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BACKGROUND: Skeletal muscle development and fat deposition have important effects on meat quality. The study of regulating skeletal muscle development and fat deposition is of great significance in improving the quality of carcass and meat. In the present study, whole transcriptome sequencing (including RNA-Seq and miRNA-Seq) was performed on the longissimus dorsi muscle (LDM) of Jinfen White pigs at 1, 90, and 180 days of age. RESULTS: The results showed that a total of 245 differentially expressed miRNAs were screened in any two comparisons, which may be involved in the regulation of myogenesis. Among them, compared with 1-day-old group, miR-22-5p was significantly up-regulated in 90-day-old group and 180-day-old group. Functional studies demonstrated that miR-22-5p inhibited the proliferation and differentiation of porcine skeletal muscle satellite cells (PSCs). Pearson correlation coefficient analysis showed that long non-coding RNA (lncRNA) LOC106505926 and CXXC5 gene had strong negative correlations with miR-22-5p. The LOC106505926 and CXXC5 were proven to promote the proliferation and differentiation of PSCs, as opposed to miR-22-5p. In terms of mechanism, LOC106505926 functions as a molecular sponge of miR-22-5p to modulate the expression of CXXC5, thereby inhibits the differentiation of PSCs. In addition, LOC106505926 regulates the differentiation of porcine preadipocytes through direct binding with FASN. CONCLUSIONS: Collectively, our results highlight the multifaceted regulatory role of LOC106505926 in controlling skeletal muscle and adipose tissue development in pigs and provide new targets for improving the quality of livestock products by regulating skeletal muscle development and fat deposition.
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Diferenciación Celular , Lipogénesis , MicroARNs , Desarrollo de Músculos , ARN Largo no Codificante , Animales , ARN Largo no Codificante/genética , Desarrollo de Músculos/genética , Porcinos , MicroARNs/genética , MicroARNs/metabolismo , Lipogénesis/genética , Diferenciación Celular/genética , Proliferación Celular , Células Satélite del Músculo Esquelético/metabolismo , Células Satélite del Músculo Esquelético/citología , Músculo Esquelético/metabolismo , Músculo Esquelético/crecimiento & desarrollo , Células CultivadasRESUMEN
The development of skeletal muscle in pigs might determine the quality of pork. In recent years, long non-coding RNAs (lncRNAs) have been found to play an important role in skeletal muscle growth and development. In this study, we investigated the whole transcriptome of the longissimus dorsi muscle (LDM) of Jinfen White pigs at three developmental stages (1, 90, and 180 days) and performed a comprehensive analysis of lncRNAs, mRNAs, and micro-RNAs (miRNAs), aiming to find the key regulators and interaction networks in Jinfen White pigs. A total of 2638 differentially expressed mRNAs (DE mRNAs) and 982 differentially expressed lncRNAs (DE lncRNAs) were identified. Compared with JFW_1d, there were 497 up-regulated and 698 down-regulated DE mRNAs and 212 up-regulated and 286 down-regulated DE lncRNAs in JFW_90d, respectively. In JFW_180d, there were 613 up-regulated and 895 down-regulated DE mRNAs and 184 up-regulated and 131 down-regulated DE lncRNAs compared with JFW_1d. There were 615 up-regulated and 477 down-regulated DE mRNAs and 254 up-regulated and 355 down-regulated DE lncRNAs in JFW_180d compared with JFW_90d. Compared with mRNA, lncRNA has fewer exons, fewer ORFs, and a shorter length. We performed GO and KEGG pathway functional enrichment analysis for DE mRNAs and the potential target genes of DE lncRNAs. As a result, several pathways are involved in muscle growth and development, such as the PI3K-Akt, MAPK, hedgehog, and hippo signaling pathways. These are among the pathways through which mRNA and lncRNAs function. As part of this study, bioinformatic screening was used to identify miRNAs and DE lncRNAs that could act as ceRNAs. Finally, we constructed an lncRNA-miRNA-mRNA regulation network containing 26 mRNAs, 7 miRNAs, and 17 lncRNAs; qRT-PCR was used to verify the key genes in these networks. Among these, XLOC_022984/miR-127/ENAH and XLOC_016847/miR-486/NRF1 may function as key ceRNA networks. In this study, we obtained transcriptomic profiles from the LDM of Jinfen White pigs at three developmental stages and screened out lncRNA-miRNA-mRNA regulatory networks that may provide crucial information for the further exploration of the molecular mechanisms during skeletal muscle development.
