Antibiotics-Basel
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2024
·Vol. 13
·期 3
·278
·
IF 4.3
Chun Wang,Yun-Yao Ren,Li-Mei Han,Peng-Cheng Yi,Wei-Xiao Wang,Cai-Yun Zhang,Xiu-Zhen Chen,Ming-Zhe Chi,Apeng Wang,Wei Chen,Chun-Mei Hu
Antimicrobial peptides (AMPs) hold promise as alternatives to combat bacterial infections, addressing the urgent global threat of antibiotic resistance. COG1410, a synthetic peptide derived from apolipoprotein E, has exhibited potent antimicrobial properties against various bacterial strains, includingMycobacterium smegmatis. However, our study reveals a previously unknown resistance mechanism developed byM. smegmatisagainst COG1410 involving ClpC. Upon subjectingM. smegmatisto serial passages in the presence of sub-MIC COG1410, resistance emerged. The comparative genomic analysis identified a point mutation in ClpC (S437P), situated within its middle domain, which led to high resistance to COG1410 without compromising bacterial fitness. Complementation of ClpC in mutant restored bacterial sensitivity. In-depth analyses, including transcriptomic profiling and in vitro assays, uncovered that COG1410 interferes with ClpC at both transcriptional and functional levels. COG1410 not only stimulated the ATPase activity of ClpC but also enhanced the proteolytic activity of Clp protease. SPR analysis confirmed that COG1410 directly binds with ClpC. Surprisingly, the identified S437P mutation did not impact their binding affinity. This study sheds light on a unique resistance mechanism against AMPs in mycobacteria, highlighting the pivotal role of ClpC in this process. Unraveling the interplay between COG1410 and ClpC enriches our understanding of AMP-bacterial interactions, offering potential insights for developing innovative strategies to combat antibiotic resistance.
研究领域:
微生物学
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药理学
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分子生物学
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DOI
PubMed
高影响因子
NUCLEIC ACIDS RESEARCH
·
2024
·
IF 16.6
Liao Fumeng,Yu Guimei,Zhang Chendi,Liu Zhikun,Li Xuzichao,He Qiuqiu,Yin Hang,Liu Xiang,Li Zhuang,Zhang Heng
Recently, a novel two-gene bacterial defense system against phages, encoding a SIR2 NADase and a HerA ATPase/helicase, has been identified. However, the molecular mechanism of the bacterial SIR2–HerA immune system remains unclear. Here, we determine the cryo-EM structures of SIR2, HerA and their complex from Paenibacillus sp. 453MF in different functional states. The SIR2 proteins oligomerize into a dodecameric ring-shaped structure consisting of two layers of interlocked hexamers, in which each subunit exhibits an auto-inhibited conformation. Distinct from the canonical AAA+ proteins, HerA hexamer alone in this antiphage system adopts a split spiral arrangement, which is stabilized by a unique C-terminal extension. SIR2 and HerA proteins assemble into a ∼1.1 MDa torch-shaped complex to fight against phage infection. Importantly, disruption of the interactions between SIR2 and HerA largely abolishes the antiphage activity. Interestingly, binding alters the oligomer state of SIR2, switching from a dodecamer to a tetradecamer state. The formation of the SIR2–HerA binary complex activates NADase and nuclease activities in SIR2 and ATPase and helicase activities in HerA. Together, our study not only provides a structural basis for the functional communications between SIR2 and HerA proteins, but also unravels a novel concerted antiviral mechanism through NAD+ degradation, ATP hydrolysis, and DNA cleavage.
研究领域:
微生物学
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结构生物学
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分子生物学
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DOI
PubMed
高影响因子
STRUCTURE
·
2025
·
IF 4.3
Shu-Cheng Fang,Liang Wang,Meng-Ting Cheng,Da Xu,Zhi-Peng Chen,Jie Wang,Wenli Liao,Yanyan Li,Cong-Zhao Zhou,Wen-Tao Hou,Yuxing Chen
The human ATP-binding cassette (ABC) transporter ABCA7 participates in the lipidation of apolipoprotein ApoE, a commonly recognized risk factor for Alzheimer’s disease (AD). How ABCA7 is involved in the molecular pathogenesis of AD remains poorly understood. Using cryoelectron microscopy (cryo-EM), we determined ABCA7 structures in the apo and substrate-bound forms, respectively. Combined with activity assays, we assigned the residues that specifically bind two molecules of phosphatidylserine (PS) that are arranged in a “tail-to-tail” manner. Pull-down assays confirmed that ApoE directly interacts with ABCA7; and moreover, both ATPase and lipid transport activities of ABCA7 were significantly enhanced in the presence of ApoE. We also measured the activities of a familial AD variant and a protective clinically reported variant in the ABCA7 gene. Our findings not only give structural insights into ABCA7-mediated PS translocation, but we also provide first biochemical evidence for its link to AD by forwarding lipids to ApoE.
