Multi-scaled temporal modeling of cardiovascular disease progression: An illustration of proximal arteries in pulmonary hypertension.

The progression of cardiovascular disease is intricately influenced by a complex interplay between physiological pathways, biochemical processes, and physical mechanisms. This study aimed to develop an in-silico physics-based approach to comprehensively model the multifaceted vascular pathophysiological adaptations. This approach focused on capturing the progression of proximal pulmonary arterial hypertension, which is significantly associated with the irreversible degradation of arterial walls and compensatory stress-induced growth and remodeling. This study incorporated critical characteristics related to the distinct time scales for the deformation, thus reflecting the impact of mean pressure on artery growth and tissue damage. The in-silico simulation of the progression of pulmonary hypertension was realized based on computational code combined with the finite element method (FEM) for the simulation of disease progression. The parametric studies further explored the consequences of these irreversible processes. This computational modeling approach may advance our understanding of pulmonary hypertension and its progression.

Local application of zoledronate inhibits early bone resorption and promotes bone formation.

Nonunion resulting from early bone resorption is common after bone transplantation surgery. In these patients, instability or osteoporosis causes hyperactive catabolism relative to anabolism, leading to graft resorption instead of fusion. Systemic zoledronate administration inhibits osteoclastogenesis and is widely used to prevent osteoporosis; however, evidence on local zoledronate application is controversial due to osteoblast cytotoxicity, uncontrolled dosing regimens, and local release methods. We investigated the effects of zolendronate on osteoclastogenesis and osteogenesis and explored the corresponding signaling pathways. In vitro cytotoxicity and differentiation of MC3T3E1 cells, rat bone marrow stromal cells (BMSCs) and preosteoclasts (RAW264.7 cells) were evaluated with different zolendronate concentrations. In vivo bone regeneration ability was tested by transplanting different concentrations of zolendronate with ß-tricalcium phosphate (TCP) bone substitute into rat femoral critical-sized bone defects. In vitro, zolendronate concentrations below 2.5 × 10-7 M did not compromise viability in the three cell lines and did not promote osteogenic differentiation in MC3T3E1 cells and BMSCs. In RAW264.7 cells, zoledronate inhibited extracellular regulated protein kinases and c-Jun n-terminal kinase signaling, downregulating c-Fos and NFATc1 expression, with reduced expression of fusion-related dendritic cell­specific transmembrane protein and osteoclast-specific Ctsk and tartrate-resistant acid phosphatase (. In vivo, histological staining revealed increased osteoid formation and neovascularization and reduced fibrotic tissue with 500 µM and 2000 µM zolendronate. More osteoclasts were found in the normal saline group after 6 weeks, and sequential osteoclast formation occurred after zoledronate treatment, indicating inhibition of bone resorption during early callus formation without inhibition of late-stage bone remodeling. In vivo, soaking ß-TCP artificial bone with 500 µM or 2000 µM zoledronate is a promising approach for bone regeneration, with potential applications in bone transplantation.

Hypomethylation-associated LINC00987 downregulation induced lung adenocarcinoma progression by inhibiting the phosphorylation-mediated degradation of SND1.

DNA methylation, an epigenetic regulatory mechanism dictating gene transcription, plays a critical role in the occurrence and development of cancer. However, the molecular underpinnings of LINC00987 methylation in the regulation of lung adenocarcinoma (LUAD) remain elusive. This study investigated LINC00987 expression in LUAD patients through analysis of The Cancer Genome Atlas data sets. Quantitative real-time polymerase chain reaction (RT-qPCR) and fluorescence in situ hybridization assays were used to assess LINC00987 expression in LUAD. The bisulfite genomic sequence PCR (BSP) assay was used to determine the methylation levels of the LINC00987 promoter. The interaction between LINC00987 and SND1 was elucidated via immunoprecipitation and RNA pull-down assays. The functional significance of LINC00987 and SND1 in Calu-3 and NCI-H1688 cells was evaluated in vitro through CCK-8, EdU, Transwell, flow cytometry, and vasculogenic mimicry (VM) tube formation assays. LINC00987 expression decreased in LUAD concomitant with hypermethylation of the promoter region, while hypomethylation of the LINC00987 promoter in LUAD tissues correlated with tumor progression. Treatment with 5-Aza-CdR augmented LINC00987 expression and inhibited tumor growth. Mechanistically, LINC00987 overexpression impeded LUAD progression and VM through direct binding with SND1, thereby facilitating its phosphorylation and subsequent degradation. Additionally, overexpression of SND1 counteracted the adverse effects of LINC00987 downregulation on cell proliferation, apoptosis, cell migration, invasion, and VM in LUAD in vitro. In conclusion, this pioneering study focuses on the expression and function of LINC00987 and reveals that hypermethylation of the LINC00987 gene may contribute to LUAD progression. LINC00987 has emerged as a potential tumor suppressor gene in tumorigenesis through its binding with SND1 to facilitate its phosphorylation and subsequent degradation.

