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JOURNAL/nrgr/04.03/01300535-202503000-00029/figure1/v/2024-06-17T092413Z/r/image-tiff It has been shown clinically that continuous removal of ischemia/reperfusion-induced reactive oxygen species is not conducive to the recovery of late stroke. Indeed, previous studies have shown that excessive increases in hypochlorous acid after stroke can cause severe damage to brain tissue. Our previous studies have found that a small amount of hypochlorous acid still exists in the later stage of stroke, but its specific role and mechanism are currently unclear. To simulate stroke in vivo, a middle cerebral artery occlusion rat model was established, with an oxygen-glucose deprivation/reoxygenation model established in vitro to mimic stroke. We found that in the early stage (within 24 hours) of ischemic stroke, neutrophils produced a large amount of hypochlorous acid, while in the recovery phase (10 days after stroke), microglia were activated and produced a small amount of hypochlorous acid. Further, in acute stroke in rats, hypochlorous acid production was prevented using a hypochlorous acid scavenger, taurine, or myeloperoxidase inhibitor, 4-aminobenzoic acid hydrazide. Our results showed that high levels of hypochlorous acid (200 µM) induced neuronal apoptosis after oxygen/glucose deprivation/reoxygenation. However, in the recovery phase of the middle cerebral artery occlusion model, a moderate level of hypochlorous acid promoted the proliferation and differentiation of neural stem cells into neurons and astrocytes. This suggests that hypochlorous acid plays different roles at different phases of cerebral ischemia/reperfusion injury. Lower levels of hypochlorous acid (5 and 100 µM) promoted nuclear translocation of ß-catenin. By transfection of single-site mutation plasmids, we found that hypochlorous acid induced chlorination of the ß-catenin tyrosine 30 residue, which promoted nuclear translocation. Altogether, our study indicates that maintaining low levels of hypochlorous acid plays a key role in the recovery of neurological function.
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BACKGROUND: Tubulins are major components of the eukaryotic cytoskeletons that are crucial in many cellular processes. Ciliated protists comprise one of the oldest eukaryotic lineages possessing cilia over their cell surface and assembling many diverse microtubular structures. As such, ciliates are excellent model organisms to clarify the origin and evolution of tubulins in the early stages of eukaryote evolution. Nonetheless, the evolutionary history of the tubulin subfamilies within and among ciliate classes is unclear. RESULTS: We analyzed the evolutionary pattern of ciliate tubulin gene family based on genomes/transcriptomes of 60 species covering 10 ciliate classes. Results showed: (1) Six tubulin subfamilies (α_Tub, ß_Tub, γ_Tub, δ_Tub, ε_Tub, and ζ_Tub) originated from the last eukaryotic common ancestor (LECA) were observed within ciliates. Among them, α_Tub, ß_Tub, and γ_Tub were present in all ciliate species, while δ_Tub, ε_Tub, and ζ_Tub might be independently lost in some species. (2) The evolutionary history of the tubulin subfamilies varied. Evolutionary history of ciliate γ_Tub, δ_Tub, ε_Tub, and ζ_Tub showed a certain degree of consistency with the phylogeny of species after the divergence of ciliate classes, while the evolutionary history of ciliate α_Tub and ß_Tub varied among different classes. (3) Ciliate α- and ß-tubulin isoforms could be classified into an "ancestral group" present in LECA and a "divergent group" containing only ciliate sequences. Alveolata-specific expansion events probably occurred within the "ancestral group" of α_Tub and ß_Tub. The "divergent group" might be important for ciliate morphological differentiation and wide environmental adaptability. (4) Expansion events of the tubulin gene family appeared to be consistent with whole genome duplication (WGD) events in some degree. More Paramecium-specific tubulin expansions were detected than Tetrahymena-specific ones. Compared to other Paramecium species, the Paramecium aurelia complex underwent a more recent WGD which might have experienced more tubulin expansion events. CONCLUSIONS: Evolutionary history among different tubulin gene subfamilies seemed to vary within ciliated protists. And the complex evolutionary patterns of tubulins among different ciliate classes might drive functional diversification. Our investigation provided meaningful information for understanding the evolution of tubulin gene family in the early stages of eukaryote evolution.
