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Introduction Establishing a scale that can easily be used to appropriately measure the impact of constipation on the quality of life in Japan is a first step toward addressing this important health issue. We developed a Japanese language version of the Constipation-Related Quality of Life scale, which has 18 items and four subscales, and then subjected it to validation testing. Methods After translation according to a standardized and commonly used procedure, the Japanese version of the Constipation-Related Quality of Life scale was administered to people in an internet-based panel, in March 2023. The participants included 1,276 adults who had constipation (median age: 60 years, 690 {54.1%} males). The outcome measures included the Constipation-Related Quality of Life scale, the Constipation Scoring System (an index of constipation severity), and the Medical Outcomes Study (MOS) eight-item short form (a measure of generic health-related quality of life). Results Confirmatory factor analysis (four-factor model) indicated that all 18 Constipation-Related Quality of Life items had sufficiently high factor loadings (0.686-0.926). Internal consistency reliability was high (Cronbach's alpha: 0.86-0.94). Scores on the social impairment subscale and on the distress subscale of the Constipation-Related Quality of Life scale were significantly worse in the participants who had worse scores on the social functioning and mental health domains, respectively, of the MOS eight-item short form, which indicates good concurrent validity. Regarding criterion-based validity, the four subscale scores differed significantly among the four constipation-severity groups. The four subscale scores were also 1.16-4.53 times more sensitive than the MOS eight-item short form's mental component score to differences among the four constipation-severity groups (relative validity: 1.16-4.53), which indicates good discriminant validity. Conclusion The Japanese version of the Constipation-Related Quality of Life scale can be used with confidence in its factor structure, its concurrent, criterion-based, and discriminant validity, and its internal consistency reliability.

Hepatocyte death is associated with liver inflammation, fibrosis and hepatocellular carcinoma (HCC). Damaged cells trigger inflammation through activation of Toll-like receptors (TLRs). Although the role of TLR4 in HCC development has been reported, the role of TLR9 in the development of HCC remains elusive. To investigate the role of TLR4 and TLR9 signaling in liver inflammation-fibrosis-cancer axis, we took advantage of mice with hepatic deletion of transforming growth factor-β-activated kinase 1 (Tak1ΔHep) that develop spontaneous liver injury, inflammation, fibrosis, and HCC, recapitulating the pathology of human HCC. We generated double knockout mice lacking genes of our interest with hepatic Tak1. Tak1ΔHep mice and Tlr4-deficient Tak1ΔHep mice had similar serum ALT levels, but Tlr4-deficient Tak1ΔHep mice exhibited significantly reduced macrophage infiltration, myofibroblast activation and tumor formation. Ablation of TLR9 reduced spontaneous liver injury, inflammation, fibrosis, and cancer development in Tak1ΔHep mice. In addition, the common adaptor, myeloid differentiation factor 88 (MyD88)-deficient Tak1ΔHep mice also attenuated liver injury, macrophage recruitment, collagen deposition, and tumor growth compared with control Tak1ΔHep mice. Genetic ablation of TNF receptor type I (TNFR) in Tak1ΔHep mice remarkably reduced liver inflammation-fibrosis-cancer axis. Surprisingly, disruption of interleukin-1 receptor (IL-1R) had no effect on liver injury and tumor formation, although Il1r-deficient Tak1ΔHep showed attenuated macrophage infiltration and collagen deposition. In conclusion, TLR4- and TLR9-MyD88 are driving forces of progression to HCC accompanied by liver inflammation and fibrosis in Tak1ΔHep mice. Importantly, TLR4 and TLR9 downstream TNFR, but not IL-1R signaling is crucial for the development of HCC in Tak1ΔHep mice.

The MAP kinase kinase kinase TGFβ-activated kinase 1 (TAK1) is activated by TLRs, IL-1, TNF, and TGFβ and in turn activates IKK-NF-κB and JNK, which regulate cell survival, growth, tumorigenesis, and metabolism. TAK1 signaling also upregulates AMPK activity and autophagy. Here, we investigated TAK1-dependent regulation of autophagy, lipid metabolism, and tumorigenesis in the liver. Fasted mice with hepatocyte-specific deletion of Tak1 exhibited severe hepatosteatosis with increased mTORC1 activity and suppression of autophagy compared with their WT counterparts. TAK1-deficient hepatocytes exhibited suppressed AMPK activity and autophagy in response to starvation or metformin treatment; however, ectopic activation of AMPK restored autophagy in these cells. Peroxisome proliferator-activated receptor α (PPARα) target genes and β-oxidation, which regulate hepatic lipid degradation, were also suppressed in hepatocytes lacking TAK1. Due to suppression of autophagy and β-oxidation, a high-fat diet challenge aggravated steatohepatitis in mice with hepatocyte-specific deletion of Tak1. Notably, inhibition of mTORC1 restored autophagy and PPARα target gene expression in TAK1-deficient livers, indicating that TAK1 acts upstream of mTORC1. mTORC1 inhibition also suppressed spontaneous liver fibrosis and hepatocarcinogenesis in animals with hepatocyte-specific deletion of Tak1. These data indicate that TAK1 regulates hepatic lipid metabolism and tumorigenesis via the AMPK/mTORC1 axis, affecting both autophagy and PPARα activity.