Neutrophil-derived nanovesicles deliver IL-37 to mitigate renal ischemia-reperfusion injury via endothelial cell targeting.

Renal ischemia-reperfusion injury (IRI) is one of the most important causes of acute kidney injury (AKI). Interleukin (IL)-37 has been suggested as a novel anti-inflammatory factor for the treatment of IRI, but its application is still limited by its low stability and delivery efficiency. In this study, we reported a novel engineered method to efficiently and easily prepare neutrophil membrane-derived vesicles (N-MVs), which could be utilized as a promising vehicle to deliver IL-37 and avoid the potential side effects of neutrophil-derived natural extracellular vesicles. N-MVs could enhance the stability of IL-37 and targetedly deliver IL-37 to damaged endothelial cells of IRI kidneys via P-selectin glycoprotein ligand-1 (PSGL-1). In vitro and in vivo evidence revealed that N-MVs encapsulated with IL-37 (N-MV@IL-37) could inhibit endothelial cell apoptosis, promote endothelial cell proliferation and angiogenesis, and decrease inflammatory factor production and leukocyte infiltration, thereby ameliorating renal IRI. Our study establishes a promising delivery vehicle for the treatment of renal IRI and other endothelial damage-related diseases.

Long noncoding RNA XIST inhibition promotes Leydig cell apoptosis by acting as a competing endogenous RNA for microRNA-145a-5p that targets SIRT1 in late-onset hypogonadism.

Leydig cell (LCs) apoptosis is responsible for decreased serum testosterone levels during late-onset hypogonadism (LOH). Our study was designed to illustrate the regulatory effect of lncRNA XIST on LCs and to clarify its molecular mechanism of action in LOH. The Leydig cells (TM3) was treated by 300 µM H2O2 for 8 h to establish Leydig cell oxidative stress model in vitro. The expression levels of lncRNA XIST in the testicular tissues of patients with LOH were measured using fluorescence in situ hybridization (FISH). The interaction between lncRNA XIST/SIRT1 and miR-145a-5p was assessed using starBase and dual-luciferase reporter gene assays. Apoptotic cells and Caspase3 activity were determined by flow cytometry (FCM) assay. Testosterone concentration was determined by ELISA. Moreover, histological assessment of testicles in mice was performed by using HE staining and the TUNEL assay was used to determine apoptosis. We found that the lncRNA XIST was downregulated in the testicular tissues of LOH patients and mice and in H2O2-induced TM3 cells. XIST siRNA significantly promoted apoptosis, enhanced Caspase3 activity and reduced testosterone levels in H2O2-stimulated TM3 cells. Further studies showed that the miR-145a-5p inhibitor reversed the effect of XIST-siRNA on H2O2-induced Leydig cell apoptosis. MiR-145a-5p negatively regulated SIRT1 expression, and SIRT1-siRNA reversed the effects of the miR-145a-5p inhibitor on H2O2 stimulated TM3 cells. The in vivo experiments indicated that silencing of the lncRNA XIST aggravated LOH symptoms in mice. Inhibition of lncRNA XIST induces Leydig cell apoptosis through the miR-145a-5p/SIRT1 axis in the progression of LOH.

Negatively charged bladder acellular matrix loaded with positively charged adipose-derived mesenchymal stem cell-derived small extracellular vesicles for bladder tissue engineering.

