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1.
Nature ; 624(7992): 672-681, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-37935376

RESUMEN

Trace-amine-associated receptors (TAARs), a group of biogenic amine receptors, have essential roles in neurological and metabolic homeostasis1. They recognize diverse endogenous trace amines and subsequently activate a range of G-protein-subtype signalling pathways2,3. Notably, TAAR1 has emerged as a promising therapeutic target for treating psychiatric disorders4,5. However, the molecular mechanisms underlying its ability to recognize different ligands remain largely unclear. Here we present nine cryo-electron microscopy structures, with eight showing human and mouse TAAR1 in a complex with an array of ligands, including the endogenous 3-iodothyronamine, two antipsychotic agents, the psychoactive drug amphetamine and two identified catecholamine agonists, and one showing 5-HT1AR in a complex with an antipsychotic agent. These structures reveal a rigid consensus binding motif in TAAR1 that binds to endogenous trace amine stimuli and two extended binding pockets that accommodate diverse chemotypes. Combined with mutational analysis, functional assays and molecular dynamic simulations, we elucidate the structural basis of drug polypharmacology and identify the species-specific differences between human and mouse TAAR1. Our study provides insights into the mechanism of ligand recognition and G-protein selectivity by TAAR1, which may help in the discovery of ligands or therapeutic strategies for neurological and metabolic disorders.


Asunto(s)
Proteínas de Unión al GTP , Receptores Acoplados a Proteínas G , Animales , Humanos , Ratones , Aminas/metabolismo , Anfetamina/metabolismo , Antipsicóticos/química , Antipsicóticos/metabolismo , Sitios de Unión , Catecolaminas/agonistas , Catecolaminas/química , Catecolaminas/metabolismo , Microscopía por Crioelectrón , Proteínas de Unión al GTP/química , Proteínas de Unión al GTP/metabolismo , Proteínas de Unión al GTP/ultraestructura , Ligandos , Simulación de Dinámica Molecular , Mutación , Polifarmacología , Receptores Acoplados a Proteínas G/química , Receptores Acoplados a Proteínas G/metabolismo , Receptores Acoplados a Proteínas G/ultraestructura , Especificidad de la Especie , Especificidad por Sustrato
2.
Small ; 20(40): e2402250, 2024 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-38837856

RESUMEN

The development of energy- and time-saving synthetic methods to prepare bifunctional and high stability catalysts are vital for overall water splitting. Here, V-doped nickel-iron hydroxide precursor by etching NiFe foam (NFF) at room temperature with dual chloride solution ("NaCl-VCl3"), is obtained then phosphating to obtain V-Ni2P-FeP/NFF as efficient bifunctional (oxygen/hydrogen exchange reaction, OER/HER) electrocatalysts, denoted as NFF(V, Na)-P. The NFF(V, Na)-P requires only 185 and 117 mV overpotentials to reach 10 mA cm-2 for OER and HER. When used as a catalyst for water splitting in a full cell, it can be stably sustained for more than 1000 h in alkaline brine electrolysis at both current densities of 100 and 500 mA cm-2. In situ Raman analyses and density functional theory (DFT) show that the V-doping-induced surface remodeling generates hydroxyl oxides as the true catalytic active centers, which not only enhances the reaction kinetics, but also reduces the free energy change in the rate-determining step. This work provides a cost-effective substrate self-derivation method to convert commercial NFF into a powerful catalyst for electrolytic brine, offering a unique route to the development of efficient electrocatalysts for saline water splitting.

