RESUMEN
The primary purpose of present study was to explore the effects of arsenic exposure on the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/nuclear transcription factor-κB (NF-κB) signaling pathway in the hippocampus of offspring mice at different developmental stages. Sodium arsenite (NaAsO2) at doses of 0, 15, 30 or 60â¯mg/L administered to female mice and their pups. The nuclear translocation levels of NF-κB were assessed by EMSA. Real-time RT-PCR was used to measure Akt, NF-κB and PI3K mRNA levels. Protein expressions of PI3K, p-Akt, inhibitor kappa B kinase (IKK), p-NF-κB, protein kinase A (PKA), inhibitor kappa B (IκB), and cAMP response element-binding protein (CREB) were measured by Western blot. Results disclosed that exposure to 60â¯mg/L NaAsO2 could suppress NF-κB levels of nuclear translocation of postnatal day (PND) 20 and PND 40 mice. Arsenic downregulated the transcriptional and translational levels of PI3K, Akt and NF-κB. Additionally, protein expressions of p-IKK, p-IκB, PKA and p-CREB also reduced. Taken together, results of present study indicated that arsenic could downregulate the PI3K/Akt/NF-κB signaling pathway, particularly on PND 40, which might be involved in the cognitive impairments.
RESUMEN
Mitochondrial oxidative phosphorylation (OXPHOS) has long been considered the primary energy source in breast cancer cells. Cytochrome c oxidase assembly factor 6 (COA6), which functions as a metal chaperone to transport copper to complex â £ during the OXPHOS process, plays a crucial role in the carcinogenesis of lung adenocarcinoma. Nevertheless, its specific function in breast cancer is undefined. The present investigation aimed to clarify COA6's expression profile and regulatory functions in breast cancer, as well as to unveil its underlying mechanisms. Initially, our findings revealed a significant upregulation of COA6 in breast cancer, as evidenced by an analysis of the TCGA database and tissue microarrays. This upregulation correlated with tumor size and histological grade. Additionally, survival analysis revealed that elevated COA6 amounts were correlated with decreased overall survival (OS) in breast cancer. To delve deeper into the functions of COA6, both COA6-overexpressing and COA6-knockdown breast cancer cell models were established. These experiments demonstrated COA6 is pivotal in regulating cell proliferation, apoptosis, migration, and invasion, thereby promoting cancer progression in vitro. Notably, functional enrichment analysis indicated COA6 might be involved in breast cancer progression by modulating oxidative phosphorylation (OXPHOS). Collectively, this study reveals an overt tumorigenic role for COA6 in breast cancer and sheds light on its potential mechanisms, offering valuable therapeutic targets for breast cancer therapy.
RESUMEN
BACKGROUND: Cancers that metastasize to the skin are rare, especially cervical squamous cell carcinoma to the skin. Here, we have reported clinical analysis of patients with cervical squamous cell carcinoma metastasize to skin, to obtain a general understanding of this malignancy for clinicians. METHODS: A retrospective analysis of patients with skin metastasis from cervical squamous cell carcinoma was conducted, focusing on clinical manifestations, histopathology, diagnosis, treatment, and prognosis. RESULTS: The average age of onset for the six patients with skin metastasis from cervical squamous cell carcinoma was 55.17±17.08 years, with four cases presenting as solitary lesions and two cases as multiple lesions. Treatment strategies included local excision for isolated lesions, chemotherapy, radiotherapy, or targeted therapy based on the extent of skin involvement, and immunotherapy was proved to have promising results in our cases. Among the six patients, three have passed away with a diagnosis-to-death time of approximately 5-6 months, while three patients are alive, with survival times ranging from 30 to 72 months. CONCLUSIONS: Skin metastasis from cervical squamous cell carcinoma is rare and often accompanies recurrent metastases to other visceral sites, necessitating early and accurate diagnosis. For isolated metastatic lesions, early detection followed by wide excision surgery and adjuvant radiotherapy can yield favorable outcomes. However, in cases of multiple skin metastases or concurrent metastases to multiple organs, treatment is challenging with a poor prognosis. Nevertheless, with advancements in medicine, combination chemotherapy, immunotherapy, and targeted therapy can effectively prolong survival, offering new hope for patients with skin metastasis from cervical cancer.
