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The PALB2 tumor suppressor plays key roles in DNA repair and has been implicated in redox homeostasis. Autophagy maintains mitochondrial quality, mitigates oxidative stress and suppresses neurodegeneration. Here we show that Palb2 deletion in the mouse brain leads to mild motor deficits and that co-deletion of Palb2 with the essential autophagy gene Atg7 accelerates and exacerbates neurodegeneration induced by ATG7 loss. Palb2 deletion leads to elevated DNA damage, oxidative stress and mitochondrial markers, especially in Purkinje cells, and co-deletion of Palb2 and Atg7 results in accelerated Purkinje cell loss. Further analyses suggest that the accelerated Purkinje cell loss and severe neurodegeneration in the double deletion mice are due to excessive oxidative stress and mitochondrial dysfunction, rather than DNA damage, and partially dependent on p53 activity. Our studies uncover a role of PALB2 in mitochondrial homeostasis and a cooperation between PALB2 and ATG7/autophagy in maintaining redox and mitochondrial homeostasis essential for neuronal survival.
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Autofagia , Mitocondrias , Animales , Autofagia/genética , Proteína 7 Relacionada con la Autofagia/genética , Encéfalo/metabolismo , Proteína del Grupo de Complementación N de la Anemia de Fanconi , Homeostasis/genética , Ratones , Mitocondrias/genética , Mitocondrias/metabolismo , Oxidación-ReducciónRESUMEN
Identifying the health risk of PM2.5 is essential for urban air pollution control. In 2013, China announced the ever-strict national Air Pollution Prevention and Control Action Plan, and its health benefit should be evaluated to provide reference for future policymaking. In this study, we conducted a seven-year (2014-2020) continuous observation of PM2.5 in Shenzhen, the third largest city in China, which has relatively good air quality. The results showed that the annual mean PM2.5 and total concentration of 21 associated metals dropped from 37.7 to 18.5 µg/m3 and from 2.4 to 1.1 µg/m3, respectively. Combining methods for source apportionment and health risk assessment, we found that the total carcinogenic risk (CR) of five hazardous metals (Cd, Cr, Ni, Co, and Pb) showed a clear decreasing trend. However, the total CR (1.8 × 10-6) in 2020 still exceeded the widely acceptable risk level (i.e., 1 × 10-6), with the primary contributor changing from industrial emissions (61%) to vehicle emissions (63%). Further analysis indicated that the CR of vehicles mainly came from Cr and Ni released by braking and tire wearing and has fluctuated in recent years, highlighting a great challenge of controlling nonexhaust emissions of vehicles (including electric cars) in the future.
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Contaminantes Atmosféricos , Contaminación del Aire , Metales Pesados , Contaminantes Atmosféricos/análisis , Contaminación del Aire/análisis , Carcinógenos , China , Monitoreo del Ambiente/métodos , Metales/análisis , Material Particulado/análisis , Medición de Riesgo , Emisiones de Vehículos/análisisRESUMEN
The inherent features of covalent organic frameworks (COFs) make them highly attractive for uranium recovery applications. A key aspect yet to be explored is how to improve the selectivity and efficiency of COFs for recovering uranium from seawater. To achieve this goal, a series of robust and hydrophilic benzoxazole-based COFs is developed (denoted as Tp-DBD, Bd-DBD, and Hb-DBD) as efficient adsorbents for photo-enhanced targeted uranium recovery. Benefiting from the hydroxyl groups and the formation of benzoxazole rings, the hydrophilic Tp-DBD shows outstanding stability and chemical reduction properties. Meanwhile, the synergistic effect of the hydroxyl groups and the benzoxazole rings in the π-conjugated frameworks significantly decrease the optical band gap, and improve the affinity and capacity to uranium recovery. In seawater, the adsorption capacity of uranium is 19.2× that of vanadium, a main interfering metal in uranium extraction.
