RESUMO
Treatment failure for the lethal brain tumor glioblastoma (GBM) is attributed to intratumoral heterogeneity and tumor evolution. We utilized 3D neuronavigation during surgical resection to acquire samples representing the whole tumor mapped by 3D spatial coordinates. Integrative tissue and single-cell analysis revealed sources of genomic, epigenomic, and microenvironmental intratumoral heterogeneity and their spatial patterning. By distinguishing tumor-wide molecular features from those with regional specificity, we inferred GBM evolutionary trajectories from neurodevelopmental lineage origins and initiating events such as chromothripsis to emergence of genetic subclones and spatially restricted activation of differential tumor and microenvironmental programs in the core, periphery, and contrast-enhancing regions. Our work depicts GBM evolution and heterogeneity from a 3D whole-tumor perspective, highlights potential therapeutic targets that might circumvent heterogeneity-related failures, and establishes an interactive platform enabling 360° visualization and analysis of 3D spatial patterns for user-selected genes, programs, and other features across whole GBM tumors.
Assuntos
Neoplasias Encefálicas , Glioblastoma , Modelos Biológicos , Humanos , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Epigenômica , Genômica , Glioblastoma/genética , Glioblastoma/patologia , Análise de Célula Única , Microambiente Tumoral , Heterogeneidade GenéticaRESUMO
Accumulation of DNA damage in the lung induces cellular senescence and promotes age-related diseases such as idiopathic pulmonary fibrosis (IPF). Hence, understanding the mechanistic regulation of DNA damage repair is important for anti-aging therapies and disease control. Here, we identified an m6A-independent role of the RNA-binding protein YTHDC1 in counteracting stress-induced pulmonary senescence and fibrosis. YTHDC1 is primarily expressed in pulmonary alveolar epithelial type 2 (AECII) cells and its AECII expression is significantly decreased in AECIIs during fibrosis. Exogenous overexpression of YTHDC1 alleviates pulmonary senescence and fibrosis independent of its m6A-binding ability, while YTHDC1 deletion enhances disease progression in mice. Mechanistically, YTHDC1 promotes the interaction between TopBP1 and MRE11, thereby activating ATR and facilitating DNA damage repair. These findings reveal a noncanonical function of YTHDC1 in delaying cellular senescence, and suggest that enhancing YTHDC1 expression in the lung could be an effective treatment strategy for pulmonary fibrosis.
Assuntos
Senescência Celular , Fibrose Pulmonar Idiopática , Proteínas do Tecido Nervoso , Fatores de Processamento de RNA , Animais , Camundongos , Envelhecimento/genética , Fibrose Pulmonar Idiopática/genética , Fibrose Pulmonar Idiopática/induzido quimicamente , Fibrose Pulmonar Idiopática/metabolismo , Pulmão/metabolismo , Fatores de Processamento de RNA/metabolismo , Proteínas do Tecido Nervoso/metabolismoRESUMO
Optimizing the root architecture of crops is an effective strategy for improving crop yields. Soil compaction is a serious global problem that limits crop productivity by restricting root growth, but the underlying molecular mechanisms are largely unclear. Here, we show that ethylene stimulates rice (Oryza sativa) crown root development in response to soil compaction. First, we demonstrate that compacted soil promotes ethylene production and the accumulation of ETHYLENE INSENSITIVE 3-LIKE 1 (OsEIL1) in rice roots, stimulating crown root primordia initiation and development, thereby increasing crown root number in lower stem nodes. Through transcriptome profiling and molecular analyses, we reveal that OsEIL1 directly activates the expression of WUSCHEL-RELATED HOMEOBOX 11 (OsWOX11), an activator of crown root emergence and growth, and that OsWOX11 mutations delay crown root development, thus impairing the plant's response to ethylene and soil compaction. Genetic analysis demonstrates that OsWOX11 functions downstream of OsEIL1. In summary, our results demonstrate that the OsEIL1-OsWOX11 module regulates ethylene action during crown root development in response to soil compaction, providing a strategy for the genetic modification of crop root architecture and grain agronomic traits.
