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Bladder cancer is one of the most common malignant tumours of the urogenital system, with high morbidity and mortality. In most cases, surgery is considered the first choice of treatment, followed by adjuvant chemotherapy. However, the 5-year recurrence rate is still as high as 65% in patients with non-invasive or in situ tumours and up to 73% in patients with slightly more advanced disease at initial diagnosis. Various treatment methods for bladder cancer have been developed, and hundreds of new immunotherapies are being tested. To date, only a small percentage of people have had success with new treatments, though studies have suggested that the combination of immunotherapy with other therapies improves treatment efficiency and positive outcomes for individuals, with great hopes for the future. In this article, we summarize the origins, therapeutic mechanisms and current status of research on immunotherapeutic agents for bladder cancer.
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Inmunoterapia , Neoplasias de la Vejiga Urinaria , Neoplasias de la Vejiga Urinaria/terapia , Neoplasias de la Vejiga Urinaria/inmunología , Humanos , Inmunoterapia/métodos , Animales , Terapia CombinadaRESUMEN
Surgical crushing of stones alone has not addressed the increasing prevalence of kidney stones. A promising strategy is to tackle the kidney damage and crystal aggregation inherent in kidney stones with the appropriate therapeutic target. FKBP prolyl isomerase 5 (FKBP5) is a potential predictor of kidney injury, but its status in calcium oxalate (CaOx) kidney stones is not clear. This study attempted to elucidate the role and mechanism of FKBP5 in CaOx kidney stones. Lentivirus and adeno-associated virus were used to control FKBP5 expression in a CaOx kidney stone model. Transcriptomic sequencing and immunological assays were used to analyze the mechanism of FKBP5 deficiency in CaOx kidney stones. The results showed that FKBP5 deficiency reduced renal tubular epithelial cells (RTEC) apoptosis and promoted cell proliferation by downregulating BOK expression. It also attenuated cell-crystal adhesion by downregulating the expression of CDH4. In addition, it inhibited M1 polarization and chemotaxis of macrophages by suppressing CXCL10 expression in RTEC. Moreover, the above therapeutic effects were exerted by inhibiting the activation of NF-κB signaling. Finally, in vivo experiments showed that FKBP5 deficiency attenuated stone aggregation and kidney injury in mice. In conclusion, this study reveals that FKBP5 deficiency attenuates cell-crystal adhesion, reduces apoptosis, promotes cell proliferation, and inhibits macrophage M1 polarization and chemotaxis by inhibiting NF-κB signaling. This provides a potential therapeutic target for CaOx kidney stones.
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Cálculos Renales , FN-kappa B , Animales , Ratones , Oxalato de Calcio , Transducción de Señal , Cálculos Renales/genética , ApoptosisRESUMEN
Circular RNA (circRNA) play important roles in the pathological processes of many diseases. By analyzing the results of the GSE100186 chip, we found that the expression of circRNA ZNF609 (circ-ZNF609) was significantly increased in renal cell carcinoma. Recently, there are studies showing that circ-ZNF609 can regulate cell proliferation and invasion ability of various cells. In this study, we investigated whether circ-ZNF609 may affect cell invasion and proliferation in renal carcinoma. Quantitative reverse transcription polymerase chain reaction was performed to detect the expression of circ-ZNF609 in renal carcinoma cell lines and renal epithelial cells. The direct interaction between microRNA-138-5p (miR-138-5p) and forkhead box P4 (FOXP4) or circ-ZNF609 was confirmed by luciferase reporter assay and RNA immunoprecipitation assay. We use Cell Counting Kit-8, 5-ethynyl-2'-deoxyuridine, and Matrigel assays to assess the effect of miR-138-5p or circ-ZNF609 on cell proliferation or invasion ability. And we found that circ-ZNF609 is significantly increased in renal carcinoma cell lines. In addition, the high expression of circ-ZNF609 promotes cell proliferation and invasion ability. In short, our current study reveals the role of the circ-ZNF609/miR-138-5p/FOXP4 regulatory network in renal carcinoma and provides a new perspective for the pathogenesis of renal carcinoma.