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Hyperphosphorylated α-synuclein in Lewy bodies and Lewy neurites is a characteristic neuropathological feature of Parkinson's disease (PD) and Dementia with Lewy bodies (DLB). The catalytic subunit of the specific phosphatase, protein phosphatase 2A (PP2A) that dephosphorylates α-synuclein, is hypomethylated in these brains, thereby impeding the assembly of the active trimeric holoenzyme and reducing phosphatase activity. This phosphatase deficiency contributes to the accumulation of hyperphosphorylated α-synuclein, which tends to fibrillize more than unmodified α-synuclein. Eicosanoyl-5-hydroxytryptamide (EHT), a fatty acid derivative of serotonin found in coffee, inhibits the PP2A methylesterase so as to maintain PP2A in a highly active methylated state and mitigates the phenotype of α-synuclein transgenic (SynTg) mice. Considering epidemiologic and experimental evidence suggesting protective effects of caffeine in PD, we sought, in the present study, to test whether there is synergy between EHT and caffeine in models of α-synucleinopathy. Coadministration of these two compounds orally for 6 mo at doses that were individually ineffective in SynTg mice and in a striatal α-synuclein preformed fibril inoculation model resulted in reduced accumulation of phosphorylated α-synuclein, preserved neuronal integrity and function, diminished neuroinflammation, and improved behavioral performance. These indices were associated with increased levels of methylated PP2A in brain tissue. A similar profile of greater PP2A methylation and cytoprotection was found in SH-SY5Y cells cotreated with EHT and caffeine, but not with each compound alone. These findings suggest that these two components of coffee have synergistic effects in protecting the brain against α-synuclein-mediated toxicity through maintenance of PP2A in an active state.
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Cafeína/farmacología , Café/química , Enfermedad por Cuerpos de Lewy/metabolismo , Neuroprotección/efectos de los fármacos , Enfermedad de Parkinson/metabolismo , Serotonina/análogos & derivados , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/patología , Modelos Animales de Enfermedad , Ácidos Grasos/metabolismo , Enfermedad por Cuerpos de Lewy/tratamiento farmacológico , Enfermedad por Cuerpos de Lewy/patología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuronas/patología , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/patología , Fosforilación , Proteína Fosfatasa 2/metabolismo , Serotonina/farmacología , alfa-Sinucleína/metabolismoRESUMEN
In this paper, we present the results of applying an electric field to activate bubbles' escape, coalescence, and departure. A simple electrowetting-on-dielectric device was utilized in this bubble dynamics study. When a copper electrode wire inserted into deionized water was positioned on one side of single or multiple bubbles, the bubble tended to continuously escape from its initial position as the voltage was turned on. Contact angle imbalance at different sides of the bubble was observed, which further promoted the bubble's escape. An analysis model with an electromechanical framework was developed to study the charging time difference on two sides of the bubble, which generated a wettability gradient and capillary force to propel it away from the electrode. Sine, ramp, and square alternating current waveforms with 60 V amplitude and 2 Hz frequency were tested for comparison. It was shown that all waveforms promoted the bubble's escape; the square wave shape manifested the farthest escape capability, followed by sine and ramp waves. An upper view of several bubbles aligning in triangle, square, pentagon, and hexagon shapes demonstrated that the bubbles tended to move outward when the electrode is placed at the geometric centers. Experiments with an electrode on one side and several bubbles positioned in a line were conducted. In these cases, the bubbles closer to the electrode reacted faster than those farther from the electrode, resulting in coalescence. Once the bubble size became larger, it departed either by overcoming the disjoining pressure in a thin film of water or via the buoyancy force in a thick film of water. Controlling bubble dynamics by the electric field, including escape, coalescence, and departure provides an active and reversible approach to move bubbles or increase departure frequency in many fluid mechanics and heat transfer studies.
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Uranium is a key resource for the development of the nuclear industry, and extracting uranium from the natural seawater is one of the most promising ways to address the shortage of uranium resources. Herein, a semiconducting covalent organic framework (named NDA-TN-AO) with excellent photocatalytic and photoelectric activities was synthesized. The excellent photocatalytic effect endowed NDA-TN-AO with a high anti-biofouling activity by generating biotoxic reactive oxygen species and promoting photoelectrons to reduce the adsorbed UVI to insoluble UIV , thereby increasing the uranium extraction capacity. Owing to the photoinduced effect, the adsorption capacity of NDA-TN-AO to uranium in seawater reaches 6.07â mg g-1 , which is 1.33 times of that in dark. The NDA-TN-AO with enhanced adsorption capacity is a promising material for extracting uranium from the natural seawater.
