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Neural Regeneration Research Feb 2025JOURNAL/nrgr/04.03/01300535-202502000-00030/figure1/v/2024-05-28T214302Z/r/image-tiff In patients with Alzheimer's disease, gamma-glutamyl transferase 5 (GGT5)...
JOURNAL/nrgr/04.03/01300535-202502000-00030/figure1/v/2024-05-28T214302Z/r/image-tiff In patients with Alzheimer's disease, gamma-glutamyl transferase 5 (GGT5) expression has been observed to be downregulated in cerebrovascular endothelial cells. However, the functional role of GGT5 in the development of Alzheimer's disease remains unclear. This study aimed to explore the effect of GGT5 on cognitive function and brain pathology in an APP/PS1 mouse model of Alzheimer's disease, as well as the underlying mechanism. We observed a significant reduction in GGT5 expression in two in vitro models of Alzheimer's disease (Aβ1-42-treated hCMEC/D3 and bEnd.3 cells), as well as in the APP/PS1 mouse model. Additionally, injection of APP/PS1 mice with an adeno-associated virus encoding GGT5 enhanced hippocampal synaptic plasticity and mitigated cognitive deficits. Interestingly, increasing GGT5 expression in cerebrovascular endothelial cells reduced levels of both soluble and insoluble amyloid-β in the brains of APP/PS1 mice. This effect may be attributable to inhibition of the expression of β-site APP cleaving enzyme 1, which is mediated by nuclear factor-kappa B. Our findings demonstrate that GGT5 expression in cerebrovascular endothelial cells is inversely associated with Alzheimer's disease pathogenesis, and that GGT5 upregulation mitigates cognitive deficits in APP/PS1 mice. These findings suggest that GGT5 expression in cerebrovascular endothelial cells is a potential therapeutic target and biomarker for Alzheimer's disease.
PubMed: 38819065
DOI: 10.4103/NRR.NRR-D-23-01525 -
Neural Regeneration Research Feb 2025Subretinal fibrosis is the end-stage sequelae of neovascular age-related macular degeneration. It causes local damage to photoreceptors, retinal pigment epithelium, and...
Subretinal fibrosis is the end-stage sequelae of neovascular age-related macular degeneration. It causes local damage to photoreceptors, retinal pigment epithelium, and choroidal vessels, which leads to permanent central vision loss of patients with neovascular age-related macular degeneration. The pathogenesis of subretinal fibrosis is complex, and the underlying mechanisms are largely unknown. Therefore, there are no effective treatment options. A thorough understanding of the pathogenesis of subretinal fibrosis and its related mechanisms is important to elucidate its complications and explore potential treatments. The current article reviews several aspects of subretinal fibrosis, including the current understanding on the relationship between neovascular age-related macular degeneration and subretinal fibrosis; multimodal imaging techniques for subretinal fibrosis; animal models for studying subretinal fibrosis; cellular and non-cellular constituents of subretinal fibrosis; pathophysiological mechanisms involved in subretinal fibrosis, such as aging, infiltration of macrophages, different sources of mesenchymal transition to myofibroblast, and activation of complement system and immune cells; and several key molecules and signaling pathways participating in the pathogenesis of subretinal fibrosis, such as vascular endothelial growth factor, connective tissue growth factor, fibroblast growth factor 2, platelet-derived growth factor and platelet-derived growth factor receptor-β, transforming growth factor-β signaling pathway, Wnt signaling pathway, and the axis of heat shock protein 70-Toll-like receptors 2/4-interleukin-10. This review will improve the understanding of the pathogenesis of subretinal fibrosis, allow the discovery of molecular targets, and explore potential treatments for the management of subretinal fibrosis.
PubMed: 38819041
DOI: 10.4103/NRR.NRR-D-23-01642 -
Neural Regeneration Research Feb 2025Retinal aging has been recognized as a significant risk factor for various retinal disorders, including diabetic retinopathy, age-related macular degeneration, and...
