RESUMEN
JOURNAL/nrgr/04.03/01300535-202507000-00029/figure1/v/2024-09-09T124005Z/r/image-tiff Autografting is the gold standard for surgical repair of nerve defects > 5 mm in length; however, autografting is associated with potential complications at the nerve donor site. As an alternative, nerve guidance conduits may be used. The ideal conduit should be flexible, resistant to kinks and lumen collapse, and provide physical cues to guide nerve regeneration. We designed a novel flexible conduit using electrospinning technology to create fibers on the innermost surface of the nerve guidance conduit and employed melt spinning to align them. Subsequently, we prepared disordered electrospun fibers outside the aligned fibers and helical melt-spun fibers on the outer wall of the electrospun fiber lumen. The presence of aligned fibers on the inner surface can promote the extension of nerve cells along the fibers. The helical melt-spun fibers on the outer surface can enhance resistance to kinking and compression and provide stability. Our novel conduit promoted nerve regeneration and functional recovery in a rat sciatic nerve defect model, suggesting that it has potential for clinical use in human nerve injuries.
RESUMEN
JOURNAL/nrgr/04.03/01300535-202506000-00028/figure1/v/2024-08-05T133530Z/r/image-tiff The pathophysiology of Huntington's disease involves high levels of the neurotoxin quinolinic acid. Quinolinic acid accumulation results in oxidative stress, which leads to neurotoxicity. However, the molecular and cellular mechanisms by which quinolinic acid contributes to Huntington's disease pathology remain unknown. In this study, we established in vitro and in vivo models of Huntington's disease by administering quinolinic acid to the PC12 neuronal cell line and the striatum of mice, respectively. We observed a decrease in the levels of hydrogen sulfide in both PC12 cells and mouse serum, which was accompanied by down-regulation of cystathionine ß-synthase, an enzyme responsible for hydrogen sulfide production. However, treatment with NaHS (a hydrogen sulfide donor) increased hydrogen sulfide levels in the neurons and in mouse serum, as well as cystathionine ß-synthase expression in the neurons and the mouse striatum, while also improving oxidative imbalance and mitochondrial dysfunction in PC12 cells and the mouse striatum. These beneficial effects correlated with upregulation of nuclear factor erythroid 2-related factor 2 expression. Finally, treatment with the nuclear factor erythroid 2-related factor 2 inhibitor ML385 reversed the beneficial impact of exogenous hydrogen sulfide on quinolinic acid-induced oxidative stress. Taken together, our findings show that hydrogen sulfide reduces oxidative stress in Huntington's disease by activating nuclear factor erythroid 2-related factor 2, suggesting that hydrogen sulfide is a novel neuroprotective drug candidate for treating patients with Huntington's disease.
RESUMEN
JOURNAL/nrgr/04.03/01300535-202502000-00034/figure1/v/2024-05-28T214302Z/r/image-tiff Several studies have found that transplantation of neural progenitor cells (NPCs) promotes the survival of injured neurons. However, a poor integration rate and high risk of tumorigenicity after cell transplantation limits their clinical application. Small extracellular vesicles (sEVs) contain bioactive molecules for neuronal protection and regeneration. Previous studies have shown that stem/progenitor cell-derived sEVs can promote neuronal survival and recovery of neurological function in neurodegenerative eye diseases and other eye diseases. In this study, we intravitreally transplanted sEVs derived from human induced pluripotent stem cells (hiPSCs) and hiPSCs-differentiated NPCs (hiPSC-NPC) in a mouse model of optic nerve crush. Our results show that these intravitreally injected sEVs were ingested by retinal cells, especially those localized in the ganglion cell layer. Treatment with hiPSC-NPC-derived sEVs mitigated optic nerve crush-induced retinal ganglion cell degeneration, and regulated the retinal microenvironment by inhibiting excessive activation of microglia. Component analysis further revealed that hiPSC-NPC derived sEVs transported neuroprotective and anti-inflammatory miRNA cargos to target cells, which had protective effects on RGCs after optic nerve injury. These findings suggest that sEVs derived from hiPSC-NPC are a promising cell-free therapeutic strategy for optic neuropathy.