3.
J Transl Med ; 22(1): 330, 2024 04 04.
Artículo en Inglés | MEDLINE | ID: mdl-38576019

RESUMEN

BACKGROUND: Lung adenocarcinoma (LUAD) is the predominant histological subtype of lung cancer and the leading cause of cancer-related mortality. Identifying effective drug targets is crucial for advancing LUAD treatment strategies. METHODS: This study employed proteome-wide Mendelian randomization (MR) and colocalization analyses. We collected data on 1394 plasma proteins from a protein quantitative trait loci (pQTL) study involving 4907 individuals. Genetic associations with LUAD were derived from the Transdisciplinary Research in Cancer of the Lung (TRICL) study, including 11,245 cases and 54,619 controls. We integrated pQTL and LUAD genome-wide association studies (GWASs) data to identify candidate proteins. MR utilizes single nucleotide polymorphisms (SNPs) as genetic instruments to estimate the causal effect of exposure on outcome, while Bayesian colocalization analysis determines the probability of shared causal genetic variants between traits. Our study applied these methods to assess causality between plasma proteins and LUAD. Furthermore, we employed a two-step MR to quantify the proportion of risk factors mediated by proteins on LUAD. Finally, protein-protein interaction (PPI) analysis elucidated potential links between proteins and current LUAD medications. RESULTS: We identified nine plasma proteins significantly associated with LUAD. Increased levels of ALAD, FLT1, ICAM5, and VWC2 exhibited protective effects, with odds ratios of 0.79 (95% CI 0.72-0.87), 0.39 (95% CI 0.28-0.55), 0.91 (95% CI 0.72-0.87), and 0.85 (95% CI 0.79-0.92), respectively. Conversely, MDGA2 (OR, 1.13; 95% CI 1.08-1.19), NTM (OR, 1.12; 95% CI 1.09-1.16), PMM2 (OR, 1.35; 95% CI 1.18-1.53), RNASET2 (OR, 1.15; 95% CI 1.08-1.21), and TFPI (OR, 4.58; 95% CI 3.02-6.94) increased LUAD risk. Notably, none of the nine proteins showed evidence of reverse causality. Bayesian colocalization indicated that RNASET2, TFPI, and VWC2 shared the same variant with LUAD. Furthermore, NTM and FLT1 demonstrated interactions with targets of current LUAD medications. Additionally, FLT1 and TFPI are currently under evaluation as therapeutic targets, while NTM, RNASET2, and VWC2 are potentially druggable. These findings shed light on LUAD pathogenesis, highlighting the tumor-promoting effects of RNASET2, TFPI, and NTM, along with the protective effects of VWC2 and FLT1, providing a significant biological foundation for future LUAD therapeutic targets. CONCLUSIONS: Our proteome-wide MR analysis highlighted RNASET2, TFPI, VWC2, NTM, and FLT1 as potential drug targets for further clinical investigation in LUAD. However, the specific mechanisms by which these proteins influence LUAD remain elusive. Targeting these proteins in drug development holds the potential for successful clinical trials, providing a pathway to prioritize and reduce costs in LUAD therapeutics.


Asunto(s)
Adenocarcinoma del Pulmón , Neoplasias Pulmonares , Humanos , Proteoma , Teorema de Bayes , Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Adenocarcinoma del Pulmón/genética , Neoplasias Pulmonares/genética , Proteínas Sanguíneas/genética , Polimorfismo de Nucleótido Simple/genética
4.
Inorg Chem ; 63(20): 9265-9274, 2024 May 20.
Artículo en Inglés | MEDLINE | ID: mdl-38724113

RESUMEN

Creating affordable electrocatalysts and understanding the real-time catalytic process of the urea oxidation reaction (UOR) are crucial for advancing urea-based technologies. Herein, a Cu-Ni based selenide electrocatalyst (CuSey/NiSex/NF) was created using a hydrothermal technique and selenization treatment, featuring a heterogeneous interface rich in Cu2-xSe, Cu3Se2, Ni3Se4, and NiSe2. This catalyst demonstrated outstanding urea electrooxidation performance, achieving 10 mA cm-2 with just 1.31 V and sustaining stability for 96 h. Through in-situ Raman spectroscopy and ex-situ characterizations, it is discovered that NiOOH is formed through surface reconstruction in the UOR process, with high-valence Ni serving as the key site for effective urea oxidation. Moreover, the electrochemical analysis revealed that CuSey had dual effects. An analysis of XPS and electrochemical tests revealed that electron transfer from CuSey to NiSex within the CuSey/NiSex/NF heterostructure enhanced the UOR kinetics of the catalyst. Additionally, according to the in-situ Raman spectroscopy findings, the existence of CuSey facilitates a easier and faster surface reconstruction of NiSex, leading to the creation of additional active sites for urea oxidation. More significantly, this work provides an excellent "precatalyst" for highly efficient UOR, along with an in-depth understanding of the mechanism behind the structural changes in electrocatalysts and the discovery of their true active sites.

