• BMB Reports
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• v.53 no.1
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• pp.28-34
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• 2020

Sphingolipids are ubiquitous building blocks of eukaryotic cell membranes that function as signaling molecules for regulating a diverse range of cellular processes, including cell proliferation, growth, survival, immune-cell trafficking, vascular and epithelial integrity, and inflammation. Recently, several studies have highlighted the pivotal role of sphingolipids in neuroinflammatory regulation. Sphingolipids have multiple functions, including induction of the expression of various inflammatory mediators and regulation of neuroinflammation by directly effecting the cells of the central nervous system. Accumulating evidence points to sphingolipid engagement in neuroinflammatory disorders, including Alzheimer's and Parkinson's diseases. Abnormal sphingolipid alterations, which involves an increase in ceramide and a decrease in sphingosine kinase, are observed during neuroinflammatory disease. These trends are observed early during disease development, and thus highlight the potential of sphingolipids as a new therapeutic and diagnostic target for neuroinflammatory diseases.

• Journal of Yeungnam Medical Science
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• v.37 no.4
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• pp.269-276
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• 2020

Fibrosis is characterized by excessive accumulation of extracellular matrix components. The fibrotic process ultimately leads to organ dysfunction and failure in chronic inflammatory and metabolic diseases such as pulmonary fibrosis, advanced kidney disease, and liver cirrhosis. Idiopathic pulmonary fibrosis (IPF) is a common form of progressive and chronic interstitial lung disease of unknown etiology. Pathophysiologically, the parenchyma of the lung alveoli, interstitium, and capillary endothelium becomes scarred and stiff, which makes breathing difficult because the lungs have to work harder to transfer oxygen and carbon dioxide between the alveolar space and bloodstream. The transforming growth factor beta (TGF-β) signaling pathway plays an important role in the pathogenesis of pulmonary fibrosis and scarring of the lung tissue. Recent clinical trials focused on the development of pharmacological agents that either directly or indirectly target kinases for the treatment of IPF. Therefore, to develop therapeutic targets for pulmonary fibrosis, it is essential to understand the key factors involved in the pathogenesis of pulmonary fibrosis and the underlying signaling pathway. The objective of this review is to discuss the role of kinase signaling cascades in the regulation of either TGF-β-dependent or other signaling pathways, including Rho-associated coiled-coil kinase, c-jun N-terminal kinase, extracellular signal-regulated kinase 5, and p90 ribosomal S6 kinase pathways, and potential therapeutic targets in IPF.

• BMB Reports
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• v.52 no.7
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• pp.451-456
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• 2019

NDRG1 has been reported to exert pivotal roles in tumor progression and metastasis via Wnt/${\beta}$-catenin signaling pathway. However, little is known about the role of NDRG3 in hepatocarcinogenesis despite its classification in the same subfamily of NDRG1. The present study was aimed to characterize the expression pattern and understand the biological roles of NDRG3 in hepatocarcinogenesis, as a means to exploit its therapeutic potential. It was observed that NDRG3 was up-regulated in HCC tissues and higher NDRG3 expression was associated with significantly shorter overall survival. Furthermore, a lower level of NDRG3 exhibited marked positive correlation with metastasis-free survival. In vitro and in vivo experiments revealed that knock-down of NDRG3 inhibits HCC metastasis and angiogenesis. We further demonstrated that activation of WNT/${\beta}$-catenin signaling and enhanced CSC-like properties were responsible for NDRG3-mediated promoting effect on HCC. In conclusion, the principal findings demonstrated that high NDRG3 expression facilitates HCC metastasis via regulating the turnover of ${\beta}$-catenin, as well as provides a potential therapeutic target for future therapeutic interventions.

