The prognostic significance of preoperative platelet-to-lymphocyte ratio and interleukin-6 level in non-muscle invasive bladder cancer.

BACKGROUND: Non-muscle invasive bladder cancer (NMIBC) is the most prevalent type of bladder cancer, typically associated with a favorable prognosis and a risk of recurrence during the follow-up period. Inflammatory markers have been used to predict prognosis in various cancer types. The aim of this study was to explore the prognostic value of the readily accessible inflammatory markers, platelet-to-lymphocyte ratio (PLR) and interleukin-6 (IL-6), in NMIBC. METHODS: The study comprised a retrospective analysis of clinical data collected from NMIBC patients diagnosed between October 2018 and October 2020. PLR was calculated using the routine preoperative blood test results, and preoperative IL-6 levels were recorded. Receiver operating characteristic (ROC) curves were generated for PLR and IL-6 level and the optimal cut-off values were determined using Youden's index. Survival curves were generated to evaluate the association between PLR and IL-6, and recurrence-free survival (RFS), and univariate and multivariate analysis were performed using the Cox proportional hazards regression model. A nomogram and calibration curve were generated to assess the clinical significance of the model. RESULTS: The ROC curves demonstrated that PLR and IL-6 levels were significantly associated with tumor pathology grade, with area under the curve (AUC) values of 0.833 (95% CI 0.757, 0.910) for PLR and 0.724 (95% CI 0.622, 0.825) for IL-6 levels. PLR and IL-6 levels were also positively associated with tumor recurrence, with AUC values of 0.647 (95% CI 0.538, 0.756) and 0.846 (95% CI 0.769, 0.924), respectively. The survival curves indicated that patients with high PLR and high IL-6 levels had shorter RFS than those with low PLR and low IL-6 level (P < 0.01). Univariate Cox proportional hazards regression analysis showed that age, tumor size, tumor number, pathological grade, PLR and IL-6 were potential risk factors for NMIBC recurrence. Multivariate analysis further revealed that tumor number, smoking, PLR, and IL-6 were independent risk factors for NMIBC recurrence (P < 0.05). CONCLUSIONS: Preoperative peripheral blood inflammatory markers (PLR and IL-6) are useful predictors of RFS in NMIBC patients at the time of initial diagnosis. High PLR and high IL-6 were identified as independent risk factors for tumor recurrence and could serve as potential biological markers for prediction of NMIBC recurrence.

Selective eradication of venetoclax-resistant monocytic acute myeloid leukemia with iron oxide nanozymes.

The clinical treatment of human acute myeloid leukemia (AML) is rapidly progressing from chemotherapy to targeted therapies led by the BCL-2 inhibitor venetoclax (VEN). Despite its unprecedented success, VEN still encounters clinical resistance. Thus, uncovering the biological vulnerability of VEN-resistant AML disease and identifying effective therapies to treat them are urgently needed. We have previously demonstrated that iron oxide nanozymes (IONE) are capable of overcoming chemoresistance in AML. The current study reports a new activity of IONE in overcoming VEN resistance. Specifically, we revealed an aberrant redox balance with excessive intracellular reactive oxygen species (ROS) in VEN-resistant monocytic AML. Treatment with IONE potently induced ROS-dependent cell death in monocytic AML in both cell lines and primary AML models. In primary AML with developmental heterogeneity containing primitive and monocytic subpopulations, IONE selectively eradicated the VEN-resistant ROS-high monocytic subpopulation, successfully resolving the challenge of developmental heterogeneity faced by VEN. Overall, our study revealed an aberrant redox balance as a therapeutic target for monocytic AML and identified a candidate IONE that could selectively and potently eradicate VEN-resistant monocytic disease.

Near-crash risk identification and evaluation for takeout delivery motorcycles using roadside LiDAR.

