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This study aims to explore the mechanisms of the inhibitory effect of kaempferol on the invasion and metastasis of gastric cancer (GC) cells through network pharmacology prediction and experimental verification. It identifies core targets via PPI network analysis and finds that kaempferol binds to these targets well. In vitro experiments showed that kaempferol could inhibit the proliferation, colony formation, migration and invasion of GC cells. Western blotting indicated kaempferol may reduce AKT and GSK3ß phosphorylation, leading to lower expression of invasion-related genes SRC, MMP9, CXCR4, KDR, and MMP2. Overall, kaempferol may prevent migration and invasion of GC cells via the AKT/GSK3ß signaling pathway.
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OBJECTIVE: This study aimed to establish a neural cell injury model in vitro by stimulating PC12 cells with lipopolysaccharide (LPS) and to examine the effects of astragaloside IV on key targets using high-throughput sequence technology and bioinformatics analyses. METHODS: PC12 cells in the logarithmic growth phase were treated with LPS at final concentrations of 0.25, 0.5, 0.75, 1, and 1.25 mg/mL for 24 h. Cell morphology was evaluated, and cell survival rates were calculated. A neurocyte inflammatory model was established with LPS treatment, which reached a 50% cell survival rate. PC12 cells were treated with 0.01, 0.1, 1, 10, or 100 µmol/L astragaloside IV for 24 h. The concentration of astragaloside IV that did not affect the cell survival rate was selected as the treatment group for subsequent experiments. NOS activity was detected by colorimetry; the expression levels of ERCC2, XRCC4, XRCC2, TNF-α, IL-1ß, TLR4, NOS and COX-2 mRNA and protein were detected by RT-qPCR and Western blotting. The differentially expressed genes (DEGs) between the groups were screened using a second-generation sequence (fold change>2, P<0.05) with the following KEGG enrichment analysis, RT-qPCR and Western blotting were used to detect the mRNA and protein expression of DEGs related to the IL-17 pathway in different groups of PC12 cells. RESULTS: The viability of PC12 cells was not altered by treatment with 0.01, 0.1, or 1 µmol/L astragaloside IV for 24 h (P>0.05). However, after treatment with 0.5, 0.75, 1, or 1.25 mg/mL LPS for 24 h, the viability steadily decreased (P<0.01). The mRNA and protein expression levels of ERCC2, XRCC4, XRCC2, TNF-α, IL-1ß, TLR4, NOS, and COX-2 were significantly increased after PC12 cells were treated with 1 mg/mL LPS for 24 h (P<0.01); however, these changes were reversed when PC12 cells were pretreated with 0.01, 0.1, or 1 µmol/L astragaloside IV in PC12 cells and then treated with 1 mg/mL LPS for 24 h (P<0.05). Second-generation sequencing revealed that 1026 genes were upregulated, while 1287 genes were downregulated. The DEGs were associated with autophagy, TNF-α, interleukin-17, MAPK, P53, Toll-like receptor, and NOD-like receptor signaling pathways. Furthermore, PC12 cells treated with a 1 mg/mL LPS for 24 h exhibited increased mRNA and protein expression of CCL2, CCL11, CCL7, MMP3, and MMP10, which are associated with the IL-17 pathway. RT-qPCR and Western blotting analyses confirmed that the DEGs listed above corresponded to the sequence assay results. CONCLUSION: LPS can damage PC12 cells and cause inflammatory reactions in nerve cells and DNA damage. astragaloside IV plays an anti-inflammatory and DNA damage protective role and inhibits the IL-17 signaling pathway to exert a neuroprotective effect in vitro.
