A newly developed PLD1 inhibitor ameliorates rheumatoid arthritis by regulating pathogenic T and B cells and inhibiting osteoclast differentiation.

Phospholipase D1 (PLD1), which catalyzes the hydrolysis of phosphatidylcholine to phosphatidic acid and choline, plays multiple roles in inflammation. We investigated the therapeutic effects of the newly developed PLD1 inhibitors A2998, A3000, and A3773 in vitro and in vivo rheumatoid arthritis (RA) model. A3373 reduced the levels of LPS-induced TNF-α, IL-6, and IgG in murine splenocytes in vitro. A3373 also decreased the levels of IFN-γ and IL-17 and the frequencies of Th1, Th17 cells and germinal-center B cells, in splenocytes in vitro. A3373 ameliorated the severity of collagen-induced arthritis (CIA) and suppressed infiltration of inflammatory cells into the joint tissues of mice with CIA compared with vehicle-treated mice. Moreover, A3373 prevented systemic bone demineralization in mice with CIA and suppressed osteoclast differentiation and the mRNA levels of osteoclastogenesis markers in vitro. These results suggest that A3373 has therapeutic potential for RA.

Impact of Acupuncture on Hot Flashes in Breast Cancer Patients Receiving Adjuvant Antiestrogen Therapy with Tamoxifen: A Randomized Controlled Trial.

Objectives: The aim of this study was to evaluate the impact of acupuncture on hot flashes in breast cancer patients taking tamoxifen as an adjuvant antiestrogen therapy in Korea. Design: This trial was a randomized, no-treatment-controlled, single-blind, multi-center trial. Participants were randomized 1:1 into the acupuncture group or into the no-treatment control group. Location: This trial was conducted at Daegu Catholic University Hospital and Daegu Haany University Korean Medicine Hospital in Daegu, Republic of Korea. Participants: Patients with moderate to severe symptoms of hot flashes while receiving adjuvant antiestrogen therapy using tamoxifen after surgery for breast cancer were included. Interventions: In the acupuncture group, acupuncture was performed three times a week for 4 consecutive weeks at five predetermined points. The control group received no treatment during the study period. Study Outcome Measures: As a primary outcome, the severity of hot flashes was measured on the visual analogue scale (VAS) and total hot flash score. In addition, the quality of life (QoL) of participants was assessed as a secondary outcome. Results: A total of 30 patients were included in this study, 15 each in the acupuncture group and the control group. The participants in the acupuncture group significantly decreased the severity of hot flashes evaluated with both VAS and total hot flash scores compared with participants in the control group. Also, the acupuncture group showed improved score of a global health status/QoL scale and functional scales assessed with the European Organisation for Research and Treatment of Cancer QoL questionnaire-core questionnaire, compared with those in the control group. This trend was maintained 4 weeks after acupuncture treatment. No adverse events have been reported in this study. Conclusions: Acupuncture was effective and safe in improving hot flashes in Korean breast cancer patients receiving adjuvant antiestrogen therapy with tamoxifen, and it improved the QoL. Clinical Trial Registration: KCT0007829.

Vitamin D Attenuates Pain and Cartilage Destruction in OA Animals via Enhancing Autophagic Flux and Attenuating Inflammatory Cell Death.

