Publications by authors named "Yunjin Jung"

108 Publications

Novel Anti-Melanogenic Compounds, ()-5-(Substituted Benzylidene)-4-thioxothiazolidin-2-one Derivatives: In Vitro and In Silico Insights.

Molecules 2021 Aug 17;26(16). Epub 2021 Aug 17.

Laboratory of Medicinal Chemistry, College of Pharmacy, Pusan National University, Busan 46241, Korea.

To confirm that the β-phenyl-α,β-unsaturated thiocarbonyl (PUSTC) scaffold, similar to the β-phenyl-α,β-unsaturated carbonyl (PUSC) scaffold, acts as a core inhibitory structure for tyrosinase, twelve ()-5-(substituted benzylidene)-4-thioxothiazolidin-2-one (()-BTTZ) derivatives were designed and synthesized. Seven of the twelve derivatives showed stronger inhibitory activity than kojic acid against mushroom tyrosinase. Compound (IC = 0.47 ± 0.97 µM) exerted a 141-fold higher inhibitory potency than kojic acid. Kinetic studies' results confirmed that compounds and are competitive tyrosinase inhibitors, which was supported by high binding affinities with the active site of tyrosinase by docking simulation. Docking results using a human tyrosinase homology model indicated that and might potently inhibit human tyrosinase. In vitro assays of and were conducted using B16F10 melanoma cells. Compounds and significantly and concentration-dependently inhibited intracellular melanin contents, and the anti-melanogenic effects of at 10 µM and at 25 µM were considerably greater than the inhibitory effect of kojic acid at 25 µM. Compounds and similarly inhibited cellular tyrosinase activity and melanin contents, indicating that the anti-melanogenic effects of both were due to tyrosinase inhibition. A strong binding affinity with the active site of tyrosinase and potent inhibitions of mushroom tyrosinase, cellular tyrosinase activity, and melanin generation in B16F10 cells indicates the PUSTC scaffold offers an attractive platform for the development of novel tyrosinase inhibitors.
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http://dx.doi.org/10.3390/molecules26164963DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8400311PMC
August 2021

Exfoliated bentonite/alginate nanocomposite hydrogel enhances intestinal delivery of probiotics by resistance to gastric pH and on-demand disintegration.

Carbohydr Polym 2021 Nov 21;272:118462. Epub 2021 Jul 21.

College of Pharmacy, Pusan National University, Busan 46241, South Korea. Electronic address:

In this study, we developed Lactobacillus rhamnosus GG (LGG)-encapsulating exfoliated bentonite/alginate nanocomposite hydrogels for protecting probiotics by delaying gastric fluid penetration into the nanocomposite and their on-demand release in the intestine. The pore size of the bentonite/alginate nanocomposite hydrogels (BA15) was two-fold smaller than that of alginate hydrogel (BA00). Following gastric pH challenge, the survival of LGG in BA15 decreased by only 1.43 log CFU/g as compared to the 6.25 log CFU/g decrease in alginate (BA00). Further, the internal pH of BA15 decreased more gradually than that of BA00. After oral administration in mice, BA15 maintained shape integrity during gastric passage, followed by appropriate disintegration within the target intestinal area. Additionally, a fecal recovery experiment in mice showed that the viable counts of LGG in BA15 were six-fold higher than those in BA00. The findings suggest the exfoliated bentonite/alginate nanocomposite hydrogel as a promising platform for intestinal delivery of probiotics.
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http://dx.doi.org/10.1016/j.carbpol.2021.118462DOI Listing
November 2021

Diethylenetriamine/NONOate-doped alginate hydrogel with sustained nitric oxide release and minimal toxicity to accelerate healing of MRSA-infected wounds.

Carbohydr Polym 2021 Oct 1;270:118387. Epub 2021 Jul 1.

College of Pharmacy, Pusan National University, Busan 46241, South Korea.. Electronic address:

This study demonstrates the development of a nitric oxide (NO)-releasing hydrogel wound dressing and its efficacy at accelerating methicillin-resistant Staphylococcus aureus (MRSA)-infected wound healing. A DETA/NONOate-doped alginate (Alg-DETA/NO) hydrogel was synthesized using alginate as a hydrogel-forming wound dressing material and diethylenetriamine/diazeniumdiolate (DETA/NONOate) as an NO donor. Alg-DETA/NO exhibited a prolonged NO release profile over a period of 4 days. The rheological properties of Alg-DETA/NO did not differ significantly from those of pure alginate. Importantly, Alg-DETA/NO showed potent antibacterial activity against MRSA, with minimal toxicity to mouse fibroblasts. The application of Alg-DETA/NO to MRSA-infected wounds in a mouse model showed a favorable wound healing with accelerated wound-size reduction and reduced skin bacterial infection. Additionally, histological examination revealed that Alg-DETA/NO reduced inflammation at the wound site and promoted re-epithelialization, angiogenesis, and collagen deposition. Thus, Alg-DETA/NO presented herein could serve as a safe and potent hydrogel dressing for the treatment of MRSA-infected wounds.
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http://dx.doi.org/10.1016/j.carbpol.2021.118387DOI Listing
October 2021

Oral delivery of natural active small molecules by polymeric nanoparticles for the treatment of inflammatory bowel diseases.

Adv Drug Deliv Rev 2021 Sep 24;176:113887. Epub 2021 Jul 24.

State Key Laboratory of Silkworm Genome Biology, College of Sericulture, Textile, and Biomass Sciences, Southwest University, Beibei, Chongqing 400715, China. Electronic address:

The incidence of inflammatory bowel disease (IBD) is rapidly rising throughout the world. Although tremendous efforts have been made, limited therapeutics are available for IBD management. Natural active small molecules (NASMs), which are a gift of nature to humanity, have been widely used in the prevention and alleviation of IBD; they have numerous advantageous features, including excellent biocompatibility, pharmacological activity, and mass production potential. Oral route is the most common and acceptable approach for drug administration, but the clinical application of NASMs in IBD treatment via oral route has been seriously restricted by their inherent limitations such as high hydrophobicity, instability, and poor bioavailability. With the development of nanotechnology, polymeric nanoparticles (NPs) have provided a promising platform that can efficiently encapsulate versatile NASMs, overcome multiple drug delivery barriers, and orally deliver the loaded NASMs to targeted tissues or cells while enhancing their stability and bioavailability. Thus, NPs can enhance the preventive and therapeutic effects of NASMs against IBD. Herein, we summarize the recent knowledge about polymeric matrix-based carriers, targeting ligands for drug delivery, and NASMs. We also discuss the current challenges and future developmental directions.
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http://dx.doi.org/10.1016/j.addr.2021.113887DOI Listing
September 2021

Development of Combination Vaccine Conferring Optimal Protection against Six Pore-Forming Toxins of Staphylococcus aureus.

Infect Immun 2021 Sep 6;89(10):e0034221. Epub 2021 Jul 6.

