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BACKGROUND: Ischemic stroke (IS) occurs when a blood vessel supplying the brain becomes obstructed, resulting in cerebral ischemia. This type of stroke accounts for approximately 87% of all strokes. Globally, IS leads to high mortality and poor prognosis and is associated with neuroinflammation and neuronal apoptosis. D-allose is a bio-substrate of glucose that is widely expressed in many plants. Our previous study showed that D-allose exerted neuroprotective effects against acute cerebral ischemic/reperfusion (I/R) injury by reducing neuroinflammation. Here, we aimed to clarify the beneficial effects D-allose in suppressing IS-induced neuroinflammation damage, cytotoxicity, neuronal apoptosis and neurological deficits and the underlying mechanism in vitro and in vivo. METHODS: In vivo, an I/R model was induced by middle cerebral artery occlusion and reperfusion (MCAO/R) in C57BL/6 N mice, and D-allose was given by intraperitoneal injection within 5 min after reperfusion. In vitro, mouse hippocampal neuronal cells (HT-22) with oxygen-glucose deprivation and reperfusion (OGD/R) were established as a cell model of IS. Neurological scores, some cytokines, cytotoxicity and apoptosis in the brain and cell lines were measured. Moreover, Gal-3 short hairpin RNAs, lentiviruses and adeno-associated viruses were used to modulate Gal-3 expression in neurons in vitro and in vivo to reveal the molecular mechanism. RESULTS: D-allose alleviated cytotoxicity, including cell viability, LDH release and apoptosis, in HT-22 cells after OGD/R, which also alleviated brain injury, as indicated by lesion volume, brain edema, neuronal apoptosis, and neurological functional deficits, in a mouse model of I/R. Moreover, D-allose decreased the release of inflammatory factors, such as IL-1ß, IL-6 and TNF-α. Furthermore, the expression of Gal-3 was increased by I/R in wild-type mice and HT-22 cells, and this factor further bound to TLR4, as confirmed by three-dimensional structure prediction and Co-IP. Silencing the Gal-3 gene with shRNAs decreased the activation of TLR4 signaling and alleviated IS-induced neuroinflammation, apoptosis and brain injury. Importantly, the loss of Gal-3 enhanced the D-allose-mediated protection against I/R-induced HT-22 cell injury, inflammatory insults and apoptosis, whereas activation of TLR4 by the selective agonist LPS increased the degree of neuronal injury and abolished the protective effects of D-allose. CONCLUSIONS: In summary, D-allose plays a crucial role in inhibiting inflammation after IS by suppressing Gal-3/TLR4/PI3K/AKT signaling pathway in vitro and in vivo.
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Despite the biogeochemical importance of phosphate fate and transport in aquatic environments, little is known about how competition with other common aqueous oxyanions affects its retention by mineral surfaces. Here, we examined the competitive uptake of phosphate and silicate on goethite over a wide pH range, using batch measurements supported by DFT calculations. The results show selective adsorption of phosphate at pH < 4 and silicate at pH > 10 with little to no competitive effect. However, between 4 < pH < 10, the total phosphate and silicate loading was found to be almost equal to that of silicate loading from single-component solution, revealing a proportionate competition for surface site types and a competitive effect controlling their mutual retention. DFT-calculated adsorption energies and charge density redistributions for various surface complexes on different charged (101) and (210) facets are consistent with the trends observed in batch measurements, suggesting that the observed behavior reflects the primary controlling influence of goethite surface chemistry at the molecular scale. An important implication is that at the circumneutral pH in most environmental systems, where iron oxyhydroxides comprise much of the reactive interfacial area, unbound phosphate concentrations may be strongly controlled by dissolved silicate concentration, and vice versa.