研究领域:
结构生物学
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神经科学
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分子生物学
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DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2024
·
IF 4.4
Du Ailin,Chen Yingying,Qiao Siyu,Dong Jiaxing,Li Yulin,Cao Bokai,Zhao Rongyu,Zhang Ruiling
Introduction: Chronic alcoholism is one of the most common neurological diseases in modern society. However, the key mechanisms underlying learning and memory impairments caused by chronic alcohol exposure remain unclear. In this study, a microRNA-messenger RNA (miRNA-mRNA) network was constructed to explore the potential function of key genes in chronic alcohol exposure, their effects on the hippocampus, and their mechanisms which facilitate brain injury in mice.Methods: The Morris water maze test was used to assess the learning ability of mice in each group. Mitochondrial ATPase activity and H2S levels in the hippocampi of mice were determined. Differentially expressed miRNAs and mRNAs in the mouse hippocampus were identified using second-generation sequencing. Using the TargetScan, miRTarBase, and miRDB databases, we predicted miRNA target genes and constructed a miRNA-mRNA regulatory network. Furthermore, using the Gene Ontology and KEGG databases we performed functional enrichment and protein-protein interaction analyses. Real-time quantitative polymerase chain reaction (qPCR) and other methods were employed to verify the mRNA expression of related genes.Results: The Morris water maze test revealed that mice exposed to chronic alcohol exhibited a significantly reduced learning ability compared to the control group (p < 0.05). Compared with the control group, the activity of mitochondrial ATPase in the hippocampal tissue of alcohol-treated mice was significantly decreased (p < 0.01), suggesting brain injury. In the model group, H2S significantly increased in the mice hippocampi (p < 0.01), indicating that chronic alcohol exposure could activate cystathionineβ-synthase (CBS) and catalyze the mass formation of H2S, suggesting brain injury. A total of 208 differentially expressed miRNAs and 377 differentially expressed mRNAs were screened through bioinformatic analysis. Enrichment analysis indicated that the main pathways were involved in neurodegeneration and regulation of the Wnt signaling pathway. The PCR detected a significant downregulation in the expressions of FOS and EGR1 genes.Discussion: Consequently, chronic alcohol exposure may regulate the expression of FOS and EGR1 in the hippocampus through miR-222-3p, miR-132-3p, miR-212-3p, and miR-191-5p, reduce the activity of hippocampal mitochondrial ATPase, activate CBS, catalyze the large amount of H2S formation, and destroy the mitochondrial structure, resulting in decreased learning ability. Our findings revealed valuable genes and miRNAs for the study of chronic alcohol exposure.
