Trends in molecular medicine最新文献

Hutchinson-Gilford progeria syndrome (HGPS) is an ultrarare genetic disease caused by progerin, a broadly expressed mutant variant of lamin A protein that accelerates aging and leads to premature death typically in adolescence. Progerin affects many organs and reproduces many characteristics of physiological aging, with the main cause of death in HGPS being atherosclerotic cardiovascular disease (CVD). Due to the rarity of HGPS, advances in understanding the disease and progress toward new therapeutic approaches are crucially dependent on preclinical models. We discuss recent research developments from a variety of HGPS experimental systems, with a special focus on in vivo studies of the role of vascular smooth muscle cells (VSMCs) and endothelial cells (ECs) that are key players in atherosclerosis.

Chronic pain affects millions of people worldwide and represents a crucial public health issue. A growing body of preclinical evidence suggests that adeno-associated virus (AAV) vectors are a powerful gene therapy tool for chronic pain management. We systematically summarize how AAV vectors, by targeting molecular pain pathways in neuronal and non-neuronal cells, may offer precise and sustained pain relief. We provide an overview of the latest findings and emerging concepts in this area, and discuss preclinical innovations in neuropathic, inflammatory and cancer-related pain. We also present clinical data on pain modulation by AAV in osteoarthritis (OA) patients. Finally, we provide a thorough analysis of key concerns about AAV therapy, including potential immune responses, toxicity, and adverse effects.

Bhatt et al. have identified two RNAome-based skeletal muscle subtypes in cancer cachexia. The first subtype is cachexia associated with weight and muscle loss, fiber atrophy, and shortened survival. Furthermore, this subtype has dysregulated post-transcriptional networks involving hub long noncoding (lnc)RNAs, neuronal, immune, and metabolic pathways. The study highlights new biomarkers and network-targeted interventions.

Systemic lupus erythematosus (SLE, lupus) remains an enigmatic diagnosis with a poor prognosis. SLE is characterised by complex biology and heterogeneous clinical manifestations that create a major hurdle to the approval of new medicines and contribute to multiple trial failures. While the pace of research has accelerated, drugs currently in development target a limited spectrum of mechanisms, tempering hope that any will be a panacea. The pace of translation lags behind advances in basic science, and this continues to cost patients dearly. The unacceptable metabolic adverse effects of glucocorticoids have rightly driven treatment guidelines towards ever more stringent dose-reduction targets, and new research is ongoing to develop a safe and reliable glucocorticoid replacement that will be active across a breadth of inflammatory pathways.

The initiation of labour in humans remains poorly understood, although there is mounting evidence for a role for decidual macrophages. These may trigger labour by promoting a proinflammatory state, thereby modulating progesterone signalling and weakening fetal membranes. Preclinical work targeting macrophages therapeutically shows promise in preventing preterm labour, underscoring their significance in this process.

Natural killer (NK) cells are innate lymphocytes that are crucial for eliminating malignant and infected cells, and have significant therapeutic potential against cancer and viral infections. However, their functionality is often impaired under pathological conditions. Emerging evidence identifies mitochondria as key regulators of NK cell metabolism, fitness, and fate. This review examines how mitochondrial dysfunction impacts on NK cell activity in cancer, viral infections, and inflammatory disorders. We discuss strategies to target mitochondrial architecture, dynamics, and function as potential therapies to restore NK cell fitness. Finally, we highlight unanswered questions and future directions to better understand mitochondrial regulation in NK cells and its implications for therapeutic development.

Dysregulation of protein homeostasis contributes to many human diseases and is an emerging therapeutic target. Proteasome-mediated degradation requires ubiquitin tagging, a process regulated by E3 ligases and reversed by deubiquitinases (DUBs). Among DUBs, the ovarian tumor protease (OTU) family exhibits poly-ubiquitin linkage-specific activity and regulates diverse cellular processes. OTU dysregulation has been linked to diseases such as cancer, highlighting their potential as drug targets. This review summarizes current knowledge of OTU functions, regulatory mechanisms, and disease associations, as well as therapeutic strategies targeting OTUs. By examining these aspects, we aim to provide insights into the pathophysiological roles of OTUs and support ongoing efforts to develop OTU-targeted therapies for human diseases.

The oxidative stress paradigm stands as a textbook example of how a simplified, early, and appealing scientific concept can become canonized and then resist revision. What began as a plausible heuristic about oxidative stress evolved into a research agenda and a pervasive cultural script.

Amyloid transthyretin (ATTR) amyloidosis is a progressive and multifaceted disorder characterized by extracellular deposition of misfolded transthyretin (TTR) in tissues, leading to irreversible damage. The rising prevalence of this disease underscores the urgent need for a deeper understanding of its complex pathology to improve diagnosis and treatment strategies. This Review explores the cellular and molecular mechanisms underlying ATTR cardiac amyloidosis (ATTR-CA), delving into the processes driving disease progression, exploring the recent progress in the experimental models used to study ATTR-CA, and highlights advances in diagnostic tools and therapeutic strategies. By integrating the latest insights, this Review aims to provide a holistic and comprehensive understanding of ATTR-CA, offering an integrated perspective on research progresses and improvements in patient outcomes.