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Membranous nephropathy (MN), an autoimmune disease, can manifest at any age and is among the most common causes of nephrotic syndrome in adults. In 80% of cases, the specific etiology of MN remains unknown, while the remaining cases are linked to drug use or underlying conditions like systemic lupus erythematosus, hepatitis B virus, or malignancy. Although about one-third of patients may achieve spontaneous complete or partial remission with conservative management, another third face an elevated risk of disease progression, potentially leading to end-stage renal disease within 10 years. The identification of phospholipase A2 receptor as the primary target antigen in MN has brought about a significant shift in disease management and monitoring. This review explores recent advancements in the pathophysiology of MN, encompassing pathogenesis, clinical presentations, diagnostic criteria, treatment options, and prognosis, with a focus on emerging developments in pathogenesis and therapeutic strategies aimed at halting disease progression. By synthesizing the latest research findings and clinical insights, this review seeks to contribute to the ongoing efforts to enhance our understanding and management of this challenging autoimmune disorder.
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Acute kidney injury (AKI) signifies a sudden and prolonged decline in kidney function characterized by tubular cell death and interstitial inflammation. Small nucleolar RNAs (snoRNAs) play pivotal roles in oxidative stress and inflammation, and may play an important role in the AKI process, which remains elusive. an elevated expression of Snord3a is revealed in renal tubules in response to AKI and demonstrates that Snord3a deficiency alleviates renal injury in AKI mouse models. Notably, the deficiency of Snord3a exhibits a mitigating effect on the stimulator of interferon genes (STING)-associated ferroptosis phenotypes and the progression of tubular injury. Mechanistically, Snord3a is shown to regulate the STING signaling axis via promoting STING gene transcription; administration of Snord3a antisense oligonucleotides establishes a significant therapeutic advantage in AKI mouse models. Together, the findings elucidate the transcription regulation mechanism of STING and the crucial roles of the Snord3a-STING axis in ferroptosis during AKI, underscoring Snord3a as a potential prognostic and therapeutic target for AKI.
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In recent years, the incidence of diabetes has been increasing rapidly, posing a serious threat to human health. Diabetic cardiomyopathy (DCM) is characterized by cardiomyocyte hypertrophy, myocardial fibrosis, apoptosis, ventricular remodeling, and cardiac dysfunction in individuals with diabetes, ultimately leading to heart failure and mortality. However, the underlying mechanisms contributing to DCM remain incompletely understood. With advancements in molecular biology technology, accumulating evidence has shown that numerous non-coding RNAs (ncRNAs) crucial roles in the development and progression of DCM. This review aims to summarize recent studies on the involvement of three types of ncRNAs (micro RNA, long ncRNA and circular RNA) in the pathophysiology of DCM, with the goal of providing innovative strategies for the prevention and treatment of DCM.
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Cardiomiopatías Diabéticas , ARN Circular , ARN Largo no Codificante , Humanos , Cardiomiopatías Diabéticas/genética , Cardiomiopatías Diabéticas/fisiopatología , Cardiomiopatías Diabéticas/metabolismo , Animales , ARN Circular/genética , ARN Circular/metabolismo , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Regulación de la Expresión Génica , ARN no Traducido/genética , ARN no Traducido/metabolismo , Transducción de Señal , Miocardio/patología , Miocardio/metabolismoRESUMEN
Mass spectrometry is a powerful and widely used tool for generating proteomics, lipidomics and metabolomics profiles, which is pivotal for elucidating biological processes and identifying biomarkers. However, missing values in mass spectrometry-based omics data may pose a critical challenge for the comprehensive identification of biomarkers and elucidation of the biological processes underlying human complex disorders. To alleviate this issue, various imputation methods for mass spectrometry-based omics data have been developed. However, a comprehensive comparison of these imputation methods is still lacking, and researchers are frequently confronted with a multitude of options without a clear rationale for method selection. To address this pressing need, we developed omicsMIC (mass spectrometry-based omics with Missing values Imputation methods Comparison platform), an interactive platform that provides researchers with a versatile framework to evaluate the performance of 28 diverse imputation methods. omicsMIC offers a nuanced perspective, acknowledging the inherent heterogeneity in biological data and the unique attributes of each dataset. Our platform empowers researchers to make data-driven decisions in imputation method selection based on real-time visualizations of the outcomes associated with different imputation strategies. The comprehensive benchmarking and versatility of omicsMIC make it a valuable tool for the scientific community engaged in mass spectrometry-based omics research. omicsMIC is freely available at https://github.com/WQLin8/omicsMIC.
