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Lipopolysaccharide (LPS) induces a strong pro-inflammatory reaction of macrophages upon activation of Toll-like receptor 4 (TLR4) with the assistance of CD14 protein. Considering a key role of plasma membrane rafts in CD14 and TLR4 activity and the significant impact exerted on that activity by endocytosis and intracellular trafficking of the both LPS acceptors, it seemed likely that the pro-inflammatory reaction could be modulated by flotillins. Flotillin-1 and -2 are scaffolding proteins associated with the plasma membrane and also with endo-membranes, affecting both the plasma membrane dynamics and intracellular protein trafficking. To verify the above hypothesis, a set of shRNA was used to down-regulate flotillin-2 in Raw264 cells, which were found to also become deficient in flotillin-1. The flotillin deficiency inhibited strongly the TRIF-dependent endosomal signaling of LPS-activated TLR4, and to a lower extent also the MyD88-dependent one, without affecting the cellular level of TLR4. The flotillin depletion also inhibited the pro-inflammatory activity of TLR2/TLR1 and TLR2/TLR6 but not TLR3. In agreement with those effects, the depletion of flotillins down-regulated the CD14 mRNA level and the cellular content of CD14 protein, and also inhibited constitutive CD14 endocytosis thereby facilitating its shedding. Ultimately, the cell-surface level of CD14 was markedly diminished. Concomitantly, CD14 recycling was enhanced via EEA1-positive early endosomes and golgin-97-positive trans-Golgi network, likely to compensate for the depletion of the cell-surface CD14. We propose that the paucity of surface CD14 is the reason for the down-regulated signaling of TLR4 and the other TLRs depending on CD14 for ligand binding. [ABSTRACT FROM AUTHOR]

Copper (Cu) and zinc (Zn) are trace minerals with multiple biological functions, playing roles in fetal development and immune regulation. Despite their known significance, research on Cu and Zn administration and supplementation for pregnant mares is insufficient. This study aims to evaluate Cu and Zn serum concentrations monthly throughout the year and through pregnancy in Polish Konik mares. The study was conducted in 2020 on 36 mares from the Polish state stud farm, with 24 mares in the pregnant group and 12 mares in the non-pregnant group. Monthly blood samples were collected, and serum Cu and Zn concentrations were measured. The total Cu concentration in the serum of all mares was higher (p < 0.0001) in August and September (13.98 ± 3.00 μmol/L) than in May, June, July, and November (11.04 ± 2.74 μmol/L). Similarly, the total Zn concentration was higher (p < 0.0001) in August, September, October, November, and December (19.80 ± 9.72 μmol/L) than in May, June, and July (14.50 ± 6.94 μmol/L). No evidence of a linear relation between Cu and Zn concentrations was demonstrated (slopes difference p < 0.001). No differences in Cu (p > 0.05) or Zn (p > 0.05) concentrations were found between pregnant (Cu: 12.08 ± 3.01 μmol/L; Zn: 18.02 ± 9.03 μmol/L) and non-pregnant (Cu: 11.23 ± 2.51 μmol/L; Zn: 18.59 ± 10.37 μmol/L) mares in any of the examined months of the year. In conclusion, the month of the year, rather than pregnancy, affects serum Cu and Zn concentrations. [ABSTRACT FROM AUTHOR]

This review describes the physiological role of cortisol in the horses' body and the usefulness of cortisol concentration measurements in assessing welfare and diagnosing diseases. Cortisol is examined in terms of its production and functions, along with the concept of circadian cortisol rhythms and potential disruptions in these patterns. The significance of cortisol concentration is emphasized, as it provides insights into stress levels, and the connection between cortisol and stereotypical horse behaviors, raising the question of whether these behaviors signify stress or serve as coping mechanisms. Moreover, cortisol concentration helps in diagnosing various health conditions such as Cushing's Disease, inflammation, and metabolic imbalances. As cortisol concentration is considered a stress indicator that may be affected by the sampling protocol, the matrices for cortisol sampling and their practical applications are summarized. In this review, three major cortisol sampling methods: plasma, salivary, and hair cortisol, are described in detail. Plasma cortisol measurements offer acute stress insights, while salivary cortisol analysis provides a non-invasive method for continuous stress monitoring. Hair cortisol, on the other hand, offers an assessment of long-term stress levels. This text underscores the importance of cortisol control in safeguarding the welfare and health of horses. [ABSTRACT FROM AUTHOR]

