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1.
Biomaterials ; 312: 122722, 2025 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-39096841

RESUMO

Ferroptosis, a recently identified form of cell death, holds promise for cancer therapy, but concerns persist regarding its uncontrolled actions and potential side effects. Here, we present a semiconducting polymer nanoprodrug (SPNpro) featuring an innovative ferroptosis prodrug (DHU-CBA7) to induce sono-activatable ferroptosis for tumor-specific therapy. DHU-CBA7 prodrug incorporate methylene blue, ferrocene and urea bond, which can selectively and specifically respond to singlet oxygen (1O2) to turn on ferroptosis action via rapidly cleaving the urea bonds. DHU-CBA7 prodrug and a semiconducting polymer are self-assembled with an amphiphilic polymer to construct SPNpro. Ultrasound irradiation of SPNpro leads to the production of 1O2 via sonodynamic therapy (SDT) of the semiconducting polymer, and the generated 1O2 activated DHU-CBA7 prodrug to achieve sono-activatable ferroptosis. Consequently, SPNpro combine SDT with the controlled ferroptosis to effectively cure 4T1 tumors covered by 2-cm tissue with a tumor inhibition efficacy as high as 100 %, and also completely restrain tumor metastases. This study introduces a novel sono-activatable prodrug strategy for regulating ferroptosis, allowing for precise cancer therapy.


Assuntos
Ferroptose , Camundongos Endogâmicos BALB C , Polímeros , Pró-Fármacos , Semicondutores , Ferroptose/efeitos dos fármacos , Pró-Fármacos/farmacologia , Pró-Fármacos/química , Pró-Fármacos/uso terapêutico , Animais , Polímeros/química , Feminino , Linhagem Celular Tumoral , Camundongos , Terapia por Ultrassom/métodos , Nanopartículas/química , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Antineoplásicos/química , Oxigênio Singlete/metabolismo
2.
Adv Healthc Mater ; : e2401376, 2024 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-39226527

RESUMO

Interleukin-12 (IL-12) is a critical cytokine with notable anticancer properties, including enhancing T-cell-mediated cancer cell killing, and curbing tumor angiogenesis. To date, many approaches are evaluated to achieve in situ overexpression of IL-12, minimizing leakage and the ensuing toxicity. Here, it is focused on circular single-stranded DNA (Css DNA), a type of DNA characterized by its unique structure, which could be expressed in mammals. It is discovered that Css DNA can induce sustained luciferase expression for half a year by intramuscular injection and showed effective antitumor results by intratumoral injection. Motivated by these findings, a folate-modified LNP system is now developed for the delivery of Css DNA expressing IL-12 for the therapy of 4T1 triple-negative breast cancer (TNBC). This delivery system effectively activates anti-cancer immune responses, slows tumor growth, significantly prolongs survival in animal models, and prevents tumor recurrence. After 6 months of long-term observation, the elevated level of IL-12 is still detectable in the lymph nodes and serum of the cured mice. This study highlights the long-term sustained expression capacity of Css DNA and its ability to inhibit recurrence, and the potential of tumor-targeted LNPs for Css DNA-based cancer therapy, providing a new insight into gene overexpression strategy.

3.
ChemMedChem ; : e202400410, 2024 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-39264862

RESUMO

Nanoparticles can enhance drugs accumulating at the tumor site and hold tremendous promise for achieving effective tumor treatment. However, due to the complexity of cancer heterogeneity and suppressive tumor microenvironment, the delivery of traditional nanoparticles has poor infiltration and off-target effects, making it difficult to control the drug release rate and causing off-target toxicity. In recent years, cell membrane-coated biomimetic nanoparticles have been developed, which have both the natural characteristics of biomembranes and the physical characteristics of traditional nanoparticles, thus improving the homologous targeting ability of nanoparticles to tumor cells and better biocompatibility. In this paper, we reviewed the application of single cell membrane and hybrid cell membrane-coated biomimetic nanoparticles in the integration for tumor diagnosis and treatment. We talked about the preparation methods of cell membrane-coated nanoparticles, the targeting mechanisms, and the effects of imaging and therapeutic outcomes of different cell membrane-coated biomimetic nanoparticles in detail. Finally, we discussed the existing problems and prospects of cell membrane-coated biomimetic nanomaterials.

