Publications by authors named "Jong-Sup Bae"

257 Publications

PEGylated nanoparticle albumin-bound steroidal ginsenoside derivatives ameliorate SARS-CoV-2-mediated hyper-inflammatory responses.

Biomaterials 2021 06 14;273:120827. Epub 2021 Apr 14.

Aging Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, 34141, Republic of Korea. Electronic address:

The rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on a global scale urges prompt and effective countermeasures. Recently, a study has reported that coronavirus disease-19 (COVID-19), the disease caused by SARS-CoV-2 infection, is associated with a decrease in albumin level, an increase in NETosis, blood coagulation, and cytokine level. Here, we present drug-loaded albumin nanoparticles as a therapeutic agent to resolve the clinical outcomes observed in severe SARS-CoV-2 patients. PEGylated nanoparticle albumin-bound (PNAB) was used to promote prolonged bioactivity of steroidal ginsenoside saponins, PNAB-Rg6 and PNAB-Rgx365. Our data indicate that the application of PNAB-steroidal ginsenoside can effectively reduce histone H4 and NETosis-related factors in the plasma, and alleviate SREBP2-mediated systemic inflammation in the PBMCs of SARS-CoV-2 ICU patients. The engineered blood vessel model confirmed that these drugs are effective in suppressing blood clot formation and vascular inflammation. Moreover, the animal model experiment showed that these drugs are effective in promoting the survival rate by alleviating tissue damage and cytokine storm. Altogether, our findings suggest that these PNAB-steroidal ginsenoside drugs have potential applications in the treatment of symptoms associated with severe SARS-CoV-2 patients, such as coagulation and cytokine storm.
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http://dx.doi.org/10.1016/j.biomaterials.2021.120827DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8046382PMC
June 2021

PF-3845, a Fatty Acid Amide Hydrolase Inhibitor, Directly Suppresses Osteoclastogenesis through ERK and NF-κB Pathways In Vitro and Alveolar Bone Loss In Vivo.

Int J Mol Sci 2021 Feb 15;22(4). Epub 2021 Feb 15.

Department of Oral Pathology and Regenerative Medicine, School of Dentistry, IHBR, Kyungpook National University, Daegu 41940, Korea.

Alveolar bone loss, the major feature of periodontitis, results from the activation of osteoclasts, which can consequently cause teeth to become loose and fall out; the development of drugs capable of suppressing excessive osteoclast differentiation and function is beneficial for periodontal disease patients. Given the difficulties associated with drug discovery, drug repurposing is an efficient approach for identifying alternative uses of commercially available compounds. Here, we examined the effects of PF-3845, a selective fatty acid amide hydrolase (FAAH) inhibitor, on receptor activator of nuclear factor kappa B ligand (RANKL)-mediated osteoclastogenesis, its function, and the therapeutic potential for the treatment of alveolar bone destruction in experimental periodontitis. PF-3845 significantly suppressed osteoclast differentiation and decreased the induction of nuclear factor of activated T-cells cytoplasmic 1 (NFATc1) and the expression of osteoclast-specific markers. Actin ring formation and osteoclastic bone resorption were also reduced by PF-3845, and the anti-osteoclastogenic and anti-resorptive activities were mediated by the suppression of phosphorylation of rapidly accelerated fibrosarcoma (RAF), mitogen-activated protein kinase (MEK), extracellular signal-regulated kinase, (ERK) and nuclear factor κB (NF-κB) inhibitor (IκBα). Furthermore, the administration of PF-3845 decreased the number of osteoclasts and the amount of alveolar bone destruction caused by ligature placement in experimental periodontitis in vivo. The present study provides evidence that PF-3845 is able to suppress osteoclastogenesis and prevent alveolar bone loss, and may give new insights into its role as a treatment for osteoclast-related diseases.
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http://dx.doi.org/10.3390/ijms22041915DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7919013PMC
February 2021

Impacts of Drug Interactions on Pharmacokinetics and the Brain Transporters: A Recent Review of Natural Compound-Drug Interactions in Brain Disorders.

Int J Mol Sci 2021 Feb 11;22(4). Epub 2021 Feb 11.

College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 41566, Korea.

Natural compounds such as herbal medicines and/or phyto-compounds from foods, have frequently been used to exert synergistic therapeutic effects with anti-brain disorder drugs, supplement the effects of nutrients, and boost the immune system. However, co-administration of natural compounds with the drugs can cause synergistic toxicity or impeditive drug interactions due to changes in pharmacokinetic properties (e.g., absorption, metabolism, and excretion) and various drug transporters, particularly brain transporters. In this review, natural compound-drug interactions (NDIs), which can occur during the treatment of brain disorders, are emphasized from the perspective of pharmacokinetics and cellular transport. In addition, the challenges emanating from NDIs and recent approaches are discussed.
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http://dx.doi.org/10.3390/ijms22041809DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7917745PMC
February 2021

Biapenem reduces sepsis mortality via barrier protective pathways against HMGB1-mediated septic responses.

Pharmacol Rep 2021 Jun 30;73(3):786-795. Epub 2021 Jan 30.

College of Pharmacy, CMRI, Research Institute of Pharmaceutical Sciences, Kyungpook National University, 80 Daehak-ro, Buk-gu, Daegu, 41566, Republic of Korea.

Background: As a late mediator of sepsis, the role of high mobility group box 1 (HMGB1) has been recognized as important, and suppression of HMGB1 release and restoration of vascular barrier integrity are regarded as potentially promising therapeutic strategies for sepsis. For repositioning of previously FDA-approved drugs to develop new therapies for human diseases, screening of chemical compound libraries, biological active, is an efficient method. Our study illustrates an example of drug repositioning of Biapenem (BIPM), a carbapenem antibiotic, for the modulation of HMGB1-induced septic responses.

Methods: We tested our hypothesis that BIPM inhibits HMGB1-induced vascular hyperpermeability and thereby increases the survival of septic mouse model from suppression of HMGB1 release upon lipopolysaccharide (LPS)-stimulation. In LPS-activated human umbilical vein endothelial cells (HUVECs) and a cecal ligation and puncture (CLP)-induced sepsis mouse model, antiseptic activity of BIPM was investigated from suppression of vascular permeability, pro-inflammatory proteins, and markers for tissue injury.

