The common aldehyde dehydrogenase 2 (ALDH2) alcohol flushing variant known as ALDH2*2 affects ∼8% of the world's population. Even in heterozygous carriers, this missense variant leads to a severe loss of ALDH2 enzymatic activity and has been linked to an increased risk of coronary artery disease (CAD). Endothelial cell (EC) dysfunction plays a determining role in all stages of CAD pathogenesis, including early-onset CAD. However, the contribution of ALDH2*2 to EC dysfunction and its relation to CAD are not fully understood.
In a large genome-wide association study (GWAS) from Biobank Japan, ALDH2*2 was found to be one of the strongest single-nucleotide polymorphisms associated with CAD. Clinical assessment of endothelial function showed that human participants carrying ALDH2*2 exhibited impaired vasodilation after light alcohol drinking. Using human induced pluripotent stem cell-derived ECs (iPSC-ECs) and CRISPR-Cas9-corrected ALDH2*2 iPSC-ECs, we modeled ALDH2*2-induced EC dysfunction in vitro, demonstrating an increase in oxidative stress and inflammatory markers and a decrease in nitric oxide (NO) production and tube formation capacity, which was further exacerbated by ethanol exposure.
We subsequently found that sodium-glucose cotransporter 2 inhibitors (SGLT2i) such as empagliflozin mitigated ALDH2*2-associated EC dysfunction. Studies in ALDH2*2 knock-in mice further demonstrated that empagliflozin attenuated ALDH2*2-mediated vascular dysfunction in vivo. Mechanistically, empagliflozin inhibited Na(+)/H(+)-exchanger 1 (NHE-1) and activated AKT kinase and endothelial NO synthase (eNOS) pathways to ameliorate ALDH2*2-induced EC dysfunction. Together, our results suggest that ALDH2*2 induces EC dysfunction and that SGLT2i may potentially be used as a preventative measure against CAD for ALDH2*2 carriers.
The relationship between alcohol consumption and cancer has no consistent results both in epidemiological studies and animal models. The inaccuracy of alcohol consumption dosage in the experimental design maybe leads to inconsistent results and makes the researchers ignore the effect of very-light alcohol consumption on cancer. To determine the effects of very-light alcohol consumption on cancer, in this study, the manner of gavage was used to control the alcohol consumption accurately. The impacts of age and time of drinking on cancer progression were also evaluated in this study. Here, we find that a certain range of alcohol consumption (from 0.5% w/v to 2.0% w/v) can suppress tumor development in the breast metastasis mouse model by controlling the alcohol consumption dosage accurately. RNA sequencing analyses were performed in primary tumors and related metastases from the NC group and 1.0% w/v group. The results of primary tumors and related metastases indicated that chronic very-light alcohol consumption downregulates breast tumor-associated oncogenes in primary tumors and regulates the immune system and metabolic system in metastatic carcinoma. To provide the public with drinking recommendations, eight commercial alcohol types were investigated at a dosage of 1.0% w/v. Two types of commercial alcohol, red wine (made in France, brand 1) and baijiu (made in China, brand 1), exerted excellent primary tumor and metastasis inhibitory effects. The untargeted metabolomic analysis of commercial alcohol by liquid chromatography-tandem mass spectrometry indicated that baijiu (brand 1) and baijiu (brand 2) exhibited a difference in compositions that can lead to their different anti-cancer effects. These results indicated that a certain range of very light alcohol dosages might have a potential human-cancer inhibition effect.
The microbiota is known to modulate the host response to influenza infection through as-yet-unclear mechanisms. We hypothesized that components of the microbiota exert effects through type I interferon (IFN), a hypothesis supported by analysis of influenza in a gain-of-function genetic mouse model.
Here we show that a microbially associated metabolite, desaminotyrosine (DAT), protects from influenza through augmentation of type I IFN signaling and diminution of lung immunopathology. A specific human-associated gut microbe, Clostridium orbiscindens, produced DAT and rescued antibiotic-treated influenza-infected mice. DAT protected the host by priming the amplification loop of type I IFN signaling.
These findings show that specific components of the enteric microbiota have distal effects on responses to lethal infections through modulation of type I IFN.
The microbiota is known to modulate the host response to influenza infection through as-yet-unclear mechanisms. We hypothesized that components of the microbiota exert effects through type I interferon (IFN), a hypothesis supported by analysis of influenza in a gain-of-function genetic mouse model. Here we show that a microbially associated metabolite, desaminotyrosine (DAT), protects from influenza through augmentation of type I IFN signaling and diminution of lung immunopathology. A specific human-associated gut microbe, Clostridium orbiscindens, produced DAT and rescued antibiotic-treated influenza-infected mice. DAT protected the host by priming the amplification loop of type I IFN signaling. These findings show that specific components of the enteric microbiota have distal effects on responses to lethal infections through modulation of type I IFN.