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all-trans retinoic acid alleviates transmissible gastroenteritis virus-induced intestinal inflammation and barrier dysfunction in weaned piglets

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Journal of Animal Science and Biotechnology 2024年第3期15卷 1131-1144页

作者： Junning Pu Daiwen Chen Gang Tian Jun He Ping Zheng Zhiqing Huang Xiangbing Mao Jie Yu Yuheng Luo Junqiu Luo Hui Yan Aimin Wu Bing Yu Institute of Animal Nutrition Sichuan Agricultural UniversityChengdu 611130SichuanPeople’s Republic of China Key Laboratory of Animal Disease-Resistance Nutrition Ministry of EducationMinistry of Agriculture and Rural AffairsKey Laboratory of Sichuan Province611130 ChengduSichuanPeople’s Republic of China

Background transmissible gastroenteritis virus(TGEV)is one of the main pathogens causing severe diarrhea of pig-lets.The pathogenesis of TGEV is closely related to intestinal inflammation.all-trans retinoic acid(ATRA)is the main active metabolite of vitamin A,which has immunomodulatory and anti-inflammatory properties.However,it is unclear whether ATRA can alleviate TGEV-induced intestinal inflammation and barrier dysfunction in piglets.This study aimed to investigate the effects of ATRA on growth performance,diarrhea,intestinal inflammation and intesti-nal barrier integrity of TGEV-challenged piglets.Methods In a 19-d study,32 weaned piglets were randomly divided into 4 treatments:Control group(basal diet),TGEV group(basal diet+TGEV challenge),TGEV+ATRA5 group(basal diet+5 mg/d ATRA+TGEV challenge)and TGEV+ATRA15 group(basal diet+15 mg/d ATRA+TGEV challenge).On d 14,piglets were orally administered TGEV or the sterile medium.Results Feeding piglets with 5 and 15 mg/d ATRA alleviated the growth inhibition and diarrhea induced by TGEV(Ptransporter related genes(GLUT2 and SLC7A1)in jejunal mucosa of TGEV-challenged piglets(P<0.05).Furthermore,5 mg/d ATRA feeding attenuated TGEV-induced intestinal inflammatory response by inhibit-ing the release of interleukin(IL)-1β,IL-8 and tumor necrosis factor-α(TNF-α),and promoting the secretion of IL-10 and secretory immunoglobulin A(sIgA)(P<0.05).Feeding 5 mg/d ATRA also down-regulated the expressions of Toll-like receptors and RIG-I like receptors signaling pathway related genes(TLR3,TLR4,RIG-I,MyD88,TRIF and MAVS)and the phosphorylation level of nuclear factor-κB-p65(NF-κB p65),and up-regulated the inhibitor kappa B alpha(IκBα)p

关键词： all-trans retinoic acid Inflammation Intestinal barrier Piglets transmissible gastroenteritis virus

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all-trans retinoic acid-incorporated Glycol Chitosan Nanoparticles Regulate Macrophage Polarization in Pg-LPS-Induced Inflammation

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Current Medical Science 2022年第5期42卷 974-980页

作者： Tian-rong HE Xiu-yu TANG Qi YAN Xin-yu WU Bin SHI Yi LIN Fujian Provincial Hospital Shengli Clinical College of Fujian Medical UniversityFuzhou350001China The State Key Laboratory Breeding Base of Basic Science of Stomatology(Hubei-MOST)&Key Laboratory for Oral Biomedical Ministry of Education School&Hospital of StomatologyWuhan UniversityWuhan430075China