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Carcinoma de Células Renales/genética , Factores de Transcripción Forkhead/genética , MicroARNs/genética , ARN Circular/genética , Carcinoma de Células Renales/patología , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Invasividad Neoplásica/genética , Invasividad Neoplásica/patología , Transducción de Señal/genéticaRESUMEN
Long noncoding RNA (lncRNA) exerts an essential role in the pathological processes of many diseases. Our previous study found that lncRNA ATB was highly expressed in renal cell carcinoma (RCC). Cell Counting Kit-8 (CCK-8), 5-ethynyl-2'-deoxyuridine (EdU), and migration-related assays were conducted to access the regulatory effects of lncRNA ATB on proliferative and migratory capacities of RCC cells. Flow cytometry was carried out to determine cell cycle and apoptosis influenced by lncRNA ATB. The interaction among lncRNA ATB, DNMT1, and p53 was evaluated through RNA immunoprecipitation (RIP), chromatin immunoprecipitation (ChIP), and western blot analyses. The results showed that lncRNA ATB knockdown in RCC cell line ACHN inhibited proliferative and migratory capacities and promoted apoptosis. Meanwhile, overexpression of lncRNA ATB in RCC cell line A-498 promoted proliferative and migratory capacities but inhibited apoptosis. RIP and ChIP assays confirmed that lncRNA ATB can bind to DNMT1 and stabilize its expression; meanwhile, it can promote the binding of DNMT1 to p53. Overexpression of p53 partially reversed the proliferative and migratory changes caused by lncRNA ATB. To sum up, our study revealed that high expression of lncRNA ATB could accelerate the proliferative and migratory rates of RCC cells and inhibit cell apoptosis through downregulating p53 via binding to DNMT1.
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Carcinoma de Células Renales/genética , Regulación Neoplásica de la Expresión Génica/genética , ARN Largo no Codificante/genética , Proteína p53 Supresora de Tumor/genética , Apoptosis/genética , Carcinoma de Células Renales/patología , Ciclo Celular/genética , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Regulación hacia Abajo/genética , HumanosRESUMEN
Interactions between the tumor cells and bone marrow (BM) microenvironment promote survival, growth, and chemoresistance of acute myeloid leukemia (AML). The mTOR pathway plays a key role in mediating the AML-BM microenvironment interactions. Here, we report the anti-AML activity of a natural monomer extracted from the Chinese medicinal herb Evodia rutaecarpa, dihydroevocarpine. Our results showed that dihydroevocarpine-induced cytotoxicity, apoptosis, and G0/G1 arrest in AML cells, and inhibited the tumor growth in an AML xenograft model. Importantly, our study revealed that the dihydroevocarpine treatment inhibited the mTOR pathway via suppressing the mTORC1/2 activity, and thus overcame the protective effect of the BM microenvironment on AML cells. Taken together, our findings suggest that dihydroevocarpine could be used as a potential anti-AML agent alone or a therapeutic adjunct in AML therapy, particularly in the presence of the BM microenvironment.
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Antineoplásicos/farmacología , Leucemia Mieloide Aguda , Diana Mecanicista del Complejo 1 de la Rapamicina/efectos de los fármacos , Diana Mecanicista del Complejo 2 de la Rapamicina/metabolismo , Extractos Vegetales/farmacología , Animales , Apoptosis/efectos de los fármacos , Médula Ósea/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Evodia/química , Células HL-60 , Humanos , Leucemia Mieloide Aguda/metabolismo , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Ratones , Ratones Desnudos , Transducción de Señal/efectos de los fármacos , Microambiente Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The CRISPR-Cas system, initially for DNA-level gene editing and transcription regulation, has expanded to RNA targeting with the Cas13d family, notably the RfxCas13d. This advancement allows for mRNA targeting with high specificity, particularly after catalytic inactivation, broadening the exploration of translation regulation. This study introduces a CRISPR-dCas13d-eIF4G fusion module, combining dCas13d with the eIF4G translation regulatory element, enhancing target mRNA translation levels. This module, using specially designed sgRNAs, selectively boosts protein translation in targeted tissue cells without altering transcription, leading to notable protein expression upregulation. This system is applied to a kidney stone disease model, focusing on ferroptosis-linked GPX4 gene regulation. By targeting GPX4 with sgRNAs, its protein expression is upregulated in human renal cells and mouse kidney tissue, countering ferroptosis and resisting calcium oxalate-induced cell damage, hence mitigating stone formation. This study evidences the CRISPR-dCas13d-eIF4G system's efficacy in eukaryotic cells, presenting a novel protein translation research approach and potential kidney stone disease treatment advancements.
