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The lack of new drugs that are effective against antibiotic-resistant bacteria has caused increasing concern in global public health. Based on this study, we report development of a modified antimicrobial drug through structure-based drug design (SBDD) and modular synthesis. The optimal modified compound, F8, was identified, which demonstrated in vitro and in vivo broad-spectrum antibacterial activity against drug-resistant bacteria and effectively mitigated the development of resistance. F8 exhibits significant bactericidal activity against bacteria resistant to antibiotics such as methicillin, polymyxin B, florfenicol (FLO), doxycycline, ampicillin and sulfamethoxazole. In a mouse model of drug-resistant bacteremia, F8 was found to increase survival and significantly reduce bacterial load in infected mice. Multi-omics analysis (transcriptomics, proteomics, and metabolomics) have indicated that ornithine carbamoyl transferase (arcB) is a antimicrobial target of F8. Further molecular docking, Isothermal Titration Calorimetry (ITC), and Differential Scanning Fluorimetry (DSF) studies verified arcB as a effective target for F8. Finally, mechanistic studies suggest that F8 competitively binds to arcB, disrupting the bacterial cell membrane and inducing a certain degree of oxidative damage. Here, we report F8 as a promising candidate drug for the development of antibiotic formulations to combat antibiotic-resistant bacteria-associated infections.
Asunto(s)
Antibacterianos , Diseño de Fármacos , Pruebas de Sensibilidad Microbiana , Antibacterianos/farmacología , Antibacterianos/química , Animales , Ratones , Simulación del Acoplamiento Molecular , Farmacorresistencia Bacteriana/efectos de los fármacos , Proteínas Bacterianas/metabolismo , Proteínas Bacterianas/genética , Bacteriemia/tratamiento farmacológico , Bacteriemia/microbiología , Farmacorresistencia Bacteriana Múltiple/efectos de los fármacos , FemeninoRESUMEN
Cluster of differentiation 38 (CD38) is a multifunctional cell surface protein involved in nicotinamide adenine dinucleotide (NAD+) homeostasis in types of cells and tissues, which can be found in many immune cells and non-immune cells. Previous studies have shown that CD38 plays an important role in regulating innate immunity. Recently, many studies have revealed the importance of CD38 in autoimmune diseases, such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), multiple sclerosis (MS), type 1 diabetes (T1D) and inflammatory bowel disease, among others. In this report, we will briefly discuss the complex immunological functions of CD38 and focus on recent advances in the role of CD38 in the development and pathogenesis of autoimmune diseases, as well as their potential as therapeutic targets for systemic diseases, intending to make a comprehensive understanding of CD38 and its promising therapeutic potential in these systemic diseases.
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Artritis Reumatoide , Enfermedades Autoinmunes , Lupus Eritematoso Sistémico , Esclerosis Múltiple , Humanos , Artritis Reumatoide/tratamiento farmacológico , Inmunidad InnataRESUMEN
Identifying key drivers of manufacturing CO2 emissions is critical to carbon reduction practices. For manufacturing, CO2 emissions are mainly determined by production capacity and production scale. However, traditional production-theoretical decomposition analysis (PDA) fails to consider production-scale-related drivers. To better support policy development and implementation, this paper improves PDA based on industrial linkage theory. The improved model can identify seven production-capacity-related drivers and five production-scale-related drivers, allowing a comprehensive understanding of CO2 emission drivers. Then this model is implemented to investigate CO2 emission changes in 18 manufacturing sectors in Hubei Province, China, from 2012 to 2017. Results show that manufacturing CO2 reduction efforts in Hubei Province have yielded some achievements, with reduced potential energy intensity and improved CO2 emission technical efficiency in most sectors. Changes in external market demand and final demand structure have contributed to CO2 reduction in most sectors. Results also reveal some problems in manufacturing in Hubei Province, such as the inability to improve CO2 emission technical efficiency and CO2 emission technology strength, the slow improvement of energy utilization technical efficiency and energy utilization technology strength, and the reduction of value-added rate.
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Dióxido de Carbono , Industrias , Dióxido de Carbono/análisis , Comercio , Carbono/análisis , Tecnología , China , Desarrollo EconómicoRESUMEN
Land use and landscape pattern highly affect water quality. Their relationship can assist in land-use management and improve land-use efficiency. In this study, a water quality survey of rivers and lakes was performed in 2020 to analyze the effects of land use and the landscape pattern on the water quality of the rivers and lakes in the Baoan Lake basin and is expected to provide a reference for land use planning. The results demonstrated that the effects of land use on water quality were generally higher during the dry season than during the wet season; however, the opposite was demonstrated for the landscape pattern index. Cropland and urban land were closely correlated with deteriorating water quality, with contributions to total nitrogen, total phosphorous, and ammonia nitrogen in the basin. The impact of the landscape pattern of the basin on water quality was controlled by the original land-use type. In addition, the landscape configuration formed different land-use types to produce different effects on water quality. The basin scale better explained the changes in water quality, especially for construction land, followed by the 250 m and 500 m scales in the buffer zone.
