ABSTRACT
Most animals require sleep, and sleep loss induces serious pathophysiological consequences, including death. Previous experimental approaches for investigating sleep impacts in mice have been unable to persistently deprive animals of both rapid eye movement sleep (REMS) and non-rapid eye movement sleep (NREMS). Here, we report a "curling prevention by water" paradigm wherein mice remain awake 96% of the time. After 4 days of exposure, mice exhibit severe inflammation, and approximately 80% die. Sleep deprivation increases levels of prostaglandin D2 (PGD2) in the brain, and we found that elevated PGD2 efflux across the blood-brain-barrier-mediated by ATP-binding cassette subfamily C4 transporter-induces both accumulation of circulating neutrophils and a cytokine-storm-like syndrome. Experimental disruption of the PGD2/DP1 axis dramatically reduced sleep-deprivation-induced inflammation. Thus, our study reveals that sleep-related changes in PGD2 in the central nervous system drive profound pathological consequences in the peripheral immune system.
Subject(s)
Sleep Deprivation , Animals , Mice , Cytokines/metabolism , Inflammation , Prostaglandin D2 , Sleep/physiology , Sleep Deprivation/genetics , Sleep Deprivation/metabolism , Syndrome , Humans , Rats , Cell Line , Cyclonic Storms , Neutrophils/metabolismABSTRACT
Ischaemic stroke causes neuron loss and long-term functional deficits. Unfortunately, effective approaches to preserving neurons and promoting functional recovery remain unavailable. Oligodendrocytes, the myelinating cells in the CNS, are susceptible to oxygen and nutrition deprivation and undergo degeneration after ischaemic stroke. Technically, new oligodendrocytes and myelin can be generated by the differentiation of oligodendrocyte precursor cells (OPCs). However, myelin dynamics and their functional significance after ischaemic stroke remain poorly understood. Here, we report numerous denuded axons accompanied by decreased neuron density in sections from ischaemic stroke lesions in human brain, suggesting that neuron loss correlates with myelin deficits in these lesions. To investigate the longitudinal changes in myelin dynamics after stroke, we labelled and traced pre-existing and newly-formed myelin, respectively, using cell-specific genetic approaches. Our results indicated massive oligodendrocyte death and myelin loss 2â weeks after stroke in the transient middle cerebral artery occlusion (tMCAO) mouse model. In contrast, myelin regeneration remained insufficient 4 and 8â weeks post-stroke. Notably, neuronal loss and functional impairments worsened in aged brains, and new myelin generation was diminished. To analyse the causal relationship between remyelination and neuron survival, we manipulated myelinogenesis by conditional deletion of Olig2 (a positive regulator) or muscarinic receptor 1 (M1R, a negative regulator) in OPCs. Deleting Olig2 inhibited remyelination, reducing neuron survival and functional recovery after tMCAO. Conversely, enhancing remyelination by M1R conditional knockout or treatment with the pro-myelination drug clemastine after tMCAO preserved white matter integrity and neuronal survival, accelerating functional recovery. Together, our findings demonstrate that enhancing myelinogenesis is a promising strategy to preserve neurons and promote functional recovery after ischaemic stroke.
