Statin use and uterine fibroid risk in hyperlipidemia patients: a nested case-control study.

BACKGROUND: Statins are 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors primarily used for treatment of hyperlipidemia. Recently, they have been shown to inhibit proliferation of uterine fibroid cells and inhibit tumor growth in fibroid animal models. OBJECTIVE: We sought to examine the association between statin use and the risk of uterine fibroids and fibroid-related symptoms in a nationally representative sample of commercially insured women diagnosed with hyperlipidemia. STUDY DESIGN: We performed a nested case-control study of >190,000 women enrolled in one of the nation's largest commercial health insurance programs. From a cohort of women aged 18-65 years diagnosed with hyperlipidemia from January 2004 through March 2011, we identified 47,713 cases (women diagnosed with uterine fibroids) and 143,139 controls (women without uterine fibroids) matched at a 1:3 ratio on event/index date (month and year) and age (±1 year). We used conditional and unconditional logistic regression to calculate odds ratios and 95% confidence intervals for the risk of uterine fibroids and fibroid-related symptoms associated with prior use of statins. RESULTS: Exposure to statins within 2 years before the event/index date was associated with a decreased risk of uterine fibroids (odds ratio, 0.85; 95% confidence interval, 0.83-0.87). In a separate subanalysis restricted to cases, statin users had a lower likelihood of having menorrhagia (odds ratio, 0.88; 95% confidence interval, 0.84-0.91), anemia (odds ratio, 0.84; 95% confidence interval, 0.79-0.88), or pelvic pain (odds ratio, 0.85; 95% confidence interval, 0.81-0.91) and of undergoing myomectomy (odds ratio, 0.76; 95% confidence interval, 0.66-0.87) compared to nonusers. CONCLUSION: The use of statins was associated with a lower risk of uterine fibroids and fibroid-related symptoms. Further studies, including randomized controlled trials, may be warranted.

Hepatitis C virus core protein increases mitochondrial ROS production by stimulation of Ca2+ uniporter activity.

Many viruses have evolved mechanisms to alter mitochondrial function. The hepatitis C virus (HCV) produces a viral core protein that targets to mitochondria and increases Ca2+-dependent ROS production. The aim of this study was to determine whether core's effects are mediated by changes in mitochondrial Ca2+ uptake. Core expression caused enhanced mitochondrial Ca2+ uptake in response to ER Ca2+ release induced by thapsigargin or ATP. It also increased mitochondrial superoxide production and mitochondrial permeability transition (MPT). Incubating mouse liver mitochondria with an HCV core (100 ng/mg) in vitro increased Ca2+ entry rate by approximately 2-fold. Entry was entirely inhibited by the mitochondrial Ca2+ uniporter inhibitor, Ru-360, but not influenced by an Na+/Ca2+ exchanger inhibitor or ROS scavengers. These results indicate that core directly increases mitochondrial Ca2+ uptake via a primary effect on the uniporter. This enhanced the ability of mitochondria to sequester Ca2+ in response to ER Ca2+ release, and increased mitochondrial ROS production and MPT. Thus, the mitochondrial Ca2+ uniporter is a newly identified target for viral modification of cell function.

Chaperone-mediated reversible inhibition of the sarcomeric myosin power stroke.

Molecular chaperones are required for successful folding and assembly of sarcomeric myosin in skeletal and cardiac muscle. Here, we show that the chaperone UNC-45B inhibits the actin translocation function of myosin. Further, we show that Hsp90, another chaperone involved in sarcomere development, allows the myosin to resume actin translocation. These previously unknown activities may play a key role in sarcomere development, preventing untimely myosin powerstrokes from disrupting the precise alignment of the sarcomere until it has formed completely.

Ubiquilin-1 overexpression increases the lifespan and delays accumulation of Huntingtin aggregates in the R6/2 mouse model of Huntington's disease.

