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In the construction of underground geological engineering, a variety of rocks were often encountered, and the engineering surrounding rocks was prone to shear fracturing. Shear mechanics tests were conducted on a variety of rocks under various joint angles. By studying the shear mechanical characteristics, acoustic emission behavior, and damage degree of the different rock types, we can obtain an insight into their bearing capacity and fracture mechanisms. An obvious inflection point from the elastic to plastic behavior can be observed for the specimens during the process of shear mechanics tests, and the shear behavior was divided into three phases. The acoustic emission signals significantly increased for coal during the second phase, while those of sandstone and shale start to increase during the third phase, which is from the peak point to fracture. The analyses of the shear failure and acoustic emission properties showed that the crack propagation angle increases as the normal stress of rock increases. It was proved that the joint angles and normal stresses of rock could effectively hinder the development of vertical fractures. Based on the shear failure and acoustic emission properties, a constitutive model capable of describing the shear behavior of different types of rocks was developed. This constitutive model can accurately describe the shear fracture properties of the various rocks. The shear failure properties and damage constitutive model of rocks in this study can be used to reduce engineering surrounding rock instability caused by shear.
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Spinal cord injury (SCI) can result in severe motor and sensory deficits, for which currently no effective cure exists. The pathological process underlying this injury is extremely complex and involves many cell types in the central nervous system. In this study, we have uncovered a novel function for macrophage G protein-coupled receptor kinase-interactor 1 (GIT1) in promoting remyelination and functional repair after SCI. Using GIT1flox/flox Lyz2-Cre (GIT1 CKO) mice, we identified that GIT1 deficiency in macrophages led to an increased generation of tumor necrosis factor-alpha (TNFα), reduced proportion of mature oligodendrocytes (mOLs), impaired remyelination, and compromised functional recovery in vivo. These effects in GIT1 CKO mice were reversed with the administration of soluble TNF inhibitor. Moreover, bone marrow transplantation from GIT1 CWT mice reversed adverse outcomes in GIT1 CKO mice, further indicating the role of macrophage GIT1 in modulating spinal cord injury repair. Our in vitro experiments showed that macrophage GIT1 plays a critical role in secreting TNFα and influences the differentiation of oligodendrocyte precursor cells (OPCs) after stimulation with myelin debris. Collectively, our data uncovered a new role of macrophage GIT1 in regulating the transformation of OPCs into mOLs, essential for functional remyelination after SCI, suggesting that macrophage GIT1 could be a promising treatment target of SCI.
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Diferenciación Celular , Macrófagos , Células Precursoras de Oligodendrocitos , Remielinización , Traumatismos de la Médula Espinal , Animales , Traumatismos de la Médula Espinal/metabolismo , Traumatismos de la Médula Espinal/patología , Macrófagos/metabolismo , Remielinización/fisiología , Diferenciación Celular/fisiología , Células Precursoras de Oligodendrocitos/metabolismo , Ratones , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ciclo Celular/genética , Ratones Endogámicos C57BL , Ratones Noqueados , Recuperación de la Función/fisiología , Modelos Animales de Enfermedad , Factor de Necrosis Tumoral alfa/metabolismo , Ratones Transgénicos , Femenino , Proteínas Activadoras de GTPasa/metabolismo , Proteínas Activadoras de GTPasa/genética , Oligodendroglía/metabolismoRESUMEN
Chromite ore processing residue (COPR) is a typical hazardous waste, which contains Cr(vi) and poses a great threat to the ecological environment and human health. In this study, solidification/stabilization (S/S) of COPR was carried out by using blast furnace slag (BFS) and fly ash (FA) to prepare alkali-activated cementitious materials (AACM). The influence of different factors (water glass modulus, liquid-solid ratio, alkali-solid content and curing temperature) on compressive strength was investigated by single-factor experiment. Additionally, solidification effect of AACM was determined according to the compressive strength and the leaching concentration of chromium (Cr(vi) and total Cr). According to the optimal conditions of the single-factor experiment, the highest compressive strength of 147.6 MPa was obtained after using the water glass modulus 1.0, liquid-solid ratio 0.28, alkali-solid content 8%, curing temperature 45 °C. The COPR was solidified in the AACM sample having highest compressive strength. The solidified body still has a good mechanical property (38.2 MPa) with 60% addition COPR. According to leaching tests, the leaching of Cr(vi) and total Cr of solidified body with 50% COPR was far lower than the limit value, which met the purpose of construction and landfill disposal. X-ray diffraction (XRD) analysis, Fourier transform infrared spectroscopy (FTIR) and scanning electron microscopy (SEM) analysis proved that heavy metal chromium was solidified in AACM by physical and chemical means.