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Sistemas CRISPR-Cas , Oxalato de Calcio , Modelos Animales de Enfermedad , Factor 4G Eucariótico de Iniciación , Ferroptosis , Ferroptosis/genética , Ratones , Animales , Oxalato de Calcio/metabolismo , Sistemas CRISPR-Cas/genética , Humanos , Factor 4G Eucariótico de Iniciación/genética , Factor 4G Eucariótico de Iniciación/metabolismo , Cálculos Renales/genética , Cálculos Renales/metabolismo , Biosíntesis de Proteínas/genética , Fosfolípido Hidroperóxido Glutatión Peroxidasa/genética , Fosfolípido Hidroperóxido Glutatión Peroxidasa/metabolismoRESUMEN
Background: Nephrolithiasis, a common and chronic urological condition, exerts significant pressure on both the general public and society as a whole. The precise mechanisms of nephrolith formation remain inadequately comprehended. Nevertheless, the utilization of proteomics methods has not been employed to examine the development of renal calculi in order to efficiently hinder and manage the creation and reappearance of nephrolith. Nowadays, with the rapid development of proteomics techniques, more efficient and more accurate proteomics technique is utilized to uncover the mechanisms underlying diseases. The objective of this study was to investigate the possible alterations of HK-2 cells when exposed to varying amounts of calcium oxalate (CaOx). The aim was to understand the precise development of stone formation and recurrence, in order to find effective preventive and treatment methods. Methods: To provide a complete view of the proteins involved in the development of nephrolithiasis, we utilized an innovative proteomics method called 4D-LFQ proteomic quantitative techniques. HK-2 cells were selected as our experimental subjects. Three groups (n = 3) of HK-2 cells were treated with intervention solutions containing 0 (negative control, NC), 1 mM, and 2 mM CaOx, respectively. For the proteins that showed differential expression, various analyses were conducted including examination of Gene Ontology (GO), Clusters of Orthologous Groups of proteins (KOG), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, enrichment analysis of protein domains, and hierarchical clustering analysis. The STRING database was used to identify the interaction network of the chosen proteins. Candidate proteins were validated using parallel reaction monitoring (PRM) in the end. Results: All three groups verified the repeatability of samples. According to the results of 4D-LFQ proteomic quantitative analysis, there were 120, 262, and 81 differentially expressed proteins (DEPs) in the 1 mM-VS-NC, 2 mM-VS-NC, and 2 mM-VS-1mM conditions, respectively. According to GO annotation, the functional enrichment analysis indicates that the differentially expressed proteins (DEPs) were notably enriched in promoting cell migration and the extracellular matrix, among other functions. Analysis of enrichment, based on the KEGG pathway, revealed significant enrichment of DEPs in complement and coagulation cascades, as well as in ECM-receptor (extracellular matrix-receptor) interaction and other related pathways. 14 DEPs of great interest were selected as candidate proteins, including FN1, TFRC, ITGA3, FBN1, HYOU1, SPP1, HSPA5, COL6A1, MANF, HIP1R, JUP, AXL, CTNNB1 and DSG2.The data from PRM demonstrated the variation trend of 14 DEPs was identical as 4D-LFQ proteomic quantitative analysis. Conclusion: Proteomics studies of CaOx-induced HK-2 cells using 4D-LFQ proteomic quantitative analysis and PRM may help to provide crucial potential target proteins and signaling pathways for elucidating the mechanism of nephrolithiasis and better treating nephrolithiasis.
