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Correlating the microscopic structural characteristics with the macroscopic electrochemical performance in electrode materials is critical for developing excellent-performance lithium-ion batteries, which however remains largely unexplored. Here, we show that the Zn2SnO4 (ZTO) nanowires (NWs) with smaller diameters (d < 5 nm) exhibit slower capacity fade rate and better cycling stability, as compared with the NWs with larger diameters ranging from tens to hundreds of nanometers. By applying in situ transmission electron microscopy (TEM), we discover a strong correlation of cracking behavior with the NW diameter. Upon the first lithiation, there exists a critical diameter of â¼80 nm, below which the NWs neither crack nor fracture, and above which the cracks could easily nucleate and propagate along the specific planes, resulting in the deteriorated cycling stability in larger sized electrodes. Further theoretical calculations based on the finite element model and the climbing image nudged elastic band method faithfully predict the size-dependent cracking behaviors, which may result from the synergistic effect of axial stress evolution as well as preferential Li-ion migration directions during the first lithiation. This work provides a real-time tracking of the tempo-spatial structural evolution of a single ZTO NW, which facilitates a fundamental understanding of how the sample size affects the electrochemical behavior and thus offers a reference for future battery design and application strategy.
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The recent development of accurate and efficient semilocal density functionals on the third rung of Jacob's ladder of density functional theory, such as the revised regularized strongly constrained and appropriately normed (r2SCAN) density functional, could enable rapid and highly reliable prediction of the elasticity and temperature dependence of thermophysical parameters of refractory elements and their intermetallic compounds using the quasi-harmonic approximation (QHA). Here, we present a comparative evaluation of equilibrium cell volumes, cohesive energy, mechanical moduli, and thermophysical properties (Debye temperature and thermal expansion coefficient) for 22 transition metals using semilocal density functionals, including the local density approximation (LDA), Perdew-Burke-Ernzerhof (PBE) and PBEsol generalized gradient approximations (GGAs), and the r2SCAN meta-GGA. PBEsol and r2SCAN deliver the same level of accuracies for structural, mechanical, and thermophysical properties. PBE and r2SCAN perform better than LDA and PBEsol for calculating cohesive energies of transition metals. Among the tested density functionals, r2SCAN provides an overall well-balanced performance for reliably computing cell volumes, cohesive energies, mechanical properties, and thermophysical properties of various 3d, 4d, and 5d transition metals using QHA. Therefore, we recommend that r2SCAN could be employed as a workhorse method to evaluate thermophysical properties of transition metal compounds and alloys in high throughput workflows.
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Fungi are the significant components of the sewer ecology system which can consume substances and exhibit pathogenicity. However, the characteristics of fungi formation and metabolism in the complex sewer environment have not been revealed in depth. In this study, gradient flow conditions were conducted in a pilot sewer and the formation characteristics of fungi were synthetically investigated. The results showed that the low flow rate at 0.1-0.4 m/s led to the loose morphology of biofilms, while the overly loose environment did not allow fungi communities to thrive in sewer. The dense biofilms were found at the middle flow condition (0.4-0.6 m/s), and the fungal communities with degradation functions were exuberant at this condition (such as Tremellales with relative abundance of 6.18% and Talaromyces with relative abundance of 6.51%). In particular, eleven kinds of fungi with known pathogenicity of the sewer biofilm were found in this study, and it is worth noting that the abundance of pathogenic fungi at medium flow rates is significantly higher than that at other flow conditions (higher than 10 %). While, excessive flow shear force (0.8-1.2 m/s) led to biofilm shedding which caused hindering the proper generation of fungi. In summary, the pollutant transformation and pathogenic exposure conducted by fungi communities could affect the sewer management process significantly, and this study could provide research foundation for wastewater quality prediction and management of pathogenic risk in sewer systems.