Laccase-induced decontamination and humification mechanisms of estrogen in water-crop matrices.

Enzymatic humification plays a crucial biogeochemical role in eliminating steroidal estrogens and expanding organic carbon stocks. Estrogenic contaminants in agroecosystems can be taken up and acropetally translocated by crops, but the roles of laccase-triggered rhizospheric humification (L-TRH) in pollutant dissipation and plant uptake remain poorly understood. In this study, the laccase-induced decontamination and humification mechanisms of 17ß-estradiol (E2) in water-crop media were investigated by performing greenhouse pot experiments with maize seedlings (Zea mays L.). The results demonstrated that L-TRH effectively dissipated E2 in the rhizosphere solution and achieved the kinetic constants of E2 dissipation at 10 and 50 µM by 8.05 and 2.75 times as much as the treatments without laccase addition, respectively. The copolymerization of E2 and root exudates (i.e. phenols and amino acids) consolidated by L-TRH produced a larger amount of humified precipitates with the richly functional carbon architectures. The growth parameters and photosynthetic pigment levels of maize seedlings were greatly impeded after a 120-h exposure to 50 µM E2, but L-TRH motivated the detoxication process and thus mitigated the phytotoxicity and bioavailability of E2. The tested E2 contents in the maize tissues initially increased sharply with the cultivation time but decreased steadily. Compared with the treatment without laccase addition, the uptake and accumulation of E2 in the maize tissues were obviously diminished by L-TRH. E2 oligomers such as dimer, trimer, and tetramer recognized in the rhizosphere solution were also detected in the root tissues but not in the shoots, demonstrating that the acropetal translocation of E2 oligomers was interrupted. These results highlight a promising strategy for decontaminating estrogenic pollutants, boosting rhizospheric humification, and realizing low-carbon emissions, which would be beneficial for agroenvironmental bioremediation and sustainability.

Metformin alters dendrite development and synaptic plasticity in rat cortical neurons.

Synaptic plasticity is crucial as it dynamically molds the strength and connectivity of neural circuits, influencing learning, memory, and the development of neurological disorders. Metformin, a widely prescribed anti-diabetic medication, has been shown to readily cross the blood-brain barrier (BBB) and the placenta. However, its prolonged impact on neuronal morphology and functions remains underexplored. In this study, we investigated the influence of metformin on dendrite development and synaptic plasticity in embryonic brains and primary rat cortical neurons. Our findings reveal a negative modulation of dendrite development by metformin, as evidenced by altered dendritic arborization, impaired dendritic spine morphology and disruptions in synaptic plasticity, suggesting a potential link between metformin exposure and aberrations in neuronal connectivity. In addition, we extend our insights to the impact of maternal metformin exposure on embryonic brains, revealing a significant inhibition of dendrite development in E18.5 rat brains. In conclusion, this study adds to the expanding knowledge base on the non-metabolic effects of metformin, emphasizing the significance of assessing its potential influence on both neuronal structure and function. There is an urgent need for further investigations into the enduring impact of prolonged metformin administration on the structural and functional aspects of neurons.

Statin-mediated reduction in mitochondrial cholesterol primes an anti-inflammatory response in macrophages by upregulating Jmjd3.