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ABSTRACT: Glucagon-like peptide 1 (GLP-1) analogs are used to treat type 2 diabetes, and they can regulate insulin secretion, energy homeostasis, inflammation, and immune cell function. This study sought to determine whether the GLP-1 analog liraglutide exerts a beneficial action in an acute lung injury model of pneumonia-induced sepsis. Methods: Wild-type FVB/NJ mice (n = 114) were infected by intratracheal injection with Pseudomonas aeruginosa Xen5 (4 × 10 4 CFU/mouse) or an equal volume (50 µL) of saline (control) with or without a subcutaneous injection of liraglutide (2 mg/kg, 30 min after infection). Mice were killed 24 h after infection. Lung tissues and BALF were analyzed. In separate experiments, the dynamic growth of bacteria and animal mortality was monitored using in vivo imaging system within 48 h after infection. In addition, primary lung alveolar type II cells isolated from mice were used to study the mechanism of liraglutide action. Result: Liraglutide improved survival ( P < 0.05), decreased bacterial loads in vivo , and reduced lung injury scores ( P < 0.01) in septic mice. Liraglutide-treated mice showed decreased levels of inflammatory cells ( P < 0.01) and proinflammatory cytokines (TNF-α and IL-6) ( P < 0.01) in the lung compared with septic controls. Liraglutide significantly increased pulmonary surfactant proteins (SP-A and SP-B) expression/secretion ( P < 0.01) and phospholipid secretion ( P < 0.01) in vivo . Primary alveolar type II cells pretreated with liraglutide improved SP-A and SP-B expression after LPS exposure ( P < 0.01). Conclusion: Liraglutide attenuates mortality and lung inflammation/injury in pneumonia-induced sepsis. The increased surfactant expression/secretion and anti-inflammatory effects of liraglutide represent potential mechanisms by GLP-1 agonists potentiate host defense and maintain alveolar respiratory function in acute lung injury.
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Lesión Pulmonar Aguda , Diabetes Mellitus Tipo 2 , Neumonía , Surfactantes Pulmonares , Sepsis , Ratones , Animales , Liraglutida/efectos adversos , Surfactantes Pulmonares/efectos adversos , Tensoactivos , Lesión Pulmonar Aguda/metabolismo , Péptido 1 Similar al Glucagón , Inflamación , Sepsis/tratamiento farmacológicoRESUMEN
Renal calculi (RC) represent a prevalent disease of the urinary system characterized by a high incidence rate. The traditional clinical diagnosis of RC emphasizes imaging and stone composition analysis. However, the significance of metabolic status in RC diagnosis and prevention remains unclear. This study aimed to investigate serum metabolites in RC patients to identify those associated with RC and to develop a metabolite-based diagnostic model. We employed nontargeted metabolomics utilizing ultra-performance liquid chromatographyâmass spectrometry (UPLCâMS) to compare serum metabolites between RC patients and healthy controls. Our findings demonstrated significant disparities in serum metabolites, particularly in fatty acids and glycerophospholipids, between the two groups. Notably, the glycerophospholipid (GP) metabolic pathway in RC patients was significantly disrupted. Logistic regression models using differentially abundant metabolites revealed that elevated levels of 2-butyl-4-methyl phenol and reduced levels of phosphatidylethanolamine (P-16:0/22:6(4Z,7Z,10Z,13Z,16Z,19Z)) had the most substantial effect on RC risk. Overall, our study indicates that RC induces notable alterations in serum metabolites and that the diagnostic model based on these metabolites effectively distinguishes RC. This research offers promising insights and directions for further diagnostic and mechanistic studies on RC.
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Oxalate is an organic dicarboxylic acid that is a common component of plant foods. The kidneys are essential organs for oxalate excretion, but excessive oxalates may induce kidney stones. Jupiter microtubule associated homolog 2 (JPT2) is a critical molecule in Ca2+ mobilization, and its intrinsic mechanism in oxalate exposure and kidney stones remains unclear. This study aimed to reveal the mechanism of JPT2 in oxalate exposure and kidney stones. Genetic approaches were used to control JPT2 expression in cells and mice, and the JPT2 mechanism of action was analyzed using transcriptomics and untargeted metabolomics. The results showed that oxalate exposure triggered the upregulation of JPT2, which is involved in nicotinic acid adenine dinucleotide phosphate (NAADP)-mediated Ca2+ mobilization. Transcriptomic analysis revealed that cell adhesion and macrophage inflammatory polarization were inhibited by JPT2 knockdown, and these were dominated by phosphatidylinositol 3-kinase (PI3K)/AKT signaling, respectively. Untargeted metabolomics indicated that JPT2 knockdown inhibited the production of succinic acid semialdehyde (SSA) in macrophages. Furthermore, JPT2 deficiency in mice inhibited kidney stones mineralization. In conclusion, this study demonstrates that oxalate exposure facilitates kidney stones by promoting crystal-cell adhesion, and modulating macrophage metabolism and inflammatory polarization via JPT2/PI3K/AKT signaling.
