RESUMEN
Complex and stubborn bacterial biofilm infections significantly hinder diabetic wound healing and threaten public health. Therefore, a dressing material that effectively clears biofilms and promotes wound healing is urgently required. Herein, we introduce a novel strategy for simultaneously dispersing extracellular polymeric substances and eradicating drug-resistant bacteria. We prepared an ultrabroad-spectrum and injectable quaternized chitosan (QCS) hydrogel loaded with trypsin, which degrades biofilm extracellular proteins. Increased temperature initiated QCS gelation to form the hydrogel, enabling the sustained release of trypsin and effective adherence of the hydrogel to irregularly shaped wounds. To reproduce clinical scenarios, biofilms formed by a mixture of Staphylococcus aureus (S. aureus), Methicillin-resistant S. aureus, and Pseudomonas aeruginosa were administered to the wounds of rats with streptozotocin-induced diabetes. Under these severe infection conditions, the hydrogel efficiently suppressed inflammation, promoted angiogenesis, and enhanced collagen deposition, resulting in accelerated healing of diabetic wounds. Notably, the hydrogel demonstrates excellent biocompatibility without cytotoxicity. In summary, we present a trypsin-loaded QCS hydrogel with tremendous clinical applications potential for the treatment of chronic infected wounds.
RESUMEN
Background: Exploration of the benefits and timing of surgical decompression in spinal cord injury (SCI) has been a research hotspot. However, despite the higher volume and increasing emphasis on quality there remains no bibliometric view on SCI and surgical decompression. In this study, we aimed to perform bibliometric analysis to reveal the core countries, affiliations, journals, authors, and developmental trends in SCI and surgical decompression across the past 50 years. Methods: Articles and reviews were retrieved from web of science core collection between 1975 and 2024. The bibliometrix package in R was used for data analysis and visualizing. Results: A total of 8,688 documents were investigated, indicating an ascending trend in annual publications. The USA and China played as the leaders in scientific productivity. The University of Toronto led in institutional productions. Core authors, such as Michael G. Fehlings, showed high productivity, and occasional authors showed widespread interests. Core journals like Spine and Spinal Cord served as beacons in this field. The interaction of core authors and international collaboration accentuated the cross-disciplinary feature of the field. Prominent documents emphasized the clinical significance of early decompression in 24 h post SCI. Conclusion: Based on comprehensive bibliometric analysis and literature review, we identified the hotspots and future directions of this field: (1) further investigation into the molecular and cellular mechanisms to provide pre-clinical evidence for biological effects of early surgical decompression in SCI animal models; (2) further evaluation and validation of the optimal time window of surgical decompression based on large cohort, considering the inherent heterogeneity of subpopulations in complicated immune responses post SCI; (3) further exploration on the benefits of early decompression on the neurological, functional, and clinical outcomes in acute SCI; (4) evaluation of the optimal surgical methods and related outcomes; (5) applications of artificial intelligence-based technologies in spinal surgical decompression.
RESUMEN
Cuproptosis plays an important role in cancer, but its role in lung cancer remains unknown. Transcriptional profiles, clinical details and mutation data were acquired from the Cancer Genome Atlas database through a variety of methods. The analysis of this publicly available data was comprehensively performed using R software along with its relevant packages, ensuring a thorough examination of the information. In this study, we conducted a detailed analysis of cuproptosis-related genes and lncRNA co-expression, identifying 129 relevant lncRNAs and establishing a prognostic model with four key lncRNAs (LINC00996, RPARP-AS1, SND1-IT1, TMPO-AS1). Utilizing data from TCGA and GEO databases, the model effectively categorized patients into high- and low-risk groups, showing significant survival differences. Correlation analysis highlighted specific relationships between individual lncRNAs and cuproptosis genes. Our survival analysis indicated a higher survival rate in the low-risk group across various cohorts. Additionally, the model's predictive accuracy was confirmed through independent prognostic analysis and ROC curve evaluations. Functional enrichment analysis revealed distinct biological pathways and immune functions between risk groups. Tumour mutation load analysis differentiated high- and low-risk groups by their mutation profiles. Drug sensitivity analysis and immune infiltration studies using the CIBERSORT algorithm further elucidated the potential treatment responses in different risk groups. This comprehensive evaluation underscores the significance of lncRNAs in cuproptosis and their potential as biomarkers for lung cancer prognosis and immune microenvironment.
