Activation of the IKK2/NF-κB pathway in VSMCs inhibits calcified vascular stiffness in CKD.

IKK2/NF-κB pathway-mediated inflammation in vascular smooth muscle cells (VSMCs) has been proposed to be an etiologic factor in medial calcification and stiffness. However, the role of the IKK2/NF-κB pathway in medial calcification remains to be elucidated. In this study, we found that chronic kidney disease (CKD) induces inflammatory pathways through the local activation of the IKK2/NF-κB pathway in VMSCs associated with calcified vascular stiffness. Despite reducing the expression of inflammatory mediators, complete inhibition of the IKK2/NF-κB pathway in vitro and in vivo unexpectedly exacerbated vascular mineralization and stiffness. In contrast, activation of NF-κB by SMC-specific IκBα deficiency attenuated calcified vascular stiffness in CKD. Inhibition of the IKK2/NF-κB pathway induced cell death of VSMCs by reducing anti-cell death gene expression, whereas activation of NF-κB reduced CKD-dependent vascular cell death. In addition, increased calcification of extracellular vesicles through the inhibition of the IKK2/NF-κB pathway induced mineralization of VSMCs, which was significantly reduced by blocking cell death in vitro and in vivo. This study reveals that activation of the IKK2/NF-κB pathway in VSMCs plays a protective role in CKD-dependent calcified vascular stiffness by reducing the release of apoptotic calcifying extracellular vesicles.

Investigation of Amino Acid and Fatty Acid Profiles of Japanese Diets Using the Food Exchange Lists for Diabetes Diet.

Dietary Reference Intakes for Japanese provide target values for proteins, fats, and carbohydrates. However, they do not provide information on reference values for amino acids (AAs) and fatty acids (FAs), which determine the quality of foods in detail. Therefore, we evaluated AAs and FAs using the Food Exchange Lists-Dietary Guidance for Persons with Diabetes (in Japanese) Utilization, Second Edition Sample Menus and Practice (FELD) as an ideal Japanese diet. Based on FELD, 15 different daily meal patterns were employed with combinations of three levels of carbohydrates %energy (high carbohydrate [HC], 60%; middle carbohydrate [MC], 55%; and low carbohydrate [LC], 50%) and five levels of energy (1,200-2,000 kcal). Using the Japanese Food Composition Table 2020 adjusted for 1,000 kcal, 18 AAs, 49 FAs, and calorie densities (CDs, kcal/g) were calculated and compared among the three groups. Dietary AA was rich in glutamic acid, aspartic acid, and leucine; in order, no significant differences were observed among HC, MC, and LC for 18 AAs. Dietary FA was higher for 18:1 total, 16:0, and 18:2 n-6. Moreover, 16:0, 20:0, and 18:1 total in LC and 22:0 and 18:3 n-3 in MC were significantly higher than those in HC. The HC, MC, and LC CD was low at 0.82, 0.84, and 0.93 kcal/g, respectively. No significant differences in 18 AAs and CD were noted among HC, MC, and LC in FELD; however, significant differences were observed in the FA profiles. This study suggests the importance of evaluating diet using AA and FA units.

Elevated luminal inorganic phosphate suppresses intestinal Zn absorption in 5/6 nephrectomized rats.

