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Here, we present an in situ U-Th dating approach of carbonate speleothems using laser ablation-inductively coupled plasma mass spectrometry (LA-ICPMS) with a detection efficiency of 1-2%. By online addition of a 229Th-233U-236U isotope triple spike to the laser-generated aerosol, instrumental mass discrimination and U/Th elemental fractionation could be monitored and corrected. With this approach, the 234U/238U and 230Th/238U activity ratios of a flowstone sample in secular equilibrium could be accurately reproduced as unity with two-sigma uncertainties ±0.053 and ±0.050, respectively. The method was used for the determination of the formation ages of individual layers in natural stalagmites ranging between 210 and 1 thousand years ago (ka). The determined ages corresponded well with those obtained using conventional solution multi collector-ICPMS techniques after isotope separation. Particularly, Holocene stalagmites, as young as 1 ka, could be accurately dated with 2 standard error of ±76 years. This developed microdomain U-Th dating approach thus can be applicable for diverse research areas, such as paleoclimatology, oceanography, geomagnetism, and archeology.
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Mild traumatic brain injury (mTBI) is a prevalent health concern with variable recovery trajectories, necessitating reliable prognostic markers. Insulin-like growth factor 1 (IGF-1) emerges as a potential candidate because of its role in cellular growth, repair, and neuroprotection. However, limited studies investigate IGF-1 as a prognostic marker in mTBI patients. This study aimed to explore the correlation of IGF-1 with cognitive functions assessed using the Wisconsin Card Sorting Test (WCST) in mTBI patients. We analyzed data from 295 mTBI and 200 healthy control participants, assessing demographic characteristics, injury causes, and IGF-1 levels. Cognitive functions were evaluated using the WCST. Correlation analyses and regression models were used to investigate the associations between IGF-1 levels, demographic factors, and WCST scores. Significant differences were observed between mTBI and control groups in the proportion of females and average education years. Falls and traffic accidents were identified as the primary causes of mTBI. The mTBI group demonstrated worse cognitive outcomes on the WCST, except for the "Learning to Learn" index. Correlation analyses revealed significant relationships between IGF-1 levels, demographic factors, and specific WCST scores. Regression models demonstrated that IGF-1, age, and education years significantly influenced various WCST scores, suggesting their roles as potential prognostic markers for cognitive outcomes in mTBI patients. We provide valuable insights into the potential correlation of IGF-1 with cognitive functions in mTBI patients, particularly in tasks requiring cognitive flexibility and problem solving.
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Blood-brain barrier (BBB) disruption is a prominent pathophysiological mechanism in stroke. Transplantation of mesenchymal stem cells (MSCs) preserves BBB integrity following ischemic stroke. Fibroblast growth factor 21 (FGF21) has been shown to be a potent neuroprotective agent that reduces neuroinflammation and protects against BBB leakage. In this study, we assessed the effects of transplantation of MSCs overexpressing FGF21 (MSCs-FGF21) on ischemia-induced neurological deficits and BBB breakdown. MSCs-FGF21 was injected into the rat brain via the intracerebroventricular route 24 h after middle cerebral artery occlusion (MCAO) surgery. The behavioral performance was assessed using modified neurological severity scores and Y-maze tests. BBB disruption was measured using Evans blue staining, IgG extravasation, and brain water content. The levels of tight junction proteins, aquaporin 4, and neuroinflammatory markers were analyzed by western blotting and immunohistochemistry. The activity of matrix metalloproteinase-9 (MMP-9) was determined using gelatin zymography. At day-5 after MCAO surgery, intraventricular injection of MSCs-FGF21 was found to significantly mitigate the neurological deficits and BBB disruption. The MCAO-induced loss of tight junction proteins, including ZO-1, occludin, and claudin-5, and upregulation of the edema inducer, aquaporin 4, were also remarkably inhibited. In addition, brain infarct volume, pro-inflammatory protein expression, and MMP-9 activation were effectively suppressed. These MCAO-induced changes were only marginally improved by treatment with MSCs-mCherry, which did not overexpress FGF21. Overexpression of FGF21 dramatically improved the therapeutic efficacy of MSCs in treating ischemic stroke. Given its multiple benefits and long therapeutic window, MSC-FGF21 therapy may be a promising treatment strategy for ischemic stroke.
