Administration of All-Trans Retinoic Acid to Pregnant Sows Improves the Developmental Defects of Hoxa1−/− Fetal Pigs

Hoxa1 mutation adversely affect fetal pig development, but whether all-trans retinoic acid (ATRA) administration to Hoxa1+/− pregnant sows can improve Hoxa1−/− fetal pig development defects has not been reported. A total of 24 healthy Hoxa1+/− sows were mated with a healthy Hoxa1+/− boar and randomly assigned to one control group and nine experiment groups. ATRA was orally administered to pregnant sows at the doses of 0, 4, 5, or 6 mg/kg maternal body weight on 12, 13, and 14 days post coitum (dpc), respectively, and a total of 146 live piglets were delivered including 37 Hoxa1−/− piglets and 109 non-Hoxa1−/− piglets. Results indicated that Hoxa1−/− piglets delivered by sows in control group had bilateral microtia, canal atresia and ear's internal defects, and had lower birth liveweight and external ear score than non-Hoxa1−/− neonatal piglets (P < 0.05). Maternal administration with ATRA can effectively correct the development defects of Hoxa1−/− fetal pigs, Hoxa1−/− neonatal piglets delivered by sows administered ATRA at a dose of 4 mg/kg body weight on 14 dpc had higher birth liveweight (P > 0.05) and higher scores of external ear (P < 0.05) compared to Hoxa1−/− neonatal piglets from the control group, but had no significantly difference in terms of birth liveweight and external ear integrity than non-Hoxa1−/− piglets from the control group (P > 0.05). The time of ATRA administration significantly affected Hoxa1−/− fetal development (P < 0.05). Administration of ATRA to Hoxa1+/− pregnant sows at 4 mg/kg body weight on 14 dpc can effectively improve the birth liveweight and ear defects of Hoxa1−/− piglets.

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Effects of Subcutaneously Injected Graded Doses of All-Trans Retinoic Acid and All-Trans Retinoyl beta-Glucuronide on the Outcome of Pregnancy in Sprague-Dawley Rats

International Journal for Vitamin and Nutrition Research ◽

10.1024/0300-9831.72.4.229 ◽

2002 ◽

Vol 72 (4) ◽

pp. 229-235 ◽

Cited By ~ 4

Author(s):

Amanda Ueltschy ◽

Desiree Gunning ◽

Arun Barua ◽

James Olson

Keyword(s):

Body Weight ◽

Retinoic Acid ◽

Equivalent Amount ◽

Sprague Dawley ◽

Subcutaneous Injections ◽

Live Births ◽

Trans Retinoic Acid ◽

All Trans Retinoic Acid ◽

Sprague Dawley Rats ◽

Dose Levels

The effects of single subcutaneous injections (sc) of graded doses (20, 40, 80, 160, 320, and 480 mumol/kg body weight (BW) of all-trans retinoic acid (RA) and all-trans retinoyl beta-glucuronide (RAG) on day 8.5 of gestation on the outcome of pregnancy in Sprague-Dawley rats was studied. At dose levels of 20, 40, and 80 mumol/kg BW, neither RA nor RAG showed any adverse maternal or fetal effects. However, at dose levels of 160, 320, and 480 mumol/kg, RA was found to be much more toxic than RAG to both mother and fetus. Fetuses of animals receiving a 160 mumol/ kg BW dose of RA were significantly reduced in weight and length, while animals receiving the same dose of RAG had fetuses of normal size. RA doses of 320 and 480 mumol/ kg BW resulted in symptoms of maternal toxicity and even death. In contrast, RAG at these high levels produced no signs of maternal toxicity. RAG doses of 320 and 480 mumol/ kg BW were also less toxic to fetuses. RA doses of 320 mumol/kg BW resulted in only 8% live births, while animals treated with an equivalent amount of RAG experienced 95% live births. Animals receiving a dose of 480 mumol/kg BW of RA had no live births, but similar doses of RAG resulted in 28% live births and pups of normal size.

