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Although circumstantial evidence supports enhanced Toll-like receptor 7 (TLR7) signalling as a mechanism of human systemic autoimmune disease1-7, evidence of lupus-causing TLR7 gene variants is lacking. Here we describe human systemic lupus erythematosus caused by a TLR7 gain-of-function variant. TLR7 is a sensor of viral RNA8,9 and binds to guanosine10-12. We identified a de novo, previously undescribed missense TLR7Y264H variant in a child with severe lupus and additional variants in other patients with lupus. The TLR7Y264H variant selectively increased sensing of guanosine and 2',3'-cGMP10-12, and was sufficient to cause lupus when introduced into mice. We show that enhanced TLR7 signalling drives aberrant survival of B cell receptor (BCR)-activated B cells, and in a cell-intrinsic manner, accumulation of CD11c+ age-associated B cells and germinal centre B cells. Follicular and extrafollicular helper T cells were also increased but these phenotypes were cell-extrinsic. Deficiency of MyD88 (an adaptor protein downstream of TLR7) rescued autoimmunity, aberrant B cell survival, and all cellular and serological phenotypes. Despite prominent spontaneous germinal-centre formation in Tlr7Y264H mice, autoimmunity was not ameliorated by germinal-centre deficiency, suggesting an extrafollicular origin of pathogenic B cells. We establish the importance of TLR7 and guanosine-containing self-ligands for human lupus pathogenesis, which paves the way for therapeutic TLR7 or MyD88 inhibition.
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Mutação com Ganho de Função , Lúpus Eritematoso Sistêmico , Receptor 7 Toll-Like , Animais , Autoimunidade/genética , Linfócitos B , GMP Cíclico/análogos & derivados , Guanosina , Humanos , Lúpus Eritematoso Sistêmico/genética , Camundongos , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/metabolismo , Receptor 7 Toll-Like/genética , Receptor 7 Toll-Like/metabolismoRESUMO
Lower olefins are widely used in the chemical industry as basic carbon-based feedstocks. Here, we report the catalytic system featuring isolated single-atom sites of iridium (Ir1) that can function within the entire temperature range of 300-600 °C and transform alkanes with conversions close to thermodynamics-dictated levels. The high turnover frequency values of the Ir1 system are comparable to those of homogeneous catalytic reactions. Experimental data and theoretical calculations both indicate that Ir1 is the primary catalytic site, while the coordinating C and N atoms help to enhance the activity and stability, respectively; all three kinds of elements cooperatively contribute to the high performance of this novel active site. We have further immobilized this catalyst on particulate Al2O3, and we found that the resulting composite system under mimicked industrial conditions could still give high catalytic performances; in addition, we have also developed and established a new scheme of periodical in situ regeneration specifically for this composite particulate catalyst.
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The synthesis of laser coherence and the accuracy of beam scanning, which are based on an optical phased array (OPA), are severely constrained by phase noise. This limitation hampers their applications in various fields. Currently, the most widely utilized calibration method is adaptive optics, which can effectively mitigate phase noise and enhance the quality of the output beam. However, because of the multiple array elements of the OPA and the large optimization range for each element, the adaptive optimization method experiences slow convergence and a high risk of falling into local optima. We propose a narrowing search range algorithm that can quickly reduce phase noise by narrowing the search range of the optimal value. After initial optimization, the SPGD algorithm was used. This study was verified through simulations and experiments utilizing the OPA of various array elements. These findings indicate that the hybrid algorithm expedites the calibration process, requires simple experimental equipment, and can be broadly utilized.
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The aromatization of light alkane is an important process for increasing the aromatic production and utilization efficiency of light alkane resources simultaneously. Herein, Ga-modified HZSM-5 catalysts were prepared and investigated by a series of characterization techniques such as X-ray diffraction, nuclear magnetic resonance spectroscopy, transmission electron microscopy, N2 adsorption-desorption, and NH3 temperature-programmed desorption to study their physicochemical properties. The catalytic performance in propane aromatization was also tested. Importantly, the structure-activity relationship, reaction pathway, and coke formation mechanism in propane aromatization were systematically explored. It was found that different Ga introduction methods would affect the amounts of Brønsted and Lewis acid sites, and Ga-HZSM-5 prepared by the hydrothermal method exhibited higher amounts of Brønsted and Lewis acid sites but a lower B/L ratio. As a result, Ga-HZSM-5 showed higher propane conversion and benzene, toluene, and xylene yield compared with that of Ga2O3/HZSM-5. The propane aromatization reaction pathway indicated that propane dehydrogenation to propene was a crucial step for aromatic formation. The increase of the Lewis acid density in Ga-HZSM-5 can effectively improve the dehydrogenation rate and promote the aromatization reaction. Furthermore, the formation of coke species was studied by thermogravimetry-mass spectrometry and Raman approaches, the results of which indicated that the graphitization degree of coke formed over spent Ga-HZSM-5 is lower, resulting in enhanced anticoking stability.