Assuntos
Regulação da Expressão Gênica de Plantas , Oryza , Proteínas de Plantas , Raízes de Plantas , Fatores de Transcrição , Etilenos/metabolismo , Regulação da Expressão Gênica de Plantas/efeitos dos fármacos , Oryza/genética , Oryza/crescimento & desenvolvimento , Oryza/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Raízes de Plantas/crescimento & desenvolvimento , Raízes de Plantas/genética , Raízes de Plantas/metabolismo , Solo/química , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genéticaRESUMO
This study aimed to compare the efficacy and safety of eltrombopag plus diacerein vs. eltrombopag alone in patients with primary immune thrombocytopenia (ITP) who were previously unresponsive to 14 days of eltrombopag treatment at the full dose. Recruited patients were randomly assigned 1:1 to receive either eltrombopag plus diacerein (n=50) or eltrombopag monotherapy (n=52). Overall response rate, defined as a platelet count at or above 30×109/L, at least doubling of the baseline platelet count, and no bleeding, was reached in 44% of patients in the eltrombopag plus diacerein group compared with 13% in the eltrombopag group at day 15 (P = .0009), and reached in 42% of patients in the combination group compared with 12% in the monotherapy group at day 28 (P = .0006). The addition of diacerein to eltrombopag also led to a longer duration of response (P = .0004). The two most common treatment-emergent adverse events were respiratory infection and gastrointestinal reactions in the combination group, and fatigue and respiratory infection in the eltrombopag group. In conclusion, eltrombopag plus diacerein was well tolerated, and induced higher overall response rates and longer duration of response than eltrombopag alone, offering a rejuvenating salvage therapy for ITP patients unresponsive to 14 days of full dosage eltrombopag. Our work has the potential to enhance the care of patients treated with thrombopoietin receptor agonists, reducing the need for rapid transitions to less-preferable therapies. This study is registered at ClinicalTrials.gov as NCT04917679.
RESUMO
Chemotherapy is still the main therapeutic strategy for gastric cancer (GC). However, most patients eventually acquire multidrug resistance (MDR). Hyperactivation of the EGFR signaling pathway contributes to MDR by promoting cancer cell proliferation and inhibiting apoptosis. We previously identified the secreted protein CGA as a novel ligand of EGFR and revealed a CGA/EGFR/GATA2 positive feedback circuit that confers MDR in GC. Herein, we outline a microRNA-based treatment approach for MDR reversal that targets both CGA and GATA2. We observed increased expression of CGA and GATA2 and increased activation of EGFR in GC samples. Bioinformatic analysis revealed that miR-107 could simultaneously target CGA and GATA2, and the low expression of miR-107 was correlated with poor prognosis in GC patients. The direct interactions between miR-107 and CGA or GATA2 were validated by luciferase reporter assays and Western blot analysis. Overexpression of miR-107 in MDR GC cells increased their susceptibility to chemotherapeutic agents, including fluorouracil, adriamycin, and vincristine, in vitro. Notably, intratumor injection of the miR-107 prodrug enhanced MDR xenograft sensitivity to chemotherapies in vivo. Molecularly, targeting CGA and GATA2 with miR-107 inhibited EGFR downstream signaling, as evidenced by the reduced phosphorylation of ERK and AKT. These results suggest that miR-107 may contribute to the development of a promising therapeutic approach for the treatment of MDR in GC.
