RESUMO
Magnesium catalysts are widely used in catalytic asymmetric reactions, and a series of catalytic strategies have been developed in recent years. Herein, in this review, we have tried to summarize asymmetric magnesium catalysis for the synthesis of important chiral scaffolds. Several important optically active motifs that are present in classic chiral ligands or natural products synthesized by Mg(II) catalytic methods are briefly discussed. Moreover, the representative mechanisms for different magnesium catalytic strategies, including in situ generated magnesium catalysts, are also shown in relation to synthetic routes for obtaining these important chiral scaffolds.
RESUMO
Gastric cancer (GC) is one of the most common human malignancies due to its invasiveness and metastasis. 5-Fu is a widely applied chemotherapeutic agent against GC. Although 5-Fu therapy has achieved improvements in GC treatment, a large fraction of patients developed drug resistance which significantly limited its clinical applications. Recent studies revealed the pivotal roles of long noncoding RNAs (lncRNAs) in tumorigenesis and progressions of various tumors, including GC. However, the biological roles and molecular mechanisms of lncRNA HAGLR in GC remain unclear. Here, we report HAGLR was upregulated in both GC tissues and cell lines. In addition, HAGLR was associated with a poorly survival rate of GC patients. Blocking HAGLR inhibited GC cells proliferation and sensitized GC cells to 5-Fu. Bioinformatical analysis and luciferase assay demonstrated that HAGLR sponged microRNA (miR)-338-3p, which functions as a tumor suppressor in GC to downregulate its expressions. Moreover, from the established 5-Fu resistant GC cell line (HGC27 5-Fu R), we detected significantly elevated HAGLR, downregulated miR-338-3p, and glucose metabolism compared with parental HGC27 cells. We identified lactate dehydrogenase-A (LDHA), a glucose metabolism key enzyme, was the direct target of miR-338-3p in GC cells. Rescue experiments demonstrated that restoration of miR-338-3p in HAGLR-overexpressing HGC27 5-Fu R cells successfully overrode the HAGLR-promoted 5-Fu resistance through targeting LDHA. Taken together, this study revealed essential roles and molecular mechanisms for the HAGLR-mediated 5-Fu resistance in GC, contributing to the development of new noncoding RNA-based therapeutic strategies against chemoresistant GC.
Assuntos
MicroRNAs , RNA Longo não Codificante , Neoplasias Gástricas , Linhagem Celular Tumoral , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Glicólise , Humanos , Lactato Desidrogenase 5 , MicroRNAs/genética , MicroRNAs/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismoRESUMO
Apatinib has experienced a long-term study in enhancing the sensitivity of various cancer cells to chemotherapy drugs. Currently, researches show that apatinib could attenuate the resistance of gastric cancer (GC) cells to paclitaxel (PTX), but the mechanism has not been fully elucidated, which therefore was explored in this study. PTX-resistant GC cell, namely HGC-27R, was established by exposure to stepwise-increasing PTX. The cell viability of HGC-27 and HGC-27R under PTX or apatinib at different concentrations was assessed by CCK-8 assay, while scratching test and invasion assay were used for investigating the harmful influence of GC cells resistance to PTX. The function of apatinib in HGC-27R was studied by performing functional experiments (flow cytometry, scratching test, and invasion assay). Western blot was performed to measure the expressions of proteins concerning apoptosis, epithelial-mesenchymal transition and janus-activated kinase (JAK)/signal transducer and activator of transcription (STAT) pathway. PTX-resistant GC cell, namely HGC-27R, was successively constructed. HGC-27R cells showed resistance to PTX by promoting migratory and invasive capabilities. Apatinib not only inhibited cell viability of HGC-27 and HGC-27R, but also combined with PTX to suppress that of HGC-27R. Apatinib enhanced apoptosis, diminished migration and invasion of HGC-27R cells, elevated proapoptotic protein expression, and reduced Bcl-2, vimentin, snail, MMP-3, MMP-2, and MMP-9 expressions. The phosphorylation of JAK2 and STAT3 was repressed by apatinib. JAK2 partially reversed the effect of apatinib on enhancing sensitivity of GC cells to PTX. Apatinib strengthened sensitivity of GC cells to PTX by inhibiting JAK/STAT3 signaling pathway.
