RESUMO
BACKGROUND: Inadequate nerve regeneration and an inhibitory local microenvironment are major obstacles to the repair of spinal cord injury (SCI). The activation and differentiation fate regulation of endogenous neural stem cells (NSCs) represent one of the most promising repair approaches. Metformin has been extensively studied for its antioxidative, anti-inflammatory, anti-aging, and autophagy-regulating properties in central nervous system diseases. However, the effects of metformin on endogenous NSCs remains to be elucidated. METHODS: The proliferation and differentiation abilities of NSCs were evaluated using CCK-8 assay, EdU/Ki67 staining and immunofluorescence staining. Changes in the expression of key proteins related to ferroptosis in NSCs were detected using Western Blot and immunofluorescence staining. The levels of reactive oxygen species, glutathione and tissue iron were measured using corresponding assay kits. Changes in mitochondrial morphology and membrane potential were observed using transmission electron microscopy and JC-1 fluorescence probe. Locomotor function recovery after SCI in rats was assessed through BBB score, LSS score, CatWalk gait analysis, and electrophysiological testing. The expression of the AMPK pathway was examined using Western Blot. RESULTS: Metformin promoted the proliferation and neuronal differentiation of NSCs both in vitro and in vivo. Furthermore, a ferroptosis model of NSCs using erastin treatment was established in vitro, and metformin treatment could reverse the changes in the expression of key ferroptosis-related proteins, increase glutathione synthesis, reduce reactive oxygen species production and improve mitochondrial membrane potential and morphology. Moreover, metformin administration improved locomotor function recovery and histological outcomes following SCI in rats. Notably, all the above beneficial effects of metformin were completely abolished upon addition of compound C, a specific inhibitor of AMP-activated protein kinase (AMPK). CONCLUSION: Metformin, driven by canonical AMPK-dependent regulation, promotes proliferation and neuronal differentiation of endogenous NSCs while inhibiting ferroptosis, thereby facilitating recovery of locomotor function following SCI. Our study further elucidates the protective mechanism of metformin in SCI, providing new mechanistic insights for its candidacy as a therapeutic agent for SCI.
Assuntos
Proteínas Quinases Ativadas por AMP , Diferenciação Celular , Proliferação de Células , Ferroptose , Metformina , Células-Tronco Neurais , Ratos Sprague-Dawley , Traumatismos da Medula Espinal , Metformina/farmacologia , Traumatismos da Medula Espinal/tratamento farmacológico , Traumatismos da Medula Espinal/patologia , Traumatismos da Medula Espinal/metabolismo , Animais , Células-Tronco Neurais/efeitos dos fármacos , Células-Tronco Neurais/metabolismo , Proliferação de Células/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Ferroptose/efeitos dos fármacos , Proteínas Quinases Ativadas por AMP/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Transdução de Sinais/efeitos dos fármacos , Ratos , Espécies Reativas de Oxigênio/metabolismo , Recuperação de Função Fisiológica/efeitos dos fármacosRESUMO
Spinal cord injury (SCI) is a severe neurological condition that involves a lengthy pathological process. This process leads to the upregulation of chondroitin sulfate proteoglycans (CSPGs) by reactive glia, which impedes repair and regeneration in the spinal cord. The role of the CSPG-specific receptor protein tyrosine phosphatase-sigma (PTP-σ) in post-SCI remains largely unexplored. Exosomes have great potential in the diagnosis, prognosis, and treatment of SCI due to their ability to easily cross the bloodâbrain barrier. Schwann cell-derived exosomes (SCDEs) promote functional recovery in mice post-SCI by decreasing CSPG deposition. However, the mechanism by which SCDEs decrease CSPGs after SCI remains unknown. Herein, we observed elevated levels of PTP-σ and increased CSPG deposition during glial scar formation after SCI in vivo. After SCDEs were injected into SCI mice, CSPG deposition decreased in scar tissue at the injury site, the expression of PTP-σ increased during axonal growth around the injury site, and motor function subsequently recovered. Additionally, we demonstrated that the use of both Rho/ROCK inhibitors and SCDEs inhibited the reparative effects of SCDEs on scar tissue after SCI. In conclusion, our study revealed that treatment with SCDEs targeting the Rho/ROCK signaling pathway reduced PTP-σ activation in the CSPG post-SCI, which inhibited scar tissue formation.