RESUMO
Abscisic acid (ABA) signaling interacts frequently with auxin signaling when it regulates plant development, affecting multiple physiological processes; however, to the best of our knowledge, their interaction during tomato development has not yet been reported. Here, we found that type 2C protein phosphatase (SlPP2C2) interacts with both flavin monooxygenase FZY, an indole-3-acetic acid (IAA) biosynthetic enzyme, and small auxin upregulated RNA (SAUR) of an IAA signaling protein and regulates their activity, thereby affecting the expression of IAA-responsive genes. The expression level of SlPP2C2 was increased by exogenous ABA, IAA, NaCl, or dehydration treatment of fruits, leaves, and seeds, and it decreased in imbibed seeds. Manipulating SlPP2C2 with overexpression, RNA interference, and CRISPR/Cas9-mediated genome editing resulted in pleiotropic changes, such as morphological changes in leaves, stem trichomes, floral organs and fruits, accompanied by alterations in IAA and ABA levels. Furthermore, the RNA-seq analysis indicated that SlPP2C2 regulates the expression of auxin-/IAA-responsive genes in different tissues of tomato. The results demonstrate that SlPP2C2-mediated ABA signaling regulates the development of both vegetative and reproductive organs via interaction with FZY/SAUR, which integrates the cross-talk of ABA and auxin signals during development and affects the expressions of development-related genes in tomato.
Assuntos
Ácido Abscísico , Regulação da Expressão Gênica de Plantas , Ácidos Indolacéticos , Proteínas de Plantas , Transdução de Sinais , Solanum lycopersicum , Solanum lycopersicum/genética , Solanum lycopersicum/metabolismo , Solanum lycopersicum/crescimento & desenvolvimento , Ácidos Indolacéticos/metabolismo , Ácido Abscísico/metabolismo , Proteínas de Plantas/metabolismo , Proteínas de Plantas/genética , Reguladores de Crescimento de Plantas/metabolismo , Proteína Fosfatase 2C/metabolismo , Proteína Fosfatase 2C/genética , Plantas Geneticamente Modificadas , Sementes/metabolismo , Sementes/crescimento & desenvolvimento , Sementes/genéticaRESUMO
Necroptosis, considered as a form of programmed cell death, contributes to neural loss. The 5-hydroxytryptamine 4 receptor (5-HT4R) is involved in neurogenesis in the enteric nervous system. However, whether the activation of 5-HT4R can alleviate diabetic enteric neuropathy by inhibiting receptor-interacting protein kinase 3 (RIPK3)-mediated necroptosis is unclear. This study aimed to explore the beneficial effects of 5-HT4R agonist on enteric neuropathy in a mouse model of diabetes and the mechanisms underlying these effects. Diabetes developed neural loss in the colon of mice. 5-HT4Rs localized in submucosal and myenteric plexuses were confirmed. Administration of 5-HT4R agonist attenuated diabetes-induced colonic hypomotility and neural loss of the colon in mice. Remarkably, RIPK3, phosphorylated RIPK3, and its downstream target mixed lineage kinase domain-like protein (MLKL), two key proteins regulating necroptosis, were significantly up-regulated in the colon of diabetic mice. Treatment with 5-HT4R agonist appeared to inhibit diabetes-induced elevation of RIPK3, phosphorylated RIPK3, and MLKL in the colon of mice. Diabetes-induced up-regulation of MLKL in both the mucosa and the muscularis of the colon was prevented by Ripk3 deletion. Moreover, diabetes-evoked neural loss and delayed colonic transit were significantly inhibited by Ripk3 removal. These findings suggest that activation of 5-HT4Rs could potentially provide a protective effect against diabetic enteric neuropathy by suppressing RIPK3-mediated necroptosis.
