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The efficacy of chemotherapeutic drugs in tumor treatment is limited by their toxicity and side effects due to their inability to selectively accumulate in tumor tissue. In addition, chemotherapeutic agents are easily pumped out of tumor cells, resulting in their inadequate accumulation. To overcome these challenges, a drug delivery system utilizing the amphiphilic peptide Pep1 was designed. Pep1 can self-assemble into spherical nanoparticles (PL/Pep1) and encapsulate paclitaxel (PTX) and lapatinib (LAP). PL/Pep1 transformed into nanofibers in an acidic environment, resulting in longer drug retention and higher drug concentrations within tumor cells. Ultimately, PL/Pep1 inhibited tumor angiogenesis and enhanced tumor cell apoptosis. The use of shape-changing peptides as drug carriers to enhance cancer cell apoptosis is promising.
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Antineoplásicos , Apoptosis , Paclitaxel , Péptidos , Apoptosis/efectos de los fármacos , Humanos , Concentración de Iones de Hidrógeno , Paclitaxel/farmacología , Paclitaxel/química , Péptidos/química , Péptidos/farmacología , Antineoplásicos/farmacología , Antineoplásicos/química , Lapatinib/química , Lapatinib/farmacología , Nanopartículas/química , Portadores de Fármacos/química , Línea Celular Tumoral , Animales , Sistemas de Liberación de MedicamentosRESUMEN
Diabetes has been associated with an elevated risk of Parkinson's disease (PD), yet the relationship between prediabetes (PreD) and the incidence of PD in the adult population remains unclear. Therefore, a systematic review and meta-analysis was conducted to evaluate if PreD is also associated with a higher risk of PD. We conducted comprehensive searches of the PubMed, Embase, and Web of Science databases to identify relevant observational studies with longitudinal follow-up. The random-effects model was employed to synthesize the data, mitigating the potential impact of study heterogeneity on the outcomes. Our analysis incorporated seven datasets from five cohort studies, encompassing 18,170,592 adult participants without a PD diagnosis at baseline. Among them, 2,432,148 (13.3%) had PreD. During the follow-up, a total of 46,682 patients were diagnosed with PD. The pooled results indicated that PreD was associated with an increased incidence of PD (risk ratio [RR] 1.09, 95% confidence interval [CI] 1.02 - 1.16; P = 0.02; I2 = 52%), after adjusting for potential confounding factors such as age, sex, body mass index (BMI), and smoking. Subsequent pilot subgroup analyses suggested that the association between PreD and PD might not be significantly influenced by the country of the study, its design, age or sex of the participants, definition of PreD, or the quality scores of the study (P for subgroup difference all > 0.05). In conclusion, adult population with PreD may have a mildly increased risk of developing PD compared to those with normoglycemia.
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Enfermedad de Parkinson , Estado Prediabético , Humanos , Enfermedad de Parkinson/epidemiología , Estado Prediabético/epidemiología , Incidencia , Factores de Riesgo , Masculino , FemeninoRESUMEN
Chemotherapy is an important cancer treatment modality, but the clinical utility of chemotherapeutics is limited by their toxic side effects, inadequate distribution and insufficient intracellular concentrations. Nanodrug delivery systems (NDDSs) have shown significant advantages in cancer diagnosis and treatment. Variable NDDSs that respond to endogenous and exogenous triggers have attracted much research interest. Here, we summarized nanomaterials commonly used for tumor therapy, such as peptides, liposomes, and carbon nanotubes, as well as the responses of NDDSs to pH, enzymes, magnetic fields, light, and multiple stimuli. Specifically, well-designed NDDSs can change in size or morphology or rupture when induced by one or more stimuli. The varying responses of NDDSs to stimulation contribute to the molecular design and development of novel NDDSs, providing new ideas for improving drug penetration and accumulation, inhibiting tumor resistance and metastasis, and enhancing immunotherapy.
