RESUMO
The primary objective of this work was to delve into the potential therapeutic advantages and dissect the molecular mechanisms of salidroside in enhancing erectile function in rats afflicted with diabetic microvascular erectile dysfunction (DMED), addressing both the whole-animal and cellular dimensions.We established a DMED model in SpragueâDawley (SD) rats and conducted in vivo experiments. The DMED rats were administered varying doses of salidroside, the effects of which on DMED were compared. Erectile function was evaluated by applying electrical stimulation to the cavernous nerves and measuring intracavernous pressure in real time. The penile tissue underwent histological examination and Western blotting. Hydrogen peroxide (H2O2) was employed in the in vitro trial to induce an oxidative stress for the purpose of identifying alterations in cell viability. The CCK-8 assay was used to measure the viability of corpus cavernous smooth muscle cells (CCSMCs) treated with vs. without salidroside. Flow cytometry was utilized to detect alterations in intracellular reactive oxygen species (ROS). Apoptosis was assessed through Western blotting and TdT-mediated dUTP nick-end labelling (TUNEL). Animal and cellular experiments indicate that the Nrf2/HO-1 signalling pathway may be upregulated by salidroside, leading to the improvement of erectile function in diabetic male rats by alleviating oxidative stress and reducing apoptosis in corpus cavernosum tissue.
Assuntos
Apoptose , Disfunção Erétil , Glucosídeos , Fator 2 Relacionado a NF-E2 , Estresse Oxidativo , Fenóis , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio , Transdução de Sinais , Animais , Masculino , Estresse Oxidativo/efeitos dos fármacos , Disfunção Erétil/tratamento farmacológico , Disfunção Erétil/metabolismo , Disfunção Erétil/etiologia , Apoptose/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , Fenóis/farmacologia , Fenóis/uso terapêutico , Glucosídeos/farmacologia , Ratos , Transdução de Sinais/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/tratamento farmacológico , Pênis/efeitos dos fármacos , Pênis/metabolismo , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/efeitos dos fármacos , Heme Oxigenase (Desciclizante)/metabolismo , Heme Oxigenase-1/metabolismo , Sobrevivência Celular/efeitos dos fármacosRESUMO
BACKGROUND: The administration of mesenchymal stem cells (MSCs) through intracavernous injection is a potential therapeutic approach for managing diabetes mellitus-induced erectile dysfunction (DMED). However, pulmonary embolism and tumorigenicity are fatal adverse events that limit the clinical application of MSCs. In this study, we examined the therapeutic efficacy and potential mechanism of MSC-derived extracellular vesicles (MSC-EVs). METHODS: In this study, forty 8-week-old male SpragueDawley (SD) rats were utilised. In the control group, ten rats were administered an intraperitoneal injection of PBS. STZ (60â¯mg/kg) was intraperitoneally injected into the remaining rats to establish a diabetes mellitus (DM) model. Afterwards, the diabetic rats were divided into three groups at random: the DM group (intracavernosal injection of PBS), the EVs group (intracavernosal injection of MSC-EVs), and the EVs-200a group (intracavernosal injection of miR-200a-3p-enriched extracellular vesicles). Erectile function was determined by measuring intracavernous pressure in real time and utilising electrical stimulation of the cavernous nerves. The smooth muscle content was evaluated through the investigation of penile tissue using immunofluorescence staining, Masson's trichrome staining, and western blotting after euthanasia. Superoxide dismutase (SOD), malondialdehyde (MDA), and glutathione (GSH) levels in the corpus cavernosum were measured via ELISA. In vitro, hydrogen peroxide (H2O2) was used to induce oxidative stress. The viability of corpus cavernosum smooth muscle cells (ccSMCs) incubated with or without H2O2 was measured