The proliferation of motorcycles in urban areas has raised concerns regarding traffic safety. However, traditional sensors struggle to obtain precise high-resolution trajectory data, which hinder the accurate identification and quantification of near-crash risks for takeout delivery motorcycles. To fill this gap, this study presents a novel approach utilizing roadside light detection and ranging (LiDAR) to identify and evaluate the risk of near crashes of takeout delivery motorcycles. First, a trajectory amendment method incorporating speed and steering angle was introduced to enhance the accuracy and continuity of the trajectory prediction. Second, a trajectory prediction method combining the steering intention and a repulsive force model was proposed for near-crash risk prediction. Subsequently, a near-crash identification method was developed that relied on the closest distance and risk radius. Finally, near-crash risk fields were constructed to quantify risk levels by leveraging velocity, position, and weight. The experimental results demonstrated 92.10 % accuracy in intention prediction, with mean absolute error (MAE) and root mean square error (RMSE) values of 0.53 m and 0.45 m, respectively. In addition to its higher accuracy, the proposed method makes it easier to quantify near-crash risk and supports a proactive approach for visualizing and analyzing traffic safety.

A supersensitive electrochemical sensor based on RCA amplification-assisted "silver chain"-linked gold interdigital electrodes and CRISPR/Cas9 for the detection of Staphylococcus aureus in food.

With the rising emphasis on food safety, technology to rapidly identify Staphylococcus aureus (S. aureus) is of great significance. Herein, we developed a novel electrochemical biosensor based on the CRISPR/Cas9 system and rolling circle amplification (RCA)-assisted "silver chain"-linked gold interdigital electrodes (Au-IDE). This sensor utilizes RCA to create DNA long chains that span the Au-IDE, and CRISPR/Cas9 as a recognition component to recognize capture/target dsDNA. Additionally, we used silver staining technology to improve detection sensitivity. Then, we detected S. aureus through impedance changes that occurred when the silver chain between the Au-IDE was connected or broke, with a limit of detection (LOD) of 7 CFU/mL and a detection time of 1.5 h. Lastly, we successfully employed this sensor to detect S. aureus in real food samples, making it a promising tool for food monitoring.

A PEDOT enhanced covalent organic framework (COF) fluorescent probe for in vivo detection and imaging of Fe3.

Simple and accurate in vivo monitoring of Fe3+ is essential for gaining a better understanding of its role in physiological and pathological processes. A novel fluorescent probe was synthesized via in situ solid-state polymerization of 3,4-ethylenedioxythiophene (PEDOT) in the pore channels of a covalent organic framework (COF). The PEDOT@COF fluorescent probe exhibited an absolute quantum yield (QY) 3 times higher than COF. In the presence of Fe3+ the PEDOT@COF 475 nm fluorescence emission, 365 nm excitation, is quenched within 180 s. Fluorescence quenching is linear with Fe3+ in the concentration range of 0-960 µM, with a detection limit of 0.82 µM. The fluorescence quenching mechanism was attributed to inner filter effect (IEF), photoinduced electron transfer (PET) and static quenching (SQE) between PEDOT@COF and Fe3+. A paper strip-based detector was designed to facilitate practical applicability, and the PEDOT@COF probe successfully applied to fluorescence imaging of Fe3+ levels in vivo. This work details a tool of great promise for enabling detailed investigations into the role of Fe3+ in physiological and pathological diseases.

Pan cancer characterization of genes whose expression has been associated with LINE-1 antisense promoter activity.

BACKGROUND: Long interspersed nuclear element-1 (LINE-1 or L1) comprises 17% of the human genome. As the only autonomous and active retrotransposons, L1 may take part in cancer initiation and progression in some ways. The studies of L1 in cancer mainly focus on the impact of L1 insertion into the new genome locus. The L1 5´ untranslated region (UTR) also contains antisense promoter (ASP) activity, generating L1-gene chimeric transcripts to a neighbor exon. Some of these ASP-associated genes have been reported to be overexpressed in cancer and promote cancer cell growth. However, little is known about overall expression patterns and the roles of L1 ASP-associated genes in human cancers. RESULTS: L1 ASP-associated genes were frequently dysregulated in cancer and associated with the cell cycle, the PI3K/AKT pathway, and the GTPase signaling pathway. The expression of L1 ASP-associated genes was correlated with tumor patient prognosis. Hub L1 ASP-associated genes CENPU and MCM2 showed a correlation with immune infiltration, clinical T stage, and cancer stemness in pan-cancer. Knockdown of L1 ASP-associated gene LINC00491 resulted in a significant decrease in tumor growth and migration ability. CONCLUSIONS: The expression of L1 ASP-associated genes is significantly dysregulated at the pan-cancer level, which is closely related to the tumor microenvironment, progression, and patient prognosis. Hub genes CENPU and MCM2 are expected to be new tumor diagnostic markers and therapeutic targets.

