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Background: The G protein-coupled receptor 55 (GPR55) is part of an expanded endocannabinoid system (ECS), and plays a pro-tumorigenic role in different cancer models, including pancreatic cancer. Next to cancer cells, various cells of the immune tumor microenvironment (TME) express receptors of the ECS that critically determine tumor growth. The role of GPR55 in cancer cells has been widely described, but its role in the immune TME is not well understood., Methods: We intended to uncover the role of GPR55 in tumor immunity in a model of pancreatic ductal adenocarcinoma (PDAC). To this end, a KPCY tumor cell line or a GPR55-overexpressing KPCY cell line (KPCY55) from murine PDAC were subcutaneously injected into wildtype (WT) and GPR55 knockout (KO) mice, and immune cell populations were evaluated by flow cytometry., Results: Deficiency of GPR55 in the TME led to reduced tumor weight and volume, and altered the immune cell composition of tumors, favoring an anti-tumorigenic environment by increasing the number of CD3 + T cells, particularly CD8 + T cells, and the expression of PDL1 on macrophages. RNA-seq pathway analysis revealed higher T cell activity in KPCY55 tumors of GPR55 KO vs. WT mice. In addition, tumors from GPR55 KO mice displayed increased levels of T cell chemokines Cxcl9 and Cxcl10. Migration of T cells from GPR55 KO mice towards CXCL9 was increased in comparison to T cells from WT mice, suggesting that a CXCR3/CXCL9 axis was involved in T cell influx into tumors of GPR55 KO mice. Notably, anti-PD-1 immunotherapy increased tumor burden in WT mice, while this effect was absent in the GPR55 KO mice., Conclusion: Our study indicates that GPR55 in TME cells may drive tumor growth by suppressing T cell functions, such as migration, in a model of PDAC, making it an interesting target for immunotherapies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2025 Ristić, Bärnthaler, Gruden, Kienzl, Danner, Herceg, Sarsembayeva, Kargl and Schicho.)

Chronic kidney disease (CKD) is often associated with decreased activity of lecithin-cholesterol acyltransferase (LCAT), an enzyme essential for HDL maturation. This reduction in LCAT activity may potentially contribute to an increased risk of cardiovascular mortality in patients with CKD. The objective of this study was to investigate the association between LCAT activity in patients with CKD and the risk of adverse outcomes. We measured serum LCAT activity and characterized lipoprotein profiles using nuclear magnetic resonance spectroscopy in 453 non-dialysis CKD patients from the CARE FOR HOMe study. LCAT activity correlated directly with smaller HDL particle size, a type of HDL potentially linked to greater cardiovascular protection. Over a mean follow-up of 5.0 ± 2.2 years, baseline LCAT activity was inversely associated with risk of death (standardized HR 0.62, 95% CI 0.50-0.76; P < 0.001) and acute decompensated heart failure (ADHF) (standardized HR 0.67, 95% CI 0.52-0.85; P = 0.001). These associations remained significant even after adjusting for other risk factors. Interestingly, LCAT activity was not associated with the incidence of atherosclerotic cardiovascular events or kidney function decline during the follow-up. To conclude, our findings demonstrate that low LCAT activity is independently associated with all-cause mortality and ADHF in patients with CKD, and is directly linked to smaller, potentially more protective HDL subclasses., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Macrophage dysfunction is a common feature of inflammatory disorders such as asthma, which is characterized by a strong circadian rhythm., Methods and Results: We monitored the protein expression pattern of the molecular circadian clock in human peripheral blood monocytes from healthy, allergic, and asthmatic donors during a whole day. Monocytes cultured of these donors allowed us to examine circadian protein expression in human monocyte-derived macrophages, M1- and M2- polarized macrophages. In monocytes, particularly from allergic asthmatics, the oscillating expression of circadian proteins CLOCK, BMAL, REV ERBs, and RORs was significantly altered. Similar changes in BMAL1 were observed in polarized macrophages from allergic donors and in tissue-resident macrophages from activated precision cut lung slices. We confirmed clock modulating, anti-inflammatory, and lung-protective properties of the inverse ROR agonist SR1001 by reduced secretion of macrophage inflammatory protein and increase in phagocytosis. Using a house dust mite model, we verified the therapeutic effect of SR1001 in vivo ., Discussion: Overall, our data suggest an interaction between the molecular circadian clock and monocytes/macrophages effector function in inflammatory lung diseases. The use of SR1001 leads to inflammatory resolution in vitro and in vivo and represents a promising clock-based therapeutic approach for chronic pulmonary diseases such as asthma., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Teppan, Schwanzer, Rittchen, Bärnthaler, Lindemann, Nayak, Reiter, Luschnig, Farzi, Heinemann and Sturm.)