5.
Immunopharmacol Immunotoxicol ; 42(1): 37-47, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-31971040

RESUMEN

Objective: The present study aimed to investigate whether recombinant human erythropoietin (rHuEPO) plays an immunomodulatory function by regulating the TLR4/NF-κB signaling pathway.Materials and methods: C57BL/6 mice were intraperitoneally injected with rHuEPO and, half an hour later, with 50% glycerol at the dose of 7.5 ml/kg to induce crush syndrome (CS)-acute kidney injury (AKI). The levels of TNF-α, IL-1ß, IL-6, serum creatinine (Scr), and creatine kinase (CK) were measured. The kidney tissues were analyzed by HE staining, and macrophage infiltration was detected by immunohistochemistry. Double immunofluorescence staining, RT-qPCR, and western blotting were conducted to analyze TLR4/NF-κB p65 expression. Ferrous myoglobin was co-cultured with RAW264.7 cells to mimic crush injury and the production of proinflammatory cytokines. The expression levels of TLR4 and NF-κB p65 were measured.Results: In vivo study results revealed that rHuEPO ameliorated renal function, tissue damage, production of proinflammatory cytokines, and macrophage infiltration in the kidneys. The protein and mRNA expression levels of genes involved in the TLR4/NF-κB signaling pathway in CS-induced AKI mice were upregulated (p < .05). Meanwhile, the expression levels of TLR4, NF-κB p65, and proinflammatory cytokines in RAW264.7 cells were downregulated in CS-AKI mice injected with rHuEPO (p < .05).Conclusions: Our results demonstrated the immunomodulatory capacity of rHuEPO and confirmed that rHuEPO exerts protective effects against CS-induced AKI by regulating the TLR4/NF-κB signaling pathway in macrophages. Therefore, our findings highlight the therapeutic potential of rHuEPO in improving the prognosis of CS-AKI patients.


Asunto(s)
Lesión Renal Aguda , Síndrome de Aplastamiento , Eritropoyetina/farmacología , Factores Inmunológicos/farmacología , Macrófagos/inmunología , FN-kappa B/inmunología , Transducción de Señal/efectos de los fármacos , Receptor Toll-Like 4/inmunología , Lesión Renal Aguda/tratamiento farmacológico , Lesión Renal Aguda/inmunología , Lesión Renal Aguda/patología , Animales , Síndrome de Aplastamiento/tratamiento farmacológico , Síndrome de Aplastamiento/inmunología , Síndrome de Aplastamiento/patología , Macrófagos/patología , Ratones , Células RAW 264.7 , Proteínas Recombinantes/farmacología , Transducción de Señal/inmunología
6.
J Food Sci Technol ; 57(12): 4671-4687, 2020 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-33087978

RESUMEN

Black pepper (Piper nigrum L.), black cumin (Nigella sativa L.) and black cardamom (Amomum subulatum) are considered as important spices, seasoning and folk medicines. They have a diverse range of bioactive compounds, especially for polyphenolic compounds. These polyphenolic compounds contribute to the putative health benefits of these black spices. The purpose of this study was to identify, characterize and quantify the phenolic profile of these black spices using LC-ESI-QTOF/MS and HPLC-PDA and to access their antioxidant potential. The LC-ESI-QTOF/MS analysis led to the identification of 138 phenolic compounds in three black spices. In HPLC-PDA, the p-hydroxybenzoic acid was the most predominant phenolic acid in black pepper and black cumin while diosmin was the most abundant flavonoid in black cardamom (> 20 mg/g). Furthermore, black spices were systematically measured for their TPC, TFC and TTC followed by measurement of their antioxidant activities using DPPH, FRAP and ABTS assays. Black pepper showed the highest TPC, TFC, TTC, DPPH and ABTS activities as compared to other black spices while black cardamom exhibited the highest FRAP activity. The obtained results highlight the importance of these black spices as promising sources of phenolic compounds and they could be potentially utilized in food, feed and nutraceutical industries.

