Biology subjects

Uesugi, M.

Publications and source records attributed to Uesugi, M..

3 recordsLinked to original sources

bioRxiv2026

Lipid A counteracts doxorubicin-induced systemic dysfunction by boosting mitochondrial activity

Vaccine adjuvants are critical for enhancing immune responses and sustaining antibody production. Although their safety profiles are well established, assessments have largely focused on metabolic and excretory organs such as the liver and kidneys, with limited attention to the heart. Here, we systematically evaluated the cardiac effects of five representative adjuvants in mice: alum, MF59, AS03, Sigma Adjuvant Systems, and lipid A. None of the adjuvants impaired baseline cardiac contractile function. Notably, lipid A uniquely enhanced mitochondrial respiratory capacity in rat and human induced pluripotent stem cell-derived cardiomyocytes and promoted mitochondrial membrane hyperpolarization. We next examined its therapeutic potential in a doxorubicin (Dox)-induced heart failure model characterized by mitochondrial dysfunction. Co-administration of lipid A with influenza hemagglutinin (HA) antigen significantly ameliorated cardiac dysfunction. In parallel, lipid A prevented the Dox-induced decline in anti-HA antibody titers, an effect associated with preservation of splenic B cell populations. Collectively, these findings reveal a previously unappreciated cytoprotective dimension of lipid A, demonstrating that it not only potentiates immune responses but also counteracts chemotherapy-induced functional decline by enhancing mitochondrial activity.

pharmacology and toxicology↗

bioRxiv2025

High efficiency organoid-derived cyst cultures as a drug discovery platform for polycystic kidney disease

Autosomal dominant polycystic kidney disease (ADPKD) causes the slow, progressive formation of fluid-filled cysts within the kidney that ultimately leads to renal failure. Despite being the most common genetic kidney disease, the range of therapies for ADPKD is limited. Ureteric bud (UB) organoids derived from human pluripotent stem cells (hPSCs) have been used to model ADPKD. Here, we describe a protocol to generate UB organoids in large-scale suspension culture that is amenable to drug discovery. When differentiated from PKD2-deficient hPSCs, the UB organoids robustly form cysts within 7 days and reach nearly 100% cyst efficiency within [~]20 days. Cystic UB organoids express ADPKD markers and are responsive to cyst-reducing compounds, such as the BET inhibitor JQ1 and the NF-{kappa}B inhibitor QNZ, but not tolvaptan. As proof-of-principle of the platform as a drug discovery tool, we screened a small molecule library comprised of nutrient conjugates and identified M1, a palmitate-glucosamine-glycine conjugate, that reduced cyst formation. These results demonstrate that our scalable method of cystic UB organoid production provides a simple and highly efficient platform for ADPKD drug discovery. TRANSLATIONAL STATEMENTAutosomal dominant polycystic kidney disease (ADPKD) affects over 12 million people worldwide, yet the currently available therapy tolvaptan only moderately delays disease progression and is burdened with adverse effects. Improved treatments that are well tolerated and effective are urgently needed. We established a human ureteric bud organoid platform that enables ADPKD-like cysts to be cultured at large scale and low cost. These cystic organoids resemble human ADPKD cysts and are suitable for drug discovery. Identification of the nutrient conjugate M1 as a new lead molecule for reducing cyst formation highlights the clinical relevance of this model.

molecular biology↗

bioRxiv2022

Novel gene-intergenic fusion involving ubiquitin E3 ligase UBE3C causes distal hereditary motor neuropathy: A new mechanism for motor neuron degeneration.

Distal hereditary motor neuropathies (dHMNs) are a group of inherited diseases involving the progressive, length-dependent axonal degeneration of the lower motor neurons. There are currently 29 reported causative genes and 4 disease loci implicated in dHMN. Despite the high genetic heterogeneity, mutations in the known genes account for less than 20% of dHMN cases with the mutations identified predominantly being point mutations or indels. We have expanded the spectrum of dHMN mutations with the identification of a 1.35 Mb complex structural variation (SV) causing a form of autosomal dominant dHMN (DHMN1 OMIM %182906). Given the complex nature of SV mutations and the importance of studying pathogenic mechanisms in a neuronal setting, we generated a patient-derived DHMN1 motor neuron model harbouring the 1.35 Mb complex insertion. The DHMN1 complex insertion creates a duplicated copy of the first 10 exons of the ubiquitin-protein E3 ligase gene (UBE3C) and forms a novel gene-intergenic fusion sense transcript by incorporating a terminal pseudo-exon from intergenic sequence within the DHMN1 locus. The UBE3C intergenic fusion (UBE3C-IF) transcript does not undergo nonsense-mediated decay and results in a significant reduction of wild type full length UBE3C (UBE3C-WT) protein levels in DHMN1 iPSC-derived motor neurons. An engineered transgenic C. elegans model expressing the UBE3C-IF transcript in GABA-ergic motor neurons shows neuronal synaptic transmission deficits. Furthermore, the transgenic animals are susceptible to heat stress which may implicate defective protein homeostasis underlying DHMN1 pathogenesis. Identification of the novel UBE3C-IF gene-intergenic fusion transcript in motor neurons highlights a potential new disease mechanism underlying axonal and motor neuron degeneration. These complementary models serve as a powerful paradigm for studying the DHMN1 complex SV and an invaluable tool for defining therapeutic targets for DHMN1.

neuroscience↗