RESUMO
There is a close regulatory relationship between the circadian clock and the abscisic acid (ABA) signaling pathway in regulating many developmental processes and stress responses. However, the exact feedback regulation mechanism between them is still poorly understood. Here, we identified the rice (Oryza sativa) clock component PSEUDO-RESPONSE REGULATOR 95 (OsPRR95) as a transcriptional regulator that accelerates seed germination and seedling growth by inhibiting ABA signaling. We also found that OsPRR95 binds to the ABA receptor gene REGULATORY COMPONENTS OF ABA RECEPTORS10 (OsRCAR10) DNA and inhibits its expression. Genetic analysis showed OsRCAR10 acts downstream of OsPRR95 in mediating ABA responses. In addition, the induction of OsPRR95 by ABA partly required a functional OsRCAR10, and the ABA-responsive element-binding factor ABSCISIC ACID INSENSITIVE5 (OsABI5) bound directly to the promoter of OsPRR95 and activated its expression, thus establishing a regulatory feedback loop between OsPRR95, OsRCAR10, and OsABI5. Taken together, our results demonstrated that the OsRCAR10-OsABI5-OsPRR95 feedback loop modulates ABA signaling to fine-tune seed germination and seedling growth, thus establishing the molecular link between ABA signaling and the circadian clock.
Assuntos
Arabidopsis , Relógios Circadianos , Oryza , Ácido Abscísico/metabolismo , Oryza/metabolismo , Relógios Circadianos/genética , Arabidopsis/genética , Germinação/fisiologia , Plântula/metabolismo , Sementes/metabolismo , Regulação da Expressão Gênica de PlantasRESUMO
Quantum dot (QD) light-emitting diodes (QLEDs) are promising for next-generation lighting and displays. Considering the optimization design of both the QD and device structure is expected to improve the QLED's performance significantly but has rarely been reported. Here, we use the thick-shell QDs combined with a dual-hole transport layer device structure to construct a high-efficiency QLED. The optimized thick-shell QDs with CdS/CdSe/CdS/ZnS seed/spherical quantum well/shell/shell geometry exhibit a high photoluminescence quantum yield of 96% at a shell thickness of 5.9â nm. The intermediate emissive CdSe layer with coherent strain ensures defect-free growth of the thick CdS and ZnS outer shells. Based on the orthogonal solvents assisted Poly-TPD&PVK dual-hole transport layer device architecture, the champion QLED achieved a maximum external quantum efficiency of 22.5% and a maximum luminance of 259955 cd m-2, which are 1.6 and 3.7 times that of thin-shell QDs based devices with single hole transport layer, respectively. Our study provides a feasible idea for further improving the performance of QLED devices.
RESUMO
Hepatic ischemia-reperfusion injury (HIRI) is of common occurrence during liver surgery and transplantation. Pinocembrin (PIN) is a kind of flavonoid monomer extracted from the local traditional Chinese medicine Penthorum chinense Pursh (P. chinense). However, the effect of PIN on HIRI has not determined. We investigated the protective effect and potential mechanism of PIN against HIRI. Model mice were subjected to partial liver ischemia for 60 min, experimental mice were pretreated with PIN orally for 7 days, and H2 O2 -induced oxidative damage model in AML12 hepatic cells was established in vitro. Histopathologic analysis and serum biochemical levels revealed that PIN had hepatoprotective activities against HIRI. The variation of GSH, SOD, MDA, and ROS levels indicated that PIN treatments attenuated oxidative stress in tissue. PIN pretreatment obviously ameliorated apoptosis, and restrained the expression of HMGB1 and TLR4 in vivo. In vitro, compared with H2 O2 group, the contents of ROS, mitochondrial membrane potential, apoptotic cells, and Bcl-2 protein were decreased, while the Bax protein expression was increased. Moreover, HMGB-1 small interfering RNA test and western blotting showed that PIN pretreatment reduced HMGB1 and TLR4 protein levels. In conclusion, PIN pretreatment effectively protected hepatocytes from HIRI and inhibited the HMGB1/TLR4 signaling pathway.
