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OBJECTIVE: To assess the correlation between lesion location and swallowing function characteristics in post-stroke dysphagia (PSD) patients. MATERIALS AND METHODS: We enrolled 133 PSD. The patients were divided into supratentorial and infratentorial stroke groups. We compared the measurements in the videofluoroscopic swallowing study (VFSS) with 3ml and 5 ml of diluted and thickened barium liquid data between supratentorial and brainstem stroke groups. We further compared the difference of VFSS measurements between patients with left hemispheric or right hemispheric lesions (further divided into unilateral hemispheric cortical and subcortical subgroups) and brianstem leison stroke group.To explore the lesion location's effect on different bolus volume, the VFSS measurements of 3ml and 5ml in each subgroups were compared respectively. The measurements of VFSS included the oral transit time, soft palate elevation duration, hyoid bone movement duration (HMD), UES opening duration, pharyngeal transit duration (PTD), stage of ansition duration, and laryngeal closure duration (LCD), the upper esophageal sphincter opening (UESO), hyoid bone superior horizontal displacement, and hyoid bone anterior horizontal displacement. General swallowing function was assessed using the Penetration Aspiration Scale (PAS) and Functional Oral Intake Scale (FOIS). We performed the paired t-test, Spearman's correlation, and Kruskal-Wallis test analysis to characterize the parameters among the groups. RESULTS: Fifty-eight patients were assessed in the final analysis. The HMD (p = 0.019), PTD (p = 0.048) and LCD (p = 0.013) were significantly different between the supratentorial and brainstem lesion groups in 5ml volume. The HMD was significantly different (p = 0.045) between the left cortical and brainstem lesion groups. Significant differences in the HMD (p = 0.037) and LCD (p = 0.032) between the left subcortical and brainstem lesion groups were found in 5ml volume bolus. There was no group different when taking the 3ml volume bolus. Regarding the relationship between food bolus volume and swallowing functions, only the UESO demonstrated a significant difference in the subcortical lesion of the right hemisphere (p = 0.0032) compared the 3 ml and 5 ml volume bolus. The PTD demonstrated a moderate correlation with the PAS scores (r = 0.38, p = 0.0044). The HMD (r = 0.32, p = 0.018) and LCD (r = 0.29, p = 0.039) demonstrated weak correlations with the PAS scores. We did not identify any correlation between the VFSS parameters and FOIS scores in each subgroup level. CONCLUSION: The PSD with brainstem lesion shows more sever dysfunction in the pharyngeal phases. The left hemisphere was engaged in both the oral and pharyngeal phases. Lesions in the bilateral cortical, subcortical, and brainstem regions may impair sensory input.
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Trastornos de Deglución , Deglución , Accidente Cerebrovascular , Grabación en Video , Humanos , Trastornos de Deglución/fisiopatología , Trastornos de Deglución/etiología , Trastornos de Deglución/diagnóstico , Trastornos de Deglución/diagnóstico por imagen , Masculino , Femenino , Anciano , Persona de Mediana Edad , Accidente Cerebrovascular/fisiopatología , Accidente Cerebrovascular/complicaciones , Accidente Cerebrovascular/diagnóstico , Fluoroscopía , Valor Predictivo de las Pruebas , Anciano de 80 o más Años , Factores de Tiempo , Factores de Riesgo , Estudios RetrospectivosRESUMEN
An interlude of dark exposure for about 1 week is known to shift excitatory/inhibitory (E/I) balance of the mammalian visual cortex, promoting plasticity and accelerating visual recovery in animals that have experienced cortical lesions during development. However, the translational impact of our understanding of dark exposure from animal studies to humans remains elusive. Here, we used magnetic resonance spectroscopy as a probe for E/I balance in the primary visual cortex (V1) to determine the effect of 60 min of dark exposure, and measured binocular combination as a behavioural assay to assess visual plasticity in 14 normally sighted human adults. To induce neuroplastic changes in the observers, we introduced 60 min of monocular deprivation, which is known to temporarily shift sensory eye balance in favour of the previously deprived eye. We report that prior dark exposure for 60 min strengthens local excitability in V1 and boosts visual plasticity in normal adults. However, we show that it does not promote plasticity in amblyopic adults. Nevertheless, our findings are surprising, given the fact that the interlude is very brief. Interestingly, we find that the increased concentration of the excitatory neurotransmitter is not strongly correlated with the enhanced functional plasticity. Instead, the absolute degree of change in its concentration is related to the boost, suggesting that the dichotomy of cortical excitation and inhibition might not explain the physiological basis of plasticity in humans. We present the first evidence that an environmental manipulation that shifts cortical E/I balance can also act as a metaplastic facilitator for visual plasticity in humans. KEY POINTS: A brief interlude (60 min) of dark exposure increased the local concentration of glutamine/glutamate but not that of GABA in the visual cortex of adult humans. After dark exposure, the degree of the shift in sensory eye dominance in favour of the previously deprived eye from short-term monocular deprivation was larger than that from only monocular deprivation. The neurochemical and behavioural measures were associated: the magnitude of the shift in the concentration of glutamine/glutamate was correlated with the boost in perceptual plasticity after dark exposure. Surprisingly, the increase in the concentration of glutamine/glutamate was not correlated with the perceptual boost after dark exposure, suggesting that the physiological mechanism of how E/I balance regulates plasticity is not deterministic. In other words, an increased excitation did not unilaterally promote plasticity.
