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Cells use mitophagy to remove damaged or unwanted mitochondria to maintain homeostasis. Here we report that the intracellular bacterial pathogen Listeria monocytogenes exploits host mitophagy to evade killing. We found that L. monocytogenes induced mitophagy in macrophages through the virulence factor listeriolysin O (LLO). We discovered that NLRX1, the only Nod-like receptor (NLR) family member with a mitochondrial targeting sequence, contains an LC3-interacting region (LIR) and directly associated with LC3 through the LIR. NLRX1 and its LIR motif were essential for L. monocytogenes-induced mitophagy. NLRX1 deficiency and use of a mitophagy inhibitor both increased mitochondrial production of reactive oxygen species and thereby suppressed the survival of L. monocytogenes. Mechanistically, L. monocytogenes and LLO induced oligomerization of NLRX1 to promote binding of its LIR motif to LC3 for induction of mitophagy. Our study identifies NLRX1 as a novel mitophagy receptor and discovers a previously unappreciated strategy used by pathogens to hijack a host cell homeostasis system for their survival.
Assuntos
Listeria monocytogenes/fisiologia , Proteínas Mitocondriais/fisiologia , Mitofagia , Animais , Autofagia , Toxinas Bacterianas/metabolismo , Linhagem Celular , Feminino , Proteínas de Choque Térmico/metabolismo , Proteínas Hemolisinas/metabolismo , Humanos , Listeria monocytogenes/patogenicidade , Listeriose/metabolismo , Listeriose/microbiologia , Macrófagos/microbiologia , Macrófagos/ultraestrutura , Masculino , Camundongos , Camundongos Knockout , Viabilidade Microbiana , Mitocôndrias/metabolismo , Mitocôndrias/ultraestrutura , Proteínas Mitocondriais/química , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Domínios Proteicos , Espécies Reativas de Oxigênio/metabolismo , Fatores de Virulência/metabolismoRESUMO
Although microbes are routinely grown in monocultures in the laboratory, they are almost never encountered as single species in the wild. Our ability to detect and identify new microorganisms has advanced significantly in recent years, but our understanding of the mechanisms that mediate microbial interactions has lagged behind. What makes this task more challenging is that microbial alliances can be dynamic, consisting of multiple phases. The transitions between phases, and the interactions in general, are often mediated by a chemical language consisting of small molecules, also referred to as secondary metabolites or natural products. In this microbial lexicon, the molecules are like words and through their effects on recipient cells they convey meaning. The current review highlights three dynamic microbial interactions in which some of the words and their meanings have been characterized, especially those that mediate transitions in selected multiphasic associations. These systems provide insights into the principles that govern microbial symbioses and a playbook for interrogating similar associations in diverse ecological niches.
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Produtos Biológicos , Interações Microbianas , Produtos Biológicos/metabolismo , Ecossistema , SimbioseRESUMO
For a long time, self-renewing and multipotent hematopoietic stem cells (HSCs) have been thought to make a major contribution to both embryonic and adult hematopoiesis. The canonical hematopoietic hierarchy illustrating HSC self-renewal and multipotency has been established mainly based on invasive functional assays (e.g. transplantation or colony-forming units in the spleen and in culture), which evaluate the cellular potentials of HSCs. With the extensive applications of non-invasive cell fate-mapping strategies, recent lineage tracing-based studies have suggested that not all native hematopoiesis is established via the hierarchical differentiation of HSCs. By contrast, hematopoietic progenitor cells (HPCs) are a dominant contributor to both embryonic and young adult hematopoiesis. These new findings help redefine the cellular origins of embryonic and adult hematopoiesis under native conditions, and emphasize the differences in revealing HSC potential versus HSC fate using distinct approaches during stress and native hematopoiesis. Here, we review recent advances in HPC and HSC development, and provide an updated perspective to incorporate these new findings with our traditional understanding of developmental and adult hematopoiesis.