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Antiinflamatorios , Supervivencia Celular , Reparación del ADN , Lipopolisacáridos , Saponinas , Triterpenos , Animales , Células PC12 , Ratas , Lipopolisacáridos/farmacología , Triterpenos/farmacología , Saponinas/farmacología , Antiinflamatorios/farmacología , Supervivencia Celular/efectos de los fármacos , Reparación del ADN/efectos de los fármacosRESUMEN
Soft materials that can produce electrical energy under mechanical stimulus or deform significantly via moderate electrical fields are important for applications ranging from soft robotics to biomedical science. Piezoelectricity, the property that would ostensibly promise such a realization, is notably absent from typical soft matter. Flexoelectricity is an alternative form of electromechanical coupling that universally exists in all dielectrics and can generate electricity under nonuniform deformation such as flexure and conversely, a deformation under inhomogeneous electrical fields. The flexoelectric coupling effect is, however, rather modest for most materials and thus remains a critical bottleneck. In this work, we argue that a significant emergent flexoelectric response can be obtained by leveraging a hierarchical porous structure found in biological materials. We experimentally illustrate our thesis for a natural dry luffa vegetable-based sponge and demonstrate an extraordinarily large mass- and deformability-specific electromechanical response with the highest-density-specific equivalent piezoelectric coefficient known for any material (50 times that of polyvinylidene fluoride and more than 10 times that of lead zirconate titanate). Finally, we demonstrate the application of the fabricated natural sponge as green, biodegradable flexible smart devices in the context of sensing (e.g., for speech, touch pressure) and electrical energy harvesting.
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Tumor multidrug resistance (MDR) remains one of the most challenging barriers to successful cancer treatment. Several previous studies have suggested that high mobility group box 1 (HMGB1) may be a promising therapeutic target for overcoming cancer drug resistance. Emerging evidence has indicated that HMGB1 functions as a 'doubleedged sword' that plays both pro and antitumor roles in the development and progression of multiple types of cancer. HMGB1 has also been found to be a key regulator of several cell death and signaling pathways, and is involved in MDR by mediating cell autophagy and apoptosis, ferroptosis, pyroptosis and multiple signaling pathways. Additionally, HMGB1 is regulated by a variety of noncoding RNAs (ncRNAs), such as microRNAs, long ncRNAs and circular RNAs that are involved in MDR. Thus far, studies have been conducted to identify strategies with which to overcome HMGB1mediated MDR by the targeted silencing of HMGB1 and the targeted interference of HMGB1 expression using drugs and ncRNAs. Therefore, HMGB1 is closely associated with tumor MDR and is a promising therapeutic target.
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Proteína HMGB1 , Neoplasias , Humanos , Proteína HMGB1/genética , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Apoptosis/genética , Autofagia/genética , Muerte CelularRESUMEN
Background: Lead poisoning is a rare but serious disease. The clinical manifestations of lead poisoning are various and nonspecific, such as abdominal pain, headache, dizziness, nightmare, fatigue and so on. Rapid diagnosis of lead poisoning is challenging because it does not have special symptoms and the morbidity is very low. Case Presentation: A 31-year-old woman presented with epigastric discomfort without any obvious cause. The patient was diagnosed with lead poisoning, as the blood levels of heavy metals were detected and the lead was 463.17 µg/L, which was very high (normal value was less than 100 µg/L). The patient was treated with intravenous drip of calcium sodium edentate and got better. The patient achieved good recovery and there was no recurrence. Conclusion: Lead poisoning is a rare disease and easy to be misdiagnosed as acute abdomen disease when present with abdominal pain. Lead poisoning should be considered when common causes of abdominal pain are excluded, especially patients with anemia and abnormal liver function. The diagnosis of lead poisoning is mainly replied on the blood or urine lead concentrations. Then we should firstly cut off the contact with lead and use metal complexing agent to facilitate lead excretion.
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Catalyst activity affects the reaction rate, and an increasing number of studies have shown that strain can significantly increase the electrocatalytic activity. Catalysts such as alloys and core-shell structures can modulate their properties through strain effects. Reasonable simulation techniques can be used to predict and design the catalytic performance based on understanding the strain action mechanism. Therefore, the methodological flow of theoretical simulations is summarised in this review. The mechanism underlying the strain-adsorption-reaction relationship is discussed using density functional theory (DFT) calculations. An introduction to DFT is given first, followed by a quick rundown of the strain classification and application. Typical electrocatalytic reactions, namely, the hydrogen and oxygen evolution reactions and oxygen reduction reaction, are taken as examples. After briefly explaining these reactions, the relevant studies on simulating the strain to tune the catalyst performance are covered. The simulation methods are summarised and analysed to observe the effects of strain on electrocatalytic properties. Finally, a summary of the issues with simulated strain-assisted design and a discussion on the perspectives and forecasts for the future design of effective catalysts are provided.