Pulmonary function testing (PFT) in mice includes biomechanical assessment of lung function relevant to physiology in health and its alteration in disease, hence, it is frequently used in preclinical modeling of human lung pathologies. Despite numerous reports of PFT in mice of various ages, there is a lack of reference data for developing mice collected using consistent methods. Therefore, we profiled PFTs in male and female C57BL/6J mice from 2 to 23 wk of age, providing reference values for age- and sex-dependent changes in mouse lung biomechanics during development and young adulthood. Although males and females have similar weights at birth, females weigh significantly less than males after 5 wk of age ( P < 0.001) with largest weight gain observed between 3 and 8 wk in females and 3 and 13 wk in males, after which weight continued to increase more slowly up to 23 wk of age. Lung function parameters including static compliance and inspiratory capacity also increased rapidly between 3 and 8 wk in female and male mice, with male mice having significantly greater static compliance and inspiratory capacity than female mice ( P < 0.001). Although these parameters appear higher in males at a given age, allometric scaling showed that static compliance and inspiratory compliance were comparable between the two sexes. This suggests that differences in measurements of lung function are likely body weight-based rather than sex-based. We expect these data to facilitate future lung disease research by filling a critical knowledge gap in our field. NEW & NOTEWORTHY This study provides reference values for changes in mouse lung biomechanics from 2 to 23 wk of age. There are rapid developmental changes in lung structure and function of male and female mice between the ages of 3 and 8 wk. Male mice become noticeably heavier than female mice at or about 5 wk of age. We identified that differences in normal lung function measurements are likely weight-based, not sex-based.

COVID-19, caused by the SARS-CoV-2 coronavirus, emerged as a global pandemic in late 2019, resulting in significant global public health challenges. The emerging evidence suggests that diminished high-density lipoprotein (HDL) cholesterol levels are associated with the severity of COVID-19, beyond inflammation and oxidative stress. Here, we used nuclear magnetic resonance spectroscopy to compare the lipoprotein and metabolic profiles of COVID-19-infected patients with non-COVID-19 pneumonia. We compared the control group and the COVID-19 group using inflammatory markers to ensure that the differences in lipoprotein levels were due to COVID-19 infection. Our analyses revealed supramolecular phospholipid composite (SPC), phenylalanine, and HDL-related parameters as key discriminators between COVID-19-positive and non-COVID-19 pneumonia patients. More specifically, the levels of HDL parameters, including apolipoprotein A-I (ApoA-I), ApoA-II, HDL cholesterol, and HDL phospholipids, were significantly different. These findings underscore the potential impact of HDL-related factors in patients with COVID-19. Significantly, among the HDL-related metrics, the cholesterol efflux capacity (CEC) displayed the strongest negative association with COVID-19 mortality. CEC is a measure of how well HDL removes cholesterol from cells, which may affect the way SARS-CoV-2 enters cells. In summary, this study validates previously established markers of COVID-19 infection and further highlights the potential significance of HDL functionality in the context of COVID-19 mortality.