Retinal aging has been recognized as a significant risk factor for various retinal disorders, including diabetic retinopathy, age-related macular degeneration, and glaucoma, following a growing understanding of the molecular underpinnings of their development. This comprehensive review explores the mechanisms of retinal aging and investigates potential neuroprotective approaches, focusing on the activation of transcription factor EB. Recent meta-analyses have demonstrated promising outcomes of transcription factor EB-targeted strategies, such as exercise, calorie restriction, rapamycin, and metformin, in patients and animal models of these common retinal diseases. The review critically assesses the role of transcription factor EB in retinal biology during aging, its neuroprotective effects, and its therapeutic potential for retinal disorders. The impact of transcription factor EB on retinal aging is cell-specific, influencing metabolic reprogramming and energy homeostasis in retinal neurons through the regulation of mitochondrial quality control and nutrient-sensing pathways. In vascular endothelial cells, transcription factor EB controls important processes, including endothelial cell proliferation, endothelial tube formation, and nitric oxide levels, thereby influencing the inner blood-retinal barrier, angiogenesis, and retinal microvasculature. Additionally, transcription factor EB affects vascular smooth muscle cells, inhibiting vascular calcification and atherogenesis. In retinal pigment epithelial cells, transcription factor EB modulates functions such as autophagy, lysosomal dynamics, and clearance of the aging pigment lipofuscin, thereby promoting photoreceptor survival and regulating vascular endothelial growth factor A expression involved in neovascularization. These cell-specific functions of transcription factor EB significantly impact retinal aging mechanisms encompassing proteostasis, neuronal synapse plasticity, energy metabolism, microvasculature, and inflammation, ultimately offering protection against retinal aging and diseases. The review emphasizes transcription factor EB as a potential therapeutic target for retinal diseases. Therefore, it is imperative to obtain well-controlled direct experimental evidence to confirm the efficacy of transcription factor EB modulation in retinal diseases while minimizing its risk of adverse effects.
PubMed: 38819040
DOI: 10.4103/NRR.NRR-D-23-02033 -
Journal of Cancer 2024Tumor angiogenesis is closely related to the progression of clear cell renal cell carcinoma (ccRCC). Long non-coding RNAs (lncRNAs) regulating angiogenesis could be...
Tumor angiogenesis is closely related to the progression of clear cell renal cell carcinoma (ccRCC). Long non-coding RNAs (lncRNAs) regulating angiogenesis could be potential biomarkers for predicting ccRCC prognosis. With this study, we aimed to construct a prognostic model based on lncRNAs and explore its underlying mechanisms. RNA data and clinical information were obtained from The Cancer Genome Atlas (TCGA) database. Angiogenesis-related genes (ARGs) were extracted from the Molecular Signatures database. Pearson correlation and LASSO and COX regression analyses were performed to identify survival-related AR-lncRNAs (sAR-lncRNAs) and construct a prognostic model. The predictive power of the prognostic model was verified according to Kaplan‒Meier curve, receiver operating characteristic (ROC) curve and nomogram analyses. The correlation between the prognostic model and clinicopathological characteristics was assessed via univariate and multivariate analyses. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis was subsequently performed to elucidate the mechanisms of the sAR-lncRNAs. In vitro qPCR, immunohistochemistry, migration and invasion assays were conducted to confirm the angiogenic function of sAR-lncRNAs. Three sAR-lncRNAs were used to construct a prognostic model. The model was moderately accurate in predicting 1- , 3- and 5-year ccRCC prognosis, and the risk score according to this model was closely related to clinicopathological characteristics such as T grade and T stage. A nomogram was constructed to precisely estimate the overall survival of ccRCC patients. KEGG enrichment analysis indicated that the MAPK and Notch pathways were highly enriched in high-risk patients. Additionally, we found that the expression of the lncRNAs AC005324.4 and AC104964.4 in the prognostic model was lower in ccRCC cell lines and cancer tissues than in the HK-2 cell line and paracancerous tissues, while the expression of the lncRNA AC087482.1 showed the opposite trend. In a coculture model, knockdown of lncRNA AC005324.4 and lncRNA AC104964.4 significantly promoted the migration and invasion of human umbilical vein endothelial cells (HUVECs), but siR-AC087482.1 transfection alleviated these effects. We constructed a prognostic model based on 3 sAR-lncRNAs and validated its value in clinicopathological characteristics and prognostic prediction of ccRCC patients, providing a new perspective for ccRCC treatment decision making.
