Ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1) is a critical deubiquitinating enzyme that is highly expressed in the central nervous system, where it participates in protein degradation and turnover as part of the ubiquitin–proteasome system (UPS). Convincing evidence supports the role of UCH-L1 dysfunction in several neurodegenerative disorders, given its unique position at the crossroad of several aetiopathogenic pathways, including those implicated in Alzheimer’s disease (AD) onset. Indeed, UCH-L1 depletion correlates with decreased levels of triggering receptor expressed on myeloid cells 2 (TREM2), with consequent effects on neuroinflammation. Notably, UCH-L1 can affect the level of phosphorylated tau protein, thus contributing to the formation of neurofibrillary tangles (NFTs). In addition, UCH-L1 influences β-Secretase 1 (BACE1) expression, resulting in the abnormal accumulation of amyloid-β plaques in brain parenchyma. These findings underline UCH-L1’s centrality in maintaining the homeostasis of protein folding and aggregation, which are significantly impaired in AD and AD-related dementias. Given these assumptions, UCH-L1 is recognized as a potential biomarker for AD, highlighting its relevance in governing the fate of crucial pathological mediators of cognitive impairment and neurodegeneration. Herein, we contextualize the involvement of UCH-L1 in different dementia-associated pathways and summarize the state of the art of UCH-L1 as a biomarker for AD diagnosis.

Advanced glycation end products (AGEs) exert a key pathogenic role in the development of obesity and insulin resistance. Thanks to its abundance in bioactive compounds, the microalga Arthrospira platensis (spirulina, SP) is proposed as a nutritional supplement. Here, we investigated the potential anti-glycating properties of SP enriched with zinc (Zn-SP) and the following impact on diet-induced metabolic derangements. Thirty male C57Bl6 mice were fed a standard diet (SD) or a high-fat high-sugar diet (HFHS) for 12 weeks, and a subgroup of HFHS mice received 350 mg/kg Zn-SP three times a week. A HFHS diet induced obesity and glucose intolerance and increased plasma levels of pro-inflammatory cytokines and transaminases. Zn-SP administration restored glucose homeostasis and reduced hepatic dysfunction and systemic inflammation. In the liver of HFHS mice, a robust accumulation of AGEs was detected, paralleled by increased expression of the main AGE receptor (RAGE) and depletion of glyoxalase-1, whereas Zn-SP administration efficiently prevented these alterations reducing local pro-inflammatory responses. 16S rRNA gene profiling of feces and ileum content revealed altered bacterial community structure in HFHS mice compared to both SD and HFHS + Zn-SP groups. Overall, our study demonstrates relevant anti-glycation properties of Zn-SP which contribute to preventing AGE production and/or stimulate AGE detoxification, leading to the improvement of diet-related dysbiosis and metabolic derangements.

Neuropeptide Y (NPY) is a key regulator of energy homeostasis, acting through various receptor subtypes in both central and peripheral systems. Increasing interest has been directed toward exploiting NPY as a pharmacological target in obesity. While the orexigenic role of NPY in the hypothalamus is well established, its downstream effects on peripheral metabolism remain less defined, particularly when perturbations to the system are introduced. Previously, we observed that female mice with limbic NPY-Y1 receptor gene (Npy1r) knockout (KO) under different dietary conditions (standard, SD, or high-fat diet, HFD) accumulated more subcutaneous white adipose tissue (WAT) compared to wild-type in the absence of gonadal hormones, despite no changes in food intake. To deepen the mechanisms underlying these effects, we conducted molecular analyses on WAT of these mice. We found that Npy gene expression was upregulated in WAT of HFD-fed mice, regardless of genotype. However, NPY peptide levels were reduced in both KO and HFD groups, suggesting post-transcriptional regulation of NPY under metabolic stress. NPY-Y2 receptor gene (Npy2r) expression in WAT was significantly increased in both KO and HFD while Npy1r expression in WAT remained unchanged across groups. Genes involved in WAT metabolism were similarly upregulated in both KO and HFD mice, indicating that limbic Npy1r KO mimics some of the metabolic effects induced by HFD. Correlation analysis suggests that dysregulated NPY signalling may promote increased lipid storage and reduce energy expenditure. Overall, these findings highlight the complex interplay between central and peripheral NPY signalling emphasizing the importance of caution when investigating therapeutic strategies targeting single NPY receptors. Overall, these findings highlight the complex interplay between central Npy1r signalling and peripheral adipose tissue regulation. They also emphasize the importance of caution when investigating new therapeutic strategies targeting single NPY receptors, as central interventions may provoke maladaptive metabolic responses in peripheral tissues.

