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1.
Proc Natl Acad Sci U S A ; 121(40): e2408711121, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39325424

RESUMO

Effective colonization by microbe in the rhizosphere is critical for establishing a beneficial symbiotic relationship with the host plant. Bacillus subtilis, a soil-dwelling bacterium that is commonly found in association with plants and their rhizosphere, has garnered interest for its potential to enhance plant growth, suppress pathogens, and contribute to sustainable agricultural practices. However, research on the dynamic distribution of B. subtilis within the rhizosphere and its interaction mechanisms with plant roots remains insufficient due to limitations in existing in situ detection methodologies. To achieve dynamic in situ detection of the rhizosphere environment, we established iRhizo-Chip, a microfluidics-based platform. Using this device to investigate microbial behavior within the rhizosphere, we found obvious diurnal fluctuations in the growth of B. subtilis in the rhizosphere. Temporal dynamic analysis of rhizosphere dissolved oxygen (DO), pH, dissolved organic carbon, and reactive oxygen species showed that diurnal fluctuations in the growth of B. subtilis are potentially related to a variety of environmental factors. Spatial dynamic analysis also showed that the spatial distribution changes of B. subtilis and DO and pH were similar. Subsequently, through in vitro control experiments, we proved that rhizosphere DO and pH are the main driving forces for diurnal fluctuations in the growth of B. subtilis. Our results show that the growth of B. subtilis is driven by rhizosphere DO and pH, resulting in diurnal fluctuations, and iRhizo-Chip is a valuable tool for studying plant rhizosphere dynamics.


Assuntos
Bacillus subtilis , Rizosfera , Microbiologia do Solo , Bacillus subtilis/metabolismo , Bacillus subtilis/fisiologia , Raízes de Plantas/microbiologia , Raízes de Plantas/metabolismo , Dispositivos Lab-On-A-Chip , Ritmo Circadiano/fisiologia , Oxigênio/metabolismo , Oxigênio/análise , Concentração de Íons de Hidrogênio , Espécies Reativas de Oxigênio/metabolismo
2.
Proc Natl Acad Sci U S A ; 121(34): e2404199121, 2024 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-39136985

RESUMO

Low phosphate (Pi) availability decreases photosynthesis, with phosphate limitation of photosynthesis occurring particularly during grain filling of cereal crops; however, effective genetic solutions remain to be established. We previously discovered that rice phosphate transporter OsPHO1;2 controls seed (sink) development through Pi reallocation during grain filling. Here, we find that OsPHO1;2 regulates Pi homeostasis and thus photosynthesis in leaves (source). Loss-of-function of OsPHO1;2 decreased Pi levels in leaves, leading to decreased photosynthetic electron transport activity, CO2 assimilation rate, and early occurrence of phosphate-limited photosynthesis. Interestingly, ectopic expression of OsPHO1;2 greatly increased Pi availability, and thereby, increased photosynthetic rate in leaves during grain filling, contributing to increased yield. This was supported by the effect of foliar Pi application. Moreover, analysis of core rice germplasm resources revealed that higher OsPHO1;2 expression was associated with enhanced photosynthesis and yield potential compared to those with lower expression. These findings reveal that phosphate-limitation of photosynthesis can be relieved via a genetic approach, and the OsPHO1;2 gene can be employed to reinforce crop breeding strategies for achieving higher photosynthetic efficiency.


