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Background: Breast cancer (BC) has the highest incidence rate among female malignant tumors. Adjuvant chemotherapy is commonly used to reduce micrometastasis in postoperative patients. However, monitoring the efficacy of chemotherapy in BC is a major challenge in clinical practice. In this study, 1H nuclear magnetic resonance (NMR) metabonomics was performed to explore the serum metabolic characteristics of BC patients before and after adjuvant chemotherapy. Methods: In this study, we collected serum samples from 51 healthy controls and 61 BC patients before and after chemotherapy for 1H NMR metabolomic analysis, and tested the performance of each metabolite and combination segment by the receiver operating characteristic (ROC) curves. Results: Nine metabolites, namely glutamine, citrate, creatine, glycerophosphatidylcholine/phosphatidylcholine, glycine, 1-methylhistidine, lactate, pyruvate and formate had significant changes in BC patients before chemotherapy compared with healthy controls. Lactate, pyruvate, 1-methylhistidine and formate were found to be inversely regulated by chemotherapy. ROC analysis showed that a combination of the four metabolites had good prediction for chemotherapy efficacy with area under the curve of 0.958, sensitivity of 98.36% and specificity of 91.30%. There was no significant correlation between chemotherapy-related metabolites and clinical indicators of cancer patients, indicating that they can be used to evaluate the chemotherapy efficacy of patients with different clinical indicators. Conclusions: Effectively, dynamic and non-invasive metabolic markers for the evaluation of the efficacy of chemotherapy were identified in this study.
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Solanum pinnatisectum exhibits strong resistance to late blight caused by Phytophthora infestans but only an incomplete genome assembly based on short Illumina reads has been published. In this study, we generated the first chromosome-level draft genome for the wild-type potato species S. pinnatisectum in China using Oxford Nanopore technology sequencing and Hi-C technology. The high-quality assembled genome size is 664 Mb with a scaffold N50 value of 49.17 Mb, of which 65.87% was occupied by repetitive sequences, and predominant long terminal repeats (42.51% of the entire genome). The genome of S. pinnatisectum was predicted to contain 34,245 genes, of which 99.34% were functionally annotated. Moreover, 303 NBS-coding disease resistance (R) genes were predicted in the S. pinnatisectum genome to investigate the potential mechanisms of resistance to late blight disease. The high-quality chromosome-level reference genome of S. pinnatisectum is expected to provide potential valuable resources for intensively and effectively investigating molecular breeding and genetic research in the future.
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OBJECTIVES: To compare the clinical effect of fast needling (without needle retaining), needle retaining acupuncture combined with occupational therapy and simple occupational therapy for hand dysfunction of spastic cerebral palsy in children. METHODS: A total of 75 children with spastic cerebral palsy were randomly divided into an occupational therapy group (25 cases), a fast needling group (25 cases, 1 case dropped out) and a needle retaining group (25 cases, 1 case dropped out). The patients in the occupational therapy group were only treated with occupational therapy for 20 min each time. The patients in the fast needling group were treated with acupuncture (without needle retaining) combined with occupational therapy, and the needle retaining group was treated with acupuncture (needle retaining) combined with occupational therapy, and acupuncture was taken at Hegu (LI 4), Houxi (SI 3), Yuji (LU 10), Waiguan (SJ 5), Jianyu (LI 15) and so on. The needles were retained for 30 min in patients of the needle retaining group. All the above treatments were performed once a day, 5 times a week for 12 weeks. The scores of fine motor function measure (FMFM) and Peabody developmental motor scale 2 (PDMS-2) were observed in patients of the three groups before and after treatment, and the safety of the fast needling group and the needle retaining group was compared. RESULTS: After treatment, the scores of FMFM and PDMS-2 in patients of the three groups were higher than those before treatment (P<0.01), and the scores of FMFM and PDMS-2 in the fast needling group and the needle retaining group were higher than those in the occupational therapy group (P<0.05, P<0.01). The incidence of acupuncture abnormalities in the fast needling group was 0.3% (5/1 440), which was lower than 1.4% (20/1 440) in the needle retaining group (P<0.05). CONCLUSIONS: Acupuncture combined with occupational therapy has better clinical effect than occupational therapy alone in improving hand dysfunction in children with spastic cerebral palsy, and there is no statistical difference in effect between fast needling acupuncture and needle retaining acupuncture, but fast needling has better safety than needle retaining acupuncture.