Assuntos
Neoplasias Gástricas , Linhagem Celular Tumoral , Humanos , Janus Quinases/metabolismo , Janus Quinases/farmacologia , Janus Quinases/uso terapêutico , Paclitaxel/farmacologia , Piridinas , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/metabolismoRESUMO
CONTEXT: Acute ischaemic stroke (AIS) is a major cause of disability and death, which is a serious threat to human health and life. Wasp venom extracted from Vespa magnifica Smith (Vespidae) could treat major neurological disorders. OBJECTIVE: This study investigated the effects of wasp venom on AIS in rats. MATERIAL AND METHODS: We used a transient middle cerebral artery occlusion (MCAO) model in Sprague-Dawley rats (260-280 g, n = 8-15) with a sham operation group being treated as negative control. MCAO rats were treated with wasp venom (0.05, 0.2 and 0.6 mg/kg, i.p.) using intraperitoneal injection. After treatment 48 h, behavioural tests, cortical blood flow (CBF), TTC staining, H&E staining, Nissl staining, TUNEL assay, immunohistochemistry (IHC) and ELISA were employed to investigate neuroprotective effects of wasp venom. RESULTS: Compared with the MCAO group, wasp venom (0.6 mg/kg) improved neurological impairment, accelerated CBF recovery (205.6 ± 52.92 versus 216.7 ± 34.56), reduced infarct volume (337.1 ± 113.2 versus 140.7 ± 98.03) as well as BBB permeability as evidenced by changes in claudin-5 and AQP4. In addition, function recovery of stroke by wasp venom treatment was associated with a decrease in TNF-α, IL-1ß, IL-6 and inhibition activated microglia as well as apoptosis. Simultaneously, the wasp venom regulated the angiogenesis factors VEGF and b-FGF in the brain. CONCLUSIONS: Wasp venom exhibited a potential neuroprotective effect for AIS. In the future, we will focus on determining whether the observed actions were due to a single compound or the interaction of multiple components of the venom.
Assuntos
Isquemia Encefálica/tratamento farmacológico , AVC Isquêmico/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Venenos de Vespas/farmacologia , Animais , Apoptose/efeitos dos fármacos , Relação Dose-Resposta a Droga , Infarto da Artéria Cerebral Média , Masculino , Neurônios/efeitos dos fármacos , Neurônios/patologia , Fármacos Neuroprotetores/administração & dosagem , Ratos , Ratos Sprague-Dawley , Venenos de Vespas/administração & dosagem , VespasRESUMO
Fiber optic extrinsic Fabry-Perot interferometric (EFPI) sensors are ideal candidates for on-line partial discharges (PDs) monitoring due to their inherent advantages, such as immunity to electromagnetic interference (EMI), highly compact sensing probes, and remote signal transmission. However, up to date, the design and fabrication of high-performance sensing diaphragms still remain challenging, and most of the reported diaphragms utilize circular structures with the peripheral sidewalls completely fixed. Herein, a novel EFPI ultrasonic sensor for on-line PDs monitoring is demonstrated. The proposed sensing diaphragm combines a silicon beam-supported diaphragm and a fixed boundary ring with a thickness of 5 µm, which was optimized through the multi-objective genetic algorithm (MOGA) revealing its high design flexibility and manufactured by using the microelectromechanical systems (MEMS) processing technology on a silicon-on-insulator (SOI) wafer. Compared with the circular and beam-supported diaphragm, the developed structure exhibits a higher sensitivity. The testing results show that the developed sensor owns the sensitivity and noise-limited minimum detectable ultrasonic pressure (MDUP) of -10 dB re. 1V/Pa and 63 µPa/sqrt(Hz) at its designed resonant frequency, respectively. Finally, the sensor's ability to detect PDs is validated in a temporary built PDs experimental environment, further proving its great potential to perform the on-line PDs monitoring.
