Effects of daily 1,000-IU vitamin D-fortified milk intake on skeletal muscle mass, power, physical function and nutrition status in Japanese.

An intervention study was conducted to investigate the effects of daily 1,000-IU vitamin D-fortified milk intake on skeletal muscle mass, power, physical function and nutrition status in 26 healthy people and 8 older adults living in a nursing home. The serum 25-hydroxyvitamin D [25(OH)D] level was 13.4 ±â€…0.8 ng / mL and it markedly increased to 29.6 ±â€…0.9 ng / mL after daily 1000-IU vitamin D-fortified milk intake for 6 months. Handgrip strength (kg) also significantly increased in the 21-50 years and total groups, and male subjects, and the timed up and go test significantly improved in the 21-50 years and total groups, and female subjects after 6-month vitamin D intake. However, there were no significant differences between baseline and post-treatment in the Barthel Index (BI), walking speed (m / sec) or skeletal muscle mass (kg, % of BW, kg / m2). Therefore, the present study suggested that vitamin D-fortified milk intake is effective at improving muscle strength and physical function in Japanese, although further studies are needed, particularly for older adults. J. Med. Invest. 68 : 249-255, August, 2021.

Cut-off values for skeletal muscle strength and physical functions in Japanese elderly with walking difficulty.

Age-related changes in muscle strength and physical functions, and the association between vitamin D status and skeletal muscle functions were investigated in 36 men (21-90 years old) and 52 women (21-104 years old). Significant ageing-related decreases in several skeletal muscle functions and serum 25-hydroxyvitamin D [25(OH)D] levels were observed in both men and women. Cut-off values for the Timed up and go (TUG) test, walking speed, handgrip strength and Barthel Index (BI) detecting walking difficulties in the receiver operating characteristic (ROC) analysis were 11.1 sec, 0.60 m / sec, 17.0 kg, and 90.0 in males, and 28.6 sec, 0.43 m / sec, 13.9 kg, and 67.5 in females, respectively. By comparing personal present data of muscle strength with these cut-off values, people can easily understand their process to walking difficulty. Therefore, these results are important and useful to avoid or to delay a handicapped and dependent status by improving the vitamin D level, rehabilitation and nursing care. J. Med. Invest. 68 : 48-52, February, 2021.

Relationship between age-related decreases in serum 25-hydroxyvitamin D levels and skeletal muscle mass in Japanese women.

A clearer understanding of skeletal muscle mass (SMM) in middle-aged and elderly individuals is important for maintaining functionality. In the present study, age-related changes in SMM, the threshold of SMM with walking difficulty, intestinal nutrient absorption rate, and various serum factors were examined in Japanese populations of different ages. We used 24-h creatinine excretion as a measure of total body SMM. Age-related decreases in SMM, intestinal nutrient absorption rates, and serum 25-hydroxyvitamin D [25(OH)D] concentrations were significantly higher in women than in men. The cut-off values for SMM (kg), its percentage of total body weight (BW), the SMM index [SMMI] (Kg / m2), and creatinine height index (CHI) (%) in elderly individuals with walking difficulty were approximately 8-10 kg, 17-20% of BW, 3.9-4.6 kg / m2, and 44%, respectively. Serum 25(OH)D concentrations were closely associated with SMM (kg, % of BW, kg / m2) and CHI (%) as well as the intestinal absorption rates of nitrogen (%) and phosphorus (%) in women, but not in men. The present results demonstrate that vitamin D is an important metabolic factor in skeletal muscle, and contributes to the optimal management of skeletal muscle and the prevention of sarcopenia. J. Med. Invest. 67 : 151-157, February, 2020.

C-SH2 point mutation converts p85ß regulatory subunit of phosphoinositide 3-kinase to an anti-aging gene.

Insulin interacts with the insulin receptor, and the activated receptor promotes activity of the phosphoinositide-3 kinase (PI3K) enzyme. A decrease in insulin or insulin-like growth factor 1 (IGF-1) signaling increases the lifespan in mammalian species. We found that a point mutation in the C-SH2 domain of the p85ß regulatory subunit of PI3K results in a prolonged lifespan. In p85ß mutant cells, nerve growth factor (NGF) activates the longevity protein FOXO, and the mutant p85ß gene produces strong resistance to oxidative stress, which contributes to aging. The p85ß gene mutation causes increased serum insulin and low blood glucose in p85ß mutant transgenic mice. Our results indicate that the p85ß mutant allele alters the activity of downstream targets of PI3K by NGF and platelet-derived growth factor (PDGF) but not by insulin. We report that a point mutation in the C-SH2 domain of p85ß transforms p85ß into a novel anti-aging gene by abnormally regulating PI3K.

Antidepressant-Like Effect of 1α-Hydroxyvitamin D3 on Mice in the Forced Swimming Test.

We examined the effect of 1α-hydroxyvitamin D3 [1α(OH)D3] on mice in the forced swimming test. Intragastric administration of 1.0 µg/kg of 1α(OH)D3 reduced immobility time in the forced swimming test. At all concentrations tested (0.5, 1.0, 2.0 µg/kg), 1α(OH)D3 had no effect on locomotor activity, compared with controls. These results suggest that 1α(OH)D3 may have antidepressant-like activity.