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Background and purpose: Intracerebral hemorrhage (ICH) enhances neurogenesis in the subventricular zone (SVZ); however, the mechanism is not fully understood. We investigated the role of brain-derived neurotrophic factor (BDNF) in post-ICH neurogenesis in a rodent model and in patients with ICH using cerebrospinal fluid (CSF). Methods: A rat model of ICH was constructed via stereotaxic injection of collagenase into the left striatum. Patients with ICH receiving an external ventricular drain were prospectively enrolled. CSF was collected from rats and patients at different post-ICH times. Primary cultured rat neural stem cells (NSCs) were treated with CSF with or without BDNF-neutralized antibody. Immunohistochemistry and immunocytochemistry were used to detect NSC proliferation and differentiation. The BDNF concentration in CSF was quantified using enzyme-linked immunosorbent assays (ELISA). Results: In the rat model of ICH, the percentage of proliferating NSCs and neuroblasts in SVZ was elevated in bilateral hemispheres. The cultured rat NSCs treated with CSF from both rats and patients showed an increased capacity for proliferation and differentiation toward neuroblasts. BDNF concentration was higher in CSF collected from rats and patients with ICH than in controls. Blocking BDNF decreased the above-noted promotion of proliferation and differentiation of cultured NSCs by CSF treatment. In patients with ICH, the BDNF concentration in CSF and the neurogenesis-promoting capacity of post-ICH CSF correlated positively with ICH volume. Conclusion: BDNF in CSF contributes to post-ICH neurogenesis, including NSC proliferation and differentiation toward neuroblasts in a rat model and patients with ICH.
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Although adjuvant tamoxifen therapy is beneficial to estrogen receptor-positive (ER+) breast cancer patients, a significant number of patients still develop metastasis or undergo recurrence. Therefore, identifying novel diagnostic and prognostic biomarkers for these patients is urgently needed. Predictive markers and therapeutic strategies for tamoxifen-resistant ER+ breast cancer are not clear, and micro (mi)RNAs have recently become a focal research point in cancer studies owing to their regulation of gene expressions, metabolism, and many other physiological processes. Therefore, systematic investigation is required to understand the modulation of gene expression in tamoxifen-resistant patients. High-throughput technology uses a holistic approach to observe differences among expression profiles of thousands of genes, which provides a comprehensive level to extensively investigate functional genomics and biological processes. Through a bioinformatics analysis, we revealed that glutamine synthetase/glutamate-ammonia ligase (GLUL) might play essential roles in the recurrence of tamoxifen-resistant ER+ patients. GLUL increases intracellular glutamine usage via glutaminolysis, and further active metabolism-related downstream molecules in cancer cell. However, how GLUL regulates the tumor microenvironment for tamoxifen-resistant ER+ breast cancer remains unexplored. Analysis of MetaCore pathway database demonstrated that GLUL is involved in the cell cycle, immune response, interleukin (IL)-4-induced regulators of cell growth, differentiation, and metabolism-related pathways. Experimental data also confirmed that the knockdown of GLUL in breast cancer cell lines decreased cell proliferation and influenced expressions of specific downstream molecules. Through a Connectivity Map (CMap) analysis, we revealed that certain drugs/molecules, including omeprazole, methacholine chloride, ioversol, fulvestrant, difenidol, cycloserine, and MK-801, may serve as potential treatments for tamoxifen-resistant breast cancer patients. These drugs may be tested in combination with current therapies in tamoxifen-resistant breast cancer patients. Collectively, our study demonstrated the crucial roles of GLUL, which provide new targets for the treatment of tamoxifen-resistant breast cancer patients.
