Stard1 promotes cholestatic liver injury and disease progression by sensitizing to bile acid hepatotoxicity.

Background And Aims: Cholestatic liver diseases (CLD) are often accompanied by hepatocellular injury, fibrosis, and cirrhosis due to the intracellular accumulation of solutes that cannot be excreted into bile, including bile acids (BAs). These are synthesized in hepatocytes from cholesterol mainly via the classic pathway and in a lower proportion through the mitochondrial acidic pathway. The latter requires STARD1-dependent cholesterol transport to the mitochondrial inner membrane for metabolism, whose contribution to BA-induced hepatotoxicity and CLD is unknown.

ApoB100 Remodeling and Stiffened Cholesteryl Ester Core Raise LDL Aggregation in Familial Hypercholesterolemia Patients.

Patients with familial hypercholesterolemia (FH) exhibit a significant residual cardiovascular risk. A new cardiovascular risk factor is the susceptibility of individual LDL particles to aggregation. This study examined LDL aggregation and its relationship with LDL lipid composition and biophysical properties in patients with FH compared to controls.

Targeting LDL aggregation decreases atherosclerotic lipid burden in a humanized mouse model of familial hypercholesterolemia: Crucial role of ApoB100 conformational stabilization.

Background And Aims: Low-density lipoprotein (LDL) aggregation is nowadays considered a therapeutic target in atherosclerosis. DP3, the retro-enantio version of the sequence Gly-Cys of LRP1, efficiently inhibits LDL aggregation and foam cell in vitro formation. Here, we investigate whether DP3 modulates atherosclerosis in a humanized ApoB100, LDL receptor (LDLR) knockout mice (LdlrhApoB100 Tg) and determine the potential LDL-related underlying mechanisms.

Palmitoylcarnitine impairs immunity in decompensated cirrhosis.

Background & Aims: In patients with cirrhosis, acute decompensation (AD) correlates with a hyperinflammatory state driven by mitochondrial dysfunction, which is a significant factor in the progression toward acute-on-chronic liver failure (ACLF). Elevated circulating levels of acylcarnitine, indicative of mitochondrial dysfunction, are predictors of mortality in ACLF patients. Our hypothesis posits that acylcarnitines not only act as biomarkers, but also actively exert detrimental effects on circulating immune cells.

Validation of ZIP4 as a tumour-associated antigen for nanotargeting.

Pancreatic ductal adenocarcinoma remains a highly aggressive and untreatable cancer. There is a need to develop a new PDAC-associated antigen-targeting drug delivery system to tackle this disease. We validated choosing ZIP4 as a putative target in PDAC theranostics.

Differentiation and Growth-Arrest-Related lncRNA (): Initial Characterization in Human Smooth Muscle and Fibroblast Cells.

Vascular smooth muscle cells (SMCs) can transition between a quiescent contractile or "differentiated" phenotype and a "proliferative-dedifferentiated" phenotype in response to environmental cues, similar to what in occurs in the wound healing process observed in fibroblasts. When dysregulated, these processes contribute to the development of various lung and cardiovascular diseases such as Chronic Obstructive Pulmonary Disease (COPD). Long non-coding RNAs (lncRNAs) have emerged as key modulators of SMC differentiation and phenotypic changes.

Heart brain axis in health and disease: role of innate and adaptive immunity.

The importance of the brain-heart interaction has been increasingly recognized as a critical physiological axis that is altered in disease. In this review, we explore the intricate relationship between the central nervous system and cardiovascular health, focusing particularly on immunological mechanisms that influence the course of both neurological and cardiovascular diseases. While previous studies have established a key role of the autonomic nervous system in linking brain and the heart, more recent studies have expanded our understanding of the multifaceted inter-organ interactions.

New insights into the effects of serotonin on Parkinson's disease and depression through its role in the gastrointestinal tract.

Neuropsychiatric and neurodegenerative disorders are frequently associated with gastrointestinal (GI) co-pathologies. Although the central and enteric nervous systems (CNS and ENS, respectively) have been studied separately, there is increasing interest in factors that may contribute to conditions affecting both systems. There is compelling evidence that serotonin (5-HT) may play an important role in several gut-brain disorders.

Mechanisms modulating foam cell formation in the arterial intima: exploring new therapeutic opportunities in atherosclerosis.

In recent years, the role of macrophages as the primary cell type contributing to foam cell formation and atheroma plaque development has been widely acknowledged. However, it has been long recognized that diffuse intimal thickening (DIM), which precedes the formation of early fatty streaks in humans, primarily consists of lipid-loaded smooth muscle cells (SMCs) and their secreted proteoglycans. Recent studies have further supported the notion that SMCs constitute the majority of foam cells in advanced atherosclerotic plaques.

Dynamic changes in immune cell populations by AXL kinase targeting diminish liver inflammation and fibrosis in experimental MASH.

