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한국응용약물학회> Biomolecules & Therapeutics(구 응용약물학회지)> Betulin Targets Lipin1/2-Meidated P2X7 Receptor as a Therapeutic Approach to Attenuate Lipid Accumulation and Metaflammation

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Betulin Targets Lipin1/2-Meidated P2X7 Receptor as a Therapeutic Approach to Attenuate Lipid Accumulation and Metaflammation

Jia-yi Dou , Yu-chen Jiang , Zhong-he Hu , Kun-chen Yao , Ming-hui Yuan , Xiao-xue Bao , Mei-jie Zhou , Yue Liu , Zhao-xu Li , Li-hua Lian , Ji-xing Nan , Yan-ling Wu
  • : 한국응용약물학회
  • : Biomolecules & Therapeutics(구 응용약물학회지) 30권3호
  • : 연속간행물
  • : 2022년 05월
  • : 246-256(11pages)
Biomolecules & Therapeutics(구 응용약물학회지)

DOI


목차

INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
CONFLICT OF INTEREST
ACKNOWLEDGMENTS
REFERENCES

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The present study focused on the potential mechanism of betulin (BT), a pentacyclic triterpenoid isolated from the bark of white birch (Betula pubescens), against chronic alcohol-induced lipid accumulation and metaflammation. AML-12 and RAW 264.7 cells were administered ethanol (EtOH), lipopolysaccharide (LPS) or BT. Male C57BL/6 mice were fed Lieber-DeCarli liquid diets containing 5% EtOH for 4 weeks, followed by single EtOH gavage on the last day and simultaneous treatment with BT (20 or 50 mg/kg) by oral gavage once per day. In vitro, MTT showed that 0-25 mM EtOH and 0-25 μM BT had no toxic effect on AML-12 cells. BT could regulate sterolregulatory-element-binding protein 1 (SREBP1), lipin1/2, P2X7 receptor (P2X7r) and NOD-like receptor family, pyrin domains-containing protein 3 (NLRP3) expressions again EtOH-stimulation. Oil Red O staining also indicated that BT significantly reduced lipid accumulation in EtOH-stimulated AML-12 cells. Lipin1/2 deficiency indicated that BT might mediate lipin1/2 to regulate SREBP1 and P2X7r expression and further alleviate lipid accumulation and inflammation. In vivo, BT significantly alleviated histopathological changes, reduced serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and triglyceride (TG) levels, and regulated lipin1/2, SREBP1, peroxisome proliferator activated receptor α/γ (PPARα/γ) and PGC-1α expression compared with the EtOH group. BT reduced the secretion of inflammatory factors and blocked the P2X7r-NLRP3 signaling pathway. Collectively, BT attenuated lipid accumulation and metaflammation by regulating the lipin1/2-mediated P2X7r signaling pathway.

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간행물정보

  • : 의약학분야  > 약화학
  • : KCI등재
  • : SCOPUS
  • : 격월
  • : 1976-9148
  • : 2005-4483
  • : 학술지
  • : 연속간행물
  • : 1993-2022
  • : 1827


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1Modulation of Reactive Oxygen Species to Overcome 5-Fluorouracil Resistance

저자 : Kyung-soo Chun , Sang Hoon Joo

발행기관 : 한국응용약물학회 간행물 : Biomolecules & Therapeutics(구 응용약물학회지) 30권 6호 발행 연도 : 2022 페이지 : pp. 479-489 (11 pages)

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5-Fluorouracil (5-FU) remains to be an important chemotherapeutic drug for treating several cancers when targeted therapy is unavailable. Chemoresistance limits the clinical utility of 5-FU, and new strategies are required to overcome the resistance. Reactive oxygen species (ROS) and antioxidants are balanced differently in both normal and cancer cells. Modulating ROS can be one method of overcoming 5-FU resistance. This review summarizes selected compounds and endogenous cellular targets modulating ROS generation to overcome 5-FU resistance.

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2Senotherapeutics and Their Molecular Mechanism for Improving Aging

저자 : Jooho Park , Dong Wook Shin

발행기관 : 한국응용약물학회 간행물 : Biomolecules & Therapeutics(구 응용약물학회지) 30권 6호 발행 연도 : 2022 페이지 : pp. 490-500 (11 pages)

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Aging is defined as physiological dysfunction of the body and a key risk factor for human diseases. During the aging process, cellular senescence occurs in response to various extrinsic and intrinsic factors such as radiation-induced DNA damage, the activation of oncogenes, and oxidative stress. These senescent cells accumulate in many tissues and exhibit diverse phenotypes, such as resistance to apoptosis, production of senescence-associated secretory phenotype, cellular flattening, and cellular hypertrophy. They also induce abnormal dysfunction of the microenvironment and damage neighboring cells, eventually causing harmful effects in the development of various chronic diseases such as diabetes, cancer, and neurodegenerative diseases. Thus, pharmacological interventions targeting senescent cells, called senotherapeutics, have been extensively studied. These senotherapeutics provide a novel strategy for extending the health span and improving age-related diseases. In this review, we discuss the current progress in understanding the molecular mechanisms of senotherapeutics and provide insights for developing senotherapeutics.

