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Chemotherapy, particularly with oxaliplatin, is a key treatment for advanced gastric cancer (GC), and exosomes derived from human bone marrow mesenchymal stem cells (hBM-MSCs) play a vital role in the tumor microenvironment. The study aims to elucidate the previously unexplored role of exosomes derived from hBM-MSCs in GC tumorigenesis, especially under the influence of chemotherapy. We conducted an experimental study, utilizing miRNA sequencing and biological experiments, to analyze the tumorigenicity of exosomal miR-424-3p secreted by hBM-MSCs and its target gene RHOXF2 in GC cell lines. The results were confirmed through experimentation using a xenograft mouse model. This study demonstrated the role of hBM-MSCs in the GC microenvironment, focusing on their epithelial-mesenchymal transition (EMT) facilitation through exosomes, which led to enhanced tumorigenicity in GC cells. Intriguingly, this pro-tumor effect was abrogated when hBM-MSCs were treated with oxaliplatin. Exosomal miRNA sequencing revealed that oxaliplatin can upregulate the levels of miR-424-3p in exosomes secreted by hBM-MSCs, thereby inhibiting the EMT process in GC cells. Furthermore, miR-424-3p was identified to target and downregulate RHOXF2 expression, impeding the malignant behavior of GC cells both in vitro and in the mouse model. These findings uncover a potential hidden mechanism of oxaliplatin's anti-tumor action and propose the delivery of miR-424-3p via exosomes as a promising avenue for anti-tumor therapy.
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Transición Epitelial-Mesenquimal , Exosomas , Células Madre Mesenquimatosas , MicroARNs , Oxaliplatino , Neoplasias Gástricas , MicroARNs/genética , MicroARNs/metabolismo , Humanos , Oxaliplatino/farmacología , Células Madre Mesenquimatosas/metabolismo , Exosomas/metabolismo , Exosomas/genética , Animales , Neoplasias Gástricas/patología , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/tratamiento farmacológico , Ratones , Línea Celular Tumoral , Transición Epitelial-Mesenquimal/efectos de los fármacos , Transición Epitelial-Mesenquimal/genética , Regulación hacia Arriba , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto , Antineoplásicos/farmacología , Microambiente Tumoral , Ratones Desnudos , Progresión de la EnfermedadRESUMEN
Transcriptional heterogeneity of tumor-associated macrophages (TAMs) has been investigated in individual cancers, but the extent to which these states transcend tumor types and represent a general feature of cancer remains unclear. We performed pan-cancer single-cell RNA sequencing analysis across nine cancer types and identified distinct monocyte/TAM composition patterns. Using spatial analysis from clinical study tissues, we assessed TAM functions in shaping the tumor microenvironment (TME) and influencing immunotherapy. Two specific TAM clusters (pro-inflammatory and pro-tumor) and four TME subtypes showed distinct immunological features, genomic profiles, immunotherapy responses, and cancer prognosis. Pro-inflammatory TAMs resided in immune-enriched niches with exhausted CD8+ T cells, while pro-tumor TAMs were restricted to niches associated with a T-cell-excluded phenotype and hypoxia. We developed a machine learning model to predict immune checkpoint blockade response by integrating TAMs and clinical data. Our study comprehensively characterizes the common features of TAMs and highlights their interaction with the TME.
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Aiming at the coexistence of antibiotics and Cu(II) in livestock wastewater, a novelty strategy for the simultaneous removal of antibiotics and Cu ions by in-situ utilization of Cu(II) (i.e., CP/Cu(II) and CP/Cu(II)/ascorbic acid (AA) systems) was proposed. The removal rate of florfenicol (FF) in the CP/Cu(II)/AA system was 6.9 times higher than that of the CP/Cu(II) system. CP/Cu(II)/AA system was also effective in removing antibiotics from real livestock tailwater. Simultaneously, the removal of Cu ions in CP/Cu(II) and CP/Cu(II)/AA systems could reach 54.5 % and 15.7 %, respectively. The added AA could significantly enhance the antibiotics degradation but inhibit the Cu ions removal. HOâ¢, O2â¢-, Cu(III), and â¢C-R were detected in the CP/Cu(II)/AA system, in which HO⢠was confirmed as the predominant contributor for FF degradation, and Cu(III) and â¢C-R also participated in FF elimination. The role of AA could accelerate HO⢠production and Cu(I)/Cu(II)/Cu(III) cycle, and form â¢C-R. The degradation products and pathways of FF in the CP/Cu(II)/AA system were proposed and the toxicity of the degradation products was evaluated by the toxicity analysis software (T.E.S.T). The results of this work suggest that without introducing complex catalysts, the feasibility of in-situ utilization of Cu(II) inherently or artificially introduced in livestock wastewater activating CP for antibiotic degradation and Cu ions removal was verified.
