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Mesenchymal stem cells (MSCs) hold promise for regenerative medicine, particularly for bone tissue engineering. However, directing MSC differentiation towards specific lineages, such as osteogenic, while minimizing undesired phenotypes remains a challenge. Here, we investigate the influence of micropatterns on the behavior and lineage commitment of rat bone marrow-derived MSCs (rBMSCs), focusing on osteogenic differentiation. Linearly aligned triangular micropatterns (TPs) and circular micropatterns (CPs) coated with fibronectin were fabricated to study their effects on rBMSC morphology and differentiation and the underlying mechanobiological mechanisms. TPs, especially TP15 (15 µm), induced the cell elongation and thinning, while CPs also promoted the cell stretching, as evidenced by the decreased circularity and increased aspect ratio. TP15 significantly promoted osteogenic differentiation, with increased expression of osteogenic genes (Runx2, Spp1, Alpl, Bglap, Col1a1) and decreased expression of adipogenic genes (Pparg, Cebpa, Fabp4). Conversely, CPs inhibited both osteogenic and adipogenic differentiation. Mechanistically, TP15 increased Piezo1 activity, cytoskeletal remodeling including the aggregates of F-actin and myosin filaments at the cell periphery, YAP1 nuclear translocation, and integrin upregulation. Piezo1 inhibition suppressed the osteogenic genes expression, myosin remodeling, and YAP1 nuclear translocation, indicating Piezo1-mediated the mechanotransduction in rBMSCs on TPs. TP15 also induced osteogenic differentiation of BMSCs from aging rats, with upregulated Piezo1 and nuclear translocation of YAP1. Therefore, triangular micropatterns, particularly TP15, promote osteogenesis and inhibit adipogenesis of rBMSCs through Piezo1-mediated myosin and YAP1 pathways. Our study provides novel insights into the mechanobiological mechanisms governing MSC behaviors on micropatterns, offering new strategies for tissue engineering and regenerative medicine.
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Medial arterial calcification (MAC) accompanying chronic kidney disease (CKD) leads to increased vessel wall stiffness, myocardial ischemia, heart failure, and increased cardiovascular morbidity and mortality. Unfortunately, there are currently no drugs available to treat MAC. The natural polyphenol epigallocatechin-3-gallate (EGCG) has been demonstrated to protect against cardiovascular disease; however, whether EGCG supplementation inhibits MAC in CKD remains unclear. In this study, we utilize a CKD-associated MAC model to investigate the effects of EGCG on vascular calcification and elucidate the underlying mechanisms involved. Our findings demonstrate that EGCG treatment significantly reduces calcium phosphate deposition and osteogenic differentiation of VSMCs in vivo and in vitro in a dose-dependent manner. In addition, through RNA sequencing (RNA-seq) analysis, we show a significant activation of the transcription factor JunB both in CKD mouse arteries and in osteoblast-like VSMCs. Notably, EGCG effectively suppresses CKD-associated MAC by inhibiting the activity of JunB. In addition, overexpression of JunB can abolish while knockdown of JunB can enhance the inhibitory effect of EGCG on the osteogenic differentiation of VSMCs. Furthermore, EGCG supplementation inhibits MAC in CKD via modulation of the JunB-dependent Ras/Raf/MEK/ERK signaling pathway. In conclusion, our study highlights the potential therapeutic value of EGCG for managing CKD-associated MAC, as it mitigates this pathological process through targeted inactivation of JunB.
