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Background: Pancreatic ductal adenocarcinoma (PDAC) often presents with liver or peritoneal metastases at diagnosis. Despite similar treatment approaches, patient outcomes vary between these metastatic sites. To improve targeted therapies for metastatic PDAC, a comprehensive analysis of the genetic profiles and evolutionary patterns at these distinct metastatic locations is essential. Methods: We performed whole exome sequencing on 44 tissue samples from 27 PDAC patients, including primary tumours and matched liver or peritoneal metastases. We analysed somatic mutation profiles, signatures, and affected pathways for each group, and examined clonal evolution using subclonal architectures and phylogenetic trees. Results: KRAS mutations remained the predominant driver alteration, with a prevalence of 89 % across all tumours. Notably, we observed site-specific differences in mutation frequencies, with KRAS alterations detected in 77.8 % (7/9) of peritoneal metastases and 87.5 % (7/8) of liver metastases. TP53 mutations exhibited a similar pattern, occurring in 55.6 % (5/9) of peritoneal and 37.5 % (3/8) of liver metastases. Intriguingly, we identified site-specific alterations in DNA repair pathway genes, including ATM and BRCA1, with distinct mutational profiles in liver versus peritoneal metastases. Furthermore, liver metastases demonstrated a significantly higher tumor mutational burden (TMB) compared to peritoneal metastases (median [IQR]: 2.14 [1.77-2.71] vs. 1.29 [1.21-1.69] mutations/Mb; P = 0.048). Conclusions: In conclusion, metastasis of pancreatic cancer may be influenced by variables other than KRAS mutations, such as TP53. PDAC peritoneal and liver metastases may differ in potential therapeutic biomarkers. Further inquiry is needed on the biological mechanisms underlying metastasis and the treatment of diverse metastases.
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Osteoporosis, a prevalent systemic bone metabolic disorder, primarily affects postmenopausal women and is characterized by increased bone fragility and a heightened risk of fractures. The efficacy of current osteoporosis treatments is often limited by non-specific drug targeting and undesirable off-target skeletal side effects. To address this challenge, we have developed a novel hydroxyapatite-responsive drug delivery system. This system utilizes a self-assembled p-phosphonatocalix[4]arene tetradodecyl ether (PC4A12C), engineered to specifically target and sustain the release of osteoporosis medication at sites of bone remodeling. Our focus centers on icariin (ICA), a drug known for its potent osteogenic properties and minimal adverse effects. In vitro, ICA-loaded PC4A12C (ICA@PC4A12C) demonstrated enhanced proliferation, differentiation, and mineralization in bone marrow mesenchymal stem cells (BMSCs). In vivo, ICA@PC4A12C exhibited superior efficacy in specifically targeting bone tissue, ensuring a controlled and slow release of icariin directly within the bone environment. In an osteoporosis mouse model, treatment with ICA@PC4A12C showed notable enhancement in osteogenic activity and a significant increase in bone density compared to ICA alone. These results demonstrate the potential of PC4A12C as an effective drug carrier in the development of advanced antiosteoporotic drug delivery systems.