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Background: The association of metabolic syndrome (MetS) with depression has been previously reported; however, the results are ambiguous due to imbalanced confounding factors. Propensity score-based analysis is of great significance to minimize the impact of confounders in observational studies. Thus, the current study aimed to clarify the influence of MetS on depression incidence in the U.S. adult population by using propensity score (PS)-based analysis. Methods: Data from 11,956 adults aged 20-85 years from the National Health and Nutrition Examination Survey (NHANES) database between 2005 and 2018 were utilized. Using 1:1 PS matching (PSM), the present cross-sectional study included 4,194 participants with and without MetS. A multivariate logistic regression model and three PS-based methods were applied to assess the actual association between MetS and depression incidence. Stratified analyses and interactions were performed based on age, sex, race, and components of MetS. Results: After PSM, the risk of developing depression in patients with MetS increased by 40% in the PS-adjusted model (OR = 1.40, 95% confidence interval [CI]: 1.202-1.619, P < 0.001), and we could still observe a positive association in the fully adjusted model (OR = 1.37, 95% CI: 1.172-1.596, P < 0.001). Regarding the count of MetS components, having four and five conditions significantly elevated the risk of depression both in the PS-adjusted model (OR = 1.78, 95% CI: 1.341-2.016, P < 0.001 vs. OR = 2.11, 95% CI: 1.626-2.699, P < 0.001) and in the fully adjusted model (OR = 1.56, 95 CI%: 1.264-1.933, P < 0.001 vs. OR = 1.90, 95% CI: 1.458-2.486, P < 0.001). In addition, an elevation in MetS component count was associated with a significant linear elevation in the mean score of PHQ-9 (F =2.8356, P < 0.001). In the sensitivity analysis, similar conclusions were reached for both the original and weighted cohorts. Further interaction analysis revealed a clear gender-based difference in the association between MetS and depression incidence. Conclusion: MetS exhibited the greatest influence on depression incidence in US adults, supporting the necessity of early detection and treatment of depressive symptoms in patients with MetS (or its components), particularly in female cases.
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Síndrome Metabólico , Adulto , Femenino , Humanos , Estudios Transversales , Depresión/epidemiología , Síndrome Metabólico/epidemiología , Encuestas Nutricionales , Puntaje de Propensión , Masculino , Adulto Joven , Persona de Mediana Edad , Anciano , Anciano de 80 o más AñosRESUMEN
All dielectric materials including ceramics, semiconductors, biomaterials, and polymers have the property of flexoelectricity, which opens a fertile avenue to sensing, actuation, and energy harvesting by a broad range of materials. However, the flexoelectricity of solids is weak at the macroscale. Here, we achieve an ultrahigh flexoelectric effect via a composite foam based on PDMS and CCTO nanoparticles. The mass- and deformability-specific flexoelectricity of the foam exceeds 10,000 times that of the solid matrix under compression, yielding a density-specific equivalent piezoelectric coefficient 120 times that of PZT. The flexoelectricity output remains stable in 1,000,000 deformation cycles, and a portable sample can power LEDs and charge mobile phones and Bluetooth headsets. Our work provides a route to exploiting flexible and light-weight materials with highly sensitive omnidirectional electromechanical coupling that have applications in sensing, actuation, and scalable energy harvesting.