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Lagos , Calidad del Agua , China , Nitrógeno/análisis , RíosRESUMEN
Proteus mirabilis is an opportunistic pathogen frequently associated with nosocomial infection and food poisoning cases. Contamination of P. mirabilis in retail meat products may be important transmission routes for human infection with P. mirabilis. In this study a total of 89 P. mirabilis strains were isolated from 347 samples in 14 food markets in China and subjected to whole-genome sequencing. Phylogenetic analysis showed that all 89 strains were divided into 81 different clones (SNPs >5), indicating high genetic diversity of P. mirabilis in food markets. Antimicrobial susceptibility testing showed that 81 (91.01%) strains displayed multidrug resistance profiles. Seventy-three different resistance genes (or variants) were found, including various clinically important antimicrobial resistance genes aac(6')-Ib-cr (77.53%), bla CTX-M (39.33%), fosA3 (30.34%), as well as multiresistance gene cfr (4.50%), tigecycline resistance gene cluster tmexCD3-toprJ1 (4.50%) and carbapenemase gene bla NDM-1 (1.12%). Diverse genetic elements including Tn7 transposon, plasmid, SXT/R391 integrative conjugative element were associated with the horizontal transfer of cfr. tmexCD3-toprJ1 and bla NDM-1 were located on ICEPmiChnJZ26 and Salmonella genomic island 1, respectively. Our study emphasized high contamination of P. mirabilis harbouring various clinically important antimicrobial resistance genes in retail meat and aquatic products, which might be an important issue in terms of food safety and human health.
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Baicalin is a major flavonoid compound purified from Scutellariae radix, which has been described as an herb in the Chinese Pharmacopoeia. Previous studies have suggested baicalin possessed extensive anti-inflammatory, anti-cancer, anti-viral properties. However, up to known, there have been no reports of safety and toxicity in the rats following oral administration of baicalin. In this present study, we showed the first evidence that treatment of baicalin (400, 800 and 1600mg/kg/day) induced significantly kidney injury and fibrosis. The collagen synthesis and fibrosis-related protein expression were increased in the kidney of Sprague-Dawley (SD) rats after treatment with high doses of baicalin. We further investigated the potential molecular mechanism of baicalin-mediated renal fibrosis and revealed that baicalin activated the transforming growth factor-ß (TGF-ß)/Smad signaling pathway in a dose-dependent manner. Moreover, we also observed that baicalin induced Smad3 interaction with transcriptional coactivator p300 accompanying with increment of Smad3 acetylation. Our results may contribute to better understanding of the future pharmacological and toxicological studies of Scutellaria baicalensis Georgi and its active compounds on the human disease.
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Flavonoides/toxicidad , Enfermedades Renales/inducido químicamente , Actinas/genética , Actinas/metabolismo , Animales , Antiinflamatorios no Esteroideos/toxicidad , Antineoplásicos/toxicidad , Antivirales/toxicidad , Factor de Crecimiento del Tejido Conjuntivo/genética , Factor de Crecimiento del Tejido Conjuntivo/metabolismo , Fibronectinas/genética , Fibronectinas/metabolismo , Fibrosis , Riñón/efectos de los fármacos , Riñón/metabolismo , Riñón/patología , Enfermedades Renales/metabolismo , Enfermedades Renales/patología , Ratas Sprague-Dawley , Scutellaria baicalensis , Transducción de Señal/efectos de los fármacos , Proteína smad3/metabolismo , Factor de Crecimiento Transformador beta1/metabolismoRESUMEN
Bacteria often sequentially utilize coexisting carbohydrates in environment and firstly select the one (frequently glucose) easiest to metabolize. This phenomenon is known as carbon catabolite repression (CCR). In existing Chinese teaching materials of molecular biology and related courses, unclear or even wrong interpretations are given about CCR mechanism. A large number of studies have shown that rather than the existence of intracellular glucose, CCR is mainly caused by the glucose transport process coupling with glucose phosphorylation via the phosphoenolpyruvate: carbohydrate phosphotransferase system PTS. The transport process leads to accumulation of dephosphorylated form of EAGlc.This form of EAGlc can bind the membrane-localized LacY protein to block the uptake of lactose inducer. cAMP functions in activation of key genes involved in PTS system to strengthen the role of inducer exclusion. In addition, dephosphorylated form of EBGlc and Yee bind global transcription repressor Mlc to ensure the expression of key genes involved in the PTS system. This review summarizes the current advancement in mechanism of Escherichia coli carbon catabolite repression.