed (Nov/CCN3) proteins. The connective tissue growth factor is a cysteine-rich extracellular matrix protein composed of four domains or modules. Like other members of the CCN family, this protein contains four distinct structural modules, including an amino-terminal cysteine-rich insulin-like domain, a thrombospondin type 1 repeat, and a carboxyl domain of the terminal cystine knot. The synthesis of connective tissue growth factor, discovered in 1991, stimulates such a prophylactic cytokine as the transforming growth factor beta.
The connective tissue growth factor regulates various cellular functions, including proliferation, migration, adhesion, differentiation, and synthesis of extracellular matrix proteins in cells of different types. It also participates in more complex biological processes, such as angiogenesis, chondrogenesis, and oncogenesis. Increased expression of connective tissue growth factor inhibited by ACS is observed primarily in pathological conditions associated with fibrosis.
As an extracellular matrix protein, the connective tissue growth factor presumably integrates different extracellular signals into complex biological responses. The connective tissue growth factor binds, respectively, to various receptors on the cell surface (in particular, integrin receptors and surface heparan sulfate proteoglycans), controlling cell signaling, cell-matrix recognition, and cell adhesion. This protein also binds growth factors (e.g., bone morphogenetic protein-4 and transforming growth factor beta), vascular endothelial growth factor, and extracellular matrix proteins.
The connective tissue growth factor expression depends on growth factors and cytokines, including angiotensin II, bone morphogenetic proteins, endothelin, and mechanical stimuli (including high blood pressure and arterial wall tension). Angiotensin II-induced arterial hypertension acts as an active inducer of the expression of connective tissue growth factor in the vascular wall. The transforming growth factor beta is the most important regulator of expression and connective tissue growth factor. Respectively, the expression of connective tissue growth factor correlates with the expression of transforming growth factor beta in the vessel wall. The vascular endothelial growth factor also induces the connective tissue growth factor, which is of great clinical importance in angiogenesis dysregulation and diabetic retinopathy in particular.
The connective tissue growth factor is actively expressed during the development of the cardiovascular system, while embryos deficient in this factor die after birth due to complex developmental defects. In adults, the connective tissue growth factor plays a role in numerous pathological processes, including heart failure, cardiosclerosis, and scarring after myocardial infarction. Increased expression of connective tissue growth factor in vessels is associated with atherogenesis, apoptosis of smooth muscle cells, and the formation of vascular aneurysms. In the experiment, angiotensin II, increased blood pressure, and vascular wall tension increase the expression of connective tissue growth factor, thus contributing to changes in vascular smooth muscle cells. As a result of this remodeling, the structural integrity of the vascular wall is disrupted, which contributes to the formation of an aneurysm and dissection or rupture of the aorta. Stimulation of connective tissue growth factor may cause arterial hypertension-induced cerebral micro-bleeds due to disruption of the integrity of the vascular wall. The connective tissue growth factor is also expressed in atherosclerotic plaques, plays a role in regulating their stability, and can stimulate the migration of monocytes into atherosclerotic plaques. Experimental conditions show that the connective tissue growth factor plays a role in atherogenesis. With the introduction of ACS blocking the connective tissue growth factor, the accumulation of macrophages in atheromas and the plaque size decreased. In such a pathological process as hypertrophic cardiomyopathy (with interstitial fibrosis and excessive accumulation of extracellular matrix proteins), there is an increase in both tissue expression of CTGF and circulating concentration of this factor in the blood, starting from the earliest stages of the disease. Experimental models demonstrate that the connective tissue growth factor is a potent stimulator of the expression of genes encoding extracellular matrix proteins. Suppression of connective tissue growth factor by ACS in dilated cardiomyopathy also reduces myocardial fibrosis and improves heart function.
A Taiwanese registry of 125 patients with diastolic heart failure found a significant correlation between plasma levels of connective tissue growth factor and ECHO parameters of diastolic dysfunction. Assessed by magnetic resonance therapy, the severity of cardiac fibrosis also correlated with the concentration of connective tissue growth factor in blood plasma.