Subject(s)
Brain Ischemia , Ischemic Stroke , Stroke , Mice , Animals , Humans , Aged , Myelin Sheath/pathology , Brain Ischemia/complications , Brain Ischemia/pathology , Stroke/complications , Stroke/pathology , Oligodendroglia/pathology , Neurons , Cell Differentiation/physiologyABSTRACT
PURPOSE: To develop a portable MR perfusion phantom for quality-controlled assessment and reproducibility of arterial spin labeled (ASL) perfusion measurement. METHODS: A 3D-printed perfusion phantom was developed that mimics the branching of arterial vessels, capillaries, and a chamber containing cellulose sponge representing tissue characteristics. A peristaltic pump circulated distilled water through the phantom, and was first evaluated at 300, 400, and 500 mL/min. Longitudinal reproducibility of perfusion was performed using 2D pseudo-continuous ASL at 20 post-label delays (PLDs, ranging between 0.2 and 7.8 s at 0.4-s intervals) over a period of 16 weeks, with three repetitions each week. Multi-PLD data were fitted into a general kinetic model for perfusion quantification (f) and arterial transit time (ATT). Intraclass correlation coefficient was used to assess intersession reproducibility. RESULTS: MR perfusion signals acquired in the 3D-printed perfusion phantom agreed well with the experimental conditions, with progressively increasing signal intensities and decreasing ATT for pump flow rates from 300 to 500 mL/min. The perfusion signal at 400 mL/min and the general kinetic model-derived f and ATT maps were similar across all PLDs for both intrasession and intersession reproducibility. Across all 48 experimental time points, the average f was 75.55 ± 3.83 × 10-3 mL/mL/s, the corresponding ATT was 2.10 ± 0.20 s, and the T1 was 1.84 ± 0.102 s. Intraclass correlation coefficient was 0.92 (95% confidence interval 0.83-0.97) for f, 0.96 (0.91-0.99) for ATT, and 0.94 (0.88-0.98) for T1 , demonstrating excellent reproducibility. CONCLUSION: A simple, portable 3D-printed perfusion phantom with excellent reproducibility of 2D pseudo-continuous ASL measurements was demonstrated that can serve for quality-controlled and reliable measurements of ASL perfusion.
Subject(s)
Cerebrovascular Circulation , Magnetic Resonance Imaging , Spin Labels , Reproducibility of Results , Perfusion , Printing, Three-DimensionalABSTRACT
Andrographolide (Andro), a labdane diterpene, possesses anti-inflammatory properties and has been used to treat numerous inflammatory diseases. Novel findings revealed that Andro might be vital in regulating pain. However, the contribution of Andro to chronic inflammatory pain has yet to be determined, and its underlying mechanism of action remains unknown. In this study, we observed that Andro attenuated mechanical allodynia in inflammatory pain mice induced by injecting complete Freund's adjuvant (CFA) into the right hind paws. This analgesic effect of Andro is mainly dependent on its inhibition of microglial overactivation and the release of proinflammatory cytokines (TNF and IL-1ß) in lumbar spinal cords of inflammatory pain model mice. More importantly, our data in vivo and in vitro revealed a negative role for Andro in regulating the TLR4/NF-κB signaling pathway, which might contribute to the inhibition of spinal microglial activation and proinflammatory cytokines production, and the improvement of paw withdrawal thresholds in a mouse model of chronic inflammatory pain evoked by CFA. We further found the potential interaction of Andro with TLR4/myeloid differentiation factor 2 heterodimer using molecular modeling, implying that TLR4 might be a potential target for Andro to exert an analgesic effect. Taken together, our findings demonstrated that the modulation of spinal microglial activation by Andro might be substantially conducive to managing chronic pain triggered by neuroinflammation.
Subject(s)
Diterpenes , Hyperalgesia , Mice , Animals , Hyperalgesia/drug therapy , Hyperalgesia/metabolism , Microglia/metabolism , Inflammation/metabolism , Toll-Like Receptor 4/metabolism , Pain/drug therapy , Pain/metabolism , Diterpenes/pharmacology , Diterpenes/therapeutic use , Diterpenes/metabolism , Cytokines/metabolism , Spinal Cord , Analgesics/pharmacology , Analgesics/therapeutic useABSTRACT