RESUMEN
Targeted protein degradation (TPD) has emerged as a powerful approach for eliminating cancer-causing proteins through an "event-driven" pharmacological mode. Proteolysis-targeting chimeras (PROTACs), molecular glues (MGs), and hydrophobic tagging (HyTing) have evolved into three major classes of TPD technologies. Natural products (NPs) are a primary source of anticancer drugs and have played important roles in the development of TPD technology. NPs potentially expand the toolbox of TPD by providing a variety of E3 ligase ligands, protein of interest (POI) warheads, and hydrophobic tags (HyTs). As a promising direction in the TPD field, NP-based degraders have shown great potential for anticancer therapy. In this review, we summarize recent advances in the development of NP-based degraders (PROTACs, MGs and HyTing) with anticancer applications. Moreover, we put forward the challenges while presenting potential opportunities for the advancement of future targeted protein degraders derived from NPs.
RESUMEN
Detection of cytosolic DNA by the cyclic GMP-AMP (cGAMP) synthase (cGAS)-stimulator of interferon genes (STING) pathway provides immune defense against pathogens and cancer but can also cause autoimmunity when overactivated. The exonuclease three prime repair exonuclease 1 (TREX1) degrades DNA in the cytosol and prevents cGAS activation by self-DNA. Loss-of-function mutations of the TREX1 gene are linked to autoimmune diseases such as Aicardi-Goutières syndrome, and mice deficient in TREX1 develop lethal inflammation in a cGAS-dependent manner. In order to determine the type of cells in which cGAS activation drives autoinflammation, we generated conditional cGAS knockout mice on the Trex1-/- background. Here, we show that genetic ablation of the cGAS gene in classical dendritic cells (cDCs), but not in macrophages, was sufficient to rescue Trex1-/- mice from all observed disease phenotypes including lethality, T cell activation, tissue inflammation, and production of antinuclear antibodies and interferon-stimulated genes. These results show that cGAS activation in cDC causes autoinflammation in response to self-DNA accumulated in the absence of TREX1.
Asunto(s)
Autoinmunidad , Células Dendríticas , Exodesoxirribonucleasas , Ratones Noqueados , Nucleotidiltransferasas , Fosfoproteínas , Animales , Exodesoxirribonucleasas/genética , Exodesoxirribonucleasas/deficiencia , Exodesoxirribonucleasas/metabolismo , Nucleotidiltransferasas/genética , Nucleotidiltransferasas/metabolismo , Nucleotidiltransferasas/deficiencia , Células Dendríticas/inmunología , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Fosfoproteínas/inmunología , Ratones , Autoinmunidad/inmunología , Malformaciones del Sistema Nervioso/genética , Malformaciones del Sistema Nervioso/inmunología , Enfermedades Autoinmunes del Sistema Nervioso/inmunología , Enfermedades Autoinmunes del Sistema Nervioso/genética , Enfermedades Autoinmunes del Sistema Nervioso/patología , Inflamación/inmunología , Inflamación/genética , Macrófagos/inmunología , Macrófagos/metabolismo , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/genéticaRESUMEN
Thiophenol (PhSH) is an important industrial intermediate but displays significant toxicity towards environmental and biological systems. Here, we introduce a supramolecular system based on ß-cyclodextrin (ß-CD) and boron dipyrromethene (BODIPY) as a ratiometric fluorescence probe to discriminate PhSH in environmental water samples, cells, and in vivo. In aqueous solutions, BODIPY shows extremely weak fluorescence intensity due to its aggregation into nanometer-sized clusters, which prevents its interaction with thiols. However, within a ß-CD environment, it can selectively and sensitively detect PhSH. Also, the stability of the probe was significantly improved. The mechanism studies based on stoichiometry, NMR spectroscopy, and theoretical calculation revealed distinct intermolecular interactions between ß-CD and BODIPY, including host-guest interactions and hydrogen bonds. Low limit of detection (10.7 nM) and rapid response time (5 min) have been achieved, and the practicality of the supramolecular system (BODIPY@ß-CD) has been verified by actual sample analysis. Furthermore, the first hydrogel-based sensing system for portable PhSH detection has been developed, facilitating rapid and on-site colorimetric visualization across both liquid and gas phases. Most importantly, using a low amount of the probe, early stages of low-dose exposure to PhSH can be visualized in living cells and zebrafish. Therefore, BODIPY@ß-CD is a robust new monitoring tool for the detection of PhSH in various scenarios, indicating the promising application value of the host-guest supramolecular probe in detecting highly toxic substances.