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BACKGROUND: A rare autosomal recessive genetic disorder, 3M syndrome, is characterized by severe intrauterine and postnatal growth retardation. Children with 3M syndrome typically exhibit short stature, facial deformities, long tubular bones, and high vertebral bodies but generally lack mental abnormalities or other organ damage. Pathogenic genes associated with 3M syndrome include CUL7, OBSL1 and CCDC8. The clinical and molecular characteristics of patient with 3M syndrome are unique and serve as important diagnostic indicators. CASE SUMMARY: In this case, the patient displayed square shoulders, scoliosis, long slender tubular bones, and normal neurological development. Notably, the patient did not exhibit the typical dysmorphic facial features, relative macrocephaly, or growth retardation commonly observed in individuals with 3M syndrome. Whole exon sequencing revealed a novel heterozygous c.56681+1G>C (Splice-3) variant and a previously reported nonsense heterozygous c.3341G>A (p.Trp1114Ter) variant of OBSL1. Therefore, it is important to note that the clinical features of 3M syndrome may not always be observable, and genetic confirmation is often required. Additionally, the identification of the c.5683+1G>C variant in OBSL1 is noteworthy because it has not been previously reported in public databases. CONCLUSION: Our study identified a new variant (c.5683+1G>C) of OBSL1 that contributes to expanding the molecular profile of 3M syndrome.
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Glial cell line-derived neurotrophic factor (GDNF) protects dopaminergic neurons in various models of Parkinson's disease (PD). Cell-based GDNF gene delivery mitigates neurodegeneration and improves both motor and non-motor functions in PD mice. As PD is a chronic condition, this study aims to investigate the long-lasting benefits of hematopoietic stem cell (HSC)-based macrophage/microglia-mediated CNS GDNF (MMC-GDNF) delivery in an MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) mouse model. The results indicate that GDNF treatment effectively ameliorated MPTP-induced motor deficits for up to 12 months, which coincided with the protection of nigral dopaminergic neurons and their striatal terminals. Also, the HSC-derived macrophages/microglia were recruited selectively to the neurodegenerative areas of the substantia nigra. The therapeutic benefits appear to involve two mechanisms: (1) macrophage/microglia release of GDNF-containing exosomes, which are transferred to target neurons, and (2) direct release of GDNF by macrophage/microglia, which diffuses to target neurons. Furthermore, the study found that plasma GDNF levels were significantly increased from baseline and remained stable over time, potentially serving as a convenient biomarker for future clinical trials. Notably, no weight loss, altered food intake, cerebellar pathology, or other adverse effects were observed. Overall, this study provides compelling evidence for the long-term therapeutic efficacy and safety of HSC-based MMC-GDNF delivery in the treatment of PD.