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This study aimed to investigate the chemical composition, structural properties, and biological properties of pectin polysaccharides (AP-FS, AP-QG, and AP-HG) isolated from different varieties of apple pomace. Based on the methylation and nuclear magnetic resonance analyses, the structure of AP-FS was determined to be composed of an α-1,4-linked homogalacturonan backbone that exhibited high levels of O-6 methylation. All pectins exhibit potent inhibitory activity against human colon cancer and human liver cancer cells, along with immunostimulatory effects. Among them, AP-FS exhibited the highest activity level. Finally, we further investigated the underlying mechanism behind the effect of AP-FS on RAW 264.7 cells using proteomics analysis. Our findings revealed that AP-FS triggers RAW 264.7 macrophage activation via NOD-like receptor (NLR), NF-κB, and mitogen-activated protein kinase (MAPK) signaling pathways. Therefore, our research contributes to a better understanding of the structure-function relationship among apple pectins, and AP-FS has the potential to be applied to dietary supplements targeting immunomodulation.
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Malus , Pectinas , Pectinas/química , Pectinas/farmacología , Malus/química , Ratones , Animales , Células RAW 264.7 , Humanos , Relación Estructura-Actividad , Metilación , FN-kappa B/metabolismoRESUMEN
A series of transition metal (Co, Ni, Fe) nanoparticles were confined in N-doped carbon nanotubes (NCNTs) prepared (Co@NCNTs, Ni@NCNTs, and Fe@NCNTs) by the polymerization method. The structure and composition of catalysts were well characterized. The catalytic activity of catalysts for activating peroxymonosulfate (PMS) was conducted via acid orange 7 (AO7) degradation. Among the catalysts, Co@NCNTs performed the best catalytic activity. Additionally, Co@NCNTs performed good catalytic activity in pH values of 2.39-10.98. Cl- and SO42- played a promoting roles in AO7 degradation. NO3- presented a weak effect on the catalytic performance of Co@NCNTs, while HCO3- and CO32- significantly suppressed the catalytic performance of Co@NCNTs. Both non-radical (1O2 and electron transfer) and free-radical (·OH and SO4·-) pathways were detected in the Co@NCNTs/PMS system. Notably, 1O2 was identified to be the main active specie in this study. The catalytic activity of Co@NCNTs gradually decreased after cycle reuse of Co@NCNTs. Finally, the toxicity of the AO7 degradation solution in the study was evaluated by Chlorella pyrenoidosa.
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Chlorella , Nanotubos de Carbono , Peróxidos/química , Radicales LibresRESUMEN
BACKGROUND: The treatment of metastatic castration-resistant prostate cancer (mCRPC) in the actual world currently presents difficulties. In light of this, it is crucial to investigate high-risk factors for the progression of advanced prostate cancer and to identify methods for delaying the onset of CRPC. AIMS: This study aimed to explore the high-risk factors that impact the progression of prostate cancer and emphasize the significance of precise diagnosis and treatment based on etiological classification in the clinical management of castration-resistant prostate cancer. METHODS: A retrospective analysis was conducted on 277 newly diagnosed cases of PCa treated with endocrine therapy. A follow-up was done on prostate-specific antigen (PSA) levels and testosterone. Additionally, a prospective analysis was performed on the clinical data of 60 patients with CRPC. Following the principle of '4W1H', 30 patients were included in the precision treatment group for a second biopsy and related tests, while another 30 patients were included in the conventional treatment group. The therapeutic effect and prognosis of the two groups were observed. RESULTS: Distant metastasis (HR = 1.879, 95% CI: 1.311 ~ 2.694, P = 0.001), PSA nadir > 0.2 ng/mL (HR = 1.843, 95% CI: 1.338 ~ 2.540, P = 0.001), testosterone nadir > 20 ng/dL (HR = 1.403, 95% CI: 1.035 ~ 1.904, P = 0.029), and time to testosterone nadir > 6 months (HR = 1.919, 95% CI: 1.364 ~ 2.701, P = 0.001) were risk factors for the progression to CRPC. Patients in the CRPC group were treated with precision therapy and conventional therapy based on their molecular subtyping. The precision treatment group showed a significantly prolonged median PSA progression-free survival compared to the conventional treatment group (16.0 months vs. 13.0 months, P=0.025). The median radiographic progression-free survival was also significantly extended in the precision treatment group compared to the conventional treatment group (21.0 months vs. 16.0 months, P=0.042). CONCLUSION: Patients with prostate cancer diagnosed with distant metastasis at initial presentation require early intervention. Close monitoring of PSA and serum testosterone changes is necessary during the process of endocrine therapy. After entering the CRPC stage, the etiological classification precision treatment can improve the therapeutic effect and improve the prognosis of patients.
