• Biomolecules & Therapeutics
• /
• v.28 no.6
• /
• pp.503-511
• /
• 2020

Autophagy is a major catabolic process that maintains cell metabolism by degrading damaged organelles and other dysfunctional proteins via the lysosome. Abnormal regulation of this process has been known to be involved in the progression of pathophysiological diseases, such as cancer and neurodegenerative disorders. Although the mechanisms for the regulation of autophagic pathways are relatively well known, the precise regulation of this pathway in the treatment of cancer remains largely unknown. It is still complicated whether the regulation of autophagy is beneficial in improving cancer. Many studies have demonstrated that autophagy plays a dual role in cancer by suppressing the growth of tumors or the progression of cancer development, which seems to be dependent on unknown characteristics of various cancer types. This review summarizes the key targets involved in autophagy and malignant transformation. In addition, the opposing tumor-suppressive and oncogenic roles of autophagy in cancer, as well as potential clinical therapeutics utilizing either regulators of autophagy or combinatorial therapeutics with anti-cancer drugs have been discussed.

• BMB Reports
• /
• v.56 no.10
• /
• pp.545-550
• /
• 2023

Osteoporosis is a major public health concern, which requires novel therapeutic strategies to prevent or mitigate bone loss. Natural compounds have attracted attention as potential therapeutic agents due to their safety and efficacy. In this study, we investigated the regulatory activities of boeravinone B (BOB), a natural rotenoid isolated from the medicinal plant Boerhavia diffusa, on the differentiation of osteoclasts and mesenchymal stem cells (MSCs), the two main cell components responsible for bone remodeling. We found that BOB inhibited osteoclast differentiation and function, as determined by TRAP staining and pit formation assay, with no significant cytotoxicity. Furthermore, our results showing that BOB ameliorates ovariectomy-induced bone loss demonstrated that BOB is also effective in vivo. BOB exerted its inhibitory effects on osteoclastogenesis by downregulating the RANKL/RANK signaling pathways, including NF-κB, MAPK, and PI3K/Akt, resulting in the suppression of osteoclast-specific gene expression. Further experiments revealed that, at least phenomenologically, BOB promotes osteoblast differentiation of bone marrow-derived MSCs but inhibits their differentiation into adipocytes. In conclusion, our study demonstrates that BOB inhibits osteoclastogenesis and promotes osteoblastogenesis in vitro by regulating various signaling pathways. These findings suggest that BOB has potential value as a novel therapeutic agent for the prevention and treatment of osteoporosis.

• Archives of Obesity and Metabolism
• /
• v.1 no.2
• /
• pp.47-52
• /
• 2022

Digital therapeutics (DTx) are emerging as a novel solution to improve lifestyle and prevent non-communicable diseases. Obesity is a complex, multi-factorial, chronic condition that requires patient-centered lifestyle modification. DTx, such as mobile applications and wearables, may offer easily accessible, efficient, and personalized care in the field of obesity and metabolic diseases. Yet, there is controversy over its clinical usefulness. This review will provide a comprehensive overview of DTx, including its potential role and current limitation in obesity care, based on recent literature.

• Biomolecules & Therapeutics
• /
• v.30 no.6
• /
• pp.553-561
• /
• 2022

Chronic myeloid leukemia (CML) is a slowly progressing hematopoietic cell disorder. Sphingosine kinase 1 (SPHK1) plays established roles in tumor initiation, progression, and chemotherapy resistance in a wide range of cancers, including leukemia. However, small-molecule inhibitors targeting SPHK1 in CML still need to be developed. This study revealed the role of SPHK1 in CML and investigated the potential anti-leukemic activity of hirsuteine (HST), an indole alkaloid obtained from the oriental plant Uncaria rhynchophylla, in CML cells. These results suggest that SPHK1 is highly expressed in CML cells and that overexpression of SPHK1 represents poor clinical outcomes in CML patients. HST exposure led to G2/M phase arrest, cellular apoptosis, and downregulation of Cyclin B1 and CDC2 and cleavage of Caspase 3 and PARP in CML cells. HST shifted sphingolipid rheostat from sphingosine 1-phosphate (S1P) towards the ceramide coupled with a marked inhibition of SPHK1. Mechanistically, HST significantly blocked SPHK1/S1P/S1PR1 and BCR-ABL/PI3K/Akt pathways. In addition, HST can be docked with residues of SPHK1 and shifts the SPHK1 melting curve, indicating the potential protein-ligand interactions between SPHK1 and HST in both CML cells. SPHK1 overexpression impaired apoptosis and proliferation of CML cells induced by HST alone. These results suggest that HST, which may serve as a novel and specific SPHK1 inhibitor, exerts anti-leukemic activity by inhibiting the SPHK1/S1P/S1PR1 and BCR-ABL/PI3K/Akt pathways in CML cells, thus conferring HST as a promising anti-leukemic drug for CML therapy in the future.

• International Journal of Oral Biology
• /
• v.38 no.4
• /
• pp.155-160
• /
• 2013

The major issue in the development of nucleic acid based therapeutics is the inefficient delivery of these agents into cells. We prepared cholesterol conjugated spermine and evaluated its usefulness as a delivery modality for antisense oligonucleotides in HeLa-Luc cells. A 2'-O-methyl antisense oligonucleotide sequence, designed to correct splicing at an aberrant intron inserted into a normal luciferase reporter gene, was used for complex formation with cholesterol conjugated spermine. Effective delivery of this antisense agent into nucleus would results in the expression of a luciferasereporter gene product. The cholesterol-spermine formed stable complexes with the antisense oligonucleotide and showed modest delivery activity. Furthermore, this delivery activity was maintained even in the presence of serum proteins, mimicking in vivo conditions. Cholesterol-spermine thus has potential as a delivery system for antisense oligonucleotides into cells.