Results: BIPM significantly suppressed release of HMGB1 both in LPS-activated HUVECs (upto 60%) and the CLP-induced sepsis mouse model (upto 54%). BIPM inhibited hyperpermeability (upto 59%) and reduced HMGB1-mediated vascular disruptions (upto 62%), mortality (upto 50%), and also tissue injury including lung, liver, and kidney in mice.

Conclusion: Reduction of HMGB1 release and septic mortality by BIPM (in vitro, from 5 to 15 μM for 6 h; in vivo, from 0.37 to 1.1 mg/kg, 24 h) indicate a possibility of successful repositioning of BIPM for the treatment of sepsis.
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http://dx.doi.org/10.1007/s43440-020-00212-0DOI Listing
June 2021

Selective inhibitory effects of HYIpro-3-1 on CYP1A2 in human liver microsomes.

Biopharm Drug Dispos 2021 Jan;42(1):35-41

BK21 FOUR Community-Based Intelligent Novel Drug Discovery Education Unit, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, Republic of Korea.

CYP1A2 is one of the main Cytochrome P450 enzymes in the human liver associated with the metabolism of several xenobiotics. CYP1A2 is especially involved in the metabolic activation of different procarcinogens. Therefore, the development of cancer may be inhibited by inhibiting CYP1A2 activity. Here, the inhibitory effect of HYIpro-3-1 and its derivatives on CYP1A2 activity in human liver microsomes (HLM) was studied through LC-MS/MS using a cocktail assay. Among the four compounds, HYIpro-3-1 showed the most selective and strongest inhibitory effect on CYP1A2 at IC values of 0.1 µM in HLMs and inhibition was confirmed using purified human CYP1A2. It was determined that inhibition is reversible because the inhibitory effect of HYIpro-3-1 is not dependent on preincubation time. HYIpro-3-1 showed a typical pattern of competitive inhibition for CYP1A2-catalyzed phenacetin O-deethylation, based on the Lineweaver-Burk plot, with a Ki value of 0.05 μM in HLMs; the secondary plot also showed a linear pattern. In our study, HYIpro-3-1 was proposed as a novel inhibitor with the capacity to selectively inhibit CYP1A activity in HLMs.
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http://dx.doi.org/10.1002/bdd.2259DOI Listing
January 2021

Natural Antioxidant and Anti-Inflammatory Compounds in Foodstuff or Medicinal Herbs Inducing Heme Oxygenase-1 Expression.

Antioxidants (Basel) 2020 Nov 27;9(12). Epub 2020 Nov 27.

College of Pharmacy, CMRI, Research Institute of Pharmaceutical Sciences, BK21 Plus KNU Multi-Omics based Creative Drug Research Team, Kyungpook National University, Daegu 41566, Korea.

Heme oxygenase-1 (HO-1) is an inducible antioxidant enzyme that catalyzes heme group degradation. Decreased level of HO-1 is correlated with disease progression, and HO-1 induction suppresses development of metabolic and neurological disorders. Natural compounds with antioxidant activities have emerged as a rich source of HO-1 inducers with marginal toxicity. Here we discuss the therapeutic role of HO-1 in obesity, hypertension, atherosclerosis, Parkinson's disease and hepatic fibrosis, and present important signaling pathway components that lead to HO-1 expression. We provide an updated, comprehensive list of natural HO-1 inducers in foodstuff and medicinal herbs categorized by their chemical structures. Based on the continued research in HO-1 signaling pathways and rapid development of their natural inducers, HO-1 may serve as a preventive and therapeutic target for metabolic and neurological disorders.
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http://dx.doi.org/10.3390/antiox9121191DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7761319PMC
November 2020

Barrier protective functions of hederacolchiside-E against HMGB1-mediated septic responses.

Pharmacol Res 2021 01 24;163:105318. Epub 2020 Nov 24.

College of Pharmacy, CMRI, Research Institute of Pharmaceutical Sciences, BK21 Plus KNU Multi-Omics Based Creative Drug Research Team, Kyungpook National University, Daegu 41566, Republic of Korea. Electronic address:

The role of high mobility group box 1 (HMGB1) has been recognized as important, and suppression of HMGB1 release and restoration of vascular barrier integrity are regarded as potentially promising therapeutic strategies against sepsis. Hederacolchiside-E (HCE), namely 3-O-{α-L-rhamnopyranosyl (1→2)-[β-D-glucopyranosyl(1→4)]-α-L-arabinopyranosyl}-28-O-[α-L-rhamnopyranosyl (1→4)-β-D-glucopyranosyl(1→6)-β-D-glucopyranosyl ester, is a bidesmosidic oleanane saponin first isolated in 1970 from the leaves of Hedera colchica. We tested our hypothesis that HCE inhibits HMGB1-induced vascular hyperpermeability and thereby increases the survival of septic mouse model from suppression of HMGB1 release upon lipopolysaccharide (LPS)-stimulation. In LPS-activated human endothelial cells and a sepsis mouse model by cecal ligation and puncture (CLP), antiseptic activity of HCE was investigated from suppression of vascular permeability, pro-inflammatory proteins, and tissue injury markers. Post-treatment of HCE significantly suppressed HMGB1 release both in LPS-activated human endothelial cells and the CLP-induced sepsis mouse model. HCE inhibited hyperpermeability and alleviated HMGB1-mediated vascular disruptions, and reduced sepsis-related mortality and tissue injury in mice. Our results suggest that reduction of HMGB1 release and septic mortality by HCE may be useful for the drug candidate of sepsis, indicating a possibility of successful repositioning of HCE.
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http://dx.doi.org/10.1016/j.phrs.2020.105318DOI Listing
January 2021

Overexpression of OsCM alleviates BLB stress via phytohormonal accumulation and transcriptional modulation of defense-related genes in Oryza sativa.

Sci Rep 2020 11 11;10(1):19520. Epub 2020 Nov 11.

Division of Plant Biosciences, School of Applied Biosciences, College of Agriculture and Life Science, Kyungpook National University, 80 Dahak-ro, Buk-gu, Daegu, 41566, Republic of Korea.

