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한국응용약물학회> Biomolecules & Therapeutics(구 응용약물학회지)> Natural Products as Sources of Novel Drug Candidates for the Pharmacological Management of Osteoarthritis: A Narrative Review

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Natural Products as Sources of Novel Drug Candidates for the Pharmacological Management of Osteoarthritis: A Narrative Review

Young-hoon Kang , Hyun Jae Lee , Choong Jae Lee , Jin-sung Park
  • : 한국응용약물학회
  • : Biomolecules & Therapeutics(구 응용약물학회지) 27권6호
  • : 연속간행물
  • : 2019년 11월
  • : 503-513(11pages)

DOI


목차

INTRODUCTION
CURRENT CONVENTIONAL PHARMACOTHERAPY FOR THE MANAGEMENT OF OSTEOARTHRITIS
SEARCH FOR NOVEL CANDIDATE AGENTS FOR REGULATING OSTEOARTHRITIS FROM MEDICINAL PLANTS AND NATURAL PRODUCTS DERIVED FROM THEM
CONCLUSION AND FUTURE DIRECTION FOR OSTEOARTHRITIS RESEARCH
CONFLICT OF INTEREST
ACKNOWLEDGMENTS
REFERENCES

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Osteoarthritis is a chronic degenerative articular disorder. Formation of bone spurs, synovial inflammation, loss of cartilage, and underlying bone restructuring have been reported to be the main pathologic characteristics of osteoarthritis symptoms. The onset and progression of osteoarthritis are attributed to various inflammatory cytokines in joint tissues and fluids that are produced by chondrocytes and/or interact with chondrocytes, as well as to low-grade inflammation in intra-articular tissues. Disruption of the equilibrium between the synthesis and degradation of the cartilage of the joint is the major cause of osteoarthritis. Hence, developing a promising pharmacological tool to restore the equilibrium between the synthesis and degradation of osteoarthritic joint cartilage can be a useful strategy for effectively managing osteoarthritis. In this review, we provide an overview of the research results pertaining to the search for a novel candidate agent for osteoarthritis management via restoration of the equilibrium between cartilage synthesis and degradation. We especially focused on investigations of medicinal plants and natural products derived from them to shed light on the potential pharmacotherapy of osteoarthritis.

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  • : 의약학분야  > 약화학
  • : KCI등재
  • : SCI,SCOPUS
  • : 격월
  • : 1976-9148
  • : 2005-4483
  • : 학술지
  • : 연속간행물
  • : 1993-2019
  • : 1615


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1Natural Products as Sources of Novel Drug Candidates for the Pharmacological Management of Osteoarthritis: A Narrative Review

저자 : Young-hoon Kang , Hyun Jae Lee , Choong Jae Lee , Jin-sung Park

발행기관 : 한국응용약물학회 간행물 : Biomolecules & Therapeutics(구 응용약물학회지) 27권 6호 발행 연도 : 2019 페이지 : pp. 503-513 (11 pages)

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Osteoarthritis is a chronic degenerative articular disorder. Formation of bone spurs, synovial inflammation, loss of cartilage, and underlying bone restructuring have been reported to be the main pathologic characteristics of osteoarthritis symptoms. The onset and progression of osteoarthritis are attributed to various inflammatory cytokines in joint tissues and fluids that are produced by chondrocytes and/or interact with chondrocytes, as well as to low-grade inflammation in intra-articular tissues. Disruption of the equilibrium between the synthesis and degradation of the cartilage of the joint is the major cause of osteoarthritis. Hence, developing a promising pharmacological tool to restore the equilibrium between the synthesis and degradation of osteoarthritic joint cartilage can be a useful strategy for effectively managing osteoarthritis. In this review, we provide an overview of the research results pertaining to the search for a novel candidate agent for osteoarthritis management via restoration of the equilibrium between cartilage synthesis and degradation. We especially focused on investigations of medicinal plants and natural products derived from them to shed light on the potential pharmacotherapy of osteoarthritis.

