Publications by authors named "Sae Kwang Ku"

351 Publications

REDD1 attenuates hepatic stellate cell activation and liver fibrosis via inhibiting of TGF-β/Smad signaling pathway.

Free Radic Biol Med 2021 Oct 3;176:246-256. Epub 2021 Oct 3.

College of Pharmacy, Chosun University, Gwangju, 61452, Republic of Korea. Electronic address:

Liver fibrosis is caused by repetitive hepatic injury. Regulated in development and DNA damage response 1 (REDD1) gene is induced by various stresses and has been studied in cell proliferation and survival. However, the role of REDD1 in hepatic stellate cell activation and hepatic fibrogenesis has not yet been investigated. In the current study, we examined the effect of REDD1 on hepatic fibrogenesis and the underlying molecular mechanism. REDD1 protein was upregulated in the activated primary hepatic stellate cells and transforming growth factor-β (TGF-β)-treated LX-2 cells. REDD1 mRNA levels were also elevated by TGF-β treatment. TGF-β signaling is primarily transduced via the activation of the Smad transcription factor. However, TGF-β-mediated REDD1 induction was not Smad-dependent. Thus, we investigated the transcription factors that influence the REDD1 expression by TGF-β. We found that c-JUN, a component of AP-1, upregulated the REDD1 expression that was specifically suppressed by p38 inhibitor. In silico analysis of the REDD1 promoter region showed putative AP-1-binding sites; additionally, its deletion mutants demonstrated that the AP-1-binding site between -716 and -587 bp within the REDD1 promoter is critical for TGF-β-mediated REDD1 induction. Moreover, REDD1 overexpression markedly inhibited TGF-β-induced plasminogen activator inhibitor-1 (PAI-1) expression and Smad phosphorylation. REDD1 adenovirus infection inhibited CCl-induced hepatic injury in mice, which was demonstrated by reduced ALT/AST levels and collagen accumulation. In addition, we observed that REDD1 inhibited CCl-induced fibrogenic gene induction and restored GSH and malondialdehyde levels. Our findings implied that REDD1 has the potential to inhibit HSC activation and protect against liver fibrosis.
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http://dx.doi.org/10.1016/j.freeradbiomed.2021.10.002DOI Listing
October 2021

Preparation and evaluation of dabrafenib-loaded, CD47-conjugated human serum albumin-based nanoconstructs for chemoimmunomodulation.

Colloids Surf B Biointerfaces 2021 Sep 1;208:112093. Epub 2021 Sep 1.

College of Pharmacy, Yeungnam University, Daehak-ro 280, Gyeongsan 38541, Republic of Korea. Electronic address:

The transmembrane proteins, CD47 and signal-regulatory protein α are overexpressed in cancer cells and macrophages, respectively, and facilitate the escape of cancer cells from macrophage-mediated phagocytosis. The immunomodulatory and targeting properties of CD47, the chemotherapeutic effects of dabrafenib (D), and the anti-programmed death-1 antibodies (PD-1) pave the way for effective chemoimmunomodulation-mediated anticancer combination therapy. In this study, CD47-conjugated, D-loaded human serum albumin (HSA) nanosystems were fabricated by modified nanoparticle albumin-bound technology. Cis-aconityl-PEG-maleimide (CA), an acid-labile linker, was used to conjugate [email protected] and CD47; the resultant [email protected]@HSA exhibited tumor-specificity through receptor targeting, as well as preferential cleavage and drug release in the acidic tumor microenvironment (pH 5) compared to normal physiological pH conditions (pH 6.5, 7.4). The successful preparation of nanosized (∼220 nm), narrowly dispersed (∼0.13) [email protected]@HSA was proven by physicochemical characterization. In vitro and in vivo internalization, accumulation, cytotoxicity, and apoptosis were observed to be higher with CD47-conjugated nanoconstructs, than with free D or non-targeted nanoconstructs. [email protected]@HSA was found to promote the infiltration of cytotoxic T cells and tumor-associated macrophages into tumors and improve in vivo tumor inhibition. Administration in combination with PD-1 further improved antitumor efficacy by promoting immune responses that blocked the immune checkpoint. No signs of toxicity were seen in mice treated with the nanoconstructs; the formulation was, therefore, thought to be biocompatible and as having potential for clinical use. The targeted chemoimmunomodulation achieved by this combination therapy was found to combat major immunosuppressive facets, making it a viable candidate for use in the treatment of cancer.
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http://dx.doi.org/10.1016/j.colsurfb.2021.112093DOI Listing
September 2021

Nanovaccines silencing IL-10 production at priming phase for boosting immune responses to melanoma.

J Control Release 2021 Oct 19;338:211-223. Epub 2021 Aug 19.

College of Pharmacy, Yeungnam University, Gyeongsan 38541, Republic of Korea. Electronic address:

Despite the significant efforts in developing cancer vaccines, there are still numerous challenges that need to be addressed to ensure their clinical efficacy. Herein, a lymphatic dendritic cell (DC)-targeted artificial nanovaccine mimicking tumor cell membrane (ATM-NV) is developed to boost effector immune response and control immunosuppression simultaneously. The NVs are formulated with lipids, tumor cell membrane proteins, imiquimod (IMQ), and IL-10 siRNA. IL-10 siRNA is incorporated to inhibit the secretion of IL-10, an immunosuppressive cytokine, of maturated DCs upon IMQ. To enhance the DC targeting ability, the nanovaccine surface was non-covalently conjugated with the anti-CD205 antibody. The IMQ and IL-10 siRNA co-loaded, CD205 receptor-targeted artificial tumor membrane NVs (IMQ/[email protected]) efficiently migrate to the tumor-draining lymph node and target DCs. Furthermore, immunization with IMQ/[email protected] reduces the production of IL-10 and increases T1-driven antitumor immunity resulted in a great tumor inhibition efficacy. Our results suggest a potential strategy to promote the vaccination's antitumor efficacy by blocking the intrinsic negative regulators in DCs.
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http://dx.doi.org/10.1016/j.jconrel.2021.08.031DOI Listing
October 2021

Combination chemotherapeutic and immune-therapeutic anticancer approach via anti-PD-L1 antibody conjugated albumin nanoparticles.

Int J Pharm 2021 Aug 20;605:120816. Epub 2021 Jun 20.

