搜索结果：Trends in molecular medicine

Interstitial lung diseases (ILDs) are a clinically and biologically diverse group of disorders characterized by varying inflammation and fibrosis of the lung parenchyma. Immunosuppressant therapy is commonly used to treat non-idiopathic pulmonary fibrosis (non-IPF) ILD, but treatment response is variable and difficult to predict. Identify and validate molecular endotypes of non-IPF ILD. Twenty plasma proteins associated with inflammation were used to perform latent class analysis in 2 observational non-IPF ILD cohorts (discovery n&#x2009;=&#x2009;676; validation n&#x2009;=&#x2009;585). Proteins were measured using a semi-quantitative Olink Explore 3072 platform. The primary outcome was 3-year transplant-free survival. Weighted Cox regression was used to assess differential response to mycophenolate or azathioprine in each cohort according to molecular endotype classification. A 2-class model best fit both cohorts (P&#x2009;<0.01), with Class 2 comprising &#x223c;30% of patients. Compared to Class 1, Class 2 was associated with significantly lower 3-year transplant-free survival in both discovery (78% vs 36%, P&#x2009;<0.001) and validation (83% vs 46%, P&#x2009;<0.001) cohorts. Significant interaction between molecular endotype and immunosuppressant exposure was observed in both cohorts (discovery Pinteraction&#x2009;=&#x2009;0.022; validation Pinteraction&#x2009;=&#x2009;0.019), with survival benefit seen only in Class 2. In pooled analysis, similar trends were observed irrespective of ILD subtype. Pathway analysis supported enrichment of inflammatory signatures in Class 2. In this multicenter observational cohort study, we identified and validated 2 distinct molecular endotypes of non-IPF ILD with divergent outcomes and response to immunosuppressant therapy. These endotypes could inform precision medicine strategies and clinical trial design in ILD.

Platelet-derived biotherapies are emerging as innovative approaches for complex neurological disorders requiring multimodal interventions. Platelet-derived products, including lysates, platelet concentrate supernatants, secretome, extracellular vesicles, and fractionated components, represent a scalable and clinically accessible biotechnology platform for precision neuromedicine. Platelets provide a reservoir of trophic factors, cytokines, chemokines, lipids, antioxidants, and noncoding RNAs with demonstrated neuroprotective, anti-inflammatory, and antiferroptotic effects in models of neurodegeneration, trauma, and aging. Preclinical and patient-derived omics and neuroimaging data can help characterize mechanisms of action, identify biomarkers, and refine platelet secretome preparations toward indication-specific formulations. Combined with virus inactivation and purification technologies adapted from plasma protein manufacturing, these advances position platelet-derived biotherapies as a rational and versatile path toward future acellular therapeutics for brain disorders.

The liver has a unique microarchitecture, with hepatic sinusoids receiving blood from the portal vein and hepatic artery and draining into the central vein. This flow establishes an oxygen gradient along the sinusoids critical for defining the liver zonation. In metabolic dysfunction-associated steatotic liver disease (MASLD), fat accumulation and fibrosis disrupt this architecture, contributing to localised hypoxia. Mounting evidence implicates hypoxia in MASLD, including the activation of canonical hypoxia sensors such as hypoxia-inducible factors. Moreover, chronic intermittent hypoxia, characteristic of obstructive sleep apnoea (OSA), is epidemiologically and mechanistically associated with MASLD progression. This review examines the intrahepatic oxygen dynamics, the interplay between OSA and MASLD, and molecular responses to hypoxia, proposing intrahepatic hypoxia as a spatial determinant of liver injury.

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.

An intact gut barrier is crucial to human health. Functional assessment of gut barrier function and permeability in humans is laborious and demanding. Blood-based biomarkers that reflect gut barrier integrity have gained increasing attention for their potential role in monitoring gut barrier impairments across various conditions. Several candidate biomarkers-including intestinal fatty acid-binding protein, citrulline, zonulin, lipopolysaccharide-binding protein, and soluble CD14-reflect epithelial damage, microbial translocation, or tight junction dysfunction. This review highlights novel technologies for quantifying blood-based biomarkers to assess gut barrier function across diseases. Furthermore, it emphasizes the value of integrating complementary blood-based biomarkers across different populations to improve disease monitoring and the development of targeted therapies.

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.

The central nervous system (CNS) orchestrates homeostatic responses and organismal behaviors by integrating cues from the whole body. Like other peripheral tissues, skeletal muscle can signal to the brain, and this occurs via muscle-secreted signaling factors (myokines/myometabolites). In this review article, we examine exercise-induced myokines and myometabolites that improve cognitive capacity and impede neurodegeneration and, conversely, detrimental myokines secreted by diseased muscles that negatively impact brain function. Cellular processes modulated by myokines in the CNS include proteostasis, angiogenesis, neurogenesis, synaptic plasticity, cell senescence, and neuroinflammation, resulting in the modulation of diverse behaviors, such as motor control, memory, foraging, and sleep. Collectively, muscle-to-brain signaling emerges as an important influencer of CNS function and aging, with the prospect of utilizing myokine-/myometabolite-based therapies for treating neurodegeneration.

