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OBJECTIVE: Obesity-induced kidney injury contributes to the development of diabetic nephropathy (DN). Here, we identified the functions of ubiquitin-specific peptidase 19 (USP19) in HK-2 cells exposed to a combination of high glucose (HG) and free fatty acid (FFA) and determined its association with TGF-beta-activated kinase 1 (TAK1). METHODS: HK-2 cells were exposed to a combination of HG and FFA. USP19 mRNA expression was detected by quantitative RT-PCR (qRT-PCR), and protein analysis was performed by immunoblotting (IB). Cell growth was assessed by Cell Counting Kit-8 (CCK-8) viability and 5-ethynyl-2'-deoxyuridine (EdU) proliferation assays. Cell cycle distribution and apoptosis were detected by flow cytometry. The USP19/TAK1 interaction and ubiquitinated TAK1 levels were assayed by coimmunoprecipitation (Co-IP) assays and IB. RESULTS: In HG+FFA-challenged HK-2 cells, USP19 was highly expressed. USP19 knockdown attenuated HG+FFA-triggered growth inhibition and apoptosis promotion in HK-2 cells. Moreover, USP19 knockdown alleviated HG+FFA-mediated PTEN-induced putative kinase 1 (PINK1)/Parkin pathway inactivation and increased mitochondrial reactive oxygen species (ROS) generation in HK-2 cells. Mechanistically, USP19 stabilized the TAK1 protein through deubiquitination. Importantly, increased TAK1 expression reversed the USP19 knockdown-mediated phenotypic changes and PINK1/Parkin pathway activation in HG+FFA-challenged HK-2 cells. CONCLUSION: The findings revealed that USP19 plays a crucial role in promoting HK-2 cell dysfunction induced by combined stimulation with HG and FFAs by stabilizing TAK1, providing a potential therapeutic strategy for combating DN.
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BACKGROUND: Bladder cancer (BLCA), which develops from the upper endometrial of the bladder, is the sixth most prevalent cancer across the globe. WDHD1 (WD repeat and HMG-box DNA binding protein 1 gene) directly affects signaling, the cell cycle, and the development of the cell skeleton. Uncertainty surrounds WDHD1's function in BLCA immunity and prognosis, though. MATERIALS AND METHODS: Using weighed gene co-expression network analysis (WGCNA), initially, we first identified 32 risk factors in genes with differential expression for this investigation. Then, using a variety of bioinformatic techniques and experimental validation, we examined the connections between WDHD1 and BLCA expression, clinical pathological traits, WDHD1-related proteins, upper-skin-intermediate conversion (EMT), immune cell immersion, convergence factors, immune markers, and drug sensitivity. RESULT: The findings demonstrated that we constructed a 32-gene risk-predicting model where WDHD1 was elevated as a representative gene expression in BLCA and related to a range of clinical traits. Furthermore, high WDHD1 expression was a standalone predictor associated with a worse survival rate. The most commonly recruited cells and their evolutionary patterns were highlighted to better comprehend WDHD1's function in cancer. High WDHD1 expression was associated with many aspects of immunology. Finally, the study found that individuals with high expression of WDHD1 were drug-sensitive to four different broad-spectrum anti-cancer drugs. CONCLUSION: These results describe dynamic changes in the tumor microenvironment in BLCA and provide evidence for the hypothesis that WDHD1 is a novel biomarker of tumor development. WDHD1 may therefore be a useful target for the detection and management of BLCA.
