Retinoic acid exacerbates experimental radiation nephropathy

Studies have shown that angiotensin-converting enzyme inhibitors and an angiotensin II receptor blocker can delay, but cannot reverse, the progression of experimentally induced radiation nephropathy. In an effort to find a method for reversing injury, three agents were tested in a rat model of radiation nephropathy. Pirfenidone (a phenyl-pyridone antifibrotic) and thiaproline (an inhibitor of collagen deposition) were not capable of retarding the development of radiation nephropathy. However, all-trans retinoic acid (an anti-inflammatory agent) exacerbated radiation nephropathy. We speculated that the detrimental effects of retinoic acid might be the result of stimulation of renal cell proliferation. However, retinoic acid had no effect on tubular or glomerular cell proliferation in normal animals and did not enhance radiation-induced proliferation. A recent report that retinoic acids inhibit nitric oxide production suggested an alternative mechanism, since inhibition of production of nitric oxide is known to exacerbate radiation nephropathy. Experiments demonstrated that retinoic acid exacerbated the radiation-induced drop in renal production of nitric oxide, suggesting that the detrimental effect of all-trans retinoic acid might be explained by inhibition of renal nitric oxide activity. Particularly in view of the recent clinical report of enhancement of radiation nephropathy by retinoic acid in patients receiving bone marrow transplantation, the combination of retinoic acid and renal irradiation should be carried out with great caution.     

Retinoic acid suppresses interleukin 6 production in normal human osteoblasts

Systemic long-term retinoid therapy for chronic skin diseases significantly reduced bone turnover markers within days and led to bone abnormalities. Retinoic acid (RA) plays a key role in the regulation of mouse bone cell proliferation, differentiation and functions. Meanwhile, there is little information of RA effect on human osteoblast and osteoclast cell development and function. Interleukin 6 (IL-6) is a pleiotropic cytokine with profound effects on bone metabolism. Thus, the present study examined the RA effect on cell differentiation, alkaline phosphatase and osteocalcin production as well as IL-6 production in normal human osteoblasts. The number of large differentiated osteoblast cells decreased in RA-treated cultures P<0.05. The production of bone specific markers, alkaline phosphatase and osteocalcin, was also reduced in RA-treated cultures. Normal human osteoblasts produced 31.0+/-4.8 pg IL-6 per ml in control cultures. Within 24 h, RA at all four concentrations reduced Il-6 production from normal human osteoblasts. The pharmacological concentration of 10(-5) M RA suppressed 90% of IL-6 production. The present study shows for the first time that RA profoundly inhibits IL-6 production in normal human osteoblasts within 24 h and in a dose-dependent manner. RA was shown previously to inhibit IL-6 production in several other normal and malignant human cell types. The associated decrease in osteoblast cell differentiation, alkaline phosphatase and osteocalcin production could result from the rapid RA-inhibition of IL-6 production. Thus, RA inhibition of IL-6 production in normal human osteoblasts may contribute to the bone abnormalities seen after systemic long-term retinoid therapy in some patients.     

Role of lactadherin in intestinal barrier integrity in experimental neonatal necrotizing enterocolitis

Necrotizing enterocolitis (NEC) is one of the most widespread and devastating gastrointestinal diseases in neonates. Destruction of the intestinal barrier is the main underlying cause of NEC. The aim of this study was to determine the role of lactadherin in preventing NEC in a neonatal rat model and investigate the molecular mechanism of lactadherin-mediated protection of the intestinal barrier. Neonatal rats were divided into three groups: dam feeding (DF), NEC (NEC), and NEC supplemented with 10 μg/(g·day) recombinant human lactadherin (NEC+L). Intestinal permeability, tissue damage, and cell junction protein expression and localization were evaluated. We found that lactadherin reduced weight loss caused by NEC, reduced the incidence of NEC from 100% to 46.7%, and reduced the mean histological score for tissue damage to 1.40 compared with 2.53 in the NEC group. Intestinal permeability of lactadherin-treated rats was significantly reduced when compared with that of the NEC group. In addition, the expression levels of JAM-A, claudin 3, and E-calcium in the ileum of NEC group animals increased compared with those in the ileum of DF group animals, and these levels decreased in the NEC+L group. Lactadherin changed the localization of claudin 3, occludin, and E-cadherin in epithelial cells. The mechanism underlying lactadherin-mediated protection of the intestinal barrier might be restoring the correct expression levels and localization of tight junction and adherent junction proteins. These findings suggest a new candidate agent for the prevention of NEC in newborns.     

