ABSTRACT
BACKGROUND: Osteoarthritis is a common degenerative joint disease that is highly prevalent in the elderly population. Along with the occurrence of sports injuries, osteoarthritis is gradually showing a younger trend. Osteoarthritis has many causative factors, and its pathogenesis is currently unknown. Cellular senescence is a stable form of cell cycle arrest exhibited by cells in response to external stimuli and plays a role in a variety of diseases. And it is only in the last decade or so that cellular senescence has gradually become cross-linked with osteoarthritis. However, there is no comprehensive bibliometric analysis in this field. The aim of this study is to present the current status and research hotspots of cellular senescence in the field of osteoarthritis, and to predict the future trends of cellular senescence in osteoarthritis research from a bibliometric perspective. METHODS: This study included 298 records of cellular senescence associated with osteoarthritis from 2009 to 2023, with data from the Web of Science Core Collection database. CiteSpace, Scimago Graphica software, VOSviewer, and the R package "bibliometrix" software were used to analyze regions, institutions, journals, authors, and keywords to predict recent trends in cellular senescence related to osteoarthritis research. RESULTS: The number of publications related to cellular senescence associated with osteoarthritis is increasing year by year. China and the United States contribute more than 70% of the publications and are the mainstay of research in this field. Central South University is the most active institution with the largest number of publications. International Journal of Molecular Sciences is the most popular journal in the field with the largest number of publications, while Osteoarthritis and Cartilage is the most cited journal. Loeser, Richard F. is not only the most prolific author, but also the most frequently cited author, contributing greatly to the field. CONCLUSION: In the last decade or so, this is the first bibliometric study that systematically describes the current status and development trend of research on cellular senescence associated with osteoarthritis. The study comprehensively and systematically summarizes and concludes the research hotspots and development trends, providing valuable references for researchers in this field.
Subject(s)
Bibliometrics , Cellular Senescence , Osteoarthritis , Osteoarthritis/pathology , Cellular Senescence/physiology , HumansABSTRACT
Induction skull melting (ISM) technology could melt metals with avoiding contamination from crucible. A long-standing problem of ISM is that the low charge energy utilization and inhomogeneous fields have obstructed its application in many critical metal materials and manufacturing processes. The present work investigated the problem through the structure optimization strategy and established a numerical electromagnetic-field model to evaluate components' eddy current loss. Based on the model, the effect of crucible and inductor structure on charge energy utilization, etc. was studied. Furtherly, the charge energy utilization was increased from 27.1 to 45.89% by adjusting the system structure. Moreover, structure modifications are proposed for enhancing electromagnetic intensity and uniformity, charge soft contact and uniform heating. The work constructed a basis for framing new solutions to the problem through ISM device structure optimization.
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AIMS: General anesthesia has been used in surgical procedures for approximately 180 years, yet the precise mechanism of anesthetic drugs remains elusive. There is significant anatomical connectivity between the ventral tegmental area (VTA) and the prelimbic cortex (PrL). Projections from VTA dopaminergic neurons (VTADA ) to the PrL play a role in the transition from sevoflurane anesthesia to arousal. It is still uncertain whether the prelimbic cortex pyramidal neuron (PrLPyr ) and its projections to VTA (PrLPyr -VTA) are involved in anesthesia-arousal regulation. METHODS: We employed chemogenetics and optogenetics to selectively manipulate neuronal activity in the PrLPyr -VTA pathway. Electroencephalography spectra and burst-suppression ratios (BSR) were used to assess the depth of anesthesia. Furthermore, the loss or recovery of the righting reflex was monitored to indicate the induction or emergence time of general anesthesia. To elucidate the receptor mechanisms in the PrLPyr -VTA projection's impact on anesthesia and arousal, we microinjected NMDA receptor antagonists (MK-801) or AMPA receptor antagonists (NBQX) into the VTA. RESULTS: Our findings show that chemogenetic or optogenetic activation of PrLPyr neurons prolonged anesthesia induction and promoted emergence. Additionally, chemogenetic activation of the PrLPyr -VTA neural pathway delayed anesthesia induction and promoted anesthesia emergence. Likewise, optogenetic activation of the PrLPyr -VTA projections extended the induction time and facilitated emergence from sevoflurane anesthesia. Moreover, antagonizing NMDA receptors in the VTA attenuates the delayed anesthesia induction and promotes emergence caused by activating the PrLPyr -VTA projections. CONCLUSION: This study demonstrates that PrLPyr neurons and their projections to the VTA are involved in facilitating emergence from sevoflurane anesthesia, with the PrLPyr -VTA pathway exerting its effects through the activation of NMDA receptors within the VTA.