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Cisplatin is commonly used for the chemotherapy of tongue squamous cell carcinoma (TSCC); however, adverse side effects and drug resistance impact its therapeutic efficacy. Capsaicin is an active ingredient in chili peppers that exerts antitumor effects, whether it exerts antitumor effects on cisplatin-resistant cells remains unknown. Therefore, in this study, we investigated the effect of capsaicin on cisplatin resistance in TSCC cells and explored the underlying mechanisms. A cisplatin-resistant TSCC cell line was established by treated with increasing cisplatin concentrations. Combined treatment with cisplatin and capsaicin decreased the glucose consumption and lactate dehydrogenase activity and increased the adenosine triphosphate production both in vitro and in vivo, suggesting the inhibition of the Warburg effect. Moreover, this combined treatment induced cell apoptosis and significantly upregulated the levels of proapoptotic proteins, such as Bax, cleaved caspase-3, -7, and -9, and apoptosis-inducing factor. In contrast, levels of the antiapoptotic protein, Bcl-2, were downregulated. Additionally, LKB1 and AMPK activities were stimulated, whereas those of AKT and mTOR were suppressed. Notably, AMPK knockdown abolished the inhibitory effects of capsaicin and cisplatin on the AKT/mTOR signaling pathway and Warburg effect. Overall, combined treatment with capsaicin and cisplatin reversed cisplatin resistance by inhibiting the Warburg effect and facilitating mitochondrial-dependent apoptosis via the AMPK/AKT/mTOR axis. Our findings suggest combination therapy with capsaicin and cisplatin as a potentially novel strategy and highlight capsaicin as a promising adjuvant drug for TSCC treatment.
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Apoptosis , Capsaicina , Cisplatino , Resistencia a Antineoplásicos , Mitocondrias , Proteínas Proto-Oncogénicas c-akt , Transducción de Señal , Serina-Treonina Quinasas TOR , Neoplasias de la Lengua , Cisplatino/farmacología , Capsaicina/farmacología , Neoplasias de la Lengua/tratamiento farmacológico , Neoplasias de la Lengua/metabolismo , Neoplasias de la Lengua/patología , Serina-Treonina Quinasas TOR/metabolismo , Apoptosis/efectos de los fármacos , Humanos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Línea Celular Tumoral , Resistencia a Antineoplásicos/efectos de los fármacos , Mitocondrias/metabolismo , Mitocondrias/efectos de los fármacos , Animales , Transducción de Señal/efectos de los fármacos , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patología , Ratones , Proteínas Quinasas Activadas por AMP/metabolismo , Efecto Warburg en Oncología/efectos de los fármacos , Antineoplásicos/farmacología , Ratones Desnudos , Ratones Endogámicos BALB CRESUMEN
Super-enhancers play prominent roles in driving robust pathological gene expression, but they are hidden in human genome at noncoding regions, making them difficult to explore. Leukemia inhibitory factor (LIF) is a multifunctional cytokine crucially involved in acute respiratory distress syndrome (ARDS) and lung cancer progression. However, the mechanisms governing LIF regulation in disease contexts remain largely unexplored. In this study, we observed elevated levels of LIF in the bronchoalveolar lavage fluid (BALF) of patients with sepsis-related ARDS compared to those with nonsepsis-related ARDS. Furthermore, both basal and LPS-induced LIF expression were under the control of super-enhancers. Through analysis of H3K27Ac ChIP-seq data, we pinpointed three potential super-enhancers (LIF-SE1, LIF-SE2, and LIF-SE3) located proximal to the LIF gene in cells. Notably, genetic deletion of any of these three super-enhancers using CRISPR-Cas9 technology led to a significant reduction in LIF expression. Moreover, in cells lacking these super-enhancers, both cell growth and invasion capabilities were substantially impaired. Our findings highlight the critical role of three specific super-enhancers in regulating LIF expression and offer new insights into the transcriptional regulation of LIF in ARDS and lung cancer.
