Xuan Yu

All Publications

• Estrogen Receptor-Phytoestrogen Interactions in Health and Aging: A Review on Estrogen Receptor Vascular Actions with Proof-of-Concept Data. Nutrients Smith, B., Myers, K., Nigro, K., Bao, S., Yu, X., Han, G. 2026; 18 (5)

  Abstract

  Background/Objectives: The menopausal decline in estrogen levels accelerates age-related changes, including visceral adiposity, insulin resistance, sarcopenia, osteoporosis, and endothelial dysfunction. While nutrition independently influences these outcomes, the interactive role of estrogen signaling and nutrient metabolism in healthy aging remains underexplored. This article evaluates these interactions. Methods: We conducted a narrative synthesis of studies examining estrogen's effects on energy balance, adipose regulation, muscle, bone, and cardiovascular health, with an emphasis on estrogen-like nutritional modulators and phytoestrogens. In addition, we present original experimental data from our laboratory investigating sex-specific vascular responses to G protein-coupled estrogen receptor (GPER) activation using functional myography in isolated rat aortic rings from young adult and middle-aged rats (n = 6-8 per group) to assess responses to the GPER agonist G-1 (1.0 μM). Results: Literature evidence demonstrates that estrogen supports macronutrient utilization, suppresses adipose inflammation, preserves bone density, and promotes endothelial function. Phytoestrogens may engage estrogen-responsive pathways to mitigate age-related physiological decline. Our original findings show that GPER agonism enhances both contractile and vasodilatory responses in female (p < 0.05) but not male rat aortas, providing mechanistic evidence of sex-specific vascular estrogen signaling. These results suggest that dietary phytoestrogens and nutrient-rich dietary patterns may, in part, activate GPER-dependent pathways to support cardiovascular resilience in aging women. Conclusions: Estrogen-nutrition interactions are central to metabolic adaptation and healthy aging. Our findings highlight GPER as a functionally resilient pathway in aging vasculature, offering a putative mechanistic link for nutritional modulation. However, direct translation of these findings to human clinical outcomes remains to be established. Precision nutrition strategies targeting GPER represent a promising framework for healthy aging, though large-scale human trials are necessary to confirm these receptor-specific effects.

  View details for DOI 10.3390/nu18050741

  View details for PubMedID 41829911

• Pesticides Inhibit ALDH2 Activity<i> In</i><i> Vitro</i> and in Primary Culture Pulmonary Vascular Endothelial Cells Rwere, F., Simon, D. J., Maehara, T., Hung, B., Yu, X., Gross, E. ELSEVIER. 2025

  View details for DOI 10.1016/j.jpet.2025.103424

  View details for Web of Science ID 001461012400010

• Uncovering newly identified aldehyde dehydrogenase 2 genetic variants that lead to acetaldehyde accumulation after an alcohol challenge. Journal of translational medicine Rwere, F., White, J. R., Hell, R. C., Yu, X., Zeng, X., McNeil, L., Zhou, K. N., Angst, M. S., Chen, C. H., Mochly-Rosen, D., Gross, E. R. 2024; 22 (1): 697

  Abstract

  Aldehyde dehydrogenase 2 (ALDH2) is critical for alcohol metabolism by converting acetaldehyde to acetic acid. In East Asian descendants, an inactive genetic variant in ALDH2, rs671, triggers an alcohol flushing response due to acetaldehyde accumulation. As alcohol flushing is not exclusive to those of East Asian descent, we questioned whether additional ALDH2 genetic variants can drive facial flushing and inefficient acetaldehyde metabolism using human testing and biochemical assays.After IRB approval, human subjects were given an alcohol challenge (0.25 g/kg) while quantifying acetaldehyde levels and the physiological response (heart rate and skin temperature) to alcohol. Further, by employing biochemical techniques including human purified ALDH2 proteins and transiently transfected NIH 3T3 cells, we characterized two newly identified ALDH2 variants for ALDH2 enzymatic activity, ALDH2 dimer/tetramer formation, and reactive oxygen species production after alcohol treatment.Humans heterozygous for rs747096195 (R101G) or rs190764869 (R114W) had facial flushing and a 2-fold increase in acetaldehyde levels, while rs671 (E504K) had facial flushing and a 6-fold increase in acetaldehyde levels relative to wild type ALDH2 carriers. In vitro studies with recombinant R101G and R114W ALDH2 enzyme showed a reduced efficiency in acetaldehyde metabolism that is unique when compared to E504K or wild-type ALDH2. The effect is caused by a lack of functional dimer/tetramer formation for R101G and decreased Vmax for both R101G and R114W. Transiently transfected NIH-3T3 cells with R101G and R114W also had a reduced enzymatic activity by ~ 50% relative to transfected wild-type ALDH2 and when subjected to alcohol, the R101G and R114W variants had a 2-3-fold increase in reactive oxygen species formation with respect to wild type ALDH2.We identified two additional ALDH2 variants in humans causing facial flushing and acetaldehyde accumulation after alcohol consumption. As alcohol use is associated with a several-fold higher risk for esophageal cancer for the E504K variant, the methodology developed here to characterize ALDH2 genetic variant response to alcohol can lead the way precision medicine strategies to further understand the interplay of alcohol consumption, ALDH2 genetics, and cancer.