College of Pharmacy, Yeungnam University, Daehak-ro 280, Gyeongsan 38541, Republic of Korea. Electronic address:

Anticancer regimens have been substantially enriched through monoclonal antibodies targeting immune checkpoints, programmed cell death-1/programmed cell death-ligand 1 (PD-L1) and cytotoxic T-lymphocyte antigen-4. Inconsistent clinical efficacy after solo immunotherapy may be compensated by nanotechnology-driven combination therapy. We loaded human serum albumin (HSA) nanoparticles with paclitaxel (PTX) via nanoparticle albumin-bound technology and pooled them with anti-PD-L1 monoclonal antibody through a pH-sensitive linker for targeting and immune response activation. Our tests demonstrated satisfactory preparation of paclitaxel-loaded, PD-L1-targeted albumin nanoparticles (PD-L1/[email protected]). They had small particle size (~200 nm) and polydispersity index (~0.12) and successfully incorporated each constituent. Relative to normal physiological pH, the formulation exhibited higher drug-release profiles favoring cancer cell-targeted release at low pH. Modifying nanoparticles with programmed cell death-ligand 1 increased cancer cell internalization in vitro and tumor accumulation in vivo in comparison with non-PD-L1-modified nanoparticles. PD-L1/[email protected] constructed by nanoparticle albumin-bound technology displayed successful tumor inhibition efficacy both in vitro and in vivo. There was successful effector T-cell infiltration, immunosuppressive programmed cell death-ligand 1, and regulatory T-cell suppression because of cytotoxic T-lymphocyte antigen-4 synergy. Moreover, PD-L1/[email protected] had low organ toxicity. Hence, the anti-tumor immune responses of PD-L1/[email protected] combined with chemotherapy and cytotoxic T-lymphocyte antigen-4 is a potential anti-tumor strategy for improving quantitative and qualitative clinical efficacy.
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http://dx.doi.org/10.1016/j.ijpharm.2021.120816DOI Listing
August 2021

Tart Cherry (Fruit of ) Concentrated Powder (TCcp) Ameliorates Glucocorticoid-Induced Muscular Atrophy in Mice.

Medicina (Kaunas) 2021 May 12;57(5). Epub 2021 May 12.

Department of Food Biotechnology, College of Medical and Life Sciences, Silla University, 140, Baegyang-daero 700beon-gil, Sasang-gu, Busan 46958, Korea.

: The present study investigated the beneficial effects of tart cherry (fruit of ) concentrated powder (TCcp) on glucocorticoid (GLU)-induced catabolic muscular atrophy in the skeletal muscle of mice. Furthermore, its potential mechanism was also studied. : Changes in calf thickness, calf muscle weight, calf muscle strength, body weight, gastrocnemius muscle histology, immunohistochemistry, serum creatinine, creatine kinase, lactate dehydrogenase, and antioxidant defense systems were measured. Malondialdehyde, reactive oxygen species, glutathione content, catalase, and superoxide dismutase activities in the gastrocnemius muscle, and muscle-specific mRNA expressions were evaluated. : After 24 days, GLU control mice showed muscular atrophy at all criteria of indexes. The muscular atrophy symptoms were significantly inhibited by oral treatment with 250 mg/kg and 500 mg/kg of TCcp through antioxidative and anti-inflammatory modulated expression of genes involved in muscle protein degradation (myostatin, atrogin-1, SIRT1, and MuRF1) and synthesis (A1R, Akt1, TRPV4, and PI3K). : This study shows that the TCcp (500 mg/kg and 250 mg/kg) could improve muscular atrophies caused by various etiologies.
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http://dx.doi.org/10.3390/medicina57050485DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8151970PMC
May 2021

Curcumin Attenuates Sarcopenia in Chronic Forced Exercise Executed Aged Mice by Regulating Muscle Degradation and Protein Synthesis with Antioxidant and Anti-inflammatory Effects.

J Agric Food Chem 2021 Jun 5;69(22):6214-6228. Epub 2021 May 5.

Department of Food Science and Biotechnology, Sejong University, 209, Neungdong-ro, Gwangjin-gu, Seoul 05006, Republic of Korea.

The aim of the current study is to investigate the effects of spray dry powders of containing 40% curcumin (CM-SD), as a new aqueous curcumin formula, on sarcopenia in chronic forced exercise executed 10 month old ICR mice. CM-SD (80 and 40 mg/kg) increased calf thicknesses and strengths, total body and calf protein amounts, and muscle weights in both gastrocnemius and soleus muscles. mRNA expressions regarding muscle growth and protein synthesis were induced, while those of muscle degradation significantly declined in CM-SD treatment. CM-SD decreased serum biochemical markers, lipid peroxidation, and reactive oxygen species and increased endogenous antioxidants and enzyme activities. It also reduced immunoreactive myofibers for apoptosis and oxidative stress markers but increased ATPase in myofibers. These results suggest that CM-SD can be an adjunct therapy to exercise-based remedy that prevents muscle disorders including sarcopenia by anti-apoptosis, anti-inflammation, and antioxidation-mediated modulation of gene expressions related to muscle degradation and protein synthesis.
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http://dx.doi.org/10.1021/acs.jafc.1c00699DOI Listing
June 2021

Hemistepsin a Induces Apoptosis of Hepatocellular Carcinoma Cells by Downregulating STAT3.

Int J Mol Sci 2021 Apr 29;22(9). Epub 2021 Apr 29.

College of Korean Medicine, Daegu Haany University, Gyeongsan 38610, Korea.

(Bunge) Bunge is a biennial medicinal plant possessing beneficial effects including anti-inflammation, and hemistepsin A (HsA) isolated from has been known as a hepatoprotective sesquiterpene lactone. In this report, we explored the cytotoxic effects of on hepatocellular carcinoma (HCC) cells and investigated the associated bioactive compounds and their relevant mechanisms. From the viability results of HCC cells treated with various extracts, HsA was identified as the major compound contributing to the -mediated cytotoxicity. HsA increased expression of cleaved PARP and cells with Sub-G1 phase, Annexin V binding, and TUNEL staining, which imply HsA induces apoptosis. In addition, HsA provoked oxidative stress by decreasing the reduced glutathione/oxidized glutathione ratio and accumulating reactive oxygen species and glutathione-protein adducts. Moreover, HsA inhibited the transactivation of signal transducer and activator of transcription 3 (STAT3) by its dephosphorylation at Y705 and glutathione conjugation. Stable expression of a constitutive active mutant of STAT3 prevented the reduction of cell viability by HsA. Finally, HsA enhanced the sensitivity of sorafenib-mediated cytotoxicity by exaggerating oxidative stress and Y705 dephosphorylation of STAT3. Therefore, HsA will be a promising candidate to induce apoptosis of HCC cells via downregulating STAT3 and sensitizing conventional chemotherapeutic agents.
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http://dx.doi.org/10.3390/ijms22094743DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8125382PMC
April 2021

Curcumin Ameliorated Oxidative Stress and Inflammation-Related Muscle Disorders in C2C12 Myoblast Cells.

Antioxidants (Basel) 2021 Mar 17;10(3). Epub 2021 Mar 17.

Department of Food Science and Biotechnology, Sejong University, 209, Neungdong-ro, Gwangjin-gu, Seoul 05006, Korea.

