Identification of ibuprofen targeting CXCR family members to alleviate metabolic disturbance in lipodystrophy based on bioinformatics and in vivo experimental verification.

Background: Lipodystrophy is a rare disease that is poorly diagnosed due to its low prevalence and frequent phenotypic heterogeneity. The main therapeutic measures for patients with clinical lipodystrophy are aimed at improving general metabolic complications such as diabetes mellitus, insulin resistance, and hypertriglyceridemia. Therefore, there is an urgent need to find new biomarkers to aid in the diagnosis and targeted treatment of patients with congenital generalized lipodystrophy (CGL). Methods: Dataset GSE159337 was obtained via the Gene Expression Omnibus database. First, differentially expressed genes (DEGs) between CGL and control samples were yielded via differential expression analysis and were analyzed for Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment to explore the functional pathways. Next, protein-protein interaction analysis and the MCC algorithm were implemented to yield candidate genes, which were then subjected to receiver operating characteristic (ROC) analysis to identify biomarkers with an area under the curve value exceeding 0.8. Moreover, random forest (RF), logistic regression, and support vector machine (SVM) analyses were carried out to assess the diagnostic ability of biomarkers for CGL. Finally, the small-molecule drugs targeting biomarkers were predicted, and ibuprofen was further validated in lipodystrophy mice. Results: A total of 71 DEGs in GSE159337 were sifted out and were involved in immune receptor activity, immune response-regulating signaling pathway, and secretory granule membrane. Moreover, CXCR2, TNFSF10, NLRC4, CCR2, CEACAM3, TLR10, TNFAIP3, and JUN were considered as biomarkers by performing ROC analysis on 10 candidate genes. Meanwhile, RF, logistic regression, and SVM analyses further described that those biomarkers had an excellent diagnosis capability for CGL. Eventually, the drug-gene network included ibuprofen-CXCR1, ibuprofen-CXCR1, cenicriviroc-CCR2, fenofibrate-JUN, and other relationship pairs. Ibuprofen treatment was also validated to downregulate CXCR1 and CXCR2 in peripheral blood mononuclear cells (PBMCs) and improve glucose tolerance, hypertriglyceridemia, hepatic steatosis, and liver inflammation in lipodystrophy mice. Conclusion: Eight biomarkers, namely, CXCR2, TNFSF10, NLRC4, CCR2, CEACAM3, TLR10, TNFAIP3, and JUN, were identified through bioinformatic analyses, and ibuprofen targeting CXCR1 and CXCR2 in PBMCs was shown to improve metabolic disturbance in lipodystrophy, contributing to studies related to the diagnosis and treatment of lipodystrophy.

Serum-volatile organic compounds in the diagnostics of esophageal cancer.

The early diagnosis of esophageal cancer (EC) is extremely challenging due to a lack of effective diagnostic methods. The study presented herein aims to assess whether serum volatile organic compounds (VOCs) could be utilised as emerging diagnostic biomarkers for EC. Gas chromatography-ion mobility spectrometry (GC-IMS) was used to detect VOCs in the serum samples of 55 patients with EC, with samples from 84 healthy controls (HCs) patients analysed as a comparison. All machine learning analyses were based on data from serum VOCs obtained by GC-IMS. A total of 33 substance peak heights were detected in all patient serum samples. The ROC analysis revealed that four machine learning models were effective in facilitating the diagnosis of EC. In addition, the random forests model for 5 VOCs had an AUC of 0.951, with sensitivities and specificities of 94.1 and 96.0%, respectively.

Enhanced direct gaseous CO2 fixation into higher bio-succinic acid production and selectivity.

Utilizing CO2 for bio-succinic acid production is an attractive approach to achieve carbon capture and recycling (CCR) with simultaneous production of a useful platform chemical. Actinobacillus succinogenes and Basfia succiniciproducens were selected and investigated as microbial catalysts. Firstly, the type and concentration of inorganic carbon concentration and glucose concentration were evaluated. 6 g C/L MgCO3 and 24 g C/L glucose were found to be the optimal basic operational conditions, with succinic acid production and carbon yield of over 30 g/L and over 40%, respectively. Then, for maximum gaseous CO2 fixation, carbonate was replaced with CO2 at different ratios. The "less carbonate more CO2" condition of the inorganic carbon source was set as carbonate: CO2 = 1:9 (based on the mass of carbon). This condition presented the highest availability of CO2 by well-balanced chemical reaction equilibrium and phase equilibrium, showing the best performance with regarding CO2 fixation (about 15 mg C/(L·hr)), with suppressed lactic acid accumulation. According to key enzymes analysis, the ratio of phosphoenolpyruvate carboxykinase to lactic dehydrogenase was enhanced at high ratios of gaseous CO2, which could promote glucose conversion through the succinic acid path. To further increase gaseous CO2 fixation and succinic acid production and selectivity, stepwise CO2 addition was evaluated. 50%-65% increase in inorganic carbon utilization was obtained coupled with 20%-30% increase in succinic acid selectivity. This was due to the promotion of the succinic acid branch of the glucose metabolism, while suppressing the pyruvate branch, along with the inhibition on the conversion from glucose to lactic acid.

