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Gut mycobiome dysbiosis has been implicated in inflammatory bowel disease (IBD). However, it remains unknown whether specific fungal species identified by sequencing directly contribute to IBD pathogenesis. Here, based on analysis of three fecal metagenome datasets of IBD cohorts and a previously established cultivated gut fungi catalog, we identify an IBD-depleted intestinal fungus Clavispora lusitaniae strain P4013B. We show P4013B attenuates DSS-induced colitis in wild-type, antibiotics-treated, and germ-free mice through activation of aryl hydrocarbon receptor (AHR). Using an activity-guided isolation strategy, we identify the P4013B metabolite indole-3-ethanol (IEt) as the AHR agonist mediating the anti-colitis activity. We further validate the role of IEt via engineering strains that overexpress pyruvate decarboxylases producing high yields of IEt. Tea polysaccharide enhanced the anti-colitis activity of P4013B by promoting its proliferation and colonization in the colon. Together, these results suggest that C. lusitaniae P4013B may be explored as a potential probiotic for the treatment and prevention of IBD. Here, the authors show that a human gut fungus, Clavispora lusitaniae P4013B, alleviates colitis in mice through the activation of the aryl hydrocarbon receptor, in turn mediated by its metabolite indole-3ethanol, indicating its potential as a probiotic for inflammatory bowel disease.

Hydrogen sulfide (H2S) is a significant actor in the virulence and pathogenicity of fungi. The analysis of endogenous H2S in fungi benefits the prevention and treatment of pathogenic infections. Herein, a H2S-activated turn-on fluorescent probe named DDX-DNP was developed for the sensitive and selective detection of H2S. Using DDX-DNP, the ability of several oral fungi strains to produce H2S was identified, which was also validated using a typical chromogenic medium. In addition, DDX-DNP was successfully used for the visual sensing of endogenous H2S in fungal cells via microscope, flow cytometry, and colony imaging, along with a specific validation with the co-incubation of H2S production inhibitors in living cells. Above all, DDX-DNP could be used for H2S detection, the fluorescent imaging of fungi, and even the identification of related fungi.

( ), which possesses various biological effects, has been widely used as traditional medicine and functional food in Asian countries, especially China. In consideration of its various biological effects on human healthcare, . was usually used in combination with other drugs. However, the potential drug-drug interaction induced by . through cytochrome P450 enzymes (CYPs) remain unknown. Using the activity assay of CYPs, the inhibitory effects of and its constituents could be evaluated. The interference of on the metabolic processes of clinical drugs could be investigated. The chemical constituents of . could be identified using LC-MS. The interaction between bioactive compounds and CYPs could be proposed through docking analysis and molecular dynamics. The dichloromethane extract of . could inhibit various CYP450 subtypes and interfere with the pharmacokinetics of four drugs in rats. Triterpenoids were identified as the main constituents of the dichloromethane extract by Q-TOF-MS in preliminary analyses. Then, a triterpenoid library containing 66 compounds was established to evaluate their inhibitory effects against CYP 1A2, 2D6, 3A4, 2A6, 2B6, 2C9, and 2C19. CYP 1A2 was inhibited by most lanostane triterpenoids, indicating a strong affinity for these compounds. Among triterpenoids, compound displayed a broad inhibitory effect against CYPs, except for CYP 3A4, 2D6, 2C9, and 2C19. Finally, compounds and exhibited interference with the metabolism of 16 drugs through the inhibition of CYPs . In silico molecular docking analyses for assaying the interaction between compound and CYPs indicated that the hydrogen bonds formed between the hydroxyl groups and amino acid residues. . displayed broad inhibitory effects on CYPs, with triterpenoids as the main bioactive constituents, which may induce potential drug-drug interaction. This information should be helpful for the rational use of . in promoting human health.

Zearalenone (ZEN), an estrogenic mycotoxin, is one of the prevalent contaminants found in food and feed, posing risks to human and animal health. In this study, we isolated a ZEN-degrading strain from soil and identified it as Rhodococcus erythropolis HQ. Analysis of degradation products clarified the mechanism by which R. erythropolis HQ degrades ZEN. The gene zenR responsible for degrading ZEN was identified from strain HQ, in which zenR is the key gene for R. erythropolis HQ to degrade ZEN, and its expression product is a hydrolase named ZenR. ZenR shared 58% sequence identity with the hydrolase ZenH from Aeromicrobium sp. HA, but their enzymatic properties were significantly different. ZenR exhibited maximal enzymatic activity at pH 8.0–9.0 and 55 °C, with a Michaelis constant of 21.14 μM, and its enzymatic activity is 2.8 times that of ZenH. The catalytic triad was identified as S132-D157-H307 via molecular docking and site-directed mutagenesis. Furthermore, the fermentation broth of recombinant Bacillus containing ZenR can be effectively applied to liquefied corn samples, with the residual amount of ZEN decreased to 0.21 μg/g, resulting in a remarkable ZEN removal rate of 93%. Thus, ZenR may serve as a new template for the modification of ZEN hydrolases and a new resource for the industrial application of biological detoxification. Consequently, ZenR could potentially be regarded as a novel blueprint for modifying ZEN hydrolases and as a fresh resource for the industrial implementation of biological detoxification.