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Transplante de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas , Diferenciação Celular , Hematopoese , Linhagem da CélulaRESUMO
During vertebrate embryogenesis, hematopoietic stem and progenitor cell (HSPC) production through endothelial-to-hematopoietic transition requires suitable developmental signals, but how these signals are accurately regulated remains incompletely understood. Cytoplasmic polyadenylation, which is one of the posttranscriptional regulations, plays a crucial role in RNA metabolism. Here, we report that Cpeb1b-mediated cytoplasmic polyadenylation is important for HSPC specification by translational control of Hedgehog (Hh) signaling during zebrafish early development. Cpeb1b is highly expressed in notochord and its deficiency results in defective HSPC production. Mechanistically, Cpeb1b regulates hemogenic endothelium specification by the Hedgehog-Vegf-Notch axis. We demonstrate that the cytoplasmic polyadenylation element motif-dependent interaction between Cpeb1b and shha messenger RNA (mRNA) in the liquid-like condensates, which are induced by Pabpc1b phase separation, is required for cytoplasmic polyadenylation of shha mRNA. Intriguingly, the cytoplasmic polyadenylation regulates translation but not stability of shha mRNA, which further enhances the Shha protein level and Hh signal transduction. Taken together, our findings uncover the role of Cpeb1b-mediated cytoplasmic polyadenylation in HSPC development and provide insights into how posttranscriptional regulation can direct developmental signals with high fidelity to translate them into cell fate transition.
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Poliadenilação , Peixe-Zebra , Animais , Peixe-Zebra/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas Hedgehog/metabolismo , Hematopoese/genéticaRESUMO
Physiological processes within the human body are regulated in approximately 24-h cycles known as circadian rhythms, serving to adapt to environmental changes. Bone rhythms play pivotal roles in bone development, metabolism, mineralization, and remodeling processes. Bone rhythms exhibit cell specificity, and different cells in bone display various expressions of clock genes. Multiple environmental factors, including light, feeding, exercise, and temperature, affect bone diurnal rhythms through the sympathetic nervous system and various hormones. Disruptions in bone diurnal rhythms contribute to the onset of skeletal disorders such as osteoporosis, osteoarthritis and skeletal hypoplasia. Conversely, these bone diseases can be effectively treated when aimed at the circadian clock in bone cells, including the rhythmic expressions of clock genes and drug targets. In this review, we describe the unique circadian rhythms in physiological activities of various bone cells. Then we summarize the factors synchronizing the diurnal rhythms of bone with the underlying mechanisms. Based on the review, we aim to build an overall understanding of the diurnal rhythms in bone and summarize the new preventive and therapeutic strategies for bone disorders.
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Osso e Ossos , Ritmo Circadiano , Humanos , Ritmo Circadiano/fisiologia , Animais , Osso e Ossos/metabolismo , Osso e Ossos/fisiologia , Doenças Ósseas/fisiopatologia , Doenças Ósseas/metabolismo , Relógios Circadianos/fisiologiaRESUMO
Abundant evidence demonstrates that mechanical stress could induce an inflammatory response in periodontal tissue, but the precise mechanism remains unclear. In the past few years, periodontal ligament cells (PDLCs), as the most force-sensitive cells, have been investigated in depth as local immune cells, associated with activation of inflammasomes and secretion of inflammatory cytokines in response to mechanical stimuli. However, this study innovatively inspected the effect of PDLCs on the other immune cells after stretch loading to reveal the detailed mechanism by which mechanical stimuli initiate immunoreaction in periodontium. In the present study, we found that cyclic stretch could stimulate human PDLCs to secret exosomes and that these exosomes could further induce the increase of phagocytic cells in the periodontium in Sprague-Dawley rats and the M1 polarization of the cultured macrophages (including the mouse macrophage cell line RAW264.7 and the bone marrow-derived macrophages from C57BL/6 mice). Furthermore, the exosomal miR-9-5p was detected to be overexpressed after mechanical stimuli in both in vivo and in vitro experiments and could trigger M1 polarization via the SIRT1/NF-κB signaling pathway in the cultured macrophages. In summary, this study revealed that PDLCs could transmit the mechanobiological signals to immune cells by releasing exosomes and simultaneously enhance periodontal inflammation through the miR-9-5p/SIRT1/NF-κB pathway. We hope that our research can improve understanding of force-related periodontal inflammatory diseases and lead to new targets for treatment.
