Cancer cachexia is associated with poor clinical outcomes in lung cancer patients; however, its economic impact in Japan remains largely uncharacterized. This study quantified the incremental healthcare costs associated with cachexia in Japanese lung cancer patients using nationwide claims data. We conducted a retrospective cohort study using the Japan Medical Data Center Claims Database. Deceased lung cancer patients were classified into cachexia (n = 447) and control (n = 10464) groups based on International Classification of Diseases, 10th Revision diagnosis codes. Between-group cost differences were assessed using generalized linear models with a gamma distribution, adjusting for survival time, demographics, histology, metastasis, and comorbidities. Within-patient cost changes were analyzed using fixed-effects regression, comparing 6-month periods before and after cachexia diagnosis. Cachexia was independently associated with 13.5% higher total medical costs (rate ratio: 1.14, 95% confidence interval [CI]: 1.06–1.21, p < 0.001). Within-patient analysis demonstrated a 57.9% cost increase in the month of diagnosis (from ¥371360 to ¥586405), with costs remaining 21.7% elevated post-diagnosis. Cost composition shifted from procedures (1.3 vs. 5.4%) toward home care (8.6 vs. 5.7%) in cachexia patients. Median survival following cachexia diagnosis was only 1.0 month, with 71% of patients dying within 3 months. Anamorelin use increased from 2.4 to 29.8% post-diagnosis, although 70.2% of patients did not receive this therapy. Cachexia diagnosis in lung cancer patients is associated with substantial cost increases in Japan. The extremely short survival after diagnosis and the shift toward supportive care highlight the need for earlier recognition and intervention. These findings provide essential data for the economic evaluation of cachexia therapies.

Muscle atrophy induced by prolonged inactivity (disuse), including denervation-induced atrophy, is accompanied by oxidative stress, inflammation, and dysregulated protein turnover, yet no effective pharmacological therapy is currently available. Cannabidiol (CBD), a non-psychoactive phytocannabinoid derived from Cannabis sativa, has been reported to exhibit anti-inflammatory and antioxidant properties; however, its potential involvement in disuse-related muscle atrophy has not been fully characterized. In this study, to evaluate the potential effects of CBD on disuse-related muscle atrophy, we employed both in vivo and in vitro models. A mouse model of sciatic nerve resection–induced muscle atrophy was used for the in vivo experiments, while C2C12 myotubes were utilized for the in vitro analyses. In the denervated mouse model, CBD attenuated the decrease in muscle mass in the tibialis anterior and gastrocnemius muscles, as well as the decline in treadmill running performance. CBD also reduced oxidative stress and suppressed the denervation-induced upregulation of Atrogin-1 and muscle RING-finger 1 (MuRF1) proteins, as well as tumor necrosis factor-α (TNF-α) mRNA. Furthermore, CBD partially restored the decreased mitochondrial markers observed following denervation. In vitro, CBD similarly suppressed MuRF1 and Atrogin-1 protein levels and TNF-α mRNA expression in C2C12 myotubes. These findings suggest that CBD is associated with protective effects against disuse-related muscle atrophy, accompanied by reductions in oxidative stress markers, alterations in proteolytic pathways, and changes in mitochondrial-related markers. This study highlights a previously underexplored biological effect of a natural phytocannabinoid and supports further investigation of CBD as a potential supportive strategy for disuse-related muscle wasting.

Magnesium deficiency (MgD) disrupts numerous physiological processes, yet its specific impact on in vivo glucose homeostasis remains unclear. This study investigated the longitudinal effects of MgD on blood glucose dynamics in freely moving rats using continuous glucose monitoring. Animals were maintained on a 2–3-week MgD or Control diet under two conditions: access to standard drinking water or a 10% glucose solution. Under standard drinking water conditions, MgD rats exhibited significantly lower mean blood glucose levels specifically during the quiescent day phase, although nonlinear fluctuation patterns remained comparable to those of controls. Conversely, when provided with the glucose solution, MgD rats increased fluid intake, exhibiting a behavioral compensation that normalized mean glucose levels despite the hypoglycemic tendency. However, detailed time-series analysis utilizing recurrence plots revealed that this compensation coincided with altered dynamics; MgD rats exhibited significant impairment in the periodicity of glucose fluctuations during the day phase under the glucose-challenge condition, indicating disrupted blood glucose homeostasis. These findings suggest that chronic MgD lowers baseline glucose levels, potentially via enhanced insulin secretion, thereby further compromising glucose stability under metabolic challenge. This study highlights the important role of magnesium (Mg) in maintaining circadian glucose rhythmicity and pancreatic functional integrity. Consequently, we propose the synergistic application of Mg assays and continuous glucose monitoring as biomarkers for metabolic disorders.

We recently demonstrated that aromatic (ar)-turmerone analogs ((E)-5-methyl-1-(p-tolyl)hexa-1,4-dien-3-one [A2] and (E)-1-(4-methoxyphenyl)-5-methylhexa-1,4-dien-3-one [A4]) activate chaperone-mediated autophagy (CMA), a pathway in the autophagy-lysosome protein degradation system, in SH-SY5Y cells. Our previous studies revealed that the impairment of CMA and microautophagy (mA), another autophagy-related pathway, and dendritic shrinkage were observed in primary cultured Purkinje cells (PCs) expressing causal proteins of spinocerebellar ataxia (SCA), an autosomal dominant neurodegenerative disease. In the present study, we first investigated the effects of A2 and A4 on lysosomal protein degradation and dendritic morphology in cerebellar primary cultured PCs. Both compounds enhanced dendritic development and activated CMA in cultured PCs. These effects were significantly suppressed by the inhibitors of nuclear factor erythroid 2-related factor 2 and p38. We next examined the effects of A2 and A4 on PCs expressing several types of SCA-causing proteins (SCA model PCs). Both chemicals ameliorated the dendritic shrinkage and restored the decreased CMA/mA activity in several SCA model PCs. These findings suggest that the ar-turmerone analogs A2 and A4 improve the in vitro phenotype of SCA model PCs through CMA activation, highlighting the therapeutic potential of these analogs for various types of SCAs.

Mitochondrial L-2-hydroxyglutarate dehydrogenase (L2HGDH) is a FAD-containing membrane protein that oxidizes L-2-hydroxyglutarate (L-2-HG) to 2-oxoglutarate (2-OG). L2HGDH dysfunction is associated with human diseases, such as neurometabolic disorders and cancer. Recently, the first crystal structure of Drosophila melanogaster L2HGDH (DmL2HGDH) bound with FAD and 2-OG was reported. Structural analysis, together with mutagenesis and activity measurements, revealed the oxidation mechanism of L-2-HG. However, the physiologically relevant electron acceptor has not yet been elucidated. While bacterial L2HGDH has been proposed to reduce ubiquinone, this remains controversial. To understand the full reaction mechanism of L2HGDH, identification of the electron acceptor and characterization of its interaction with the enzyme are necessary. In this study, we demonstrate that DmL2HGDH transfers electrons from L-2-HG to decylubiquinone, a ubiquinone analog that is sparingly soluble in aqueous buffers and used for in vitro studies. The reaction was moderately inhibited by ferulenol, which inhibits some quinone reductases, including the homologous enzyme malate–quinone oxidoreductase (MQO). Interestingly, the observed kinetic behavior differs from that of MQO. Using AlphaFold3 and molecular dynamics, we provide insights into the interaction between DmL2HGDH and ubiquinone and propose a mechanism for ubiquinone reduction.