using a CCK8 assay. Flow cytometry was used to assess the levels of reactive oxygen species (ROS) and apoptosis in ccSMCs. Furthermore, a dual-luciferase reporter assay was performed to validate the relationship between miR-200a-3p and Keap1. RESULTS: Reversal of erectile function was observed in the EVs groups, especially in the EVs-200a group. DM increased the MDA level and decreased the SOD and GSH levels. In the DM group, the expression of alpha-smooth muscle actin (α-SMA) and smooth muscle 22 alpha (SM22α) was decreased, and the expression of osteopontin (OPN) was increased. Western blotting revealed decreased Nrf2, HO-1, and Bcl2 expression and increased Keap1, Bax and cleaved caspase3 expression in the cavernous tissue. miR-200a-3p-enriched extracellular vesicles (EVs-200a) reversed these changes and inhibited the loss of smooth muscle content and cavernous fibrosis. In vitro, H2O2 induced high ROS levels in ccSMCs and increased apoptosis, and these effects reversed by EVs-200a. H2O2 reduced Nrf2, HO-1, and Bcl2 expression and increased Keap1, Bax and cleaved caspase-3 expression, and these effects were reversed by MSC-EVs, especially EVs-200a. The of dual-luciferase reporter assay results indicated that miR-200a-3p directly targeted Keap1 in a negative manner. CONCLUSION: MSC-EVs, especially EVs-200a, alleviated erectile dysfunction in diabetic rats through the regulation of phenotypic switching, apoptosis and fibrosis. Mechanistically, miR-200a-3p targeted the Keap1/Nrf2 pathway to attenuate oxidative stress in diabetic rats.
Assuntos
Diabetes Mellitus Experimental , Disfunção Erétil , Vesículas Extracelulares , Proteína 1 Associada a ECH Semelhante a Kelch , Células-Tronco Mesenquimais , MicroRNAs , Ratos Sprague-Dawley , Animais , Masculino , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/metabolismo , Disfunção Erétil/terapia , Disfunção Erétil/etiologia , Disfunção Erétil/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch/genética , MicroRNAs/genética , MicroRNAs/metabolismo , Vesículas Extracelulares/metabolismo , Ratos , Células-Tronco Mesenquimais/metabolismo , Estresse Oxidativo , Ereção Peniana , Transplante de Células-Tronco Mesenquimais/métodosRESUMO
Neuroinflammation plays an important role in the pathogenesis of neurodegenerative diseases, and interrupting the microglial-mediated neuroinflammation has been suggested as a promising strategy to delay or prevent the progression of neurodegeneration. In this study, we investigated the effects of JE-133, an optically active isochroman-2H-chromene conjugate containing a 1,3-disubstituted isochroman unit, on lipopolysaccharide (LPS)-induced microglial neuroinflammation and underlying mechanisms both in vitro and in vivo. First, JE-133 treatment decreased LPS-induced overproduction of interleukin-1 beta (IL-1ß), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), nitrite, and nitric oxide synthase (iNOS) in BV2 microglial cells. Further study revealed that JE-133 downregulated the phosphorylation level of JAK/STAT and upregulated the protein level of Nrf2/HO-1 in LPS-stimulated BV2 microglial cells and verified that JE-133 directly bound to Keap1 by a pull-down assay. Next, JE-133 administration also inhibited neuroinflammation in vivo, as indicated by a reduced CD11b protein level and an overexpressed mRNA level of the pro-inflammatory cytokine TNF-α in the hippocampus of LPS-injected mice. Moreover, the regulative effects of JE-133 on the JAK/STAT and Nrf2/HO-1 pathways were also verified in the hippocampus of LPS-injected mice. Taken together, our study for the first time reports that JE-133 exhibits inhibitory effects against LPS-stimulated neuroinflammation both in vitro and in vivo, which might be associated with the simultaneous regulation of the JAK/STAT and Nrf2 pathways. Our findings may provide important clues for the discovery of effective drug leads/candidates against neuroinflammation-associated neurodegeneration.