Subject(s)
Receptors, N-Methyl-D-Aspartate , Ventral Tegmental Area , Ventral Tegmental Area/metabolism , Sevoflurane/pharmacology , Receptors, N-Methyl-D-Aspartate/metabolism , Dopaminergic Neurons/metabolism , Pyramidal Cells , Anesthesia, General , ArousalABSTRACT
Depression has emerged as the predominant psychiatric affliction affecting individuals. Prior research has substantiated the antidepressant properties exhibited by numerous anesthetics. Sevoflurane, a widely utilized inhalant anesthetic in clinical practice, remains relatively uncharted in terms of its specific antidepressant effects. In this study, we used open field test, forced swimming test and novelty-suppressed feeding test to investigate the anxiety and depression-like behaviors in C57BL/6 mice following the inhalation of sevoflurane. We then used western blotting to scrutinized the expression levels of proteins associated with the brain-derived neurotrophic factor (BDNF)-tryosine receptor kinase B (TrkB) pathway in the hippocampus and prefrontal cortex. To further investigate whether sevoflurane exerts antidepressant-like effects via the BDNF-TrkB pathway, we downregulated TrkB expression by administering siRNA into the lateral ventricle. We found that the inhalation of 2.5 % sevoflurane exerted a significant antidepressant-like effect, accompanied by an elevation in p-TrkB expression levels in the hippocampus and prefrontal cortex. Intriguingly, this antidepressant-like effect was abrogated following the downregulation of TrkB expression through the microinjection of siRNA into the lateral ventricle. In conclusion, this study provides evidence supporting the notion that sevoflurane exerts its antidepressant-like effect via the BDNF-TrkB signaling pathway.
Subject(s)
Brain-Derived Neurotrophic Factor , Depression , Mice , Animals , Depression/drug therapy , Depression/metabolism , Brain-Derived Neurotrophic Factor/metabolism , Sevoflurane/pharmacology , Receptor, trkB/metabolism , Mice, Inbred C57BL , Antidepressive Agents/pharmacology , Antidepressive Agents/metabolism , Hippocampus/metabolism , RNA, Small Interfering/metabolism , Stress, Psychological/metabolism , Disease Models, AnimalABSTRACT
PURPOSE: This study aims to explore the emerging trends, dynamic development, and research hotspots of clustered regularly interspaced short palindromic repeats (CRISPR) technology associated with extracellular vesicles during the past 7 years and demonstrate them by visualization. METHODS: A total of 219 records related to CRISPR technology associated with extracellular vesicles from 2015 to 2022 in the Web of Science Core Collection (WoSCC) database were collected. R language, VOSviewer, CiteSpace, and GraphpadPrism software packages were used to analyze the history of this research, the general characteristics of the literature, and keywords. Finally, the hotspots and latest trends in CRISPR technology associated with extracellular vesicles are predicted. RESULTS: A total of 219 articles were collected for this study. The production of publications about CRISPR technology associated with extracellular vesicles has increased annually. Researchers from China, the USA, and Germany made the most important contributions to this trend, while RLUK Research Libraries UK offers the largest amount of literature in this field. Shenzhen University, Nanjing Medicine University, and Peking University exhibited the closest cooperation. Additionally, active topics burst during different periods, as identified according to 317 keywords belonging to 39 disciplines. Keywords were clustered into seven research subareas, namely exosome, nanovesicles, DNA, gene editing, gene therapy, cancer therapy, and endometrial stromal cells. The alluvial map of keywords reveals that the most enduring concepts are gene therapy, nanovesicles, etc., while the emerging keywords are genome, protein delivery, plasma, etc. CONCLUSIONS: We reviewed 219 previous publications and conducted the first bibliometric study of CRISPR technology related to extracellular vesicles from 2015 to 2022. This comprehensive summary constructed a knowledge map and demonstrates the trends in this area. The current trends and potential hotpots for this topic are also identified, which will be a great help for researchers in the future.
