Eosinophils are multifunctional granulocytes that contribute to the initiation and modulation of inflammation.Accumulating evidence suggests that eosinophils are adaptable leukocytes that orchestrate the resolution of...Eosinophils are multifunctional granulocytes that contribute to the initiation and modulation of inflammation.Accumulating evidence suggests that eosinophils are adaptable leukocytes that orchestrate the resolution of inflammatory responses.The most prevalent chronic inflammatory illness,rheumatoid arthritis(RA),is typified by persistent synovitis thatmakes it hard for the disease to go away on its own.Interestingly,a unique subset of eosinophils known as regulatory eosinophils has been found in RA patients’synovium,especially while the disease is in remission.Pro-resolving signatures of regulatory eosinophils in the synovium are distinct from those of their lung counterparts.The most recent research on eosinophils and their function in this disease pathogenesis is compiled in this review.Based on the role of regulatory eosinophils,a new pathological model of inflammation resolution in RA is proposed,and potential therapeutic strategies aimed at enhancing the action of regulatory eosinophils in RA are proposed.展开更多
Neutrophil extracellular traps(NET)have emerged as critical players in the pathogenesis of atherosclerosis and other cardiovascular diseases(CVD).These web-like structures,composed of DNA,histones,and granule proteins...Neutrophil extracellular traps(NET)have emerged as critical players in the pathogenesis of atherosclerosis and other cardiovascular diseases(CVD).These web-like structures,composed of DNA,histones,and granule proteins released by neutrophils,contribute significantly to both inflammation and thrombosis.This manuscript offers a comprehensive review of the recent literature on the involvement of NET in atherosclerosis,highlighting their interactions with various pathophysiological processes and their potential as biomarkers for CVD.Notably,the impact of radiation on NET formation is explored,emphasising how oxidative stress and inflammatory responses drive NET release,contributing to plaque instability.The role of histones,particularly citrullinated histones,in endothelial dysfunction and plaque progression is discussed,highlighting their significance in the pathophysiology of atherosclerosis.Furthermore,the complex relationship between lipoproteins and NET formation is examined,with a focus on how elevated low-density lipoprotein(LDL)and decreased high-density lipoprotein(HDL)levels facilitate NET release,thus promoting vascular inflammation and plaque instability.The influence of cholesterol on NET formation is also explored,underscoring its contribution to plaque development and stability.The role of Peptidylarginine deiminase 4(PAD4)in the regulation of NETosis is reviewed,with attention given to how PAD4-driven citrullination of histones affects atherosclerosis progression.Moreover,the manuscript examines the potential of NET components—such as double-stranded DNA,myeloperoxidase–DNA complexes,and citrullinated histone H3—as biomarkers for assessing disease severity and predicting adverse cardiovascular events,including ST-elevation myocardial infarction(STEMI)and stroke.Elevated levels of these biomarkers correlate with worse clinical outcomes,suggesting their utility in guiding therapeutic interventions.In contrast to the existing body of work,this review highlights the novelty of integrating recent findings on NET interactions with lipid metabolism,histone modifications,and PAD4 activity in the context of atherosclerosis.Overall,NET plays an integral role in the inflammatory and thrombotic processes underpinning atherosclerosis,and their components hold promise as both diagnostic markers and therapeutic targets in cardiovascular disease management.展开更多
Garlic(Allium sativum) is a widely known medicinal plant, potential of which remains to be fully evaluated. Its wide-range beneficial effects appear to be relevant for treatment and prevention of atherosclerosis and r...Garlic(Allium sativum) is a widely known medicinal plant, potential of which remains to be fully evaluated. Its wide-range beneficial effects appear to be relevant for treatment and prevention of atherosclerosis and related diseases. It is generally believed that garlic-based preparations are able to improve lipid profile in humans, inhibit cholesterol biosynthesis, suppress low density lipoprotein oxidation, modulate blood pressure, suppress platelet aggregation, lower plasma fibrinogen level and increase fibrinolytic activity, thus providing clinically relevant cardioprotective and anti-atherosclerotic effects. It is important to assess the level of evidence available for different protective effects of garlic and to understand the underlying mechanisms. This information will allow adequate integration of garlic-based preparations to clinical practice. In this review, we discuss the mechanisms of anti-atherosclerotic effects of garlic preparations, focusing on antihyperlipidemic, hypotensive, anti-platelet and direct anti-atherosclerotic activities of the medicinal plant. We also provide an overview of available meta-analyses and a number of clinical trials that assess the beneficial effects of garlic.展开更多
AIM: To examine whether the heteroplasmy level for 15059G】A mutation in the mitochondrial genome might be associated with essential hypertension. METHODS: This cross-sectional study involved 196 unrelated participant...AIM: To examine whether the heteroplasmy level for 15059G】A mutation in the mitochondrial genome might be associated with essential hypertension. METHODS: This cross-sectional study involved 196 unrelated participants randomly selected from general population (90 males and 106 females) who underwent a regular medical check-up at the Institute for Ath-erosclerosis Research (Moscow, Russia). One hundred and twenty of them (61%) had essential hypertension, and 76 (39%) were apparently healthy normotensive persons. The level of heteroplasmy for 15059G】A mutation occurring in the coding region of cytochrome b gene (MT-CYB) of mtDNA isolated from the blood leukocytes, was quantified using DNA pyrosequencing method. RESULTS: The 15059G】A heteroplasmy level ranged between 4% and 83%, with a median level of 31%. Between the upper and lower quartiles of 15059G】A heteroplasmy distribution, significant differences were observed for patients’ age, systolic blood pressure, and triglyceride levels. 15059G】A heteroplasmy correlated both with age (r = 0.331, P 【 0.001) and the presence of hypertension (r = 0.228, P = 0.002). Regression analysis revealed that the age explains 12% variability of 15059G】A heteroplasmy, and hypertension independently explains more 5% variability. The 15059G】A heteroplasmy exceeding 31% was found to be significantly associated with a higher risk of essential hypertension (odds ratio 2.76; P (Fisher) 0.019]. The study participants with high 15059G】A heteroplasmy level were found to have significantly higher age (P 【 0.001) and the prevalence of essential hypertension (P = 0.033), as compared to those with low 15059G】A heteroplasmy level. These observations suggested a positive correlation between the level of 15059G】A heteroplasmy and essential hypertension. CONCLUSION: This study provides the evidence of association of mtDNA 15059G】A mutation heteroplasmy with essential hypertension.展开更多
