Trends in molecular medicine最新文献

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.

Glucagon-like peptide-1 receptor agonists (GLP1-RAs), widely used for type 2 diabetes mellitus, are emerging as promising neuroprotective therapies in Alzheimer's disease (AD) and Parkinson's disease (PD). Agents such as exenatide, lixisenatide, and liraglutide have demonstrated disease-modifying potential in preclinical and clinical studies. However, translation remains hindered by the absence of validated biomarkers to guide patient selection, track target engagement, and monitor progression. Here, we review the mechanistic links between GLP1-RA signaling and neurodegeneration, summarize the evolving clinical evidence, and highlight emerging blood-based and molecular biomarkers, including those tied to insulin signaling, neurodegeneration, and metabolic and cardiovascular dysfunction, that may accelerate therapeutic development. Integrating these biomarkers with digital phenotyping and artificial intelligence could enable precision approaches to advance GLP1-RA research and clinical use in neurodegeneration.

Tuberculosis (TB) remains a major global health burden, prompting heightened efforts towards host-directed therapies (HDT). Autophagy, a key antimicrobial and immunomodulatory process, is a promising candidate for HDT. However, despite encouraging preclinical results, autophagy-targeting strategies have shown limited clinical success, in part due to the lack of accurate profiling of patient-derived autophagy flux across the TB spectrum. This gap limits our understanding of baseline autophagy dynamics and hinders the rational design of HDT. This review highlights patient-derived autophagic flux as a dynamic, quantitative readout of autophagy activity and an underutilized element in TB biomarker and therapeutic research. We examine autophagy flux assessment methodologies and propose its role as a biomarker for TB diagnosis, prognosis, and patient stratification in personalized HDT strategies.

Immunotherapy resistance, orchestrated largely by the tumor microenvironment, remains a major clinical challenge. Recent advances highlight metabolic reprogramming as a key driver of this resistance. In this review we focus on cholesterol metabolism, a central hub that profoundly reshapes the tumor immune landscape. We dissect how dysregulated cholesterol pathways fortify tumor cells against immune attack while simultaneously suppressing effector immune cells. We conceptualize cholesterol metabolism as a critical metabolic-immune checkpoint, a novel framework for understanding this tumor-immune crosstalk. Finally, we comprehensively review emerging therapeutic strategies targeting this checkpoint, illuminating a promising translational path to dismantle metabolic barriers and overcome immunotherapy resistance.

In this opinion, we propose that compromised microvascular perfusion and inflammation are fundamental drivers of chronic pain syndromes, with many of these conditions sharing a common etiology involving suboptimal blood flow and inflammatory cascades. This hypothesis links capillary constriction, hypoxia, inflammation, and nociceptor activation into a unified framework for understanding pain mechanisms. For each example syndrome, we explore specific nuances, molecular mechanisms, and therapeutic opportunities, focusing on the interplay between hypoxia and inflammation. Current treatments often emphasize anti-angiogenic or broad-spectrum approaches, which may neglect the microvascular and hypoxic origins. We review studies investigating microvascular hypoperfusion and inflammation in pain and suggest that targeted therapies addressing vascular deficits and inflammatory responses could better disrupt the hypoxia-inflammation cycle, offering novel avenues for treatment.

To date, research on premature ovarian insufficiency (POI) primarily centers on ovarian dysfunction and systemic hormonal imbalances, with limited attention given to associated endometrial alterations. Given the critical role of the endometrium in reproductive function and its potential contribution to POI-related infertility, in this review, we bridge the knowledge gap regarding endometrial aspects of POI. We discuss the physiology and pathophysiology alterations in the POI endometrium, the multilevel endometrial changes spanning histological architecture, molecular signatures, and functional capacity, and clinical ramifications for fertility potential. In addition, we critically evaluate both established and novel therapeutic interventions targeting these endometrial abnormalities, paying particular attention to their potential to restore reproductive function.

Peptide-ionizable lipids (PILs) establish a rational design paradigm for RNA delivery, defining a chemical code that programs organ tropism and enables systemic prime editing. By achieving precise mRNA and genome editing beyond the liver, this platform opens a new era of multi-organ RNA therapeutics and precision genetic medicine.

In a recent Science study, Shenoy et al. reveal that maternal milk IgG programs neonatal immunity in mice. During the first postnatal week, IgG forms complexes with gut microbes, calibrating T cell responses at weaning and establishing long-term tolerance, uncovering a critical early-life window that shapes lifelong immune function.

Toll-like receptors (TLRs) play a pivotal role in both innate and adaptive immunity, primarily by detecting pathogen-associated molecular patterns (PAMPs) and orchestrating immune responses. Although TLR-driven activation of dendritic cells (DCs) and subsequent T cell differentiation are well characterized, the function of TLRs in B cells remains underexplored. In the context of obesity, excessive adipose tissue accumulation triggers chronic inflammation driven in part by activation of TLR signaling. This review explores the expression, function, and signaling mechanisms of TLRs in B cells, and emphasizes their role in modulating immune responses associated with obesity. Furthermore, we discuss how TLR-mediated inflammatory activity in B cells may contribute to metabolic dysregulation, and offer insights into the crosstalk between immune function and metabolic disease in obesity.