Activating the Nrf2-mediated antioxidant response element restores barrier function in the alveolar epithelium of HIV-1 transgenic rats.

The master transcription factor nuclear factor (erythroid-derived 2)-like 2 (Nrf2) regulates the expression of antioxidant and phase II-metabolizing enzymes by activating the antioxidant response element (ARE) and thereby protects cells and tissues from oxidative stress. Pulmonary complications remain the leading cause of death in human immunodeficiency virus (HIV)-1-infected individuals, who display systemic oxidative stress and glutathione deficiency that can be modeled in transgenic rats where HIV-1-related viral proteins decrease glutathione levels and cause epithelial barrier dysfunction within the alveolar space by as yet unknown mechanisms. We hypothesized that HIV-1-related proteins inhibit Nrf2-mediated antioxidant defenses and thereby disrupt the normally tight alveolar epithelial barrier. Nrf2 RNA silencing dampened Nrf2/ARE activity, decreased the expression of the tight junction proteins zonula occludens-1, occludin, and claudin-18, increased paracellular permeability of alveolar epithelial monolayers derived from wild-type rats, and therefore reproduced the effects of HIV-1 transgene expression on the epithelial barrier that we had previously described. In contrast, upregulating Nrf2 activity, either by plasmid-mediated overexpression or treatment with the Nrf2 activator sulforaphane, increased the expression of ARE-dependent antioxidants, including NAD(P)H dehydrogenase, quinone 1 and glutathione, improved the expression of tight junction proteins, and restored the ability to form tight barriers in alveolar epithelial cells from HIV-1 transgenic rats. Taken together, these new findings argue that HIV-1-related proteins downregulate Nrf2 expression and/or activity within the alveolar epithelium, which in turn impairs antioxidant defenses and barrier function, thereby rendering the lung susceptible to oxidative stress and injury. Furthermore, this study suggests that activating the Nrf2/ARE pathway with the dietary supplement sulforaphane could augment antioxidant defenses and lung health in HIV-1-infected individuals.

Osteoporosis treatment for patients with stroke.

PURPOSE: Little is known about the frequency of use of medications to maintain bone health for patients with stroke. This study was undertaken at an urban academic rehabilitation center to determine the prevalence of use of agents that could reduce bone loss in the stroke population. METHOD: A clinical database was searched for all patients 18 years old and over with stroke. The sample included 1,219 inpatients and 2,776 outpatients. Demographic information (age, gender, and race) and medications were obtained for each patient. RESULTS: Among inpatients with stroke, 7.1% were taking osteoporosis medications (bisphosphonates, calcitonin, parathyroid hormone, or hormone replacement therapy), 11.3% were taking calcium supplements, 5.9% were taking vitamin D supplements, and 45.1% were taking multivitamin supplements. Among outpatients with stroke, 5.7% were taking osteoporosis medication, 5.8% were taking calcium supplements, 2.2% were taking vitamin D supplements, and 16.0% were taking multivitamin supplements. Patients being treated with specific osteoporosis therapies tended to be older and female by calculated odds ratios. The use of multivitamins was not related to age, gender, or race. CONCLUSION: Overall, relatively few stroke patients were taking osteoporosis medications or supplements. There is a need to increase the recognition, prevention, and treatment of bone loss in this high-risk population.