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1.
Cytotechnology ; 76(3): 351-361, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38736728

RESUMO

Pancreatic cancer is difficult to manage owing to the challenges involved in its treatment and nursing. This study aimed to clarify the roles and mechanisms of action of Poly (A)-binding protein cytoplasmic 1 (PABPC1) on pancreatic cancer. The expression of PABPC1 in pancreatic cancer tissues and cell lines was detected using RT-qPCR and western blotting. The effects of PABPC1 on proliferation, apoptosis, epithelial-mesenchymal transition (EMT), and the PI3K/AKT signaling pathway in pancreatic cancer cells were further investigated using MTT assays, flow cytometry, and western blotting. The expression of PABPC1 was significantly upregulated in pancreatic cancer tissues and cells, whereas PABPC1 downregulation inhibited pancreatic cancer cell proliferation, induced apoptosis, decreased the expression of EMT-associated proteins, and exerted a regulatory effect by inhibiting the PI3K/AKT signaling pathway. In addition, the findings indicated that PABPC1 over-expression significantly promoted pancreatic cancer cell proliferation, inhibited apoptosis, decreased the expression of E-cadherin, enhanced N-cadherin expression, and activating the PI3K/AKT signaling pathway. PABPC1 silencing significantly inhibited proliferation and EMT and induced apoptosis in pancreatic cancer cells. These findings provide novel insights into the role of PABPC1 in the development of pancreatic cancer. Supplementary Information: The online version contains supplementary material available at 10.1007/s10616-024-00626-1.

2.
ACS Appl Mater Interfaces ; 16(19): 24781-24795, 2024 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-38695117

RESUMO

Aqueous zinc-ion batteries (ZIBs) are regarded as a type of promising energy-storage device because of their high safety and low cost, and polyaniline (PANI) is normally employed as a cathode material for ZIBs owing to its unique electrochemical properties and high environmental stability. However, a low specific capacity and a short cycle life limit the development and applications of PANI-based electrodes. Herein, we have developed a novel type of highly stable PANI-based cathode material enabled by phosphene (PR) for aqueous Zn-PANI batteries through in situ chemical oxidative polymerization. The introduction of PR nanoflakes not only inhibits the degradation of PANI and generates more active sites for Zn2+ storage but also enables a synergistic effect of the Zn2+ insertion/extraction and P-Zn alloying reaction. This promotes a high reversible specific capacity of 240.2 mAh g-1 at 0.2 A g-1 and excellent rate performance for the PR/PANI nanocomposite cathode material. Compared to the pristine PANI cathode material, the PR/PANI nanocomposite cathode material is more suitable for the Zn-PANI battery, thanks to its higher specific capacity and better cycle stability. This study provides an innovative approach for developing the next generation of reliable PR-based electrode materials for aqueous energy-storage devices.

3.
Sensors (Basel) ; 24(9)2024 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-38732862

RESUMO

Online monitoring and real-time feedback on inclusions in molten metal are essential for metal quality control. However, existing methods for detecting aluminum melt inclusions face challenges, including interference, prolonged processing times, and latency. This paper presents the design and development of an online monitoring system for molten metal inclusions. Initially, the system facilitates real-time adjustment of signal acquisition parameters through a multiplexer. Subsequently, it employs a detection algorithm capable of swiftly extracting pulse peaks, with this task integrated into our proprietary host computer software to ensure timely detection and data visualization. Ultimately, we developed a monitoring device integrated with this online monitoring system, enabling the online monitoring of the aluminum alloy filtration process. Our findings indicate that the system can accurately measure the size and concentration of inclusions during the filtration process in real time, offering enhanced detection speed and stability compared to the industrial LiMCA CM (liquid metal cleanliness analyzer continuous monitoring) standard. Furthermore, our evaluation of the filtration process demonstrates that the effectiveness of filtration significantly improves with the increase in inclusion sizes, and the synergistic effect of combining CFF (ceramic foam filter) and MCF (metallics cartridge filter) filtration methods exceeds the performance of the CFF method alone. This system thus provides valuable technical support for optimizing filtration processes and controlling inclusion quality.