Background: Major cardiac surgery related blood loss is associated with increased postoperative morbidity and mortality. Platelet dysfunction is believed to contribute to post-cardiopulmonary bypass (CPB)-induced microvascular bleeding. We hypothesised that moderately hypothermic CPB induces platelet dysfunction and that supplemental fibrinogen can restore in vitro thrombus formation., Methods: Blood from 18 patients, undergoing first-time elective isolated aortic valve surgery was drawn before CPB, 30 min after initiation of CPB, and after CPB and protamine administration, respectively. Platelet aggregation was quantified by optical aggregometry, platelet activation by flow-cytometric detection of platelet surface expression of P-selectin, annexin V, and activated glycoprotein IIb/IIIa, thrombus formation under flow and effect of supplemental fibrinogen (4 mg ml -1 ) on in vitro thrombogenesis., Results: Post-CPB adenosine-diphosphate and TRAP-6-induced aggregation decreased by 40% and 10% of pre-CPB levels, respectively (P<0.0001). Although CPB did not change glycoprotein IIb/IIIa receptor expression, it increased the percentage of unstimulated P-selectin (1.2% vs 7%, P<0.01) positive cells and annexin V mean fluorescence intensity (15.5 vs 17.2, P<0.05), but decreased percentage of stimulated P-selectin (52% vs 26%, P<0.01) positive cells and annexin V mean fluorescence intensity (508 vs 325, P<0.05). Thrombus area decreased from 6820 before CPB to 5230 after CPB (P<0.05, arbitrary units [a.u.]). Supplemental fibrinogen increased thrombus formation to 20 324 and 11 367 a.u. before CPB and after CPB, respectively (P<0.001), thereby restoring post-CPB thrombus area to levels comparable with or higher than pre-CPB baseline., Conclusions: Single valve surgery using moderately hypothermic CPB induces partial platelet dysfunction. Thrombus formation was restored in an experimental study design by ex vivo supplementation of fibrinogen., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive disorder of unknown origin and the most common interstitial lung disease. It progresses with the recruitment of fibroblasts and myofibroblasts that contribute to the accumulation of extracellular matrix (ECM) proteins, leading to the loss of compliance and alveolar integrity, compromising the gas exchange capacity of the lung. Moreover, while there are therapeutics available, they do not offer a cure. Thus, there is a pressing need to identify better therapeutic targets. With the advent of transcriptomics, proteomics, and metabolomics, the cellular mechanisms underlying disease progression are better understood. Metabolic homeostasis is one such factor and its dysregulation has been shown to impact the outcome of IPF. Several metabolic pathways involved in the metabolism of lipids, protein and carbohydrates have been implicated in IPF. While metabolites are crucial for the generation of energy, it is now appreciated that metabolites have several non-metabolic roles in regulating cellular processes such as proliferation, signaling, and death among several other functions. Through this review, we succinctly elucidate the role of several metabolic pathways in IPF. Moreover, we also discuss potential therapeutics which target metabolism or metabolic pathways., Competing Interests: Declaration of Competing Interest The authors have no conflict of interests to declare., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Idiopathic pulmonary fibrosis (IPF) is a progressive and ultimately fatal disease. Recent findings have shown a marked metabolic reprogramming associated with changes in mitochondrial homeostasis and autophagy during pulmonary fibrosis. The microRNA-33 (miR-33) family of microRNAs (miRNAs) encoded within the introns of sterol regulatory element binding protein (SREBP) genes are master regulators of sterol and fatty acid (FA) metabolism. miR-33 controls macrophage immunometabolic response and enhances mitochondrial biogenesis, FA oxidation, and cholesterol efflux. Here, we show that miR-33 levels are increased in bronchoalveolar lavage (BAL) cells isolated from patients with IPF compared with healthy controls. We demonstrate that specific genetic ablation of miR-33 in macrophages protects against bleomycin-induced pulmonary fibrosis. The absence of miR-33 in macrophages improves mitochondrial homeostasis and increases autophagy while decreasing inflammatory response after bleomycin injury. Notably, pharmacological inhibition of miR-33 in macrophages via administration of anti-miR-33 peptide nucleic acids (PNA-33) attenuates fibrosis in different in vivo and ex vivo mice and human models of pulmonary fibrosis. These studies elucidate a major role of miR-33 in macrophages in the regulation of pulmonary fibrosis and uncover a potentially novel therapeutic approach to treat this disease.

People with diabetes have an increased risk of experiencing adverse COVID-19 outcomes. COVID-19 vaccination is, therefore, highly recommended. However, people with diabetes have an inherently elevated risk of thrombotic events and the impact of the vaccination on the coagulation system in this patient population remains to be elucidated. The aim of this study was to investigate the impact of COVID-19 vaccination on the haemostatic system in people with type 1 or type 2 diabetes. We evaluated the effects of COVID-19 vaccination (BioNTech Pfizer, Moderna, AstraZeneca) on standard coagulation parameters, whole blood coagulation (Thrombelastometry), platelet function (impedance aggregation), and thrombin generation (calibrated automated thrombography) in people with type 1 diabetes mellitus ( n = 41) and type 2 diabetes mellitus ( n = 37). Blood sampling points were prior to vaccination and two weeks after the respective vaccination. Thrombelastometry measurements indicated moderately increased clot formation post-vaccination in people with type 1, as well as with type 2, diabetes: "Clot formation times" were significantly shorter, and both "maximum clot firmness" and "alpha angles" were significantly higher, as compared to the respective pre-vaccination values. Therefore, TEM parameters were not altered after vaccination in patients receiving ASA. Moreover, platelet aggregation was enhanced in people with type 1 diabetes, and plasma levels of D-Dimer were increased in people with type 2 diabetes, following COVID-19 vaccination. All other standard coagulation parameters, as well as thrombin generation, were not affected by the vaccination. The coagulation responses of people with diabetes to COVID-19 vaccination were only subclinical and comparable to those observed in healthy individuals. Our findings suggest that people with diabetes do not face an increased activation of the coagulation post-vaccination.