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KEY MESSAGE: Thirty-three stable QTL for 13 yield-related traits across ten environments were identified in the PD34/MY47 RIL population, and a candidate gene TaGS5-3D in Qmt.nwafu.3D was preliminarily identified to affect grain-related traits through accumulation of specific transcripts. Dissecting the genetic basis of yield-related traits is pivotal for improvement of wheat yield potential. In this study, a recombinant inbred line (RIL) population genotyped by SNP markers was used to detect quantitative trait loci (QTL) related to yield-related traits in ten environments. A total of 102 QTL were detected, including 33 environmentally stable QTL and 69 putative QTL. Among them, Qmt.nwafu.3D was identified as a pleiotropic QTL in the physical interval of 149.77-154.11 Mb containing a potential candidate gene TaGS5-3D. An SNP (T > C) was detected in its ninth intron, and TaGS5-3D-C was validated as a superior allele associated with larger grains using a CAPS marker. Interestingly, we found that TaGS5-3D-C was closely related to significantly up-regulated expression of intron-retained transcript (TaGS5-3D-PD34.1), while TaGS5-3D-T was related to dominant expression of normal splicing transcript (TaGS5-3D-MY47.1). Our results indicated that alternative splicing associated with the SNP T/C could be involved in the regulation of grain-related traits, laying a foundation for the functional analysis of TaGS5-3D and its greater potential application in high-yield wheat breeding.
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Melhoramento Vegetal , Triticum , Triticum/genética , Íntrons , Alelos , Grão Comestível/genética , NucleotídeosRESUMO
Alkane catalytic cracking is regarded as one of the most significant processes for light olefin production; however, it suffers from serve catalyst deactivation due to coke formation. Herein, HZSM-5/MCM-41 composites with different Si/Al2 ratios were first prepared by the hydrothermal method. The physicochemical properties of the prepared catalysts were analyzed by a series of bulk and surface characterization methods, and the catalytic performance was tested in n-decane catalytic cracking. It was found that HZSM-5/MCM-41 showed a higher selectivity to light olefins and a lower deactivation rate compared with the parent HZSM-5 due to an enhanced diffusion rate and decreased acid density. Moreover, the structure-reactivity relationship revealed that conversion, light olefin selectivity, and the deactivation rate strongly depended on the total acid density. Furthermore, HZSM-5/MCM-41 was further extruded with γ-Al2O3 to obtain the catalyst pellet, which showed an even higher selectivity to light olefins (â¼48%) resulting from the synergy effect of the fast diffusion rate and passivation of external acid density.
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In recent years, the silicon-based optical phased array has been widely used in the field of light detection and ranging (LIDAR) due to its great solid-state steering ability. At the same time, the optical phased array transceiver integration scheme provides a feasible solution for low-cost information exchange of small devices in the future. Based on this, this paper designs a two-dimensional optical phased array transceiver with high efficiency and a large field of view, which can realize a dense array with antenna spacing of 5.5 µm × 5.5 µm by using low crosstalk waveguide wiring. Additionally, it can realize the conversion between the receiving mode and the transmitting mode by using the optical switch. The simulation results show that the scanning range of 16.3° × 16.3° can be achieved in the transmitting mode, and the overall loss is lower than 10dB. In the receiving mode, we can achieve a collection efficiency of more than 27%, and the antenna array receiving loss is lower than 12.1 dB.