Assuntos
Oryza , Fosfatos , Fotossíntese , Oryza/genética , Oryza/metabolismo , Oryza/crescimento & desenvolvimento , Fosfatos/metabolismo , Folhas de Planta/metabolismo , Folhas de Planta/genética , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Regulação da Expressão Gênica de Plantas , Proteínas de Transporte de Fosfato/genética , Proteínas de Transporte de Fosfato/metabolismo , Plantas Geneticamente Modificadas
3.
Brief Bioinform ; 25(2)2024 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-38385874

RESUMO

The three-dimensional (3D) structure of bacterial chromosomes is crucial for understanding chromosome function. With the growing availability of high-throughput chromosome conformation capture (3C/Hi-C) data, the 3D structure reconstruction algorithms have become powerful tools to study bacterial chromosome structure and function. It is highly desired to have a recommendation on the chromosome structure reconstruction tools to facilitate the prokaryotic 3D genomics. In this work, we review existing chromosome 3D structure reconstruction algorithms and classify them based on their underlying computational models into two categories: constraint-based modeling and thermodynamics-based modeling. We briefly compare these algorithms utilizing 3C/Hi-C datasets and fluorescence microscopy data obtained from Escherichia coli and Caulobacter crescentus, as well as simulated datasets. We discuss current challenges in the 3D reconstruction algorithms for bacterial chromosomes, primarily focusing on software usability. Finally, we briefly prospect future research directions for bacterial chromosome structure reconstruction algorithms.


Assuntos
Bactérias , Estruturas Cromossômicas , Células Procarióticas , Cromossomos Bacterianos/genética , Algoritmos , Escherichia coli/genética
4.
Brief Bioinform ; 25(4)2024 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-38975892

RESUMO

Understanding the biological functions and processes of genes, particularly those not yet characterized, is crucial for advancing molecular biology and identifying therapeutic targets. The hypothesis guiding this study is that the 3D proximity of genes correlates with their functional interactions and relevance in prokaryotes. We introduced 3D-GeneNet, an innovative software tool that utilizes high-throughput sequencing data from chromosome conformation capture techniques and integrates topological metrics to construct gene association networks. Through a series of comparative analyses focused on spatial versus linear distances, we explored various dimensions such as topological structure, functional enrichment levels, distribution patterns of linear distances among gene pairs, and the area under the receiver operating characteristic curve by utilizing model organism Escherichia coli K-12. Furthermore, 3D-GeneNet was shown to maintain good accuracy compared to multiple algorithms (neighbourhood, co-occurrence, coexpression, and fusion) across multiple bacteria, including E. coli, Brucella abortus, and Vibrio cholerae. In addition, the accuracy of 3D-GeneNet's prediction of long-distance gene interactions was identified by bacterial two-hybrid assays on E. coli K-12 MG1655, where 3D-GeneNet not only increased the accuracy of linear genomic distance tripled but also achieved 60% accuracy by running alone. Finally, it can be concluded that the applicability of 3D-GeneNet will extend to various bacterial forms, including Gram-negative, Gram-positive, single-, and multi-chromosomal bacteria through Hi-C sequencing and analysis. Such findings highlight the broad applicability and significant promise of this method in the realm of gene association network. 3D-GeneNet is freely accessible at https://github.com/gaoyuanccc/3D-GeneNet.


Assuntos
Redes Reguladoras de Genes , Software , Algoritmos , Biologia Computacional/métodos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Escherichia coli K12/genética , Escherichia coli K12/metabolismo , Escherichia coli/genética , Escherichia coli/metabolismo
5.
Nat Chem Biol ; 20(6): 770-778, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38409364

RESUMO

Metal-binding proteins (MBPs) have various and important biological roles in all living species and many human diseases are intricately linked to dysfunctional MBPs. Here, we report a chemoproteomic method named 'metal extraction-triggered agitation logged by thermal proteome profiling' (METAL-TPP) to globally profile MBPs in proteomes. The method involves the extraction of metals from MBPs using chelators and monitoring the resulting protein stability changes through thermal proteome profiling. Applying METAL-TPP to the human proteome with a broad-spectrum chelator, EDTA, revealed a group of proteins with reduced thermal stability that contained both previously known MBPs and currently unannotated MBP candidates. Biochemical characterization of one potential target, glutamine-fructose-6-phosphate transaminase 2 (GFPT2), showed that zinc bound the protein, inhibited its enzymatic activity and modulated the hexosamine biosynthesis pathway. METAL-TPP profiling with another chelator, TPEN, uncovered additional MBPs in proteomes. Collectively, this study developed a robust tool for proteomic discovery of MBPs and provides a rich resource for functional studies of metals in cell biology.


