Cathepsin D is essential for the degradomic shift of macrophages required to resolve liver fibrosis.

Background And Objectives: Fibrosis contributes to 45% of deaths in industrialized nations and is characterized by an abnormal accumulation of extracellular matrix (ECM). There are no specific anti-fibrotic treatments for liver fibrosis, and previous unsuccessful attempts at drug development have focused on preventing ECM deposition. Because liver fibrosis is largely acknowledged to be reversible, regulating fibrosis resolution could offer novel therapeutical options.

Selection and characterization of human scFvs targeting the SARS-CoV-2 nucleocapsid protein isolated from antibody libraries of COVID-19 patients.

In 2019, the novel SARS-CoV-2 coronavirus emerged in China, causing the pneumonia named COVID-19. At the beginning, all research efforts were focused on the spike (S) glycoprotein. However, it became evident that the nucleocapsid (N) protein is pivotal in viral replication, genome packaging and evasion of the immune system, is highly immunogenic, which makes it another compelling target for antibody development alongside the spike protein.

Whole exome data prioritization unveils the hidden weight of Mendelian causes of male infertility. A report from the first Italian cohort.

Almost 40% of infertile men cases are classified as idiopathic when tested negative to the current diagnostic routine based on the screening of karyotype, Y chromosome microdeletions and CFTR mutations in men with azoospermia or oligozoospermia. Rare monogenic forms of infertility are not routinely evaluated. In this study we aim to investigate the unknown potential genetic causes in couples with pure male idiopathic infertility by applying variant prioritization to whole exome sequencing (WES) in a cohort of 99 idiopathic Italian patients.

Ductular reaction-associated neutrophils promote biliary epithelium proliferation in chronic liver disease.

Background & Aims: Ductular reaction expansion is associated with poor prognosis in patients with advanced liver disease. However, the mechanisms promoting biliary cell proliferation are largely unknown. Here, we identify neutrophils as drivers of biliary cell proliferation and the defective wound-healing response.

Ductular reaction promotes intrahepatic angiogenesis through Slit2-Roundabout 1 signaling.

Background And Aims: Ductular reaction (DR) expands in chronic liver diseases and correlates with disease severity. Besides its potential role in liver regeneration, DR plays a role in the wound-healing response of the liver, promoting periductular fibrosis and inflammatory cell recruitment. However, there is no information regarding its role in intrahepatic angiogenesis.

The multifaceted role of cathepsins in liver disease.

Proteases are the most abundant enzyme gene family in vertebrates and they execute essential functions in all living organisms. Their main role is to hydrolase the peptide bond within proteins, a process also called proteolysis. Contrary to the conventional paradigm, proteases are not only random catalytic devices, but can perform highly selective and targeted cleavage of specific substrates, finely modulating multiple essential cellular processes.

Cathepsins in the Pathophysiology of Mucopolysaccharidoses: New Perspectives for Therapy.

Cathepsins (CTSs) are ubiquitously expressed proteases normally found in the endolysosomal compartment where they mediate protein degradation and turnover. However, CTSs are also found in the cytoplasm, nucleus, and extracellular matrix where they actively participate in cell signaling, protein processing, and trafficking through the plasma and nuclear membranes and between intracellular organelles. Dysregulation in CTS expression and/or activity disrupts cellular homeostasis, thus contributing to many human diseases, including inflammatory and cardiovascular diseases, neurodegenerative disorders, diabetes, obesity, cancer, kidney dysfunction, and others.

Heparan sulfate in chronic kidney diseases: Exploring the role of 3-O-sulfation.

One of the main feature of chronic kidney disease is the development of renal fibrosis. Heparan Sulfate (HS) is involved in disease development by modifying the function of growth factors and cytokines and creating chemokine gradients. In this context, we aimed to understand the function of HS sulfation in renal fibrosis.

Lysosomal protease deficiency or substrate overload induces an oxidative-stress mediated STAT3-dependent pathway of lysosomal homeostasis.

Diverse cellular processes depend on the lysosomal protease system but how cells regulate lysosomal proteolytic capacity is only partly understood. We show here that cells can respond to protease/substrate imbalance in this compartment by de novo expression of multiple lysosomal hydrolases. This response, exemplified here either by loss of asparagine endopeptidase (AEP) or other lysosomal cysteine proteases, or by increased endocytic substrate load, is not dependent on the transcription factor EB (TFEB) but rather is triggered by STAT3 activation downstream of lysosomal oxidative stress.

Chronic psychosocial defeat differently affects lipid metabolism in liver and white adipose tissue and induces hepatic oxidative stress in mice fed a high-fat diet.

It is widely accepted that chronic stress may alter the homeostatic mechanisms of body weight control. In this study, we followed the metabolic changes occurring in mice when chronic stress caused by psychosocial defeat (CPD) is associated with ad libitum exposure to a palatable high-fat diet (HFD). In this model, CPD mice consumed more HFD than unstressed (Un) mice without gaining body weight.

Mitochondrial-Lysosomal Axis in Acetaminophen Hepatotoxicity.

Acetaminophen (APAP) toxicity is the most common cause of acute liver failure and a major indication for liver transplantion in the United States and Europe. Although significant progress has been made in understanding the molecular mechanisms underlying APAP hepatotoxicity, there is still an urgent need to find novel and effective therapies against APAP-induced acute liver failure. Hepatic APAP metabolism results in the production of the reactive metabolite -acetyl--benzoquinone imine (NAPQI), which under physiological conditions is cleared by its conjugation with glutathione (GSH) to prevent its targeting to mitochondria.