RESUMEN
Tissue engineering technology has advanced rapidly in recent years, offering opportunities to construct biologically active tissues or organ substitutes to repair or even enhance the functions of diseased tissues and organs. Tissue-engineered scaffolds rebuild the extracellular microenvironment by mimicking the extracellular matrix. Fibrin-based scaffolds possess numerous advantages, including hemostasis, high biocompatibility, and good degradability. Fibrin scaffolds provide an initial matrix that facilitates cell migration, differentiation, proliferation, and adhesion, and also play a critical role in cell-matrix interactions. Fibrin scaffolds are now widely recognized as a key component in tissue engineering, where they can facilitate tissue and organ defect repair. This review introduces the properties of fibrin, including its composition, structure, and biology. In addition, the modification and cross-linking modes of fibrin are discussed, along with various forms commonly used in tissue engineering. We also describe the biofunctionalization of fibrin. This review provides a detailed overview of the use and applications of fibrin in skin, bone, and nervous tissues, and provides novel insights into future research directions for clinical treatment.
RESUMEN
BACKGROUND: The role of the geriatric nutritional risk index (GNRI) as a prognostic factor in intensive care unit (ICU) patients with acute kidney injury (AKI) remains uncertain. OBJECTIVES: The aim of this study was to investigate the impact of the GNRI on mortality outcomes in critically ill patients with AKI. METHODS: For this retrospective study, we included 12,058 patients who were diagnosed with AKI based on ICD-9 codes from the eICU Collaborative Research Database. Based on the values of GNRI, nutrition-related risks were categorized into four groups: major risk (GNRI < 82), moderate risk (82 ≤ GNRI < 92), low risk (92 ≤ GNRI < 98), and no risk (GNRI ≥ 98). Multivariate analysis was used to evaluate the relationship between GNRI and outcomes. RESULTS: Patients with higher nutrition-related risk tended to be older, female, had lower blood pressure, lower body mass index, and more comorbidities. Multivariate analysis showed GNRI scores were associated with in-hospital mortality. (Major risk vs. No risk: OR, 95% CI: 1.90, 1.54-2.33, P < 0.001, P for trend < 0.001). Moreover, increased nutrition-related risk was negatively associated with the length of hospital stay (Coefficient: -0.033; P < 0.001) and the length of ICU stay (Coefficient: -0.108; P < 0.001). The association between GNRI scores and the risks of in-hospital mortality was consistent in all subgroups. CONCLUSIONS: GNRI serves as a significant nutrition assessment tool that is pivotal to predicting the prognosis of critically ill patients with AKI.
Asunto(s)
Lesión Renal Aguda , Enfermedad Crítica , Mortalidad Hospitalaria , Evaluación Nutricional , Humanos , Femenino , Lesión Renal Aguda/mortalidad , Masculino , Enfermedad Crítica/mortalidad , Estudios Retrospectivos , Anciano , Persona de Mediana Edad , Evaluación Geriátrica/métodos , Estado Nutricional , Anciano de 80 o más Años , Unidades de Cuidados Intensivos , Medición de Riesgo/métodos , Factores de RiesgoRESUMEN
The simultaneous construction of multiple stereogenic elements in a single step is highly appealing and desirable in the field of asymmetric synthesis. Furthermore, the catalytic enantioselective synthesis of inherently chiral calix[n]arenes with high enantiopurity has long been a challenging endeavor. Herein, we report an enantioselective cobalt-catalyzed C-H activation/annulation for the efficient construction of inherently chiral calix[4]arenes bearing multiple C-N axially chiral element. By employing the benzamide tethered calix[4]arene as the substrate, the C-H annulation with alkynes can be successfully accomplished, leading to the generation of multiple stereogenic elements. A wide range of calix[4]arenes and alkynes are found to be well compatible, and exhibit good yields, high enantioselectivity and excellent diastereoselectivity. Notably, the gram-scale reaction, catalytic application, synthetic transformations, and chiral recognition further showcase the potential applications of this protocol.
