Ϫ/Ϫ mice and their wild-type littermates were fed either a normal diet or a rescue diet (high calcium, phosphate, and lactose) starting from weaning until 3 mo of age. We then determined serum calcium and phosphorus levels, assessed gonadotropin and gonadal hormone production, and evaluated folliculogenesis, corpus luteum formation, ovarian angiogenesis, uterus development, and fertility. Results showed that hypocalcemic and hypophosphatemic female 1␣(OH)ase Ϫ/Ϫ mice developed infertility accompanied by decreased estrogen and progestogen levels, elevated follicle-stimulating hormone and luteinizing hormone levels, defects in follicular development and corpus luteum formation, uterine hypoplasia, and decreased ovarian expression of angiogenic factors including vascular endothelial growth factor (VEGF), angiopoietin-1 and -2, and Tie-2. When serum calcium and phosphorus were normalized by the rescue diet, the defective reproductive phenotype in the female 1␣(OH)ase Ϫ/Ϫ mice, including the dysfunction in the hypothalamic-pituitary-ovarian axis, and ovarian angiogenesis were reversed. These results indicate that the infertility seen in 1,25(OH)2D-deficient mice is not a direct effect of active vitamin D deficiency on the reproductive system but is an indirect effect mediated by extracellular calcium and phosphorus. ] mice developed hypocalcemia, hypophosphatemia, hyperparathyroidism, retarded growth, and the skeletal abnormalities characteristic of rickets when they were fed a diet of regular mouse chow after weaning. Other laboratories have reported mouse models with targeted ablation of the VDR gene (6,15,29). These VDR Ϫ/Ϫ mice developed manifestations similar to those of 1␣(OH)ase Ϫ/Ϫ mice, although VDR Ϫ/Ϫ mice also display alopecia. To investigate whether deficiencies of 1,25(OH) 2 D and the VDR produce the same alterations in skeletal and calcium homeostasis and whether calcium could subserve the skeletal functions of 1,25(OH) 2 D and the VDR (17), we previously compared the phenotypes of 1␣(OH)ase Ϫ/Ϫ , VDR Ϫ/Ϫ , and double mutants. These animals were fed either a normal diet containing 1% calcium and 0.67% phosphorus, on which the mice were hypocalcemic and hypophosphatemic, or a "rescue" diet containing 2% calcium, 1.25% phosphorus, and 20% lactose. Lactose in this high-calcium, high-phosphorus rescue diet facilitated mineral absorption and normalization of serum calcium and phosphorus (17). Normalization of serum calcium and phosphorus led to phenotypic changes in the parathyroid glands and skeleton that disclosed selective and overlapping modulation by these minerals and the vitamin D system of parathyroid and skeletal function. In contrast, other studies using VDR Ϫ/Ϫ mice (14) and 1␣(OH)ase Ϫ/Ϫ mice (30) have revealed that in the cardiovascular system the 1,25(OH) 2 D/ VDR system, independent of ambient serum calcium and phosphorus levels, provides protection against the resulting hypertension by repressing the renin-angiotensin system.Early studies reported that female vitamin D-deficient rats could g...

Epidemiological and clinical studies have indicated that low vitamin D activity is not only associated with an increased cancer risk and a more aggressive tumor growth, but also connected with an aggravated liver damage caused by chronic inflammation. Meanwhile, increasing evidence has demonstrated that 1,25(OH)2D3 (the most biologically active metabolite of vitamin D) can inhibit inflammatory response in some chronic inflammatory associated cancer, which is considered to have the anti-tumor potency. However, the interaction between 1,25(OH)2D3 and inflammation during hepatocellular carcinoma (HCC) initiation and progression is not yet clear. Here, we report an anti-tumorigenesis effect of 1,25(OH)2D3 via decreasing inflammatory cytokine secretion in HCC and hypothesize the possible underlying mechanism. Firstly, we show that the enhanced tumor growth is associated with elevated inflammatory cytokine IL-6 and TNF-α in 1α(OH)ase gene-knockout mice. Secondly, 1,25(OH)2D3 can inhibit vitamin D receptor (VDR) shRNA interfered tumor cell growth through decreasing inflammatory cytokine secretion in vitro and in vivo. Finally, using p27kip1 gene knock-out mouse model, we demonstrate that the effect of 1,25(OH)2D3 in inhibiting immune cell related inflammatory cytokine secretion, exerts in a p27kip1 gene dependent way. Collectively, 1,25(OH)2D3 inhibits HCC development through up-regulating the expression of p27kip1 in immune cell and reducing inflammatory cytokine production.