CONTEXT: Coix [Coix lacryma-jobi L. var. mayuen (Roman.) Stapf (Poaceae)], a crop of medicinal and edible significance, contains coixol, which has demonstrated anticancer properties. However, the limited solubility of coixol restricts its potential therapeutic applications. OBJECTIVE: This study prepared a water-soluble coixol-ß-cyclodextrin polymer (CDP) inclusion compound and evaluated its anticancer effect. MATERIALS AND METHODS: The coixol-CDP compound was synthesized through a solvent-stirring and freeze-drying technique. Its coixol content was quantified using HPLC, and its stability was tested under various conditions. The anticancer effects of the coixol-CDP compound (4.129, 8.259, 16.518, and 33.035 mg/L for 24, 48, and 72 h) on the proliferation of non-small cell lung cancer (NSCLC) A549 cells were evaluated using an MTT assay; cell morphology was examined by Hoechst nuclear staining; apoptosis and cell cycle was detected by flow cytometry; and the expression of apoptosis-related proteins was assessed by Western blots. RESULTS: The water-soluble coixol-CDP inclusion compound was successfully prepared with an inclusion ratio of 86.6% and an inclusion yield rate of 84.1%. The coixol content of the compound was 5.63% and the compound remained stable under various conditions. Compared to coixol alone, all 24, 48, and 72 h administrations with the coixol-CDP compound exhibited lower IC50 values (33.93 ± 2.28, 16.80 ± 1.46, and 6.93 ± 0.83 mg/L) in A549 cells; the compound also showed stronger regulatory effects on apoptosis-related proteins. DISCUSSION AND CONCLUSIONS: These findings offer a new perspective for the potential clinical application of Coix in NSCLC therapy and its future research.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Coix , Lung Neoplasms , beta-Cyclodextrins , Humans , Carcinoma, Non-Small-Cell Lung/drug therapy , Polymers/pharmacology , Lung Neoplasms/drug therapy , beta-Cyclodextrins/pharmacology , WaterABSTRACT
Zintl compounds often feature complex structural fragments and small band gaps, favoring promising thermoelectric properties. In this work, a new phase Ca2ZnSb2 is synthesized and characterized to be a LiGaGe-type structure. It is isotypic to Yb2MnSb2 with half vacancies at transition metal sites and undergoes a phase transition to Ca9Zn4+xSb9 after annealing. Interestingly, Ca2ZnSb2 and Yb2MnSb2 are amenable to diverse doping mechanisms at different sites. Here, by substituting smaller Li on cation sites, two novel layered compounds Ca1.84(1)Li0.16(1)Zn0.84(1)Sb2 and Yb1.82(1)Li0.18(1)Mn0.96(1)Sb2 with the P63/mmc space group are discovered, which can be viewed as derivatives of LiGaGe type. Despite having lower occupancy, the structural stability is improved compared with the prototype compounds owing to the reduced interlayered distances. Besides, the band structure analyses demonstrate that the bands near the Fermi level are mainly governed by the interlayered interaction. Due to the highly disordered structure, Yb1.82Li0.18Mn0.96Sb2 features ultralow thermal conductivity from 0.79 to 0.47 W·m-1·K-1 among the testing range; in addition, a remarkable Seebeck coefficient of 270.77 µV·K-1 at 723 K is observed. The discovery of the Ca2ZnSb2 phase enriches the 2-1-2 map, and the size effect induced by cations provides new ideas for material designing.
ABSTRACT
Tumour-associated macrophages (TAMs) abundantly infiltrate high-grade gliomas and orchestrate immune response, but their diversity in isocitrate dehydrogenase (IDH)-differential grade 4 gliomas remains largely unknown. This study aimed to dissect the transcriptional states, spatial distribution, and clinicopathological significance of distinct monocyte-derived TAM (Mo-TAM) and microglia-derived TAM (Mg-TAM) clusters across glioblastoma-IDH-wild type and astrocytoma-IDH-mutant-grade 4 (Astro-IDH-mut-G4). Single-cell RNA sequencing was performed on four cases of human glioblastoma and three cases of Astro-IDH-mut-G4. Cell clustering, single-cell regulatory network inference, and gene set enrichment analysis were performed to characterize the functional states of myeloid clusters. The spatial distribution of TAM subsets was determined in human glioma tissues using multiplex immunostaining. The prognostic value of different TAM-cluster specific gene sets was evaluated in the TCGA glioma cohort. Profiling and unbiased clustering of 24,227 myeloid cells from glioblastoma and Astro-IDH-mut-G4 identified nine myeloid cell clusters including monocytes, six Mo/Mg-TAM subsets, dendritic cells, and proliferative myeloid clusters. Different Mo/Mg-TAM clusters manifest functional and transcriptional diversity controlled by specific regulons. Multiplex immunostaining of subset-specific markers identified spatial enrichment of distinct TAM clusters at peri-vascular/necrotic areas in tumour parenchyma or at the tumour-brain interface. Glioblastoma harboured a substantially higher number of monocytes and Mo-TAM-inflammatory clusters, whereas Astro-IDH-mut-G4 had a higher proportion of TAM subsets mediating antigen presentation. Glioblastomas with a higher proportion of monocytes exhibited a mesenchymal signature, increased angiogenesis, and worse patient outcome. Our findings provide insight into myeloid cell diversity and its clinical relevance in IDH-differential grade 4 gliomas, and may serve as a resource for immunotherapy development. © 2022 The Pathological Society of Great Britain and Ireland.
