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The study focuses on the effects of fluvastatin on immunomarkers of the M1 and M2 macrophages and its direct role in macrophage (M0) polarization. Moreover, it investigates the dependency of immunomodulatory properties of fluvastatin on the mevalonate pathway. Macrophages (M0, M1, M2), differentiated from human blood monocytes, were treated with fluvastatin. Mevalonate and geranylgeranyl pyrophosphate intermediates were introduced to assess the mevalonate pathway dependence. The immunomarkers were evaluated with qPCR, ELISA, Griess assay, and flow cytometry. Fluvastatin significantly reduces the pro-inflammatory gene expression (NFκB, IL-1β, IL-6, iNOS) in M1 while enhancing the anti-inflammatory markers (Arg-1, TGFβ) in M2 macrophages. The production of the TNFα, IL-1β, and IL-6 cytokines is reduced in M1, and IL-10 production increased in M2 macrophages. Fluvastatin decreases the iNOS activity in M1 macrophages. The intermediates reverse the fluvastatin’s effects on anti-inflammatory gene expression by M2 macrophages, cytokine production (by M1 and M2 macrophages), and iNOS activity (by M1 macrophages). Their impact on surface marker expression was somewhat limited. These findings demonstrate that fluvastatin exerts anti-inflammatory effects on polarized macrophages without affecting polarization per se and also highlight the dependency on the mevalonate pathway. This study deepens the understanding of statins’ immunomodulatory mechanisms, suggesting potential applications in treating inflammatory diseases.

Preclinical biomedical research is limited by the predictiveness of in vivo and in vitro models. While in vivo models offer the most complex system for experimentation, they are also limited by ethical, financial, and experimental constraints. In vitro models are simplified models that do not offer the same complexity as living animals but do offer financial affordability and more experimental freedom; therefore, they are commonly used. Traditional 2D cell lines cannot fully simulate the complexity of the epithelium of healthy organs and limit scientific progress. The One Health Initiative was established to consolidate human, animal, and environmental health while also tackling complex and multifactorial medical problems. Reverse translational research allows for the sharing of knowledge between clinical research in veterinary and human medicine. Recently, organoid technology has been developed to mimic the original organ’s epithelial microstructure and function more reliably. While human and murine organoids are available, numerous other organoids have been derived from traditional veterinary animals and exotic species in the last decade. With these additional organoid models, species previously excluded from in vitro research are becoming accessible, therefore unlocking potential translational and reverse translational applications of animals with unique adaptations that overcome common problems in veterinary and human medicine.

Atherosclerosis is a chronic inflammatory disease of the blood vessels caused by elevated levels of lipoproteins. The hyperlipoproteinemia triggers a series of cellular changes, particularly the activation of the macrophages, which play a crucial role in the development and progression of atherosclerosis. The presence of free cholesterol (FC) in lipoproteins may contribute to macrophage stimulation. However, the mechanisms linking the accumulation of FC in macrophages to their pro‐inflammatory activation remain poorly understood. Our research found a positive correlation between the number of pro‐inflammatory macrophages (CD14 + CD16 + CD36high) in visceral adipose tissue and the levels of LDL‐C and cholesterol remnant particles in 56 healthy people. In contrast, the proportion of anti‐inflammatory, alternatively activated macrophages (CD14 + CD16‐CD163+) correlated negatively with HDL‐C. Additionally, our in vitro study demonstrated that macrophages accumulating FC promoted a pro‐inflammatory response, activating the TNF‐α and chemokine CCL3 genes. Furthermore, the accumulation of FC in macrophages alters the surface receptors on macrophages (CD206 and CD16) and increases cellular granularity. Notably, the CD36 surface receptor and the ACAT and CD36 genes did not show a response. These results suggest a link between excessive FC accumulation and systemic inflammation to underlie the development of atherosclerosis.