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Axônios , Proteoglicanas de Sulfatos de Condroitina , Exossomos , Células de Schwann , Traumatismos da Medula Espinal , Quinases Associadas a rho , Animais , Traumatismos da Medula Espinal/metabolismo , Traumatismos da Medula Espinal/patologia , Células de Schwann/metabolismo , Exossomos/metabolismo , Quinases Associadas a rho/metabolismo , Proteoglicanas de Sulfatos de Condroitina/metabolismo , Axônios/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais/fisiologia , Feminino , Proteínas Tirosina Fosfatases Classe 2 Semelhantes a Receptores/metabolismo , Proteínas rho de Ligação ao GTP/metabolismoRESUMO
PURPOSE: This study explored the incidence of IRCs used in the procedures of the femur in children with osteogenesis imperfecta (OI) and investigated the independent risk factors of IRCs. METHODS: Three hundred eight-eight cases of surgical data about children with OI were included, who were treated with plate, elastic nail, Kirschner wire and telescopic rod. The choice of different procedures depended on the age of children, the status of femur and the availability of devices. Patient demographics and major IRCs were recorded to compare the outcomes of the four procedures. Then, Cox proportional hazard regression was used to analyse the independent risk factors of IRC, and subgroup analysis was applied to further verify the above results. RESULTS: The total incidence of IRC in the four groups was 90.1% (191/212) for plate, 96.8% (30/31) for Kirschner wire, 87.7% (57/65) for elastic nail and 30.0% (24/80) for telescopic rod. The incidence of IRC in the telescopic rod was lower than that in plate, elastic nail and Kirschner wire (P < 0.001). Cox proportional hazard regression analysis confirmed that procedure was the independent risk factor of IRC (HR, 0.191; 95% CI, 0.126-0.288; P < 0.001), fracture (HR, 0.193; 95% CI, 0.109-0.344; P < 0.001) and deformity (HR, 0.086; 95% CI, 0.027-0.272; P < 0.001). In addition, age of surgery was the independent risk factor of fracture (HR, 0.916; 95% CI, 0.882-0.952; P < 0.001) and deformity (HR, 1.052; 95% CI, 1.008-1.098; P = 0.019). Subgroup analysis confirmed that age of surgery, gender, classification, preoperative state and angle did not affect the effect of telescopic rod on reducing the risk of IRCs. CONCLUSIONS: In our cohort, lower incidence of IRCs was observed in telescopic rod group compared with plate, Kirschner wire and elastic nail. Procedure and age of surgery were independent risk factors of fracture. Likewise, procedure and age of surgery were independent risk factors of deformity, and procedure was independent risk factors of IRC.
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Pinos Ortopédicos , Fraturas do Fêmur , Osteogênese Imperfeita , Humanos , Osteogênese Imperfeita/complicações , Osteogênese Imperfeita/cirurgia , Masculino , Feminino , Criança , Incidência , Pré-Escolar , Fatores de Risco , Pinos Ortopédicos/efeitos adversos , Fraturas do Fêmur/cirurgia , Fraturas do Fêmur/epidemiologia , Fraturas do Fêmur/etiologia , Fêmur/cirurgia , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Estudos Retrospectivos , Placas Ósseas/efeitos adversos , Lactente , Adolescente , Fios Ortopédicos , Modelos de Riscos ProporcionaisRESUMO
BACKGROUND: Urinary extracellular vesicles (EVs) have gained increasing interest in recent years as a potential source of noninvasive biomarkers of diseases related to urinary organs, but knowledge of the mechanism is still limited. The current study sought to clarify the mechanism of urinary EVs behind di-(2-ethylhexyl) phthalate (DEHP)-induced hypospadias via PFN2 delivery. METHOD: PFN2 expression in hypospadias was predicted by bioinformatics analysis. Following the induction of a hypospadias rat model using DEHP, rats were injected with EVs and/or underwent alteration of PFN2 and TGF-ß1 to assess their effects in vivo. The extracted rat urothelial cells (UECs) were co-cultured with EVs extracted from urine for in vitro experiments. RESULT: Microarray analysis predicted poor PFN2 expression in hypospadias. Upregulated PFN2 was found in urinary EVs, and restrained epithelial-mesenchymal transition (EMT) was observed in DEHP-exposed rats. Urinary EVs or PFN2 overexpression increased SMAD2, SMAD3, and TGF-ß1 protein expression and SMAD2 and SMAD3 phosphorylation in UECs