7.
J Cell Mol Med ; 23(9): 6260-6270, 2019 09.
Artículo en Inglés | MEDLINE | ID: mdl-31286669

RESUMEN

Fatty acid-binding protein 4 (FABP4) has been confirmed to be involved in the pathogenesis of ischaemia/reperfusion- and rhabdomyolysis-induced acute kidney injury (AKI), and targeting inhibition of FABP4 might be a potential strategy for AKI. Cisplatin as a commonly used cancer chemotherapeutic drug possessed a dose-limited side effect of nephrotoxicity. However, whether FABP4 inhibition exerted a favourable renoprotection against cisplatin-induced AKI and the involved mechanisms remained unknown. In the study, cisplatin-injected mice developed severe AKI symptom as indicated by renal dysfunction and pathological changes, companied by the high expression of FABP4 in tubular epithelial cells. Selective inhibition of FABP4 by BMS309403 at 40 mg/kg/d for 3 days and genetic knockout of FABP4 significantly attenuated the serum creatinine, blood urea nitrogen level and renal tubular damage. Mechanistically, cisplatin injection induced the increased apoptosis and regulated the corresponding protein expression of BCL-2, BCL-XL, BAX, cleaved caspase 3 and caspase 12 in the injured kidney tissues. Cisplatin also triggered multiple signal mediators of endoplasmic reticulum (ER) stress including double-stranded RNA-activated protein kinase-like ER kinase, activating transcription factor-6 and inositol-requiring enzyme-1 pathway, as well as CHOP, GRP78 and p-JNK proteins in the kidneys. Oral administration of BMS309403 significantly reduced the number of renal TUNEL-positive apoptotic cells. Knockout of FABP4 and BMS309403 notably improved ER stress-related apoptotic responses. In summary, pharmacological and genetic inhibition of FABP4 modulated apoptosis via the inactivation of ER stress in the tubular epithelial cells of cisplatin-induced AKI.


Asunto(s)
Lesión Renal Aguda/genética , Cisplatino/efectos adversos , Estrés del Retículo Endoplásmico/efectos de los fármacos , Proteínas de Unión a Ácidos Grasos/genética , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/patología , Animales , Apoptosis/efectos de los fármacos , Compuestos de Bifenilo/farmacología , Línea Celular , Cisplatino/farmacología , Modelos Animales de Enfermedad , Chaperón BiP del Retículo Endoplásmico , Estrés del Retículo Endoplásmico/genética , Proteínas de Unión a Ácidos Grasos/antagonistas & inhibidores , Humanos , Túbulos Renales/efectos de los fármacos , Túbulos Renales/patología , Ratones , Ratones Noqueados , Neoplasias/complicaciones , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Pirazoles/farmacología , ARN Bicatenario/genética
8.
J Sci Food Agric ; 97(12): 4235-4241, 2017 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-28251668

RESUMEN

BACKGROUND: The promotion effect on proliferation of Streptococcus thermophilus by enzymatic hydrolysates of aquatic products was firstly studied. The effect of influencing factors of the hydrolysis on the growth of S. thermophilus was investigated. RESULT: Grass Carp fish skin was hydrolysed to peptides by enzymatic hydrolysis using protease ProteAX, and for the S. thermophilus growth, the optimal enzymatic hydrolysis conditions were temperature of 60 °C, initial pH of 9.0, enzyme concentration of 10 g kg-1 , hydrolysis time of 80 min, and ratio of material to liquid of 1:2. The Grass Carp fish skin hydrolysate (GCFSH) prepared under the optimum conditions was fractionated to five fragments (GCFSH 1, GCFSH 2, GCFSH 3, GCFSH 4, GCFSH 5) according to molecular weight sizes, in which the fragments GCFSH 4 and GCFSH 5, with molecular weights of less than 1000 Da, significantly promoted the growth of S. thermophilus. CONCLUSION: The hydrolysis process of Grass Carp fish skin can be simplified, and the peptides with molecular weights below 1000 Da in the hydrolysates are the best nitrogen source for proliferation of S. thermophilus. This work can provide a fundamental theoretical basis for the production of multi-component functional foods, especially in milk drinks or yogurt. © 2017 Society of Chemical Industry.


Asunto(s)
Carpas , Proteínas de Peces/química , Hidrolisados de Proteína/química , Piel/química , Streptococcus thermophilus/citología , Animales , Biocatálisis , Medios de Cultivo/química , Medios de Cultivo/metabolismo , Proteínas de Peces/metabolismo , Hidrólisis , Péptido Hidrolasas/química , Hidrolisados de Proteína/metabolismo , Streptococcus thermophilus/crecimiento & desarrollo , Streptococcus thermophilus/metabolismo
9.
Ren Fail ; 38(3): 442-50, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-26887433

