Biology subjects

Yoshihara, E.

Publications and source records attributed to Yoshihara, E..

4 recordsLinked to original sources

bioRxiv2026

Paternal Metabolic Reversal Remodels Sperm RNA Profiles and Ameliorates Intergenerational Metabolic Disorder in Mice

Paternal obesity increases metabolic risk in offspring, but whether this risk can be reduced by restoring paternal health before conception remains unresolved. We developed a within-sire induction-and-reversal model in outbred CD1 mice in which high-fat diet (HFD)-exposed males generated offspring before and after transition to an ingredient-matched control diet with voluntary exercise. HFD caused obesity, glucose intolerance, insulin resistance, and extensive remodeling of sperm mRNA, lncRNA, and sncRNA profiles, together with transcriptomic changes in metabolic tissues. Diet and exercise reversal normalized paternal metabolic indices and broadly restored tissue RNA profiles, although sperm retained a limited transcriptional memory of prior HFD exposure. Offspring sired before reversal developed sex-dependent metabolic dysfunction despite control-diet rearing, whereas offspring sired after reversal showed substantial improvement. These findings show that paternal metabolic risk is modifiable before conception and that this reversibility is linked to remodeling of sperm RNA. (140 words) HighlightsO_LIPaternal HFD-Ex induces obesity, glucose intolerance and insulin resistance in CD1 males C_LIO_LISperm shows much stronger RNA response than four metabolic organs profiled C_LIO_LIDiet and exercise reversal restores metabolism and RNA profiles in sperm and four metabolic organs analyzed C_LIO_LIOffspring metabolic risk is reduced when sires conceive after reversal through diet and exercise intervention C_LI eTOC BlurbChen, Magalhaes, et al. show that paternal metabolic recovery before conception remodels sperm RNA and reduces transmission of HFD-associated metabolic risk to offspring in a within-sire mouse model.

genetics↗

bioRxiv2026

FXR and BET signaling orchestrate to protect β cells

In both type 1 and type 2 diabetes (T1D and T2D), insulin-producing {beta} cells undergo progressive dysfunction due to inflammation, leading to impaired glucose responsiveness, dedifferentiation, and cell loss. While bile acid (BA) dysregulation under diabetic conditions is known to influence metabolic and inflammatory pathways, its mechanistic role in {beta} cell regulation remains incompletely defined1-3. Here we show that bile acid sensor Farnesoid X receptor (FXR) and Bromodomain and Extra-Terminal motif (BET) signaling cooperatively regulates {beta} cell inflammatory response and {beta} cell identity. We identified the physiological protein-protein interaction between FXR and the bromodomain-containing protein 4 (BRD4) as a regulatory axis that protects against {beta} cell dysfunction. We show that FXR activation by Fexaramine (Fex) together with BRD4 inhibition by JQ1 synergistically suppressed IL-1{beta}-induced inflammation while also improving {beta} cell identity and insulin secretion in both db/db model and high-fat diet (HFD) plus multi low-dose streptozotocin (MLD-STZ) model of diabetes. Importantly, this cooperative effect is abolished in {beta} cell-specific FXR knockout ({beta}FXRKO) mice, establishing that FXR is required for the functional synergy between these pathways in vivo. Mechanistically, structure-guided modeling and mutational analyses identified a direct interaction between FXR and the BD2 domain of BRD4, depending on specific lysine acetylation sites. Additionally, inhibition of the BD2 domain of BET combined with FXR activation markedly improved {beta} cell survival in human T1D and T2D models established from human pluripotent stem cell (hPSC)-derived islet-like organoids (HILOs). Collectively, these findings establish a BA-bromodomain axis as a transcriptional interface linking metabolic signaling and chromatin regulation, and highlight FXR-BET targeting as a promising strategy to counter progressive {beta} cell failure in diabetes.

molecular biology↗

bioRxiv2024

Antimicrobial activity of the BAM complex-targeting peptides against multidrug-resistant gram-negative bacteria

Multidrug-resistant (MDR) Gram-negative bacteria represent a notable public health threat, necessitating the urgent development of new antimicrobial agents. The {beta}-barrel assembly machinery (BAM) complex, crucial for the biogenesis of outer membrane proteins in Gram-negative bacteria, emerges as a promising target for drug development. The BAM complex comprises five proteins (BamA-E), and its functionality might be disrupted by peptides targeting the BamA and BamB interface. We synthesized the peptide LTLR, located in the BamB interaction region with BamA in Pseudomonas aeruginosa, and assessed its anti-P. aeruginosa activity. This peptide demonstrated potential in enhancing antibiotic efficacy against P. aeruginosa. Conversely, LRTL, a scrambled version of LTLR, lacked activity, underscoring the importance of specific target site binding for the peptides adjuvant effect. Subsequently, we tested the hypothesis that peptide dimerization enhances its effectiveness. A dimeric peptide, composed of two LTLR sequences, was tested and found to possess bactericidal activity against P. aeruginosa, an outcome not observed with the monomeric form. Importantly, this dimeric peptide also showed bactericidal activity against MDR P. aeruginosa strains. In summary, our findings offer a foundation for developing novel antimicrobial agents against MDR Gram-negative bacteria. IMPORTANCEThis work demonstrates that (1) the {beta}-barrel assembly machinery (BAM) complex-targeting peptides can exhibit antimicrobial activity and that (2) the dimeric forms of these peptides exhibit bactericidal activity against multidrug-resistant (MDR) strains of P. aeruginosa and A. baumannii.

microbiology↗

bioRxiv2021

Bisphenol A derivatives act as novel coactivator binding inhibitors for estrogen receptor β

Bisphenol A and its derivatives are recognized endocrine disruptors based on their complex effects on estrogen receptor (ER) signaling. While the effects of bisphenol derivatives on ER have been thoroughly evaluated, how these chemicals affect ER{beta} signaling is not well understood. Herein, we identified novel ER{beta} ligands by screening a chemical library of bisphenol derivatives. Many of the compounds identified showed intriguing dual activities as ER agonists and ER{beta} antagonists. Docking simulations suggested that these compounds act as coactivator binding inhibitors (CBIs). Direct binding experiments using wild-type and mutated ER{beta} demonstrated the presence of a second ligand interaction position at the coactivator binding site in ER{beta}. Our study is the first to propose that bisphenol derivatives act as CBIs, presenting a critical view point for future ER signaling-based drug development.

biochemistry↗