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BACKGROUND: Antithrombin (AT) is the main physiological anticoagulant involved in hemostasis. Hereditary AT deficiency is a rare autosomal dominant thrombotic disease mainly caused by mutations in SERPINC1, which was usually manifested as venous thrombosis and pulmonary embolism. In this study, we analyzed the clinical characteristics and screened for mutant genes in two pedigrees with hereditary AT deficiency, and the functional effects of the pathogenic mutations were evaluated. METHODS: Candidate gene variants were analyzed by next-generation sequencing to screen pathogenic mutations in probands, followed by segregation analysis in families by Sanger sequencing. Mutant and wild-type plasmids were constructed and transfected into HEK293T cells to observe protein expression and cellular localization of SERPINC1. The structure and function of the mutations were analyzed by bioinformatic analyses. RESULTS: The proband of pedigree A with AT deficiency carried a heterozygous frameshift mutation c.1377delC (p.Asn460Thrfs*20) in SERPINC1 (NM000488.3), a 1377C base deletion in exon 7 resulting in a backward shift of the open reading frame, with termination after translation of 20 residues, and a different residue sequence translated after the frameshift. Bioinformatics analysis suggests that the missing amino acid sequence caused by the frameshift mutation might disrupt the disulfide bond between Cys279 and Cys462 and affect the structural function of the protein. This newly discovered variant is not currently included in the ClinVar and HGMD databases. p.Arg229* resulted in a premature stop codon in exon 4, and bioinformatics analysis suggests that the truncated protein structure lost its domain of interaction with factor IX (Ala414 site) after the deletion of nonsense mutations. However, considering the AT truncation protein resulting from the p.Arg229* variant loss a great proportion of the molecule, we speculate the variant may affect two functional domains HBS and RCL and lack of the corresponding function. The thrombophilia and decreased-AT-activity phenotypes of the two pedigrees were separated from their genetic variants. After lentiviral plasmid transfection into HEK293T cells, the expression level of AT protein decreased in the constructed c.1377delC mutant cells compared to that in the wild-type, which was not only reduced in c.685C > T mutant cells but also showed a significant band at 35 kDa, suggesting a truncated protein. Immunofluorescence localization showed no significant differences in protein localization before and after the mutation. CONCLUSIONS: The p.Asn460Thrfs*20 and p.Arg229* variants of SERPINC1 were responsible for the two hereditary AT deficiency pedigrees, which led to AT deficiency by different mechanisms. The p.Asn460Thrfs*20 variant is reported for the first time.
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The chemical constituents in the ethanol extract of Hypericum wightianum(Hypericaceae) were purified by column chromatography and identified via magnetic resonance imaging(NMR), high-resolution mass spectrum, and circular dichroism. A total of 22 compounds were identified, including eight polyprenylated phloroglucinols(1-8), three chromones(9-11), and three terpenoids(14-16) and so on. Among them, compounds 16 and 17 were first reported in the genus Hypericum, and compounds 1-11, 14, 15, and 19 were first isolated from H. wightianum. Compounds 1-4 were previously reported as two pairs of enantiomers. This study reported the chiral resolutions and absolute configurations of compounds 1-4 for the first time.
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Medicamentos de Ervas Chinesas , Hypericum , Floroglucinol , Hypericum/química , Estrutura Molecular , Espectroscopia de Ressonância Magnética , Medicamentos de Ervas Chinesas/químicaRESUMO
Sepsis is the major culprit of death among critically ill patients who are hospitalized in intensive care units (ICUs). Although sepsis-related mortality is steadily declining year-by-year due to the continuous understanding of the pathophysiological mechanism on sepsis and improvement of the bundle treatment, sepsis-associated hospitalization is rising worldwide. Surviving Sepsis Campaign (SSC) guidelines are continuously updating, while their content is extremely complex and comprehensive for a precisely implementation in clinical practice. As a consequence, a standardized step-by-step approach for the diagnosis and treatment of sepsis is particularly important. In the present study, we proposed a standardized step-by-step approach for the diagnosis and treatment of sepsis using our daily clinical experience and the latest researches, which is close to clinical practice and is easy to implement. The proposed approach may assist clinicians to more effectively diagnose and treat septic patients and avoid the emergence of adverse clinical outcomes.
