Molecular and Cellular Biochemistry最新文献

Interstitial lung diseases (ILDs) are a group of pulmonary disorders characterized by fibrosis, inflammation, and lung tissue deterioration. Anti-melanoma differentiation-associated gene 5-positive dermatomyositis-associated interstitial lung disease (MDA5-ILD), a subtype, is associated with high mortality due to rapid progression and severe lung damage. Volatile organic compounds (VOCs) in exhaled breath, reflecting metabolic changes, have been identified as potential non-invasive biomarkers for various diseases, including respiratory conditions. However, their role in MDA5-ILD has not been extensively studied. This retrospective cohort study included 45 exhaled breath samples from 19 ILD patients, with 31 samples from 9 patients with MDA5-ILD and 10 samples from 7 patients with non-MDA5-ILD. VOCs were collected using thermal desorption tubes and analyzed via gas chromatography-mass spectrometry (GC-MS). Clinical data, including the APACHE II score, were integrated with VOC profiles. Two logistic regression models were developed: Model 1 based on 11 clinical indicators, and Model 2 integrating 11 clinical indicators with 5 VOC features. Model performance was evaluated using receiver operating characteristic (ROC) curve analysis, sensitivity, specificity, and accuracy metrics. Five VOCs-N-(2-Aziridinyl)ethanamine, Cyclohexanone, Nonanal, Dodecamethylcyclohexasiloxane, and 4-Methyltetradecane-were identified as significant biomarkers distinguishing MDA5-ILD from non-MDA5-ILD. Model 2, which integrated VOC data, outperformed Model 1, achieving an area under the curve (AUC) of 0.93 compared to 0.70. Model 2 also demonstrated enhanced accuracy (84.6% vs. 76.9%), specificity (66.7% vs. 33.3%), precision (90.0% vs. 81.8%), and F1-score (90.0% vs. 85.7%). Additionally, 1,3-Pentadiene and 3-Methylundecane were identified as potential markers of disease severity, with 1,3-Pentadiene negatively correlating and 3-Methylundecane positively correlating with both APACHE II scores and creatinine levels. VOCs in exhaled breath significantly enhance the diagnostic sensitivity and accuracy for detecting MDA5-ILD. In addition, VOCs show promise as disease severity markers, potentially aiding in the assessment of disease severity and progression. While the integration of VOCs holds great potential for improving diagnostic performance, further validation through larger, multicenter studies is necessary.

Stem cell-derived extracellular vesicles (SC-EVs) are one huge promise in skin regenerative medicine, similar in advantages to stem cells with low immunerejection and tumor formations. These microvesicles are laden with microRNAs, which assist in wound healing via angiogenesis and immune modulation. However, quick degradation and poor cellular uptake limit their regenerative capacity. Thanks to their adjustable characteristics, hydrogels can act as vehicles for transporting and sustainably releasing miRNA-SC-EVs at injury sites. Therefore, a systematic literature review was conducted on miRNA-enriched SC-EVs incorporated into hydrogels in animal skin regeneration models published from 2010 to 2024 (PROSPERO ID: CRD42024588072). Out of the 89 records, 12 met the criteria. Diabetic wounds are characterized by chronic inflammation, oxidative stress, and defective macrophage polarization, resulting in less satisfactory regeneration. The hydrogels tackled these issues by shifting macrophages from a pro-inflammatory M1 phenotype to a healing M2 phenotype, promoting collagen production, enhancing fibroblast movement, and boosting angiogenesis. Burn injuries frequently lead to slow recovery due to hypertrophic scarring, extended inflammation, and infection. Hyaluronic acid (HA)-derived hydrogels, infused with miR-21-5p and surface-treated with polydopamine and cationic antimicrobial peptides, promoted wound healing by lowering scarring and demonstrating anti-inflammatory, anti-apoptotic, and pro-angiogenic characteristics. The cell adhesion of these hydrogels can be enhanced by adding MOFs, chitosan, and extracellular matrix elements. The application of stimulus-responsive or stage-specific hydrogels is another mode of targeted healing. Further research and clinical trials will enhance the wound-healing efficiency of hybrid hydrogels.

Previous studies have shown that ginger-derived extracellular vesicles (Gin-EVs) can alleviate alcohol-induced liver injury. It remained unknown and needs to be further verified that whether the vesicles has therapeutic potential to alleviate the progression of liver fibrosis. Moreover, the relevant mechanisms need to be further studied. Herein, we provide evidence that Gin-EVs effectively interact with human hepatic stellate cells (LX-2), offering protection against carbon tetrachloride (CCL4) or lipopolysaccharides (LPS)-induced liver fibrosis. The treatment with Gin-EVs was observed to mitigate fibrosis and enhance cell viability in LX-2 cells exposed to CCL4 or LPS. Mechanistically, Gin-EVs counteracted mitochondrial dysfunction by restoring mitochondrial dynamics imbalance characterized by enhanced fusion and reduced fission events while promoting mitochondrial biogenesis, thereby potentially preventing fibrotic processes in LX-2 cells. Collectively, the findings highlight the direct cytoprotective effects of Gin-EVs on LX-2 cells and suggest their promising role as a therapeutic option for hepatic fibrosis.