Xanthomonas oryzae is a serious pathogen causing bacterial leaf blight (BLB) disease in rice, markedly reducing its yield. In this study, the rice chorismate mutase (OsCM) gene was overexpressed in a bacterial leaf blight-susceptible rice line to investigate the functional role of OsCM in response to bacterial leaf blight stress. We reported that overexpression of OsCM altered the downstream pathway of aromatic amino acids, mitigating pathogen stress by altering stress-responsive genes and hormonal accumulation. Phenotypic evaluation showed that the lesion length in the transgenic line was significantly lesser than that in the wild-type, suggesting greater resistance in the transgenic line. Further analysis revealed that OsCM expression induced phenylalanine accumulation and suppressed tyrosine accumulation in response to bacterial leaf blight stress. Furthermore, bacterial leaf blight stress induced genes downstream of the phenylpropanoid pathway in conjunction with OsCM, suggesting that the phenylpropanoid pathway is dependent on OsCM gene expression. We reported high SA and low JA accumulation in response to bacterial leaf blight stress in the transgenic line. This higher SA accumulation suggested that SA induces immune responses by functioning as a promoter of nonexpresser pathogenesis-related genes 1 (NPR1) transcriptional regulation. Xa7 expression was induced with increase in nonexpresser pathogenesis-related genes 1, which is thought to be responsible for Xa7 expression, which is responsible for mitigating bacterial leaf blight stress.
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http://dx.doi.org/10.1038/s41598-020-76675-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7658211PMC
November 2020

Fisetin Suppresses Pulmonary Inflammatory Responses Through Heme Oxygenase-1 Mediated Downregulation of Inducible Nitric Oxide Synthase.

J Med Food 2020 Nov 14;23(11):1163-1168. Epub 2020 Oct 14.

College of Pharmacy, CMRI, Research Institute of Pharmaceutical Sciences, BK21 Plus KNU Multi-Omics Based Creative Drug Research Team, Kyungpook National University, Daegu, Korea.

The effects of a mixture of fisetin on cytokine-mediated pulmonary damages have not been studied, despite its known antiviral, neuroprotective, and anti-inflammatory activities. Using lipopolysaccharide (LPS)-activated human pulmonary artery endothelial cells (HPAECs), we determined the effects of fisetin on the induction of heme oxygenase-1 (HO-1), inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2). In the lung tissue of LPS-treated mice, fisetin was also evaluated for its effect on the regulation of iNOS and tumor necrosis factor (TNF)-. In LPS-activated HPAECs, fisetin increased nuclear factor erythrocyte 2-related factor 2-antioxidant response element (Nrf2-ARE) reporter activity through the nuclear translocation of Nrf2, and the expression of HO-1, and decreased IL-1 and iNOS/NO production. In particular, the suppression of iNOS/NO expression by the administration of fisetin was dependent on HO-1. Current findings indicate that the anti-inflammatory activity of fisetin was due to its HO-1 dependent downregulation of p-STAT-1 and nuclear factor kappa B (NF-B) and the resultant inhibition of iNOS, and also suggest TNF- as a potential target for HO-1. We propose that administration of fisetin may be a novel approach, ideal for the treatment of inflammatory pulmonary disease.
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http://dx.doi.org/10.1089/jmf.2020.4755DOI Listing
November 2020

Recent progress in therapeutic drug delivery systems for treatment of traumatic CNS injuries.

Future Med Chem 2020 10 8;12(19):1759-1778. Epub 2020 Oct 8.

College of Pharmacy, CMRI, Research Institute of Pharmaceutical Sciences, BK21 Plus KNU Multi-Omics based Creative Drug Research Team, Kyungpook National University, Daegu, 41566, Republic of Korea.

Most therapeutics for the treatment of traumatic central nervous system injuries, such as traumatic brain injury and spinal cord injury, encounter various obstacles in reaching the target tissue and exerting pharmacological effects, including physiological barriers like the blood-brain barrier and blood-spinal cord barrier, instability rapid elimination from the injured tissue or cerebrospinal fluid and off-target toxicity. For central nervous system delivery, nano- and microdrug delivery systems are regarded as the most suitable and promising carriers. In this review, the pathophysiology and biomarkers of traumatic central nervous system injuries (traumatic brain injury and spinal cord injury) are introduced. Furthermore, various drug delivery systems, novel combinatorial therapies and advanced therapies for the treatment of traumatic brain injury and spinal cord injury are emphasized.
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http://dx.doi.org/10.4155/fmc-2020-0178DOI Listing
October 2020

The Role of Natural Compounds and their Nanocarriers in the Treatment of CNS Inflammation.

Biomolecules 2020 10 1;10(10). Epub 2020 Oct 1.

College of Pharmacy, CMR1, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 41566, Korea.

Neuroinflammation, which is involved in various inflammatory cascades in nervous tissues, can result in persistent and chronic apoptotic neuronal cell death and programmed cell death, triggering various degenerative disorders of the central nervous system (CNS). The neuroprotective effects of natural compounds against neuroinflammation are mainly mediated by their antioxidant, anti-inflammatory, and antiapoptotic properties that specifically promote or inhibit various molecular signal transduction pathways. However, natural compounds have several limitations, such as their pharmacokinetic properties and stability, which hinder their clinical development and use as medicines. This review discusses the molecular mechanisms of neuroinflammation and degenerative diseases of CNS. In addition, it emphasizes potential natural compounds and their promising nanocarriers for overcoming their limitations in the treatment of neuroinflammation. Moreover, recent promising CNS inflammation-targeted nanocarrier systems implementing lesion site-specific active targeting strategies for CNS inflammation are also discussed.
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http://dx.doi.org/10.3390/biom10101401DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7601486PMC
October 2020

Inhibitory functions of cardamonin against particulate matter-induced lung injury through TLR2,4-mTOR-autophagy pathways.

Fitoterapia 2020 Oct 15;146:104724. Epub 2020 Sep 15.

