Modulation Of Alpha Research Articles

Docking study of triphenylphosphonium cations as estrogen receptor alpha modulators

Virtual high throughput screening (VHTS) was performed to assess possible interactions which might occur between commercially available triphenylphosphonium (TPP) cations and estrogen receptor alpha (ERalpha) that could be exploited to design novel ERalpha modulators. One application of TPP cations is for delivering bioactive molecules to targets in mitochondria as the large membrane potential of mitochondria leads cations to accumulate inside them. The estrogen receptors (ERs) alpha and beta, normally activated by the endogenous hormone 17beta-estradiol, are responsible for controlling transcription of nuclear DNA necessary for human development and reproduction. ERs are also associated with the plasma membrane and have been found in the mitochondria of a variety of cell types. Selective estrogen receptor modulators (SERMs) are synthetic compounds which are used to modulate ER activity. Different SERMs display varying combinations of agonistic, antagonistic and neutral effects upon estrogen receptors depending upon the tissue type and cellular location of the receptor. Thus, they are being employed to treat a range of ER-related disorders. A common feature shared by many SERMs is the close arrangement of three aromatic rings similar to TPP cations. Given this structural similarity, the estrogenic activity of triphenyl phosphonium salts was investigated using the automated docking program eHiTS. Compounds were docked into ten different crystal structures of ERalpha. Structures were chosen based upon eHiTS ability to accurately identify the majority of estrogenically active compounds given a set of active and decoy molecules. The results of the VHTS suggest hybrids of TPP cations and known SERMs could serve as potent mitochondrial SERMs.

Age-and Gender-Specific Modulation of Serum Osteopontin and Interferon Alpha by Osteopontin Genotype in Systemic Lupus Erythematosus

Age-and Gender-Specific Modulation of Serum Osteopontin and Interferon Alpha by Osteopontin Genotype in Systemic Lupus Erythematosus

Developmental excitation of corticothalamic neurons by nicotinic acetylcholine receptors.

In this study, we show robust nicotinic excitation of pyramidal neurons in layer VI of prefrontal cortex. This layer contains the corticothalamic neurons, which gate thalamic activity and play a critical role in attention. Our experiments tested nicotinic excitation across postnatal development, using whole-cell recordings in prefrontal brain slices from rats. These experiments showed that layer VI neurons have peak nicotinic currents during the first postnatal month, a time period of intensive cortical development in rodents. We demonstrate that these currents are mediated directly by postsynaptic nicotinic receptors and can be suppressed by a competitive antagonist of alpha(4)beta(2)* nicotinic receptors. To record from identified corticothalamic neurons, we performed stereotaxic surgery to label the neurons projecting to medial dorsal thalamus. As hypothesized, recordings from these retrogradely labeled neurons in layer VI showed prominent nicotinic currents. Finally, we examined the effects of the drug nicotine on layer VI neurons and probed for the potential involvement of the accessory subunit, alpha(5), in their receptors. A level of nicotine similar to that found in the blood of smokers elicits a stable inward current in layer VI neurons, yet this exposure desensitizes approximately 50% of the subsequent current elicited by acetylcholine. An allosteric modulator of alpha(4)beta(2)alpha(5) receptors resulted in a 2.5-fold potentiation of submaximal nicotinic currents. This result is consistent with the expression of the relatively rare alpha(5) nicotinic subunit in layer VI. In summary, we show that layer VI corticothalamic neurons can be strongly excited during development by an unusual subtype of nicotinic receptor.

Modulation of the IL-1 cytokine network in keratinocytes by intracellular IL-1 alpha and IL-1 receptor antagonist.