Inflammation plays an essential role in the development of atherosclerosis. The initiation and growth of atherosclerotic plaques is accompanied by recruitment of inflammatory and precursor cells from the bloodstream a...Inflammation plays an essential role in the development of atherosclerosis. The initiation and growth of atherosclerotic plaques is accompanied by recruitment of inflammatory and precursor cells from the bloodstream and their differentiation towards pro-inflammatory phenotypes. This process is orchestrated by the production of a number of pro-inflammatory cytokines and chemokines. Human arterial intima consists of structurally distinct leaflets, with a proteoglycan-rich layer lying immediately below the endothelial lining. Recent studies reveal the important role of stellate pericyte-like cells(intimal pericytes) populating the proteoglycan-rich layer in the development of atherosclerosis. During the pathologic process, intimal pericytes may participate in the recruitment of inflammatory cells by producing signalling molecules and play a role in the antigen presentation. Intimal pericytes are also involved in lipid accumulation and the formation of foam cells. This review focuses on the role of pericytelike cells in the development of atherosclerotic lesions.展开更多
AIM:To assess clinical and endoscopic response to propionyl-L-carnitine hydrochloride(PLC) in colonic inflammatory bowel disease.METHODS:Patients suffering from mild to moderate ulcerative colitis(UC) or Crohn's d...AIM:To assess clinical and endoscopic response to propionyl-L-carnitine hydrochloride(PLC) in colonic inflammatory bowel disease.METHODS:Patients suffering from mild to moderate ulcerative colitis(UC) or Crohn's disease(CD) colitis,with disease activity index(DAI) between 3 and 10 and under stable therapy with oral aminosalicylates,mercaptopurine or azathioprine,for at least 8 wk prior to baseline assessments,were considered suitable for enrollment.Fourteen patients were enrolled to assume PLC 2 g/d(two active tablets twice daily) orally.Clinical-endoscopic and histological activity were assessed by DAI and histological index(HI),respectively,following a colonoscopy performed immediately before and after 4 wk treatment.Clinical response was defined as a lowering of at least 3 points in DAI and clinical remission as a DAI score ≤ 2.Histological response was defined as an improvement of HI of at least 1 point.We used median values for the analysis.Differences pre-and post-treatment were analyzed by Wilcoxon signed rank test.RESULTS:All patients enrolled completed the study.One patient,despite medical advice,took deflazacort 5 d before follow-up colonoscopy examination.No side effects were reported by patients during the trial.After treatment,71%(SE 12%) of patients achieved clinical response,while 64%(SE 13%) obtained remission.Separating UC from CD patients,we observed a clinical response in 60%(SE 16%) and 100%,respectively.Furthermore 60%(SE 16%) of UC patients and 75%(SE 25%) of CD patients were in clinical remission after therapy.The median DAI was 7 [interquartile range(IQR):4-8] before treatment and decreased to 2(IQR:1-3)(P < 0.01) after treatment.Only patients with UC showed a significant reduction of DAI,from a median 6.5(IQR:4-9) before treatment to 2(IQR:1-3) after treatment(P < 0.01).Conversely,in CD patients,although displaying a clear reduction of DAI from 7(IQR:5.5-7.5) before therapy to 1.5(IQR:0.5-2.5) after therapy,differences observed were not significant(P = 0.06).Seventy-nine percent(SE 11%) of patients showed improvement of HI of at least 1 point,while only one CD and two UC patients showed HI stability;none showed HI worsening.Median HI decreased from 1(IQR:1-2),to 0.5(IQR:0-1) at the endoscopic control in the whole population(P < 0.01),while it changed from 1(IQR:1-2) to 0.5(IQR:0-1) in UC patients(P < 0.01) and from 1.5(IQR:1-2) to 0.5(IQR:0-1) in CD patients(P = not significant).The two sample tests of proportions showed no significant differences in clinical and histological response or in clinical remission between UC and CD patients.No side effects were reported during treatment or at 4 wk follow-up visit.CONCLUSION:PLC improves endoscopic and histological activity of mild to moderate UC.Further studies are required to evaluate PLC efficacy in colonic CD patients.展开更多
Hypoxic preconditioning is able to increase the body’s resistance to hypoxic/ischemic stress. Understanding how to apply the hypoxic response to initiate the protective mechanism of ischemic preconditioning is a high...Hypoxic preconditioning is able to increase the body’s resistance to hypoxic/ischemic stress. Understanding how to apply the hypoxic response to initiate the protective mechanism of ischemic preconditioning is a high priority. However, the relationship between innate resistance to hypoxic stress and preconditioning efficiency of moderate hypoxia has been poorly studied. In our work, the efficiency of single moderate hypobaric hypoxia (HBH) for resistance to severe hypobaric hypoxia (SHBH) was studied on intact rats and those pre-tested under SHBH with low, intermediate and high resistance to hypoxia. HBH has a significant preconditioning action on the resistance to hypoxia over a wide range from 270 to 1464 s (4.5 to 24.5 min) and at the same time eliminates the differences in the endurance under SHBH between all rat groups. It is concluded that 1) HBH preconditioning efficiency does not depend on an innate resistance to SHBH and prior hypoxic experience of rats;and 2) the pretesting to severe hypoxia has no value for predicting the hypoxic preconditioning efficiency and study of adaptive mechanisms.展开更多
The work is a study of the influence of Ca2+ (0.01 - 1 mM) on neuronal CI-, HCO3-, -ATPase complex: an enzyme that is a CI--pump which is functionally and structurally coupled to GABAA-receptors. It is found that infl...The work is a study of the influence of Ca2+ (0.01 - 1 mM) on neuronal CI-, HCO3-, -ATPase complex: an enzyme that is a CI--pump which is functionally and structurally coupled to GABAA-receptors. It is found that influence of Ca2+ on the multifunctional complex starts at concentration of 50·M and at concentration of 0.1 mM, it reduces the “basal” one and increases the CI-, HCO3-, -stimulated Mg2+-ATPase activities. GABA (0.1 - 100μM) activates the “basal” Mg2+-ATPase activity in the ab-sence of calcium. The effect of GABA on the enzyme in the presence of 0.01 ·M Ca2+ does not change. At the same time, 1 mM Ca2+eliminates the GABA effect on the “basal” Mg2+-ATPase activity. Competitive blocker of GABAA-receptors bicuculline (5 - 20 μM) in the absence of Ca2+ ions elimi-nates the stimulation of the “basal” Mg2+-ATPase by anions. When 0.25 mM Ca2+ is added to the in-cubation medium the inhibitory bicuculline effect on the enzyme does not appear. We found that 0.1 mM o-vanadate (protein tyrosine phosphatase blocker) reduces the GABA-activated ATPase activity. At the same time, 0.1 mM genistein (a protein tyrosine kinase blocker) has no effect on enzyme activity. In the presence of Ca2+ (0.25 mM), the effect of o-vanadate on the “basal” and CI-, HCO3-, -ATPase activities does not appear. It is shown for the first time that high concentrations of Ca2+prevent the action of GABAA-ergic ligands on the study ATPase. It is assumed that there is the involvement of protein kinases and protein phosphatases in the modulation of the enzyme activity by calcium. The observed effect of calcium on the ATPase may play an important role in the study of the mechanisms of epileptogenesis and seizure activity.展开更多
Moderate one-off hypobaric hypoxia (HBH) provokes preconditioning and prolongs the resistance (T, the time before apnoea) to severe hypobaric hypoxia (SHBH). Hypoxic preconditioning has therapeutic potential;however, ...Moderate one-off hypobaric hypoxia (HBH) provokes preconditioning and prolongs the resistance (T, the time before apnoea) to severe hypobaric hypoxia (SHBH). Hypoxic preconditioning has therapeutic potential;however, the efficiency of hypoxic preconditioning varies greatly and the methods for its preliminary evaluation are absent in both animals and humans. This rodent study evaluates the dependence of SHBH resistance, initiated by HBH, on the rate of sensorimotor gating estimated in the model of the acoustic startle prepulse inhibition (PPI). A stable negative correlation was found between PPI and T. Low doses of the α7 nicotinic receptor agonist, PNU-282987 (PNU), and more pronouncedly dimethyl sulfoxide (DMSO) (a PNU solvent), inverted the correlation between PPI and T from negative to positive. The DMSO and PNU effects were reversed at PPIs of 0.36 - 0.40 (36% - 40%). DMSO increased T values by 52.2% ± 9.7% in the region of lower HBH efficiency (PPI ≥ 0.40) and reduced it by 35.2% ± 9.3% in the region of higher HBH efficiency (PPI < 0.40). PNU reduced both DMSO effects. The involvement of the central cholinergic mechanisms was substantiated in both DMSO and PNU influences on HBH. In conclusion, 1) PPI can be used to predict the efficiency of hypoxic preconditioning and to study its mechanisms, 2) two opposite cholinergic PPI-related mechanisms participate in the preconditioning effects of HBH, 3) the sensitivity of rats to DMSO and PNU diverges when the PPI is 0.36 - 0.40, and 4) DMSO can enhance resistance to severe hypoxia in the region of the lower preconditioning efficiency of HBH at PPI ≥ 0.4.展开更多