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Compostos de Ferro , Fosfatos , Adsorção , Teoria da Densidade Funcional , Concentração de Íons de Hidrogênio , Compostos de Ferro/química , Minerais/química , Fosfatos/química , SilicatosRESUMO
Although it is well known that phosphate retention in soils and sediments is strongly influenced by binding to secondary iron oxides, there have been relatively few studies examining its adsorption/desorption behavior on multicomponent particles of realistic natural complexity. In this study, natural Mn-rich limonite (LM), was used to prepare naturally complex Fe- and Mn-oxide composite materials to examine phosphate adsorption/desorption. To clarify the role of the Mn-oxides, results for the LM sample were compared to those for an acid treated version (LAT), in which the acid-extractable Mn-oxide fraction has been selectively eliminated while leaving the Fe-oxide fraction intact. The saturated adsorption capacity on LAT was almost double that on LM, suggesting that phosphate adsorption to the iron oxides is strongly occluded by the Mn-oxide fraction. This result is reinforced by the comparing the pH dependence and fits to adsorption isotherms, and by desorption experiments and STEM-EDS mapping showing that phosphate loading on Mn-oxides was limited. Hence, although the collective results confirm that phosphate uptake and strong binding is selectively controlled by the Fe-oxide fraction, our study reveals that the Mn-oxide fraction strongly interferes with this process. Therefore, phosphate uptake behavior on metal oxides cannot be predicted solely on the basis of the Fe-oxide fraction present, but instead must take into account the deleterious impacts of other intimately associated phases. For co-diagenetic Fe/Mn-oxide composites in particular, Mn-oxides appear to severely limit phosphate uptake on the Fe-oxide fraction, either by hindering access to binding sites on the Fe-oxide or by lowering their affinity for P.
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Ferro , Fosfatos , Adsorção , Ferro/química , Oxirredução , Compostos de Manganês/química , Óxidos/química , Cinética , SoloRESUMO
Chronic cerebral hypoperfusion (CCH)-induced white matter lesions (WMLs) are region-specific with the optic tract (OT) displaying the most severe damages and leading to visual-based behavioral impairment. Previously we have demonstrated that anti-high-mobility group box 1 (HMGB1) neutralizing antibody (Ab) prevents CCH-induced hippocampal damages via inhibition of neuroinflammation. Here we tested the protective role of the Ab on CCH-induced OT injuries. Rats were treated with permanent occlusion of common carotid arteries (2-VO) or a sham surgery, and then administered with PBS, anti-HMGB1 Ab, or paired control Ab. Pupillary light reflex examination, visual water maze, and tapered beam-walking were performed 28 days post-surgery to investigate the behavioral deficits. Meanwhile, WMLs were measured by Klüver-Barrera (KB) and H&E staining, and glial activation was further assessed to evaluate inflammatory responses in OT. Results revealed that anti-HMGB1 Ab ameliorated the morphological damages (grade scores, vacuoles, and thickness) in OT area and preserved visual abilities. Additionally, the increased levels of inflammatory responses and expressions of TLR4 and NF-κB p65 and phosphorylated NF-κB p65 (p-p65) in OT area were partly down-regulated after anti-HMGB1 treatment. Taken together, these findings suggested that HMGB1 neutralization could ease OT injuries and visual-guided behavioral deficits via suppressing inflammatory responses.
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Regulação para Baixo , Proteína HMGB1/metabolismo , Inflamação/patologia , Testes de Neutralização , Trato Óptico/irrigação sanguínea , Trato Óptico/lesões , Substância Branca/irrigação sanguínea , Substância Branca/patologia , Animais , Anticorpos/farmacologia , Comportamento Animal , Masculino , Aprendizagem em Labirinto , NF-kappa B/metabolismo , Neuroglia/metabolismo , Trato Óptico/patologia , Ratos Wistar , Transdução de Sinais , Receptor 4 Toll-Like/metabolismoRESUMO
Objective: Ras association domain family 1 A (RASSF1A) has been regarded as a biomarker predicting the prognosis of non-small cell lung cancer (NSCLC), but previous findings are inconsistent. This meta-analysis of prospective studies aimed to assess the value of RASSF1A methylation in predicting the prognosis of NSCLC patients. Methods: Studies were searched in PubMed and Web of Science. The estimates of the effects and the corresponding 95% confidence intervals (95% CIs) were used for the analyses. The overall effects of RASSF1A methylation on overall survival (OS) were estimated, after which subgroup analysis based on regions was conducted. Sensitivity analyses were conducted to restrict the studies with certain features. Results: A total of 16 studies with 2210 participants were included in this meta-analysis. The overall analysis result indicated that RASSF1A methylation had no statistically significant effects on OS of NSCLC patients (HR = 1.28; 95% CI 0.86-1.70), which were confirmed by the subgroup analysis. However, the sensitivity analysis indicated that RASSF1A methylation from lung cancer tissues was significantly associated with lower OS (HR = 1.24; 95% CI 1.04-1.45). Conclusion: RASSF1A methylation in lung cancer tissue can serve as a prognostic factor of NSCLC. More studies are needed to uncover the underlying mechanisms.
