Microbiology Spectrum
·
2025
·
IF 3.8
Xianduo Sun,Gaosheng Hu,Yuting Li,Wenjing Li,Yong Wang,Hui Yan,Guoqing Long,Long Zhao,Anhua Wang,Jingming Jia
Gut microbiota have been found to promote hypoxia-induced intestinal injury. However, the role of gut microbiota in high-altitude pulmonary edema (HAPE), the preventive effect of synbiotic on HAPE, and the mechanisms by which they might work remain unknown. In this study, we aimed to investigate the role of gut microbiota in the pathogenesis of HAPE and to explore the underlying mechanisms involved. We performed a fecal microbiome analysis and found a significant decrease in intestinal Klebsiella and Escherichia-Shigella, along with a notable increase in intestinal Bifidobacterium and Lactobacillus, as volunteers recovered from acute mountain sickness (AMS). Gavage colonization with Klebsiella pneumoniae and Escherichia coli induced plasma inflammation, increased plasma lysophosphatidylcholine (LPC) levels, and contributed to HAPE in rats at a simulated altitude of 6,500 m. Conversely, a synbiotic containing Bifidobacterium, Lactiplantibacillus, fructooligosaccharides, and isomaltose-oligosaccharides significantly reduced the severity of HAPE. Cellular experiments and molecular dynamics simulations revealed that LPCs can cause damage and permeability to human pulmonary microvascular endothelial cell (HPMEC) and human pulmonary alveolar epithelial cell (HPAEpiC) monolayers under hypoxic conditions by disrupting cell membrane integrity. In addition, tail vein injection of LPCs promoted HAPE in mice at a simulated altitude of 6,500 m. In conclusion, this study describes a gut microbiota-LPCs/inflammation-HAPE axis, an important new insight into HAPE that will help open avenues for prevention and treatment approaches.
研究领域:
医学
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微生物学
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生理学
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产品关联
DOI
PubMed
高影响因子
Microbiology Spectrum
·
2025
·
IF 3.8
Xiaojuan Tan,Jingjing Xiao,Qianqian Liu,Ting Yang,Dandan Feng,Ruyi Zheng,Liping Luo,Xi Cheng,Dongsheng Du,Minghui Li,Jinwei Zhou,Guoping Zhu
Several key virulence factors of Pseudomonas aeruginosa are regulated by quorum-sensing systems, small noncoding RNAs (sRNAs), and environmental stress, leading to a high mortality rate. Our previous studies indicated that the alkaline phosphatase LapA regulated P. aeruginosa PAO1 biofilm formation in a chronic wound model established with ex vivo porcine skin explants. Notably, one particular sRNA located upstream of the lapA gene was highly expressed in the model. Therefore, the sRNA was further characterized via northern blotting and rapid amplification of cDNA ends. The results revealed that the sRNA we named LapS is 197 nucleotides in length and is derived from the 5´ UTR and sequence internal to the lapA gene. Next, LapS mutation, overexpression, and complementation strains were constructed from the PAO1 strain, and phenotypic experiments associated with lapA were performed and compared with those of the ΔlapA and wild-type strains. The results indicated that LapS is involved in regulating swarming motility, rhamnolipid and alkaline phosphatase production, las/rhl quorum-sensing systems, and biofilm formation by controlling the level of lapA mRNA under phosphate-depleted conditions. Therefore, this LapS-lapA signaling cascade is beneficial for balancing the virulence regulation of P. aeruginosa. Additionally, an in vitro study indicated that LapS directly and post-transcriptionally regulated at least one unlinked gene, putA, which encodes bifunctional proline dehydrogenase, a virulence factor of P. aeruginosa. Collectively, our findings reveal a previously unstudied regulatory sRNA and advance the understanding of the roles of sRNAs in the pathogenicity of P. aeruginosa.