Zinc (Zn) is an essential trace element in various biological processes. Chronic kidney disease (CKD) often leads to hypozincemia, resulting in further progression of CKD. In CKD, intestinal Zn absorption, the main regulator of systemic Zn metabolism, is often impaired; however, the mechanism underlying Zn malabsorption remains unclear. Here, we evaluated intestinal Zn absorption capacity in a rat model of CKD induced by 5/6 nephrectomy (5/6 Nx). Rats were given Zn and the incremental area under the plasma Zn concentration-time curve (iAUC) was measured as well as the expression of ZIP4, an intestinal Zn transporter. We found that 5/6 Nx rats showed lower iAUC than sham-operated rats, but expression of ZIP4 protein was upregulated. We therefore focused on other Zn absorption regulators to explore the mechanism by which Zn absorption was substantially decreased. Because some phosphate compounds inhibit Zn absorption by coprecipitation and hyperphosphatemia is a common symptom in advanced CKD, we measured inorganic phosphate (Pi) levels. Pi was elevated in not only serum but also the intestinal lumen of 5/6 Nx rats. Furthermore, intestinal intraluminal Pi administration decreased the iAUC in a dose-dependent manner in normal rats. In vitro, increased Pi concentration decreased Zn solubility under physiological conditions. Furthermore, dietary Pi restriction ameliorated hypozincemia in 5/6 Nx rats. We conclude that hyperphosphatemia or excess Pi intake is a factor in Zn malabsorption and hypozincemia in CKD. Appropriate management of hyperphosphatemia will be useful for prevention and treatment of hypozincemia in patients with CKD.NEW & NOTEWORTHY We demonstrated that elevated intestinal luminal Pi concentration can suppress intestinal Zn absorption activity without decreasing the expression of the associated Zn transporter. Increased intestinal luminal Pi led to the formation of an insoluble complex with Zn while dietary Pi restriction or administration of a Pi binder ameliorated hypozincemia in chronic kidney disease model rats. Therefore, modulation of dietary Pi by Pi restriction or a Pi binder might be useful for the treatment of hypozincemia and hyperphosphatemia.

All-trans retinoic acid induces lipophagy through the activation of the AMPK-Beclin1 signaling pathway and reduces Rubicon expression in adipocytes.

Lipophagy is defined as a lipolysis pathway that degrades lipid droplet (LD) via autophagy. All-trans retinoic acid (atRA), a metabolite of vitamin A, stimulates lipolysis through hormone-sensitive lipase and ß-oxidation. However, the regulation of lipolysis by atRA-induced autophagy in adipocytes remains unclear. In this study, we investigated the effect of atRA on autophagy in epididymal fat of mice and the molecular mechanisms of autophagy in 3T3-L1 adipocytes. Western blotting showed that atRA decreased the expression of p62, a cargo receptor for autophagic degradation, and increased the expression of the lipidated LC3B (LC3B-II), an autophagy marker, in epididymal fat. Next, we confirmed that atRA increased autophagic flux in differentiated 3T3-L1 cells using the GFP-LC3-RFP-LC3ΔG probe. Immunofluorescent staining revealed that the colocalization of LC3B with perilipin increased in differentiated 3T3-L1 cells treated with atRA. The knockdown of Atg5, an essential gene in autophagy induction, partly suppressed the atRA-induced release of non-esterified fatty acid (NEFA) from LDs in differentiated 3T3-L1 cells. atRA time-dependently elicited the phosphorylation of AMPK and Beclin1, autophagy-inducing factors, in mature 3T3-L1 adipocytes. Inversely, atRA decreased the protein expression of Rubicon, an autophagy repressor, in differentiated 3T3-L1 cells and epididymal fat. Interestingly, the expression of ALDH1A1, atRA-synthesizing enzymes, increased in epididymal fat with decreased protein expression of Rubicon in aged mice. These results suggest that atRA may partially induce lipolysis through lipophagy by activating the AMPK-Beclin1 signaling pathway in the adipocytes and increased atRA levels may contribute to decreased Rubicon expression in the epididymal fat of aged mice. (248/250 words).

Humoral and cellular factors inhibit phosphate-induced vascular calcification during the growth period.

Hyperphosphatemia is an independent and non-classical risk factor of cardiovascular disease and mortality in patients with chronic kidney disease (CKD). Increased levels of extracellular inorganic phosphate (Pi) are known to directly induce vascular calcification, but the detailed underlying mechanism has not been clarified. Although serum Pi levels during the growth period are as high as those observed in hyperphosphatemia in adult CKD, vascular calcification does not usually occur during growth. Here, we have examined whether the defence system against Pi-induced vascular calcification can exist during the growth period using mice model. We found that calcification propensity of young serum (aged 3 weeks) was significantly lower than that of adult serum (10 months), possibly due to high fetuin-A levels. In addition, when the aorta was cultured in high Pi medium in vitro, obvious calcification was observed in the adult aorta but not in the young aorta. Furthermore, culture in high Pi medium increased the mRNA level of tissue-nonspecific alkaline phosphatase (TNAP), which degrades pyrophosphate, only in the adult aorta. Collectively, our findings indicate that the aorta in growing mouse may be resistant to Pi-induced vascular calcification via a mechanism in which high serum fetuin-A levels and suppressed TNAP expression.

