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Ferroptosis, a defensive strategy commonly employed by the host cells to restrict pathogenic infections, has been implicated in the development and therapeutic responses of various types of cancer. However, the role of ferroptosis in oncogenic Kaposi's sarcoma-associated herpesvirus (KSHV)-induced cancers remains elusive. While a growing number of non-histone proteins have been identified as acetylation targets, the functions of these modifications have yet to be revealed. Here, we show KSHV reprogramming of host acetylation proteomics following cellular transformation of rat primary mesenchymal precursor. Among them, SERPINE1 mRNA binding protein 1 (SERBP1) deacetylation is increased and required for KSHV-induced cellular transformation. Mechanistically, KSHV-encoded viral interleukin-6 (vIL-6) promotes SIRT3 deacetylation of SERBP1, preventing its binding to and protection of lipoyltransferase 2 (Lipt2) mRNA from mRNA degradation resulting in ferroptosis. Consequently, a SIRT3-specific inhibitor, 3-TYP, suppresses KSHV-induced cellular transformation by inducing ferroptosis. Our findings unveil novel roles of vIL-6 and SERBP1 deacetylation in regulating ferroptosis and KSHV-induced cellular transformation, and establish the vIL-6-SIRT3-SERBP1-ferroptosis pathways as a potential new therapeutic target for KSHV-associated cancers.
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Ferroptosis , Herpesvirus Humano 8 , Neoplasias , Sarcoma de Kaposi , Sirtuina 3 , Ratas , Animales , Herpesvirus Humano 8/genética , Sirtuina 3/genética , Sirtuina 3/metabolismo , Transformación Celular Neoplásica , Proteínas Virales/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismoRESUMEN
Mycobacterium tuberculosis, the pathogen of the deadly disease tuberculosis, depends on the redox cofactor mycofactocin (MFT) to adapt to and survive under hypoxic conditions. MftR is a TetR family transcription regulator that binds upstream of the MFT gene cluster and controls MFT synthesis. To elucidate the structural basis underlying MftR regulation, we determined the crystal structure of Mycobacterium tuberculosis MftR (TB-MftR). The structure revealed an interconnected hydrogen bond network in the α1-α2-α3 helices of helix-turn-helix (HTH) DNA-binding domain that is essential for nucleic acid interactions. The ligand-binding domain contains a hydrophobic cavity enclosing long-chain fatty acyl-CoAs like the key regulatory ligand oleoyl-CoA. Despite variations in ligand-binding modes, comparative analyses suggest regulatory mechanisms are largely conserved across TetR family acyl-CoA sensors. By elucidating the intricate structural mechanisms governing DNA and ligand binding by TB-MftR, our study enhances understanding of the regulatory roles of this transcription factor under hypoxic conditions, providing insights that could inform future research into Mycobacterium tuberculosis pathogenesis.
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Proteínas Bacterianas , Mycobacterium tuberculosis , Mycobacterium tuberculosis/metabolismo , Mycobacterium tuberculosis/genética , Proteínas Bacterianas/metabolismo , Proteínas Bacterianas/química , Proteínas Bacterianas/genética , Regulación Bacteriana de la Expresión Génica , Cristalografía por Rayos X , Factores de Transcripción/metabolismo , Factores de Transcripción/química , Factores de Transcripción/genética , Modelos Moleculares , Secuencia de AminoácidosRESUMEN
Cancer progression is associated with the evolutionary accumulation of genetic mutations that are biologically significant. Mutations of the androgen receptor (AR) are associated with the development of prostate cancer (PCa) by responding to non-androgenic hormones, and the lack of annotations in their responsiveness to hormone ligands remains a daunting challenge. Here, we have used a yeast reporter system to quickly evaluate the responsiveness of all fifty clinical AR mutations to a variety of steroidal ligands including dihydrotestosterone (DHT), 17ß-estradiol (E2), progesterone (PROG), and cyproterone acetate (CPA). Based on an AR-driven reporter that synthesizes histidine, a basic amino acid required for yeast survival and propagation, the yeast reporter system enabling clonal selection was further empowered by combining with a random DNA mutagenesis library to simulate the natural evolution of AR gene under the selective pressures of steroidal ligands. In a time-frame of 1-2 weeks, 19 AR mutants were identified, in which 11 AR mutants were validated for activation by tested steroidal compounds. The high efficiency of our artificial evolution strategy was further evidenced by a sequential selection that enabled the discovery of multipoint AR mutations and evolution directions under the pressure of steroidal ligands. In summary, our designer yeast is a portable reporter module that can be readily adapted to streamline high-throughput AR-compound screening, used as a PCa clinical reference, and combined with additional bioassay systems to further extend its potential.