Asunto(s)
Biomarcadores de Tumor , Regulación Neoplásica de la Expresión Génica , Neoplasias Pulmonares , ARN Largo no Codificante , Microambiente Tumoral , Humanos , ARN Largo no Codificante/genética , Microambiente Tumoral/genética , Microambiente Tumoral/inmunología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/mortalidad , Pronóstico , Biomarcadores de Tumor/genética , Mutación , Perfilación de la Expresión Génica , Bases de Datos Genéticas , Curva ROCRESUMEN
BACKGROUND: Ketone ß-hydroxybutyrate (BHB) has been reported to prevent tumor cell proliferation and improve drug resistance. However, the effectiveness of BHB in oxaliplatin (Oxa)-resistant colorectal cancer (CRC) and the underlying mechanism still require further proof. METHODS: CRC-Oxa-resistant strains were established by increasing concentrations of CRC cells to Oxa. CRC-Oxa cell proliferation, apoptosis, invasion, migration, and epithelial-mesenchymal transition (EMT) were checked following BHB intervention in vitro. The subcutaneous and metastasis models were established to assess the effects of BHB on the growth and metastasis of CRC-Oxa in vivo. Eight Oxa responders and seven nonresponders with CRC were enrolled in the study. Then, the serum BHB level and H3K79me, H3K27ac, H3K14ac, and H3K9me levels in tissues were detected. DOT1L (H3K79me methyltransferase) gene knockdown or GNE-049 (H3K27ac inhibitor) use was applied to analyze further whether BHB reversed CRC-Oxa resistance via H3K79 demethylation and/or H3K27 deacetylation in vivo and in vitro. RESULTS: Following BHB intervention based on Oxa, the proliferation, migration, invasion, and EMT of CRC-Oxa cells and the growth and metastasis of transplanted tumors in mice were suppressed. Clinical analysis revealed that the differential change in BHB level was associated with drug resistance and was decreased in drug-resistant patient serum. The H3K79me, H3K27ac, and H3K14ac expressions in CRC were negatively correlated with BHB. Furthermore, results indicated that H3K79me inhibition may lead to BHB target deletion, resulting in its inability to function. CONCLUSIONS: ß-hydroxybutyrate resensitized CRC cells to Oxa by suppressing H3K79 methylation in vitro and in vivo.
Asunto(s)
Ácido 3-Hidroxibutírico , Proliferación Celular , Neoplasias Colorrectales , Resistencia a Antineoplásicos , Histonas , Oxaliplatino , Oxaliplatino/farmacología , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Humanos , Ácido 3-Hidroxibutírico/farmacología , Animales , Ratones , Histonas/metabolismo , Metilación , Línea Celular Tumoral , Resistencia a Antineoplásicos/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto , Masculino , Transición Epitelial-Mesenquimal/efectos de los fármacos , Femenino , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Movimiento Celular/efectos de los fármacos , Apoptosis/efectos de los fármacos , Ratones DesnudosRESUMEN
Background: Wuhan is located in the hinterland of China, in the east of Hubei Province, at the intersection of the Yangtze River and Hanshui River. It is a national historical and cultural city, an important industrial, scientific, and educational base, and a key transportation hub. There are many schools in Wuhan, with nearly a thousand of all kinds. The number of students is ~2.2 million, accounting for nearly one-fifth of the resident population; college or university students account for ~60% of the total student population. The geographical location of these colleges is relatively concentrated, and the population density is relatively high, making it prone to tuberculosis cluster epidemic. Objective: This study analyzed the epidemiological characteristics and influencing factors of tuberculosis aggregation in schools in Wuhan, China, during 2017-2022 to provide the basis for the scientific development of tuberculosis prevention and control strategies and measures in schools. Methods: This study adopted the methods of descriptive epidemiology to analyze the epidemic characteristics of tuberculosis aggregation in schools in Wuhan from January 2017 to December 2022, collecting the relevant data on tuberculosis prevention and control in all kinds of schools in the city using Questionnaire Star, an application of the China network questionnaire survey, and analyze the influencing factors of tuberculosis aggregation by using multifactor logistic regression analysis. Results: From 2017 to 2022, 54 outbreaks of pulmonary tuberculosis aggregation in schools were reported in Wuhan, which involved 37 different schools, including 32 colleges or universities and five senior high schools; 176 cases were reported, among which 73 were positive for pathogens and 18 were rifampicin or izoniazid resistant. The median duration of a single cluster epidemic was 46 (26,368) days. Universities were more prone to cluster outbreaks than middle schools (χ2 = 105.160, P = 0.001), and the incidence rate among male students was higher than that of female students in cluster epidemics (χ2 = 12.970, P = 0.001). The multivariate logistic regression analysis results showed that boarding in school (OR = 7.60) is the risk factor for a tuberculosis cluster epidemic in schools. The small number of students (OR = 0.50), the location of the school in the city (OR = 0.60), carry out physical examinations for freshmen (OR = 0.44), carry out illness absence and cause tracking (OR = 0.05), dormitories and classrooms are regularly ventilated with open windows (OR = 0.16), strict implement the management of sick student's suspension from school (OR = 0.36), and seeking timely medical consultation (OR = 0.32) were the protective factors for a tuberculosis cluster epidemic in schools. Conclusion: We successfully identified the epidemiological characteristics and influencing factors of tuberculosis aggregation in schools in Wuhan. The results revealed the influence and status of various factors and indicated ways for schools to improve their TB prevention and control measures in their daily activities. These measures can effectively help curb the cluster epidemic of tuberculosis in schools.
