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1.
PeerJ ; 11: e16316, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37927783

RESUMO

Background: Renal cell carcinoma (RCC) originates from renal tubular epithelial cells and is mainly classified into three histological types, including clear cell renal cell carcinoma (ccRCC) which accounts for about 75% of all kidney cancers and is characterized by its strong invasiveness and poor prognosis. Hence, it is imperative to understand the mechanisms underlying the occurrence and progression of ccRCC to identify effective biomarkers for the early diagnosis and the prognosis prediction. Methods: The mRNA level of TTC13 was quantified by RT-PCR, while the protein level was determined by western blot and immunohistochemistry (IHC) staining. Cell proliferation was measured by cck-8, and cell apoptosis was detected by flow cytometry. The binding of STAT3 to the promoter region of TTC13 was determined by the luciferase reporter assay and chip experiments. STAT3 nuclear translocation was assessed by immunofluorescence staining. Results: We found that TTC13 was up-regulated in ccRCC, and TTC13 promoted cell proliferation as well as inhibited cell apoptosis and autophagy of ccRCC through wnt/ß-catenin and IL6-JAK-STAT3 signaling pathways. Furthermore, TTC13 might play a role in the immune infiltration and immunotherapy of ccRCC. Mechanistically, STAT3 activated the transcription of TTC13 gene. Conclusions: STAT3 directly regulated TTC13 expression through a positive feedback loop mechanism to promote ccRCC cell proliferation as well as reduce cell apoptosis and autophagy. These findings suggested new and effective therapeutic targets for more accurate and personalized treatment strategies.


Assuntos
Carcinoma de Células Renais , Carcinoma , Neoplasias Renais , Humanos , Carcinoma de Células Renais/genética , Retroalimentação , Linhagem Celular Tumoral , Neoplasias Renais/genética , Processos Neoplásicos , Fator de Transcrição STAT3/genética
2.
Am J Transl Res ; 15(4): 2443-2459, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37193150

RESUMO

OBJECTIVES: To investigate the role of DNA methylation regulators in the prognosis of clear cell renal cell carcinoma (ccRCC) and to construct a DNA methylation regulator-based signature for predicting patient outcome. METHODS: Data from the TCGA dataset were downloaded and analyzed to identify differentially expressed DNA methylation regulators and their interaction as well as correlation. Consensus clustering was used to establish groups of ccRCC with distinct clinical outcomes. A prognostic signature based on two sets of DNA methylation regulators was established and validated in an independent cohort. RESULTS: Our analysis revealed that the expression levels of DNMT3B, MBD1, SMUG1, DNMT1, DNMT3A, TDG, TET3, MBD2, UHRF2, MBD3, UHRF1, and TET2 were significantly upregulated in ccRCC samples, while UNG, ZBTB4, TET1, ZBTB38, and MECP2 were markedly downregulated. UHRF1 was identified as a hub gene in the DNA methylation regulator interaction network. Significant differences were found regarding overall survival, gender, tumor status, and grade between ccRCC patients in the two risk groups. The prognostic signature, based on two sets of DNA methylation regulators, was an independent prognostic indicator, and these findings were validated in an external, independent cohort. CONCLUSIONS: The study provides evidence that DNA methylation regulators play a significant role in the prognosis of ccRCC and the developed DNA methylation regulator-based signature could effectively predict patient outcome.