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Aguas del Alcantarillado , Aguas Residuales , Aguas del Alcantarillado/microbiología , Virulencia , Biopelículas , HongosRESUMEN
Acute spinal cord injury (SCI) always results in sustainable recruitment of inflammatory cells driven by sequentially generated chemokines, thereby eliciting excessive neuroinflammation. However, the underlying mechanism of temporally produced chemokines remains elusive. Reactive astrocytes are known to be the main sources of chemokines at the lesion site, which can be immediately activated by thrombin following SCI. In the present study, SCI was shown to induce a sequential production of chemokines CCL2 and CCL5 from astrocytes, which were associated with a persistent infiltration of macrophages/microglia. The rapidly induced CCL2 and later induced CCL5 from astrocytes were regulated by thrombin at the damaged tissues. Investigation of the regulatory mechanism revealed that thrombin facilitated astrocytic CCL2 production through activation of ERK/JNK/NFκB pathway, whereas promoted CCL5 production through PLCß3/NFκB and ERK/JNK/NFκB signal pathway. Inhibition of thrombin activity significantly decreased production of astrocytic CCL2 and CCL5, and reduced the accumulation of macrophages/microglia at the lesion site. Accordingly, the locomotor function of rats was remarkably improved. The present study has provided a new regulatory mechanism on thrombin-mediated sequential production of astrocytic chemokines, which might be beneficial for clinical therapy of CNS neuroinflammation.
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Astrocitos , Traumatismos de la Médula Espinal , Ratas , Animales , Astrocitos/metabolismo , Trombina/farmacología , Enfermedades Neuroinflamatorias , Quimiocinas/metabolismo , Médula Espinal/metabolismoRESUMEN
The synthesis and characterization of platinum(II) and palladium(II) complexes bearing two (dimers Pt(Lpc)2Cl2 and Pd(Lpc)2Cl2), one (monomers Pt(Lpc)(Lref)Cl2 and Pd(Lpc)(Lref)Cl2), or no (reference compounds Pt(Lref)2Cl2 and Pd(Lref)2Cl2) pentacene-based pyridyl ligands are presented. Photophysical properties of the dimers are probed by means of steady-state and time-resolved transient absorption measurements in comparison to the monomer and model compounds. Our results document that despite enhanced spin-orbit coupling from the presence of heavy atoms, intramolecular singlet fission (iSF) is not challenged by intersystem crossing. iSF thus yields correlated triplet pairs and even uncorrelated triplet excited states upon decoherence. Importantly, significant separation of the two pentacenyl groups facilitates decoupling of the two chromophores. Furthermore, the mechanism of iSF is altered depending on the respective metal center, that is, Pt(II) versus Pd(II). The dimer based on Pt(II), Pt(Lpc)2Cl2, exhibits a direct pathway for the iSF and forms a correlated triplet pair with singlet-quintet spin-mixing within 10 ns in variable solvents. On the other hand, the dimer based on Pd(II), Pd(Lpc)2Cl2, leads to charge transfer mixing during the population of the correlated triplet pair that is dependent on solvent polarity. Moreover, Pd(Lpc)2Cl2 gives rise to a stable equilibrium between singlet and quintet correlated triplet pairs with lifetimes of up to 170 ns. Inherent differences in the size and polarizability, when contrasting platinum(II) with palladium(II), are the most likely rationale for the underlying trends.
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Photon energy conversion can be accomplished in many different ways, including the two opposing manners, down-conversion (i.e., singlet fission, SF) and up-conversion (i.e., triplet-triplet annihilation up-conversion, TTA-UC). Both processes have the potential to help overcome the detailed balance limit of single-junction solar cells. Tetracene, in which the energies of the lowest singlet excited state and twice the triplet excited state are comparable, exhibits both down- and up-conversion. Here, we have designed meta-diethynylphenylene- and 1,3-diethynyladamantyl-linked tetracene dimers, which feature different electronic coupling, to characterize the interplay between intramolecular SF (intra-SF) and intramolecular TTA-UC (intra-TTA-UC) via steady-state and time-resolved absorption and fluorescence spectroscopy. Furthermore, we have used Pd-phthalocyanine as a sensitizer to enable intra-TTA-UC in the two dimers via indirect photoexcitation in the near-infrared part of the solar spectrum. The work is rounded off by temperature-dependent measurements, which outline key aspects of how thermal effects impact intra-SF and intra-TTA-UC in different dimers.