Subject(s)
Exosomes , Extracellular Vesicles , Humans , Clustered Regularly Interspaced Short Palindromic Repeats , Bibliometrics , Databases, FactualABSTRACT
BACKGROUND: The COVID-19 pandemic has a heavy impact on the mental health of elderly surgical patients worldwide. In particular, the elderly patients faced considerable psychological stress due to various environmental and medical factors during the outbreak. This study aims to examine changes in mental health trends among non-cardiac surgical patients aged 65 and above in China during the COVID-19 pandemic. METHODS: This multi-center, convenient sampling, longitudinal observational study was conducted from April 1, 2020 to April 30, 2022. Primary outcome was the prevalence of postoperative depression. Secondary outcome was the prevalence of postoperative anxiety. Follow-up was conducted separately at 7 days and 30 days after surgery. Depression symptoms were assessed using the Patient Health Questionnaire 9 (PHQ-9) scale. Anxiety symptoms were assessed using Generalized Anxiety Disorder-7 (GAD-7) scale, with scores of ≥5 defining positive depression or anxiety symptoms. Multivariate logistic regression analysis was used to investigate risk factors of mental health status in more elderly patients undergoing non-cardiac surgery. RESULTS: A total of 4639 patients were included, of whom 2279 (46.0 %) were male, 752 (15.2 %) were over the age of 75, and 4346 (93.7 %) were married. The monthly prevalence trends demonstrated that compared to the outbreak period, a significant reduction in the prevalence of depression and anxiety symptoms in elderly patients who underwent surgery during the post-pandemic period. In post-pandemic period, a statistically significant decrease in the prevalence of all severity depression and anxiety patients was noted at the 7-day follow-up, but no significant decrease was observed for severe depression and anxiety in the 30-day follow-up. In COVID-19 low-risk area, a significant overall decrease in prevalence of mental health was observed during the post-pandemic period compared to the outbreak period, including 7-day depression, 7-day anxiety, 30-day depression, and 30-day anxiety (all with P < 0.001). Female and patients with ≥2 comorbidities appeared to be more susceptible to postoperative depression and anxiety during the pandemic. LIMITATION: The absence of data from the early days of the COVID-19 outbreak. CONCLUSIONS: This study analyzed the prevalence of depression and anxiety in elderly non-cardiac patients during and after the COVID-19 pandemic, focusing on dimensions such as severity, risk-areas, gender, and comorbidity. Our findings revealed a significant decrease in the prevalence of depression and anxiety in elderly surgery patients during the post-pandemic period.
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The mechanism of general anesthesia remains elusive. The ventrolateral periaqueductal gray (vlPAG) in the midbrain regulates sleep and awake states. However, the role of vlPAG and its circuits in anesthesia is unclear. We utilized opto/chemogenetics, righting reflex, and electroencephalographic recording to assess consciousness changes. We employed fiber photometry to measure the activity of neurons and neurotransmitters. As a result, photometry recording showed that the activity of GABA neurons in vlPAG decreased during sevoflurane anesthesia and was reactivated after anesthesia. Activating GABAergic neurons in vlPAG promoted arousal during anesthesia, while inhibiting them delayed this process. Furthermore, medial prefrontal cortex (mPFC) to vlPAG pyramidal neurons projections and vlPAG to ventral tegmental area (VTA) GABAergic projections played a prominent role in the anesthesia-awake transition. GABA neurotransmitter activity of VTA synchronized with mPFC-vlPAG pyramidal neuron projections. Therefore, the cortico-midbrain circuits centered on vlPAG GABAergic neurons exert an arousal-promoting effect during sevoflurane anesthesia.
