Kegg Pathway: Retinol metabolism

Biosci Rep. 2008 Aug 29;
Zhang Q, Li Y, Liu G, Xu X, Song X, Liang B, Li R, Xie J, Du M, Xiao L, Gan X, Huang D

The DHRS4 gene cluster, consisting of DHRS4 and its copy gene DHRS4L2, is localized on 14q11.2. The DHRS4 gene product NADP(H)-dependent Retinol oxidoreductase participates in the metabolism of retinoids. The expression patterns of DHRS4 gene cluster were investigated in human neuroblastoma cells. Transcript analysis of the DHRS4 gene cluster using 3'- and 5'-RACE, reverse transcription PCR and bioinformatics approaches showed an alternative transcription start site in the copy gene DHRS4L2 generating two transcripts, DHRS4A1 (GenBank accession no. AY616183) and DHRS4A2 (AY943857), together with at least 6 alternative splicing variants (DHRS4A_v1-6) (GenBank accession no. AY920361, AY920362, DN237886, DN237887, DN237890, DN237892), resulted from alternative splicing. DHRS4A1 and DHRS4A2 were specifically transcribed in neuroblastoma cells. RNA structural analysis on DHRS4A1 and DHRS4A2 suggested that they are non-coding RNA. Expression analysis by quantitative real-time PCR and western blotting showed lack of correlation between the levels of transcription and translation in the tissues examined. Bisulfite genomic sequencing PCR experiments indicated that the expression of DHRS4L2 was regulated by methylation of its CpG-islands.

Clin Endocrinol (Oxf). 2008 Aug 15;
Choi KM, Kim TN, Yoo HJ, Lee KW, Cho GJ, Hwang TG, Baik SH, Choi DS, Kim SM

Objective Lipocalin family proteins, including adipocyte fatty acid binding protein (A-FABP), lipocalin-2, and Retinol binding protein 4 (RBP4), have recently been identified as novel adipokines associated with obesity, type 2 diabetes and the metabolic syndrome. We evaluated the effect of exercise training on lipocalin family proteins and inflammatory markers. Study subjects Thirty obese Korean women and 15 age-matched non-obese control subjects were studied. Design The concentrations of the lipocalin family proteins were compared between obese and non-obese women and were evaluated before and 3 months after an exercise program, consisting of aerobic exercise (45 min/session, 300 Kcal/day) and muscle strength training (20 min/session, 100 Kcal/day) 5 times per week. Results Obese women exhibited higher A-FABP levels compared to non-obese women (21.4 +/- 6.4 microg/l vs. 13.6 +/- 4.4 microg/l, P <0.001). However, neither lipocalin-2 nor RBP4 levels were significantly different between the two groups, although the difference in lipocalin-2 was marginally significant (P = 0.054). Circulating A-FABP levels were significantly associated with body mass index (BMI), waist circumference, triglyceride, alanine aminotransferase (ALT), lipocalin-2 and high-sensitivity C-reactive protein (hsCRP) levels. After 3 months of the exercise training program, serum A-FABP levels significantly decreased from 21.4 +/- 6.4 microg/l to 19.3 +/- 6.8 microg/l (P = 0.038), along with a reduction in weight, BMI, waist circumference, fasting glucose and total cholesterol levels. There was no significant change in the lipocalin-2 and RBP4 levels, although IL-6 levels increased after the exercise program. Conclusion Exercise training with weight loss induced a significant reduction in circulating A-FABP levels in obese Korean women.

J Wildl Dis. 2008 Jul; 44(3): 664-9
Kroenlein KR, Sleeman JM, Holladay SD, Joyner PH, Brown JD, Griffin M, Saunders G, Smith SA

Previously, we reported that wild eastern box turtles (Terrapene carolina carolina) with aural abscesses contained higher body burdens of organochlorine (OC) compounds than those without the lesion. This lesion in captive chelonians is associated with turtles that are fed diets deficient in vitamin A. To examine the pathophysiology of this lesion and evaluate the relationship between OC burdens and vitamin A metabolism, we maintained red-eared sliders (Trachemys scripta elegans) under different conditions of OC exposure and dietary vitamin A concentrations from August 2005 to February 2006. Dietary vitamin A concentration (0 or 5 international units/g in the diet) and OC exposure (no OC compound or the mixture of 2 mg/kg chlordane, 0.25 mg/kg aroclor, and 1 mg/kg lindane) did not affect histologic score based on degree of squamous metaplasia of the tympanic epithelium or levels of plasma or liver vitamin A among the study groups. The results of this study suggest that 6 mo of exposure to the selected OC compounds, or similar duration of reduced dietary vitamin A concentrations do not influence the formation of squamous metaplasia and aural abscesses in red-eared sliders. Further studies are required to determine whether the duration of the experiment was insufficient, the OC compounds selected were inappropriate, the dosing was incorrect, and whether there are other unknown mechanisms causing the reported association between OC exposure and aural abscesses seen in eastern box turtles.