Assuntos
Lipopolissacarídeos , Fator 2 Relacionado a NF-E2 , Camundongos , Animais , Lipopolissacarídeos/toxicidade , Fator 2 Relacionado a NF-E2/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Doenças Neuroinflamatórias , Fator de Necrose Tumoral alfa/metabolismo , Transdução de Sinais , Microglia , Interleucina-6 , NF-kappa B/metabolismo , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Óxido Nítrico Sintase Tipo II/farmacologia , Óxido Nítrico Sintase Tipo II/uso terapêuticoRESUMO
Cephalopods are an essential component of marine ecosystems, which are of great significance for the development of marine resources, ecological balance, and human food supply. At the same time, the preservation of cephalopod resources and the promotion of sustainable utilization also require attention. Many studies on the classification of cephalopods focus on the analysis of their beaks. In this study, we propose a feature fusion-based method for the identification of beaks, which uses the convolutional neural network (CNN) model as its basic architecture and a multi-class support vector machine (SVM) for classification. First, two local shallow features are extracted, namely the histogram of the orientation gradient (HOG) and the local binary pattern (LBP), and classified using SVM. Second, multiple CNN models were used for end-to-end learning to identify the beaks, and model performance was compared. Finally, the global deep features of beaks were extracted from the Resnet50 model, fused with the two local shallow features, and classified using SVM. The experimental results demonstrate that the feature fusion model can effectively fuse multiple features to recognize beaks and improve classification accuracy. Among them, the HOG+Resnet50 method has the highest accuracy in recognizing the upper and lower beaks, with 91.88% and 93.63%, respectively. Therefore, this new approach facilitated identification studies of cephalopod beaks.
RESUMO
Background: Erectile dysfunction (ED) occurs in an increasing number of patients after radical prostatectomy and cystectomy, and the phenotypic modulation of corpus cavernosum smooth muscle cells is closely related to ED. Aim: To determine whether endoplasmic reticulum stress (ERS) is implicated in the phenotypic modulation of ED induced by bilateral cavernous nerve injury (BCNI). Methods: In total, 36 Sprague-Dawley rats were randomly divided into 3 groups: sham, in which rats received sham surgery with bilateral cavernous nerve exposure plus phosphate-buffered saline; control, in which rats received BCNI plus phosphate-buffered saline; and experimental, in which rats received BCNI plus 4-phenylbutyric acid. Analysis of variance and a Bonferroni multiple-comparison test were utilized to evaluate differences among groups. Outcomes: Erectile function, smooth muscle/collagen ratios, and the expression levels of phenotypic modulation and ERS were measured. Results: Two ratios-maximum intracavernosal pressure/mean arterial pressure and smooth muscle/collagen-were decreased in the control group as compared with the sham group. In penile tissue, there was increased expression of GRP78 (78-kDa glucose-regulated protein), p-PERK/PERK (phosphorylated protein kinase R-like endoplasmic reticulum kinase/protein kinase R-like endoplasmic reticulum kinase), caspase 3, CHOP (C/EBP homologous protein), and OPN (osteopontin) but decreased expression of nNOS (neuronal nitric oxide synthase) and α-SMA (α-smooth muscle actin). As compared with the control group, erectile function was improved and pathologic changes were partially recovered in the experimental group. Clinical Translation: The present study demonstrated that ERS is involved in ED caused by cavernous nerve injury, thereby providing a new target and theoretical basis for clinical treatment. Strengths and Limitations: The present study demonstrated for the first time that ERS is related to ED caused by cavernous nerve injury. Inhibition of ERS reverses phenotypic modulation and improves erectile function in rats with BCNI. Additional in vitro studies should be performed to verify these conclusions and explore the specific mechanism of phenotypic modulation. Conclusion: The present study demonstrated that inhibiting ERS reverses phenotypic modulation and enhances erectile function in rats with BCNI.
