Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie最新文献

Chemoresistance in colorectal cancer (CRC) represents a core bottleneck in clinical treatment, primarily driven by the cross-regulatory network formed by cancer stem cells (CSCs) and epithelial-mesenchymal transition (EMT). Non-coding RNAs (ncRNAs) play a central role in this regulatory network, providing crucial molecular targets for chemoresistance intervention. However, the clinical translation of ncRNAs is limited by delivery challenges. The nanoscale "Trojan Horse" drug delivery system achieves precise delivery through triple-targeting design: at the tissue level, tumor accumulation is realized via the enhanced permeability and retention effect and targeted modification; at the cellular level, it targets CSCs and other chemoresistant cells; at the molecular level, it interferes with core pathways of stemness, EMT, and chemoresistance. Additionally, this system enables synergistic combination of chemotherapy with gene therapy, immunotherapy, phototherapy, and other modalities through multi-drug co-delivery, while integrating theranostic functions to synchronize chemoresistance monitoring and treatment. This review systematically elaborates on the mechanisms of ncRNA-mediated regulation of CRC chemoresistance, the design strategies and application efficacy of the nanoscale "Trojan Horse" system, providing critical insights for overcoming CRC cross-resistance and advancing the clinical translation of ncRNA nanotherapies.

Combination therapy with targeted agents and immune checkpoint inhibitors (ICIs) represents a major advance in the treatment of advanced hepatocellular carcinoma (HCC), yet clinical efficacy remains modest. In the phase III COSMIC-312 trial, cabozantinib plus atezolizumab prolonged progression-free survival but did not improve overall survival, indicating the presence of tumor-intrinsic resistance mechanisms. In this study, we investigated the therapeutic and immunological effects of cabozantinib, celecoxib, and anti-programmed death-1 (anti-PD1), administered individually or in combination, in orthotopic and spontaneous metastatic HCC mouse models. Cabozantinib demonstrated hallmarks of immunogenic cell death (ICD) but concurrently activated COX-2/PGE₂-mediated immunosuppression, thereby limiting its antitumor efficacy. Celecoxib selectively inhibited PGE₂ production without affecting ICD, thereby enhancing dendritic cell activation and strengthening cytotoxic T-cell responses. Notably, triple therapy with cabozantinib, celecoxib, and anti-PD1 produced the most potent therapeutic outcome, markedly suppressing primary tumor growth, reducing lung metastases, and depleting regulatory T cells. These results reveal that celecoxib mitigates COX-2/PGE₂-driven immunosuppression while preserving ICD, thereby augmenting the efficacy of cabozantinib-anti-PD1 immunotherapy. This combination provides a strong mechanistic rationale for clinical translation and may inform future strategies to improve the durability of immune-based treatments for advanced HCC. This strategy may also guide future clinical trial designs and support the development of more effective, personalized therapies for patients with advanced HCC.

Cerebral ischemic stroke (CIS) represents a leading global cause of mortality and long-term disability, posing a significant public health challenge. The pathogenesis of CIS is complex, and effective therapies remain limited. Therefore, elucidating the underlying neurobiological mechanisms of CIS and exploring novel therapeutic strategies are essential. Extracellular signal-regulated kinase (ERK) has emerged as a critical regulator in CIS pathogenesis, playing pivotal roles in cellular processes such as growth, proliferation, differentiation, and signal transduction, while also demonstrating substantial neuroprotective potential. Targeted modulation of ERK signaling holds promise for mitigating multiple pathological cascades in CIS, including endoplasmic reticulum stress, oxidative stress, mitochondrial dysfunction, apoptosis, excitotoxicity, autophagy, and neuroinflammation, while potentially promoting neural regeneration. Consequently, ERK represents an attractive potential therapeutic target for alleviating CIS. This review first delineates the structure, function, and activation of the ERK pathway. Subsequently, it summarizes current understandings of CIS pathogenesis and critically examines the involvement of ERK signaling in CIS pathophysiology. Finally, the review discusses the mechanistic basis and therapeutic potential of targeting the ERK pathway to ameliorate CIS, providing a scientific rationale for further investigation of ERK as a therapeutic target.

