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The goal of this work was to explore the total iron burden of cerebral microbleeds (CMBs) using a semi-automatic quantitative susceptibility mapping and to establish its effect on brain atrophy through the mediating effect of white matter hyperintensities (WMH). A total of 95 community-dwelling people were enrolled. Quantitative susceptibility mapping (QSM) combined with a dynamic programming algorithm (DPA) was used to measure the characteristics of 1309 CMBs. WMH were evaluated according to the Fazekas scale, and brain atrophy was assessed using a 2D linear measurement method. Histogram analysis was used to explore the distribution of CMBs susceptibility, volume, and total iron burden, while a correlation analysis was used to explore the relationship between volume and susceptibility. Stepwise regression analysis was used to analyze the risk factors for CMBs and their contribution to brain atrophy. Mediation analysis was used to explore the interrelationship between CMBs and brain atrophy. We found that the frequency distribution of susceptibility of the CMBs was Gaussian in nature with a mean of 201 ppb and a standard deviation of 84 ppb; however, the volume and total iron burden of CMBs were more Rician in nature. A weak but significant correlation between the susceptibility and volume of CMBs was found (r = -0.113, P < 0.001). The periventricular WMH (PVWMH) was a risk factor for the presence of CMBs (number: ß = 0.251, P = 0.014; volume: ß = 0.237, P = 0.042; total iron burden: ß = 0.238, P = 0.020) and was a risk factor for brain atrophy (third ventricle width: ß = 0.325, P = 0.001; Evans's index: ß = 0.323, P = 0.001). PVWMH had a significant mediating effect on the correlation between CMBs and brain atrophy. In conclusion, QSM along with the DPA can measure the total iron burden of CMBs. PVWMH might be a risk factor for CMBs and may mediate the effect of CMBs on brain atrophy.
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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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Hipertensão , Arteriosclerose Intracraniana , Ataque Isquêmico Transitório , AVC Isquêmico , Placa Aterosclerótica , Acidente Vascular Cerebral , Humanos , Acidente Vascular Cerebral/etiologia , AVC Isquêmico/complicações , Círculo Arterial do Cérebro , Valor Preditivo dos Testes , Imageamento por Ressonância Magnética/efeitos adversos , Hipertensão/complicações , Placa Aterosclerótica/complicações , Arteriosclerose Intracraniana/complicaçõesRESUMO
BACKGROUND: Individuals with non-suicidal self-injury (NSSI) behavior are usually prone to repeated, intentional, direct harm to their own bodies that is not allowed by society without suicidal ideation. Under this behavior guidance, childhood traumatic experience may easily cause a series of psychological comorbidity symptoms, such as anxiety and depression, finally leading to a suicidal tendency. METHODS: A total of 311 adolescent NSSI behavioral patients were recruited at the Ningbo Kangning hospital, Zhejiang Province according to the DSM-5 diagnostic criteria. Demographic data, childhood abuse and neglect, internet addiction, self-esteem, anxiety, and suicidal tendency were evaluated. A structural equation model with a path induction mechanism was constructed to evaluate the relationship between distal and proximal factors related to suicidal tendencies due to childhood traumatic experiences in NSSI behavioral individuals. RESULTS: Among the 311 subjects included in the survey, 250 (80.39%) suffered traumatic experiences, such as emotional abuse/physical abuse/sexual abuse/emotional neglect or physical neglect in their childhood, 303 (97.43%) had suicidal ideation, 271 (87.14%) showed the total score of self-esteem, 148 (47.59%) had different degrees of Internet addiction tendency, and 286 (91.96%) showed obvious anxiety. The established path model fit well (GFI = 0.996, RMSEA = 0.03), and the model showed that self-esteem, anxiety, and childhood traumatic experience had standardized coefficients of -0.235 (z = -4.742, p < 0.01), 0.322 (z = 6.296, p < 0.01), 0.205 (z = 4.047, p < 0.01), respectively, with suicidal ideation path, suggesting that self-esteem, Internet addiction, and anxiety showed significant mediating effects in the process of childhood traumatic experience affecting suicidal ideation. CONCLUSION: In the context of childhood traumatic experience, it is often accompanied by a series of regulatory behaviors such as Internet addiction, self-esteem, and so on, which finally leads to anxiety, mental symptoms, and even suicidal tendencies. The results provide effective support for the structural equation modeling to evaluate the multi-level influence of NSSI behavior individuals and emphasize that childhood familial factors may lead to psychiatric comorbidity symptoms and suicidal behavior.