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Glutamina , Corteza Visual , Animales , Humanos , Adulto , Corteza Visual/fisiología , Predominio Ocular , Plasticidad Neuronal/fisiología , Privación Sensorial/fisiología , MamíferosRESUMEN
Membraneless organelles formed by liquid-liquid phase separation of proteins or nucleic acids are involved in diverse biological processes in eukaryotes. However, such cellular compartments have yet to be discovered or created synthetically in prokaryotes. Here, we report the formation of liquid protein condensates inside the cells of prokaryotic Escherichia coli upon heterologous overexpression of intrinsically disordered proteins such as spider silk and resilin. In vitro reconstitution under conditions that mimic intracellular physiologically crowding environments of E. coli revealed that the condensates are formed via liquid-liquid phase separation. We also show functionalization of these condensates via targeted colocalization of cargo proteins to create functional membraneless compartments able to fluoresce and to catalyze biochemical reactions. The ability to form and functionalize membraneless compartments may serve as a versatile tool to develop artificial organelles with on-demand functions in prokaryotes for applications in synthetic biology.
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Membrana Celular , Escherichia coli/fisiología , Orgánulos , Citosol/química , Citosol/metabolismo , Dispersión Dinámica de Luz , Fibroínas/química , Regulación Bacteriana de la Expresión Génica , Proteínas Fluorescentes Verdes/química , Microscopía Confocal , Microscopía Electrónica de Transmisión , Microscopía FluorescenteRESUMEN
Spatially directed synthesis of quantum dots (QDs) is intriguing yet challenging in organisms, due to the dispersed feature of templating biomolecules and precursors. Whether this task could be accomplished by biomolecular condensates, an emerging type of membraneless compartments in cells remains unknown. Here we report synthetic protein condensates for templated synthesis of QDs in bacterium Escherichia coli. This was realized by overexpression of spider silk protein to bind precursor ions and recruit other necessary components, which induced the spidroin to form more ß-sheet structures for assembly and maturation of the protein condensates. This in turn enabled formation and co-localization of the fluorescent QDs to "light up" the condensates, and alleviated cytotoxicity of the precursor heavy metal ions and resulting QDs. Thus, our results suggest a new strategy for nanostructure synthesis and deposition in subcellular compartments with great potential for in situ applications.
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Fibroínas , Puntos Cuánticos , Fibroínas/química , Puntos Cuánticos/química , Escherichia coli , Seda/química , IonesRESUMEN
An actively Q-switched eye-safe orthogonally-polarized dual-wavelength intracavity Raman laser was demonstrated for the first time, to the best of our knowledge. The gain balanced dual-wavelength operation at 1314 and 1321 nm within an in-band pumped Nd:YLF laser was realized by slightly titling the cavity mirrors. Owing to the KGW bi-axial properties, two sets of simultaneous orthogonally-polarized dual-wavelength Raman lasers at 1470, 1490 nm and 1461, 1499 nm were achieved by simply rotating the KGW crystal for 90°, respectively. With an incident pump power of 30 W and an optimized pulse repetition frequency of 5 kHz, the maximum dual-wavelength Raman output powers of 2.6 and 2.4 W were obtained with the pulse widths of 5.8 and 6.3 ns, respectively, corresponding to the peak powers up to 89.7 and 76.5 kW.
