Rheumatoid arthritis (RA) is a representative autoimmune disease that is primarily characterized by persistent inflammation and progressive destruction of synovial joints. RA has a complex and heterogeneous pathophysiology, involving interactions among various immune and joint stromal cells and a diverse network of cytokines and intracellular signaling pathways. With improved understanding of RA, over the past decades, therapeutic strategies have become considerably advanced and now included targeted molecular therapies, such as tumor necrosis factor inhibitors, IL-6 blockers, B-cell depletion agents, as well as inhibitors of T-cell co-stimulation and Janus kinases. However, a considerable proportion of RA patients experience refractory disease and interrupted treatment owing to the associated risk of developing serious infections and cancers. In contrast, although IL-1β, IL-17A, and p38α play significant roles in RA pathogenesis, several drugs targeting these factors have not been approved because of their low efficacy and severe adverse effects. In this review, we provide an overview of the working mechanism, advantages, and limitations of the currently available targeted drugs for RA. Additionally, we suggest potential mechanistic causes for clinically approved and failed drugs. Thus, this review provides perspectives on approaches for basic and translational studies that hold promise for identifying future next-generation therapeutics for RA.
Park Hyun-Jeong;Ko Sung-Min;Kim Yong-Sun;Chang Yongmin
Investigative Magnetic Resonance Imaging
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v.8
no.1
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pp.32-41
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2004
Purpose : To measure the NMR relaxation properties of MnPC, to observe the characteristics of liver enhancement patterns on MR images in experimentally implanted rabbit VX2 tumor model, and to estimate the possibility of tissue specific contrast agent for MnPC in comparison with the hepatobiliary agent. Materials and Methods : Phthalocyanine (PC) was chelated with paramagnetic ions, manganese (Mn). 2.01 g (5.2 mmol) of phthalocyanine was mixed with 0.37 g (1.4 nlmol) of Mn chloride at $310^{\circ}C$ for 36 hours and then purified by chromatography ($CHCl_3:\;CH_3OH=98:2$, volume ratio) to obtain 1.04 g $(46\%)$ of MnPC (molecular weight = 2000 daltons). The T1/T2 relaxivity (R1/R2) for MnPC were determined at a 1.5 T (64 MHz) MR spectrometer. VX2 tumor model was experimentally implanted in the liver parenchyma of rabbits. All MR studies were performed on 1.5 T. The human extremity radio frequency coil of a bird cage type was employed. MR images were acquired at 17 to 24 days after VX2 carcinoma implantation.4 mmol/kg MnPC and 0.01 mmol/kg Mn-DPDP were injected via the ear vein of rabbits. T1-weighted images were obtained with spin-echo (TR/TE=516/14 msec) and fast multiplanar spoiled gradient recalled (TR/TE : 80/4 msec, $60^{\circ}$ flip angle) pulse sequence. Fast spin-echo (TR/TE=1200/85 msec) was used to obtain the T2-weighted images. Results : The value of T1/T2 relaxivity (R1/R2) of MnPC was $7.28\;mM^{-1}S^{-1}$ and $55.56\;mM^{-1}S^{-1}$ respectively at 1.5 T (64 MHz). Because the T2 relaxivity of MnPC that bonded strongly, covalently manganese with phthalocyanine was very high, the signal intensity of liver parenchyma was decreased on postcontrast T2-weighted images and we could easily distinguish the VX2 carcinoma within the liver parenchyma. When MnPC was administrated intravenously, the tumor margin delineation was more remarkable than Mn-DPDP-enhanced images. The enhancement of liver parenchyma with MnPC persisted at relatively high levels over at least one hour after injection of the contrast agents. Conclusion : The hepatic uptake and biliary excretion of MnPC, which are similar to Mn-DPDP, suggest that this agent is a new liver-specific agent. Also, MnPC seems to be used as a dual contrast agent (T1 and T2) with high T2 relaxivity. However, it is warranted that MnPC needs further investigation as a potential contrast agent for MR imaging of the liver. That is, further characterizations of MnPC are needed in vivo and in vitro before clinical trials. The diagnostic potential of MnPC will also have to be examined more in the animal models of additional types.
