Chronic inflammation causes muscle wasting. Because most inflammatory cytokine signals are mediated via TGF-β-activated kinase-1 (TAK1) activation, inflammatory cytokine-induced muscle wasting may be ameliorated by the inhibition of TAK1 activity. The present study was undertaken to clarify whether TAK1 inhibition can ameliorate inflammation-induced muscle wasting. SKG/Jcl mice as an autoimmune arthritis animal model were treated with a small amount of mannan as an adjuvant to enhance the production of TNF-α and IL-1β. The increase in these inflammatory cytokines caused a reduction in muscle mass and strength along with an induction of arthritis in SKG/Jcl mice. Those changes in muscle fibers were mediated via the phosphorylation of TAK1, which activated the downstream signaling cascade via NF-κB, p38 MAPK, and ERK pathways, resulting in an increase in myostatin expression. Myostatin then reduced the expression of muscle proteins not only via a reduction in MyoD1 expression but also via an enhancement of Atrogin-1 and Murf1 expression. TAK1 inhibitor, LL-Z1640-2, prevented all the cytokine-induced changes in muscle wasting. Thus, TAK1 inhibition can be a new therapeutic target of not only joint destruction but also muscle wasting induced by inflammatory cytokines.

Xanthine oxidoreductase (XOR) is a rate-limiting enzyme in purine catabolism that acts as a novel regulator of adipogenesis. In pathological states, xanthine oxidoreductase activity increases to produce excess reactive oxygen species (ROS). The nuclear factor erythroid 2-related factor 2 (Nrf2) is a critical inducer of antioxidants, which is bound and repressed by a kelch-like ECH-associated protein 1 (Keap1) in the cytoplasm. The Keap1-Nrf2 axis appears to be a major mechanism for robust inducible antioxidant defenses. Here, we demonstrate that febuxostat, a xanthine oxidase inhibitor, alleviates the increase in adipose tissue mass in obese mouse models with a high-fat diet or ovariectomy. Febuxostat disrupts in vitro adipocytic differentiation in adipogenic media. Adipocytes appeared at day 7 in absence or presence of febuxostat were 160.8 ± 21.2 vs. 52.5 ± 12.7 (p < 0.01) in 3T3–L1 cells, and 126.0 ± 18.7 vs. 55.3 ± 13.4 (p < 0.01) in 10T1/2 cells, respectively. Adipocyte differentiation was further enhanced by the addition of hydrogen peroxide, which was also suppressed by febuxostat. Interestingly, febuxostat, but not allopurinol (another xanthine oxidase inhibitor), rapidly induced the nuclear translocation of Nrf2 and facilitated the degradation of Keap1, similar to the electrophilic Nrf2 activator omaveloxolone. These results suggest that febuxostat alleviates adipogenesis under oxidative conditions, at least in part by suppressing ROS production and Nrf2 activation. Regulation of adipocytic differentiation by febuxostat is expected to inhibit obesity due to menopause or overeating.

Objective : To examine diagnostic performance of corticotropin-releasing hormone (CRH) test combined with baseline dehydroepiandrosterone sulfate (DHEA-S) in patients with a suspect of central adrenal insufficiency. Methods : Patients (n=215) requiring daily or intermittent hydrocortisone replacement, or no replacement were retrospectively checked with their peak cortisol after CRH test and baseline DHEA-S. Results : None of 106 patients with the peak cortisol ≥ 17.5 µg / dL after CRH test required replacement, and all 64 patients with the peak cortisol < 10.0 µg / dL required daily replacement. Among 8 patients with 10.0 µg / dL ≤ the peak cortisol < 17.5 µg / dL and baseline DHEA-S below the reference range, 6 patients required daily replacement and 1 patient was under intermittent replacement. Among 37 patients with 10.0 µg / dL ≤ the peak cortisol < 17.5 µg / dL and baseline DHEA-S within the reference range, 10 and 6 patients were under intermittent and daily replacement, respectively. Conclusions : No patients with the peak cortisol ≥ 17.5 µg / dL required hydrocortisone replacement, and all patients with the peak cortisol below 10.0 µg / dL required daily replacement. Careful clinical evaluation was required to determine requirement for replacement in patients with 10.0 µg / dL ≤ the peak cortisol < 17.5 µg / dL even in combination with baseline DHEA-S. J. Med. Invest. 69 : 287-293, August, 2022