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BACKGROUND: Cytochrome c oxidase subunit VB (COX5B), a subunit of mammalian COX, takes roles in COX assembling and functions. Online database predicts high COX5B transcription may be associated with worse disease-free survival (DFS). However, the clinical implications of COX5B in breast cancer remain unclear. METHODS: We carried out immunohistochemistry on tissue microarrays of 244 patients with invasive ductal breast carcinoma to detected COX5B expression. RESULTS: Our results suggest that COX5B protein level might be associated with tumor size. COX5B overexpression indicated a worse DFS (p < 0.05) in breast cancer. Furthermore, high COX5B expression may act as an independent factor for worse DFS in breast cancer. CONCLUSIONS: Cumulatively, our findings suggest that COX5B might serve as an important prognostic factor for breast cancer.
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Biomarcadores de Tumor , Neoplasias de la Mama/genética , Neoplasias de la Mama/mortalidad , Complejo IV de Transporte de Electrones/genética , Expresión Génica , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/patología , Complejo IV de Transporte de Electrones/metabolismo , Femenino , Humanos , Inmunohistoquímica , Persona de Mediana Edad , Clasificación del Tumor , Metástasis de la Neoplasia , Estadificación de Neoplasias , Pronóstico , Análisis de SupervivenciaRESUMEN
Formaldehyde (FA) is a carcinogen that is not only widespread in the environment, but is also produced endogenously by metabolic processes. In organisms, FA is converted to formic acid in a glutathione (GSH)-dependent manner by alcohol dehydrogenase 5 (ADH5). The abnormal accumulation of FA in the body can cause a variety of diseases, especially cognitive impairment leading to Alzheimer's disease (AD). In this study, melatonin derivative 6a (MD6a) markedly improved the survival and chemotactic performance of wild-type Caenorhabditis elegans exposed to high concentrations of FA. MD6a lowered FA levels in the nematodes by enhancing the release of covalently-bound GSH from S-hydroxymethyl-GSH in an adh-5-dependent manner. In addition, MD6a protected against mitochondrial dysfunction and cognitive impairment in beta-amyloid protein (Aß) transgenic nematodes by lowering endogenous FA levels and reducing Aß aggregation in an adh-5-dependent manner. Our findings suggest that MD6a detoxifies FA via ADH5 and protects against Aß toxicity by reducing endogenous FA levels in the C. elegans AD models. Thus, ADH5 might be a potential therapeutic target for FA toxicity and AD.
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Both continuous oxidative stress and poly (ADP-ribose) polymerase 1 (PARP-1) activation occur in neurodegenerative diseases such as Parkinson's disease. PARP-1 inhibition can reverse mitochondrial damage and has a neuroprotective effect. In a previous study, we synthesized melatonin derivative 6a (MD6a) and reported that it has excellent antioxidant activity and significantly reduces α-synuclein aggregation in Caenorhabditis elegans; however, the underlying mechanism is largely unknown. In the present study, we revealed that MD6a is a potential PARP-1 inhibitor, leading to mammalian targe of rapamycin/heat shock factor 1 signaling downregulation and reducing heat shock protein 4 and 6 expression, thus helping to maintain protein homeostasis and improve mitochondrial function. Together, these findings suggest that MD6a might be a viable candidate for the prevention and treatment of Parkinson's disease.
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In this study, twenty-three ent-eudesmane sesquiterpenoids (1-23) including fifteen previously undescribed ones, named eutypelides A-O (1-15) were isolated from the marine-derived fungus Eutypella sp. F0219. Their planar structures and relative configurations were established by HR-ESIMS and extensive 1D and 2D NMR investigations. The absolute configurations of the previously undescribed compounds were determined by single-crystal X-ray diffraction analyses, modified Mosher's method, and ECD calculations. Structurally, eutypelide A (1) is a rare 1,10-seco-ent-eudesmane, whereas 2-15 are typically ent-eudesmanes with 6/6/-fused bicyclic carbon nucleus. The anti-neuroinflammatory activity of all isolated compounds (1-23) was accessed based on their ability to NO production in LPS-stimulated BV2 microglia cells. Compound 16 emerged as the most potent inhibitor. Further mechanistic investigation revealed that compound 16 modulated the inflammatory response by decreasing the protein levels of iNOS and increasing ARG 1 levels, thereby altering the iNOS/ARG 1 ratio and inhibiting macrophage polarization. qRT-PCR analysis showed that compound 16 reversed the LPS-induced upregulation of pro-inflammatory cytokines, including iNOS, TNF-α, IL-6, and IL-1ß, at both the transcriptional and translational levels. These effects were linked to the inhibition of the NF-κB pathway, a key regulator of inflammation. Our findings suggest that compound 16 may be a potential structure basis for developing neuroinflammation-related disease therapeutic agents.
