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BACKGROUND: Long non-coding RNAs (lncRNAs) are RNA transcripts of more than 200 nucleotides that do not encode canonical proteins. Their biological structure is similar to messenger RNAs (mRNAs). To distinguish between lncRNA and mRNA transcripts quickly and accurately, we upgraded the PLEK alignment-free tool to its next version, PLEKv2, and constructed models tailored for both animals and plants. RESULTS: PLEKv2 can achieve 98.7% prediction accuracy for human datasets. Compared with classical tools and deep learning-based models, this is 8.1%, 3.7%, 16.6%, 1.4%, 4.9%, and 48.9% higher than CPC2, CNCI, Wen et al.'s CNN, LncADeep, PLEK, and NcResNet, respectively. The accuracy of PLEKv2 was > 90% for cross-species prediction. PLEKv2 is more effective and robust than CPC2, CNCI, LncADeep, PLEK, and NcResNet for primate datasets (including chimpanzees, macaques, and gorillas). Moreover, PLEKv2 is not only suitable for non-human primates that are closely related to humans, but can also predict the coding ability of RNA sequences in plants such as Arabidopsis. CONCLUSIONS: The experimental results illustrate that the model constructed by PLEKv2 can distinguish lncRNAs and mRNAs better than PLEK. The PLEKv2 software is freely available at https://sourceforge.net/projects/plek2/ .
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RNA Longo não Codificante , RNA Mensageiro , RNA Longo não Codificante/genética , RNA Mensageiro/genética , Humanos , Animais , Software , Biologia Computacional/métodosRESUMO
Hydroxychloroquine (HCQ), 2-([4-([7-Chloro-4-quinolyl]amino)pentyl]ethylamino)ethanol, exhibited significant biological activity, while its side effects cannot be overlooked. The RP-HPLC enantio-separation was investigated for cost-effective and convenient optical purity analysis of HCQ. The thermodynamic resolution of Rac-HCQ, driven by enthalpy and entropy, was achieved on the C18 column using Carboxymethyl-ß-cyclodextrin (CM-ß-CD) as the chiral mobile phase agent (CMPA). The effects of CCM-ß-CD, pH, and triethylamine (TEA) V% on the enantio-separation process were explored. Under the optimum conditions at 24°C, the retention times for the two enantiomers were t R 1 = 29.39 min $$ {t}_{R1}=29.39\ \min $$ and t R 2 = 32.42 min $$ {t}_{R2}=32.42\ \min $$ , resulting in R s = 1.87 $$ {R}_s=1.87 $$ . The resolution via diastereomeric salt formation of Rac-HCQ was developed to obtain the active pharmaceutical ingredient of single enantiomer S-HCQ. Di-p-Anisoyl-L-Tartaric Acid (L-DATA) was proved effective as the resolution agent for Rac-HCQ. Surprisingly, it was found that refluxing time was a key fact affecting the resolution efficiency, which meant the kinetic dominate during the process of the resolution. Four factors-solvent volume, refluxing time, filtration temperature, and molar ratio-were optimized using the single-factor method and the response surface method. Two cubic models were established, and the reliability was subsequently verified. Under the optimal conditions, the less soluble salt of 2L-DATA:S-HCQ was obtained with a yield of 96.9% and optical purity of 63.0%. The optical purity of this less soluble salt increases to 99.0% with a yield of 74.2% after three rounds recrystallization.