Adipose-derived mesenchymal stem cell-derived small extracellular vesicles (Ad-MSC-sEVs/AMEs) combined with scaffold materials are used in tissue-engineered bladders; however, the lack of retention leads to limited distribution of AMEs in the scaffold areas and low bioavailability of AMEs after bladder reconstruction. To improve retention of AMEs, we developed a novel strategy that modifies the surface charge of the bladder acellular matrix (BAM) via oxidative self-polymerization of dopamine-reducing graphene oxide (GO) and AMEs using ε-polylysine-polyethylene-distearyl phosphatidylethanolamine (PPD). We evaluated two BAM surface modification methods and evaluated the biocompatibility of materials and PPD and electrostatic adherence effects between PPD-modified AMEs and rGO-PDA/BAM in vivo and in vitro. Surface modification increased retention of AMEs, enhanced regeneration of bladder structures, and increased electrical conductivity of rGO-PDA/BAM, thereby improving bladder function recovery. RNA-sequencing revealed 543 miRNAs in human AMEs and 514 miRNAs in rat AMEs. A Venn diagram was used to show target genes of miRNA with the highest proportion predicted by the four databases; related biological processes and pathways were predicted by KEGG and GO analyses. We report a strategy for improving bioavailability of AMEs for bladder reconstruction and reveal that enriched miR-21-5p targets PIK3R1 and activates the PI3K/Akt pathway to promote cell proliferation and migration.

Endoscopic dilation using two guidewires: a novel approach for establishing access tract during percutaneous nephrolithotomy under ultrasonographic guidance.

OBJECTIVE: To evaluate the efficacy and safety of a novel endoscopic dilation (END) method during percutaneous nephrolithotomy under ultrasonographic guidance. METHODS: We retrospectively reviewed the clinical records of 138 patients who underwent percutaneous nephrolithotomy from June 2020 to December 2021. The patients were divided into three groups based on the method of nephrostomy tract creation: those who underwent fascial Amplatz serial fascial dilation (AMD) (n = 45), one-shot dilation (OSD) (n = 45), and END (n = 48). For END, a 20-Fr dilator with sheath was accessed over the first guidewire. A second guidewire was inserted into the collecting system via the endoscope. The nephroscope was then accessed to enlarge the renal puncture point using both guidewires. Demographic variables and important intraoperative and postoperative findings were compared among the three groups. RESULTS: The preoperative characteristics were similar among the three groups. The END group had a significantly shorter access time than both the AMD and OSD groups and significantly less severe hemoglobin loss than the OSD group. There were no significant differences in the other important perioperative findings. CONCLUSION: Use of this novel END method with two guidewires may be associated with less blood loss and a reduced access time.

Porous gelatin microspheres implanted with adipose mesenchymal stromal cells promote angiogenesis via protein kinase B/endothelial nitric oxide synthase signaling pathway in bladder reconstruction.

BACKGROUND AIMS: Cell failure and angiogenesis are the key to bladder wall regeneration. Three-dimensional (3D) culture using porous gelatin microspheres (GMs) as a vehicle promotes stem cell proliferation and improves the paracrine capacity of cells. This study aimed to evaluate the therapeutic potential of GMs constructed from adipose-derived mesenchymal stromal cells (ADSCs) (ADSC-GMs) combined with bladder acellular matrix (BAM) in tissue-engineered bladders. METHODS: Isolation of ADSCs, flow cytometry, scanning electron microscopy and cell counting kit-8, ß-galactosidase and enzyme-linked immunosorbent assays were performed in vitro to compare two-dimensional (2D) and 3D cultures. In the in vivo study, male Sprague-Dawley rats were randomly divided into three groups: the BAM replacement alone (BAM) group, ADSCs grown on BAM in replacement (ADSC) group and ADSC-GMs combined with BAM followed by replacement (ADSC-GM) group. Bladder function assessed by urodynamics after 12 weeks of bladder replacement, and the rats were sacrificed at 4 and 12 weeks for further experiments. RESULTS: The in vitro results showed that GM culture promoted ADSC proliferation, inhibited apoptosis and delayed senescence compared with those in the 2D culture. In addition, ADSC-GMs increased the secretion of the angiogenic factors vascular endothelial growth factor, platelet-derived growth factor-BB, and basal fibroblast growth factor. In vivo experiments revealed that ADSC-GMs adhered to the BAM for longer than ADSCs. Moreover, ADSC-GMs significantly promoted the regeneration of bladder vessels and smooth muscle, thereby facilitating the recovery of bladder function. The expression of phosphorylated protein kinase B (AKT) and phosphorylated endothelial nitric oxide synthase (eNOS) was significantly greater in the ADSC-GMs group compared with the BAM and ADSCs groups. CONCLUSIONS: ADSC-GMs increased retention of ADSCs on the BAM, thereby promoting the regeneration and functional recovery of the bladder tissue. ADSC-GMs promoted angiogenesis by activating the AKT/eNOS pathway.