Host Defense Protein Laboratory, College of Pharmacy, Pusan National Universitygrid.262229.f, Busan, Republic of Korea.

In the Gram-positive pathogen Staphylococcus aureus, pore-forming toxins (PFTs), such as leukocidins and hemolysins, play prominent roles in staphylococcal pathogenesis by killing host immune cells and red blood cells (RBCs). However, it remains unknown which combination of toxin antigens would induce the broadest protective immune response against those toxins. In this study, by targeting six major staphylococcal PFTs (i.e., gamma-hemolysin AB [HlgAB], gamma-hemolysin CB [HlgCB], leukocidin AB [LukAB], leukocidin ED [LukED], Panton-Valentine leukocidin [LukSF-PV], and alpha-hemolysin [Hla]), we generated 10 recombinant toxins or toxin subunits, 3 toxoids, and their rabbit antibodies. Using the cytolytic assay for RBCs and polymorphonuclear cells (PMNs), we determined the best combination of toxin antibodies conferring the broadest protection against those staphylococcal PFTs. Although anti-HlgA IgG (HlgA-IgG) showed low cross-reactivity to other toxin components, it was essential to protect rabbit and human RBCs and human PMNs. For the protection of rabbit RBCs, Hla toxoid-IgG was also required, whereas for human PMNs, LukS-IgG and LukAB-IgG were essential too. When the toxin/toxoid antigens HlgA, LukS-PV, Hla, and LukAB were used to immunize rabbits, they increased rabbit survival; however, they did not block staphylococcal abscess formation in kidneys. Based on these results, we proposed that the combination of HlgA, LukS, Hla, and LukAB is the optimal vaccine component to protect human RBCs and PMNs from staphylococcal PFTs. We also concluded that a successful S. aureus vaccine requires not only those toxin antigens but also other antigens that can induce immune responses blocking staphylococcal colonization.
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http://dx.doi.org/10.1128/IAI.00342-21DOI Listing
September 2021

Tumor-Penetrable Nitric Oxide-Releasing Nanoparticles Potentiate Local Antimelanoma Therapy.

ACS Appl Mater Interfaces 2021 Jul 23;13(26):30383-30396. Epub 2021 Jun 23.

College of Pharmacy, Pusan National University, Busan, South Korea.

Although nitric oxide (NO) has been emerging as a novel local anticancer agent because of its potent cytotoxic effects and lack of off-target side effects, its clinical applications remain a challenge because of the short effective diffusion distance of NO that limits its anticancer activity. In this study, we synthesized albumin-coated poly(lactic--glycolic acid) (PLGA)-conjugated linear polyethylenimine diazeniumdiolate (LP/NO) nanoparticles (Alb-PLP/NO NPs) that possess tumor-penetrating and NO-releasing properties for an effective local treatment of melanoma. Sufficient NO-loading and prolonged NO-releasing characteristics of Alb-PLP/NO NPs were acquired through PLGA-conjugated LP/NO copolymer (PLP/NO) synthesis, followed by nanoparticle fabrication. In addition, tumor penetration ability was rendered by the electrostatic adsorption of the albumin on the surface of the nanoparticles. The Alb-PLP/NO NPs showed enhanced intracellular NO delivery efficiency and cytotoxicity to B16F10 murine melanoma cells. In B16F10-tumor-bearing mice, the Alb-PLP/NO NPs showed improved extracellular matrix penetration and spatial distribution in the tumor tissue after intratumoral injection, resulting in enhanced antitumor activity. Taken together, the results suggest that Alb-PLP/NO NPs represent a promising new modality for the local treatment of melanoma.
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http://dx.doi.org/10.1021/acsami.1c07407DOI Listing
July 2021

Preparation and Evaluation of Colon-Targeted Prodrugs of the Microbial Metabolite 3-Indolepropionic Acid as an Anticolitic Agent.

Mol Pharm 2021 04 4;18(4):1730-1741. Epub 2021 Mar 4.

College of Pharmacy, Pusan National University, Busan 46241, Republic of Korea.

Microbial metabolites play a critical role in mucosal homeostasis by mediating physiological communication between the host and colonic microbes, whose perturbation may lead to gut inflammation. The microbial metabolite 3-indolepropionic acid (3-IPA) is one such communication mediator with potent antioxidative and anti-inflammatory activity. To apply the metabolite for the treatment of colitis, 3-IPA was coupled with acidic amino acids to yield colon-targeted 3-IPA, 3-IPA-aspartic acid (IPA-AA) and 3-IPA-glutamic acid (IPA-GA). Both conjugates were activated to 3-IPA in the cecal contents, which occurred faster for IPA-AA. Oral gavage of IPA-AA (oral IPA-AA) delivered a millimolar concentration of IPA-AA to the cecum, liberating 3-IPA. In a 2,4-dinitrobenzene sulfonic acid (DNBS)-induced rat colitis model, oral IPA-AA ameliorated rat colitis and was less effective than sulfasalazine (SSZ), a current anti-inflammatory bowel disease drug. To enhance the anticolitic activity of 3-IPA, it was azo-linked with the GPR109 agonist 5-aminonicotinic acid (5-ANA) to yield IPA-azo-ANA, expecting a mutual anticolitic action. IPA-azo-ANA (activated to 5-ANA and 2-amino-3-IPA) exhibited colon specificity in in vitro and in vivo experiments. Oral IPA-azo-ANA mitigated colonic damage and inflammation and was more effective than SSZ. These results suggest that colon-targeted 3-IPA ameliorated rat colitis and its anticolitic activity could be enhanced by codelivery of the GPR109A agonist 5-ANA.
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http://dx.doi.org/10.1021/acs.molpharmaceut.0c01228DOI Listing
April 2021

Discovery and SAR studies of 3-amino-4-(phenylsulfonyl)tetrahydrothiophene 1,1-dioxides as non-electrophilic antioxidant response element (ARE) activators.

Bioorg Chem 2021 03 5;108:104614. Epub 2021 Jan 5.

College of Pharmacy, Pusan National University, Busan 46241, Republic of Korea; Department of Chemistry, The Scripps Research Institute, 10550, North Torrey Pines, La Jolla, CA 92037, United States. Electronic address:

The transcription factor NRF2 controls resistance to oxidative insult and is thus a key therapeutic target for treating a number of disease states associated with oxidative stress and aging. We previously reported CBR-470-1, a bis-sulfone which activates NRF2 by increasing the levels of methylglyoxal, a metabolite that covalently modifies NRF2 repressor KEAP1. Here, we report the design, synthesis, and structure activity relationship of a series of bis-sulfones derived from this unexplored chemical template. We identify analogs with sub-micromolar potencies, 7f and 7g, as well as establish that efficacious NRF2 activation can be achieved by non-toxic analogs 7c, 7e, and 9, a key limitation with CBR-470-1. Further efforts to identify non-covalent NRF2 activators of this kind will likely provide new insight into revealing the role of central metabolism in cellular signaling.
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http://dx.doi.org/10.1016/j.bioorg.2020.104614DOI Listing
March 2021

The N2N3 domains of ClfA, FnbpA and FnbpB in Staphylococcus aureus bind to human complement factor H, and their antibodies enhance the bactericidal capability of human blood.