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Hidroxicloroquina , Hidroxicloroquina/química , Estereoisomerismo , Cromatografia Líquida de Alta Pressão/métodos , Concentração de Íons de Hidrogênio , beta-Ciclodextrinas/química , Cromatografia de Fase Reversa/métodos , Etilaminas/química , Termodinâmica , Sais/químicaRESUMO
BACKGROUND: While epidemiological studies have established a firm link between circadian disruption and tumorigenesis, the role and mechanism are not fully understood, complicating the design of therapeutic targets related to circadian rhythms (CR). Here, we aimed to explore the intertumoral heterogeneity of CR and elucidate its impact on the tumor microenvironment (TME), drug sensitivity, and immunotherapy. METHODS: Based on unsupervised clustering of 28 CR genes, two distinct CR subtypes (cluster-A and cluster-B) were identified in the TCGA cohort. We further constructed a circadian rhythm signature (CRS) based on the CR genes primarily responsible for clustering to quantify CR activity and to distinguish CR subtypes of individual patients from external datasets. CR subtypes were evaluated by TME characteristics, functional annotation, clinical features, and therapeutic response. RESULTS: The cluster-B (low-CRS) group was characterized by highly enriched immune-related pathways, high immune cell infiltration, and high anti-tumor immunity, while the cluster-A (high-CRS) group was associated with immunosuppression, synaptic transmission pathways, EMT activation, poor prognosis, and drug resistance. Immunohistochemistry (IHC) results demonstrated that high CD8+ T cell infiltration was associated with low-CR-protein expression. Importantly, patients with low CRS were more likely to benefit from immune checkpoint blockade (ICB) treatment, possibly due to their higher tumor mutation burden (TMB), increased immune checkpoint expression, and higher proportion of "hot" immunophenotype. CONCLUSION: In a nutshell, the cross talk in CR could reflect the TME immunoreactivity in breast cancer. Besides providing the first comprehensive pathway-level analysis of CR in breast cancer, this work highlights the potential clinical utility of CR for immunotherapy.
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Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/terapia , Imunoterapia , Terapia de Imunossupressão , Linfócitos T CD8-Positivos , Carcinogênese , Microambiente Tumoral , PrognósticoRESUMO
Phosphoinositide 3-kinases (PI3Ks) generate lipids that control multitudinous intracellular cell signaling events which participate in cell survival and proliferation. In addition, PI3K signaling also contributes to metabolism, immunity, angiogenesis and cardiovascular homeostasis, and many diseases. The diverse actions of PI3K stem from the existence of their various isoforms and a variety of protein effectors. Hence, PI3K isoform-specific inhibitors have already achieved a wonderful effect on treating cancer. Herein, we summarize the molecular mechanism of PI3K inhibitors in preventing the permeability of vessels and neovascularization. Additionally, we briefly illustrate how PI3K signaling modulates blood vessel growth and discuss the different roles that PI3K isoforms play in angiogenesis.
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Fosfatidilinositol 3-Quinase , Fosfatidilinositol 3-Quinases , Fosfatidilinositol 3-Quinases/metabolismo , Transdução de Sinais , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Isoformas de Proteínas/metabolismoRESUMO
A non-noble Cu-catalyzed transfer aza-benzyl Michael addition via the C-C bond cleavage of aza-benzyl alcohols has been disclosed. The unstrained C(sp3)-C(sp3) bond of an alcohol was selectively cleaved. This aza-benzyl transfer strategy provides a selective and environmentally benign approach for the C-alkylation of α,ß-unsaturated carbonyl compounds that employs readily available alcohols as carbon nucleophiles and is characterized by a wide range of substrates and good to excellent yields.
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N6 -methyladenosine (m6 A), the sixth N methylation of adenylate (A) in RNA, is the most abundant transcriptome modification in eukaryotic messenger RNA (mRNAs). m6 A modification exists in both coding mRNA and noncoding RNAs, and its functions are controlled by methyltransferase, demethylase, and m6 A reading proteins. Methylation modification of m6 A can regulate RNA cleavage, transport, stability, and expression. This review summarizes the enzymes involved in RNA m6 A methylation and the commonly used detection methods. The role of m6 A modification in physiological processes is described, and its impact on tumorigenesis, viral infection, and diabetes is further highlighted. Moreover, up-to-date knowledge of the implications of RNA m6 A modification in ocular diseases such as uveal melanoma and diabetic retinopathy is introduced. Clarifying the mechanism of RNA m6 A methylation will help elucidate the pathogenesis of various diseases, providing options for subsequent treatment.