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3p38 MAPK Inhibitor NJK14047 Suppresses CDNB-Induced Atopic Dermatitis-Like Symptoms in BALB/c Mice

저자 : Ju-hyun Lee , Seung-hwan Son , Nam-jung Kim , Dong-soon Im

발행기관 : 한국응용약물학회 간행물 : Biomolecules & Therapeutics(구 응용약물학회지) 30권 6호 발행 연도 : 2022 페이지 : pp. 501-509 (9 pages)

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Atopic dermatitis (AD) is a chronic inflammatory skin disorder. Suppression of MAPKs and NF-κB is implicated as a vital mechanism of action of several traditional Chinese medicines for AD therapy. Although overexpression of MAPK mRNA in the skin tissue has been shown in the AD model, the roles of each MAPK in AD pathogenesis have rarely been studied. This study examined the effect of NJK14047, an inhibitor of p38 MAPKs, on AD-like skin lesions induced in BALB/c mice by sensitization and challenges with 1-chloro-2,4-dinitrobenzene (CDNB) on dorsal skin and ears, respectively. After induction of AD, NJK14047 (2.5 mg/kg) or dexamethasone (10 mg/kg) was administrated for 3 weeks via intraperitoneal injection. Following its administration, NJK14047 suppressed CDNB-induced AD-like symptoms such as skin hypertrophy and suppressed mast cell infiltration into the skin lesions. It also reduced CDNB-induced increase in TH2 cytokine (IL-13) and TH1 cytokines (interferon-γ and IL-12A) levels but did not decrease serum IgE level. Furthermore, NJK14047 blocked CDNB-induced lymph node enlargement. These results suggest that NJK14047, a p38 MAPK inhibitor, might be an optimal therapeutic option with unique modes of action for AD treatment.

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4Effects of Dextran Sulfate Sodium-Induced Ulcerative Colitis on the Disposition of Tofacitinib in Rats

저자 : Sung Hun Bae , Hyo Sung Kim , Hyeon Gyeom Choi , Sun-young Chang , So Hee Kim

발행기관 : 한국응용약물학회 간행물 : Biomolecules & Therapeutics(구 응용약물학회지) 30권 6호 발행 연도 : 2022 페이지 : pp. 510-519 (10 pages)

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Tofacitinib, a Janus kinase 1 and 3 inhibitor, is mainly metabolized by CYP3A1/2 and CYP2C11 in the liver. The drug has been approved for the chronic treatment of severe ulcerative colitis, a chronic inflammatory bowel disease. This study investigated the pharmacokinetics of tofacitinib in rats with dextran sulfate sodium (DSS)-induced ulcerative colitis. After 1-min of intravenous infusion of tofacitinib (10 mg/kg), the area under the plasma concentration-time curves from time zero to time infinity (AUC) of tofacitinib significantly increased by 92.3%. The time-averaged total body clearance decreased significantly by 47.7% in DSS rats compared with control rats. After the oral administration of tofacitinib (20 mg/kg), the AUC increased by 85.5% in DSS rats. These results could be due to decreased intrinsic clearance of the drug caused by the reduction of CYP3A1/2 and CYP2C11 in the liver and intestine of DSS rats. In conclusion, ulcerative colitis inhibited CYP3A1/2 and CYP2C11 in the liver and intestines of DSS rats and slowed the metabolism of tofacitinib, resulting in increased plasma concentrations of tofacitinib in DSS rats.

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5AT9283, 1-Cyclopropyl-3-(3-(5-(Morpholinomethyl)-1H-Benzo[d] Imidazole-2-yl)-1H-Pyrazol-4-yl) Urea, Inhibits Syk to Suppress Mast Cell-Mediated Allergic Response

저자 : Su Jeong Kim , Min Yeong Choi , Keun Young Min , Min Geun Jo , Jie Min Kim , Hyung Sik Kim , Young Mi Kim

발행기관 : 한국응용약물학회 간행물 : Biomolecules & Therapeutics(구 응용약물학회지) 30권 6호 발행 연도 : 2022 페이지 : pp. 520-528 (9 pages)