Asunto(s)
Instituciones Académicas , Tuberculosis , Humanos , China/epidemiología , Masculino , Femenino , Instituciones Académicas/estadística & datos numéricos , Tuberculosis/epidemiología , Tuberculosis/prevención & control , Adolescente , Encuestas y Cuestionarios , Estudiantes/estadística & datos numéricos , Factores de Riesgo , NiñoRESUMEN
ABSTRACT: Background: The high mortality rates of patients who are resuscitated from cardiac arrest (CA) are attributed to post cardiac arrest syndrome (PCAS). This study evaluated the effect of hyperoxygenation and targeted temperature management (TTM) on PCAS in rats with different causes of CA. Methods and Results: One hundred sixty-eight Sprague-Dawley rats were equally divided into asphyxial and dysrhythmic groups. Animals were further randomized into four subgroups immediately after resuscitation: normoxia-normothermia (NO-NT), ventilated with 21% oxygen under normothermia; hyperoxia-normothermia (HO-NT), ventilated with 100% oxygen for 3 hours under normothermia; normoxia-hypothermia (NO-HT), ventilated with 21% oxygen for 3 hours under hypothermia; and hyperoxia-hypothermia (HO-HT), ventilated with 100% oxygen for 3 hours under hypothermia. Post resuscitation cardiac dysfunction, neurological recovery, and pathological analysis were assessed. For asphyxial CA, HO-NT and HO-HT (68.8% and 75.0%) had significantly higher survival than NO-NT and NO-HT (31.3% and 31.3%). For dysrhythmic CA, NO-HT and HO-HT (81.3% and 87.5%) had significantly higher survival than NO-NT and HO-NT (44.0% and 50.0%). When all of the rats were considered, the survival rate was much higher in HO-HT (81.3%). Compared with NO-NT (57.7% ± 14.9% and 40.3% ± 7.8%), the collagen volume fraction and the proportion of fluoro-jade B-positive area in HO-HT (14.0% ± 5.7% and 28.0% ± 13.3%) were significantly reduced. Conclusion: The beneficial effects of hyperoxygenation and TTM are dependent on the cause of arrest: hyperoxygenation benefits asphyxial, whereas TTM benefits dysrhythmic CA. The combination of hyperoxygenation and TTM could effectively improve the functional outcome of PCAS regardless of the cause of CA.
Asunto(s)
Hipotermia Inducida , Ratas Sprague-Dawley , Animales , Ratas , Hipotermia Inducida/métodos , Masculino , Síndrome de Paro Post-Cardíaco/terapia , Reanimación Cardiopulmonar/métodos , Terapia por Inhalación de Oxígeno/métodos , Paro Cardíaco/terapiaRESUMEN
Interleukin (IL)-32 is induced by pro-inflammatory cytokines and promotes the release of inflammatory cytokines. Therefore, it can promote inflammatory responses. The present review article summarized the role of the receptors required for IL-32 action, the biological function of IL-32 and its mechanism of action in tumors. Moreover, it assessed the significance of aberrant IL-32 expression in associated diseases and analyzed the effects of IL-32 on four key types of cancer: Colorectal, gastric, breast and lung. However, the mechanism of action of IL-32 needs to be further demonstrated by assessing the role of this cytokine in cancer to elucidate novel and reliable targets for future cancer treatments.
RESUMEN
BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common cancers in the world and a nonnegligible health concern on a worldwide scale. Disulfidptosis is a novel mode of cell death, which is mainly caused by the collapse of the actin skeleton. Although many studies have demonstrated that various types of cell death are associated with cancer treatment, the relationship between disulfidptosis and HCC has not been elucidated. METHODS: Here, we mainly applied bioinformatics methods to construct a disulfidptosis related risk model in HCC patients. Specifically, transcriptome data and clinical information were downloaded from the Gene Expression Omnibus (GEO), International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA) database. A total of 45 co-expressed genes were extracted between the disulfidptosis-related genes (DRGs) and the differential expression genes (DEGs) of liver hepatocellular carcinoma (LIHC) in the TCGA database. The LIHC cohort was divided into two subgroups with different prognosis by k-mean consensus clustering and functional enrichment analysis was performed. Subsequently, three hub genes (CDCA8, SPP2 and RDH16) were screened by Cox regression and LASSO regression analysis. In addition, a risk signature was constructed and the HCC cohort was divided into high risk score and low risk score subgroups to compare the prognosis, clinical features and immune landscape between the two subgroups. Finally, the prognostic model of independent risk factors was constructed and verified. CONCLUSIONS: High DRGs-related risk score in HCC individuals predict poor prognosis and are associated with poor immunotherapy response, which indicates that risk score assessment model can be utilized to guide clinical treatment strategy.
Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/terapia , Pronóstico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/terapia , InmunoterapiaRESUMEN
OBJECTIVES: Nrf2/BACH1/HO-1 proteins have been implicated in the development and progression of tumors. However, their clinical relevance in breast cancer remains unclear and understudied. This study evaluated Nrf2/BACH1/HO-1 protein expression and its relationship with age, tumor grade, tumor stage, TNM, ER, PR, HER2, and histologic type. METHODS: 114 female breast cancer and 30 noncancerous tissues were evaluated for Nrf2/BACH1/HO-1 protein expression using immunohistochemistry and Western blot. The relationships between the expression and clinicopathologic factors were assessed using the χ2 test. RESULTS: 74% of the cancerous samples had high Nrf2 protein expression, and 26% of them had low Nrf2 protein expression. Regarding the non-cancer samples, 43% had high Nrf2 protein expression and 57% had low Nrf2 protein expression (p < 0.002). 39% of the cancerous samples had high BACH1 protein expression, and 61% had low BACH1 protein expression. For the non-cancer samples, 80% had high BACH1 protein expression and 20% had low BACH1 protein expression (p < 0.031). 67% of the cancerous samples had high HO-1 protein expression, and 33% had low HO-1 protein expression. However, for the non-cancer samples, 17% of them had high HO-1 protein expression and 83% had low HO-1 protein expression (p < 0.001). The expression of Nrf2 and HO-1 significantly correlated with tumor grade, while BACH1 was significantly associated with tumor stage (p < 0.05). CONCLUSION: Nrf2, BACH1, and HO-1 could be explored as a biomarker for cancer stage, progression, and prognosis.
Asunto(s)
Factores de Transcripción con Cremalleras de Leucina de Carácter Básico , Biomarcadores de Tumor , Neoplasias de la Mama , Hemo-Oxigenasa 1 , Factor 2 Relacionado con NF-E2 , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Humanos , Femenino , Persona de Mediana Edad , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/genética , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/metabolismo , Hemo-Oxigenasa 1/genética , Hemo-Oxigenasa 1/metabolismo , Valor Predictivo de las Pruebas , Regulación Neoplásica de la Expresión Génica , Biomarcadores de Tumor/análisis , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismoRESUMEN
The sex of an animal impacts glucose sensitivity, but little information is available regarding the mechanisms causing that difference, especially during acute inflammation. We examined sex-specific differences in the role of the P2Y2 receptor (P2Y2R) in glucose flux with and without LPS challenge. Male and female wild-type and P2Y2R knockout mice (P2Y2R-/-) were injected with LPS or saline and glucose tolerance tests (GTT) were performed. P2Y2R, insulin receptor, and GLUT4 transporter gene expression was also evaluated. Female mice had reduced fasting plasma glucose and females had reduced glucose excursion times compared to male mice during GTT. P2Y2R-/- males had significantly decreased glucose flux throughout the GTT as compared to all female mice. Acute inflammation reduced fasting plasma glucose and the GTT area under the curve in both sexes. While both wild-type and P2Y2R-/- male animals displayed reduced fasting glucose in LPS treatment, female mice did not have significant difference in glucose tolerance, suggesting that the effects of P2Y2R are specific to male mice, even under inflammatory conditions. Overall, we conclude that the role for the purinergic receptor, P2Y2R, in regulating glucose metabolism is minimal in females but plays a large role in male mice, particularly in the acute inflammatory state.