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BACKGROUND: The purpose of this study was to investigate the predictive value of the 5-factor modified frailty index (mFI-5) for postoperative mortality, delirium and pneumonia in patients over 65 years of age undergoing elective lung cancer surgery. METHODS: Data were collected from a single-center retrospective cohort study conducted in a general tertiary hospital from January 2017 to August 2019. In total, the study included 1372 elderly patients aged over 65 who underwent elective lung cancer surgery. They were divided into frail group (mFI-5, 2-5), prefrail group (mFI-5, 1) and robust group (mFI-5, 0) on the basis of mFI-5 classification. The primary outcome was postoperative 1-year all-cause mortality. Secondary outcomes were postoperative pneumonia and postoperative delirium. RESULTS: Frailty group had the highest incidence of postoperative delirium (frailty 31.2% versus prefrailty 1.6% versus robust 1.5%, p < 0.001), postoperative pneumonia (frailty 23.5% versus prefrailty 7.2% versus robust 7.7%, p < 0.001), and postoperative 1-year mortality (frailty 7.0% versus prefrailty 2.2% versus robust 1.9%. p < 0.001). Frail patients have significantly longer length of hospitalization than those in the robust group and prefrail patients (p < 0.001). Multivariate analysis showed a clear link between frailty and increased risk of postoperative delirium (aOR 2.775, 95% CI 1.776-5.417, p < 0.001), postoperative pneumonia (aOR 3.291, 95% CI 2.169-4.993, p < 0.001) and postoperative 1-year mortality (aOR 3.364, 95% CI, 1.516-7.464, p = 0.003). CONCLUSIONS: mFI-5 has potential clinical utility in predicting postoperative death, delirium and pneumonia incidence in elderly patients undergoing radical lung cancer surgery. Frailty screening of patients (mFI-5) may provide benefits in risk stratification, targeted intervention efforts, and assist physicians in clinical decision-making.
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General anaesthetics have been widely applied to induce reversible loss and recovery of consciousness in clinical practice and have been shown to have reliably safe profiles. Since brief exposure to general anaesthetics can result in long-lasting and global changes in neuronal structures and function, these drugs also exhibit strong therapeutic potential for mood disorders. Preliminary and clinical studies have suggested that the inhalational anaesthetic drug sevoflurane might relieve symptoms of depression. However, the antidepressant effects of sevoflurane and the underlying mechanisms remain elusive. In the present study, we confirmed that the antidepressant and anxiolytic effects of inhaling 2.5% sevoflurane for 30 min were comparable to those of ketamine and could be sustained for 48 h. Activation of GABAergic (γ-aminobutyric acidergic) neurons in the nucleus accumbens core by chemogenetics was shown to mimic the antidepressant effects of inhaled sevoflurane, whereas inhibition of these neurons significantly prevented these effects. Considered together, these results suggested that sevoflurane might exert rapid and long-lasting antidepressant effects via modulation of neuronal activities in the nucleus accumbens core nucleus.
Subject(s)
Anesthetics, Inhalation , Nucleus Accumbens , Sevoflurane/pharmacology , Antidepressive Agents/pharmacology , GABAergic Neurons , Anesthetics, Inhalation/pharmacologyABSTRACT
Calycosin is a natural product extracted from some plant families and exhibits various biological properties. But the effect of calycosin on cerebral ischemia-reperfusion injury has not been fully elucidated. In this study, the neuroprotective effect of calycosin treatment on the differentiated SH-SY5Y cells exposed to OGD was evaluated using MTT and flow cytometry. Rats that were pretreatment with calycosin were subjected to MCAO, neurological behavior scores and brain infarct volume were evaluated. The protein expression of pERK/ERK were assessed using Western blot. siRNA-pERK and U0126 were administered to investigate the impact of the ERK pathway on calycosin preconditioning. The results demonstrated the neuronal viability in the calycosin-treated SH-SY5Y cells increased significantly, and the rate of apoptosis decreased compared with the Oxygen-glucose deprivation only SH-SY5Y cells. Calycosin pretreatment reduced infarct volume and improved neurological outcome in rats subjected to MCAO. Administration of calycosin increased the ratio of pERK/ERK expression, which was down-regulated in ischemia-reperfusion group. Down-regulation of pERK/ERK significantly attenuated the neuroprotective effect induced by calycosin pretreatment in vitro and in vivo. We concluded calycosin treatment could induce a neuroprotective effect against ischemia, which was related to the regulation of the ERK1/2 pathway.
