Repressive Effect Research Articles

γ-Glutamylcyclotransferase is transcriptionally regulated by c-Jun and controls proliferation of glioblastoma stem cells through Notch1 levels.

Glioblastoma stem cells (GSCs) have been reported to cause poor prognosis of glioblastoma by contributing to therapy resistance. γ-Glutamylcyclotransferase (GGCT) is highly expressed in various cancer types, including glioblastoma, and its inhibition suppresses cancer cell growth. However, the mechanism of GGCT overexpression and its function in GSCs are unknown. In this study, we show that GGCT is highly expressed in GSCs established from a mouse glioblastoma model and its knockdown suppresses their proliferation. Effects of NRas and its downstream transcription factor c-Jun on GGCT expression were analyzed; NRas knockdown reduced c-Jun and GGCT expression. Knockdown of c-Jun also reduced expression levels of GGCT and inhibited cell proliferation. Consistent with this, pharmacological inhibition of c-Jun with SP600125 reduced GGCT and inhibited GSC proliferation. Furthermore, the GGCT promoter-reporter assay with mutagenesis demonstrated that c-Jun regulates the activity of the GGCT promoter via AP-1 consensus sequence. Gene expression analysis revealed that GGCT knockdown showed a repressive effect on the Delta-Notch pathway and decreased Notch1 expression. Notch1 knockdown alone inhibited the GSC proliferation, confirming that Notch1 is functional in this model. Forced expression of the Notch1 intracellular domain restored the growth inhibitory effect of GGCT knockdown. Moreover, GGCT knockdown inhibited GSC tumorigenic potential in vivo. These results indicate that GGCT, whose expression is promoted by c-Jun, plays an important role in the proliferation and tumorigenic potential of GSCs, and that the phenotype caused by its knockdown is contributed by a decrease in Notch1. Thus, GGCT may represent a novel therapeutic target for attacking GSCs.

OPEN LETTERS IN CLOSED SOCIETIES: THE VALUES OF HISTORIANS UNDER ATTACK

ABSTRACTThis article explores a question of practical ethics: To which values do historians appeal when they come under sustained attack from political power? An important instrument of historians living in closed societies to express their values is the open letter, defined as an unauthorized public statement cast in epistolary form and addressed to either political leaders or fellow historians, but always with the general public as a silent reader in the background. Limited to the post‐1945 period, a search for such open letters yielded 106 examples from 39 countries in closed and open societies. Four types of open letters were identified: those describing repression effects, those rebutting official historical views, those defending basic principles, and those presenting transitional historiography. Nine telling cases from six closed societies were then reviewed in detail and analyzed from a variety of angles (authorship, rhetoric, audience, impact, criticism, regime stage, and regime type). When these cases were examined in light of the initial question, it was found that most letters contained a great diversity of values but focused on how the human rights of historians were threatened. Invariably, their theme was historical writing in its full breadth, including its documentary infrastructure and its ramifications in education and the public sphere. Respect for historical truth was invoked more than any other value. It was a minimalist truth conception, however, understood as the absence of historical lies and falsification. The reason for this emphasis on an integrity‐oriented conception of historical truth may lie in an old and deep‐seated professional fear: the fear that the dictator's corrupted and divisive version of history survives and triumphs as the final verdict.

Bie Jia Jian pill ameliorates BDL-induced cholestatic hepatic fibrosis in rats by regulating intestinal microbial composition and TMAO-mediated PI3K/AKT signaling pathway