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Cilióforos , Evolução Molecular , Filogenia , Tubulina (Proteína) , Tubulina (Proteína)/genética , Cilióforos/genética , Cilióforos/classificação , Família Multigênica , MicrotúbulosRESUMO
BACKGROUND: Doxorubicin (DOX) is a first-line chemotherapeutic drug for various malignancies that causes cardiotoxicity. Plant-derived exosome-like nanovesicles (P-ELNs) are growing as novel therapeutic agents. Here, we investigated the protective effects in DOX cardiotoxicity of ELNs from Momordica charantia L. (MC-ELNs), a medicinal plant with antioxidant activity. RESULTS: We isolated MC-ELNs using ultracentrifugation and characterized them with canonical mammalian extracellular vesicles features. In vivo studies proved that MC-ELNs ameliorated DOX cardiotoxicity with enhanced cardiac function and myocardial structure. In vitro assays revealed that MC-ELNs promoted cell survival, diminished reactive oxygen species, and protected mitochondrial integrity in DOX-treated H9c2 cells. We found that DOX treatment decreased the protein level of p62 through ubiquitin-dependent degradation pathway in H9c2 and NRVM cells. However, MC-ELNs suppressed DOX-induced p62 ubiquitination degradation, and the recovered p62 bound with Keap1 promoting Nrf2 nuclear translocation and the expressions of downstream gene HO-1. Furthermore, both the knockdown of Nrf2 and the inhibition of p62-Keap1 interaction abrogated the cardioprotective effect of MC-ELNs. CONCLUSIONS: Our findings demonstrated the therapeutic beneficials of MC-ELNs via increasing p62 protein stability, shedding light on preventive approaches for DOX cardiotoxicity.
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Cardiotoxicidade , Doxorrubicina , Exossomos , Momordica charantia , Fator 2 Relacionado a NF-E2 , Animais , Cardiotoxicidade/prevenção & controle , Cardiotoxicidade/metabolismo , Momordica charantia/química , Exossomos/metabolismo , Ratos , Fator 2 Relacionado a NF-E2/metabolismo , Linhagem Celular , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Masculino , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Ratos Sprague-Dawley , Proteína Sequestossoma-1/metabolismoRESUMO
Antiferromagnets are competitive candidates for the next generation of spintronic devices owing to their superiority in small-scale and low-power-consumption devices. The electrical manipulation of the magnetization and exchange bias (EB) driven by spin-orbit torque (SOT) in ferromagnetic (FM)/antiferromagnetic (AFM) systems has become focused in spintronics. Here, the realization of a large perpendicular EB field in Co/IrMn and the effective manipulation of the magnetic moments of the magnetic Co layer and EB field by SOT in Pt/Co/IrMn system is reported. During the SOT-driven switching process, an asymmetrically manipulated state is observed. Current pulses with the same amplitude but opposite directions induce different magnetization states. Magneto-optical Kerr measurements reveal that this is due to the coexistence of stable and metastable antiferromagnetic domains in the AFM. Exploiting the asymmetric properties of these FM/AFM structures, five spin logic gates, namely AND, OR, NOR, NAND, and NOT, are realized in a single cell via SOT. This study provides an insight into the special ability of SOT on AFMs and also paves an avenue to construct the logic-in-memory and neuromorphic computing cells based on the AFM spintronic system.
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Caspase-12 is a caspase family member for which functions in regulating cell death and inflammation have previously been suggested. In this study, we used caspase-12 lacZ reporter mice to elucidate the expression pattern of caspase-12 in order to obtain an idea about its possible in vivo function. Strikingly, these reporter mice showed that caspase-12 is expressed explicitly in Purkinje neurons of the cerebellum. As this observation suggested a function for caspase-12 in Purkinje neurons, we analyzed the brain and behavior of caspase-12 deficient mice in detail. Extensive histological analyses showed that caspase-12 was not crucial for establishing cerebellum structure or for maintaining Purkinje cell numbers. We then performed behavioral tests to investigate whether caspase-12 deficiency affects memory, motor, and psychiatric functions in mice. Interestingly, while the absence of caspase-12 did not affect memory and motor function, caspase-12 deficient mice showed depression and hyperactivity tendencies, together resembling manic behavior. Next, suggesting a possible molecular mechanistic explanation, we showed that caspase-12 deficient cerebella harbored diminished signaling through the brain-derived neurotrophic factor/tyrosine kinase receptor B/cyclic-AMP response binding protein axis, as well as strongly enhanced expression of the neuronal activity marker c-Fos. Thus, our study establishes caspase-12 expression in mouse Purkinje neurons and opens novel avenues of research to investigate the role of caspase-12 in regulating psychiatric behavior.
