Indoleacrylic acid produced by Parabacteroides distasonis alleviates type 2 diabetes via activation of AhR to repair intestinal barrier.

BACKGROUND: Anti-inflammatory therapy is an effective strategy in the treatment of type 2 diabetes (T2D). Studies found that inflammatory responses in vivo were strongly associated with defects in the mucosal barrier function of the gut epithelium. While some microbial strains could help repair the intestinal mucosa and maintain the integrity of the intestinal barrier, the specific mechanisms remain to be fully elucidated. The present study investigated the effects of Parabacteroides distasonis (P. distasonis) on the intestinal barrier and the inflammation level in T2D rats and explored the specific mechanisms. RESULTS: By analyzing the intestinal barrier function, the inflammatory conditions, and the gut microbiome, we found that P. distasonis could attenuate insulin resistance by repairing the intestinal barrier and reducing inflammation caused by the disturbed gut microbiota. We quantitatively profiled the level of tryptophan and indole derivatives (IDs) in rats and fermentation broth of the strain, demonstrating that indoleacrylic acid (IA) was the most significant factor correlated with the microbial alterations among all types of endogenous metabolites. Finally, we used molecular and cell biological techniques to determine that the metabolic benefits of P. distasonis were mainly attributed to its ability to promote IA generation, active the aryl hydrocarbon receptor (AhR) signaling pathway, and increase the expression level of interleukin-22 (IL-22), thus enhancing the expression of intestinal barrier-related proteins. CONCLUSIONS: Our study revealed the effects of P. distasonis in the treatment of T2D via intestinal barrier repairment and inflammation reduction and highlighted a host-microbial co-metabolite indoleacrylic acid that could active AhR to perform its physiological effects. Our study provided new therapeutic strategies for metabolic diseases by targeting the gut microbiota and tryptophan metabolism.

[Effects of drought stress on glandular trichomes,stomatal density and volatile exudates of Schizonepeta tenuifolia].

In this research,we explored the effect of three groups of water treatments,including severe drought(the corresponding water content of cultivated substrate 5%-10%),moderate drought(45%-50%) and control(85%-90%),and different drought stress time(15,30,45 d) on the glandular trichome density(TD),stomatal density(SD) and volatile exudates of Schizonepeta tenuifolia.The results showed that there were two kinds of glandular trichomes on the surface of S. tenuifolia leaves: peltate and capitate glandular trichomes. The density of capitate glandular trichomes(CTD) was higher than that of peltate glandular trichomes(PTD). Both CTD and PTD on the abaxial surface of leaf were higher than those on the adaxial surface. Under severe drought stress,the CTD and SD were higher than the other two treatments. Under the same stress time,the biomass and leaf surface area of S. tenuifolia decreased with the deepening of stress degree. As the stress time prolonged,the surface area of leaves and biomass gradually increased,and the TD and SD decreased. The most abundant compound in volatile exudates of S. tenuifolia was pulegone. Under drought stress,the relative content of pulegone decreased,and the relative content of other monoterpenoids such as D-limonene and menthone increased. The n-hexadeconic acid and 2-methyl-1-hexadecanol were detected only at the stress of 15 d,while menthone was detected at the stress of 30 d and45 d. Drought stress affected the leaf growth and secondary metabolism of S. tenuifolia.

Synthesis of vinyl-substituted alcohols using acetylene as a C2 building block.

Vinyl-substituted alcohols represent a highly useful class of molecular skeletons. The current method typically requires either stoichiometric metallic reagents or preformed precursors. Herein, we report a nickel catalysis-enabled synthesis of vinyl-substituted alcohols via a 5-membered oxa-metallacycle. In this protocol, acetylene, the simplest alkyne and abundant feedstock, is employed as an ideal C2 synthon. The reaction features mild conditions, good functional group tolerance and broad substrate scope. Mechanistic exploration implies that the oxa-metallacycle originated from the cyclometallation of aldehyde and acetylene is the key intermediate for this transformation, which is then terminated by a silane-mediated σ-bond metathesis and subsequent reductive elimination.

Correction: Synthesis of vinyl-substituted alcohols using acetylene as a C2 building block.

[This corrects the article DOI: 10.1039/D2SC06400F.].

Development, assessment and validation of a novel prediction nomogram model for risk identification of tracheobronchial tuberculosis in patients with pulmonary tuberculosis.

