α-Tocopherol-loaded multi-layer nanoemulsion using chitosan, and dextran sulfate: Cellular uptake, antioxidant activity, and in vitro bioaccessibility.

The potential of multi-layer nanoemulsions (NEs) for improving the cellular uptake, antioxidant activity, and in vitro bioaccessibility of α-tocopherol (ToC) was examined. ToC-loaded multi-layer NEs were prepared using lecithin (primary-NEs, P-NEs), chitosan (secondary-NEs, S-NEs), and dextran sulfate (tertiary-NEs, T-NEs) as wall materials. The bioadhesion, cellular permeability, and uptake of the multi-layer NEs were significantly higher than that of the free coumarin 6 (C6). As a result of cellular uptake, the mean fluorescence intensity of T-NEs was the highest among the three types of multi-layer NEs and was 9.8-fold higher than that of free C6. The cellular antioxidant abilities of P-NEs, S-NEs, and T-NEs were 40, 45, and 50 %, respectively. Multi-layer nanoencapsulation sustains free fatty acid release after digestion. Moreover, the bioavailability of T-NEs exhibited a two-fold increase compared with that of the free ToC. These findings indicate that by multi-layer NEs using a layer-by-layer method, the cellular uptake, in vitro bioaccessibility, and antioxidant activity of ToC can be improved. Furthermore, T-NEs using chitosan and dextran sulfate can potentially enhance the cellular uptake, in vitro bioaccessibility, and antioxidant activity of ToC. These findings would facilitate the application of multi-layer NEs for lipophilic bioactive compounds using biopolymers.

Cinchonine inhibits osteoclast differentiation by regulating TAK1 and AKT, and promotes osteogenesis.

Cinchonine (CN) has been known to exert antimalarial, antiplatelet, and antiobesity effects. It was also recently reported to inhibit transforming growth factor ß-activated kinase 1 (TAK1) and protein kinase B (AKT) through binding to tumor necrosis factor receptor-associated factor 6 (TRAF6). However, its role in bone metabolism remains largely unknown. Here, we showed that CN inhibits osteoclast differentiation with decreased expression of nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1), a key determinant of osteoclastogenesis. Immunoblot and quantitative real-time polymerase chain reaction analysis as well as the reporter assay revealed that CN inhibits nuclear factor-κB and activator protein-1 by regulating TAK1. CN also attenuated the activation of AKT, cyclic AMP response element-binding protein, and peroxisome proliferator-activated receptor-γ coactivator 1ß (PGC1ß), an essential regulator of mitochondrial biogenesis. Collectively, these results suggested that CN may inhibit TRAF6-mediated TAK1 and AKT activation, which leads to downregulation of NFATc1 and PGC1ß resulting in the suppression of osteoclast differentiation. Interestingly, CN not only inhibited the maturation and resorption function of differentiated osteoclasts but also promoted osteoblast differentiation. Furthermore, CN protected lipopolysaccharide- and ovariectomy-induced bone destruction in mouse models, suggesting its therapeutic potential for treating inflammation-induced bone diseases and postmenopausal osteoporosis.

Benzydamine inhibits osteoclast differentiation and bone resorption via down-regulation of interleukin-1 ß expression.

Bone diseases such as osteoporosis and periodontitis are induced by excessive osteoclastic activity, which is closely associated with inflammation. Benzydamine (BA) has been used as a cytokine-suppressive or non-steroidal anti-inflammatory drug that inhibits the production of pro-inflammatory cytokines or prostaglandins. However, its role in osteoclast differentiation and function remains unknown. Here, we explored the role of BA in regulating osteoclast differentiation and elucidated the underlying mechanism. BA inhibited osteoclast differentiation and strongly suppressed interleukin-1ß (IL-1ß) production. BA inhibited osteoclast formation and bone resorption when added to bone marrow-derived macrophages and differentiated osteoclasts, and the inhibitory effect was reversed by IL-1ß treatment. The reporter assay and the inhibitor study of IL-1ß transcription suggested that BA inhibited nuclear factor-κB and activator protein-1 by regulating IκB kinase, extracellular signal regulated kinase and P38, resulting in the down-regulation of IL-1ß expression. BA also promoted osteoblast differentiation. Furthermore, BA protected lipopolysaccharide- and ovariectomy-induced bone loss in mice, suggesting therapeutic potential against inflammation-induced bone diseases and postmenopausal osteoporosis.

Skullcapflavone II inhibits osteoclastogenesis by regulating reactive oxygen species and attenuates the survival and resorption function of osteoclasts by modulating integrin signaling.