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Nanopartículas , Nanotubos de Carbono , Neoplasias , Humanos , Inmunoterapia , Neoplasias/tratamiento farmacológico , Sistema de Administración de Fármacos con NanopartículasRESUMEN
BACKGROUND: The circle of Willis (CoW) plays a significant role in intracranial atherosclerosis (ICAS). This study investigated the relationship between different types of CoW, atherosclerosis plaque features, and acute ischemic stroke (AIS). METHODS: We investigated 97 participants with AIS or transient ischemic attacks (TIA) underwent pre- and post-contrast 3T vessel wall cardiovascular magnetic resonance within 7 days of the onset of symptoms. The culprit plaque characteristics (including enhancement grade, enhancement ratio, high signal in T1, irregularity of plaque surface, and normalized wall index), and vessel remodeling (including arterial remodeling ratio and positive remodeling) for lesions were evaluated. The anatomic structures of the anterior and the posterior sections of the CoW (A-CoW and P-CoW) were also evaluated. The plaque features were compared among them. The plaque features were also compared between AIS and TIA patients. Finally, univariate and multivariate regression analysis was performed to evaluate the independent risk factors for AIS. RESULT: Patients with incomplete A-CoW showed a higher plaque enhancement ratio (P = 0.002), enhancement grade (P = 0.01), and normalized wall index (NWI) (P = 0.018) compared with the patients with complete A-CoW. A higher proportion of patients with incomplete symptomatic P-CoW demonstrated more culprit plaques with high T1 signals (HT1S) compared with those with complete P-CoW (P = 0.013). Incomplete A-CoW was associated with a higher enhancement grade of the culprit plaques [odds ratio (OR):3.84; 95% CI: 1.36-10.88, P = 0.011], after adjusting for clinical risk factors such as age, sex, smoking, hypertension, hyperlipemia, and diabetes mellitus. Incomplete symptomatic P-CoW was associated with a higher probability of HT1S (OR:3.88; 95% CI: 1.12-13.47, P = 0.033), after adjusting for clinical risk factors such as age, sex, smoking, hypertension, hyperlipemia, and diabetes mellitus. Furthermore, an irregularity of the plaque surface (OR: 6.24; 95% CI: 2.25-17.37, P < 0.001), and incomplete symptomatic P-CoW (OR: 8.03, 95% CI: 2.43-26.55, P = 0.001) were independently associated with AIS. CONCLUSIONS: This study demonstrated that incomplete A-CoW was associated with enhancement grade of the culprit plaque, and incomplete symptomatic side P-CoW was associated with the presence of HT1S of culprit plaque. Furthermore, an irregularity of plaque surface and incomplete symptomatic side P-CoW were associated with AIS.
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Hipertensión , Arteriosclerosis Intracraneal , Ataque Isquémico Transitorio , Accidente Cerebrovascular Isquémico , Placa Aterosclerótica , Accidente Cerebrovascular , Humanos , Accidente Cerebrovascular/etiología , Accidente Cerebrovascular Isquémico/complicaciones , Círculo Arterial Cerebral , Valor Predictivo de las Pruebas , Imagen por Resonancia Magnética/efectos adversos , Hipertensión/complicaciones , Placa Aterosclerótica/complicaciones , Arteriosclerosis Intracraneal/complicacionesRESUMEN