The purpose of the current study was to investigate antioxidant and anti-inflammatory effects of spray dry powder containing 40% curcumin (CM-SD) in C2C12 myoblast cells. CM-SD increased DPPH radical scavenging activity in a dose-dependent manner, and up to 30 μg/mL of CM-SD did not express cytotoxicity in C2C12 cells. Exposure to hydrogen peroxide (HO) drastically decreased the viability of C2C12 cells, but pre-treatment of CM-SD significantly increased the cell viability ( < 0.01). CM-SD significantly transactivated the nuclear factor erythroid-2-related factor 2 (Nrf2)-dependent luciferase activity in a dose-dependent manner and enhanced the levels of heme oxygenase (HO)-1, glutamate cysteine ligase catalytic subunit (GCLC), and NAD(P)H-dependent quinone oxidoreductase (NQO)-1. CM-SD also significantly reduced reactive oxygen species (ROS) production and lipid peroxidation and restored glutathione (GSH) depletion in HO-treated C2C12 cells. Moreover, CM-SD significantly reduced lipopolysaccharides (LPS)-mediated interleukin (IL)-6 production in the conditioned medium. Results from the current study suggest that CM-SD could be a useful candidate against oxidative stress and inflammation-related muscle disorders.
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http://dx.doi.org/10.3390/antiox10030476DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8002759PMC
March 2021

Anti-inflammatory, expectorant, and antitussive properties of in ICR mice.

Pharm Biol 2021 Dec;59(1):321-334

Department of in Food Biotechnology, College of Medical and Life Sciences, Silla University, Busan, Republic of Korea.

Context: (KOG) is a traditional mixed herb preparation consisting of CA Meyer (Araliaceae), Wolf (Polyporaceae), (Gaertner) Liboschitz ex Steudel (Orobanchaceae), and honey. Various pharmacological effects of KOG are reported, but the efficacy on respiratory diseases has not been evaluated.

Objective: The anti-inflammatory, expectorant, and antitussive properties of KOG were examined using animal models of respiratory diseases.

Materials And Methods: KOG (100, 200, and 400 mg/kg) was orally administered to ICR mice ( = 8) once a day for 11 days. Anti-inflammatory effects of vehicle, xylene, KOG and DEXA (1 mg/kg) were determined by monitoring edoema and redness of treated ears, and measuring the relative and absolute weight of each ear. Expectorant properties of vehicle, KOG and AM (250 mg/kg) were evaluated by observing body surface redness, and the amount of mucous secreted by the trachea. The antitussive potential of vehicle, NHOH, KOG and TB (50 mg/kg) was evaluated by monitoring changes in the number of coughs (for 6 min).

Results: KOG (400 mg/kg) treated mice showed 31.29% and 30.72% ( < 0.01) decreases in the relative and absolute weights of each ear relative to xylene control mice, 39.06% increases ( < 0.01) in TLF OD values relative to intact vehicle control mice, and 59.53% decrease ( < 0.01) in coughing compared to NHOH control mice. Dose-dependent changes were observed in all experimental models.

Conclusions: KOG may be a potential therapeutic agent for the treatment of various respiratory diseases, particularly those caused by environmental toxins.
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http://dx.doi.org/10.1080/13880209.2021.1892155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8008926PMC
December 2021

Neoagarooligosaccharide Protects against Hepatic Fibrosis via Inhibition of TGF-β/Smad Signaling Pathway.

Int J Mol Sci 2021 Feb 18;22(4). Epub 2021 Feb 18.

College of Pharmacy, Chosun University, Seoseok-dong, Gwangju 61452, Korea.

Hepatic fibrosis occurs when liver tissue becomes scarred from repetitive liver injury and inflammatory responses; it can progress to cirrhosis and eventually to hepatocellular carcinoma. Previously, we reported that neoagarooligosaccharides (NAOs), produced by the hydrolysis of agar by β-agarases, have hepatoprotective effects against acetaminophen overdose-induced acute liver injury. However, the effect of NAOs on chronic liver injury, including hepatic fibrosis, has not yet been elucidated. Therefore, we examined whether NAOs protect against fibrogenesis in vitro and in vivo. NAOs ameliorated PAI-1, α-SMA, CTGF and fibronectin protein expression and decreased mRNA levels of fibrogenic genes in TGF-β-treated LX-2 cells. Furthermore, downstream of TGF-β, the Smad signaling pathway was inhibited by NAOs in LX-2 cells. Treatment with NAOs diminished the severity of hepatic injury, as evidenced by reduction in serum alanine aminotransferase and aspartate aminotransferase levels, in carbon tetrachloride (CCl)-induced liver fibrosis mouse models. Moreover, NAOs markedly blocked histopathological changes and collagen accumulation, as shown by H&E and Sirius red staining, respectively. Finally, NAOs antagonized the CCl-induced upregulation of the protein and mRNA levels of fibrogenic genes in the liver. In conclusion, our findings suggest that NAOs may be a promising candidate for the prevention and treatment of chronic liver injury via inhibition of the TGF-β/Smad signaling pathway.
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http://dx.doi.org/10.3390/ijms22042041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7922480PMC
February 2021

Pre- and Post-Transcriptional Regulation of cFLIP for Effective Cancer Therapy Using pH-Ultrasensitive Nanoparticles.

ACS Appl Mater Interfaces 2021 Feb 28;13(5):5999-6010. Epub 2021 Jan 28.

College of Pharmacy, Yeungnam University, Gyeongsan 38541, Republic of Korea.

Cellular FLIP (cFLIP) is a crucial player of apoptosis-regulated pathways that is frequently overexpressed in solid cancers. To inhibit c-FLIP, pre- and post-transcriptionally, a multifunctional nanoparticle (NP) was created to deliver cFLIP-specific small interfering RNA (siRNA) into cancer cells. Specifically, Vorinostat (Vor)-loaded mesoporous silica nanoparticles (MSN) were conjugated with polyethylenimine-biotin (PB), followed by electrostatically binding with cFLIP siRNA (Vor/[email protected]). To stabilize and prolong the circulation time of nanoparticles, a bialdehyde-modified poly(ethylene glycol) (PEG) was cross-linked onto the polyethylenimine (PEI) backbone via the formation of the imine linkage (Schiff base) (Vor/[email protected]). The Schiff base is highly stable at physiological pH 7.4 but labile under slightly acidic pH conditions. In the acidic tumor microenvironment (TME), the PEG outer layer could be rapidly cleaved, resulting in the switching of the nanoparticle surface charge to positive, which specifically enhances internalization of the NPs to the biotin-positive tumor cells. Our results demonstrated the successful preparation of Vor/[email protected] NPs, in which the siRNA was effectively protected in serum and regulated the expression of cFlip, post-transcriptionally. The presence of the PEG layer resulted in high tumor accumulation and high efficacy in tumor inhibition, which was a result of the efficient cFLIP suppression. Furthermore, in the low-dose regimen of Vorinostat-the pre-transcriptional cFLIP suppressor, treatment with Vor/[email protected] NPs was found to be safe with the treated mice, indicating a promising combination regimen for cancer therapy.
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http://dx.doi.org/10.1021/acsami.0c20624DOI Listing
February 2021

Redox/photo dual-responsive, self-targeted, and photosensitizer-laden bismuth sulfide nanourchins for combination therapy in cancer.

Nanoscale 2021 Jan;13(2):1231-1247

College of Pharmacy, Yeungnam University, Gyeongsan 38541, Republic of Korea.