2Role of Helix 8 in Dopamine Receptor Signaling

저자 : Han-sol Yang , Ningning Sun , Xiaodi Zhao , Hee Ryung Kim , Hyun-ju Park , Kyeong-man Kim , Ka Young Chung

발행기관 : 한국응용약물학회 간행물 : Biomolecules & Therapeutics(구 응용약물학회지) 27권 6호 발행 연도 : 2019 페이지 : pp. 514-521 (8 pages)

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G protein-coupled receptors (GPCRs) are membrane receptors whose agonist-induced dynamic conformational changes trigger heterotrimeric G protein activation, followed by GRK-mediated phosphorylation and arrestin-mediated desensitization. Cytosolic regions of GPCRs have been studied extensively because they are direct contact sites with G proteins, GRKs, and arrestins. Among various cytosolic regions, the role of helix 8 is least understood, although a few studies have suggested that it is involved in G protein activation, receptor localization, and/or internalization. In the present study, we investigated the role of helix 8 in dopamine receptor signaling focusing on dopamine D1 receptor (D1R) and dopamine D2 receptor (D2R). D1R couples exclusively to Gs, whereas D2R couples exclusively to Gi. Bioinformatic analysis implied that the sequences of helix 8 may affect GPCR-G protein coupling selectivity; therefore, we evaluated if swapping helix 8 between D1R and D2R changed G protein selectivity. Our results suggest that helix 8 is not involved in D1R-Gs or D2R-Gi coupling selectivity. Instead, we observed that D1R with D2R helix 8 or D1R with an increased number of hydrophobic residues in helix 8 relative to wild-type showed diminished β-arrestin-mediated desensitization, resulting in increased Gs signaling.

3S1P1 Regulates M1/M2 Polarization toward Brain Injury after Transient Focal Cerebral Ischemia

저자 : Bhakta Prasad Gaire , Young Joo Bae , Ji Woong Choi

발행기관 : 한국응용약물학회 간행물 : Biomolecules & Therapeutics(구 응용약물학회지) 27권 6호 발행 연도 : 2019 페이지 : pp. 522-529 (8 pages)

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M1/M2 polarization of immune cells including microglia has been well characterized. It mediates detrimental or beneficial roles in neuroinflammatory disorders including cerebral ischemia. We have previously found that sphingosine 1-phospate receptor subtype 1 (S1P1) in post-ischemic brain following transient middle cerebral artery occlusion (tMCAO) can trigger microglial activation, leading to brain damage. Although the link between S1P1 and microglial activation as a pathogenesis in cerebral ischemia had been clearly demonstrated, whether the pathogenic role of S1P1 is associated with its regulation of M1/M2 polarization remains unclear. Thus, this study aimed to determine whether S1P1 was associated with regulation of M1/M2 polarization in post-ischemic brain. Suppressing S1P1 activity with its functional antagonist, AUY954 (5 mg/kg, p.o.), attenuated mRNA upregulation of M1 polarization markers in post-ischemic brain at 1 day and 3 days after tMCAO challenge. Similarly, suppressing S1P1 activity with AUY954 administration inhibited M1-polarizatioin-relevant NF-κB activation in post-ischemic brain. Particularly, NF-κB activation was observed in activated microglia of post-ischemic brain and markedly attenuated by AUY954, indicating that M1 polarization through S1P1 in post-ischemic brain mainly occurred in activated microglia. Suppressing S1P1 activity with AUY954 also increased mRNA expression levels of M2 polarization markers in post-ischemic brain, further indicating that S1P1 could also influence M2 polarization in post-ischemic brain. Finally, suppressing S1P1 activity decreased phosphorylation of M1-relevant ERK1/2, p38, and JNK MAPKs, but increased phosphorylation of M2-relevant Akt, all of which were downstream pathways following S1P1 activation. Overall, these results revealed S1P1-regulated M1/M2 polarization toward brain damage as a pathogenesis of cerebral ischemia.