Simultaneous volatile fatty acids promotion and antibiotic resistance genes reduction in fluoranthene-induced sludge alkaline fermentation: Regulation of microbial consortia and cell functions.

The impact and mechanism of fluoranthene (Flr), a typical polycyclic aromatic hydrocarbon highly detected in sludge, on alkaline fermentation for volatile fatty acids (VFAs) recovery and antibiotic resistance genes (ARGs) transfer were studied. The results demonstrated that VFAs production increased from 2189 to 4272 mg COD/L with a simultaneous reduction of ARGs with Flr. The hydrolytic enzymes and genes related to glucose and amino acid metabolism were provoked. Also, Flr benefited for the enrichment of hydrolytic-acidifying consortia (i.e., Parabacteroides and Alkalibaculum) while reduced VFAs consumers (i.e., Rubrivivax) and ARGs potential hosts (i.e., Rubrivivax and Pseudomonas). Metagenomic analysis indicated that the genes related to cell wall synthesis, biofilm formation and substrate transporters to maintain high VFAs-producer activities were upregulated. Moreover, cell functions of efflux pump and Type IV secretion system were suppressed to inhibit ARGs proliferation. This study provided intrinsic mechanisms of Flr-induced VFAs promotion and ARGs reduction during alkaline fermentation.

Active components and mechanisms of total flavonoids from Rhizoma Drynariae in enhancing cranial bone regeneration: An investigation employing serum pharmacochemistry and network pharmacology approaches.

ETHNOPHARMACOLOGICAL RELEVANCE: Rhizoma Drynariae, as the dried rhizome of Drynaria fortunei (Kunze ex Mett.) J. Sm., is a traditional Chinese medicine for treating the injury and bone broken of falling and beating. Total flavonoids is considered as the major and effective compounds for the therapeutic efficacy of Rhizoma Drynariae. AIM OF THE STUDY: To explore the effect of total flavonoids from Rhizoma Drynariae (TFRD) on bone regeneration and the underlying mechanisms. MATERIALS AND METHODS: The effect of TFRD in various doses on bone reconstruction in cranial bone defect rats was explored in vivo. The active ingredients in TFRD-medicated serum were characterized by serum pharmacochemistry and integrated by network pharmacology analysis and target prediction. To elucidate the underlying mechanism of TFRD on bone regeneration, experimental validation in vitro was executed to assess the influence of different concentrations of TFRD-medicated serum on osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). RESULTS: Micro-CT, histological examination, immunohistochemical analysis, and ELSA demonstrated that administration of TFRD could promote bone reconstruction in a rat cranial defect model. We identified 27 active components of TFRD using ultra-high-performance liquid chromatography coupled with tandem mass spectrometry (UHPLC-MS/MS). Results from CCK8, ALP, and Alizarin Red S staining revealed that TFRD-medicated serum notably enhanced BMSCs proliferation and osteogenic differentiation. qRT-PCR and Western blot harvested results consistent with those predicted by network pharmacology, providing further evidence that TFRD activated the TGF-ß signaling pathway to benefit bone regeneration. CONCLUSION: The active components of TFRD modulate the TGF-ß signaling pathway to facilitate osteogenesis, thereby repairing cranial bone defects.

Association between bile acid metabolism and bone mineral density in postmenopausal women

OBJECTIVES: Previous studies have not shown any correlation between bile acid metabolism and bone mineral density (BMD) in women with postmenopausal osteoporosis. Thus, the current study evaluated the association between bile acid levels as well as BMD and bone turnover marker levels in this group of women. METHODS: This single-center cross-sectional study included 150 postmenopausal Chinese women. According to BMD, the participants were divided into three groups: osteoporosis group, osteopenia group, and healthy control group. Serum bile acid, fibroblast growth factor 19 (FGF19), and bone turnover biomarker levels were assessed. Moreover, the concentrations of parathyroid hormone, 25-hydroxy vitamin D [25(OH)D], procollagen type I N-peptide (P1NP), and beta-CrossLaps of type I collagen containing cross-linked C-terminal telopeptide (β-CTX) were evaluated. The BMD of the lumbar spine and proximal femur were examined via dual-energy X-ray absorptiometry. RESULTS: The serum total bile acid levels in the osteoporosis and osteopenia groups (5.28±1.56 and 5.31±1.56 umol/L, respectively) were significantly lower than that in the healthy control group (6.33±2.04 umol/L; p=0.002 and 0.018, respectively). Serum bile acid level was positively associated with the BMD of the lumbar spine, femoral neck, and total hip. However, it negatively correlated with β-CTX concentration. Moreover, no correlation was observed between bile acid and P1NP levels, and the levels of the other biomarkers that were measured did not differ between the groups. CONCLUSION: Serum bile acid was positively correlated with BMD and negatively correlated with bone turnover biomarkers reflecting bone absorption in postmenopausal women. Thus, bile acid may play an important role in bone metabolism.