Background And Aims: Metabolic dysfunction-associated steatohepatitis (MASH) is a significant health concern with limited treatment options. AXL, a receptor tyrosine kinase activated by the GAS6 ligand, promotes MASH through activation of hepatic stellate cells and inflammatory macrophages. This study identified cell subsets affected by MASH progression and the effect of AXL inhibition.

Scn1a haploinsufficiency in the prefrontal cortex leads to cognitive impairment and depressive phenotype.

Altered development and function of the prefrontal cortex (PFC) during adolescence is implicated in the origin of mental disorders. Deficits in the GABAergic system prominently contribute to these alterations. Nav1.

ER stress in mouse serotonin neurons triggers a depressive phenotype alleviated by ketamine targeting eIF2α signaling.

Depression is a devastating mood disorder that causes significant disability worldwide. Current knowledge of its pathophysiology remains modest and clear biological markers are lacking. Emerging evidence from human and animal models reveals persistent alterations in endoplasmic reticulum (ER) homeostasis, suggesting that ER stress-related signaling pathways may be targets for prevention and treatment.

Control compounds for preclinical drug-induced liver injury assessment: Consensus-driven systematic review by the ProEuroDILI network.

Background & Aims: Idiosyncratic drug-induced liver injury (DILI) is a complex and unpredictable event caused by drugs, and herbal or dietary supplements. Early identification of human hepatotoxicity at preclinical stages remains a major challenge, in which the selection of validated in vitro systems and test drugs has a significant impact. In this systematic review, we analyzed the compounds used in hepatotoxicity assays and established a list of DILI-positive and -negative control drugs for validation of in vitro models of DILI, supported by literature and clinical evidence and endorsed by an expert committee from the COST Action ProEuroDILI Network (CA17112).

S-Adenosyl-l-methionine restores brain mitochondrial membrane fluidity and GSH content improving Niemann-Pick type C disease.

Niemann-Pick type C (NPC) disease is a lysosomal storage disorder characterized by impaired motor coordination due to neurological defects and cerebellar dysfunction caused by the accumulation of cholesterol in endolysosomes. Besides the increase in lysosomal cholesterol, mitochondria are also enriched in cholesterol, which leads to decreased membrane fluidity, impaired mitochondrial function and loss of GSH, and has been shown to contribute to the progression of NPC disease. S-Adenosyl-l-methionine (SAM) regulates membrane physical properties through the generation of phosphatidylcholine (PC) from phosphatidylethanolamine (PE) methylation and functions as a GSH precursor by providing cysteine in the transsulfuration pathway.

Elevated cholesterol in ATAD3 mutants is a compensatory mechanism that leads to membrane cholesterol aggregation.

Aberrant cholesterol metabolism causes neurological disease and neurodegeneration, and mitochondria have been linked to perturbed cholesterol homeostasis via the study of pathological mutations in the ATAD3 gene cluster. However, whether the cholesterol changes were compensatory or contributory to the disorder was unclear, and the effects on cell membranes and the wider cell were also unknown. Using patient-derived cells, we show that cholesterol perturbation is a conserved feature of pathological ATAD3 variants that is accompanied by an expanded lysosome population containing membrane whorls characteristic of lysosomal storage diseases.

Roadmap to DILI research in Europe. A proposal from COST action ProEuroDILINet.

In the current article the aims for a constructive way forward in Drug-Induced Liver Injury (DILI) are to highlight the most important priorities in research and clinical science, therefore supporting a more informed, focused, and better funded future for European DILI research. This Roadmap aims to identify key challenges, define a shared vision across all stakeholders for the opportunities to overcome these challenges and propose a high-quality research program to achieve progress on the prediction, prevention, diagnosis and management of this condition and impact on healthcare practice in the field of DILI. This will involve 1.

Enhanced Activation of the S1PR2-IL-1β-Src-BDNF-TrkB Pathway Mediates Neuroinflammation in the Hippocampus and Cognitive Impairment in Hyperammonemic Rats.

Hyperammonemia contributes to hepatic encephalopathy. In hyperammonemic rats, cognitive function is impaired by altered glutamatergic neurotransmission induced by neuroinflammation. The underlying mechanisms remain unclear.

Thalamic Foxp2 regulates output connectivity and sensory-motor impairments in a model of Huntington's Disease.

Background: Huntington's Disease (HD) is a disorder that affects body movements. Altered glutamatergic innervation of the striatum is a major hallmark of the disease. Approximately 30% of those glutamatergic inputs come from thalamic nuclei.

Uric Acid: A Translational Journey in Cerebroprotection That Spanned Preclinical and Human Data.

Uric acid (UA) is a strong endogenous antioxidant that neutralizes the toxicity of peroxynitrite and other reactive species on the neurovascular unit generated during and after acute brain ischemia. The realization that a rapid reduction of UA levels during an acute ischemic stroke was associated with a worse stroke outcome paved the way to investigate the value of exogenous UA supplementation to counteract the progression of redox-mediated ischemic brain damage. The long translational journey for UA supplementation recently reached a critical milestone when the results of the multicenter NIH stroke preclinical assessment network (SPAN) were reported.