Myocardial infarction is a cardiovascular disease that poses a serious threat to human health. The traditional view is that adult mammalian cardiomyocytes have almost no regenerative ability, but recent studies have shown that they have regenerative potential under specific conditions. This article comprehensively describes the research progress of post-infarction cardiomyocyte regeneration, including the characteristics of cardiomyocytes and post-infarction changes, regeneration mechanisms, influencing factors, potential therapeutic strategies, challenges and future development directions, and deeply discusses the specific pathways and targets included in the regeneration mechanism, aiming to provide new ideas and methods for the treatment of myocardial infarction.

The association between insulin resistance (IR), type 2 diabetes mellitus (T2DM), and cancer is increasingly recognized and poses an escalating global health challenge, as the incidence of these conditions continues to rise. Studies indicate that individuals with T2DM have a 10-20% increased risk of developing various solid tumors, including colorectal, breast, pancreatic, and liver cancers. The relative risk (RR) varies depending on cancer type, with pancreatic and liver cancers showing a particularly strong association (RR 2.0-2.5), while colorectal and breast cancers demonstrate a moderate increase (RR 1.2-1.5). Understanding these epidemiological trends is crucial for developing integrated management strategies. Given the global rise in T2DM and cancer cases, exploring the complex relationship between these conditions is critical. IR contributes to hyperglycemia, chronic inflammation, and altered lipid metabolism. Together, these factors create a pro-tumorigenic environment conducive to cancer development and progression. In individuals with IR, hyperinsulinemia triggers the insulin-insulin-like growth factor (IGF1R) signaling pathway, activating cancer-associated pathways such as mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PIK3CA), which promote cell proliferation and survival, thereby supporting tumor growth. Both IR and T2DM are linked to increased morbidity and mortality in patients with cancer. By providing an in-depth analysis of the molecular links between insulin resistance and cancer, this review offers valuable insights into the role of metabolic dysfunction in tumor progression. Addressing insulin resistance as a co-morbidity may open new avenues for risk assessment, early intervention, and the development of integrated treatment strategies to improve patient outcomes.

Cytosolic free Zn²⁺ level ([Zn²⁺]_Cyt) is tightly regulated by Zn²⁺ transporters, under both physiological and pathological conditions. At the cellular level, dysregulated free Zn²⁺ levels have been linked to metabolic and cardiovascular diseases, primarily through their association with various Zn²⁺ transporters. However, the role and localization of ZnT6 in cardiomyocytes remain unclear. Previous studies have shown a significant increase in ZnT6 expression in insulin-resistant cardiomyocytes, suggesting a potential link between ZnT6 dysregulation and cardiac cell dysfunction. Therefore, here, we investigated the impact of ZnT6 overexpression (ZnT6-OE) on cellular Zn²⁺ distribution, mitochondrial dynamics, and autophagy-induced apoptosis in H9c2 cardiomyocytes. Using confocal imaging, biochemical assays, and electron microscopy, we demonstrated the mitochondrial localization of ZnT6 and its role in H9c2 cells. Our findings showed that ZnT6 overexpression led to a significant increase in mitochondrial free Zn²⁺ level ([Zn²⁺]_Mit) with a significant reduction in [Zn²⁺]_Cyt, which seems to be associated with enhanced numbers of mitochondria and mitochondrial fission process. Specifically, the ZnT6-OE cells exhibited increased dynamin-related protein 1 (DRP1) translocation to mitochondria which is an indication of excessive fission activity. We also determined severe mitochondrial dysfunction in ZnT6-OE cells, such as depolarization in mitochondrial membrane potential, production of excessive reactive oxygen species (ROS), reduced ATP levels, and autophagosome accumulation. Furthermore, these impairments were accompanied by elevated apoptotic markers, indicating autophagy-induced apoptosis. Our findings highlight ZnT6 as a critical regulator of mitochondrial dynamics and function in cardiomyocytes, contributing to disruption Zn²⁺ homeostasis by its overexpression, triggering excessive DRP1-mediated mitochondrial fission and leading to mitochondrial dysfunction, oxidative stress, and apoptotic cell death, suggesting an important impact of ZnT6 dysregulation on cardiomyocyte pathophysiology in metabolic disorders.

