Retinoic Acid-Containing Liposomes for the Induction of Antigen-Specific Regulatory T Cells as a Treatment for Autoimmune Diseases

The current treatment of autoimmune and chronic inflammatory diseases entails systemic immune suppression, which is associated with increased susceptibility to infections. To restore immune tolerance and reduce systemic side effects, a targeted approach using tolerogenic dendritic cells (tolDCs) is being explored. TolDCs are characterized by the expression of CD11c, the major histocompatibility complex (MHC)II and low levels of co-stimulatory molecules CD40 and CD86. In this study, tolDCs were generated using a human-proteoglycan-derived peptide (hPG) and all-trans retinoic acid (RA). RA-tolDCs not only display a tolerogenic phenotype but also can induce an antigen-specific regulatory T cell (Treg) response in vitro. However, further analysis showed that RA-tolDCs make up a heterogeneous population of DCs, with only a small proportion being antigen-associated tolDCs. To increase the homogeneity of this population, 1,2-distearoyl-sn-glycero-3-phosphoglycerol (DSPG)-containing liposomes were used to encapsulate the relevant antigen together with RA. These liposomes greatly enhanced the proportion of antigen-associated tolDCs in culture. In addition, in mice, we showed that the liposomal co-delivery of antigen and RA can be a more targeted approach to induce antigen-specific tolerance compared to the injection of RA-tolDCs, and that these liposomes can stimulate the generation of antigen-specific Tregs. This work highlights the importance of the co-delivery of an antigen and immunomodulator to minimize off-target effects and systemic side effects and provides new insights in the use of RA for antigen-specific immunotherapy for autoimmune and chronic inflammatory diseases.

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Enhanced Oral Absorption of All-trans Retinoic Acid upon Encapsulation in Solid Lipid Nanoparticles

Pharmaceutical Nanotechnology ◽

10.2174/2211738508999201027220825 ◽

2020 ◽

Vol 8 (6) ◽

pp. 495-510

Author(s):

Manoj Kumar ◽

Garima Sharma ◽

Dinesh Singla ◽

Sukhjeet Singh ◽

Vandita Kakkar ◽

...

Keyword(s):

Retinoic Acid ◽

Side Effects ◽

Solid Lipid Nanoparticles ◽

In Vitro Release ◽

Lipid Nanoparticles ◽

Solid Lipid ◽

Trans Retinoic Acid ◽

All Trans Retinoic Acid ◽

Vitro Release

Background:: All-trans retinoic acid (ATRA) is widely employed in the treatment of various proliferative and inflammatory diseases. However, its therapeutic efficacy is imperiled due to its poor solubility and stability. Latter was surmounted by its incorporation into a solid matrix of lipidic nanoparticles (SLNs). Methods:: ATRA loaded SLNs (ATRA-SLNs) were prepared using a novel microemulsification technique (USPTO 9907758) and an optimal composition and were characterized in terms of morphology, differential scanning calorimetry (DSC), and powder X-ray diffraction studies (PXRD). In vitro release, oral plasma pharmacokinetics (in rats) and stability studies were also done. Results:: Rod-shaped ATRA-SLNs could successfully incorporate 3.7 mg/mL of ATRA, increasing its solubility (from 4.7 μg/mL) by 787 times, having an average particle size of 131.30 ± 5.0 nm and polydispersibility of 0.283. PXRD, DSC, and FTIR studies confirmed the formation of SLNs. Assay/total drug content and entrapment efficiency of ATRA-SLNs was 92.50 ± 2.10% and 84.60 ± 3.20% (n=6), respectively, which was maintained even on storage for one year under refrigerated conditions as an aqueous dispersion. In vitro release in 0.01 M phosphate buffer (pH 7.4) with 3% tween 80 was extended 12 times from 2h for free ATRA to 24 h for ATRA-SLNs depicting Korsmeyer Peppas release. Oral administration in rats showed 35.03 times enhanced bioavailability for ATRA-SLNs. Conclusion:: Present work reports preparation and evaluation of bioenhanced ATRA-SLNs containing a high concentration of ATRA (>15 times than that reported by others). Latter is attributed to the novel preparation process and intelligent selection of components. Lay Summary: All-trans retinoic acid (ATRA) shows an array of pharmacological activities but its efficacy is limited due to poor solubility, stability and side effects. In present study its solubility and efficacy is improved by 787 and 35.5 times, respectively upon incorporation into solid lipid nanoparticles (ATRA-SLNs). Latter extended its release by 12 times and provided stability for at least a year under refrigeration. A controlled and sustained release will reduce dose related side effects. ATRA-SLNs reported presently can thus be used in treatment /prophylaxis of disorders like cancers, tuberculosis, age related macular degeneration and acne and as an immune-booster.