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Sepse , Choque Séptico , Fidelidade a Diretrizes , Humanos , Unidades de Terapia Intensiva , Sepse/diagnóstico , Sepse/terapiaRESUMO
BACKGROUND: Protein S deficiency (PSD) is an autosomal dominant hereditary disease. In 1984, familial PSD was reported to be prone to recurrent thrombosis. Follow-up studies have shown that heterozygous protein S (PROS1) mutations increase the risk of thrombosis. More than 300 PROS1 mutations have been identified; among them, only a small number of mutations have been reported its possible mechanism to reduce plasma protein S (PS) levels. However, whether PROS1 mutations affect protein structure and why it can induce PSD remains unknown. METHODS: The clinical phenotypes of the members of a family with thrombosis were collected. Their PS activity was measured using the coagulation method, whereas their protein C and antithrombin III activities were measured using methods such as the chromogenic substrate method. The proband and her parents were screened for the responsible mutation using second-generation whole exon sequencing, and the members of the family were verified for suspected mutations using Sanger sequencing. Mutant and wild type plasmids were constructed and transfected into HEK293T cells to detect the mRNA and protein expression of PROS1. RESULTS: In this family, the proband with venous thrombosis of both lower extremities, the proband's mother with pulmonary embolism and venous thrombosis of both lower extremities, and the proband's younger brother had significantly lower PS activity and carried a PROS1 c. 1820 T > C:p.Leu607Ser heterozygous mutation (NM_000313.3). However, no such mutations were found in family members with normal PS activity. The PS expression in the cell lysate and supernatant of the Leu607Ser mutant cells decreased, while mRNA expression increased. Immunofluorescence localization showed that there was no significant difference in protein localization before and after mutation. CONCLUSIONS: The analysis of family phenotype, gene association, and cell function tests suggest that the PROS1 Leu607Ser heterozygous mutation may be a pathogenic mutation. Serine substitution causes structural instability of the entire protein. These data indicate that impaired PS translation and synthesis or possible secretion impairment is the main pathogenesis of this family with hereditary PSD and thrombophilia.
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Gephyromycin C (GC), a natural compound isolated from a marine-derived actinomycete Streptomyces sp. SS13I, which exerts anti-proliferative effect on PC3 cells. However, its underlying mechanism of the anti-cancer effect remains unknown. The results of SRB assays showed that GC inhibited the proliferation of PC3 cells with an IC50 value of 1.79 ± 0.28 µM. GC also induced G2/M cell cycle arrest which was accompanied by declining levels of cyclin proteins. Possible mechanisms were investigated and it was found that GC bound to Hsp90 and caused the degradation of Hsp90 client proteins (AKT, CHK1, P53, CDK4, Raf-b, and Raf-1). The fluorescent polarization assay with FITC-labeled geldanamycin (FITC-GA) demonstrated that GC was able to compete with FITC-GA in binding to wild type Hsp90 with an IC50 of 2.15 µM. Results of a docking study also suggested that GC interacted with the N-terminal domain of Hsp90. Our results showed that GC could bind to Hsp90, which resulted in down-regulation of Hsp90 client proteins and G2/M arrest in PC3 cells. Since the antitumor effects of this kind of angucycline via targeting Hsp90 has not been reported before, our results indicate that GC is a novel inhibitor of Hsp90 from marine resources and worthy of further study.
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Antraquinonas/farmacologia , Apoptose/efeitos dos fármacos , Hidrocarbonetos Aromáticos com Pontes/farmacologia , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Pontos de Checagem da Fase M do Ciclo Celular/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/farmacologia , Antraquinonas/química , Hidrocarbonetos Aromáticos com Pontes/química , Proteínas de Ciclo Celular/metabolismo , Proliferação de Células/efeitos dos fármacos , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Modelos Moleculares , Células PC-3 , Proteólise/efeitos dos fármacosRESUMO
As part of our efforts toward search for structurally new and bioactive natural products from marine-derived microorganisms, one new compound (1) was characterized from a marine-derived actinomycete Streptomyces sp. SS13M. The structure of new compound was elucidated by the analysis of HRESIMS, 1D, and 2D NMR spectroscopic data, and the absolute configuration was determined by ECD calculations.[Formula: see text].