4.
Food Chem ; 460(Pt 2): 140623, 2024 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-39096798

RESUMO

Milk alternative attracts more attention due to nutrition benefits, but the low solubility and the calcium deficiency of plant protein hinder the development of milk alternatives. Therefore, pH shifting was optimized to improve chickpea protein solubility and calcium fortification while ensuring good digestibility. The results showed that pH shifting reduced the particle size from 2197.67 ± 178.2 nm to 80.2 ± 2 nm, and increased the net ζ potential from -0.48 ± 0.24 to -21.27 ± 0.65 due to the unfolding of secondary protein structure, by which chickpea protein bring better solution stability. Additionally, the whiteness of the solution with chickpea protein increased. The calcium addition kept the solution stable with small particle size despite a slight increase. The microstructure of chickpea protein during digestion was well disrupted even with fortifying calcium. This study provides proof of the positive effect of pH shifting on chickpea protein stability and calcium fortification.


Assuntos
Cálcio , Cicer , Alimentos Fortificados , Proteínas de Plantas , Cicer/química , Concentração de Íons de Hidrogênio , Cálcio/química , Proteínas de Plantas/química , Animais , Alimentos Fortificados/análise , Solubilidade , Substitutos do Leite/química , Digestão , Leite/química , Tamanho da Partícula
5.
Mol Biol Evol ; 41(9)2024 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-39213378

RESUMO

Polyploidization drives regulatory and phenotypic innovation. How the merger of different genomes contributes to polyploid development is a fundamental issue in evolutionary developmental biology and breeding research. Clarifying this issue is challenging because of genome complexity and the difficulty in tracking stochastic subgenome divergence during development. Recent single-cell sequencing techniques enabled probing subgenome-divergent regulation in the context of cellular differentiation. However, analyzing single-cell data suffers from high error rates due to high dimensionality, noise, and sparsity, and the errors stack up in polyploid analysis due to the increased dimensionality of comparisons between subgenomes of each cell, hindering deeper mechanistic understandings. In this study, we develop a quantitative computational framework, called "pseudo-genome divergence quantification" (pgDQ), for quantifying and tracking subgenome divergence directly at the cellular level. Further comparing with cellular differentiation trajectories derived from single-cell RNA sequencing data allows for an examination of the relationship between subgenome divergence and the progression of development. pgDQ produces robust results and is insensitive to data dropout and noise, avoiding high error rates due to multiple comparisons of genes, cells, and subgenomes. A statistical diagnostic approach is proposed to identify genes that are central to subgenome divergence during development, which facilitates the integration of different data modalities, enabling the identification of factors and pathways that mediate subgenome-divergent activity during development. Case studies have demonstrated that applying pgDQ to single-cell and bulk tissue transcriptomic data promotes a systematic and deeper understanding of how dynamic subgenome divergence contributes to developmental trajectories in polyploid evolution.


Assuntos
Poliploidia , Análise de Célula Única , Análise de Célula Única/métodos , Animais , Biologia Computacional/métodos
6.
Nucleic Acids Res ; 52(17): 10220-10234, 2024 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-39149894

RESUMO

The 3D chromatin organization plays a major role in the control of gene expression. However, our comprehension of the governing principles behind nuclear organization remains incomplete. Particularly, the spatial segregation of loci with similar repressive transcriptional states in plants poses a significant yet poorly understood puzzle. In this study, employing a combination of genetics and advanced 3D genomics approaches, we demonstrated that a redistribution of facultative heterochromatin marks in regions usually occupied by constitutive heterochromatin marks disrupts the 3D genome compartmentalisation. This disturbance, in turn, triggers novel chromatin interactions between genic and transposable element (TE) regions. Interestingly, our results imply that epigenetic features, constrained by genetic factors, intricately mold the landscape of 3D genome organisation. This study sheds light on the profound genetic-epigenetic interplay that underlies the regulation of gene expression within the intricate framework of the 3D genome. Our findings highlight the complexity of the relationships between genetic determinants and epigenetic features in shaping the dynamic configuration of the 3D genome.