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Mast cells are an effector cell that plays a pivotal role in type I hypersensitive immune responses. Mast cells exist in connective tissues, such as skin and mucosal tissue, and contain granules which contain bioactive substances such as histamine and heparin in cells. The granules of mast cells are secreted by antigen stimulation to cause the type I allergic hypersensitivity. In addition, stimulated by antigen, mast cells synthesize and secrete various eicosanoids and cytokines. While AT9283 is known to have anticancer effects, the therapeutic effect of AT9283 on allergic disorders is completely unknown. In this study, it was found that AT9283 reversibly inhibited antigen-IgE binding-induced degranulation in mast cells (IC50, approx. 0.58 μM) and suppressed the secretion of the inflammatory cytokines IL-4 (IC50, approx. 0.09 μM) and TNF-α (IC50, approx. 0.19 μM). For a mechanism of mast cell inhibition, while not inhibiting Syk phosphorylation, AT9283 suppressed the activation of LAT, a downstream substrate protein of Syk, in a dose-dependent manner. As expected, AT9283 also inhibited the activation of PLCγ1 and Akt, downstream signaling molecules of Syk/LAT, and MAP kinases such as JNK, Erk1/2, and P38. In an in vitro protein tyrosine kinase assay, AT9283 directly inhibited Syk activity. Next, AT9283 dose-dependently inhibited passive cutaneous anaphylaxis (PCA), an IgE-mediated allergic acute response, in mice (ED50, approx. 34 mg/kg, p.o.). These findings suggest that AT9283 has potential to use as a new drug for alleviating the symptoms of IgE-mediated allergic disorders.

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6A Novel Therapeutic Effect of a New Variant of CTLA4-Ig with Four Antennas That Are Terminally Capped with Sialic Acid in the CTLA4 Region

저자 : Yongwei Piao , So Yoon Yun , Hee Soo Kim , Bo Kyung Park , Hae Chan Ha , Zhicheng Fu , Ji Min Jang , Moon Jung Back , In Chul Shin , Jong Hoon Won , Dae Kyong Kim

발행기관 : 한국응용약물학회 간행물 : Biomolecules & Therapeutics(구 응용약물학회지) 30권 6호 발행 연도 : 2022 페이지 : pp. 529-539 (11 pages)

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Rheumatoid arthritis (RA) is a multifactorial immune-mediated disease, the pathogenesis of which involves different cell types. T-cell activation plays an important role in RA. Therefore, inhibiting T-cell activation is one of the current therapeutic strategies. Cytotoxic T-lymphocyte antigen 4-immunoglobulin (CTLA4-Ig), also known as abatacept, reduces cytokine secretion by inhibiting T-cell activation. To achieve a homeostatic therapeutic effect, CTLA4-Ig has to be administered repeatedly over several weeks, which limits its applicability in RA treatment. To overcome this limitation, we increased the number of sialic acid-capped antennas by genetically engineering the CTLA4 region to increase the therapeutic effect of CTLA4-Ig. N-acetylglucosaminyltransferase (GnT) and α2,6-sialyltransferase (α2,6-ST) were co-overexpressed in Chinese hamster ovary (CHO) cells to generate a highly sialylated CTLA4-Ig fusion protein, named ST6. The therapeutic and immunogenic effects of ST6 and CTLA4-Ig were compared. ST6 dose-dependently decreased paw edema in a mouse model of collagen-induced arthritis and reduced cytokine levels in a co-culture cell assay in a similar manner to CTLA4-Ig. ST6- and CTLA4-Ig-induced T cell-derived cytokines were examined in CD4 T cells isolated from peripheral blood mononuclear cells after cell killing through irradiation followed by flow- and magnetic-beadassisted separation. Interestingly, compared to CTLA4-Ig, ST6 was substantially less immunogenic and more stable and durable. Our data suggest that ST6 can serve as a novel, less immunogenic therapeutic strategy for patients with RA.

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7Betulin, an Anti-Inflammatory Triterpenoid Compound, Regulates MUC5AC Mucin Gene Expression through NF-kB Signaling in Human Airway Epithelial Cells

저자 : Rajib Hossain , Kyung-il Kim , Fengri Jin , Hyun Jae Lee , Choong Jae Lee

발행기관 : 한국응용약물학회 간행물 : Biomolecules & Therapeutics(구 응용약물학회지) 30권 6호 발행 연도 : 2022 페이지 : pp. 540-545 (6 pages)

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Betulin is a triterpenoid natural product contained in several medicinal plants including Betulae Cortex. These medicinal plants have been used for controlling diverse inflammatory diseases in folk medicine and betulin showed anti-inflammatory, antioxidative, and anticancer activities. In this study, we tried to examine whether betulin exerts a regulative effect on the gene expression of MUC5AC mucin under the status simulating a pulmonary inflammation, in human airway epithelial cells. Confluent NCI-H292 cells were pretreated with betulin for 30 min and then stimulated with phorbol 12-myristate 13-acetate (PMA) for 24 h or the indicated periods. The MUC5AC mucin mRNA expression and mucin glycoprotein production were measured by reverse transcription - polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA), respectively. To elucidate the action mechanism of betulin, effect of betulin on PMA-induced nuclear factor kappa B (NF-kB) signaling pathway was also investigated by western blot analysis. The results were as follows: 1) Betulin significantly suppressed the production of MUC5AC mucin glycoprotein and down-regulated MUC5AC mRNA expression induced by PMA in NCI-H292 cells. 2) Betulin inhibited NF-κB activation stimulated by PMA. Suppression of inhibitory kappa B kinase (IKK) by betulin led to the inhibition of the phosphorylation and degradation of inhibitory kappa B alpha (IκBα), and the nuclear translocation of NF-κB p65. This, in turn, led to the down-regulation of MUC5AC glycoprotein production in NCI-H292 cells. These results suggest betulin inhibits the gene expression of mucin through regulation of NF-kB signaling pathway, in human airway epithelial cells.