Natural chitosan-based carbon dots as an eco-friendly and effective corrosion inhibitor for mild steel in HCl solution.

Polysaccharide chitosan and L-histidine were applied to synthesize chitosan-based carbon dots (CA-CDs) by a simple laser ablation method. After characterization of the CA-CDs by FT-IR, UV-vis, Raman, XRD, TEM, and XPS, the CA-CDs were introduced as an eco-friendly and high-performance corrosion inhibitor for mild steel (MS) in 1.0 M HCl solution. The inhibition action and mechanism of CA-CDs were determined by weight loss and electrochemical measurements, in combination with SEM, AFM, and XPS. The results show that CA-CDs as mixed-type inhibitors could effectively weaken the corrosion of MS in 1.0 M HCl solution, and their maximum inhibition efficiency reaches 97.4 % at 40 mg L-1. The adsorption behavior of CA-CDs well obeys the Langmuir adsorption isotherm containing both chemisorption and physisorption. The chemisorption mainly results from the multiple adsorption sites in the CA-CDs, and the physical adsorption is due to the blocking and barrier effect of CA-CD nanoparticles. Both adsorption behaviors were proposed to elucidate the corrosion inhibition mechanism of CA-CDs.

Cell type-specific NRBF2 orchestrates autophagic flux and adult hippocampal neurogenesis in chronic stress-induced depression.

Dysfunctional autophagy and impairment of adult hippocampal neurogenesis (AHN) each contribute to the pathogenesis of major depressive disorder (MDD). However, whether dysfunctional autophagy is linked to aberrant AHN underlying MDD remains unclear. Here we demonstrate that the expression of nuclear receptor binding factor 2 (NRBF2), a component of autophagy-associated PIK3C3/VPS34-containing phosphatidylinositol 3-kinase complex, is attenuated in the dentate gyrus (DG) under chronic stress. NRBF2 deficiency inhibits the activity of the VPS34 complex and impairs autophagic flux in adult neural stem cells (aNSCs). Moreover, loss of NRBF2 disrupts the neurogenesis-related protein network and causes exhaustion of aNSC pool, leading to the depression-like phenotype. Strikingly, overexpressing NRBF2 in aNSCs of the DG is sufficient to rescue impaired AHN and depression-like phenotype of mice. Our findings reveal a significant role of NRBF2-dependent autophagy in preventing chronic stress-induced AHN impairment and suggest the therapeutic potential of targeting NRBF2 in MDD treatment.

Surface Dual Metal Occupations in Fe-Doped FexBi2-xO3 Induce Highly Efficient Photocatalytic CO2 Reduction.

CO2 possesses extraordinary thermodynamic stability, and its reduction reaction involves multiple electron-transfer processes. Thus, high-density electron occupation on a catalyst surface is an effective driving force for improving the photocatalytic activity. Here, we report on the fabrication of Fe-doped Bi2O3 catalysts (denoted as FexBi2-xO3) with different Fe contents using the solvothermal method. The self-assembled catalyst has a nanoflower-like morphology, and its performance of CO2 reduction to CO is improved largely dependent on the Fe content. In the sample with a 7.0% Fe content (Fe0.07Bi1.93O3), the CO evolution rate reaches 30.06 µmol g-1 h-1, which is about 6 times higher than the 4.95 µmol g-1 h-1 of pristine Bi2O3, and shows excellent photostability after three cycles, with each cycle lasting for 7 h. Theoretical calculation and spectral characterization reveal that such a good CO2 reduction reaction performance arises from effective surface occupation of Fe, which not only enhances sunlight absorption but also significantly increases the surface electron density on the double metal active sites. This work provides a new strategy for improving the photocatalytic performance by surface metal doping in some metal oxide photocatalysts.

A Selective Nano Cell Cycle Checkpoint Inhibitor Overcomes Leukemia Chemoresistance.

