ABSTRACT
Myocardial infarction activates an intense fibro-inflammatory reaction that is essential for cardiac remodeling and heart failure (HF). Bioactive peptide galanin plays a critical role in regulating cardiovascular homeostasis; however, its specific functional relevance in post-infarction fibro-inflammatory reprogramming remains obscure. Here, we show that galanin coordinates the fibro-inflammatory trajectory and mitochondrial integrity in post-infarction reperfusion injury. Aberrant deposition of collagen was associated with a marked increase in CD68-positive macrophage infiltration in cardiac tissue in mice subjected to myocardial ischemia/reperfusion (I/R) for 14 days compared to sham controls. Furthermore, we found that the myocardial expression level of a specific marker of M2 macrophages, CD206, was significantly down-regulated in I/R-challenged mice. In contrast, galanin treatment started during the reperfusion phase blunted the fibro-inflammatory responses and promoted the expression of CD206 in I/R-remodeled hearts. In addition, we found that the anti-apoptotic and anti-hypertrophic effects of galanin were associated with the preservation of mitochondrial integrity and promotion of mitochondrial biogenesis. These findings depict galanin as a key arbitrator of fibro-inflammatory responses to cardiac I/R injury and offer a promising therapeutic trajectory for the treatment of post-infarct cardiovascular complications.
Subject(s)
Galanin , Macrophages , Myocardial Reperfusion Injury , Animals , Galanin/metabolism , Galanin/pharmacology , Mice , Myocardial Reperfusion Injury/metabolism , Myocardial Reperfusion Injury/pathology , Macrophages/metabolism , Male , Myocardial Infarction/metabolism , Myocardial Infarction/pathology , Mitochondria/metabolism , Mice, Inbred C57BL , Receptors, Cell Surface/metabolism , Inflammation/metabolism , Inflammation/pathology , Mannose Receptor , Lectins, C-Type/metabolism , Myocardium/metabolism , Myocardium/pathology , Mannose-Binding Lectins/metabolism , Disease Models, Animal , ApoptosisABSTRACT
Lead is known to be highly toxic to humans, causing various disorders infetal development. An experiment was conducted to examine the effects of lead acetate on the structural organization of female rat ovaries. The study involved 40 non-linear female rats divided into four groups: a control group, a low-dose group, a moderate-dose group, and a high-dose group. The rats were given lead acetate solutions in varying doses for 30 days, and their ovarian tissue was examined using light microscopy.The results showed that increasing doses of lead acetate led to morphological changes in the cortex and medulla of the rat ovaries. The changes were characterized by a decrease in ovarian mass, alterations in the thickness of the tunica albuginea (protein envelope), and a reduction in the number of follicles. Light microscopy revealed that exposure to lead acetate resulted in a significant decrease in the number of follicles in all experimental groups, with the high-dose group experiencing the most significant decrease.These findings suggest that lead acetate has a dose-dependent negative impact on the morphology and function of female rat ovaries. Further studies are needed to investigate the potential impact of lead on human ovarian tissue.
ABSTRACT
The regulatory peptide galanin is broadly distributed in the central nervous systems and peripheral tissues where it modulates numerous physiological and pathological processes through binding to its three G-protein-coupled receptors, GalR1-3. However, the function and identity of the galaninergic system in the heart remain unclear. Therefore, we investigated the expression of the galanin receptors in cardiac cells and tissues and found that GalR2 is the dominant receptor subtype in adult mouse hearts, cardiomyocytes and H9C2 cardiomyoblasts. In vivo, genetic suppression of GalR2 promotes cardiac hypertrophy, fibrosis and mitochondrial oxidative stress in the heart. In vitro, GalR2 silencing by siRNA abolished the beneficial effects of galanin on cell hypertrophy and mitochondrial reactive oxygen species (ROS) production. These findings unravel new insights into the role of galaninergic system in the heart and suggest novel therapeutic strategies in heart disease.