J Biochem 2021 Jul;169(5):543-553

Host Defense Protein Laboratory, College of Pharmacy, Pusan National University, Busan 46241, Republic of Korea.

In the complement system, the opsonin C3b binds to the bacterial cell surface and mediates the opsonophagocytosis. However, the cell-wall protein SdrE of Staphylococcus aureus inhibits the C3b activity by recruiting the complement regulatory protein factor H (fH). SdrE binds to fH via its N-terminal N2N3 domain, which are also found in six other staphylococcal cell-wall proteins. In this study, we report that not only the N2N3 domain of SdrE but also those of ClfA, FnbpA and FnbpB can bind to fH. When immobilized on a microplate, the N2N3 domains recruited fH and enhanced the factor I (fI)-mediated cleavage of C3b. When mixed with fH and S. aureus cells, the N2N3 domains inhibited the fH binding to S. aureus cells and reduced the fI-mediated C3b cleavage on the bacterial cell surface. The F(ab)'2 fragments of the rabbit N2N3 antibodies also inhibited the fH binding to the S. aureus cell surface. When added to human blood, the N2N3 antibodies or the N2N3 domain proteins significantly increased the bactericidal activity. Based on these results, we conclude that, in S. aureus, not only SdrE but also ClfA, FnbpA and FnbpB can contribute to the inhibition of C3b-mediated opsonophagocytosis.
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http://dx.doi.org/10.1093/jb/mvaa142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8254515PMC
July 2021

Preparation and Evaluation of Amino Acid Conjugates of Celecoxib as Prodrugs to Improve the Pharmacokinetic and Therapeutic Properties of Celecoxib.

Pharmaceutics 2020 Oct 30;12(11). Epub 2020 Oct 30.

College of Pharmacy, Pusan National University, Busan 46241, Korea.

Although celecoxib is quite effective in the management of inflammation-related diseases, especially arthritis, its use is limited by concerns including low bioavailability (BA), non-linear pharmacokinetic (PK) profile, and peak concentration-related toxicity. To overcome these issues, we designed and prepared hydrophilic celecoxib prodrugs, namely -glycyl-aspart-1yl celecoxib (-GA1C), glutam-1-yl celecoxib (G1C), and aspart-1yl celecoxib (A1C), for the sustained release of celecoxib in the intestine with limited systemic absorption. The celecoxib derivatives were converted to celecoxib in the intestinal contents. The conversion rates were in order of N-GA1C > G1C > A1C. Oral administration of the celecoxib derivatives (oral celecoxib derivatives) sustained the plasma concentration of celecoxib for 24 h, improving the BA and linearity of the PK profile of celecoxib. The peak concentrations (C) of celecoxib after oral celecoxib derivatives were lower than that after oral celecoxib. In a carrageenan-induced rat paw edema model, oral N-GA1C exhibited greater anti-inflammatory activity for a longer duration compared with oral celecoxib. The order of efficacy of the celecoxib derivatives was N-GA1C > G1C > A1C. Taken together, the prodrug approach is a feasible strategy to improve the PK and therapeutic properties of celecoxib, and among the celecoxib derivatives, N-GA1C may be the most promising prodrug of celecoxib.
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http://dx.doi.org/10.3390/pharmaceutics12111043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7693880PMC
October 2020

Colitis-targeted hybrid nanoparticles-in-microparticles system for the treatment of ulcerative colitis.

Acta Biomater 2020 10 13;116:368-382. Epub 2020 Sep 13.

College of Pharmacy, Pusan National University, Busan609-735, South Korea. Electronic address:

Nanoparticle (NP)-based drug delivery systems accumulate in the disrupted epithelium of inflamed colon tissue in ulcerative colitis. However, premature early drug release and uptake or degradation of NPs during their passage through the harsh gastric or intestinal environment compromise their therapeutic outcomes. This study aimed to develop an advanced colitis-targeted hybrid nanoparticles-in-microparticles (NPsinMPs) drug delivery system to overcome the aforementioned challenges. First, sustained drug releasing poly(lactic-co-glycolic acid) NPs were generated and further encapsulated in pH-sensitive Eudragit FS30D MPs to ensure complete drug protection in a gastric-like pH and for selective delivery of NPs to the colon. SEM and confocal microscopy for the NPsinMPs revealed successful NP encapsulation. NPsinMPs prevented drug release in an acidic gastric-like and intestinal-like pH and presented a sustained release thereafter at an ileal and colonic pH, indicating the degradation of the outer pH-sensitive MPs and release of NPs. Furthermore, in vivo imaging of gastrointestinal tract of a colitis mouse orally administered with fluorescent NPsinMPs revealed higher fluorescence intensities selectively in the colon, demonstrating the release of loaded NPs and their concomitant accumulation at the site of colon inflammation. NPsinMPs markedly mitigated experimental colitis in mice indicated by improved histopathological analysis, decreased myeloperoxidase activity, neutrophils and macrophage infiltration, and expression of proinflammatory cytokines in colonic tissues compared with NP-treated mice. The present results show the successful formulation of an NPsinMP-based drug delivery system and provide a platform to improve NP-based colon-targeted drug delivery through improved protection of encapsulated NPs and their payload in the early small intestine.
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http://dx.doi.org/10.1016/j.actbio.2020.09.017DOI Listing
October 2020

A Colon-Targeted Prodrug, 4-Phenylbutyric Acid-Glutamic Acid Conjugate, Ameliorates 2,4-Dinitrobenzenesulfonic Acid-Induced Colitis in Rats.

Pharmaceutics 2020 Sep 3;12(9). Epub 2020 Sep 3.

College of Pharmacy, Pusan National University, Busan 46241, Korea.

An elevated level of endoplasmic reticulum (ER) stress is considered an aggravating factor for inflammatory bowel disease (IBD). To develop an ER-stress attenuator that is effective against colitis, 4-phenylbutyric acid (4-PBA), a chemical chaperone that alleviates ER stress, was conjugated with acidic amino acids to yield 4-PBA-glutamic acid (PBA-GA) and 4-PBA-aspartic acid (PBA-AA) conjugates. The PBA derivatives were converted to 4-PBA in the cecal contents, and the conversion was greater with PBA-GA than that with PBA-AA. After oral administration of PBA-GA (oral PBA-GA), up to 2.7 mM PBA was detected in the cecum, whereas 4-PBA was not detected in the blood, indicating that PBA-GA predominantly targeted the large intestine. In 2,4-dinitrobenzenesulfonic acid-induced colitis in rats, oral PBA-GA alleviated the damage and inflammation in the colon and substantially reduced the elevated levels of ER stress marker proteins in the inflamed colon. Moreover, PBA-GA was found to be as effective as the currently used anti-IBD drug, sulfasalazine. In conclusion, PBA-GA is a colon-targeted prodrug of 4-PBA and is effective against rat colitis probably via the attenuation of ER stress in the inflamed colon.
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http://dx.doi.org/10.3390/pharmaceutics12090843DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7558321PMC
September 2020

Curcumin Nanocrystal/pH-Responsive Polyelectrolyte Multilayer Core-Shell Nanoparticles for Inflammation-Targeted Alleviation of Ulcerative Colitis.