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Receptores Androgénicos , Saccharomyces cerevisiae , Masculino , Humanos , Saccharomyces cerevisiae/genética , Receptores Androgénicos/genética , Mutación , Mutagénesis , Selección GenéticaRESUMEN
Gram-negative (G-) bacterial infections remain one of the most urgent global health threats, because the distinctive envelope structure hinders the penetration of therapeutics. Here, we showed that a perfluorooctyl bromide nanoemulsion (PFOB NE) uniquely interacts with G- bacteria. After cell envelope attachment, the PFOB can infiltrate the cell and was diffused throughout. In this process, it impaired the membranes by disintegrating phospholipid molecules, enhancing the consequent ultrasonic cavitation to break the envelope. We identified through ultrasound that the NE had remarkable bactericidal effects against various antibiotic-resistant pathogens. Using in situ sterilization, this approach accelerated the recovery of bacteria-infected murine skin wounds. Thus, combining PFOB and ultrasound might be an alternative tool for conquering the growing threat of G- pathogens.
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Fluorocarburos , Hidrocarburos Bromados , Ratones , Animales , Bacterias Gramnegativas , Fluorocarburos/química , Antibacterianos/farmacología , Antibacterianos/químicaRESUMEN
This study aimed to explore the expression, function, and mechanisms of TBC1D10B in colon cancer, as well as its potential applications in the diagnosis and treatment of the disease.The expression levels of TBC1D10B in colon cancer were assessed by analyzing the TCGA and CCLE databases. Immunohistochemistry analysis was conducted using tumor and adjacent non-tumor tissues from 68 colon cancer patients. Lentiviral infection techniques were employed to silence and overexpress TBC1D10B in colon cancer cells. The effects on cell proliferation, migration, and invasion were evaluated using CCK-8, EDU, wound healing, and Transwell invasion assays. Additionally, GSEA enrichment analysis was used to explore the association of TBC1D10B with biological pathways related to colon cancer. TBC1D10B was significantly upregulated in colon cancer and closely associated with patient prognosis. Silencing of TBC1D10B notably inhibited proliferation, migration, and invasion of colon cancer cells and promoted apoptosis. Conversely, overexpression of TBC1D10B enhanced these cellular functions. GSEA analysis revealed that TBC1D10B is enriched in the AKT/PI3K/mTOR signaling pathway and highly correlated with PAK4. The high expression of TBC1D10B in colon cancer is associated with poor prognosis. It influences cancer progression by regulating the proliferation, migration, and invasion capabilities of colon cancer cells, potentially acting through the AKT/PI3K/mTOR signaling pathway. These findings provide new targets and therapeutic strategies for the treatment of colon cancer.
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Apoptosis , Movimiento Celular , Proliferación Celular , Neoplasias del Colon , Proteínas Activadoras de GTPasa , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Transducción de Señal , Serina-Treonina Quinasas TOR , Quinasas p21 Activadas , Humanos , Serina-Treonina Quinasas TOR/metabolismo , Serina-Treonina Quinasas TOR/genética , Neoplasias del Colon/genética , Neoplasias del Colon/patología , Neoplasias del Colon/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Proto-Oncogénicas c-akt/genética , Proliferación Celular/genética , Proteínas Activadoras de GTPasa/metabolismo , Proteínas Activadoras de GTPasa/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Fosfatidilinositol 3-Quinasas/genética , Quinasas p21 Activadas/metabolismo , Quinasas p21 Activadas/genética , Movimiento Celular/genética , Apoptosis/genética , Línea Celular Tumoral , Progresión de la Enfermedad , Regulación Neoplásica de la Expresión Génica , Masculino , Femenino , Persona de Mediana Edad , PronósticoRESUMEN
Quasi-2D perovskites exhibit impressive optoelectronic properties and hold significant promise for future light-emitting devices. However, the efficiency of perovskite light-emitting diodes (PeLEDs) is seriously limited by defect-induced nonradiative recombination and imbalanced charge injection. Here, the defect states are passivated and charge injection balance is effectively improved by introducing the additive cyclohexanemethylammonium (CHMA) to bromide-based Dion-Jacobson (D-J) structure quasi-2D perovskite emission layer. CHMA participates in the crystallization of perovskite, leading to high quality film composed of compact and well-contacted grains with enhanced hole transportation and less defects. As a result, the corresponding PeLEDs exhibit stable pure blue emission at 466 nm with a maximum external quantum efficiency (EQE) of 9.22%. According to current knowledge, this represents the highest EQE reported for pure-blue PeLEDs based on quasi-2D bromide perovskite thin films. These findings underscore the potential of quasi-2D perovskites for advanced light-emitting devices and pave the way for further advancements in PeLEDs.