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Terapia por Acupuntura , Paralisia Cerebral , Terapia Ocupacional , Criança , Humanos , Paralisia Cerebral/terapia , Indução Percutânea de Colágeno , Extremidade Superior , Mãos , Resultado do Tratamento , Pontos de AcupunturaRESUMO
BACKGROUND: Allogeneic hepatocyte transplantation is an emerging approach to treat acute liver defects. However, durable engraftment of the transplanted cells remains a daunting task, as they are actively cleared by the recipient's immune system. Therefore, a detailed understanding of the innate or adaptive immune cells-derived responses against allogeneic transplanted hepatic cells is the key to rationalize cell-based therapies. METHODS: Here, we induced an acute inflammatory regenerative niche (3-96 h) on the surface of the liver by the application of cryo-injury (CI) to systematically evaluate the innate immune response against transplanted allogeneic hepatic progenitors in a sustained micro-inflammatory environment. RESULTS: The resulting data highlighted that the injured site was significantly repopulated by alternating numbers of innate immune cells, including neutrophils, monocytes and Kupffer cells (KCs), from 3 to 96 h. The transplanted allo-HPs, engrafted 6 h post-injury, were collectively eliminated by the innate immune response within 24 h of transplantation. Selective depletion of the KCs demonstrated a delayed recruitment of monocytes from day 2 to day 6. In addition, the intrasplenic engraftment of the hepatic progenitors 54 h post-transplantation was dismantled by KCs, while a time-dependent better survival and translocation of the transplanted cells into the injured site could be observed in samples devoid of KCs. CONCLUSION: Overall, this study provides evidence that KCs ablation enables a better survival and integration of allo-HPs in a sustained liver inflammatory environment, having implications for rationalizing the cell-based therapeutic interventions against liver defects.
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Transplante de Células-Tronco Hematopoéticas , Células de Kupffer , Células de Kupffer/fisiologia , Fígado , Hepatócitos/transplante , Regeneração Hepática/fisiologiaRESUMO
OBJECTIVE: To perform a systematic review of risk prediction models for cardiovascular (CV) events in hemodialysis (HD) patients, and provide a reference for the application and optimization of related prediction models. METHODS: PubMed, The Cochrane Library, Web of Science, and Embase databases were searched from inception to 1 February 2023. Two authors independently conducted the literature search, selection, and screening. The Prediction model Risk Of Bias Assessment Tool (PROBAST) was applied to evaluate the risk of bias and applicability of the included literature. RESULTS: A total of nine studies containing 12 models were included, with performance measured by the area under the receiver operating characteristic curve (AUC) lying between 0.70 and 0.88. Age, diabetes mellitus (DM), C-reactive protein (CRP), and albumin (ALB) were the most commonly identified predictors of CV events in HD patients. While the included models demonstrated good applicability, there were still certain risks of bias, primarily related to inadequate handling of missing data and transformation of continuous variables, as well as a lack of model performance validation. CONCLUSION: The included models showed good overall predictive performance and can assist healthcare professionals in the early identification of high-risk individuals for CV events in HD patients. In the future, the modeling methods should be improved, or the existing models should undergo external validation to provide better guidance for clinical practice.
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Doenças Cardiovasculares , Diálise Renal , Humanos , Prognóstico , Diálise Renal/efeitos adversos , Medição de Risco , Proteína C-Reativa , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etiologiaRESUMO
The DNA damage response (DDR) is essential for the maintenance of genomic stability. Protein posttranslational modifications play pivotal roles in regulating the DDR process. Here, we found that SUMOylated RNF168 undergoes liquid-liquid phase separation (LLPS), which restricts the recruitment of RNF168 to DNA damage sites, reduces RNF168-catalyzed H2A ubiquitination, restrains 53BP1 in nuclear condensates, and ultimately impairs nonhomologous DNA end joining repair efficiency. Sentrin/SUMO-specific protease 1 (SENP1) was identified as a specific deSUMOylase of RNF168, and it was highly expressed in colorectal adenocarcinoma. In response to DNA damage, SENP1 decreased RNF168 SUMOylation and prevented RNF168 from forming nuclear condensates, thus promoting damage repair efficiency and cancer cell resistance to DNA damaging agents. Moreover, high SENP1 expression correlated with poor prognosis in patients with cancer, and SENP1 depletion sensitized cancer cells to chemotherapy. In summary, these findings reveal DDR is suppressed by SUMOylation-induced LLPS of RNF168 and suggest that SENP1 is a potential target for cancer therapy. SIGNIFICANCE: Sentrin/SUMO-specific protease 1 decreases RNF168 SUMOylation and liquid-liquid phase separation to promote DNA damage repair, safeguarding genomic integrity and driving chemotherapy resistance.