The present study aimed to evaluate the pathogenesis of type 2 diabetes mellitus (T2DM) and the anti-diabetic effect of berberine in Zucker diabetic fatty (ZDF) rats. A urinary metabolomics analysis was performed with ultra-performance liquid chromatography/electrospray ionization synapt high-definition mass spectrometry. Pattern recognition approaches were integrated to discover differentiating metabolites. We identified 29 ions (13 in negative mode and 16 in positive mode) as 'differentiating metabolites' with this metabolomic approach. A functional pathway analysis revealed that the alterations were mainly associated with glyoxylate and dicarboxylate metabolism, pentose and glucuronate interconversions and sphingolipid metabolism. These results indicated that the dysfunctions of glycometabolism and lipometabolism are involved in the pathological process of T2DM. Berberine could decrease the serum levels of glycosylated hemoglobin, total cholesterol and triglyceride and increase the secretion of insulin. The urinary metabolomics analysis showed that berberine could reduce the concentrations of citric acid, tetrahydrocortisol, ribothymidine and sphinganine to a near-normal state. These results suggested that the anti-diabetic effect of berberine occurred mainly via its regulation of glycometabolism and lipometabolism and activation of adenosine 5'-monophosphate-activated protein kinase. Our work not only provides a better understanding of the anti-diabetic effect of berberine in ZDF rats but also supplies a useful database for further study in humans and for investigating the pharmacological actions of drugs. Copyright © 2016 John Wiley & Sons, Ltd.

<b><i>Background:</i></b> Since the outbreak of COVID-19 in December 2019, it has spread rapidly and widely, bringing great psychological pressure to the public. In order to prevent the epidemic, traffic lockdown was required in many areas of China, which led to inconvenience of treatment for dialysis patients. This study was conducted to explore the psychological distress and the psychological demand induced by CO­VID-19 in the patients undergoing dialysis and compare the difference between hemodialysis (HD) and peritoneal dialysis (PD) patients during the traffic lockdown period. <b><i>Methods:</i></b> Questionnaires were given to the dialysis patients in the West China Hospital of Sichuan University. The Impact of Event Scale (IES) was used to investigate the patients’ trauma-related distress in response to COVID-19. <b><i>Results:</i></b> 232 eligible respondents were enrolled in this cross-section study, consisting of 156 PD patients and 76 HD patients. The median IES score for all the enrolled patients was 8.00 (2.00–19.00), which belonged to the subclinical dimension of post-traumatic stress symptoms (PTSS). HD patients had a significant higher IES score than PD patients (11.50 vs. 8.00) (<i>p</i> &#x3c; 0.05). HD patients already got more psychological support from the medical staff. According to IES scores, 22.4% HD patients and 13.4% PD patients were classified as having moderate or severe PTSS, which need psychological support (<i>p</i> &#x3c; 0.05). But more patients of both groups considered psychological support was necessary (HD: 50%, PD: 45.5%) (<i>p</i> &#x3e; 0.05). In the multivariate regression analysis, we found that dialysis vintage, the impact of COVID-19 on the severity of illness and daily life, and confidence in overcoming the disease contributed to IES score (<i>p</i> &#x3c; 0.05). <b><i>Conclusions:</i></b> HD patients had more severe trauma-related stress symptoms than PD patients. When major public healthy events occurred, careful psychological estimate and sufficient psychological support should be provided to the dialysis patients, especially to the HD patients.

Purpose The purpose of this study was to explore the predictive value of the ratio of the product of neutrophils and hemoglobin to lymphocytes (NHL) in patients with non‐muscular invasive bladder cancer (NMIBC). Materials and Methods We retrospectively collected clinical and pathological data of patients with NMIBC who underwent transurethral resection of bladder tumor (TURBT) at our hospital between 2013 and 2018. The ratio of neutrophils to lymphocytes (NLR), the Systemic Immune Inflammation Index (SII), and NHL were obtained based on routine blood settlement within a week before surgery. The receiver operating characteristic curve was used to determine the optimal cutoff value of each index, and different groups were grouped accordingly. Kaplan‐Meier survival curve and Cox regression model were used to study the factors affecting the prognosis of NMIBC patients. Results There was significant difference in recurrence‐free survival (RFS) rate between the high NLR group and the low NLR group, the high SII group and the low SII group, and the high NHL group and the low NHL group. Cox univariate regression analysis showed that tumor number, tumor size, tumor pathological grade, tumor pathological stage, NLR, SII, and NHL were related to postoperative RFS in patients with NMIBC. The tumor number, tumor pathological grade, SII, and NHL were independent predictors of RFS in multivariate analysis. Conclusions The preoperative clinical inflammatory indexes NLR, SII, and NHL have certain predictive value for postoperative RFS in NMIBC patients.

Epithelial-mesenchymal transition (EMT) refers to the transition of epithelial cells into mesenchymal cells. Emerging evidence suggests that EMT is a key point in renal interstitial fibrosis (RIF). Traditional Chinese Medicine Shenqiwan (SQW) is widely used in clinical treatment of chronic kidney disease, but the underlying mechanism remains unclear. The purpose of this study is to investigate the effect of SQW on renal fibrosis and its association with TGF-β1/Smads signaling pathway. A rat model of adenine (150 mg/kg) was established and intragastrically treated with various concentrations of SQW at dose of 1.5 g/kg, 3 g/kg, and 6 g/kg. Control group and model group were given the same volume of saline. Meanwhile, the positive control group was treated with Enalapril (4 mg/kg). Animals were sacrificed on 21st day after administration. The results showed that SQW could significantly relieve renal pathological damage caused by adenine, increase gene and protein expression of E-cadherin, and decrease the expression of Vimentin in kidney samples. In addition, SQW efficiently inhibited the mRNA and protein expression of p-Smad2/3 by upregulating Smad7. These results suggest that SQW could slow down the progression of renal fibrosis, possibly by inhibiting TGF-β1/Smads signaling pathway.

