Biomolecules & Therapeutics.2017;25(2):222-222. doi:10.4062/biomolther.2017.222
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Biomolecules & Therapeutics
2008 to Present ISSN: 1976-9148
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Enforced Expression of CXCR5 Drives T Follicular Regulatory-Like Features in Foxp3⁺ T Cells.
Biomolecules & Therapeutics.2017;25(2):130-139. doi:10.4062/biomolther.2016.075
CXCR5⁺ T follicular helper (Tfh) cells are associated with aberrant autoantibody production in patients with antibody-mediated autoimmune diseases including lupus. Follicular regulatory T (Tfr) cells expressing CXCR5 and Bcl6 have been recently identified as a specialized subset of Foxp3+ regulatory T (Treg) cells that control germinal center reactions. In this study, we show that retroviral transduction of CXCR5 gene in Foxp3⁺ Treg cells induced a stable expression of functional CXCR5 on their surface. The Cxcr5-transduced Treg cells maintained the expression of Treg cell signature genes and the suppressive activity. The expression of CXCR5 as well as Foxp3 in the transduced Treg cells appeared to be stable in vivo in an adoptive transfer experiment. Moreover, Cxcr5-transduced Treg cells preferentially migrated toward the CXCL13 gradient, leading to an effective suppression of antibody production from B cells stimulated with Tfh cells. Therefore, our results demonstrate that enforced expression of CXCR5 onto Treg cells efficiently induces Tfr cell-like properties, which might be a promising cellular therapeutic approach for the treatment of antibody-mediated autoimmune diseases.
Adoptive Transfer ; Antibody Formation ; Autoimmune Diseases ; B-Lymphocytes ; Germinal Center ; Humans ; T-Lymphocytes* ; T-Lymphocytes, Regulatory ; Zidovudine
Adoptive Transfer ; Antibody Formation ; Autoimmune Diseases ; B-Lymphocytes ; Germinal Center ; Humans ; T-Lymphocytes* ; T-Lymphocytes, Regulatory ; Zidovudine
Biomolecules & Therapeutics.2017;25(2):112-121. doi:10.4062/biomolther.2016.076
Drug-induced liver injury (DILI) is the serious and fatal drug-associated adverse effect, but its incidence is very low and individual variation in severity is substantial. Acetaminophen (APAP)-induced liver injury accounts for >50% of reported DILI cases but little is known for the cause of individual variations in the severity. Intrinsic genetic variation is considered a key element but the identity of the genes was not well-established. Here, pre-biopsy method and microarray technique was applied to uncover the key genes for APAP-induced liver injury in mice, and a cause and effect experiment employing quantitative real-time PCR was conducted to confirm the correlation between the uncovered genes and APAP-induced hepatotoxicity. We identified the innately and differentially expressed genes of mice susceptible to APAP-induced hepatotoxicity in the pre-biopsied liver tissue before APAP treatment through microarray analysis of the global gene expression profiles (Affymetrix GeneChip® Mouse Gene 1.0 ST for 28,853 genes). Expression of 16 genes including Gdap10, Lpl, Gabra3 and Ccrn4l were significantly different (t-test: FDR <10%) more than 1.5 fold in the susceptible animals than resistant. To confirm the association with the susceptibility to APAP-induced hepatotoxicity, another set of animals were measured for the expression level of selected 4 genes (higher two and lower two genes) in the liver pre-biopsy and their sensitivity to APAP-induced hepatotoxicity was evaluated by post hoc. Notably, the expressions of Gabra3 and Lpl were significantly correlated with the severity of liver injury (p<0.05) demonstrating that these genes may be linked to the susceptibility to APAP-induced hepatotoxicity.