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Chronic obstructive pulmonary disease (COPD) is the most prevalent chronic respiratory disorder that is becoming the leading cause of morbidity and mortality on a global scale. There is an unmet need to investigate the underlying pathophysiological mechanisms and unlock novel therapeutic avenues for COPD. Recent research has shed light on the significant roles played by diverse noncoding RNAs (ncRNAs), including microRNAs (miRNAs), long noncoding RNAs (lncRNAs), and circular RNAs (circRNAs), in orchestrating the development and progression of COPD. This review provides an overview of the regulatory roles of ncRNAs in COPD, elucidating their underlying mechanisms, and illuminating the potential prospects of RNA-based therapeutics in the management of COPD.
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BACKGROUND: Social detachment includes the subjective aspect "loneliness" and the objective aspect "social isolation," but tools to assess both dimensions are limited. This study aims to develop a questionnaire, the Social Detachment Questionnaire for Older Population (SDQO), that considers multiple dimensions of social detachment simultaneously. METHODS: The study collected 600 valid samples from individuals aged 55 and above to examine the psychometric properties of the developed SDQO. Item analysis was conducted to assess the performance of each item, and exploratory factor analysis (EFA) was employed to analyze its initial structure and eliminate less ideal items. Subsequently, confirmatory factor analysis (CFA) was used to examine the model fit of the suggested structure by EFA, using different subsamples. Internal consistency, concurrent validity, and other analyses were also performed. RESULTS: The original 27-item SDQO was reduced to 17 items after removing 4 questions in item analysis and 6 questions in EFA. The Cronbach's alpha for the 17-item version of SDQO was 0.80. Both EFA and CFA supported its 6-factor structure, with factors identified as community activities, loneliness, personal resources, leisure activities, friendship, and family resources. SDQO also demonstrated expected performance in concurrent validity. CONCLUSION: The 17-item version of SDQO exhibited good reliability and validity, measuring various aspects of social detachment behavior, feelings, and resources. It holds value for future research applications.
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Nosebleeds and intracranial hemorrhage from brain arteriovenous malformations (bAVMs) are among the most devastating symptoms of patients with hereditary hemorrhagic telangiectasis (HHT). All available managements have limitations. We showed that intravenous (i.v.) delivery of soluble Feline McDonough Sarcoma (FMS)-related tyrosine kinase 1 using an adeno-associated viral vector (AAV9-sFLT1) reduced bAVM severity of endoglin deficient mice. However, minor liver inflammation and growth arrest in young mice were observed. To identify AAV variants and delivery methods that can best transduce brain and nasal tissue with an optimal transduction profile, we compared 3 engineered AAV capsids (AAV.cc47, AAV.cc84, and AAV1RX) with AAV9. A single-stranded CBA promoter driven tdTomato transgene was packaged in these capsids and delivered i.v. or intranasally (i.n.) to wild-type mice. A CMV promoter driven Alk1 transgene was packaged into AAV.cc84 and delivered to PdgfbiCre;Alk1f/f mice through i.v. followed by bAVM induction. Transduced cells in organs, vessel density, abnormal vessels in the bAVMs, and liver inflammation were analyzed histologically. Liver and kidney function were measured enzymatically. Compared to other viral vectors, AAV.cc84, after i.v. delivery, transduced a high percentage of brain endothelial cells (ECs) and few hepatocytes; whereas after i.n. delivery, AAV.cc84 transduced ECs and perivascular cells in the brain, and ECs, epithelial cells, and muscles in the nose with minimum hepatocyte transduction. No changes to liver or kidney function were detected. The delivery of AAV.cc84-Alk1 through i.v. to PdgfbiCre;Alk1f/f mice reduced bAVM severity. In summary, we propose that AAV.cc84-Alk1 is a promising candidate for developing gene therapy in HHT patients.