,25-Dihydroxyvitamin D3 contributes to regulating mammary calcium transport and modulates neonatal skeletal growth and turnover cooperatively with calcium. Am J Physiol Endocrinol Metab 301: E889-E900, 2011. First published July 26, 2011; doi:10.1152/ajpendo.00173.2011To assess the interaction of 1,25(OH)2D3 and dietary calcium on mammary calcium transport in lactating dams and skeletal growth and turnover in the neonate, female lactating 1␣(OH)ase ϩ/Ϫ or 1␣(OH)ase Ϫ/Ϫ mice were fed either a high-calcium diet containing 1.5% calcium in the drinking water or a "rescue diet." Dietary effects on the expression of molecules mediating mammary calcium transport were determined in the dams, and the effects of milk calcium content were assessed on skeletal growth and turnover in 2-wk-old 1,25(OH)2D3-deficient pups. Results showed that the reduction of milk calcium levels in the 1␣(OH)ase Ϫ/Ϫ dams and the elevation of milk calcium levels in dams fed the rescue diet were associated with the down-or upregulation of calbindin D9k and plasma membrane Ca 2ϩ ATPase isoform 2b expression, respectively, in mammary epithelial cells. The action of ambient calcium in stimulating skeletal growth in the neonates appeared to supercede the direct action of 1,25(OH)2D3, and the response of chondrocytes in the neonates to elevated calcium was more sensitive in hypocalcemic animals. Osteopenia was more apparent in pups nursed by dams with lower milk calcium than in 1,25(OH)2D3-deficient pups nursed by dams with higher milk calcium. Bone formation parameters were increased significantly in all pups fed by dams on the rescue diet but were still lower in 1␣(OH)ase Ϫ/Ϫ pups than in 1␣(OH)ase ϩ/Ϫ pups. Consequently, there is an important contributory role of calcium in conjunction with 1,25(OH)2D3 to mammary calcium transport in lactating dams and skeletal growth and turnover in the neonate. vitamin D; dietary calcium VITAMIN D IS ESSENTIAL FOR THE MAINTENANCE of a mineralized skeleton. We (29) and others (9) have previously described a mouse model with targeted ablation of the gene encoding the enzyme 25-hydroxyvitamin D 1␣hydroxylase [1␣(OH)ase] that results in 1␣,25(OH) 2 D deficiency. After weaning, mice fed regular mouse chow developed secondary hyperparathyroidism, retarded growth, and skeletal abnormalities characteristic of rickets and osteomalacia. These abnormalities mimic those described in the human genetic disorder VDDR-I (11, 13). When the phenotype of 1␣(OH)ase Ϫ/Ϫ mice was analyzed, we found that the skeletal phenotype was different before and after weaning. At 2 wk of age, the trabecular volume and osteoblast numbers in the 1␣(OH)ase Ϫ/Ϫ mice were decreased, and the osteoid volume was not increased significantly (45). In contrast, at 4 mo of age, the trabecular volume, osteoblast number, and osteoid volume were all increased significantly in the 1␣(OH)ase Ϫ/Ϫ mice, even on a high-calcium diet of 1.5% calcium in the drinking water (28). These differences were thought to result from the elevations in circulating parathyroid horm...

Objective: Despite the achievement of blood glucose, blood pressure targets, the risk for kidney injury remains high among older adults. This observational retrospective study investigated whether high TG or high WC contribute to this high residual risk for kidney injury. Methods: A total of 843 elderly from Dongli Community, Tianjin, China, we selected 666 individuals with a baseline estimated glomerular filtration rate (eGFR) 60 mL/min/1.73 m 2 and negative microalbuminuria completing a 3-year follow-up. At baseline, subjects were grouped according to the levels of TG and WC. The primary outcome was the incidence of kidney injury, defined as low eGFR (eGFR <60 mL/min/1.73 m 2) or reduced eGFR (eGFR reduced >25%) or UACR 30 mg/g. Results: Overall, 6.01% developed low eGFR, 11.11% reduced eGFR, 25.98% UACR 30 mg/g, and 3.45% low eGFR and UACR 30mg/g after 3-year follow-up. TG 1.7 mmol/L increased the risk of eGFR <60 mL/min/1.73 m 2 by 1.44-fold, of UACR 30 mg/g by 32%, and of developing both abnormality by 1.41-fold in model 1; further adjustment for potential confounders factors, the association is slightly weakened in model 2 and 3; WC (90 cm in men and 85 cm in women) were associated with a 1.68-fold higher risk of eGFR <60 mL/min/1.73 m 2 and a 1.43fold risk of UACR 30 mg/g and a 1.89-fold risk of developing both abnormality in model 1. Further adjustment for potential confounders factors, the association is slightly weakened in model 2 and 3. Conclusions: In a population of Chinese community-dwelling older adults, high TG and central obesity were risk factors for the development of kidney injury over 3 years.