Assuntos
Arabidopsis , Elementos de DNA Transponíveis , Epigênese Genética , Genoma de Planta , Heterocromatina , Elementos de DNA Transponíveis/genética , Heterocromatina/metabolismo , Heterocromatina/genética , Arabidopsis/genética , Arabidopsis/metabolismo , Regulação da Expressão Gênica de Plantas , Cromatina/metabolismo , Cromatina/genética , Histonas/metabolismo , Histonas/genética , Genômica/métodos
7.
Artigo em Inglês | MEDLINE | ID: mdl-39154931

RESUMO

BACKGROUND: Major depressive disorder (MDD) and schizophrenia (SCZ) are heritable brain disorders characterized by alterations in cortical thickness. However, the shared genetic basis for cortical thickness changes in these disorders remains unclear. METHODS: We conducted a systematic literature search on cortical thickness in MDD and SCZ through PubMed and Web of Science. A coordinate-based meta-analysis was performed to identify cortical thickness changes. Additionally, utilizing summary statistics from the largest genome-wide association studies for depression (Ncase = 268,615, Ncontrol = 667,123) and SCZ (Ncase = 53,386, Ncontrol = 77,258), we explored shared genomic loci using conjunctional false discovery rate (conjFDR) analysis. Transcriptome-neuroimaging association analysis was then employed to identify shared genes associated with cortical thickness alterations, and enrichment analysis was finally carried out to elucidate the biological significance of these genes. RESULTS: Our search yielded 34 MDD (Ncase = 1621, Ncontrol = 1507) and 19 SCZ (Ncase = 1170, Ncontrol = 1043) neuroimaging studies for cortical thickness meta-analysis. Specific alterations in the left supplementary motor area were observed in MDD, while SCZ exhibited widespread reductions in various brain regions, particularly in the frontal and temporal areas. The conjFDR approach identified 357 genomic loci jointly associated with MDD and SCZ. Within these loci, 55 genes were found to be associated with cortical thickness alterations in both disorders. Enrichment analysis revealed their involvement in nervous system development, apoptosis, and cell communication. CONCLUSION: This study revealed the shared genetic architecture underlying cortical thickness alterations in MDD and SCZ, providing insights into common neurobiological pathways. The identified genes and pathways may serve as potential transdiagnostic markers, informing precision medicine approaches in psychiatric care.


Assuntos
Córtex Cerebral , Transtorno Depressivo Maior , Estudo de Associação Genômica Ampla , Esquizofrenia , Humanos , Transtorno Depressivo Maior/genética , Transtorno Depressivo Maior/patologia , Transtorno Depressivo Maior/diagnóstico por imagem , Esquizofrenia/genética , Esquizofrenia/patologia , Esquizofrenia/diagnóstico por imagem , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/patologia , Espessura Cortical do Cérebro , Neuroimagem
8.
Reprod Sci ; 2024 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-39090336

RESUMO

Infertility affects approximately 15% of couples at child-bearing ages and assisted reproductive technologies (ART), especially in vitro fertilization and embryo transfer (IVF-ET), provided infertile patients with an effective solution. The current paradox is that multiple embryo transfer that may leads to severe obstetric and perinatal complications seems to be the most valid measure to secure high success rate in the majority of clinic centers. Therefore, to avoid multiple transfer of embryos, it is urgent to explore biomarkers for IVF prognosis to select high-quality oocytes and embryos. Follicular fluid (FF), a typical biofluid constituted of the plasma effusion and granulosa-cell secretion, provides essential intracellular substances for oocytes maturation and its variation in composition reflects oocyte developmental competence and embryo viability. With the advances in metabolomics methodology, metabolomics, as an accurate and sensitive analyzing method, has been utilized to explore predictors in FF for ART success. Although FF metabolomics has provided a great possibility for screening markers with diagnostic and predictive value, its effectiveness is still doubted by some researchers. This may be resulted from the ignorance of the impact of sterility causes on the FF metabolomic profiles and thus its predictive ability might not be rightly illustrated. Therefore, in this review, we categorically demonstrate the study of FF metabolomics according to specific infertility causes, expecting to reveal the predicting value of metabolomics for IVF outcomes.