Construction of tissue-engineered bladders using an artificial acellular nanocomposite scaffold loaded with stromal vascular fraction secretome.

Tissue engineering approaches offer promising alternative strategies for reconstructing bladder tissue; however, the low retention of transplanted cells and the possible risk of rejection limit their therapeutic efficacy. Clinical applicability is further limited by the lack of suitable scaffold materials to support the needs of various cell types. In the present study, we developed an artificial nanoscaffold system consisting of stromal vascular fraction (SVF) secretome (Sec) loaded onto zeolitic imidazolate framework-8 (ZIF-8) nanoparticles, which were then incorporated into bladder acellular matrix. This artificial acellular nanocomposite scaffold (ANS) can achieve gradient degradation and slowly release SVF-Sec to promote tissue regeneration. Furthermore, even after long-term cryopreservation, this completely acellular bladder nanoscaffold material still maintains its efficacy. In a rat bladder replacement model, ANS transplantation demonstrated potent proangiogenic ability and induced M2 macrophage polarization to promote tissue regeneration and restore bladder function. Our study demonstrates the safety and efficacy of the ANS, which can play a stem cell-like role while avoiding the disadvantages of cell therapy. Furthermore, the ANS can replace the bladder regeneration model based on cell-binding scaffold materials and has the potential for clinical application. STATEMENT OF SIGNIFICANCE: This study aimed to develop a gradient-degradable artificial acellular nanocomposite scaffold (ANS) loaded with stromal vascular fraction (SVF) secretome for rehabilitating bladders. Using various in vitro methods as well as rat- and zebrafish-based in vivo models, the developed ANS was assessed for efficacy and safety. Results indicated that the ANS achieved gradient degradation and slowly released the SVF secretome to promote tissue regeneration, even after long-term cryopreservation. Furthermore, ANS transplantation demonstrated a potent pro-angiogenic ability and induced M2 macrophage polarization to promote tissue regeneration and restore bladder function in a bladder replacement model. Our study demonstrates that ANS may replace bladder regeneration models based on cell-binding scaffold materials and have potential clinical application.

Analyzing factors driving of eutrophication of river-type urban landscape lakes.

The eutrophication of river-type urban landscape (RTUL) lakes is different from that of natural lakes. In this study, Xiaofu Lake, a typical RTUL lake with high anthropogenic interference, was used as the study area. Monitoring data from 2018 to 2020 were used to analyze the temporal and spatial distribution characteristics of chlorophyll a (Chl-a) concentrations with meteorological, hydrodynamic, and nutrient factors. Correlation and regression analyses were used to identify the relationship between the factors influencing eutrophication and the Chl-a. The MIKE21 model is used to simulate changes in water quality indicators. The study determined the relationship between river water quality and environmental factors and explored the causes of eutrophication in the water bodies of Xiaofu Lake. The results showed that from 2018 to 2020, the water quality showed seasonal variation and differences in spatial distribution. Except for total nitrogen, which remained at a high level (average 8.23 mg/L), other water qualities remained between classes II and IV. The proportions of mild, moderate, and severe eutrophication in the study area were 25%, 69%, and 6%, respectively. Indicators that were highly correlated with water eutrophication were turbidity, water temperature, total phosphorus, and permanganate index. The contribution of water temperature, ammonia nitrogen, and permanganate index to eutrophication was 30.5%, 22.6%, and 20.9%, respectively. The high proportion of sewage in the source of recharge water is one of the reasons for the deterioration of water quality. In addition, the change in water eutrophication was closely related to the gate operation in the region. PRACTITIONER POINTS: There are differences between river-type urban landscape (RTUL) lakes and natural lakes, and the conditions that cause eutrophication are different. RTUL are subject to strong human interference and rely on water transfer and gate scheduling to maintain water quantity. The high proportion of sewage treatment plant tailwater in upstream water is the main reason for the long-term pollution of RTUL. The indicators highly correlated with water eutrophication are turbidity, water temperature, total phosphorus, and permanganate index.