OBJECTIVE: Tracheobronchial tuberculosis (TBTB), a specific subtype of pulmonary tuberculosis (PTB), can lead to bronchial stenosis or bronchial occlusion if not identified early. However, there is currently no available means for predicting the risk of associated TBTB in PTB patients. The objective of this study was to establish a risk prediction nomogram model for estimating the associated TBTB risk in every PTB patient. METHODS: A retrospective cohort study was conducted with 2153 PTB patients. Optimised characteristics were selected using least absolute shrinkage and selection operator regression. Multivariate logistic regression was applied to build a predictive nomogram model. Discrimination, calibration and clinical usefulness of the prediction model were assessed using C-statistics, receiver operator characteristic curves, calibration plots and decision analysis. The developed model was validated both internally and externally. RESULTS: Among all PTB patients who underwent bronchoscopies (n=2153), 40.36% (n=869) were diagnosed with TBTB. A nomogram model incorporating 11 predictors was developed and displayed good discrimination with a C-statistics of 0.782, a sensitivity of 0.661 and a specificity of 0.762 and good calibration with a calibration-in-the-large of 0.052 and a calibration slope of 0.957. Model's discrimination was favourable in both internal (C-statistics, 0.782) and external (C-statistics, 0.806) validation. External validation showed satisfactory accuracy (sensitivity, 0.690; specificity, 0.804) in independent cohort. Decision curve analysis showed that the model was clinically useful when intervention was decided on at the exacerbation possibility threshold of 2.3%-99.2%. A clinical impact curve demonstrated that our model predicted high-risk estimates and true positives. CONCLUSION: We developed a novel and convenient risk prediction nomogram model that enhances the risk assessment of associated TBTB in PTB patients. This nomogram can help identify high-risk PTB patients who may benefit from early bronchoscopy and aggressive treatment to prevent disease progression.

Qing-Kai-Ling oral liquid alleviated pneumonia via regulation of intestinal flora and metabolites in rats.

Background: Qing-Kai-Ling (QKL) oral liquid, evolving from a classical Chinese formula known as An-Gong-Niu-Huang pills, is a well-established treatment for pneumonia with its mechanism remaining muddled. Studies have shown that the regulation of both intestinal flora and host-microbiota co-metabolism may contribute to preventing and treating pneumonia. The study aimed to investigate the potential mechanism by which QKL alleviates pneumonia from the perspective of 'microbiota-metabolites-host' interaction. Methods: We evaluated the therapeutic effects of QKL on lipopolysaccharide (LPS)-induced pneumonia rats. To explore the protective mechanism of QKL treatment, a multi-omics analysis that included 16S rDNA sequencing for disclosing the key intestinal flora, the fecal metabolome to discover the differential metabolites, and whole transcriptome sequencing of lung tissue to obtain the differentially expressed genes was carried out. Then, a Spearman correlation was employed to investigate the association between the intestinal flora, the fecal metabolome and inflammation-related indices. Results: The study demonstrated that pneumonia symptoms were significantly attenuated in QKL-treated rats, including decreased TNF-α, NO levels and increased SOD level. Furthermore, QKL was effective in alleviating pneumonia and provided protection equivalent to that of the positive drug dexamethasone. Compared with the Model group, QKL treatment significantly increased the richness and αlpha diversity of intestinal flora, and restored multiple intestinal genera (e.g., Bifidobacterium, Ruminococcus_torques_group, Dorea, Mucispirillum, and Staphylococcus) that were correlated with inflammation-related indices. Interestingly, the intestinal flora demonstrated a strong correlation with several metabolites impacted by QKL. Furthermore, metabolome and transcriptome analyses showed that enrichment of several host-microbiota co-metabolites [arachidonic acid, 8,11,14-eicosatrienoic acid, LysoPC (20:0/0:0), LysoPA (18:0e/0:0), cholic acid, 7-ketodeoxycholic acid and 12-ketodeoxycholic acid] levels and varying lung gene (Pla2g2a, Pla2g5, Alox12e, Cyp4a8, Ccl19, and Ccl21) expression were observed in the QKL group. Moreover, these metabolites and genes were involved in arachidonic acid metabolism and inflammation-related pathways. Conclusion: Our findings indicated that QKL could potentially modulate intestinal flora dysbiosis, improve host-microbiota co-metabolism dysregulation and regulate gene expression in the lungs, thereby mitigating LPS-induced pneumonia in rats. The study may provide new ideas for the clinical application and further development of QKL.

Specific Tumor Cell Detection by a Metabolically Targeted Aggregation-Induced Emission-Based Gold Nanoprobe.

Detection of circulating tumor cells (CTCs) could be widely used for early diagnosis and real-time monitoring of tumor progression in liquid biopsy samples. Compared with normal cells, tumor cells exhibit relatively strong negative surface charges due to the high rate of glycolysis. In this study, a cationic fluorescence "turn-on" aggregation-induced emission (AIE) nanoprobe based on gold nanorods (GNRs) was designed and tested to detect tumor cells specifically. In brief, tetraphenylethene (TPE), an AIE dye, was conjugated to the cationic polymer polyethylenimine (PEI) yielding TPEI. TPEI-PEG-SH was obtained by further functionalizing TPEI with a thiol group. TPEI-PEG-SH was grafted to the surface of GNRs, yielding the cationic AIE nanoprobe, named as GNRs-PEG-TPEI. The nanoprobe was characterized to have a uniform particle size of 172 nm, a strong positive surface charge (+54.87 mV), and a surface modification load of ∼40%. The in vitro stability of GNRs-PEG-TPEI was verified. The cellular imaging results demonstrated that the nanoprobe could efficiently recognize several types of tumor cells including MCF-7, HepG2, and Caco-2 while exhibiting specific fluorescence signals only after interacting with tumor cells and minimal background interference. In addition, the study investigated the toxicity of the nanoprobe to the captured cells and proved the safety of the nanoprobe. In conclusion, a specific and efficient nanoprobe was developed for capture and detection of different types of tumor cells based on their unique metabolic characteristics. It holds great promise for achieving early diagnosis and monitoring the tumor progression by detecting the CTCs in clinical liquid biopsy samples.