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Phenotypic switching (from contractile to synthetic) of vascular smooth muscle cells (VSMCs) is essential in the progression of atherosclerosis. The damaged endothelium in the atherosclerotic artery exposes VSMCs to increased interstitial fluid shear stress (IFSS). However, the precise mechanisms by which increased IFSS influences VSMCs phenotypic switching are unrevealed. Here, we employed advanced numerical simulations to calculate IFSS values accurately based on parameters acquired from patient samples. We then carefully investigated the phenotypic switching and extracellular vesicles (EVs) secretion of VSMCs under various IFSS conditions. By employing a comprehensive set of approaches, we found that VSMCs exhibited synthetic phenotype upon atherosclerotic IFSS. This synthetic phenotype is the upstream regulator for the enhanced secretion of pro-calcified EVs. Mechanistically, as a mechanotransducer, the epidermal growth factor receptor (EGFR) initiates the flow-based mechanical cues to MAPK signaling pathway, facilitating the nuclear accumulation of the transcription factor krüppel-like factor 5 (KLF5). Furthermore, pharmacological inhibiting either EGFR or MAPK signaling pathway blocks the nuclear accumulation of KLF5 and finally results in the maintenance of contractile VSMCs even under increased IFSS stimulation. Collectively, targeting this signaling pathway holds potential as a novel therapeutic strategy to inhibit VSMCs phenotypic switching and mitigate the progression of atherosclerosis.
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Receptores ErbB , Vesículas Extracelulares , Factores de Transcripción de Tipo Kruppel , Músculo Liso Vascular , Miocitos del Músculo Liso , Estrés Mecánico , Vesículas Extracelulares/metabolismo , Receptores ErbB/metabolismo , Factores de Transcripción de Tipo Kruppel/metabolismo , Factores de Transcripción de Tipo Kruppel/genética , Humanos , Músculo Liso Vascular/metabolismo , Miocitos del Músculo Liso/metabolismo , Líquido Extracelular/metabolismo , Fenotipo , Animales , Aterosclerosis/metabolismo , Sistema de Señalización de MAP Quinasas , Transducción de SeñalRESUMEN
Hepatocellular carcinoma (HCC) hematogenous dissemination is a leading cause of HCC-related deaths. The inflammatory facilitates this process by promoting the adhesion and invasion of tumor cells in the circulatory system. But the contribution of hemodynamics to this process remains poorly understood due to the lack of a suitable vascular flow model for investigation. This study develops a vascular flow model to examine the impact of hemodynamics on endothelial inflammation-mediated HCC metastasis. This work finds the increasing shear stress will reduce the recruitment of HCC cells by disturbing adhesion forces between endothelium and HCC cells. However, this reduction will be restored by the inflammation. When applying high FSS (4-6 dyn cm-2) to the inflammatory endothelium, there will be a 4.8-fold increase in HCC cell adhesions compared to normal condition. Nevertheless, the increase fold of cell adhesions is inapparent, around 1.5-fold, with low and medium FSS. This effect can be attributed to the FSS-induced upregulation of ICAM-1 and VCAM-1 of the inflammatory endothelium, which serve to strengthen cell binding forces. These findings indicate that hemodynamics plays a key role in HCC metastasis during endothelial inflammation by regulating the expression of adhesion-related factors.
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Carcinoma Hepatocelular , Hemodinámica , Inflamación , Neoplasias Hepáticas , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/metabolismo , Humanos , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/metabolismo , Inflamación/patología , Inflamación/metabolismo , Metástasis de la Neoplasia , Adhesión Celular , Molécula 1 de Adhesión Intercelular/metabolismo , Endotelio Vascular/patología , Endotelio Vascular/metabolismo , Molécula 1 de Adhesión Celular Vascular/metabolismo , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Línea Celular Tumoral , Biomimética/métodosRESUMEN
Postmenopausal osteoporosis is recognized to be one of the major skeleton diseases strongly associated with impaired bone formation. Previous reports have indicated that the importance of bone morphogenetic protein (BMP) signaling of osteoblast lineage in bone development via classical Smad signaling, however, its critical role in osteoporosis is still not well understood. In the current study, we aim to investigate the pathological role of BMPR1A, a key receptor of BMPs, in osteoporosis and its underlying mechanism. We first found that knockdown of BMPR1A by using Col1a1-creER in osteoblasts mitigated early bone loss of osteoporosis in mice, yet along with late bone maturation defects by reducing mineral adherence rate and bone formation rate in vivo. At the cellular level, we then observed that BMPR1A deficiency promoted the proliferation of pre-osteoblasts under osteoporotic conditions but hindered their late-stage mineralization. We finally elucidated that BMPR1A deficiency compensatorily triggered mTOR-autophagy perturbation by a higher level in early osteoporotic pre-osteoblasts thus resulting in the enhancement of transient cell proliferation but impairment of final mineralization. Taken together, this study indicated the significance of BMPR1A-mTOR/autophagy axis, as a double-edged sword, in osteoporotic bone formation and provided new cues for therapeutic strategies in osteoporosis.