Sig1R activates extracellular matrix-induced bladder cancer cell proliferation and angiogenesis by combing ß-integrin.

The extracellular matrix (ECM) regulates many biological functions involved in tumorigenesis and tumor development; however, the underlying mechanism remains unknown. Sigma 1 receptor (Sig1R), a stress-activated chaperone, regulates the crosstalk between the ECM and tumor cells and is related to the malignant characteristics of several tumors. However, the link between Sig1R overexpression and ECM during malignancy has not been established in bladder cancer (BC). Here, we analyzed the interaction of Sig1R and ß-integrin in BC cells and its role in ECM-mediated cell proliferation and angiogenesis. We found that Sig1R forms a complex with ß-integrin to promote ECM-mediated BC cell proliferation and angiogenesis, which enhances the aggressiveness of the tumor cells. This leads to poor survival. Our research revealed that Sig1R mediates the cross-talk between BC cells and their ECM microenvironment, thereby driving the progression of BC. Promisingly, targeting an ion channel function through Sig1R inhibition may serve as a potential approach for BC treatment.

Immunomagnetic Delivery of Adipose-Derived Endothelial Progenitor Cells for the Repair of Renal Ischemia-Reperfusion Injury in a Rat Model.

Renal ischemia-reperfusion injury (IRI) is a significant cause of acute kidney injury (AKI) and usually brings severe public health consequences. Adipose-derived endothelial progenitor cell (AdEPCs) transplantation is beneficial for AKI but suffers from low delivery efficiency. This study was conducted to explore the protective effects of magnetically delivered AdEPCs on the repair of renal IRI. Two types of magnetic delivery methods, namely the endocytosis magnetization (EM) method and the immunomagnetic (IM) method were fabricated using PEG@Fe3O4 and CD133@Fe3O4, and their cytotoxicities in AdEPCs were assessed. In the renal IRI rat model, magnetic AdEPCs were injected via the tail vein and a magnet was placed beside the injured kidney for magnetic guidance. The distribution of transplanted AdEPCs, renal function, and tubular damage were evaluated. Our results suggested that CD133@Fe3O4 had the minimum negative effects on the proliferation, apoptosis, angiogenesis, and migration of AdEPCs compared with PEG@Fe3O4. Renal magnetic guidance could significantly enhance the transplantation efficiency and the therapeutic outcomes of AdEPCs-PEG@Fe3O4 and AdEPCs-CD133@Fe3O4 in the injured kidneys. However, under renal magnetic guidance, AdEPCs-CD133@Fe3O4 had stronger therapeutic effects than PEG@Fe3O4 after renal IRI. The immunomagnetic delivery of AdEPCs with CD133@Fe3O4 could be a promising therapeutic strategy for renal IRI.

Deep learning based on 68Ga-PSMA-11 PET/CT for predicting pathological upgrading in patients with prostate cancer.