Asunto(s)
Glucemia , Lipopolisacáridos , Femenino , Masculino , Animales , Ratones , Receptores Purinérgicos P2Y , Glucosa , Ratones Noqueados , InflamaciónRESUMEN
Peroxisome proliferator-activated receptors (PPARs) are essential for cellular physiological processes. However, there is less research on the PPAR-related genes in lung adenocarcinoma (LUAD). Open-access data were get from the cancer genome atlas (TCGA) and gene expression omnibus (GEO) databases. All the analysis were conducted in the R software based on different R packages. In this study, we gauged the PPAR score employing a set of 72 PPAR-associated genes and probed the biological impact of this score on lung adenocarcinoma (LUAD). Subsequently, we established a unique signature composed of eight PPAR-related genes (ANGPTL4, ACSL3, ADIPOQ, FABP1, SLC27A1, ACOX2, PPARD and OLR1) to forecast the prognosis of LUAD. The signature's effectiveness in predicting survival was validated through the receiver operating characteristic curve in the TCGA-LUAD cohort. As per the pathway enrichment analysis, several crucial oncogenic pathways and metabolic processes were enriched in high-risk individuals. Further, we observed that these high-risk patients exhibited heightened genomic instability. Additionally, compared to the low-risk cohort, high-risk patients demonstrated diminished immune components and function. Intriguingly, high-risk patients exhibited a potential heightened sensitivity to immunotherapy and certain drugs, including Gefitinib, Afatinib, Erlotinib, IAP_5620, Sapitinib, LCL161, Lapatinib and AZD3759. The prognosis model based on eight PPAR-related genes has satisfactory prognosis prediction efficiency. Meanwhile, our results can provide direction for future studies in the relevant aspects.
RESUMEN
Objective: To investigate the clinical characteristics and risk factors of Kawasaki disease (KD) complicated with hip synovitis. Methods: Children with KD admitted from January 1, 2011, to December 31, 2020, in the KD database of Yuying Children's Hospital Affiliated with Wenzhou Medical University were retrospectively included. We selected KD children with hip synovitis as the case group and KD children without hip synovitis as the control group to analyze the possible risk factors of hip synovitis in KD children. Results: Among 2,871â KD children admitted to our center in recent years, 28 had hip synovitis. In this study 140â KD children were enrolled, including 28â KD children with hip synovitis and 112 children with general KD (within one month of admission). The onset age of KD patients with hip synovitis was 30.92 (23.23-49.99) months, and there were 17 cases of bilateral hip involvement. The course of synovitis (limited movement, joint pain, lameness, unwillingness to stand, etc.) ranged from 1 to 19 days, with an average of (8.8 ± 4.6) days. We treated all KD children with IVIG (Intravenous immunoglobulin) plus aspirin, among which five patients in the case group developed coronary artery damage, six acquired IVIG resistance, and synovial inflammation disappeared within two weeks. Age, weight, length of stay, and incidence of IVIG resistance significantly differed between the two groups (P = 0.001, 0.005, <0.001, and 0.035, respectively). Logistic regression analysis showed that KD combined with hip synovitis was an independent risk factor for developing propyl pellet resistance, with an OR value of 4.625 (95% CI: 1.095, 19.526). Conclusion: KD combined with hip synovitis mainly involves bilateral hip joints, and joint pain and limited movement are the main clinical features. The symptoms are mild and self-limiting. KD combined with hip synovitis is a risk factor for IVIG resistance. Hip synovitis is a good predictor of IVIG resistance.
RESUMEN
BACKGROUND: Intervertebral disk degeneration (IDD) is a degenerative disease that underlies various musculoskeletal and spinal disorders and is positively correlated with age. tRNA-derived small RNAs (tsRNA), as a new small noncoding RNAs, its function in IDD is unclear. Herein, our goal was to find the key tsRNA that affects IDD independently of age and explore the underlying mechanisms. METHODS: Small RNA sequencing was performed in nucleus pulposus (NP) tissues of traumatic lumbar fracture individuals, young IDD (IDDY) patients, and old IDD (IDDO) patients. The biological functions of tsRNA-04002 in NP cells (NPCs) were investigated by qRT-PCR, western blot, and flow cytometry analysis. The molecular mechanism of tsRNA-04002 was demonstrated by luciferase assays and rescue experiments. Furthermore, the therapeutic effects of tsRNA-04002 on IDD rat model were used and evaluated in vivo. RESULTS: Compared with fresh traumatic lumbar fracture patients, a total of 695 disordered tsRNAs is obtained (398 down-regulated tsRNAs and 297 up-regulated tsRNAs). These disordered tsRNAs were mainly involved in Wnt signaling pathway and MAPK signaling pathway. tsRNA-04002 was an age-independent key target in IDD, which was both lower expressed in IDDY and IDDO groups than control group. Overexpression of tsRNA-04002 restrained inflammatory cytokines IL-1ß and TNF-α expression, increased the COL2A1, and inhibited the NPCs apoptosis. Furthermore, we determined that PRKCA was the target gene of tsRNA-04002 and was negatively regulated by tsRNA-04002. The rescue experiment results suggested that the high expression of PRKCA reversed the inhibitory effect of tsRNA-04002 mimics on NPCs inflammation and apoptosis, and promotive effect of COL2A1. Moreover, tsRNA-04002 treatment dramatically ameliorated the IDD process in the puncture-induced rat model, together with the blockade of PRKCA in vivo. CONCLUSION: Collectively, our results substantiated that tsRNA-04002 could alleviate IDD by targeting PRKCA to inhibit apoptosis of NPCs. tsRNA-04002 may be a novel therapeutic target of IDD progression.