Assuntos
Proteoma , Proteômica , Humanos , Proteoma/metabolismo , Proteômica/métodos , Quelantes/química , Quelantes/farmacologia , Metais/metabolismo , Metais/química , Zinco/metabolismo , Zinco/química , Temperatura , Glutamina-Frutose-6-Fosfato Transaminase (Isomerizante)/metabolismo , Glutamina-Frutose-6-Fosfato Transaminase (Isomerizante)/antagonistas & inibidores , Estabilidade Proteica
6.
Nat Chem Biol ; 2024 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-39300230

RESUMO

Clustered regularly interspaced short palindromic repeats-Cas13 effectors are used for RNA editing but the adeno-associated virus (AAV) packaging limitations because of their big sizes hinder their therapeutic application. Here we report the identification of the Cas13j family, with LepCas13j (529 aa) and ChiCas13j (424 aa) being the smallest and most highly efficient variants for RNA interference. The miniaturized Cas13j proteins enable the development of compact RNA base editors. Chi-RESCUE-S, by fusing dChiCas13j with hADAR2dd, demonstrates high efficiency and specificity in A-to-G and C-to-U conversions. Importantly, this system is compatible with single-AAV packaging without the need for protein sequence truncation. It successfully corrected pathogenic mutations, such as APOC3D65N and SCN9AR896Q, to the wild-type forms. In addition, we developed an optimized system, Chi-RESCUE-S-mini3, which pioneered efficient in vivo C-to-U RNA editing of PCSK9 in mice through single-AAV delivery, resulting in reduced total cholesterol levels. These results highlight the potential of Cas13j to treat human diseases.

7.
Nature ; 583(7818): 771-774, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32728236

RESUMO

Seeing-the angular size of stellar images blurred by atmospheric turbulence-is a critical parameter used to assess the quality of astronomical sites at optical/infrared wavelengths. Median values at the best mid-latitude sites are generally in the range of 0.6-0.8 arcseconds1-3. Sites on the Antarctic plateau are characterized by comparatively weak turbulence in the free atmosphere above a strong but thin boundary layer4-6. The median seeing at Dome C is estimated to be 0.23-0.36 arcseconds7-10 above a boundary layer that has a typical height of 30 metres10-12. At Domes A and F, the only previous seeing measurements have been made during daytime13,14. Here we report measurements of night-time seeing at Dome A, using a differential image motion monitor15. Located at a height of just 8 metres, it recorded seeing as low as 0.13 arcseconds, and provided seeing statistics that are comparable to those at a height of 20 metres at Dome C. This indicates that the boundary layer was below 8 metres for 31 per cent of the time, with median seeing of 0.31 arcseconds, consistent with free-atmosphere seeing. The seeing and boundary-layer thickness are found to be strongly correlated with the near-surface temperature gradient. The correlation confirms a median thickness of approximately 14 metres for the boundary layer at Dome A, as found from a sonic radar16. The thinner boundary layer makes it less challenging to locate a telescope above it, thereby giving greater access to the free atmosphere.

8.
Nat Chem Biol ; 19(5): 548-555, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-36593274

RESUMO

Metal ions have various important biological roles in proteins, including structural maintenance, molecular recognition and catalysis. Previous methods of predicting metal-binding sites in proteomes were based on either sequence or structural motifs. Here we developed a co-evolution-based pipeline named 'MetalNet' to systematically predict metal-binding sites in proteomes. We applied MetalNet to proteomes of four representative prokaryotic species and predicted 4,849 potential metalloproteins, which substantially expands the currently annotated metalloproteomes. We biochemically and structurally validated previously unannotated metal-binding sites in several proteins, including apo-citrate lyase phosphoribosyl-dephospho-CoA transferase citX, an Escherichia coli enzyme lacking structural or sequence homology to any known metalloprotein (Protein Data Bank (PDB) codes: 7DCM and 7DCN ). MetalNet also successfully recapitulated all known zinc-binding sites from the human spliceosome complex. The pipeline of MetalNet provides a unique and enabling tool for interrogating the hidden metalloproteome and studying metal biology.


