The tumor suppressive role of CAMK2N1 in castration-resistant prostate cancer.

Prostate cancer at advanced stages including metastatic and castration-resistant cancer remains incurable due to the lack of effective therapies. The CAMK2N1 gene, cloned and characterized as an inhibitor of CaMKII (calcium/calmodulin-dependent protein kinase II), has been shown to affect tumorigenesis and tumor growth. However, it is still unknown whether CAMK2N1 plays a role in prostate cancer development. We first examined the protein and mRNA levels of CAMK2N1 and observed a significant decrease in human prostate cancers comparing to normal prostate tissues. Re-expression of CAMK2N1 in prostate cancer cells reduced cellular proliferation, arrested cells in G0/G1 phases, and induced apoptotic cell death accompanied by down-regulation of IGF-1, ErbB2, and VEGF downstream kinases PI3K/AKT, as well as the MEK/ERK-mediated signaling pathways. Conversely, knockdown of CAMK2N1 had a significant opposite effects on these phenotypes. Our analyses suggest that CAMK2N1 plays a tumor suppressive role in prostate cancer cells. Reduced CAMK2N1 expression correlates to human prostate cancer progression and predicts poor clinical outcome, indicating that CAMK2N1 may serve as a biomarker. The inhibition of tumor growth by expressing CAMK2N1 established a role of CAMK2N1 as a therapeutic target

CAMK2N1 inhibits prostate cancer progression through androgen receptor-dependent signaling.

Castration resistance is a major obstacle to hormonal therapy for prostate cancer patients. Although androgen independence of prostate cancer growth is a known contributing factor to endocrine resistance, the mechanism of androgen receptor deregulation in endocrine resistance is still poorly understood. Herein, the CAMK2N1 was shown to contribute to the human prostate cancer cell growth and survival through AR-dependent signaling. Reduced expression of CAMK2N1 was correlated to recurrence-free survival of prostate cancer patients with high levels of AR expression in their tumor. CAMK2N1 and AR signaling form an auto-regulatory negative feedback loop: CAMK2N1 expression was down-regulated by AR activation; while CAMK2N1 inhibited AR expression and transactivation through CAMKII and AKT pathways. Knockdown of CAMK2N1 in prostate cancer cells alleviated Casodex inhibition of cell growth, while re-expression of CAMK2N1 in castration-resistant cells sensitized the cells to Casodex treatment. Taken together, our findings suggest that CAMK2N1 plays a tumor suppressive role and serves as a crucial determinant of the resistance of prostate cancer to endocrine therapies

Prevalence and Risk Factors of Reduced Bone Mineral Density in Systemic Lupus Erythematosus Patients: A Meta-Analysis

Background. We aimed to conduct a meta-analysis concerning the frequency and risk factors of reduced bone mineral density (BMD) in systemic lupus erythematosus (SLE) with evidence from published studies. Methods. A comprehensive literature search was conducted based on the EMBASE, Web of Science, PubMed, and Cochrane Library databases up to March 5th, 2017. Eligible studies reported any prevalence of reduced BMD in SLE patients. All risk factors with odds ratios or risk ratios associated with reduced BMD were extracted. Results. 71 reports with 33527 SLE patients were included. Low BMD, osteopenia, and osteoporosis at any site were presented, respectively, in 45%, 38%, and 13% of the SLE patients. The prevalence of osteoporosis increased with the advancing of age, while U-shaped associations between age and the prevalence of low BMD and osteopenia were found. Lumbar spine was indicated to have higher prevalence of osteoporosis. Age, disease duration, drugs use, and many other factors were identified as predictors of reduced BMD. Conclusion. Low BMD, osteoporosis, and osteopenia appeared to be prevalent in patients with SLE. Risk factors of reduced BMD were various

Pregnancy Outcomes in Chinese Patients with Systemic Lupus Erythematosus (SLE): A Retrospective Study of 109 Pregnancies.

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease that primarily affects women during their reproductive years. The interaction between SLE and pregnancy remains debated. The objective of this study was to analyze the fetal and maternal outcomes of Chinese women with SLE. A total of 109 pregnancies in 83 SLE patients from June 2004 to June 2014 at a tertiary university hospital were reviewed retrospectively. Patients' characteristics, clinical and laboratory data during pregnancy were obtained from electronic medical records. After exclusion of elective abortions, the live birth rate was 61.5%. Significantly, APS (antiphospholipid syndrome), disease activity, hypertension, hypocomplementemia, thrombocytopenia, and anemia during pregnancy were more commonly observed in fetal loss pregnancies than in live birth pregnancies. Compared to the 64 women with a history of SLE, 19 women with new-onset lupus during pregnancy had worse pregnancy outcome. Furthermore, the 64 patients with a history of SLE were divided into lupus nephritis group and SLE group (non-renal involvement). We found that the lupus nephritis group had worse maternal outcome than the SLE group. We conclude that new-onset lupus during pregnancy predicts both adverse maternal and fetal outcomes, while a history of lupus nephritis predicts adverse maternal outcomes. It is essential to provide SLE women with progestational counseling and regular multispecialty care during pregnancy