Cell cycle checkpoint activation promotes DNA damage repair, which is highly associated with the chemoresistance of various cancers including acute myeloid leukemia (AML). Selective cell cycle checkpoint inhibitors are strongly demanded to overcome chemoresistance, but remain unexplored. A selective nano cell cycle checkpoint inhibitor (NCCI: citric acid capped ultra-small iron oxide nanoparticles) that can catalytically inhibit the cell cycle checkpoint of AML to boost the chemotherapeutic efficacy of genotoxic agents is now reported. NCCI can selectively accumulate in AML cells and convert H2 O2 to • OH to cleave heat shock protein 90, leading to the degradation of ataxia telangiectasia and Rad3-related proteinand checkpoint kinase 1, and the subsequent dysfunction of the G2/M checkpoint. Consequently, NCCI revitalizes the anti-AML efficacy of cytarabine that is previously ineffective both in vitro and in vivo. This study offers new insights into designing selective cell cycle checkpoint inhibitors for biomedical applications.

α-MSH-catabolic enzyme prolylcarboxypeptidase in nucleus accumbens shell ameliorates stress susceptibility in mice through regulating synaptic plasticity.

Emerging evidence demonstrates the vital role of synaptic transmission and structural remodeling in major depressive disorder. Activation of melanocortin receptors facilitates stress-induced emotional behavior. Prolylcarboxypeptidase (PRCP) is a serine protease, which splits the C-terminal amino acid of α-MSH and inactivates it. In this study, we asked whether PRCP, the endogenous enzyme of melanocortin system, might play a role in stress susceptibility via regulating synaptic adaptations. Mice were subjected to chronic social defeat stress (CSDS) or subthreshold social defeat stress (SSDS). Depressive-like behavior was assessed in SIT, SPT, TST and FST. Based on to behavioral assessments, mice were divided into the susceptible (SUS) and resilient (RES) groups. After social defeat stress, drug infusion or viral expression and behavioral tests, morphological and electrophysiological analysis were conducted in PFX-fixed and fresh brain slices containing the nucleus accumbens shell (NAcsh). We showed that PRCP was downregulated in NAcsh of susceptible mice. Administration of fluoxetine (20 mg·kg-1·d-1, i.p., for 2 weeks) ameliorated the depressive-like behavior, and restored the expression levels of PRCP in NAcsh of susceptible mice. Pharmacological or genetic inhibition of PRCP in NAcsh by microinjection of N-benzyloxycarbonyl-L-prolyl-L-prolinal (ZPP) or LV-shPRCP enhanced the excitatory synaptic transmission in NAcsh, facilitating stress susceptibility via central melanocortin receptors. On the contrary, overexpression of PRCP in NAcsh by microinjection of AAV-PRCP alleviated the depressive-like behavior and reversed the enhanced excitatory synaptic transmission, abnormal dendritogenesis and spinogenesis in NAcsh induced by chronic stress. Furthermore, chronic stress increased the level of CaMKIIα, a kinase closely related to synaptic plasticity, in NAcsh. The elevated level of CaMKIIα was reversed by overexpression of PRCP in NAcsh. Pharmacological inhibition of CaMKIIα in NAcsh alleviated stress susceptibility induced by PRCP knockdown. This study has revealed the essential role of PRCP in relieving stress susceptibility through melanocortin signaling-mediated synaptic plasticity in NAcsh.

A thalamic circuit facilitates stress susceptibility via melanocortin 4 receptor-mediated activation of nucleus accumbens shell.

AIMS: Central melanocortin 4 receptor (MC4R) has been reported to induce anhedonia via eliciting dysfunction of excitatory synapses. It is evident that metabolic signals are closely related to chronic stress-induced depression. Here, we investigated that a neural circuit is involved in melanocortin signaling contributing to susceptibility to stress. METHODS: Chronic social defeat stress (CSDS) was used to develop depressive-like behavior. Electrophysiologic and chemogenetic approaches were performed to evaluate the role of paraventricular thalamus (PVT) glutamatergic to nucleus accumbens shell (NAcsh) circuit in stress susceptibility. Pharmacological and genetic manipulations were applied to investigate the molecular mechanisms of melanocortin signaling in the circuit. RESULTS: CSDS increases the excitatory neurotransmission in NAcsh through MC4R signaling. The enhanced excitatory synaptic input in NAcsh is projected from PVT glutamatergic neurons. Moreover, chemogenetic manipulation of PVTGlu -NAcsh projection mediates the susceptibility to stress, which is dependent on MC4R signaling. Overall, these results reveal that the strengthened excitatory neurotransmission in NAcsh originates from PVT glutamatergic neurons, facilitating the susceptibility to stress through melanocortin signaling. CONCLUSIONS: Our results make a strong case for harnessing a thalamic circuit to reorganize excitatory synaptic transmission in relieving stress susceptibility and provide insights gained on metabolic underpinnings of protection against stress-induced depressive-like behavior.