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One of the most difficult problems that hinder the development and application of herbal medicine is how to illuminate the global effects of herbs on the human body. Currently, the chemo-centric network pharmacology methodology regards herbs as a mixture of chemical ingredients and constructs the 'herb-compound-target-disease' connections based on bioinformatics methods, to explore the pharmacological effects of herbal medicine. However, this approach is severely affected by the complexity of the herbal composition. Alternatively, gene-expression profiles induced by herbal treatment reflect the overall biological effects of herbs and are suitable for studying the global effects of herbal medicine. Here, we develop an online transcriptome-based multi-scale network pharmacology platform (TMNP) for exploring the global effects of herbal medicine. Firstly, we build specific functional gene signatures for different biological scales from molecular to higher tissue levels. Then, specific algorithms are designed to measure the correlations of transcriptional profiles and types of gene signatures. Finally, TMNP uses pharmacotranscriptomics of herbal medicine as input and builds associations between herbs and different biological scales to explore the multi-scale effects of herb medicine. We applied TMNP to a single herb Astragalus membranaceus and Xuesaitong injection to demonstrate the power to reveal the multi-scale effects of herbal medicine. TMNP integrating herbal medicine and multiple biological scales into the same framework, will greatly extend the conventional network pharmacology model centering on the chemical components, and provide a window for systematically observing the complex interactions between herbal medicine and the human body. TMNP is available at http://www.bcxnfz.top/TMNP.
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Medicina de Hierbas , Farmacología en Red , Transcriptoma , Algoritmos , Astragalus propinquus , Biología Computacional , Medicamentos Herbarios Chinos , Humanos , Medicina Tradicional China/métodos , Plantas Medicinales , SaponinasRESUMEN
PDZ and LIM domain protein 1 (PDLIM1) is a cytoskeletal protein and is associated with the malignant pathological features of several tumors. However, the prognostic value of PDLIM1 and the molecular mechanisms by which it is involved in the metabolism and progression in gastric cancer (GC) are still unclear. The GEPIA database was used to predict the expression and prognosis of PDLIM1 in GC. qRT-PCR and western blot assays were applied to detect the mRNA and protein expression in GC tissues and cells. Loss- and gain-of-function experiments were performed to evaluate the biological role of PDLIM1 in GC cells. The Warburg effect was detected by a battery of glycolytic indicators. The interaction of PDLIM1 and hexokinase 2 (HK2) was determined by a co-immunoprecipitation assay. Furthermore, the modulatory effects of PDLIM1 and HK2 on Wnt/ß-catenin signaling were assessed. The results showed that PDLIM1 expression was upregulated in GC tissues and cells and was associated with a poor prognosis for GC patients. PDLIM1 inhibition reduced GC cell proliferation, migration and invasion and promoted cell apoptosis. In the glucose deprivation (GLU-D) condition, the PDLIM1 level was reduced and PDLIM1 overexpression led to an increase in glycolysis. Besides, mechanistic investigation showed that PDLIM1 interacted with HK2 to mediate biological behaviors and the glycolysis of GC through Wnt/ß-catenin signaling under glucose deprivation. In conclusion, PDLIM1 interacts with HK2 to promote gastric cancer progression by enhancing the Warburg effect via Wnt/ß-catenin signaling.
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Neoplasias Gástricas , Humanos , beta Catenina/metabolismo , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Regulación Neoplásica de la Expresión Génica , Glucosa , Hexoquinasa/genética , Hexoquinasa/metabolismo , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patología , Vía de Señalización Wnt/genéticaRESUMEN
Psoriasis is a chronic, proliferative, and inflammatory skin disease closely associated with inflammatory cytokine production. Cyclophilin A (CypA) is an important proinflammatory factor; however, its role in psoriasis remains unclear. The present data indicate that CypA levels are increased in the lesion skin and serum of patients with psoriasis, which is positively correlated with the psoriasis area severity index. Furthermore, extracellular CypA (eCypA) triggered psoriasis-like inflammatory responses in keratinocytes. Moreover, anti-CypA mAb significantly reduced pathological injury, keratinocyte proliferation, cytokine expression in imiquimod-induced mice. Notably, the therapeutic effect of anti-CypA mAb was better than that of the clinically used anti-IL-17A mAb and methotrexate. Mechanistically, eCypA binds to ACE2 and CD147 and is blocked by anti-CypA mAb. eCypA not only induces the dimerization and phosphorylation of ACE2 to trigger the JAK1/STAT3 signaling pathway for cytokine expression but also interacts with CD147 to promote PI3K/AKT/mTOR signaling-mediated keratinocyte proliferation. These findings demonstrate that the binding of eCypA to ACE2 and CD147 cooperatively triggers psoriasis-like inflammation and anti-CypA mAb is a promising candidate for the treatment of psoriasis.