Dietary phosphate disturbs of gut microbiome in mice.

Disorder of phosphate metabolism is a common pathological condition in chronic kidney disease patients. Excessive intake of dietary phosphate deteriorates chronic kidney disease and various complications including cardiovascular and infectious diseases. Recent reports have demonstrated that gut microbiome disturbance is associated with both the etiology and progression of chronic kidney disease. However, the relationship between dietary phosphate and gut microbiome remains unknown. Here, we examined the effects of excessive intake of phosphate on gut microbiome. Five-week-old male C57BL/6J mice were fed either control diet or high phosphate diet for eight weeks. Analysis of the gut microbiota was carried out using MiSeq next generation sequencer, and short-chain fatty acids were determined with GC-MS. In analysis of gut microbiota, significantly increased in Erysipelotrichaceae and decreased in Ruminococcaceae were observed in high phosphate diet group. Furthermore, high phosphate diet induced reduction of microbial diversity and decreased mRNA levels of colonic tight junction markers. These results suggest that the excessive intake of dietary phosphate disturbs gut microbiota and affects intestinal barrier function.

Workplace factors associated with willingness to undergo human immunodeficiency virus testing during workplace health checkups.

BACKGROUND: To examine workplace factors associated with willingness to undergo human immunodeficiency virus (HIV) testing during workplace health checkups. METHODS: This cross-sectional study used an Internet-based self-administered questionnaire to obtain data from a pool of 24,287 Japanese workers. Binary and multiple logistic regression analyses evaluated the association between workplace factors and HIV testing. Data were adjusted for sex, age, marital status, education, and history of HIV testing. RESULTS: We gathered information from 4,143 (17.1%) respondents, of whom 1,129 (27.3%) were willing to be tested for HIV as part of a workplace health checkup. The participants were 20-59 years old. Approximately half of the participants were male (49.9%), half were married (48.9%), and half had completed higher education (47.6%). Workplace hepatitis testing was offered to 15.6% of the respondents, and most participants underwent health checkups without their colleagues (52.1%) at a medical facility (60.2%). Willingness to undergo HIV testing was positively correlated with having an increased risk of occupational blood exposure (vs. not at risk, adjusted odds ratio [OR]: 1.74, 95% confidence interval [CI]: 1.41-2.15) or working in medical and welfare roles (vs. manufacturing, OR: 1.40, 95% CI: 1.07-1.84). The presence of occupational health staff at the workplace (vs. their absence, adjusted OR: 1.35, 95% CI: 1.16-1.59) and hepatitis testing (vs. not testing, adjusted OR: 2.02, 95% CI: 1.66-2.44) increased willingness to undergo HIV testing. CONCLUSIONS: A pilot HIV-testing program involving individuals at an increased risk of occupational blood exposure and undergoing hepatitis tests in workplaces providing occupational health staff support is recommended.

Activation of the IKK2-NFκB pathway in VSMCs inhibits calcified vascular stiffness in CKD by reducing the secretion of calcifying extracellular vesicles.

IKK2-NFκB pathway mediated-inflammation in vascular smooth muscle cells (VSMCs) has been proposed to be an etiologic factor in medial calcification and stiffness. However, the role of the IKK2-NFκB pathway in medial calcification remains to be elucidated. In this study, we found that CKD induces inflammatory pathways through the local activation of the IKK2-NFκB pathway in VMSCs associated with calcified vascular stiffness. Despite reducing the expression of inflammatory mediators, complete inhibition of the IKK2-NFκB pathway in vitro and in vivo unexpectedly exacerbated vascular mineralization and stiffness. In contrast, activation of NFκB by SMC-specific IκB deficiency attenuated calcified vascular stiffness in CKD. Inhibition of the IKK2-NFκB pathway induced apoptosis of VSMCs by reducing anti-apoptotic gene expression, whereas activation of NFκB reduced CKD-dependent vascular cell death. In addition, increased calcifying extracellular vesicles through the inhibition of the IKK2-NFκB pathway induced mineralization of VSMCs, which was significantly reduced by blocking cell death. This study reveals that activation of the IKK2-NFκB pathway in VSMCs plays a protective role in CKD-dependent calcified vascular stiffness by reducing the release of apoptotic calcifying extracellular vesicles.