ABSTRACT
Due to the problem of treating some types of burns, it is necessary to develop new drugs. For this purpose, pharmacological studies of developed gel "Xeliogel" (based on biological material with regenerating action), which accelerates the healing of superficial burns, have been developed and previously carried out. AIM: The aim of this work was to establish the histological changes of the burn wound in the dynamics and after the experimental thermal injury and in the conditions of application of the gel "Xeliogel". MATERIALS AND METHODS: The experiments were performed on mature Wistar rats of both sexes weighing 250-260 g, randomly divided equally into four groups: 1 - group of intact animals; 2 - control pathology group; 3 - group for the treatment of which used the developed gel "Xeliogel" and 4 - group of animals with the comparison drug "Solcoseryl" (Legacy Pharmaceuticals Switzerland GmbH, Switzerland). Histological indicators of the effect of gels were recorded 3 times: on the 3rd (stage of burn shock), 7th (stage of early toxemia) and 14th (stage of late toxemia) days of the experiment. Examination of micropreparations was performed on a Nicon Eclipse CI-E microscope. Microscopy of microscopic images was performed using a Sigeta M3CMOS 14000 camcorder and Toup View software on a personal computer. RESULTS: During using the developed gel "Xeliogel" it is established that on the 3rd day of the experiment the wound surface is covered with a crust, which is formed by plasma proteins and with destroyed elements of blood. On day 7 after the experimental thermal injury, both "Xeliogel" gel and "Solcoseryl" gel were found to show that the skin defect area was also covered with a film, the main components of which were destroyed blood cells and fibrinous mass. When examining the area of the defect on the 14th day of the experiment with the use of the comparison drug "Solcoseryl" gel, wounds healing covered with an epithelial layer with a clear-layered structure was observed. CONCLUSIONS: The histological evaluation of the use of "Xeliogel" gel established that the developed gel provides healing of the wound defect on the 14th day of the experiment. There is a well-defined marginal regeneration of the epidermis, the formation of the basement membrane, the restoration of the papillary layer of the dermis and capillary system.
Subject(s)
Burns , Animals , Burns/drug therapy , Female , Gels , Male , Rats , Rats, Wistar , Regeneration , Wound HealingABSTRACT
Diabetes is a major risk factor for the development of cardiovascular disease with a higher incidence of myocardial infarction. This study explores the role of metformin, a first-line antihyperglycemic agent, in postinfarction fibrotic and inflammatory remodeling in mice. Three-month-old C57BI/6J mice were submitted to 30 min cardiac ischemia followed by reperfusion for 14 days. Intraperitoneal treatment with metformin (5 mg/kg) was initiated 15 min after the onset of reperfusion and maintained for 14 days. Real-time PCR was used to determine the levels of COL3A1, αSMA, CD68, TNF-α and IL-6. Increased collagen deposition and infiltration of macrophages in heart tissues are associated with upregulation of the inflammation-associated genes in mice after 14 days of reperfusion. Metformin treatment markedly reduced postinfarction fibrotic remodeling and CD68-positive cell population in mice. Moreover, metformin resulted in reduced expression of COL3A1, αSMA and CD68 after 14 days of reperfusion. Taken together, these results open new perspectives for the use of metformin as a drug that counteracts adverse myocardial fibroticand inflammatory remodeling after MI.
Subject(s)
Fibrosis/drug therapy , Hypoglycemic Agents/pharmacology , Inflammation/drug therapy , Metformin/pharmacology , Myocardial Infarction/complications , Myocardium/pathology , Animals , Fibrosis/etiology , Fibrosis/pathology , Inflammation/etiology , Inflammation/pathology , Male , Mice , Mice, Inbred C57BL , Ventricular RemodelingABSTRACT
Autophagy and apoptosis are powerful regulators of multiple facets of cellular metabolism and homeostasis. Here, we uncover that galanin, a pleiotropic peptide, regulates cardiac autophagy and deactivates apoptotic cell death through the Forkhead box protein O1 (FoxO1) pathway. In hypertrophied heart, galanin promotes autophagy and metabolic shift from fatty acid (FA) to glucose oxidation and preserves mitochondrial integrity. In cardiomyoblasts, galanin triggers autophagosome formation and alleviates hypertrophy, apoptotic cell death, and mitochondrial stress. Mechanistically, galanin dictates cell autophagic and anti-apoptotic phenotypes through FoxO1 pathway. Together, these findings uncover a previously unknown role for galanin in the regulation of cardiac autophagy and provide new insights into the molecular mechanisms supporting cell survival in the hypertrophic reprogramming of the heart.
