tretinoin and Weight-Loss

Intestinal epithelial apical membrane Cl-/HCO3- exchanger DRA (downregulated in adenoma, SLC26A3) has emerged as an important therapeutic target for diarrhea, emphasizing the potential therapeutic role of agents that upregulate DRA. All-trans retinoic acid (ATRA), a key vitamin A metabolite, was earlier shown by us to stimulate DRA expression in intestinal epithelial cells. However, its role in modulating DRA in gut inflammation has not been investigated.. Our aim was to analyze the efficacy of ATRA in counteracting inflammation-induced decrease in DRA in vitro and in vivo.. Interferon-γ (IFN-γ)-treated Caco-2 cells and dextran sulfate sodium (DSS)-treated C57BL/6J mice served as in vitro and in vivo models of gut inflammation, respectively. The effect of ATRA on IFN-γ-mediated inhibition of DRA function, expression, and promoter activity were elucidated. In the DSS colitis model, diarrheal phenotype, cytokine response, in vivo imaging, myeloperoxidase activity, and DRA expression were measured in the distal colon.. All-trans retinoic acid (10 μM, 24 h) abrogated IFN-γ (30 ng/mL, 24 h)-induced decrease in DRA function, expression, and promoter activity in Caco-2 cells. All-trans retinoic acid altered IFN-γ signaling via blocking IFN-γ-induced tyrosine phosphorylation of STAT-1. All-trans retinoic acid cotreatment (1 mg/kg BW, i.p. daily) of DSS-treated mice (3% in drinking water for 7 days) alleviated colitis-associated weight loss, diarrheal phenotype, and induction of IL-1β and CXCL1 and a decrease in DRA mRNA and protein levels in the colon.. Our data showing upregulation of DRA under normal and inflammatory conditions by ATRA demonstrate a novel role of this micronutrient in alleviating IBD-associated diarrhea.

Topics: Animals; Antiporters; Caco-2 Cells; Chloride-Bicarbonate Antiporters; Colitis; Colon; Dextran Sulfate; Diarrhea; Disease Models, Animal; Epithelial Cells; Humans; Inflammation; Interferon-gamma; Intestinal Mucosa; Male; Mice; Mice, Inbred C57BL; RNA, Messenger; Sulfate Transporters; Tretinoin; Up-Regulation; Weight Loss

One suitable approach to enhancing multiple sclerosis (MS) treatment is combination of available medications to provide more desirable outcomes. Immunomodulatory effects of atorvastatin and/or all-trans retinoic acid (ATRA) were determined in previous studies. The present study was set out to investigate the synergistic effects of combination therapy by suboptimal doses of atorvastatin and ATRA in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. EAE was induced by MOG35-55 in female C57BL/6 mice. Therapies were initiated at day 12 post immunization when the mice developed a disability score and continued throughout the study until the day 33 when animals were sacrificed. Therapeutic treatment with half doses of atorvastatin and ATRA in combination has synergistic benefits causing the regression of clinical and neuropathological features of EAE more favorable than treatment with full doses of either drug alone. Without any advantage in anti-proliferative effect, combination treatment significantly reduced the secretion of pro-inflammatory cytokine interleukin-17 and conversely, increased the production of anti-inflammatory cytokine interleukin-10 more prominent than either drug alone. Furthermore, FoxP3+Treg cells were significantly increased only in combination treatment. In conclusion, combined atorvastatin and ATRA have immunomodulatory synergistic benefits and this pharmacological approach may be as a useful strategy to control MS.

Topics: Animals; Atorvastatin; Brain; Cytokines; Disease Models, Animal; Drug Synergism; Encephalomyelitis, Autoimmune, Experimental; Female; Forkhead Transcription Factors; Heptanoic Acids; Mice; Multiple Sclerosis; Pyrroles; T-Lymphocytes, Regulatory; Tretinoin; Weight Loss

An earlier study showed that all-trans-retinoic acid (ATRA) prevents the development of monocrotalin-induced pulmonary hypertension (PH). The purpose of the present study was to determine the effect of ATRA on another model of chronic hypoxia-induced PH.. Male Sprague-Dawley rats were given 30 mg/kg ATRA or vehicle only by gavage once daily for 14 days during hypobaric hypoxic exposure. Chronic hypoxic exposure induced PH, right ventricular hypertrophy (RVH), and hypertensive pulmonary vascular changes. Quantitative morphometry of the pulmonary arteries showed that ATRA treatment significantly reduced the percentage of muscularized arteries in peripheral pulmonary arteries only with an external diameter between 15 and 50 microm. ATRA treatment also significantly reduced the medial wall thickness in small muscular arteries only with an external diameter between 50 and 100 microm. Unfortunately, these reductions did not accompany the lowering of pulmonary artery pressure nor decrease in RVH. Chronic hypoxia-induced PH rats with ATRA had a loss in body weight. Chronic hypoxia increased the expression of endothelial nitric oxide synthase in the lung on western blotting and immunohistochemistry, in which ATRA treatment had no effect.. The administration of ATRA might not have a therapeutic role in preventing the development of chronic hypoxia-induced PH, because of body weight loss and the subtle preventable effects of vascular changes.