Targeted and stimuli-sensitive nanobombs for the release of therapeutic agents after laser irradiation of the tumor site are gaining widespread attention as personalized anticancer regimens. In this study, redox and photo dual-responsive, folate receptor-targeted nanourchin carriers for chemo-, photodynamic, and photothermal therapy were constructed by the amalgamation of an outer layer of polyethylene glycol (PEG)-S-S-methotrexate (MTX) and an inner core of indocyanine green (ICG)-loaded bismuth sulfide (Bi2S3) nanoparticles for cancer treatment. MTX introduces the carrier to folate receptors resulting in the internalization of nanoparticles into cancer cells, specifically and increasingly. In the reducing environment inside cancer cells, MTX was cleaved, resulting in a burst release that effectively inhibited tumor growth. Simultaneously, the fusion of Bi2S3 and ICG in the inner core absorbed energy from a near-infrared radiation (NIR) laser to generate heat and reactive oxygen species, which further ablated the tumors and synergistically enhanced the anticancer activity of MTX. These results indicate the successful preparation of combined nanourchins (NUs) showing GSH-induced and laser-responsive release of MTX and ICG, accompanied by hyperthermia via Bi2S3 and ICG. Effective in vitro cellular internalization, cellular cytotoxicity, and pro-apoptotic behavior of the nanosystem were achieved through a targeting, redox, and NIR-responsive combination strategy. In vivo biodistribution and photothermal imaging also revealed tumor-selective and -retentive, as well as thermally responsive attributes. Ultimately, this in vivo antitumor study shows an effective tumor ablation by these nanourchins without affecting the vital organs. Our findings indicate that using these targeted redox- and laser-responsive combination therapeutic carriers can be a promising strategy in folate receptor-expressing tumors.
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http://dx.doi.org/10.1039/d0nr07736dDOI Listing
January 2021

Localized therapy using anti-PD-L1 anchored and NIR-responsive hollow gold nanoshell (HGNS) loaded with doxorubicin (DOX) for the treatment of locally advanced melanoma.

Nanomedicine 2021 04 9;33:102349. Epub 2021 Jan 9.

College of Pharmacy, Keimyung University, Daegu, South Korea. Electronic address:

Drug resistance and inefficient localization of chemotherapeutic agent limit the current treatment strategy in locally advanced melanoma (MEL), accounting to the 10-year survival rate from 24% to 68%. In this study we constructed anti-PD-L1 conjugated and doxorubicin loaded hollow gold nanoshell (T-HGNS-DOX) for targeted and localized chemo-photothermal therapy of MEL by the conjugation of LA-PEG-anti-PD-L1 antibody and short PEG chain on the surface of HGNS-DOX. Near infrared (NIR) as well as pH dependent drug release profile was observed. Significant uptake of DOX following NIR due to high PD-L1 receptors resulted in pronounced anticancer effect of T-HGNS-DOX. Following intratumoral administration, maximum nanoparticles retention with the significant reduction in tumor growth was observed as a result of elevated apoptosis marker (cleaved caspase-3, cleaved PARP) as well as downregulation of proliferative (Ki-67) and angiogenesis marker (CD31). Cumulatively, our system avoids the systemic toxicities of the nanosystem thereby providing maximum chemotherapeutic retention in tumor.
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http://dx.doi.org/10.1016/j.nano.2020.102349DOI Listing
April 2021

Negative correlation of urinary miR-199a-3p level with ameliorating effects of sarpogrelate and cilostazol in hypertensive diabetic nephropathy.

Biochem Pharmacol 2021 02 23;184:114391. Epub 2020 Dec 23.

Department of Pharmacy and BK21FOUR Advanced Program for SmartPharma Leaders, Graduate School of The Catholic University of Korea, Gyeonggi-do 14662, Republic of Korea; Integrated Research Institute for Pharmaceutical Sciences, The Catholic University of Korea, Gyeonggi-do 14662, Republic of Korea; College of Pharmacy, The Catholic University of Korea, Gyeonggi-do 14662, Republic of Korea. Electronic address:

The prevalence of chronic kidney disease is increasing globally; however, effective therapeutic options are limited. In this study, we aimed to identify urinary miRNAs reflecting the effect of therapeutic intervention in rats with comorbid hypertension and diabetes. Additionally, the potential beneficial effects of anti-platelet sarpogrelate and cilostazol were investigated. Nephropathy progression in streptozotocin (STZ)-treated spontaneously hypertensive rats (SHRs), including albuminuria, collagen deposition, and histopathological changes, was alleviated by sarpogrelate and antihypertensive agent telmisartan. Global analysis of urinary miRNAs identified that miR-199a-3p was commonly reduced by sarpogrelate and telmisartan treatment. In vitro analysis suggested CD151 as a target gene of miR-199a-3p: miR-199a-3p overexpression repressed CD151 levels and miR-199a-3p interacted with the 3'-untranslated region of the CD151 gene. In addition, we demonstrated that the miR-199a-3p/CD151 axis is associated with the transforming growth factor-β1 (TGF-β1)-induced fibrogenic pathway. TGF-β1 treatment led to miR-199a-3p elevation and CD151 suppression, and miR-199a-3p overexpression or CD151-silencing enhanced TGF-β1-inducible collagen IV and α-smooth muscle actin (α-SMA) levels. In vivo analysis showed that the decrease in CD151 and the increase in collagen IV and α-SMA in the kidney from STZ-treated SHR were restored by sarpogrelate and telmisartan administration. In an additional animal experiment using cilostazol and telmisartan, there was a correlation between urinary miR-199a-3p reduction and the ameliorating effects of cilostazol or combination with telmisartan. Collectively, these results indicate that urinary miR-199a-3p might be utilized as a marker for nephropathy treatment. We also provide evidence of the benefits of antiplatelet sarpogrelate and cilostazol in nephropathy progression.
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http://dx.doi.org/10.1016/j.bcp.2020.114391DOI Listing
February 2021

Macrophage-Membrane-Camouflaged Disintegrable and Excretable Nanoconstruct for Deep Tumor Penetration.

ACS Appl Mater Interfaces 2020 Dec 8;12(51):56767-56781. Epub 2020 Dec 8.

College of Pharmacy, Yeungnam University, Gyeongsan 38541, Republic of Korea.

The consolidation of nanovectors with biological membranes has recently been a subject of interest owing to the prolonged systemic circulation time and delayed clearance by the reticuloendothelial system of such systems. Among the different biomembranes, the macrophage membrane has a similar systemic circulation time, with an additional chemotactic aptitude, targeting integrin proteins. In this study, we aimed to establish a laser-activated, disintegrable, and deeply tumor-penetrative nanoplatform. We used a highly tumor-ablative and laser-responsive disintegrable copper sulfide nanoparticle, loaded it with paclitaxel, and camouflaged it with the macrophage membrane for the fabrication of [email protected]@MMNPs. The paclitaxel release profile was favorable for release in the tumor microenvironment, and the release was accelerated after laser exposure. Cellular internalization was improved by membrane encapsulation. Cellular uptake, cytotoxicity, reactive oxygen species generation, and apoptosis induction of [email protected]@MMNPs were further improved upon laser exposure, and boosted permeation was achieved by co-administration of the tumor-penetrating peptide iRGD. tumor accumulation, tumor inhibition rate, and apoptotic marker expression induced by [email protected]@MMNPs were significantly improved by laser irradiation and iRGD co-administration. [email protected]@MMNPs induced downregulation of cellular proliferation and angiogenic markers but no significant changes in body weight, survival, or significant toxicities in vital organs after laser exposure, suggesting their biocompatibility. The disintegrability of the nanosystem, accredited to biodegradability, favored efficient elimination from the body. In conclusion, [email protected]@MMNPs showed promising traits in combination therapies for excellent tumor eradication.
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http://dx.doi.org/10.1021/acsami.0c17235DOI Listing
December 2020

Protective Effects of Traditional Polyherbs on Cisplatin-Induced Acute Kidney Injury Cell Model by Inhibiting Oxidative Stress and MAPK Signaling Pathway.