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Factor Inhibidor de Leucemia , Neoplasias Pulmonares , Síndrome de Dificultad Respiratoria , Humanos , Síndrome de Dificultad Respiratoria/metabolismo , Síndrome de Dificultad Respiratoria/genética , Síndrome de Dificultad Respiratoria/patología , Factor Inhibidor de Leucemia/metabolismo , Factor Inhibidor de Leucemia/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Líquido del Lavado Bronquioalveolar/química , Elementos de Facilitación Genéticos , Proliferación Celular , MasculinoRESUMEN
OBJECTIVES: The splicing factor transformer-2 homolog beta (Tra2ß) plays a pivotal role in various cancers. Nonetheless, its role in oral squamous cell carcinoma (OSCC) has not been comprehensively explored. This study sought to discern the influence of Tra2ß on OSCC and its underlying mechanisms. MATERIALS AND METHODS: We assessed Tra2ß expression in OSCC utilizing immunohistochemistry, qRT-PCR, and western blotting techniques. siRNA transfection was used to silence Tra2ß. Whole transcriptome RNA sequencing (RNA-seq) analysis was carried out to reveal the alternative splicing (AS) events. KEGG pathway analysis enriched the related pathways. Colony formation, transwell, wound healing, and Annexin V-FITC/PI were employed to appraise the consequences of Tra2ß silencing on OSCC. RESULTS: Tra2ß was highly expressed in both OSCC tissues and cell lines. Knockdown of Tra2ß-regulated AS events with skipped exon (SE) accounts for the highest proportion. Meanwhile, downregulation of Tra2ß reduced cell proliferation, migration, and invasion, however increasing cell apoptosis. Moreover, Wnt signaling pathway involved in the function of Tra2ß knockdown which was demonstrated directly by a discernible reduction in the expression of GSK3/ß-catenin signaling axis. CONCLUSIONS: These findings suggest that knockdown of Tra2ß may exert anti-tumor effects through the GSK3/ß-catenin signaling pathway in OSCC.
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BACKGROUND: TikTok is emerging as a vital platform for health information dissemination. Despite myopia being a global public health issue, the high-quality myopia information shared by health educators often fails to go viral. It is imperative to analyze the factors influencing video quality and popularity, especially from diverse perspectives of researchers, health educators, and audiences. METHODS: TikTok myopia-related videos were retrieved using TikTok's default comprehensive search (DCS) and most liked search (MLS) strategies. Venn diagrams were employed to illustrate the relationships and commonalities between the two strategies across four sample sizes (top 200, 150, 100, and 50). Video metadata, including details such as creator information, production properties, upload time, video duration, and viewer engagement, were collected. Video quality was assessed using the DISCERN tool. Video content covering six aspects of myopia were evaluated. The impact of search strategies, video sample sizes, production properties, and myopia content on video quality and audience engagement was analyzed through single-factor or multi-factor analysis. RESULTS: DCS and MLS retrieval strategies, as well as varying sample sizes, resulted in differences in audience engagement for myopia videos (P < 0.039), while The DISCERN quality scores remained comparable (P > 0.221). Videos published by healthcare professionals (HCPs) and non-profit organizations (NPOs) were associated with high-quality (P ≤ 0.014) but comparatively lower popularity (P < 0.033). Videos that reported contents of risk factors, management, and outcomes showed high popularity (P < 0.018), while longer video duration (> 60s) exhibited the opposite trend (P < 0.032). Content on myopia evaluation (P ≤ 0.001) and management (P ≤ 0.022) and video duration were positively correlated with higher DISCERN quality. CONCLUSION: Videos created by HCPs and NPOs deserve greater attention. Rather than pursuing entertaining effects, professional educators should emphasize producing concise, and high-quality myopia content that readily resonates with the audience and has the potential to go viral on the platform.