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Acid sphingomyelinase (ASM) is a membrane lipid hydrolase, acting to generate ceramide and regulate cell functions and inflammatory responses.The roles of ASM in mediating T cell functions are postulated whereas its function in regulation of macrophages remains uncertain. The study was performed to explore ASM activity in control of macrophage functions. RAW 264.7 cells were pretreated with desipramine, an ASM inhibitor, prior to LPS challenge in vitro. LPS initiated ASM activity in RAW 264.7 cells. Conversely, inhibition of ASM activity by desipramine diminished LPS induced ASM activities and TNF production of RAW 264.7 cells. The DSS colitis in mice was induced, and desipramine was administered to the mice two days post induction of colitis. Murine colitis was characterized by elevation of ASM activities in colon tissues. Desipramine administration overrode ASM activities in colon, and ameliorated DSS-induced colitis evidenced with the reduced disease activities and the decreased cytokine levels. Together, our data show a crucial role of ASM activity in regulation of macrophage functions and responses, and suggest that ASM represents a novel therapeutic approach for the management of immune diseases.
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Colitis/inducido químicamente , Colitis/enzimología , Sulfato de Dextran/farmacología , Inhibidores Enzimáticos/farmacología , Esfingomielina Fosfodiesterasa/antagonistas & inhibidores , Animales , Colitis/tratamiento farmacológico , Colitis/inmunología , Colon/efectos de los fármacos , Colon/inmunología , Citocinas/metabolismo , Inhibidores Enzimáticos/uso terapéutico , Femenino , Inmunidad Innata/efectos de los fármacos , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Ratones , Ratones Endogámicos C57BL , Células RAW 264.7RESUMEN
Aggregation-induced emission has been extensively found in organic compounds and metal complexes. In contrast, aggregation-induced electrochemiluminescence (AI-ECL) is rarely observed. Here, we employ two tridentate ligands [2,2':6',2â³-terpyridine (tpy) and 1,3-bis(1 H-benzimidazol-2-yl)benzene (bbbiH3)] to construct a cyclometalated iridium(III) complex, [Ir(tpy)(bbbi)] (1), showing strong AI-ECL. Its crystal structure indicates that neighboring [Ir(tpy)(bbbi)] molecules are connected through both π-π-stacking interactions and hydrogen bonds. These supramolecular interactions can facilitate the self-assembly of complex 1 into nanoparticles in an aqueous solution. The efficient restriction of molecular vibration in these nanoparticles leads to strong AI-ECL emission of complex 1. In a dimethyl sulfoxide-water (H2O) mixture with a gradual increase in the H2O fraction from 20% to 98%, complex 1 showed a â¼39-fold increase in the electrochemiluminescence (ECL) intensity, which was â¼4.04 times as high as that of [Ru(bpy)3]2+ under the same experimental conditions. Moreover, the binding of bovine serum albumin to the nanoparticles of complex 1 can improve the ECL emission of this complex, facilitating the understanding of the mechanism of AI-ECL for future applications.
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Objective: To understand the control status of malaria at hotspots in Yingjiang County and provide measures for malaria elimination in the China-Myanmar border areas of Yunnan Province. Methods: A survey was made in 4 villages with indigenous malaria cases or imported cases in Nabang and Tongbiguan of Yingjiang County in Yunnan Province in June and July 2015. Peripheral blood samples were collected from the neighboring residents around patients and examined by malaria rapid diagnostic test ï¼RDTï¼. The results were further verified by nested-PCR. Mosquitoes were collected by overnight trapping with light traps in Jingpo, Lilisu, Jiema, and Mengxiangyang villages or by human landing catches in Jingpo and Lisu villages. Nested-PCR was performed on part of the captured Anopheles minimus to detect the malaria parasites. Results: One hundred and ninety-four filter blood samples were collected from 11 malaria cases in two sites. All were detected to be negative for Plasmodium by RDT. In contrast, two samples originated from Jingpo and Lisu villages with indigenous cases were detected to be positive for Plasmodium vivax by nested-PCR. A total of 2 374 mosquitoes were captured, belonging to 22 species of 4 genera: Anopheles, Culex, Aedes and Armigeres. The mosquitoes were predominated by genus Culex, followed by genus Anophelesï¼11.33%, 269/2 374ï¼ which was dominated by A. minimusï¼49.07%, 132/269ï¼, then was A. sinensisï¼4.09%, 11/269ï¼, A. maculatusï¼2.23%, 6/269ï¼, A. jeyporiensisï¼0.74%, 2/269ï¼and so on. The mean indoor man-biting rate of mosquitoes was 5.78 and 3.20 per person per hour for Jingpo and Lisu villages, and the mean outdoor man-biting rate of mosquitoes was 2.30 per person per hour for Lisu Village. The 14 A. minimus were negative for sporozoite infection as detected by nested-PCR. Conclusion: Nested-PCR showed that there are asymptomatic Plasmodium carriers in Yingjiang's border area of Yunnan Province. Four major mosquito species as malaria vectors exist with A. minimus as the dominant one.
