• IMMUNE NETWORK
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• 제23권5호
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• pp.37.1-37.11
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• 2023

Forkhead box P3-positive (Foxp3⁺)-inducible Tregs (iTregs) are readily generated by TGF-β1 at low TCR signaling intensity. TGF-β1-mediated Foxp3 expression is further enhanced by retinoic acid (RA) and lactoferrin (LF). However, the intensity of TCR signaling required for induction of Foxp3 expression by TGF-β1 in combination with RA and LF is unknown. Here, we found that either RA or LF alone decreased TGF-β1-mediated Foxp3 expression at low TCR signaling intensity. In contrast, at high TCR signaling intensity, the addition of either RA or LF strongly increased TGF-β1-mediated Foxp3 expression. Moreover, decreased CD28 stimulation was more favorable for TGF-β1/LF-mediated Foxp3 expression. Lastly, we found that at high signaling intensities of both TCR and CD28, combined treatment with TGF-β1, RA, and LF induced robust expression of Foxp3, in parallel with powerful suppressive activity against responder T cell proliferation. Our findings that TGFβ/RA/LF strongly generate high affinity Ag-specific iTreg population would be useful for the control of unwanted hypersensitive immune reactions such as various autoimmune diseases.

• Asian-Australasian Journal of Animal Sciences
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• 제33권6호
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• pp.1012-1022
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• 2020

Objective: Caseins and fatty acids of milk are synthesized and secreted by the epithelial cells of the mammary gland. All-trans retinoic acid (ATRA), an active metabolite of vitamin A, has been shown to promote mammary development. This study was conducted to determine the effect of ATRA on casein synthesis and fatty acid composition in MAC-T cells. Methods: MAC-T cells were allowed to differentiate for 4 d, treated with ATRA (0, 1.0, 1.5, and 2.0 μM), and incubated for 3 d. We analyzed the fatty acid composition, the mRNA expression of casein and fatty acid synthesis-related genes, and the phosphorylation of casein synthesis-related proteins of MAC-T cells by gas chromatography, quantitative polymerase chain reaction, and western blotting, respectively. Results: In MAC-T cells, ATRA increased the mRNA levels of α_S1-casein and β-casein, janus kinase 2 (JAK2) and E74-like factor 5 of the signal transducer and activator of transcription 5 β (STAT5-β) pathway, ribosomal protein S6 kinase beta-1 (S6K1) and eukaryotic translation initiation factor 4E binding protein 1 of the mammalian target of rapamycin (mTOR) pathway, inhibited the mRNA expression of phosphoinositide 3-kinase and eukaryotic initiation factor 4E of the mTOR pathway, and promoted the phosphorylation of STAT5-β and S6K1 proteins. Additionally, ATRA increased the de novo synthesis of fatty acids, reduced the content of long-chain fatty acids, the ratio of monounsaturated fatty acids to saturated fatty acids (SFA), the ratio of polyunsaturated fatty acids (PUFA) to SFA, and the ratio of ω-6 to ω-3 PUFA. The mRNA levels of acetyl-CoA carboxylase 1, fatty acid synthase, lipoprotein lipase, stearoyl-CoA desaturase, peroxisome proliferator-activated receptor gamma, and sterol regulatory element-binding protein 1 (SREBP1) were enhanced by ATRA. Conclusion: ATRA promotes the synthesis of casein by regulating JAK2/STAT5 pathway and downstream mTOR signaling pathway, and it improves the fatty acid composition of MAC-T cells by regulating SREBP1-related genes.