Biomacromolecules 2020 09 17;21(9):3571-3581. Epub 2020 Aug 17.

College of Pharmacy, Pusan National University, Busan 46241, South Korea.

In this study, we developed oral core-shell nanoparticles composed of curcumin nanocrystals in the core and chitosan/alginate multilayers in the shell for inflammation-targeted alleviation of ulcerative colitis (UC). The release rate of curcumin from the core-shell nanoparticles was low at a pH mimicking the stomach and small intestine, whereas it was higher at a pH mimicking the colon. Further, biodistribution studies in the gastrointestinal tract of mice showed that distribution of nanoparticles was significantly higher in the colon than that in the stomach and small intestine. Quantitative analysis of drugs in colonic tissues and confocal imaging of colons revealed preferential accumulation of nanoparticles in inflamed tissues than that in healthy tissues. anti-inflammatory studies revealed that nanoparticles exhibit enhanced efficacy in alleviating inflammation-related symptoms in a mouse colitis model. The results suggest that the core-shell nanoparticles presented here can be exploited as efficient colon-targeted drug delivery systems for UC therapy.
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http://dx.doi.org/10.1021/acs.biomac.0c00589DOI Listing
September 2020

miR-23a-3p is a Key Regulator of IL-17C-Induced Tumor Angiogenesis in Colorectal Cancer.

Cells 2020 06 1;9(6). Epub 2020 Jun 1.

College of Pharmacy, Pusan National University, Busan 46241, Korea.

MicroRNAs (miRNAs) have emerged as key players in tumor angiogenesis. Interleukin-17C (IL-17C) was identified to promote colorectal cancer (CRC) progression. Therefore, we aimed to investigate the effect of IL-17C on tumor angiogenesis, the involvement of miR-23a-3p in IL-17C signaling, and the direct target gene of miR-23a-3p in CRC. In vitro and ex vivo angiogenesis, a mouse xenograft experiment, and immunostaining were performed to test the effect of IL-17C on tumor angiogenesis. ELISA, quantitative real time PCR, and gene silencing were used to uncover the underlying mechanism. IL-17C induced angiogenesis of intestinal endothelial cells, subsequently enhancing cell invasion and migration of DLD-1 cells. IL-17C-stimulated DLD-1 cells produced vascular endothelial growth factor (VEGF) to enhance angiogenesis. Moreover, IL-17C markedly accelerated xenograft tumor growth, which was manifested by substantially reduced tumor growth when treated with the VEGF receptor 2 inhibitor Ki8751. Accordingly, Ki8751 suppressed the expression of IL-17C-stimulated PECAM and VE-cadherin in xenografts. Furthermore, IL-17C activated STAT3 to increase the expression of miR-23a-3p that suppressed semaphorin 6D (SEMA6D) expression, thereby permitting VEGF production. Taken together, our study demonstrates that IL-17C promotes tumor angiogenesis through VEGF production via a STAT3/miR-23a-3p/SEMA6D axis, suggesting its potential as a novel target for anti-CRC therapy.
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http://dx.doi.org/10.3390/cells9061363DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7348989PMC
June 2020

Isolation and Characterization of Exosomes from Mouse Feces.

Bio Protoc 2020 Apr;10(8)

Institute for Biomedical Sciences, Center for Diagnostics and Therapeutics, Digestive Disease Research Group, Georgia State University, Atlanta, Georgia, 30302, United States.

Exosomes secreted by colonic epithelial cells are present in feces and contain valuable epigenetic information, such as miRNAs, proteins, and metabolites. An in-depth study of this information is conducive to the diagnosis or treatment of relevant diseases. A crucial prerequisite of such a study is to establish an efficient isolation method, through which we can obtain a relatively more significant amount of exosomes from feces. This protocol is designed to effectively isolate a large number of exosomes from contaminants and other particles in feces by a combined method with fast filtration and sucrose density gradient ultracentrifugation. Exosomes generated by this method are suitable for further RNA, protein, and lipid analysis.
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http://dx.doi.org/10.21769/bioprotoc.3584DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7241525PMC
April 2020

Advances in colon-targeted nano-drug delivery systems: challenges and solutions.

Arch Pharm Res 2020 Jan 27;43(1):153-169. Epub 2020 Jan 27.

College of Pharmacy, Pusan National University, Busan, South Korea.

Nano-drug delivery systems (NDDS) for colon-targeted drug delivery are an active area of research on local diseases affecting the colon, such as ulcerative colitis, Crohn's disease, colon cancer, and for the delivery of peptide or protein drugs and vaccinations. In particular, targeted nano-drug delivery to the colon is advantageous for colon-specific diseases because nanoparticles can accumulate in diseased parts, improve the efficacies of therapeutics, and enable localized treatments, which reduces systemic toxicity. However, there are many hurdles, such as burst drug release, enzyme and acidic degradation of drug and carrier in the stomach, pH variations, mucus entrapment, and systemic uptake in the upper small intestine, which could challenge and compromise the successful delivery of NDDS to the colon. With advancements in NDDS, it may be possible to overcome these challenges leading to efficient drug delivery for colon-specific disorders. This review describes a few of the potential colon-specific drug delivery areas and the challenges faced by colon-targeted orally administered delivery systems, and provides an updated summary of recent advances in the development of orally administered NDDS for colon targeting, and the future advances in this research.
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http://dx.doi.org/10.1007/s12272-020-01219-0DOI Listing
January 2020

5-Aminosalicylic Acid Azo-Coupled with a GPR109A Agonist Is a Colon-Targeted Anticolitic Codrug with a Reduced Risk of Skin Toxicity.

Mol Pharm 2020 01 3;17(1):167-179. Epub 2019 Dec 3.

College of Pharmacy , Pusan National University , Busan , Republic of Korea.

