Pharmacological research最新文献

The aberrant tumor vasculature fosters a permissive microenvironment that impedes immune effector cell infiltration and simultaneously promotes neoplastic progression. CD93 is an important target for antiangiogenic normalization therapy. Here, we found that the expression of CD93 and its ligand IGFBP7 were significantly upregulated in cancers and closely associated with various pro-angiogenic factors. Next, we identified the CD93 binding peptides (CBP). After systematic D-amino acid modification and retro-inversion, CBP-D8 peptide exhibited the highest blocking activity on CD93/IGFBP7 interaction, and potent inhibition on the migration of endothelial cells. Besides, CBP-D8 peptide significantly facilitated cytotoxic CD8⁺ T cells and NK cells infiltration through enhanced blood perfusion and increased coverage of pericytes and vascular smooth muscle cells. More importantly, CBP-D8 peptide combined with radiotherapy significantly abrogated tumor growth and elicited systemic antitumor immune response. Our study identified a novel peptide blocking CD93/IGFBP7 interaction to normalize tumor vascular function, as well as revealed an approach to promote a favorable tumor microenvironment for the therapeutic intervention.

We recently showed that METRNL (Meteorin-like) protects against atherosclerosis. However, the mechanism for METRNL in atherosclerosis is largely unclear. This study aimed to demonstrate the relative importance of endothelial METRNL in atherosclerosis by comparing the effects of whole-body METRNL deficiency to endothelial-specific deficiency, and to show the subcellular distribution of endothelial METRNL and its role in mitochondrial homeostasis against atherosclerosis. Our study demonstrated that a deficiency in either endothelial or global METRNL exacerbated atherosclerosis to a similar degree in both spontaneous (age-related) and high fat diet-induced atherosclerosis, suggesting that endothelial METRNL is pivotal in the progression of atherosclerosis due to METRNL deficiency. Endothelial METRNL was diffusely distributed in the cytoplasm with subcellular localization to mitochondria, nucleus, endoplasmic reticulum, and Golgi apparatus (especially enriched in mitochondria and nucleus). In both an in vivo apolipoprotein E-deficient (ApoE^-/-) mouse model and an in vitro oxidized low density lipoprotein (ox-LDL)-treated endothelial cell model, METRNL inhibited ox-LDL- or high fat diet-induced atherosclerosis by alleviating endothelial mitochondrial dysfunction and apoptosis which was achieved through a balance between PPARγ co-activator-1α (PGC-1α)-mediated mitochondrial biogenesis and PTEN induced putative kinase protein 1 (PINK1)-Parkin-mediated mitophagy. These findings highlight the pivotal importance of endothelial METRNL against atherosclerosis by comparison with whole-body METRNL. This is the first demonstration of METRNL localization to mitochondria in endothelial cells and its role in maintaining endothelial mitochondrial stability against atherosclerosis. Furthermore, targeting METRNL to stabilize endothelial mitochondrial function represents a novel and promising therapeutic strategy for atherosclerotic cardiovascular diseases.

Traditional antibody-drug conjugates (ADCs) that target antigens expressed not only on tumor cells but also on nonmalignant cells are often associated with unavoidable on-target off-tumor toxicities. Probodies are masked antibody prodrugs that remain inactive until proteolytically activated in the tumor microenvironment (TME). However, most probodies are produced on the basis of a monoresponsive design and achieve a narrow therapeutic index owing to tumor heterogeneity and nonspecific payload-conjugation. Here, we generated different probodies targeting the cluster of differentiation 147 (CD147) antigen based on the design of multiple-protease-activated linker peptide and HcHAb18 antibody epitope-derived masking peptides. Three anti-CD147 probody-drug conjugates (PDCs) were produced via site-specific conjugation with cytotoxic monomethyl auristatin E (MMAE) through mild cysteine-selective chemical reactions. The created probodies and PDCs can be activated through cleavage by the proteases legumain, matrix-metalloproteinases 9, and urokinase-type plasminogen activator, but exhibit different CD147-targeting potentials. Importantly, PDC1, one of the conditional antibody architectures, exhibits highly selective targeting and strongest cytotoxicity to ovarian cancer cells. More importantly, PDC1 demonstrated promising targeting selectivity and improved the tumor-inhibition efficiency in ovarian cancer-xenograft mouse models without systemic toxicity. This multiple protease-activated, disulfide-bridging PDC strategy provides a novel, precise and safe ADC-targeted therapeutics against ovarian cancer.