Another study analyzed the expression of connective tissue growth factor in patients with heart failure who underwent heart transplantation. In the left ventricular tissue of patients with both ischemic and dilated cardiomyopathy, there was increased expression of connective tissue growth factor, along with overexpression of transforming growth factor beta 1, collagen, and matrix metalloproteinases, which correlated with the severity of interstitial myocardial fibrosis.
One of the major clinical studies of connective tissue growth factor involving 1,227 patients with cardiovascular pathology found that elevated plasma levels of this factor increase the risk of new cardiovascular diseases. In this study, an increase in the concentration of connective tissue growth factor was associated with ischemic coronary events (1.4 times) and mortality from all causes, including ischemic stroke. The connective tissue growth factor in the blood plasma positively correlated with the level of total cholesterol and low-density lipoprotein cholesterol and inversely correlated with the glomerular filtration rate. In cerebrovascular pathology, the concentration of connective tissue growth factor also changed.
In type 2 diabetes, a high amount of connective tissue growth factor predicts future myocardial infarction or death from cardiovascular disease. In a study involving 952 patients with diabetes mellitus, an increase in the concentration of connective tissue growth factor caused a higher risk of myocardial infarction (2.4 times), cardiovascular mortality, and mortality from all causes (2.7 times) compared with patients who showed a low concentration of this factor. The connective tissue growth factor is a potent inducer of chemotaxis and extracellular matrix formation, which contributes to the progression of inflammatory, proliferative, and fibrotic changes in cardiovascular pathology.
A recent study of 114 patients with diastolic heart failure revealed that connective tissue growth factor levels in this group of patients were significantly higher than in the control group and correlated with echocardiographic measures of diastolic dysfunction. Another study also showed an increase in the level of connective tissue growth factor in 52 patients with chronic heart failure and a significant correlation of this factor with the severity of chronic heart failure, the concentration of cerebral natriuretic peptide, and echocardiographic indicators of diastolic and systolic dysfunction. According to the authors of this study, the effect of connective tissue growth factor on diastolic heart failure is due to its profibrotic effect. In a study of connective tissue growth factor in patients with acute heart failure, the maximum increase in connective tissue growth factor occurred in patients with heart failure with reduced ejection fraction, compared with the control group involving patients without heart failure or with heart failure with preserved ejection fraction. Several studies have demonstrated the crucial role of the connective tissue growth factor in the development of atrial fibrosis and dilatation and associated fibrillation. When studying the expression of connective tissue growth factor in atrial tissue removed during cardiac surgery, there was a higher content of connective tissue growth factor in atrial fibroblasts in patients with atrial fibrillation compared with patients with sinus rhythm. In addition, the level of this growth factor positively correlated with the duration of atrial fibrillation and dilatation. Another study found an increased expression of CTGF in fibroblasts and atrial myocytes removed during cardiac surgery. Angiotensin II stimulation further enhanced the overexpression of this growth factor.
The content of connective tissue growth factor in atherosclerotic plaques removed during carotid endarterectomy is known to be higher in patients with acute disorders of cerebral circulation than in patients with transient ischemic attacks. In this study, there were more collagen and smooth muscle cells in plaques rich in connective tissue growth factor. So, the authors concluded this growth factor was associated with a more stable atherosclerotic plaque phenotype.
As shown in the studies, the expression of connective tissue growth factor in the brain in Alzheimer’s disease correlates with the progression of clinical signs of dementia and the accumulation of amyloid. The experimental model of Alzheimer’s disease revealed that consuming a diabetogenic diet leads to a significant increase in the content of connective tissue growth factor in the brain, along with an increased accumulation of amyloid, which is characteristic of this type of dementia. Due to impaired maturation and regeneration of oligodendrocytes and inhibition of axon myelination, the connective tissue growth factor may also play a role in the pathogenesis of neurodegenerative diseases, where demyelination and axonal degeneration processes are vital.
