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Xp11.2 translocation renal cell carcinomas (tRCC) are a rare and highly malignant type of renal cancer, lacking efficient diagnostic indicators and therapeutic targets. Through the analysis of public databases and our cohort, we identified NMRK2 as a potential diagnostic marker for distinguishing Xp11.2 tRCC from kidney renal clear cell carcinoma (KIRC) and kidney renal papillary cell carcinoma (KIRP) due to its specific upregulation in Xp11.2 tRCC tissues. Mechanistically, we discovered that TFE3 fusion protein binds to the promoter of the NMRK2 gene, leading to its upregulation. Importantly, we established RNA- and protein-based diagnostic methods for identifying Xp11.2 tRCC based on NMRK2 expression levels, and the diagnostic performance of our methods was comparable to a dual-color break-apart fluorescence in situ hybridization assay. Moreover, we successfully identified fresh Xp11.2 tRCC tissues after surgical excision using our diagnostic methods and established an immortalized Xp11.2 tRCC cell line for further research purposes. Functional studies revealed that NMRK2 promotes the progression of Xp11.2 tRCC by upregulating the NAD+/NADH ratio, and supplementation with ß-nicotinamide mononucleotide (NMN) or nicotinamide riboside chloride (NR), effectively rescued the phenotypes induced by the knockdown of NMRK2 in Xp11.2 tRCC. Taken together, these data introduce a new diagnostic indicator capable of accurately distinguishing Xp11.2 tRCC and highlight the possibility of developing novel targeted therapeutics. © 2024 The Pathological Society of Great Britain and Ireland.
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Serine metabolic reprogramming is known to be associated with oncogenesis and tumor development. The key metabolic enzyme PSAT1 has been identified as a potential prognostic marker for various cancers, but its role in ccRCC remains unkown. In this study, we investigated expression of PSAT1 in ccRCC using the TCGA database and clinical specimens. Our results showed that PSAT1 exhibited lower expression in tumor tissue compared to adjacent normal tissue, but its expression level increased with advancing stages and grades of ccRCC. Patients with elevated expression level of PSAT1 exhibited an unfavorable prognosis. Functional experiments have substantiated that the depletion of PSAT1 shows an effective activity in inhibiting the proliferation, migration and invasion of ccRCC cells, concurrently promoting apoptosis. RNA sequencing analysis has revealed that the attenuation of PSAT1 can diminish tumor resistance to therapeutic drugs. Furthermore, the xenograft model has indicated that the inhibition of PSAT1 can obviously impact the tumorigenic potential of ccRCC and mitigate lung metastasis. Notably, pharmacological targeting PSAT1 by Aminooxyacetic Acid (AOA) or knockdown of PSAT1 increased the susceptibility of sunitinib-resistant cells. Inhibition of PSAT1 increased the sensitivity of drug-resistant tumors to sunitinib in vivo. Collectively, our investigation identifies PSAT1 as an independent prognostic biomarker for advanced ccRCC patients and as a prospective therapeutic target.
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Carcinoma de Células Renales , Neoplasias Renales , Humanos , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/metabolismo , Línea Celular Tumoral , Proliferación Celular/genética , Resistencia a Medicamentos , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/genética , Neoplasias Renales/metabolismo , Sunitinib , Regulación hacia Arriba/genéticaRESUMEN
Obstructive nephropathy is one of the leading causes of kidney injury and renal fibrosis in pediatric patients. Although considerable advances have been made in understanding the pathophysiology of obstructive nephropathy, most of them were based on animal experiments and a comprehensive understanding of obstructive nephropathy in pediatric patients at the molecular level remains limited. Here, we performed a comparative proteomics analysis of obstructed kidneys from pediatric patients with ureteropelvic junction obstruction and healthy kidney tissues. Intriguingly, the proteomics revealed extensive metabolic reprogramming in kidneys from individuals with ureteropelvic junction obstruction. Moreover, we uncovered the dysregulation of NAD+ metabolism and NAD+-related metabolic pathways, including mitochondrial dysfunction, the Krebs cycle, and tryptophan metabolism, which led to decreased NAD+ levels in obstructed kidneys. Importantly, the major NADase CD38 was strongly induced in human and experimental obstructive nephropathy. Genetic deletion or pharmacological inhibition of CD38 as well as NAD+ supplementation significantly recovered NAD+ levels in obstructed kidneys and reduced obstruction-induced renal fibrosis, partially through the mechanisms of blunting the recruitment of immune cells and NF-κB signaling. Thus, our work not only provides an enriched resource for future investigations of obstructive nephropathy but also establishes CD38-mediated NAD+ decline as a potential therapeutic target for obstruction-induced renal fibrosis.
