The incidence of acute kidney injury (AKI) due to ischemia-reperfusion (IR) injury is increasing. There is no effective treatment for AKI, and because of this clinical challenge, AKI often progresses ...to chronic kidney disease, which is closely associated with poor patient outcomes and high mortality rates. Small extracellular vesicles from human umbilical cord mesenchymal stem cells (hUCMSC-sEVs) play increasingly vital roles in protecting tissue function from the effects of various harmful stimuli owing to their specific biological features. In this study, we found that miR-100-5p was enriched in hUCMSC-sEVs, and miR-100-5p targeted FKBP5 and inhibited HK-2 cell apoptosis by activating the AKT pathway. HK-2 cells that were exposed to IR injury were cocultured with hUCMSC-sEVs, leading to an increase in miR-100-5p levels, a decrease in FKBP5 levels, and an increase in AKT phosphorylation at Ser 473 (AKT-473 phosphorylation). Notably, these effects were significantly reversed by transfecting hUCMSCs with an miR-100-5p inhibitor. Moreover, miR-100-5p targeted FKBP5, as confirmed by a dual luciferase reporter assay. In vivo, intravenous infusion of hUCMSC-sEVs into mice suffering from IR injury resulted in significant apoptosis inhibition, functional maintenance and renal histological protection, which in turn decreased FKBP5 expression levels. Overall, this study revealed an effect of hUCMSC-sEVs on inhibiting apoptosis; hUCMSC-sEVs reduced renal IR injury by delivering miR-100-5p to HK-2 cells, targeting FKBP5 and thereby promoting AKT-473 phosphorylation to activate the AKT pathway. This study provides novel insights into the role of hUCMSC-sEVs in the treatment of AKI.
Renal ischemia-reperfusion (I/R) injury is a leading cause of acute kidney injury (AKI), with high mortality. Recent studies have reported that human umbilical cord mesenchymal stem cells (HucMSCs) ...play an important role in repairing organ and tissue injuries because of their unique characteristics. However, the potential of HucMSC extracellular vesicles (HucMSC-EVs) to promote the repair of renal tubular cells remains to be explored. This study found that HucMSC-EVs derived from HucMSCs played a protective role and were associated with kidney I/R injury. We found that miR-148b-3p in HucMSC-EVs had a protective effect against kidney I/R injury. HK-2 cells overexpressing miR-148b-3p were protected against I/R injury by inhibiting apoptosis. Next, the target mRNA of miR-148b-3p was predicted online, and the target mRNA, pyruvate dehydrogenase kinase 4 (
), was identified and verified using dual luciferase. We discovered that I/R injury significantly increased endoplasmic reticulum (ER) stress, whereas siR-PDK4 inhibited these effects and protected against I/R injury. Interestingly, after administrating HucMSC-EVs to HK-2 cells,
expression and ER stress induced by I/R injury were significantly inhibited. HK-2 ingested miR-148b-3p from HucMSC-EVs, and its ER induced by I/R injury was significantly deregulated. This study suggests that HucMSC-EVs protect kidneys from I/R injury during the early I/R stage. These results suggest a new mechanism for HucMSC-EVs in treating AKI and provide a new treatment strategy for I/R injury.
This retrospective study aimed to describe our institutional experience with cytoreductive cystectomy (Cx) in patients with pathological T4 (pT4) bladder cancer (BCa) and to investigate the ...clinicopathologic factors that can predict patient survival outcomes.
We reviewed the baseline demographics, clinicopathologic features, perioperative complications, and follow-up data of 44 patients who underwent Cx for pT4 BCa at our institution between 2013 and 2021. The Kaplan-Meier curve and the log-rank test were used to analyze progression-free survival (PFS) and overall survival (OS). Univariate and multivariate analyses were performed using the Cox regression model.
The median age of the patients was 68 years 95% confidence interval (CI) 49-81. Overall, 21 patients (47.7%) were estimated to have a high age-adjusted Charlson comorbidity index (ACCI) score (>4), and nine patients (20.5%) had pT4b substage BCa. None of the patients died of complications within 30-90 days after surgery. Severe complications occurred in 16% (
= 7) of patients within 30-90 days. During a median follow-up of 51 months, disease progression was detected in 25 patients (56.8%), and 29 patients (65.9%) died of any cause. The median PFS and OS were 15.0 and 21.0 months, respectively. The Kaplan-Meier analysis indicated that patients with high ACCI scores or pT4b BCa had worse PFS (
= 0.003 and
= 0.002, respectively) and OS (
= 0.016 and
= 0.034, respectively) than those with low ACCI scores or pT4a BCa. On multivariate analysis, pT4b substage hazard ratio (HR), 4.166; 95% CI, 1.549-11.206;
= 0.005 and ACCI score >4 (HR, 2.329; 95% CI, 1.105-4.908;
= 0.026) remained independent risk factors for PFS and OS, respectively.