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Adenosina , Oftalmopatias , Metiltransferases , RNA , Adenosina/análogos & derivados , Adenosina/metabolismo , Oftalmopatias/metabolismo , Humanos , Metilação , Metiltransferases/metabolismo , RNA/metabolismo , RNA MensageiroRESUMO
Humor is a special human expression style, an important "lubricant" for daily communication for people; people can convey emotional messages that are not easily expressed through humor. At present, artificial intelligence is one of the popular research domains; "discourse understanding" is also an important research direction, and how to make computers recognize and understand humorous expressions similar to humans has become one of the popular research domains for natural language processing researchers. In this paper, a humor recognition model (MLSN) based on current humor theory and popular deep learning techniques is proposed for the humor recognition task. The model automatically identifies whether a sentence contains humor expression by capturing the inconsistency, phonetic features, and ambiguity of a joke as semantic features. The model was experimented on three publicly available wisecrack datasets and compared with state-of-the-art language models, and the results demonstrate that the proposed model has better humor recognition accuracy and can contribute to the research on discourse understanding.
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Inteligência Artificial , Web Semântica , Humanos , Idioma , Processamento de Linguagem Natural , SemânticaRESUMO
OBJECTIVES: The weakness and dialysis of lens zonule after cataract surgery may lead to dislocation of intraocular lens (IOL). It has been shown that cataract surgery could induce or aggravate posterior vitreous detachment (PVD) due to postoperative inflammation and increased volume of vitreous cavity. PVD is associated with the occurrence of several vitreoretinal diseases, such as rhegmatogenous retinal detachment and macular hole. This study aims to explore risk factors for dislocation of IOL concurring with vitreoretinal disease, such as retinal detachment and macular hole, and to evaluate the efficacy and complications of surgical intervention for these abnormalities concurrently. METHODS: Ten patients (10 eyes) who diagnosed as rhegmatogenous retinal detachment, traumatic macular hole, high myopic macular hole, and combined with IOL dislocation at the Department of Ophthalmology of Xiangya Hospital from January 2004 to December 2020 were enrolled. The patients received vitreoretinal surgery and reposition of IOL by scleral suturing. Medical records were reviewed to figure out the time and type of IOL dislocation. Preoperative and 1 year of postoperative best corrected visual acuity, intraocular pressure, corneal endothelial density, and complications of surgical management were analyzed. RESULTS: Ten patients including 4 high myopia, 4 ocular contusion, and 2 who experienced IOL dislocation during the posterior capsulotomy were included in this study. Coexistence of IOL dislocation and vitreoretinal abnormalities occurred in patients with high myopia, ocular contusion, and capsulotomy. IOL dislocation happened in the vitreoretinal surgery in patients with high myopia or intraoperative capsulotomy. IOL dislocation occurred preoperatively in patients with ocular contusion. IOL capsular bag complex dislocation and out-of-the-bag IOL dislocation were found in 4 and 6 patients, respectively. Surgical relocation of dropped IOL and repair of vitreoretinal disease improved the best corrected visual acuity from preoperative 1.79±0.39 to postoperative 1.13±0.45 (P<0.001). The density of corneal endothelial cells in patients was lower than that before surgery [(1 806.40±181.20) cells/mm2 vs (1 914.00±182.22) cells/mm2, P<0.001]. There was no significant difference in intraocular pressure before and after surgery (P=0.099). Postoperative complications included high intraocular pressure and recurrent retinal detachment. CONCLUSIONS: Dislocation of IOL may be concurrent with vitreoretinal disease. High myopia, blunt contusion, and capsulectomy might be the risk factors for intraocular lens dislocation. The surgical technique used in the present study is successful in manipulating these disorders with optimal functional results and less severe complications.