3.
J Psychiatr Res ; 161: 188-198, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-36933445

RESUMO

Posttraumatic stress disorder (PTSD) is very common after exposure to trauma, mental stress or violence. Because objective biological markers for PTSD are lacking, exactly diagnosing PTSD is a challenge for clinical psychologists. In-depth research on the pathogenesis of PTSD is a key for solving this problem. In this work, we used male Thy1-YFP transgenic mice, in which neurons are fluorescently labeled, to research the effects of PTSD on neurons in vivo. We initially discovered that pathological stress associated with PTSD increased the activation of glycogen synthesis kinase-beta (GSK-3ß) in neurons and induced the translocation of the transcription factor forkhead box-class O3a (FoxO3a) from the cytoplasm to the nucleus, which decreased the expression of uncoupling protein 2 (UCP2) and increased mitochondrial production of reactive oxygen species (ROS) to trigger neuronal apoptosis in the prefrontal cortex (PFC). Furthermore, the PTSD model mice showed increased freezing and anxiety-like behaviors and more severe decrease of memory and exploratory behavior. Additionally, leptin attenuated neuronal apoptosis by increasing the phosphorylation of signal transducer and activator of transcription 3 (STAT3), which further elevated the expression of UCP2 and inhibited the mitochondrial production of ROS induced by PTSD, thus reducing neuronal apoptosis and ameliorating PTSD-related behaviors. Our study is expected to promote the exploration of PTSD-related pathogenesis in neural cells and the clinical effectiveness of leptin for PTSD.


Assuntos
Transtornos de Estresse Pós-Traumáticos , Camundongos , Masculino , Animais , Transtornos de Estresse Pós-Traumáticos/metabolismo , Leptina , Camundongos Transgênicos , Espécies Reativas de Oxigênio , Glicogênio Sintase Quinase 3 beta
4.
Mol Psychiatry ; 28(7): 3044-3054, 2023 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-36991130

RESUMO

Neuropathological mechanisms of manic syndrome or manic episodes in bipolar disorder remain poorly characterised, as the research progress is severely limited by the paucity of appropriate animal models. Here we developed a novel mania mice model by combining a series of chronic unpredictable rhythm disturbances (CURD), which include disruption of circadian rhythm, sleep deprivation, exposure to cone light, with subsequent interference of followed spotlight, stroboscopic illumination, high-temperature stress, noise disturbance and foot shock. Multiple behavioural and cell biology tests comparing the CURD-model with healthy controls and depressed mice were deployed to validate the model. The manic mice were also tested for the pharmacological effects of various medicinal agents used for treating mania. Finally, we compared plasma indicators of the CURD-model mice and the patients with the manic syndrome. The CURD protocol produced a phenotype replicating manic syndrome. Mice exposed to CURD presented manic behaviours similar to that observed in the amphetamine manic model. These behaviours were distinct from depressive-like behaviours recorded in mice treated with a depression-inducing protocol of chronic unpredictable mild restraint (CUMR). Functional and molecular indicators in the CURD mania model showed multiple similarities with patients with manic syndrome. Treatment with LiCl and valproic acid resulted in behavioural improvements and recovery of molecular indicators. A novel manic mice model induced by environmental stressors and free from genetic or pharmacological interventions is a valuable tool for research into pathological mechanisms of mania.


Assuntos
Transtorno Bipolar , Mania , Humanos , Animais , Camundongos , Modelos Animais de Doenças , Ácido Valproico , Privação do Sono
5.
Neurochem Res ; 48(4): 1180-1190, 2023 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35750877

RESUMO

Accumulating evidence suggests that the activation of nucleotide-binding domain and leucine-rich repeat protein-3 (NLRP3) inflammasome contributes to the pathophysiology of post-traumatic stress disorder (PTSD). Astrocytes, the homeostatic cells of the central nervous system are intimately involved into pathophysiology of various mental disorders including PTSD. We demonstrated previously that leptin exerts neuroprotection and ameliorates chronic sleep deprivation-induced depressive-like behaviours. Here, we extended the study of therapeutic effects of leptin to PTSD model mice. We discovered that PTSD is associated with significant activation of NLRP3 inflammasome in astrocytes sorted from GFAP-GFP transgenic mice, while administration of leptin markedly suppressed the activation of astrocytic NLRP3 inflammasome. Leptin effectively improved PTSD-associated behavioural alterations including fear memory, cognitive impairments, and depressive-like behaviours. Therapeutic effects of leptin were mediated by the signal transducer and activator of transcription 3 (STAT3) in astrocytes. In addition, the PTSD-related activation of NLRP3 inflammasome impairs astrocytic mitochondria suppressing ATP synthesis and leading to an increased ROS production. Leptin reversed mitochondrial inhibition by stimulating STAT3 in astrocytes. We propose leptin as a novel candidate for the pharmacological treatment of PTSD.