Ethnopharmacological relevanceAs a compound of traditional Chinese medicine (TCM), Bie Jia Jian pill (BJJP) is extensively used to treat the clinical chronic liver disease. Nevertheless, the specific mechanism through which BJJP affects hepatic fibrosis (HF) remains unknown. Aim of the studyTo explore the role and potential mechanism of BJJP involved in treating HF. Materials and methodsHF model of Sprague-Dawley (SD) rats was induced by a bile duct ligation (BDL). The function of BJJP involved in the intestinal microbiota (IM) and its metabolites in BDL-induced HF rats were explored through the 16S rRNA sequencing and untargeted metabolomics technologies. Network pharmacology was used to forecast mechanism underlying BJJP's anti-HF effects, which were validated in BDL-induced rats and trimethylamine N-oxide (TMAO)-induced LX-2 and HSC-T6 cells. ResultsBJJP effectively ameliorated pathological liver damage, inflammation, and fibrosis of the BDL-induced HF rats. BJJP regulated IM diversity and composition and interfered with trimethylamine (TMA)-flavin monooxygenase 3 (FMO3)-TMAO process. In vitro, BJJP significantly inhibited the TMAO-induced activation of hepatic stellate cells (HSCs) (rat HSC cell line, HSC-T6; human HSC cell line, LX-2). Network pharmacology results demonstrated that PI3K/AKT signal pathway is crucially involved in BJJP treatment of HF. Further research revealed that BJJP inhibited the PI3K/AKT signal pathway in BDL-induced HF rats. Moreover, TMAO activated the PI3K/AKT pathway, whereas BJJP suppressed TMAO-induced activation. Subsequent intervention with 740Y-P (the PI3K agonist) successfully neutralized the repression effect on PI3K/AKT signal pathway by BJJP. ConclusionThese results clearly show that BJJP attenuates HF by regulating the IM, as well as inhibiting PI3K/AKT pathway mediated by TMAO.

Hypomethylation-associated ELF3 helps nasopharyngeal carcinoma to escape immune surveillance via MUC16-mediated glycolytic metabolic reprogramming.

Immune escape and metabolic reprogramming are two essential hallmarks of cancer. Mucin-16 (MUC16) has been linked to glycolysis and immune response in different cancers. However, its involvement in nasopharyngeal carcinoma (NPC) has not been well described. We seek to dissect the functions and detailed mechanisms of MUC16 in NPC. Bioinformatics prediction was performed to identify NPC-related molecules. MUC16 was significantly enhanced in NPC tissues, which was correlated with the advanced tumor stage of patients. Lentiviral plasmids-mediated MUC16 deletion inhibited the malignant behavior of NPC cells, and glycolysis inhibition by MUC16 deletion blocked immune escape in NPC cells. E74-like factor 3 (ELF3) bound to the MUC16 promoter promotes the transcription of MUC16. MUC16 overexpression reversed the repressive effect of ELF3 silencing on glycolysis and immune escape in NPC and accelerated tumor growth in vivo. Overexpression of ELF3 in NPC was associated with reduced DNA methylation in its promoter. Our findings revealed the role of the ELF3/MUC16 axis in the immune escape and metabolic reprogramming of NPC, providing potential therapeutic targets for NPC.NEW & NOTEWORTHY We identified the functions of E74-like factor 3 (ELF3) in glycolysis and immune escape of nasopharyngeal carcinoma cells for the first time. As a transcription factor, ELF3 promoted mucin-16 (MUC16) expression by binding to its promoter, leading to the glycolysis-mediated immune escape of nasopharyngeal carcinoma (NPC) cells. Targeting the ELF3/MUC16 axis generates a superior antitumor immune response, which will help establish a novel approach to restore protective antitumor immunity for NPC immunotherapy.

Authoritarian cue effect of state repression

AbstractState repression in autocracies has long been assumed to elicit explicit or implicit disapproval from citizens. Recent studies suggest that authoritarian governments can garner support for repressive policies through active information manipulation or exploiting social cleavages. However, is it possible for citizens to support repression even without government manipulation? We propose the “authoritarian cue effect,” arguing that citizens’ attitudes toward state repression can be endogenously shaped by instances of state repression, which may be interpreted as cueing messages signaling the regime's disapproval of the punished behaviors. Using a novel belief correction survey experiment, we empirically demonstrate that state repression can induce the public to pick up on cues and automatically adopt the state's stance, perceiving repressed behavior as having more negative externalities and supporting state repression more. This cue effect suggests that authoritarian state repression can self‐legitimize and evade public opinion backlash in a less costly manner than previously presumed.

Notch signaling mediated repressive effects of resveratrol in inducing caspasedependent apoptosis in MCF-7 breast cancer cells.

