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This study aimed to determine changes in the hydrolysis of vicagrel, a substrate drug of arylacetamide deacetylase (Aadac) and carboxylesterase 2 (Ces2), in P-glycoprotein (P-gp)-deficient or P-gp-inhibited mice and to elucidate the mechanisms involved.Male wild-type (WT) and P-gp knock-out (KO) mice were used to investigate the systemic exposure of vicagrel thiol active metabolite H4 and platelet response to vicagrel, and the mRNA and protein expression levels of intestinal Aadac and Ces2. Moreover, WT mice were administered vicagrel alone or in combination with elacridar (a potent P-gp inhibitor) to determine drug-drug interactions.Compared with WT mice, P-gp KO mice exhibited significant increases in the systemic exposure of H4, the protein expression levels of intestinal Aadac and Ces2, and inhibition of ADP-induced platelet aggregation by vicagrel. However, the H4 exposure was positively correlated with intestinal Aadac protein expression levels but did not vary with short-term inhibition of P-gp efflux activity by elacridar.P-gp-deficient mice, rather than elacridar-treated mice, exhibited significant upregulation of intestinal Aadac and Ces2 and thus, enhanced metabolic activation of and platelet response to vicagrel, suggesting that the metabolic activation of vicagrel may vary with P-gp deficiency, not P-gp inhibition, in mice.
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Background: After tumor resection, lymphadenectomy, and radiotherapy, recurrent lymphatic fluid leakage and infection can occur in the inguinal region, contributing to severe localized tissue fibrosis. When wounds form in this region, they tend to heal slowly over extended periods, and no optimal approach for treating these complex wounds has yet been established. Methods: Groin wound debridement and dissection of the vessels in the wound recipient site were performed by the burn surgeon. A general surgeon performed the laparoscopic partial omentum excision. One portion of the omentum was used to fill the large inguinal space, whereas the other portion was laid flat on the wound sites in the groin and anterior perineum to facilitate the restoration of appropriate lymphatic fluid reflux. The vessels of the omentum were microsurgically anastomosed with the vessels in the recipient site. Thin split-thickness slices of skin were then taken from this donor site based on the size of the wound. Results: After the successful establishment of revascularization between the flap and recipient sites, lymphatic fluid leakage was not observed in this patient. No inguinal wounding or lymphatic exudate were evident in the patient during follow-up, and significant improvements in lymphedema of the lower extremities were evident. Conclusions: In this article, we discuss the advantages and disadvantages of vascularized omentum lymphatic transplantation. Overall, this procedure represents a promising new approach for the treatment of refractory wounds caused by lymphatic fistulas.
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Indoor volatile formaldehyde is a serious health hazard. The development of low-temperature and efficient nonhomogeneous oxidation catalysts is crucial for protecting human health and the environment but is also quite challenging. Single-atom catalysts (SACs) with active centers and coordination environments that are precisely tunable at the atomic level exhibit excellent catalytic activity in many catalytic fields. Among two-dimensional materials, the nonmagnetic monolayer material g-C3N4 may be a good platform for loading single atoms. In this study, the effect of nitrogen defect formation on the charge distribution of g-C3N4 is discussed in detail using density functional theory (DFT) calculations. The effect of nitrogen defects on the activated molecular oxygen of Pt/C3N4 was systematically revealed by DFT calculations in combination with molecular orbital theory. Two typical reaction mechanisms for the catalytic oxidation of formaldehyde were proposed based on the Eley-Rideal (E-R) mechanism. Pt/C3N4-V3N was more advantageous for path 1, as determined by the activation energy barrier of the rate-determining step and product desorption. Finally, the active centers and chemical structures of Pt/C3N4 and Pt/C3N4-V3N were verified to have good stability at 375 K by determination of the migration energy barriers and ab initio molecular dynamics simulations. Therefore, the formation of N defects can effectively anchor single-atom Pt and provide additional active sites, which in turn activate molecular oxygen to efficiently catalyze the oxidation of formaldehyde. This study provides a better understanding of the mechanism of formaldehyde oxidation by single-atom Pt catalysts and a new idea for the development of Pt as well as other metal-based single-atom oxidation catalysts.