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Osteoporosis , Transducción de Señal , Ratones , Animales , Proteínas Morfogenéticas Óseas/metabolismo , Osteoporosis/tratamiento farmacológico , Osteoblastos/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , AutofagiaRESUMEN
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths in the world. Due to the insidious onset and rapid progression and a lack of effective treatments, the prognosis of patients with HCC is extremely poor, with the average 5-year survival rate being less than 10%. The tumor microenvironment (TME), the internal environment in which HCC develops, can regulate the oncogenesis, development, invasion, and metastasis of HCC. During the process of cancer progression, HCC cells can regulate the biological behaviors of tumor cells, cancer-associated fibroblasts, cancer-associated immune cells, and other cells in the TME by releasing exosomes containing specific signals, thereby promoting cancer progression. However, the exact molecular mechanisms and the roles of exosomes in the specific cellular regulation of these processes are not fully understood. Herein, we summarized the TME components of HCC, the sources and the biological traits of exosomes in the TME, and the impact of mechanical factors on exosomes. In addition, special attention was given to the discussion of the effects of HCC-exosomes on different types of cells in the microenvironment. There are still many difficulties to be overcome before exosomes can be applied as carriers in clinical cancer treatment. First of all, the homogeneity of exosomes is difficult to ensure. Secondly, exosomes are mainly administered through subcutaneous injection. Although this method is simple and easy to implement, the absorption efficiency is not ideal. Thirdly, exosome extraction methods are limited in number and inefficient, making it difficult to prepare exosomes in large quantities. It is important to ensure that exosomes are used in sufficient quantities to trigger an effective tumor immune response, especially for exosome-mediated tumor immunotherapy. With the improvement in identification, isolation, and purification technology, exosomes are expected to be successfully used in the clinical diagnosis of early-stage HCC and the clinical treatment of liver cancer.
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Carcinoma Hepatocelular , Exosomas , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/patología , Microambiente Tumoral , Comunicación CelularRESUMEN
Objective: To investigate the mechanical responses of mitochondrial morphology to extracellular matrix stiffness in human mesenchymal stem cells (hMSCs) and the role of AMP-activated protein kinase (AMPK) in the regulation of mitochondrial mechanoresponses. Methods: Two polyacrylamide (PAAm) hydrogels, a soft one with a Young's modulus of 1 kPa and a stiff one of 20 kPa, were prepared by changing the monomer concentrations of acrylamide and bis-acrylamide. Then, hMSCs were cultured on the soft and stiff PAAm hydrogels and changes in mitochondrial morphology were observed using a laser confocal microscope. Western blot was performed to determine the expression and activation of AMPK, a protein associated with mitochondrial homeostasis. Furthermore, the activation of AMPK was regulated on the soft and stiff matrixes by AMPK activator A-769662 and the inhibitor Compound C, respectively, to observe the morphological changes of mitochondria. Results: The morphology of the mitochondria in hMSCs showed heterogeneity when there was a change in gel stiffness. On the 1 kPa soft matrix, 74% mitochondria exhibited a dense, elongated filamentous network structure, while on the 20 kPa stiff matrix, up to 63.3% mitochondria were fragmented or punctate and were sparsely distributed. Western blot results revealed that the phosphorylated AMPK (p-AMPK)/AMPK ratio on the stiff matrix was 1.6 times as high as that on the soft one. Immunofluorescence assay results revealed that the expression of p-AMPK was elevated on the hard matrix and showed nuclear localization, which indicated that the activation of intracellular AMPK increased continuously along with the increase in extracellular matrix stiffness. When the hMSCs on the soft matrix were treated with A-769662, an AMPK activator, the mitochondria transitioned from a filamentous network morphology to a fragmented morphology, with the ratio of filamentous network decreasing from 74% to 9.5%. Additionally, AMPK inhibition with Compound C promoted mitochondrial fusion on the stiff matrix and significantly reduced the generation of punctate mitochondria. Conclusion: Extracellular matrix stiffness regulates mitochondrial morphology in hMSCs through the activation of AMPK. Stiff matrix promotes the AMPK activation, resulting in mitochondrial fission and the subsequent fragmentation of mitochondria. The impact of matrix stiffness on mitochondrial morphology can be reversed by altering the level of AMPK phosphorylation.