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Carcinoma Pulmonar de Células não Pequenas/genética , Metilação de DNA/genética , Proteínas Supressoras de Tumor/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Prognóstico , Regiões Promotoras GenéticasRESUMO
BACKGROUND: Drug combination therapies using cisplatin and natural products are common practice in the treatment of human lung cancer. Osthole is a natural compound extracted from a number of medicinal plants and has been shown to exert strong anticancer activities with low toxicity. METHODS: In the present study, NBM-T-BMX-OS01 (BMX), derived from the semi-synthesis of osthole, was evaluated in cisplatin treated A549 cells to investigate its effect on cisplatin resistance in human lung cancer. The anticancer effect of BMX were measured by cell viablity' colony formation' TUNEL staining' flow cytometry and cell cycle assay. The fluorescence staining was performed to detect intracellular and mitochondrial reactive oxygen species (ROS) generation. Western blot analysis, antagonists pretreatment and small interfering RNA (siRNA) transfection were used to determine the potential mechanism. RESULTS: It was found that, in comparison with single cisplatin treatment, the combination of BMX and cisplatin resulted in greater efficacy in inhibition of proliferation and colony formation, apoptosis induction and cell cycle arrest. The results of fluorescence staining showed that the combination effect of BMX and cisplatin was due to oxidative stress induced by mitochondrial ROS generation. In addition, BMX significantly attenuated the phosphorylation of ERK and Akt, two important pro-survival kinases. In contrast, BMX inhibited the activation of AMPK, and knockdown of AMPK using specific siRNA partially reversed BMX-induced inhibition of ERK and Akt, as well as its synthetic effects on cisplatin induced anticancer activity in A549 cells. CONCLUSION: Taken together, this study provides that BMX might modulate cisplatin resistance through AMPK-ERK and AMPK-Akt pathways. These results also support the role of BMX as a potential drug candidate for use in combination with cisplatin in the treatment of human lung cancer.
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Adjuvantes Imunológicos/farmacologia , Antineoplásicos/farmacologia , Cisplatino/farmacologia , Cumarínicos/farmacologia , Células Epiteliais/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Proteínas Quinases Ativadas por AMP/antagonistas & inibidores , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sinergismo Farmacológico , Quimioterapia Combinada , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Humanos , Proteína Quinase 1 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 1 Ativada por Mitógeno/genética , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 3 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Estresse Oxidativo , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Espécies Reativas de Oxigênio/agonistas , Espécies Reativas de Oxigênio/metabolismo , Mucosa Respiratória/efeitos dos fármacos , Mucosa Respiratória/metabolismo , Mucosa Respiratória/patologia , Transdução de SinaisRESUMO
Despite the great potential of sulfur-based autotrophic denitrification, an improvement in nitrate removal rate is still needed. This study used the desulfurized products of Mn ore to develop the MnS-S0-limestone autotrophic denitrification system (MSLAD). The feasibility of MSLAD for denitrification was explored and the possible mechanism was proposed. The nitrate (100 mg/L) was almost removed within 24 h in batch experiment in MSLAD. Also, an average TN removal of 98 % (472.0 mg/L/d) at hydraulic retention time of 1.5 h in column experiment (30 mg/L) was achieved. MnS and S0 could act as coupled electron donors and show synergistic effects for nitrate removal. γ-MnS with smaller particle size and lower crystallinity was more readily utilized by the bacterium and had higher nitrate removal efficiency than that of α-MnS. Thiobacillus and Sulfurimonas were the core functional bacterium in denitrification. Therefore, MnS-S0-limestone bio-denitrification provides an efficient alternative method for nitrate removal in wastewater.