RESUMO
A novel fiber optic extrinsic Fabry-Perot interferometric (EFPI) ultrasonic sensor with two resonant frequencies for detecting the partial discharges (PDs) in switchgear is demonstrated. The key sensing element consists of two 5-µm-thickness and beam-supported silicon diaphragms, whose natural frequencies are designed differently to enable the sensor to achieve the resonant responses at two different frequencies, thus obtaining a broadened frequency response. The sensing element is fabricated by employing the microelectromechanical systems (MEMS) technology on a silicon-on-insulator (SOI) wafer. The experimental results show that the sensor possesses two resonant frequencies of 31 kHz and 63 kHz, and obviously, shows a highly sensitive frequency response over a broader range compared with the approach composed of a single sensing diaphragm with only one resonant frequency. The noise-limited minimum detectable ultrasonic pressure (MDUP) reaches 251 µPa/Hz1/2@ 31 kHz and 316 µPa/Hz1/2@ 63 kHz, respectively.
RESUMO
Sound sensing finds wide applications in various fields, such as underwater detection, structural health monitoring, and medical diagnosis, to name just a few. Based on our previously developed MEMS-on-fiber sensors, showing the advantages of low cost, small volume, and high performance, a three-dimensional ultrasonic localization system employing four such sensors was established in this work. A time difference of arrival (TDOA) algorithm was utilized to analyze the acquired data and then calculate the accurate position of the ultrasonic signal source. Plenty of practical measurements were performed, and the derived localization deviation in the region of 2 m × 2 m × 1 m was about 2-5 mm. Outside this region, the deviation tended to increase due to the directional sensitivity existing in these sensors. As a result, for a more accurate localization requirement, more sensing probes are needed in order to depict a completely suitable application situation for MEMS technology.
Assuntos
Sistemas Microeletromecânicos/métodos , Som , Algoritmos , Humanos , Sistemas Microeletromecânicos/instrumentação , Transdutores , UltrassomRESUMO
Latent fingerprints, as one of the most frequently encountered traces in crime scene investigation and also one of the largest sources of forensic evidence, can play a critical role in determining the identity of a person who may be involved in a crime. Due to the invisible characteristic of latent fingerprints, exploring efficient techniques to visualize them (especially the ones resided on metallic surfaces) while retain the biological and chemical information (e.g., touch DNA) has become a multidisciplinary research focus. Herein we reported a new and highly sensitive electrochemical interfacial strategy of simultaneously developing and enhancing latent fingerprints on stainless steel based on synchronous electrodeposition and electrochromism of manganese oxides in a neutral aqueous electrolyte. By utilizing a specially designed device for electrochemical testing and image capture, a series of electrochemical measurements, physical characterization and image analysis have been applied to evaluate the feasibility, development accuracy and enhancement efficacy of the proposed electrochemical system. The qualitative and quantitative analysis on the in situ and ex situ fingerprint images indicates that the three levels of fingerprint features can be precisely developed and effectively enhanced. Forensic DNA typing has also been performed to reveal actual impact of the proposed electrochemical system on subsequent analysis of touch DNA in fingerprint residues. The ratio of detected loci after electrochemical treatment reaches up to 98.5 %, showing non-destructive nature of this fingerprint development and enhancement technique.
RESUMO
By development of ProPhenol/Ti(IV) catalysts, a catalytic enantioselective hydroxylative dearomatization of naphthols is achieved by using TBHP as a simple oxidative reagent. The side coordinative chain equipped on the C1-position of ß-naphthols plays an important role for initiating this asymmetric hydroxylative reaction, which might be a result of the proper cocoordination effects to the titanium center in the catalyst. A reasonable catalytic cycle is proposed, the catalytic system is applied to a reasonable range of this type of phenolic compound, and related concise transformations are carried out.