Objectives: To explore the feasibility and importance of deep learning (DL) based on 68Ga-prostate-specific membrane antigen (PSMA)-11 PET/CT in predicting pathological upgrading from biopsy to radical prostatectomy (RP) in patients with prostate cancer (PCa). Methods: In this retrospective study, all patients underwent 68Ga-PSMA-11 PET/CT, transrectal ultrasound (TRUS)-guided systematic biopsy, and RP for PCa sequentially between January 2017 and December 2022. Two DL models (three-dimensional [3D] ResNet-18 and 3D DenseNet-121) based on 68Ga-PSMA-11 PET and support vector machine (SVM) models integrating clinical data with DL signature were constructed. The model performance was evaluated using area under the receiver operating characteristic curve (AUC), accuracy, sensitivity, and specificity. Results: Of 109 patients, 87 (44 upgrading, 43 non-upgrading) were included in the training set and 22 (11 upgrading, 11 non-upgrading) in the test set. The combined SVM model, incorporating clinical features and signature of 3D ResNet-18 model, demonstrated satisfactory prediction in the test set with an AUC value of 0.628 (95% confidence interval [CI]: 0.365, 0.891) and accuracy of 0.727 (95% CI: 0.498, 0.893). Conclusion: A DL method based on 68Ga-PSMA-11 PET may have a role in predicting pathological upgrading from biopsy to RP in patients with PCa.

Exosomal AP000439.2 from clear cell renal cell carcinoma induces M2 macrophage polarization to promote tumor progression through activation of STAT3.

BACKGROUND: Tumorigenic phenotype of M2 tumor-associated macrophages promote tumor progression in response to exosomes cues imposed by tumor cells. However, the effect and underlying mechanisms of clear cell renal cell carcinoma (ccRCC)-derived exosomes (ccRCC-exo) on instructing macrophages phenotype remains unclear. METHODS: Macrophages were cocultured with ccRCC-exo and then evaluate the polarization of macrophages and migration of ccRCC cells. The effect and mechanism of lncRNA AP000439.2 overexpressed or deleted exosomes on macrophages M2 polarization were examined. Xenograft tumor mice model was used for in vivo validation. RESULTS: The ccRCC-exo significantly activated macrophages to M2 phenotype presented by increased expression of transforming growth factor-beta (TGF-ß) and interleukin 10 (IL-10) at mRNA and protein levels, and these M2 macrophages in turn facilitating the migration of ccRCC cells. LncRNA AP000439.2 was highly enriched in the ccRCC-exo. Overexpression of exosomal AP000439.2 promoted M2 macrophage polarization whereas AP000439.2-deficient exosome had the opposite effects. Nuclear-localized AP000439.2 directly interacted with signal transducer and activator of transcription 3 (STAT3) proteins and phosphorylated STAT3 in macrophages. RNA-Seq results showed overexpression of AP000439.2 activated NF-κB signaling pathway. Silencing of STAT3 suppressed overexpression of AP000439.2-induced up-regulation of TGF-ß and IL-10 expression, and p65 phosphorylation. AP000439.2-deleted exosome inhibited tumor growth in vivo. CONCLUSION: Exosomes from ccRCC deliver AP000439.2 to promote M2 macrophage polarization via STAT3, thus enhancing ccRCC progression, indicating exosomal AP000439.2 might be a novel therapeutic target in ccRCC. Video Abstract.

Circ_0051079 functions as an oncogenic regulator in osteosarcoma by leading to MAFB expression upregulation by competitively interacting with miR-1286.

BACKGROUND: Circular RNAs are involved in various cellular processes of bone diseases by acting as miRNA sponges to regulate gene expression levels, including osteosarcoma (OS). This research concentrated on the molecular mechanism of circ_0051079 in OS progression. METHODS: Reverse transcription-quantitative polymerase chain reaction assay was used for expression detection of circ_0051079, microRNA-1286 (miR-1286), and musculoaponeurotic fibrosarcoma oncogene homolog B (MAFB). Cell Counting Kit-8 assay and Edu assay were used for cell proliferation analysis. Cell apoptosis was evaluated using flow cytometry. Western blot was performed to measure protein levels. Migration and invasion were assessed via transwell assay. Interaction of circ_0051079/miR-1286 or miR-1286/MAFB was explored through a dual-luciferase reporter assay. In vivo research was carried out via tumor xenograft assay and immunohistochemistry staining. RESULTS: Circ_0051079 expression was upregulated in OS. Downregulation of circ_0051079 reduced OS cell proliferation, migration, invasion, and accelerated apoptosis. Circ_0051079 interacted with miR-1286, and the tumor-inhibitory function of si-circ_0051079 was abolished by miR-1286 inhibition in OS cells. MAFB served as a target for miR-1286. OS cell progression was suppressed by miR-1286 overexpression via downregulating MAFB. Circ_0051079/miR-1286 resulted in expression change of MAFB in OS cells. Silencing circ_0051079 inhibited tumor growth in vivo via regulating the miR-1286/MAFB axis. CONCLUSION: The collective results elucidated that circ_0051079 contributed to OS progression via miR-1286-mediated upregulation of MAFB, confirming the interaction of circ_0051079/miR-1286/MAFB axis in OS.