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BACKGROUND: Macrophage migration inhibitory factor (MIF) is an important mediator of neuropathology in various central nervous system (CNS) diseases. However, little is known about its inducers for production from the nerve cells, as well as the underlying regulatory mechanism. Injury-induced HIF-1α has been shown to exacerbate neuroinflammation by activating multiple downstream target molecules. It is postulated that HIF-1α is involved in the regulation of MIF following spinal cord injury (SCI). METHODS: SCI model of Sprague-Dawley rats was established by cord contusion at T8-T10. The dynamic changes of HIF-1α and MIF protein levels at lesion site of rat spinal cord were determined by Western blot. The specific cell types of HIF-1α and MIF expression were examined by immunostaining. Primary astrocytes were isolated from the spinal cord, cultured and stimulated with various agonist or inhibitor of HIF-1α for analysis of HIF-1α-mediated expression of MIF. Luciferase report assay was used to determine the relationship between HIF-1α and MIF. The Basso, Beattie, and Bresnahan (BBB) locomotor scale was used to assess the locomotor function following SCI. RESULTS: The protein levels of HIF-1α and MIF at lesion site were significantly elevated by SCI. Immunofluorescence demonstrated that both HIF-1α and MIF were abundantly expressed in the astrocytes of the spinal cord. By using various agonists or inhibitors of HIF-1α, it was shown that HIF-1α sufficiently induced astrocytic production of MIF. Mechanistically, HIF-1α promoted MIF expression through interaction with MIF promoter. Inhibition of HIF-1α activity using specific inhibitor markedly reduced the protein levels of MIF at lesion site following SCI, which in turn favored for the functional recovery. CONCLUSION: SCI-induced activation of HIF-1α is able to promote MIF production from astrocytes. Our results have provided new clues for SCI-induced production of DAMPs, which may be helpful for clinical treatment of neuroinflammation.
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Factores Inhibidores de la Migración de Macrófagos , Traumatismos de la Médula Espinal , Ratas , Animales , Ratas Sprague-Dawley , Factores Inhibidores de la Migración de Macrófagos/metabolismo , Factores Inhibidores de la Migración de Macrófagos/farmacología , Factores Inhibidores de la Migración de Macrófagos/uso terapéutico , Astrocitos/metabolismo , Enfermedades Neuroinflamatorias , Traumatismos de la Médula Espinal/patología , Médula Espinal/metabolismo , Recuperación de la FunciónRESUMEN
Xanthomonas oryzae pv. oryzae (Xoo) is a causative agent of rice bacterial blight (BB). In 2020-2022, BB re-emerged, and there was a break out in the Yangtze River area, China. The pandemic Xoo strain, LA20, was isolated and identified from cultivar Quanyou1606 and demonstrated to be the Chinese R9 Xoo strain, which is able to override the widely adopted xa5-, Xa7- and xa13-mediated resistance in rice varieties in Yangtze River. Here, we report the complete genome of LA20 by PacBio and Illumina sequencing. The assembled genome consists of one circular chromosome of 4,960,087 bp, sharing 99.65% sequence identity with the traditional representative strain, YC11 (R5), in the Yangtze River. Comparative genome analysis of LA20 and YC11 revealed the obvious variability in Tal genes (the uppermost virulence determinants) in numbers and sequences. Particularly, six Tal genes were only found in LA20, but not in YC11, among which Tal1b (pthXo1)/Tal4 (pthXo6), along with the lost one, pthXo3 (avrXa7), might be the major factors for LA20 to overcome xa5-, Xa7- and xa13-mediated resistance, thus, leading to the resurgence of BB. This complete genome of the new pandemic Xoo strain will provide novel insights into pathogen evolution, the traits of pathogenicity on genomic level and the epidemic disease status in China.