Assuntos
Proteína HMGB1 , Traumatismo por Reperfusão , Camundongos , Animais , Espécies Reativas de Oxigênio/metabolismo , Receptor 4 Toll-Like/metabolismo , Fígado , Transdução de Sinais , Traumatismo por Reperfusão/tratamento farmacológico , ApoptoseRESUMO
BACKGROUND: The adverse effects of climate change on crop production are constraining breeders to develop high-quality environmentally stable varieties. Hence, efforts are being made to identify key genes that could be targeted for enhancing crop tolerance to environmental stresses. ERF transcription factors play an important role in various abiotic stresses in plants. However, the roles of the ERF family in abiotic stresses tolerance are still largely unknown in sesame, the "queen" of oilseed crops. RESULTS: In total, 114 sesame ERF genes (SiERFs) were identified and characterized. 96.49% of the SiERFs were distributed unevenly on the 16 linkage groups of the sesame genome. The phylogenetic analysis with the Arabidopsis ERFs (AtERFs) subdivided SiERF subfamily proteins into 11 subgroups (Groups I to X; and VI-L). Genes in the same subgroup exhibited similar structure and conserved motifs. Evolutionary analysis showed that the expansion of ERF genes in sesame was mainly induced by whole-genome duplication events. Moreover, cis-acting elements analysis showed that SiERFs are mostly involved in environmental responses. Gene expression profiles analysis revealed that 59 and 26 SiERFs are highly stimulated under drought and waterlogging stress, respectively. In addition, qRT-PCR analyses indicated that most of SiERFs are also significantly up-regulated under osmotic, submerge, ABA, and ACC stresses. Among them, SiERF23 and SiERF54 were the most induced by both the abiotic stresses, suggesting their potential for targeted improvement of sesame response to multiple abiotic stresses. CONCLUSION: This study provides a comprehensive understanding of the structure, classification, evolution, and abiotic stresses response of ERF genes in sesame. Moreover, it offers valuable gene resources for functional characterization towards enhancing sesame tolerance to multiple abiotic stresses.
Assuntos
Arabidopsis , Sesamum , Arabidopsis/genética , Regulação da Expressão Gênica de Plantas , Família Multigênica , Filogenia , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Sesamum/metabolismo , Estresse Fisiológico/genéticaRESUMO
BACKGROUND: Although liver fibrosis is a key pathologic process in many liver diseases, therapeutic approaches for inhibiting liver fibrosis are still very limited. N-Acetyl-l-tryptophan (l-NAT) has a hepatoprotective effect via inhibiting the destruction of liver cells, enhancing cell viability and reducing the inflammation. However, the effect of l-NAT on liver fibrosis is not determined. PURPOSE: The present study investigated the effect of l-NAT on liver fibrosis and explored it potential molecular mechanism. METHODS: To address this concern, this study was carried out via fibrotic mice model induced by CCl4 and many approaches such as various histological staining methods, western blot assay, etc. RESULT: l-NAT decreased the levels of alanine aminotransferase (ALT) and aspartate transaminase (AST) in fibrotic mice model induced by carbon tetrachloride (CCl4). Histological staining showed that l-NAT ameliorated liver injury and fibrosis, and reduced the expression of α-smooth muscle actin (α-SMA) and Collagen I protein. l-NAT also attenuated apoptosis by down-regulating the level of pro-apoptotic protein Bax and up-regulating that of anti-apoptotic protein Bcl-2. Moreover, l-NAT inhibited the expressions of TGF-ß1/SMAD and matrix metalloproteinase 9 (MMP9) proteins, and reversed the expression of YAP1 protein in CCl4-induced liver fibrosis. CONCLUSION: These results clearly demonstrated that l-NAT attenuated CCl4-induced liver fibrosis in mice, and this protective mechanism might relate to TGF-ß1/SMAD and Hippo/YAP1 signaling pathway. Thus, this study provided data basis for the prevention and treatment of liver fibrosis.