Our study revealed that the pT4b substage is associated with a poor prognosis and that the ACCI score is a relevant and practical method to evaluate survival outcomes in patients with pT4 BCa after Cx.
Ferroptosis is a predominant contributor to graft kidney ischemia‒reperfusion injury (IRI), resulting in delayed graft function (DGF). However, much less is known about the early predicting ...biomarkers and therapeutic targets of DGF, especially aiming at ferroptosis. Here, we propose a precise predicting model for DGF, relying on the Akirin1 level in extracellular vesicles (EVs) derived from recipient urine 48 h after kidney transplant. In addition, we decipher a new molecular mechanism whereby Akirin1 induces ferroptosis by strengthening TP53‐mediated suppression of SLC7A11 during the graft kidney IRI process, that is, Akirin1 activates the EGR1/TP53 axis and inhibits MDM2‐mediated TP53 ubiquitination, accordingly upregulating TP53 in two ways. Meanwhile, we present the first evidence that miR‐136‐5p enriched in EVs secreted by human umbilical cord mesenchymal stem cells (UM‐EVs) confers robust protection against ferroptosis and graft kidney IRI by targeted inhibition of Akirin1 but knockout of miR‐136‐5p in UM sharply mitigates the protection of UM‐EVs. The functional and mechanistic regulation of Akirin1 is further corroborated in an allograft kidney transplant model in wild‐type and Akirin1‐knockout mice. In summary, these findings suggest that Akirin1, which prominently induces ferroptosis, is a pivotal biomarker and target for early diagnosis and treatment of graft kidney IRI and DGF after kidney transplant.
Proposed model for how UM‐EVs mitigate ferroptosis and protect against graft kidney IRI. Akirin1, which is prominently elevated in the kidney IRI process, promotes EGR1‐mediated TP53 expression and suppresses MDM2‐mediated TP53 ubiquitination and degradation, accordingly upregulating TP53 in two ways. This further enhances TP53‐mediated suppression of SLC7A11 and thus facilitates ferroptosis. MiR‐136‐5p enriched in UM‐EVs protects against ferroptosis and graft kidney IRI by inhibiting Akirin1.
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•The far-field effects of the Indian-Asian collision and the crust-mantle processes triggered by the paleo-Pacific plate formed the Weihe Graben in the Paleogene.•The eastward ...extrusion of the Tibetan Plateau controls the evolution of the Weihe Graben since the Neogene.•The Weihe Graben was formed by a strike-slip and extensional combined mechanism in the Paleogene, but an extensional mechanism since the Neogene.
The Weihe Graben is located in the composite area of the Tethys-Himalayan tectonic and circum-pacific tectonic domains and is an essential structural feature related to Cenozoic intracontinental deformation. However, two different hypotheses, sinistral strike-slip, and extensional mechanism, are proposed for the origin of this graben. In this study, we designed crust-scale analog models based on fault kinematics to better understand the deformation and dynamic mechanisms of the Weihe Graben. Fault kinematics shows early sinistral strike-slip and NW-SE extensional deformation and late NE-SW, S-N, and NW-SE extensional deformation. Our experimental results reveal that Model C1 (sinistral strike-slip + NW-SE extension) is the most similar to the geological structure of the Weihe Graben in the Paleogene. Furthermore, the NE-SW extension results in two larger subsidence areas in the northeast and southwest of the basin, similar to the formation of the two depressions during the Miocene. The S-N extension causes the basin to expand southward and northward, consistent with the sedimentary characteristics of Weihe Graben in the Pliocene. The NW-SE extension leads to relatively strong fault activity in the northwest and southeast of the basin, resembling the active fault characteristics since the Quaternary. Therefore, we propose that the Weihe Graben formed by a strike-slip and extensional combined mechanism in the Eocene-Oligocene, influenced by the far-field effects of the Indian-Asian collision and crust-mantle processes triggered by the stagnant paleo-Pacific plate. Subsequently, during the Neogene-Quaternary, the graben’s development shifted towards an extensional regime under the influence of the eastward extrusion of the Tibetan Plateau.