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Acute kidney injury (AKI) induced by renal ischemia reperfusion (RIR) is typically observed in renal surgeries and is a leading cause of renal failure. However, there is still an unmet medical need currently in terms of clinical treatments. Herein, we report the effect of Urolithin A (UA) in a mouse RIR model, wherein we demonstrated its underlying mechanism both in vitro and in vivo. The expression levels of p62 and Keap1 significantly decreased, while that of nuclear Nrf2 increased in vitro in a hypoxia cell model after UA treatment. Furthermore, the apoptosis of tubular cells was attenuated and the reactive oxygen species (ROS) levels were reduced in the kidneys in a mouse RIR model after UA administration. In this study, we demonstrated that UA can alleviate oxidative stress and promote autophagy by activating the p62-Keap1-Nrf2 signaling pathway, which could protect the kidneys from ischemia reperfusion injury.
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Injúria Renal Aguda , Traumatismo por Reperfusão , Injúria Renal Aguda/tratamento farmacológico , Injúria Renal Aguda/etiologia , Animais , Cumarínicos , Isquemia , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Camundongos , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismo , Reperfusão , Traumatismo por Reperfusão/complicações , Traumatismo por Reperfusão/tratamento farmacológico , Transdução de SinaisRESUMO
OBJECTIVE: This study examined the relationships between skeletal deformities and the pharyngeal airway of patients with nonsyndromic unilateral cleft lip and palate (UCLP). DESIGN: Retrospective study. SETTING: Orthodontics and Oral and Maxillofacial Surgery Departments in the Affiliated Hospital of Stomatology, Nanjing Medical University, China. PATIENTS, PARTICIPANTS: The sample comprised 30 nonsyndromic UCLP patients and 30 healthy controls. Each group has 23 males and 7 females. INTERVENTIONS: All cone-beam computed tomography images were obtained with the participant in the standard supine position and asked to bite with intercuspal position without swallowing or moving their heads and tongues during scanning. MAIN OUTCOME MEASURE(S): SNA, SNB, ANB, anterior cranial base, Wits appraisal, maxillary length (PTM-ANS || FH), maxillary position (S-PTM || FH), mandibular length (Go-Pog || MP), FMA, posterior face height, anterior face height, Posterior-Anterior face height, lower face height, pharyngeal airway volumes, and areas were evaluated by Dolphin imaging software. RESULTS: The UCLP group showed significantly decreased SNA, SNB, ANB, PTM-ANS || FH, S-PTM || FH, P-A Face Height compared with the controls. However, the airway volumes and areas showed no significant difference between 2 groups. The total airway volume and minimum cross-sectional area in UCLP patients were related to the Go-Pog || MP and FMA. CONCLUSIONS: Patients with UCLP have both the maxillary and mandibular deficiencies in the sagittal dimension. Both the sagittal and vertical relationships of the jaw might affect the airway volume and area. However, no significant difference was detected in airway volume and area in UCLP patients when compared with the controls.
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Fenda Labial , Fissura Palatina , Cefalometria , China , Tomografia Computadorizada de Feixe Cônico , Feminino , Humanos , Masculino , Estudos RetrospectivosRESUMO
AIM: The contemporary article aims to review and compare various literatures concerning different conclusions regarding the correlation between tooth size discrepancy (TSD) and Angle's malocclusion groups. BACKGROUND: Acquiring the ideal occlusion plays one of the major roles while designing the treatment plan for an orthodontic patient, any alterations in the individual tooth sizes are called TSD and will hinder this prime requirement. By determining the correct tooth size ratio, it further helps in acquiring the accurate interdigitation, balanced occlusion, and also predicting the orthodontic treatment results. Various investigations were carried out to know the correlation between tooth size discrepancies and different malocclusion groups, of which, a few reported a statistically significant difference whereas others reported no significant difference. REVIEW RESULTS: A computerized database quest was operated utilizing the Medline database (Pubmed/Medline) for original research and review articles. Publications between 1946 and 2018 were included. Four hundred twenty-one articles were recovered from database search and, among them, 66 articles were selected to review the full-article. CONCLUSION: Although a comparison was done between the tooth-size ratios and malocclusion groups (classes I, II, and III), many investigators noted no significant difference but there is an inadequacy in the data particularly related to subgroups of Angle's classification of malocclusion among these investigations; therefore, further studies are required to interpret this correlation. CLINICAL SIGNIFICANCE: As there is high incidence of tooth size discrepancies noted in the previous literature orthodontist, Bolton's analysis regardless of malocclusion group, sex, and ethnicity is highly recommended.