9.
Artigo em Inglês | MEDLINE | ID: mdl-39217212

RESUMO

PURPOSE: Obesity is commonly linked to both adenotonsillar hypertrophy (ATH) and allergic disorders, in which the roles of adipokines are not fully illuminated. This study aims to investigate the levels of leptin and adiponectin and their associations with allergic sensitization in pediatric ATH. METHODS: Serum levels of specific immunoglobulin E (IgE), leptin and adiponectin were quantified in 35 controls and 111 ATH children, in which 54 were non-atopic and 57 were atopic. Spearman's correlation analysis and polynomial linear trend test were conducted. The odds ratios and 95% confidence intervals were calculated by binary logistic regression after multivariable adjustment. RESULTS: The serum level of leptin and leptin/adiponectin (L/A) ratio was significantly increased in children with ATH. An increase in leptin level and L/A ratio and a decrease in adiponectin level were observed in atopic children compared with non-atopic children. Among ATH children, the level of adiponectin was negatively while L/A ratio was positively correlated with specific IgE. After multivariable adjustment, leptin was significantly associated with increased risk of atopy to D. pteronyssinus and D. farina, and adiponectin was significantly associated with decreased risk of atopy to willow and mugwort. Leptin was associated with higher odds while adiponectin was associated with lower odds of overall atopy. Besides, significant multiplicative interactions of obesity with leptin and adiponectin on atopy were observed respectively. CONCLUSION: Leptin and adiponectin were both associated with allergic sensitization and function differently in pediatric ATH. Mechanistic studies are needed to elucidate the involvement of adipokines in allergic sensitization of pediatric ATH.

10.
Brain Topogr ; 37(6): 1118-1138, 2024 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-38990422

RESUMO

Shooting is a fine sport that is greatly influenced by mental state, and the neural activity of brain in the preparation stage of shooting has a direct influence on the level of shooting. In order to explore the brain neural mechanism in the preparation stage of pistol shooting under audiovisual restricted conditions, and to reveal the intrinsic relationship between brain activity and shooting behavior indicators, the electroencephalography (EEG) signals and seven shooting behaviors including shooting performance, gun holding stability, and firing stability, were experimentally captured from 30 shooters, these shooters performed pistol shooting under three conditions, normal, dim, and noisy. Using EEG microstates combined with standardized low-resolution brain electromagnetic tomography (sLORETA) traceability analysis method, we investigated the difference between the microstates characteristics under audiovisual restricted conditions and normal condition, the relationship between the microstates characteristics and the behavioral indicators during the shooting preparation stage under different conditions. The experimental results showed that microstate 1 corresponded to microstate A, microstate 2 corresponded to microstate B, and microstate 4 corresponded to microstate D; Microstate 3 was a unique template, which was localized in the occipital lobe, its function was to generate the "vision for action"; The dim condition significantly reduced the shooter's performance, whereas the noisy condition had less effect on the shooter's performance; In audiovisual restricted conditions, the microstate characteristics were significantly different from those in the normal condition. Microstate 4' parameters decreased significantly while microstate 3' parameters increased significantly under restricted visual and auditory conditions; Dim condition required more shooting skills from the shooter; There was a significant relationship between characteristics of microstates and indicators of shooting behavior; It was concluded that in order to obtain good shooting performance, shooters should improve attention and concentrate on the adjustment of collimator and target's center leveling relation, but the focus was slightly different in the three conditions; Microstates that are more important for accomplishing the task have less variation in their characteristics over time; Similar conclusions to previous studies were obtained at the same time, i.e., increased visual attention prior to shooting is detrimental to shooting performance, and there is a high positive correlation with microstate D for task completion. The experimental results further reveal the brain neural mechanism in the shooting preparation stage, and the extracted neural markers can be used as effective functional indicators for monitoring the brain state in the shooting preparation stage of pistols.