Background: Diabetes mellitus, or hyperglycemia, is an independent risk factor for cognitive impairment. Here we systematically analyzed whether glycemic control could improve cognitive impairment in patients with diabetes mellitus (DM), hyperglycemia, or insulin resistance. Methods: Three databases (PubMed, EMBASE, and Cochrane Library) and ClinicalTrials.gov were searched for randomized controlled trials analyzing the relationship between glycemic control and cognitive function assessments, published from database inception to June 2022. Patients in experimental groups were treated with antidiabetic drugs, while control groups were treated with a placebo or alternative antidiabetic drugs. Data analysis was conducted using RevMan 5.3 and StataSE-64, and standardized mean difference (SMD) and 95% confidence intervals (CIs) were calculated. Results: Thirteen studies comprising 19,314 participants were included. Analysis revealed that glycemic control significantly attenuated the degree of decline in cognitive function assessment scores (SMD = 0.15; 95% CI 0.05, 0.26; p < 0.00001), and funnel plots confirmed no publication bias. Seven studies used Mini-Mental State Examination as the primary cognitive function assessment, showing that glycemic control significantly delayed the degree of decline in cognitive function assessment scores (SMD = 0.18; 95% CI 0.03, 0.34; p = 0.02). Similar results were seen in two studies using the Montreal Cognitive Assessment scale, but without significant difference (SMD = 0.05; 95% CI-0.10, 0.21; p = 0.51). One study using Auditory Word Learning Test (AVLT) showed that glycemic control significantly delayed the decline in cognitive function assessment scores (SMD = 0.52; 95% CI 0.11,0.93; p = 0.01), and another used Wechsler Memory Scale Revised, showing similar results (SMD = 1.45; 95% CI 0.86, 2.04; p < 0.00001). Likewise, a study that used Modified Mini-Mental State scale showed that glycemic control significantly delayed the decline in cognitive function assessment scores (SMD = -0.10; 95% CI-0.16, -0.03; p = 0.005). Lastly, one study used AVLT subtests to show that glycemic control delayed the decline in cognitive function assessment scores, although not statistically significant (SMD = 0.09; 95% CI-0.53, 0.71; p = 0.78). Conclusion: Glycemic control through antidiabetic treatment correlates with the improvement of cognitive impairment in patients with DM, hyperglycemia or insulin resistance. However, further studies are needed to validate the results of this study. Systematic Review Registration: PROSPERO, identifier CRD42022342260.
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AIM: To demonstrate the role of IL-6 and pSTAT3 in the inflammatory response to cerebral ischemia/reperfusion following folic acid deficiency (FD). METHODS: The middle cerebral artery occlusion/reperfusion (MCAO/R) model was established in adult male Sprague-Dawley rats in vivo, and cultured primary astrocytes were exposed to oxygen-glucose deprivation/reoxygenation (OGD/R) to emulate ischemia/reperfusion injury in vitro. RESULTS: Glial fibrillary acidic protein (GFAP) expression significantly increased in astrocytes of the brain cortex in the MCAO group compared to the SHAM group. Nevertheless, FD did not further promote GFAP expression in astrocytes of rat brain tissue after MCAO. This result was further confirmed in the OGD/R cellular model. In addition, FD did not promote the expressions of TNF-α and IL-1ß but raised IL-6 (Peak at 12 h after MCAO) and pSTAT3 (Peak at 24 h after MCAO) levels in the affected cortices of MCAO rats. In the in vitro model, the levels of IL-6 and pSTAT3 in astrocytes were significantly reduced by treatment with Filgotinib (JAK-1 inhibitor) but not AG490 (JAK-2 inhibitor). Moreover, the suppression of IL-6 expression reduced FD-induced increases in pSTAT3 and pJAK-1. In turn, inhibited pSTAT3 expression also depressed the FD-mediated increase in IL-6 expression. CONCLUSIONS: FD led to the overproduction of IL-6 and subsequently increased pSTAT3 levels via JAK-1 but not JAK-2, which further promoted increased IL-6 expression, thereby exacerbating the inflammatory response of primary astrocytes.