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Nosebleeds and intracranial hemorrhage from brain arteriovenous malformations (bAVMs) are among the most devastating symptoms of patients with hereditary hemorrhagic telangiectasis (HHT). All available managements have limitations. We showed that intravenous delivery of soluble FMS-related tyrosine kinase 1 using an adeno-associated viral vector (AAV9-sFLT1) reduced bAVM severity of endoglin deficient mice. However, minor liver inflammation and growth arrest in young mice were observed. To identify AAV variants and delivery methods that can best transduce brain and nasal tissue with an optimal transduction profile, we compared 3 engineered AAV capsids (AAV.cc47, AAV.cc84 and AAV1RX) with AAV9. A single-stranded CBA promoter driven tdTomato transgene was packaged in these capsids and delivered intravenously (i.v.) or intranasally (i.n.) to wild-type mice. A CMV promoter driven Alk1 transgene was packaged into AAV.cc84 and delivered to PdgfbiCre;Alk1 f/f mice through i.v. injection followed by brain AVM induction. Transduced cells in different organs, vessel density and abnormal vessels in the bAVMs, and liver inflammation were analyzed histologically. Liver and kidney function were measured enzymatically. Compared to other viral vectors, AAV.cc84, after i.v. delivery, transduced a high percentage of brain ECs and few hepatocytes; whereas after i.n. delivery, AAV.cc84 transduced ECs and perivascular cells in the brain, and ECs, epithelial cells, and skeletal muscles in the nose with minimum hepatocyte transduction. No changes to liver or kidney function were detected. Delivery of AAV.cc84-Alk1 through i.v. to PdgfbiCre;Alk1 f/f mice reduced bAVM severity. In summary, we propose that AAV.cc84-Alk1 is a promising candidate for developing gene therapy in HHT patients.
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OBJECTIVES: This study investigated the impact of social activities on cognitive functioning and psychopathological symptoms. METHODS: Participants aged 55 or older were enrolled through communities. Initial measures assessed demographic data, neuropsychological functioning, psychopathological state, and happiness. Social activities were evaluated using a modified 12-item tool, with 3-4 activities as the cutoff. Follow-up after 6-9 months included Mini-Mental State Examination (MMSE), Beck Depression Inventory - II (BDI-II), Beck Anxiety Inventory (BAI), Health Assessment Questionnaire (HAQ), and Patient Health Questionnaire-15 (PHQ-15) measurements. Predictive models for psychiatric and cognitive statuses were built using multiple linear regression, adjusting for baseline conditions. RESULTS: Initially, 516 older individuals enrolled, with 403 undergoing follow-up. During follow-up, the low participation group reported lower MMSE scores, higher BAI scores, and increased PHQ-15 risk. Negative correlations between social activity numbers and PHQ-15 results were found. Engagement in social clubs correlated positively with higher MMSE scores, while regular interactions with one's adult child(ren) were linked to decreased BAI scores. CONCLUSIONS: The quantity of social activities was associated with lower somatic distress. Social club engagement positively influenced cognition, and regular interactions with one's adult child(ren) mitigated anxiety among older individuals. CLINICAL IMPLICATIONS: Enough types of social activities, participating in social clubs, and adequate interactions with children protected against psychopathologies.
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In recent years, the development of spatial transcriptomic technologies has enabled us to gain an in-depth understanding of the spatial heterogeneity of gene expression in biological tissues. However, a simple and efficient tool is required to analyze multiple spatial targets, such as mRNAs, miRNAs, or genetic mutations, at high resolution in formalin-fixed paraffin-embedded (FFPE) tissue sections. In this study, we developed hydrogel pathological sectioning coupled with the previously reported Sampling Junior instrument (HPSJ) to assess the spatial heterogeneity of multiple targets in FFPE sections at a scale of 180 µm. The HPSJ platform was used to demonstrate the spatial heterogeneity of 9 ferroptosis-related genes (TFRC, NCOA4, FTH1, ACSL4, LPCAT3, ALOX12, SLC7A11, GLS2, and GPX4) and 2 miRNAs (miR-185-5p and miR522) in FFPE tissue samples from patients with triple-negative breast cancer (TNBC). The results validated the significant heterogeneity of ferroptosis-related mRNAs and miRNAs. In addition, HPSJ confirmed the spatial heterogeneity of the L858R mutation in 7 operation-sourced and 4 needle-biopsy-sourced FFPE samples from patients with lung adenocarcinoma (LUAD). The successful detection of clinical FFPE samples indicates that HPSJ is a precise, high-throughput, cost-effective, and universal platform for analyzing spatial heterogeneity, which is beneficial for elucidating the mechanisms underlying drug resistance and guiding the prescription of mutant-targeted drugs in patients with tumors.