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Miopía , Grabación en Video , Humanos , Miopía/terapia , Difusión de la Información/métodosRESUMEN
Piglets may experience a variety of stress injuries, but the molecular regulatory mechanisms underlying these injuries are not well understood. In this study, we analysed the ileum of Large White (LW) and Mashen (MS) piglets at different times of starvation using chemical staining and transcriptome analysis. The intestinal barrier of piglets was damaged after starvation stress, but the intestinal antistress ability of MS piglets was stronger than LW piglets. A total of 8021 differentially expressed genes (DEGs) were identified in two breeds. Interestingly, the immune capacity (CHUK, TLR3) of MS piglets increased significantly after short-term starvation stress, while energy metabolism (NAGS, PLA2G12B, AGCG8) was predominant in LW piglets. After long-term starvation stress, the level of energy metabolism (PLIN5, PLA2G12B) was significantly increased in MS piglets. The expression of immune (HLA-DQB1, IGHG4, COL3A1, CD28, LAT) and disease (HSPA1B, MINPPI, ADH1C, GAL3ST1) related genes were significantly increased in two breeds of piglets. These results suggest that short-term stress mainly enhances immunity and energy metabolism in piglets, while long-term starvation produces greater stress on piglets, making it difficult for them to compensate for the damage to their bodies through self-regulation. This information can help improve the stress resistance of piglets through molecular breeding.
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Perfilación de la Expresión Génica , Intestino Delgado , Porcinos , Animales , Intestino Delgado/metabolismo , Perfilación de la Expresión Génica/veterinaria , Intestinos , RNA-SeqRESUMEN
Background: Hepatocellular carcinoma (HCC), a prevalent cancer, is linked to cuproptosis in tumor progression. However, cuproptosis's impact on HCC prognosis and its role in the tumor microenvironment remain unclear. We aimed to explore the correlation between cellular cuproptosis and the immune microenvironment in HCC, providing potential immunotherapeutic insights. Methods: Examining cuproptosis-related genes and the immune microenvironment through consensus clustering and WGCNA. Risk models were constructed using LASSO Cox analysis and validated in an independent cohort. Gene expression data from The Cancer Genome Atlas (TCGA) database and single-cell RNA sequencing (scRNA-seq) data from the Gene Expression Omnibus (GEO) database were utilized. We scored cuproptosis expression and explored immunoinfiltration and cell-cell communication. Differential signals in T_memory cells were compared across different cuproptosis levels. Results: Cuproptosis genes associated with fibroblast recruitment (GLS) and macrophage infiltration (FDX1). Liver cancer patients categorized into two subtypes based on cuproptosis gene expression. High expression of DLAT, GLS, and CDKN2A linked to immunosuppression (TGF-ß), while high FDX1, MTF1, LIAS, and LIPT1 expression enhanced communication with non-immune cells. Developed reliable prognostic signature score and nomogram using cuproptosis-related genes. Single-cell analysis revealed differences in T_memory and TAM infiltration based on cuproptosis scores, with SPP1 and MIF as dominant signaling molecules. Finally, the results of in vitro experiments showed that when DLAT or CDKN2A was knocked down, the proliferation, migration, and invasion of HCC cells were significantly decreased. Conclusion: Our study demonstrates that cuproptosis affects the immune microenvironment and cell-cell communication. Identified 9 genetic markers predicting survival outcomes and immunotherapy responses. Evaluating cuproptosis signaling can optimize immunotherapeutic strategies for hepatocellular carcinoma.
