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Twelve guaianolide-type sesquiterpene oligomers with diverse structures were isolated from the whole plants of Ainsliaea fragrans, including a novel trimer (1) and two new dimers (2, 3). The chemical structures of the new compounds were elucidated through spectroscopic data interpretation and computational calculations. Ainsfragolide (1) is an unusual guaianolide sesquiterpene trimer generated with a novel C-C linkage at C2'-C15″, which may be biosynthesized prospectively through a further Michael addition. Cytotoxicity results showed that ainsfragolide (1) was the most potent compound against five cancer cell lines with IC50 values in the range of 0.4-8.3 μM.

Ankylosing spondylitis (AS) is a systemic, chronic, and inflammatory rheumatic disease that affects 0.2% of the population. Current diagnostic criteria for disease activity rely on subjective Bath Ankylosing Spondylitis Disease Activity Index scores. Here, we aimed to discover a panel of serum protein biomarkers. First, tandem mass tag (TMT)-based quantitative proteomics was applied to identify differential proteins between 15 pooled active AS and 60 pooled healthy subjects. Second, cohort 1 of 328 humans, including 138 active AS and 190 healthy subjects from two independent centers, was used for biomarker discovery and validation. Finally, biomarker panels were applied to differentiate among active AS, stable AS, and healthy subjects from cohort 2, which enrolled 28 patients with stable AS, 26 with active AS, and 28 healthy subjects. From the proteomics study, a total of 762 proteins were identified and 46 proteins were up-regulated and 59 proteins were down-regulated in active AS patients compared to those in healthy persons. Among them, C-reactive protein (CRP), complement factor H-related protein 3 (CFHR3), α-1-acid glycoprotein 2 (ORM2), serum amyloid A1 (SAA1), fibrinogen γ (FG-γ), and fibrinogen β (FG-β) were the most significantly up-regulated inflammation-related proteins and S100A8, fatty acid-binding protein 5 (FABP5), and thrombospondin 1 (THBS1) were the most significantly down-regulated inflammation-related proteins. From the cohort 1 study, the best panel for the diagnosis of active AS vs healthy subjects is the combination of CRP and SAA1. The area under the receiver operating characteristic (ROC) curve was nearly 0.900, the sensitivity was 0.970%, and the specificity was 0.805% at a 95% confidence interval from 0.811 to 0.977. Using 0.387 as the cutoff value, the predictive values reached 92.00% in the internal validation set (62 with active AS vs 114 healthy subjects) and 97.50% in the external validation phase (40 with active AS vs 40 healthy subjects). From the cohort 2 study, a panel of CRP and SAA1 can differentiate well among active AS, stable AS, and healthy subjects. For active AS vs stable AS, the area under the ROC curve was 0.951, the sensitivity was 96.43%, the specificity was 88.46% at a 95% confidence interval from 0.891 to 1, and the coincidence rate was 92.30%. For stable AS vs healthy humans, the area under the ROC curve was 0.908, the sensitivity was 89.29%, the specificity was 78.57% at a 95% confidence interval from 0.836 to 0.980, and the coincidence rate was 83.93%. For active AS vs healthy subjects, the predictive value was 94.44%. The results indicated that the CRP and SAA1 combination can potentially diagnose disease status, especially for active or stable AS, which will be conducive to treatment recommendation for patients with AS.

Three new polyketide dimers named huoshanmycins A‒C (

Twelve guaianolide-type sesquiterpene oligomers with diverse structures were isolated from the whole plants of

Two new terragine analogs (

To identify potential lipid biomarkers by studying changes in the blood lipid profile of patients with systemic lupus erythematosus (SLE) using lipidomics.Serum samples were collected from 115 SLE patients and 115 age- and sex-matched healthy controls (HCs). Lipid profiles were assessed using ultrahigh-performance liquid chromatography coupled with Q Exactive spectrometry, and possible lipid biomarkers were screened and evaluated by univariate and multivariate analyses.Metabolic phenotypes related to SLE disease activity index (SLEDAI) scores were detected in the serum of SLE patients, and these phenotypes indicated the activity of the disease. Alterations in energy metabolism, fatty acid metabolism and other pathways were observed in patients with SLE. Phosphatidylethanolamine (16:0/18:2), lysophosphatidylethanolamine (18:0), and acylcarnitine (11:0) can be used as biomarkers for the clinical diagnosis of SLE, and receiver operating characteristic (ROC) analysis indicated their effectiveness in diagnosing this disease.Our study identified serum biomarkers related to disease activity in patients with SLE, providing a basis for its clinical diagnosis.