4.
Sensors (Basel) ; 24(9)2024 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-38732873

RESUMO

Traditional methods for assessing the cleanliness of liquid metal are characterized by prolonged detection times, delays, and susceptibility to variations in sampling conditions. To address these limitations, an online cleanliness-analyzing system grounded in the method of the electrical sensing zone has been developed. This system facilitates real-time, in situ, and quantitative analysis of inclusion size and amount in liquid metal. Comprising pneumatic, embedded, and host computer modules, the system supports the continuous, online evaluation of metal cleanliness across various metallurgical processes in high-temperature environments. Tests conducted with gallium liquid at 90 °C and aluminum melt at 800 °C have validated the system's ability to precisely and quantitatively detect inclusions in molten metal in real time. The detection procedure is stable and reliable, offering immediate data feedback that effectively captures fluctuations in inclusion amount, thereby meeting the metallurgical industry's demand for real-time analyzing and control of inclusion cleanliness in liquid metal. Additionally, the system was used to analyze inclusion size distribution during the hot-dip galvanizing process. At a zinc melt temperature of 500 °C, it achieved a detection limit of 21 µm, simultaneously providing real-time data on the size and amount distribution of inclusions. This represents a novel strategy for the online monitoring and quality control of zinc slag throughout the hot-dip galvanizing process.

5.
Inorg Chem ; 2024 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-38758008

RESUMO

Antimony selenide is a promising P-type photocatalyst, but it has a large number of deep energy level defects, leading to severe carrier recombination. The construction of a heterojunction is a common way to resolve this problem. However, the conventional heterojunction system inevitably introduces interface defects. Herein, we employ in situ synthesis to epitaxially grow In2Se3 nanosheets on Sb2Se3 nanorods and form In-Sb covalent interfacial bonds. This petal-shaped heterostructure reduced interface defects and enhanced the efficiency of carrier separation and transport. In this work, the photocurrent density in the proposed Sb2Se3/In2Se3 photocathode is 0.485 mA cm-2 at 0 VRHE, which is 30 times higher than that of pristine Sb2Se3 and it has prominent long-term stability for 24 h without obvious decay. The results reveal that the synergy of the bidirectional built-in electric field constructed between In2Se3 and Sb2Se3 and the solid In-Sb interfacial bonds together build a high-efficiency transport channel for the photogenerated carriers that display enhanced photoelectrochemical (PEC) water-splitting performance. This work provides efficient guidance for reducing interface defects via the in situ synthesis and construction of interfacial bonds.

6.
Langmuir ; 40(20): 10759-10768, 2024 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-38712734

RESUMO

Bouncing dynamics of a trailing drop off-center impacting a leading drop with varying time intervals and Weber numbers are investigated experimentally. Whether the trailing drop impacts during the spreading or receding process of the leading drop is determined by the time interval. For a short time interval of 0.15 ≤ Δt* ≤ 0.66, the trailing drop impacts during the spreading of the leading drop, and the drops completely coalesce and rebound; for a large time interval of 0.66 < Δt* ≤ 2.21, the trailing drop impacts during the receding process, and the drops partially coalesce and rebound. Whether the trailing drop directly impacts the surface or the liquid film of the leading drop is determined by the Weber number. The trailing drop impacts the surface directly at moderate Weber numbers of 16.22 ≤ We ≤ 45.42, while it impacts the liquid film at large Weber numbers of 45.42 < We ≤ 64.88. Intriguingly, when the trailing drop impacts the surface directly or the receding liquid film, the contact time increases linearly with the time interval but independent of the Weber number; when the trailing drop impacts the spreading liquid film, the contact time suddenly increases, showing that the force of the liquid film of the leading drop inhibits the receding of the trailing drop. Finally, a theoretical model of the contact time for the drops is established, which is suitable for different impact scenarios of the successive off-center impact. This study provides a quantitative relationship to calculate the contact time of drops successively impacting a superhydrophobic surface, facilitating the design of anti-icing surfaces.