Mechanical forces regulate development, homeostasis, and repair in the skin, lung, and cornea-external barrier organs that are exposed to stretch, shear, and stiffness. Dysregulated mechanotransduction drives fibrosis, inflammation, and impaired repair via conserved pathways [Piezo1 (Piezo-type mechanosensitive ion channel 1), TRPV4 (transient receptor potential vanilloid 4), and integrin-YAP (Yes-associated protein)]. Targeting these circuits with small molecules, biologics, or stiffness-tuned biomaterials offers a novel category of cross-organ therapies. As mechanosensitive pathways and mechanically informed biomaterials advance toward clinical testing, an integrated cross-organ perspective is urgently needed to address unmet therapeutic needs in chronic barrier diseases. This review unifies disparate insights into biophysics, molecular biology, and clinical practice to reveal how shared mechanisms underpin barrier pathologies and enable breakthrough mechanomedicine treatments.

TANGO2 deficiency disorder (TDD) is an ultrarare, autosomal recessive disease characterized by neuromuscular impairment, intellectual disability, and recurrent metabolic crises leading to life-threatening ventricular arrhythmias. Intrafamilial phenotypic variability and overlapping manifestations with other metabolic diseases complicate timely and accurate diagnosis. This review summarizes the clinical spectrum and emerging molecular mechanisms of TDD, integrating insights from structural biology and experimental disease models. Evidence suggests that high-dose vitamin B complex supplementation can reduce the frequency of metabolic crises and improve neurocognitive outcomes, underscoring the importance of early diagnosis and intervention. By integrating recent advances, this review aims to provide a thorough understanding of TANGO2 deficiency, identify key unmet needs, and define future research priorities.

Circadian rhythms play a central role in how bone tissue is formed, resorbed, and remodelled during the 24-h cycle. Bone cells express core clock proteins, which coordinate the timing of these processes, each contributing differently to the balance between bone formation and resorption. These intrinsic bone-cell clocks are further influenced by external temporal cues, including hormonal effects and mechanical forces such as exercise. Taken together, these features indicate that skeletal bone tissue is significantly influenced by the peripheral clock. In this review, we summarise recent advances on how intrinsic and extrinsic timing cues interact to regulate skeletal physiology, and we discuss how emerging insights into bone circadian biology might inform therapeutic and regenerative strategies aimed at improving skeletal health.

Most solid tumors remain immunologically 'cold' and refractory to therapy, making immunogenic cell death (ICD) induction a central therapeutic goal. Z-DNA binding protein 1 (ZBP1) acts as a sensor, converting intrinsic nucleic acid stress into ICD programs. This review establishes ZBP1 as a convergence point linking distinct nucleic acid stress signals, including DNA damage response, telomere crisis, replication stress, dysregulated RNA splicing, endogenous retroelement re-expression, and mitochondrial stress response, to PANoptosis. We highlight recent therapeutic strategies, ranging from biological inducers and direct agonists to Z-DNA proteolysis targeting chimeras and pharmacological stressors, that harness nucleic acid stress responses to engage ZBP1. Finally, we propose a translational roadmap emphasizing combination strategies and biomarker-guided patient selection to engage the ZBP1 signaling axis and promote durable antitumor immunity.

Myelination is increasingly recognized as a dynamic and adaptive process regulated by oligodendrocytes throughout life. Beyond providing electrical insulation, myelin supports axonal metabolism and may serve as an energy reservoir under metabolic stress, highlighting the importance of physiological myelin turnover. Dysregulation of myelin dynamics contributes to a wide spectrum of neurological disorders, including demyelinating, neurodegenerative, and neuropsychiatric diseases. Growing evidence indicates that neurotransmitter signaling through G protein-coupled receptors (GPCRs) expressed by oligodendrocyte lineage cells regulates myelin formation, remodeling, and repair. In this review, we discuss how neurotransmitter-activated GPCRs control oligodendrocyte function and myelin plasticity, and we explore their potential as targets to promote myelin regeneration and restore neural circuit function.

The placenta is an essential organ that supports fetal development during pregnancy. The establishment of human trophoblast stem cells has enhanced our understanding of placental development; however, their limited diversity constrains our ability to capture interindividual variation. Patient-specific trophoblast stem cells (pTSCs), derived from induced pluripotent stem cells, fibroblasts, cytotrophoblasts, or chorionic villus tissue, retain the unique genetic and epigenetic backgrounds of individual patients. Notably, chorionic villus-derived trophoblast stem cells can be obtained without terminating a pregnancy, allowing for integration with prospective clinical data. pTSCs, therefore, provide powerful platforms to investigate the pathogenesis of placental disorders, assess individual risk, and advance personalized therapeutic strategies. This review highlights recent advances in pTSC derivation and discusses their potential applications.

