Restricted and epitaxial growth of MnO2-x nano-flowers in/out carbon nanofibers for long-term cycling stability supercapacitor electrodes.

Carbon nanofibers (CFs) have been widely applied as electrodes for energy storage devices owing to the features of increased contact area between electrodes and electrolyte, and shortened transmission route of electrons. However, the poor electrochemical activity and severe waste of space hinder their further application as supercapacitors electrodes. In this work, MnO2-x nanoflowers restricted and epitaxial growth in/out carbon nanofibers (MnO2/MnO@CF) were prepared as excellent electrode materials for supercapacitors. With the synergistic effect of uniquely designed structure and the introduction of MnO and MnO2 nanoflowers, the prepared interconnected MnO2/MnO@CF electrodes demonstrated satisfactory electrochemical performance. Furthermore, the MnO2/MnO@CF//activated carbon (AC) asymmetric supercapacitor offered an outstanding long-term cycle stability. Besides, kinetic analysis of MnO2/MnO@CF-90 was conducted and the diffusion-dominated storage mechanism was well-revealed. This concept of "internal and external simultaneous decoration" with different valence states of manganese oxides was proven to improve the electrochemical performance of carbon nanofibers, which could be generalized to the preparation and performance improvement of other fiber-based electrodes.

SLFN11 promotes clear cell renal cell carcinoma progression via the PI3K/AKT signaling pathway.

SLFN11 is abnormally expressed and associated with survival outcomes in various human cancers. However, the role of SLFN11 in clear cell renal cell carcinoma (ccRCC) remains unclear. This study aimed to investigate the clinical value and potential functions of SLFN11 in ccRCC. Comprehensive bioinformatics analyses were performed using online databases. Quantitative real-time PCR (qPCR) and western blotting were used to validate the expression data. CCK8, flow cytometry analysis, and EdU staining were performed to determine the level of cell proliferation. Flow cytometry analysis was also used to detect cell apoptosis. Wound-healing assay and Transwell assays were performed to assess cell migration and invasion capability, respectively. SLFN11 was overexpressed and was an independent prognostic factor in ccRCC. SLFN11 knockdown inhibited cell proliferation, migration, and invasion and promoted apoptosis. Functional and pathway enrichment analyses suggested that SLFN11 may have an impact on tumorigenesis in ccRCC through regulation of the inflammatory response, the PI3K/AKT signaling pathway and other effectors. Furthermore, SLFN11 knockdown inhibited the phosphorylation of the PI3K/AKT signaling pathway and could be activated by 740 Y-P. Finally, we demonstrated that miR-183 may specifically target SLFN11, and miR-183 expression was correlated with predicted survival. SLFN11 may play a critical role in ccRCC progression and may serve as a novel prognostic biomarker in ccRCC.

Identification and structural characterization of key prebiotic fraction of soluble dietary fiber from grapefruit peel sponge layer and its regulation effect on gut microbiota.

In this study, the key prebiotic fraction of grapefruit peel sponge layer soluble dietary fiber (GSLSDF) was identified, and its structure characteristics and modulatory effect on intestinal microorganisms were investigated. Firstly, two fractions (GSLSDF-1 and GSLSDF-2) were isolated from GSLSDF, and the GSLSDF-1 showed a better prebiotic activity. Subsequently, GSLSDF-1 was found to have a low molecular weight and crystallinity, a loose and porous microstructure, and a high glucose content. Meanwhile, GSLSDF-1 was a dextran with a main chain linked by ß-1, 4 glycosidic bonds and branched by a ß-1, 6 glycosidic bonds. These structural characteristics were responsible for the favorable prebiotic activity of GSLSDF-1. Finally, the regulation effect of GSLSDF-1 on gut microbiota was analyzed in vitro fecal fermentation. Compared with the blank and GSLSDF groups, GSLSDF-1 could increase the relative abundances of Lactobacillus, Bacteroides, Bifidobacterium and Faecalibacterium coupled with decrease the relative abundances of Clostridium and Clostridioides. Furthermore, GSLSDF-1 promoted the production of short-chain fatty acids (SCFAs) by modulating the SCFAs synthesis pathway of intestinal microorganisms, while the NH3-N synthesis of intestinal microorganisms was inhibited by GSLSDF-1. Above results indicated that GSLSDF-1 was the key prebiotic fraction of GSLSDF, which could effectively optimize the intestinal microorganism composition.