Assuntos
Diabetes Mellitus Experimental , Proteínas Quinases , Camundongos , Animais , Proteínas Quinases/metabolismo , Serotonina/metabolismo , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/tratamento farmacológico , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Apoptose , Fosforilação/fisiologiaRESUMO
Several starch synthesis regulators have been identified, but these regulators are situated in the terminus of the regulatory network. Their upstream regulators and the complex regulatory network formed between these regulators remain largely unknown. A previous study demonstrated that NAM, ATAF, and CUC (NAC) transcription factors, OsNAC20 and OsNAC26 (OsNAC20/26), redundantly and positively regulate the accumulation of storage material in rice (Oryza sativa) endosperm. In this study, we detected OsNAC25 as an upstream regulator and interacting protein of OsNAC20/26. Both OsNAC25 mutation and OE resulted in a chalky seed phenotype, decreased starch content, and reduced expression of starch synthesis-related genes, but the mechanisms were different. In the osnac25 mutant, decreased expression of OsNAC20/26 resulted in reduced starch synthesis; however, in OsNAC25-overexpressing plants, the OsNAC25-OsNAC20/26 complex inhibited OsNAC20/26 binding to the promoter of starch synthesis-related genes. In addition, OsNAC20/26 positively regulated OsNAC25. Therefore, the mutual regulation between OsNAC25 and OsNAC20/26 forms a positive regulatory loop to stimulate the expression of starch synthesis-related genes and meet the great demand for starch accumulation in the grain filling stage. Simultaneously, a negative regulatory loop forms among the 3 proteins to avoid the excessive expression of starch synthesis-related genes. Collectively, our findings demonstrate that both promotion and inhibition mechanisms between OsNAC25 and OsNAC20/26 are essential for maintaining stable expression of starch synthesis-related genes and normal starch accumulation.
Assuntos
Regulação da Expressão Gênica de Plantas , Oryza , Proteínas de Plantas , Amido , Fatores de Transcrição , Oryza/genética , Oryza/metabolismo , Amido/metabolismo , Amido/biossíntese , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Endosperma/metabolismo , Endosperma/genéticaRESUMO
Our recent investigation has indicated that the global deletion of MBD2 can mitigate the progression of AKI induced by VAN. Nevertheless, the role and regulatory mechanisms of proximal tubular MBD2 in this pathophysiological process have yet to be elucidated. Our preceding investigation revealed that autophagy played a crucial role in advancing AKI induced by VAN. Consequently, we postulated that MBD2 present in the proximal tubule could upregulate the autophagic process to expedite the onset of AKI. In the present study, we found for the first time that MBD2 mediated the autophagy production induced by VAN. Through the utilization of miRNA chip analysis, we have mechanistically demonstrated that MBD2 initiates the activation of miR-597-5p through promoter demethylation. This process leads to the suppression of S1PR1, which results in the induction of autophagy and apoptosis in renal tubular cells. Besides, PT-MBD2-KO reduced autophagy to attenuate VAN-induced AKI via regulation of the miR-597-5p/S1PR1 axis, which was reversed by rapamycin. Finally, the overexpression of MBD2 aggravated the diminished VAN-induced AKI in autophagy-deficient mice (PT-Atg7-KO). These data demonstrate that proximal tubular MBD2 facilitated the process of autophagy via the miR-597-5p/S1PR1 axis and subsequently instigated VAN-induced AKI through the induction of apoptosis. The potentiality of MBD2 being a target for AKI was established.
Assuntos
Injúria Renal Aguda , MicroRNAs , Animais , Camundongos , Vancomicina , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/genética , Rim , MicroRNAs/genética , Apoptose/fisiologia , AutofagiaRESUMO
OBJECTIVES: Observational studies link elevated plasma homocysteine (Hcy) with vascular disease. Our aim was to assess the gender difference in the association between the plasma tHcy level and brain atrophy and identify the possible influencer. We employed Mendelian randomization (MR) to explore the causal relationship between plasma tHcy level, estradiol level, and brain atrophy. METHODS: A total of 687 patients with brain atrophy were included, and gender-specific subgroup analyses in association between tHcy and brain atrophy are conducted. From genome-wide association studies, we selected genetic variants (P < 5 × 10-8) for the plasma tHcy level and estradiol level. We investigated the degree of brain atrophy (including gray matter volume and total brain volume) in the UK biobank (n = 7,916). The inverse variance-weighted and several sensitivity MR regression analyses were carried out. RESULTS: The plasma tHcy level was significantly associated with brain atrophy for females, but not for males. An MR study showed that there was little evidence of the causal link between elevated plasma tHcy and brain atrophy. On the other hand, we found evidence to support causality for genetically decreased estradiol with higher risk of brain atrophy. Furthermore, genetic predisposition to elevated plasma tHcy was associated with a lower estradiol level. CONCLUSIONS: The influence of estradiol on the association between tHcy and brain atrophy deserves further investigation.