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8Immune Responses to Plant-Derived Recombinant Colorectal Cancer Glycoprotein EpCAM-FcK Fusion Protein in Mice

저자 : Chae-yeon Lim , Deuk-su Kim , Yangjoo Kang , Ye-rin Lee , Kibum Kim , Do Sun Kim , Moon-soo Kim , Kisung Ko

발행기관 : 한국응용약물학회 간행물 : Biomolecules & Therapeutics(구 응용약물학회지) 30권 6호 발행 연도 : 2022 페이지 : pp. 546-552 (7 pages)

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Epidermal cell adhesion molecule (EpCAM) is a tumor-associated antigen (TAA), which has been considered as a cancer vaccine candidate. The EpCAM protein fused to the fragment crystallizable region of immunoglobulin G (IgG) tagged with KDEL endoplasmic reticulum (ER) retention signal (EpCAM-FcK) has been successfully expressed in transgenic tobacco (Nicotiana tabacum cv. Xanthi) and purified from the plant leaf. In this study, we investigated the ability of the plant-derived EpCAM-FcK (EpCAM-FcKP) to elicit an immune response in vivo. The animal group injected with the EpCAM-FcKP showed a higher differentiated germinal center (GC) B cell population (~9%) compared with the animal group injected with the recombinant rhEpCAM-Fc chimera (EpCAM-FcM). The animal group injected with EpCAM-FcKP (~42%) had more differentiated T follicular helper cells (Tfh) than the animal group injected with EpCAM-FcM (~7%). This study demonstrated that the plant-derived EpCAM-FcK fusion antigenic protein induced a humoral immune response in mice.

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9Growth Inhibitory and Pro-Apoptotic Effects of Hirsuteine in Chronic Myeloid Leukemia Cells through Targeting Sphingosine Kinase 1

저자 : Shan Gao , Tingting Guo , Shuyu Luo , Yan Zhang , Zehao Ren , Xiaona Lang , Gaoyong Hu , Duo Zuo , Wenqing Jia , Dexin Kong , Haiyang Yu , Yuling Qiu

발행기관 : 한국응용약물학회 간행물 : Biomolecules & Therapeutics(구 응용약물학회지) 30권 6호 발행 연도 : 2022 페이지 : pp. 553-566 (14 pages)

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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.

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10Clinical Factors Affecting the Serum Retention of a Teratogenic Etretinate after the Acitretin Administration

저자 : Jong Heon Jeong , Gyu Hwan Hyun , Yu Jeong Park , Sung Won Kwon , Ai-young Lee

발행기관 : 한국응용약물학회 간행물 : Biomolecules & Therapeutics(구 응용약물학회지) 30권 6호 발행 연도 : 2022 페이지 : pp. 562-573 (12 pages)

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Etretinate, an acitretin metabolite, has a long retention duration in adipose tissues with a teratogenic potential. FDA advises a contraceptive period of at least three years after discontinuing acitretin. However, the effect of accumulated etretinate in adipose tissues on fetus is unknown. Although the teratogenic threshold for serum concentration of etretinate has been presented as higher than 2 ng/mL, that of acitretin is unknown. To examine factors affecting body retention of acitretin and etretinate, effects of acitretin dosage, acitretin-taking duration, elapsed time after stopping acitretin, age, sex, concomitant alcohol consumption, and foods and supplements rich in vitamin A intake on serum concentrations of acitretin and etretinate were analyzed in 14 acitretintaken patients and 58 controls without taking acitretin or etretinate. Serum concentrations of acitretin, but not etretinate, tended to be inversely related to the discontinuation duration. They were also related to old age. Different from a published result that alcohol consumption could promote the metabolism of acitretin into etretinate, alcohol intake did not affect serum concentrations of etretinate. Unexpectedly, more frequent intake of vitamin A or provitamin A-rich food and supplements was associated with higher serum acitretin, whereas less frequent intake of vitamin A or provitamin A-rich food and supplements was associated with higher serum levels of etretinate in acitretin-taken patients. Despite preliminary data, inter-individual variations in serum retention of etretinate suggest the necessity of further research before applying the same guidelines to everyone to minimize unnecessary contraception.

