Pharmacological research最新文献

Chimeric antigen receptor (CAR) T-cell therapy remains ineffective in most solid tumors due to extracellular matrix (ECM)-mediated stromal barriers. While prior ECM-remodeling strategies using multiple matrix metalloproteinases (MMPs) improved tumor infiltration, they increased vector complexity and raised translational concerns; conversely, single MMP7 overexpression enhanced infiltration without improving tumor control. Here, we identify matrix metalloproteinase-2 (MMP2) as a single ECM-degrading enzyme that simultaneously enhances CAR-T cell infiltration and antitumor efficacy. Mesothelin- and B7H3-targeted CAR-T cells co-expressing MMP2 preserved T-cell fitness while exhibiting superior ECM traversal and cytotoxicity in vitro, and these effects were abolished by the pan-MMP inhibitor GM6001. In a physiologically relevant, cancer-associated fibroblast (CAF)-enriched xenograft model, MMP2-engineered CAR-T cells displayed increased intratumoral accumulation and durable tumor control. These findings establish MMP2-based single-enzyme ECM remodeling as a simple, scalable, and clinically translatable strategy to overcome stromal resistance and advance CAR-T therapy for solid tumors.

Chronic pain is a significant global health burden often resistant to conventional analgesics. Evidence implicates that mitochondrial dysfunction is not only a cellular consequence of injury, but also a fundamental driver of pain chronification. This review synthesizes current insights into how mitochondrial impairment contributes to pain chronification across diverse pathological contexts. Bioenergetic failure marked by ATP depletion and electron transport chain defects plays a central role. This energy crisis converges with oxidative stress, calcium overload, and neuroinflammation to promote neuronal hyperexcitability. Meanwhile, impaired mitophagy, suppressed biogenesis, and abnormal dynamics all contribute to the disrupted mitochondrial quality control, which further perpetuates cellular stress. Crucially, the efficacy of multiple mitochondria-targeted therapeutic strategies was summarized in this review. Despite gaps in current research, we emphasize that developments in biomarker and exploration of neuro-glial immune interactions could advance mitochondria-based precision medicine for pain management.

Lung fibrosis is a severe disease with limited therapeutic options. The vascular niche is critical for lung function and fibrotic diseases, but the mechanisms by which endothelial cells (ECs) are regulated during lung injury and fibrosis remain largely unknown. As a critical regulatory pathway in lung development, regeneration, and fibrosis, the role of Hippo/YAP1 in the endothelial niche remains elusive. Here, we provide evidence that endothelial Hippo facilitates lung fibrosis via regulating the neutrophil niche. The YAP1 is activated in ECs of fibrotic lungs in mice and humans. Activating YAP1 via depleting the upstream repressor SAV1 in ECs promotes bleomycin-induced lung fibrosis, while endothelial YAP1 deficiency reverses lung fibrosis. Mechanism study reveals that endothelial YAP1 regulates the expression of CXCL1, which recruits CXCR2⁺ neutrophil in injured lungs. Blocking neutrophil recruitment via CXCR2 antagonist reduces lung fibrosis and blocks the effects of endothelial YAP1 activation. Therapeutically, inhibition of YAP1 with verteporfin reduces endothelial CXCL1 expression, neutrophil recruitment and lung fibrosis. Collectively, these findings demonstrate the roles of Hippo/YAP1 in regulating endothelial-neutrophil niche to participate in lung fibrosis.

Bone metastasis is a frequent and incurable consequence of advanced prostate cancer (PC). This process originates through an interplay between disseminated tumor cells and heterogeneous bone resident cells in the metastatic niche. Melanoma differentiation associated gene-9 (mda-9/Syntenin) is a pro-metastatic gene expressed in multiple organs, including bone marrow-derived mesenchymal stromal cells (BM-MSCs), under both physiological and pathological conditions. MDA-9/Syntenin coordinates the interactions between tumor cells and BM-MSCs, which promote establishment of metastatic tumors in the bone niche. Considering the importance of protein-protein interactions in regulating MDA-9/Syntenin functions, we focused on developing small molecule inhibitors of these interactions. We describe the translational potential of IVMT-Rx-4, an intermediate synthesis product of PDZ1i, in inhibiting PC bone metastasis. IVMT-Rx-4 has similar bioactivity as PDZ1i but with improved druggable properties, e.g., higher solubility and lower efflux. It promotes potent anti-invasive and anti-metastatic effects by inhibiting the MDA-9/Syntenin dependent tumor-derived platelet derived growth factor, PDGF-AA, and its related signalling in BM-MSCs. In addition, the combination of IVMT-Rx-4 and docetaxel enhances survival in experimental bone metastasis models. These observations reinforce the concept that together with metastasis suppression, IVMT-Rx-4 can boost the effectiveness of standard-of-care treatment. Collectively, the present work provides a framework for translational strategies to ameliorate health complications and morbidity associated with advanced PC.