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Oryza , Xanthomonas , Oryza/genética , Ríos , Factores de Virulencia/genética , Xanthomonas/genética , Genómica , Enfermedades de las Plantas/microbiologíaRESUMEN
AIMS: Gecko, the "sky dragon" named by Traditional Chinese Medicine, undergoes rapid coagulation and scarless regeneration following tail amputation in the natural ecology, providing a perfect opportunity to develop the efficient and safe drug for blood clotting. Here, gecko thrombin (gthrombin) was recombinantly prepared and comparatively studied on its procoagulant activity. METHODS: The 3D structure of gthrombin was constructed using the homology modeling method of I-TASSER. The active gthrombin was prepared by the expression of gecko prethrombin-2 in 293 T cells, followed by purification with Ni2+ -chelating column chromatography prior to activation by snake venom-derived Ecarin. The enzymatic activities of gthrombin were assayed by hydrolysis of synthetic substrate S-2238 and the fibrinogen clotting. The vulnerable nerve cells were used to evaluate the toxicity of gthrombin at molecular and cellular levels. RESULTS: The active recombinant gthrombin showed super-high catalytic and fibrinogenolytic efficiency than those of human under different temperatures and pH conditions. In addition, gthrombin made nontoxic effects on the central nerve cells including neurons, contrary to those of mammalian counterparts, which contribute to neuronal damage, astrogliosis, and demyelination. CONCLUSIONS: A super-high activity but safe procoagulant candidate drug was identified from reptiles, which provided a promising perspective for clinical application in rapid blood clotting.
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Lagartos , Trombina , Animales , Humanos , Trombina/farmacología , Trombina/metabolismo , Coagulación Sanguínea , Lagartos/metabolismo , Mamíferos/metabolismoRESUMEN
The low intrinsic growth capacity of neurons and an injury-induced inhibitory milieu are major contributors to the failure of sensory and motor functional recovery following spinal cord injury. Heat shock transcription factor 1 (HSF1), a master regulator of the heat shock response, plays neurogenetic and neuroprotective roles in the damaged or diseased central nervous system. However, the underlying mechanism has not been fully elucidated. In the present study, we used a gecko model of spontaneous nerve regeneration to investigate the potential roles of gecko HSF1 (gHSF1) in the regulation of neurite outgrowth and inflammatory inhibition of macrophages following spinal cord injury. gHSF1 expression in neurons and microglia at the lesion site increased dramatically immediately after tail amputation. gHSF1 overexpression in gecko primary neurons significantly promoted axonal growth by suppressing the expression of suppressor of cytokine signaling-3, and facilitated neuronal survival via activation of the mitogen-activated extracellular signal-regulated kinase/extracellular regulated protein kinases and phosphatidylinositol 3-kinase/protein kinase B pathways. Furthermore, gHSF1 efficiently inhibited the macrophage-mediated inflammatory response by inactivating IkappaB-alpha/NF-kappaB signaling. Our findings show that HSF1 plays dual roles in promoting axonal regrowth and inhibiting leukocyte inflammation, and provide new avenues of investigation for promoting spinal cord injury repair in mammals.
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BACKGROUND: The matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases that play a variety of physiological and pathological roles in development, remodeling of tissues and diseases, mainly through degradation of various components of the extracellular matrix (ECM). Particularly, the MMPs have increasingly been found to mediate neuropathology following spinal cord injury (SCI). Proinflammatory mediators are potent activators of the MMPs. However, how the spinal cord regenerative vertebrates circumvent MMPs-mediated neuropathogenesis following SCI remains unclear. METHODS: Following the establishment of gecko tail amputation model, the correlation of MMP-1 (gMMP-1) and MMP-3 (gMMP-3) expression with that of macrophage migration inhibitory factor in gecko (gMIF) was assayed by RT-PCR, Western blot and immunohistochemistry. Transcriptome sequencing of primary astrocytes was performed to analyze the intracellular signal transduction of macrophage migration inhibitory factor (MIF). The effects of MMP-1 and MMP-3 induced by MIF on astrocyte migration were assessed by transwell migration assay. RESULTS: The expression of gMIF significantly increased at lesion site of the injured cord, in parallel with those of gMMP-1 and gMMP-3 in the gecko astrocytes (gAS). Transcriptome sequencing and in vitro cell model revealed that gMIF efficiently promoted the expression of gMMP-1 and gMMP-3 in gAS, which in turn contributed to the migration of gAS. Inhibition of gMIF activity following gecko SCI remarkably attenuated astrocytic expression of the two MMPs, and further influenced gecko tail regeneration. CONCLUSIONS: Gecko SCI following tail amputation promoted production of gMIF, which induced the expression of gMMP-1 and gMMP-3 in gAS. The gMIF-mediated gMMP-1 and gMMP-3 expression was involved in gAS migration and successful tail regeneration.