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Neoplasias da Mama , Glutamato-Amônia Ligase , MicroRNAs , Feminino , Humanos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/genética , Fulvestranto/uso terapêutico , Regulação Neoplásica da Expressão Gênica , Glutamato-Amônia Ligase/genética , Glutamato-Amônia Ligase/metabolismo , Tamoxifeno/farmacologia , Tamoxifeno/uso terapêutico , Microambiente Tumoral/genéticaRESUMO
The variability of the northern westerlies has been considered as one of the key elements for modern and past climate evolution. Their multiscale behavior and underlying control mechanisms, however, are incompletely understood, owing to the complex dynamics of Atlantic sea-level pressures. Here, we present a multi-annually resolved record of the westerly drift over the past 6,500 years from northern Italy. In combination with more than 20 other westerly-sensitive records, our results depict the non-stationary westerly-affected regions over mainland Europe on multi-decadal to multi-centennial time scales, showing that the direction of the westerlies has changed with respect to the migrations of the North Atlantic centers of action since the middle Holocene. Our findings suggest the crucial role of the migrations of the North Atlantic dipole in modulating the westerly-affected domain over Europe, possibly modulated by Atlantic Ocean variability.
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Clima , Vento , Europa (Continente) , Oceano Atlântico , ItáliaRESUMO
Monkeypox virus (MPV) is a smallpox-like virus belonging to the genus Orthopoxvirus of the family Poxviridae. Unlike smallpox with no animal reservoir identified and patients suffering from milder symptoms with less mortality, several animals were confirmed to serve as natural hosts of MPV. The reemergence of a recently reported monkeypox epidemic outbreak in nonendemic countries has raised concerns about a global outburst. Since the underlying mechanism of animal-to-human transmission remains largely unknown, comprehensive analyses to discover principal differences in gene signatures during disease progression have become ever more critical. In this study, two MPV-infected in vitro models, including human immortal epithelial cancer (HeLa) cells and rhesus monkey (Macaca mulatta) kidney epithelial (MK2) cells, were chosen as the two subjects to identify alterations in gene expression profiles, together with co-regulated genes and pathways that are affected during monkeypox disease progression. Using Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and MetaCore analyses, we discovered that elevated expression of genes associated with interleukins (ILs), G protein-coupled receptors (GPCRs), heat shock proteins (HSPs), Toll-like receptors (TLRs), and metabolic-related pathways play major roles in disease progression of both monkeypox-infected monkey MK2 and human HeLa cell lines. Interestingly, our analytical results also revealed that a cluster of differentiation 40 (CD40), plasmin, and histamine served as major regulators in the monkeypox-infected monkey MK2 cell line model, while interferons (IFNs), macrophages, and neutrophil-related signaling pathways dominated the monkeypox-infected human HeLa cell line model. Among immune pathways of interest, apart from traditional monkeypox-regulated signaling pathways such as nuclear factor- (NF-κB), mitogen-activated protein kinases (MAPKs), and tumor necrosis factors (TNFs), we also identified highly significantly expressed genes in both monkey and human models that played pivotal roles during the progression of monkeypox infection, including CXCL1, TNFAIP3, BIRC3, IL6, CCL2, ZC3H12A, IL11, CSF2, LIF, PTX3, IER3, EGR1, ADORA2A, and DUOX1, together with several epigenetic regulators, such as histone cluster family gene members, HIST1H3D, HIST1H2BJ, etc. These findings might contribute to specific underlying mechanisms related to the pathophysiology and provide suggestions regarding modes of transmission, post-infectious sequelae, and vaccine development for monkeypox in the future.
