Dysfunctional adipose tissue (AT) in the context of obesity promotes a chronic inflammatory state, associated with worse cancer progression and prognosis. Interleukin (IL)-36γ is a proinflammatory factor increased in obesity. The aim was to analyse the role of IL-36γ in colon cancer (CC) development in patients with obesity. Samples obtained from 74 volunteers (27 with normal weight (NW) and 47 with obesity (OB)) were used in a case–control study. Participants were also subclassified according to the presence of CC (45 without and 29 with CC). HT-29 cells were treated with pro-inflammatory factors, adipocyte conditioned media (ACM) and IL-36γ to evaluate the expression levels of inflammation- and extracellular matrix (ECM) remodelling-related molecules. Increased gene expression levels of IL36G and IL36R in visceral AT from patients with OB and CC were found. Moreover, mRNA levels of IL36G were significantly associated with the gene expression levels of its receptor and relevant genes involved in AT inflammation (ASC, IL1B and NLRP6). Consistently, IL36G expression was upregulated by hypoxia, inflammation-related factors (LPS, TNF-α and leptin) and by the adipocyte secretome from patients with obesity in HT-29 cancer cells. Furthermore, we revealed that IL-36γ increased the gene expression levels of inflammation-related genes (IL36G, IL1 A, IL1B, IL6, IL8 and NGAL) as well as ECM markers (MMP9, SPP1 and TNC) in HT-29 cells. Increased gene expression levels of IL36G in VAT from patients with OB and CC may promote a pro-inflammatory microenvironment favourable for tumour progression and migration.Key messagesObesity and colon cancer increase gene expression levels of IL36G and IL36R in visceral adipose tissue.Hypoxia, inflammation-related factors and the adipocyte secretome from patients with obesity upregulate mRNA levels of IL36G in HT-29 cancer cells.IL-36γ increase the gene expression levels of inflammation-related genes (IL36G, IL1A, IL1B, IL6, IL8 and NGAL) as well as ECM markers (MMP9, SPP1 and TNC) in HT-29 cells.

The relationship between rheumatic diseases (RDs) and endothelial dysfunction (ED) is intricate and multifaceted, with chronic inflammation and immune system dysregulation playing key roles. RDs, including Osteoarthritis (OA), Rheumatoid arthritis (RA), Systemic Lupus erythematosus (SLE), Ankylosing spondylitis (AS), Psoriatic arthritis (PsA), Sjogren’s syndrome (SS), Systemic sclerosis (SSc), Polymyalgia rheumatica (PMR) are characterized by chronic inflammation and immune dysregulation, leading to ED. ED is marked by reduced nitric oxide (NO) production, increased oxidative stress, and heightened pro-inflammatory and prothrombotic activities, which are crucial in the development of cardiovascular disease (CVD) and systemic inflammation. This association persists even in RD patients without conventional cardiovascular risk factors, suggesting a direct impact of RD-related inflammation on endothelial function. Studies also show that ED significantly contributes to atherosclerosis, thereby elevating cardiovascular risk in RD patients. This review synthesizes the molecular mechanisms connecting major RDs and ED, highlighting potential biomarkers and therapeutic targets. Ultimately, the review aims to enhance understanding of the complex interactions leading to ED in rheumatic patients and inform strategies to mitigate cardiovascular risks and improve patient outcomes.