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Processos Autotróficos , Carbonato de Cálcio , Desnitrificação , Nitratos , Enxofre , Nitratos/metabolismo , Carbonato de Cálcio/química , Enxofre/metabolismo , Sulfetos/química , Sulfetos/metabolismo , Estudos de Viabilidade , Thiobacillus/metabolismo , Compostos de Manganês/química , Purificação da Água/métodos , ManganêsRESUMO
Circular aptamers are promising candidates for analytical and therapeutic applications due to their enhanced biological and structural stability. However, the process of circular aptamer selection remains a great challenge, as it requires multiple rounds of binding-separation-amplification that involves issues with nonspecific binding and amplification bias. Here, we develop a highly practical solution for reliable selection of circular aptamers in a single round based on magnetosome-like magnetic chain cross-linked graphene oxide (separation efficiency ≈ 105). High-affinity aptamer candidates can be rapidly selected from a preenriched circular DNA library, while low-affinity candidates are effectively adsorbed and separated by magnetosome-like magnetic chain cross-linked graphene oxide. With lipopolysaccharide as a representative model, the single-round selected lipopolysaccharide circular aptamer has been identified to have a high binding affinity with a Kd value of low to nanomolar range. Using this method, circular aptamers for protein and small-molecule targets were also successfully generated. We envision that this approach will accelerate the discovery of various new circular aptamers and open up a new avenue for analytical and therapeutic studies.
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BACKGROUND: Osthole, the main bioactive compounds isolated from the traditional Chinese medical herb broad Cnidium monnieri (L.) cusson, has been shown to exert spectrum of pharmacologic activities. The aim of this study was to investigate the potential neuroprotective effects of osthole against spinal cord ischemia-reperfusion injury in rats. MATERIALS AND METHODS: Osthole was administrated at the concentration of 0.1, 1, 10, 50, or 200 mg/kg (intraperitoneally) 1 h before spinal cord ischemia. The effects on spinal cord injury were measured by spinal cord water content, infarct volume, hematoxylin and eosin staining, and neurologic assessment. Mitochondria were purified from injured spinal cord tissue to determine mitochondrial function. RESULTS: We found that treatment with osthole (10 and 50 mg/kg) significantly decreased spinal cord water content and infarct volume, preserved normal motor neurons, and improved neurologic functions. These protective effects can be also observed even if the treatment was delayed to 4 h after reperfusion. Osthole treatment preserved mitochondrial membrane potential level, reduced reactive oxygen species production, increased adenosine triphosphate generation, and inhibited cytochrome c release in mitochondrial samples. Moreover, osthole increased mitochondria respiratory chain complex activities in spinal cord tissue, with no effect on mitochondrial DNA content and the expression of mitochondrial-specific transcription factors. CONCLUSIONS: All these findings demonstrate the neuroprotective effect of osthole in spinal cord ischemia-reperfusion injury model and suggest that oshtole-induced neuroprotection was mediated by mitochondrial biogenesis-independent inhibition of mitochondrial dysfunction.
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Cumarínicos/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Doenças Mitocondriais/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismos da Medula Espinal/tratamento farmacológico , Animais , Bloqueadores dos Canais de Cálcio/farmacologia , Cnidium/química , Hemodinâmica/efeitos dos fármacos , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/fisiologia , Doenças Mitocondriais/metabolismo , Doenças Mitocondriais/fisiopatologia , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/fisiopatologia , Traumatismos da Medula Espinal/metabolismo , Traumatismos da Medula Espinal/fisiopatologiaRESUMO
Background: The association between combined environmental factors and the risk of arthritis is still scarcely studied. The present study performed cross-sectional and cohort studies to explore the association between risk score of living environment quality and the risk of arthritis in middle-aged and older adults in China. Methods: The study was based on China Health and Retirement Longitudinal Study (CHARLS), and it recruited 17,218 participants in the cross-sectional study and 11,242 participants in the seven-year follow-up study. The living environment quality was measured by household fuel types, household water sources, room temperature, residence types, and ambient concentration of PM2.5. Logistic regression and Cox proportional hazard regression models were utilized to examine the association between the living environment quality and the risk of arthritis. Competing risk models and stratified analyses were applied to further verify our results. Results: Compared with individuals in the suitable environment group, people who lived in moderate (OR:1.28, 95%CI: 1.14-1.43) and unfavorable environments (OR:1.49, 95%CI:1.31-1.70) showed higher risks of arthritis when considering the multiple living environmental factors (P for trend <0.001) in the cross-sectional analysis. In the follow-up study, similar results (P for trend = 0.021), moderate environment group (HR:1.26, 95%CI:1.01-1.56) and unfavorable environment group (HR: 1.36, 95%CI: 1.07-1.74), were founded. Conclusion: Inferior living environment might promote the development of arthritis. It is necessary for the public, especially old people, to improve the living environment, which may be the key to the primary prevention of arthritis.