Osteoarthritis (OA) is the most common form of arthritis associated with ageing. Vitamin D has diverse biological effect on bone and cartilage, and observational studies have suggested it potential benefit in OA progression and inflammation process. However, the effect of vitamin D on OA is still contradictory. Here, we investigated the therapeutic potential of vitamin D in OA. Six-week-old male Wistar rats were injected with monosodium iodoacetate (MIA) to induce OA. Pain severity, cartilage destruction, and inflammation were measured in MIA-induced OA rats. Autophagy activity and mitochondrial function were also measured. Vitamin-D (1,25(OH)2D3) and celecoxib were used to treat MIA-induced OA rats and OA chondrocytes. Oral supplementation of vitamin D resulted in significant attenuations in OA pain, inflammation, and cartilage destruction. Interestingly, the expressions of MMP-13, IL-1ß, and MCP-1 in synovial tissues were remarkably attenuated by vitamin D treatment, suggesting its potential to attenuate synovitis in OA. Vitamin D treatment in OA chondrocytes resulted in autophagy induction in human OA chondrocytes and increased expression of TFEB, but not LC3B, caspase-1 and -3, in inflamed synovium. Vitamin D and celecoxib showed a synergistic effect on antinociceptive and chondroprotective properties in vivo. Vitamin D showed the chondroprotective and antinociceptive property in OA rats. Autophagy induction by vitamin D treatment may be a promising treatment strategy in OA patients especially presenting vitamin D deficiency. Autophagy promoting strategy may attenuate OA progression through protecting cells from damage and inflammatory cell death.

Acupuncture for hot flashes in hormone receptor-positive breast cancer, a coordinated multinational study: Rationale and design of the study protocol.

BACKGROUND: Acupuncture has been reported to reduce hot flashes in patients with breast cancer undergoing adjuvant hormonal therapy. Although hot flashes are common, the prevalence varies among cultures, races, and ethnicities; the efficacy of acupuncture across cultures has not been investigated. METHODS: This is a coordinated multinational study, including three parallel randomized trials with a planned analysis of individual patient data, to test the effectiveness of acupuncture on hot flash-related symptoms in hormone receptor-positive breast cancer patients on adjuvant endocrine therapy. Using a standardized acupuncture protocol (total across all three studies of n = 80) versus usual care (total n = 80), symptoms are assessed using changes in the Endocrine Symptom Subscale of Functional Assessment of Cancer Therapy-Endocrine Symptoms. Secondary outcomes include hot flash severity, quality of life, and sleep quality. Differences in response to acupuncture between participants in the three countries will also be explored. DISCUSSION: Here we describe the design of a protocol for a coordinated multinational study, with attention to the complex considerations in developing a multinational research effort testing a non-pharmacologic intervention. This protocol and approach provide guidance for future efforts to evaluate and test non-pharmacologic interventions across multinational populations. TRIAL REGISTRATION: clinicaltrials.gov (Identifier: NCT00797732, registered on December 21, 2018), Chinese Clinical Trial Registry (ChiCTR2100045888), and The Clinical Research Information Service (CRIS) of Korea (Registration number: KCT0003618).

Developing and implementing a self-monitoring toolkit for a coordinated multinational randomized acupuncture trial.

BACKGROUND: In 2019, investigators from China, South Korea and the United States of America initiated a coordinated multinational trial. The trial included three parallel randomized studies with a planned pooled analysis of individual patient data, to test the effectiveness of acupuncture on hot flash-related symptoms in hormone receptor-positive breast cancer patients prescribed adjuvant endocrine therapy. Given the study's approach, there was no central coordinating center or data monitoring committee for the study, so a site performance self-monitoring toolkit was developed and implemented to support study teams in collecting and maintaining high-quality regulatory information, and consistent review of study data and documentation. METHODS: The site performance self-monitoring toolkit was created based on best practices related to post-approval quality assurance/quality improvement (QA/QI) procedures that support data quality. The toolkit included: (1) a binder of essential study management documents and related monitoring logs for sites to complete and maintain (herein called regulator binder), (2) a study start-up checklist, (3) a self-assessment study conduct and oversight checklist to be completed regularly, and (4) a study close-out checklist. In addition, a process of regular virtual meetings to discuss documentation progress coupled with periodic external remote review of completed logs and checklists provided accountability checks. RESULTS: Over the course of the study, the sites in China and South Korea completed the entirety of the site performance self-monitoring toolkit, and successfully submitted their completed materials for review. The process of implementing a self-monitoring toolkit in a multinational integrative medicine study is described qualitatively. Periodic external review of the completed toolkit materials revealed categories of findings. Written follow-up reports were provided to sites and discussion of the documents occurred via separate virtual meetings. CONCLUSIONS: Site study team self-monitoring provides a feasible, consistent, and effective way to review the collection and maintenance of data and regulatory documentation for quality assessment in minimal risk clinical research studies and can augment formal study monitoring activities in higher risk studies. Iterative feedback and support appeared to drive a disciplined approach to maintaining regulatory document compliance and helped sustain investigator and study team engagement in the process. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT03783546 (21/12/2018).