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Malaria , Animales , Anopheles , China , Ambiente , Humanos , Mosquitos Vectores , Plasmodium , Reacción en Cadena de la Polimerasa , Encuestas y CuestionariosRESUMEN
Eight previously undescribed diterpenoids, caesamins A-H (1-8), were separated and identified from the seeds of Caesalpinia minax Hance. Their structures were characterized by extensive spectroscopic data and X-ray crystallographic analysis. Structurally, caesamin A (1) is the first cassane-type diterpenoid with a C23 carbon skeleton containing an unusual isopropyl. Caesamin F (6) represents the first example of cleistanthane diterpenoid from the genus Caesalpinia. Caesamins B (2) and F (6) exhibited inhibitory activity against LPS-induced nitric oxide production in RAW 264.7 macrophages with IC50 values of 45.67 ± 0.92 and 42.99 ± 0.24 µM, comparable to positive control 43.69 ± 2.62 µM of NG-Monomethyl-L-arginine. Furthermore, the chemotaxonomic significance of the isolates was discussed.
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Caesalpinia , Diterpenos , Óxido Nítrico , Semillas , Caesalpinia/química , Diterpenos/química , Diterpenos/farmacología , Diterpenos/aislamiento & purificación , Ratones , Semillas/química , Animales , Células RAW 264.7 , Óxido Nítrico/antagonistas & inhibidores , Óxido Nítrico/biosíntesis , Estructura Molecular , Lipopolisacáridos/farmacología , Lipopolisacáridos/antagonistas & inhibidores , Macrófagos/efectos de los fármacos , Relación Estructura-Actividad , Relación Dosis-Respuesta a DrogaRESUMEN
Three undescribed cassane diterpenoids, caesalpanins D-F (1-3), and seven known ones were isolated from the seeds of Caesalpinia sappan. Structures and absolute configurations of 1-3 were elucidated based on the extensive spectroscopic analysis, single-crystal X-ray diffraction analysis, and ECD calculations. Structurally, compound 1 was the first example of 18-norcassane diterpenoid and 2 was a rare 20-norcassane diterpenoid having an unusual five-membered oxygen bridge between C-10/C-18. The anti-proliferative activity of 1, 3, and 4-10 against PANC-1 cells (pancreatic ductal adenocarcinoma cell line) was evaluated, and phanginin H (4) was found to exhibit anti-cancer activity with IC50 value of 18.13 ± 0.63 µM. Compound 4 inhibited PANC-1 cell growth by arresting the cell cycle at G2/M phase via regulation of cyclin-dependent kinases, and the self-renewal and metastasis of PANC-1 cells by suppressing cancer cell stemness. Furthermore, compound 4 induced ROS generation and subsequently activated autophagy, which was demonstrated by the formation of autophagic vacuoles and dynamic change of autophagic flux. The induced ROS accumulation resulted in AMPK activation and subsequently regulation of mTORC1 activity and ULK phosphorylation, indicating that 4 triggered autophagy through ROS/AMPK/mTORC1 pathway. These findings suggested that 4 might potentially be an autophagy inducer for the therapy of pancreatic cancer.