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Comportamento Autodestrutivo , Ideação Suicida , Adolescente , Humanos , Criança , Comportamento Autodestrutivo/psicologia , Ansiedade , Comorbidade , Inquéritos e Questionários , Fatores de RiscoRESUMO
Spinal cord injury (SCI) is one kind of severe trauma for central nervous system. Myelin debris clearance and axon regeneration are essential for nerve regeneration after SCI. Metformin, a glucose-lowering drug, has been demonstrated to promote the locomotor functional recovery after SCI. In this study, we investigated the role and molecular mechanism of metformin on myelin preservation in a rat SCI model. SCI was induced in rats by compression at T9 level using a vascular clip. We showed that administration of metformin (50 mg·kg-1·d-1, ip) for 28 days significantly improved locomotor function in SCI rats. Metformin also ameliorated SCI-induced neuronal apoptosis and promoted axon regeneration in the spinal cord. Using co-immunofluorescence of IBa-1 and MBP, and luxol fasting blue (LFB) staining, we demonstrated that metformin promoted the transformation of M1 to M2 phenotype polarization of microglial cells, then greatly facilitated myelin debris clearance and protected the myelin in SCI rats. Furthermore, metformin ameliorated SCI-induced blockade of autophagic flux in the spinal cord, and enhanced the fusion of autophagosome and lysosome by inhibiting the AMPK-mTOR signaling pathway. Moreover, metformin significantly attenuated inflammatory responses in the spinal cord. In LPS-treated BV2 cells, pretreatment with metformin (2 mM) significantly enhanced autophagy level, suppressed inflammation and cell apoptosis. The protective effects were blocked in the presence of an autophagy inhibitor 3-methyladenine (3-MA, 5 mM), suggesting that the effect of metformin on autophagy in microglial cells is essential for the myelin preservation during nerve recovery. This study reveals a novel therapeutic effect of metformin in SCI recovery by regulating the activation of microglial cells and enhancing its autophagy level.
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Metformina , Traumatismos da Medula Espinal , Animais , Axônios/metabolismo , Metformina/farmacologia , Metformina/uso terapêutico , Microglia , Bainha de Mielina/metabolismo , Regeneração Nervosa , Ratos , Ratos Sprague-Dawley , Recuperação de Função Fisiológica , Medula Espinal/metabolismo , Traumatismos da Medula Espinal/tratamento farmacológicoRESUMO
As a serious metabolic disease, diabetes causes series of complications that seriously endanger human health. The liver is a key organ for metabolizing glucose and lipids, which substantially contributes to the development of insulin resistance and type 2 diabetes mellitus (T2DM). Exogenous fibroblast growth factor 1 (FGF1) has a great potential for the treatment of diabetes. Receptor of advanced glycation end products (RAGE) is a receptor for advanced glycation end products that involved in the development of diabetes-triggered complications. Previous study has demonstrated that FGF1 significantly ameliorates diabetes-mediated liver damage (DMLD). However, whether RAGE is involved in this process is still unknown. In this study, we intraperitoneally injected db/db mice with 0.5 mg/kg FGF1. We confirmed that FGF1 treatment not only significantly ameliorates diabetes-induced elevated apoptosis in the liver, but also attenuates diabetes-induced inflammation, then contributes to ameliorate liver dysfunction. Moreover, we found that diabetes triggers the elevated RAGE in hepatocytes, and FGF1 treatment blocks it, suggesting that RAGE may be a key target during FGF1 treatment of diabetes-induced liver injury. Thus, we further confirmed the role of RAGE in FGF1 treatment of AML12 cells under high glucose condition. We found that D-ribose, a RAGE agonist, reverses the protective role of FGF1 in AML12 cells. These findings suggest that FGF1 ameliorates diabetes-induced hepatocyte apoptosis and elevated inflammation via suppressing RAGE pathway. These results suggest that RAGE may be a potential therapeutic target for the treatment of DMLD.