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Isquemia Encefálica , Deficiencia de Ácido Fólico , Daño por Reperfusión , Animales , Masculino , Ratas , Astrocitos/metabolismo , Isquemia Encefálica/metabolismo , Deficiencia de Ácido Fólico/metabolismo , Infarto de la Arteria Cerebral Media/metabolismo , Interleucina-6/metabolismo , Ratas Sprague-Dawley , Reperfusión , Daño por Reperfusión/metabolismoRESUMEN
OBJECTIVES: The characteristic of nonmotor symptoms in patients with multiple system atrophy (MSA) has varied among previous studies. The objective was to investigatethe nonmotor characteristics in MSA patients with different phenotypes, sex and different onset patterns. METHODS: We performed a retrospective review of 1492 MSA patients. All cases were evaluatedby neurologists and assessed with motormanifestations, nonmotor symptoms, auxiliary examinationand brain MRI scans. RESULTS: Multiple system atrophy-cerebellar ataxia (MSA-C) was the predominant phenotype in 998 patients. Average age of onset (56.8 ± 9.2 years) was earlier, the disease duration (2.4 ± 2.2 year) was shorter and brain MRI abnormalities (49.2 %) were more frequently in MSA-C (P < 0.001). Multiple system atrophy-parkinsonism (MSA-P) patients were more likely to have nonmotor symptoms. After adjusted significant parameters, urinary dysfunction (OR 1.441, 95 %CI = 1.067-1.946, P = 0.017), constipation (OR 1.482, 95 %CI = 1.113-1.973, P = 0.007), cognitive impairment (OR 1.509, 95 %CI = 1.074-2.121, P = 0.018) and drooling (OR 2.095, 95 %CI = 1.248-3.518, P = 0.005) were associated with the MSA-P phenotype. Males were more likely to have orthostatic hypotension, urinary dysfunction, sexual dysfunction, drooling and females in constipation and probable RBD. In different onset patterns, constipation (59.2 %) and probable RBD (28.4 %) were more frequently in autonomiconset pattern. CONCLUSIONS: MSA-C is the predominant phenotype in Chinese patients, while many nonmotor symptoms are more common in MSA-P phenotype. Patients with different sex and onset patterns have different nonmotor characteristics. The different clinical features identified could help the physician counseling of MSA patients more easily and more accurately.
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Atrofia de Múltiples Sistemas , Trastornos Parkinsonianos , Sialorrea , Masculino , Femenino , Humanos , Atrofia de Múltiples Sistemas/complicaciones , Atrofia de Múltiples Sistemas/diagnóstico por imagen , Estreñimiento/complicaciones , FenotipoRESUMEN
Folic acid, a water-soluble B-vitamin, has been demonstrated to decrease the risk of first stroke and improve its poor prognosis. However, the molecular mechanisms responsible for the beneficial effect of folic acid on recovery from ischemic insult remain largely unknown. Excessive activation of the N-methyl-d-aspartate receptors (NMDARs) has been shown to trigger synaptic dysfunction and excitotoxic neuronal death in ischemic brains. Here, we hypothesized that the effects of folic acid on cognitive impairment may involve the changes in synapse loss and NMDAR expression and function following cerebral ischemia/reperfusion injury. The ischemic stroke models were established by middle cerebral artery occlusion/reperfusion (MCAO/R) and by oxygen-glucose deprivation and reperfusion (OGD/R)-treated primary neurons. The results showed that folic acid supplemented diets (8.0 mg/kg for 28 days) improved cognitive performances of rats after MCAO/R. Folic acid also caused a reduction in the number of neuronal death, an increase in the number of synapses and the expressions of synapse-related proteins including SNAP25, Syn, GAP-43 and PSD95, and a decrease in p-CAMKII expression in ischemic brains. Similar changes in synaptic functions were observed in folic acid (32 µM)-treated OGD/R neurons. Furthermore, NMDA treatment reduced folic acid-induced upregulations of synapse-associated proteins and Ca2+ influx, whereas downregulations of NMDARs by NR1 or both NR2A and NR2B siRNA further enhanced the expressions of synapse-related proteins raised by folic acid in OGD/R neurons. Our findings suggest that folic acid improves cognitive dysfunctions and ameliorates ischemic brain injury by strengthening synaptic functions via the NMDARs.
