• Biomolecules & Therapeutics
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• 제28권5호
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• pp.482-489
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• 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.

• BMB Reports
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• 제56권10호
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• pp.545-550
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• 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.

• Journal of the Korean Academy of Child and Adolescent Psychiatry
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• 제34권4호
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• pp.192-203
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• 2023

Digital therapeutics based on software, such as artificial intelligence, virtual reality, games, and smartphone applications, are in the spotlight as new therapeutic alternatives in child and adolescent psychiatry. It draws attention to overcoming conventional therapeutics' limitations, such as toxicity, cost, and accessibility, and encourages patients to participate in the treatment attractively. The growth potential of the digital therapeutics market for psychiatric disorders in children and adolescents in Korea and abroad has been highlighted. Clinical studies and Food and Drug Administration approvals for digital therapeutics have increased, and cases approved by the Ministry of Food and Drug Safety have emerged in Korea. As seen above, digital transformation in child and adolescent psychiatry will change treatment paradigms significantly. Therefore, as this new field has just begun to emerge, it is necessary to verify the effectiveness and scope of the application of digital therapeutics and consider preparing a compensation system and institutional arrangements. Accordingly, this study analyzed the development trends and application status of digital therapeutics in children and adolescents and presented limitations and development directions from the perspective of application in healthcare. Further, the study is expected to identify the utility and limitations of digital therapeutics for children and adolescents and establish effective application measures.

• 대한임상약리학회:학술대회논문집
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• 대한임상약리학회 2007년도 추계학술대회
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• pp.81-81
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• 2007

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• Bulletin of the Korean Chemical Society
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• 제31권9호
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• pp.2665-2667
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• 2010

• BMB Reports
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• 제43권6호
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• pp.383-388
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• 2010

The number of cancer patients has increased due to longer life spans and treatment has become a universal problem. Since molecular-targeted therapies were introduced as a new developmental strategy, certain targets have been examined hundreds of times, with developers overlapping their research efforts. We need to focus our energy and resources on novel drug candidate identification and optimization, in order to enhance the entry of early-stage drug candidates into the therapeutics pipeline. This presents a major opportunity for Korea to jump the decades-old development gap between our programs and those that are more advanced in other countries. Although this country does not have a specific center for validation and development of cancer therapeutics, we do have cutting-edge scientists performing research in many institutions. In this paper, I will review cancer drug development in Korea and suggest future directions, while urging colleagues to utilize their networking expertise so we can move toward a new paradigm of novel therapeutics development. An example of such efforts has begun with the Drug Development Consortium, which was described in the KSBMB chapter. This consortium was launched in 2010 by biochemists, chemists, cell and molecular biologists and pharmacologists. It is clear that effective cancer therapeutics will be developed more efficiently when we all strive for the same goal.

• Journal of Microbiology and Biotechnology
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• 제32권9호
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• pp.1073-1085
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• 2022

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has continued for over 2 years, following the outbreak of coronavirus-19 (COVID-19) in 2019. It has resulted in enormous casualties and severe economic crises. The rapid development of vaccines and therapeutics against SARS-CoV-2 has helped slow the spread. In the meantime, various mutations in the SARS-CoV-2 have emerged to evade current vaccines and therapeutics. A better understanding of SARS-CoV-2 pathogenesis is a prerequisite for developing efficient, advanced vaccines and therapeutics. Since the outbreak of COVID-19, a tremendous amount of research has been conducted to unveil SARS-CoV-2 pathogenesis, from clinical observations to biochemical analysis at the molecular level upon viral infection. In this review, we discuss the molecular mechanisms of SARS-CoV-2 propagation and pathogenesis, with an update on recent advances.

• 한국임상약학회지
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• 제33권4호
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• pp.221-241
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• 2023

Background: The purpose of this systematic review was to investigate the effects of digital therapeutics for insomnia on sleep disorders and mental health improvement compared to the control group. Methods: Following the guidelines on systematic review(PRISMA, NECA), a literature search was conducted through PubMed, Cochrane Library, EMBASE, RISS, KISS, and KoreaMed using keywords. The Cochrane Risk of Bias Tool and Review Manager version 5.3 were used for risk of bias and effect size assessment. Results: Thirty eight RCT met criteria for inclusion. When compared against three control conditions, the digital therapeutics for insomnia was an effective intervention for improvement sleep disorders and mental health in comparison to waiting list and Patient-directed care with some intervention by medical staff. However, digital therapeutics for insomnia were no more effective than face-to-face CBT-I control group. Conclusion: The efficacy of digital therapeutics for insomnia was evaluated differently depending on the control group. Therefore, in phase 3 clinical trials for efficacy evaluation, it is necessary to review whether the control group has been properly established.

• The Korean Journal of Physiology and Pharmacology
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• 제16권4호
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• pp.273-279
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• 2012

Busulfan is an antineoplastic agent with a narrow therapeutic window. A post-hoc population pharmacokinetic analysis of a prospective randomized trial for comparison of four-times daily versus once-daily intravenous busulfan was carried out to search for predictive factors of intravenous busulfan (iBu) pharmacokinetics (PK). In this study the population PK of iBu was characterized to provide suitable dosing recommendations. Patients were randomized to receive iBu, either as 0.8 mg/kg every 6 h or 3.2 mg/kg daily over 4 days prior to hematopoietic stem cell transplantation. In total, 295 busulfan concentrations were analyzed with NONMEM. Actual body weight and sex were significant covariates affecting the PK of iBu. Sixty patients were included in the study (all Korean; 23 women, 37 men; mean [SD] age, 36.5 [10.9] years; weight, 66.5 [11.3] kg). Population estimates for a typical patient weighing 65 kg were: clearance (CL) 7.6 l/h and volume of distribution (Vd) 32.2 l for men and 29.1 L for women. Inter-individual random variabilities of CL and $V_d$ were 16% and 9%. Based on a CL estimate from the final PK model, a simple dosage scheme to achieve the target $AUC_{0-inf}$ (defined as median AUC0-inf with a once-daily dosage) of 26.18 $mg/l{\cdot}hr$, was proposed: $24.79{\cdot}ABW^{0.5}mg$ q24h, where ABW represents the actual body weight in kilograms. The dosing scheme reduced the unexplained interindividual variabilities of CL and Vd of iBu with ABW being a significant covariate affecting clearance of iBU. We propose a new simple dosing scheme for iBu based only on ABW.

• Biomolecules & Therapeutics
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• 제30권6호
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• pp.553-561
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• 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.