Asunto(s)
Carcinoma de Células Escamosas , Neoplasias Cutáneas , Neoplasias del Cuello Uterino , Humanos , Femenino , Neoplasias Cutáneas/terapia , Neoplasias Cutáneas/patología , Carcinoma de Células Escamosas/terapia , Carcinoma de Células Escamosas/secundario , Neoplasias del Cuello Uterino/terapia , Neoplasias del Cuello Uterino/patología , Persona de Mediana Edad , Estudios Retrospectivos , Adulto , Anciano , PronósticoRESUMEN
To enhance therapeutic approaches, we created a distinctive pattern utilizing the cell demise indicator (CDI) to predict the effectiveness of immunotherapy in individuals with bladder carcinoma (BLCA). Hub prognostic CDIs were identified from the TCGA database using differential gene expression and survival analysis, encompassing 763 genes across 13 death modes. The subtype assessment was employed to evaluate the impact of these genes on the prognosis and immunotherapeutic outcomes in patients with BLCA. The LASSO regression method was used to identify significant CDIs, while Cox regression and nomogram analyses were conducted to explore the impact of CDIs on prognosis. CHMP4C and GSDMB were selected as the hub genes for the following research. Subsequently, These two central genes underwent further investigation to explore their association with immunotherapy, followed by an analysis of their potential regulatory network. Subtype analysis showed that these CDIs were significantly associated with the prognosis and immunotherapy of BLCA patients. The regulatory network in BLCA was evaluated through the establishment of the lncRNA XIST/NEAT1-CDIs-miR-146a-5p/miR-429 axis. Immunohistochemical analysis revealed a significant up-regulation of CHMP4C in bladder cancer tissues, which was strongly associated with an unfavorable prognosis for BLCA patients. Moreover, our findings provide compelling evidence that CHMP4C plays a pivotal role in promoting BLCA progression through the activation of the epithelial-mesenchymal transition (EMT) pathway. These findings highlight the negative impact of CHMP4C on BLCA patient prognosis, while also providing insights into the oncogenic mechanisms and immunotherapy in which CHMP4C may be involved.
RESUMEN
A lower concentration of cadmium (Cd), a hazardous and non-essential element for plant growth, will have deleterious effects on plants and endanger human health. Histone demethylase (JHDM) is important for plants' ability to withstand abiotic stress, according to an increasing number of studies. The degree of expression of the SlJMJ18 and SlJMJ23 genes in different tomato tissues was confirmed by this study. These two genes were responsive to the heavy metals Cd, Hg, Pb, and Cu stress, according to fluorescence quantification and GUS staining. Interestingly, the overexpression transgenic Arabidopsis plants of two genes have different responses to Cd stress. While SlJMJ18-OE lines consistently display Cd resistance but an early-flowering phenotype, SlJMJ23-OE plants have sensitivity during the post-germination stage and then greater tolerance to Cd stress. It was discovered that these two genes may affect cadmium tolerance of plants by regulating the expression of hormone synthesis related genes and hormone contents (BRs and ABA). Moreover, SlJMJ23 may resist cadmium stress by increasing the total phenol content in plants. The functional significance of JMJs is better understood in this study, which also offers a theoretical foundation for the use of molecular technology to develop plants resistant to Cd and an experimental basis for the efficient use of land resources.