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Burn wounds often bring high risks of delayed healing process and even death. Reactive oxygen species (ROS) play a crucial role in burn wound repair. However, the dynamic process in wound healing requires both the generation of ROS to inhibit bacteria and the subsequent reduction of ROS levels to initiate and promote tissue regeneration, which calls for a more intelligent ROS regulation dressing system. Hence, a dual-layered hydrogel (Dual-Gel) tailored to the process of burn wound repair is designed: the inner layer hydrogel (Gel 2) first responds to bacterial hyaluronidase (Hyal) to deliver aggregation-induced emission photosensitizer functionalized adipose-derived stem cell nanovesicles, which generate ROS upon light irradiation to eliminate bacteria; then the outer layer hydrogel (Gel 1) continuously starts a long-lasting consumption of excess ROS at the wound site to accelerate tissue regeneration. Simultaneously, the stem cell nanovesicles trapped in the burns wound also provide nutrients and mobilize neighboring tissues to thoroughly assist in inflammation regulation, cell proliferation, migration, and angiogenesis. In summary, this study develops an intelligent treatment approach on burn wounds by programmatically regulating ROS and facilitating comprehensive wound tissue repair.
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Quemaduras , Hidrogeles , Especies Reactivas de Oxígeno , Células Madre , Cicatrización de Heridas , Cicatrización de Heridas/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Quemaduras/terapia , Quemaduras/metabolismo , Quemaduras/patología , Animales , Hidrogeles/química , Células Madre/citología , Células Madre/metabolismo , Ratones , Regeneración/efectos de los fármacos , Humanos , Hialuronoglucosaminidasa/metabolismo , Nanoestructuras/química , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/farmacología , Proliferación Celular/efectos de los fármacosRESUMEN
The design of tuned mass damper (TMD) parameters is influenced by the soil-structure-TMD coupling system; thus, it is important to consider the soil-structure interaction (SSI) for the vibration control effect of the TMD. Recently, the acquisition of TMD parameters considering soil-structure interactions has only remained at the theoretical stage, lacking relevant experimental verification. Traditional TMD face the problems of occupying a large building space, increasing construction costs, and non-replaceable components. In this study, an assembled wall-type damping TMD was designed. By comparing the dynamic response of the uncontrolled and controlled structures equipped with the newly assembled wall-type damping TMD in the shaking table test on a soft soil foundation, we analyzed whether the SSI effect was considered in the TMD design parameters on the damping effect of the newly assembled wall-type tuned mass damper. The TMD parameters optimized using the artificial intelligence algorithm were verified experimentally. The results indicated that the traditional TMD design parameters were discordant because the SSI effect was not considered. The SSI effect in the soil effectively reduces the dynamic response of the superstructure. By considering the SSI effect and improving the multi-population genetic algorithm, a wall-type damping TMD with optimized parameters can achieve a good damping effect.