Assuntos
Inflamassomos , Transtornos de Estresse Pós-Traumáticos , Camundongos , Animais , Proteína 3 que Contém Domínio de Pirina da Família NLR , Astrócitos , Leptina , Medo
6.
Cell Death Dis ; 13(4): 406, 2022 04 25.
Artigo em Inglês | MEDLINE | ID: mdl-35468877

RESUMO

Alzheimer's disease (AD) is the prevalent cause of dementia in the ageing world population. Apolipoprotein E4 (ApoE4) allele is the key genetic risk factor for AD, although the mechanisms linking ApoE4 with neurocognitive impairments and aberrant metabolism remains to be fully characterised. We discovered a significant increase in the ApoE4 content of serum exosomes in old healthy subjects and AD patients carrying ApoE4 allele as compared with healthy adults. Elevated exosomal ApoE4 demonstrated significant inverse correlation with serum level of thyroid hormones and cognitive function. We analysed effects of ApoE4-containing peripheral exosomes on neural cells and neurological outputs in aged or thyroidectomised young mice. Ageing-associated hypothyroidism as well as acute thyroidectomy augmented transport of liver-derived ApoE4 reach exosomes into the brain, where ApoE4 activated nucleotide-binding oligomerisation domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome by increasing cholesterol level in neural cells. This, in turn, affected cognition, locomotion and mood. Our study reveals pathological potential of exosomes-mediated relocation of ApoE4 from the periphery to the brain, this process can represent potential therapeutic target.


Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Exossomos , Idoso , Envelhecimento , Doença de Alzheimer/metabolismo , Animais , Apolipoproteína E4/genética , Apolipoproteína E4/metabolismo , Encéfalo/metabolismo , Disfunção Cognitiva/genética , Disfunção Cognitiva/patologia , Exossomos/metabolismo , Humanos , Fígado/metabolismo , Camundongos , Glândula Tireoide/metabolismo
7.
Oxid Med Cell Longev ; 2022: 5910575, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35401923

RESUMO

Background: Cancer is a major threat to human health worldwide. Although recent innovations and advances in early detection and effective therapies such as targeted drugs and immune checkpoint inhibitors have saved more lives of cancer patients and improved their quality of life, our knowledge about cancer remains largely unknown. CCNA2 belongs to the cell cyclin family and has been demonstrated to be a tumorigenic gene in multiple solid tumor types. The aim of the present study was to make a comprehensive analysis on the role of CCNA2 at a pancancer level. Methods: Multidatabases were collected to evaluate the different expression, prognostic value, DNA methylation, tumor mutation burden, microsatellite instability, mismatch repair, tumor immune microenvironment, and drug sensitivity of CCNA2 across pancancer. IHC was utilized to validate the expression and prognostic value of CCNA2 in ccRCC patients from SMMU cohort. Results: CCNA2 was differentially expressed in most cancer types vs. normal tissues. CCNA2 may significantly influence the prognosis of multiple cancer types, especially clear cell renal cell carcinoma (ccRCC). CCNA2 was also frequently mutated in most cancer types. Notably, CCNA2 was significantly correlated with immune cell infiltration and immune checkpoint inhibitory genes. In addition, CCNA2 was also strongly related to drug resistance. Conclusion: CCNA2 may prove to be a new biomarker for prognostic prediction, tumor immunity assessment, and drug susceptibility evaluation in pancancer level, especially in ccRCC.