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Lesão Pulmonar Aguda/tratamento farmacológico , Complicações do Diabetes/tratamento farmacológico , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Tipo 2/complicações , Fator 1 de Crescimento de Fibroblastos/farmacologia , Inflamação/tratamento farmacológico , Receptor para Produtos Finais de Glicação Avançada/antagonistas & inibidores , Lesão Pulmonar Aguda/etiologia , Lesão Pulmonar Aguda/metabolismo , Lesão Pulmonar Aguda/patologia , Animais , Apoptose , Complicações do Diabetes/etiologia , Complicações do Diabetes/metabolismo , Complicações do Diabetes/patologia , Inflamação/etiologia , Inflamação/metabolismo , Inflamação/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
DL-3-n-Butylphthalide (DL-NBP), a small molecular compound extracted from the seeds of Apium graveolens Linn (Chinese celery), has been shown to exert neuroprotective effects due to its anti-inflammatory, anti-oxidative and anti-apoptotic activities. DL-NBP not only protects against ischemic cerebral injury, but also ameliorates vascular cognitive impairment in dementia patients including AD and PD. In the current study, we investigated whether and how DL-NBP exerted a neuroprotective effect against diabetes-associated cognitive decline (DACD) in db/db mice, a model of type-2 diabetes. db/db mice were orally administered DL-NBP (20, 60, 120 mg· kg-1· d-1) for 8 weeks. Then the mice were subjected to behavioral test, their brain tissue was collected for morphological and biochemical analyses. We showed that oral administration of DL-NBP significantly ameliorated the cognitive decline with improved learning and memory function in Morris water maze testing. Furthermore, DL-NBP administration attenuated diabetes-induced morphological alterations and increased neuronal survival and restored the levels of synaptic protein PSD95, synaptophysin and synapsin-1 as well as dendritic density in the hippocampus, especially at a dose of 60 mg/kg. Moreover, we revealed that DL-NBP administration suppressed oxidative stress by upregulating Nrf2/HO-1 signaling, and increased brain-derived neurotrophic factor (BDNF) expression by activating PI3K/Akt/CREB signaling in the hippocampus. These beneficial effects of DL-NBP were observed in high glucose-treated PC12 cells. Our results suggest that DL-NBP may be a potential pharmacologic agent for the treatment of DACD.
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Benzofuranos/uso terapêutico , Disfunção Cognitiva/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Disfunção Cognitiva/etiologia , Dendritos/efeitos dos fármacos , Diabetes Mellitus Tipo 2/complicações , Hipocampo/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Teste do Labirinto Aquático de Morris/efeitos dos fármacos , Células PC12 , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Sinapses/efeitos dos fármacosRESUMO
PURPOSE: Preoperative fasting is a necessary experience for pediatric patients undergoing elective surgery. The American Society of Anesthesiologist guideline shows that preoperative fasting times were reduced and safe (no solid food up to 8 hours, no fluid or formula up to 6 hours, no breast milk up to 4 hours, and no clear fluids up to 2 hours before surgery). However, preoperative fasting is usually more prolonged than the suggested time. This study aimed to investigate the duration of preoperative fasting for elective surgery at a pediatric hospital in Shanghai, China, and compare it with the evidence from guidelines. DESIGN: The study used a descriptive cross-sectional design. METHODS: A total of 211 children under anesthesia in a Shanghai's pediatric hospital were included in the study. The preoperative fasting status was assessed using a self-administered record card of preoperative fasting developed by Chinese researchers. FINDINGS: The results indicated that the length of time fasted preoperatively was longer for all participants than that recommended by the American Society of Anesthesiologists. With the long length of fasting time, it is evident that the majority of children experienced hunger (17.5%), thirst (19.4%), and anxiety (16.1%) as indicated with 8 points of the Likert 10-point scale. The degrees of these experiences were relevant to the length of preoperative fasting time. CONCLUSIONS: A big gap was revealed between the recommendation and actual practice, and children underwent an uncomfortable experience before the surgery. These results suggest that evidence-based clinical improvement is required, and the recommended preoperative fasting instruction transform into clinical practice should be promoted.
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Jejum , Hospitais Pediátricos , Criança , China , Estudos Transversais , Humanos , Cuidados Pré-Operatórios , Lacunas da Prática ProfissionalRESUMO
Type-2 diabetes (T2D) is a common metabolic disorder, which causes several physiological and pathological complications. Spleen is regarded as an important organ, which regulates immune system and iron metabolism in the body. Precious few studies have been conducted to explore the pathological and deleterious roles of diabetes on spleen. In our current study, we have explored and confirmed the pathological effects of diabetes on spleen in db/db experimental mice model. In our current study, 0.5 mg/kg fibroblast growth factor 1 (FGF1) dose was intraperitoneally administrated to db/db mice. We found that diabetes evidently induced spleen enlargement and fibrosis progression in the db/db mice. Additionally, our studies demonstrate that iron has hugely deposited in the spleen in db/db mice. Several studies have documented that diabetes largely disrupts the inflammatory cells distribution, immune homeostasis, proliferation and oxidative stress with the down-regulation of anti-inflammatory cytokines and antioxidant activities. Moreover, we have observed that FGF1 administration significantly reversed the deleterious effect of diabetes on spleen enlargement and dysfunction. In summary, these substantial findings clearly demonstrate that diabetes plays deleterious roles in maintaining the spleen structure and functions. Therefore, our investigations suggest that FGF1 can effectively prevent diabetes-mediated splenomegaly progression.
