A consortium of three-bacteria isolated from human feces inhibits formation of atherosclerotic deposits and lowers lipid levels in a mouse model.

By a survey of metagenome-wide association studies (MWAS), we found a robust depletion of Bacteroides cellulosilyticus, Faecalibacterium prausnitzii, and Roseburia intestinalis in individuals with atherosclerotic cardiovascular disease (ACVD). From an established collection of bacteria isolated from healthy Chinese individuals, we selected B. cellulosilyticus, R. intestinalis, and Faecalibacterium longum, a bacterium related to F. prausnitzii, and tested the effects of these bacteria in an Apoe/- atherosclerosis mouse model. We show that administration of these three bacterial species to Apoe-/- mice robustly improves cardiac function, reduces plasma lipid levels, and attenuates the formation of atherosclerotic plaques. Comprehensive analysis of gut microbiota, plasma metabolome, and liver transcriptome revealed that the beneficial effects are associated with a modulation of the gut microbiota linked to a 7α-dehydroxylation-lithocholic acid (LCA)-farnesoid X receptor (FXR) pathway. Our study provides insights into transcriptional and metabolic impact whereby specific bacteria may hold promises for prevention/treatment of ACVD.

Combined therapy of prednisone and mTOR inhibitor sirolimus for treating retroperitoneal fibrosis.

OBJECTIVES: Retroperitoneal fibrosis (RPF) is a rare autoimmune disease with fibrous tissue growth and inflammation in retroperitoneum. Its current treatments involve long-term uptake of glucocorticoids (e.g., prednisone) for controlling inflammation; however, side effects are common. We strived for an improved therapy for fibrosis remission while reducing side effects. METHODS: We surveyed gene-disease-drug databases and discovered that mammalian target of rapamycin (mTOR) was a key signalling protein in RPF and the mTOR inhibitor compound sirolimus affected many RPF pathways. We designed a therapy combining a gradual reduction of prednisone with a long-term, stable dosage of sirolimus. We then implemented a single-arm clinical trial and assessed the effects in eight RPF patients at 0, 12 and 48 weeks of treatment by measuring fibrous tissue mass by CT, markers of inflammation and kidney functions by lab tests, immune cell profiles by flow cytometry and plasma inflammatory proteins by Olink proteomics. RESULTS: With the combined therapy, fibrous tissue shrunk about by half, markers of acute inflammation reduced by 70% and most patients with abnormal kidney functions had them restored to normal range. Molecularly, fibrosis-related T cell subsets, including TH2, TH17 and circulating TFH cells, were reduced and tumour necrosis factor and related cytokines restored to healthy levels. No severe long-term side effects were observed. CONCLUSIONS: Our combined therapy resulted in significant fibrosis remission and an overall regression of the immune system towards healthy states, while achieving good tolerance. We concluded that this new therapy had the potential to replace the steroid monotherapy for treating RPF.

Cardiac disorder-related adverse events for aryl hydrocarbon receptor agonists: a safety review.

BACKGROUND: Although cardiac disorder-related adverse events (AEs) have been reported in patients treated with aryl hydrocarbon receptor (AHR) agonists, their safety profiles remain unknown. Here, we identified significant cardiac disorders associated with AHR agonists and further evaluated their relevance. RESEARCH DESIGN AND METHODS: Database queries were performed using OpenVigil 2.1 and AEs voluntarily submitted to Food and Drug Administration Adverse Event Reporting System (FAERS) between 2004 and 2020 were included. This study based on the Medical Dictionary for Regulatory Activities and the standardized MedDRA Queries to define the preferred terms, and we used reporting odd ratio to detect signals. RESULTS: In the FAERS database, 14,078 cardiac disorder-related AEs were identified in patients receiving AHR agonists. Among all AHR agonists, the number of cardiac disorder-related PTs with positive signals for AHR agonists was 93. Peripheral swelling (n = 1572) and atrial fibrillation (n = 1277) were the most reported cardiac disorder-related AEs among AHR agonists in disproportionately reported PTs. Moreover, several AHR agonists were highly associated with tachyarrhythmia. CONCLUSIONS: By mining the FAERS database, we provided more information on the association between AHR agonist use and cardiac disorder-related AEs.

Free Triiodothyronine Connected With Metabolic Changes in Patients With Coronary Artery Disease by Interacting With Other Functional Indicators.

This study aims to evaluate the association between free triiodothyronine (FT3) and outcomes of coronary artery disease (CAD) patients, as well as to assess the predictive power of FT3 and related functional markers from the perspective of potential mechanism. A total of 5104 CAD patients with an average follow-up of three years were enrolled into our study. Multivariate Cox regression was used to evaluate the associations between FT3, FT4 (free thyroxin), FT3/FT4 and death, MACE. We developed and validated an age, biomarker, and clinical history (ABC) model based on FT3 indicators to predict the prognosis of patients with CAD. In the multivariable Cox proportional hazards model, FT3 and FT3/FT4 were independent predictors of mortality (Adjusted HR = 0.624, 95% CI = 0.486-0.801; adjusted HR = 0.011, 95% CI = 0.002-0.07, respectively). Meanwhile, emerging markers pre-brain natriuretic peptide, fibrinogen, and albumin levels are significantly associated with low FT3 (p < 0.001). The new risk death score based on biomarkers can be used to well predict the outcomes of CAD patients (C index of 0.764, 95% CI = 0.731-0.797). Overall, our findings suggest that low levels of FT3 and FT3/FT4 are independent predictors of death and MACE risk in CAD patients. Besides, the prognostic model based on FT3 provides a useful tool for the death risk stratification of CAD patients.

[Effect of ulinastatin on thromboxane B2 and deep vein thrombosis in elderly patients after hip joint replacement].

OBJECTIVE: To determine the effect of ulinastatin on plasma thromboxane B(2) and deep vein thrombosis(DVT) in elderly patients after hip joint replacement. METHODS: Eighty ASAI-IIpatients aged 65-81 years undergoing hip joint replacement were randomly divided into 4 groups (n=20): Group U1 (ulinastatin 5 000 U/kg);Group U2 (ulinastatin 10 000 U/kg); Group U3 (ulinastatin 20 000 U/kg); and Group C (the same volume of saline as control).The blood samples were collected at 5 time points: preoperation (T(1)), immediately after the operation (T(2)), 1 d (T(3)), 2 d (T(4)) and 3 d after the operation (T(5)), respectively. Thromboxane B(2) was detected, and DVT was also examined through color Doppler ultrasonography 3 d after the operation. RESULTS: Compared with T(1), the level of thromboxane B(2) significantly increased in Group C at T(2)-5, in Group U1 at T(2-4), in Group U2 and U3 at T(2) (P<0.01). Compared with Group C, the concentration of thromboxane B(2) decreased in Group U1 at T(2-3), in Group U2 and U3 at T(2-4) (P<0.01). Compared with Group U1, thromboxane B(2) significantly decreased in Group U2 and U3 at T(2-4) (P<0.01).The incidence rate of DVT was 40% in Group C, 10% in Group U1. There was no incidence of DVT in the Group U2 and U3 (P>0.05). CONCLUSION: Ulinastatin can inhibit blood thromboxane B(2) level in dose dependent manner and prevent DVT in elderly patients after hip joint replacement.