Assuntos
Carcinoma de Células Renais , Ciclina A2 , Neoplasias Renais , Biomarcadores Tumorais/genética , Carcinoma de Células Renais/genética , Ciclina A2/genética , Humanos , Neoplasias Renais/genética , Qualidade de Vida , Microambiente Tumoral/genética
8.
Front Immunol ; 13: 842069, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35281041

RESUMO

Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal carcinoma and is associated with poor prognosis and notorious for its immune dysfunction characteristic. SNRPA1 is a spliceosome component responsible for processing pre-mRNA into mRNA, while the biological effect of SNRPA1 in ccRCC remains elusive. The aim of this study was to decipher the effect of SNRPA1 on clinical effect and tumor immunity for ccRCC patients. Multi-databases were collected to evaluate the different expression, prognostic value, DNA methylation, tumor immune microenvironment, and drug sensitivity of SNRPA1 on ccRCC. IHC was utilized to validate the expression and prognostic value of SNRPA1 in ccRCC patients from the SMMU cohort. The knockout expression of SNRPA by sgRNA plasmid inhibited the cell proliferation, migration, and metastasis ability and significantly increased the sensitivity of sunitinib treatment. In addition, we explored the role of SNRPA1 in pan-cancer level. The results indicated that SNRPA1 was differentially expressed in most cancer types. SNRPA1 may significantly influence the prognosis of multiple cancer types, especially in ccRCC patients. Notably, SNRPA1 was significantly correlated with immune cell infiltration and immune checkpoint inhibitory genes. In addition, the aggressive and immune inhibitory effects shown in SNRPA1 overexpression and the effect of SNRPA1 on ccRCC cell line invasion, metastasis, and drug sensitivity in vitro were observed. Moreover, SNRPA1 was related to Myc, MTORC, G2M, E2F, and DNA repair pathways in various cancer types. In all, SNRPA1 may prove to be a new biomarker for prognostic prediction, effect tumor immunity, and drug susceptibility in ccRCC.


Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Biomarcadores Tumorais/genética , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/metabolismo , Feminino , Humanos , Neoplasias Renais/genética , Masculino , Prognóstico , Sunitinibe/farmacologia , Sunitinibe/uso terapêutico , Microambiente Tumoral
9.
Commun Biol ; 5(1): 105, 2022 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-35115638

RESUMO

Stroke causes degeneration and death of neurones leading to the loss of motor function and frequent occurrence of cognitive impairment and depression. Lithium (Li+), the archetypal mood stabiliser, is neuroprotective in animal models of stroke, albeit underlying mechanisms remain unknown. We discover that Li+ inhibits activation of nucleotide-binding oligomerisation domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasomes in the middle cerebral artery occlusion (MCAO) stroke model in mice. This action of Li+ is mediated by two signalling pathways of AKT/GSK3ß/ß-catenin and AKT/FoxO3a/ß-catenin which converge in suppressing the production of reactive oxygen species (ROS). Using immunocytochemstry, MRI imaging, and cell sorting with subsequent mRNA and protein quantification, we demonstrate that Li+ decreases the infarct volume, improves motor function, and alleviates associated cognitive and depressive impairments. In conclusion, this study reveals molecular mechanisms of Li+ neuroprotection during brain ischaemia, thus providing the theoretical background to extend clinical applications of Li+ for treatment of ischemic stroke.


Assuntos
AVC Isquêmico/tratamento farmacológico , Lítio/farmacologia , Fármacos Neuroprotetores/farmacologia , Animais , Disfunção Cognitiva/tratamento farmacológico , Depressão/tratamento farmacológico , Regulação da Expressão Gênica/efeitos dos fármacos , AVC Isquêmico/patologia , Masculino , Camundongos , Camundongos Transgênicos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Distribuição Aleatória
10.
Oxid Med Cell Longev ; 2022: 3617775, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35028006