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Administration of All-Trans Retinoic Acid to Pregnant Sows Alters Gut Bacterial Community of Neonatal Piglets With Different Hoxa1 Genotypes

Frontiers in Microbiology ◽

10.3389/fmicb.2021.712212 ◽

2021 ◽

Vol 12 ◽

Author(s):

Haimei Zhou ◽

Huadong Wu ◽

Yixin Chen ◽

Wanjie Zou ◽

Wei Lu ◽

...

Keyword(s):

Small Intestine ◽

Species Richness ◽

Retinoic Acid ◽

Proline Metabolism ◽

Bacterial Composition ◽

Neonatal Piglets ◽

Trans Retinoic Acid ◽

All Trans Retinoic Acid ◽

Relative Abundances ◽

Bacterial Genes

Administration of all-trans retinoic acid (ATRA) to pregnant sows improves developmental defects of Hoxa1–/– fetal pigs, and this study aimed to explore the influence of maternal ATRA administration during pregnancy on gut microbiota of neonatal piglets. Samples of jejunal and ileal meconium of neonatal piglets before suckling were collected including 5 Hoxa1–/– and 20 non-Hoxa1–/– (Hoxa1+/+ and Hoxa1+/−) neonatal piglets from the control group and 5 Hoxa1–/– and 7 non-Hoxa1–/– neonatal piglets from the experimental group. Results indicated that Hoxa1 mutation shaped the bacterial composition of the jejunum and ileum of neonatal piglets and Hoxa1–/– neonatal piglets had significantly higher diversity and species richness, higher relative abundance of phylum Bacteroidetes, lower relative abundances of phylum Firmicutes and genus Lactobacillus, and lower ratio of Firmicutes to Bacteroidetes than non-Hoxa1–/– neonatal piglets. After maternal ATRA administration, Hoxa1–/– neonatal piglets had significantly higher diversity and species richness, higher relative abundances of two bacterial phyla (Bacteroidetes and Proteobacteria), and lower relative abundances of phylum Firmicutes and genus Lactobacillus in the jejunum than non-Hoxa1–/– neonatal piglets. Hoxa1–/– neonatal piglets delivered by sows with maternal ATRA administration had lower diversity and species richness and higher relative abundance of phylum Firmicutes in the jejunum than Hoxa1–/– neonatal piglets born by sows with no maternal ATRA administration. Non-Hoxa1–/– neonatal piglets delivered by sows with maternal ATRA administration had higher diversity and species richness and significantly lower relative abundances of phyla Firmicutes and Actinobacteria and genus Lactobacillus in the ileum than non-Hoxa1–/– neonatal piglets born by sows with no maternal ATRA administration. Hoxa1 mutation decreased the expression of bacterial genes involved in ABC transporters, purine metabolism, and aminoacyl-tRNA biosynthesis and increased the expression of bacterial genes involved in two-component system, starch and sucrose metabolism, and arginine and proline metabolism. Maternal ATRA administration decreased the expression of bacterial genes involved in arginine and proline metabolism, peptidoglycan biosynthesis, and fatty acid biosynthesis. Hoxa1 mutation resulted in bacterial dysbiosis of the small intestine of Hoaxa1–/– neonatal piglets, and maternal ATRA administration restored the bacterial dysbiosis of Hoxa1–/– neonatal piglets and altered the bacterial composition of the small intestine of non-Hoxa1–/– neonatal piglets.