Acetaminophen ; Animals ; Drug-Induced Liver Injury ; Genetic Variation ; Incidence ; Lipoprotein Lipase* ; Lipoproteins* ; Liver ; Methods ; Mice ; Microarray Analysis ; Real-Time Polymerase Chain Reaction ; Receptors, GABA-A* ; Toxicogenetics ; Transcriptome
Acetaminophen ; Animals ; Drug-Induced Liver Injury ; Genetic Variation ; Incidence ; Lipoprotein Lipase* ; Lipoproteins* ; Liver ; Methods ; Mice ; Microarray Analysis ; Real-Time Polymerase Chain Reaction ; Receptors, GABA-A* ; Toxicogenetics ; Transcriptome
Biomolecules & Therapeutics.2017;25(2):105-111. doi:10.4062/biomolther.2016.035
It has been known that RA, one of major constituents of Perilla frutescens which has been used as a traditional folk remedy for sedation in oriental countries, shows the anxiolytic-like and sedative effects. This study was performed to know whether RA may enhance pentobarbital-induced sleep through γ-aminobutyric acid (GABA)(A)-ergic systems in rodents. RA (0.5, 1.0 and 2.0 mg/kg, p.o.) reduced the locomotor activity in mice. RA decreased sleep latency and increased the total sleep time in pentobarbital (42 mg/kg, i.p.)-induced sleeping mice. RA also increased sleeping time and number of falling sleep mice after treatment with sub-hypnotic pentobarbital (28 mg/kg, i.p.). In electroencephalogram (EEG) recording, RA (2.0 mg/kg) not only decreased the counts of sleep/wake cycles and REM sleep, but also increased the total and NREM sleep in rats. The power density of NREM sleep showed the increase in δ-waves and the decrease in α-waves. On the other hand, RA (0.1, 1.0 and 10 μg/ml) increased intracellular Cl− influx in the primary cultured hypothalamic cells of rats. RA (p.o.) increased the protein expression of glutamic acid decarboxylase (GAD(65/67) ) and GABA(A) receptors subunits except β1 subunit. In conclusion, RA augmented pentobarbital-induced sleeping behaviors through GABA(A)-ergic transmission. Thus, it is suggested that RA may be useful for the treatment of insomnia.
Accidental Falls ; Animals ; Electroencephalography ; Eye Movements* ; Glutamate Decarboxylase ; Hand ; Hypnotics and Sedatives ; Medicine, Traditional ; Mice ; Motor Activity ; Pentobarbital ; Perilla frutescens ; Rats ; Receptors, GABA-A ; Rodentia ; Sleep Initiation and Maintenance Disorders ; Sleep, REM
Accidental Falls ; Animals ; Electroencephalography ; Eye Movements* ; Glutamate Decarboxylase ; Hand ; Hypnotics and Sedatives ; Medicine, Traditional ; Mice ; Motor Activity ; Pentobarbital ; Perilla frutescens ; Rats ; Receptors, GABA-A ; Rodentia ; Sleep Initiation and Maintenance Disorders ; Sleep, REM
Therapeutic Potential of Medicinal Plants and Their Constituents on Lung Inflammatory Disorders.
Biomolecules & Therapeutics.2017;25(2):91-104. doi:10.4062/biomolther.2016.187
Acute bronchitis and chronic obstructive pulmonary diseases (COPD) are essentially lung inflammatory disorders. Various plant extracts and their constituents showed therapeutic effects on several animal models of lung inflammation. These include coumarins, flavonoids, phenolics, iridoids, monoterpenes, diterpenes and triterpenoids. Some of them exerted inhibitory action mainly by inhibiting the mitogen-activated protein kinase pathway and nuclear transcription factor-κB activation. Especially, many flavonoid derivatives distinctly showed effectiveness on lung inflammation. In this review, the experimental data for plant extracts and their constituents showing therapeutic effectiveness on animal models of lung inflammation are summarized.
Bronchitis ; Coumarins ; Diterpenes ; Flavonoids ; Iridoids ; Lung Diseases, Obstructive ; Lung* ; Models, Animal ; Monoterpenes ; Phenol ; Plant Extracts ; Plants, Medicinal* ; Pneumonia ; Protein Kinases ; Pulmonary Disease, Chronic Obstructive ; Therapeutic Uses
Bronchitis ; Coumarins ; Diterpenes ; Flavonoids ; Iridoids ; Lung Diseases, Obstructive ; Lung* ; Models, Animal ; Monoterpenes ; Phenol ; Plant Extracts ; Plants, Medicinal* ; Pneumonia ; Protein Kinases ; Pulmonary Disease, Chronic Obstructive ; Therapeutic Uses
Biomolecules & Therapeutics.2015;23(5):486-492. doi:10.4062/biomolther.2015.041
Drug metabolism mostly occurs in the liver. Cytochrome P450 (CYP) is a drug-metabolizing enzyme that is responsible for many important drug metabolism reactions. Recently, the US FDA and EU EMA have suggested that CYP enzyme induction can be measured by both enzymatic activity and mRNA expression. However, these experiments are time-consuming and their inter-assay variability can lead to misinterpretations of the results. To resolve these problems and establish a more powerful method to measure CYP induction, we determined CYP induction by using luminescent assay. Luminescent CYP assays link CYP enzyme activity to firefly luciferase luminescence technology. In this study, we measured the induction of CYP isozymes (1A2, 2B6, 2C9, and 3A4) in cryopreserved human hepatocytes (HMC424, 478, and 493) using a luminometer. We then examined the potential induction abilities (unknown so far) of mesalazine, a drug for colitis, and mosapride citrate, which is used as an antispasmodic drug. The results showed that mesalazine promotes CYP2B6 and 3A4 activities, while mosapride citrate promotes CYP1A2, 2B6, and 3A4 activities. Luminescent CYP assays offer rapid and safe advantages over LC-MS/MS and qRT-PCR methods. Furthermore, luminescent CYP assays decrease the interference between the optical properties of the test compound and the CYP substrates. Therefore, luminescent CYP assays are less labor intensive, rapid, and can be used as robust tools for high-throughput CYP screening during early drug discovery.