Coenzyme Q10 encapsulated in micelles ameliorates osteoarthritis by inhibiting inflammatory cell death.

BACKGROUND: Osteoarthritis (OA) is the most common degenerative joint disease and is characterized by breakdown of joint cartilage. Coenzyme Q10 (CoQ10) exerts diverse biological effects on bone and cartilage; observational studies have suggested that CoQ10 may slow OA progression and inflammation. However, any effect of CoQ10 on OA remains unclear. Here, we investigated the therapeutic utility of CoQ10-micelles. METHODS: Seven-week-old male Wistar rats were injected with monosodium iodoacetate (MIA) to induce OA. CoQ10-micelles were administered orally to MIA-induced OA rats; celecoxib served as the positive control. Pain, tissue destruction, and inflammation were measured. The expression levels of catabolic and inflammatory cell death markers were assayed in CoQ10-micelle-treated chondrocytes. RESULTS: Oral supplementation with CoQ10-micelles attenuated OA symptoms remarkably, including pain, tissue destruction, and inflammation. The expression levels of the inflammatory cytokines IL-1ß, IL-6, and MMP-13, and of the inflammatory cell death markers RIP1, RIP3, and pMLKL in synovial tissues were significantly reduced by CoQ10-micelle supplementation, suggesting that CoQ10-micelles might attenuate the synovitis of OA. CoQ10-micelle addition to cultured OA chondrocytes reduced the expression levels of catabolic and inflammatory cell death markers. CONCLUSIONS: CoQ10-micelles might usefully treat OA.

Drug Survival of Biologic Therapy in Elderly Patients With Rheumatoid Arthritis Compared With Nonelderly Patients: Results From the Korean College of Rheumatology Biologics Registry.

OBJECTIVE: Although the proportion of elderly patients with rheumatoid arthritis (RA) is increasing, the persistency of biologic therapy in elderly patients requires additional investigation. This study evaluated the drug survival of biologic therapy and associated factors in elderly compared with nonelderly patients. METHODS: This longitudinal observational study included RA patients who were enrolled in the Korean College of Rheumatology Biologics Registry (NCT01965132, started from January 1, 2013) between 2013 and 2015. We compared the retention rate of biologic therapy between elderly (age ≥70 years) and nonelderly (age <70 years) patients, and investigated the causes and predictors of biologic withdrawal in both groups. RESULTS: Of 682 patients, 122 were aged 70 years or older. The retention rate of biologic therapy at 24 months was 57.8% and 46.5% in nonelderly and elderly patients, respectively (p = 0.027). Biologic withdrawal due to adverse events and inefficacy within 24 months was not significantly different between the 2 groups, although adverse events were more common in elderly patients (20.6% vs 12.8%, p = 0.360). Drug withdrawal due to patient refusal was more common in elderly patients (9.8% vs 1.8%, p < 0.001). In elderly patients, biologic withdrawal was associated with current smoking and older age at disease onset, whereas the use of tumor necrosis factor inhibitors, nonuse of methotrexate, and combination of corticosteroid were important in nonelderly patients. CONCLUSIONS: Elderly RA patients are more likely to discontinue biologic agents within 24 months. To increase the retention rate of biologic therapy, rheumatologists should consider patient characteristics before and during biologic therapy.

A green-lipped mussel reduces pain behavior and chondrocyte inflammation and attenuated experimental osteoarthritis progression.