Assuntos
Estudo de Associação Genômica Ampla , Doenças Neurodegenerativas , Masculino , Feminino , Humanos , Análise da Randomização Mendeliana , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Doenças Neurodegenerativas/patologia , Atrofia/patologia , EstradiolRESUMO
Macrophage polarization is closely related to inflammation development, yet how macrophages are polarized remains unclear. In our study, the number of M1 macrophages was markedly increased in Fam76b knockout U937 cells vs. wild-type U937 cells, and FAM76B expression was decreased in M1 macrophages induced from different sources of macrophages. Moreover, Fam76b knockout enhanced the mRNA and protein levels of M1 macrophage-associated marker genes. These results suggest that FAM76B inhibits M1 macrophage polarization. We then further explored the mechanism by which FAM76B regulates macrophage polarization. We found that FAM76B can regulate PI3K/Akt/NF-κB pathway-mediated M1 macrophage polarization by stabilizing PIK3CD mRNA. Finally, FAM76B was proven to protect against inflammatory bowel disease (IBD) by inhibiting M1 macrophage polarization through the PI3K/Akt/NF-κB pathway in vivo. In summary, FAM76B regulates M1 macrophage polarization through the PI3K/Akt/NF-κB pathway in vitro and in vivo, which may inform the development of future therapeutic strategies for IBD and other inflammatory diseases.
Assuntos
Doenças Inflamatórias Intestinais , NF-kappa B , Humanos , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas c-akt/genética , Macrófagos , RNA Mensageiro/genética , Classe I de Fosfatidilinositol 3-Quinases/genéticaRESUMO
BACKGROUND: The ZFHX3 gene plays vital roles in embryonic development, cell proliferation, neuronal differentiation and neuronal death. This study aims to explore the relationship between ZFHX3 variants and epilepsy. METHODS: Whole-exome sequencing was performed in a cohort of 378 patients with partial (focal) epilepsy. A Drosophila Zfh2 knockdown model was used to validate the association between ZFHX3 and epilepsy. RESULTS: Compound heterozygous ZFHX3 variants were identified in eight unrelated cases. The burden of ZFHX3 variants was significantly higher in the case cohort, shown by multiple/specific statistical analyses. In Zfh2 knockdown flies, the incidence and duration of seizure-like behaviour were significantly greater than those in the controls. The Zfh2 knockdown flies exhibited more firing in excitatory neurons. All patients presented partial seizures. The five patients with variants in the C-terminus/N-terminus presented mild partial epilepsy. The other three patients included one who experienced frequent non-convulsive status epilepticus and two who had early spasms. These three patients had also neurodevelopmental abnormalities and were diagnosed as developmental epileptic encephalopathy (DEE), but achieved seizure-free after antiepileptic-drug treatment without adrenocorticotropic-hormone/steroids. The analyses of temporal expression (genetic dependent stages) indicated that ZFHX3 orthologous were highly expressed in the embryonic stage and decreased dramatically after birth. CONCLUSION: ZFHX3 is a novel causative gene of childhood partial epilepsy and DEE. The patients of infantile spasms achieved seizure-free after treatment without adrenocorticotropic-hormone/steroids implies a significance of genetic diagnosis in precise treatment. The genetic dependent stage provided an insight into the underlying mechanism of the evolutional course of illness.
Assuntos
Epilepsias Parciais , Proteínas de Homeodomínio , Espasmos Infantis , Animais , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Epilepsias Parciais/genética , Epilepsias Parciais/tratamento farmacológico , Sequenciamento do Exoma , Predisposição Genética para Doença , Proteínas de Homeodomínio/genética , Mutação , Espasmos Infantis/genética , DrosophilaRESUMO
Nitrogen is one of the most essential elements for plant growth and development. In this study, the growth, physiology, and transcriptome of Toona sinensis (A. Juss) Roem seedlings were compared between low-nitrogen (LN) and normal-nitrogen (NN) conditions. These results indicate that LN stress adversely influences T. sinensis seedling growth. The activities of key enzymes related to nitrogen assimilation and phytohormone contents were altered by LN stress. A total of 2828 differentially expressed genes (DEGs) in roots and 1547 in leaves were identified between the LN and NN treatments. A differential enrichment analysis of Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways indicated that nitrogen and sugar metabolism, flavonoid biosynthesis, plant hormone signal transduction, and ABC transporters, were strongly affected by LN stress. In summary, this research provides information for further understanding the response of T. sinensis to LN stress.