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Subjects are often willing to pay a cost for information. In a procedure that promotes paradoxical choices, animals choose between a richer option followed by a cue that is rewarded 50% of the time (No Info) vs. a leaner option followed by one of two cues that signal certain outcomes: one always rewarded (100%) and the other never rewarded, 0% (Info). Since decisions involve comparing the subjective value of options after integrating all their features, preference for information may rely on cortico-amygdalar circuitry. To test this, male and female rats were prepared with bilateral inhibitory Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) in the anterior cingulate cortex, orbitofrontal cortex, basolateral amygdala, or null virus (control). We inhibited these regions after stable preference was acquired. We found that inhibition of the anterior cingulate cortex destabilized choice preference in female rats without affecting latency to choose or response rate to cues. A logistic regression fit revealed that previous choice predicted current choice in all conditions, however previously rewarded Info trials strongly predicted preference in all conditions except in female rats following anterior cingulate cortex inhibition. The results reveal a causal, sex-dependent role for the anterior cingulate cortex in decisions involving information.
Assuntos
Complexo Nuclear Basolateral da Amígdala , Humanos , Feminino , Masculino , Animais , Ratos , Giro do Cíngulo , Tonsila do Cerebelo , Sinais (Psicologia) , Córtex Pré-FrontalRESUMO
Exciton-polaritons, hybrid quasiparticles from the strong coupling of excitons and cavity photons in semiconductor microcavities, offer a platform for exploring quantum coherence and nonlinear optical properties. The unique polariton parametric scattering (PPS) laser is of interest for its potential in quantum technologies and nonlinear devices. However, direct resonant excitation of polaritons in strong-coupling microcavities is challenging. This study proposes an innovative two-photon absorption (TPA) pump mechanism to address this. We observe TPA-driven PPS lasing in a strongly coupled microcavity at room temperature. High K-value exciton injections promote coherent stimulated emission of polariton scattering through intermode channels. Angle-resolved spectra confirm a TPA process, showing evolution from pump-state to signal-state. Hanbury Brown-Twiss measurement of second-order correlation g2(τ) of signal state indicates a phase transition from a classical thermal state to a quantum coherent state. Theoretical modeling provides insights into the physical mechanisms of PPS. Our work advances nonlinear phenomena exploration in strongly coupled light-matter systems, contributing to quantum polaritonics and nonlinear optics.
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Antidepressants, while effective in treating depression and anxiety disorders, also induce deficits in sensory (particularly auditory) processing, which in turn may exacerbate psychiatric symptoms. How antidepressants cause auditory signature deficits remains largely unknown. Here, we found that fluoxetine-treated adult female rats were significantly less accurate when performing a tone-frequency discrimination task compared with age-matched control rats. Their cortical neurons also responded less selectively to sound frequencies. The degraded behavioral and cortical processing was accompanied by decreased cortical perineuronal nets, particularly those wrapped around parvalbumin-expressing inhibitory interneurons. Furthermore, fluoxetine induced critical period-like plasticity in their already mature auditory cortices; therefore, a brief rearing of these drug-treated rats under an enriched acoustic environment renormalized auditory processing degraded by fluoxetine. The altered cortical expression of perineuronal nets was also reversed as a result of enriched sound exposure. These findings suggest that the adverse effects of antidepressants on auditory processing, possibly because of a reduction in intracortical inhibition, can be substantially alleviated by simply pairing drug treatment with passive, enriched sound exposure. They have important implications for understanding the neurobiological basis of antidepressant effects on hearing and for designing novel pharmacological treatment strategies for psychiatric disorders.SIGNIFICANCE STATEMENT Clinical experience suggests that antidepressants adversely affect sensory (particularly auditory) processing, which can exacerbate patients' psychiatric symptoms. Here, we show that the antidepressant fluoxetine reduces cortical inhibition in adult rats, leading to degraded behavioral and cortical spectral processing of sound. Importantly, fluoxetine induces a critical period-like state of plasticity in the mature cortex; therefore, a brief rearing under an enriched acoustic environment is sufficient to reverse the changes in auditory processing caused by the administration of fluoxetine. These results provide a putative neurobiological basis for the effects of antidepressants on hearing and indicate that antidepressant treatment combined with enriched sensory experiences could optimize clinical outcomes.
