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OBJECTIVE: To investigate the use of inhaled nitric oxide (iNO) in hospitalized preterm infants in China over 10 years and its clinical outcomes. METHODS: A total of 616 premature infants who were administered iNO in the Neonatology Departments of 5 Class A tertiary hospitals in China for ten years from January 2013 to December 2022 were included retrospectively. Based on their enrollment periods, the patients were divided into two groups: Group 1 from January 2013 to December 2017 and Group 2 from January 2018 to December 2022, respectively. The perinatal characteristics, short-term clinical outcomes, and mortality rates were compared between these two groups. RESULTS: The utilization of iNO in preterm infants grew annually over the past10 years; the utilization of iNO in Group 2 infants increased approximately one-fold when compared with Group 1 (1.52% vs. 0.80%, p < .001), and the increase was greater in gestational age (GA) < 34 weeks compared with 34-36 weeks preterm infants. Moreover, the iNO usage in Group 1 infants with GA < 34 weeks increased from 1.14% to 2.46% and 0.60% to 0.99% in 34-36 weeks preterm infants (p < .001) in Group 2, respectively. Apart from a smaller GA (32.9 w vs. 33.5 w, p < .001) and birth weight (BW, 1900 g vs. 2141 g, p < .001), the initial [14 parts per million (ppm) versus 10 ppm, p < .001] and maximum (15 ppm vs. 10 ppm, p < .001) doses of Group 2 were larger; however, their recent clinical outcomes did not improve with increasing iNO utilization (p > .05)as compared to Group 1, respectively. Although the overall iNO preterm mortality rates over the past 10 years were 25.8%, the mortality rates for preterm infants at 34-36 weeks were significantly lower than for preterm infants at GA < 34 weeks (15.4% vs. 33.8%, p < .001). Nonetheless, no improvement in mortality was observed in Group 2 preterm infants with GA < 34 weeks for the past 5 years when compared with Group 1 (32.9% vs. 35.8%, p > .05) infants, and significantly lower mortality rates were noticed in preterm infants with 34-36 weeks (11.2% vs. 22.7%, p < .001). Patients with hypoxic respiratory failure (HRF) or persistent pulmonary hypertension of the newborn (PPHN) iNO preterm infants did not show lower mortality rates with the increase of iNO use rate (p > .05). The overall mortality rates of preterm PPHN infants with iNO were lower than that of HRF (20.2% vs. 36.5%, p < .001), while the mortality rates of Group 2 preterm PPHN infants with iNO significantly lower than that of HRF (17.7% vs 36.0%, p < .001). CONCLUSION: The iNO has been extensively used in Chinese preterm infants over the past 10 years, this increase was more significant in preterm infants with GA < 34 weeks. Moreover, preterm infants using iNO have lower GA and BW, larger initial and maximum doses, and more aggressive strategies in the last past 5 years. Although iNO use in preterm infants with GA of 34-36 weeks has significantly reduced mortality, mortality rates and short-term clinical outcomes of iNO in preterm infants <34 weeks of GA has no obvious improvement. Further studies are required to investigate the efficacy and safety of iNO in preterm infants <34 weeks of GA.