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Artrite , Pessoa de Meia-Idade , Humanos , Idoso , Estudos Longitudinais , Estudos Transversais , Seguimentos , Estudos de Coortes , Artrite/epidemiologiaRESUMO
Background: Increasing evidence has demonstrated that there was a strong correlation between COVID-19 and idiopathic pulmonary fibrosis (IPF). However, the studies are limited, and the real biological mechanisms behind the IPF progression were still uncleared. Methods: GSE70866 and GSE 157103 datasets were downloaded. The weight gene co-expression network analysis (WGCNA) algorithms were conducted to identify the most correlated gene module with COVID-19. Then the genes were extracted to construct a risk signature in IPF patients by performing Univariate and Lasso Cox Regression analysis. Univariate and Multivariate Cox Regression analyses were used to identify the independent value for predicting the prognosis of IPF patients. What's more, the Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Ontology (GO), and gene set enrichment analysis (GSEA) were conducted to unveil the potential biological pathways. CIBERSORT algorithms were performed to calculate the correlation between the risk score and immune cells infiltrating levels. Results: Two hundred thirty three differentially expressed genes were calculated as the hub genes in COVID-19. Fourteen of these genes were identified as the prognostic differentially expressed genes in IPF. Three (MET, UCHL1, and IGF1) of the fourteen genes were chosen to construct the risk signature. The risk signature can greatly predict the prognosis of high-risk and low-risk groups based on the calculated risk score. The functional pathway enrichment analysis and immune infiltrating analysis showed that the risk signature may regulate the immune-related pathways and immune cells. Conclusion: We identified prognostic differentially expressed hub genes related to COVID-19 in IPF. A risk signature was constructed based on those genes and showed great value for predicting the prognosis in IPF patients. What's more, three genes in the risk signature may be clinically valuable as potential targets for treating IPF patients and IPF patients with COVID-19.
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Background: The surgical treatment of the extended endoscopic endonasal approach (EEEA) is a safe and effective treatment for suprasellar craniopharyngiomas. However, due to damage to the hypothalamus and third ventricle floor (TVF), EEEA is generally regarded as unsuitable in treating intrinsic third ventricle craniopharyngioma (ITVC) that is entirely within the third ventricle. Until now, there have been only a small number of reports using EEEA to treat TVC via a supra-infrachiasmatic approach. Given that the translamina terminalis (TLT) corridor was used in the transcranial subfrontal approach, EEEA via a suprachiasmatic approach may be feasible and practical to treat ITVC. In the current study, we accumulated experience applying the suprachiasmatic translamina terminalis (STLT) corridor for anterior treatment of ITVC. Methods: From March 2016 to December 2020, 14 patients with ITVC in our center were analyzed retrospectively. All patients underwent surgery by EEEA via an STLT corridor. The multilayer reconstruction technique was adopted to achieve skull base reconstruction. Data concerning the patient's tumor resection, vision, hypophyseal hormone, and complications were collected. Results: Gross-total resection was achieved in 13 (92.8%) of14 patients, with achievement of near-total (90%) resection in the remaining 1 patient. Nine cases (64.3%) were papillary craniopharyngiomas, and the other 5 cases were adamantinomatous subtypes. Postoperatively, 3 patients with pituitary insufficiency received hormone replacement therapy. No permanent diabetes insipidus or hypothalamic obesity was found. All pairs showed significant improvement or stability in vision except 1 patient who encountered visual deterioration. No other neurological deficit occurred postoperatively. Observation results for the exudation of nasal tissue and the length of hospitalization were satisfactory. After a mean follow-up period of 26.2 months, tumor recurrence was not observed. Conclusion: TLT is a minimally invasive corridor used in EEEA for treating anterior ITVC without increasing risks of visual and hormonal deficits. The multilayered reconstruction technique we used is a safe and effective method for achieving watertight closure and avoiding cerebrospinal fluid leaks and infection. The endonasal approach via STLT provides a new, safe and efficacious operative strategy that should be considered a surgical alternative in treating ITVC.
