The homeostasis of metal ions, such as iron, copper, zinc and calcium, in the brain is crucial for maintaining normal physiological functions. Studies have shown that imbalance of these metal ions in ...the brain is closely related to the onset and progression of Alzheimer's disease (AD), the most common neurodegenerative disorder in the elderly.
Erroneous deposition/distribution of the metal ions in different brain regions induces oxidative stress. The metal ions imbalance and oxidative stress together or independently promote amyloid-β (Aβ) overproduction by activating β- or γ-secretases and inhibiting α-secretase, it also causes tau hyperphosphorylation by activating protein kinases, such as glycogen synthase kinase-3β (GSK-3β), cyclin-dependent protein kinase-5 (CDK5), mitogen-activated protein kinases (MAPKs), etc., and inhibiting protein phosphatase 2A (PP2A). The metal ions imbalances can also directly or indirectly disrupt organelles, causing endoplasmic reticulum (ER) stress; mitochondrial and autophagic dysfunctions, which can cause or aggravate Aβ and tau aggregation/accumulation, and impair synaptic functions. Even worse, the metal ions imbalance-induced alterations can reversely exacerbate metal ions misdistribution and deposition. The vicious cycles between metal ions imbalances and Aβ/tau abnormalities will eventually lead to a chronic neurodegeneration and cognitive deficits, such as seen in AD patients.
The metal ions imbalance induces Aβ and tau pathologies by directly or indirectly affecting multiple cellular/subcellular pathways, and the disrupted homeostasis can reversely aggravate the abnormalities of metal ions transportation/deposition. Therefore, adjusting metal balance by supplementing or chelating the metal ions may be potential in ameliorating AD pathologies, which provides new research directions for AD treatment.
Graphene quantum dots (GQDs) as novel nanomaterials, have received significant interest in the field of biomedical applications. It is worth noting that a large amount of research is devoted to ...GQDs-based nanocomposites for cancer treatment, especially for photodynamic therapy (PDT), in that they can act not only as more favorable photosensitizers (PSs) but also nanoplatforms for delivering PSs. In this review, the biological behavior and physicochemical properties of GQDs for PDT are described in detail, and the application of GQDs-based nanocomposites in improved PDT and PDT-based combination therapies is analyzed, which may provide a new strategy for designing efficient PDT systems for cancer treatment.
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•The synthesis methods of GQDs have important effects on their physicochemical properties.•GQDs exhibit excellent biocompatibility and optical properties.•GQDs have great potential in photodynamic therapy.•PDT-based combination therapies show good synergistic effects.•Precisely tailoring properties of GQDs plays a key role in their application.
This present study was designed to investigate the effects of alpha-1-antitrypsin (AAT) on oxidative stress in preeclampsia (PE) by regulating p38 mitogen-activated protein kinase (p38MAPK) signaling ...pathway. HTR8/SVneo cells were randomly assigned into normal, hypoxia/reoxygenation (H/R), HR + AAT and HR + siRNA-AAT groups. Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting were used to detect the mRNA and protein expressions of p-p38MAPK, AAT, signal transducer and activator of transcription 1 (STAT1) and activating transcription factor2 (ATF2). Flow cytometry, scratch test, cell counting kit-8 (CCK-8) assay and the 3-(4,5)-dimethylthiazol (-z-y1)-3,5-di- phenyltetrazolium bromide (MTT) assay were conducted to detect reactive oxygen species (ROS) and cell apoptosis, cell migration, proliferation and cytotoxicity, respectively. Mouse models in PE were established, which were divided into normal pregnancy (NP), PE and PE + AAT groups with blood pressure and urine protein measured. Chromatin immunoprecipitation (ChIP) and enzyme-linked immunosorbent assay (ELISA) were conducted to detect the activity of oxidative stress-related kinases and expressions of inflammatory cytokines and coagulation-related factors in cells and mice placenta. Immunohistochemistry, Western blotting and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay were performed to detect AAT and p38MAPK expressions, apoptosis-related protein expressions, and apoptosis rate in mice placenta. Compared with the normal group, the H/R group had decreased expression of AAT, activity of superoxide dismutase (SOD) and GSH-Px, cell proliferation and migration, but increased p38MAPK, STAT1, ATF2, MDA, H2O2, inflammatory cytokines, coagulation-related factors, cell cytotoxicity, ROS, apoptotic factors and apoptosis rate. Compared with the H/R group, the HR + ATT group had increased expressions of AAT, activity of SOD and GSH-Px, cell proliferation and migration but decreased p38MAPK, STAT1, ATF2, malonyldialdehyde (MDA), H2O2, inflammatory cytokines and coagulation-related factors, cell cytotoxicity, ROS, apoptotic factors and apoptosis rate, while opposite results were observed in the HR + siRNA-ATT group. Compared with the NP group, the PE group had decreased activity of SOD and GSH-Px but increased MDA, H2O2, AAT, p38MAPK, inflammatory cytokines, coagulation-related factors and apoptosis rate. The indexes in the PE + AAT group were between the NP and PE groups. Thus, we concluded that AAT suppressed oxidative stress in PE by inhibiting p38MAPK signaling pathway.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background
Pulmonary arterial hypertension (PAH) is characterized by the apoptosis resistance and hyperproliferation of pulmonary artery smooth muscle cells (PASMCs). Its pathogenesis has not been ...revealed. Here, we carried out experiments to investigate the functions of miR‐140‐5p and tumor necrosis factor‐α (TNF‐α).
Methods
We selected GSE703 from Gene Expression Omnibus (GEO) Database to conduct microarray analysis using R software and Gene Set Enrichment Analysis (GSEA). Combing bioinformatics results, the upregulation of miR‐140‐5p inhibited PAH progression through targeting TNF‐α. RNA expression was measured by quantitative real‐time polymerase chain reaction (RT‐qPCR) and protein level was measured by western blot analysis and enzyme‐linked immunosorbent assays (ELISA). We conducted monocrotaline (MCT) injection to rats to form PAH animal models. The lung tissues were observed by hematoxylin–eosin (HE) staining and Sirius red‐picric acid staining. Right ventricular systolic pressure (RVSP) and the ratio of right ventricle (RV)‐to‐left ventricle (LV) plus septum (S) weight (RV/LV + S) were measured in MCT‐induced animal models. Overexpression of miR‐140‐5p and TNF‐α were utilized to research the proliferation, migration, and phenotypic variation of hypoxia‐mediated PASMCs. The binding between miR‐140‐5p and TNF‐α 3′‐untranslated region (3′‐UTR) was confirmed via luciferase reporter assay.
Results
Downregulation of miR‐140‐5p and upregulation of TNF‐α were observed in PAH rat model and hypoxia‐mediated PASMCs. And we proved that overexpression of miR‐140‐5p could suppress the proliferation, migration, and phenotypic variation of PASMCs, therefore inhibiting PAH pathogenesis. Luciferase assay verified that miR‐140‐5p targeted TNF‐α directly. A converse correlation was also shown between miR‐140‐5p and TNF‐α in PASMCs.
Conclusions
miR‐140‐5p and TNF‐α are important regulators in PAH pathology and may serve as a therapeutic target for PAH.
miR‐140‐5p might inhibit the occurrence and development of pulmonary arterial hypertension (PAH) by repressing tumor necrosis factor‐α (TNF‐α) expression via the TNF signaling pathway. These findings may help in the search of promising strategies for achieving better treatment outcome in patients diagnosed with PAH.
Summary
Adventitious roots (ARs) are an important root type for plants and display a high phenotypic plasticity in response to different environmental stimuli. Previous studies found that dark–light ...transition can trigger AR formation from the hypocotyl of etiolated Arabidopsis thaliana, which was used as a model for the identification of regulators of AR biogenesis. However, the central regulatory machinery for darkness‐induced hypocotyl AR (HAR) remains elusive. Here, we report that photoreceptors suppress HAR biogenesis through regulating the molecular module essential for lateral roots. We found that hypocotyls embedded in soil or in continuous darkness are able to develop HARs, wherein photoreceptors act as negative regulators. Distinct from wound‐induced ARs that require WOX11 and WOX12, darkness‐induced HARs are fully dependent on ARF7, ARF19, WOX5/7, and LBD16. Further studies established that PHYB interacts with IAA14, ARF7, and ARF9. The interactions stabilize IAA14 and inhibit the transcriptional activities of ARF7 and ARF19 and thus suppress biogenesis of darkness‐induced HARs. This finding not only revealed the central machinery controlling HAR biogenesis but also illustrated that AR formation could be initiated by multiple pathways.