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Neoplasias do Colo , Ubiquitina-Proteína Ligases , Humanos , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , Peptídeo Hidrolases/metabolismo , Reparo do DNA , Ubiquitinação , Dano ao DNA , Endopeptidases , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/genética , Resistência a Medicamentos , Proteínas Modificadoras Pequenas Relacionadas à Ubiquitina/metabolismo , Cisteína Endopeptidases/genética , Cisteína Endopeptidases/metabolismoRESUMO
Acidithiobacillus ferrooxidans serves as a model chemolithoautotrophic organism in extremely acidic environments, which has attracted much attention due to its unique metabolism and strong adaptability. However, little was known about the divergences along the evolutionary process based on whole genomes. Herein, we isolated six strains of A. ferrooxidans from mining areas in China and Zambia, and used comparative genomics to investigate the intra-species divergences. The results indicated that A. ferrooxidans diverged into three groups from a common ancestor, and the pan-genome is 'open'. The ancestral reconstruction of A. ferrooxidans indicated that genome sizes experienced a trend of increase in the very earliest days before a decreasing tendency during the evolutionary process, suggesting that both gene gain and gene loss played crucial roles in A. ferrooxidans genome flexibility. Meanwhile, 23 single-copy orthologous groups (OGs) were under positive selection. The differences of rusticyanin (Rus) sequences (the key protein in the iron oxidation pathway) and type IV secretion system (T4SS) composition in the A. ferrooxidans were both related to their group divergences, which contributed to their intraspecific diversity. This study improved our understanding of the divergent evolution and environmental adaptation of A. ferrooxidans at the genome level in extreme conditions, which provided theoretical support for the survival mechanism of living creatures at the extreme.
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Acidithiobacillus , Acidithiobacillus/genética , Acidithiobacillus/metabolismo , Genômica/métodos , Ferro/metabolismo , Adaptação Fisiológica/genéticaRESUMO
BACKGROUND: The genus Acidithiobacillus has been widely concerned due to its superior survival and oxidation ability in acid mine drainage (AMD). However, the contribution of insertion sequence (IS) to their biological evolution and environmental adaptation is very limited. ISs are the simplest kinds of mobile genetic elements (MGEs), capable of interrupting genes, operons, or regulating the expression of genes through transposition activity. ISs could be classified into different families with their own members, possessing different copies. RESULTS: In this study, the distribution and evolution of ISs, as well as the functions of the genes around ISs in 36 Acidithiobacillus genomes, were analyzed. The results showed that 248 members belonging to 23 IS families with a total of 10,652 copies were identified within the target genomes. The IS families and copy numbers among each species were significantly different, indicating that the IS distribution of Acidithiobacillus were not even. A. ferrooxidans had 166 IS members, which may develop more gene transposition strategies compared with other Acidithiobacillus spp. What's more, A. thiooxidans harbored the most IS copies, suggesting that their ISs were the most active and more likely to transpose. The ISs clustered in the phylogenetic tree approximately according to the family, which were mostly different from the evolutionary trends of their host genomes. Thus, it was suggested that the recent activity of ISs of Acidithiobacillus was not only determined by their genetic characteristics, but related with the environmental pressure. In addition, many ISs especially Tn3 and IS110 families were inserted around the regions whose functions were As/Hg/Cu/Co/Zn/Cd translocation and sulfur oxidation, implying that ISs could improve the adaptive capacities of Acidithiobacillus to the extremely acidic environment by enhancing their resistance to heavy metals and utilization of sulfur. CONCLUSIONS: This study provided the genomic evidence for the contribution of IS to evolution and adaptation of Acidithiobacillus, opening novel sights into the genome plasticity of those acidophiles.