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Algoritmos , Suelo , Suelo/química , Terremotos , VibraciónRESUMEN
Electroactive bacteria, exemplified by Shewanella oneidensis MR-1, have garnered significant attention due to their unique extracellular electron-transfer (EET) capabilities, which are crucial for energy recovery and pollutant conversion. However, the practical application of MR-1 is constrained by its EET efficiency, a key limiting factor, due to the complexity of research methodologies and the challenges associated with the practical use of gene editing tools. To address this challenge, a novel gene integration system, INTEGRATE, was developed, utilizing CRISPR-mediated transposase technologies for precise genomic insertion within the S. oneidensis MR-1 genome. This system facilitated the insertion of extensive gene segments at different sites of the Shewanella genome with an efficiency approaching 100%. The inserted cargo genes could be kept stable on the genome after continuous cultivation. The enhancement of the organism's EET efficiency was realized through two primary strategies: the integration of the phenazine-1-carboxylic acid synthesis gene cluster to augment EET efficiency and the targeted disruption of the SO3350 gene to promote anodic biofilm development. Collectively, our findings highlight the potential of utilizing the INTEGRATE system for strategic genomic alterations, presenting a synergistic approach to augment the functionality of electroactive bacteria within bioelectrochemical systems.
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Sistemas CRISPR-Cas , Shewanella , Transposasas , Shewanella/genética , Shewanella/metabolismo , Transporte de Electrón , Transposasas/genética , Transposasas/metabolismo , Sistemas CRISPR-Cas/genética , Edición Génica/métodos , Genoma Bacteriano , Biopelículas , Fuentes de Energía Bioeléctrica/microbiologíaRESUMEN
Alternative polyadenylation (APA) modulates mRNA processing in the 3'-untranslated regions (3' UTR), affecting mRNA stability and translation efficiency. Research into genetically regulated APA has the potential to provide insights into cancer risk. In this study, we conducted large APA-wide association studies to investigate associations between APA levels and cancer risk. Genetic models were built to predict APA levels in multiple tissues using genotype and RNA sequencing data from 1,337 samples from the Genotype-Tissue Expression project. Associations of genetically predicted APA levels with cancer risk were assessed by applying the prediction models to data from large genome-wide association studies of six common cancers among European ancestry populations: breast, ovarian, prostate, colorectal, lung, and pancreatic cancers. A total of 58 risk genes (corresponding to 76 APA sites) were associated with at least one type of cancer, including 25 genes previously not linked to cancer susceptibility. Of the identified risk APAs, 97.4% and 26.3% were supported by 3'-UTR APA quantitative trait loci and colocalization analyses, respectively. Luciferase reporter assays for four selected putative regulatory 3'-UTR variants demonstrated that the risk alleles of 3'-UTR variants, rs324015 (STAT6), rs2280503 (DIP2B), rs1128450 (FBXO38), and rs145220637 (LDHA), significantly increased the posttranscriptional activities of their target genes compared with reference alleles. Furthermore, knockdown of the target genes confirmed their ability to promote proliferation and migration. Overall, this study provides insights into the role of APA in the genetic susceptibility to common cancers. Significance: Systematic evaluation of associations of alternative polyadenylation with cancer risk reveals 58 putative susceptibility genes, highlighting the contribution of genetically regulated alternative polyadenylation of 3'UTRs to genetic susceptibility to cancer.
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Regiones no Traducidas 3' , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Neoplasias , Poliadenilación , Humanos , Neoplasias/genética , Regiones no Traducidas 3'/genética , Sitios de Carácter Cuantitativo , Polimorfismo de Nucleótido Simple , Femenino , Masculino , Regulación Neoplásica de la Expresión Génica , ARN Mensajero/genética , ARN Mensajero/metabolismo , Línea Celular TumoralRESUMEN
Background: The pivotal role of phospholipase A2 group VII (PLA2G7) has been identified in specific human cancers, such as prostate cancer, diffuse large B cell lymphoma, and melanoma. Given PLA2G7's significant involvement in established tumors, exploring its role in other cancers is highly relevant. Methods: In this study, we acquired and analyzed data from The Cancer Genome Atlas database, the UCSC XENA website, and other online platforms including Gene Set Cancer Analysis, cBioPortal, Tumor Immune Estimation Resource, and TISIDB to investigate PLA2G7's role in human cancers, including renal cancer. Furthermore, in vitro experiments, including immunofluorescence, western blotting, and CCK-8 assays, were conducted to elucidate PLA2G7's role in renal cancer. Finally, the relationship between PLA2G7 and various drug sensitivity was explored. Results: Our findings demonstrate that PLA2G7 is highly expressed and may serve as a valuable candidate biomarker in pan-cancer. PLA2G7 exhibits distinct alteration frequencies across human cancers and is correlated with tumor mutation burden, tumor microenvironment, DNA stemness score, RNA stemness score, tumorigenesis, tumor immunity, and microsatellite instability in pan-cancer. Immunofluorescence and western blotting revealed a relative high level of PLA2G7 protein in renal cancer cell lines (ACHN and 786-O), predominantly localized in the cytoplasm. Treatment with a PLA2G7 gene inhibitor (darapladib) significantly decreased the viability of ACHN and 786-O cell lines. Additionally, we observed an association between PLA2G7 mRNA levels and various drug sensitivity. Conclusions: Our study suggests that PLA2G7 has the potential to serve as a valuable biomarker and therapeutic target for cancer, particularly in the context of renal cancer.