RESUMO
The efficacy of electrical stimulation facilitating peripheral nerve regeneration is evidenced extensively, while the associated secondary damage resulting from repeated electrode invasion and indiscriminate stimulation is inevitable. Here, we present an optogenetics strategy that utilizes upconversion nanoparticles (UCNPs) to convert deeply penetrating near-infrared excitation into blue emission, which activates an adeno-associated virus-encoding ChR2 photoresponsive ion channel on cell membranes. The induced Ca2+ flux, similar to the ion flux in the electrical stimulation approach, efficiently regulates viability and proliferation, secretion of nerve growth factor, and neural function of RSC96 cells. Furthermore, deep near-infrared excitation is harnessed to stimulate autologous Schwann cells in situ via a UCNP-composited scaffold, which enhances nerve sprouting and myelination, consequently promoting functional recovery, electrophysiological restoration, and reinnervation of damaged nerves. This developed postoperatively noninvasive optogenetics strategy presents a novel, minimally traumatic, and enduring therapeutic stimulus to effectively promote peripheral nerve repair.
Assuntos
Nanopartículas , Regeneração Nervosa , Optogenética , Células de Schwann , Nervo Isquiático , Animais , Optogenética/métodos , Nanopartículas/química , Ratos , Dependovirus/genética , Linhagem Celular , Traumatismos dos Nervos Periféricos/terapiaRESUMO
Heart failure is a leading cause of death in the elderly. Traditional Chinese medicine, a verified alternative therapeutic regimen, has been used to treat heart failure, which is less expensive and has fewer adverse effects. In this study, a total of 15 active ingredients of Astragalus membranaceus (Huangqi, HQ) were obtained; among them, Isorhamnetin, Quercetin, Calycosin, Formononetin, and Kaempferol were found to be linked to heart failure. Ang II significantly enlarged the cell size of cardiomyocytes, which could be partially reduced by Quercetin, Isorhamnetin, Calycosin, Kaempferol, or Formononetin. Ang II significantly up-regulated ANP, BNP, ß-MHC, and CTGF expressions, whereas Quercetin, Isorhamnetin, Calycosin, Kaempferol or Formononetin treatment partially downregulated ANP, BNP, ß-MHC and CTGF expressions. Five active ingredients of HQ attenuated inflammation in Ang II-induced cardiomyocytes by inhibiting the levels of TNF-α, IL-1ß, IL-18 and IL-6. Molecular docking shows Isorhamnetin, Quercetin, Calycosin, Formononetin and Kaempferol can bind with its target protein ESR1 in a good bond by intermolecular force. Quercetin, Calycosin, Kaempferol or Formononetin treatment promoted the expression levels of ESR1 and phosphorylated ESR1 in Ang II-stimulated cardiomyocytes; however, Isorhamnetin treatment had no effect on ESR1 and phosphorylated ESR1 expression levels. In conclusion, our results comprehensively illustrated the bioactives, potential targets, and molecular mechanism of HQ against heart failure. Isorhamnetin, Quercetin, Calycosin, Formononetin and Kaempferol might be the primary active ingredients of HQ, dominating its cardioprotective effects against heart failure through regulating ESR1 expression, which provided a basis for the clinical application of HQ to regulate cardiac hypertrophy and heart failure.