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Background: For patients with rectal and sigmoid colon cancer, dissecting No. 253 lymph nodes and preserving the left colic artery are the essentials of radical surgery. In clinical work, some surgeons prefer to dissect lymph nodes with skeletonization, believing that lymph nodes can be dissected completely by this method, while other surgeons prefer to dissect lymph nodes with venation. They believe that their method can not only dissect lymph nodes completely but also ensure the safety of patients. This study aimed to investigate whether lymphadenectomy with skeletonization is superior to lymphadenectomy with venation for patients with rectal and sigmoid colon cancer. Methods: We performed a retrospective cohort study between August, 2017 and October, 2019 at the Department of General Surgery, the Affiliated Hospital of Nanjing University Medical School. The inclusion criteria were as follows: diagnosed as rectum or sigmoid colon adenocarcinoma by electronic colonoscopy and histopathology; 18-80 years of age; underwent radical resection. The exclusion criteria were as follows: received neoadjuvant therapy before surgery; combined with distant metastasis. According to the method of lymph node dissection, patients were divided into the skeletonization group and venation group. We then compared the curative effect and safety between the 2 groups. Results: A total of 211 patients were recruited in this retrospective study and assigned as follows: 62 cases to the skeletonization group and 149 patients to the venation group. There were no statistical differences in the total number of lymph nodes (P=0.082), number of positive lymph nodes (P=0.097), total number of No. 253 lymph nodes (P=0.096), number of positive No. 253 lymph nodes (P=0.813), and nodal staging (P=0.254) between the 2 groups. However, the amount of bleeding in the skeletonization group was significantly higher than that in the venation group (P≤0.001), and the operation time in the skeletonization group was also significantly longer than that in the venation group (P≤0.001). Conclusions: Lymphadenectomy with venation is preferred in the radical resection of patients with rectal and sigmoid colon cancer.
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Neoplasias del Recto , Robótica , Canal Anal , Humanos , Neoplasias del Recto/cirugía , Resultado del TratamientoRESUMEN
To investigate that the bacteriological concentration and pH value in peritoneal drainage fluid might serve as indicators of early diagnosis of anastomotic leakage following rectal resection. We prospectively analyzed consecutive patients who were treated for rectal diseases with anastomosis at the department of general surgery, the affiliated hospital of Nanjing University Medical School between August 2018 and December 2020. The bacteriological concentration and the pH value in peritoneal drainage fluid were tested on the first, fourth, seventh days postoperatively. A total of 300 consecutive patients underwent rectal resection were tested. 21 patients present with AL and the overall AL rate was 7%. The bacteriological concentration in peritoneal drainage fluid of AL group was significantly higher than that in non-AL group. The AUC value was 0.98 (95% confidence intervals 0.969-1.000) according to the ROC curve. The best cut-off value was 1143/uL. The sensitivity and specificity were 100% and 93.19% respectively. There was no difference of pH value between the AL and non-AL groups. According the results of present study, a high bacteriological concentration in peritoneal drainage fluid is a good marker for predicting and diagnosing AL following rectal resection. However, owing to the limitation of the sample, there was no validation attempt in the study. A large sample study is needed to validate the conclusion.
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Fuga Anastomótica/etiología , Líquido Ascítico/metabolismo , Líquido Ascítico/microbiología , Bacterias/metabolismo , Proctectomía/efectos adversos , Adulto , Anciano , Anciano de 80 o más Años , Anastomosis Quirúrgica , Área Bajo la Curva , Biomarcadores de Tumor/metabolismo , Drenaje , Heces , Femenino , Flatulencia , Gastroenterología , Humanos , Concentración de Iones de Hidrógeno , Masculino , Persona de Mediana Edad , Peritoneo/cirugía , Periodo Posoperatorio , Estudios Prospectivos , Curva ROC , Neoplasias del Recto/cirugía , Recto/cirugía , Sensibilidad y Especificidad , Supuración , Adulto JovenRESUMEN
Many gut disease etiologies are attributed to the presence of robust inflammatory cell recruitment. The recruitment of neutrophils plays a vital role in inflammatory infiltration. Neutrophils have various antimicrobial effector mechanisms, including phagocytosis, oxidative burst, and degranulation. It is suggested that neutrophils could release neutrophil extracellular traps (NETs) to kill pathogens. However, recent evidence indicates that neutrophil infiltration within the gut is associated with disrupted local immunological microenvironment and impaired epithelial barrier. Growing evidence implies that NETs are involved in the progression of many diseases, including cancer, diabetes, thrombosis, and autoimmune disease. Increased NET formation was found in acute or chronic conditions, including infection, sterile inflammation, cancer, and ischemia/reperfusion injury (IRI). Here, we present a comprehensive review of recent advances in the understanding of NETs, focusing on their effects in gut disease. We also discuss NETs as a potential therapeutic target in gut disease.