Stains are known to be anti-inflammatory, but the mechanism remains poorly understood. Here we show that macrophages, either treated with statin in vitro or from statin-treated mice, have reduced cholesterol levels and higher expression of Jmjd3, a H3K27me3 demethylase. We provide evidence that lowering cholesterol levels in macrophages suppresses the ATP synthase in the inner mitochondrial membrane (IMM) and changes the proton gradient in the mitochondria. This activates NFkB and Jmjd3 expression to remove the repressive marker H3K27me3. Accordingly, the epigenome is altered by the cholesterol reduction. When subsequently challenged by the inflammatory stimulus LPS (M1), both macrophages treated with statins in vitro or isolated from statin-treated mice in vivo, express lower levels pro-inflammatory cytokines than controls, while augmenting anti-inflammatory Il10 expression. On the other hand, when macrophages are alternatively activated by IL4 (M2), statins promote the expression of Arg1, Ym1, and Mrc1. The enhanced expression is correlated with the statin-induced removal of H3K27me3 from these genes prior to activation. In addition, Jmjd3 and its demethylase activity are necessary for cholesterol to modulate both M1 and M2 activation. We conclude that upregulation of Jmjd3 is a key event for the anti-inflammatory function of statins on macrophages.

[Effects of organic fertilizer from traditional Chinese medicine residues on growth and soil microbial community of Salvia miltiorrhiza by metagenomic technique].

Soil microbiome is a key evaluation index of soil health. Previous studies have shown that organic fertilizer from traditional Chinese medicine(TCM)residues can improve the yield and quality of cultivated traditional Chinese medicinal materials. However, there are few reports on the effects of organic fertilizer from TCM residues on soil microbiome. Therefore, on the basis of evaluating the effects of organic fertilizer from TCM residues on the yield and quality of cultivated Salvia miltiorrhiza, the metagenomic sequencing technique was used to study the effects of organic fertilizer from TCM residues on rhizosphere microbiome community and function of cultivated S. miltiorrhiza. The results showed that:(1) the application of organic fertilizer from TCM residues promoted the growth of S. miltiorrhiza and the accumulation of active components, and the above-ground and underground dry weight and fresh weight of S. miltiorrhiza increased by 371.4%, 288.3%, 313.4%, and 151.9%. The increases of rosmarinic acid and salvianolic acid B were 887.0% and 183.0%.(2)The application of organic fertilizer from TCM residues significantly changed the rhizosphere bacterial and fungal community structures, and the microbial community composition was significantly different.(3)The relative abundance of soil-beneficial bacteria, such as Nitrosospira multiformis, Bacillus subtilis, Lysobacter enzymogenes, and Trichoderma was significantly increased by the application of organic fertilizer from TCM residues.(4)KEGG function prediction analysis showed that metabolism-related microorganisms were more easily enriched in the soil environment after organic fertilizer application. The abundance of functional genes related to nitrification and denitrification could also be increased after the application of organic fertilizer from TCM residues. The results of this study provide guidance for the future application of organic fertilizer from TCM residues in the cultivation of traditio-nal Chinese medicinal materials and enrich the content of green cultivation technology of traditional Chinese medicinal materials.

ARID1A regulates DNA repair through chromatin organization and its deficiency triggers DNA damage-mediated anti-tumor immune response.

AT-rich interaction domain protein 1A (ARID1A), a SWI/SNF chromatin remodeling complex subunit, is frequently mutated across various cancer entities. Loss of ARID1A leads to DNA repair defects. Here, we show that ARID1A plays epigenetic roles to promote both DNA double-strand breaks (DSBs) repair pathways, non-homologous end-joining (NHEJ) and homologous recombination (HR). ARID1A is accumulated at DSBs after DNA damage and regulates chromatin loops formation by recruiting RAD21 and CTCF to DSBs. Simultaneously, ARID1A facilitates transcription silencing at DSBs in transcriptionally active chromatin by recruiting HDAC1 and RSF1 to control the distribution of activating histone marks, chromatin accessibility, and eviction of RNAPII. ARID1A depletion resulted in enhanced accumulation of micronuclei, activation of cGAS-STING pathway, and an increased expression of immunomodulatory cytokines upon ionizing radiation. Furthermore, low ARID1A expression in cancer patients receiving radiotherapy was associated with higher infiltration of several immune cells. The high mutation rate of ARID1A in various cancer types highlights its clinical relevance as a promising biomarker that correlates with the level of immune regulatory cytokines and estimates the levels of tumor-infiltrating immune cells, which can predict the response to the combination of radio- and immunotherapy.