Endocrinology. 2008 Jul 31;
Pang W, Li C, Zhao Y, Wang S, Dong W, Jiang P, Zhang J

Environmental light is involved in the regulation of photochemical reaction in mouse retina. It remains unclear whether light-mediated increase in all-trans retinoic acid (ATRA) synthesis in retina will result in altering the circulatory levels of ATRA and regulating downstream gene expression and physiological function. Here we showed circulatory levels of ATRA decreased in mice under constant darkness and elevated by light exposure. Fat gene pancreatic lipase-related protein 2 (mPlrp2) and its partner procolipase (mClps), but not hepatic lipase (mHl), activated in livers for responding to lack of light illuminating. Light-triggered alterations in circulatory ATRA levels regulated ecto-5'-nucleotidase (Cd73) gene expression by retinoic acid receptor RARalpha and modulated 5'-adenosine monophosphate (5'-AMP) levels in blood and were associated with mPlrp2 and mClps expression in the livers. Mice deficient in adenosine receptors displayed mPlrp2 and mClps expression in livers under 12h/12h light/dark cycles. Caffeine blocked adenosine receptors and induced hepatic mPlrp2 and mClps expression in wild type mice. Mice activated in hepatic mPlrp2 and mClps expression lowered hepatic and serum lipid levels and markedly elevated circulatory levels of all-trans Retinol (ATR). Our results suggest environmental light influence hepatic lipid homeostasis by light-modulated retinoic acid signaling associated with mPlrp2 and mClps gene expression in livers.

Invest Ophthalmol Vis Sci. 2008 Aug; 49(8): 3259-61
Winkler BS

It is undisputed that glutathione (GSH) is an important cellular antioxidant. Although it is commonly believed that GSH is present in all retinal cells, several publications show that GSH is not immunologically detectable in outer segments of rod and cone photoreceptor cells, but is present in inner retinal cells and the pigment epithelium. Using these intriguing and surprising findings as a starting point, an hypothesis is proposed that the renewal of outer segments serves as a surrogate antioxidant for GSH and that the exceptional vulnerability of photoreceptor cells to certain toxic chemicals is linked to the deficiency in GSH in outer segments as a reductant, a detoxicant, and as an enzymatic cofactor. It is suggested that this deficiency of GSH is not damaging to outer segments under normal conditions, because renewal serves to replace any damaged molecules before they increase to detrimental levels. However, when photoreceptors are stressed, the renewal of outer segments alone is not capable of overcoming the higher rates of oxidizing and detrimental chemical reactions, and the health of the entire photoreceptor cell is at risk. The hypothesis is supported by a consideration of the essential role of the NADPH-dependent Retinol reductase, by the different localization within photoreceptor cells of two key metabolic enzymes that are sensitive to oxidation, glyceraldehyde-3-phosphate dehydrogenase and the sodium-potassium ATPase, and by a consideration of the effects of toxic chemicals that selectively damage photoreceptor cells.

Int J Food Sci Nutr. 2008 Jul 24; 1-6
Priyadarshani AM, Lamabadusuriya SP, Seneviratne TR, Jansz ER, Peiris H