Risk signature identification and NPRL2 affects sunitinib sensitivity in clear cell renal cell carcinoma.

Tumor suppressor genes (TSGs) play a crucial role in tumorigenesis and drug resistance. We analyzed the subtypes of clear cell renal cell carcinoma (ccRCC) mediated by 8 genes contained in the 3p21.3 tumor suppressor gene cluster and their effects on TME cell infiltration based on the TCGA database. The risk score model was established by principal component analysis. The hub gene NPRL2 was selected by protein-protein interactions (PPI) analysis. The effect of NPRL2 on sunitinib sensitivity of ccRCC was verified by using CCK-8, colony formation assay, wound healing assay, transwell assay and xenograft tumor model. Changes in protein expression were detected by Western blotting. We found that 8 TSGs were all differentially expressed in ccRCC samples, which could divide ccRCC into two subtypes. The constructed risk score model could predict the prognosis and drug sensitivity of ccRCC patients, and was an independent prognostic factor for ccRCC. Over-expression of NPRL2 promoted apoptosis, inhibited EMT, decreased the phosphorylation of the PI3K/AKT/mTOR signaling pathway to inhibit its activity, and promoted the sensitivity of sunitinib to ccRCC cells. Collectively, our findings increased the understanding of TSGs in ccRCC, suggesting that NPRL2 as a TSG could enhance sunitinib sensitivity to ccRCC cells.

Bone marrow mesenchymal stem cells alleviate stress-induced hyperalgesia via restoring gut microbiota and inhibiting neuroinflammation in the spinal cord by targeting the AMPK/NF-κB signaling pathway.

Aim Spinal neuroinflammation contributes to the mechanism of stress-induced hyperalgesia (SIH). Recent research has demonstrated that bone marrow mesenchymal stem cells (BMSCs) alleviate chronic pain. However, what remains unidentified is whether BMSCs could improve hyperalgesia induced by chronic restraint stress (CRS). In another dimension, our previous study proved that gut microbiota played an important role in CRS-induced hyperalgesia in mice. Yet, whether BMSCs treatments change gut microbiota composition in CRS mice remains unexplored. MAIN METHODS: Mechanical allodynia and thermal hyperalgesia were used to assess pain behavior. Composition of fecal samples were verified by 16S rRNA analysis. Western blot was used to investigate the expression of adenosine monophosphate-activated protein kinase (AMPK)/ nuclear factor kappa B (NF-κB) signaling pathway, pro-inflammatory cytokines [interleukin-1 beta (IL-1ß), tumor necrosis factor alpha (TNF-α), IL-6], and the markers of microglia and astrocytes. The morphology of glia cells was evaluated by immunofluorescence staining. KEY FINDINGS: CRS down-regulated phosphorylated AMPK (p-AMPK), up-regulated phosphorylated NF-κB p65 (p-NF-κB p65), activated microglia and astrocytes and promoted the secretion of IL-1ß, TNF-α and IL-6 in the spinal cord. BMSCs alleviated CRS-induced hyperalgesia by inhibiting the activation of microglia and astrocytes and by reducing neuroinflammation via improving the disrupted AMPK/NF-κB pathway. Furthermore, BMSCs also raised the relative abundance of Muribaculaceae and Lachnospiraceae in CRS mice feces, which was significantly related to its effect of relieving hyperalgesia. SIGNIFICANCE: Our results support that BMSCs could alleviate CRS-induced hyperalgesia by reducing AMPK/NF-κB-dependent neuroinflammation in the spinal cord and restoring the homeostasis of gut microbiota.

Construction of Pyroptosis-Related Prognostic and Immune Infiltration Signature in Bladder Cancer.