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Teoría Funcional de la Densidad , Formaldehído , Oxidación-Reducción , Platino (Metal) , Formaldehído/química , Catálisis , Platino (Metal)/química , Compuestos de Nitrógeno/química , Simulación de Dinámica Molecular , Oxígeno/química , GrafitoRESUMEN
STUDY DESIGN: Animal studies OBJECTIVES: To evaluate the therapeutic effect of olfactory mucosa mesenchymal stem cell (OM-MSCs) transplantation in mice with spinal cord injury (SCI) and to explore the mechanism by which OM-MSCs inhibit neuroinflammation and improve SCI. SETTING: Xiangya Hospital, Central South University; Affiliated Hospital of Guangdong Medical University. METHODS: Mice (C57BL/6, female, 6-week-old) were randomly divided into sham, SCI, and SCI + OM-MSC groups. The SCI mouse model was generated using Allen's method. OM-MSCs were immediately delivered to the lateral ventricle after SCI using stereotaxic brain injections. One day prior to injury and on days 1, 5, 7, 14, 21, and 28 post-injury, the Basso Mouse Scale and Rivlin inclined plate tests were performed. Inflammation and microglial polarization were evaluated using histological staining, immunofluorescence, and qRT-PCR. RESULTS: OM-MSCs originating from the neuroectoderm have great potential in the management of SCI owing to their immunomodulatory effects. OM-MSCs administration improved motor function, alleviated inflammation, promoted the transformation of the M1 phenotype of microglia into the M2 phenotype, facilitated axonal regeneration, and relieved spinal cord injury in SCI mice. CONCLUSIONS: OM-MSCs reduced the level of inflammation in the spinal cord tissue, protected neurons, and repaired spinal cord injury by regulating the M1/M2 polarization of microglia.
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Trasplante de Células Madre Mesenquimatosas , Ratones Endogámicos C57BL , Microglía , Mucosa Olfatoria , Traumatismos de la Médula Espinal , Animales , Traumatismos de la Médula Espinal/terapia , Traumatismos de la Médula Espinal/patología , Trasplante de Células Madre Mesenquimatosas/métodos , Mucosa Olfatoria/citología , Microglía/fisiología , Ratones , Femenino , Modelos Animales de Enfermedad , Células Madre Mesenquimatosas/fisiología , Recuperación de la Función/fisiología , Polaridad Celular/fisiologíaRESUMEN
Indoor formaldehyde pollution seriously jeopardizes human health. The development of efficient and stable non-precious metal catalysts for low-temperature catalytic degradation of formaldehyde is a promising approach. In this study, TiO2 {001} and {101} supports were loaded with different ratios of Mn and Ce active components, and the effects of the ratios of the active components on the catalytic activity were investigated. The elemental oxidation states, redox capacities, active oxygen mobilities and acid site distributions of the catalysts were determined using characterization techniques such as XPS, H2-TPR, O2-TPD, and NH3-TPD. In situ infrared spectroscopy was utilized to reveal the differences in the two-step dehydrogenation reactions of dioxymethylene (DOM) in 5Mn1Ce/Ti-NS and 5Mn1Ce/Ti-NP. Density-functional theory was used to investigate the differences in the catalytic steps and maximum energy barriers of Mn-Ce/Ti-NS and Mn-Ce/Ti-NP for HCHO. The differences in catalytic activity due to the influence of the manganese and cerium active components on the {001} and {101} crystal faces of anatase titanium dioxide are comprehensively revealed. Exposure of the supported crystalline surfaces alters the catalytic activity centers and reaction pathways at the molecular level. This study provides experimental and theoretical guidance for the selection of exposed crystalline surfaces for loaded catalysts.
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Alzheimer's disease (AD) is the most common cause of dementia worldwide. Due to its uncertain pathogenesis, there is currently no treatment available for AD. Increasing evidences have linked cellular senescence to AD, although the mechanism triggering cellular senescence in AD requires further exploration. To investigate the involvement of cellular senescence in AD, we explored the effects of cadmium chloride (CdCl2) exposure, one of the potential environmental risk factors for AD, on neuron senescence in vivo and in vitro. ß-amyloid (Aß) and tubulin-associated protein (tau) pathologies were found to be enhanced by CdCl2 exposure in the in vitro models, while p53/p21/Rb cascade-related neuronal senescence pathways were activated. Conversely, the use of melatonin, a cellular senescence inhibitor, or a cadmium ion chelator suppressed CdCl2-induced neuron senescence, along with the Aß and tau pathologies. Mechanistically, CdCl2 exposure activated the suppressor enhancer Lin-12/Notch 1-like (SEL1L)/HMG-CoA reductase degradation 1 (HRD1)-regulated endoplasmic reticulum-associated degradation (ERAD), which enhanced the ubiquitin degradation of sigma-1 receptor (SigmaR1) by specifically recognizing its K142 site, resulting in the activation of the p53/p21/Rb pathway via the induction of Ca2+ dyshomeostasis and mitochondrial dysfunction. In the in vivo models, the administration of the SigmaR1 agonist ANAVEX2-73 rescues neurobehavioral inhibition and alleviates cellular senescence and AD-like pathology in the brain tissue of CdCl2-exposed mice. Consequently, the present study revealed a novel senescence-associated regulatory route for the SEL1L/HRD1/SigmaR1 axis that affects the pathological progression of CdCl2 exposure-associated AD. CdCl2 exposure activated SEL1L/HRD1-mediated ERAD and promoted the ubiquitinated degradation of SigmaR1, activating p53/p21/Rb pathway-regulated neuronal senescence. The results of the present study suggest that SigmaR1 may function as a neuroprotective biomarker of neuronal senescence, and pharmacological activation of SigmaR1 could be a promising intervention strategy for AD therapy.