RESUMEN

BACKGROUD: Fatigue is considered as a common symptom in patients with end-stage renal disease (ESRD) and can significantly decrease patients' quality of life. This study aimed to assess fatigue in hemodialysis patients and to investigate risk factors of fatigue in Chinese patients receiving maintenance hemodialysis (MHD) in China. METHODS: Eligible patients completed questionnaires including demographic information, a Chinese version of the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue), the Family APGAR Index (APGAR), the medical outcomes study health status-Social Functioning subscale (SF-36,SocF), and the Pittsburgh sleep quality index (PSQI). Laboratory parameters were abstracted by medical records review. The multiple linear regression model was used to relate parameters with the FACIT-Fatigue score. RESULTS: A total of 345 MHD patients (216 men and 129 women, age 55.6 ± 12.8) were recruited in this study. The score of FACIT-Fatigue was 39 (Interquartile Range, 31-44). Fatigue was correlated with PSQI scores (p < 0.001), SocF scores (p < 0.001), comorbidity (p = 0.006), exercise time <1 hour per day (p = 0.003), adequacy of dialysis (Kt/V) < 1.2 (p = 0.016), APGAR scores (p = 0.014), and high Scr (p = 0.043). CONCLUSIONS: Fatigue is related to sleep disturbance, social and family functioning, taking physical exercise time, comorbidity condition, Kt/V and serum creatinine level in Chinese MHD patients. Future studies and interventions should focus on developing strategies and improving the quality of life in patients by addressing these significant contributing factors.


Asunto(s)
Fatiga/complicaciones , Fallo Renal Crónico/complicaciones , Fallo Renal Crónico/terapia , Diálisis Renal/efectos adversos , Diálisis Renal/psicología , Adulto , Anciano , Ansiedad/complicaciones , China , Comorbilidad , Estudios Transversales , Depresión/complicaciones , Femenino , Humanos , Modelos Lineales , Masculino , Persona de Mediana Edad , Análisis Multivariante , Calidad de Vida , Trastornos del Sueño-Vigilia/complicaciones , Encuestas y Cuestionarios , Centros de Atención Terciaria
10.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 46(1): 22-6, 2015 Jan.
Artículo en Zh | MEDLINE | ID: mdl-25807790

RESUMEN

OBJECTIVE: To explore the pathogenic mechanism of myoglobin-induced endoplasmic reticulum stress (ERS) and apoptosis in tubular epithelial cells in acute kidney injury (AKI) mouse model of crush syndrome. METHODS: Eighteen C56BL/6 mice were randomly divided into control group, modeling 8 h group and modeling 24 h group. The AKI model of crush syndrome was established by intramuscular injection of 50% glycerol saline solution into thigh (8 microL/g), while equivalent volume of physiological saline was injected in control group. AKI was diagnosed when serum creatinine (sCr) level increased to double value of control group. The mice in the experimental groups were sacrificed at the time points of 8 h and 24 h after injection respectively. Serum Cr was detected and renal tissues was observed under electron microscopy. Apoptosis was detected by TUNEL technique. Marker proteins and mRNA of apoptosis and ERS were detected by immunohistochemistry and real-time PCR. Human kidney proximal tubular cell (HK-2) cells cultured in vitro were randomly divided into control, intervention 6 h and intervention 12 h groups. Control group were incubated in standard cell culture (DMEM/F12) and the two intervention groups were incubated in special DMEM/F12 in which ferrohemoglobin was added. After 6 h and 12 h incubation, the cells were collected and apoptosis was detected by flow cytometry. RESULTS: AKI model of crush syndrome was successfully established, which was proved with sCr doubling at the 8 h after the intramuscular injection of glycerol saline. Swelling of endoplasmic reticulum and mitochondria in proximal tubular epithelial cells was more obvious in the two model groups than that in control group. TUNEL staining showed the percentage of positive cells in AKI groups was higher than that in control group (P<0.05). Immunohistochemistry and real-time PCR showed the expressions of caspase3, caspase12 and CHOP in AKI groups were higher than those in control group (P<0.05). Flow cytometry showed cell apoptosis ratio was higher in model groups than control groiap (P<0.05). CONCLUSION: Myoglobin induced ERS and apoptosis may be involved in the pathogenesis of AKI in crush syndrome.