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Produtos Biológicos , Streptomyces , Espectroscopia de Ressonância Magnética , Estrutura MolecularRESUMO
Hypericum stellatum is an important ethnomedicinal plant endemic to southwest China. Ultra high performance liquid chromatography with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS) was applied to analyze the chemical constituents of H. stellatum. Seventeen compounds from H. stellatum were tentatively identified using UPLC-Q-TOF-MS data. Antioxidant activity and total phenolic content were investigated by DPPH assay and Folin-Ciocalted methods. The EtOAc extract with high total phenolic content showed prominent antioxidant activity. The EtOAc extract of H. stellatum was separated and purified by column chromatography, including silica gel, Sephedex LH-20, and RP-HPLC. The isolates were defined by 1D, 2D NMR data. As a result, ten compounds were isolated and assigned as quercetin (â ), quercetin 3-O-ß-D-glucopyranoside (â ¡), 1,3,6,7-tetrahydroxylxanthone (â ¢), 1,3,5,6-tetrahydroxyxanthone (â £), 1,3,7-trihydroxyxanthone (â ¤), 3, 6, 7-trihydroxy-1-methoxyxanthone (â ¥), calycinoxanthon D (â ¦), caffeic acid ethyl ester (â §), chlorogenic acid (â ¨) and chlorogenic acid ethyl ester (â ©). This is the first report on chemical constituents and bioactivity of H. stellatum. The antioxidant activity of chemical constituents was tentatively found, which provided a foundation for further researches on the genus Hypericum and the traditional uses of H. stellatum.
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Antioxidantes/farmacologia , Hypericum/química , Fenóis/farmacologia , Compostos Fitoquímicos/farmacologia , Antioxidantes/isolamento & purificação , China , Cromatografia Líquida de Alta Pressão , Espectrometria de Massas , Fenóis/isolamento & purificação , Compostos Fitoquímicos/isolamento & purificaçãoRESUMO
The antioxidative properties of a novel curcumin analogue (2E,6E)-2,6-bis(3,5-dimethoxybenzylidene)cyclohexanone (MCH) were assessed by several in vitro models, including superoxide anion, hydroxyl radical and 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging and PC12 cell protection from H2O2 damage. MCH displayed superior O2â¢- quenching abilities compared to curcumin and vitamin C. In vitro stability of MCH was also improved compared with curcumin. Exposure of PC12 cells to 150 µM H2O2 caused a decrease of antioxidant enzyme activities, glutathione (GSH) loss, an increase in malondialdehyde (MDA) level, and leakage of lactate dehydrogenase (LDH), cell apoptosis and reduction in cell viability. Pretreatment of the cells with MCH at 0.63-5.00 µM before H2O2 exposure significantly attenuated those changes in a dose-dependent manner. MCH enhanced cellular expression of transcription factor NF-E2-related factor 2 (Nrf2) at the transcriptional level. Moreover, MCH could mitigate intracellular accumulation of reactive oxygen species (ROS), the loss of mitochondrial membrane potential (MMP), and the increase of cleaved caspase-3 activity induced by H2O2. These results show that MCH protects PC12 cells from H2O2 injury by modulating endogenous antioxidant enzymes, scavenging ROS, activating the Nrf2 cytoprotective pathway and prevention of apoptosis.