Subject(s)
Brain Ischemia , Neuroblastoma , Neuroprotective Agents , Reperfusion Injury , Animals , Rats , Humans , Neuroprotective Agents/pharmacology , MAP Kinase Signaling System , Brain Ischemia/metabolism , Rats, Sprague-Dawley , Reperfusion Injury/metabolism , ApoptosisABSTRACT
Girdin, an Akt substrate, has been reported to promote tumorigenesis in various tumors. However, the role of Girdin in a spontaneous tumor model has not yet been explored. Here, we studied the role of Girdin in lung adenocarcinoma (LUAD) using the autochthonous mouse model and found that Girdin led to LUAD progression and chemoresistance by enhancing the Warburg effect. Mechanistically, Girdin interacted with pyruvate kinase M2 (PKM2), which played a vital role in aerobic glycolysis. Furthermore, Girdin impaired Platelet Derived Growth Factor Receptor Beta (PDGFRß) degradation, which in turn, promoted PKM2 tyrosine residue 105 (Y105) phosphorylation and inhibited PKM2 activity, subsequently promoting aerobic glycolysis in cancer cells. Taken together, our study demonstrates that Girdin is a crucial regulator of tumor growth and may be a potential therapeutic target for overcoming the resistance of LUAD cells to chemotherapy.
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CNS inflammation is known to be an important pathogenetic mechanism of perioperative neurocognitive disorder (PND), and iron overload was reported to participate in this process accompanied by oxidative stress. Ferroptosis is an iron-dependent form of cell death, and occurs in multiple neurodegenerative diseases with cognitive disorder. However, the effect of ferroptosis in inflammation-related PND is unknown. In this study, we found that the ferroptosis inhibitor liproxstatin-1 ameliorated memory deficits in the mouse model of lipopolysaccharide (LPS)-induced cognitive impairment. Moreover, liproxstatin-1 decreased the activation of microglia and the release of interleukin (IL)-6 and tumor necrosis factor-alpha (TNF)-α, attenuated oxidative stress and lipid peroxidation, and further weakened mitochondrial injury and neuronal damage after LPS exposure. Additionally, the protective effect of liproxstatin-1 was related to the alleviation of iron deposition and the regulation of the ferroptosis-related protein family TF, xCT, Fth, Gpx4, and FtMt. These findings enhance our understanding of inflammation-involved cognitive dysfunction and shed light on future preclinical studies.
Subject(s)
Cognitive Dysfunction , Ferroptosis , Mice , Animals , Lipopolysaccharides/toxicity , Cognitive Dysfunction/chemically induced , Cognitive Dysfunction/drug therapy , Inflammation/metabolism , Iron/metabolismABSTRACT
Metabolic alteration of articular cartilage is associated with the pathogenesis of Osteoarthritis (OA). This study aims to identify the metabolism-related genes, corresponding transcription factors (TFs), and relevant pathways. Overall, RNA sequencing profiles of articular cartilage were collected from the GEO database. Metabolism-related genes and OA-related hallmarks were collected from the MSigDB v7.1. Differential expression analysis, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, and Gene Set Variation Analysis (GSVA) were conducted to identify pathways or hallmarks that were related to the pathogenesis of OA. The Pearson correlation analysis was used to establish the regulatory network among transcription factors, metabolism-related genes, and hallmarks. To further confirm the regulation of the identified transcription factors, Chromatin Immunoprecipitation-sequencing (ChIP-seq) was conducted, and single-cell sequencing was used to locate the cell clusters. Connectivity Map (CM) analysis were also conducted to identify the potential specific bioactive small molecules targeting the metabolic alteration of osteoarthritis. scTPA database was used to detect activated signaling pathways. Collectively, a total of 74 and 38 differentially expressed metabolism-related genes and TFs were retrieved. Skeletal system development, extracellular matrix, and cell adhesion molecule binding were important pathways in GO analysis. Human papillomavirus infection, PI3K-Akt signaling pathway, and Human T-cell leukemia virus 1 infection were the top 3 pathways in KEGG. 7 and 12 hallmarks were down- and up-regulated in GSVA, respectively. Ten bioactive small molecules may be potential treatments of OA by regulating the metabolism of articular cartilage. ChIP-seq analysis showed high relativity between transcription factors and their target genes. Furthermore, single-cell sequencing confirms the high expression of identified transcription factors in chondrocytes. To conclude, we established a comprehensive network integrated with transcription factors, metabolism-related genes, and hallmarks.