Conditions in rat and turtle small intestine tissue where glucose and glycine transport is inhibited while glucose-induced Na+ transport is preserved are described. The generally accepted model for the Na+-dependent t...Conditions in rat and turtle small intestine tissue where glucose and glycine transport is inhibited while glucose-induced Na+ transport is preserved are described. The generally accepted model for the Na+-dependent transporter (а single channel for the Na+ and nutrient) does not account for the data obtained from the analysis of the interaction between the transport of glucose, glycine, and Na+ at different temperatures and the effect of inhibitors оn these рroсеssеs. The phenomenon of temperature uncoupling of Na+ and nutrient transport саn best bе described bу а two-pathway model with а gate mechanism. According to this model, the Na+-dependent transporter has at least two pathways: оnе for Na+ and another for nutrients. The model рrovidеs for the passage of Na+ in both directions along а channel opened bу glucose. Experiments are carried out using the addition of glucose and glycine on backgrounds of glycine and glucose, respectively. It has been hypothesized that when all three transporters (for Na+, glucose and glycine) are unite in a single structure, then there should be “competitive relations” between short-circuit current changes on glycine and glucose for sodium ions passing through its transporter.展开更多
Recently, in our experiments, we used the short-circuit current technique to study the kinetic constants for nutrient transporters in rat gastric-intestinal tract and the thickness of the intestinal unstirred layer ne...Recently, in our experiments, we used the short-circuit current technique to study the kinetic constants for nutrient transporters in rat gastric-intestinal tract and the thickness of the intestinal unstirred layer near the mucosa surface. It was shown that, during the process of aging, the number of nutrient monomer transporters in the small intestine increases twofold, whereas the affinity of transporters to the correspondent nutrients remains unchanged. The situation for peptides may be opposite. The layer thickness in the vicinity of the mucosa surface, measured through glucose, decreased during the process of aging. It was suggested that, in old rats, the role of the digestive volume is more important, which results in an increase of the number of nutrient monomer transporters.展开更多
Connexins family in humans consists of 21 highly conserved proteins that are responsible for contact formation between cells. On the cell surface, connexins form hemichannels, or connexons. Two hemichannels brought to...Connexins family in humans consists of 21 highly conserved proteins that are responsible for contact formation between cells. On the cell surface, connexins form hemichannels, or connexons. Two hemichannels brought together form a gap junction, a form of intercellular contact that allows for direct transfer of material and signals between the adjacent cells. Gap junctions serve for transporting ions and other soluble, low molecular weight molecules therefore synchronizing the microenvironment of the contacting cells and maintaining cell and tissue homeostasis. Impairment of gap junctions is associated with different pathological conditions. Importantly, it has been described in atherosclerosis, which causes local cellular dysfunction in the arterial wall tissues followed by the development of atherosclerotic plaque. There are 3 main connexins expressed in human cardiovascular system: Cx37, Cx40, and Cx43. Alterations in the arterial wall cells observed in atherosclerosis include changes in the expression pattern of the main connexins and impairment of intercellular contacts and communication. According to the currently available data, Cx37 and Cx40 have anti-atherogenic and vasculoprotective properties, while Cx43 appears to be more pro-atherogenic. However, the effects of connexins are cell type-dependent and in many cases, remain to be studied in detail. In this review, we summarize the available knowledge on connexins of the arterial wall cells involved in atherosclerosis development.展开更多
Mitochondrial DNA(mtDNA) is particularly prone to oxidation due to the lack of histones and a deficient mismatch repair system.This explains an increased mutation rate of mtDNA that results in heteroplasmy,e.g.,the co...Mitochondrial DNA(mtDNA) is particularly prone to oxidation due to the lack of histones and a deficient mismatch repair system.This explains an increased mutation rate of mtDNA that results in heteroplasmy,e.g.,the coexistence of the mutant and wild-type mtDNA molecules within the same mitochondrion.In diabetes mellitus,glycotoxicity,advanced oxidative stress,collagen cross-linking,and accumulation of lipid peroxides in foam macrophage cells and arterial wall cells may significantly decrease the mutation threshold required for mitochondrial dysfunction,which in turn further contributes to the oxidative damage of the diabetic vascular wall,endothelial dysfunc-tion,and atherosclerosis.展开更多
Objective:To elucidate the effects of chlorogenic acid(CGA),a bioactive polyphenol compound prevalent in traditional Chinese medicine and various foods,including Lonicera japonica Thunb.(Jin Yin Hua),Eucommia ulmoides...Objective:To elucidate the effects of chlorogenic acid(CGA),a bioactive polyphenol compound prevalent in traditional Chinese medicine and various foods,including Lonicera japonica Thunb.(Jin Yin Hua),Eucommia ulmoides Oliv.(Du Zhong Ye),tea,and coffee,on cardiomyocyte ferroptosis and heart failure.Methods: We assessed the effect of CGA on cardiac function using a mouse model of heart failure induced by transverse aortic constriction(TAC).These indicators included the left ventricular ejection fraction(LVEF),fractional shortening(LVFS),end-systolic volume(LVESV),end-diastolic volume(LVEDV),end-systolic diameter(LVESD),and end-diastolic diameter(LVEDD).An isoprenaline hydrochloride(ISO)-induced H9c2 cardiomyocyte cell model was also established,and the cells were treated with various concentrations of CGA.To assess the effect of CGA on ferroptosis in cardiomyocytes,we measured cell viability and evaluated the levels of intracellular reactive oxygen species(ROS),ferrous ions(Fe^(2+)),and lipid peroxidation using fluorescent staining.To clarify the ferroptosis signaling pathway regulated by CGA,western blotting was used to examine the expression of ferroptosis biomarkers,specifically solute carrier family 7 member 11(SLC7A11)and glutathione peroxidase 4(GPX4),in H9c2 cardiomyocytes and mouse myocardial tissues.Results: CGA significantly enhanced cardiac performance indices such as LVEF,LVFS,LVESV,LVEDV,LVESD,and LVEDD.H9c2 cardiomyocytes exposed to ISO showed decreased cell viability and increased ROS levels,Fe^(2+)content,and lipid peroxidation levels.However,CGA treatment significantly ameliorated these changes.Additionally,in both H9c2 cardiomyocytes and myocardial tissue obtained from mice with TAC,CGA increased the expression of ferroptosis-related proteins,including SLC7A11 and GPX4.Conclusion: CGA has the potential to enhance cardiac function and diminish lipid peroxidation and ROS levels in cardiomyocytes via the SLC7A11/GPX4 signaling pathway.This process alleviates ferroptosis in cardiomyocytes.These results provide new insights into the clinical use of CGA and the management of heart failure.展开更多