Pyroptosis is a kind of programmed cell death related to inflammation, which is closely related to cancer. The goal of this study is to establish and verify pyroptosis-related gene signature to predict the prognosis of patients with bladder cancer (BLCA) and explore its relationship with immunity. Somatic mutation, copy number variation, correlation, and expression of 33 pyroptosis-related genes were evaluated based on The Cancer Genome Atlas (TCGA) database. BLCA cases were divided into two clusters by consistent clustering and found that pyroptosis-related genes were related to the overall survival (OS) of BLCA. The least absolute shrinkage and selection operator (LASSO) Cox regression was used to construct the signature (including 7 pyroptosis-realated genes). Survival analysis curve and receiver operating characteristic curve (ROC) showed that this signature could predict the prognosis of BLCA patients. Univariate and multivariate Cox regression analysis showed the independent prognostic value of this model. Immune infiltration analysis showed that the six types of immune cells have significantly different infiltrations. The effect of immunotherapy is better in the low-risk group. In summary, our effort indicated the potential role of pyroptosis-related genes in BLCA and provided new perspectives on the prognosis of BLCA and new ideas for immunotherapy.

Inhibition of (Pro)renin Receptor-Mediated Oxidative Stress Alleviates Doxorubicin-Induced Heart Failure.

Aim: Clinical utility of doxorubicin (DOX) is limited by its cardiotoxic side effect, and the underlying mechanism still needs to be fully elucidated. This research aimed to examine the role of (pro)renin receptor (PRR) in DOX-induced heart failure (HF) and its underlying mechanism. Main Methods: Sprague Dawley (SD) rats were injected with an accumulative dosage of DOX (15 mg/kg) to induce HF. Cardiac functions were detected by transthoracic echocardiography examination. The levels of lactate dehydrogenase (LDH) and creatine kinase (CK) in serum were detected, and oxidative stress related injuries were evaluated. Furthermore, the mRNA expression of PRR gene and its related genes were detected by real-time PCR (RT-PCR), and protein levels of PRR, RAC1, NOX4 and NOX2 were determined by Western blot. Reactive oxygen species (ROS) were determined in DOX-treated rats or cells. Additionally, PRR and RAC1 were silenced with their respective siRNAs to validate the in vitro impacts of PRR/RAC1 on DOX-induced cardiotoxicity. Moreover, inhibitors of PRR and RAC1 were used to validate their effects in vivo. Key Findings: PRR and RAC1 expressions increased in DOX-induced HF. The levels of CK and LDH as well as oxidative stress indicators increased significantly after DOX treatment. Oxidative injury and apoptosis of cardiomyocytes were attenuated both in vivo and in vitro upon suppression of PRR or RAC1. Furthermore, the inhibition of PRR could significantly down-regulate the expressions of RAC1 and NOX4 but not that of NOX2, while the inhibition of RAC1 did not affect PRR. Significance: Our findings showed that PRR inhibition could weaken RAC1-NOX4 pathway and alleviate DOX-induced HF via decreasing ROS production, thereby suggesting a promising target for the treatment of DOX-induced HF.

FOXO1 inhibits prostate cancer cell proliferation via suppressing E2F1 activated NPRL2 expression.

Previous studies in our lab suggest that nitrogen permease regulator 2-like (NPRL2) upregulation in prostate cancer is associated with malignant behavior and poor prognosis. However, the underlying mechanisms of NPRL2 dysregulation remain poorly understood. This study aimed to explore the transcription factors (TFs) contributing to NPRL2 dysregulation in prostate cancer. Potential TFs were identified using prostate tissue/cell-specific chromatin immunoprecipitation (ChIP)-seq data collected in the Cistrome Data Browser and Signaling Pathways Project. Dual-luciferase assay and ChIP-qPCR assay were conducted to assess the binding and activating effect of TFs on the gene promoter. Cell Counting Kit-8 and colony formation assays were performed to assess cell proliferation. Results showed that E2F1 is a TF that bound to the NPRL2 promoter and activated its transcription. NPRL2 inhibition significantly alleviated E2F1 enhanced cell proliferation. Kaplan-Meier survival analysis indicated that E2F1 upregulation was associated with unfavorable progression-free survival and disease-specific survival. FOXO1 interacted and E2F1 in both PC3 and LNCaP cells and weakened the binding of E2F1 to the NPRL2 promoter. Functionally, FOXO1 overexpression significantly slowed the proliferation of PC3 and LNCaP cells and also decreased E2F1 enhanced cell proliferation. In summary, this study revealed a novel FOXO1/E2F1-NPRL2 regulatory axis in prostate cancer. E2F1 binds to the NPRL2 promoter and activates its transcription, while FOXO1 interacts with E2F1 and weakens its transcriptional activating effects. These findings help expand our understanding of the prostate cancer etiology and suggest that the FOXO1/E2F1-NPRL2 signaling axis might be a potential target.