RESUMO
AIMS: Acute rupture or erosion of unstable atherosclerotic plaques is a major cause of adverse consequences of atherosclerotic cardiovascular disease, often leading to myocardial infarction or stroke. High uric acid (HUA) is associated with the increasing risk of cardiovascular events and death. However, the mechanism by which HUA promotes atherosclerosis and whether HUA affects plaque stability are still unclear. METHODS: We constructed an atherosclerotic Apoe-/- mouse model with HUA. The progression of atherosclerosis and plaques was determined by Oil Red O staining, hematoxylin and eosin (H&E) staining, and Masson staining. TdT-mediated dUTP nick-end labeling assay and immunohistochemistry were used to observe the changes of apoptosis and autophagy in plaques, respectively. Then, we validated the in vivo results with RAW 264.7 cell line. RESULTS: HUA promoted atherosclerosis and exacerbated plaque vulnerability, including significantly increased macrophage infiltration, lipid accumulation, enlarged necrotic cores, and decreased collagen fibers. HUA increased cell apoptosis and inhibited autophagy in plaques. In vitro results showed that HUA decreased cell viability and increased cell apoptosis in foam cells macrophages treated with oxidized low-density lipoprotein. An activator of autophagy, rapamycin, can partially reverse the increasing apoptosis. CONCLUSION: HUA promoted atherosclerosis and exacerbated plaque vulnerability, and HUA facilitates foam cell apoptosis by inhibiting autophagy.
Assuntos
Aterosclerose , Placa Aterosclerótica , Camundongos , Animais , Placa Aterosclerótica/metabolismo , Ácido Úrico , Camundongos Knockout , Aterosclerose/metabolismo , Autofagia , ApoptoseRESUMO
Objective: To evaluate the safety and effectiveness of nimotuzumab in combination with chemoradiotherapy for locally advanced cervical esophageal squamous cell carcinoma. Methods: Retrospective analysis was conducted from September 2012 to February 2017 among 50 locoregional-advanced cervical esophageal carcinoma (CEC) patients who received concurrent chemoradiotherapy (CRT) combined with or without nimotuzumab at Ningbo Medical Center Lihuili Hospital. Intensity-modulated radiotherapy (IMRT) was administrated on all patients. All patients were divided into two groups, of which 26 (Group A) received 200 mg (22 of 50) or 400 mg (4 of 50) of nimotuzumab per week with CRT and 24 (Group B) received definitive CRT. Results: The median follow-up time was 23 months. The median overall survival (OS) and progression-free survival (PFS) were 40.6 and 21.1 months for all, respectively. The 1-, 2-, and 3-year OS rates on the whole were 79.6%, 62.1%, and 47.8%. There was no statistical difference in overall response rate and disease control rate between the two groups. Patients treated with nimotuzumab (group A) had better PFS than the definitive CRT group (group B) (P < 0.05). However, the median OS was 41.4 months in group A and 32.4 months in group B, respectively (P = 0.517). Multivariate analysis showed that PFS among those with lower Eastern Cooperative Oncology Group (ECOG) score (HR = 5.11; P < 0.01), stage II (HR = 9.52; P < 0.01) and the application of nimotuzumab combined with CRT (HR = 0.16; P < 0.01) was much longer. Furthermore, ECOG, stage, C-reactive protein (CRP) baseline, and histological grade can also be used as independent predictors of OS. Grade >3 adverse reactions were not observed. The most common adverse event related to nimotuzumab was mild fever and the occurrence rate was 19% (5 of 26). The incidence of anemia was 65.4% in group A and 87.5% in group B (P < 0.05). Conclusions: For locoregional-advanced CEC, nimotuzumab combined with IMRT and concomitant chemotherapy was tolerated and effective. In addition, patients with a normal pretherapeutic serum CRP level (CRP < 10 mg/L) can achieve better OS.
RESUMO
Swine influenza virus (SIV) is an important zoonosis pathogen. The 2009 pandemic of H1N1 influenza A virus (2009/H1N1) highlighted the importance of the role of pigs as intermediate hosts. Liaoning province, located in northeastern China, has become one of the largest pig-farming areas since 2016. However, the epidemiology and evolutionary properties of SIVs in Liaoning are largely unknown. We performed systematic epidemiological and genetic dynamics surveillance of SIVs in Liaoning province during 2020. In total, 33,195 pig nasal swabs were collected, with an SIV detection rate of 2%. Our analysis revealed that multiple subtypes of SIVs are co-circulating in the pig population in Liaoning, including H1N1, H1N2 and H3N2 SIVs. Furthermore, 24 H1N1 SIVs were confirmed to belong to the EA H1N1 lineage and divided into two genotypes. The two genotypes were both triple reassortant, and the predominant one with polymerase, nucleoprotein (NP), and matrix protein (M) genes originating from 2009/H1N1; hemagglutinin (HA) and neuraminidase (NA) genes originating from EA H1N1; and the nonstructural protein (NS) gene originating from triple reassortant H1N2 (TR H1N2) was detected in Liaoning for the first time. According to our evolutionary analysis, the EA H1N1 virus in Liaoning will undergo further genome variation.