Many bone diseases, such as osteoporosis and rheumatoid arthritis, are attributed to an increase in osteoclast number or activity; therefore, control of osteoclasts has significant clinical implications. This study shows how skullcapflavone II (SFII), a flavonoid with anti-inflammatory activity, regulates osteoclast differentiation, survival, and function. SFII inhibited osteoclastogenesis with decreased activation of MAPKs, Src, and cAMP response element-binding protein (CREB), which have been known to be redox sensitive. SFII decreased reactive oxygen species by scavenging them or activating nuclear factor-erythroid 2-related factor 2 (Nrf2), and its effects were partially reversed by hydrogen peroxide cotreatment or Nrf2 deficiency. In addition, SFII attenuated survival, migration, and bone resorption, with a decrease in the expression of integrin ß3, Src, and p130 Crk-associated substrate, and the activation of RhoA and Rac1 in differentiated osteoclasts. Furthermore, SFII inhibited osteoclast formation and bone loss in an inflammation- or ovariectomy-induced osteolytic mouse model. These findings suggest that SFII inhibits osteoclastogenesis through redox regulation of MAPKs, Src, and CREB and attenuates the survival and resorption function by modulating the integrin pathway in osteoclasts. SFII has therapeutic potential in the treatment and prevention of bone diseases caused by excessive osteoclast activity.-Lee, J., Son, H. S., Lee, H. I., Lee, G.-R., Jo, Y.-J., Hong, S.-E., Kim, N., Kwon, M., Kim, N. Y., Kim, H. J., Lee, Y. J., Seo, E. K., Jeong, W. Skullcapflavone II inhibits osteoclastogenesis by regulating reactive oxygen species and attenuates the survival and resorption function of osteoclasts by modulating integrin signaling.

A Case of Graves' Disease Accompanied with Acute Hepatitis A Virus Infection.

Concurrent presentation of acute hepatitis A virus (HAV) infection and Graves' disease has not been reported in literature worldwide. Although there is no well-established mechanism that explains the induction of Graves' disease by HAV to date, our case suggests that HAV infection may be responsible for inducing Graves' disease. A healthy 27-year-old female presented fever, palpitation, and diarrhea, and she was subsequently diagnosed as acute HAV infection. Concurrently, she showed hyperthyroidism, and the diagnosis was made as Graves' disease. She had never had symptoms that suggested hyperthyroidism, and previous thyroid function test was normal. Acute HAV infection was recovered by conservative management, however, thyroid dysfunction was maintained even after normalization of liver enzymes. Methimazole was used to treat Graves' disease. We report a case of concurrent acute HAV infection and Graves' disease in a patient without preexisting thyroid disease. This suggests that HAV infection may be a trigger for an autoimmune thyroid disease in susceptible individuals.

Euphorbia factor L1 inhibits osteoclastogenesis by regulating cellular redox status and induces Fas-mediated apoptosis in osteoclast.

Excessive bone resorption caused by increased osteoclast number or activity leads to a variety of bone diseases including osteoporosis, rheumatoid arthritis and periodontitis. Thus, the therapeutic strategy for these diseases has been focused primarily on the inhibition of osteoclast formation and function. This study shows that euphorbia factor L1 (EFL1), a diterpenoid isolated from Euphorbia lathyris, inhibited osteoclastogenesis and induced osteoclast apoptosis. EFL1 suppressed osteoclast formation and bone resorption at both initial and terminal differentiation stages. EFL1 inhibited receptor activator of NF-κB ligand (RANKL)-induced NFATc1 induction with attenuated NF-κB activation and c-Fos expression. EFL1 decreased the level of reactive oxygen species by scavenging them or activating Nrf2, and inhibited PGC-1ß that regulates mitochondria biogenesis. In addition, EFL1 induced apoptosis in differentiated osteoclasts by increasing Fas ligand expression followed by caspase activation. Moreover, EFL1 inhibited inflammation-induced bone erosion and ovariectomy-induced bone loss in mice. These findings suggest that EFL1 inhibits osteoclast differentiation by regulating cellular redox status and induces Fas-mediated apoptosis in osteoclast, and may provide therapeutic potential for preventing or treating bone-related diseases caused by excessive osteoclast.

Acute kidney injury can predict in-hospital and long-term mortality in elderly patients undergoing hip fracture surgery.

