Polyproline-Polyornithine Diblock Copolymers with Inherent Mitochondria Tropism.

Mitochondria play critical roles in regulating cell fate, with dysfunction correlating with the development of multiple diseases, emphasizing the need for engineered nanomedicines that cross biological barriers. Said nanomedicines often target fluctuating mitochondrial properties and/or present inefficient/insufficient cytosolic delivery (resulting in poor overall activity), while many require complex synthetic procedures involving targeting residues (hindering clinical translation). The synthesis/characterization of polypeptide-based cell penetrating diblock copolymers of poly-L-ornithine (PLO) and polyproline (PLP) (PLO-PLP, n:m ratio 1:3) are described as mitochondria-targeting nanocarriers.

Ectopic expression of DNMT3L in human trophoblast stem cells restores features of the placental methylome.

The placental DNA methylation landscape is unique, with widespread partially methylated domains (PMDs). The placental "methylome" is conserved across mammals, a shared feature of many cancers, and extensively studied for links with pregnancy complications. Human trophoblast stem cells (hTSCs) offer exciting potential for functional studies to better understand this epigenetic feature; however, whether the hTSC epigenome recapitulates primary trophoblast remains unclear.

Modulation of Mitochondria-Endoplasmic Reticulum Contacts (MERCs) by Small Molecules as a New Strategy for Restoring Lipid Metabolism in an Amyotrophic Lateral Sclerosis Model.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease without effective treatment. The progressive motoneuron death in ALS is associated with alterations in lipid metabolism. As its regulation occurs in mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs), modulation of mitochondria-ER contacts (MERCs) is emerging as a crucial factor in MAM formation and lipid metabolism control.

Peroxynitrite is involved in the mitochondrial dysfunction induced by Sorafenib in liver cancer cells.

Background: Sorafenib is a tyrosine kinase inhibitor (TKI) that belongs to the landscape of treatments for advanced stages of hepatocellular carcinoma (HCC). The induction of cell death and cell cycle arrest by Sorafenib has been associated with mitochondrial dysfunction in liver cancer cells. Our research aim was to decipher underlying oxidative and nitrosative stress induced by Sorafenib leading to mitochondrial dysfunction in liver cancer cells.

Targeting immune evasion in hepatocellular carcinoma-initiating cells.

Tumor-initiating cells (TICs) are particularly efficient at evading detection and elimination by the human immune system. Recent data from Yang and collaborators demonstrate that - at least in preclinical hepatocellular carcinoma models - the immunological privilege of CD49f TICs can be limited by targeting CD155, resulting in restored sensitivity to immune checkpoint inhibitors.

A novel pharmacological entity toward integrated multimodal immunotherapy.

Most solid tumors are insensitive to single-agent immunotherapy, calling for the development of combinatorial treatment regimens. Recently, Lin and collaborators developed a pharmacological platform enabling the combination of different immunotherapies into a single chemical entity. This approach may effectively circumvent obstacles associated with the simultaneous delivery of multiple immunotherapeutic agents.

Docosahexaenoic Acid (DHA) Supplementation in a Triglyceride Form Prevents from Polyglutamine-Induced Dysfunctions in .

A common hallmark of neurodegenerative diseases is the accumulation of polypeptide aggregates in neurons. Despite the primary cause of these diseases being inherently genetic, their development can be delayed with proper preventive treatments. Long-chain polyunsaturated fatty acids (ω-3 LCPUFA) are promising bioactive nutrients that are beneficial for brain health.

A transient blood IL-17 increase triggers neuroinflammation in cerebellum and motor incoordination in hyperammonemic rats.

Patients with liver cirrhosis may show minimal hepatic encephalopathy (MHE) with motor incoordination which is reproduced in hyperammonemic rats. Hyperammonemia induces peripheral inflammation which triggers neuroinflammation and enhanced GABAergic neurotransmission in cerebellum and motor incoordination. The mechanisms involved remain unknown.

Lipid metabolism in MASLD and MASH: From mechanism to the clinic.

Metabolic dysfunction-associated steatotic liver disease/steatohepatitis (MASLD/MASH) is recognised as a metabolic disease characterised by excess intrahepatic lipid accumulation due to lipid overflow and synthesis, alongside impaired oxidation and/or export of these lipids. But where do these lipids come from? The main pathways related to hepatic lipid accumulation are lipogenesis and excess fatty acid transport to the liver (due to increased lipolysis, adipose tissue insulin resistance, as well as excess dietary fatty acid intake, in particular of saturated fatty acids). Not only triglycerides but also other lipids are secreted by the liver and are associated with a worse histological profile in MASH, as shown by lipidomics.

Copper-cobalt peroxide nanoparticles: a biomimetic cascade reaction for enhanced Fenton-like therapy at physiologically relevant pH.

Traditional Fenton-like reactions, commonly employed in chemodynamic therapy (CDT) for cancer treatment, face limitations due to the mildly acidic tumor microenvironment (TME) and scarce HO availability. Aiming to overcome these hurdles, we report herein the preparation of copper-cobalt peroxide (CCp) nanoparticles, a novel catalyst that enables a pH-activated, self-supplying HO-mediated cascade reaction. In the slightly acidic TME (pH 6.

G9a/DNMT1 co-targeting inhibits non-small cell lung cancer growth and reprograms tumor cells to respond to cancer-drugs through SCARA5 and AOX1.