Radiotherapy is a vital treatment agent for lung adenocarcinoma (LUAD) patients, while radioresistance remains a major factor in treatment failure. Here, we aimed to elucidate how signal transducer and activator of transcription 1 (STAT1) affected sensitivity to carbon ion irradiation for LUAD cells in vivo and in vitro. The results of colony formation, CCK-8, EdU, and calcein-AM/PI double-staining assays demonstrated that the overexpression of STAT1 markedly enhanced the inhibitory effect of carbon ion irradiation on the viability of LUAD cells (A549 and PC9 cells). Lactate dehydrogenase (LDH) leakage assays identified ferroptosis as the predominant form of cell death induced by STAT1 overexpression in LUAD cells. Meanwhile, the ferroptosis-related PCR array confirmed heme oxygenase 1 (HO-1) as a potential effector molecule of STAT1-induced ferroptosis. Mechanistically, STAT1 overexpression resulted in phosphorylation at the serine 727 residue, triggering the upregulation of HO-1 expression and subsequent labile iron pool (LIP) accumulation. This process amplified the Fenton reaction, leading to increased reactive oxygen species (ROS), lipid peroxides (LPO), and glutathione (GSH) depletion. HO-1 knockdown eliminated the ferroptosis induced by the overexpression of STAT1. Furthermore, in vivo experiments showed that STAT1 overexpression enhanced the effect of carbon ion irradiation in inhibiting the growth of subcutaneous tumors in nude mice. These findings provide the foundation for the development of the STAT1-HO-1 axis as a radiosensitization target for LUAD patients.

We report the identification of two pathogenic variants in the ABCG2 gene, encoding a urate exporter, in two probands (male and female) with severe familial gouty phenotypes and hyperuricemia. Clinico-genetic analyses identified p.I63YfsTer54 (rs565722112) and p.G74D (rs199976573) as potentially causal mutations; functional analyses demonstrated that these two variants are deficient in plasma membrane localization and functionally null. Our data show that dysfunctional variants in the ABCG2 gene are strong risk factors for hyperuricemia and gout in both males and females.

Chondrocytes in articular cartilage can secrete extracellular matrix to maintain cartilage homeostasis. It is well known that articular cartilage chondrocytes are sensitive to mechanical loading and that mechanical stimuli can be translated to biological processes. This study provides deep insight into the impact of mechanical loading on chondrocytes via single-cell RNA sequencing (scRNA-seq). Five cartilage tissue samples from the high-loading region of medial cartilage from the upper tibia (the TL group) and six cartilage tissue samples from the low-loading region of lateral cartilage from the upper tibia (the TN group) were obtained from six donors and subjected to scRNA-seq. TL and TN cartilage tissues from another donor were subjected to immunohistochemical staining. In total, 132,685 cells were analyzed and assigned to 11 cell types. The functions, developmental relationships and interactions of these cell types were determined, and gene transcription data were also evaluated. In addition, differentially expressed genes between the TL and TN groups and their functions were identified. The hub genes for the TL group were identified as GAPDH, FN1, VEGFA, LDHA, SOD1, CTGF, DCN, SERPINE1, ENO1 and CAV1, whereas the hub genes for the TN group included ACTB, CD44, MMP2, COL1A1, COL1A2, SPP1, CTGF, MYC, CCL2, and IGF1. The different enrichment terms indicated that physiological mechanical loading may induce reactive oxygen species accumulation and thus cause ferroptosis in chondrocytes.

The acute and large area skin healing has been an intractable problem for both clinician and patient. Exosomes derived from human-induced pluripotent stem cells (hiPSC-Exos) have been a novel promising cell-free treatment on skin damage repair. In this study, in vivo skin trauma model of full-layer skin damage on mouse back and in vitro skin-like trauma model of human keratinocytes (HaCaT) scratches were established to investigate the effects of hiPSC-Exos on the acute wound healing, and its potential regulation mechanism would be tried to explore. Our in vivo results showed that hiPSC-Exos labeled with PKH26 could be well taken up by cells in the wound area, and could effectively accelerate acute skin wound healing by inhibiting the mRNA expressions of inflammation factors and chemokines such as Il-1β, Ccl2, Cxcl5, Ccl7 as well as promoting PCNA positive cell ratio. The in vitro data showed that hiPCS-Exos could markedly increase the numbers of EdU positive keratinocytes and expedite keratinocyte migration, which could be reversed by fibroblast growth factor receptor 3 (FGFR3) antagonist AZD4547 and p38 inhibitor SB203580. In addition, fibroblast growth factor 2 (FGF-2) was existent in hiPSC-Exos, and hiPSC-Exos could upregulate the p-p38/p38 level, which could be significantly reversed by AZD4547, but not affect the p-ERK/ERK and p-JNK/JNK levels in wound model tissues and cells. In conclusion, hiPSC-Exos may have the potential to promote wound healing by inhibiting cell inflammation as well as promoting cell proliferation and migration based on inherent FGF-2 targeting to FGFR3 to activate p38 pathway, which may serve as a promising candidate for skin healing.