Selective induction of Rab9-dependent alternative mitophagy using a synthetic derivative of isoquinoline alleviates mitochondrial dysfunction and cognitive deficits in Alzheimer's disease models.

Rationale: Promotion of mitophagy is considered a promising strategy for the treatment of neurodegenerative diseases including Alzheimer's disease (AD). The development of mitophagy-specific inducers with low toxicity and defined molecular mechanisms is essential for the clinical application of mitophagy-based therapy. The aim of this study was to investigate the potential of a novel small-molecule mitophagy inducer, ALT001, as a treatment for AD. Methods: ALT001 was developed through chemical optimization of an isoquinolium scaffold, which was identified from a chemical library screening using a mitophagy reporter system. In vitro and in vivo experiments were conducted to evaluate the potential of ALT001 as a mitophagy-targeting therapeutic agent and to investigate the molecular mechanisms underlying ALT001-induced mitophagy. The therapeutic effect of ALT001 was assessed in SH-SY5Y cells expressing mutant APP and mouse models of AD (5×FAD and PS2APP) by analyzing mitochondrial dysfunction and cognitive defects. Results: ALT001 specifically induces mitophagy both in vitro and in vivo but is nontoxic to mitochondria. Interestingly, we found that ALT001 induces mitophagy through the ULK1-Rab9-dependent alternative mitophagy pathway independent of canonical mitophagy pathway regulators such as ATG7 and PINK1. Importantly, ALT001 reverses mitochondrial dysfunction in SH-SY5Y cells expressing mutant APP in a mitophagy-dependent manner. ALT001 induces alternative mitophagy in mice and restores the decreased mitophagy level in a 5×FAD AD model mouse. In addition, ALT001 reverses mitochondrial dysfunction and cognitive defects in the PS2APP and 5×FAD AD mouse models. AAV-mediated silencing of Rab9 in the hippocampus further confirmed that ALT001 exerts its therapeutic effect through alternative mitophagy. Conclusion: Our results highlight the therapeutic potential of ALT001 for AD via alleviation of mitochondrial dysfunction and indicate the usefulness of the ULK1-Rab9 alternative mitophagy pathway as a therapeutic target.

South Korean Nurses' Experiences of Speaking up for Patient Safety and Incident Prevention.

Despite the importance of speaking up for patient safety, hesitancy to do so remains a major contributing factor to communication failure. This study aimed to investigate the experiences of South Korean nurses in speaking up to prevent patient safety incidents. Twelve nurses responsible for patient safety tasks or with experience in patient safety education were recruited from five hospitals (three university hospitals, two general hospitals) in city "B". Data were collected through open-ended questions and in-depth interviews, transcribed, and analyzed using the inductive content analysis method. The study resulted in the identification of four main categories and nine subcategories that captured commonalities among the experience of the 12 nurses. The four main categories were as follows: the current scenario of speaking up, barriers to speaking up, strategies for speaking, and confidence training. There is a scarcity of research on speaking-up experiences for patient safety among nurses in South Korean. Overall, it is necessary to overcome cultural barriers and establish an environment that encourages speaking up. In addition, developing speaking-up training programs for nursing students and novice nurses is imperative to prevent patient safety incidents.

Incidence and Predictors of Cataract among People with Type 2 Diabetes Mellitus: Using Secondary Data Analysis from the Ansan Cohort of the Korean Genome and Epidemiology Study.

PURPOSE: This study investigated the incidence and risk factors of cataract in people with diabetes mellitus (DM) using data from Ansan cohort of the Korean Genome and Epidemiology Study (KoGES). METHODS: Data from a total of 329 patients with type 2 DM without cataract who participated in Ansan cohort of the KoGES from baseline survey (2001-2002) to fifth follow-up visit (2011-2012) were examined. The characteristics of the subjects were analyzed with frequency and percentage, and mean and standard deviation. Cataract incidence was measured as incidence proportion (%). For risk factors of cataract, hazard ratio (HR) and 95% confidence interval (CI) were obtained using the Cox proportional hazard model. RESULTS: The cataract incidence over a 10-year follow-up period was 19.1% (15.1 in males and 25.8 in females), and mean age at the incidence of cataract was 63.48 years (61.58 years in males and 65.31 years in females). Age (HR=1.09, 95% CI=1.05-1.13) and HbA1c (HR=1.21, 95% CI=1.07-1.37) or the duration of DM (HR=1.05, 95% CI=1.00-1.09) were found to be independently associated with cataract development. CONCLUSION: Cataract development in people with DM is common, and its likelihood increases with age, HbA1c, and the duration of DM. Considering negative effect of cataract on their quality of life and economic burden, nurses should identify people with DM at a higher risk of cataract development, and plan individual eye examination programs to detect cataract development as early as possible.