The IL-1 cytokine network in epidermal cells was studied in vitro, using the spontaneously transformed HaCAT human keratinocyte line. Intracellular (ic) IL-1 alpha and IL-1 receptor antagonist protein (IL-1Ra) following cell lysis were readily identified assayed using a capture ELISA; whereas in culture supernatants IL-1Ra was not detected, and IL-1 alpha was present at only very low levels. Confluent cultures of HaCAT cells were shown to provide optimal conditions for the study, since confluence increased the icIL-1Ra:IL-1 alpha ratio to a level as seen in vivo, which was independent of Ca2+ concentration in the culture medium. The IL-1Ra extracted from HaCAT cell lysates was functionally active, as demonstrated in the mouse thymocyte co-proliferation assay which could be blocked using a rabbit anti-IL-1Ra antibody. Transforming growth factor-beta (TGF-beta 1) stimulated a dose-dependent increase in HaCAT cell IL-1 alpha without changing IL-1Ra concentration, with a resultant reduction in the icIL-1Ra: IL-1 alpha ratio from 320:1 to 100:1. Similarly, TGF-alpha, interferon-gamma (IFN-gamma), IL-6, and tumour necrosis factor-alpha (TNF-alpha) substantially increased HaCAT cell IL-1 alpha, but had no effect on the IL-1Ra, with a concomitant reduction in the icIL-1Ra:IL-1 alpha ratio. In contrast to their effects on monocytes, IL-4 and IL-10 at biologically active levels had no effect on IL-1 alpha, IL-1Ra or the icIL-1Ra: IL-1 alpha ratio in confluent HaCAT cells. Hydrocortisone reduced IL-1 alpha to below the limit of sensitivity of the ELISA, and induced a small increase in IL-1Ra of questionable biological significance. Thus, regulation of the IL-1 cytokine network in keratinocytes involves modulation of icIL-1 alpha rather than of icIL-1Ra levels, and is markedly different from that noted in monocytes.

Ovariectomy, but Not Estrogen Deficiency, Increases CYP4A Modulation of 1-Adrenergic Vasoconstriction in Aging Female Rats

Postmenopausal women are more likely to develop cardiovascular disease (CVD) than premenopausal women. Increased vasoconstriction in the peripheral vasculature may underlie this risk. In vascular smooth muscle, cytochrome P450 4A (CYP4A) enzymes form the vasoconstrictor 20-hydroxyeicosatetraenoic acid (20-HETE). CYP4A modulation of alpha(1)-adrenergic vasoconstriction is increased in aging male rats; however, this pathway has not been investigated in aging females. To generate an appropriate model of menopause, we ovariectomized aged Sprague-Dawley rats to create an aged, ovarian-depleted phenotype. Because estrogen has profound effects on the peripheral vasculature, we also determined the effect of estrogen replacement on CYP4A modulation of vasoconstriction. Aged (15-16 months) rats were assigned to be intact or ovariectomized. Ovariectomized rats received either placebo (OVX) or 17beta-estradiol (OVX-E) subcutaneously for 4 weeks. Mesenteric arteries were isolated and constricted with the alpha(1)-adrenergic agonist phenylephrine or intraluminal pressure in the absence or presence of the CYP4A inhibitor, DDMS. Ovariectomy increased CYP4A modulation of alpha(1)-adrenergic vasoconstriction. This was unaffected by estrogen replacement. Arteries from OVX-E animals exhibited increased phenylephrine sensitivity and forced dilation relative to arteries from intact and OVX animals. Myogenic tone was increased in both OVX and OVX-E animals relative to intact rats; however, CYP4A inhibition had no effect on myogenic tone in any group. In aged female rats, ovariectomy caused an increase in CYP4A modulation of alpha(1)-adrenergic vasoconstriction that was not prevented by estrogen replacement. Future study of these pathways may provide important targets for the prevention of CVD in aging women.