RESUMEN
The innovative use of real-world data (RWD) can answer questions that cannot be addressed using data from randomized clinical trials (RCTs). While the sponsors of RCTs have a central database containing all individual patient data (IPD) collected from trials, analysts of RWD face a challenge: regulations on patient privacy make access to IPD from all regions logistically prohibitive. In this research, we propose a double inverse probability weighting (DIPW) approach for the analysis sponsor to estimate the population average treatment effect (PATE) for a target population without the need to access IPD. One probability weighting is for achieving comparable distributions in confounders across treatment groups; another probability weighting is for generalizing the result from a subpopulation of patients who have data on the endpoint to the whole target population. The likelihood expressions for propensity scores and the DIPW estimator of the PATE can be written to only rely on regional summary statistics that do not require IPD. Our approach hinges upon the positivity and conditional independency assumptions, prerequisites to most RWD analysis approaches. Simulations are conducted to compare the performances of the proposed method against a modified meta-analysis and a regular meta-analysis.
RESUMEN
The engineered TadA variants used in cytosine base editors (CBEs) present distinctive advantages, including a smaller size and fewer off-target effects compared to cytosine base editors that rely on natural deaminases. However, the current TadA variants demonstrate a preference for base editing in DNA with specific motif sequences and possess dual deaminase activity, acting on both cytosine and adenosine in adjacent positions, limiting their application scope. To address these issues, we employ TadA orthologs screening and multi sequence alignment (MSA)-guided protein engineering techniques to create a highly effective cytosine base editor (aTdCBE) without motif and adenosine deaminase activity limitations. Notably, the delivery of aTdCBE to a humanized mouse model of Duchenne muscular dystrophy (DMD) mice achieves robust exon 55 skipping and restoration of dystrophin expression. Our advancement in engineering TadA ortholog for cytosine editing enriches the base editing toolkits for gene-editing therapy and other potential applications.
Asunto(s)
Adenosina , Citosina , Edición Génica , Distrofia Muscular de Duchenne , Citosina/metabolismo , Animales , Edición Génica/métodos , Adenosina/metabolismo , Ratones , Humanos , Distrofia Muscular de Duchenne/genética , Distrofia Muscular de Duchenne/metabolismo , Ingeniería de Proteínas , Distrofina/genética , Distrofina/metabolismo , Adenosina Desaminasa/metabolismo , Adenosina Desaminasa/genética , Modelos Animales de Enfermedad , Exones/genética , Células HEK293 , Sistemas CRISPR-Cas , Proteínas de Escherichia coliRESUMEN
Tire microplastics (TMPs) and antibiotics are emerging pollutants that widely exist in water environments. The coexistence of these pollutants poses severe threats to aquatic organisms. However, the toxicity characteristics and key molecular factors of the combined exposure to TMPs in aquatic organisms remain unknown. Therefore, the joint toxicity of styrene-butadiene rubber TMPs (SBR-TMPs) and 32 antibiotics (macrolides, fluoroquinolones, ß-lactams, sulfonamides, tetracyclines, nitroimidazoles, highly toxic antibiotics, high-content antibiotics, and common antibiotics) in zebrafish was investigated using a full factorial design, molecular docking, and molecular dynamics simulation. Sixty-four combinations of antibiotics were designed to investigate the hepatotoxicity of the coexistence of SBR-TMPs additives and antibiotics in zebrafish. Results indicated that low-order effects of antibiotics (e.g., enoxacin-lomefloxacin and ofloxacin-enoxacin-lomefloxacin) had relatively notable toxicity. The van der Waals interaction between additives and zebrafish cytochrome P450 enzymes primarily affected zebrafish hepatotoxicity. Zebrafish hepatotoxicity was also affected by the ability of SBR-TMPs to adsorb antibiotics, the relation between antibiotics, the affinity of antibiotics docking to zebrafish cytochrome P450 enzymes, electronegativity, atomic mass, and the hydrophobicity of the antibiotic molecules. This study aimed to eliminate the joint toxicity of TMPs and antibiotics and provide more environmentally friendly instructions for using different chemicals.