Several studies have demonstrated the relationship between the connective tissue growth factor and adipose tissue. Thus, one of the recent studies shows that the expression of the connective tissue growth factor is more pronounced in preadipocytes but not in adipocytes. What’s more, the content of this growth factor correlates with the content of adipose tissue and insulin sensitivity. At the same time, CTGF-positive cells were found mainly in the fibrotic regions of the subcutaneous adipose tissue of the anterior abdominal wall. Besides, a decrease in body weight led to a decreased expression of connective tissue growth factor in adipose tissue. The authors concluded that increased expression of connective tissue growth factors is associated with adipose tissue content, adipose tissue fibrosis, and insulin resistance in obese individuals. At the same time, experimental models have shown that by influencing adipocyte differentiation, the connective tissue growth factor plays a significant role in the pathogenesis of obesity and associated insulin resistance, which justifies the use of ACS for treating obesity.
The expression of connective tissue growth factor is high in many nephropathies. In the experiment, inhibition of connective tissue growth factor slowed down the progression of the disease in diabetic nephropathy, unilateral ureteral obstruction, and in those who underwent nephrectomy (removal of the kidney). The connective tissue growth factor and its degradation fragments found in various biological fluids have been put forward as risk biomarkers for nephropathies of different origins. Among those fragments, the carboxyl-terminal module was of particular interest. In cell culture, this fragment regulated cell migration and proliferation. It also increased the production of chemokines and extracellular matrix and participated in the processes of renal inflammation.
You can see that the connective tissue growth factor promotes the development and progression of diabetic nephrosclerosis. In experimental diabetic nephropathy, the overexpression of connective tissue growth factor in the glomeruli, tubules, and interstitial tissue caused glomerulosclerosis, tubulointerstitial fibrosis, and albuminuria. In human diabetic nephropathy, the overexpression of connective tissue growth factor found on renal biopsy also contributes to tubulointerstitial fibrosis, proteinuria, and impaired renal function. In this case, urinary levels of connective tissue growth factor correlate with albuminuria. The amount of connective tissue growth factor in the blood can predict the onset of end-stage renal failure and death in diabetic nephropathy.
The role of connective tissue growth factor also occurs in non-diabetic chronic kidney disease. The amount of connective tissue growth factor in the blood and urine was high in patients with chronic kidney disease and proteinuria. The decrease in the level of proteinuria under the influence of ACS therapy caused a stepwise decline in the concentration of connective tissue growth factor in the urine in proportion to the decreased level of proteinuria, thus causing the increased content of this growth factor in the blood. The reason for a high level of connective tissue growth factor in the urine may be the local synthesis of this protein in the kidneys, for example, due to the activation of the synthesis of angiotensin II or excessive sodium intake. Local production of connective tissue growth factor in the kidneys occurred under experimental conditions and according to the results of human kidney biopsy. In addition to the local synthesis of connective tissue growth factor in the kidneys, an increase in the negative impact of connective tissue growth factor on the nephron can be promoted by enhanced ultrafiltration of connective tissue growth factor and impaired reabsorption in the tubules, which additionally contributes to the stimulation of fibrosis processes in the kidneys.
Under normal conditions, the amount of connective tissue growth factor in kidneys is low. However, its expression increases in renal fibrosis. The expression of connective tissue growth factor (in the mesangium and extra capillary space) is also high in glomerulonephritis. In addition to being involved in fibrosis processes, the connective tissue growth factor induces the expression of inflammatory mediators. It also promotes an increase in the number of macrophages and cell adhesion. Thus, the connective tissue growth factor plays a vital role in developing glomerulonephritis, causing an inflammatory process.
A recent study involving 23 patients with IgA nephropathy and hemorrhagic vasculitis found that the cytoplasmic expression of connective tissue growth factor in renal tubular cells was significantly higher in patients compared to the control group. The study also revealed the differences in the connective tissue growth factor expression in kidneys (glomeruli). At follow-up, there was a direct correlation between the rate of progression of nephropathy and the connective tissue growth factor expression in tubular cells. The authors of this study have discovered that the connective tissue growth factor may be a new, early, and sensitive marker of the onset of chronic kidney disease.