Assuntos
Vírus da Influenza A Subtipo H1N1 , Vírus da Influenza A , Infecções por Orthomyxoviridae , Doenças dos Suínos , Animais , Vírus da Influenza A Subtipo H1N1/genética , Vírus da Influenza A Subtipo H1N2/genética , Vírus da Influenza A Subtipo H3N2/genética , Vírus da Influenza A/genética , Infecções por Orthomyxoviridae/epidemiologia , Infecções por Orthomyxoviridae/veterinária , Filogenia , Prevalência , Vírus Reordenados/genética , Suínos , Doenças dos Suínos/epidemiologiaRESUMO
Acute ischemic stroke triggers complex systemic pathological responses for which the exploration of drug resources remains a challenge. Wasp venom extracted from Vespa magnifica (Smith, 1852) is most commonly used to treat rheumatoid arthritis as well as neurological disorders. Vespakinin-M (VK), a natural peptide from wasp venom, has remained largely unexplored for stroke. Herein, we first confirmed the structure, stability, toxicity and distribution of VK as well as its penetration into the blood-brain barrier. VK (150 and 300 µg/kg, i.p.) was administered to improve stroke constructed by middle cerebral artery occlusion in mice. Our results indicate that VK promote functional recovery in mice after ischemia stroke, including an improvement of neurological impairment, reduction of infarct volume, maintenance of blood-brain barrier integrity, and an obstruction of the inflammatory response and oxidative stress. In addition, VK treatment led to reduced neuroinflammation and apoptosis associated with the activation of PI3K-AKT and inhibition of IκBα-NF-κB signaling pathways. Simultaneously, we confirmed that VK can combine with bradykinin receptor 2 (B2R) as detected by molecular docking, the B2R antagonist HOE140 could counteract the neuro-protective effects of VK on stroke in mice. Overall, targeting the VK-B2R interaction can be considered as a practical strategy for stroke therapy.
Assuntos
Bradicinina/análogos & derivados , AVC Isquêmico/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Recuperação de Função Fisiológica/efeitos dos fármacos , Vespas/química , Animais , Barreira Hematoencefálica/fisiopatologia , Bradicinina/química , Bradicinina/farmacologia , Proteínas de Insetos/química , Proteínas de Insetos/farmacologia , Masculino , Camundongos , Fármacos Neuroprotetores/químicaRESUMO
Uric acid (UA), the end-product of purine metabolism, is closely related to hepatic insulin resistance (IR). Autophagy is a conserved intracellular degradation process maintaining cellular homeostasis. Autophagy plays a protective role in obesity-related hepatic IR, but whether it occurs in high uric acid (HUA)-induced hepatic IR is unclear. In this study, spontaneously elevated UA level induced hepatic IR and facilitated hepatic autophagy degradation in uricase knockout (Uox-/-) mice. In vitro, HepG2 cells stimulated with HUA medium showed decreased glucose uptake and inhibition of insulin signaling pathways, concomitant with activation of autophagy, as manifested by increased conversion of LC3B-I to -II. Rapamycin, the autophagy activator, alleviated but the autophagy inhibitor trimethyl adenine (3-MA) aggravated HUA-induced IR in HepG2 cells. Similarly, rapamycin ameliorated and 3-MA worsened HUA-induced blood glucose level and hepatic IR in Uox-/- mice. Mechanistically, HUA enhanced AMPKα phosphorylation (p-AMPKα) and inhibited mammalian target of rapamycin phosphorylation (p-mTOR) in HepG2 cells. The levels of p-AMPKα and LC3B-II/I were downregulated in HepG2 cells transfected with small interfering RNA (siRNA) against AMPKα, which suggests that the AMPKα-mTOR pathway was involved in HUA-induced autophagy. Antioxidant N-acetyl-L-cysteine reversed elevated reactive oxygen species levels induced by HUA in HepG2 cells, and AMPKα level was also inhibited, which suggests that AMPKα activation may be derived from reactive oxygen species. Collectively, these findings demonstrate that HUA increased hepatic autophagy, and autophagy activation plays a protective role in hepatic IR, which may suggest a potential therapeutic target for hepatic IR derived from HUA.