Emotional and motivational disorders in adults are often considered to be the result of altered neurodevelopment. Clinical and experimental data provide evidence that serine protease dipeptidyl peptidase-IV (DPP-IV, E...Emotional and motivational disorders in adults are often considered to be the result of altered neurodevelopment. Clinical and experimental data provide evidence that serine protease dipeptidyl peptidase-IV (DPP-IV, EC 3.4.14.5) is involved in the pathophysiology of psycho-emotional disorders. Recently, we have shown that adolescent and adult rats exhibit an increase in anxiety and depression-related behaviors after neonatal administration of a synthetic non-competitive inhibitor of DPP-IV, methionyl-2(S)-cyano-pyrrolidine. In the present study, we tested the effects of two competitive, selective DPP-IV inhibitors, sitagliptin (4 mg/kg) and diprotin A (2 mg/kg), administered at postnatal days 5 - 18 on the emotional and motivational behavior of adolescent and adult rats. We observed increased anxiety in one-month-old diprotin A- or sitagliptin-treated rats in the elevated plus maze;diprotin A also enhanced the animals’ anxiety score using a ranked scale for evaluating anxiety and phobias. In the sucrose consumption and preference test, depressive-like behavior was pronounced in both the diprotin A- and sitagliptin-treated one-month-old animals, while only the diprotin A-treated rats exhibited a decrease in sucrose consumption at the age of 2 months. The diprotin A-treated rats also demonstrated behavioral despair and decreased activity in the forced swimming test within 1 - 3 months of age. Increased aggression was observed in 1 - 3-month-old diprotin A-treated rats and in two-month-old sitagliptin-treated rats. These findings support the hypothesis that DPP-IV is involved in the genesis of emotional and motivational disorders. Additionally, the results show that diprotin А impairs the adolescent and adult rats’ behavior more significantly than sitagliptin when the animals were treated with the DPP-IV inhibitors in the early postnatal period.展开更多
AIM To explore the influence of Infliximab(IFX) on cancer progression in a murine model of colonic cancer associated to chronic colitis.METHODS AOM/DSS model was induced in C57BL/6 mice. Mice were injected with IFX(5 ...AIM To explore the influence of Infliximab(IFX) on cancer progression in a murine model of colonic cancer associated to chronic colitis.METHODS AOM/DSS model was induced in C57BL/6 mice. Mice were injected with IFX(5 mg/kg) during each DSS cycle while control mice received saline. Body weight, occult blood test and stool consistency were measured to calculate the disease activity index(DAI). Mice were sacrificed at week 10 and colons were analyzed macroscopically and microscopically for number of cancers and degree of inflammation. MTT assay was performed on CT26 to evaluate the potential IFX role on metabolic activity and proliferation. Cells were incubated with TNF-α or IFX or TNF-α plus IFX, and cell vitality was evaluated after 6, 24 and 48 h. The same setting was used after pre-incubation with TNF-α for 24 h.RESULTS IFX significantly reduced DAI and body weight loss in mice compared with controls, preserving also colon length at sacrifice. Histological score was also reduced in treated mice. At macroscopic analysis, IFX treated mice showed a lower number of tumor lesions compared to controls. This was confirmed at microscopic analysis, although differences were not statistically significant. In vitro, IFX treated CT26 maintained similar proliferation ability at MTT test, both when exposed to IFX alone and when associated to TNF-α.CONCLUSION IFX did not increase colonic cancer risk in AOM-DSS model of cancer on chronic colitis nor influence directly the proliferation of murine colon cancer epithelial cells.展开更多
Atherosclerosis is extremely widespread.Traditionally,it is considered a disease of older people,who most often experience problems with the heart and blood vessels.While much attention from the scientific community h...Atherosclerosis is extremely widespread.Traditionally,it is considered a disease of older people,who most often experience problems with the heart and blood vessels.While much attention from the scientific community has been paid to studying the association between aging and atherosclerosis,as well as its consequences,there is evidence that atherosclerosis occurs at an early age.Atherosclerosis may form both during intrauterine development and in childhood.Nutrition plays an important role in childhood atherosclerosis,along with previous infectious diseases and excess weight of both the child and the mother.In the present review,we examined the development of atherosclerosis and the prerequisites in childhood.展开更多
This paper focuses on a bioenergetic mechanism responding to hypoxia. This response involves hypoxia-induced reprogramming of respiratory chain function and switching from oxidation of complex I (NAD-related substrate...This paper focuses on a bioenergetic mechanism responding to hypoxia. This response involves hypoxia-induced reprogramming of respiratory chain function and switching from oxidation of complex I (NAD-related substrates) to complex II (succinate oxidation). Transient, reversible, compensatory activation of respiratory chain complex II is a major mechanism of urgent adaptation to hypoxia, which is necessary for 1) succinate-related energy synthesis in the conditions of oxygen shortage and formation of urgent resistance;2) succinate-related stabilization of HIF-1α and initiation of its transcriptional activity related with formation of long-term adaptation;3) succinate-dependent activation of the succinate-specific receptor GPR91. Thus, mitochondria perform a signaling function with succinate as a signaling molecule. Effects of succinate in hypoxia occur at three levels, intramitochondrial, intracellular and intercellular. In these settings, succinate displays antihypoxic activity. The review is focused on tactics and strategy for development of the antihypoxic defense and antihypoxants with energotropic properties.展开更多
This paper focuses on a bioenergetic mechanism responding to hypoxia. This response involves hypoxia-induced reprogramming of respiratory chain function and switching from oxidation of complex I (NAD-related substrate...This paper focuses on a bioenergetic mechanism responding to hypoxia. This response involves hypoxia-induced reprogramming of respiratory chain function and switching from oxidation of complex I (NAD-related substrates) to complex II (succinate oxidation). Transient, reversible, compensatory activation of respiratory chain complex II is a major mechanism of urgent adaptation to hypoxia, which is necessary for 1) succinate-related energy synthesis in the conditions of oxygen shortage and formation of urgent resistance;2) succinate-related stabilization of HIF-1α and initiation of its transcriptional activity related with formation of long-term adaptation;3) succinate-dependent activation of the succinate-specific receptor GPR91. Thus, mitochondria perform a signaling function with succinate as a signaling molecule. Effects of succinate in hypoxia occur at three levels, intramitochondrial, intracellular and intercellular. In these settings, succinate displays antihypoxic activitie. The review is focused on tactics and strategy for development of the antihypoxic defense and antihypoxants with energotropic properties.展开更多
基金supported by NIH grants to M Bukrinsky P30 AI117970by the“Creation of Experimental Laboratories in the Natural Sciences Program”and Basic Research Program at the Higher School of Economics University.