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Má Oclusão Classe III de Angle , Má Oclusão Classe II de Angle , Má Oclusão Classe I de Angle , Má Oclusão , Dente , Humanos , OdontometriaRESUMO
The aim of this study was to investigate whether overexpression of STAMP2 improves insulin resistance by regulating angiogenesis in adipose tissues. The characteristics of diabetic mice were measured by serial metabolite and pathology tests. Samples were obtained from epididymal, subcutaneous and brown adipose tissues. Histological and morphological analysis demonstrated that STAMP2 gene overexpression reduced adipocyte size, angiogenesis in epididymal and brown adipose tissues. On aortic ring assay, microvessels sprouting from aortas were significantly inhibited after STAMP2 gene overexpression. The cellular effect of STAMP2 on angiogenesis was explored in human umbilical vein endothelial cells (HUVECs) model. Correlation of STAMP2 and angiogenesis was validated by Ad-STAMP2 transfection and STAMP2 siRNA inhibition. In vitro, overexpression of STAMP2 significantly inhibited endothelial cell migration, tube formation. The effects of Ad-STAMP2 transfection on HUVECs were abolished by treatment with PPARγ antagonist GW9662 (2.5 µM), and the roles of STAMP2 siRNA on HUVECs were also reversed by treatment with PPARγ agonist rosiglitazone (RSG) (0.1 mM). RT-PCR indicated that STAMP2 could regulate levels of adhesion molecules, vascular endothelial growth factor A and CD36. The expression of PPARγ and CD36 was decreased when STAMP2 was inhibited by siRNA, while PPARγ and CD36 were highly expressed after overexpression of STAMP2. Our results suggested that STAMP2 gene overexpression may improve insulin resistance via attenuating angiogenesis in epididymal and brown adipose tissues through the PPARγ/CD36 signalling pathway.
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Tecido Adiposo/metabolismo , Antígenos CD36/genética , Diabetes Mellitus Experimental/terapia , Proteínas de Membrana/genética , Neovascularização Patológica/prevenção & controle , PPAR gama/genética , Tecido Adiposo/irrigação sanguínea , Tecido Adiposo/patologia , Animais , Apolipoproteínas E/deficiência , Apolipoproteínas E/genética , Antígenos CD36/metabolismo , Movimento Celular , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/patologia , Regulação da Expressão Gênica , Células Endoteliais da Veia Umbilical Humana/citologia , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Resistência à Insulina , Masculino , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Knockout , Neovascularização Patológica/genética , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , PPAR gama/metabolismo , Receptores de LDL/deficiência , Receptores de LDL/genética , Transdução de Sinais , EstreptozocinaRESUMO
The family Pseudoalteromonas is highly adaptable to dissimilar ecological habitats and plays an important ecological role in the marine environment. In this study, a new Pseudoalteromonas phage PH1 was isolated from the Yellow Sea. To better understand the bacteriophage, its biological properties, including morphology, host range, growth phenotype, thermal and pH stability, and nucleic acid composition, were investigated in detail. The result showed that the phage PH1 is a Podoviridae-phage with an icosahedral head (60 nm of diameter) and a short tail (26 nm in length). The phage PH1 genome consists of 42,685 bp length double-stranded DNA with a G+C content of 42.24% and is predicted to have 55 open reading frames (ORFs) with an average length of 740 bp nucleotides each. The phage PH1 genome adds a new Podoviridae-phage genome to marine bacteriophage dataset, which will provide useful basic information for further molecular research on interaction mechanisms between bacteriophages and their hosts.
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Bacteriófagos/isolamento & purificação , Genoma Viral , Podoviridae/isolamento & purificação , Pseudoalteromonas/virologia , Análise de Sequência de DNA , Bacteriófagos/classificação , Bacteriófagos/genética , Bacteriófagos/ultraestrutura , Composição de Bases , DNA/química , DNA/genética , DNA Viral/química , DNA Viral/genética , Especificidade de Hospedeiro , Concentração de Íons de Hidrogênio , Fases de Leitura Aberta , Podoviridae/classificação , Podoviridae/genética , Podoviridae/ultraestrutura , Água do Mar/virologia , Temperatura , Vírion/ultraestruturaRESUMO
A novel Siphoviridae family Phage BS5, which infects Pseudoalteromonas atlantica, was isolated from the surface waters of the Yellow Sea. Morphological study by transmission electron microscopy revealed that the novel phage belongs to Siphoviridae. The complete genome sequence of PBS5 contained a linear, double-strand 39949-bp DNA molecule with a G + C content of 40.6% and 65 putative open reading frames. Twelve conserved domains were detected by BLASTP in NCBI, and of these the functions of 5 were known. The genome was grouped into four modules as follows: phage structure, phage packaging, DNA replication and regulation, and some additional functions.16 S rDNA sequence analysis was also applied to identify the host bacteria. After initial characterization of bacteriophage PBS5, it was found that the optimal pH was 7.0, the optimal temperature was 30 °C, and the burst size was about 95 virions per cell. This information will provide an important benchmark for further research on the interaction between bacteriophages and their hosts.