Asunto(s)
Degeneración del Disco Intervertebral , Núcleo Pulposo , Ratas , Animales , Degeneración del Disco Intervertebral/genética , Degeneración del Disco Intervertebral/metabolismo , Núcleo Pulposo/metabolismo , Apoptosis/genética , ARN/genética , Vía de Señalización Wnt/genéticaRESUMEN
Spinal cord injury (SCI) leads to mental abnormalities such as dementia and depression; however, the molecular mechanism of SCI-induced dementia remains a matter of debate. Asparagine endopeptidase (AEP) mediated dementia by enhancing amyloid plaque and Tau hyperphosphorylation, indicating that it played an important role in neurodegeneration. Here we revealed that SCI stimulated AEP activation in mice with T9 contusion injury. Activated-AEP cleaved APP and Tau, resulting in APP C586 and Tau N368 formations, and consequentially accelerated Aß deposit and Tau hyperphosphorylation, respectively. At 9 months following injury, mice demonstrated a severe deterioration in cognitive-behavioral function, which was corroborated by the presence of accumulated AD-specific pathologies. Surprisingly, activated AEP was found in the brains of mice with spinal cord injury. In contrast, AEP knockout reduced SCI-induced neuronal death and neuroinflammation, resulting in cognitive-behavioral restoration. Interestingly, compared to the full-length proteins, truncated Tau N368 and APP C586 were easier to bind to each other. These AEP-processed fragments can not only be induced to pre-formed fibrils, but also amplified their abilities of spreading and neurotoxicity in vitro. Furthermore, as a critical transcription factor of AEP, C/EBPß was activated in injured spinal cord. Elevated C/EBPß level, as well as microglia population and inflammatory cytokines were also noticed in the cortex and hippocampus of SCI mice. These neuroinflammation pathologies were close related to the amount of Tau N368 and APP C586 in brain. Moreover, administration with the AEP-specific inhibitor, compound #11, was shown to decelerate Aß accumulation, tauopathy and C/EBPß level in both spinal cord and brain of SCI mice. Thus, this study highlights the fact that spinal cord injury is a potential risk factor for dementia, as well as the possibility that C/EBPß-AEP axis may play a role in SCI-induced cognitive impairment.
Asunto(s)
Proteína beta Potenciadora de Unión a CCAAT , Disfunción Cognitiva , Cisteína Endopeptidasas , Traumatismos de la Médula Espinal , Traumatismos de la Médula Espinal/fisiopatología , Disfunción Cognitiva/etiología , Animales , Ratones , Proteína beta Potenciadora de Unión a CCAAT/metabolismo , Proteínas tau/metabolismo , Demencia , Precursor de Proteína beta-Amiloide/metabolismo , Ratones Noqueados , Enfermedades Neuroinflamatorias , Cisteína Endopeptidasas/metabolismo , Ratones Endogámicos C57BL , Masculino , FemeninoRESUMEN
Numerous metabolic reactions and pathways use adenosine 5'-triphosphate (ATP) as an energy source and as a phosphorous or pyrophosphorous donor. Based on three-dimensional (3D)-printing, enzyme immobilization can be used to improve ATP regeneration and operability and reduce cost. However, due to the relatively large mesh size of 3D-bioprinted hydrogels soaked in a reaction solution, the lower-molecular-weight enzymes cannot avoid leaking out of the hydrogels readily. Here, a chimeric adenylate-kinase-spidroin (ADK-RC) is created, with ADK serving as the N-terminal domain. The chimera is capable of self-assembling to form micellar nanoparticles at a higher molecular scale. Although fused to spidroin (RC), ADK-RC remains relatively consistent and exhibits high activity, thermostability, pH stability, and organic solvent tolerance. Considering different surface-to-volume ratios, three shapes of enzyme hydrogels are designed, 3D bioprinted, and measured. In addition, a continuous enzymatic reaction demonstrates that ADK-RC hydrogels have higher specific activity and substrate affinity but a lower reaction rate and catalytic power compared to free enzymes in solution. With ATP regeneration, the ADK and ADK-RC hydrogels significantly increase the production of d-glucose-6-phosphate and obtain an efficient usage frequency. In conclusion, enzymes fused to spidroin might be an efficient strategy for maintaining activity and reducing leakage in 3D-bioprinted hydrogels under mild conditions.