Asunto(s)
Lesión Renal Aguda/patología , Apoptosis , Síndrome de Aplastamiento/patología , Estrés del Retículo Endoplásmico , Mioglobina/farmacología , Animales , Caspasa 12/metabolismo , Caspasa 3/metabolismo , Línea Celular , Creatinina/sangre , Células Epiteliales/patología , Humanos , Túbulos Renales Proximales/citología , Ratones , Ratones Endogámicos C57BL , Mitocondrias/patología , Factor de Transcripción CHOP/metabolismo
11.
J Colloid Interface Sci ; 668: 110-119, 2024 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-38669988

RESUMEN

CeO2 has been identified as a significant cocatalyst to enhance the electrocatalytic activity of transition metal phosphides (TMPs). However, the electrocatalytic mechanism by which CeO2 enhances the catalytic activity of TMP remains unclear. In this study, we have successfully developed a unique CeO2-CoP-1-4 multishell microsphere heterostructure catalyst through a simple hydrothermal and calcination process. CeO2-CoP-1-4 exhibits great potential for electrocatalytic oxygen evolution reaction (OER), requiring only an overpotential of 254 mV to achieve a current density of 10 mA cm-2. Moreover, CeO2-CoP-1-4 demonstrates excellent operating durability lasting for 55 h. The presence of CeO2 as a cocatalyst can regulate the microsphere structure of CoP, the resulting multishell microsphere structure can shorten the mass transfer distance, and improve the utilization rate of the active site. Furthermore, in situ Raman and ex situ characterizations, and DFT theoretical calculation results reveal that CeO2 can effectively regulates the electronic structure of Co species, reduces the reaction free energy of rate-limiting step, thus increase the reaction kinetic. Overall, this study provides experimental and theoretical evidence to better comprehend the mechanism and structure evolution of CeO2 in enhancing the OER performance of CoP, offering a unique design inspiration for the development of efficient hollow heterojunction electrocatalysts.

12.
Environ Pollut ; 346: 123608, 2024 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-38428792

RESUMEN

To explore contaminant concerns as a result of anthropogenic disturbance of the river system, this study provided the first extensive investigation of the contamination profiles, possible driving factors, and ecological risks of 40 target compounds including pharmaceuticals and personal care products (PPCPs), neonicotinoid pesticides (NNIs), polybrominated diphenyl ethers (PBDEs), and polychlorinated biphenyls (PCBs) in sediments of the whole Yangtze River (the world's third longest river). Among these target compounds, PPCPs were the dominant contaminants with a total concentration (∑15PPCPs) of 2.13-14.99 ng/g, followed by ∑7PCBs (

Asunto(s)
Bifenilos Policlorados , Contaminantes Químicos del Agua , Bifenilos Policlorados/análisis , Éteres Difenilos Halogenados/análisis , Efectos Antropogénicos , Contaminantes Químicos del Agua/análisis , Ríos/química , Plásticos , Monitoreo del Ambiente/métodos , Sedimentos Geológicos/química , China
13.
Sci Total Environ ; 885: 163772, 2023 Aug 10.
Artículo en Inglés | MEDLINE | ID: mdl-37149176

RESUMEN

This work is the first time to investigate the annual flux, spatiotemporal changes and sources of PCBs and PBDEs in water and sediment from the middle reach of Yangtze River (Wuhan, China), which was particularly based on the monthly monitoring data in a one-year-round study. The concentrations of PCBs and PBDEs in water were

Asunto(s)
Bifenilos Policlorados , Contaminantes Químicos del Agua , Bifenilos Policlorados/análisis , Ríos , Éteres Difenilos Halogenados/análisis , Monitoreo del Ambiente/métodos , Ecosistema , Contaminantes Químicos del Agua/análisis , Sedimentos Geológicos/análisis , China , Agua/análisis
14.
MedComm (2020) ; 4(5): e380, 2023 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-37752942

RESUMEN

Genetic heterogeneity poses a challenge to research and clinical translation of autism spectrum disorder (ASD). In this study, we conducted a plasma proteomic and metabolomic study of children with ASD with and without risk genes (de novo mutation) and controls to explore the impact of genetic heterogeneity on the search for biomarkers for ASD. In terms of the proteomic and metabolomic profiles, the groups of children with ASD carrying and those not carrying de novo mutation tended to cluster and overlap, and integrating them yielded differentially expressed proteins and differential metabolites that effectively distinguished ASD from controls. The mechanisms associated with them focus on several common and previously reported mechanisms. Proteomics results highlight the role of complement, inflammation and immunity, and cell adhesion. The main pathways of metabolic perturbations include amino acid, vitamin, glycerophospholipid, tryptophan, and glutamates metabolic pathways and solute carriers-related pathways. Integrating the two omics analyses revealed that L-glutamic acid and malate dehydrogenase may play key roles in the pathogenesis of ASD. These results suggest that children with ASD may have important underlying common mechanisms. They are not only potential therapeutic targets for ASD but also important contributors to the study of biomarkers for the disease.