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Acidithiobacillus , Metais Pesados , Humanos , Elementos de DNA Transponíveis/genética , Filogenia , Enxofre/metabolismoRESUMO
Cellular senescence is a major process affected by multiple signals and coordinated by a complex signal response network. Identification of novel regulators of cellular senescence and elucidation of their molecular mechanisms will aid in the discovery of new treatment strategies for aging-related diseases. In the present study, we identified human coilin-interacting nuclear ATPase protein (hCINAP) as a negative regulator of aging. Depletion of cCINAP significantly shortened the lifespan of Caenorhabditis elegans and accelerated primary cell aging. Moreover, mCINAP deletion markedly promoted organismal aging and stimulated senescence-associated secretory phenotype in the skeletal muscle and liver from mouse models of radiation-induced senescence. Mechanistically, hCINAP functions through regulating MDM2 status by distinct mechanisms. On the one hand, hCINAP decreases p53 stability by attenuating the interaction between p14ARF and MDM2; on the other hand, hCINAP promotes MDM2 transcription via inhibiting the deacetylation of H3K9ac in the MDM2 promoter by hindering the HDAC1/CoREST complex integrity. Collectively, our data demonstrate that hCINAP is a negative regulator of aging and provide insight into the molecular mechanisms underlying the aging process.
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Adenosina Trifosfatases , Proteína Supressora de Tumor p14ARF , Camundongos , Animais , Humanos , Proteína Supressora de Tumor p14ARF/metabolismo , Adenosina Trifosfatases/metabolismo , Núcleo Celular/metabolismo , Envelhecimento , Senescência Celular , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Histona Desacetilase 1/metabolismoRESUMO
Nonalcoholic fatty liver disease (NAFLD) is prevalent worldwide; about 25% of NAFLD silently progress into steatohepatitis, in which some of them may develop into fibrosis, cirrhosis and liver failure. However, few drugs are available for NAFLD, partly because of an incomplete understanding of its pathogenic mechanisms. Here, using in vivo and in vitro gain- and loss-of-function approaches, we identified up-regulated DKK1 plays a pivotal role in high-fat diet-induced NAFLD and its progression. Mechanistic analysis reveals that DKK1 enhances the capacity of hepatocytes to uptake fatty acids through the ERK-PPARγ-CD36 axis. Moreover, DKK1 increased insulin resistance by activating the JNK signaling, which in turn exacerbates disorders of hepatic lipid metabolism. Our finding suggests that DKK1 may be a potential therapeutic and diagnosis candidate for NAFLD and metabolic disorder progression.
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Hepatopatia Gordurosa não Alcoólica , Humanos , Dieta Hiperlipídica , Hepatócitos , Peptídeos e Proteínas de Sinalização Intercelular , Metabolismo dos Lipídeos/genética , Cirrose Hepática , Hepatopatia Gordurosa não Alcoólica/genética , Antígenos CD36/metabolismoRESUMO
Introduction: Many studies have collected normative developmental EEG data to better understand brain function in early life and associated changes during both aging and pathology. Higher cognitive functions of the brain do not normally stem from the workings of a single brain region that works but, rather, on the interaction between different brain regions. In this regard studying the connectivity between brain regions is of great importance towards understanding higher cognitive functions and its underlying mechanisms. Methods: In this study, EEG data of children (N = 253; 3-10 years old; 113 females, 140 males) from pre-school to schoolage was collected, and the weighted phase delay index and directed transfer function method was used to find the electrophysiological indicators of both functional connectivity and effective connectivity. A general linear model was built between the indicators and age, and the change trend of electrophysiological indicators analyzed for age. Results: The results showed an age trend for the functional and effective connectivity of the brain of children. Discussion: The results are of importance in understanding normative brain development and in defining those conditions that deviate from typical growth trajectories.
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Atherosclerosis is the most common disease of the vascular system and the metabolic disorder is one of its important molecular mechanisms. SAP protein is found to be highly expressed in atherosclerotic blood vessels. Our previous study found that SAP deficiency can significantly inhibit the development of atherosclerosis. However, the regulatory effect of SAP deficiency on AS metabolism is unknown. Based on 1H-NMR metabonomics, this study investigated the serum metabolic changes in ApoE-/-;SAP-/- mice compared with ApoE-/- mice during the whole progression of atherosclerosis. The results showed that acetate, pyruvate, choline and VLDL + LDL were statistically regulated to the normal levels as in C57 mice by SAP deficiency in ApoE-/-;SAP-/- mice at 8 w (without obvious plaques). With the appearance and aggravation of atherosclerotic plaques (8 + 4 w and 8 + 8 w), the four metabolites of acetate, pyruvate, choline and VLDL + LDL were continuously regulated, which were denoted as the metabolic regulatory markers of SAP deficiency. We also found that the changes in these four metabolites had nothing to do with high-fat diet. Therefore, it was revealed that SAP deficiency regulated the metabolic disorders in ApoE-/- prior to the appearance of obvious atherosclerotic plaques, which is one of the important mechanisms leading to the inhibition of atherosclerosis, providing a new basis for the application of SAP in atherosclerosis.