Subject(s)
Astrocytoma , Brain Neoplasms , Glioblastoma , Glioma , Astrocytoma/genetics , Astrocytoma/pathology , Brain Neoplasms/genetics , Brain Neoplasms/pathology , Glioblastoma/genetics , Glioblastoma/pathology , Glioma/genetics , Humans , Isocitrate Dehydrogenase/genetics , Mutation , Tumor-Associated MacrophagesABSTRACT
BACKGROUND: Protein acetylation is an important post-translational modification (PTM) that widely exists in organisms. As a reversible PTM, acetylation modification can regulate the function of proteins with high efficiency. In the previous study, the acetylation sites of silkworm proteins were identified on a large scale by nano-HPLC/MS/MS (nanoscale high performance liquid chromatography-tandem secondary mass spectrometry), and a total of 11 acetylation sites were discovered on Bombyx mori nutrient-storage protein SP3 (BmSP3). The purpose of this study was to investigate the effect of acetylation level on BmSP3. METHODS AND RESULTS: In this study, the acetylation of BmSP3 was further verified by immunoprecipitation (IP) and Western blotting. Then, it was confirmed that acetylation could up-regulate the expression of BmSP3 by improving its protein stability in BmN cells. Co-IP and RNAi experiments showed acetyltransferase BmCBP could bind to BmSP3 and catalyze its acetylation modification, then regulate the expression of BmSP3. Furthermore, the knock-down of BmCBP could improve the ubiquitination level of BmSP3. Both acetylation and ubiquitination occur on the side chain of lysine residues, therefore, we speculated that the acetylation of BmSP3 catalyzed by BmCBP could competitively inhibit its ubiquitination modification and improve its protein stability by inhibiting ubiquitin-mediated proteasome degradation pathway, and thereby increase the expression and intracellular accumulation. CONCLUSIONS: BmCBP catalyzes the acetylation of BmSP3 and may improve the stability of BmSP3 by competitive ubiquitination. This conclusion provides a new functional basis for the extensive involvement of acetylation in the regulation of nutrient storage and utilization in silkworm, Bombyx mori.
Subject(s)
Bombyx , Animals , Bombyx/genetics , Acetylation , Tandem Mass Spectrometry , Protein Processing, Post-Translational , Nutrients , AcetyltransferasesABSTRACT
AIMS: Based on our previous research on the specific miRNAs identified from Gastrodia elata, we selected Gas-miR2-3p to investigate its effects on neuroinflammation via in vitro and in vivo experiments. RESULTS: RT-qPCR analysis indicated that G. elata specific Gas-miR2-3p was detected in all murine tissues post-oral administration, suggesting their potential as orally bioavailable miRNA. The analysis of RT-qPCR, Western blotting and ELISA assays consistently demonstrate that the expression of inflammatory factors as TNF-α, IL-6, IL-1ß was decreased and the expression levels of p-p65 and p-IκBα were downregulated after the action of Gas-miR2-3p in both cell and animal experiments. CONCLUSION: Gas-miR2-3p can attenuate neuroinflammation by regulating the inflammation factors and suppressing the activation of the NF-κB signaling pathway. Our findings indicate that G. elata miRNAs, as novel active components, perform a modulatory role in the NF-κB signaling pathway associated with neuroinflammation in a cross-species way.
ABSTRACT
The glucose regulated protein (GRP78) is an important chaperone for various environmental and physiological stimulations. Despite the importance of GRP78 in cell survival and tumor progression, the information regarding GRP78 in silkworm Bombyx mori L. is poorly explored. We previously identified that GRP78 expression was significantly upregulated in the silkworm Nd mutation proteome database. Herein, we characterized the GRP78 protein from silkworm B. mori (hereafter, BmGRP78). The identified BmGRP78 protein encoded a 658 amino acid residues protein with a predicted molecular weight of approximately 73 kDa and comprised of two structural domains, a nucleotide-binding domain (NBD) and a substrate-binding domain (SBD). BmGRP78 was ubiquitously expressed in all examined tissues and developmental stages by quantitative RT-PCR and Western blotting analysis. The purified recombinant BmGRP78 (rBmGRP78) exhibited ATPase activity and could inhibit the aggregating thermolabile model substrates. Heat-induction or Pb/Hg-exposure strongly stimulated the upregulation expression at the translation levels of BmGRP78 in BmN cells, whereas no significant change resulting from BmNPV infection was found. Additionally, heat, Pb, Hg, and BmNPV exposure resulted in the translocation of BmGRP78 into the nucleus. These results lay a foundation for the future identification of the molecular mechanisms related to GRP78 in silkworms.