College of Pharmacy, CMRI, Research Institute of Pharmaceutical Sciences, BK21 Plus KNU Multi-Omics based Creative Drug Research Team, Kyungpook National University, Daegu 41566, Republic of Korea. Electronic address:

Particulate matter with an aerodynamic diameter equal to or less than 2.5 μm (PM) is a form of air pollutant that causes significant lung damage when inhaled. Cardamonin, a flavone found in Alpinia katsumadai Heyata seeds, has been reported to have anti-inflammatory and anticoagulative activity. The aim of this study was to determine the protective effects of cardamonin on PM-induced lung injury. Mice were treated with cardamonin via tail-vein injection 30 min after the intratracheal instillation of PM. The results showed that cardamonin markedly reduced the pathological lung injury, lung wet/dry weight ratio, and hyperpermeability caused by PM. Cardamonin also significantly inhibited PM-induced myeloperoxidase (MPO) activity in lung tissue, decreased the levels of PM-induced inflammatory cytokines and effectively attenuated PM-induced increases in the number of lymphocytes in the bronchoalveolar lavage fluid (BALF). And, cardamonin increased the phosphorylation of mammalian target of rapamycin (mTOR) and dramatically suppressed the PM-stimulated expression of toll-like receptor 2 and 4 (TLR 2,4), MyD88, and the autophagy-related proteins LC3 II and Beclin 1. In conclusion, these findings indicate that cardamonin has a critical anti-inflammatory effect due to its ability to regulate both the TLR2,4-MyD88 and mTOR-autophagy pathways and may thus be a potential therapeutic agent against PM-induced lung injury.
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http://dx.doi.org/10.1016/j.fitote.2020.104724DOI Listing
October 2020

Acetylated K676 TGFBIp as a severity diagnostic blood biomarker for SARS-CoV-2 pneumonia.

Sci Adv 2020 07 31;6(31). Epub 2020 Jul 31.

Aging Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Republic of Korea.

The outbreak of the highly contagious and deadly severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), also known as coronavirus disease 2019 (COVID-19), has posed a serious threat to public health across the globe, calling for the development of effective diagnostic markers and therapeutics. Here, we report a highly reliable severity diagnostic biomarker, acetylated 676th lysine transforming growth factor-beta-induced protein (TGFBIp K676Ac). TGFBIp K676Ac was consistently elevated in the blood of patients with SARS-CoV-2 pneumonia ( = 113), especially in patients in the intensive care unit (ICU) compared to non-ICU patients. Patients' blood samples showed increased cytokines and lymphopenia, which are exemplary indicators of SARS-CoV-2 pneumonia. Treatment with TGFBIp neutralizing antibodies suppressed the cytokine storm. The increased level of TGFBIp K676Ac in ICU patients suggests the promise of this protein as a reliable severity diagnostic biomarker for severe SARS-CoV-2 disease.
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http://dx.doi.org/10.1126/sciadv.abc1564DOI Listing
July 2020

Tie2-mediated vascular remodeling by ferritin-based protein C nanoparticles confers antitumor and anti-metastatic activities.

J Hematol Oncol 2020 09 14;13(1):123. Epub 2020 Sep 14.

BK21 Plus KNU Multi-Omics Creative Drug Research Team, Daegu, Republic of Korea.

Background: Conventional therapeutic approaches for tumor angiogenesis, which are primarily focused on the inhibition of active angiogenesis to starve cancerous cells, target the vascular endothelial growth factor signaling pathway. This aggravates hypoxia within the tumor core and ultimately leads to increased tumor proliferation and metastasis. To overcome this limitation, we developed nanoparticles with antiseptic activity that target tumor vascular abnormalities.

Methods: Ferritin-based protein C nanoparticles (PCNs), known as TFG and TFMG, were generated and tested in Lewis lung carcinoma (LLC) allograft and MMTV-PyMT spontaneous breast cancer models. Immunohistochemical analysis was performed on tumor samples to evaluate the tumor vasculature. Western blot and permeability assays were used to explore the role and mechanism of the antitumor effects of PCNs in vivo. For knocking down proteins of interest, endothelial cells were transfected with siRNAs. Statistical analysis was performed using one-way ANOVA followed by post hoc Dunnett's multiple comparison test.

Results: PCNs significantly inhibited hypoxia and increased pericyte coverage, leading to the inhibition of tumor growth and metastasis, while increasing survival in LLC allograft and MMTV-PyMT spontaneous breast cancer models. The coadministration of cisplatin with PCNs induced a synergistic suppression of tumor growth by improving drug delivery as evidenced by increased blood prefusion and decreased vascular permeability. Moreover, PCNs altered the immune cell profiles within the tumor by increasing cytotoxic T cells and M1-like macrophages with antitumor activity. PCNs induced PAR-1/PAR-3 heterodimerization through EPCR occupation and PAR-1 activation, which resulted in Gα13-RhoA-mediated-Tie2 activation and stabilized vascular tight junctions via the Akt-FoxO3a signaling pathway.

Conclusions: Cancer treatment targeting the tumor vasculature by inducing antitumor immune responses and enhancing the delivery of a chemotherapeutic agent with PCNs resulted in tumor regression and may provide an effective therapeutic strategy.
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http://dx.doi.org/10.1186/s13045-020-00952-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7489044PMC
September 2020

COVID-19-activated SREBP2 disturbs cholesterol biosynthesis and leads to cytokine storm.

Signal Transduct Target Ther 2020 09 3;5(1):186. Epub 2020 Sep 3.

Aging Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, 34141, Republic of Korea.

Sterol regulatory element binding protein-2 (SREBP-2) is activated by cytokines or pathogen, such as virus or bacteria, but its association with diminished cholesterol levels in COVID-19 patients is unknown. Here, we evaluated SREBP-2 activation in peripheral blood mononuclear cells of COVID-19 patients and verified the function of SREBP-2 in COVID-19. Intriguingly, we report the first observation of SREBP-2 C-terminal fragment in COVID-19 patients' blood and propose SREBP-2 C-terminal fragment as an indicator for determining severity. We confirmed that SREBP-2-induced cholesterol biosynthesis was suppressed by Sestrin-1 and PCSK9 expression, while the SREBP-2-induced inflammatory responses was upregulated in COVID-19 ICU patients. Using an infectious disease mouse model, inhibitors of SREBP-2 and NF-κB suppressed cytokine storms caused by viral infection and prevented pulmonary damages. These results collectively suggest that SREBP-2 can serve as an indicator for severity diagnosis and therapeutic target for preventing cytokine storm and lung damage in severe COVID-19 patients.
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http://dx.doi.org/10.1038/s41392-020-00292-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7471497PMC
September 2020

Identification of suberosin metabolites in human liver microsomes by high-performance liquid chromatography combined with high-resolution quadrupole-orbitrap mass spectrometer.