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Cloruro de Cadmio , Senescencia Celular , Degradación Asociada con el Retículo Endoplásmico , Neuronas , Receptores sigma , Animales , Senescencia Celular/efectos de los fármacos , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Cloruro de Cadmio/toxicidad , Receptores sigma/metabolismo , Degradación Asociada con el Retículo Endoplásmico/efectos de los fármacos , Péptidos beta-Amiloides/metabolismo , Ratones , Proteínas tau/metabolismo , Masculino , Enfermedad de Alzheimer/metabolismo , Humanos , Melatonina/farmacología , Ratones Endogámicos C57BLRESUMEN
BACKGROUND: Bone marrow mesenchymal stem cells (BMSCs) can undergo inadequate osteogenesis or excessive adipogenesis as they age due to changes in the bone microenvironment, ultimately resulting in decreased bone density and elevated risk of fractures in senile osteoporosis. This study aims to investigate the effects of osteocyte senescence on the bone microenvironment and its influence on BMSCs during aging. RESULTS: Primary osteocytes were isolated from 2-month-old and 16-month-old mice to obtain young osteocyte-derived extracellular vesicles (YO-EVs) and senescent osteocyte-derived EVs (SO-EVs), respectively. YO-EVs were found to significantly increase alkaline phosphatase activity, mineralization deposition, and the expression of osteogenesis-related genes in BMSCs, while SO-EVs promoted BMSC adipogenesis. Neither YO-EVs nor SO-EVs exerted an effect on the osteoclastogenesis of primary macrophages/monocytes. Our constructed transgenic mice, designed to trace osteocyte-derived EV distribution, revealed abundant osteocyte-derived EVs embedded in the bone matrix. Moreover, mature osteoclasts were found to release osteocyte-derived EVs from bone slices, playing a pivotal role in regulating the functions of the surrounding culture medium. Following intravenous injection into young and elderly mouse models, YO-EVs demonstrated a significant enhancement of bone mass and biomechanical strength compared to SO-EVs. Immunostaining of bone sections revealed that YO-EV treatment augmented the number of osteoblasts on the bone surface, while SO-EV treatment promoted adipocyte formation in the bone marrow. Proteomics analysis of YO-EVs and SO-EVs showed that tropomyosin-1 (TPM1) was enriched in YO-EVs, which increased the matrix stiffness of BMSCs, consequently promoting osteogenesis. Specifically, the siRNA-mediated depletion of Tpm1 eliminated pro-osteogenic activity of YO-EVs both in vitro and in vivo. CONCLUSIONS: Our findings suggested that YO-EVs played a crucial role in maintaining the balance between bone resorption and formation, and their pro-osteogenic activity declining with aging. Therefore, YO-EVs and the delivered TPM1 hold potential as therapeutic targets for senile osteoporosis.
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Vesículas Extracelulares , Células Madre Mesenquimatosas , Osteocitos , Osteogénesis , Tropomiosina , Animales , Masculino , Ratones , Adipogénesis , Diferenciación Celular , Células Cultivadas , Vesículas Extracelulares/metabolismo , Células Madre Mesenquimatosas/metabolismo , Células Madre Mesenquimatosas/citología , Ratones Endogámicos C57BL , Ratones Transgénicos , Osteoclastos/metabolismo , Osteocitos/metabolismo , Osteoporosis/metabolismo , Tropomiosina/metabolismo , Tropomiosina/genéticaRESUMEN
Hypertension is a prominent contributor to vascular injury. Deubiquinatase has been implicated in the regulation of hypertension-induced vascular injury. In the present study we investigated the specific role of deubiquinatase YOD1 in hypertension-induced vascular injury. Vascular endothelial endothelial-mesenchymal transition (EndMT) was induced in male WT and YOD1-/- mice by administration of Ang II (1 µg/kg per minute) via osmotic pump for four weeks. We showed a significantly increased expression of YOD1 in mouse vascular endothelial cells upon Ang II stimulation. Knockout of YOD1 resulted in a notable reduction in EndMT in vascular endothelial cells of Ang II-treated mouse; a similar result was observed in Ang II-treated human umbilical vein endothelial cells (HUVECs). We then conducted LC-MS/MS and co-immunoprecipitation (Co-IP) analyses to verify the binding between YOD1 and EndMT-related proteins, and found that YOD1 directly bound to ß-catenin in HUVECs via its ovarian tumor-associated protease (OTU) domain, and histidine at 262 performing deubiquitination to maintain ß-catenin protein stability by removing the K48 ubiquitin chain from ß-catenin and preventing its proteasome degradation, thereby promoting EndMT of vascular endothelial cells. Oral administration of ß-catenin inhibitor MSAB (20 mg/kg, every other day for four weeks) eliminated the protective effect of YOD1 deletion on vascular endothelial injury. In conclusion, we demonstrate a new YOD1-ß-catenin axis in regulating Ang II-induced vascular endothelial injury and reveal YOD1 as a deubiquitinating enzyme for ß-catenin, suggesting that targeting YOD1 holds promise as a potential therapeutic strategy for treating ß-catenin-mediated vascular diseases.