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Mpox , Varíola , Animais , Progressão da Doença , Células HeLa , Humanos , Macaca mulatta , Mpox/patologia , Monkeypox virus/genética , TranscriptomaRESUMO
The complexity of breast cancer includes many interacting biological processes that make it difficult to find appropriate therapeutic treatments. Therefore, identifying potential diagnostic and prognostic biomarkers is urgently needed. Previous studies demonstrated that 26S proteasome delta subunit, non-ATPase (PSMD) family members significantly contribute to the degradation of damaged, misfolded, abnormal, and foreign proteins. However, transcriptional expressions of PSMD family genes in breast cancer still remain largely unexplored. Consequently, we used a holistic bioinformatics approach to explore PSMD genes involved in breast cancer patients by integrating several high-throughput databases, including The Cancer Genome Atlas (TCGA), cBioPortal, Oncomine, and Kaplan-Meier plotter. These data demonstrated that PSMD1, PSMD2, PSMD3, PSMD7, PSMD10, PSMD12, and PSMD14 were expressed at significantly higher levels in breast cancer tissue compared to normal tissues. Notably, the increased expressions of PSMD family genes were correlated with poor prognoses of breast cancer patients, which suggests their roles in tumorigenesis. Meanwhile, network and pathway analyses also indicated that PSMD family genes were positively correlated with ubiquinone metabolism, immune system, and cell-cycle regulatory pathways. Collectively, this study revealed that PSMD family members are potential prognostic biomarkers for breast cancer progression and possible promising clinical therapeutic targets.
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Neoplasias da Mama , Complexo de Endopeptidases do Proteassoma/genética , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Humanos , Prognóstico , Complexo de Endopeptidases do Proteassoma/metabolismo , Transcriptoma/genética , Transcriptoma/imunologiaRESUMO
We applied a new geoarchaeological method with two carbonate archives, which are fossil snails from Sakitari Cave and stalagmites from Gyokusen Cave, on Okinawa Island, Japan, to reconstruct surface air temperature changes over the northwestern Pacific since the last glacial period. Oxygen isotope ratios (δ18O) of modern and fossil freshwater snail shells were determined to infer seasonal temperature variations. The observational and analytical data confirm that δ18O values of fluid inclusion waters in the stalagmite can be regarded as those of spring waters at the sites where snails lived. Our results indicate that the annual mean, summer, and winter air temperatures were lower by 6-7 °C at ca. 23 thousand years ago (ka) and 4-5 °C at ca. 16-13 ka than those of the present day. Our reconstruction implies that surface air cooling was possibly two times greater than that of seawater around the Ryukyu Islands during the Last Glacial Maximum, which potentially enhanced the development of the East Asian summer monsoon during the last deglaciation. Considering the potential uncertainties in the temperature estimations, the climatic interpretations of this study are not necessarily definitive due to the limited number of samples. Nevertheless, our new geoarchaeological approach using coupled δ18O determinations of fossil snails and stalagmite fluid inclusion waters will be useful for reconstructing snapshots of seasonally resolved time series of air temperatures during the Quaternary.
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Ischemic stroke is the leading cause of mortality and long-term disability worldwide. Disruption of the blood-brain barrier (BBB) is a prominent pathophysiological mechanism, responsible for a series of subsequent inflammatory cascades that exacerbate the damage to brain tissue. However, the benefit of recanalization is limited in most patients because of the narrow therapeutic time window. Recently, mesenchymal stem cells (MSCs) have been assessed as excellent candidates for cell-based therapy in cerebral ischemia, including neuroinflammatory alleviation, angiogenesis and neurogenesis promotion through their paracrine actions. In addition, accumulating evidence on how MSC therapy preserves BBB integrity after stroke may open up novel therapeutic targets for treating cerebrovascular diseases. In this review, we focus on the molecular mechanisms of MSC-based therapy in the ischemia-induced prevention of BBB compromise. Currently, therapeutic effects of MSCs for stroke are primarily based on the fundamental pathogenesis of BBB breakdown, such as attenuating leukocyte infiltration, matrix metalloproteinase (MMP) regulation, antioxidant, anti-inflammation, stabilizing morphology and crosstalk between cellular components of the BBB. We also discuss prospective studies to improve the effectiveness of MSC therapy through enhanced migration into defined brain regions of stem cells. Targeted therapy is a promising new direction and is being prioritized for extensive research.