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Carcinoma Hepatocelular , Comunicación Celular , Neoplasias Hepáticas , Microambiente Tumoral , Carcinoma Hepatocelular/inmunología , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/mortalidad , Carcinoma Hepatocelular/patología , Humanos , Neoplasias Hepáticas/inmunología , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/mortalidad , Microambiente Tumoral/inmunología , Microambiente Tumoral/genética , Pronóstico , Regulación Neoplásica de la Expresión Génica , Masculino , Biomarcadores de Tumor/genética , Femenino , Persona de Mediana Edad , Perfilación de la Expresión GénicaRESUMEN
BACKGROUND: Anaplastic lymphoma kinase (ALK)-positive large B-cell lymphoma (LBCL) is an aggressive and rare variant of diffuse LBCL. Herein, we report an uncommon case of stage IE extranodal ALK-positive LBCL initially originating in the bulbar conjunctiva. CASE SUMMARY: A 63-year-old woman presented with a mass in the left bulbar conjunctiva that had persisted for six months, accompanied by swelling and pain that had persisted for 3 d. Eye examination revealed an 8 mm slightly elevated pink mass in the lower conjunctival sac of the left eye. Microscopically, the tumor was composed of large immunoblastic and plasmablastic large lymphoid cells with scattered anaplastic or multinucleated large cells. Immunophenotypically, the neoplastic cells were positive for ALK, CD10, CD138, Kappa, MUM1, BOB.1, OCT-2, CD4, CD45, EMA, CD79a, CD38, and AE1/AE3, and negative for CD20, PAX5, Lambda, BCL6, CD30 and all other T-cell antigens. The results of gene rearrangement tests showed monoclonal IGH/IGK/IGL and TCRD rearrangements. Fluorescence in situ hybridization studies did not reveal any BCL2, BCL6 or MYC rearrangements. Furthermore, Epstein-Barr virus was not detected by in situ hybridization in the lesions. Based on the histopathological and imaging examinations, the neoplasm was classified as stage IE ALK-positive LBCL. No further treatments were administered. At the 6, 15, and 21 mo postoperative follow-up visits, the patient was in good condition, without obvious discomfort. This case represents the first example of primary extranodal ALK-positive LBCL presenting as a bulbar conjunctival mass, which is extremely rare and shares morphological and immunohistochemical features with a variety of other neoplasms that can result in misdiagnosis. CONCLUSION: Awareness of the condition presented in this case report is necessary for early and accurate diagnosis and appropriate treatment.
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In the process of applying exotic plants to wetland ecological restoration, insufficiently evaluated alien species may exhibit strong competitiveness and fecundity. Once introduced, they can displace native flora, disrupt the original ecological balance, diminish biodiversity, and even induce ecosystem dysfunction. Furthermore, exotic plants have the potential to alter soil microbial community structure, including the composition and activity of beneficial symbiotic microorganisms such as arbuscular mycorrhizal fungi (AMF), thereby impacting soil nutrient cycling and interplant nutrient competition. Here, we conducted three consecutive years of sampling experiments to investigate the succession of AMF communities associated with the invasive plant Spartina alterniflora along an initial introduction chronosequence, and to identify the key environmental factors influencing its response to S. alterniflora invasion. Our findings reveal that early-stage invasion by S. alterniflora alters the composition of soil AMF communities with unclassified_c__Glomeromycetes and Glomus-viscosum-VTX00063 consistently dominating. Additionally, as the duration of introduction increases, the diversity of rhizosphere soil AMF significantly decreases, while its evenness remains relatively stable. It's indicated that soil ω, AN, AK and N/P ratio were the main influencing factors of the integral AMF community. Notably, soil available phosphorus (AP) emerges as a positive influence on the important AMF taxa. The results confirm the mutual feedback effect between the invasion of the perennial herb S. alterniflora and AMF, in which specific AMF assist in nutrient absorption to promote S. alterniflora growth, potentially facilitating its rapid and successful invasion of new habitats. Given the likely differential effects of AMF communities on various plant species, our findings could contribute to anticipating future AMF-mediated effects during the introduction of alien plants.