Subject(s)
Osteoarthritis , Transcription Factors , Humans , Transcription Factors/genetics , Gene Expression Profiling , Phosphatidylinositol 3-Kinases/genetics , Proto-Oncogene Proteins c-akt/genetics , Osteoarthritis/metabolism , Cell Adhesion Molecules/genetics , Gene Regulatory NetworksABSTRACT
Reconstruction of the knee meniscus remains a significant clinical challenge owing to its complex anisotropic tissue organization, complex functions, and limited healing capacity in the inner region. The development of in situ tissue-engineered meniscal scaffolds, which provide biochemical signaling to direct endogenous stem/progenitor cell (ESPC) behavior, has the potential to revolutionize meniscal tissue engineering. In this study, a fiber-reinforced porous scaffold was developed based on aptamer Apt19S-mediated mesenchymal stem cell (MSC)-specific recruitment and dual growth factor (GF)-enhanced meniscal differentiation. The aptamer, which can specifically recognize and recruit MSCs, was first chemically conjugated to the decellularized meniscus extracellular matrix (MECM) and then mixed with gelatin methacrylate (GelMA) to form a photocrosslinkable hydrogel. Second, connective tissue growth factor (CTGF)-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) and transforming growth factor-ß3 (TGF-ß3)-loaded PLGA microparticles (MPs) were mixed with aptamer-conjugated MECM to simulate anisotropic meniscal regeneration. These three bioactive molecules were delivered sequentially. Apt19S, which exhibited high binding affinity to synovium-derived MSCs (SMSCs), was quickly released to facilitate the mobilization of ESPCs. CTGF incorporated within PLGA NPs was released rapidly, inducing profibrogenic differentiation, while sustained release of TGF-ß3 in PLGA MPs remodeled the fibrous matrix into fibrocartilaginous matrix. The in vitro results showed that the sequential release of Apt19S/GFs promoted cell migration, proliferation, and fibrocartilaginous differentiation. The in vivo results demonstrated that the sequential release system of Apt/GF-scaffolds increased neomeniscal formation in rabbit critical-sized meniscectomies. Thus, the novel delivery system shows potential for guiding meniscal regeneration in situ.
ABSTRACT
Lung adenocarcinoma (LUAD) is the most common type of lung cancers, which remains the leading cause of cancer-related death worldwide. Drebrin can promote cell migration and invasion with poor prognosis, but its roes in LUAD tumor progression remains unknown. We showed that the expression of Drebrin was upregulated in clinical LUAD samples. A Kaplan-Meier survival analysis showed that a high expression of Drebrin predicated poor prognosis in LUAD. In vitro, Drebrin promoted anchorage-independent growth and migration of LUAD cells. Drebrin interacted with dynamin through CT domain, and served as an adaptor to promote LUAD cell migration through inducing integrin ß1 endocytosis. Thus, this study demonstrated the critical role of Drebrin in LUAD and associated mechanism.
