Current Molecular Medicine (v.11, #7)

Prostacyclin Receptor Regulation --- from Transcription to Trafficking by C. Midgett, J. Stitham, K.A. Martin, J. Hwa (517-527).
The prostacyclin receptor (IP - International Union of Pharmacology nomenclature) is a member ofthe seven transmembrane G-protein coupled receptor (GPCR) superfamily. Recent concerns with selectiveand non-selective COX-1/COX-2 inhibition have exposed an important cardioprotective role for IP in preventingatherothrombosis. Receptor dysfunction (genetic variants) or reduced signaling (COX-2 inhibition) in highcardiovascular risk patients leads to increased cardiovascular events. These clinical observations have alsobeen confirmed genetically by mouse knockout studies. Thus, receptor regulation is paramount in ensuringcorrect function in the prevention of atherothrombosis. This review summarizes recent literature on how thisimportant receptor is regulated, from transcription to transport (to and from the membrane surface). Theseregulatory processes are critical in ensuring that IP receptors are adequately expressed and functional on thecell surface.

Glaucoma is a major cause of irreversible blindness, affecting more than 70 million individualsworldwide. Elevated intraocular pressure (IOP) is a major risk factor in the development of glaucoma and in theprogression of glaucomatous damage. High IOP usually occurs as a result of an increase in aqueous humoroutflow resistance in trabecular meshwork (TM). Primary open angle glaucoma (POAG) is characterized byquantifiable parameters including the IOP, the aqueous outflow facility, and geometric measurements of theoptic disc and visual defects.Morphological and biochemical analyses of the TM of POAG patients revealed loss of cells, increasedaccumulation of extracellular matrix (ECM), changes in the cytoskeleton, cellular senescence and the processof subclinical inflammation. Various biochemical and molecular biology biomarkers of TM cells senescence areconsidered in the article. Oxidative stress is becoming an important factor more likely to be involved in thepathogenesis of POAG. Treatment of TM cells with oxidative stress induced POAG-typical changes like ECMaccumulation, cell death, disarrangement of the cytoskeleton, advanced senescence and the release ofinflammatory markers. Oxidative stress is able to induce characteristic glaucomatous TM changes and theseoxidative stress-induced TM changes can be minimized by the use of antioxidants, such as carnosine -relatedanalogues and IOP-lowering substances. There is evidence demonstrating that carnosine related analoguesmay have antioxidative capacities, can prevent cellular senescence and the attrition of telomeres during theaction of oxidative stress.Prevention of oxidative stress exposure to the TM with N-acetylcarnosine ophthalmic prodrug of carnosine andoral formulation of non-hydrolized carnosine may help to reduce the progression of POAG. The previous workhas demonstrated that carnosine is able to reach the TM directly via the transcorneal and systemic pathwaysof administration with N-acetylcarnosine ophthalmic prodrug and oral formulation of non-hydrolized carnosine.We suggest in this article that dual therapy with N-acetylcarnosine lubricant eye drops, oral formulation of nonhydrolizedcarnosine combined with anti-glaucoma adrenergic drug may become the first-line therapy inglaucoma due to their efficiency in reducing IOP, prevention and reversal of oxidative stress-induced damagesin TM and the low rate of severe side effects during combined treatment.

Metastatic melanoma is one of the most intractable tumors, with all current regimens showing limitedsurvival impact. Failure of most agents is attributed to development of therapy resistance. Accumulatedevidence points to the apoptotic defect of melanoma cells and the surge of survival signals stimulated bycytotoxic drugs, as a way that tumors circumvent cytotoxic chemotherapy. An overview of inhibitors developedagainst these growth/survival factors, which are potential partners to be combined with systemicchemotherapy, will be discussed. The escape mechanism from molecular inhibitors also suggests a “vertical”or “horizontal” combination of molecularly targeted therapies. A better understanding of the interactionsbetween simultaneously used regimens and of the rationale for combination therapy will provide new insightsto improve survival and quality of life in patients with advanced melanoma.

Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide, with a poor prognosisand limited therapeutic options. Due to its overexpression in the majority of HCCs, alpha-fetoprotein (AFP)represents one of the most useful markers for hepatocarcinomas and for monitoring patients’ response totherapy. Although it was earlier reported that AFP has immunosuppressive properties, it has been recentlydemonstrated that AFP induces spontaneous T and B cells responses in HCC patients. The characterization ofAFP-immunogenic epitopes gives the opportunity to design AFP-based cancer vaccines for human HCC. Theactivity of AFP-based vaccines has been investigated in HCC mouse models in order to develop novelstrategies to treat patients with HCC. This review will discuss the rationale for using the AFP-based vaccinationstrategy and recent results corroborating the usefulness of AFP vaccines as a potential tool for cancer therapy.

Many cellular processes depend on the establishment of selective stable or transient interactionsbetween proteins. Therefore, the ability to identify and characterize these contacts in physiologically relevantenvironments is crucial to understanding the networks of contacts that allow the transmission and integration ofbiological information in living cells. Protein-fragment complementation assays (PCA) have emerged asapproaches that report on the proximity of two given proteins in the cell at a given location and time. Inparticular, bimolecular fluorescence complementation (BIFC) allows noninvasive imaging of protein binding inliving cells at high spatial resolution and without the requirement for exogenous substrates. In the presentreview, we discuss PCA and BIFC fundamentals, the implementation of BIFC assays and selected applicationsof BIFC in drug discovery, developmental studies or neurological disorders.

Current Prospective of Aldose Reductase Inhibition in the Therapy of Allergic Airway Inflammation in Asthma by K.V. Ramana, U.C.S. Yadav, W.J. Calhoun, S.K. Srivastava (599-608).
The prevalence of asthma and costs of its care have been continuously increasing, but noveltherapeutic options to treat this inflammatory disease have not been brought to the US market. Currenttherapies such as inhaled steroids, long-acting beta-agonist bronchodilators, antihistamines andimmunomodulators may control the symptoms of allergic asthma but fail to modify the underlying disease.Excessive use of steroids and other immunosuppresents alter the patient’s quality of life, produce undesirabletoxicities, and increase the risk of other pathologies such as diabetes. Hence novel therapeutic options tomanage asthma are desirable. In the present review, we have discussed the role of the polyol pathwayenzyme aldose reductase (AR) in the amplification of allergic airway inflammation. Recent studies haveindicated that AR inhibition prevents the NF-κB-dependent generation of pro-inflammatory cytokines andchemokines in mouse models of allergic airway inflammation indicating the potential use of AR inhibition as anovel tool to control allergic responses. Since orally available AR inhibitors have already undergone phase IIIclinical trials for diabetic neuropathy and appear to have a manageable side effects profile, they could bereadily developed as potential new drugs for the treatment of asthma and related complications.