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Córtex Auditivo , Fluoxetina , Ratos , Feminino , Animais , Fluoxetina/farmacologia , Percepção Auditiva/fisiologia , Som , Córtex Auditivo/fisiologia , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Estimulação Acústica/métodosRESUMO
The antagonism between gibberellin (GA) and abscisic acid (ABA) signaling pathways is vital to balance plant growth and stress response. Nevertheless, the mechanism by which plants determine the balance remains to be elucidated. Here, we report that rice NUCLEAR FACTOR-Y A3 (OsNF-YA3) modulates GA- and ABA-mediated balance between plant growth and osmotic stress tolerance. OsNF-YA3 loss-of-function mutants exhibit stunted growth, compromised GA biosynthetic gene expression, and decreased GA levels, while its overexpression lines have promoted growth and enhanced GA content. Chromatin immunoprecipitation-quantitative polymerase chain reaction analysis and transient transcriptional regulation assays demonstrate that OsNF-YA3 activates GA biosynthetic gene OsGA20ox1 expression. Furthermore, the DELLA protein SLENDER RICE1 (SLR1) physically interacts with OsNF-YA3 and thus inhibits its transcriptional activity. On the other side, OsNF-YA3 negatively regulates plant osmotic stress tolerance by repressing ABA response. OsNF-YA3 reduces ABA levels by transcriptionally regulating ABA catabolic genes OsABA8ox1 and OsABA8ox3 by binding to their promoters. Furthermore, OSMOTIC STRESS/ABA-ACTIVATED PROTEIN KINASE 9 (SAPK9), the positive component in ABA signaling, interacts with OsNF-YA3 and mediates OsNF-YA3 phosphorylation, resulting in its degradation in plants. Collectively, our findings establish OsNF-YA3 as an important transcription factor that positively modulates GA-regulated plant growth and negatively controls ABA-mediated water-deficit and salt tolerance. These findings shed light on the molecular mechanism underlying the balance between the growth and stress response of the plant.
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Oryza , Oryza/metabolismo , Pressão Osmótica , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Giberelinas/metabolismo , Desenvolvimento Vegetal , Regulação da Expressão Gênica de Plantas , Ácido Abscísico/metabolismoRESUMO
BACKGROUND: Previous studies have shown that protein kinase MoKin1 played an important role in the growth, conidiation, germination and pathogenicity in rice blast fungus, Magnaporthe oryzae. ΔMokin1 mutant showed significant phenotypic defects and significantly reduced pathogenicity. However, the internal mechanism of how MoKin1 affected the development of physiology and biochemistry remained unclear in M. oryzae. RESULT: This study adopted a multi-omics approach to comprehensively analyze MoKin1 function, and the results showed that MoKin1 affected the cellular response to endoplasmic reticulum stress (ER stress). Proteomic analysis revealed that the downregulated proteins in ΔMokin1 mutant were enriched mainly in the response to ER stress triggered by the unfolded protein. Loss of MoKin1 prevented the ER stress signal from reaching the nucleus. Therefore, the phosphorylation of various proteins regulating the transcription of ER stress-related genes and mRNA translation was significantly downregulated. The insensitivity to ER stress led to metabolic disorders, resulting in a significant shortage of carbohydrates and a low energy supply, which also resulted in severe phenotypic defects in ΔMokin1 mutant. Analysis of MoKin1-interacting proteins indicated that MoKin1 really took participate in the response to ER stress. CONCLUSION: Our results showed the important role of protein kinase MoKin1 in regulating cellular response to ER stress, providing a new research direction to reveal the mechanism of MoKin1 affecting pathogenic formation, and to provide theoretical support for the new biological target sites searching and bio-pesticides developing.