BACKGROUND: Hip fracture is a common health problem in the elderly that is associated with increased mortality. Acute kidney injury (AKI) is a frequent complication in elderly patients undergoing surgery and is associated with the clinical outcome. We evaluated the incidence and risk factors of AKI in elderly patients undergoing hip fracture surgery and the impact of AKI on short- and long-term clinical outcomes. METHODS: We performed a retrospective cohort study of 450 elderly patients who underwent hip fracture surgery between January 2010 and December 2012. We defined AKI according to the Acute Kidney Injury Network (AKIN) criteria and investigated the effect of AKI on the duration of hospital stay and in-hospital and long-term mortality. RESULTS: Of the 450 patients, 95 (21.1%) developed AKI during hospitalization and 178 (39.6%) died, with a mean follow-up of 3.6 ± 1.0 years. The baseline serum creatinine level, use of angiotensin-converting enzyme inhibitors or angiotensin-II receptor antagonists, red blood cell transfusion volume, and history of coronary artery disease were independent risk factors for AKI. Patients with AKI during hospitalization had significantly longer hospital stays and higher in-hospital and long-term mortality than those without AKI. Multivariate analysis revealed that age, history of coronary artery disease, serum albumin level, and AKI were independent predictors of long-term mortality. CONCLUSIONS: AKI is a frequent complication in elderly patients undergoing hip fracture surgery and is independently associated with increased in-hospital and long-term mortality.

Effective killing of cancer cells and regression of tumor growth by K27 targeting sulfiredoxin.

Cancer cells have been suggested to be more susceptible to oxidative damages and highly dependent on antioxidant capacity in comparison with normal cells, and thus targeting antioxidant enzymes has been a strategy for effective cancer treatment. Sulfiredoxin (Srx) is an enzyme that catalyzes the reduction of sulfinylated peroxiredoxins and thereby reactivates them. In this study we developed a Srx inhibitor, K27 (N-[7-chloro-2-(4-fluorophenyl)-4-quinazolinyl]-N-(2-phenylethyl)-ß-alanine), and showed that it induces the accumulation of sulfinylated peroxiredoxins and oxidative stress, which leads to mitochondrial damage and apoptotic death of cancer cells. The effects of K27 were significantly reversed by ectopic expression of Srx or antioxidant N-acetyl cysteine. In addition, K27 led to preferential death of tumorigenic cells over non-tumorigenic cells, and suppressed the growth of xenograft tumor without acute toxicity. Our results suggest that targeting Srx might be an effective therapeutic strategy for cancer treatment through redox-mediated cell death.

Sulfiredoxin inhibitor induces preferential death of cancer cells through reactive oxygen species-mediated mitochondrial damage.

Recent studies have shown that many types of cancer cells have increased levels of reactive oxygen species (ROS) and enhance antioxidant capacity as an adaptation to intrinsic oxidative stress, suggesting that cancer cells are more vulnerable to oxidative insults and are more dependent on antioxidant systems compared with normal cells. Thus, disruption of redox homeostasis caused by a decline in antioxidant capacity may provide a method for the selective death of cancer cells. Here we show that ROS-mediated selective death of tumor cells can be caused by inhibiting sulfiredoxin (Srx), which reduces hyperoxidized peroxiredoxins, leading to their reactivation. Srx inhibitor increased the accumulation of sulfinic peroxiredoxins and ROS, which led to oxidative mitochondrial damage and caspase activation, resulting in the death of A549 human lung adenocarcinoma cells. Srx depletion also inhibited the growth of A549 cells like Srx inhibition, and the cytotoxic effects of Srx inhibitor were considerably reversed by Srx overexpression or antioxidants such as N-acetyl cysteine and butylated hydroxyanisol. Moreover, Srx inhibitor rendered tumorigenic ovarian cells more susceptible to ROS-mediated death compared with nontumorigenic cells and significantly suppressed the growth of A549 xenografts without acute toxicity. Our results suggest that Srx might serve as a novel therapeutic target for cancer treatment based on ROS-mediated cell death.

Metastatic cardiac tumor manifested by persistent ST-segment elevation with coexisting reciprocal changes on electrocardiography.

In cases with metastatic invasion of the heart, electrocardiographic abnormalities are commonly seen. However, most of these electrocardiographic changes are nonspecific; certain findings may be highly suggestive of myocardial involvement of the tumor. We report a patient with lung cancer who presented with persistent ST-segment elevation with coexisting reciprocal changes on electrocardiography due to myocardial invasion of the lung cancer.

Exercise-Induced Intrapulmonary Arteriovenous Shunt in a Patient Complaining of Dyspnea during Strenuous Exercise.

A 51-year-old highly fit man presented for dyspnea with strenuous aerobic exercise. The patient was asymptomatic and all tests were normal at rest. With increasing exercise intensity, he suddenly complained of dyspnea and showed a severe exercise-induced hypoxemia with an excessive alveolar-arterial oxygen tension difference. In agitated saline contrast echocardiography at peak exercise, a large amount of left to right shunt was identified after > 5 cardiac cycles, which suggests the presence of exercise-induced intrapulmonary arteriovenous shunt in this patient.