GRIM19 Impedes Obesity by Regulating Inflammatory White Fat Browning and Promoting Th17/Treg Balance.

Obesity, a condition characterized by excessive accumulation of body fat, is a metabolic disorder related to an increased risk of chronic inflammation. Obesity is mediated by signal transducer and activator of transcription (STAT) 3, which is regulated by genes associated with retinoid-interferon-induced mortality (GRIM) 19, a protein ubiquitously expressed in various human tissues. In this study, we investigated the role of GRIM19 in diet-induced obese C57BL/6 mice via intravenous or intramuscular administration of a plasmid encoding GRIM19. Splenocytes from wild-type and GRIM19-overexpressing mice were compared using enzyme-linked immunoassay, real-time polymerase chain reaction, Western blotting, flow cytometry, and histological analyses. GRIM19 attenuated the progression of obesity by regulating STAT3 activity and enhancing brown adipose tissue (BAT) differentiation. GRIM19 regulated the differentiation of mouse-derived 3T3-L1 preadipocytes into adipocytes, while modulating gene expression in white adipose tissue (WAT) and BAT. GRIM19 overexpression reduced diet-induced obesity and enhanced glucose and lipid metabolism in the liver. Moreover, GRIM19 overexpression reduced WAT differentiation and induced BAT differentiation in obese mice. GRIM19-transgenic mice exhibited reduced mitochondrial superoxide levels and a reciprocal balance between Th17 and Treg cells. These results suggest that GRIM19 attenuates the progression of obesity by controlling adipocyte differentiation.

The Relationships of End-of-life Care Stress with Compassionate Competence and Attitudes toward End-of-life Care among Pediatric Nurses.

Purpose: This study aimed to provide basic data for developing interventions to relieve the end-of-life care stress experienced by pediatric nurses by examining the relationships of end-of-life care stress with compassionate competence and attitudes toward end-of-life care. Methods: Data were collected via a survey that was conducted from September 10 to September 30, 2018 and administered to 113 nurses who had worked for more than 6 months in a pediatric unit at a tertiary hospital in Seoul, South Korea. The data were analyzed for frequency, percentage, mean, and standard deviation, and the independent t-test, one-way analysis of variance, and Pearson correlation analysis were conducted using SPSS version 25.0. Results: End-of-life care stress among pediatric nurses had a weak positive correlation (r=0.216, P<0.05) with compassionate competence and had no significant correlation with attitudes toward end-of-life care. Among the sub-factors of end-of-life care stress, psychological difficulties had a weak positive correlation with sensitivity (r=0.309, P<0.01) and communication (r=0.230, P<0.05), which are aspects of compassionate competence. Lack of knowledge about end-of-life care had a weak positive correlation with communication (r=0.209, P<0.05) as an aspect of compassionate competence. Conclusion: To improve the quality of end-of-life care provided by pediatric nurses, it is necessary to improve their compassionate competence and reduce their end-of-life care stress by developing education and support programs tailored to the characteristics of children and specific communication methods.

Development and Evaluation of an SBAR-based Fall Simulation Program for Nursing Students.

PURPOSE: The purpose of this study was to develop an Situation-Background-Assessment-Recommendation (SBAR) fall simulation program for Korean nursing students and to evaluate its effectiveness. METHODS: This study used a single-blind randomized control pretest-posttest design. The 54 nursing students in their third semester at a college in Korea were selected through convenience sampling (SBAR group 26, handoff group 28). The SBAR-based program was provided to the experimental group, while the general handoff-based program was given to the control group. The program was designed for a total of three sessions each and no more than 120 minutes each. Measurement variables included the knowledge, skill, attitude, communication ability, and its clarity related to falls. The data were analyzed with x2 test, t test, and repeated measures of ANOVA using the SPSS 18.0 program. RESULTS: The SBAR group showed the improved fall-related skill and communication clarity compared with the handoff group. There was a significant difference in the fall-related knowledge only in a time-dependent manner before and after intervention, while there was no statistically significant difference in the attitude and communication ability related to falls. CONCLUSIONS: SBAR-based simulation program revealed positive results in terms of patient safety of nursing college students compared with the general handoff-based method. Therefore, the SBAR-based simulation program is expected to be used as an educational intervention for nursing students not only to improve abilities in reporting and communication but to prevent or handle patient safety accidents efficiently.