The treatment of non-small cell lung cancer (NSCLC) patients has significantly improved with recent therapeutic strategies; however, many patients still do not benefit from them. As a result, new treatment approaches are urgently needed. In this study, we evaluated the antitumor efficacy of co-targeting G9a and DNMT1 enzymes and its potential as a cancer drug sensitizer.

Disruption of CAD Oligomerization by Pathogenic Variants.

CAD, the multi-enzymatic protein essential for initiating the de novo biosynthesis of pyrimidine nucleotides, forms large hexamers whose structure and function are not fully understood. Defects in CAD cause a severe neurometabolic disorder that is challenging to diagnose. We developed a cellular functional assay to identify defective CAD variants, and in this study, we characterized five pathogenic missense mutations in CAD's dihydroorotase (DHO) and aspartate transcarbamoylase (ATC) domains.

Breaking barriers in obesity research: 3D models of dysfunctional adipose tissue.

Obesity is a global health crisis characterised by excessive accumulation of adipose tissue (AT). Under obesogenic conditions, this metabolically active tissue undergoes fibrosis and inflammation, leading to obesity-linked comorbidities. Modelling AT is essential for understanding its pathophysiology and developing treatments to protect against metabolic complications.

Author Correction: Limited oxygen in standard cell culture alters metabolism and function of differentiated cells.

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Rational design of a poly-L-glutamic acid-based combination conjugate for hormone-responsive breast cancer treatment.

Breast cancer represents the most prevalent tumor type worldwide, with hormone-responsive breast cancer the most common subtype. Despite the effectiveness of endocrine therapy, advanced disease forms represent an unmet clinical need. While drug combination therapies remain promising, differences in pharmacokinetic profiles result in suboptimal ratios of free drugs reaching tumors.

Unveiling the impact of circulating tumor cells: Two decades of discovery and clinical advancements in solid tumors.

Circulating tumor cells (CTCs) enumeration and molecular profiling hold promise in revolutionizing the management of solid tumors. Their understanding has evolved significantly over the past two decades, encompassing pivotal biological discoveries and clinical studies across various malignancies. While for some tumor types, such as breast, prostate, and colorectal cancer, CTCs are ready to enter clinical practice, for others, additional research is required.

Fetal growth restriction and placental defects in obese mice are associated with impaired decidualisation: the role of increased leptin signalling modulators SOCS3 and PTPN2.

Decidualisation of the endometrium is a key event in early pregnancy, which enables embryo implantation. Importantly, the molecular processes impairing decidualisation in obese mothers are yet to be characterised. We hypothesise that impaired decidualisation in obese mice is mediated by the upregulation of leptin modulators, the suppressor of cytokine signalling 3 (SOCS3) and the protein tyrosine phosphatase non-receptor type 2 (PTPN2), together with the disruption of progesterone (P4)-signal transducer and activator of transcription (STAT3) signalling.

The impact of sex on gene expression in the brain of schizophrenic patients: a systematic review and meta-analysis of transcriptomic studies.

Background: Schizophrenia is a severe neuropsychiatric disorder characterized by altered perception, mood, and behavior that profoundly impacts patients and society despite its relatively low prevalence. Sex-based differences have been described in schizophrenia epidemiology, symptomatology and outcomes. Different studies explored the impact of schizophrenia in the brain transcriptome, however we lack a consensus transcriptomic profile that considers sex and differentiates specific cerebral regions.

Profile of plasma microRNAs as a potential biomarker of Wilson's disease.

Background: Wilson's disease (WD) is a rare condition resulting from autosomal recessive mutations in ATP7B, a copper transporter, manifesting with hepatic, neurological, and psychiatric symptoms. Timely diagnosis and appropriate treatment yield a positive prognosis, while delayed identification and/or insufficient therapy lead to a poor outcome. Our aim was to establish a prognostic method for WD by characterising biomarkers based on circulating microRNAs.

Golexanolone reduces glial activation in the striatum and improves non-motor and some motor alterations in a rat model of Parkinson's disease.

Background: Parkinson's disease (PD) affects more than 6 million people worldwide. Along with motor impairments, patients and animal models exhibiting PD symptoms also experience cognitive impairment, fatigue, anxiety, and depression. Currently, there are no drugs available for PD that alter the progression of the disease.

SMIM1 absence is associated with reduced energy expenditure and excess weight.

Background: Obesity rates have nearly tripled in the past 50 years, and by 2030 more than 1 billion individuals worldwide are projected to be obese. This creates a significant economic strain due to the associated non-communicable diseases. The root cause is an energy expenditure imbalance, owing to an interplay of lifestyle, environmental, and genetic factors.

ProteoCure: A European network to fine-tune the proteome.

Proteins are essential molecular actors in every cellular process. From their synthesis to their degradation, they are subject to continuous quality control mechanisms to ensure that they fulfil cellular needs in proper and timely fashion. Proteostasis is a key process allowing cells or organisms to maintain an appropriate but dynamic equilibrium of their proteome (the ensemble of all their proteins).

Bacteria in metastatic sites: Unveiling hidden players in cancer progression.

Bacteria exhibit key features of cancer metastasis, such as motility, invasion, and modulation of the tumor microenvironment. They migrate through lymphatic and blood systems, invade metastatic tissues, and alter local microenvironments to support metastatic growth. Bacteria also shape the tumor microenvironment, affecting immune responses and inflammation, which influence tumor progression and therapy response.