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Objective The aim of the study is to summarize and analyze the efficacy of the multilayered skull base reconstruction using in situ bone flap in endoscopic endonasal approach (EEA) for craniopharyngiomas. Methods A retrospective review of 65 patients who underwent resection of their histopathology confirmed craniopharyngiomas performed at a single institution. Based on the team's understanding and mastery of skull base reconstruction techniques, patients were divided into two groups according to the methods of reconstruction in two periods. First (March 2015 through August 2016), osseous reconstruction was not adopted and served as the control group (34 cases). Second (September 2016 through July 2019), in situ bone flap repair of the skull base (complete osseous reconstruction) served as observation group (31 cases). The length of hospitalization and nasal exudation, bed rest time of hospital discharge, the incidence of cerebrospinal fluid leaks, lumbar drainage, and intracranial/pulmonary infections were collected and compared. Results Compared with the control group, patients in the observation group had obviously less lumbar drainage and CSF leakage ( p < 0.05), but had no significant difference in cases of re-operation, meningitis, and pulmonary infection. At the meantime, cases of nasal exudation, bed rest, and hospitalization of the observation group were significantly reduced ( p < 0.05) in the observation group. Conclusion The multilayered reconstruction technique (especially using in situ bone flap, combined with vascularized pedicled nasoseptal flap) is a safe and effective method in achieving watertight closure after EEEA, and can significantly reduce the incidence of cerebrospinal fluid leaks, and facilitate rehabilitation in skull base reconstruction of craniopharyngiomas.
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Stroke causes degeneration and death of neurones leading to the loss of motor function and frequent occurrence of cognitive impairment and depression. Lithium (Li+), the archetypal mood stabiliser, is neuroprotective in animal models of stroke, albeit underlying mechanisms remain unknown. We discover that Li+ inhibits activation of nucleotide-binding oligomerisation domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasomes in the middle cerebral artery occlusion (MCAO) stroke model in mice. This action of Li+ is mediated by two signalling pathways of AKT/GSK3ß/ß-catenin and AKT/FoxO3a/ß-catenin which converge in suppressing the production of reactive oxygen species (ROS). Using immunocytochemstry, MRI imaging, and cell sorting with subsequent mRNA and protein quantification, we demonstrate that Li+ decreases the infarct volume, improves motor function, and alleviates associated cognitive and depressive impairments. In conclusion, this study reveals molecular mechanisms of Li+ neuroprotection during brain ischaemia, thus providing the theoretical background to extend clinical applications of Li+ for treatment of ischemic stroke.
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AVC Isquêmico/tratamento farmacológico , Lítio/farmacologia , Fármacos Neuroprotetores/farmacologia , Animais , Disfunção Cognitiva/tratamento farmacológico , Depressão/tratamento farmacológico , Regulação da Expressão Gênica/efeitos dos fármacos , AVC Isquêmico/patologia , Masculino , Camundongos , Camundongos Transgênicos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Distribuição AleatóriaRESUMO
Alzheimer's disease (AD) is the prevalent cause of dementia in the ageing world population. Apolipoprotein E4 (ApoE4) allele is the key genetic risk factor for AD, although the mechanisms linking ApoE4 with neurocognitive impairments and aberrant metabolism remains to be fully characterised. We discovered a significant increase in the ApoE4 content of serum exosomes in old healthy subjects and AD patients carrying ApoE4 allele as compared with healthy adults. Elevated exosomal ApoE4 demonstrated significant inverse correlation with serum level of thyroid hormones and cognitive function. We analysed effects of ApoE4-containing peripheral exosomes on neural cells and neurological outputs in aged or thyroidectomised young mice. Ageing-associated hypothyroidism as well as acute thyroidectomy augmented transport of liver-derived ApoE4 reach exosomes into the brain, where ApoE4 activated nucleotide-binding oligomerisation domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome by increasing cholesterol level in neural cells. This, in turn, affected cognition, locomotion and mood. Our study reveals pathological potential of exosomes-mediated relocation of ApoE4 from the periphery to the brain, this process can represent potential therapeutic target.