Clinical Research Coordinators' Attitude Toward Risk-Based Monitoring.

BACKGROUND: Clinical research coordinators (CRCs) are persons who collect, record, and maintain clinical trial data in accordance with the principles of Good Clinical Practice at investigators' sites. This study was conducted to examine attitudes of clinical research coordinators (CRCs) toward risk-based monitoring (RBM) prior to full-scale implementation of RBM in Korea. METHODS: The study subjects were 607 CRCs, and data were collected using a self-reported questionnaire. Collected data were analyzed by frequency, percentage, χ2 test and Fisher exact test. RESULTS: Among CRCs, 42.3% had heard of RBM and 44.6% were found to oppose its implementation. Those opposed believed that implementation of RBM would increase the workload of CRCs and CRAs' work support for CRCs. In addition, they showed many negative opinions such as poor accuracy of test data input and failure to increase the overall quality of clinical tests. In particular, such attitudes were more noticeable in CRCs with 5 or more years of experience. CONCLUSION: Before the implementation of RBM, it is necessary to come up with administrative measures such as education for practitioners and recruitment of human resources to help CRCs properly understand RBM.

Changes in the Number and Employment Conditions of Clinical Research Coordinators in South Korea.

BACKGROUND: This study was aimed to examine the number and employment conditions of clinical research coordinators (CRCs) in Korea, with comparison to data from 2010 to identify changes. METHODS: The descriptive study examined 65 sites that participated in a survey or phone interviews among 184 sites registered as clinical trial sites by the Ministry of Food and Drug Safety, and 2 site management organizations. The data were analyzed for mean, standard deviation or median, range, frequency, and percentage. RESULTS: There were 2855 CRCs in 65 sites and 3711 CRCs nationwide, which reflected an increase of 268 people every year on average since 2010. The most common employment system (60.6%) was where CRCs were hired by sites and allocated to clinical trial departments. As for employment type, 48.5% of posts were full-time, and monthly wage payment was the most common at 54.5%. An employment/personnel management department was reported at 87.9% of sites. The average duration from hiring to resignation was 19 months. CONCLUSIONS: The number of CRCs was increased, and such an increase of CRCs was attributed to the increase of investigator-affiliated CRCs rather than site-affiliated CRCs. Though the employment conditions of CRCs have been improved, most improvements were confined to site-affiliated CRCs. It is recommended that each site have a CRC registration and management system for both site-affiliated CRCs and investigator-affiliated CRCs, standardized CRC employment guidelines, and support for CRCs to participate in the training program for the overall improvement of employment conditions of CRCs in Korea.

Kaempferol targeting on the fibroblast growth factor receptor 3-ribosomal S6 kinase 2 signaling axis prevents the development of rheumatoid arthritis.

Rheumatoid arthritis (RA) is a systemic inflammatory disease that mainly affects the synovial joints. Although involvement of the fibroblast growth factor (FGF) signaling pathway has been suggested as an important modulator in RA development, no clear evidence has been provided. In this study, we found that synovial fluid basic FGF (bFGF) concentration was significantly higher in RA than in osteoarthritis (OA) patients. bFGF stimulates proliferation and migration of human fibroblast-like synoviocytes (FLSs) by activation of the bFGF-FGF receptor 3 (FGFR3)-ribosomal S6 kinase 2 (RSK2) signaling axis. Moreover, a molecular docking study revealed that kaempferol inhibited FGFR3 activity by binding to the active pocket of the FGFR3 kinase domain. Kaempferol forms hydrogen bonds with the FGFR3 backbone oxygen of Glu555 and Ala558 and the side chain of Lys508. Notably, the inhibition of bFGF-FGFR3-RSK2 signaling by kaempferol suppresses the proliferation and migration of RA FLSs and the release of activated T-cell-mediated inflammatory cytokines, such as IL-17, IL-21, and TNF-α. We further found that activated phospho-FGFR3 and -RSK2 were more highly observed in RA than in OA synovium. The hyperplastic lining and sublining lymphoid aggregate layers of RA synovium showed p-RSK2-expressing CD68+ macrophages with high frequency, while pRSK2-expressing CD4+ T-cells was observed at a lower frequency. Notably, kaempferol administration in collagen-induced arthritis mice relieved the frequency and severity of arthritis. Kaempferol reduced osteoclast differentiation in vitro and in vivo relative to the controls and was associated with the inhibition of osteoclast markers, such as tartrate-resistant acid phosphatase, integrin ß3, and MMP9. Conclusively, our data suggest that bFGF-induced FGFR3-RSK2 signaling may play a critical role during the initiation and progression of RA in terms of FLS proliferation and enhanced osteoclastogenesis, and that kaempferol may be effective as a new treatment for RA.