RESUMO

METHODS: This study was based on the multiomics data (including mRNA, lncRNA, miRNA, methylation, and WES) of 258 ccRCC patients from TCGA database. Firstly, we screened the feature values that had impact on the prognosis and obtained two subtypes. Then, we used 10 algorithms to achieve multiomics clustering and conducted pseudotiming analysis to further validate the robustness of our clustering method, based on which the two subtypes of ccRCC patients were further subtyped. Meanwhile, the immune infiltration was compared between the two subtypes, and drug sensitivity and potential drugs were analyzed. Furthermore, to analyze the heterogeneity of patients at the multiomics level, biological functions between two subtypes were compared. Finally, Boruta and PCA methods were used for dimensionality reduction and cluster analysis to construct a renal cancer risk model based on mRNA expression. RESULTS: A prognosis predicting model of ccRCC was established by dividing patients into the high- and low-risk groups. It was found that overall survival (OS) and progression-free interval (PFI) were significantly different between the two groups (p < 0.01). The area under the OS time-dependent ROC curve for 1, 3, 5, and 10 years in the training set was 0.75, 0.72, 0.71, and 0.68, respectively. CONCLUSION: The model could precisely predict the prognosis of ccRCC patients and may have implications for drug selection for ccRCC patients.


Assuntos
Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Análise de Dados , Humanos , Prognóstico
11.
Front Oncol ; 11: 755212, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34804944

RESUMO

BACKGROUND: Pyroptosis is essential for tumorigenesis and progression of neoplasm. However, the heterogeneity of pyroptosis and its relationship with the tumor microenvironment (TME) in clear cell renal cell carcinoma (ccRCC) remain unclear. The purpose of the present study was to identify pyroptosis-related subtypes and construct a prognosis prediction model based on pyroptosis signatures. METHODS: First, heterogenous pyroptosis subgroups were explored based on 33 pyroptosis-related genes and ccRCC samples from TCGA, and the model established by LASSO regression was verified by the ICGC database. Then, the clinical significance, functional status, immune infiltration, cell-cell communication, genomic alteration, and drug sensitivity of different subgroups were further analyzed. Finally, the LASSO-Cox algorithm was applied to narrow down the candidate genes to develop a robust and concise prognostic model. RESULTS: Two heterogenous pyroptosis subgroups were identified: pyroptosis-low immunity-low C1 subtype and pyroptosis-high immunity-high C2 subtype. Compared with C1, C2 was associated with a higher clinical stage or grade and a worse prognosis. More immune cell infiltration was observed in C2 than that in C1, while the response rate in the C2 subgroup was lower than that in the C1 subgroup. Pyroptosis-related genes were mainly expressed in myeloid cells, and T cells and epithelial cells might influence other cell clusters via the pyroptosis-related pathway. In addition, C1 was characterized by MTOR and ATM mutation, while the characteristics of C2 were alterations in SPEN and ROS1 mutation. Finally, a robust and promising pyroptosis-related prediction model for ccRCC was constructed and validated. CONCLUSION: Two heterogeneous pyroptosis subtypes were identified and compared in multiple omics levels, and five pyroptosis-related signatures were applied to establish a prognosis prediction model. Our findings may help better understand the role of pyroptosis in ccRCC progression and provide a new perspective in the management of ccRCC patients.