Cajal–Retzius cells in the mouse neocortex receive two types of pre‐ and postsynaptically distinct GABAergic inputs

Cajal-Retzius (CR) cells are principal cells of layer I in the developing neocortex. They are able to generate action potentials, make synaptic contacts in layer I and receive excitatory GABAergic inputs before birth. Although CR cells participate in neuronal network activity in layer I, the properties of their synaptic inputs are not yet characterized. We recorded miniature (mIPSCs) and evoked (eIPSCs) postsynaptic currents using the whole-cell patch-clamp technique. Most of CR cells displayed two types of mIPSCs, namely those with fast (mIPSC(F)) and slow (mIPSC(S)) rise kinetics. The mIPSC(F) mean amplitude was significantly larger than that of mIPSC(S), while their decay rates were not different. Peak-scaled non-stationary noise analysis revealed that mIPSC(S) and mIPSC(F) differed in their weighted single-channel conductance. In addition, zolpidem (100 nm), a modulator of alpha(1) subunit-containing GABA(A) receptors, selectively affected mIPSC(S) suggesting that different postsynaptic GABA(A) receptors mediate mIPSC(F) and mIPSC(S). eIPSCs also split into two populations with different rise kinetics. Fast eIPSCs (eIPSC(F)) displayed higher paired-pulse ratio (PPR) and lower GABA release probability than slowly rising eIPSCs (eIPSC(S)). As CGP55845, a GABA(B) receptor antagonist, eliminated the observed difference in PPR, the lower release probability at IPSC(F) connections probably reflects a stronger tonic GABA(B) receptor-mediated inhibition of IPSC(F) synapses. At low (0.1 Hz) stimulation frequency both inputs can effectively convert presynaptic action potentials into postsynaptic ones; however, only IPSC(F) connections reliably transfer the presynaptic activity patterns at higher stimulation rates. Thus, CR cells receive two GABAergic inputs, which differ in the quantal amplitude, the probability of GABA release and the frequency dependence of signal transfer.

Inhibition of tumour necrosis factor-? secretion from EpiDermTMtissues by a novel small molecule, UTL-5d

UTL-5d [N-(4-chlorophenyl)-3-carboxyamidyl-5-methylisoxazole] is a small-molecule tumour necrosis factor (TNF)-alpha modulator being investigated for its potential in several immune-mediated diseases, including psoriasis. We aimed to determine whether UTL-5d represents a potential antipsoriasis agent. Firstly, a keratinocyte cell-based study was used to study the inhibition of TNF-alpha and gene suppression by UTL-5d in vitro. Secondly, a multilayered human epidermis tissue model, consisting of normal human-derived epidermal keratinocytes, was used to study the dose-dependent reduction of TNF-alpha by UTL-5d as well as the feasibility of using UTL-5d in a lotion formulation. The cell-based study showed that UTL-5d significantly reduced TNF-alpha secretion from keratinocytes (68% reduction at 17 mug mL(-1)) and suppressed JAK3 and MAP3K2 genes by 70% and 40%, respectively. In the human epidermis tissue model, reduction of TNF-alpha by UTL-5d appeared to be dose dependent (8.35-33.4 microg mL(-1)); UTL-5d also reduced cell death induced by ultraviolet (UV) B. Tissues treated by UTL-5d in a preliminary lotion formulation showed significant reduction of TNF-alpha induced by UVB. Our results indicate that UTL-5d may be worthy of further investigation for its potential as a topical agent for psoriasis.

Medicinal Chemistry and Emerging Strategies Applied to the Development of Selective Estrogen Receptor Modulators (SERMs)

Selective estrogen receptor modulators (SERMs), known previously as "antiestrogens", are a new category of therapeutic agents used for the prevention and treatment of diseases such as osteoporosis and breast cancer. SERMs act as ER-agonist in some tissues while acting as ER-antagonist in others based on conformational change of the receptors, particularly at the helix 12. Currently, there are two classes of clinically approved SERMs; triphenylethylene derivatives (e.g., tamoxifen) and benzothiophene derivatives (e.g., raloxifene). Tamoxifen, raloxifene and toremifene are the most widely used SERMs. Tamoxifen, an antagonist of the breast tissue, is the first clinically identified compound with noticeable SERM activity. Although tamoxifen has been very successful in breast cancer treatment, its agonistic effect on the uterus is said to be associated with increase risk of developing endometrial cancer. Ideally, it is presumed that SERMs should selectively act as an agonist in the bone and brain while simultaneously acting as an antagonist in the breast and uterus. Therefore, the therapeutic goal of SERMs is the prevention of estrogen deficiency diseases without promoting estrogen-associated tumor growth. Therefore, the objective of this review is to summarize various effects that have been applied in improving the tissue-selectivity of SERMs, highlighting the emerging understanding of their mechanism of actions in selected target tissues and the development of the SERMs. The significance in recent discovery of selective estrogen receptor alpha modulators, SERAMs will also be reviewed.