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NAD , Obstrucción Ureteral , Animales , Niño , Humanos , Fibrosis , Riñón/metabolismo , NAD/metabolismo , Proteómica , Obstrucción Ureteral/complicaciones , Obstrucción Ureteral/tratamiento farmacológico , Obstrucción Ureteral/metabolismoRESUMEN
Analysis of T-cell receptor (TCR) repertoires in different stages of hepatocellular carcinoma (HCC) might help to elucidate its pathogenesis and progression. This study aimed to investigate TCR profiles in liver biopsies and peripheral blood mononuclear cells (PBMCs) in different Barcelona Clinic liver cancer (BCLC) stages of HCC. Ten patients in early stage (BCLC_A), 10 patients in middle stage (BCLC_B), and 10 patients in late stage (BCLC_C) cancer were prospectively enrolled. The liver tumor tissues, adjacent tissues, and PBMCs of each patient were collected and examined by TCR ß sequencing. Based on the ImMunoGeneTics (IMGT) database, we aligned the V, D, J, and C gene segments and identified the frequency of CDR3 sequences and amino acids sequence. Diversity of TCR in PBMCs was higher than in both tumor tissues and adjacent tissues, regardless of BCLC stage and postoperative recurrence. TCR clonality was increased in T cells from peripheral blood in advanced HCC, compared with the early and middle stages. No statistical differences were observed between different BCLC stages, either in tumors or adjacent tissues. TCR clonality revealed no significant difference between recurrent tumor and non-recurrent tumor, therefore PBMCs was better to be representative of TCR characteristics in different stages of HCC compared to tumor tissues. Clonal expansion of T cells was associated with low risk of recurrence in HCC patients.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/patología , Leucocitos Mononucleares/patología , Resultado del Tratamiento , Estadificación de Neoplasias , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/patología , Receptores de Antígenos de Linfocitos T/genética , Estudios RetrospectivosRESUMEN
BACKGROUND: Inflammation is considered to be one of the driving factors of cancer, and chronic inflammation plays a crucial role in tumor growth and metastasis. The aim of this study was to examine the predictive value of preoperative inflammatory biomarkers for overall survival (OS) in patients with metastatic renal cell carcinoma (mRCC), including preoperative neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), and aspartate aminotransferase-to-lymphocyte ratio (ALR), a novel inflammatory biomarker. METHOD: This study included 198 patients with mRCC from a single center from 2006 to 2022. The optimal cut-off levels for the three biomarkers were derived using the receiver operating characteristic curve (ROC). Cox univariate and multivariate analyses were used to assess independent prognostic inflammatory biomarkers. Finally, independent prognostic inflammatory biomarkers were incorporated into the prognostic model to establish a nomogram to predict the postoperative survival of patients with mRCC. RESULT: The area under the ROC curve for NLR, LMR, and ALR, respectively, is 0.71 (CI: 0.635-0.784), 0.68 (CI: 0.604-0.755), and 0.75 (CI: 0.680-0.819). The optimal LMR, NLR, and ALR cut-off levels as evaluated by the ROC curve were 3.836, 3.106, and 68.056, respectively. Patients with NLR and ALR higher than the cut-off level and LMR lower than the cut-off level had a significant relationship with OS. Multivariate analysis revealed that tumor necrosis, lower LMR, and higher ALR were independent risk factors for OS. In addition, a nomogram that includes independent prognostic inflammatory biomarkers can accurately predict the OS in patients with mRCC. CONCLUSION: ALR and LMR are independent risk factors for the prognosis of individuals with mRCC. By monitoring ALR and LMR postoperatively, the prognosis of patients with mRCC can be better evaluated.
