Metabolomics reveals that influenza virus infection significantly reduced the concentrations of secondary bile acid (BA) in feces at 7 post-infection (dpi). Oral administration of B. dorei increased bile salt hydrolase (BSH) activity and restored the BA metabolism, thereby protecting wild-type but not TGR5-deficient mice from influenza virus infection. B.dorei-mediated TGR5 activation inhibited influenza virus-induced lung inflammation via cAMP-PKA pathway. Supplementing exogenous Ursodeoxycholic acid (UDCA) and Hyodeoxycholic acid (HDCA), two metabolites changed dramatically after B. dorei treatment, reproduced the protective effect of B. dorei.
UDCA and HDCA alleviate the severity of influenza infection
To explore whether UDCA or HDCA alone was sufficient to protect against influenza infection, the mice were also administered orally with UDCA or HDCA, as described previously. The results showed that UDCA slightly reduced weight loss, but significantly decreased lung index, protected the intestine, and inhibited viral replication at 7 dpi. HDCA dramatically reduced weight loss and lung index. No statistically significant differences were observed in colon shortening or M1 gene expression with HDCA treatment (Fig. 6A-D). Both UDCA and HDCA reduced inflammatory cell infiltration in lung tissue and the number of nucleated cells in BALF, which increased significantly after lung injury (Fig. 6E-F). As expected, UDCA and HDCA reduced the secretion of inflammatory factors in the lung caused by influenza virus, especially IL-1β (Fig. 6G). Western blot results also confirmed the activation of TGR5-cAMP-PKA pathway and inhibition of NLRP3 inflammasome activation (Fig. 6H). The above results suggest that UDCA and HDCA may provide protection against influenza infection and relieve lung inflammation, and UDCA has better effect than HDCA.
UDCA and HDCA inhibit NLRP3 inflammasome activation via cAMP-PKA pathway
Hallmarks of sensorineural hearing loss are elevated hearing thresholds and defects in temporal auditory processing, the former being often caused by outer hair cell (OHC) damage, and the latter by the loss of synapses between inner hair cells (IHCs) and spiral ganglion neurons. In the well-studied CBA/CaJ mouse strain, these impairments are disconnected, IHC synaptopathy preceding OHC loss. We have investigated the relationship between IHC synaptopathy and OHC loss in the C57BL/6J (B6) and ICR mouse strains that model accelerated age-related hearing loss. Regression analysis revealed a strong correlation between these variables across the high-to-low frequency axis of the cochlea. Using the fluorescent dye FM1–43 as a proxy for mechanotransduction (MET) in the hair-cell stereocilia bundle, we found that MET malfunction coexisted with synaptopathy in IHCs. Thus, our results suggest that a MET defect drives IHC synaptopathy in the B6 and ICR strains known to carry a missense mutation of Cadherin 23, encoding a stereocilia bundle protein. Previous data have suggested that OHC stereocilia abnormalities could trigger OHC death. Therefore, stereocilia defect could be a trigger of intracellular stress that drives both IHC synaptopathy and OHC loss. To determine whether tauroursodeoxycholic acid (TUDCA), known to target several stress signalling pathways, could influence cochlear pathology, we conducted long-term TUDCA delivery to ICR mice. TUDCA provided partial protection against IHC synaptopathy but did not prevent OHC loss. These results in two mouse models of accelerated cochlear pathology provide novel insights into the mechanisms behind age-related hearing loss.
Considering that TUDCA administration is well-tolerated in long-term use, shown in human studies as well (Parry et al., 2010, Zucchi et al., 2023), TUDCA might have potential as a pharmacotherapeutic agent against auditory synaptopathy. TUDCA might slow down ribbon synapse loss with age, like it has been shown to attenuate neurodegeneration in an animal model of spinocerebellar ataxia type 3 (Duarte-Silva et al., 2024). It could be speculated that TUDCA’s efficiency in the cochlea is better when IHC synapse loss has a slower path, like in ageing B6 mice and in humans (Wu et al., 2019). To progress to validate TUDCA’s therapeutic potential in the pathological cochlea, understanding of its mode of action is needed, including its impact on the poorly understood molecular pathways promoting ribbon synapse maintenance.
Our hypothesis was that UDCA protects the post-MI failing heart against dangerous arrhythmia through its dual effect as an anti-fibrotic and anti-arrhythmic agent.
We investigated the effect of UDCA upon a 16-week post-MI rat model.