The green-lipped mussel (GLM) contains novel omega-3 polyunsaturated fatty acids, which exhibit anti-inflammatory and joint-protecting properties. Osteoarthritis (OA) is a degenerative joint disease characterized by a progressive loss of cartilage; oxidative stress plays a role in the pathogenesis of OA. The objectives of this study were to investigate the in vivo effects of the GLM on pain severity and cartilage degeneration using an experimental rat OA model, and to explore the mode of action of GLM. OA was induced in rats by intra-articular injection of monosodium iodoacetate (MIA) into the knee. Oral GLM was initiated on the day after 3dyas of MIA injection. Limb nociception was assessed by measuring the paw withdrawal latency and threshold. Samples were analyzed both 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. Also, the GLM was applied to OA chondrocyte, and the expression on catabolic marker and necroptosis factor were evaluated by real-time polymerase chain reaction. Administration of the GLM improved pain levels by preventing cartilage damage and inflammation. GLM significantly attenuated the expression levels of mRNAs encoding matrix metalloproteinase-3 (MMP-3), MMP-13, and ADAMTS5 in IL-1ß-stimulated human OA chondrocytes. GLM decreased the expression levels of the necroptosis mediators RIPK1, RIPK3, and the mixed lineage kinase domain-like protein (MLKL) in IL-1ß-stimulated human OA chondrocytes. Thus, GLM reduced pain and cartilage degeneration in rats with experimentally induced OA. The chondroprotective properties of GLM included suppression of oxidative damage and inhibition of catabolic factors implicated in the pathogenesis of OA cartilage damage. We suggest that GLM may usefully treat human OA.

Oral Administration of Lactobacillus rhamnosus Ameliorates the Progression of Osteoarthritis by Inhibiting Joint Pain and Inflammation.

Osteoarthritis (OA) is the most common form of arthritis and age-related degenerative joint disorder, which adversely affects quality of life and causes disability. However, the pathogenesis of OA remains unclear. This study was performed to examine the effects of Lactobacillus rhamnosus in OA progression. OA was induced in 6-week-old male Wistar rats by monosodium iodoacetate (MIA) injection, and the effects of oral administration of L. rhamnosus were examined in this OA rat model. Pain severity, cartilage destruction, and inflammation were measured in MIA-induced OA rats. The small intestines were isolated from OA rats, and the intestinal structure and inflammation were measured. Protein expression in the dorsal root ganglion was analyzed by immunohistochemistry. The effects of L. rhamnosus on mRNA and protein expression in chondrocytes stimulated with interleukin (IL)-1ß and lipopolysaccharide (LPS) were analyzed by real-time polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA). Pain severity was decreased in L. rhamnosus-treated MIA-induced OA rats. The levels of expression of MCP-1, a potential inflammatory cytokine, and its receptor, CCR2, were decreased, and GABA and PPAR-γ expression were increased in L. rhamnosus-treated OA rats. The inflammation, as determined by IL-1ß, and cartilage destruction, as determined by MMP3, were also significantly decreased by L. rhamnosus in OA rats. Additionally, intestinal damage and inflammation were improved by L. rhamnosus. In human OA chondrocytes, TIMP1, TIMP3, SOX9, and COL2A1 which are tissue inhibitors of MMP, and IL-10, an anti-inflammatory cytokine, were increased by L. rhamnosus. L. rhamnosus treatment led to decreased pain severity and cartilage destruction in a rat model of OA. Intestinal damage and inflammation were also decreased by L. rhamnosus treatment. Our findings suggested the therapeutic potential of L. rhamnosus in OA.

Liposome/gold hybrid nanoparticle encoded with CoQ10 (LGNP-CoQ10) suppressed rheumatoid arthritis via STAT3/Th17 targeting.