Assuntos
Estresse do Retículo Endoplasmático , Proteínas Fúngicas , Oryza , Proteômica , Oryza/microbiologia , Oryza/genética , Proteínas Fúngicas/metabolismo , Proteínas Fúngicas/genética , Doenças das Plantas/microbiologia , Regulação Fúngica da Expressão Gênica , Proteínas Quinases/metabolismo , Proteínas Quinases/genética , Mutação , Multiômica , AscomicetosRESUMO
Perivascular cerebrospinal fluid (pCSF) flow is a key component of the glymphatic system. Arterial pulsation has been proposed as the main driving force of pCSF influx along the superficial and penetrating arteries; however, evidence of this mechanism in humans is limited. We proposed an experimental framework of dynamic diffusion tensor imaging with low b-values and ultra-long echo time (dynDTIlow-b) to capture pCSF flow properties during the cardiac cycle in human brains. Healthy adult volunteers (aged 17-28 years; seven men, one woman) underwent dynDTIlow-b using a 3T scanner (MAGNETOM Prisma, Siemens Healthcare, Erlangen, Germany) with simultaneously recorded cardiac output. The results showed that diffusion tensors reconstructed from pCSF were mainly oriented in the direction of the neighboring arterial flow. When switching from vasoconstriction to vasodilation, the axial and radial diffusivities of the pCSF increased by 5.7 % and 4.94 %, respectively, suggesting that arterial pulsation alters the pCSF flow both parallel and perpendicular to the arterial wall. DynDTIlow-b signal intensity at b=0 s/mm2 (i.e., T2-weighted, [S(b=0 s/mm2)]) decreased in systole, but this change was â¼7.5 % of a cardiac cycle slower than the changes in apparent diffusivity, suggesting that changes in S(b=0 s/mm2) and apparent diffusivity arise from distinct physiological processes and potential biomarkers associated with perivascular space volume and pCSF flow, respectively. Additionally, the mean diffusivities of white matter showed cardiac-cycle dependencies similar to pCSF, although a delay relative to the peak time of apparent diffusivity in pCSF was present, suggesting that dynDTIlow-b could potentially reveal the dynamics of magnetic resonance imaging-invisible pCSF surrounding small arteries and arterioles in white matter; this delay may result from pulse wave propagation along penetrating arteries. In conclusion, the vasodilation-induced increases in axial and radial diffusivities of pCSF and mean diffusivities of white matter are consistent with the notion that arterial pulsation can accelerate pCSF flow in human brain. Furthermore, the proposed dynDTIlow-b technique can capture various pCSF dynamics in artery pulsation.
Assuntos
Líquido Cefalorraquidiano , Imagem de Tensor de Difusão , Sistema Glinfático , Humanos , Adulto , Feminino , Masculino , Adulto Jovem , Imagem de Tensor de Difusão/métodos , Adolescente , Líquido Cefalorraquidiano/fisiologia , Líquido Cefalorraquidiano/diagnóstico por imagem , Sistema Glinfático/diagnóstico por imagem , Sistema Glinfático/fisiologia , Encéfalo/fisiologia , Encéfalo/diagnóstico por imagem , Encéfalo/irrigação sanguínea , Fluxo Pulsátil/fisiologia , Artérias Cerebrais/diagnóstico por imagem , Artérias Cerebrais/fisiologiaRESUMO
Noncentrosymmetric nanostructures are an attractive synthetic target as they can exhibit complex interparticle interactions useful for numerous applications. However, generating uniform, colloidally stable, noncentrosymmetric nanoparticles with low aspect ratios is a significant challenge using solution self-assembly approaches. Herein, we outline the synthesis of noncentrosymmetric multiblock co-nanofibers by subsequent living crystallization-driven self-assembly of block co-polymers, spatially confined attachment of nanoparticles, and localized nanofiber fragmentation. Using this strategy, we have fabricated uniform diblock and triblock noncentrosymmetric π-conjugated nanofiber-nanoparticle hybrid structures. Additionally, in contrast to Brownian motion typical of centrosymmetric nanoparticles, we demonstrated that these noncentrosymmetric nanofibers undergo ballistic motion in the presence of H2O2 and thus could be employed as nanomotors in various applications, including drug delivery and environmental remediation.