Asunto(s)
Adenilato Quinasa , Fibroínas , Adenilato Quinasa/química , Adenilato Quinasa/metabolismo , Hidrogeles , Adenosina Trifosfato/química , CatálisisRESUMEN
BACKGROUND: Syringaresinol processes anti-inflammatory and antioxidative activity. However, the effects of syringaresinol on cardiorenal fibrosis caused by cardiorenal syndrome type 2 (CRS2) are unclear. METHODS: Molecular docking predicted binding activity of syringaresinol to heat shock protein 90 (HSP90). The toxicity of a 4-weeks treatment with 20 mg/kg of syringaresinol was observed by measuring serum pro-inflammatory cytokines levels and by cardiorenal pathology. A CRS2 rad model was established by myocardial infarction using ligation over an 8 week-period. Rats were divided into five groups, including sham, CRS2, pimitespib, syringaresinol, and HSP90 + syringaresinol. Rats were received a 4-weeks daily treatment with 10 mg/kg pimitespib (a HSP90 inhibitor) or 20 mg/kg syringaresinol. Recombinant adeno-associated virus (rAAV) carrying a periostin (PE) promoter driving the expression of wild-type HSP90 (rAAV9-PE-HSP90, 1 × 1011 µg) was treated intravenously once in CRS2 model rats. Cardiorenal function and pathology were assessed. Expressions of HSP90 and TGF-ß1 in the myocardium and kidney were measured by immunohistochemistry and western blotting. RESULTS: Syringaresinol showed good binding activity with HSP90, and no signs of toxicity in rats following treatment. Pimitespib or syringaresinol significantly improved the cardiorenal function and fibrosis in rats with CRS2. Meanwhile, the rAAV9-PE-HSP90 injection obviously blocked the effects of syringaresinol. CONCLUSIONS: Syringaresinol targets HSP90 to suppress CRS2-induced cardiorenal fibrosis, providing a promising therapeutic drug for CRS2.
Asunto(s)
Síndrome Cardiorrenal , Ratas , Animales , Síndrome Cardiorrenal/tratamiento farmacológico , Síndrome Cardiorrenal/etiología , Síndrome Cardiorrenal/metabolismo , Simulación del Acoplamiento Molecular , Riñón/patología , FibrosisRESUMEN
Spinal cord injury (SCI), a debilitating medical condition that can cause irreversible loss of neurons and permanent paralysis, currently has no cure. However, regenerative medicine may offer a promising treatment. Given that numerous regenerative strategies aim to deliver cells and materials in the form of tissue-engineered therapies, understanding and characterising the mechanical properties of the spinal cord tissue is very important. In this study, we have systematically characterised the spatiotemporal changes in elastic stiffness (elastic modulus, Pa) and viscosity (drop in peak force, %) of injured rat thoracic spinal cord tissues at distinct time points after crush injury using the indentation technique. Our results demonstrate that in comparison with uninjured spinal cord tissue, the injured tissues exhibited lower stiffness (median 3281 Pa versus 9632 Pa; P < 0.001) but demonstrated elevated viscosity (median 80% versus 57%; P < 0.001) at 3 days postinjury. Between 4 and 6 weeks after SCI, the overall viscoelastic properties of injured tissues returned to baseline values. At 12 weeks after SCI, in comparison with uninjured tissue, the injured spinal cord tissues displayed a significant increase in both elasticity (median 13698 Pa versus 9920 Pa; P < 0.001) and viscosity (median 64% versus 58%; P < 0.001). This work constitutes the first quantitative mapping of spatiotemporal changes in spinal cord tissue elasticity and viscosity in injured rats, providing a mechanical basis of the tissue for future studies on the development of biomaterials for SCI repair. STATEMENT OF SIGNIFICANCE: Spinal cord injury (SCI) is a devastating disease often leading to permanent paralysis. While enormous progress in understanding the molecular pathomechanisms of SCI has been made, the mechanical properties of injured spinal cord tissue have received considerably less attention. This study provides systematic characterization of the biomechanical evolution of rat spinal cord tissue after SCI using a microindentation test method. We find spinal cord tissue behaves significantly softer but more viscous immediately postinjury. As time passes, the lesion site gradually returns to baseline values and then displays pronounced increased viscoelastic properties. As host tissue mechanical properties are a crucial consideration for any biomaterial implanted into central nervous system, our results may have important implications for further studies of SCI repair.
