RESUMEN
Animal models of authentic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection require operation in biosafety level 3 (BSL-3) containment. In the present study, we established a mouse model employing a single-cycle infectious virus replicon particle (VRP) system of SARS-CoV-2 that can be safely handled in BSL-2 laboratories. The VRP [ΔS-VRP(G)-Luc] contains a SARS-CoV-2 genome in which the spike gene was replaced by a firefly luciferase (Fluc) reporter gene (Rep-Luci), and incorporates the vesicular stomatitis virus glycoprotein on the surface. Intranasal inoculation of ΔS-VRP(G)-Luc can successfully transduce the Rep-Luci genome into mouse lungs, initiating self-replication of Rep-Luci and, accordingly, inducing acute lung injury mimicking the authentic SARS-CoV-2 pathology. In addition, the reporter Fluc expression can be monitored using a bioluminescence imaging approach, allowing a rapid and convenient determination of viral replication in ΔS-VRP(G)-Luc-infected mouse lungs. Upon treatment with an approved anti-SARS-CoV-2 drug, VV116, the viral replication in infected mouse lungs was significantly reduced, suggesting that the animal model is feasible for antiviral evaluation. In summary, we have developed a BSL-2-compliant mouse model of SARS-CoV-2 infection, providing an advanced approach to study aspects of the viral pathogenesis, viral-host interactions, as well as the efficacy of antiviral therapeutics in the future.IMPORTANCESevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is highly contagious and pathogenic in humans; thus, research on authentic SARS-CoV-2 has been restricted to biosafety level 3 (BSL-3) laboratories. However, due to the scarcity of BSL-3 facilities and trained personnel, the participation of a broad scientific community in SARS-CoV-2 research had been greatly limited, hindering the advancement of our understanding on the basic virology as well as the urgently necessitated drug development. Previously, our colleagues Jin et al. had generated a SARS-CoV-2 replicon by replacing the essential spike gene in the viral genome with a Fluc reporter (Rep-Luci), which can be safely operated under BSL-2 conditions. By incorporating the Rep-Luci into viral replicon particles carrying vesicular stomatitis virus glycoprotein on their surface, and via intranasal inoculation, we successfully transduced the Rep-Luci into mouse lungs, developing a mouse model mimicking SARS-CoV-2 infection. Our model can serve as a useful platform for SARS-CoV-2 pathological studies and antiviral evaluation under BSL2 containment.
Asunto(s)
Antivirales , COVID-19 , Modelos Animales de Enfermedad , Genes Reporteros , SARS-CoV-2 , Replicación Viral , Animales , SARS-CoV-2/fisiología , SARS-CoV-2/genética , Ratones , COVID-19/virología , Antivirales/farmacología , Antivirales/uso terapéutico , Humanos , Pulmón/virología , Pulmón/patología , Betacoronavirus/fisiología , Betacoronavirus/genética , Neumonía Viral/virología , Infecciones por Coronavirus/virología , Contención de Riesgos Biológicos , Pandemias , Glicoproteína de la Espiga del Coronavirus/genética , Glicoproteína de la Espiga del Coronavirus/metabolismo , Femenino , Ratones Endogámicos BALB C , Chlorocebus aethiops , Replicón , Células Vero , Luciferasas de Luciérnaga/genética , Luciferasas de Luciérnaga/metabolismoRESUMEN
BACKGROUND: There is a close association between diet and abdominal pain; however, relationship between inflammatory diet and characteristics of abdominal pain has not been characterized yet. METHODS: This study analyzed baseline data from the UK Biobank, 3-item DHQ-Abdominal Pain Questionnaire (DHQ-3Q), which including abdominal pain in the past 3 months, severity of abdominal pain, and frequency of abdominal pain, and data from the National Health and Nutrition Examination Survey (NHANES) from 2017 to 2020. Energy-adjusted Dietary Inflammatory Index (E-DII), constructed based on 26 or 27 nutrients, was analyzed using continuous or categorical methods. Logistic regression and restricted cubic spline analyses examined the association between E-DII and abdominal pain. RESULTS: In UK Biobank, compared to participants in the lowest quintile of E-DII, the adjusted ORs for the highest quintile were 1.12 (95% CI 1.02-1.24; P = .022), 1.05 (95% CI 1.00-1.09; P = .030), 1.26 (95% CI 1.17-1.36; P < .001), and 1.10 (95% CI 1.00-1.20; P = .044) for chronic abdominal pain, abdominal pain in the past three months, severity of abdominal pain, and frequency of abdominal pain, respectively. In NHANES, compared to participants in the lowest quintile of E-DII, the adjusted ORs for the highest quintile were 1.46 (95% CI 1.20-1.77;P < .001), 1.75 (95% CI 1.20-2.60; P = .005), 1.45 (95% CI 1.14-1.87; P = .003), and 1.18 (95% CI 0.82-1.72; P = .380) for abdominal pain in the past year, upper left abdominal pain, upper middle abdominal pain, and upper right abdominal pain. Additionally, there was a nonlinear correlation between E-DII score and DHQ-3Q (P nonlinear <.001). CONCLUSION: Following a pro-inflammatory diet is linked to a higher likelihood of experiencing abdominal pain, as well as increased severity and frequency of such pain. Therefore, further longitudinal studies are necessary to investigate this relationship.