Assuntos
Metaloproteínas , Proteoma , Humanos , Sequência de Aminoácidos , Proteoma/química , Metais/metabolismo , Metaloproteínas/metabolismo , Sítios de Ligação , Escherichia coli/metabolismo , Aprendizado de Máquina
9.
BMC Genomics ; 25(1): 129, 2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-38297226

RESUMO

BACKGROUND: Lipid metabolism plays a pivotal role in asthma pathogenesis. However, a comprehensive analysis of the importance of lipid metabolism-related genes (LMRGs) in regulating the immune microenvironment in asthma remains lacking. The transcriptome matrix was downloaded from the Gene Expression Omnibus (GEO) dataset. Differentially expressed analysis and weighted gene coexpression network analysis (WGCNA) were conducted on the GSE74986 dataset to select hub LMRGs, and gene set enrichment analysis (GSEA) was conducted to explore their biological functions. The CIBERSORT algorithm was used to determine immune infiltration in the asthma and control groups, and the correlation of diagnostic biomarkers and immune cells was performed via Spearman correlation analysis. Subsequently, a competitive endogenous RNA (ceRNA) network was constructed to investigate the hidden molecular mechanism of asthma. The expression levels of the hub genes were further validated in the GSE143192 dataset, and RT‒qPCR and immunofluorescence were performed to verify the reliability of the results in the OVA asthma model. Lastly, the ceRNA network was confirmed by qRT-PCR and RNAi experiments in the characteristic cytokine (IL-13)-induced asthma cellular model. RESULTS: ASAH1, ACER3 and SGPP1 were identified as hub LMRGs and were mainly involved in protein secretion, mTORC1 signaling, and fatty acid metabolism. We found more infiltration of CD8+ T cells, activated NK cells, and monocytes and less M0 macrophage infiltration in the asthma group than in the healthy control group. In addition, ASAH1, ACER3, and SGPP1 were negatively correlated with CD8+ T cells and activated NK cells, but positively correlated with M0 macrophages. Within the ceRNA network, SNHG9-hsa-miR-615-3p-ACER3, hsa-miR-212-5p and hsa-miR-5682 may play crucial roles in asthma pathogenesis. The low expression of ASAH1 and SGPP1 in asthma was also validated in the GSE74075 dataset. After SNHG9 knockdown, miR-615-3p expression was significantly upregulated, while that of ACER3 was significantly downregulated. CONCLUSION: ASAH1, ACER3 and SGPP1 might be diagnostic biomarkers for asthma, and are associated with increased immune system activation. In addition, SNHG9-hsa-miR-615-3p-ACER3 may be viewed as effective therapeutic targets for asthma. Our findings might provide a novel perspective for future research on asthma.


Assuntos
Asma , MicroRNAs , Humanos , Linfócitos T CD8-Positivos , Metabolismo dos Lipídeos , Reprodutibilidade dos Testes , Asma/genética , Hidrolases , Biomarcadores
10.
J Am Chem Soc ; 146(32): 22413-22423, 2024 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-39096292