Resveratrol, a potent anticancer bioactive compound, has been shown to trigger apoptosis in numerous cancer cells. Although Notch signaling promotes breastcancer apoptosis, it is unclear whether resveratrolinduces apoptosis in MCF-7cells via influencing the Notch pathway. This study aimed to evaluate the effect of resveratrolon modulating Notch signaling targetsand provide critical information for employing resveratrolin breastcancer therapy. Thus, in this study, we have deciphered the effect of resveratrol against three potent genes (Notch1, Jagged1, and DLL4) of the notch signaling pathway. For mechanistic studies, in silico, and in vitro analysis was executed to investigate the apoptotic-inducing potential of resveratrol against three selected oncogenes involved in the progression of breast cancer. Docking analysis revealed the inhibitory potential of resveratrol against all three selected targets of the Notch pathway (Notch1: -5.0; Jagged-1: -5.9; DLL4: -5.8). In vitro, findings further displayed a significant reduction in cell viability in resveratrol-treated MCF-7 cancer cells, which were concomitantly related to the downregulation of Notch-1, Jagged-1, and DLL4. Moreover, the antiproliferative efficacy of resveratrol was correlated with apoptosis and modulation in the expression of Bax, Bcl-2, cyclin D1, CDK4, p21, and caspase-3 activation. Taken together, these experimental findings suggested that apoptotic inducing potential of resveratrol was mediated through a novel mechanism involving suppression of the Notch signaling pathway.

Sex-dependent regulation of retinal pigment epithelium and retinal function by Pgc-1α.

Age-related macular degeneration (AMD) is a major cause of blindness that affects people over 60. While aging is the prominent factor in AMD, studies have reported a higher prevalence of AMD in women compared to age-matched men. Higher levels of the innate immune response's effector proteins complement factor B and factor I were also found in females compared to males in intermediate AMD. However, the mechanisms underlying these differences remain elusive. Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) is a key regulator of mitochondrial biogenesis and metabolic pathways. Previously, we showed that Pgc-1α repression and high-fat diet induce drastic AMD-like phenotypes in mice. Our recent data revealed that Pgc-1α repression alone can also induce retinal pigment epithelium (RPE) and retinal dysfunction in mice, and its inhibition in vitro results in lipid droplet accumulation in human RPE. Whether sex is a contributing factor in these phenotypes remains to be elucidated. Using electroretinography, we demonstrate that sex could influence RPE function during aging independent of Pgc-1α in wild-type (WT) mice. We further show that Pgc-1α repression exacerbates RPE and retinal dysfunction in females compared to aged-match male mice. Gene expression analyses revealed that Pgc-1α differentially regulates genes related to antioxidant enzymes and mitochondrial dynamics in males and females. RPE flat mounts immunolabeled with TOMM20 and DRP1 indicated a sex-dependent role for Pgc-1α in regulating mitochondrial fission. Analyses of mitochondrial network morphology suggested sex-dependent effects of Pgc-1α repression on mitochondrial dynamics. Together, our study demonstrates that inhibition of Pgc-1α induces a sex-dependent decline in RPE and retinal function in mice. These observations on the sex-dependent regulation of RPE and retinal function could offer novel insights into targeted therapeutic approaches for age-related RPE and retinal degeneration.

Dynamic m6A mRNA methylation reveals the involvement of AcALKBH10 in ripening-related quality regulation in kiwifruit.

Kiwifruit ripening is a complex and highly coordinated process that occurs in conjunction with the formation of fruit edible quality. The significance of epigenetic changes, particularly the impact of N6-methyladenosine (m6A) RNA modification on fruit ripening and quality formation, has been largely overlooked. We monitored m6A levels and gene expression changes in kiwifruit at four different stages using LC-MS/MS, MeRIP, RNA-seq, and validated the function of AcALKBH10 through heterologous transgenic expression in tomato. Notable m6A modifications occurred predominantly at the stop codons and the 3' UTRs and exhibited a gradual reduction in m6A levels during the fruit ripening process. Moreover, these m6A modifications in the aforementioned sites demonstrated a discernible inverse relationship with the levels of mRNA abundance throughout the ripening process, suggesting a repression effect of m6A modification in the modulation of kiwifruit ripening. We further demonstrated that AcALKBH10 rather than AcECT9 predominantly regulates m6A levels in ripening-related genes, thereby exerting the regulatory control over the ripening process and the accumulation of soluble sugars and organic acids, ultimately influencing fruit ripening and quality formation. In conclusion, our findings illuminate the epi-regulatory mechanism involving m6A in kiwifruit ripening, offering a fresh perspective for cultivating high-quality kiwifruit with enhanced nutritional attributes.

