Trends in molecular medicine最新文献

Most people affected by systemic lupus erythematosus (SLE) are women. Although the role of sex hormones has been appreciated, we discuss emerging evidence that links X-linked genes escaping from dosage compensation to female predisposition to lupus. This is exemplified by TLR7 and CXorf21 whose female-biased expression may converge to enhance interferon responses and promote autoantibody-producing B cells, which are hallmarks of SLE. Notably, autosomal transcription factors with female overexpression may regulate molecular programs in the skin that are sufficient to induce lupus. These findings indicate a multifactorial basis for female vulnerability; however, several areas remain elusive, including the epigenetic landscape of X-chromosome inactivation (XCI) in SLE, the interplay with environmental factors, and the role of male-specific factors such as Y-linked genes.

Cellular senescence is a key hallmark of aging. It has now emerged as a key mediator in normal tissue turnover and is associated with a variety of age-related diseases, including organ-specific fibrosis and systemic sclerosis (SSc). This review discusses the recent evidence of the role of senescence in tissue fibrosis, with an emphasis on SSc, a systemic autoimmune rheumatic disease. We discuss the physiological role of these cells, their role in fibrosis, and that targeting these cells specifically could be a new therapeutic avenue in fibrotic disease. We argue that targeting senescent cells, with senolytics or senomorphs, is a viable therapeutic target in fibrotic diseases which remain largely intractable.

Type 1 diabetes (T1D) is a devastating autoimmune disease for which advanced mass spectrometry (MS) methods are increasingly used to identify new biomarkers and better understand underlying mechanisms. For example, integration of MS analysis and machine learning has identified multimolecular biomarker panels. In mechanistic studies, MS has contributed to the discovery of neoepitopes, and pathways involved in disease development and identifying therapeutic targets. However, challenges remain in understanding the role of tissue microenvironments, spatial heterogeneity, and environmental factors in disease pathogenesis. Recent advancements in MS, such as ultra-fast ion-mobility separations, and single-cell and spatial omics, can play a central role in addressing these challenges. Here, we review recent advancements in MS-based molecular measurements and their role in understanding T1D.

Alzheimer's disease (AD) poses a significant health challenge worldwide, and the development of effective treatments necessitates a comprehensive understanding of its pathophysiology. Mouse models have been instrumental in offering insights into the crucial pathogenesis of AD. However, current models rarely recapitulate all aspects of AD pathology in patients; thus, translating the findings from mouse to human clinical trials has proved to be complex. In this review, we outline the development of some prevalently used AD mice, with a particular emphasis on the latest advances in newly generated models. In addition, we discuss the advantages and limitations in mouse models of AD and their applications in blood-based biomarkers. Finally, we speculate on potential future research directions.

The identification of biomarkers for amyotrophic lateral sclerosis (ALS) is a central issue in disease research. In a recent article, Chatterjee et al. show that blood extracellular vesicles (EVs) with high levels of transactive response DNA-binding protein 43 (TDP-43) accurately discriminate patients with ALS from controls and correlate with disease severity, providing a promising biomarker for early diagnosis and monitoring.

Aging is a major risk factor for pathologies that manifest later in life. Much attention is devoted towards elucidating how prolonged environmental exposures and inflammation promote biological (accelerated) tissue aging. Granzymes, a family of serine proteases, are increasingly recognized for their emerging roles in biological aging and disease. Widely recognized as intracellular mediators of cell death, granzymes, particularly granzyme B (GzmB), also accumulate in the extracellular milieu of tissues with age, contributing to chronic tissue injury, inflammation, and impaired healing. Consequently, this has prompted the field to reconsider how GzmB regulation, accumulation, and proteolysis impact health and disease with age. While GzmB is observed in numerous age-related conditions, the current review focuses on mechanistic studies where proof-of-concept has been forwarded.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver condition. MASLD is a sexually dimorphic condition, with its development and progression influenced by sex chromosomes and hormones. Estrogens typically protect against, whereas androgens promote, MASLD. Therapeutic approaches for a sex-specific personalized medicine include estrogen replacement, androgen blockers, and novel drugs targeting hormonal pathways. However, the interactions between hormonal factors and inherited genetic variation impacts MASLD risk, necessitating more tailored therapies. Understanding sex disparities and the role of estrogens could improve MASLD interventions and management, whereas clinical trials addressing sex differences are crucial for advancing personalized treatment. This review explores the underappreciated impact of sexual dimorphism in MASLD and discusses the potential therapeutic application of sex-related hormones.