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Lagartos , Factores Inhibidores de la Migración de Macrófagos , Traumatismos de la Médula Espinal , Animales , Factores Inhibidores de la Migración de Macrófagos/metabolismo , Factores Inhibidores de la Migración de Macrófagos/farmacología , Astrocitos/metabolismo , Metaloproteinasa 3 de la Matriz/metabolismo , Metaloproteinasa 3 de la Matriz/farmacología , Metaloproteinasa 1 de la Matriz/metabolismo , Metaloproteinasa 1 de la Matriz/farmacología , Médula Espinal/metabolismo , Traumatismos de la Médula Espinal/metabolismo , Lagartos/metabolismoRESUMEN
Deformation twinning merits attention because of its intrinsic importance as a mode of energy dissipation in solids. Herein, through the atomistic electron microscopy observations, the size-dependent twinning mechanisms in refractory body-centered cubic molybdenum nanocrystals (NCs) under tensile loading are shown. Two distinct twinning mechanisms involving the nucleation of coherent and inclined twin boundaries (TBs) are uncovered in NCs with smaller (diameter < ≈5 nm) and larger (diameter > ≈5 nm) diameters, respectively. Interestingly, the ultrahigh pseudo-elastic strain of ≈41% in sub-5 nm-sized crystals is achieved through the reversible twinning mechanism. A typical TB cross-transition mechanism is found to accommodate the NC re-orientation during the pseudo-elastic deformation. More importantly, the effects of different types of TBs on the electrical conductivity based on the repeatable experimental measurements and first-principles calculations are quantified. These size-dependent mechanical and electrical properties may prove essential in advancing the design of next-generation flexible nanoelectronics.
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Many coastal areas are hotspots of aquaculture expansion, where the overuse of artificial feeds results in the accumulation of organic carbon in nearshore aquaculture ponds. In rural areas, wastewater from the aquaculture ponds is discharged to the nearshore waters through artificial ditches causing lateral carbon export from the land to the ocean. Such flux may be meaningful in coastal carbon budgets since aquaculture is the hotspot of carbon sequestration and storage. To quantify the magnitude and temporal dynamics of lateral carbon export from aquaculture ponds, we used high-frequency in-situ monitoring of turbidity, fluorescent dissolved organic matter, etc. across different temporal scales. We measured water levels and velocity profiles in a ditch cross-section to obtain year-round water exchange. Carbon export was integrated from water fluxes and organic carbon concentrations. Our results suggested that aquaculture ponds were a source of particular organic carbon (POC) and dissolved organic carbon (DOC). The net lateral flux of POC and DOC was 148 ± 38 kg yr-1 and 296 ± 18 kg yr-1. Temporally, the export of POC and DOC is influenced by both tides and wastewater discharge. Under the disturbance with aquaculture wastewater discharge, the mean DOC export in the ditch increased by 497 kg, which was 1.5 times that of the undisturbed; the mean POC export increased by 190 kg, which was 1.8 times that of the undisturbed. Thus, aquaculture activities can considerably disturb the coastal carbon balance by facilitating carbon-rich fluid exchange from onshore farms to nearshore estuaries. As aquaculture expands across Asia and the globe, this study provides important insights into the impacts of aquaculture on coastal carbon budgets.