RESUMO
Renal cancer stem cells (RCSCs) derived from clear cell renal cell carcinoma (ccRCC) tissues with higher microvessel density (MVD) have strong stemness and endothelial progenitor cells-like (EPCs-like) characteristics. A high level of lncRNA PVT1 expression is essential for simultaneously retaining strong RCSC stemness and EPCs-like characteristics. PVT1 binds with TAZ protein and prevents its phosphorylation, which promotes RCSC stemness. Moreover, RCSCs support endothelial differentiation and angiogenesis, which are mediated via the PVT1/miR-15b/KDR axis. This report provides insight into the determinants of RCSC impact on stemness and highlights the critical role of RCSC in angiogenesis. The presented findings suggest that targeting RCSC through PVT1 expression may be a new treatment strategy for ccRCC.
Assuntos
Carcinoma de Células Renais , Células Progenitoras Endoteliais , Neoplasias Renais , MicroRNAs , RNA Longo não Codificante , Humanos , Carcinoma de Células Renais/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Células Progenitoras Endoteliais/metabolismo , Regulação Neoplásica da Expressão Gênica , Neoplasias Renais/genética , MicroRNAs/genética , Células-Tronco Neoplásicas/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismoRESUMO
Erectile dysfunction (ED) is a common sexual dysfunction in men that can occur with the onset of sexual activity or even earlier, and the development of ED involves a variety of pathophysiologic mechanisms. Organic erectile dysfunction refers to a type of erectile dysfunction that is primarily caused by physical or organic factors rather than psychological or emotional factors. Worldwide, the incidence and prevalence of ED are high. Currently, the mainstay of ED treatment is the use of medications such as phosphodiesterase type 5 inhibitors (PDE5Is). However, these medications cause adverse effects such as flushing, indigestion and headaches and are not effective for some ED patients. Therefore, there is an urgent need to explore new targets of action for the treatment of ED. Ferroptosis is a type of iron-dependent regulated cell death initiated by lipid peroxidation and is a novel form of programmed cell death associated with the pathogenesis of various diseases. Prior research has provided evidence that the ferroptosis pathway plays a pivotal role in the modulation of ED, establishing this pathway as a significant foundation for the development of potential therapeutic interventions for ED. Experiments have shown that the inhibition of ferroptosis can improve ED. This article systematically introduces the role and influence of ferroptosis in various types of organic erectile dysfunction and describes the molecular mechanism, related pathways, and potential targets, providing a theoretical basis for the clinical diagnosis and treatment of ED.
Assuntos
Disfunção Erétil , Ferroptose , Masculino , Humanos , Disfunção Erétil/tratamento farmacológico , Inibidores da Fosfodiesterase 5/uso terapêutico , Exame FísicoRESUMO
In the user-centric, cell-free, massive multi-input, multi-output (MIMO) orthogonal frequency division multiplexing (OFDM) system, a large number of deployed access points (APs) serve user equipment (UEs) simultaneously, using the same time-frequency resources, and the system is able to ensure fairness between each user; moreover, it is robust against fading caused by multi-path propagation. Existing studies assume that cell-free, massive MIMO is channel-hardened, the same as centralized massive MIMO, and these studies address power allocation and energy efficiency optimization based on the statistics information of each channel. In cell-free, massive MIMO systems, especially APs with only one antenna, the channel statistics information is not a complete substitute for the instantaneous channel state information (CSI) obtained via channel estimation. In this paper, we propose that energy efficiency is optimized by power allocation with instantaneous CSI in the user-centric, cell-free, massive MIMO-OFDM system, and we consider the effect of CSI exchanging between APs and the central processing unit. In addition, we design different resource block allocation schemes, so that user-centric, cell-free, massive MIMO-OFDM can support enhanced mobile broadband (eMBB) for high-speed communication and massive machine communication (mMTC) for massive device communication. The numerical results verify that the proposed energy efficiency optimization scheme, based on instantaneous CSI, outperforms the one with statistical information in both scenarios.