Relationship between objective cognitive functioning and work performance among Japanese workers.

OBJECTIVES: We aimed to explore the relationship between objective cognitive functioning and work performance among Japanese workers. METHODS: From February to November 2019, this cross-sectional study enrolled workers aged 18-65 years from 10 companies located in a metropolitan area of Japan. We emailed invitations to participate to employees of companies that had agreed to cooperate with the study. We measured work performance with the question, "How would you rate your performance (compared with your optimum performance) over the past 4 weeks?" Responses were made via a visual analog scale (range: 0-100). Cognitive functioning was assessed using the THINC-integrated tool (THINC-it®). THINC-it® is a brief, objective computerized cognitive assessment battery. Associations between work performance and cognitive functioning tests were examined using logistic regression analysis. RESULTS: In total, 353 individuals provided e-consent to participate, of whom 276 were included in the analysis (after omitting those with missing values). The median work performance was used to divide participants into high- (scoring ≥ 80%) and low- (scoring < 80%) performing groups. The P-values for trends indicated that association between cognitive domains, such as attention, executive functioning and working memory was significant (P < .05). Work performance was significantly associated with cognitive function for the two tests that assess attention, executive functioning, and working memory in general workers. CONCLUSIONS: Our results suggest that objective cognitive functioning may be related to work performance. Longitudinal investigations may allow for the establishment of causality.

25-hydroxyvitamin D-1α-hydroxylase (CYP27B1) induces ectopic calcification.

Vascular calcification is an important pathogenesis related to cardiovascular disease and high mortality rate in chronic kidney disease (CKD) patients. It has been well-known that hyper-phosphatemia induces osteochondrogenic transition of vascular smooth muscle cells (VSMCs) resulting ectopic calcification in aortic media, cardiac valve, and kidney. However, the detailed mechanism of the ectopic calcification has been not clarified yet. Here, we found that the co-localization of CYP27B1 with the calcified lesions of aorta and arteries in kidney of klotho mutant (kl/kl) mice, and then investigated the role of CYP27B1 in the mineralization of the VSMCs. Under high phosphate condition, overexpression of CYP27B1 induced calcification and osteocalcin mRNA expression in the VSMCs. Inversely, siRNA-CYP27B1 inhibited high phosphate-induced calcification of the VSMCs. We also found that the accumulated CYP27B1 protein was glycosylated in the kidney of kl/kl mice. Therefore, overexpression of CYP27B1-N310A and CYP27B1-T439A, which are a mutation for N-linked glycosylation site (N310A) and a mutation for O-linked glycosylation site (T439A) in CYP27B1, decreased calcium deposition and expression of RUNX2 induced by high phosphate medium in VSMCs compared with wild-type CYP27B1. These results suggest that extra-renal expression of glycosylated CYP27B1 would be required for ectopic calcification of VSMCs under hyperphosphatemia.

Sulforaphane induces lipophagy through the activation of AMPK-mTOR-ULK1 pathway signaling in adipocytes.