and DEHP-exposed rats. UEC migration, invasion, and EMT were augmented by EV co-culture or upregulation of PFN2. Of note, the silencing of TGF-ß1 counterweighed the effect of PFN2. Besides, EV co-culture or overexpression of PFN2 or TGF-ß1 elevated the body weight, anal-genital distance (AGD), anal-genital index (AGI), and EMT of DEHP-exposed rats. CONCLUSION: In summary, urinary EVs activated the SMAD/TGF-ß1 pathway to induce EMT via PFN2 delivery, thus protecting against DEHP-induced hypospadias. (1) EMT in epithelial cells inhibits DEHP-induced hypospadias. (2) Urine-derived EVs deliver PFN2 to promote EMT in epithelial cells. (3) PFN2 can activate the SMAD/TGF-ß1 signaling axis. (4) Urine-derived EVs can transmit PFN2 to activate the SMAD/TGF-ß1 signaling axis, thus promoting EMT and inhibiting the occurrence of hypospadias.
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Dietilexilftalato , Hipospadia , Humanos , Masculino , Ratos , Animais , Fator de Crescimento Transformador beta1/metabolismo , Transição Epitelial-Mesenquimal , Hipospadia/induzido quimicamente , Dietilexilftalato/toxicidade , Profilinas/farmacologiaRESUMO
As a commonly used physical intervention, electrical stimulation (ES) has been demonstrated to be effective in the treatment of central nervous system disorders. Currently, researchers are studying the effects of electrical stimulation on individual neurons and neural networks, which are dependent on factors such as stimulation intensity, duration, location, and neuronal properties. However, the exact mechanism of action of electrical stimulation remains unclear. In some cases, repeated or prolonged electrical stimulation can lead to changes in the morphology or function of the neuron. In this study, immunofluorescence staining and Sholl analysis are used to assess changes in the neurite number and axon length to determine the optimal pattern and stimulation parameters of ES for neurons. Neuronal death and plasticity are detected by TUNEL staining and microelectrode array assays, respectively. mRNA sequencing and bioinformatics analysis are applied to predict the key targets of the action of ES on neurons, and the identified targets are validated by western blot analysis and qRT-PCR. The effects of alternating current stimulation (ACS) on neurons are more significant than those of direct current stimulation (DCS), and the optimal parameters are 3 µA and 20 min. ACS stimulation significantly increases the number of neurites, the length of axons and the spontaneous electrical activity of neurons, significantly elevates the expression of growth-associated protein-43 (GAP-43) without significant changes in the expression of neurotrophic factors. Furthermore, application of PI3K/AKT-specific inhibitors significantly abolishes the beneficial effects of ACS on neurons, confirming that the PI3K/AKT pathway is an important potential signaling pathway in the action of ACS.
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Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Neurônios/metabolismo , Transdução de Sinais , Crescimento Neuronal/fisiologia , Células CultivadasRESUMO
Spinal cord injury (SCI) is catastrophic to humans and society. However, there is currently no effective treatment for SCI. Autophagy is known to serve critical roles in both the physiological and pathological processes of the body, but its facilitatory and/or deleterious effects in SCI are yet to be completely elucidated. This study aimed to use primary Schwann cell-derived exosomes (SCDEs) to treat rats after SCI. In the present study, SCDEs were purified and their efficacy in ameliorating the components of SCI was examined. Using both in vivo and in vitro experiments, it was demonstrated that SCDEs increased autophagy and decreased apoptosis after SCI, which promoted axonal protection and the recovery of motor function. Furthermore, it was discovered that an increased number of SCDEs resulted in a decreased expression level of EGFR, which subsequently inhibited the Akt/mTOR signaling pathway, which upregulated the level of autophagy to ultimately induce microtubule acetylation and polymerization. Collectively, the present study identified that SCDEs could induce axonal protection after SCI by increasing autophagy and decreasing apoptosis, and it was suggested that this may involve the EGFR/Akt/mTOR signaling pathway.