Asunto(s)
Arabidopsis , Cadmio , Proteínas de Plantas , Plantas Modificadas Genéticamente , Solanum lycopersicum , Arabidopsis/genética , Arabidopsis/metabolismo , Arabidopsis/fisiología , Cadmio/metabolismo , Cadmio/toxicidad , Solanum lycopersicum/genética , Solanum lycopersicum/metabolismo , Solanum lycopersicum/fisiología , Plantas Modificadas Genéticamente/genética , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Reguladores del Crecimiento de las Plantas/metabolismo , Regulación de la Expresión Génica de las Plantas , Histona Demetilasas/metabolismo , Histona Demetilasas/genéticaRESUMEN
BACKGROUND: Identifying new targets in triple negative breast cancer (TNBC) remains critical. REG3A (regenerating islet-derived protein 3 A), a calcium-dependent lectin protein, was thoroughly investigated for its expression and functions in breast cancer. METHODS: Bioinformatics and local tissue analyses were employed to identify REG3A expression in breast cancer. Genetic techniques were employed to modify REG3A expression, and the resulting effects on the behaviors of breast cancer cells were examined. Subcutaneous xenograft models were established to investigate the involvement of REG3A in the in vivo growth of breast cancer cells. RESULTS: Analysis of the TCGA database uncovered increased REG3A levels in human breast cancer tissues. Additionally, REG3A mRNA and protein levels were elevated in TNBC tissues of locally treated patients, contrasting with low expression in adjacent normal tissues. In primary human TNBC cells REG3A shRNA notably hindered cell proliferation, migration, and invasion while triggering caspase-mediated apoptosis. Similarly, employing CRISPR-sgRNA for REG3A knockout showed significant anti-TNBC cell activity. Conversely, REG3A overexpression bolstered cell proliferation and migration. REG3A proved crucial for activating the Akt-mTOR cascade, as evidenced by decreased Akt-S6K1 phosphorylation upon REG3A silencing or knockout, which was reversed by REG3A overexpression. A constitutively active mutant S473D Akt1 (caAkt1) restored Akt-mTOR activation and counteracted the proliferation inhibition and apoptosis induced by REG3A knockdown in breast cancer cells. Crucially, REG3A played a key role in maintaining mTOR complex integrity. Bioinformatics identified zinc finger protein 680 (ZNF680) as a potential REG3A transcription factor. Knocking down or knocking out ZNF680 reduced REG3A expression, while its overexpression increased it in primary breast cancer cells. Additionally, enhanced binding between ZNF680 protein and the REG3A promoter was observed in breast cancer tissues and cells. In vivo, REG3A shRNA significantly inhibited primary TNBC cell xenograft growth. In REG3A-silenced xenograft tissues, reduced REG3A levels, Akt-mTOR inhibition, and activated apoptosis were evident. CONCLUSION: ZNF680-caused REG3A overexpression drives tumorigenesis in breast cancer possibly by stimulating Akt-mTOR activation, emerging as a promising and innovative cancer target.
Asunto(s)
Apoptosis , Movimiento Celular , Proliferación Celular , Regulación Neoplásica de la Expresión Génica , Proteínas Asociadas a Pancreatitis , Proteínas Proto-Oncogénicas c-akt , Neoplasias de la Mama Triple Negativas , Humanos , Neoplasias de la Mama Triple Negativas/genética , Neoplasias de la Mama Triple Negativas/metabolismo , Neoplasias de la Mama Triple Negativas/patología , Femenino , Proteínas Asociadas a Pancreatitis/metabolismo , Proteínas Asociadas a Pancreatitis/genética , Animales , Ratones , Línea Celular Tumoral , Apoptosis/genética , Movimiento Celular/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Carcinogénesis/genética , Transducción de Señal , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Esophageal squamous cell carcinoma (ESCC) is a deadly malignancy with notable metabolic reprogramming, yet the pivotal metabolic feature driving ESCC progression remains elusive. Here, we show that methionine cycle exhibits robust activation in ESCC and is reversely associated with patient survival. ESCC cells readily harness exogenous methionine to generate S-adenosyl-methionine (SAM), thus promoting cell proliferation. Mechanistically, methionine augments METTL3-mediated RNA m6A methylation through SAM and revises gene expression. Integrative omics analysis highlights the potent influence of methionine/SAM on NR4A2 expression in a tumor-specific manner, mediated by the IGF2BP2-dependent stabilization of methylated NR4A2 mRNA. We demonstrate that NR4A2 facilitates ESCC growth and negatively impacts patient survival. We further identify celecoxib as an effective inhibitor of NR4A2, offering promise as a new anti-ESCC agent. In summary, our findings underscore the active methionine cycle as a critical metabolic characteristic in ESCC, and pinpoint NR4A2 as a novel methionine-responsive oncogene, thereby presenting a compelling target potentially superior to methionine restriction.