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Carbono , Monitoreo del Ambiente , Carbono/análisis , Estuarios , Acuicultura , AguaRESUMEN
Claudin-5 has recently attracted increasing attention by its potential as a novel treatment target in the early stage of heart failure. However, whether Claudin-5 produces beneficial effects on myocardial ischemia and reperfusion (IR) injury has not been elucidated yet. In this study, we identified reduced levels of Claudin-5 in the hearts of mice subjected to acute myocardial IR injury and murine HL-1 cardiomyocytes subjected to hypoxia and reoxygenation (HR). We then constructed cardiac-specific Cldn5-overexpressing mice using an adeno-associated virus (AAV9) vector and demonstrated that Cldn5 overexpression ameliorated cardiac dysfunction and myocardial damage in mice subjected to myocardial IR injury. Moreover, Cldn5 overexpression attenuated myocardial oxidative stress (DHE and protein levels of Nrf2, HO-1, and NQO1), inflammatory response (levels of MPO, F4/80, Ly6C, and circulating inflammatory cells), mitochondrial dysfunction (protein levels of PGC-1α, NRF1, and TFAM), endoplasmic reticulum stress (protein levels of GRP78, ATF6, and CHOP and p-PERK), energy metabolism disorder (p-AMPK and ACC), and apoptosis (TUNEL assay and protein levels of Bax and Bcl2) in mice subjected to myocardial IR. Next, we generated Cldn5 knockdown cells by lentiviral shRNA and observed that Cldn5 knockdown inhibited cell viability and affected the expression or activation of these IR-related signalings in HL-1 cardiomyocytes subjected to HR. Mechanistically, SIRT1 was proved to be involved in regulating the expression of Claudin-5 by co-immunoprecipitation analysis and Sirt1 knockdown experiments. Our data demonstrated that targeting Claudin-5 may represent a promising approach for preventing and treating acute myocardial IR injury.
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Claudina-5 , Isquemia Miocárdica , Daño por Reperfusión Miocárdica , Proteínas Quinasas Activadas por AMP/metabolismo , Animales , Claudina-5/genética , Claudina-5/metabolismo , Ratones , Isquemia Miocárdica/metabolismo , Daño por Reperfusión Miocárdica/genética , Daño por Reperfusión Miocárdica/metabolismo , Daño por Reperfusión Miocárdica/prevención & control , Miocitos Cardíacos/metabolismo , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , ARN Interferente Pequeño/metabolismo , Sirtuina 1/metabolismo , Proteína X Asociada a bcl-2/metabolismo , Proteína X Asociada a bcl-2/farmacologíaRESUMEN
Metal halide perovskites quantum dots (MHPQDs) have aroused enormous interest in the photovoltaic and photoelectric disciplines because of their marvelous properties and size characteristics. However, one of the key problems of how to systematically analyze charge carriers trapped by defects is still a challenging task. Here, we study multiphonon processes of the charge carrier trapping by various defects in MHPQDs based on the well-known Huang-Rhys model, in which a method of a full-configuration defect, including different defect species with variable depth and lattice relaxation strength, is developed by introducing a localization parameter in the quantum defect model. With the help of this method, these fast trapping channels for charge carriers transferring from the quantum dot ground state to different defects are found. Furthermore, the dependence of the trapping time on the radius of quantum dot, the defect depth, and temperature is given. These results not only enrich the knowledge of charge carrier trapping processes by defects, but also bring light to the designs of MHPQDs-based photovoltaic and photoelectric devices.
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Cardiac dysfunction resulting from sepsis causes high morbidity and mortality. Silibinin (SIL) is a secondary metabolite isolated from the seed extract of the milk thistle plant with various properties, including anti-inflammatory, anti-fibrotic, and anti-oxidative activities. This study, for the first time, examined the effects and mechanisms of SIL pretreatment, posttreatment and in combination with classical antibiotics in septic myocardial injury. The survival rate, sepsis score, anal temperature, routine blood parameters, blood biochemical parameters, cardiac function indicators, pathological indicators of myocardial injury, NR1H3 signaling pathway, and several sepsis-related signaling pathways were detected 8 h following cecal ligation and puncture (CLP). Our results showed that SIL pretreatment showed a significant protective effect on sepsis and septic myocardial injury, which was explained by the attenuation of inflammation, inhibition of oxidative stress, improvement of mitochondrial function, regulation of endoplasmic reticulum stress (ERS), and activation of the NR1H3 pathway. SIL posttreatment and the combination of SIL and azithromycin (AZI) showed a certain therapeutic effect. RNA-seq detection further clarified the myocardial protective mechanisms of SIL. Taken together, this study provides a theoretical basis for the application strategy and combination of SIL in septic myocardial injury.