7.
Environ Res ; 254: 119152, 2024 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-38754612

RESUMO

Several soil functions of alpine wetland depend on microbial communities, including carbon storage and nutrient cycling, and soil microbes are highly sensitive to hydrological conditions. Wetland degradation is often accompanied by a decline in water table. With the water table drawdown, the effects of microbial network complexity on various soil functions remain insufficiently understood. In this research, we quantified soil multifunctionality of flooded and non-flooded sites in the Lalu Wetland on the Tibetan Plateau. We employed high-throughput sequencing to investigate the microbial community responses to water table depth changes, as well as the relationships between microbial network properties and soil multifunctionality. Our findings revealed a substantial reduction in soil multifunctionality at both surface and subsurface soil layers (0-20 cm and 20-40 cm) in non-flooded sites compared to flooded sites. The α-diversity of bacteria in the surface soil of non-flooded sites was significantly lower than that in flooded sites. Microbial network properties (including the number of nodes, number of edges, average degree, density, and modularity of co-occurrence networks) exhibited significant correlations with soil multifunctionality. This study underscores the adverse impact of non-flooded conditions resulting from water table drawdown on soil multifunctionality in alpine wetland soils, driven by alterations in microbial community structure. Additionally, we identified soil pH and moisture content as pivotal abiotic factors influencing soil multifunctionality, with microbial network complexity emerging as a valuable predictor of multifunctionality.

8.
FEBS Open Bio ; 2024 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-38710666

RESUMO

The regenerative capability of the liver is remarkable, but further research is required to understand the role that neutrophils play in this process. In the present study, we reanalyzed single-cell RNA sequencing data from a mouse partial hepatectomy (PH) model to track the transcriptional changes in hepatocytes and non-parenchymal cells. Notably, we unraveled the regenerative capacity of hepatocytes at diverse temporal points after PH, unveiling the contributions of three distinct zones in the liver regeneration process. In addition, we observed that the depletion of neutrophils reduced the survival and liver volume after PH, confirming the important role of neutrophils in liver regeneration. CellChat analysis revealed an intricate crosstalk between neutrophils and macrophages promoting liver regeneration and, using weighted gene correlation network analysis, we identified the most significant genetic module associated with liver regeneration. Our study found that hepatocytes in the periportal zone of the liver are more active than in other zones, suggesting that the crosstalk between neutrophils and macrophages might be a potential target for liver regeneration treatment.

9.
Int J Gen Med ; 17: 1635-1649, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38706742

RESUMO

Kidney stones refer to abnormal crystal formation that occurs in the kidney. Among a variety of components of kidney stones, calcium oxalate (CaOx) is the most common type. Despite many efforts to investigate the pathogenesis of CaOx stones, the pathogenesis remains an issue of debate. With high occurrence and recurrence, individuals with stone formation are prone to frequently consult a doctor and to be hospitalized, and the treatment of kidney stones poses a heavy burden on the patients. Concerns should be focused not only on treatment but also on prevention. Herein, we reviewed the studies on prevention methods of CaOx stones through diet, lifestyle, and medication extending until the current time frame. As hyperoxaluria is the most common metabolic disorder among CaOx stone formations, we also included several studies on the treatment and prevention of hyperoxaluria. Our objective was to outline the effective methods to prevent renal CaOx stone formation.

10.
Front Oncol ; 14: 1368996, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38756660

RESUMO

Malignant peripheral nerve sheath tumors (MPNSTs) are a complex group of malignant tumors originating from nerve cells or benign peripheral nerve sheath tumors and are commonly found in major plexus/nerve root sites such as the limbs, head, and neck. Malignant peripheral nerve sheath tumors originating in the ureter are extremely rare. Herein, we report the case of a 63-year-old patient with a malignant peripheral nerve sheath tumor of the right ureter who underwent laparoscopic radical resection of the right kidney and ureter. The patient also had stage 5 chronic kidney disease (CKD). Therefore, chemotherapy and radiotherapy were not considered. No tumor recurrence was observed during the follow-up period.

11.
J Colloid Interface Sci ; 670: 114-123, 2024 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-38759266

RESUMO

For high energy density lithium-ion batteries (LIBs) with nickel-rich ternary cathodes, the chemical degradation of electrolytes caused by free radical reactions and the hazards of thermal runaway have always been significant challenges. Inspired by the free radical scavenging of living organisms and multiphase synergistic flame retardant mechanism, we innovatively designed and prepared a multifunctional flame retardant HCCP-TMP that combines flame retardancy and free radical scavenging by combining hindered amine and cyclophosphazene. Only 1 wt% HCCP-TMP can make the polyacrylate-based gel polymer electrolyte (GPE) incombustible. Moreover, the equipped NCM811//Graphite pouch cells don't exhibit combustion behavior after thermal runaway and can resist mechanical abuse. Based on the above noncombustible GPE, the NCM811//Li battery exhibits capacity retention rate of 82.2 % after 100 cycles at a current density of 2 C and in the voltage range of 3.0-4.7 V, exhibiting excellent cyclability under high voltage. This simple molecular design simultaneously improves the fire safety and high voltage stability, demonstrating enormous application potential in the field of advanced LIBs with high safety and high energy density.