• Asian Pacific Journal of Cancer Prevention
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• 제13권5호
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• pp.1809-1817
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• 2012

Background: Gastric cancer is frequently lethal despite aggressive multimodal therapies, and new treatment approaches are therefore needed. Retinoids are potential candidate drugs: they prevent cell differentiation, proliferation and malignant transformation in gastric cancer cell lines. They interact with nuclear retinoid receptors (the retinoic acid receptors [RARs] and retinoid X receptors [RXRs]), which function as transcription factors, each with three subclasses, ${\alpha}$, ${\beta}$ and ${\gamma}$. At present, little is known about retinoid expression and influence on prognosis in gastric cancers. Patients and Methods: We retrospectively analyzed the expression of the subtypes RARa, $RAR{\beta}$, $RAR{\gamma}$, RXRa, $RXR{\beta}$, $RXR{\gamma}$ by immunohistochemistry in 147 gastric cancers and 51 normal gastric epithelium tissues for whom clinical follow-up data were available and correlated the results with clinical characteristics. In addition, we quantified the expression of retinoid receptor mRNA using real-time PCR (RT-PCR) in another 6 gastric adenocarcinoma and 3 normal gastric tissues. From 2008 to 2010, 80 patients with gastric cancers were enrolled onto therapy with all-trans-retinoic acid (ATRA). Results: RARa, $RAR{\beta}$, $RAR{\gamma}$ and $RXR{\gamma}$ positively correlated with each other (p < 0.001) and demonstrated significantly lower levels in the carcinoma tissue sections (p < 0.01), with lower $RAR{\beta}$, $RAR{\gamma}$ and RXRa expression significantly related to advanced stages (p < =0.01). Tumors with poor histopathologic grade had lower levels of RARa and $RAR{\beta}$ in different histological types of gastric carcinoma (p < 0.01). Patients whose tumors exhibited low levels of RARa expression had significantly lower overall survival compared with patients who had higher expression levels of this receptor (p < 0.001, HR=0.42, 95.0% CI 0.24-0.73), and patients undergoing ATRA treatment had significantly longer median survival times (p = 0.007, HR=0.41, 95.0% CI 0.21-0.80). Conclusions: Retinoic acid receptors are frequently expressed in epithelial gastric cancer with a decreased tendency of expression and RARa may be an indicator of a positive prognosis. This study provides a molecular basis for the therapeutic use of retinoids against gastric cancer.

• 대한수의학회지
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• 제36권1호
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• pp.151-159
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• 1996

This study was carried out to evaluate the effects of all-trans retinoic acid(RA) on the development of cholangiocarcinoma in hamsters. Eighty six female Syrian golden hamsters were divided into four groups. Group I was for the induction of the cholangiocarcinoma, which was infected orally with C sinensis and given dimethylnitrosamine(DMN, 15ppm) in drinking water for 4 weeks. Group II was for evaluating the effect of all-trans RA treatment on the cholangiocarcinogenesis, which was treated the same as group I and orally given RA(1mg/kg, 5 times per week) for 15 weeks. Group III was given only RA hr 15 weeks. Control group IV was given only soybean oil which was solvent for RA treatment. More than 5 heads of hamsters in each group were sacrificed at 4, 7, 11 and 15 weeks after the begining of the experiment. The livers were examined grossly, histopathologically, and immunohistochemically. The results obtained were as follows : 1. Death of animals started from the 11 weeks after the begining of the experiment. One of the total 22 animals(5%) and 7 of the total 24 animals(29%) died in group I and group II, respectively. 2. Proliferation of oval cell was peaked at 11 weeks in group I and at 7 weeks in group II, and decreased gradually after those periods of the time. 3. Cholangiocarcinomas were found in 1 of 6 animals(17%) at 11 weeks and in 4 of 6 animals(67%) at 15 weeks in group I, respectively. But in group II, the cholangiocarcinomas occured in 1 of 5 animals(20%) at 7 weeks, in 7 of 12 animals(58%) at 11 weeks and in 2 of the rest animals(100%) at 15 weeks, respectively. 4. Expression of $\alpha$-fetoprotein(AFP) of the oval cells in the group II showed the same degree of positive reaction at that of group I at 4 weeks. But AFP postive oval cells decreased gradually and AFP negative oval cells(ductlike oval cells) increased gradually. 5. Expression of cytokeratin of the oval cells in group II was shown slightly at 4 weeks and the degree of expression increased moderately from the 7 weeks. But the expression of the oval cells in group I was shown slightly after the 7 weeks. These results suggested that all-trans RA promoted the occurrence and the rate of cholangiocarcinoma by inducing differentiation of small cells and oval cells in the liver of hamsters infected with C sinensis and treated with DMN.