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BACKGROUND: Intravitreal injections of angiogenesis inhibitors have proved efficacious in the majority of patients with ocular angiogenesis. However, one-fourth of all treated patients fail to derive benefits from intravitreal injections. tRNA-derived small RNA (tsRNA) emerges as a crucial class of non-coding RNA molecules, orchestrating key roles in the progression of human diseases by modulating multiple targets. Through our prior sequencing analyses and bioinformatics predictions, tRNA-Cys-5-0007 has shown as a potential regulator of ocular angiogenesis. This study endeavors to elucidate the precise role of tRNA-Cys-5-0007 in the context of ocular angiogenesis. METHODS: Quantitative reverse transcription PCR (qRT-PCR) assays were employed to detect tRNA-Cys-5-0007expression. EdU assays, sprouting assays, transwell assays, and Matrigel assays were conducted to elucidate the involvement of tRNA-Cys-5-0007 in endothelial angiogenic effects. STZ-induced diabetic model, OIR model, and laser-induced CNV model were utilized to replicate the pivotal features of ocular vascular diseases and evaluate the influence of tRNA-Cys-5-0007 on ocular angiogenesis and inflammatory responses. Bioinformatics analysis, luciferase activity assays, RNA pull-down assays, and in vitro studies were employed to elucidate the anti-angiogenic mechanism of tRNA-Cys-5-0007. Exosomal formulation was employed to enhance the synergistic anti-angiogenic and anti-inflammatory efficacy of tRNA-Cys-5-0007. RESULTS: tRNA-Cys-5-0007 expression was down-regulated under angiogenic conditions. Conversely, tRNA-Cys-5-0007 overexpression exhibited anti-angiogenic effects in retinal endothelial cells, as evidenced by reduced proliferation, sprouting, migration, and tube formation abilities. In diabetic, laser-induced CNV, and OIR models, tRNA-Cys-5-0007 overexpression led to decreased ocular vessel leakage, inhibited angiogenesis, and reduced ocular inflammation. Mechanistically, these effects were attributed to the targeting of vascular endothelial growth factor A (VEGFA) and TGF-ß1 by tRNA-Cys-5-0007. The utilization of an exosomal formulation further potentiated the synergistic anti-angiogenic and anti-inflammatory efficacy of tRNA-Cys-5-0007. CONCLUSIONS: Concurrent targeting of tRNA-Cys-5-0007 for anti-angiogenic and anti-inflammatory therapy holds promise for enhancing the effectiveness of current anti-angiogenic therapy.
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Inibidores da Angiogênese , Anti-Inflamatórios , Inibidores da Angiogênese/farmacologia , Inibidores da Angiogênese/uso terapêutico , Animais , Anti-Inflamatórios/farmacologia , Humanos , RNA de Transferência/metabolismo , RNA de Transferência/genética , Camundongos Endogâmicos C57BL , Proliferação de Células/efeitos dos fármacos , Neovascularização de Coroide/patologia , Neovascularização de Coroide/tratamento farmacológico , Neovascularização de Coroide/metabolismo , Masculino , Oftalmopatias/tratamento farmacológico , Oftalmopatias/patologia , Oftalmopatias/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , Neovascularização Patológica , Retinopatia Diabética/tratamento farmacológico , Retinopatia Diabética/patologia , Retinopatia Diabética/metabolismo , Camundongos , Células Endoteliais da Veia Umbilical Humana/metabolismoRESUMO
Neurovascular dysfunction is a preclinical manifestation of diabetic complications, including diabetic retinopathy (DR). Herein, we report that a transfer RNA-derived RNA fragment, tRF-3001a, is significantly upregulated under diabetic conditions. tRF-3001a downregulation inhibits Müller cell activation, suppresses endothelial angiogenic effects, and protects against high-glucose-induced retinal ganglion cell injury in vitro. Furthermore, tRF-3001a downregulation alleviates retinal vascular dysfunction, inhibits retinal reactive gliosis, facilitates retinal ganglion cell survival, and preserves visual function and visually guided behaviors in STZ-induced diabetic mice and db/db diabetic mice. Mechanistically, tRF-3001a regulates neurovascular dysfunction in a microRNA-like mechanism by targeting GSK3B. Clinically, tRF-3001a is upregulated in aqueous humor (AH) samples of DR patients. tRF-3001a downregulation inhibits DR-induced human retinal vascular endothelial cell and Müller cell dysfunction in vitro and DR-induced retinal neurovascular dysfunction in C57BL/6J mice. Thus, targeting tRF-3001a-mediated signaling is a promising strategy for the concurrent treatment of vasculopathy and neuropathy in diabetes mellitus.