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BACKGROUND: A short instrument would enhance the viability of a study. Therefore, we aimed to shorten the specific module (SPD-10) of the Quality of Life Instrument for Chronic Diseases - Chronic Renal Failure (QLICD-CRF) for assessing the quality of life of patients with chronic renal failure. METHODS: The 10-item SPD-10 was self-administered to 164 patients with chronic renal failure. A shortened form was first obtained by a tandem use of the classical test theory (CTT), the generalizability theory (GT), and the item response theory (IRT). In addition, we also shortened the SPD-10 by the Optimal Test Assembly (OTA). RESULTS: Both the tandem use of GT, CTT and IRT, and the OTA derived the same 7-item shortened version (SPD-7). It included items CRF1, CRF2, CRF3, CRF4, CRF6, CRF8, and CRF9 of the SPD-10. The SPD-7 had a Cronbach alpha of 0.78. The correlation coefficients of its total and factor scores with those of the SPD-10 were 0.96 and 0.98, respectively. Confirmatory factor analysis confirmed the unidimensional structure of the SPD-7, with the comparative fit index=0.96, the Tucker-Lewis index=0.94, and the root mean square error of approximation=0.09. CONCLUSION: The short-form SPD-7 is reliable and valid for assessing the impact of clinical symptoms and side effects on the quality of life of patients with chronic renal failure. It is an efficient option without compromising the measurement performance of the SPD-10.
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Falência Renal Crônica , Qualidade de Vida , Humanos , Psicometria , Inquéritos e Questionários , Reprodutibilidade dos Testes , Falência Renal Crônica/terapiaRESUMO
Thyroid cancer is the most common form of endocrine cancer around the world, and among which papillary thyroid carcinoma (PTC) is the most ubiquitous pathological sub-kind. Sushi repeat-containing protein X-linked 2 (SRPX2) was reported to be an independent prognostic factor and significantly overexpressed in advanced PTC patients. However, the biological functions of SRPX2 remain ambiguous in PTC. Here, we explored SRPX2 expression profiles and functions in PTC, finding that SRPX2 expression was remarkably upregulated in PTC tissues and cell lines. Further colony formation, CCK-8, as well as transwell assay, suggested that SRPX2 silencing remarkably dampened PTC growth and migration. Mouse xenograft models were established to find that SRPX2 silence remarkably suppressed PTC proliferation and migration in vivo. Following mechanism studies revealed that SRPX2 realized its functions in the PTC process partially through activating the Focal adhesion kinase (FAK) phosphorylation. In conclusion, this study investigated the functions and mechanisms of the SRPX2/FAK pathway in PTC progression. SRPX2 could act as a prospective biologic signature and therapeutic target molecule for PTC.
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Strategies to enhance the ratio of the molecular horizontal emitting dipole orientation (Θ⥠) for thermally activated delayed fluorescence (TADF) emitters have unlocked the full potential of efficiencies for the evaporated devices, which, however, remain elusive for the solution-processed ones. Here, a strategic molecular design for solution processable TADF emitters featuring high Θ⥠s is proposed by attaching flexible chains ended with bipolar 9,9'-spirobi[fluorene] subunits as anchoring groups onto TADF emitting core. It's unveiled that the anchoring groups not only enhance the horizontal orientation via enlarging molecular planarity, but also benefit the high photoluminescence in pristine films. The corresponding non-doped solution processable OLEDs substantiate an unprecedented maximum external quantum efficiency (EQEmax )>30 %. Meanwhile, combining these compounds as TADF sensitizers, and multiple resonance final emitter, solution-processed OLEDs achieve an EQEmax of 25.6 % with a narrow full width at half maximum of 29â nm.