J Mass Spectrom 2021 Apr 30;56(4):e4623. Epub 2020 Jul 30.

BK21 Plus KNU Multi-Omics Based Creative Drug Research Team, College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, 41566, Republic of Korea.

Suberosin is a natural prenylated coumarin derivative isolated from Citropsis articulata. It has various pharmacological properties, especially as an anticoagulant, for which it has been used since antiquity. However, its metabolic pathway and metabolites have not yet been studied. Therefore, this study characterizes its metabolic pathway and metabolites in human liver microsomes (HLMs) using high-resolution quadrupole-orbitrap mass spectrometry (HRMS/MS). Eight metabolites (M1-M8) were found, including three monohydroxylated (M1-M3), one hydrated (M4), three dihydroxylated (M5-M7), and one glucuronide conjugate (M8). Furthermore, forms of cytochrome P450 (CYPs) responsible for suberosin metabolism in HLMs were characterized. CYP1A2 was identified as a major enzyme for the production of M1 and M5 metabolites. The M2, M3, and M7 metabolites were predominantly generated by CYP2B6. M8 was the only phase II metabolite, identified as a glucuronide conjugate from either M1 or M2. This glucuronide conjugate may be the only promising metabolite from phase II metabolism. Phase I metabolism, especially hydroxylation, was found to provide a predominant metabolic pathway of suberosin in HLMs. Further studies should be conducted to explore the metabolites, examining their efficacy and their toxicity in an in vivo system.
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http://dx.doi.org/10.1002/jms.4623DOI Listing
April 2021

Inhibitory effect of oolonghomobisflavan B on osteoclastogenesis by suppressing p38 MAPK activation.

Bioorg Med Chem Lett 2020 09 21;30(18):127429. Epub 2020 Jul 21.

Department of Oral Pathology and Regenerative Medicine, School of Dentistry, IHBR, Kyungpook National University, Daegu 41940, Republic of Korea. Electronic address:

Suppression of differentiation and/or function of osteoclasts is considered an effective therapeutic strategy for osteolytic bone diseases such as periodontitis and osteoporosis. Evidence regarding the health benefits of oolong tea consumption is accumulating, and tea polyphenols have various pharmacological properties such as anti-cancer and anti-diabetes effects. In this study, we investigated the effect of oolonghomobisflavan B (OFB), a polyphenolic compound in oolong tea, on osteoclast differentiation. OFB suppressed receptor activator of nuclear factor-κB (RANKL)-induced formation of tartate-resistant acid phosphatase-positive multinuclear cells without cytotoxicity. OFB also significantly attenuated p38 phosphorylation, which is essential for RANKL-induced osteoclastogenesis, and inhibited the expressions of nuclear factor of activated T cells, cytoplasmic 1 (NFATc1) and osteoclast-specific target genes, including dendritic cell-specific transmembrane protein and cathepsin K. Our findings suggest that OFB exhibits an anti-osteoclastogenic activity by inhibiting RANKL-mediated p38 activation, which is useful for the prevention and treatment of osteolytic bone diseases.
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http://dx.doi.org/10.1016/j.bmcl.2020.127429DOI Listing
September 2020

[Formula: see text], a Rare Protopanaxatriol-Type Ginsenoside Fraction from Black Ginseng, Suppresses Inflammatory Gene iNOS via the Iinhibition of p-STAT-1 and NF-[Formula: see text]B.

Am J Chin Med 2020 ;48(5):1091-1102

College of Pharmacy, CMRI, Research Institute of Pharmaceutical Sciences, BK21 Plus KNU Multi-Omics Based Creative Drug Research Team, Kyungpook National University, Daegu 41566, Republic of Korea.

Black ginseng (BG), which is ginseng that has been steamed and dried nine times, and its main protopanaxatriol-type ginsenosides Rg4, Rg6, Rh4, and Rg2 have been reported to exhibit various forms of biological activity, including antiseptic, antidiabetic, wound-healing, immune-stimulatory, and anti-oxidant activity. The aim of the this study was to examine the effects of [Formula: see text] (a rare protopanaxatriol-type ginsenoside fraction; Rg2, Rg4, Rg6, Rh1, and Rh4) on heme oxygenase-1 (HO-1) induction and on the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX-)2 in lipopolysaccharide (LPS)-activated human pulmonary artery endothelial cells (HPAECs). [Formula: see text] was tested to determine its effect on iNOS protein expression and inflammatory markers (interleukin [IL]-1[Formula: see text] and tumor necrosis factor [TNF]-[Formula: see text] in the lung tissue of LPS-treated mice. The results showed that [Formula: see text] induced the expression of HO-1, reduced LPS-activated NF-[Formula: see text]B-luciferase activity, and inhibited iNOS/NO and COX-2/PGE2, which contributed to the inhibition of STAT-1 phosphorylation. In particular, [Formula: see text] induced the translocation of Nrf2 from the cytosol to the nucleus by increasing Nrf2-ARE activity and decreased IL-1[Formula: see text] production in LPS-activated HPAECs. This reduction in iNOS/NO expression due to [Formula: see text] was reversed by siHO-1 RNA transfection. In LPS-treated mice, [Formula: see text] significantly reduced lung tissue iNOS protein levels and TNF-[Formula: see text] levels in the bronchoalveolar lavage fluid. In conclusion, these findings indicate that [Formula: see text] has a critical anti-inflammatory effect due to its ability to regulate iNOS via the inhibition of p-STAT-1 and NF-[Formula: see text]B, and thus it may be suitable for the treatment of inflammatory disease.
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http://dx.doi.org/10.1142/S0192415X20500536DOI Listing
October 2020

Protective Effect of Tetrahydroquinolines from the Edible Insect on LPS-Induced Vascular Inflammatory Responses.

Int J Mol Sci 2020 May 12;21(10). Epub 2020 May 12.