Astragaloside IV Alleviates Tacrolimus-Induced Chronic Nephrotoxicity via p62-Keap1-Nrf2 Pathway.

Tacrolimus-induced chronic nephrotoxicity (TIN) hinders its long-term use in patients. However, there are no drugs available in the clinic to relieve it at present. Astragaloside IV (AS-IV) is a saponin extract of the Astragalus which is widely used in the treatment of kidney disease. This study aimed to investigate the effect of AS-IV on TIN and its underlying mechanism. Herein, C57BL/6 mice were treated with tacrolimus and/or AS-IV for 4 weeks, and then the renal function, fibrosis, oxidative stress and p62-Keap1-Nrf2 pathway were evaluated to ascertain the contribution of AS-IV and p62-Keap1-Nrf2 pathway to TIN. Our results demonstrated that AS-IV significantly improved renal function and alleviated tubulointerstitial fibrosis compared with the model group. The expression of fibrosis-related proteins, including TGF-ß1, Collagen I and α-SMA, were also decreased by AS-IV. Furthermore, AS-IV relieved the inhibition of tacrolimus on antioxidant enzymes. The data in HK-2 cells also proved that AS-IV reduced tacrolimus-induced cell death and oxidative stress. Mechanistically, AS-IV markedly promoted the nuclear translocation of Nrf2 and the renal protective effects of AS-IV were abolished by Nrf2 inhibitor. Further researches showed that phosphorylated p62 was significantly increased after AS-IV pretreatment. Moreover, AS-IV failed to increase nuclear translocation of Nrf2 and subsequent anti-oxidative stress in HK-2 cells transfected with p62 siRNA. Collectively, these findings indicate that AS-IV relieve TIN by enhancing p62 phosphorylation, thereby increasing Nrf2 nuclear translocation, and then alleviating ROS accumulation and renal fibrosis.

Structural determinants for histamine H(1) affinity, hERG affinity and QTc prolongation in a series of terfenadine analogs.

In the late 1980's reports linking the non-sedating antihistamines terfenadine and astemizole with torsades de pointes, a form of ventricular tachyarrhythmia that can degenerate into ventricular fibrillation and sudden death, appeared in the clinical literature. A substantial body of evidence demonstrates that the arrhythmogenic effect of these cardiotoxic antihistamines, as well as a number of structurally related compounds, results from prolongation of the QT interval due to suppression of specific delayed rectifier ventricular K+ currents via blockade of the hERG-IKr channel. In order to better understand the structural requirements for hERG and H(1) binding for terfenadine, a series of analogs of terfenadine has been prepared and studied in both in vitro and in vivo hERG and H(1) assays.

N-Acetyltransferase Mpr1 confers ethanol tolerance on Saccharomyces cerevisiae by reducing reactive oxygen species.

N-Acetyltransferase Mpr1 of Saccharomyces cerevisiae can reduce intracellular oxidation levels and protect yeast cells under oxidative stress, including H(2)O(2), heat-shock, or freeze-thaw treatment. Unlike many antioxidant enzyme genes induced in response to oxidative stress, the MPR1 gene seems to be constitutively expressed in yeast cells. Based on a recent report that ethanol toxicity is correlated with the production of reactive oxygen species (ROS), we examined here the role of Mpr1 under ethanol stress conditions. The null mutant of the MPR1 and MPR2 genes showed hypersensitivity to ethanol stress, and the expression of the MPR1 gene conferred stress tolerance. We also found that yeast cells exhibited increased ROS levels during exposure to ethanol stress, and that Mpr1 protects yeast cells from ethanol stress by reducing intracellular ROS levels. When the MPR1 gene was overexpressed in antioxidant enzyme-deficient mutants, increased resistance to H(2)O(2) or heat shock was observed in cells lacking the CTA1, CTT1, or GPX1 gene encoding catalase A, catalase T, or glutathione peroxidase, respectively. These results suggest that Mpr1 might compensate the function of enzymes that detoxify H(2)O(2). Hence, Mpr1 has promising potential for the breeding of novel ethanol-tolerant yeast strains.