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Endoscopic angle-resolved light scattering methods have been developed for early cancer detection but they typically require multi-element coherent fiber optic bundles to recover scattering distributions from tissues. Recent work has focused on using a single multimode fiber (MMF) to measure angle resolved scattering but this approach has practical limitations to overcome before clinical translation. Here we address these limitations by proposing an MMF-based endoscope capable of measuring angular scattering patterns suitable for determining structure. Significantly, this approach implements a spectrally resolved detection scheme to reduce speckle and leverages the azimuthal symmetry of the angular scattering patterns to enable measurements that are robust to fiber bending. This results in a unique method that does not require matrix inversion or machine learning to measure a transmitted scattering distribution. The MMF utilized here is 1000 mm in length with a 200â µm core and is demonstrated to recover angular scattering distributions even with bending displacements of up to 30â cm. This advance has a significant impact on the clinical translation of biomedical endoscopic diagnostic techniques that use angular scattering to determine the size of cell nuclei to detect early cancer.
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BACKGROUND: The neurotoxic potential of gadolinium (Gd)-based contrast agents (GBCAs) retention in the brains of patients with type 2 diabetes mellitus (T2DM) is unclear. PURPOSE: To determine the deposition and clearance of GBCAs in T2DM rats and the mechanism by which Gd enhances nucleotide-binding oligomerization domain-3 (NLRP3) inflammasome activation. STUDY TYPE: Cross-sectional, prospective. ANIMAL MODEL: 104 T2DM male Wistar rats. FIELD STRENGTH/SEQUENCE: 9.4-T, T1-weighted fast spin echo sequence. ASSESSMENT: T2DM (male Wistar rats, n = 52) and control group (healthy, male Wistar rats, n = 52) rats received saline, gadodiamide, Gd-diethylenetriaminepentaacetic acid, and gadoterate meglumine for four consecutive days per week for 7 weeks. The distribution and clearance of Gd in the certain brain were assessed by MRI (T1 signal intensity and relaxation rate R1, on the last day of each week), inductively coupled plasma mass-spectroscopy, ultraperformance liquid chromatography mass spectrometry, and transmission electron microscopy. Behavioral tests, histopathological features, and the effects of GBCAs on neuroinflammation were also analyzed. STATISTICAL TESTS: One-way analysis of variance, bonferroni method, and unpaired t-test. A P-value <0.05 was considered statistically significant. RESULTS: The movement distance and appearance time in the open field test of the T2DM rats in the gadodiamide group were significantly shorter than in the other groups. Furthermore, the expression of NLRP3, Pro-Caspase-1, interleukin-1ß (IL-1ß), and apoptosis-associated speck-like protein containing a CARD protein in neurons was significantly higher in the gadodiamide group than in the saline group, as shown by Western blot. Gadodiamide also induced differentiation of microglia into M1 type, decreased the neuronal mitochondrial membrane potential, and significantly increased neuronal apoptosis from flow cytometry. DATA CONCLUSION: T2DM may affect both the deposition and clearance of GBCAs in the brain. Informed by the T2DM model, gadodiamide could mediate the neuroinflammatory response by NLRP3 inflammasome activation. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY: Stage 1.
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Nutritional status is an essential factor in the occurrence of complications in patients with esophageal cancer. We sought to assess the relationship between malnutrition and complications using various nutritional assessment indicators. We conducted a comprehensive literature search of medical databases for articles published up to July 2023. The primary outcome indicator is the occurrence of complications, for which we combined 95% confidence intervals (CIs) and odds ratios (ORs) for postoperative complications and analyzed them using a random effects model. The analysis was carried out using STATA15.0 software. A total of 33 study groups from 22 publications with 5,675 subjects were included. Pooled results show that nutritional indicators are strongly correlated with the occurrence of postoperative complications (OR = 1.45, 95% CI: 1.30-1.62). In the subgroup analyses, comprehensive indicators and the skeletal muscle index were significantly associated with complications, whereas laboratory indicators were not associated with complications (comprehensive indicators OR = 2.68, 95% CI: 1.80-4.00; skeletal muscle index OR = 2.93, 95% CI: 1.44-5.99; laboratory indicators OR = 1.05, 95% CI: 0.96-1.16). Patients with normal body mass index and hospitalized patients were more likely to develop complications. Malnutrition is strongly associated with the development of complications. Nutritional indicators and patient characteristics influenced this relationship.