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Proteínas Quinasas Activadas por AMP , Antineoplásicos Fitogénicos , Autofagia , Caesalpinia , Proliferación Celular , Diterpenos , Ensayos de Selección de Medicamentos Antitumorales , Diana Mecanicista del Complejo 1 de la Rapamicina , Neoplasias Pancreáticas , Especies Reactivas de Oxígeno , Semillas , Caesalpinia/química , Humanos , Diterpenos/farmacología , Diterpenos/química , Diterpenos/aislamiento & purificación , Semillas/química , Autofagia/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/metabolismo , Proteínas Quinasas Activadas por AMP/metabolismo , Antineoplásicos Fitogénicos/farmacología , Antineoplásicos Fitogénicos/aislamiento & purificación , Antineoplásicos Fitogénicos/química , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Diana Mecanicista del Complejo 1 de la Rapamicina/antagonistas & inhibidores , Proliferación Celular/efectos de los fármacos , Estructura Molecular , Línea Celular Tumoral , Relación Estructura-Actividad , Relación Dosis-Respuesta a DrogaRESUMEN
Background: Extracellular cold-inducible RNA-binding protein (eCIRP) plays a vital role in the inflammatory response during cerebral ischaemia. However, the potential role and regulatory mechanism of eCIRP in traumatic brain injury (TBI) remain unclear. Here, we explored the effect of eCIRP on the development of TBI using a neural-specific CIRP knockout (KO) mouse model to determine the contribution of eCIRP to TBI-induced neuronal injury and to discover novel therapeutic targets for TBI. Methods: TBI animal models were generated in mice using the fluid percussion injury method. Microglia or neuron lines were subjected to different drug interventions. Histological and functional changes were observed by immunofluorescence and neurobehavioural testing. Apoptosis was examined by a TdT-mediated dUTP nick end labelling assay in vivo or by an annexin-V assay in vitro. Ultrastructural alterations in the cells were examined via electron microscopy. Tissue acetylation alterations were identified by non-labelled quantitative acetylation via proteomics. Protein or mRNA expression in cells and tissues was determined by western blot analysis or real-time quantitative polymerase chain reaction. The levels of inflammatory cytokines and mediators in the serum and supernatants were measured via enzyme-linked immunoassay. Results: There were closely positive correlations between eCIRP and inflammatory mediators, and between eCIRP and TBI markers in human and mouse serum. Neural-specific eCIRP KO decreased hemispheric volume loss and neuronal apoptosis and alleviated glial cell activation and neurological function damage after TBI. In contrast, eCIRP treatment resulted in endoplasmic reticulum disruption and ER stress (ERS)-related death of neurons and enhanced inflammatory mediators by glial cells. Mechanistically, we noted that eCIRP-induced neural apoptosis was associated with the activation of the protein kinase RNA-like ER kinase-activating transcription factor 4 (ATF4)-C/EBP homologous protein signalling pathway, and that eCIRP-induced microglial inflammation was associated with histone H3 acetylation and the α7 nicotinic acetylcholine receptor. Conclusions: These results suggest that TBI obviously enhances the secretion of eCIRP, thereby resulting in neural damage and inflammation in TBI. eCIRP may be a biomarker of TBI that can mediate the apoptosis of neuronal cells through the ERS apoptotic pathway and regulate the inflammatory response of microglia via histone modification.
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PURPOSE: Previous studies showed that chick retinal pigment epithelium (RPE) cells can be reprogrammed by a specific gene to take on the path of photoreceptor differentiation. In this study, we tested whether this reprogramming scheme could be applied to mammalian RPE cells. METHODS: Human RPE cell lines ARPE-19, a spontaneously transformed line of RPE cells derived from a 19-year-old person, and hTERT-RPE1, a telomerase-immortalized RPE cell line derived from a 1-year-old person, were commercially obtained and cultured as recommended. Primary RPE cell cultures were established using RPE isolated from 3- to 6-month-old pig and postnatal day 5 mouse. Cultured cells were transduced with a virus expressing neuroD, neurogenin1 (ngn1), or ngn3, basic helix-loop-helix (bHLH) genes previously identified as capable of inducing RPE-to-photoreceptor reprogramming in the chick system. Alternatively, cells in the culture were transfected chemically or physically through electroporation with vector DNA expressing one of the three genes. The cultures were then analyzed for RPE-to-photoreceptor reprogramming with in situ hybridization and/or immunostaining for photoreceptor gene expression. RESULTS: Both hTERT-RPE1 and ARPE-19 cultures gave rise to cells bearing markers of photoreceptors after transduction or transfection with vehicles expressing neuroD or ngn1. The new cells expressed genes encoding photoreceptor proteins, including interphotoreceptor retinoid-binding protein IRBP), recoverin, retinal cone arrestin 3, transducin α-subunit, Cone-rod homeobox protein (Crx), and red opsin. They displayed morphologies resembling differentiating photoreceptor cells. In primary porcine and mouse RPE cell cultures, transduction with lenti virus (Lvx-IRES-ZsGreen1) expressing ngn1 or ngn3 resulted in the emergence of ZsGreen1+ cells that exhibited morphologies reminiscent of differentiating photoreceptor cells. Immunochemistry showed that some ZsGreen1+ cells were positive for neural marker microtubule-associated protein 2 (Map2) and photoreceptor hallmark proteins red opsin and rhodopsin. CONCLUSIONS: The results suggest that cells in human RPE cell lines and in primary cultures of porcine and mouse RPE respond to gene-induced reprogramming by giving rise to photoreceptor-like cells. The responsiveness of primary RPE cells, especially those from porcine cells, enhances the biologic feasibility of exploring RPE-to-photoreceptor reprogramming for in situ mammalian photoreceptor replacement without cell transplantation.