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1Epithelial-Mesenchymal Transition-Inducing Factors Involved in the Progression of Lung Cancers

저자 : Min-woo Nam , Cho-won Kim , Kyung-chul Choi

발행기관 : 한국응용약물학회 간행물 : Biomolecules & Therapeutics(구 응용약물학회지) 30권 3호 발행 연도 : 2022 페이지 : pp. 213-220 (8 pages)

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Although there have been advances in cancer therapy and surgical improvement, lung cancer has the lowest survival rate (19%) at all stages. This is because most patients are diagnosed with concurrent metastasis, which occurs due to numerous related reasons. Especially, lung cancer is one of the most common and malignant cancers in the world. Although there are advanced therapeutic strategies, lung cancer remains one of the main causes of cancer death. Recent work has proposed that epithelial-mesenchymal transition (EMT) is the main cause of metastasis in most cases of human cancers including lung cancer. EMT involves the conversion of epithelial cells, wherein the cells lose their epithelial abilities and become mesenchymal cells involved in embryonic development, such as gastrulation and neural crest formation. In addition, recent research has indicated that EMT contributes to altering the cancer cells into cancer stem cells (CSCs). Although EMT is important in the developmental stages, this process also activates lung cancer progression, including complicated and diverse signaling pathways. Despite the numerous investigations on signaling pathways involved in the progression of lung cancer, this malignancy is considered critical for treatment. EMT in lung cancer involves many transcription factors and inducers, for example, Snail, TWIST, and ZEB are the master regulators of EMT. EMT-related factors and signaling pathways are involved in the progression of lung cancer, proposing new approaches to lung cancer therapy. In the current review, we highlight the signaling pathways implicated in lung cancer and elucidate the correlation of these pathways, indicating new insights to treat lung cancer and other malignancies.

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2The Role of Adiponectin in the Skin

저자 : Jieun Oh , Yeongyeong Lee , Sae-woong Oh , Tiantian Li , Jiwon Shin , See-hyoung Park , Jongsung Lee

발행기관 : 한국응용약물학회 간행물 : Biomolecules & Therapeutics(구 응용약물학회지) 30권 3호 발행 연도 : 2022 페이지 : pp. 221-231 (11 pages)

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Adiponectin (Ad), a 30 kDa molecule, is an anti-diabetic adipokine; although derived from adipose tissue, it performs numerous activities in various other tissues. It binds to its own receptors, namely adiponectin receptor 1(AdipoR1), adiponectin receptor 2 (AdipoR2), and T-cadherin (CDH13). Ad plays several roles, especially as a regulator. It modulates lipid and glucose metabolism and promotes insulin sensitivity. This demonstrates that Ad has a robust correlation with fat metabolism. Furthermore, although Ad is not in direct contact with other tissues, including the skin, it can be delivered to them by diffusion or secretion via the endocrine system. Recently it has been reported that Ad can impact skin cell biology, underscoring its potential as a therapeutic biomarker of skin diseases. In the present review, we have discussed the association between skin cell biology and Ad. To elaborate further, we described the involvement of Ad in the biology of various types of cells in the skin, such as keratinocytes, fibroblasts, melanocytes, and immune cells. Additionally, we postulated that Ad could be employed as a therapeutic target to maintain skin homeostasis.

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3Autism-Like Behavioral Phenotypes in Mice Treated with Systemic N-Methyl-D-Aspartate

저자 : Keremkleroo Jym Adil , Edson Luck Gonzales , Chilly Gay Remonde , Kyung-jun Boo , Se Jin Jeon , Chan Young Shin

발행기관 : 한국응용약물학회 간행물 : Biomolecules & Therapeutics(구 응용약물학회지) 30권 3호 발행 연도 : 2022 페이지 : pp. 232-237 (6 pages)

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Autism spectrum disorder (ASD) having core characteristics of social interaction problems and repetitive behaviors and interests affects individuals at varying degrees and comorbidities, making it difficult to determine the precise etiology underlying the symptoms. Given its heterogeneity, ASD is difficult to treat and the development of therapeutics is slow due to the scarcity of animal models that are easy to produce and screen with. Based on the theory of excitation/inhibition imbalance in the brain with ASD which involves glutamatergic and/or GABAergic neurotransmission, a pharmacologic agent to modulate these receptors might be a good starting point for modeling. N-methyl-D-aspartic acid (NMDA) is an amino acid derivative acting as a specific agonist at the NMDA receptor and therefore imitates the action of the neurotransmitter glutamate on that receptor. In contrast to glutamate, NMDA selectively binds to and regulates the NMDA receptor, but not other glutamate receptors such as AMPA and kainite receptors. Given this role, we aimed to determine whether NMDA administration could result in autistic-like behavior in adolescent mice. Both male and female mice were treated with saline or NMDA (50 and 75 mg/kg) and were tested on various behavior experiments. Interestingly, acute NMDA-treated mice showed social deficits and repetitive behavior similar to ASD phenotypes. These results support the excitation/inhibition imbalance theory of ASD and that NMDA injection can be used as a pharmacologic model of ASD-like behaviors.