Coenzyme Q10 (CoQ10), also known as ubiquinone, is a fat-soluble antioxidant. Although CoQ10 has not been approved as medication by the Food and Drug Administration, it is widely used in dietary supplements. Some studies have shown that CoQ10 has anti-inflammatory effects on various autoimmune disorders. In this study, we investigated the anti-inflammatory effects of liposome/gold hybrid nanoparticles encoded with CoQ10 (LGNP-CoQ10). Both CoQ10 and LGNP-CoQ10 were administered orally to mice with collagen-induced arthritis (CIA) for 10 weeks. The inflammation pathology of joint tissues of CIA mice was then analyzed using hematoxylin and eosin and Safranin O staining, as well as immunohistochemistry analysis. We obtained immunofluorescence staining images of spleen tissues using confocal microscopy. We found that pro-inflammatory cytokines were significantly decreased in LGNP-CoQ10 injected mice. Th17 cell and phosphorylated STAT3-expressed cell populations were also decreased in LGNP-CoQ10 injected mice. When human peripheral blood mononuclear cells (PBMCs) were treated with CoQ10 and LGNP-CoQ10, the IL-17 expression of PBMCs in the LGNP-CoQ10-treated group was significantly reduced. Together, these results suggest that LGNP-CoQ10 has therapeutic potential for the treatment of rheumatoid arthritis.

Combinatmarion treatment with Lactobacillus acidophilus LA-1, vitamin B, and curcumin ameliorates the progression of osteoarthritis by inhibiting the pro-inflammatory mediators.

Disease-modifying osteoarthritis (OA) therapy is not yet available. Several adjuvant therapies have demonstrated promising results in the treatment of OA. The present study aimed to investigate the therapeutic effects and underlying mechanisms of a combination of Lactobacillus acidophilus, vitamin B, and curcumin in the treatment of OA. Monosodium iodoacetate (MIA)-induced arthritis of the knee joint in rat was used as an animal model of human OA. The combination of L. acidophilus LA-1, vitamin B, and curcumin or a saline solution was given orally. Pain was measured according to the paw withdrawal latency, and paw withdrawal threshold. Cartilage destruction was analyzed using histomorphological techniques and the Mankin scoring system. Protein expression in the joint was examined using immunohistochemistry. The effects of the combination of L. acidophilus LA-1, vitamin B, and curcumin on mRNA levels in chondrocytes stimulated with interleukin (IL)-1ß were analyzed using real-time polymerase chain reaction. The combination of L. acidophilus, vitamin B, and curcumin effectively downregulated Th17 cells and the related cytokine IL-17, thereby maintained the Treg population, and increased the expression of the Treg-related cytokine IL-10 in human peripheral blood mononuclear cells. The OA animal model exhibited reduced pain and preservation of cartilage in response to the combination treatment. The expression levels of pro-inflammatory cytokines and the catabolic, matrix metalloproteinase-13 (MMP-13), were decreased, whereas the expression of the anabolic tissue inhibitors of metalloproteinases (TIMPs) were upregulated in response to the drug combination. The combination of L. acidophilus, vitamin B, and curcumin was beneficial in OA treatment, controlling the inflammatory response via regulation of the Th17/Treg population and reducing the expression of pro-inflammatory cytokines in human peripheral blood mononuclear cells. The combination treatment also preserved cartilage, suppressed osteoclastogenesis, and regulated the anabolic/catabolic imbalance. These findings indicate the therapeutic potential of combination use of L. acidophilus, vitamin B, and curcumin in patients with OA.

Cottonseed Oil Protects Against Intestinal Inflammation in Dextran Sodium Sulfate-Induced Inflammatory Bowel Disease.