Asunto(s)
Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Metionina , Miembro 2 del Grupo A de la Subfamilia 4 de Receptores Nucleares , Animales , Humanos , Ratones , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/patología , Neoplasias Esofágicas/genética , Carcinoma de Células Escamosas de Esófago/metabolismo , Carcinoma de Células Escamosas de Esófago/patología , Carcinoma de Células Escamosas de Esófago/genética , Regulación Neoplásica de la Expresión Génica , Metionina/metabolismo , Ratones Desnudos , Miembro 2 del Grupo A de la Subfamilia 4 de Receptores Nucleares/metabolismo , Miembro 2 del Grupo A de la Subfamilia 4 de Receptores Nucleares/genética , OncogenesRESUMEN
SET domain bifurcated 1 (SETDB1), a pivotal histone lysine methyltransferase, is transported to the cytoplasm via a chromosome region maintenance 1 (CMR1)dependent pathway, contributing to nonhistone methylation. However, the function and underlying mechanism of cytoplasmic SETDB1 in breast cancer remain elusive. In the present study, immunohistochemistry revealed that elevated cytoplasmic SETDB1 was correlated with lymph node metastasis and more aggressive breast cancer subtypes. Functionally, wound healing and Transwell assays showed that cytoplasmic SETDB1 is key for cell migration and invasion, as well as induction of epithelialmesenchymal transition (EMT), which was reversed by leptomycin B (LMB, a CMR1 inhibitor) treatment. Furthermore, RNAseq and metabolite detection revealed that cytoplasmic SETDB1 was associated with metabolism pathway and elevated levels of metabolites involved in the Warburg effect, including glucose, pyruvate, lactate and ATP. Immunoblotting and reverse transcriptionquantitative PCR verified that elevation of cytoplasmic SETDB1 contributed to elevation of cMYC expression and subsequent upregulation of lactate dehydrogenase A (LDHA) expression. Notably, gain and lossoffunction approaches revealed that LDHA overexpression in T47D cells enhanced migration and invasion by inducing EMT, while its depletion in SETDB1overexpressing MCF7 cells reversed SETDB1induced migration and invasion, as well as the Warburg effect and EMT. In conclusion, subcellular localization of cytoplasmic SETDB1 may be a pivotal factor in breast cancer progression. The present study offers valuable insight into the novel functions and mechanisms of cytoplasmic SETDB1.
Asunto(s)
Neoplasias de la Mama , Dominios PR-SET , Femenino , Humanos , Neoplasias de la Mama/patología , Línea Celular Tumoral , Movimiento Celular/genética , Citoplasma/metabolismo , Regulación Neoplásica de la Expresión Génica , N-Metiltransferasa de Histona-Lisina/genética , N-Metiltransferasa de Histona-Lisina/metabolismo , Lactato Deshidrogenasa 5/genética , Lactato Deshidrogenasa 5/metabolismoRESUMEN
Recent studies have demonstrated the crucial role of Cytochrome P450 enzymes (CYPs) in the production of secondary metabolites, phytohormones and antioxidants in plants. However, their functional characterization specifically under alkaline stress remains elusive. CYP82C4 was the key gene screened from a family of wild soybean CYPs in our previous studies. The aim of this present study was to clone the Glycine soja GsCYP82C4 gene and characterize its functions in Arabidopsis and Glycine max. The results showed that the GsCYP82C4 gene displayed a high expression in different plant tissues at mature stages compared to young stages. Further, higher temporal expression of the GsCYP82C4 gene was noted at 6, 12 and 24 h time points after alkali treatment in leaves compared to roots. In addition, overexpression of GsCYP82C4 improved alkaline stress tolerance in Arabidopsis via increased root lengths and fresh biomass and strengthened the antioxidant defense system via a reduction in superoxide radicals in transgenic lines compared to wild type (WT) and atcyp82c4 mutants. Further, the expression levels of stress-related marker genes were up-regulated in GsCYP82C4 OX lines under alkali stress. The functional analysis of GsCYP82C4 overexpression in soybean displayed better hairy root growth, increased fresh weight, higher antioxidant enzyme activities and reduced lipid peroxidation rates in OX lines compared to the soybean WT (K599) line. In total, our study displayed positive roles of GsCYP82C4 overexpression in both Arabidopsis and Glycine max to alleviate alkaline stress via altering expression abundance of stress responsive genes, stronger roots, higher antioxidant enzyme activities as well as reduced rates of lipid peroxidation and superoxide radicals.