Over-consumption of absorbable carotenoids causes hypercarotenemia. Although hypercarotenemia is detected in Sri Lanka, a detailed study on this condition has not been carried out previously. Two millilitres of venous blood was drawn from hypercarotenemic patients (n=8) and examined by high-performance liquid chromatography for carotenoids and vitamin A. A common high-performance liquid chromatographic pattern in serum was shown by six of the cases with beta-carotene (9.9-35.7 microg/dl), beta-cryptoxanthin and monohydroxy metabolites collectively (5.3-48.5 microg/dl), and six to eight metabolites of dihydroxy, trihydroxy and polyhydroxy metabolites (22.5-282.1 microg/dl). Vitamin A levels were within the normal range (32-61 microg/dl). However, two cases identified were abnormal. The first of these showed low beta-carotene (3.5 microg/dl) and no beta-cryptoxanthin and monohydroxy metabolites, but normal dihydroxy, trihydroxy and polyhydroxy metabolites (128.2 microg/dl). However, the vitamin A level was high (75.2 microg/dl). The other case showed high beta-carotene (212.3 microg/dl) and beta-cryptoxanthin (49.3 microg/dl) but no normal monohydroxy, dihydroxy, trihydroxy and polyhydroxy metabolites. Instead there was an atypical metabolite (343.9 microg/dl). According to the present study, excessive intake of boiled, homogenized carrot and ripe papaw is the main causative factor for hypercarotenemia. Over-consumption of carotenoids-rich plant foods may be complicated in the case of individuals having defects of either the control of the 15,15'-dioxygenase activity or metabolism of carotenoids.

Arch Dis Child. 2008 Aug; 93(8): 660-4
Christian P, Darmstadt GL, Wu L, Khatry SK, Leclerq SC, Katz J, West KP, Adhikari RK

OBJECTIVE: Micronutrient deficiencies during pregnancy may be linked to poor newborn health and poor host defences against infection. We assessed newborn morbidity to determine the effect of four combinations of antenatal micronutrient supplements. DESIGN: Cluster-randomised, double-masked, controlled trial. SETTING: Rural community in Nepal. INTERVENTIONS: Women received daily supplements from early pregnancy through to 3 months postpartum of vitamin A alone (control) or vitamin A with folic acid, folic acid plus iron, folic acid plus iron plus zinc or a multiple micronutrient supplement containing these and 11 other nutrients. MAIN OUTCOME MEASURES: Infants were visited in their home at birth (n = 3927) and for each of 9 days thereafter to elicit a 24-h history of nine infant morbidity symptoms, measure infant respiratory rate and axial temperature, and assess the infant for chest indrawing. At 6 weeks of age, infants were visited again in their homes to elicit a 30-day and 7-day history of 10 morbidity symptoms using parental recall. RESULTS: Maternal micronutrient supplementation had no effect on 10-day morbidity or morbidity 30-day and 7-day morbidity assessed at 6 weeks of age all relative risks were close to 1. Symptoms of birth asphyxia increased by about 60% (p<0.05) in infants of women who received the multiple micronutrient supplement compared with the control. Symptoms of combinations of sepsis, preterm and birth asphyxia were associated with 8- to 14-fold increased odds of 6-month infant mortality. CONCLUSIONS: None of the combinations of antenatal micronutrient supplements tested improved symptoms of neonatal morbidity in the first 10 days of life or at 6 weeks of age. Further research is needed to elucidate the association and mechanism of increased risk of birth asphyxia following maternal multiple micronutrient supplementation. Trial registration numbers: NCT00115271.

J Nutr. 2008 Aug; 138(8): 1512-9
Lackey DE, Ashley SL, Davis AL, Hoag KA

Myeloid dendritic cells (DC) are professional antigen presenting cells (APC) that migrate to secondary lymphoid tissues upon antigen stimulation, where they activate naïve T cells. Vitamin A is essential for normal immune function. We investigated the ability of all-trans retinoic acid (atRA), a bioactive metabolite of vitamin A, to modulate DC adhesion in culture. Male BALB/cJ mouse bone marrow cells cultured with granulocyte-macrophage colony-stimulating factor in the presence of retinoic acid receptor (RAR) alpha-specific antagonist showed an increase in the percentage of developing DC that remained adherent compared with cells rescued with atRA treatment from d 8 to 10 of culture (P < 0.05). Replacement of the RARalpha antagonist with atRA on d 8 of the culture period decreased DC surface expression of the adhesion molecule CD11a (P < 0.0001) but not the gene expression. Rescue with atRA also dramatically increased gene and protein expression of pro-matrix metalloproteinase (MMP)-9 (P < 0.05). However, gene expression and protein production of tissue inhibitor of metalloproteinase (TIMP)-1 was unaffected by atRA rescue, altering the molar ratio of secreted pro-MMP-9:TIMP-1, resulting in a fold excess of pro-MMP-9 to its primary inhibitor (P < 0.05). These data suggest that atRA is essential to augment MMP-9 expression in myeloid DC and can alter their surface expression of adhesion molecules.