The human chloride channel regulator, calcium-activated (CLCA) 4 is discussed as a driver of epithelial-to-mesenchymal transition as well as a biomarker for colorectal cancer (CRC) and ulcerative colitis. In contrast to humans, the Clca4 gene is duplicated in the mouse, a common model species to study gene functions. However, the relevance of the functional murine Clca4 variants in healthy and diseased intestine is largely unknown. Here, we characterized the spatiotemporal expression patterns of the murine Clca4a and Clca4b genes in the healthy intestinal tract as well as in dextran sulfate sodium (DSS)-induced colitis and colitis-associated colon cancer (CAC) mouse model using RT-qPCR and in situ-hybridization. Similarly, we analyzed expression of the human CLCA4 in healthy, inflamed and cancerous intestinal tracts at single cell level. Murine Clca4a and -4b but not the human CLCA4 were detected in small intestine enterocytes of the respective species. Conversely, healthy colonocytes expressed the human CLCA4 and its murine ortholog Clca4a but not the murine Clca4b. Under inflammatory conditions, de novo expression of Clca4b was observed with both murine homologs abundantly expressed in enterocytes adjacent to ulcerations. Neoplastic colonocytes expressed none or only minimal amounts of the CLCA4 homologs both in humans and mice, whereas adjacent non-neoplastic colonocytes strongly up-regulated the human or both murine homologs, respectively. Our results suggest marked species- and homolog-specific differences in the expression patterns of the three CLCA4 homologs. Moreover, all three seem to play a role in reactive, non-neoplastic colonocytes adjacent to ulcerated and neoplastic lesions.Key messagesHuman CLCA4 and murine Clca4a, but not Clca4b, are expressed in healthy colonocytes.Inflammation leads to a de novo expression of the murine Clca4b in colonocytes.Human and murine CLCA4 homologs are absent from neoplastic enterocytes.Human and murine CLCA4s are highly expressed in tumor-adjacent, reactive colonocytes.

Neuroblastoma (NB) is a formidable challenge in pediatric oncology due to its intricate molecular landscape, necessitating multifaceted therapeutic approaches. ONC201 is an imipridone antibiotic compound with a promising drug candidate leveraging its potent anticancer properties against the mitochondrial proteases ClpP and ClpX. Despite demonstrating early clinical promise, particularly in MYCN-amplified NB, its efficacy in non-MYCN-amplified NB remains a subject worthy of investigation. In this study, we extended the coverage of ONC201 to treat non-MYCN-amplified NB, and our data implicated ONC201’s inability to reduce tumor growth in animal models harboring SK-N-AS or SK-N-FI cell lines. Interestingly, ONC201 induced the expression of oncogenic markers c-Myc and LGR5 while downregulating the tumor suppressor ATRX. While it fails to attenuate tumor neovascularization in non-MYCN-amplified NB xenografts, its effectiveness differs from that of its MYCN-amplified counterpart. Rho zero (ρ0)-SK-N-AS cells treated with ONC201 showed comparable observed trends in parental SK-N-AS cells, including LGR5 upregulation and ATRX downregulation, suggesting that ONC201’s multifaceted actions extend beyond mitochondrial targets. Our elucidation highlights the need to discern molecular signatures when deploying ONC201 monotherapy against NB, which lacks MYCN-amplification.

Tuberculous mycobacterial infections pose a substantial global health burden because of their prevalence and multi-drug resistance. The current approach to tackling these infections primarily involves developing new antibiotics or combining existing ones, an approach that often proves ineffective in the specific targeting of mycobacteria.We investigated the effect of sphingosine on tuberculous Mycobacteria in vitro and mycobacterial infections in vivo to test whether sphingosine could potentially be used as a novel drug against tuberculosis. Sphingosine inhibited mycobacterial growth and eradicated mycobacteria in vitro. Mechanistically, sphingosine increased bacterial membrane permeability and induced marked changes on the bacterial plasma membrane evidenced by electron microscopy studies. Administration of sphingosine in a mouse model of pulmonary infection with Bacillus Calmette–Guérin (BCG) greatly reduced the number of bacteria in the lung and prevented pulmonary inflammation. Furthermore, infection of ex vivo human lung tissue samples with BCG and treatment with sphingosine showed that sphingosine also kills BCG in human bronchi. Our findings suggest that sphingosine may be a potential therapeutic intervention against mycobacterial infections.Key messagesSphingosine inhibits mycobacterial growth in vitro.Sphingosine disrupts bacterial membrane integrity.Sphingosine reduces bacterial load in mouse pulmonary infection model.Sphingosine eradicates mycobacteria in human bronchi ex vivo.