Long noncoding RNA Gm2694 drives depressive-like behaviors in male mice by interacting with GRP78 to disrupt endoplasmic reticulum homeostasis.

Long noncoding RNAs (lncRNAs) are involved in various biological processes and implicated in the regulation of neuronal activity, but the potential role of lncRNAs in depression remains largely unknown. Here, we identified that lncRNA Gm2694 was increased in the medial prefrontal cortex (mPFC) of male mice subjected to chronic social defeat stress (CSDS). The down-regulation of Gm2694 in the mPFC alleviated CSDS-induced depressive-like behaviors through enhanced excitatory synaptic transmission. Furthermore, we found that Gm2694 preferentially interacted with the carboxyl-terminal domain of 78-kilodalton glucose-regulated protein (GRP78), which abrogated GRP78 function and disrupted endoplasmic reticulum homeostasis, resulting in a reduction of the surface expression of AMPA receptors (AMPARs). Overexpression of GRP78 in the mPFC promoted the surface expression of AMPARs and attenuated the CSDS-induced depressive-like behaviors of mice. Together, our results unraveled a previously unknown role of Gm2694 in regulating endoplasmic reticulum homeostasis and excitatory synaptic transmission in depression.

Activation hypoxia inducible factor-1α gene affected the tumor microenvironment and induced recurrence and invasion of bladder cancer in vitro.

OBJECTIVE: This work aimed to investigate the molecular mechanism of the activation of hypoxia-inducible factors under different low oxygen partial pressures. METHODS: Strictly follow in vitro aseptic culture of bladder cancer cell line UMUC3 and when the cells grow in the logarithmic phase, culture the cells under different low oxygen partial pressures. Among these groups, two groups of cells were transfected with small interfering-hypoxia inducible factor 1α (si-HIF-1α) liposome plasmids to silencing the HIF-1α expression. RESULTS: Cell cloning experiment showed that HIF-1α will increase cell adhesion and proliferation under hypoxia. Matrigel angiogenesis experiment showed that hypoxia has a negative impact on the angiogenesis of tumor cells. Cell scratch test indicated that hypoxia has a greater impact on the migration ability of cancer cells, and HIF-1α has a significant impact on the migration process. Cell invasion test proved that hypoxia has a greater impact on the invasion ability of cancer cells, and HIF-1α has a great impact on the invasion process. CONCLUSION: HIF-1α can target the regulatory gene vascular endothelial growth factor to promote tumor cell proliferation, migration, invasion, neovascularization and lymph node metastasis.

OBJETIVO: Por lo tanto, este trabajo investiga el mecanismo molecular de la activación de factores inducibles por hipoxia bajo diferentes presiones parciales de oxígeno bajas. MÉTODOS: Siga estrictamente el cultivo aséptico in vitro de la línea celular de cáncer de vejiga UMUC3 y cuando las células crezcan en la fase logarítmica, cultive las células bajo diferentes presiones parciales de oxígeno bajas. Entre estos grupos, se transfectaron dos grupos de células con plásmidos de liposomas si-HIF-1α para silenciar la expresión de HIF-1α. RESULTADOS: El experimento de clonación celular mostró que HIF-1α aumentará la adhesión y proliferación celular bajo hipoxia. El experimento de angiogénesis de Matrigel mostró que la hipoxia tiene un impacto negativo en la angiogénesis de las células tumorales. La prueba de raspado celular indicó que la hipoxia tiene un mayor impacto en la capacidad de migración de las células cancerosas, y HIF-1α tiene un impacto significativo en el proceso de migración. La prueba de invasión celular demostró que la hipoxia tiene un mayor impacto en la capacidad de invasión de las células cancerosas y HIF-1α tiene un gran impacto en el proceso de invasión. CONCLUSIÓN: HIF-1α puede dirigirse al gen regulador vascular endothelial growth factor para promover la proliferación, migración, invasión, neovascularización y metástasis en los ganglios linfáticos de las células tumorales.

Effective Electro-Activation Process of Hydrogen Peroxide/Peroxydisulfate Induced by Atomic Hydrogen for Rapid Oxidation of Norfloxacin over the Carbon-Based Pd Nanocatalyst.