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Repeat dipeptides such as poly(proline-arginine) (polyPR) are generated from the hexanucleotide GGGGCC repeat expansions in the C9orf72 gene. These dipeptides are often considered as the genetic cause of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). In the study, fluorescein isothiocyanate (FITC) labeled PR20 is used to investigate PR20-induced cell death. The findings reveal that the cell death induced by PR20 is dependent on its nuclear distribution and can be blocked by a nuclear import inhibitor called importazole. Further investigation reveals that BRD4 inhibitors, such as JQ-1 and I-BET762, restrict cytoplasmic localization of PR20, thereby reducing its cytotoxic effect. Mechanistically, the inhibition of BRD4 leads to an increase in the expression of numerous histones, resulting in the accumulation of histones in the cytoplasm. These cytoplasmic histones associate with PR20 and limit its distribution within the nucleus. Notably, the ectopic expression of histones alone is enough to confer protection to cells treated with PR20. In addition, phenylephrine (PE) induces cellular hypertrophy and cytoplasmic distribution of histone, which also helps protect cells from PR20-induced cell death. The research suggests that temporarily inducing the presence of cytoplasmic histones may alleviate the neurotoxic effects of dipeptide repeat proteins.
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Histonas , Proteínas Nucleares , Histonas/genética , Histonas/metabolismo , Histonas/farmacología , Proteína C9orf72/genética , Proteína C9orf72/metabolismo , Proteína C9orf72/farmacología , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Proteínas Nucleares/farmacología , Expansión de las Repeticiones de ADN , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Factores de Transcripción/farmacología , Dipéptidos/genética , Dipéptidos/metabolismo , Dipéptidos/farmacología , Muerte Celular/genéticaRESUMEN
Subsequently to the publication of the above paper, the authors drew to the attention of the Editorial Office that they had assembled the data shown for the cell migration assay experiments in Fig. 4F (on p. 8), incorrectly; essentially, the 'Control' data panel had inadvertently been copied across for the '10 µg/ml' data panel. The revised version of Fig. 4, showing the correct data panel for the '10 µg/ml' experiment in Fig. 4F, is shown on the next page. Note that the replacement of the erroneous data does not affect either the results or the conclusions reported in this paper, and all the authors agree to the publication of this Corrigendum. The authors are grateful to the Editor of Molecular Medicine Reports for granting them this opportunity to publish a Corrigendum, and apologize to the readership for any inconvenience caused. [Molecular Medicine Reports 27: 88, 2023; DOI: 10.3892/mmr.2023.12975].
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This research investigated the relationships between school climates and bullying behaviors in Chinese adolescents, and tested the mediating effect of prosocial tendency according to the seesaw effect. School climates were operationalized using three constructs: subjective diversity of student development goals, teacher support, and peer trust. Bullying behaviors included traditional (i.e., physical, nonphysical, and relational) and cyber bullying behaviors. We recruited 538 adolescents from three schools in Beijing, China (286 girls, 252 boys; average age = 12.47) and asked them to fill out the surveys measuring school climates and prosocial tendency at the outset and to report school bullying behaviors three months later. The results showed that subjective diversity of student development goals and peer trust were directly associated with less cyber bullying behavior. Moreover, teacher support and peer trust were indirectly associated with less traditional bullying behaviors via prosocial tendency. Our findings extend the existing literature on the relationships between school climates and bullying behaviors by incorporating different types of bullying behaviors, concentrating on Chinese adolescents from a cultural viewpoint, and tapping into the underlying mechanism via revealing prosocial tendency as a mediator. Theoretical and empirical contributions of this study, as well as practical implications are discussed.
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Conducta del Adolescente , Acoso Escolar , Grupo Paritario , Instituciones Académicas , Humanos , Femenino , Masculino , Adolescente , Acoso Escolar/estadística & datos numéricos , China , Niño , Estudiantes/psicología , Conducta Social , Confianza/psicología , Ciberacoso/estadística & datos numéricos , Ciberacoso/psicología , Pueblos del Este de AsiaRESUMEN
BACKGROUND: Eosinophilic solid and cystic (ESC) renal cell carcinoma (RCC), a unique and emerging subtype of RCC, has an indolent nature; in some rare instances, it may exhibit metastatic potential. Current cases are inadequate to precisely predict the clinical outcome of ESC RCC and determine treatment choices. CASE SUMMARY: Herein, we report two patients with ESC RCC. Patient 1 was a young woman with classical pathological characteristics. Patient 2 was a 52-year-old man with multifocal metastases, involving the pulmonary hilar and mediastinal lymph nodes, liver, brain, mesosternum, vertebra, rib, femur, and symphysis pubis. Awareness of ESC RCC, along with its characteristic architecture and immunophenotype, would contribute to making a definitive diagnosis, even on core biopsy samples. CONCLUSION: The discovery of ESC RCC molecular signatures may provide new therapeutic strategies in the future.