Non-regular workers came to the fore while working class formation was in retreat along with the democratic labor movement of regular workers. The formation of principal agents, however, is yet to occur. Then, why non-regular workers' struggles could not yield a consequence in that regard? What kind of factors are to determine the outcome of the struggles and how do they do it? It is the aim of this study to answer those questions. In contrast with regular workers' struggles, non-regular workers' struggles tend to break out in response to capitalist offensives, rely on atypical and, often, extreme measures of struggle rather than strike in the form of work stoppage, drag out for too long, and appeal for social solidarity outside when the solidarity of regular workers is not available. Non-regular workers' struggles tend to end up with failure rather than success, and with weakening rather than strengthening of their organizational strength. So as to overcome the tendency to fail, non-regular workers' struggles need regular workers' solidarity in addition to their own strong mobilization power, while social solidarity or positional power could substitute for regular workers' solidarity in some cases. So as to build up their organizational strength, non-regular workers' struggles should win victories in the struggles, while a victory could turn into a trap in the case of conversion. Both regular workers' solidarity and the internal integration of the struggles are two foremost important factors in achieving the victory of struggles and the building-up of organizational strength. Those who have got involved in struggles are from the best organized sector among all the non-regular workers. As they have gone through weakening of organizational strength, it becomes more difficult for non-regular workers to form principal agents. Without non-regular workers' struggles, however, the capitalist offensives must have carried the day. In that sense, non-regular workers' struggles did a role in at least detaining capitalist offensives, if not stopping them. The practical implication of non-regular workers' struggles is that, if non-regular workers redefine the ultimate goal of their struggles as the formation of their principal agents for working class formation, it would be a strategically rational choice to identify the strategic objective of struggles with the maintaining and strengthening of their organizational strength rather than the achievement of their immediate demands.
Purpose : To evaluate the NMR relaxation properties and imaging characteristics of tissue-specificity for a newly developed macromolecular MR agent. Materials and methods : Phthalocyanine (PC) was chelated with paramagnetic ion, Mn.2.01g (5.2 mmol) of Phthalocyanine was mixed with 0.37g (1.4 mmol) of Mn chloride at $310^{\circ}C$ for 36 hours and then purified by chromatography (CHC13/CH3OH 98/2 v/v, Rf, 0.76) to obtain 1.04g (46%) of MnPC (molecular weight= 2000d). The $T1}T2$ relaxivity of MnPC was measured in 1.5T(64 MHz) MR using 0.1 mM MnPC. The MR image characteristics of MnPC was evaluated using spin-echo (TR/TE=500/14 msec) and gradient-echo (FLASH) (TR/TE=80/4 msec, flip angle=60) techniques in 1.57 MR scanner. The images of rabbit liver were obtained every 10 minutes up to 4 hours. To study the effect of concentration on image, 20 mM, 50 mM, 100 mM of MnPC were tested. Results : The relaxivities of MnPC at 1.5T(64MHz) were Rl=7.28 $mM^{-1}S^{-1},{\;}R2=55.56mM^{-1}S^{-1}$. Compared to the values of Gd-DTPA (Rl[=4.8 $mM^{-1}S^{-1})$], R2[=5.2 $mM^{-1}S^{-1}])$]), both T1/T2 relaxivities of MnPC were higher than those of Gd-DTPA. For both of SE and FLASH techniques, the contrast enhancement reached maximum at 10 minutes after bolus injection and the enhancement continued for more than 2 hours. When compared with small molecular weight liver agents such as Gd-EOB-DTPA, Gd-BOPTA and MnDPDP, MnPC was characterized by more prolonged enhancement time. The time course of MR images also revealed biliary excretion of MnPC. Conclusion : We developed a new macromolecular MR agent, MnPC. The relaxivities of MnPC were higher than those of small molecular weight Gd-chelate. Hepatic uptake and biliary excretion of MnPC suggests that this agent is a new liver-specific MR agent.