Subject(s)
Adenocarcinoma of Lung , Lung Neoplasms , Neuropeptides , Adenocarcinoma of Lung/pathology , Cell Line, Tumor , Cell Movement , Cell Proliferation , Endocytosis , Gene Expression Regulation, Neoplastic , Humans , Integrin beta1/genetics , Integrin beta1/metabolism , Lung Neoplasms/pathology , Neuropeptides/geneticsABSTRACT
Clinically, microfracture is the most commonly applied surgical technique for cartilage defects. However, an increasing number of studies have shown that the clinical improvement remains questionable, and the reason remains unclear. Notably, recent discoveries revealed that signals from regenerated niches play a critical role in determining mesenchymal stem cell fate specification and differentiation. We speculate that a microenvironmentally optimized scaffold that directs mesenchymal stem cell fate will be a good therapeutic strategy for cartilage repair. Therefore, we first explored the deficiency of microfractures in cartilage repair. The microfracture not only induced inflammatory cell aggregation in blood clots but also consisted of loose granulation tissue with increased levels of proteins related to fibrogenesis. We then fabricated a functional cartilage scaffold using two strong bioactive cues, transforming growth factor-ß3 and decellularized cartilage extracellular matrix, to modulate the cell fate of mesenchymal stem cells. Additionally, poly(ε-caprolactone) was also coprinted with extracellular matrix-based bioinks to provide early mechanical support. The in vitro studies showed that microenvironmentally optimized scaffolds exert powerful effects on modulating the mesenchymal stem cell fate, such as promoting cell migration, proliferation and chondrogenesis. Importantly, this strategy achieved superior regeneration in sheep via scaffolds with biomechanics (restored well-organized collagen orientation) and antiapoptotic properties (cell death-related genes were also downregulated). In summary, this study provides evidence that microenvironmentally optimized scaffolds improve cartilage regeneration in situ by regulating the microenvironment and support further translation in human cartilage repair. STATEMENT OF SIGNIFICANCE: Although microfracture (MF)-based treatment for chondral defects has been commonly used, critical gaps exist in understanding the biochemistry of MF-induced repaired tissue. More importantly, the clinically unsatisfactory effects of MF treatment have prompted researchers to focus on tissue engineering scaffolds that may have sufficient therapeutic efficacy. In this manuscript, a 3D printing ink containing cartilage tissue-specific extracellular matrix (ECM), methacrylate gelatin (GelMA), and transforming growth factor-ß3 (TGF-ß3)-embedded polylactic-coglycolic acid (PLGA) microspheres was coprinted with poly(ε-caprolactone) (PCL) to fabricate tissue engineering scaffolds for chondral defect repair. The sustained release of TGF-ß3 from scaffolds successfully directed endogenous stem/progenitor cell migration and differentiation. This microenvironmentally optimized scaffold produced improved tissue repair outcomes in the sheep animal model, explicitly guiding more organized neotissue formation and therefore recapitulating the anisotropic structure of native articular cartilage. We hypothesized that the cell-free scaffolds might improve the clinical applicability and become a new therapeutic option for chondral defect repair.
Subject(s)
Cartilage, Articular , Fractures, Stress , Animals , Chondrogenesis , Humans , Printing, Three-Dimensional , Regeneration , Sheep , Tissue Engineering/methods , Tissue Scaffolds/chemistry , Transforming Growth Factor beta/pharmacology , Transforming Growth Factor beta3/metabolism , Transforming Growth Factor beta3/pharmacology , Transforming Growth Factors/pharmacologyABSTRACT
Transforming growth factor-ß (TGF-ß) is an important inducing factor for the differentiation of mesenchymal stem cells and the secretion of collagen II, but the inaccessibility and instability limit its application in clinical practice. In this study, the TGF-ß1-simulating peptide LIANAK (CM) was connected with the self-assembling peptide Ac-(RADA)4-CONH2 (RAD) to obtain the functionalized self-assembling peptide Ac-(RADA)4-GG-LIANAK-CONH2 (RAD-CM). The results indicated that the CM-functionalized RAD hydrogel contributed to the enhanced expressions of chondrogenic genes and extracellular matrix deposition. The self-assembling peptides were then combined with decellularized cartilage extracellular matrix (DCM) to construct a composite scaffold for articular cartilage repair. The CM-functionalized composite scaffold RAD/RAD-CM/DCM (R/C/D) exhibited good bioactivity and structural stability and exhibited satisfactory performance in promoting neocartilage restoration and the reconstruction of the osteochondral unit. This study provides a promising strategy for in situ cartilage regeneration via the stable presentation of TGF-ß1-simulating peptide. STATEMENT OF SIGNIFICANCE: Deficiency of effective chondrogenic inducers (especially, the TGF-ß family) significantly limits the self-regeneration of cartilage in osteochondral defect cases. Oligopeptide LIANAK, named CM, could simulate TGF-ß1's bioactivity with particular structure, but traditional chemical crosslinking to polymer scaffolds resulted in risks of safety and complication, which is unfavorable for clinical applications. Here, self-assembling peptide RAD was used to load CM, to obtain a TGF-ß1 mimetic peptide hydrogel. Depending on the homology (amino acids) of RAD and CM, the synthesis of the whole peptide only needs simply extended sequences of CM following that of RAD by automated solid-phase peptide synthesis. The modified peptide effectively demonstrated osteochondrogenic bioactivity, ensured the convenience, safety, and mass production, which displayed great potential in tissue engineering research and translational medicine.