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Carcinoma de Células Renales , Neoplasias Renales , Humanos , Carcinoma de Células Renales/cirugía , Pronóstico , Neoplasias Renales/cirugía , Nomogramas , InflamaciónRESUMEN
Clear cell renal cell carcinoma (ccRCC) is one of the most common malignant tumors and is characterized by a poor prognosis. Although G2- and S -phase expressed-1 (GTSE1) is known to be involved in the progression and metastasis of various cancers, its significance and mechanism in ccRCC remain unknown. In the present study, we found that GTSE1 was overexpressed in ccRCC tissues, especially in metastatic samples. Moreover, high GTSE1 expression was positively correlated with higher pT stage, tumor size, clinical stage, and WHO/ISUP grade and worse prognosis. And GTSE1 expression served as an independent prognostic factor for overall survival (OS). In addition, GTSE1 knockdown inhibited ccRCC cell proliferation, migration, and invasion, and enhanced cell apoptosis in vitro and in vivo. GTSE1 was crucial for epithelial-mesenchymal transition (EMT) in ccRCC. Mechanistically, GTSE1 depletion could upregulate the expression of Krüppel-like factor 4 (KLF4), which acts as a tumor suppressor in ccRCC. Downregulation of KLF4 effectively rescued the inhibitory effect induced by GTSE1 knockdown and reversed the EMT process. Overall, our results revealed that GTSE1 served as an oncogene regulating EMT through KLF4 in ccRCC, and that GTSE1 could also serve as a novel prognostic biomarker and may represent a promising therapeutic target for ccRCC.
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Carcinoma de Células Renales , Neoplasias Renales , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Regulación Neoplásica de la Expresión Génica , Humanos , Factor 4 Similar a Kruppel , Proteínas Asociadas a Microtúbulos , Procesos Neoplásicos , PronósticoRESUMEN
Previous studies have suggested the role of CD4+Foxp3+ regulatory T cells (Tregs) in protection against kidney ischemia reperfusion injury via their immunosuppressive properties. Unfortunately, the associated mechanisms of Tregs in kidney ischemia reperfusion injury have not been fully elucidated. Semaphorin 4A (Sema4A) is essential for maintaining the immunosuppressive capacity of Tregs in tumors. However, whether Sema4A can alleviate kidney ischemia reperfusion injury through Tregs has not yet been demonstrated. Here, we investigated the effect and mechanism of Sema4A on the development of kidney ischemia reperfusion injury. Administration of recombinant human Sema4A-Fc chimera protein prior to ischemia reperfusion injury promoted the expansion and function of Tregs and decreased the accumulation of neutrophils and proinflammatory macrophages thereby attenuating functional and histological injury of the injured kidneys. Depletion of Tregs abrogated the protective effect of Sema4A on kidney ischemia reperfusion injury, suggesting Tregs as the main target cell type for Sema4A in the development of this injury. Mechanistically, Sema4A bound to neuropilin 1 (Nrp1), a cell surface receptor for Sema4A and other ligands and a key regulator of Tregs, which then promoted recruitment of phosphatase and tensin homologue and suppressed the Akt-mTOR pathway in Foxp3Cre mice but not in Nrp1f/fFoxp3Cre mice. Consistently, Treg-specific deletion of Nrp1 blocked the effect of Sema4A on the expansion and function of Treg cells. Thus, our results demonstrate that the Sema4A-Nrp1 axis alleviates the development of ischemia reperfusion injury by promoting the stability and function of Tregs in mouse kidneys.