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Oxalate-induced damage to renal tubular epithelial cells (RTECs) is an essential factor in the incident kidney stone, but the specific mechanism is unclear. Recent research has pinpointed interacting areas within the endoplasmic reticulum and mitochondria, called mitochondria-associated membranes (MAMs). These studies have linked endoplasmic reticulum stress (ERS) and oxidative imbalance to kidney disease development. The sigma-1 receptor (S1R), a specific protein found in MAMs, is involved in various physiological processes, but its role in oxalate-induced kidney stone formation remains unclear. In this study, we established cellular and rat models of oxalate-induced kidney stone formation to elucidate the S1R's effects against ERS and apoptosis and its mechanism in oxalate-induced RTEC injury. We found that oxalate downregulated S1R expression in RTECs and escalated oxidative stress and ERS, culminating in increased apoptosis. The S1R agonist dimemorfan up-regulated S1R expression and mitigated ERS and oxidative stress, thereby reducing apoptosis. This protective effect was mediated through S1R inhibition of the CHOP pathway. Animal experiments demonstrated that S1R's activation attenuated oxalate-induced kidney injury and alleviated kidney stone formation. This is the first study to establish the connection between S1R and kidney stones, suggesting S1R's protective role in inhibiting ERS-mediated apoptosis to ameliorate kidney stone formation.
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Apoptosis , Estrés del Retículo Endoplásmico , Retículo Endoplásmico , Células Epiteliales , Túbulos Renales , Mitocondrias , Nefrolitiasis , Receptores sigma , Receptor Sigma-1 , Receptores sigma/metabolismo , Animales , Estrés del Retículo Endoplásmico/efectos de los fármacos , Apoptosis/efectos de los fármacos , Ratas , Células Epiteliales/metabolismo , Células Epiteliales/efectos de los fármacos , Túbulos Renales/metabolismo , Túbulos Renales/patología , Nefrolitiasis/metabolismo , Mitocondrias/metabolismo , Mitocondrias/efectos de los fármacos , Retículo Endoplásmico/metabolismo , Retículo Endoplásmico/efectos de los fármacos , Masculino , Estrés Oxidativo/efectos de los fármacos , Ratas Sprague-DawleyRESUMEN
BACKGROUND: Clinically, using ileal conduit for urinary diversion often caused many serious complications. Tissue engineering technology may offer an alternative method for urinary diversion after radical cystectomy. In this study, we aimed to make a tissue-engineered tubular graft (TETG) using bladder epithelial cells and bladder acellular matrix (BAM) for urinary diversion in rabbits. METHODS: Bladder epithelial cells of rabbit were cultivated and expanded in vitro, which were then seeded on BAM and cultured for 7 d. Then, cell-seeded grafts of 4 cm length and 0.8 cm diameter were used to make TETGs and transferred into the omentum for 2 wk before urinary diversion. In the experimental group, bladders of the rabbits were removed. The proximal ends of TETGs were anastomosed with ureters, and the distal ends were anastomosed with the abdominal stomas. In the control group, TETGs were constructed using unseeded BAM. Newly formed tissue structures were functionally and microscopically evaluated using urography and immunohistochemistry at 1, 2, 4, and 8 wk after operation, respectively. Histologic examination with hematoxylin and eosin staining was conducted to assess tissue regeneration. Immunohistochemistry was performed with AE1/AE3, uroplakin â ¢a, and zonula occludens 1 (ZO-1) antibodies. RESULTS: All animals were alive in the experimental group. Hematoxylin and eosin staining showed epithelial coverage in TETG. Immunohistochemistry showed positive stain with AE1/AE3, uroplakin â ¢a, and ZO-1, which indicated mature and functional epithelial cells on the lumen of TETG. Intravenous urography showed that there were no obstructions in TETGs. In the control group, four rabbits were dead within 2 wk, and scar formation, atresia, and severe hydronephrosis were found. CONCLUSIONS: It was feasible that TETG constructed using bladder epithelial cells and BAM for urinary diversion after radical cystectomy in rabbits.