研究领域:
微生物学
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分子生物学
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病原体研究
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF VETERINARY MEDICAL SCIENCE
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2024
·
IF 1.1
Nianyuan CHEN,Qingxiu CAI,Shujing WANG,Qingyang SONG,Ying XIE,Huijuan SHI,Hongmei LI,Xiaomin ZHAO,Ningning ZHAO,Xiao ZHANG
Protozoan parasites such as Eimeria tenella and Toxoplasma gondii pose significant health challenges in livestock and humans. The limited treatment options and rising drug resistance underscore the urgent need for new therapies. This study investigates myrcene, a monoterpene hydrocarbon classified for its antiprotozoal potential against E. tenella and T. gondii infections. Initially, we examined its effect on the sporulation process of E. tenella oocysts in vitro and its anti-E. tenella activity in vivo. Myrcene significantly reduced the sporulation rate of E. tenella oocysts at 3 and 4 mg/kg. In vivo experiments demonstrated that treatment with 4 mg/kg myrcene significantly reduced E. tenella load and oocyst output, as well as cecal lesion and weight loss caused by E. tenella infection, showing moderate anti-E. tenella activity, with an Anticoccidial Index (ACI) of 161.4. Furthermore, we investigated the anti-T. gondii activity of myrcene both in vitro and in vivo. In vitro studies showed that treatment with myrcene effectively inhibited the invasion rate and intracellular proliferation ability of T. gondii tachyzoite in DF-1 cells in a dose-dependent manner. In vivo administration prolonged the survival time in T. gondii-infected mice, suggesting notable protective effects. Additionally, it mitigated T. gondii-induced hepatosplenic toxicity by reducing parasite load in the liver and spleen, and ameliorating liver function as evidenced by decreased serum transaminase levels. In conclusion, the findings demonstrate promising anti-E. tenella and anti-T. gondii activity exhibited by myrcene warranting further exploration into its mechanisms and potential therapeutic applications.
研究领域:
兽医学
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寄生虫学
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药理学
✓ 已验证
DOI
PubMed
高影响因子
Translational Lung Cancer Research
·
2024
·
IF 4
Yunlong Li,Chenmei Li,Jiamin Li,Dong Han,Gang Xu,Daolong Zhu,Huiming Cai,Yiqing Wang,Dong Wang
Background Accurate real-time tumor delineation is essential for achieving curative resection (R0 resection) during non-small cell lung cancer (NSCLC) surgery. The unique characteristics of lung tissue structure significantly challenge the use of video-assisted thoracoscopic surgery in the identification of lung nodules. This difficulty often results in an inability to discern the margins of lung nodules, necessitating either an expansion of the resection scope, or a transition to open surgery. Due to its high spatial resolution, ease of operation, and capacity for real-time observation, near-infrared fluorescence (NIRF) navigation in oncological surgery has emerged as a focal point of clinical research. Targeted NIRF probes, which accumulate preferentially in tumor tissues and are rapidly cleared from normal tissues, enhance diagnostic sensitivity and surgical outcomes. The imaging effect of the clinically approved NIRF probe indocyanine green (ICG) varies significantly from person to person. Therefore, we hope to develop a new generation of targeted NIRF probes targeting lung tumor-specific targets. Methods First, the peptide iRGD (sequence: CRGDKGPDC) fluorescent tracer was synthesized, and characterized through mass spectrometry (MS), proton nuclear magnetic resonance ( 1 H NMR), and high-performance liquid chromatography (HPLC). Fluorescence properties were tested subsequently. Safety was performed in vitro using both human normal liver cells and human normal breast cells. Second, Metabolism and optimal imaging time were determined by tail vein injection of iRGD fluorescent tracer. Finally, Orthotopic and metastatic lung tumor models were used to evaluate the targeting properties of the iRGD fluorescent tracer. Results We successfully synthesized an iRGD fluorescent tracer specifically designed to target NSCLC. The molecular docking analyses indicated that this tracer has receptor affinity comparable to that of iRGD for αvβ3 integrin, with a purity ≥98%. Additionally, the tracer is highly soluble in water, and its excitation and emission wavelengths are 767 and 799 nm, respectively, positioning it within the near-infrared spectrum. The cellular assays confirmed the tracer’s minimal cytotoxicity, underscoring its excellent biosafety profile. In vivo studies further validated the tracer’s capacity for specific NSCLC