Subject(s)
Galanin , Signal Transduction , Apoptosis , Autophagy , Cardiomegaly , Forkhead Box Protein O1/genetics , Forkhead Box Protein O1/metabolism , HumansABSTRACT
Among the high-tech methods of wound therapy, the leading place belongs to the technology of manufacture and use of cryolyophilized tissues and bioorganic drugs. Crushed xenoderm's powder stimulates the regenerative processes of the skin and improves the healing process of wounds, as it is enriched with macro- and microelements, amino acids and other cellular elements necessary for skin regeneration. AIM: The aim of this work was to study the wound-healing effectiveness of the developed gel "Xeliogel" on the animal model of aseptic superficial burns. MATERIALS AND METHODS: Evaluation of the degree of catabolism and membrane-destructive processes was performed by determining the marker enzymes of cytolysis - aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in serum, total protein and middle molecular mass in animals with experimental thermal burns. The developed gel "Xeliogel" was applied to the animals for therapeutic purposes. "Xeliogel" is based on aqueous extraction of xenoderm and with lidocaine hydrochloride. In the second group for comparison the Solcoseryl was applied in the form of a gel (Switzerland). This medicine belongs to the group containing active pharmaceutical ingredients of natural origin, namely protein-free dialysate from the blood of calves, and is intended for the treatment of burns of I-II degrees. RESULTS: When using the developed gel "Xeliogel" in experimental thermal burns, normalization of total protein was observed on 14-th days, which is on 7 days faster than under burn conditions, decrease the levels of ALT and AST in the serum with a return to a normal on a 7 day, relative to the control pathology group. In the groups of animals, on whose burn wounds "Xeliogel" gel was applied, already on the 14-th day endogenous intoxication was significantly reduced by 29 % compared with the control group of animals. During the experiment to reduce the area of the wound surface, it was determined that the developed gel "Xeliogel" showed a pharmacological effect similar to the comparison drug "Solkoseryl" gel. CONCLUSIONS: On the model of aseptic burn injury in rats, was determined that the developed gel provides a significant reduction in necrotic processes, the level of endogenous intoxication against the background of restoring the level of total protein in the circulating blood. The results of the research confirm the effectiveness of using the developed gel "Xeliogel" for local treatment of burns of I-II degrees, as the duration of treatment of burns reduced by 4 days compared to the control group and the developed gel is similar to the comparison drug.
Subject(s)
Burns , Animals , Burns/drug therapy , Cattle , Humans , Rats , Skin , Wound HealingABSTRACT
The number of cancer patients is growing in all countries. Due to the malignant progression of cancer, inflammatory processes are observed, which are inextricably linked with the response of the immune system. AIM: The aim of this research was to study the effectiveness of the cytostatic Vincristine on the background of sorption correction of disorders by the carbon sorbent AUT-M (activated carbon tissue material) in adenocarcinoma of the colon. MATERIALS AND METHODS: To simulate carcinogenesis, 1,2-dimethylhydrazine (DMH) was administered subcutaneously to 76 rats for 30 weeks at a dose of 7.2 mg / kg body weight. The evolution of adenocarcinoma of the colon in experimental animals was confirmed by histological examination. After simulation of colon cancer, the animals were intragastrically administered entorosorbent at a dose of 1 ml of suspension (corresponding to 0.2 g of net weight of the drug) per 100 g of body weight of the animal, during 21 days. After detoxification therapy, rats with simulated carcinogenesis were administered the daily cytostatic Vincristine at a dose of 0.23 mg/kg for 14 days. In the above groups of experimental rats, the state of the humoral part of the immune system was studied by the content of serum IgA, IgM, IgG and circulating immune complexes. According to the content of pro- and anti-inflammatory cytokines, inflammatory processes in experimental animals with induced carcinogenesis of the colon on the background of enterosorption and cytostatic corrections were studied. The changes are confirmed by parametric and nonparametric methods of evaluation of the obtained data. RESULTS: It was found that long-term administration of the carcinogen is accompanied by changes in the humoral part of the immune system, as evidenced by the increase in serum IgA, IgM, IgG and CEC level. The results of the research showed that the introduction of 1,2- dimethylhydrazine to animals is accompanied by a change in the cytokine profile, increases the level of pro-inflammatory IL-6 and decreases the level of anti-inflammatory IL-4. CONCLUSIONS: Simultaneous use of enterosorption and cytostatic therapy helped to restore the cytokine balance and indicators of the humoral part of immunological protection.
Subject(s)
Colonic Neoplasms , Immunity, Humoral , 1,2-Dimethylhydrazine/toxicity , Animals , Carcinogenesis , Colon , Colonic Neoplasms/chemically induced , Colonic Neoplasms/drug therapy , Cytokines , Humans , RatsABSTRACT
Cardiovascular complications are the most prevalent cause of morbidity and mortality in diabetic patients. Metformin is currently the first-line blood glucose-lowering agent with potential relevance to cardiovascular diseases. However, the underpinning mechanisms of action remain elusive. Here, we report that metformin represses cardiac apoptosis at least in part through inhibition of Forkhead box O1 (FoxO1) pathway. In a mouse model of ischemia-reperfusion (I/R), treatment with metformin attenuated cardiac and hypertrophic remodeling after 14 days of post-reperfusion. Additionally, cardiac expression of brain-like natriuretic peptide (BNP) was significantly reduced in metformin-treated mice after 14 days of cardiac I/R. In cultured H9C2 cells, metformin counteracted hypertrophic and apoptotic responses to metabolic or hypoxic stress. FoxO1 silencing by siRNA abolished anti-apoptotic effect of metformin under hypoxic stress in H9C2 cells. Taken together, these results suggest that metformin protects the heart against hypertrophic and apoptotic remodeling after myocardial infarction.