• Biomolecules & Therapeutics
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• v.12 no.3
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• pp.145-150
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• 2004

Inflammation is a frequent radiation-induced reaction following therapeutic irradiation. Treatment of human umbilical endothelial cells (HUVEC) with ${\gamma}$-irradiation (${\gamma}$IR) induces the expression of adhesion proteins such as intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin. Since the upregulation of these proteins on endothelial cell Surface has been known to be associated with inflammation, interfering with the expression of adhesion molecules is an important therapeutic target. In the present study, we demonstrate that vitamin C inhibits ${\gamma}$IR induced expression of ICAM-1, VCAM-1, and E-selectin on HUVEC in a dose- and time dependent manner. Vitamin C a1so inhibited the production of Nitric oxide (NO) induced by ${\gamma}$IR. These data suggest that vitamin C has therapeutic potential for the treatment of various inflammatory disorder associated with an increase of endothelial leukocyte adhesion molecules.

• Journal of Ginseng Research
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• v.37 no.1
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• pp.8-29
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• 2013

Ginseng is one of the most widely used herbal medicines in human. Central nervous system (CNS) diseases are most widely investigated diseases among all others in respect to the ginseng's therapeutic effects. These include Alzheimer's disease, Parkinson's disease, cerebral ischemia, depression, and many other neurological disorders including neurodevelopmental disorders. Not only the various types of diseases but also the diverse array of target pathways or molecules ginseng exerts its effect on. These range, for example, from neuroprotection to the regulation of synaptic plasticity and from regulation of neuroinflammatory processes to the regulation of neurotransmitter release, too many to mention. In general, ginseng and even a single compound of ginsenoside produce its effects on multiple sites of action, which make it an ideal candidate to develop multi-target drugs. This is most important in CNS diseases where multiple of etiological and pathological targets working together to regulate the final pathophysiology of diseases. In this review, we tried to provide comprehensive information on the pharmacological and therapeutic effects of ginseng and ginsenosides on neurodegenerative and other neurological diseases. Side by side comparison of the therapeutic effects in various neurological disorders may widen our understanding of the therapeutic potential of ginseng in CNS diseases and the possibility to develop not only symptomatic drugs but also disease modifying reagents based on ginseng.

• Korean Journal of Clinical Pharmacy
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• v.20 no.3
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• pp.221-228
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• 2010

In 2009, American Journal of Health-System Pharmacy (AJHP) recommended that targeting vancomycin trough concentrations of 10 mg/L or more because of therapeutic failure and potential risk of developing vancomycin resistance. Therefore, new dosage guidelines that could achieve to these higher target were needed. The aims of this study were to develop dosage guidelines targeting new vancomycin trough concentration and to evaluate the performance of these new guidelines. All data analysis were performed using NONMEM(R). Population pharmacokinetic model was first developed from vancomycin dosage and concentration data collected retrospectively during routine therapeutic drug monitoring in 441 patients, then new vancomycin dosage guidelines were developed by using the model to predict vancomycin trough and peak concentrations in a simulated dataset. The estimates, such as, vancomycin concentration trough level, time to achieve target level, mean error were performed to evaluate and compare difference between conventional dosage and new dosage guidelines. The proposed dosage guidelines were predicted to achieve 43.5% of vancomycin trough level within 10~20 mg/L, which is significantly higher than current guidelines (26.3%). Time to achieve target trough level was 19.4 hours in new guidelines comparing to 93.1 hours in the conventional dosage. Thus, new vancomycin dosage guidelines have been developed to achieve new target trough concentrations earlier and more consistently than conventional guidelines.

• Biomolecules & Therapeutics
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• v.23 no.6
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• pp.493-509
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• 2015

Antibody-drug conjugates utilize the antibody as a delivery vehicle for highly potent cytotoxic molecules with specificity for tumor-associated antigens for cancer therapy. Critical parameters that govern successful antibody-drug conjugate development for clinical use include the selection of the tumor target antigen, the antibody against the target, the cytotoxic molecule, the linker bridging the cytotoxic molecule and the antibody, and the conjugation chemistry used for the attachment of the cytotoxic molecule to the antibody. Advancements in these core antibody-drug conjugate technology are reflected by recent approval of Adectris$^{(R)}$(anti-CD30-drug conjugate) and Kadcyla$^{(R)}$(anti-HER2 drug conjugate). The potential approval of an anti-CD22 conjugate and promising new clinical data for anti-CD19 and anti-CD33 conjugates are additional advancements. Enrichment of antibody-drug conjugates with newly developed potent cytotoxic molecules and linkers are also in the pipeline for various tumor targets. However, the complexity of antibody-drug conjugate components, conjugation methods, and off-target toxicities still pose challenges for the strategic design of antibody-drug conjugates to achieve their fullest therapeutic potential. This review will discuss the emergence of clinical antibody-drug conjugates, current trends in optimization strategies, and recent study results for antibody-drug conjugates that have incorporated the latest optimization strategies. Future challenges and perspectives toward making antibody-drug conjugates more amendable for broader disease indications are also discussed.