Molecules 2020 Nov 30;25(23). Epub 2020 Nov 30.

Department of Anatomy and Histology, College of Korean Medicine, Daegu Haany University, Gyeongsan 38610, Korea.

Acute kidney injury (AKI) is a disease caused by sudden renal dysfunction, which is an important risk factor for chronic renal failure. However, there is no effective treatment for renal impairment. Although some traditional polyherbs are commercially available for renal diseases, their effectiveness has not been reported. Therefore, we examined the nephroprotective effects of polyherbs and their relevant mechanisms in a cisplatin-induced cell injury model. Rat NRK-52E and human HK-2 subjected to cisplatin-induced AKI were treated with four polyherbs, Injinhotang (IJ), Ucha-Shinki-Hwan (US), Yukmijihwang-tang (YJ), and Urofen (Uro) similar with Yondansagan-tang, for three days. All polyherbs showed strong free radical scavenging activities, and the treatments prevented cisplatin-induced cell death in both models, especially at 1.2 mg/mL. The protective effects involved antioxidant effects by reducing reactive oxygen species and increasing the activities of superoxide dismutase and catalase. The polyherbs also reduced the number of annexin V-positive apoptotic cells and the expression of cleaved caspase-3, along with inhibited expression of mitogen-activated protein kinase-related proteins. These findings provide evidence for promoting the development of herbal formulas as an alternative therapy for treating AKI.
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http://dx.doi.org/10.3390/molecules25235641DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7730198PMC
November 2020

Manipulating immune system using nanoparticles for an effective cancer treatment: Combination of targeted therapy and checkpoint blockage miRNA.

J Control Release 2021 01 21;329:524-537. Epub 2020 Sep 21.

College of Pharmacy, Yeungnam University, Gyeongsan 38541, Republic of Korea. Electronic address:

Accumulating clinical data shows that less than half of patients are beneficial from PD-1/PD-L1 blockage therapy owing to the limited infiltration of effector immune cells into the tumor and abundant of the immunosuppressive factors in the tumor microenvironment. In this study, PD-L1 inhibition therapy and BRAF-targeted therapy, which showed clinical benefit, were combined in a CXCR4-targeted nanoparticle co-delivering dabrafenib (Dab), a BRAF inhibitor, and miR-200c which can down-regulate PD-L1 expression. The cationic PCL-PEI core containing Dab- and miR-200c- were coated with poly-L-glutamic acid conjugated with LY2510924, a CXCR-4 antagonist peptide, (PGA-pep) to obtain [email protected]/[email protected] nanoformulation. The stimulus pH- and redox- reactive of PGA-pep was ascribed to exhibit an enhanced release of drug in the tumor microenvironment as well as improve the stability of miR-200c during the blood circulation. In addition, the presence of LY2510924 peptide would enhance the binding affinity of [email protected]/[email protected] NPs to cancer cells, leading to improved cellular uptake, cytotoxicity, and in vivo accumulation into tumor area. The in vivo results indicated that both, the immunogenic cell death (ICD) and the inhibition of PD-L1 expression, induced by treatment with CXCR-4 targeted nanoparticles, enables to improve the DC maturation in lymph node and CD8 T cell activation in the spleen. More importantly, effector T cells were increasingly infiltrated into the tumor, whereas the immunosuppressive factors like PD-L1 expression and regulatory T cells were significantly reduced. They, all together, promote the immune responses against the tumor, indicating the therapeutic efficiency of the current strategy in cancer treatment.
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http://dx.doi.org/10.1016/j.jconrel.2020.09.034DOI Listing
January 2021

Anti-Diabetic Obesity Effects of Matsum Leaf Extract on 45% Kcal High-Fat Diet-Fed Mice.

Nutrients 2020 Sep 16;12(9). Epub 2020 Sep 16.

Department of Histology and Anatomy, College of Korean Medicine, Daegu Haany University, 1, Haanydaero, Gyeongsan, Gyeongsangbuk-Do 38610, Korea.

The present study examined the effects of Wasabi leaf (WL) on 45% Kcal high-fat diet (HFD)-fed mild diabetic obese mice. In particular, the hepatoprotective (i.e., liver weight, histopathology of liver, serum aspartate aminotransferase, alanine aminotransferase, and gamma-glutamyltransferase) effects of 12 weeks of continuous oral administration of 250 mg/kg metformin, and 200, 100, or 50 mg/kg WL were investigated. In addition, the hypolipidemic (i.e., serum triglyceride, total cholesterol, high-density lipoprotein-cholesterol, and low-density lipoprotein levels), hypoglycemic (i.e., glycated hemoglobin, blood glucose and insulin levels, pancreatic weight, and immunohistochemical-histopathological analysis of the pancreas), and anti-obesity effects (i.e., body weight, mean food consumption, total and abdominal body fat mass, periovarian fat weight, and histopathology of the periovarian and abdominal wall adipocytes) were monitored. The liver and general antioxidant defense systems were also assessed by lipid metabolism-related gene expression. All diabetes manifestations and related complications, including obesity and non-alcoholic fatty liver disease (NAFLD), were dose-dependently reduced after 84 days of oral treatment with metformin or each of the three dosages of WL. In particular, 50 mg/kg WL showed effective suppression effects against HFD-induced diabetes and related complications of obesity, NAFLD, and hyperlipidemia, comparable to the effects of metformin.
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http://dx.doi.org/10.3390/nu12092837DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7551095PMC
September 2020

Hyaluronic acid wreathed, trio-stimuli receptive and on-demand triggerable nanoconstruct for anchored combinatorial cancer therapy.

Carbohydr Polym 2020 Dec 1;249:116815. Epub 2020 Aug 1.

College of Pharmacy, Yeungnam University, 214-1, Dae-Dong, Gyeongsan 712-749, South Korea. Electronic address:

Hyaluronic acid (HA) assisted effective internalization into CD44 receptor-overexpressing cancer cells, which could offer an excellent cytotoxic profile and tumor alterations. In this study, duo-photothermal agents (copper sulfide (CuS) and graphene oxide (GO)), chemotherapeutic drug (doxorubicin (DOX)), and targeting moiety (HA) were incorporated into a complexed nanoconstruct for trio-responsive chemo-phototherapy. The nanosystem (CuS(DOX)-GO-HA) was demonstrating its responsive drug release and escalated photothermal behavior. The hyperthermia and photodynamic effect were observed along with efficient ROS generation in the presence of dual photosensitizers. The in vivo biodistribution and photothermal profile reflected a high accumulation and retention of the nanoconstruct in the tumor. Importantly, nanoconstructs effectively inhibit tumor growth based on tumor volume analysis and the altered expression of apoptosis, cell proliferation, and angiogenesis markers. Collectively, these findings suggest that this nanoconstruct has excellent antitumor effects in CD44 overexpressed cells showing the potential for clinical translation in the future.
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http://dx.doi.org/10.1016/j.carbpol.2020.116815DOI Listing
December 2020

Retrofractamide C Derived from Alleviates Xylene-Induced Mouse Ear Edema and Inhibits Phosphorylation of ERK and NF-κB in LPS-Induced J774A.1.