Assuntos
Encéfalo , Eletroencefalografia , Armas de Fogo , Humanos , Masculino , Eletroencefalografia/métodos , Encéfalo/fisiologia , Adulto , Adulto Jovem , Percepção Visual/fisiologia , Mapeamento Encefálico/métodos , Desempenho Psicomotor/fisiologia , Feminino , Estimulação Luminosa/métodos
11.
Front Aging Neurosci ; 16: 1418455, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39021706

RESUMO

Background: Cognitive function (CF) deterioration is a pressing concern in geriatric research. This study aimed to explore the relationship between physical activity (PA) and CF in older adults. Methods: This study adopted a dual approach, employing both observational and genetic approaches through data from the National Health and Nutrition Examination Survey (NHANES) 2011-2014 and Mendelian Randomization (MR) analysis. For the NHANES component, PA levels were evaluated using the Global Physical Activity Questionnaire, and CF was assessed via standardized tests. Multivariate regression, threshold effect analysis, smoothing curve fitting, and subgroup analyses were conducted to examine the association between PA and CF. In parallel, MR methods, using genetic variants as instrumental variables, assessed the causal impact of PA on CF and related conditions such as Alzheimer's disease and dementia. Results: Observational findings from NHANES demonstrated a positive correlation between PA and CF, notably among female participants. The detailed analysis identified specific thresholds of PA that correlate with cognitive enhancements. However, MR results did not support a significant causal relationship between PA and CF or dementia-related outcomes, indicating an absence of a direct genetic basis for the observational associations. Conclusion: Although observational data from NHANES suggest that PA is positively associated with CF in older adults, particularly among women, MR analysis did not confirm these findings as causally related. The discrepancy highlights the complexity of the PA-CF relationship and underscores the need for further research. These results emphasize the potential of PA as a modifiable risk factor for CF, though causal effects remain to be definitively established.

12.
Proc Natl Acad Sci U S A ; 121(28): e2400737121, 2024 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-38968127

RESUMO

In recent years, the exploration of genome three-dimensional (3D) conformation has yielded profound insights into the regulation of gene expression and cellular functions in both animals and plants. While animals exhibit a characteristic genome topology defined by topologically associating domains (TADs), plants display similar features with a more diverse conformation across species. Employing advanced high-throughput sequencing and microscopy techniques, we investigated the landscape of 26 histone modifications and RNA polymerase II distribution in tomato (Solanum lycopersicum). Our study unveiled a rich and nuanced epigenetic landscape, shedding light on distinct chromatin states associated with heterochromatin formation and gene silencing. Moreover, we elucidated the intricate interplay between these chromatin states and the overall topology of the genome. Employing a genetic approach, we delved into the role of the histone modification H3K9ac in genome topology. Notably, our investigation revealed that the ectopic deposition of this chromatin mark triggered a reorganization of the 3D chromatin structure, defining different TAD-like borders. Our work emphasizes the critical role of H3K9ac in shaping the topology of the tomato genome, providing valuable insights into the epigenetic landscape of this agriculturally significant crop species.


Assuntos
Epigenoma , Histonas , Solanum lycopersicum , Solanum lycopersicum/genética , Solanum lycopersicum/metabolismo , Histonas/metabolismo , Histonas/genética , Epigênese Genética , Genoma de Planta , Cromatina/metabolismo , Cromatina/genética , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Regulação da Expressão Gênica de Plantas , Heterocromatina/metabolismo , Heterocromatina/genética , Código das Histonas/genética
13.
Heliyon ; 10(13): e33988, 2024 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-39050416

RESUMO

Background: Limited evidence exists regarding the clinical baseline characteristics at admission for acute kidney injury (AKI) before and after interventional cardiac procedures (ICP) in elderly patients with coronary artery disease (CAD). Methods: A total of 488 elderly patients were enrolled in this retrospective single-center study conducted from January 2019 to July 2022, and a classification and regression tree (CART) analysis was performed to identify the high-risk population. Results: The AKI incidence was 21.1 % (103/488) in this study, with 27 and 76 individuals developing AKI before and after ICP, respectively. CART analysis revealed that exposure to nephrotoxic drugs and diuretics had the strongest predictive capacities for identifying patients at risk of developing pre-ICP AKI, with the incidence among these high-risk patients ranging from 6.5 % to 13.8 %. Meanwhile, the optimum discriminators for identifying those at high risk of post-ICP AKI were the administration of diuretics, D-value ≤ -860 mL, age >73 years, and administration of nephrotoxic drugs, and the latter model predicted that the AKI incidence among high-risk patients was between 50.0 % and 60.0 %. Conclusions: Elderly patients with CAD exhibited an elevated incidence of AKI. CART models suggested that exposure to nephrotoxic drugs and diuretics, D-value, and age were significantly associated with AKI in the elderly with CAD. Importantly, these baseline characteristics at admission could be utilized to identify elderly patients at high risk of pre- and post-ICP AKI.