PubMed: 38817877
DOI: 10.7150/jca.94685 -
Journal of Cancer 2024The innate immune system serves as the body's primary physiological defense against the intrusion of pathogenic microorganisms, playing a pivotal role in restricting...
The innate immune system serves as the body's primary physiological defense against the intrusion of pathogenic microorganisms, playing a pivotal role in restricting viral infections. However, current research on the interplay between innate immune pathways and cancer is limited, with reported effects often inconsistent. Therefore, we aimed to elucidate the relationship between innate immune pathways and tumors through an amalgamation of bioinformatics and extensive data analysis. Conducting a pan-cancer analysis encompassing expression, genomic alterations, and clinical prognosis, we identified a close association between the innate immune pathway and cholangiocarcinoma. Subsequently, our focus shifted to unraveling the role of innate immune pathway proteins in cholangiocarcinoma. TIMER database analysis showed that the innate immune pathway predominantly influences the infiltration of macrophages and B cells in cholangiocarcinoma. Additionally, gene ontology (GO) and pathway analyses were performed for significantly differentially expressed genes correlated with the innate immune pathway in cholangiocarcinoma. Single-cell transcriptome analysis in cholangiocarcinoma demonstrated that genes in the innate immune pathway are primarily expressed in malignant cells, endothelial cells, monocytes and macrophages. To further validate the expression of proteins in the innate immune pathway in the tumor tissues of patients with cholangiocarcinoma, tumor tissue slices from patients with liver intrahepatic cholangiocarcinoma and normal tissue slices from the HPA database were analyzed. These results indicated pronounced activation of the innate immune pathway in the tumor tissues of patients with cholangiocarcinoma. Finally, proteomic data from patients with or without intrahepatic cholangiocarcinoma metastasis were analyzed. The results revealed a significant correlation between the expression and phosphorylation of IKKε and the occurrence of intrahepatic cholangiocarcinoma metastasis. These findings not only demonstrate the significance of the innate immune pathway in cholangiocarcinoma but also its potential as a prospective prognostic biomarker and therapeutic target for this malignancy.
PubMed: 38817870
DOI: 10.7150/jca.94194 -
Journal of Cancer 2024Platinum-based chemotherapy is effective but limited by resistance in high-grade serous ovarian cancer (HGSOC). Single-cell RNA sequencing (scRNA-seq) can reveal tumour...
Platinum-based chemotherapy is effective but limited by resistance in high-grade serous ovarian cancer (HGSOC). Single-cell RNA sequencing (scRNA-seq) can reveal tumour cell heterogeneity and subclonal differentiation. We aimed to analyze resistance mechanisms and potential targets in HGSOC using scRNA-seq. We performed 10× genomics scRNA-seq sequencing on tumour tissues from 3 platinum-sensitive and 3 platinum-resistant HGSOC patients. We analyzed cell subcluster communication networks and spatial distribution using cellchat. We performed RNA-seq analysis on TACSTD2, a representative resistance gene in the E0 subcluster, to explore its molecular mechanism. Epithelial cells, characterized by distinct chemotherapy resistance traits and highest gene copy number variations, revealed a specific cisplatin-resistant cluster (E0) associated with poor prognosis. E0 exhibited malignant features related to resistance, fostering growth through communication with fibroblasts and endothelial cells. Spatially, E0 promoted fibroblasts to protect tumour cells and impede immune cells infiltration. Furthermore, TACSTD2 was identified as a representative gene of the E0 subcluster, elucidating its role in platinum resistance through the Rap1/PI3K/AKT pathway. Our study reveals a platinum-resistant epithelial cell subcluster E0 and its association with TACSTD2 in HGSOC, uncovers new insights and evidence for the platinum resistance mechanism, and provides new ideas and targets for the development of therapeutic strategies against TACSTD2+ epithelial cancer cells.
PubMed: 38817863
DOI: 10.7150/jca.95269 -
World Journal of Stem Cells May 2024Atherosclerosis (AS), a chronic inflammatory disease of blood vessels, is a major contributor to cardiovascular disease. Dental pulp stem cells (DPSCs) are capable of...