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Formaldeído , MicroRNAs , Inclusão em Parafina , Humanos , Formaldeído/química , MicroRNAs/genética , MicroRNAs/análise , Fixação de Tecidos/métodos , Microdissecção/métodos , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia , RNA Mensageiro/genética , Feminino , Ferroptose/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Mutação , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologiaRESUMO
BACKGROUND: Immunity play a pivotal role in the risk of ischemic stroke, and studies have also shown a relationship between ischemic stroke and autoimmune diseases. In light of this we conducted a prospective cohort study to elucidate the impact of antiphospholipid antibodies (aPLs), antinuclear antibodies (ANA), and anti-extractable nuclear antigen autoantibodies (anti-ENA) on the prognosis of ischemic stroke. METHODS: 245 stroke patients were recruited in this single-center study and followed up with for 3 years. Autoantibodies, including aPLs (ACA, anti-ß2GPI, LA), ANA and anti-ENA were evaluated in recurrent ischemic stroke (RIS) and nonrecurrent ischemic stroke (nonRIS). Stroke severity was judged using the National Institutes of Health Stroke Scale (NIHSS). For preventive treatment, 42 IS patients with positive aPLs + ANA/anti-ENA were randomized 1:1 into a hydroxychloroquine (HCQ) treatment group and a control group, and the prognoses were compared. RESULTS: The positive rate of ACA IgG (p = 0.018), anti-ß2GPI IgG (p = 0.047), LA (p = 0.023), and aPLs + ANA/anti-ENA (p = 0.000) were significantly higher in patients with RIS compared to patients with nonRIS, and aPLs + ANA/anti-ENA (HR2.31, 95 % CI1.02-5.25, p = 0.046) and hypertension (HR2.50, 95 % CI1.17-5.35, p = 0.018) were the independent risk factors of recurrence. There were differences in NIHSS at month 36 between those positive and negative for aPLs + ANA/anti-ENA (p = 0.001, Eta2 = 0.052), anti-ENA (p = 0.016, Eta2 = 0.030), ANA (p = 0.035, Eta2 = 0.022), and LA (p = 0.016, Eta2 = 0.028). Furthermore, the recurrence rate of the HCQ treatment group was lower than that of the control group (p = 0.024). CONCLUSIONS: Co-positivity of aPLs and ANA/anti-ENA is an independent risk factor for RIS. However, HCQ therapy may reduce the recurrence rate of IS for these patients.
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OBJECTIVE: The objective of this study was to investigate the correlation between serum levels of matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-9 (MMP-9), and tissue inhibitor of metalloproteinases-1 (TIMP-1) levels and their ratios with the severity of white matter hyperintensities (WMHs) in patients with cerebral small vessel disease (CSVD). METHODS: This cross-sectional study was done on a prospective cohort of patients with CSVD. Qualitative and quantitative analyses of WMHs were performed using Fazekas grading and lesion prediction algorithm (LPA) methods. Biomarkers MMP-2, MMP-9, and TIMP-1 were measured to explore their correlation with the severity of WMHs. RESULTS: The sample consisted of 144 patients with CSVD. There were 63 male and 81 female patients, with an average age of 67.604 ± 8.727 years. Among these, 58.33% presented with white matter hyperintensities at Fazekas grading level 1, with an average total template volume of WMHs of 4.305 mL. MMP-2 (P = 0.025), MMP-9 (P = 0.008), TIMP-1 (P = 0.026), and age (P = 0.007) were identified as independent correlates of WMHs based on Fazekas grading. Independent correlates of the total template volume of WMHs included MMP-2 (P = 0.023), TIMP-1 (P = 0.046), age (P = 0.047), systolic blood pressure (P = 0.047), and homocysteine (Hcy) (P = 0.014). In addition, age (P = 0.003; P < 0.001), interleukin-6 (IL-6) (P < 0.001; P = 0.044), Hcy (P < 0.001; P < 0.001), glycated hemoglobin (HbA1c) (P = 0.016; P = 0.043), and chronic kidney disease (P < 0.001; P < 0.001) were associated with both WMHs Fazekas grading and the total template volume of WMHs. CONCLUSION: Serum levels of MMP-9, MMP-2, and TIMP-1 were independently associated with the Fazekas grading, while serum TIMP-1 and MMP-2 levels were independently related to the total template volume of WMHs. The association of TIMP-1 and MMP-2 with the severity of CSVD-related WMHs suggests their potential role as disease-related biomarkers. However, further research is required to uncover the specific mechanisms underlying these interactions.