12.
Heliyon ; 10(7): e26474, 2024 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-38689967

RESUMO

Corporate procurement management assumes a pivotal role within the contemporary business landscape, yet confronts an array of challenges as markets continue to evolve and globalize. Conventional procurement management systems frequently grapple with issues of inefficiency, resource depletion, and noncompliance, necessitating the exploration of innovative avenues for optimization. This paper delves into the realm of risk mitigation associated with collusion behavior in the administration of intelligent procurement systems, presenting a novel procurement collusion identification model founded on a convolutional neural network (CNN) with reinforcement learning techniques. This framework commences with the application of a CNN and Long Short-Term Memory (LSTM) network for in-depth feature analysis and initial identification of historical procurement data, subsequently leveraging reinforcement learning methodologies to enhance the model's autonomy and intelligence for the purpose of optimization. Throughout the experimental phase, diverse domains of procurement data were meticulously selected for analysis. The empirical findings unequivocally demonstrate the model's proficiency, with an average recognition accuracy of 95.1% across five publicly available datasets. This performance surpasses existing machine learning methodologies employed in contemporary research and common recognition networks, thereby offering a pioneering reference point for the intelligent administration and optimization of future procurement systems.

13.
Acta Pharm Sin B ; 14(4): 1605-1623, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38572102

RESUMO

Immune-mediated liver injury (ILI) is a condition where an aberrant immune response due to various triggers causes the destruction of hepatocytes. Fibroblast growth factor 4 (FGF4) was recently identified as a hepatoprotective cytokine; however, its role in ILI remains unclear. In patients with autoimmune hepatitis (type of ILI) and mouse models of concanavalin A (ConA)- or S-100-induced ILI, we observed a biphasic pattern in hepatic FGF4 expression, characterized by an initial increase followed by a return to basal levels. Hepatic FGF4 deficiency activated the mitochondria-associated intrinsic apoptotic pathway, aggravating hepatocellular apoptosis. This led to intrahepatic immune hyper-reactivity, inflammation accentuation, and subsequent liver injury in both ILI models. Conversely, administration of recombinant FGF4 reduced hepatocellular apoptosis and rectified immune imbalance, thereby mitigating liver damage. The beneficial effects of FGF4 were mediated by hepatocellular FGF receptor 4, which activated the Ca2+/calmodulin-dependent protein kinasekinase 2 (CaMKKß) and its downstream phosphatase and tensin homologue-induced putative kinase 1 (PINK1)-dependent B-cell lymphoma 2-like protein 1-isoform L (Bcl-XL) signalling axis in the mitochondria. Hence, FGF4 serves as an early response factor and plays a protective role against ILI, suggesting a therapeutic potential of FGF4 and its analogue for treating clinical immune disorder-related liver injuries.

14.
J Med Chem ; 67(7): 5866-5882, 2024 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-38556760

RESUMO

MERTK and AXL are members of the TAM (TYRO3, AXL, MERTK) family of receptor tyrosine kinases that are aberrantly expressed and have been implicated as therapeutic targets in a wide variety of human tumors. Dual MERTK and AXL inhibition could provide antitumor action mediated by both direct tumor cell killing and modulation of the innate immune response in some tumors such as nonsmall cell lung cancer. We utilized our knowledge of MERTK inhibitors and a structure-based drug design approach to discover a novel class of macrocyclic dual MERTK/AXL inhibitors. The lead compound 43 had low-nanomolar activity against both MERTK and AXL and good selectivity over TYRO3 and FLT3. Its target engagement and selectivity were also confirmed by NanoBRET and cell-based MERTK and AXL phosphorylation assays. Compound 43 had excellent pharmacokinetic properties (large AUC and long half-life) and mediated antitumor activity against lung cancer cell lines, indicating its potential as a therapeutic agent.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , c-Mer Tirosina Quinase/metabolismo , Receptor Tirosina Quinase Axl , Proteínas Proto-Oncogênicas/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Linhagem Celular Tumoral
15.
Nat Commun ; 15(1): 3220, 2024 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-38622115