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Bacteriófagos/isolamento & purificação , Genoma Viral , Siphoviridae/isolamento & purificação , Bacteriófagos/classificação , Bacteriófagos/genética , Composição de Bases , Fases de Leitura Aberta , Filogenia , Pseudoalteromonas/virologia , Siphoviridae/classificação , Siphoviridae/genética , Proteínas Virais/genéticaRESUMO
BACKGROUND: Diabetic nephropathy (DN) is a common microvascular complication of diabetes mellitus (DM). Ferroptosis is an atypical form of iron-dependent, modulated cell death that has been shown to occur in human umbilical vein endothelial cells (HUVECs). Leonurine (LEO) is a single active ingredient extracted from Leonurus japonicus Houtt. It has various biological activities, including anti-inflammatory and anti-cancer effects. However, whether LEO affects ferroptosis in DN has yet to be investigated. METHODS: An animal model of DN was established by subjecting C57/BL6 mice to a high-fat diet (HFD) while being induced with Streptozotocin (STZ). A cellular model of DN was established by exposing HUVECs to a high glucose (HG) concentration of 30 mM. RESULTS: LEO was found to improve DN and to attenuate the degree of glomerulosclerosis and tubular atrophy in the mouse model. Additionally, it markedly decreased the levels of ferroptosis markers. Molecular analyses revealed that LEO inhibited HG-induced oxidative stress in HUVECs, thereby decreasing endothelial cell (EC) dysfunction. Furthermore, LEO was found to reduce ferroptosis and reverse EC dysfunction by increasing the expression of glutathione peroxidase 4 (GPX4) and nuclear factor erythroid 2-related factor 2 (Nrf2). The suppression of Nrf2 in HG-induced HUVECs inhibited LEO-GPX4 axis-mediated ferroptosis and increased EC dysfunction. CONCLUSIONS: LEO exerts anti-DN effects both in vivo and in vitro by suppressing GPX4-mediated EC ferroptosis. Mechanistically, LEO appears to induce Nrf2-mediated GPX4 expression to inhibit ferroptosis, thereby reducing EC dysfunction. This study provides a new perspective on the treatment of diseases using natural medicines. It involves a novel form of cell death that could potentially lead to better treatment of DN.
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Diabetes Mellitus Experimental , Nefropatias Diabéticas , Ferroptose , Ácido Gálico , Células Endoteliais da Veia Umbilical Humana , Fosfolipídeo Hidroperóxido Glutationa Peroxidase , Animais , Humanos , Masculino , Camundongos , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/complicações , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Dieta Hiperlipídica/efeitos adversos , Ferroptose/efeitos dos fármacos , Ácido Gálico/análogos & derivados , Ácido Gálico/farmacologia , Ácido Gálico/uso terapêutico , Glucose/metabolismo , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Camundongos Endogâmicos C57BL , Fator 2 Relacionado a NF-E2/metabolismo , Fator 2 Relacionado a NF-E2/genética , Estresse Oxidativo/efeitos dos fármacos , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/genéticaRESUMO
BACKGROUND: Pain is a rapid response mechanism that compels organisms to retreat from the harmful stimuli and triggers a repair response. Nonetheless, when pain persists for extended periods, it can lead to adverse changes into in the individual's brain, negatively impacting their emotional state and overall quality of life. Microglia, the resident immune cells in the central nervous system (CNS), play a pivotal role in regulating a variety of pain-related disorders. Specifically, recent studies have shed light on the central role that microglial purinergic ligand-gated ion channel 7 receptor (P2X7R) plays in regulating pain. In this respect, the P2X7R on microglial membranes represents a potential therapeutic target. AIMS: To expound on the intricate link between microglial P2X7R and pain, offering insights into potential avenues for future research. METHODS: We reviewed 140 literature and summarized the important role of microglial P2X7R in regulating pain, including the structure and function of P2X7R, the relationship between P2X7R and microglial polarization, P2X7R-related signaling pathways, and the effects of P2X7R antagonists on pain regulation. RESULTS: P2X7R activation is related to M1 polarization of microglia, while suppressing P2X7R can transfer microglia from M1 into M2 phenotype. And targeting the P2X7R-mediated signaling pathways helps to explore new therapy for pain alleviation. P2X7R antagonists also hold potential for translational and clinical applications in pain management. CONCLUSIONS: Microglial P2X7R holds promise as a potential novel pharmacological target for clinical treatments due to its distinctive structure, function, and the development of antagonists.