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Factor Neurotrófico Derivado de la Línea Celular Glial , Macrófagos , Microglía , Enfermedad de Parkinson , Animales , Masculino , Ratones , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina , Modelos Animales de Enfermedad , Neuronas Dopaminérgicas/metabolismo , Exosomas/metabolismo , Terapia Genética/métodos , Factor Neurotrófico Derivado de la Línea Celular Glial/metabolismo , Factor Neurotrófico Derivado de la Línea Celular Glial/farmacología , Factor Neurotrófico Derivado de la Línea Celular Glial/uso terapéutico , Trasplante de Células Madre Hematopoyéticas/métodos , Células Madre Hematopoyéticas/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Ratones Endogámicos C57BL , Microglía/efectos de los fármacos , Microglía/metabolismo , Enfermedad de Parkinson/terapia , Enfermedad de Parkinson/metabolismo , Sustancia Negra/metabolismoRESUMEN
Background: Bladder cancer is a common malignant tumor of the urinary system. The progression of the condition is associated with a poor prognosis, so it is necessary to identify new biomarkers to improve the diagnostic rate of bladder cancer. Methods: In this study, 338 urine samples (144 bladder cancer, 123 healthy control, 32 cystitis, and 39 upper urinary tract cancer samples) were collected, among which 238 samples (discovery group) were analyzed by LC-MS. The urinary proteome characteristics of each group were compared with those of bladder cancer, and the differential proteins were defined by bioinformatics analysis. The pathways and functional enrichments were annotated. The selected proteins with the highest AUC score were used to construct a diagnostic panel. One hundred samples (validation group) were used to test the effect of the panel by ELISA. Results: Compared with the healthy control, cystitis and upper urinary tract cancer samples, the number of differential proteins in the bladder cancer samples was 325, 158 and 473, respectively. The differentially expressed proteins were mainly related to lipid metabolism and iron metabolism and were involved in the proliferation, metabolism and necrosis of bladder cancer cells. The AUC of the panel of APOL1 and ITIH3 was 0.96 in the discovery group. ELISA detection showed an AUC of 0.92 in the validation group. Conclusion: This study showed that urinary proteins can reflect the pathophysiological changes in bladder cancer and that important molecules can be used as biomarkers for bladder cancer screening. These findings will benefit the application of the urine proteome in clinical research.
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Chromite ore processing residue (COPR) is a hazardous waste because of leachable chromium, especially Cr(vi). Therefore, ascorbic acid (AA) and blast furnace slag (BFS) have been used to detoxify and solidify COPR. On this basis, environmental stability experiments with high temperature and freeze-thaw cycles were carried out to explore the stability performance of a solidified body with 40% COPR. The environmental stability performance was analyzed through changes in edge length, mass loss, compressive strength development, and leaching concentration of Cr(vi). The result indicated that the high-temperature environment had much more effect on the solidified body than the freeze-thaw cycle environment in these four aspects: after being maintained at 900 °C for 2 h, the compressive strength of the solidified bodies reached its minimum value (35.76 MPa). However, in the freeze-thaw cycle experiments, the compressive strength of the solidified bodies consistently remained above 80 MPa, and the leaching of hexavalent chromium was below the limit (5 mg L-1). In addition, X-ray diffraction (XRD) and Fourier transform infrared spectrometry (FTIR) analysis verified that COPR was effectively solidified through physical and chemical means. Moreover, high temperature changes the molecular structure of the solidified body, thus reducing the compressive strength and curing ability of the solidified body, while the freeze-thaw cycle experiment has little effect on it.
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BACKGROUND: Vague spinal anatomical landmarks in patients with ankylosing spondylitis (AS) make intraoperative insertion of pedicle screws difficult under direct vision. Currently, the clinical outcome is significantly improved with robot guidance. This study aims to explore the efficacy of robot-assisted pedicle screw insertion in treating AS combined with spinal fractures. METHODS: Forty patients (341 screws) who underwent pedicle screw insertion with AS complicated with spinal fractures were included. According to different surgical methods, 16 patients (135 screws) were classified into the robot group and 24 (206 screws) into the free-hand group. Intraoperative blood loss, operative duration, and adverse events were compared between the 2 groups. Gertzbein and Robbins classification was used to classify the accuracy of screw position. Clinical outcomes were evaluated by Visual Analog Scale, Japanese Orthopedic Association, and Oswestry Disability Index. RESULTS: No statistically significant differences between baseline data of the groups. The difference in the blood loss between groups wasn't significant, nor was the operative duration. No severe adverse events related to pedicle screw insertion were reported in either group. Notably, the accuracy of screw insertion was significantly higher in the robot group (129/135) than in the free-hand group (182/206). The lateral perforation prevalence didn't differ among groups. Visual Analog Scale in the third month postoperatively was lower in the robot group than in the free-hand group, with a significant difference. CONCLUSIONS: The study demonstrates statistically superior accuracy and surgical outcome of robot-assisted pedicle screw insertion in the treatment of AS complicated with spinal fractures compared with the traditional free-hand operation.