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Antiinflamatorios , Lipopolisacáridos , Microglía , Sesquiterpenos de Eudesmano , Animales , Ratones , Lipopolisacáridos/farmacología , Lipopolisacáridos/antagonistas & inhibidores , Sesquiterpenos de Eudesmano/farmacología , Sesquiterpenos de Eudesmano/química , Sesquiterpenos de Eudesmano/aislamiento & purificación , Antiinflamatorios/farmacología , Antiinflamatorios/química , Antiinflamatorios/aislamiento & purificación , Microglía/efectos de los fármacos , Estructura Molecular , Óxido Nítrico/biosíntesis , Óxido Nítrico/antagonistas & inhibidores , Relación Estructura-Actividad , FN-kappa B/antagonistas & inhibidores , FN-kappa B/metabolismo , Relación Dosis-Respuesta a Droga , Antiinflamatorios no Esteroideos/farmacología , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/aislamiento & purificación , Sesquiterpenos/farmacología , Sesquiterpenos/química , Sesquiterpenos/aislamiento & purificaciónRESUMEN
It is a vital requirement to explore high-efficiency and stable electrocatalysts for oxygen reduction reaction (ORR) to further relieve energy depletion. However, it is a critical challenge to develop low cost and high-quality carbon-based catalysts. Herein, a caffeine chelation-triggered pyrolysis approach was developed to construct graphene-wrapped Fe3C nanoparticles incorporated in hierarchically porous FeNC nanosheets (G-Fe3C/FeNC). The present Fe salt and its content as well as the pyrolysis temperature were carefully investigated in the control groups. The G-Fe3C/FeNC catalyst showed a more positive onset potential (Eonset = 1.09 V) and half-wave potential (E1/2 = 0.88 V) in a 0.1 M KOH solution, which outperformed commercial Pt/C (E1/2 = 0.83 V, Eonset = 0.95 V), showing the excellent catalytic performance for the ORR activity, coupled with remarkable stability (only 0.18 mV negative shift in E1/2 after 2000 cycles). This work provides some valuable insights for developing advanced electrocatalysts for energy storage and conversion related research.
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Objectives: The child-caregiver relationship is the foundation for which intervention occurs. Therefore, the acceptability of the intervention should be considered for both parties. Indices of happiness (IOH) have shown to be effective in assessing social validity and providing insight to improving interventions to promote better quality of life. However, to date, there is limited attention to the integration of IOH in very early caregiver-led intervention. The purpose of this study is to explore how researchers and clinicians might collect direct data on IOH to assess the acceptability of an intervention. Methods: Participants in this study included 4 children, ages 19-26 months old, identified as "at-risk" for autism, and their caregivers. Caregiver-led intervention focused on pairing, play, and following the child's lead. IOH data was collected on both child and caregiver using 10 s partial-interval recording. Data analysis from the intervention is presented using three different approaches: pre/post-analysis on an individual level, pre/post-analysis on a dyad level, and during intervention as a primary dependent variable. Results: Variations were seen in levels of happiness, both on an individual level and dyad level. IOH for caregivers increased in relation as their fidelity increased but child IOH decreased as they acquired the targeted skill. Conclusions: Direct observation of happiness data is likely to provide valuable insight into participants perception of an intervention. And retrospective analysis may be a valuable tool for reflection and guidance and planning of future interventions. Supplementary Information: The online version contains supplementary material available at 10.1007/s41252-022-00288-0.