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Proteínas Quinasas Activadas por AMP , Matriz Extracelular , Células Madre Mesenquimatosas , Mitocondrias , Humanos , Acrilamidas/análisis , Acrilamidas/metabolismo , Proteínas Quinasas Activadas por AMP/análisis , Proteínas Quinasas Activadas por AMP/metabolismo , Compuestos de Bifenilo , Células Cultivadas , Matriz Extracelular/química , Matriz Extracelular/metabolismo , Hidrogeles/análisis , Hidrogeles/metabolismo , Pironas , TiofenosRESUMEN
Long-term ischemia leads to insufficient cerebral microvascular perfusion and dysfunction. Reperfusion restores physiological fluid shear stress (FSS) but leads to serious injury. The mechanism underlying FSS-induced endothelial injury in ischemia-reperfusion injury (IRI) remains poorly understood. In this study, a rat model of middle cerebral artery occlusion was constructed to explore cerebrovascular endothelial function and inflammation in vivo. Additionally, the rat brain microvascular endothelial cells (rBMECs) were exposed to a laminar FSS of 0.5 dyn/cm2 for 6 h and subsequently restored to physiological fluid shear stress level (2 dyn/cm2) for 2 and 12 h, respectively. We found that reperfusion induced endothelial-to-mesenchymal transition (EndMT) in endothelial cells, leading to serious blood-brain barrier dysfunction and endothelial inflammation, accompanied by the nuclear accumulation of Yes-associated protein (YAP). During the later stage of reperfusion, cerebral endothelium was restored to the endothelial phenotype with a distinct change in mesenchymal-to-endothelial transition (MEndT), while YAP was translocated and phosphorylated in the cytoplasm. Knockdown of YAP or inhibition of actin polymerization markedly impaired the EndMT in rBMECs. These findings suggest that ischemia-reperfusion increased intensity of FSS triggered an EndMT process and, thus, led to endothelial inflammation and tissue injury, whereas continuous FSS induced a time-dependent reversal MEndT event contributing to the endothelial repair. This study provides valuable insight for therapeutic strategies targeting IRI.
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It is well-recognized that blood flow at branches and bends of arteries generates disturbed shear stress, which plays a crucial in driving atherosclerosis. Flow-generated fluid shear stress (FSS), as one of the key hemodynamic factors, is appreciated for its critical involvement in regulating angiogenesis to facilitate wound healing and tissue repair. Endothelial cells can directly sense FSS but the mechanobiological mechanism by which they decode different patterns of FSS to trigger angiogenesis remains unclear. In the current study, laminar shear stress (LSS, 15 dyn/cm2) was employed to mimic physiological blood flow, while disturbed shear stress (DSS, ranging from 0.5 ± 4 dyn/cm2) was applied to simulate pathological conditions. The aim was to investigate how these distinct types of blood flow regulated endothelial angiogenesis. Initially, we observed that DSS impaired angiogenesis and downregulated endogenous vascular endothelial growth factor B (VEGFB) expression compared to LSS. We further found that the changes in membrane protein, migration and invasion enhancer 1 (MIEN1) play a role in regulating ERK/MAPK signaling, thereby contributing to endothelial angiogenesis in response to FSS. We also showed the involvement of MIEN1-directed cytoskeleton organization. These findings suggest the significance of shear stress in endothelial angiogenesis, thereby enhancing our understanding of the alterations in angiogenesis that occur during the transition from physiological to pathological blood flow.