4Etoposide Induces Mitochondrial Dysfunction and Cellular Senescence in Primary Cultured Rat Astrocytes

저자 : Minji Bang , Do Gyeong Kim , Edson Luck Gonzales , Kyoung Ja Kwon , Chan Young Shin

발행기관 : 한국응용약물학회 간행물 : Biomolecules & Therapeutics(구 응용약물학회지) 27권 6호 발행 연도 : 2019 페이지 : pp. 530-539 (10 pages)

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Brain aging is an inevitable process characterized by structural and functional changes and is a major risk factor for neurodegenerative diseases. Most brain aging studies are focused on neurons and less on astrocytes which are the most abundant cells in the brain known to be in charge of various functions including the maintenance of brain physical formation, ion homeostasis, and secretion of various extracellular matrix proteins. Altered mitochondrial dynamics, defective mitophagy or mitochondrial damages are causative factors of mitochondrial dysfunction, which is linked to age-related disorders. Etoposide is an anti-cancer reagent which can induce DNA stress and cellular senescence of cancer cell lines. In this study, we investigated whether etoposide induces senescence and functional alterations in cultured rat astrocytes. Senescence-associated β-galactosidase (SA-β-gal) activity was used as a cellular senescence marker. The results indicated that etoposide-treated astrocytes showed cellular senescence phenotypes including increased SA-β-gal-positive cells number, increased nuclear size and increased senescence-associated secretory phenotypes (SASP) such as IL-6. We also observed a decreased expression of cell cycle markers, including Phospho- Histone H3/Histone H3 and CDK2, and dysregulation of cellular functions based on wound-healing, neuronal protection, and phagocytosis assays. Finally, mitochondrial dysfunction was noted through the determination of mitochondrial membrane potential using tetramethylrhodamine methyl ester (TMRM) and the measurement of mitochondrial oxygen consumption rate (OCR). These data suggest that etoposide can induce cellular senescence and mitochondrial dysfunction in astrocytes which may have implications in brain aging and neurodegenerative conditions.

5Alyssin and Iberin in Cruciferous Vegetables Exert Anticancer Activity in HepG2 by Increasing Intracellular Reactive Oxygen Species and Tubulin Depolymerization

저자 : Piman Pocasap , Natthida Weerapreeyakul , Kanjana Thumanu

발행기관 : 한국응용약물학회 간행물 : Biomolecules & Therapeutics(구 응용약물학회지) 27권 6호 발행 연도 : 2019 페이지 : pp. 540-552 (13 pages)

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To determine the chemopreventive potential of alyssin and iberin, the in vitro anticancer activities and molecular targets of isothiocyanates (ITCs) were measured and compared to sulforaphane in hepatocellular carcinoma cell HepG2. The SR-FTIR spectra observed a similar pattern vis-à-vis the biomolecular alteration amongst the ITCs-treated cells suggesting a similar mode of action. All of the ITCs in this study cause cancer cell death through both apoptosis and necrosis in concentration dependent manner (20-80 µM). We found no interactions of any of the ITCs studied with DNA. Notwithstanding, all of the ITCs studied increased intracellular reactive oxygen species (ROS) and suppressed tubulin polymerization, which led to cell-cycle arrest in the S and G2/M phase. Alyssin possessed the most potent anticancer ability; possibly due to its ability to increase intracellular ROS rather than tubulin depolymerization. Nevertheless, the structural influence of alkyl chain length on anticancer capabilities of ITCs remains inconclusive. The results of this study indicate an optional, potent ITC (viz., alyssin) because of its underlying mechanisms against hepatic cancer. As a consequence, further selection and development of effective chemotherapeutic ITCs is recommended.

6Rab25 Deficiency Perturbs Epidermal Differentiation and Skin Barrier Function in Mice

저자 : Haengdueng Jeong , Kyung-min Lim , James R Goldenring , Ki Taek Nam

발행기관 : 한국응용약물학회 간행물 : Biomolecules & Therapeutics(구 응용약물학회지) 27권 6호 발행 연도 : 2019 페이지 : pp. 553-561 (9 pages)