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Objective: Theory suggests that impaired executive functioning (EF) might explain several symptoms of autism spectrum disorder (ASD) in children. However, only a few studies have examined the efficacy of EF training for the children using randomized control trial designs, and only two of them found significant benefits of the training. Method: We designed Comprehensive Attention Training System (CATS), and tested this new EF intervention for children with ASD in a small-sampled randomized controlled trial. Twenty-five children with ASD aged six to twelve were randomly assigned to either the CATS or the control training and were assessed pre- and post-training. Results: Relative to the control group, the CATS group improved on EF as measured by the trail-making test, avoiding perseverative errors, and forming conceptual responses in the Wisconsin Card Sorting Task. There were also indications that CATS contributed to long-term communication skills as measured by the Vineland adaptive behavior scales. Conclusions: We report preliminary evidence that the CATS intervention may improve the EF of school-aged children with ASD compared to a control intervention. We discuss the results in terms of their generalizability to other developmental disorders.
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To enhance the overall water splitting efficiency, it is widely attractive yet challenging to develop low price, abundance and efficient bifunctional electrocatalysts towards oxygen evolution reaction (OER) and hydrogen evolution reaction (HER). Herein, Fe,Rh-codoped Ni2P nanosheets arrays were in situ anchored on three-dimension (3D) Ni foam under hydrothermal condition and successive phosphorization, denoted as Fe,Rh-Ni2P/NF for simplicity. The unique nanosheets arrays effectively enriched the active sites with easy accessibility. By virtue of the unique sheet-like arrays and 3D porous conductive substrate, the prepared Fe,Rh-Ni2P/NF showed the low overpotentials of 226 mV at 30 mA cm-2 towards the OER and 73 mV at 10 mA cm-2 for the HER. Moreover, the electrocatalyst effectively worked as anode and cathode for overall water splitting system, showing a small voltage of 1.62 V to drive a current density of 10 mA cm-2. The present work provides alternative option for fabricating advanced catalysts in electrocatalysis and energy devices.
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The development of low-cost and high-efficiency electrocatalysts is very important for electrocatalytic hydrogen evolution reaction (HER) in water splitting system. Herein, ultrathin rhodium-iridium nanosheets were facilely in-situ grown on nickel foam (RhIr NSs/NF) by a one-pot aqueous strategy at room temperature. The sheet-like structures with the film thickness of 78â¯nm were identified by scanning electron microscopy and transmission electron microscopy. The catalyst showed greatly high HER features in both 1.0â¯M KOH and 0.5â¯M H2SO4 with the overpotentials of 15 and 14â¯mV to achieve 10â¯mAâ¯cm-2, respectively, surpassing most Pt-free catalysts. Also, the RhIr NSs/NF exhibited amazing catalytic stability during the long-term operation. This study offers a facile and rational pathway for design and synthesis of advanced HER electrocatalysts for energy conversion devices.
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Melatonin (MT) is a hormone with antioxidant activity secreted by the pineal gland in the human brain, which is highly efficient in scavenging free radicals and plays an important role in the neuro-immuno-endocrine system. Emerging evidence showed that MT supplementation was a potential therapeutic strategy for Parkinson's disease (PD), which inhibits pathways associated with oxidative stress in PD. In this study, we reported a C7-selective olefination of melatonin under rhodium catalysis with the aid of PIII-directing groups and synthesized 10 new melatonin-C7-cinnamic acid derivatives (6a-6j). The antioxidant potential of the compounds was evaluated both by ABTS and ORAC methods. Among these newly synthesized melatonin derivatives, 6a showed significantly higher activity than MT at 10-5 M. In the transgenic Caenorhabditis elegans model of PD, 6a significantly reduces alpha-synuclein aggregation and dopaminergic neuronal damage in nematodes while reducing intracellular ROS levels and recovers behavioral dysfunction induced by dopaminergic neurodegeneration. Further study of the mechanism of action of this compound can provide new therapeutic ideas and treatment strategies for PD.