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Extracellular elastin-derived peptides (EDPs) accumulate in the aging brain and have been associated with vascular dementia and Alzheimer's disease (AD). The activation of inflammatory processes in glial cells with EDP treatment has received attention, but not in neurons. To properly understand EDPs' pathogenic significance, the impact on neuronal function and neuron-microglia crosstalk was explored further. Among the EDP molecules, Val-Gly-Val-Ala-Pro-Gly (VGVAPG) is a typical repeating hexapeptide. Here, we observed that EDPs-VGVAPG influenced neuronal survival and morphology in a dose-dependent manner. High concentrations of VGVAPG induced synapse loss and microglia hyperactivation in vivo and in vitro. Following EDP incubation, galectin 3 (Gal-3) released by neurons served as a chemokine, attracting microglial engulfment. Blocking Gal-3 and EDP binding remedied synapse loss in neurons and phagocytosis in microglia. In response to the accumulation of EDPs, proteomics in matrix remodeling and cytoskeleton dynamics, such as a disintegrin and metalloproteinase (ADAM) family, were engaged. These findings in extracellular EDPs provided more evidence for the relationship between aging and neuron dysfunction, increasing the insight of neuroinflammatory responses and the development of new specialized extracellular matrix remolding-targeted therapy options for dementia or other neurodegenerative disease.
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Envelhecimento , Encéfalo , Elastina , Microglia , Neurônios , Neurônios/metabolismo , Neurônios/patologia , Animais , Elastina/metabolismo , Microglia/metabolismo , Microglia/patologia , Envelhecimento/metabolismo , Envelhecimento/patologia , Encéfalo/metabolismo , Encéfalo/patologia , Oligopeptídeos/farmacologia , Oligopeptídeos/metabolismo , Camundongos , Masculino , Comunicação Celular/fisiologia , Camundongos Endogâmicos C57BL , Células Cultivadas , Galectina 3/metabolismo , HumanosRESUMO
In SARS-CoV-2 infection, it has been observed that viral replication lasts longer in the nasal mucosa than in the lungs, despite the presence of a high viral load at both sites. In hamsters, we found that the nasal mucosa exhibited a mild inflammatory response and minimal pathological injuries, whereas the lungs displayed a significant inflammatory response and severe injuries. The underlying cellular events may be induced by viral infection in three types of cell death: apoptosis, pyroptosis, and necroptosis. Our findings indicate that apoptosis was consistently activated during infection in the nasal mucosa, and the levels of apoptosis were consistent with the viral load. On the other hand, pyroptosis and a few instances of necroptosis were observed only on 7 dpi in the nasal mucosa. In the lungs, however, both pyroptosis and apoptosis were prominently activated on 3 dpi, with lower levels of apoptosis compared to the nasal mucosa. Interestingly, in reinfection, obvious viral load and apoptosis in the nasal mucosa were detected on 3 dpi, while no other forms of cell death were detected. We noted that the inflammatory reactions and pathological injuries in the nasal mucosa were milder, indicating that apoptosis may play a role in promoting lower inflammatory reactions and milder pathological injuries and contribute to the generation of long-term viral replication in the nasal mucosa. Our study provides valuable insights into the differences in cellular mechanisms during SARS-CoV-2 infection and highlights the potential significance of apoptosis regulation in the respiratory mucosa for controlling viral replication.
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Apoptose , COVID-19 , Mesocricetus , Mucosa Nasal , Piroptose , SARS-CoV-2 , Carga Viral , Animais , COVID-19/virologia , COVID-19/patologia , Mucosa Nasal/virologia , Mucosa Nasal/patologia , SARS-CoV-2/fisiologia , SARS-CoV-2/patogenicidade , Reinfecção/virologia , Pulmão/virologia , Pulmão/patologia , Cricetinae , Replicação Viral , Masculino , NecroptoseRESUMO
Podocyte apoptosis or loss is the pivotal pathological characteristic of diabetic kidney disease (DKD). Insulin-like growth factor-binding protein 2 (IGFBP2) have a proinflammatory and proapoptotic effect on diseases. Previous studies have shown that serum IGFBP2 level significantly increased in DKD patients, but the precise mechanisms remain unclear. Here, we found that IGFBP2 levels obviously increased under a diabetic state and high glucose stimuli. Deficiency of IGFBP2 attenuated the urine protein, renal pathological injury and glomeruli hypertrophy of DKD mice induced by STZ, and knockdown or deletion of IGFBP2 alleviated podocytes apoptosis induced by high concentration of glucose or in DKD mouse. Furthermore, IGFBP2 facilitated apoptosis, which was characterized by increase in inflammation and oxidative stress, by binding with integrin α5 (ITGA5) of podocytes, and then activating the phosphorylation of focal adhesion kinase (FAK)-mediated mitochondrial injury, including membrane potential decreasing, ROS production increasing. Moreover, ITGA5 knockdown or FAK inhibition attenuated the podocyte apoptosis caused by high glucose or IGFBP2 overexpression. Taken together, these findings unveiled the insight mechanism that IGFBP2 increased podocyte apoptosis by mitochondrial injury via ITGA5/FAK phosphorylation pathway in DKD progression, and provided the potential therapeutic strategies for diabetic kidney disease.