BACKGROUND
Atherosclerosis (AS), a chronic inflammatory disease of blood vessels, is a major contributor to cardiovascular disease. Dental pulp stem cells (DPSCs) are capable of exerting immunomodulatory and anti-inflammatory effects by secreting cytokines and exosomes and are widely used to treat autoimmune and inflammation-related diseases. Hepatocyte growth factor (HGF) is a pleiotropic cytokine that plays a key role in many inflammatory and autoimmune diseases.
AIM
To modify DPSCs with HGF (DPSC-HGF) and evaluate the therapeutic effect of DPSC-HGF on AS using an apolipoprotein E-knockout (ApoE) mouse model and an cellular model.
METHODS
ApoE mice were fed with a high-fat diet (HFD) for 12 wk and injected with DPSC-HGF or Ad-Null modified DPSCs (DPSC-Null) through tail vein at weeks 4, 7, and 11, respectively, and the therapeutic efficacy and mechanisms were analyzed by histopathology, flow cytometry, lipid and glucose measurements, real-time reverse transcription polymerase chain reaction (RT-PCR), and enzyme-linked immunosorbent assay at the different time points of the experiment. An inflammatory cell model was established by using RAW264.7 cells and human aortic endothelial cells (HAOECs), and indirect co-cultured with supernatant of DPSC-Null (DPSC-Null-CM) or DPSC-HGF-CM, and the effect and mechanisms were analyzed by flow cytometry, RT-PCR and western blot. Nuclear factor-κB (NF-κB) activators and inhibitors were also used to validate the related signaling pathways.
RESULTS
DPSC-Null and DPSC-HGF treatments decreased the area of atherosclerotic plaques and reduced the expression of inflammatory factors, and the percentage of macrophages in the aorta, and DPSC-HGF treatment had more pronounced effects. DPSCs treatment had no effect on serum lipoprotein levels. The FACS results showed that DPSCs treatment reduced the percentages of monocytes, neutrophils, and M1 macrophages in the peripheral blood and spleen. DPSC-Null-CM and DPSC-HGF-CM reduced adhesion molecule expression in tumor necrosis factor-α stimulated HAOECs and regulated M1 polarization and inflammatory factor expression in lipopolysaccharide-induced RAW264.7 cells by inhibiting the NF-κB signaling pathway.
CONCLUSION
This study suggested that DPSC-HGF could more effectively ameliorate AS in ApoE mice on a HFD, and could be of greater value in stem cell-based treatments for AS.
PubMed: 38817328
DOI: 10.4252/wjsc.v16.i5.575 -
World Journal of Stem Cells May 2024Bone healing is a complex process involving early inflammatory immune regulation, angiogenesis, osteogenic differentiation, and biomineralization. Fracture repair poses...
BACKGROUND
Bone healing is a complex process involving early inflammatory immune regulation, angiogenesis, osteogenic differentiation, and biomineralization. Fracture repair poses challenges for orthopedic surgeons, necessitating the search for efficient healing methods.
AIM
To investigate the underlying mechanism by which hydrogel-loaded exosomes derived from bone marrow mesenchymal stem cells (BMSCs) facilitate the process of fracture healing.
METHODS
Hydrogels and loaded BMSC-derived exosome (BMSC-exo) gels were characterized to validate their properties. evaluations were conducted to assess the impact of hydrogels on various stages of the healing process. Hydrogels could recruit macrophages and inhibit inflammatory responses, enhance of human umbilical vein endothelial cell angiogenesis, and promote the osteogenic differentiation of primary cranial osteoblasts. Furthermore, the effect of hydrogel on fracture healing was confirmed using a mouse fracture model.
RESULTS
The hydrogel effectively attenuated the inflammatory response during the initial repair stage and subsequently facilitated vascular migration, promoted the formation of large vessels, and enabled functional vascularization during bone repair. These effects were further validated in fracture models.
CONCLUSION
We successfully fabricated a hydrogel loaded with BMSC-exo that modulates macrophage polarization and angiogenesis to influence bone regeneration.
PubMed: 38817325
DOI: 10.4252/wjsc.v16.i5.499 -
PloS One 2024Coronary microvascular dysfunction (CMD) is a critical pathogenesis of cardiovascular diseases. Lower endothelial nitric oxide synthase (eNOS) phosphorylation leads to...