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Cistectomía/métodos , Ingeniería de Tejidos/métodos , Vejiga Urinaria/cirugía , Derivación Urinaria/métodos , Animales , Células Epiteliales/fisiología , Masculino , Conejos , Vejiga Urinaria/citologíaRESUMEN
The high incidence, recurrence and treatment costs of urolithiasis have a serious impact on patients and society. For a long time, countless scholars have been working tirelessly on studies related to the etiology of urolithiasis. A comprehensive understanding of the current status will be beneficial to the development of this field. We collected all literature about the etiology of urolithiasis from 1990 to 2022 using the Web of Science (WoS) database. VOSviewer, Bibliometrix and CiteSpace software were used to quantitatively analyze and visualize the data as well. The query identified 3177 articles for final analysis, of which related to the etiology of urolithiasis. The annual number of publications related to urolithiasis research has steadily increased during the latest decade. United States (1106) and China (449) contributed the most publications. University of Chicago (92) and Indiana University (86) have the highest number of publications. Urolithiasis and Journal of Urology have published the most articles in the field. Coe FL is the most productive author (63 articles), whose articles have obtained the most citations in all (4141 times). The keyword, such as hypercalciuria, hyperoxaluria, citrate, oxidative stress, inflammation, Randall's plaque, are the most attractive targets for the researchers. Our review provides a global landscape of studies related to the etiology of urolithiasis, which can serve as a reference for future studies in this field.
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Bibliometría , Urolitiasis , Humanos , China , Bases de Datos Factuales , Urolitiasis/etiologíaRESUMEN
Background: Lymphovascular invasion (LVI) is a high-risk factor for testicular germ-cell tumors (TGCT), but a prognostic model for TGCT-LVI patients is lacking. This study aimed to develop a nomogram for predicting the overall survival (OS) of TGCT-LVI patients. Methods: A complete cohort of 3288 eligible TGCG-LVI patients (training cohort, 2300 cases; validation cohort, 988 cases) were obtained from the Surveillance, Epidemiology, and End Results database. Variables screened by multivariate Cox regression analysis were used to construct a nomogram, which was subsequently evaluated using the consistency index (C-index), time-dependent receiver operating characteristic curve (ROC), and calibration plots. The advantages and disadvantages of the American Joint Committee on Cancer (AJCC) staging system and the nomogram were assessed by integrated discrimination improvement (IDI) and net reclassification improvement (NRI). Decision-analysis curve (DCA) was used to measure the net clinical benefit of the nomogram versus the AJCC staging system. Finally, Kaplan-Meier curves were used to evaluate the ability to identify different risk groups between the traditional AJCC staging system and the new risk-stratification system built on the nomogram. Results: Nine variables were screened by multivariate Cox regression analysis to construct the nomogram. The C-index (training cohort, 0.821; validation cohort, 0.819) and time-dependent ROC of 3-, 5-, and 9-year OS between the two cohorts suggested that the nomogram had good discriminatory ability. Calibration curves showed good consistency of the nomogram. The NRI values of 3-, 5-, and 9-year OS were 0.308, 0.274, and 0.295, respectively, and the corresponding values for the validation cohort were 0.093, 0.093, and 0.099, respectively (P<0.01). Additionally, the nomogram had more net clinical benefit as shown by the DCA curves, and the new risk-stratification system provided better differentiation than the AJCC staging system. Conclusions: A prognostic nomogram and new risk-stratification system were developed and validated to assist clinicians in assessing TGCT-LVI patients.