Citric Acid* ; Colitis ; Cytochrome P-450 CYP1A2 ; Cytochrome P-450 Enzyme System* ; Cytochromes* ; Drug Discovery ; Enzyme Induction* ; Fireflies ; Hepatocytes ; Humans* ; Isoenzymes ; Liver ; Luciferases ; Luminescence ; Luminescent Measurements* ; Mass Screening ; Mesalamine* ; Metabolism ; RNA, Messenger
Citric Acid* ; Colitis ; Cytochrome P-450 CYP1A2 ; Cytochrome P-450 Enzyme System* ; Cytochromes* ; Drug Discovery ; Enzyme Induction* ; Fireflies ; Hepatocytes ; Humans* ; Isoenzymes ; Liver ; Luciferases ; Luminescence ; Luminescent Measurements* ; Mass Screening ; Mesalamine* ; Metabolism ; RNA, Messenger
Sedative-Hypnotic and Receptor Binding Studies of Fermented Marine Organisms.
Biomolecules & Therapeutics.2015;23(5):479-485. doi:10.4062/biomolther.2014.122
This study was performed to investigate the sedative-hypnotic activity of gamma-aminobutyric acid (GABA)-enriched fermented marine organisms (FMO), including sea tangle (FST) and oyster (FO) by Lactobacillus brevis BJ20 (L. brevis BJ20). FST and FO were tested for their binding activity of the GABA(A)-benzodiazepine and 5-HT(2C) receptors, which are well-known molecular targets for sleep aids. We also measured the sleep latency and sleep duration during pentobarbital-induced sleep in mice after oral administration of FST and FO. In GABA(A) and 5-HT(2C) receptor binding assays, FST displayed an effective concentration-dependent binding affinity to GABA(A) receptor, similar to the binding affinity to 5-HT(2C) receptor. FO exhibited higher affinity to 5-HT(2C) receptor, compared with the GABA(A) receptor. The oral administration of FST and FO produced a dose-dependent decrease in sleep latency and increase in sleep duration in pentobarbital-induced hypnosis. The data demonstrate that FST and FO possess sedative-hypnotic activity possibly by modulating GABA(A) and 5-HT(2C) receptors. We propose that FST and FO might be effective agents for treatment of insomnia.
Administration, Oral ; Animals ; Aquatic Organisms* ; gamma-Aminobutyric Acid ; Hypnosis ; Lactobacillus brevis ; Mice ; Ostreidae ; Receptor, Serotonin, 5-HT2C ; Receptors, GABA-A ; Sleep Initiation and Maintenance Disorders
Administration, Oral ; Animals ; Aquatic Organisms* ; gamma-Aminobutyric Acid ; Hypnosis ; Lactobacillus brevis ; Mice ; Ostreidae ; Receptor, Serotonin, 5-HT2C ; Receptors, GABA-A ; Sleep Initiation and Maintenance Disorders
Biomolecules & Therapeutics.2015;23(5):471-478. doi:10.4062/biomolther.2015.039
Colon cancer is considered as the precarious forms of cancer in many developed countries, with few to no symptoms; the tumor is often diagnosed in the later stages of cancer. Monoterpenes are a major part of plant essential oils found largely in fruits, vegetables and herbs. The cellular and molecular activities show therapeutic progression that may reduce the risk of developing cancer by modulating the factors responsible for colon carcinogenesis. Colon cancer was induced with DMH with a dose of (20 mg/Kg/body weight) for 15 weeks by subcutaneous injection once in a week. Myrtenal treatment was started with (230 mg/Kg/body weight) by intragastric administration, one week prior to DMH induction and continued till the experimental period of 30 weeks. The Invivo results exhibit the elevated antioxidant and lipid peroxidation levels in DMH treated animals. The Histopathological analysis of colon tissues well supported the biochemical alterations and inevitably proves the protective role of Myrtenal. Treatment with myrtenal to cancer bearing animals resulted in a remarkable increase in the inherent antioxidants and excellent modulation in the morphological and physiological nature of the colon tissue. It is thus concluded that myrtenal exhibits excellent free radical scavenging activity and anticancer activity through the suppression of colon carcinoma in Wistar albino rats.