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Barreira Hematoencefálica/metabolismo , Isquemia Encefálica/metabolismo , Encéfalo/metabolismo , Células-Tronco Mesenquimais/metabolismo , Animais , Humanos , Metaloproteinases da Matriz/metabolismoRESUMO
Breast cancer is a complex disease, and several processes are involved in its development. Therefore, potential therapeutic targets need to be discovered for these patients. Proteasome 26S subunit, ATPase gene (PSMC) family members are well reported to be involved in protein degradation. However, their roles in breast cancer are still unknown and need to be comprehensively researched. Leveraging publicly available databases, such as cBioPortal and Oncomine, for high-throughput transcriptomic profiling to provide evidence-based targets for breast cancer is a rapid and robust approach. By integrating the aforementioned databases with the Kaplan-Meier plotter database, we investigated potential roles of six PSMC family members in breast cancer at the messenger RNA level and their correlations with patient survival. The present findings showed significantly higher expression profiles of PSMC2, PSMC3, PSMC4, PSMC5, and PSMC6 in breast cancer compared to normal breast tissues. Besides, positive correlations were also revealed between PSMC family genes and ubiquinone metabolism, cell cycle, and cytoskeletal remodeling. Meanwhile, we discovered that high levels of PSMC1, PSMC3, PSMC4, PSMC5, and PSMC6 transcripts were positively correlated with poor survival, which likely shows their importance in breast cancer development. Collectively, PSMC family members have the potential to be novel and essential prognostic biomarkers for breast cancer development.
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Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Regulação Neoplásica da Expressão Gênica , Complexo de Endopeptidases do Proteassoma/genética , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Conjuntos de Dados como Assunto , Intervalo Livre de Doença , Feminino , Perfilação da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Prognóstico , RNA Mensageiro/genéticaRESUMO
B-cell-specific Moloney murine leukemia virus integration site 1 (BMI1) appears to be essential for promoting certain types of cancer, and its inhibition effectively reduced the stemness of cancer cells. Therefore, this study aimed to investigate the potential role of BMI1 in glioma. To this end, we first investigated BMI1 expression in brain tumors using microarray datasets in ONCOMINE, which indicated that BMI1 levels were not commonly increased in clinical brain tumors. Moreover, survival plots in PROGgeneV2 also showed that BMI1 expression was not significantly associated with reduced survival in glioma patients. Interestingly, stressful serum deprivation and anchorage independence growth conditions led to an increased BMI1 expression in glioma cells. A stress-responsive pathway, HDAC/Sp1, was further identified to regulate BMI1 expression. The HDAC inhibitor vorinostat (SAHA) prevented Sp1 binding to the BMI1 promoter, leading to a decreased expression of BMI1 and attenuating tumor growth of TMZ-resistant glioma xenografts. Importantly, we further performed survival analysis using PROGgeneV2 and found that an elevated expression of HDAC1,3/Sp1/BMI1 but not BMI1 alone showed an increased risk of death in both high- and low-grade glioma patients. Thus, HDAC-mediated Sp1 deacetylation is critical for BMI1 regulation to attenuate stress- and therapy-induced death in glioma cells, and the HDAC/Sp1 axis is more important than BMI1 and appears as a therapeutic target to prevent recurrence of malignant glioma cells persisting after primary therapy.