For this study copper ions-containing bioactive glass nanoparticles commonly used in mineral trioxide aggregate (MTA) was developed to improve the mechanical properties and promote antibacterial effect of MTA with the original material. The mechanical properties and antibacterial activity of Cu-BGn incorporating varying amounts cooper incorporated bioactive glass nano particles(BGn) 0.5,1.0,2.0 and 4.0 wt% in MTA were characterized composition of the resulting were investigated. The compressive strength was calculated by weighing specimens with a diameter of 4 mm and a thickness of 6 mm according to ISO 6876 (2012). The antimicrobial effect was evaluated using two strains of S. mutans and E. faecalis. The mechanical properties of the test results was Cu-BGn increased no statistically significant difference was observed (p>0.05). Adhesion experiment results S. mutans in contrast to the control group Ortho MTA, 4.0 wt% of Cu-BGn added experimental group showed a significant difference was observed (p<0.05). Also, E. faecalis statistical analysis indicated a significant difference for antibacterial agents between control and Cu-BGn containing(p<0.05). It seems that this Cu-BGn proved that even a antibacterial effect was demonstrated. Therefore, it was suggest that it is necessary for in-depth research into various environments that can reproduce the oral environment.
Kim, Ji-Youn;Kim, Hee Sook;Lee, Song Min;Park, Hye-Jung;Lee, Sang-Hyeon;Jang, Jeong Su;Lee, Mun Hyon
Microbiology and Biotechnology Letters
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v.48
no.1
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pp.38-47
/
2020
This study was conducted to investigate both plant growth-promoting and plant disease- controlling activities of bacterial strains isolated from soil. All the isolated strains were able to grow at various temperatures. All the strains, except ANG40, showed antagonistic effects against various phytopathogenic fungi. This antagonism can be ascribed to the production of siderophores and antibiotic substances. In addition, all the strains showed abilities such as nitrogen fixation, phosphate solubilization, and siderophore production. These results suggest that nitrogen, phosphorus, and iron can be converted into forms that can be easily absorbed by the plants for their growth. Analysis of the growth-promoting properties revealed that ANG51 produced 1-aminocyclopropane-1-carboxylic acid (ACC) deaminase and indole-3-acetic acid (IAA) both of which are related to ethylene production. In contrast, the other strains were found to have only IAA-producing ability. Therefore, this study suggests that Pseudomonas geniculata ANG3, Exiguobacterium acetylicum ANG40, and Burkholderia stabilis ANG51, which were selected through analysis of comparative advantages for both plant growth promotion and disease-controlling activity, may be used as biological agents.
The oriental traditional medicine, Aruncus dioicus var kamtschaticus (ADK) is used for hemostasis (blood stopping) and the promotion of blood circulation. Recently, the demands of the aerial part of ADK as edible mountain herbs are rapidly increased due to its unique fragrance and bioactivity. In this study, to evaluate the anti-thrombosis activity of ADK, ethanol extract and organic solvent fractions were prepared from aerial parts of ADK, and their anticoagulation and anti-platelet aggregation activities were determined. In an anticoagulation activity assay, the ethanol extract of ADK increased the thrombin time, prothrombin time, and activated partial thromboplastin time (aPTT) 1.4-2.3 times at a concentration of 5 mg/ml. Among the fractions, the ethylacetate fraction showed strong inhibitory effects against blood clotting factors, as shown in an extension of the aPTT. In contrast, the butanol fraction strongly promoted blood clotting. In an anti-platelet aggregation assay, the activity of the ethanol extract was comparable to that of aspirin, a commercial anti-platelet aggregation agent, and the butanol fraction showed 2-fold higher aggregation inhibitory activity than aspirin. The aforementioned ethanol extract and active fractions have ignorable hemolytic activity against human red blood cells up to a concentration of 0.5 mg/ml. Considering the high content of total polyphenol, total flavonoid, and total sugar of the ethylacetate and butanol fractions, the purified active substances have potential as safe and novel anti-thrombosis agents. This report provides the first evidence of anti-thrombosis activity of ADK.
