This study aimed to develop a practical and high-affinity fluorescent probe for uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1), a key conjugative enzyme responsible for the elimination and ...detoxification of many potentially harmful compounds. Several substrates derived from N-butyl-4-phenyl-1,8-naphthalimide were designed and synthesized on the basis of the substrate preference of UGT1A1 and the principle of photoinduced electron transfer (PET). Following the preliminary screening, substrate 2 was found with a high specificity and high affinity toward UGT1A1, while such biotransformation brought remarkable changes in fluorescence emission. Both inhibition kinetic analyses and molecular docking simulations demonstrated that 2 could bind on UGT1A1 at the same ligand-binding site as bilirubin. Furthermore, this newly developed probe was successfully used for sensing UGT1A1 activities and the high-throughput screening of UGT1A1 modulators in complex biological samples. In conclusion, a practical and high-affinity fluorescent probe for UGT1A1 was designed and well-characterized, which could serve as a good surrogate for bilirubin to investigate UGT1A1-ligand interactions.
Pyroptosis is a novel proinflammatory programmed cell death process. This study was designed to investigate the functional mechanisms of long noncoding RNA growth arrest‐specific transcript 5 (lncRNA ...GAS5) on lipopolysaccharide (LPS)‐induced human bronchial epithelial cell (HBEC) pyroptosis. LPS was used to induce pyroptosis in HBECs, followed by the detection of the expression of GAS5, forkhead box O3 (FOXO3), and nuclear factor E2‐related factor 2/heme oxygenase 1 (Nrf2/HO‐1) signaling pathway‐related factors. Cell viability was evaluated using CCK‐8 assay, lactate dehydrogenase (LDH) release was assessed by LDH assay kit and caspase‐1 activity by flow cytometry. Furthermore, expression of NOD‐like receptor family pyrin domain containing 3 and pyroptosis‐related proteins was evaluated using Western blot analysis, while enzyme‐linked immunosorbent assay was used to determine the levels of inflammatory factors. The interaction between GAS5 and FOXO3 was confirmed using bioinformatic prediction, RNA immunoprecipitation assay, RNA pull‐down, and dual‐luciferase reporter gene assay. Treatment of HBECs with LPS upregulated the expression of GAS5 and FOXO3, resulting in the inactivation of the Nrf2/HO‐1 signaling pathway. On the other hand, inhibition of both GAS5 and FOXO3 promoted cell viability, reduced LDH release, pyroptosis, and inflammatory response in LPS‐induced HBECs. Furthermore, FOXO3 could interact with GAS5, while FOXO3 overexpression reversed the inhibitory effect of GAS5 knockdown on cell pyroptosis. Thus, mechanistically, inhibition of FOXO3 activates the Nrf2/HO‐1 pathway to suppress LPS‐induced pyroptosis in HBECs. This study revealed that GAS5 knockdown attenuates FOXO3 expression thereby activating the Nrf2/HO‐1 pathway to inhibit LPS‐induced pyroptosis in HBECs. These findings may contribute to identifying novel targets that inhibit pyroptosis in HBECs.
Two new open-chain cytochalasins, xylarchalasins A and B (1 and 2), together with six known analogues (3-8), were isolated from the endophytic fungus Xylaria sp. GDGJ-77B from the Chinese medicinal ...plant Sophora tonkinensis. Their structures were elucidated on the basis of comprehensive spectroscopic analysis. Compound 2 displayed moderate antibacterial activities against Bacillus subtilis and Escherichia coli with MIC values of 25 and 12.5 μg/mL, respectively.
Objective Rhizosphere microorganisms play crucial roles in the growth and development of plants, disease resistance, and environmental adaptability. As the only wild pepper variety resource in China, ...domesticated Capsicum frutescens Linn. (Xiaomila) exhibits varying beneficial traits and affects rhizosphere microbial composition compared with its wild counterparts. In this study, we aimed to identify specific rhizosphere microbiome and metabolism patterns established during the domestication process. Methods The rhizosphere microbial diversity and composition of domesticated and wild C. frutescens were detected and analyzed by metagenomics. Non-targeted metabolomics were used to explore the differences of metabolites in rhizosphere soil between wild and domesticated C. frutescens . Results We found that the rhizosphere microbial diversity of domesticated variety was significantly different from that of the wild variety, with Massilia being its dominant bacteria. However, the abundance of certain beneficial microbes such as Gemmatimonas, Streptomyces, Rambibacter, and Lysobacter decreased significantly. The main metabolites identified in the wild variety included serylthreonine, deoxyloganic acid, vitamin C, among others. In contrast, those identified in the domesticated group were 4-hydroxy- l -glutamic acid and benzoic acid. Furthermore, the differentially enriched pathways were concentrated in tyrosine and tryptophan biosynthesis, histidine and purine-derived alkaloids biosynthesis, benzoic acid family, two-component system, etc. Conclusion This study revealed that C. frutescens established specific rhizosphere microbiota and metabolites during domestication, which has important significance for the efficient utilization of beneficial microorganisms in breeding and cultivation practices.