Assuntos
Proteínas Smad , Fator de Crescimento Transformador beta1 , Animais , Tetracloreto de Carbono , Via de Sinalização Hippo , Fígado , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/metabolismo , Camundongos , Transdução de Sinais , Proteínas Smad/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Triptofano/metabolismo , Proteínas de Sinalização YAP/metabolismoRESUMO
BACKGROUND: Low temperature (LT) often occurs at the seedling stage in the early rice-growing season, especially for direct seeded early-season indica rice, and using flooding irrigation can mitigate LT damage in rice seedlings. The molecular mechanism by which flooding mitigates the damage induced by LT stress has not been fully elucidated. Thus, LT stress at 8 °C, LT accompanied by flooding (LTF) and CK (control) treatments were established for 3 days to determine the transcriptomic, proteomic and physiological response in direct seeded rice seedlings at the seedling stage. RESULTS: LT damaged chloroplasts, and thylakoid lamellae, and increased osmiophilic bodies and starch grains compared to CK, but LTF alleviated the damage to chloroplast structure caused by LT. The physiological characteristics of treated plants showed that compared with LT, LTF significantly increased the contents of rubisco, chlorophyll, PEPCK, ATP and GA3 but significantly decreased soluble protein, MDA and ABA contents. 4D-label-free quantitative proteomic profiling showed that photosynthesis-responsive proteins, such as phytochrome, as well as chlorophyll and the tricarboxylic acid cycle were significantly downregulated in LT/CK and LTF/CK comparison groups. However, compared with LT, phytochrome, chlorophyllide oxygenase activity and the glucan branching enzyme in LTF were significantly upregulated in rice leaves. Transcriptomic and proteomic studies identified 72,818 transcripts and 5639 proteins, and 4983 genes that were identified at both the transcriptome and proteome levels. Differentially expressed genes (DEGs) and differentially expressed proteins (DEPs) were significantly enriched in glycine, serine and threonine metabolism, biosynthesis of secondary metabolites, glycolysis/gluconeogenesis and metabolic pathways. CONCLUSION: Through transcriptomic, proteomic and physiological analyses, we determined that a variety of metabolic pathway changes were induced by LT and LTF. GO and KEGG enrichment analyses demonstrated that DEGs and DEPs were associated with photosynthesis pathways, antioxidant enzymes and energy metabolism pathway-related proteins. Our study provided new insights for efforts to reduce the damage to direct seeded rice caused by low-temperature stress and provided a breeding target for low temperature flooding-resistant cultivars. Further analysis of translational regulation and metabolites may help to elucidate the molecular mechanisms by which flooding mitigates low-temperature stress in direct seeded early indica rice at the seedling stage.
Assuntos
Oryza , Plântula , Regulação da Expressão Gênica de Plantas , Oryza/genética , Oryza/metabolismo , Melhoramento Vegetal , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Proteômica , Plântula/genética , Plântula/metabolismo , Estresse Fisiológico/genética , Temperatura , TranscriptomaRESUMO
Genome editing (GE) has revolutionized the biological sciences by creating a novel approach for manipulating the genomes of living organisms. Many tools have been developed in recent years to enable the editing of complex genomes. Therefore, a reliable and rapid approach for increasing yield and tolerance to various environmental stresses is necessary to sustain agricultural crop production for global food security. This critical review elaborates the GE tools used for crop improvement. These tools include mega-nucleases (MNs), such as zinc-finger nucleases (ZFNs), and transcriptional activator-like effector nucleases (TALENs), and clustered regularly interspaced short palindromic repeats (CRISPR). Specifically, this review addresses the latest advancements in the role of CRISPR/Cas9 for genome manipulation for major crop improvement, including yield and quality development of biotic stress- and abiotic stress-tolerant crops. Implementation of this technique will lead to the production of non-transgene crops with preferred characteristics that can result in enhanced yield capacity under various environmental stresses. The CRISPR/Cas9 technique can be combined with current and potential breeding methods (e.g., speed breeding and omics-assisted breeding) to enhance agricultural productivity to ensure food security. We have also discussed the challenges and limitations of CRISPR/Cas9. This information will be useful to plant breeders and researchers in the thorough investigation of the use of CRISPR/Cas9 to boost crops by targeting the gene of interest.