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Biomarcadores Tumorais/metabolismo , Glioma/diagnóstico , Glioma/metabolismo , Células-Tronco Neoplásicas/metabolismo , Complexo Repressor Polycomb 1/metabolismo , Animais , Linhagem Celular , Regulação Neoplásica da Expressão Gênica , Glioma/patologia , Histona Desacetilase 1/metabolismo , Histona Desacetilases/metabolismo , Humanos , Masculino , Camundongos , Prognóstico , Regiões Promotoras Genéticas/genética , Fator de Transcrição Sp1/metabolismo , Regulação para CimaRESUMO
This study aims to evaluate the relationship between traumatic brain injury (TBI) and sleep disorders (SDs). We first initiated a questionnaire-based clinical survey to assess sleep problems in the early stage after a TBI, followed by a population-based cohort study to evaluate the long-term risk of SDs in TBI patients. For short-term clinical survey, mild (m)TBI patients and healthy controls were recruited to evaluate the sleep quality and daytime sleepiness using the Pittsburg Sleep Quality Index (PSQI) and Epworth Sleepiness Scale (ESS) within two weeks after a TBI. For long-term observation, a 5-year nationwide population-based cohort study that utilized a large administrative database was conducted. In the short-term survey, 236 mTBI patients and 223 controls were analyzed. Total scores of the PSQI and ESS were significantly higher in mTBI patients than in the controls. In the long-term cohort study, 6932 TBI cases and 34,660 matched controls were included. TBI cases had a 1.36-fold greater risk of SDs compared to the non-TBI controls during the 5-year follow-up period. Results showed that patients with TBI had a significantly higher risk of SDs than did controls both in the early stage and during a 5-year follow-up period.
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Lesões Encefálicas Traumáticas , Transtornos do Sono-Vigília , Lesões Encefálicas Traumáticas/complicações , Lesões Encefálicas Traumáticas/epidemiologia , Estudos de Coortes , Humanos , Estudos Longitudinais , Transtornos do Sono-Vigília/epidemiologia , Transtornos do Sono-Vigília/etiologia , Inquéritos e QuestionáriosRESUMO
Breast cancer is the most common cancer type in females, and exploring the mechanisms of disease progression is playing a crucial role in the development of potential therapeutics. Pituitary tumor-transforming gene (PTTG) family members are well documented to be involved in cell-cycle regulation and mitosis, and contribute to cancer development by their involvement in cellular transformation in several tumor types. The critical roles of PTTG family members as crucial transcription factors in diverse types of cancers are recognized, but how they regulate breast cancer development still remains mostly unknown. Meanwhile, a holistic genetic analysis exploring whether PTTG family members regulate breast cancer progression via the cell cycle as well as the energy metabolism-related network is lacking. To comprehensively understand the messenger RNA expression profiles of PTTG proteins in breast cancer, we herein conducted a high-throughput screening approach by integrating information from various databases such as Oncomine, Kaplan-Meier Plotter, Metacore, ClueGo, and CluePedia. These useful databases and tools provide expression profiles and functional analyses. The present findings revealed that PTTG1 and PTTG3 are two important genes with high expressions in breast cancer relative to normal breast cells, implying their unique roles in breast cancer progression. Results of our coexpression analysis demonstrated that PTTG family genes were positively correlated with thiamine triphosphate (TTP), deoxycytidine triphosphate (dCTP) metabolic, glycolysis, gluconeogenesis, and cell-cycle related pathways. Meanwhile, through Cytoscape analyzed indicated that in addition to the metastasis markers AURKA, AURKB, and NDC80, many of the kinesin superfamily (KIF) members including KIFC1, KIF2C, KIF4A, KIF14, KIF20A, KIF23, were also correlated with PTTG family transcript expression. Finally, we revealed that high levels of PTTG1 and PTTG3 transcription predicted poor survival, which provided useful insights into prospective research of cancer associated with the PTTG family. Therefore, these members of the PTTG family would serve as distinct and essential prognostic biomarkers in breast cancer.