J Nutr. 2008 Aug; 138(8): 1407-10
Bhat PV, Manolescu DC

Vitamin A (Retinol) and its analogs (retinoids) are important regulators of cell proliferation, differentiation, immune function, and apoptosis. The kidneys are target organs for vitamin A action. Retinoic acid (RA), a vitamin A metabolite, is involved in embryonic kidney patterning through the control of receptor tyrosine kinase expression, which modulates ureteric bud branching morphogenesis. Vitamin A status of the mother profoundly affects kidney organogenesis of the newborn. In rodents, mild vitamin A deficiency results in a 20% reduction of nephron number. In adult humans, nephron number varies between 0.3 and 1.3 million per kidney, which is accepted as normal. However, recent studies indicate that humans at the low end of nephron number are predisposed to primary hypertension. Because RA regulates nephron mass, its optimal availability during nephrogenesis is critical. RA levels in the embryo are affected by several factors, such as maternal vitamin A nutrition and disturbances in Retinol metabolism. Maternal vitamin A deficiency during pregnancy is widespread in developing countries and segments of these populations may be exposed to low vitamin A during fetal life when nephron number is determined. Infants are likely to be born with suboptimal nephrons and may develop primary hypertension later in life. Although maternal vitamin A deficiency is not common in developed countries, congenital nephron number nevertheless varies widely, indicating low fetal RA levels due to common variants of the enzymes that convert Retinol to RA. These infants might require heightened surveillance for hypertension later in life.

Exp Biol Med (Maywood). 2008 Jul 18;
Mills JP, Furr HC, Tanumihardjo SA

Elevated serum Retinol-binding protein (RBP) concentration has been associated with obesity and insulin resistance, but accompanying Retinol values have not been reported. Assessment of Retinol is required to discriminate between apo-RBP, which may act as an adipokine, and holo-RBP, which transports vitamin A. The relations between serum RBP, Retinol, retinyl esters, BMI, and measures of insulin resistance were determined in obese adults. Fasting blood (> 8 h) was collected from obese men and women (n = 76) and blood chemistries were obtained. Retinol and retinyl esters were quantified by HPLC and RBP by ELISA. RBP and Retinol were determined in age and sex-matched, nonobese individuals (n = 41) for comparison. Serum apo-RBP was two-fold higher in obese (0.90 +/- 0.62 microM) than nonobese subjects (0.44 +/- 0.56 microM) (P < 0.001). The Retinol to RBP ratio (Retinol:RBP) was significantly lower in obese (0.73 +/- 0.13) than nonobese subjects (0.90 +/- 0.22) (P < 0.001) and RBP was strongly associated with Retinol in both groups (r = 0.71 and 0.90, respectively, P < 0.0001). In obese subjects, RBP was associated with insulin (r = 0.26, P < 0.05), homeostatic model assessment of insulin resistance (r = 0.29, P < 0.05), and quantitative insulin sensitivity check index (r = -0.27, P < 0.05). RBP was associated with BMI only when obese and nonobese subjects were combined (r = 0.25, P < 0.01). Elevated serum RBP, derived in part from apo-RBP, was more strongly associated with Retinol than with BMI or measures of insulin resistance in obese adults. Investigations into the role of RBP in obesity and insulin resistance should include Retinol to facilitate the measurement of apo-RBP and Retinol:RBP. When evaluating the therapeutic potential of lowering serum RBP, consideration of the consequences on vitamin A metabolism is paramount.

Biochem Biophys Res Commun. 2008 Sep 26; 374(3): 460-4
Mello T, Nakatsuka A, Fears S, Davis W, Tsukamoto H, Bosron WF, Sanghani SP

Approximately 80% of the body vitamin A is stored in liver stellate cells with in the lipid droplets as retinyl esters. In low vitamin A status or after liver injury, stellate cells are depleted of the stored retinyl esters by their hydrolysis to Retinol. However, the identity of retinyl ester hydrolase(s) expressed in stellate cells is unknown. The expression of carboxylesterase and lipase genes in purified liver cell-types was investigated by real-time PCR. We found that six carboxylesterase and hepatic lipase genes were expressed in hepatocytes. Adipose triglyceride lipase was expressed in Kupffer cells, stellate cells and endothelial cells. Lipoprotein lipase expression was detected in Kupffer cells and stellate cells. As a function of stellate cell activation, expression of adipose triglyceride lipase decreased by twofold and lipoprotein lipase increased by 32-fold suggesting that it may play a role in Retinol ester hydrolysis during stellate cell activation.