Assuntos
Sistemas CRISPR-Cas , Produtos Agrícolas/genética , Edição de Genes , Melhoramento Vegetal , Resistência à Doença/genética , Qualidade dos Alimentos , Abastecimento de Alimentos , Engenharia Genética , Genoma de Planta , Genômica/métodos , Plantas Geneticamente ModificadasRESUMO
BACKGROUND: Text matching is one of the basic tasks in the field of natural language processing. Owing to the particularity of Chinese language and medical texts, text matching has greater application and research value in the medical field. In 2019, at the China Health Information Processing Conference (CHIP), 30,000 sets of real disease Q&A data in Chinese on diabetes, hypertension, hepatitis B, AIDS, and breast cancer were released for public evaluation. A total of 90 teams participated in the evaluation. PURPOSE: To explore the best method of text matching of Chinese medical Q&A data by participating in an evaluation competition. METHOD: After analyzing the Chinese medical Q&A data provided by the competition, we used the bidirectional encoder representations from transformers (BERT) model and a boosted tree model to compare the effects. At the same time, we analyzed the importance of the features extracted through feature engineering. Finally, we integrated the BERT and boosted tree models, and proved the effectiveness of the ensemble through a correlation analysis. RESULTS: The final F1 score of the ensemble model is 0.90825, ranking first among the 90 participating teams. The highest F1 score of the single BERT model is 0.87443, whereas the highest F1 score of the boosted tree single model is only 0.86915. The F1 score of the BERT multi-model ensemble is 0.87473 (an average increase of 0.756% compared to the single model), and the F1 score of the boosted tree multi-model ensemble is 0.86720 (an average decrease of 0.03% compared to the single model). In the feature importance experiment, the out-degree and in-degree of the Q&A sentence are of utmost importance. In the correlation experiment, the correlation coefficients between models of the same type are all as high as 0.9, which shows a high similarity. The correlation coefficient between different types of models is approximately 0.7, which shows a certain degree of discrimination. With the ensemble of the two types of models, the F1 score reached 0.90825, which is 3.88% higher than that of the optimal single model. CONCLUSION: In our study, the proposed model ensemble method was shown to effectively improve the performance of a single model. It achieves good results in Chinese medical Q&A tasks and has a good generalization property.
Assuntos
Idioma , Processamento de Linguagem Natural , ChinaRESUMO
Phosphorus (P) is one of the essential macronutrients for rice. In this study, we used 120 rice backcross recombinant inbred lines (BRILs) derived from a cross indica cv. Changhui 891 and japonica cv. 02428. To elucidate the genetic control of P deficiency tolerance in rice, we have used high quality SNPs bin markers to identify some important loci underlying phosphorus deficiency. The bin map was generated which includes 3057 bins covering distance of 1266.5 cM with an average of 0.41 cM between markers. Based on this map, 50 loci, including four novel loci, qSL-3, qRL-11, qSDW-1, qRDW-1 with phenotypic variance 23.26%, 12.06%, 9.89% associated with P deficiency-related seedling traits were identified. No significant QTLs was found for root length under P+, shoot fresh weight P- and root length, shoot fresh weight for P+, P- and their ratio respectively. Root fresh weight, and root dry weight were strongly correlated to each other, and QTLs for these variables were located on the same chromosome 1 at the same region. Notably, 3 pleiotropic regions is the pioneer of our study, and these regions would facilitate map-based cloning to expedite the MAS selection for developing low phosphorous tolerant varieties. This study not only improves our knowledge about molecular processes associated with P deficiency, but also provides useful information to understand the genetic architecture of low phosphorous tolerance.