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Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Recidiva Local de Neoplasia/epidemiologia , Securina/genética , Mama/patologia , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Neoplasias da Mama/terapia , Linhagem Celular Tumoral , Conjuntos de Dados como Assunto , Intervalo Livre de Doença , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Recidiva Local de Neoplasia/genética , Oncogenes , PrognósticoRESUMO
Mesenchymal stem cells (MSCs) are emerging as an attractive approach for restorative medicine in central nervous system (CNS) diseases and injuries, such as traumatic brain injury (TBI), due to their relatively easy derivation and therapeutic effect following transplantation. However, the long-term survival of the grafted cells and therapeutic efficacy need improvement. Here, we review the recent application of MSCs in TBI treatment in preclinical models. We discuss the genetic modification approaches designed to enhance the therapeutic potency of MSCs for TBI treatment by improving their survival after transplantation, enhancing their homing abilities and overexpressing neuroprotective and neuroregenerative factors. We highlight the latest preclinical studies that have used genetically modified MSCs for TBI treatment. The recent developments in MSCs' biology and potential TBI therapeutic targets may sufficiently improve the genetic modification strategies for MSCs, potentially bringing effective MSC-based therapies for TBI treatment in humans.
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Lesões Encefálicas Traumáticas/terapia , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Animais , Lesões Encefálicas Traumáticas/etiologia , Lesões Encefálicas Traumáticas/metabolismo , Lesões Encefálicas Traumáticas/patologia , Terapia Baseada em Transplante de Células e Tecidos , Gerenciamento Clínico , Suscetibilidade a Doenças , Técnicas de Transferência de Genes , Engenharia Genética/métodos , Terapia Genética , Humanos , Transplante de Células-Tronco Mesenquimais/métodos , NeurogêneseRESUMO
Traumatic brain injury (TBI) is a progressive and complex pathological condition that results in multiple adverse consequences, including impaired learning and memory. Transplantation of mesenchymal stem cells (MSCs) has produced limited benefits in experimental TBI models. Fibroblast growth factor 21 (FGF21) is a novel metabolic regulator that has neuroprotective effects, promotes remyelination, enhances angiogenesis, and elongates astrocytic processes. In this study, MSCs were genetically engineered to overexpress FGF21 in order to improve their efficacy in TBI. MSCs overexpressing FGF21 (MSC-FGF21) were transplanted to mouse brain by intracerebroventricular injection 24 h after TBI was induced by controlled cortical impact (CCI). Hippocampus-dependent spatial learning and memory, assessed by the Morris water maze test, was markedly decreased 3-4 weeks after TBI, a deficit that was robustly recovered by treatment with MSC-FGF21, but not MSC-mCherry control. Hippocampus-independent learning and memory, assessed by the novel object recognition test, was also impaired; these effects were blocked by treatment with both MSC-FGF21 and MSC-mCherry control. FGF21 protein levels in the ipsilateral hippocampus were drastically reduced 4 weeks post-TBI, a loss that was restored by treatment with MSC-FGF21, but not MSC-mCherry. MSC-FGF21 treatment also partially restored TBI-induced deficits in neurogenesis and maturation of immature hippocampal neurons, whereas MSC-mCherry was less effective. Finally, MSC-FGF21 treatment also normalized TBI-induced impairments in dendritic arborization of hippocampal neurons. Taken together, the results indicate that MSC-FGF21 treatment significantly improved TBI-induced spatial memory deficits, impaired hippocampal neurogenesis, and abnormal dendritic morphology. Future clinical investigations using MSC-FGF21 to improve post-TBI outcomes are warranted.
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Lesões Encefálicas Traumáticas/patologia , Fatores de Crescimento de Fibroblastos/metabolismo , Transplante de Células-Tronco Mesenquimais/métodos , Neurogênese , Recuperação de Função Fisiológica , Animais , Modelos Animais de Doenças , Hipocampo/patologia , Aprendizagem em Labirinto , Memória , Camundongos , Camundongos Endogâmicos C57BL , Neurogênese/fisiologiaRESUMO
Stem cell-based therapies for brain injuries, such as traumatic brain injury (TBI), are a promising approach for clinical trials. However, technical hurdles such as invasive cell delivery and tracking with low transplantation efficiency remain challenges in translational stem-based therapy. This article describes an emerging technique for stem cell labeling and tracking based on the labeling of the mesenchymal stem cells (MSCs) with superparamagnetic iron oxide (SPIO) nanoparticles, as well as intranasal delivery of the labeled MSCs. These nanoparticles are fluorescein isothiocyanate (FITC)-embedded and safe to label the MSCs, which are subsequently delivered to the brains of TBI-induced mice by the intranasal route. They are then tracked non-invasively in vivo by real-time magnetic resonance imaging (MRI). Important advantages of this technique that combines SPIO for cell labeling and intranasal delivery include (1) non-invasive, in vivo MSC tracking after delivery for long tracking periods, (2) the possibility of multiple dosing regimens due to the non-invasive route of MSC delivery, and (3) possible applications to humans, owing to the safety of SPIO, non-invasive nature of the cell-tracking method by MRI, and route of administration.