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Angiotensina II , Células Endoteliales de la Vena Umbilical Humana , Ratones Endogámicos C57BL , Ratones Noqueados , beta Catenina , Animales , beta Catenina/metabolismo , Humanos , Angiotensina II/farmacología , Angiotensina II/metabolismo , Masculino , Ratones , Transición Epitelial-Mesenquimal/efectos de los fármacos , Transición Endotelial-MesenquimatosaRESUMEN
Indoor formaldehyde (HCHO) pollution poses a major risk to human health. Low-temperature catalytic oxidation is an effective method for HCHO removal. The high activity and selectivity of single atomic catalysts provide a possibility for the development of efficient non-precious metal catalysts. In this study, the most stable single-atom catalyst Ti-Ti4C3O2 was screened by density functional theory among many single atomic catalysts with two-dimensional (2D) monolayer Ti4C3O2 as the support. The computational results show that Ti-Ti4C3O2 is highly selective to HCHO and O2 in complex environments. The HCHO oxidation reaction pathways are proposed based on the Eley-Rideal (E-R) and Langmuir-Hinshelwood (L-H) mechanisms. According to the reaction energy and energy span models, the E-R mechanism has a lower maximum energy barrier and higher catalytic efficiency than the L-H mechanism. In addition, the stability of the Ti-Ti4C3O2 structure and active center was verified by diffusion energy barrier and ab initio molecular dynamics simulations. The above results indicate that Ti-Ti4C3O2 is a promising non-precious metal catalyst. The present study provides detailed theoretical insights into the catalytic oxidation of HCHO by Ti-Ti4C3O2, as well as an idea for the development of efficient non-precious metal catalysts based on 2D materials.
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Teoría Funcional de la Densidad , Formaldehído , Oxidación-Reducción , Titanio , Formaldehído/química , Catálisis , Titanio/química , Contaminación del Aire Interior , Contaminantes Atmosféricos/química , Simulación de Dinámica MolecularRESUMEN
Papillary thyroid carcinoma (PTC) is generally recognized as a slow-growing tumor. However, a small subset of patients may still experience relapse or metastasis shortly after therapy, leading to a poor prognosis and raising concerns about excessive medical treatment. One major challenge lies in the inadequacy of effective biomarkers for accurate risk stratification. Long non-coding RNAs (lncRNAs), which are closely related to malignant characteristics and poor prognosis, play a significant role in the genesis and development of PTC through various pathways. The objective of this review is to provide a comprehensive summary of the biological functions of lncRNAs in PTC, identify prognosis-relevant lncRNAs, and explore their potential mechanisms in drug resistance to BRAF kinase inhibitors, tumor dedifferentiation, and lymph node metastasis. By doing so, this review aims to offer valuable references for both basic research and the prediction of PTC prognosis.