Modulation of alpha and beta crystallin expression in rat retinas with ocular hypertension-induced ganglion cell degeneration

The expression of alpha (αA and αB) and beta (βA1/A3, βA2, βA4, and βB2) crystallin genes were analyzed at the mRNA and protein levels in rat retinas with ocular hypertension-induced ganglion cell death. An animal model with progressive loss of retinal ganglion cells (RGC) was generated by elevation of intraocular pressure (IOP). The estimated RGC loss was approximately 8% and 20% at 2 and 5 weeks post IOP elevation, respectively. mRNA and protein quantification showed that alpha and beta crystallin genes were downregulated at both transcriptional (αA, αB, βA1/A3, βA4, and βB2 approximately 50% and βA2 ~ 40%) and protein (αA ~ 50%, αB ~ 63%, βA1/A3 ~ 70%, and βB2 ~ 38%) levels 2 weeks after IOP elevation. In experimental retinas 5 weeks after IOP elevation, the levels of crystallin mRNAs were higher than at 2 weeks and were comparable to that of control retinas. However, the levels of the corresponding proteins were still lower (αA, αB, and βB2 approximately 37% and βA1/A3 ~ 70%) than in control retinas. Furthermore, we found that the expression of these genes in the retina is predominantly localized to the cells in the GCL and to a lesser degree in the INL and ONL. Colocalization of the crystallin-positive and Fluorogold retrogradely labeled cells indicated that the cells expressing alpha and beta crystallins in the GCL are RGCs. In summary, we showed that alpha and beta crystallins are expressed in the retina predominantly by RGCs and that their expression is affected by ocular hypertension.

Modulation of hypoxia-inducible factor-1 alpha in cultured primary cells by intracellular ascorbate

Control of the transcription factor hypoxia inducible factor (HIF)-1 is mediated by hydroxylation by proline and asparagine hydroxylases. These enzymes require ascorbate for optimal activity, but little attention has been given to the effect of ascorbate on HIF-1 activation. Furthermore, cells in culture are ascorbate deficient. We investigated the effect of intracellular ascorbate on HIF-1α protein levels and on HIF-1-mediated gene expression in two human primary cell lines (umbilical vein endothelial cells and skin fibroblasts) and one human cancer cell line (A431 epithelial cells). Under normal culture conditions the cells contained no ascorbate and adding ascorbate to the medium increased intracellular concentrations in a dose-dependent manner. A basal level of HIF-1α detected in nonsupplemented cells under normoxic conditions disappeared when 10 μM ascorbate was added to the medium. Induction of HIF-1α by hypoxia (1% O 2) or by CoCl 2 was markedly inhibited by ascorbate and loading with physiological levels resulted in almost complete reversal of HIF-1α stabilisation. Gene expression was similarly affected, with VEGF mRNA and GLUT-1 up-regulation being inhibited by ascorbate. Hence intracellular ascorbate is a major regulator of the hypoxic response in normal cells and optimal levels of this vitamin will have a profound effect on HIF-1-regulated processes.

Lessons for lupus from tumour necrosis factor blockade

Systemic lupus erythematosus (SLE) is a systemic non-organ specific autoimmune disease associated with multiple autoantibodies targeting autoantigens from the nucleus. Given the complex pathophysiology of SLE and the role of TNF alpha in that disease, modulation of TNF alpha (in SLE or non-SLE patients) using TNF blockers could either be detrimental or beneficial in some patients. In this review we will focus on lupus autoantibodies and clinical manifestations after TNF blockade in SLE patients and conversely on drug-induced-SLE in non-SLE patients. Some hypotheses regarding the mechanism of induction of autoantibodies in RA patients treated with TNF blockers are proposed.