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Effect of All-Trans Retinoic Acid (ATRA) against expression of Matrix Metalloproteinase-2 (MMP-2) in model mice (Rattus norvegicus) periodontitis

Padjadjaran Journal of Dentistry ◽

10.24198/pjd.vol29no2.13612 ◽

2017 ◽

Vol 29 (2) ◽

Author(s):

Ilma Soraya ◽

Nadya Octoraputri Herdiana ◽

Rifan Hanggoro ◽

Haris Budi Widodo

Keyword(s):

Retinoic Acid ◽

Matrix Metalloproteinase ◽

Rattus Norvegicus ◽

Chronic Inflammatory Disease ◽

Matrix Metalloproteinase 2 ◽

Control Group ◽

Control Group Design ◽

Inflammatory Conditions ◽

Trans Retinoic Acid ◽

All Trans Retinoic Acid

Introduction: Periodontitis is a common chronic inflammatory disease characterised by destruction of the supporting structures of the teeth, generally caused by bacteria Phorphyromonas gingivalis (P.g). Matrix metalloproteinase-2 (MMP-2) is an enzyme that plays an important role in inflammatory conditions. All-trans retinoic acid is a metabolite of vitamin A which plays a role in healing the inflamed tissue and maintain the immune system. The purpose of this study was to determine the effect of ATRA on the expression of MMP-2 in periodontitis models of mouse Rattus norvegicus. Methods: this was a laboratory experimental study using post-test only with control group design. This study used 25 male Wistar mice that was divided into 5 groups. Group 1 is a group of healthy mice, Group 2 is a group of periodontitis induced mice without treatment, Group 3 is a group of periodontitis mice treated with 5 mg/kgBW doses of ATRA, Group 4 is a group of periodontitis mice treated with 10 mg/kgBW doses of ATRA, and Group 5 is a group of periodontitis mice treated with 20 mg/kgBW doses of ATRA. The periodontitis was induced using Phorphyromonas gingivalis bacteria every 3 days for 28 days and followed by administration of ATRA for 7 days. Expression of MMP-2 from gingival tissues and periodontal ligament was obtained by immunohistochemical methods. The results were analyzed using the Shapiro-Wilk Test and Mann-Whitney Test. Results: The results showed there were significant differences in the positive area of MMP-2 and MMP-2 color intensity (p<0.05) between Groups. Conclusion: ATRA dose of 20 mg/kgBW is the most effective dose in inhibiting the expression of MMP-2 in mice models of periodontitis when compared with other doses.

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Novel Markers of the Metabolic Impact of Exogenous Retinoic Acid with A Focus on Acylcarnitines and Amino Acids

International Journal of Molecular Sciences ◽

10.3390/ijms20153640 ◽

2019 ◽

Vol 20 (15) ◽

pp. 3640 ◽

Cited By ~ 2

Author(s):

Joan Ribot ◽

Andrea Arreguín ◽

Ondrej Kuda ◽

Jan Kopecky ◽

Andreu Palou ◽

...

Keyword(s):

Amino Acids ◽

Body Weight ◽

Retinoic Acid ◽

Vitamin A ◽

Atra Treatment ◽

Placebo Controls ◽

Trans Retinoic Acid ◽

All Trans Retinoic Acid ◽

Brown Adipose ◽

Stimulation Of

Treatment with all-trans retinoic acid (ATRA), the carboxylic form of vitamin A, lowers body weight in rodents by promoting oxidative metabolism in multiple tissues including white and brown adipose tissues. We aimed to identify novel markers of the metabolic impact of ATRA through targeted blood metabolomics analyses, with a focus on acylcarnitines and amino acids. Blood was obtained from mice treated with a high ATRA dose (50 mg/kg body weight/day, subcutaneous injection) or placebo (controls) during the 4 days preceding collection. LC-MS/MS analyses with a focus on acylcarnitines and amino acids were conducted on plasma and PBMC. Main results showed that, relative to controls, ATRA-treated mice had in plasma: increased levels of carnitine, acetylcarnitine, and longer acylcarnitine species; decreased levels of citrulline, and increased global arginine bioavailability ratio for nitric oxide synthesis; increased levels of creatine, taurine and docosahexaenoic acid; and a decreased n-6/n-3 polyunsaturated fatty acids ratio. While some of these features likely reflect the stimulation of lipid mobilization and oxidation promoted by ATRA treatment systemically, other may also play a causal role underlying ATRA actions. The results connect ATRA to specific nutrition-modulated biochemical pathways, and suggest novel mechanisms of action of vitamin A-derived retinoic acid on metabolic health.

