Trends in molecular medicine最新文献

Increased understanding of the pathophysiology of migraine has resulted in the development of therapies targeting calcitonin gene-related peptide and its receptor. Ditans, which are serotonin 5HT_1F receptor agonists, have demonstrated efficacy in acute management and bypass vascular risks associated with triptans, which are 5HT_1B/1D receptor agonists. However, despite favourable safety and efficacy data, many patients do not respond to these therapies. Treatments targeting pituitary adenylate cyclase activating polypeptide and other potential targets, including amylin and adrenomedullin and their receptors, K_ATP and transient receptor potential ion channels, as well as neuronal nitric oxide synthase, are emerging. Improving our understanding of patient heterogeneity in migraine biology may pave the way for precision medicine in migraine management.

A recent study by Angelino et al. uncovered an intracellular signaling pathway involved in musculoskeletal mitochondrial dysfunction in cancer cachexia. Both humans and mice with cancer cachexia display impaired 3',5'-cyclic adenosine monophosphate (cAMP)-protein kinase A-cAMP response element-binding protein 1 signaling, which leads to mitochondrial dysfunction. By rescuing this pathway with a phosphodiesterase-4 inhibitor, the authors highlight a potential therapeutic strategy for cancer cachexia.

Precision medicines for monogenic brain disorders are rapidly advancing. Voltage-gated sodium channel (VGSC) genes are the leading monogenic cause of severe epilepsy and profound autism spectrum disorder (ASD), most notably SCN1A, SCN2A, SCN3A, and SCN8A. Recent advances in animal and human induced pluripotent stem cell (hiPSC) disease models provide a powerful platform for advancing precision medicines. Thanks to the genomic revolution, many gene therapies are in preclinical studies and clinical trials for VGSC-related diseases, including viral vector gene replacement, clustered regularly interspaced short palindromic repeats (CRISPR) base editing, prime editing, and genetic modulation strategies including antisense oligonucleotides, engineered tRNAs, and CRISPR activation/interference (CRISPRa/i). This review highlights the latest advances in disease modeling and next-generation therapeutic development to advance precision medicine for VGSC-related brain disorders.

Pediatric acute megakaryoblastic leukemia (AMKL) associated with the CBFA2T3::GLIS2 (CG2) gene fusion is distinctive by virtue of its aggressiveness and ability to transform normal cells in a single event. The dismal therapeutic response of children to this disease has stimulated comprehensive studies on the molecular mechanism of CG2-driven tumorigenesis. In this Opinion, we highlight various investigative strategies, used in parallel by multiple independent research teams, that point to a specific dependence of CG2-expressing leukemias on the B cell leukemia/lymphoma-2 (BCL-2) family of antiapoptotic proteins. We propose that this intrinsic feature renders these leukemias particularly vulnerable to BCL-2 homology 3 (BH3) mimetics.

Men have a higher incidence of specific types of cancer and neurodegenerative disease. Mounting evidence suggests that androgen receptor (AR)-mediated androgen signaling is a key determinant at the core of this sex discrepancy. Herein we review the role of androgens in disorders characterized by altered AR activity, focusing on transcriptional coregulators that shape receptor specificity. In particular, we highlight the roles of protein arginine methyltransferase 6 (PRMT6) and lysine-specific demethylase 1 (LSD1), enzymes associated with epigenetic repression, yet functioning as AR coactivators. By enhancing AR transcriptional output, PRMT6 and LSD1 contribute to malignant transformation and progression across multiple cell types. We further explore how these insights inform combinatorial therapeutic strategies targeting AR, PRMT6, and LSD1, with implications for both cancer and neurodegeneration.

The Integrator complex, composed of at least 19 subunits, associates with RNA polymerase II (RNAPII) and exerts critical roles in transcriptional regulation. By interacting with the C-terminal domain (CTD) of RNAPII, it cleaves nascent RNA transcripts, leading to termination of non-productive transcription in protein-coding genes and processing of diverse noncoding RNAs. Beyond RNA cleavage, Integrator regulates transcription initiation, pause-release, and elongation, while also processing enhancer RNAs. It contributes to genome stability by modulating RNAPII activity during DNA damage and replication stress. Dysfunction of Integrator subunits has been linked to neurodevelopmental disorders and cancer, underscoring its broad physiological significance. This review highlights recent advances in structure and function that illuminate Integrator's essential roles in development, neurobiology, and disease.

The angiopoietin-like protein (ANGPTL)3/8 complex regulates triglyceride partitioning, and its selective blockade lowers triglycerides while raising HDL-cholesterol (HDL-C). Clinical and genetic evidence support ANGPTL3/8 antagonism as a precision therapy for mixed dyslipidemia, monogenic hypertriglyceridemia (CREBH or APOA5 deficiency), and diabetic dyslipidemia by correcting a fundamental disturbance in lipid partitioning.

Aging is the gradual decline in physiological function essential for survival and reproduction. Unlike age-associated diseases, aging affects all individuals within a species, causing progressive impairments across multiple systems. Research shows that altering specific genes or dietary factors can extend lifespan, implicating molecular pathways in controlling senescence. Chronological age (CA) is a common measure of aging, but other hallmarks like telomere shortening better quantify functional decline. Identifying age-related hallmarks can help manipulate aging, spurring interest in aging clocks. These clocks predict biological age (BA) more precisely than CA, reflecting actual physiological health. As global life expectancy continues to rise, aging clocks hold promise for developing therapies to extend healthspan and improve life quality during aging.

Hyaluronan synthases (HASs) are essential enzymes for hyaluronic acid (HA) production; a key component for joint lubrication and cartilage health. Dysregulated HA synthesis contributes to joint dysfunction. In this Forum, we discuss the role of HAS in matrix assembly, inflammation and the pathogenesis of osteoarthritis (OA).