The Modulation of Aromatase and Estrogen Receptor Alpha in Cultured Human Dermal Papilla Cells by Dexamethasone: A Novel Mechanism for Selective Action of Estrogen via Estrogen Receptor Beta?

Steroid hormones have important modulatory effects on the hair follicle, but the mechanisms by which they regulate human hair growth are still poorly understood. It is now clear that there are two distinct estrogen receptors (estrogen receptor alpha (ERalpha) and estrogen receptor beta (ERbeta)) that bind 17beta-estradiol. Since the follicular dermal papilla is known to control hair growth, and steroid hormones regulate receptor and aromatase expression in other tissues, we tested the hypothesis that steroid hormones would similarly modulate estrogen receptor and/or aromatase expression in cultured dermal papilla cells derived from human hair follicles. Primary cultures of non-balding occipital and frontal scalp and beard dermal papilla cells (n = 10) were established. Immunocytochemical studies showed the expression of ERalpha in both the cytoplasm and nucleus, whereas ERbeta was confined to the nuclei. The cells derived from occipital scalp were also incubated for 24 hours with 10 nM of either 17beta-estradiol, estrone, testosterone, 5alpha-dihydrotestosterone, 5alpha-androstane-3alpha, 17beta-diol, 5alpha-androstane-3beta, 17beta-diol, or 100 nM tamoxifen or dexamethasone in phenol red-free, serum-free medium to measure the steady-state levels of ERalpha, ERbeta, and aromatase mRNA by semiquantitative reverse transcriptase-PCR. Although androgens and estrogens did not alter ERalpha mRNA levels, treatment with dexamethasone significantly reduced ERalpha levels to 38% of the untreated control. By contrast, ERbeta mRNA levels were unaffected by any steroid treatment. Furthermore, dexamethasone significantly stimulated the expression of aromatase mRNA approximately 9-fold. Aromatase activity, assayed by the tritiated water method, was stimulated in both frontal scalp and beard dermal papilla cell cultures by dexamethasone. These observations provide evidence for a glucocorticoid-dependent mechanism whereby the selective action of estradiol via ERbeta may be promoted. Additionally, upregulation of aromatase combined with downregulation of ERalpha provides a basis for selective action of estradiol produced locally by autocrine or paracrine mechanisms.

Insulin-like growth factor 1 is a potent stimulator of cervical cancer cell invasiveness and proliferation that is modulated by α v β 3 integrin signaling

Insulin-like growth factor 1 (IGF-1) has been implicated in promoting mitogenic, metastatic and antiapoptotic phenotypes in several types of cancer. But little is known about the signal interaction of IGF-1 and integrin in the regulation of cervical cancer development and progression. This study is to investigate the regulatory mechanism of IGF-1 receptor (IGF-1R) signaling and its importance in cervical cancer formation. The growth and invasiveness of cervical cancer cells (SiHa and CaSki) were dose-dependently stimulated by IGF-1, whereas those of normal cervical epithelial cells were not. The immunoblot showed that IGF-1R proteins were abundant in cervical cancer cell lines. In contrast, IGF-1R protein was nearly undetectable in normal cervical epithelial cells. IGF-1-stimulated invasion and proliferation were abolished by functional-blocking monoclonal antibody against IGF-1R, whereas these cellular functions were unaffected by either IgG or monoclonal antibody to insulin receptor. Functional-blocking monoclonal antibody against integrins alpha(v)beta3, but not alpha2 alpha3, alpha4 alpha6 beta1, beta4 or alpha2beta1, inhibited the IGF-1-stimulated invasion and proliferation in cervical cancer cells. alpha(v)beta3 integrin modulated IGF-1R phosphorylation by altering the rate of Src homology 2-containing phosphotyrosine phosphatase (SHP-2) recruitment to the activated IGF-1R. The modulation of alpha(v)beta3 occupancy also affected the activation of IGF-1R downstream-signaling elements, including activation of Akt and extracellular signal-regulated protein kinases 1/2 (Erk1/2). The treatment of blocking antibody of alpha(v)beta3 integrin or IGF-1R significantly inhibited tumor growth and caused tumor regression in SCID mice model. Immunoblots of tumor tissues confirmed that the phosphorylation of IGF-1R and downstream targets of Akt and Erk1/2 were remarkably decreased in SCID mice treated with blocking antibodies of alpha(v)beta3 or IGF-1R. Thus, these data suggest that the signal interaction between IGF-1R and alpha(v)beta3 integrin plays an important role in promoting the development and progression of cervical cancer.

