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1.
J Chem Neuroanat ; 128: 102229, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36592695

RESUMO

Rab7 belongs to the Ras small GTPase superfamily, and abnormal expression of Rab7 can cause neuropathy and lipid metabolism diseases. Studies have shown that Rab7 plays a crucial role in the inner membrane translocase. However, the role of Rab7 in the regulatory mechanisms of cell survival in spinal cord injury remains unknown. We used a rat spinal cord injury (SCI) model to explore the cellular localization and expression of Rab7 after SCI in this study. Western blot analysis showed that Rab7 was expressed in the spinal cord tissue. On the first day, it significantly increased and peaked after SCI on the third day. Furthermore, western blotting also demonstrated that pyroptosis-related protein Gasdermin D (GSDMD), Caspase-1, apoptosis-associated speck-like protein (ASC) expression peaked after the third-day post-injury. Importantly, the immunohistochemistry analysis revealed that Rab7 was completely colocalized with ASC in neurons after SCI. These results suggested that Rab7 was colocalized with NeuN and ASC, involved in the pyroptosis of neurons, and closely related to the spinal cord after injury.


Assuntos
Piroptose , Traumatismos da Medula Espinal , Animais , Ratos , Neurônios/metabolismo , Ratos Sprague-Dawley , Medula Espinal/metabolismo , Traumatismos da Medula Espinal/metabolismo , Regulação para Cima
2.
Int J Mol Sci ; 23(22)2022 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-36430330

RESUMO

In the human body, copper is an important trace element and is a cofactor for several important enzymes involved in energy production, iron metabolism, neuropeptide activation, connective tissue synthesis, and neurotransmitter synthesis. Copper is also necessary for cellular processes, such as the regulation of intracellular signal transduction, catecholamine balance, myelination of neurons, and efficient synaptic transmission in the central nervous system. Copper is naturally present in some foods and is available as a dietary supplement. Only small amounts of copper are typically stored in the body and a large amount of copper is excreted through bile and urine. Given the critical role of copper in a breadth of cellular processes, local concentrations of copper and the cellular distribution of copper transporter proteins in the brain are important to maintain the steady state of the internal environment. The dysfunction of copper metabolism or regulatory pathways results in an imbalance in copper homeostasis in the brain, which can lead to a myriad of acute and chronic pathological effects on neurological function. It suggests a unique mechanism linking copper homeostasis and neuronal activation within the central nervous system. This article explores the relationship between impaired copper homeostasis and neuropathophysiological progress in brain diseases.


Assuntos
Encefalopatias , Cobre , Humanos , Sistema Nervoso Central , Encéfalo , Homeostase
3.
Acta Biomater ; 154: 259-274, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36402296