detection at the cellular level, alongside a prolonged imaging window of 6 days or more. Notably, the tracer demonstrated superior specificity in localizing very small lung nodules, which are otherwise clinically indiscernible, outperforming non-targeted ICG. Fluorescence intensity analyses across various organs revealed that the tracer is predominantly metabolized by the liver and kidneys, with excretion via bile and urine, and exhibits minimal toxicity to these organs as well as the lungs. Conclusions The iRGD fluorescent tracer selectively accumulates in NSCLC tissues by specifically targeting αvβ3 receptors, which are overexpressed on the surface of tumor cells. This targeted approach facilitates the real-time intraoperative localization of NSCLC, presenting an improved strategy for intraoperative tumor identification with significant potential for clinical application. Click here to view. (86K, pdf)
研究领域:
肿瘤学
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生物医学工程
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药学
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分子生物学
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DOI
PubMed
高影响因子
mSystems
·
2024
·
IF 5
Lvjing Wang,Xiaoyu Wang,Hao Wu,Haixia Wang,Zhenmei Lu
Metabolic exchange plays a crucial role in shaping microbial community interactions and functions, including the exchange of small molecules such as cofactors. Cofactors are fundamental to enzyme catalytic activities; however, the role of cofactors in microbial stress tolerance is unclear. Here, we constructed a synergistic consortium containing two strains that could efficiently mineralize di-(2-ethylhexyl) phthalate under hyperosmotic stress. Integration of transcriptomic analysis, metabolic profiling, and a genome-scale metabolic model (GEM) facilitated the discovery of the potential mechanism of microbial interactions. Multi-omics analysis revealed that the vitamin B12-dependent methionine-folate cycle could be a key pathway for enhancing the hyperosmotic stress tolerance of synergistic consortium. Further GEM simulations revealed interspecies exchange of S-adenosyl-L-methionine and riboflavin, cofactors needed for vitamin B12 biosynthesis, which was confirmed by in vitro experiments. Overall, we proposed a new mechanism of bacterial hyperosmotic stress tolerance: bacteria might promote the production of vitamin B12 to enhance biofilm formation, and the species collaborate with each other by exchanging cofactors to improve consortium hyperosmotic stress tolerance. These findings offer new insights into the role of cofactors in microbial interactions and stress tolerance and are potentially exploitable for environmental remediation.
研究领域:
微生物学
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环境科学
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生物化学
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系统生物学
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DOI
PubMed
高影响因子
mSphere
·
2024
·
IF 3.7
Xiao-die Cui,Xiao-kang Liu,Xiao-yuan Ma,Shuai-hua Li,Jun-kai Zhang,Rong-jia Han,Kai-fang Yi,Jian-hua Liu,Yu-shan Pan,Dan-dan He,Gong-zheng Hu,Ya-jun Zhai
The appearance and prevalence of multidrug-resistance (MDR) Gram-negative bacteria (GNB) have limited our antibiotic capacity to control bacterial infections. The clinical efficacy of colistin (COL), considered as the “last resort” for treating GNB infections, has been severely hindered by its increased use as well as the emergence and prevalence of mobile colistin resistance (MCR)-mediated acquired drug resistance. Identifying promising compounds to restore antibiotic activity is becoming an effective strategy to alleviate the crisis of increasing MDR. We first demonstrated that the combination of berberine (BBR) and EDTA substantially restored COL sensitivity against COL-resistant Salmonella and Escherichia coli. Molecular docking indicated that BBR can interact with MCR-1 and the efflux pump system AcrAB-TolC, and BBR combined with EDTA downregulated the expression level of mcr-1 and tolC. Mechanically, BBR combined with EDTA could increase bacterial membrane damage, inhibit the function of multidrug efflux pump, and promote oxidative damage, thereby boosting the action of COL. In addition, transcriptome analysis found that the combination of BBR and EDTA can accelerate the tricarboxylic acid cycle, inhibit cationic antimicrobial peptide (CAMP) resistance, and attenuate Salmonella virulence. Notably, the combination of BBR and EDTA with COL significantly reduced the bacterial load in the liver and spleen of a mice model infected with Salmonella. Our findings revealed that BBR and EDTA can be used as adjuvants collectively with COL to synergistically reverse the COL resistance of bacteria.