• BMB Reports
• /
• v.48 no.4
• /
• pp.234-237
• /
• 2015

Aptamers, composed of single-stranded DNA or RNA oligonucleotides that interact with target molecules through a specific three-dimensional structure, are selected from pools of combinatorial oligonucleotide libraries. With their high specificity and affinity for target proteins, ease of synthesis and modification, and low immunogenicity and toxicity, aptamers are considered to be attractive molecules for development as anticancer therapeutics. Two aptamers - one targeting nucleolin and a second targeting CXCL12 - are currently undergoing clinical trials for treating cancer patients, and many more are under study. In this mini-review, we present the current clinical status of aptamers and aptamer-based cancer therapeutics. We also discuss advantages, limitations, and prospects for aptamers as cancer therapeutics. [BMB Reports 2015; 48(4): 234-237]

• 대한임상약리학회:학술대회논문집
• /
• 2006.11a
• /
• pp.99-99
• /
• 2006

• Molecules and Cells
• /
• v.46 no.10
• /
• pp.627-636
• /
• 2023

Periodontal disease is a chronic inflammatory disease that leads to the gradual destruction of the supporting structures of the teeth including gums, periodontal ligaments, alveolar bone, and root cementum. Recently, interests in alleviating symptoms of periodontitis (PD) using natural compounds is increasing. Avenanthramide-C (Avn-C) is a polyphenol found only in oats. It is known to exhibit various biological properties. To date, the effect of Avn-C on PD pathogenesis has not been confirmed. Therefore, this study aimed to verify the protective effects of Avn-C on periodontal inflammation and subsequent alveolar bone erosion in vitro and in vivo. Upregulated expression of catabolic factors, such as matrix metalloproteinase 1 (MMP1), MMP3, interleukin (IL)-6, IL-8, and COX2 induced by lipopolysaccharide and proinflammatory cytokines, IL-1β, and tumor necrosis factor α (TNF-α), was dramatically decreased by Avn-C treatment in human gingival fibroblasts and periodontal ligament cells. Moreover, alveolar bone erosion in the ligature-induced PD mouse model was ameliorated by intra-gingival injection of Avn-C. Molecular mechanism studies revealed that the inhibitory effects of Avn-C on the upregulation of catabolic factors were mediated via ERK (extracellular signal-regulated kinase) and NF-κB pathway that was activated by IL-1β or p38 MAPK and JNK signaling that was activated by TNF-α, respectively. Based on this study, we recommend that Avn-C may be a new natural compound that can be applied to PD treatment.

• International Journal of Oral Biology
• /
• v.44 no.3
• /
• pp.108-114
• /
• 2019

In the present study, rutile phase titanium dioxide nanoparticles ($R-TiO_2$ NPs) were prepared by hydrolysis of titanium tetrachloride in an aqueous solution followed by calcination at $900^{\circ}C$. The composition of $R-TiO_2$ NPs was determined by the analysis of X-ray diffraction data, and the characteristic features of $R-TiO_2$ NPs such as the surface functional group, particle size, shape, surface topography, and morphological behavior were analyzed by Fourier-transform infrared spectroscopy, scanning electron microscopy and energy dispersive X-ray spectroscopy, transmission electron microscopy, dynamic light scattering, and zeta potential measurements. The average size of the prepared $R-TiO_2$ NPs was 76 nm, the surface area was $19m^2/g$, zeta potential was -20.8 mV, and average hydrodynamic diameter in dimethyl sulfoxide (DMSO)-$H_2O$ solution was 550 nm. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and morphological observations revealed that $R-TiO_2$ NPs were cytocompatible with oral cancer cells, with no inhibition of cell growth and proliferation. This suggests the efficacy of $R-TiO_2$ NPs for the aesthetic white pigmentation of teeth.

• Biomolecules & Therapeutics
• /
• v.28 no.5
• /
• pp.482-489
• /
• 2020

G protein-coupled receptor kinase 5 (GRK5) has been considered as a potential target for the treatment of heart failure as it has been reported to be an important regulator of pathological cardiac hypertrophy. To discover novel scaffolds that selectively inhibit GRK5, we have identified a novel small molecule inhibitor of GRK5, KR-39038 [7-((3-((4-((3-aminopropyl)amino)butyl)amino)propyl)amino)-2-(2-chlorophenyl)-6-fluoroquinazolin-4(3H)-one]. KR-39038 exhibited potent inhibitory activity (IC₅₀ value=0.02 µM) against GRK5 and significantly inhibited angiotensin II-induced cellular hypertrophy and HDAC5 phosphorylation in neonatal cardiomyocytes. In the pressure overload-induced cardiac hypertrophy mouse model, the daily oral administration of KR-39038 (30 mg/kg) for 14 days showed a 43% reduction in the left ventricular weight. Besides, KR-39038 treatment (10 and 30 mg/kg/day, p.o.) showed significant preservation of cardiac function and attenuation of myocardial remodeling in a rat model of chronic heart failure following coronary artery ligation. These results suggest that potent GRK5 inhibitor could effectively attenuate both cardiac hypertrophy and dysfunction in experimental heart failure, and KR-39038 may be useful as an effective GRK5 inhibitor for pharmaceutical applications.