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Doença de Alzheimer , Disfunção Cognitiva , Exossomos , Idoso , Envelhecimento , Doença de Alzheimer/metabolismo , Animais , Apolipoproteína E4/genética , Apolipoproteína E4/metabolismo , Encéfalo/metabolismo , Disfunção Cognitiva/genética , Disfunção Cognitiva/patologia , Exossomos/metabolismo , Humanos , Fígado/metabolismo , Camundongos , Glândula Tireoide/metabolismoRESUMO
INTRODUCTION: The endoscopic endonasal approach (EEA) is a safe and effective treatment for pituitary adenomas (PAs). Since extracapsular resection (ER) of PAs improves tumor resection and endocrine remission rates, the interface between the pseudocapsule and gland draws increasing attention. However, it is difficult to precisely dissect the tumor along the exact boundary, and complete removal of the tumor increases the risks of normal tissue damage and cerebrospinal fluid (CSF) leakage. In this study, we investigated the extracapsular resection as well as the pseudocapsule histology to evaluate the effectiveness and safety of pseudocapsule-related surgical interventions. METHODS: From December 2017 to December 2019, 189 patients of PAs via EEA in our single center were analyzed retrospectively. The images, operative details, and clinical follow-up of patients were collected. Sixty-four patients underwent pseudocapsule-based ER, and 125 patients also underwent traditional intracapsular resection (IR) with or without intensive excision for FPAs. The clinical characteristics, tumor resection, endocrinological outcomes, and postoperative morbidities of the two groups were compared. Informed consent for publication of our article was obtained from each patient. Histological examination of pseudocapsule was performed using hematoxylin and eosin and reticulin staining. RESULTS: The gross total recession was 62 (96.9%) in the ER group and 107 (85.6%) cases in the IR group, whereas the endocrine remission rate was 29/31 (93.5%) and 40/53 (75.5%) cases, respectively. Anterior pituitary functions were not aggravated postoperatively in any patient, but transient diabetes insipidus (DI) occurred more in the IR group (64.0%) than in ER (48.4%). Pseudocapsule specimens were obtained in 93 patients, and clusters of small cell aggregation were detected in 11 pseudocapsule specimens (11.8%) whereas other patients showed no remarkable developed pseudocapsule. Intraoperative CSF leak occurred more in the ER group (28.1%) than in the IR group (13.6%), but no difference was seen between two groups postoperatively. No case of intracranial hematoma or pituitary crisis occurred in both groups. After a mean follow-up of 22.8 months, tumor recurrence was observed in 4 (2.1%) cases. CONCLUSION: Pseudocapsule-based extracapsular resection of PAs via EEA is an effective and safe procedure to achieve complete resection with high and sustained endocrine remission and without deteriorating pituitary function.
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Metal implants are used worldwide, with millions of nails, plates, and fixtures grafted during orthopedic surgeries. Iron is the most common element of these metal implants. As time passes, implants can be corroded and iron can be released. Ionized iron permeates the surrounding tissues and enters circulation; importantly, iron ions pass through the blood-brain barrier. Can iron from implants represent a risk factor for neurological diseases? This remains an unanswered question. In this study, we discovered that patients with metal implants delivered through orthopedic surgeries have higher incidence of Parkinson's disease or ischemic stroke compared to patients who underwent similar surgeries but did not have implants. Concentration of serum iron and ferritin was increased in subjects with metal implants. In experiments in vivo, we found that injection of iron dextran selectively decreased the presence of divalent metal transporter 1 (DMT1) in neurons through increasing the expression of Ndfip1, which degrades DMT1 and does not exist in glial cells. At the same time, excess of iron increased expression of DMT1 in astrocytes and microglial cells and triggered reactive astrogliosis and microgliosis. Facing the attack of excess iron, glial cells act as neuroprotectors to accumulate more extracellular iron by upregulating DMT1, whereas neurons limit iron uptake through increasing DMT1 degradation. Cerebral accumulation of iron in animals is associated with impaired cognition, locomotion, and mood. Excess iron from surgical implants thus can affect neural cells and may be regarded as a risk factor for neurodegeneration.