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Microglia , Receptores Purinérgicos P2X7 , Humanos , Receptores Purinérgicos P2X7/metabolismo , Qualidade de Vida , Dor/metabolismo , Transdução de Sinais , Antagonistas do Receptor Purinérgico P2X/farmacologia , Antagonistas do Receptor Purinérgico P2X/uso terapêutico , Antagonistas do Receptor Purinérgico P2X/metabolismoRESUMO
Pulpitis is a common dental emergency that presents with intense pain; there is still no specific medicine to treat pulpitis-induced pain to date. Herein, differentially expressed genes in mouse anterior cingulate cortex (ACC) were investigated 7 days after pulp exposure via a combination of high-throughput transcriptomic and proteomic analyses. We screened 34 key genes associated with 8 critical pathways. Among these, genes (Elovl5, Ikbke, and Nbeal2) involved in immune or inflammatory responses exhibited exclusive regulation at the transcriptomic level, as confirmed by qRT-PCR. We also investigated the comprehensive expression profiles of genes (Erg1, Shank2, Bche, Serinf1, and Pax6) related to synaptic plasticity. Furthermore, the underlying mechanisms for pulpitis-induced pain through immune or inflammatory responses and synaptic plasticity were discussed. Taken together, our findings shed light on the mechanisms underlying pulpitis-induced pain, deepening our understanding of the molecular pathways and providing potential therapeutic and diagnostic targets.
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ABBREVIATIONS: AKI: acute kidney injury; ATP: adenosine triphosphate; BUN: blood urea nitrogen; CLP: cecal ligation and puncture; eGFR: estimated glomerular filtration rate; H&E: hematoxylin and eosin staining; LCN2/NGAL: lipocalin 2; LPS: lipopolysaccharide; LTL: lotus tetragonolobus lectin; mKeima: mitochondria-targeted Keima; mtDNA: mitochondrial DNA; PAS: periodic acid - Schiff staining; RTECs: renal tubular epithelial cells; SAKI: sepsis-induced acute kidney injury; Scr: serum creatinine; SIRT3: sirtuin 3; TFAM: transcription factor A, mitochondrial; TMRE: tetramethylrhodamine.
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Injúria Renal Aguda , Melatonina , Sepse , Sirtuína 3 , Humanos , Mitofagia , Autofagia , Lipopolissacarídeos , DNA Mitocondrial , Sepse/complicações , Rim , Proteínas de Ligação a DNA , Fatores de Transcrição , Proteínas MitocondriaisRESUMO
Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease with a clear genetic component. While most SLE patients carry rare gene variants in lupus risk genes, little is known about their contribution to disease pathogenesis. Amongst them, SH2B3-a negative regulator of cytokine and growth factor receptor signaling-harbors rare coding variants in over 5% of SLE patients. Here, we show that unlike the variant found exclusively in healthy controls, SH2B3 rare variants found in lupus patients are predominantly hypomorphic alleles, failing to suppress IFNGR signaling via JAK2-STAT1. The generation of two mouse lines carrying patients' variants revealed that SH2B3 is important in limiting the number of immature and transitional B cells. Furthermore, hypomorphic SH2B3 was shown to impair the negative selection of immature/transitional self-reactive B cells and accelerate autoimmunity in sensitized mice, at least in part due to increased IL-4R signaling and BAFF-R expression. This work identifies a previously unappreciated role for SH2B3 in human B cell tolerance and lupus risk.