文摘Eosinophils are multifunctional granulocytes that contribute to the initiation and modulation of inflammation.Accumulating evidence suggests that eosinophils are adaptable leukocytes that orchestrate the resolution of inflammatory responses.The most prevalent chronic inflammatory illness,rheumatoid arthritis(RA),is typified by persistent synovitis thatmakes it hard for the disease to go away on its own.Interestingly,a unique subset of eosinophils known as regulatory eosinophils has been found in RA patients’synovium,especially while the disease is in remission.Pro-resolving signatures of regulatory eosinophils in the synovium are distinct from those of their lung counterparts.The most recent research on eosinophils and their function in this disease pathogenesis is compiled in this review.Based on the role of regulatory eosinophils,a new pathological model of inflammation resolution in RA is proposed,and potential therapeutic strategies aimed at enhancing the action of regulatory eosinophils in RA are proposed.
基金supported by NIH grants to MI Bukrinsky(R01NS124477 and P30AI117970)by the“Creation of Experimental Laboratories in the Natural Sciences Program”and Basic Research Programat Higher School of Economics University.
文摘Neutrophil extracellular traps(NET)have emerged as critical players in the pathogenesis of atherosclerosis and other cardiovascular diseases(CVD).These web-like structures,composed of DNA,histones,and granule proteins released by neutrophils,contribute significantly to both inflammation and thrombosis.This manuscript offers a comprehensive review of the recent literature on the involvement of NET in atherosclerosis,highlighting their interactions with various pathophysiological processes and their potential as biomarkers for CVD.Notably,the impact of radiation on NET formation is explored,emphasising how oxidative stress and inflammatory responses drive NET release,contributing to plaque instability.The role of histones,particularly citrullinated histones,in endothelial dysfunction and plaque progression is discussed,highlighting their significance in the pathophysiology of atherosclerosis.Furthermore,the complex relationship between lipoproteins and NET formation is examined,with a focus on how elevated low-density lipoprotein(LDL)and decreased high-density lipoprotein(HDL)levels facilitate NET release,thus promoting vascular inflammation and plaque instability.The influence of cholesterol on NET formation is also explored,underscoring its contribution to plaque development and stability.The role of Peptidylarginine deiminase 4(PAD4)in the regulation of NETosis is reviewed,with attention given to how PAD4-driven citrullination of histones affects atherosclerosis progression.Moreover,the manuscript examines the potential of NET components—such as double-stranded DNA,myeloperoxidase–DNA complexes,and citrullinated histone H3—as biomarkers for assessing disease severity and predicting adverse cardiovascular events,including ST-elevation myocardial infarction(STEMI)and stroke.Elevated levels of these biomarkers correlate with worse clinical outcomes,suggesting their utility in guiding therapeutic interventions.In contrast to the existing body of work,this review highlights the novelty of integrating recent findings on NET interactions with lipid metabolism,histone modifications,and PAD4 activity in the context of atherosclerosis.Overall,NET plays an integral role in the inflammatory and thrombotic processes underpinning atherosclerosis,and their components hold promise as both diagnostic markers and therapeutic targets in cardiovascular disease management.
基金supported by the Russian Science Foundation(No.19-15-00010)
文摘Garlic(Allium sativum) is a widely known medicinal plant, potential of which remains to be fully evaluated. Its wide-range beneficial effects appear to be relevant for treatment and prevention of atherosclerosis and related diseases. It is generally believed that garlic-based preparations are able to improve lipid profile in humans, inhibit cholesterol biosynthesis, suppress low density lipoprotein oxidation, modulate blood pressure, suppress platelet aggregation, lower plasma fibrinogen level and increase fibrinolytic activity, thus providing clinically relevant cardioprotective and anti-atherosclerotic effects. It is important to assess the level of evidence available for different protective effects of garlic and to understand the underlying mechanisms. This information will allow adequate integration of garlic-based preparations to clinical practice. In this review, we discuss the mechanisms of anti-atherosclerotic effects of garlic preparations, focusing on antihyperlipidemic, hypotensive, anti-platelet and direct anti-atherosclerotic activities of the medicinal plant. We also provide an overview of available meta-analyses and a number of clinical trials that assess the beneficial effects of garlic.
基金Supported by The Russian Ministry of Science and Education
文摘AIM: To examine whether the heteroplasmy level for 15059G】A mutation in the mitochondrial genome might be associated with essential hypertension. METHODS: This cross-sectional study involved 196 unrelated participants randomly selected from general population (90 males and 106 females) who underwent a regular medical check-up at the Institute for Ath-erosclerosis Research (Moscow, Russia). One hundred and twenty of them (61%) had essential hypertension, and 76 (39%) were apparently healthy normotensive persons. The level of heteroplasmy for 15059G】A mutation occurring in the coding region of cytochrome b gene (MT-CYB) of mtDNA isolated from the blood leukocytes, was quantified using DNA pyrosequencing method. RESULTS: The 15059G】A heteroplasmy level ranged between 4% and 83%, with a median level of 31%. Between the upper and lower quartiles of 15059G】A heteroplasmy distribution, significant differences were observed for patients’ age, systolic blood pressure, and triglyceride levels. 15059G】A heteroplasmy correlated both with age (r = 0.331, P 【 0.001) and the presence of hypertension (r = 0.228, P = 0.002). Regression analysis revealed that the age explains 12% variability of 15059G】A heteroplasmy, and hypertension independently explains more 5% variability. The 15059G】A heteroplasmy exceeding 31% was found to be significantly associated with a higher risk of essential hypertension (odds ratio 2.76; P (Fisher) 0.019]. The study participants with high 15059G】A heteroplasmy level were found to have significantly higher age (P 【 0.001) and the prevalence of essential hypertension (P = 0.033), as compared to those with low 15059G】A heteroplasmy level. These observations suggested a positive correlation between the level of 15059G】A heteroplasmy and essential hypertension. CONCLUSION: This study provides the evidence of association of mtDNA 15059G】A mutation heteroplasmy with essential hypertension.