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Reprogramación Celular , Células Epiteliales/citología , Mamíferos/metabolismo , Células Fotorreceptoras de Vertebrados/citología , Epitelio Pigmentado de la Retina/citología , Animales , Animales Recién Nacidos , Células Cultivadas , Células Epiteliales/metabolismo , Regulación de la Expresión Génica , Proteínas Fluorescentes Verdes/metabolismo , Humanos , Ratones , Células Fotorreceptoras de Vertebrados/metabolismo , Retroviridae/metabolismo , Sus scrofa , Telomerasa/metabolismo , Transfección , Adulto JovenRESUMEN
OBJECTIVE: To study the effect of intracellular reactive oxygen species (ROS) levels on T cell activation and apoptosis of synovial cells in collagen induced arthritis (CIA) rats, and to explore the mechanism of Fengshining Capsule (FSN) in the treatment of rheumatoid arthritis (RA). METHODS: Sixty rats were randomly divided into the normal control group, the CIA model group, the Tripterygium Poly-glycoside Tablet (TPT) group, the low dose FSN group (at the daily dose of 0.33 g/kg), the middle dose FSN group (at the daily dose of 0.66 g/kg), and the high dose FSN group (at the daily dose of 1.32 g/kg), 10 in each group. T lymphocyte subsets were detected by flow cytometry. The content of interferon-gamma (IFN-gamma) and interleukin-4 (IL-4) in plasma of rats were detected by ELISA. Its expression of hydroxyl radicals was detected by ultraviolet spectrophotometry. Caspase-3 and Caspase-9 protein expressions were measured by Western blot. RESULTS: Compared with the CIA model group, the levels of ROS were elevated in each dose FSN group (P < 0.01). The level of CD4+ / CD8 was significantly reduced in the middle dose FSN group (P < 0.01). The content of IFN-gamma was obviously lowered in each dose FSN group (P < 0.01), while that of IL-4 was obviously elevated in the high dose FSN group (P < 0.01). Meanwhile, the expression of Caspase-9 and Caspase-3 significantly increased in each dose FSN group (P < 0.05). Besides, the average gray scale of Caspase-9 was significantly higher in the low and middle FSN groups than in the TPT group (P < 0.05, P < 0.01). CONCLUSION: The mechanism of FSN for regulating the immune hyperfunction and inhibiting the proliferation of synovial cells in CIA rats might be associated with up-regulating in vivo ROS levels.