Asunto(s)
Dolor Abdominal , Dieta , Encuestas Nutricionales , Humanos , Dolor Abdominal/epidemiología , Femenino , Masculino , Persona de Mediana Edad , Reino Unido/epidemiología , Estudios Transversales , Estudios de Casos y Controles , Anciano , Adulto , Inflamación , Bancos de Muestras Biológicas , Biobanco del Reino UnidoRESUMEN
Previous studies have suggested that exposure to air pollutants may be associated with specific blood indicators or anemia in certain populations. However, there is insufficient epidemiological data and prospective evidence to evaluate the relationship between environmental air pollution and specific types of anemia. We conducted a large-scale prospective cohort study based on the UK Biobank. Annual average concentrations of NO2, PM2.5, PM2.5-10, and PM10 were obtained from the ESCAPE study using the Land Use Regression (LUR) model. The association between atmospheric pollutants and different types of anemia was investigated using the Cox proportional hazards model. Furthermore, restricted cubic splines were used to explore exposure-response relationships for positive associations, followed by stratification and effect modification analyses by gender and age. After adjusting for demographic characteristics, 3-4 of the four types of air pollution were significantly associated with an increased risk of iron deficiency, vitamin B12 deficiency and folate deficiency anemia, while there was no significant association with other defined types of anemia. After full adjustment, we estimated that the hazard ratios (HRs) of iron deficiency anemia associated with each 10 µg/m3 increase in NO2, PM2.5, and PM10 were 1.04 (95%CI: 1.02, 1.07), 2.00 (95%CI: 1.71, 2.33), and 1.10 (95%CI: 1.02, 1.20) respectively. The HRs of folate deficiency anemia with each 10 µg/m3 increase in NO2, PM2.5, PM2.5-10, and PM10 were 1.25 (95%CI: 1.12, 1.40), 4.61 (95%CI: 2.03, 10.47), 2.81 (95%CI: 1.11, 7.08), and 1.99 (95%CI: 1.25, 3.15) respectively. For vitamin B12 deficiency anemia, no significant association with atmospheric pollution was found. Additionally, we estimated almost linear exposure-response curves between air pollution and anemia, and interaction analyses suggested that gender and age did not modify the association between air pollution and anemia. Our research provided reliable evidence for the association between long-term exposure to PM10, PM2.5, PM2.5-10, NO2, and several types of anemia. NO2, PM2.5, and PM10 significantly increased the risk of iron deficiency anemia and folate deficiency anemia. Additionally, we found that the smaller the PM diameter, the higher the risk, and folate deficiency anemia was more susceptible to air pollution than iron deficiency anemia. No association was observed between the four types of air pollution and hemolytic anemia, aplastic anemia, and other types of anemia. Although the mechanisms are not well understood, we emphasize the need to limit the levels of PM and NO2 in the environment to reduce the potential impact of air pollution on folate and iron deficiency anemia.