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Effect of Size and Loading of Retinoic Acid in Polyvinyl Butyrate Nanoparticles on Amelioration of Colitis

Polymers ◽

10.3390/polym13091472 ◽

2021 ◽

Vol 13 (9) ◽

pp. 1472

Author(s):

Jinting Li ◽

Yunmei Mu ◽

Yiwei Liu ◽

Akihiro Kishimura ◽

Takeshi Mori ◽

...

Keyword(s):

Retinoic Acid ◽

Controlled Release ◽

Side Effects ◽

Therapeutic Effect ◽

Trans Retinoic Acid ◽

All Trans Retinoic Acid ◽

Bowel Diseases ◽

Inflammatory Bowel ◽

High Concentrations

Butyrate has been used in the treatment of inflammatory bowel diseases (IBD). However, the controlled release of butyrate has been indicated to be necessary in order to avoid the side effects verified at high concentrations. We previously developed nanoparticles (NPs) of polyvinyl butyrate (PVBu) as an oral butyrate donor for the controlled release of butyrate for the treatment of colitis. To examine the effect of the size of NPs on the therapeutic effect of colitis, here we prepared PVBu NPs with different sizes (100 nm and 200 nm). Both sizes of PVBu NPs significantly suppressed the inflammatory response in macrophages in vitro. PVBu NPs with 200 nm showed better effects on the amelioration of colitis compared with the 100 nm-NPs. We found unexpectedly that 200 nm-NP incorporated with all-trans retinoic acid (ATRA) showed a much better therapeutic effect than those with unloaded 200 nm-NPs, although ATRA alone was reported to worsen the inflammation. The synergistic effect of ATRA with butyrate shows evidence of being a promising approach for IBD treatment.

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Exploiting Anti-Inflammation Effects of Flavonoids in Chronic Inflammatory Diseases

Current Pharmaceutical Design ◽

10.2174/1381612826666200408101550 ◽

2020 ◽

Vol 26 (22) ◽

pp. 2610-2619 ◽

Cited By ~ 2

Author(s):

Tarique Hussain ◽

Ghulam Murtaza ◽

Huansheng Yang ◽

Muhammad S. Kalhoro ◽

Dildar H. Kalhoro

Keyword(s):

Oxidative Stress ◽

Chronic Diseases ◽

Inflammatory Diseases ◽

Therapeutic Option ◽

Cellular Level ◽

Antiinflammatory Drugs ◽

Suitable Alternative ◽

Chronic Inflammatory Diseases

Background: Inflammation is a complex response of the host defense system to different internal and external stimuli. It is believed that persistent inflammation may lead to chronic inflammatory diseases such as, inflammatory bowel disease, neurological and cardiovascular diseases. Oxidative stress is the main factor responsible for the augmentation of inflammation via various molecular pathways. Therefore, alleviating oxidative stress is effective a therapeutic option against chronic inflammatory diseases. Methods: This review article extends the knowledge of the regulatory mechanisms of flavonoids targeting inflammatory pathways in chronic diseases, which would be the best approach for the development of suitable therapeutic agents against chronic diseases. Results: Since the inflammatory response is initiated by numerous signaling molecules like NF-κB, MAPK, and Arachidonic acid pathways, their encountering function can be evaluated with the activation of Nrf2 pathway, a promising approach to inhibit/prevent chronic inflammatory diseases by flavonoids. Over the last few decades, flavonoids drew much attention as a potent alternative therapeutic agent. Recent clinical evidence has shown significant impacts of flavonoids on chronic diseases in different in-vivo and in-vitro models. Conclusion: Flavonoid compounds can interact with chronic inflammatory diseases at the cellular level and modulate the response of protein pathways. A promising approach is needed to overlook suitable alternative compounds providing more therapeutic efficacy and exerting fewer side effects than commercially available antiinflammatory drugs.