Macrophages are critical components of the innate immune system that adapt their function based on local microenvironmental cues. In adipose tissue, macrophage polarization is intimately linked to metabolic regulation and inflammation. In this pilot study, we performed lipidomic profiling to characterize the phospholipid composition of pro-inflammatory (PI-ATM) and non-inflammatory (NI-ATM) macrophages isolated from visceral adipose tissue of living kidney donors. Tissue samples were processed, and macrophages were isolated and sorted using CD14 and CD16 markers. Lipids were extracted by methyl tert -butyl ether, and differences in the lipidome were analyzed using the optimized UHPLC-MS method. PI-ATM exhibited a higher abundance of lipids across various lipid classes than NI-ATM. Phosphatidylethanolamines and ether lipids derived from phosphatidylethanolamines and phosphatidylcholines were most frequently found among the significantly altered lipids. The majority of significantly altered lipid species contained an octadecenoic aliphatic chain. These findings suggest that alterations in membrane lipid composition - particularly ether lipids and phosphatidylethanolamines - may play a pivotal role in macrophage polarization and adipose tissue inflammation. Our study provides novel insights into the lipidomic regulation of macrophage function in human adipose tissue and identifies potential targets for therapeutic intervention in metabolic disorders.

While two-dimensional (2D) cell cultures, such as Caco-2 and Madin–Darby canine kidney (MDCK) cells are widely used in a variety of biological models, these two-dimensional in vitro systems present inherent limitations in replicating the complexities of in vivo biology. Recent progress in three-dimensional organoid technology has the potential to address these limitations. In this study, the characteristics of conventional 2D cell culture systems were compared to those of canine intestinal organoids (enteroids, ENT, and colonoids, COL). Light microscopy and transmission electron microscopy were employed to evaluate the microanatomy of ENT, COL, Caco-2, and MDCK cell monolayers, while transepithelial electrical resistance (TEER) values were measured to assess monolayer integrity. The TEER values of canine ENT monolayers more closely approximated reported TEER values for human small intestines compared to Caco-2 and MDCK monolayers. Additionally, canine ENT demonstrated greater monolayer stability than Caco-2 and MDCK cells. Notably, while all systems displayed desmosomes, canine ENT and COL exclusively produced mucus. These findings highlight the potential of the canine organoid system as a more biologically relevant model for in vitro studies, addressing the limitations of conventional 2D cell culture systems.

The importance of macrophage polarization through atherogenesis is established. However, most studies rely on immunohistological approaches, which have several limitations, such as precluding comprehensive phenotypic analysis. The aim of this study was to perform an alternative analysis of macrophage phenotypes in advanced human atherosclerotic plaques and compare them with their presence in non‐atherosclerotic arteries. Atherosclerotic plaques from 70 individuals indicated for carotid endarterectomy, and samples of non‐atherosclerotic arterial tissue (renal artery, control group) from 45 living kidney donors were processed to obtain immunocytes and incubated with antibodies (CD45, CD14, CD16, CD36, CD163, and CD206) to be analyzed by flow cytometry. Macrophages in the atherosclerotic plaques tend to express CD16 more intensively than in non‐atherosclerotic arterial tissue (transient, CD16low p < 0.001, pro‐inflammatory, CD16high p < 0.001), and the expression is more closely associated with CD36 expression. Both transient and pro‐inflammatory macrophages are linked with the CD206−CD163+ or CD206+CD163+ phenotype in atherosclerotic plaques, while CD206−CD163− dominates within the anti‐inflammatory (CD16neg) population in the control group. Interestingly, when evaluating all macrophages (regardless of CD16 expression), almost all are CD163+ in both groups, supporting the critical importance of using a combination of specific markers. Our results provide a deeper insight into macrophage subpopulations in advanced human atherosclerotic plaques compared with those in non‐atherosclerotic vessels. Additionally, our data highlight the critical importance of using appropriate techniques, such as flow cytometry, allowing for simultaneous analysis of multiple markers to accurately and comprehensively characterize macrophages within the atherosclerotic plaque. The transition from a non‐atherosclerotic to an atherosclerotic artery is associated with a shift in macrophage phenotypes. In the homeostatic environment of a non‐atherosclerotic artery, macrophages are predominantly anti‐inflammatory, anti‐atherogenic. In contrast, atherosclerotic plaques contain more diverse and pro‐inflammatory macrophage populations, shaped by the inflammatory microenvironment during atherogenesis. Green macrophages represent anti‐inflammatory (CD16neg), orange intermediate (CD16low) and red pro‐inflammatory (CD16high) phenotypes.