Infrared thermography is a valuable tool adapted for veterinary diagnostics with an increasing number of uses. However, proper image acquisition is hard, not only due to various factors affecting the image but also because informative image processing is a struggle. Thus, this study aims to quantify the area of maximum temperature (Area of Tmax) on the lateral surface of horses and foals to compare the Areas of Tmax between horses and foals and to compare two new approaches to the Area of Tmax quantification in horses. Infrared images were acquired with a thermographic camera from 12 horses and 12 foals in the same ambient condition. The backgrounds of the images were removed, and the images were then processed in Rainbow HC and a grayscale palette. Then, 10 images were created, showing the Areas of Tmax in gradually decreasing ranges. The evaluation of the Area of Tmax with two image processing methods showed higher maximum temperatures in foals, although the high-temperature values covered less of their total body area than in adult horses. The results indicate the struggles of foals with thermal homeostasis. The proposed methods—multi-colored annotated pixels on Rainbow HC and red-annotated pixels on grayscale—provide a common quality in the thermogram evaluation of foals and adult horses. Further research is essential to determine their diagnostic application. [ABSTRACT FROM AUTHOR]

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The subject matter of this study is connected to the functions of socially responsible business, which has become an essential topic within the insurance sector during the COVID-19 pandemic. This issue has received increasing attention from scientific, business, and political communities. Our study is devoted to the social, economic, and financial dimensions of the problem concerning sustainable development, and is analysed from the perspective of the financial market, including the insurance sector, during the COVID-19 pandemic. Our research indicates that the emerging social, economic, and financial phenomena offer an adequate description of the changes in the global economy. This study could become the basis for a better strategy against the COVID-19 pandemic than the current view of the economy, and may lead to a breakthrough in the development of social sciences. We attempt to integrate the environments and concepts into the starting point of a central question: does the social responsibility of a business allow for the chance of sustainable growth from social, economic, and financial perspectives? Thus, this study deals with the hypothesis that the social, economic, and financial aspects concerning the development of Poland are connected to the behaviours of the financial market, which compose their strategy by taking socially responsible actions both during the COVID-19 pandemic and after it into account by modelling sustainable growth. Statistical data from the Central Statistical Office from the years 2010–2020 concerning age, place of residence, and level of education was a selection basis while creating the layers. The methodological concept of the study was theoretical and empirical. In the empirical section, the research was conducted in the territory of the Polish state using proprietary indicators of sustainable development and a questionnaire. Moreover, a theoretical and historical analysis has been conducted. Within sustainable development, there is a noticeable attitude among the respondents who are aware of the COVID-19 threat characteristic of mature customers. Customers of insurance companies in Poland expect to receive a good-quality insurance product and to be well served in the event of an insurance accident. Moreover, it is expected that, as CSR develops, insurers will continue to serve as shock absorbers for the economy and society. [ABSTRACT FROM AUTHOR]

TLR4 is activated by the bacterial endotoxin lipopolysaccharide (LPS) and triggers two proinflammatory signaling cascades: a MyD88‐dependent one in the plasma membrane, and the following TRIF‐dependent one in endosomes. An inadequate inflammatory reaction can be detrimental for the organism by leading to sepsis. Therefore, novel approaches to therapeutic modulation of TLR4 signaling are being sought after. The TLR4 activity is tightly connected with the presence of CD14, a GPI‐anchored protein that transfers LPS monomers to the receptor and controls its endocytosis. In this study we focused on CD14 trafficking as a still poorly understood factor affecting TLR4 activity. Two independent assays were used to show that after endocytosis CD14 can recycle back to the plasma membrane in both unstimulated and stimulated cells. This route of CD14 trafficking can be controlled by sorting nexins (SNX) 1, 2 and 6, and is important for maintaining the surface level and the total level of CD14, but can also affect the amount of TLR4. Silencing of these SNXs attenuated especially the CD14‐dependent endosomal signaling of TLR4, making them a new target for therapeutic regulation of the inflammatory response of macrophages to LPS. [ABSTRACT FROM AUTHOR]

The online version of the original article can be found at https://doi.org/10.1007/s00018-024-05221-3.Cellular and Molecular Life Sciences (2024) 81:191In this article the author name Ichrak Ben Amor was incorrectly written as Ichrak Ben Amore.The original article has been corrected.Publisher's NoteSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.By Orest V. Matveichuk; Anna Ciesielska; Aneta Hromada-Judycka; Natalia Nowak; Ichrak Ben Amor; Gabriela Traczyk and Katarzyna KwiatkowskaReported by Author; Author; Author; Author; Author; Author; Author [Extracted from the article]