Significance Statement
The hypocotyl adventitious root (HAR) is a special type of root, which is important for environmental adaptation of plants in the seedling stage. Here we report that darkness improves HAR formation and photoreceptors inhibit this process through stabilizing IAA14 and suppressing ARF7 and ARF19.
The Zn content in cereal seeds is an important trait for crop production as well as for human health. However, little is known about how Zn is loaded to plant seeds. Here, through a genome‐wide ...association study (GWAS), we identify the Zn‐NA (nicotianamine) transporter gene ZmYSL2 that is responsible for loading Zn to maize kernels. High promoter sequence variation in ZmYSL2 most likely drives the natural variation in Zn concentrations in maize kernels. ZmYSL2 is specifically localized on the plasma membrane facing the maternal tissue of the basal endosperm transfer cell layer (BETL) and functions in loading Zn‐NA into the BETL. Overexpression of ZmYSL2 increases the Zn concentration in the kernels by 31.6%, which achieves the goal of Zn biofortification of maize. These findings resolve the mystery underlying the loading of Zn into plant seeds, providing an efficient strategy for breeding or engineering maize varieties with enriched Zn nutrition.
Synopsis
The metal‐NA (Nicotianamine) transporter ZmYSL2 loads Zn from the maternal tissue into maize kernels. Overexpression of ZmYSL2 increases the amount of Zn in maize kernels, providing a potential approach for breeding Zn‐rich crop.
Polymorphisms in basal endosperm transfer cell layer (BETL) localized ZmYSL2 correlate with natural variations in the Zn concentration of maize kernels.
The opaque phenotype of ZmYSL2 mutants is due to deficiency of Zn rather than Fe in the kernels.
Overexpression of ZmYSL2 increases the Zn concentration in the kernels by 31.6%, which achieves the goal of Zn biofortification of maize.
The metal‐NA (Nicotianamine) transporter ZmYSL2 loads Zn from the maternal tissue into maize kernels. Overexpression of ZmYSL2 increases the amount of Zn in maize kernels, providing a potential approach for breeding Zn‐rich crop.
Arabidopsis thaliana high-affinity potassium transporter 1 (AtHKT1) limits the root-to-shoot sodium transportation and is believed to be essential for salt tolerance in A. thaliana. Nevertheless, ...natural accessions with 'weak allele' of AtHKT1, e.g. Tsu-1, are mainly distributed in saline areas and are more tolerant to salinity. These findings challenge the role of AtHKT1 in salt tolerance and call into question the involvement of AtHKT1 in salinity adaptation in A. thaliana. Here, we report that AtHKT1 indeed drives natural variation in the salt tolerance of A. thaliana and the coastal AtHKT1, so-called weak allele, is actually hyper-functional in reducing flowers sodium content upon salt stress. Our data showed that AtHKT1 positively contributes to saline adaptation in a linear manner. Forward and reverse genetics analysis established that the single AtHKT1 locus is responsible for the variation in the salinity adaptation between Col-0 and Tsu-1. Reciprocal grafting experiments revealed that shoot AtHKT1 determines the salt tolerance of Tsu-1, whereas root AtHKT1 primarily drives the salt tolerance of Col-0. Furthermore, evidence indicated that Tsu-1 AtHKT1 is highly expressed in stems and is more effective compared to Col-0 AtHKT1 at limiting sodium flow to the flowers. Such efficient retrieval of sodium to the reproductive organ endows Tsu-1 with stronger fertility compared to Col-0 upon salt stress, thus improving Tsu-1 adaptation to a coastal environment. To conclude, our data not only confirm the role of AtHKT1 in saline adaptation, but also sheds light on our understanding of the salt tolerance mechanisms in plants.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Summary
Protein sorting is an essential biological process in all organisms. Trafficking membrane proteins generally relies on the sorting machinery of the Golgi apparatus. However, many proteins ...have been found to be delivered to target locations via Golgi‐independent pathways, but the mechanisms underlying this delivery system remain unknown.