RESUMO
MAIN CONCLUSION: Sesame harbors a large diversity in root morphological and anatomical traits and a high root biomass improves the plant aboveground biomass as well as the seed yield. Sesame provides one of the most nutritious and healthy vegetable oils, sparking an increasing demand of its seeds. However, with the low yield and productivity of sesame, there is still a huge gap between the seed demand and supply. Improving the root system has a high potential to increase crop productivity, but information on the diversity of the sesame root systems is still lacking. In this study, 40 diverse sesame varieties were grown in soil and hydroponics systems and the diversity of the root system was investigated. The results showed that sesame holds a large root morphological and anatomical diversity, which can be harnessed in breeding programmes. Based on the clustering of the genotypes in hydroponics and soil culture systems, we found that similar genotypes were commonly clustered either in the small-root or in the big-root group, indicating that the hydroponics system can be employed for a large-scale root phenotyping. Our results further revealed that the root biomass positively contributes to increased seed yield in sesame, based on multi-environmental trials. By comparing the root transcriptome of two contrasting genotypes, 2897 differentially expressed genes were detected and they were enriched in phenylpropanoid biosynthesis, starch and sucrose metabolism, stilbenoid, diarylheptanoid and gingerol biosynthesis, flavonoid biosynthesis, suggesting that these pathways are crucial for sesame root growth and development. Overall, this study sheds light on the diversity of sesame root system and offers the basis for improving root traits and increasing sesame seed yield.
Assuntos
Sesamum/genética , Transcriptoma , Biomassa , Genótipo , Fenótipo , Óleos de Plantas/metabolismo , Proteínas de Plantas/genética , Raízes de Plantas/anatomia & histologia , Raízes de Plantas/genética , Raízes de Plantas/crescimento & desenvolvimento , Sesamum/anatomia & histologia , Sesamum/crescimento & desenvolvimentoRESUMO
Nonlinear transport behavior is one of the signatures of the formation of electronic crystals such as charge density wave (CDW), as it provides evidence for their collective motion. Such experimental evidence has been widely reported in quasi-1D materials but is rarely studied in 2D systems. Only a few studies on the RTe$_{3}$ materials have been previsouly reported. Here we report for the first time the observation of CDW depinning and sliding in the layered 1$T$-TiSe$_{2}$ compound, based on the observation of (1) nonlinear voltage-current characteristics and (2) the electrical noise, which are associated with the CDW depinning and sliding process. Similar measurements are also conducted on quasi-1D system NbSe$_{3}$. The depinning behavior of the CDWs with different dimensionalities in these two systems are compared. It is found that the threshold electric field ($E_{T}$) increases linearly with decreasing temperature for the 2D case, consistent with previous results on RTe$_{3}$, while it demonstrated an activated behavior in 1D, as expected within the weak-pinning Fukuyama-Lee-Rice (FLR) framework. Such a distinction of the threshold behavior in CDW systems of different dimensions therefore indicates a possible strong pinning picture in higher-dimensional CDW systems in general. $E_{T}$ is found to be much higher in 1$T$-TiSe$_{2}$, consistent with a strong pinning picture, and could account for the scarcity of the depinning study in these 2D systems. Our results thus pave the way for a unified understanding of the CDW collective motion in different dimensionalities.
RESUMO
Gastrointestinal (GI) cancer is a prevalent disease and is recognized as the primary cause of cancer-related mortality globally. Therefore, there is an urgent need for novel diagnostic and treatment approaches for GC. The methylation of the O(6)-methylguanine DNA methyltransferase (MGMT) gene promoter is a significant factor in the development of colorectal cancer (CRC), namely in roughly 30-40% of cases where the cancer has spread. MGMT plays a role in the repair of DNA damage caused by methylating drugs like temozolomide (TMZ) and chloroethylating compounds like carmustine. As a result, it contributes to the resistance of chemotherapy when these agents are utilized. Although MGMT's role in the development of CRC is well established, its prognostic significance remains a subject of debate. Only a limited number of research have been conducted to examine the prognostic significance of MGMT methylation, yielding varying outcomes. This review explores the structural functions and repair processes of MGMT, focusing on the putative structural and functional significance of the N-terminal domain of MGMT. It also investigates the advancement of cancer treatment techniques that specifically target MGMT.