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Daño por Reperfusión , Semaforinas , Animales , Riñón , Ratones , Ratones Endogámicos C57BL , Neuropilina-1/genética , Daño por Reperfusión/prevención & control , Semaforinas/genética , Linfocitos T ReguladoresRESUMEN
Mitochondrial fusion is linked to heart and liver ischemia-reperfusion (IR) insult. Unfortunately, there is no report to elucidate the detailed influence of mitochondrial fusion in renal IR injury. This study principally investigated the mechanism by which mitochondrial fusion protected kidney against IR injury. Our results indicated that sirtuin 3 (Sirt3) was inhibited after renal IR injury in vivo and in vitro. Overexpression of Sirt3 improved kidney function, modulated oxidative injury, repressed inflammatory damage, and reduced tubular epithelial cell apoptosis. The molecular investigation found that Sirt3 overexpression attenuated IR-induced mitochondrial damage in renal tubular epithelial cells, as evidenced by decreased reactive oxygen species production, increased antioxidants sustained mitochondrial membrane potential, and inactivated mitochondria-initiated death signaling. In addition, our information also illuminated that Sirt3 maintained mitochondrial homeostasis against IR injury by enhancing optic atrophy 1 (OPA1)-triggered fusion of mitochondrion. Inhibition of OPA1-induced fusion repressed Sirt3 overexpression-induced kidney protection, leading to mitochondrial dysfunction. Further, our study illustrated that OPA1-induced fusion could be affected through ERK; inhibition of ERK abolished the regulatory impacts of Sirt3 on OPA1 expression and mitochondrial fusion, leading to mitochondrial damage and tubular epithelial cell apoptosis. Altogether, our results suggest that renal IR injury is closely associated with Sirt3 downregulation and mitochondrial fusion inhibition. Regaining Sirt3 and/or activating mitochondrial fission by modifying the ERK-OPA1 cascade may represent new therapeutic modalities for renal IR injury.
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Lesión Renal Aguda/enzimología , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , GTP Fosfohidrolasas/metabolismo , Riñón/enzimología , Mitocondrias/enzimología , Dinámicas Mitocondriales , Daño por Reperfusión/enzimología , Sirtuina 3/metabolismo , Lesión Renal Aguda/genética , Lesión Renal Aguda/patología , Animales , Apoptosis , Modelos Animales de Enfermedad , Activación Enzimática , Riñón/patología , Células LLC-PK1 , Ratones Transgénicos , Mitocondrias/patología , Estrés Oxidativo , Daño por Reperfusión/genética , Daño por Reperfusión/patología , Transducción de Señal , Sirtuina 3/genética , PorcinosRESUMEN
New dicinnamoyl (caffeoyl, feruloyl, ortho and para-coumaroyl) 4-deoxyquinic acid and esters were synthesized by using a new 4-deoxy quinic acid triol intermediate. The optimisation of both coupling and deprotection steps allowed the preparation in good yields of the target products either as the carboxylic acid or the methyl ester form. Eight new compounds were evaluated for their ability to influence the feeding behaviour of the pea aphid Acyrthosiphon pisum. Artificial diet bioassays showed that two compounds are toxic (mortality and growth inhibition) at lower concentrations than the reference 3,5-dicaffeoyl quinic acid.
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Áfidos/efectos de los fármacos , Cinamatos/síntesis química , Cinamatos/toxicidad , Ésteres/química , Ésteres/toxicidad , Insecticidas/síntesis química , Insecticidas/toxicidad , Ácido Quínico/análogos & derivados , Ácido Quínico/síntesis química , Ácido Quínico/toxicidad , Animales , Áfidos/crecimiento & desarrollo , Cinamatos/química , Relación Dosis-Respuesta a Droga , Ésteres/síntesis química , Conducta Alimentaria/efectos de los fármacos , Insecticidas/química , Estructura Molecular , Ácido Quínico/químicaRESUMEN
To promote sustainable intensification and provide guidance for decisionmakers, we must understand the potential for mitigating greenhouse gas emissions in greenhouse cultivation. Therefore, this study aimed to evaluate the greenhouse gas emission mitigation potential of agricultural plastic greenhouses in China using a combination of life cycle assessment, data envelopment analysis, and scenario analysis. We found that: (1) In China, the mean mitigation potential for greenhouse gas emission intensity related to the crop production inputs of agricultural plastic greenhouses is 1.67 kt CO2-eq/km2, demonstrating a remarkable mitigation rate of 47 %. This mitigation potential, driven mostly by fertilizer use, exhibited a spatial pattern characterized by high mitigation rates in the southern regions compared to those in the northern regions; (2) in scenarios S1 and S2, the greenhouse gas emission intensity mitigation potential of greenhouse construction materials was 0.645 kt CO2-eq/km2 and 0.968 kt CO2-eq/km2, respectively, with steel being the primary contributor to mitigation; (3) under scenarios S1 and S2, the greenhouse gas emission mitigation rates for China's agricultural plastic greenhouses were 42 % and 48 %, respectively. This study highlights the greenhouse gas emission mitigation potential of China's agricultural plastic greenhouses. To ensure sustainability in plastic greenhouses, emphasis should be placed on optimizing fertilizers and extending the lifespan of construction materials.
