ABSTRACT
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.
Subject(s)
AMP-Activated Protein Kinases , Cell Differentiation , Cell Proliferation , Ferroptosis , Metformin , Neural Stem Cells , Rats, Sprague-Dawley , Spinal Cord Injuries , Metformin/pharmacology , Spinal Cord Injuries/drug therapy , Spinal Cord Injuries/pathology , Spinal Cord Injuries/metabolism , Animals , Neural Stem Cells/drug effects , Neural Stem Cells/metabolism , Cell Proliferation/drug effects , Cell Differentiation/drug effects , Ferroptosis/drug effects , AMP-Activated Protein Kinases/metabolism , Neurons/drug effects , Neurons/metabolism , Signal Transduction/drug effects , Rats , Reactive Oxygen Species/metabolism , Recovery of Function/drug effectsABSTRACT
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.
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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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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.
Subject(s)
Axons , Chondroitin Sulfate Proteoglycans , Exosomes , Schwann Cells , Spinal Cord Injuries , rho-Associated Kinases , Animals , Spinal Cord Injuries/metabolism , Spinal Cord Injuries/pathology , Schwann Cells/metabolism , Exosomes/metabolism , rho-Associated Kinases/metabolism , Chondroitin Sulfate Proteoglycans/metabolism , Axons/metabolism , Mice , Mice, Inbred C57BL , Signal Transduction/physiology , Female , Receptor-Like Protein Tyrosine Phosphatases, Class 2/metabolism , rho GTP-Binding Proteins/metabolismABSTRACT
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.
Subject(s)
Cell Proliferation , Exosomes , Hypospadias , Syndecan-1 , beta Catenin , Hypospadias/metabolism , Exosomes/metabolism , Animals , Male , Humans , Syndecan-1/metabolism , Rats , beta Catenin/metabolism , beta Catenin/genetics , Rats, Sprague-Dawley , Epithelial Cells/metabolism , Apoptosis , Cell Movement , Disease Models, Animal , UrineABSTRACT
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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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.
Subject(s)
Bone Nails , Femoral Fractures , Osteogenesis Imperfecta , Humans , Osteogenesis Imperfecta/complications , Osteogenesis Imperfecta/surgery , Male , Female , Child , Incidence , Child, Preschool , Risk Factors , Bone Nails/adverse effects , Femoral Fractures/surgery , Femoral Fractures/epidemiology , Femoral Fractures/etiology , Femur/surgery , Postoperative Complications/epidemiology , Postoperative Complications/etiology , Retrospective Studies , Bone Plates/adverse effects , Infant , Adolescent , Bone Wires , Proportional Hazards ModelsABSTRACT
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.
Subject(s)
Contusions , Spinal Cord Injuries , Rats , Animals , Reproducibility of Results , Gait , Hindlimb , Recovery of Function , Spinal Cord/pathology , Disease Models, AnimalABSTRACT
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.
Subject(s)
Diethylhexyl Phthalate , Hypospadias , Humans , Male , Rats , Animals , Transforming Growth Factor beta1/metabolism , Epithelial-Mesenchymal Transition , Hypospadias/chemically induced , Diethylhexyl Phthalate/toxicity , Profilins/pharmacologyABSTRACT
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.
Subject(s)
Phosphatidylinositol 3-Kinases , Proto-Oncogene Proteins c-akt , Proto-Oncogene Proteins c-akt/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Neurons/metabolism , Signal Transduction , Neuronal Outgrowth/physiology , Cells, CulturedABSTRACT
Prenylated and reverse-prenylated indolines are privileged scaffolds in numerous naturally occurring indole alkaloids with a broad spectrum of important biological properties. Development of straightforward and stereoselective methods to enable the synthesis of structurally diverse prenylated and reverse-prenylated indoline derivatives is highly desirable and challenging. In this context, the most direct approaches to achieve this goal generally rely on transition-metal-catalyzed dearomative allylic alkylation of electron-rich indoles. However, the electron-deficient indoles are much less explored, probably due to their diminished nucleophilicity. Herein, a photoredox-catalyzed tandem Giese radical addition/Ireland-Claisen rearrangement is disclosed. Diastereoselective dearomative prenylation and reverse-prenylation of electron-deficient indoles proceed smoothly under mild conditions. An array of tertiary α-silylamines as radical precursors is readily incorporated in 2,3-disubstituted indolines with high functional compatibility and excellent diastereoselectivity (>20:1 d.r.). The corresponding transformations of the secondary α-silylamines provide the biologically important lactam-fused indolines in one-pot synthesis. Subsequently, a plausible photoredox pathway is proposed based on control experiments. The preliminary bioactivity study reveals a potential anticancer property of these structurally appealing indolines.
