RESUMEN
BACKGROUNDS: KLKs have been proved to be key regulators of the tumor microenvironment. In this study, we explored the potential of Kallikrein-related peptidases (KLKs) as clinical diagnostic and prognostic markers in patients with kidney renal clear cell carcinoma (KIRC) as well as their relationship with common immuno-inhibitor and immune cell infiltration in the tumor microenvironment to provide new targets and novel ideas for KIRC therapy. METHODS: Oncomine, Gene Expression Profiling Interactive Analysis (GEPIA), UCSC Xena, Genotype-Tissue Expression (GTEx), Kaplan-Meier plotter, cBioPortal, STRING, GeneMANIA, and TISIDB were used to analyze the differential expression, prognostic value, gene changes, molecular interaction, and immune infiltration of KLKs in patients with KIRC. RESULTS: From the gene expression level, it can be determined that KLK1, KLK6, and KLK7 are differentially expressed in KIRC and normal tissues. From the perspective of clinical prognosis, KLK1, KLK13, and KLK14 are highly correlated with the clinical prognosis of KIRC. The expression of KLKs is regulated by various immunosuppressive agents, with KDR, PVRL2, and VTCN1 being the most significant. The expression of KLKs is significantly correlated with the infiltration of various immune cells, of which Eosinophils and Neutrophils are the most significant. CONCLUSIONS: KLK1, KLK6, KLK7, KLK13, and KLK14 have potential as diagnostic and prognostic biomarkers, among which KLK1 is the most significant. This study may provide detailed immune information and promising targets for KIRC immunotherapy to assist in designing new immunotherapies.
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Carcinoma de Células Renales , Biología Computacional , Calicreínas , Neoplasias Renales , Humanos , Calicreínas/genética , Calicreínas/metabolismo , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/patología , Neoplasias Renales/genética , Neoplasias Renales/patología , Neoplasias Renales/inmunología , Biología Computacional/métodos , Regulación Neoplásica de la Expresión Génica , Pronóstico , Microambiente Tumoral/genética , Microambiente Tumoral/inmunología , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Perfilación de la Expresión GénicaRESUMEN
BACKGROUND: Multiple studies have reported that stem cell therapy has beneficial effects in animal models of intracerebral hemorrhage (ICH). However, this finding remains inconclusive. This study was performed to systematically determine the effect size of stem cell therapy in ICH animal models by pooling and analyzing data from newly published studies. METHODS: A literature search identified studies of stem cells in animal models of ICH. We searched mainstream databases from inception to November, 2021. And pooled effect size of stem cells was determined for diversified neurobehavioral scales and structural endpoints using random effects models. RESULTS: The median quality score of 62 included studies was 5.32. Our results revealed an overall positive effect of stem cell therapy. More specifically, the SMD was - 2.27 for mNSS, - 2.14 for rotarod test, - 2.06 for MLPT, - 1.33 for cylinder test, - 1.95 for corner turn test, - 1.42 for tissue loss, and - 1.86 for brain water content. For mNSS, classifying comparisons by quality score showed significant differences in estimates of effect size (p = 0.013), and high-quality comparisons showed a better outcome (SMD = - 2.57) compared with low-quality comparisons (SMD = - 1.59). Besides, different delivery routes also showed a significant difference in the estimates of effect size for mNSS (p = 0.002), and the intraperitoneal route showed the best outcome (SMD = - 4.63). For tissue loss, the autologous blood-induced ICH model showed a better outcome (SMD = - 1.84) compared with the collagenase-induced ICH model (SMD = - 0.94, p = 0.035). Additionally, stem cell therapy initiated within 8 h post-ICH showed the greatest efficacy on tissue loss reduction, followed by initiated with 24 h post-ICH. Finally, stem cells with different sources and types showed similar beneficial effects for mNSS as well as tissue loss. CONCLUSIONS: Our results suggested that stem cell therapy had remarkable benefits on ICH animals on both the functional and structural outcomes in animal models of ICH, with very large effect size. These findings support the utility of further studies to translate stem cells in the treatment of ICH in humans. Moreover, the results should be interpreted in the light of the limitations in experimental design and the methodological quality of the studies included in the meta-analysis.