Asunto(s)
Contaminantes Atmosféricos , Anemia , Material Particulado , Humanos , Masculino , Femenino , Contaminantes Atmosféricos/análisis , Contaminantes Atmosféricos/efectos adversos , Persona de Mediana Edad , Reino Unido/epidemiología , Material Particulado/análisis , Material Particulado/efectos adversos , Anemia/epidemiología , Anemia/sangre , Estudios Prospectivos , Anciano , Adulto , Dióxido de Nitrógeno/análisis , Dióxido de Nitrógeno/efectos adversos , Modelos de Riesgos Proporcionales , Bancos de Muestras Biológicas , Medición de Riesgo , Contaminación del Aire/efectos adversos , Contaminación del Aire/análisis , Exposición a Riesgos Ambientales/efectos adversos , Exposición a Riesgos Ambientales/análisis , Deficiencia de Ácido Fólico/epidemiología , Deficiencia de Ácido Fólico/sangre , Biobanco del Reino UnidoRESUMEN
Aqueous zinc-ion batteries (AZIBs) have attracted the attention of researchers because of their high theoretical capacity and safety. Among the many vanadium-based AZIB cathode materials, zinc vanadate is of great interest as a typical phase in the dis-/charge process. Here, a remarkable method to improve the utilization rate of zinc vanadate cathode materials is reported. In situ growth of Zn2 (V3 O8 )2 on carbon cloth (CC) as the cathode material (ZVO@CC) of AZIBs. Compared with the Zn2 (V3 O8 )2 cathode material bonded on titanium foil (ZVO@Ti), the specific capacity increases from 300 to 420 mAh g-1 , and the utilization rate of the material increases from 69.60% to 99.2%. After the flexible device is prepared, it shows the appropriate specific capacity (268.4 mAh g-1 at 0.1 A g-1 ) and high safety. The method proposed in this work improves the material utilization rate and enhances the energy density of AZIB and also has a certain reference for the other electrochemical energy storage devices.
RESUMEN
The ongoing pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has posed a major public health threat worldwide and emphasizes an urgent need for effective therapeutics. Recently, Ordonez et al. identified sulforaphane (SFN) as a novel coronavirus inhibitor both in vitro and in mice, but the mechanism of action remains elusive. In this study, we independently discovered SFN for its inhibitory effect against SARS-CoV-2 using a target-based screening approach, identifying the viral 3-chymotrypsin-like protease (3CLpro ) as a target of SFN. Mechanistically, SFN inhibits 3CLpro in a reversible, mixed-type manner. Moreover, enzymatic kinetics studies reveal that SFN is a slow-binding inhibitor, following a two-step interaction. Initially, an encounter complex forms by specific binding of SFN to the active pocket of 3CLpro ; subsequently, the isothiocyanate group of SFN as "warhead" reacts covalently to the catalytic cysteine in a slower velocity, stabilizing the SFN-3CLpro complex. Our study has identified a new lead of the covalent 3CLpro inhibitors which has potential to be developed as a therapeutic agent to treat SARS-CoV-2 infection.
Asunto(s)
COVID-19 , SARS-CoV-2 , Animales , Ratones , Quimasas , Inhibidores de Proteasas/farmacología , Inhibidores de Proteasas/uso terapéutico , Isotiocianatos/farmacología , Antivirales/uso terapéuticoRESUMEN
BACKGROUND: The vacuole/lysosome is the final destination of autophagic pathways, but can also itself be degraded in whole or in part by selective macroautophagic or microautophagic processes. Diverse molecular mechanisms are involved in these processes, the characterization of which has lagged behind those of ATG-dependent macroautophagy and ESCRT-dependent endosomal multivesicular body pathways. RESULTS: Here we show that as yeast cells gradually exhaust available nutrients and approach stationary phase, multiple vacuolar integral membrane proteins with unrelated functions are degraded in the vacuolar lumen. This degradation depends on the ESCRT machinery, but does not strictly require ubiquitination of cargos or trafficking of cargos out of the vacuole. It is also temporally and mechanistically distinct from NPC-dependent microlipophagy. The turnover is facilitated by Atg8, an exception among autophagy proteins, and an Atg8-interacting vacuolar membrane protein, Hfl1. Lack of Atg8 or Hfl1 led to the accumulation of enlarged lumenal membrane structures in the vacuole. We further show that a key function of Hfl1 is the membrane recruitment of Atg8. In the presence of Hfl1, lipidation of Atg8 is not required for efficient cargo turnover. The need for Hfl1 can be partially bypassed by blocking Atg8 delipidation. CONCLUSIONS: Our data reveal a vacuolar membrane protein degradation process with a unique dependence on vacuole-associated Atg8 downstream of ESCRTs, and we identify a specific role of Hfl1, a protein conserved from yeast to plants and animals, in membrane targeting of Atg8.