Objective The occurrence and development of inflammation are closely correlated to the polarization of macrophages.all-trans retinoic acid(ATRA)has been proven to promote the polarization of macrophages from M1 to M2,but this lacks an effective carrier to participate in the biological response.The present study aims to determine whether retinoic acid-incorporated glycol chitosan(RA-GC)nanoparticles can regulate macrophage polarization in Porphyromonas gingivalis-lipopolysaccharide(Pg-LPS)-induced inflammation.Methods Mouse 264.7 cell lines were treated with 1µg/mL Pg-LPS to induce inflammation.After the effects of ATRA and RA-GC on the activity of macrophages were detected by CCK-8 assay,cells induced with Pg-LPS were assigned to the blank control group(GC)nanoparticles without ATRA,and experimental groups(GC nanoparticles loaded with different concentrations of ATRA:1,10 and 100µg/mL).The effects of RA-GC on inflammatory cytokines tumor necrosis factor-α,interleukin(IL)-10 and IL-12 in macrophages were detected by enzyme-linked immunosorbent assay(ELISA).Subsequently,the effects of GC nanoparticles loaded with/without ATRA on macrophage polarization in an inflammatory environment were detected by RT-PCR and Western blotting.Results The results revealed that RA-GC had no significant effect on macrophage activity.However,RA-GC could effectively inhibit the Pg-LPS-induced inflammatory factor expression in macrophages.Meanwhile,the experimental results confirmed that RA-GC could downregulate the expression of inducible nitric oxide synthase(iNOS)(a marker of M1 macrophages)and upregulate the expression of mannose receptor and Arginase-1(a marker of M2 macrophages)in a dose-dependent manner.Conclusion The present study confirms that RA-GC can promote the M2 polarization of macrophages in an inflammatory environment,and proposes this as a promising target for the clinical treatment of Pg-LPS-related diseases.

关键词： macrophage polarization all-trans retinoic acid lipopolysaccharide inflammation

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Nano transdermal system combining mitochondria-targeting cerium oxide nanoparticles with all-trans retinoic acid for psoriasis

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Asian Journal of Pharmaceutical Sciences 2023年第5期18卷 112-124页

作者： Wei Wang Xinyi Xu Yanling Song Lan Lan Jun Wang Xinchang Xu Yongzhong Du Department of Pharmacy Hangzhou Third People’s HospitalAffiliated Hangzhou Dermatology HospitalZhejiang University School of MedicineHangzhou 310009China College of Pharmaceutical Sciences Zhejiang UniversityHangzhou 310058China Department of Dermatology Affiliated Hangzhou Dermatology HospitalZhejiang University School of MedicineHangzhou 310009China Innovation Center of translational Pharmacy Jinhua Institute of Zhejiang UniversityJinhua 321299China

Psoriasis is an inflammatory skin disease that is intricately linked to oxidative stress.Antioxidation and inhibition of abnormal proliferation of keratinocytes are pivotal strategies for psoriasis.Delivering drugs with these effects to the site of skin lesions is a challenge that needs to be solved.Herein,we reported a nanotransdermal delivery system composed of all-trans retinoic acid(TRA),triphenylphosphine(TPP)-modified cerium oxide(CeO2)nanoparticles,flexible nanoliposomes and gels(TCeO_(2)-TRA-FNL-Gel).The results revealed that TCeO_(2)synthesized by the anti-micelle method,with a size of approximately 5 nm,possessed excellent mitochondrial targeting ability and valence conversion capability related to scavenging reactive oxygen species(ROS).TCeO_(2)-TRA-FNL prepared by the film dispersion method,with a size of approximately 70 nm,showed high drug encapsulation efficiency(>96%).TCeO_(2)-TRA-FNL-Gel further showed sustained drug release behaviors,great transdermal permeation ability,and greater skin retention than the free TRA.The results of in vitro EGF-induced and H2O2-induced models suggested that TCeO_(2)-TRA-FNL effectively reduced the level of inflammation and alleviated oxidative stress in HaCat cells.The results of in vivo imiquimod(IMQ)-induced model indicated that TCeO_(2)-TRA-FNL-Gel could greatly alleviate the psoriasis symptoms.In summary,the transdermal drug delivery system designed in this study has shown excellent therapeutic effects on psoriasis and is prospective for the safe and accurate therapy of psoriasis.