Calcium channel blockers are established in treating hypertension or arrhythmias. They have also been suggested to have anti-atherosclerotic effects, although most such studies are limited mainly to histological or biochemical parameters. Therefore, the aim was to test the hypothesis that amlodipine (AMLO) improves vascular function in atherosclerosis in particular. Here, PCSK9^DY-injected C57BL/6N-mice on a Western diet (WD) were orally treated with either AMLO (10 mg/kg_bw) or vehicle (VEH), while controls received adeno-associated virus vector (AAV) and a chow diet. Pulse wave velocity (PWV) was measured in vivo by ultrasound. Cortical stiffness was determined ex vivo by atomic force microscopy and in vitro in endothelial cells. Compared to controls, plaque burden and calcification deposits in the thoracic aorta and plasma levels of lipids, TNFα, IL6, and NO were increased in PCSK9^DY+WD^VEH mice. Upon AMLO treatment, NO, calcification, and plaque burden were reduced, but not lipids. PWV (1.267 ± 0.232 vs. 0.908 ± 0.173 m/s) and cortical stiffness (1.412 ± 0.033 vs. 0.992 ± 0.015 pN/nm) were higher in the PCSK9^DY+WD^VEH than in AAV+chow^VEH mice but remained almost normal despite PCSK9^DY+WD intervention when treated with AMLO (0.987 ± 0.119 m/s or 1.181 ± 0.026 pN/nm). AMLO reduced PWV and stiffness in AAV+chow mice and decreased cortical stiffness and increased glycocalyx height in endothelial cells. We conclude that AMLO improves vascular function in atherosclerosis as PWV and cortical stiffness become normalized. Since AMLO also improved function in AAV+chow controls and in endothelial cells, we further conclude that the effect is independent of the development of atherosclerosis. Furthermore, our in vivo results point to a NO-dependent mechanism.

Purpose: Oxidative stress, inflammation, and ferroptosis drive retinal disease. Methotrexate (MTX) and dexamethasone (DEX) are clinically used to counter these insults, but their effects on retinal pigment epithelium (RPE) homeostasis remain unclear. This study investigates how MTX, DEX, and their combination affect cell viability, redox balance, inflammatory signaling, and ferroptosis-related gene expression in human RPE cells under basal and oxidative stress conditions.

Methods: Human RPE cells were exposed to 100 µM H₂O₂ for 24 h and treated with MTX (100 µg/ml), DEX (50 µg/ml), or their combination. Cell viability was assessed using MTT assay. Total oxidant status (TOS), malondialdehyde (MDA), catalase (CAT), and superoxide dismutase (SOD) were measured from cell lysates. IL-6, IL-8, IL-10, and TGF-β levels were quantified by ELISA, and GPX4, ACSL4, and SLC7A11 mRNA expression was measured by qPCR.

Results: Under basal conditions, treatments did not affect viability. DEX and combination increased TOS, with MDA elevated by combination only. CAT activity increased with DEX. MTX reduced IL-8, DEX reduced IL-6, and combination reduced IL-6, IL-8, and TGF-β. GPX4, ACSL4, and SLC7A11 decreased with all treatments. Under oxidative stress, viability declined. DEX restored CAT activity; IL-6 and IL-8 were reduced by both drugs, while combination additionally reduced TGF-β and IL-10. GPX4 increased with MTX and combination, ACSL4 with combination, and SLC7A11 with MTX.

Conclusions: MTX and DEX exert context-dependent effects in RPE cells. Basally, they induce adaptive preconditioning; under oxidative stress, combination therapy triggers a coordinated protective response. These findings support strategies integrating redox modulation, immune regulation, and ferroptosis control to preserve RPE function.