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Catarata , Contusões , Subluxação do Cristalino , Miopia , Descolamento Retiniano , Perfurações Retinianas , Catarata/etiologia , Contusões/complicações , Células Endoteliais , Humanos , Implante de Lente Intraocular , Subluxação do Cristalino/complicações , Subluxação do Cristalino/cirurgia , Miopia/complicações , Miopia/cirurgia , Complicações Pós-Operatórias/epidemiologia , Descolamento Retiniano/complicações , Perfurações Retinianas/complicações , Estudos Retrospectivos , Fatores de Risco , Resultado do Tratamento , Acuidade Visual , Vitrectomia/efeitos adversos , Vitrectomia/métodosRESUMO
Retinal diseases are characterized by the degeneration of retinal neural cells, and are the main cause of blindness. Although the development of stem cell including retinal stem cell therapies raises hope for retinal neuron replacement, currently, there is still no efficient method to regenerate retinal neurons. To realize the potential roles of the production of retinal neurons, neurotrophic factor direct the differentiation of retinal stem cells should be extensively identified. In this article, we characterized growth/differentiation 5 (GDF5), which caused the activation of Smad signaling, can induce neurogenesis and neurite outgrowth in retinal stem cell differentiation. Moreover, a bHLH transcription factor, Atoh8 modulates the effects stimulated by GDF5. These data suggested that GDF5 regulates neuron differentiation through mediating Atoh8 and help us to understand the pathophysiological function of GDF5 in retinal regeneration.
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Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Diferenciação Celular/fisiologia , Fator 5 de Diferenciação de Crescimento/metabolismo , Células-Tronco Neurais/metabolismo , Neurônios/metabolismo , Retina/metabolismo , Animais , Camundongos , Células-Tronco Neurais/citologia , Neurogênese/fisiologia , Neurônios/citologia , Retina/citologiaRESUMO
Rhodopsin mutations cause autosomal dominant form of retinitis pigmentosa (RP). T17M rhodopsin predisposes cells to endoplasmic reticulum stress induced apoptosis. However, the pathogenic role of T17M rhodopsin in RP is not completely understood. Complement C3 has a protective role in RP pathogenesis. This study aimed to investigate whether T17M rhodopsin regulates C3 secretion in retinal pigment epithelium. The human retinal pigment epithelial cell line (ARPE-19) was engineered to overexpress wide-type (WT) and T17M rhodopsin. Gene expression was detected by RT-PCR and Western blot analysis. C3 secretion was detected by ELISA. The overexpression of T17M rhodopsin significantly induced ROS and reduced C3 secretion and transcription in ARPE-19 cells, but ROS scavengers could partially rescue reduced C3 secretion and transcription. Mechanistically, we found that ROS suppressed transcription factor TWIST1 which is responsible for activated transcription of C3. In conclusion, our data provide the first evidence that T17M rhodopsin mutant disrupts C3 secretion via the induction of ROS and the suppression of TWIST1. These findings reveal novel insight into the pathogenic role of mutant rhodopsin in RP. J. Cell. Biochem. 118: 4914-4920, 2017. © 2017 Wiley Periodicals, Inc.
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Complemento C3/metabolismo , Regulação para Baixo , Mutação , Proteínas Nucleares/biossíntese , Espécies Reativas de Oxigênio/metabolismo , Epitélio Pigmentado da Retina/metabolismo , Rodopsina/metabolismo , Proteína 1 Relacionada a Twist/biossíntese , Linhagem Celular , Complemento C3/genética , Humanos , Proteínas Nucleares/genética , Epitélio Pigmentado da Retina/citologia , Rodopsina/genética , Proteína 1 Relacionada a Twist/genéticaRESUMO
OBJECTIVE: To elucidate the role of insulin gene enhancer protein ISL-1 (Islet-1) in angiogenesis and regulation of vascular endothelial growth factor (VEGF) expression in vitro and in vivo. METHODS: siRNA targeting Islet-1 was transfected to human umbilical vein endothelial cell lines (HUVECs). The expression of Islet-1 and VEGF in the cultured cells was measured using real-time PCR and immunoblotting. 3-[4,5-dimethylthiazol-2-yl]-2,5- diphenyltetrazolium bromide; thiazolyl blue (MTT) assay was used to analyze the proliferation of HUVECs affected by Islet-1. Wound healing and Transwell assays were conducted to assess the motility of HUVECs. The formation of capillary-like structures was examined using growth factor-reduced Matrigel. siRNA targeting Islet-1 was intravitreally injected into the murine model of oxygen-induced retinopathy (OIR). Retinal neovascularization was evaluated with angiography using fluorescein-labeled dextran and then quantified histologically. Real-time PCR and immunoblotting were used to determine whether local Islet-1 silencing affected the expression of Islet-1 and VEGF in murine retinas. RESULTS: The expression of Islet-1 and VEGF in HUVECs was knocked down by siRNA. Reduced endogenous Islet-1 levels in cultured cells greatly inhibited the proliferation, migration, and tube formation in HUVECs in vitro. Retinal neovascularization following injection of Islet-1 siRNA was significantly reduced compared with that of the contralateral control eye. Histological analysis indicated that the neovascular nuclei protruding into the vitreous cavity were decreased. Furthermore, the Islet-1 and VEGF expression levels were downregulated in murine retinas treated with siRNA against Islet-1. CONCLUSIONS: Reducing the expression of endogenous Islet-1 inhibits proliferation, migration, and tube formation in vascular endothelial cells in vitro and suppresses retinal angiogenesis in vivo. Endogenous Islet-1 regulates angiogenesis via VEGF.