College of Pharmacy, Chungnam National University, Daejeon 34134, Korea.

The larva of (family Scarabaeidae) is an edible insect that is registered in the Korean Food Standards Codex as a food resource. The chemical study on the larvae of resulted in the isolation of three new tetrahydroquinolines, allomyrinaines A-C (-), one new dopamine derivative, allomyrinamide A (), and four known compounds (-). The structures were elucidated on the basis of 1D and 2D nuclear magnetic resonance (NMR) and MS spectroscopic data analysis. Allomyrinaines A-C (-) possessed three stereogenic centers at C-2, C-3, and C-4, whose relative configurations were determined by analyses of the coupling constants and the nuclear Overhauser enhancement spectroscopy (NOESY) data, as well as DP4+ calculation. The anti-inflammatory effects of compounds - were evaluated in human endothelial cells. Allomyrinaines A-C (-) could stabilize vascular barrier integrity on lipopolysaccharide (LPS)-induced vascular inflammation via inhibition of the nuclear factor-κB (NF-κB) pathway. The physiologically relevant concentration was confirmed by Q-TOF-MS-based quantitative analysis on allomyrinaines A-C in crude extract. This study suggests that allomyrinaines A-C (-) are bioactive constituents of to treat vascular inflammatory disorder.
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http://dx.doi.org/10.3390/ijms21103406DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7279263PMC
May 2020

Novel factor Xa inhibitor, maslinic acid, with antiplatelet aggregation activity.

J Cell Physiol 2020 12 30;235(12):9445-9456. Epub 2020 Apr 30.

Department of Pharmacy, College of Pharmacy, CMRI, Research Institute of Pharmaceutical Sciences, BK21 Plus KNU Multi-Omics based Creative Drug Research Team, Kyungpook National University, Daegu, Republic of Korea.

As antithrombotic effects of maslinic acid (MA) have not yet been studied, MA-mediated downregulation of coagulation factor Xa (FXa) and platelet aggregation was studied. We show that MA inhibited the enzymatic activity of FXa and platelet aggregation, induced by adenosine diphosphate (ADP) and a thromboxane A (TXA ) analog, U46619 with a similar antithrombotic efficacy to rivaroxaban, a direct FXa inhibitor used as a positive control. Mechanistically, MA suppressed U46619- or ADP-induced phosphorylation of myristoylated alanine-rich C kinase substrate, and the expression of P-selectin, and activated PAC-1 in platelets. MA increased generation of nitric oxide, but downregulated excessive secretion of endothelin-1 in ADP- or U46619-treated human umbilical vein endothelial cells. In arterial and pulmonary thrombosis mouse model, MA showed prominent anticoagulant and antithrombotic effects. Our data suggest MA as a candidate molecule for a new class of drugs targeting anti-FXa and antiplatelet.
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http://dx.doi.org/10.1002/jcp.29749DOI Listing
December 2020

Dual peptide-dendrimer conjugate inhibits acetylation of transforming growth factor β-induced protein and improves survival in sepsis.

Biomaterials 2020 07 28;246:120000. Epub 2020 Mar 28.

College of Pharmacy, CMRI, Research Institute of Pharmaceutical Sciences, BK21 Plus KNU Multi-Omics Based Creative Drug Research Team, Kyungpook National University, Daegu, 41566, Republic of Korea. Electronic address:

Sepsis is a potentially fatal complication of infections and there are currently no effective therapeutic options for severe sepsis. In this study, we revealed the secretion mechanism of transforming growth factor β-induced protein (TGFBIp) that was recently identified as a therapeutic target for sepsis, and designed TGFBIp acetylation inhibitory peptide (TAIP) that suppresses acetylation of lysine 676 in TGFBIp. To improve bioavailability and biodegradation of the peptide, TAIP was conjugated to polyamidoamine (PAMAM) dendrimers. Additionally, the cell-penetrating peptide (CPP) was conjugated to the TAIP-modified PAMAM dendrimers for the intracellular delivery of TGFBIp. The resulting nanostructures, decorated with TAIP and CPP via poly(ethylene glycol) linkage, improved the mortality and organ damage in the septic mouse model and suppressed lipopolysaccharide-activated severe vascular inflammatory responses in endothelial cells. Thus, the dendrimer-based nanostructures for delivery of TAIP using CPP show great promise in practical applications in sepsis therapy.
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http://dx.doi.org/10.1016/j.biomaterials.2020.120000DOI Listing
July 2020

Inhibitory functions of maslinic acid, a natural triterpene, on HMGB1-mediated septic responses.

Phytomedicine 2020 Apr 4;69:153200. Epub 2020 Mar 4.

College of Pharmacy, CMRI, Research Institute of Pharmaceutical Sciences, BK21 Plus KNU Multi-Omics based Creative Drug Research Team, Kyungpook National University, 80 Daehak-ro, Buk-gu, Daegu 41566, Republic of Korea. Electronic address:

Background: Maslinic acid (MA), a natural triterpenoid from Olea europaea, prevents oxidative stress and pro-inflammatory cytokine generation. High mobility group box 1 (HMGB1) has been recognized as a late mediator of sepsis, and the inhibition of the release of HMGB1 and the recovery of vascular barrier integrity have emerged as attractive therapeutic strategies for the management of sepsis.

Methods: We tested the hypothesis that MA induces sirtuin 1 and heme oxygenase-1, which inhibit the release of HMGB1 in lipopolysaccharide (LPS)-stimulated cells, thus inhibiting HMGB1-induced hyperpermeability and increasing the survival of septic mice. MA was administered after LPS or HMGB1 challenge, and the antiseptic activity of MA was determined based on permeability, the activation of pro-inflammatory proteins, and the production of markers for tissue injury in HMGB1-activated human umbilical vein endothelial cells (HUVECs) and a cecal ligation and puncture (CLP)-induced sepsis mouse model.

Results: MA significantly reduced the release of HMGB1 in LPS-activated HUVECs and attenuated the CLP-induced release of HMGB1. Additionally, MA alleviated HMGB1-mediated vascular disruption and inhibited hyperpermeability in mice, and in vivo analysis revealed that MA reduced sepsis-related mortality and tissue injury.