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Rab25, a member of the Rab11 small GTPase family, is central to achieving cellular polarity in epithelial tissues. Rab25 is highly expressed in epithelial cells of various tissues including breast, vagina, cervix, the gastrointestinal tract, and skin. Rab25 plays key roles in tumorigenesis, mainly by regulating epithelial differentiation and proliferation. However, its role in skin physiology is relatively unknown. In this study, we demonstrated that Rab25 knock-out (KO) mice show a skin barrier dysfunction with high trans-epidermal water loss and low cutaneous hydration. To examine this observation, we investigated the histology and epidermal differentiation markers of the skin in Rab25 KO mice. Rab25 KO increased cell proliferation at the basal layer of epidermis, whereas the supra-basal layer remained unaffected. Ceramide, which is a critical lipid component for skin barrier function, was not altered by Rab25 KO in its distribution or amount, as determined by immunohistochemistry. Notably, levels of epidermal differentiation markers, including loricrin, involucrin, and keratins (5, 14, 1, and 10) increased prominently in Rab25 KO mice. In line with this, depletion of Rab25 with single hairpin RNA increased the expression of differentiation markers in a human keratinocyte cell line, HaCaT. Transcriptomic analysis of the skin revealed increased expression of genes associated with skin development, epidermal development, and keratinocyte differentiation in Rab25 KO mice. Collectively, these results suggested that Rab25 is involved in the regulation of epidermal differentiation and proliferation.

7Niacinamide Protects Skin Cells from Oxidative Stress Induced by Particulate Matter

저자 : Ao Xuan Zhen , Mei Jing Piao , Kyoung Ah Kang , Pincha Devage Sameera Madushan Fernando , Hee Kyoung Kang , Young Sang Koh , Joo Mi Yi , Jin Won Hyun

발행기관 : 한국응용약물학회 간행물 : Biomolecules & Therapeutics(구 응용약물학회지) 27권 6호 발행 연도 : 2019 페이지 : pp. 562-569 (8 pages)

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Niacinamide (NIA) is a water-soluble vitamin that is widely used in the treatment of skin diseases. Moreover, NIA displays antioxidant effects and helps repair damaged DNA. Recent studies showed that particulate matter 2.5 (PM2.5) induced reactive oxygen species (ROS), causing disruption of DNA, lipids, and protein, mitochondrial depolarization, and apoptosis of skin keratinocytes. Here, we investigated the protective effects of NIA on PM2.5-induced oxidative stress in human HaCaT keratinocytes. We found that NIA could inhibit the ROS generation induced by PM2.5, as well block the PM2.5-induced oxidation of molecules, such as lipids, proteins, and DNA. Furthermore, NIA alleviated PM2.5-induced accumulation of cellular Ca2+, which caused cell membrane depolarization and apoptosis, and reduced the number of apoptotic cells. Collectively, the findings show that NIA can protect keratinocytes from PM2.5-induced oxidative stress and cell damage.

8Particulate Matter-Induced Aryl Hydrocarbon Receptor Regulates Autophagy in Keratinocytes

저자 : Hye Sung Jang , Ji Eun Lee , Cheol Hwan Myung , Jong Il Park , Chan Song Jo , Jae Sung Hwang

발행기관 : 한국응용약물학회 간행물 : Biomolecules & Therapeutics(구 응용약물학회지) 27권 6호 발행 연도 : 2019 페이지 : pp. 570-576 (7 pages)

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Particulate matter (PM), which refers to the mixture of particles present in the air, can have harmful effects. Damage to cells by PM, including disruption of organelles and proteins, can trigger autophagy, and the relationship between autophagy and PM has been well studied. However, the cellular regulators of PM-induced autophagy have not been well characterized, especially in keratinocytes. The Aryl Hydrocarbon Receptor (AhR) is expressed in the epidermis and is activated by PM. In this study, we investigated the role of the AhR in PM-induced autophagy in HaCaT cells. Our results showed that PM led to AhR activation in keratinocytes. Activation of the AhR-target gene CYP1A1 by PM was reduced by co-treatment with α-naphthoflavone (α-NF), an AhR inhibitor. We also evaluated activation of the autophagy pathway in PM-treated keratinocytes. In HaCaT cells, treatment with PM treatment led to the induction of microtubules-associated proteins light chain 3 (LC3) and p62/SQSTM1, which are essential components of the autophagy pathway. To study the role of the AhR in mediating PM-induced autophagy, we treated cells with α-NF or used an siRNA against AhR. Expression of LC3-∥ induced by PM was decreased in a dose dependent manner by α-NF. Furthermore, knockdown of AhR with siAhR diminished PM-induced expression of LC3-∥ and p62. Together, these results suggest that inhibition of the AhR decreases PM-induced autophagy. We confirmed these results using the autophagy-inhibitors BAF and 3-MA. Taken together, our results indicate that exposure to PM induces autophagy via the AhR in HaCaT keratinocytes.