MTFR2 accelerates hepatocellular carcinoma mediated by metabolic reprogramming via the Akt signaling pathway

Metabolic reprogramming has recently been identified as a hallmark of malignancies. The shift from oxidative phosphorylation to glycolysis in hepatocellular carcinoma (HCC) meets the demands of rapid cell growth and provides a microenvironment for tumor progression. This study sought to uncover the function and mechanism of MTFR2 in the metabolic reprogramming of HCC. Elevated MTFR2 expression was associated with poor patient prognosis. Downregulation of MTFR2 blocked malignant behaviors, epithelial-to-mesenchymal transition (EMT), and glycolysis in HCC cells. Nuclear transcription factor Y subunit gamma (NFYC) was also associated with poor patient prognosis, and NFYC bound to the promoter of MTFR2 to activate transcription and promote Akt signaling. The repressive effects of NFYC knockdown on EMT and glycolysis in HCC cells were compromised by MTFR2 overexpression, elicited through the activation of the Akt signaling. Knockdown of NFYC slowed the growth and intrahepatic metastasis in vivo, which was reversed by MTFR2 overexpression. In conclusion, our work shows that activation of MTFR2 by the transcription factor NFYC promotes Akt signaling, thereby potentiating metabolic reprogramming in HCC development. Targeting the NFYC/MTFR2/Akt axis may represent a therapeutic strategy for HCC.

Hypoxia represses pattern-triggered immune responses in Arabidopsis.

Biotic and abiotic stresses frequently co-occur in nature, yet relatively little is known about how plants co-ordinate the response to combined stresses. Protein degradation by the ubiquitin/proteasome system is central to the regulation of multiple independent stress response pathways in plants. The Arg/N-degron pathway is a subset of the ubiquitin/proteasome system that targets proteins based on their N termini and has been specifically implicated in the responses to biotic and abiotic stresses, including hypoxia, via accumulation of group VII ETHYLENE RESPONSE FACTOR (ERF-VII) transcription factors that orchestrate the onset of the hypoxia response program. Here, we investigated the role of the Arabidopsis (Arabidopsis thaliana) Arg/N-degron pathway in mediating the crosstalk between combined abiotic and biotic stresses using hypoxia treatments and the flg22 elicitor of pattern-triggered immunity (PTI), respectively. We uncovered a link between the plant transcriptional responses to hypoxia and flg22. Combined hypoxia and flg22 treatments showed that hypoxia represses the flg22 transcriptional program, as well as the expression of pattern recognition receptors, mitogen-activated protein kinase (MAPK) signalling and callose deposition during PTI through mechanisms that are mostly independent from the ERF-VIIs. These findings improve our understanding of the trade-offs between plant responses to combined abiotic and biotic stresses in the context of our efforts to increase crop resilience to global climate change. Our results also show that the well-known repressive effect of hypoxia on innate immunity in animals also applies to plants.

A global transcriptional atlas of the effect of acute sleep deprivation in the mouse frontal cortex

Sleep deprivation (SD) has negative effects on brain and body function. Sleep problems are prevalent in a variety of disorders, including neurodevelopmental and psychiatric conditions. Thus, understanding the molecular consequences of SD is of fundamental importance in biology. In this study, we present the first simultaneous bulk and single-nuclear RNA sequencing characterization of the effects of SD in the male mouse frontal cortex. We show that SD predominantly affects glutamatergic neurons, specifically in layers 4 and 5, and produces isoform switching of over 1500 genes, particularly those involved in splicing and RNA binding. At both the global and cell-type specific level, SD has a large repressive effect on transcription, downregulating thousands of genes and transcripts. As a resource we provide extensive characterizations of cell-types, genes, transcripts, and pathways affected by SD. We also provide publicly available tutorials aimed at allowing readers adapt analyses performed in this study to their own datasets.

At the crossroads: strigolactones mediate changes in cytokinin synthesis and signalling in response to nitrogen limitation.

Strigolactones (SLs) are key regulators of shoot growth and responses to environmental stimuli. Numerous studies have indicated that nitrogen (N) limitation induces SL biosynthesis, suggesting that SLs may play a pivotal role in coordinating systemic responses to N availability, but this idea has not been clearly demonstrated. Here, we generated triple knockout mutants in the SL synthesis gene TaDWARF17 (TaD17) in bread wheat and investigated their phenotypic and transcriptional responses under N limitation, aiming to elucidate the role of SLs in the adaptation to N limitation. Tad17 mutants display typical SL mutant phenotypes, and fail to adapt their shoot growth appropriately to N. Despite exhibiting an increased tillering phenotype, Tad17 mutants continued to respond to N limitation by reducing tiller number, suggesting that SLs are not the sole regulators of tillering in response to N availability. RNA-seq analysis of basal nodes revealed that the loss of D17 significantly altered the transcriptional response of N-responsive genes, including changes in the expression profiles of key N response master regulators. Crucially, our findings suggest that SLs are required for the transcriptional downregulation of cytokinin (CK) synthesis and signalling in response to N limitation. Collectively, our results suggest that SLs are essential for the appropriate morphological and transcriptional adaptation to N limitation in wheat, and that the repressive effect of SLs on shoot growth is partly mediated by their repression of CK synthesis.