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Angiogénesis , Células Endoteliales , Hemodinámica , Humanos , Aterosclerosis/patología , Células Cultivadas , Células Endoteliales/fisiología , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Proteínas de Neoplasias/metabolismo , Estrés Mecánico , Factor B de Crecimiento Endotelial Vascular/metabolismoRESUMEN
Osteoporosis is a widely observed condition characterized by the systemic deterioration of bone mass and microarchitecture, which increases patient susceptibility to fragile fractures. The intricate mechanisms governing bone homeostasis are substantially impacted by extracellular vesicles (EVs), which play crucial roles in both pathological and physiological contexts. EVs derived from various sources exert distinct effects on osteoporosis. Specifically, EVs released by osteoblasts, endothelial cells, myocytes, and mesenchymal stem cells contribute to bone formation due to their unique cargo of proteins, miRNAs, and cytokines. Conversely, EVs secreted by osteoclasts and immune cells promote bone resorption and inhibit bone formation. Furthermore, the use of EVs as therapeutic modalities or biomaterials for diagnosing and managing osteoporosis is promising. Here, we review the current understanding of the impact of EVs on bone homeostasis, including the classification and biogenesis of EVs and the intricate regulatory mechanisms of EVs in osteoporosis. Furthermore, we present an overview of the latest research progress on diagnosing and treating osteoporosis by using EVs. Finally, we discuss the challenges and prospects of translational research on the use of EVs in osteoporosis.
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Vesículas Extracelulares , MicroARNs , Osteoporosis , Humanos , Células Endoteliales , Densidad ÓseaRESUMEN
Atherosclerosis, the primary cause of cardiovascular diseases (CVDs), is characterized by phenotypic changes in fibrous proliferation, chronic inflammation and lipid accumulation mediated by vascular endothelial cells (ECs) and vascular smooth muscle cells (SMCs) which are correlated with the stiffening and ectopic remodeling of local extracellular matrix (ECM). The native residents, ECs and SMCs, are not only affected by various chemical factors including inflammatory mediators and chemokines, but also by a range of physical stimuli, such as shear stress and ECM stiffness, presented in the microenvironmental niche. Especially, ECs, as a semi-selective barrier, can sense mechanical forces, respond quickly to changes in mechanical loading and provide context-specific adaptive responses to restore homeostasis. However, blood arteries undergo stiffening and lose their elasticity with age. Reports have shown that the ECM stiffening could influence EC fate by changing the cell adhesion, spreading, proliferation, cell to cell contact, migration and even communication with SMCs. The cell behaviour changes mediated by ECM stiffening are dependent on the activation of a signaling cascade of mechanoperception and mechanotransduction. Although the substantial evidence directly indicates the importance of ECM stiffening on the native ECs, the understanding about this complex interplay is still largely limited. In this review, we systematically summarize the roles of ECM stiffening on the behaviours of endothelial cells and elucidate the underlying details in biological mechanism, aiming to provide the process of how ECs integrate ECM mechanics and the highlights for bioaffinity of tissue-specific engineered scaffolds.