研究领域:
微生物学
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药理学
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传染病学
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分子生物学
✓ 已验证
DOI
PubMed
高影响因子
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
·
2025
·Vol. 69
·期 5
·
IF 4.5
Pusheng Xu,Yi Li,Bihan Xu,Dan Cao,Xu Dong,Yanghui Xiang,Xiuzhi Jiang,Xin Yuan,Yuwei Qiu,Ying Zhang
Mycobacterium abscessus is a fast-growing nontuberculous mycobacterium that can cause severe disease and poses a significant challenge for clinical management. New drugs are urgently needed for more effective treatment. Nitroxoline, an antibiotic used for treating urinary tract infections in Europe, has recently been shown to have promising activity against M. abscessus. However, the mechanism of its modified activity is not known. In anticipation for its potential clinical use, in this study, we investigated the mechanism of nitroxoline activity modification through mutant selection followed by whole-genome sequencing. We identified mutations in a transcriptional repressor MarR (MAB_2648c) controlling the expression of efflux pumps MmpS5-MmpL5 family that are associated with nitroxoline activity modification. Complementation of the mutants with the wild-type marR gene restored the MIC values to levels comparable to those of the wild-type strain. This study elucidates the key mechanism of how M. abscessus mutations modify the activity of nitroxoline, which has significant implications for rapid molecular detection of drug-resistant M. abscessus and for further studies on resistance mechanisms.
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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产品关联
DOI
PubMed
高影响因子
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
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2025
·
IF 4.5
Jinyao Liu,Yingying Pang,Wenyan Li,Juanjuan Sun,Yujie He,Yonghong Guo,Jing Dong
Linezolid, an oxazolidinone antibiotic, is used in patients with liver or kidney disease. However, the effects and mechanisms of hepatic impairment or renal failure on the pharmacokinetics of linezolid and its metabolites (PNU-142586 and PNU-142300) remain unclear. We used carbon tetrachloride-induced impaired hepatic function and 5/6 nephrectomy-induced renal failure rat models to investigate linezolid and metabolite pharmacokinetics. Isolated primary rat hepatocytes were used to evaluate the impact of hepatic impairment or renal failure on linezolid metabolism. Uptake and efflux transport studies were also conducted. The influence of hepatic impairment or renal failure on the pharmacokinetics of linezolid and two metabolites did not differ between intragastric gavage and intravenous administration in rats. Linezolid did not accumulate in the brain, heart, lung, liver, kidney, and small intestinal tissues of the hepatic impairment or renal failure rats. And PNU-142300 did not accumulate in the liver or kidney tissue. Compared to the isolated normal rat hepatocytes, the in vitro hepatic clearance of linezolid in hepatic impairment and renal failure rat hepatocytes decreased by 61.3% and 44.1%, respectively. Organic anion transporting polypeptide (OATP)1B1, OATP1B3, OATP2B1, Na+-taurocholate co-transporting polypeptide (NTCP), organic anion transporter (OAT)1, OAT3, multidrug resistance-associated protein 2 (MRP2), or multidrug resistance protein 1 (MDR) did not mediate linezolid transport. Hepatic impairment primarily increases linezolid exposure through reduced hepatic metabolism, whereas renal failure increases both linezolid and two metabolites exposure through reduced hepatic metabolism and renal glomerular filtration. These findings guide adjusting the dose of linezolid in patients with hepatic and renal insufficiency.