Sensitive electrochemical flow injection analysis of H2O2 released from cells with a pass-through mode.

Conventional plate electrodes were commonly used in electrochemical flow injection analysis and only part of molecules diffused to the plane of electrodes could be detected, which would limit the performance of electrochemical detection. In this study, a low-cost native stainless steel wire mesh (SSWM) electrode was integrated into a 3D-printed device for electrochemical flow injection analysis with a pass-through mode, which is different compared with previous flow-through mode. This strategy was applied for sensitive analysis of hydrogen peroxide (H2O2) released from cells. Under the optimal conditions (the applied potentials, the flow rate and the sample volume), the device exhibits high sensitivity toward H2O2. Linear relationships could be achieved between electrochemical responses and the concentration of H2O2 ranging from 1 nM to 1 mM. The excellent analytical performance of the SSWM-based device could be attributed to the pass-through mode based on the mesh microstructure and intrinsic catalytic properties for H2O2 by stainless steel. This approach could be further successfully extended for screening of H2O2 released from HeLa cells with electrochemical responses linear to the number of cells in a range of 3 - 1.35 × 104 cells with an injection volume of 30 µL. This study revealed the potential of mesh electrodes in electrochemical flow injection analysis for cellular function and pathology and its possible extension in cell counting and on-line analysis.

Effect of the ROCK inhibitor fasudil on the brain proteomic profile in the tau transgenic mouse model of Alzheimer's disease.

Introduction: The goal of this study is to explore the pharmacological potential of the amyloid-reducing vasodilator fasudil, a selective Ras homolog (Rho)-associated kinases (ROCK) inhibitor, in the P301S tau transgenic mouse model (Line PS19) of neurodegenerative tauopathy and Alzheimer's disease (AD). Methods: We used LC-MS/MS, ELISA and bioinformatic approaches to investigate the effect of treatment with fasudil on the brain proteomic profile in PS19 tau transgenic mice. We also explored the efficacy of fasudil in reducing tau phosphorylation, and the potential beneficial and/or toxic effects of its administration in mice. Results: Proteomic profiling of mice brains exposed to fasudil revealed the activation of the mitochondrial tricarboxylic acid (TCA) cycle and blood-brain barrier (BBB) gap junction metabolic pathways. We also observed a significant negative correlation between the brain levels of phosphorylated tau (pTau) at residue 396 and both fasudil and its metabolite hydroxyfasudil. Conclusions: Our results provide evidence on the activation of proteins and pathways related to mitochondria and BBB functions by fasudil treatment and support its further development and therapeutic potential for AD.

The palmitoylation of gasdermin D directs its membrane translocation and pore formation during pyroptosis.

Plasma membrane perforation elicited by caspase cleavage of the gasdermin D (GSDMD) N-terminal domain (GSDMD-NT) triggers pyroptosis. The mechanisms underlying GSDMD membrane translocation and pore formation are not fully understood. Here, using a proteomic approach, we identified fatty acid synthase (FASN) as a GSDMD-binding partner. S-palmitoylation of GSDMD at Cys191/Cys192 (human/mouse), catalyzed by palmitoyl acyltransferases ZDHHC5 and ZDHHC9 and facilitated by reactive oxygen species (ROS), directly mediated membrane translocation of GSDMD-NT but not full-length GSDMD (GSDMD-FL). Palmitoylation of GSDMD-FL could be induced before inflammasome activation by stimuli such as lipopolysaccharide (LPS), consequently serving as an essential molecular event in macrophage priming. Inhibition of GSDMD palmitoylation suppressed macrophage pyroptosis and IL-1ß release, mitigated organ damage, and enhanced the survival of septic mice. Thus, GSDMD-NT palmitoylation is a key regulatory mechanism controlling GSDMD membrane localization and activation, which may offer an additional target for modulating immune activity in infectious and inflammatory diseases.