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Biomarcadores de Tumor , Transición Epitelial-Mesenquimal , Neoplasias de la Vejiga Urinaria , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/inmunología , Neoplasias de la Vejiga Urinaria/patología , Neoplasias de la Vejiga Urinaria/mortalidad , Humanos , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Pronóstico , Transición Epitelial-Mesenquimal/genética , Regulación Neoplásica de la Expresión Génica , Redes Reguladoras de GenesRESUMEN
Glucan-dependent biofilm formation is a crucial process in the establishment of Streptococcus mutans as a cariogenic oral microbe. The process of glucan formation has been investigated in great detail, with glycosyltransferases GtfB, GtfC, and GtfD shown to be indispensable for the synthesis of glucans from sucrose. Glucan production can be visualized during biofilm formation through fluorescent labeling, and its abundance, as well as the effect of glucans on general biofilm architecture, is a common phenotype to study S. mutans virulence regulation. Here, we describe an entirely new phenotype associated with glucan production, caused by a mutation in the open reading frame SMU_848, which is located in an operon encoding ribosome-associated proteins. This mutation led to the excess production and accumulation of glucan-containing droplets on the surface of biofilms formed on agar plates after prolonged incubation. While not characterized in S. mutans, SMU_848 shows homology to the phage-related ribosomal protease Prp, essential in cleaving off the N-terminal extension of ribosomal protein L27 for functional ribosome assembly in Staphylococcus aureus. We present a further characterization of SMU_848/Prp, demonstrating that the deletion of this gene leads to significant changes in S. mutans gtfBC expression. Surprisingly, it also profoundly impacts the interkingdom interaction between S. mutans and Candida albicans, a relevant dual-species interaction implicated in severe early childhood caries. The presented data support a potential broader role for SMU_848/Prp, possibly extending its functionality beyond the ribosomal network to influence important ecological processes. IMPORTANCE: Streptococcus mutans is an important member of the oral biofilm and is implicated in the initiation of caries. One of the main virulence mechanisms is the glucan-dependent formation of biofilms. We identified a new player in the regulation of glucan production, SMU_848, which is part of an operon that also encodes for ribosomal proteins L27 and L21. A mutation in SMU_848, which encodes a phage-related ribosomal protease Prp, leads to a significant accumulation of glucan-containing droplets on S. mutans biofilms, a previously unknown phenotype. Further investigations expanded our knowledge about the role of SMU_848 beyond its role in glucan production, including significant involvement in interkingdom interactions, thus potentially playing a global role in the virulence regulation of S. mutans.
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Proteínas Bacterianas , Biopelículas , Glucanos , Streptococcus mutans , Streptococcus mutans/genética , Streptococcus mutans/metabolismo , Streptococcus mutans/enzimología , Biopelículas/crecimiento & desarrollo , Glucanos/metabolismo , Proteínas Bacterianas/metabolismo , Proteínas Bacterianas/genética , Regulación Bacteriana de la Expresión Génica , Ribosomas/metabolismo , Mutación , Proteínas Ribosómicas/metabolismo , Proteínas Ribosómicas/genéticaRESUMEN
Since 2007, h9.4.2.5 has emerged as the most predominant branch of H9N2 avian influenza viruses (AIVs) that affects the majority of the global poultry population. The spread of this viral branch in vaccinated chicken flocks has not been considerably curbed despite numerous efforts. The evolutionary fitness of h9.4.2.5-branched AIVs must consequently be taken into consideration. The glycosylation modifications of hemagglutinin (HA) play a pivotal role in regulating the balance between receptor affinity and immune evasion for influenza viruses. Sequence alignment showed that five major HA glycosylation patterns have evolved over time in h9.4.2.5-branched AIVs. Here, we compared the adaptive phenotypes of five virus mutants with different HA glycosylation patterns. According to the results, the mutant with 6 N-linked glycans displayed the best acid and thermal stability and a better capacity for multiplication, although having a relatively lower receptor affinity than 7 glycans. The antigenic profile between the five mutants revealed a distinct antigenic distance, indicating that variations in glycosylation level have an impact on antigenic drift. These findings suggest that changes in the number of glycans on HA can not only modulate the receptor affinity and antigenicity of H9N2 AIVs, but also affect their stability and multiplication. These adaptive phenotypes may underlie the biological basis for the dominant strain switchover of h9.4.2.5-branched AIVs. Overall, our study provides a systematic insight into how changes in HA glycosylation patterns regulate the evolutionary fitness and epidemiological dominance drift of h9.4.2.5-branched H9N2 AIVs, which will be of great benefit for the glycosylation-dependent vaccine design.