关键词： Psoriasis Cerium oxide nanoparticles all-trans retinoic acid Flexible nanoliposomes transdermal delivery

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all-trans retinoic acid inhibits the malignant behaviors of hepatocarcinoma cells by regulating ferroptosis

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Genes & Diseases 2022年第6期9卷 1742-1756页

作者： Yanting Sun Yun He Jishuang Tong Daijiang Liu Haodong Zhang Tongchuan He Yang Bi Stem Cell Biology and Therapy Laboratory Children’s Hospital of Chongqing Medical UniversityNational Clinical Research Center for Child Health and DisordersMinistry of Education Key Laboratory of Child Development and DisordersChongqing Key Laboratory of PediatricsChongqing 400014PR China Department of Pediatric Surgery Children’s Hospital of Chongqing Medical UniversityChongqing 400014PR China Department of Gastroenterology Chongqing Emergency Medical CentreChongqing 400014PR China Molecular Oncology Laboratory Department of SurgeryThe University of Chicago Medical CentreChicagoIL 60637USA

all-trans retinoic acid(ATRA)can reverse the malignant behaviors of hepatocellular carcinoma(HCC)cells,thereby exerting anti-HCC effect;however,the underlying mechanism is yet to be understood.This study aimed to demonstrate that ATRA is vital to ferroptosis in HCC.Ferroptosis-related genes exhibit different expression in patients with HCC compared to that in healthy individuals.A total of 20 amino acid products were detected in HepG2 cells,the expression level of 5 was decreased after ATRA treatment.ATRA improved the levels of lipid ROS,MDA,and NAPDt/NADPH,and reduced the mt-DNA copy number and changed the structure of mitochondria,in HepG2 and Hep3B cells.We found the expression of genes positively correlated with ferroptosis to increase and those negatively correlated to decrease with ATRA treatment.Inhibition of ferroptosis by Ferrostatin-1 reversed ATRA-inhibited proliferation of HCC cells,along with cell migration and invasion.GSH synthesis was blocked by ATRA,accompanied by decreased cystine content and increased glutamate content,and downregulation of the expression of GSH synthesis-related genes.Our findings suggested that ATRA inhibited the malignancy of HCC cells by improving ferroptosis,and that inhibition of GSH synthesis contributed to ATRA-induced ferroptosis.

关键词： all-trans retinoic acid Ferroptosis Hepatocarcinoma Invasion Migration

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Downregulation of Astrocyte Elevated Gene-1 Expression Combined with all-trans retinoic acid Inhibits Development of Vasculogenic Mimicry and Angiogenesis in Glioma

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Current Medical Science 2022年第2期42卷 397-406页

作者： Chen LIANG Ling YANG Shi-wen GUO Rui-chun LI Department of Neurosurgery First Affiliated Hospital of Xi’an Jiaotong UniversityXi’an710061China Department of Aeromedical Physical Examination Xi’an Civil Aviation HospitalXi’an710082China

Objective This study aimed to investigate the effects of downregulating astrocyte elevated gene-1(AEG-1)expression combined with all-trans retinoic acid(ATRA)on vasculogenic mimicry(VM)formation and angiogenesis in glioma.Methods U87 glioma cells were transfected with AEG-1 shRNA lentiviral vectors(U87-siAEG-1)and incubated in a medium containing 20µmol/L ATRA.Matrigel-based tube formation assay was performed to evaluate VM formation,and the cell counting kit-8(CCK-8)assay was used to analyze the proliferation of glioma cells in vitro.Reverse transcription-quantitative polymerase chain reaction and Western blot analysis were used to investigate the mRNA and protein expression of related genes,respectively.Glioma xenograft models were generated via subcutaneous implantation of glioma cells in nude mice.Tumor-bearing mice received an intraperitoneal injection of ATRA(10 mg/kg per day).Immunohistochemistry was used to evaluate the expression of related genes and the microvessel density(MVD)in glioma xenograft models.CD34/periodic acid-Schiff double staining was performed to detect VM channels in vivo.The volume and weight of tumors were measured,and a tumor growth curve was drawn to evaluate tumor growth.Results A combination of ATRA intervention and downregulation of AEG-1 expression significantly inhibited the proliferation of glioma cells in vitro and glioma VM formation in vitro and in vivo.It also significantly decreased MVD and inhibited tumor growth.Further,the expression levels of matrix metalloproteinase(MMP)-2,MMP-9,vascular endothelial-cadherin(VE-cadherin),and vascular endothelial growth factor(VEGF)in glioma significantly decreased in vivo and in vivo.Conclusion Hence,a combinatorial approach might be effective in treating glioma through regulating MMP-2,MMP-9,VEGF,and VE-cadherin expression.