The Application of Emodin Treatment on Nasopharyngeal Carcinoma Therapy.

Nasopharyngeal carcinoma (NPC) is a malignancy prevailing in Taiwan, Hong Kong, Southern China, Southeast Asia, and North Africa. Although early-stage NPC responds well to the primary treatment of radio-chemotherapy, the mortality rate of advanced NPC remains high. Therefore, developing new therapies for nasopharyngeal carcinoma is an urgent task. Emodin is an anthraquinone derivative mainly found in Rheum palmatum. Emodin has been found to possess many anti-cancer functions against various types of cancers, but they are less discussed in the treatment of NPC. This review organized the different studies about the anti-NPC activity of emodin and discussed the potential and challenges of emodin treatment in NPC therapy.

The complement pathway as a therapeutic target for neovascular age-related macular degeneration-mediated subretinal fibrosis.

Neovascular age-related macular degeneration (nAMD) is the leading cause of blindness in the elderly in developed countries. Intravitreal injection of VEGF inhibitors is the mainstream therapy for nAMD, although nearly 50% of the patients do not respond or respond poorly to the therapy. One of the main reasons for the poor outcome of the therapy is the development of subretinal macular fibrosis, a process of excessive deposition of extracellular matrix proteins around the diseased blood vessels. Currently, there is no medication to prevent or treat the condition. Here, we discussed recent advances in the pathogenesis of nAMD-mediated macular fibrosis, with a focus on the role of the complement system. We further proposed approaches to target the complement system for the management of macular fibrosis and highlighted the area of further research for future clinical applications of complement-based therapy.

Lipopeptide C17 Fengycin B Exhibits a Novel Antifungal Mechanism by Triggering Metacaspase-Dependent Apoptosis in Fusarium oxysporum.

Fusarium wilt is a worldwide soil-borne fungal disease caused by Fusarium oxysporum that causes serious damage to agricultural products. Therefore, preventing and treating fusarium wilt is of great significance. In this study, we purified ten single lipopeptide fengycin components from Bacillus subtilis FAJT-4 and found that C17 fengycin B inhibited the growth of F. oxysporum FJAT-31362. We observed early apoptosis hallmarks, including reactive oxygen species accumulation, mitochondrial dysfunction, and phosphatidylserine externalization in C17 fengycin B-treated F. oxysporum cells. Further data showed that C17 fengycin B induces cell apoptosis in a metacaspase-dependent manner. Importantly, we found that the expression of autophagy-related genes in the TOR signaling pathway was significantly upregulated; simultaneously, the accumulation of acidic autophagy vacuoles in F. oxysporum cell indicated that the autophagy pathway was activated during apoptosis induced by C17 fengycin B. Therefore, this study provides new insights into the antifungal mechanism of fengycin.

Using Sparse Parts in Fused Information to Enhance Performance in Latent Low-Rank Representation-Based Fusion of Visible and Infrared Images.

Latent Low-Rank Representation (LatLRR) has emerged as a prominent approach for fusing visible and infrared images. In this approach, images are decomposed into three fundamental components: the base part, salient part, and sparse part. The aim is to blend the base and salient features to reconstruct images accurately. However, existing methods often focus more on combining the base and salient parts, neglecting the importance of the sparse component, whereas we advocate for the comprehensive inclusion of all three parts generated from LatLRR image decomposition into the image fusion process, a novel proposition introduced in this study. Moreover, the effective integration of Convolutional Neural Network (CNN) technology with LatLRR remains challenging, particularly after the inclusion of sparse parts. This study utilizes fusion strategies involving weighted average, summation, VGG19, and ResNet50 in various combinations to analyze the fusion performance following the introduction of sparse parts. The research findings show a significant enhancement in fusion performance achieved through the inclusion of sparse parts in the fusion process. The suggested fusion strategy involves employing deep learning techniques for fusing both base parts and sparse parts while utilizing a summation strategy for the fusion of salient parts. The findings improve the performance of LatLRR-based methods and offer valuable insights for enhancement, leading to advancements in the field of image fusion.