Glutaminolysis Was Induced by TGF-β1 through PP2Ac Regulated Raf-MEK-ERK Signaling in Endothelial Cells

<div><p>Vascular endothelial cells can survive under hypoxic and inflammatory conditions by alterations of the cellular energy metabolism. In addition to high rates of glycolysis, glutaminolysis is another important way of providing the required energy to support cellular sprouting in such situations. However, the exact mechanism in which endothelial cells upregulate glutaminolysis remains unclear. Here we demonstrated that protein phosphatase 2A (PP2A)-mediated Raf-MEK-ERK signaling was involved in glutaminolysis in endothelial cells. Using models of human umbilical vein endothelial cells (HUVECs) treated with transforming growth factor-β1 (TGF-β1), we observed a dramatic induction in cellular glutamate levels accompanied by Raf-MEK-ERK activation. By addition of U0126, the specific inhibitor of MEK1/2, the expression of kidney-type glutaminase (KGA, a critical glutaminase in glutaminolysis) was significantly decreased. Moreover, inhibition of PP2A by okadaic acid (OA), a specific inhibitor of PP2A phosphatase activity or by depletion of its catalytic subunit (PP2Ac), led to a significant inactivation of Raf-MEK-ERK signaling and reduced glutaminolysis in endothelial cells. Taken together, these results indicated that PP2A-dependent Raf-MEK-ERK activation was involved in glutaminolysis and inhibition of PP2A signals was sufficient to block Raf-MEK-ERK pathway and reduced glutamine metabolism in endothelial cells.</p></div

Glutaminolysis is induced by TGF-β1 in HUVECs.

<p>The cells were treated with 10ng/ml of TGF-β1 for different indicated periods, from 15 minutes to 48 hours. (a) KGA protein expression was up-regulated by TGF-β1. Representative western blot of KGA in each group is shown. (b) Densitometry analysis of KGA protein expression was plotted (n≥3). (c) Intracellular glutamate level in the medium was analyzed using theAmplex^®Red Glutamic Acid / Glutamate Oxidase Assay Kit (n≥3). *P<0.05 compared to control group. Bars represented means ± SEM.</p

PP2Ac protein expression and PP2A activity in TGF-β1-treated HUVECs.

<p>The cells were treated with 10ng/ml of TGF-β1 for different indicated periods, from 15 minutes to 24 hours. (a) PP2Ac protein expression was measured by Western blot analysis. (b) PP2Ac activity was detected by using the Serine/Threonine Phosphatase Assay System in TGF-β1-treated HUVECs (n≥3). *P<0.05 compared to control group. Bars represented means ± SEM.</p

Diagram of the mechanism by which glutaminolysis is induced by TGF-β1 through PP2Ac regulated Raf-MEK-ERK signaling in endothelial cells.

<p>The solid arrows mean stimulation, and dotted arrows mean inhibitory effect.</p

Knockdown of PP2Ac by siRNA prevents the activation of Raf/MEK/ERK pathway in response to TGF-β1.

<p>(a) HUVECs were transiently transfected with 100 nmol/L of PP2Ac siRNA or control siRNA for 12 h. PP2Ac protein expression was detected to confirm the knockdown effect. A representative western blot was shown. (b) Densitometry analysis of PP2Ac protein expression was plotted (n≥3). (c, d, e, f) After transfection of PP2Ac siRNA, cells were incubated with TGF-β1 for 15 min and 60 min, respectively. A representative western blot of p-c-Raf (Ser 259), T-c-Raf, p-ERK 1/2, T-ERK 1/2 in each group were shown. The histograms showed the ratio of p-c-Raf/T-c-Raf and p-ERK/T-ERK (n≥3).*P<0.05 compared to control group. Bars represented means ±SEM.</p

Rhabdomyolysis-Induced Acute Kidney Injury Under Hypoxia and Deprivation of Food and Water

Background: To investigate the renal pathophysiologyin rhabdomyolysis-induced acute kidney injury (AKI) in rats under hypoxia and deprivation of food and water (HDFW), thus broadening the knowledge about rhabdomyolysis-induced AKI in massive earthquake. Methods: Male Wistar rats weighing 200-230g were randomized into control, rhabdomyolysis (R), HDFW and rhabdomyolysis in combination with HDFW (R/HDFW) group. Experimental rhabdomyolysis rat model was established through clamping hind limb muscles, HDFW model rats were kept in 10% hypoxic chamber unavailable to food and water. At 1, 3, 5, 7, 9, 11d after treatment, serum creatinine (Scr) level, renal index, renal structural changes and cell apoptosis were analyzed. Results: After R, HDFW, R/HDFW treatment, the animals showed significantly higher Scr levels than the control group. Renal index in R and R/HDFW groups elevated remarkably compared with that in control and HDFW group. The results of histopathology, ultra-structure and apoptosis assay suggested that rhabdomyolysis caused renal tubular injury, HDFW treatment resulted in renal vascular dilation, tissue congestion and tubular cell damage. In addition, more severe renal lesion appeared in R/HDFW. Conclusions: We conclude that the association of experimental rhabdomyolysis with HDFW results in a different functional and histological pattern. The rhabdomyolysis-HDFW combination causes more severe renal injury