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Isquemia Encefálica , Daño por Reperfusión , Accidente Cerebrovascular , Ratas , Animales , Receptores de N-Metil-D-Aspartato/genética , Ácido Fólico/farmacología , Isquemia Encefálica/tratamiento farmacológico , Isquemia Encefálica/metabolismo , Daño por Reperfusión/tratamiento farmacológico , Infarto de la Arteria Cerebral Media/tratamiento farmacológicoRESUMEN
Background: Cerebrospinal fluid (CSF) and serum tau (t-tau, p-tau) are potential biomarkers for neurodegeneration in Alzheimer disease (AD), but their role in amyotrophic lateral sclerosis (ALS) is unclear. Objectives: The aim of our study was to evaluate CSF and serum p-tau and t-tau in patients with ALS and to analyze the correlation and clinical parameters between them. Methods: CSF and serum samples were obtained from 90 patients with ALS, 48 other neurological disease (OND), and 20 with AM (ALS mimic, AM) diseases. The levels of p-tau and t-tau in the CSF and serum were assessed with an enzyme-linked immunosorbent assay, and disease progression parameters, including the duration, the ALSFRS-R score, disease progression rate (DPR), the upper motor neuron (UMN) score, the Mini-mental State Examination (MMSE) score, the Montreal Cognitive Assessment (MoCA) score, and the Edinburgh Cognitive and Behavioral ALS Screen (ECAS) results, were analyzed by registered neurologists. Statistical analyses were performed using Prism software. Results: Compared with controls, patients with ALS displayed significantly lower levels of CSF p-tau and p-tau:t-tau ratio. The CSF p-tau level in patients with ALS and cognition impairment was higher than that in patients with ALS who did not have cognition impairment. CSF p-tau level was negatively correlated with MMSE, MoCA, and ECAS total score and the specific score of ECAS in patients with ALS and cognition impairment. Conclusions: The CSF p-tau level and p-tau:t-tau ratio were lower in patients with ALS than patients with OND and AM. Results suggest that CSF p-tau may be used as an index of cognition impairment in patients with ALS.
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Purpose: To investigate the correlation between plasma levels of high mobility group protein N1 (HMGN1) and the severity of neurological deficits and prognosis in patients with acute cerebral infarction (ACI). Patients and Methods: The plasma HMGN1 levels of 108 patients with ACI were detected by ELISA. The National Institutes of Health Stroke Scale (NIHSS) and the modified Rankin Scale (mRS) were used to assess the neurological impairment and outcomes of these patients, respectively. The correlation between HMGN1 levels and clinical parameters was analyzed. Results: The plasma HMGN1 levels of patients with ACI were positively correlated with their NIHSS and mRS scores. Patients with the large artery atherosclerosis (LAA) subtype in the Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification had higher plasma HMGN1 levels than patients with other subtypes. Conclusion: HMGN1 levels are positively correlated with the severity of ACI and could be used to predict the prognosis of these patients. HMGN1 can be used as a biological marker and potential target for clinical assessment and therapy of ACI.
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Parkinson's disease is a brain disorder that is featured by shaking palsy, which affect the motor system. The pathogenesis of Parkinson's disease has been ascribed to neurodegenerative disorder, neural oxidative stress, neuroinflammation, and neurotransmitter disorder. In the present study, we explored the influence of Sirt1/PGC1α pathway in regulating BV-2 cells viability under TNFα treatment. Our results demonstrated that the activity of Sirt1/PGC1α pathway was significantly downregulated in response to TNFα treatment. Reactivation of Sirt1/PGC1α pathway through supplementation of SRT1720 significantly elevated the viability of BV-2 cells under an in vitro neuroinflammation model. Therefore, our results report a novel signaling pathway responsible for the survival of neuron under neuroinflammation. Re-activation of Sirt1/PGC1α pathway may be a potential therapeutic approach for the treatment of Parkinson's disease through enhancing neuronal viability.
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Enfermedad de Parkinson , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma , Sirtuina 1 , Animales , Línea Celular , Ratones , Enfermedades Neuroinflamatorias , Estrés Oxidativo , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/genética , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/genética , Sirtuina 1/genética , Sirtuina 1/metabolismoRESUMEN
Temporal persistence is as important for nanocarriers as spatial accuracy. However, because of the insufficient aggreagtion and short retention time of chemotherapy drugs in tumors, their clinical application is greatly limited. A drug delivery approach dependent on the sensitivity to an enzyme present in the microenvironment of the tumor is designed to exhibit different sizes in different sites, achieving enhanced drug permeability and retention to improve tumor nanotherapy efficacy. In this work, we report a small-molecule peptide drug delivery system containing both tumor-targeting groups and enzyme response sites. This system enables the targeted delivery of peptide nanocarriers to tumor cells and a unique response to alkaline phosphatase (ALP) in the tumor microenvironment to activate morphological transformation and drug release. The amphiphilic peptide AYR self-aggregated into a spherical nanoparticle structure after encapsulating the lipid-soluble model drug doxorubicin (DOX) and rapidly converted to nanofibers via the induction of ALP. This morphological transformation toward a high aspect ratio allowed rapid, as well as effective drug release to tumor location while enhancing specific toxicity to tumor cells. Interestingly, this "transformer"-like drug delivery strategy can enhance local drug accumulation and effectively inhibit drug efflux. In vitro along with in vivo experiments further proved that the permeability and retention of antitumor drugs in tumor cells and tissues were significantly enhanced to reduce toxic side effects, and the therapeutic effect was remarkably improved compared with that of nondeformable drug-loaded peptide nanocarriers. The developed AYR nanoparticles with the ability to undergo morphological transformation in situ can improve local drug aggregation and retention time at the tumor site. Our findings provide a new and simple method for nanocarrier morphology transformation in novel cancer treatments.