基金Supported by The Russian Scientific Foundation,Moscow,Russian Federation,No.14-15-00112
文摘Inflammation plays an essential role in the development of atherosclerosis. The initiation and growth of atherosclerotic plaques is accompanied by recruitment of inflammatory and precursor cells from the bloodstream and their differentiation towards pro-inflammatory phenotypes. This process is orchestrated by the production of a number of pro-inflammatory cytokines and chemokines. Human arterial intima consists of structurally distinct leaflets, with a proteoglycan-rich layer lying immediately below the endothelial lining. Recent studies reveal the important role of stellate pericyte-like cells(intimal pericytes) populating the proteoglycan-rich layer in the development of atherosclerosis. During the pathologic process, intimal pericytes may participate in the recruitment of inflammatory cells by producing signalling molecules and play a role in the antigen presentation. Intimal pericytes are also involved in lipid accumulation and the formation of foam cells. This review focuses on the role of pericytelike cells in the development of atherosclerotic lesions.
文摘AIM:To assess clinical and endoscopic response to propionyl-L-carnitine hydrochloride(PLC) in colonic inflammatory bowel disease.METHODS:Patients suffering from mild to moderate ulcerative colitis(UC) or Crohn's disease(CD) colitis,with disease activity index(DAI) between 3 and 10 and under stable therapy with oral aminosalicylates,mercaptopurine or azathioprine,for at least 8 wk prior to baseline assessments,were considered suitable for enrollment.Fourteen patients were enrolled to assume PLC 2 g/d(two active tablets twice daily) orally.Clinical-endoscopic and histological activity were assessed by DAI and histological index(HI),respectively,following a colonoscopy performed immediately before and after 4 wk treatment.Clinical response was defined as a lowering of at least 3 points in DAI and clinical remission as a DAI score ≤ 2.Histological response was defined as an improvement of HI of at least 1 point.We used median values for the analysis.Differences pre-and post-treatment were analyzed by Wilcoxon signed rank test.RESULTS:All patients enrolled completed the study.One patient,despite medical advice,took deflazacort 5 d before follow-up colonoscopy examination.No side effects were reported by patients during the trial.After treatment,71%(SE 12%) of patients achieved clinical response,while 64%(SE 13%) obtained remission.Separating UC from CD patients,we observed a clinical response in 60%(SE 16%) and 100%,respectively.Furthermore 60%(SE 16%) of UC patients and 75%(SE 25%) of CD patients were in clinical remission after therapy.The median DAI was 7 [interquartile range(IQR):4-8] before treatment and decreased to 2(IQR:1-3)(P < 0.01) after treatment.Only patients with UC showed a significant reduction of DAI,from a median 6.5(IQR:4-9) before treatment to 2(IQR:1-3) after treatment(P < 0.01).Conversely,in CD patients,although displaying a clear reduction of DAI from 7(IQR:5.5-7.5) before therapy to 1.5(IQR:0.5-2.5) after therapy,differences observed were not significant(P = 0.06).Seventy-nine percent(SE 11%) of patients showed improvement of HI of at least 1 point,while only one CD and two UC patients showed HI stability;none showed HI worsening.Median HI decreased from 1(IQR:1-2),to 0.5(IQR:0-1) at the endoscopic control in the whole population(P < 0.01),while it changed from 1(IQR:1-2) to 0.5(IQR:0-1) in UC patients(P < 0.01) and from 1.5(IQR:1-2) to 0.5(IQR:0-1) in CD patients(P = not significant).The two sample tests of proportions showed no significant differences in clinical and histological response or in clinical remission between UC and CD patients.No side effects were reported during treatment or at 4 wk follow-up visit.CONCLUSION:PLC improves endoscopic and histological activity of mild to moderate UC.Further studies are required to evaluate PLC efficacy in colonic CD patients.
文摘Hypoxic preconditioning is able to increase the body’s resistance to hypoxic/ischemic stress. Understanding how to apply the hypoxic response to initiate the protective mechanism of ischemic preconditioning is a high priority. However, the relationship between innate resistance to hypoxic stress and preconditioning efficiency of moderate hypoxia has been poorly studied. In our work, the efficiency of single moderate hypobaric hypoxia (HBH) for resistance to severe hypobaric hypoxia (SHBH) was studied on intact rats and those pre-tested under SHBH with low, intermediate and high resistance to hypoxia. HBH has a significant preconditioning action on the resistance to hypoxia over a wide range from 270 to 1464 s (4.5 to 24.5 min) and at the same time eliminates the differences in the endurance under SHBH between all rat groups. It is concluded that 1) HBH preconditioning efficiency does not depend on an innate resistance to SHBH and prior hypoxic experience of rats;and 2) the pretesting to severe hypoxia has no value for predicting the hypoxic preconditioning efficiency and study of adaptive mechanisms.
文摘The work is a study of the influence of Ca2+ (0.01 - 1 mM) on neuronal CI-, HCO3-, -ATPase complex: an enzyme that is a CI--pump which is functionally and structurally coupled to GABAA-receptors. It is found that influence of Ca2+ on the multifunctional complex starts at concentration of 50·M and at concentration of 0.1 mM, it reduces the “basal” one and increases the CI-, HCO3-, -stimulated Mg2+-ATPase activities. GABA (0.1 - 100μM) activates the “basal” Mg2+-ATPase activity in the ab-sence of calcium. The effect of GABA on the enzyme in the presence of 0.01 ·M Ca2+ does not change. At the same time, 1 mM Ca2+eliminates the GABA effect on the “basal” Mg2+-ATPase activity. Competitive blocker of GABAA-receptors bicuculline (5 - 20 μM) in the absence of Ca2+ ions elimi-nates the stimulation of the “basal” Mg2+-ATPase by anions. When 0.25 mM Ca2+ is added to the in-cubation medium the inhibitory bicuculline effect on the enzyme does not appear. We found that 0.1 mM o-vanadate (protein tyrosine phosphatase blocker) reduces the GABA-activated ATPase activity. At the same time, 0.1 mM genistein (a protein tyrosine kinase blocker) has no effect on enzyme activity. In the presence of Ca2+ (0.25 mM), the effect of o-vanadate on the “basal” and CI-, HCO3-, -ATPase activities does not appear. It is shown for the first time that high concentrations of Ca2+prevent the action of GABAA-ergic ligands on the study ATPase. It is assumed that there is the involvement of protein kinases and protein phosphatases in the modulation of the enzyme activity by calcium. The observed effect of calcium on the ATPase may play an important role in the study of the mechanisms of epileptogenesis and seizure activity.