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Diabetes Mellitus Experimental/complicações , Fator 1 de Crescimento de Fibroblastos/uso terapêutico , Inflamação/patologia , Estresse Oxidativo , Esplenomegalia/tratamento farmacológico , Esplenomegalia/etiologia , Animais , Proliferação de Células/efeitos dos fármacos , Progressão da Doença , Fator 1 de Crescimento de Fibroblastos/administração & dosagem , Fator 1 de Crescimento de Fibroblastos/farmacologia , Fibrose , Inflamação/complicações , Ferro/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacos , Baço/efeitos dos fármacos , Baço/patologiaRESUMO
BACKGROUND: Diabetes induces central nervous system damage, leading to cognitive decline. Fibroblast growth factor 1 (FGF1) has dual function of neuroprotection and normalizing hyperglycemia. To date, the precise mechanisms and potential treating strategies of FGF1 for diabetes-induced cognitive decline (DICD) hasn't been fully elucidated. METHODS: In this study, db/db mice were used as DICD animal model. We found that diabetes remarkably suppressed FGF1 expression in hippocampus. Thus, exogenous FGF1 had been treated for db/db mice and SH-SY5Y cells. RESULTS: FGF1 significantly ameliorates DICD with better spatial learning and memory function. Moreover, FGF1 blocked diabetes-induced morphological structure change, neuronal apoptosis and Aß1-42 deposition and synaptic dysfunction in hippocampus. But normalizing glucose may not the only contributed factor for FGF1 treating DICD with evidencing that metformin-treated db/db mice has a inferior cognitive function than that in FGF1 group. Current mechanistic study had found that diabetes inhibits cAMP-response element binding protein (CREB) activity and subsequently suppresses brain derived neurotrophic factor (BDNF) level via coordinately regulating PERK signaling and PI3K/AKT signaling in hippocampus, which were reversed by FGF1. CONCLUSION: We conclude that FGF1 exerts its neuroprotective role and normalizing hyperglycemia effect, consequently ameliorates DICD, implying FGF1 holds a great promise to develop a new treatment for DICD. Video abstract.
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Disfunção Cognitiva/tratamento farmacológico , Complicações do Diabetes/tratamento farmacológico , Fator 1 de Crescimento de Fibroblastos/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , eIF-2 Quinase/metabolismo , Animais , Linhagem Celular , Disfunção Cognitiva/metabolismo , Complicações do Diabetes/metabolismo , Diabetes Mellitus/fisiopatologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Transdução de SinaisRESUMO
The ability to "see" both incoming and circulating nutrients plays an essential role in the maintenance of energy homeostasis. As such, nutrient-sensing mechanisms in both the gastrointestinal tract and the brain have been implicated in the regulation of energy intake and glucose homeostasis. The intestinal wall is able to differentiate individual nutrients through sensory machinery expressed in the mucosa and provide feedback signals, via local gut peptide action, to maintain energy balance. Furthermore, both the hypothalamus and hindbrain detect circulating nutrients and respond by controlling energy intake and glucose levels. Conversely, nutrient sensing in the intestine plays a role in stimulating food intake and preferences. In this review, we highlight the emerging evidence for the regulation of energy balance through nutrient-sensing mechanisms in the intestine and the brain, and how disruption of these pathways could result in the development of obesity and type 2 diabetes.