Pregnancy suppresses experimental autoimmune encephalomyelitis through immunoregulatory cytokine production

Women with multiple sclerosis (MS) often experience a decrease in relapse rate during pregnancy, most notably during the third trimester, with a flare of disease activity 3-6 mo postpartum. Studies in experimental autoimmune encephalomyelitis (EAE), an animal model for MS, have shown that pregnancy delays the onset and decreases the incidence of disease. We investigated the effect of pregnancy and the postpartum period in a remitting-relapsing model of murine EAE. When immunization occurs during pregnancy, mice show a reduction in the incidence of EAE as well as a decrease in clinical severity, while mice immunized during the postpartum period exhibit more severe disease. No differences in lymphocyte proliferation or expression of activation markers were noted when immunization occurred during pregnancy as compared with the nonpregnant controls. Mice immunized during pregnancy produced less TNF-alpha and IL-17, and showed an increased number of IL-10-secreting cells within the CD11b+, CD11c+, CD19+, and CD4+/CD25+ populations. No differences were noted in the production of IFN-gamma, IL-2, IL-4, and IL-5. These results suggest that when an Ag is introduced during pregnancy, an immunoregulatory rather than an immunosuppressive or Th2 environment predominates.     

Epidermal growth factor reduces intestinal apoptosis in an experimental model of necrotizing enterocolitis

Necrotizing enterocolitis (NEC) is a devastating intestinal disease of premature infants. Although end-stage NEC is characterized histopathologically as extensive necrosis, apoptosis may account for the initial loss of epithelium before full development of disease. We have previously shown that epidermal growth factor (EGF) reduces the incidence of NEC in a rat model. Although EGF has been shown to protect intestinal enterocytes from apoptosis, the mechanism of EGF-mediated protection against NEC is not known. The aim of this study was to investigate if EGF treatment elicits changes in expression of apoptotic markers in the ileum during the development of NEC. With the use of a well-established neonatal rat model of NEC, rats were divided into the following three experimental groups: dam fed (DF), milk formula fed (NEC), or fed with formula supplemented with 500 ng/ml EGF (NEC+EGF). Changes in ileal morphology, gene and protein expression, and histological localization of apoptotic regulators were evaluated. Anti-apoptotic Bcl-2 mRNA levels were markedly reduced and pro-apoptotic Bax mRNA levels were markedly elevated in the NEC group compared with DF controls. Supplementation of EGF into formula significantly increased anti-apoptotic Bcl-2 mRNA, whereas pro-apoptotic Bax was significantly decreased. The Bax-to-Bcl-2 ratio for mRNA and protein was markedly decreased in NEC+EGF animals compared with the NEC group. The presence of caspase-3-positive epithelial cells was markedly reduced in EGF-treated rats. These data suggest that alteration of the balance between pro-and anti-apoptotic proteins in the site of injury is a possible mechanism by which EGF maintains intestinal integrity and protects intestinal epithelium against NEC injury.     

Erythropoietin protects intestinal epithelial barrier function and lowers the incidence of experimental neonatal necrotizing enterocolitis

The impermeant nature of the intestinal barrier is maintained by tight junctions (TJs) formed between adjacent intestinal epithelial cells. Disruption of TJs and loss of barrier function are associated with a number of gastrointestinal diseases, including neonatal necrotizing enterocolitis (NEC), the leading cause of death from gastrointestinal diseases in preterm infants. Human milk is protective against NEC, and the human milk factor erythropoietin (Epo) has been shown to protect endothelial cell-cell and blood-brain barriers. We hypothesized that Epo may also protect intestinal epithelial barriers, thereby lowering the incidence of NEC. Our data demonstrate that Epo protects enterocyte barrier function by supporting expression of the TJ protein ZO-1. As immaturity is a key factor in NEC, Epo regulation of ZO-1 in the human fetal immature H4 intestinal epithelial cell line was examined and demonstrated Epo-stimulated ZO-1 expression in a dose-dependent manner through the PI3K/Akt pathway. In a rat NEC model, oral administration of Epo lowered the incidence of NEC from 45 to 23% with statistical significance. In addition, Epo treatment protected intestinal barrier function and prevented loss of ZO-1 at the TJs in vivo. These effects were associated with elevated Akt phosphorylation in the intestine. This study reveals a novel role of Epo in the regulation of intestinal epithelial TJs and barrier function and suggests the possible use of enteral Epo as a therapeutic agent for gut diseases.     