Molecules 2020 Sep 5;25(18). Epub 2020 Sep 5.

Immunoregulatory Material Research Center, Korea Research Institute of Bioscience and Biotechnology, Jeongeup-si, Jeonbuk 56212, Korea.

Many studies have reported the biological activities of retrofractamide C (RAC). However, few studies have investigated the anti-inflammatory effect of RAC. In the present study, we investigated the anti-inflammatory effect of RAC using lipopolysaccharide (LPS)-induced J774A.1 cells and a xylene-induced mouse ear edema model. Treatment with RAC decreased LPS-induced nitric oxide (NO) and prostaglandin E2 (PGE2) secretion and inducible NO synthase (iNOS) and cyclooxygenase 2 (COX2) protein expression. It also downregulated the LPS-induced production of interleukin-1β (IL-1β) and interleukin-6 (IL-6) but not tumor necrosis factor α (TNF-α). In the LPS-induced signaling pathway, RAC inhibited the phosphorylation of extracellular signal-regulated kinase (ERK) and nuclear factor kappa light chain enhancer of activated B cells (NF-κB) but not c-Jun N-terminal kinase (JNK) or p38. In a xylene-induced mouse ear edema model, RAC treatment alleviated edema formation and inflammatory cell infiltration. In conclusion, the present study indicates that RAC has the potential to have anti-inflammatory effects and could be a prospective functional food.
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http://dx.doi.org/10.3390/molecules25184058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7570867PMC
September 2020

Protective Effects of Traditional Herbal Formulas on Cisplatin-Induced Nephrotoxicity in Renal Epithelial Cells via Antioxidant and Antiapoptotic Properties.

Evid Based Complement Alternat Med 2020 17;2020:5807484. Epub 2020 Aug 17.

Department of Anatomy and Histology, College of Korean Medicine, Daegu Haany University, Gyeongsan 38610, Republic of Korea.

Acute kidney injury (AKI) is characterized by a rapid loss of renal function. Drug-induced AKI accounts for up to 60% of all cases, resulting in a severe threat particularly to hospitalized patients, but there are no effective treatments. Four polyherbal formulas, (BJ), (PJ), (OR), and (WR), have long been used for treatments of symptoms of kidney disease in traditional Korean medicine. Even though they are commercially available, evidences supporting the efficacy on AKI are still lacking. Therefore, the effectiveness of polyherbs on AKI and the underlying mechanisms were examined. Renal cell damage was induced by cisplatin at 20 M and 16 M in proximal tubular epithelial cell lines of rat NRK-52E and human HK-2, respectively. The cells were treated with the polyherbal formals for 3 days, and the cell viability, antioxidant activities, and apoptosis were examined. In addition, the proliferative effects were assessed under serum-free conditions. The results were compared with those of the vehicle-treated cells as a control. Three polyherbs BJ, PJ, and WR but not OR showed strong free radical scavenging activities in the 1,1-diphenyl-2-picrylhydrazyl (DPPH) assay. The treatments of BJ, PJ, OR, and WR significantly increased the cell viabilities under cisplatin-induced nephrotoxicity. Consistent with the results of the DPPH assay, superoxide dismutase and catalase activities were increased in the cisplatin-induced cell model treated with BJ, PJ, and WR but not with OR. However, annexin-V-positive cells and cleaved caspase 3 expression were significantly reduced in the cell model treated with all of the polyherbs. Cell proliferation was observed in treatment with all of the polyherbs, which was particularly evident in the OR-treated cells. This provides effective complementary evidences to promote the development of traditional herbal formulas to treat AKI.
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http://dx.doi.org/10.1155/2020/5807484DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7448203PMC
August 2020

Hemistepsin A inhibits T0901317-induced lipogenesis in the liver.

BMB Rep 2021 Feb;54(2):106-111

College of Korean Medicine, Daegu Haany University, Gyeongsan 38610, Korea.

Hemistepsin A (HsA) is a guaianolide sesquiterpene lactone that inhibits hepatitis and liver fibrosis. We evaluated the effects of HsA on liver X receptor (LXR)-mediated hepatic lipogenesis in vitro and in vivo. Up to 10 μM, HsA did not affect the viability of HepG2 and Huh7 cells. Pretreatment with 5-10 μM HsA significantly decreased the luciferase activity of the LXR response element, which was transactivated by T0901317, GW 3965, and LXRα/retinoid X receptor α overexpression. In addition, it significantly inhibited the mRNA expression of LXRα in HepG2 and Huh7 cells. It also suppressed the expression of sterol regulatory element-binding protein-1c and lipogenic genes and reduced the triglyceride accumulation triggered by T0901317. Intraperitoneal injection of HsA (5 and 10 mg/kg) in mice significantly alleviated the T0901317-mediated increases in hepatocyte diameter and the percentage of regions in hepatic parenchyma occupied by lipid droplets. Furthermore, HsA significantly attenuated hepatic triglyceride accumulation by restoring the impaired expression of LXRα-dependent lipogenic genes caused by T0901317. Therefore, based on its inhibition of the LXRα-dependent signaling pathway, HsA has prophylactic potential for steatosis. [BMB Reports 2021; 54(2): 106-111].
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7907741PMC
February 2021

Photothermally Modulatable and Structurally Disintegratable Sub-8-nm AuAg Embedded Nanoblocks for Combination Cancer Therapy Produced by Plug-in Assembly.

ACS Nano 2020 09 25;14(9):11040-11054. Epub 2020 Aug 25.

School of Mechanical Engineering, Yeungnam University, Gyeongsan 38541, Republic of Korea.

As well as the exploration of translatable delivery nanosystems for cancer therapeutic agents, the development of automatable continuous-flow manufacturing technology comprising digitally controlled reactions for the on-demand production of pharmaceuticals is an important challenge in anticancer nanomedicine. Most attempts to resolve these issues have involved the development of alternative reactions, formulations, or constructs containing stimulus components aimed at producing multiple approaches for highly efficacious combination cancer therapies. However, there has been no report of a platform based on plug-in execution that enables continuous-flow manufacture in a compact, reconfigurable manner, although an optimal platform technology may be a prerequisite for the timely translation of recently developed nanomedicines. To this end, we describe the development of a platform toward digitizable, continuous manufacture by a serial combination of plug-in reactionwares (heating plates, a spraying cup, and a photochamber) for single-pass flow fabrication. Specifically, we fabricated three different composite nanoblocks consisting of AuAg (<8 nm; stimulus component), docetaxel (an anticancer drug), and bovine serum albumin (a protective and targeting agent) using our system, with the result of producing nanoblocks with photothermally modulatable and structurally disintegratable properties. These were examined for effectiveness in near-infrared-induced chemothermal cancer therapy and renal excretion of AuAg particles and exhibited high anticancer efficacy and warrantable biosafety.
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http://dx.doi.org/10.1021/acsnano.9b09731DOI Listing
September 2020

Anti-CTLA-4 antibody-functionalized dendritic cell-derived exosomes targeting tumor-draining lymph nodes for effective induction of antitumor T-cell responses.