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Diabetes Mellitus Experimental , Retinopatia Diabética , Hiperglicemia , Camundongos , Humanos , Animais , Diabetes Mellitus Experimental/complicações , Camundongos Endogâmicos C57BL , Retina , Retinopatia Diabética/tratamento farmacológico , Retinopatia Diabética/etiologia , Hiperglicemia/complicaçõesRESUMO
Compared to individual UV or chlorine disinfection, the combined UV and chlorine (i.e., UV/chlorine) can substantially promote the degradation of antibiotic resistance genes (ARGs) in the effluent by generating radicals. However, the mechanisms of ARG degradation induced by radicals during UV/chlorine treatment remain largely unknown, limiting further enhancement of ARG degradation by process optimization. Herein, we aimed to uncover the role of different radicals in ARG degradation and the molecular mechanisms of ARG degradation by radicals in UV/chlorine process. The ClO was proven to be responsible for the enhanced ARG degradation during UV/chlorine treatment, while the other radicals (OH, Cl, and Cl2-) played a minor role. This is because ClO possessed both high steady-state concentration and high reactivity toward ARGs (rate constant: 4.29 × 1010 M-1 s-1). The ClO might collaborate with free chlorine to degrade ARG. The ClO degraded ARGs by selectively attacking guanine and thymine but failed to induce strand breakage, while chlorine could break the strand of ARGs. Ultimately, ClO cooperated with chlorine to degrade ARGs quickly by hydroxylation and chlorination of bases and produce many chlorine- and nitrogen-containing products as revealed by high-resolution mass spectrometry. The uncovered degradation mechanisms of ARGs by UV/chlorine provide useful guidelines for process optimization to achieve deep removal of effluent ARGs.
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Compostos Clorados , Poluentes Químicos da Água , Purificação da Água , Antibacterianos , Cloro , Resistência Microbiana a Medicamentos/genética , Desinfecção , Cloretos , Purificação da Água/métodos , Raios Ultravioleta , Cinética , Poluentes Químicos da Água/análise , OxirreduçãoRESUMO
Diabetic kidney disease is an important microvascular complication of diabetes and the leading cause of end-stage renal disease. Its pathological characteristics mainly include epithelial mesenchymal transition(EMT) in glomerulus, podocyte apoptosis and autophagy, and damage of glomerular filtration barrier. Transforming growth factor-ß(TGF-ß)/Smad signaling pathway is specifically regulated by a variety of mechanisms, and is a classic pathway involved in physiological activities such as apoptosis, proliferation and differentiation. At present, many studies have found that TGF-ß/Smad signaling pathway plays a key role in the pathogenesis of diabetic kidney disease. Traditional Chinese medicine has significant advantages in the treatment of diabetic kidney disease for its multi-component, multi-target and multi-pathway characteristics, and some traditional Chinese medicine extracts, traditional Chinese medicines and traditional Chinese medicine compound prescription improve the renal injury of diabetic kidney disease by regulating TGF-ß/Smad signaling pathway. This study clarified the mechanism of TGF-ß/Smad signaling pathway in diabetic kidney disease by expounding the relationship between the key targets of the pathway and diabetic kidney disease, and summarized the research progress of traditional Chinese medicine in the treatment of diabetic kidney disease by interfering with TGF-ß/Smad signaling pathway in recent years, to provide reference for drug research and clinical treatment of diabetic kidney disease in the future.