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4Differentially Expressed Genes in Period 2-Overexpressing Mice Striatum May Underlie Their Lower Sensitivity to Methamphetamine Addiction-Like Behavior

저자 : Leandro Val Sayson , Mikyung Kim , Se Jin Jeon , Raly James Perez Custodio , Hyun Jun Lee , Darlene Mae Ortiz , Jae Hoon Cheong , Hee Jin Kim

발행기관 : 한국응용약물학회 간행물 : Biomolecules & Therapeutics(구 응용약물학회지) 30권 3호 발행 연도 : 2022 페이지 : pp. 238-245 (8 pages)

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Previous reports have demonstrated that genetic mechanisms greatly mediate responses to drugs of abuse, including methamphetamine (METH). The circadian gene Period 2 (Per2) has been previously associated with differential responses towards METH in mice. While the behavioral consequences of eliminating Per2 have been illustrated previously, Per2 overexpression has not yet been comprehensively described; although, Per2-overexpressing (Per2 OE) mice previously showed reduced sensitivity towards METH-induced addiction-like behaviors. To further elucidate this distinct behavior of Per2 OE mice to METH, we identified possible candidate biomarkers by determining striatal differentially expressed genes (DEGs) in both drug-naïve and METH-treated Per2 OE mice relative to wild-type (WT), through RNA sequencing. Of the several DEGs in drug naïve Per2 OE mice, we identified six genes that were altered after repeated METH treatment in WT mice, but not in Per2 OE mice. These results, validated by quantitative real-time polymerase chain reaction, could suggest that the identified DEGs might underlie the previously reported weaker METH-induced responses of Per2 OE mice compared to WT. Gene network analysis also revealed that Asic3, Hba-a1, and Rnf17 are possibly associated with Per2 through physical interactions and predicted correlations, and might potentially participate in addiction. Inhibiting the functional protein of Asic3 prior to METH administration resulted in the partial reduction of METH-induced conditioned place preference in WT mice, supporting a possible involvement of Asic3 in METH-induced reward. Although encouraging further investigations, our findings suggest that these DEGs, including Asic3, may play significant roles in the lower sensitivity of Per2 OE mice to METH.

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5Betulin Targets Lipin1/2-Meidated P2X7 Receptor as a Therapeutic Approach to Attenuate Lipid Accumulation and Metaflammation

저자 : Jia-yi Dou , Yu-chen Jiang , Zhong-he Hu , Kun-chen Yao , Ming-hui Yuan , Xiao-xue Bao , Mei-jie Zhou , Yue Liu , Zhao-xu Li , Li-hua Lian , Ji-xing Nan , Yan-ling Wu

발행기관 : 한국응용약물학회 간행물 : Biomolecules & Therapeutics(구 응용약물학회지) 30권 3호 발행 연도 : 2022 페이지 : pp. 246-256 (11 pages)

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The present study focused on the potential mechanism of betulin (BT), a pentacyclic triterpenoid isolated from the bark of white birch (Betula pubescens), against chronic alcohol-induced lipid accumulation and metaflammation. AML-12 and RAW 264.7 cells were administered ethanol (EtOH), lipopolysaccharide (LPS) or BT. Male C57BL/6 mice were fed Lieber-DeCarli liquid diets containing 5% EtOH for 4 weeks, followed by single EtOH gavage on the last day and simultaneous treatment with BT (20 or 50 mg/kg) by oral gavage once per day. In vitro, MTT showed that 0-25 mM EtOH and 0-25 μM BT had no toxic effect on AML-12 cells. BT could regulate sterolregulatory-element-binding protein 1 (SREBP1), lipin1/2, P2X7 receptor (P2X7r) and NOD-like receptor family, pyrin domains-containing protein 3 (NLRP3) expressions again EtOH-stimulation. Oil Red O staining also indicated that BT significantly reduced lipid accumulation in EtOH-stimulated AML-12 cells. Lipin1/2 deficiency indicated that BT might mediate lipin1/2 to regulate SREBP1 and P2X7r expression and further alleviate lipid accumulation and inflammation. In vivo, BT significantly alleviated histopathological changes, reduced serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and triglyceride (TG) levels, and regulated lipin1/2, SREBP1, peroxisome proliferator activated receptor α/γ (PPARα/γ) and PGC-1α expression compared with the EtOH group. BT reduced the secretion of inflammatory factors and blocked the P2X7r-NLRP3 signaling pathway. Collectively, BT attenuated lipid accumulation and metaflammation by regulating the lipin1/2-mediated P2X7r signaling pathway.