Acta Biomater 2020 10 13;115:371-382. Epub 2020 Aug 13.

College of Pharmacy, Yeungnam University, Gyeongsan 38541, Republic of Korea. Electronic address:

The therapeutic efficacy of current cancer vaccines is far from optimal, mainly because of insufficient induction of antigen-specific T cells and because tumor cells can hijack immunosuppressive mechanisms to evade the immune responses. Generating specific, robust, and long-term immune responses against cancer cells and the attenuating of immunosuppressive factors are critical for effective cancer vaccination. Recently, the engineering of exosomes specifically bind to T cells, and then stimulating tumor-specific T-cell immune responses has emerged as a potential alternative strategy for cancer vaccination. In this study, we generated a bifunctional exosome combining the strategy of vaccination and checkpoint blockade. Exosomes prepared from Ovalbumin (OVA)-pulsed, activated dendritic cells were modified with anti-CTLA-4 antibody (EXO-OVA-mAb) to block this inhibitory molecule and to enhance the specificity of the exosomes toward T cells. Our study provides a unique strategy for functionalizing exosome membrane with anti-CTLA-4 antibody via lipid-anchoring method to synergize efficacy of cancer vaccination and immune checkpoint blockade against the tumor. STATEMENT OF SIGNIFICANCE: We designed T-cell-targeting exosomes (EXO-OVA-mAb) decorated with costimulatory molecules, MHCs, antigenic OVA peptide, and anti-CTLA-4 antibody, combining the strategies of vaccines and checkpoint blockade. The exosomes showed enhanced binding to T cells in tumor-draining lymph nodes, effectively induced T-cell activation, and improved the tumor homing of effector T cells, ultimately significantly restraining tumor growth. Thus, EXO-OVA-mAb greatly facilitates T-cell targeting, induces a strong tumor-specific T-cell response, and increased the ratio of effector T cells/regulatory T cells within tumors, resulting in appreciable tumor growth inhibition.
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http://dx.doi.org/10.1016/j.actbio.2020.08.008DOI Listing
October 2020

Stealth Polymer-Coated Graphene Oxide Decorated Mesoporous Titania Nanoplatforms for In Vivo Chemo-Photodynamic Cancer Therapy.

Pharm Res 2020 Aug 4;37(8):162. Epub 2020 Aug 4.

College of Pharmacy, Yeungnam University, Gyeongsan, 38541, Republic of Korea.

Purpose: The goal of this study was to develop chemotherapeutic drug-loaded photoactivable stealth polymer-coated silica based- mesoporous titania nanoplatforms for enhanced antitumor activity.

Methods: Both in vitro and in vivo models of solvothermal treated photoactivable nanoplatforms were evaluated for efficient chemo-photothermal activity. A versatile nanocomposite that combined silica based- mesoporous titania nanocarriers (S-MTN) with the promising photoactivable agent, graphene oxide (G) modified with a stealth polymer (P) was fabricated to deliver chemotherapeutic agent, imatinib (I), (referred as [email protected]) for near-infrared (NIR)-triggered drug delivery and enhanced chemo-photothermal therapy.

Results: The fabricated [email protected] nanoplatform showed higher drug loading (~20%) and increased drug release (~60%) in response to light in acidic condition (pH 5.0). As prepared nanoplatform significantly converted NIR light into thermal energy (43.2°C) to produce reactive oxygen species (ROS). The pronounced cytotoxic effect was seen in both colon cancer cells (HCT-116 and HT-29) that was mediated through the chemotherapeutic effect of imatinib and the photothermal and ROS generation effects of graphene oxide. In vivo study also showed that [email protected] could significantly accumulate into the tumor area and suppress the tumor growth under NIR irradiation without any biocompatibility issues.

Conclusion: Cumulatively, the above results showed promising effects of [email protected] for effective chemo-phototherapy of colon cancer.
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http://dx.doi.org/10.1007/s11095-020-02900-1DOI Listing
August 2020

Acyclic Triterpenoid Isolated from Alleviates Formalin-Induced Chronic Mouse Paw Inflammation by Inhibiting the Phosphorylation of ERK and NF-κB.

Molecules 2020 Jul 23;25(15). Epub 2020 Jul 23.

Immunoregulatory Material Research Center, Korea Research Institute of Bioscience and Biotechnology, Jeongeup-si, Jeonbuk 56212, Korea.

Chronic and excessive inflammation can destroy host organs and cause inflammatory diseases such as inflammatory bowel disease, asthma, and rheumatoid arthritis. In this study, we investigated the anti-inflammatory effects of seed-derived 2,3,5,22,23-pentahydroxy-2,6,10,15,19,23-hexamethyl-tetracosa-6,10,14,18-tetraene (PHT) using lipopolysaccharide (LPS)-stimulated J774 cells and a formalin-induced chronic paw inflammation mouse model. The in vitro results showed that PHT exhibited no cytotoxicity and decreased LPS-induced NO secretion. Additionally, PHT inhibited LPS-induced inducible NO synthase (iNOS) and cyclooxygenase 2 (COX2) protein expression. The quantitative real-time PCR results showed that PHT downregulated the gene expression of the proinflammatory cytokines interleukin-1β (IL-1β) and interleukin-6 (IL-6) but not tumor necrosis factor α (TNF-α). PHT inhibited the LPS-induced phosphorylation of extracellular signal-regulated kinase (ERK) and nuclear factor kappa light chain enhancer of activated B cells (NF-κB). In a mouse model, oral administration of 50 mg/kg PHT significantly alleviated both mouse paw thickness and volume. These results indicate that PHT has potential anti-inflammatory effects and should be considered a possible functional material.
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http://dx.doi.org/10.3390/molecules25153345DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7435458PMC
July 2020

Hepatoprotective Effect of Extract Is Mediated via Antagonism of Oxidative Stress.

Evid Based Complement Alternat Med 2020 9;2020:6761842. Epub 2020 Jul 9.