Coronary microvascular dysfunction (CMD) is a critical pathogenesis of cardiovascular diseases. Lower endothelial nitric oxide synthase (eNOS) phosphorylation leads to reduced endothelium-derived relaxing factor nitric oxide (NO) generation, causing and accelerating CMD. Endoplasmic reticulum stress (ER stress) has been shown to reduce NO production in umbilical vein endothelial cells. Oxidized low-density lipoprotein (ox-LDL) damages endothelial cell function. However, the relationship between ox-LDL and coronary microcirculation has yet to be assessed. Short-chain fatty acid (SCFA), a fermentation product of the gut microbiome, could improve endothelial-dependent vasodilation in human adipose arterioles, but the effect of SCFA on coronary microcirculation is unclear. In this study, we found ox-LDL stimulated expression of ER chaperone GRP78. Further, we activated downstream PERK/eIF2a, IRE1/JNK, and ATF6 signaling pathways, decreasing eNOS phosphorylation and NO production in human cardiac microvascular endothelial. Furthermore, SCFA-propionate can inhibit ox-LDL-induced eNOS phosphorylation reduction and raise NO production; the mechanism is related to the inhibition of ER stress and downstream signaling pathways PERK/eIF2a, IRE1/JNK, and ATF6. In summary, we demonstrate that ox-LDL induced CMD by activating ER stress, propionate can effectively counteract the adverse effects of ox-LDL and protect coronary microcirculation function via inhibiting ER stress.
Topics: Humans; Endoplasmic Reticulum Stress; Lipoproteins, LDL; Nitric Oxide Synthase Type III; Endoplasmic Reticulum Chaperone BiP; Propionates; Nitric Oxide; Signal Transduction; Phosphorylation; Endothelial Cells; Coronary Vessels; Fatty Acids, Volatile; eIF-2 Kinase; Activating Transcription Factor 6; Microcirculation; Heat-Shock Proteins
PubMed: 38814895
DOI: 10.1371/journal.pone.0304551 -
Arteriosclerosis, Thrombosis, and... May 2024Pulmonary hypertension (PH) represents an important phenotype in heart failure with preserved ejection fraction (HFpEF). However, management of PH-HFpEF is challenging...
BACKGROUND
Pulmonary hypertension (PH) represents an important phenotype in heart failure with preserved ejection fraction (HFpEF). However, management of PH-HFpEF is challenging because mechanisms involved in the regulation of PH-HFpEF remain unclear.
METHODS
We used a mass spectrometry-based comparative plasma proteomics approach as a sensitive and comprehensive hypothesis-generating discovery technique to profile proteins in patients with PH-HFpEF and control subjects. We then validated and investigated the role of one of the identified proteins using in vitro cell cultures, in vivo animal models, and independent cohort of human samples.
RESULTS
Plasma proteomics identified high protein abundance levels of B2M (β2-microglobulin) in patients with PH-HFpEF. Interestingly, both circulating and skeletal muscle levels of B2M were increased in mice with skeletal muscle SIRT3 (sirtuin-3) deficiency or high-fat diet-induced PH-HFpEF. Plasma and muscle biopsies from a validation cohort of PH-HFpEF patients were found to have increased B2M levels, which positively correlated with disease severity, especially pulmonary capillary wedge pressure and right atrial pressure at rest. Not only did the administration of exogenous B2M promote migration/proliferation in pulmonary arterial vascular endothelial cells but it also increased PCNA (proliferating cell nuclear antigen) expression and cell proliferation in pulmonary arterial vascular smooth muscle cells. Finally, deletion improved glucose intolerance, reduced pulmonary vascular remodeling, lowered PH, and attenuated RV hypertrophy in mice with high-fat diet-induced PH-HFpEF.
CONCLUSIONS
Patients with PH-HFpEF display higher circulating and skeletal muscle expression levels of B2M, the magnitude of which correlates with disease severity. Our findings also reveal a previously unknown pathogenic role of B2M in the regulation of pulmonary vascular proliferative remodeling and PH-HFpEF. These data suggest that circulating and skeletal muscle B2M can be promising targets for the management of PH-HFpEF.
PubMed: 38813697
DOI: 10.1161/ATVBAHA.123.320270