Cardiovascular Disease (CVDs), as a major life-threatening disease, has attracted worldwide attention. Seeking novel and effective therapeutic strategies is still among the important in the cardiovascular field. Forkhead box O (FoxO) family comprises a group of transcription factors with highly conserved structures that have a major role in a plethora of biological functions. Recently, a considerable amount of research has shown the physiological and pathological roles of Fox family (especially FoxO1) in CVDs (including myocardial ischemia-reperfusion injury, myocardial hypertrophy, myocardial infarction, myocardial fibrosis, cardiomyopathy, and atherosclerosis), and they affect the plasticity, stress response, and metabolism of the heart by regulating various signaling pathways and biological functions. In this review, we outline the structure of the Fox family and FoxO1. Next, we summarize the various pathological and physiological mechanisms of FoxO1 (inflammation, oxidative stress, autophagy, endothelial dysfunction, lipid metabolism and angiogenesis), as well as the regulatory style of FoxO1 (phosphorylation, methylation, ubiquitination and acetylation). Finally, we also reviewe the latest research advancements and potential future research directions concerning FoxO1 regulators in CVDs, laying the foundation for its transformation into a new and powerful clinical application.

Resveratrol (RESV) is a naturally occurring polyphenol with well-established antioxidant and anti-inflammatory properties, supporting its therapeutic potential in chronic respiratory diseases such as asthma. To enhance its efficacy, we developed a hybrid compound, R-TBZ, in which RESV is chemically linked to 4-hydroxythiobenzamide (TBZ), a slow-releasing hydrogen sulfide (H₂S) donor. This design aimed to improve chemical stability, bioavailability, and controlled activation while minimizing the toxicity associated with fast H₂S release. R-TBZ was synthesized via esterification of RESV with TBZ and showed high chemical stability, remaining over 95 % intact after 24 h under neutral and acidic conditions. Enzymatic hydrolysis occurred gradually (t₁/₂ ≈ 20 h), releasing RESV as the sole detectable product. In allergen-challenged bronchial epithelial cells, R-TBZ demonstrated superior efficacy compared with RESV or TBZ alone. It enhanced mitochondrial antioxidant defenses, reduced mucus production, and suppressed pro-inflammatory cytokines (IL-6, IL-1β, and TNF-α). R-TBZ inhibited allergen-induced epithelial-mesenchymal transition and TGF-β-induced fibroblast activation, reducing α-SMA and vimentin expression more effectively than the parent compounds, indicating synergistic anti-remodeling activity. In a murine model of allergic asthma, R-TBZ improved lung function, reduced airway hyperresponsiveness, restored β₂-agonist responsiveness, and attenuated eosinophilic inflammation, Th2 cytokine production, and plasma IgE levels. Importantly, R-TBZ reversed airway structural remodeling, reducing peribronchial α-SMA expression and preserving epithelial and goblet cell morphology, effects not fully achieved by RESV alone. Overall, R-TBZ combines dual anti-inflammatory and anti-remodeling activities, overcoming key limitations of RESV and H₂S donors. This hybrid represents a promising multi-target therapeutic strategy for asthma, particularly for steroid-resistant airway remodeling.

Neuropilin-1 (NRP-1) is a pleiotropic transmembrane receptor critical in embryonic development of neurological and vascular systems. Increasing evidence suggests that NRP-1 has a major role in immunity. However, the role of NRP-1 in regulating the profibrotic function of macrophages during liver fibrosis has not been defined. In this study, we collected human liver samples from 20 patients with fibrosis and 5 controls, finding significantly elevated NRP-1 expression in macrophages from fibrotic livers. Using macrophage-specific NRP-1 deficient mice subjected to CCl₄-induced liver fibrosis, we demonstrated that NRP-1 deficiency effectively attenuated fibrotic progression. Further experiments revealed that NRP-1 enhances profibrotic macrophage polarization and subsequent hepatic stellate cell activation both in vivo and in vitro. Mechanistically, NRP-1 binds to interleukin-13 receptor alpha1 (IL13Rα1) via its extracellular domain, stabilizing the IL13Rα1-IL13 interaction. This activates IL13 signaling, leading to Tyk2 phosphorylation. The IL13Rα1-Tyk2/Stat6 axis then upregulates the transcription factor EHF, which in turn activates NRP-1 expression in macrophages, establishing a positive feedback loop that amplifies profibrotic functions. Our conclusions indicate that NRP-1 promotes liver fibrosis progression, and targeting macrophage NRP-1 is a potential therapeutic strategy against liver fibrosis.