RESUMO
BACKGROUND: To improve diagnostic precision in pediatric vertigo, particularly in Vestibular Migraine of Childhood (VMC), probable VMC (pVMC), Recurrent Vertigo of Childhood (RVC), and unspecified categories, by delineating clinical characteristics and prevalence to refine diagnostics and treatments. METHODS: Retrospective analysis of 102 pediatric patients (five to 18 years; 46 females, 56 males) at the Dizziness Center of the Otolaryngology Department in a tertiary-level hospital from January 2019 to December 2023. Patients were classified into VMC, pVMC, RVC, and indeterminate groups. Evaluations included audiometry and vestibular tests (video head impulse test [vHIT] or caloric testing), conducted in the audiology unit and vestibular testing laboratory. Data were analyzed using IBM SPSS 20.0. RESULTS: Diagnoses were 8.8% VMC, 31.4% pVMC, 51.0% RVC, and 8.8% indeterminate. Nausea and vomiting were common in VMC and pVMC; cochlear symptoms like tinnitus and hearing loss predominated in VMC. Although vestibular testing showed no significant group differences, VMC had more vHIT abnormalities and RVC had more caloric test anomalies. CONCLUSIONS: This study highlights the need for comprehensive diagnostics in pediatric vestibular disorders, revealing unique and overlapping traits across VMC, pVMC, and RVC. Insights call for further research to refine diagnostic criteria and improve treatment methods.
Assuntos
Transtornos de Enxaqueca , Centros de Atenção Terciária , Vertigem , Humanos , Feminino , Masculino , Criança , Adolescente , Vertigem/diagnóstico , Vertigem/etiologia , Transtornos de Enxaqueca/diagnóstico , Transtornos de Enxaqueca/complicações , Estudos Retrospectivos , Pré-Escolar , Doenças Vestibulares/diagnóstico , Recidiva , Testes de Função Vestibular , Teste do Impulso da Cabeça , Testes CalóricosRESUMO
Cultivating high nitrogen use efficient varieties is a sustainable solution to mitigating adverse effects on the environment caused by excessive nitrogen fertilizer application. However, in sesame, although immoderate nitrogen fertilizers are used to promote yield, the molecular basis of high nitrogen use efficiency (NUE) is largely unknown. Hence, this study aimed to identify high NUE black sesame variety and dissect the underlying physiological and molecular mechanisms. To achieve this, seventeen seedling traits of 30 black sesame varieties were evaluated under low nitrogen (LN) and high nitrogen (HN) conditions. Dry matter accumulation, root parameters, shoot nitrogen accumulation, and chlorophyll content are important factors for evaluating the NUE of sesame genotypes. The variety 17-156 was identified as the most efficient for N utilization. Comparative physiological and transcriptomics analyses revealed that 17-156 possesses a sophisticated nitrogen metabolizing machinery to uptake and assimilate higher quantities of inorganic nitrogen into amino acids and proteins, and simultaneously improving carbon metabolism and growth. Specifically, the total nitrogen and soluble protein contents significantly increased with the increase in nitrogen concentrations. Many important genes, including nitrate transporters (NPFs), amino acid metabolism-related (GS, GOGAT, GDH, etc.), phytohormone-related, and transcription factors, were significantly up-regulated in 17-156 under HN condition. In addition, 38 potential candidate genes were identified for future studies toward improving sesame's NUE. These findings offer valuable resources for deciphering the regulatory network of nitrogen metabolism and developing sesame cultivars with improved NUE.