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Hemorragia Cerebral , Trasplante de Células Madre , Animales , Encéfalo , Hemorragia Cerebral/terapia , Modelos Animales de Enfermedad , HumanosRESUMEN
Stroke is one of the leading causes of death and disability in the world. However, the pathophysiological process of stroke is still not fully clarified. Mitochondria play an important role in promoting nerve survival and are an important drug target for the treatment of stroke. Mitochondrial dysfunction is one of the hallmarks of stroke. Mitochondria are in a state of continuous fission and fusion, which are termed as mitochondrial dynamics. Mitochondrial dynamics are very important for maintaining various functions of mitochondria. In this review, we will introduce the structure and functions of mitochondrial fission and fusion related proteins and discuss their role in the pathophysiologic process of stroke. A better understanding of mitochondrial dynamin in stroke will pave way for the development of new therapeutic options.
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Dinaminas , Accidente Cerebrovascular , Sistemas de Liberación de Medicamentos , Dinaminas/metabolismo , Humanos , Mitocondrias/metabolismo , Dinámicas Mitocondriales/fisiología , Proteínas Mitocondriales/metabolismo , Accidente Cerebrovascular/metabolismoRESUMEN
BACKGROUND: In March 2021, the supervision group of our hospital inspected the daily work of the outpatient department in the branch and found many problems in the process, such as an excessive number of daily check-up forms, nurses' confusion regarding the daily check-up process, and the omission of daily check-up items. Therefore, focusing on these problem, our hospital established a quality improvement team to conduct a status survey and perform this study. This study evaluated the feasibility, availability and sustainability of using a daily goals sheet in the routine work of a stomatological outpatient department and investigated the satisfaction of the nursing staff with the sheet. METHODS: After determining the theme of this study through the status survey, 60 nurses were randomly selected and divided into an experimental group and a control group by a random grouping method. Then, the study was divided into two stages: Applying the PDCA cycle method and following the MECE (Mad Exclusive, Collectively Exhaustive) principle to design, manufacture and apply the daily goals sheet. After the expert group performed Stage one, an analysis of work efficiency and routine omissions and a staff satisfaction survey were carried out. The results of the groups either using the daily goals sheet (n = 30) or not (n = 30) were analysed and compared. RESULTS: The average work time of the daily goals sheet group was 15.20 ± 1.70 min, and that of the nondaily goals sheet group was 25.30 ± 2.70 min (P < 0.001). The omission rate was 0% in the daily goals sheet group and 16.67% in the nondaily goals sheet group. Staff satisfaction with the use of the daily goals sheet was high. CONCLUSION: The daily goals sheet can make routine work more efficient and convenient in a stomatological outpatient department. It is recommended for use in stomatological outpatient departments or hospitals.
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Personal de Enfermería en Hospital , Satisfacción Personal , Objetivos , Hospitales , Humanos , Satisfacción en el Trabajo , Pacientes Ambulatorios , Mejoramiento de la CalidadRESUMEN
Cerebral ischemia-reperfusion induces mitochondrial fragmentation and dysfunction, which plays a critical role in the subsequent neuronal death and neurological impairment. Protection of mitochondria is an effective strategy to prevent neuronal damage after cerebral ischemia-reperfusion injury. USP30 is a deubiquitinating enzyme that localizes to the outer mitochondrial membrane. USP30 participates in the regulation of mitophagy and maintenance of mitochondrial morphology. In this study, the neuroprotective effect of USP30 and the underlying mechanisms were assessed in an ischemia-reperfusion injury model. SK-N-BE (2) cells were subjected to oxygen-glucose deprivation/reperfusion (OGDR) insult. Ubiquitination of mitochondrial proteins is increased during the early stage of reperfusion after oxygen-glucose deprivation (OGD), but the ubiquitination of cytoplasmic proteins exhibits no obvious changes. OGDR insult also induces rapid ubiquitination and degradation of the mitochondrial fusion protein mitofusin 2 (MFN2) in the early stage of reperfusion after OGD. Overexpression of MFN2 attenuates OGDR induced mitochondrial fragmentation. USP30 overexpression suppresses OGDR-induced ubiquitination and degradation of MFN2, and protects against mitochondrial fragmentation. Therefore, precisely targeting USP30 may provide a novel therapeutic strategy for cerebral ischemia-reperfusion related disorders.