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Pollos , Glicoproteínas Hemaglutininas del Virus de la Influenza , Subtipo H9N2 del Virus de la Influenza A , Gripe Aviar , Glicosilación , Subtipo H9N2 del Virus de la Influenza A/genética , Subtipo H9N2 del Virus de la Influenza A/inmunología , Subtipo H9N2 del Virus de la Influenza A/metabolismo , Animales , Glicoproteínas Hemaglutininas del Virus de la Influenza/genética , Glicoproteínas Hemaglutininas del Virus de la Influenza/metabolismo , Glicoproteínas Hemaglutininas del Virus de la Influenza/química , Gripe Aviar/virología , Pollos/virología , Mutación , Polisacáridos/metabolismo , Replicación Viral , Células de Riñón Canino Madin Darby , Enfermedades de las Aves de Corral/virologíaRESUMEN
Purpose: Hepatocellular carcinoma is the most common primary liver cancer, with poor prognosis. Complex immune microenvironment of the liver is linked to the development of HCC. PVALB is a calcium-binding protein which has been described as a cancer suppressor gene in thyroid cancer and glioma. Nevertheless, the role of PVALB in HCC is unknown. Materials and Methods: We obtained data from TCGA and GSE54236 datasets. MCP-counter, WGCNA and LASSO model were applied to identify PVALB. With UALCAN, MethSurv, and other websites, we probed the expression, methylation and survival of PVALB. LinkedOmics and GSEA were adopted for functional analysis, while TIMER, TISIDB, Kaplan-Meier plotter, TIDE databases were utilized to evaluate the relevance of PVALB to the tumor immune microenvironment and predict immunotherapy efficacy. TargetScan, DIANA, LncRNASNP2 databases and relevant experiments were employed to construct ceRNA network. Finally, molecular docking and drug sensitivity of PVALB were characterized by GeneMANIA, CTD, and so on. Results: PVALB was recognized as a gene associated with HCC and NK cell. Its expression was down-regulated in HCC tissue, which lead to adverse prognosis. Besides, the hypomethylation of PVALB was related to its reduced expression. Notably, PVALB was tightly linked to immune, and its reduced expression attenuated the anticancer effect of NK cells via the Fas/FasL pathway, leading to a adverse outcome. The lnc-YY1AP1-3/hsa-miR-6735-5p/PVALB axis may regulate the PVALB expression. Finally, we found immunotherapy might be a viable treatment option. Conclusion: In a word, PVALB is a prognostic indicator, whose low expression facilitates HCC progression by impacting NK cell infiltration.
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BACKGROUND: Glioma, a highly invasive and deadly form of human neoplasm, presents a pressing need for the exploration of potential therapeutic targets. While the lysosomal protein transmembrane 4A (LATPM4A) has been identified as a risk factor in pancreatic cancer patients, its role in glioma remains unexplored. METHODS: The analysis of differentially expressed genes (DEG) was conducted from The Cancer Genome Atlas (TCGA) glioma dataset and the Genotype Tissue Expression (GTEx) dataset. Through weighted gene co-expression network analysis (WGCNA), the key glioma-related genes were identified. Among these, by using Kaplan-Meier (KM) analysis and univariate/multivariate COX methods, LAPTM4A emerged as the most influential gene. Moreover, the bioinformatics methods and experimental verification were employed to analyze its relationships with diagnosis, clinical parameters, epithelial-mesenchymal transition (EMT), metastasis, immune cell infiltration, immunotherapy, drug sensitivity, and ceRNA network. RESULTS: Our findings revealed that LAPTM4A was up-regulated in gliomas and was associated with clinicopathological features, leading to poor prognosis. Furthermore, functional enrichment analysis demonstrated that LATPM4A played a role in the immune system and cancer progression. In vitro experiments indicated that LAPTM4A may influence metastasis through the EMT pathway in glioma. Additionally, we found that LAPTM4A was associated with the tumor microenvironment (TME) and immunotherapy. Notably, drug sensitivity analysis revealed that patients with high LAPTM4A expression were sensitive to doxorubicin, which contributed to a reduction in LAPTM4A expression. Finally, we uncovered the FGD5-AS1-hsa-miR-103a-3p-LAPTM4A axis as a facilitator of glioma progression. CONCLUSIONS: In conclusion, our study identifies LATPM4A as a promising biomarker for prognosis and immune characteristics in glioma.