Asunto(s)
Saccharomyces cerevisiae , Vacuolas , Animales , Autofagia , Familia de las Proteínas 8 Relacionadas con la Autofagia/genética , Complejos de Clasificación Endosomal Requeridos para el Transporte/genética , Proteínas de la Membrana/genética , Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/genéticaRESUMEN
Due to the poor conductivity of Fe based, Cu based and Co based electrode materials commonly used in the electrochemical detection of glucose, and the uneven stirring and poor conductivity of the traditional preparation method based on glassy carbon electrode. In order to solve the above problems, in this work, CdIn2O4with high electrical conductivity was directly grown on three-dimensional (3D) Ni foam to prepare electrode materials for non-enzymatic glucose sensors. CdIn2O4nanoparticles is prepared from cadmium acetate and indium nitrate hydrate in benzyl alcohol by non-aqueous sol-gel method. The electrocatalytic oxidation performances of CdIn2O4electrode material for non-enzymatic glucose are studied. The results show that the proposed CdIn2O4electrode material has good electrochemical properties and sensing performance for glucose detection. The electrochemical response of CdIn2O4electrode material to glucose is recorded that calibration plot for glucose concentrations ranging from 1.0µM to 1.0 mM (R2 = 0.99), a limit detection of 0.08µM, an excellent sensitivity of 3.2925 mA.mM-1.cm-2, a rapid response time of 1.58 s, a good selectivity and a good long-term stability. These demonstrate the significant potential of CdIn2O4electrode material based on 3D Ni foam as non-enzymatic glucose sensors, which makes it possible to use it as a practical glucose detector. This work could introduce a new concept of nanoparticles modified electrode material grown directly on 3D Ni foam, thus a simple and reliable electrochemical glucose sensor platform is realized. This study was completed in 2019 in the school of materials and energy, Yunnan University.
Asunto(s)
Técnicas Electroquímicas/métodos , Glucosa/análisis , Metales Pesados/química , Nanopartículas/química , Óxidos/química , Electrodos , Humanos , Límite de Detección , Modelos LinealesRESUMEN
Effectively and quantificationally detecting hazardous gas n-butanol is very significant in daily life, which can bring about a safe living condition for humans. In this study, the one-dimensional In2O3nanorods were successfully synthesized via hydrothermal route and post-heat treatment. Noticeably, one-dimensional nanorods structures were obtained and the products presented a superior growth orientation along with (222) plane. Additionally, systematical gas-sensing measurements of the sensor made from In2O3nanorods towards hazardous n-butanol gas were conducted. Results exhibited that the fabricated sensor showed excellent n-butanol sensing properties, with aspects to a superior response value of 342.20 with concentration 100 ppm at 240 °C, remarkable selectivity, fast response/recovery times (77.5/34.2 s) and good stability. More interestingly, the detection limit of sensor as low as 500 ppb and a good linearity relationship between response values and n-butanol concentrations was presented. Gas-sensitive properties of this sensor are better than previously reported in n-butanol detection. All results demonstrate that one-dimensional In2O3nanorod is a promising sensor material to practical applications in effectively detecting n-butanol gas.
RESUMEN
Aqueous zinc-ion batteries (ZIBs) is a potential energy storage system due to its advantages of low cost, good safety, and high theoretical capacity (820 mAh g-1). However, the lack of cathode materials with long cycle stability severely restricts the development of ZIBs. In this paper, V2O5/ NaV6O15nanocomposites are synthesized by molten salt method in one step and used as cathode material for ZIBs, which have good electrochemical performances. The specific capacity of the materials remain 160 mAh g-1when the current density is 0.5 A g-1after 1000 cycles, and the capacity retention rate is 102.03% when the current density is 5 A g-1for 1000 cycles. This is mainly due to the large number of active sites generated by crystal defects and the synergistic interaction between the dual-phase materials, which reduces the stress of ions inserted/extracted during the Zn2+storage process and improves the electrochemical performance.