Toll-like receptor (TLR) 4 belongs to the TLR family of receptors inducing pro-inflammatory responses to invading pathogens. TLR4 is activated by lipopolysaccharide (LPS, endotoxin) of Gram-negative bacteria and sequentially triggers two signaling cascades: the first one involving TIRAP and MyD88 adaptor proteins is induced in the plasma membrane, whereas the second engaging adaptor proteins TRAM and TRIF begins in early endosomes after endocytosis of the receptor. The LPS-induced internalization of TLR4 and hence also the activation of the TRIF-dependent pathway is governed by a GPI-anchored protein, CD14. The endocytosis of TLR4 terminates the MyD88-dependent signaling, while the following endosome maturation and lysosomal degradation of TLR4 determine the duration and magnitude of the TRIF-dependent one. Alternatively, TLR4 may return to the plasma membrane, which process is still poorly understood. Therefore, the course of the LPS-induced pro-inflammatory responses depends strictly on the rates of TLR4 endocytosis and trafficking through the endo-lysosomal compartment. Notably, prolonged activation of TLR4 is linked with several hereditary human diseases, neurodegeneration and also with autoimmune diseases and cancer. Recent studies have provided ample data on the role of diverse proteins regulating the functions of early, late, and recycling endosomes in the TLR4-induced inflammation caused by LPS or phagocytosis of E. coli. In this review, we focus on the mechanisms of the internalization and intracellular trafficking of TLR4 and CD14, and also of LPS, in immune cells and discuss how dysregulation of the endo-lysosomal compartment contributes to the development of diverse human diseases. [ABSTRACT FROM AUTHOR]

Bacterial LPS strongly induces pro‐inflammatory responses of Mϕs after binding to CD14 protein and the TLR4/MD‐2 receptor complex. The LPS‐triggered signaling can be modulated by extracellular lysophosphatidic acid (LPA), which is of substantial importance for Mϕ functioning under specific pathophysiological conditions, such as atherosclerosis. The molecular mechanisms of the crosstalk between the LPS‐ and LPA‐induced signaling, and the LPA receptors involved, are poorly known. In this report, we show that LPA strongly inhibits the LPS‐induced TNF‐α production at the mRNA and protein levels in primary Mϕs and Mϕ‐like J774 cells. The decreased TNF‐α production in LPA/LPS‐stimulated cells is to high extent independent of NF‐κB but is preceded by enhanced expression and secretion of the anti‐inflammatory cytokine IL‐10. The IL‐10 elevation and TNF‐α reduction are both abrogated upon depletion of the LPA5 and LPA6 receptors in J774 cells and can be linked with LPA‐mediated activation of p38. We propose that the binding of LPA to LPA5 and LPA6 fine‐tunes the LPS‐induced inflammatory response by activating p38, and up‐regulating IL‐10 and down‐regulating TNF‐α production. [ABSTRACT FROM AUTHOR]

S-palmitoylation is a reversible, enzymatic posttranslational modification of proteins in which palmitoyl chain is attached to a cysteine residue via a thioester linkage. S-palmitoylation determines the functioning of proteins by affecting their association with membranes, compartmentalization in membrane domains, trafficking, and stability. In this review, we focus on S-palmitoylation of proteins, which are crucial for the interactions of pathogenic bacteria and viruses with the host. We discuss the role of palmitoylated proteins in the invasion of host cells by bacteria and viruses, and those involved in the host responses to the infection. We highlight recent data on protein S-palmitoylation in pathogens and their hosts obtained owing to the development of methods based on click chemistry and acyl-biotin exchange allowing proteomic analysis of protein lipidation. The role of the palmitoyl moiety present in bacterial lipopolysaccharide and lipoproteins, contributing to infectivity and affecting recognition of bacteria by innate immune receptors, is also discussed. [ABSTRACT FROM AUTHOR]