Conclusion: Taken together, the present results suggest that MA reduced HMGB1 release and septic mortality and thus may be useful in the treatment of sepsis.
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http://dx.doi.org/10.1016/j.phymed.2020.153200DOI Listing
April 2020

Biapenem as a Novel Insight into Drug Repositioning against Particulate Matter-Induced Lung Injury.

Int J Mol Sci 2020 Feb 21;21(4). Epub 2020 Feb 21.

College of Pharmacy, CMRI, Research Institute of Pharmaceutical Sciences, BK21 Plus KNU Multi-Omics based Creative Drug Research Team, Kyungpook National University, Daegu 41566, Korea.

The screening of biologically active chemical compound libraries can be an efficient way to reposition Food and Drug Adminstration (FDA)-approved drugs or to discover new therapies for human diseases. Particulate matter with an aerodynamic diameter equal to or less than 2.5 μm (PM) is a form of air pollutant that causes significant lung damage when inhaled. This study illustrates drug repositioning with biapenem (BIPM) for the modulation of PM-induced lung injury. Biapenem was used for the treatment of severe infections. Mice were treated with BIPM via tail-vein injection after the intratracheal instillation of PM. Alterations in the lung wet/dry weight, total protein/total cell count and lymphocyte count, inflammatory cytokines in the bronchoalveolar lavage fluid (BALF), vascular permeability, and histology were monitored in the PM-treated mice. BIPM effectively reduced the pathological lung injury, lung wet/dry weight ratio, and hyperpermeability caused by PM. Enhanced myeloperoxidase (MPO) activity by PM in the pulmonary tissue was inhibited by BIPM. Moreover, increased levels of inflammatory cytokines and total protein by PM in the BALF were also decreased by BIPM treatment. In addition, BIPM markedly suppressed PM-induced increases in the number of lymphocytes in the BALF. Additionally, the activity of mammalian target of rapamycin (mTOR) was increased by BIPM. Administration of PM increased the expression levels of toll-like receptor 4 (TLR4), MyD88, and the autophagy-related proteins LC3 II and Beclin 1, which were suppressed by BIPM. In conclusion, these findings indicate that BIPM has a critical anti-inflammatory effect due to its ability to regulate both the TLR4-MyD88 and mTOR-autophagy pathways, and may thus be a potential therapeutic agent against diesel PM-induced pulmonary injury.
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http://dx.doi.org/10.3390/ijms21041462DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7073049PMC
February 2020

Suppressive effects of aloin on polyphosphate-mediated vascular inflammatory responses.

J Asian Nat Prod Res 2021 Jan 20;23(1):89-99. Epub 2020 Feb 20.

College of Pharmacy, CMRI, Research Institute of Pharmaceutical Sciences, BK21 plus KNU Multi-Omics based Creative Drug Research Team, Kyungpook National University, Daegu 41566, Republic of Korea.

Human endothelial cells-derived polyphosphate (PolyP) is one of the pro-inflammatory mediators as suggested by the previous reports. Aloin is the major anthraquinone glycoside obtained from the species and exhibits anti-inflammatory and anti-oxidative activities. Aloin inhibits PolyP-mediated barrier disruption, the expressions of cell adhesion molecules, and adhesion/migration of leukocyte to HUVEC. PolyP-induced NF-κB activation and the productions of TNF-α and IL-6 were inhibited by aloin in HUVECs. These anti-inflammatory functions of aloin were confirmed in PolyP-injected mice. In conclusion, based on the anti-inflammatory effects of aloin in PolyP-mediated septic response, aloin has therapeutic potential for various systemic inflammatory diseases.
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http://dx.doi.org/10.1080/10286020.2020.1724969DOI Listing
January 2021

Inhibitory functions of maslinic acid on particulate matter-induced lung injury through TLR4-mTOR-autophagy pathways.

Environ Res 2020 04 5;183:109230. Epub 2020 Feb 5.

College of Pharmacy, CMRI, Research Institute of Pharmaceutical Sciences, BK21 Plus KNU Multi-Omics Based Creative Drug Research Team, Kyungpook National University, Daegu, 41566, Republic of Korea. Electronic address:

Particulate matter (PM), the collection of all liquid and solid particles suspended in air, includes both organic and inorganic particles, many of which are health-hazards. PM particles with a diameter equal to or less than 2.5 μm (PM) is a form of air pollutant that causes significant lung damage when inhaled. Maslinic acid (MA) prevents oxidative stress and pro-inflammatory cytokine generation, but there is little information available regarding its role in PM-induced lung injury. Therefore, the purpose of this study was to determine the protective activity of MA against PM-induced lung injury. The mice were divided into seven groups (n = 10 each): a mock control group, an MA control (0.8 mg/kg mouse body weight) group, an opted PM produced from diesel (10 mg/kg mouse body weight) group, a diesel PM+MA (0.2, 0.4, 0.6, and 0.8 mg/kg mouse body weight) groups. Mice were treated with MA via tail-vein injection 30 min after the intratracheal instillation of a diesel PM. Changes in the wet/dry weight ratio of the lung tissue, total protein/total cell and lymphocyte counts, inflammatory cytokines in the bronchoalveolar lavage fluid (BALF), vascular permeability, and histology were monitored in diesel PM-treated mice. The results showed that MA reduced pathological lung injury, the wet/dry weight ratio of the lung tissue, and hyperpermeability caused by diesel PM. MA also inhibited diesel PM-induced myeloperoxidase (MPO) activity in the lung tissue, decreased the levels of diesel PM-induced inflammatory cytokines, including tumor necrosis factor (TNF)-α and interleukin (IL)-1β, reduced nitric oxide (NO) and total protein in the BALF, and effectively attenuated diesel PM-induced increases in the number of lymphocytes in the BALF. In addition, MA increased the protein phosphorylation of the mammalian target of rapamycin (mTOR) and dramatically suppressed diesel PM-stimulated expression of toll-like receptor 4 (TLR4), MyD88, and the autophagy-related proteins LC3 II and Beclin 1. In conclusion, these findings indicate that MA has a critical anti-inflammatory effect due to its ability to regulate both the TLR4-MyD88 and mTOR-autophagy pathways and may thus be a potential therapeutic agent against diesel PM-induced lung injury.
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http://dx.doi.org/10.1016/j.envres.2020.109230DOI Listing
April 2020

Maslinic Acid Ameliorates Inflammation via the Downregulation of NF-κB and STAT-1.