Bacillus microorganisms play an important role in the zearalenone (ZEA) biotransformation process in natural environments. The phosphotransferase pathway in Bacillus is both widespread and relatively well conserved. However, the reaction kinetics of these phosphotransferases remain poorly understood, and their catalytic activities are suboptimal. In this study, a ZEA phosphotransferase, ZPH1101, was identified from Bacillus subtilis 1101 using genome sequencing. The product transformed by ZPH1101 was identified as phosphorylated ZEA (ZEA-P) through LC-TOF-MS/MS analysis. The experiments conducted on MCF-7 cells demonstrated that ZEA-P exhibited a lower level of estrogenic toxicity than ZEA. The optimal reaction conditions for ZPH1101 were determined to be 45 °C and pH 8.0. The maximum velocity (Vmax), Michaelis constant (Km), and catalytic constant (kcat) were calculated through fitting to be 16.40 μM·s−1·mg−1, 18.18 μM, and 54.69 s−1, respectively. Furthermore, adding 1 mmol/L Fe2+ or Fe3+ to the reaction system increased the efficiency of ZPH1101 in converting ZEA by 100% relative to the system containing solely 1 mmol/L ATP and 1 mmol/L Mg2+, suggesting that low concentrations of Fe2+ or Fe3+ can improve the ZPH1101-mediated transformation of ZEA. This study contributes to the enzymatic removal of ZEA and broadens the spectrum of strain and enzyme options available to researchers for ZEA detoxification efforts.

Elemene is widely recognized as an effective anti-cancer compound and is routinely administered in Chinese clinical settings for the management of several solid tumors, including non-small cell lung cancer (NSCLC). However, its detailed molecular mechanism has not been adequately demonstrated. In this research, it was demonstrated that elemene effectively curtailed NSCLC growth in the patient-derived xenograft (PDX) model. Mechanistically, employing high-throughput screening techniques and subsequent biochemical validations such as microscale thermophoresis (MST), microRNA-145-5p (miR-145-5p) was pinpointed as a critical target through which elemene exerts its anti-tumor effects. Interestingly, elemene serves as a binding stabilizer for miR-145-5p, demonstrating a strong binding affinity (dissociation constant (KD) = 0.39 ± 0.17 μg/mL) and preventing its degradation both in vitro and in vivo, while not interfering with the synthesis of the primary microRNA transcripts (pri-miRNAs) and precursor miRNAs (pre-miRNAs). The stabilization of miR-145-5p by elemene resulted in an increased level of this miRNA, subsequently suppressing NSCLC progression through the miR-145-5p/mitogen-activated protein kinase kinase kinase 3 (MAP3K3)/nuclear factor kappaB (NF-κB) pathway. Our findings provide a new perspective on revealing the interaction patterns between clinical anti-tumor drugs and miRNAs. [Display omitted] •miR-145-5p is a new potential anti-tumor target of elemene.•Elemene stabilizes miR-145-5p by binding to its 3’-terminal cytosine, without affecting its pre- or pri-miRNAs.•Elemene does not affect the activity of RNA-degrading enzymes.•The study provides novel insights into the potential interaction of antitumor small molecules with miRNAs.