To develop a 5-aminosalicylic acid (5-ASA)-based anticolitic drug with enhanced therapeutic activity, a colon-targeted codrug constituting 5-ASA and a GPR109A agonist was designed. 5-ASA azo-coupled with nicotinic acid (ASA-azo-NA) was synthesized, and the colon specificity and anticolitic effects were evaluated. Approximately 89% of ASA-azo-NA was converted to 5-aminonicotinic acid (5-ANA) and 5-ASA after 24 h of incubation in the cecal contents. 5-ANA was identified as a GPR109A agonist (concentration that gives half-maximal response (EC): 18 μM) in a cell-based assay. Upon oral gavage of ASA-azo-NA (oral ASA-azo-NA) and sulfasalazine (oral SSZ), a colon-targeted 5-ASA prodrug, cecal accumulation of 5-ASA was comparable, and 5-ANA was barely detectable in the blood, while it was detected up to 62.7 μM with oral 5-ANA. In parallel, oral ASA-azo-NA did not elicit an adverse skin response. In murine macrophage and human colon carcinoma cells, activation of GPR109A by 5-ANA elevated the level of the anti-inflammatory cytokine IL-10, suppressed NF-κB activation, and potentiated the inhibitory activity of 5-ASA on NF-κB. Oral ASA-azo-NA ameliorated rat colitis and was more effective than oral SSZ, which were substantially blunted following cotreatment with the GPR109A antagonist, mepenzolate. In conclusion, ASA-azo-NA is a colon-targeted anticolitic codrug with a reduced risk of skin toxicity induced by the GPR109A agonist, therapeutically surpassing a current 5-ASA-based anti-inflammatory bowel disease drug in a rat colitis model.
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http://dx.doi.org/10.1021/acs.molpharmaceut.9b00872DOI Listing
January 2020

Autologous Exosome Transfer: A New Personalised Treatment Concept to Prevent Colitis in a Murine Model.

J Crohns Colitis 2020 Jul;14(6):841-855

Digestive Disease Research Group, Institute for Biomedical Sciences, Georgia State University, Atlanta, GA, USA.

Background And Aims: Epigenetic information delivered by intestinal exosomes can be useful for diagnosing intestinal diseases, such as ulcerative colitis, but the therapeutic effects of intestinal exosomes have not been fully exploited. We herein developed an autologous exosome therapy that could treat intestinal disease without any risk of inducing a systemic immunological reaction.

Methods: Intestinal exosomes were isolated and purified from faeces by our newly developed multi-step sucrose gradient ultracentrifugation method. Lipopolysaccharide [LPS]-activated macrophages were employed to test the in vitro anti-inflammatory ability of intestinal exosomes. To evaluate the in vivo anti-inflammatory activity of our system, we gavaged dextran sulphate sodium [DSS]-induced colitic mice with their own healing phase intestinal exosomes.

Results: Mouse intestinal exosomes are round extracellular vesicles with a hydrodynamic diameter of ~140 [±20] nm and a surface charge of ~-12 [±3] mV. Among the exosomes obtained at four different stages of DSS-induced ulcerative colitis [1, before treatment; 2, DSS-treated; 3, healing phase; and 4, back to normal], the healing phase exosomes showed the best in vitro anti-inflammatory effects and promotion of wound healing. Moreover, oral co-administration of autologous healing phase exosomes with DSS was found to significantly reduce the risk of a second round of DSS-induced ulcerative colitis in mice.

Conclusions: Intestinal exosomes obtained during the healing phase that follows induced intestinal inflammation could strongly promote wound healing in the host. Oral administration of autologous exosomes from the healing phase could be a safe and effective approach for treating the ulcerative colitis of a given patient in the context of personalised medicine.
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http://dx.doi.org/10.1093/ecco-jcc/jjz184DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7346889PMC
July 2020

Conjugation of Amisulpride, an Anti-Psychotic Agent, with 5-Aminosalicylic Acid via an Azo Bond Yields an Orally Active Mutual Prodrug against Rat Colitis.

Pharmaceutics 2019 Nov 7;11(11). Epub 2019 Nov 7.

College of Pharmacy, Pusan National University, Busan 46241, Korea.

Amisulpride (ASP), an anti-psychotic agent, is a pharmacologically equivalent to sulpiride (SP). Because SP demonstrates anti-ulcer and anti-colitic activities, ASP with an aniline moiety was azo-coupled to salicylic acid to generate 5-(aminoethanoylsulfamoyl)--[(1-ethylpyrrolidin-2-yl)methyl]-2-methoxybenzamide (ASP-azo-ASA), with the expectation that it would act as a colon-specific mutual prodrug against colitis. Following a 24 h incubation, approximately 80% of ASP-azo-ASA was cleaved to form ASP and 5-aminosalicylic acid (5-ASA) in the cecal contents, whereas it remained stable in the small intestinal contents. Oral gavage of ASP-azo-ASA (oral ASP-azo-ASA) delivered 5-ASA to the cecum to levels comparable with those observed for sulfasalazine (SSZ; clinical colon-specific prodrug of 5-ASA) and without detectable concentrations of ASP in the blood, indicating efficient colonic delivery. Oral ASP-azo-ASA ameliorated 2, 4-dinitrobenzenesulfonic acid hydrate (DNBS)-induced colitis in rats more effectively than oral SSZ. Additionally, oral ASP-azo-ASA lowered the levels of inflammatory mediators in the inflamed distal colon more effectively than oral SSZ. Combined treatment with 5-ASA and ASP via the rectal route more effectively reversed colonic damage and inflammation than treatment with 5-ASA or ASP alone, confirming the mutual anti-colitic actions of 5-ASA and ASP. In conclusion, ASP-azo-ASA is an orally active mutual prodrug against rat colitis with limited systemic absorption of ASP.
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http://dx.doi.org/10.3390/pharmaceutics11110585DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6920822PMC
November 2019

Sofalcone, a gastroprotective drug, covalently binds to KEAP1 to activate Nrf2 resulting in anti-colitic activity.

Eur J Pharmacol 2019 Dec 12;865:172722. Epub 2019 Oct 12.

College of Pharmacy, Pusan National University, Busan, Republic of Korea. Electronic address:

Sofalcone is a synthetic chalcone being used as a gastric mucosa protective agent in Japan. Sofalcone contains a 1,3-diaryl-2-propen-1-one moiety, which is a common chemical scaffold in naturally occurring chalcones. The α,β-unsaturated carbonyl group (Michael reaction acceptor) has electrophilic properties. We investigated the biochemical mechanisms by which sofalcone activated the cytoprotective and anti-inflammatory nuclear factor-erythroid 2 (NF-E2) p45-related factor 2 (Nrf2)-heme oxygenase (HO)-1 pathway. Furthermore, we investigated whether the activation of this pathway was involved in sofalcone -mediated protective effects in an experimental colitis model. Sofalcone induced HO-1 protein expression, which was dependent on increased nuclear accumulation of Nrf2 in human colon carcinoma cells. In addition, Sofalcone reacted with nucleophilic thiol compounds to form Michael adducts. A reduced form of sofalcone (SFCR) in which the Michael reaction acceptor was deactivated, did not exert biological or chemical activity. Biotin-tagged sofalcone bound to Kelch-like ECH-associated protein 1 (KEAP1), a cytosolic repressor of Nrf2. This binding was prevented by pretreatment with sofalcone and a thiol compound but not with SFCR. Furthermore, sofalcone treatment induced dissociation of the Nrf2-KEAP1 complex. Rectal administration of sofalcone alleviated colon damage and inflammation and increased colon nuclear accumulation of Nrf2 and HO-1 levels in a dinitrobenzene sulfonic acid-induced rat colitis model. The protective effects of sofalcone against colon damage and inflammation were significantly inhibited by co-administration of an HO-1 inhibitor. In conclusion, sofalcone activated the Nrf2-HO-1 pathway by covalently binding to KEAP1 via Michael addition, and may confer anti-colitic effects by inducing Nrf2 activation.
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http://dx.doi.org/10.1016/j.ejphar.2019.172722DOI Listing
December 2019

In Staphylococcus aureus, the Particulate State of the Cell Envelope Is Required for the Efficient Induction of Host Defense Responses.