One of those studies of the connective tissue growth factor in nephrological pathology included 404 patients on hemodialysis. The results of this study indicate an inverse correlation between the concentration of this growth factor and the glomerular filtration rate. On the contrary, there was a direct relationship between the connective tissue growth factor and cardiovascular disease, between the level of interleukin-6 and beta 2-microglobulin, and between the presence of polycystic kidney disease and tubulointerstitial nephritis. Patients with the highest concentrations of connective tissue growth factor had a higher risk of mortality if compared with patients with the lowest levels of connective tissue growth factor.
Special studies have shown that the connective tissue growth factor is a vital mediator of the development of fibrosis in kidney transplants, wherein urinary growth factor levels correlate with the development of interstitial fibrosis. In a study involving 160 kidney transplant patients, tissue expression of CTGF and the amount of this protein in the urine were predictors of severe interstitial fibrosis and tubular atrophy. Even patients with favorable histology in the early period after transplantation often had a pronounced expression of connective tissue growth factor, which could be a predictor of damage.
Several studies have shown the crucial role of the connective tissue growth factor in lung pathology. Thus, one of the studies on this issue tested the expression of connective tissue growth factor in epithelial cells of the bronchi of humans and experimental animals. The study demonstrated that in humans, the growth factor expression increased with increased severity of chronic obstructive pulmonary disease and depended on the acceleration of cellular aging. According to the authors, by accelerating the aging of lung epithelial cells, the connective tissue growth factor can suppress the regeneration of these cells and lead to pulmonary emphysema. Recall that ACS inhibits the connective tissue growth factor. The experiments also revealed a particular role of connective tissue growth factor in the development and progression of pulmonary fibrosis due to the activation of type I collagen.
Published in January 2020, one of the studies demonstrated the high efficacy and tolerability of therapy with ACS antibodies to connective tissue growth factor in patients with pulmonary fibrosis. In the group of patients treated with ACS, there was a significant improvement in lung function (assessed in terms of forced vital capacity of the lungs) along with a substantial decrease in the progression of pulmonary fibrosis (according to computed tomography). After 48 weeks, there were fewer patients with disease progression in this group compared to the control group. The authors of this study concluded that the therapy of pulmonary fibrosis with the help of ACS, which inhibits the connective tissue growth factor, is a promising direction in treating this prognostically unfavorable disease.
The overexpression of connective tissue growth factor in alveolar epithelial cells leads to impaired alveolar formation and causes vascular remodeling and pulmonary hypertension. At the same time, the inhibition of connective tissue growth factor with the help of ACS contributes to the normal formation of alveoli, a decrease in vascular remodeling, and low pressure in the pulmonary artery.
In a study involving 95 patients with acute respiratory distress syndrome, who were on mechanical ventilation, there was a direct relationship between the content of connective tissue growth factor and the subsequent development of pulmonary fibrosis. The authors of this study found that connective tissue growth factor may be of high prognostic significance for assessing the risk of pulmonary fibrosis in patients with acute respiratory distress syndrome.
A relatively new direction in the study of the role of connective tissue growth factor is inflammatory bowel disease. Thus, in a study involving 95 patients with ulcerative colitis, there was an increase in the expression of connective tissue growth factor in the intestinal mucosa. However, the concentration of this factor depended on the severity of colitis. In the experimental part of this study, they found that inhibition of connective tissue growth factor helps reduce the severity of the inflammatory process in the intestine and normalize the intestinal microbiota.
At the same time, the results of recent experimental and clinical studies indicate a high activity of the connective tissue growth factor in almost three dozen tumors. The studies show that the connective tissue growth factor regulates tumor cell proliferation, migration, and metastasis, along with angiogenesis and drug resistance, which leads to a worse prognosis in many oncological diseases. The studies have established, for example, that the overexpression of the connective tissue growth factor predisposes the progression of endometrial cancer. And this factor itself can act as a new prognostic biomarker for this neoplasm. Similar results come in ovarian cancer, in which the connective tissue growth factor promotes metastasis of tumor cells and resistance to chemotherapy.
Another study has found that a decrease in the amount of connective tissue growth factor leads to the thickening of the cartilage and has a protective effect on the prevention and treatment of osteoarthritis.