  View details for DOI 10.1186/s12967-024-05507-x

  View details for PubMedID 39075523

  View details for PubMedCentralID 4840924

• Effects of Short-term Electronic(e)-Cigarette Aerosol Exposure in the Mouse Larynx. The Laryngoscope Easwaran, M., Maria, C. S., Martinez, J. D., Hung, B., Yu, X., Soo, J., Kimura, A., Gross, E. R., Erickson-DiRenzo, E. 2023

  Abstract

  The effects of electronic cigarettes (e-cigarettes) on the larynx are relatively unknown. This study examined the short-term effects of e-cigarette inhalation on cellular and inflammatory responses within the mouse laryngeal glottic and subglottic regions after exposure to pod-based devices (JUUL).Male C57BL6/J mice (8-9 weeks) were assigned to control (n = 9), JUUL flavors Mint (JMi; n = 10) or Mango (JMa; n = 10). JUUL mice were exposed to 2 h/day for 1, 5, and 10 days using the inExpose inhalation system. Control mice were in room air. Vocal fold (VF) epithelial thickness, cell proliferation, subglandular area and composition, inflammatory cell infiltration, and surface topography were evaluated in the harvested larynges. Mouse body weight and urinary nicotine biomarkers were also measured. Chemical analysis of JUUL aerosols was conducted using selective ion flow tube mass spectrometry.JUUL-exposed mice had reduced body weight after day 5. Urinary nicotine biomarker levels indicated successful JUUL exposure and metabolism. Quantitative analysis of JUUL aerosol indicated that chemical constituents differ between JMi and JMa flavors. VF epithelial thickness, cellular proliferation, glandular area, and surface topography remained unchanged after JUUL exposures. Acidic mucus content increased after 1 day of JMi exposure. VF macrophage and T-cell levels slightly increased after 10 days of JMi exposures.Short-term e-cigarette exposures cause minimal flavor- and region-specific cellular and inflammatory changes in the mouse larynx. This work provides a foundation for long-term studies to determine if these responses are altered with multiple e-cigarette components and concentrations.N/A Laryngoscope, 2023.

  View details for DOI 10.1002/lary.31043

  View details for PubMedID 37698394

• Characterization of novel genetic mutations in aldehyde dehydrogenase 2 that cause alcohol flushing in humans Rwere, F., Hell, R. C. R., Yu, X., Gross, E. R. AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS. 2023

  View details for DOI 10.1124/jpet.122.208930

  View details for Web of Science ID 001043657700244

• Statins improve endothelial function via suppression of epigenetic-driven EndMT. Nature cardiovascular research Liu, C., Shen, M., Tan, W. L., Chen, I. Y., Liu, Y., Yu, X., Yang, H., Zhang, A., Liu, Y., Zhao, M. T., Ameen, M., Zhang, M., Gross, E. R., Qi, L. S., Sayed, N., Wu, J. C. 2023; 2 (5): 467-485

  Abstract

  The pleiotropic benefits of statins in cardiovascular diseases that are independent of their lipid-lowering effects have been well documented, but the underlying mechanisms remain elusive. Here we show that simvastatin significantly improves human induced pluripotent stem cell-derived endothelial cell functions in both baseline and diabetic conditions by reducing chromatin accessibility at transcriptional enhanced associate domain elements and ultimately at endothelial-to-mesenchymal transition (EndMT)-regulating genes in a yes-associated protein (YAP)-dependent manner. Inhibition of geranylgeranyltransferase (GGTase) I, a mevalonate pathway intermediate, repressed YAP nuclear translocation and YAP activity via RhoA signaling antagonism. We further identified a previously undescribed SOX9 enhancer downstream of statin-YAP signaling that promotes the EndMT process. Thus, inhibition of any component of the GGTase-RhoA-YAP-SRY box transcription factor 9 (SOX9) signaling axis was shown to rescue EndMT-associated endothelial dysfunction both in vitro and in vivo, especially under diabetic conditions. Overall, our study reveals an epigenetic modulatory role for simvastatin in repressing EndMT to confer protection against endothelial dysfunction.

  View details for DOI 10.1038/s44161-023-00267-1

  View details for PubMedID 37693816

  View details for PubMedCentralID PMC10489108

• SGLT2 inhibitor ameliorates endothelial dysfunction associated with the common ALDH2 alcohol flushing variant. Science translational medicine Guo, H., Yu, X., Liu, Y., Paik, D. T., Justesen, J. M., Chandy, M., Jahng, J. W., Zhang, T., Wu, W., Rwere, F., Zhao, S. R., Pokhrel, S., Shivnaraine, R. V., Mukherjee, S., Simon, D. J., Manhas, A., Zhang, A., Chen, C. H., Rivas, M. A., Gross, E. R., Mochly-Rosen, D., Wu, J. C. 2023; 15 (680): eabp9952

  Abstract

  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.