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Modelos Animais de Doenças , Proteínas com Homeodomínio LIM/fisiologia , Neovascularização Retiniana/metabolismo , Fatores de Transcrição/fisiologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Animais , Animais Recém-Nascidos , Western Blotting , Movimento Celular , Proliferação de Células , Células Cultivadas , Colágeno , Combinação de Medicamentos , Angiofluoresceinografia , Células Endoteliais da Veia Umbilical Humana , Humanos , Immunoblotting , Laminina , Camundongos , Camundongos Endogâmicos C57BL , Neovascularização Fisiológica , Proteoglicanas , RNA Interferente Pequeno/genética , Reação em Cadeia da Polimerase em Tempo Real , Neovascularização Retiniana/diagnóstico , TransfecçãoRESUMO
BACKGROUND: Netrin-1 has been reported to promote retinal neovascularization in oxygen-induced retinopathy (OIR). However, netrin-1 receptors, which may mediate netrin-1 action during retinal neovascularization, have not been characterized. In this study, we investigated netrin-1 receptor subtype expression and associated changes in the retinas of mice with OIR. METHODS: C57BL/6J mice were exposed to 75±2% oxygen for 5 days and then returned to normal air to induce retinal neovascularization. Reverse transcriptase polymerase chain reaction (RT-PCR) and Western blot were used to examine the expression of netrin-1 receptor subtypes in the mouse retinas. Double staining of netrin-1 receptor subtypes and isolectin B4 was used to determine the location of the netrin-1 receptor subtypes in the retinas. Inhibition of retinal neovascularization was achieved by UNC5B shRNA plasmid intravitreal injection. Retinal neovascularization was examined by fluorescein angiography and quantification of preretinal neovascular nuclei in retinal sections. RESULTS: RT-PCR results showed that, except for UNC5A, netrin-1 receptor subtypes UNC5B, UNC5C, UNC5D, DCC, neogenin, and A2b were all expressed in the retinas of OIR mice 17 days after birth. Western blots showed that only UNC5B expression was significantly increased on that day, and immunofluorescence results showed that only UNC5B and neogenin were expressed in retinal vessels. Treatment of OIR mice with the UNC5B shRNA plasmid dramatically reduced neovascular tufts and neovascular outgrowth into the inner limiting membrane. CONCLUSIONS: UNC5B may promote retinal neovascularization in OIR mice.