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Antioxidantes/farmacologia , Curcumina/análogos & derivados , Curcumina/farmacologia , Cicloexanonas/farmacologia , Preparações de Plantas/farmacologia , Substâncias Protetoras/farmacologia , Animais , Antioxidantes/química , Apoptose/efeitos dos fármacos , Compostos de Bifenilo/antagonistas & inibidores , Compostos de Bifenilo/metabolismo , Western Blotting , Caspase 3/metabolismo , Catalase/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Curcumina/química , Cicloexanonas/química , Sequestradores de Radicais Livres/química , Sequestradores de Radicais Livres/farmacologia , Expressão Gênica/efeitos dos fármacos , Glutationa/metabolismo , Peróxido de Hidrogênio/farmacologia , Radical Hidroxila/antagonistas & inibidores , Radical Hidroxila/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Estrutura Molecular , Fator 2 Relacionado a NF-E2/genética , Oxidantes/farmacologia , Células PC12 , Picratos/antagonistas & inibidores , Picratos/metabolismo , Preparações de Plantas/química , Substâncias Protetoras/química , Ratos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Superóxido Dismutase/metabolismo , Superóxidos/antagonistas & inibidores , Superóxidos/metabolismoRESUMO
Most in silico evolutionary studies commonly assumed that core genes are essential for cellular function, while accessory genes are dispensable, particularly in nutrient-rich environments. However, this assumption is seldom tested genetically within the pangenome context. In this study, we conducted a robust pangenomic Tn-seq analysis of fitness genes in a nutrient-rich medium for Sinorhizobium strains with a canonical open pangenome. To evaluate the robustness of fitness category assignment, Tn-seq data for three independent mutant libraries per strain were analyzed by three methods, which indicates that the Hidden Markov Model (HMM)-based method is most robust to variations between mutant libraries and not sensitive to data size, outperforming the Bayesian and Monte Carlo simulation-based methods. Consequently, the HMM method was used to classify the fitness category. Fitness genes, categorized as essential (ES), advantage (GA), and disadvantage (GD) genes for growth, are enriched in core genes, while nonessential genes (NE) are over-represented in accessory genes. Accessory ES/GA genes showed a lower fitness effect than core ES/GA genes. Connectivity degrees in the cofitness network decrease in the order of ES, GD, and GA/NE. In addition to accessory genes, 1599 out of 3284 core genes display differential essentiality across test strains. Within the pangenome core, both shared quasi-essential (ES and GA) and strain-dependent fitness genes are enriched in similar functional categories. Our analysis demonstrates a considerable fuzzy essential zone determined by cofitness connectivity degrees in Sinorhizobium pangenome and highlights the power of the cofitness network in understanding the genetic basis of ever-increasing prokaryotic pangenome data.
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Multiple factors have engaged in the progression of thyroid cancer (TC). Recent studies have shown that viral infection can be a critical factor in the pathogenesis of TC. Viruses, such as Epstein-Barr virus (EBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), may play an essential role in the occurrence, development, and even prognosis in TC. This review mainly explored the potential role of viral infection in the progress of TC. The possible mechanisms could be recognizing the host cell, binding to the receptors, affecting oncogenes levels, releasing viral products to shape a beneficial environment, interacting with immune cells to induce immune evasion, and altering the pituitary-thyroid axis. Thus, comprehensive knowledge may provide insights into finding molecular targets for diagnosing and treating virus-related TC.
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In recent years, ground-level-ozoneï¼O3ï¼ pollution in urban areas in the Bohai Rim has attracted wide attention. Based on the analysis of the spatiotemporal distribution characteristics of O3 concentration in Dongying, a representative city in the Bohai Rim from 2017 to 2022, the effects of meteorological factors and sea-land breeze circulation on O3 concentration were evaluated. The results showed thatï¼ â From 2017 to 2022, the annual assessment value of O3 concentration in Dongying showed a fluctuating upward trend, and the pollution days with O3 as the primary pollutant increased. O3 pollution mainly occurred in spring, summer, and autumn, with the most severe O3 pollution episodes typically occurring in May and June, and the duration of O3 pollution season tended to be longer. The monthly variation in the daily maximum 8-h average ozone ï¼MDA8 O3ï¼ presented a bimodal distribution, with significant increases in the 5th and 25th percentiles, and the spatial distribution was "high in the north and south, low in the middle." In addition, the nocturnal O3 concentration in recent years in Dongying also showed a significant increase trend. â¡ Meteorological factors greatly influenced O3 concentration in Dongying. When the temperature was greater than 30â, the relative humidity was less than 50%, and the wind direction was south-southwest or east-northeast, a high O3 value was more likely to occur. Meteorological factors contributed 30% of the MDA8 O3 variation in Dongying during the study period. In the case of moderate and severe O3 pollution, the contribution of meteorological factors to the change in MDA8 O3 could be as high as 40%. ⢠To some extent, sea-land breeze contributed to the occurrence of MDA8 O3 exceeding the secondary standard limit value of the National Ambient Air Quality Standard. In the afternoon, the hourly concentration of O3 during the sea-land breeze days was approximately 20 µg·m-3 higher than that during the non-sea-land breeze days. On the days of moderate and severe O3 pollution, the O3 concentration during the sea-land breeze days from 10ï¼00 to 16ï¼00 was higher than that during non-sea-land breeze days, and the O3 concentration was also at a high level from 20ï¼00 to 23ï¼00 on sea-land breeze days. In the O3 pollution season, the sea-land breeze could significantly affect the O3 level in coastal cities, which could bring significant challenges for O3 pollution prevention and control in this region. In the future, cities in the Bohai Rim need to further strengthen regional joint prevention and control of O3 pollution and increase emission reduction efforts of nitrogen oxides and volatile organic compounds. This strategy could effectively lower pollutant concentrations within the land breeze air mass, consequently reducing the impact of the sea breeze air mass on air quality in cities in the Bohai Rim.