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Exossomos , Traumatismos da Medula Espinal , Animais , Apoptose , Autofagia , Exossomos/metabolismo , Ratos , Ratos Sprague-Dawley , Recuperação de Função Fisiológica , Células de Schwann/metabolismo , Medula Espinal , Traumatismos da Medula Espinal/metabolismoRESUMO
The ubiquity of sulfur-containing molecules in biologically active natural products and pharmaceuticals has long attracted synthetic chemists to develop efficient strategies towards their synthesis. The strategy of direct α-C(sp3 )-H modification of sulfides provides a streamlining access to complex sulfur-containing molecules. Herein, we report a photoinduced chemo-, site- and stereoselective α-C(sp3 )-H functionalization of sulfides using isatins as the photoredox reagent and coupling partner catalyzed by a chiral gallium(III)-N,N'-dioxide complex. The reaction proceeds through a verified single-electron transfer (SET) mechanism with high efficiency, excellent functional group tolerance, as well as a broad substrate scope. Importantly, this cross-coupling protocol is highly selective for the direct late-stage functionalization of methionine-related peptides, regardless of the inherent structural similarity and complexity of diverse residues.
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Sulfetos , Enxofre , CatáliseRESUMO
Nephroblastoma, a pediatric kidney cancer, caused by pluripotent embryonic renal precursors. Long noncoding RNAs (lncRNAs) are commonly abnormal expressed in many cancers. In the present study, we fousced on one newly discrovered lncRNA, MYLK Antisense RNA 1 (MYLK-AS1), and its functional role in proliferation and cycle distribution of nephroblastoma cells. Micorarray-based analysis revealed the highly expressed Cyclin E1 (CCNE1) and MYLK-AS1 in nephroblastoma. After nephroblastoma tissue sample collection, RT-qPCR confirmed the upregulated expression of MYLK-AS1 and CCNE1 in nephroblastoma tissues and cells. Kaplan-Meier curve exhibited that patients with elevated CCNE1 had lower overall survival rate in follow-up study. RNA binding protein immunoprecipitation, chromatin immunoprecipitation, and dual-luciferase reporter gene assay were employed to determine the relationship among MYLK-AS1, TCF7L2, and CCNE1, which validated that transcription factor 7-like 2 (TCF7L2) could specifically bind to MYLK-AS1 and TCF7L2 could positively promote CCNE1. After gain- and loss-of function assays, the conclusion that silencing of MYLK-AS1 could inhibit expression of CCNE1 through the transcription factor TCF7L2 to regulate the cell proliferation and cell cycle distribution of nephroblastoma cells was obtained. Subsequently, the subcutaneous tumor formation ability of nephroblastoma cell in nude mice was observed and the silencing of MYLK-AS1 exerts suppressive role in the tumorigenic ability of nephroblastoma cells in vivo. Taken together, MYLK-AS1 constitutes a promising biomarker for the early detection and treatment of nephroblastoma.