9Functional Characterization of Pharmcogenetic Variants of Human Cytochrome P450 2C9 in Korean Populations

저자 : Myung-a Cho , Jihoon G Yoon , Vitchan Kim , Harim Kim , Rowoon Lee , Min Goo Lee , Donghak Kim

발행기관 : 한국응용약물학회 간행물 : Biomolecules & Therapeutics(구 응용약물학회지) 27권 6호 발행 연도 : 2019 페이지 : pp. 577-583 (7 pages)

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Human cytochrome P450 2C9 is a highly polymorphic enzyme that is required for drug and xenobiotic metabolism. Here, we studied eleven P450 2C9 genetic variants―including three novel variants F69S, L310V, and Q324X―that were clinically identified in Korean patients. P450 2C9 variant enzymes were expressed in Escherichia coli and their bicistronic membrane fractions were prepared The CO-binding spectra were obtained for nine enzyme variants, indicating P450 holoenzymes, but not for the M02 (L90P) variant. The M11 (Q324X) variant could not be expressed due to an early nonsense mutation. LC-MS/MS analysis was performed to measure the catalytic activities of the P450 2C9 variants, using diclofenac as a substrate. Steady-state kinetic analysis revealed that the catalytic efficiency of all nine P450 2C9 variants was lower than that of the wild type P450 2C9 enzyme. The M05 (R150L) and M06 (P279T) variants showed high kcat values; however, their Km values were also high. As the M01 (F69S), M03 (R124Q), M04 (R125H), M08 (I359L), M09 (I359T), and M10 (A477T) variants exhibited higher Km and lower kcat values than that of the wild type enzyme, their catalytic efficiency decreased by approximately 50-fold compared to the wild type enzyme. Furthermore, the novel variant M07 (L310V) showed lower kcat and Km values than the wild type enzyme, which resulted in its decreased (80%) catalytic efficiency. The X-ray crystal structure of P450 2C9 revealed the presence of mutations in the residues surrounding the substrate-binding cavity. Functional characterization of these genetic variants can help understand the pharmacogenetic outcomes.

10Sleep Promoting Effect of Luteolin in Mice via Adenosine A1 and A2A Receptors

저자 : Tae-ho Kim , Raly James Custodio , Jae Hoon Cheong , Hee Jin Kim , Yi-sook Jung

발행기관 : 한국응용약물학회 간행물 : Biomolecules & Therapeutics(구 응용약물학회지) 27권 6호 발행 연도 : 2019 페이지 : pp. 584-590 (7 pages)

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Luteolin, a widespread flavonoid, has been known to have neuroprotective activity against various neurologic diseases such as epilepsy, and Alzheimer's disease. However, little information is available regarding the hypnotic effect of luteolin. In this study, we evaluated the hypnotic effect of luteolin and its underlying mechanism. In pentobarbital-induced sleeping mice model, luteolin (1, and 3 mg/kg, p.o.) decreased sleep latency and increased the total sleep time. Through electroencephalogram (EEG) and electromyogram (EMG) recording, we demonstrated that luteolin increased non-rapid eye movement (NREM) sleep time and decreased wake time. To evaluate the underlying mechanism, we examined the effects of various pharmacological antagonists on the hypnotic effect of luteolin. The hypnotic effect of 3 mg/kg of luteolin was not affected by flumazenil, a GABAA receptorbenzodiazepine (GABAAR-BDZ) binding site antagonist, and bicuculine, a GABAAR-GABA binding site antagonist. On the other hand, the hypnotic effect of 3 mg/kg of luteolin was almost completely blocked by caffeine, an antagonist for both adenosine A1 and A2A receptor (A1R and A2AR), 8-Cyclopentyl-1,3-dipropylxanthine (DPCPX), an A1R antagonist, and SCH-58261, an A2AR antagonist. From the binding affinity assay, we have found that luteolin significantly binds to not only A1R but also A2AR with IC50 of 1.19, 0.84 µg/kg, respectively. However, luteolin did not bind to either BDZ-receptor or GABAAR. From these results, it has been suggested that luteolin has hypnotic efficacy through A1R and A2AR binding.

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