RESUMO

Traumatic brain injury (TBI) remains the major cause of disability and mortality worldwide due to the persistent neuroinflammation and neuronal death induced by TBI. Among them, pyroptosis, a specific type of programmed cell death (PCD) triggered by inflammatory signals, plays a significant part in the pathological process after TBI. Inhibition of neuroinflammation and pyroptosis is considered a possible strategy for the treatment of TBI. In our previous study, exogenous hydrogen sulfide(H2S) exerted a neuroprotective effect after TBI. Here, we developed a surface-fill H2S-releasing silk fibroin (SF) hydrogel (H2S@SF hydrogel) to achieve small-dose local administration and avoid volatile and toxic side effects. We used a controlled cortical impact (CCI) to establish a mild TBI model in mice to examine the effect of H2S@SF hydrogel on TBI-induced pyroptosis. We found that H2S@SF hydrogel inhibited the expression of H2S synthase in neurons after TBI and significantly inhibited TBI-induced neuronal pyroptosis. In addition, immunofluorescence staining results showed that the necroptosis protein receptor-interacting serine/threonine-protein kinase 1 (RIPK1) partially colocalized with the pyroptosis protein Gasdermin D (GSDMD) in the same cells. H2S@SF hydrogel can also inhibit the expression of the necroptosis protein. Moreover, H2S@SF hydrogel also alleviates brain edema and the degree of neurodegeneration in the acute phase of TBI. The neuroprotective effect of H2S@SF hydrogel was further confirmed by wire-grip test, open field test, Morris water maze, beam balance test, radial arm maze, tail suspension, and forced swimming test. Lastly, we also measured spared tissue volume, reactive astrocytes and activated microglia to demonstrate H2S@SF hydrogel impacts on long-term prognosis in TBI. Our study provides a new theoretical basis for the treatment of H2S after TBI and the clinical application of H2S@SF hydrogel. STATEMENT OF SIGNIFICANCE: Silk fibroin (SF) hydrogel controls the release of hydrogen sulfide (H2S) to inhibit neuronal pyroptosis and neuroinflammation in injured brain tissue. In this study, we synthesized a surface-fill H2S-releasing silk fibroin hydrogel, which could slowly release H2S to reshape the homeostasis of endogenous H2S in injured neurons and inhibit neuronal pyroptosis in a mouse model of traumatic brain injury. Meanwhile, H2S@SF hydrogel could alleviate brain edema and the degree of neurodegeneration, improve motor dysfunction, anxious behavior and memory impairment caused by TBI, reduce tissue loss and ameliorate neuroinflammation. Our study provides a new theoretical basis for the treatment of H2S after TBI and the clinical application of H2S@SF hydrogel.


Assuntos
Edema Encefálico , Lesões Encefálicas Traumáticas , Fibroínas , Sulfeto de Hidrogênio , Fármacos Neuroprotetores , Animais , Camundongos , Edema Encefálico/tratamento farmacológico , Edema Encefálico/patologia , Fibroínas/farmacologia , Sulfeto de Hidrogênio/farmacologia , Hidrogéis/farmacologia , Hidrogéis/uso terapêutico , Encéfalo/patologia , Lesões Encefálicas Traumáticas/patologia
4.
Biomater Adv ; 135: 212743, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35929216

RESUMO

Hydrogen sulfide (H2S), an important endogenous signaling molecule, plays an important neuroprotective role in the central nervous system. However, there is no ideal delivery material or method involving the sustained and controlled release of H2S for clinical application in brain diseases. Silk fibroin (SF)-based hydrogels have become a potentially promising strategy for local, controlled, sustained drug release in the treatment of various disorders. Here, we show a silk fibroin (SF)-based hydrogel with sustained H2S delivery (H2S@SF hydrogel) is effective in treating brain injury through stereotactic orthotopic injection in a severe intracerebral hemorrhage (ICH) mouse model. In this study, we observed H2S@SF hydrogel sustained H2S release in vitro and in vivo. The physicochemical properties of H2S@SF hydrogel were studied using FE-SEM, Raman spectroscopy and Rheological analysis. Treatment with H2S@SF hydrogel attenuated brain edema, reduced hemorrhage volume and improved the recovery of neurological deficits after severe ICH following stereotactic orthotopic injection. Double immunofluorescent staining also revealed that H2S@SF hydrogel may reduce cell pyroptosis in the striatum, cortex and hippocampus. However, when using endogenous H2S production inhibitor AOAA, H2S@SF hydrogel could not suppress ICH-induced cell pyroptosis. Hence, the therapeutic effect of the H2S@SF hydrogel may be partly the result of the slow-release of H2S and/or the effect of the SF hydrogel on the production of endogenous H2S. Altogether, the results exhibit promising attributes of injectable silk fibroin hydrogel and the utility of H2S-loaded injectable SF hydrogel as an alternative biomaterial toward brain injury treatment for clinical application.