At present, the pathogenesis of Sjögren's syndrome (SS) remains unclear. This research aimed to identify differential metabolites that contribute to SS diagnosis and discover the disturbed metabolic pathways.Recent advances in mass spectrometry have allowed the identification of hundreds of unique metabolic signatures and the exploration of altered metabolite profiles in disease. In this study, 505 candidates including healthy controls (HCs) and SS patients were recruited and the serum samples were collected. A non-targeted gas chromatography-mass spectrometry (GC-MS) serum metabolomics method was used to explore the changes in serum metabolites.We found SS patients and HCs can be distinguished by 21 significant metabolites. The levels of alanine, tryptophan, glycolic acid, pelargonic acid, cis-1-2-dihydro-1-2-naphthalenediol, diglycerol, capric acid, turanose, behenic acid, dehydroabietic acid, stearic acid, linoleic acid, heptadecanoic acid, valine, and lactic acid were increased in serum samples from SS patients, whereas levels of catechol, anabasine, 3-6-anhydro-D-galactose, beta-gentiobiose, 2-ketoisocaproic acid and ethanolamine were decreased. The significantly changed pathways included the following: Linoleic acid metabolism; unsaturated fatty acid biosynthesis; aminoacyl-tRNA biosynthesis; valine, leucine, and isoleucine biosynthesis; glycerolipid metabolism; selenocompound metabolism; galactose metabolism; alanine, aspartate and glutamate metabolism; glyoxylate and dicarboxylate metabolism; glycerophospholipid metabolism; and valine, leucine and isoleucine degradation.These findings enhance the informative capacity of biochemical analyses through the identification of serum biomarkers and the analysis of metabolic pathways and contribute to an improved understanding of the pathogenesis of SS.

Two new terragine analogs (1‒2) with special succinimide and aminopentane moieties were isolated from the fermentation broth of Bacillus sp. SH-1.2-ROOT-18, an endophyte previously discovered from the root of Dendrobium officinale. The structures were elucidated base on comprehensive 1 D/2D NMR and MS data analysis. Complete NMR assignments for the first reported naturally occurring metabolite 3 was also provided.

Rheumatoid arthritis (RA), afflicting over 1% of the population, is an inflammatory joint disease leading to cartilage damage and ultimately impaired joint function. Disease-modifying anti-rheumatic drugs are considered as the first-line treatment to inhibit the progression of RA, and the treatment depends on the disease status assessment. The disease activity score 28 as clinical gold standard is extensively used for RA assessment, but it has the limitations of delayed assessment and the need for specialized expertise. It is necessary to discover biomarkers that can precisely monitor disease activity, and provide optimized treatment for RA patients. A total of 1,244 participants from two independent centers were divided into five cohorts. Cohorts 1-4 constituted sera samples of moderate to high active RA, low active RA, RA in remission and healthy subjects. Cohort 5 consisted of sera of RA, osteoarthritis (OA), ankylosing spondylitis (AS), systemic lupus erythematosus (SLE), primary Sjogren's syndrome (pSS) and healthy subjects. Biomarkers were found from cohorts 1-2 (screening sets), cohort 3 (discovery and external validation sets), cohort 4 (drug intervention set) and cohort 5 (biomarker-specific evaluation set). We found 68 upregulated and 74 downregulated proteins by TMT-labeled proteomics in cohort 1, and fibrinogen-like protein 1 (FGL1) had the highest area under the receiver operating characteristic curve (AUC) values in cohort 2. In cohort 3, in cross-comparison among moderate/high active RA, low active RA, RA in remission and healthy subjects, FGL1 had AUC values of approximately 0.9000 and predictive values of 90%. Additionally, FGL1 had a predictive value of 91.46% for moderate/high active RA vs. remission/low active RA and 80.77% for RA in remission vs. low active RA in cohort 4. Importantly, FGL1 levels had no significant difference in OA and AS compared with healthy persons. The concentrations in SLE and pSS were improved, but approximately 3-fold lower than that in active RA in cohort 5. In summary, FGL1 is a novel and specific biomarker that could be clinically useful for predicting progression of RA.