Assuntos
Resistência à Insulina , Animais , Autofagia , Insulina/metabolismo , Resistência à Insulina/fisiologia , Mamíferos/metabolismo , Camundongos , Espécies Reativas de Oxigênio/metabolismo , Ácido Úrico/metabolismoRESUMO
Insulin resistance (IR) promotes atherosclerosis and increases the risk of diabetes and cardiovascular diseases. Our previous studies have demonstrated that high uric acid (HUA) increased oxidative stress, leading to IR in cardiomyocytes and pancreatic ß cells. However, whether HUA can induce IR in monocytes/macrophages, which play critical roles in all stages of atherosclerosis, is unclear. Recent findings revealed that thioredoxin-interacting protein (TXNIP) negatively regulates insulin signaling; however, the roles and mechanisms of TXNIP in HUA-induced IR remain unclear. Therefore, in this study, we investigated the function of TXNIP in macrophages treated with UA. Transcriptomic profiling revealed TXNIP as one of the most upregulated genes, and subsequent RT-PCR and Western blot analyses confirmed that TXNIP was upregulated by HUA. HUA treatment significantly increased mitochondrial reactive oxygen species (MtROS) levels and decreased insulin-stimulated glucose uptake. Silencing TXNIP by RNA interference significantly diminished HUA-induced oxidative stress and IR. Mechanistically, silencing TXNIP reversed the inhibition of the phosphorylation of insulin receptor substrate 2 (IRS2)/protein kinase B (AKT) pathway induced by HUA. Additional study revealed that HUA induced the activation of the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase 1 (HO-1) signaling pathway, but silencing TXNIP abolished it. Moreover, Nrf2 inhibitor (ML385) ameliorated HUA-induced IR independent of IRS2/AKT signaling. Probenecid, a well-known UA-lowering drug, significantly suppressed the activation of TXNIP and Nrf2/HO-1 signaling. Furthermore, RNA-seq revealed that activation of the TXNIP-related redox pathway may be a key regulator in patients with asymptomatic hyperuricemia. These data suggest that silencing TXNIP could ameliorate HUA-induced IR via the IRS2/AKT and Nrf2/HO-1 pathways in macrophages. Additionally, TXNIP might be a promising therapeutic target for preventing and treating oxidative stress and IR induced by HUA.
Assuntos
Resistência à Insulina , Ácido Úrico , Proteínas de Transporte/genética , Heme Oxigenase-1/genética , Heme Oxigenase-1/metabolismo , Humanos , Proteínas Substratos do Receptor de Insulina/genética , Proteínas Substratos do Receptor de Insulina/metabolismo , Macrófagos/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Espécies Reativas de Oxigênio/metabolismoRESUMO
Atherosclerotic vascular disease (ASVD) is the leading cause of death worldwide. Hyperuricemia is the fourth risk factor for atherosclerosis after hypertension, diabetes, and hyperlipidemia. The mechanism of hyperuricemia affecting the occurrence and development of atherosclerosis has not been fully elucidated. Mononuclear macrophages play critical roles in all stages of atherosclerosis. Studies have confirmed that both hyperuricemia and ferroptosis promote atherosclerosis, but whether high level of uric acid (HUA) promotes atherosclerosis by regulating ferroptosis in macrophages remains unclear. We found that HUA significantly promoted the development of atherosclerotic plaque and downregulated the protein level of the NRF2/SLC7A11/GPX4 signaling pathway in ApoE-/- mice. Next, we evaluated the effect of HUA and ferroptosis inhibitor ferrostatin-1 (Fer-1) treatment on the formation of macrophage-derived foam cells. HUA promoted the formation of foam cells, decreased cell viability, and increased iron accumulation and lipid peroxidation in macrophages treated with oxidized low-density lipoprotein (oxLDL); these effects were reversed by Fer-1 treatment. Mechanistically, HUA significantly inhibited autophagy and the protein level of the NRF2/SLC7A11/GPX4 signaling pathway. Fer-1 activated autophagy and upregulated the level of ferroptosis-associated proteins. Moreover, an NRF2 inducer (tertbutyl hydroquinone (TBHQ)) and autophagy activator (rapamycin (RAPA)) could reverse the inhibitory effect of HUA on foam cell survival. Our results suggest that HUA-induced ferroptosis of macrophages is involved in the formation of atherosclerotic plaques. More importantly, enhancing autophagy and inhibiting ferroptosis by activating NRF2 may alleviate HUA-induced atherosclerosis. These findings might contribute to a deeper understanding of the role of HUA in the pathogenesis of atherosclerosis and provide a therapeutic target for ASVD associated with hyperuricemia.