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Acute kidney injury (AKI) is defined as a rapid decline in renal function, in which persistent kidney dysfunction gradually progresses to chronic kidney disease (CKD) due to the irreversible loss of nephrons and their maladaptive repair. In recent years, the incidence of AKI has been increasing concerning diverse etiologies, including volume depletion, sepsis, nephrotoxicity, muscle injury, and major trauma, in which ischemia-reperfusion injury (IRI) accounts for most episodes. Development of the IRI model in mice is induced by surgical clamping of the renal pedicles, which provides powerful and controllable tools for preclinical models of AKI. Importantly, the IRI model is deployed at different stages of the AKI development, especially in the processes of AKI to CKD. Despite the IRI model being widely practiced in many laboratories, a series of variables still influence the results of this model. Here, we describe the procedure of IRI model development to provide a repeatable and reliable method for researchers to explore the underlying pathogenesis in the development of AKI and the progression of AKI to CKD.
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Lesión Renal Aguda , Insuficiencia Renal Crónica , Daño por Reperfusión , Ratones , Animales , Riñón/patología , Lesión Renal Aguda/complicaciones , Insuficiencia Renal Crónica/etiología , Daño por Reperfusión/patología , Isquemia , Reperfusión , Ratones Endogámicos C57BLRESUMEN
Bacterial nanocellulose (BNC) is an attractive green-synthesized biomaterial for biomedical applications and various other applications. However, effective engineering of BNC production has been limited by our poor knowledge of the related metabolic processes. In contrast to the traditional perception that genome critically determines biosynthesis behaviors, here we discover that the glucose metabolism could also drastically affect the BNC synthesis in Gluconacetobacter hansenii. The transcriptomic profiles of two model BNC-producing strains, G. hansenii ATCC 53582 and ATCC 23769, which have highly similar genomes but drastically different BNC yields, were compared. The results show that their BNC synthesis capacities were highly related to metabolic activities such as ATP synthesis, ion transport protein assembly, and carbohydrate metabolic processes, confirming an important role of metabolism-related transcriptomes in governing the BNC yield. Our findings provide insights into the microbial biosynthesis behaviors from a transcriptome perspective, potentially guiding cellular engineering for biomaterial synthesis.