BACKGROUND: Endophyte has now become a potential source for the discovery of novel natural products, as they participate in biochemical pathways of their hosts and produce analogous or novel bioactive compounds. As an epiphytic plant, Dendrobium officinale is one of precious Chinese medicines with various activities. It is well known for containing diverse endophytes, but so far not much is known about their secondary metabolites. METHODS: the plant tissues were cut and cultured on agar plates to isolate and purify the endophytic bacteria from Dendrobium officinale. Taxonomical identification of strains was performed by 16s rRNA. At the same time, the crude extracts of the strains were tested for antibacterial and cytotoxic activities to screen out one endophyte, Streptomyces sp. SH-1.2-R-15 for further study. After scale-up fermentation, isolation, purification and structure elucidation by using MS, 1D/2D-NMR spectroscopic method, secondary metabolites were identified and submitted for biological activity test. RESULTS: Fifty-eight endophytic strains representing 9 genera were obtained, with 50% of strains were Streptomyces. One of the most active strain, Streptomyces sp. 1.2-R-15, was selected for bioassay-guided isolation, which led to the discovery of two new peptide-type compounds 1 and 2, as well as a bioactive chartreusin, and four other known natural products. Their structures were determined by comprehensive spectroscopic techniques. Chartreusin showed potent cytotoxicity against Hep3B2.1-7 (IC(50) =18.19 µM) and H1299 (IC(50) =19.74 µM) cancer cell lines, and antibacterial activity against S. aureus (IC(50) =23.25 µM). CONCLUSIONS: This study highlights the endophytic bacteria from medical plant D. officinale have potential bioactivity and natural product diversity, thus implicates them as a valuable source for new anticancer and antibiotics agents.

Systemic lupus erythematosus (SLE) is a multisystem chronic autoimmune disease characterized by specific clinical and serological changes. Currently, the pathogenesis of SLE remains unclear. This study aimed to identify potential diagnostic biomarkers for SLE and discover the metabolic pathways associated with the disease. We collected serum samples from 260 subjects, including patients with SLE and healthy controls (HCs). Metabolite profiles were analyzed using a nontargeted gas chromatography-mass spectrometry (GC–MS) serum metabolomics method, and differentially altered metabolites were screened and assessed using univariate and multivariate analyses. In this study, patients with SLE and HCs were distinguished by 14 significant metabolites. The levels of pipecolinic acid, glutamine, creatine, stearic acid, asparagine and uric acid were increased in serum samples from patients with SLE, whereas levels of allo-inositol, trans-4-hydroxy-L-proline, glycerol-1-phosphate, N-acetyl-L-aspartic acid, malic acid, phosphate, arabitol and ribose were decreased. Arabitol, asparagine and stearic acid were identified as potential biomarkers, and their diagnostic performance was evaluated by performing a receiver operating characteristic (ROC) curve analysis. Significantly altered pathways included aspartate metabolism, glycine and serine metabolism, cardiolipin biosynthesis, riboflavin metabolism, plasmalogen synthesis, mitochondrial beta-oxidation of long-chain saturated fatty acids, ammonia recycling, pentose phosphate pathway, arginine and proline metabolism and purine metabolism. By identifying serum biomarkers and analyzing metabolic pathways, our study contributes to a better understanding of the pathogenesis of SLE.

Rheumatoid arthritis (RA) is a common chronic inflammatory disorder characterized by inflammation of the synovium which causes joint damage, chronic pain, and disability. Changes in lipid profile are seen before overt RA disease manifestations suggesting that lipids contribute to the inflammation-driven metabolic changes in tumor necrosis factor. Currently, the pathogenesis of RA is unclear. Moreover, it is important to search for lipids biomarkers for early diagnosis of the disease. Herein, we compared the lipid profile of healthy individuals and RA patients to provide evidence for the diagnosis and management of persons with RA. Serum samples were collected from 511 RA patients and 396 health controls (HC). The samples were analyzed by ultra-performance liquid chromatography Q-Exactive mass spectrometry. Potential lipid biomarkers were screened and validated using the partial least squares discriminant analysis (PLS-DA), orthogonal partial least squares-discriminant analysis (OPLS-DA), random forest, binary logistic regression (BLR), receiver operating characteristic (ROC) and counter propagation artificial neural network (CP-ANN) analysis. A total of 36 differential lipid metabolites were identified, including phosphatidylethanolamine (PE), triglyceride (TG), acylcarnitine (ACar) and phosphatidylcholine (PC). Among them, PE 16:0-18:2, TG 18:0-18:1-18:2 and PE 18:2-18:2 were identified as specific biomarkers for differential diagnosis of RA. ROC analysis showed that the biomarkers had a sensitivity of 68% with a specificity of 63% in discriminating RA from HC individuals. The resulting CP-ANN can be used to identify unknown RA samples with predictive accuracy of 97% as determined through cross validation. The external validation accuracy of CP-ANN was 100% in all evaluated cases. The three lipid serum biomarkers were associated with the disease activity in RA. These lipid biomarkers showed that lipid peroxidation is disrupted in RA.