Sepsis-associated encephalopathy (SAE) is a diffuse dysfunction of the central nervous system and a major manifestation of sepsis, associated with acute clinical deterioration and poor prognosis. Despite advances in understanding its pathophysiology and sepsis-induced cerebral alterations, effective pharmacological treatments remain unavailable. Cyclin-dependent kinase 9 (CDK9) is a ubiquitous kinase implicated in several inflammatory processes, however, its role in sepsis remains poorly understood. This study investigated whether CDK9 activity contributes to SAE pathophysiology and whether its pharmacological inhibition confers protection in a clinically relevant sepsis model. Polymicrobial sepsis was induced in male C57BL/6OlaHsd mice using caecal ligation and puncture (CLP). One hour after the procedure, mice received the selective CDK9 inhibitor LDC000067 (50 mg/kg i.v.) or vehicle. At 24 h, sepsis induced marked CDK9 activation in the prefrontal cortex, accompanied by neuroinflammation, evidenced by microglial activation, and blood-brain barrier (BBB) disruption, reflected by increased plasma neurofilament light chain levels. Treatment with LDC000067 attenuated septic alterations both centrally and peripherally, reducing multiorgan dysfunction, the systemic cytokine storm, and clinical severity. In vitro, exposure of human microglial cells to a sepsis-like inflammatory stimulus increased NF-κB-related transcriptional responses, which were significantly reduced by CDK9 inhibition. Similarly, exposure of brain microvascular endothelial cells to the same stimulus resulted in endothelial barrier dysfunction, mitigated by CDK9 inhibition through preservation of claudin-5 expression and barrier integrity. Altogether, these findings identify a previously unreported role for CDK9 in SAE pathogenesis and show that its pharmacological inhibition attenuates key features of SAE, including microglial activation and BBB disruption.

Chronic low-grade inflammation (metaflammation) is a key contributor to obesity-associated metabolic disorders and their cardiovascular complications. This study investigated the effects of CXT29, a novel dual cyclooxygenase-2 (COX-2) inhibitor and thromboxane prostanoid receptor (TP) antagonist, in comparison with its parent compound etodolac, in a murine model of diet-induced metabolic dysfunction. Four-week-old male C57BL/6 mice were fed either a standard diet or a high-fat diet for 18 weeks and subsequently treated with etodolac (20 mg/kg/day) or CXT29 (25 mg/kg/day) by oral gavage for 5 weeks. High-fat-diet-fed mice developed increased body weight, impaired glucose tolerance, altered circulating metabolic hormones, liver dysfunction, steatosis, inflammatory cell infiltration, and systemic inflammation. Both treatments attenuated systemic inflammation and improved the metabolic alterations induced by the obesogenic diet. Notably, CXT29, but not etodolac, attenuated the increase in circulating plasminogen activator inhibitor-1 (PAI-1), a biomarker associated with cardiovascular risk. These findings indicate that pharmacological inhibition of COX-2 improves metabolic dysfunction associated with diet-induced obesity. Furthermore, the additional TP antagonism provided by CXT29 does not compromise the metabolic benefits associate with COX-2 inhibition, while displaying a distinct effect on circulating PAI-1, supporting further investigation of this dual-target approach in obesity-associated metabolic dysfunction.