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Diabetes Mellitus , Nefropatias Diabéticas , Humanos , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/genética , Medicina Tradicional Chinesa , Rim/patologia , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo , Transdução de Sinais , Transição Epitelial-Mesenquimal , Proteínas Smad/genética , Proteínas Smad/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Diabetes Mellitus/tratamento farmacológico , Diabetes Mellitus/genéticaRESUMO
Background: Capillary dysfunction has been implicated in a series of life- threatening vascular diseases characterized by pericyte and endothelial cell (EC) degeneration. However, the molecular profiles that govern the heterogeneity of pericytes have not been fully elucidated. Methods: Single-cell RNA sequencing was conducted on oxygen-induced proliferative retinopathy (OIR) model. Bioinformatics analysis was conducted to identify specific pericytes involved in capillary dysfunction. qRT-PCRs and western blots were conducted to detect Col1a1 expression pattern during capillary dysfunction. Matrigel co-culture assays, PI staining, and JC-1 staining was conducted to determine the role of Col1a1 in pericyte biology. IB4 and NG2 staining was conducted to determine the role of Col1a1 in capillary dysfunction. Results: We constructed an atlas of > 76,000 single-cell transcriptomes from 4 mouse retinas, which could be annotated to 10 distinct retinal cell types. Using the sub-clustering analysis, we further characterized retinal pericytes into 3 different subpopulations. Notably, GO and KEGG pathway analysis demonstrated that pericyte sub-population 2 was identified to be vulnerable to retinal capillary dysfunction. Based on the single-cell sequencing results, Col1a1 was identified as a marker gene of pericyte sub-population 2 and a promising therapeutic target for capillary dysfunction. Col1a1 was abundantly expressed in pericytes and its expression was obviously upregulated in OIR retinas. Col1a1 silencing could retard the recruitment of pericytes toward endothelial cells and aggravated hypoxia-induced pericyte apoptosis in vitro. Col1a1 silencing could reduce the size of neovascular area and avascular area in OIR retinas and suppressed pericyte-myofibroblast transition and endothelial-mesenchymal transition. Moreover, Col1a1 expression was up-regulated in the aqueous humor of the patients with proliferative diabetic retinopathy (PDR) or retinopathy of prematurity (ROP) and up-regulated in the proliferative membranes of PDR patients. Conclusions: These findings enhance the understanding of the complexity and heterogeneity of retinal cells and have important implications for future treatment of capillary dysfunction.
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Retinopatia Diabética , Pericitos , Camundongos , Animais , Pericitos/metabolismo , Células Endoteliais/metabolismo , Retina/metabolismo , Retinopatia Diabética/tratamento farmacológico , Análise de Sequência de RNARESUMO
The transformation of extracellular antibiotic resistance genes (eARGs) is largely influenced by their inevitable photodegradation in environments where they tend to be adsorbed by ubiquitous clay minerals instead of being in a free form. However, the photodegradation behaviors and mechanisms of the adsorbed eARGs may be quite different from those of the free form and still remain unclear. Herein, we found that kaolinite, a common 1:1-type clay, markedly enhanced eARG photodegradation and made eARGs undergo direct photodegradation under UVA. The decrease in the transformation efficiency of eARGs caused by photodegradation was also promoted. Spectroscopy methods combined with density functional theory calculations revealed that the Lewis acid-base interaction between P-O in eARGs and Al-OH on kaolinite delocalized electrons of eARGs, thus resulting in increased photon absorption ability of eARGs. This ultimately led to enhanced photodegradation of kaolinite-adsorbed eARGs. Additionally, divalent Ca2+ could reduce the Lewis acid-base interaction-mediated adsorption of eARGs by kaolinite, thereby weakening the enhanced photodegradation of eARGs caused by electron delocalization. In contrast, the 2:1-type clay montmorillonite without strong Lewis acid sites was unable to delocalize the electrons to enhance the photodegradation of eARGs. This work allowed us to better evaluate eARGs' fate and risk in real aqueous environments.