Infect Immun 2019 12 18;87(12). Epub 2019 Nov 18.

Host Defense Protein Laboratory, College of Pharmacy, Pusan National University, Busan, Republic of Korea

Upon microbial infection, host immune cells recognize bacterial cell envelope components through cognate receptors. Although bacterial cell envelope components function as innate immune molecules, the role of the physical state of the bacterial cell envelope (i.e., particulate versus soluble) in host immune activation has not been clearly defined. Here, using two different forms of the staphylococcal cell envelope of RN4220 and USA300 LAC strains, we provide biochemical and immunological evidence that the particulate state is required for the effective activation of host innate immune responses. In a murine model of peritoneal infection, the particulate form of the staphylococcal cell envelope (PCE) induced the production of chemokine (C-X-C motif) ligand 1 (CXCL1) and CC chemokine ligand 2 (CCL2), the chemotactic cytokines for neutrophils and monocytes, respectively, resulting in a strong influx of the phagocytes into the peritoneal cavity. In contrast, compared with PCE, the soluble form of cell envelope (SCE), which was derived from PCE by treatment with cell wall-hydrolyzing enzymes, showed minimal activity. PCE also induced the secretion of calprotectin (myeloid-related protein 8/14 [MRP8/14] complex), a phagocyte-derived antimicrobial protein, into the peritoneal cavity at a much higher level than did SCE. The injected PCE particles were phagocytosed by the infiltrated neutrophils and monocytes and then delivered to mediastinal draining lymph nodes. More importantly, intraperitoneally (i.p.) injected PCE efficiently protected mice from infection, which was abolished by the depletion of either monocytes/macrophages or neutrophils. This study demonstrated that the physical state of bacterial cells is a critical factor for efficient host immune activation and the protection of hosts from staphylococcal infections.
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http://dx.doi.org/10.1128/IAI.00674-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6867855PMC
December 2019

Pro-apoptotic effect of the novel benzylidene derivative MHY695 in human colon cancer cells.

Oncol Lett 2019 Sep 25;18(3):3256-3264. Epub 2019 Jul 25.

College of Pharmacy, Pusan National University, Geumjeong-gu, Busan 46241, Republic of Korea.

The induction of apoptosis is a useful strategy in anti-cancer research. Various Moon Hyung Yang (MHY) compounds have been developed as novel anti-cancer drug candidates; in the present study, the pro-apoptotic effects of ()-5-(3-ethoxy-4- hydroxybenzylidene)-2-thioxothiazolidin-4-one (MHY695) on HCT116 human colon cancer cells were assessed. MTT assays were performed to investigate the dose-dependent cytotoxic effects of MHY695 on HCT116 cells. Immunofluorescence staining and flow cytometry analyses were performed to identify apoptotic cell death, and western blot analysis was used to investigate the apoptotic-signaling pathways. A mouse xenograft model was also used to determine the effects of MHY695 . MHY695 decreased the viability of HCT116 cells and induced apoptotic cytotoxicity. The apoptotic mechanisms induced by MHY695 involved the dephosphorylation of Bcl-2-associated agonist of cell death protein following protein kinase B inactivation, induced myeloid leukaemia cell differentiation protein and BH3-interacting domain death agonist truncation, caspase-3 and -9 activation and poly (ADP-ribose) polymerase cleavage. In addition, MHY695 significantly suppressed tumor growth in the mouse xenograft model, compared with the vehicle control. Notably, MHY695 exhibited potent anti-cancer effects in four different types of human colon cancer cell line, including Caco-2, DLD-1, HT-29 and HCT116. Additionally, MHY695 showed reduced cytotoxicity in NCM460, normal colonic epithelial cells. Furthermore, MHY-induced cytotoxicity in colon cancer cells was independent of the tumor suppressor protein p53. Collectively, these observations suggested that MHY695 may be a novel drug for the treatment of colon cancer.
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http://dx.doi.org/10.3892/ol.2019.10664DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6704326PMC
September 2019

Colon-Targeted Delivery Facilitates the Therapeutic Switching of Sofalcone, a Gastroprotective Agent, to an Anticolitic Drug via Nrf2 Activation.

Mol Pharm 2019 09 16;16(9):4007-4016. Epub 2019 Aug 16.

College of Pharmacy , Pusan National University , Busan , Republic of Korea.

We investigated if the therapeutic switching of sofalcone (SFC), a gastroprotective agent, to an anticolitic agent is feasible using colon-targeted drug delivery. SFC can activate the anti-inflammatory nuclear factor (erythroid-derived 2)-like 2 (Nrf2)-hemeoxygenase-1 (HO-1) pathway in human colon epithelial cells and murine macrophages. For the efficient treatment of colitis, SFC was coupled with acidic amino acids to yield SFC-aspartic acid (SFC-AA) and SFC-glutamic acid, and their colon targetability and therapeutic effects were assessed as an anticolitic agent in a 2,4-dinitrobenezenesulfonic acid-induced rat colitis model. The SFC derivatives were decoupled up to 72% in the cecal contents but remained stable in the small intestinal contents. Oral gavage of SFC-AA (oral SFC-AA, equivalent to 1.67 mg/kg of SFC) delivered SFC (maximal cecal concentration: 57.36 μM) to the cecum, while no SFC was detected with oral gavage of SFC (oral SFC, 1.67 mg/kg). Moreover, oral SFC-AA (equivalent to 10 mg/kg of SFC) did not afford detectable concentration of SFC in the blood but detected up to 4.64 μM with oral SFC (10 mg/kg), indicating efficient colonic delivery and limited systemic absorption of SFC upon oral SFC-AA. Oral SFC-AA ameliorated colonic damage and inflammation in rat colitis with elevating colonic levels of HO-1 and nuclear Nrf2 protein, and the anticolitic effects of SFC-AA were significantly undermined by an HO-1 inhibitor. At an equivalent dose of SFC, oral SFC-AA but not oral SFC increased colonic HO-1 and nuclear Nrf2 levels, and oral SFC-AA was more effective than oral SFC in treating rat colitis. Moreover, oral SFC-AA was as effective against colitis as oral sulfasalazine being used for the treatment of inflammatory bowel disease. In conclusion, colon-targeted delivery of SFC facilitated the therapeutic switching of the drug to an anticolitic drug via Nrf2 activation.
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http://dx.doi.org/10.1021/acs.molpharmaceut.9b00664DOI Listing
September 2019

Pharmacokinetic Evaluation of Metabolic Drug Interactions between Repaglinide and Celecoxib by a Bioanalytical HPLC Method for Their Simultaneous Determination with Fluorescence Detection.