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Marine sponges are well known as prolific producers of structurally diverse molecules with valuable pharmacological potential. As part of our ongoing program to discover bioactive compounds from marine sponges collected from the Xisha Islands in the South China Sea, a chemical study on the specimens of Hippospongia lachne was conducted. As a result, eight undescribed compounds, including four zwitterionic alkylpyridinium salts, hippospondines A-D (1-4), and four 3-alkylpyridine alkaloids, hippospondines E (5), F (6), and (±)-hippospondine G (7), were isolated from the marine sponge H. lachne, together with one known 3-alkylpyridine alkaloid (8). The undescribed structures were elucidated by HRESIMS, NMR, DP4+ and CP3 probability analysis, and the Snatzke's method. Hippospondines A-D (1-4) represent the rare example of inner salt type alkylpyridinium alkaloid with a farnesyl moiety. Compounds 1-3 and 8 were subjected to cytotoxic and lymphocyte proliferation assays. Compound 3 exhibited a weak promotion effect on the ConA-induced T lymphocyte proliferation.
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Alcaloides , Antineoplásicos , Poríferos , Animais , Espectroscopia de Ressonância Magnética , Antineoplásicos/química , Alcaloides/química , China , Estrutura MolecularRESUMO
Chronic pain often develops severe mood changes such as depression. However, how chronic pain leads to depression remains elusive and the mechanisms determining individuals' responses to depression are largely unexplored. Here we found that depression-like behaviors could only be observed in 67.9% of mice with chronic neuropathic pain, leaving 32.1% of mice with depression resilience. We determined that the spike discharges of the ventral tegmental area (VTA)-projecting lateral habenula (LHb) glutamatergic (Glu) neurons were sequentially increased in sham, resilient and susceptible mice, which consequently inhibited VTA dopaminergic (DA) neurons through a LHbGlu-VTAGABA-VTADA circuit. Furthermore, the LHbGlu-VTADA excitatory inputs were dampened via GABAB receptors in a pre-synaptic manner. Regulation of LHb-VTA pathway largely affected the development of depressive symptoms caused by chronic pain. Our study thus identifies a pivotal role of the LHb-VTA pathway in coupling chronic pain with depression and highlights the activity-dependent contribution of LHbGlu-to-VTADA inhibition in depressive behavioral regulation.
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Dor Crônica , Habenula , Camundongos , Animais , Área Tegmentar Ventral/metabolismo , Habenula/metabolismo , Depressão , Ácido gama-Aminobutírico/metabolismoRESUMO
Two new 9,11-secosterols, hipposponols A (1) and B (2), together with five known analogues, aplidiasterol B (3), (3ß,5α,6ß)-3,5,6-triol-cholest-7-ene (4), (3ß,5α,6ß,22E)-3,5,6-triol-ergosta-7,22-diene (5), and one pair of inseparable C-24 epimers of (3ß,5α,6ß,22E)-3,5,6-triol-stigmasta-7,22-diene (6/7), were isolated from the marine sponge Hippospongia lachne de Laubenfels. The structures of isolated compounds were extensively elucidated based on HRESIMS and NMR data. Compounds 2 - 5 showed cytotoxicity against PC9 cells with IC50 values ranging from 34.1 ± 0.9 to 38.9 ± 1.0 µM and compound 4 displayed cytotoxicity against MCF-7 cells with IC50 value of 39.0 ± 0.4 µM.