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Aterosclerosis , Células Endoteliales , Humanos , Células Endoteliales/metabolismo , Mecanotransducción Celular , Adhesión Celular , Matriz Extracelular/metabolismo , Aterosclerosis/metabolismoRESUMEN
Matrix vesicles (MVs) have shown strong effects in diseases such as vascular ectopic calcification and pathological calcified osteoarthritis and in wound repair of the skeletal system due to their membranous vesicle characteristics and abundant calcium and phosphorus content. However, the role of MVs in the progression of osteoporosis is poorly understood. Here, we report that annexin A5, an important component of the matrix vesicle membrane, plays a vital role in bone matrix homeostasis in the deterioration of osteoporosis. We first identified annexin A5 from adherent MVs but not dissociative MVs of osteoblasts and found that it could be sharply decreased in the bone matrix during the occurrence of osteoporosis based on ovariectomized mice. We then confirmed its potential in mediating the mineralization of the precursor osteoblast lineage via its initial binding with collagen type I to achieve MV adhesion and the subsequent activation of cellular autophagy. Finally, we proved its protective role in resisting bone loss by applying it to osteoporotic mice. Taken together, these data revealed the importance of annexin A5, originating from adherent MVs of osteoblasts, in bone matrix remodeling of osteoporosis and provided a new strategy for the treatment and intervention of bone loss.
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Enfermedades Óseas Metabólicas , Osteoporosis , Calcificación Vascular , Animales , Ratones , Anexina A5/metabolismo , Calcificación Fisiológica/fisiología , Matriz Ósea/metabolismoRESUMEN
The technology of aggregation-induced emission (AIE) presents a promising avenue for fluorescence imaging-guided photodynamic cancer therapy. However, existing near-infrared AIE photosensitizers (PSs) frequently encounter limitations, including tedious synthesis, poor tumor retention, and a limited understanding of the underlying molecular biology mechanism. Herein, an effective molecular design paradigm of anion-π+ interaction combined with the inherently crowded conformation that could enhance fluorescence efficacy and reactive oxygen species generation was proposed through a concise synthetic method. Mechanistically, upon photosensitization, the Hippo signaling pathway contributes to the death of melanoma cells and promotes the nuclear location of its downstream factor, yes-associated protein, which regulates the transcription and expression of apoptosis-related genes. The finding in this study would trigger the development of high-performance and versatile AIE PSs for precision cancer therapy based on a definite regulatory mechanism.
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Neoplasias , Fotoquimioterapia , Humanos , Vía de Señalización Hippo , Medicina de Precisión , Neoplasias/tratamiento farmacológico , Fotoquimioterapia/métodos , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/uso terapéutico , Especies Reactivas de Oxígeno/metabolismoRESUMEN
The mineralization of the extracellular matrix (ECM) is an essential and crucial process for physiological bone formation and pathological calcification. The abnormal function of ECM mineralization contributes to the worldwide risk of developing mineralization-related diseases; for instance, vascular calcification is attributed to the hyperfunction of ECM mineralization, while osteoporosis is due to hypofunction. AnnexinA6 (AnxA6), a Ca2+-dependent phospholipid-binding protein, has been extensively reported as an essential target in mineralization-related diseases such as osteoporosis, osteoarthritis, atherosclerosis, osteosarcoma, and calcific aortic valve disease. To date, AnxA6, as the largest member of the Annexin family, has attracted much attention due to its significant contribution to matrix vesicles (MVs) production and release, MVs-ECM interaction, cytoplasmic Ca2+ influx, and maturation of hydroxyapatite, making it an essential target in ECM mineralization. In this review, we outlined the recent advancements in the role of AnxA6 in mineralization-related diseases and the potential mechanisms of AnxA6 under normal and mineralization-related pathological conditions. AnxA6 could promote ECM mineralization for bone regeneration in the manner described previously. Therefore, AnxA6 may be a potential osteogenic target for ECM mineralization.