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Single-cell RNA sequencing (scRNA-seq) is a cutting-edge technology that provides insights at the individual cell level. In contrast to traditional bulk RNA-seq, which captures gene expression at an average level and may overlook important details, scRNA-seq examines each individual cell as a fundamental unit and is particularly well-suited for identifying rare cell populations. Analogous to a microscope that distinguishes various cell types within a tissue sample, scRNA-seq unravels the heterogeneity and diversity within a single cell species, offering great potential as a leading sequencing method in the future. In the context of prostate cancer (PCa), a disease characterized by significant heterogeneity and multiple stages of progression, scRNA-seq emerges as a powerful tool for uncovering its intricate secrets.
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In the field of biomagnetic measurements, one of the most important recent challenges is to perform measurements in a magnetically unshielded environment. This first requires that atomic magnetometers can operate in a finite magnetic field, and have enough high sensitivity. To meet these requirements, we develop a light-narrowed parametric resonance (LPR) magnetometer. By adding a modulation magnetic field to the large longitudinal magnetic field, our LPR magnetometer can measure small transverse magnetic fields with an intrinsic sensitivity of 3.5 fT/Hz1/2 in a longitudinal magnetic field of µT range. Moreover, we have also demonstrated that in contrast to the previous light-narrowed scalar magnetometers, our LPR magnetometer has the potential to achieve higher sensitivity. Because in our case spin-exchange relaxation suppression by using light narrowing can lead to an improvement of fundamental sensitivity limit regardless of which quantum noise is dominant, and hence the fundamental sensitivity is no longer limited by spin-exchange, and approaches the fundamental limit set by the spin-exchange and spin-destruction cross sections.
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As the most common modification of RNA, N6-methyladenosin (m6A) has been confirmed to be involved in the occurrence and development of various cancers. However, the relationship between m6A and castration resistance prostate cancer (CRPC), has not been fully studied. By m6A-sequencing of patient cancer tissues, we identified that the overall level of m6A in CRPC was up-regulated than castration sensitive prostate cancer (CSPC). Based on the analysis of m6A-sequencing data, we found m6A modification level of HRas proto-oncogene, GTPase (HRAS) and mitogen-activated protein kinase kinase 2 (MEK2 or MAP2K2) were enhanced in CRPC. Specifically, tissue microarray analysis and molecular biology experiments confirmed that METTL3, an m6A "writer" up-regulated after castration, activated the ERK pathway to contribute to malignant phenotype including ADT resistance, cell proliferation and invasion. We revealed that METTL3-mediated ERK phosphorylation by stabilizing the transcription of HRAS and positively regulating the translation of MEK2. In the Enzalutamide-resistant (Enz-R) C4-2 and LNCap cell line (C4-2R, LNCapR) established in the current study, the ERK pathway was confirmed to be regulated by METTL3. We also found that applying antisense oligonucleotides (ASOs) to target the METTL3/ERK axis can restore Enzalutamide resistance in vitro and in vivo. In conclusion, METTL3 activated the ERK pathway and induced the resistance to Enzalutamide by regulating the m6A level of critical gene transcription in the ERK pathway.