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Neoplasias Esofágicas , Desnutrición , Estado Nutricional , Complicaciones Posoperatorias , Humanos , Complicaciones Posoperatorias/etiología , Complicaciones Posoperatorias/epidemiología , Neoplasias Esofágicas/cirugía , Neoplasias Esofágicas/complicaciones , Desnutrición/etiología , Evaluación Nutricional , Periodo Preoperatorio , Índice de Masa CorporalRESUMEN
PURPOSE: The aim of this study was to explore the benefit the metastasectomy for patients with metastatic non-clear cell carcinoma (non-ccRCC). METHODS: This study enrolled 120 patients with confirmed metastatic non-ccRCC from the RCC database of our center from 2008 to 2021. Patients without metastasectomy were grouped as radical nephrectomy without metastasectomy patients. The clinical outcomes included overall survival (OS) and progression-free survival (PFS). Cox regression and Kaplan-Meier analyses were used to assess potential factors that predict clinical benefits from metastasectomy. RESULTS: A total of 100 patients received radical nephrectomy alone, while the remaining 20 patients underwent both radical nephrectomy and metastasectomy. There was no significant difference in age between the two groups. Out of 100 patients who underwent radical nephrectomy, 60 were male, and out of 20 patients who had both radical nephrectomy and metastasectomy, 12 were male. Patients who underwent systemic therapy plus radical nephrectomy and metastasectomy had significantly better PFS (27.1 vs. 14.0, p = 0.032) and OS (67.3 vs. 24.0, p = 0.043) than those who underwent systemic therapy plus radical nephrectomy alone. Furthermore, for patients without liver metastasis (n = 54), systemic therapy plus radical nephrectomy and metastasectomy improved both PFS (p = 0.028) and OS (p = 0.043). Similarly, for patients with metachronous metastasis, systemic therapy plus radical nephrectomy and metastasectomy improved both PFS (p = 0.043) and OS (p = 0.032). None of the patients experienced serious perioperative complications (Clavien-Dindo Classification ≥ III grade). CONCLUSION: Metastasectomy in patients with metastatic non-ccRCC may provide clinical benefits in terms of improved PFS and OS, especially in patients without liver metastasis and those with metachronous metastasis.
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Carcinoma de Células Renales , Neoplasias Renales , Metastasectomía , Nefrectomía , Humanos , Masculino , Neoplasias Renales/patología , Neoplasias Renales/cirugía , Neoplasias Renales/mortalidad , Femenino , Estudios Retrospectivos , Persona de Mediana Edad , Nefrectomía/métodos , Tasa de Supervivencia , Carcinoma de Células Renales/secundario , Carcinoma de Células Renales/cirugía , Carcinoma de Células Renales/mortalidad , Anciano , Estudios de Cohortes , AdultoRESUMEN
Mixed lineage kinase domain-like protein (MLKL) is the terminal effector of necroptosis, a form of regulated necrosis. Optimal activation of necroptosis, which eliminates infected cells, is critical for antiviral host defense. MicroRNAs (miRNAs) regulate the expression of genes involved in various biological and pathological processes. However, the roles of miRNAs in necroptosis-associated host defense remain largely unknown. We screened a library of miRNAs and identified miR-324-5p as the most effective suppressor of necroptosis. MiR-324-5p downregulates human MLKL expression by specifically targeting the 3'UTR in a seed region-independent manner. In response to interferons (IFNs), miR-324-5p is downregulated via the JAK/STAT signaling pathway, which removes the posttranscriptional suppression of MLKL mRNA and facilitates the activation of necroptosis. In influenza A virus (IAV)-infected human primary macrophages, IFNs are induced, leading to the downregulation of miR-324-5p. MiR-324-5p overexpression attenuates IAV-associated necroptosis and enhances viral replication, whereas deletion of miR-324-5p potentiates necroptosis and suppresses viral replication. Hence, miR-324-5p negatively regulates necroptosis by manipulating MLKL expression, and its downregulation by IFNs orchestrates optimal activation of necroptosis in host antiviral defense.
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Virus de la Influenza A , MicroARNs , Antivirales , Humanos , Interferones , MicroARNs/genética , MicroARNs/metabolismo , Necroptosis , Replicación Viral/fisiologíaRESUMEN
Mercury, a neurotoxic substance, circulates globally, significantly stored in soils through atmospheric deposition and plant decay. Despite being deposited, mercury can be remobilized and released into the atmosphere and water, enhancing its global cycle. Recent research suggests that climate warming may amplify the remobilization of soil mercury, facilitating its incorporation into food webs that humans exploit. However, the potential geospatial feedback of soil mercury levels in response to warming remains unclear. By leveraging up-to-date soil measurements and observation-driven models, we determined the amount of mercury stored in global 0-100 cm soils to be 4.3 Tg (interquartile range: 2.5-6.3 Tg). Furthermore, our analysis indicates that warming likely aggravates global soil mercury levels, particularly in many temperate areas in East Asia, North Europe, and North America (>20 ng g-1 increase by 2100) due to warming-induced vegetation greening. Critically, observation-driven models raise the possibility that implementing ambitious mercury-emission-control schemes alone may be insufficient to counterbalance the positive feedback of soil mercury concentration, while process-based biogeochemical modeling demonstrates consistent patterns that reinforce this concern. These findings hold broad implications; for example, such feedback may catalyze mercury remobilization in land-ocean continuums and exacerbate human risks, stressing the necessity for continued reductions in greenhouse gas and mercury emissions.