14.
Cell Biochem Biophys ; 82(3): 2373-2385, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38877335

RESUMO

Prostate cancer (PCa) remains a leading cause of cancer-related incidence and mortality in men. Disruptions in amino acid (AA) metabolism contribute to the disease progression, with brucine, a glycine antagonist, exhibiting antitumor effects. This study explores the antitumor impact of brucine on PCa and investigates its mechanisms in regulating AA metabolic pathways. The study employed the PCa cell line DU-145, characterized by high sarcosine (Sar) levels, for various assays including Cell Counting Kit-8 (CCK8), wound healing, Transwell, 5-Ethynyl-2'-deoxyuridine (EDU), TdT mediated dUTP Nick End Labeling (TUNEL), flow cytometry, Western blot, and ultra-high-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Network pharmacological analysis determined the anticancer mechanisms of brucine. Sar levels in DU-145 cells were significantly higher than in normal prostatic epithelial cells RWPE-1. Treatment with brucine resulted in a marked decrease in cell viability, proliferation, invasion, and migration, while promoting apoptosis in a dose-dependent manner. Sar levels decreased with increasing brucine concentration. Network pharmacology analysis linked brucine's anticancer effect to the AA metabolism and glycine N-methyltransferase (GNMT) pathways. GNMT expression in prostate cancer tissues and The Cancer Genome Atlas database was significantly elevated compared to controls. Treatment with brucine led to downregulation of GNMT expression in DU-145 cells without significant effect on sarcosine dehydrogenase (SARDH). Addition of recombinant GNMT partially reversed the inhibitory effects of brucine on DU-145 cells. Treatment with brucine downregulates GNMT expression in DU-145 cells, reducing Sar accumulation and inhibiting tumor progression. These findings provide new insights into the antitumor mechanisms of brucine in PCa.


Assuntos
Apoptose , Regulação para Baixo , Glicina N-Metiltransferase , Glicina , Neoplasias da Próstata , Sarcosina , Estricnina , Masculino , Humanos , Sarcosina/análogos & derivados , Sarcosina/farmacologia , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Neoplasias da Próstata/tratamento farmacológico , Linhagem Celular Tumoral , Regulação para Baixo/efeitos dos fármacos , Estricnina/análogos & derivados , Estricnina/farmacologia , Glicina/análogos & derivados , Glicina/farmacologia , Apoptose/efeitos dos fármacos , Glicina N-Metiltransferase/metabolismo , Glicina N-Metiltransferase/genética , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Progressão da Doença , Movimento Celular/efeitos dos fármacos , Antineoplásicos/farmacologia , Redes e Vias Metabólicas/efeitos dos fármacos
15.
J Pharm Biomed Anal ; 248: 116313, 2024 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-38878453

RESUMO

Hypericum perforatum L. (HPL), also known as St. John's wort, is one of the extensively researched domestically and internationally as a medicinal plant. In this study, non-targeted metabolomics combined with machine learning methods were used to identify reasonable quality indicators for the holistic quality control of HPL. First, the high-resolution MS data from different samples of HPL were collected, and visualized the chemical compounds through the MS molecular network. A total of 122 compounds were identified. Then, the orthogonal partial least squares-discriminant analysis (OPLS-DA) model was established for comparing the differences in metabolite expression between flower, leaf, and branches. A total of 46 differential metabolites were screened out. Subsequently, analyzing the pharmacological activities of these differential metabolites based on protein-protein interaction (PPI) network. A total of 25 compounds associated with 473 gene targets were retrieved. Among them, 13 highly active compounds were selected as potential quality markers, and five compounds were ultimately selected as quality control markers for HPL. Finally, three different classifiers (support vector machine (SVM), random forest (RF), and K-nearest neighbor (KNN)) were used to validate whether the selected quality control markers are qualified. When the feature count is set to 122 and 46, the RF model demonstrates optimal performance. As the number of variables decreases, the performance of the RF model degrades. The KNN model and the SVM model also exhibit a decrease in performance but still manage to satisfy the intended requirements. The strategy can be applied to the quality control of HPL and can provide a reference for the quality control of other herbal medicines.