J Acquir Immune Defic Syndr. 2008 Aug 1; 48(4): 444-9
Israel-Ballard KA, Abrams BF, Coutsoudis A, Sibeko LN, Cheryk LA, Chantry CJ

BACKGROUND: World Health Organization advocates heat treatment of expressed breastmilk (EBM) as one method to reduce postnatal transmission of human immunodeficiency virus (HIV) in developing countries. Flash-heat is a simple heat treatment method shown to inactivate cell-free HIV. OBJECTIVE: To determine the effect of flash-heat on vitamin content of milk. METHODS: Fresh EBM was collected from 50 HIV+ mothers in Durban, South Africa. Mothers washed their hands and then manually expressed 75-150 mL EBM into sterile jars. Milk was aliquoted to unheated controls or flash-heat (50 mL EBM in a glass jar heated in a 450-mL water jacket in an aluminum pan until water boiled, then EBM removed) simulating field conditions with an open flame. Samples were stored at -70 degrees C and then analyzed for the effect of flash-heat on vitamins [A, ascorbic acid, riboflavin (B2), pyridoxal-5-phosphate (B6), folate, and B12]. RESULTS: Vitamin A was not significantly affected by flash-heat and vitamins B12 and C and folate increased significantly. Vitamins B2 and B6 were decreased to 59% (95% confidence interval 44 to 81) and 96% (95% confidence interval 92 to 99), respectively, of that found in unheated milk. CONCLUSIONS: The percentage remaining after flash-heat suggests that most vitamin concentrations are retained after heating. Flash-heat may be a practical and nutritious infant feeding method for mothers in developing countries.

Biomed Res. 2008 Jun; 29(3): 141-5
Suzuki T, Ishigami Y, Okada N, Kaneko A, Fukutomi R, Isemura M

Employing the DNA microarray technique, we previously reported the alteration in gene expression of nucleocytoplasmic transport factors, importins and exportins, induced by 1,25-dihydroxyvitamin D3 (DVD) in human leukemia HL-60 cells. Here, we used the quantitative reverse transcription-polymerase chain reaction method to confirm such previous findings, and compared them with those from the cells treated with all-trans-retinoic acid (ATRA). The results indicated that the gene expression of the transport factors examined was mostly down-regulated following differentiation induced by DVD and ATRA, but importin alpha5 gene expression was up-regulated in either case. The differences were found in the gene expression of importin alpha3 and exportin 6 between the cells after treatments with DVD and ATRA. These variations may be related to the difference between HL-60 cell lineages differentiating into monocytes/macrophages and granulocytes. The present findings provide further evidence to support the important roles of importins and exportins in cell differentiation.

Proc Natl Acad Sci U S A. 2008 Jul 15; 105(28): 9540-5
Nowickyj SM, Chithalen JV, Cameron D, Tyshenko MG, Petkovich M, Wyatt GR, Jones G, Walker VK

The retinoid X receptor (RXR) is activated by its often elusive cognate ligand, 9-cis-retinoic acid (9-cis-RA). In flies and moths, molting is mediated by a heterodimer ecdysone receptor consisting of the ecdysone monomer (EcR) and an RXR homolog, ultraspiracle (USP); the latter is believed to have diverged from its RXR origin. In the more primitive insect, Locusta migratoria (Lm), RXR is more similar to human RXRs than to USPs. LmRXR was detected in early embryos when EcR transcripts were absent, suggesting another role apart from ecdysone signaling. Recombinant LmRXRs bound 9-cis-RA and all-trans-RA with high affinity (IC(50) = 61.2-107.7 nM; K(d) = 3 nM), similar to human RXR. To determine whether specific binding had functional significance, the presence of endogenous retinoids was assessed. Embryos were extracted by using modified Bligh and Dyer and solid-phase protocols to avoid the oily precipitate that makes this material unsuitable for assay. These extracts contained retinoids (5.4 nM) as assessed by RA-inducible Cyp26A1-promoter luciferase reporter cell lines. Furthermore, the use of HPLC and MS confirmed the presence of retinoids and identified in any embryo, 9-cis-RA, in addition to all-trans-RA. We estimate that whole embryos contain 3 nM RA, including 9-cis-RA at a concentration of 1.6 nM. These findings strongly argue for a functional role for retinoids in primitive insects and favor a model where signaling through the binding of 9-cis-RA to its RXR is established relatively early in evolution and embryonic development.