Estrogen Receptor Ligands. Part 15: Synthesis of Benzothiopyran-based Selective Estrogen Receptor Alpha Modulators (SERAM)

Benzothiopyran (2) was prepared and the bioactive (+)-2 was found to exhibit a reduced affinity toward the estrogen receptors (ERα/β) when compared to the corresponding dihydrobenzoxathiin (+)-1.

Anesthesia-specific protection from endotoxic shock is not mediated through the vagus nerve

We have shown recently that volatile anesthetics significantly decrease inflammatory cytokine production and dramatically increase survival among rodents challenged with lipopolysaccharide (LPS). Because acetylcholine's interaction with nicotine receptors on tissue macrophages during vagus nerve stimulation has been implicated in the modulation of LPS-stimulated tumor necrosis factor alpha (TNF-alpha) production, we hypothesized that the mechanism of anesthetic immunoprotection is mediated through the vagus nerve. Male Sprague-Dawley rats underwent bilateral cervical vagotomy (n = 20) or sham operation (n = 6). Twenty-four hours postoperatively, vagotomized rats were randomized into 3 groups: LPS injection (V+LPS, n = 6), LPS injection followed by 60 minutes of isoflurane anesthesia (V+LPS+ISO, n = 7), or saline injection (V+S, n = 7). Sham animals were also given LPS (Sham+LPS). A sublethal dose of LPS (8 mg/kg) was used. Blood samples were collected via cardiac puncture 90 minutes after LPS or saline injection, and plasma was isolated for the measurement of cytokines by enzyme-linked immunosorbent assay. Statistical differences between groups were detected by 1-way analysis of variance. Serum TNF-alpha was reduced significantly and interleukin (IL)-6 was abrogated completely among V+LPS+ISO rats, compared with both V+LPS and Sham+LPS animals (P < or = .05 for all). In contrast, levels of the anti-inflammatory cytokine IL-10 were similar among all LPS groups. Isoflurane anesthesia administered simultaneously with the injection of LPS decreases serum production of TNF-alpha and IL-6 despite bilateral transection of the vagus nerve. Isoflurane-mediated attenuation of proinflammatory cytokine production occurs via a mechanism other than modulation of vagal output.

Hepatic Cytochrome P450 Gene Regulation during Endotoxin-Induced Inflammation in Nuclear Receptor Knockout Mice