ARHGEF39 targeted by E2F1 fosters hepatocellular carcinoma metastasis by mediating fatty acid metabolism

BackgroundHepatocellular carcinoma (HCC) stands as the prevailing manifestation of primary liver cancer. Previous studies have implicated ARHGEF39 in various cancer progression processes, but its impact on HCC metastasis remains unclear. MethodsBioinformatics analysis and qRT-PCR were employed to test ARHGEF39 expression in HCC tissues and cells, identified enriched pathways associated with ARHGEF39, and investigated its regulatory relationship with E2F1. The impact of ARHGEF39 overexpression or knockdown on cellular phenotypes in HCC was assessed through the implementation of CCK-8 and Transwell assays. Accumulation of neutral lipids was determined by BODIPY 493/503 staining, while levels of triglycerides and phospholipids were measured using specific assay kits. Expression of E-cadherin, Vimentin, MMP-2, MMP-9, and FASN were analyzed by Western blot. The interaction between ARHGEF39 and E2F1 was validated through ChIP and dual-luciferase reporter assays. ResultsOur study demonstrated upregulated expression of both ARHGEF39 and E2F1 in HCC, with ARHGEF39 being associated with fatty acid metabolism (FAM) pathways. Additionally, ARHGEF39 was identified as a downstream target gene of E2F1. Cell-based experiments unmasked that high expression of ARHGEF39 mediated the promotion of HCC cell viability, migration, and invasion via enhanced FAM. Moreover, rescue assays demonstrated that the promotion of HCC cell metastasis by high ARHGEF39 expression was attenuated upon treatment with Orlistat. Conversely, the knockdown of E2F1 suppressed HCC cell metastasis and FAM, while the upregulation of ARHGEF39 counteracted the repressive effects of E2F1 downregulation on the metastatic potential of HCC cells. ConclusionOur findings confirmed the critical role of ARHGEF39 in HCC metastasis and unmasked potential molecular mechanisms through which ARHGEF39 fostered HCC metastasis via FAM, providing a theoretical basis for exploring novel molecular markers and preventive strategies for HCC metastasis.

The political partnership between Israel and authoritarian Uruguay, 1972–1980

ABSTRACT Between 1972 and 1980, Israel and authoritarian Uruguay developed a political partnership based on their shared self-perception as misunderstood Western bastions fighting terrorism and the proxies of communist expansion, as well as shared concerns about détente and Western human rights discourse. While Uruguay remained the most consequential anti-PLO South American regime, Israel helped the Uruguayan dictatorship manipulate public opinion and cover up antisemitism and Nazi sympathies within its repressive apparatus. When dealing with the effects of Uruguayan repression of leftist Jews, Israeli diplomats tended to prioritise their alliance with the regime over their ethnic-ideological commitment to Jewish solidarity.

LINC01370 suppresses hepatocellular carcinoma proliferation and metastasis by regulating the PI3K/AKT pathway

BackgroundHepatocellular carcinoma (HCC) poses a serious threat to human health worldwide. lncRNA dysregulation is frequently observed in various cancers, including HCC. However, the function of LINC01370 in HCC progression and its underlying mechanisms remain unclear.MethodsLINC01370 expression in HCC tissues with cells was analyzed by applying the GEO and GEPIA databases and qRT-PCR. CCK-8 and Transwell assays were used to assess HCC cell proliferation, migration, and invasion. The PI3K, AKT, with p-AKT protein expression were analyzed by western blotting.ResultsGene Expression Omnibus (GEO) and Gene Expression Profiling Interactive Analysis (GEPIA) showed that LINC01370 expression was significantly lower in HCC tissues than in normal tissues. LINC01370 overexpression markedly repressed HepG2 SMMC-7721 cells proliferation, migration, and invasion. To understand the downstream mechanism of LINC01370 regulation, we further analyzed the genes co-expressed with LINC01370 in GSE136247 and GSE132037 and then performed KEGG analysis. The PA pathway was found to be a downstream pathway regulated by LINC01370 in GSE136247 and GSE132037 via gene co-expression and KEGG analysis. Furthermore, PI3K and p-AKT protein levels decreased after LINC01370 overexpression. Importantly, rescue experiments showed that activation of the PI3K/AKT pathway disrupted the repressive effect of LINC01370 overexpression on the proliferation, migration, and invasion of HepG2 of SMMC-7721 cells.ConclusionsThis study verified that LINC01370 suppresses HCC proliferation with metastasis by regulating the PI3K/AKT pathway.