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Preparaciones de Acción Retardada , Sistemas de Liberación de Medicamentos , Flavonoides , Células Madre Mesenquimatosas , Osteogénesis , Osteoporosis , Animales , Osteoporosis/tratamiento farmacológico , Sistemas de Liberación de Medicamentos/métodos , Femenino , Osteogénesis/efectos de los fármacos , Células Madre Mesenquimatosas/efectos de los fármacos , Flavonoides/administración & dosificación , Flavonoides/química , Flavonoides/farmacología , Ratones , Diferenciación Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Conservadores de la Densidad Ósea/administración & dosificación , Densidad Ósea/efectos de los fármacos , Durapatita/química , Durapatita/administración & dosificación , Ratones Endogámicos C57BL , Liberación de FármacosRESUMEN
Maternal exposure to elevated levels of steroid hormones during pregnancy is associated with the development of chronic conditions in offspring that manifest in adulthood. However, the effects of progesterone (P4) administration during early pregnancy on fetal development and subsequent offspring behavior remain poorly understood. In this study, we aimed to investigate the effects of P4 treatment during early pregnancy on the transcript abundance in the fetal brain and assess the behavioral consequences in the offspring during adolescence and adulthood. Using RNA-seq analysis, we examined the impact of P4 treatment on the fetal brain transcriptome in a dosage-dependent manner. Our results revealed differential regulation of genes involved in neurotransmitter transport, synaptic transmission, and transcriptional regulation. Specifically, we observed bidirectional regulation of transcription factors (TFs) by P4 at different doses, highlighting the critical role of these TFs in neurodevelopment. To assess behavioral outcomes, we conducted open field and elevated plus maze tests. Offspring treated with low-dose P4 (LP4) displayed increased exploratory behavior during both adolescence and adulthood. In contrast, the high-dose P4 (HP4) group exhibited impaired exploration and heightened anxiety-like behaviors compared to the control mice. Moreover, in a novel object recognition test, HP4-treated offspring demonstrated impaired object recognition memory during both developmental stages. Additionally, both LP4 and HP4 groups showed reduced social interaction in the three-chamber test. These results suggest that prenatal exposure to P4 exerts a notable influence on the expression of genes associated with neurodevelopment and may induce alterations in behavioral characteristics in progeny, highlighting the need to monitor progesterone levels during pregnancy for long-term impacts on fetal brain development and behavior.
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Conducta Animal , Encéfalo , Conducta Exploratoria , Efectos Tardíos de la Exposición Prenatal , Progesterona , Transcriptoma , Animales , Embarazo , Progesterona/farmacología , Femenino , Efectos Tardíos de la Exposición Prenatal/metabolismo , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/crecimiento & desarrollo , Ratones , Transcriptoma/efectos de los fármacos , Masculino , Conducta Animal/efectos de los fármacos , Conducta Exploratoria/efectos de los fármacos , Ansiedad , Ratones Endogámicos C57BL , Reconocimiento en Psicología/efectos de los fármacos , Progestinas/farmacologíaRESUMEN
Endplate sclerosis is a notable aspect of spine degeneration or aging, but the mechanisms remain unclear. Here, we report that senescent macrophages accumulate in the sclerotic endplates of lumbar spine instability (LSI) or aging male mouse model. Specifically, knockout of cdkn2a (p16) in macrophages abrogates LSI or aging-induced angiogenesis and sclerosis in the endplates. Furthermore, both in vivo and in vitro studies indicate that IL-10 is the primary elevated cytokine of senescence-related secretory phenotype (SASP). Mechanistically, IL-10 increases pSTAT3 in endothelial cells, leading to pSTAT3 directly binding to the promoters of Vegfa, Mmp2, and Pdgfb to encourage their production, resulting in angiogenesis. This study provides information on understanding the link between immune senescence and endplate sclerosis, which might be useful for therapeutic approaches.
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Senescencia Celular , Interleucina-10 , Animales , Masculino , Ratones , Angiogénesis , Células Endoteliales , Interleucina-10/genética , Macrófagos , EsclerosisRESUMEN
Chirality, one of the most fundamental properties of natural molecules, plays a significant role in biochemical reactions. Nanomaterials with chiral characteristics have superior properties, such as catalytic properties, optoelectronic properties, and photothermal properties, which have significant potential for specific applications in nanomedicine. Biomolecular modifications such as nucleic acids, peptides, proteins, and polysaccharides are sources of chirality for nanomaterials with great potential for application in addition to intrinsic chirality, artificial macromolecules, and metals. Two-dimensional (2D) nanomaterials, as opposed to other dimensions, due to proper surface area, extensive modification sites, drug loading potential, and simplicity of preparation, are prepared and utilized in diagnostic applications, drug delivery research, and tumor therapy. Current advanced studies on 2D chiral nanomaterials for biomedicine are focused on novel chiral development, structural control, and materials sustainability applications. However, despite the advances in biomedical research, chiral 2D nanomaterials still confront challenges such as the difficulty of synthesis, quality control, batch preparation, chiral stability, and chiral recognition and selectivity. This review aims to provide a comprehensive overview of the origins, synthesis, applications, and challenges of 2D chiral nanomaterials with biomolecules as cargo and chiral modifications and highlight their potential roles in biomedicine.