RESUMEN
OBJECTIVE: To analyze the clinical phenotype and genetic characterization of a child with early infantile epileptic encephalopathy. METHODS: The proband was subjected to history taking and was diagnosed based on his clinical manifestation, magnetic resonance imaging (MRI) and whole exome sequencing (WES). Sanger sequencing was carried out to determine the origin of pathogenic variant. RESULTS: The proband unconsciously tilts his head to one side with squint, which revealed an abnormal discharge. MRI indicated suspicious abnormal signal shadow in the left posterior frontal cortex in addition with inflammation signs in the right maxillary sinus and ethmoid sinus. WES revealed that the proband has carried a heterozygous c.5789G>A variant in the CACNAIA gene. The result of Sanger sequencing was in keeping with that of WES. Neither of his parents has carried the same variant. CONCLUSION: The heterozygous c.5789G>A variant of the CACNAIA gene probably underlay the early infantile epileptic encephalopathy 42 in the proband, which has a de novo origin.
Asunto(s)
Canales de Calcio/genética , Pruebas Genéticas , Espasmos Infantiles/genética , Heterocigoto , Humanos , Lactante , Mutación , Espasmos Infantiles/diagnóstico , Secuenciación del ExomaRESUMEN
Three new compounds, monarubins A-C (1, 6 and 13), together with ten known compounds, including four alkaloids (2-5), two isocoumarins (7 and 8) and four polyketides (9-12), were isolated from marine shellfish-associated fungus Monascus ruber BB5. The structures were determined on the basis of the 1D and 2D NMR, MS, UV and IR data. The absolute configurations of compounds 3, 6 and 13 were determined by ECD calculations. The NMR data of compounds deoxyhydroxyaspergillic acid (3) and 2-hydroxy-6-(1-hydroxy-1-methylpropyl)-3-sec-buthylpyrazine (4) were first reported. All of the isolated compounds were evaluated for their cytotoxic activities against human nasopharyngeal carcinoma cell lines CNE1, CNE2, SUNE1 and HONE1 and hepatocellular carcinoma cell lines QGY7701 and HepG2. Monarubin B (6) displayed potent cytotoxicities against the cancer cell lines HepG2 and QGY7701 with IC50 values of 1.72 and 0.71 µΜ, respectively; lunatinin (7) showed moderate cytotoxic activities against the cancer cell lines HepG2, QGY7701 and SUNE1 with the IC50 values of 9.60, 7.12 and 28.12 µΜ, respectively.
Asunto(s)
Antineoplásicos/aislamiento & purificación , Monascus/metabolismo , Alcaloides/administración & dosificación , Alcaloides/aislamiento & purificación , Alcaloides/farmacología , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacología , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Células Hep G2 , Humanos , Isocumarinas/aislamiento & purificación , Isocumarinas/farmacología , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/patología , Monascus/aislamiento & purificación , Carcinoma Nasofaríngeo/tratamiento farmacológico , Carcinoma Nasofaríngeo/patología , Neoplasias Nasofaríngeas/tratamiento farmacológico , Neoplasias Nasofaríngeas/patología , Policétidos/aislamiento & purificación , Policétidos/farmacología , Mariscos/microbiologíaRESUMEN
The composition of the culture medium has great influence on the metabolite production of the marine fungus Pseudallescheria boydii F44-1. By adding amino acids to GPY culture medium, two new bisindole alkaloids, pseudboindoles A and B (1 and 2), together with 11 known indole alkaloids were isolated from the culture broth. Their structures were elucidated by comprehensive analysis of the NMR, MS, IR, and UV spectra. The 3,3'-cyclohexylidenebis(1H-indole) (3) showed cytotoxic activity against various cancer cell lines.
Asunto(s)
Aminoácidos/química , Antineoplásicos/farmacología , Supervivencia Celular/efectos de los fármacos , Alcaloides Indólicos/farmacología , Pseudallescheria/química , Antineoplásicos/química , Línea Celular Tumoral , Humanos , Alcaloides Indólicos/química , Estructura MolecularRESUMEN
NiCO2S4 with different morphology was controllably fabricated by a facile hydrothermal and solvothermal route. The as-obtained samples were analyzed and characterized by X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), and scanning electron microscopy (SEM). The results reveal that the sample (NCS-1) prepared by hydrothermal method manifest a mixture of nanorods and nanospheres. The sample (NCS-2) synthesized by solvothermal process takes on spherical nanoparticles (NPs). It is found that the morphology of the sample has much influence on the electrochemical property. When applied as anode for lithium-ion batteries (LIBs), the NiCO2S4 NPs (NCS-2) possess the highest reversible discharge capacity of 1469.8 mAh g-1 compared with other two samples at the current density of 100 mA g-1 in the voltage window of 0.01-3 V. Additionally, it remains a specific capacity of 1163.7 mAh g-1 at a current density of 100 mAg-1 after 100 cycles. This excellent electrochemical performance arises from its unique mesoporous structure, which can reduce the transport lengths of both lithium ions and electrons. The mesoporous NiCO2S4 NPs show the great potential development of high-capacity anode materials for LIBs.