Retinoic acid and hindbrain patterning

Retinoid signaling plays an important role in the developmental patterning of the hindbrain. Studies of the teratogenic effects of retinoids showed early on that the hindbrain suffered patterning defects in cases of retinoid excess or deficiency. Closer examination of these effects in animal models suggested that retinoids might play a physiological role in specifying the antero-posterior axis of the hindbrain. This idea was supported by the localization of retinoid synthetic and degradative enzymes, binding proteins, and receptors to the hindbrain and neighboring regions of the neuroepithelium and the mesoderm. In parallel, it became clear that the molecular patterning of the hindbrain, in terms of the regionalized expression of Hox genes and other developmental regulatory genes, is profoundly influenced by retinoid signaling.     

High-fat-diet-associated intestinal microbiota exacerbates psoriasis-like inflammation by enhancing systemic γδ T cell IL-17 production

1. Download : Download high-res image (116KB)
2. Download : Download full-size image

     

Retinoic acid in development and regeneration

Retinoids are low molecular weight, lipophilic derivatives of vitamin A which have profound effects upon the development of various embryonic systems. Here I review the effects on developing and regenerating limbs, regenerating amphibian tails and the developing central nervous system (CNS). In the regenerating amphibian limb, retinoids can proximalize, posteriorize and ventralize the axes of the blastema. In the chick limb bud retinoids can only posteriorize the tissue. In the regenerating amphibian tail retinoids can homeotically transform tail tissue into hindlimb tissue. In the developing and regenerating limb retinoic acid has been detected endogenously, confirming that this molecule plays a role in the generation of pattern and we have shown that limbs cannot develop in the absence of retinoic acid. In the developing CNS retinoic acid specifically affects the hindbrain where it causes a transformation of anterior rhombomeres into more posterior ones. Again, endogenous retinoic acid has been detected in the CNS and in the absence of retinoids the posterior hindbrain has been found to be affected. The effects of retinoids on the CNS are most likely to be mediated via theHox genes acting in the mesoderm after gastrulation. It has also been proposed that the establishment of the head-to-tail axis in the mesoderm is established by retinoic acid. These data show that retinoids play an important role in both the development and regeneration of various systems in the embryo and post-embryonically     

Retinoic acid and mammalian craniofacial morphogenesis

Retinoic acid is a morphogenetic signalling molecule in vertebrate embryos, one being known to perform a specific function in organizing the body pattern along the anteroposterior axis. This molecule has especially attracted research attention because retinoic acid treatment will also induce abnormal morphogenesis, particularly in the craniofacial structures. The present review discusses recent molecular insights revealing how the retinoic acid signal is transduced within a cell, specifically focusing on the involvement of cranial neural crest cells in retinoic acid-induced abnormal morphogenesis in the mammalian head     

Retinoic acid can be produced from excentric cleavage of beta-carotene in human intestinal mucosa.

The hypothesis that retinoic acid (RA) is produced from the excentric cleavage of beta-carotene was tested in human intestinal homogenates in vitro. Significant amounts of RA were identified by HPLC and derivatization after incubation of intestinal mucosal homogenates with retinal, beta-carotene, or beta-apocarotenals at 37 degrees C for 60 min. RA formation was inhibited, in a dose-dependent fashion, when retinal was incubated in the presence of 0.1-3.0 mM citral (3,7-dimethyl-2,6-octadienal) under identical experimental conditions. The formation of RA from both beta-carotene and beta-apocarotenals was dose and time dependent and RA was the major metabolite of both beta-apo-8'-carotenal and beta-apo-12'-carotenal after the incubation. However, citral (0.1 to 4 mM) did not inhibit the formation of beta-apocarotenals and RA from 2 microM beta-carotene (P greater than 0.05), which proves the existence of an excentric cleavage mechanism for beta-carotene conversion into retinoids. Furthermore, RA formation from both beta-apo-8'-carotenal and beta-apo-12'-carotenal in human intestinal homogenate occurred in the presence of citral, which demonstrates that RA can be produced from excentric cleavage of beta-carotene via a series of beta-apocarotenals as intermediates.     