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Nanoestructuras , Ácidos Nucleicos , Nanoestructuras/química , Nanomedicina , Sistemas de Liberación de MedicamentosRESUMEN
Purpose: N4-acetylcytidine (ac4C) is a post-transcriptional RNA modification catalyzed by N-acetyltransferase 10 (NAT10), a critical factor known to influence mRNA stability. However, the role of ac4C in visual development remains unexplored. Methods: Analysis of public datasets and immunohistochemical staining were conducted to assess the expression pattern of nat10 in zebrafish. We used CRISPR/Cas9 and RNAi technologies to knockout (KO) and knockdown (KD) nat10, the zebrafish ortholog of human NAT10, and evaluated its effects on early development. To assess the impact of nat10 knockdown on visual function, we performed comprehensive histological evaluations and behavioral analyses. Transcriptome profiling and real-time (RT)-PCR were utilized to detect alterations in gene expression resulting from the nat10 knockdown. Dot-blot and RNA immunoprecipitation (RIP)-PCR analyses were conducted to verify changes in ac4C levels in both total RNA and opsin mRNA specifically. Additionally, we used the actinomycin D assay to examine the stability of opsin mRNA following the nat10 KD. Results: Our study found that the zebrafish NAT10 protein shares similar structural properties with its human counterpart. We observed that the nat10 gene was prominently expressed in the visual system during early zebrafish development. A deficiency of nat10 in zebrafish embryos resulted in increased mortality and developmental abnormalities. Behavioral and histological assessments indicated significant vision impairment in nat10 KD zebrafish. Transcriptomic analysis and RT-PCR identified substantial downregulation of retinal transcripts related to phototransduction, light response, photoreceptors, and visual perception in the nat10 KD group. Dot-blot and RIP-PCR analyses confirmed a pronounced reduction in ac4C levels in both total RNA and specifically in opsin messenger RNA (mRNA). Additionally, by evaluating mRNA decay in zebrafish treated with actinomycin D, we observed a significant decrease in the stability of opsin mRNA in the nat10 KD group. Conclusions: The ac4C-mediated mRNA modification plays an essential role in maintaining visual development and retinal function. The loss of NAT10-mediated ac4C modification results in significant disruptions to these processes, underlining the importance of this RNA modification in ocular development.
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Acetiltransferasas , Pez Cebra , Humanos , Animales , Pez Cebra/genética , Dactinomicina , Opsinas , Opsinas de Bastones , ARN/genética , ARN Mensajero/genéticaRESUMEN
BACKGROUND AND PURPOSE: Overexpression of astrocytic lactoferrin (Lf) was observed in the brain of Alzheimer's disease (AD) patients, whereas the role of astrocytic Lf in AD progression remains unexplored. In this study, we aimed to evaluate the effects of astrocytic Lf on AD progression. EXPERIMENTAL APPROACH: Male APP/PS1 mice with astrocytes overexpressing human Lf were developed to evaluate the effects of astrocytic Lf on AD progression. N2a-sw cells also were employed to further uncover the mechanism of astrocytic Lf on ß-amyloid (Aß) production. KEY RESULTS: Astrocytic Lf overexpression increased protein phosphatase 2A (PP2A) activity and reduced amyloid precursor protein (APP) phosphorylation, Aß burden and tau hyperphosphorylation in APP/PS1 mice. Mechanistically, astrocytic Lf overexpression promoted the uptake of astrocytic Lf into neurons in APP/PS1 mice, and conditional medium from astrocytes overexpressing Lf inhibited p-APP (Thr668) expression in N2a-sw cells. Furthermore, recombinant human Lf (hLf) significantly enhanced PP2A activity and inhibited p-APP expression, whereas inhibition of p38 or PP2A activities abrogated the hLf-induced p-APP down-regulation in N2a-sw cells. Additionally, hLf promoted the interaction of p38 and PP2A via p38 activation, thereby enhancing PP2A activity, and low-density lipoprotein receptor-related protein 1 (LRP1) knockdown significantly reversed the hLf-induced p38 activation and p-APP down-regulation. CONCLUSIONS AND IMPLICATIONS: Our data suggested that astrocytic Lf promoted neuronal p38 activation, via targeting to LRP1, subsequently promoting p38 binding to PP2A to enhance PP2A enzyme activity, which finally inhibited Aß production via APP dephosphorylation. In conclusion, promoting astrocytic Lf expression may be a potential strategy against AD. LINKED ARTICLES: This article is part of a themed issue From Alzheimer's Disease to Vascular Dementia: Different Roads Leading to Cognitive Decline. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v181.6/issuetoc.