关键词： astrocyte elevated gene-1 glioma all-trans retinoic acid vasculogenic mimicry angiogenesis

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Safety and efficacy of Compound Huangdai Tablets combined with all-trans retinoic acid for treatment of acute promyelocytic leukemia:Clinical evidence and potential mechanisms

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Chinese Herbal Medicines 2022年第1期14卷 154-165页

作者： Qianqian Huang Tao Wang Yan Xiong Liping Qu Qiaozhi Yin Wenjun Zou College of Pharmacy Chengdu University of Traditional Chinese MedicineChengdu 611137China School of Medical and Life Sciences Chengdu University of Traditional Chinese MedicineChengdu 610041China

Objective:To evaluate the safety and efficacy of Compound Huangdai Tablets(Realgar-Indigo Naturalis formula,RIF)combined with all-trans retinoic acid(ATRA)to treat acute promyelocytic leukemia(APL).Methods:This study was registered in PROSPERO(CRD42018108118).The relevant literatures on RIF treatment of APL were systematically searched in the following databases:China National Knowledge Infrastructure,Wanfang,VIP Medical Information System,Chinese Biomedical Database,EMBASE,Cochrane Library,and PubMed.The quality of the included studies was evaluated and Review Manager 5.3 software and Stata 13.0 software were used to perform the Meta-analysis.In addition,this study used the method of network pharmacology to conduct a preliminary exploration of the mechanism of RIF on APL.Results:The study included 12 studies involving 775 APL patients.The Meta-analysis showed that there was no significant difference(P>0.05)between the RIF group and the arsenic trioxide(ATO)group for primary outcomes,secondary outcomes apart from liver dysfunction.The incidence of liver dysfunction(P=0.006)in the RIF group were significantly lower than those in the ATO group.In addition,the cost of maintenance therapy in the RIF group was significantly lower(Ptranscription of cell cycle genes,nuclear receptor transcription pathway.Conclusion:There was no significant difference in efficacy of oral RIF combined with ATRA compared with intravenous ATO combined with ATRA for the treatment of APL.The oral RIF exposed patients to less risk,offered more convenience and had lower prices.RIF can treat APL by multi-target and multipathway interventions that inducing apoptosis of APL cells and inhibiting the proliferation of APL cells,and so on.Therefore,oral RIF in the treatment of APL is worthy of further research and develo

关键词： acute promyelocytic leukemia all-trans retinoic acid network pharmacology Realgar-Indigo Naturalis formula

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all-trans retinoic acid regulates the expression of MMP-2 and TGF-β2 via RDH5 in retinal pigment epithelium cells

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International Journal of Ophthalmology(English edition) 2023年第6期16卷 849-854页

作者： Yu-Mei Mao Chang-Jun Lan Qing-Qing Tan Gui-Mei Zhou Xiao-Ling Xiang Jia Lin Xuan Liao Department of Ophthalmology Affiliated Hospital of North Sichuan Medical CollegeNanchong 637000Sichuan ProvinceChina Medical School of Ophthalmology and Optometry North Sichuan Medical CollegeNanchong 637000Sichuan ProvinceChina