Treatment of rapid weight loss in a donor with hepatic steatosis in living donor liver transplantation: a case report.

The use of steatotic livers for transplantation is often associated with increased primary non-function. To reduce the risk of liver injury, steatosis of the donor liver in living donor liver transplantation (LDLT) was treated with restricted diet and exercise. A 21-year-old male donor, 167cm in height and 87kg in body weight, initially received a 1800kcal/day diet for 9 days which was then gradually reduced using a 1600kcal/day diet for 43 days, followed by a 1500kcal/day diet for one day and was finally maintained on a 1400kcal/day diet for 52 days. Daily exercise consumed 500kcal/day. The non-protein respiratory quotient (npRQ) gradually increased while the non-esterified fatty acids (NEFA) decreased during the course of the 105-day treatment. Consequently, the initial 80% steatosis was reduced to 10% and was accompanied by 13% weight loss for 81 days. The npRQ values and NEFA concentrations in the later period of dietary and exercise treatment were higher and lower, respectively, than in the early treatment period, indicating compensation through long-term treatment. Therefore, energy metabolism and NEFA levels represent important biomarkers for short-term intensive treatment by restricted diet and exercise in donors with hepatic steatosis.

Inhibitory effect of 1α-hydroxyvitamin D3 on N-nitrosobis(2-oxopropyl)amine-induced cholangiocarcinogenesis in Syrian hamsters.

Sixty-three male 5-week-old Syrian hamsters received the carcinogen N-nitrosobis(2-oxopropyl)amine (BOP) s.c. in 5 weekly injections (the first, 70 mg/kg body, and the remaining, 20mg/kg each). The hamsters that received BOP were given intragastric administration of 0.2 ml of medium chain triglyceride (MCT) with or without 0.04 µg of 1α-hydroxyvitamin D3 [1α(OH)D3] through a feeding tube for 12 weeks. Thus, 3 groups were assigned:Group 1;BOP alone (n＝20), Group 2;BOP＋MCT (n＝18) and Group 3;BOP＋1α(OH)D3 (n＝25). The mean body weight of Group 3 was lower than those of Groups 1 and 2 at the end of the experiment (p＜0.001,Tukey-Kramer HSD test). At the end of week 12, all surviving hamsters were put to sleep. The incidences of liver tumors were 80%, 72% and 32% in Groups 1, 2 and 3, respectively. The incidence of tumors in Group 3 was significantly lower than in Group 1 and Group 2 (p＜0.05, χ2-test). All tumors were cholangiocarcinoma. These results indicated that BOP-induced cholangiocarcinogenesis was suppressed by the supplemental administration of 1α(OH)D3.

The effect of leg hyperthermia using far infrared rays in bedridden subjects with type 2 diabetes mellitus.

We examined the effect of leg hyperthermia on oxidative stress in bedridden subjects with type 2 diabetes mellitus using 15-min sessions of far infrared rays over a two-week period. Four subjects (male 1, female 3) incapacitated by a stroke were recruited for this study. All patients were admitted to Takahashi Central Hospital and ate the same hospital meals. Fasting plasma glucose, HbA1c, tumor necrosis factor (TNF)alpha, free fatty acid, leptin, adiponectin and plasma 8-epi-prostaglandin F2alpha (8-epi-PGF2alpha) levels as a marker of oxidative stress were measured on admission, just before and 2 weeks after local heating of the leg. Results showed that plasma total 8-epi-PGF2alpha levels were decreased significantly while TNFalpha levels were increased significantly. On the other hand, glucose, HbA1c, free fatty acid, leptin and adiponectin levels were not changed during the study period. These results suggest that repeated leg hyperthermia may protect against oxidative stress.

Increasing early insulin secretion compensate adequately for hepatic insulin resistance in CCl4-induced cirrhosis rats.

A number of recent publications have reported an increased frequency prevalence of glucose intolerance with hyperinsulinemia in liver cirrhosis. The aim of this work was to detect, in CCl(4)-induced liver cirrhosis rat, the presence and starting point of muscle and liver insulin resistance. Eighteen rats received intraperitoneal injection of 2 ml of soybean oil containing of CCl(4) twice a week for 20 weeks. We executed standard oral glucose tolerance and clamp study to evaluate systemic insulin resistance. Hepatic glucose uptake was much lower in CCl(4) group than that in control group, but peripheral glucose uptake was not decreased in this study. In contrast, early-phase insulin secretion was enhanced in CCl(4) rat using oral glucose load during clamp methods. These data suggested that increased early insulin secretion compensate adequately for hepatic insulin resistance in rats. However there was a report that peripheral glucose uptake was decreased in the case of human liver cirrhosis, which was formed in the course of time. In a chronic condition, this may be associated with reduced insulin content and developed systemic insulin resistance in liver cirrhosis. Then a long term observation study will be required to examine the presence of muscle insulin resistance in liver cirrhosis.

[Phosphorus intake and bone mineral density (BMD)].