A novel DDIT3 activator dehydroevodiamine effectively inhibits tumor growth and tumor cell stemness in pancreatic cancer.

BACKGROUND: The existence of pancreatic cancer stem cells (PCSCs) results in limited survival benefits from current treatment options. There is a scarcity of effective agents for treating pancreatic cancer patients. Dehydroevodiamine (DeHE), a quinazoline alkaloid isolated from the traditional Chinese herb Evodiae fructus, exhibited potent inhibition of pancreatic ductal adenocarcinoma (PDAC) cell proliferation and tumor growth both in vitro and in vivo. METHODS: The cytotoxic effect of DeHE on PDAC cells was assessed using CCK-8 and colony formation assays. The antitumor efficacy of DeHE were appraised in human PANC-1 xenograft mouse model. Sphere formation assay and flow cytometry were employed to quantify the tumor stemness. RNA-Seq analysis, drug affinity responsive target stability assay (DARTS), and RNA interference transfection were conducted to elucidate potential signaling pathways. Western blotting and immunohistochemistry were utilized to assess protein expression levels. RESULTS: DeHE effectively inhibited PDAC cell proliferation and tumor growth in vitro and in vivo, and exhibited a better safety profile compared to the clinical drug gemcitabine (GEM). DeHE inhibited PCSCs, as evidenced by its suppression of self-renewal capabilities of PCSCs, reduced the proportion of ALDH+ cells and downregulated stemness-associated proteins (Nanog, Sox-2, and Oct-4) both in vitro and in vivo. Furthermore, there is potential involvement of DDIT3 and its downstream DDIT3/TRIB3/AKT/mTOR pathway in the suppression of stemness characteristics within DeHE-treated PDAC cells. Additionally, results from the DARTS assay indicated that DeHE interacts with DDIT3, safeguarding it against degradation mediated by pronase. Notably, the inhibitory capabilities of DeHE on PDAC cell proliferation and tumor stemness were partially restored by siDDIT3 or the AKT activator SC-79. CONCLUSION: In summary, our study has identified DeHE, a novel antitumor natural product, as an activator of DDIT3 with the ability to suppress the AKT/mTOR pathway. This pathway is intricately linked to tumor cell proliferation and stemness characteristics in PDAC. These findings suggest that DeHE holds potential as a promising candidate for the development of innovative anticancer therapeutics.

Salidroside protects pulmonary artery endothelial cells against hypoxia-induced apoptosis via the AhR/NF-κB and Nrf2/HO-1 pathways.

BACKGROUND: The apoptosis of pulmonary artery endothelial cells (PAECs) is an important factor contributing to the development of pulmonary hypertension (PH), a serious cardio-pulmonary vascular disorder. Salidroside (SAL) is a bioactive compound derived from an herb Rhodiola, but the potential protective effects of SAL on PAECs and the underlying mechanisms remain elusive. PURPOSE: The objective of this study was to determine the role of SAL in the hypoxia-induced apoptosis of PAECs and to dissect the underlying mechanisms. STUDY DESIGN: Male Sprague-Dawley (SD) rats were subjected to hypoxia (10% O2) for 4 weeks to establish a model of PH. Rats were intraperitoneally injected daily with SAL (2, 8, and 32 mg/kg/d) or vehicle. To define the molecular mechanisms of SAL in PAECs, an in vitro model of hypoxic cell injury was also generated by exposed PAECs to 1% O2 for 48 h. METHODS: Various techniques including hematoxylin and eosin (HE) staining, immunofluorescence, flow cytometry, CCK-8, Western blot, qPCR, molecular docking, and surface plasmon resonance (SPR) were used to determine the role of SAL in rats and in PAECs in vitro. RESULTS: Hypoxia stimulation increases AhR nuclear translocation and activates the NF-κB signaling pathway, as evidenced by upregulated expression of CYP1A1, CYP1B1, IL-1ß, and IL-6, resulting in oxidative stress and inflammatory response and ultimately apoptosis of PAECs. SAL inhibited the activation of AhR and NF-κB, while promoted the nuclear translocation of Nrf2 and increased the expression of its downstream antioxidant proteins HO-1 and NQO1 in PAECs, ameliorating the hypoxia-induced oxidative stress in PAECs. Furthermore, SAL lowered right ventricular systolic pressure, and decreased pulmonary vascular remodeling and right ventricular hypertrophy in hypoxia-exposed rats. CONCLUSIONS: SAL may attenuate the apoptosis of PAECs by suppressing NF-κB and activating Nrf2/HO-1 pathways, thereby delaying the progressive pathology of PH.