研究领域:
神经生物学
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分子生物学
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生物信息学
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产品关联
DOI
PubMed
高影响因子
ENVIRONMENTAL POLLUTION
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2017
·
IF 5.099
Hong-cui Liu,Tian-yi Chu,Li-li Chen,Wen-jun Gui,Guo-nian Zhu
The health risk of triadimefon (TF) to cardiovascular system of human is still unclear, especially to pesticide suicides population, occupational population (farmers, retailers and pharmaceutical workers), and special population (young children and infants, pregnant women, older people, and those with compromised immune systems) who are at a greater risk. Therefore, firstly we explored the toxic effects and possible mechanism of cardiovascular toxicity induced by TF using zebrafish model. Zebrafish at stage of 48 h post fertilization (hpf) exposed to TF for 24 h exhibited morphological malformations which were further confirmed by histopathologic examination, including pericardial edema, circulation abnormalities, serious venous thrombosis and increased distance between the sinus venosus (SV) and bulbus arteriosus (BA) regions of the heart. In addition to morphological changes, TF induced functional deficits in the heart of zebrafish, including bradycardia and a significant reduced cardiac output that became more serious at higher concentrations. To better understand the possible molecular mechanisms underlying cardiovascular toxicity in zebrafish, we investigated the transcriptional level of genes related to calcium signaling pathway and cardiac muscle contraction . Q-PCR (quantitative real-time polymerase chain reaction) results demonstrated that the expression level of genes related to ATPase ( atp2a1l , atp1b2b , atp1a3b ), calcium channel ( cacna1ab , cacna1da ) and cardiac troponin C ( tnnc1a ) were significantly decreased after TF exposure. For the first time, the present study revealed that TF exposure had observable morphological and functional negative impacts on cardiovascular system of zebrafish. Mechanistically, this toxicity might result from the pressure of down-regulation of genes associated with calcium signaling pathway and cardiac muscle contraction following TF exposure. These findings generated here can provide information for better pesticide poisoning treatments, occupational disease prevention, and providing theoretical foundation for risk management measures.
研究领域:
毒理学
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环境健康
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分子生物学
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药理学
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产品关联
DOI
PubMed
高影响因子
FOOD CHEMISTRY
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2021
·
IF 7.514
Zhiwen Qi,Xingying Xue,Hao Zhou,Hua Yuan,Wenjun Li,Guliang Yang,Pujun Xie,Chengzhang Wang
To valorise olive mill wastewater phenols (OPs) potentially applied in food preservation, a novel stable and regularly spherical OPs-AgNPs ( D avg = 78 nm) were successfully assembled in aqueous solution under the optimized conditions (pH 8.0, 5 mM AgNO 3 , 35C and 30 min). The results of antimicrobial zone diameters indicated that 50 μg/mL of promising OPs-AgNPs presented excellent antimicrobial effects. Especially, the cell wall damages of E. coli ATCC 23,815 were caused when OPs-AgNPs concentration was exceeded its MIC (8.58 μg/mL). Also, a significant down-regulating of the Ca 2+ -ATPase activity in E. coli was revealed, and the intracellular Ca 2+ concentrations were thus decreased from 12.5 to 1.35 µg/mL after a treatment for 3 h. The apoptosis level of E. coli was significantly increased more than the control (55.13% of OPs-AgNPs vs 9.90% of control). In sum, OPs exerts enhanced antimicrobial function via penetrating cell membrane and targeting Ca 2+ -ATPase after chelated with AgNPs.
研究领域:
环境科学
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材料科学
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微生物学
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食品科学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2018
·
IF 3.412
Lujia Li,Qingxue Fu,Mengxin Xia,Lei Xin,Hongyi Shen,Guowen Li,Guang Ji,Qianchao Meng,Yan Xie
Phytic acid (IP6) is a natural phosphorylated inositol, which is abundantly present in most cereal grains and seeds. This study investigated the effects of IP6 regulation on P-glycoprotein (P-gp) and its potential mechanisms using in situ and in vitro models. The effective permeability of the typical P-gp substrate rhodamine 123 (R123) in colon was significantly increased from (1.69 ± 0.22) × 10–5 cm/s in the control group to (3.39 ± 0.417) × 10–5 cm/s (p < 0.01) in the 3.5 mM IP6 group. Additionally, IP6 can concentration-dependently decrease the R123 efflux ratio in both Caco-2 and MDCK II-MDR1 cell monolayers and increase intracellular R123 accumulation in Caco-2 cells. Furthermore, IP6 noncompetitively inhibited P-gp by impacting R123 efflux kinetics. The noncompetitive inhibition of P-gp by IP6 was likely due to decreases in P-gp ATPase activity and P-gp molecular conformational changes induced by IP6. In summary, IP6 is a promising P-gp inhibitor candidate.