Assuntos
Aterosclerose , Ferroptose , Hiperuricemia , Placa Aterosclerótica , Animais , Aterosclerose/patologia , Autofagia , Camundongos , Fator 2 Relacionado a NF-E2/metabolismo , Ácido ÚricoRESUMO
Ultrasonic wave is a powerful tool for many applications, such as structural health monitoring, medical diagnosis and partial discharges (PDs) detection. The fiber optic extrinsic Fabry-Perot interferometric (EFPI) sensor has become an ideal candidate for detecting weak ultrasonic signals due to its inherent advantages, and each time with a performance enhancement, it can bring great application potential in broadened fields. Herein, an EFPI ultrasonic sensor for PDs detection is proposed. The sensing diaphragm uses a 5-µm-thickness and beam-supported structure to improve the responsive sensitivity of the sensor at the resonant frequency. Furthermore, the ability of the sensor to detect characteristic ultrasonic signal of PDs is further enhanced by assembling a Fresnel-zone-plate (FZP)-based ultrasonic lens with the sensing probe to amplify the ultrasonic wave before it excites the sensing diaphragm. The final testing results show that the originally developed sensor owns the sensitivity of - 19.8 dB re. 1 V/Pa at resonant frequency. While, when the FZP is assembled with the probe, the sensitivity reaches to - 12.4 dB re. 1 V/Pa, and leads to a narrower frequency band, which indicates that the proposed method has a great potential to enhance the detection ability of sensor to characteristic ultrasonic wave of PDs.
RESUMO
BACKGROUND: To evaluate the efficacy and toxicity of docetaxel, cisplatin, and fluorouracil (TPF) regimen followed by intensity modulated radiotherapy (IMRT) on locally advanced nasopharyngeal carcinoma (NPC). METHODS: A total of 150 patients with locally advanced NPC [American Joint Committee on Cancer (AJCC) 2009 stage IIIa-IVb] received 2 or 3 cycles of a TPF regimen as induction chemotherapy. A group of 67 participants (TPF group) continued to receive TPF chemotherapy and radiotherapy, and the remaining 83 participants (P group) received cisplatin chemotherapy and radiotherapy. RESULTS: A median follow-up of 35 months (4-66 months) showed that there was no significant difference between P group and TPF group in progression-free survival (PFS) and overall survival (OS). The incidence rate of myelosuppression at 3-4 degrees was 16.9% and 34.3% in the P group and TPF group (P=0.029), respectively, and the oral mucosa reaction at 3-4 degrees was 18.1% and 37.3% in the P group and TPF group, respectively (P=0.007). The 3-4-degree skin reaction in the P group and TPF group was 15.7% and 29.9% (P=0.030), respectively. The rate of liver function injury in the P group was significantly lower than that in TPF group (P<0.05). CONCLUSIONS: Compared with concurrent cisplatin chemotherapy and radiotherapy, the concurrent TPF regimen and IMRT showed no significant improvement in OS and PFS in patients with advanced NPC, but exhibited more severe hematologic toxicity, oral mucosal responses, skin reactions, and liver functional impairment.