Background Albuminuria, an important marker of decreased kidney function in chronic kidney disease (CKD), is not routinely used for CKD detection or proteinuria appearance. Its relationships with biochemical parameters and blood pressure in dogs are poorly understood. Objectives This study aimed to evaluate the relationship of albuminuria with various CKD markers, its correlation with the urinary protein to creatinine ratio (UPC), and hypertension in dogs with early stages of CKD. It also sought to determine the usability of the urinary albumin to creatinine ratio (UAC) for CKD screening. Methods The study reviewed records of 102 dogs, categorising them into four groups based on disease status. UAC and UPC ratio, biochemistry and haematology variables, age, and systolic blood pressure were determined. Results The Pearson's correlation coefficient between log‐transformed values of UPC and UAC was r = 0.902 (95% CI: 0.87 to 0.93). Median UAC ratio values were 2.1 mg/g for the Healthy control group (n = 17), 54.2 mg/g for early stages CKD (n = 42), 5.8 mg/g for Acute sick control (n = 30), and 104 mg/g for Chronic sick control (n = 13). Thresholding UAC ratio as an indicator for impaired kidney function with the threshold of 10 mg/g (established based on the receiver operating characteristic curve) had a sensitivity 81.8%, specificity of 89.4%, positive predictive value (PPV) 90%, and negative predictive value (NPV) 80.1%. The correlation of UAC with biochemistry and haematology variables was statistically significant; for SDMA (μg/L), it was r = 0.566 and for other variables, it was weak to moderate. UAC was markedly elevated in cases of severe hypertension. Conclusions UAC ratio was significantly different among dogs with impaired and not impaired kidney function. The correlation strength for the UAC and UPC ratios was high. UAC ratio may be a promising marker for proteinuria analysis in dogs with CKD or other kidney function alterations. A total of 102 records were reviewed to establish the relationship between albuminuria and various markers of kidney function in canine chronic kidney disease. The urinary albumin to creatinine ratio significantly differed between dogs with impaired and nonimpaired kidney function. We propose a threshold for screening impaired kidney function.

The high mortality of coronary heart disease (CHD) among Czech men—one of the highest worldwide—began to decline in 1991 soon after the abolition of government subsidies to all foodstuffs rich in animal fat. As participants in the WHO MONICA Project, we were able to analyze the CHD risk factors just before and after this major economic change. We had previously documented that the originally subsidized prices decreased animal fat consumption and consequently non-HDL cholesterol concentrations in the population. By the early 1990s, no progress had been made in the treatment of acute myocardial infarction, statins were unavailable as was not the currently more effective antihypertensive therapy. Our recent research proved a close relationship between cholesterolemia and proinflammatory macrophages in adipose tissue and accelerated macrophage polarization with increased palmitate and palmitoleate contents in cell membrane phospholipids. By contrast, the proportion of proinflammatory macrophages decreases with increasing presence of n-3 fatty acids in the cell membrane. The combination of non-HDL cholesterol drop and a decreased proportion of proinflammatory macrophages due to replacement of alimentary fat decreased CHD mortality immediately.

Membrane cholesterol is essential for cell membrane properties, just as serum cholesterol is important for the transport of molecules between organs. This review focuses on cholesterol transport between lipoproteins and lipid rafts on the surface of macrophages. Recent studies exploring this mechanism and recognition of the central dogma—the key role of macrophages in cardiovascular disease—have led to the notion that this transport mechanism plays a major role in the pathogenesis of atherosclerosis. The exact molecular mechanism of this transport remains unclear. Future research will improve our understanding of the molecular and cellular bases of lipid raft-associated cholesterol transport.