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Schizandrin B (SchB) protects against oxidative, inflammatory, and ferroptotic injury. Oxidative stress and inflammation are indispensably involved in nephrolithiasis and ferroptosis also plays an important role in stone formation. It is unclear whether SchB can ameliorate nephrolithiasis; its underlying mechanism is also unknown. First, we employed bioinformatics to investigate the mechanisms of nephrolithiasis. To evaluate the efficacy of SchB, HK-2 cell models of oxalate-induced damage, Erastin-induced ferroptosis, and the Sprague Dawley rat model of Ethylene Glycol-induced nephrolithiasis were established. Then, Nrf2 siRNA and GSK3ß overexpression plasmids were transfected into HK-2 cells to elucidate the role of SchB in regulating oxidative stress-mediated ferroptosis. In our study, oxidative stress and inflammation were strongly associated with nephrolithiasis. Administration of SchB attenuated the cell viability, dysfunctional mitochondria, oxidative stress and inflammatory response in vitro and alleviated renal injury and crystal deposition in vivo. SchB treatment also reduced the levels of cellular Fe2+ accumulation, lipid peroxidation and MDA, and regulated ferroptosis-related proteins, including XCT, GPX4, FTH1 and CD71, in Erastin-induced or oxalate-induced HK-2 cells. Mechanistically, SchB facilitated Nrf2 nuclear translocation, and silencing Nrf2 or overexpressing GSK3ß worsened oxalate-induced oxidative injury and abolished the beneficial effect of SchB against ferroptosis in vitro. To summarize, SchB could alleviate nephrolithiasis by positively regulating GSK3ß/Nrf2 signaling-mediated ferroptosis.
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Ferroptosis , Nefrolitiasis , Ratas , Animales , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , Glucógeno Sintasa Quinasa 3 beta , Ratas Sprague-Dawley , Inflamación , Oxalatos/farmacologíaRESUMEN
The Holmium (Ho:YAG) laser is presently the most extensively employed in laser lithotripsy for the management of kidney stones. Despite its adoption as the gold standard for laser lithotripsy, Ho:YAG laser lithotripsy poses three significant challenges, namely thermal effect, insufficient stone fragmentation, and stone displacement, which have garnered increased attention from urologic surgeons. Nowadays, the femtosecond laser is regarded as a potential alternative to the Ho:YAG laser due to its capacity to ablate diverse materials with minimal thermal effect. In our ex vivo investigation, we assessed the dimensions of ablation pits, the efficacy of ablation, the degree of stone fragmentation, the alterations in water temperature surrounding stones, and the degree of tissue damage associated with Femtosecond laser lithotripsy utilizing adjustable power settings (1-50 W). Our findings indicate that the ablation pits generated by the Femtosecond laser exhibited uniform geometries, and the effectiveness of ablation and fragmentation for Femtosecond laser lithotripsy were significantly and positively correlated with laser power. When the laser power remained constant, the Femtosecond laser with higher pulse energy demonstrated superior efficiency in stone ablation, but inferior performance in stone fragmentation. Conversely, the Femtosecond laser with higher pulse frequency exhibited the opposite behavior. Furthermore, the thermal effect increased proportionally with laser power, leading to a tentative recommendation of 10W laser power for future investigations. Our in vitro findings suggest that the Femtosecond laser holds promise as a safe and effective alternative to holmium lasers.
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Cálculos Renales , Láseres de Estado Sólido , Litotripsia por Láser , Litotricia , Humanos , Litotripsia por Láser/efectos adversos , Litotripsia por Láser/métodos , Litotricia/efectos adversos , Cálculos Renales/cirugía , Láseres de Estado Sólido/uso terapéutico , HolmioRESUMEN
Introduction: Pneumonia-induced sepsis can cause multiple organ dysfunction including acute lung and kidney injury (ALI and AKI). Surfactant protein A (SP-A), a critical innate immune molecule, is expressed in the lung and kidney. Extracellular vesicles like exosomes are involved in the processes of pathophysiology. Here we tested one hypothesis that SP-A regulates pneumonia-induced AKI through the modulation of exosomes and cell death. Methods: Wild-type (WT), SP-A knockout (KO), and humanized SP-A transgenic (hTG, lung-specific SP-A expression) mice were used in this study. Results: After intratracheal infection with Pseudomonas aeruginosa, KO mice showed increased mortality, higher injury scores, more severe inflammation in the lung and kidney, and increased serum TNF-α, IL-1ß, and IL-6 levels compared to WT and hTG mice. Infected hTG mice exhibited similar lung injury but more severe kidney injury than infected WT mice. Increased renal tubular apoptosis and pyroptosis in the kidney of KO mice were found when compared with WT and hTG mice. We found that serum exosomes from septic mice cause ALI and AKI through mediating apoptosis and proptosis when mice were injected intravenously. Furthermore, primary proximal tubular epithelial cells isolated from KO mice showed more sensitivity than those from WT mice after exposure to septic serum exosomes. Discussion: Collectively, SP-A attenuates pneumonia-induced ALI and AKI by regulating inflammation, apoptosis and pyroptosis; serum exosomes are important mediators in the pathogenesis of AKI.