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Regulação da Expressão Gênica no Desenvolvimento , RNA Mensageiro/genética , Receptores de Superfície Celular/genética , Doenças Retinianas/genética , Animais , Animais Recém-Nascidos , Western Blotting , Modelos Animais de Doenças , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Receptores de Netrina , Oxigênio/toxicidade , Reação em Cadeia da Polimerase em Tempo Real , Receptores de Superfície Celular/biossíntese , Doenças Retinianas/induzido quimicamente , Doenças Retinianas/metabolismoRESUMO
Glaucoma is a chronic, neurodegenerative disease that often leads to blindness. A common treatment is to reduce intraocular pressure (IOP), but this approach does not halt visual loss caused by the death of retinal ganglion cells (RGCs). Therefore, there is an important need for therapies that protect against RGCs degeneration. The present study in a rat glaucoma model aimed to determine whether retinal stem cells (RSCs) transplantation plus vaccination with a glatiramer acetate copolymer-1 (COP-1) could confer neuroprotection. Rats were immunized with COP-1 on the same day as IOP induction by argon laser photocoagulation of the episcleral veins and limbal plexus. RSCs were cultured and transplanted intravitreally 1week after laser treatment. The expression of brain-derived neurotrophic factor (BDNF) and insulin-like growth factor I (IGF-I) was detected by immunohistochemical staining, RT-PCR, and western blotting. RGCs survival was assessed by TUNEL staining and RGCs counting. We found that the expression of BDNF and IGF-I in the RSCs/COP-1 group was significantly higher than in other groups (P<0.05). In addition, the number of the apoptotic RGCs in the RSCs/COP-1 group was notably lower than in other groups (P<0.05), and the number of RGCs in the RSCs/COP-1 group was higher than in other groups (P<0.05). We conclude, therefore, that the combined effects between RSCs transplantation and COP-1 immunization protect RGCs from apoptosis in our rat model of glaucoma. The increase in levels of secreted BDNF and IGF-I may be one of the mechanisms underlying the neuro-protection of RGCs.
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Glaucoma/terapia , Imunoterapia Ativa , Células-Tronco Neurais/transplante , Peptídeos/imunologia , Retina/citologia , Animais , Apoptose , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Modelos Animais de Doenças , Feminino , Acetato de Glatiramer , Glaucoma/patologia , Fator de Crescimento Insulin-Like I/genética , Fator de Crescimento Insulin-Like I/metabolismo , Células-Tronco Neurais/citologia , Células-Tronco Neurais/metabolismo , Ratos , Ratos Sprague-Dawley , Células Ganglionares da Retina/citologia , Células Ganglionares da Retina/metabolismo , Células Ganglionares da Retina/patologia , Transcrição GênicaRESUMO
Transmembrane ion transport modality has received a widespread attention due to its apoptotic activation toward anticancer cell activities. In this study, G-quadruplex-based potassium-specific transmembrane channels have been developed to facilitate the intracellular K+ efflux, which perturbs the cellular ion homeostasis thereby inducing cancer cell apoptosis. Cholesterol-tag, a lipophilic anchor moiety, serves as a rudiment for the G-quadruplex immobilization onto the membrane, while G-quadruplex channel structure as a transport module permits ion binding and migration along the channels. A c-Myc sequence tagged with two-cholesterol is designed as a representative lipophilic G-quadruplex, which forms intramolecular parallel G-quadruplex with three stacks of G-quartets (Ch2-Para3). Fluorescence transport assay demonstrates Ch2-Para3 a high transport activity (EC50 = 10.9 × 10-6 m) and an ion selectivity (K+/Na+ selectivity ratio of 84). Ch2-Para3 mediated K+ efflux in cancer cells is revealed to purge cancer cells through K+ efflux-mediated cell apoptosis, which is confirmed by monitoring the changes in membrane potential of mitochondria, leakage of cytochrome c, reactive oxygen species yield, as well as activation of a family of caspases. The lipophilic G-quadruplex exhibits obvious antitumor activity in vivo without systemic toxicity. This study provides a functional scheme aimed at generating DNA-based selective artificial membrane channels for the purpose of regulating cellular processes and inducing cell apoptosis, which shows a great promising for anticancer therapy in the future.