Gemcitabine resistance is one of the leading causes of bladder cancer (BCa) recurrence and progression. The dysregulation of ferroptosis is involved in this process; however, the underlying ...mechanisms remain unclear. In the current study, we found a prominent increase in long non-coding RNA (lncRNA) small nucleolar RNA host gene 16 (SNHG16) in tumor samples, which was related to advanced tumor grade and poor prognosis. SNHG16 is overexpressed in the starving tumor microenvironment (STME) and induces gemcitabine resistance by inhibiting ferroptosis in BCa. SNHG16 knockdown promotes ferroptosis and increases chemosensitivity to gemcitabine. Mechanistically, the transcription factor MEF2A was markedly upregulated in the STME, facilitating SNHG16 expression. SNHG16 acts as a competing endogenous RNA that sponges miR-425-5p and promotes NOTCH2 expression. SNHG16/miR-425-5p/NOTCH2 is demonstrated, for the first time, to suppress ferroptosis by inducing SLC7A11 and GPX4 expression in vitro and in vivo. Upregulation of miR-425-5p reverses NOTCH2-mediated inhibition of ferroptosis, thereby mitigating gemcitabine resistance. In conclusion, these findings reveal that the STME-activated MEF2A/SNHG16/miR-425-5p/NOTCH2 axis induces gemcitabine resistance by inhibiting ferroptosis and implicate SNHG16 as a potential therapeutic target for chemoresistance.
•The expression of lncRNA SNHG16 is significantly increased in bladder cancer.•Starving tumor microenvironment enhances SNHG16 expression by activating transcription factor MEF2A.•SNHG16 promotes GEM resistance of bladder cancer by inhibiting ferroptosis.•SNHG16 inhibits ferroptosis by sponging miR-425-5p to regulate NOTCH2 expression.
Ferroptosis is a predominant contributor to renal ischemia reperfusion injury (IRI) after kidney transplant, evoking delayed graft function and poorer long-term outcomes. The wide propagation of ...ferroptosis among cell populations in a wave-like manner, developing the "wave of ferroptosis" causes a larger area of tubular necrosis and accordingly aggravates renal allograft IRI. In this study, we decipher a whole new metabolic mechanism underlying ferroptosis and propose a novel spreading pathway of the "wave of ferroptosis" in the renal tissue microenvironment, in which renal IRI cell-secreted small extracellular vesicles (IRI-sEVs) delivering lncRNA WAC-AS1 reprogram glucose metabolism in adjacent renal tubular epithelial cell populations by inducing GFPT1 expression and increasing hexosamine biosynthesis pathway (HBP) flux, and consequently enhances O-GlcNAcylation. Additionally, BACH2 O-GlcNAcylation at threonine 389 in renal tubular epithelial cells prominently inhibits its degradation by ubiquitination and promotes importin α5-mediated nuclear translocation. We present the first evidence that intranuclear BACH2 suppresses SLC7A11 and GPX4 transcription by binding to their proximal promoters and decreases cellular anti-peroxidation capability, accordingly facilitating ferroptosis. Inhibition of sEV biogenesis and secretion by GW4869 and knockout of lncRNA WAC-AS1 in IRI-sEVs both unequivocally diminished the "wave of ferroptosis" propagation and protected against renal allograft IRI. The functional and mechanistic regulation of IRI-sEVs was further corroborated in an allograft kidney transplant model and an in situ renal IRI model. In summary, these findings suggest that inhibiting sEV-mediated lncRNA WAC-AS1 secretion and targeting HBP metabolism-induced BACH2 O-GlcNAcylation in renal tubular epithelial cells may serve as new strategies for protecting against graft IRI after kidney transplant.
To ensure the safety of high-strength bolt materials in an ocean hydrogen-rich environment, this work first studies the H-effect on GS80A steel by mechanical tests and fracture surface observations. ...The experimental mechanical properties with/without the H-effect are compared with each other, showing a strong hydrogen-induced reduction of ductility, ultimate tensile strength, yield strength, and full-cycle fatigue life. To reproduce the S-N curve based on the experimental fatigue life with/without the H-effect, a neural network model and a typical gray theory are used in this paper for the first time. Reasonable agreement is found between these two models. Finally, the H-affected P-S-N curves are obtained based on the Bootstrap method, indicating the fatigue life obtained by the same condition convergence to Weibull distribution.
In this study, a hybrid amorphous strontium titanate (STO) and terahertz metasurface were studied. Because of the excellent physical properties of amorphous STO, such as its dielectric properties and ...high transmittance in the terahertz region, it plays a core role in realizing a novel terahertz (THz) temperature sensor with high performance in the temperature range of 500–608 K. A blue shift of the absorption peaks appeared for the THz wave as the temperature increased, which confirmed the temperature-sensing function. The physical mechanisms underlying this phenomenon were also investigated. After optimization, the best THz temperature sensor with a sensitivity of 2.08 GHz/K was obtained, in which the thickness of the amorphous strontium titanate film was approximately 0.36 µm. This study provides a new opportunity for amorphous STO materials to be applied in THz sensors and demonstrates the realization of amorphous STO-based THz temperature sensors with high performance, low cost, and simple processes.