Dietary products may protect against inflammatory bowel disease (IBD) through mechanisms such as forming gut microbiota structures and providing substrates for microbial metabolism. Recently, many studies have been conducted on diets that potentially alleviate or suppress IBD development. To assess the efficacy of dietary oils in treating IBD, we examined the protective effects of olive oil, coconut oil, corn oil, and cottonseed oil in a dextran sodium sulfate (DSS)-induced colitis mouse model. Treatment with cottonseed oil or corn oil ameliorated the severity of DSS-induced colitis, alleviating weight loss and preventing the shortening of the intestine. Moreover, cottonseed oil or corn oil treatment significantly reduced the expression of inflammatory cytokines such as tumor necrosis factor-α, interleukin (IL)-1ß, IL-6, and IL-17, as well as the expression of oxidative stress markers, including 8-hydroxyguanosine and nitrotyrosine in colon sections, compared with vehicle treatment. Cottonseed oil treatment inhibited intestinal fibrosis by reducing the expression of α-smooth muscle actin and type I collagen, compared with vehicle treatment in mice with DSS-induced colitis. Cottonseed oil protects against intestinal inflammation and the development of intestinal fibrosis by reducing inflammatory cytokines and oxidative stress markers, and may therefore be useful as a dietary product with therapeutic benefits for IBD.

Acupuncture for the Treatment of Taxane-Induced Peripheral Neuropathy in Breast Cancer Patients: A Pilot Trial.

OBJECTIVES: Some chemotherapy drugs can damage the nerves and cause peripheral neuropathy which is accompanied by severe neuropathic pain or gait impairment. The purpose of this study was to assess the feasibility and the safety of acupuncture for the treatment of peripheral neuropathy following chemotherapy in Korean breast cancer patients. DESIGN: This study was a prospective single-arm observational study using before and after measurements in breast cancer patients presenting with taxane-induced peripheral neuropathy. SETTINGS/LOCATION: This study was performed at East-West Medical Center at Daegu Catholic University Hospital, Daegu, South Korea. INTERVENTIONS: Acupuncture was administered 3 times a week for 4 consecutive weeks, for 25 ± 5 minutes at each session. OUTCOME MEASURES: The primary outcome measure was severity of CIPN using the Neuropathic Pain Symptom Inventory (NPSI) assessed by a self-administered questionnaire and Nerve Conduction Study (NCS) of extremities. The secondary outcome measure was quality of life (QoL) assessed by a self-administered questionnaire using the 36-Item Short From Health Survey (SF-36). RESULTS: Acupuncture significantly reduced the severity of CIPN assessed by NPSI score. Four weeks after the last treatment, the symptoms were not aggravated. According to NCS, 42.9% of participants showed improvement of sensory neuropathy. At the end of the treatment, SF-36 scores were significantly increased for variables including physical functioning, role limitations due to physical health problems, social functioning, and general health perceptions compared to those of baseline measurement. CONCLUSIONS: Acupuncture improved symptoms of CIPN and QoL in Korean women suffering from peripheral neuropathy after chemotherapy using taxane for breast cancer. The effects of acupuncture lasted for at least 1 month after the treatment.

Toxicological Evaluation of Brassica napus Extract Containing Vanadium, Nutricultured in Jeju Water.

This study evaluated the mutagenicity and acute toxicity of the juice extract of nutricultured Brassica napus containing vanadium (BECV). The BECV was prepared by nutriculture for 7 days in Jeju water containing vanadium. The mutagenic effects of BECV were investigated using the bacterial reverse mutation test, chromosome aberration test, and micronucleus test. Based on the results of the mutagenicity test, we propose that BECV is not a mutagenicity-inducing agent. In the acute oral toxicity study, male and female Sprague-Dawley rats were administered a single limiting dose of 0.014, 0.14, or 1.4 µg BECV/kg body weight; the rats were then observed for 7 days. No acute lethal effect was observed at the maximal dose of 1.4 µg BECV/kg body weight. In the subacute study, male and female rats were administered once daily, by oral gavage, a dose of 0.028, 0.14, and 0.7 µg/kg body weight of BECV for 28 days. No significant toxicity was observed not only hematological, biochemical, and pathological parameters but also the body and organ weights when compared to controls. The level of BECV with no observed adverse effects in male and female rats was 0.7 µg/kg body weight (concentration of vanadium in BECV) in the subacute toxicity study.

Lactobacillus acidophilus ameliorates pain and cartilage degradation in experimental osteoarthritis.