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Tornillos Pediculares , Procedimientos Quirúrgicos Robotizados , Robótica , Fracturas de la Columna Vertebral , Fusión Vertebral , Espondilitis Anquilosante , Humanos , Procedimientos Quirúrgicos Robotizados/métodos , Fracturas de la Columna Vertebral/complicaciones , Fracturas de la Columna Vertebral/cirugía , Espondilitis Anquilosante/complicaciones , Espondilitis Anquilosante/cirugía , Vértebras Lumbares/cirugía , Estudios Retrospectivos , Fusión Vertebral/métodos , Resultado del TratamientoRESUMEN
Coal chemical-induced climate change has become a global concern. However, the dearth of comprehensive case studies and fundamental data has obstructed the accurate quantification of volatile organic compounds (VOCs) emissions. This has failed to equip coal chemical industries with the necessary guidelines to implement effective emission reduction strategies. In response to this, the present study meticulously examined and contrasted the VOCs emissions from five distinct coal chemical enterprises in China. This was achieved through the application of life cycle assessment (LCA), a tool used to discern the primary factors influencing VOCs emissions and to identify potential avenues for VOCs emissions reduction. The analysis revealed that BT exhibited the highest emission intensity (5.58E-04 tons/ton), followed by ED (4.89E-04 tons/ton), YL (4.23E-04 tons/ton), XJ (2.94E-04 tons/ton), and SM (1.74E-04 tons/ton). Among these enterprises, coal-to-olefins enterprises predominantly discharged VOCs via sewage treatment (average 69.12%), while coal-to-methanol enterprises primarily emitted VOCs during circulating water cooling (40.02%). In coal-to-oil enterprises, storage and blending emerged as the principal source of VOCs emissions (56.83%). As a result, this study advocates that coal chemical enterprises concentrate on curbing VOCs emissions from highly concentrated wastewater, regulating the concentration of purgeable organic carbon in circulating water cooling systems, and instituting effective treatment methods for methanol storage tank emissions. These findings proffer invaluable insights for devising VOCs control measures in regions affected by intensive coal chemical production.
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Contaminantes Atmosféricos , Petróleo , Compuestos Orgánicos Volátiles , Compuestos Orgánicos Volátiles/análisis , Carbón Mineral/análisis , Contaminantes Atmosféricos/análisis , Metanol/análisis , Petróleo/análisis , China , Agua/análisis , Monitoreo del AmbienteRESUMEN
Interfering with the assembly of hepatitis B virus (HBV) capsid is a promising approach for treating chronic hepatitis B (CHB). In order to enhance the metabolic stability and reduce the strong hERG inhibitory effect of HBV capsid assembly modulator (CAM) GLS4, we rationally designed a series of carboxyl-containing heteroaryldihydropyrimidine (HAP) derivatives based on structural biology information combined with medicinal chemistry strategies. The results from biological evaluation demonstrated that compound 6a-25 (EC50 = 0.020 µM) exhibited greater potency than the positive drug lamivudine (EC50 = 0.09 µM), and was comparable to the lead compound GLS4 (EC50 = 0.007 µM). Furthermore, it was observed that 6a-25 reduced levels of core protein (Cp) and capsid in cells. Preliminary assessment of drug-likeness revealed that 6a-25 exhibited superior water solubility (pH 2.0: 374.81 µg mL-1; pH 7.0: 6.85 µg mL-1; pH 7.4: 25.48 µg mL-1), liver microsomal metabolic stability (t1/2 = 108.2 min), and lower hERG toxicity (10 µM inhibition rate was 72.66%) compared to the lead compound GLS4. Overall, compound 6a-25 holds promise for further investigation.