Assuntos
Neoplasias Nasofaríngeas , Radioterapia de Intensidade Modulada , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Humanos , Quimioterapia de Indução , Carcinoma Nasofaríngeo/tratamento farmacológico , Carcinoma Nasofaríngeo/radioterapia , Neoplasias Nasofaríngeas/tratamento farmacológico , Neoplasias Nasofaríngeas/radioterapia , Radioterapia de Intensidade Modulada/efeitos adversos , Estudos Retrospectivos , Taxoides/uso terapêuticoRESUMO
Alzheimer's disease (AD) is a serious neurodegenerative disease. Senile plaques (SPs) in the extracellular space and neurofibrillary tangles (NFTs) in the intracellular areas of the brain are two typical features of AD. SPs and NFTs are composed of amyloid-ß (Aß) aggregates and hyperphosphorylated Tau, respectively. (m)RVD-hemopressin (RVD), which is derived from mouse brain peptide, binds to the cannabinoid 1 receptor (CB1R) as an agonist. Our previous study indicated that RVD reversed Aß1-42-induced memory impairment in mice. Here, we investigated the underlying molecular mechanism of RVD on Aß1-42-induced neurotoxicity in retinoic acid-differentiated human neuroblastoma SH-SY5Y cells. Cell viability and neurite outgrowth were investigated by live cell imaging and analysis instrument. We found that RVD reversed Aß1-42-induced Tau phosphorylation, apoptosis and suppression of neurite outgrowth and the synapse-associated protein postsynaptic density protein 95 (PSD-95) by inhibiting the activity of protein kinase A (PKA) and glycogen synthase kinase 3ß (GSK-3ß). Combined treatment with AM251 (a CB1R antagonist) blocked the effects of RVD. In conclusion, RVD may be a potential therapeutic agent for the treatment of cognitive dysfunctions, such as Alzheimer's disease.
Assuntos
Peptídeos beta-Amiloides/metabolismo , Apoptose/efeitos dos fármacos , Neuritos/efeitos dos fármacos , Neuritos/metabolismo , Fragmentos de Peptídeos/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular , Humanos , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/metabolismo , Fragmentos de Peptídeos/administração & dosagemRESUMO
BACKGROUND AND AIMS: In patients with nasopharyngeal carcinoma (NPC), local treatment failure and distant metastasis contribute largely to poor outcomes. The nasopharynx is an important lymphoid tissue, and NPC tumourigenesis and development are partly attributed to immune system disorders. Human leukocyte antigen F (HLA-F) has shown a close correlation with NPC in many genome-wide association studies (GWASs). However, clinical studies rarely explore the relationship of HLA-F expression with the clinical parameters and outcomes in patients with NPC. METHODS: In this study, we used immunohistochemistry to evaluate HLA-F expression in 74 paraffin-embedded NPC tissue sections and then analysed the association between HLA-F expression and clinical parameters and outcomes. The plasma concentration of soluble HLA-F (sHLA-F) in NPC patients and normal controls was also detected, via enzyme-linked immunosorbent assay (ELISA). RESULTS: Low, moderate, and high HLA-F expression levels were observed in 47.3% (35/74), 35.1% (26/74), and 17.6% (13/74), respectively, of the tissue samples. HLA-F expression showed a significant correlation with local recurrence (p = 0.037) and distant metastasis (p = 0.024) and was also an independent factor for local recurrence-free survival (LRFS; p = 0.016) and distant metastasis-free survival (DMFS; p = 0.004). Although the mean concentration of plasma sHLA-F in the NPC patients was higher than that in the normal controls (13.63 pg/ml vs. 10.06 pg/ml), no statistical significance was observed (p = 0.118). CONCLUSIONS: Our study provides the first evidence that high HLA-F expression is associated with NPC local recurrence and distant metastasis and may be regarded as a poor prognostic factor for NPC patients. Additional studies using larger sample sizes may be necessary to determine whether sHLA-F is a feasible NPC diagnostic indicator.