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Neoplasias de la Próstata Resistentes a la Castración , Humanos , Masculino , Neoplasias de la Próstata Resistentes a la Castración/patología , Andrógenos , Receptores Androgénicos/metabolismo , Resistencia a Antineoplásicos , Línea Celular Tumoral , Nitrilos , Proliferación Celular , MetiltransferasasRESUMEN
PURPOSE: As the population ages, there is an increased risk of fracture and morbidity diseases associated with aging, such as age-related osteoporosis and other bone diseases linked to aging skeletons. RESULTS: Several bone-related cells, including multipotent bone mesenchymal stem cells, osteoblasts that form bone tissue, and osteoclasts that break it down, are in symbiotic relationships throughout life. Growing evidence indicates that epigenetic modifications of cells caused by aging contribute to compromised bone remodeling and lead to osteoporosis. A number of epigenetic mechanisms are at play, including DNA/RNA modifications, histone modifications, microRNAs (miRNAs), and long noncoding RNAs (lncRNAs), as well as chromatin remodeling. CONCLUSION: In this review, we summarized the epigenetic modifications of different bone-related cells during the development and progression of osteoporosis associated with aging. Additionally, we described a compensatory recovery mechanism under epigenetic regulation that may lead to new strategies for regulating bone remodeling in age-related osteoporosis.
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Enfermedades Óseas , MicroARNs , Osteoporosis , Humanos , Epigénesis Genética , Osteoporosis/genética , MicroARNs/genética , Enfermedades Óseas/genética , Remodelación Ósea/genéticaRESUMEN
Background: The cell cycle gene centromere protein K (CENPK) is upregulated in various cancers; however, the clinical value and mechanism of CENPK in prostate cancer (PCa) and castration-resistant prostate cancer (CRPC) remain unclear. Methods: The expression of CENPK in PCa was analyzed in both patients with PCa and cell lines using immunohistochemistry (IHC), real-time quantitative reverse transcription PCR (qRT-PCR), Western blot and bioinformatics analyses. Knockdown of CENPK in PCa cells was achieved by transfecting siRNAs and assessed using qRT-PCR and Western blotting. MTT and colony formation assays were used to assess the growth of PCa cells. The cell cycle was analyzed using propidium iodide (PI) staining and flow cytometry. To study the possible biological function of CENPK, pathway enrichment analysis was performed by dividing these groups into a high CENPK expression group and a low CENPK expression group based on the median CENPK expression level. Finally, the correlation between CENPK expression in PCa and clinical parameters was evaluated. Results: Our study revealed that CENPK was expressed at high levels in CRPC tissues and cell lines compared to primary PCa. The downregulation of CENPK significantly inhibited cell viability and reduced the number of colonies formed by LNCaP-AI and DU145 cells (two CRPC cell lines). Gene enrichment and flow cytometry analyses showed that high CENPK expression was linked to mitotic spindles and the cell cycle and may be involved in mitosis in the cell cycle of cancer cells to modulate cell proliferation and promote the development of CRPC. Moreover, patients exhibiting higher expression of the CENPK mRNA experienced shorter disease-free survival (DFS) and overall survival (OS) than the lower expression group. Conclusions: This study provides novel molecular insights into the role of CENPK in castration-resistant PCa cells and reveals that an increase in CENPK expression may indicate shorter DFS and a poor prognosis for patients with PCa. Targeting CENPK may be a novel strategy for the treatment of PCa.
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With the development of satellite load technology and very large-scale integrated (VLSI) circuit technology, on-board real-time synthetic aperture radar (SAR) imaging systems have facilitated rapid response to disasters. A key goal of the on-board SAR imaging system design is to achieve high real-time processing performance under severe size, weight, and power consumption constraints. This paper presents a multi-node prototype system for real-time SAR imaging processing. We decompose the commonly used chirp scaling (CS) SAR imaging algorithm into two parts according to the computing features. The linearization and logic-memory optimum allocation methods are adopted to realize the nonlinear part in a reconfigurable structure, and the two-part bandwidth balance method is used to realize the linear part. Thus, float-point SAR imaging processing can be integrated into a single Field Programmable Gate Array (FPGA) chip instead of relying on distributed technologies. A single-processing node requires 10.6 s and consumes 17 W to focus on 25-km swath width, 5-m resolution stripmap SAR raw data with a granularity of 16,384 × 16,384. The design methodology of the multi-FPGA parallel accelerating system under the real-time principle is introduced. As a proof of concept, a prototype with four processing nodes and one master node is implemented using a Xilinx xc6vlx315t FPGA. The weight and volume of one single machine are 10 kg and 32 cm × 24 cm × 20 cm, respectively, and the power consumption is under 100 W. The real-time performance of the proposed design is demonstrated on Chinese Gaofen-3 stripmap continuous imaging.