RESUMO
Thermo-enhanced photocatalysis combines the advantages of thermocatalysis and photocatalysis and provides a very promising approach for the selective oxidation of organic compounds to value-added chemicals. In this work, the amino group in MIL-125-NH2 first reacts with formaldehyde to form the reducing group (-NH-CH2OH), which can in situ auto reduce the introduced Ag+ ions to Ag clusters/nanoparticles in the cavities. Then the formed MIL-125-NH-CH2OH@Ag was further coated with a covalent organic framework (COF) through imine bonds to form a series of MIL-125-NH-CH2OH@Ag@COF hybrids. Oxidative coupling of amines was selected to evaluate the photocatalytic performance of these materials under visible light at set temperatures (20-60 °C). With an optimized composition, MIL-125-NH-CH2OH@Ag-0.5@COF-2 not only improves the optical properties, but also exhibits the highest conversion (almost 100%) of benzylamine under visible light at 60 °C and good stability for at least three cycles. Free radical capture experiments and electron spin resonance detection demonstrated that holes (h+), hydroxyl (ËOH) and superoxide radicals (O2Ë-) were the active species. The results prove that the MIL-125-NH-CH2OH@Ag@COF hybrid possessed higher photocatalytic performance than individual MIL-125-NH2, Ag and COF on account of the efficient separation and transfer of photoinduced electrons and holes. Moreover, the promotion of the reaction temperature on the photocatalytic oxidation of amines has been reported, revealing that the conversion of benzylamine over MIL-125-NH-CH2OH@Ag-0.5@COF-2 at 60 °C is nearly twice as high as that at 20 °C under visible light irradiation. Therefore, the thermo-enhanced photocatalytic oxidation performance of the MOF@Ag@COF hybrid demonstrates the great potential of thermal energy for further improving the photocatalytic selective oxidation performance.
RESUMO
In centralized massive multiple-input multiple-output (MIMO) systems, the channel hardening phenomenon can occur, in which the channel behaves as almost fully deterministic as the number of antennas increases. Nevertheless, in a cell-free massive MIMO system, the channel is less deterministic. In this paper, we propose using instantaneous channel state information (CSI) instead of statistical CSI to obtain the power control coefficient in cell-free massive MIMO. Access points (APs) and user equipment (UE) have sufficient time to obtain instantaneous CSI in a slowly time-varying channel environment. We derive the achievable downlink rate under instantaneous CSI for frequency division duplex (FDD) cell-free massive MIMO systems and apply the results to the power control coefficients. For FDD systems, quantized channel coefficients are proposed to reduce feedback overhead. The simulation results show that the spectral efficiency performance when using instantaneous CSI is approximately three times higher than that achieved using statistical CSI.
RESUMO
FPS-ZM1 is an inhibitor of the receptor for advanced glycation end products (RAGE). Nevertheless, there are few reports about its direct effects on microglial inflammation, and the underlying molecular mechanisms remain to be clarified. The present study investigated the potential effects of FPS-ZM1 on lipopolysaccharide (LPS)-mediated microglial inflammation both in vivo and in vitro, and further elucidated the possible molecular mechanisms of action. FPS-ZM1 decreased LPS-induced overproduction of interleukin-1 beta (IL-1ß), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α) and cyclooxygenase 2 (COX-2), in both BV-2 cells and primary microglial cells. FPS-ZM1 (10 mg/kg, i.p.) ameliorated proliferation and activation of microglia in the hippocampus of C57BL/6J mice subjected to LPS challenge (5 mg/kg, i.p.). Meanwhile, overproduction of pro-inflammatory cytokines IL-1ß and TNF-α in the hippocampus was alleviated after treatment with FPS-ZM1. RNA-Sequencing (RNA-Seq) analysis showed involvement of Janus kinase (JAK)-signal transducers and activators of transcription (STAT) signaling pathway in the regulation of FPS-ZM1 on LPS-induced microglial inflammation. Further investigations demonstrated that FPS-ZM1 downregulated LPS-mediated increases in the phosphorylation levels of JAK/STAT both in vivo and in vitro. FPS-ZM1 also suppressed the nuclear translocation of transcription factor STAT1/3/5 in BV-2 cells. In addition, inhibition of JAK/STAT signaling pathway had an anti-inflammatory effect similar to FPS-ZM1 treatment. Taken together, our results verified the inhibitory effects of FPS-ZM1 against LPS-stimulated microglial inflammation, and for the first time demonstrated such anti-inflammatory activities on microglia are associated with regulation of JAK/STAT signaling pathway both in vivo and in vitro, which may shed new light on the pharmacological mechanisms of FPS-ZM1 against microglial inflammation.