• Maxillofacial Plastic and Reconstructive Surgery
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• 제31권2호
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• pp.103-115
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• 2009

In vertebrates, the face is mainly formed with neural crest derived neural crest cells by the inherent programs and the interactive environmental factors. Extracellular signaling-regulated kinase (Erk) is one of such programs to regulate the various cellular functions. And retinoic acid (RA) also plays an important role as a regulator in differentiation process at various stages of vertebrate embryogenesis. We wanted to know that the segregation as well as the patterning of maxillary and mandibular structure is greatly influenced by the maxillomandibular cleft (MMC) and the failure of this development may result in the maxillomandibular fusion (syngnathia) or other patterning related disorder. It has been well documented that the epithelium at this cleft region has significant expression of Fibroblast growth factor (Fgf) 8, and it is essential for the patterning of the first arch derived structures. By the morphological, skeletal, cell proliferation and apoptotic, and hybridization analysis, we checked the effects of Erk inhibition and/or RA activation onto MMC and could observe that Erk and RA signaling is individually and synergically involved in the facial patterning in terms of FGF signaling pathway via Barx-l. So RA and Erk signaling work together for the MMC patterning and the segregation of maxilla-mandible by controlling the Fgf-related signaling pathways. And the abnormality in MMC brought by aberrant Fgf signaling may result in the disturbances of maxillary-mandibular segregation.

• Molecules and Cells
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• 제19권3호
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• pp.310-317
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• 2005

The Xenopus FGF-8a and FGF-8b isoforms have been reported to be neural crest and neuronal inducers, respectively. However, cloning of Xenopus FGF-8b (XFGF-8b) has not been reported previously and the two isoforms do not seem to have been clearly distinguished in Xenopus experiments. Here, we describe the cloning and expression of XFGF-8b and compare the effects of the two isoforms. XFGF-8b has an 11 amino acid insert in its N-terminal region compared with XFGF-8a. Both isoforms are expressed in the anterior neural regions of the early embryo, and in the apical ectodermal ridge of limb buds and tips of growing digits in the larval stages. However, XFGF-8b is more abundant than XFGF-8a throughout early development. The two isoforms are also regulated in similar fashion by retinoic acid in early development. However, although both XFGF-8a and XFGF-8b induce ectopic neurogenesis, only XFGF-8a appears to be involved in neural crest induction.

• IMMUNE NETWORK
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• 제16권4호
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• pp.249-255
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• 2016

Exogenous nucleic acids induce an innate immune response in mammalian host cells through activation of the retinoic acid-inducible gene I (RIG-I). We evaluated RIG-I protein for RNA binding and ATPase stimulation with RNA ligands to investigate the correlation with the extent of immune response through RIG-I activation in cells. RIG-I protein favored blunt-ended, double-stranded RNA (dsRNA) ligands over sticky-ended dsRNA. Moreover, the presence of the 5'-triphosphate (5'-ppp) moiety in dsRNA further enhanced binding affinity to RIG-I. Two structural motifs in RNA, blunt ends in dsRNA and 5'-ppp, stimulated the ATP hydrolysis activity of RIG-I. These structural motifs also strongly induced IFN expression as an innate immune response in cells. Therefore, we suggest that IFN induction through RIG-I activation is mainly determined by structural motifs in dsRNA that increase its affinity for RIG-I protein and stimulate ATPase activity in RIG-I.