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Perfilación de la Expresión Génica , Transcriptoma , Transcriptoma/genética , Materiales Biocompatibles , Ingeniería Celular , Transporte IónicoRESUMEN
Myocardial ischemia/reperfusion (I/R) injury is a pathological damage secondary to myocardial ischemia that can further aggravate tissue and organ injuries. Therefore, there is an urgent need to develop an effective approach for alleviating myocardial I/R injury. Trehalose (TRE) is a natural bioactive substance that has been shown to have extensive physiological effects in various animals and plants. However, TRE's protective effects against myocardial I/R injury remain unclear. This study aimed to evaluate the protective effect of TRE pre-treatment in mice with acute myocardial I/R injury and to explore the role of pyroptosis in this process. Mice were pre-treated with trehalose (1 mg/g) or an equivalent amount of saline solution for 7 days. The left anterior descending coronary artery was ligated in mice from the I/R and I/R + TRE groups, followed by 2-h or 24-h reperfusion after 30 min. Transthoracic echocardiography was performed to assess cardiac function in mice. Serum and cardiac tissue samples were obtained to examine the relevant indicators. We established an oxygen-glucose deprivation and re-oxygenation model in neonatal mouse ventricular cardiomyocytes and validated the mechanism by which trehalose affects myocardial necrosis via overexpression or silencing of NLRP3. TRE pre-treatment significantly improved cardiac dysfunction and reduced the infarct size in mice after I/R, accompanied by a decrease in the I/R-induced levels of CK-MB, cTnT, LDH, reactive oxygen species, pro-IL-1ß, pro-IL-18, and TUNEL-positive cells. Furthermore, TRE intervention suppressed the expression of pyroptosis-related proteins following I/R. TRE attenuates myocardial I/R injury in mice by inhibiting NLRP3-mediated caspase-1-dependent pyroptosis in cardiomyocytes.
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Daño por Reperfusión Miocárdica , Ratones , Animales , Daño por Reperfusión Miocárdica/tratamiento farmacológico , Daño por Reperfusión Miocárdica/patología , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Trehalosa/farmacología , Trehalosa/uso terapéutico , Piroptosis , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Transcriptome-wide association studies (TWAS) have identified many putative susceptibility genes for colorectal cancer (CRC) risk. However, susceptibility miRNAs, critical dysregulators of gene expression, remain unexplored. We genotyped DNA samples from 313 CRC East Asian patients and performed small RNA sequencing in their normal colon tissues distant from tumors to build genetic models for predicting miRNA expression. We applied these models and data from genome-wide association studies (GWAS) including 23 942 cases and 217 267 controls of East Asian ancestry to investigate associations of predicted miRNA expression with CRC risk. Perturbation experiments separately by promoting and inhibiting miRNAs expressions and further in vitro assays in both SW480 and HCT116 cells were conducted. At a Bonferroni-corrected threshold of P < 4.5 × 10-4, we identified two putative susceptibility miRNAs, miR-1307-5p and miR-192-3p, located in regions more than 500 kb away from any GWAS-identified risk variants in CRC. We observed that a high predicted expression of miR-1307-5p was associated with increased CRC risk, while a low predicted expression of miR-192-3p was associated with increased CRC risk. Our experimental results further provide strong evidence of their susceptible roles by showing that miR-1307-5p and miR-192-3p play a regulatory role, respectively, in promoting and inhibiting CRC cell proliferation, migration, and invasion, which was consistently observed in both SW480 and HCT116 cells. Our study provides additional insights into the biological mechanisms underlying CRC development.
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Neoplasias Colorrectales , MicroARNs , Humanos , MicroARNs/genética , MicroARNs/metabolismo , Transcriptoma/genética , Estudio de Asociación del Genoma Completo , Neoplasias Colorrectales/metabolismo , Células HCT116 , Regulación Neoplásica de la Expresión Génica/genética , Proliferación Celular/genéticaRESUMEN
BACKGROUND AND AIMS: Extrachromosomal circular DNAs (eccDNAs) are prevalent in cancer genomes and emerge as a class of crucial yet less characterized oncogenic drivers. However, the structure, composition, genome-wide frequency, and contribution of eccDNAs in HCC, one of the most fatal and prevalent cancers, remain unexplored. In this study, we provide a comprehensive characterization of eccDNAs in human HCC and demonstrate an oncogenic role of microRNA (miRNA)-17-92-containing eccDNAs in tumor progression. APPROACH AND RESULTS: Using the circle-sequencing method, we identify and characterize more than 230,000 eccDNAs from 4 paired samples of HCC tumor and adjacent nontumor liver tissues. EccDNAs are highly enriched in HCC tumors, preferentially originate from certain chromosomal hotspots, and are correlated with differential gene expression. Particularly, a series of eccDNAs carrying the miRNA-17-92 cluster are validated by outward PCR and Sanger sequencing. Quantitative PCR analyses reveal that miRNA-17-92-containing eccDNAs, along with the expression of their corresponding miRNAs, are elevated in HCC tumors and associated with poor outcomes and the age of HCC patients. More intriguingly, exogenous expression of artificial DNA circles harboring the miR-17-92 cluster, which is synthesized by the ligase-assisted minicircle accumulation method, can significantly accelerate HCC cell proliferation and migration. CONCLUSIONS: These findings delineate the genome-wide eccDNAs profiling of HCC and highlight the functional significance of miRNA-containing eccDNAs in tumorigenesis, providing insight into HCC pathogenesis and cancer therapy, as well as eccDNA and miRNA biology.