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Carcinoma Papilar , ARN Largo no Codificante , Neoplasias de la Tiroides , Humanos , Cáncer Papilar Tiroideo/genética , Pronóstico , Neoplasias de la Tiroides/patología , ARN Largo no Codificante/genética , Carcinoma Papilar/patología , Recurrencia Local de Neoplasia , Proteínas Proto-Oncogénicas B-raf/metabolismoRESUMEN
BACKGROUND: Optical genome mapping (OGM) is a novel assay for detecting structural variants (SVs) and has been retrospectively evaluated for its performance. However, its prospective evaluation in prenatal diagnosis remains unreported. This study aimed to prospectively assess the technical concordance of OGM with standard of care (SOC) testing in prenatal diagnosis. METHODS: A prospective cohort of 204 pregnant women was enrolled in this study. Amniotic fluid samples from these women were subjected to OGM and SOC testing, which included chromosomal microarray analysis (CMA) and karyotyping (KT) in parallel. The diagnostic yield of OGM was evaluated, and the technical concordance between OGM and SOC testing was assessed. RESULTS: OGM successfully analyzed 204 cultured amniocyte samples, even with a cell count as low as 0.24 million. In total, 60 reportable SVs were identified through combined OGM and SOC testing, with 22 SVs detected by all 3 techniques. The diagnostic yield for OGM, CMA, and KT was 25% (51/204), 22.06% (45/204), and 18.14% (37/204), respectively. The highest diagnostic yield (29.41%, 60/204) was achieved when OGM and KT were used together. OGM demonstrated a concordance of 95.56% with CMA and 75.68% with KT in this cohort study. CONCLUSIONS: Our findings suggest that OGM can be effectively applied in prenatal diagnosis using cultured amniocytes and exhibits high concordance with SOC testing. The combined use of OGM and KT appears to yield the most promising diagnostic outcomes.
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Diagnóstico Prenatal , Humanos , Femenino , Embarazo , Estudios Prospectivos , Diagnóstico Prenatal/métodos , Adulto , Cariotipificación , Mapeo Cromosómico , Líquido Amniótico/química , Líquido Amniótico/citologíaRESUMEN
Autophagy is implicated in the pathogenesis of pulmonary arterial hypertension (PAH). We aimed to investigate whether the p62-Keap1-Nrf2 pathway affects the development of PAH by mediating autophagy. A PAH rat model was established using monocrotaline (MCT). Pulmonary artery smooth muscle cells (PASMCs) were extracted, and the changes in proliferation, migration, autophagy, and oxidative stress were analyzed following overexpression or knockdown of p62. The impact of p62 on the symptoms of PAH rats was assessed by the injection of an adenovirus overexpressing p62. We found that the knockdown of p62 increased the proliferation and migration of PASMCs, elevating the oxidative stress of PASMCs and upregulating gene expression of NADPH oxidases. Co-IP assay results demonstrated that p62 interacted with Keap1. p62 knockdown enhanced Keap1 protein stability and Nrf2 ubiquitination. LC3II/I and ATG5 were expressed more often when p62 was knocked down. Treating with an inhibitor of autophagy reversed the impact of p62 knockdown on PASMCs. Nrf2 inhibitor treatment reduced the expression of Nrf2 and p62, while increasing the expression of Keap1, LC3II/I, and ATG5 in PASMCs. However, overexpressing p62 diminished mRVP, SPAP, and Fulton index in PAH rats and attenuated pulmonary vascular wall thickening. Overexpression of p62 also decreased the expression of Keap1, LC3II/I, and ATG5 and increased the nuclear expression of Nrf2 in PAH rats. Importantly, overexpression of p62 reduced oxidative stress and the NADPH oxidase expression in PAH rats. Overall, activation of the p62-Keap1-Nrf2 positive feedback signaling axis reduces the proliferation and migration of PASMCs and alleviates PAH by inhibiting autophagy and oxidative stress.
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Hipertensión Arterial Pulmonar , Animales , Ratas , Autofagia/fisiología , Proliferación Celular , Proteína 1 Asociada A ECH Tipo Kelch/genética , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Monocrotalina , Miocitos del Músculo Liso/metabolismo , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , Hipertensión Arterial Pulmonar/patología , Arteria Pulmonar/metabolismoRESUMEN
A large number of burnt rocks in some open-pit mines in Xinjiang, Inner Mongolia and Ningxia have a great influence on the blasting effect. For this kind of rock, through the analysis of physical and chemical changes, combined with ANSYS/LS-DYNA and PFC 2D numerical simulation software, a burnt rock model with multiple joint cracks and irregular distribution is constructed to simulate the blasting process of burnt rock under the combined action of stress wave and detonation gas. The results show that the fracture of rock mass affects the propagation of blasting cracks in the fracture area, resulting in stress concentration and stress hindrance. The action time of stress wave is reduced, and the energy of blasting gas is partially absorbed by the fracture, resulting in uneven stress on the burnt rock bench and seriously affecting the bench blasting effect.