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BACKGROUND: Spinal cord injury (SCI) remains a significant health concern, with limited available treatment options. This condition poses significant medical, economic, and social challenges. SCI is typically categorized into primary and secondary injuries. Inflammation, oxidative stress, scar formation, and the immune microenvironment impede axon regeneration and subsequent functional restoration. Numerous studies have shown that the destruction of the blood-brain barrier (BBB) and microvessels is a crucial factor in severe secondary injury. Additionally, reactive oxygen species (ROS)-induced lipid peroxidation significantly contributes to endothelial cell death. Pericytes are essential constituents of the BBB that share the basement membrane with endothelial cells and astrocytes. They play a significant role in the establishment and maintenance of BBB. RESULTS: Immunofluorescence staining at different time points revealed a consistent correlation between pericyte coverage and angiogenesis, suggesting that pericytes promote vascular repair via paracrine signaling. Pericytes undergo alterations in cellular morphology and the transcriptome when exposed to hypoxic conditions, potentially promoting angiogenesis. We simulated an early ischemia-hypoxic environment following SCI using glucose and oxygen deprivation and BBB models. Co-culturing pericytes with endothelial cells improved barrier function compared to the control group. However, this enhancement was reduced by the exosome inhibitor, GW4869. In vivo injection of exosomes improved BBB integrity and promoted motor function recovery in mice following SCI. Subsequently, we found that pericyte-derived exosomes exhibited significant miR-210-5p expression based on sequencing analysis. Therefore, we performed a series of gain- and loss-of-function experiments in vitro. CONCLUSION: Our findings suggest that miR-210-5p regulates endothelial barrier function by inhibiting JAK1/STAT3 signaling. This process is achieved by regulating lipid peroxidation levels and improving mitochondrial function, suggesting a potential mechanism for restoration of the blood-spinal cord barrier (BSCB) after SCI.
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MicroARNs , Traumatismos de la Médula Espinal , Ratones , Animales , Pericitos/metabolismo , Células Endoteliales/metabolismo , Peroxidación de Lípido , Axones , Regeneración Nerviosa , Traumatismos de la Médula Espinal/metabolismo , Transducción de Señal , MicroARNs/genética , MicroARNs/metabolismoRESUMEN
Saposhnikovia divaricata (Turcz.) Schischk (S. divaricata, Fangfeng) is a herb in the Apiaceae family, and its root has been used since the Western Han Dynasty (202 B.C.). Chromones and coumarins are the pharmacologically active substances in S. divaricata. Modern phytochemical and pharmacological studies have demonstrated their antipyretic, analgesic, anti-inflammatory, antioxidant, anti-tumor, and anticoagulant activities. Technological and analytical strategy theory advancements have yielded novel results; however, most investigations have been limited to the main active substances-chromones and coumarins. Hence, we reviewed studies related to the chemical composition and pharmacological activity of S. divaricata, analyzed the developing trends and challenges, and proposed that research should focus on components' synergistic effects. We also suggested that, the structure-effect relationship should be prioritized in advanced research.
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Apiaceae , Medicamentos Herbarios Chinos , Medicamentos Herbarios Chinos/farmacología , Cumarinas/farmacología , Apiaceae/química , CromonasRESUMEN
Background: The pathophysiology of bone defects (BDs) is complex, and the treatment for bone defects, in particular massive bone defects, remains a major clinical challenge. Our study was conducted to explore the molecular events related to the progression of bone defects a common clinical condition. Methods: First, microarray data of GSE20980 were obtained from the Gene Expression Omnibus (GEO) database, where 33 samples in total were used to analyze the molecular biological processes related to bone defects. Next, the original data were normalized and differentially expressed genes (DEGs) were identified. Additionally, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted. Finally, a protein-protein interaction (PPI) network was constructed and the trends of the different genes were confirmed. Results: Compared with the samples of non-critical size defects (NCSD), the samples of critical size defects (CSD) had 2057, 827, and 1,024 DEGs at 7, 14, and 21 days post injury, respectively. At day 7, the DEGs were significantly enriched in metabolic pathways, at day 14 the DEGs were predominantly enriched in G-protein coupled signaling pathways and the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling pathway, and at day 21 the DEGs were mainly enriched in circadian entrainment and synaptic-related functions. The PPI network showed similar results. Quantitative real-time PCR (qRT-PCR) and western blot (WB) were performed to validate the partial results of sequencing. Conclusion: This study provides some clues about the molecular mechanism behind bone defects, which should contribute to scientific research and clinical treatment of this condition.