Regulator of Calcineurin 3 Ameliorates Autoimmune Arthritis by Suppressing Th17 Cell Differentiation.

Regulator of calcineurin 3 (RCAN3), an endogenous regulator of the calcineurin-nuclear factor of activated T cells (NFAT) signaling pathway, inhibits the phosphatase activity of calcineurin, the nuclear translocation of NFAT, and the NFAT downstream pathway. To investigate the effects of RCAN3 on T-cell regulatory function and the development and progression of inflammatory arthritis, we studied the effects of RCAN3 transfection on regulation of Th17 cell differentiation in a murine T-lymphoma cell line and primary splenic CD4+ T cells. Overexpression of RCAN3 suppressed Th17 cell differentiation through the down-regulation of RAR receptor orphan receptor γT mRNA and up-regulation of forkhead box P3 mRNA. In mice with collagen-induced arthritis, injection of an RCAN3-overexpression vector controlled arthritis development in vivo. Injection of RCAN3 reduced the formation of osteoclasts and expression of inflammatory cytokines in vivo. Antioxidants stimulated the expression of RCAN3 in vitro, and combination therapy with pcDNA-RCAN3 had a synergistic suppressive effect on the development of arthritis. These data suggest that RCAN3 may be an effective treatment for rheumatoid arthritis.

[Development and Evaluation of a Motivational Interviewing Program for Exercise Improvement in Persons with Physical Disabilities].

PURPOSE: The aims of this study were to develop a motivational interviewing program for exercise improvement in persons with physical disabilities and to examine the effect of this motivational interviewing intervention. METHODS: The study employed a nonequivalent control group pretest and posttest design. A total of 62 persons with physical disabilities (30 in the experimental group, 32 in the control group) were recruited from 2 community rehabilitation centers. The experimental group received 8 sessions of a group motivational interviewing program, scheduled once a week, with each session lasting 60 minutes. Test measures were completed before the intervention, immediately after the end of the intervention, 2 weeks later, and 6 weeks after the end of the intervention. Measures included self-efficacy for exercise, decisional balance for exercise, stage of change for exercise, regularity of exercise, exercise maintenance, and independent living ability. Data were analyzed using the χ²-test, Fisher's exact test, Independent samples t-test, and repeated measures ANOVA, conducted using IBM SPSS Statistics version 18. RESULTS: The experimental group showed a significant increase in self-efficacy for exercise (F=50.98, p<.001), benefit (pros) of exercise (F=24.16, p<.001), and independent living ability (F=50.94, p<.001), and a significant decrease in loss (cons) of exercise (F=26.50, p<.001). There were significant differences between the two groups in stages of change for exercise (p<.001), regularity of exercise (p<.001), and exercise maintenance (χ²=26.61, p<.001). CONCLUSION: The motivational interviewing program has the potential to improve exercise levels in persons with physical disabilities.

Rebamipide ameliorates atherosclerosis by controlling lipid metabolism and inflammation.

RESULTS: The oral administration of rebamipide decreased plaque formation in atherosclerotic lesions as well as the markers of metabolic disorder in ApoE-deficient mice with atherosclerosis. Pro-inflammatory cytokines were also suppressed by rebamapide. In addition, the population of Th17 was decreased, whereas Treg was increased in the spleen of rebamipide-treated ApoE deficient mice. Rebamipide also ameliorated the severity of obese arthritis and has the capability to reduce the development of atherosclerosis by controlling the balance between Th17 and Treg cells. Thus, rebamipide could be a therapeutic agent to improve the progression of inflammation in metabolic diseases.

Metformin Prevents Fatty Liver and Improves Balance of White/Brown Adipose in an Obesity Mouse Model by Inducing FGF21.