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All-trans retinoic acid: tolerance and biologic effects in myelodysplastic syndrome.

Journal of Clinical Oncology ◽

10.1200/jco.1993.11.8.1489 ◽

1993 ◽

Vol 11 (8) ◽

pp. 1489-1495 ◽

Cited By ~ 40

Author(s):

R Kurzrock ◽

E Estey ◽

M Talpaz

Keyword(s):

Retinoic Acid ◽

Side Effects ◽

Myelodysplastic Syndrome ◽

Acid Tolerance ◽

Maximum Tolerated Dose ◽

Significant Activity ◽

Trans Retinoic Acid ◽

All Trans Retinoic Acid ◽

Biologic Effects ◽

Dose Levels

PURPOSE We conducted a study to evaluate the tolerance to and biologic effects of all-trans retinoic acid in patients with myelodysplastic syndrome. PATIENTS AND METHODS Thirty-nine patients with myelodysplastic syndrome were treated with oral all-trans retinoic acid for 6 weeks. Dose levels were 10, 25, 50, 100, 150, 200, and 250 mg/m2/d. At least three patients were treated on each dose level. RESULTS The most common side effects were mucocutaneous dryness and erythema, and hypertriglyceridemia. Dose-limiting side effects were diverse and included dermatitic problems, sensorineural hearing loss, headaches, nausea and vomiting, myalgias, and dyspnea. The maximum-tolerated dose was 150 mg/m2/d. Only one response was seen among 29 patients considered assessable for response. CONCLUSION All-trans retinoic acid can be safely administered to patients at doses up to 150 mg/m2/d for 6 weeks. However, as administered in this study, this compound does not appear to have significant activity in myelodysplastic syndromes.

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All-Trans Retinoic Acid Increases DRP1 Levels and Promotes Mitochondrial Fission

Cells ◽

10.3390/cells10051202 ◽

2021 ◽

Vol 10 (5) ◽

pp. 1202

Author(s):

Bojjibabu Chidipi ◽

Syed Islamuddin Shah ◽

Michelle Reiser ◽

Manasa Kanithi ◽

Amanda Garces ◽

...

Keyword(s):

Retinoic Acid ◽

Mitochondrial Fission ◽

Normal Function ◽

Mitochondrial Network ◽

Protein Levels ◽

Trans Retinoic Acid ◽

All Trans Retinoic Acid ◽

Area And Perimeter

In the heart, mitochondrial homeostasis is critical for sustaining normal function and optimal responses to metabolic and environmental stressors. Mitochondrial fusion and fission are thought to be necessary for maintaining a robust population of mitochondria, and disruptions in mitochondrial fission and/or fusion can lead to cellular dysfunction. The dynamin-related protein (DRP1) is an important mediator of mitochondrial fission. In this study, we investigated the direct effects of the micronutrient retinoid all-trans retinoic acid (ATRA) on the mitochondrial structure in vivo and in vitro using Western blot, confocal, and transmission electron microscopy, as well as mitochondrial network quantification using stochastic modeling. Our results showed that ATRA increases DRP1 protein levels, increases the localization of DRP1 to mitochondria in isolated mitochondrial preparations. Our results also suggested that ATRA remodels the mitochondrial ultrastructure where the mitochondrial area and perimeter were decreased and the circularity was increased. Microscopically, mitochondrial network remodeling is driven by an increased rate of fission over fusion events in ATRA, as suggested by our numerical modeling. In conclusion, ATRA results in a pharmacologically mediated increase in the DRP1 protein. It also results in the modulation of cardiac mitochondria by promoting fission events, altering the mitochondrial network, and modifying the ultrastructure of mitochondria in the heart.