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Parkinson's disease (PD), ranking as the second most prevalent neurodegenerative disorder globally, presents a pressing need for innovative animal models to deepen our understanding of its pathophysiology and explore potential therapeutic interventions. The development of such animal models plays a pivotal role in unraveling the complexities of PD and investigating promising treatment avenues. In this study, we employed transcriptome sequencing on BmN cells treated with 1 µg/ml rotenone, aiming to elucidate the underlying toxicological mechanisms. The investigation brought to light a significant reduction in mitochondrial membrane potential induced by rotenone, subsequently triggering mitophagy. Notably, the PTEN induced putative kinase 1 (PINK1)/Parkin pathway emerged as a key player in the cascade leading to rotenone-induced mitophagy. Furthermore, our exploration extended to silkworms exposed to 50 µg/ml rotenone, revealing distinctive motor dysfunction as well as inhibition of Tyrosine hydroxylase (TH) gene expression. These observed effects not only contribute valuable insights into the impact and intricate mechanisms of rotenone exposure on mitophagy but also provide robust scientific evidence supporting the utilization of rotenone in establishing a PD model in the silkworm. This comprehensive investigation not only enriches our understanding of the toxicological pathways triggered by rotenone but also highlights the potential of silkworms as a valuable model organism for PD research.
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BACKGROUND: Accurate prognostication of oncological outcomes is crucial for the optimal management of patients with renal cell carcinoma (RCC) after surgery. Previous prediction models were developed mainly based on retrospective data in the Western populations, and their predicting accuracy remains limited in contemporary, prospective validation. We aimed to develop contemporary RCC prognostic models for recurrence and overall survival (OS) using prospective population-based patient cohorts and compare their performance with existing, mostly utilized ones. METHODS: In this prospective analysis and external validation study, the development set included 11 128 consecutive patients with non-metastatic RCC treated at a tertiary urology center in China between 2006 and 2022, and the validation set included 853 patients treated at 13 medical centers in the USA between 1996 and 2013. The primary outcome was progression-free survival (PFS), and the secondary outcome was OS. Multivariable Cox regression was used for variable selection and model development. Model performance was assessed by discrimination [Harrell's C-index and time-dependent areas under the curve (AUC)] and calibration (calibration plots). Models were validated internally by bootstrapping and externally by examining their performance in the validation set. The predictive accuracy of the models was compared with validated models commonly used in clinical trial designs and with recently developed models without extensive validation. RESULTS: Of the 11 128 patients included in the development set, 633 PFS and 588 OS events occurred over a median follow-up of 4.3 years [interquartile range (IQR) 1.7-7.8]. Six common clinicopathologic variables (tumor necrosis, size, grade, thrombus, nodal involvement, and perinephric or renal sinus fat invasion) were included in each model. The models demonstrated similar C-indices in the development set (0.790 [95% CI 0.773-0.806] for PFS and 0.793 [95% CI 0.773-0.811] for OS) and in the external validation set (0.773 [0.731-0.816] and 0.723 [0.731-0.816]). A relatively stable predictive ability of the models was observed in the development set (PFS: time-dependent AUC 0.832 at 1 year to 0.760 at 9 years; OS: 0.828 at 1 year to 0.794 at 9 years). The models were well calibrated and their predictions correlated with the observed outcome at 3, 5, and 7 years in both development and validation sets. In comparison to existing prognostic models, the present models showed superior performance, as indicated by C-indices ranging from 0.722 to 0.755 (all P <0.0001) for PFS and from 0.680 to 0.744 (all P <0.0001) for OS. The predictive accuracy of the current models was robust in patients with clear-cell and non-clear-cell RCC. CONCLUSIONS: Based on a prospective population-based patient cohort, the newly developed prognostic models were externally validated and outperformed the currently available models for predicting recurrence and survival in patients with non-metastatic RCC after surgery. The current models have the potential to aid in clinical trial design and facilitate clinical decision-making for both clear-cell and non-clear-cell RCC patients at varying risk of recurrence and survival.