Assuntos
Nitrogênio , Sesamum , Nitrogênio/metabolismo , Sesamum/genética , Sesamum/metabolismo , Perfilação da Expressão Gênica , Genótipo , FenótipoRESUMO
BACKGROUND: Cervical spondylotic myelopathy (CSM) is a degenerative pathology that affects both upper and lower extremity mobility and sensory function, causing significant pressure on patients and society. Prior research has suggested that ginsenosides may have neuroprotective properties in central nervous system diseases. However, the efficacy and mechanism of ginsenosides for CSM have yet to be investigated. PURPOSE: This study aims to analyze the composition of ginsenosides using UPLC-MS, identify the underlying mechanism of ginsenosides in treating CSM using network pharmacology, and subsequently confirm the efficacy and mechanism of ginsenosides in rats with chronic spinal cord compression. METHODS: UPLC-Q-TOF-MS was utilized to obtain mass spectrum data of ginsenoside samples. The chemical constituents of the samples were analyzed by consulting literature reports and relevant databases. Ginsenoside and CSM targets were obtained from the TCMSP, OMIM, and GeneCards databases. GO and KEGG analyses were conducted, and a visualization network of ginsenosides-compounds-key targets-pathways-CSM was constructed, along with molecular docking of key bioactive compounds and targets, to identify the signaling pathways and proteins associated with the therapeutic effects of ginsenosides on CSM. Chronic spinal cord compression rats were intraperitoneally injected with ginsenosides (50 mg/kg and 150 mg/kg) and methylprednisolone for 28 days, and motor function was assessed to investigate the therapeutic efficacy of ginsenosides for CSM. The expression of proteins associated with TNF, IL-17, TLR4/MyD88/NF-κB, and NLRP3 signaling pathways was assessed by immunofluorescence staining and western blotting. RESULTS: Using UPLC-Q-TOF-MS, 37 compounds were identified from ginsenoside samples. Furthermore, ginsenosides-compounds-key targets-pathways-CSM visualization network indicated that ginsenosides may modulate the PI3K-Akt signaling pathway, TNF signaling pathway, MAPK signaling pathway, IL-17 signaling pathway, Toll-like receptor signaling pathway and Apoptosis by targeting AKT1, TNF, MAPK1, CASP3, IL6, and IL1B, exerting a therapeutic effect on CSM. By attenuating neuroinflammation through the TNF, IL-17, TLR4/MyD88/NF-κB, and MAPK signaling pathways, ginsenosides restored the motor function of rats with CSM, and ginsenosides 150 mg/kg showed better effect. This was achieved by reducing the phosphorylation of NF-κB and the activation of the NLRP3 inflammasome. CONCLUSIONS: The results of network pharmacology indicate that ginsenosides can inhibit neuroinflammation resulting from spinal cord compression through multiple pathways and targets. This finding was validated through in vivo tests, which demonstrated that ginsenosides can reduce neuroinflammation by inhibiting NLRP3 inflammasomes via multiple signaling pathways, additionally, it should be noted that 150 mg/kg was a relatively superior dose. This study is the first to verify the intrinsic molecular mechanism of ginsenosides in treating CSM by combining pharmacokinetics, network pharmacology, and animal experiments. The findings can provide evidence for subsequent clinical research and drug development.
Assuntos
Experimentação Animal , Medicamentos de Ervas Chinesas , Ginsenosídeos , Compressão da Medula Espinal , Doenças da Medula Espinal , Humanos , Animais , Ratos , Ginsenosídeos/farmacologia , Interleucina-17 , Proteína 3 que Contém Domínio de Pirina da Família NLR , NF-kappa B , Cromatografia Líquida , Simulação de Acoplamento Molecular , Fator 88 de Diferenciação Mieloide , Farmacologia em Rede , Doenças Neuroinflamatórias , Fosfatidilinositol 3-Quinases , Receptor 4 Toll-Like , Espectrometria de Massas em Tandem , Medicamentos de Ervas Chinesas/farmacologiaRESUMO
Tuberous sclerosis complex 1 (TSC1) plays important roles in regulating innate immunity. However, the precise role of TSC1 in macrophages in the regulation of oxidative stress response and hepatic inflammation in liver ischemia/reperfusion injury (I/R) remains unknown. In a mouse model of liver I/R injury, deletion of myeloid-specific TSC1 inhibited AKT and MST1 phosphorylation, and decreased NRF2 accumulation, whereas activated TLR4/NF-κB pathway, leading to increased hepatic inflammation. Adoptive transfer of AKT- or MST1-overexpressing macrophages, or Keap1 disruption in myeloid-specific TSC1-knockout mice promoted NRF2 activation but reduced TLR4 activity and mitigated I/R-induced liver inflammation. Mechanistically, TSC1 in macrophages promoted AKT and MST1 phosphorylation, and protected NRF2 from Keap1-mediated ubiquitination. Furthermore, overexpression AKT or MST1 in TSC1-knockout macrophages upregulated NRF2 expression, downregulated TLR4/NF-κB, resulting in reduced inflammatory factors, ROS and inflammatory cytokine-mediated hepatocyte apoptosis. Strikingly, TSC1 induction in NRF2-deficient macrophages failed to reverse the TLR4/NF-κB activity and production of pro-inflammatory factors. Conclusions: Macrophage TSC1 promoted the activation of the AKT/MST1 signaling pathway, increased NRF2 levels via reducing Keap1-mediated ubiquitination, and modulated oxidative stress-driven inflammatory responses in liver I/R injury. Our findings underscore the critical role of macrophage TSC1 as a novel regulator of innate immunity and imply the therapeutic potential for the treatment of sterile liver inflammation in transplant recipients. Schematic illustration of macrophage TSC1-mediated AKT/MST1/NRF2 signaling pathway in I/R-triggered liver inflammation. Macrophage TSC1 can be activated in I/R-stressed livers. TSC1 activation promotes phosphorylation of AKT and MST1, which in turn increases NRF2 expression and inhibits ROS production and TLR4/NF-κB activation, resulting in reduced hepatocellular apoptosis in I/R-triggered liver injury.