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Trampas Extracelulares/metabolismo , Enfermedades Intestinales/metabolismo , Intestinos/metabolismo , Infiltración Neutrófila , Neutrófilos/metabolismo , Animales , Trampas Extracelulares/efectos de los fármacos , Fármacos Gastrointestinales/uso terapéutico , Humanos , Enfermedades Intestinales/tratamiento farmacológico , Enfermedades Intestinales/inmunología , Enfermedades Intestinales/patología , Intestinos/efectos de los fármacos , Intestinos/inmunología , Intestinos/patología , Infiltración Neutrófila/efectos de los fármacos , Neutrófilos/efectos de los fármacos , Neutrófilos/inmunologíaRESUMEN
Objective: A limited number of scholars concentrated on the relationship between carotid atherosclerosis (CAS) and white matter hyperintensity (WMH) (i.e., CAS-WMH relationship). The current research aimed to clarify the CAS-WMH relationship in Japanese population. Methods: All participants underwent MRI of head and ultrasonography of the carotid artery. WMH was diagnosed from MRI results. The carotid ultrasound findings, carotid artery plaque score (PS), and plaque number (PN) could be achieved to indicate the severity of CAS. We also employed multivariate logistic regression models to estimate the CAS-WMH relationship. Interaction and stratified analyses were undertaken on the basis of a number of factors (e.g., gender, age, smoking status, drinking habit, and history of chronic diseases). Results: A total of 1,904 Japanese subjects were included, and the prevalence of WMH was 54.8% (1,044/1,904). It was unveiled that frequency of CAS was greater in cases with WMH. In a fully adjusted model, high PS was associated with the frequency of WMH, followed by high PN. Further analyses revealed a dose-response relationship between PS and incidence of WMH. Conclusion: PS and PN exhibited the greatest influences on determining the frequency of WMH, highlighting the potentially important pathophysiological role of large artery atherosclerosis in intensifying WMH.
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This study aimed to evaluate whether carbon nanoparticles could improve the accuracy of nodal staging in colorectal cancer (CRC). We performed a randomized controlled trial with CRC at the department of general surgery, the affiliated hospital of Nanjing University Medical School. A total of 160 patients were recruited in this research and 132 patients were included in the safety analyses. Among these patients, 72 cases were classified into control group and 60 cases into study group. The mean number of lymph nodes harvested from patients in study group was 19.3 ± 6.7 (range from 4 to 38), which was higher than that in control group (15.1 ± 5.7 (range from 3 to 29)) (p < 0.001). The mean number of positive lymph nodes got from patients in study group was 1.7 ± 3.5 (range from 0 to 22), which was also higher than that in control group (0.7 ± 1.4 (range from 0 to 7)) (p = 0.045). In study group, there were 30 patients (50%) proved to be N0, and remaining 30 patients (50%) were N1 or N2. However, 50 patients (69.4%) were N0 and 22 patients (30.6%) were N1 or N2 in control group. The rate of N0 in control group was significantly higher than that in study group (p = 0.023). Injecting carbon nanoparticle suspension could get a more accurate nodal staging to receive enough chemoradiotherapy, improving prognosis. Besides, injecting carbon nanoparticles suspension at four points 5 cm, 10 cm, 15 cm and 20 cm away from the anus by "sandwich" method was a new try.Trial registration: This study was registered with ClinicalTrials.gov, number ChiCTR1900025127 on 12/8/2019.
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Escisión del Ganglio Linfático/métodos , Estadificación de Neoplasias/métodos , Neoplasias del Recto/diagnóstico , Adulto , Anciano , Carbono/química , China , Femenino , Humanos , Ganglios Linfáticos/patología , Metástasis Linfática/patología , Masculino , Persona de Mediana Edad , Nanopartículas/química , Pronóstico , Neoplasias del Recto/metabolismo , SuspensionesRESUMEN
Silicon (Si) is a promising candidate as an anode material for lithium-ion batteries. However, its application is hindered by poor cycling stability and rate-capability due to structural degradation, resulting from large volume changes during cyclic charging and discharging. In this paper, we report that uniform-sized Si@void@C nanoparticles can be prepared by magnesiothermic reduction of SiO2@void@C. Si nanoparticles are in hollow carbon shells with a large void space between the carbon shell and particles. Thus, each Si particle can expand freely within the well-designed void space without destroying the outer carbon shell, and benefit the solid-electrolyte interphase film stabilization on the carbon shell. The new material shows a high capacity of 1598 mA h g-1 at a current density of 1 A g-1, a long cycle life of 1500 cycles with 85% capacity retention, and a high Coulombic efficiency of 99.6% as well, and might be a promising Si-based anode material for Li-ion battery applications.