Background: Dyspnea is the most common presenting symptom among patients hospitalized for acute heart failure (AHF). Dyspnea relief constitutes a clinically relevant therapeutic target and endpoint for clinical trials and regulatory approval. However, there have been no widely accepted dyspnea measurement standards in AHF. By systematic review and mapping the current evidence of the applied scales, timing, and results of measurement, we hope to provide some new insights and recommendations for dyspnea measurement. Methods: PubMed, Embase, Cochrane Library, and Web of Science were searched from inception until August 27, 2020. Randomized controlled trials (RCTs) with dyspnea severity measured as the endpoint in patients with AHF were included. Results: Out of a total of 63 studies, 28 had dyspnea as the primary endpoint. The Likert scale (34, 54%) and visual analog scale (VAS) (22, 35%) were most widely used for dyspnea assessment. Among the 43 studies with detailed results, dyspnea was assessed most frequently on days 1, 2, 3, and 6 h after randomization or drug administration. Compared with control groups, better dyspnea relief was observed in the experimental groups in 21 studies. Only four studies that assessed tolvaptan compared with control on the proportion of dyspnea improvement met the criteria for meta-analyses, which did not indicate beneficial effect of dyspnea improvement on day 1 (RR: 1.16; 95% CI: 0.99–1.37; p = 0.07; I 2 = 61%). Conclusion: The applied scales, analytical approaches, and timing of measurement are in diversity, which has impeded the comprehensive evaluation of clinical efficacy of potential therapies managing dyspnea in patients with AHF. Developing a more general measurement tool established on the unified unidimensional scales, standardized operation protocol to record the continuation, and clinically significant difference of dyspnea variation may be a promising approach. In addition, to evaluate the effect of experimental therapies on dyspnea more precisely, the screening time and blinded assessment are factors that need to be considered.

Zearalenone (ZEN), an estrogenic mycotoxin, is one of the prevalent contaminants found in food and feed, posing risks to human and animal health. In this study, we isolated a ZEN-degrading strain from soil and identified it as Rhodococcus erythropolis HQ. Analysis of degradation products clarified the mechanism by which R. erythropolis HQ degrades ZEN. The gene zenR responsible for degrading ZEN was identified from strain HQ, in which zenR is the key gene for R. erythropolis HQ to degrade ZEN, and its expression product is a hydrolase named ZenR. ZenR shared 58% sequence identity with the hydrolase ZenH from Aeromicrobium sp. HA, but their enzymatic properties were significantly different. ZenR exhibited maximal enzymatic activity at pH 8.0–9.0 and 55 °C, with a Michaelis constant of 21.14 μM, and its enzymatic activity is 2.8 times that of ZenH. The catalytic triad was identified as S132-D157-H307 via molecular docking and site-directed mutagenesis. Furthermore, the fermentation broth of recombinant Bacillus containing ZenR can be effectively applied to liquefied corn samples, with the residual amount of ZEN decreased to 0.21 μg/g, resulting in a remarkable ZEN removal rate of 93%. Thus, ZenR may serve as a new template for the modification of ZEN hydrolases and a new resource for the industrial application of biological detoxification. Consequently, ZenR could potentially be regarded as a novel blueprint for modifying ZEN hydrolases and as a fresh resource for the industrial implementation of biological detoxification.

Hepatitis B virus (HBV) X protein (HBx) is implicated in the development of hepatocellular carcinoma (HCC). Yes-associated protein 1 (YAP) is an important proto-oncogene, which is a downstream effector molecule in the Hippo signaling pathway. The aim of the present study was to investigate the association between HBx expression in HCC samples and YAP expression in the Hippo pathway. A total of 20 pathologically confirmed HCC samples, 20 corresponding adjacent non-tumor liver tissues and 5 normal liver tissue samples were collected. The expression of HBx and YAP in the tissues was analyzed by quantitative reverse transcription-polymerase chain reaction and western blot analysis. The intensity and location of YAP expression were analyzed by immunohistochemistry. YAP mRNA and protein expression levels in HCC samples infected with HBV were significantly higher than those of normal liver tissues. Furthermore, YAP expression was positively correlated with HBx expression in HBV-positive HCC samples. Immunohistochemical staining revealed that YAP was predominantly expressed in the nuclei in HBV-positive HCC tissues. YAP expression was significantly decreased in the normal liver tissue and corresponding adjacent liver tissue when compared with the HCC tissues and by contrast to HCC tissues, YAP was predominantly located in the cytoplasm. In conclusion, these results indicate that the YAP gene is a key driver of HBx-induced liver cancer. Therefore, YAP may present a novel target in the treatment of HBV-associated HCC.

Platelet factor 4 (PF4), also referred to as CXCL4, is a significant component of the C-X-C chemokine family, predominantly localized within the alpha granules of platelets. It is recognized for its anti-heparin and anti-angiogenic properties. However, the involvement of PF4 in inflammatory processes has not been extensively investigated. This article aims to explore the diverse functions of PF4 in the context of inflammatory diseases, emphasizing its potential dual regulatory roles across various immune cell types and pathological conditions. Recent research has enhanced our comprehension of PF4, revealing its production not only in platelets but also in macrophages and activated T cells, thereby extending its functional repertoire beyond its conventional roles. Consequently, this review provides a thorough analysis of PF4's influence on inflammatory diseases and offers perspectives and recommendations for future research endeavors.