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It is recognized that the changes in the physical properties of extracellular matrix (ECM) result in fine-tuned cell responses including cell morphology, proliferation and differentiation. In this study, a novel patterned equidistant micropillar substrate based on polydimethylsiloxane (PDMS) is designed to mimic the collagen fiber-like network of the cartilage matrix. By changing the component of the curing agent to an oligomeric base, micropillar substrates with the same topology but different stiffnesses are obtained and it is found that chondrocytes seeded onto the soft micropillar substrate maintain their phenotype by gathering type II collagen and aggrecan more effectively than those seeded onto the stiff micropillar substrate. Moreover, chondrocytes sense and respond to micropillar substrates with different stiffnesses by altering the ECM-cytoskeleton-focal adhesion axis. Further, it is found that the soft substrate-preserved chondrocyte phenotype is dependent on the activation of Wnt/ß-catenin signaling. Finally, it is indicated that the changes in osteoid-like region formation and cartilage phenotype loss in the stiffened sclerotic area of osteoarthritis cartilage to validate the changes triggered by micropillar substrates with different stiffnesses. This study provides the cell behavior changes that are more similar to those of real chondrocytes at tissue level during the transition from a normal state to a state of osteoarthritis.
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Condrocitos , Osteoartritis , Humanos , Biomimética , Cartílago , Matriz Extracelular/químicaRESUMEN
Powder electrocatalysts for oxygen evolution reactions usually need adhesives for electrocatalytic performance tests, leading to the increase of resistance, reduction of catalyst loading, and easy stripping of the catalyst under long-time or high current operation. In this study, Ce-doped CoFe layered double hydroxides were uniformly grown on nickel foam by a one-step hydrothermal route. A nanostructured self-supported electrode Ce-CoFe-LDH/NF without adhesive was obtained directly, which has a regular nanoneedle morphology with a length of â¼1.2 µm and tip width of â¼20 nm. Adopting Ce3+ ions with a large radius to partially displace Fe3+ ions with a small radius produced lattice distortion and more defects in the host layer of CoFe-LDH, whereby possessing the great potential to enhance catalytic behaviors. Once used as an electrocatalyst for the oxygen evolution reaction, Ce-CoFe-LDH/NF shows an outstanding electrocatalytic performance, including an optimized overpotential of 225 mV at 10 mA cm-2, a decreased Tafel slope of 34.34 mV dec-1, and a low charge transfer impedance of 2.4 Ω in 1 M KOH electrolyte. Moreover, the overpotential of the working electrode increased by only 0.04 V after 24 hours and was maintained at a current density of 50 mA cm-2. These results demonstrate a low-cost strategy compared to using noble metal OER electrocatalysts. Thus, this study highlights a ready universal approach to fabricate high-performance supported catalysts for energy-related applications.
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Thoracic aortic dissection (TAD) is a cardiovascular disease entailing a high lethality between 65% and 85%. Surgery-assissed implant/interventional stenting is the prevailing treatment of TAD. However, surgical treatment can cause severe postoperative complications and patients incur a relatively higher risk of postoperative mortality. Since the pathogenic mechanism underlying TAD is not clear, effective medication therapies are still not available. In recent years, along with advances in single-cell sequencing and other molecular biological technologies, there have been prelimiary findings suggesting the special role of dysfunctional vascular smooth muscle cells (VSMCs) in the pathogenesis and development of TAD. Furthermore, the molecular mechanisms regulating the dysfunction of VSMCs have been initially explored. It is expected that these new findings will contribute to the development of new strategies to prevent TAD and lead to new ideas for the identifiction of potential drug therapeutic targets. Herein, we summarized the critical role of dysfunctional VSMCs in the pathogenesis and development of TAD and presented in detail the biological factors and the related molecular mechanisms that regulate the dysfunction of VSMCs. We hope this review will provide a reference for further investigation into the central role of dysfunctional VSMCs in the pathogenesis and development of TAD and exploration for effective molecular drug targets for TAD.