J Chemother. 2008 Jun; 20(3): 324-6
Coscia A, Maiorca D, Martano C, Rossi C, Appino I, Cirina P, Alessi D, Fabris C

Since aminoglycoside efficacy is proportional to serum peak/MIC ratio and linked to post antibiotic effect, use of netilmicin once rather than twice a day has been proposed. On the other hand netilmicin might play a role in drug-induced nephrotoxicity, mainly on proximal tubule. Urinary Retinol binding protein (RBP) and alpha1 microglobulin (alpha1m) are early and specific indicators of tubular damage and dysfunction. 21 preterm neonates (GA < 37 weeks) were divided in two groups on the basis of netilmicin administration modality (1: once a day, 2: twice a day, both for 7 days, at 5 mg/kg/die) and differences in netilmicin tolerability were assessed by evaluation of alpha1m and RBP levels by immunonephelometric method. No significant differences were found between the two groups either considering levels at time 1 and at time 2, or considering the difference between time 1 and 2 (Delta1/2). In our study once-daily dosing schedule shows similar low rates of nephrotoxicity, compared with multiple daily dosing schedule: this result may support the general adoption of once-daily dosing of netilmicin in clinical practice.

J Steroid Biochem Mol Biol. 2008 Sep; 111(3-5): 225-31
Aboghe DH, Bolduc C, Yoshioka M, St-Amand J

Breast cancer is the most common cancer among women. Androgens, the male sexual hormones produced by ovary, act as protector of mammary gland. To elucidate the possible effects of dihydrotestosterone (DHT) on the transcriptome of mammary gland, serial analysis of gene expression was carried out on three groups of gonadectomized mice. After gonadectomy (GDX), DHT was injected 3 or 24h before sacrifice, whereas the control (GDX) group received vehicle solution. Approximately 42,000 tags were sequenced in each group. Genes involved in the cytoskeletal and extracellular matrix, such as troponin I skeletal fast 2 and keratin complex 1 acidic gene 14, were upregulated. In the immunity, complement component 1 q subcomponent gamma polypeptide and expressed sequence tag similar to lectin galactose binding soluble 3 were downregulated by DHT, whereas serine (or cystein) proteinase inhibitor clade A member 1a was upregulated. In the energy metabolism, the gene expression level of cytochrome c oxidase subunit I was upregulated by DHT, while NADH dehydrogenase subunit 2 was downregulated. In addition, transcripts involved in transport metabolism, such as apolipoprotein A-1, were upregulated by DHT, whereas Retinol binding protein 4 plasma was downregulated. Several previously unknown sequence tags were identified, which may allow to characterize new molecules of interest. These results suggest the suppression of immune response in normal mammary gland after DHT injection. This study can assist in refining research on the role of androgens in mammary gland homeostasis and breast cancer.

Expert Rev Mol Diagn. 2008 May; 8(3): 289-99
von Eynatten M, Humpert PM

Retinol-binding protein-4 (RBP4), a 21-kDa protein synthesized in the liver and adipose tissue, has recently been described as a murine adipokine involved in the development of insulin resistance. The expression of the gene encoding RBP4 was increased in the adipose tissue, but not in the liver, of insulin-resistant adipose GLUT4(-/-) mice and five other mouse models of obesity and insulin resistance. In addition, intraperitoneal injection or transgenic overexpression of RBP4 in mice induced insulin resistance. While experimental clinical approaches (mostly applying clamp techniques) in humans confirmed correlations of RBP4 with insulin resistance, studies in larger groups out of clinical routine failed to demonstrate a connection with alternative measures of insulin sensitivity. Yet, significant associations of RBP4 with atherogenic lipids were found and a focus of future studies should be the influence on atherosclerosis and related complications. Based on current data, the function of RBP4 as an adipokine exerting metabolic effects in glucose metabolism in humans remains uncertain and might be restricted to rodent models.