Obesity and its associated metabolic disorders are related to the onset of fatty liver and the balance of white adipose tissue (WAT) and brown adipose tissue (BAT). We hypothesized that metformin, an effective pharmacological treatment for type 2 diabetes, would inhibit white adipogenesis, fatty liver, and metabolic dysfunction. Metformin was treated daily for 14 weeks in a high-fat dieting C57BL/6J mice. Serum biomarkers were analyzed and protein level was assessed using confocal staining or flow cytometry. The development of lipid drops in the liver cells and white adipocyte was measured using hematoxylin and eosin or Oil Red O stains. Gene expressions were analyzed with quantitative real-time PCR. Metformin treatment decreased the body weight and improved the metabolic profile of obese mice. In obese mice, metformin also induced the expression of BAT-related markers and increased fibroblast growth factor (FGF) 21 expression in the liver and in white adipocyte. Metformin suppressed white adipocyte differentiation via induction of FGF21. Metformin improves Treg/Th17 balance in CD4+ T cells in mice with high-fat diet-induced obesity. Metformin also improves glucose metabolism and metabolic disorder. Interleukin-17 deficiency also decreases inflammation in mice. Therefore, metformin may be therapeutically useful for the treatment of obesity and metabolic dysfunction.

Combination therapy with metformin and coenzyme Q10 in murine experimental autoimmune arthritis.

Metformin (Met) and coenzyme Q10 (CoQ10) are reported to have therapeutic functions in several inflammatory diseases. These drugs have shown anti-inflammatory effects and have been utilized in mouse models of rheumatoid arthritis (RA). However, there is no evidence of the additive effect of Met and CoQ10 in RA. Although Met and CoQ10 may be involved in the improvement of mitochondrial dysfunction, limited information is available regarding whether this effect can improve mitochondrial dysfunction in RA in particular. In this study, we sought to determine whether Met and CoQ10 attenuate the severity of collagen-induced arthritis (CIA) and show an additive effect in a mouse model. The combination of Met and CoQ10 improved CIA, reducing joint inflammation, Th17 differentiation and IgG production. In contrast, the combination of Met and CoQ10 induced Treg differentiation. Osteoclastogenesis was reduced by the combination of Met and CoQ10. The protein expression of interleukin-1ß, interleukin-6 and tumor necrosis factor-alpha in mice splenocytes exposed to lipopolysaccharide decreased after drug combination therapy. We also found that the expression of JC-1 and COX IV were enhanced by treatment with the combination of Met and CoQ10. Moreover, the combination of Met and CoQ10 promoted mitochondrial O2 consumption. These findings suggest that the combination of Met and CoQ10 reduced CIA severity, improving mitochondrial dysfunction compared to Met or CoQ10 alone. These results present a novel, significant preventive targets in RA and may enhance our understanding of its pathogenesis.

The relationship between chronotype and mood fluctuation in the general population.

There is a lack of evidence for the relationship between chronotype and subthreshold mood fluctuation. The present study aims to investigate the relationship between chronotypes and mood fluctuation in the general population. Participants (n=302) who have had no experience of major mood episodes were included. The Korean version of the Composite Scale of Morningness (CSM) was used to classify participants according to three chronotypes. Mood fluctuation was measured using the Mood Disorder Questionnaire (MDQ) and the Bipolar Spectrum Diagnostic Scale (BSDS). Mean scores achieved by the three chronotype groups on the MDQ and the BSDS were compared. There were no significant differences in the frequency of positive responses on the MDQ for the three chronotype groups. However, there was a significant group difference in total BSDS scores. The eveningness group had significantly higher BSDS-D scores than did either the morningness or the intermediate group have. In addition, the eveningness group had significantly higher BSDS-M scores than the morningness group. After adjusting for age by the analysis of covariance (ANCOVA), there were still significant group differences in total BSDS scores. The present results suggest that eveningness may be more related to mood fluctuation than morningness. The eveningness may be an important factor related to soft bipolarity or mood fluctuation.

Coenzyme Q10 suppresses Th17 cells and osteoclast differentiation and ameliorates experimental autoimmune arthritis mice.