Peroxydisulfate (PDS) can be activated by electrochemistry, for which using atom H* as an activator is feasibly favorable in theoretical and experimental applications. Studies have shown that atomic H* can cleave the peroxide bond as a single-electron reducing agent in Na2S2O8 to generate SO4•-, thus achieving the degradation of pollutants. Herein, Pd nanoparticles synthesized by in an in situ solution were dispersed in carbon black and then loaded on carbon felt, called Pd/C@CF, as the cathode for peroxydisulfate activation. This showed an ideal degradation effect on a small electrode (10 mm × 10 mm). Cyclic voltammetry (CV) and linear sweep voltammetry (LSV) tests were taken to verify the significant increase in the yield of the reduction of Na2S2O8 by H*. The degradation experiments and free-radical scavenging experiment confirmed that the atomic H* was the dominant component triggering the activation of PDS to generate SO4•-. A Pd/C@CF composite electrodes have low pH dependence, high stability and recyclability, etc., which has many potential practical applications in wastewater treatment. In addition, H* can also reduce H2O2 to •OH by breaking the peroxide bond, so the removal of pollutants by the same amount of H2O2 and Na2S2O8 under the same conditions is compared, and their application prospects are analyzed and compared.

Efficient Delivery of P3H4 siRNA and Chlorin e6 by cRGDfK-Installed Polyarginine Nanoparticles for Tumor-Targeting Therapy of Bladder Cancer.

PURPOSE: Prolyl 3-hydroxylase family member 4 (P3H4) is a potent prognostic oncogene in bladder cancer (BC), and the inhibition of P3H4 suppresses BC tumor growth. This study aimed to evaluate the efficiency of P3H4 inhibition for BC tumor therapy via tumor-targeting nanoparticles. METHODS AND RESULTS: A linear polyarginine peptide (R9) was synthesized, azide-modified, and then assembled with cyclic pentapeptide cRGDfK. Chlorin e6 (ce6)-conjugated CH3-R9-RGD nanoparticles were prepared for the delivery of siP3H4 into T24 cells in vitro and BC tumors in vivo. Dynamic light scattering analysis identified that the optimum CH3-R9-RGD@siP3H4 molar ratio was 30/1. CH3-R9-RGD@ce6/siP3H4 nanocomposites decreased P3H4 expression and cell proliferation and promoted reactive oxygen species production, apoptosis, and calreticulin exposure in T24 cells in vitro. In vivo experiments showed that CH3-R9-RGD@ce6/siP3H4 nanocomposites caused pathological changes, suppressed BC tumor growth, promoted caspase 3 expression, and enhanced calreticulin exposure in tumor cells. CONCLUSIONS: The tumor-targeting CH3-R9-RGD nanocomposites encapsulating siP3H4 and ce6 might be an alternative therapeutic strategy or intravesical instillation chemotherapy for BC.

Repeated vagus nerve stimulation produces anxiolytic effects via upregulation of AMPAR function in centrolateral amygdala of male rats.

Repeated vagus nerve stimulation (rVNS) exerts anxiolytic effect by activation of noradrenergic pathway. Centrolateral amygdala (CeL), a lateral subdivision of central amygdala, receives noradrenergic inputs, and its neuronal activity is positively correlated to anxiolytic effect of benzodiazepines. The activation of ß-adrenergic receptors (ß-ARs) could enhance glutamatergic transmission in CeL. However, it is unclear whether the neurobiological mechanism of noradrenergic system in CeL mediates the anxiolytic effect induced by rVNS. Here, we find that rVNS treatment produces an anxiolytic effect in male rats by increasing the neuronal activity of CeL. Electrophysiology recording reveals that rVNS treatment enhances the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR)-mediated excitatory neurotransmission in CeL, which is mimicked by ß-ARs agonist isoproterenol or blocked by ß-ARs antagonist propranolol. Moreover, chemogenetic inhibition of CeL neurons or pharmacological inhibition of ß-ARs in CeL intercepts both enhanced glutamatergic neurotransmission and the anxiolytic effects by rVNS treatment. These results suggest that the amplified AMPAR trafficking in CeL via activation of ß-ARs is critical for the anxiolytic effects induced by rVNS treatment.

Nano-drug delivery system for the treatment of acute myelogenous leukemia.