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Encéfalo/fisiologia , Metabolismo Energético/fisiologia , Intestinos/fisiologia , Fenômenos Fisiológicos da Nutrição/fisiologia , Metabolismo dos Carboidratos/fisiologia , Homeostase , Humanos , Metabolismo dos Lipídeos/fisiologia , Proteínas/metabolismoRESUMO
Prostate cancer (PCa) is the second leading cause of death in males. It has been reported that δ-catenin expression is upregulated during the late stage of prostate cancer. Palmitoylation promotes protein transport to the cytomembrane and regulates protein localization and function. However, the effect of δ-catenin palmitoylation on the regulation of cancer remains unknown. In this study, we utilized prostate cancer cells overexpressing mutant δ-catenin (J6A cells) to induce a depalmitoylation phenotype and investigate its effect on prostate cancer. Our results indicated that depalmitoylation of δ-catenin not only reduced its membrane expression but also promoted its degradation in the cytoplasm, resulting in a decrease in the effect of EGFR and E-cadherin signaling. Consequently, depalmitoylation of δ-catenin reduced the proliferation and metastasis of prostate cancer cells. Our findings provide novel insights into potential therapeutic strategies for controlling the progression of prostate cancer through palmitoylation-based targeting of δ-catenin.
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Caderinas , Cateninas , Proliferação de Células , delta Catenina , Progressão da Doença , Lipoilação , Neoplasias da Próstata , Masculino , Humanos , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Neoplasias da Próstata/genética , Cateninas/metabolismo , Cateninas/genética , Linhagem Celular Tumoral , Caderinas/metabolismo , Caderinas/genética , Receptores ErbB/metabolismo , Receptores ErbB/genética , Transdução de Sinais , Animais , Movimento Celular , Regulação Neoplásica da Expressão GênicaRESUMO
Background: Non-suicidal self-injury (NSSI), of which the predisposing factors are complex and diverse, profoundly affects the physical and mental health of young people. Therefore, this work established an NSSI intermediary network model considering the interaction of multiple factors. A mediating effect between attention-deficit/hyperactivity disorder (ADHD) and NSSI, considering the influence of comorbidities, such as depression, anxiety, and impulsive personality, was proposed based on sex differences. Methods: A total of 2,689 middle school students in Ningbo City, Zhejiang Province, China, were randomly sampled and participated in this study. Data regarding their demographic characteristics, attention deficit, hyperactivity/impulsivity, NSSI, anxiety, depression, internet addiction, and other comorbid symptoms were collected and analyzed. After initially screening the data, variables were assessed for significance using a single-factor inter-group difference analytic method, and a binary logistic regression analysis was performed. The intermediary effect of factors influencing NSSI in males and females was also analyzed. Results: The overall NSSI rate was 15.16%. The results showed that the impact of individual impulsivity characteristics (impulsiveness, the ADHD with hyperactivity/impulsivity subtype) on NSSI behavior was not significant (regression results, P > 0.05). The degree of association between ADHD with attention deficit and ADHD with comprehension deficit subtypes, and other comorbid symptoms (depression, anxiety, and internet addiction disorder) and NSSI, with odds ratios (ORs) of 7.6/6.42/436.68/3.82/1.86, and 95% bootstrap confidence intervals (CIs) of 4.64, 12.87/3.46, 12.67/137.42, 2659.13/2.32, 6.37/1.31, 2.82, respectively. The results also showed significant effects of ADHD subtypes on comorbid symptoms and the path effects of NSSI (P < 0.01). Among them, the mediating effect was the strongest when anxiety was the mediating variable, and the mediating effect of girls was higher than that of boys. Conclusion: The results of this work demonstrated the influence of ADHD symptoms on NSSI behavior. Among patients with ADHD, patients with subtypes with obvious attention deficit characteristics were more likely to exhibit NSSI behavior, whereas the hyperactive impulse subtype had no direct impact on NSSI. We conclude that adolescent impulsivity may not be directly related to NSSI behavior and that impulsive characteristics jointly affect NSSI behavior through a series of NSSI comorbid symptoms. Notably, the probability of symptom onset and the degree of comorbidity was significantly higher in girls than in boys of the same age, and girls were more prone to NSSI behavior. These findings provide effective theoretical support for the prevention and treatment of adolescent NSSI behavior.