RESUMO

Induced oncoproteins degradation provides an attractive anti-cancer modality. Activation of anaphase-promoting complex (APC/CCDH1) prevents cell-cycle entry by targeting crucial mitotic proteins for degradation. Phosphorylation of its co-activator CDH1 modulates the E3 ligase activity, but little is known about its regulation after phosphorylation and how to effectively harness APC/CCDH1 activity to treat cancer. Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN1)-catalyzed phosphorylation-dependent cis-trans prolyl isomerization drives tumor malignancy. However, the mechanisms controlling its protein turnover remain elusive. Through proteomic screens and structural characterizations, we identify a reciprocal antagonism of PIN1-APC/CCDH1 mediated by domain-oriented phosphorylation-dependent dual interactions as a fundamental mechanism governing mitotic protein stability and cell-cycle entry. Remarkably, combined PIN1 and cyclin-dependent protein kinases (CDKs) inhibition creates a positive feedback loop of PIN1 inhibition and APC/CCDH1 activation to irreversibly degrade PIN1 and other crucial mitotic proteins, which force permanent cell-cycle exit and trigger anti-tumor immunity, translating into synergistic efficacy against triple-negative breast cancer.


Assuntos
Proteínas de Ciclo Celular , Proteômica , Ciclo Celular/fisiologia , Ciclossomo-Complexo Promotor de Anáfase/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Fosforilação , Estabilidade Proteica , Peptidilprolil Isomerase de Interação com NIMA/genética , Peptidilprolil Isomerase de Interação com NIMA/metabolismo , Mitose
16.
Comput Methods Programs Biomed ; 249: 108159, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38583291

RESUMO

BACKGROUND AND OBJECTIVE: Colorectal cancer (CRC) is one of the most commonly diagnosed cancers worldwide. The accurate survival prediction for CRC patients plays a significant role in the formulation of treatment strategies. Recently, machine learning and deep learning approaches have been increasingly applied in cancer survival prediction. However, most existing methods inadequately represent and leverage the dependencies among features and fail to sufficiently mine and utilize the comorbidity patterns of CRC. To address these issues, we propose a self-attention-based graph learning (SAGL) framework to improve the postoperative cancer-specific survival prediction for CRC patients. METHODS: We present a novel method for constructing dependency graph (DG) to reflect two types of dependencies including comorbidity-comorbidity dependencies and the dependencies between features related to patient characteristics and cancer treatments. This graph is subsequently refined by a disease comorbidity network, which offers a holistic view of comorbidity patterns of CRC. A DG-guided self-attention mechanism is proposed to unearth novel dependencies beyond what DG offers, thus augmenting CRC survival prediction. Finally, each patient will be represented, and these representations will be used for survival prediction. RESULTS: The experimental results show that SAGL outperforms state-of-the-art methods on a real-world dataset, with the receiver operating characteristic curve for 3- and 5-year survival prediction achieving 0.849±0.002 and 0.895±0.005, respectively. In addition, the comparison results with different graph neural network-based variants demonstrate the advantages of our DG-guided self-attention graph learning framework. CONCLUSIONS: Our study reveals that the potential of the DG-guided self-attention in optimizing feature graph learning which can improve the performance of CRC survival prediction.


Assuntos
Neoplasias Colorretais , Aprendizado de Máquina , Humanos , Redes Neurais de Computação , Período Pós-Operatório , Curva ROC
17.
Aging (Albany NY) ; 16(8): 7141-7152, 2024 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-38643465

RESUMO

Disrupted mitochondrial dynamics and mitophagy contribute to functional deterioration of skeletal muscle (SM) during aging, but the regulatory mechanisms are poorly understood. Our previous study demonstrated that the expression of thyroid hormone receptor α (TRα) decreased significantly in aged mice, suggesting that the alteration of thyroidal elements, especially the decreased TRα, might attenuate local THs action thus to cause the degeneration of SM with aging, while the underlying mechanism remains to be further explored. In this study, decreased expression of myogenic regulators Myf5, MyoD1, mitophagy markers Pink1, LC3II/I, p62, as well as mitochondrial dynamic factors Mfn1 and Opa1, accompanied by increased reactive oxygen species (ROS), showed concomitant changes with reduced TRα expression in aged mice. Further TRα loss- and gain-of-function studies in C2C12 revealed that silencing of TRα not only down-regulated the expression of above-mentioned myogenic regulators, mitophagy markers and mitochondrial dynamic factors, but also led to a significant decrease in mitochondrial activity and maximum respiratory capacity, as well as more mitochondrial ROS and damaged mitochondria. Notedly, overexpression of TRα could up-regulate the expression of those myogenic regulators, mitophagy markers and mitochondrial dynamic factors, meanwhile also led to an increase in mitochondrial activity and number. These results confirmed that TRα could concertedly regulate mitochondrial dynamics, autophagy, and activity, and myogenic regulators rhythmically altered with TRα expression. Summarily, these results suggested that the decline of TRα might cause the degeneration of SM with aging by regulating mitochondrial dynamics, mitophagy and myogenesis.