Subject(s)
Bombyx , Endoplasmic Reticulum Chaperone BiP , Insect Proteins , Animals , Bombyx/genetics , Bombyx/metabolism , Bombyx/virology , Endoplasmic Reticulum Chaperone BiP/genetics , Endoplasmic Reticulum Chaperone BiP/metabolism , Insect Proteins/genetics , Insect Proteins/metabolism , Lead/toxicity , Nucleopolyhedroviruses/geneticsABSTRACT
Alzheimer's disease (AD) is currently the most common neurodegenerative disease. Glycogen synthase kinase 3ß (GSK-3ß) is a pivotal factor in AD pathogenesis. Recent research has demonstrated that plant miRNAs exert cross-kingdom regulation on the target genes in animals. Gastrodia elata (G. elata) is a valuable traditional Chinese medicine that has significant pharmacological activity against diseases of the central nervous system (CNS). Our previous studies have indicated that G. elata-specific miRNA plays a cross-kingdom regulatory role for the NF-κB signaling pathway in mice. In this study, further bioinformatics analysis suggested that Gas-miR36-5p targets GSK-3ß. Through western blot, RT-qPCR, and assessments of T-AOC, SOD, and MDA levels, Gas-miR36-5p demonstrated its neuroprotective effects in an AD cell model. Furthermore, Gas-miR36-5p was detected in the murine brain tissues. The results of the Morris water maze test and western blot analysis provided positive evidence for reversing the learning deficits and hyperphosphorylation of Tau in AD mice, elucidating significant neuroprotective effects in an AD model following G. elata RNA administration. Our research emphasizes Gas-miR36-5p as a novel G. elata-specific miRNA with neuroprotective properties in Alzheimer's disease by targeting GSK-3ß. Consequently, our findings provide valuable insights into the cross-kingdom regulatory mechanisms underlying G. elata-specific miRNA, presenting a novel perspective for the treatment of Alzheimer's disease.
Subject(s)
Alzheimer Disease , Animal Diseases , Gastrodia , MicroRNAs , Neurodegenerative Diseases , Neuroprotective Agents , Animals , Mice , Alzheimer Disease/drug therapy , Alzheimer Disease/genetics , Alzheimer Disease/metabolism , Gastrodia/genetics , Glycogen Synthase Kinase 3 beta/drug effects , Glycogen Synthase Kinase 3 beta/genetics , Glycogen Synthase Kinase 3 beta/metabolism , MicroRNAs/metabolism , MicroRNAs/pharmacology , Neuroprotection , Neuroprotective Agents/pharmacology , Neuroprotective Agents/therapeutic use , Phosphorylation , tau Proteins/metabolismABSTRACT
We theoretically study the electromagnetic forces (optical gradient force, optical torque and vacuum friction) acting on a spherical anisotropic nanoparticle, which can be characterized by multilayer hyperbolic metamaterials (mHMMs). We find three important results about these forces: (i) Firstly, we theoretically demonstrate that the optical gradient force produced on a mHMMs nanoparticle can be flexibly tuned, from pushing the particle to pulling it, just via changing incident angle of illuminating plane light wave. (ii) Secondly, we find the optical torque acting on the mHMMs nanoparticle (its filling factor is around 0.3) can be tuned between positive and negative via changing the incident angle of circularly polarized plane light. Therefore, the rotating mHMMs nanoparticle with designed filling factor can be accelerated or decelerated by the optical torque. (iii) Finally, due to the large fluctuations of dipole polarizability of mHMMs nanoparticle with appropriate filling factor, we propose a new method to obtain the large enhancement of vacuum friction torque by designing the filling factor of the rotating mHMMs nanoparticle.