RESUMEN
PbS and Ag2S nanorods have been synthesized using a polyol process in the presence of poly(vinylpyrrolidone) (PVP). First, the production of Pb or Ag was realized via the thermal decomposition of a lead/silver salt. Then the Pb or Ag precursor was directly combined with S power under heating, leading to the formation of the final products. The samples were characterized by X-ray powder diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM) and energy dispersive X-ray spectroscopy (EDS). PbS cubes and cubes with a hole in the center were prepared under different reaction conditions. Possible formation mechanisms of different PbS or Ag2S morphologies have briefly been discussed.
RESUMEN
Ischemic stroke is caused when blood flow to the brain is stopped and is a major cause of death and long term disability across the globe. Excessive release of neurotransmitters is triggered in the brain by ischemia that mediates neuronal damage and causes ischemic injury. In this study, a simple, sensitive, and on-line preconcentration capillary electrophoresis method based on electrokinetic supercharging (EKS) was developed for the determination of the biogenic amines including dopamine (DA), epinephrine (E), and norepinephrine (NE) in C57BL/6 mice brain. Under the optimized conditions, the analytes were concentrated and detected within 10 min. The detection limits for the analytes ranged from 0.42 to 0.57 ng mL(-1) for a mice brain matrix. With the proposed method, the analyses of three neurochemical amines in C57BL/6 mice brain tissue during cerebral ischemic/reperfusion had been performed successfully.
Asunto(s)
Aminas Biogénicas/análisis , Encéfalo/metabolismo , Electroforesis Capilar/métodos , Animales , Aminas Biogénicas/aislamiento & purificación , Isquemia Encefálica/metabolismo , Límite de Detección , Ratones , Ratones Endogámicos C57BL , Reproducibilidad de los ResultadosRESUMEN
microRNAs play an important role in the progression of hepatocellular carcinoma (HCC). In this study, we found that miR-582-5p expression was downregulated in hepatoma tissues and HCC cell lines. Upregulation of miR-582-5p reduced colony number, inhibited cellular proliferation, and arrested cell cycle in G0/G1 phase. When miR-582-5p was inhibited, the colony number was increased and cellular proliferation and cell cycle were promoted. Further studies showed that miR-582-5p regulated the progression of HCC through directly inhibiting the expression of CDK1 and AKT3, and indirectly inhibiting the expression of cyclinD1.
Asunto(s)
Carcinoma Hepatocelular/genética , Quinasas Ciclina-Dependientes/biosíntesis , Neoplasias Hepáticas/genética , MicroARNs/genética , Proteínas Proto-Oncogénicas c-akt/biosíntesis , Proteína Quinasa CDC2 , Carcinoma Hepatocelular/patología , Ciclo Celular/genética , Línea Celular Tumoral , Proliferación Celular/genética , Quinasas Ciclina-Dependientes/genética , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Hepáticas/patología , MicroARNs/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-akt/genéticaRESUMEN
Diabetes mellitus, commonly characterized by hyperglycemia, is a group of metabolic diseases. Some oral anti-diabetic drugs show poor tolerability during chronic treatment, and associate with undesired side effects. Recent advances in the understanding of physiological functions of incretins and their degrading enzyme dipeptidyl peptidase DPP-IV have led to the discovery of DPP-IV inhibitors as a new class of oral anti-diabetic drugs. Several DPP-IV inhibitors have different chemical structures of which the xanthine scaffold has specific advantages. Combining previous work with the research strategy of pharmacophore hybridization, we retained this scaffold and synthesized a new series of amino-alcohol or diamino-modified xanthine compounds. Some xanthines exhibited submicromolar inhibitory activities against DPP-IV. The most potent compound 40 [Formula: see text] exhibits a good in vivo efficacy in reducing glucose excursion at a single dose and a better chronic effect in reducing body weight than metformin in DIO mice. In other words, the combined effect improved the pathological state of DIO mice.