Assuntos
Astragalus propinquus , Medicamentos de Ervas Chinesas , Insuficiência Cardíaca , Simulação de Acoplamento Molecular , Miócitos Cardíacos , Farmacologia em Rede , Astragalus propinquus/química , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Animais , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/química , Quercetina/farmacologia , Quercetina/química , Quercetina/análogos & derivados , Angiotensina II/metabolismo , Quempferóis/farmacologia , Quempferóis/química , Ratos , Humanos , Isoflavonas/farmacologia , Isoflavonas/químicaRESUMO
Acne vulgaris represents a chronic inflammatory condition, the pathogenesis of which is closely associated with the altered skin microbiome. Recent studies have implicated a profound role of Gram-negative bacteria in acne development, but there is a lack of antiacne agents targeting these bacteria. Polyphyllins are major components of Rhizoma Paridis with great anti-inflammatory potential. In this study, we aimed to evaluate the antiacne effects and the underlying mechanisms of PPH and a PPH-enriched Rhizoma Paridis extract (RPE) in treating the Gram-negative bacteria-induced acne. PPH and RPE treatments significantly suppressed the mRNA and protein expressions of interleukin (IL)-1ß and IL-6 in lipopolysaccharide (LPS)-induced RAW 264.7 and HaCaT cells, along with the intracellular reactive oxygen species (ROS) generation. Furthermore, PPH and RPE inhibited the nuclear translocation of nuclear factor kappa-B (NF-κB) P65 in LPS-induced RAW 264.7 cells. Based on molecular docking, PPH could bind to kelch-like ECH-associated protein 1 (KEAP1) protein. PPH and RPE treatments could activate nuclear factor erythroid 2-related factor 2 (NRF2) and upregulate haem oxygenase-1 (HO-1). Moreover, RPE suppressed the mitogen-activated protein kinase (MAPK) pathway. Therefore, PPH-enriched RPE showed anti-inflammatory and antioxidative effects in vitro, which is promising for alternative antiacne therapeutic.
Assuntos
Acne Vulgar , Saponinas , Humanos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Lipopolissacarídeos/efeitos adversos , Saponinas/farmacologia , Saponinas/uso terapêutico , Simulação de Acoplamento Molecular , Anti-Inflamatórios/uso terapêutico , NF-kappa B/metabolismo , Bactérias Gram-Negativas/metabolismo , Acne Vulgar/tratamento farmacológico , Heme Oxigenase-1/genética , Heme Oxigenase-1/metabolismo , Inflamação/metabolismoRESUMO
BACKGROUND: Pod shell thickness (PST) is an important agronomic trait of peanut because it affects the ability of shells to resist pest infestations and pathogen attacks, while also influencing the peanut shelling process. However, very few studies have explored the genetic basis of PST. RESULTS: An F2 segregating population derived from a cross between the thick-shelled cultivar Yueyou 18 (YY18) and the thin-shelled cultivar Weihua 8 (WH8) was used to identify the quantitative trait loci (QTLs) for PST. On the basis of a bulked segregant analysis sequencing (BSA-seq), four QTLs were preliminarily mapped to chromosomes 3, 8, 13, and 18. Using the genome resequencing data of YY18 and WH8, 22 kompetitive allele-specific PCR (KASP) markers were designed for the genotyping of the F2 population. Two major QTLs (qPSTA08 and qPSTA18) were identified and finely mapped, with qPSTA08 detected on chromosome 8 (0.69-Mb physical genomic region) and qPSTA18 detected on chromosome 18 (0.15-Mb physical genomic region). Moreover, qPSTA08 and qPSTA18 explained 31.1-32.3% and 16.7-16.8% of the phenotypic variation, respectively. Fifteen genes were detected in the two candidate regions, including three genes with nonsynonymous mutations in the exon region. Two molecular markers (Tif2_A08_31713024 and Tif2_A18_7198124) that were developed for the two major QTL regions effectively distinguished between thick-shelled and thin-shelled materials. Subsequently, the two markers were validated in four F2:3 lines selected. CONCLUSIONS: The QTLs identified and molecular markers developed in this study may lay the foundation for breeding cultivars with a shell thickness suitable for mechanized peanut shelling.