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Proteínas de Ligação ao Cálcio/genética , Ciclina E/genética , Quinase de Cadeia Leve de Miosina/genética , Proteínas Oncogênicas/genética , Proteína 2 Semelhante ao Fator 7 de Transcrição/genética , Tumor de Wilms/genética , Adolescente , Adulto , Animais , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Regulação para Baixo , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Masculino , Camundongos Nus , Pessoa de Meia-Idade , RNA Longo não Codificante/genética , Adulto JovemRESUMO
BACKGROUND: Traumatic spinal cord injury (SCI) is a severely disabling disease that leads to loss of sensation, motor, and autonomic function. As exosomes have great potential in diagnosis, prognosis, and treatment of SCI because of their ability to easily cross the blood-brain barrier, the function of Schwann cell-derived exosomes (SCDEs) is still largely unknown. METHODS: A T10 spinal cord contusion was established in adult female mice. SCDEs were injected into the tail veins of mice three times a week for 4 weeks after the induction of SCI, and the control group was injected with PBS. High-resolution transmission electron microscope and western blot were used to characterize the SCDEs. Toll-like receptor 2 (TLR2) expression on astrocytes, chondroitin sulfate proteoglycans (CSPGs) deposition and neurological function recovery were measured in the spinal cord tissues of each group by immunofluorescence staining of TLR2, GFAP, CS56, 5-HT, and ß-III-tublin, respectively. TLR2f/f mice were crossed to the GFAP-Cre strain to generate astrocyte specific TLR2 knockout mice (TLR2-/-). Finally, western blot analysis was used to determine the expression of signaling proteins and IKKß inhibitor SC-514 was used to validate the involved signaling pathway. RESULTS: Here, we found that TLR2 increased significantly on astrocytes post-SCI. SCDEs treatment can promote functional recovery and induce the expression of TLR2 on astrocytes accompanied with decreased CSPGs deposition. The specific knockout of TLR2 on astrocytes abolished the decreasing CSPGs deposition and neurological functional recovery post-SCI. In addition, the signaling pathway of NF-κB/PI3K involved in the TLR2 activation was validated by western blot. Furthermore, IKKß inhibitor SC-514 was also used to validate this signaling pathway. CONCLUSION: Thus, our results uncovered that SCDEs can promote functional recovery of mice post-SCI by decreasing the CSPGs deposition via increasing the TLR2 expression on astrocytes through NF-κB/PI3K signaling pathway.
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Astrócitos/metabolismo , Proteoglicanas de Sulfatos de Condroitina/metabolismo , Exossomos/metabolismo , Células de Schwann/metabolismo , Traumatismos da Medula Espinal/metabolismo , Receptor 2 Toll-Like/metabolismo , Animais , Modelos Animais de Doenças , Feminino , Proteína Glial Fibrilar Ácida/metabolismo , Camundongos , Camundongos Knockout , Recuperação de Função Fisiológica/fisiologia , Serotonina/metabolismo , Medula Espinal/metabolismo , Receptor 2 Toll-Like/genética , Tubulina (Proteína)/metabolismoRESUMO
Low-intensity pulsed ultrasound (LIPUS) is widely used to regulate stem cell proliferation and differentiation. However, the effect of LIPUS stimulation on neural stem cells (NSCs) is not well documented. In this study, we have identified the optimal parameters, and investigated the cellular mechanisms of LIPUS to regulate the proliferation and differentiation of NSCs in vitro. NSCs were obtained and identified by nestin immunostaining. The proliferation of NSCs were measured by using Cell Counting Kit-8 (CCK-8). The expressions of nutritional factors (NTFs) were detected with immunoassay (ELISA). NSCs differentiation were detected by immunofluorescence and immunoblotting analysis. The expression level of proteins involved in the Notch signaling pathway was also measured by immunoblotting assay. Our results showed the intensity of 69.3 mW/cm2 (1 MHz, 8 V) was applicable for LIPUS stimulation. ELISA analysis demonstrated that LIPUS treatment promoted the expression of nutritional factors of NSCs in vitro. Immunofluorescence and immunoblotting analyses suggested that the LIPUS not only reduced the astrocyte differentiation, but also stimulated the differentiation to neurons. Additionally, LIPUS stimulation significantly upregulated expression level of Notch1 and Hes1. Results from our study suggest that LIPUS triggers NSCs proliferation and differentiation by modulating the Notch signaling pathway. This study implies LIPUS as a potential and promising therapeutic platform for the optimization of stem cells and enable noninvasive neuromodulation for central nervous system diseases.