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Lesión Renal Aguda , Exosomas , Neumonía , Animales , Ratones , Proteína A Asociada a Surfactante Pulmonar/metabolismo , Exosomas/metabolismo , Lesión Renal Aguda/metabolismo , Neumonía/complicaciones , Inflamación , Riñón/patología , Pulmón/patologíaRESUMEN
Background: The identification of uropathogens (UPBs) and urinary tract colonizing bacteria (UCB) conduces to guide the antimicrobial therapy to reduce resistant bacterial strains and study urinary microbiota. This study established a nomogram based on the nanopore-targeted sequencing (NTS) and other infectious risk factors to distinguish UPB from UCB. Methods: Basic information, medical history, and multiple urine test results were continuously collected and analyzed by least absolute shrinkage and selection operator (LASSO) regression, and multivariate logistic regression was used to determine the independent predictors and construct nomogram. Receiver operating characteristics, area under the curve, decision curve analysis, and calibration curves were used to evaluate the performance of the nomogram. Results: In this study, the UPB detected by NTS accounted for 74.1% (401/541) of all urinary tract microorganisms. The distribution of ln(reads) between UPB and UCB groups showed significant difference (OR = 1.39; 95% CI, 1.246-1.551, p < 0.001); the reads number in NTS reports could be used for the preliminary determination of UPB (AUC=0.668) with corresponding cutoff values being 7.042. Regression analysis was performed to determine independent predictors and construct a nomogram, with variables ranked by importance as ln(reads) and the number of microbial species in the urinary tract of NTS, urine culture, age, urological neoplasms, nitrite, and glycosuria. The calibration curve showed an agreement between the predicted and observed probabilities of the nomogram. The decision curve analysis represented that the nomogram would benefit clinical interventions. The performance of nomogram with ln(reads) (AUC = 0.767; 95% CI, 0.726-0.807) was significantly better (Z = 2.304, p-value = 0.021) than that without ln(reads) (AUC = 0.727; 95% CI, 0.681-0.772). The rate of UPB identification of nomogram was significantly higher than that of ln(reads) only (χ2 = 7.36, p-value = 0.009). Conclusions: NTS is conducive to distinguish uropathogens from colonizing bacteria, and the nomogram based on NTS and multiple independent predictors has better prediction performance of uropathogens.
Asunto(s)
Microbiota , Secuenciación de Nanoporos , Nanoporos , Nomogramas , Bacterias/genéticaRESUMEN
Bioinspired surfaces with special wettabilities attract increasing attention due to their extensive applications in many fields. However, the characterizations of surface wettability by contact angle (CA) and sliding angle (SA) have clear drawbacks. Here, by using an array of triangular micropillars (ATM) prepared by soft lithography, the merits of measuring the friction force of a water droplet on ATM over measurements of CA and SA in characterizing the surface wettability are demonstrated. The CA and SA measurements show ignorable differences in the wettabilities of ATM in opposite directions (1.13%) and that with different periodic parameters under the elongation ranging from 0 to 70%. In contrast, the friction measurement reveals a difference of > 10% in opposite directions. Moreover, the friction force shows a strong dependence on the periodic parameters which is regulated by mechanical stretching. Increasing the elongation from 0 to 50% increases the static and kinetic friction force up to 23.0% and 22.9%, respectively. Moreover, the stick-slip pattern during kinetic friction can reveal the periodic features of the measured surface. The friction force measurement is a sensitive technique that could find applications in the characterization of surface wettabilities.