Assuntos
Hypericum , Aprendizado de Máquina , Metabolômica , Controle de Qualidade , Espectrometria de Massas em Tandem , Hypericum/química , Espectrometria de Massas em Tandem/métodos , Cromatografia Líquida de Alta Pressão/métodos , Metabolômica/métodos , Máquina de Vetores de Suporte , Extratos Vegetais/química , Extratos Vegetais/análise , Análise dos Mínimos Quadrados , Mapas de Interação de Proteínas/efeitos dos fármacos , Análise Discriminante , Plantas Medicinais/química
16.
Int J Biol Macromol ; 269(Pt 1): 132083, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38705327

RESUMO

Arginine deiminase (ADI) has garnered significant interest because of its ability to objectively eradicate cancer cells and produce L-citrulline. To meet the production demands, this study focused on enhancing the enzyme activity and thermal stability of ADI. In this study, 24 ADI mutants were obtained through computer aid site-specific mutation in the ADI of Enterobacter faecalis. Notably, the specific enzyme activities of F44W, N163P, E220I, E220L, N318E, A336G, T340I, and N382F increased, reaching 1.33-2.53 times that of the original enzyme. This study confirmed that site-specific mutations are critical for optimizing enzyme function. Additionally, the F44W, N163P, E220I, T340I, and A336G mutants demonstrated good thermal stability. The optimal pH for mutant F44W increased to 8, whereas mutants E220I, I244V, A336G, T340I, and N328F maintained an optimal pH of 7.5. Conversely, the M109L, N163P, E220L, I244L, and N318E mutants shad an optimal pH of 7. This study revealed that mutant enzymes with increased activity were more likely to contain mutation sites situated near the four loops associated with catalytic residues, whereas mutations at the dimer junction sites had a higher tendency to enhance enzyme stability. These findings contribute to the development of ADI industrial applications and its modifications.


Assuntos
Estabilidade Enzimática , Hidrolases , Hidrolases/química , Hidrolases/genética , Hidrolases/metabolismo , Concentração de Íons de Hidrogênio , Mutação , Cinética , Engenharia de Proteínas/métodos , Biocatálise , Mutagênese Sítio-Dirigida , Modelos Moleculares , Temperatura
17.
Adv Mater ; 36(30): e2310731, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38805174

RESUMO

As a central metabolic molecule, nicotinamide adenine dinucleotide (NAD+) can potentially treat acute kidney injury (AKI) and chronic kidney disease (CKD); however, its bioavailability is poor due to short half-life, instability, the deficiency of targeting, and difficulties in transmembrane transport. Here a physiologically adaptive gallic acid-NAD+ nanoparticle is designed, which has ultrasmall size and pH-responsiveness, passes through the glomerular filtration membrane to reach injured renal tubules, and efficiently delivers NAD+ into the kidneys. With an effective accumulation in the kidneys, it restores renal function, immune microenvironment homeostasis, and mitochondrial homeostasis of AKI mice via the NAD+-Sirtuin-1 axis, and exerts strong antifibrotic effects on the AKI-to-CKD transition by inhibiting TGF-ß signaling. It also exhibits excellent stability, biodegradable, and biocompatible properties, ensuring its long-term safety, practicality, and clinical translational feasibility. The present study shows a potential modality of mitochondrial repair and immunomodulation through nanoagents for the efficient and safe treatment of AKI and CKD.


Assuntos
Injúria Renal Aguda , Anti-Inflamatórios , Rim , Mitocôndrias , NAD , Nanopartículas , Polifenóis , Insuficiência Renal Crônica , Injúria Renal Aguda/tratamento farmacológico , Injúria Renal Aguda/metabolismo , Injúria Renal Aguda/patologia , Animais , NAD/metabolismo , NAD/química , Camundongos , Mitocôndrias/metabolismo , Mitocôndrias/efeitos dos fármacos , Insuficiência Renal Crônica/tratamento farmacológico , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/patologia , Polifenóis/química , Polifenóis/farmacologia , Nanopartículas/química , Anti-Inflamatórios/química , Anti-Inflamatórios/uso terapêutico , Anti-Inflamatórios/farmacologia , Rim/metabolismo , Rim/patologia , Progressão da Doença , Ácido Gálico/química , Ácido Gálico/farmacologia , Humanos
19.
Toxicol Appl Pharmacol ; 485: 116909, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38521370