Transl Res. 2008 Jul; 152(1): 31-7
Hernández-Pedro N, Ordóñez G, Ortiz-Plata A, Palencia-Hernández G, García-Ulloa AC, Flores-Estrada D, Sotelo J, Arrieta O

Local diminution of the neural growth factor (NGF) contributes to the apparition of diabetic neuropathy. All-trans retinoic acid (RA) increases the expression of neural growth factor and its receptor participating in translation pathways. This study evaluates RA as a treatment of diabetic neuropathy: 120 mice were assigned randomly to 4 groups. Group A (n = 30) was taken as control; group B (n = 30) received 50 mg/kg intraperitoneal streptozotocin (STZ); group C (n = 30) received STZ, and after diabetic neuropathy developed, they were treated with subcutaneous RA 20 mg/kg daily during 60 days; and group D (n = 30) only received RA. Plasma glucose, thermosensitive tests, serum, and the nerve contents of NGF were measured in all animals. Evaluation by electron microscopy was performed in search of morphologic changes secondary to neuropathy and nerve regeneration. Diabetic mice had an increased threshold to pain. Treatment with RA in diabetic mice reverted changes in sensitivity as compared with diabetic mice that received placebo (P < 0.001). No differences in pain threshold among controls, RA, and diabetes mellitus (DM) + RA groups were found. Glucose levels were not affected by the treatment with RA. NGF diminished significantly in the sciatic nerve in diabetic mice as compared with controls and with the RA group. Animals with DM + RA had a significant increase of NGF in nerves as compared with the other groups. RA also regressed the ultrastructural changes induced by diabetes that showed increased neural regeneration. RA can revert functional and ultrastructural changes and induce neural regeneration after the establishment of diabetic neuropathy, possibly because of the increased of NGF concentrations in nerve terminals.

Biol Pharm Bull. 2008 Jul; 31(7): 1306-11
Sriram N, Kalayarasan S, Sudhandiran G

Oxidative stress resulting from an imbalance between radical-generating and radical scavenging systems plays an important role in the pathogenesis of pulmonary fibrosis. Epigallocatechin-3-gallate (EGCG), a polyphenol and a major component of green tea, possess a potent antioxidant property. This study was designed to evaluate the potential antioxidative activity of EGCG in the plasma and lungs during bleomycin induced experimental pulmonary fibrosis. Intratracheal administration of bleomycin (6.5 U/kg body weight) to rats resulted in significant reduction of body weight, enzymic antioxidants (superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase) and non-enzymic antioxidants (reduced glutathione, vitamin C, vitamin E and vitamin A). Elevations in lung W/D (wet weight/dry weight) ratio, hydroxyproline content was observed with a synchronized increase in lipid peroxidation markers (thiobarbituric acid reactive substances and hydroperoxides). Intraperitoneal administration of EGCG at a dose of 20 mg/kg body weight significantly improved the body weight, enzymic and non enzymic antioxidants and considerably decreased the W/D ratio, hydroxyproline and lipid peroxidation marker levels. Histological observations also correlated with the biochemical parameters. Thus, this study confirms the beneficial use of EGCG in alleviating the oxidative stress induced during pulmonary fibrosis.

Reprod Sci. 2008 Jun 30;
Savaris RF, Hamilton AE, Lessey BA, Giudice LC

Human endometrium undergoes modifications in preparation for embryonic implantation. This study investigated in vivo the endocrine effects of pregnancy on the endometrium, using the model of ectopic pregnancy. Endometrial biopsies from 9 subjects with ectopic pregnancy (Preg) were compared with 8 and 6 samples of mid and late secretory endometrium, respectively. After hybridizing with Affymetrix HGU133 Plus 2 chips, data were analyzed using GeneSpring GX and Ingenuity Pathways Analysis. From 54 675 genes, 3021 genes were significantly differentiated when mid-secretory endometrium was compared with the Preg (Volcano plot; P < .05, >/=2-fold change). The complement and coagulation cascade, phospholid degradation, glycosphingolipid biosynthesis (globoseries), Retinol metabolism, antigen presentation pathway, glycosphingolipid biosynthesis, and O-glycan biosynthesis were main significant canonical pathways found in Preg samples. Validation was done with reverse transcriptase polymerase chain reaction. In conclusion, the ectopic embryo has a significant impact, by an endocrine mechanism, on endometrium, when compared with the window of implantation.