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Hepatitis B virus (HBV) infection is a major global health problem that puts people at high risk of death from cirrhosis and liver cancer. The presence of covalently closed circular DNA (cccDNA) in infected cells is considered to be the main obstacle to curing chronic hepatitis B. At present, the cccDNA cannot be completely eliminated by standard treatments. There is an urgent need to develop drugs or therapies that can reduce HBV cccDNA levels in infected cells. We summarize the discovery and optimization of small molecules that target cccDNA synthesis and degradation. These compounds are cccDNA synthesis inhibitors, cccDNA reducers, core protein allosteric modulators, ribonuclease H inhibitors, cccDNA transcriptional modulators, HBx inhibitors and other small molecules that reduce cccDNA levels.
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Hepatitis B Crónica , Hepatitis B , Neoplasias Hepáticas , Humanos , Virus de la Hepatitis B/genética , Virus de la Hepatitis B/metabolismo , ADN Circular/metabolismo , ADN Circular/uso terapéutico , Replicación Viral , Hepatitis B/genética , Hepatitis B/metabolismo , ADN Viral/genética , ADN Viral/metabolismo , ADN Viral/uso terapéutico , Hepatitis B Crónica/tratamiento farmacológico , Hepatitis B Crónica/genéticaRESUMEN
Approved or licensed antiviral drugs have limited applications because of their drug resistance and severe adverse effects. By contrast, by stabilizing or destroying the viral capsid, compounds known as capsid modulators prevent viral replication by acting on new targets and, therefore, overcoming the problem of clinical drug resistance. For example, computer-aided drug design (CADD) methods, using strategies based on structures of biological targets (structure-based drug design; SBDD), such as docking, molecular dynamics (MD) simulations, and virtual screening (VS), have provided opportunities for fast and effective development of viral capsid modulators. In this review, we summarize the application of CADD in the discovery, optimization, and mechanism prediction of capsid-targeting small molecules, providing new insights into antiviral drug discovery modalities.
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Cápside , Diseño Asistido por Computadora , Diseño de Fármacos , Descubrimiento de Drogas , Antivirales/farmacología , Antivirales/químicaRESUMEN
Fibrotic scars appear after spinal cord injury (SCI) and are mainly composed of fibroblasts and excess extracellular matrix (ECM), including different types of collagen. The temporal and spatial distribution and role of excess collagens and ECM after SCI are not yet fully understood. Here, we identified that the procollagen type I C-terminal propeptide (PICP), a marker of collagen type I deposition, and bone morphogenetic protein 1 (BMP1), a secreted procollagen c-proteinase (PCP) for type I collagen maturation, were significantly elevatedin cerebrospinal fluid of patients with SCI compared with healthy controls, and were associated with spinal cord compression and neurological symptoms. We revealed the deposition of type I collagen in the area damaged by SCI in mice and confirmed that BMP1 was the only expressed PCP and induced collagen deposition. Furthermore, transforming growth factor-ß (TGF-ß), tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß) can activate the expression of BMP1. However, inhibition of BMP1 at the acute phase eliminated fibrotic scars in the damaged area and inhibited activation and enrichment of astrocytes, which made the damage difficult to repair and increased hematoma. Unexpectedly, knockdown of Bmp1 by adeno-associated virus or the inhibition of BMP1 biological function by specific inhibitors and monoclonal antibodies at different time points after injury led to distinct therapeutic effects. Only delayed inhibition of BMP1 improved axonal regeneration and myelin repair at the subacute stage post-injury, and led to the recovery of motor function, suggesting that scarring had a dual effect. Early inhibition of the scarring was not conducive to limiting inflammation, while excessive scar formation inhibited the growth of axons. After SCI, the collagen deposition indicators increased in both human cerebrospinal fluid and mouse spinal cord. Therefore, suppression of BMP1 during the subacute phase improves nerve function after SCI and is a potential target for scar reduction.
