Significance: Receptor–ligand interactions on the cell surface or intrinsic stress signals can commit mammalian cells to apoptosis. In this study, we discover how hexokinases confer resistance to receptor-mediated apoptosis through specific inhibition of B-cell lymphoma 2 (BCL-2) proteins. Hexokinases retrotranslocate activator and effector BCL-2 proteins from the mitochondria into the cytosol. Hexokinase-dependent BCL-2 protein retrotranslocation can protect cells from apoptosis despite death receptor signaling.

Osteoarthritis (OA) is one of the most common chronic diseases in human and animal joints. The joints undergo several morphological and histological changes during the development of radiographically visible osteoarthritis. The most discussed changes include synovial inflammation, the massive destruction of articular cartilage and ongoing joint destruction accompanied by massive joint pain in the later stadium. Either the increased apoptosis of chondrocytes or the insufficient apoptosis of inflammatory macrophages and synovial fibroblasts are likely to underly this process. In this review, we discuss the current state of research on the pathogenesis of OA with special regard to the involvement of apoptosis.

The regulated cell death apoptosis enables redundant or compromised cells in ontogeny and homeostasis to remove themselves receptor-dependent after extrinsic signaling or after internal stress by BCL-2 proteins on the outer mitochondrial membrane (OMM). Mitochondrial BCL-2 proteins are also often needed for receptor-mediated signaling in apoptosis. Then, the truncated BH3-only protein BID (tBID) blocks retrotranslocation of the pro-apoptotic BCL-2 proteins BAX and BAK from the mitochondria into the cytosol. BAX and BAK in turn permeabilize the OMM. Although the BCL-2 proteins are controlled by a complex regulatory network, a specific mechanism for the inhibition of tBID remained unknown. Curiously, it was suggested that hexokinases, which channel glucose into the metabolism, have an intriguing function in the regulation of apoptosis. Recent analysis of transient hexokinase interactions with BAX revealed its participation in the inhibition of BAX and also BAK by retrotranslocation from mitochondria to the cytosol. In contrast to general apoptosis inhibition by anti-apoptotic BCL-2 proteins, hexokinase I and hexokinase 2 specifically inhibit tBID and thus the mitochondrial apoptosis pathway in response to death receptor signaling. Mitochondrial hexokinase localization and BH3 binding of cytosolic hexokinase domains are prerequisites for protection against receptor-mediated cell death, whereas glucose metabolism is not. This mechanism protects cells from apoptosis induced by cytotoxic T cells.

Current lifestyles are leading to a worldwide increase in metabolic liver diseases that favor the development of liver disease. Changes in hepatocytes are caused by altered lipid concentrations, oxidative stress or toxicity by individual lipids. The complexity of the underlying processes and differences of the pathology to proposed rodent models makes the development of an effective targeted therapy difficult. The lipid mobilization that occurs in dairy cows in the postpartum period could be a natural model for the metabolic stress commonly observed in the development of liver diseases. We therefore used gas chromatography and histopathological staining techniques to analyze lipid patterns in diparous and multiparous cows during the peripartum period. The most striking change in lipid composition is the homogenous increase in palmitoleic acid (C16:1n7) content in all cows around the time of calving, with multiparous cows exhibiting consistently higher C16:1n7 levels by the end of the study. Elevated C16:1n7 levels have a potential key role in the development of non-alcoholic steatohepatitis (NASH) and tumorigenesis in the liver. Changes in C16:1n7, therefore, support the idea that lipid mobilization in dairy cows could serve as model for various liver diseases, such as nonalcoholic fatty liver disease (NAFLD) or NASH development.