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Apoptose , Diabetes Mellitus Experimental , Nefropatias Diabéticas , Proteína 2 de Ligação a Fator de Crescimento Semelhante à Insulina , Mitocôndrias , Podócitos , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Nefropatias Diabéticas/genética , Podócitos/metabolismo , Podócitos/patologia , Animais , Camundongos , Proteína 2 de Ligação a Fator de Crescimento Semelhante à Insulina/metabolismo , Proteína 2 de Ligação a Fator de Crescimento Semelhante à Insulina/genética , Humanos , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Experimental/genética , Masculino , Quinase 1 de Adesão Focal/metabolismo , Quinase 1 de Adesão Focal/genética , Estresse Oxidativo , Integrina alfa5/metabolismo , Integrina alfa5/genética , Camundongos Endogâmicos C57BL , Transdução de Sinais , Fosforilação , Proteína-Tirosina Quinases de Adesão Focal/metabolismo , Proteína-Tirosina Quinases de Adesão Focal/genética , Camundongos Knockout , IntegrinasRESUMO
Inaccurate or cumbersome clinical pathogen diagnosis between Gram-positive bacteria (G+) and Gram-negative (G-) bacteria lead to delayed clinical therapeutic interventions. Microelectrode-based electrochemical sensors exhibit the significant advantages of rapid response and minimal sample consumption, but the loading capacity and discrimination precision are weak. Herein, we develop reversible fusion-fission MXene-based fiber microelectrodes for G+/G- bacteria analysis. During the fissuring process, the spatial utilization, loading capacity, sensitivity, and selectivity of microelectrodes were maximized, and polymyxin B and vancomycin were assembled for G+/G- identification. The surface-tension-driven reversible fusion facilitated its reusability. A deep learning model was further applied for the electrochemical impedance spectroscopy (EIS) identification in diverse ratio concentrations of G+ and G- of (1:100-100:1) with higher accuracy (>93%) and gave predictable detection results for unknown samples. Meanwhile, the as-proposed sensing platform reached higher sensitivity toward E. coli (24.3 CFU/mL) and S. aureus (37.2 CFU/mL) in 20 min. The as-proposed platform provides valuable insights for bacterium discrimination and quantification.
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Microeletrodos , Bactérias Gram-Positivas/isolamento & purificação , Bactérias Gram-Negativas/isolamento & purificação , Escherichia coli/isolamento & purificação , Staphylococcus aureus/isolamento & purificação , Técnicas Eletroquímicas/instrumentação , Vancomicina/farmacologia , Antibacterianos/farmacologia , Antibacterianos/análise , Polimixina B/química , Polimixina B/farmacologia , Espectroscopia DielétricaRESUMO
Sleep deprivation (SD) weakens the immune system and leads to increased susceptibility to infectious or inflammatory diseases. However, it is still unclear how SD affects humoral immunity. In the present study, sleep disturbance was conducted using an sleep deprivation instrument, and the bacterial endotoxin lipopolysaccharide (LPS) was used to activate the immune response. It was found that SD-pretreatment reduced LPS-induced IgG2b+ B cells and IgG2b isotype antibody production in lymphocytes of spleen. And, SD-pretreatment decreased the proportion of CD4+T cells, production of CD4+T cells derived TGF-ß1 and its contribution in helping IgG2b production. Additionally, BMAL1 and CLOCK were selectively up-regulated in lymphocytes after SD. Importantly, BMAL1 and CLOCK deficiency contributed to TGF-ß1 expression and production of IgG2b+ B cells. Thus, our results provide a novel insight to explain the involvement of BMAL1 and CLOCK under SD stress condition, and their roles in inhibiting TGF-ß1 expression and contributing to reduction of LPS induced IgG2b production.