ABSTRACT
Site-specific DNA double-strand breaks have been used to generate knock-in through the homology-dependent or -independent pathway. However, low efficiency and accompanying negative impacts such as undesirable indels or tumorigenic potential remain problematic. In this study, we present an enhanced reduced-risk genome editing strategy we named as NEO, which used either site-specific trans or cis double-nicking facilitated by four bacterial recombination factors (RecOFAR). In comparison to currently available approaches, NEO achieved higher knock-in (KI) germline transmission frequency (improving from zero to up to 10% efficiency with an average of 5-fold improvement for 8 loci) and 'cleaner' knock-in of long DNA fragments (up to 5.5 kb) into a variety of genome regions in zebrafish, mice and rats. Furthermore, NEO yielded up to 50% knock-in in monkey embryos and 20% relative integration efficiency in non-dividing primary human peripheral blood lymphocytes (hPBLCs). Remarkably, both on-target and off-target indels were effectively suppressed by NEO. NEO may also be used to introduce low-risk unrestricted point mutations effectively and precisely. Therefore, by balancing efficiency with safety and quality, the NEO method reported here shows substantial potential and improves the in vivo gene-editing strategies that have recently been developed.
Subject(s)
Bacterial Proteins/metabolism , Gene Editing/methods , Animals , DNA Breaks, Double-Stranded , DNA-Binding Proteins/metabolism , Female , Gene Knock-In Techniques , Genomics , Homologous Recombination , Humans , INDEL Mutation , Macaca fascicularis , Mice , Rats, Sprague-Dawley , Rec A Recombinases/metabolism , Zebrafish/geneticsABSTRACT
AIM: We present two cases of triplet pregnancy with complete hydatidiform mole (CHM) in contrasting outcomes and discuss the complications of mothers and outcomes of fetuses through a literature review, raising an important issue on the management of this special pregnancy. METHODS: We share our manage experience for two cases of triplet pregnancy with CHM and retrospectively analyze 18 similar pregnancies reported previously with different pregnancy outcomes. RESULTS: In our cases, one case receiving Clomiphene ovulation induction delivered two live fetuses by cesarean section at 30+ weeks without GTN (gestational trophoblastic neoplasia), unfortunately, the other case following ICSI-ET terminated the pregnancy in the setting of complications at 18+ weeks without GTN. No severe complications were detected during pregnancy and no pGTD was developed after delivery in neither of the pregnant. CONCLUSIONS: Co-existing complete hydatidiform mole in multiple pregnancies may become more common owing to the spreading use of ART. The decision for whether continue pregnancy depending on the personalized conditions including the complications of the pregnancy, the outcomes of the fetuses, the gestational age for delivery, and the potential progression of persistent gestational trophoblastic disease (pGTD). Furthermore, close monitor is necessary for the pregnant with triplet pregnancy with CHM who want to continue pregnancy.
Subject(s)
Gestational Trophoblastic Disease , Hydatidiform Mole , Pregnancy, Triplet , Uterine Neoplasms , Cesarean Section , Female , Humans , Pregnancy , Retrospective StudiesABSTRACT
MAIN CONCLUSION: Genome-wide identification, expression analysis of the MYC family in Camellia sinensis, and potential functional characterization of CsMYC2.1 have laid a solid foundation for further research on CsMYC2.1 in jasmonate (JA)-mediated response. Myelocytomatosis (MYC) of basic helix-loop-helix (bHLH) plays a major role in JA-mediated plant growth and developmental processes through specifically binding to the G-box in the promoters of their target genes. In Camellia sinensis, studies on the MYC gene family are limited. Here, we identified 14 C. sinensis MYC (CsMYC) genes, and further analyzed the evolutionary relationship, gene structure, and motif pattern among them. The expression patterns of these CsMYC genes in different tissues suggested their important roles in diverse function in tea plant. Four MYC transcription factors with the highest homology to MYC2 in Arabidopsis were localized in the nucleus. Two of them, named CsMYC2.1 and CsMYC2.2, exhibited transcriptional self-activating activity, and, therefore, could significantly activate the promoter containing G-box motif, whereas CsJAM1.1 and CsJAM1.2 lack the transcriptional self-activating activity, indirectly mediating the JA pathway through interacting with CsMYC2.1 and CsMYC2.2. Furthermore, Yeast Two-Hybrid (Y2H) and Bimolecular Fluorescent Complimentary (BiFC) assays showed that CsMYC2.1 could interact with CsJAZ3/7/8 proteins. Genetically, the complementation of CsMYC2.1 in myc2 mutants conferred the ability to restore the sensitivity to JA signals. The results provide a comprehensive characterization of the 14 CsMYCs in C. sinensis, establishing a solid foundation for further research on CsMYCs in JA-mediated response.