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OBJECTIVE: To analyze the changes rule of serum procalcitonin (PCT) levels in patients with traumatic brain injury in plateau areas, and to evaluate its value in assessing the severity and prognosis of the patients. METHODS: A prospective cohort study was conducted. The patients with traumatic brain injury admitted to the critical care medicine departments of Xining Third People's Hospital (at an altitude of 2 260 metres) and Golmud City People's Hospital (at an altitude of 2 780 metres) from May 2018 to September 2022 were enrolled. According to the Glasgow coma scale (GCS) score at admission, the patients were divided into mild injury group (GCS score 13-15), severe injury group (GCS score 9-12), and critical injury group (GCS score 3-8). All patients received active treatment. Chemiluminescence immunoassay was used to measure the serum PCT levels of patients on the 1st, 3rd, 5th, and 7th day of admission. The Kendall tau-b correlation method was used to analyze the correlation between serum PCT levels at different time points and the severity of the disease. The patients were followed up until October 30, 2022. The prognosis of the patients was collected. The baseline data of patients with different prognosis were compared. The Cox regression method was used to analyze the relationship between baseline data, serum PCT levels at different time points and prognosis. Receiver operator characteristic curve (ROC curve) was drawn to analyze the predictive value of serum PCT levels at different time points for death during follow-up. RESULTS: Finally, a total of 120 patients with traumatic brain injury were enrolled, including 52 cases in the mild injury group, 40 cases in the severe injury group, and 28 cases in the critical injury group. The serum PCT levels of patients in the mild injury group showed a continuous downward trend with the prolongation of admission time. The serum PCT levels in the severe injury and critical injury groups reached their peak at 3 days after admission, and were significantly higher than those in the mild injury group (µg/L: 3.53±0.68, 4.47±0.63 vs. 0.40±0.14, both P < 0.05), gradually decreasing thereafter, but still significantly higher than the mild injured group at 7 days. Kendall tau-b correlation analysis showed that there was a significant positive correlation between serum PCT levels on days 1, 3, 5, and 7 of admission and the severity of disease (r value was 0.801, 0.808, 0.766, 0.528, respectively, all P < 0.01). As of October 30, 2022, 92 out of 120 patients with traumatic brain injury survived and 28 died, with a mortality of 23.33%. Compared with the survival group, the GCS score, serum interleukin-6 (IL-6) levels, white blood cell count (WBC) in peripheral blood, and PCT levels in cerebrospinal fluid at admission in the death group were significantly increased [GCS score: 5.20±0.82 vs. 4.35±0.93, IL-6 (ng/L): 1.63±0.45 vs. 0.95±0.27, blood WBC (×109/L): 14.31±2.03 vs. 11.95±1.98, PCT in cerebrospinal fluid (µg/L): 11.30±1.21 vs. 3.02±0.68, all P < 0.01]. The serum PCT levels of patients in the survival group showed a continuous downward trend with prolonged admission time. The serum PCT level in the death group peaked at 3 days after admission and was significantly higher than that in the survival group (µg/L: 4.11±0.62 vs. 0.52±0.13, P < 0.01), gradually decreasing thereafter, but still significantly higher than the survival group at 7 days. Cox regression analysis showed that serum IL-6 levels [hazard ratio (HR) = 17.347, 95% confidence interval (95%CI) was 5.874-51.232], WBC in peripheral blood (HR = 1.383, 95%CI was 1.125-1.700), PCT levels in cerebrospinal fluid (HR = 1.952, 95%CI was 1.535-2.482) at admission and serum PCT levels on admission days 1, 3, 5, and 7 [HR (95%CI) was 6.776 (1.844-24.906), 1.840 (1.069-3.165), 3.447 (1.284-9.254), and 6.666 (1.214-36.618), respectively] were independent risk factors for death during follow-up in patients with traumatic brain injury (all P < 0.05). ROC curve analysis showed that the AUC of serum PCT levels on days 1, 3, 5, and 7 for predicting death during follow-up in patients with traumatic brain injury was all > 0.8 [AUC (95%CI) was 0.898 (0.821-0.975), 0.800 (0.701-0.899), 0.899 (0.828-0.970), 0.865 (0.773-0.958), respectively], indicating ideal predictive value. The optimal cut-off value for serum PCT level at 3 days of admission was 1.88 µg/L, with the sensitivity of 78.6% and specificity of 88.0% for predicting death during follow-up. CONCLUSIONS: Abnormal expression of serum PCT levels in patients with traumatic brain injury on the 3rd day of admission was found. The serum PCT levels greater than 3 µg/L may be related to severe illness. The serum PCT levels greater than 1.88 µg/L can predict the poor prognosis of patients. Dynamic observation of changes in serum PCT levels has good evaluation value for the severity and prognosis of patients with traumatic brain injury in plateau areas.