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The exploitation of polymetallic deposits produces large amounts of mine drainage, which poses great challenges to the surrounding aquatic ecosystem. However, the prokaryotic microbial community assembly and co-existence patterns in the polluted area are poorly understood, especially in high-altitude localities. Herein, we investigated the prokaryotic microbial assembly, co-existence patterns and their potential functional responses in surrounding river sediments of a Cu-polymetallic deposit in Tibet. The sediments from mine drainage and surrounding tributaries exhibited distinct geochemical gradients, especially the changes in Cu content. The microbial community structure changed significantly, accompanied by decreased richness and diversity with increased Cu content. Interestingly, the relative abundances of some potential functional bacteria (e.g., Planctomycetota) actually increased as the Cu levels raised. In low contaminated area, ecological drift was the most important assembly process, whereas deterministic processes gained importance with pollution levels. Meanwhile, negative interactions in co-occurrence networks were more frequent with higher modularity and reduced keystone taxa in high contaminated area. Notably, the functions related to ABC transporters and quorum sensing (QS) were more abundant with high Cu content, which helped bacteria work together to cope with the stressful environment. Taken together, the physicochemical gradients dominated by Cu content drove the distribution, assembly and co-existence patterns of microbial communities in surrounding river sediments of a Cu-polymetallic deposit. These findings provide new insights into the maintenance mechanisms of prokaryotic microbial communities in response to heavy metal stress at high altitudes.
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Metais Pesados , Microbiota , Transportadores de Cassetes de Ligação de ATP , Bactérias , Sedimentos Geológicos/química , Metais Pesados/análise , Rios/química , TibetRESUMO
Multiple endocrine neoplasia type 1 (MEN1) is an inherited disease caused by mutations in the MEN1 gene encoding a nuclear protein menin. Among those different endocrine tumors of MEN1, the pancreatic neuroendocrine tumors (PNETs) are life-threatening and frequently implicated. Since there are uncertainties in genotype and phenotype relationship and there are species differences between humans and mice, it is worth it to replenish the mice model with human cell resources. Here, we tested whether the patient-origin induced pluripotent stem cell (iPSC) lines could phenocopy some defects of MEN1. In vitro ß-cell differentiation revealed that the percentage of insulin-positive cells and insulin secretion were increased by at least two-fold in MEN1-iPSC derived cells, which was mainly resulted from significantly higher proliferative activities in the pancreatic progenitor stage (Day 7-13). This scenario was paralleled with increased expressions of prohormone convertase1/3 (PC1/3), glucagon-like peptide-1 (GLP-1), GLP-1R, and factors in the phosphatidylinositol 3-kinase (PI3K)/AKT signal pathway, and the GLP-1R was mainly expressed in ß-like cells. Blockages of either GLP-1R or PI3K significantly reduced the percentages of insulin-positive cells and hypersecretion of insulin in MEN1-derived cells. Furthermore, in transplantation of different stages of MEN1-derived cells into immune-deficient mice, only those ß-like cells produced tumors that mimicked the features of the PNETs from the original patient. To the best of our knowledge, this was the first case using patient-origin iPSCs modeling most phenotypes of MEN1, and the results suggested that GLP-1R may be a potential therapeutic target for MEN1-related hyperinsulinemia.
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Células-Tronco Pluripotentes Induzidas , Neoplasia Endócrina Múltipla Tipo 1 , Tumores Neuroectodérmicos Primitivos , Animais , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Insulina/metabolismo , Insulina Regular Humana , Camundongos , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-OncogênicasRESUMO
The DNA damage response (DDR) is critical for maintaining cellular homeostasis and genome integrity. Mounting evidence has shown that posttranslational protein modifications play vital roles in the DDR. In this study, we showed that deubiquitinase OTUD6A is involved in the DDR and is important for maintaining genomic stability. Mechanistically, in response to DNA damage, the abundance of OTUD6A was increased; meanwhile, PP2A interacted with OTUD6A and dephosphorylated OTUD6A at sites S70/71/74, which promoted nuclear localization of OTUD6A. Subsequently, OTUD6A was recruited to the damage site, where it interacted with TopBP1 and blocked the interaction between TopBP1 and its ubiquitin E3 ligase UBR5, decreasing K48-linked polyubiquitination and increasing the stability of TopBP1. OTUD6A depletion impaired CHK1 S345 phosphorylation and blocked cell cycle progression under DNA replication stress. Consistently, knockout of OTUD6A rendered mice hypersensitive to irradiation, shortened survival, and inhibited tumor growth by regulating TopBP1 in xenografted nude mice. Moreover, OTUD6A is expressed at high levels in breast cancer, and OTUD6A overexpression promotes cell proliferation, migration and invasion, indicating that dysregulation of OTUD6A expression contributes to genomic instability and is associated with tumor development. In summary, this study demonstrates that OTUD6A plays a critical role in promoting tumor cell resistance to chemoradiotherapy by deubiquitinating and stabilizing TopBP1.
