Intramuscular adipose tissue (IMAT) formation derived from muscle fibro-adipogenic progenitors (FAPs) has been recognized as a pathological feature of sarcopenia. This study aimed to explore whether g Show more
Intramuscular adipose tissue (IMAT) formation derived from muscle fibro-adipogenic progenitors (FAPs) has been recognized as a pathological feature of sarcopenia. This study aimed to explore whether genetic and pharmacological gastric inhibitory polypeptide (GIP) receptor antagonism suppresses IMAT accumulation and ameliorates sarcopenia in mice. Whole body composition, grip strength, skeletal muscle weight, tibialis anterior (TA) muscle fibre cross-sectional area (CSA) and TA muscle IMAT area were measured in young and aged male C57BL/6 strain GIP receptor (Gipr)-knockout (Gipr Body composition analysis revealed that 104-week-old Gipr GIP promotes the differentiation of muscle FAPs into adipocytes and its receptor antagonism suppresses IMAT accumulation and promotes muscle regeneration. Pharmacological GIP receptor antagonism may serve as a novel therapeutic approach for sarcopenia. Show less
The interleukin-6 (IL-6)/IL-12 family of cytokines plays critical roles in the induction and regulation of innate and adaptive immune responses. Among the various cytokines, only this family has the u Show more
The interleukin-6 (IL-6)/IL-12 family of cytokines plays critical roles in the induction and regulation of innate and adaptive immune responses. Among the various cytokines, only this family has the unique characteristic of being composed of two distinct subunits, α- and β-subunits, which form a heterodimer with subunits that occur in other cytokines as well. Recently, we found a novel intracellular role for one of the α-subunits, Epstein-Barr virus-induced gene 3 (EBI3), in promoting the proper folding of target proteins and augmenting its expression at the protein level by binding to its target protein and a well-characterized lectin chaperone, calnexin, presumably through enhancing chaperone activity. Because calnexin is ubiquitously and constitutively expressed but EBI3 expression is inducible, these results could open an avenue to establish a new paradigm in which EBI3 plays an important role in further increasing the expression of target molecules at the protein level in collaboration with calnexin under inflammatory conditions. This theory well accounts for the heterodimer formation of EBI3 with p28, and probably with p35 and p19 to produce IL-27, IL-35, and IL-39, respectively. In line with this concept, another β-subunit, p40, plays a critical role in the assembly-induced proper folding of p35 and p19 to produce IL-12 and IL-23, respectively. Thus, chaperone-like activities in proper folding and maturation, which allow the secretion of biologically active heterodimeric cytokines, have recently been highlighted. This review summarizes the current understanding of chaperone-like activities of EBI3 to form heterodimers and other associations together with their possible biological implications. Show less
Valproic acid, which is widely used to treat various types of epilepsy, may cause severe hyperammonemia. However, the mechanism responsible for this side effect is not readily apparent. Polymorphisms Show more
Valproic acid, which is widely used to treat various types of epilepsy, may cause severe hyperammonemia. However, the mechanism responsible for this side effect is not readily apparent. Polymorphisms in the genes encoding carbamoyl-phosphate synthase 1 (CPS1) and N-acetylglutamate synthase (NAGS) were recently reported to be risk factors for the development of hyperammonemia during valproic acid-based therapy. This study aimed to examine the influence of patient characteristics, including polymorphisms in CPS1 4217C>A and NAGS -3064C>A, on the development of hyperammonemia in Japanese pediatric epilepsy patients. The study included 177 pediatric epilepsy patients. The presence of a 4217C>A polymorphism in CPS1 was determined using an allele-specific polymerase chain reaction (PCR)-based method, and the presence of a -3064C>A polymorphism in NAGS was determined using a PCR-based restriction fragment length polymorphism method. Hyperammonemia was defined as a plasma ammonia level exceeding 200 μg/dL. We observed a significant difference between the combination of valproic acid with phenytoin and the development of hyperammonemia in both univariate and multivariate analyses. With regard to the CPS1 4217C>A polymorphism, we did not observe a significant association with the development of hyperammonemia. In conclusion, CPS1 4217C>A polymorphism may not be associated with the development of hyperammonemia in Japanese population. Show less