Non-alcoholic fatty liver disease is the most rapidly growing form of liver disease and if left untreated can result in non-alcoholic steatohepatitis, ultimately resulting in liver cirrhosis and failure. Biliverdin reductase A (BVRA) is a multifunctioning protein primarily responsible for the reduction of biliverdin to bilirubin. Also, BVRA functions as a kinase and transcription factor, regulating several cellular functions. We report here that liver BVRA protects against hepatic steatosis by inhibiting glycogen synthase kinase 3β (GSK3β) by enhancing serine 9 phosphorylation, which inhibits its activity. We show that GSK3β phosphorylates serine 73 (Ser(P)) of the peroxisome proliferator-activated receptor α (PPARα), which in turn increased ubiquitination and protein turnover, as well as decreased activity. Interestingly, liver-specific BVRA KO mice had increased GSK3β activity and Ser(P) of PPARα, which resulted in decreased PPARα protein and activity. Furthermore, the liver-specific BVRA KO mice exhibited increased plasma glucose and insulin levels and decreased glycogen storage, which may be due to the manifestation of hepatic steatosis observed in the mice. These findings reveal a novel BVRA-GSKβ-PPARα axis that regulates hepatic lipid metabolism and may provide unique targets for the treatment of non-alcoholic fatty liver disease.

Bladder cancer is observed worldwide having been associated with a host of environmental and lifestyle risk factors. Recent investigations on anti-inflammatory glucocorticoid signaling point to a pathway that may impact bladder cancer. Here we show an inverse effect on the glucocorticoid receptor (GR) isoform signaling that may lead to bladder cancer. We found similar GRα expression levels in the transitional uroepithelial cancer cell lines T24 and UMUC-3. However, the T24 cells showed a significant (p < 0.05) increased expression of GRβ compared to UMUC-3, which also correlated with higher migration rates. Knockdown of GRβ in the T24 cells resulted in a decreased migration rate. Mutational analysis of the 3′ untranslated region (UTR) of human GRβ revealed that miR144 might positively regulate expression. Indeed, overexpression of miR144 increased GRβ by 3.8 fold. In addition, miR144 and GRβ were upregulated during migration. We used a peptide nucleic acid conjugated to a cell penetrating-peptide (Sweet-P) to block the binding site for miR144 in the 3′UTR of GRβ. Sweet-P effectively prevented miR144 actions and decreased GRβ expression, as well as the migration of the T24 human bladder cancer cells. Therefore, GRβ may have a significant role in bladder cancer, and possibly serve as a therapeutic target for the disease.

Bladder cancer is encountered worldwide having been associated with a host of environmental and lifestyle risk factors. The disease has a male to female prevalence of 3 : 1. This disparity has raised the possibility of the androgen receptor (AR) pathway being involved in the genesis of the disease; indeed, research has shown that AR is involved in and is likely a driver of bladder cancer. Similarly, an inflammatory response has been implicated as a major player in bladder carcinogenesis. Consistent with this concept, recent work on anti-inflammatory glucocorticoid signaling points to a pathway that may impact bladder cancer. The glucocorticoid receptor- (GR-) α isoform has an important role in suppressing inflammatory processes, which may be attenuated by AR in the development of bladder cancer. In addition, a GR isoform that is inhibitory to GRα, GRβ, is proinflammatory and has been shown to induce cancer growth. In this paper, we review the evidence of inflammatory mediators and the relationship of AR and GR isoforms as they relate to the propensity for bladder cancer.

The use of thiazolidinedione (TZD) therapy in type II diabetic patients has proven useful in the lowering of blood glucose levels. However, recent investigations have shown that there may be potential health concerns associated, including the risk of developing bladder cancer as well as complications in the cardiovasculature. TZDs are ligands for the nuclear receptor PPARγ, and activation causes lipid uptake and insulin sensitization, both of which are critical processes for diabetic patients whose bodies are unable to utilize insulin effectively. Several studies have shown that PPARγ/TZDs decrease IGF-1 levels and, thus, reduce cancer growth in carcinomas such as the pancreas, colon, liver, and prostate. However, other studies have shed light on the potential of the receptor as a biomarker for uroepithelial carcinomas, particularly due to its stimulatory effect on migration of bladder cancer cells. Furthermore, PPARγ may provide the tumor-promoting microenvironment by de novo synthesis of nutrients that are needed for bladder cancer development. In this review, we closely examine the TZD class of drugs and their effects on PPARγ in patient studies along with additional molecular factors that are positive modulators, such as protein phosphatase 5 (PP5), which may have considerable implications for bladder cancer therapy.

Transient changes in the dry matter (DM) concentration of silages often occur, which will cause transient changes in the ration. To determine the effects of a transient change in silage DM, 24 Holstein cows (116 d in milk) were used in an 8 replicated 3×3 Latin square design with 21-d periods. Treatments were (1) control, (2) unbalanced (UNBAL), and (3) balanced (BAL). The control diet was designed to have a consistent day-to-day forage:concentrate ratio of 55:45 on a DM basis. The UNBAL and BAL diets were the same as the control diet for most of the period except during two 3-d bouts when water was added to the silage (simulating a rain event) to cause a 10-percentage unit decrease in silage DM concentration. During the bouts, the UNBAL diet was the same as that of the control on an as-fed basis, but on a DM basis, the forage:concentrate ratio decreased to 49:51, which reduced dietary concentrations of DM (63.9 vs. 66.2%) and forage NDF (21.0 vs. 23.6%), and increased starch (30.4 vs. 28.4%). The BAL treatment corrected for the change in silage DM by an increase in the inclusion of wet silage and had the same composition as the control diet on a DM basis, except for ration DM (66.2 vs. 63.9%). Over the 21-d period, treatment did not affect DM intake (DMI; 24.0 kg/d); however, DMI of cows on the UNBAL and BAL treatments tended to decrease during the wet bouts, especially during the second bout. The day following both bouts, DMI of cows fed BAL and UNBAL diets were greater than that of cows fed the control diet, which contributed to the lack of a treatment effect on DMI over the entire period. Milk production was greater for the UNBAL than control cows (39.8 vs. 39.3 kg/d) over the 21-d period. That difference was largely caused by increased milk yield during the first bout by cows on the UNBAL diet. Over the 21-d period, milk yield did not differ between control and BAL cows. Some small differences in milk fat and protein concentrations (≤ 0.1 percentage units) were observed between treatments. Total-tract digestibility of most nutrients was not affected by treatment. Overall, a 10-percentage unit decrease in silage DM over short-term bouts (with or without total mixed ration adjustment) had only minor effects on DMI, milk yield, and composition.