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All-Trans Retinoic Acid Enhances the Anti-Leukemia Effect of Venetoclax on Acute Myeloid Leukemia Cells

Blood ◽

10.1182/blood-2019-128551 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5055-5055 ◽

Cited By ~ 2

Author(s):

Dongbei Li ◽

Sha Liu ◽

Lin Chen ◽

Ruihua Fan ◽

Cheng Cheng ◽

...

Keyword(s):

Cell Cycle ◽

Flow Cytometry ◽

Cell Proliferation ◽

Retinoic Acid ◽

Cell Lines ◽

Drug Group ◽

Control Group ◽

Trans Retinoic Acid ◽

All Trans Retinoic Acid ◽

Gsk 3Β

Objective: Acute myeloid leukemia (AML) is a malignant disease of the hematopoietic system in which arrested maturation, excessive proliferation and inhibition of apoptosis have been observed in the process of hematopoietic stem cell differentiation. Some patients, especially elderly patients, do not tolerate cytotoxic chemotherapy, and some patients are resistant to chemotherapeutic drugs, consequently molecular targeting therapy has brought new hope for AML treatment. Venetoclax (ABT-199) is a selective inhibitor of the antiapoptotic protein Bcl-2. Increased expression of Bcl-2 is an important factor in the inhibition of apoptosis in leukemia cells. The use of a single drug is often limited because of resistance, and a better curative effect can be obtained in combination with other drugs. All-trans retinoic acid (all-trans-retinoic acid, ATRA) was first used by Chinese doctor to treat acute promyelocytic leukemia (APL). Many studies have shown that ATRA can inhibit the expression of Bcl-2 in AML cells and promote apoptosis. We aimed to test for the first time whether the combination of ATRA and venetoclax would produce a stronger anti-AML effect. Methods: The effects of ATRA and ABT-199 on the ABT-199-resistant AML cell lines OCI-AML3 and THP-1 and the sensitive cell lines MV-4-11 and MOLM-13 were observed in vitro. The following methods were used in this study. 1. CCK8 assay was used to detect cell proliferation. 2. Annexin V/FITC and PI double staining were used to detect apoptosis rate by flow cytometry. 3. Flow cytometry was used to detect the expression of CD11b. 4. PI single staining and flow cytometry were used to study the cell cycle. 5. Western blotting was used to detect the expression of Bcl-2, Bax, Mcl-1, PARP, caspase3, GSK-3β and Cyclin-D1 proteins in OCI-AML3 cells. Results:1. Compared with the control group and the ATRA or ABT-199 single drug group, cell proliferation was significantly inhibited in the combined drug group, the apoptosis rate was significantly increased, and the cell cycle was blocked in G1 phase. 2. The expression of CD11b in the ATRA or ABT-199 group and combination group was significantly higher than that in the control group. 3. In OCI-AML3 cells, compared with the ABT-199 drug group, the expression of Bcl-2, Mcl-1 and Cyclin-D1 decreased, and the expression of Bax, cleaved-PARP, cleaved caspase3 and p-GSK-3β expression increased in the combined treatment group. Conclusion: All-trans retinoic acid (ATRA) can enhance the anti-leukemia effect of ABT-199 on AML cell lines by inhibiting cell proliferation as seen by the cell cycle arrest of AML cells in G1 phase, promoting apoptosis and inducing differentiation. ATRA can reverse the drug resistance of AML cells to ABT-199 by inhibiting the expression of Bcl-2 and Mcl-1. Our observations may provide new strategies and theoretical support for the clinical treatment of AML. Key Wor ds :AML, Venetoclax, ATRA, Apoptosis Disclosures No relevant conflicts of interest to declare.

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