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Background: Glaucoma is the leading cause of irreversible blindness worldwide. Emerged evidence has shown that glaucoma is considered an immune system related disorder. The gut is the largest immune organ in the human body and the gut microbiota (GM) plays an irreversible role in maintaining immune homeostasis. But, how the GM influences glaucoma remains unrevealed. This study aimed at investigating the key molecules/pathways mediating the GM and the glaucoma to provide new biomarkers for future predictive, preventive, and personalized medicine. Methods: Datasets from the primary open-angle glaucoma (POAG) patients (GSE138125) and datasets for target genes of GM/GM metabolites were downloaded from a public database. For GSE138125, the differentially expressed genes (DEGs) between healthy and POAG samples were identified. And the online Venn diagram tool was used to obtain the DEGs from POAG related to GM. After which GM-related DEGs were analyzed by correlation analysis, pathway enrichment analysis, and protein-protein interaction (PPI) network analysis. Human trabecular meshwork cells were used for validation, and the mRNA level of hub genes was verified by quantitative real-time polymerase chain reaction (RT-qPCR) in the in vitro glaucoma model. Results: A total of 16 GM-related DEGs in POAG were identified from the above 2 datasets (9 upregulated genes and 7 downregulated genes). Pathway enrichment analysis indicated that these genes are mostly enriched in immune regulation especially macrophages-related pathways. Then 6 hub genes were identified by PPI network analysis and construction of key modules. Finally, RT-qPCR confirmed that the expression of the hub genes in the in vitro glaucoma model was consistent with the results of bioinformatics analysis of the mRNA chip. Conclusion: This bioinformatic study elucidates NFKB1, IL18, KITLG, TLR9, FKBP2, and HDAC4 as hub genes for POAG and GM regulation. Immune response modulated by macrophages plays an important role in POAG and may be potential targets for future predictive, preventive, and personalized diagnosis and treatment. Supplementary Information: The online version contains supplementary material available at 10.1007/s13167-023-00336-2.
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Metabolomics refers to the high-through untargeted or targeted screening of metabolites in biofluids, cells, and tissues. Metabolome reflects the functional states of cells and organs of an individual, influenced by genes, RNA, proteins, and environment. Metabolomic analyses help to understand the interaction between metabolism and phenotype and reveal biomarkers for diseases. Advanced ocular diseases can lead to vision loss and blindness, reducing patients' quality of life and aggravating socio-economic burden. Contextually, the transition from reactive medicine to the predictive, preventive, and personalized (PPPM / 3P) medicine is needed. Clinicians and researchers dedicate a lot of efforts to explore effective ways for disease prevention, biomarkers for disease prediction, and personalized treatments, by taking advantages of metabolomics. In this way, metabolomics has great clinical utility in the primary and secondary care. In this review, we summarized much progress achieved by applying metabolomics to ocular diseases and pointed out potential biomarkers and metabolic pathways involved to promote 3P medicine approach in healthcare.
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The endoplasmic reticulum (ER) functions as a quality-control organelle for protein homeostasis, or "proteostasis". The protein quality control systems involve ER-associated degradation, protein chaperons, and autophagy. ER stress is activated when proteostasis is broken with an accumulation of misfolded and unfolded proteins in the ER. ER stress activates an adaptive unfolded protein response to restore proteostasis by initiating protein kinase R-like ER kinase, activating transcription factor 6, and inositol requiring enzyme 1. ER stress is multifaceted, and acts on aspects at the epigenetic level, including transcription and protein processing. Accumulated data indicates its key role in protein homeostasis and other diverse functions involved in various ocular diseases, such as glaucoma, diabetic retinopathy, age-related macular degeneration, retinitis pigmentosa, achromatopsia, cataracts, ocular tumors, ocular surface diseases, and myopia. This review summarizes the molecular mechanisms underlying the aforementioned ocular diseases from an ER stress perspective. Drugs (chemicals, neurotrophic factors, and nanoparticles), gene therapy, and stem cell therapy are used to treat ocular diseases by alleviating ER stress. We delineate the advancement of therapy targeting ER stress to provide new treatment strategies for ocular diseases.
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Defeitos da Visão Cromática , Estresse do Retículo Endoplasmático , Humanos , Estresse do Retículo Endoplasmático/genética , Resposta a Proteínas não Dobradas/genética , Autofagia/genética , EpigenômicaRESUMO
When clustering gene expression, it is expected that correlation coefficients of genes in the same clusters are high, and that gene ontology (GO) enrichment analysis of most clusters will be significant. However, existing short-term gene expression clustering algorithms have limitations. To address this problem, we proposed a novel clustering process based on angular features for short-term gene expression. Our method (named AngClust) uses angular features to indicate the change of trend in gene expression levels at two neighboring time points. The changes of angles at multiple time points reflects the change of trend of the overall expression levels. Such changes are used to measure whether the expression trends of different genes are similar. To obtain functionally significant clusters from the clustering results, we evaluated numbers of genes in clusters, average correlation coefficient, fluctuation, and their correlation with GO term enrichment. The efficacy of AngClust outperform two other measures, Euclidean distance (ED) and dynamic time warping of correlation (DTW), on a dataset of yeast gene expression. The ratios of GO and pathway term-enriched of clusters of AngClust is higher than or equal to that of STEM and TMixClust on human, mouse, and yeast time series of gene expression.