Topics: Animals; Body Weight; Chronic Disease; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Hypoxia; Lung; Male; Nitric Oxide Synthase Type III; Pulmonary Artery; Rats; Rats, Sprague-Dawley; Tretinoin; Weight Loss

Retinoic acid (RA) exerts beneficial effects on vascular remodelling and experimental nephritis, and plays a role in kidney development. Pathological changes caused by acute renal failure (ARF) result in high mortality. We determined whether RA ameliorates ARF-induced pathology caused by potassium dichromate (PD).. Adult Wistar female rats (210-250 g) were randomly allocated to four groups: (i) an ARF group that received PD [15 mg/kg body weight (bw), single dose subcutaneously]; (ii) a group that received PD plus RA (1 mg/kg bw) beginning at 5 days before PD and that continued for 14 additional days; (iii) a group that received PD plus thyroxine (T(4); 8 micro g/100 g bw) with RA; and (iv) a group that received only the vehicle for PD (saline solution). We evaluated functional, biochemical and morphological characteristics of the kidneys.. PD-induced alterations in serum creatinine, creatinine clearance (C(cr)) and fractional excretion of sodium (FeNa) were less severe when rats received RA. PD increased lipoperoxidation and this alteration was partially blocked by RA. Animals undergoing ARF showed severe histological injury (brush border loss, acidophilia, oedema, pyknosis, karyorhexis, cell detachment and disruption of the basement membrane). These alterations were less severe in RA-treated rats, indicating a protective effect on functional and morphological alterations. Alterations in urinary sediment were reduced by RA. The simultaneous administration of T(4) with RA did not produce additional protection.. RA exerted beneficial effects on the duration and severity of renal damage induced by PD in a model of renal failure resembling ARF in humans. The protective effect of RA may be mediated by diminished lipoperoxidative damage.

Topics: Acute Kidney Injury; Animals; Creatinine; Diuresis; Drug Combinations; Drug Synergism; Female; Lipid Peroxidation; Natriuresis; Potassium Dichromate; Rats; Rats, Wistar; Severity of Illness Index; Thyroxine; Tretinoin; Weight Loss

Histone deacetylase inhibitors (HDACIs) inhibit the growth of a variety of transformed cells in culture. We demonstrated previously that the hybrid-polar HDACI m-carboxycinnamic acid bis-hydroxamide (CBHA) induces apoptosis of human neuroblastoma in vitro and is effective in lower doses when combined with retinoids. The current study investigates the effect of CBHA on the growth of human neuroblastoma in vivo, both alone and in combination with all-trans retinoic acid (atRA), using a severe combined immunodeficiency-mouse xenograft model. CBHA (50, 100, and 200 mg/kg/day) inhibited growth of SMS-KCN-69n tumor xenografts in a dose-dependent fashion, with 200 mg/kg CBHA resulting in a complete suppression of tumor growth. The efficacy of 50 and 100 mg/kg CBHA was enhanced by the addition of 2.5 mg/kg atRA. This dose of atRA was ineffective when administered alone. Treatment was accompanied by mild weight loss in all groups except the lowest dose of CBHA. Our results suggest HDACIs alone or combined with retinoids may have therapeutic utility for neuroblastoma.

Topics: Acetylation; Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cell Division; Cinnamates; Dose-Response Relationship, Drug; Drug Synergism; Enzyme Inhibitors; Female; Growth Inhibitors; Histone Deacetylase Inhibitors; Histones; Humans; Mice; Mice, SCID; Neuroblastoma; Tretinoin; Tumor Cells, Cultured; Weight Loss; Xenograft Model Antitumor Assays

Retinoids have chemopreventive activity for epithelial tumors in a variety of systems, including the two-stage tumorigenesis system of mouse skin in which only the promotion stage is inhibited. We asked whether dietary vitamin A deficiency could affect the skin tumorigenic response, prior to major changes in body weight or general health of the animals. Two regimens were tested to induce vitamin A deficiency. SENCAR mice were either (a) fed a vitamin A-deficient diet from 4 or 9 weeks of age or (b) their mothers were fed the diet from the time of birth of the experimental animals which were then weaned on the same diet. The latter regimen produced typical symptoms of vitamin A deficiency in the offspring by Weeks 12-14 and all the mice died by Week 19; the former regimen permitted sufficient accumulation of retinol and its esters to sustain life for up to 45 and 75 weeks, respectively, in the majority of mice. For our experiments, vitamin A depletion was produced by placing the mothers on the deficient diet at birth of the experimental animals. A single topical dose of 20 micrograms of 7,12-dimethylbenz(a)anthracene (DMBA) was used as the initiator at 3 weeks of age and 1 to 2 micrograms of 12-O-tetradecanoylphorbol-13-acetate (TPA) once weekly as the tumor promoter for 10 weeks (from Week 4 through 13 of the experiment). Fifty-five % of mice (n = 40) on Purina laboratory chow (mean body weight, 31.4 g) developed skin tumors (2.58 per mouse) at 12 weeks, versus 2.5% (0.05 papillomas per mouse) of mice (n = 40) kept on the purified vitamin A-deficient diet (mean body weight, 30.3 g), a 98% decrease in tumor/mouse. Retinoic acid (RA) (1-3 micrograms/g diet) supplementation after Week 12 caused a rapid tumorigenic response in 95% of the mice by week 22. This tumor response occurred to a reduced extent in the absence of continued TPA treatment up to Week 13. Even though tumor incidence increased within 1 week of RA and 95% of the mice showed the tumorigenic response, the number of tumors per mouse was about 50% of that observed in mice maintained on standard Purina diet. This was confirmed in an experiment in which the mice were maintained for life either on Purina or on the RA (3 micrograms/g) containing purified diet, the latter being the control group for the effect of vitamin A deficiency on skin tumorigenesis.(ABSTRACT TRUNCATED AT 400 WORDS)

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; beta Carotene; Carotenoids; Cocarcinogenesis; Diet; Female; Liver; Male; Mice; Neoplasms, Experimental; Skin Neoplasms; Tetradecanoylphorbol Acetate; Tretinoin; Vitamin A Deficiency; Weight Loss