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Migration from rhizosphere to rhizoplane is a key selecting process in root microbiome assembly, but not fully understood. Rhizobiales members are overrepresented in the core root microbiome of terrestrial plants, and here we report a genome-wide transposon-sequencing of rhizoplane fitness genes of beneficial Sinorhizobium fredii on wild soybean, cultivated soybean, rice, and maize. There were few genes involved in broad-host-range rhizoplane colonization. The fadL mutant lacking a fatty acid transporter exhibited high colonization rates, while mutations in exoFQP (encoding membrane proteins directing exopolysaccharide polymerization and secretion), but not those in exo genes essential for exopolysaccharide biosynthesis, led to severely impaired colonization rates. This variation was not explainable by their rhizosphere and rhizoplane survivability, and associated biofilm and exopolysaccharide production, but consistent with their migration ability toward rhizoplane, and associated surface motility and the mixture of quorum-sensing AHLs (N-acylated-L-homoserine lactones). Genetics and physiology evidences suggested that FadL mediated long-chain AHL uptake while ExoF mediated the secretion of short-chain AHLs which negatively affected long-chain AHL biosynthesis. The fadL and exoF mutants had elevated and depleted extracellular long-chain AHLs, respectively. A synthetic mixture of long-chain AHLs mimicking that of the fadL mutant can improve rhizobial surface motility. When this AHL mixture was spotted into rhizosphere, the migration toward roots and rhizoplane colonization of S. fredii were enhanced in a diffusible way. This work adds novel parts managing extracellular AHLs, which modulate bacterial migration toward rhizoplane. The FadL-ExoFQP system is conserved in Alphaproteobacteria and may shape the "home life" of diverse keystone rhizobacteria.
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Rhizobium , Bactérias/genética , Percepção de Quorum , Biofilmes , Ácidos Graxos , Acil-Butirolactonas/metabolismoRESUMO
Background: Veno-venous extracorporeal membrane oxygenation (ECMO) was successfully performed for the rescue of an adult patient with severe acute respiratory distress syndrome (ARDS) induced by fulminant psittacosis, and then a near-fatal pulmonary embolism (PE) and cardiac arrest (CA) of the same patient was cured through catheter-directed thrombolysis. Case presentation: A 51-year-old female patient was admitted to the hospital on September 10, 2021 due to slurred speech, weakness in lower limbs, dizziness, and nausea. Subsequently, she developed confusion and was transferred to the intensive care unit (ICU), where she received anti-shock, antibiotics, invasive mechanical ventilation (IMV), and veno-venous ECMO due to the diagnosis of severe pneumonia, severe ARDS, and septic shock based on comprehensive physical examination, laboratory tests, and imaging findings. The metagenomic next-gengeration sequencing (m-NGS) in the bronchoalveolar lavage fluid (BALF) suggested that the pathogen was chlamydia psittaci, so the antibiotics were adjusted to doxycycline combined with azithromycin. After withdrawal from ECMO, ultrasound (US) re-examination of the left lower limb revealed inter-muscular vein thrombosis, following which heparin was replaced by subcutaneous injection of 0.4ml enoxaparin sodium twice daily for anti-coagulation therapy. After withdrawal from IMV, the patient suffered sudden CA and successful cardiopulmonary resuscitation (CPR), and emergency pulmonary angiography (PA) was performed to show bilateral main pulmonary artery embolism. After immediate catheter-directed thrombolysis and placement of an inferior vena cava filter, the patient's condition gradually stabilized. Conclusions: Veno-venous ECMO can be successfully performed as an emergency life-saving treatment for patients with severe ARDS induced by fulminant psittacosis, and during ECMO regular examinations should be conducted to detect and manage thrombosis in time, thereby avoiding the occurrence of near-fatal PE and CA.