The Multifaceted Role of the Lysosomal Protease Cathepsins in Kidney Disease.

Kidney disease is worldwide the 12th leading cause of death affecting 8-16% of the entire population. Kidney disease encompasses acute (short-lasting episode) and chronic (developing over years) pathologies both leading to renal failure. Since specific treatments for acute or chronic kidney disease are limited, more than 2 million people a year require dialysis or kidney transplantation.

The NF-κB1 is a key regulator of acute but not chronic renal injury.

The NF-κB family of transcription factors is important for many cellular functions, in particular initiation and propagation of inflammatory and immune responses. However, recent data has suggested that different subunits of the NF-κB family can suppress the inflammatory response. NF-κB1, from the locus nfκb1, can inhibit transcription, acting as a brake to the recognised pro-inflammatory activity of other NF-κB subunits.

A sketch of known and novel MYCN-associated miRNA networks in neuroblastoma.

Neuroblastoma (NB) originates from neural crest-derived precursors and represents the most common childhood extracranial solid tumour. MicroRNAs (miRNAs), a class of small non-coding RNAs that participate in a wide variety of biological processes by regulating gene expression, appear to play an essential role within the NB context. High-throughput next generation sequencing (NGS) was applied to study the miRNA transcriptome in a cohort of NB tumours with and without MYCN-amplification (MNA and MNnA, respectively) and in dorsal root ganglia (DRG), as a control.

A Review of Research-Grade Human Induced Pluripotent Stem Cells Qualification and Biobanking Processes.

Human induced pluripotent stem cell (hiPSC) biobanks are invaluable resources for basic and clinical research, since they provide a sustainable supply of accessible cell lines that meet high quality and safety standards. hiPSCs are particularly useful for understanding disease mechanisms, creating cell models for drug development, and generating novel clinical therapies. For clinical applications and drug discovery, it is fundamental that the acquired pluripotent cell lines never touch animal-derived products nor xenogeneic reagents (Good Manufacturing Practice-grade); whereas for research grade, it is sufficient to operate under Good Laboratory Practice conditions.

Increased intake of energy-dense diet and negative energy balance in a mouse model of chronic psychosocial defeat.

Purpose: Chronic exposure to stress may represent a risk factor for developing metabolic and eating disorders, mostly driven by the overconsumption of easily accessible energy-dense palatable food, although the mechanisms involved remain still unclear. In this study, we used an ethologically oriented murine model of chronic stress caused by chronic psychosocial defeat (CPD) to investigate the effects of unrestricted access to a palatable high fat diet (HFD) on food intake, body weight, energy homeostasis, and expression of different brain neuropeptides. Our aim was to shed light on the mechanisms responsible for body weight and body composition changes due to chronic social stress.

Cysteine cathepsins control hepatic NF-κB-dependent inflammation via sirtuin-1 regulation.

Sirtuin-1 (SIRT1) regulates hepatic metabolism but its contribution to NF-κB-dependent inflammation has been overlooked. Cysteine cathepsins (Cathepsin B or S, CTSB/S) execute specific functions in physiological processes, such as protein degradation, having SIRT1 as a substrate. We investigated the roles of CTSB/S and SIRT1 in the regulation of hepatic inflammation using primary parenchymal and non-parenchymal hepatic cell types and cell lines.

Hedonic sensitivity to natural rewards is affected by prenatal stress in a sex-dependent manner.

Palatable food is a strong activator of the reward circuitry and may cause addictive behavior leading to eating disorders. How early life events and sex interact in shaping hedonic sensitivity to palatable food is largely unknown. We used prenatally restraint stressed (PRS) rats, which show abnormalities in the reward system and anxious/depressive-like behavior.

Lysosomal protease cathepsin D; a new driver of apoptosis during acute kidney injury.

Acute kidney injury (AKI) is an abrupt reduction in kidney function caused by different pathological processes. It is associated with a significant morbidity and mortality in the acute phase and an increased risk of developing End Stage Renal Disease. Despite the progress in the management of the disease, mortality rates in the last five decades remain unchanged at around 50%.

Histone Modifications in a Mouse Model of Early Adversities and Panic Disorder: Role for Asic1 and Neurodevelopmental Genes.

Hyperventilation following transient, CO2-induced acidosis is ubiquitous in mammals and heritable. In humans, respiratory and emotional hypersensitivity to CO2 marks separation anxiety and panic disorders, and is enhanced by early-life adversities. Mice exposed to the repeated cross-fostering paradigm (RCF) of interference with maternal environment show heightened separation anxiety and hyperventilation to 6% CO2-enriched air.

Inhibition of lysosomal protease cathepsin D reduces renal fibrosis in murine chronic kidney disease.

During chronic kidney disease (CKD) there is a dysregulation of extracellular matrix (ECM) homeostasis leading to renal fibrosis. Lysosomal proteases such as cathepsins (Cts) regulate this process in other organs, however, their role in CKD is still unknown. Here we describe a novel role for cathepsins in CKD.

In-depth characterization of breast cancer tumor-promoting cell transcriptome by RNA sequencing and microarrays.

Numerous studies have reported the existence of tumor-promoting cells (TPC) with self-renewal potential and a relevant role in drug resistance. However, pathways and modifications involved in the maintenance of such tumor subpopulations are still only partially understood. Sequencing-based approaches offer the opportunity for a detailed study of TPC including their transcriptome modulation.