15.
Mol Biomed ; 4(1): 46, 2023 Dec 04.
Artículo en Inglés | MEDLINE | ID: mdl-38047990

RESUMEN

G protein-coupled receptors (GPCRs) are versatile and vital proteins involved in a wide array of physiological processes and responses, such as sensory perception (e.g., vision, taste, and smell), immune response, hormone regulation, and neurotransmission. Their diverse and essential roles in the body make them a significant focus for pharmaceutical research and drug development. Currently, approximately 35% of marketed drugs directly target GPCRs, underscoring their prominence as therapeutic targets. Recent advances in structural biology have substantially deepened our understanding of GPCR activation mechanisms and interactions with G-protein and arrestin signaling pathways. This review offers an in-depth exploration of both traditional and recent methods in GPCR structure analysis. It presents structure-based insights into ligand recognition and receptor activation mechanisms and delves deeper into the mechanisms of canonical and noncanonical signaling pathways downstream of GPCRs. Furthermore, it highlights recent advancements in GPCR-related drug discovery and development. Particular emphasis is placed on GPCR selective drugs, allosteric and biased signaling, polyphamarcology, and antibody drugs. Our goal is to provide researchers with a thorough and updated understanding of GPCR structure determination, signaling pathway investigation, and drug development. This foundation aims to propel forward-thinking therapeutic approaches that target GPCRs, drawing upon the latest insights into GPCR ligand selectivity, activation, and biased signaling mechanisms.

16.
Cell Res ; 33(4): 312-324, 2023 04.
Artículo en Inglés | MEDLINE | ID: mdl-36806352

RESUMEN

The complement system plays an important role in the innate immune response to invading pathogens. The complement fragment C5a is one of its important effector components and exerts diverse physiological functions through activation of the C5a receptor 1 (C5aR1) and associated downstream G protein and ß-arrestin signaling pathways. Dysfunction of the C5a-C5aR1 axis is linked to numerous inflammatory and immune-mediated diseases, but the structural basis for activation and biased signaling of C5aR1 remains elusive. Here, we present cryo-electron microscopy structures of the activated wild-type C5aR1-Gi protein complex bound to each of the following: C5a, the hexapeptidic agonist C5apep, and the G protein-biased agonist BM213. The structures reveal the landscape of the C5a-C5aR1 interaction as well as a common motif for the recognition of diverse orthosteric ligands. Moreover, combined with mutagenesis studies and cell-based pharmacological assays, we deciphered a framework for biased signaling using different peptide analogs and provided insight into the activation mechanism of C5aR1 by solving the structure of C5aR1I116A mutant-Gi signaling activation complex induced by C089, which exerts antagonism on wild-type C5aR1. In addition, unusual conformational changes in the intracellular end of transmembrane domain 7 and helix 8 upon agonist binding suggest a differential signal transduction process. Collectively, our study provides mechanistic understanding into the ligand recognition, biased signaling modulation, activation, and Gi protein coupling of C5aR1, which may facilitate the future design of therapeutic agents.


Asunto(s)
Receptor de Anafilatoxina C5a , Transducción de Señal , Microscopía por Crioelectrón , Inmunidad Innata , Complemento C5a/metabolismo
17.
Nanotechnology ; 23(6): 065402, 2012 Feb 17.
Artículo en Inglés | MEDLINE | ID: mdl-22248758

RESUMEN

In this paper, the soluble salt-assisted route has been extended to the low-cost and scalable preparation of ZnO nanostructures via the simple oxidation of Zn-Na2SO4 mixture followed by washing with water. The as-prepared ZnO nanopowders are of nanoscaled size, hexagonal phase, and pure, without being stained by Na2SO4. Their optical band gap is 3.22 eV, exhibiting a red-shift of 0.15 eV in comparison with pure ZnO bulk, and their optical absorbance is strong in the region of 200-400 nm, suggesting their full utilization of most of the UV light in sunlight. The product shows evident photocatalytic activity in degradation of RhB under solar light irradiation, and then its solar light degradation efficiency is close to that under UV irradiation, indicating that there is a possibility of practical application. More importantly, the obtained ZnO nanoparticles, because of the quick precipitation by themselves in solution with no stirring, could be easily recycled without any accessorial means such as high-speed centrifuge. The low-cost and scalable preparation, high photocatalytic activity, and convenient recycling of this ZnO nanomaterial gives it potential in purifying waste water. Hence the interesting results in this study indicate the wide range of the soluble salt-assisted route for the industrial preparation of many other advanced nanomaterials.