RESUMO

BACKGROUND: Obstructive sleep apnea (OSA) is considered to be an important contributor of dyslipidemia. However, there lacks observational studies focusing on the potential effect of lipid management on OSA risk. Thus, we aimed to investigate the genetic association of lipid-modifying therapy with risk of OSA. METHODS: A drug-target mendelian randomization (MR) study using both cis-variants and cis-expression quantitative trait loci (eQTLs) of lipid-modifying drug targets was performed. The MR analyses used summary-level data of genome wide association studies (GWAS). Primary MR analysis was conducted using inverse-variance-weighted (IVW) method. Sensitivity analysis was performed using weighted median (WM) and MR-pleiotropy residual sum and outlier (MR-PRESSO) methods. RESULTS: Genetically proxied low-density lipoprotein cholesterol (LDL-C)-lowering effect of cholesteryl ester transfer protein (CETP) was associated with reduced risk of OSA (odds ratio [OR] =0.75, 95% confidence interval [CI]: 0.60-0.94, false discovery rate [FDR] q value = 0.046). A significant MR association with risk of OSA was observed for CETP expression in subcutaneous adipose tissue (OR = 0.94, 95%CI: 0.89-1.00, FDR q value = 0.049), lung (OR = 0.94, 95%CI: 0.89-1.00, FDR q value = 0.049) and small intestine (OR = 0.96, 95%CI: 0.93-1.00, FDR q value = 0.049). No significant effects of high-density lipoprotein cholesterol (HDL-C)-raising effect of CETP inhibition, LDL-C-lowering and triglycerides-lowering effect of other drug targets on OSA risk were observed. CONCLUSIONS: The present study presented genetic evidence supporting the association of LDL-C-lowering therapy by CETP inhibition with reduced risk of OSA. These findings provided novel insights into the role of lipid management in patients with OSA and encouraged further clinical validations and mechanistic investigations.


Assuntos
Proteínas de Transferência de Ésteres de Colesterol , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Apneia Obstrutiva do Sono , Apneia Obstrutiva do Sono/genética , Humanos , Proteínas de Transferência de Ésteres de Colesterol/genética , LDL-Colesterol/sangue , Dislipidemias/genética , Dislipidemias/tratamento farmacológico , Dislipidemias/epidemiologia , Dislipidemias/sangue , Locos de Características Quantitativas , Hipolipemiantes/uso terapêutico , Fatores de Risco , Polimorfismo de Nucleotídeo Único
20.
Physiol Plant ; 176(2): e14254, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38499939

RESUMO

Together with rice, weeds strive for nutrients and space in farmland, resulting in reduced rice yield and quality. Planting herbicide-resistant rice varieties is one of the effective ways to control weeds. In recent years, a series of breakthroughs have been made to generate herbicide-resistant germplasm, especially the emergence of biotechnological tools such as gene editing, which provides an inherent advantage for the knock-out or knock-in of the desired genes. In order to develop herbicide-resistant rice germplasm resources, gene manipulation has been conducted to enhance the herbicide tolerance of rice varieties through the utilization of techniques such as physical and chemical mutagenesis, as well as genome editing. Based on the current research and persisting problems in rice paddy fields, research on the generation of herbicide-resistant rice still needs to explore genetic mechanisms, stacking multiple resistant genes in a single genotype, and transgene-free genome editing using the CRISPR system. Current rapidly developing gene editing technologies can be used to mutate herbicide target genes, enabling targeted genes to maintain their biological functions, and reducing the binding ability of target gene encoded proteins to corresponding herbicides, ultimately resulting in herbicide-resistant crops. In this review article, we have summarized the utilization of conventional and modern approaches to develop herbicide-resistant cultivars in rice as an effective strategy for weed control in paddy fields, and discussed the technology and research directions for creating herbicide-resistant rice in the future.


Assuntos
Herbicidas , Oryza , Oryza/genética , Herbicidas/farmacologia , Plantas Daninhas , Biotecnologia , Produtos Agrícolas/genética , Resistência a Herbicidas/genética
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