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Enfermedad de Alzheimer , Precursor de Proteína beta-Amiloide , Humanos , Masculino , Ratones , Animales , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Ratones Transgénicos , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Proteína Fosfatasa 2/metabolismo , Lactoferrina/farmacología , Astrocitos/metabolismo , Péptidos beta-Amiloides/metabolismo , Modelos Animales de Enfermedad , Presenilina-1/metabolismoRESUMEN
Zinc is a crucial trace element in the human body, playing a role in various physiological processes such as oxidative stress, neurotransmission, protein synthesis, and DNA repair. The zinc transporters (ZnTs) family members are responsible for exporting intracellular zinc, while Zrt- and Irt-like proteins (ZIPs) are involved in importing extracellular zinc. These processes are essential for maintaining cellular zinc homeostasis. Imbalances in zinc metabolism have been linked to the development of neurodegenerative diseases. Disruptions in zinc levels can impact the survival and activity of neurons, thereby contributing to the progression of neurodegenerative diseases through mechanisms like cell apoptosis regulation, protein phase separation, ferroptosis, oxidative stress, and neuroinflammation. Therefore, conducting a systematic review of the regulatory network of zinc and investigating the relationship between zinc dysmetabolism and neurodegenerative diseases can enhance our understanding of the pathogenesis of these diseases. Additionally, it may offer new insights and approaches for the treatment of neurodegenerative diseases.
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Proteínas de Transporte de Catión , Enfermedades Neurodegenerativas , Humanos , Proteínas de Transporte de Catión/genética , Proteínas de Transporte de Catión/metabolismo , Progresión de la Enfermedad , Homeostasis , Zinc/metabolismoRESUMEN
Innovative therapeutic strategies are urgently needed for Alzheimer's disease (AD) due to the increasing size of the aging population and the lack of effective drug treatment. Here, we report the therapeutic effects of extracellular vesicles (EVs) secreted by microglia, including macrosomes and small EVs, on AD-associated pathology. Macrosomes strongly inhibited ß-amyloid (Aß) aggregation and rescued cells from Aß misfolding-induced cytotoxicity. Furthermore, macrosome administration reduced Aß plaques and ameliorated cognitive impairment in mice with AD. In contrast, small EVs slightly promoted Aß aggregation and did not improve AD pathology. Proteomic analysis of small EVs and macrosomes revealed that macrosomes harbor several important neuroprotective proteins that inhibit Aß misfolding. In particular, the small integral membrane protein 10-like protein 2B in macrosomes has been shown to inhibit Aß aggregation. Our observations provide an alternative therapeutic strategy for the treatment of AD over conventional ineffective drug treatments.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Ratones , Animales , Enfermedad de Alzheimer/metabolismo , Proteómica , Péptidos beta-Amiloides/metabolismo , Microglía/metabolismo , Modelos Animales de EnfermedadRESUMEN
Glioblastoma (GBM) is one of the most malignant tumors of the central nervous system and has a poor prognosis. GBM cells are highly sensitive to ferroptosis and heat, suggesting thermotherapy-ferroptosis as a new strategy for GBM treatment. With its biocompatibility and photothermal conversion efficiency, graphdiyne (GDY) has become a high-profile nanomaterial. Here, the ferroptosis inducer FIN56 was employed to construct GDY-FIN56-RAP (GFR) polymer self-assembled nanoplatforms against GBM. GDY could effectively load FIN56 and FIN56 released from GFR in a pH-dependent manner. The GFR nanoplatforms possessed the advantages of penetrating the BBB and acidic environment-induced in situ FIN56 release. Moreover, GFR nanoplatforms induced GBM cell ferroptosis by inhibiting GPX4 expression, and 808 nm irradiation reinforced GFR-mediated ferroptosis by elevating the temperature and promoting FIN56 release from GFR. In addition, the GFR nanoplatforms were inclined to locate in tumor tissue, inhibit GBM growth, and prolong lifespan by inducing GPX4-mediated ferroptosis in an orthotopic xenograft mouse model of GBM; meanwhile, 808 nm irradiation further improved these GFR-mediated effects. Hence, GFR may be a potential nanomedicine for cancer therapy, and GFR combined with photothermal therapy may be a promising strategy against GBM.