Department of Psychopharmacology, Qiqihar Medical University, Qiqihar 161006, China.

has been extensively used in traditional Oriental medicine to treat gastric disorders and has anti-inflammatory and antioxidative activities. Therefore, the present study examined a possible hepatoprotective effect of a extract (PZE) and investigated the underlying molecular mechanisms. We employed an model of arachidonic acid (AA) + iron-induced hepatocyte damage and an model of CCl-induced liver injury to assess the effects of PZE and evaluated the relevant molecular targets using biochemical assays, flow cytometry analysis, Western blot, and histopathological analysis. The PZE inhibited AA + iron-induced hepatotoxicity in HepG2 cells, improved mitochondrial dysfunction, and reversed an increase in the cellular HO production and a decrease in the reduced GSH levels induced by AA + iron. Treatment with either 30 or 100 g/ml PZE significantly increased the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) protein, and the latter dose also increased the antioxidant response element- (ARE-) driven luciferase activity and enhanced the protein expressions of glutamate-cysteine ligase catalytic subunit and NAD(P)H:quinone oxidoreductase 1. In addition, treatment with 100 g/ml PZE for 3 or 6 h increased the phosphorylation rates of Nrf2 and the extracellular signal-regulated kinase. In the experiment, oral treatment with both 100 and 300 mg/kg PZE inhibited the plasma aspartate aminotransferase activity, and the latter also inhibited the plasma alanine aminotransferase activity. In addition, both doses of PZE ameliorated the parenchymal degeneration and necrosis in the liver induced by CCl administration, which was associated with reduced expressions of cleaved caspase-3, cleaved poly (ADP-ribose) polymerase, nitrotyrosine, and 4-hydroxynonenal by PZE. These findings suggest that PZE has protective effects against hepatotoxicity both and , which are mainly mediated via its antioxidant activity.
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http://dx.doi.org/10.1155/2020/6761842DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7368226PMC
July 2020

Lemon balm and dandelion leaf extract synergistically alleviate ethanol-induced hepatotoxicity by enhancing antioxidant and anti-inflammatory activity.

J Food Biochem 2020 08 4;44(8):e13232. Epub 2020 Jun 4.

Department of Foodscience and Biotechnology, Sungkyunkwan University, Suwon, Republic of Korea.

We investigated the effect of a 2:1 (w/w) mixture of lemon balm and dandelion extracts (LD) on ethanol (EtOH)-mediated liver injury and explored the underlying mechanisms. Administration of LD synergistically reduced relative liver weight and decreased the levels of serum biomarkers of hepatic injury. Histopathological and biochemical analyses indicated that LD synergistically attenuated hepatic accumulation of triacylglycerides (TGs) and restored the levels of mRNAs related to fatty acid metabolism. In addition, LD significantly reduced EtOH-induced hepatic oxidative stress by attenuating the reduction in levels of nuclear factor E2-related factor 2 (Nrf2) mRNA and enhancing antioxidant activity. Moreover, LD decreased the EtOH-mediated increase in levels of hepatic tumor necrosis factor-α (TNF-α) mRNA. In vitro, LD significantly scavenged free radicals, increased cell viability against tert-butylhydroperoxide (tBHP), and transactivated Nrf2 target genes in HepG2 cells. Furthermore, LD decreased levels of pro-inflammatory mediators in lipopolysaccharide-stimulated Raw264.7 cells. Therefore, LD shows promise for preventing EtOH-mediated liver injury. PRACTICAL APPLICATIONS: There were no approved therapeutic agents for preventing and/or treating alcoholic liver diseases. In this study, a 2:1 (w/w) mixture of lemon balm and dandelion leaf extract (DL) synergistically ameliorated EtOH-induced hepatic injury by inhibiting lipid accumulation, oxidative stress, and inflammation. Our findings will enable the development of a novel food supplement for the prevention or treatment of alcohol-mediated liver injury.
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http://dx.doi.org/10.1111/jfbc.13232DOI Listing
August 2020

Luteolin prevents liver from tunicamycin-induced endoplasmic reticulum stress via nuclear factor erythroid 2-related factor 2-dependent sestrin 2 induction.

Toxicol Appl Pharmacol 2020 07 11;399:115036. Epub 2020 May 11.

College of Korean Medicine, Daegu Haany University, Gyeongsan, Gyeongsangbuk-do 38610, Republic of Korea. Electronic address:

Endoplasmic reticulum (ER) stress designates a cellular response to the accumulation of misfolded proteins, which is related to disease progression in the liver. Luteolin (3',4',5,7-tetrahydroxyflavone) is a phytochemical found frequently in medicinal herbs. Although luteolin has been reported to possess the therapeutic potential to prevent diverse stage of liver diseases, its role in hepatic ER stress has not been established. Thus, the present study aimed to determine the role of luteolin in tunicamycin (Tm)-induced ER stress, and to identify the relevant mechanisms involved in its hepatoprotective effects. In hepatocyte-derived cells and primary hepatocytes, luteolin significantly decreased Tm- or thapsigargin-mediated C/EBP homologous protein (CHOP) expression. In addition, luteolin reduced the activation of three canonical signaling pathways related to the unfolded protein response, and decreased mRNA levels of glucose-regulated protein 78, ER DNA J domain-containing protein 4, and asparagine synthetase. Luteolin also significantly upregulated sestrin 2 (SESN2), and luteolin-mediated CHOP inhibition was blocked in SESN2 (+/-) cells. Moreover, luteolin resulted in phosphorylation of nuclear factor erythroid 2-related factor 2 (Nrf2), as well as increased nuclear Nrf2 expression. Deletion of the antioxidant response element in the human SESN2 promoter inhibited increased luciferase activation by luteolin, suggesting that Nrf2 is a critical transcription factor for luteolin-dependent SESN2 expression. In a Tm-mediated liver injury model, luteolin decreased serum alanine aminotransferase and aspartate aminotransferase activities, prevented degenerative changes and apoptosis of hepatocytes, and inhibited CHOP and glucose-regulated protein 78 expression in hepatic tissues. Therefore, luteolin may be an effective phytochemical to manage ER stress-related liver injury.
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http://dx.doi.org/10.1016/j.taap.2020.115036DOI Listing
July 2020

Effects of Balneotherapy in Jeju Magma-Seawater on Knee Osteoarthritis Model.

Sci Rep 2020 04 20;10(1):6620. Epub 2020 Apr 20.

Department of Anatomy and Histology, College of Korean Medicine, Daegu Haany University, Gyeongsan, Gyeongsangbuk-do, Republic of Korea.

Balneotherapy is a common non-pharmacological treatment for osteoarthritis (OA), however, the efficacy is controversial in knee OA. Jeju magma-seawater (JMS) has high contents of various minerals, which has anti-inflammatory and antioxidant properties via an oral route. Thus, we examined the effects of JMS bathing on knee OA and the combination effects with diclofenac sodium as an anti-inflammatory drug. Knee OA was induced by transection of the anterior cruciate ligament and the partial meniscectomy in rat. The rats were administered subcutaneously saline or diclofenac sodium in saline, followed by bathing in thermal distilled water or JMS for 8 weeks. The model represented the characteristic changes of the cartilage degradation, osteophyte formation and synovial inflammation, and the relevant symptoms of the joint swelling and stiffness. However, the JMS bathing reduced the joint thickness and improved the mobility. It also contributed to a well-preserved tissue supported by increases in bone mineral density of the joint and decreases in Mankin scores in the cartilages. The effects involved anti-inflammation, chondroprotection, anti-apoptosis, and chondrogenesis. Overall, the JMS bathing in combination with diclofenac sodium showed a similar trend associated with synergic effects. It suggests that JMS bathing can be promising for a clinical use in knee OA.
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http://dx.doi.org/10.1038/s41598-020-62867-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7171195PMC
April 2020
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