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Transtorno do Deficit de Atenção com Hiperatividade , Comportamento Autodestrutivo , Adolescente , Humanos , Masculino , Feminino , Transtorno do Deficit de Atenção com Hiperatividade/epidemiologia , Comportamento Autodestrutivo/psicologia , Saúde Mental , Comorbidade , Ansiedade/epidemiologiaRESUMO
Oxidative stress (OS) is one of the crucial molecular events of secondary spinal cord injury (SCI). Basic fibroblast growth factor (bFGF) is a multipotent cell growth factor with an anti-oxidant effect. However, bFGF has a short half-life in vivo, which limits its therapeutic application. Biodegradable polymers with excellent biocompatibility have been recently applied in SCI. The negative aspect is that polymers cannot provide a significant therapeutic effect. Betulinic acid (BA), a natural anti-inflammatory compound, has been polymerized into poly (betulinic acid) (PBA) to serve as a drug carrier for bFGF. This study explores the therapeutic effects and underlying molecular mechanisms of PBA nanoparticles (NPs) loaded with bFGF (PBA-bFGF NPs) in SCI. Results show that PBA-bFGF NPs produce remarkable biocompatibility in vivo and in vitro. The results also demonstrate that local delivery of PBA-bFGF NPs enhances motor function recovery, inhibits OS, mitigates neuroinflammation, and alleviates neuronal apoptosis following SCI. Furthermore, the results indicate that local delivery of PBA-bFGF NPs activates the nuclear factor erythroid 2-related factor 2 (Nrf-2) signaling pathway following SCI. In summary, results suggest that local delivery of PBA-bFGF NPs delivers potential therapeutic advantages in the treatment and management of SCI.
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Ácido Betulínico , Fator 2 de Crescimento de Fibroblastos , Nanopartículas , Traumatismos da Medula Espinal , Animais , Masculino , Ratos , Apoptose/efeitos dos fármacos , Ácido Betulínico/química , Portadores de Fármacos/química , Fator 2 de Crescimento de Fibroblastos/administração & dosagem , Fator 2 de Crescimento de Fibroblastos/química , Fator 2 de Crescimento de Fibroblastos/farmacologia , Nanopartículas/química , Nanopartículas/uso terapêutico , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Polímeros/química , Ratos Sprague-Dawley , Recuperação de Função Fisiológica/efeitos dos fármacos , Traumatismos da Medula Espinal/tratamento farmacológicoRESUMO
Hemodialysis patients exhibit anemia-related cerebral hyperperfusion and iron deposition (ID). However, the mechanisms underlying the pathology of cerebral ID are not clear. We investigated the role of cerebral blood flow (CBF) in the pathophysiology of cerebral ID in hemodialysis patients with anemia. This study recruited 33 hemodialysis patients with anemia and thirty-three healthy controls (HCs). All the subjects underwent quantitative susceptibility mapping (QSM) and arterial spin labeling (ASL) to measure ID and CBF in the cerebral nuclei. Furthermore, we evaluated lacunar infarction (LI), cerebral microbleeds, and total white matter hyperintensity volume (TWMHV). Hemodialysis patients with anemia showed significantly higher ID and CBF in some nuclei compared to the HCs after adjusting for age, sex, and total intracranial volume (TIV) [P < 0.05, false discovery rate (FDR) corrected]. CBF showed a positive correlation with ID in both patients and HCs after adjustments for age, gender, and TIV (P < 0.05, FDR corrected). Serum phosphorus, calcium, TWMHV, hypertension, and dialysis duration were independently associated with ID (P < 0.05). Hemoglobin, serum phosphorus, and LI were independently associated with CBF (P < 0.05). Mediation analysis demonstrated that CBF mediated the effects between hemoglobin and ID. Our study demonstrated that CBF mediated aberrant cerebral ID in hemodialysis patients with anemia.
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Anemia , Sobrecarga de Ferro , Humanos , Imageamento por Ressonância Magnética , Diálise Renal/efeitos adversos , Circulação Cerebrovascular/fisiologia , Fósforo , Marcadores de SpinRESUMO
Hematologic malignancies (HMs) pose a serious threat to patients' health and life, and the five-year overall survival of HMs remains low. The lack of understanding of the pathogenesis and the complex clinical symptoms brings immense challenges to the diagnosis and treatment of HMs. Traditional therapeutic strategies for HMs include radiotherapy, chemotherapy, targeted therapy and hematopoietic stem cell transplantation. Although immunotherapy and cell therapy have made considerable progress in the last decade, nearly half of patients still relapse or suffer from drug resistance. Recently, studies have emerged that nanomaterials, nanotechnology and nanomedicine show great promise in cancer therapy by enhancing drug targeting, reducing toxicity and side effects and boosting the immune response to promote durable immunological memory. In this review, we summarized the strategies of recently developed nanomaterials, nanotechnology and nanomedicines against HMs and then proposed emerging strategies for the future designment of nanomedicines to treat HMs based on urgent clinical needs and technological progress.
