Current Molecular Medicine - Volume 10, Issue 6, 2010

Adipose tissue is an endocrine organ able to produce a wide series of pleiotropic molecules, defined “adipokines”. In addition to the regulation of food intake and energy metabolism, adipokines are also implicated in the complex control of bone biology and specifically of bone remodeling. Leptin, the most studied adipokine, promotes satiety and energy expenditure and its circulating levels are proportional to fat mass. Some paradoxical findings originally suggested the involvement of leptin in controlling bone mass. For example, obese postmenopausal women, with elevated circulating leptin and leptin resistance, appear protected against the development of osteoporosis. Moreover, genetically leptin-deficient mice, which are hypogonadal and obese, display a decreased trabecular volume in long bones, but an increased vertebral bone mass, which is reduced by leptin administration. The complex mechanisms of leptin regulation of bone mass appear to involve selected hypothalamic neuronal populations and the sympathetic outflow, with an important role of osteoblastic β2-adrenergic receptors. Adiponectin is another adipokine, which promotes insulin sensitivity and is reduced in obese and diabetic subjects. Adiponectin appears to exert a negative effect on bone mass and seems to be an independent predictor of lower bone mass. Although the adipokines resistin and visfatin do not seem to significantly affect bone metabolism, the potential impact of them and other adipokines is still to be determined. Moreover, the molecular adipokine-bone interactions should also be considered in the context of the adipokine changes observed in diseases such as obesity and the metabolic syndrome.

FOXP3 is essential for the development and function of regulatory CD4+CD25hi T (Treg) cells. However, recent evidence suggests that FOXP3 alone is not sufficient to completely explain the regulatory phenotype of these key players in autoimmunity and inflammation: after being activated, conventional human CD4+ T cells transiently up-regulate FOXP3 without acquiring a regulatory function. Researchers have recently found that glycoprotein A repetitions predominantly (GARP, or LRRC32) is a Treg-specific receptor that binds latent TGF-β and dominantly controls FOXP3 and the regulatory phenotype via a positive feedback loop. This finding provides a missing link in our molecular understanding of FOXP3 in Treg cells. This viewpoint focuses on GARP as safeguard of FOXP3 and the regulatory phenotype.

Aldose reductase, although identified initially as a glucose-reducing enzyme via polyol pathway, is believed to be an important component of antioxidant defense system as well as a key mediator of oxidative stress-induced molecular signaling. The dual role played by AR has made it a very important enzyme for the regulation of not only the cellular redox state by detoxifying the reactive lipid-aldehydes generated by lipid peroxidation which is crucial in the cellular homeostasis, but also in the regulation of molecular signaling cascade that may regulate oxidative stress-induced cytotoxic events. Search for the new molecular targets to restrain the oxidative stress-induced inflammation has resulted in the identification of AR as an unanticipated mediator of oxidative stress-induced signaling. Although, in last one decade or so AR has been implicated in various inflammation-related disease conditions ranging from diabetes, sepsis, cancer, cardiovascular and airway inflammation, however, a critical evaluation of the clinical efficacy of AR inhibitors awaits a better understanding of the role of AR in regulating inflammation, especially in ocular inflammation.

Enteroviruses are common human pathogens involved in a wide spectrum of clinical outcomes ranging from mild or non-symptomatic illness to severe diseases with neurological and/or cardiac manifestation. Despite being responsible for significant morbidity and mortality especially in immunocompromised patients and infants, to date no effective vaccines or specific antiviral treatment modalities are available to prevent or treat non-polio enteroviral infections. The discovery of the endogenous RNA interference pathway as an innate defence mechanism conferring intracellular immunity against foreign genetic elements has provided exciting possibilities in the fight against so far intractable, enteroviral diseases. We and others have shown the encouraging potential of RNA interference to limit enteroviral infections, leading to significant suppression of viral replication and cytopathogenicity, in vitro as well as in vivo. Yet, considerable limitations concerning efficacy, stability, specificity as well as viral escape need to be addressed to translate the anti-enteroviral potential into a novel treatment modality.