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Biomarcadores de Tumor , Neoplasias Encefálicas , Biología Computacional , Glioma , Proteínas de la Membrana , Femenino , Humanos , Masculino , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/metabolismo , Línea Celular Tumoral , Transición Epitelial-Mesenquimal/genética , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Redes Reguladoras de Genes , Glioma/genética , Glioma/patología , Glioma/metabolismo , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , PronósticoRESUMEN
BACKGROUND: Analyses of extensive, nationally representative databases indicate a rising prevalence of venous thromboembolism (VTE) among critically ill children. However, the majority of studies on childhood VTE have primarily concentrated on Caucasian populations in the United States and European countries. There is a lack of epidemiological studies on VTE in Chinese children. METHODS: We conducted a retrospective cohort study of data from the Pediatric Intensive Care (PIC) database. Data were obtained and extracted by using Structured Query Language (SQL) and the administrative platform pgAdmin4 for PostgreSQL. Bivariate analyses were conducted in which categorical variables were analyzed by a chi-square test and continuous variables were analyzed by a Student's t-test. Separate multivariable logistic regressions were employed to investigate the associations between VTE and sociodemographic factors as well as clinical factors. RESULTS: Our study included 12,881 pediatric patients from the PIC database, spanning the years 2010 to 2018. The incidence rate of pediatric VTE was 0.19% (24/12,881). The venous thrombotic locations were deep venous thrombosis extremities (n = 18), superior vena cava (n = 1), cerebral sinovenous (n = 1), and other deep venous thrombosis (n = 4). Univariate analysis showed that age, weight, shock, sepsis, cancer and vasopressor receipt were statistically significant risk factors for pediatric VTE (all p ≤ 0.05). After multivariable logistic regression analysis, only shock (aOR: 6.77, 95%CI: 1.33-34.73, p = 0.019) and admission for sepsis (aOR: 6.09, 95%CI: 1.76-21.09, p = 0.004) were statistically significant associated with pediatric VTE. CONCLUSIONS: In conclusion, data obtained from the Pediatric Intensive Care (PIC) database revealed a prevalence of VTE in pediatric patients of 0.19%. The most common location for venous thrombi was deep venous thrombosis (DVT) in the extremities. We identified that shock and sepsis were statistically significant factors associated with pediatric VTE.
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Tissue adhesion is one of the most common postoperative complications, which is frequently accompanied by inflammation, pain, and even dyskinesia, significantly reducing the quality of life of patients. Thus, to prevent the formation of tissue adhesions, various strategies have been explored. Among these methods, placing anti-adhesion membranes over the injured site to separate the wound from surrounding tissues is a simple and prominently favored method. Recently, electrospun nanofibers have been the most frequently investigated antiadhesive membranes due to their tunable porous structure and high porosities. They not only can act as an essential barrier and functional carrier system but also allow for high permeability and nutrient transport, showing great potential for preventing tissue adhesion. Herein, we provide a short review of the most recent applications of electrospun nanofibrous antiadhesive membranes in tendons, the abdominal cavity, dural sac, pericardium, and meninges. Firstly, each section highlights the most representative examples and they are sorted based on the latest progress of related research. Moreover, the design principles, preparation strategies, overall performances, and existing problems are highlighted and evaluated. Finally, the current challenges and several future ways to develop electrospun nanofibrous antiadhesive membranes are proposed. The systematic discussion and proposed directions can shed light on ideas and guide the reasonable design of electrospun nanofibrous membranes, contributing to the development of exceptional tissue anti-adhesive materials in the foreseeable future.