Asunto(s)
Traumatismos de la Médula Espinal , Ratas , Animales , Traumatismos de la Médula Espinal/terapia , Traumatismos de la Médula Espinal/patología , Médula Espinal/patología , Elasticidad , Fenómenos Mecánicos , Parálisis/patologíaRESUMEN
Due to their advantages in structural stability and versatility, cysteine-rich peptides, which are secreted from the venom glands of venomous animals, constitute a naturally occurring pharmaceutical arsenal. However, the correct folding of disulfide bonds is a challenging task in the prokaryotic expression system like Escherichia coli due to the reducing environment. Here, a secretory expression plasmid pSE-G1M5-SUMO-HWTX-I for the spider neurotoxin huwentoxin-I (HWTX-I) with three disulfides as a model of cysteine-rich peptides was constructed. By utilizing the signal peptide G1M5, the fusion protein 6 × His-SUMO-HWTX-I was successfully secreted into extracellular medium of BL21(DE3). After enrichment using cation-exchange chromatography and purification utilizing the Ni-NTA column, 6 × His-SUMO-HWTX-I was digested via Ulp1 kinase to release recombinant HWTX-I (rHWTX-I), which was further purified utilizing RP-HPLC. Finally, both impurities with low and high molecular weights were completely removed. The molecular mass of rHWTX-I was identified as being 3750.8 Da, which was identical to natural HWTX-I with three disulfide bridges. Furthermore, by utilizing whole-cell patch clamp, the sodium currents of hNav1.7 could be inhibited by rHWTX-I and the IC50 value was 419 nmol/L.
Asunto(s)
Venenos de Araña , Arañas , Animales , Neurotoxinas/química , Neurotoxinas/farmacología , Cisteína/metabolismo , Arañas/química , Arañas/metabolismo , Escherichia coli/genética , Escherichia coli/metabolismo , Venenos de Araña/genética , Venenos de Araña/química , Venenos de Araña/metabolismo , Péptidos/metabolismo , Disulfuros/metabolismoRESUMEN
We demonstrate a systematic study optimizing the properties of CoCrFeNi medium entropy alloy (MEA) thin films by tuning the deposition parameters of the pulsed direct current (DC) magnetron sputtering process. The chemical composition and microstructure of thin films were studied with energy dispersive X-ray spectroscopy (EDS), an X-ray diffractometer (XRD) and a transmission electron microscope (TEM). Abundant nanotwins and the dual face-centered cubic-hexagonal close-packed (FCC-HCP) phases were formed in some specimens. The Taguchi experimental method and analysis of variance (ANOVA) were applied to find the optimized parameters. The control factors are five deposition parameters: substrate bias, substrate temperature, working pressure, rotation speed and pulsed frequency. According to the signal-to-noise ratio results, the optimized parameters for low electrical resistivity (98.2 ± 0.8 µΩ·cm), low surface roughness (0.5 ± 0.1 nm) and high hardness (9.3 ± 0.2 GPa) were achieved and verified with confirmed experiments.
RESUMEN
Background: Post-cardiac arrest (CA) brain injury is the main cause of death in patients resuscitated from CA. Previous studies demonstrated that hydrogen inhalation mitigates post-CA brain injury. However, factors affecting the efficacy of hydrogen remain unknown. In the present study, we investigated the influence of oxygen concentration and targeted temperature on neuroprotective effect in a CA rat model of ventricular fibrillation (VF). Methods: Cardiopulmonary resuscitation (CPR) was initiated after 7 min of untreated VF in adult male Sprague-Dawley rats. Immediately following successful resuscitation, animals were randomized to be ventilated with 21% oxygen and 79% nitrogen (21%O2); 2% hydrogen, 21% oxygen, and 77% nitrogen (2%H2 + 21%O2); 2% hydrogen, 50% oxygen, and 48% nitrogen (2%H2 + 50%O2); or 2% hydrogen and 98% oxygen (2%H2 + 98%O2) for 3 h. For each group, the target temperature was 37.5°C for half of the animals and 35.0°C for the other half. Results: No statistical differences in baseline measurements and CPR characteristics were observed among groups. For animals with normothermia, 2%H2 + 50%O2 (123 [369] vs. 500 [393], p = 0.041) and 2%H2 + 98%O2 (73 [66] vs. 500 [393], p = 0.002) groups had significantly lower neurological deficit scores (NDSs) at 96 h and significantly higher survival (75.0 vs. 37.5%, p = 0.033 and 81.3 vs. 37.5%, p = 0.012) than 21%O2 group. For animals with hypothermia, no statistical difference in NDS among groups but 2%H2 + 98%O2 has significantly higher survival than the 21%O2 group (93.8 vs. 56.3%, p = 0.014). Conclusion: In this CA rat model, inhaling 2% hydrogen combined with a high concentration of oxygen improved 96-h survival, either under normothermia or under hypothermia.