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The dynamics of evaporating water droplets on heated graphene-poly(dimethylsiloxane) (PDMS) composites is investigated experimentally and theoretically. By inserting graphene nucleates in PDMS, we report the effect of change in thermal resistance on the evaporation process of water droplets on the heated graphene-PDMS composite surface. By dispersing graphene within the PDMS matrix, the evaporation of water droplets is enhanced. The graphene nucleate density over the surface was controlled by varying graphene wt % from 0 to 2%, which in turn controls the thermal resistance and hence the evaporation rate. Experimentally, the maximum evaporation rate of 0.0044 µL/s was observed for the sample of 2 wt % graphene-PDMS composite. The evaporation rate on a 2 wt % graphene-PDMS composite surface is about 1.5 times higher compared to that of plain PDMS without graphene. A theoretical model confirms that the initial contact angle and the presence of thermal coupling between liquid droplets and the substrate play an important role in evaporation dynamics. Thermal conductance increases 3 times with the increase in graphene wt % from 0.1 to 2.0 wt % in PDMS. The heat-storing capacity of graphene is responsible for the enhanced evaporation. The experimental findings are in good agreement with theoretical results. These samples were found insensitive to degradation and may find potential applications where high efficiency and high heat flux are needed.
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Both nitric oxide (NO) dysfunction and oxidative stress have been regarded as the important factors in the development and progression of diabetes and its complications. Multifunctional compounds with hypoglycemic, NO supplementation and anti-oxidation will be the promising agents for treatment of diabetes. In this study, six phenylfuroxan nitric oxide (NO) donor phenols were synthesized, which were designed via a combination approach with phenylfuroxan NO-donor and natural phenols. These novel synthetic compounds were screened in vitro for α-glucosidase inhibition, NO releasing, anti-oxidation, anti-glycation and anti-platelet aggregation activity as well as vasodilatation effects. The results exhibited that compound T5 displayed more excellent activity than other compounds. Moreover, T5 demonstrated significant hypoglycemic activity in diabetic mice and oral glucose tolerance test (OGTT) mice. T5 also showed NO releasing and anti-oxidation in diabetic mice. Based on these results, compound T5 deserves further study as potential new multifunctional anti-diabetic agent with antioxidant, NO releasing, anti-platelet aggregation and vasodilatation properties.
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Antioxidantes/farmacología , Inhibidores de Glicósido Hidrolasas/farmacología , Hipoglucemiantes/farmacología , Donantes de Óxido Nítrico/farmacología , Fenoles/farmacología , Inhibidores de Agregación Plaquetaria/farmacología , Animales , Antioxidantes/síntesis química , Antioxidantes/química , Compuestos de Bifenilo/antagonistas & inhibidores , Diabetes Mellitus Experimental/inducido químicamente , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/metabolismo , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Inhibidores de Glicósido Hidrolasas/síntesis química , Inhibidores de Glicósido Hidrolasas/química , Hipoglucemiantes/síntesis química , Hipoglucemiantes/química , Masculino , Ratones , Ratones Endogámicos ICR , Estructura Molecular , Donantes de Óxido Nítrico/síntesis química , Donantes de Óxido Nítrico/química , Fenoles/síntesis química , Fenoles/química , Picratos/antagonistas & inhibidores , Agregación Plaquetaria/efectos de los fármacos , Inhibidores de Agregación Plaquetaria/síntesis química , Inhibidores de Agregación Plaquetaria/química , Estreptozocina , Relación Estructura-Actividad , alfa-Glucosidasas/metabolismoRESUMEN
Lithium-sulfur batteries have received intensive attention, due to their high specific capacity, but the shuttle effect of soluble polysulfide results in a decrease in capacity. In response to this issue, we develop a novel tannic acid and Au nanoparticle functionalized separator. The tannic acid and gold nanoparticles were modified onto commercial polypropylene separator through a two-step solution process. Due to a large number of phenolic hydroxyl groups contained in the modified layer and the strong polarity of the gold nanoparticles, the soluble polysulfide generated during battery cycling is well stabilized on the cathode side, slowing down the capacity fade brought by the shuttle effect. In addition, the modification effectively improves the electrolyte affinity of the separator. As a result of these benefits, the novel separator exhibits improved battery performance compared to the pristine polypropylene separator.