Uddin, Md. Hafiz;Li, Shunyu;Jin, Yan;Choi, Min-Ho;Jang, Ja June;Hong, Sung-Tae
Parasites, Hosts and Diseases
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v.54
no.3
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pp.281-289
/
2016
Clonorchis sinensis is a Group-I bio-carcinogen, associated with cholangiocarcinoma (CCA). The hamster is the only experimental model of C. sinensis-mediated CCA, but we oblige another animal model. The present study intended to develop a C. sinensis (Cs) mediated CCA model using C3H/He mice, co-stimulated with N-nitrosodimethylamine (NDMA) and dicyclanil (DC). The mice were divided into 8 groups with different combinations of Cs, NDMA, and DC. Six months later the mice were sacrificed and subjected to gross and histopathological examination. The body weights were significantly reduced among the groups treated with 2 or more agents (eg. Cs+NDMA, Cs+DC, NDMA+DC, and Cs+NDMA+DC). In contrast, liver weight percentages to body weight were increased in above groups by 4.1% to 4.7%. A Change of the spleen weight was observed only in Cs+NDMA group. Though C. sinensis infection is evident from hyperplastic changes, only 1 worm was recovered. Two mice, 1 from Cs and the other from Cs+DC group, showed mass forming lesions; 1 ($281.2mm^3$) from the Cs group was a hepatocellular adenoma and the other ($280.6mm^3$) from the Cs+DC group was a cystic mass (peliosis). Higher prevalence of gray-white nodules was observed in Cs group (42.9%) followed by Cs+NDMA+DC group (21.4%). The mice of the Cs+NDMA+DC group showed hyper-proliferation of the bile duct with fibrotic changes. No characteristic change for CCA was recognized in any of the groups. In conclusion, C3H/He mice produce no CCA but extensive fibrosis when they are challenged by Cs, NDMA, and DC together.
Technetium labeled isonitrile analogues are widely used as myocardial perfusion imaging agents. We synthesized and characterized a new isonitrile compound, ethyl 3-isocyanobutyrate(EIB). Proton and $^{13}C$ NMR spectroscopy and thin layer chromatography with a $C_{18}$ coat was performed. EIB was easily labeled with $^{99m}TcO_4^-$- with sodium dithionite. The labeling efficiency measured by RP-HPLC was over 95%. The labeled product was stable with dilution in normal saline and with prolonged incubation at room temperature. There was no formation of secondary products or free $^{99m}TcO_4^-$. In vivo kinetics study of $^{99m}Tc$ (I) labeled EIB in rabbits showed adequate myocardial uptake, good contrast against lung background, and relatively rapid liver clearance. The heart to lung ratio was over 2.5 and the heart to liver ratio was approximately from 0.4 to 5 at 60 minutes post injection. Hepatic clearance of $^{99m}Tc-MIBI$ was faster ($t_{1/2}$=6 minutes) than that of $^{99m}Tc-MIBI$. In vivo kinetics observed in dog was similar to that in rabbit but there was faster gallbladder filling, and thus lower liver background. SPECT imaging of the canine myocardium showed favorable imaging characteristics. However, biodistribution in mice demonstrated a myocardial % injected dose/organ of less than 0.1%. This was thought to be due to interspecies difference in plasma esterase activity. In human plasma, $^{99m}Tc$ ( I ) labeled EIB was stable for at least 2 hours, without production of secondary products by HPLC. We conclude that ethyl 3-isocyanobutyrate may be a potential new myocardial perfusion imaging agent and deserves further investigation as to its usefulness for clinical use.
Alteration of physical and chemical characteristics and the effect of removal of mineral substances in waterlogged archaeological woods by different cleaning processes were examined using oak wood(Quercus spp.) that was excavated from wetland near Gwangju, Korea. Cleaning methods employed in the present work were (1) tools, (2) deaeration, (3) EDTA and (4) ultrasonic cleaning, which are being currently applied in the field of preservation treatment. Cleaning process were performed independently or continuously. Composition of mineral substances in the waterlogged archaeological wood was almost same as the that of soil in which waterlogged archaeological woods were buried. In case of independent cleaning, tools cleaning efficiently removed the mineral substances on surface. Surface color become brighter after cleaning with EDTA. In contrast, deaeration and ultrasonic cleaning did not show any significant removal of mineral substances. In continuous cleaning process, tool cleaning as the first step treatment showed the same effect as shown in independent cleaning. Although deaeration as the second step cleaning did not remove the mineral substances, it could be assumed to contribute the infiltration of dimensional agents by homogenization of wood. EDTA treatment (the third step cleaning) removed the iron(Fe) and increased the whiteness of wood color. The ultrasonic treatment (the fourth step cleaning) removed the sodium(Na) remained after EDTA treatment and the fine mineral substances.
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