• 한국발생생물학회지:발생과생식
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• 제2권1호
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• pp.53-62
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• 1998

리소솜 acid phosphatase(LAP)를 포함하는 리소솜 산성 가수 분해 효소는 세포 내,외 성분의 분해에 중요한 기능을 수행하며, 유미 양서류의 다리 재생 과정에서 LAP의 효소 활성도는 탈분화시기에 특이적으로 증가하는 것으로 알려져 있다. 본 연구에서는 멕시코산 도룡뇽의 일종인 axolotl(Ambystoma mexicanum)의 다리 재생 가정에서 정상적인 다리 재생 조직과 retinoic acid (RA)가 처리된 다리 재생 조직에서 LAP의 분포 및 발현을 면역 화학적 방법으로 조사하였다. Axolotl의 다리 재생 조직에서 한국산 도룡뇽(Hynobius leechii)의 LAP에 대한 단일 항체를 이용한 면역 반응도는 줄 탈분화시기에 있는 wound epidermis와 미분화된 중배엽성 세포인 blastema 세포, 탈분화 상태의 근육과 연골 부위 세포에서 나타나는 것으로 조사되었다. 또한 LAP의 면역 반응도는 재생단게의 초기에 점차 증가하여 탈분화시기 동안 최대치에 도달하였으며, 재분화가 시작되면서 basal level 까지 서서히 감소하는 것으로 나타나\ulcorner. 유미 양서류의 다리 재생 과정에서 골격 패턴의 복제를 유발시키는 것으로 알려져 있는 RA 처리는 LAP의 면역 반응도를 강화시키는 것으로 나타나\ulcorner. 즉, RA가 처리된 다리 재생 조직에서 LAP의 면역 반응도는 정상적인 다리 재생 조직에서 보다 강하게 나타났으며, 면역 반응도가 나타나는 시기 또한 연장되는 것으로 조사되었다. 이와 같은 결과는 다리 재생 조직에서 RA 처리가 탈분화시기의 연장에 관여한다는 것을 시사하고 있다.

• 폴리머
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• 제26권6호
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• pp.710-717
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• 2002

주형분자로서 all-trans-retinoic acid를 사용하여 methacrylic acid (MAA)를 가교 중합함으로써 분자각인고분자를 제조하였다 제조된 분자각인고분자가 충전된 HPLC컬럼의 분리특성을 살펴본 결과 레티노이드 유도체에 대해 좋은 분리 특성을 보였다. 주형분자의 양이 일정할 경우 주형분자대비 MAA의 양이 증가할수록 컬럼의 성능인자와 선택도는 높게 나타났으며, 이는 확률적으로 보다 많은 호스트분자와 주형분자간의 결합소를 제공한데 따른 결과이다. 유화중합에 의해 제조된 분자각인 고분자입자는 둥근 형태로 관찰되었으며 그 크기도 용액중합에 의해 제조된 것에 비해 훨씬 일정하게 분산되었으나, 분리특성은 효율이 떨어짐을 알 수 있었다 이러한 이유는 유화중합에 의한 분자각인고분자 제조시 물과 MAA 또는 물과 주형분자간의 수소결합에 의해 MAA와 주형분자간의 결합력 및 결합소의 수에 손실이 있었기 때문이다.

• 대한화장품학회지
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• 제30권3호
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• pp.405-408
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• 2004

레티노이드 효과가 나타나는 것을 목적으로 하여 다양한 히드록삼산 유도체를 합성하였고, 레티노익산 수용체에 대한 전사 활성을 측정하여 스크리닝하였다. 합성된 화합물 중에서 N-(4-N-hydroxycarbamoyl)phenyl) [4-(tort-butyl)phenyl] carboxamide (2f)가 수용체에 대한 가장 강력한 적합성을 나타내었다. 히드록삼산 구조에서 산도를 나타내는 히드록시기는 쉽게 이온화하여 음이온을 형성한다. 형성된 히드록삼산의 음이온은 레티노익산의 음이온과 유사한 역할을 한다. 이와 같이 히드록삼산 화합물이 레티노이드 효과를 나타내는 예는 이전에 알려진 바가 없다. 화합물 2f의 레티노이드 효과는 레티노이드와 연관된 유전자의 발현 증가 효과로 한번 더 검증하였다. 노화 원료로서의 가능성을 확인하기 위해서 MMP-1의 발현 억제능을 레티노익산, 레티놀과 비교하여 살펴보았다. 10 uM 농도에서 화합물 2f는 MMP-1의 발현을 억제하였다. 이와 같은 결과로 화합물 2f는 항노화 원료로서의 가능성을 가지고 있다.