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Lesões Encefálicas Traumáticas/patologia , Rastreamento de Células/métodos , Nanopartículas de Magnetita , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , Animais , Lesões Encefálicas Traumáticas/terapia , Modelos Animais de Doenças , Compostos Férricos , Imageamento por Ressonância Magnética/métodos , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
BACKGROUND: Insulin-like growth factor 1 (IGF-1) is an important pleiotropic hormone that exerts neuroprotective and neuroreparative effects after a brain injury. However, the roles of IGF-1 variants in mild traumatic brain injury (mTBI) are not yet fully understood. This study attempted to elucidate the effects of IGF-1 variants on the risk and neuropsychiatric outcomes of mTBI. METHODS: Based on 176 recruited mTBI patients and 1517 control subjects from the Taiwan Biobank project, we first compared the genotypic distributions of IGF-1 variants between the two groups. Then, we analyzed associations of IGF-1 variants with neuropsychiatric symptoms after mTBI, including anxiety, depression, dizziness, and sleep disturbances. Functional annotation of IGF-1 variants was also performed through bioinformatics databases. RESULTS: The minor allele of rs7136446 was over-represented in mTBI patients compared to community-based control subjects. Patients carrying minor alleles of rs7136446 and rs972936 showed more dizziness and multiple neuropsychiatric symptoms after brain injury. CONCLUSIONS: IGF-1 variants were associated with the risk and neuropsychiatric symptoms of mTBI. The findings highlight the important role of IGF-1 in the susceptibility and clinical outcomes of mTBI.
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Ansiedade/genética , Concussão Encefálica/genética , Depressão/genética , Tontura/genética , Fator de Crescimento Insulin-Like I/genética , Polimorfismo Genético , Transtornos do Sono-Vigília/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Ansiedade/etiologia , Concussão Encefálica/complicações , Depressão/etiologia , Tontura/etiologia , Feminino , Humanos , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Transtornos do Sono-Vigília/etiologia , Taiwan , Adulto JovemRESUMO
Tropical rainfall variability is closely linked to meridional shifts of the Intertropical Convergence Zone (ITCZ) and zonal movements of the Walker circulation. The characteristics and mechanisms of tropical rainfall variations on centennial to decadal scales are, however, still unclear. Here, we reconstruct a replicated stalagmite-based 2,700-y-long, continuous record of rainfall for the deeply convective northern central Indo-Pacific (NCIP) region. Our record reveals decreasing rainfall in the NCIP over the past 2,700 y, similar to other records from the northern tropics. Notable centennial- to decadal-scale dry climate episodes occurred in both the NCIP and the southern central Indo-Pacific (SCIP) during the 20th century [Current Warm Period (CWP)] and the Medieval Warm Period (MWP), resembling enhanced El Niño-like conditions. Further, we developed a 2,000-y-long ITCZ shift index record that supports an overall southward ITCZ shift in the central Indo-Pacific and indicates southward mean ITCZ positions during the early MWP and the CWP. As a result, the drying trend since the 20th century in the northern tropics is similar to that observed during the past warm period, suggesting that a possible anthropogenic forcing of rainfall remains indistinguishable from natural variability.