研究领域:
药理学
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细胞生物学
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药物递送
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产品关联
DOI
PubMed
高影响因子
CELL RESEARCH
·
2024
·
IF 28.1
Feng Ran,Liu Feng,Li Ruofei,Zhou Zhifen,Lin Zhuoheng,Lin Song,Deng Shengcheng,Li Yingying,Nong Baoting,Xia Ying,Li Zhiyi,Zhong Xiaoqin,Yang Shuhan,Wan Gang,Ma Wenbin,Wu Su,Songyang Zhou
Rheb is a small G protein that functions as the direct activator of the mechanistic target of rapamycin complex 1 (mTORC1) to coordinate signaling cascades in response to nutrients and growth factors. Despite extensive studies, the guanine nucleotide exchange factor (GEF) that directly activates Rheb remains unclear, at least in part due to the dynamic and transient nature of protein–protein interactions (PPIs) that are the hallmarks of signal transduction. Here, we report the development of a rapid and robust proximity labeling system named Pyrococcus horikoshii biotin protein ligase ( Ph BPL)-assisted biotin identification (PhastID) and detail the insulin-stimulated changes in Rheb-proximity protein networks that were identified using PhastID. In particular, we found that the lysosomal V-ATPase subunit ATP6AP1 could dynamically interact with Rheb. ATP6AP1 could directly bind to Rheb through its last 12 amino acids and utilizes a tri-aspartate motif in its highly conserved C-tail to enhance Rheb GTP loading. In fact, targeting the ATP6AP1 C-tail could block Rheb activation and inhibit cancer cell proliferation and migration. Our findings highlight the versatility of PhastID in mapping transient PPIs in live cells, reveal ATP6AP1’s role as an unconventional GEF for Rheb, and underscore the importance of ATP6AP1 in integrating mTORC1 activation signals through Rheb, filling in the missing link in Rheb/mTORC1 activation.
研究领域:
分子生物学
·
细胞信号传导
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癌症生物学
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蛋白质组学
✓ 已验证
DOI
高影响因子
BIOMATERIALS
·
2024
·
IF 12.8
Huan Wang,Xinchen Liu,Xiangyu Yan,Yong Du,Fang Pu,Jinsong Ren,Xiaogang Qu
Anticancer nanomedicines used for ferroptosis therapy generally rely on the direct delivery of Fenton catalysts to drive lipid peroxidation in cancer cells. However, the therapeutic efficacy is limited by the ferroptosis resistance caused by the intracellular anti-ferroptotic signals. Herein, we report the intrinsic ATPase-mimicking activity of a vanadium carbide MXene nanozyme (PVCMs) to pharmacologically modulate the nuclear factor erythroid 2-related factor 2 (Nrf2) program, which is the master anti-ferroptotic mediator in the ironclad defense system in triple-negative breast cancer (TNBC) cells. The PVCMs perform high ATPase-like activity that can effectively and selectively catalyze the dephosphorylation of ATP to generate ADP. Through a cascade mechanism initiated by falling energy status, PVCMs can powerfully hinder the Nrf2 program to selectively drive ferroptosis in TNBC cells in response to PVCMs-induced glutathione depletion. This study provides a paradigm for the use of pharmacologically active nanozymes to moderate specific cellular signals and elicit desirable pharmacological activities for therapeutic applications.
研究领域:
纳米医学
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癌症生物学
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药理学
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生物化学
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产品关联
DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2021
·
IF 5.811
Zou Meina,Chen Yanrong,Zheng Zongji,Sheng Shuyue,Jia Yijie,Wang Xiangyu,Ren Shijing,Yang Yanling,Li Xiaomin,Dong Wenhui,Guan Meiping,Zhang Qian,Xue Yaoming
High-salt intake leads to kidney damage and even limits the effectiveness of drugs. However, it is unclear whether excessive intake of salt affects renal tubular energy metabolism and the efficacy of dapagliflozin on renal function in diabetic kidney disease (DKD). In this study, we enrolled 350 DKD patients and examined the correlation between sodium level and renal function, and analyzed influencing factors. The results demonstrated that patients with macroalbuminuria have higher 24 h urinary sodium levels. After establishment of type 2 diabetes mellitus model, the animals received a high-salt diet or normal-salt diet. In the presence of high-salt diet, the renal fibrosis was aggravated with fatty acid metabolism dysregulation. Furthermore, Na+/K+-ATPase expression was up-regulated in the renal tubules of diabetic mice, while the fatty acid metabolism was improved by inhibiting Na+/K+-ATPase of renal tubular epithelial cells. Of note, the administration with dapagliflozin improved renal fibrosis and enhanced fatty acid metabolism. But high salt weakened the above-mentioned renal protective effects of dapagliflozin in DKD. Similar results were recapitulated in vitro after incubating proximal tubular epithelial cells in high-glucose and high-salt medium. In conclusion, our results indicate that high salt can lead to fatty acid metabolism disorders by increasing Na+/K+-ATPase expression in the renal tubules of DKD. High salt intake diminishes the reno-protective effect of dapagliflozin in DKD.