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Hypolipidemic effects of the newly synthesized 5-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione-based fibrates were evaluated in Triton WR-1339 and high-fat diet (HFD)-induced hyperlipidemic mice. Preliminary screening of all the synthesized compounds was done by using an acute model (Triton WR-1339 model), in which compound 6 shown more significant antidyslipidemic activity than fenofibrate (FF). The compound 6 was also found to reduce serum triglyceride (TG), total cholesterol (TC) and low density lipoprotein cholesterin (LDL) in HFD-induced hyperlipidemic mice. Moreover, compound 6 displayed hepatoprotective effect, a significant amelioration in hepatic indices (AST and ALT) toxicity was observed and the histological examination showed that compound 6 inhibited the development of hepatic lipid accumulation and ameliorated the damage in hepatic tissue compared to model mice. Additional effects such as the potent antioxidant and anti-inflammatory action confirmed and reinforced the efficacy of compound 6 as a new agent of dual-effect hypolipidemic and hepatoprotective activities.
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Ácidos Fíbricos/química , Ácidos Fíbricos/uso terapéutico , Hiperlipidemias/tratamiento farmacológico , Hipolipemiantes/química , Hipolipemiantes/uso terapéutico , Tionas/química , Tionas/uso terapéutico , Tiofenos/química , Tiofenos/uso terapéutico , Animales , Dieta Alta en Grasa/efectos adversos , Ácidos Fíbricos/farmacología , Hiperlipidemias/sangre , Hiperlipidemias/etiología , Hiperlipidemias/metabolismo , Hipolipemiantes/farmacología , Metabolismo de los Lípidos/efectos de los fármacos , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Masculino , Ratones , Sustancias Protectoras/química , Sustancias Protectoras/farmacología , Sustancias Protectoras/uso terapéutico , Tionas/farmacología , Tiofenos/farmacologíaRESUMEN
Oxidative stress has been regarded as the leading mechanism of the hepatotoxicity of clofibrate (CF). To achieve multifunctional novel hypolipidemic agents with hypolipidemia, antioxidant, and ameliorating liver injury, clofibric acid derivative hydroxytyrosol-clofibrate (CF-HT) was synthesized by molecular hybridization. CF-HT exhibited significant hypolipidemia, reducing serum triglyceride (TG), total cholesterol (TC), and malonaldehyde (MDA) by 30%, 33%, and 29% in hyperlipidemic mice induced by Triton WR 1339. CF-HT also shown hepatoprotective effect, a significant decrease in hepatic indices toxicity was observed, i.e. aspartate and lactate transaminases (AST and ALT) activities, alkalines phosphatases (ALP), and total bilirubin (TBIL) levels. The liver weight and liver coefficient were also ameliorated. Serum superoxide dismutase (SOD) was significantly elevated, and serum catalase (CAT) and malondialdehyde (MDA) content were remarkably restored. The hepatic glutathione (GSH) content was obviously increased and hepatic oxidized glutathione (GSSG) content was reduced dramatically by CF-HT, as compared to the CF treated mice (pâ¯<â¯0.05). Moreover, the histopathological damage that hepatocyte hyperplasia and hypertrophy was also significantly ameliorated by treatment with CF-HT. Therefore, the results indicated that CF-HT exerted more potent hypolipidemic activity and definite hepatoprotective effect which may mainly be associated with its antioxidative property in mice.