荒木 琢磨

BACKGROUND: The liver is a central organ involved in lipid metabolism. Hepatocytes synthesize fatty acids and triglycerides under conditions of excess energy while decomposing fats by β-oxidation under conditions of energy deficiency. When fatty acid metabolism is impaired due to metabolic syndrome, excessive lipid accumulation in the liver increases the risk of fatty liver disease, chronic hepatitis, and liver cancer. Excessive fat accumulation causes various types of cell damage, such as oxidative stress, which causes lipotoxicity. There is a difference in lipotoxicity between saturated and unsaturated fatty acids among various fatty acids, and saturated fatty acids are more toxic. However, there are still many unknowns about the role of unsaturated fatty acids in steatohepatitis remains unclear. METHODS: In the present study, we evaluated the lipotoxicity of saturated and unsaturated fatty acids in a human induced pluripotent stem (iPS) cell-derived hepatocyte culture system. After inducing the differentiation of hepatic progenitor cells and hepatocytes from human iPS cells, palmitic and oleic acids were added. Tunicamycin and thapsigargin were added to induce endoplasmic reticulum (ER) stress. Cell viability and gene expression were analyzed. RESULTS: When a saturated fatty acid (palmitic acid) was added to human iPS cell-derived hepatocytes, fatty acids alone induced cell death and expression of ER stress-related factors. However, unsaturated fatty acids (such as oleic acid) alone do not exhibit such activity. When oleic acid and ER stress inducers (tunicamycin and thapsigargin) were added simultaneously, strong induction of cell death was observed. Furthermore, the addition of unsaturated fatty acids and the induction of ER stress strongly suppressed the expression of enzymes in the fatty acid synthesis system. These results indicated that saturated fatty acid accumulation induced ER stress, whereas unsaturated fatty acid accumulation alone did not induce ER stress. CONCLUSION: The combination of unsaturated fatty acid accumulation and ER stress induces hepatocyte death, thus indicating the importance of endoplasmic reticulum stress in the process of fatty acid-induced cell death. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12876-026-04616-9.

The mutation of the X-linked protocadherin (PCDH) 19 gene in heterozygous females causes epilepsy. However, because of the erosion of X-chromosome inactivation (XCI) in female human pluripotent stem cells, precise disease modeling often leads to failure. In this study, using a mathematical approach and induced pluripotent stem cells retaining XCI derived from patients with PCDH19 missense mutations, we found that heterotypic conditions, which are composed of wild-type and missense PCDH19, led to significant cell-to-cell proximity and impaired neuronal differentiation, accompanied by the aberrant accumulation of doublecortin, a microtubule-associated protein. Our findings suggest that ease of adhesion between cells expressing either wild-type or missense PCDH19 might lead to aberrant cell aggregation in early embryonic phases, causing poor neuronal development.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the accumulation of extracellular amyloid-beta peptides (Aβ) resulting in senile plaques and intracellular hyperphosphorylated tau protein resulting in neurofibrillary tangles (NFTs). Mucuna beans (Mucuna pruriences (L.) DC. var. utilis) are unique plants containing 3-9% L-3,4-dihydroxyphenylalanine (L-DOPA). Here we investigated the effect of the administration of Mucuna beans on AD prevention by feeding triple-transgenic mice (3 × Tg-AD mice) with a diet containing Mucuna beans for 13 months. The levels of Aβ oligomers and detergent-insoluble phosphorylated tau decreased in the brain of mice fed with Mucuna beans (Mucuna group) compared to those of the Control group. Aβ accumulation and phosphorylated tau accumulation in the brain in the Mucuna group were also reduced. In addition, administration of Mucuna beans improved cognitive function. These results suggest that administration of Mucuna beans may have a preventive effect on AD development in 3 × Tg-AD mice.

Epstein-Barr virus (EBV) causes malignant carcinomas including B cell lymphomas accompanied by the systemic inflammation. Previously, we observed that phosphatidylserine (PS)-exposing subset of extracellular vesicles (EVs) secreted from an EBV strain Akata-transformed lymphoma (Akata EVs) convert surrounding phagocytes into tumor-associated macrophages (TAMs) via induction of inflammatory response, which is in part mediated by EBV-derived micro RNAs. However, it is still unclear about EV-carried other potential inflammatory factors associated with TAM formation in EBV lymphomas. To this end, we sought to explore proteomic and phospholipidomic profiles of PS-exposing EVs derived from EBV-transformed lymphomas. Mass spectrometric analysis revealed that several immunomodulatory proteins including integrin αLβ2 and fibroblast growth factor 2 (FGF2) were highly expressed in PS-exposing Akata EVs compared with another EBV strain B95-8-transformed lymphoma-derived counterparts which significantly lack TAM-inducing ability. Pharmacological inhibition of either integrin αLβ2 or FGF2 hampered cytokine induction in monocytic cultured cells elicited by PS-exposing Akata EVs, suggesting the involvement of these proteins in EV-mediated TAM induction in EBV lymphomas. In addition, phospholipids containing precursors of immunomodulatory lipid mediators were also enriched in PS-exposing Akata EVs compared with B95-8 counterparts. Phospholipidomic analysis of fractionated Akata EVs by density gradient centrifugation further demonstrated that PS-exposing Akata EVs might be identical to certain Akata EVs in low density fractions containing exosomes. Therefore, we concluded that a variety of immunomodulatory cargo molecules in a certain EV subtype are presumably conducive to the development of EBV lymphomas.