Epstein-Barr Virus BRLF1 Induces PD-L1 Expression in Nasopharyngeal Carcinoma Cells.

Nasopharyngeal carcinoma (NPC) is a specific human malignancy with unique geographic distribution and genetic backgrounds. Although early treatment with radio-chemotherapy has been proven effective for NPC therapy, its therapeutic efficacy substantially diminishes in the late stages of this malignancy. In the tumor microenvironment of NPC, PD-L1 has been demonstrated as a critical factor in impairing T cell activation. As an etiological role for NPC development, it is found that Epstein-Barr virus (EBV) latent proteins upregulated PD-L1 expression. However, whether EBV lytic protein affects PD-L1 expression remains unclear. In this study, through monitoring the mRNA expression pattern of lytic genes and PD-L1 in EBV-positive NPC cell line NA, EBV immediately-early gene BRLF1(Rta) was found to have the potential for PD-L1 activation. Furthermore, we identified that Rta expression enhanced PD-L1 expression in mRNA and protein levels through quantitative real-time polymerase chain reaction and western blotting analysis. The luciferase reporter assay revealed that Rta expression enhanced PD-L1 promoter activity. We also demonstrated that Rta-induced PD-L1 expressions could impair interleukin 2 secretion of T cells, and this mechanism may be through ERK activation. These results displayed the importance of EBV Rta in PD-L1 expression in NPC and may give an alternative target for NPC therapy.

MiRNA-296-5p promotes the sensitivity of nasopharyngeal carcinoma cells to cisplatin via targeted inhibition of STAT3/KLF4 signaling axis.

Improving drug sensitivity is an important strategy in chemotherapy of cancer and accumulating evidence indicates that miRNAs are involved in the regulation of drug sensitivity, but the specific mechanism is still unclear. Our previous study has found that miR-296-5p was significantly downregulated in nasopharyngeal carcinoma (NPC). Here, we aim to explore whether miR-296-5p is involved in regulating cisplatin sensitivity in NPC by regulating STAT3/KLF4 signaling axis. The cell proliferation and clonogenic capacity of NPC cells were evaluated by CCK8 Assay and plate colony assay, respectively. The Annexin V-FITC staining kit was used to determine and quantify the apoptotic cells using flow cytometry. The drug efflux ability of NPC cells were determined by Rhodamine 123 efflux experiment. The expression of miR-296-5p, apoptosis-related genes and protein in NPC cell lines were detected by qPCR and Western blot, respectively. Animal study was used to evaluate the sensitivity of NPC cells to DDP treatment in vivo. Our results showed that elevated miR-296-5p expression obviously promoted the sensitivity of NPC cells to DDP by inhibiting cell proliferation and clonogenic capacity, and inducing apoptosis. In addition, we found that miR-296-5p inhibited the expression of STAT3 and KLF4 in NPC cells, while overexpression of exogenous STAT3 reversed miR-296-5p-mediated enhancement in cell death of DDP-treated NPC cells. In vivo studies further confirmed that miR-296-5p promotes the sensitivity of NPC cells to DDP treatment. miRNA-296-5p enhances the drug sensitivity of nasopharyngeal carcinoma cells to cisplatin via STAT3/KLF4 signaling pathway.