·AIM: To investigate the effect of all-trans retinoic acid(ATRA) on retinol dehydrogenase 5(RDH5), matrix metalloproteinase-2(MMP-2) and transforming growth factor-β2(TGF-β2) transcription levels, and the effect of RDH5 on MMP-2 and TGF-β2 in retinal pigment epithelium(RPE) cells.·METHODS: After adult RPE cell line-19(ARPE-19 cells) intervened with gradient concentrations of ATRA(0-20 μmol/L) for 24h, flow cytometry was used to detect the proliferation and apoptosis of cells in each group, and quantitative realtime polymerase chain reaction(q RT-PCR) was used to detect RDH5, MMP-2 and TGF-β2 m RNA expression. Then, after ARPE-19 cells transfected with three different si RNA targets for 48h, the RDH5 knockdown efficiency of each group and expression of MMP-2 and TGF-β2 m RNA within them was detected by q RT-PCR. ·RESULTS: Flow cytometry results showed that ATRA could inhibit the proliferation of RPE cells and promote the apoptosis of RPE cells, and the difference of apoptosis was statistically significant when the ATRA concentration exceeded 5 μmol/L and compared with the normal control group(P=0.027 and P=0.031, respectively). q RT-PCR results showed that ATRA could significantly inhibit the expression level of RDH5 m RNA(Pally when treated with 5 μmol/L ATRA. The knockdown efficiency of RDH5 si RNA varies with different targets, among which RDH5 si RNA-435 had the highest knockdown efficiency, i.e., more than 50% lower than that of the negative control group(P=0.02). When RDH5 was knocked down for 48h, the results of q RT-PCR showed that the expressions of MMP-2 and TGF-β2 m RNA were significantly up-regulated(Ptransition of RPE cells mediated by ATRA.

关键词： KEYWORDS:retinol dehydrogenase 5 matrix metalloproteinase-2 transforming growth factor-β2 all-trans retinoic acid ARPE-19

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all-trans retinoic acid inhibited angiotensin Ⅱ-induced increase in cell growth and collagen secretion of neonatal cardiac fibroblasts

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Acta Pharmacologica Sinica 2006年第4期27卷 423-429页

作者： Yan HE~2 Ying HUANG~2 Li ZHOU~2 Li-min LU~2 Yi-chun ZHU~2 Tai YAO~(2,3,4) ~2Department of Physiology and Pathophysiology,and ~3State Key Laboratory for Medical Neurobiology.Fudan University Shanghai Medical College.Shanghai 200032.China Department of Physiology and Pathophysiology Fudan University Shanghai Medical College Shanghai China State Key Laboratory for Medical Neurobiology Fudan University Shanghai Medical College Shanghai China

Aim:To determine whether all-trans retinoic acid(atRA)acts to modulate angio-tensin Ⅱ(Ang Ⅱ)-induced cardiac fibroblast cell growth and collagen secretion.Methods:Cultured neonatal rat cardiac fibroblasts(CF)were used in the experiment.A 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide(MTT)assay wasused to detect cell growth of the CF;and immunocytochemistry and Westernblotting were used to measure the production and secretion of collagen and theexpression of transforming growth factor-β1(TGF-β1)by the CF.Results:atRA(1×10-7to 1×10-5mol/L)inhibited the Ang Ⅱ-induced increase in cell growth of CF(P<0.05).Ang Ⅱ stimulated the secretion of collagen types Ⅰ and Ⅲ by the CF.This effect was blocked by AT1receptor antagonist losartan(1×10-6mol/L),butnot by AT2receptor antagonist PD 123319 (up to 1×10-6mol/L).Exposure of CF toatRA(1×10-5mol/L)attenuated the Ang Ⅱ-induced increase in the secretion ofcollagen types Ⅰ and Ⅲ(P<0.05).atRA (1×10-5mol/L)also blocked the Ang Ⅱ-induced increase in the expression of TGF-β1.Conclusion:atRA inhibits the AngⅡ-induced increase in cell growth and collagen secretion of neonatal rat CF.Theeffect of atRA is possibly mediated by lowering the TGF-β1level.These observa-tions support the notion that atRA is a potential candidate for the prevention andtherapy of cardiac remodeling.

关键词： cardiac fibroblast angiotensin Ⅱ all-trans retinoic acid collagen secretion transforming growth factor-β1

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all-trans retinoic acid(ATRA)inhibits insufficient radiofrequency ablation(IRFA)-induced enrichment of tumor-initiating cells in hepatocellular carcinoma

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Chinese Journal of Cancer Research 2021年第6期33卷 694-707页