Coenzyme Q10 (CoQ10) is a lipid-soluble antioxidant synthesized in human body. This enzyme promotes immune system function and can be used as a dietary supplement. Rheumatoid arthritis (RA) is an autoimmune disease leading to chronic joint inflammation. RA results in severe destruction of cartilage and disability. This study aimed to investigate the effect of CoQ10 on inflammation and Th17 cell proliferation on an experimental rheumatoid arthritis (RA) mice model. CoQ10 or cotton seed oil as control was orally administrated once a day for seven weeks to mice with zymosan-induced arthritis (ZIA). Histological analysis of the joints was conducted using immunohistochemistry. Germinal center (GC) B cells, Th17 cells and Treg cells of the spleen tissue were examined by confocal microscopy staining. mRNA expression was measured by real-time PCR and protein levels were estimated by enzyme-linked immunosorbent assay (ELISA). Flow cytometric analysis (FACS) was used to evaluate Th17 cells and Treg cells. CoQ10 mitigated the severity of ZIA and decreased serum immunoglobulin concentrations. CoQ10 also reduced RANKL-induced osteoclastogenesis, inflammatory mediators and oxidant factors. Th17/Treg axis was reciprocally controlled by CoQ10 treatment. Moreover, CoQ10 treatment on normal mouse and human cells cultured in Th17 conditions decreased the number of Th17 cells and enhanced the number of Treg cells. CoQ10 alleviates arthritis in mice with ZIA declining inflammation, Th17 cells and osteoclast differentiation. These findings suggest that CoQ10 can be a potential therapeutic substance for RA.

Eupatilin Exerts Antinociceptive and Chondroprotective Properties in a Rat Model of Osteoarthritis by Downregulating Oxidative Damage and Catabolic Activity in Chondrocytes.

Increases in oxidative stress are thought to be associated with the development of osteoarthritis (OA). Eupatilin, one of the major compounds present in artemisia species, was shown to have both anti-oxidative and anti-inflammatory properties. Here, we investigated the in vivo effects of eupatilin on pain severity and cartilage degradation in an experimental rat model of OA, along with the mechanisms of action underlying these effects. Experimental OA was induced via an intra-articular injection of monosodium iodoacetate (MIA), with oral administration of eupatilin initiated on the day of MIA injection. Pain was assessed by measuring the paw withdrawal latency and threshold. Cartilage destruction was analyzed macroscopically and histomorphologically. The effects of eupatilin on mRNA expression were investigated in interleukin-1ß (IL-1ß)-stimulated human OA chondrocytes. Eupatilin treatment exhibited clear antinociceptive effects, along with an attenuation of cartilage degradation in OA rats. Additionally, the number of osteoclasts present in the subchondral bone region was significantly decreased following eupatilin treatment. Eupatilin reduced the expression of interleukin-1ß (IL-1ß), interleukin-6 (IL-6), nitrotyrosine and inducible nitric oxide synthase (iNOS) in cartilage. mRNA levels of matrix metalloproteinase-3 (MMP-3), MMP13, and a disintegrin and metalloproteinase with thrombospondin motifs-5 (ADAMTS-5) were reduced in IL-1ß-stimulated human OA chondrocytes, while tissue inhibitor of metalloproteinases-1 (TIMP-1) was induced. Phosphorylated protein levels of the c-jun N-terminal kinase (JNK) was reduced by eupatilin. Taken together, these results suggest that eupatilin suppresses oxidative damage and reciprocally enhances extracellular matrix production in articular chondrocytes, making eupatilin a promising therapeutic option for the treatment of OA.

Rebamipide suppresses collagen-induced arthritis through reciprocal regulation of th17/treg cell differentiation and heme oxygenase 1 induction.

OBJECTIVE: Rebamipide, a gastroprotective agent, has the ability to scavenge reactive oxygen radicals. Increased oxidative stress is implicated in the pathogenesis of rheumatoid arthritis (RA). We undertook this study to investigate the impact of rebamipide on the development of arthritis and the pathophysiologic mechanisms by which rebamipide attenuates arthritis severity in a murine model of RA. METHODS: Collagen-induced arthritis (CIA) was induced in DBA/1J mice. Anti-type II collagen antibody titers and interleukin-17 (IL-17) levels were determined using enzyme-linked immunosorbent assay. The expression of transcription factors was analyzed by immunostaining and Western blotting. Frequencies of IL-17-producing CD4+ T cells (Th17 cells) and CD4+CD25+FoxP3+ Treg cells were analyzed by flow cytometry. RESULTS: Rebamipide reduced the clinical arthritis score and severity of histologic inflammation and cartilage destruction in a dose-dependent manner. The joints isolated from rebamipide-treated mice with CIA showed decreased expression of nitrotyrosine, an oxidative stress marker. Rebamipide-treated mice showed lower circulating levels of type II collagen-specific IgG, IgG1, and IgG2a. Whereas the number of Th17 cells in spleens was decreased in rebamipide-treated mice with CIA, a significant increase in the number of Treg cells in spleens was observed. In vitro, rebamipide inhibited Th17 cell differentiation through STAT-3/retinoic acid receptor-related orphan nuclear receptor γt and reciprocally induced Treg cell differentiation through FoxP3. Rebamipide increased Nrf2 nuclear activities in murine CD4+ T cells and LBRM-33 murine T lymphoma cells. Heme oxygenase 1 (HO-1) expression in the spleens was markedly increased in rebamipide-treated mice. CONCLUSION: The inhibitory effects of rebamipide on joint inflammation are associated with recovery from an imbalance between Th17 cells and Treg cells and with activation of an Nrf2/HO-1 antioxidant pathway.