Pharmaceutics 2019 Aug 2;11(8). Epub 2019 Aug 2.

Department of Manufacturing Pharmacy, College of Pharmacy, Pusan National University, Busan 46241, Korea.

Since diabetes mellitus and osteoarthritis are highly prevalent diseases, combinations of antidiabetic agents like repaglinide (REP) and non-steroidal anti-inflammatory drugs (NSAID) like celecoxib (CEL) could be commonly used in clinical practice. In this study, a simple and sensitive bioanalytical HPLC method combined with fluorescence detector (HPLC-FL) was developed and fully validated for simultaneous quantification of REP and CEL. A simple protein precipitation procedure and reversed C18 column with an isocratic mobile phase (mixture of ACN and pH 6.0 phosphate buffer) were employed for sample preparation and chromatographic separation. The fluorescence detector was set at a single excitation/emission wavelength pair of 240 nm/380 nm. The linearity (10-2000 ng/mL), accuracy, precision, extraction recovery, matrix effect, and stability for this method were validated as per the current FDA guidance. The bioanalytical method was applied to study pharmacokinetic interactions between REP and CEL in vivo, successfully showing that concurrent administration with oral REP significantly altered the pharmacokinetics of oral CEL. Furthermore, an in vitro metabolism and protein binding study using human materials highlighted the possibility of metabolism-based interactions between CEL and REP in clinical settings.
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http://dx.doi.org/10.3390/pharmaceutics11080382DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6723536PMC
August 2019

PEI/NONOates-doped PLGA nanoparticles for eradicating methicillin-resistant Staphylococcus aureus biofilm in diabetic wounds via binding to the biofilm matrix.

Mater Sci Eng C Mater Biol Appl 2019 Oct 14;103:109741. Epub 2019 May 14.

Department of Manufacturing Pharmacy, College of Pharmacy, Pusan National University, Busan 46241, South Korea. Electronic address:

Wounds infected with methicillin-resistant Staphylococcus aureus (MRSA) biofilm represent a high risk in patients with diabetes. Nitric oxide (NO) has shown promise in dispersing biofilm and wound healing. For an effective treatment of MRSA biofilm-infected wounds, however, NO needs to be supplied to the biofilm matrix in a sustainable manner due to a short half-life and limited diffusion distance of NO. In this study, polyethylenimine/diazeniumdiolate (PEI/NONOate)-doped PLGA nanoparticles (PLGA-PEI/NO NPs) with an ability to bind to the biofilm matrix are developed to facilitate the NO delivery to MRSA biofilm-infected wound. In simulated wound fluid, PLGA-PEI/NO NPs show an extended NO release over 4 days. PLGA-PEI/NO NPs firmly bind to the MRSA biofilm matrix, resulting in a greatly enhanced anti-biofilm activity. Moreover, PLGA-PEI/NO NPs accelerate healing of MRSA biofilm-infected wounds in diabetic mice along with complete biofilm dispersal and reduced bacterial burden. These results suggest that the biofilm-binding NO-releasing NPs represent a promising NO delivery system for the treatments of biofilm-infected chronic wounds.
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http://dx.doi.org/10.1016/j.msec.2019.109741DOI Listing
October 2019

Bacteria-Targeted Clindamycin Loaded Polymeric Nanoparticles: Effect of Surface Charge on Nanoparticle Adhesion to MRSA, Antibacterial Activity, and Wound Healing.

Pharmaceutics 2019 May 15;11(5). Epub 2019 May 15.

College of Pharmacy, Pusan National University, Busan 46241, Korea.

Adhesion of nanoparticles (NPs) to the bacterial cell wall by modifying their physicochemical properties can improve the antibacterial activity of antibiotic. In this study, we prepared positively charged clindamycin-loaded poly (lactic-co-glycolic acid)-polyethylenimine (PLGA-PEI) nanoparticles (Cly/PPNPs) and negatively charged clindamycin-loaded PLGA NPs (Cly/PNPs) and investigated the effect of NP adhesion to bacteria on the treatment of methicillin-resistant (MRSA)-infected wounds. The Cly/PPNPs and Cly/PNPs were characterized according to particle size, polydispersity index, surface charge, and drug loading. Both Cly/PPNPs and Cly/PNPs exhibited sustained drug release over 2 days. The Cly/PPNPs bind to the MRSA surface, thereby enhancing bactericidal efficacy against MRSA compared with the Cly/PNPs. Furthermore, compared with other groups, Cly/PPNPs significantly accelerated the healing and re-epithelialization of wounds in a mouse model of a MRSA-infected wounds. We also found that both NPs are harmless to healthy fibroblast cells. Therefore, our results suggest that the Cly/PPNPs developed in this study improve the efficacy of clindamycin for the treatment of MRSA-infected wounds.
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http://dx.doi.org/10.3390/pharmaceutics11050236DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6571677PMC
May 2019

Mesalazine Activates Adenosine Monophosphate-activated Protein Kinase: Implication in the Anti-inflammatory Activity of this Anti-colitic Drug.

Curr Mol Pharmacol 2019 ;12(4):272-280

College of Pharmacy, Pusan National University, Busan 609-735, South Korea.

Objective: Mesalazine, 5-aminosalicylic acid (5-ASA), is an anti-inflammatory drug that is most widely used for the treatment of Inflammatory Bowel Disease (IBD). Despite extensive clinical use, the exact pharmacological mechanism underlying the anti-colitic effects of 5-ASA has not yet been elucidated. A potential molecular mechanism underlying 5-ASA-mediated anti-colitic activity was investigated.

Methods: An anti-inflammatory pharmacology of 5-ASA was scrutinized in human colon carcinoma cells and murine macrophages and in a TNBS-induced rat colitis model.

