ACS Infectious Diseases
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2025
·
IF 3.8
Feifei Zhao,Yizhen Zhu,Lingxiang Mao,Honghao Huang,Wei Wei,Qiangcheng Deng,Youzhi Tang,Ning Han,Zhenling Zeng
Staphylococcus aureus poses a global threat to livestock health and public health security, necessitating a novel antibiotic. Pleuromutilin, a natural antibiotic, has served as a promising foundation for developing new antibacterial agents through structural modification. This study aims to evaluate the antibacterial potential, safety, and pharmacokinetic profile of a novel pleuromutilin derivative 2-3 (22-[2-(L-prolylamino)phenylsulfanyl]-22-deoxypleuromutilin). The compound 2–3 exhibited potent antibacterial activity (MIC = 0.25 μg/mL), concentration-dependent bactericidal effects, and prolonged post-antibiotic effects (PAEs). Safety assessments revealed low cytotoxicity (CC50 = 62.63 μg/mL) and no observable hemolytic activity. In vitro metabolic studies indicated species-dependent clearance, primarily mediated by CYP3A4. Pharmacokinetic in rats showed rapid absorption and elimination, with oral and intramuscular bioavailability of 16.03% ± 8.82% and 53.36% ± 12.27%, respectively. Notably, 2–3 demonstrated superior efficacy over tiamulin in a neutropenic murine thigh infection model. Molecular docking revealed a stronger binding free energy between 2–3 and the 50S ribosomal subunit compared to tiamulin. Collectively, these results highlight 2–3 as a promising clinical candidate against S. aureus infections, characterized by enhanced efficacy and a favorable safety profile.
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Scientific Reports
·
2014
·Vol. 4
·期 1
·1-9
·
IF 5.078
Gu Yong,Lee Waisin,Shen Jiangang
Site-2 protease (S2P) is a membrane-embedded protease that site-specifically cleaves intramembrane transcription factors, a necessary step for their maturation. S2P is well known to regulate cholesterol biosynthesis and endoplasmic reticulum stress in mammalian cells. In this study, we hypothesized that S2P could be responsible for the regulation of cellular oxidative injury under oxidative stress. Wild type Chinese hamster ovary (WT CHO) cells and their mutant M19 cells with defective S2P gene were exposed to different oxidative stress conditions. Results showed that oxidative stress significantly up-regulated S2P expression in WT CHO cells. Notably, M19 cells had remarkably higher level of superoxide and elevated rates of cell death than WT CHO cells. The vulnerability to oxidative stress was reversed by the transfection of S2P gene but not rescued by exogenous supplement of cholesterol, oleate and mevalonate, indicating that lack of S2P gene leads cells to be more vulnerable to oxidative stress. Furthermore, compared with WT CHO cells, M19 cells had higher nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity and lower paraoxonase-2 expression. Taken together, these results suggest that S2P can be a protease responding to oxidative stress and has the function of regulating cellular oxidative injury.
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Journal of Future Foods
·
2025
·
IF 7.2
Fangqin Xiang,Yuxing Li,Yumeng Zhang,Yuning Yang,Bailiang Li,Sufang Duan
Ulcerative colitis (UC) is a chronic disease with an increasing incidence worldwide. 2’-Fucosyllactose (2’-FL) is the most abundant fucosylated neutral human milk oligosaccharides (HMOs), accounting for approximately 31% of the total HMOs content, and shows considerable potential in alleviating UC. This study aimed to investigate the therapeutic effect of 2’-FL on DSS-induced colitis in mice and explore its potential mechanisms. The results showed that HMO alleviated the symptoms of DSS-induced colitis in mice by alleviating weight loss, reducing the disease activity index (DAI), increasing the length of the mouse colon and improving the spleen index; HMO enhanced intestinal barrier function by repairing colon tissue damage, reducing intestinal permeability (DAO and D-LA), increasing the expression of Tight junctions (TJs), promoting the production of anti-inflammatory factor IL-10, and inhibiting cytokines (IL-1β, IL-6, and TNF-α). In addition, the activation of the colitis-related NF-κB pathway was significantly inhibited after HMO intervention. Furthermore, metagenomic analysis revealed that HMO intervention in colitis mice significantly increased the relative abundance of Bacteroidetes, Parabacteroidetes, Parabacteroides and Prevotella .; non-targeted metabolomics analysis demonstrated that HMO modulated the host's bile acid metabolism by preserving the level of deoxycholic acid. To further investigate the molecular mechanisms affecting bile acid metabolism, enzyme scanning was performed based on species-level genome enriched in different groups. The results showed that the bacteria mainly enriched in the HMO treatment group showed greater potential in encoding bile salt hydrolases (BSH) responsible for the dissociation of primary bile acids and 7α-hydroxysteroid dehydrogenases (7α-HSDs) that produce secondary bile acids. In summary, this study showed that HMO intervention changed the composition of the intestinal flora, and the specially enriched intestinal microorganisms regulated the host's secondary bile acid metabolism, thereby effectively alleviating colon inflammation in mice.