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Células-Tronco Neurais , Receptores Notch/metabolismo , Ondas Ultrassônicas , Diferenciação Celular , Proliferação de Células , Humanos , Neurogênese , Neurônios/metabolismo , Transdução de Sinais , Fatores de Transcrição HES-1/metabolismo , Regulação para CimaRESUMO
OBJECTIVE: To assess the effectiveness and safety of therapeutic ultrasound with sham ultrasound on pain relief and functional improvement in knee osteoarthritis patients. As phonophoresis is a unique therapeutic ultrasound, we also compared the effects of phonophoresis with conventional non-drug ultrasound. DATA SOURCES: PubMed, EMBASE, and the Cochrane Library were systematically searched for randomized controlled trials from inception up to June 2019. REVIEW METHODS: Randomized controlled trials comparing therapeutic ultrasound with sham ultrasound in knee osteoarthritis patients were included. Phonophoresis in the experimental and control groups were compared through conventional ultrasound, and corresponding trials were also included. Two reviewers independently identified eligible studies and extracted data. Risk of bias assessments and therapeutic ultrasound safety assessments were also performed. RESULTS: Fifteen studies including three phonophoresis-related studies with 1074 patients were included. Meta-analyses demonstrated that therapeutic ultrasound significantly relieved pain (P < 0.00001) and reduced the Western Ontario and McMaster Universities (WOMAC) physical function score (P = 0.03). In addition, therapeutic ultrasound increased the active range of motion (P < 0.00001) and reduced the Lequesne index (P < 0.00001). Subgroup analysis of phonophoresis ultrasound illustrated significant differences on the visual analogue scale (P = 0.009), but no significant differences on WOMAC pain subscales (P = 0.10), and total WOMAC scores were observed (P = 0.30). There was no evidence to suggest that ultrasound was unsafe treatment. CONCLUSIONS: Therapeutic ultrasound is a safe treatment to relieve pain and improve physical function in patients with knee osteoarthritis. However, phonophoresis does not produce additional benefits to functional improvement, but may relieve pain compared to conventional non-drug ultrasound.
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Osteoartrite do Joelho/terapia , Fonoforese , Terapia por Ultrassom , Humanos , Resultado do TratamentoRESUMO
BACKGROUND: Wilms tumor (WT) is the most common pediatric renal malignancy. Previous genome-wide association studies have identified that the LINC00673 rs11655237 C>T polymorphism is associated with the risk of several types of cancer. However, few studies have investigated the association between LINC00673 rs11655237 C>T and WT susceptibility. METHOD: We genotyped LINC00673 rs11655237 C>T in 145 patients with WT and 531 cancer-free controls recruited from southern Chinese children. The strength of association was estimated by odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Our study indicated that there was no significant association between LINC00673 rs11655237 C>T polymorphism and WT risk under all the tested genetic models (CT vs CC: adjusted OR = 0.94, 95% CI = 0.63-1.40; TT vs CC: adjusted OR = 0.60, 95% CI = 0.22-1.59; TT/CT vs CC: adjusted OR = 0.89, 95% CI = 0.61-1.31; and TT vs CC/CT: adjusted OR = 0.61, 95% CI = 0.23-1.61). Further stratified analysis detected no significant association, either. CONCLUSION: In conclusion, we failed to find any association between the LINC00673 rs11655237 C>T polymorphism and WT risk. This finding needs to be verified in larger studies and other populations.
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Estudos de Associação Genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único/genética , RNA Longo não Codificante/genética , Tumor de Wilms/genética , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Medição de RiscoRESUMO
BACKGROUND: Wilms tumor (WT) is the most common urologic cancer in children. However, genetic bases underlying WT remain largely unknown. Previous studies indicated that Lin28 homolog B (LIN28B) level is significantly elevated in some WTs. Enforced expression of Lin28b during kidney development could induce WT. Genetic variations in the LIN28B gene may be related to WT susceptibility. METHOD: In this study, we aimed to assess the association between LIN28B gene polymorphisms and WT susceptibility in Chinese children. Four potentially functional polymorphisms in the LIN28B gene (rs314276 C>A, rs221634 A>T, rs221635 T>C and rs9404590 T>G) were genotyped in 145 cases and 531 cancer-free controls, using Taqman method. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to evaluate the strength of the associations. RESULTS: Our results showed that the rs314276 CA genotype was associated with a decreased WT risk (CA vs CC: adjusted OR=0.65, 95% CI=0.43-0.98, P=.042). Moreover, we found that carriers of the 1-3 risk genotypes had a significantly increased WT risk when compared to the non-carriers (adjusted OR=1.51, 95% CI=1.03-2.20, P=.035). The association with risk genotypes was more predominant in children 18 month old or younger and in females. CONCLUSION: In summary, these results indicated that the LIN28B gene rs314276 C>A polymorphism alone and three combined polymorphisms may be able to modify WT susceptibility in Southern Chinese children. Our findings call for further validation in large studies with different ethnicities involved.
