DC-SIGN:Binding receptor for HCV?

DC-SIGN,a dendritic Cell-specific adhesion receptor and atype Ⅱ transmembrane mannose-binding C-type lectin,isvery important in the function of DC,both in mediating naiveT cell interactions through ICAM-3 and as a rolling receptorthat mediates the DC-specific ICAM-2-dependent migrationprocesses.It can be used by viral and bacterial pathogensincluding Human Immunodeficiency Virus (HIV),HCV,EbolaVirus,CMV and Mycobacterium tuberculosis to facilitateinfection.Both DC-SIGN and DC-SIGNR can act either in cis,by concentrating virus on target cells,or in trans,by transmissionof bound virus to a target cell expressing appropropriateentry receptors.Recent work showed that DC-SIGN are high-affinity binding receptors for HCV.Besides playing a role inentry into DC,HCV E2 interaction with DC-SIGN might alsobe detrimental for the interaction of DC with T cells duringantigen presentation.The clinical strategies that target DC-SIGN may be successful in restricting HCV dissemination andpathogenesis as well as directing the migration of DCs tomanipulate appropriate immune responses in autoimmunityand tumorigenic situations.     

Platelet-collagen interaction: is GPVI the central receptor?

At sites of vascular injury, platelets come into contact with subendothelial collagen, which triggers their activation and the formation of a hemostatic plug. Besides glycoprotein Ib (GPIb) and alphaIIbbeta3 integrin, which indirectly interact with collagen via von Willebrand factor (VWF), several collagen receptors have been identified on platelets, most notably alpha2beta1 integrin and the immunoglobulin (Ig) superfamily member GPVI. Within the last few years, major advances have been made in understanding platelet-collagen interactions including the molecular cloning of GPVI, the generation of mouse strains lacking individual collagen receptors, and the development of collagen receptor-specific antibodies and synthetic peptides. It is now recognized that platelet adhesion to collagen requires prior activation of integrins through "inside-out" signals generated by GPVI and reinforced by released second-wave mediators adenosine diphosphate (ADP) and thromboxane A2. These developments have led to revision of the original "2-site, 2-step" model, which now places GPVI in a central position in the complex processes of platelet tethering, activation, adhesion, aggregation, degranulation, and procoagulant activity on collagen. This review discusses these recent developments and proposes possible mechanisms for how GPVI acts in concert with other receptors and signaling pathways to initiate hemostasis and arterial thrombosis.     

Angiotensin receptor blockers: how important is selectivity?

During the last decade, angiotensin-receptor blockers have established themselves as effective antihypertensive agents with impressive safety profile and placebo-like tolerability. Additionally, these compounds provide benefits beyond the reduction in blood pressure, in conditions such as heart failure and in patients with type 2 diabetes and renal insufficiency. It is tempting to group all angiotensin-receptor blockers together as a class, but a closer look reveals differences, for example, in chemical structure, metabolism, dissociation rates, and receptor affinities. Recent findings on the respective roles of the angiotensin receptors AT(1) and AT(2) have raised the possibility that the degree of selectivity for AT(1) over AT(2) might affect the performance of the drug. This review attempts to put the concept of selectivity in context and to assess the potential benefits in different organs, with focus on the kidney, endothelium and the heart.     

Impaired adaptive receptor regulation: an index of aging?

Many neuroendocrine functions are altered in old animals and their study may represent important steps in the understanding of the mechanisms of aging. A deeper insight, however, can be achieved by investigating the responsiveness to stimuli, which may reveal alterations not evident in the unstimulated conditions. At this level of study, many of such impairments have been found to be caused by receptor changes. In the present paper a third level of study is suggested in order to gain evidence of some remote failure of adaptive processes strictly linked to intimate mechanisms of aging. As at the second level of study different receptor characteristics can frequently be found at the basis of age-related alterations of biological responsiveness, at the proposed third level altered capacity of receptor regulation may be hypothesized as responsible for altered cell adaptation following hormone and drug stimuli. Experimental data are given which support this view. The possibility that receptor regulation may be used as an index of aging is suggested. This hypothesis leads to the problem of judging the validity of biological parameters deputed to represent good indices of aging. In order to solve this problem, the potential use of a mathematical model of mortality kinetics is discussed.     

16α-hydroxyprogesterone: origin, biosynthesis and receptor interaction

The metabolism of progesterone (PROG) by cytochrome P450 17α-hydroxylase/17,20-lyase (CYP17A1) results in the formation of both 17α-hydroxyprogesterone (17-OHPROG) and 16α-hydroxyprogesterone (16-OHPROG) in humans. Unlike 17-OHPROG, 16-OHPROG is not metabolised further in steroidogenic tissue. While this metabolite can be readily detected in serum and urine, its physiological role remains unclear. This paper reviews the production of 16-OHPROG by human CYP17A1 by providing insight into the catalysis of PROG by CYP17A1 and highlights the role of Ala105 in the 16α-hydroxylation reaction. As 16-OHPROG has been putatively linked to reproductive function, we investigated the interaction of this steroid metabolite with both isoforms of the human progesterone receptor (hPR). We show for the first time that 16-OHPROG can bind to both hPR-A and hPR-B and act as an agonist for both receptors.     

Angiotensin-II receptor blockers: benefits beyond blood pressure reduction?