Huntington's Disease (HD) is a neurodegenerative disorder that is caused by abnormal expansion of a polyglutamine tract in huntingtin (htt) protein. The expansion leads to increased htt aggregation and toxicity. Factors that aid in the clearance of mutant huntingtin proteins should relieve the toxicity. We previously demonstrated that overexpression of ubiqulin-1, which facilitates protein clearance through the proteasome and autophagy pathways, reduces huntingtin aggregates and toxicity in mammalian cell and invertebrate models of HD. Here we tested whether overexpression of ubiquilin-1 delays or prevents neurodegeneration in R6/2 mice, a well-established model of HD. We generated transgenic mice overexpressing human ubiquilin-1 driven by the neuron-specific Thy1.2 promoter. Immunoblotting and immunohistochemistry revealed robust and widespread overexpression of ubiquilin-1 in the brains of the transgenic mice. Similar analysis of R6/2 animals revealed that ubiquilin is localized in huntingtin aggregates and that ubiquilin levels decrease progressively to 30% during the end-stage of disease. We crossed our ubiquilin-1 transgenic line with R6/2 mice to assess whether restoration of ubiquilin levels would delay HD symptoms and pathology. In the double transgenic progeny, ubiquilin levels were fully restored, and this correlated with a 20% increase in lifespan and a reduction in htt inclusions in the hippocampus and cortex. Furthermore, immunoblots indicated that endoplasmic reticulum stress response that is elevated in the hippocampus of R6/2 animals was attenuated by ubiquilin-1 overexpression. However, ubiquilin-1 overexpression neither altered the load of htt aggregates in the striatum nor improved motor impairments in the mice.

Post-burn hepatic insulin resistance is associated with endoplasmic reticulum (ER) stress.

Insulin resistance with its associated hyperglycemias represents one significant contributor to mortality in burned patients. A variety of cellular stress-signaling pathways are activated as a consequence of burn. A key player in the cellular stress response is the endoplasmic reticulum (ER). Here, we investigated a possible role for ER-stress pathways in the progression of insulin function dysregulation postburn. Rats received a 60% total body surface area thermal injury, and a laparotomy was performed at 24, 72, and 192 h postburn. Liver was harvested before and 1 min after insulin injection (1 IU/kg) into the portal vein, and expression patterns of various proteins known to be involved in insulin and ER-stress signaling were determined by Western blotting. mRNA expression of glucose-6-phosphatase and glucokinase were determined by reverse-transcriptase-polymerase chain reaction and fasting serum glucose and insulin levels by standard enzymatic and enzyme-linked immunosorbent assay techniques, respectively. Insulin resistance indicated by increased glucose and insulin levels occurred starting 24 h postburn. Burn injury resulted in activation of ER stress pathways, reflected by significantly increased accumulation of phospho-PKR-like ER-kinase and phosphorylated inositol requiring enzyme 1, leading to an elevation of phospho-c-Jun N-terminal kinase and serine phosphorylation of insulin receptor substrate (IRS) 1 postburn. Insulin administration caused a significant increase in tyrosine phosphorylation of IRS-1, leading to activation of the phosphatidylinositol 3 kinase/Akt pathway in normal liver. Postburn tyrosine phosphorylation of IRS-1 was significantly impaired, associated with an inactivation of signaling molecules acting downstream of IRS-1, leading to significantly elevated transcription of glucose-6-phosphatase and significantly decreased mRNA expression of glucokinase. Activation of ER-stress signaling cascades may explain metabolic abnormalities involving insulin action after burn.

Effect of insulin on the inflammatory and acute phase response after burn injury.

After a severe burn, the liver plays a pivotal role by modulating inflammatory processes, metabolic pathways, immune functions, and the acute phase response. Therefore, liver integrity and function are important for recovery. A thermal injury, however, causes hepatic damage by inducing hepatic edema, fatty infiltration, hepatocyte apoptosis, and metabolic derangements associated with insulin resistance and impaired insulin signaling. In preliminary studies, we found that these pathophysiological processes are related to hepatic inflammation, altered intracellular signaling, and mitochondrial dysfunction. We hypothesize that modulation of these processes with insulin could improve hepatic structure and function and, therefore, outcome of burned and critically ill patients. Insulin administration improves survival and decreases the rate of infections in severely burned and critically ill patients. Here, we show that insulin administration decreases the synthesis of proinflammatory cytokines and signal transcription factors and improves hepatic structure and function after a severe burn injury; insulin also restores hepatic homeostasis and improves hepatic dysfunction postburn via alterations in the signaling cascade.