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Povo Asiático , Predisposição Genética para Doença , Proteínas de Ligação a RNA/genética , Tumor de Wilms , Povo Asiático/genética , Povo Asiático/estatística & dados numéricos , Estudos de Casos e Controles , Criança , Pré-Escolar , China , Feminino , Predisposição Genética para Doença/epidemiologia , Predisposição Genética para Doença/genética , Humanos , Lactente , Masculino , Polimorfismo Genético/genética , Tumor de Wilms/epidemiologia , Tumor de Wilms/genéticaRESUMO
Wilms' tumor is one of the most common solid tumors of childhood; however, the genetic basis underlying the majority of cases remains largely unknown. HACE1 is a putative Wilms' tumor susceptibility gene. We investigated the association between five HACE1 gene polymorphisms and Wilms' tumor susceptibility in a Chinese population consisting of 145 patients and 531 controls. We found a significant association between HACE1 rs9404576 polymorphism and decreased Wilms' tumor risk. No significant association was detected for other polymorphisms in the overall analysis. Our results indicated that HACE1 rs9404576 polymorphism may be associated with Wilms' tumor susceptibility in the Chinese population.
Assuntos
Povo Asiático/genética , Polimorfismo de Nucleotídeo Único , Ubiquitina-Proteína Ligases/genética , Tumor de Wilms/genética , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Masculino , Estadiamento de Neoplasias , Tumor de Wilms/patologiaRESUMO
PURPOSE: Urethral hypospadias, a common congenital malformation in males, is closely linked with disruptions in uroepithelial cell (UEC) processes. Evidence exists reporting that urine-derived exosomes (Urine-Exos) enhance UEC proliferation and regeneration, suggesting a potential role in preventing hypospadias. However, the specific influence of Urine-Exos on urethral hypospadias and the molecular mechanisms involved are not fully understood. This study focuses on investigating the capability of Urine-Exos to mitigate urethral hypospadias and aims to uncover the underlying molecular mechanisms. METHODS: Bioinformatics analysis was performed to identify key gene targets in Urine-Exos potentially involved in hypospadias. Subsequent in vitro and in vivo experiments were conducted to validate the regulatory effects of Urine-Exos on hypospadias. RESULTS: Bioinformatics screening revealed syndecan-1 (SDC1) as a potential pivotal gene for the prevention of hypospadias. In vitro experiments demonstrated that Urine-Exos enhanced the proliferation and migration of UECs by transferring SDC1 and inhibiting cell apoptosis. Notably, Urine-Exos upregulated ß-catenin expression through SDC1 transfer, further promoting UEC proliferation and migration. These findings were confirmed in a congenital hypospadias rat model induced by di(2-ethylhexyl) phthalate (DEHP). CONCLUSION: This study reveals the therapeutic potential of Urine-Exos in hypospadias, mediated by the SDC1/ß-catenin axis. Urine-Exos promote UEC proliferation and migration, thereby inhibiting the progression of hypospadias. These findings offer new insights and potential therapeutic targets for the management of congenital malformations.
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Proliferação de Células , Exossomos , Hipospadia , Sindecana-1 , beta Catenina , Hipospadia/metabolismo , Exossomos/metabolismo , Animais , Masculino , Humanos , Sindecana-1/metabolismo , Ratos , beta Catenina/metabolismo , beta Catenina/genética , Ratos Sprague-Dawley , Células Epiteliais/metabolismo , Apoptose , Movimento Celular , Modelos Animais de Doenças , UrinaRESUMO
Herein, a photoredox-driven practical protocol for fluorinated alkene synthesis using easily accessible and modular thianthrenium salts with electron-withdrawing alkynes or propargyl alcohols is reported. Vinyl radical intermediates, formed by the reaction between the alkyl or trifluoromethyl thianthrenium salts and electronically diverse alkynes, can mediate the key 1,5-HAT process of regioselective C(sp3)-H fluorination and vinylation. This protocol provides straightforward access to structurally diverse trifluoromethyl- or distally fluoro-functionalized alkene products in 21-79% yields with a broad substrate range under mild photocatalytic conditions.