Wilson disease (WD) is a potentially fatal metabolic disorder caused by the inactivation of the copper (Cu) transporter ATP7B, resulting in systemic Cu overload and fibroinflammatory liver disease. The molecular mechanism and effects of elevated Cu on cytoskeletal dynamics in liver fibrogenesis are not clear. Here, we tested the regulation of hepatic cytoskeleton and fibrogenesis with respect to Cu overload in WD. Atp7b−/− (knockout) mice with established liver disease, hepatocyte-specific Atp7b△Hep knockout mice without fibroinflammatory disease, and the age-and sex-matched controls were compared using Western blotting, real-time quantitative reverse transcription PCR (qRT-PCR), immunohistochemical (IHC) staining and transcriptomics (RNA-sequencing) analysis. In Atp7b−/− mice with developed liver disease, there is a significant increase in cytoskeletal protein expression with a reduction in α-tubulin acetylation. In these mice before the onset of liver pathology, no significant changes in cytoskeletal nor hepatic stellate cell activation are observed. As hepatic copper levels rise, an increase in cytoskeletal proteins with a decrease in acetylated-α-tubulin/α-tubulin ratio occurs. RNA-sequencing, qRT-PCR, and immunostaining confirm that the tubulin is upregulated at the transcriptional level and hepatocytes are the primary source of early tubulin increases before fibrosis. An increase in α-tubulin with a decrease in α-tubulin acetylation via Hdac6 and Sirt2 induction facilitates fibrosis as reflected by concomitant increases in desmin and α-SMA immunostaining in Atp7b−/− mice at 20 weeks. Moreover, strongly positive correlations between α-tubulin and α-tubulin deacetylase with the expression of liver fibrosis markers are observed in animal and human WD. Hepatocyte-specific Atp7b△Hep mice lack significant changes in tubulin as well as fibrosis despite hepatic steatosis. This study provides evidence that microtubule destabilization causes cytoskeletal rearrangement and facilitates hepatic stellate cell (HSC) activation and fibrosis in the murine model of WD.Key MessagesHepatic cytoskeleton system is induced in Wilson disease.Hepatic microtubules acetylation is dysregulated in murine Wilson disease.Microtubules destabilization is positively associated with liver fibrosis in Wilson disease.Microtubules destabilization concomitant with fibrogenesis exacerbates WD progression.

COVID-19 vaccines are crucial in reducing SARS-CoV-2 transmission and severe health outcomes. Despite widespread administration, their long-term systemic effects on human metabolism remain inadequately understood. This longitudinal study aims to evaluate IgG responses, 34 cytokines, 112 lipoproteins, and 21 low-molecular-weight metabolites in 33 individuals receiving two to four COVID-19 vaccine doses. Changes in metabolic profiles for the first 16 days post each dose of vaccine, and up to 480 days post-initial dose, were compared to baseline (before vaccination). Additionally, metabolic profiles of vaccinated participants were compared to a reference cohort of unvaccinated individuals without prior exposure to SARS-CoV-2 infection (controls) and SARS-CoV-2 cases. Positive IgG responses were observed in 78.8% (N = 26) of participants after the first dose, reaching 100% with subsequent doses. The most common side effects were localized pain at the injection site and “flu-like” symptoms, reported by > 50% of participants. Systemic side effects, e.g., sore lymph nodes, fatigue, and brain fog, were reported but showed no significant correlations to IgG responses. Transient temporal changes were observed for cytokine IP10 (CXCL10) and glutamic acid around the third vaccine dose. Compared to the reference cohort, 497 vaccinated samples (95.0%) had profiles similar to the controls, while the remaining 26 samples with prior infection exposures were similar to mild cases of SARS-CooV-2 infection. In conclusion, COVID-19 vaccination did not induce lasting changes in inflammatory and metabolic responses, nor did it induce changes similar to mild cases of SARS-CoV-2 infection. This supports the metabolic safety of the vaccine and contributes to increased vaccine confidence.Key messagesMinimal changes in inflammatory/metabolic markers up to 480 days post-vaccination.Transient increase in IP10 (CXCL10) and glutamic acid around the third dose.Post-vaccination IgG response did not alter metabolic profiles like SARS-CoV-2 cases.Our findings provide insights into the safety of repeated COVID-19 vaccinations.