Asunto(s)
Arabidopsis , Fabaceae , Especies Reactivas de Oxígeno/metabolismo , Antioxidantes/metabolismo , Superóxidos/metabolismo , Arabidopsis/genética , Arabidopsis/metabolismo , Fabaceae/genética , Glycine max/genética , Álcalis/metabolismo , Glicina/metabolismo , Plantas Modificadas Genéticamente/genética , Regulación de la Expresión Génica de las Plantas , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Estrés Fisiológico/genéticaRESUMEN
Cytochrome P450s are a large family of protein-encoding genes in plant genomes, many of which have not yet been comprehensively characterized. Here, a novel P450 gene, CYP82D47, was isolated and functionally characterized from cucumber (Cucumis sativus L.). Quantitative real-time reverse-transcription polymerase chain reaction analysis revealed that CYP82D47 expression was triggered by salicylic acid (SA) and ethephon (ETH). Expression analysis revealed a correlation between CYP82D47 transcript levels and plant defense responses against powdery mildew (PM) and Fusarium oxysporum f. sp. cucumerinum (Foc). Although no significant differences were observed in disease resistance between CYP82D47-RNAi and wild-type cucumber, overexpression (OE) of CYP82D47 enhanced PM and Foc resistance in cucumber. Furthermore, the expression levels of SA-related genes (PR1, PR2, PR4, and PR5) increased in CYP82D47-overexpressing plants 7 days post fungal inoculation. The levels of ETH-related genes (EIN3 and EBF2) were similarly upregulated. The observed enhanced resistance was associated with the upregulation of SA/ETH-signaling-dependent defense genes. These findings indicate the crucial role of CYP82D47 in pathogen defense in cucumber. CYP82D47-overexpressing cucumber plants exhibited heightened susceptibility to both diseases. The study results offer important insights that could aid in the development of disease-resistant cucumber cultivars and elucidate the molecular mechanisms associated with the functions of CYP82D47.
Asunto(s)
Cucumis sativus , Fusarium , Compuestos Organofosforados , Cucumis sativus/genética , Regulación hacia Arriba , Resistencia a la Enfermedad/genética , Ácido Salicílico/farmacologíaRESUMEN
BACKGROUND: Cervical cancer (CC) is a serious global disease with poor prognoses and a significant recurrence rate in patients with advanced disease. Oxidative stress (OS) greatly influences many types of human cancers, making it crucial to understand the functional mechanisms of OS-related genes in CC. METHODS: The transcriptome and clinical data of three normal samples and 306 patients with CC were obtained from The Cancer Genome Atlas dataset. The GSE44001 dataset was acquired from the Gene Expression Omnibus database. OS-related subtypes in the cohort with CC were identified using unsupervised hierarchical clustering, univariate Cox analysis, gene set enrichment analysis (GSEA), and least absolute shrinkage and selection operator regression analysis. Additionally, molecular pathways that differ across subtypes were determined and OS-related genes linked to the prognosis of patients of CC were determined. Finally, a clinical prognostic gene signature was developed and validated. The relative infiltration level of immune cell subpopulations in different risk groups and subtypes was evaluated using the cell-type identification by estimating relative subsets of RNA transcripts (CIBERPORT) algorithm and single-sample GSEA (ssGSEA) techniques. RESULTS: The present study established two distinct OS subtypes (OS clusters A and B). Analysis using ssGSEA and CIBERSPORT revealed that OS cluster B exhibited a significant level of immune infiltration. A clinical prognostic gene signature was established using OS-related characteristic genes identified by examining the differentially expressed genes across both subtypes. Furthermore, patients with CC were grouped into high- and low-risk groups, with the low-risk group showing higher survival rates. Additionally, these individuals exhibited significant advantages in terms of survival and immunotherapy. Receiver operating characteristic curve analysis demonstrated the higher predictive value of the clinical prognostic gene signature. The outcomes of the validation group depicted congruence with those recorded in the training group. CONCLUSIONS: A new model was constructed based on eight OS-related characteristic genes to aid the prediction of the survival rates of individuals with CC. The present study contributes to the existing literature on the mechanisms of OS genes in CC and offers a fresh perspective for future advancements in immunotherapy for such individuals.
Asunto(s)
Neoplasias del Cuello Uterino , Humanos , Femenino , Neoplasias del Cuello Uterino/genética , Neoplasias del Cuello Uterino/terapia , Estrés Oxidativo/genética , Algoritmos , Análisis por Conglomerados , InmunoterapiaRESUMEN
Among abiotic stresses, plants are the most vulnerable to salt and drought stresses. These stresses affect plant growth and development. Glycosyltransferases are involved in the responses of plants to abiotic stresses. In this study, a UDP-glycosyltransferase gene (SlUGT73C1) from Solanum lycopersicum was isolated and identified, which exhibited induction under salt or drought stress. The full length of SlUGT73C1 was 1485 bp, encoding 494 amino acids. Stress-related cis-acting elements were present in the promoter sequence of SlUGT73C1, such as ARE, LTR, and GC motifs. Compared with the wild-type plants, Arabidopsis thaliana overexpressing SlUGT73C1 exhibited increased seed germination rate and SOD and POD activities, decreased MDA content, and increased expression levels of osmotic stress regulators genes, rate-limiting enzymes genes in the proline synthesis pathway, Na+/K+ reverse transporter genes, and rate-limiting genes in the ABA biosynthesis pathway under salt or drought stress. These results indicated that SlUGT73C1 plays an important role in regulating salt and drought tolerance in plants.