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Neoplasias Hematológicas , Nanoestruturas , Neoplasias , Humanos , Nanomedicina , Recidiva Local de Neoplasia/tratamento farmacológico , Nanotecnologia , Nanoestruturas/uso terapêutico , Sistemas de Liberação de Medicamentos , Neoplasias Hematológicas/tratamento farmacológico , Neoplasias/terapiaRESUMO
Background: Nonsuicidal self-injury (NSSI) behaviors-an important factor that profoundly affects the physical and mental health of young people-are induced by complex and diverse factors, while showing significant differences at the gender level. We examined mediating behaviors among parenting styles, students' coping styles, and endogenous and exogenous influencing variables of adolescents' NSSI behaviors. Methods: In this cross-sectional study, Secondary school students in Ningbo, Zhejiang Province, China (n = 2,689; F/M:1532/1157) were surveyed for basic attributes, parenting styles, coping styles, and NSSI behaviors. After the initial screening of the sample data, several external derivatives were screened based on the single factor analysis method. On this basis, the construction of path analysis models under multivariate multiple elicitations was carried out. Results: The overall prevalence of NSSI was 15.16%, and the incidence of NSSI in boys was lower than that in girls (OR = 0.334, 95% CI [0.235-0.474]). The path analysis model data fit well; the indicators of female and male part are: CFI = 0.913/0.923, GFI = 0.964/0.977, SRMR = 0.055/0.047, RMSEA = 0.097/0.069 with 90% confidence interval (CI) [0.084-0.111]/[0.054-0.084]. For female, when negative coping style and extreme education affect NSSI respectively, the standardized path coefficient values are 0.478 (z = 20.636, P = 0.000 < 0.01) and 0.151 (z = 6.524, P = 0.000 < 0.01) respectively, while for male, the corresponding values become 0.225 (z = 7.057, P < 0.001) and 0.104 (z = 3.262, P < 0.001). Conclusion: In particular, we investigated the mediating effects of gender-specific NSSI influences and found that NSSI behaviors were strongly associated with environmental variables and individual factors, especially family parenting style and adolescent coping style, which influenced NSSI in a gender-specific manner. The results showed that males were the target of both positive and negative parenting styles, whereas females were more likely to choose negative coping styles directed towards emotions in response to external stimuli, and instead showed a more significant predisposition towards NSSI behaviors. This phenomenon seems to be influenced by multilevel factors such as sociocultural, individual value identity, and physiological structure differences. In the path analysis model with the introduction of mediating effects, the influence of gender differences on NSSI behavior becomes more pronounced under the interaction of multiple factors: women seem to be more significantly influenced by the external derivatives in the internal derivatives than male subjects, and are more likely to trigger NSSI behavior under the interaction of multiple factors. These findings effectively reveal the significant role of different end-influencing factors in NSSI behaviors at the level of gender differences, which can provide effective theoretical support to prevent and treat NSSI behaviors in adolescents.
Assuntos
Poder Familiar , Comportamento Autodestrutivo , Adolescente , Humanos , Masculino , Feminino , Estudos Transversais , Comportamento Autodestrutivo/epidemiologia , Adaptação Psicológica , EmoçõesRESUMO
OBJECTIVE: Depression disorder is accompanied by cognitive impairments. However, there is limited research focused on cognitive impairments and their neurological mechanism in adolescents with depression. The purpose of the current study is to illustrate the differences in brain activity patterns between depressed adolescents and healthy controls (HCs). METHOD: A total of 72 adolescents with depression, as well as 74 HCs, were recruited. We utilized functional near-infrared spectroscopy (fNIRS) to monitor the concentrations of oxyhemoglobin (Oxy-Hb) in the brains of participants while they performed the verbal fluency task (VFT) to examine cognitive impairment in adolescents with depression. RESULTS: Our study demonstrated that adolescents with depression had significantly less cortical activation in the hemodynamic responses of Oxy-Hb at channels mainly located in the prefrontal cortex (PFC) than HCs during the 60-s task period (false discovery rate (FDR)-corrected p < 0.05). The mean channel-to-channel connectivity was 0.400 for HCs (SD = 0.149) and 0.303 (SD = 0.138) for adolescents with depression, and the HC group had a higher mean channel-to-channel connectivity strength than the depression group (t = -15.586, p < 0.001). For the patient group, we found significant negative correlations between HAMD scores and mean Oxy-Hb changes in Channel 38 (r = -0.33, p < 0.01), Channel 39 (r = -0.34, p < 0.01), Channel 41 (r = -0.25, p < 0.05), Channel 42 (r = -0.28, p < 0.05), and Channel 44 (r = -0.27, p < 0.05), and these channels were mainly located in areas with little difference between groups. CONCLUSIONS: Our study provides neurological evidence about the executive function (EF) in depressed adolescents. Adolescents with depression exhibited an abnormal activation pattern and decreased task-related functional connectivity compared to HCs. The changed Oxy-Hb concentration of PFC during VFT was not sensitive to depression symptoms.