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Apoptosis/efectos de los fármacos , Artritis Reumatoide/metabolismo , Medicamentos Herbarios Chinos/farmacología , Activación de Linfocitos/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Linfocitos T/metabolismo , Animales , Caspasa 3/metabolismo , Caspasa 9/metabolismo , Interferón gamma/sangre , Interleucina-4/sangre , Masculino , Ratas , Ratas Sprague-Dawley , Membrana Sinovial/citología , Membrana Sinovial/patología , Linfocitos T/efectos de los fármacosRESUMEN
Lupus nephritis (LN) is a major cause death in patients with systemic lupus erythematosus. We aimed to find the differentially expressed genes (DEGs) in LN and confirm the regulatory mechanism on LN. The mouse model of LN was constructed by subcutaneous injection of pristane. RNA-seq screened 392 up-regulated and 447 down-regulated DEGs in LN mouse model, and KEGG analysis found that the top 20 DEGs were enriched in arachidonic acid metabolism, tryptophan metabolism, etc. The hub genes, Kynu, Spidr, Gbp3, Cbr1, Cyp4b1, and Cndp2 were identified, in which Gbp3 was selected for following study. Afterwards, the function of Gbp3 on the proliferation, inflammation, and pyroptosis of LN was verified by CCK-8, ELISA, and WB in vitro. The results demonstrated that si-Gbp3 promoted cell proliferation and inhibited the levels of inflammatory factors (IL-1ß, TNF-α and IL-8) and pyroptosis-related proteins (GSDMD, Caspase-1 and NLRP3) in a cell model of LN. In constrast, Gbp3 overexpression played an opposite role. In summary, Gbp3 promoted the progression of LN via inhibiting cell proliferation and facilitating inflammation and pyroptosis.
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Lupus Eritematoso Sistémico , Nefritis Lúpica , Animales , Ratones , Nefritis Lúpica/genética , Piroptosis , Inflamación/genética , Proliferación Celular , Modelos Animales de Enfermedad , Proteínas de Unión al GTPRESUMEN
Spinal cord injury (SCI) often leads to physical limitations, persistent pain, and major lifestyle shifts, enhancing the likelihood of prolonged psychological stress and associated disorders such as anxiety and depression. The mechanisms linking stress with regeneration remain elusive, despite understanding the detrimental impact of chronic stress on SCI recovery. In this study, we investigated the effect of chronic stress on primary sensory axon regeneration using a preconditioning lesions mouse model. Our data revealed that chronic stress-induced mitochondrial cristae loss and a decrease in oxidative phosphorylation (OXPHOS) within primary sensory neurons, impeding central axon regrowth. Corticosterone, a stress hormone, emerged as a pivotal player in this process, affecting satellite glial cells by reducing Kir4.1 expression. This led to increased neuronal hyperactivity and reactive oxygen species levels, which, in turn, deformed mitochondrial cristae and impaired OXPHOS, crucial for axonal regeneration. Our study underscores the need to manage psychological stress in patients with SCI for effective sensory-motor rehabilitation.
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Axones , Traumatismos de la Médula Espinal , Humanos , Ratones , Animales , Axones/metabolismo , Regeneración Nerviosa/fisiología , Fosforilación Oxidativa , Neuronas/metabolismo , Traumatismos de la Médula Espinal/patologíaRESUMEN
INTRODUCTION: Rheumatoid arthritis (RA) is a systemic chronic autoimmune disease in adults that is associated with significant joint issues and systemic inflammation. One of the signs of bone damage in RA is osteoporosis (OP). Leptin is an inflammatory protein that has been reported to be related to RA. The potential relationships among leptin, disease activity, and OP in Chinese patients with RA are not well known. METHODS: In total, 245 patients with RA and 120 healthy controls were included in this study. Detailed data on the clinical characteristics and laboratory features were collected. Information about physical activity and functional status was recorded using specific questionnaires. Bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry (DXA). The MECALL castor-50-hf model X-ray scanner was used for the two-hand (including wrist) photographs. RESULTS: Serum leptin levels differed significantly between the RA group and healthy control subjects (1.27/3.29 vs. 0.17/0.24, Z=13.29, P<0.001). The positive rate of leptin protein in RA patients was 86.35%, which was higher than that in controls (19.55%) (χ2=28.51, P<0.001). Pearson's correlation test showed that morning stiffness, disease duration, joint swelling, joint tenderness, swollen joint count (SJC), tender joint count (TJC), health assessment questionnaire (HAQ) score, and Sharp-van der Heijde method (Sharp) score were positively correlated with the level of serum leptin (r=0.212, r=0.312, r=0.322, r=0.501, r=0.291, r=0.334, P<0.05). There was a clear increasing trend in the level of serum leptin according to the different disease activity scores and in the 28 joint activity (DAS28) groups (F=13.936, P<0.001). Elevated leptin was a risk factor for increased disease activity and OP according to logistic regression analysis. The median leptin level differed significantly between the normal bone mass group, osteopenia group, and OP group (P<0.001). An increased serum leptin level was a risk factor for RA-induced osteoporosis according to logistic regression analysis (P<0.001). CONCLUSION: These results suggest that the level of serum leptin is associated with disease activity and secondary OP among Chinese patients with RA. Key Points ⢠Serum leptin levels in RA patients are higher than those in normal control group. ⢠Leptin was associated with disease activity. ⢠Leptin was associated with the occurrence of systemic osteoporosis and affects bone erosion in RA patients.