RESUMEN
Grasslands are being threatened by global drought and warming. Economic assessments of changing grassland carbon sequestration, a prerequisite for nature-based climate-change mitigation policies, are limited when researchers inadequate consider interactions between drought and warming. Here, we quantified the responses of 35 grass biomasses to combined drought and warming, based on manipulation experiments from 34 peer-reviewed papers; subsequently, we matched them with grasslands in northern China-the eastern range of the larger Eurasian Steppe-and further projected the economic implications for carbon market trading and carbon-sequestration costs. The results show that carbon sequestration in all grassland types, except for forbrich steppe, was significantly reduced by the synergistic interactions of drought and warming. Approximately 10 % of the grasslands in central Xinjiang, identified as forbrich steppe, showed resilience to these stressors. In contrast, the rest of northern China's grasslands suffered increased carbon losses due to drought and warming. The combined effects of drought and warming have caused a loss of 1.6 × 104 million Chinese yuan (CNY) in revenue and excess carbon-sequestration costs exceeding 1.1 × 105 million CNY. Overall, our study results indicate that the synergistic effects of drought and warming significantly undermine the economic viability of carbon sequestration in most of northern China's grasslands. As climate change intensifies, understanding and incorporating the complex interactions of drought and warming can aid in the sustainable management of grassland ecosystems and the development of effective climate-change mitigation policies in arenas, including carbon markets.
RESUMEN
Plants encounter numerous adversities during growth, necessitating the identification of common stress activators to bolster their resistance. However, the current understanding of these activators' mechanisms remains limited. This study identified three anti-stress activators applicable to apple trees, all of which elevate plant proline content to enhance resistance against various adversities. The results showed that the application of these sugar substitutes increased apple proline content by two to three times compared to the untreated group. Even at a lower concentration, these activators triggered plant stress resistance without compromising apple fruit quality. Therefore, these three sugar substitutes can be exogenously sprayed on apple trees to augment proline content and fortify stress resistance. Given their effectiveness and low production cost, these activators possess significant application value. Since they have been widely used in the food industry, they hold potential for broader application in plants, fostering apple industry development.
Asunto(s)
Malus , Prolina , Estrés Fisiológico , Azúcares , Malus/metabolismo , Malus/fisiología , Prolina/metabolismo , Azúcares/metabolismo , Frutas/metabolismo , Regulación de la Expresión Génica de las PlantasRESUMEN
Evolutionary pressures sculpt population genetics, whereas immune adaptation fortifies humans against life-threatening organisms. How the evolution of selective genetic variation in adaptive immune receptors orchestrates the adaptation of human populations to contextual perturbations remains elusive. Here, we show that the G396R coding variant within the human immunoglobulin G1 (IgG1) heavy chain presents a concentrated prevalence in Southeast Asian populations. We uncovered a 190-kb genomic linkage disequilibrium block peaked in close proximity to this variant, suggestive of potential Darwinian selection. This variant confers heightened immune resilience against various pathogens and viper toxins in mice. Mechanistic studies involving severe acute respiratory syndrome coronavirus 2 infection and vaccinated individuals reveal that this variant enhances pathogen-specific IgG1+ memory B cell activation and antibody production. This G396R variant may have arisen on a Neanderthal haplotype background. These findings underscore the importance of an IGHG1 variant in reinforcing IgG1 antibody responses against life-threatening organisms, unraveling the intricate interplay between human evolution and immune adaptation.