RESUMO

Stereochemically pure saccharides have indispensable roles in fields ranging from medicinal chemistry to materials science and organic synthesis. However, the development of a simple, stereoselective, and efficient glycosylation protocol to access α- and ß-C-glycosides (particularly 2-deoxy entities) remains a persistent challenge. Existing studies have primarily focused on C1 modification of carbohydrates and transformation of glycosyl radical precursors. Here, we innovate by harnessing the in situ generated glycosyl-Ni species to achieve one-pot borylation and glycosylation in a cascade manner, which is enabled by an earth-abundant nickel-catalyzed carboboration of readily accessible glycals without any ligand. This work reveals the potential for the development of a modular and multifunctional glycosylation platform to facilitate the simultaneous introduction of C-C and C-B bonds at the stereogenic center of saccharides, a largely unexploited research area. Preliminary experimental and computational studies indicate that the endocyclic O and the C3 group play important roles in stereoseclectively forging glycosidic bonds. As a result, a diverse range of C-R (R = alkyl, aryl, and alkenyl) and 2-deoxygenated glycosides bearing modifiable boron groups could be rapidly made with excellent stereocontrol and exhibit remarkable functional group tolerance. The synthetic potential is underscored in the late-stage glycosylation of natural products and commercial drugs as well as the facile preparation of various rare sugars, bioactive conjugates, and key intermediates to prorocentin, phomonol, and aspergillide A.

11.
Anal Chem ; 96(42): 16802-16810, 2024 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-39388386

RESUMO

De novo protein sequencing via a bottom-up approach requires various proteases to produce overlapping peptides. However, peptides generated by proteases other than trypsin, LysC, and ArgC often yield C-terminal fragments with suboptimal ionization in positive mode mass spectrometry (MS). This study introduces a novel peptide labeling strategy that involves modifying peptides at the C-terminal and at the carboxyl groups of Aspartic and Glutamic acid with arginine methyl ester (R-met) to improve peptide fragmentation and resolve isobaric ambiguities encountered during sequencing. An amidation reaction is used with coupling reagents to conjugate R-met to the peptide's C-terminal end, introducing a functional group that enhances the detectability of C-terminal peptide fragment ions by mass spectrometry. Subsequently, selecting a charge state of +2 or higher can facilitate optimal fragmentation of the derivatized peptides using electron-transfer/higher energy collision dissociation (EThcD), thereby generating essential w-ions to resolve common isobaric ambiguities. Demonstrating this strategy across diverse protein types, including albumin and antibodies and using different proteases for digestion, highlights the unique characteristics of combining the proposed amidation reaction with the specific proteases tested.


Assuntos
Análise de Sequência de Proteína , Análise de Sequência de Proteína/métodos , Peptídeos/química , Transporte de Elétrons , Sequência de Aminoácidos , Humanos , Proteínas/química , Animais
12.
Drug Metab Rev ; : 1-24, 2024 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-38895934

RESUMO

With contributions from colleagues across academia and industry, we have put together the annual reviews of research advances on drug biotransformation and bioactivation since 2016 led by Cyrus Khojasteh. While traditional small molecules and biologics are still predominant in drug discovery, we start to notice a paradigm shift toward new drug modalities (NDMs) including but not limited to peptide and oligonucleotide therapeutics, protein degraders (heterobifunctional degraders and molecule glues), conjugated drugs and covalent inhibitors. The readers can learn more on each new drug modality from several recent comprehensive reviews (Blanco et al. 2022; Hillebrand et al. 2024; Phuna et al. 2024). Based on this trend, we put together this stand-alone review branched from our previous efforts (Baillie et al. 2016; Khojasteh et al. 2023) with a focus on the metabolism of NDMs. We collected 11 articles which exemplify recent discoveries and perspectives in this field.

13.
Drug Metab Rev ; : 1-33, 2024 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-38989688

RESUMO

This annual review marks the eighth in the series starting with Baillie et al. (2016) Our objective is to explore and share articles which we deem influential and significant in the field of biotransformation. Its format is to highlight important aspects captured in synopsis followed by a commentary with relevant figure and references.