文摘Moderate one-off hypobaric hypoxia (HBH) provokes preconditioning and prolongs the resistance (T, the time before apnoea) to severe hypobaric hypoxia (SHBH). Hypoxic preconditioning has therapeutic potential;however, the efficiency of hypoxic preconditioning varies greatly and the methods for its preliminary evaluation are absent in both animals and humans. This rodent study evaluates the dependence of SHBH resistance, initiated by HBH, on the rate of sensorimotor gating estimated in the model of the acoustic startle prepulse inhibition (PPI). A stable negative correlation was found between PPI and T. Low doses of the α7 nicotinic receptor agonist, PNU-282987 (PNU), and more pronouncedly dimethyl sulfoxide (DMSO) (a PNU solvent), inverted the correlation between PPI and T from negative to positive. The DMSO and PNU effects were reversed at PPIs of 0.36 - 0.40 (36% - 40%). DMSO increased T values by 52.2% ± 9.7% in the region of lower HBH efficiency (PPI ≥ 0.40) and reduced it by 35.2% ± 9.3% in the region of higher HBH efficiency (PPI < 0.40). PNU reduced both DMSO effects. The involvement of the central cholinergic mechanisms was substantiated in both DMSO and PNU influences on HBH. In conclusion, 1) PPI can be used to predict the efficiency of hypoxic preconditioning and to study its mechanisms, 2) two opposite cholinergic PPI-related mechanisms participate in the preconditioning effects of HBH, 3) the sensitivity of rats to DMSO and PNU diverges when the PPI is 0.36 - 0.40, and 4) DMSO can enhance resistance to severe hypoxia in the region of the lower preconditioning efficiency of HBH at PPI ≥ 0.4.
文摘Conditions in rat and turtle small intestine tissue where glucose and glycine transport is inhibited while glucose-induced Na+ transport is preserved are described. The generally accepted model for the Na+-dependent transporter (а single channel for the Na+ and nutrient) does not account for the data obtained from the analysis of the interaction between the transport of glucose, glycine, and Na+ at different temperatures and the effect of inhibitors оn these рroсеssеs. The phenomenon of temperature uncoupling of Na+ and nutrient transport саn best bе described bу а two-pathway model with а gate mechanism. According to this model, the Na+-dependent transporter has at least two pathways: оnе for Na+ and another for nutrients. The model рrovidеs for the passage of Na+ in both directions along а channel opened bу glucose. Experiments are carried out using the addition of glucose and glycine on backgrounds of glycine and glucose, respectively. It has been hypothesized that when all three transporters (for Na+, glucose and glycine) are unite in a single structure, then there should be “competitive relations” between short-circuit current changes on glycine and glucose for sodium ions passing through its transporter.
文摘Recently, in our experiments, we used the short-circuit current technique to study the kinetic constants for nutrient transporters in rat gastric-intestinal tract and the thickness of the intestinal unstirred layer near the mucosa surface. It was shown that, during the process of aging, the number of nutrient monomer transporters in the small intestine increases twofold, whereas the affinity of transporters to the correspondent nutrients remains unchanged. The situation for peptides may be opposite. The layer thickness in the vicinity of the mucosa surface, measured through glucose, decreased during the process of aging. It was suggested that, in old rats, the role of the digestive volume is more important, which results in an increase of the number of nutrient monomer transporters.
基金the Russian Science Foundation (Grant # 18-15-00254).
文摘Connexins family in humans consists of 21 highly conserved proteins that are responsible for contact formation between cells. On the cell surface, connexins form hemichannels, or connexons. Two hemichannels brought together form a gap junction, a form of intercellular contact that allows for direct transfer of material and signals between the adjacent cells. Gap junctions serve for transporting ions and other soluble, low molecular weight molecules therefore synchronizing the microenvironment of the contacting cells and maintaining cell and tissue homeostasis. Impairment of gap junctions is associated with different pathological conditions. Importantly, it has been described in atherosclerosis, which causes local cellular dysfunction in the arterial wall tissues followed by the development of atherosclerotic plaque. There are 3 main connexins expressed in human cardiovascular system: Cx37, Cx40, and Cx43. Alterations in the arterial wall cells observed in atherosclerosis include changes in the expression pattern of the main connexins and impairment of intercellular contacts and communication. According to the currently available data, Cx37 and Cx40 have anti-atherogenic and vasculoprotective properties, while Cx43 appears to be more pro-atherogenic. However, the effects of connexins are cell type-dependent and in many cases, remain to be studied in detail. In this review, we summarize the available knowledge on connexins of the arterial wall cells involved in atherosclerosis development.
基金Supported by The Russian Ministry of Science and Education
文摘Mitochondrial DNA(mtDNA) is particularly prone to oxidation due to the lack of histones and a deficient mismatch repair system.This explains an increased mutation rate of mtDNA that results in heteroplasmy,e.g.,the coexistence of the mutant and wild-type mtDNA molecules within the same mitochondrion.In diabetes mellitus,glycotoxicity,advanced oxidative stress,collagen cross-linking,and accumulation of lipid peroxides in foam macrophage cells and arterial wall cells may significantly decrease the mutation threshold required for mitochondrial dysfunction,which in turn further contributes to the oxidative damage of the diabetic vascular wall,endothelial dysfunc-tion,and atherosclerosis.
基金supported by the National Natural Science Foundation of China(82174206)National Natural Science Foundation of China,International(Regional)Cooperation and Exchange Program(82261138556).
文摘Objective:To elucidate the effects of chlorogenic acid(CGA),a bioactive polyphenol compound prevalent in traditional Chinese medicine and various foods,including Lonicera japonica Thunb.(Jin Yin Hua),Eucommia ulmoides Oliv.(Du Zhong Ye),tea,and coffee,on cardiomyocyte ferroptosis and heart failure.Methods: We assessed the effect of CGA on cardiac function using a mouse model of heart failure induced by transverse aortic constriction(TAC).These indicators included the left ventricular ejection fraction(LVEF),fractional shortening(LVFS),end-systolic volume(LVESV),end-diastolic volume(LVEDV),end-systolic diameter(LVESD),and end-diastolic diameter(LVEDD).An isoprenaline hydrochloride(ISO)-induced H9c2 cardiomyocyte cell model was also established,and the cells were treated with various concentrations of CGA.To assess the effect of CGA on ferroptosis in cardiomyocytes,we measured cell viability and evaluated the levels of intracellular reactive oxygen species(ROS),ferrous ions(Fe^(2+)),and lipid peroxidation using fluorescent staining.To clarify the ferroptosis signaling pathway regulated by CGA,western blotting was used to examine the expression of ferroptosis biomarkers,specifically solute carrier family 7 member 11(SLC7A11)and glutathione peroxidase 4(GPX4),in H9c2 cardiomyocytes and mouse myocardial tissues.Results: CGA significantly enhanced cardiac performance indices such as LVEF,LVFS,LVESV,LVEDV,LVESD,and LVEDD.H9c2 cardiomyocytes exposed to ISO showed decreased cell viability and increased ROS levels,Fe^(2+)content,and lipid peroxidation levels.However,CGA treatment significantly ameliorated these changes.Additionally,in both H9c2 cardiomyocytes and myocardial tissue obtained from mice with TAC,CGA increased the expression of ferroptosis-related proteins,including SLC7A11 and GPX4.Conclusion: CGA has the potential to enhance cardiac function and diminish lipid peroxidation and ROS levels in cardiomyocytes via the SLC7A11/GPX4 signaling pathway.This process alleviates ferroptosis in cardiomyocytes.These results provide new insights into the clinical use of CGA and the management of heart failure.