Protective effect of fluoxetine against oxidative stress induced by renal ischemia-reperfusion injury via the regulation of miR-450b-5p/Nrf2 axis.

The present study was performed to assess the protective effect of fluoxetine (FLX) on renal ischemia-reperfusion injury (IRI) via the regulation of miR-450b-5p/Nrf2 axis in male rats. In vivo, these male rats were randomly divided into different treatment groups. The rats were administered with FLX (20 mg/kg, intraperitoneally) once daily for 3 days before operation. The pathomorphological changes of renal tissues were assessed by histological examination and Masson staining. In vitro, HK-2 cells were used to detect the activity by CCK-8 assay in Hypoxia/Reoxygenation (H/R) group and Hypoxia/Reoxygenation+Fluoxetine (H/R+FLX) group. In addition, the oxidative stress biomarkers were evaluated. Subsequently, Nrf2, NF-κB, and Nrf2-dependent antioxidant enzymes, were detected by Western blot assay. In vivo, the pathological changes and serological renal function were significantly relieved in the rats with the pre-treatment of FLX, compared to IRI group. After FLX stimulation, the expression levels of oxidative stress indices significantly decreased, while tissue antioxidant indices significantly increased, compared to IRI group. The differently expressed miRNAs on renal IRI in male rats were screened out by miRNA microarray, especially showing that miR-450b-5p was selected as the target miRNA. Following miR-450b-5p agomir injection, the pathological changes and oxidative stress biomarkers significantly aggravated, whether in IRI group or IRI+FLX group. Bioinformatics analysis and double-luciferase reporter assay demonstrated that miR-450b-5p directly targeted Nrf2. The expression level of NF-κB significantly increased, while the expression levels of Nrf2 and Nrf2-dependent antioxidant enzymes significantly decreased after miR-450b-5p agomir injection. Furthermore, the expression levels of Nrf2 and it-dependent antioxidant enzymes were apparently increased in ischemic kidney after the transfection of miR-450b-5p mimic+recombination protein Nrf2, as well as the decreased expression levels of intracellular ROS and iNOS. In vitro, FLX significantly increased HK-2 cell viability, and relieved H/R HK-2 cell oxidative injury via down-regulating ROS and iNOS. In addition, H/R-induced oxidative damage was recovered with miR-450b-5p mimic and recombination protein Nrf2. Consequently, FLX played an important protective role in renal IRI-induced oxidative damage by promoting antioxidation via targeting miR-450b-5p/Nrf2 axis.

Development and validation of 68Ga-PSMA-11 PET/CT-based radiomics model to detect primary prostate cancer.