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Carcinoma de Células Renales , Neoplasias Renales , Humanos , Carcinoma de Células Renales/patología , Neoplasias Renales/patología , Estudios Retrospectivos , Pronóstico , NefrectomíaRESUMEN
Terraces on the Loess Plateau play essential roles in soil conservation, as well as agricultural productivity in this region. However, due to the unavailability of high-resolution (<10 m) maps of terrace distribution for this area, current research on these terraces is limited to specific regions. We developed a deep learning-based terrace extraction model (DLTEM) using texture features of the terraces, which have not previously been applied regionally. The model utilizes the UNet++ deep learning network as its framework, with high-resolution satellite images, a digital elevation model, and GlobeLand30 as the interpreted data and topography and vegetation correction data sources, respectively, and incorporates manual correction to produce a 1.89 m spatial resolution terrace distribution map for the Loess Plateau (TDMLP). The accuracy of the TDMLP was evaluated using 11,420 test samples and 815 field validation points, yielding classification results of 98.39% and 96.93%, respectively. The TDMLP provides an important basis for further research on the economic and ecological value of terraces, facilitating the sustainable development of the Loess Plateau.
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OBJECTIVE: Exercise helps enhance cognitive function in Alzheimer's patients, although the most effective forms of exercise remain unknown. METHODS: This network meta-analysis was registered in INPLASY (INPLASY202330066). According to predetermined criteria, this investigation comprised randomized controlled studies involving exercise therapies in people with Alzheimer's disease. The exercise intervention was ranked using surface under the cumulative ranking curve (SUCRA) and mean ranking, with the critical goal outcomes being overall cognition, executive function, and memory function. RESULTS: Resistance exercise is the most likely strategy to be beneficial for slowing down overall cognitive function loss in Alzheimer's patients (72.4%). Additionally, multi-component exercise was the most effective way to improve executive function (30.4%). The only type of exercise that significantly affects memory function is resistance exercise. Memory is the cognitive function that is least responsive to exercise. CONCLUSION: Resistance exercise may be an efficient intervention for overall cognitive function decline in patients with Alzheimer's and conjointly for their memory function. Multi-component exercise is more effective in improving executive function in patients with Alzheimer's disease.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Humanos , Enfermedad de Alzheimer/terapia , Enfermedad de Alzheimer/psicología , Metaanálisis en Red , Cognición , Disfunción Cognitiva/etiología , Disfunción Cognitiva/terapia , Disfunción Cognitiva/psicología , Terapia por EjercicioRESUMEN
Background: Germline pathogenic variants are estimated to affect 3-5% of patients with renal cell carcinoma (RCC). The identification of patients with hereditary RCC is important for cancer screening and treatment guidance. Methods: Whole-exome sequencing (WES) (n=69) or gene panel sequencing containing 139 genes (n=54) related to germline cancer predisposition was used to analyze germline mutations in 123 patients with RCC admitted to Department of Urology, The Third Medical Center of Chinese PLA General Hospital. Chi-square test (χ2) was used to analyze relationship between clinicopathologic parameters and germline mutations. Results: A total of 13 (10.57%) patients carried pathogenic or likely pathogenic germline mutations in 10 cancer predisposition genes, including VHL, FH, FLCN, SDHB, MUTYH, RAD51C, NBN, RAD50, FANCI, and FANCM. A total of 6 of these 10 cancer predisposition genes were associated with maintenance of genomic stability and DNA repair. Patients harboring pathogenic germline mutations tended to have an earlier RCC onset. The prevalence of deleterious mutations was higher in patients with bilateral or multifocal RCC compared to patients without bilateral or multifocal RCC. Patients with non-clear cell RCC (nccRCC) were significantly more likely to have RCC-associated gene mutations. Conclusions: To our knowledge, this is the first report of pathogenic germline mutations in the FANCI and FANCM genes and heterozygous germline missense mutation in exon 5 of the FH gene c.563A>T:p.N188I in RCC. Young RCC patients, patients with bilateral or multifocal RCC, or patients with nccRCC are more likely to have pathogenic/potentially pathogenic germline mutations.