Research on laboratory and domestic animals is a key element of current biomedical research. Animal 9 models offer more insights into disease mechanisms than in vitro and in silico models, and can help 10 bypass ethical and legal hurdles associated with human clinical trials. To be useful, an animal model 11 must replicate the pathology of the human disease. Some animal models, especially rodent models, can 12 fall short because they mimic only certain facets of a pathology. The reasons for the potentially low 13 translational relevance of laboratory animals are manifold and include, beside sheer differences 14 in size, histological, functional, and behavioral characteristics that are not shared with humans.Human activities alter the nutrition and living environments of many mammals, in particular those 16 of domestic animals as dogs, cats, pigs, and cattle. It's therefore not surprising that humans and 17 domestic or farm animals share a number of diseases, including those due to cell degeneration. 18Disorders like neurodegenerative diseases and cancers are becoming increasingly important to our 19 domestic animals, and studying them can help to better understand human diseases. This special 20 issue's articles (3 original research papers, a perspective, and 3 review articles) delve into the 21 different aspects of these fascinating translational connections. We anticipate that this collection will 22 help shape unifying concepts and clear the path for future progress. 23Vogel and colleagues studied the fatty acid (FA) composition in the liver fat of German Holstein cows 24 by comparing cows in their second lactation and those that had three or more lactations and examining 25 differences in the periparturient phase, which ranges from two weeks before to two weeks after 26 parturition. The most important results highlight significant differences in the FA C16:1n7 and 27 polyunsaturated FA (PUFA) content in triacylglycerol (TAG) and free FAs. Therefore, the number of 28 lactations influences the FA composition in the liver fat of cows. In particular, younger cows have a 29 more favorable profile of beneficial FAs in the early postpartum period. These findings will aid 30 understanding of dairy cows' metabolic adaptations and inspire research into the role of fat metabolism 31 in hepatocyte damage and liver disease. 32Baalmann and colleagues studied the role of P2RY14, a UDP-glucose receptor, in kidney function.They focused on its effects on urine volume and sphingolipid metabolism in mice. P2ry14-deficient 34 mice had significantly lower urine volumes compared to the wild type, which was not attributed to 35 differences in urine osmolality and thus impaired water reabsorption. Quantitative analysis revealed 36 changes in the number and structure of glomeruli in the area, indicating that P2RY14 is involved in 37 maintaining kidney structure. Key differences in sphingolipid species suggests that P2RY14 influences 38 kidney lipid metabolism. Overall, the results highlight the importance of P2RY14 for kidney health: it 39 affects urine production, kidney structure, and sphingolipid metabolism. 40 Mitochondrial apoptosis appears to exert a significant influence and has been identified as an 51 underlying cause in diseases such as the autoimmune illness Sjögren's syndrome. The results of these 52 studies could offer new therapeutic and/or regenerative approaches for salivary gland diseases. 53In their comprehensive review of osteoarthritis (OA) in small animals, Theyse and Mazur emphasize 54 the impact of this debilitating disease. OA is characterized by degradation of the articular cartilage, 55 inflammation of the synovial membrane, and changes in the subchondral bone. These changes cause 56 pain, hinder movement, and reduce the quality of life of affected animals. Adipokines derived from 57 adipose tissue, such as leptin, influence inflammation and cartilage metabolism. Dogs and cats can 58 serve as valuable models for the study of obesity and OA, particularly with regard to the implications 59 of adipokine interactions. This approach could lead to more effective treatments and improve our 60 understanding of disease mechanisms. 61Complementarily, Jia and colleagues explored the protective role of irisin, a myokine induced by 62 exercise, against chondrocyte pyroptosis in OA, using a rat model. The study identified genes that are 63 differentially expressed in response to exercise in Sprague-Dawley rats using the GSE74898 dataset. 64The authors identified a total of 389 overlapping genes, suggesting modulation of inflammatory 65 responses in chondrocytes by exercise. Significant downregulation of irisin levels was observed in the 66 damaged areas of articular cartilage in patients with knee OA. Irisin could therefore play a protective 67 role in maintaining cartilage integrity. In rats that underwent treadmill training, knee joint inflammation 68 and cell death markers decreased, while histological values improved. and treatment are crucial. The author emphasizes that knowing the immunogenic properties of 87 chlamydial proteins is key to developing vaccine candidates. Understanding chlamydial infections in 88 pigs better, including how they spread and the immune system's response, will improve animal health 89 and reduce the risk of transmission to humans. 90