Phosphorus regulates the bone formation and inhibits the bone resorption. It is still expected as one of anti-osteoporosis nutrients. The amounts of phosphorus intake with calcium are increasing from 1960 to 1995. Because phosphorus affects the regulation of calcium metabolism, the balance of these nutrients is important. Tuero suggested that more than 1,000 mg/day of calcium intake and more than 0.74 of Ca/P were associated with better bone mineral density (BMD) values in young women. However, there are few reports of correlations between appropriate phosphorus intake, Ca/P rate and BMD.

1 alpha,25-Dihydroxyvitamin D(3) is a preventive factor in the metastasis of lung cancer.

1alpha,25-Dihydroxyvitamin D(3) [1alpha,25(OH)(2)D(3)], the major regulator of calcium homeostasis, has potent antiproliferative and anti-invasive properties in vitro in cancer cells. Studies in vivo demonstrated that 1alpha,25(OH)(2)D(3) slows the progression of breast, prostate and other carcinomas. A key question is whether 1alpha,25(OH)(2)D(3) exerts its anticarcinogenic effects in vivo by a mechanism that is dependent on its capacity to limit the proliferation and invasiveness of cancer cells in vitro. It has not been clear whether the calcemic activity and regulation of the host defenses by 1alpha,25(OH)(2)D(3) contribute to the effect on cancer cells. In this study we have focused on the influence of 1alpha,25(OH)(2)D(3) on the metastasis of lung cancer, without involvement of the calcemic activity and other effects of 1alpha,25(OH)(2)D(3) in the host. We used metastatic Lewis lung carcinoma cells expressing green fluorescent protein (LLC-GFP cells) and examined metastatic activity in vitamin D receptor (VDR) null mutant (VDR(-/-)) mice and their wild-type counterparts (VDR(+/+) mice). VDR(-/-) mice exhibit hypocalcemia and extremely high serum levels of 1alpha,25(OH)(2)D(3). We expected that serum 1alpha,25(OH)(2)D(3) would act in vivo to directly inhibit the metastatic growth of VDR-positive LLC-GFP cells in VDR(-/-) mice. The metastatic activities of LLC-GFP cells were remarkably reduced in VDR(-/-) mice compared with VDR(+/+) mice. To test the hypothesis that serum 1alpha,25(OH)(2)D(3) is an intrinsic factor that inhibits metastatic growth of lung cancer cells, we corrected hypocalcemia and/or hypervitaminosis D in VDR(-/-) mice by dietary manipulation. The metastatic growth of LLC-GFP cells was remarkably reduced in response to serum levels of 1alpha,25(OH)(2)D(3), but not to serum calcium levels. Furthermore, we found that VDR(+/+) mice fed the manipulated diets displayed an apparent inverse relationship between the physiological levels of serum 1alpha,25(OH)(2)D(3) (8-15 pg/ml) and tumorigenesis. Here we show that 1alpha,25(OH)(2)D(3) inhibits the metastatic growth of lung cancer cells in a defined animal model.

Metastatic growth of lung cancer cells is extremely reduced in Vitamin D receptor knockout mice.

Lung metastatic neoplasms are the major cause of cancer mortality. Despite the progress of diagnostic techniques and improvements in surgical procedures, the prognosis of patients with lung cancer is generally poor, even in the early stages of cancer [Cancer: Principles and Practice of Oncology, vol. 1, fifth ed., Lippincott-Raven, New York, 1997, p. 849]. Epidemiological studies indicate a positive correlation with the prevalence of cancers and low serum levels of Vitamin D metabolites [Am. J. Clin. Nutr. 54 (1991) 193s; Cancer Epidemiol. Biomark. Prev. 9 (2000) 1059]. 1alpha,25-Dihydroxyvitamin D(3) [1alpha,25(OH)(2)D(3)] is a potent inhibitor of cancer cell proliferation in vitro [Proc. Natl. Acad. Sci. U.S.A. 78 (1981) 4990; Endocrinol. 139 (1998) 1046; Mol. Endocr. 15 (2001) 1127]. There is, however, no report demonstrating that 1alpha,25(OH)(2)D(3) is operative in vivo to inhibit metastatic growth of cancer cells. To verify this possibility, we generated a stable transfectant of the Lewis lung carcinoma (LLC) cell expressing green fluorescent protein (GFP) and examined its metastatic activity in wild-type mice and Vitamin D receptor (VDR) knockout mice that exhibit no Vitamin D-dependent calcemic activity and extremely high serum levels of 1alpha,25(OH)(2)D(3) due to the overexpression of the 1alpha-hydroxylase gene [Nat. Genet. 16 (1997) 391; Proc. Natl. Acad. Sci. U.S.A. 94 (1997) 9831]. Here, we show that 1alpha,25(OH)(2)D(3) inhibits metastatic growth of lung cancer cells in the defined animal model and may work as an intrinsic factor for prevention of metastasis in intact animals. These findings establish a critical role for 1alpha,25(OH)(2)D(3) in lung metastatic neoplasms and provide a new model for metastasis of malignant cells.