BACKGROUND: This study aimed to develop a novel analytic approach based on a radiomics model derived from 68Ga-prostate-specific membrane antigen (PSMA)-11 PET/CT for predicting intraprostatic lesions in patients with prostate cancer (PCa). METHODS: This retrospective study included consecutive patients with or without PCa who underwent surgery or biopsy after 68Ga-PSMA-11 PET/CT. A total of 944 radiomics features were extracted from the images. A radiomics model was constructed using the least absolute shrinkage and selection operator (LASSO) algorithm with tenfold cross-validation in the training set. PET/CT images for the test set were reviewed by experienced nuclear medicine radiologists. The sensitivity, specificity, positive predictive value, negative predictive value, and area under the receiver operating characteristic curve (AUC) were calculated for the model and radiologists' results. The AUCs were compared. RESULTS: The total of 125 patients (86 PCa, 39 benign prostate disease [BPD]) included 87 (61 PCa, 26 BPD) in the training set and 38 (61 PCa, 26 BPD) in the test set. Nine features were selected to construct the radiomics model. The model score differed between PCa and BPD in the training and test sets (both P < 0.001). In the test set, the radiomics model performed better than the radiologists' assessment (AUC, 0.85 [95% confidence interval 0.73, 0.97] vs. 0.63 [0.47, 0.79]; P = 0.036) and showed higher sensitivity (model vs radiologists, 0.84 [0.63, 0.95] vs. 0.74 [0.53, 0.88]; P = 0.002). CONCLUSION: Radiomics analysis based on 68Ga-PSMA-11 PET may non-invasively predict intraprostatic lesions in patients with PCa.

Curative Effect of Prebiotics/Probiotics Preparations Combined with Zoledronic Acid + Calcitriol Regimen on Patients with Primary Osteoporosis and Their Influences on Bone Metabolism Markers.

Objective: To explore the curative effect of prebiotics/probiotics preparations combined with zoledronic acid + calcitriol regimen on patients with primary osteoporosis (POP) and the influences of prebiotics/probiotics preparations combined with zoledronic acid + calcitriol regimen on markers of bone metabolism. Methods: 126 elderly hospitalized patients with POP in our hospital from January 2020 to December 2021 were divided into the control group (n = 63) and the observation group (n = 63) by the random number table method. The patients in the control group were treated with zoledronic acid and calcitriol, while the patients in the observation group were additionally treated with prebiotics/probiotics preparations. The clinical curative effect, bone metabolism, calcium-phosphorus metabolism indexes, intestinal floras, and cytokines levels before and via treatment between the two groups were compared. Results: The total efficiency of the observation group was higher than that of the control group (P < 0.05). After treatment, the levels of bone gla protein (BGP), total propeptide of type I procollagen (PINP), and ß-crosslaps (ß-CTX) in both groups were lower than those before treatment, and the levels of BGP, total PINP, and ß-CTX in the observation group were lower than those in the control group (P < 0.05). The levels of serum P in the both groups after treatment were lower than those before treatment, and the level of serum P in the observation group was lower than that in the control group (P < 0.05). The number of Escherichia coli after treatment in the two groups were less than that before treatment, and the number of Escherichia coli in the observation group was less than that in the control group (P < 0.05). The number of bifidobacteria and lactobacilli in the two groups after treatment were more than that before treatment, and the number of bifidobacteria and lactobacilli in the observation group were more than those in the control group (P < 0.05). After treatment, the levels of IL-6 and TNF-α in the two groups were lower than those before treatment, and the levels of IL-6 and TNF-α in the observation group was lower than those in the control group (P < 0.05). The levels of IGF-1 in the two groups after treatment were higher than those before treatment, and the levels of IGF-1 in the observation group was higher than that in the control group (P < 0.05). Conclusion: The response rate of prebiotics/probiotics preparations combined with zoledronic acid + calcitriol regimen is high in the treatment of POP patients, which ameliorates bone metabolism and intestinal floras, and suppresses cytokines release in patients with POP.

Sirtuin 4 Inhibits Prostate Cancer Progression and Metastasis by Modulating p21 Nuclear Translocation and Glutamate Dehydrogenase 1 ADP-Ribosylation.