Results: 5-ASA induced phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) and its substrate acetyl-CoA carboxylase in cells. 5-ASA activation of AMPK occurred regardless of the presence of the pro-inflammatory mediators, Tumor Necrosis Factor Alpha (TNF-α) and lipopolysaccharide. 5-ASA inhibits TNF-α-dependent Nuclear Factor-Kappa B (NF-κB) activation, which was dampened by AMPK inhibition. Oral gavage of sulfasalazine (a colon-specific prodrug of 5- ASA) or rectal administration of 5-ASA ameliorated 2,4,6-trinitrobenzene sulfonic acid (TNBS)- induced rat colitis and activated AMPK in the inflamed colonic tissues while markedly diminishing the levels of NF-κB-regulated pro-inflammatory mediators cyclooxygenase-2, inducible nitric oxide synthase, and cytokine-induced neutrophil chemoattractant-3, elevated by the induction of inflammation. Rectal co-administration of 5-ASA and an AMPK inhibitor undermined 5-ASA-mediated activation of AMPK and its anti-colitic effects.

Conclusion: These findings suggest that the activation of AMPK is involved in 5-ASA-mediated anticolitic effects at least partly via interference with pro-inflammatory NF-κB signaling.
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http://dx.doi.org/10.2174/1874467212666190308103448DOI Listing
July 2020

A colon-specific prodrug of metoclopramide ameliorates colitis in an experimental rat model.

Drug Des Devel Ther 2019 28;13:231-242. Epub 2018 Dec 28.

College of Pharmacy, Pusan National University, Busan 609-735, South Korea,

Background: We examined whether metoclopramide (MCP), a modulator of dopamine and serotonin receptors, alleviated colitis and had synergistic effects when coadministered with 5-aminosalicylic acid (5-ASA) in an experimental model of colitis.

Methods: MCP azo-linked to 5-ASA (5-[4-chloro-2-{2-(diethylamino)ethylcarbamoyl}- 1-methoxyphenyl]azosalicylic acid, MCP-azo-ASA) was synthesized, where 5-ASA was used as a colon-targeting carrier and an anti-colitic agent, and the ability of MCP-azo-ASA to target the colon in vitro and in vivo was evaluated.

Results: Our results indicate that MCP-azo-ASA was cleaved to MCP and 5-ASA in the cecal contents, but not in the contents of the small intestine. Oral gavage with equimolar concentrations of MCP-azo-ASA and sulfasalazine (SSZ, a colon-specific prodrug of 5-ASA widely used clinically) demonstrated that the two prodrugs delivered comparable amounts of 5-ASA to the cecum. MCP was barely detected in the blood after oral gavage with MCP-azo-ASA. In a rat model of 2,4-dinitrobenzene sulfonic acid hydrate (DNBS)-induced colitis, MCP-azo-ASA alleviated colonic damage in a dose-dependent manner. Moreover, MCP-azo-ASA reduced the concentrations of inflammatory mediators in the inflamed colon. At low equimolar doses, MCP-azo-ASA, but not SSZ, resulted in significant anti-colitic effects, which indicates that MCP has anti-colitic activity. MCP-azo-ASA had anti-colitic effects equal to those of SSZ at high equimolar doses.

Conclusion: Thus, our results indicate that MCP-azo-ASA is a colon-specific prodrug of MCP. Targeted delivery of MCP to the colon ameliorated DNBS-induced colitis in rats, and we did not observe any synergistic effects of MCP after co-delivery with 5-ASA.
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http://dx.doi.org/10.2147/DDDT.S185257DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6312693PMC
May 2019

Therapeutic switching of sulpiride, an anti-psychotic and prokinetic drug, to an anti-colitic drug using colon-specific drug delivery.

Drug Deliv Transl Res 2019 02;9(1):334-343

College of Pharmacy, Pusan National University, Pusan, 609-735, Republic of Korea.

To test whether sulpiride (SP), an anti-psychotic and prokinetic drug, shows beneficial effects on experimental murine colitis, a colon-targeted prodrug of SP, 5-(aminoethanoylsulfamoyl)-N-[(1-ethylpyrrolidin-2-yl)methyl]-2-methoxybenzamide (glycylsulpiride (GSP)), was synthesized and its colonic delivery and therapeutic activity against 2,4-dinitrobenzenesulfonic acid (DNBS)-induced rat colitis were assessed. Synthesis of GSP was verified by infrared and proton nuclear magnetic resonance spectroscopy. GSP was converted to SP when incubated with the cecal contents but not when incubated with the small intestinal contents. The percent conversion was about 50.5% at 6 h and 67.7% at 10 h. Colonic delivery of GSP was examined by comparison with sulfasalazine (SSZ), a colon-specific prodrug of 5-aminosalicylic acid currently used for the treatment of inflammatory bowel disease. The two prodrugs accumulated similar concentrations of the corresponding parent drugs in the cecum at 2, 4, and 6 h after oral gavage. Although oral gavage of GSP released millimolar level of SP in the large intestine, SP was hardly detected in the blood. GSP improved colonic damage score and reduced myeloperoxidase activity up to 80.5% in the inflamed colon in a dose-dependent manner. Moreover, GSP was able to reduce the levels of inflammatory mediators in the inflamed colon. Overall, the anti-colitic effectiveness of GSP and SSZ was similar. In conclusion, colonic delivery of SP ameliorates DNBS-induced colitis in rats with no significant systemic absorption of SP. Thus, colon-targeted SP may be therapeutically switched to an anti-colitic drug.
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http://dx.doi.org/10.1007/s13346-018-00599-7DOI Listing
February 2019

S-Nitrosoglutathione loaded poly(lactic-co-glycolic acid) microparticles for prolonged nitric oxide release and enhanced healing of methicillin-resistant Staphylococcus aureus-infected wounds.

Eur J Pharm Biopharm 2018 Nov 14;132:94-102. Epub 2018 Sep 14.

College of Pharmacy, Pusan National University, Busan, South Korea. Electronic address:

Methicillin-resistant Staphylococcus aureus (MRSA)-infected wounds have become a significant clinical issue worldwide. Recently, nitric oxide (NO) has emerged as a potent antibacterial agent against MRSA infections and a wound-healing enhancer. Nevertheless, clinical applications of NO have been largely restricted by its gaseous state and short half-life. In this study, our aim was to develop S-nitrosoglutathione (GSNO, an endogenous NO donor)-loaded poly(lactic-co-glycolic acid) [PLGA] microparticles (GSNO-MPs) that release NO over a prolonged period, to accelerate the healing of MRSA-infected wounds with less frequent dosing. GSNO was successfully encapsulated into PLGA microparticles by a solid-in-oil-in-water emulsion solvent evaporation method. Scanning electron microscopy and X-ray diffraction analyses confirmed the successful fabrication of GSNO-MPs. The latter released NO in a prolonged manner over 7 days and exerted a remarkable antibacterial activity against MRSA in a concentration- and time-dependent manner. Moreover, GSNO-MPs had good antibacterial efficacy and were found to accelerate wound healing in a mouse model of MRSA-infected wounds. Therefore, NO-releasing MPs devised in this study may be a promising option for the treatment of cutaneous wounds infected by drug-resistant bacteria such as MRSA.
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http://dx.doi.org/10.1016/j.ejpb.2018.09.009DOI Listing
November 2018
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