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Ferroptosis, an iron-dependent form of programmed cell death, is a promising strategy for cancer treatment. Bromodomain-containing protein 4 (BRD4) is an epigenetic reader and a promising target for cancer therapeutics. However, the role of BRD4 in ferroptosis is controversial and the value of the interaction between BRD4 inhibitors and ferroptosis inducers remains to be explored. Here, we found that BRD4 inhibition greatly enhanced erastin-induced ferroptosis in different types of cells, including HEK293T, HeLa, HepG2, RKO, and PC3 cell lines. Knocking down BRD4 in HEK293T and HeLa cells also promoted erastin-induced cell death. BRD4 inhibition by JQ-1 and I-BET-762 or BRD4 knockdown resulted in substantial accumulation of reactive oxygen species (ROS) in both HEK293T and HeLa cells. The effect of BRD4 inhibition on ferroptosis-associated genes varied in different cells. After using BRD4 inhibitors, the expression of FTH1, Nrf2, and GPX4 increased in HEK293T cells, while the levels of VDAC2, VDAC3, and FSP1 decreased. In HeLa cells, the expression of FTH1, VDAC2, VDAC3, Nrf2, GPX4, and FSP1 was reduced upon treatment with JQ-1 and I-BET-762. Consistently, the level of FSP1 was greatly reduced in HEK293T and HeLa cells with stable BRD4 knockdown compared to control cells. Furthermore, ChIP-sequencing data showed that BRD4 bound to the promoter of FSP1, but the BRD4 binding was greatly reduced upon JQ-1 treatment. Our results suggest that ROS accumulation and FSP1 downregulation are common mechanisms underlying increased ferroptosis with BRD4 inhibitors. Thus, BRD4 inhibitors might be more effective in combination with ferroptosis inducers, especially in FSP1-dependent cancer cells.
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Circular RNA is a special category of non-coding RNA that has emerged as epigenetic regulator of adipose tissue development. However, the mechanism governing intramuscular adipogenesis of circRNA remains largely uncharted. In this study, circMEF2C(2, 3), looped by MEF2C exons 2 and 3, was identified from the pig MEF2C gene. Expression of circMEF2C(2, 3) is upregulated in early stage of intramuscular adipogenesis and muscular tissue of lean pigs (DLY pig). Subsequently, overexpression or knockdown of circMEF2C(2, 3) reflected that it participates in promoting proliferation and inhibiting adipogenic differentiation in porcine intramuscular preadipocytes and murine C3H10T1/2 cells. Mechanically, circMEF2C(2, 3) competitively combined with miR-383 and miR-671-3p to the 3'-UTR of MEF2C, which maintains MEF2C expression in regulating proliferation and adipogenesis. In summary, circMEF2C(2, 3) is a key regulator in the proliferation and adipogenic differentiation of intramuscular adipogenesis, suggesting its potential as a multi-target strategy for adipose development and associated diseases.
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In the swine industry, meat quality, color, and texture are influenced by the excessive differentiation of fat cells. miRNAs have emerged as integral regulators of adipose development. This study delves into the influence of miR-10a-5b on the proliferation and differentiation of pig preadipocytes. Our findings reveal that miR-10a-5b is prevalent across various tissues. It hinders preadipocyte proliferation, amplifies the expression of adipogenic genes, promotes lipid accumulation, and, as a result, advances preadipocyte differentiation. We predict that KLF11 is the target gene of miRNA. A dual-fluorescence reporter assay was conducted to validate the binding sites of miR-10a-5b on the 3'UTR of the KLF11 mRNA. Results showed that miR-10a-5b targeted KLF11 3'UTR and reduced the fluorescence activity of the dual-fluorescent reporter vector. Our research also indicates that miR-10a-5b targets and downregulates the expression of both mRNA and the protein levels of KLF11. During the differentiation of the preadipocytes, KLF11 inhibited adipose differentiation and was able to suppress the promotion of adipose differentiation by miR-10a-5b. This underscores miR-10a-5b's potential as a significant regulator of preadipocyte behavior by modulating KLF11 expression, offering insights into the role of functional miRNAs in fat deposition.
