These results suggest that for 3 months at both standard and accelerated environmental conditions, the formulated IQP-0410 transdermal films are stable products. The human immunodeficiency virus has infected over 40 million individuals over the last decade, with more than 5 million residing in sub-Saharan Africa. Although highly active antiretroviral therapy enhances life expectancy and quality of infected individuals, there is increased emphasis on HAART-mediated metabolic derangements and its potential risk for cardiovascular diseases in the longterm. Protease inhibitors form an integral part of HAART and side-effects include development of dyslipidemia, i.e. greater production of plasma triglycerides and lipids together with an adverse cholesterol profile. Together such derangements elicit inflammation, stress the myocardium, and may potentially predict the onset of insulin resistance and cardiac dysfunction. PIs are also linked to increased risk for myocardial infarction and cardiovascular abnormalities, with many changes resembling coronary artery disease. It is unclear whether metabolic side effects of PIs are independently and/or causally linked with cardiovascular perturbations. Moreover, the effects of PIs per se on the heart in this context are also poorly understood. Therefore, an emerging focus is to identify key metabolic and transcriptional pathways that may mediate NSC 136476 company PI-induced cardio-metabolic pathophysiology. For example, we recently found that rats exposed to 8 weeks of PI treatment displayed cardiac dysfunction. Moreover, PI-treated HIVinfected individuals exhibit elevated reactive oxygen species production that may trigger the activation of detrimental signaling and cell death pathways. HIV-PIs may also exert unfavorable effects at the gene transcriptional level, e.g. activating sterol regulatory element binding protein, a key lipid transcriptional modulator expressed in major metabolic tissues. Upon activation, SREBP binds to sterol-regulatory-element containing promoter sequences in lipogenic and cholesterogenic genes that ultimately results in the production of cholesterol and sterol components. The ubiquitin-proteasome system �C responsible for removal of misfolded or damaged proteins �C is also implicated in the onset of such metabolic side effects. For example, the PI Ritonavir attenuates chymotrypsin- and trypsin-like activities of the 20S UPS subunit in hepatocytes. As a result, Nilotinib degradation of apolipoprotein B was diminished thus providing a potential mechanism for PI-induced hyperlipidemia. Furthermore, SREBPs are ubiquitinated and degraded by the UPS raising the possibility that an inhibition of this system may also contribute to development of dyslipidemia in HIV-infected individuals treated with PIs. Together this may establish a pro-atherogenic profile and increase the risk for the onset of CVD. Despite such progress, the underlying molecular mechanisms responsible for HAART-induced cardio-metabolic side effects are poorly understood, and little is known about the earliest events driving this process. Whether these molecular alterations occur as a direct result of PI treatment or through the activation of additional pathways throughout the body at a later stage remain elusive. For the current study, we therefore hypothesized that PI treatment enhances myocardial oxidative stress and concomitantly inhibits the UPS, having a knock-on effect on important downstream regulators such as gap junctions and ion channels essential in cardiac physiology. We also evaluated several nonoxidative glucose metabolic circuits i.e. the polyol pathway, hexosamine biosynthetic pathway, advanced glycation end products, and PKC activation since previous work found its activation can elicit the onset of cardio-metabolic complications. Since our previous ex vivo rat heart study implicated altered calcium homeostasis in PI-mediated cardiac dysfunction, we further investigated calcium signaling and mitochondrial energetic regulators in an established rat model of chronic PI drug delivery. These data may explain and suggest an association between molecular changes and depressed cardiac contractile function. Although HAART markedly improves the quality of life and prognosis of HIV-infected individuals, it also elicits cardiometabolic side effects in the long-term.