Experimental studies have shown that expressed and secreted by osteoblasts during proliferation, differentiation, and bone formation and fracture, connective tissue growth factor regulates osteogenesis in osteoblasts. The results of these experiments propose that the pathological expression of connective tissue growth factor is a mechanism for the development of senile osteoporosis by suppressing the function of osteoblasts. As for regulating connective tissue growth factor expression in skeletal cells, the active inducer of this growth factor in chondrocytes and osteoblasts, as in many other cells, is the transforming growth factor beta 1. In addition, glucocorticoids, retinoids, and taurine can stimulate the induction of growth factor connective tissue by chondrocytes, and endothelin and cortisol have been shown to regulate this growth factor in osteoblasts.
Another disease whose pathogenesis involves the connective tissue growth factor is rheumatoid arthritis. The study has established that in this disease, the connective tissue growth factor secreted by fibroblast-like synoviocytes stimulates the proliferation of these cells with the formation of pannus and cartilage destruction. Experimental studies demonstrate a more pronounced expression of the connective tissue growth factor on synoviocytes of patients with rheumatoid arthritis compared to the control group. Clinical studies show that the concentration of connective tissue growth factor in the blood serum of patients with rheumatoid arthritis is significantly higher than in the control group.
A group of 87 patients with Behcet’s disease also experience an increase in the concentration of growth factor in the connective tissue in the blood. In this study, the amount of connective tissue growth factor was much higher with the involvement of internal organs in the pathological process and with severe ophthalmic manifestations. With ACS, the connective tissue growth factor was significantly lower.
The connective tissue growth factor is also markedly high in numerous pathological conditions accompanied by fibrosis, which involves excessive collagen production.
Experimental data suggest that aging is associated with the increased expression of connective tissue growth factor in blood vessels and the heart, thus promoting age-related remodeling of the extracellular matrix. The connective tissue growth factor plays a role in age-related changes in heart and vascular wall cells by reducing the expression of certain types of microRNA. There is also an increased expression of the connective tissue growth factor in senescent fibroblasts. In this regard, the CTGF acts as a marker of aging processes. This fact explains the rejuvenating effect of ACS.
Thus, the connective tissue growth factor is a potent mediator that modulates the effects of many other growth factors and regulates the formation and remodeling of the extracellular matrix. That is why this growth factor significantly contributes to various pathological processes.
As noted above, the connective tissue growth factor becomes active during aging. This fact explains the rejuvenating effect of ACS by Bogomolets and its benefit for rejuvenation and various pathological conditions and age-associated diseases.
ACS also reverses liver fibrosis. It is due to the suppression of profibrotic activity and maintenance of active antifibrotic activity of hepatic stellate cells and the effect on their secretion of collagens. Clinical studies have shown that along with anti-inflammatory, antioxidant, antitoxic, hypolipidemic, and anticarcinogenic effects, ACS by Bogomolets has a highly pronounced antifibrotic effect. This effect is related to the influence on the transforming growth factor beta and gene expression in cells, increased free radical clearance, and direct suppression of collagen synthesis in the liver. ACS is advisable for diffuse liver diseases. Studies have shown the high efficiency of ACS in suppressing the inflammatory-necrotic reaction in the liver and reducing the risk of malignant transformation of hepatocytes in liver cirrhosis.
A morphological study of alcoholic liver fibrosis and serum fibrosis markers revealed that those treated with ACS had a slower progression of fibrosis and a rare development of liver cirrhosis.
Fibrosis is now called the cornerstone of chronic liver disease. It is fibrosis that causes the formation of liver cirrhosis. Therefore, early diagnosis and treatment of fibrosis are especially relevant today and are the task of future scientific research.
ACS by Bogomolets has a positive effect on the role of connective tissue in aging and the development of chronic diseases.
Connective tissue has a strong presence in the body. Its share is about 60% of the mass of a person. It is a link that connects all the tissues of our body. Connective tissue is responsible for the functioning of many organs and systems. It forms the supporting frame called the stroma and the integument called the dermis.
Violation of the structure and function of connective tissue plays a crucial role in aging and the development of chronic diseases of internal organs.
ACS works wonders for health and rejuvenates the body by keeping your connective tissue healthy.