Assuntos
Disfunção Cognitiva , Depressão , Adolescente , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/etiologia , Humanos , Testes Neuropsicológicos , Oxiemoglobinas/metabolismo , Córtex Pré-Frontal/metabolismo , Espectroscopia de Luz Próxima ao Infravermelho/métodosRESUMO
In previous research on the resistance of cotton to Verticillium wilt (VW), Gossypium hirsutum and G. barbadense were usually used as the susceptible and resistant cotton species, despite their different genetic backgrounds. Herein, we present data independent acquisition (DIA)-based comparative proteomic analysis of two G. barbadense cultivars differing in VW tolerance, susceptible XH7 and resistant XH21. A total of 4,118 proteins were identified, and 885 of them were differentially abundant proteins (DAPs). Eight co-expressed modules were identified through weighted gene co-expression network analysis. GO enrichment analysis of the module that significantly correlated with V. dahliae infection time revealed that oxidoreductase and peroxidase were the most significantly enriched GO terms. The last-step rate-limiting enzyme for ascorbate acid (AsA) biosynthesis was further uncovered in the significantly enriched GO terms of the 184 XH21-specific DAPs. Additionally, the expression of ascorbate peroxidase (APX) members showed quick accumulation after inoculation. Compared to XH7, XH21 contained consistently higher AsA contents and rapidly increased levels of APX expression, suggesting their potential importance for the resistance to V. dahliae. Silencing GbAPX1/12 in both XH7 and XH 21 resulted in a dramatic reduction in VW resistance. Our data indicate that APX-mediated oxidoreductive metabolism is important for VW resistance in cotton.
RESUMO
Hypothalamic regulation of lipid and glucose homeostasis is emerging, but whether the dorsal vagal complex (DVC) senses nutrients and regulates hepatic nutrient metabolism remains unclear. Here, we found in rats DVC oleic acid infusion suppressed hepatic secretion of triglyceride-rich very-low-density lipoprotein (VLDL-TG), which was disrupted by inhibiting DVC long-chain fatty acyl-CoA synthetase that in parallel disturbed lipid homeostasis during intravenous lipid infusion. DVC glucose infusion elevated local glucose levels similarly as intravenous glucose infusion and suppressed hepatic glucose production. This was independent of lactate metabolism as inhibiting lactate dehydrogenase failed to disrupt glucose sensing and neither could DVC lactate infusion recapitulate glucose effect. DVC oleic acid and glucose infusion failed to lower VLDL-TG secretion and glucose production in high-fat fed rats, while inhibiting DVC farnesoid X receptor enhanced oleic acid but not glucose sensing. Thus, an impairment of DVC nutrient sensing may lead to the disruption of lipid and glucose homeostasis in metabolic syndrome.
RESUMO
Diabetic nephropathy (DN) is a common diabetes associated complication. Thus, it is important to understand the pathological mechanism of DN and find the appropriate therapeutic strategy for it. Dl-3-n-Butylphthalide (DL-NBP) has anti-inflammatory and antioxidant effects, and been widely used for the treatment of stroke and cardiovascular diseases. In this study, we selected three different doses (20, 60, and 120 mgâ kg-1 d-1) of DL-NBP and attempted to elucidate its role and molecular mechanism underlying DN. We found that DL-NBP, especially at the dose of 60 or 120 mgâ kg-1 d-1, could significantly ameliorate diabetes-induced elevated blood urea nitrogen (BUN) and creatinine level, and alleviate renal fibrosis. Additionally, the elevated expressions of collagen and α-smooth muscle actin (α-SMA) in the kidney from db/db mice were found to be significantly suppressed after DL-NBP treatment. Furthermore, mechanistic studies revealed that DL-NBP inhibits pro-inflammatory cytokine levels, thereby ameliorating the development of renal fibrosis. Moreover, we found that DL-NBP could not only reduce the endoplasmic reticulum stress (ERS), but also suppress activation of the renin-angiotensin system to inhibit vascular endothelial growth factor (VEGF) level, which subsequently reduces the podocyte apoptosis in kidney of db/db mice. In a word, our findings suggest that DL-NBP may be a potential therapeutic drug in the treatment of DN.