Dimethyl sulfoxide effects on hERG channels expressed in HEK293 cells.

INTRODUCTION: Dimethyl sulfoxide (DMSO) is widely used as a solvent to facilitate formulation of test substances in cell perfusion solutions. However, DMSO concentration in bath (extracellular) solution is usually limited to 0.1-0.3% to avoid DMSO-induced changes in cell morphology and membrane properties due to elevation of osmolality. The purpose of this study was to examine whether DMSO-induced hyperosmotic effects on hERG expressing cells could be compensated by adding an equivalent amount of DMSO in pipette (intracellular) solution, to investigate DMSO effects on hERG channels, and to determine the impact of DMSO on the potency of hERG channel blockers. METHOD: Whole-cell patch clamp method was used to record hERG currents in HEK293 cells. DMSO at concentrations of 0.1% to 2% was applied to bath and pipette solutions. Various voltage protocols were used to examine DMSO effects on hERG channel properties and to evaluate DMSO impacts on the potency of terfenadine and E-4031. RESULTS: When DMSO was added simultaneously in bath and pipette solutions, normal cell morphology and the proper current recording conditions could be maintained with application of up to 2% DMSO. DMSO slightly shifted the current-voltage relationship, activation curve, and inactivation curve of the hERG channel to more positive voltages. DMSO had little effect on the concentration-response relationship of hERG channel blockers we assessed. The IC50 for terfenadine and E-4031 were not significantly changed in the presence of 0.3, 0.5, 1 and 2% DMSO. DISCUSSION: Our results demonstrate that changes in cell morphology induced by extracellular DMSO can be prevented by application of DMSO in pipette solution. By utilizing this approach, we successfully performed hERG current recordings using bath solution containing up to 2% DMSO. DMSO-induced shifts of the voltage-dependence of hERG channel gating had little impact on the potency of hERG channel blockers.

N-acetyltransferase Mpr1 confers freeze tolerance on Saccharomyces cerevisiae by reducing reactive oxygen species.

N-Acetyltransferase Mpr1 of Saccharomyces cerevisiae can reduce intracellular oxidation levels and protect yeast cells under oxidative stress. We found that yeast cells exhibited increased levels of reactive oxygen species during freezing and thawing. Gene disruption and expression experiments indicated that Mpr1 protects yeast cells from freezing stress by reducing the intracellular levels of reactive oxygen species. The combination of Mpr1 and l-proline could further enhance the resistance to freezing stress. Hence, Mpr1 as well as l-proline has promising potential for the breeding of novel freeze-tolerant yeast strains.

Estimation of potency of HERG channel blockers: impact of voltage protocol and temperature.

INTRODUCTION: The HERG channel is widely used for the assessment of proarrhythmic risk for new drugs. HERG channel blockers obstruct channel functions through various mechanisms, which usually show time dependence, voltage dependence, and state dependence. The voltage protocol and temperature may affect the estimation of drug potency, but limited information is available in this regard. The purpose of this study was to evaluate the influence of voltage protocol and temperature on predicting the potency of HERG channel blockers, and to determine electrophysiological approaches for new drugs screening studies. METHOD: Whole-cell patch-clamp electrophysiology was carried out by utilizing different voltage step protocols to examine the potency of compounds known to preferentially block the channel in the closed (ketoconazole and BeKm-1), open, and/or inactivated states (E-4031, astemizole, and terfenadine) in HEK293 cells transfected with HERG cDNA at room temperature and near-physiological temperature. RESULTS: Drug potency determined using different voltage protocols varied dependent on the mechanisms of drug actions. For most compounds, the IC(50) values obtained with a long pulse step protocol at room temperature were close to those determined with the voltage protocols designed to disclose their intrinsic potency. Relative to room temperature, the potency of E-4031, terfenadine, and ketoconazole was not changed at approximately 35 degrees C, but potency of astemizole was reduced. DISCUSSION: The long pulse step protocol with room temperature can be selected for HERG channel safety screening studies. Alternative voltage protocols or temperatures should be considered if HERG study results are not consistent with other cardiac safety assessments.