Assuntos
Anti-Inflamatórios/farmacologia , Benzamidas/farmacologia , Inflamação/tratamento farmacológico , Janus Quinases/metabolismo , Microglia/metabolismo , Fatores de Transcrição STAT/metabolismo , Animais , Linhagem Celular , Ciclo-Oxigenase 2/metabolismo , Hipocampo/metabolismo , Mediadores da Inflamação/metabolismo , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Lipopolissacarídeos , Camundongos , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , NF-kappa B/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Underwater wireless sensor networks (UWSNs) have emerged as a promising technology to monitor and explore the oceans instead of traditional undersea wireline instruments. Traditional routing protocols are inefficient for UWSNs due to the specific nature of the underwater environment. In contrast, Opportunistic Routing (OR) protocols establish an online route for each transmission, which can well adapt with time-varying underwater channel. Cross-layer design is an effective approach to combine the metrics from different layers to optimize an OR routing in UWSNs. However, typical cross-layer OR routing protocols that are designed for UWSNs suffer from congestion problem at high traffic loads. In this paper, a Cross-Layer-Aided Opportunistic Routing Protocol (CLOR) is proposed to reduce the congestion in multi-hop sparse UWSNs. The CLOR consists of a negotiation phase and transmission phase. In the negotiation phase, the cross-layer information in fuzzy logic is utilized to attain an optimal forwarder node. In the transmission phase, to improve the transmission performance, a burst transmission strategy with network coding is exploited. Finally, we perform simulations of the proposed CLOR protocol in a specific sea region. Simulation results show that CLOR significantly improves the network performances at various traffic rates compared to existing protocols.
RESUMO
Development of glycogen synthase kinase-3ß (GSK-3ß) inactivation-centric agents with polypharmacological profiles is increasingly recognized as a promising therapeutic strategy against the multifactorial etiopathology of Alzheimer's disease (AD). In this respect, a series of disubstituted aminopyrazole derivatives were designed and synthesized as a new class of GSK-3ß inhibitors. Most of these derivatives possess GSK-3ß inhibitory activities with IC50 values in the micromolar ranges, among which bisindole-substituted aminopyrazole derivative 6h displayed moderate GSK-3ß inhibition (IC50 = 1.76 ± 0.19 µM), and alleviative effects against lipopolysaccharide (LPS)-induced glial inflammation in BV-2 cells and glutamate-induced oxidative neurotoxicity in HT-22 cells. Further in vivo studies indicated that compound 6h had potent anti-inflammatory effect, by showing markedly reduced microglial activation and astrocyte proliferation in the brain of LPS-injected mice. Overall, the simultaneous modulation of 6h on multiple dysfunctions of disease network highlights this structural distinctively bisindole-substituted aminopyrazole could be a useful prototype for the discovery of novel therapeutic agents to tackle AD and other GSK-3ß associated complex neurological syndromes.
Assuntos
Doença de Alzheimer , Glicogênio Sintase Quinase 3 beta/antagonistas & inibidores , Microglia , Pirazóis/farmacologia , Animais , Inflamação/tratamento farmacológico , Camundongos , Estresse OxidativoRESUMO
An amendment to this paper has been published and can be accessed via the original article.