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Artritis Reumatoide , Leptina , Osteoporosis , Adulto , Humanos , Absorciometría de Fotón , Artritis Reumatoide/complicaciones , Densidad Ósea , Pueblos del Este de Asia , Leptina/sangre , Osteoporosis/complicacionesRESUMEN
In this work, we consider the inelastic scattering of incident electrons as a key process for analyzing the significant differences in secondary electron (SE) emission between diamond and graphite. Dielectric functions and energy- and momentum-dependent energy loss functions were obtained by first-principle calculations. These were then used to calculate the inelastic mean free path (IMFP) and stopping power in different directions. The results show that the properties of diamond are very close in different directions, and its IMFP is lower than that of graphite when the electron energy is higher than 30 eV. In graphite, the incident electrons may exhibit directional preferences in their motion. These results indicate that, in graphite, SEs are excited in deeper positions than in diamond, and more SEs move in a horizontal direction than in a vertical direction, which leads to the difference in secondary electron yield (SEY).
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Sepsis-associated encephalopathy (SAE), the most popular cause of coma in the intensive care unit (ICU), is the diffuse cerebral damage caused by the septic challenge. SAE is closely related to high mortality and extended cognitive impairment in patients in septic shock. At present, many studies have demonstrated that SAE might be mainly associated with blood-brain barrier damage, abnormal neurotransmitter secretion, oxidative stress, and neuroimmune dysfunction. Nevertheless, the precise mechanism which initiates SAE and contributes to the long-term cognitive impairment remains largely unknown. Recently, a growing body of evidence has indicated that there is close crosstalk between SAE and peripheral immunity. The excessive migration of peripheral immune cells to the brain, the activation of glia, and resulting dysfunction of the central immune system are the main causes of septic nerve damage. This study reviews the update on the pathogenesis of septic encephalopathy, focusing on the over-activation of immune cells in the central nervous system (CNS) and the "neurocentral-endocrine-immune" networks in the development of SAE, aiming to further understand the potential mechanism of SAE and provide new targets for diagnosis and management of septic complications.
RESUMEN
INTRODUCTION: Malaria importation can be caused by cross-border movement either of both people and anopheline mosquitoes. However, there still lacks robust evidence of imported malaria caused by Plasmodium spp. infected anopheles along international border areas (border-spill malaria). The objectives of this study were to confirm whether an outbreak of Plasmodium vivax malaria is border-spill malaria and assess the effects of China's public health response along China-Myanmar border. METHODS: Epidemiological, parasitological and entomological investigations were conducted to investigate the outbreak of border-spill malaria. Meanwhile, comprehensive interventions were carried out to prevent further transmission and reintroduction of malaria. RESULTS: Rapid diagnostic testing, microscopy and polymerase chain reaction were performed and the infections were confirmed as P. vivax. A total of 22 (9.21%) of 239 workers contracted P. vivax during the outbreak. Multivariate logistic regression analysis identified that the distance of worker shelters in China within 300 meters to the internally displaced person (IDP) camps in Myanmar was a risk factors associated with malaria infection (adjusted odds ratio 7.5920; 95% confidence interval, 2.6079-22.1013; P = 0.0002). After comprehensive interventions, malaria transmission was successfully interpreted and prevented at the project site till the completion of project on 14 January 2020, and recurrence of P. vivax malaria was not detected by the end of 2020. CONCLUSION: This study provided robust evidence of border-spill malaria along China-Myanmar border. Malaria parasite reservoir and distance travelled by female anopheline mosquitoes are two determinants for border-spill malaria. The public health response to the outbreak indicates that the malaria surveillance and response system works well in preventing reintroduction of malaria. However, prevention of border-spill malaria is still a major challenge in the Yunnan border area, China.