Inflammatory agents such as lipopolysaccharide (LPS) down-regulate the hepatic expression of many cytochrome P450 (P450) mRNAs and proteins. Previous studies suggested that suppression of some P450 mRNAs could involve the regulation or modulation of the nuclear receptors peroxisome proliferator-activated receptor alpha (PPARalpha) or pregnane X receptor (PXR). To determine the involvement of these receptors in P450 down-regulation, PPARalpha knockout (KO), PXR KO, and appropriate wild-type (WT) mice were administered either saline or 1 mg/kg LPS. Hepatic mRNA and protein expression of several P450 isoforms, interleukin (IL)-1beta, IL-6, tumor necrosis factor (TNF) alpha, alpha1-acid glycoprotein (AGP), and fibrinogen (FBG) were examined 16 h later. LPS administration significantly decreased the hepatic expression of CYP1A2, 2A5, 2C29, 2E1, 3A11, 4A10, and 4A14 mRNAs in both groups of PPARalpha and PXR mice, whereas CYP3A13 mRNA was increased slightly in PPARalpha WT and KO mice, but not in PXR mice. Effects of LPS administration on mouse hepatic P450 proteins (probed using rat P450 2C, 3A, 4A, and 2E antibodies) were consistent with mRNA results in most cases. LPS treatment significantly increased IL-1beta, IL-6, TNFalpha, AGP, and FBG mRNA in both PPARalpha and PXR mice, with the greatest effect observed with TNFalpha. Because decreases in P450 mRNA expression were essentially identical in both WT and KO mice for both nuclear receptors, these data indicate that down-regulation of P450 during inflammation does not require the nuclear receptors PPARalpha and PXR.

Estrogen receptor ligands. Part 6: Synthesis and binding affinity of dihydrobenzodithiins

Dihydrobenzodithiin compounds (1–6) were prepared to explore the expansion of the dihydrobenzoxathiin lead compounds I–III as SERAMs (Selective Estrogen Receptor Alpha Modulators). The dihydrobenzodithiin compounds generally maintained a high degree of selectivity for ERα over ERβ, however, they lacked the in vivo antagonism/agonism activity exhibited by the lead class in an immature rat uterine growth model.

L-Carnitine is a modulator of the glucocorticoid receptor alpha.

L-Carnitine (LC) is a nutrient with an essential role in cellular energy production. At high doses, LC can mimic some of the biological activities of glucocorticoids, particularly immunomodulation. To explore the molecular bases of this property, we tested the influence of LC on glucocorticoid receptor-a (GRalpha) functions. LC reduced the binding capacity of GRalpha, induced its nuclear translocation, and stimulated its transcriptional activity. Moreover, LC suppressed TNFalpha and IL-12 release from human monocytes in glucocorticoid-like fashion. We conclude that pharmacologic doses of LC can activate GRalpha and, via this mechanism, regulate glucocorticoid-responsive genes, potentially sharing some of the biological and therapeutic properties of glucocorticoids.

The modulation of thymosin alpha 1 in the maturation, differentiation and function of murine bone marrow-derived dendritic cells in the absence or presence of tumor necrosis factor-alpha

Thymosin alpha 1 (Tα1) has immunomodulatory effects on T-cells, NK-cells and macrophages, but its action on dendritic cells (DCs), which are recognized as the sole professional antigen presenting cells (APCs) capable of priming naı̈ve T-cells, is poorly understood. In this study, the effect of Tα1 in vitro on murine bone marrow-derived DCs (BMDCs) maturation, differentiation, and function with or without tumor necrosis factor-alpha (TNF-α), which is one of the important inflammatory parameters, has been investigated. We have shown, through flow cytometry, ELISA and mixed leukocyte reaction (MLR), that Tα1 promoted CD4-expressed DC differentiation and the expression of activation markers, but did not influence IL-12 production and T cell-stimulatory capacity of DCs in the absence of TNFα during BMDCs maturation. Furthermore, in the presence of TNF-α, Tα1 has been shown not only to promote the expression of CD4 on MHC class II + DCs and enhance the up-regulated levels of mature markers induced by TNF-α, but also to suppress the up-regulated IL-12 production. Particularly, thus effects seen were obvious at pharmacological Tα1 concentrations. However, Tα1 did not inhibit TNF-α-induced T-cell stimulating function of DCs. This is the first reported example of a direct Tα1-DC interaction and suggests a mechanism by which Tα1 may in part affect T-cell responses by acting at the DC level and it may play an important role in the modulation of the local inflammatory responses in vivo.

Modulation of alpha 7 nicotinic receptors as a strategy for therapy in schizophrenia

Modulation of alpha 7 nicotinic receptors as a strategy for therapy in schizophrenia