RESUMO
Whether serine protease inhibitor Kazal type 1 (SPINK1) being associated with enzalutamide (Enz) resistance and metastasis of castration-resistant prostate cancer (CRPC) has not been clear. SPINK1 promoted Enz resistance by upregulating Androgen receptor splicing variant 7 (ARv7), and enhanced the invasion/migration of Enz-resistant cells via ERK/p38/ MMP9 signaling. Furthermore, miR-5089-5p suppressed SPINK1 mRNA through direct binding to its 3'UTR, and reversed its pro-proliferative and pro-metastatic effects. Mice bearing SPINK1-knockdown Enz-resistant PCa tumors showed significantly longer survival compared with those bearing wild-type tumors, while treatment with miR-5089-5p inhibitor abrogated the protective effects of SPINK1 knockdown. Taken together, SPINK1 can be used as a biomarker of resistance to Enz, and the miR-5089-5p/SPINK1/MAPK/MMP9 axis is a suitable therapeutic target against Enz-resistant and metastatic CRPC.Methods: The expression of SPINK1 in Enz-resistant prostate cancer (PCa) cell lines was detected through next-generation sequencing data and metastatic PCa patients. In vivo and in vitro experiments were performed to investigate the role of SPINK1 in Enz-resistance and metastasis.
Assuntos
Antineoplásicos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , MicroRNAs/farmacologia , Feniltioidantoína/análogos & derivados , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Processamento Alternativo , Animais , Benzamidas , Humanos , Sistema de Sinalização das MAP Quinases , Masculino , Metaloproteinase 9 da Matriz/genética , Camundongos , Camundongos Endogâmicos BALB C , Proteínas Quinases Ativadas por Mitógeno/genética , Metástase Neoplásica , Nitrilas , Feniltioidantoína/uso terapêutico , Receptores Androgênicos/genética , Análise de Sobrevida , Inibidor da Tripsina Pancreática de Kazal/genética , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Bladder cancer (BC) is the most common malignancy involving the urinary system, and is characterized by a high recurrence rate. It is important to identify potential lncRNA signatures capable of predicting tumour recurrence risk and assessing recurrence prognosis in BC patients. We extracted data from The Cancer Genome Atlas and identified 381 differentially expressed lncRNAs, 855 mRNAs and 70 miRNAs between non-recurrent and recurrent BC tissues. Subsequently, a competing endogenous RNA (ceRNA) network composed of 29 lncRNAs, 13 miRNAs and 4 mRNAs was established. We used univariate and multivariate Cox regression to analyse the relationship between the 29 lncRNAs and recurrence-free survival (RFS) in BC patients. Six lncRNAs had significant prognostic values, and their cumulative risk score indicated that this 6-lncRNA signature independently predicted RFS in BC patients. We applied a receiver operating characteristic (ROC) analysis to assess the efficiency of our prognostic models. High-risk patients exhibited a poorer prognosis than low-risk patients did. Additionally, the 6-lncRNA signature showed a significant correlation with BC clinicopathological characteristics, which indicates that it could be used for effective risk stratification. The current study provides novel insights into the lncRNA-related ceRNA network and this 6-lncRNA signature may be an independent prognostic factor in predicting the recurrence of BC patients.
RESUMO
BACKGROUND: Clear cell renal cell carcinoma (CCRCC) is characterized by a highly metastatic potential. The stromal communication between stem cells and cancer cells critically influences metastatic dissemination of cancer cells. METHODS: The effect of exosomes isolated from cancer stem cells (CSCs) of CCRCC patients on the progress of epithelial-mesenchymal transition (EMT) and lung metastasis of CCRCC cells were examined. RESULTS: CSCs exosomes promoted proliferation of CCRCC cells and accelerated the progress of EMT. Bioactive miR-19b-3p transmitted to cancer cells by CSC exosomes induced EMT via repressing the expression of PTEN. CSCs exosomes derived from CCRCC patients with lung metastasis produced the strongest promoting effect on EMT. Notably, CD103+ CSC exosomes were enriched in tumor cells and in lung as well, highlighting the organotropism conferred by CD103. In addition, CD103+ exosomes were increased in blood samples from CCRCC patients with lung metastasis. CONCLUSIONS: CSC exosomes transported miR-19b-3p into CCRCC cells and initiated EMT promoting metastasis. CD103+ acted to guide CSC exosomes to target cancer cells and organs, conferring the higher metastatic capacity of CCRCC to lungs, suggesting CD103+ exosomes as a potential metastatic diagnostic biomarker. á .