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Nanofibras , Humanos , Nanofibras/química , Adherencias Tisulares/prevención & control , Calidad de Vida , Tendones/cirugía , Inflamación/patologíaRESUMEN
BACKGROUND: The study aimed to investigate the diagnostic value of lupus-related pattern recognition receptors (PRRs) genes in peripheral blood mononuclear cells (PBMCs) and monocytes (MONs) for lupus nephritis (LN). METHODS: PBMCs were isolated from a cohort with 37 LN patients and 39 healthy controls (HCs), and MONs were derived from another cohort with 70 LN patients and 66 HCs. Q-PCR was used to measure the mRNA levels of CGAS, IFNB1, AIM2, IL1Β, NLRC4, NLRP3, NLRP12 and ZBP1 in the PBMCs and MONs. The Mann-Whitney U test was used to compare the data in LN patients and HCs. Eleven GEO datasets of SLE/LN were used to perform differentially expressed genes (DEGs) analysis to these PRR genes. Receiver operating characteristic (ROC) curve analysis was employed to assess the performance of individual genes or the disease prediction model established by combining multiple genes in LN diagnosis. Spearman correlation method was done to analyze the correlation between these PRRs and other clinical characteristics. RESULTS: The mRNA levels of five genes (AIM2, NLRC4, IL1B, NLRP12 and ZBP1) in PBMCs, and seven genes (CGAS, IFNB1, AIM2, IL1B, NLRP3, NLRP12 and ZBP1) in MONs of LN patients were significantly higher than those of HCs (P < 0.05). DEGs analysis based on the GEO datasets showed that ZBP1, AIM2 and IL1B were significantly increased in several datasets. The ROC curve analysis indicated that the area under curve (AUC) of the LN prediction models derived from PBMCs or MONs were 0.82 or 0.91 respectively. In addition, the expression levels of these PRRs were correlated with other clinical features in LN patients, including Anti-Sm, ESR, serum Cr, and C3. CONCLUSION: Our study suggests that these lupus-related PRRs might be served as potential biomarkers of LN.
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Lupus Eritematoso Sistémico , Nefritis Lúpica , Humanos , Nefritis Lúpica/diagnóstico , Nefritis Lúpica/genética , Nefritis Lúpica/metabolismo , Leucocitos Mononucleares/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR , Monocitos/metabolismo , Biomarcadores , ARN Mensajero/genética , Nucleotidiltransferasas , Curva ROCRESUMEN
BACKGROUND: Uterine corpus endometrial carcinoma (UCEC) is one of the most common gynecological malignancies and its incidence and mortality continue apace. Lysosome-associated membrane protein 3 (LAMP3) is the third member of the LAMP family and its overexpression has been described to be involved in the progression of breast, ovarian and cervical cancers, but there has been an absence of research focusing on its role in UCEC. METHODS: WGCNA, TIMER, LinkedOmics, GSEA, Cytoscape, Kaplan-Meier plotter, GDC, GeneMANIA, cBioPortal, PDB, RNAinter, miRNet were applied in this research. RESULTS: Our study uncovers that LAMP3 possesses higher expression levels in UCEC compared to normal tissues, and this differential expression profile is tightly aligned with clinical and pathological features, and patients demonstrating high LAMP3 expression tend to have a shorter survival expectancy. The high expression of LAMP3 is modulated by the designated ceRNA network. LAMP3 is engaged in UCEC progression by functioning in a variety of biological roles of relevance to immunity. Furthermore, we predicted several prospering drugs based on drug sensitivity. Finally, we also constructed possible docking patterns of LAMP3 with ABCA3, RAB9A, and SGTB. CONCLUSIONS: LAMP3 is a formidable biomarker for UCEC and could be a prospective candidate for the diagnosis, treatment and prognostic assessment of UCEC.
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Mama , Carcinoma Endometrioide , Humanos , Femenino , Pronóstico , Proteínas de Neoplasias , Proteína 3 de la Membrana Asociada a LisosomaRESUMEN
Nipah virus (NiV) causes severe, lethal encephalitis in humans and pigs. However, there is no licensed vaccine available to prevent NiV infection. In this study, we used the reverse genetic system based on the attenuated rabies virus strain SRV9 to construct two recombinant viruses, rSRV9-NiV-F and rSRV9-NiV-G, which displayed the NiV envelope glycoproteins F and G, respectively. Following three immunizations in BALB/c mice, the inactivated rSRV9-NiV-F and rSRV9-NiV-G alone or in combination, mixed with the adjuvants ISA 201 VG and poly (I:C), were able to induce the antigen-specific cellular and Th1-biased humoral immune responses. The specific antibodies against rSRV9-NiV-F and rSRV9-NiV-G had reactivity with two constructed bacterial-like particles displaying the F and G antigens of NiV. These data demonstrate that rSRV9-NiV-F or rSRV9-NiV-G has the potential to be developed into a promising vaccine candidate against NiV infection.