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Theranostics
·
2020
·
IF 8.579
Xi Chen,Ying Zhao,Wu Luo,Sian Chen,Feng Lin,Xi Zhang,Shijie Fan,Xian Shen,Yi Wang,Guang Liang
Background: Oxidative stress from elevated reactive oxygen species (ROS) has been reported to induce cell apoptosis and may provide a means to target cancer cells. Celastrol is a natural bioactive compound that was recently shown to increase ROS levels and cause apoptosis in cancer cells. However, the underlying mechanism for this cytotoxic action remains unclear and direct molecular targets of Celastrol have not been identified. Methods: Proteome microarray, surface plasmon resonance, isothermal titration calorimetry and molecular simulation were used to identify the molecular target of Celastrol. Binding and activity assays were used to validate the interaction of Celastrol with target protein in cell-free and gastric cancer cell lysates. We then assessed target transcript levels in in biopsy specimens obtained from patients with gastric cancer. Gastric cancer growth-limiting and cytotoxic activity of Celastrol was evaluated in BALB/c nu/nu mice. Results: Our data show that Celastrol directly binds to an antioxidant enzyme, peroxiredoxin-2 (Prdx2), which then inhibits its enzyme activity at both molecular and cellular level. Inhibition of Prdx2 by Celastrol increased cellular ROS levels and led to ROS-dependent endoplasmic reticulum stress, mitochondrial dysfunction, and apoptosis in gastric cancer cells. Functional tests demonstrated that Celastrol limits gastric cancer cells, at least in part, through targeting Prdx2. Celastrol treatment of mice implanted with gastric cancer cells also inhibited tumor growth, associated with Prdx2 inhibition and increased ROS. Analysis of human gastric cancer also showed increased Prdx2 levels and correlation with survival. Conclusion: Our studies have uncovered a potential Celastrol-interacting protein Prdx2 and a ROS-dependent mechanism of its action. The findings also highlight Prdx2 as a potential target for the treatment of gastric cancer.
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Biomedical Optics Express
·
2022
·Vol. 13
·期 9
·4592-4605
·
IF 3.562
Qin Tan,Shengnan Wu,Shengnan Wu,Shengnan Wu,Shengnan Wu,Zhenchao Liu,Xun Wu,Erik Forsberg,Sailing He,Sailing He,Sailing He,Sailing He
Since the outbreak of coronavirus disease 2019 (COVID-19), efficient real-time monitoring has become one of the challenges faced in SARS-CoV-2 virus detection. A compact all-fiber Mach-Zehnder interferometer optofluidic sensor based on a hollow eccentric core fiber (HECF) for the detection and real-time monitoring of SARS-CoV-2 spike glycoprotein (SARS-CoV-2 S2) is proposed, analyzed and demonstrated. The sensor is comprised of fusion splicing single mode fiber (SMF), hollow core fiber (HCF) and HECF. After the incident light passes through the HCF from the SMF, it uniformly enters the air hole and the suspended micrometer-scale fiber core of the HECF to form a compact all-fiber Mach-Zehnder interferometer (MZI). HECF is side polished to remove part of the cladding that the suspended fiber core can contact the external environment. Subsequently, the mouse anti SARS-CoV-2 S2 antibody is fixed on the surface of the suspended-core for the sake of achieving high sensitivity and specific sensing of SARS-CoV-2 S2. The limit of detection (LOD) of the sensor is 26.8 pM. The proposed sensor has high sensitivity, satisfactory selectivity, and can be fabricated at low cost making it highly suitable for point-of-care testing and high-throughput detection of early stage of COVID-19 infection.