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Proteínas de Ligação a DNA , Enzimas Desubiquitinantes , Neoplasias , Animais , Camundongos , Proteínas de Transporte/metabolismo , Enzimas Desubiquitinantes/metabolismo , DNA , Dano ao DNA , Proteínas de Ligação a DNA/metabolismo , Instabilidade Genômica , Camundongos Nus , HumanosRESUMO
Acute promyelocytic leukemia (APL) is a hematological malignancy driven by the oncoprotein PML-RARα, which can be treated with arsenic trioxide (As2O3) or/and all-trans retinoic acid. The protein arginine methyltransferase 5 (PRMT5) is involved in tumorigenesis. However, little is known about the biological function and therapeutic potential of PRMT5 in APL. Here, we show that PRMT5 is highly expressed in APL patients. PRMT5 promotes APL by interacting with PML-RARα and suppressing its ubiquitination and degradation. Mechanistically, PRMT5 attenuates the interaction between PML-RARα and its ubiquitin E3 ligase RNF4 by methylating RNF4 at Arg164. Notably, As2O3 treatment triggers the dissociation of PRMT5 from PML nuclear bodies, attenuating RNF4 methylation and promoting RNF4-mediated PML-RARα ubiquitination and degradation. Moreover, knockdown of PRMT5 and pharmacological inhibition of PRMT5 with the specific inhibitor EPZ015666 significantly inhibit APL cells growth. The combination of EPZ015666 with As2O3 shows synergistic effects on As2O3-induced differentiation of bone marrow cells from APL mice, as well as on apoptosis and differentiation of primary APL cells from APL patients. These findings provide mechanistic insight into the function of PRMT5 in APL pathogenesis and demonstrate that inhibition of PRMT5, alone or in combination with As2O3, might be a promising therapeutic strategy against APL.
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Resistencia a Medicamentos Antineoplásicos , Leucemia Promielocítica Aguda , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Trióxido de Arsênio/farmacologia , Trióxido de Arsênio/uso terapêutico , Linhagem Celular Tumoral/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Resistencia a Medicamentos Antineoplásicos/fisiologia , Humanos , Isoquinolinas/farmacologia , Isoquinolinas/uso terapêutico , Leucemia Promielocítica Aguda/tratamento farmacológico , Leucemia Promielocítica Aguda/genética , Leucemia Promielocítica Aguda/metabolismo , Leucemia Promielocítica Aguda/patologia , Metilação , Camundongos , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Proteínas de Fusão Oncogênica/uso terapêutico , Proteína-Arginina N-Metiltransferases/antagonistas & inibidores , Proteína-Arginina N-Metiltransferases/genética , Proteína-Arginina N-Metiltransferases/metabolismo , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , UbiquitinaçãoRESUMO
Acidiferrobacter spp. are facultatively anaerobic acidophiles that belong to a distinctive Acidiferrobacteraceae family, which are similar to Ectothiorhodospiraceae phylogenetically, and are closely related to Acidithiobacillia class/subdivision physiologically. The limited genome information has kept them from being studied on molecular taxonomy and environmental adaptation in depth. Herein, Af. thiooxydans ZJ was isolated from acid mine drainage (AMD), and the complete genome sequence was reported to scan its genetic constitution for taxonomic and adaptative feature exploration. The genome has a single chromosome of 3,302,271 base pairs (bp), with a GC content of 63.61%. The phylogenetic tree based on OrthoANI highlighted the unique position of Af. thiooxydans ZJ, which harbored more unique genes among the strains from Ectothiorhodospiraceae and Acidithiobacillaceae by pan-genome analysis. The diverse mobile genetic elements (MGEs), such as insertion sequence (IS), clustered regularly interspaced short palindromic repeat (CRISPR), prophage, and genomic island (GI), have been identified and characterized in Af. thiooxydans ZJ. The results showed that Af. thiooxydans ZJ may effectively resist the infection of foreign viruses and gain functional gene fragments or clusters to shape its own genome advantageously. This study will offer more evidence of the genomic plasticity and improve our understanding of evolutionary adaptation mechanisms to extreme AMD environment, which could expand the potential utilization of Af. thiooxydans ZJ as an iron and sulfur oxidizer in industrial bioleaching.