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , MicroARNs , Familia de Multigenes , Humanos , Carcinoma Hepatocelular/genética , ADN Circular/genética , Neoplasias Hepáticas/genética , MicroARNs/genética , Reacción en Cadena de la PolimerasaRESUMEN
Alternative polyadenylation (APA) modulates mRNA processing in the 3' untranslated regions (3'UTR), which affect mRNA stability and translation efficiency. Here, we build genetic models to predict APA levels in multiple tissues using sequencing data of 1,337 samples from the Genotype-Tissue Expression, and apply these models to assess associations between genetically predicted APA levels and cancer risk with data from large genome-wide association studies of six common cancers, including breast, ovary, prostate, colorectum, lung, and pancreas among European-ancestry populations. At a Bonferroni-corrected P â¡<â¡0.05, we identify 58 risk genes, including seven in newly identified loci. Using luciferase reporter assays, we demonstrate that risk alleles of 3'UTR variants, rs324015 ( STAT6 ), rs2280503 ( DIP2B ), rs1128450 ( FBXO38 ) and rs145220637 ( LDAH ), could significantly increase post-transcriptional activities of their target genes compared to reference alleles. Further gene knockdown experiments confirm their oncogenic roles. Our study provides additional insight into the genetic susceptibility of these common cancers.
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Polyhydroxybutyrate (PHB) is an attractive biodegradable polymer that can be produced through the microbial fermentation of organic wastes or wastewater. However, its mass production has been restricted by the poor utilization of organic wastes due to the presence of inhibitory substances, slow microbial growth, and high energy input required for feedstock sterilization. Here, Vibrio natriegens, a fast-growing bacterium with a broad substrate spectrum and high tolerance to salt and toxic substances, was genetically engineered to enable efficient PHB production from nonsterilized fermentation of organic wastes. The key genes encoding the PHB biosynthesis pathway of V. natriegens were identified through base editing and overexpressed. The metabolically engineered strain showed 166-fold higher PHB content (34.95 wt %) than the wide type when using glycerol as a substrate. Enhanced PHB production was also achieved when other sugars were used as feedstock. Importantly, it outperformed the engineered Escherichia coli MG1655 in PHB productivity (0.053 g/L/h) and tolerance to toxic substances in crude glycerol, without obvious activity decline under nonsterilized fermentation conditions. Our work demonstrates the great potential of engineered V. natriegens for low-cost PHB bioproduction and lays a foundation for exploiting this strain as a next-generation model chassis microorganism in synthetic biology.
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Glicerol , Polihidroxibutiratos , Vibrio , Glicerol/metabolismo , Fermentación , Hidroxibutiratos/metabolismoRESUMEN
Mass spectrometry is a powerful and widely used tool for generating proteomics, lipidomics, and metabolomics profiles, which is pivotal for elucidating biological processes and identifying biomarkers. However, missing values in spectrometry-based omics data may pose a critical challenge for the comprehensive identification of biomarkers and elucidation of the biological processes underlying human complex disorders. To alleviate this issue, various imputation methods for mass spectrometry-based omics data have been developed. However, a comprehensive and systematic comparison of these imputation methods is still lacking, and researchers are frequently confronted with a multitude of options without a clear rationale for method selection. To address this pressing need, we developed omicsMIC (mass spectrometry-based omics with Missing values Imputation methods Comparison platform), an interactive platform that provides researchers with a versatile framework to simulate and evaluate the performance of 28 diverse imputation methods. omicsMIC offers a nuanced perspective, acknowledging the inherent heterogeneity in biological data and the unique attributes of each dataset. Our platform empowers researchers to make data-driven decisions in imputation method selection based on real-time visualizations of the outcomes associated with different imputation strategies. The comprehensive benchmarking and versatility of omicsMIC make it a valuable tool for the scientific community engaged in mass spectrometry-based omics research. OmicsMIC is freely available at https://github.com/WQLin8/omicsMIC.
