Trends in pharmacological sciences最新文献

GlycoRNAs are glycosylated noncoding RNAs displayed on the cell surface. Emerging studies reveal their roles in intercellular communication and their dysregulation in inflammation and cancer, highlighting therapeutic potential. This review summarizes disease-related insights into glycoRNAs and outlines current strategies and challenges in developing glycoRNA-targeted interventions.

The constitutive presence of immune cells within brain parenchyma under homeostatic conditions is debated. Recent findings by Yoshida et al. have shown that the subfornical organ harbors gut- and adipose-derived T cells that secrete IFN-γ to regulate brain homeostasis and adaptive behavior in the gut-fat-brain immune axis.

Amphiregulin (AREG), a ligand of the epidermal growth factor receptor (EGFR), plays critical roles in immune homeostasis, cell proliferation, and tissue repair. Recent preclinical studies have shown that AREG is markedly upregulated in various fibrotic diseases and contributes to disease progression through distinct cell sources and signaling mechanisms. These advances highlight AREG as a fibrotic mediator with cellular and organ heterogeneity, suggesting that AREG-targeted therapies can be tailored with great specificity. This review synthesizes recent insights into AREG's expression dynamics, cellular sources, target cell types, and signaling mechanisms in fibrotic diseases, and presents a novel perspective on how this emerging knowledge may inform the development of selective, context-aware antifibrotic therapies.

KRAS^G12V-driven cancers remain therapeutically elusive. Recently, Stanland and colleagues developed EFTX-G12V, a GE11-conjugated small interfering RNA (siRNA) that selectively silences KRAS^G12V and achieves tumor regression by inhibiting oncogenic signaling and angiogenesis and enhancing anti-tumor immunity. EFTX-G12V represents an innovative RNAi-based precision oncology strategy for previously undruggable oncogenic mutations.

Human carbonic anhydrases (hCAs) are a superfamily of metalloenzymes with considerable, though yet poorly exploited therapeutic potential. They were primarily implicated in ocular and renal diseases and are targeted by antiglaucoma and diuretic drugs. However, emerging evidence has expanded our understanding of the roles of hCA modulators in other pathologies, including obesity, inflammation, hypoxic tumors, neurodegeneration, and neuropathic pain. In this review, we trace the evolution of our knowledge of hCA modulators, from their discovery to recent advances and future prospects. We also highlight the dysregulation of CAs in various diseases and current progress in developing hCA modulators for therapeutic use.

Glioblastoma (GBM) is a highly aggressive and lethal form of brain tumor in human adults that resists standard of care (SOC) and immunotherapy. Tumor-associated macrophages and microglia (TAMs) represent the most abundant cell population within the GBM tumor microenvironment (TME), comprising up to 50% of the whole tumor mass. TAMs play a pivotal role in promoting tumor progression, driving immunosuppression and inducing therapy resistance. Recent advances have revealed TAM heterogeneity - including their cellular identity (e.g., bone marrow-derived macrophages versus microglia) and the presence of distinct activation/function states and subpopulations within each subtype - in GBM tumors. Targeting the context-dependent TAM infiltration, reprogramming, new subpopulations, survival, phagocytosis, and their interactions with GBM cells in the TME has emerged as a promising therapeutic strategy. Herein we review recent advances in pharmacological targeting of the TAM biology and highlight how these strategies may enhance the effectiveness of SOC and immunotherapies in GBM.

In most drug discovery efforts targeting regulator of G-protein signaling (RGS) proteins, inhibiting their activity is the end-goal. A recent article by Aryal et al. presents a novel strategy to stabilize RGS2 by blocking its degradation via the ubiquitin-proteasomal system rather than inhibiting its function, a shift from developing small-molecule inhibitors targeting RGS proteins to modulate G-protein-coupled receptor (GPCR) signaling.

SWI/SNF chromatin remodeling complexes are essential epigenetic regulators that control chromatin accessibility and transcriptional programs. Alterations in SWI/SNF components are common across a wide spectrum of human cancers, driving tumorigenesis through diverse mechanisms. Increasing insights into the oncogenic roles of aberrant SWI/SNF complexes have spurred the development of novel therapeutic strategies. In this review, we integrate large-scale cancer genomic data towards understanding tumorigenesis driven by alterations in subunits of SWI/SNF complexes. We also evaluate strategies exploiting vulnerabilities in SWI/SNF-mutant cancers, including direct targeting of residual complex components and unique dependencies in critical cellular processes. Among them, one drug has been approved, and several others are in clinical trials.

Historically, the clinical application of cell-free RNA (cfRNA) liquid biopsies has been limited by background noise. In a recent study, Nesselbush et al. developed a method for denoising cfRNA analysis, resulting in RARE-seq, a versatile liquid biopsy platform that enables transcriptomic profiling, and cancer detection and monitoring, unlocking the potential of this exciting analyte.