Effective treatment of hypertension is essential to reduce the risk of renal and cardiovascular (CV) morbidity. The risks associated with hypertension are modulated by the presence of other factors. This has prompted the quest for agents that have benefits beyond blood pressure (BP) lowering. The angiotensin II receptor blocker (ARB) class of antihypertensive agents represents an important addition to the therapeutic options for elevated BP. Their ability to control BP is equivalent to existing therapies and there is a considerable and mounting evidence-base for their ability to reduce hypertension-associated target organ damage and comorbidities. Studies show that ARBs have clinical benefits across the spectrum of disease severity. In particular, recent large studies have demonstrated that these benefits extend to patients with conditions predisposing to CV events, such as diabetes, left ventricular hypertrophy and microalbuminuria, and where risk factors coexist. Data from these studies suggest that the CV protective effects of ARBs are at least, in part, independent from the BP lowering action. In addition, ARBs are extremely well tolerated, and strong evidence suggests that compliance with therapy--a key factor in achieving adequate BP control--with ARBs is higher than with other antihypertensive agents. Furthermore, flexible dosing and good tolerability profile mean that, where necessary, ARBs can be combined with other classes of antihypertensive agents to achieve adequate BP control and reduce the risk of hypertension-associated morbidity.     

Treatment of chronic heart failure with β-adrenergic receptor antagonists: a convergence of receptor pharmacology and clinical cardiology

Despite the absence of a systematic development plan, β-blockers have reached the top tier of medical therapies for chronic heart failure. The successful outcome was due to the many dedicated investigators who produced, over a 30-year period, increasing evidence that β-blocking agents should or actually did improve the natural history of dilated cardiomyopathies and heart failure. It took 20 years for supportive evidence to become undeniable, at which time in 1993 the formidable drug development resources of large pharmaceutical companies were deployed into Phase 3 trials. Success then came relatively quickly, and within 8 years multiple agents were on the market in the United States and Europe. Importantly, there is ample room to improve antiadrenergic therapy, through novel approaches exploiting the nuances of receptor biology and/or intracellular signaling, as well as through pharmacogenetic targeting.     

Calcium-sensing receptor in cancer: good cop or bad cop?

The extracellular calcium-sensing receptor (CaR) is a versatile ‘sensor’ for di- and polycationic molecules in the body. CaR plays a key role in the defense against hypercalcemia by “sensing” extracellular calcium levels in the parathyroid and kidney, the key organs maintaining systemic calcium homeostasis. Although mutation of CaR gene has so far not been associated with any malignancy, aberrant functions of CaR have implications in malignant progression. One situation is loss of CaR expression, resulting in loss of growth suppressing effects of elevated extracellular Ca²⁺ by CaR, reported in parathyroid adenoma and in colon carcinoma. Another situation is activation of CaR, resulting in increased production of parathyroid hormone-related peptide (PTHrP), a primary causal factor in hypercalcemia of malignancy and a contributor to metastatic processes involving bone. CaR signaling and effects have been studied in several cancers including ovarian cancers, gastrinomas, and gliomas in addition to comparatively detailed studies in breast, prostate, and colon cancers. Studies on H-500 rat Leydig cells, a xenotransplantable model of humoral hypercalcemia of malignancy has shed much light on the mechanisms of CaR-induced cancer cell growth and survival. Pharmacological agonists and antagonists of CaR hold therapeutic promise depending on whether activation of CaR is required such as in case of colon cancer or inactivating the receptor is required as in the case of breast- and prostate tumors. Bandana Chakravarti and Shailendra Kumar Dhar Dwivedi contributed equally.     

The androgen receptor CAG repeat: a modifier of carcinogenesis?

The first exon of the human androgen receptor (AR) contains a translated CAG (poly-glutamine) repeat. The repeat length is polymorphic in the normal population ranging from 8 to 35 repeats. Expansions to over 40 repeats lead to spinal bulbar muscular atrophy (SBMA), a late onset neurodegenerative disease. The repeat is located between the two parts of a bipartite amino-terminal transactivation function and the repeat length, also within in the normal range, is inversely correlated to the transactivation power of the receptor. P160 type co-activators bind more strongly to shorter repeats. A correlation between AR CAG repeat length and total risk, age at diagnosis, recurrence after surgery and aggressive growth has been reported for tumors of classical androgen target tissues. In the prostate, where androgens exert a mitogenic effect, the cancer risk increases with decreasing AR-CAG repeat length. In contrast, in the breast, where the hormone probably acts as anti-mitogen, a higher risk and earlier onset of breast cancer has been reported for carriers of BRCA1 mutations who also have long CAG repeats in the receptor gene. Somatic alterations during carcinogenesis appear to be frequent in endometrial and in colon cancer. In the endometrium the AR CAG repeat prevalently undergoes expansions consistent with the putative protective function of androgens in this tissue. Frequent repeat reductions during colon carcinogenesis would be consistent with a mitogenic effect of androgens. Analysis of AR protein expression by Western blot reveals expression of the AR in healthy and neoplastic colon tissues. Normal mucosa of the colon expresses both AR-isoforms of 110 and 87 kDa, while the tumor samples have lost the expression of the 110-kDa isoform. The 87-kDa isoform is devoid of the amino-terminal portion of the receptor molecule that also contains the poly-glutamine tract. The temporal and causal relation between isoform switch and somatic repeat reductions during colon carcinogenesis is as yet unclear, but the two events could both enhance p160 mediated androgen signaling. The recent finding that smad3 interacts with the AR in a way similar to p160 links the AR to TGFbeta signaling. Interruption of this signaling pathway is a frequent event in colon carcinogenesis.