Subject(s)
Cartilage, Articular , Chondrogenesis , Hydrogels/chemistry , Hydrogels/pharmacology , Peptides/chemistry , Peptides/pharmacology , Tissue Engineering/methods , Tissue Scaffolds/chemistry , Transforming Growth Factor beta/pharmacology , Transforming Growth Factor beta1/metabolismABSTRACT
Developing light structure materials that work stably at elevated temperatures is a long-standing challenge for many application fields, particularly in the development of aerospace equipment. Zn/Cd alloying elements were prospected to improve the stability of the lightest Mg-Li based alloys; however, little is known about the intermediate-temperature mechanical properties of such alloys. The present work investigated the tensile behaviors of a cold-rolled Mg-Li-Al-Cd-Zn alloy in a temperature range of 30-150 °C. The results indicate that the alloy can host a tensile strength σUTS of 108~121 MPa, a yield strength σYP of 97~109 MPa and elongation εB of 14-15 % at 150 °C, dependent on the tensile direction. The mechanical properties intensively are modulated by temperature through the competition between work hardening and softening. Work hardening due to dislocation blocking by the precipitated MgLi2X phase dominated the deformation at low temperatures, while softening that resulted from dynamic recrystallization was the main effect at high temperatures. Correspondingly, a quasi-cleavage mechanism dominated the fracture at temperatures near room temperature, and microvoid coalescence worked at high temperatures above 100 °C. Our results offer a new experimental understanding of the elevated-temperature mechanical behaviors of Mg-Li alloys and will advance the development of new light magnesium alloys with high stability.
ABSTRACT
Traumatic brain injury (TBI) is an important cause of death in young adults and children. Till now, the treatment of TBI in the short- and long-term complications is still a challenge. Our previous evidence implied aquaporin 4 (AQP4) and hypoxia inducible factor-1α (HIF-1α) might be potential targets for TBI. In this study, we explored the roles of AQP4 and HIF-1α on brain edema formation, neuronal damage and neurological functional deficits after TBI using the controlled cortical injury (CCI) model. The adult male Sprague Dawley rats were randomly divided into sham and TBI group, the latter group was further divided into neutralized-AQP4 antibody group, 2-methoxyestradiol (2-ME2) group, and their corresponding control, IgG and isotonic saline groups, respectively. Brain edema was examined by water content. Hippocampal neuronal injury was assessed by neuron loss and neuronal skeleton related protein expressions. Spatial learning and memory deficits were evaluated by Morris water maze test and memory-related proteins were detected by western blot. Our data showed that increased AQP4 protein level was closely correlated with severity of brain edema after TBI. Compared with that in the control group, both blockage of AQP4 with neutralized-AQP4 antibody and inhibition of HIF-1α with 2-ME2 for one-time treatment within 30-60 min post TBI significantly ameliorated brain edema on the 1st day post-TBI, and markedly alleviated hippocampal neuron loss and spatial learning and memory deficits on the 21st day post-TBI. In summary, our preliminary study revealed the short-term and long-term benefits of targeting HIF-1α-AQP4 axis after TBI, which may provide new clues for the selection of potential therapeutic targets for TBI in clinical practice.