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Lesiones Cardíacas , Sepsis , Estrés del Retículo Endoplásmico , Lesiones Cardíacas/patología , Humanos , Receptores X del Hígado/metabolismo , Miocardio/metabolismo , Sepsis/complicaciones , Silibina/metabolismo , Silibina/farmacología , Silibina/uso terapéuticoRESUMEN
BACKGROUND: The danger-associated molecular patterns (DAMPs) are critical contributors to the progressive neuropathology and thereafter affect the functional outcomes following spinal cord injury (SCI). Up to now, the regulatory mechanisms on their inducible production from the living cells remain elusive, aside from their passive release from the necrotic cells. Thrombin is immediately activated by the damaged or stressed central nervous system (CNS), which potently mediates inflammatory astrocytic responses through proteolytic cleavage of protease-activated receptors (PARs). Therefore, SCI-activated thrombin is conceived to induce the production of DAMPs from astrocytes at lesion site. METHODS: Rat SCI model was established by the cord contusion at T8-T10. The expression of thrombin and macrophage migration inhibitory factor (MIF) was determined by ELISA and Western blot. The PAR1, PAR3, and PAR4 receptors of thrombin were examined by PCR and immunohistochemistry. Primary astrocytes were isolated and purified from the spinal cord, followed by stimulation with different concentrations of thrombin either for transcriptome sequencing or for analysis of thrombin-mediated expression of MIF and related signal pathways in the presence or absence of various inhibitors. The post-injury locomotor functions were assessed using the Basso, Beattie, and Bresnahan (BBB) locomotor scale. RESULTS: MIF protein levels were significantly elevated in parallel with those of thrombin induced by SCI. Immunostaining demonstrated that PAR1 receptor, together with MIF, was abundantly expressed in astrocytes. By transcriptome sequencing and bioinformatical analysis of thrombin-stimulated primary astrocytes, MIF was identified to be dynamically regulated by the serine protease. Investigation of the underlying mechanism using various inhibitors revealed that thrombin-activated PAR1 was responsible for the MIF production of astrocytes through modulation of JNK/NFκB pathway. Administration of PAR1 inhibitor at lesion sites following SCI significantly reduced the protein levels of MIF and ameliorated functional deficits of rat locomotion. CONCLUSION: SCI-activated thrombin is a robust inducer of MIF production from astrocytes. Exploring the roles of thrombin in promoting the production of DAMPs from astrocytes at lesion site will provide an alternative strategy for the clinical therapy of CNS inflammation.
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Factores Inhibidores de la Migración de Macrófagos , Traumatismos de la Médula Espinal , Animales , Astrocitos/metabolismo , Factores Inhibidores de la Migración de Macrófagos/farmacología , Ratas , Receptor PAR-1/metabolismo , Traumatismos de la Médula Espinal/metabolismo , Trombina/metabolismo , Trombina/farmacologíaRESUMEN
Aging-related diseases such as cancer, cardiovascular diseases, diabetes, and neurodegenerative diseases are often accompanied by fibrosis. The NLRP3 inflammasome triggers the inflammatory response and subsequently promotes fibrosis through pathogen-associated molecular patterns (PAMPs). In this review, we first introduce the general background and specific mechanism of NLRP3 in fibrosis. Second, we investigate the role of NLRP3 in fibrosis in different organs/tissues. Third, we discuss the relationship between NLRP3 and fibrosis during aging. In summary, this review describes the latest progress on the roles of NLRP3 in fibrosis and aging and reveals the possibility of NLRP3 as an antifibrotic and anti-aging treatment target.