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Podocyte lipotoxicity mediated by impaired cellular cholesterol efflux plays a crucial role in the development of diabetic kidney disease (DKD), and the identification of potential therapeutic targets that regulate podocyte cholesterol homeostasis has clinical significance. Coiled-coil domain containing 92 (CCDC92) is a novel molecule related to metabolic disorders and insulin resistance. However, whether the expression level of CCDC92 is changed in kidney parenchymal cells and the role of CCDC92 in podocytes remain unclear. In this study, we found that Ccdc92 was significantly induced in glomeruli from type 2 diabetic mice, especially in podocytes. Importantly, upregulation of Ccdc92 in glomeruli was positively correlated with an increased urine albumin-to-creatinine ratio (UACR) and podocyte loss. Functionally, podocyte-specific deletion of Ccdc92 attenuated proteinuria, glomerular expansion and podocyte injury in mice with DKD. We further demonstrated that Ccdc92 contributed to lipid accumulation by inhibiting cholesterol efflux, finally promoting podocyte injury. Mechanistically, Ccdc92 promoted the degradation of ABCA1 by regulating PA28α-mediated proteasome activity and then reduced cholesterol efflux. Thus, our studies indicate that Ccdc92 contributes to podocyte injury by regulating the PA28α/ABCA1/cholesterol efflux axis in DKD.
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Transportador 1 de Casete de Unión a ATP , Colesterol , Diabetes Mellitus Tipo 2 , Nefropatías Diabéticas , Ratones Endogámicos C57BL , Podocitos , Animales , Podocitos/metabolismo , Podocitos/patología , Colesterol/metabolismo , Transportador 1 de Casete de Unión a ATP/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Nefropatías Diabéticas/metabolismo , Nefropatías Diabéticas/patología , Ratones , Masculino , Diabetes Mellitus Experimental/metabolismo , Ratones Noqueados , Humanos , Complejo de la Endopetidasa Proteasomal/metabolismoRESUMEN
Extrachromosomal circular DNAs (eccDNAs) carrying random genomic segments are broadly found across different cancer types, but their molecular functions and impact in gastric cancer (GC) are rarely known. In this study, we aimed to investigate the potential role of eccDNA in GC. Using the Circle-seq strategy, we observed the eccDNA abundance in gastric cancer tissues (GCT) was aberrantly higher than that of normal adjacent tissues (NAT). The high abundance of eccDNAs carrying oncogene-segments in GCT may represent the DNA damage products of amplified oncogenes. Analysis of GCT over-represented eccDNA carrying enhancer (eccEnhancer) based on data from FANTOM5 project combined with TCGA database suggested the GC over-represented eccEnhancers may contribute to development of GC. GC over-represented eccDNAs carrying pre-miRNA (eccMIR) were enriched to multiple cancer-relevant signal pathways by KEGG analysis. We then synthesized the top six GC over-represented eccMIRs and found four of them enabled high expression of miRNAs and down-regulation of miRNA-target genes in MGC803 cells. Furthermore, we observed the inheritance of GC over-represented eccMIRs benefited host cell proliferation and promoted the aggressive features of host cells. Altogether, this study revealed the GC over-represented eccDNAs carrying functional genomic segments were related to the carcinogenesis of GC and presented the capability to facilitate cancer progression, suggesting the cancerous eccDNAs may serve as a dynamic reservoir for genome plasticity and rapid adaptive evolution of cancer. Therefore, blocking the pathways for eccDNAs generation may provide a novel therapeutic strategy for the treatment of gastric cancer.