Lipophagy, a form of selective autophagy, degrades lipid droplet (LD) in adipose tissue and the liver. The chemotherapeutic isothiocyanate sulforaphane (SFN) contributes to lipolysis through the activation of hormone-sensitive lipase and the browning of white adipocytes. However, the details concerning the regulation of lipolysis in adipocytes by SFN-mediated autophagy remain unclear. In this study, we investigated the effects of SFN on autophagy in the epididymal fat of mice fed a high-fat diet (HFD) or control-fat diet and on the molecular mechanisms of autophagy in differentiated 3T3-L1 cells. Western blotting revealed that the protein expression of lipidated LC3 (LC3-II), an autophagic substrate, was induced after 3T3-L1 adipocytes treatment with SFN. In addition, SFN increased the LC3-II protein expression in the epididymal fat of mice fed an HFD. Immunofluorescence showed that the SFN-induced LC3 expression was co-localized with LDs in 3T3-L1 adipocytes and with perilipin, the most abundant adipocyte-specific protein, in adipocytes of mice fed an HFD. Next, we confirmed that SFN activates autophagy flux in differentiated 3T3-L1 cells using the mCherry-EGFP-LC3 and GFP-LC3-RFP-LC3ΔG probe. Furthermore, we examined the induction mechanisms of autophagy by SFN in 3T3-L1 adipocytes using western blotting. ATG5 knockdown partially blocked the SFN-induced release of fatty acids from LDs in mature 3T3-L1 adipocytes. SFN time-dependently elicited the phosphorylation of AMPK, the dephosphorylation of mTOR, and the phosphorylation of ULK1 in differentiated 3T3-L1 cells. Taken together, these results suggest that SFN may provoke lipophagy through AMPK-mTOR-ULK1 pathway signaling, resulting in partial lipolysis of adipocytes.

All-trans retinoic acid changes muscle fiber type via increasing GADD34 dependent on MAPK signal.

All-trans retinoic acid (ATRA) increases the sensitivity to unfolded protein response in differentiating leukemic blasts. The downstream transcriptional factor of PERK, a major arm of unfolded protein response, regulates muscle differentiation. However, the role of growth arrest and DNA damage-inducible protein 34 (GADD34), one of the downstream factors of PERK, and the effects of ATRA on GADD34 expression in muscle remain unclear. In this study, we identified ATRA increased the GADD34 expression independent of the PERK signal in the gastrocnemius muscle of mice. ATRA up-regulated GADD34 expression through the transcriptional activation of GADD34 gene via inhibiting the interaction of homeobox Six1 and transcription co-repressor TLE3 with the MEF3-binding site on the GADD34 gene promoter in skeletal muscle. ATRA also inhibited the interaction of TTP, which induces mRNA degradation, with AU-rich element on GADD34 mRNA via p-38 MAPK, resulting in the instability of GADD34 mRNA. Overexpressed GADD34 in C2C12 cells changes the type of myosin heavy chain in myotubes. These results suggest ATRA increases GADD34 expression via transcriptional and post-transcriptional regulation, which changes muscle fiber type.

A Cross-Sectional Study of Psychosocial Factors and Sickness Presenteeism in Japanese Workers During the COVID-19 Pandemic.

BACKGROUND: We examined the association between socioeconomic and health status, and lifestyle and sickness presenteeism among Japanese workers during the COVID-19 epidemic. METHODS: A cross-sectional study using an Internet-monitor survey was conducted in December, 2020 in Japan. Of 33,302 survey participants, we analyzed 27,036 participants (13,814 men and 13,222 women) who reported experience with sickness presenteeism. RESULTS: The odds ratio (OR) of sickness presenteeism associated with unmarried versus married status was 1.15. Respective figures for other variables were 1.11 for manual laboring work compared to desk work; 1.79 and 2.29 for loss of employment at the time the pandemic began and continuation of unemployment compared with maintaining employment during the pandemic; and 3.34 for a feeling of financial instability compared with stability. CONCLUSION: The issue of sickness presenteeism has become more prominent under the COVID-19 epidemic.

Free Deoxycholic Acid Exacerbates Vascular Calcification in CKD through ER Stress-Mediated ATF4 Activation.

BACKGROUND: Our metabolome approach found that levels of circulating, free deoxycholic acid (DCA) is associated with the severity of vascular calcification in patients with CKD. However, it is not known whether DCA directly causes vascular calcification in CKD. METHODS: Using various chemicals and animal and cell culture models, we investigated whether the modulation of DCA levels influences vascular calcification in CKD. RESULTS: CKD increased levels of DCA in mice and humans by decreasing urinary DCA excretion. Treatment of cultured VSMCs with DCA but no other bile acids (BAs) induced vascular calcification and osteogenic differentiation through endoplasmic reticulum (ER) stress-mediated activating transcription factor-4 (ATF4) activation. Treatment of mice with Farnesoid X receptor (FXR)-specific agonists selectively reduced levels of circulating cholic acid-derived BAs, such as DCA, protecting from CKD-dependent medial calcification and atherosclerotic calcification. Reciprocal FXR deficiency and DCA treatment induced vascular calcification by increasing levels of circulating DCA and activating the ER stress response. CONCLUSIONS: This study demonstrates that DCA plays a causative role in regulating CKD-dependent vascular diseases through ER stress-mediated ATF4 activation.