14.
Drug Metab Rev ; : 1-38, 2024 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-38963129

RESUMO

Advances in the field of bioactivation have significantly contributed to our understanding and prediction of drug-induced liver injury (DILI). It has been established that many adverse drug reactions, including DILI, are associated with the formation and reactivity of metabolites. Modern methods allow us to detect and characterize these reactive metabolites in earlier stages of drug development, which helps anticipate and circumvent the potential for DILI. Improved in silico models and experimental techniques that better reflect in vivo environments are enhancing predictive capabilities for DILI risk. Further, studies on the mechanisms of bioactivation, including enzyme interactions and the role of individual genetic differences, have provided valuable insights for drug optimizations. Cumulatively, this progress is continually refining our approaches to drug safety evaluation and personalized medicine.

15.
Chembiochem ; 25(12): e202400105, 2024 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-38639074

RESUMO

Cell senescence is defined as irreversible cell cycle arrest, which can be triggered by telomere shortening or by various types of genotoxic stress. Induction of senescence is emerging as a new strategy for the treatment of cancer, especially when sequentially combined with a second senolytic drug capable of killing the resulting senescent cells, however severely suffering from the undesired off-target side effects from the senolytic drugs. Here, we prepare a bimetalic platinum-aluminum salen complex (Alumiplatin) for cancer therapy-a combination of pro-senesence chemotherapy with in situ senotherapy to avoid the side effects. The aluminum salen moiety, as a G-quadruplex stabilizer, enhances the salen's ability to induce cancer cell senescence and this phenotype is in turn sensitive to the cytotoxic activity of the monofunctional platinum moiety. It exhibits an excellent capability for inducing senescence, a potent cytotoxic activity against cancer cells both in vitro and in vivo, and an improved safety profile compared to cisplatin. Therefore, Alumiplatin may be a good candidate to be further developed into safe and effective anticancer agents. This novel combination of cell senescence inducers with genotoxic drugs revolutionizes the therapy options of designing multi-targeting anticancer agents to improve the efficacy of anticancer therapies.


Assuntos
Alumínio , Antineoplásicos , Senescência Celular , Etilenodiaminas , Platina , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/química , Etilenodiaminas/química , Etilenodiaminas/farmacologia , Senescência Celular/efeitos dos fármacos , Platina/química , Platina/farmacologia , Alumínio/química , Alumínio/farmacologia , Animais , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Complexos de Coordenação/uso terapêutico , Camundongos , Proliferação de Células/efeitos dos fármacos , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Compostos Organoplatínicos/farmacologia , Compostos Organoplatínicos/química
16.
Bioinformatics ; 39(11)2023 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-37847746

RESUMO

MOTIVATION: Reconstruction of 3D structure models is of great importance for the study of chromosome function. Software tools for this task are highly needed. RESULTS: We present a novel reconstruction algorithm, called EVRC, which utilizes co-clustering coefficients and error-vector resultant for chromosome 3D structure reconstruction. As an update of our previous EVR algorithm, EVRC now can deal with both single and multiple chromosomes in structure modeling. To evaluate the effectiveness and accuracy of the EVRC algorithm, we applied it to simulation datasets and real Hi-C datasets. The results show that the reconstructed structures have high similarity to the original/real structures, indicating the effectiveness and robustness of the EVRC algorithm. Furthermore, we applied the algorithm to the 3D conformation reconstruction of the wild-type and mutant Arabidopsis thaliana chromosomes and demonstrated the differences in structural characteristics between different chromosomes. We also accurately showed the conformational change in the centromere region of the mutant compared with the wild-type of Arabidopsis chromosome 1. Our EVRC algorithm is a valuable software tool for the field of chromatin structure reconstruction, and holds great promise for advancing our understanding on the chromosome functions. AVAILABILITY AND IMPLEMENTATION: The software is available at https://github.com/mbglab/EVRC.