Asunto(s)
Dipeptidil Peptidasa 4/química , Inhibidores de la Dipeptidil-Peptidasa IV/química , Diseño de Fármacos , Glucosa/metabolismo , Homeostasis , Xantina/química , Animales , Dipeptidil Peptidasa 4/metabolismo , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Homeostasis/efectos de los fármacos , Ratones , Factores de Tiempo , Xantina/farmacologíaRESUMEN
Some functionalized 1,2,4,5-tetrasubstituted imidazole derivatives were synthesized using a one-pot, four component reaction involving 1,2-diketones, aryl aldehydes, ammonium acetate and substituted aromatic amines. The synthesis has been efficiently carried out in a solvent free medium using ß-cyclodextrin-propyl sulfonic acid as a catalyst to afford the target compounds in excellent yields. The local anesthetic effect of these derivatives was assessed in comparison to lidocaine as a standard using a rabbit corneal and mouse tail anesthesia model. The three most potent promising compounds were subjected to a rat sciatic nerve block assay where they showed considerable local anesthetic activity, along with minimal toxicity. Among the tested analogues, 4-(1-benzyl-4,5-diphenyl-1H-imidazol-2-yl)-N,N-dimethylaniline (5g) was identified as most potent analogue with minimal toxicity. It was further characterized by a more favourable therapeutic index than the standard.
Asunto(s)
Anestésicos Locales/síntesis química , Anestésicos Locales/farmacología , Imidazoles/síntesis química , Imidazoles/farmacología , Ácidos Sulfónicos/química , beta-Ciclodextrinas/química , Anestésicos Locales/administración & dosificación , Animales , Catálisis , Córnea/efectos de los fármacos , Córnea/fisiología , Imidazoles/administración & dosificación , Concentración 50 Inhibidora , Lidocaína/administración & dosificación , Lidocaína/farmacología , Masculino , Ratones , ConejosRESUMEN
Triglycerides are the main part of fats and half of the lipids in hepatocytes, and play an important role in metabolism as energy sources and transporters of dietary fat. In this study, 33 derivatives based on 3-methyl-5-phenylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione were synthesized and evaluated for their lipid-lowering activity. Among them, compound 1i was found to exhibit potent triglyceride-lowering potency in 3T3-L1 adipocytes which was comparable to that of the adenosine monophosphate-activated protein kinase (AMPK) agonist Acadesine (AIACR). Furthermore, oral administration of 1i at a dose of 50 mg kg(-1) d(-1) for 5 weeks could reduce the mean body weight and liver weight by 12.02% and 32.00%, respectively, and regulated serum levels of triglycerides in diet-induced obese mice. The results indicate that compound 1i is a potential small-molecule for the treatment of diet-induced obesity and related diseases.
Asunto(s)
Obesidad/tratamiento farmacológico , Hipernutrición , Pirimidinonas/uso terapéutico , Células 3T3-L1 , Animales , Cromatografía Líquida de Alta Presión , Humanos , Ratones , Obesidad/etiología , Espectroscopía de Protones por Resonancia Magnética , Pirimidinonas/síntesis química , Espectrometría de Masa por Ionización de ElectrosprayRESUMEN
Leptin, the product of the obese gene, is an adipocyte-secreted protein hormone playing a key role in the progression of obesity and hepatic steatosis. In this study, 28 novel (thio)urea and guanidine-based analogues have been synthesized and N-(1-(4-(3-(2-chloroethyl)ureido)benzyl)piperidin-4-yl)-3-(trifluoromethyl) benzamide (7i) was found to be a potent regulator of leptin expression in 3T3-L1 adipocytes. Treatment with 7i at a dose of 50 mg/kg/day for 35 days reduced the body weight and liver weight of diet-induced obesity mice by 13.5% and 18.4%, respectively, while also improving the serum levels of triglyceride, total cholesterol, leptin, adiponectin, LDL-c, HDL-c. Hematoxylin-eosin (H&E) and Oil Red O staining also confirmed that 7i ameliorated fat deposition in liver tissue and restricted the size of adipocytes in obesity-related fatty liver disease.