Osteoarthritis (OA) is a chronic and degenerative disease that causes pain, cartilage deformation, and joint inflammation. Lactobacillus species have been used as dietary supplements to induce the production of antimicrobial and anti-inflammatory factors. The goal of this study was to determine whether Lactobacillus acidophilus ameliorates monosodium iodoacetate-induced OA. L. acidophilus showed anti-nociceptive properties and protected against cartilage destruction. It also downregulated the levels of proinflammatory cytokines and increased the levels of anti-inflammatory cytokines in the joints of OA rats. L. acidophilus additionally restored the balance between anabolic and catabolic factors in chondrocytes from OA patients. These results suggest that L. acidophilus can alleviate OA-associated pain and delay the progression of the disease by inhibiting proinflammatory cytokine production and reducing cartilage damage.

Assessment of Quality of Life and Safety in Postmenopausal Breast Cancer Patients Receiving Letrozole as an Early Adjuvant Treatment.

PURPOSE: There are few reports from Asian countries about the long-term results of aromatase inhibitor adjuvant treatment for breast cancer. This observational study aimed to evaluate the long-term effects of letrozole in postmenopausal Korean women with operable breast cancer. METHODS: Self-reported quality of life (QoL) scores were serially assessed for 3 years during adjuvant letrozole treatment using the Korean version of the Functional Assessment of Cancer Therapy-Breast questionnaires (version 3). Changes in bone mineral density (BMD) and serum cholesterol levels were also examined. RESULTS: All 897 patients received the documented informed consent form and completed a baseline questionnaire before treatment. Adjuvant chemotherapy was administered to 684 (76.3%) subjects, and 410 (45.7%) and 396 (44.1%) patients had stage I and II breast cancer, respectively. Each patient completed questionnaires at 3, 6, 12, 18, 24, 30, and 36 months after enrollment. Of 897 patients, 749 (83.5%) completed the study. The dropout rate was 16.5%. The serial trial outcome index, the sum of the physical and functional well-being subscales, increased gradually and significantly from baseline during letrozole treatment (p<0.001). The mean serum cholesterol level increased significantly from 199 to 205 after 36 months (p=0.042). The mean BMD significantly decreased from -0.39 at baseline to -0.87 after 36 months (p<0.001). CONCLUSION: QoL gradually improved during letrozole treatment. BMD and serum cholesterol level changes were similar to those in Western countries, indicating that adjuvant letrozole treatment is well tolerated in Korean women, with minimal ethnic variation.

YinYang1 deficiency ameliorates joint inflammation in a murine model of rheumatoid arthritis by modulating Th17 cell activation.

Yin Yang 1 (YY1) is a ubiquitously expressed transcription factor that functions in cooperation with various cofactors to regulate gene expression. In the immune system, YY1 enhances cytokine production and T helper (Th) 2 effector cell differentiation, resulting in the activation of inflammation. However, no studies have reported the role of YY1 in Th17 cell regulation, which is implicated in rheumatoid arthritis (RA). We investigated the expression of YY1 in Th17 cells in vitro and revealed increased levels of YY1 mRNA and protein. To elucidate the function of YY1 pathogenesis in RA, we used a collagen-induced arthritis (CIA) mouse model with YY1 deficiency. Deficiency of YY1 reduced the severity of arthritis and joint destruction. Moreover, Th17 cells were dramatically reduced in YY1-deficient mice. The cytokine interleukin (IL)-17 was decreased in YY1-deficient CD4+ T cells ex vivo and in vivo. Interestingly, the level of signal transducer and activator of transcription 3 (STAT3), tumor necrosis factor-α, IL-17, IL-6, and IL-1ß were markedly decreased in YY1-deficient mice with CIA. The cytokine-inducing function of YY1 was more specific to IL-17 than to interferon-γ. YY1 plays a role in Th17 cell differentiation and RA pathogenesis. Our findings suggest that future RA therapies should target the regulatory mechanism involved in Th17 cell differentiation, in which YY1 may cooperate with the STAT3 signaling pathway.