12.
Int J Biol Sci ; 17(12): 3158-3172, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34421357

RESUMO

DEAD-box protein 39 (DDX39) has been demonstrated to be a tumorigenic gene in multiple tumor types, but its role in the progression and immune microenvironment of clear cell renal cell cancer (ccRCC) remains unclear. The aim of the present study was to investigate the role of DDX39 in the ccRCC tumor progression, immune microenvironment and efficacy of immune checkpoint therapy. The DDX39 expression level was first detected in tumors in the public data and then verified in ccRCC samples from Changzheng Hospital. The prognostic value of DDX39 expression was assessed in the Cancer Genome Atlas (TCGA) and ccRCC patients from Changhai Hospital. The role of DDX39 in promoting ccRCC was analyzed by bioinformatic analysis and in vitro experiments. The association between DDX39 expression and immune cell infiltration and immune inhibitory markers was analyzed, and its value in predicting the immune checkpoint therapy efficacy in ccRCC were evaluated in the public database. DDX39 expression was elevated in Oncomine, GEO and TCGA ccRCC databases, as well as in Changzheng ccRCC samples. In TCGA ccRCC patients, increased DDX39 expression predicted worse overall survival (OS) (p<0.0001) and progression-free interval (PFI) (p<0.0001), and was shown as an independent predictive factor for OS (p=0.002). These findings were consistent with those from Changhai ccRCC patients. In addition, GO and GSEA analysis identified DDX39 as a pro-ccRCC gene. In vitro experiments confirmed the role of DDX39 in promoting ccRCC cell. Finally, DDX39 was found to be positively correlated with a variety of immune inhibitory markers, and could predict the adverse efficacy of immune checkpoint therapy in TIDE analysis. In conclusion, Increased DDX39 in ccRCC patients predicted worse clinical prognosis, promoted ccRCC cell proliferation, migration and invasion, and also predicted adverse efficacy of immune checkpoint therapy.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma de Células Renais/tratamento farmacológico , RNA Helicases DEAD-box/genética , Regulação Neoplásica da Expressão Gênica/fisiologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Western Blotting , Carcinoma de Células Renais/diagnóstico , Carcinoma de Células Renais/genética , Proliferação de Células , Biologia Computacional , Feminino , Humanos , Neoplasias Renais/diagnóstico , Neoplasias Renais/genética , Masculino , Pessoa de Meia-Idade , Prognóstico , Reação em Cadeia da Polimerase em Tempo Real , Microambiente Tumoral
13.
Commun Biol ; 4(1): 525, 2021 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-33953326

RESUMO

Iron is the fundamental element for numerous physiological functions. Plasmalemmal divalent metal ion transporter 1 (DMT1) is responsible for cellular uptake of ferrous (Fe2+), whereas transferrin receptors (TFR) carry transferrin (TF)-bound ferric (Fe3+). In this study we performed detailed analysis of the action of Fe ions on cytoplasmic free calcium ion concentration ([Ca2+]i) in astrocytes. Administration of Fe2+ or Fe3+ in µM concentrations evoked [Ca2+]i in astrocytes in vitro and in vivo. Iron ions trigger increase in [Ca2+]i through two distinct molecular cascades. Uptake of Fe2+ by DMT1 inhibits astroglial Na+-K+-ATPase, which leads to elevation in cytoplasmic Na+ concentration, thus reversing Na+/Ca2+ exchanger and thereby generating Ca2+ influx. Uptake of Fe3+ by TF-TFR stimulates phospholipase C to produce inositol 1,4,5-trisphosphate (InsP3), thus triggering InsP3 receptor-mediated Ca2+ release from endoplasmic reticulum. In summary, these findings reveal the mechanisms of iron-induced astrocytic signalling operational in conditions of iron overload.


Assuntos
Astrócitos/metabolismo , Sinalização do Cálcio/efeitos dos fármacos , Cálcio/metabolismo , Proteínas de Transporte de Cátions/metabolismo , Compostos Férricos/farmacologia , Compostos Ferrosos/farmacologia , Receptores da Transferrina/metabolismo , Animais , Astrócitos/citologia , Astrócitos/efeitos dos fármacos , Transporte Biológico , Camundongos , Camundongos Endogâmicos C57BL , Sódio/metabolismo
14.
Neurochem Res ; 46(10): 2731-2745, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33527219