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Lesiones Traumáticas del Encéfalo , Sepsis , Humanos , Polipéptido alfa Relacionado con Calcitonina , Estudios Prospectivos , Interleucina-6 , Pronóstico , Lesiones Traumáticas del Encéfalo/diagnóstico , Curva ROC , Estudios Retrospectivos , Sepsis/metabolismoRESUMEN
Adipose tissue-derived stem cells (ADSCs) are a kind of stem cells with multi-directional differentiation potential, which mainly restore tissue repair function and promote cell regeneration. It can be directionally differentiated into Schwann-like cells to promote the repair of peripheral nerve injury. Glial cell line-derived neurotrophic factor (GDNF) plays an important role in the repair of nerve injury, but the underlying mechanism remains unclear, which seriously limits its further application.The study aimed to identify the molecular mechanism by which overexpression of glial cell line-derived neurotrophic factor (GDNF) facilitates the differentiation of ADSCs into Schwann cells, enhancing nerve regeneration after injury. In vitro, ADSCs overexpressing GDNF for 48 h exhibited changes in their morphology, with 80% of the cells having two or more prominences. Compared with that of ADSCs, GDNF-ADSCs exhibited increased expression of the Schwann cell marker S100, nerve damage repair-related factors.ADSC cells in normal culture and ADSC cells were overexpressing GDNF(GDNF-ADSCs) were analysed using TMT-Based Proteomic Analysis and revealed a significantly higher expression of MTA1 in GDNF-ADSCs than in control ADSCs. Hes1 expression was significantly higher in GDNF-ADSCs than in ADSCs and decreased by MTA1 silencing, along with a simultaneous decrease in the expression of S100 and nerve damage repair factors. These findings indicate that GDNF promotes the differentiation of ADSCs into Schwann cells and induces factors that accelerate peripheral nerve damage repair.
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Factor Neurotrófico Derivado de la Línea Celular Glial , Proteómica , Factor Neurotrófico Derivado de la Línea Celular Glial/genética , Regeneración Nerviosa , Tejido Adiposo , Diferenciación Celular , Células de SchwannRESUMEN
BACKGROUND: Pulmonary fibrosis (PF) is a progressive fibrosing interstitial pneumonia that leads to respiratory failure and other complications, which is ultimately fatal. Mesenchymal stem cells (MSCs) transplant is a promising strategy to solve this problem, while the procurement of MSCs from the patient for autotransplant remains a challenge. METHODS: Here, we presented olfactory mucosa mesenchymal stem cells (OM-MSCs) from mouse turbinate and determined the preventing efficacy of allotransplant for PF. We demonstrated the antiinflammation and immunomodulatory effects of OM-MSCs. Flow cytometric analysis was used to verify the effect of OM-MSCs on monocyte-derived macrophage populations in the lung. RESULTS: Administration of OM-MSCs reduces inflammation, attenuates the matrix metallopeptidase 13 (MMP13) expression level and restores the bleomycin (BLM)-induced pulmonary fibrosis by assessing the architecture of lung, collagen type I; (COL1A1), actin alpha 2, smooth muscle, aorta (ACTA2/α-SMA) and hydroxyproline. This therapeutic effect of OM-MSCs was related to the increase in the ratio of nonclassical monocytes to proinflammatory monocytes in the lung. CONCLUSIONS: This study suggests that transplant of OM-MSCs represents an effective and safe treatment for PF.
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Células Madre Mesenquimatosas , Fibrosis Pulmonar , Humanos , Ratones , Animales , Fibrosis Pulmonar/inducido químicamente , Fibrosis Pulmonar/terapia , Fibrosis Pulmonar/metabolismo , Inflamación/metabolismo , Células Madre Mesenquimatosas/metabolismo , Inmunomodulación , Mucosa Olfatoria/metabolismoRESUMEN
Previous studies have indicated a potential connection between plasma levels of Dickkopf-1 (DKK1) and platelet-derived growth factor subunit-B (PDGF-B) with the development of atherosclerosis. However, the causal relationship between DKK1, PDGF-B, and the risk of acute myocardial infarction (AMI) is yet to be established. To address this research gap, we conducted Mendelian randomization (MR) and mediation analyses to investigate the potential mediating role of PDGF-B in the association between DKK1 and AMI risk. Summary statistics for DKK1 (n = 3,301) and PDGF-B (n = 21,758) were obtained from the GWAS meta-analyses conducted by Sun et al. and Folkersen et al., respectively. Data on AMI cases (n = 3,927) and controls (n = 333,272) were retrieved from the UK Biobank study. Our findings revealed that genetic predisposition to DKK1 (odds ratio [OR]: 1.00208; 95% confidence interval [CI]: 1.00056-1.00361; P = 0.0072) and PDGF-B (OR: 1.00358; 95% CI: 1.00136-1.00581; P = 0.0015) was associated with an increased risk of AMI. Additionally, genetic predisposition to DKK1 (OR: 1.38389; 95% CI: 1.07066-1.78875; P = 0.0131) was linked to higher PDGF-B levels. Furthermore, our MR mediation analysis revealed that PDGF-B partially mediated the association between DKK1 and AMI risk, with 55.8% of the effect of genetically predicted DKK1 being mediated through genetically predicted PDGF-B. These findings suggest that genetic predisposition to DKK1 is positively correlated with the risk of AMI, and that PDGF-B partially mediates this association. Therefore, DKK1 and PDGF-B may serve as promising targets for the prevention and treatment of AMI.