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Fosfatasa Alcalina/química , Antibióticos Antineoplásicos/farmacología , Doxorrubicina/farmacología , Nanopartículas/química , Péptidos/química , Fosfatasa Alcalina/metabolismo , Animales , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/metabolismo , Proliferación Celular/efectos de los fármacos , Doxorrubicina/química , Doxorrubicina/metabolismo , Portadores de Fármacos/química , Portadores de Fármacos/metabolismo , Sistemas de Liberación de Medicamentos , Liberación de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Neoplasias Hepáticas Experimentales/diagnóstico por imagen , Neoplasias Hepáticas Experimentales/tratamiento farmacológico , Neoplasias Hepáticas Experimentales/metabolismo , Ratones , Ratones Desnudos , Estructura Molecular , Nanopartículas/metabolismo , Tamaño de la Partícula , Péptidos/metabolismo , Propiedades de Superficie , Células Tumorales Cultivadas , Microambiente Tumoral/efectos de los fármacosRESUMEN
Spatial accuracy is crucial in drug delivery, especially to increase the efficacy and reduce the side effects of antitumor drugs. In this study, we developed a simple and broadly applicable strategy in which a target peptide ligand was introduced to construct a pH-responsive drug-loading system to achieve targeted delivery and drug release in lesions. In addition to reaching the tumor tissue through passive targeting modalities such as the enhanced permeability and retention (EPR) effect, active targeting nanoparticles used RGD motifs coupled to nanocarriers to specifically bind certain integrins, such as ανß3, which is expressed on the surface of tumor cells, to achieve active tumor cell targeting. Self-assembling peptides have significant advantages in their structural design. The amphiphilic peptide LKR could form a spherical and self-assembled nanoparticle, which encapsulated the fat-soluble antitumor drug doxorubicin (Dox) in neutral medium. The Dox-encapsulating peptide nanoparticles swelled and burst, rapidly releasing Dox in an acidic microenvironment. Flow cytometry and fluorescence detection showed that the self-assembled LKR nanoparticles enhanced the drug accumulation in tumor cells compared with normal mammalian cells. The Dox-encapsulating peptide nanoparticles exhibited desirable antitumor effects in vivo. In summary, the acidic microenvironment of tumors was used to induce drug release from a targeted peptide drug-loading system to enhance cellular uptake and therapeutic effects in situ, providing a promising therapeutic approach for the treatment of major diseases such as hepatoma.
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Nanopartículas , Neoplasias , Animales , Línea Celular Tumoral , Doxorrubicina/farmacología , Portadores de Fármacos , Sistemas de Liberación de Medicamentos , Liberación de Fármacos , Concentración de Iones de Hidrógeno , Neoplasias/tratamiento farmacológico , OligopéptidosRESUMEN
Although dramatic progress has been achieved in the understanding and treatment of multiple sclerosis (MS) and ischemic stroke (IS), more precise and instructive support is required for further research. Recent large-scale genome-wide association studies (GWASs) have already revealed risk variants for IS and MS, but the common genetic etiology between MS and IS remains an unresolved issue. This research was designed to overlapping genes between MS and IS and unmask their transcriptional features. We designed a three-section analysis process. Firstly, we computed gene-based analyses of MS GWAS and IS GWAS data sets by VGEAS2. Secondly, overlapping genes of significance were identified in a meta-analysis using the Fisher's procedure. Finally, we performed gene expression analyses to confirm transcriptional changes. We identified 24 shared genes with Bonferroni correction (P combined < 2.31E-04), and five (FOXP1, CAMK2G, CLEC2D, LBH, and SLC2A4RG) had significant expression differences in MS and IS gene expression omnibus data sets. These meaningful shared genes between IS and MS shed light on the underlying genetic etiologies shared by the diseases. Our results provide a basis for in-depth genomic studies of associations between MS and IS.