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Autoimunidade , Lúpus Eritematoso Sistêmico , Animais , Humanos , Camundongos , Autoimunidade/genética , Fator Ativador de Células B/metabolismo , Linfócitos B , Lúpus Eritematoso Sistêmico/genética , Células Precursoras de Linfócitos BRESUMO
Background: Hepatocellular carcinoma (HCC), as an aggressive cancer with a high mortality rate, needs high-efficiency and low-toxicity drug therapy. Natural products have great potential as candidate lead compounds for the development of new HCC drugs. Crebanine is an isoquinoline alkaloid derived from Stephania with various potential pharmacological effects such as anti-cancer. However, the molecular mechanism underlying crebanine-induced liver cancer cells apoptosis has not been reported. Here, we investigated the effect of crebanine on HCC and identified a potential mechanism of action. Methods: In this paper, we intend to detect the toxic effects of crebanine on hepatocellular carcinoma HepG2 cells through a series of in vitro experiments, including detecting the effects of crebanine on the proliferation of HepG2 cells using the CCK8 method and plate cloning assay, observing the growth status and morphological changes of crebanine on HepG2 cells by inverted microscopy; and using the Transwell method to determine the the effect of crebanine on the migration and invasion ability of HepG2 cells; using Hoechst 33258 assay to stain cancer cells, thus observing the effect of crebanine on the morphology of HepG2 apoptotic cells, and detecting the apoptotic state and level of HepG2 cells by flow cytometry; using ROS kit and JC-1 assay kit to detect the changes of reactive oxygen species and mitochondrial membrane potential of HepG2 The immunofluorescence assay was taken to verify whether crebanine had an effect on the expression of p-FoxO3a in cancer cells; the Wetern blot assay was also used to examine the effect of crebanine on proteins related to the mitochondrial apoptotic pathway and its effect on the regulation of the relative protein expression of AKT/FoxO3a axis; after this, NAC and AKT inhibitor LY294002 were used to cells were pretreated with NAC and AKT inhibitor LY294002, respectively, in order to further validate the inhibitory effect of crebanine. Results: It was shown that crebanine effectively inhibited the growth and capacity of HepG2 cells migration and invasion in a dose-dependent manner. Furthermore, the effect of crebanine on the morphology of HepG2 cells was observed through microscopy. Meanwhile, crebanine induced apoptosis by causing reactive oxygen species (ROS) burst and mitochondrial membrane potential (MMP) disrupt. We found that crebanine could down-regulate Bcl-2 and up-regulate Bax, cleaved-PARP, cleaved-caspase-3 and cleaved-caspase-9, but these effects were overturned by ROS inhibitor N-acetylcysteine (NAC). Crebanine also down-regulated p-AKT and p-FoxO3a, and the PI3K inhibitor LY294002 significantly enhances this effect. We also found that the expression of AKT/FoxO3a signaling pathway was ROS-dependent. As shown by Western blots, NAC could partially attenuate the inhibitory effect of crebanine on AKT and FoxO3a phosphorylation. Conclusion: Based on our results, our results suggest that crebanine, as a compound with potential anticancer activity, has significant cytotoxic effects on hepatocellular carcinoma,and it likely induces apoptosis via ROS in the mitochondrial pathway and simultaneously affects the biological function of HCC via the ROS-AKT-FoxO3a signaling axis.
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Physiologically, the intestinal barrier plays a crucial role in homeostasis and nutrient absorption and prevents pathogenic entry, harmful metabolites, and endotoxin absorption. Recent advances have highlighted the association between severely damaged intestinal barriers and diabetes, obesity, fatty liver, and cardiovascular diseases. Evidence indicates that an abated intestinal barrier leads to endotoxemia associated with systemic inflammation, insulin resistance, diabetes, and lipid accumulation, accelerating obesity and fatty liver diseases. Nonetheless, the specific mechanism of intestinal barrier damage and the effective improvement of the intestinal barrier remain to be explored. Here, we discuss the crosstalk between changes in the intestinal barrier and metabolic disease. This paper also highlights how to improve the gut barrier from the perspective of natural medicine, gut microbiota remodeling, lifestyle interventions, and bariatric surgery. Finally, potential challenges and prospects for the regulation of the gut barrier-metabolic disease axis are discussed, which may provide theoretical guidance for the treatment of metabolic diseases.