Assuntos
Estruturas Cromossômicas , Cromossomos , Cromossomos/genética , Algoritmos , Software , Centrômero , Análise por Conglomerados
17.
Drug Metab Dispos ; 52(3): 236-241, 2024 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-38123963

RESUMO

Rifampicin (RIF) is a mixed-mode perpetrator that produces pleiotropic effects on liver cytochrome P450 enzymes and drug transporters. To assess the complex drug-drug interaction liabilities of RIF in vivo, a known probe substrate, midazolam (MDZ), along with multiple endogenous biomarkers were simultaneously monitored in beagle dogs before and after a 7-day treatment period by RIF at 20 mg/kg per day. Confirmed by the reduced MDZ plasma exposure and elevated 4ß-hydroxycholesterol (4ß-HC, biomarker of CYP3A activities) level, CYP3A was significantly induced after repeated RIF doses, and such induction persisted for 3 days after cessation of the RIF administration. On the other hand, increased plasma levels of coproporphyrin (CP)-I and III [biomarkers of organic anion transporting polypeptides 1b (Oatp1b) activities] were observed after the first dose of RIF. Plasma CPs started to decline as RIF exposure decreased, and they returned to baseline 3 days after cessation of the RIF administration. The data suggested the acute (inhibitory) and chronic (inductive) effects of RIF on Oatp1b and CYP3A enzymes, respectively, and a 3-day washout period is deemed adequate to remove superimposed Oatp1b inhibition from CYP3A induction. In addition, apparent self-induction of RIF was observed as its terminal half-life was significantly altered after multiple doses. Overall, our investigation illustrated the need for appropriate timing of modulator dosing to differentiate between transporter inhibition and enzyme induction. As further indicated by the CP data, induction of Oatp1b activities was not likely after repeated RIF administration. SIGNIFICANCE STATEMENT: This investigation demonstrated the utility of endogenous biomarkers towards complex drug-drug interactions by rifampicin (RIF) and successfully determined the optimal timing to differentiate between transporter inhibition and enzyme induction. Based on experimental evidence, Oatp1b induction following repeated RIF administration was unlikely, and apparent self-induction of RIF elimination was observed.


Assuntos
Citocromo P-450 CYP3A , Rifampina , Cães , Animais , Rifampina/farmacologia , Preparações Farmacêuticas , Midazolam , Interações Medicamentosas , Biomarcadores
18.
Respir Res ; 25(1): 105, 2024 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-38419020

RESUMO

BACKGROUND: Increasing evidence is appearing that ozone has adverse effects on health. However, the association between long-term ozone exposure and lung function is still inconclusive. OBJECTIVES: To investigate the associations between long-term exposure to ozone and lung function in Chinese young adults. METHODS: We conducted a prospective cohort study among 1594 college students with a mean age of 19.2 years at baseline in Shandong, China from September 2020 to September 2021. Lung function indicators were measured in September 2020 and September 2021, including forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), forced expiratory flow at the 25th, 50th, and 75th percentile of the FVC (FEF25, FEF50, and FEF75) and mean flow rate between 25% and 75% of the FVC (FEF25-75) were measured. Daily 10 km×10 km ozone concentrations come from a well-validated data-fusion approach. The time-weighted average concentrations in 12 months before the lung function test were defined as the long-term ozone exposure. The associations between long-term ozone exposure and lung function indicators in Chinese young adults were investigated using a linear mixed effects model, followed by stratified analyses regarding sex, BMI and history of respiratory diseases. RESULTS: Each interquartile range (IQR) (8.9 µg/m3) increase in long-term ozone exposure were associated with a -204.3 (95% confidence interval (CI): -361.6, -47.0) ml/s, -146.3 (95% CI: -264.1, -28.4) ml/s, and - 132.8 (95% CI: -239.2, -26.4) ml/s change in FEF25, FEF50, and FEF25-75, respectively. Stronger adverse associations were found in female participants or those with BMI ≥ 24 kg/m2 and history of respiratory diseases. CONCLUSION: Long-term exposure to ambient ozone is associated with impaired small airway indicators in Chinese young adults. Females, participants with BMI ≥ 24 kg/m2 and a history of respiratory disease have stronger associations.