Retinoic acid and retinoic acid receptors in craniofacial development

Interest in retinoids and craniofacial development originated independently from nutritional and teratological studies; however, the site of action of retinoids in normal development remains contentious. Recent transgenic strategies have shown that retinoic acid and nuclear retinoid receptors are required for the morphogenetic specification of cranial neural crest cells and their mesenchymal derivatives during craniofacial development. Interestingly, while some aspects of the RA teratogenicity have been shown to be receptor-mediated, there is as yet no clear evidence that this is the case for the embryonic head and face. Hox genes are one important set of targets for RA in the developing neural primordium and cranial neural crest, but it remains unclear as to how retinoid-mediated regulation of such targets is realized as the morphogenetic specification of cell fate.     

The interaction between intestinal mucus glycoproteins and enteric infections

Adherence of pathogenic enteric organisms to specific receptors on mucosal surfaces is widely recognized as an important first step in the initiation of infectious diseases. The specific interactions whereby parasites and bacteria exploit mucus substrates for colonization, and the host uses them as a nonimmunological defense mechanism, is only now being unravelled. In this review, Sil-King Tse and Kris Chadee discuss various hypothetical models for interaction, including the role of the immune system in the regulation of mucus secretion.     

Retinoic acid and CO2 laser resurfacing

The purpose of this study was to analyze the effect of retinoic acid on wound healing and depth of injury in an animal skin model resurfaced with a CO2 laser. The dorsal skin of 21 Hartley guinea pigs was divided into halves. One-half received a daily application of 0.05% retinoic acid for 28 days, whereas the other half served as the control. The animals were divided into three treatment groups of seven animals. Group A was laser resurfaced with one pass of the Coherent UltraPulse CO2 laser (300 mJ, 60 W, density 40 percent). Group B received two passes, and group C received three passes. Histologic studies were obtained before laser resurfacing and days 1, 4, and 7 after resurfacing. Depth of injury, thickness, number of squamous cell and granular cell layers, and epithelialization rates were measured. We found that the depth of injury was statistically less in animals pretreated with retinoic acid. Granular cells were thicker and more numerous at day 4 in pretreated animals but similar to controls by day 7. Animals pre-treated with retinoic acid overall seemed to heal wounds earlier. In conclusion, pretreatment with retinoic acid may reduce the depth of injury in laser resurfacing and speed healing rates.     

Retinoic acid production by endocardium and epicardium is an injury response essential for zebrafish heart regeneration

1. Download : Download high-res image (85KB)
2. Download : Download full-size image

Highlights? Cardiac injury induces structural and molecular changes in zebrafish endocardium ? Endocardial and epicardial cells at the site of injury synthesize retinoic acid (RA) ? The extent of this injury response correlates with a species' regenerative capacity ? Regenerative cardiomyocyte proliferation in zebrafish requires retinoic acid signaling     

Effect of experimental azotemia on intestinal transport of butyric acid

Earlier studies have revealed an impairment of jejunal absorption of long chain fatty acids in experimental uremia. We investigated the intestinal absorption of butyric acid which is a short chain fatty acid in experimental renal failure (RF). Sprague-Dawley rats were randomized into the RF group which had subtotal nephrectomy, a sham-operated control group, and a pair-fed group. In vivo recirculating perfusion (n = 5) and in vitro everted sac incubation (n = 8) were employed. The in vitro experiments were repeated substituting the serosal buffer by either predialysis or postdialysis sera from uremic individuals, or normal serum (n = 10). The rate of in vivo butyric acid absorption was significantly lower while the in vitro absorption was significantly higher in the RF group than those observed in the sham-operated and pair-fed groups which showed comparable values. The normality of butyric acid absorption in the pair-fed animals despite comparable weight loss with the RF group tends to exclude anorexia and weight loss as a cause of altered butyric acid transport in RF animals. The disparity between the in vivo and in vitro data is suggestive of an inhibitory influence of uremic environment which is present in vivo and absent in vitro. This viewpoint was corroborated by the observed fall in butyric acid absorption by sacs containing predialysis uremic serum as compared with those containing normal or postdialysis sera. The latter further suggests that the inhibitory factor(s) is dialyzable.