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Ferroptosis , Glioblastoma , Grafito , Humanos , Animales , Ratones , Glioblastoma/tratamiento farmacológico , Glioblastoma/patología , Terapia Fototérmica , Línea Celular TumoralRESUMEN
Alzheimer's disease (AD), characterized by the ß-amyloid protein (Aß) deposition and tau hyperphosphorylation, is the most common dementia with uncertain etiology. The clinical trials of Aß monoclonal antibody drugs have almost failed, giving rise to great attention on the other etiologic hypothesis regarding AD such as metal ions dysmetabolism and chronic neuroinflammation. Mounting evidence revealed that the metal ions (iron, copper, and zinc) were dysregulated in the susceptible brain regions of AD patients, which was highly associated with Aß deposition, tau hyperphosphorylation, neuronal loss, as well as neuroinflammation. Further studies uncovered that iron, copper and zinc could not only enhance the production of Aß but also directly bind to Aß and tau to promote their aggregations. In addition, the accumulation of iron and copper could respectively promote ferroptosis and cuproptosis. Therefore, the metal ion chelators were recognized as promising agents for treating AD. This review comprehensively summarized the effects of metal ions on the Aß dynamics and tau phosphorylation in the progression of AD. Furthermore, taking chronic neuroinflammation contributes to the progression of AD, we also provided a summary of the mechanisms concerning metal ions on neuroinflammation and highlighted the metal ion chelators may be potential agents to alleviate neuroinflammation under the condition of AD. Nevertheless, more investigations regarding metal ions on neuroinflammation should be taken into practice, and the effects of metal ion chelators on neuroinflammation should gain more attention. Running title: Metal chelators against neuroinflammation.
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Enfermedad de Alzheimer , Humanos , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Cobre/metabolismo , Enfermedades Neuroinflamatorias , Metales , Quelantes/farmacología , Quelantes/uso terapéutico , Péptidos beta-Amiloides/metabolismo , Hierro/metabolismo , Zinc/metabolismo , IonesRESUMEN
Alzheimer's disease (AD) is one of the most common neurodegenerative diseases worldwide. The occult nature of the onset and the uncertainty of the etiology largely impede the development of therapeutic strategies for AD. Previous studies revealed that the disorder of energy metabolism in the brains of AD patients appears far earlier than the typical pathological features of AD, suggesting a tight association between energy crisis and the onset of AD. Energy crisis in the brain is known to be induced by the reductions in glucose uptake and utilization, which may be ascribed to the diminished expressions of cerebral glucose transporters (GLUTs), insulin resistance, mitochondrial dysfunctions, and lactate dysmetabolism. Notably, the energy sensors such as peroxisome proliferators-activated receptor (PPAR), transcription factor EB (TFEB), and AMP-activated protein kinase (AMPK) were shown to be the critical regulators of autophagy, which play important roles in regulating beta-amyloid (Aß) metabolism, tau phosphorylation, neuroinflammation, iron dynamics, as well as ferroptosis. In this study, we summarized the current knowledge on the molecular mechanisms involved in the energy dysmetabolism of AD and discussed the interplays existing between energy crisis, autophagy, and ferroptosis. In addition, we highlighted the potential network in which autophagy may serve as a bridge between energy crisis and ferroptosis in the progression of AD. A deeper understanding of the relationship between energy dysmetabolism and AD may provide new insight into developing strategies for treating AD; meanwhile, the energy crisis in the progression of AD should gain more attention.