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The purpose of the study was to investigate baseline inflammatory, hemostatic indicators and new-onset deep vein thrombosis (DVT) with the risk of mortality in COVID-19 inpatients. In this single-center study, a total of 401 COVID-19 patients hospitalized in Sir Run Run Shaw Hospital, Zhejiang University School of Medicine were enrolled from December 1, 2022 to January 31, 2023. The basic information, first laboratory examination results, imaging examination, and outcome-related indicators were compared between patients in the moderate and severe subgroups. We found that baseline D-dimer and baseline absolute neutrophil count (ANC) levels were associated with new-onset DVT and death in severe hospitalized patients with COVID-19. The odds ratio (OR) of baseline D-dimer and baseline ANC with mortality was 1.18 (95% confidence interval [CI], 1.08-1.28; P < .001) and 1.13 (95% CI, 1.06-1.21; P < .001). Baseline ANC was associated with the risk of death in severe hospitalized COVID-19 patients, irrespective of the DVT status. In addition, a significantly higher serum neutrophil activity was observed in severe COVID-19 inpatients with DVT or those deceased during hospital stay. New-onset DVT partially mediated the association between baseline D-dimer (indirect effect: 0.011, estimated mediating proportion: 67.0%), baseline ANC (indirect effect: 0.006, estimated mediating proportion: 48.7%), and mortality in severe hospitalized patients with COVID-19. In summary, baseline D-dimer and baseline absolute neutrophil count (ANC) levels were associated with the mortality in severe hospitalized patients with COVID-19, especially DVT inpatients. New-onset DVT partially mediated the association between baseline D-dimer, baseline ANC, and mortality in severe hospitalized patients with COVID-19.
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COVID-19 , Produtos de Degradação da Fibrina e do Fibrinogênio , SARS-CoV-2 , Humanos , COVID-19/mortalidade , COVID-19/sangue , COVID-19/complicações , Masculino , Feminino , Estudos Retrospectivos , Pessoa de Meia-Idade , Produtos de Degradação da Fibrina e do Fibrinogênio/análise , Produtos de Degradação da Fibrina e do Fibrinogênio/metabolismo , Idoso , Neutrófilos , Trombose Venosa/sangue , Trombose Venosa/mortalidade , Inflamação/sangue , Fatores de Risco , Índice de Gravidade de Doença , Hemostasia , Pacientes Internados/estatística & dados numéricos , Contagem de Leucócitos , Adulto , China/epidemiologiaRESUMO
This comprehensive review inspects the therapeutic potential of mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) across multiple organ systems. Examining their impact on the integumentary, respiratory, cardiovascular, urinary, and skeletal systems, the study highlights the versatility of MSC-EVs in addressing diverse medical conditions. Key pathways, such as Nrf2/HO-1, consistently emerge as central mediators of their antioxidative and anti-inflammatory effects. From expediting diabetic wound healing to mitigating oxidative stress-induced skin injuries, alleviating acute lung injuries, and even offering solutions for conditions like myocardial infarction and renal ischemia-reperfusion injury, MSC-EVs demonstrate promising therapeutic efficacy. Their adaptability to different administration routes and identifying specific factors opens avenues for innovative regenerative strategies. This review positions MSC-EVs as promising candidates for future clinical applications, providing a comprehensive overview of their potential impact on regenerative medicine.