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Neoplasias Gástricas , Humanos , Neoplasias Gástricas/genética , ADN Circular/genética , Genoma , ADN , Carcinogénesis/genéticaRESUMEN
OBJECTIVE: To investigate the effectiveness of Baduanjin exercise on executive function in community-dwelling older adults with cognitive frailty. DESIGN: Randomized controlled trial. SETTING: Community residential centers. SUBJECTS: 120 eligible older adults. INTERVENTIONS: Baduanjin training group received supervised Baduanjin training, 60â min sessions three times per week for 24 weeks. The control group did not receive any exercise intervention. MAIN MEASURES: Primary outcome was executive function, assessed using Clock Drawing Test. Secondary outcomes included the subcomponents of executive function (working memory, inhibitory control and cognitive flexibility), attention and cognitive frailty (global cognitive function, physical frailty) assessed using Verbal Fluency Test, Trail Making Test-A/B, Stroop Test, Montreal Cognitive Assessment and Edmonton Frailty Scale, respectively, at baseline and 24 weeks after intervention. RESULTS: After the 24-week intervention, the scores of Clock Drawing Test and Verbal Fluency Test, the Trail Making Test-B time and the Card correct numbers of Stroop Test in Baduanjin training group showed significant improvement compared with control group (all P < 0.05) with small to moderate effect sizes and the significant interaction effect of group by time in the Clock Drawing Test and Trail Making Test-B test (P = 0.003 and P = 0.043); cognitive frailty variables, including Montreal Cognitive Assessment and Edmonton Frail Scale scores, also showed significant improvement (P = 0.002 and P = 0.004) with a moderate effect sizes and a significant interaction effect (P < 0.001, P = 0.013). No adverse events were reported. CONCLUSION: Regular Baduanjin training may be an effective and safe intervention to improve cognitive frailty and executive function in community-dwelling older adults with cognitive frailty. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR2100050857. Data of registration: 8/5/2020, https://www.chictr.org.cn/showproj.html?proj = 133037.
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Función Ejecutiva , Fragilidad , Humanos , Anciano , Terapia por Ejercicio , Ejercicio Físico , CogniciónRESUMEN
BACKGROUND: Peracetic acid and irradiation are common sterilization methods for allograft tendons; however, under some conditions, both methods adversely affect the fiber arrangement and ultimate load of the tendon. An in vitro study showed that low-dose peracetic acid combined with irradiation may be less detrimental to allograft tendon structure and properties, possibly because the breakdown of peracetic acid can lead to an enlargement of the interstitial spaces and an increase in porosity. QUESTIONS/PURPOSES: Using a rabbit Achilles tendon model, we asked: What is the effect of peracetic acid-ethanol combined irradiation on (1) the histopathology and fiber diameter of the allograft tendon, (2) tensile creep and load-to-failure biomechanical properties of allograft tendons, and (3) healing of the treated tendon in vivo compared with fresh-frozen allograft and peracetic acid-ethanol sterilization at 4 and 8 weeks? METHODS: The Achilles tendons used in this study were sourced from euthanized 10-week-old male New Zealand White rabbits previously used for ophthalmic experiments. All allografts were divided into three groups: fresh-frozen group (control group, n = 20), peracetic acid-ethanol sterilization group (n =20), and peracetic acid-ethanol combined irradiation group (n = 20). The sterilization protocols were performed per a predetermined plan. In the peracetic acid-ethanol sterilization group, the tendon tissues were covered with the peracetic acid-ethanol sterilization solution (1% peracetic acid for 30 minutes). In the peracetic acid-ethanol combined irradiation group, the tendon tissues were covered with the peracetic acid-ethanol sterilization solution (0.2% peracetic acid for 30 minutes) and were subjected to 15 kGy gamma irradiation. Thirty 10-week-old male New Zealand White rabbits received bilateral Achilles tendon allografts surgically. Tendon samples from each group were harvested at 4 weeks (n = 30) and 8 weeks (n = 30) postoperatively. For each timepoint, eight tissues were used for histologic staining and electron microscopy, 15 tissues were used for biomechanical testing, and seven tissues were used for hydroxyproline assay and quantitative polymerase chain reaction. Histopathology was determined qualitatively by hematoxylin and eosin and Masson staining, while fiber diameter was measured quantitatively by transmission electron microscopy. Biomechanical properties were measured using cyclic loading tests and load-to-failure tests. The healing outcome was quantitatively judged through healing-related genes and proteins. RESULTS: At 4 weeks and 8 weeks postoperatively, the peracetic acid-ethanol combined irradiation group visually demonstrated the best continuity and minimal peripheral adhesions. Histologic