RESUMO

Major depressive disorders (MDD) a worldwide psychiatric disease, is yet to be adequately controlled by therapies; while the mechanisms of action of antidepressants are yet to be fully characterised. In the last two decades, an increasing number of studies have demonstrated the role of astrocytes in the pathophysiology and therapy of MDD. Selective serotonin reuptake inhibitors (SSRIs) are the most widely used antidepressants. It is generally acknowledged that SSRIs increase serotonin levels in the central nervous system by inhibiting serotonin transporters, although the SSRIs action is not ideal. The SSRIs antidepressant effect develops with considerable delay; their efficacy is low and frequent relapses are common. Neither cellular nor molecular pharmacological mechanisms of SSRIs are fully characterised; in particular their action on astrocytes remain underappreciated. In this paper we overview potential therapeutic mechanisms of SSRIs associated with astroglia and report the results of meta-analysis of studies dedicated to MDD, SSRIs and astrocytes. In particular, we argue that fluoxetine, the representative SSRI, improves depressive-like behaviours in animals treated with chronic mild stress and reverses depression-associated decrease in astrocytic glial fibrillary acidic protein (GFAP) expression. In addition, fluoxetine upregulates astrocytic mRNA expression of 5-hydroxytriptamin/serotonin2B receptors (5-HT2BR). In summary, we infer that SSRIs exert their anti-depressant effect by regulating several molecular and signalling pathways in astrocytes.


Assuntos
Antidepressivos/uso terapêutico , Astrócitos/efeitos dos fármacos , Transtorno Depressivo Maior/tratamento farmacológico , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Animais , Astrócitos/metabolismo , Comportamento Animal/efeitos dos fármacos , Contagem de Células , Transtorno Depressivo Maior/metabolismo , Proteína Glial Fibrilar Ácida/metabolismo , Humanos , Camundongos , Ratos , Receptores 5-HT2 de Serotonina/metabolismo
15.
Function (Oxf) ; 2(2): zqab003, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-35330817

RESUMO

Metal implants are used worldwide, with millions of nails, plates, and fixtures grafted during orthopedic surgeries. Iron is the most common element of these metal implants. As time passes, implants can be corroded and iron can be released. Ionized iron permeates the surrounding tissues and enters circulation; importantly, iron ions pass through the blood-brain barrier. Can iron from implants represent a risk factor for neurological diseases? This remains an unanswered question. In this study, we discovered that patients with metal implants delivered through orthopedic surgeries have higher incidence of Parkinson's disease or ischemic stroke compared to patients who underwent similar surgeries but did not have implants. Concentration of serum iron and ferritin was increased in subjects with metal implants. In experiments in vivo, we found that injection of iron dextran selectively decreased the presence of divalent metal transporter 1 (DMT1) in neurons through increasing the expression of Ndfip1, which degrades DMT1 and does not exist in glial cells. At the same time, excess of iron increased expression of DMT1 in astrocytes and microglial cells and triggered reactive astrogliosis and microgliosis. Facing the attack of excess iron, glial cells act as neuroprotectors to accumulate more extracellular iron by upregulating DMT1, whereas neurons limit iron uptake through increasing DMT1 degradation. Cerebral accumulation of iron in animals is associated with impaired cognition, locomotion, and mood. Excess iron from surgical implants thus can affect neural cells and may be regarded as a risk factor for neurodegeneration.


Assuntos
Ferro , Neurônios , Animais , Ferro/metabolismo , Neurônios/metabolismo , Neuroglia/metabolismo , Barreira Hematoencefálica/metabolismo , Doença Iatrogênica
17.
ACS Appl Mater Interfaces ; 11(26): 23623-23631, 2019 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-31184463