Objective The relationship between serum lipid variations in SS and healthy controls was investigated to identify potential predictive lipid biomarkers. Methods Serum samples from 230 SS patients and 240 healthy controls were collected. The samples were analysed by ultrahigh-performance liquid chromatography coupled with Q Exactive™ spectrometry. Potential lipid biomarkers were screened through orthogonal projection to latent structures discriminant analysis and further evaluated by receiver operating characteristic analysis. Results A panel of three metabolites [phosphatidylcholine (18:0/22:5), triglyceride (16:0/18:0/18:1) and acylcarnitine (12:0)] was identified as a specific biomarker of SS. The receiver operating characteristic analysis showed that the panel had a sensitivity of 84.3% with a specificity of 74.8% in discriminating patients with SS from healthy controls. Conclusion Our approach successfully identified serum biomarkers associated with SS patients. The potential lipid biomarkers indicated that SS metabolic disturbance might be associated with oxidized lipids, fatty acid oxidation and energy metabolism.

Background: Ankylosing Spondylitis (AS) is a systemic, chronic and inflammatory rheumatic disease, which affected 0.2% of the population. Current diagnostic criteria relys on a composite of clinical and rediological changes, with an average of 14 years from AS symptoms onset to diagnosis. Here, we aimed to discover a panel of potential biomarkers for AS diagnosis. Methods: A cohort of 403 patients including 153 AS and 250 healthy subjects from 2 independent centers was studied. In the discovery set 1, TMT-based quantitative proteomics method was applied to identify serum proteins. In the discovery set 2, ELISA method was further performed to quantify and validate the levels of differential proteins from proteomics. An array of potential biomarkers were screened by the area under the receiver operating characteristic (ROC) curve. Finally, an accurate and reliable biomarkers panel was evaluated by the prediction accuracies in internal and external validation sets. Findings: A total of 762 proteins were identified from 15 pooled AS and 60 pooled healthy serum samples. Among them, 46 up-regulated and 59 down-regulated proteins were identified in AS compared to healthy subjects. The AS responsive proteins including CRP, SAA1, ORM2, FG-γ and THBS1 were validated successfully by ELISA using sera of 36 AS and 36 healthy subjects. The area under the ROC curve of the CRP and SAA1 combination was high, near by 0.9. The sensitivity was 0.970, specificity was 0.805 at 95% confidence interval from 0.811 to 0.977. The predictive values reached 92.00% in the internal validation set (62 AS vs 114 healthy subjects) and 97.50% in the external validation phase (40 AS vs 40 healthy subjects). Interpretation: A panel of two acute phase proteins (CRP and SAA1) as potential biomarkers could be useful for complementary diagnosis of AS. Funding: This work is financially supported by the National Natural Science Foundation of China, the Natural Science Foundation of Jiangsu province, Jiangsu Provincial Medical Youth Talent (No. QNRC2016642), the Young Elite Scientists Sponsorship Program by CAST (No. QNRC2-B04), Science and technology projects of Jiangsu Province Hospital of TCM (No. Y18010) and the top six talent project of Jiangsu province 2016 (WSN-051). Declaration of Interest: There is no any conflict of interest with regard to our work. Ethical Approval: All procedures were approved by the medical ethics committee of the affiliated Hospital of Nanjing University of Chinese Medicine and followed the tenets of the Declaration of Helsinki. The experimental protocol was reviewed and approved by the Institutional Review Board of the affiliated Hospital of Nanjing University of Chinese Medicine (2018NL-106-02).