Cardiovascular disease (CVD) represents a significant global public health challenge, with its high incidence and mortality rates imposing a substantial socioeconomic burden. Tribbles family proteins (TRIB1, TRIB2, and TRIB3), functioning as pseudokinases, play a pivotal role in the pathogenesis and progression of various CVDs, including coronary heart disease, heart failure, hypertension, cardiomyopathy, and pulmonary hypertension. The progression of CVD is modulated by the tribbles family proteins through key mechanisms such as the regulation of inflammatory responses, apoptosis, endoplasmic reticulum stress, and insulin signaling pathways. Furthermore, polymorphisms within the tribbles family genes are strongly associated with genetic susceptibility to CVDs, thereby influencing disease risk and clinical manifestations. Multiple therapeutic strategies targeting the tribbles family have demonstrated potential in improving cardiac and vascular function, offering novel avenues for CVD treatment. This review provides an in-depth analysis of the structural characteristics of tribbles family proteins and elucidates the mechanisms of tribbles in CVDs and their potential as therapeutic targets.

Identifying the factors that regulate female reproduction is crucial to understanding how the environment affects female reproductive health. The vitamin D receptor (VDR) and its ligands (primarily 1,25(OH)₂D₃) have a recognized role in calcium homeostasis; however, their broader impact on female reproduction remains underexplored. We demonstrate that the VDR and its ligands are involved in the hormonal induction of uterine decidualization. Mice fed a vitamin D-deficient diet displayed an impaired hormonally induced decidual response. In a human telomerase reverse transcriptase-immortalized human endometrial stromal cell line (T-HESC), VDR decreased during in vitro decidualization. Small interfering RNA (siRNA) knockdown of VDR in T-HESC enhanced in vitro decidualization, while overexpression of VDR inhibited it. Chromatin accessibility and histone modification analyses revealed that VDR functions as a chromatin regulator, restricting accessibility and repressing transcription in specific genomic regions. Transcriptomic analyses confirmed that VDR broadly modulates gene expression, with most ligand-mediated effects occurring through the VDR. These findings identify VDR as a key regulator of transcriptional and chromatin landscapes in human endometrial stromal cells, offering novel insights into vitamin D signaling in reproduction. This study highlights the potential of targeting vitamin D pathways to treat uterine disorders associated with impaired decidualization and reduced fertility.

Small sample sizes in preclinical research limit the extraction of reliable knowledge and hinder translational progress. We propose genESOM, a generative artificial intelligence method based on emergent self‑organizing maps. genESOM is designed to augment small biomedical datasets while controlling α‑error inflation. It separates structure learning from data synthesis and integrates error propagation mitigation through dimensionality modulation, enabling safe and interpretable data augmentation. Using lipid signaling data from a preclinical multiple sclerosis study employing the experimental autoimmune encephalomyelitis (EAE) model (26 female SJL/J mice, three treatment groups, and 62 lipid mediators), we intentionally reduced the sample size from 26 to 18 animals. This reduction abolished detectable group differences by both statistical and machine learning analyses. Augmenting the reduced dataset with AI‑generated cases restored treatment‑specific segregation and recovered the original key lipid mediators. genESOM achieved consistent fidelity without introducing false positives. In contrast, Gaussian mixture and conditional GAN models failed under comparable constraints. These results demonstrate that genESOM provides a robust, error‑controlled framework for enhancing knowledge extraction from limited preclinical samples. While synthetic augmentation cannot substitute for biological replication, it can support exploratory analyses and help reduce the need for additional animal experimentation.

Dietary lignans (Diet-LIG) are a class of estrogenic plant polyphenols whose improve potential for perimenopausal depression (PMD), a condition driven by estrogen deficiency, remains unexplored. This study aims to investigate whether Diet-LIG intake can alleviate perimenopausal depressive symptoms and to explore the underlying mechanisms. The randomized controlled trial conducted in the study revealed that one-month supplementation significantly alleviated depressive and anxiety symptoms and elevated serum estradiol in perimenopausal women. This clinical benefit was associated with increased fecal levels of gut bacterial metabolites (enterolactone and enterodiol) the enzyme β-glucuronidase, and the enrichment of specific bacteria, notably Bacteroides ovatus. Animal studies showed that Diet-LIG upregulated ERβ protein expression in the hippocampal tissue of PMD mice. KEGG analysis of hippocampal proteomics showed that differentially expressed proteins between the Diet-LIG intervention and PMD groups were primarily enriched in the glutamatergic synapse pathway. Golgi staining and Western blot analysis confirmed that Diet-LIG supplementation improved neuronal plasticity, with significantly increased expression of GluN2A and PSD95 proteins. Humanized fecal microbiota transplantation experiments and in vitro cell interventions with Bacteroides ovatus monoculture medium revealed that the antidepressant effects of Diet-LIG are not directly mediated solely by the modulated gut microbiota, but instead rely on the bioactivity of metabolites produced through gut microbiota-driven conversion. In vitro validation experiments, the knockdown of ERβ in HT22 cells significantly suppressed GluN2A and PSD95 expression and blocked their induction by Diet-LIG metabolites. In conclusion, gut microbiota drives Diet-LIG to activate hippocampal ERβ, which regulates the GluN2A/PSD95 pathway and enhances hippocampal neuronal plasticity, thereby ameliorating perimenopausal depressive symptoms. (Chinese Clinical Trial Registry [ChiCTR], ID Number: ChiCTR2400082537.).