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6Urushiol V Suppresses Cell Proliferation and Enhances Antitumor Activity of 5-FU in Human Colon Cancer Cells by Downregulating FoxM1

저자 : Ji Hye Jeong , Jae-ha Ryu

발행기관 : 한국응용약물학회 간행물 : Biomolecules & Therapeutics(구 응용약물학회지) 30권 3호 발행 연도 : 2022 페이지 : pp. 257-264 (8 pages)

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Colorectal cancer (CRC) is one of the most common malignant tumor. 5-FU is commonly used for the treatment of CRC. However, the development of drug resistance in tumor chemotherapy can seriously reduce therapeutic efficacy of 5-FU. Recent data show that FoxM1 is associated with 5-FU resistance in CRC. FoxM1 plays a critical role in the carcinogenesis and drug resistance of several malignancies. It has been reported that urushiol V isolated from the cortex of Rhus verniciflua Stokes is cytotoxic to several types of cancer cells. However, the underlying molecular mechanisms for its antitumor activity and its potential to attenuate the chemotherapeutic resistance in CRC cells remain unknown. Here, we found that urushiol V could inhibit the cell proliferation and induced S-phase arrest of SW480 colon cancer cells. It inhibited protein expression level of FoxM1 through activation of AMPK. We also investigated the combined effect of urushiol V and 5-FU. The combination treatment reduced FoxM1 expression and consequently reduced cell growth and colony formation in 5-FU resistant colon cancer cells (SW480/5-FUR). Taken together, these result suggest that urushiol V from Rhus verniciflua Stokes can suppress cell proliferation by inhibiting FoxM1 and enhance the antitumor capacity of 5-FU. Therefore, urushiol V may be a potential bioactive compound for CRC therapy.

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7The Endoplasmic Reticulum Stress Response Mediates Shikonin-Induced Apoptosis of 5-Fluorouracil-Resistant Colorectal Cancer Cells

저자 : Mei Jing Piao , Xia Han , Kyoung Ah Kang , Pincha Devage Sameera Madushan Fernando , Herath Mudiyanselage Udari Lakmini Herath , Jin Won Hyun

발행기관 : 한국응용약물학회 간행물 : Biomolecules & Therapeutics(구 응용약물학회지) 30권 3호 발행 연도 : 2022 페이지 : pp. 265-273 (9 pages)

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Resistance to chemotherapeutic drugs is a significant problem in the treatment of colorectal cancer, resulting in low response rates and decreased survival. Recent studies have shown that shikonin, a naphthoquinone derivative, promotes apoptosis in colon cancer cells and cisplatin-resistant ovarian cells, raising the possibility that this compound may be effective in drug-resistant colorectal cancer. The aim of this study was to characterize the molecular mechanisms underpinning shikonin-induced apoptosis, with a focus on endoplasmic reticulum (ER) stress, in a 5-fluorouracil-resistant colorectal cancer cell line, SNU-C5/5-FUR. Our results showed that shikonin significantly increased the proportion of sub-G1 cells and DNA fragmentation and that shikonin-induced apoptosis is mediated by mitochondrial Ca2+ accumulation. Shikonin treatment also increased the expression of ER-related proteins, such as glucose regulatory protein 78 (GRP78), phospho-protein kinase RNA-like ER kinase (PERK), phospho-eukaryotic initiation factor 2 (eIF2α), phospho-phosphoinositol-requiring protein-1 (IRE1), spliced X-box-binding protein-1 (XBP-1), cleaved caspase-12, and C/EBP-homologous protein (CHOP). In addition, siRNA-mediated knockdown of CHOP attenuated shikonin-induced apoptosis, as did the ER stress inhibitor TUDCA. These data suggest that ER stress is a key factor mediating the cytotoxic effect of shikonin in SNU-C5/5-FUR cells. Our findings provide an evidence for a mechanism in which ER stress leads to apoptosis in shikonin-treated SNU-C5/5-FUR cells. Our study provides evidence to support further investigations on shikonin as a therapeutic option for 5-fluorouracil-resistant colorectal cancer.

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8Combination Therapy of the Active KRAS-Targeting Antibody inRas37 and a PI3K Inhibitor in Pancreatic Cancer

저자 : Ji Eun Lee , Min Gyu Woo , Kyung Hee Jung , Yeo Wool Kang , Seung-min Shin , Mi Kwon Son , Zhenghuan Fang , Hong Hua Yan , Jung Hee Park , Young-chan Yoon , Yong-sung Kim , Soon-sun Hong

발행기관 : 한국응용약물학회 간행물 : Biomolecules & Therapeutics(구 응용약물학회지) 30권 3호 발행 연도 : 2022 페이지 : pp. 274-283 (10 pages)