Assuntos
Envelhecimento , Mitofagia , Músculo Esquelético , Espécies Reativas de Oxigênio , Sarcopenia , Receptores alfa dos Hormônios Tireóideos , Animais , Sarcopenia/metabolismo , Sarcopenia/patologia , Camundongos , Receptores alfa dos Hormônios Tireóideos/genética , Receptores alfa dos Hormônios Tireóideos/metabolismo , Envelhecimento/metabolismo , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Espécies Reativas de Oxigênio/metabolismo , Mitocôndrias Musculares/metabolismo , Masculino , Dinâmica Mitocondrial , Mitocôndrias/metabolismo , Linhagem Celular
19.
Cell Death Discov ; 10(1): 186, 2024 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-38649363

RESUMO

Neuroblastoma (NB) is a common childhood tumor with a high incidence worldwide. The regulatory role of RNA N6-methyladenosine (m6A) in gene expression has attracted significant attention, and the impact of methyltransferase-like 14 (METTL14) on tumor progression has been extensively studied in various types of cancer. However, the specific influence of METTL14 on NB remains unexplored. Using data from the Target database, our study revealed significant upregulation of METTL14 expression in high-risk NB patients, with strong correlation with poor prognosis. Furthermore, we identified ETS1 and YY1 as upstream regulators that control the expression of METTL14. In vitro experiments involving the knockdown of METTL14 in NB cells demonstrated significant inhibition of cell proliferation, migration, and invasion. In addition, suppressing METTL14 inhibited NB tumorigenesis in nude mouse models. Through MeRIP-seq and RNA-seq analyses, we further discovered that YWHAH is a downstream target gene of METTL14. Mechanistically, we observed that methylated YWHAH transcripts, particularly those in the 5' UTR, were specifically recognized by the m6A "reader" protein YTHDF1, leading to the degradation of YWHAH mRNA. Moreover, the downregulation of YWHAH expression activated the PI3K/AKT signaling pathway, promoting NB cell activity. Overall, our study provides valuable insights into the oncogenic effects of METTL14 in NB cells, highlighting its role in inhibiting YWHAH expression through an m6A-YTHDF1-dependent mechanism. These findings also suggest the potential utility of a biomarker panel for prognostic prediction in NB patients.

20.
Artigo em Inglês | MEDLINE | ID: mdl-38658737

RESUMO

Trace amine-associated receptor 1 (TAAR1) is an intracellular expressed G-protein-coupled receptor that is widely expressed in major dopaminergic areas and plays a crucial role in modulation of central dopaminergic neurotransmission and function. Pharmacological studies have clarified the roles of dopamine D1 receptor (D1R) in the medial prefrontal cortex (mPFC) in cognitive function and social behaviors, and chronic stress can inhibit D1R expression due to its susceptibility. Recently, we identified TAAR1 in the mPFC as a potential target for treating chronic stress-induced cognitive and social dysfunction, but whether D1R is involved in mediating the effects of TAAR1 agonist remains unclear. Combined genomics and transcriptomic studies revealed downregulation of D1R in the mPFC of TAAR1-/- mice. Molecular dynamics simulation showed that hydrogen bond, salt bridge, and Pi-Pi stacking interactions were formed between TAAR1 and D1R indicating a stable TAAR1-D1R complex structure. Using pharmacological interventions, we found that D1R antagonist disrupted therapeutic effect of TAAR1 partial agonist RO5263397 on stress-related cognitive and social dysfunction. Knockout TAAR1 in D1-type dopamine receptor-expressing neurons reproduced adverse effects of chronic stress, and TAAR1 conditional knockout in the mPFC led to similar deficits, along with downregulation of D1R expression, all of these effects were ameliorated by viral overexpression of D1R in the mPFC, suggesting the functional interaction between TAAR1 and D1R. Collectively, our data elucidate the possible molecular mechanism that D1R in the mPFC mediates the effects of TAAR1 activation on chronic stress-induced cognitive and social deficits.

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