Are natural resources a curse, a blessing, or a double-edged sword? Implications for environmental sustainability

Natural resources have a significant impact on economic and political landscapes of developing countries which determines environmental sustainability. This study explores the convoluted connection between governance and natural resources, examining how resource abundance might influence governance quality. The main components of this dynamic that the theoretical framework considers are the Rentier effects, the repression effects, and the obstruction of modernization. This study creates a governance index applying principal component analysis (PCA) on several governance characteristics, such as political stability, rule of law, government efficacy, regulation and control of corruption, to measure governance comprehensively. Natural resource exports, rents, and the differentiation between renewable and non-renewable natural resources are the three proxies used to quantify natural resources, providing a more nuanced view. To calculate the effect of renewable and non-renewable natural resources on governance in developing nations, the econometric methodology uses a dynamic panel model and system GMM. This analysis reveals that the ability of renewable resources to promote inclusive development has a favourable impact on governance. On the other hand, non-renewable resources show a negative correlation, mainly because of their vulnerability to swings in the world price and their propensity to consolidate power and promote corruption. The significance of differentiating between natural resource types is highlighted in this study, along with the possible advantages of renewable resources for governance and the disadvantages of an over-reliance on non-renewable resources. Policymakers, researchers, and practitioners interested in the development and governance difficulties encountered by resource-rich developing nations can benefit greatly from this research's larger and more complex understanding of the link between natural resources and governance.

Engineering xylose induction in Vibrio natriegens for biomanufacturing applications.

Xylose is an abundant, inexpensive and readily available carbohydrate common in minimally processed feedstocks such as seaweed and algae. While a wide variety of marine microbes have evolved to utilize seaweed and algae, only a few currently have the requisite characteristics and genetic engineering tools necessary to entertain the use of these underutilized feedstocks. The rapidly growing Gram-negative halophilic bacterium Vibrio natriegens is one such chassis. In this study, we engineered and tested xylose induction in V. natriegens as a tool for scalable bioproduction applications. First, we created a sensing construct based on the xylose operon from Escherichia coli MG1665 and measured its activity using a fluorescent reporter and identified that cellular import plays a key role in induction strength and that expression required the XylR transcription factor. Next, we identified that select deletions of the promoter region enhance gene expression, limiting the effect of carbohydrate repression when xylose is used as an inducer in the presence of industrially relevant carbon sources. Lastly, we used the optimized constructs to produce the biopolymer melanin using seawater mimetic media. One of these formulations utilized a nori-based seaweed extract as an inducer and demonstrated melanin yields comparable to previously optimized methods using a more traditional and costly inducer. Together, the results demonstrate that engineering xylose induction in V. natriegens can provide an effective and lower cost option for timed biosynthesis in scalable biomanufacturing applications using renewable feedstocks.

Ropivacaine synergizes with sorafenib to induce apoptosis of hepatocellular carcinoma cells via the IL-6/STAT3 pathway.

The development of resistance in hepatocellular carcinoma (HCC) cells limits the effectiveness of sorafenib, but combination therapy with other drugs may have a positive effect. However, the effect of ropivacaine combined with sorafenib on the treatment of HCC cells and its potential regulatory mechanisms remain unclear. The proliferation and apoptosis of HCC cells treated with ropivacaine, sorafenib, and ropivacaine plus sorafenib were analyzed by cell-counting kit 8 and flow cytometry. The protein levels were measured by Western blot. The antitumor effect of ropivacaine, sorafenib, and their combination was verified by a tumor xenograft model. Ropivacaine and sorafenib markedly impeded the viability of HCC cells in a concentration-dependent manner. Compared with ropivacaine or sorafenib treatment alone, ropivacaine and sorafenib combination treatment impeded HCC cell proliferation, facilitated apoptosis, enhanced cleaved caspase-3, cleaved caspase-9, and cyclin D1 protein expression, while it reduced IL-6 and p-STAT3 expression and inhibited tumor growth invivo. Importantly, the activation of the IL-6/STAT3 pathway could reverse the repressive or stimulative effects of ropivacaine and sorafenib on the proliferation and apoptosis in HCC cells. In summary, ropivacaine synergistically induces sorafenib-stimulated apoptosis of HCC cells via the IL-6/STAT3 pathway. Ropivacaine is a potential drug for the treatment of HCC when combined with sorafenib.