Protein posttranslational modification regulates several biological mechanisms, including tumor progression. In this study, we show that the mitochondrial Sirtuin 4 (SIRT4), which has ADP-ribosylation activity, plays a role in prostate cancer (PCa) progression. Firstly, SIRT4 expression was verified in PCa tissues and cell lines by quantitative real-time PCR (qRT-PCR) and western blotting. Subsequently, we established stable PC-3 and 22rv1 cells that overexpressed SIRT4 and knocked down SIRT4, respectively. The functions of SIRT4 in PCa were explored through various phenotype experiments. The mechanism underlying the functions of SIRT4 was investigated through western blotting, immunoprecipitation, immunofluorescence, and nuclear and cytoplasmic extraction assays. We revealed that SIRT4 inhibited cell progression both in vivo and in vitro. Mechanistically, on the one hand, SIRT4 promoted the ADP-ribosylation of glutamate dehydrogenase 1 to inhibit the glutamine metabolism pathways. On the other hand, SIRT4 inhibited the phosphorylation of AKT, thereby affecting p21 phosphorylation and its cellular localization for cell cycle arrest. In conclusion, our study indicates that SIRT4 is directly associated with PCa progression and could be a novel target for PCa therapy.

The Role of P4HA1 in Multiple Cancer Types and its Potential as a Target in Renal Cell Carcinoma.

Background: Prolyl 4-hydroxylase subunit alpha 1 (P4HA1) provides the majority of the catalytic site of the active P4H enzyme. Emerging evidence has revealed that P4HA1 participates in the initiation and development of several malignant tumors. However, a pan-cancer analysis of P4HA1 has not been performed. Methods: In this study, we carried out an in-depth analysis of the expression patterns and prognostic value of P4HA1 using the datasets of The Cancer Genome Atlas (TCGA) and Kaplan-Meier Plotter. Genomic and epigenetic alterations of P4HA1 and the correlation of P4HA1 with DNA methylation in different cancers were also analyzed across multiple databases. In addition, the purity-adjusted partial Spearman's correlation test was utilized to evaluate the correlation between P4HA1 expression and immune cell infiltration. We also further explored the biological function and mechanism of P4HA1 in renal cell carcinoma (RCC). Results: We characterized the expression profiles and prognostic values of P4HA1 in multiple cancer types. P4HA1 expression was increased in clear cell renal cell carcinoma (RCC) compared to adjacent normal tissues, and P4HA1 positively correlated with the overall survival (OS) and disease-free survival (DFS) in papillary RCC. In addition, a positive correlation between P4HA1 expression and immune cell infiltration was observed in clear cell RCC. We also identified a strong correlation between P4HA1 expression and immune checkpoint gene expression, microsatellite instability, and tumor mutation burden in chromophobe RCC. Finally, the results of in vitro experiments verified that overexpression of P4HA1 promoted the proliferation, migration, invasion, and epithelial-mesenchymal transition of RCC cells. Conclusion: Overall, our study has suggested that P4HA1 might play a significant role in tumorigenesis in RCC and may be a prognostic biomarker and therapeutic target for several malignant tumors, including RCC.

Comprehensive insight into endothelial progenitor cell-derived extracellular vesicles as a promising candidate for disease treatment.

Endothelial progenitor cells (EPCs), which are a type of stem cell, have been found to have strong angiogenic and tissue repair capabilities. Extracellular vesicles (EVs) contain many effective components, such as cellular proteins, microRNAs, messenger RNAs, and long noncoding RNAs, and can be secreted by different cell types. The functions of EVs depend mainly on their parent cells. Many researchers have conducted functional studies of EPC-derived EVs (EPC-EVs) and showed that they exhibit therapeutic effects on many diseases, such as cardiovascular disease, acute kidney injury, acute lung injury, and sepsis. In this review article, we comprehensively summarized the biogenesis and functions of EPCs and EVs and the potent role of EPC-EVs in the treatment of various diseases. Furthermore, the current problems and future prospects have been discussed, and further studies are needed to compare the therapeutic effects of EVs derived from various stem cells, which will contribute to the accelerated translation of these applications in a clinical setting.