Tumor necrosis factor-alpha is associated with mineral bone disorder and growth impairment in children with chronic kidney disease.

BACKGROUND: Mineral and bone disorder (MBD) and growth impairment are common complications of pediatric chronic kidney disease (CKD). Chronic inflammation detrimentally affects bone health and statural growth in non-CKD settings, but the impact of inflammation on CKD-MBD and growth in pediatric CKD remains poorly understood. This study assessed associations between inflammatory cytokines with biomarkers of CKD-MBD and statural growth in pediatric CKD. METHODS: This is a cross-sectional study of children with predialysis CKD stages II-V. Cytokines (IL-1b, IL-4, IL-6, IL-8, IL-10, IL-12, IL-13, TNF-α, interferon-γ), bone alkaline phosphatase (BAP), and procollagen type 1 N-terminal propeptide (P1NP) were measured at the same time as standard CKD-MBD biomarkers. Associations between cytokines, CKD-MBD biomarkers, and height z-score were assessed using linear regression analysis. RESULTS: Among 63 children, 52.4% had stage 3 CKD, 76.2% non-glomerular CKD etiology, and 21% short stature. TNF-α was the only cytokine associated with parathyroid hormone (PTH) independent of glomerular filtration rate. After stratification by low, medium, and high TNF-α tertiles, significant differences in PTH, serum phosphorus, alkaline phosphatase, BAP, P1NP, and height z-score were found. In a multivariate analysis, TNF-α positively associated with phosphorus, PTH, and alkaline phosphatase and inversely associated with height z-score, independent of kidney function, age, sex, and active vitamin D analogue use. CONCLUSIONS: TNF-α is positively associated with biomarkers of CKD-MBD and inversely associated with height z-score, indicating that inflammation likely contributes to the development of CKD-MBD and growth impairment in pediatric CKD. Prospective studies to definitively assess causative effects of inflammation on bone health and growth in children with CKD are warranted.

Interleukin-6 Contributes to the Development of Anemia in Juvenile CKD.

INTRODUCTION: Anemia is a common complication of chronic kidney disease (CKD) in children; however, the role of inflammation in its pathogenesis remains incompletely understood. METHODS: To elucidate the role of interleukin (IL)-6 in renal anemia, we induced CKD by adenine diet in juvenile wild-type (WT) and IL-6 deficient (Il6KO) mice, and examined serum IL-6 and relevant parameters in children with CKD. RESULTS: WT-CKD mice developed anemia despite increases in serum erythropoietin and displayed low serum iron and elevated serum IL-6. IL-6 deficiency resulted in a significant improvement of red blood cell count and hemoglobin in CKD mice. This effect was associated with improvement of hypoferremia by Il6 deletion, likely mediated by hepcidin. However, correction of hypoferremia by oral iron supplementation in WT-CKD mice did not fully replicate the protective effects of Il6 deletion, suggesting an additional iron-independent role for IL-6 in CKD-anemia. Indeed, Il6 deletion mitigated the severity of renal fibrosis and alleviated relative erythropoietin insufficiency in CKD mice. Cytokine profiling in a pediatric CKD cohort demonstrated that of 10 cytokines (IL-1ß, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, IL-13, tumor necrosis factor (TNF)-α, and interferon-γ), only IL-6 was significantly (inversely) associated with hemoglobin when adjusted for glomerular filtration rate (GFR). The association between IL-6 and hemoglobin in children with CKD remained significant after adjustment for CKD stage, iron therapy, and hepcidin. DISCUSSION: IL-6 contributes to development of anemia in juvenile CKD, through mechanisms that include induction of hypoferremia, aggravation of renal fibrosis, and alteration of the erythropoietin axis. IL-6 appears to be a promising therapeutic target in the management of CKD-anemia.

17α-Estradiol and genistein inhibit high fat diet induced prostate gene expression and prostate growth in the rat.

PURPOSE: High dietary fat and low phytoestrogen intake are associated with prostate cancer development and progression. Our previous study showed that exposure to a high fat diet significantly increased prostate 5α-reductase-2 mRNA and prostate growth in the rat. In the current experiments we determined the effects of genistein and 17α-estradiol on the modulation of dietary fat induced prostate 5α-reductase-2 and insulin-like growth factor-1 gene expression, and prostate growth. MATERIALS AND METHODS: At weaning male ACI/Seg rats (Harlan® Sprague-Dawley®) were fed a low or a high fat diet, with or without genistein or 17α-estradiol for 2, 4 or 10 weeks. The prostate was dissected and weighed. We determined the levels of prostate 5α-reductase-2 mRNA, insulin-like growth factor-1 mRNA, dihydrotestosterone, and plasma insulin-like growth factor-1, dihydrotestosterone and testosterone. RESULTS: Two-week exposure to a high fat diet significantly increased prostate insulin-like growth factor-1 mRNA without significant changes in plasma insulin-like growth factor-1, which was blocked by genistein and 17α-estradiol. Genistein but not 17α-estradiol also inhibited prostate 5α-reductase-2 mRNA and intraprostatic dihydrotestosterone induced by the high fat diet at 2 weeks. Genistein and 17α-estradiol completely blocked high fat diet induced prostate growth at 10 weeks of dietary treatment. However, neither genistein nor 17α-estradiol had any significant effect when co-administered with the low fat diet. CONCLUSIONS: Results indicate that genistein and 17α-estradiol can inhibit dietary fat induced changes in prostate 5α-reductase-2 and insulin-like growth factor-1 gene expression, and prostate growth in the rat. This may be beneficial to prevent dietary fat associated prostate diseases such as prostate cancer.