Subject(s)
Arabidopsis Proteins , Camellia sinensis , Arabidopsis Proteins/metabolism , Camellia sinensis/genetics , Camellia sinensis/metabolism , Cyclopentanes , Gene Expression Regulation, Plant , Oxylipins , Plants, Genetically Modified/metabolism , Repressor Proteins/genetics , Transcription Factors/geneticsABSTRACT
BACKGROUND: Alzheimer's disease (AD) and glioblastoma are the most common and devastating diseases in the neurology and neurosurgery departments, respectively. Our previous research reports that the AD-related protein Presenilin1 represses cell proliferation by inhibiting the Wnt/ß-catenin pathway in glioblastoma. However, the function of Presenilin1 and the underlying mechanism need to be further investigated. METHODS: The correlations of two genes were conducted on the R2 microarray platform and CGGA. Wound healing, Transwell assays and glioblastoma transplantation were performed to detect invasion ability. Phalloidin staining was employed to show cell morphology. Proximity ligation assays and protein docking assays were employed to detect two protein locations. We also employed western blotting to detect protein expression. RESULTS: We found that Presenilin1 clearly repressed the migration, invasion and mesenchymal transition of glioblastoma cells. Intriguingly, we observed that the expression of Presenilin1 was positively correlated with Sortilin, which is identified as a pro-invasion molecule in glioma. Furthermore, Presenilin1 interacted with Sortilin at the transmembrane domain and repressed Sortilin expression by cleaving it in glioblastoma cells. First, we found that Sortilin introduced the function of Presenilin1 in phosphorylating ß-catenin and repressing invasion in glioblastoma cells. Last, Presenilin1 stimulation sharply suppressed the invasion and mesenchymal transition of glioblastoma in mouse subcutaneous and intracranial transplantation models. CONCLUSIONS: Our study reveals that Sortilin mediates the regulation of ß-catenin by Presenilin1 and transduces the anti-invasive function of Presenilin1, which may provide novel therapeutic targets for glioblastoma treatment. Video Abstract.
Subject(s)
GlioblastomaABSTRACT
Glioma is the most common primary malignant tumor of the central nervous system and has a poor prognosis. Therefore, exploring the key molecular targets is a new opportunity for basic research and clinical treatment of glioma. Previous studies found that circRNA-hsa_circ_0073237 was upregulated in gliomas. Our further analyses of the biological function and molecular mechanism of hsa_circ_0073237 showed that hsa_circ_0073237 was also upregulated in glioma cell lines and could combine with miR-345 to inhibit its expression. miR-345 was downregulated in glioma tissues and cells, and targeted to regulate the expression of hepatoma-derived growth factor (HDGF), while HDGF expression was enhanced in glioma. Hsa_circ_0073237 promoted the expression of HDGF in glioma cells by adsorbing miR-345. Hsa_circ_0073237 siRNA, miR-345, and HDGF siRNA effectively inhibited cell viability and invasion and promoted cell apoptosis. When expression of hsa_circ_0073237 and miR-345 was inhibited simultaneously, cell viability, apoptosis, and invasion did not change significantly; however, after transfection with HDGF overexpression vector, the effects of hsa_circ_0073237 siRNA and miR-345 on glioma cell viability, apoptosis, and invasion were obviously reversed. Further construction of glioma xenograft models in nude mice confirmed that the introduction of miR-345 in vivo effectively inhibited tumor growth, significantly reduced tumor diameter and weight, and obviously decreased the expression of HDGF. Therefore, hsa_circ_0073237 can regulate the biological functions of glioma cells through miR-345/HDGF, thereby affecting the progression of tumors, indicating that the hsa_circ_0073237/miR-345/HDGF pathway may be a key target for the treatment of glioma.