We found that chronic dietary supplementation of UDCA prevents adverse remodelling of the myocardium, maintaining function so that it was comparable to sham. UDCA attenuated the structural and functional remodelling of the LV in the MI rat heart, when monitored by echocardiogram. At 16 weeks post-surgery the LVEDd, LVESd, area at diastole and area at systole of the MI group were significantly higher than the sham group (Figure 1Ai, ii, iv and v), this corresponded with a reduction of LV ejection fraction and fractional area shortening (Figure 1Aiii and vi). UDCA-treated animals showed a significant improvement over the MI group in LVEDd, LVESd and area at systole, but not area at diastole. The UDCA-treated animals were comparable to the sham group in all parameters at 8 and 16 weeks post-MI.
Transferring our experimental data to an in silico 3D human LV model, we found that a combination of reduced arrhythmic substrate area and improved CV (two identified benefits of UDCA-treated post-MI rats) acted together to reduce arrhythmogenicity.
This study identifies that UDCA is anti-fibrotic and anti-arrhythmic in post-MI rat. We found that simulation of UDCA treatment on a human model reduced the occurrence of VT. This indicates that UDCA is a candidate treatment for the prevention of post-MI HF (& arrhythmia) through anti-fibrotic and anti-arrhythmic effects.
A total of 5,863 patients taking UDCA and 17,164 matched controls were analyzed. In both cohorts after IPTW, roughly 56% of patients had cholelithiasis, 16% had cholecystitis, and 28% had cholecystectomy. Age and sex were balanced at baseline between cohorts (UDCA: 70.5 ± 9.54 years old and 58.6% female; controls: 70.3 ± 9.59 years old and 57.4% female). In the UDCA cohort, 384/5,705 (6.74%) were diagnosed with AMD. In the control cohort, 1,559/17,322 (9.00%) were diagnosed with AMD. This corresponded to a significantly decreased hazard of AMD (adjusted hazard ratio = 0.65, 95% CI: 0.58–0.74, P < 0.0001).
Polyethylene terephthalate microplastics (PET-MPs), a major microplastics component identified in human vasculature, pose emerging environmental health risks. This study systemically profiled MPs in human aortic tissues and investigated the mechanisms underlying PET-MPs-induced aortic injury in vivo and in vitro. Chronic oral exposure of Sprague-Dawley rats to PET-MPs (1.0-100 mg/L) resulted in endothelial glycocalyx loss and structural impairment of aortic elastic fibers, with MPs accumulating within aortic endothelial cells. Transcriptomic and biochemical analyses revealed that PET-MPs triggered endoplasmic reticulum stress (ERS) and reactive oxygen species (ROS) generation in human aortic endothelial cells (HAECs), driving glycocalyx degradation and NF-κB-mediated inflammation. Proteomic profiling identified endothelial-derived IL-1β as a key mediator, which subsequently induced phenotypic switching in human aortic smooth muscle cells (HASMCs) in vitro. Pharmacological inhibition of ERS (TUDCA), ROS (NAC), or IL-1β (Canakinumab) attenuated this pathogenic cascade. Crucially, restoration of the glycocalyx using Sulodexide mitigated endothelial dysfunction and downstream HASMC phenotypic switching. These findings establish endothelial glycocalyx degradation via ERS-ROS as a novel mechanism for PET-MPs-induced vascular injury and highlight glycocalyx protection as a potential strategy against environmental microplastic hazards.
ROS not only poses a direct threat to glycocalyx but also enhances its proteolysis by activating matrix metalloproteinases (MMPs) and inactivating endogenous protease inhibitors.(29, 30) Furthermore, existing literature reports that ER stress accompanies vascular calcification in mice and rats.(54, 55) NAC is a broad-spectrum antioxidant that directly scavenges ROS and enhances glutathione synthesis, while TUDCA inhibits the source of ER stress by blocking PERK/IRE1 pathway activation, thereby indirectly alleviating ER oxidative stress. Following treatment with TUDCA or NAC, PET-MPs-induced endothelial glycocalyx damage was significantly mitigated. This indicates that, distinct from factors like inflammation or mechanical stress dysregulation, PET-MPs elevate ROS by inducing ER oxidative stress, subsequently damaging the endothelial glycocalyx via oxidative stress. Notably, the inhibitory effect of TUDCA surpassed that of NAC, suggesting that ER oxidative stress may be the primary trigger for endothelial glycocalyx disruption.
@AlexKChen: TUDCA to protect from microplastics’ harm?