Here, we report that Sec24C mediates the direct secretory trafficking of the phytochelatin transporters ABCC1 and ABCC2 from the endoplasmic reticulum (ER) to prevacuolar compartments (PVCs) in Arabidopsis thaliana.
Genetic analysis showed that the sec24c mutants are hypersensitive to cadmium (Cd) and arsenic (As) treatments due to mislocalisation of ABCC1 and ABCC2, which results in defects in the vacuole compartmentalisation of the toxic metals. Furthermore, we found that Sec24C recognises ABCC1 and ABCC2 through direct interactions to mediate their exit from the ER to PVCs, which is independent of brefeldin A‐sensitive post‐Golgi trafficking pathway.
These findings expand our understanding of Golgi‐independent trafficking, which also provide key insights regarding the mechanism of tonoplast protein sorting and open a new perspective on the function of Sec24 proteins.
BACKGROUND:GTP cyclohydrolase 1 (GCH1) deficiency is critical for endothelial nitric oxide synthase uncoupling in endothelial dysfunction. MicroRNAs (miRs) are a class of regulatory RNAs that ...negatively regulate gene expression. We investigated whether statins prevent endothelial dysfunction via miR-dependent GCH1 upregulation.
METHODS:Endothelial function was assessed by measuring acetylcholine-induced vasorelaxation in the organ chamber. MiR-133a expression was assessed by quantitative reverse transcription polymerase chain reaction and fluorescence in situ hybridization.
RESULTS:We first demonstrated that GCH1 mRNA is a target of miR-133a. In endothelial cells, miR-133a was robustly induced by cytokines/oxidants and inhibited by lovastatin. Furthermore, lovastatin upregulated GCH1 and tetrahydrobiopterin, and recoupled endothelial nitric oxide synthase in stressed endothelial cells. These actions of lovastatin were abolished by enforced miR-133a expression and were mirrored by a miR-133a antagomir. In mice, hyperlipidemia- or hyperglycemia-induced ectopic miR-133a expression in the vascular endothelium, reduced GCH1 protein and tetrahydrobiopterin levels, and impaired endothelial function, which were reversed by lovastatin or miR-133a antagomir. These beneficial effects of lovastatin in mice were abrogated by in vivo miR-133a overexpression or GCH1 knockdown. In rats, multiple cardiovascular risk factors including hyperglycemia, dyslipidemia, and hyperhomocysteinemia resulted in increased miR-133a vascular expression, reduced GCH1 expression, uncoupled endothelial nitric oxide synthase function, and induced endothelial dysfunction, which were prevented by lovastatin.
CONCLUSIONS:Statin inhibits aberrant miR-133a expression in the vascular endothelium to prevent endothelial dysfunction by targeting GCH1. Therefore, miR-133a represents an important therapeutic target for preventing cardiovascular diseases.
The formation of particulate deposits on flue gas heat exchanger surfaces will reduce heat transfer efficiency, increase the instability of equipment operation and introduce a major uncertainty into ...the heat exchanger design. In this paper, a numerical model was developed to predict the flue-ash particle deposition rate by considering particles transport, sticking and rebound behaviors based on the software FLUENT, extended by user-defined functions (UDFs). The numerical model was applied to cross-flow tube bundle heat exchangers with a 6-row tube arrangement. The effects of six parameters (particle diameter, flow velocity, spanwise tube pitch, longitudinal tube pitch, tube geometry shape, and arrangement) on fouling rate, as well as on the heat transfer and hydrodynamics performance, were examined. It was found that particle deposits accumulated primarily in the flow stagnation region, recirculation region, the vortex separation and reattachment regions. Increasing particle diameter moved the deposition zones towards the windward side of tubes. Using both oval tubes and staggered arrangements can reduce the fouling rate. With the increase in longitudinal tube pitch, both the particulate deposit rate and the heat transfer performance increased. To account for fouling and heat transfer performance, a tube spacing value of 2 was recommended.
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