Subject(s)
Glioma , MicroRNAs , Animals , Cell Movement , Cell Proliferation/genetics , Gene Expression Regulation, Neoplastic , Glioma/genetics , Intercellular Signaling Peptides and Proteins , Mice , Mice, Nude , MicroRNAs/genetics , RNA, CircularABSTRACT
A series of Mg/Mn mixed intermetallic compounds Mg1-xMn2+xAs2 (x = 0.17, 0.48, 0.69) were synthesized by using metal flux reactions. Single-crystal X-ray diffraction measurements indicated that CaAl2Si2-type phases with Mn and Mg atoms located on the cation sites (Wickoff site: 1a) were obtained. The special structure of these Mg1-xMn2+xAs2 compounds corresponded to unique magnetic behavior, which led to increased divergence between zero-field-cooling (ZFC) and field-cooling magnetic susceptibilities with decreasing temperature. The small magnetic hysteresis loop measured at 300 K for Mg0.31(2)Mn2.69As2 revealed its room-temperature ferromagnetism, and its ZFC exchange bias behavior at low temperatures indicated the existence of both ferromagnetic (FM) and antiferromagnetic (AFM) interactions. Spin-polarized density functional theory calculations were also performed to verify the magnetic ground state, and these were consistent with the experimental results.
ABSTRACT
Zintl phases with nominal 9-4-9 formulas are very interesting for their potential applications as thermoelectric materials. However, the formation of such phases usually requires divalent transition metals, for example, Zn, Mn, and Cd, which are covalently bonded to the pnictogen atoms. In this report, for the first time, two Mg-containing compounds with such structures as Sr9Mg4.45(1)Bi9 and Sr9Mg4.42(1)Sb9 were synthesized and their structures were determined by the single-crystal X-ray diffraction method. Both title compounds crystallize in the orthorhombic space group Pnma and are isostructural with Ca9Mn4.41(1)Sb9, which features complex polyanion structures compared to the classical 9-4-9 phases. For Sr9Mg4.45(1)Bi9, its low thermal conductivity, combined with its high electrical conductivity and moderate Seebeck coefficient, leads to a decent figure of merit of 0.57 at 773 K, which obviously prevails in the unoptimized 9-4-9 phases. The discovery of such Mg-containing 9-4-9 phases is very significant, as the discovery not only enriches the structure map of the well-known 9-4-9 family but also provides very valuable thermoelectric candidates surely deserving of more in-depth investigation.
ABSTRACT
Cadmium (Cd), a highly toxic heavy metal, is widespreadly distributed in the environment. Chronic exposure to Cd is associated with the development of several diseases including cancers. Over the decade, many researches have been carried on various models to examine the acute effects of Cd; yet, limited knowledge is known about the long-term Cd exposure, especially in the human lung cells. Previously, we showed that chronic Cd-exposed human bronchial epithelial BEAS-2B cells exhibited transformed cell properties, such as anchorage-independent growth, augmented cell migration, and epithelial-mesenchymal transition (EMT). To study these Cd-transformed cells more comprehensively, here, we further characterized their subproteomes. Overall, a total of 63 differentially expressed proteins between Cd-transformed and passage-matched control cells among the five subcellular fractions (cytoplasmic, membrane, nuclear-soluble, chromatin-bound, and cytoskeletal) were identified by mass spectrometric analysis and database searching. Interestingly, we found that the thiol protease ubiquitin carboxyl-terminal hydrolase isozyme L1 (UCHL1) is one of the severely downregulated proteins in the Cd-transformed cells. Notably, the EMT phenotype of Cd-transformed cells can be suppressed by forced ectopic expression of UCHL1, suggesting UCHL1 as a crucial modulator in the maintenance of the proper differentiation status in lung epithelial cells. Since EMT is considered as a critical step during malignant cell transformation, finding novel cellular targets that can antagonize this transition may lead to more efficient strategies to inhibit cancer development. Our data report for the first time that UCHL1 may play a function in the suppression of EMT in Cd-transformed human lung epithelial cells, indicating that UCHL1 might be a new therapeutic target for chronic Cd-induced carcinogenesis. Graphical abstract.