Subject(s)
Antipsychotic Agents , Electrons , Prenylation , Alkylation , Indoles , CatalysisABSTRACT
Photosynthesis is essential for the growth of all green plants, and the presence of an Epichloë endophyte enhances the photosynthesis of Achnatherum inebrians (drunken horse grass, DHG), including when it is under attack by fungal pathogens. However, few studies have examined the mechanism of the increased photosynthetic activity at the molecular level of A. inebrians when it is under pathogen stress. The present study investigated the effects of the presence of the Epichloë endophyte on the net photosynthetic rate, intercellular CO2 concentration, stomatal conductance, and transpiration rate of DHG plants under a Blumeria graminis infection condition, and we compared the transcriptomes using RNA sequencing. The results showed that the photosynthetic rate of Epichloë endophyte-infected (E+) plants was higher under the B. graminis infection condition, and also without this pathogen, when it was compared with Epichloë endophyte-free (E-) plants. The E+ plants uninfected with B. graminis had 15 up-regulated unigenes that are involved in photosynthesis which were compared to the E- plants that were uninfected with this pathogen. This suggests that the presence of an Epichloë endophyte up-regulates the genes that are involved in the process of photosynthesis.
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In the driving process, the driver's visual attention area is of great significance to the research of intelligent driving decision-making behavior and the dynamic research of driving behavior. Traditional driver intention recognition has problems such as large contact interference with wearing equipment, the high false detection rate for drivers wearing glasses and strong light, and unclear extraction of the field of view. We use the driver's field of vision image taken by the dash cam and the corresponding vehicle driving state data (steering wheel angle and vehicle speed). Combined with the interpretability method of the deep neural network, a method of imaging the driver's attention area is proposed. The basic idea of this method is to perform attention imaging analysis on the neural network virtual driver based on the vehicle driving state data, and then infer the visual attention area of the human driver. The results show that this method can realize the reverse reasoning of the driver's intention behavior during driving, image the driver's visual attention area, and provide a theoretical basis for the dynamic analysis of the driver's driving behavior and the further development of traffic safety analysis.
Subject(s)
Automobile Driving , Neural Networks, Computer , HumansABSTRACT
We report a vinyl radical-mediated 1,5-hydrogen atom transfer (1,5-HAT) strategy for the remote C(sp3)-H functionalization reaction, which includes cyanation, oxidation, and etherification under visible-light-induced photochemical conditions. This reaction is achieved using readily available alkyl N-hydroxyphthalimide esters as radical precursors, which can efficiently react with diverse alkynes to form key vinyl radical intermediates followed by a 1,5-HAT process. A series of structurally diverse γ-cyano, γ-carbonyl, and γ-oxygenated alkenes with excellent stereoselectivity can be efficiently constructed by this synthetic protocol.
Subject(s)
Alkenes , Hydrogen , Alkynes , Catalysis , EstersABSTRACT
Di-(2-ethylhexyl) phthalate (DEHP) is a kind of environmental endocrine disruptors (EEDs), which has been confirmed to cause serious consequences, such as cryptorchidism. Patients with unilateral cryptorchidism still had oligospermia or infertility even if they received orchidopexy before puberty. Testicular dysgenesis syndrome (TDS) attributes this kind of problems to the abnormal testicular development during the embryonic period, and considers that the environmental exposure factors during pregnancy play a major role. Therefore, for unilateral cryptorchidism, even if one testicle has dropped to scrotum, it may be exposed to these substances and cause damage. Cystic fibrosis transmembrane conduction regulator (CFTR) is very important for the maturation of male reproductive system. Previously, cryptorchidism was thought to cause abnormal expression of heat sensitive protein CFTR in testis, but the expression of CFTR in healthy side (descended side) testis was not clear. In this study, we established SD rats with unilateral cryptorchidism by exposure to DEHP (500 mg/kg/day) during pregnancy, and detected the expression of CFTR and downstream signal NF-κB/COX-2/PGE2 in bilateral testis. Finally, we found that the expression of CFTR and downstream signal NF-κB/COX-2/PGE2 in the undescended testis was significantly abnormal, but the expression of them in the descended testis was also abnormal to some extent. Therefore, we speculate that in addition to high temperature will affect the expression of CFTR, there may be other factors that cause abnormal expression of CFTR induced by DEHP, and lead to abnormal male reproductive function eventually, but the specific mechanism needs to be further studied.