It has previously been unclear whether the accumulation of advanced glycation end products, which can be measured using skin autofluorescence (SAF), has a significant role in diabetic kidney disease (DKD), including glomerular injury and tubular injury. This study was therefore carried out to determine whether SAF correlates with the progression of DKD in people with type 2 diabetes (T2D). In 350 Japanese people with T2D, SAF values were measured using an AGE Reader^®, and both urine albumin-to-creatinine ratio (uACR), as a biomarker of glomerular injury, and urine liver-type fatty acid-binding protein (uLFABP)-to-creatinine ratio (uL-FABPCR), as a biomarker of tubular injury, were estimated as indices of the severity of DKD. Significant associations of SAF with uACR (p < 0.01), log-transformed uACR (p < 0.001), uL-FABPCR (p < 0.001), and log-transformed uL-FABPCR (p < 0.001) were found through a simple linear regression analysis. Although SAF was positively associated with increasing uL-FABPCR (p < 0.05) and increasing log-transformed uL-FABPCR (p < 0.05), SAF had no association with increasing uACR or log-transformed uACR after adjusting for clinical confounding factors. In addition, the annual change in SAF showed a significant positive correlation with annual change in uL-FABPCR regardless of confounding factors (p = 0.026). In conclusion, SAF is positively correlated with uL-FABP but not with uACR in people with T2D. Thus, there is a possibility that SAF can serve as a novel predictor for the development of diabetic tubular injury.

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) causes progressive liver fibrosis. Although erythrocyte mean corpuscular volume (MCV) has been shown to have a positive correlation with all-cause mortality, the association between MCV and the development of MASLD has not been fully elucidated. Here, we examined the clinical significance of the association between MCV and MASLD. Methods: A cross-sectional study was carried out in 1009 Japanese individuals (including 186 individuals aged < 60 years and 823 individuals aged ≥ 60 years) with metabolic disorders. The relationships between MCV and noninvasive clinical markers of liver fibrosis, including fibrosis-4 (FIB-4) index, aspartate aminotransferase-to-platelet ratio index (APRI), and non-alcoholic fatty liver disease (NAFLD) fibrosis score (NFS), were statistically evaluated. Results: Using multiple and logistic regression analyses in overall subjects, it was found that MCV was positively and independently associated with the values of FIB-4 index, APRI, NFS, and the prevalence of liver fibrosis defined by each index. However, the associations between the MCV value and MASLD indices were found to be positive in subjects aged ≥ 60 years but not in those aged < 60 years. Conclusions: MCV might be a simple and useful biomarker for the development of MASLD in the elderly.

Dehydroepiandrosterone sulfate (DHEAS) is thought to be associated with life expectancy and anti-aging. Although skeletal muscle disorders are often found in diabetic people, the clinical significance of DHEAS in skeletal muscle remains unclear. Therefore, we aimed to determine whether DHEAS is associated with the development of skeletal muscle disorders in individuals with type 2 diabetes (T2D). A cross-sectional study was conducted in 361 individuals with T2D. Serum DHEAS levels, skeletal muscle mass index (SMI), handgrip strength (HS), and gait speed (GS) were measured in the participants. Pre-sarcopenia, sarcopenia, and dynapenia were defined according to the definitions of the AWGS 2019 criteria. DHEAS level was positively associated with HS but not with SMI or GS after adjustment of confounding factors. Multiple logistic regression analyses in total subjects showed that DHEAS level had an inverse association with the prevalence of dynapenia but not with the prevalence of pre-sarcopenia or sarcopenia. Furthermore, a significant association between DHEAS level and dynapenia was found in males but not in females. ROC curve analysis indicated that cutoff values of serum DHEAS for risk of dynapenia in males was 92.0 μg/dL. Therefore, in male individuals with T2D who have low serum levels of DHEAS, adequate exercise might be needed to prevent dynapenia.