• Journal of the Korean Society of Physical Medicine
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• v.13 no.3
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• pp.141-150
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• 2018

PURPOSE: This study was conducted to understand the adaptive responses of different modes of physical exercises utilizing skeletal muscle and the comprehensive relevance of AMPK signaling that can be activated by physical exercise as a potential molecular target in human health problems such as neuromuscular disorders (NMDs). METHODS: Most of the contents in this review article are based on recent publications concerning the main topics of interest. The reference literatures cited were obtained by basic searches of overseas academic databases such as PubMed and ScienceDirect using EndNote X7.8. RESULTS: The phenotypic adaptive responses of skeletal muscle during endurance- and resistance-based exercise training (ET and RT respectively) appear to be distinct. To explain the adaptive responses in each single mode of exercises (ET, RT) along with combined exercise training (CT), AMPK signaling is proposed as an important molecular link among those differential modes of exercise and a promising molecular target of NMDs. CONCLUSION: Based on the available evidence, intracellular AMPK signaling activated by diverse stimuli including physical exercise can be a potential and promising therapeutic target for the prevention, amelioration or cure of various human health problems including NMDs and may also be beneficial for physical rehabilitation and emergency situations that may elicit acute metabolic stresses.

• The Korean Journal of Physiology and Pharmacology
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• v.17 no.5
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• pp.375-383
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• 2013

Hepatocellular carcinoma (HCC) related to hepatitis B virus (HBV) and hepatitis C virus (HCV) infections is thought to account for more than 80% of primary liver cancers. Both HBV and HCV can establish chronic liver inflammatory infections, altering hepatocyte and liver physiology with potential liver disease progression and HCC development. Cyclophilin A (CypA) has been identified as an essential host factor for the HCV replication by physically interacting with the HCV non structural protein NS5A that in turn interacts with RNA-dependent RNA polymerase NS5B. CypA, a cytosolic binding protein of the immunosuppressive drug cyclosporine A, is overexpressed in many cancer types and often associated with malignant transformation. Therefore, CypA can be a good target for molecular cancer therapy. Because of antiviral activity, the CypA inhibitors have been tested for the treatment of chronic hepatitis C. Nonimmunosuppressive Cyp inhibitors such as NIM811, SCY-635, and Alisporivir have attracted more interests for appropriating CypA for antiviral chemotherapeutic target on HCV infection. This review describes CypA inhibitors as a potential HCC treatment tool that is contrived by their obstructing chronic HCV infection and summarizes roles of CypA in cancer development.

• BMB Reports
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• v.42 no.8
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• pp.535-539
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• 2009

Voltage-gated $K^+$ (Kv) channels are widely expressed in the plasma membranes of numerous cells such as epithelial cells. Recently, it has been demonstrated that Kv channels are associated with the proliferation of several types of cancer cells. Specifically, Kv1.3 seems to be involved in cancer cell proliferation and apoptosis. In the present study, we examined the expression of Kv1.3 in immortalized and tumorigenic human mammary epithelial cells. We also evaluated the expression level of Kv1.3 in each stage of breast cancer using mRNA isolated from breast cancer patients. In addition, treatment with tetraethylammonium, a Kv channel blocker, suppressed tumorigenic human mammary epithelial cell proliferation. Therefore, Kv1.3 may serve as a novel molecular target for breast cancer therapy while its stage-specific expression pattern may provide a potential diagnostic marker for breast cancer development.