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Aeonium arboreum 'Halloween', a popular indoor ornamental succulent in China, changes its leaf colour to red on light exposure. However, the underlying molecular mechanisms is still vague. Comparative analysis of transcriptome data from 'Halloween' leaves treated under dark and light conditions revealed two R2R3-MYB transcription factors, AaMYB113 and AaMYB114, that may mediate anthocyanin accumulation. In this study, we cloned the AaMYB113 and AaMYB114 genes, encoding proteins of 279 and 248 amino acids, respectively. Transcriptional activity analysis revealed that AaMYB113 exhibits strong transcriptional activity, in contrast to AaMYB114, which demonstrates minimal activity. Transient expression studies in tobacco leaves demonstrated that AaMYB113 induced red pigmentation, whereas AaMYB114 did not. Subsequent stable overexpression in Arabidopsis thaliana confirmed that AaMYB113, but not AaMYB114, could similarly turn Arabidopsis leaves red. Further stable transformation of AaMYB113 in tobacco affected multiple floral components, including leaves, petals, calyx, flower tubes, and filaments, turning them red. Quantitative real-time PCR (qRT-PCR) assay in leaves of AaMYB113 stably transformed tobacco and Arabidopsis revealed upregulation of anthocyanin biosynthesis-related structural genes and TT8-like transcription factors. Moreover, the dual luciferase analysis confirmed that AaMYB113 can activate the promoters of 'Halloween' anthocyanin synthesis structural genes, AaCHS, AaCHI, AaF3H, AaDFR and AaANS. The above results indicate that AaMYB113 can promote anthocyanin synthesis, while AaMYB114 does not have this function. This study contributes significantly to the limited body of research on the molecular mechanisms of anthocyanin synthesis in succulents, advancing our understanding of how these pathways are regulated in 'Halloween' succulents and potentially other species.
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Antocianinas , Arabidopsis , Regulação da Expressão Gênica de Plantas , Nicotiana , Folhas de Planta , Proteínas de Plantas , Fatores de Transcrição , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Arabidopsis/genética , Arabidopsis/metabolismo , Nicotiana/genética , Nicotiana/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Antocianinas/biossíntese , Antocianinas/metabolismo , Antocianinas/genética , Folhas de Planta/genética , Folhas de Planta/metabolismo , Plantas Geneticamente Modificadas/genética , Pigmentação/genética , Calycanthaceae/genética , Calycanthaceae/metabolismoRESUMO
OBJECTIVE: The role of gamma-aminobutyric acid-ergic (GABAergic) neuron impairment in Alzheimer's disease (AD), and if and how transplantation of healthy GABAergic neurons can improve AD, remain unknown. METHODS: Human-derived medial ganglionic eminence progenitors (hiMGEs) differentiated from programmed induced neural precursor cells (hiNPCs) were injected into the dentate gyrus region of the hippocampus (HIP). RESULTS: We showed that grafts migrate to the whole brain and form functional synaptic connections in amyloid precursor protein gene/ presenilin-1 (APP/PS1) chimeric mice. Following transplantation of hiMGEs, behavioral deficits and AD-related pathology were alleviated and defective neurons were repaired. Notably, exosomes secreted from hiMGEs, which are rich in anti-inflammatory miRNA, inhibited astrocyte activation invitro and in vivo, and the mechanism was related to regulation of CD4+ Th1 cells mediated tumor necrosis factor (TNF) pathway. INTERPRETATION: Taken together, these findings support the hypothesis that hiMGEs transplantation is an alternative treatment for neuronal loss in AD and demonstrate that exosomes with anti-inflammatory activity derived from hiMGEs are important factors for graft survival. ANN NEUROL 2024;96:488-507.
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Astrócitos , Exossomos , Neurônios GABAérgicos , Células-Tronco Neurais , Animais , Exossomos/transplante , Exossomos/metabolismo , Camundongos , Astrócitos/metabolismo , Humanos , Neurônios GABAérgicos/metabolismo , Células-Tronco Neurais/transplante , Células-Tronco Neurais/metabolismo , Doença de Alzheimer/metabolismo , Camundongos Transgênicos , Cognição/fisiologia , MasculinoRESUMO
Kidneys from donors with prolonged warm and cold ischemia are prone to posttransplant T cell-mediated rejection (TCMR) due to ischemia-reperfusion injury (IRI). However, the precise mechanisms still remain obscure. Renal tubular epithelial cells (TECs) are the main target during IRI. Meanwhile, we have previously reported that murine double minute 2 (MDM2) actively participates in TEC homeostasis during IRI. In this study, we established a murine model of renal IRI and a cell model of hypoxia-reoxygenation by culturing immortalized rat renal proximal tubule cells (NRK-52E) in a hypoxic environment for different time points followed by 24 h of reoxygenation and incubating NRK-52E cells in a chemical anoxia-recovery environment. We found that during renal IRI MDM2 expression increased on the membrane of TECs and aggregated mainly on the basolateral side. This process was accompanied by a reduction of a transmembrane protein, programmed death ligand 1 (PD-L1), a coinhibitory second signal for T cells in TECs. Using mutant plasmids of MDM2 to anchor MDM2 on the cell membrane or nuclei, we found that the upregulation of membrane MDM2 could promote the ubiquitination of PD-L1 and lead to its ubiquitination-proteasome degradation. Finally, we set up a coculture system of TECs and CD4+ T cells in vitro; our results revealed that the immunogenicity of TECs was enhanced during IRI. In conclusion, our findings suggest that the increased immunogenicity of TECs during IRI may be related to ubiquitinated degradation of PD-L1 by increased MDM2 on the cell membrane, which consequently results in T-cell activation and TCMR.NEW & NOTEWORTHY Ischemic acute kidney injury (AKI) donors can effectively shorten the waiting time for kidney transplantation but increase immune rejection, especially T cell-mediated rejection (TCMR), the mechanism of which remains to be elucidated. Our study demonstrates that during ischemia-reperfusion injury (IRI), the translocation of tubular murine double minute 2 leads to basolateral programmed death ligand 1 degradation, which ultimately results in the occurrence of TCMR, which may provide a new therapeutic strategy for preventing AKI donor-associated TCMR.