Hypothermia is a condition in which body temperature falls below 35 °C, resulting from exposure to low environmental temperatures or underlying medical conditions. Postmortem examinations have revealed increased levels of fatty acids in blood and lipid droplet formation in renal tubules during hypothermia. However, the causes and implications of these findings are unclear. This study aimed to analyze the biological significance of these phenomena through lipidomics and transcriptomics analyses of specimens from emergency hypothermia patients and mouse hypothermia models. Both human hypothermia patients and murine models exhibited elevated plasma concentrations of fatty acids and their derivatives compared with controls. Hypothermic mouse kidneys displayed lipid droplet formation, with gene expression analysis revealing enhanced fatty acid uptake and β-oxidation in renal tubular cells. In primary cultured mouse renal proximal tubular cells, low temperatures increased the expression levels of Fatty acid transport protein 1 (FATP1), a fatty acid transporter, and boosted oxygen consumption via β-oxidation. Mice treated with FATP1 inhibitors showed a more rapid decrease in body temperature upon exposure to low temperatures compared with untreated mice. In conclusion, increased fatty acid uptake mediated by FATP1 in renal tubular cells plays a protective role during hypothermia.Key messagesLow temperatures increase FATP1 expression and fatty acid uptake in renal proximal tubular cells, resulting in enhanced β-oxidation.Renal proximal tubular cells play an important role in the resistance to hypothermia via lipid uptake.Maintaining renal lipid metabolism is essential for cold stress adaptation.

Abdominal aortic aneurysm (AAA) and peripheral arterial disease (PAD) are two cardiovascular diseases associated with considerable morbidity, mortality and quality of life impairment. As they are multifactorial diseases, several factors contribute to their pathogenesis, including oxidative stress and lipid peroxidation, and these may have key roles in the development of these pathologies. Alterations of the lipid metabolism and lipid profile have been reported in cardiovascular diseases but to a lesser extent in AAA and PAD. Modifications in the profile of some molecular lipid species, in particular, native phospholipid and triglyceride species were mainly reported for AAA, while alterations in the fatty acid profile were noticed in the case of PAD. Oxidized phospholipids were also reported for AAA. Although AAA and PAD have a common atherosclerotic root, lipidomics demonstrates the existence of distinct lipid. Lipidomic research regarding AAA and PAD is still scarce and should be set in motion to increase the knowledge on the lipid changes that occur in these diseases, contributing not only to the discovery of new biomarkers for diagnosis and prognosis assessment but also to tailor precision medicine in the clinical field.

A common hallmark of several neuropsychiatric conditions is an altered protein homeostasis. In this context, ubiquitination has emerged as one of the most important post-translational modifications, regulating various intracellular processes such as protein degradation, autophagy, protein activation, and protein–protein interactions. Ubiquitination can be reversed by the activity of several deubiquitinating enzymes (DUBs), and it is of utmost importance that both processes remain in balance. Understanding the extent to which this system is involved in specific brain disorders opens up new possibilities for treating a broader spectrum of patients by targeting this central hub. In recent years, the attention to one of those DUBs, called CYLD, has increased sharply, but with relatively little focus on the central nervous system (CNS): 55 results for “CYLD Brain” vs. 895 results for “CYLD” in total (NCBI Pubmed search, 17.01.2025). Thus, we aim to provide a first overview of the new findings from the past decade specifically related to the role of CYLD in the physiology and pathology of the CNS.