Peripheral nerve regeneration declines with aging and prolonged denervation, yet the underlying mechanisms have remained elusive. Recent studies identify senescent Schwann cells (senSCs) as a key contributor. Following injury, repair Schwann cells (SCs) enter a senescent state marked by p16INK4a/p21CIP1 upregulation and secretion of a senescence-associated secretory phenotype (SASP) that impairs axonal regrowth. Clearing senSCs in preclinical models restores regeneration, suggesting that failed repair results from active inhibition rather than diminished capacity. Moreover, SASP-like signatures emerge across neuropathies of diverse etiology, suggesting broader relevance. In this review, we synthesize emerging evidence linking SC senescence to impaired regeneration and chronic neuropathies and outline therapeutic strategies targeting senescence. We also examine translational challenges and explore how these approaches could advance nerve repair and neuropathy treatment.

Ferroptosis, an iron-dependent form of regulated cell death, is increasingly recognized as a key mechanism in disease pathogenesis and treatment. As essential biomedical models, mice have played an instrumental role in uncovering the relationship between ferroptosis and disease. However, a systematic synthesis of phenotypic outcomes and mechanistic insights derived from these studies remains lacking. This review outlines the important molecular pathways of ferroptosis, including dysregulated iron metabolism, lipid peroxidation, and antiferroptotic defense systems, and highlights key genes involved in its regulation. We further integrate functional evidence from gene-edited mouse models to provide deeper insights into the pathophysiological relevance of ferroptosis across different disease contexts. Finally, promising yet underexplored areas are discussed to facilitate the clinical translation of ferroptosis research.

Hepatocellular carcinoma (HCC) remains a major global health challenge, with rising incidence, frequent development of drug resistance, and limited long-term survival despite advances in systemic therapies. Within the tumor microenvironment, the interaction between hyaluronic acid (HA) and cluster of differentiation 44 (CD44) is linked to tumor progression and therapeutic failure. Accordingly, targeting the HA-CD44 signaling axis represents a promising strategy to overcome resistance. This review highlights potential approaches, including inhibition of HA synthesis, enzymatic HA degradation, CD44 blockade, and HA-based nanocarriers for selective drug delivery, alone or combined with existing therapies. Leveraging HA-CD44 biology may help refine profiling and support the development of more personalized treatments, ultimately enhancing outcomes for HCC patients.

Metabolic dysfunction-associated steatotic liver disease (MASLD) has become one of the leading causes of hepatocellular carcinoma (HCC), yet the mechanisms of tumor microenvironment (TME)-metabolic crosstalk remain incomplete. This review summarizes the current understanding of the bidirectional interaction between TME remodeling and metabolic reprogramming in MASLD-related HCC. We discuss how chronic inflammation, lipotoxicity, and oxidative stress reshape the TME, elaborate on key metabolic pathways, and highlight emerging metabolomic profiling approaches. The interplay between immune cells and metabolic changes fosters immunosuppressive tumor niches. Metabolomic biomarkers arising from TME-metabolic interactions are vital for disease progression and therapeutic resistance. This integrated view underscores the potential of metabolomic biomarkers for early diagnosis, disease stratification, and personalized therapies, advancing precision medicine in MASLD-related HCC.

This article explores the expanding role of molecular diagnostics in breast pathology. It emphasizes how immunohistochemistry, fluorescence in situ hybridization, and next-generation sequencing define tumor subtypes with recurrent genetic alterations, while predictive biomarkers such as ESR1, human epidermal growth factor receptor 2, PD-L1, and BRCA1/2 direct targeted therapies. The article highlights the diagnostic value of entity-specific fusions and mutations, the therapeutic implications of rare molecular events, and the promise of artificial intelligence-driven gene expression-based prediction models in cancers of unknown primary. These advances illustrate how molecular tools complement morphology, refine classification, and enable precision medicine in breast cancer care.

Immune cells mediate acute and chronic renal failure in native and transplanted kidneys, initiating auto- and allo-immunity, and acting as effectors in other diseases such as diabetes, hypertension, and cancer. Many drugs already in use or in development for these diseases target the putative immune mechanisms at play, based on in vitro cell experiments and animal models. Here, we review how recent and upcoming advanced tissue imaging techniques-many of them applicable to human kidney samples as well as animal models-could further improve drug development by providing insights into immune cell types, activation states, and behaviours in kidney disease. We illustrate an innovative cross-scale multimodal imaging pipeline and its application to the investigation of immune cells in human kidney samples.