Assuntos
Poluentes Atmosféricos , Ozônio , Doenças Respiratórias , Humanos , Feminino , Adulto Jovem , Adulto , Pulmão , Estudos Longitudinais , Estudos Prospectivos , Exposição Ambiental/efeitos adversos , Exposição Ambiental/análise , Ozônio/toxicidade , Estudos de Coortes , Volume Expiratório Forçado , Doenças Respiratórias/induzido quimicamente , Doenças Respiratórias/diagnóstico , Doenças Respiratórias/epidemiologia , Poluentes Atmosféricos/análise
19.
Nitric Oxide ; 153: 26-40, 2024 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-39374645

RESUMO

Ischemic stroke is a major cause of death and disability. The activation of neuronal nitric oxide synthase (nNOS) and the resulting production of nitric oxide (NO) via NMDA receptor-mediated calcium influx play an exacerbating role in cerebral ischemia reperfusion injury. The NO rapidly reacts with superoxide (O2-) to form peroxynitrite (ONOO-), a toxic molecule may modify proteins through tyrosine residue nitration, ultimately worsening neuronal damage. SIRT6 has been proven to be crucial in regulating cell proliferation, death, and aging in various pathological settings. We have previous reported that human SIRT6 tyrosine nitration decreased its intrinsic catalytic activity in vitro. However, the exact role of SIRT6 function in the process of cerebral ischemia reperfusion injury is not yet fully elucidated. Herein, we demonstrated that an increase in the nitration of SIRT6 led to reduce its enzymatic activity and aggravated hippocampal neuronal damage in a rat model of four-artery cerebral ischemia reperfusion. In addition, reducing SIRT6 nitration resulted in increase the activity of SIRT6, alleviating hippocampal neuronal damage. Moreover, SIRT6 nitration affected its downstream molecule activity such as PARP1 and GCN5, promoting the process of neuronal ischemic injury in rat hippocampus. Additionally, treatment with NMDA receptor antagonist MK801, or nNOS inhibitor 7-NI, and resveratrol (an antioxidant) diminished SIRT6 nitration and the catalytic activity of downstream molecules like PARP1 and GCN5, thereby reducing neuronal damage. Finally, in the biochemical regulation of SIRT6 activity, tyrosine 257 was essential for its activity and susceptibility to nitration. Replacing tyrosine 257 with phenylalanine in rat SIRT6 attenuated the death of SH-SY5Y neurocytes under oxygen-glucose deprivation (OGD) conditions. These results may offer further understanding of SIRT6 function in the pathogenesis of cerebral ischemic diseases.

20.
Environ Sci Technol ; 58(33): 14718-14725, 2024 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-39110125

RESUMO

Cadmium (Cd) contamination poses a significant global threat to human health, primarily through dietary intake, with rice serving as a major source. While Cd predominantly resides in bound states in soil, the physiological processes by which rice facilitates Cd absorption in the rhizosphere remain largely elusive. This study delves into the mechanisms governing Cd uptake by rice plants in the rhizosphere, emphasizing the impact of daytime and nighttime fluctuations in microenvironmental conditions. Employing a microfluidic chip setup, the research reveals that radial oxygen loss from rice roots triggers dissolution of Cd in the rhizosphere. Notably, Cd mobility exhibits distinct diurnal fluctuations, peaking at 44.0 ± 4.1 nM during the daytime and dropping to 8.3 ± 1.3 nM during the nighttime. Further investigations reveal that variations in dissolved oxygen and hydroxyl radical concentrations influence Cd release, while pH changes and microbial reduction reactions play crucial roles in Cd immobilization. These findings provide insights into the intricate processes governing Cd mobilization in the rice rhizosphere, highlighting the importance of regulating these processes for effective Cd adsorption control in rice crops and safeguarding public health.


Assuntos
Cádmio , Oryza , Oxigênio , Rizosfera , Oryza/metabolismo , Cádmio/metabolismo , Oxigênio/metabolismo , Poluentes do Solo/metabolismo , Raízes de Plantas/metabolismo
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