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Journal of Materials Chemistry B
·
2017
·Vol. 5
·期 24
·4633-4647
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IF 4.543
Yanjun Chai,Dan Lin,Yifan Ma,Yuan Yuan,Changsheng Liu
With the worldwide rising need of severe bone defect treatment, the development of available bone substitutes with optimal mechanical strength, sustained drug release, cell affinity and osteoinductivity remains a great challenge. In this study, an rhBMP-2 loaded polymer-coated mesoporous bioactive glass (MBG) composite scaffold was developed. The uncrosslinked poly(glycerol sebacate) (PGS) or PEGylated PGS (PEGS) coating modification had enhanced the mechanical strength of the composite scaffold, solved the brittleness problem of the MBG matrix, increased the cell affinity of the material surface, and diminished the initial burst release of rhBMP-2 from mesopores of MBG. The results indicated that the PGS coating promoted the proliferation of rat bone marrow stem cells (rBMSCs), while the PEGS coating exhibited an enhancement in the osteogenic differentiation of rBMSCs. The in vivo ectopic bone formation results provide strong evidence that the rhBMP-2-loaded MBG/PEGS composite scaffolds exhibited a rapid bone forming capacity and might yield extraordinary achievements in the field of bone tissue engineering. The design considerations can be extended to other artificial scaffolds and are expected to provide new thoughts on the development of future tissue engineering materials.
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JOURNAL OF ORGANIC CHEMISTRY
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2025
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IF 3.6
Huanhuan Cui,Chunyu Hu,Xiulin Qiao,Tiesheng Shi,Chao Chen,Wei Wei,Zu-Li Wang,Zhuoming Ma
An efficient visible-light-induced EDA strategy has been developed for constructing 3-difluoroalkylated quinoxalin-2(1H)-ones through the C–H difluoroalkylation of quinoxalin-2(1H)-ones with fluoroalkyl bromides. This transformation could provide a series of 3-difluoroalkylated quinoxalin-2(1H)-ones in moderate to good yields under mild and metal-free conditions. Mechanistic studies revealed that the formation of the EDA complex between fluoroalkyl bromide and TMEDA was essential to initiate this transformation.
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TALANTA
·
2022
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IF 6.556
Bin Yang,Xiaowei Zeng,Jin Zhang,Jilie Kong,Xueen Fang
Delta (B.1.617.2), a highly infectious variant of SARS-CoV-2, has been sweeping the world, and threatening the safety of human life seriously. It is urgent to develop a highly selective and sensitive assay to accurately identify the SARS-CoV-2 variant Delta. In this work, we constructed a graphene/CRISPR-dCas9 electrochemical biosensor to accurately identify SARS-CoV-2 variant Delta, where the signal was further amplified by embedded electrochemical probe [Ru(phen) 2 dppz]BF 4 . This detection assay could be finished within 47 min totally, with the detection limit of 1.2 pM and good reproducibility with a C·V.% of 2.48% (n = 5). And the biosensor could selectively identify Delta among SARS-CoV-2 and other variants, including Alpha, Beta, Gamma. This assay was further validated by 26 real clinical samples, showing 100% clinical sensitivity and 100% clinical specificity, which provides a new direction for identifying other SARS-CoV-2 variants in the future.
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INTERNATIONAL DAIRY JOURNAL
·
2025
·
IF 3.4
Simiao Liu,Yaqi Tu,Yujie Pan,Meixi Liu,Jia Liu,Chunhua Wu,Xin Liu,Fazheng Ren,Xuemei Wang,Hao Zhang
2′-Fucosyllactose (2′-FL), a human milk oligosaccharide with prebiotic properties, has been incorporated into infant formula. α-Lactalbumin (α-LA), a key milk protein, may undergo the Maillard reaction with 2′-FL upon heating and extended storage. However, the impact of this reaction on the prebiotic activity of 2′-FL remains unclear. This study confirmed the formation of Maillard reaction products (MRPs) through the measurement of furosine and free 2′-FL levels. Mass spectrometry analysis identified that α-LA can conjugate with seven 2′-FL molecules, resulting in high-molecular-weight MRPs. In vitro assays revealed that α-LA-2′-FL complexes significantly reduced the growth and metabolism of Bifidobacterium , as evidenced by a 47 % decrease in Bifidobacterium density and a 62 % decrease in the production of short-chain fatty acids. These findings highlight for the first time the reduced prebiotic properties of 2′-FL upon interaction with α-LA, providing valuable insights for preserving the functional properties of infant formula during formulation and storage.