Assuntos
Lesões Encefálicas , Fibroínas , Sulfeto de Hidrogênio , Animais , Hemorragia Cerebral/tratamento farmacológico , Hidrogéis/química , Sulfeto de Hidrogênio/farmacologia , Camundongos , Piroptose
5.
Oxid Med Cell Longev ; 2022: 2076680, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35547640

RESUMO

Silk fibroin, a natural macromolecular protein without physiological activity, has been widely used in different fields, such as the regeneration of bones, cartilage, nerves, and other tissues. Due to irrevocable neuronal injury, the treatment and prognosis of neurological diseases need to be investigated. Despite attempts to propel neuroprotective therapeutic approaches, numerous attempts to translate effective therapies for brain disease have been largely unsuccessful. As a good candidate for biomedical applications, hydrogels based on silk fibroin effectively amplify their advantages. The ability of nerve tissue regeneration, inflammation regulation, the slow release of drugs, antioxidative stress, regulation of cell death, and hemostasis could lead to a new approach to treating neurological disorders. In this review, we introduced the preparation of SF hydrogels and then delineated the probable mechanism of silk fibroin in the treatment of neurological diseases. Finally, we showed the application of silk fibroin in neurological diseases.


Assuntos
Fibroínas , Doenças do Sistema Nervoso , Materiais Biocompatíveis/uso terapêutico , Osso e Ossos , Fibroínas/farmacologia , Fibroínas/uso terapêutico , Humanos , Hidrogéis/uso terapêutico , Doenças do Sistema Nervoso/tratamento farmacológico
6.
Nat Commun ; 13(1): 1685, 2022 03 30.
Artigo em Inglês | MEDLINE | ID: mdl-35354794

RESUMO

Hydrogen sulfide (H2S) as an important biological gasotransmitter plays a pivotal role in many physiological and pathological processes. The sensitive and quantitative detection of H2S level is therefore crucial for precise diagnosis and prognosis evaluation of various diseases but remains a huge challenge due to the lack of accurate and reliable analytical methods in vivo. In this work, we report a smart, H2S-responsive and depleting nanoplatform (ZNNPs) for quantitative and real-time imaging of endogenous H2S for early diagnosis and treatment of H2S-associated diseases. We show that ZNNPs exhibit unexpected NIR conversion (F1070 → F720) and ratiometric photoacoustic (PA680/PA900) signal responsiveness towards H2S, allowing for sensitive and quantitative visualization of H2S in acute hepatotoxicity, cerebral hemorrhage model as well as colorectal tumors in living mice. ZNNPs@FA simultaneously scavenges the mitochondrial H2S in tumors leading to significant ATP reduction and severe mitochondrial damage, together with the activated photodynamic effect, resulting in efficient suppression of colorectal tumor growth in mice. We believe that this platform may provide a powerful tool for studying the vital impacts of H2S in related diseases.


Assuntos
Sulfeto de Hidrogênio , Neoplasias , Fotoquimioterapia , Animais , Camundongos , Neoplasias/diagnóstico por imagem , Neoplasias/tratamento farmacológico
7.
Oxid Med Cell Longev ; 2021: 6617256, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34113420

RESUMO

Mitochondria are multifaceted organelles that serve to power critical cellular functions, including act as power generators of the cell, buffer cytosolic calcium overload, production of reactive oxygen species, and modulating cell survival. The structure and the cellular location of mitochondria are critical for their function and depend on highly regulated activities such as mitochondrial quality control (MQC) mechanisms. The MQC is regulated by several sets of processes: mitochondrial biogenesis, mitochondrial fusion and fission, mitophagy, and other mitochondrial proteostasis mechanisms such as mitochondrial unfolded protein response (mtUPR) or mitochondrial-derived vesicles (MDVs). These processes are important for the maintenance of mitochondrial homeostasis, and alterations in the mitochondrial function and signaling are known to contribute to the dysregulation of cell death pathways. Recent studies have uncovered regulatory mechanisms that control the activity of the key components for mitophagy. In this review, we discuss how mitophagy is controlled and how mitophagy impinges on health and disease through regulating cell death.


Assuntos
Morte Celular/genética , Mitofagia/genética , Humanos , Transdução de Sinais
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