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Saccharomyces cerevisiae , Transcriptoma , Humanos , Animais , Camundongos , Fatores de Tempo , Saccharomyces cerevisiae/genética , Algoritmos , Análise por ConglomeradosRESUMO
Our aim was to assess the therapeutic efficacy of a modified single-arm suture technique on traumatic cyclodialysis cleft with vitreoretinal injury. The procedure involved fixing a detached ciliary body using a single-armed 10-0 polypropylene suture under the assistance of a 29-gauge needle. Patients with a traumatic cyclodialysis cleft combined with an anterior and posterior segment injury who underwent modified internal cyclopexy together with vitreoretinal surgery were enrolled in this study. Ultrasound biomicroscopy (UBM) was used to diagnose and evaluate the cyclodialysis and anterior segment injury. B-scan ultrasonography was performed to assess the condition of the vitreous, retina and choroid. The surgical time and successful rate for repairing the cyclodialysis cleft were recorded. Preoperative and postoperative best-corrected visual acuity (BCVA), and intraocular pressure (IOP) were documented for assessment. The study included 20 eyes. The extent of the cyclodialysis cleft was from 30° to 360°. Besides a traumatic cyclodialysis cleft, the included cases also combined this with vitreous hemorrhages, retinal detachment, macular holes, choroid avulsion, and suprachoroidal hemorrhage. All the clefts were anatomically closed in one surgery. The average surgical time for fixing the cyclodialysis cleft was 2.68 ± 0.54 min/30° cleft. A significant improvement in LogMAR BCVA was observed from 2.94 ± 0.93 preoperatively to 1.81 ± 1.11 at the 6-month follow-up. IOP was elevated from 10.90 ± 6.18 mmHg preoperatively to 14.45 ± 2.35 mmHg at the 6-month follow-up. The modified single-armed suture technique was proved to be an effective method to fix the traumatic cyclodialysis cleft, which could facilitate the use of the procedure to repair chorioretinal disorders. It improved the BCVA and maintained the IOP with less postoperative complications.
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This study investigated whether brain-derived neurotrophic factor (BDNF) regulates the L-glutamate/L-aspartate transporter (GLAST) and glutamine synthetase (GS) in mouse retinal Müller cells (RMCs) under normal and hypoxic conditions. Mouse RMCs were treated with recombinant human BDNF (50, 75, 100, 125, or 150 ng/ml) for 24 h or underwent hypoxia induced by CoCl(2) (125 µM; 6, 12, 24, 48, or 72 h). An additional group underwent combined treatment with BDNF (100 ng/ml; 24, 48, 72, or 96 h) and CoCl(2) (125 µM/ml; 72 h). GLAST and GS mRNA and protein expression, L-[3,4-3H]-glutamic acid uptake, and apoptosis were assessed. BDNF dose-dependently up-regulated GLAST and GS mRNA and protein and increased glutamate uptake. Similarly, in early-stage CoCl(2)-induced hypoxia, GLAST and GS were up-regulated and glutamate uptake increased, but these decreased over time. BDNF also up-regulated GLAST and GS and increased glutamate uptake when RMCs under CoCl(2) induced hypoxic condition. However, BDNF treatment 24 h before CoCl(2) had no effect on GLAST or GS expression. CoCl(2) alone or combined with BDNF did not induce apoptosis. Hypoxia rapidly increased GLAST and GS expressions. This effect was transient, perhaps due to compensatory mechanisms that reduce GLAST and GS by 72 h. BDNF can up-regulate GLAST and GS and increase glutamate uptake during hypoxia, and these functions may underlie its neuroprotective effects.