Administration of therapeutic drugs has been the core strategy for acute myelogenous leukemia (AML), but it is generally limited by its low bioavailability, toxic side effects and intravenous administration. The nano-drug delivery system significantly improves the anti-AML activity through targeted optimization of the drug delivery system. Organic nanocarriers include polymers, liposomes, nanoemulsion, nanomicelle and proteins, which have the advantages of high loading capacity, biocompatibility and functionalization. Inorganic nanocarriers include gold nanoparticles, silicon nanoparticles, iron nanoparticles and other inorganic nanoparticles, which exhibit diverse physical and chemical properties, and have a wide range of biomedical applications including drug carriers. Both organic and inorganic nanocarriers exhibit the potential to alter the pharmacokinetics and pharmacodynamics of drugs. This article reviews the recent progress of nanocarriers as drug delivery system in clinical applications of AML treatment.

Melatonin decreases androgen-sensitive prostate cancer growth by suppressing SENP1 expression.

BACKGROUND: Melatonin is a hormone naturally produced by the pineal gland in the brain. In addition to modulating circadian rhythms, it has pleiotropic biological effects including antioxidant, immunomodulatory, and anti-cancer effects. Herein, we report that melatonin has the ability to decrease the growth and metastasis of androgen-dependent prostate cancer. METHODS: To evaluate the anti-cancer effect of melatonin on androgen-sensitive prostate cancer in vitro or in vivo, the effects of cell proliferation, apoptosis, migration and invasion were analyzed by using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), colony formation, flow cytometry, Transwell assay, and immunohistochemistry (IHC), respectively. Next, the interaction between androgen receptor (AR) and SUMO specific protease 1 (SENP1) was detected by real-time quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and western blotting, and confirmed by luciferase reporter assay. Furthermore, the Small Ubiquitin-like Modifier (SUMO) proteins are a group of small proteins that are covalently attached to and detached from other proteins in cells to modify their function. (SUMOylation) of histone deacetylases 1 (HDAC1) was measured by proximity ligation assay (PLA). RESULTS: The treatment of melatonin cripples the transcriptional activity of AR, which is essential for the growth of the androgen-dependent prostate cancer cell, LNCaP. The lower activity of AR was dependent on melatonin induced SUMOylation of HDAC1, which has been established as a key factor for the transcriptional activity of AR. Mechanistically, the effect of melatonin on AR was due to the decreased SENP1 protein level and the subsequent increased HDAC1 SUMOylation level. The overexpression of SENP1 abrogated the anti-cancer ability of melatonin on LNCaP cells. CONCLUSIONS: These findings indicate that melatonin is a suppressor of androgen-dependent prostate cancer tumorigenesis.

P3H4 and PLOD1 expression associates with poor prognosis in bladder cancer.

PURPOSE: The prolyl 3-hydroxylase family member 4 gene (P3H4) is involved in the development of human cancers. The association of P3H4 with bladder cancer (BC) prognosis is unclear. This study aimed to analyze the association of P3H4 with BC prognosis. METHODS: RNA-Seq data were downloaded from The Cancer Genome Atlas project and BC microarray datasets (GSE13507, GSE31684, and GSE32548) were downloaded from the Gene Expression Omnibus database. We analyzed the differences in P3H4 expression levels between BC tumors and non-tumor tissues and between samples with different clinical information. The association of P3H4 and P3H4-related genes with BC prognosis and the possibility of using P3H4 expression as a prognostic biomarker in BC patients were also analyzed. RevMan was used to perform the meta-analysis. RESULTS: P3H4 was upregulated in BC tissues compared with the adjacent non-tumor tissues (p = 4.06e-08). Univariate Cox regression analysis and meta-analysis showed that high P3H4 expression level contributed to a poor BC prognosis (Hazard ratio, HR = 1.348, 95% CI 1.140-1.594, p = 4.89e-04; meta-analysis: HR = 1.45, 95% CI 1.10-1.91; p = 9.00e-03). Among the genes related to P3H4, the PLOD1 gene was closely associated with P3H4 expression (r = 0.620, p = 2.49e-44). Also, a meta-analysis showed that PLOD1 expression was associated with a poor prognosis in BC patients (HR = 1.77, 95% CI 1.31-2.38; p = 2.00e-04). CONCLUSIONS: The P3H4 and PLOD1 genes might be used as reliable prognostic biomarkers for BC.