Identification of Dietary Phytochemicals Capable of Enhancing the Autophagy Flux in HeLa and Caco-2 Human Cell Lines.

Autophagy is a major degradation system for intracellular macromolecules. Its decline with age or obesity is related to the onset and development of various intractable diseases. Although dietary phytochemicals are expected to enhance autophagy for preventive medicine, few studies have addressed their effects on the autophagy flux, which is the focus of the current study. Herein, 67 dietary phytochemicals were screened using a green fluorescent protein (GFP)-microtubule-associated protein light chain 3 (LC3)-red fluorescent protein (RFP)-LC3ΔG probe for the quantitative assessment of autophagic degradation. Among them, isorhamnetin, chrysoeriol, 2,2',4'-trihydroxychalcone, and zerumbone enhanced the autophagy flux in HeLa cells. Meanwhile, analysis of the structure-activity relationships indicated that the 3'-methoxy-4'-hydroxy group on the B-ring in the flavone skeleton and an ortho-phenolic group on the chalcone B-ring were crucial for phytochemicals activities. These active compounds were also effective in colon carcinoma Caco-2 cells, and some of them increased the expression of p62 protein, a typical substrate of autophagic proteolysis, indicating that phytochemicals impact p62 levels in autophagy-dependent and/or -independent manners. In addition, these compounds were characterized by distinct modes of action. While isorhamnetin and chrysoeriol enhanced autophagy in an mTOR signaling-dependent manner, the actions of 2,2',4'-trihydroxychalcone and zerumbone were independent of mTOR signaling. Hence, these dietary phytochemicals may prove effective as potential preventive or therapeutic strategies for lifestyle-related diseases.

Effects of toner-handling work on respiratory function, chest X-ray findings, and biomarkers of inflammation, allergy, and oxidative stress: a 10-year prospective Japanese cohort study.

BACKGROUND: Exposure to toner, a substance used in photocopiers and printers, has been associated with siderosilicosis and other adverse effects. However, these findings are limited, and there is insufficient evidence on the long-term effects of toner exposure. Using longitudinal analysis, this study aimed to examine the effects of work involving toner exposure on the respiratory system over time. METHODS: We conducted a prospective cohort study in a Japanese toner and copier manufacturing enterprise between 2003 and 2013. The cohort included a total of 1468 workers, which comprised 887 toner-handling workers and 581 non-toner-handling workers. We subdivided the toner-handling workers into two groups according to the toner exposure concentration, based on the baseline survey in 2003. We compared the chest X-ray results, respiratory function indicators, and serum and urinary biomarkers of inflammation, allergy, and oxidative stress among the three groups: high-concentration toner exposure group, low-concentration toner exposure group, and non-toner-handling group. To consider the effects of individual differences on the longitudinal data, we used a linear mixed model. RESULTS: Similar chest X-ray results, the biomarkers, and most of the respiratory function indicators were found in the non-toner-handling and toner-handling groups. There were no significant yearly changes in the percentage of vital capacity (%VC) in the high-concentration toner exposure group, while there was a significant yearly increase in %VC in the low-concentration toner exposure group and non-toner-handling group. The yearly change in each group was as follows: high-concentration toner exposure group, - 0.11% (95% confidence interval [CI], - 0.29 to 0.08; P = 0.250); low-concentration toner exposure group, 0.13% (95% CI, 0.09-0.17; P < 0.001); and non-toner-handling group, 0.15% (95% CI, 0.01-0.20; P < 0.001). CONCLUSIONS: In our 10-year prospective study, toner-handling work was not associated with the deterioration of respiratory function and an increase in biomarker values for inflammation, allergy, and oxidative stress. This finding suggests that toner-handling work is irrelevant to the onset of respiratory disease and has minimal adverse effects on the respiratory system under a well-managed work environment.

