笹倉 寛之

Abstract <p> Pyrroloquinoline quinone (PQQ) is a multifunctional natural coenzyme that plays important roles in innate immunity, nutritional physiology, and redox biology, including the activation of dual oxidases (DUOXs). Although native PQQ has been extensively studied, the biological consequences of its chemical modification remain poorly understood. Here, we synthesized several PQQ derivatives and identified PQQMe, a monomethyl ester derivative that activates DUOX more potently than native PQQ, even at low concentrations. PQQMe induced rapid lethality in C. elegans , as well as internal hatching resulting from severe defects in the egg-laying apparatus, a phenotype that occurred independently of DUOX. This outcome contrasted sharply with the lifespan-extending effects observed with native PQQ and its prodrug derivative, the acetone adduct ACTPQQ, indicating that esterification profoundly reshapes the biological activity spectrum of PQQ. Despite its pronounced biological effects, PQQMe exhibited greater tolerability than PQQ in mammalian cells and mice. Together, these findings identify PQQMe as a chemically modified PQQ derivative that enhances DUOX activation and induces a distinct lethal phenotype in C. elegans , suggesting that chemical modification of a multifunctional coenzyme is a useful strategy for inducing new biological functions. </p>

Patients undergoing long-term peritoneal dialysis (PD) frequently develop peritoneal fibrosis and angiogenesis, leading to membrane dysfunction. Transglutaminase 2 (TG2) stabilizes the extracellular matrix against proteases. In an animal model, inhibition of TG2 reduced peritoneal fibrosis, angiogenesis, and inflammation. We investigated the expression of TG2 in 163 human peritoneal membrane tissue samples, including controls, tissues exposed to conventional acidic or low-glucose degradation product (GDP) pH-neutral solutions, and those with peritonitis or encapsulating peritoneal sclerosis (EPS), and explored the role of TG2 in high-glucose-induced pathophysiology in mesothelial cells. TG2 expression was upregulated in association with peritoneal membrane injury and was the highest in peritonitis. TG2 expression was correlated with peritoneal membrane thickness, CD68-positive macrophages, and myofibroblast expression. TG2 was expressed in mesothelial cells, α-smooth muscle actin-positive myofibroblast expression, macrophages, and endothelial cells in the diseased state. In cultured mesothelial cells, high-glucose-induced upregulation of collagen 1, TGF-β1, and TG2 was suppressed by a TG2 inhibitor or by TGF-β1 small interfering RNA. TG2 is involved in the development of peritoneal injury during PD. High-glucose dialysate is involved in the induction of peritoneal fibrosis through the interactive regulation of TGF-β and TG2. Targeting TG2 may offer therapeutic potential for managing PD complications and EPS.

The trigeminal spinal tract nucleus receives primary afferent input from the orofacial region, serving as a relay between peripheral terminals and secondary neurons. The trigeminal nerve is divided into ophthalmic, maxillary, and mandibular. While it is known that primary afferent terminals synapse with secondary neurons, the interaction between different primary terminals remains unclear. Recent studies have shown that trigeminal neurons with lost input can be activated through electrical stimulation of other afferent terminals. Therefore, we examined the possibility of inducing neural activity using synaptic organizers to promote circuit reorganization. To assess the regeneration of the injured inferior alveolar nerve (third division of the trigeminal nerve), the potential involvement of input from the infraorbital nerve (second division of the trigeminal nerve) in the regeneration of the injured inferior alveolar nerve (third division of the trigeminal nerve) was investigated. Intact and injured groups were created for the second and third divisions to facilitate comparative analysis. A synapse organizer was applied to establish input between the primary afferent terminals of these divisions. This study aimed to determine if central connections between different terminals can activate trigeminal neurons with lost input, ultimately promoting peripheral nerve regeneration. In this research, male C57BL/6J mice (seven to nine weeks old) (total n=40) underwent transection of the inferior alveolar nerve. They were divided into three groups: intact (n=10), injured (saline control) (n=10), and synapse organizer (n=10). In addition, the mice were divided into two groups: one group underwent inferior alveolar nerve transection only (II, intact; III, injured, n=5), and the other group underwent transection of both the infraorbital and inferior alveolar nerves (II, injured; III, injured, n=5), followed by local administration of a synapse organizer. Regeneration was assessed using immunostaining, sensory tests, and retrograde tracing. Regeneration was confirmed by retrograde tracing and functional recovery of sensory thresholds in the skin of the mental region. These findings align with previous observations that infraorbital nerve transection reduced regeneration activity, suggesting that infraorbital input triggered regeneration in the mandibular nerve. Thus, the results propose a novel therapeutic approach where mandibular nerve injury can be treated by stimulating the infraorbital nerve immediately after injury, enhancing peripheral nerve regeneration.

Chondroitin extends lifespan and healthspan in C. elegans, but the relationship between extracellular chondroitin and intracellular anti-aging mechanisms is unknown. The basement membrane (BM) that contains chondroitin proteoglycans is anchored to cells via hemidesmosomes (HDs), and it accumulates damage with aging. In this study, we found that chondroitin regulates aging through the formation of HDs and inhibition of tubular lysosomes (TLs). Reduction of chondroitin due to a mutation in sqv-5/Chondroitin synthase (ChSy) causes the earlier and excessive formation of TLs and leakage of the lysosomal nuclease in a manner dependent on VHA-7, the a-subunit of V-type ATPase. VHA-7, whose mutation suppresses the short lifespan of the sqv-5 mutant, is initially localized to the basal side of the hypodermal cells and transported to lysosomes with aging. These results demonstrate that endogenous chondroitin suppresses aging by inhibiting the earlier excessive formation of TLs. This is a novel anti-aging mechanism that is controlled by the BM.

Chondroitin, a class of glycosaminoglycan polysaccharides, is found as proteoglycans in the extracellular matrix, plays a crucial role in tissue morphogenesis during development and axonal regeneration. Ingestion of chondroitin prolongs the lifespan of C. elegans. However, the roles of endogenous chondroitin in regulating lifespan and healthspan mostly remain to be investigated. Here, we demonstrate that a gain-of-function mutation in MIG-22, the chondroitin polymerizing factor (ChPF), results in elevated chondroitin levels and a significant extension of both the lifespan and healthspan in C. elegans. Importantly, the remarkable longevity observed in mig-22(gf) mutants is dependent on SQV-5/chondroitin synthase (ChSy), highlighting the pivotal role of chondroitin in controlling both lifespan and healthspan. Additionally, the mig-22(gf) mutation effectively suppresses the reduced healthspan associated with the loss of MIG-17/ADAMTS metalloprotease, a crucial for factor in basement membrane (BM) remodeling. Our findings suggest that chondroitin functions in the control of healthspan downstream of MIG-17, while regulating lifespan through a pathway independent of MIG-17.