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Antibacterianos , Caulim , Argila , Caulim/química , Ácidos de Lewis , Elétrons , Fotólise , Minerais/química , Resistência Microbiana a Medicamentos/genética , AdsorçãoRESUMO
Transfer RNA-derived fragments (tRFs) are a novel class of non-coding RNA transcripts and play important roles in several physiological/pathological processes. However, the role of tRFs in ocular angiogenesis remains elusive. Herein, we investigate whether the intervention of tRF-1001 expression could suppress pathological ocular angiogenesis. The results show that the levels of tRF-1001 expression were reduced in the retinas of an oxygen-induced retinopathy (OIR) model, choroidal neovascularization model, and endothelial sprouting model in vitro. Increased tRF-1001 expression could suppress ocular angiogenesis and endothelial sprouting in vivo and reduce endothelial migration, specification, and sprouting in vitro. Mechanistically, tRF-1001 regulated endothelial angiogenic effects via tRF-1001/METTL3/RBPJ-MAML1 signaling. The levels of tRF-1001 expression were downregulated in the aqueous humor of age-related macular degeneration (AMD) patients. tRF-1001 upregulation could suppress AMD aqueous humor-induced endothelial sprouting and pathological angiogenesis. Collectively, tRF-1001 acts as an anti-angiogenic factor during ocular angiogenesis. Targeting tRF-1001-mediated signaling is a therapeutic option for ocular neovascular diseases.
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With carbon fiber, it is difficult to load semiconductor photocatalysts and easy to shed off thanks to its smooth surface and few active groups, which has always been a problem in the synthesis of photocatalysts. In the study, SrTiO3 nanoparticles were loaded onto the Tencel fibers using the solvothermal method, and then the Tencel fibers were carbonized at a high temperature under the condition of inert gas to form carbon fibers, thus SrTiO3@CF photocatalytic composite materials with solid core shell structure were prepared. Meanwhile, Mn ions were added into the SrTiO3 precursor reagent in the solvothermal experiment to prepare Mn-doped Mn-SrTiO3@CF photocatalytic composite material. XPS and EPR tests showed that the prepared Mn-SrTiO3@CF photocatalytic composite was rich in oxygen vacancies. The existence of these oxygen vacancies formed oxygen defect states (VOs) below the conduction band, which constituted the capture center of photogenerated electrons and significantly improved the photocatalytic activity. The photocatalytic hydrogen experimental results showed that the photocatalytic hydrogen production capacity of Mn-SrTiO3@CF composite material with 5% Mn-doped was six times that of the SrTiO3@CF material, and the doping of Mn ions not only promoted the red shift of the light absorption boundary and the extension to visible light, but also improved the separation and migration efficiency of photocarriers. In the paper, the preparation method solves the difficulty of loading photocatalysts on CF and provides a new design method for the recycling of catalysts, and we improve the hydrogen production performance of photocatalysts by Mn-doped modification and the introduction of oxygen vacancies, which provides a theoretical method for the practical application of hydrogen energy.
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Ischemic retinal diseases are the major cause of vision impairment worldwide. Currently, there are no available treatments for ischemiainduced retinal neurodegeneration. Circular RNAs (circRNAs) have emerged as important regulators of several biological processes and human diseases. The present study investigated the role of circRNAZYG11B (circZYG11B; hsa_circ_0003739) in retinal neurodegeneration. Reverse transcription quantitative polymerase chain reaction (RTqPCR) demonstrated that circZYG11B expression was markedly increased during retinal neurodegeneration in vivo and in vitro. Cell Counting Kit8, TUNEL and caspase3 activity assays revealed that silencing of circZYG11B was able to protect against oxidative stress or hypoxic stressinduced retinal ganglion cell (RGC) injury. Furthermore, immunofluorescence staining and hematoxylin and eosin staining revealed that silencing of circZYG11B alleviated ischemia/reperfusioninduced retinal neurodegeneration, as indicated by reduced RGC injury and decreased retinal reactive gliosis. In addition, luciferase reporter, biotincoupled miRNA capture and RNA immunoprecipitation assays revealed that circZYG11B could regulate RGC function through circZYG11B/microRNA620/PTEN signaling. Clinically, RTqPCR assays demonstrated that circZYG11B expression was markedly increased in the aqueous humor of patients with glaucoma. In conclusion, circZYG11B may be considered a promising target for the diagnosis and treatment of retinal ischemic diseases.