Assuntos
Traumatismo por Reperfusão , Esclerose Tuberosa , Animais , Camundongos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo , Esclerose Tuberosa/metabolismo , Fígado/metabolismo , Transdução de Sinais , Macrófagos/metabolismo , Inflamação/metabolismo , Traumatismo por Reperfusão/metabolismoRESUMO
What is already known about this topic?: Given the common modes of transmission, outbreaks of both human immunodeficiency virus (HIV) and syphilis are primarily observed in men who have sex with men (MSM). However, minimal research has been conducted to concurrently evaluate the rates and trends of HIV and syphilis incidence within this community in China. What is added by this report?: This manuscript presents the incidence rates and associated factors of HIV and syphilis in MSM in Tianjin based on data derived from a decade-long cohort study. Intriguingly, it depicts a decreasing trend in HIV incidence juxtaposed with an increasing incidence of syphilis among this population in Tianjin. What are the implications for public health practice?: The interconnected risk factors for HIV and syphilis pose significant hindrances to disease control. Our study underscores the urgent need for improved intervention strategies specifically aimed at MSM to mitigate the propagation of both infections.
RESUMO
Isolated otolith dysfunction(iOD) involves a group of unexplained vestibular syndromes that manifest clinically as a sense of translation, tilting or floating, and blurred vision with head movement, with normal semicircular canal function but abnormal otolith function on laboratory vestibular testing. As vestibular medicine has gained widespread popularity in recent years, increasing attention has also been paid to iOD and case reports, clinical studies and diagnostic criteria have been published. However, there is no consensus document to guide the diagnosis of this disease in China. In this context, the Special Committee on Vertigo of China Medical Education Association organized a group of domestic experts in vestibular medicine and formulated this diagnostic consensus after thorough discussion based on the latest evidence in China and abroad, in order to promote the best clinical practice for iOD.
Assuntos
Doenças Vestibulares , Vestíbulo do Labirinto , Humanos , Membrana dos Otólitos , Doenças Vestibulares/diagnóstico , Vertigem/diagnóstico , Canais SemicircularesRESUMO
Missing data can pose a challenge for machine learning (ML) modeling. To address this, current approaches are categorized into feature imputation and label prediction and are primarily focused on handling missing data to enhance ML performance. These approaches rely on the observed data to estimate the missing values and therefore encounter three main shortcomings in imputation, including the need for different imputation methods for various missing data mechanisms, heavy dependence on the assumption of data distribution, and potential introduction of bias. This study proposes a Contrastive Learning (CL) framework to model observed data with missing values, where the ML model learns the similarity between an incomplete sample and its complete counterpart and the dissimilarity between other samples. Our proposed approach demonstrates the advantages of CL without requiring any imputation. To enhance interpretability, we introduce CIVis, a visual analytics system that incorporates interpretable techniques to visualize the learning process and diagnose the model status. Users can leverage their domain knowledge through interactive sampling to identify negative and positive pairs in CL. The output of CIVis is an optimized model that takes specified features and predicts downstream tasks. We provide two usage scenarios in regression and classification tasks and conduct quantitative experiments, expert interviews, and a qualitative user study to demonstrate the effectiveness of our approach. In short, this study offers a valuable contribution to addressing the challenges associated with ML modeling in the presence of missing data by providing a practical solution that achieves high predictive accuracy and model interpretability.