This study sought to identify the spatial, temporal, and spatiotemporal clusters of COVID-19 cases in 366 cities in mainland China with the highest risks and to explore the possible influencing ...factors of imported risks and environmental factors on the spatiotemporal aggregation, which would be useful to the design and implementation of critical preventative measures. The retrospective analysis of temporal, spatial, and spatiotemporal clustering of COVID-19 during the period (January 15 to February 25, 2020) was based on Kulldorff’s time-space scanning statistics using the discrete Poisson probability model, and then the logistic regression model was used to evaluate the impact of imported risk and environmental factors on spatiotemporal aggregation. We found that the spatial distribution of COVID-19 cases was nonrandom; the Moran’s
I
value ranged from 0.017 to 0.453 (
P
< 0.001). One most likely cluster and three secondary likely clusters were discovered in spatial cluster analysis. The period from February 2 to February 9, 2020, was identified as the most likely cluster in the temporal cluster analysis. One most likely cluster and seven secondary likely clusters were discovered in spatiotemporal cluster analysis. Imported risk, humidity, and inhalable particulate matter PM
2.5
had a significant impact on temporal and spatial accumulation, and temperature and PM
10
had a low correlation with the spatiotemporal aggregation of COVID-19. The information is useful for health departments to develop a better prevention strategy and potentially increase the effectiveness of public health interventions.
Sepsis-associated encephalopathy (SAE), characterized by cognitive and emotional impairments, is not well investigated in sepsis survivors. Growth arrest-specific gene 6 (Gas6) has been extensively ...used to treat cerebral diseases. This study aimed to evaluate the neuroprotective effects of Gas6 in post-septic mice and to determine the underlying mechanisms of action.
Mice underwent cecal ligation and puncture (CLP) for sepsis induction. Mice were then immediately injected with 6 µg of Gas6 via the tail vein, and the effect was evaluated after 24 hours. The neurological severity score (NSS) was used to assess neurological deficits in post-septic mice. In addition, brain edema was evaluated by measuring the brain water content and blood-brain barrier (BBB) permeability using Evans blue (EB) dye extravasation. Western blotting and immunofluorescence assays were performed to determine the expression of tight junction (TJ)-associated proteins such as occludin and zonula occludens-1 (ZO-1).
Post-septic mice exhibited increased NSS, brain edema, and BBB permeability. However, acute Gas6 treatment attenuated the severe effects of sepsis on neurologic function in mice. Therefore, Gas6 attenuates brain edema and restores BBB permeability. These findings suggest that Gas6 could alleviate neurological deficits, brain edema, BBB damage, and reverse the decreased expression of occludin and ZO-1 in the brain tissue to protect against SAE.
Gas6 protects against SAE by restoring the impaired BBB permeability.
Chronic and recurrent inflammatory disorders of the gastrointestinal tract caused by a complex interplay between genetics and intestinal dysbiosis are called inflammatory bowel disease. As a result ...of the interaction between the liver and the gut microbiota, bile acids are an atypical class of steroids produced in mammals and traditionally known for their function in food absorption. With the development of genomics and metabolomics, more and more data suggest that the pathophysiological mechanisms of inflammatory bowel disease are regulated by bile acids and their receptors. Bile acids operate as signalling molecules by activating a variety of bile acid receptors that impact intestinal flora, epithelial barrier function, and intestinal immunology. Inflammatory bowel disease can be treated in new ways by using these potential molecules. This paper mainly discusses the increasing function of bile acids and their receptors in inflammatory bowel disease and their prospective therapeutic applications. In addition, we explore bile acid metabolism and the interaction of bile acids and the gut microbiota.
Cytochrome P450 1A is one of the vital subfamilies of heme-containing cytochrome P450 enzymes belonging to an important exogenous metabolizing CYP in human. The abnormal of endoplasmic reticulum (ER) ...may directly affect the functional activity of ER-located CYP1A and be associated with the occurrence and development of various diseases. In the present study, we constructed a selective two-photon fluorescent probe
for rapid and visual detection of endogenous CYP1A that was localized in the ER.
could target the ER and detect the enzymatically active CYP1A in living cells and tissues. The monitoring ability of
for the fluctuations in functionality level of CYP1A was confirmed using ER stressed A549 cell. Based on the ER-targeting two-photon probe for CYP1A, the close association of ER state and the functional activity of ER-locating CYP1A was confirmed, which would promote the deep understanding of the biofunction of CYP1A in various ER-related diseases.
A highly selective long-wavelength fluorescent probe TCFB has been developed for the detection of hCE2. The probe can be used for real-time monitoring of hCE2 activity in complex biological systems.
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