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Vancomycin remains the mainstay of treatment for methicillin-resistant Staphylococcus aureus (MRSA) pneumonia. This study assessed risk factors for vancomycin failure in 63 patients with MRSA pneumonia through detailed clinical, microbiological, pharmacokinetic/pharmacodynamic, and genetic analyses of prospective multicenter studies conducted from February 2012 to July 2018. Therapeutic drug monitoring was performed during vancomycin treatment, and the 24-h area under the curve (AUC0-24) was calculated. All baseline strains were collected for MIC determination, heterogeneous vancomycin-intermediate S. aureus (hVISA) screening, and biofilm determination. Whole-genome sequencing was performed on the isolates to analyze their molecular typing and virulence and adhesion genes. Clinical signs and symptoms improved in 44 patients (44/63, 69.8%), with vancomycin daily dose (P = 0.045), peak concentration (P = 0.020), and sdrC (P = 0.047) being significant factors. Isolates were eradicated in 51 patients (51/63, 81.0%), with vancomycin daily dose (P = 0.009), cardiovascular disease (P = 0.043), sequence type 5 (ST5; P = 0.017), tst (P = 0.050), and sec gene (P = 0.044) associated with bacteriological failure. Although the AUC0-24/MIC was higher in the groups with bacterial eradication, the difference was not statistically significant (P = 0.108). Multivariate analysis showed that no variables were associated with clinical efficacy; ST5 was a risk factor for bacterial persistence (adjusted odds ratio, 4.449; 95% confidence interval, 1.103 to 17.943; P = 0.036). ST5 strains had higher frequencies of the hVISA phenotype, biofilm expression, and presence of some adhesion and virulence genes such as fnbB, tst, and sec than non-ST5 strains. Our study suggests that ST5 is a possible predictor of bacterial persistence in MRSA pneumonia treated with vancomycin. IMPORTANCE Few studies have simultaneously examined the influence of clinical characteristics of patients with pneumonia, the vancomycin pharmacokinetic/pharmacodynamic (PK/PD) index, and the phenotypic and genetic characteristics of methicillin-resistant Staphylococcus aureus (MRSA) strains. We assessed risk factors for vancomycin failure in patients with MRSA pneumonia by analyzing these influences in a prospective multicenter study. Sequence type 5 (ST5) was a possible predictor of bacterial persistence in adult patients with MRSA pneumonia (adjusted odds ratio, 4.449). We found that this may be related to ST5 strains having higher levels of vancomycin heterogeneous resistance, biofilms, and the presence of adhesion and virulence genes such as fnbB, tst, and sec.
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Staphylococcus aureus Resistente a Meticilina , Neumonía , Infecciones Estafilocócicas , Humanos , Vancomicina/farmacología , Vancomicina/uso terapéutico , Staphylococcus aureus Resistente a Meticilina/genética , Infecciones Estafilocócicas/tratamiento farmacológico , Infecciones Estafilocócicas/microbiología , Staphylococcus aureus/genética , Estudios Prospectivos , Pruebas de Sensibilidad Microbiana , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Neumonía/tratamiento farmacológicoRESUMEN
Rosiglitazone has been reported to exert dual effects on liver steatosis, and it could exacerbate liver steatosis in obese animal models, which was suggested to be closely related to the elevated hepatic expression of FABP4. This study aimed to investigate whether combined treatment with FABP4 inhibitor I-9 could alleviate rosiglitazone-induced liver steatosis in obese diabetic db/db mice. Male C57BL/KsJ-db/db mice were orally treated with rosiglitazone, rosiglitazone combined with I-9 daily for 8 weeks. The liver steatosis was evaluated by triglyceride content and H&E staining. The expression of hepatic lipogenic genes or proteins in liver tissue or in FFA-treated hepatocytes and PMA-stimulated macrophages were determined by real-time quantitative polymerase chain reaction (RT-qPCR) or western blotting. Results showed that combined treatment with I-9 decreased rosiglitazone-induced increase in serum FABP4 level and expression of lipogenic genes in liver, especially FABP4, and ameliorated liver steatosis in db/db mice. Rosiglitazone-induced intracellular TG accumulation and increased expression of FABP4 in the cultured hepatocytes and macrophages were also suppressed by combined treatment. We concluded that combined treatment with FABP4 inhibitor I-9 could ameliorate rosiglitazone-exacerbated elevated serum FABP4 level and ectopic liver fat accumulation in obese diabetic db/db mice without affecting its anti-diabetic efficacy.