RESUMO

The magical fantasy of decades-old transformer characters is becoming closer to scientific reality, as transformable materials can change their shapes in response to thermal, mechanical, electrical, and chemical stimuli. However, precise and prompt control of plastic shaping remains to be wanted. Photoresponsive materials provide a promising alternative for rapid optomechanical shaping with limited success. Here, we report a new class of photoplastic transformation based on dynamic covalently crosslinked polytriazole (PTA) networks, in which crosslinking points are comprised of photocleaveable hexaarylbiimidazole (HABI). Upon sub-500 nm light irradiation, HABI is dissociated into two triphenylimidazole radicals (TPIRs) followed by spontaneous recombination back to the initial state. This photoswitching effect is demonstrated to generate nonthermal shape change in the PTA-HABI gel network at will upon light stimulus. A unique photoalignment phenomenon has also been discovered which can form oriented nanoscale patterning in the PTA-HABI gel network upon laser irradiation. The solvent-free PTA-HABI elastomer exhibits photoenhanced automatic self-healing properties at temperatures ranging from 25 °C to freezing points, which is attributed to the dynamic equilibrium between TPIRs and HABI. A photoplastic spring is fabricated and exhibits photoswitchable plastic behavior, i.e., a reversible transformation between plastic strain and elastic strain upon light irradiation. HABI-based polymer networks, including solvated gel and solvent-free elastomer, are promising as smart materials for nonthermal photoactivated shape changing, transformation, and self-healing applications.

18.
ACS Appl Mater Interfaces ; 9(12): 10338-10343, 2017 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-28281748

RESUMO

We have designed and synthesized an amphiphilic photoswitchable fluorophore, PEGylated perylenemonoimide-dithienylethene (PEG-PMI-DTE), which exhibits evident bistable photochromism, fluorescence switching, and fatigue resistance. The fine nanostructures of liposomes can be observed directly under super-resolution fluorescent microscopy by aid of the amphiphilic photoswitchable fluorophore as a staining agent, with an optical resolution of 30 nm.


Assuntos
Imidas/química , Perileno/análogos & derivados , Lipossomos , Microscopia de Fluorescência , Perileno/química
19.
Chem Commun (Camb) ; 53(18): 2669-2672, 2017 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-28217792

RESUMO

Self-assembly of an amphiphilic photoswitchable fluorescent macrocycle methoxy-tetraethylene glycol-substituted hexaarylbiimidazole-borondipyrromethene can be observed directly under a super-resolution fluorescence microscope, with the nanoscale resolution beyond the optical diffraction limitation.

20.
Faraday Discuss ; 196: 439-454, 2017 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-27905612

RESUMO

We report the design and synthesis of a tetraphenylethene substituted with naphthalimide at the 4, 6 positions, named NI-2TPE. NI-2TPE exhibits strong solvent-dependent emission properties with combined ICT and AIE characteristics in THF-H2O systems. This probe was used directly on test papers to distinguish normal organic solvents using their emission colours under UV light based on its AIE and ICT nature. Thanks to the vinyl group in NI-2TPE, we synthesized a copolymer of NIPAM and NI-2TPE, termed P(NIPAM-co-NI-2TPE). The resulting polymer is highly soluble and fluorescent in water (ΦF = 15.4%). Due to the well-known thermo-responsive character of NIPAM, P(NIPAM-co-NI-2TPE) exhibits an interesting fluorescence change in response to various temperatures. Due to the thermo-induced shrinking of the PNIPAM chain, the fluorescence intensity gradually increased from 20 to 34 °C. As the temperature further increased from 34 to 90 °C, the fluorescence intensity decreased sharply, which was caused by the well-known thermal effects. Furthermore, we synthesized a P(HEA-co-NI-2TPE-TPP acrylate) copolymer, in which HEA is a hydrophilic unit, TPP is a mitochondria label and NI-2TPE a fluorescent probe. The corresponding polymer probe is highly soluble in water with FLQY = 7% and we have further applied this probe as a mitochondria targeted imaging tracker in HeLa cells successfully.


Assuntos
Células/química , Fluorescência , Corantes Fluorescentes/química , Naftalimidas/química , Imagem Óptica , Estilbenos/química , Corantes Fluorescentes/síntese química , Células HeLa , Humanos , Imagem Molecular , Estrutura Molecular , Polimerização , Raios Ultravioleta
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