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Evaluation of semiquantitative reverse transcriptase-polymerase chain reaction assay of PML/retinoic acid receptor .ALPHA. mRNA and in vitro differentiation assay as prognostic prediction in acute promyelocytic leukemia treated with all-trans retinoic acid.

Journal of Nippon Medical School ◽

10.1272/jnms1923.63.259 ◽

1996 ◽

Vol 63 (4) ◽

pp. 259-267

Author(s):

Rika Iwakiri ◽

Koiti Inokuchi ◽

Kazuo Dan ◽

Ichiji Wakabayashi

Keyword(s):

Retinoic Acid ◽

Retinoic Acid Receptor ◽

Promyelocytic Leukemia ◽

In Vitro Differentiation ◽

Chain Reaction ◽

Trans Retinoic Acid ◽

All Trans Retinoic Acid ◽

Polymerase Chain ◽

Prognostic Prediction

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Differential regulation of GPI‐linked molecules on leukaemic promyelocytes treated in vitro with all‐ trans retinoic acid

British Journal of Haematology ◽

10.1046/j.1365-2141.1996.4861027.x ◽

1996 ◽

Vol 93 (2) ◽

pp. 392-393 ◽

Cited By ~ 4

Author(s):

R. DI NOTO ◽

E. M. SCHIAVONE ◽

C. LO PARDO ◽

F. FERRARA ◽

C. MANZO ◽

...

Keyword(s):

Retinoic Acid ◽

Differential Regulation ◽

Trans Retinoic Acid ◽

All Trans Retinoic Acid

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Restoration of Retinoid Sensitivity by MDR1 Ribozymes in Retinoic Acid–Resistant Myeloid Leukemic Cells

Blood ◽

10.1182/blood.v91.7.2452.2452_2452_2458 ◽

1998 ◽

Vol 91 (7) ◽

pp. 2452-2458 ◽

Cited By ~ 1

Author(s):

Hiromichi Matsushita ◽

Masahiro Kizaki ◽

Hiroyuki Kobayashi ◽

Hironori Ueno ◽

Akihiro Muto ◽

...

Keyword(s):

Retinoic Acid ◽

Cellular Proliferation ◽

Therapeutic Potential ◽

Acquired Resistance ◽

Leukemic Cells ◽

Dependent Manner ◽

P Glycoprotein ◽

All Trans Retinoic Acid ◽

Mdr1 Mrna

Complete remission is achieved in a high proportion of patients with acute promyelocytic leukemia (APL) after all-trans retinoic acid (RA) treatment, but most patients relapse and develop RA-resistant APL. We have previously reported that both RA-resistant HL-60 (HL-60R) and APL cells express P-glycoprotein and MDR1 transcripts; and these cells differentiate to mature granulocytes after culture with RA and P-glycoprotein antagonist. Ribozymes have been shown to be able to intercept a target RNA by catalytic activity. To address the role of MDR1 in overcoming RA-resistance in APL cells, we investigated the biologic effects of ribozymes against the MDR1 transcript in HL-60R cells. These ribozymes efficiently cleaved MDR1 mRNA at a specific site in vitro. The 196 MDR1 ribozyme was cloned into an expression vector, and stably transfected (HL-60R/196Rz) cells were obtained. Expression of MDR1 transcripts was decreased in HL-60R/196Rz cells compared with parental HL-60R and empty vector-transfected (HL-60R/neo) cells. Interestingly, RA inhibited cellular proliferation and induced differentiation of HL-60R/196Rz cells in a dose-dependent manner, suggesting reversal of drug resistance in HL-60R cells by the MDR1 ribozyme. These data are direct evidence that P-glycoprotein/MDR1 is responsible in part for acquired resistance to RA in myeloid leukemic cells. The MDR1 ribozyme may be a useful tool for investigating the biology of retinoid resistance and may have therapeutic potential for patients with RA-resistant APL.

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