In vivo antitumor activity of ZYD88, a Chinese herbal medicine, in animal models with S180 sarcoma and Ehrlich tumor.

Cancer is a leading cause of death in the world. The continuous development of effective and nontoxic therapeutic agents is a major task in the battle of cancer. We report the in vivo effects of a Chinese herbal medicine, ZYD88, on the inhibition of tumor growth in an S(180) xenograft animal model and the improvement of animal survival in the Ehrlich tumor model. Oral administration of ZYD88 in mice with the xenograft S(180) sarcoma significantly inhibited tumor growth in a dose-dependent manner. Moreover, ZYD88 given to the animals with Ehrlich ascitic tumors by gavage significantly prolonged the life span compared with that of animals treated with saline. In both animal models, the effects of ZYD88 were comparable to those of a standard chemotherapeutic agent, cyclophosphamide, although it had few side effects. These results clearly demonstrated the in vivo anticancer activity of ZYD88 in two different animal models and suggest that ZYD88 is a potential agent for the clinical management of cancer and warrants further preclinical and clinical investigations.

Inhibition of tumor growth and tumor metastasis by a Chinese herbal formula--ZYD88, in an animal model with metastatic Lewis lung carcinoma.

Tumor metastasis is the leading cause of cancer death. In the present study, we determined the effectiveness of ZYD88, a Chinese herbal formula, in the inhibition of tumor growth and distant tumor metastases to the lung and liver in an animal model with metastatic Lewis lung carcinoma (LLC). Treatment with ZYD88 in adult C57BL/6 mice with metastatic LLC produced dose-dependent deceases in primary tumor weight, the mitotic tumor cell number, microvessel density, distant tumor metastases and red blood cell immune complexes, while it significantly increased tumor necrosis, thymus cortical thickness, the thymus medullar reticular epithelial cell (REC) number, and the activity of red blood cell C3b receptors. Although cyclophosphamide inhibited tumor growth, it had no significant effects on distant tumor metastases, thymus cortical thickness, the thymus medullar REC number, red blood cell C3b receptor activity and red blood cell immune complexes. These results indicate that ZYD88 possesses significant anti-angiogenic, anti-tumor and anti-metastatic effects in this animal model, and warrants further investigation.

Sex differences in mental rotation: top-down versus bottom-up processing.

Functional MRI during performance of a validated mental rotation task was used to assess a neurobiological basis for sex differences in visuospatial processing. Between-sex group analysis demonstrated greater activity in women than in men in dorsalmedial prefrontal and other high-order heteromodal association cortices, suggesting women performed mental rotation in an effortful, "top-down" fashion. In contrast, men activated primary sensory cortices as well as regions involved in implicit learning (basal ganglia) and mental imagery (precuneus), consistent with a more automatic, "bottom-up" strategy. Functional connectivity analysis in association with a measure of behavioral performance showed that, in men (but not women), accurate performance was associated with deactivation of parieto-insular vestibular cortex (PIVC) as part of a visual-vestibular network. Automatic evocation by men to a greater extent than women of this network during mental rotation may represent an effective, unconscious, bottom-up neural strategy which could reasonably account for men's traditional visuospatial performance advantage.

The Chinese medicinal herbal formula ZYD88 inhibits cell growth and promotes cell apoptosis in prostatic tumor cells.

Prostate cancer is a leading cause of cancer death in American males. Currently, there is no curative therapy available once prostate cancer has metastasized. A major systemic therapy for metastatic prostate cancer is anti-androgen therapy. Unfortunately this therapy is only palliative and rarely curative, and eventually the tumor cells develop resistance to further hormone manipulation. It is therefore imperative to develop alternative effective therapies. In the present study, the effect of a Chinese herbal formula, ZYD88, on regulation of cell growth and cell apoptosis was examined in prostatic tumor cells. ZYD88 decreased cell viability of multiple prostatic tumor cell lines, DU-145, PC-3, MDA-PCa 2b and LNCaP in a time- and dose-dependent manner. It also produced a rapid and dose-dependent increase in caspase 3 activity in LNCaP and PC-3 cells, and induced DNA fragmentation in LNCaP cells, indicating cell apoptosis. In cotransfection assays, ZYD88 inhibited androgen-induced prostate specific antigen (PSA) gene promoter activity, and induced estrogen-target gene promoter activity. These data suggest that ZYD88 is a potential agent for prostate cancer therapy, and deserves further study.