Extrachromosomal circular DNA promotes prostate cancer progression through the FAM84B/CDKN1B/MYC/WWP1 axis

BackgroundExtrachromosomal circular DNA (eccDNA), a kind of circular DNA that originates from chromosomes, carries complete gene information, particularly the oncogenic genes. This study aimed to examine the contributions of FAM84B induced by eccDNA to prostate cancer (PCa) development and the biomolecules involved.MethodsThe presence of eccDNA in PCa cells and the FAM84B transcripts that eccDNA carries were verified by outward and inward PCR. The effect of inhibition of eccDNA synthesis on FAM84B expression in PCa cells was analyzed by knocking down Lig3. The impact of FAM84B on the growth and metastases of PCa cells was verified by Cell Counting Kit-8 (CCK8), EdU, transwell assays, and a xenograft mouse model. Chromatin immunoprecipitation quantitative PCR (ChIP-qPCR) and dual-luciferase reporter assays were carried out to examine the effect of FAM84B/MYC on WWP1 transcription, and a co-immunoprecipitation (Co-IP) assay was conducted to verify the modification of CDKN1B by WWP1. The function of this molecular axis in PCa was explored by rescue assays.ResultsThe inhibited eccDNA synthesis significantly downregulated FAM84B in PCa cells, thereby attenuating the growth and metastasis of PCa. FAM84B promoted the transcription of WWP1 by MYC by activating the expression of MYC coterminous with the 8q24.21 gene desert in a beta catenin-dependent approach. WWP1 transcription promoted by MYC facilitated the ubiquitination and degradation of CDKN1B protein and inversely attenuated the repressive effect of CDKN1B on MYC expression. Exogenous overexpression of CDKN1B blocked FAM84B-activated MYC/WWP1 expression, thereby inhibiting PCa progression.ConclusionsFAM84B promoted by eccDNA mediates degradation of CDKN1B via MYC/WWP1, thereby accelerating PCa progression.

Platr3/NUDT21/NF-κB Axis Mediates P. gingivalis-Suppressed Cementoblast Mineralization.

Porphyromonas gingivalis (P. gingivalis) is one of the major pathogens causing periodontitis and apical periodontitis (AP). Long noncoding RNA (lncRNA) can regulate cellular mineralization and inflammatory diseases. The aim of this study was to investigate the role and mechanism of lncRNA in P. gingivalis-stimulated cementoblast mineralization. In vivo, C57BL/6 mice were divided into the healthy, the AP, and AP + P. gingivalis groups (n = six mice per group). Micro computed tomography, immunohistochemistry staining, and fluorescence in situ hybridization were used to observe periapical tissue. In vitro, cementoblasts were treated with osteogenic medium or P. gingivalis. Pluripotency associated transcript 3 (Platr3), interleukin 1 beta (IL1B), and osteogenic markers were analyzed by quantitative real-time polymerase chain reaction and western blot. RNA pull-down and RNA immunoprecipitation assays were used to detect proteins that bind to Platr3. RNA sequencing was performed in Platr3-silenced cementoblasts. In vivo, P. gingivalis promoted periapical tissue destruction and IL1B expression, but inhibited Platr3 expression. In vitro, P. gingivalis facilitated IL1B expression (P < 0.001), whereas suppressed the expression of Platr3 (P < 0.001) and osteogenic markers (P < 0.01 or 0.001). In contrast, Platr3 overexpression alleviated the repressive effect of P. gingivalis on cementoblast mineralization (P < 0.01 or 0.001). Furthermore, Platr3 bound to nudix hydrolase 21 (NUDT21) and regulated the nuclear factor-κB (NF-κB) signaling pathway. Knocking down NUDT21 suppressed osteogenic marker expression and activated the above signaling pathway. Collectively, the results elucidated that Platr3 mediated P. gingivalis-suppressed cementoblast mineralization through the NF-κB signaling pathway by binding to NUDT21.