Asunto(s)
Arabidopsis , Solanum lycopersicum , Arabidopsis/genética , Arabidopsis/metabolismo , Solanum lycopersicum/genética , Resistencia a la Sequía , Ácido Abscísico/metabolismo , Plantas Modificadas Genéticamente/genética , Cloruro de Sodio/farmacología , Sequías , Glicosiltransferasas/genética , Glicosiltransferasas/metabolismo , Uridina Difosfato , Regulación de la Expresión Génica de las Plantas , Estrés Fisiológico/genética , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismoRESUMEN
Plaque accumulation and microbial community changes are important causes of periodontal disease. Cleaned plaque microorganisms will reattach to form biofilms, but the recovery and outcome of plaque microbial communities in different periodontal health states remain unknown. In this study, we tracked the biofilm remodeling process in 206 dental plaque samples from 40 healthy periodontal, gingivitis and periodontitis volunteers at 6 time points before and after supragingival scaling. We found that microbial communities of different periodontal states changed asynchronously during the process, and the more severe the periodontal disease condition, the more lagged the recovery of plaque microorganisms to their original state after cleaning; this reflected a higher degree of plaque development in periodontitis samples. The plaque index and bleeding index were significantly correlated with plaque recovery, especially the recovery of bacteria such as Abiotrophia and Capnocytophaga. Meanwhile, we found that the microbial community structure of different periodontal health states was most similar at the Day 3 after plaque cleaning, and the communities gradually differentiated and developed in different directions. Abiotrophia and other bacteria might play an important role in determining the development trend of plaque biofilms. The discovery of specific time points and bacteria was of great value in clarifying the pathogenesis of periodontal disease and in seeking targets for prevention and treatment.
Asunto(s)
Gingivitis , Enfermedades Periodontales , Periodontitis , Humanos , Periodontitis/microbiología , Gingivitis/microbiología , Bacterias/genéticaRESUMEN
Diffuse large B-cell lymphoma is the most common subtype of lymphoma, representing â¼25 % of non-Hodgkin lymphoid malignancies. EZH2 is highly expressed in Diffuse large B-cell lymphoma and â¼22 % of patients contain EZH2 mutations. EZH2 have been studied as a potential therapeutic target for a decade, but efficient inhibition of EZH2 did not robustly kill lymphoma cells. Here, we found that EZH2 mediates repression of oncogenic genes STAT3 and USP7 in Diffuse large B-cell lymphoma cells. Inhibition of EZH2 leads to upregulation of STAT3 and USP7 at both RNA and protein levels. Along with USP7 upregulation, MDM2 is upregulated and its ubiquitylation substrate, Tumor suppressor P53, is downregulated. Upregulation of STAT3 and downregulation of p53 can strength cell proliferation and prevent cells from apoptosis, which suggests resistance mechanisms by which cells survive EZH2 inhibition-induced cell death. Short-course co-inhibition of USP7 and EZH2 showed increased apoptosis and cell proliferation prevention with the concentration as low as 0.08 µM. In STAT3 and USP7 depleted cells, EZH2 inhibition shows superior efficacy of apoptosis, and in EZH2 depleted cells, USP7 inhibition also shows superior efficacy of apoptosis. Thus, our findings suggest a new precision therapy by combinational inhibition of EZH2 with STAT3 or USP7 for Diffuse large B-cell lymphoma.
RESUMEN
CDK4/6 are important regulators of cell cycle and their inhibitors have been approved as anti-cancer drugs. Here, we report a STING-dependent anti-tumor immune mechanism responsible for tumor suppression by CDK4/6 blockade. Clinical datasets show that in human tissues, CDK4 and CDK6 are over-expressed and their expressions are negatively correlated with patients' overall survival and T cell infiltration. Deletion of Cdk4 or Cdk6 in tumor cells significantly reduce tumor growth. Mechanistically, we find that Cdk4 or Cdk6 deficiency contributes to an increased level of endogenous DNA damage, which triggers the cGAS-STING signaling pathway to activate type I interferon response. Knockout of Sting is sufficient to reverse and partially reverse the anti-tumor effect of Cdk4 and Cdk6 deficiency respectively. Therefore, our findings suggest that CDK4/6 inhibitors may enhance anti-tumor immunity through the STING-dependent type I interferon response.