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Background: Homeobox (HOX) A11 antisense RNA (HOXA11-AS) has been identified as a cancer promoting lncRNA and is overexpressed in nephroblastoma. However, how HOXA11-AS is regulated in a hypoxic inflammatory environment has not been studied. Methods: In this study, gene expression and epithelial-mesenchymal transition (EMT) ability were detected in the nephroblastoma cell line WiT49 under conditions of hypoxia and inflammation. Next, HOXA11-AS transcription factors were predicted by datasets and subsequently confirmed by CHIP-QPCR, EMSA, and dual-luciferase reporter assays. Moreover, the regulatory relationships of HOXA11-AS and its transcription factors were further confirmed by rescue experiments. Results: Our results showed that a hypoxic microenvironment promoted HOXA11-AS expression and nephroblastoma progression, induced EMT, and activated the Wnt signaling pathway. Combined hypoxia and inflammation had a more substantial effect on nephroblastoma than either hypoxia or inflammation alone. HIF-1α and C/EBPß were confirmed to be the transcription factors for HOXA11-AS. Silencing of HIF-1α or C/EBPß downregulated HOXA11-AS expression and suppressed EMT and the Wnt signaling pathway in nephroblastoma cells exposed to a hypoxic or inflammatory microenvironment. HOXA11-AS overexpression partly reversed the effect of HIF-1α or C/EBPß knockdown. Conclusion: We demonstrated that hypoxia/inflammation-induced upregulation of HIF-1α and C/EBPß promoted nephroblastoma EMT by improving HOXA11-AS transcription. HOXA11-AS might be a therapy target for nephroblastoma.
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In preclinical studies of spinal cord injury (SCI), behavioral assessments are crucial for evaluating treatment effectiveness. Commonly used methods include Basso, Beattie, Bresnahan (BBB) score and the Louisville swim scale (LSS), relying on subjective observations. The CatWalk automated gait analysis system is also widely used in SCI studies, providing extensive gait parameters from footprints. However, these parameters are often used independently or combined simply without utilizing the vast amount of data provided by CatWalk. Therefore, it is necessary to develop a novel approach encompassing multiple CatWalk parameters for a comprehensive and objective assessment of locomotor function. In this work, we screened 208 CatWalk XT gait parameters and identified 38 suitable for assessing hindlimb motor function recovery in a rat thoracic contusion SCI model. Exploratory factor analysis was used to reveal structural relationships among these parameters. Weighted scores for Coordination effectively differentiated hindlimb motor function levels, termed as the Coordinated Function Index (CFI). CFI showed high reliability, exhibiting high correlations with BBB scores, LSS, and T2WI lesion area. Finally, we simplified CFI based on factor loadings and correlation analysis, obtaining a streamlined version with reliable assessment efficacy. In conclusion, we developed a systematic assessment indicator utilizing multiple CatWalk parameters to objectively evaluate hindlimb motor function recovery in rats after thoracic contusion SCI.
Assuntos
Contusões , Traumatismos da Medula Espinal , Ratos , Animais , Reprodutibilidade dos Testes , Marcha , Membro Posterior , Recuperação de Função Fisiológica , Medula Espinal/patologia , Modelos Animais de DoençasRESUMO
Background: Normalized decision support system for lumbar disc herniation (LDH) will improve reproducibility compared with subjective clinical diagnosis and treatment. Magnetic resonance imaging (MRI) plays an essential role in the evaluation of LDH. This study aimed to develop an MRI-based decision support system for LDH, which evaluates lumbar discs in a reproducible, consistent, and reliable manner. Methods: The research team proposed a system based on machine learning that was trained and tested by a large, manually labeled data set comprising 217 patients' MRI scans (3255 lumbar discs). The system analyzes the radiological features of identified discs to diagnose herniation and classifies discs by Pfirrmann grade and MSU classification. Based on the assessment, the system provides clinical advice. Results: Eventually, the accuracy of the diagnosis process reached 95.83%. An 83.5% agreement was observed between the system's prediction and the ground-truth in the Pfirrmann grade. In the case of MSU classification, 95.0% precision was achieved. With the assistance of this system, the accuracy, interpretation efficiency and interrater agreement among surgeons were improved substantially. Conclusion: This system showed considerable accuracy and efficiency, and therefore could serve as an objective reference for the diagnosis and treatment procedure in clinical practice.