Chronic sleep deprivation (CSD) is increasingly recognized as a contributor to gut dysbiosis, systemic inflammation, and neurobehavioral impairments via the gut-brain axis. γ-Aminobutyric acid (GABA)-producing postbiotics, derived from microbial fermentation, offer potential in mitigating such dysfunctions. This study investigates the effects of GABA-producing postbiotics produced by Levilactobacillus brevis on CSD-induced gut and brain disturbances in mice. Male C57BL/6 mice were subjected to 30 days of sleep fragmentation and treated with low (250 mg/kg) or high (500 mg/kg) doses of postbiotics. Behavioral tests revealed that GABA-producing postbiotics significantly alleviated anxiety- and depression-like behaviors. Postbiotic treatment restored intestinal tight junction protein expression (ZO-1, Claudin-1), increased glutathione peroxidase activity, and reduced serum lipopolysaccharide and TNF-α levels, indicating improved intestinal barrier function and attenuated systemic inflammation. Postbiotic treatment promote the growth of beneficial genera such as Ruminococcus and Akkermansia, while also elevating fecal propanoic acid concentrations. In the brain, postbiotics upregulated blood-brain barrier (BBB) associated genes and reduced neuroinflammatory gene expression. Correlation analysis highlighted microbial signatures linked to short-chain fatty acids, intestinal tight junction proteins, serum LPS and TNF-α levels, as well as hypothalamic inflammatory, BBB gene expressions and anxiety. These findings suggest that GABA-producing postbiotics ameliorate CSD-induced gut-brain axis disruption by modulating the microbiota, restoring barrier functions, and suppressing systemic and neuroinflammation. This study supports the potential application of GABA-producing postbiotics as a dietary strategy to mitigate sleep loss-related physiological and behavioral impairments.

Hypertension remains a leading global cause of cardiovascular morbidity and mortality, with a significant proportion attributed to central nervous system (CNS) dysregulation. Emerging evidence implicates NADPH oxidases (Nox), particularly Nox2 and Nox4, as pivotal sources of reactive oxygen species (ROS) in brain regions critical for blood pressure control. This review explores the region-specific expression, activation mechanisms, and downstream effects of Nox isoforms within the CNS, focusing on the blood pressure regulatory brain regions, including paraventricular nucleus (PVN), rostral ventrolateral medulla (RVLM), nucleus tractus solitarius (NTS), and circumventricular organs (CVOs). Nox-derived ROS disrupt redox homeostasis, impair baroreflex sensitivity, induce neuroinflammation, and enhance sympathetic nervous system (SNS) activity. The interplay between Nox, the renin-angiotensin system (RAS), and mitochondrial ROS amplifies oxidative signaling and establishes a vicious cycle of neurovascular dysfunction. Furthermore, we will highlight the potential of Nox-targeted interventions and antioxidant therapies, emphasizing their therapeutic promise in attenuating neurogenic hypertension. A deeper understanding of CNS Nox signaling may pave the way for more effective and precise antihypertensive strategies.

Unraveling complex mechanisms of telomere biology is central to understanding the close link between aging and inflammation. Telomeres are repetitive heterochromatin DNA structures at the ends of eukaryotic chromosomes, and their length is universally accepted as a marker of biological aging. Telomeres progressively shorten with every cell division until they ultimately trigger cellular senescence and apoptosis. Telomere shortening is also promoted by chronic inflammation and oxidative stress. Chronic inflammation and oxidative stress have been shown to be key drivers of age-related diseases, including neurodegeneration, cardiovascular disease, and cancer. Telomerase is central regulator at the intersection of genomic stability, mitochondrial function, epigenetic integrity, and proteostasis. Through its direct and indirect actions, telomerase modulates inflammatory pathways that drive aging and age-related diseases, highlighting its potential as a therapeutic target to mitigate inflammaging and extend healthspan.