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Enfermedad de Alzheimer , Ferroptosis , Humanos , Enfermedad de Alzheimer/tratamiento farmacológico , Péptidos beta-Amiloides/metabolismo , Autofagia , HierroRESUMEN
The m6A methylation is reported to function in multiple physiological and pathological processes. However, the functional relevance of m6A modification to post-spinal cord injured (SCI) damage is not yet clear. In the present study, methylated RNA immunoprecipitation combined with microarray analysis showed that the global RNA m6A levels were decreased following SCI. Then, gene ontology (GO) and kyoto encyclopedia of genes and genomes (KEGG) analyses were conducted to demonstrate the potential function of differential m6A-tagged transcripts and the altered transcripts with differential m6A levels. In addition, we found that the m6A "writer," METTL3, significantly decreased after SCI in mice. The immunostaining validated that the expression of METTL3 mainly changed in GFAP or Iba-1+ cells. Together, this study shows the alteration of m6A modification following SCI in mice, which might contribute to the pathophysiology of the spinal cord after trauma.
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Researchers continue to explore drug targets to treat the characteristic pathologies of Alzheimer's disease (AD). Some drugs relieve the pathological processes of AD to some extent, but the failed clinical trials indicate that multifunctional agents seem more likely to achieve the therapy goals for this neurodegenerative disease. Herein, a novel compound named melatonin-trientine (TM) has been covalently synthesized with the natural antioxidant compounds melatonin and the metal ion chelator trientine. After toxicological and pharmacokinetic verification, we elucidated the effects of intraperitoneal administration of TM on AD-like pathology in 6-month-old mice that express both the ß-amyloid (Aß) precursor protein and presenilin-1 (APP/PS1). We found that TM significantly decreased Aß deposition and neuronal degeneration in the brains of the APP/PS1 double transgenic mice. This result may be due to the upregulation of iron regulatory protein-2 (IRP2), insulin degrading enzyme (IDE), and low density lipoprotein receptor related protein 1 (LRP1), which leads to decreases in APP and Aß levels. Additionally, TM may promote APP non-amyloidogenic processing by activating the melatonin receptor-2 (MT2)-dependent signaling pathways, but not MT1. In addition, TM plays an important role in blocking γ-secretase, tau hyperphosphorylation, neuroinflammation, oxidative stress, and metal ion dyshomeostasis. Our results suggest that TM may effectively maximize the therapeutic efficacy of targeting multiple mechanisms associated with AD pathology.