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Nonsense-mediated mRNA decay (NMD) is a quality control mechanism that degrades mRNAs carrying a premature termination codon. Its inhibition, alone or in combination with other approaches, could be exploited to develop therapies for genetic diseases caused by a nonsense mutation. This, however, requires molecules capable of inhibiting NMD effectively without inducing toxicity. We have built a new screening system and used it to identify and validate two new molecules that can inhibit NMD at least as effectively as cycloheximide, a reference NMD inhibitor molecule. These new NMD inhibitors show no cellular toxicity at tested concentrations and have a working concentration between 6.2 and 12.5 µM. We have further validated this NMD-inhibiting property in a physiopathological model of lung cancer in which the TP53 gene carries a nonsense mutation. These new molecules may potentially be of interest in the development of therapies for genetic diseases caused by a nonsense mutation.
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Water consumption and energy consumption are inevitable in grain production, but few studies have focused on the integrated assessment of these two indicators and their relationships. To address the research deficiency, taking the North China Plain (NCP) as a case study, this paper quantifies the changes in grain crop planting structure and the accompanying changes in irrigation water consumption (IWC) and energy consumption (EC) in the NCP. On this basis, the water-energy coupling index (CI) is constructed to analyze the water-energy coupling relationship in the context of grain crop planting structure change. The results revealed that the sown area of three of the four main grain crops in the NCP, namely winter wheat, summer maize, and rice, roughly increased in the south and decreased in the north, while the sown area of spring maize increased in most counties where it was planted in the NCP from 2000 to 2015. With the change of grain crop planting structure, IWC and EC of winter wheat in the NCP decreased by 19.87 × 106 m3 and 16.78 × 108 MJ, respectively, mainly distributed in the Beijing-Tianjin-Hebei region, while IWC and EC of other crops all increased. In terms of CI values, although that of spring maize increased, those of winter wheat, summer maize, and rice all decreased, and the overall CI values of grain production in the NCP decreased from 0.442 in 2000 to 0.438 in 2015, indicating that grain crop distribution has been optimized toward a less water- and energy-intensive and more sustainable layout in the NCP. This paper can add case and methodological support to the food-water-energy (FEW) nexus research and can also provide policy suggestions for regional crop optimization layout and conservation of both water and energy resources.
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Oryza , Agua , Agricultura/métodos , China , Productos Agrícolas , Grano Comestible , Triticum , Zea maysRESUMEN
Acute myocardial infarction (AMI) is the most severe form of coronary heart disease caused by ischemia and hypoxia. The study is aimed at investigating the role of neuropeptides and the mechanism of electroacupuncture (EA) in acute myocardial infarction (AMI) treatment. Compared with the normal population, a significant increase in substance P (SP) was observed in the serum of patients with AMI. PGI2 expression was increased in the SP-treated AMI mouse model, and TXA2 expression was decreased. And PI3K pathway-related genes, including Pik3ca, Akt, and Mtor, were upregulated in myocardial tissue of SP-treated AMI patients. Human cardiomyocyte cell lines (HCM) treated with SP increased mRNA and protein expression of PI3K pathway-related genes (Pik3ca, Pik3cb, Akt, and Mtor). Compared to MI control and EA-treated MI rat models, Myd88, MTOR, Akt1, Sp, and Irak1 were differentially expressed, consistent with in vivo and in vitro studies. EA treatment significantly enriched PI3K/AKT signaling pathway genes within MI-associated differentially expressed genes (DEGs) according to Kyoto Encyclopedia of Genes and Genomes (KEGG). Furthermore, it was confirmed by molecular docking analysis that PIK3CA, AKT1, and mTOR form stable dockings with neuropeptide SP. PI3K/AKT pathway activity may be affected directly or indirectly by EA via SP, which corrects the PGI2/TXA2 metabolic imbalance in AMI. MI treatment is now better understood as a result of this finding.