Cyclic phosphatidic acids (cPAs) are naturally occurring, very active signalling molecules, which are involved in several pathological states, such as cancer, diabetes or obesity. As molecules of highly lipidic character found in the circulatory system, cPAs are bound and transported by the main extracellular lipid binding protein–serum albumin. Here, we present the detailed interactions between human serum albumin (HSA) and equine serum albumin (ESA) with a derivative of cPA, 1-O-myristoyl-sn-glycerol-2,3-cyclic phosphorodithioate (Myr-2S-cPA). Initial selection of the ligand used for the structural study was made by the analysis of the therapeutically promising properties of the sulfur containing analogues of cPA in respect to the unmodified lysophospholipids (LPLs). Substitution of one or two non-bridging oxygen atoms in the phosphate group with one or two sulfur atoms increases the cytotoxic effect of cPAs up to 60% on the human prostate cancer (PC) cells. Myr-2S-cPA reduces cancer cell viability in a dose-dependent manner, with IC50 value of 29.0 μM after 24 h incubation, which is almost 30% lower than IC50 of single substituted phosphorothioate cPA. Although, the structural homology between HSA and ESA is big, their crystal complexes with Myr-2S-cPA demonstrate significantly different mode of binding of this LPL analogue. HSA binds three molecules of Myr-2S-cPA, whereas ESA only one. Moreover, none of the identified Myr-2S-cPA binding sites overlap in both albumins. [ABSTRACT FROM AUTHOR]

You are what you eat - this well-known phrase properly describes the phenomenon of the effects of diet on acute and chronic inflammation. Several lipids and lipophilic compounds that are delivered with food or are produced in situ in pathological conditions exert immunomodulatory activity due to their interactions with the plasma membrane. This group of compounds includes cholesterol and its oxidized derivatives, fatty acids, α-tocopherol, and polyphenols. Despite their structural heterogeneity, all these compounds ultimately induce changes in plasma membrane architecture and fluidity. By doing this, they modulate the dynamics of plasma membrane receptors, such as TLR4. This receptor is activated by lipopolysaccharide, triggering acute inflammation during bacterial infection, which often leads to sepsis and is linked with diverse chronic inflammatory diseases. In this review, we discuss how the impact on plasma membrane properties contributes to the immunomodulatory activity of dietary compounds, pointing to the therapeutic potential of some of them. Also watch the . [ABSTRACT FROM AUTHOR]

Palmitic acid (C16:0) is the most abundant saturated fatty acid in animals serving as a substrate in synthesis and β-oxidation of other lipids, and in the modification of proteins called palmitoylation. The influence of dietary palmitic acid on protein S-palmitoylation remains largely unknown. In this study we performed high-throughput proteomic analyses of a membrane-enriched fraction of murine liver to examine the influence of a palm oil-rich diet (HPD) on S-palmitoylation of proteins. HPD feeding for 4 weeks led to an accumulation of C16:0 and C18:1 fatty acids in livers which disappeared after 12-week feeding, in contrast to an accumulation of C16:0 in peritoneal macrophages. Parallel proteomic studies revealed that HPD feeding induced a sequence of changes of the level and/or S-palmitoylation of diverse liver proteins involved in fatty acid, cholesterol and amino acid metabolism, hemostasis, and neutrophil degranulation. The HPD diet did not lead to liver damage, however, it caused progressing obesity, hypercholesterolemia and hyperglycemia. We conclude that the relatively mild negative impact of such diet on liver functioning can be attributed to a lower bioavailability of palm oil-derived C16:0 vs. that of C18:1 and the efficiency of mechanisms preventing liver injury, possibly including dynamic protein S-palmitoylation. [ABSTRACT FROM AUTHOR]

Flotillin-1 and flotillin-2 are ubiquitously expressed, membrane-associated proteins involved in multifarious cellular events from cell signaling, endocytosis, and protein trafficking to gene expression. They also contribute to oncogenic signaling. Flotillins bind the cytosolic leaflet of the plasma membrane and endomembranes and, upon hetero-oligomerization, serve as scaffolds facilitating the assembly of multiprotein complexes at the membrane–cytosol interface. Additional functions unique to flotillin-1 have been discovered recently. The membrane-binding of flotillins is regulated by S-palmitoylation and N-myristoylation, hydrophobic interactions involving specific regions of the polypeptide chain and, to some extent, also by their oligomerization. All these factors endow flotillins with an ability to associate with the sphingolipid/cholesterol-rich plasma membrane domains called rafts. In this review, we focus on the critical input of lipids to the regulation of the flotillin association with rafts and thereby to their functioning. In particular, we discuss how the recent developments in the field of protein S-palmitoylation have contributed to the understanding of flotillin1/2-mediated processes, including endocytosis, and of those dependent exclusively on flotillin-1. We also emphasize that flotillins affect directly or indirectly the cellular levels of lipids involved in diverse signaling cascades, including sphingosine-1-phosphate and PI(4,5)P2. The mutual relations between flotillins and distinct lipids are key to the regulation of their involvement in numerous cellular processes. [ABSTRACT FROM AUTHOR]