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Death associated protein kinase 1 (DAPK1) was initially discovered in the progress of gamma-interferon induced programmed cell death, it is a key factor in the central nervous system, including Parkinson's disease (PD). However, the underlying mechanisms of DAPK1 in PD remain unclear and this research work aims to explore the potential mechanisms of DAPK1 in PD. In the study, we exposed SH-SY5Y cells to MPP+ and treated mice with MPTP to investigate the roles of DAPK1 in PD and the underlying mechanisms. The results indicated that the expression of DAPK1 is significantly upregulated and negatively correlated with miR-124-3p levels in SH-SY5Y cells treated by MPP+ , and miR-124-3p mimics could effectively inhibit DAPK1 expressions and alleviate MPP+ -induced cell apoptosis. In addition, knockdown MALAT1 reduces the levels of DAPK1 and the ratio of SH-SY5Y cell apoptosis, which is reversed via miR-124-3p inhibitor in vitro. Similarly, knockdown MALAT1 could improve behavioral changes and reduce apoptosis by miR-124-3p upregulation and DAPK1 downregulation in MPTP induced PD mice. Taken together, our data showed that lncRNA MALAT1 positively regulates DAPK1 expression by targeting miR-124-3p, and mediates cell apoptosis and motor disorders in PD. In summary, these results suggest that MALAT1/miR-124-3p /DAPK1 signaling cascade mediates cell apoptosis in vitro and in vivo, which may provide experimental evidence of developing potential therapeutic strategies for PD.
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The geometry of nanoparticles plays an important role in the process of drug encapsulation and release. In this study, an acid-responsive amphiphilic polypeptide consisting of lysine and leucine was prepared. In neutral media, the amphiphilic peptide L6K4 self-assembled to form spherical nanoparticles and encapsulated fat-soluble antitumor drugs. The intratumoral accumulation of the drug-loaded nanoparticles was improved in HeLa cells compared with normal cells. Compared to a neutral environment, increasingly acidic solutions changed the secondary structure of the peptide. In addition, the drug-loaded nanoparticles expanded and decomposed, rapidly releasing the poorly soluble antitumor drug doxorubicin (DOX). In addition, the amphiphilic peptide L6K4 had antitumor properties, and the antitumor performance of the combination of L6K4 and DOX was better than that of free DOX. Our results indicate that the use of acid responsiveness to induce geometric changes in drug-loaded peptide nanoparticles could be a promising strategy for antitumor drug delivery.
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Antineoplásicos/farmacología , Portadores de Fármacos/química , Péptidos/química , Tensoactivos/química , Animales , Muerte Celular/efectos de los fármacos , Liberación de Fármacos , Endocitosis , Células HeLa , Humanos , Hidrodinámica , Concentración de Iones de Hidrógeno , Ratones , Células 3T3 NIH , Nanopartículas/química , Nanopartículas/ultraestructura , Tamaño de la Partícula , Electricidad EstáticaRESUMEN
The geometry of nanoparticles plays an important role in their performance as drug carriers. However, the pH-triggered geometrical shape switching of a cationic peptide consisting of isoleucine and lysine is seldom reported. In this work, we designed a cationic peptide with acid reactivity that can be loaded with the poorly soluble antitumor drug (doxorubicin (DOX)) to enhance tumor cell uptake and drug delivery. In a weakly acidic environment, a large portion of random coil structures formed, which subsequently led to nanoparticle destruction and rapid DOX release. In vitro studies demonstrated that this cationic peptide exhibits low toxicity to normal cells. The amount of DOX-encapsulating peptide nanoparticles taken up by tumor cells was greater than that taken up by normal cells. Our results indicated that the use of a weakly acidic microenvironment to induce geometric shape switching in drug-loaded peptide nanoparticles should be a promising strategy for antitumor drug delivery.