A probiotic complex, rosavin, zinc, and prebiotics ameliorate intestinal inflammation in an acute colitis mouse model.

BACKGROUND: An altered gut microbiota balance is involved in the pathogenesis of inflammatory bowel disease (IBD), and several probiotic strains are used as dietary supplements to improve intestinal health. We evaluated the therapeutic effect of 12 probiotics in combination with prebiotics, rosavin, and zinc in the dextran sodium sulfate (DSS)-induced colitis mouse model. METHODS: The probiotic complex or the combination drug was administered orally to mice with DSS-induced colitis, and the body weight, disease activity index, colon length, and histopathological parameters were evaluated. Also, the combination drug was applied to HT-29 epithelial cells, and the expression of monocyte chemoattractant protein 1 (MCP-1) was evaluated by real-time polymerase chain reaction. RESULTS: Administration of the combination drug attenuated the severity of DSS-induced colitis. Moreover, the combination drug significantly reduced the levels of the proinflammatory cytokines tumor necrosis factor-α, interleukin (IL)-6, IL-1ß, and IL-17, and significantly increased the levels of Foxp3 and IL-10 in colon sections. Additionally, treatment with the combination drug reduced MCP-1 expression in HT-29 cells. Treatment with the combination drug decreased the levels of α-smooth muscle actin and type I collagen compared with vehicle treatment in mice with DSS-induced colitis. CONCLUSION: These results suggest that the combination of a probiotic complex with rosavin, zinc, and prebiotics exerts a therapeutic effect on IBD by modulating production of pro- and anti-inflammatory cytokines and the development of fibrosis.

The Combination of Probiotic Complex, Rosavin, and Zinc Improves Pain and Cartilage Destruction in an Osteoarthritis Rat Model.

Osteoarthritis (OA), a degenerative disorder, induces pain, joint inflammation, and destruction of the articular cartilage matrix. Probiotic complex, rosavin, and zinc have been used as dietary supplements that exhibit anti-inflammatory and antioxidant properties. However, there is no evidence demonstrating a synergic effect in OA. This study aims to determine whether combination with probiotic complex, rosavin, and zinc decreases progression of monosodium iodoacetate (MIA)-induced OA rat model. The combination improved pain levels by preventing cartilage damage. The expression of proinflammatory cytokines and catabolic factors was reduced by the combination within the joint tissue. However, the combination increased anti-inflammatory cytokines as well as the anabolic factor production. The gene level of catabolic factors was decreased with treatment of the combination in chondrocytes isolated from OA patients. These results suggest that the combination can improve MIA development through the inhibition of proinflammatory cytokines and cartilage destruction, thus playing a key role as a therapeutic candidate for OA treatment.

A Combination with Probiotic Complex, Zinc, and Coenzyme Q10 Attenuates Autoimmune Arthritis by Regulation of Th17/Treg Balance.

Probiotic complex, zinc, and coenzyme Q10 (CoQ10) are recognized dietary supplements with an anti-inflammatory role. Although these supplementations are individually known to benefit rheumatoid arthritis (RA), there is no evidence suggesting any synergic effect. The primary goal of this study is to determine whether probiotic complex, zinc, and CoQ10 attenuate the development of collagen-induced arthritis (CIA). The combination of probiotic complex, zinc, and CoQ10 reduced CIA severity by downregulating the levels of IgG, IgG1, and IgG2a in serum. Joint inflammation, bone destruction, and cartilage damage were also improved by the complex. There was a decrease in the expression of tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-6, IL-17, and vascular endothelial growth factor (VEGF) in the joint synovium. The balance between helper T 17 (Th17) cells and regulatory T (Treg) cells was shown to be controlled reciprocally by the complex. These findings suggest that the combination of probiotic complex, zinc, and CoQ10 can ameliorate the development of CIA by inhibiting the expression of proinflammatory cytokines, and is thus an important therapeutic candidate for RA treatment.