研究领域:
药理学
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肝脏病学
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肾脏病学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF BACTERIOLOGY
·
2025
·
IF 3
Congjuan Xu,Jie Feng,Yuchen Zhou,Huan Ren,Xiaolei Pan,Shuiping Chen,Xuehua Liu,Guanxian Li,Jinjin Li,Bin Geng,Linlin Gao,Zhihui Cheng,Yongxin Jin,Un-Hwan Ha,Shouguang Jin,Iain L. Lamont,Daniel Pletzer,Weihui Wu
Antibiotic combinations can slow down resistance development and/or achieve synergistic therapeutic effects. In this study, we observed that a combined use of ceftazidime-avibactam (CZA) with azithromycin effectively repressed CZA resistance development in Pseudomonas aeruginosa. Transcriptome analysis revealed that subinhibitory concentrations of azithromycin reduced the expression of genes involved in stress-induced mutagenesis, including the stress response sigma factor rpoS. Interestingly, ribosome profiling revealed global redistribution of ribosomes by azithromycin, among which ribosome stalling was significantly intensified near the 5´ terminus of the rpoS mRNA. Further DNA mutational analysis revealed that azithromycin represses the translation of rpoS through its 5´-terminal rare codons, which in turn reduced its transcription. These in vitro observations have been recapitulated in vivo where azithromycin-repressed CZA resistance development when P. aeruginosa was passaged in mice. Overall, our study revealed the molecular mechanism of azithromycin-mediated repression of antibiotic resistance development, providing a promising antibiotic combination for the treatment of P. aeruginosa infections.
研究领域:
微生物学
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分子生物学
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感染病学
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产品关联
DOI
PubMed
高影响因子
mSystems
·
2024
·
IF 5
Lei Tang,Xizhong Yang,Mengting Zhou,Lingxin Feng,Cuijie Ji,Jie Liang,Bei Zhang,Ruowu Shen,Luoyang Wang
Growing evidence indicates that gut microbiota is involved in the regulation of the host’s sex hormone levels, such as through interfering with the sex hormone metabolism in the intestine. However, if gut microbiota or its metabolites directly influence the sex hormone biosynthesis in the gonad remains largely unknown. Our previous study showed that colistin, as a narrow-spectrum antibiotic, can significantly downregulate the serum testosterone levels and thus enhance the antitumor efficiency of anti-PD-L1 in male mice; however, the underlying mechanism for the regulation of the host’s testosterone levels remains uninvestigated. In the present study, we analyzed the impact of colistin on the immune microenvironment of the testis as well as the composition and metabolism of gut microbiota in male mice. Our results showed that colistin has an impact on the immune microenvironment of the testis and can downregulate serum testosterone levels in male mice through inhibition of Akkermansia, leading to destroyed inosine metabolism. Supplement with inosine can restore testosterone secretion probably by prompting the recovery of the intestinal mucus barrier and the serum lipopolysaccharides levels. All these findings reveal a new pathway for the regulation of the host’s sex hormone levels by gut microbiota.