RESUMEN
Flavonoid natural products are emerging as a promising approach for treating Ulcerative Colitis (UC) due to their natural origin and minimal toxicity. This study investigates the effects of Neohesperidin (NEO), a natural flavonoid, on Dextran Sodium Sulfate (DSS)-induced UC in mice, focusing on the underlying molecular mechanisms. Early intervention with NEO (25 and 50 mg/kg) mitigated colon shortening, restored damaged barrier proteins, and significantly reduced the inflammatory cytokine levels. Moreover, NEO inhibited the MAPK/NF-κB signaling pathway and enhanced the levels of intestinal barrier proteins (Claudin-3 and ZO-1). Additionally, NEO increased beneficial intestinal probiotics (S24-7 and Lactobacillaceae) while reducing harmful bacteria (Erysipelotrichi, Enterobacteriaceae). Fecal microbial transplantation (FMT) results demonstrated that NEO (50 mg/kg) markedly improved UC symptoms. In conclusion, early NEO intervention may alleviate DSS-induced UC by inhibiting inflammatory responses, preserving intestinal barrier integrity and modulating gut microbiota.
RESUMEN
Purpose: With the widespread application of silicone oil in vitreoretinal surgery, the purpose of this study was to determine the risk factors of long-term vision loss 12 months post oil removal in retina-detached eyes treated with vitrectomy and silicone oil tamponade. Methods: Of the 592 patients approached, eligible eyes completed the investigation up to 12 months post-oil-removal. Eligible eyes underwent pars-plana vitrectomy following oil tamponade. Oil removal was performed after 3 to 28 months in different individuals, under the condition that the retina has reattached as well as the hemorrhage and inflammation has dissolved. Postoperative best-corrected visual acuity (BCVA), age, sex, and interval between tamponade and removal were recorded, and retinal thickness was determined using optical coherence tomography (OCT). Results: Fifty eyes of 50 participants aged 31 to 83 years were enrolled. BCVA (LogMAR) 12 months post-oil-removal improved in 25 of 40 (62.5%) patients, varying from 0.05 (20/22) to 1.0 (20/200) (mean ± SD = 0.55 ± 0.32). Pre-oil-removal nasal perifoveal retinal nerve fiber layer thickness varied from 16 to 83 µm (38.40 ± 18.50), and was significantly linked with post-oil-removal BCVA (0.5%, 95% confidence interval 0.0%-1.0%; P = 0.046). Conclusions: This study demonstrates the risk factors and prognosis of visual function after long-term regeneration post vitrectomy, oil tamponade, and oil removal, thereby underscoring the need for a complete, dynamic examination of retinal structure via OCT measurement. Related studies should be conducted on a larger scale to facilitate the stratification of late-period vision damage in retina-detached eyes. Translational Relevance: This study developed OCT-based clinical markers for the postoperative visual prognosis of eyes affected by retinal detachment.
Asunto(s)
Desprendimiento de Retina , Aceites de Silicona , Tomografía de Coherencia Óptica , Agudeza Visual , Vitrectomía , Humanos , Masculino , Femenino , Persona de Mediana Edad , Anciano , Vitrectomía/efectos adversos , Adulto , Anciano de 80 o más Años , Desprendimiento de Retina/cirugía , Aceites de Silicona/administración & dosificación , Aceites de Silicona/farmacología , Fibras Nerviosas/patología , Endotaponamiento/métodos , Factores de Riesgo , Estudios de SeguimientoRESUMEN
Using the organic base as the organic electron donors, the reductive coupling of diaryhalomethanes was smoothly achieved under transition-metal-free reaction conditions, giving a series of synthetically important tetraarylethylenes and tetraarylethanes in high yields. The mechanistic study revealed that the organic bases acting as the electron donor initiated the generation of a radical intermediate, realizing the construction of tetraarylethylene and tetraarylethane skeletons.
RESUMEN
Artificial light at night (ALAN) is a common form of light pollution worldwide, and the intensity, timing, duration, and wavelength of light exposure can affect biological rhythms, which can lead to metabolic, reproductive, and immune dysfunctions and consequently, host-pathogen interactions. Insect vector-borne diseases are a global problem that needs to be addressed, and ALAN plays an important role in disease transmission by affecting the habits and physiological functions of vector organisms. In this work, we describe the mechanisms by which ALAN affects host physiology and biochemistry, host-parasite interactions, and vector-borne viruses and propose preventive measures for related infectious diseases to minimize the effects of artificial light on vector-borne diseases.