Reduction of stearoyl-CoA desaturase (SCD) contributes muscle atrophy through the excess endoplasmic reticulum stress in chronic kidney disease.

Skeletal muscle atrophy is associated with mortality and poor prognosis in patients with chronic kidney disease (CKD). However, underlying mechanism by which CKD causes muscle atrophy has not been completely understood. The quality of lipids (lipoquality), which is defined as the functional features of diverse lipid species, has recently been recognized as the pathology of various diseases. In this study, we investigated the roles of the stearoyl-CoA desaturase (SCD), which catalyzes the conversion of saturated fatty acids into monounsaturated fatty acids, in skeletal muscle on muscle atrophy in CKD model animals. In comparison to control rats, CKD rats decreased the SCD activity and its gene expression in atrophic gastrocnemius muscle. Next, oleic acid blocked the reduction of the thickness of C2C12 myotubes and the increase of the endoplasmic reticulum stress induced by SCD inhibitor. Furthermore, endoplasmic reticulum stress inhibitor ameliorated CKD-induced muscle atrophy (the weakness of grip strength and the decrease of muscle fiber size of gastrocnemius muscle) in mice and the reduction of the thickness of C2C12 myotubes by SCD inhibitor. These results suggest that the repression of SCD activity causes muscle atrophy through excessive endoplasmic reticulum stress in CKD.

Phosphatemic Index Is a Novel Evaluation Tool for Dietary Phosphorus Load: A Whole-Foods Approach.

OBJECTIVE: Dietary phosphorus (P) restriction is crucial to treat hyperphosphatemia and reduce cardiovascular disease risk and mortality in patients with chronic kidney disease (CKD) and the wider population. Various methods for dietary P restriction exist, but the bioavailability of P in food should also be considered when making appropriate food choices to maintain patients' quality of life. Here, we propose the "Phosphatemic Index" (PI) as a novel tool for evaluating dietary P load based on P bioavailability; we also evaluated the effect of continuous intake of different PI foods in mixed meals on serum intact fibroblast growth factor 23 concentration. DESIGN AND METHODS: A 2-stage crossover study was conducted: Study 1: 20 healthy participants consumed 10 different foods containing 200 mg of P, and the PI was calculated from the area under the curve of a time versus serum P concentration curve; Study 2: 10 healthy participants consumed 4 different test meals (low, medium, or high PI meals or a control) over a 5-day period. RESULTS: Study 1 showed milk and dairy products had high PI values, pork and ham had medium PI values, and soy and tofu had low PI values. In Study 2, ingestion of high PI test meals showed higher fasting serum intact fibroblast growth factor 23 levels and lower serum 1,25-dihydroxyvitamin D levels compared with ingestion of low PI test meals. CONCLUSION: These findings suggest that the PI can usefully evaluate the dietary P load of various foods and may help to make appropriate food choices for dietary P restriction in CKD patients.

GPAT4-Generated Saturated LPAs Induce Lipotoxicity through Inhibition of Autophagy by Abnormal Formation of Omegasomes.

Excessive levels of saturated fatty acids are toxic to vascular smooth muscle cells (VSMCs). We previously reported that mice lacking VSMC-stearoyl-CoA desaturase (SCD), a major enzyme catalyzing the detoxification of saturated fatty acids, develop severe vascular calcification from the massive accumulation of lipid metabolites containing saturated fatty acids. However, the mechanism by which SCD deficiency causes vascular calcification is not completely understood. Here, we demonstrate that saturated fatty acids significantly inhibit autophagic flux in VSMCs, contributing to vascular calcification and apoptosis. Mechanistically, saturated fatty acids are accumulated as saturated lysophosphatidic acids (LPAs) (i.e. 1-stearoyl-LPA) possibly synthesized through the reaction of GPAT4 at the contact site between omegasomes and the MAM. The accumulation of saturated LPAs at the contact site causes abnormal formation of omegasomes, resulting in accumulation of autophagosomal precursor isolation membranes, leading to inhibition of autophagic flux. Thus, saturated LPAs are major metabolites mediating autophagy inhibition and vascular calcification.