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OBJECTIVES: Systemic lupus erythematosus is an autoimmune disease that involves multiple organ systems. One of its major complications, lupus nephritis (LN), is associated with a high mortality rate, and children-onset LN have a more severe course and worse prognosis than adults. Oxidative stress and inflammatory responses are involved in LN development and pathogenesis. Thus, this study aimed to explore the role of signaling regulation of the Nrf2/HMGB1/TLR/NF-κB pathway in LN pathogenesis and unravel the expression of TLR4+CXCR4+ plasma cells subset (PCs) in LN. METHODS: C57BL/6 and MRL/lpr mice were divided into four groups: control, model, vector control, and Nrf2 overexpression groups. The vector control and Nrf2 overexpression groups were injected with adenoviral vectors into the kidney in situ. Pathological changes in kidney tissues were observed by hematoxylin-eosin staining. The expression of Nrf2, HMGB1, TLR4, NF-κB, and downstream inflammatory factors in kidney samples was analyzed by quantitative polymerase chain reaction, western blotting, and enzyme-linked immunosorbent assay. The ratios of TLR4+CXCR4+ PC subsets in the blood and kidneys of mice were determined by flow cytometry. RESULTS: In MRL/lpr mice, Nrf2 was downregulated while HMGB1/TLR4/NF-κB pathway proteins were upregulated. Nrf2 overexpression decreased the expression of HMGB1, TLR4, NF-κB, and its downstream inflammatory cytokines (IL-1ß and TNFα). These cytokines were negatively correlated with an increase in Nrf2 content. PC and TLR4 + CXCR4 + PCs in the blood and kidney samples were significantly increased in MRL/lpr mice; however, they were decreased upon Nrf2 overexpression. CONCLUSION: This study showed severe kidney injury in an LN mouse model and an increased ratio of TLR4 + CXCR4 + PCs. Furthermore, we observed that Nrf2 regulates LN immune response through the Nrf2/HMGB1/TLR4/NF-κB pathway, which can be considered an important target for LN treatment. The clinical value of the findings of our study requires further investigation.
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Nefrite Lúpica , Fator 2 Relacionado a NF-E2 , Transdução de Sinais , Animais , Criança , Humanos , Camundongos , Citocinas/metabolismo , Proteína HMGB1/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos MRL lpr , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Receptor 4 Toll-Like/metabolismoRESUMO
Background: Gray matter volume (GMV) alteration in specific brain regions has been widely regarded as one of the most important neuroplasticity features in chronic pain patients with depressive symptoms (CP-D). However, the consistent and significant results were still lacking. Thus, further exploration was suggested to be performed. Objectives: This study aimed to comprehensively collect the voxel-based morphometry (VBM) studies on GMV alteration between CP-D and healthy controls (HCs). And a systemic review and meta-analysis were made to explore the characteristic brain regions in chronic pain and depression comorbidity. Methods: Search of PubMed, MEDLINE, Web of Science, and Cochrane Library databases updated to July 13, 2021. The altered GMV between CP-D and HCs in VBM studies was included in this meta-analysis. In total, 18 studies (20 datasets) and 1320 participants (520 patients and 800 HCs) were included. The significant coordinate information (x, y, z) reported in standard space and the effect size (t-value or z-score) were extracted and analyzed by anisotropic effect size-signed differential mapping (AES-SDM) 5.15 software. Results: According to the main analysis results, CP-D showed significant and consistent increased GMV in the left hippocampus (HIP. L) and decreased GMV in the medial part of the left superior frontal gyrus (SFG. L, BA 10) compared to HCs. Subgroup analysis showed significant decreased GMV in the medial orbital part of SFG.R (BA 10) in neuropathic pain, as well as significant increased GMV in the right parahippocampal gyrus (PHG.R, BA 35), left hippocampus (HIP.L, BA 20), and right middle frontal gyrus (MFG.R) in musculoskeletal pain. Furthermore, meta-regression showed a positive relationship between the decreased GMV in the medial part of SFG.L and the percentage of female patients. Conclusion: GMV abnormality in specific brain areas (e.g., HIP.L and SFG) was robust and reproducible, which could be significantly involved in this comorbidity disease. The findings in this study may be a valuable reference for future research. Systematic Review Registration: [www.crd.york.ac.uk/prospero/].