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Ferroptosis in tubules has been implicated in the pathogenesis of acute kidney injury (AKI), whereas the regulatory mechanism remains unclear. The stimulator of interferon genes (STING) is previously recognized as a critical mediator of innate immunity via a DNA-sensing pathway and has been increasingly linked to lipid peroxidation, a hallmark of ferroptosis. Herein we investigated the role and the underlying mechanism of STING in AKI models established by ischemia/reperfusion (IR) in C57BL mice. The expression level of STING was predominantly increased in tubules of kidney after IR treatment. Besides, STING deficiency markedly alleviated IR-induced lipid peroxidation, tissue damage and renal dysfunction. Consistently, in vitro experiments demonstrated that the increase in ferroptotic cell death, lipid ROS production and the decrease in GSH peroxidase 4 (GPX4) expression in renal tubular cells subjected to ferroptosis agonist or hypoxia/reoxygenation intervention were all mitigated by genetic deficiency or pharmacological inhibition of STING, while all exacerbated by STING overexpression. Further, these detrimental effects of STING overexpression relied on the induction of ferritinophagy, i.e. autophagic degradation of ferritin, leading to iron overload. Mechanistically, STING mediated the initiation of ferritinophagy through interacting with nuclear receptor coactivator 4 (NCOA4), a fundamental receptor for the transfer of ferritin into lysosome. Collectively, STING contributes to ferroptosis during ischemic AKI through facilitating NCOA4-mediated ferritinophagy and shows the potential as a promising therapeutic choice for AKI.
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Lesión Renal Aguda , Ferroptosis , Animales , Ratones , Lesión Renal Aguda/genética , Ferritinas , Ferroptosis/genética , Riñón , Ratones Endogámicos C57BLRESUMEN
Background: Cisplatin is a widely used anti-tumor agent but its use is frequently limited by nephrotoxicity. Transient receptor potential melastatin 2 (TRPM2) is a non-selective cation channel which is generally viewed as a sensor of oxidative stress, and increasing evidence supports its link with autophagy, a critical process for organelle homeostasis. Methods: Cisplatin-induced cell injury and mitochondrial damage were both assessed in WT and Trpm2-knockout mice and primary cells. RNA sequencing, immunofluorescence staining, immunoblotting and flowcytometry were applied to interpret the mechanism of TRPM2 in cisplatin nephrotoxicity. Results: Knockout of TRPM2 exacerbates renal dysfunction, tubular injury and cell apoptosis in a model of acute kidney injury (AKI) induced by treatment with cisplatin. Cisplatin-caused tubular mitochondrial damage is aggravated in TRPM2-deficient mice and cells and, conversely, alleviated by treatment with Mito-TEMPO, a mitochondrial ROS scavenger. TRPM2 deficiency hinders cisplatin-induced autophagy via blockage of Ca2+ influx and subsequent up-regulation of AKT-mTOR signaling. Consistently, cisplatin-induced tubular mitochondrial damage, cell apoptosis and renal dysfunction in TRPM2-deficient mice are mitigated by treatment with a mTOR inhibitor. Conclusion: Our results suggest that the TRPM2 channel plays a protective role in cisplatin-induced AKI via modulating the Ca2+-AKT-mTOR signaling pathway and autophagy, providing novel insights into the pathogenesis of kidney injury.