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MicroRNAs , Fármacos Neuroprotetores , Doenças Retinianas , Humanos , Isquemia/metabolismo , MicroRNAs/metabolismo , Fármacos Neuroprotetores/farmacologia , RNA Circular/genética , Retina/metabolismo , Doenças Retinianas/metabolismoRESUMO
As a natural flavone, apigenin is abundantly present in vegetables, fruits, oregano, tea, chamomile, wheat sprout and is regarded as a major component of the Mediterranean diet. Apigenin is known to inhibit proliferation in different cancer cell lines by inducing G2/M arrest, but it is unclear whether this action is predominantly imposed on G2 or M phases. In this study, we demonstrate that apigenin arrests prostate cancer cells at G2 phase by flow cytometric analysis of prostate cancer cells co-stained for phospho-Histone H3 and DNA. Concurrently, apigenin also reduces the mRNA and protein levels of the key regulators that govern G2-M transition. Further analysis using chromatin immunoprecipitation (ChIP) confirmed the diminished transcriptional activities of the genes coding for these regulators. Unravelling the inhibitory effect of apigenin on G2-M transition in cancer cells provides the mechanistic understanding of its action and supports the potential for apigenin as an anti-cancer agent.
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Rationale: Microvascular complication is a major cause of morbidity and mortality among the patients with diabetes. Pericyte dysfunction is the predominant pathological manifestation of microvascular complication. N6-methyladenosine (m6A) serves as the most prevalent modification in eukaryotic mRNAs. However, the role of m6A RNA modification in pericyte dysfunction is still unclear. Methods: Quantitative polymerase chain reactions and western blots were conducted to detect the change of m6A RNA modification in pericytes and mouse retinas following diabetic stress. MTT assay, transwell migration assay, caspase 3/7 activity assay, calcein-AM/propidium iodide (PI) staining, and TUNEL staining were conducted to determine the role of METTL3 in pericyte biology in vitro. Retinal trypsin digestion, vascular permeability assay, and IB4-NG2 double immunofluorescent staining were conducted to determine the role of METTL3 in retinal pericyte dysfunction and vascular complication. RNA sequencing, RNA pull-down assays and immunoblots were conducted to clarify the mechanism of METTL3-mediated pericyte dysfunction and vascular complication. Results: The levels of m6A RNA methylation were significantly up-regulated in pericytes and mouse retinas following diabetic stress, which were caused by increased expression of METTL3. METTL3 regulated the viability, proliferation, and differentiation of pericytes in vitro. Specific depletion of METTL3 in pericytes suppressed diabetes-induced pericyte dysfunction and vascular complication in vivo. METTL3 overexpression impaired pericyte function by repressing PKC-η, FAT4, and PDGFRA expression, which was mediated by YTHDF2-dependent mRNA decay. Conclusion: METTL3-mediated m6A methylation epigenetically regulates diabetes-induced pericyte dysfunction. METTL3-YTHDF2-PKC-η/FAT4/PDGFRA signaling axis could be therapeutically targeted for treating microvascular complications.
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Diabetes Mellitus/metabolismo , Retinopatia Diabética/metabolismo , Metiltransferases/metabolismo , Pericitos/metabolismo , Animais , Linhagem Celular , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pericitos/patologiaRESUMO
Endothelial tip cell specialization plays an essential role in angiogenesis, which is tightly regulated by the complicated gene regulatory network. Circular RNA (circRNA) is a type of covalently closed non-coding RNA that regulates gene expression in eukaryotes. Here, we report that the levels of circMET expression are significantly upregulated in the retinas of mice with oxygen-induced retinopathy, choroidal neovascularization, and diabetic retinopathy. circMET silencing significantly reduces pathological angiogenesis and inhibits tip cell specialization in vivo. circMET silencing also decreases endothelial migration and sprouting in vitro. Mechanistically, circMET regulates endothelial sprouting and pathological angiogenesis by acting as a scaffold to enhance the interaction between IGF2BP2 and NRARP/ESM1. Clinically, circMET is significantly upregulated in the clinical samples of the patients of diabetic retinopathy. circMET silencing could reduce diabetic vitreous-induced endothelial sprouting and retinal angiogenesis in vivo. Collectively, these data identify a circRNA-mediated mechanism that coordinates tip cell specialization and pathological angiogenesis. circMET silencing is an exploitable therapeutic approach for the treatment of neovascular diseases.