Integrated microbiome-metabolomics analysis reveals the potential therapeutic mechanism of Zuo-Jin-Wan in ulcerative colitis.

BACKGROUND: Dysregulation in gut microbiota and host cometabolome contributes to the complicated pathology of ulcerative colitis (UC), while Zuo-Jin-Wan (ZJW), a traditional Chinese medicine has shown therapeutic effects against UC with its underlying mechanism remains elusive. PURPOSE: This study utilized an integrated analysis combining gut microbiome and host cometabolism to disclose the potential therapeutic mechanism of ZJW on dextran sulfate sodium (DSS)-induced UC in rats. METHODS: We first evaluated the therapeutic effects of ZJW treatment in DSS-induced rat model. 16S rRNA sequencing, 1H NMR spectroscopy-based metabolomics and Spearman correlation analysis were conducted to explore the potential therapeutic mechanism during the treatment. RESULTS: Our results showed that UC symptoms in ZJW rats were significantly attenuated. Marked decline in microbial diversity in ZJW group was accompanied by its correspondent function adjustment. Specific enrichment of genus Bacteroides, Sutterella, Akkermansia and Roseburia along with the major varying amino acid metabolism and lipid metabolism were observed meantime. Metabolic data further corroborated that ZJW-related metabolic changes were basically gathered in amino acid metabolism, carbohydrate/energy metabolism and lipid metabolism. Of note, some biochemical parameters were deeply implicated with the discriminative microbial genera and metabolites involved in tricarboxylic acid (TCA) cycle and amino acid metabolism, indicating the microbiome-metabolome association in gut microbiota-metabolite-phenotype axis during UC treatment of ZJW. CONCLUSION: For the first time, integrated microbiome-metabolome analysis depicted that ZJW could alleviate DSS-induced UC in rats via a crosstalk between gut microbiota and host cometabolites.

Structural Characterization and Immunoenhancing Effects of a Polysaccharide from the Soft Coral Lobophytum sarcophytoides.

Previous studies on the soft coral Lobophytum sarcophytoides (Lobophytum sp.) are mainly about small molecules, and there has been no systematic research on polysaccharides. In the study, a novel polysaccharide (LCPs-1-A) with immunoenhancing functions was successfully extracted and purified from the soft coral Lobophytum sp. After preliminary analysis, our data indicated that LCPs-1-A was composed of glucose and had a molecular weight of 4.90 × 106 Da. Moreover, our findings showed that LCPs-1-A could promote the proliferation and phagocytosis of RAW264.7 cells, stimulate the production of NO and ROS, and increase the mRNA expression of IL-1ß, IL-6, and TNF-α, which indicated that LCPs-1-A had a good immunoenhancing activity. Through further studies, we found that LCPs-1-A might play an immunoenhancing role through the TLR4/NF-κB signaling pathway. Therefore, our results demonstrated that LCPs-1-A might be a natural immunostimulant for use in medical and food industries.

Incidence, laboratory diagnosis and predictors of tracheobronchial tuberculosis in patients with pulmonary tuberculosis in Chongqing, China.

Tracheobronchial tuberculosis (TBTB) is reported in 10-40% of patients with pulmonary tuberculosis (PTB). Due to its non-specific presentation, the diagnosis and management are frequently delayed. The aim of the present study was to investigate the incidence, predictors and laboratory diagnosis of concomitant TBTB and PTB in Chongqing, China. Bronchoscopy was performed in all patients with newly diagnosed or relapsed PTB in order to detect TBTB between January 2018 and April 2019 in a sub-tertiary hospital in Chongqing, China. The clinical characteristics and laboratory data were analyzed to identify predictors and determine the diagnostic yield of TBTB. A total of 341 (31.4%) of the 1,085 patients with PTB who underwent the bronchoscopic examination presented with concomitant TBTB. The parameters of female sex [odds ratio (OR)=2.57], clinical symptoms (OR=6.26) and atelectasis (OR=4.3) were independent predictors of TBTB. Cough (OR=32.48) and atelectasis (OR=3.14) were independent predictors of TBTB-associated tracheobronchial stenosis. The diagnostic yields of sputum smear, bronchial brush smear, sputum culture, GeneXpert Mycobacterium tuberculosis/rifampicin resistance (GX) using sputum, GX using brushings and in bronchial brush culture used for the diagnosis of TBTB were 44.2, 44.2, 63.5, 57.7, 71.2 and 75%, respectively. GX brushings had higher diagnostic yields compared with sputum or brush smears; however, there was no significant difference between sputum/brushings cultures and GX with sputum. The incidence of TBTB in PTB was 31.4% in Chongqing, China. The parameters of female sex, atelectasis and cough were the major predictors of concomitant TBTB and associated tracheobronchial stenosis. Although GX is an accurate and rapid test to detect TBTB, additional laboratory techniques should also be adopted to improve diagnostic yields in the detection of TBTB in patients with PTB.