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Colágeno Tipo I , Traumatismos de la Médula Espinal , Humanos , Ratones , Animales , Proteína Morfogenética Ósea 1/genética , Proteína Morfogenética Ósea 1/metabolismo , Colágeno Tipo I/metabolismo , Cicatriz/patología , Colágeno/genética , Colágeno/metabolismo , Traumatismos de la Médula Espinal/genética , Traumatismos de la Médula Espinal/metabolismo , Traumatismos de la Médula Espinal/patología , FibrosisRESUMEN
Spinal cord ischemia-reperfusion (IR) injury (SCIRI) is a significant secondary injury that causes damage to spinal cord neurons, leading to the impairment of spinal cord sensory and motor functions. Excessive reactive oxygen species (ROS) production is considered one critical mechanism of neuron damage in SCIRI. Nonetheless, the molecular mechanisms underlying the resistance of neurons to ROS remain elusive. Our study revealed that the deletion of Git1 in mice led to poor recovery of spinal cord motor function after SCIRI. Furthermore, we discovered that Git1 has a beneficial effect on neuron resistance to ROS production. Mechanistically, Git1 interacted with PGK1, regulated PGK1 phosphorylation at S203, and affected the intermediate products of glycolysis in neurons. The influence of Git1 on glycolysis regulates the dimerization of Keap1, which leads to changes in Nrf2 ubiquitination and plays a role in resisting ROS. Collectively, we show that Git1 regulates the Keap1/Nrf2 axis to resist ROS in a PGK1-dependent manner and thus is a potential therapeutic target for SCIRI.
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Daño por Reperfusión , Isquemia de la Médula Espinal , Animales , Ratones , Proteínas de Ciclo Celular , Proteínas Activadoras de GTPasa , Proteína 1 Asociada A ECH Tipo Kelch/genética , Factor 2 Relacionado con NF-E2/genética , Especies Reactivas de Oxígeno/metabolismo , Daño por Reperfusión/tratamiento farmacológico , Isquemia de la Médula Espinal/complicaciones , Isquemia de la Médula Espinal/prevención & controlRESUMEN
Disruption of the blood-spinal cord barrier (BSCB) leads to inflammatory cell infiltration and neural cell death, thus, contributing to poor functional recovery after spinal cord injury (SCI). Previous studies have suggested that Sirtuin 1 (SIRT1), an NAD+-dependent class III histone deacetylase, is abundantly expressed in endothelial cells and promotes endothelial homeostasis. However, the role of SIRT1 in BSCB function after SCI remains poorly defined. Here, we report that SIRT1 is highly expressed in spinal cord endothelial cells, and its expression significantly decreases after SCI. Using endothelial cell-specific SIRT1 knockout mice, we observed that endothelial cell-specific knockout of SIRT1 aggravated BSCB disruption, thus, resulting in widespread inflammation, neural cell death and poor functional recovery after SCI. In contrast, activation of SIRT1 by the agonist SRT1720 had beneficial effects. In vitro, knockdown of SIRT1 exacerbated IL-1ß-induced endothelial barrier disruption in bEnd.3 cells, whereas overexpression of SIRT1 was protective. Using RNA-seq and IP/MS analysis, we identified p66Shc, a redox protein, as the potential target of SIRT1. Further studies demonstrated that SIRT1 interacts with and deacetylates p66Shc, thereby attenuating oxidative stress and protecting endothelial barrier function. Overall, our results indicate that SIRT1 decreases endothelial ROS production and attenuates BSCB disruption by deacetylating p66Shc after SCI, and suggest that SIRT1 activation has potential as a therapeutic approach to promote functional recovery against BSCB disruption following SCI.