作者： Song Wang Jingtao Liu Hao Wu Anna Jiang Kun Zhao Kun Yan Wei Wu Haibo Han Yanhua Zhang Wei Yang Key Laboratory of Carcinogenesis and translational Research(Ministry of Education/Beijing) Department of UltrasoundPeking University Cancer Hospital&InstituteBeijing 100142China Key Laboratory of Carcinogenesis and translational Research(Ministry of Education/Beijing) Department of PharmacyPeking University Cancer Hospital&InstituteBeijing 100142China Key Laboratory of Carcinogenesis and translational Research(Ministry of Education/Beijing) Department of Clinical LaboratoryPeking University Cancer Hospital&InstituteBeijing 100142China

Objective:Local recurrence of hepatocellular carcinoma(HCC)after radiofrequency ablation(RFA)treatment remains a serious problem.Tumor-initiating cells(TICs)are thought to be responsible for tumor relapse.Here,we investigated the effect of the TIC differentiation inducer,all-trans retinoic acid(ATRA),on RFA and explored the potential molecular mechanisms.Methods:The proportions of CD133+and epithelial cell adhesion molecule(Ep CAM);TICs in recurrent HCC after RFA and primary HCC were first determined in clinic.Then,the effect of heat intervention or insufficient RFA(IRFA)on the malignant potential of HCC cells,including cell migration,sphere formation ability,tumor growth,the proportion of CD133+and Ep CAM+TICs and expression of stem cell-related genes,was evaluated in vitro and in vivo.Finally,the effect of ATRA on the tumor growth and the proportion of TICs was evaluated.Results:In clinical data,a higher proportion of CD133+and Ep CAM+TICs was found in recurrent tumors than in primary tumors.In vitro heat intervention promoted the cell migration and sphere formation ability.Additionally,it increased the proportion of CD133+and Ep CAM+TICs and the expression of stem cell-related genes.In addition,after IRFA the residual tumors in xenografts grew faster and had more TICs than untreated tumors.ATRA remarkably inhibited residual tumor growth after IRFA by elimination of TICs though the PI3 K/AKT pathway.Combination treatment with ATRA resulted in longer survival outcomes in mouse xenografts than RFA alone.Conclusions:ATRA,as a TIC differentiation inducer,could help to improve the effect of RFA treatment,which was partially attributed to its effect against TICs.The data indicated its potential as an alternative drug in the development of better therapeutic strategies for use in combination with RFA.

关键词： Radiofrequency ablation hepatocellular carcinoma tumor-initiating cell all-trans retinoic acid tumor differentiation

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Inhibition of matrix metalloproteinases expression in human dental pulp cells by all-trans retinoic acid

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International Journal of Oral Science 2014年第3期6卷 150-153页

作者： Jin Man Kim Sang Wook Kang Su-Mi Shin Duck Su Kim Kyong-Kyu Choi Eun-Cheol Kim Sun-Young Kim Department of Conservative Dentistry School of Dentistry Kyung Hee University Department of Maxillofacial Tissue Regeneration School of Dentistry Kyung Hee University

all-trans retinoic acid（ATRA） inhibits matrix metalloproteinase（MMP）-2 and MMP-9 in synovial fibroblasts, skin fibroblasts,bronchoalveolar lavage cells and cancer cells, but activates MMP-9 in neuroblast and leukemia cells. Very little is known regarding whether ATRA can activate or inhibit MMPs in human dental pulp cells（HDPCs）. The purpose of this study was to determine the effects of ATRA on the production and secretion of MMP-2 and-9 in HDPCs. The productions and messenger RNA（mRNA） expressions of MMP-2 and-9 were accessed by gelatin zymography and real-time polymerase chain reaction（PCR）, respectively. ATRA was found to decrease MMP-2 level in a dose-dependent manner. Significant reduction in MMP-2 mRNA expression was also observed in HDPCs treated with 25 mmol？L21ATRA. However, HDPCs treated with ATRA had no effect on the pattern of MMP-9 produced or secreted in either cell extracts or conditioned medium fractions. Taken together, ATRA had an inhibitory effect on MMP-2 expression in HDPCs,which suggests that ATRA could be a candidate as a medicament which could control the inflammation of pulp tissue in vital pulp therapy and regenerative endodontics.

关键词： all-trans retinoic acid human dental pulp cell matrix metalloproteinase zymography

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