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The geological conditions of the Bortala River basin are complex, and the transformation of surface water and groundwater is frequent. It is great significance to study the hydrochemical characteristics and transformation relationship of surface water and groundwater for the reasonable development and allocation of water resources in the basin. Based on 15 surface water samples and 39 groundwater samples collected in April and May 2021, the APCS/MLR model and the combination of stable hydrogen and oxygen isotopes with hydrochemistry were used in this study to analyze the hydrochemical types and the distribution characteristics of hydrogen and oxygen isotopes, the source contribution of chemical components, and the transformation relationship between surface water and groundwater. The results showed that the surface water was mainly HCO3·SO4-Ca type and HCO3-Ca type, and the groundwater was mainly HCO3·SO4-Ca·Na type, HCO3-Ca type, and HCO3·SO4-Ca type. The contribution rates of the dissolution-migration-enrichment factor, human activities factor, environment factor, and native geological factor to the chemical components were 28.8%, 17.7%, 12.0%, and 6.5%, respectively. Bortala River water D and 18O was enriched along the distance, and groundwater D and 18O in the north bank was generally more enriched than groundwater in the south bank as a whole. Under the control of geological conditions such as geological structure and hydrogeological conditions, the transformation of river water and groundwater was concentrated in the middle reaches of the Bortala River, which was generally manifested in both unconfined groundwater and spring overflow in the sides of the recharge river water, and the recharge proportion ranged from 1.0% to 70.9%.
Assuntos
Água Subterrânea , Poluentes Químicos da Água , Monitoramento Ambiental , Água Subterrânea/química , Humanos , Hidrogênio , Isótopos de Oxigênio , Rios/química , Água , Poluentes Químicos da Água/análiseRESUMO
Occlusal disharmony has a negative impact on emotion. The mesencephalic trigeminal nucleus (Vme) neurons are the primary afferent nuclei that convey proprioceptive information from proprioceptors and low-threshold mechanoreceptors in the periodontal ligament and jaw muscles in the cranio-oro-facial regions. The dorsomedial part of the principal sensory trigeminal nucleus (Vpdm) and the ventral posteromedial nucleus (VPM) of thalamus have been proven to be crucial relay stations in ascending pathway of proprioception. The VPM sends numerous projections to primary somatosensory areas (SI), which modulate emotion processing. The present study aimed to demonstrate the ascending trigeminal-thalamic-cortex pathway which would mediate malocclusion-induced negative emotion. Unilateral anterior crossbite (UAC) model created by disturbing the dental occlusion was applied. Tract-tracing techniques were used to identify the existence of Vme-Vpdm-VPM pathway and Vpdm-VPM-SI pathway. Chemogenetic and optogenetic methods were taken to modulate the activation of VpdmVGLUT1 neurons and the Vpdm-VPM pathway. Morphological evidence indicated the involvement of the Vme-Vpdm-VPM pathway, Vpdm-VPM-SI pathway and VpdmVGLUT1-VPM pathway in orofacial proprioception in wild-type mice and vesicular glutamate transporter 1 (VGLUT1): tdTomato mice, respectively. Furthermore, chemogenetic inhibition of VpdmVGLUT1 neurons and the Vpdm-VPM pathway alleviated anxiety-like behaviors in a unilateral anterior crossbite (UAC) model, whereas chemogenetic activation induced anxiety-like behaviors in controls and did not aggravate these behaviors in UAC mice. Finally, optogenetic inhibition of the VpdmVGLUT1-VPM pathway in VGLUT1-IRES-Cre mice reversed UAC-induced anxiety comorbidity. In conclusion, these results suggest that the VpdmVGLUT1-VPM neural pathway participates in the modulation of malocclusion-induced anxiety comorbidity. These findings provide new insights into the links between occlusion and emotion and deepen our understanding of the impact of occlusal disharmony on brain dysfunction.