Subject(s)
Cryptorchidism , Diethylhexyl Phthalate , Endocrine Disruptors , Animals , Female , Male , Pregnancy , Rats , Cryptorchidism/chemically induced , Cryptorchidism/metabolism , Cyclooxygenase 2/metabolism , Cystic Fibrosis Transmembrane Conductance Regulator , Diethylhexyl Phthalate/toxicity , Dinoprostone , Endocrine Disruptors/toxicity , NF-kappa B/metabolism , Rats, Sprague-DawleyABSTRACT
Although plenty of evidences from preclinical studies have led to potential treatments for patients with spinal cord injury (SCI), the failure to translate promising preclinical findings into clinical advances has long puzzled researchers. Thus, a more reliable combination of anatomical assessment and behavioral testing is urgently needed to improve the translational worth of preclinical studies. To address this issue, the present study was designed to relate magnetic resonance imaging (MRI)-based anatomical assessment to behavioral outcome in a rat contusion model. Rats underwent contusion with three different heights to simulate various severities of SCI, and their locomotive functions were evaluated by the grid-walking test, Louisville swim scale (LSS), especially catwalk gait analysis system and basic testing, and Basso, Beattie, Bresnahan (BBB) score. The results showed that the lesion area (LA) is a better indicator for damage assessment compared with other parameters in sagittal T2-weighted MRI (T2WI). Although two samples are marked as outliers by the box plot analysis, LA correlated closely with all of the behavioral testing without ceiling effect and floor effect. Moreover, with a moderate severity of SCI in a contusion height of 25 mm, the smaller the LA of the spinal cord measured on sagittal T2WI the better the functional performance, the smaller the cavity region and glial scar, the more spared the myelin, the higher the volatility, and the thicker the bladder wall. We found that LA significantly related with behavior outcomes, which indicated that LA could be a proxy of damage assessment. The combination of sagittal T2WI and four types of behavioral testing can be used as a reliable scheme to evaluate the prognosis for preclinical studies of SCI.
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Background: The etiological mechanism of hypospadias is multifactorial and may be heterogeneous by severity. To date, very limited analyses on proteome in hypospadias have been conducted, and there are still no severe hypospadias proteomics analyses. Methods: In our study, tandem mass tag (TMT)-based quantitative proteomics was performed, exploring the clinical samples from hypospadias patients and healthy donators, in order to identify distinctly expressed proteins for severe hypospadias. To further uncover the mechanistic links in these complex proteomics data, we performed several core ingenuity pathway analyses (IPA) to predict, based on these observed different expression of proteins (DEPs). Results: Compared with the unaffected controls, 299 proteins were found to be down-regulated and 176 proteins up-regulated in severe hypospadias foreskin tissues. Functional annotation revealed that these DEPs were mainly in the extracellular space and were associated with complement activation and coagulation cascades. Similarly, the IPA core analysis revealed enriched pathways of the acute phase response signaling and complement system, demonstrating that by mediating their targeted, differentiated expressed proteins (A2M, APOE, C4A/C4B, C5, CAT, CD74, CFP, CREB1, CTSB, FGA, FGB, FGG, FN1, FOS, HP, LYZ, PF4, RBP1, S100A12, SERPINA3, SLC2A1, and THBS1) may be involved in the activation of myeloid cell degranulation, phagocytes degranulation, molecule secretion, and were mainly regulated by CSF1, JNK, STAT1, and STAT3. Conclusions: Our findings raise questions regarding the role of inflammatory activity in the pathology of severe hypospadias. This approach highlights the possibility of the use of non-surgical approaches to limit fibrotic signals and function, which is a promising potential therapeutic strategy for hypospadias patients.
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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.
Subject(s)
Sulfides , Sulfur , CatalysisABSTRACT
To enhance the efficiency of photogenerated electron transport in the photo-Fenton reaction, we report a Fe-doped UiO-66 containing Fe-O-Zr bonds for the photo-Fenton reaction system. The modulation changes the energy bandgap from 3.89 eV to 2.02 eV, and its absorption edge is red-shifted from the UV region to the visible range. Simultaneously, Fe-O-Zr reduces the redox internal resistance, enhances the photocurrent and catalytic process, and suppresses the compounding of photogenerated electrons and holes. These promote the valence cycling of Fe(III)/Fe(II) in the photo-Fenton reaction. Compared with UiO-66, the hydroxyl radical generation efficiency of this reaction system was increased by 5.8 times (UiO-66: 0.0009 mM/min, FeUiO-1: 0.0053 mM/min). The degradation efficiency of BPA was increased by 100.8 times (UiO-66: 0.0012 min-1, FeUiO-1: 0.121 min-1), and the removal rate of TOC also reached 69.55%. The removal rate of BPA was maintained at more than 85% through 5 cycles. The reaction system was able to maintain a removal rate more than 97% at pH:3-9. In the presence of anions, such as Cl-, SO42-, NO32- (10 mM), the degradation rates of BPA were still above 94%. The catalytic efficiency was 2.02 times higher under natural light than relative to dark conditions. It was demonstrated by EPR and inhibition experiments that the main active species in the reaction were hydroxyl radicals and vacancies. The HOMO energy level and LUMO energy level of the intermediates were analyzed, and the possible degradation pathways of the active species were speculated. Evaluation of the biological toxicity of intermediates demonstrated that the system can effectively detoxify BPA. This investigation provides a reference method to enhance the efficiency of the photo-Fenton reaction of MOFs.