  View details for DOI 10.1126/scitranslmed.abp9952

  View details for PubMedID 36696485

• A human TRPV1 genetic variant within the channel gating domain regulates pain sensitivity in rodents. The Journal of clinical investigation He, S., Zambelli, V. O., Sinharoy, P., Brabenec, L., Bian, Y., Rwere, F., Hell, R. C., Stein Neto, B., Hung, B., Yu, X., Zhao, M., Luo, Z., Wu, C., Xu, L., Svensson, K. J., McAllister, S. L., Stary, C. M., Wagner, N. M., Zhang, Y., Gross, E. R. 2022

  Abstract

  Pain signals are relayed to the brain via a nociceptive system, and in rare situations, this nociceptive system contains genetic variants that can limit pain response. Here we questioned whether a human transient receptor potential vanilloid 1 (TRPV1) missense variant causes a resistance to noxious stimuli and further if we can target this region by a cell-permeable peptide as a pain therapeutic. Initially using a computational approach, we identified a human K710N TRPV1 missense variant in an otherwise highly conserved region of mammalian TRPV1. After generating a TRPV1K710N knock-in mouse using CRISPR/Cas9, we discovered the K710N variant reduced capsaicin-induced calcium influx in dorsal root ganglion neurons. The TRPV1K710N rodents also had less acute behavioral response to chemical noxious stimuli and less hypersensitivity to nerve injury-induced pain, while leaving the response to noxious heat intact. Furthermore, blocking this K710 region in wild-type rodents by a cell-penetrating peptide limited acute behavioral responses to noxious stimuli and rescued pain hypersensitivity induced by nerve injury back to baseline. These findings identify K710 TRPV1 as a discrete site crucial for the control of nociception and provides new insights into how to leverage rare genetic variants in humans to uncover fresh strategies for developing pain therapeutics.

  View details for DOI 10.1172/JCI163735

  View details for PubMedID 36472910

• E-cigarette aerosol exacerbates cardiovascular oxidative stress in mice with an inactive aldehyde dehydrogenase 2 enzyme. Redox biology Yu, X., Zeng, X., Xiao, F., Chen, R., Sinharoy, P., Gross, E. R. 2022; 54: 102369

  Abstract

  E-cigarette aerosol containing aldehydes, including acetaldehyde, are metabolized by the enzyme aldehyde dehydrogenase 2 (ALDH2). However, little is known how aldehyde exposure from e-cigarettes, when coupled with an inactivating ALDH2 genetic variant, ALDH2*2 (present in 8% of the world population), affects cardiovascular oxidative stress.The study was to determine how e-cigarette aerosol exposure, coupled with genetics, impacts cardiovascular oxidative stress in wild type ALDH2 and ALDH2*2 knock-in mice.Using selective ion flow mass spectrometry, we determined e-cigarette aerosol contains acetaldehyde levels 10-fold higher than formaldehyde or acrolein. Based on this finding, we tested how isolated ALDH2*2 primary cardiomyocytes respond to acetaldehyde and how intact ALDH2*2 knock-in rodents instrumented with telemeters respond physiologically and at the molecular level to 10 days of e-cigarette aerosol exposure relative to wild type ALDH2 rodents.For ALDH2*2 isolated cardiomyocytes, acetaldehyde (1 μM) caused a 4-fold greater peak calcium influx, 2-fold increase in ROS production and 2-fold increase in 4-HNE-induced protein adducts relative to wild-type ALDH2 cardiomyocytes. The heart rate in ALDH2*2 mice increased ∼200 beats/min, while, heart rate in ALDH2 mice increased ∼150 beats/min after 10 days of e-cigarette exposure, relative to air-exposed mice. E-cigarette aerosol exposure triggered ∼1.3 to 2-fold higher level of protein carbonylation, lipid peroxidation, and phosphorylation of NF-κB for both strains of mice, with this response exacerbated for ALDH2*2 mice.Our findings indicate people carrying an ALDH2*2 genetic variant may be more susceptible to increases in cardiovascular oxidative stress from e-cigarette aerosol exposure.

  View details for DOI 10.1016/j.redox.2022.102369

  View details for PubMedID 35751982

• Aldehydes, Aldehyde Metabolism, and the ALDH2 Consortium. Biomolecules Rwere, F., Yu, X., Chen, C., Gross, E. R. 2022; 12 (6)

  Abstract

  The discovery of aldehydes dates back to 1774 when Carl Wilhelm Scheele synthesized acetaldehyde [...].

  View details for DOI 10.3390/biom12060763

  View details for PubMedID 35740888

• E-cigarette Aerosol Elevates Cardiovascular Oxidative Stress in Mice With Aldehyde Dehydrogenase 2 Deficiency Yu, X., Zeng, X., Chen, R., Sinharoy, P., Gross, E. R. LIPPINCOTT WILLIAMS & WILKINS. 2020

  View details for DOI 10.1161/res.127.suppl_1.491Circulation

  View details for Web of Science ID 000606541500228