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KRAS activating mutations, which are present in more than 90% of pancreatic cancers, drive tumor dependency on the RAS/mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K)/AKT signaling pathways. Therefore, combined targeting of RAS/MAPK and PI3K/AKT signaling pathways may be required for optimal therapeutic effect in pancreatic cancer. However, the therapeutic efficacy of combined MAPK and PI3K/AKT signaling target inhibitors is unsatisfactory in pancreatic cancer treatment, because it is often accompanied by MAPK pathway reactivation by PI3K/AKT inhibitor. Therefore, we developed an inRas37 antibody, which directly targets the intra-cellularly activated GTP-bound form of oncogenic RAS mutation and investigated its synergistic effect in the presence of the PI3K inhibitor BEZ-235 in pancreatic cancer. In this study, inRas37 remarkably increased the drug response of BEZ-235 to pancreatic cancer cells by inhibiting MAPK reactivation. Moreover, the co-treatment synergistically inhibited cell proliferation, migration, and invasion and exhibited synergistic anticancer activity by inhibiting the MAPK and PI3K pathways. The combined administration of inRas37and BEZ-235 significantly inhibited tumor growth in mouse models. Our results demonstrated that inRas37 synergistically increased the antitumor activity of BEZ-235 by inhibiting MAPK reactivation, suggesting that inRas37 and BEZ-235 co-treatment could be a potential treatment approach for pancreatic cancer patients with KRAS mutations.

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9Direct Contact with Platelets Induces Podoplanin Expression and Invasion in Human Oral Squamous Cell Carcinoma Cells

저자 : Se-young Park , Sun Kyoung Lee , Mihwa Lim , Bomi Kim , Byeong-oh Hwang , Eunae Sandra Cho , Xianglan Zhang , Kyung-soo Chun , Won-yoon Chung , Na-young Song

발행기관 : 한국응용약물학회 간행물 : Biomolecules & Therapeutics(구 응용약물학회지) 30권 3호 발행 연도 : 2022 페이지 : pp. 284-290 (7 pages)

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Oral squamous cell carcinoma (OSCC) is mostly diagnosed at an advanced stage, with local and/or distal metastasis. Thus, locoregional and/or local control of the primary tumor is crucial for a better prognosis in patients with OSCC. Platelets have long been considered major players in cancer metastasis. Traditional antiplatelet agents, such as aspirin, are thought to be potential chemotherapeutics, but they need to be used with caution because of the increased bleeding risk. Podoplanin (PDPN)-expressing cancer cells can activate platelets and promote OSCC metastasis. However, the reciprocal effect of platelets on PDPN expression in OSCC has not been investigated. In this study, we found that direct contact with platelets upregulated PDPN and integrin β1 at the protein level and promoted invasiveness of human OSCC Ca9.22 cells that express low levels of PDPN. In another human OSCC HSC3 cell line that express PDPN at an abundant level, silencing of the PDPN gene reduced cell invasiveness. Analysis of the public database further supported the co-expression of PDPN and integrin β1 and their increased expression in metastatic tissues compared to normal and tumor tissues of the oral cavity. Taken together, these data suggest that PDPN is a potential target to regulate platelet-tumor interaction and metastasis for OSCC treatment, which can overcome the limitations of traditional antiplatelet drugs.

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10Transcriptome Analysis of Long-Term Exposure to Blue Light in Retinal Pigment Epithelial Cells

저자 : Hong Lan Jin , Kwang Won Jeong

발행기관 : 한국응용약물학회 간행물 : Biomolecules & Therapeutics(구 응용약물학회지) 30권 3호 발행 연도 : 2022 페이지 : pp. 291-297 (7 pages)

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Dry age-related macular degeneration (AMD) is a type of progressive blindness that is primarily due to dysfunction and the loss of retinal pigment epithelium (RPE). The accumulation of N-retinylidene-N-retinylethanolamine (A2E), a by-product of the visual cycle, causes RPE and photoreceptor degeneration that impairs vision. Genes associated with dry AMD have been identified using a blue light model of A2E accumulation in the retinal pigment epithelium and transcriptomic studies of retinal tissue from patients with AMD. However, dry macular degeneration progresses slowly, and current approaches cannot reveal changes in gene transcription according to stages of AMD progression. Thus, they are limited in terms of identifying genes responsible for pathogenesis. Here, we created a model of long-term exposure to identify temporally-dependent changes in gene expression induced in human retinal pigment epithelial cells (ARPE-19) exposed to blue light and a non-cytotoxic dose of A2E for 120 days. We identified stage-specific genes at 40, 100, and 120 days, respectively. The expression of genes corresponding to epithelial-mesenchymal transition (EMT) during the early stage, glycolysis and angiogenesis during the middle stage, and apoptosis and inflammation pathways during the late stage was significantly altered by A2E and blue light. Changes in the expression of genes at the late stages of the EMT were similar to those found in human eyes with late-stage AMD. Our results provide further insight into the pathogenesis of dry AMD induced by blue light and a novel model in vitro with which relevant genes can be identified in the future.

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