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Aneurisma de la Aorta Torácica , Disección Aórtica , Disección de la Aorta Torácica , Humanos , Aneurisma de la Aorta Torácica/patología , Aorta Torácica/patologíaRESUMEN
Intracranial aneurysm (IA) is a severe cerebrovascular disease characterized by abnormal bulging of cerebral vessels that may rupture and cause a stroke. The expansion of the aneurysm accompanies by the remodeling of vascular matrix. It is well-known that vascular remodeling is a process of synthesis and degradation of extracellular matrix (ECM), which is highly dependent on the phenotype of vascular smooth muscle cells (VSMCs). The phenotypic switching of VSMC is considered to be bidirectional, including the physiological contractile phenotype and alternative synthetic phenotype in response to injury. There is increasing evidence indicating that VSMCs have the ability to switch to various phenotypes, including pro-inflammatory, macrophagic, osteogenic, foamy and mesenchymal phenotypes. Although the mechanisms of VSMC phenotype switching are still being explored, it is becoming clear that phenotype switching of VSMCs plays an essential role in IA formation, progression, and rupture. This review summarized the various phenotypes and functions of VSMCs associated with IA pathology. The possible influencing factors and potential molecular mechanisms of the VSMC phenotype switching were further discussed. Understanding how phenotype switching of VSMC contributed to the pathogenesis of unruptured IAs can bring new preventative and therapeutic strategies for IA.
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Aneurisma Intracraneal , Músculo Liso Vascular , Humanos , Músculo Liso Vascular/metabolismo , Aneurisma Intracraneal/genética , Aneurisma Intracraneal/metabolismo , Aneurisma Intracraneal/patología , Transducción de Señal , Miocitos del Músculo Liso/patología , Fenotipo , Células Cultivadas , Proliferación CelularRESUMEN
Cardiovascular disease (CVD) is a serious health challenge, causing more deaths worldwide than cancer. The vascular endothelium, which forms the inner lining of blood vessels, plays a central role in maintaining vascular integrity and homeostasis and is in direct contact with the blood flow. Research over the past century has shown that mechanical perturbations of the vascular wall contribute to the formation and progression of atherosclerosis. While the straight part of the artery is exposed to sustained laminar flow and physiological high shear stress, flow near branch points or in curved vessels can exhibit 'disturbed' flow. Clinical studies as well as carefully controlled in vitro analyses have confirmed that these regions of disturbed flow, which can include low shear stress, recirculation, oscillation, or lateral flow, are preferential sites of atherosclerotic lesion formation. Because of their critical role in blood flow homeostasis, vascular endothelial cells (ECs) have mechanosensory mechanisms that allow them to react rapidly to changes in mechanical forces, and to execute context-specific adaptive responses to modulate EC functions. This review summarizes the current understanding of endothelial mechanobiology, which can guide the identification of new therapeutic targets to slow or reverse the progression of atherosclerosis.
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Aterosclerosis , Enfermedades Cardiovasculares , Humanos , Células Endoteliales/patología , Aterosclerosis/patología , Endotelio Vascular , Hemodinámica , Estrés Mecánico , Mecanotransducción CelularRESUMEN
Atherosclerosis is a chronic inflammatory disease, occurring preferentially in bifurcation, branching, and bending of blood vessels exposed to disturbed flow. Disturbed flow in atheroprone areas activates elevated proteases, degrading elastin lamellae and collagenous matrix, resulting in endothelial dysfunction and vascular remodeling. As a mediator for extracellular matrix protein degradation, cathepsin K (CTSK) was directly regulated by hemodynamics and contributed to atherosclerosis. The mechanism of CTSK responding to disturbed flow and contributing to disturbed flow-induced atherosclerosis is unclear. In this study, the partial carotid ligation model of mice and in vitro disturbed shear stress model were constructed to explore the contribution and potential mechanism of CTSK in atherosclerosis. Our results indicated that CTSK elevated in the disturbed flow area in vivo and in vitro along with endothelial inflammation and atherogenesis. Additionally, the expression of integrin αvß3 was upregulated in these atheroprone areas. We found that inhibition of the integrin αvß3-cytoskeleton pathway could significantly block the activation of NF-κB and the expression of CTSK. Collectively, our findings unraveled that disturbed flow induces increased CTSK expression, and contributes to endothelial inflammation and vascular remodeling, leading to atherogenesis eventually. This study is helpful to provide new enlightenment for the therapy of atherosclerosis.