Ursodeoxycholic Acid ameliorates pain severity and cartilage degeneration in monosodium iodoacetate-induced osteoarthritis in rats.

Osteoarthritis (OA) is a degenerative joint disease characterized by a progressive loss of cartilage. And, increased oxidative stress plays a relevant role in the pathogenesis of OA. Ursodeoxycholic acid (UDCA) is a used drug for liver diseases known for its free radical-scavenging property. The objectives of this study were to investigate the in vivo effects of UDCA on pain severity and cartilage degeneration using an experimental OA model and to explore its mode of actions. OA was induced in rats by intra-articular injection of monosodium iodoacetate (MIA) to the knee. Oral administration UDCA was initiated on the day of MIA injection. Limb nociception was assessed by measuring the paw withdrawal latency and threshold. Samples were analyzed macroscopically and histologically. Immunohistochemistry was used to investigate the expression of interleukin-1ß (IL-1ß), IL-6, nitrotyrosine and inducible nitric oxide synthase (iNOS) in knee joints. UDCA showed an antinociceptive property and attenuated cartilage degeneration. OA rats given oral UDCA significantly exhibited a decreased number of osteoclasts in subchondral bone legion compared with the vehicle-treated OA group. UDCA reduced the expression of IL-1ß, IL-6, nitrotyrosine and iNOS in articular cartilage. UDCA treatment significantly attenuated the mRNA expression of matrix metalloproteinase-3 (MMP-3), -13, and ADAMTS5 in IL-1ß-stimulated human OA chondrocytes. These results show the inhibitory effects of UDCA on pain production and cartilage degeneration in experimentally induced OA. The chondroprotective properties of UDCA were achieved by suppressing oxidative damage and inhibiting catabolic factors that are implicated in the pathogenesis of cartilage damage in OA.

Coenzyme Q10 ameliorates pain and cartilage degradation in a rat model of osteoarthritis by regulating nitric oxide and inflammatory cytokines.

OBJECTIVE: To investigate the effect of CoenzymeQ10 (CoQ10) on pain severity and cartilage degeneration in an experimental model of rat osteoarthritis (OA). MATERIALS AND METHODS: OA was induced in rats by intra-articular injection of monosodium iodoacetate (MIA) to the knee. Oral administration of CoQ10 was initiated on day 4 after MIA injection. Pain severity was assessed by measuring secondary tactile allodynia using the von Frey assessment test. The degree of cartilage degradation was determined by measuring cartilage thickness and the amount of proteoglycan. The mankin scoring system was also used. Expressions of matrix metalloproteinase-13 (MMP-13), interleukin-1ß (IL-1ß), IL-6, IL-15, inducible nitric oxide synthase (iNOS), nitrotyrosine and receptor for advanced glycation end products (RAGE) were analyzed using immunohistochemistry. RESULTS: Treatment with CoQ10 demonstrated an antinociceptive effect in the OA animal model. The reduction in secondary tactile allodynia was shown by an increased pain withdrawal latency and pain withdrawal threshold. CoQ10 also attenuated cartilage degeneration in the osteoarthritic joints. MMP-13, IL-1ß, IL-6, IL-15, iNOS, nitrotyrosine and RAGE expressions were upregulated in OA joints and significantly reduced with CoQ10 treatment. CONCLUSION: CoQ10 exerts a therapeutic effect on OA via pain suppression and cartilage degeneration by inhibiting inflammatory mediators, which play a vital role in OA pathogenesis.