Antioxidants (Basel) 2020 Jan 25;9(2). Epub 2020 Jan 25.

College of Pharmacy, CMRI, Research Institute of Pharmaceutical Sciences, BK21 Plus KNU Multi-Omics based Creative Drug Research Team, Kyungpook National University, Daegu 41566, Korea.

Maslinic acid (MA), a natural compound of the triterpenoid group derived from olive, prevents the generation of pro-inflammatory cytokines and oxidative stress. In human umbilical vein endothelial cells (HUVECs) treated with lipopolysaccharide (LPS), we characterized the effects of MA on the regulation of heme oxygenase (HO)-1, cyclooxygenase (COX-)2, and inducible nitric oxide synthase (iNOS). MA was tested in the lung tissues of LPS-treated mice, to determine its effect on levels of iNOS expression and representative inflammatory mediators such as interleukin (IL)-1 and tumor necrosis factor (TNF)-. We show that MA induced the expression of HO-1, reduced LPS-induced NF-κB-luciferase activity, and inhibited iNOS/NO and COX-2/PGE2, resulting in the downregulation of STAT-1 phosphorylation. Furthermore, our data show that MA induced the nuclear translocation of Nrf2, increased the binding of Nrf2 to ARE, and decreased IL-1 production in LPS-treated HUVECs. The MA-induced reduction in iNOS/NO expression was reversed by RNAi suppression of HO-1. In mice treated with LPS, MA significantly downregulated levels of iNOS in lung tissue and TNF- in the bronchoalveolar lavage fluid. Taken together, our findings indicate that MA exerts a critical anti-inflammatory effect by modulating iNOS via the downregulation of NF-κB and p-STAT-1. Thus, we propose that MA may be an ideal substance to treat inflammatory diseases.
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http://dx.doi.org/10.3390/antiox9020106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7070941PMC
January 2020

Inhibitory effects of aloin on TGFBIp-mediated septic responses.

J Asian Nat Prod Res 2021 Feb 24;23(2):189-203. Epub 2020 Jan 24.

College of Pharmacy, CMRI, Research Institute of Pharmaceutical Sciences, BK21 Plus KNU Multi-Omics Based Creative Drug Research Team, Kyungpook National University, Daegu 41566, Republic of Korea.

Aloin is the major anthraquinone glycoside obtained from the species. Transforming growth factor β-induced protein (TGFBIp) is an extracellular matrix protein and released by primary human umbilical vein endothelial cells (HUVECs) and functions as a mediator of experimental sepsis. We hypothesized that aloin could reduce TGFBIp-mediated severe inflammatory responses in HUVECs and mice. Aloin effectively inhibited lipopolysaccharide (LPS)-induced release of TGFBIp and suppressed TGFBIp-mediated septic responses. Aloin suppressed TGFBIp-induced sepsis lethality and pulmonary injury. Therefore, aloin is a potential therapeutic agent for various severe vascular inflammatory diseases, with inhibition of the TGFBIp signaling pathway as the mechanism of action. [Formula: see text].
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http://dx.doi.org/10.1080/10286020.2019.1711066DOI Listing
February 2021

Collismycin C reduces HMGB1-mediated septic responses and improves survival rate in septic mice.

J Asian Nat Prod Res 2021 Jan 31;23(1):55-72. Epub 2019 Dec 31.

College of Pharmacy, CMRI, Research Institute of Pharmaceutical Sciences, BK21 plus KNU Multi-Omics based Creative Drug Research Team, Kyungpook National University, Daegu 41566, Republic of Korea.

We examined the effects of a 2,2'-bipyridine containing natural product, collismycin C on high mobility group box 1 (HMGB1, septic mediator)-mediated septic responses and survival rate in a mouse sepsis model. Collismycin C inhibited the HMGB1 release and downregulated HMGB1-mediated inflammatory responses in human endothelial cells. Collismycin C also inhibited HMGB1-induced hyperpermeability and leukocyte migration in mice. In addition, collismycin C treatment reduced CLP-induced HMGB1 release and sepsis-related mortality and pulmonary damage . Our results indicate that collismycin C is a potential therapeutic agent for the treatment of severe vascular inflammatory diseases by inhibiting HMGB1 signaling pathway.
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http://dx.doi.org/10.1080/10286020.2019.1706497DOI Listing
January 2021

Suppressive functions of collismycin C in TGFBIp-mediated septic responses.

J Nat Med 2020 Mar 23;74(2):387-398. Epub 2019 Nov 23.

College of Pharmacy, CMRI, Research Institute of Pharmaceutical Sciences, BK21 Plus KNU Multi-Omics Based Creative Drug Research Team, Kyungpook National University, 80 Dahak-ro, Buk-gu, Daegu, 41566, Republic of Korea.

Transforming growth factor β-induced protein (TGFBIp) is an extracellular matrix protein; its expression by several cell types is greatly increased by TGF-β. TGFBIp is released by primary human umbilical vein endothelial cells (HUVECs) and functions as a mediator of experimental sepsis. 2,2'-Bipyridine-containing natural products are generally accepted to have antimicrobial, cytotoxic and anti-inflammatory properties. We hypothesized that a 2,2'-bipyridine containing natural product, collismycin C, could reduce TGFBIp-mediated severe inflammatory responses in human endothelial cells and mice. Here we investigated the effects and underlying mechanisms of collismycin C against TGFBIp-mediated septic responses. Collismycin C effectively inhibited lipopolysaccharide-induced release of TGFBIp and suppressed TGFBIp-mediated septic responses. In addition, collismycin C suppressed TGFBIp-induced sepsis lethality and pulmonary injury. This suppression of TGFBIp-mediated and CLP-induced septic responses indicates that collismycin C is a potential therapeutic agent for various severe vascular inflammatory diseases, with inhibition of the TGFBIp signaling pathway as the mechanism of action.
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http://dx.doi.org/10.1007/s11418-019-01374-9DOI Listing
March 2020