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Enfermedad de Alzheimer , Melatonina , Enfermedades Neurodegenerativas , Enfermedad de Alzheimer/metabolismo , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Péptidos beta-Amiloides/metabolismo , Animales , Quelantes/farmacología , Modelos Animales de Enfermedad , Melatonina/farmacología , Melatonina/uso terapéutico , Ratones , Ratones Transgénicos , Trientina/uso terapéuticoRESUMEN
Growing evidence indicates that circulating lactoferrin (Lf) is implicated in peripheral cholesterol metabolism disorders. It has emerged that the distribution of Lf changes in astrocytes of aging brains and those exhibiting neurodegeneration; however, its physiological and/or pathological role remains unknown. Here, we demonstrate that astrocyte-specific knockout of Lf (designated cKO) led to decreased body weight and cognitive abnormalities during early life in mice. Accordingly, there was a reduction in neuronal outgrowth and synaptic structure in cKO mice. Importantly, Lf deficiency in the primary astrocytes led to decreased sterol regulatory element binding protein 2 (Srebp2) activation and cholesterol production, and cholesterol content in cKO mice and/or in astrocytes was restored by exogenous Lf or a Srebp2 agonist. Moreover, neuronal dendritic complexity and total dendritic length were decreased after culture with the culture medium of the primary astrocytes derived from cKO mice and that this decrease was reversed after cholesterol supplementation. Alternatively, these alterations were associated with an activation of AMP-activated protein kinase (AMPK) and inhibition of SREBP2 nuclear translocation. These data suggest that astrocytic Lf might directly or indirectly control in situ cholesterol synthesis, which may be implicated in neurodevelopment and several neurological diseases.
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Astrocitos , Proteína 2 de Unión a Elementos Reguladores de Esteroles , Proteínas Quinasas Activadas por AMP/metabolismo , Animales , Astrocitos/metabolismo , Colesterol/metabolismo , Lactoferrina/genética , Lactoferrina/metabolismo , Lactoferrina/farmacología , Ratones , Proteína 2 de Unión a Elementos Reguladores de Esteroles/genética , Proteína 2 de Unión a Elementos Reguladores de Esteroles/metabolismoRESUMEN
PURPOSE: VBT is a novel alternative to spinal fusion surgery to treat skeletally immature AIS and was approved to correct idiopathic scoliosis in August 2019 by US Federal Drug Administration (FDA). To systemically review the preliminary outcomes of vertebral body tethering (VBT) in treating adolescent idiopathic scoliosis. METHODS: The electronic databases PubMed, EMBASE, and Web of Science were queried up to January 2022 for articles regarding VBT. Basic characteristics of patients, changes of radiographic parameters in coronal and sagittal planes, and clinical outcomes of surgical treatment of VBT including complication and revision rates were summarized. RESULTS: Twenty five studies met the inclusion criteria. Most studies (23/25) included patients with only skeletal immaturity. The average % correction of the main/tethered curve at final follow-up, and % correction of thoracic kyphosis at final follow-up were reported to be 15.6-106.5% and - 31.8 to 20.0%, respectively. The most common complications for VBT were tether breakage (n = 145;21.3%), pulmonary complications (n = 49; 6.9%), and overcorrection (n = 30; 4.2%). The revision rate was 13.1%. CONCLUSION: VBT could effectively and safely correct spinal deformity in skeletally immature patients with AIS and preserve the motion and growth of the spine. However, VBT has a relatively high complication and revision rates. Therefore, surgeons should cautiously consider VBT for treating AIS. Future research efforts are needed to lower the complication and revision rates. Whatever, VBT is still in its infancy and may have a promising future as a non-fusion solution for AIS.
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Cifosis , Escoliosis , Humanos , Adolescente , Escoliosis/diagnóstico por imagen , Escoliosis/cirugía , Cuerpo Vertebral , Vértebras Torácicas/diagnóstico por imagen , Vértebras Torácicas/cirugía , Resultado del TratamientoRESUMEN
The objective of this study was to investigate the effects of co-exposure of iron and microplastics (MPs) on the cognitive function of aged humans and animals. It was already known that individual iron or MPs exposure can initiate potential neurotoxicity. However, the combined effect of MPs and iron remained to be elucidated. In this study, the toxicity of iron, MPs, co-treatment of MPs & iron, and the underlying mechanisms were evaluated in vivo. Our findings suggest that 5 µm MPs could enter the aging mice brain and accumulate in cortex and hippocampus. In addition, MPs and iron have a good binding ability, therefore, co-exposure of MPs & iron cause significant iron overload and cognitive deficits as compared to control and individual treatments of iron and MPs. Moreover, the lipid peroxidation and inflammation, which are involved in ferroptosis, get significantly elevated by co-exposure of iron and MPs. Taken together, our results provide compelling evidence that co-exposure of iron and MPs could aggravate the cognitive impairment via disturbing brain iron homeostasis and inducing ferroptosis in cognitive-related brain areas, what's more, the results warn that MPs may act as vectors of pollutants (mostly heavy metals) increasing the health burden on body.