Transforming growth factor-beta (TGFβ) is a pleiotropic multifunctional cytokine that regulates several essential cellular processes in many parts of the body including the cornea. Three isoforms of TGFβ are known in mammals and the human cornea expresses all of them. TGFβ1 has been shown to play a central role in scar formation in adult corneas whereas TGFβ2 and TGFβ3 have been implicated to play a critical role in corneal development and scarless wound healing during embryogenesis. The biological effects of TGFβ in the cornea have been shown to follow Smad-dependent as well as Smad-independent signaling pathways depending upon cellular responses and microenvironment. Corneal TGFβ expression is necessary for maintaining corneal integrity and corneal wound healing. On the other hand, TGFβ is perhaps the most important cytokine in the pathogenesis of fibrotic disease in the cornea. Although the transformation of keratocytes to myofibroblasts induced by TGFβ is largely believed to cause corneal fibrosis or scarring, the precise molecular mechanism(s) involved in this process is still unknown. Currently no drugs are available to treat corneal scarring effectively without causing significant side effects. Many approaches to treat TGFβ- mediated corneal scarring are under investigation. These include blocking of TGFβ, TGFβ receptor, TGFβ function and/or TGFβ maturation. Other strategies such as modulating keratocyte proliferation, apoptosis, transcription and DNA condensation are also being investigated. The potential of gene therapy to neutralize the pathologic effects of TGFβ has also been demonstrated recently.

In addition to their role in dietary lipid absorption bile acids are signaling modules activating nuclear receptors and at least one G-protein coupled receptor named the TGR5. With a different rank of potency primary and secondary bile acids activate a subset of nuclear receptors including the farnesoid-X-receptor (FXR, NR1H4); the constitutive androstane receptor (CAR, NR1H3), the pregnane-x- receptor (PXR, NR1H2), and the vitamin D receptor (VDR, NR1H1). Originally, these receptors were characterized for their role as bile acid and xenobiotic sensors, emerging evidence, however, indicates that FXR, PXR and VDR and their ligands are important for the modulation of immune and inflammatory reactions in entero-hepatic tissues. The immune phenotype FXR deficient mice indicates that these receptors are essential for the maintenance of immune homeostasis. A common theme of all bile acid-activated receptor is their ability to counter-regulate effector activities of cells of innate immunity establishing that signals generated by these receptors and their ligands function as braking signals for inflammation in entero-hepatic tissues. In this review, we will spotlight the molecular mechanisms of receptor/ligand function and how bile acid-activated receptors regulate the innate immunity in the gastrointestinal tract and liver. The ability of these receptors to integrate metabolic and inflammatory signaling makes them particularly attractive targets for intervention in immune-mediated diseases.

Pharmacodynamic (PD) biomarkers play a pivotal role in anti-tumor drug development as a biochemical measurement to estimate the level of drug interaction with the target, or to assess the downstream impact of its interaction with the target. Although immunohistochemistry (IHC)-based protein biomarkers have been conventionally used as PD biomarkers, gene expression-based PD biomarkers have recently emerged as quantitative biomarkers. This review introduces examples of gene expression-based mRNA biomarkers that have been validated in preclinical or clinical studies of several anti-tumor agents including HDAC, mTOR, and B-RAF inhibitors. The measurement of PD biomarker levels in tumors has proven to be ideal; however, in clinical studies, easily accessible surrogate tissues have been used for analysis. In the present review, we also discuss the advantages and disadvantages in using surrogate tissues, such as peripheral blood mononuclear cells (PBMCs), skin tissue, and circulating tumor cells, in the assessment of PD biomarkers. PD biomarkers are generally classified into two categories: 1) target engagement biomarkers and 2) early efficacy biomarkers. This classification depends on their respective distance from target intervention. The strategies used to identify and distinguish between these two types of PD biomarkers via expression profiling are also discussed. Finally, we propose two novel approaches for PD marker identification. One approach utilizes mRNA expression profiling of tumors prior to drug treatment rather than post-treatment samples. The second method involves the application of microRNA expression profiles to determine PD effects. In conclusion, the recent advances in mRNA and microRNA profiling and the identification of gene expression-based PD biomarkers may aid investigators to drive drug development through the establishment of quantitative PD effects.