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ETHNOPHARMACOLOGICAL RELEVANCE: As a traditional Chinese medicine, the flower of Rhododendron molle G. Don (RMF) is record in the Chinese pharmacopoeia, and is commonly utilized for treating rheumatoid arthritis (RA) in clinical practice. However, its precise mechanisms necessitate further exploration. AIM OF THE STUDY: To expound the effective components, targets, metabolites, and pathways participated in RMF's anti-RA effects by metabolomics integrated network pharmacology. MATERIALS AND METHODS: CIA rats were intragastric administered RMF for 2 weeks, following which the therapeutic effects were comprehensively evaluated. Serum metabolomics was adopted to investigate the differential metabolites (DEMs). UHPLC-Q-Exactive-MS method was applied to identify the components of RMF, and then network pharmacology was utilize to select the component-RA-targets. Molecular docking and Western blotting were utilized to validate the key targets. RESULTS: RA symptoms were alleviated by RMF through the inhibition secretion of pro-inflammatory factors IL-1ß, IL-6 and TNF-α, along with relief in bone destruction observed in CIA rats. Four targets, namely AKR1B1, TPH1, CYP1A1, and CYP1A2, were identified, along with their corresponding metabolites, namely D-glucose, D-mannose, L-tryptophan, 11-deoxycorticosterone, and 17α-hydroxyprogesterone. These were found to be involved in three key metabolic pathways: steroid hormone biosynthesis, tryptophan metabolism, and galactose metabolism. Additionally, five significant anti-RA active components were identified from RMF, including Rhodojaponin (Rj)-â ¡, Rj-â ¢, Rj-â ¤, Rj-â ¥, and quercetin. CONCLUSIONS: The anti-RA mechanisms of RMF were investigated in this study, focusing on active components, upstream targets, and downstream metabolites. These findings lay a foundation for the clinical practice and drug development of RMF.
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Artritis Experimental , Artritis Reumatoide , Flores , Metabolómica , Farmacología en Red , Rhododendron , Animales , Rhododendron/química , Flores/química , Artritis Reumatoide/tratamiento farmacológico , Ratas , Artritis Experimental/tratamiento farmacológico , Artritis Experimental/metabolismo , Masculino , Antirreumáticos/farmacología , Antirreumáticos/aislamiento & purificación , Simulación del Acoplamiento Molecular , Medicamentos Herbarios Chinos/farmacología , Ratas Sprague-Dawley , Extractos Vegetales/farmacologíaRESUMEN
BACKGROUND: The role of Claudin-1 in tongue squamous cell carcinoma (TSCC) metastasis needs further clarification, particularly its impact on cell migration. Herein, our study aims to investigate the role of Claudin-1 in TSCC cell migration and its underlying mechanisms. METHODS: 36 TSCC tissue samples underwent immunohistochemical staining for Claudin-1. Western blotting and immunofluorescence analyses were conducted to evaluate Claudin-1 expression and distribution in TSCC cells. Claudin-1 knockdown cell lines were established using short hairpin RNA transfection. Migration effects were assessed through wound healing assays. Furthermore, the expression of EMT-associated molecules was measured via western blotting. RESULTS: Claudin-1 expression decreased as TSCC malignancy increased. Adenosine monophosphate-activated protein kinase (AMPK) activation led to increased Claudin-1 expression and membrane translocation, inhibiting TSCC cell migration and epithelial-mesenchymal transition (EMT). Conversely, Claudin-1 knockdown reversed these inhibitory effects on migration and EMT caused by AMPK activation. CONCLUSIONS: Our results indicated that AMPK activation suppresses TSCC cell migration by targeting Claudin-1 and EMT pathways.