Animals* ; Antioxidants ; Carcinogenesis ; Colon* ; Colonic Neoplasms* ; Developed Countries ; Dimenhydrinate ; Fruit ; Injections, Subcutaneous ; Lipid Peroxidation ; Monoterpenes ; Oils, Volatile ; Plants ; Rats ; Vegetables
Animals* ; Antioxidants ; Carcinogenesis ; Colon* ; Colonic Neoplasms* ; Developed Countries ; Dimenhydrinate ; Fruit ; Injections, Subcutaneous ; Lipid Peroxidation ; Monoterpenes ; Oils, Volatile ; Plants ; Rats ; Vegetables
Antiviral Activity of Chrysin Derivatives against Coxsackievirus B3 in vitro and in vivo.
Biomolecules & Therapeutics.2015;23(5):465-470. doi:10.4062/biomolther.2015.095
Chrysin is a 5,7-dihydroxyflavone and was recently shown to potently inhibit enterovirus 71 (EV71) by suppressing viral 3C protease (3Cpro) activity. In the current study, we investigated whether chrysin also shows antiviral activity against coxsackievirus B3 (CVB3), which belongs to the same genus (Enterovirus) as EV71, and assessed its ability to prevent the resulting acute pancreatitis and myocarditis. We found that chrysin showed antiviral activity against CVB3 at 10 muM, but exhibited mild cellular cytotoxicity at 50 muM, prompting us to synthesize derivatives of chrysin to increase the antiviral activity and reduce its cytotoxicity. Among four 4-substituted benzyl derivatives derived from C(5) benzyl-protected derivatives 7, 9-11 had significant antiviral activity and showed the most potent activity against CVB3 with low cytotoxicity in Vero cells. Intraperitoneal injection of CVB3 in BALB/c mice with 1x106 TCID50 (50% tissue culture infective dose) of CVB3 induced acute pancreatitis with ablation of acinar cells and increased serum CXCL1 levels, whereas the daily administration of 9 for 5 days significantly alleviated the pancreatic inflammation and reduced the elevation in serum CXCL1 levels. Collectively, we assessed the anti-CVB3 activities of chrysin and its derivatives, and found that among 4-substituted benzyl derivatives, 9 exhibited the highest activity against CVB3 in vivo, and protected mice from CVB3-induced pancreatic damage, simultaneously lowering serum CXCL1 levels.
Acinar Cells ; Animals ; Enterovirus ; Inflammation ; Injections, Intraperitoneal ; Mice ; Myocarditis ; Pancreatitis ; Vero Cells
Acinar Cells ; Animals ; Enterovirus ; Inflammation ; Injections, Intraperitoneal ; Mice ; Myocarditis ; Pancreatitis ; Vero Cells
Biomolecules & Therapeutics.2015;23(5):458-464. doi:10.4062/biomolther.2015.052
Sennoside A (erythro) and sennoside B (threo) are dianthrone glycosides and diastereomers. We investigated their abilities to prevent the gastric lesions associated with diseases, such as, gastritis and gastric ulcer. To elucidate their gastroprotective effects, the inhibitions of HCl*EtOH-induced gastritis and indomethacin-induced gastric ulcers were assessed in rats. It was observed that both sennoside A and sennoside B increased prostaglandin E2 (PGE2) levels and inhibited H+/K+-ATPase (proton pump). In a rat model, both compounds reduced gastric juice, total acidity and increased pH, indicating that proton pump inhibition reduces gastric acid secretion. Furthermore, sennoside A and B increased PGE2 in a concentration-dependent manner. In a gastric emptying and intestinal transporting rate experiment, both sennoside A and sennoside B accelerated motility. Our results thus suggest that sennoside A and sennoside B possess significant gastroprotective activities and they might be useful for the treatment of gastric disease.
Animals ; Dinoprostone* ; Gastric Acid ; Gastric Emptying ; Gastric Juice ; Gastritis ; Glycosides ; Hydrogen-Ion Concentration ; Models, Animal ; Proton Pumps ; Rats ; Stomach Diseases ; Stomach Ulcer ; Up-Regulation*
Animals ; Dinoprostone* ; Gastric Acid ; Gastric Emptying ; Gastric Juice ; Gastritis ; Glycosides ; Hydrogen-Ion Concentration ; Models, Animal ; Proton Pumps ; Rats ; Stomach Diseases ; Stomach Ulcer ; Up-Regulation*
Country
Republic of Korea
Publisher
Korean Society of Applied Pharmacology
ElectronicLinks
http://koreamed.org/JournalVolume.php?id=213Editor-in-chief
Young Ae Joe
editor@biomolther.org
Abbreviation
Biomol Ther
Vernacular Journal Title
ISSN
1976-9148
EISSN
2005-4483
Year Approved
2014
Current Indexing Status
Currently Indexed
Start Year
2008
Description
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