Assuntos
Antígenos CD/genética , Carcinoma de Células Renais/genética , Exossomos/metabolismo , Cadeias alfa de Integrinas/genética , Neoplasias Renais/genética , Neoplasias Pulmonares/genética , MicroRNAs/genética , PTEN Fosfo-Hidrolase/genética , Animais , Antígenos CD/metabolismo , Transporte Biológico , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/secundário , Comunicação Celular , Linhagem Celular Tumoral , Proliferação de Células , Transição Epitelial-Mesenquimal/genética , Exossomos/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Cadeias alfa de Integrinas/metabolismo , Neoplasias Renais/metabolismo , Neoplasias Renais/patologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/secundário , Metástase Linfática , Camundongos Nus , MicroRNAs/metabolismo , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , PTEN Fosfo-Hidrolase/metabolismo , Transdução de Sinais , Células Estromais/metabolismo , Células Estromais/patologia , Microambiente Tumoral/genética , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
This paper studies an adaptive coding scheme for B5G (beyond 5th generation) mobile system-enhanced transmission technology. Different from the existing works, the authors develop a class of rate-compatible, non-binary, low-density parity check (RC-NB-LDPC) codes, which expresses the strong connection between the algebra-based and graph-theoretic-based constructions. The constructed codes can not only express rate-compatible (RC) features, but also possess a quasi-cyclic (QC) structure that facilitates the encoding implementation. Further, in order to achieve the code rate-adaptive allocation scheme, the authors propose using the K-means++ clustering algorithm to cluster different channel environments, considering various factors that affect channel characteristics. Finally, in order to present the advantages of the adaptive coding scheme, the authors construct a coding scheme for image transmission. The numerical results demonstrate that the developed code can obtain better waterfall performance in a larger code rate range, which is more suitable for data transmission; the adaptive coding transmission scheme can obtain higher reconstructed image quality compared to the fixed code rate-coding scheme. Moreover, when considering unequal error protection (UEP), the proposed scheme can further improve the reconstructed image quality.
RESUMO
Frizzled class receptor 1 (FZD1), a receptor for Wnt signaling pathway. Overexpression of FZD1 has been detected in many cancer tissues and cells resulting in tumor development and drug resistance. However, its expression status and prognostic merit in renal cancer still remains unclear. We screened the FZD1 mRNA in clear cell renal cell carcinoma (ccRCC) and papillary renal cell carcinoma (pRCC) from TCGA database and Oncomine database. We then detected FZD1 mRNA expression in sunitinib-resistant cells and the corresponding parental cells by qRT-PCR. FZD1 level was significantly upregulated in renal cancer tissues, renal cancer cell lines and their corresponding sunitinib-resistant cells. FZD1 level was also associated with the clinicopathological characteristics of ccRCC patients that could discriminate metastasis, pathological stage, recurrence and prognosis in ccRCC patients. The Kaplan-Meier survival curve and the log-rank test revealed FZD1 was higher in lower clinical stage and grade that correlated with better overall survival (OS) and disease-free survival (DFS) in total and subgroups of ccRCC patients. Both univariate and multivariate cox regression analysis indicated that high FZD1 level was an independent predictor of good prognosis for OS (HR 0.569, P=0.001) and DFS (HR 0.559, P=0.036) in ccRCC patients. Using cBioportal program, less than 1% mutation in the patients with renal cancer was observed, the alterations in FZD1 were correlated with better OS (P=0.0404) in ccRCC patients. Finally, the result of KEGG pathway analysis predicted seven potential pathways that FZD1 and its related genes got involved in ccRCC, including Hippo signaling pathway. This indicated potential therapeutic targets of ccRCC. In conclusion, our results suggested that expression status of FZD1 had a diagnostic value and prognostic value in ccRCC patients, it also may serve as a potential drug target to relieve sunitinib resistance in renal cancer patients.