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Ferro , Neurônios , Animais , Ferro/metabolismo , Neurônios/metabolismo , Neuroglia/metabolismo , Barreira Hematoencefálica/metabolismo , Doença IatrogênicaRESUMO
Iron is the fundamental element for numerous physiological functions. Plasmalemmal divalent metal ion transporter 1 (DMT1) is responsible for cellular uptake of ferrous (Fe2+), whereas transferrin receptors (TFR) carry transferrin (TF)-bound ferric (Fe3+). In this study we performed detailed analysis of the action of Fe ions on cytoplasmic free calcium ion concentration ([Ca2+]i) in astrocytes. Administration of Fe2+ or Fe3+ in µM concentrations evoked [Ca2+]i in astrocytes in vitro and in vivo. Iron ions trigger increase in [Ca2+]i through two distinct molecular cascades. Uptake of Fe2+ by DMT1 inhibits astroglial Na+-K+-ATPase, which leads to elevation in cytoplasmic Na+ concentration, thus reversing Na+/Ca2+ exchanger and thereby generating Ca2+ influx. Uptake of Fe3+ by TF-TFR stimulates phospholipase C to produce inositol 1,4,5-trisphosphate (InsP3), thus triggering InsP3 receptor-mediated Ca2+ release from endoplasmic reticulum. In summary, these findings reveal the mechanisms of iron-induced astrocytic signalling operational in conditions of iron overload.
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Astrócitos/metabolismo , Sinalização do Cálcio/efeitos dos fármacos , Cálcio/metabolismo , Proteínas de Transporte de Cátions/metabolismo , Compostos Férricos/farmacologia , Compostos Ferrosos/farmacologia , Receptores da Transferrina/metabolismo , Animais , Astrócitos/citologia , Astrócitos/efeitos dos fármacos , Transporte Biológico , Camundongos , Camundongos Endogâmicos C57BL , Sódio/metabolismoRESUMO
The preparation of 1-deoxy-d-xylulose 5-phosphate, the key intermediate of MEP biosynthetic pathway for terpenoids by using recombinant 1-deoxy-d-xylulose 5-phosphate synthase of Rhodobacter capsulatus was optimized. The simple one-pot synthesis coupling with a newly established ion-exchange purification process affords the target compound with more than 80% yield and high purity (>95%). The procedure can also be employed to synthesize isotope labeled 1-deoxy-d-xylulose 5-phosphate by using isotope labeled starting materials.
Assuntos
Pentosefosfatos/biossíntese , Transferases/química , Concentração de Íons de Hidrogênio , Pentosefosfatos/química , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Rhodobacter capsulatus/enzimologia , Temperatura , Transferases/genética , Transferases/metabolismoRESUMO
Testosterone is often used to improve the physiological function. But increased testosterone levels affect blood lipids and cause inflammation and oxidative stress, which are risk factors for vascular diseases. This study aimed at investigating the effects of testosterone on cerebral vascular injury using an established intracranial aneurysm (IA) model. Sixteen-week-old female C57Bl/6 mice were subcutaneously infused with testosterone propionate (TP; 5 mg/kg day) or plain soybean oil (controls) for 6 weeks. After 2 weeks of treatment, mice were given angiotensin II-elastase for another 4 weeks. The results showed that TP significantly increased cell apoptosis and reactive oxygen species production in cerebral artery, together with increases in plasma tumor necrosis factor-α (TNF-α) levels and in urinary 8-isoprostane levels. Plasma assays showed that 2 weeks after TP or soybean oil administration, the high-density lipoprotein (HDL) level was higher in the TP group than in controls. In vitro studies showed that testosterone increased TNF-α and monocyte chemotactic protein-1 mRNA and protein expression levels in RAW 264.7 macrophages. In summary, by reducing the HDL level, TP aggravates cerebral artery injury by increasing cell apoptosis, inflammation, and oxidative stress.