Assuntos
Arachis , Locos de Características Quantitativas , Arachis/genética , Mapeamento Cromossômico , Melhoramento Vegetal , FenótipoRESUMO
Exploring high-sloping-capacity carbons is of great significance in the development of high-power lithium-ion batteries/capacitors (LIBs/LICs). Herein, an ion-catalyzed self-template method is utilized to synthesize the hydrogen-rich carbon nanoribbon (HCNR), achieving high specific and rate capacity (1144.2/471.8 mAh g-1 at 0.1/2.5 A g-1). The Li+ storage mechanism of the HCNR is elucidated by in situ spectroscopic techniques. Intriguingly, the protonated aromatic sp2-hybridized carbon (C(sp2)-H) can provide additional active sites for Li+ uptake via reversible rehybridization to sp3-C, which is the origin of the high sloping capacity. The presence of this sloping feature suggests a highly capacitance-dominated storage process, characterized by rapid kinetics that facilitates superior rate performance. For practical usage, the HCNR-based LIC device can deliver high energy/power densities of 198.3 Wh kg-1/17.9 kW kg-1. This work offers mechanistic insights on the crucial role of aromatic C(sp2)-H in boosting Li+ storage and opens up new avenues to develop such sloping-type carbons for high-performance rechargeable batteries/capacitors.
RESUMO
Due to the extensive genetic and antigenic variation in Porcine Reproductive and Respiratory Syndrome Virus (PRRSV), as well as its rapid mutability and evolution, PRRS prevention and control can be challenging. An expeditious and sensitive neutralization assay for PRRSV is presented to monitor neutralizing antibodies (NAbs) in serum during vaccine research. Here, a PRRSV expressing eGFP was successfully rescued with reverse genetics based on the infectious clone HuN4-F112-eGFP which we constructed. The fluorescent protein expressions of the reporter viruses remained stable for at least five passages. Based on this reporter virus, the neutralization assay can be easily used to evaluate the level of NAbs by counting cells with green fluorescence. Compared with the classical CPE assay, the newly developed assay increases sensitivity by one- to four-fold at the early antibody response stage, thus saving 2 days of assay waiting time. By using this assay to unveil the dynamics of neutralizing antibodies against PRRSV, priming immunity through either a single virulent challenge or only vaccination could produce limited NAbs, but re-infection with PRRSV would induce a faster and stronger NAb response. Overall, the novel HuN4-F112-eGFP-based neutralization assay holds the potential to provide a highly efficient platform for evaluating the next generation of PRRS vaccines.
RESUMO
BACKGROUND: Little progress has been made in determining the prognostic factors for children and adolescents with high-grade mature B-cell non-Hodgkin lymphoma (HG B-NHL). Based on the important role of body mass index (BMI) in cancer, this study explored the effect of BMI on the prognosis of patients with HG B-NHL. METHODS: Patients aged <18 years with newly diagnosed HG B-NHL were enrolled. Patients were divided into normal, overweight, obese, and emaciated BMI groups according to the growth criteria for children and adolescents. RESULTS: In total, 435 patients were enrolled in this study. There were 329 (75.6%), 46 (10.6%), 13 (3.0%), and 47 (10.8%) patients stratified into the normal, overweight, obese, and emaciated BMI groups, respectively. The event-free survival and overall survival rates of the entire cohort were 89.3% and 92.4%, respectively. The 5-year event-free survival rate for the patients with obese BMI was worse than those with overweight BMI (76.2% vs. 95.6%, p = .04). The 5-year overall survival rate for the patients with emaciated BMI was worse than those with normal (84.5% vs. 93.1%, p = .04) or overweight BMI (84.5% vs. 97.7%, p = .03). Cox multivariate analysis showed that obese or emaciated BMI at diagnosis was associated with an increased risk of death (p = 0.04; HR, 2.26) and was identified as an independent adverse prognostic factor in pediatric HG B-NHL. CONCLUSION: Obese or emaciated BMI at diagnosis is associated with poor prognosis in pediatric HG B-NHL and can be used for risk stratification.