研究领域:
肾病学
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内分泌学
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药理学
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代谢学
✓ 已验证
DOI
PubMed
高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
·
2022
·
IF 7.129
Sihong Li,Ruimeng Liu,Shun Xia,Gaoqiang Wei,Muhammad Ishfaq,Yixin Zhang,Xiuying Zhang
This study set out to assess the mitigative effects of curcumin on AFB1-induced necroptosis and inflammation in chicken liver. Ninety-six one-day-old AA broiler chickens were separated into four groups, including control group, AFB1 (1 mg/kg) group, curcumin (300 mg/kg) + AFB1 (1 mg/kg) group and curcumin (300 mg/kg) group. After 28 days treatment, livers were collected for different experimental analyses. The morphological observation results showed obvious necrotic characteristics, including cell swelling, rupture of cell and mitochondrial membranes and inflammation in chicken livers. AFB1 exposure increased oxidative stress index (ROS and MDA) and decreased the antioxidant activity markers (SOD, CAT and GSH) and ATPase activities in chickens’ liver. ELISA results showed that AFB1 exposure significantly induced the cytokines (TNF-α, iNOS, IL-6 and IL-1β) release from the liver tissues. While, western blot and qRT-PCR results showed that the protein and mRNA expressions of inflammatory (TLR4/myd88/NF-κB) and necroptosis (RIPK1/RIPK3/MLKL) genes were up-regulated by AFB1 exposure. We suspect that signal crosstalk between TLR4 and TNF-α triggers inflammation and RIPK1/RIPK3 mediating necroptosis in AFB1-induced chicken liver injury. Curcumin can regulate the TLR4/RIPK signaling pathway, reduced oxidative stress biomarkers and inflammatory cytokines levels and attenuated the expression of necroptosis and inflammation genes altered by AFB1 to reduce necroptosis of chicken liver tissue. In conclusion, curcumin can protect against AFB1-induced necroptosis and inflammation by TLR4/RIPK pathway in chicken liver.
研究领域:
兽医学
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毒理学
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分子生物学
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免疫学
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产品关联
DOI
PubMed
高影响因子
NUCLEIC ACIDS RESEARCH
·
2022
·Vol. 50
·期 10
·5850-5863
·
IF 19.16
Lei Yixuan,Fei Panyu,Song Bin,Shi Wenjia,Luo Cheng,Luo Dahai,Li Dan,Chen Wei,Zheng Jie
DDX58 encodes RIG-I, a cytosolic RNA sensor that ensures immune surveillance of nonself RNAs. Individuals with RIG-IE510V and RIG-IQ517H mutations have increased susceptibility to Singleton-Merten syndrome (SMS) defects, resulting in tissue-specific (mild) and classic (severe) phenotypes. The coupling between RNA recognition and conformational changes is central to RIG-I RNA proofreading, but the molecular determinants leading to dissociated disease phenotypes remain unknown. Herein, we employed hydrogen/deuterium exchange mass spectrometry (HDX-MS) and single molecule magnetic tweezers (MT) to precisely examine how subtle conformational changes in the helicase insertion domain (HEL2i) promote impaired ATPase and erroneous RNA proofreading activities. We showed that the mutations cause a loosened latch-gate engagement in apo RIG-I, which in turn gradually dampens its self RNA (Cap2 moiety:m7G cap and N1-2-2′-O-methylation RNA) proofreading ability, leading to increased immunopathy. These results reveal HEL2i as a unique checkpoint directing two specialized functions, i.e. stabilizing the CARD2-HEL2i interface and gating the helicase from incoming self RNAs; thus, these findings add new insights into the role of HEL2i in the control of antiviral innate immunity and autoimmunity diseases.
研究领域:
免疫学
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分子生物学
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遗传学
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生物化学
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产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）