研究领域:
微生物学
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免疫学
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内分泌学
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药理学
✓ 已验证
DOI
PubMed
高影响因子
EXPERIMENTAL ANIMALS
·
2024
·
IF 2.2
Zhi-Hui GUAN,Di YANG,Yi WANG,Jia-Bin MA,Guo-Nian WANG
Ischemia/reperfusion (I/R) is a pathological process that occurs in numerous organs and is often associated with severe cellular damage and death. Ectodysplasin-A2 receptor (EDA2R) is a member of the TNF receptor family that has anti-inflammatory and antioxidant effects. However, to the best of our knowledge, its role in the progression of myocardial I/R injury remains unclear. The present study aimed to investigate the role of EDA2R during myocardial I/R injury and the molecular mechanisms involved. In vitro, dexmedetomidine (DEX) exhibited a protective effect on hypoxia/reoxygenation (H/R)-induced cardiomyocyte injury and downregulated EDA2R expression. Subsequently, EDA2R silencing enhanced cell viability and reduced the apoptosis of cardiomyocytes. Furthermore, knockdown of EDA2R led to an elevated mitochondrial membrane potential (MMP), repressed the release of Cytochrome C and upregulated Bcl-2 expression. EDA2R knockdown also resulted in downregulated expression of Bax, and decreased activity of Caspase-3 and Caspase-9 in cardiomyocytes, reversing the effects of H/R on mitochondria-mediated apoptosis. In addition, knockdown of EDA2R suppressed H/R-induced oxidative stress. Mechanistically, EDA2R knockdown inactivated the NF-κB signaling pathway. Additionally, downregulation of EDA2R weakened myocardial I/R injury in mice, as reflected by improved left ventricular function and reduced infarct size, as well as suppressed apoptosis and oxidative stress. Additionally, EDA2R knockdown repressed the activation of NF-κB signal in vivo. Collectively, knockdown of EDA2R exerted anti-apoptotic and antioxidant effects against I/R injury in vivo and in vitro by suppressing the NF-κB signaling pathway.
研究领域:
心脏病学
·
分子生物学
·
细胞生物学
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药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Translational Lung Cancer Research
·
2024
·Vol. 13
·期 10
·2698
·
IF 4
Ziying Zhao,Xiaoqing Feng,Huijuan Wu,Shuisheng Chen,Changsong Ma,Ziyun Guan,Luwen Lei,Kejing Tang,Xiao Chen,Yong Dong,Yubo Tang
Background Lung cancer is one of the most common malignant tumors worldwide. Despite advances in lung cancer treatment, patients still face challenges related to drug resistance and recurrence. Current methods for evaluating anti-cancer drug activity are insufficient, as they rely on two-dimensional (2D) cell culture and animal models. Therefore, the development of an in vitro drug evaluation model capable of predicting individual sensitivity to anti-cancer drugs would greatly enhance the success rate of drug treatments for lung cancer patients. The purpose of this research is to utilise conditional reprogramming technology to cultivate patient-derived lung cancer cells and to construct an in vitro 3D culture model using sodium alginate (SA) and gelatin. The aim is to study the biological characteristics of cells in the 3D culture model and to further investigate the sensitivity of anti-cancer drugs based on the alginate-gelatin 3D culture model. This approach provides new means and insights for personalized precision anti-cancer therapy and the development of new anti-cancer drugs. Methods Conditional reprogramming technology was used to generate conditionally reprogrammed lung adenocarcinoma cells (CRLCs). Alginate-gelatin hydrogel micro-beads were created to explore their potential use in the assessment of anti-cancer drugs. Cell proliferation was also examined using the MTS assay method. Live/dead staining was performed to estimate cell distribution and viability using calcein acetoxymethyl ester/propidium iodide (calcein-AM/PI) double staining. Protein expression was assessed by Western blot. Results The cells grown in the three-dimensional (3D) culture were in a state of continuous proliferation, and there was an obvious phenomenon of cell mass growth. The drug sensitivity assay results demonstrated that compared with the 2D-grown cells, the CRLCs grown in the alginate-gelatin hydrogel micro-beads exhibited more resistance to anti-cancer drugs. The results also showed that the 3D-cultured CRLCs showed greater protein expression levels of stem cell hallmarks, such as Nanog Homeobox (NANOG), SRY-Box Transcription Factor 2 (SOX-2), and aldehyde dehydrogenase 1 family member A1 (ALDH1A1), than the 2D-grown cells. Conclusions These findings suggest that the 3D hydrogel cell culture models more closely mimicked the in vivo biological and clinical behavior of cells, and demonstrated higher innate resistance to anti-cancer drugs than the 2D cell culture models, and thus could serve as valuable tools for diagnosis, drug screening, and personalized medicine.
研究领域:
肿瘤学
·
药理学
·
生物技术
·
细胞生物学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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