Asunto(s)
Nanoestructuras/química , Fotólisis , Rodaminas/química , Sales (Química)/química , Óxido de Zinc/química , Catálisis , Nanoestructuras/ultraestructura , Nanotecnología/métodos , Luz Solar , Rayos Ultravioleta
18.
Biomed Res Int ; 2022: 4310841, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36093392

RESUMEN

Heart failure is the final stage of the development of heart disease, with a high mortality and disability rate. It poses a serious threat to human health and brings tremendous pressure to human society. Preventing respiratory infections in patients with heart failure is also the first priority of care. This article is aimed at studying the nursing analysis of respiratory tract care based on big data exchanges to prevent respiratory tract infections in patients with heart failure. This article uses benchmark and sample collection. Studies have shown that for Pseudomonas aeruginosa, its resistance to ampicillin, amoxicillin/clavulanic acid, cefazolin, cefuroxime, ceftriaxone, cefotaxime, and cefoxitin has reached more than 80%. It is also suitable for piperacillin, ticarcillin/clavulanic acid, piperacillin/tazobactam, cefepime, aztreonam, gentamicin, tobramycin, ciprofloxacin, and levofloxacin. The resistance rate of stars is within 10%-30%. These antibiotics are effective and can be used for clinical treatment. The drug resistance rates of ceftazidime, imipenem, meropenem, and amikacin were all lower than 10%, and the drug resistance rates of ceftazidime and imipenem were much lower than those reported in the 2016 literature. These antibiotics have become the most effective drugs for the treatment of Pseudomonas aeruginosa infections. Basically, good communication of respiratory care data is realized, thereby preventing respiratory care analysis of patients with heart failure.


Asunto(s)
Insuficiencia Cardíaca , Infecciones del Sistema Respiratorio , Antibacterianos/uso terapéutico , Macrodatos , Ceftazidima , Ácido Clavulánico , Comunicación , Insuficiencia Cardíaca/tratamiento farmacológico , Humanos , Imipenem , Pruebas de Sensibilidad Microbiana , Piperacilina , Infecciones del Sistema Respiratorio/tratamiento farmacológico
19.
Guang Pu Xue Yu Guang Pu Fen Xi ; 31(6): 1601-5, 2011 Jun.
Artículo en Zh | MEDLINE | ID: mdl-21847942

RESUMEN

The interaction between Elsinochrome A (EA) and myoglobin (Mb) was investigated using UV-Vis and fluorescence spectroscopy. The results suggested that there was a strong interaction between EA and Mb. In the dark, the interaction occurred on the surfaces amidic acid of Mb, but when illuminated, the interactions happened both on amidic acid and the interior structure of hemachrome of Mb. According to the values of the quenching constant, the thermodynamics parameters, the binding constants and the binding sites, it was showed that the binding interaction of EA and Mb was mainly hydrophobic in nature and the quenching mechanism was static quenching procedure. The change in the micro-circumstance of aminos of myoglobin was studied by synchronous fluorescence spectroscopy.


Asunto(s)
Mioglobina/química , Perileno/análogos & derivados , Quinonas/química , Espectrometría de Fluorescencia , Sitios de Unión , Interacciones Hidrofóbicas e Hidrofílicas , Perileno/química , Unión Proteica , Termodinámica
20.
Precis Clin Med ; 4(1): 45-55, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-35693122

RESUMEN

Sepsis is a life-threatening organ failure exacerbated by a maladaptive infection response from the host, and is one of the major causes of mortality in the intensive care unit. In recent decades, several extracorporeal blood purification techniques have been developed to manage sepsis by acting on both the infectious agents themselves and the host immune response. This research aims to summarize recent progress on extracorporeal blood purification technologies applied for sepsis, discuss unanswered questions on renal replacement therapy for septic patients, and present a decision-making strategy for practitioners.

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