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Electroacupuntura , Infarto del Miocardio , Animales , Fosfatidilinositol 3-Quinasa Clase I/metabolismo , Biología Computacional , Homeostasis , Humanos , Ratones , Simulación del Acoplamiento Molecular , Factor 88 de Diferenciación Mieloide/metabolismo , Infarto del Miocardio/genética , Infarto del Miocardio/terapia , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , ARN Mensajero , Ratas , Receptores de Epoprostenol/metabolismo , Receptores de Tromboxano A2 y Prostaglandina H2/metabolismo , Sustancia P/genética , Sustancia P/metabolismo , Serina-Treonina Quinasas TOR/genética , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
Objective: A case-control study was conducted to explore the effect of acupuncture combined with rehabilitation training on limb function and nerve injury rehabilitation in elderly patients with stroke. Methods: A total of 72 elderly patients with stroke treated from March 2019 to June 2021 in our hospital were enrolled as the object of study. The clinical data were collected and divided into two groups according to their different treatment methods. The patients cured with routine treatment combined with rehabilitation training were taken as the control group and the patients cured with acupuncture combined with rehabilitation training as the study group. The clinical efficacy was recorded, and the cognition and activities of daily living were evaluated by Terrell Cognitive Assessment scale, limb motor function score, and activities of daily living scale. The National Institutes of Health Stroke Scale (NIHSS) and Glasgow Coma Scale (GCS) were employed to compare the neurological function before and after treatment. Glasgow Outcome Scale (GOS) and Disability Rating Scale (DRS) were adopted to evaluate the functional prognosis. The simplified Fugl-Meyer assessment of motor recovery score was employed to evaluate the limb function of the patients. The Wolf Motor Function Test (WMFT) score was adopted to evaluate the functional rehabilitation effect of the patients. Enzyme-linked immunosorbent assay (ELISA) was adopted to determine the serum neurological function indexes such as nerve growth factor, Smur100B protein, and glial fibrillary acidic protein. The cerebral blood flow (CBF), peak time, average transit time, and cerebral blood volume were measured by CT perfusion imaging, and the incidence of side effects during treatment was recorded. Results: Regarding the recovery of cognitive function and daily function after treatment, after treatment, the MoCA and ADL scores were increased, and the comparison indicated that the MoCA and ADL scores of the study group were remarkably higher compared to the control group (P < 0.05). With regard to the FMA-UE scores after treatment, the Fugl-Meyer scores were gradually increased, and the Fugl-Meyer scores in the study group were remarkably higher compared to the control group (P < 0.05) in the next two months. After 2 weeks, 4 weeks, 6 weeks, and 6 weeks of treatment, the WMFT scores gradually increased, and the WMFT score of the study group was remarkably higher compared to the control group. After treatment, the levels of nerve growth factor and S-100B protein were decreased, and the level of glial fibrillary acidic protein was increased. Comparison between the two groups, it indicated the improvement degree of each neurological function index in the study group was remarkably better (P < 0.05). With regard to cerebral hemodynamic indexes after treatment, 1 week after treatment, the CBF and average transit time of the observation group were remarkably higher compared to the control group, and the levels of cerebral blood volume and peak time were remarkably lower compared to the control group (P < 0.05). After 4 weeks of treatment, the cerebral hemodynamic indexes of the observation group did not change remarkably, and they were all lower than 1 week after the treatment. In the terms of side effects, 1 case of limb dysfunction, 1 case of swallowing dysfunction, 1 case of electrolyte disturbance, and none of infection in the study group, the incidence of adverse reactions was 8.33%. In the control group, there were 3 cases of limb dysfunction, 2 cases of swallowing dysfunction, 2 cases of electrolyte disturbance, and 3 cases of infection, and the incidence of adverse reactions was 27.78%. Compared between groups, the incidence of adverse reactions in the study group was lower (P < 0.05). Conclusion: Early use of acupuncture combined with rehabilitation training has a remarkable therapeutic effect on elderly stroke patients. It can remarkably promote the recovery of the patient's condition, remarkably enhance their neurological function, cognitive function, motor function, and daily life function, and effectively strengthen the patient's prognosis score. It has important clinical application value to reduce the incidence of adverse reactions.