Assuntos
Injúria Renal Aguda , Proteínas Proto-Oncogênicas c-mdm2 , Traumatismo por Reperfusão , Animais , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/imunologia , Traumatismo por Reperfusão/patologia , Injúria Renal Aguda/metabolismo , Injúria Renal Aguda/imunologia , Injúria Renal Aguda/patologia , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Proteínas Proto-Oncogênicas c-mdm2/genética , Masculino , Ratos , Camundongos Endogâmicos C57BL , Antígeno B7-H1/metabolismo , Ubiquitinação , Modelos Animais de Doenças , Células Epiteliais/metabolismo , Células Epiteliais/imunologia , Células Epiteliais/patologia , Camundongos , Transporte Proteico , Túbulos Renais Proximais/metabolismo , Túbulos Renais Proximais/imunologia , Túbulos Renais Proximais/patologia , Linhagem Celular , Membrana Celular/metabolismo , Hipóxia Celular , Transplante de RimRESUMO
Objectives: To investigate the role of MRI measurements of peri-prostatic adipose tissue (PPAT) in predicting bone metastasis (BM) in patients with newly diagnosed prostate cancer (PCa). Methods: We performed a retrospective study on 156 patients newly diagnosed with PCa by prostate biopsy between October 2010 and November 2022. Clinicopathologic characteristics were collected. Measurements including PPAT volume and prostate volume were calculated by MRI, and the normalized PPAT (PPAT volume/prostate volume) was computed. Independent predictors of BM were determined by univariate and multivariate logistic regression analysis, and a new nomogram was developed based on the predictors. Receiver operating characteristic (ROC) curves were used to estimate predictive performance. Results: PPAT and normalized PPAT were associated with BM (P<0.001). Normalized PPAT positively correlated with clinical T stage(cT), clinical N stage(cN), and Grading Groups(P<0.05). The results of ROC curves indicated that PPAT and normalized PPAT had promising predictive value for BM with the AUC of 0.684 and 0.775 respectively. Univariate and multivariate analysis revealed that high normalized PPAT, cN, and alkaline phosphatase(ALP) were independently predictors of BM. The nomogram was developed and the concordance index(C-index) was 0.856. Conclusions: Normalized PPAT is an independent predictor for BM among with cN, and ALP. Normalized PPAT may help predict BM in patients with newly diagnosed prostate cancer, thus providing adjunctive information for BM risk stratification and bone scan selection.
RESUMO
Light-chain proximal tubulopathy (LCPT) is typically characterized by the intracytoplasmic deposition of light chains within the proximal tubular epithelial cells, which is usually classified into crystalline and noncrystalline subgroups. Membranous nephropathy (MN) is a common glomerular disease characterized by diffused subepithelial electron-dense deposits along the capillary loop accompanied by the effacement and microvillus transformation of the foot process. Here, we report a biopsy-confirmed case of a concurrence of LCPT with crystals (κ light chains restricted) and antigen-undetermined MN in a male patient. The patient presented with low-molecular-weight proteinuria, increased serum creatinine levels, and incomplete Fanconi syndrome. To our knowledge, this is the first report of a concurrence of LCPT and independent MN of unknown target antigens, which may enrich our recognition of monoclonal gammopathy of renal significance with synchronous MN.