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Neovascularização de Coroide , Retinopatia Diabética , Animais , Neovascularização de Coroide/genética , Retinopatia Diabética/tratamento farmacológico , Retinopatia Diabética/genética , Células Endoteliais/metabolismo , Humanos , Camundongos , Camundongos Endogâmicos C57BL , RNA Circular/genética , Proteínas de Ligação a RNA/metabolismo , Retina/metabolismoRESUMO
Cancer recurrence poses a significant challenge. At the cellular level, recurrence takes place as a result of reactivation of dormant cancer cells residing at G0 phase. The aim of the study was to identify compounds that can trap prostate and lung cancer cells in G0 phase from a new Chinese herb recipe, Astringent recipe, consisting of Radix Paeoniae Alba, Agrimonia pilosa Ledeb, Fructus Mume, Fritillaria thunbergii Miq., Ganoderma Lucidum Karst, and Astragalus membranaceus (Fisch.) Bunge. Astringent recipe impeded cell cycle progression in prostate and lung cancer cells by rounding them up at G0 phase by flow cytometric analysis of cancer cells stained with Hoechst 33342 and Pyronin Y, respectively, for DNA and RNA. The anti-cancer efficacy of the recipe was found to be attributable to Agrimonia pilosa Ledeb. Further study established that agrimol B, a polyphenol derived from Agrimonia pilosa Ledeb, contributed to the activity of the herb. The action of agrimol B on the cancer cells was likely derived from its effect on c-MYC, SKP2 and p27 by immunoblotting and immunofluorescence. Oral administration of Agrimonia pilosa Ledeb or agrimol B reduced growth of prostate cancer cell xenograft in animal. In conclusion, Agrimol B can enrich for prostate and lung cancer cells in G0 state and influence key regulators that govern G0 status.
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Agrimonia , Antineoplásicos Fitogênicos/farmacologia , Butanonas/farmacologia , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Fenóis/farmacologia , Extratos Vegetais/farmacologia , Carga Tumoral/efeitos dos fármacos , Células A549 , Animais , Antineoplásicos Fitogênicos/isolamento & purificação , Butanonas/isolamento & purificação , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/fisiologia , Relação Dose-Resposta a Droga , Ácido Elágico/farmacologia , Pontos de Checagem da Fase G1 do Ciclo Celular/fisiologia , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Fenóis/isolamento & purificação , Extratos Vegetais/isolamento & purificação , Carga Tumoral/fisiologiaRESUMO
Long noncoding RNAs (lncRNAs) have emerged as the key regulators in the pathogenesis of human disorders. This study aimed to investigate the role of lncRNA-IPW in the progression of choroidal neovascularization (CNV) and the underlying molecular mechanism. IPW was significantly up-regulated in the choroidal tissues of laser-induced CNV mice and in the endothelial cells in response to hypoxic stress. IPW silencing led to reduced formation of CNV in laser-induced CNV model and ex vivo choroidal sprouting model, which could achieve similar therapeutic effects of anti-VEGF on CNV formation. Silencing or transgenic overexpression of IPW could alter endothelial cell viability, proliferation, migration, and tube formation ability in vitro. Mechanistically, IPW silencing led to increased expression of miR-370. Increased miR-370 could mimic the effects of IPW silencing on CNV formation and endothelial angiogenic phenotypes in vivo and in vitro. This study suggests that IPW silencing is a promising strategy for the treatment of neovascular ocular diseases.
