摘要: Osteosarcoma (OS) is a primary bone tumour that occurs mostly in adolescents and is associated with a high degree of malignancy, early metastasis, and poor prognosis. Pyropheophorbide-a methyl ester-Photodynamic therapy (MPPa-PDT) is a new approach for the clinical treatment of osteosarcoma that develops after surgery and radiotherapy; however, the presence of MPPa-PDT resistance in osteosarcoma greatly limits its efficacy. In this study, we found that Rho-associated coiled-coil containing protein kinase 2 (ROCK2) expression increased in osteosarcoma cells after MPPa-PDT treatment. ROCK2 inhibition results in osteosarcoma sensitivity to MPPa-PDT and is accompanied by a decrease in cellular autophagy levels. Rescue experiments further showed that ROCK2 mediates MPPa-PDT resistance in osteosarcoma by regulating autophagy. Mechanistic studies have shown that ROCK2 mediates autophagy in osteosarcoma cells by regulating the Hippo signalling pathway. ROCK2 overexpression resulted in increased levels of the ROCK2-Salvador homology 1 (SAV1) complex and decreased levels of the mammalian STE20-like protein kinase 1 (MST1)-SAV1 complex, thereby inhibiting activation of the Hippo pathway, which in turn led to osteosarcoma MPPa-PDT resistance by regulating cellular autophagy. ROCK2 competes with MST1 for binding to the aa 28-198 region of SAV1. We also confirmed from a clinical perspective that ROCK2 is an independent prognostic factor in patients with osteosarcoma, is associated with worse patient prognosis, and correlates with the Hippo pathway. Targeted inhibition of ROCK2 by screening for J059-0149 increases the sensitivity of osteosarcoma to MPPa-PDT. In conclusion, our study establishes a novel mechanism to reverse MPPa-PDT resistance in osteosarcoma by targeting ROCK2-mediated autophagy, providing new targets and research ideas for the clinical treatment of osteosarcoma MPPa-PDT resistance.

摘要: High altitude pulmonary hypertension (HAPH) is a complex disease featured by hypoxia-induced pulmonary vasoconstriction and remodelling of small pulmonary arterioles, which could lead to increased pulmonary pressures and right ventricular hypertrophy and eventually result in heart failure. The temporal trajectory of HAPH progression can be divided into three overlapping phases: hypoxic pulmonary arterioles vasoconstriction, hypoxic pulmonary arterioles remodelling and even right heart failure. Each phase is governed by distinct molecular engines and cellular effectors that translate hypoxia physiological adaption into irreversible cardiopulmonary dysfunction. This review describes the intricate cellular signalling networks involved in the pathogenesis of HAPH, integrating canonical pathways such as HIF, MAPK and BMP with emerging targets like Wnt/beta-catenin, Notch, Hippo-YAP and IL-6. Inhibiting the HIF signalling pathway, modulating the MAPK pathway and suppressing the BMP, Wnt/beta-catenin, Notch, Hippo-YAP and IL-6 pathways have shown potential in reducing vascular remodelling and right ventricular dysfunction. Despite encouraging progress, the clinical translation remains constrained by a lack of deeper understanding of the signalling networks in HAPH. A comprehensive understanding of these signalling pathways in HAPH may yield critical insights into the disease's pathogenesis and facilitate the development of targeted intervention strategies. Future research should focus on elucidating the molecular mechanisms underlying these pathways, exploring genetic and environmental interactions, validating intervention targets, developing biomarkers, utilising systems biology approaches and conducting clinical trials.

摘要: Breast cancer remains the most prevalent malignancy among women, and radiotherapy plays a pivotal role in reducing local recurrence and improving prognosis. However, the emergence of radioresistance in a subset of patients significantly compromises treatment efficacy, underscoring the need for a deeper understanding of the underlying molecular mechanisms. In recent years, non-coding RNAs (ncRNAs) have emerged as key regulators of gene expression and have garnered increasing attention for their roles in mediating radioresistance in breast cancer. This review systematically summarises the major molecular mechanisms by which ncRNAs contribute to breast cancer radioresistance, including cell cycle regulation, DNA damage repair, programmed cell death (e.g., apoptosis, autophagy and ferroptosis), oxidative stress response, tumour microenvironment remodelling and maintenance of cancer stem cell properties. On the translational front, RNA-based therapeutic approaches-including antisense oligonucleotides (ASOs), small interfering RNAs (siRNAs), miRNA mimics and CRISPR/Cas9-offer promising avenues for radiosensitisation, yet face substantial clinical hurdles. These include immune activation, poor delivery specificity, intracellular trafficking barriers and limited stability. Advances in chemical modifications and nanoparticle-based delivery systems-such as redox-responsive nanocarriers-have shown potential in enhancing the efficacy and safety of ncRNA-targeted therapies. Despite encouraging progress, clinical translation remains constrained by a lack of methodological standardisation, insufficient high-quality clinical data, limited biomarker reliability, suboptimal target selection and unresolved safety concerns. Future efforts should prioritise optimisation of delivery platforms, validation of multi-ncRNA biomarker panels in large, multicentre cohorts and integration of multi-omics data to reconstruct comprehensive regulatory networks, ultimately accelerating the clinical deployment of ncRNA-based radiosensitisation strategies.

摘要: Melasma is a recurrent and treatment-resistant hyperpigmentation disorder characterized by a complex and multifactorial pathogenesis. However, the lack of a stable and reliable animal model has hindered systematic investigations into its onset and progression. In this study, we established a melasma-like model in C57BL/6J mice by combining broadband UVB irradiation, intramuscular progesterone administration, and induced emotional stress. The affected skin areas exhibited irregular, brown hyperpigmented patches. Histopathological analysis revealed an accumulation of melanin granules in the epidermis and superficial dermis, elevated levels of tyrosinase (TYR) in both skin and plasma, systemic oxidative stress imbalance, and reduced autophagic activity in the lesional skin. Furthermore, this model displayed distinct differences from a UV-induced post-inflammatory hyperpigmentation (PIH) model. Notably, the melasma-like mice responded to tranexamic acid treatment in a manner that closely resembled clinical outcomes observed in human patients. Collectively, these findings establish a stable, reproducible, and clinically relevant mouse model of melasma, providing a valuable platform for future research into its pathogenesis and treatment.

摘要: Metabolic disorders could cause dysregulated glucose and lipid at the systemic level, but how inter-tissue/organ communications contribute to glucolipotoxicity is difficult to dissect in animal models. To solve this problem, myocardium and nerve tissues were modelled by 3D engineered heart tissues (EHTs) and neural organoids (NOs), which were co-cultured in a generalised medium with normal or elevated glucose/fatty acid contents. Morphology, gene expression, cell death and functional assessments detected no apparent alterations of EHTs and NOs in co-culture under normal conditions. By contrast, NOs significantly ameliorated glucolipotoxicity in EHTs. Transcriptomic and protein secretion assays identified the extracellular matrix protein versican as a key molecule that was transferred from NOs into EHTs in the high-glucose/fatty acid condition. Recombinant versican protein treatment was sufficient to reduce glucolipotoxicity in EHTs. Adeno-associated virus-delivered versican overexpression was sufficient to ameliorate cardiac dysfunction in a murine model of diabetic cardiomyopathy. These data provide the proof-of-concept evidence that inter-tissue/organ communications exist in the co-culture of engineered tissues and organoids, which could be systemically studied to explore potential pathological mechanisms and therapeutic strategies for multi-organ diseases in vitro.