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With the development of satellite load technology and very large scale integrated (VLSI) circuit technology, onboard real-time synthetic aperture radar (SAR) imaging systems have become a solution for allowing rapid response to disasters. A key goal of the onboard SAR imaging system design is to achieve high real-time processing performance with severe size, weight, and power consumption constraints. In this paper, we analyse the computational burden of the commonly used chirp scaling (CS) SAR imaging algorithm. To reduce the system hardware cost, we propose a partial fixed-point processing scheme. The fast Fourier transform (FFT), which is the most computation-sensitive operation in the CS algorithm, is processed with fixed-point, while other operations are processed with single precision floating-point. With the proposed fixed-point processing error propagation model, the fixed-point processing word length is determined. The fidelity and accuracy relative to conventional ground-based software processors is verified by evaluating both the point target imaging quality and the actual scene imaging quality. As a proof of concept, a field- programmable gate array-application-specific integrated circuit (FPGA-ASIC) hybrid heterogeneous parallel accelerating architecture is designed and realized. The customized fixed-point FFT is implemented using the 130 nm complementary metal oxide semiconductor (CMOS) technology as a co-processor of the Xilinx xc6vlx760t FPGA. A single processing board requires 12 s and consumes 21 W to focus a 50-km swath width, 5-m resolution stripmap SAR raw data with a granularity of 16,384 × 16,384.
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Src homolog domain-containing phosphatase 2 (Shp2) signals a variety of cellular and physiological functions including learning and memory. Dysregulation of ERK signaling is known to be responsible for the cognitive deficits associated with gain-of-function mutated Shp2 mimicking Noonan syndrome. However, here, we report that CaMKIIα-cre induced knockout (CaSKO) of Shp2 in hippocampal pyramidal neurons resulted in increased Src activity, upregulated phosphorylation of N-methyl-D-aspartate receptors (NMDARs) at Y1325 of GluN2A and at Y1472 of GluN2B, disrupted the balance of synaptic transmission, and impaired long-term potentiation and remote contextual fear memory. Administration of PP2, a specific Src family kinase inhibitor, reversed the tyrosine phosphorylation of NMDARs, restored basal synaptic transmission, and rescued the contextual fear memory deficit in CaSKO mice without altering the phospho-ERK level. Taken together, our results reveal a novel role of Shp2 in NMDAR-dependent synaptic function and fear memory via the Src signaling pathway rather than the ERK pathway, and suggest a complicated mechanism for Shp2-associated cognitive deficits.
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Potenciales Postsinápticos Excitadores/fisiología , Miedo/fisiología , Memoria/fisiología , Prosencéfalo/metabolismo , Proteína Tirosina Fosfatasa no Receptora Tipo 11/deficiencia , Transmisión Sináptica/fisiología , Animales , Activación Enzimática/efectos de los fármacos , Activación Enzimática/fisiología , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Miedo/efectos de los fármacos , Masculino , Memoria/efectos de los fármacos , Trastornos de la Memoria/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Prosencéfalo/efectos de los fármacos , Pirimidinas/farmacología , Transmisión Sináptica/efectos de los fármacos , Familia-src QuinasasRESUMEN
Cu2+ is an essential metal ion that plays a critical role in the regulation of a number of ion channels and receptors in addition to acting as a cofactor in a variety of enzymes. Here, we showed that human melastatin transient receptor potential 2 (hTRPM2) channel is sensitive to inhibition by extracellular Cu2+. Cu2+ at concentrations as low as 3 µM inhibited the hTRPM2 channel completely and irreversibly upon washing or using Cu2+ chelators, suggesting channel inactivation. The Cu2+-induced inactivation was similar when the channels conducted inward or outward currents, indicating the permeating ions had little effect on Cu2+-induced inactivation. Furthermore, Cu2+ had no effect on singe channel conductance. Alanine substitution by site-directed mutagenesis of His995 in the pore-forming region strongly attenuated Cu2+-induced channel inactivation, and mutation of several other pore residues to alanine altered the kinetics of channel inactivation by Cu2+. In addition, while introduction of the P1018L mutation is known to result in channel inactivation, exposure to Cu2+ accelerated the inactivation of this mutant channel. In contrast with the hTRPM2, the mouse TRPM2 (mTRPM2) channel, which contains glutamine at the position equivalent to His995, was insensitive to Cu2+. Replacement of His995 with glutamine in the hTRPM2 conferred loss of Cu2+-induced channel inactivation. Taken together, these results suggest that Cu2+ inactivates the hTRPM2 channel by interacting with the outer pore region. Our results also indicate that the amino acid residue difference in this region gives rise to species-dependent effect by Cu2+ on the human and mouse TRPM2 channels.