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Neovascularização de Coroide/genética , MicroRNAs/genética , RNA Longo não Codificante/genética , Animais , Neovascularização de Coroide/patologia , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Regulação da Expressão Gênica , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
Retinal ischemia-reperfusion (I/R) is involved in the pathogenesis of many vision-threatening diseases. circRNAs act as key players in gene regulation and human diseases. However, the global circRNA expression profile in retinal I/R injury has not been fully uncovered. Herein, we established a murine model of retinal I/R injury and performed circRNA microarrays to identify I/R-related circRNAs. 1265 differentially expressed circRNAs were identified between I/R retinas and normal retinas. Notably, the detection of cWDR37 level in aqueous humor could discriminate glaucoma patients from cataract patients (AUC = 0.9367). cWdr37 silencing protected against hypoxic stress- or oxidative stress-induced retinal ganglion cell (RGC) injury. cWdr37 silencing alleviated IR-induced retinal neurodegeneration as shown by increased NeuN staining, reduced retinal reactive gliosis, and decreased retinal apoptosis. Collectively, this study provides a novel insight into the pathogenesis of retinal I/R injury. cWdr37 is a promising target for the diagnosis or treatment of I/R-related ocular diseases.
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Glaucoma , Traumatismo por Reperfusão , Animais , Apoptose , Glaucoma/genética , Humanos , Camundongos , RNA Circular/genética , Traumatismo por Reperfusão/genética , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , RetinaRESUMO
Endothelial progenitor cells (EPCs) are involved in the pathogenesis of microvascular dysfunction in diabetic retinopathy (DR). MicroRNAs (miRNAs) serve as crucial regulators in many biological process and human diseases. Herein, to investigate the expression profile and possible role of miRNAs in EPCs, small RNA sequencing was conducted to identify EPC dysfunction-related miRNAs in DR. A total of 72 miRNAs were differentially expressed in EPCs following high glucose stress. Based on Gene Ontology (GO) analysis, the target genes of differentially expressed miRNAs were targeted to "protein binding," "cell differentiation," and "cytoskeleton." Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed that cGMP-PKG signaling pathway was tightly associated with miRNA-mediated EPC function. Furthermore, miR-375-3p was verified to be up-regulated in the clinical samples of DR patients. Inhibition of miR-375-3p protected against hyperglycemic stress- or hypoxic stress-induced EPC injury, which increased the viability, proliferation, migration, and tube formation ability of EPCs and retarded the development of apoptosis. Collectively, this study provides a novel insight into the pathogenesis of EPC dysfunction in DR. miR-375-3p is a potential target for the diagnosis or treatment of DR.
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Cinnamic acid (AC) and cinnamic aldehyde (AL) are two chemicals enriched in cinnamon and have been previously proved to improve glucolipid metabolism, thus ameliorating metabolic disorders. In this study, we employed transcriptomes and proteomes on AC and AL treated db/db mice in order to explore the underlying mechanisms for their effects. Db/db mice were divided into three groups: the control group, AC group and AL group. Gender- and age-matched wt/wt mice were used as a normal group. After 4 weeks of treatments, mice were sacrificed, and liver tissues were used for further analyses. Functional enrichment of differentially expressed genes (DEGs) and differentially expressed proteins (DEPs) were performed using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases. DEPs were further verified by parallel reaction monitoring (PRM). The results suggested that AC and AL share similar mechanisms, and they may improve glucolipid metabolism by improving mitochondrial functions, decreasing serotonin contents and upregulating autophagy mediated lipid clearance. This study provides an insight into the molecular mechanisms of AC and AL on hepatic transcriptomes and proteomes in disrupted metabolic situations and lays a foundation for future experiments.