文摘Emotional and motivational disorders in adults are often considered to be the result of altered neurodevelopment. Clinical and experimental data provide evidence that serine protease dipeptidyl peptidase-IV (DPP-IV, EC 3.4.14.5) is involved in the pathophysiology of psycho-emotional disorders. Recently, we have shown that adolescent and adult rats exhibit an increase in anxiety and depression-related behaviors after neonatal administration of a synthetic non-competitive inhibitor of DPP-IV, methionyl-2(S)-cyano-pyrrolidine. In the present study, we tested the effects of two competitive, selective DPP-IV inhibitors, sitagliptin (4 mg/kg) and diprotin A (2 mg/kg), administered at postnatal days 5 - 18 on the emotional and motivational behavior of adolescent and adult rats. We observed increased anxiety in one-month-old diprotin A- or sitagliptin-treated rats in the elevated plus maze;diprotin A also enhanced the animals’ anxiety score using a ranked scale for evaluating anxiety and phobias. In the sucrose consumption and preference test, depressive-like behavior was pronounced in both the diprotin A- and sitagliptin-treated one-month-old animals, while only the diprotin A-treated rats exhibited a decrease in sucrose consumption at the age of 2 months. The diprotin A-treated rats also demonstrated behavioral despair and decreased activity in the forced swimming test within 1 - 3 months of age. Increased aggression was observed in 1 - 3-month-old diprotin A-treated rats and in two-month-old sitagliptin-treated rats. These findings support the hypothesis that DPP-IV is involved in the genesis of emotional and motivational disorders. Additionally, the results show that diprotin А impairs the adolescent and adult rats’ behavior more significantly than sitagliptin when the animals were treated with the DPP-IV inhibitors in the early postnatal period.
基金Supported by Crohn’s and Colitis Foundation of America,Research Fellowship Award,No.CON125252(to Lopetuso LR)European Crohn’s and Colitis Organization Grant(to Scaldaferri F)Societa?Italiana di Gastroenterologia prize(to Scaldaferri F)
文摘AIM To explore the influence of Infliximab(IFX) on cancer progression in a murine model of colonic cancer associated to chronic colitis.METHODS AOM/DSS model was induced in C57BL/6 mice. Mice were injected with IFX(5 mg/kg) during each DSS cycle while control mice received saline. Body weight, occult blood test and stool consistency were measured to calculate the disease activity index(DAI). Mice were sacrificed at week 10 and colons were analyzed macroscopically and microscopically for number of cancers and degree of inflammation. MTT assay was performed on CT26 to evaluate the potential IFX role on metabolic activity and proliferation. Cells were incubated with TNF-α or IFX or TNF-α plus IFX, and cell vitality was evaluated after 6, 24 and 48 h. The same setting was used after pre-incubation with TNF-α for 24 h.RESULTS IFX significantly reduced DAI and body weight loss in mice compared with controls, preserving also colon length at sacrifice. Histological score was also reduced in treated mice. At macroscopic analysis, IFX treated mice showed a lower number of tumor lesions compared to controls. This was confirmed at microscopic analysis, although differences were not statistically significant. In vitro, IFX treated CT26 maintained similar proliferation ability at MTT test, both when exposed to IFX alone and when associated to TNF-α.CONCLUSION IFX did not increase colonic cancer risk in AOM-DSS model of cancer on chronic colitis nor influence directly the proliferation of murine colon cancer epithelial cells.
基金funded by the Russian Science Foundation(Grant No.23-45-00031).
文摘Atherosclerosis is extremely widespread.Traditionally,it is considered a disease of older people,who most often experience problems with the heart and blood vessels.While much attention from the scientific community has been paid to studying the association between aging and atherosclerosis,as well as its consequences,there is evidence that atherosclerosis occurs at an early age.Atherosclerosis may form both during intrauterine development and in childhood.Nutrition plays an important role in childhood atherosclerosis,along with previous infectious diseases and excess weight of both the child and the mother.In the present review,we examined the development of atherosclerosis and the prerequisites in childhood.
文摘This paper focuses on a bioenergetic mechanism responding to hypoxia. This response involves hypoxia-induced reprogramming of respiratory chain function and switching from oxidation of complex I (NAD-related substrates) to complex II (succinate oxidation). Transient, reversible, compensatory activation of respiratory chain complex II is a major mechanism of urgent adaptation to hypoxia, which is necessary for 1) succinate-related energy synthesis in the conditions of oxygen shortage and formation of urgent resistance;2) succinate-related stabilization of HIF-1α and initiation of its transcriptional activity related with formation of long-term adaptation;3) succinate-dependent activation of the succinate-specific receptor GPR91. Thus, mitochondria perform a signaling function with succinate as a signaling molecule. Effects of succinate in hypoxia occur at three levels, intramitochondrial, intracellular and intercellular. In these settings, succinate displays antihypoxic activity. The review is focused on tactics and strategy for development of the antihypoxic defense and antihypoxants with energotropic properties.
文摘This paper focuses on a bioenergetic mechanism responding to hypoxia. This response involves hypoxia-induced reprogramming of respiratory chain function and switching from oxidation of complex I (NAD-related substrates) to complex II (succinate oxidation). Transient, reversible, compensatory activation of respiratory chain complex II is a major mechanism of urgent adaptation to hypoxia, which is necessary for 1) succinate-related energy synthesis in the conditions of oxygen shortage and formation of urgent resistance;2) succinate-related stabilization of HIF-1α and initiation of its transcriptional activity related with formation of long-term adaptation;3) succinate-dependent activation of the succinate-specific receptor GPR91. Thus, mitochondria perform a signaling function with succinate as a signaling molecule. Effects of succinate in hypoxia occur at three levels, intramitochondrial, intracellular and intercellular. In these settings, succinate displays antihypoxic activitie. The review is focused on tactics and strategy for development of the antihypoxic defense and antihypoxants with energotropic properties.