staining showed that tendon fibers in the peracetic acid-ethanol combined irradiation group maintained consistent alignment without notable disruptions or discontinuities, and there was a qualitatively observed increase in the number of infiltrating cells compared with the control group at the 4-week timepoint (444 ± 49 /mm 2 versus 256 ± 43 /mm 2 , mean difference 188 /mm 2 [95% confidence interval 96 to 281]; p < 0.001). At 8 weeks postoperatively, the tendon fiber diameter in the peracetic acid-ethanol combined irradiation groups was similar to that of the control group (0.23 ± 0.04 µm versus 0.21 ± 0.03 µm, mean difference 0.02 µm [95% CI -0.04 to 0.08]; p = 0.56). At 8 weeks postoperatively, the peracetic acid-ethanol combined irradiation group exhibited better properties in terms of both ultimate load (129 ± 15 N versus 89 ± 20 N, mean difference 40 N [95% CI 7 to 73]; p = 0.02) and energy absorption density (17 ± 6 kJ/m 2 versus 8 ± 4 kJ/m 2 , mean difference 8 kJ/m 2 [95% CI 0.7 to 16]; p = 0.004) compared with the control group. Gene expression analysis revealed higher expression levels of COL1A1 (2.1 ± 0.8 versus 1.0 ± 0, mean difference 1.1 [95% CI 0.1 to 2.1]; p = 0.003) and MMP13 (2.0 ± 0.8 versus 1.0 ± 0, mean difference 1.0 [95% CI 0.4 to 1.6]; p = 0.03) in the peracetic acid-ethanol combined irradiation group than in the control group. There was a higher amount of collagen Type I in tendons treated with peracetic acid-ethanol combined irradiation than in the control group (0.36 ± 0.03 versus 0.31 ± 0.04, mean difference 0.05 [95% CI 0.01 to 0.09]; p = 0.02). CONCLUSION: Treatment with peracetic acid-ethanol combined irradiation did not have any discernible adverse effect on the histology, fiber diameter, enzymatic resistance, collagen content, or biomechanical strength of the allograft tendons compared with the control group. Peracetic acid-ethanol combined irradiation treatment had a positive impact on remodeling of the extracellular matrix and realignment of collagen fibers. CLINICAL RELEVANCE: This sterilization method could be helpful to expand the scope and frequency with which allogeneic materials are applied. The long-term healing effect and strength of allograft tendons must be tested before clinical use, and it is necessary to conduct comparative studies on autografts and synthetic materials that are currently widely used clinically.
Asunto(s)
Tendón Calcáneo , Aloinjertos , Etanol , Ácido Peracético , Esterilización , Cicatrización de Heridas , Animales , Conejos , Masculino , Cicatrización de Heridas/efectos de la radiación , Cicatrización de Heridas/efectos de los fármacos , Ácido Peracético/farmacología , Etanol/farmacología , Esterilización/métodos , Tendón Calcáneo/cirugía , Tendón Calcáneo/efectos de la radiación , Tendón Calcáneo/patología , Resistencia a la Tracción , Fenómenos Biomecánicos , Factores de Tiempo , Traumatismos de los Tendones/cirugíaRESUMEN
The purpose of this paper was to construct a prognostic model, miRNA-mRNA regulatory network and protein-protein interaction (PPI) network for lung squamous cell carcinoma (LUSC) used data from the cancer genome atlas (TCGA) database. In this study, we first downloaded and sorted out the expression matrix containing 19962 mRNA transcripts (including 502 LUSC and 51 normal control (NC) samples) and the expression matrix containing 2205 miRNA transcripts (including 478 LUSC and 45 NC samples) from the TCGA database. We obtained 389 differentially expressed miRNAs (DE-miRNAs), of which 305 were upregulated and 84 down-regulated DE-miRNAs. Next, a total of 7 prognosis-related DE-miRNAs (PDE-miRNAs) were identified by Cox regression analysis, and the prognosis model consisting of three PDE-miRNAs (hsa-miR-4746-5p, hsa-miR-556-3p and hsa-miR-489-3p) was optimized. Then, we drew the survival curves and found that the survival rates of the three PDE-miRNA high and low expression groups and the survival rates of the high-risk and low-risk patients in the prognosis model had significant statistical differences. In addition, the receiver operating characteristics (ROC) curve analysis and independent prognostic analysis confirmed that the prognostic model we built has a relatively accurate ability to predict the grouping and prognosis of LUSC patients. Finally, Cox regression analysis were used to construct the miRNA-mRNA regulatory network, which showed the regulatory relationship between PDE-miRNAs and targeted mRNAs. Moreover, we constructed the PPI network composed of 145 targeted mRNAs and the subnetwork composed of 10 hub-targeted mRNAs (FCGR3A, IL13, CCR2, PPARGC1A, FCGR3B, ACSL1, PLXNA4, LPL, KAT2B and AOC3), which showed the interaction between targeted mRNAs. The above results indicated that the prognosis model we built can predict LUSC patients relatively accurately. The miRNA-mRNA regulatory network and the PPI network of targeted mRNAs illustrated the regulatory mechanisms and interactions between RNAs, which were of certain reference significance for us to further understand the molecular pathogenesis of LUSC and for clinical early diagnosis and treatment.