Association of gut microbiome and metabolites with onset and treatment response of patients with pemphigus vulgaris.

Background: Gut dysbiosis and gut microbiome-derived metabolites have been implicated in both disease onset and treatment response, but this has been rarely demonstrated in pemphigus vulgaris (PV). Here, we aim to systematically characterize the gut microbiome to assess the specific microbial species and metabolites associated with PV. Methods: We enrolled 60 PV patients and 19 matched healthy family members, and collected 100 fecal samples (60 treatment-naïve, 21 matched post-treatment, and 19 controls). Metagenomic shotgun sequencing and subsequent quality control/alignment/annotation were performed to assess the composition and microbial species, in order to establish the association between gut microbiome with PV onset and treatment response. In addition, we evaluated short-chain fatty acids (SCFAs) in PV patients through targeted metabolomics analysis. Results: The diversity of the gut microbiome in PV patients deviates from the healthy family members but not between responder and non-responder, or before and after glucocorticoid treatment. However, the relative abundance of several microbial species, including the pathogenic bacteria (e.g., Escherichia coli) and some SCFA-producing probiotics (e.g., Eubacterium ventriosum), consistently differed between the two groups in each comparison. Escherichia coli was enriched in PV patients and significantly decreased after treatment in responders. In contrast, Eubacterium ventriosum was enriched in healthy family members and significantly increased particularly in responders after treatment. Consistently, several gut microbiome-derived SCFAs were enriched in healthy family members and significantly increased after treatment (e.g., butyric acid and valeric acid). Conclusions: This study supports the association between the gut microbiome and PV onset, possibly through disrupting the balance of gut pathogenic bacteria and probiotics and influencing the level of gut microbiome-derived SCFAs. Furthermore, we revealed the potential relationship between specific microbial species and glucocorticoid treatment.

Association of anti-TNF-α treatment with gut microbiota of patients with ankylosing spondylitis.

OBJECTIVE: Gut dysbiosis contributes to multiple autoimmune diseases, including ankylosing spondylitis, which is commonly treated with tumor necrosis factor (TNF)-α inhibitors (TNFis). Because host TNF-α levels are considered to interact with gut microbiota, we aimed to systematically investigate the microbiota profile of ankylosing spondylitis patients with anti-TNF-α-based treatment and identify potential key bacteria. METHODS: Fecal samples were collected from 11 healthy controls and 24 ankylosing spondylitis patients before/after anti-TNF-α treatment, the microbiota profiles of which were evaluated by 16S ribosomal DNA amplicon sequencing and subsequent bioinformatic analysis. RESULTS: Significantly different microbial compositions were observed in samples from ankylosing spondylitis patients compared with healthy controls, characterized by a lower abundance of short-chain fatty acid (SCFA)-producing bacteria. All patients exhibited a positive response after anti-TNF-α treatment, accompanied by a trend of restoration in the microbiota compositions and functional profile of ankylosing spondylitis patients to healthy controls. In particular, the abundance of SCFA-producing bacteria (e.g. Megamonsa and Lachnoclostridium ) was not only significantly lower in ankylosing spondylitis patients than in healthy controls and restored after anti-TNF-α treatment but also negatively correlated with disease severity (e.g. cor = -0.52, P = 8 × 10 -5 for Megamonsa ). In contrast, Bacilli and Haemophilus may contribute to ankylosing spondylitis onset and severity. CONCLUSIONS: Microbiota dysbiosis in ankylosing spondylitis patients can be restored after anti-TNF-α treatment, possibly by impacting SCFA-producing bacteria.

Six genes involved in prognosis of hepatocellular carcinoma identified by Cox hazard regression.

BACKGROUND: Hepatocellular carcinoma (HCC), derived from hepatocytes, is the main histological subtype of primary liver cancer and poses a serious threat to human health due to the high incidence and poor prognosis. This study aimed to establish a multigene prognostic model to predict the prognosis of patients with HCC. RESULTS: Gene expression datasets (GSE121248, GSE40873, GSE62232) were used to identify differentially expressed genes (DEGs) between tumor and adjacent or normal tissues, and then hub genes were screened by protein-protein interaction (PPI) network and Cytoscape software. Seventeen genes among hub genes were significantly associated with prognosis and used to construct a prognostic model through COX hazard regression analysis. The predictive performance of this model was evaluated with TCGA data and was further validated with independent dataset GSE14520. Six genes (CDKN3, ZWINT, KIF20A, NUSAP1, HMMR, DLGAP5) were involved in the prognostic model, which separated HCC patients from TCGA dataset into high- and low-risk groups. Kaplan-Meier (KM) survival analysis and risk score analysis demonstrated that low-risk group represented a survival advantage. Univariate and multivariate regression analysis showed risk score could be an independent prognostic factor. The receiver operating characteristic (ROC) curve showed there was a better predictive power of the risk score than that of other clinical indicators. At last, the results from GSE14520 demonstrated the reliability of this prognostic model in some extent. CONCLUSION: This prognostic model represented significance for prognosis of HCC, and the risk score according to this model may be a better prognostic factor than other traditional clinical indicators.

An unexpected amide bond cleavage: poly (ethylene glycol) transport forms of vancomycin. 2.

PEG-amide vancomycin derivatives (V(3) position) have been synthesized and found to behave as prodrugs in vivo, demonstrating anti-microbial activity in mice when challenged with Staphylococcus aureus. The corresponding PEG-carbamate derivatives do not manifest this in vivo activity, although both classes of compounds have similar in vitro rat plasma stability. Thus, it appears that extra vascular cleavage of the amide bond can occur if the condition of extended circulation of the conjugate is met, resulting in the release of vancomycin.

Structure of a de novo designed protein model of radical enzymes.

The use of side chains as catalytic cofactors for protein mediated redox chemistry raises significant mechanistic issues as to how these amino acids are activated toward radical chemistry in a controlled manner. De novo protein design has been used to examine the structural basis for the creation and maintenance of a tryptophanyl radical in a three-helix bundle protein maquette. Here we report the detailed structural analysis of the protein by multidimensional NMR methods. An interesting feature of the structure is an apparent pi-cation interaction involving the sole tryptophan and a lysine side chain. Hybrid density functional calculations support the notion that this interaction raises the reduction potential of the W degrees /WH redox pair and helps explain the redox characteristics of the protein. This model protein system therefore provides a powerful model for exploring the structural basis for controlled radical chemistry in protein.

Cooperativity and specificity of association of a designed transmembrane peptide.

Thermodynamics studies aimed at quantitatively characterizing free energy effects of amino acid substitutions are not restricted to two state systems, but do require knowing the number of states involved in the equilibrium under consideration. Using analytical ultracentrifugation and NMR methods, we show here that a membrane-soluble peptide, MS1, designed by modifying the sequence of the water-soluble coiled-coil GCN4-P1, exhibits a reversible monomer-dimer-trimer association in detergent micelles with a greater degree of cooperativity in C14-betaine than in dodecyl phosphocholine detergents.