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Fatores de Transcrição ARNTL , Formação de Anticorpos , Proteínas CLOCK , Imunoglobulina G , Privação do Sono , Privação do Sono/genética , Privação do Sono/imunologia , Imunoglobulina G/genética , Imunoglobulina G/imunologia , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Ratos Sprague-Dawley , Camundongos Endogâmicos C57BL , Fatores de Transcrição ARNTL/genética , Fatores de Transcrição ARNTL/imunologia , Proteínas CLOCK/genética , Proteínas CLOCK/imunologia , Linfócitos B/imunologia , Linfócitos T CD4-Positivos/imunologia , Formação de Anticorpos/efeitos dos fármacos , Formação de Anticorpos/genética , Estresse Fisiológico/imunologia , Animais , Camundongos , Ratos , Células CultivadasRESUMO
BACKGROUND: Establishing whether there is a potential relationship between glucagon-like peptide 1 receptor agonists (GLP-1RAs) and suicidal or self-injurious behaviors (SSIBs) is crucial for public safety. This study investigated the potential association between GLP-1RAs and SSIBs by exploring the FDA Adverse Event Reporting System (FAERS) database. METHODS: A disproportionality analysis was conducted using post-marketing data from the FAERS repository (2018 Q1 to 2022 Q4). SSIB cases associated with GLP-1RAs were identified and analyzed through disproportionality analysis using the information component. The parametric distribution with a goodness-of-fit test was employed to analyze the time-to-onset, and the Ω shrinkage was used to evaluate the potential effect of co-medication on the occurrence of SSIBs. RESULTS: In total, 204 cases of SSIBs associated with GLP-1RAs, including semaglutide, liraglutide, dulaglutide, exenatide, and albiglutide, were identified in the FAERS database. Time-of-onset analysis revealed no consistent mechanism for the latency of SSIBs in patients receiving GLP-1RAs. The disproportionality analysis did not indicate an association between GLP-1RAs and SSIBs. Co-medication analysis revealed 81 cases with antidepressants, antipsychotics, and benzodiazepines, which may be proxies of mental health comorbidities. CONCLUSIONS: We found no signal of disproportionate reporting of an association between GLP-1RA use and SSIBs. Clinicians need to maintain heightened vigilance on patients premedicated with neuropsychotropic drugs. This contributes to the greater acceptance of GLP-1RAs in patients with type 2 diabetes mellitus or obesity.
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Diabetes Mellitus Tipo 2 , Humanos , Diabetes Mellitus Tipo 2/complicações , Hipoglicemiantes/uso terapêutico , Agonistas do Receptor do Peptídeo 1 Semelhante ao Glucagon , Farmacovigilância , Ideação SuicidaRESUMO
Superelastic aerogels with rapid response and recovery times, as well as exceptional shape recovery performance even from large deformation, are in high demand for wearable sensor applications. In this study, a novel conductive and superelastic cellulose-based aerogel is successfully developed. The aerogel incorporates networks of cellulose sub-micron fibers and carbon black (SMF/CB) nanoparticles, achieved through a combination of dual ice templating assembly and electrostatic assembly methods. The incorporation of assembled cellulose sub-micron fibers imparts remarkable superelasticity to the aerogel, enabling it to retain 94.6% of its original height even after undergoing 10 000 compression/recovery cycles. Furthermore, the electrostatically assembled CB nanoparticles contribute to exceptional electrical conductivity in the cellulose-based aerogel. This combination of electrical conductivity and superelasticity results in an impressive response time of 7.7 ms and a recovery time of 12.8 ms for the SMF/CB aerogel, surpassing many of the aerogel sensors reported in previous studies. As a proof of concept, the SMF/CB aerogel is utilized to construct a pressure sensor and a sensing array, which exhibit exceptional responsiveness to both minor and substantial human motions, indicating its significant potential for applications in human health monitoring and human-machine interaction.