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Disfunción Cognitiva , Ferroptosis , Contaminantes Químicos del Agua , Envejecimiento , Animales , Disfunción Cognitiva/inducido químicamente , Hierro/toxicidad , Ratones , Microplásticos , Plásticos , Poliestirenos/toxicidad , Contaminantes Químicos del Agua/toxicidadRESUMEN
We used NHANES data to explore the association between dietary quality estimated by the HEI-2015 and osteoporosis in middle-aged and elderly US adults. We found that higher dietary quality is significantly associated with a reduced risk of osteoporosis among middle-aged and elderly Americans. INTRODUCTION: Through this research, we assess whether increasing the overall dietary quality reduces the risk of osteoporosis. METHODS: For our analyses, we combined data collected from four NHANES 2-year cycles (2007-2008, 2009-2010, 2013-2014, and 2017-2018), including 10,033 participants. Associations between osteoporosis and HEI-2015 total/component scores among middle-aged and elderly adults were examined using logistic regression models. Osteoporosis was defined as femur neck BMD values equal to or less than 2.5 standard deviations (SDs) below the mean of the young adult reference group, and dietary intake data were obtained from two NHANES 24-h recall interviews. RESULTS: After multivariable adjustment, middle-aged and elderly populations with quintile 4 (OR: 0.54, 95% CI 0.34, 0.84; P = 0.007) and quintile 5 HEI-2015 total scores (OR: 0.43, 95% CI 0.26, 0.70; P = 0.001) were associated with reduced odds of osteoporosis compared with quintile 1. Higher intake of total vegetables, greens and beans, total fruits, whole fruits, and whole grains was associated with decreased odds of osteoporosis among elderly adults. Surprisingly, saturated fat intake can also protect against osteoporosis. CONCLUSION: Higher dietary quality estimated from HEI-2015 total and component food scores was significantly associated with a reduced risk of osteoporosis among the middle-aged and elderly Americans participating in NHANES included in this study.
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Dieta Saludable , Osteoporosis , Anciano , Estudios Transversales , Dieta , Humanos , Persona de Mediana Edad , Encuestas Nutricionales , Osteoporosis/epidemiología , Osteoporosis/etiología , Osteoporosis/prevención & control , Estados Unidos/epidemiología , Adulto JovenRESUMEN
Vitamin D deficiency and iron accumulation are prevalent in the brains of Alzheimer's disease (AD) patients, however, whether Vitamin D has a role in the regulations of iron metabolism in the condition of AD remains unknown. Our previous studies revealed that vitamin D deficiency promotes ß-amyloid (Aß) deposition in the APP/PS1 mouse brains, while supplemented with a specific agonist of vitamin D receptor (VDR), paricalcitol (PAL), significantly reduced Aß production via promoting the lysosomal degradation of ß-site APP cleavage enzyme 1 (BACE1). In this study, our data suggested that activation of VDR by PAL significantly reduced the iron accumulation in the cortex and hippocampus of APP/PS1 mice through downregulation of Transferrin receptor (TFR) by reducing iron-regulatory protein 2 (IRP2) expression. Furthermore, activation of VDR effectively reduced the phosphorylations of Tau at Ser396 and Thr181 sites via inhibiting the GSK3ß phosphorylation (Tyr216). Taken together, our data suggest that activation of VDR could inhibit the phosphorylations of Tau possibly by repressing the iron accumulation-induced upregulation of GSK3ß activity in the brains of APP/PS1 mice. Thus, activation of VDR may be an effective strategy for treating AD.