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GTP Fosfohidrolasas/genética , Glucosa/deficiencia , Mitocondrias/metabolismo , Proteínas Mitocondriales/genética , Mitofagia , Oxígeno/metabolismo , Daño por Reperfusión/metabolismo , Tioléster Hidrolasas/genética , Ubiquitinación , Humanos , Fármacos Neuroprotectores/farmacologíaRESUMEN
Melatonin is a potent antioxidant and anti-inflammatory agent that is showing promising results in acute brain injury. The aim of this study was to systematically evaluate the pre-clinical evidence on the effectiveness of melatonin in improving outcome after intracerebral hemorrhage (ICH). We searched mainstream databases from the inception to the end of June 2020. Outcomes were measured by neurobehavioral scores or brain water content. Meta-analyses were performed with Stata 12.0 and Review Manager 5.3. Finally, 8 articles published from 2008 to 2019 met the inclusion criteria. Meta-analysis of pre-clinical data revealed an overall positive effect on neurobehavioral outcome with a standardized mean difference (SMD) of -0.81 (95% CI: -1.47, -0.15; p = 0.016) with significant heterogeneity (Q = 41.49, I2 = 68.7%; p = 0.000). Further subgroup analysis were performed from methodological differences, especially dose and timing of treatments. Furthermore, melatonin reduced cerebral edema by an SMD of -0.78 (95% CI: -1.23, -0.34; p = 0.001) with low heterogeneity. In conclusion, melatonin treatment significantly improves both behavioral and pathological outcomes in animal models of ICH. In addition, the results should be interpreted in light of the limitations in experimental design and methodological quality of the studies included in the meta-analysis.
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Hemorragia Cerebral/tratamiento farmacológico , Melatonina/uso terapéutico , Fármacos Neuroprotectores/uso terapéutico , Animales , Antiinflamatorios/uso terapéutico , Antioxidantes/uso terapéutico , Modelos Animales de Enfermedad , Resultado del TratamientoRESUMEN
Recanalization therapy by intravenous thrombolysis or endovascular therapy is critical for the treatment of cerebral infarction. However, the recanalization treatment will also exacerbate acute brain injury and even severely threatens human life due to the reperfusion injury. So far, the underlying mechanisms for cerebral ischaemia-reperfusion injury are poorly understood and effective therapeutic interventions are yet to be discovered. Therefore, in the research, we subjected SK-N-BE(2) cells to oxygen-glucose deprivation/reperfusion (OGDR) insult and performed a pooled genome-wide CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 (CRISPR-associated protein 9) knockout screen to discover new potential therapeutic targets for cerebral ischaemia-reperfusion injury. We used Metascape to identify candidate genes which might involve in OGDR resistance. We found that the genes contributed to OGDR resistance were primarily involved in neutrophil degranulation, mitochondrial translation, and regulation of cysteine-type endopeptidase activity involved in apoptotic process and response to oxidative stress. We then knocked down some of the identified candidate genes individually. We demonstrated that MRPL19, MRPL32, MRPL52 and MRPL51 inhibition increased cell viability and attenuated OGDR-induced apoptosis. We also demonstrated that OGDR down-regulated the expression of MRPL19 and MRPL51 protein. Taken together, our data suggest that genome-scale screening with Cas9 is a reliable tool to analyse the cellular systems that respond to OGDR injury. MRPL19 and MRPL51 contribute to OGDR resistance and are supposed to be promising targets for the treatment of cerebral ischaemia-reperfusion damage.
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Sistemas CRISPR-Cas , Glucosa/deficiencia , Proteínas Mitocondriales/antagonistas & inhibidores , Neuroblastoma/patología , Oxígeno/metabolismo , Daño por Reperfusión/fisiopatología , Proteínas Ribosómicas/antagonistas & inhibidores , Regulación de la Expresión Génica , Humanos , Proteínas Mitocondriales/genética , Neuroblastoma/genética , Neuroblastoma/metabolismo , Estrés Oxidativo , Proteínas Ribosómicas/genética , Células Tumorales CultivadasRESUMEN
The ubiquitin-proteasome pathway and autophagy-lysosome pathway are two major routes for clearance of aberrant cellular components to maintain protein homeostasis and normal cellular functions. Accumulating evidence shows that these two pathways are impaired during cerebral ischemia, which contributes to ischemic-induced neuronal necrosis and apoptosis. This review aims to critically discuss current knowledge and controversies on these two pathways in response to cerebral ischemic stress. We also discuss molecular mechanisms underlying the impairments of these protein degradation pathways and how such impairments lead to neuronal damage after cerebral ischemia. Further, we review the recent advance on the understanding of the involvement of these two pathways in the pathological process during many therapeutic approaches against cerebral ischemia. Despite recent advances, the exact role and molecular mechanisms of these two pathways following cerebral ischemia are complex and not completely understood, of which better understanding will provide avenues to develop novel therapeutic strategies for ischemic stroke.