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Aterosclerosis , Infarto del Miocardio , Humanos , Análisis de la Aleatorización Mendeliana , Infarto del Miocardio/genética , Predisposición Genética a la Enfermedad , Proteínas Proto-Oncogénicas c-sis , Estudio de Asociación del Genoma Completo , Polimorfismo de Nucleótido SimpleRESUMEN
Introduction: The repair of extensive tissue defects remains a challenge, although great progress has been made in reconstructive surgery. The transplantation of a single huge flap or several flaps in combination will inevitably result in donor-site morbidity. Here we report our experience in the repair of these wounds with laparoscopically harvested great omentum flaps. Methods: Twelve patients with extensive tissue defects caused by deep burn injury, avulsion injury, and open fracture underwent free omental flap transplantation and split-thickness skin grafting. The patient demographics, wound characteristics, and complications postsurgical operation were recorded. Prior to omentum flap transplantation, these patients underwent debridement, vacuum sealing drainage treatment, and/or fixation of fractures. All omentum flaps harvested using laparoscopic technique were anastomosed to recipient vessels, and split-thickness skin grafting was performed 14 days after omental flap transplantation. Results: The mean defect size was 471 cm2 and the mean omental flap size was 751.1 cm2. Among all 12 cases, the omental flaps survived well except for distal partial necrosis in one case. Skin grafting was also achieved in all cases, and all patients achieved complete wound coverage. All donor sites achieved primary healing without major complications. The mean follow-up time was 30 months with satisfactory appearance and functional outcome. Conclusion: For the reconstruction of extensive tissue defects in complex wounds, the free transfer of an omental flap may be an ideal option because of its well-vascularized and pliable tissue with reliable vascular anatomy, as well as minimized donor-site morbidity.
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Endothelial cells (ECs) and bone marrow stromal cells (BMSCs) play crucial roles in supporting hematopoiesis and hematopoietic regeneration. However, whether ECs are a source of BMSCs remains unclear. Here, we evaluate the contribution of endothelial-to-mesenchymal transition to BMSC generation in postnatal mice. Single-cell RNA sequencing identifies ECs expressing BMSC markers Prrx1 and Lepr; however, this could not be validated using Prrx1-Cre and Lepr-Cre transgenic mice. Additionally, only a minority of BMSCs are marked by EC lineage tracing models using Cdh5-rtTA-tetO-Cre or Tek-CreERT2. Moreover, Cdh5+ BMSCs and Tek+ BMSCs show distinct spatial distributions and characteristic mesenchymal markers, suggestive of their origination from different progenitors rather than CDH5+ TEK+ ECs. Furthermore, myeloablation induced by 5-fluorouracil treatment does not increase Cdh5+ BMSCs. Our findings indicate that ECs hardly convert to BMSCs during homeostasis and myeloablation-induced hematopoietic regeneration, highlighting the importance of using appropriate genetic models and conducting careful data interpretation in studies concerning endothelial-to-mesenchymal transition.
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Células Endoteliales , Células Madre Mesenquimatosas , Ratones , Animales , Médula Ósea , Ratones TransgénicosRESUMEN
Silicon modulators are key components to support the dense integration of electro-optic functional elements for various applications. Despite numerous advances in promoting the modulation speed, a bandwidth ceiling emerges in practices and becomes an obstacle toward Tbps-level throughput on a single chip. Here, we demonstrate a compact pure silicon modulator that shatters present bandwidth ceiling to 110 gigahertz. The proposed modulator is built on a cascade corrugated waveguide architecture, which gives rise to a slow-light effect. By comprehensively balancing a series of merits, the modulators can benefit from the slow light for better efficiency and compact size while remaining sufficiently high bandwidth. Consequently, we realize a 110-gigahertz modulator with 124-micrometer length, enabling 112 gigabits per second on-off keying operation. Our work proves that silicon modulators with 110 gigahertz are feasible, thus shedding light on its potentials in ultrahigh bandwidth applications such as optical interconnection and photonic machine learning.