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Journal of Toxicologic Pathology
·
2022
·
IF 1.25
Wen-Ling Mou,Shi-Ru Chen,Zhen-Ting Wu,Li-Hua Hu,Ji-Ye Zhang,Hong-Jie Chang,Hang Zhou,Ying Liu
Liver fibrosis results from liver inflammation and progresses to liver cirrhosis or liver cancer. It is known that nonalcoholic liver disease is mediated by the Toll-like receptor 4 (TLR4)/myeloid differentiation factor-2 (MD-2)–tumor necrosis factor-alpha (TNF-α) signaling pathway. This study aimed to investigate whether alcoholic liver disease is also mediated by this pathway. To this end, we first established rat models of liver fibrosis by administering alcohol. Next, the rats were injected with anti-TLR4 and anti-MD-2 antibodies. Real Time Quantitative PCR (RT-qPCR) and Western blotting were used to detect the activation of the TLR4/MD-2–TNF-α signaling pathway and hepatic stellate cells (HSCs). Moreover, the expression of molecules related to liver fibrosis was estimated. The morphology of rat liver tissue was observed through hematoxylin–eosin staining and Masson staining. For in vitro studies, Kupffer cells (KCs) isolated from the liver were transfected with si-TLR4 and si-MD-2 and co-cultured with HSCs to determine the activity of HSCs. It was found that alcohol treatment activated the TLR4/MD-2–TNF-α signaling pathway and upregulated the molecules associated with liver fibrosis. However, inhibition of TLR4 and MD-2 partially reversed this trend. Notably, in vitro studies indicated that knockdown of TLR4 and MD-2 in KCs partially inhibited LPS-induced activation of KCs and HSCs. Overall, this study showed that alcohol induces liver fibrosis via the LPS-TLR4/MD-2–TNF-α signaling pathway.
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JOURNAL OF MOLECULAR ENDOCRINOLOGY
·
2015
·Vol. 55
·期 2
·119-31
·
IF 3.081
Leping Zhao,Yong Pan,Kesong Peng,Zhe Wang,Jieli Li,Dan Li,Chao Tong,Yi Wang,Guang Liang
11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) controls the production of active glucocorticoid (GC) and has been proposed as a new target for the treatment of type 2 diabetes. We have previously reported that a natural product, curcumin, exhibited moderate inhibition and selectivity on 11β-HSD1. By analyzing the models of protein, microsome, cells and GCs-induced mice in vitro and in vivo, this study presented a novel curcumin analog, LG13, as a potent selective 11β-HSD1 inhibitor. In vivo, Type 2 diabetic mice were treated with LG13 for 42 days to assess the pharmacological benefits of 11β-HSD1 inhibitor on hepatic glucose metabolism. In vitro studies revealed that LG13 selectively inhibited 11β-HSD1 with IC50 values at nanomolar level and high selectivity over 11β-HSD2. Targeting 11β-HSD1, LG13 could inhibit prednisone-induced adverse changes in mice, but had no effects on dexamethasone-induced ones. Further, the 11β-HSD1 inhibitors also suppressed 11β-HSD1 and GR expression, indicating a possible positive feedback system in the 11β-HSD1/GR cycle. In type 2 diabetic mice induced by high fat diet plus low-dosage STZ injection, oral administration with LG13 for 6 weeks significantly decreased fasting blood glucose, hepatic glucose metabolism, structural disorders, and lipid deposits. LG13 exhibited better pharmacological effects in vivo than insulin sensitizer pioglitazone and potential 11β-HSD1 inhibitor PF-915275. These pharmacological and mechanistic insights on LG13 also provide us novel agents, leading structures, and strategy for the development of 11β-HSD1 inhibitors treating metabolic syndromes.
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MOLECULES
·
2025
·Vol. 30
·期 23
·4526
·
IF 4.6
Mingjun Yu,Xin Zhang,Hui Zhu,Xiaoqian Zhang
A series of 4-phenylurea chalcones (2a–2s) as VEGFR-2 inhibitors has been designed, synthesized, and evaluated for in vitro cytotoxic activity against K562, SiHa, and B16 cancer cells. Compared to sorafenib, the compounds exhibited strong cytotoxicity against K562, SiHa and B16 cells. Compounds2r,2o, and2lexhibited remarkable cytotoxicity against K562, SiHa, and B16 cells, with IC50values of 0.97 μM, 1.22 μM, and 1.39 μM, respectively. Moreover, compound2lexhibited potent cytotoxicity against K562, SiHa, and B16, with IC50values ranging from 1.25 μM to 1.39 μM. Compounds2land2oalso exhibited excellent inhibitory activity on VEGFR-2 kinase, with IC50values of 0.42 ± 0.03 and 0.31 ± 0.02 μM, respectively. Molecular docking proved that the target compounds had strong binding interactions with VEGFR-2 proteins. Flow cytometry analysis showed that compound2linduced apoptosis and arrested the cell cycle at the G1 and S phases.
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