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Antibióticos Antineoplásicos/farmacología , Péptidos Catiónicos Antimicrobianos/química , Doxorrubicina/farmacología , Sistemas de Liberación de Medicamentos , Nanopartículas/química , Antibióticos Antineoplásicos/química , Péptidos Catiónicos Antimicrobianos/síntesis química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Doxorrubicina/química , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Concentración de Iones de Hidrógeno , Tamaño de la Partícula , Propiedades de SuperficieRESUMEN
Patients with cancer have reduced immune function and are susceptible to bacterial infection after surgery, chemotherapy, or radiotherapy. Spherical nanoparticles formed by the self-assembled peptide V6K3 can be used as carriers for poorly soluble antitumor drugs to effectively deliver drugs into tumor cells. V6K3 was designed to achieve nanoparticle-to-nanofiber geometric transformation under induction by plasma amine oxidase (PAO). PAO is commercially available and functionally similar to lysyl oxidase (LO), which is widely present in serum. After the addition of fetal bovine serum (FBS) or PAO, the secondary structure of the peptide changed, while the spherical nanoparticles stretched and transformed into nanofibers. The conversion of the self-assembled morphology reveals the susceptibility of this amphiphilic peptide to subtle chemical modifications and may lead to promising strategies to control self-assembled architecture via enzyme induction. Enzymatically self-assembled V6K3 had bactericidal properties after PAO addition that were surprisingly superior to those before PAO addition, enabling this peptide to be used to prevent infection. The amphiphilic peptide V6K3 displayed antitumor properties and low toxicity in mammalian cells, demonstrating good biocompatibility, as well as bactericidal properties, to prevent bacterial contamination. These advantages indicate that enzymatically self-assembled V6K3 has great biomedical application potential in cancer therapy.
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Antibacterianos , Antineoplásicos , Portadores de Fármacos , Monoaminooxidasa/metabolismo , Nanofibras , Nanopartículas , Péptidos , Animales , Antibacterianos/química , Antibacterianos/farmacología , Antineoplásicos/química , Antineoplásicos/farmacología , Portadores de Fármacos/química , Portadores de Fármacos/farmacología , Células HeLa , Humanos , Ratones , Células 3T3 NIH , Nanofibras/química , Nanofibras/uso terapéutico , Nanopartículas/química , Nanopartículas/uso terapéutico , Péptidos/química , Péptidos/farmacologíaRESUMEN
The O antigen is indispensable for the full function and virulence of pathogenic bacteria. During O-repeating unit (RU) biosynthesis, committed glycosyltransferases (GTs) transfer various sugars from an activated sugar donor to the appropriate lipid carrier sequentially. While the nucleotide sequence specific for O antigen of pathogenic bacteria is already known, the exact substrate specificity of most hypothetical GTs have yet be characterized. In the present paper, we report the biochemical characterization of one alpha-glucosyltransferase, WfgE, a member of GT family 4. This enzyme is implicated in the pentasaccharide RU biosynthetic pathway of E. coli O152 O antigen. A chemoenzymatically synthesized acceptor (GlcGlcNAc α-PP-O(CH2)10CH3) was used to characterize the WfgE activity. The enzyme product was determined to have a 1,2-linkage using strategy based on collision-induced dissociation electrospray ionization ion trap multiple tandem MS (CID-ESI-IT-MSn). The lack of a DxD motif and its high activity without divalent metal ions suggests that WfgE belongs to the GT-B fold superfamily. The enzyme is specific for beta-glucose or galactose-terminating acceptor substrates, and in particular UDP-glucose but also UDP-galactose as donor substrates. Our results suggest that WfgE catalyses the addition of the third sugar residue of the E. coli O152 O-RU. The recombinant GST-WfgE was solubilized and further purified to homogeneity via GST affinity chromatography, paving the way for structure-function relationship studies.