Asunto(s)
Quinasa 4 Dependiente de la Ciclina , Quinasa 6 Dependiente de la Ciclina , Interferón Tipo I , Neoplasias , Humanos , Quinasa 4 Dependiente de la Ciclina/genética , Quinasa 4 Dependiente de la Ciclina/metabolismo , Quinasa 6 Dependiente de la Ciclina/genética , Quinasa 6 Dependiente de la Ciclina/metabolismo , Inmunidad , Interferón Tipo I/farmacología , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Nucleotidiltransferasas/genética , Nucleotidiltransferasas/metabolismo , Transducción de SeñalRESUMEN
[This corrects the article DOI: 10.3389/fmicb.2023.1196700.].
RESUMEN
SOS2-like protein kinases (PKS/CIPK) family genes are known to be involved in various abiotic stresses in plants. Even though, its functions have been well characterized under salt and drought stresses. The roles of PKS genes associated with alkaline stress response are not fully established yet. In this study, we identified 56 PKS family genes which could be mainly classified into three groups in wild soybean (Glycine soja). PKS family genes transcript profiles revealed different expression patterns under alkali stress. Furthermore, we confirmed the regulatory roles of GsPKS24 in response to NaHCO3, pH and ABA treatments. Overexpression of GsPKS24 enhanced plant tolerance to pH stress in Arabidopsis and soybean hairy roots but conferred suppressed pH tolerance in Arabidopsis atpks mutant. Additionally, Overexpression of GsPKS24 decreased the ABA sensitivity compared to Arabidopsis atpks mutant which displayed more sensitivity towards ABA. Moreover, upregulated expression of stress responsive and ABA signal-related genes were detected in GsPKS24 overexpression lines. In conclusion, we identified the wild soybean PKS family genes, and explored the roles of GsPKS24 in positive response to pH stress tolerance, and in alleviation of ABA sensitivity.
Asunto(s)
Arabidopsis , Fabaceae , Arabidopsis/genética , Calcineurina , Transducción de Señal , Glicina , Concentración de Iones de HidrógenoRESUMEN
Bartonellae are considered to be emerging opportunistic pathogens. The bacteria are transmitted by blood-sucking arthropods, and their hosts are a wide range of mammals including humans. After a protective barrier breach in mammals, Bartonella colonizes endothelial cells (ECs), enters the bloodstream, and infects erythrocytes. Current research primarily focuses on investigating the interaction between Bartonella and ECs and erythrocytes, with recent attention also paid to immune-related aspects. Various molecules related to Bartonella's pathogenicity have been identified. The present review aims to provide a comprehensive overview of the newly described molecular and immune responses associated with Bartonella's pathogenicity.
RESUMEN
Strigolactone (SL) is a new plant hormone, which not only plays an important role in stimulating seed germination, plant branching, and regulating root development, but also plays an important role in the response of plants to abiotic stresses. In this study, the full-length cDNA of a soybean SL signal transduction gene (GmMAX2a) was isolated, cloned and revealed an important role in abiotic stress responses. Tissue-specific expression analysis by qRT-PCR indicated that GmMAX2a was expressed in all tissues of soybean, but highest expression was detected in seedling stems. Moreover, upregulation of GmMAX2a transcript expression under salt, alkali, and drought conditions were noted at different time points in soybean leaves compared to roots. Additionally, histochemical GUS staining studies revealed the deep staining in PGmMAX2a: GUS transgenic lines compared to WT indicating active involvement of GmMAX2a promoter region to stress responses. To further investigate the function of GmMAX2a gene in transgenic Arabidopsis, Petri-plate experiments were performed and GmMAX2a OX lines appeared with longer roots and improved fresh biomass compared to WT plants to NaCl, NaHCO3, and mannitol supplementation. Furthermore, the expression of several stress-related genes such as RD29B, SOS1, NXH1, AtRD22, KIN1, COR15A, RD29A, COR47, H+-APase, NADP-ME, NCED3, and P5CS were significantly high in GmMAX2a OX plants after stress treatment compared to WT plants. In conclusion, GmMAX2a improves soybean tolerance towards abiotic stresses (salt, alkali, and drought). Hence, GmMAX2a can be considered a candidate gene for transgenic breeding against various abiotic stresses in plants.