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Sirtuina 1 , Traumatismos de la Médula Espinal , Animales , Ratones , Barrera Hematoencefálica , Células Endoteliales/metabolismo , Ratones Noqueados , Sirtuina 1/genética , Sirtuina 1/metabolismo , Traumatismos de la Médula Espinal/tratamiento farmacológico , Traumatismos de la Médula Espinal/genética , Traumatismos de la Médula Espinal/metabolismo , Proteína Transformadora 1 que Contiene Dominios de Homología 2 de Src/genética , Proteína Transformadora 1 que Contiene Dominios de Homología 2 de Src/metabolismoRESUMEN
Deep venous thrombosis (DVT) is a common medical complication in patients with lumbar fractures. The current study aimed to investigate the predictive value of neutrophil extracellular traps (NETs) in postoperative DVT formation in patients with lumbar fractures and to develop a nomogram relating clinical admission information for prediction. Patients who underwent open reduction and pedicle screw internal fixation in the treatment of single-segment lumbar fracture in the Department of Spine Surgery, the First Affiliated Hospital of Nanjing Medical University, from December 2020 to June 2022 were enrolled in this study. Baseline data and laboratory results were collected from enrollees, and the primary study endpoint event was the occurrence of DVT in patients after surgery. Multivariable logistic regression analysis was used to identify risk factors associated with higher odds of DVT after surgery. A nomogram was constructed using the results of the multivariable model. The calibration plot and receiver operating characteristics (ROC) curve were used to show the satisfactory predictive capacity of the model. Of these 393 patients who did not have DVT preoperatively, 79 patients developed it postoperatively, and 314 did not, respectively. Multivariate analysis showed that higher body mass index (BMI) (BMI between 24 and 28: RR = 1.661, 95% CI = 0.891-3.094; BMI ≤28: RR = 5.625, 95% CI = 2.590-12.217; reference: BMI <24), neutrophils (RR = 1.157, 95% CI 1.042-1.285), D-dimer (RR = 1.098, 95% CI 1.000-1.206), and citrullinated histone H3 (CitH3) (RR = 1.043, 95% CI 1.026-1.060) were independent risk factors for postoperative DVT. Using the multivariable analysis, we then constructed a nomogram to predict DVT, which was found to have an area under the curve of 0.757 (95% CI = 0.693-0.820). Calibration plots also showed the satisfied discrimination and calibration of the nomogram. In conclusion, patients with lumbar fractures with postoperative DVT had higher levels of NETs in the circulation preoperatively compared to those without postoperative DVT. Furthermore, based on BMI, D-dimer, neutrophils, and CitH3, we developed a predictive model to predict postoperative DVT incidence in these patients.
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INTRODUCTION: Boron has attracted extensive interest due to several FDA-approved boron-containing drugs and other pharmacological agents in clinical trials. As a semimetal, it has peculiar biochemical characteristics which could be utilized in designing novel drugs against drug-resistant viruses. Emerging and reemerging viral pandemics are major threats to human health. Accordingly, we aim to comprehensively review the current status of antiviral boron-containing compounds. AREAS COVERED: This review focuses on the utilization of boron to design molecules against viruses from two perspectives: (i) single boron atom-containing compounds acting on miscellaneous viral targets and (ii) boron clusters. The peculiar properties of antiviral boron-containing compounds and their diverse binding modes with viral targets are described in detail in this review. EXPERT OPINION: Compounds bearing boronic acid can interact with viral targets by forming covalent or robust hydrogen bonds. This feature is valuable for combating resistant viruses. Furthermore, boron clusters can form dihydrogen bonds and bear features such as three-dimensional aromaticity, hydrophobicity, and biological stability. All these features demonstrated boron as a probable essential element with immense potential for drug design.