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Proteínas de Unión a Ácidos Grasos/antagonistas & inhibidores , Hígado Graso/tratamiento farmacológico , Rosiglitazona/farmacología , Animales , Diabetes Mellitus Tipo 2/complicaciones , Combinación de Medicamentos , Proteínas de Unión a Ácidos Grasos/sangre , Proteínas de Unión a Ácidos Grasos/metabolismo , Hígado Graso/etiología , Hígado Graso/patología , Hepatocitos/efectos de los fármacos , Metabolismo de los Lípidos/efectos de los fármacos , Hígado/efectos de los fármacos , Hígado/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Modelos Animales , Obesidad/complicaciones , Cultivo Primario de Células , Triglicéridos/metabolismoRESUMEN
Fatty acid-binding protein 4 (FABP4) and fatty acid-binding protein 5 (FABP5) are promising therapeutic targets for the treatment of various metabolic diseases. However, the weak potency, low selectivity over FABP3, or poor pharmacokinetic profiles of currently reported dual FABP4/5 inhibitors impeded further research. Here, we described the characterization of a series of dual FABP4/5 inhibitors with improved metabolic stabilities and physicochemical properties based on our previous studies. Among the compounds, D9 and E1 exhibited good inhibitory activities against FABP4/5 and favorable selectivity over FABP3 in vitro. In cell-based assays, D9 and E1 exerted a decrease of FABP4 secretion, a strong anti-lipolytic effect in mature adipocytes, and suppression of MCP-1 expression in THP-1 macrophages. Moreover, D9 and E1 possessed good metabolic stabilities in mouse hepatic microsomes and acceptable pharmacokinetics profiles in ICR mice. Further in vivo experiments showed that D9 and E1 could potently decrease serum FABP4 levels and ameliorate glucose metabolism disorders in obese diabetic db/db mice. These results demonstrated that D9 and E1 could serve as lead compounds for the development of novel anti-diabetic drugs.
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Diabetes Mellitus Tipo 2/tratamiento farmacológico , Proteínas de Unión a Ácidos Grasos/uso terapéutico , Animales , Proteínas de Unión a Ácidos Grasos/farmacología , Humanos , Ratones , Estructura MolecularRESUMEN
The accumulation of excessive reactive oxygen species can exacerbate any injury of retinal tissue because free radicals can trigger lipid peroxidation, protein damage and DNA fragmentation. Increased oxidative stress is associated with the common pathological process of many eye diseases, such as glaucoma, diabetic retinopathy and ischemic optic neuropathy. Many studies have demonstrated that Lycium barbarum polysaccharides (LBP) protects against oxidative injury in numerous cells and tissues. For the model of hypoxia we used cultured retinal ganglion cells and induced hypoxia by incubating with 200 µM cobalt chloride (CoCl2) for 24 hours. To investigate the protective effect of LBP and its mechanism of action against oxidative stress injury, the retinal tissue was pretreated with 0.5 mg/mL LBP for 24 hours. The results of flow cytometric analysis showed LBP could effectively reduce the CoCl2-induced retinal ganglion cell apoptosis, inhibited the generation of reactive oxygen species and the reduction of mitochondrial membrane potential. These findings suggested that LBP could protect retinal ganglion cells from CoCl2-induced apoptosis by reducing mitochondrial membrane potential and reactive oxygen species.
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The clinical value of local surgery in the breast cancer patients with distant metastasis is still unclear. A total of 8,922 primary metastatic breast cancer patients from the Surveillance, Epidemiology, and End Results (SEER) database were analyzed in the current study. Primary outcome variables included breast cancer-specific survival (BCSS) and overall survival (OS). Among the patients, 1,724 (19.3%) who underwent surgical treatment (ST) of primary breast tumor had increased OS (p < 0.001) and BCSS (p < 0.001) compared with those in the nonsurgical treatment (NST) group. Multivariate analysis revealed that surgery improved survival and was an independent prognostic factor for OS (hazard ratio [HR] = 0.617; 95% confidence interval [CI], 0.562-0.676, p < 0.001) and BCSS (HR = 0.623; 95% CI, 0.565-0.686, p < 0.001). Further result showed that ST tended to prolong the survival of patients with 1 or 2 distant metastatic sites (p < 0.05 for OS, p < 0.05 for BCSS). However, no differences were found in prognostic outcomes between different surgical procedure groups (p = 0.886 for OS, p = 0.943 for BCSS). In conclusion, our study suggested that local surgery appeared to confer a survival benefit, which may provide new understanding of treatment for these patients.